STABILIZATION OF IMMUNOGLOBULINS AND OTHER PROTEINS THROUGH AQUEOUS FORMULATIONS WITH SODIUM CHLORIDE AT WEAK ACIDIC TO NEUTRAL ph

Abstract

The present invention provides, among other aspects, storage stabile aqueous formulations of labile proteins at a mildly acidic to neutral pH. The present invention also provides methods for stabilizing a labile therapeutic protein composition at a mildly acidic to neutral pH. Advantageously, the methods and formulations provided herein allow stabile aqueous compositions of labile proteins at mildly acidic to neutral pH useful for parenteral administration.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional Application No. 61/384,209, filed Sep. 17, 2010, the content of which is expressly incorporated herein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

Biologics are medicinal products created by biological processes, including preparations isolated from natural sources (e.g., human plasma) and recombinant DNA technologies. Within the healthcare and pharmaceutical industries, biologics are becoming increasingly important for patient treatment and overall revenue growth (Goodman M. Nat Rev Drug Discov. (2009) November; 8(11):837). One important class of biologic drugs is therapeutic proteins, both isolated from natural sources and recombinantly produced. For example, plasma proteins are manufactured for therapeutic administration by isolation from pooled human plasma (e.g., GAMMAGARD LIQUID® [IVIG, Immune Globulin Intravenous (Human) 10%]; Baxter International, Deerfield, Ill.) and recombinant means (e.g., ADVATE® [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method]; Baxter International, Deerfield, Ill.).

The administration of therapeutic proteins are primarily performed by intravenous (IV), subcutaneous (SQ), and intramuscular administration, although other routes of administration may be used depending upon the therapeutic protein and condition being treated. Most of the immunoglobulins are administered intravenously as larger volumes can be delivered rapidly by the intravenous route to provide the physiologic levels of IgG needed for the effective treatment of various diseases, such as primary immune deficiencies (PID), immune (idiopathic) thrombocytopenic purpura (ITP) and the Kawasaki syndrome. Due to the nature of IV administration, therapy via this route is a slow and timely process, leading to problems with patient compliance.

Subcutaneous (SQ) administration of therapeutic proteins is a convenient alternative to intravenous administration. Compared to IV infusions, SQ administration has several advantages. For example, it can reduce the incidence of systemic reactions, it does not require sometimes-difficult IV access, and gives patients more independence.

In order to improve patient compliance, it would be convenient to provide the protein in a liquid ready to use formulation. However, many human or humanized therapeutic proteins are highly unstable when formulated at or near neutral pH. A variety of degradation pathways exist for proteins especially in liquid formulations, implicating both chemical and physical instability. Chemical instability includes deamination, aggregation, clipping of the peptide backbone, and oxidation of methionine residues. Physical instability encompasses many phenomena, including, for example, aggregation. Protein instability is particularly problematic for labile proteins that are unstable at mildly acidic to neutral pH. To combat these issues, intravenously administrable immunoglobulins have been formulated at acidic pH, effectively increasing their stability in the formulation (products that are formulated at acidic pH are, e.g., Gamunex (Talecris), Gammagard Liquid (Baxter) or Privigen (CSL).

To combat these issues, therapeutic protein compositions are often formulated at acidic pH, effectively increasing their stability in the formulation. Unfortunately, scientific publications have reported that, for example, intramuscular administration of acidic aqueous preparations can cause pain, and potentially could result in tissue damage (Steen et al., 2001; Sluka et al., 2000, the disclosures of which are incorporated by reference herein in their entireties for all purposes). In other cases, where aqueous formulations have been found not to adequately stabilize the therapeutic proteins, lyophilized formulations are used which must be reconstituted prior to administration. In both cases, these factors can cause a less satisfactory drug administration experience and/or inconvenience for the patient, resulting in reduced patient compliance.

As such, there is a need in the art for formulations and methods of formulation that stabilize these labile therapeutic proteins in compositions (e.g., aqueous compositions) at mildly acidic to neutral pH. The present invention satisfies these and other needs by, among other aspects, providing immunoglobulin compositions formulated with histidine at mild acidic to neutral pH that stabilize labile therapeutic proteins.

BRIEF SUMMARY OF INVENTION

The present invention is based in part by the surprising finding that the addition of alkali metal salts to aqueous formulations at mildly acidic to neutral pH stabilizes both plasma-derived and recombinant labile therapeutic proteins. As shown by the present studies, immunoglobulins and coagulation factors formulated at mildly acidic to neutral pH with less than 75 mM of an alkali metal chloride salt are highly unstable. However, the addition of greater than 75 mM of an alkali metal chloride salt (e.g., 100 mM or 150 mM sodium chloride) unexpectedly stabilizes these formulations. This finding is contrary to the result of adding alkali metal chloride salts to formulations at acidic pH values, which is shown herein to destabilize these compositions.

Advantageously, the ability to stably formulate labile proteins (e.g., immunoglobulins, coagulation factors, etc.) at mildly acidic and neutral pH allows for the production of therapeutic formulations that are simpler to self-administer. Furthermore, the ability to stably formulate labile therapeutic proteins at mildly acidic to neutral pH allows for the manufacture of pharmaceutical compositions that may be administered subcutaneously (SQ) or intramuscularly (IM) without the pain and potential for tissue damage that is associated with the SQ and IM administration of compositions formulated at acidic pH.

In one aspect, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.5.

In a specific embodiment of the compositions provided above, the composition comprises from 100 mM to 200 mM of an alkali metal chloride salt.

In a specific embodiment of the compositions provided above, the composition comprises from 125 mM to 175 mM of an alkali metal chloride salt.

In a specific embodiment of the compositions provided above, the composition comprises 150±15 mM an alkali metal chloride salt.

In a specific embodiment of the compositions provided above, the alkali metal chloride salt is sodium chloride.

In a specific embodiment of the compositions provided above, the alkali metal chloride salt is potassium chloride.

In a specific embodiment of the compositions provided above, the amino acid is selected from the group consisting of glycine, proline, and histidine.

In a specific embodiment of the compositions provided above, the amino acid is glycine.

In a specific embodiment of the compositions provided above, the amino acid is proline.

In a specific embodiment of the compositions provided above, the amino acid is histidine.

In a specific embodiment of the compositions provided above, the concentration of the amino acid is from 50 mM to 500 mM.

In a specific embodiment of the compositions provided above, the concentration of the amino acid is from 100 mM to 400 mM.

In a specific embodiment of the compositions provided above, the concentration of the amino acid is from 150 mM to 350 mM.

In a specific embodiment of the compositions provided above, the concentration of the amino acid is from 200 mM to 300 mM.

In a specific embodiment of the compositions provided above, the concentration of the amino acid is from 225 mM to 275 mM.

In a specific embodiment of the compositions provided above, the concentration of the amino acid is 250±10 mM.

In a specific embodiment of the compositions provided above, the pH of the composition is from 5.5 to 7.0.

In a specific embodiment of the compositions provided above, the pH of the composition is from 5.5 to 6.5.

In a specific embodiment of the compositions provided above, the pH of the composition is from 5.5 to 6.0.

In a specific embodiment of the compositions provided above, the pH of the composition is from 6.0 to 7.5.

In a specific embodiment of the compositions provided above, the pH of the composition is from 6.0 to 7.0.

In a specific embodiment of the compositions provided above, the pH of the composition is from 6.0 to 6.5.

In a specific embodiment of the compositions provided above, the pH of the composition is from 6.5 to 7.5.

In a specific embodiment of the compositions provided above, the pH of the composition is from 6.5 to 7.0.

In a specific embodiment of the compositions provided above, the pH of the composition is from 7.0 to 7.5.

In a specific embodiment of the compositions provided above, the labile therapeutic protein is a human or humanized protein.

In a specific embodiment of the compositions provided above, the labile therapeutic protein is an immunoglobulin.

In a specific embodiment of the compositions provided above, the immunoglobulin is an IgG immunoglobulin.

In a specific embodiment of the compositions provided above, the immunoglobulin is a polyclonal immunoglobulin.

In a specific embodiment of the compositions provided above, the immunoglobulin is a monoclonal immunoglobulin.

In a specific embodiment of the compositions provided above, the immunoglobulin is a recombinant immunoglobulin.

In a specific embodiment of the compositions provided above, the immunoglobulin is enriched from pooled human plasma.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is 50±5 g/L.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is less than 50 g/L.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is at least 50 g/L.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is from 50 g/L to 150 g/L.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is 100±10 g/L.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is at least 100 g/L.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is 150±15 g/L.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is from 150 g/L to 250 g/L.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is 200±20 g/L.

In a specific embodiment of the compositions provided above, the concentration of the immunoglobulin is at least 200 g/L.

In a specific embodiment of the compositions provided above, at least 95% of the protein in the composition is immunoglobulin.

In a specific embodiment of the compositions provided above, at least 95% of the protein in the composition is IgG immunoglobulin.

In a specific embodiment of the compositions provided above, at least 98% of the protein in the composition is IgG immunoglobulin.

In a specific embodiment of the compositions provided above, the composition is stable for at least 6 months when stored at between about 28° C. and about 32° C.

In a specific embodiment of the compositions provided above, the composition is stable for at least 1 year when stored at between about 28° C. and about 32° C.

In a specific embodiment of the compositions provided above, the composition is stable for at least 2 years when stored at between about 28° C. and about 32° C.

In a specific embodiment of the compositions provided above, the composition is stable for at least 1 month when stored at between about 38° C. and about 42° C.

In a specific embodiment of the compositions provided above, the composition is stable for at least 3 months when stored at between about 38° C. and about 42° C.

In a specific embodiment of the compositions provided above, the composition is stable for at least 6 months when stored at between about 38° C. and about 42° C.

In a specific embodiment of the compositions provided above, the composition is stable for at least 1 year when stored at between about 28° C. and about 32° C.

In a specific embodiment of the compositions provided above, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is between 0% and 5%.

In a specific embodiment of the compositions provided above, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is between 0% and 2%.

In a specific embodiment of the compositions provided above, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is from 0% to 5% and the percentage of immunoglobulin in the monomeric state is from 80% to 100%.

In a specific embodiment of the compositions provided above, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is from 0% to 2% and the percentage of immunoglobulin in the monomeric state is from 85% to 100%.

In a specific embodiment of the compositions provided above, the labile therapeutic protein is a coagulation factor.

In a specific embodiment of the compositions provided above, the coagulation factor is selected from the group consisting of Factor VII, Factor VIII, Factor IX, and von Willebrand Factor (vWF).

In a specific embodiment of the compositions provided above, the coagulation factor is Factor VIII.

In a specific embodiment of the compositions provided above, the pH of the composition is between about 6.0 and about 7.0.

In a specific embodiment of the compositions provided above, the pH of the composition is 6.5±0.2.

In a specific embodiment of the compositions provided above, the composition retains at least 80% of its Factor VIII activity when stored at a temperature between about 2° C. and about 8° C. for at least 1 month.

In a specific embodiment of the compositions provided above, the composition retains at least 80% of its Factor VIII activity when stored at a temperature between about 2° C. and about 8° C. for at least 2 months.

In a specific embodiment of the compositions provided above, the composition retains at least 80% of its Factor VIII activity when stored at a temperature between about 2° C. and about 8° C. for at least 3 months.

In a specific embodiment of the compositions provided above, the coagulation factor is Factor VII.

In a specific embodiment of the compositions provided above, the coagulation factor is Factor IX.

In a specific embodiment of the compositions provided above, the coagulation factor is von Willebrand Factor (vWF).

In a specific embodiment of the compositions provided above, the coagulation factor is a protein K-dependent coagulation complex.

In a specific embodiment of the compositions provided above, the protein K-dependent coagulation complex comprises the coagulation factors Factor II, Factor IX, and Factor X.

In a specific embodiment of the compositions provided above, the protein K-dependent coagulation complex further comprises Factor VII.

In a specific embodiment of the compositions provided above, the labile protein is stable for less than 3 months in an aqueous formulation containing: from 0 mM to 50 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.

In a specific embodiment of the compositions provided above, the labile protein is stable for less than 2 months in an aqueous formulation containing: from 0 mM to 50 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.

In a specific embodiment of the compositions provided above, the labile protein is stable for less than 1 month in an aqueous formulation containing: from 0 mM to 50 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.

In a specific embodiment of the compositions provided above, the labile protein is stable for less than 2 weeks in an aqueous formulation containing: (a) from 0 mM to 50 mM of an alkali metal chloride salt; (b) an amino acid; and (c) a pH of from 5.5 to 7.

In a specific embodiment of the compositions provided above, the composition is formulated for subcutaneous and/or intramuscular administration.

In another aspect, the present invention provides a method for stabilizing an aqueous composition of a labile therapeutic protein, the method comprising formulating the composition at a pH between 5.5 and 7.0, wherein the formulated composition comprises: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; and an amino acid.

In a specific embodiment of the methods provided above, the formulated composition comprises from 100 mM to 200 mM of an alkali metal chloride salt.

In a specific embodiment of the methods provided above, the formulated composition comprises from 125 mM to 175 mM of an alkali metal chloride salt.

In a specific embodiment of the methods provided above, the formulated composition comprises 150±15 mM an alkali metal chloride salt.

In a specific embodiment of the methods provided above, the alkali metal chloride salt is sodium chloride.

In a specific embodiment of the methods provided above, the alkali metal chloride salt is potassium chloride.

In a specific embodiment of the methods provided above, the amino acid is selected from the group consisting of glycine, proline, and histidine.

In a specific embodiment of the methods provided above, the amino acid is glycine.

In a specific embodiment of the methods provided above, the amino acid is proline.

In a specific embodiment of the methods provided above, the amino acid is histidine.

In a specific embodiment of the methods provided above, the formulated composition comprises from 50 mM to 500 mM of the amino acid.

In a specific embodiment of the methods provided above, the formulated composition comprises from 100 mM to 400 mM of the amino acid.

In a specific embodiment of the methods provided above, the formulated composition comprises from 150 mM to 350 mM of the amino acid.

In a specific embodiment of the methods provided above, the formulated composition comprises from 200 mM to 300 mM of the amino acid.

In a specific embodiment of the methods provided above, the formulated composition comprises from 225 mM to 275 mM of the amino acid.

In a specific embodiment of the methods provided above, the formulated composition comprises from 250±10 mM of the amino acid.

In a specific embodiment of the methods provided above, the pH of the formulated composition is from 5.5 to 7.0.

In a specific embodiment of the methods provided above, the pH of the formulated composition is from 5.5 to 6.5.

In a specific embodiment of the methods provided above, the pH of the formulated composition is from 5.5 to 6.0.

In a specific embodiment of the methods provided above, the pH of the formulated composition is from 6.0 to 7.5.

In a specific embodiment of the methods provided above, the pH of the formulated composition is from 6.0 to 7.0.

In a specific embodiment of the methods provided above, the pH of the formulated composition is from 6.0 to 6.5.

In a specific embodiment of the methods provided above, the pH of the formulated composition is from 6.5 to 7.5.

In a specific embodiment of the methods provided above, the pH of the formulated composition is from 6.5 to 7.0.

In a specific embodiment of the methods provided above, the pH of the formulated composition is from 7.0 to 7.5.

In a specific embodiment of the methods provided above, the labile therapeutic protein is a human or humanized protein.

In a specific embodiment of the methods provided above, the labile therapeutic protein is an immunoglobulin.

In a specific embodiment of the methods provided above, the immunoglobulin is an IgG immunoglobulin.

In a specific embodiment of the methods provided above, the immunoglobulin is a polyclonal immunoglobulin.

In a specific embodiment of the methods provided above, the immunoglobulin is a monoclonal immunoglobulin.

In a specific embodiment of the methods provided above, the immunoglobulin is a recombinant immunoglobulin.

In a specific embodiment of the methods provided above, the immunoglobulin is enriched from pooled human plasma.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is 50±5 g/L.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is less than 50 g/L.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is at least 50 g/L.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is from 50 g/L to 150 g/L.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is 100±10 g/L.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is at least 100 g/L.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is 150±15 g/L.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is from 150 g/L to 250 g/L.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is 200±20 g/L.

In a specific embodiment of the methods provided above, the concentration of the immunoglobulin is at least 200 g/L.

In a specific embodiment of the methods provided above, at least 95% of the protein in the formulated composition is immunoglobulin.

In a specific embodiment of the methods provided above, at least 95% of the protein in the formulated composition is IgG immunoglobulin.

In a specific embodiment of the methods provided above, at least 98% of the protein in the formulated composition is IgG immunoglobulin.

In a specific embodiment of the methods provided above, the formulated composition is stable for at least 6 months when stored at between about 28° C. and about 32° C.

In a specific embodiment of the methods provided above, the formulated composition is stable for at least 1 year when stored at between about 28° C. and about 32° C.

In a specific embodiment of the methods provided above, the formulated composition is stable for at least 2 years when stored at between about 28° C. and about 32° C.

In a specific embodiment of the methods provided above, the formulated composition is stable for at least 1 month when stored at between about 38° C. and about 42° C.

In a specific embodiment of the methods provided above, the formulate composition is stable for at least 3 months when stored at between about 38° C. and about 42° C.

In a specific embodiment of the methods provided above, the formulated composition is stable for at least 6 months when stored at between about 38° C. and about 42° C.

In a specific embodiment of the methods provided above, the formulated composition is stable for at least 1 year when stored at between about 28° C. and about 32° C.

In a specific embodiment of the methods provided above, the formulated composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is between 0% and 5%.

In a specific embodiment of the methods provided above, the formulated composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is between 0% and 2%.

In a specific embodiment of the methods provided above, the formulated composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is from 0% to 5% and the percentage of immunoglobulin in the monomeric state is from 80% to 100%.

In a specific embodiment of the methods provided above, the formulated composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is from 0% to 2% and the percentage of immunoglobulin in the monomeric state is from 85% to 100%.

In a specific embodiment of the methods provided above, the labile therapeutic protein is a coagulation factor.

In a specific embodiment of the methods provided above, the coagulation factor is selected from the group consisting of Factor VII, Factor VIII, Factor IX, and von Willebrand Factor (vWF).

In a specific embodiment of the methods provided above, the coagulation factor is Factor VIII.

In a specific embodiment of the methods provided above, the pH of the composition is between about 6.0 and about 7.0.

In a specific embodiment of the methods provided above, the pH of the composition is 6.5±0.2.

In a specific embodiment of the methods provided above, the formulated composition retains at least 80% of its Factor VIII activity when stored at a temperature between about 2° C. and about 8° C. for at least 1 month.

In a specific embodiment of the methods provided above, the formulated composition retains at least 80% of its Factor VIII activity when stored at a temperature between about 2° C. and about 8° C. for at least 2 months.

In a specific embodiment of the methods provided above, the formulated composition retains at least 80% of its Factor VIII activity when stored at a temperature between about 2° C. and about 8° C. for at least 3 months.

In a specific embodiment of the methods provided above, the coagulation factor is Factor VII.

In a specific embodiment of the methods provided above, the coagulation factor is Factor IX.

In a specific embodiment of the methods provided above, the coagulation factor is von Willebrand Factor (vWF).

In a specific embodiment of the methods provided above, the coagulation factor is a protein K-dependent coagulation complex.

In a specific embodiment of the methods provided above, the protein K-dependent coagulation complex comprises the coagulation factors Factor II, Factor IX, and Factor X.

In a specific embodiment of the methods provided above, the protein K-dependent coagulation complex further comprises Factor VII.

In a specific embodiment of the methods provided above, the labile protein is stable for less than 3 months in an aqueous formulation containing: from 0 mM to 50 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.

In a specific embodiment of the methods provided above, the labile protein is stable for less than 2 months in an aqueous formulation containing: from 0 mM to 50 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.

In a specific embodiment of the methods provided above, the labile protein is stable for less than 1 month in an aqueous formulation containing: from 0 mM to 50 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.

In a specific embodiment of the methods provided above, the labile protein is stable for less than 2 weeks in an aqueous formulation containing: from 0 mM to 50 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.

In a specific embodiment of the methods provided above, the composition is formulated for subcutaneous and/or intramuscular administration.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1. Aggregation of 20% IgG formulations after 6 months storage at 38 to 42° C.

FIG. 2. Aggregate formation in Tetabulin NG formulated at neutral pH in the presence of 150 mM sodium chloride during storage at 28 to 32° C.

FIG. 3. Aggregate formation in Partobulin NG formulated at neutral pH in the presence of 150 mM sodium chloride during storage at 28 to 32° C.

FIG. 4. Differences in Tetanus Anti-toxin potency of Tetabulin NG formulated with 150 mM sodium chloride in a pH range of 5.5 to 7.5 during storage at 28 to 32° C.

FIG. 5. Differences in Anti-D potency of Partobulin NG formulated with 150 mM sodium chloride in a pH range of 5.5 to 7.5 during storage at 28° C. to 32° C.

FIG. 6. Anti-MIF titer after three months storage at 38° C. to 42° C.

FIG. 7. The Factor VIII activity during 12 weeks storage of the aqueous formulation at 2 to 8° C. without sodium chloride.

FIG. 8. The Factor VIII activity during 12 weeks storage of the aqueous formulation at 2 to 8° C. with 150 mM sodium chloride.

DETAILED DESCRIPTION OF INVENTION

I. Introduction

Therapeutic proteins are often times formulated at acidic pH or as lyophilized compositions due to their labile nature in aqueous solution at or near neutral pH. As discussed above, these formulations are less convenient, may cause pain and/or tissue damage upon administration, and likely reduce patient compliance. Advantageously, the present invention provides means for stably formulating these labile proteins in aqueous solution at or near neutral pH. In one aspect, the present invention provides labile therapeutic protein compositions stabilized by the addition of moderate levels of alkali metal chloride salts (e.g., 75 mM to 200 mM, preferably 100 mM to 200 mM) to formulations at mildly acidic to neutral pH. The present invention is based in part on the surprising discovery that labile therapeutic proteins are significantly stabilized at mildly acidic to neutral pH by the addition of an alkali metal chloride salt at a final concentration of between about 75 mM and about 200 mM.

Our new studies provided herein demonstrate that purified plasma-derived immunoglobulin preparations formulated in 0.25 M glycine could be stabilized by the addition of sodium chloride in a pH dependent manner. Examples 1 and 2 shows that these immunoglobulin preparations, having a final concentration of between about 90 g/L and about 220 g/L, were stabilized for at least 24 months when stored at a temperature of 28° C. to 32° C., and for at least 6 months when stored at a temperature of 38° C. to 42° C. Maximum stability was observed with addition of 150 mM sodium chloride.

Under these conditions, the addition of sodium chloride to formulations at pH values at and above 7.0 resulted in considerably higher aggregation and fragmentation rates, compared to samples formulated at a pH between 5.5 and 7.0 (Table 5 and Table 6). Similarly, it was previously observed that sodium chloride significantly destabilized immunoglobulin formulations with acidic pH values (under 5.0).

Similar stabilizing effects were demonstrated with the addition of 150 mM sodium chloride to two hyper-immune immunoglobulin preparations, Partobulin® NG and Tetabulin® NG. Example 3 demonstrates that addition of 150 mM sodium chloride to these plasma-derived immunoglobulin preparations results in reduced protein aggregation at pH values between 5.5 and 6.5 and reduced loss of anti-D titer for Partobulin® NG between pH 5.5 and pH 6.5, while stabilizing the Tetanus anti-toxin titer across the entire range of pH investigated.

Next, it was demonstrated that sodium chloride would also stabilize recombinant antibody preparations formulated at mildly acidic to neutral pH. Example 4 shows that a recombinant anti-MIF antibody formulated at pH 5.6 to 6.5 with 0.25 M glycine and 150 mM sodium chloride Was stabilized upon storage at elevated temperatures (38° C. to 42° C.) for six months. Consistent with the previous observations, sodium chloride enhanced degradation when the antibody was formulated at low pH (4.5) and increased aggregation when formulated at a higher pH (pH 7.3).

Finally, to investigate whether or not the stabilizing effect of sodium chloride at mildly acidic to neutral pH can be applied to non-immunoglobulin labile therapeutic proteins, formulations of recombinant Factor VIII (rFVIII) were prepared. As the foundation for the rFVIII formulation, the protein was formulated as in the reconstituted ADVATE® (Baxter International; Deerfield Ill.) product. Despite the presence of several traditional stabilizing agents, including mannitol, trehalose, histidine, calcium chloride, polysorbate-80 and glutathione, rFVIII is extremely unstable, even at 2° C. to 8° C., in aqueous formulation. As such, ADVATE® is marketed as a lyophilized formulation that is reconstituted immediately prior to administration.

Remarkably, as shown in Example 5, the inclusion of 150 mM sodium chloride almost completely stabilizes rFVIII activity at pH 6.0 to 7.0, when stored in aqueous formulation at 2° C. to 8° C. for at least 12 weeks. Accordingly, it has now been demonstrated that intermediate levels of an alkali metal chloride salt can stabilize a wide range of labile therapeutic proteins when formulated at a mildly acidic to neutral pH.

II. Definitions

As used herein, a “labile therapeutic protein” refers to a class of therapeutically useful proteins that are unstable when formulated at mildly acid to neutral pH in the absence of an alkali metal chloride salt. Generally, protein stability can be measured by several different metrics, including aggregation, loss of enzymatic activity, loss of antigenic titer, or degradation. Labile therapeutic proteins will display one or more of these unwanted characteristics when stored at mildly acidic to neutral pH in the absence of an alkali metal chloride salt. The absolute time for which a labile protein is stable will be dependent upon the individual characteristics of the protein, which can be readily determined by the skilled artisan. For example, certain blood coagulations proteins (e.g., Factor VIII) are stable for less than two months under refrigeration when formulated a mildly acidic to neutral pH in the absence of suitable levels of an alkali metal chloride salt. In other cases, for example plasma derived immunoglobulin preparations, a labile therapeutic protein may be stable at room temperature for less than six months when formulated a mildly acidic to neutral pH in the absence of suitable levels of an alkali metal chloride salt, as compared to more than two years in the presence of moderate levels of an alkali metal chloride salt.

In the context of the present invention, a labile protein will show a marked increase in stability upon the addition of an alkali metal chloride salt to a formulation at mildly acid to neutral pH. Inclusion of an alkali metal chloride salt may, for example, reduce aggregation of the labile protein by at least about 20%; maintain at least about 20% more enzymatic activity; maintain at least about 20% more antigenic titer; and/or reduce degradation by at least about 20%, when stored for a given period of time. For the purposes of the present invention, a labile therapeutic protein may be isolated from a natural source (e.g., plasma-derived) or recombinantly produced. For example, in certain embodiments, labile plasma derived blood proteins, such as immunoglobulins, and blood coagulation factors (e.g., Factor VIII) are particularly well suited for formulation as described herein. Non-limiting examples of coagulation proteins include, Factor II (prothrombin), Factor III (platelet tissue factor), Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, von Willebrand Factor (vWF). Likewise, labile recombinant proteins, such as antibodies and blood coagulation factors may be stabilized according to the formulations and methods provided herein.

As used herein, a “storage stable” aqueous composition refers to a protein solution that has been formulated to increase the stability of the protein in solution, for example by at least 20%, over a given storage time. In the context of the present invention, a labile protein solution formulated at a mildly acidic to neutral pH can be made “storage stable” by the addition of a moderate level (about 75 mM to about 200 mM, preferably about 100 mM to about 200 mM) of an alkali metal chloride salt. The stability of the protein in any given formulation can be measured, for example, by monitoring the formation of aggregates, loss of bulk enzymatic activity, loss of antigenic titer or formation of degradation products, over a period of time. The absolute stability of a formulation, and the stabilizing effects of the alkali metal chloride salt, will vary dependent upon the labile protein being stabilized.

As used herein, the term “time of stability” refers to the length of time a composition is considered stable. For example, the time of stability for a composition may refer to the length of time for which the level of protein aggregation and/or degradation in the composition remains below a certain threshold (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.), the length of time a composition maintains an enzymatic activity above a certain threshold (e.g., 100%, 95%, 90, 85, 80, 75, 70, 65, 60, 55, 50, etc. of the amount of activity present in the composition at the start of the storage period), or the length of time a composition maintains an antigenic titer (e.g., 100%, 95%, 90, 85, 80, 75, 70, 65, 60, 55, 50, etc. of the antigenic titer present in the composition at the start of the storage period). In the context of the present invention, a storage stable aqueous composition of a labile therapeutic protein formulated at mildly acidic to neutral pH with a moderate level of an alkali metal chloride salt will have a longer time of stability than a composition of the same labile therapeutic protein formulated at mildly acidic to neutral pH without a moderate level of an alkali metal chloride salt. A storage stable aqueous composition of a labile therapeutic protein, as provided herein, will have a time of stability that is, for example, at least 20% greater than the time of stability for the same composition formulated in the absence of a moderate level of an alkali metal chloride salt, or at least 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190% greater, or at least 2 times greater, or at least 2.5, 3.0 times, 3.5 times, 4.0 times, 4.5 times, 5.0 times, 5.5 times, 6.0 times, 6.5 times, 7.0 times, 7.5 times, 8.0 times, 8.5 times, 9.0 times, 9.5 times, 10 times, or more times greater than the time of stability for the same composition formulated in the absence of a moderate level of an alkali metal chloride salt.

As used herein, the term “stable” refers to a state of a protein composition (e.g., an immunoglobulin solution) suitable for pharmaceutical administration. In the context of the present invention, an immunoglobulin solution is generally considered to be stable when the level of immunoglobulin aggregation and/or degradation in the composition remains below a certain threshold (e.g., below 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.) or the when the antigenic titer remains above a certain threshold (e.g., above 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, etc. of the antigenic titer present in the composition at the start of a storage period).

The European Pharmacopoeia (Ph. Eur.) standard for normal human immunoglobulins is that the composition has: (i) a monomer and dimer content equal to or greater than 85% of the total area of a standard chromatogram; and (ii) a polymer and aggregate sum content of not more than 10% of the total area of the chromatogram. For IGIV the sum of the peak areas of the monomer and dimer represents not less than 95 percent and the maximum amount of polymers and aggregates is no more than 2%. Accordingly, in one embodiment, a storage-stable immunoglobulin composition provided herein is considered to be stable when at least 85% of the immunoglobulin content is monomeric and no more than 5%, preferably no more than 2%, of the immunoglobulin content is aggregated.

As used herein, “storage” means that a formulation is not immediately administered to a subject once prepared, but is kept for a period of time under particular conditions (e.g. at a particular temperature, under a particular atmosphere, protected from light, etc.) prior to use. For example, a liquid formulation can be kept for days, weeks, months or years, prior to administration to a subject under varied temperatures such as refrigerated (0° to 10° C.) or room temperature (e.g., between about 20° C. and 25° C.).

For the purposes of the present invention, when referring to a concentration of an individual component of a composition, the phrases “no more than X” and “from 0 to X” are equivalent and refer to any concentration between and including 0 and X. For example, the phrases “a concentration of no more than 2%” and “a concentration of from 0% to 2%” are equivalent and include 0%, 1%, and 2%.

For the purposes of the present invention, when referring to a concentration of an individual component of a composition, the phrases “no less than X” refers to any concentration X or higher. For example, the phrase “a concentration of no less than 98%” includes 98%, 99%, and 100%.

For the purposes of the present invention, when referring to a concentration of an individual component of a composition, the phrases “between X and Y” and “from X to X” are equivalent and refer to any concentration between and including X and Y. For example, the phrases “a concentration of between 49% and 51%” and “a concentration of from 49% to 51%” are equivalent and include 49%, 50%, and 51%.

As used herein, an “alkali metal chloride salt” refers to an inorganic salt of an alkali metal and chlorine. For the purposes of the present invention, the alkali metal chloride salt will be a pharmaceutically acceptable salt, most commonly sodium or potassium chloride. In a preferred embodiment, the salt is sodium chloride.

Likewise, an “alkali metal cation” will most commonly refer to a sodium cation (Na⁺) or potassium cation (K⁺) and can be contributed by an alkali metal chloride salt or other source. In the context of the present invention, a hydrogen ion is not considered an alkali metal cation, and thus the inclusion of hydrochloric acid will not contribute to the alkali metal cation content of the formulation.

As used herein, a “coagulation factor” refers to a protein involved in the intrinsic (contact activation) or extrinsic (tissue factor) pathway of the coagulation cascade. Non-limiting examples of coagulation proteins include, Factor II (prothrombin), Factor III (platelet tissue factor), Factor. V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, von Willebrand Factor (vWF), and the like. Coagulation proteins stabilized by the formulations and methods provided herein may be plasma-derived or recombinantly produced.

As used herein, the term “core coagulation factor” refers to any one of Factor VII, Factor VIII, Factor IX, and von Willebrand Factor (vWF), as well as conservative or natural variants, biologically active fragments, and natural isoforms thereof.

As used herein, the term “Factor VIII” or “FVIII” refers to any form of factor VIII molecule with the typical characteristics of blood coagulation factor VIII, whether derived from blood plasma or produced through the use of recombinant DNA techniques, and including all modified forms of factor VIII. Factor VIII (FVIII) exists naturally and in therapeutic preparations as a heterogeneous distribution of polypeptides arising from a single gene product (see, e.g., Anderson et al., Proc. Natl. Acad. Sci. USA, 83:2979-2983 (1986)). Commercially available examples of therapeutic preparations containing Factor VIII include those sold under the trade names of HEMOFIL M, ADVATE, and RECOMBINATE (available from Baxter Healthcare Corporation, Deerfield, Ill., U.S.A.).

As used herein, an “antibody” refers to a polypeptide substantially encoded by an immunoglobulin gene or immunoglobulin genes, or fragments thereof, which specifically bind and recognize an analyte (antigen). The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD, and IgE, respectively.

An exemplary immunoglobulin (antibody) structural unit is composed of two pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively. In a particular exemplary embodiment, the immunoglobulin will consist of an immunoglobulin preparation isolated from pooled plasma (preferably human plasma) comprising IgG immunoglobulins.

As used herein, the term “about” denotes an approximate range of plus or minus 10% from a specified value. For instance, the language “about 20%” encompasses a range of 18-22%. As used herein, about also includes the exact amount. Hence “about 20%” means “about 20%” and also “20%.”

By “therapeutically effective amount or dose” or “sufficient/effective amount or dose,” it is meant a dose that produces effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

As used herein, a “stabilizing agent” refers to a chemical, other than an alkali metal chloride salt, which aids in the stabilization of a labile therapeutic agent in an aqueous formulation under mildly acid to neutral pH. Examples of suitable stabilizing agents for the formulations and methods provided herein include, without limitation, buffering agents (e.g., TRIS, HEPES, potassium or sodium phosphate, amino acids, etc.), osmolytes (e.g., sugars, sugar alcohols, etc.), bulking agents (e.g., amino acids, etc.), divalent salts, surfactants, and the like.

As used herein, “amino acids” refers to any natural or non-natural pharmaceutically acceptable amino acid. Non-limiting examples of amino acids include, isoleucine, alanine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, proline, selenocysteine, serine, tyrosine, arginine, histidine, ornithine, taurine, and the like.

Any sugar such as mono-, di-, or polysaccharides, or water-soluble glucans, including for example fructose, glucose, mannose, sorbose, xylose, maltose, lactose, sucrose, dextran, trehalose, pullulan, dextrin, cyclodextrin, soluble starch, hydroxyethyl starch, and carboxymethylcellulose may be used.

As used herein, a “sugar alcohol” refers to a hydrocarbon having between about 4 and about 8 carbon atoms and at least one hydroxyl group. Non-limiting examples of sugar alcohols that may be used in formulations provided herein include, mannitol, sorbitol, inositol, galactitol, dulcitol, xylitol, and arabitol.

As used herein, the term “activity” refers to a functional activity or activities of a polypeptide or portion thereof associated with a full-length (complete) protein. Functional activities include, but are not limited to, biological activity, catalytic or enzymatic activity, antigenicity (i.e., the ability to bind or compete with a polypeptide for binding to an anti-polypeptide antibody), immunogenicity, ability to form multimers, and the ability to specifically bind to a receptor or ligand for the polypeptide.

III. Formulations

Among other aspects, the present invention provides stabilized formulations of labile proteins for therapeutic administration. The following embodiments are based in part on the unexpected discovery that the addition of moderate levels of an alkali metal chloride salt (i.e., about 75 mM to about 200 mM, preferably about 100 mM to about 200 mM) to formulations at mildly acidic to neutral pH stabilize various plasma-derived and recombinant proteins that are otherwise labile at these pH values.

The labile therapeutic protein compositions provided by the present invention take advantage of the increased stability afforded when these proteins are formulated at mildly acidic to neutral pH. Generally, this includes pH values between about 5.5 and about 7.5. In a preferred embodiment, the pH value is between about 5.5 and about 7.0. However, the range of pH values at which any individual labile therapeutic protein is stabilized by the addition of a moderate level (i.e., between about 75 mM and about 200 mM, preferably between about 100 mM and about 200 mM) of an alkali metal chloride salt may vary slightly, dependent upon the properties of the individual protein. For example, in one embodiment, a storage stable formulation will have a pH between about 5.5 and about 7.0. In another embodiment, a storage stable formulation will have a pH between about 5.5 and about 6.5. In other embodiments, the pH of the stabilizing formulation will be between about 6.0 and about 7.0. In another embodiment, the pH of the stabilizing formulation will be between about 5.5 and about 6.0. In one embodiment, the pH of the stabilizing formulation will be between about 6.0 and about 6.5. In another embodiment, the pH of the stabilizing formulation will be between about 6.5 and about 7.0. In another embodiment, a storage stable formulation will have a pH between about 6.0 and about 7.5. In another embodiment, a storage stable formulation will have a pH between about 6.5 and about 7.5. In another embodiment, a storage stable formulation will have a pH between about 7.0 and about 7.5. In other embodiments, the pH of the stabilizing formulation is 5.5±0.2, 5.6±0.2, 5.7±0.2, 5.8±0.2, 5.9±0.2, 6.0±0.2, 6.1±0.2, 6.2±0.2, 6.3±0.2, 6.4±0.2, 6.5±0.2, 6.6±0.2, 6.7±0.2, 6.8±0.2, 6.9±0.2, 7.0±0.2, 7.1±0.2, 7.2±0.2, 7.3±0.2, 7.4±0.2, or 7.5±0.2. In other embodiments, the pH of the stabilizing formulation is 5.5±0.1, 5.6±0.1, 5.7±0.1, 5.8±0.1, 5.9±0.1, 6.0±0.1, 6.1±0.1, 6.2±0.1, 6.3±0.1, 6.4±0.1, 6.5±0.1, 6.6±0.1, 6.7±0.1, 6.8±0.1, 6.9±0.1, 7.0±0.1, 7.1±0.1, 7.2±0.1, 7.3±0.1, 7.4±0.1, or 7.5±0.1. In yet other embodiments, the pH of the stabilizing formulation is 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, or 7.5.

In addition to the alkali metal chloride salt, the pharmaceutical compositions provided herein include one or more stabilizing agents. In a specific embodiment, the stabilizing agent is a buffering agent suitable for intravenous, intravitreal, subcutaneous, and/or intramuscular administration. Non-limiting examples of buffering agents suitable for formulating the storage stable compositions provided herein include glycine, histidine, proline, or other amino acids, salts like citrate, phosphate, acetate, glutamate, tartrate, benzoate, lactate, gluconate, malate, succinate, formate, propionate, carbonate, or any combination thereof adjusted to an appropriate pH. Generally, the buffering agent will be sufficient to maintain a suitable pH in the formulation for an extended period of time.

A. Labile Proteins

Among other aspects, the present invention provides stabilized formulations of labile therapeutic proteins for therapeutic administration. The following embodiments are based in part on the unexpected discovery that the formulation of labile therapeutic proteins, including but not limited to immunoglobulin and coagulation factors, with a moderate amount of an alkali metal chloride salt at mildly acidic to neutral pH stabilizes proteins that are otherwise labile at these pH values and/or labile when formulated with an alkali metal chloride salt an acidic pH.

As will be recognized by one of skill in the art, the formulation of a protein composition at a particular pH may introduce residual counter ions contributed from one or more pH modifying agents. For example, the storage stable compositions provided herein may contain chloride anions contributed from hydrochloric acid, acetate anions contributed from glacial acetic acid, sodium cations contributed from sodium hydroxide, and the like. In the context of the present invention, a storage stable labile therapeutic protein composition consisting of or consisting essentially of: a labile therapeutic protein, a moderate concentration of an alkali metal chloride salt, and a stabilizing agent may further comprise one or more counter ion, as necessitated by the formulation process at the desired pH.

In one embodiment, a labile therapeutic protein that may benefit from a formulation or method provided herein is stable for less than 3 months at a temperature between 28° C. and 32° C. when in an aqueous formulation containing less than 50 mM of an alkali metal chloride salt at a pH between 5.5 and 7.5, preferably between 5.5 and 7.0. In another embodiment, the labile therapeutic protein is stable for less than 2 months at a temperature between 28° C. and 32° C. in an aqueous formulation containing less than 50 mM of an alkali metal chloride salt at a pH between 5.5 and 7.5, preferably between 5.5 and 7.0. In another embodiment, the labile therapeutic protein is stable for less than 1 month at a temperature between 28° C. and 32° C. in an aqueous formulation containing less than 50 mM of an alkali metal chloride salt at a pH between 5.5 and 7.5, preferably between 5.5 and 7.0. In yet another embodiment, the labile therapeutic protein is stable for less than 2 weeks at a temperature between 28° C. and 32° C. in an aqueous formulation containing less than 50 mM of an alkali metal chloride salt at a pH between 5.5 and 7.5, preferably between 5.5 and 7.0. In a preferred embodiment, the labile therapeutic protein is an immunoglobulin.

In a related embodiment, a labile therapeutic protein that may benefit from a formulation or method provided herein is stable for less than 3 months at a temperature between 2° C. and 8° C. when in an aqueous formulation containing less than 50 mM of an alkali metal chloride salt at a pH between 5.5 and 7.5, preferably between 6.0 and 7.5. In another embodiment, the labile therapeutic protein is stable for less than 2 months at a temperature between 2° C. and 8° C. in an aqueous formulation containing less than 50 mM of an alkali metal chloride salt at a pH between 5.5 and 7.5, preferably between 6.0 and 7.5. In another embodiment, the labile therapeutic protein is stable for less than 1 month at a temperature between 2° C. and 8° C. in an aqueous formulation containing less than 50 mM of an alkali metal chloride salt at a pH between 5.5 and 7.5, preferably between 6.0 and 7.5. In yet another embodiment, the labile therapeutic protein is stable for less than 2 weeks at a temperature between 2° C. and 8° C. in an aqueous formulation containing less than 50 mM of an alkali metal chloride salt at a pH between 5.5 and 7.5, preferably between 6.0 and 7.5. In a specific embodiment, the labile therapeutic protein is a coagulation factor. In a preferred embodiment, the labile therapeutic protein is Factor VIII.

In preferred embodiments of the invention, the labile therapeutic protein will be a human protein, a chimeric protein (e.g., a mouse/human chimera or rat/human chimera), or a humanized protein. For example, in one preferred embodiment, the labile therapeutic protein will be a recombinant chimeric or humanized monoclonal antibody. In other preferred embodiment, the labile therapeutic protein will be a plasma protein, either recombinant or plasma-derived, e.g., a protein composition isolated from pooled human plasma. Non-limiting examples of plasma-derived labile proteins that may be formulated according to the present invention include: Factor II (prothrombin), Factor III (platelet tissue factor), Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, and von Willebrand Factor (vWF).

The final concentration of the labile therapeutic protein in the formulations provided herein will be dependent upon many factors, including without limitation, the potency and specific activity of the protein, the disease or condition being treated, the route of administration, and other factors that will be well understood by the skilled practitioner. In one embodiment, the labile therapeutic protein will be formulated at a low protein concentration, for example, between 0.05 mg/mL and 10 mg/mL, or between 0.1 mg/mL and 20 mg/mL, or between 0.5 mg/mL and 10 mg/mL, or between 0.1 mg/mL and 0.5 mg/mL. In other embodiments, the labile therapeutic protein will be formulated at a moderate protein concentration, between 20 mg/mL and 80 mg/mL. For example, between 20 mg/mL and 40 mg/mL. Or between 40 mg/mL and 60 mg/mL. Or between 60 mg/mL and 80 mg/mL. In yet other embodiments, the labile therapeutic protein will be formulated at a high protein concentration, between 80 mg/mL and 250 mg/mL. For example, in one embodiment, the protein concentration will be between 80 mg/mL and 120 mg/mL. In another embodiment, the protein concentration will be between 120 mg/mL and 180 mg/mL. In yet another embodiment, the protein concentration will be between 180 mg/mL and 250 mg/mL.

In certain embodiments, the final protein concentration may be between 0.5% and 25%. In another embodiment, the final protein concentration may be between 0.5% and 20%. In another embodiment, the final protein concentration may be between 0.5% and 15%. In another embodiment, the final protein concentration may be between 0.5% and 10%. In another embodiment, the final protein concentration may be between 0.5% and 5%. In one embodiment, a composition with a final protein concentration as described above will be formulated for intravenous administration.

In certain embodiments, the final protein concentration may be between 5% and 25%. In another embodiment, the final protein concentration may be between 10% and 25%. In another embodiment, the final protein concentration may be between 15% and 25%. In another embodiment, the final protein concentration may be between 20% and 25%. In one embodiment, a composition with a final protein concentration as described above will be formulated for subcutaneous or intramuscular administration.

In certain embodiments, the labile therapeutic protein will be formulated at a final concentration of from 0.05 g/L to 250 g/L. In certain embodiments, the labile protein is formulated at a final concentration of 0.05±0.01 g/L, 0.06±0.01 g/L, 0.07±0.01 g/L, 0.08±0.01 g/L, 0.09±0.01 g/L, 0.1±0.01 g/L, 0.2±0.02 g/L, 0.3±0.03 g/L, 0.4±0.04 g/L, 0.5±0.05 g/L, 0.6±0.06 g/L, 0.7±0.07 g/L, 0.8±0.08 g/L, 0.9±0.09 g/L, 1±0.1 g/L, 210.2 g/L, 3±0.3 g/L, 4±0.4 g/L, 5±0.5 g/L, 6±0.6 g/L, 7±0.7 g/L, 8±0.8 g/L, 9±0.9 g/L, 10±1 g/L, 11±1.1 g/L, 12±1.2 g/L, 13±1.3 g/L, 14±1.4 g/L, 15±1.5 g/L, 16±1.6 g/L, 17±1.7 g/L, 18±1.8 g/L, 19±1.9 g/L, 20±2 g/L, 21±2.1 g/L, 22±2.2 g/L, 23±2.3 g/L, 24±2.4 g/L, 25±2.5 g/L, 26±2.6 g/L, 27±2.7 g/L, 28±2.8 g/L, 29±2.9 g/L, 30±3 g/L, 35±3.5 g/L, 40±4 g/L, 45±4.5 g/L, 50±5 g/L, 55±5.5 g/L, 60±6 g/L, 65±6.5 g/L, 70±7 g/L, 75±7.5 g/L, 80±8 g/L, 85±8.5 g/L, 90±9 g/L, 95±9.5 g/L, 100±10 g/L, 110±11 g/L, 120±12 g/L, 130±13 g/L, 140±14 g/L, 150±15 g/L, 160±16 g/L, 170±17 g/L, 180±18 g/L, 190±19 g/L, 200±20 g/L, 210±21 g/L, 220±22 g/L, 230±23 g/L, 240±24 g/L, 250±25 g/L, or higher concentrations, depending upon the characteristics of the protein being formulated, the intended therapeutic use of the protein, and the preferred method of administration. In yet other embodiments, the final concentration of the labile protein in the formulation is 0.05 g/L, 0.06 g/L, 0.07 g/L, 0.08 g/L, 0.09 g/L, 0.1 g/L, 0.2 g/L, 0.3 g/L, 0.4 g/L, 0.5 g/L, 0.6 g/L, 0.7 g/L, 0.8 g/L, 0.9 g/L, 1 g/L, 2 g/L, 3 g/L, 4 g/L, 5 g/L, 6 g/L, 7 g/L, 8 g/L, 9 g/L, 10 g/L, 11 g/L, 12 g/L, 13 g/L, 14 g/L, 15 g/L, 16 g/L, 17 g/L, 18 g/L, 19 g/L, 20 g/L, 21 g/L, 22 g/L, 23 g/L, 24 g/L, 25 g/L, 26 g/L, 27 g/L, 28 g/L, 29 g/L, 30 g/L, 35 g/L, 40 g/L, 45 g/L, 50 g/L, 55 g/L, 60 g/L, 65 g/L, 70 g/L, 75 g/L, 80 g/L, 85 g/L, 90 g/L, 95 g/L, 100 g/L, 110 g/L, 120 g/L, 130 g/L, 140 g/L, 150 g/L, 160 g/L, 170 g/L, 180 g/L, 190 g/L, 200 g/L, 210 g/L, 220 g/L, 230 g/L, 240 g/L, 250 g/L, or higher

In certain embodiments, the formulations provided herein will stabilize a labile therapeutic protein composition when stored at a temperature between 2° C. and 42° C. In one embodiments, a labile therapeutic protein will be stabilized by the formulations provided herein when stored under refrigeration, i.e., stored at a temperature between 2° C. and 8° C. In another embodiment, a labile therapeutic protein will be stabilized by the formulations provided herein when stored at room temperature, i.e., stored at a temperature between 20° C. and 25° C. In other embodiments, the protein may be stabilized when stored at a temperature between 28° C. and 32° C. In yet another embodiment, the protein may be stabilized when stored at a temperature between 38° C. and 42° C. The temperatures at which a labile therapeutic protein will be stabilized by the formulations provided herein will be dependent upon the characteristics of the individual protein, which can readily be determined by one of skill in the art.

Likewise, the extent of time for which a labile protein is stabilized by the formulations provided herein will depend upon the individual protein. For example, in one embodiment, a storage stable, aqueous composition provided herein will be stable for at least 2 months. In another embodiment, the composition will be stable for at least 3 months. In yet other embodiment, the composition will be stable for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or more months. In a preferred embodiment, the composition will be stable for at least 6 months. In a more preferred embodiment, the composition will be stable for at least 1 year. In another preferred embodiment, the composition will be stable for at least 2 years.

The extent to which a labile therapeutic protein is stabilized by the formulations provided herein may also be expressed as a percentage increase in the time the composition is stable under standard storage conditions. For example, in one embodiment, a labile therapeutic protein composition may be stable under storage conditions for at least 25% longer when formulated with an alkali metal chloride salt at a mildly acidic to neutral pH, as provided herein, as compared to the stability of the same protein under mildly acidic to neutral pH in the absence of the alkali metal chloride salt. In other embodiments, the composition may be stable for at least 50% longer when formulated according to the present invention, or at least 75%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, or longer when formulated according to the present invention. For example, in one embodiment, the labile therapeutic protein composition may be stable under storage conditions for from 25% to 1000% longer when formulated with an alkali metal chloride salt at a mildly acidic to neutral pH, as provided herein, as compared to the stability of the same protein under mildly acidic to neutral pH in the absence of the alkali metal chloride salt. In other embodiments, the composition may be stable for from 50% to 1000%, 100% to 1000%, 200% to 1000%, 300% to 1000%, 400% to 1000%, 500% to 1000%, 600% to 1000%, or 700% to 1000%, when formulated according to the present invention.

Protein stability may be measured using various metrics, including but not limited to, the extent or rate of protein aggregation, the loss of enzymatic activity, the loss of anti-antigen titer, and/or the extent or rate of protein degradation. One of skill in the art will recognize that certain metrics will be more or less relevant to individual proteins. For example, the stability of an enzyme may be determined by monitoring the loss of enzymatic activity over time, but not by monitoring the loss of an anti-antigen titer. Conversely, the stability of an antibody may be measured by monitoring the loss of anti-antigen titer, but not by enzymatic activity.

Accordingly, in one embodiment, a labile immunoglobulin composition is an immunoglobulin composition that losses from 20% to 100% of its anti-antigen titer when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 6 months. In another embodiment, a labile immunoglobulin composition is an immunoglobulin composition that losses from 30% to 100% of its anti-antigen titer when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 6 months. In another embodiment, a labile immunoglobulin composition is an immunoglobulin composition that losses from 40% to 100% of its anti-antigen titer when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 6 months. In another embodiment, a labile immunoglobulin composition is an immunoglobulin composition that losses from 50% to 100% of its anti-antigen titer when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 6 months.

In one embodiment, the stability of a labile protein composition may be determined by monitoring the extent or rate of protein aggregation within the formulation. Protein aggregation may be determined for example, by size exclusion chromatography (SEC), high performance size exclusion chromatography (HP-SEC), dynamic light scattering, non-denaturing gel electrophoresis and the like. Although the absolute aggregation level at which a labile protein composition will be considered unstable will vary from protein to protein, the level of aggregation that results in a significant loss of the therapeutic value of the composition will generally be regarded as unstable.

In another embodiment, wherein the labile therapeutic protein is an enzyme, the stability of the composition may be determined by monitoring the loss of bulk enzymatic activity in the preparation. For example, in one embodiment, a 20% loss of enzymatic activity will correspond to an unstable composition. In other embodiments, a 10% loss of enzymatic activity, or a 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or higher loss of enzymatic activity will correspond to an unstable composition.

In one embodiment, a labile protein composition is an enzyme composition that losses from 10% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.5 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 1 month. In another embodiment, a labile protein composition is an enzyme composition that losses from 20% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 1 month. In one embodiment, a labile protein composition is an enzyme composition that losses from 30% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 1 month. In one embodiment, a labile protein composition is an enzyme composition that losses from 40% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 1 month. In one embodiment, a labile protein composition is an enzyme composition that losses from 50% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 1 month.

In one embodiment, a labile protein composition is an enzyme composition that losses from 10% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.5 and stored at a particular temperature (e.g.; from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 2 months. In another embodiment, a labile protein composition is an enzyme composition that losses from 20% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 2 months. In one embodiment, a labile protein composition is an enzyme composition that losses from 30% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 2 months. In one embodiment, a labile protein composition is an enzyme composition that losses from 40% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 2 months. In one embodiment, a labile protein composition is an enzyme composition that losses from 50% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 2 months.

In one embodiment, a labile protein composition is an enzyme composition that losses from 10% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.5 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 3 months. In another embodiment, a labile protein composition is an enzyme composition that losses from 20% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 3 months. In one embodiment, a labile protein composition is an enzyme composition that losses from 30% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 3 months. In one embodiment, a labile protein composition is an enzyme composition that losses from 40% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 3 months. In one embodiment, a labile protein composition is an enzyme composition that losses from 50% to 100% of enzymatic activity when formulated with less than 75 mM (i.e., between 0 mM and 75 mM) of an alkali metal chloride salt at a pH from 5.5 to 7.0 and stored at a particular temperature (e.g., from 2° C. to 8° C., from 20° C. to 25° C., from 28° C. to 32° C., or from 38° C. to 42° C.) for between 1 day and 3 months.

In another embodiment, the stability of a labile protein composition may be determined by monitoring the extent or rate of protein degradation within the formulation. Protein degradation may be determined for example, by size exclusion chromatography (SEC), high performance size exclusion chromatography (HP-SEC), dynamic, light scattering, non-denaturing gel electrophoresis and the like. Although the absolute degradation level at which a labile protein composition will be considered unstable will vary from protein to protein, the level of degradation that results in a significant loss of the therapeutic value of the composition will generally be regarded as unstable.

Accordingly, in one aspect, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein, the composition comprising between 75 mM and 200 mM of an alkali metal chloride salt, a stabilizing agent, and a pH between 5.5 and 7.5. In a specific embodiment, the stabilizing agent is a buffer. In a more specific embodiment, the stabilizing agent is an amino acid. In a yet more specific embodiment, the amino acid is glycine, histidine, or proline. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein, the composition consisting essentially of: between 75 mM and 200 mM of an alkali metal chloride salt, a stabilizing agent, and a pH between 5.5 and 7.5. In a specific embodiment, the stabilizing agent is a buffer. In a more specific embodiment, the stabilizing agent is an amino acid. In a yet more specific embodiment, the amino acid is glycine, histidine, or proline. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein, the composition consisting of: between 75 mM and 200 mM of an alkali metal chloride salt, a stabilizing agent, and a pH between 5.5 and 7.5. In a specific embodiment, the stabilizing agent is a buffer. In a more specific embodiment, the stabilizing agent is an amino acid. In a yet more specific embodiment, the amino acid is glycine, histidine, or proline. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a closely related embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein, the composition comprising: between about 75 mM and about 200 mM of an alkali metal chloride salt, a stabilizing agent, and a pH between about 5.5 and about 7.5. In a specific embodiment, the stabilizing agent is a buffer. In a more specific embodiment, the stabilizing agent is an amino acid. In a yet more specific embodiment, the amino acid is glycine, histidine, or proline. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein, the composition consisting essentially of: between about 75 mM and about 200 mM of an alkali metal chloride salt, a stabilizing agent, and a pH between about 5.5 and about 7.5. In a specific embodiment, the stabilizing agent is a buffer. In a more specific embodiment, the stabilizing agent is an amino acid. In a yet more specific embodiment, the amino acid is glycine, histidine, or proline. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein, the composition consisting of: between about 75 mM and about 200 mM of an alkali metal chloride salt, a stabilizing agent, and a pH between about 5.5 and about 7.5. In a specific embodiment, the stabilizing agent is a buffer. In a more specific embodiment, the stabilizing agent is an amino acid. In a yet more specific embodiment, the amino acid is glycine, histidine, or proline. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

1. Alkali Metal Chloride Salts

Surprisingly, it was found that the addition of a moderate level of an alkali metal chloride salt to an aqueous composition of a labile therapeutic protein formulated at a mildly acidic to neutral pH significantly stabilized the labile protein, regardless of the identity of the protein. In one embodiment, a stabilizing formulation provided herein contains between 75 mM and 200 mM of an alkali metal chloride salt. In a preferred embodiment, the formulation contains between 100 mM and 200 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 150 mM and 200 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 75 mM and 175 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 75 mM and 150 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 75 mM and 125 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 100 mM and 175 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 100 mM and 150 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 100 mM and 125 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 125 mM and 200 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 125 mM and 175 mM of an alkali metal chloride salt. In another embodiment, the formulation contains between 125 mM and 150 mM of an alkali metal chloride salt. In yet other embodiments, the formulation contains 70±7 mM, 75±7.5 mM, 80±8 mM, 90±9 mM, 100 mM±10, 110±11 mM, 120 mM±12, 125±12.5 mM, 130±13 mM, 140±14 mM, 150±15 mM, 160±16 mM, 170±17 mM, 175±17.5 mM, 180±18 mM, 190±19 mM, 200±20 mM, 210±21 mM, or 220±22 mM of an alkali metal chloride salt. In yet other more specific embodiments, the formulation contains 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 155 mM, 160 mM, 165 mM, 170 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, or 220 mM of an alkali metal chloride salt. In one preferred embodiment, the alkali metal chloride salt is sodium chloride. In another preferred embodiment, the alkali metal chloride salt is potassium chloride.

Accordingly, in one aspect, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; 150±15 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; 150±15 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; 150±15 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride.

TABLE 1
Particular combinations of alkali metal chloride salt concentration and pH useful for the aqueous
formulation of labile therapeutic proteins.
	Alkali Metal Chloride Salt (mM)
pH	75-250	75-225	75-200	75-175	75-150	75-125	100-250	100-225
5.5-7.5	Var. 1	Var. 73	Var. 145	Var. 217	Var. 289	Var. 361	Var. 433	Var. 505
5.5-7.0	Var. 2	Var. 74	Var. 146	Var. 218	Var. 290	Var. 362	Var. 434	Var. 506
5.5-6.5	Var. 3	Var. 75	Var. 147	Var. 219	Var. 291	Var. 363	Var. 435	Var. 507
5.5-6.0	Var. 4	Var. 76	Var. 148	Var. 220	Var. 292	Var. 364	Var. 436	Var. 508
6.0-7.5	Var. 5	Var. 77	Var. 149	Var. 221	Var. 293	Var. 365	Var. 437	Var. 509
6.0-7.0	Var. 6	Var. 78	Var. 150	Var. 222	Var. 294	Var. 366	Var. 438	Var. 510
6.0-6.5	Var. 7	Var. 79	Var. 151	Var. 223	Var. 295	Var. 367	Var. 439	Var. 511
6.5-7.5	Var. 8	Var. 80	Var. 152	Var. 224	Var. 296	Var. 368	Var. 440	Var. 512
6.5-7.0	Var. 9	Var. 81	Var. 153	Var. 225	Var. 297	Var. 369	Var. 441	Var. 513
5.5 ± 0.2	Var. 10	Var. 82	Var. 154	Var. 226	Var. 298	Var. 370	Var. 442	Var. 514
5.6 ± 0.2	Var. 11	Var. 83	Var. 155	Var. 227	Var. 299	Var. 371	Var. 443	Var. 515
5.7 ± 0.2	Var. 12	Var. 84	Var. 156	Var. 228	Var. 300	Var. 372	Var. 444	Var. 516
5.8 ± 0.2	Var. 13	Var. 85	Var. 157	Var. 229	Var. 301	Var. 373	Var. 445	Var. 517
5.9 ± 0.2	Var. 14	Var. 86	Var. 158	Var. 230	Var. 302	Var. 374	Var. 446	Var. 518
6.0 ± 0.2	Var. 15	Var. 87	Var. 159	Var. 231	Var. 303	Var. 375	Var. 447	Var. 519
6.1 ± 0.2	Var. 16	Var. 88	Var. 160	Var. 232	Var. 304	Var. 376	Var. 448	Var. 520
6.2 ± 0.2	Var. 17	Var. 89	Var. 161	Var. 233	Var. 305	Var. 377	Var. 449	Var. 521
6.3 ± 0.2	Var. 18	Var. 90	Var. 162	Var. 234	Var. 306	Var. 378	Var. 450	Var. 522
6.4 ± 0.2	Var. 19	Var. 91	Var. 163	Var. 235	Var. 307	Var. 379	Var. 451	Var. 523
6.5 ± 0.2	Var. 20	Var. 92	Var. 164	Var. 236	Var. 308	Var. 380	Var. 452	Var. 524
6.6 ± 0.2	Var. 21	Var. 93	Var. 165	Var. 237	Var. 309	Var. 381	Var. 453	Var. 525
6.7 ± 0.2	Var. 22	Var. 94	Var. 166	Var. 238	Var. 310	Var. 382	Var. 454	Var. 526
6.8 ± 0.2	Var. 23	Var. 95	Var. 167	Var. 239	Var. 311	Var. 383	Var. 455	Var. 527
6.9 ± 0.2	Var. 24	Var. 96	Var. 168	Var. 240	Var. 312	Var. 384	Var. 456	Var. 528
7.0 ± 0.2	Var. 25	Var. 97	Var. 169	Var. 241	Var. 313	Var. 385	Var. 457	Var. 529
7.1 ± 0.2	Var. 26	Var. 98	Var. 170	Var. 242	Var. 314	Var. 386	Var. 458	Var. 530
7.2 ± 0.2	Var. 27	Var. 99	Var. 171	Var. 243	Var. 315	Var. 387	Var. 459	Var. 531
7.3 ± 0.2	Var. 28	Var. 100	Var. 172	Var. 244	Var. 316	Var. 388	Var. 460	Var. 532
7.4 ± 0.2	Var. 29	Var. 101	Var. 173	Var. 245	Var. 317	Var. 389	Var. 461	Var. 533
7.5 ± 0.2	Var. 30	Var. 102	Var. 174	Var. 246	Var. 318	Var. 390	Var. 462	Var. 534
5.5 ± 0.1	Var. 31	Var. 103	Var. 175	Var. 247	Var. 319	Var. 391	Var. 463	Var. 535
5.6 ± 0.1	Var. 32	Var. 104	Var. 176	Var. 248	Var. 320	Var. 392	Var. 464	Var. 536
5.7 ± 0.1	Var. 33	Var. 105	Var. 177	Var. 249	Var. 321	Var. 393	Var. 465	Var. 537
5.8 ± 0.1	Var. 34	Var. 106	Var. 178	Var. 250	Var. 322	Var. 394	Var. 466	Var. 538
5.9 ± 0.1	Var. 35	Var. 107	Var. 179	Var. 251	Var. 323	Var. 395	Var. 467	Var. 539
6.0 ± 0.1	Var. 36	Var. 108	Var. 180	Var. 252	Var. 324	Var. 396	Var. 468	Var. 540
6.1 ± 0.1	Var. 37	Var. 109	Var. 181	Var. 253	Var. 325	Var. 397	Var. 469	Var. 541
6.2 ± 0.1	Var. 38	Var. 110	Var. 182	Var. 254	Var. 326	Var. 398	Var. 470	Var. 542
6.3 ± 0.1	Var. 39	Var. 111	Var. 183	Var. 255	Var. 327	Var. 399	Var. 471	Var. 543
6.4 ± 0.1	Var. 40	Var. 112	Var. 184	Var. 256	Var. 328	Var. 400	Var. 472	Var. 544
6.5 ± 0.1	Var. 41	Var. 113	Var. 185	Var. 257	Var. 329	Var. 401	Var. 473	Var. 545
6.6 ± 0.1	Var. 42	Var. 114	Var. 186	Var. 258	Var. 330	Var. 402	Var. 474	Var. 546
6.7 ± 0.1	Var. 43	Var. 115	Var. 187	Var. 259	Var. 331	Var. 403	Var. 475	Var. 547
6.8 ± 0.1	Var. 44	Var. 116	Var. 188	Var. 260	Var. 332	Var. 404	Var. 476	Var. 548
6.9 ± 0.1	Var. 45	Var. 117	Var. 189	Var. 261	Var. 333	Var. 405	Var. 477	Var. 549
7.0 ± 0.1	Var. 46	Var. 118	Var. 190	Var. 262	Var. 334	Var. 406	Var. 478	Var. 550
7.1 ± 0.1	Var. 47	Var. 119	Var. 191	Var. 263	Var. 335	Var. 407	Var. 479	Var. 551
7.2 ± 0.1	Var. 48	Var. 120	Var. 192	Var. 264	Var. 336	Var. 408	Var. 480	Var. 552
7.3 ± 0.1	Var. 49	Var. 121	Var. 193	Var. 265	Var. 337	Var. 409	Var. 481	Var. 553
7.4 ± 0.1	Var. 50	Var. 122	Var. 194	Var. 266	Var. 338	Var. 410	Var. 482	Var. 554
7.5 ± 0.1	Var. 51	Var. 123	Var. 195	Var. 267	Var. 339	Var. 411	Var. 483	Var. 555
5.5	Var. 52	Var. 124	Var. 196	Var. 268	Var. 340	Var. 412	Var. 484	Var. 556
5.6	Var. 53	Var. 125	Var. 197	Var. 269	Var. 341	Var. 413	Var. 485	Var. 557
5.7	Var. 54	Var. 126	Var. 198	Var. 270	Var. 342	Var. 414	Var. 486	Var. 558
5.8	Var. 55	Var. 127	Var. 199	Var. 271	Var. 343	Var. 415	Var. 487	Var. 559
5.9	Var. 56	Var. 128	Var. 200	Var. 272	Var. 344	Var. 416	Var. 488	Var. 560
6	Var. 57	Var. 129	Var. 201	Var. 273	Var. 345	Var. 417	Var. 489	Var. 561
6.1	Var. 58	Var. 130	Var. 202	Var. 274	Var. 346	Var. 418	Var. 490	Var. 562
6.2	Var. 59	Var. 131	Var. 203	Var. 275	Var. 347	Var. 419	Var. 491	Var. 563
6.3	Var. 60	Var. 132	Var. 204	Var. 276	Var. 348	Var. 420	Var. 492	Var. 564
6.4	Var. 61	Var. 133	Var. 205	Var. 277	Var. 349	Var. 421	Var. 493	Var. 565
6.5	Var. 62	Var. 134	Var. 206	Var. 278	Var. 350	Var. 422	Var. 494	Var. 566
6.6	Var. 63	Var. 135	Var. 207	Var. 279	Var. 351	Var. 423	Var. 495	Var. 567
6.7	Var. 64	Var. 136	Var. 208	Var. 280	Var. 352	Var. 424	Var. 496	Var. 568
6.8	Var. 65	Var. 137	Var. 209	Var. 281	Var. 353	Var. 425	Var. 497	Var. 569
6.9	Var. 66	Var. 138	Var. 210	Var. 282	Var. 354	Var. 426	Var. 498	Var. 570
7	Var. 67	Var. 139	Var. 211	Var. 283	Var. 355	Var. 427	Var. 499	Var. 571
7.1	Var. 68	Var. 140	Var. 212	Var. 284	Var. 356	Var. 428	Var. 500	Var. 572
7.2	Var. 69	Var. 141	Var. 213	Var. 285	Var. 357	Var. 429	Var. 501	Var. 573
7.3	Var. 70	Var. 142	Var. 214	Var. 286	Var. 358	Var. 430	Var. 502	Var. 574
7.4	Var. 71	Var. 143	Var. 215	Var. 287	Var. 359	Var. 431	Var. 503	Var. 575
7.5	Var. 72	Var. 144	Var. 216	Var. 288	Var. 360	Var. 432	Var. 504	Var. 576

TABLE 2
Particular combinations of histidine concentration and pH useful for the formulation of immunoglobulins.
	Alkali Metal Chloride Salt (mM)
pH	100-200	100-175	100-150	100-125	125-250	125-225	125-200	125-175
5.5-7.5	Var. 577	Var. 649	Var. 721	Var. 793	Var. 865	Var. 937	Var. 1009	Var. 1081
5.5-7.0	Var. 578	Var. 650	Var. 722	Var. 794	Var. 866	Var. 938	Var. 1010	Var. 1082
5.5-6.5	Var. 579	Var. 651	Var. 723	Var. 795	Var. 867	Var. 939	Var. 1011	Var. 1083
5.5-6.0	Var. 580	Var. 652	Var. 724	Var. 796	Var. 868	Var. 940	Var. 1012	Var. 1084
6.0-7.5	Var. 581	Var. 653	Var. 725	Var. 797	Var. 869	Var. 941	Var. 1013	Var. 1085
6.0-7.0	Var. 582	Var. 654	Var. 726	Var. 798	Var. 870	Var. 942	Var. 1014	Var. 1086
6.0-6.5	Var. 583	Var. 655	Var. 727	Var. 799	Var. 871	Var. 943	Var. 1015	Var. 1087
6.5-7.5	Var. 584	Var. 656	Var. 728	Var. 800	Var. 872	Var. 944	Var. 1016	Var. 1088
6.5-7.0	Var. 585	Var. 657	Var. 729	Var. 801	Var. 873	Var. 945	Var. 1017	Var. 1089
5.5 ± 0.2	Var. 586	Var. 658	Var. 730	Var. 802	Var. 874	Var. 946	Var. 1018	Var. 1090
5.6 ± 0.2	Var. 587	Var. 659	Var. 731	Var. 803	Var. 875	Var. 947	Var. 1019	Var. 1091
5.7 ± 0.2	Var. 588	Var. 660	Var. 732	Var. 804	Var. 876	Var. 948	Var. 1020	Var. 1092
5.8 ± 0.2	Var. 589	Var. 661	Var. 733	Var. 805	Var. 877	Var. 949	Var. 1021	Var. 1093
5.9 ± 0.2	Var. 590	Var. 662	Var. 734	Var. 806	Var. 878	Var. 950	Var. 1022	Var. 1094
6.0 ± 0.2	Var. 591	Var. 663	Var. 735	Var. 807	Var. 879	Var. 951	Var. 1023	Var. 1095
6.1 ± 0.2	Var. 592	Var. 664	Var. 736	Var. 808	Var. 880	Var. 952	Var. 1024	Var. 1096
6.2 ± 0.2	Var. 593	Var. 665	Var. 737	Var. 809	Var. 881	Var. 953	Var. 1025	Var. 1097
6.3 ± 0.2	Var. 594	Var. 666	Var. 738	Var. 810	Var. 882	Var. 954	Var. 1026	Var. 1098
6.4 ± 0.2	Var. 595	Var. 667	Var. 739	Var. 811	Var. 883	Var. 955	Var. 1027	Var. 1099
6.5 ± 0.2	Var. 596	Var. 668	Var. 740	Var. 812	Var. 884	Var. 956	Var. 1028	Var. 1100
6.6 ± 0.2	Var. 597	Var. 669	Var. 741	Var. 813	Var. 885	Var. 957	Var. 1029	Var. 1101
6.7 ± 0.2	Var. 598	Var. 670	Var. 742	Var. 814	Var. 886	Var. 958	Var. 1030	Var. 1102
6.8 ± 0.2	Var. 599	Var. 671	Var. 743	Var. 815	Var. 887	Var. 959	Var. 1031	Var. 1103
6.9 ± 0.2	Var. 600	Var. 672	Var. 744	Var. 816	Var. 888	Var. 960	Var. 1032	Var. 1104
7.0 ± 0.2	Var. 601	Var. 673	Var. 745	Var. 817	Var. 889	Var. 961	Var. 1033	Var. 1105
7.1 ± 0.2	Var. 602	Var. 674	Var. 746	Var. 818	Var. 890	Var. 962	Var. 1034	Var. 1106
7.2 ± 0.2	Var. 603	Var. 675	Var. 747	Var. 819	Var. 891	Var. 963	Var. 1035	Var. 1107
7.3 ± 0.2	Var. 604	Var. 676	Var. 748	Var. 820	Var. 892	Var. 964	Var. 1036	Var. 1108
7.4 ± 0.2	Var. 605	Var. 677	Var. 749	Var. 821	Var. 893	Var. 965	Var. 1037	Var. 1109
7.5 ± 0.2	Var. 606	Var. 678	Var. 750	Var. 822	Var. 894	Var. 966	Var. 1038	Var. 1110
5.5 ± 0.1	Var. 607	Var. 679	Var. 751	Var. 823	Var. 895	Var. 967	Var. 1039	Var. 1111
5.6 ± 0.1	Var. 608	Var. 680	Var. 752	Var. 824	Var. 896	Var. 968	Var. 1040	Var. 1112
5.7 ± 0.1	Var. 609	Var. 681	Var. 753	Var. 825	Var. 897	Var. 969	Var. 1041	Var. 1113
5.8 ± 0.1	Var. 610	Var. 682	Var. 754	Var. 826	Var. 898	Var. 970	Var. 1042	Var. 1114
5.9 ± 0.1	Var. 611	Var. 683	Var. 755	Var. 827	Var. 899	Var. 971	Var. 1043	Var. 1115
6.0 ± 0.1	Var. 612	Var. 684	Var. 756	Var. 828	Var. 900	Var. 972	Var. 1044	Var. 1116
6.1 ± 0.1	Var. 613	Var. 685	Var. 757	Var. 829	Var. 901	Var. 973	Var. 1045	Var. 1117
6.2 ± 0.1	Var. 614	Var. 686	Var. 758	Var. 830	Var. 902	Var. 974	Var. 1046	Var. 1118
6.3 ± 0.1	Var. 615	Var. 687	Var. 759	Var. 831	Var. 903	Var. 975	Var. 1047	Var. 1119
6.4 ± 0.1	Var. 616	Var. 688	Var. 760	Var. 832	Var. 904	Var. 976	Var. 1048	Var. 1120
6.5 ± 0.1	Var. 617	Var. 689	Var. 761	Var. 833	Var. 905	Var. 977	Var. 1049	Var. 1121
6.6 ± 0.1	Var. 618	Var. 690	Var. 762	Var. 834	Var. 906	Var. 978	Var. 1050	Var. 1122
6.7 ± 0.1	Var. 619	Var. 691	Var. 763	Var. 835	Var. 907	Var. 979	Var. 1051	Var. 1123
6.8 ± 0.1	Var. 620	Var. 692	Var. 764	Var. 836	Var. 908	Var. 980	Var. 1052	Var. 1124
6.9 ± 0.1	Var. 621	Var. 693	Var. 765	Var. 837	Var. 909	Var. 981	Var. 1053	Var. 1125
7.0 ± 0.1	Var. 622	Var. 694	Var. 766	Var. 838	Var. 910	Var. 982	Var. 1054	Var. 1126
7.1 ± 0.1	Var. 623	Var. 695	Var. 767	Var. 839	Var. 911	Var. 983	Var. 1055	Var. 1127
7.2 ± 0.1	Var. 624	Var. 696	Var. 768	Var. 840	Var. 912	Var. 984	Var. 1056	Var. 1128
7.3 ± 0.1	Var. 625	Var. 697	Var. 769	Var. 841	Var. 913	Var. 985	Var. 1057	Var. 1129
7.4 ± 0.1	Var. 626	Var. 698	Var. 770	Var. 842	Var. 914	Var. 986	Var. 1058	Var. 1130
7.5 ± 0.1	Var. 627	Var. 699	Var. 771	Var. 843	Var. 915	Var. 987	Var. 1059	Var. 1131
5.5	Var. 628	Var. 700	Var. 772	Var. 844	Var. 916	Var. 988	Var. 1060	Var. 1132
5.6	Var. 629	Var. 701	Var. 773	Var. 845	Var. 917	Var. 989	Var. 1061	Var. 1133
5.7	Var. 630	Var. 702	Var. 774	Var. 846	Var. 918	Var. 990	Var. 1062	Var. 1134
5.8	Var. 631	Var. 703	Var. 775	Var. 847	Var. 919	Var. 991	Var. 1063	Var. 1135
5.9	Var. 632	Var. 704	Var. 776	Var. 848	Var. 920	Var. 992	Var. 1064	Var. 1136
6	Var. 633	Var. 705	Var. 777	Var. 849	Var. 921	Var. 993	Var. 1065	Var. 1137
6.1	Var. 634	Var. 706	Var. 778	Var. 850	Var. 922	Var. 994	Var. 1066	Var. 1138
6.2	Var. 635	Var. 707	Var. 779	Var. 851	Var. 923	Var. 995	Var. 1067	Var. 1139
6.3	Var. 636	Var. 708	Var. 780	Var. 852	Var. 924	Var. 996	Var. 1068	Var. 1140
6.4	Var. 637	Var. 709	Var. 781	Var. 853	Var. 925	Var. 997	Var. 1069	Var. 1141
6.5	Var. 638	Var. 710	Var. 782	Var. 854	Var. 926	Var. 998	Var. 1070	Var. 1142
6.6	Var. 639	Var. 711	Var. 783	Var. 855	Var. 927	Var. 999	Var. 1071	Var. 1143
6.7	Var. 640	Var. 712	Var. 784	Var. 856	Var. 928	Var. 1000	Var. 1072	Var. 1144
6.8	Var. 641	Var. 713	Var. 785	Var. 857	Var. 929	Var. 1001	Var. 1073	Var. 1145
6.9	Var. 642	Var. 714	Var. 786	Var. 858	Var. 930	Var. 1002	Var. 1074	Var. 1146
7	Var. 643	Var. 715	Var. 787	Var. 859	Var. 931	Var. 1003	Var. 1075	Var. 1147
7.1	Var. 644	Var. 716	Var. 788	Var. 860	Var. 932	Var. 1004	Var. 1076	Var. 1148
7.2	Var. 645	Var. 717	Var. 789	Var. 861	Var. 933	Var. 1005	Var. 1077	Var. 1149
7.3	Var. 646	Var. 718	Var. 790	Var. 862	Var. 934	Var. 1006	Var. 1078	Var. 1150
7.4	Var. 647	Var. 719	Var. 791	Var. 863	Var. 935	Var. 1007	Var. 1079	Var. 1151
7.5	Var. 648	Var. 720	Var. 792	Var. 864	Var. 936	Var. 1008	Var. 1080	Var. 1152

TABLE 3
Particular combinations of histidine concentration and pH useful for the formulation of immunoglobulins.
	Alkali Metal Chloride Salt (mM)
pH	125-150	150-250	150-225	150-200	150-175	75 ± 7.5	100 ± 10	125 ± 12.5
5.5-7.5	Var. 1153	Var. 1225	Var. 1297	Var. 1369	Var. 1441	Var. 1513	Var. 1585	Var. 1657
5.5-7.0	Var. 1154	Var. 1226	Var. 1298	Var. 1370	Var. 1442	Var. 1514	Var. 1586	Var. 1658
5.5-6.5	Var. 1155	Var. 1227	Var. 1299	Var. 1371	Var. 1443	Var. 1515	Var. 1587	Var. 1659
5.5-6.0	Var. 1156	Var. 1228	Var. 1300	Var. 1372	Var. 1444	Var. 1516	Var. 1588	Var. 1660
6.0-7.5	Var. 1157	Var. 1229	Var. 1301	Var. 1373	Var. 1445	Var. 1517	Var. 1589	Var. 1661
6.0-7.0	Var. 1158	Var. 1230	Var. 1302	Var. 1374	Var. 1446	Var. 1518	Var. 1590	Var. 1662
6.0-6.5	Var. 1159	Var. 1231	Var. 1303	Var. 1375	Var. 1447	Var. 1519	Var. 1591	Var. 1663
6.5-7.5	Var. 1160	Var. 1232	Var. 1304	Var. 1376	Var. 1448	Var. 1520	Var. 1592	Var. 1664
6.5-7.0	Var. 1161	Var. 1233	Var. 1305	Var. 1377	Var. 1449	Var. 1521	Var. 1593	Var. 1665
5.5 ± 0.2	Var. 1162	Var. 1234	Var. 1306	Var. 1378	Var. 1450	Var. 1522	Var. 1594	Var. 1666
5.6 ± 0.2	Var. 1163	Var. 1235	Var. 1307	Var. 1379	Var. 1451	Var. 1523	Var. 1595	Var. 1667
5.7 ± 0.2	Var. 1164	Var. 1236	Var. 1308	Var. 1380	Var. 1452	Var. 1524	Var. 1596	Var. 1668
5.8 ± 0.2	Var. 1165	Var. 1237	Var. 1309	Var. 1381	Var. 1453	Var. 1525	Var. 1597	Var. 1669
5.9 ± 0.2	Var. 1166	Var. 1238	Var. 1310	Var. 1382	Var. 1454	Var. 1526	Var. 1598	Var. 1670
6.0 ± 0.2	Var. 1167	Var. 1239	Var. 1311	Var. 1383	Var. 1455	Var. 1527	Var. 1599	Var. 1671
6.1 ± 0.2	Var. 1168	Var. 1240	Var. 1312	Var. 1384	Var. 1456	Var. 1528	Var. 1600	Var. 1672
6.2 ± 0.2	Var. 1169	Var. 1241	Var. 1313	Var. 1385	Var. 1457	Var. 1529	Var. 1601	Var. 1673
6.3 ± 0.2	Var. 1170	Var. 1242	Var. 1314	Var. 1386	Var. 1458	Var. 1530	Var. 1602	Var. 1674
6.4 ± 0.2	Var. 1171	Var. 1243	Var. 1315	Var. 1387	Var. 1459	Var. 1531	Var. 1603	Var. 1675
6.5 ± 0.2	Var. 1172	Var. 1244	Var. 1316	Var. 1388	Var. 1460	Var. 1532	Var. 1604	Var. 1676
6.6 ± 0.2	Var. 1173	Var. 1245	Var. 1317	Var. 1389	Var. 1461	Var. 1533	Var. 1605	Var. 1677
6.7 ± 0.2	Var. 1174	Var. 1246	Var. 1318	Var. 1390	Var. 1462	Var. 1534	Var. 1606	Var. 1678
6.8 ± 0.2	Var. 1175	Var. 1247	Var. 1319	Var. 1391	Var. 1463	Var. 1535	Var. 1607	Var. 1679
6.9 ± 0.2	Var. 1176	Var. 1248	Var. 1320	Var. 1392	Var. 1464	Var. 1536	Var. 1608	Var. 1680
7.0 ± 0.2	Var. 1177	Var. 1249	Var. 1321	Var. 1393	Var. 1465	Var. 1537	Var. 1609	Var. 1681
7.1 ± 0.2	Var. 1178	Var. 1250	Var. 1322	Var. 1394	Var. 1466	Var. 1538	Var. 1610	Var. 1682
7.2 ± 0.2	Var. 1179	Var. 1251	Var. 1323	Var. 1395	Var. 1467	Var. 1539	Var. 1611	Var. 1683
7.3 ± 0.2	Var. 1180	Var. 1252	Var. 1324	Var. 1396	Var. 1468	Var. 1540	Var. 1612	Var. 1684
7.4 ± 0.2	Var. 1181	Var. 1253	Var. 1325	Var. 1397	Var. 1469	Var. 1541	Var. 1613	Var. 1685
7.5 ± 0.2	Var. 1182	Var. 1254	Var. 1326	Var. 1398	Var. 1470	Var. 1542	Var. 1614	Var. 1686
5.5 ± 0.1	Var. 1183	Var. 1255	Var. 1327	Var. 1399	Var. 1471	Var. 1543	Var. 1615	Var. 1687
5.6 ± 0.1	Var. 1184	Var. 1256	Var. 1328	Var. 1400	Var. 1472	Var. 1544	Var. 1616	Var. 1688
5.7 ± 0.1	Var. 1185	Var. 1257	Var. 1329	Var. 1401	Var. 1473	Var. 1545	Var. 1617	Var. 1689
5.8 ± 0.1	Var. 1186	Var. 1258	Var. 1330	Var. 1402	Var. 1474	Var. 1546	Var. 1618	Var. 1690
5.9 ± 0.1	Var. 1187	Var. 1259	Var. 1331	Var. 1403	Var. 1475	Var. 1547	Var. 1619	Var. 1691
6.0 ± 0.1	Var. 1188	Var. 1260	Var. 1332	Var. 1404	Var. 1476	Var. 1548	Var. 1620	Var. 1692
6.1 ± 0.1	Var. 1189	Var. 1261	Var. 1333	Var. 1405	Var. 1477	Var. 1549	Var. 1621	Var. 1693
6.2 ± 0.1	Var. 1190	Var. 1262	Var. 1334	Var. 1406	Var. 1478	Var. 1550	Var. 1622	Var. 1694
6.3 ± 0.1	Var. 1191	Var. 1263	Var. 1335	Var. 1407	Var. 1479	Var. 1551	Var. 1623	Var. 1695
6.4 ± 0.1	Var. 1192	Var. 1264	Var. 1336	Var. 1408	Var. 1480	Var. 1552	Var. 1624	Var. 1696
6.5 ± 0.1	Var. 1193	Var. 1265	Var. 1337	Var. 1409	Var. 1481	Var. 1553	Var. 1625	Var. 1697
6.6 ± 0.1	Var. 1194	Var. 1266	Var. 1338	Var. 1410	Var. 1482	Var. 1554	Var. 1626	Var. 1698
6.7 ± 0.1	Var. 1195	Var. 1267	Var. 1339	Var. 1411	Var. 1483	Var. 1555	Var. 1627	Var. 1699
6.8 ± 0.1	Var. 1196	Var. 1268	Var. 1340	Var. 1412	Var. 1484	Var. 1556	Var. 1628	Var. 1700
6.9 ± 0.1	Var. 1197	Var. 1269	Var. 1341	Var. 1413	Var. 1485	Var. 1557	Var. 1629	Var. 1701
7.0 ± 0.1	Var. 1198	Var. 1270	Var. 1342	Var. 1414	Var. 1486	Var. 1558	Var. 1630	Var. 1702
7.1 ± 0.1	Var. 1199	Var. 1271	Var. 1343	Var. 1415	Var. 1487	Var. 1559	Var. 1631	Var. 1703
7.2 ± 0.1	Var. 1200	Var. 1272	Var. 1344	Var. 1416	Var. 1488	Var. 1560	Var. 1632	Var. 1704
7.3 ± 0.1	Var. 1201	Var. 1273	Var. 1345	Var. 1417	Var. 1489	Var. 1561	Var. 1633	Var. 1705
7.4 ± 0.1	Var. 1202	Var. 1274	Var. 1346	Var. 1418	Var. 1490	Var. 1562	Var. 1634	Var. 1706
7.5 ± 0.1	Var. 1203	Var. 1275	Var. 1347	Var. 1419	Var. 1491	Var. 1563	Var. 1635	Var. 1707
5.5	Var. 1204	Var. 1276	Var. 1348	Var. 1420	Var. 1492	Var. 1564	Var. 1636	Var. 1708
5.6	Var. 1205	Var. 1277	Var. 1349	Var. 1421	Var. 1493	Var. 1565	Var. 1637	Var. 1709
5.7	Var. 1206	Var. 1278	Var. 1350	Var. 1422	Var. 1494	Var. 1566	Var. 1638	Var. 1710
5.8	Var. 1207	Var. 1279	Var. 1351	Var. 1423	Var. 1495	Var. 1567	Var. 1639	Var. 1711
5.9	Var. 1208	Var. 1280	Var. 1352	Var. 1424	Var. 1496	Var. 1568	Var. 1640	Var. 1712
6	Var. 1209	Var. 1281	Var. 1353	Var. 1425	Var. 1497	Var. 1569	Var. 1641	Var. 1713
6.1	Var. 1210	Var. 1282	Var. 1354	Var. 1426	Var. 1498	Var. 1570	Var. 1642	Var. 1714
6.2	Var. 1211	Var. 1283	Var. 1355	Var. 1427	Var. 1499	Var. 1571	Var. 1643	Var. 1715
6.3	Var. 1212	Var. 1284	Var. 1356	Var. 1428	Var. 1500	Var. 1572	Var. 1644	Var. 1716
6.4	Var. 1213	Var. 1285	Var. 1357	Var. 1429	Var. 1501	Var. 1573	Var. 1645	Var. 1717
6.5	Var. 1214	Var. 1286	Var. 1358	Var. 1430	Var. 1502	Var. 1574	Var. 1646	Var. 1718
6.6	Var. 1215	Var. 1287	Var. 1359	Var. 1431	Var. 1503	Var. 1575	Var. 1647	Var. 1719
6.7	Var. 1216	Var. 1288	Var. 1360	Var. 1432	Var. 1504	Var. 1576	Var. 1648	Var. 1720
6.8	Var. 1217	Var. 1289	Var. 1361	Var. 1433	Var. 1505	Var. 1577	Var. 1649	Var. 1721
6.9	Var. 1218	Var. 1290	Var. 1362	Var. 1434	Var. 1506	Var. 1578	Var. 1650	Var. 1722
7	Var. 1219	Var. 1291	Var. 1363	Var. 1435	Var. 1507	Var. 1579	Var. 1651	Var. 1723
7.1	Var. 1220	Var. 1292	Var. 1364	Var. 1436	Var. 1508	Var. 1580	Var. 1652	Var. 1724
7.2	Var. 1221	Var. 1293	Var. 1365	Var. 1437	Var. 1509	Var. 1581	Var. 1653	Var. 1725
7.3	Var. 1222	Var. 1294	Var. 1366	Var. 1438	Var. 1510	Var. 1582	Var. 1654	Var. 1726
7.4	Var. 1223	Var. 1295	Var. 1367	Var. 1439	Var. 1511	Var. 1583	Var. 1655	Var. 1727
7.5	Var. 1224	Var. 1296	Var. 1368	Var. 1440	Var. 1512	Var. 1584	Var. 1656	Var. 1728

TABLE 4
Particular combinations of histidine concentration and
pH useful for the formulation of immunoglobulins.
	Alkali Metal Chloride Salt (mM)
		175 ±
pH	150 ± 15	17.5	200 ± 20	225 ± 22.5	250 ± 25
5.5-7.5	Var. 1729	Var. 1801	Var. 1873	Var. 1945	Var. 2017
5.5-7.0	Var. 1730	Var. 1802	Var. 1874	Var. 1946	Var. 2018
5.5-6.5	Var. 1731	Var. 1803	Var. 1875	Var. 1947	Var. 2019
5.5-6.0	Var. 1732	Var. 1804	Var. 1876	Var. 1948	Var. 2020
6.0-7.5	Var. 1733	Var. 1805	Var. 1877	Var. 1949	Var. 2021
6.0-7.0	Var. 1734	Var. 1806	Var. 1878	Var. 1950	Var. 2022
6.0-6.5	Var. 1735	Var. 1807	Var. 1879	Var. 1951	Var. 2023
6.5-7.5	Var. 1736	Var. 1808	Var. 1880	Var. 1952	Var. 2024
6.5-7.0	Var. 1737	Var. 1809	Var. 1881	Var. 1953	Var. 2025
5.5 ± 0.2	Var. 1738	Var. 1810	Var. 1882	Var. 1954	Var. 2026
5.6 ± 0.2	Var. 1739	Var. 1811	Var. 1883	Var. 1955	Var. 2027
5.7 ± 0.2	Var. 1740	Var. 1812	Var. 1884	Var. 1956	Var. 2028
5.8 ± 0.2	Var. 1741	Var. 1813	Var. 1885	Var. 1957	Var. 2029
5.9 ± 0.2	Var. 1742	Var. 1814	Var. 1886	Var. 1958	Var. 2030
6.0 ± 0.2	Var. 1743	Var. 1815	Var. 1887	Var. 1959	Var. 2031
6.1 ± 0.2	Var. 1744	Var. 1816	Var. 1888	Var. 1960	Var. 2032
6.2 ± 0.2	Var. 1745	Var. 1817	Var. 1889	Var. 1961	Var. 2033
6.3 ± 0.2	Var. 1746	Var. 1818	Var. 1890	Var. 1962	Var. 2034
6.4 ± 0.2	Var. 1747	Var. 1819	Var. 1891	Var. 1963	Var. 2035
6.5 ± 0.2	Var. 1748	Var. 1820	Var. 1892	Var. 1964	Var. 2036
6.6 ± 0.2	Var. 1749	Var. 1821	Var. 1893	Var. 1965	Var. 2037
6.7 ± 0.2	Var. 1750	Var. 1822	Var. 1894	Var. 1966	Var. 2038
6.8 ± 0.2	Var. 1751	Var. 1823	Var. 1895	Var. 1967	Var. 2039
6.9 ± 0.2	Var. 1752	Var. 1824	Var. 1896	Var. 1968	Var. 2040
7.0 ± 0.2	Var. 1753	Var. 1825	Var. 1897	Var. 1969	Var. 2041
7.1 ± 0.2	Var. 1754	Var. 1826	Var. 1898	Var. 1970	Var. 2042
7.2 ± 0.2	Var. 1755	Var. 1827	Var. 1899	Var. 1971	Var. 2043
7.3 ± 0.2	Var. 1756	Var. 1828	Var. 1900	Var. 1972	Var. 2044
7.4 ± 0.2	Var. 1757	Var. 1829	Var. 1901	Var. 1973	Var. 2045
7.5 ± 0.2	Var. 1758	Var. 1830	Var. 1902	Var. 1974	Var. 2046
5.5 ± 0.1	Var. 1759	Var. 1831	Var. 1903	Var. 1975	Var. 2047
5.6 ± 0.1	Var. 1760	Var. 1832	Var. 1904	Var. 1976	Var. 2048
5.7 ± 0.1	Var. 1761	Var. 1833	Var. 1905	Var. 1977	Var. 2049
5.8 ± 0.1	Var. 1762	Var. 1834	Var. 1906	Var. 1978	Var. 2050
5.9 ± 0.1	Var. 1763	Var. 1835	Var. 1907	Var. 1979	Var. 2051
6.0 ± 0.1	Var. 1764	Var. 1836	Var. 1908	Var. 1980	Var. 2052
6.1 ± 0.1	Var. 1765	Var. 1837	Var. 1909	Var. 1981	Var. 2053
6.2 ± 0.1	Var. 1766	Var. 1838	Var. 1910	Var. 1982	Var. 2054
6.3 ± 0.1	Var. 1767	Var. 1839	Var. 1911	Var. 1983	Var. 2055
6.4 ± 0.1	Var. 1768	Var. 1840	Var. 1912	Var. 1984	Var. 2056
6.5 ± 0.1	Var. 1769	Var. 1841	Var. 1913	Var. 1985	Var. 2057
6.6 ± 0.1	Var. 1770	Var. 1842	Var. 1914	Var. 1986	Var. 2058
6.7 ± 0.1	Var. 1771	Var. 1843	Var. 1915	Var. 1987	Var. 2059
6.8 ± 0.1	Var. 1772	Var. 1844	Var. 1916	Var. 1988	Var. 2060
6.9 ± 0.1	Var. 1773	Var. 1845	Var. 1917	Var. 1989	Var. 2061
7.0 ± 0.1	Var. 1774	Var. 1846	Var. 1918	Var. 1990	Var. 2062
7.1 ± 0.1	Var. 1775	Var. 1847	Var. 1919	Var. 1991	Var. 2063
7.2 ± 0.1	Var. 1776	Var. 1848	Var. 1920	Var. 1992	Var. 2064
7.3 ± 0.1	Var. 1777	Var. 1849	Var. 1921	Var. 1993	Var. 2065
7.4 ± 0.1	Var. 1778	Var. 1850	Var. 1922	Var. 1994	Var. 2066
7.5 ± 0.1	Var. 1779	Var. 1851	Var. 1923	Var. 1995	Var. 2067
5.5	Var. 1780	Var. 1852	Var. 1924	Var. 1996	Var. 2068
5.6	Var. 1781	Var. 1853	Var. 1925	Var. 1997	Var. 2069
5.7	Var. 1782	Var. 1854	Var. 1926	Var. 1998	Var. 2070
5.8	Var. 1783	Var. 1855	Var. 1927	Var. 1999	Var. 2071
5.9	Var. 1784	Var. 1856	Var. 1928	Var. 2000	Var. 2072
6	Var. 1785	Var. 1857	Var. 1929	Var. 2001	Var. 2073
6.1	Var. 1786	Var. 1858	Var. 1930	Var. 2002	Var. 2074
6.2	Var. 1787	Var. 1859	Var. 1931	Var. 2003	Var. 2075
6.3	Var. 1788	Var. 1860	Var. 1932	Var. 2004	Var. 2076
6.4	Var. 1789	Var. 1861	Var. 1933	Var. 2005	Var. 2077
6.5	Var. 1790	Var. 1862	Var. 1934	Var. 2006	Var. 2078
6.6	Var. 1791	Var. 1863	Var. 1935	Var. 2007	Var. 2079
6.7	Var. 1792	Var. 1864	Var. 1936	Var. 2008	Var. 2080
6.8	Var. 1793	Var. 1865	Var. 1937	Var. 2009	Var. 2081
6.9	Var. 1794	Var. 1866	Var. 1938	Var. 2010	Var. 2082
7	Var. 1795	Var. 1867	Var. 1939	Var. 2011	Var. 2083
7.1	Var. 1796	Var. 1868	Var. 1940	Var. 2012	Var. 2084
7.2	Var. 1797	Var. 1869	Var. 1941	Var. 2013	Var. 2085
7.3	Var. 1798	Var. 1870	Var. 1942	Var. 2014	Var. 2086
7.4	Var. 1799	Var. 1871	Var. 1943	Var. 2015	Var. 2087
7.5	Var. 1800	Var. 1872	Var. 1944	Var. 2016	Var. 2088

2. Stabilizing Agents

The pharmaceutical compositions provided herein will typically comprise one or more buffering agents or pH stabilizing agents suitable for intravenous, intravitreal, subcutaneous, and/or intramuscular administration. Non-limiting examples of buffering agents suitable for formulating the storage stable compositions provided herein include glycine, histidine, proline, or other amino acids, salts like citrate, phosphate, acetate, glutamate, tartrate, benzoate, lactate, gluconate, malate, succinate, formate, propionate, carbonate, or any combination thereof adjusted to an appropriate pH. Generally, the buffering agent will be sufficient to maintain a suitable pH in the formulation for an extended period of time.

In a preferred embodiment, the stabilizing agent employed in the storage stable, labile therapeutic protein formulations provided herein is an amino acid. Non-limiting examples of amino acids include, isoleucine, alanine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, proline, selenocysteine, serine, tyrosine, arginine, histidine, ornithine, taurine, combinations thereof, and the like. In one embodiment, the stabilizing amino acids include arginine, histidine, lysine, serine, proline, glycine, alanine, threonine, and a combination thereof. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In yet another preferred embodiment, the amino acid is histidine.

For purposes of further stabilizing the compositions provided herein, the amino acid will typically be added to the formulation at a concentration between 5 mM and 0.75 M. In one embodiment, at least 100 mM of the amino acid is added to the formulation. In another embodiment, at least 200 mM of the amino acid is added to the formulation. In yet another embodiment, at least 250 mM of the amino acid is added to the formulation. In yet other embodiments, the formulations provided herein will contain at least 25 mM, 50 mM, 75 mM, 100 mM, 150 mM, 200 mM, 250 mM, 300 mM, 350 mM, 400 mM, 450 mM, 500 mM, 550 mM, 600 mM, 650 mM, 700 mM, 750 mM, or more of the amino acid.

In one embodiment, the concentration of buffering agent in the formulation will be at or about between 5 mM and 500 mM. In certain embodiments, the concentration of the buffering agent in the formulation will be at or about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 50 mM, 75 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 225 mM, 250 mM, 275 mM, 300 mM, 325 mM, 350 mM, 375 mM, 400 mM, 425 mM, 450 mM, 475 mM, 500 mM or higher.

Accordingly, in one aspect, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another aspect, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 5.5 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 5.5 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 5.5 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another aspect, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 5.5 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 5.5 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 5.5 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another aspect, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 5.5 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 5.5 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 5.5 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

3. Excipients

In certain embodiments, the storage stable labile therapeutic protein aqueous compositions provided herein further comprise one or more excipients. Non-limiting examples of excipients that can be included in the formulations provided herein include non-ionic surfactants, bulking agents (e.g., sugars and sugar alcohols), antioxidants, polysaccharides, and pharmaceutically acceptable water-soluble polymers (e.g., poly(acrylic acid), poly(ethylene oxide), poly(ethylene glycol), poly(vinyl pyrrolidone), hydroxyethyl cellulose, hydroxypropyl cellulose, and starch).

In one embodiment, the excipient is an agent for adjusting the osmolarity of the composition. Non-limiting examples of osmolarity agents include mannitol, sorbitol, glycerol, sucrose, glucose, dextrose, levulose, fructose, lactose, trehalose, polyethylene glycols, phosphates, calcium chloride, calcium gluconoglucoheptonate, dimethyl sulfone, and the like.

Accordingly, in one aspect, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 5.5 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant, and a pH of from 5.5 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 5.5 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment; the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

Accordingly, in one aspect, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 5.5 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol, and a pH of from 5.5 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 5.5 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In another embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: a labile therapeutic protein; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In one embodiment, the pH of the formulation is between 5.5 and 7.0. In a specific embodiment, the pH of the formulation is between 5.5 and 6.5. In yet another embodiment, the pH of the formulation is between 6.0 and 7.0.

4. Administration

Formulations of the storage stable composition provided herein are delivered to the individual by any pharmaceutically suitable means of administration. Various delivery systems are known and can be used to administer the composition by any convenient route. In one embodiment the compositions of the invention are administered systemically. For systemic use, the composition is formulated for parenteral (e.g. intradermal, subcutaneous, transdermal implant, intracavernous, intravitreal, transscleral, intracerebral, intrathecal, epidural, intravenous, intracardiac, intramuscular, intraosseous, intraperitoneal, and nanocell injection) or enteral (e.g., oral, vaginal or rectal) delivery according to conventional methods. The formulations can be administered continuously by infusion or by bolus injection. Some formulations encompass slow release systems. Preferred routes of administration will depend upon the indication being treated, managed, or prevented.

Single or multiple administrations of the compositions are carried out with the dose levels and pattern being selected by the treating physician. For the prevention or treatment of disease, the appropriate dosage depends on the type of disease to be treated, the severity and course of the disease, whether drug is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the therapeutic protein, and the discretion of the attending physician.

In a preferred embodiment, the storage stable compositions provided herein are formulated for parenteral administration including, but not limited to, intradermal, subcutaneous, transdermal implant, intracavernous, intravitreal, transscleral, intracerebral, intrathecal, epidural, intravenous, intracardiac, intramuscular, intraosseous, intraperitoneal, and nanocell injection administration. In one preferred embodiment, the compositions provided herein will be formulated for intravenous administration. In another preferred embodiment, the compositions provided herein will be formulated for subcutaneous administration. In yet another preferred embodiment, the compositions provided herein will be formulated for intramuscular administration.

B. Immunoglobulins

In one aspect, the present invention provides storage stable, aqueous immunoglobulin compositions formulated at mildly acidic to neutral pH with a moderate concentration of a metal chloride salt and a stabilizing agent.

Any immunoglobulin may be stabilized by the formulations provided herein. Non-limiting examples of immunoglobulin preparations that may be stabilized include, plasma-derived immunoglobulin preparations, recombinant polyclonal or monoclonal preparations, minibodies, diabodies, triabodies, antibody fragments such as Fv, Fab and F(ab)2 or fragmented antibodies such as monovalent or multivalent single chain Fvs (scFv, sc(Fv)2, minibodies, diabodies, and triabodies such as scFv dimers) in which the variable regions of an antibody are joined together via a linker such as a peptide linker, and the like. Recombinant antibodies include murine antibodies, rodent antibodies, human antibodies, chimeric human antibodies (e.g., human/murine chimeras), humanized antibodies (e.g., humanized murine antibodies), and the like. In preferred embodiments, the recombinant antibody is a human, chimeric human, or humanized antibody suitable for administration to a human. In a preferred embodiment, the immunoglobulin in a full length, or near full length immunoglobulin, which will generally be more labile then engineered fragments thereof.

Generally, storage stable immunoglobulin formulations provided herein will be stabilized at room temperature (i.e., between 20° C. and 25° C.) for an extended period of time. For example, in one embodiment, a storage stable, aqueous immunoglobulin composition will be stable when stored at room temperature for at least about 2 months. In another embodiment, the composition will be stable for at least about 3 months. In yet other embodiment, the composition will be stable for at least 1 about month, or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or more months. In a preferred embodiment, the composition will be stable for at least about 6 months. In a more preferred embodiment, the composition will be stable for at least about 1 year. In a more preferred embodiment, the composition will be stable for at least about 2 years.

In one embodiment, the storage stable, aqueous immunoglobulin composition will be stable for at least six months at a temperature between about 28° C. and about 32° C. In a specific embodiment, the storage stable, aqueous immunoglobulin composition will be stable for at least one year at a temperature between about 28° C. and about 32° C. In a more specific embodiment, the storage stable, aqueous immunoglobulin composition will be stable for at least two years at a temperature between about 28° C. and about 32° C. In another embodiment, the storage stable, aqueous immunoglobulin composition will be stable for at least one month at a temperature between about 38° C. and about 42° C. In a specific embodiment, the storage stable, aqueous immunoglobulin composition will be stable for at least three months at a temperature between about 38° C. and about 42° C. In a more specific embodiment, the storage stable, aqueous immunoglobulin composition will be stable for at least one year at a temperature between about 38° C. and about 42° C.

In one embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 10%. In a preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 9%. In a more preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 8%. In a more preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 7%. In a more preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 6%. In a more preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 5%. In a more preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 4%. In a more preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 3%. In a most preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 2%.

In one embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 10% and the percentage of immunoglobulin in the monomeric state is no less than 85%. In a preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 9% and the percentage of immunoglobulin in the monomeric state is no less than 85%. In a preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 8% and the percentage of immunoglobulin in the monomeric state is no less than 85%. In a preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 7% and the percentage of immunoglobulin in the monomeric state is no less than 85%. In a preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 6% and the percentage of immunoglobulin in the monomeric state is no less than 85%. In a preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 5% and the percentage of immunoglobulin in the monomeric state is no less than 85%. In a preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 4% and the percentage of immunoglobulin in the monomeric state is no less than 85%. In a preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 3% and the percentage of immunoglobulin in the monomeric state is no less than 85%. In a most preferred embodiment, the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state no more than 2% and the percentage of immunoglobulin in the monomeric state is no less than 85%.

In one embodiment, wherein the labile therapeutic protein is an antibody or fragment thereof, the stability of the composition may be determined by monitoring the loss of anti-antigen titer. The level of anti-antigen titer may be determined, for example, by an immunoassay. A variety of immunoassay formats may be used for this purpose. For example, solid-phase ELISA immunoassays are routinely used to determine antigen titer (see, e.g., Harlow & Lane, Using Antibodies, A Laboratory Manual (1998) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity). In one embodiment, a 20% loss of anti-antigen titer will correspond to an unstable composition. In other embodiments, a 10% loss of anti-antigen titer, or a 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or higher loss of anti-antigen titer will correspond to an unstable composition.

After formulation, the storage stable, aqueous immunoglobulin compositions provided herein are typically sterile filtered and dispensed into a sterile containment vessel, which is sealed air-tight, for example, using a rubber stopper. Immunoglobulin compositions in the air-tight vessels are preferably protected from ambient light by storage in a dark place, the use of a tinted vessel material (typically glass or plastic), and/or covering the surface of the vessel with an opaque substance.

In certain embodiments, the headspace air in the containment vessel is replaced with an inert gas. The inert gas helps to maintain an inert atmosphere above the liquid composition. In one embodiment, the liquid is overlaid with inert gas. In another embodiment the liquid is degassed before overlaying it with inert gas, meaning that residual oxygen in the atmosphere may vary. In the context of the present invention, when an immunoglobulin composition is stored in a vessel in which the headspace air has been replaced with an inert gas, the composition has been overlaid with inert gas, or the composition is degassed prior to overlaying with inert gas, the composition is said to be “stored under inert gas.” Non-limiting examples of inert gasses than may be used in conjunction with the present invention include, nitrogen, argon, carbon dioxide, helium, krypton, and xenon. In one particular embodiment, the inert gas is nitrogen. In another particular embodiment, the inert gas is argon.

1. Plasma-Derived Immunoglobulins

Preparations of concentrated immunoglobulins (especially IgG) isolated from pooled human plasma are used for treating a variety of medical conditions, including immune deficiencies, inflammatory and autoimmune diseases, and acute infections. One IgG product, intravenous immunoglobulin or IVIG, is formulated for intravenous administration, for example, at a concentration of at or about 10% IgG. Concentrated immunoglobulins may also be formulated for subcutaneous or intramuscular administration, for example, at a concentration at or about 20% IgG.

Generally, plasma-derived immunoglobulin preparations formulated according to the present invention can be prepared from any suitable starting materials, for example, recovered plasma or source plasma. In a typical example, blood or plasma is collected from healthy donors. Immunoglobulins are isolated from the blood or plasma by suitable procedures, such as, for example, precipitation (alcohol fractionation or polyethylene glycol fractionation), chromatographic methods (ion exchange chromatography, affinity chromatography, immunoaffinity chromatography, etc.) ultracentrifugation, and electrophoretic preparation, and the like. (See, e.g., Cohn et al., J. Am. Chem. Soc. 68:459-75 (1946); Oncley et al., J. Am. Chem. Soc. 71:541-50 (1949); Barandun et al., Vox Sang. 7:157-74 (1962); Koblet et al., Vox Sang. 13:93-102 (1967); U.S. Pat. Nos. 5,122,373 and 5,177,194; PCT/US10/36470; and WO 2010/138736 the disclosures of which are hereby incorporated by reference in their entireties for all purposes).

In many cases, immunoglobulins are prepared from gamma globulin-containing compositions produced by alcohol fractionation and/or ion exchange and affinity chromatography methods well known to those skilled in the art. For example, purified Cohn Fraction II is commonly used as a starting point for the further purification of immunoglobulins. The starting Cohn Fraction II paste is typically about 95 percent IgG and is comprised of the four IgG subtypes. The different subtypes are present in Fraction II in approximately the same ratio as they are found in the pooled human plasma from which they are obtained. The Fraction II is further purified before formulation into an administrable product. For example, the Fraction II paste can be dissolved in a cold purified aqueous alcohol solution and impurities removed via precipitation and filtration. Following the final filtration, the immunoglobulin suspension can be dialyzed or diafiltered (e.g., using ultrafiltration membranes having a nominal molecular weight limit of less than or equal to 100,000 daltons) to remove the alcohol. The solution can be concentrated or diluted to obtain the desired protein concentration and can be further purified by techniques well known to those skilled in the art.

Furthermore, additional preparative steps can be used to enrich a particular isotype or subtype of immunoglobulin. For example, protein A, protein G or protein H sepharose chromatography can be used to enrich a mixture of immunoglobulins for IgG, or for specific IgG subtypes. See generally, Harlow and Lane, Using Antibodies, Cold Spring Harbor Laboratory Press (1999); Harlow and Lane, Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press (1988); and U.S. Pat. No. 5,180,810, the disclosures of which are hereby incorporated by reference in their entireties for all purposes.

As will be recognized by one of skill in the art, immunoglobulin compositions isolated from pooled plasma contain impurities carried over from the starting plasma. Typically, pharmaceutically acceptable plasma-derived immunoglobulin compositions will contain at least 90% immunoglobulins, preferably at least 95% immunoglobulins, more preferably at least 98% immunoglobulins; most preferably at least 99% immunoglobulins, expressed as a function of total protein content. For example, GAMMAGARD® LIQUID (Baxter International; Deerfield, Ill.) is a plasma-derived immunoglobulin composition formulated at 100 g/L protein. According to the specifications, at least 98% of the protein is immune globulin, the average immunoglobulin A (IgA) concentration is 37 μg/mL, and immunoglobulin M is present in trace amounts (GAMMAGARD® LIQUID Prescribing Information). Accordingly, unless otherwise specified, an immunoglobulin composition provided herein comprising; consisting essentially of; or consisting of “a plasma-derived immunoglobulin” may contain up to 10% plasma protein impurities carried through during the manufacturing process.

In a particular embodiment, the immunoglobulin composition isolated from pooled plasma comprises at least 90% IgG immunoglobulins. In a specific embodiment, the immunoglobulin composition isolated from pooled plasma comprises at least 95% IgG immunoglobulins. In a more specific embodiment, the immunoglobulin composition isolated from pooled plasma comprises at least 98% IgG immunoglobulins. In a yet more specific embodiment, the immunoglobulin composition isolated from pooled plasma comprises at least 99% IgG immunoglobulins. In certain embodiments, the IgG immunoglobulin composition isolated from pooled plasma further comprises IgA and/or IgM immunoglobulins.

In another embodiment, the immunoglobulin composition isolated from pooled plasma comprises at least 10% IgA. In a specific embodiment, the immunoglobulin composition isolated from pooled plasma comprises at least 25% IgA. In a more specific embodiment, immunoglobulin composition isolated from pooled plasma comprises at least 50% IgA. In yet other embodiments, the immunoglobulin composition isolated from pooled plasma comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more IgA. In certain embodiments, the IgA immunoglobulin composition isolated from pooled plasma further comprises IgG and/or IgM immunoglobulins.

In another embodiment, the immunoglobulin composition isolated from pooled plasma comprises at least 10% IgM. In a specific embodiment, the immunoglobulin composition isolated from pooled plasma comprises at least 25% IgM. In a more specific embodiment, immunoglobulin composition isolated from pooled plasma comprises at least 50% IgM. In yet other embodiments, the immunoglobulin composition isolated from pooled plasma comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more IgM. In certain embodiments, the IgM immunoglobulin composition isolated from pooled plasma further comprises IgG and/or IgA immunoglobulins.

Accordingly, in one aspect, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In one embodiment, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a plasma-derived immunoglobulin; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a plasma-derived immunoglobulin; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a plasma-derived immunoglobulin; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the plasma-derived immunoglobulin comprises IgG.

a. Hyper-Immune Immunoglobulins

In a specific embodiment, the storage stable, plasma derived immunoglobulin composition is a hyper-immune immunoglobulin preparation. For example, in certain embodiments, the hyper-immune preparation may be an anti-tetanus, anti-D, anti-varicella, anti-rabies, anti-CMV, anti-hepatitis A, or anti-hepatitis B immunoglobulin preparation.

As demonstrated in Example 3, plasma derived anti-tetanus and anti-D preparations are stabilized by the addition of between about 100 mM and about 200 mM of an alkali metal chloride salt (e.g., sodium chloride) at a pH between about 5.5 and about 6.5. As shown in FIGS. 2 and 3, maximum stability for the hyper-immune immunoglobulin formulations is found between pH 5.5 and 6.0.

Accordingly, in one embodiment, the present invention provides a storage stable, plasma derived hyper-immune immunoglobulin aqueous composition comprising between about 75 mM and about 200 mM of an alkali metal chloride salt, a stabilizing agent, and a pH between about 5.5 and about 6.5. In a preferred embodiment, the composition comprises between about 100 mM and about 200 mM of an alkali metal chloride salt, a stabilizing agent, and a pH between about 5.5 and about 6.5. In another preferred embodiment, the composition comprises between about 100 mM and about 200 mM of an alkali metal chloride salt, a stabilizing agent, and a pH between about 5.5 and about 6.0. In a preferred embodiment, the salt is sodium chloride. In another preferred embodiment, the salt is potassium chloride.

In one embodiment, the storage stable, plasma derived hyper-immune immunoglobulin aqueous compositions provided herein have a protein concentration of between about 30 g/L and about 250 g/L. In certain embodiments, the protein concentration of the hyper-immune immunoglobulin composition is between about 50 g/L and about 200 g/L, or between about 70 g/L and about 150 g/L, or between about 90 g/L and about 120 g/L, or any suitable concentration within these ranges, for example about 30 g/L, or about 35 g/L, 40 g/L, 45 g/L, 50 g/L, 55 g/L, 60 g/L, 65 g/L, 70 g/L, 75 g/L, 80 g/L, 85 g/L, 90 g/L, 95 g/L, 100 g/L, 105 g/L, 110 g/L, 115 g/L, 120 g/L, 125 g/L, 130 g/L, 135 g/L, 140 g/L, 145 g/L, 150 g/L, 155 g/L, 160 g/L, 165 g/L, 170 g/L, 175 g/L, 180 g/L, 185 g/L, 190 g/L, 195 g/L, 200 g/L, 205 g/L, 210 g/L, 215 g/L, 220 g/L, 225 g/L, 230 g/L, 235 g/L, 240 g/L, 245 g/L, 250 g/L, or higher. In a preferred embodiment, the aqueous hyper-immune immunoglobulin composition will have a concentration of between about 100 g/L and about 170 g/L.

The storage stable plasma derived hyper-immune immunoglobulin aqueous compositions provided herein will be stabilized at room temperature for an extended period of time. For example, in one embodiment, the storage stable, aqueous hyper-immune immunoglobulin composition will be stable for at least about 2 months. In another embodiment, the composition will be stable for at least about 3 months. In yet other embodiment, the composition will be stable for at least 1 about month, or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or more months. In a preferred embodiment, the composition will be stable for at least about 6 months. In a more preferred embodiment, the composition will be stable for at least about 1 year. In a more preferred embodiment, the composition will be stable for at least about 2 years.

2. Recombinant Immunoglobulins

In one aspect, the present invention provides storage stable, recombinant immunoglobulin preparations. Methods for obtaining recombinant antibodies, such as recombinant human antibodies are well known in the art. For example, a desired human antibody having a binding activity for a desired antigen can be obtained by in vitro immunizing human lymphocytes with the desired antigen or a cell expressing the desired antigen and fusing the immunized lymphocytes to human myeloma cells. A desired human antibody can also be obtained by immunizing a transgenic animal having all human antibody gene repertoires with an antigen (see, International Publications Nos. WO 93/12227, WO 92/03918, WO 94/02602, WO 94/25585, WO 96/34096, WO 96/33735). Methods for obtaining a human antibody by panning using a human antibody library are also known. For example, phages binding to an antigen can be selected by expressing the variable regions of a human antibody as single chain antibody fragments (scFv) on phage surfaces by a phage display method. The DNA sequences encoding the variable regions of the human antibody binding to the antigen can be determined by analyzing the genes of the selected phages. A whole human antibody can be obtained by preparing a suitable expression vector containing the determined DNA sequences of the scFv fragments binding to the antigen. These methods have already been well known from WO 92/01047, WO 92/20791, WO 93/06213, WO 93/11236, WO 93/19172, WO 95/01438, and WO 95/15388.

Methods for the expression of recombinant immunoglobulins are also well known in the art. For example, recombinant antibodies can be expressed in tissue or cell culture after transforming a recombinant gene for the construct into a suitable host. Suitable eukaryotic cells for use as hosts include animal, plant and fungal cells. Known animal cells include (1) mammalian cells such as CHO, COS, myeloma, BHK (baby hamster kidney), HeLa and Vero cells; (2) amphibian cells such as Xenopus oocytes; or (3) insect sells such as sf9, sf21 and Tn5. Known plant cells include cells of Nicotiana such as Nicotiana tabacum, which can be used as callus cultures. Known fungi include yeasts such as Saccharomyces spp., e.g. Saccharomyces serevisiae and filamentous fungi such as Aspergillus spp., e.g. Aspergillus niger. Prokaryotic cells can be used as producing systems using bacterial cells. Known bacterial cells include E. coli and Bacillus subtilis. Antibodies can be obtained by transforming these cells with an antibody gene of interest and culturing the transformed cells in vitro.

In one embodiment of the present invention, the media used to express a recombinant protein can be animal protein-free and chemically defined. Methods of preparing animal protein-free and chemically defined culture mediums are known in the art, for example in US 2008/0009040 and US 2007/0212770, which are both incorporated herein for all purposes. “Protein free” and related terms refers to protein that is from a source exogenous to or other than the cells in the culture, which naturally shed proteins during growth. In another embodiment, the culture medium is polypeptide free. In another embodiment, the culture medium is serum free. In another embodiment the culture medium is animal protein free. In another embodiment the culture medium is animal component free. In another embodiment, the culture medium contains protein, e.g., animal protein from serum such as fetal calf serum. In another embodiment, the culture has recombinant proteins exogenously added. In another embodiment, the proteins are from a certified pathogen free animal. The term “chemically defined” as used herein shall mean, that the medium does not comprise any undefined supplements, such as, for example, extracts of animal components, organs, glands, plants, or yeast. Accordingly, each component of a chemically defined medium is accurately defined. In a preferred embodiment, the media are animal-component free and protein free.

Typically a recombinant antibody formulated as provided herein is specific for a polypeptide associated with a disease or disorder. Non-limiting examples of such polypeptides include macrophage migration inhibitory factor (MIF), tissue factor pathway inhibitor (TFPI); alpha-1-antitrypsin; insulin A-chain; insulin B-chain; proinsulin; follicle stimulating hormone; calcitonin; luteinizing hormone; glucagon; clotting factors such as Factor II (prothrombin), Factor III (platelet tissue factor), Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, and von Willebrand factor; anti-clotting factors such as Antithrombin III (ATIII), Protein C; atrial natriuretic factor; lung surfactant; a plasminogen activator, such as urokinase or human urine or tissue-type plasminogen activator (t-PA); bombesin; thrombin; hemopoietic growth factor; tumor necrosis factor-alpha and -beta; enkephalinase; RANTES (regulated on activation normally T-cell expressed and secreted); human macrophage inflammatory protein (MIP-1-alpha); a serum albumin such as human serum albumin; Muellerian-inhibiting substance; relaxin A-chain; relaxin B-chain; prorelaxin; mouse gonadotropin-associated peptide; a microbial protein, such as beta-lactamase; DNase; IgE; a cytotoxic T-lymphocyte associated antigen (CTLA), such as CTLA-4; inhibin; activin; vascular endothelial growth factor (VEGF); receptors for hormones or growth factors; protein A or D; rheumatoid factors; a neurotrophic factor such as bone-derived neurotrophic factor (BDNF), neurotrophin-3, -4, -5, or -6 (NT-3, NT-4, NT-5, or NT-6), or a nerve growth factor such as NGF-b; platelet-derived growth factor (PDGF); fibroblast growth factor such as aFGF and bFGF; epidermal growth factor (EGF); transforming growth factor (TGF) such as TGF-alpha and TGF-beta, including TGF-b1, TGF-b2, TGF-b3, TGF-b4, or TGF-b5; a tumor necrosis factor (TNF) such as TNF-alpha or TNF-beta; insulin-like growth factor-I and -II (IGF-I and IGF-II); des(1-3)-IGF-I (brain IGF-I), insulin-like growth factor binding proteins; CD proteins such as CD3, CD4, CD8, CD19, CD20, CD22 and CD40; erythropoietin; osteoinductive factors; immunotoxins; a bone morphogenetic protein (BMP); an interferon such as interferon-alpha, -beta, and -gamma; colony stimulating factors (CSFs), e.g., M-CSF, GM-CSF, and G-CSF; interleukins (ILs), e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9 and IL-10; superoxide dismutase; T-cell receptors; surface membrane proteins; decay accelerating factor; viral antigen such as, for example, a portion of the AIDS envelope; transport proteins; homing receptors; addressins; regulatory proteins; integrins such as CD11a, CD11b, CD11c, CD18, an ICAM, VLA-4 and VCAM; a tumor associated antigen such as HER2, HER3 or HER4 receptor; and fragments of any of the above-listed polypeptides.

Accordingly, in one aspect, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 5.5 to 7.0. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid.

In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In one embodiment, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal, chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 5.5 to 7.0. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 5.5 to 7.0. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a recombinant immunoglobulin; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a recombinant immunoglobulin; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a recombinant immunoglobulin; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.0 and 7.0. In a specific embodiment, the recombinant immunoglobulin is a monoclonal antibody. In a more specific embodiment, the recombinant antibody is an anti-MIF antibody.

C. Coagulation Proteins

Surprisingly, it was found that the stabilizing effects of alkali metal chloride salts (e.g., sodium and potassium chloride) are applicable to a wide range of labile therapeutic proteins ranging from plasma derived immunoglobulin preparations to recombinant coagulation factors. Accordingly, in one aspect, the present invention provides storage stable, aqueous compositions of labile coagulation factors formulated at mildly acidic to neutral pH with a moderate concentration of a metal chloride salt and a stabilizing agent.

In certain embodiments, the labile coagulation factor is a plasma derived protein or preparation. In other embodiments, the labile coagulation protein is a recombinantly expressed coagulation protein. Methods for manufacturing recombinant and plasma derived coagulation factors are well known in the art. Non-limiting examples of labile coagulation factors that may be formulated according to the methods provided herein include, Factor II (prothrombin), Factor III (platelet tissue factor), Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, von Willebrand Factor (vWF), and the like. In a preferred embodiment, the labile coagulation protein is selected from Factor VII, Factor VIII, Factor IX, and von Willebrand Factor (vWF). In another preferred embodiment, the labile coagulation protein is a vitamin-K dependent protein complex, for example, comprising Factor II, Factor IX, and Factor X, or comprising Factor II, Factor VII, Factor IX, and Factor X.

In one embodiment, the labile therapeutic coagulation protein is isolated from pooled plasma, i.e., plasma-derived coagulation factors. Methods for the isolation of many different coagulation factors are well known in the art. For example, Furuya et al. (“Implementation of a 20-nm pore-size filter in the plasma-derived factor VIII manufacturing process” Vox Sang. 2006 August; 91(2):119-25) describe a method for the purification of a virally reduced plasma-derived Factor VIII composition from pooled human plasma. Similarly, Kisiel et al. (“Activation of Bovine Factor VII (Proconvertin) by Factor XIIa (Activated Hageman Factor)” Biochemistry (1977) 16 (9):4189-4193) and Broze and Majerus (“Purification and Properties of Human Coagulation Factor VII” J Biol Chem. 1980 Feb. 25; 255(4):1242-7) describe methods for the purification of plasma-derived Factor VII. Methods for the purification of plasma-derived Protein K dependent coagulation complexes (e.g., Prothromplex, FEIBA) are described, for example, in U.S. Pat. Nos. 5,409,990 and 5,281,661. Finally, among other teachings, U.S. Pat. No. 4,786,726 and PCT Publication No. WO 2007/046631, describe purification of plasma-derived Factor FIX.

In other embodiments, the labile therapeutic coagulation protein is expressed recombinantly, i.e., recombinant coagulation factors. Methods for the expression and purification of many different coagulation factors are well known in the art. For example, U.S. Pat. Nos. 5,470,954; 6,100,061; 6,475,725; 6,555,391; 6,936,441; 7,094,574; 7,253,262; 6,919,311; 7,544,660; and 7,381,796, all of which are hereby incorporated by reference in their entireties for all purposes, describe the expression and purification of recombinant Factor VIII. Methods for the manufacture of recombinant Factor IX are also well known in the art and are described in, for example, U.S. Patent Application Publication 2008/207879, U.S. Pat. Nos. 4,770,999, and 5,521,070. Likewise, methods for the manufacture of recombinant Factor VII are described in, for example, U.S. Patent Application Publication Nos. 2010/120093 and 2009/047723.

In one embodiment of the present invention, the media used to express a recombinant coagulation factor can be animal protein-free and chemically defined. Methods of preparing animal protein-free and chemically defined culture mediums are known in the art, for example in US 2008/0009040 and US 2007/0212770, which are both incorporated herein for all purposes. “Protein free” and related terms refers to protein that is from a source exogenous to or other than the cells in the culture, which naturally shed proteins during growth. In another embodiment, the culture medium is polypeptide free. In another embodiment, the culture medium is serum free. In another embodiment the culture medium is animal protein free. In another embodiment the culture medium is animal component free. In another embodiment, the culture medium contains protein, e.g., animal protein from serum such as fetal calf serum. In another embodiment, the culture has recombinant proteins exogenously added. In another embodiment, the proteins are from a certified pathogen free animal. The term “chemically defined” as used herein shall mean, that the medium does not comprise any undefined supplements, such as, for example, extracts of animal components, organs, glands, plants, or yeast. Accordingly, each component of a chemically defined medium is accurately defined. In a preferred embodiment, the media are animal-component free and protein free.

Accordingly, in one aspect, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In one embodiment, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a′ pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: a coagulation factor; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: a coagulation factor; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: a coagulation factor; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the coagulation factor is a core coagulation factor.

1. Factor VIII

As demonstrated in Example 5, recombinant Factor VIII (rFVIII) is stabilized by the addition of between about 100 mM and about 200 mM of an alkali metal chloride salt (e.g., sodium chloride) at a pH between about 6.0 and about 7.5. In one specific embodiment, methods are provided for the stabilization of Factor VIII formulated at a pH between 6.0 and 7.5, preferably at a pH from 6.5 to 7.0.

In one embodiment, the storage stable, aqueous FVIII compositions provided herein have a protein concentration of between 0.05 g/L and 10 g/L. In certain embodiments, the protein concentration of the FVIII composition is between 0.05 g/L and 2 g/L, or between 0.1 g/L and 1 g/L, or between 0.1 g/L and 0.5 g/L, or any suitable concentration within these ranges, for example 0.05 g/L, or 0.06 g/L, 0.07 g/L, 0.08 g/L, 0.09 g/L, 0.1 g/L, 0.15 g/L, 0.2 g/L, 0.25 g/L, 0.3 g/L, 0.35 g/L, 0.4 g/L, 0.45 g/L, 0.5 g/L, 0.55 g/L, 0.6 g/L, 0.65 g/L, 0.7 g/L, 0.75 g/L, 0.8 g/L, 0.85 g/L, 0.9 g/L, 0.95 g/L, 1 g/L, 1.25 g/L, 1.5 g/L, 1.75 g/L, 2.0 g/L, 2.25 g/L, 2.5 g/L, 2.75 g/L, 3.0 g/L, 3.25 g/L, 3.5 g/L, 3.75 g/L, 4.0 g/L, 4.25 g/L, 4.5 g/L, 4.75 g/L, 5.0 g/L, 5.5 g/L, 6.0 g/L, 6.5 g/L, 7.0 g/L, 7.5 g/L, 8.0 g/L, 8.5 g/L, 9.0 g/L, 9.5 g/L, 10.0 g/L, or higher. In a preferred embodiment, the aqueous FVIII composition will have a concentration of between 0.1 g/L and 0.5 g/L. In yet other embodiments, the concentration of Factor VIII in a storage-stable aqueous formulation is 0.05±0.01 g/L, or 0.06±0.01 g/L, 0.07±0.01 g/L, 0.08±0.01 g/L, 0.09±0.01 g/L, 0.1±0.01 g/L, 0.15±0.01 g/L, 0.2±0.02 g/L, 0.25±0.02 g/L, 0.3±0.03 g/L, 0.35±0.03 g/L, 0.4±0.04 g/L, 0.45±0.04 g/L, 0.5±0.05 g/L, 0.55±0.05 g/L, 0.6±0.06 g/L, 0.65±0.06 g/L, 0.7±0.07 g/L, 0.75±0.07 g/L, 0.8±0.08 g/L, 0.85±0.08 g/L, 0.9±0.09 g/L, 0.95±0.09 g/L, 1±0.1 g/L, 1.25±0.12 g/L, 1.5±0.15 g/L, 1.75±0.17 g/L, 2.0±0.2 g/L, 2.25±0.22 g/L, 2.5±0.25 g/L, 2.75±0.27 g/L, 3.0±0.3 g/L, 3.25±0.32 g/L, 3.5±0.35 g/L, 3.75±0.37 g/L, 4.0±0.4 g/L, 4.25±0.42 g/L, 4.5±0.45 g/L, 4.75±0.47 g/L, 5.0±0.5 g/L, 5.5±0.55 g/L, 6.0±0.6 g/L, 6.5±0.65 g/L, 7.0±0.7 g/L, 7.5±0.75 g/L, 8.0±0.8 g/L, 8.5±0.85 g/L, 9.0±0.9 g/L, 9.5±0.95 g/L, 10.0±1 g/L, or higher.

In one embodiment, the storage stable, aqueous FVIII composition will be stable under refrigeration (i.e., between about 2° C. and about 8° C.) for at least about 1 month. In other embodiments, the storage stable, aqueous FVIII composition will be stable under refrigeration for at least about 2 months. In a preferred embodiment, the storage stable, aqueous FVIII composition will be stable under refrigeration for at least about 3 months. In yet another embodiment, the storage stable, aqueous FVIII composition will be stable under refrigeration for at least about 6 months. In yet other embodiments, the storage stable, aqueous FVIII composition will be stable under refrigeration for at least about 2 weeks, or at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 weeks or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or more months under refrigeration.

Accordingly, in one aspect, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 125 mM to 175 mM of an alkali metal chloride salt; a stabilizing agent; and a pH of from 6.0 to 7.5. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting essentially of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein consisting of: a labile therapeutic protein; a stabilizing agent; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a more specific embodiment, the stabilizing agent is an amino acid. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In one embodiment, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; an amino acid; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM glycine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 5 mM to 500 mM glycine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM glycine. In a more specific embodiment, the composition contains from 100 mM to 400 mM glycine. In a more specific embodiment, the composition contains from 150 mM to 350 mM glycine. In a more specific embodiment, the composition contains from 200 mM to 300 mM glycine. In a more specific embodiment, the composition contains 250±25 mM glycine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM proline; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 5 mM to 500 mM proline; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM proline. In a more specific embodiment, the composition contains from 100 mM to 400 mM proline. In a more specific embodiment, the composition contains from 150 mM to 350 mM proline. In a more specific embodiment, the composition contains from 200 mM to 300 mM proline. In a more specific embodiment, the composition contains 250±25 mM proline. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another aspect, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; from 5 mM to 500 mM histidine; and a pH of from 6.0 to 7.5. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 5 mM to 500 mM histidine; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the composition contains from 25 mM to 500 mM histidine. In a more specific embodiment, the composition contains from 100 mM to 400 mM histidine. In a more specific embodiment, the composition contains from 150 mM to 350 mM histidine. In a more specific embodiment, the composition contains from 200 mM to 300 mM histidine. In a more specific embodiment, the composition contains 250±25 mM histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; an antioxidant; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; an amino acid; an antioxidant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; a sugar and/or sugar alcohol; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In another embodiment, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; an amino acid; a sugar and/or sugar alcohol; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains calcium.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; mannitol; trehalose; calcium; a non-ionic surfactant; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains an antioxidant. In a specific embodiment, the concentration of mannitol is 38±7 g/L. In another specific embodiment, the concentration of trehalose is 10±2 g/L. In another specific embodiment, the concentration of histidine is 12±2 mM. In another specific embodiment, the concentration of calcium is 1.9±0.4 mM. In another embodiment, the non-ionic surfactant is polysorbate-80 at a concentration of 0.15±0.03 g/L.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; mannitol; trehalose; calcium; a non-ionic surfactant; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains an antioxidant. In a specific embodiment, the concentration of mannitol is 38±7 g/L. In another specific embodiment, the concentration of trehalose is 10±2 g/L. In another specific embodiment, the concentration of histidine is 12±2 mM. In another specific embodiment, the concentration of calcium is 1.9±0.4 mM. In another embodiment, the non-ionic surfactant is polysorbate-80 at a concentration of 0.15±0.03 g/L.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; from 75 mM to 200 mM of an alkali metal chloride salt; an amino acid; mannitol; trehalose; calcium; a non-ionic surfactant; Tris; glutathione; and a pH of from 6.0 to 7.5. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific, embodiment, the composition also contains an antioxidant. In a specific embodiment, the concentration of mannitol is 38±7 g/L. In another specific embodiment, the concentration of trehalose is 10±2 g/L. In another specific embodiment, the concentration of histidine is 12±2 mM. In another specific embodiment, the concentration of calcium is 1.9±0.4 mM. In another embodiment, the non-ionic surfactant is polysorbate-80 at a concentration of 0.15±0.03 g/L.

In one aspect, the present invention provides a storage stable, aqueous composition comprising: Factor VIII; an amino acid; mannitol; trehalose; calcium; a non-ionic surfactant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains an antioxidant. In a specific embodiment, the concentration of mannitol is 38±7 g/L. In another specific embodiment, the concentration of trehalose is 10±2 g/L. In another specific embodiment, the concentration of histidine is 12±2 mM. In another specific embodiment, the concentration of calcium is 1.9±0.4 mM. In another embodiment, the non-ionic surfactant is polysorbate-80 at a concentration of 0.15±0.03 g/L.

In a specific embodiment, the present invention provides a storage stable, aqueous composition consisting essentially of: Factor VIII; an amino acid; mannitol; trehalose; calcium; a non-ionic surfactant; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains an antioxidant. In a specific embodiment, the concentration of mannitol is 38±7 g/L. In another specific embodiment, the concentration of trehalose is 10±2 g/L. In another specific embodiment, the concentration of histidine is 12±2 mM. In another specific embodiment, the concentration of calcium is 1.9±0.4 mM. In another embodiment, the non-ionic, surfactant is polysorbate-80 at a concentration of 0.15±0.03 g/L.

In a more specific embodiment, the present invention provides a storage stable, aqueous composition consisting of: Factor VIII; an amino acid; mannitol; trehalose; calcium; a non-ionic surfactant; Tris; glutathione; and an alkali metal salt/pH combination selected from any one of variations 1 to 2088, as set forth in Table 1, Table 2, Table 3, and Table 4. In a specific embodiment, the amino acid is glycine, proline, or histidine. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline. In another preferred embodiment, the amino acid is histidine. In one embodiment, the metal chloride salt is sodium chloride. In another embodiment, the metal chloride salt is potassium chloride. In a preferred embodiment, the pH of the formulation is between 6.5 and 7.5. In a specific embodiment, the composition also contains an antioxidant. In a specific embodiment, the concentration of mannitol is 38±7 g/L. In another specific embodiment, the concentration of trehalose is 10±2 g/L. In another specific embodiment, the concentration of histidine is 12±2 mM. In another specific embodiment, the concentration of calcium is 1.9±0.4 mM. In another embodiment, the non-ionic surfactant is polysorbate-80 at a concentration of 0.15±0.03 g/L.

D. Methods for Stabilizing Labile Proteins

In the context of the present invention, a labile therapeutic protein is unstable when formulated at mildly acidic to neutral pH in the absence of an alkaline metal chloride salt. Surprisingly, it has been found that a wide range of labile therapeutic proteins are stabilized by the addition of a moderate concentration (i.e., between about 75 mM and about 200 mM, preferably between about 100 mM and about 200 mM) of an alkaline metal chloride salt. This effect of alkali metal chloride salts provides methods for stabilizing aqueous formulations of labile therapeutic proteins. Accordingly, in one aspect of the present invention, methods are provided for the stabilization of an aqueous labile therapeutic protein composition. These methods allow for aqueous formulations of labile therapeutic proteins at mildly acidic to neutral pH, which previously required lyophilization, freezing in the presence of several stabilizers, or formulation at extreme pH values.

In one embodiment, the method comprises the addition of alkali metal chloride salt to a final concentration of between about 75 mM and about 200 mM to an aqueous formulation of a labile therapeutic protein at a pH between about 5.5 and about 7.5. In a preferred embodiment, the method further comprises the addition of a stabilizing agent, such as an amino acid, to the formulation.

In another embodiment, the method comprises the addition of alkali metal chloride salt to a final concentration of between about 100 mM and about 200 mM to an aqueous formulation of a labile therapeutic protein at a pH between about 5.5 and about 7.5. In a preferred embodiment, the method further comprises the addition of a stabilizing agent, such as an amino acid, to the formulation.

In another embodiment, the method comprises the addition of alkali metal chloride salt to a final concentration of between about 100 mM and about 200 mM to an aqueous formulation of a labile therapeutic protein at a pH between about 5.5 and about 7.0. In a preferred embodiment, the method further comprises the addition of a stabilizing agent, such as an amino acid, to the formulation.

In yet another embodiment, the method comprises the addition of alkali metal chloride salt to a final concentration of between about 75 mM and about 200 mM to an aqueous formulation of a labile therapeutic protein at a pH between about 5.5 and about 7.0. In a preferred embodiment, the method further comprises the addition of a stabilizing agent, such as an amino acid, to the formulation.

In certain embodiments, the methods provided herein for the stabilization of a labile therapeutic protein will further comprise the addition of a stabilizing agent to the formulation. In a preferred embodiment, the stabilizing agent will be an amino acid. Exemplary amino acids that may be used for this purpose include, without limitation, arginine, histidine, lysine, serine, proline, glycine, alanine, threonine, and a combination thereof. In a preferred embodiment, the amino acid is glycine. In another preferred embodiment, the amino acid is proline.

For purposes of further stabilizing the compositions provided herein, the amino acid will typically be added to the formulation at a concentration between about 25 mM and about 0.75 M. In one embodiment, at least about 100 mM of the amino acid is added to the formulation. In another embodiment, at least about 200 mM of the amino acid is added to the formulation. In yet another embodiment, at least about 250 mM of the amino acid is added to the formulation. In yet other embodiments, the formulations provided herein will contain at least about 25 mM of the amino acid, or at least about 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or more of the amino acid.

In a preferred embodiment, the labile therapeutic protein is a human protein, a humanized protein, or a chimeric human protein. The human protein may be either purified from a natural source (e.g., pooled human plasma) or expressed recombinantly, for example in a mammalian cell or tissue culture. In a preferred embodiment, the labile therapeutic protein is a plasma-derived protein, preferably a plasma-derived coagulation factor or immunoglobulin preparation. In another preferred embodiment, the human, humanized, or chimeric protein in a recombinant antibody or fragment thereof.

In one embodiment, the methods for stabilizing a formulation of a labile therapeutic protein provided herein comprise the addition of between about 75 mM and about 200 mM of an alkali metal chloride salt to the formulation. In a preferred embodiment, the methods for stabilizing a formulation of a labile therapeutic protein provided herein comprise the addition of between about 100 mM and about 200 mM of an alkali metal chloride salt to the formulation. In certain embodiments, the methods comprise the addition of between about 150 mM and about 200 mM of an alkali metal chloride salt. In other embodiments, the method comprises the addition of between about 150 mM and about 200 mM of an alkali metal chloride salt. In yet other embodiments, the comprise the addition of at or about 70 mM or at or about 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 155 mM, 160 mM, 165 mM, 170 mM, 175 mM, 180 mM, 185 mM, 190 mM, 195 mM, 200 mM, 205 mM, 210 mM, 215 mM, or at or about 220 mM of an alkali metal chloride salt. In one preferred embodiment, the alkali metal chloride salt is sodium chloride. In another preferred embodiment, the alkali metal chloride salt is potassium chloride.

The methods for stabilizing a labile therapeutic protein provided by the present invention comprise formulating the labile protein, in the presence of an alkali metal chloride salt, at a mildly acidic to neutral pH. Generally, this includes pH values between about 5.5 and about 7.5. However, the range of pH values at which any individual labile therapeutic protein is stabilized by the addition of a moderate level (i.e., between about 75 mM and about 200 mM, preferably between about 100 mM and about 200 mM) of an alkali metal chloride salt may vary slightly, dependent upon the properties of the individual protein. In a preferred embodiment, the method will comprise formulating a storage stable composition of a labile therapeutic protein at a pH between about 5.5 and about 7.0. In another embodiment, the method will comprise formulating a storage stable composition of a labile therapeutic protein at a pH between about 5.5 and about 6.5. In other embodiments, the pH of the stabilizing formulation will be between about 6.0 and about 7.0. In another embodiment, the pH of the stabilizing formulation will be between about 5.5 and about 6.0. In one embodiment, the pH of the stabilizing formulation will be between about 6.0 and about 6.5. In another embodiment, the pH of the stabilizing formulation will be between about 6.5 and about 7.0. In another embodiment, the pH of the stabilizing formulation will be between about 6.0 and about 7.5. In another embodiment, the pH of the stabilizing formulation will be between about 6.5 and about 7.5. In another embodiment, the pH of the stabilizing formulation will be between about 7.0 and about 7.5. In yet other embodiments, the pH of the stabilizing formulation may be at or about 5.5, or at or about 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, or at or about 7.5.

In certain embodiments, the method will further comprise formulating the storage stable, labile therapeutic protein for parenteral administration including, but not limited to, intradermal, subcutaneous, transdermal implant, intracavernous, intravitreal, transscleral, intracerebral, intrathecal, epidural, intravenous, intracardiac, intramuscular, intraosseous, intraperitoneal, and nanocell injection administration. In one preferred embodiment, the compositions provided herein will be formulated for intravenous administration. In another preferred embodiment, the compositions provided herein will be formulated for subcutaneous administration. In yet another preferred embodiment, the compositions provided herein will be formulated for intramuscular administration.

In certain embodiments, the method for stabilizing a labile therapeutic protein will comprise formulating the protein at a final concentration of between about 0.05 mg/mL to about 250 mg/mL. In certain embodiments, the labile protein will be formulated at a final concentration of about 0.05 mg/mL, 0.06 mg/mL, 0.07 mg/mL, 0.08 mg/mL, 0.09 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL or about 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 23 mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, 55 mg/mL, 60 mg/mL, 65 mg/mL, 70 mg/mL, 75 mg/mL, 80 mg/mL, 85 mg/mL, 90 mg/mL, 95 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, 200 mg/mL, 210 mg/mL, 220 mg/mL, 230 mg/mL, 240 mg/mL, 250 mg/mL, or higher concentrations, depending upon the characteristics of the protein being formulated, the intended therapeutic use of the protein, and the preferred method of administration.

In one embodiment, the method will comprise formulating the labile therapeutic protein at a low final protein concentration of between about 0.05 mg/mL and about 20 mg/mL. In another embodiment, the final protein concentration may be between about 0.5 mg/mL and about 15 mg/mL. In another embodiment, the final protein concentration may be between about 0.5 mg/mL and about 10 mg/mL. In another embodiment, the final protein concentration may be between about 0.5 mg/mL and about 5 mg/mL. In one embodiment, a composition with a final protein concentration as described above will be formulated for intravenous administration.

In other embodiments, the method will comprise formulating the labile therapeutic protein at a moderate final protein concentration of between about 5 mg/mL and about 25 mg/mL. In another embodiment, the final protein concentration may be between about 10 mg/mL and about 25 mg/mL. In another embodiment, the final protein concentration may be between about 15 mg/mL and about 25 mg/mL. In another embodiment, the final protein concentration may be between about 20 mg/mL and about 25 mg/mL. In one embodiment, a composition with a final protein concentration as described above will be formulated for subcutaneous or intramuscular administration.

In certain embodiments, the final protein concentration may be between about 0.5% and about 25%. In another embodiment, the final protein concentration may be between about 0.5% and about 20%. In another embodiment, the final protein concentration may be between about 0.5% and about 15%. In another embodiment, the final protein concentration may be between about 0.5% and about 10%. In another embodiment, the final protein concentration may be between about 0.5% and about 5%. In one embodiment, a composition with a final protein concentration as described above will be formulated for intravenous administration.

In certain embodiments, the final protein concentration may be between about 5% and about 25%. In another embodiment, the final protein concentration may be between about 10% and about 25%. In another embodiment, the final protein concentration may be between about 15% and about 25%. In another embodiment, the final protein concentration may be between about 20% and about 25%. In one embodiment, a composition with a final protein concentration as described above will be formulated for subcutaneous or intramuscular administration.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile plasma derived protein at a pH between about 5.5 and about 7.5, the method comprising adding an alkali metal chloride salt to the formulation at a final concentration of between about 75 mM and about 200 mM. In a preferred embodiment, the compositions comprise between about 100 mM and about 200 mM of an alkali metal chloride salt. In another preferred embodiment, the mildly acidic to neutral pH is between about 5.5 and about 7.0. In a preferred embodiment, the alkali metal chloride salt is sodium chloride. In another preferred embodiment, the alkali metal chloride salt is potassium chloride.

The methods provided herein allow for the stabilization of a labile protein at a mildly acidic to neutral pH for an extended period of time. For example, in one embodiment, the storage stable, aqueous labile therapeutic protein composition will be stable for at least about 2 months. In another embodiment, the composition will be stable for at least about 3 months. In yet other embodiment, the composition will be stable for at least 1 about month, or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or more months. In a preferred embodiment, the composition will be stable for at least about 6 months. In a more preferred embodiment, the composition will be stable for at least about 1 year. In a more preferred embodiment, the composition will be stable for at least about 2 years.

Dependent upon the individual characteristics of the labile protein being stabilized in the methods provided herein, the formulation will be stabile for an extended period of time at a temperature between about 2° C. and about 42° C. In one embodiments, a labile therapeutic protein will be stabilized by the methods provided herein when stored under refrigeration, i.e., stored at a temperature between about 2° C. and about 8° C. In another embodiment, a labile therapeutic protein will be stabilized by the methods provided herein when stored at room temperature, i.e., stored at a temperature between about 20° C. and about 25° C. In other embodiments, the protein may be stabilized when stored at a temperature between about 28° C. and about 32° C. In yet another embodiment, the protein may be stabilized when stored at a temperature between about 38° C. and about 42° C. The temperatures at which a labile therapeutic protein will be stabilized by the methods provided herein will be dependent upon the characteristics of the individual protein, which can readily be determined by one of skill in the art.

In certain embodiments, the methods provided herein for the stabilization of a labile therapeutic protein comprise the addition of a stabilizing agent. In one embodiment, the stabilizing agent comprises one or more buffering agents or pH stabilizing agents suitable for intravenous, intravitreal, subcutaneous, and/or intramuscular administration. Non-limiting examples of buffering agents suitable for formulating the storage stable compositions provided herein include glycine, histidine, or other amino acids, salts like citrate, phosphate, acetate, glutamate, tartrate, benzoate, lactate, gluconate, malate, succinate, formate, propionate, carbonate, or any combination thereof adjusted to an appropriate pH. Generally, the buffering agent will be sufficient to maintain a suitable pH in the formulation for an extended period of time.

In some embodiments, the concentration of buffering agent in the formulation will be at or about between 5 mM and 500 mM. In certain embodiments, the concentration of the buffering agent in the formulation will be at or about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 50 mM, 75 mM, 100 mM, 125 mM, 150 mM, 175 mM, 200 mM, 225 mM, 250 mM, 275 mM, 300 mM, 325 mM, 350 mM, 375 mM, 400 mM, 425 mM, 450 mM, 475 mM, 500 mM or higher.

In another embodiment, the stabilizing agent will comprise an agent for adjusting the osmolarity of the composition. Non-limiting examples of osmolarity agents include mannitol, sorbitol, glycerol, sucrose, glucose, dextrose, levulose, fructose, lactose, polyethylene glycols, phosphates, calcium chloride, calcium gluconoglucoheptonate, dimethyl sulfone, and the like.

In a preferred embodiment, the stabilizing agent employed in the storage stable, labile immunoglobulin formulations provided herein will be an amino acid. Stabilizing amino acids include arginine, histidine, lysine, serine, proline, glycine, alanine, threonine, and a combination thereof. In a preferred embodiment, the amino acid is glycine. For purposes of further stabilizing the compositions provided herein, the amino acid will typically be added to the formulation at a concentration between about 25 mM and about 0.75 M. In one embodiment, at least about 100 mM of the amino acid is added to the formulation. In another embodiment, at least about 200 mM of the amino acid is added to the formulation. In yet another embodiment, at least about 250 mM of the amino acid is added to the formulation. In yet other embodiments, the formulations provided herein will contain at least about 25 mM of the amino acid, or at least about 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, or more of the amino acid.

In a specific embodiment, the labile plasma derived protein is an immunoglobulin preparation. As demonstrated in Examples 1 and 2, plasma derived IgG preparations are stabilized by the addition of between about 100 mM and about 200 mM of an alkali metal chloride salt (e.g., sodium chloride) at a pH between about 6.0 and about 7.0. As shown in FIG. 1, maximum stability for the IgG formulations is found between pH 6.0 and 6.5.

Accordingly, in one embodiment, the present invention provides method for stabilizing a plasma derived IgG aqueous composition formulated at a pH between about 6.0 and about 7.0, the method comprising adding between about 75 mM and about 200 mM, preferably between about 100 mM and about 200 mM of an alkali metal chloride salt to the formulation. In a preferred embodiment, the method further comprises adding a stabilizing agent to the formulation. In another preferred embodiment, the method comprises the addition of between about 75 mM and about 200 mM, preferably between about 100 mM and about 200 mM, of an alkali metal chloride salt to a plasma derived immunoglobulin preparation formulated at a pH between about 6.0 and about 6.5. In a preferred embodiment, the salt is sodium chloride. In another preferred embodiment, the salt is potassium chloride.

In one embodiment, the method for stabilizing a labile plasma derived immunoglobulin composition will comprise formulating the protein at a final concentration of between about 30 g/L and about 250 g/L. In certain embodiments, the method comprises formulating the immunoglobulin composition at a final protein concentration of between about 50 g/L and about 200 g/L, or between about 70 g/L and about 150 g/L, or between about 90 g/L and about 120 g/L, or any suitable concentration within these ranges, for example about 30 g/L, or about 35 g/L, 40 g/L, 45 g/L, 50 g/L, 55 g/L, 60 g/L, 65 g/L, 70 g/L, 75 g/L, 80 g/L, 85 g/L, 90 g/L, 95 g/L, 100 g/L, 105 g/L, 110 g/L, 115 g/L, 120 g/L, 125 g/L, 130 g/L, 135 g/L, 140 g/L, 145 g/L, 150 g/L, 155 g/L, 160 g/L, 165 g/L, 170 g/L, 175 g/L, 180 g/L, 185 g/L, 190 g/L, 195 g/L, 200 g/L, 205 g/L, 210 g/L, 215 g/L, 220 g/L, 225 g/L, 230 g/L, 235 g/L, 240 g/L, 245 g/L, 250 g/L, or higher. In a preferred embodiment, the aqueous IgG composition will have a concentration of at or about 100 g/L. In a related embodiment, the aqueous IgG composition will have a concentration of between about 70 g/L and about 130 g/L. In another preferred embodiment, the aqueous IgG composition will have a concentration of at or about 200 g/L. In a related embodiment, the aqueous IgG composition will have a concentration of between about 170 g/L and about 230 g/L.

In one aspect, the present invention provides methods for stabilizing recombinant immunoglobulin preparations at a pH between about 5.5 and about 7.5 comprising the addition of between about 75 mM and about 200 mM of an alkali metal chloride salt to the formulation. In a preferred embodiment, the compositions comprise between about 100 mM and about 200 mM of an alkali metal chloride salt. In another preferred embodiment, the mildly acidic to neutral pH is between about 5.5 and about 7.0. In a preferred embodiment, the methods further comprise the addition of a stabilizing agent to the formulation. In one preferred embodiment, the salt is sodium chloride. In another preferred embodiment, the salt is potassium chloride.

In another specific embodiment, the storage stable, immunoglobulin composition is a recombinant antibody preparation. As demonstrated in Example 4, a recombinant anti-MIF monoclonal antibody preparation is stabilized by the addition of between about 100 mM and about 200 mM of an alkali metal chloride salt (e.g., sodium chloride) at a pH between about 5.5 and about 6.5.

Accordingly, in one embodiment, the present invention provides methods for stabilizing aqueous compositions of recombinant immunoglobulins formulated at a pH between about 5.5 and about 6.5 by the addition of between about 75 mM and about 200 mM, preferably between about 100 mM and about 200 mM, of an alkali metal chloride salt and optionally, a stabilizing agent to the formulation. In a preferred embodiment, the salt is sodium chloride. In another preferred embodiment, the salt is potassium chloride.

In one embodiment, the methods for stabilizing a recombinant immunoglobulin aqueous composition provided herein comprise the formulation of the recombinant immunoglobulin at a final protein concentration of between about 1 g/L and about 250 g/L. In certain embodiments, the protein concentration of the recombinant immunoglobulin composition is between about 50 g/L and about 200 g/L, or between about 70 g/L and about 150 g/L, or between about 90 g/L and about 120 g/L, or any suitable concentration within these ranges, for example about 1 g/L, 2 g/L, 3 g/L, 4 g/L, 5 g/L, 6 g/L, 7 g/L, 8 g/L, 9 g/L, 10 g/L, 11 g/L, 12 g/L, 13 g/L, 14 g/L, 15 g/L, 16 g/L, 17 g/L, 18 g/L, 19 g/L, 20 g/L, 25 g/L, 30 g/L, or about 35 g/L, 40 g/L, 45 g/L, 50 g/L, 55 g/L, 60 g/L, 65 g/L, 70 g/L, 75 g/L, 80 g/L, 85 g/L, 90 g/L, 95 g/L, 100 g/L, 105 g/L, 110 g/L, 115 g/L, 120 g/L, 125 g/L, 130 g/L, 135 g/L, 140 g/L, 145 g/L, 150 g/L, 155 g/L, 160 g/L, 165 g/L, 170 g/L, 175 g/L, 180 g/L, 185 g/L, 190 g/L, 195 g/L, 200 g/L, 205 g/L, 210 g/L, 215 g/L, 220 g/L, 225 g/L, 230 g/L, 235 g/L, 240 g/L, 245 g/L, 250 g/L, or higher.

In another embodiment, the present invention provides methods for stabilizing a labile coagulation factor formulated at a pH between about 5.5 and about 7.5 comprising the addition of between about 75 mM and about 200 mM of an alkali metal chloride salt to the formulation. In a preferred embodiment, the compositions comprise between about 100 mM and about 200 mM of an alkali metal chloride salt. In another preferred embodiment, the mildly acidic to neutral pH is between about 5.5 and about 7.0. In a preferred embodiment, the methods further comprise the addition of a stabilizing agent to the formulation. In one preferred embodiment, the salt is sodium chloride. In another preferred embodiment, the salt is potassium chloride.

In certain embodiments, the labile coagulation protein is a plasma derived protein or preparation. In other embodiments, the labile coagulation protein is a recombinantly expressed coagulation protein. Methods for manufacturing recombinant and plasma derived coagulation factors are well known in the art. Non-limiting examples of coagulation factors that may be formulated according to the methods provided herein include, Factor II (prothrombin), Factor III (platelet tissue factor), Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, von Willebrand Factor (vWF), and the like. In a preferred embodiment, the labile coagulation protein is selected from Factor VII, Factor VIII, Factor IX, and von Willebrand Factor (vWF). In another preferred embodiment, the labile coagulation protein is a vitamin-K dependent protein complex, for example, comprising Factor II, Factor IX, and Factor X, or comprising Factor II, Factor VII, Factor IX, and Factor X.

In one specific embodiment, methods are provided for the stabilization of Factor VIII formulated at a pH between about 6.5 and about 7.0. As shown in Example 5, recombinant Factor VIII (rFVIII) is stabilized by the addition of between about 100 mM and about 200 mM of an alkali metal chloride salt (e.g., sodium chloride) at a pH between about 6.5 and about 7.0.

Accordingly, in one embodiment the present invention provides a method for stabilizing an aqueous composition of FVIII, the method comprising formulating a FVIII composition at a pH between about 6.5 and about 7.0 with between about 75 mM and about 200 mM, preferably between about 100 mM and about 200 mM, of an alkali metal chloride salt. In a preferred embodiment, the alkali metal chloride salt is sodium chloride. In another preferred embodiment, the alkali metal chloride salt is potassium chloride.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile therapeutic protein at a pH between about 5.5 and about 7.5, the method comprising addition of an alkali metal chloride salt at a concentration of between about 75 mM and about 200 mM. In a preferred embodiment, the compositions comprise between about 100 mM and about 200 mM of an alkali metal chloride salt. In another preferred embodiment, the mildly acidic to neutral pH is between about 5.5 and about 7.0. In a preferred embodiment, the salt is sodium chloride. In certain embodiments, the method further comprises the addition of a stabilizing agent. In one embodiment, the stabilizing agent is an amino acid. In preferred embodiments, the amino acid is glycine or proline.

In another embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile therapeutic protein at a pH between about 5.5 and about 6.5, the method comprising addition of an alkali metal chloride salt at a concentration of between about 100 mM and about 200 mM. In a preferred embodiment, the salt is sodium chloride. In certain embodiments, the method further comprises the addition of a stabilizing agent. In one embodiment, the stabilizing agent is an amino acid. In preferred embodiments, the amino acid is glycine or proline.

In one embodiment of the methods provided herein, the labile therapeutic protein is a human or humanized protein. In another embodiment of the methods provided herein, the labile therapeutic protein is a recombinant protein. In yet another embodiment of the methods provided herein, the labile therapeutic protein is a plasma-derived protein.

In a specific embodiment of the methods provided herein, the labile therapeutic protein is an immunoglobulin. In one embodiment, the immunoglobulin is an IgG preparation. In another embodiment, the immunoglobulin is a recombinant antibody.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile immunoglobulin preparation at a pH between about 5.5 and about 7.5, the method comprising addition of an alkali metal chloride salt at a concentration of between about 75 mM and about 200 mM, wherein the method stabilizes the immunoglobulin composition for at least 6 months when stored at a temperature at or below about 42° C., for example, at a temperature between about 38° C. and about 42° C. In a preferred embodiment, the pH of the immunoglobulin formulation is between about 5.5 and about 6.5.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile immunoglobulin preparation at a pH between about 5.5 and about 7.0, the method comprising addition of an alkali metal chloride salt at a concentration of between about 100 mM and about 200 mM, wherein the method stabilizes the immunoglobulin composition for at least 6 months when stored at a temperature at or below about 42° C., for example, at a temperature between about 38° C. and about 42° C. In a preferred embodiment, the pH of the immunoglobulin formulation is between about 5.5 and about 6.5.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile immunoglobulin preparation at a pH between about 5.5 and about 7.0, the method comprising addition of an alkali metal chloride salt at a concentration of between about 100 mM and about 200 mM, wherein the method stabilizes the immunoglobulin composition for at least about one year when stored at a temperature at or below about 32° C., for example, at a temperature between about 28° C. and about 32° C. In a preferred embodiment, the pH of the immunoglobulin formulation is between about 5.5 and about 6.5.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile immunoglobulin preparation at a pH between about 5.5 and about 7.5, the method comprising addition of an alkali metal chloride salt at a concentration of between about 75 mM and about 200 mM, wherein the method stabilizes the immunoglobulin composition for at least about one year when stored at a temperature at or below about 32° C., for example, at a temperature between about 28° C. and about 32° C. In a preferred embodiment, the pH of the immunoglobulin formulation is between about 5.5 and about 6.5.

In a specific embodiment of the methods provided herein, the labile therapeutic protein is a labile coagulation protein. In one embodiment, the coagulation protein is Factor VIII. In another embodiment, the coagulation protein is Factor VII. In yet another embodiment, the coagulation protein is Factor IX. In another embodiment, the coagulation protein is a protein K-dependent coagulation complex, for example, comprising Factor II, Factor IX, and Factor X, or comprising Factor II, Factor VII, Factor IX, and Factor X.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile coagulation protein at a pH between about 5.5 and about 7.5, the method comprising addition of an alkali metal chloride salt at a concentration of between about 75 mM and about 200 mM, wherein the method stabilizes the coagulation protein for at least 3 months when stored at a refrigerated temperature, for example, at a temperature between about 2° C. and about 10° C.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile coagulation protein at a pH between about 5.5 and about 7.0, the method comprising addition of an alkali metal chloride salt at a concentration of between about 100 mM and about 200 mM, wherein the method stabilizes the coagulation protein for at least 3 months when stored at a refrigerated temperature, for example, at a temperature between about 2° C. and about 10° C.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile coagulation protein at a pH between about 5.5 and about 7.0, the method comprising addition of an alkali metal chloride salt at a concentration of between about 100 mM and about 200 mM, wherein the method stabilizes the coagulation protein for at least 6 months when stored at a refrigerated temperature, for example, at a temperature between about 2° C. and about 10° C.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile coagulation protein at a pH between about 5.5 and about 7.5, the method comprising addition of an alkali metal chloride salt at a concentration of between about 75 mM and about 200 mM, wherein the method stabilizes the coagulation protein for at least 6 months when stored at a refrigerated temperature, for example, at a temperature between about 2° C. and about 10° C.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile coagulation protein at a pH between about 5.5 and about 7.0, the method comprising addition of an alkali metal chloride salt at a concentration of between about 100 mM and about 200 mM, wherein the method stabilizes the coagulation protein for at least about one year when stored at a refrigerated temperature, for example, at a temperature between about 2° C. and about 10° C.

In one embodiment, the present invention provides a method for stabilizing an aqueous formulation of a labile coagulation protein at a pH between about 5.5 and about 7.5, the method comprising addition of an alkali metal chloride salt at a concentration of between about 75 mM and about 200 mM, wherein the method stabilizes the coagulation protein for at least about one year when stored at a refrigerated temperature, for example, at a temperature between about 2° C. and about 10° C.

E. Specific Embodiments

In one embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: between about 75 mM and about 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH between about 5:5 and about 7.5.

In one embodiment, the present invention provides a storage stable, aqueous composition of a labile therapeutic protein comprising: between about 100 mM and about 200 mM of an alkali metal chloride salt; a stabilizing agent; and a pH between about 5.5 and about 7.0.

In a specific embodiment of the compositions provided above, the labile therapeutic protein is a human or humanized protein.

In a specific embodiment of the compositions provided above, the protein is a recombinant protein.

In a specific embodiment of the compositions provided above, the protein is a plasma-derived protein.

In a specific embodiment of the compositions provided above, the protein is an immunoglobulin.

In a specific embodiment of the compositions provided above, the immunoglobulin is an IgG preparation.

In a specific embodiment of the compositions provided above, the protein concentration of the IgG preparation is at least about 100 mg/mg.

In a specific embodiment of the compositions provided above, the protein concentration of the IgG preparation is at least about 200 mg/mL.

In a specific embodiment of the compositions provided above, the immunoglobulin is a recombinant antibody.

In a specific embodiment of the compositions provided above, the composition is stable for at least 6 months when stored at between about 38° C. and about 42° C.

In a specific embodiment of the compositions provided above, the composition is stable for at least 1 year when stored at between about 28° C. and about 32° C.

In a specific embodiment of the compositions provided above, the pH of the composition is between about 5.5 and about 6.5.

In a specific embodiment of the compositions provided above, the protein is a coagulation factor.

In a specific embodiment of the compositions provided above, the coagulation factor is Factor VIII.

In a specific embodiment of the compositions provided above, the pH of the composition is between about 6.0 and about 7.0.

In a specific embodiment of the compositions provided above, the pH of the composition is 6.5±0.2.

In a specific embodiment of the compositions provided above, the composition retains at least 80% of its Factor VIII activity when stored at a temperature between about 2° C. and about 8° C. for at least 3 months.

In a specific embodiment of the compositions provided above, the coagulation factor is Factor VII.

In a specific embodiment of the compositions provided above, the coagulation factor is Factor IX.

In a specific embodiment of the compositions provided above, the coagulation factor is von Willebrand Factor (vWF).

In a specific embodiment of the compositions provided above, the coagulation factor is a protein K-dependent coagulation complex.

In a specific embodiment of the compositions provided above, the protein K-dependent coagulation complex comprises the coagulation factors Factor II, Factor IX, and Factor X.

In a specific embodiment of the compositions provided above, the protein K-dependent coagulation complex further comprises Factor VII.

In a specific embodiment of the compositions provided above, the labile protein is stable for less than 3 months in an aqueous formulation containing less than about 50 mM of an alkali metal chloride salt at a pH between about 5.5 and about 7.5.

In a specific embodiment of the compositions provided above, the labile protein is stable for less than 2 months in an aqueous formulation containing less than about 50 mM of an alkali metal chloride salt at a pH between about 5.5 and about 7.5.

In a specific embodiment of the compositions provided above, the labile protein is stable for less than 1 month in an aqueous formulation containing less than about 50 mM of an alkali metal chloride salt at a pH between about 5.5 and about 7.5.

In a specific embodiment of the compositions provided above, the labile protein is stable for less than 2 weeks in an aqueous formulation containing less than about 50 mM of an alkali metal chloride salt at a pH between about 5.5 and about 7.5.

In a specific embodiment of the compositions provided above, the concentration of the labile therapeutic protein is at least about 50 mg/mL.

In a specific embodiment of the compositions provided above, the concentration of the labile therapeutic protein is at least about 100 mg/mL.

In a specific embodiment of the compositions provided above, the concentration of the labile therapeutic protein is at least about 150 mg/mL.

In a specific embodiment of the compositions provided above, the composition is formulated for subcutaneous or intramuscular administration.

In a specific embodiment of the compositions provided above, the alkali metal chloride salt is sodium chloride.

In a specific embodiment of the compositions provided above, the stabilizing agent is an amino acid.

In a specific embodiment of the compositions provided above, the amino acid is glycine.

In a specific embodiment of the compositions provided above, the concentration of the amino acid is at least about 100 mM.

In a specific embodiment of the compositions provided above, the composition is stable for at least about 3 months.

In a specific embodiment of the compositions provided above, the composition is stable for at least about 6 months.

In a specific embodiment of the compositions provided above, the composition is stable for at least about 1 year.

In a specific embodiment of the compositions provided above, the composition is stable for at least about 2 years.

In one embodiment, the present invention provides a method for stabilizing a aqueous formulation of a labile therapeutic protein at a pH between about 5.5 and about 7.5, the method comprising addition of an alkali metal chloride salt at a concentration of between about 75 mM and about 200 mM.

In one embodiment, the present invention provides a method for stabilizing a aqueous formulation of a labile therapeutic protein at a pH between about 5.5 and about 7.0, the method comprising addition of an alkali metal chloride salt at a concentration of between about 100 mM and about 200 mM.

In a specific embodiment of the methods provided above, the solution further comprises a stabilizing agent.

In a specific embodiment of the methods provided above, the labile therapeutic protein is a human or humanized protein.

In a specific embodiment of the methods provided above, the protein is a recombinant protein.

In a specific embodiment of the methods provided above, the protein is a plasma-derived protein.

In a specific embodiment of the methods provided above, the protein is an immunoglobulin.

In a specific embodiment of the methods provided above, the immunoglobulin is an IgG preparation.

In a specific embodiment of the methods provided above, the protein concentration of the IgG preparation is at least about 150 mg/mg.

In a specific embodiment of the methods provided above, the protein concentration of the IgG preparation is at least about 200 mg/mg.

In a specific embodiment of the methods provided above, the immunoglobulin is a recombinant antibody.

In a specific embodiment of the methods provided above, the method stabilizes the immunoglobulin composition for at least 6 months when stored at between about 38° C. and about 42° C.

In a specific embodiment of the methods provided above, the method stabilizes the immunoglobulin composition for at least 1 year when stored at between about 28° C. and about 32° C.

In a specific embodiment of the methods provided above, the pH of the composition is between about 5.5 and about 6.5.

In a specific embodiment of the methods provided above, the protein is a coagulation protein.

In a specific embodiment of the methods provided above, the coagulation protein is Factor VIII.

In a specific embodiment of the methods provided above, the pH of the composition is between about 6.0 and about 7.0.

In a specific embodiment of the methods provided above, the pH of the composition is 6.5±0.2.

In a specific embodiment of the methods provided above, the method stabilizes the composition such that at least 80% of the Factor VIII activity is retained after storage at a temperature between about 2° C. and about 8° C. for at least 3 months.

In a specific embodiment of the methods provided above, the coagulation protein is Factor VII.

In a specific embodiment of the methods provided above, the coagulation protein is Factor IX.

In a specific embodiment of the methods provided above, the coagulation protein is von Willebrand Factor (vWF).

In a specific embodiment of the methods provided above, the coagulation protein is a protein K-dependent coagulation complex.

In a specific embodiment of the methods provided above, the protein K-dependent coagulation complex comprises the coagulation factors Factor II, Factor IX, and Factor X.

In a specific embodiment of the methods provided above, the protein K-dependent coagulation complex further comprises Factor VII.

In a specific embodiment of the methods provided above, the labile protein is stable for less than 3 months in an aqueous formulation containing less than about 50 mM of an alkali metal chloride salt at a pH between about 5.5 and about 7.5.

In a specific embodiment of the methods provided above, the labile protein is stable for less than 2 months in an aqueous formulation containing less than about 50 mM of an alkali metal chloride salt at a pH between about 5.5 and about 7.5.

In a specific embodiment of the methods provided above, the labile protein is stable for less than 1 month in an aqueous formulation containing less than about 50 mM of an alkali metal chloride salt at a pH between about 5.5 and about 7.5.

In a specific embodiment of the methods provided above, the labile protein is stable for less than 2 weeks in an aqueous formulation containing less than about 50 mM of an alkali metal chloride salt at a pH between about 5.5 and about 7.5.

In a specific embodiment of the methods provided above, the concentration of the labile therapeutic protein is at least about 50 mg/mL.

In a specific embodiment of the methods provided above, the concentration of the labile therapeutic protein is at least about 100 mg/mL.

In a specific embodiment of the methods provided above, the concentration of the labile therapeutic protein is at least about 150 mg/mL.

In a specific embodiment of the methods provided above, the composition is formulated for subcutaneous or intramuscular administration.

In a specific embodiment of the methods provided above, the alkali metal chloride salt is sodium chloride.

In a specific embodiment of the methods provided above, the stabilizing agent is an amino acid.

In a specific embodiment of the methods provided above, the amino acid is glycine.

In a specific embodiment of the methods provided above, the concentration of the amino acid is at least about 100 mM.

In a specific embodiment of the methods provided above; the method increases the time of stability for the composition by at least 25%.

In a specific embodiment of the methods provided above, the method increases the time of stability for the composition by at least 50%.

In a specific embodiment of the methods provided above, the method increases the time of stability for the composition by at least 100%.

In a specific embodiment of the methods provided above, the method increases the time of stability for the composition by at least 200%.

IV. Examples

Example 1

To determine the role pH and salt concentration have on a plasma-derived 20% IgG composition, a two year stability study was conducted. This study revealed that the inclusion of sodium chloride and/or the formulation at neutral to mildly acid pH imparted a stabilizing effect on the 20% IgG composition.

Briefly, two IgG compositions prepared from pooled plasma according to the Gammagard SD process outlined in Teschner et al. (Vox Sang. 2007 January; 92(1):42-55) were concentrated to a final protein concentration of 20%. These preparations were then divided into several samples which were differentially formulated at pHs 6.5, 7.0, or 7.5 with and without 50 mM sodium chloride. The aqueous formulations were then stored at between 28° C. and 32° C. for 24 months. After the two year incubation period, the molecular size distributions of the IgG in the various formulations were investigated by high performance size exclusion chromatography (HP-SEC), the results of which are provided in Table 5.

TABLE 5
Molecular size distribution of 20% IgG (IGSC61 and IGSC63)
formulations after two years storage at 28° C. to 32° C.
	T	Poly-	Oligo/
Sample	(° C.)	mers	Dimers	Monomers	Fragments
IGSC61
pH 6.5	24 months	28-32	3.57	20.68	68.92	6.83
pH 7.0	24 months	28-32	10.32	19.78	60.96	8.94
pH 7.5	24 months	28-32	11.76	20.01	57.70	10.53
pH 6.5 3 g/L	24 months	28-32	3.16	20.52	69.75	6.57
NaCl
pH 7.0 3 g/L	24 months	28-32	9.53	19.68	61.69	9.11
NaCl
pH 7.5 3 g/L	24 months	28-32	10.26	20.25	58.97	10.53
NaCl
IGSC63
pH 6.5	24 months	28-32	2.34	20.99	68.84	7.83
pH 7.0	24 months	28-32	3.48	20.95	64.37	11.20
pH 7.5	24 months	28-32	6.00	23.23	58.39	12.39
pH 6.5 3 g/L	24 months	28-32	1.92	19.33	70.36	8.40
NaCl
pH 7.0 3 g/L	24 months	28-32	2.63	21.10	64.98	11.29
NaCl
pH 7.5 3 g/L	24 months	28-32	5.51	23.13	59.24	12.12
NaCl

The results shown in Table 5 indicate that, within the pH range of 6.5 to 7.5, increases in pH result in increased aggregation of the IgG preparation, as shown by the increasing percentage of IgG polymers in the formulations at pH 7.0 and 7.5 compared to the formulations at pH 6.5. Inclusion of 50 mM sodium chloride in each formulation stabilizes the lower molecular weight IgG species, resulting in a nearly 14% reduction in the level of IgG polymers in the samples. This is in contrast to IgG compositions formulated as low pH (4.4 to 4.9), which are destabilized by the addition of sodium chloride.

Example 2

To further characterize the stabilizing effect that sodium chloride has on IgG compositions formulated at mildly acid to neutral pH, an accelerated stability study was performed. For the accelerated study, elevated temperatures (38° C. to 42° C.) were used to simulate longer time periods at room temperature (20° C. to 25° C.). Briefly, a 20% IgG composition, prepared as in Example 1, was divided into samples that were formulated with increasing salt concentrations (0 mM, 50 mM, 100 mM, and 150 mM) at mildly acid to neutral pHs (pH 5.5, 6.0, 6.5, 7.0, and 7.5). The aqueous formulations were then stored at between 38° C. and 42° C. for 6 months. After the 6 month incubation period, the molecular size distributions of the IgG in the various formulations were investigated by high performance size exclusion chromatography (HP-SEC). The percentage of IgG aggregates present in the various formulations is shown in FIG. 1.

As seen in FIG. 1, the stability of the immunoglobulin preparation is dependent upon both the pH and the salt concentration of the formulation. Addition of 100 mM or 150 mM sodium chloride in the formulation provided additional stability, as compared to the protective effects seen for 50 mM sodium chloride in Example 1, at pHs between 6.0 and 7.5. Significantly, inclusion of 150 mM sodium chloride in of IgG compositions formulates at pHs between 6.0 and 7.5 reduced IgG aggregation by more than 50% on average. Optimal stabilization was seen in formulations containing 150 mM sodium chloride at pH 6.5, in which aggregate formation was reduced more than 50% as compared to formulations with 50 mM sodium chloride and about 60% as compared to formulations with no sodium chloride. Consistent with previous observations, the addition of sodium chloride in IgG formulations at lower pH (5.5) results in a destabilizing effect.

Example 3

To evaluate the stabilizing effects of sodium chloride on other immunoglobulin preparations formulated at mildly acidic to neutral pH, preparations of Partobulin® NG (Baxter Biosciences) and Tetabulin® NG (Baxter Biosciences) were formulated accordingly and tested for stability, via aggregation formation, and activity, via anti-antigen potency, over a 6 month time frame. Partobulin® is a plasma-derived human anti-D antigen immunoglobulin preparation used for antenatal anti-D prophylaxis in Rh(D) negative pregnant women carrying Rh(D) positive fetuses, as well as for the treatment of Rh(D) negative persons after incompatible transfusions of Rh(D) positive blood or erythrocyte concentrate. Tetabulin® is a plasma-derived human tetanus immunoglobulin used for post-tetanus exposure prophylaxis and therapy of clinically manifest tetanus. Both Partobulin® and Tetabulin® are typically formulated at between 100 g/L and 170 g/L human protein (of which at least 90% are immunoglobulin G) for intramuscular administration.

Briefly, feasibility lots of Partobulin® NG and Tetabulin® NG were stored at low pH for one year at 2° C. to 8° C. prior to the addition of sodium chloride to 150 mM and adjustment of the pH to between 5.5 and 7.5. Prior to the formulation with sodium chloride and pH adjustment, the bulk was formulated at pH 4.7 in the presence of 250 mM glycine like for GGL/KIOVIG. The stability of the formulations at 28° C. to 32° C. was then tracked for 6 months by periodically monitoring the Tetanus anti-toxin or Anti-D titers as well as the molecular size distributions of the formulations.

Aggregate formation over the course of 6 months for Tetabulin® NG and Partobulin® NG are shown in FIGS. 2 and 3, respectively. Strikingly, no additional immunoglobulin aggregation occurred over the entire six months for either preparation formulated at pH 5.5 or 6.0 with 150 mM NaCl. Similarly, only slight aggregation was seen beginning at six months for both compositions at pH 6.5. In comparison, significant aggregation occurred within three months of storage at 28° C. to 32° C. for both Tetabulin® NG and Partobulin® NG formulated at pH 7.0 and 7.5. After six months of storage, both the Tetabulin® NG and Partobulin® NG formulations at pH 7.0 contained twice the starting amount of aggregates and both formulations at pH 7.5 contained about three times more immunoglobulin aggregates than at the start of the storage period.

Despite the increased aggregation seen in the Tetabulin® NG formulations at pH 7.0 and 7.5, no significant loss in Tetanus anti-toxin titer was found over the course of the six month storage period (FIG. 4). Conversely, a 25% to 40% drop in anti-D titer was observed over the six month storage period over the entire pH range (FIG. 5). However, the loss of anti-D titer was reduced at pH 5.5 and 6.0.

Example 4

To determine if the stabilizing effect of sodium chloride at mildly acidic to neutral pH was specific to plasma-derived immunoglobulin preparations or broadly applicable to all immunoglobulin products, the stability of a recombinant anti-MIF antibody was determined in an accelerated stability assay. Briefly, samples of bulk recombinant anti-MIF antibody at 120 g/L were formulated with 150 mM sodium chloride and 0.25 M glycine at pH 4.5, 5.6, 6.5, and 7.3 and stored at between 38° C. and 42° C. for three months.

The molecular size distributions of the IgG in the various formulations were determined by high performance size exclusion chromatography (HPLC-SEC) at the start of the storage period, after two weeks, 1 month, and 3 months of storage. The results of these characterizations are provided in Table 6.

TABLE 6
Molecular size distribution in Anti-MIF formulations during storage at 38° C. to 42° C.
				Oligo-/
Formulation	Sample	T ° C.	Aggregates	Dimers	Monomers	Fragments
No NaCl	pH	Bulk		2-8	<0.1%	3.7%	96.1%	0.2%
	5.99
150 mM NaCl	pH 4.5	1F	Start	2-8	<0.1%	4.1%	95.6%	0.2%
	pH 5.6	2F	Start	2-8	<0.1%	3.8%	96.1%	0.1%
	pH 6.5	3F	Start	2-8	<0.1%	3.8%	96.0%	0.2%
	pH 7.3	4F	Start	2-8	<0.1%	3.8%	96.0%	0.2%
150 mM NaCl	pH 4.5	1F	2 Weeks	38-42	0.3%	5.4%	91.4%	3.0%
	pH 5.6	2F	2 Weeks	38-42	0.1%	5.5%	93.6%	0.9%
	pH 6.5	3F	2 Weeks	38-42	0.3%	6.2%	93.0%	0.5%
	pH 7.3	4F	2 Weeks	38-42	0.4%	7.7%	91.3%	0.6%
150 mM NaCl	pH 4.5	1F	1 Month	38-42	0.1%	5.4%	90.0%	4.5%
	pH 5.6	2F	1 Month	38-42	0.1%	7.0%	91.3%	1.7%
	pH 6.5	3F	1 Month	38-42	0.4%	8.4%	90.2%	1.0%
	pH 7.3	4F	1 Month	38-42	0.7%	12.2%	85.9%	1.2%
150 mM NaCl	pH 4.5	1F	3 Months	38-42	0.3%	7.9%	83.7%	8.0%
	pH 5.6	2F	3 Months	38-42	0.3%	13.4%	84.1%	2.2%
	pH 6.5	3F	3 Months	38-42	1.5%	14.6%	81.7%	2.2%
	pH 7.3	4F	3 Months	38-42	4.3%	24.0%	69.6%	2.0%

As seen in Table 6, fragmentation of the recombinant anti-MIF antibody is most pronounced at acidic pH (pH 4.5), even after only 2 weeks storage. Likewise, as seen for the concentrated IgG preparation in Example 1 and Tetabulin® and Partobulin® formulations in Example 3, sodium chloride reduced aggregation of the recombinant anti-MIF antibodies at mildly acid conditions (pH 5.6 and 6.5), while aggregation occurred more quickly at neutral pH (pH 7.5).

To further characterize the stabilizing effects of sodium chloride in these formulations, anti-MIF titers were determined by ELISA for each formulation at the start of the storage period, and after 2 weeks, 1 month, and 3 months of storage at elevated temperatures (38° C. to 42° C.). As seen in FIG. 6, despite low aggregation rates for the recombinant anti-MIF antibodies formulated at acid pH (pH 4.5), the Anti-MIF titer of this formulation dropped by 40% to 50% over the three month storage. Similarly, the Anti-MIF titer of the antibody preparation formulated at neutral pH (pH 7.3) was reduced by at least 20% over three months. However, the antibody preparations formulated at mildly acidic pH (pH 5.6 and 6.5) lost only about 10% of their starting Anti-MIF titer over the three month storage at elevated temperatures.

Example 5

Factor VIII, a coagulation factor, is a highly labile therapeutic protein that is commonly formulated as a lyophilized powder that must be reconstituted prior to administration. In order to determine if the addition of sodium chloride can also stabilize non-immunoglobulin labile protein formulations at mildly acidic to neutral pH, stability tests were performed on recombinant Factor VIII formulations. Briefly, frozen recombinant Factor VIII was slowly thawed and formulated by buffer exchange according to the reconstituted formulation for ADVATE (recombinant FVIII; Baxter Healthcare Corporation, Westlake Village, Calif.), given in Table 7. Samples of the FVIII preparation were then aliquoted and the pH adjusted to pH 5.5, 6.0, 6.5, 7.0, 7.5, or 8.0 with and without addition of 150 mM sodium chloride to give formulations with a starting Factor VIII activity in solution of 500 IU/mL. The samples were stored at 2° C. to 8° C. for 12 weeks, during which time the residual FVIII activity was periodically monitored.

In the absence of sodium chloride in the formulation, a continuous drop in FVIII activity was seen for all formulation (FIG. 7), with the most pronounced loss of activity seen at the extremes of the investigated pH range. Strikingly, all of the rFVIII samples except for the formulation at pH 6.5 lost at least 20% of their starting activity within four weeks. Furthermore, most of the samples lost at least 40% of their starting FVIII activity within 9 weeks and at least 60% of their FVIII activity within 12 weeks. The notable exception to this was the sample formulated at pH 6.0, which appears to be a statistical outlier. It was also noticed that all of the formulations lacking sodium chloride became turbid within two weeks of storage at 2° C. to 8° C.

Conversely, addition of sodium chloride in the rFVIII formulations resulted in a marked increase in the stability of FVIII activity at pH above 6.0 (FIG. 8). Surprisingly, at pH 6.5 and 7.0, the addition of 150 mM sodium chloride leads to a aqueous formulation in which FVIII activity is stable at 2° C. to 8° C. for at least 12 weeks. At the lower end of the investigated pH range (pH 5.5) addition of sodium chloride showed no stabilizing effect of the Factor VIII activity. Notably, the FVIII formulations at pH 6.5 and 7.0 remained clear for at least three weeks, while all other formulations became turbid in this same time period. Notably, these samples showed only slight turbidity over the entire course of the storage period.

TABLE 7
Reconstituted formulation for ADVATE ®.
ADVATE ® Formulation
38	g/L	mannitol
10	g/L	trehalose
108	mEq/L	sodium
12	mM	histidine
12	mM	Tris
1.9	mM	calcium
0.15	g/L	polysorbate-80
0.10	g/L	glutathione

Example 6

The effect sodium chloride has on the stability of an IgG composition formulated at acidic pH (4.4 to 4.9) was investigated. Briefly, an IgG composition was formulated with 0.25 M glycine, pH 4.4 to 4.9, at a final protein concentration of 10%. Sodium chloride was then added to aliquots of the formulation to a final concentration of 0 mM, 10 mM, 50 mM, or 100 mM. The molecular size distribution was then monitored by HPLC analysis after 1, 3, 6, 9, 12, 19, and 24 months of storage under refrigerated conditions (between 2° C. and 8° C.). The fixation of complement in the samples was also measured to determine the tolerability of the formulation. The results of the analysis are given in Table 8.

As can be seen in Table 8, Storage of the 10% IgG preparation at between 2° C. and 8° C., with different amounts of sodium chloride added, revealed that the presence of sodium chloride seriously impacts the ACA value and therefore the tolerability of the product, as well as the oligo/dimmer content of the samples. Compared to the final container without sodium chloride, which meets the required specifications for the product over the entire storage time, a content of 10 mM sodium chloride is sufficient to reduce the storage period to 19 months, a content of 50 mM to 12 months and a concentration of 100 mM to 9 months.

TABLE 8
Influence of sodium chloride content on the stability of
a 10% IgG preparation stored under refrigeration.
	HPLC	ACA-Titer
	Aggregates	Oligo/Dimers	Monomers	Fragments	CH50 U/cons.
No NaCl. 10% Protein. pH 4.7/0.25M Glycine
prior incubation	0.41	6.83	92.76	0.00	20.3%
after incubation	0.43	7.52	91.92	0.15	36.2%
1 month +2 to +8° C.	0.22	7.28	92.28	0.22	41.2%
3 months +2 to +8° C.	0.55	11.88	87.37	0.19	31.6%
6 months +2 to +8° C.	0.38	9.19	90.08	0.35	44.0%
9 months +2 to +8° C.	0.30	7.55	91.98	0.18	33.7%
12 months +2 to +8° C.	0.62	7.50	91.54	0.34	42.5%
19 months +2 to +8° C.	0.74	12.43	86.55	0.28	46.2%
24 months +2 to +8° C.	0.59	8.76	90.53	0.11	46.9%
10 mM NaCl. 10% Protein. pH 4.7/0.25M Glycine
prior incubation	0.32	7.13	92.55	0.00	25.7%
after incubation	0.35	8.08	91.39	0.17	47.7%
1 month +2 to +8° C.	0.25	9.79	89.76	0.21	46.8%
3 months +2 to +8° C.	0.53	12.52	86.72	0.23	35.0%
6 months +2 to +8° C.	0.44	11.13	88.26	0.18	42.9%
9 months +2 to +8° C.	0.36	8.22	91.12	0.29	40.6%
12 months +2 to +8° C.	0.63	10.57	88.65	0.15	48.0%
19 months +2 to +8° C.	0.86	13.32	85.59	0.23	49.0%
24 months +2 to +8° C.	0.88	9.15	89.96	0.00	50.5%
50 mM NaCl. 10% Protein. pH 4.7/0.25M Glycine
prior incubation	0.25	7.46	92.29	0.00	38.2%
after incubation	0.30	9.30	90.19	0.21	57.0%
1 month +2 to +8° C.	0.29	10.47	89.02	0.22	58.3%
3 months +2 to +8° C.	0.58	13.61	85.57	0.23	35.8%
6 months +2 to +8° C.	0.49	11.82	87.39	0.33	47.7%
9 months +2 to +8° C.	0.46	11.21	88.07	0.26	43.6%
12 months +2 to +8° C.	0.58	11.36	87.86	0.20	45.9%
19 months +2 to +8° C.	0.89	14.36	84.58	0.17	58.7%
24 months +2 to +8° C.	0.80	11.16	88.04	0.00	67.9%
100 mM NaCl. 10% Protein. pH 4.7/0.25M Glycine
prior incubation	0.24	7.41	92.34	0.00	43.9%
after incubation	0.29	9.72	89.88	0.11	59.7%
1 month +2 to +8° C.	0.31	10.92	88.63	0.14	54.5%
3 months +2 to +8° C.	0.64	13.40	85.81	0.15	45.9%
6 months +2 to +8° C.	0.50	11.96	87.31	0.24	41.1%
9 months +2 to +8° C.	0.46	11.15	88.17	0.22	48.2%
12 months +2 to +8° C.	0.59	11.88	87.36	0.17	51.8%
19 months +2 to +8° C.	0.91	14.26	84.49	0.35	68.4%
24 months +2 to +8° C.	0.80	11.30	87.89	0.00	73.8%

To confirm the negative effect sodium chloride has on the stability of immunoglobulin compositions formulated at acidic pH, the experiment was repeated with storage at room temperature (28° C. to 30° C.). As can be seen in Table 9, the results of the second experiment confirm the data obtained for storage between 2° C. and 8° C. The ACA values are generally lower, while the fragmentation and aggregation is accelerated. The negative effect of the addition of sodium chloride at acidic pH is confirmed with this experiment.

TABLE 9
Influence of sodium chloride content on the stability of a
10% IgG preparation stored at room temperature.
	HPLC	ACA-Titer
	Aggregates	Oligo/Dimers	Monomers	Fragments	C′H50 U/cons.
No NaCl. 10% Protein. pH 4.7/0.25M Glycine
prior incubation	0.41	6.83	92.76	0.00	20.3%
after incubation	0.43	7.52	91.92	0.15	36.2%
1 month +28 to +30° C.	0.24	6.68	92.8	0.27	37.5%
3 months +28 to +30° C.	0.65	9.92	88.92	0.50	29.8%
6 months +28 to +30° C.	0.48	8.06	90.39	1.08	37.8%
9 months +28 to +30° C.	0.59	8.07	90.15	1.19	28.7%
12 months +28 to +30° C.	1.18	8.59	88.69	1.54	32.4%
19 months +28 to +30° C.	1.83	12.63	83.28	2.26	35.9%
24 months +28 to +30° C.	2.32	11.41	83.98	2.29	36.2%
10 mM NaCl. 10% Protein. pH 4.7/0.25M Glycine
prior incubation	0.32	7.13	92.55	0.00	25.7%
after incubation	0.35	8.08	91.39	0.17	47.7%
1 month +28 to +30° C.	0.24	7.59	91.81	0.37	42.5%
3 months +28 to +30° C.	0.56	10.50	88.47	0.46	34.2%
6 months +28 to +30° C.	0.48	9.33	89.16	1.03	37.8%
9 months +28 to +30° C.	0.61	9.01	89.33	1.05	39.3%
12 months +28 to +30° C.	0.98	10.47	87.04	1.51	39.7%
19 months +28 to +30° C.	1.86	13.06	83.11	1.98	44.4%
24 months +28 to +30° C.	2.43	12.78	82.40	2.39	37.8%
50 mM NaCl. 10% Protein. pH 4.7/0.25M Glycine
prior incubation	0.25	7.46	92.29	0.00	38.2%
after incubation	0.30	9.30	90.19	0.21	57.0%
1 month +28 to +30° C.	0.27	9.98	89.50	0.26	45.1%
3 months +28 to +30° C.	0.48	11.38	87.63	0.51	36.1%
6 months +28 to +30° C.	0.61	10.54	87.98	0.87	44.0%
9 months +28 to +30° C.	0.78	97.4	88.32	1.17	46.7%
12 months +28 to +30° C.	1.12	11.39	86.15	1.34	51.8%
19 months +28 to +30° C.	1.93	13.20	82.33	2.53	58.3%
24 months +28 to +30° C.	2.79	12.94	81.78	2.49	50.5%
1000 mM NaCl. 10% Protein. pH 4.7/0.25M Glycine
prior incubation	0.24	7.41	92.34	0.00	43.9%
after incubation	0.29	9.72	89.88	0.11	59.7%
1 month +28 to +30° C.	0.31	10.45	88.86	0.38	50.0%
3 months +28 to +30° C.	0.52	11.47	87.51	0.50	35.0%
6 months +28 to +30° C.	0.64	10.73	87.66	0.96	47.2%
9 months +28 to +30° C.	0.77	9.54	88.54	1.15	56.1%
12 months +28 to +30° C.	1.10	11.22	88.26	1.43	58.9%
19 months +28 to +30° C.	1.71	12.79	83.02	2.47	64.8%
24 months +28 to +30° C.	2.30	12.63	82.48	2.60	60.8%

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A storage stable, aqueous composition of a labile therapeutic protein comprising:

(a) a labile therapeutic protein;

(b) from 75 mM to 200 mM of an alkali metal chloride salt;

(c) an amino acid; and

(d) a pH of from 5.5 to 7.5.

2. The composition of claim 1, comprising from 100 mM to 200 mM of an alkali metal chloride salt.

3. The composition of claim 2, comprising from 125 mM to 175 mM of an alkali metal chloride salt.

4. The composition of claim 3, comprising 150±15 mM an alkali metal chloride salt.

5. The composition of claim 1, wherein the alkali metal chloride salt is sodium chloride.

6. The composition of claim 1, therein the alkali metal chloride salt is potassium chloride.

7. The composition of claim 1, wherein the amino acid is selected from the group consisting of glycine, proline, and histidine.

8. The composition of claim 7, wherein the amino acid is glycine.

9. The composition of claim 7, wherein the amino acid is proline.

10. The composition of claim 7, wherein the amino acid is histidine.

11. The composition of claim 1, wherein the concentration of the amino acid is from 50 mM to 500 mM.

12. The composition of claim 11, wherein the concentration of the amino acid is from 100 mM to 400 mM.

13. The composition of claim 11, wherein the concentration of the amino acid is from 150 mM to 350 mM.

14. The composition of claim 11, wherein the concentration of the amino acid is from 200 mM to 300 mM.

15. The composition of claim 11, wherein the concentration of the amino acid is from 225 mM to 275 mM.

16. The composition of claim 11, wherein the concentration of the amino acid is 250±10 mM.

17. The composition of claim 1, wherein the pH of the composition is from 5.5 to 7.0.

18. The composition of claim 1, wherein the pH of the composition is from 5.5 to 6.5.

19. The composition of claim 1, wherein the pH of the composition is from 5.5 to 6.0.

20. The composition of claim 1, wherein the pH of the composition is from 6.0 to 7.5.

21. The composition of claim 1, wherein the pH of the composition is from 6.0 to 7.0.

22. The composition of claim 1, wherein the pH of the composition is from 6.0 to 6.5.

23. The composition of claim 1, wherein the pH of the composition is from 6.5 to 7.5.

24. The composition of claim 1, wherein the pH of the composition is from 6.5 to 7.0.

25. The composition of claim 1, wherein the pH of the composition is from 7.0 to 7.5.

26. The composition of claim 1, wherein the labile therapeutic protein is a human or humanized protein.

27. The composition of claim 1, wherein the labile therapeutic protein is an immunoglobulin.

28. The composition of claim 27, wherein the immunoglobulin is an IgG immunoglobulin.

29. The composition of claim 27, wherein the immunoglobulin is a polyclonal immunoglobulin.

30. The composition of claim 27, wherein the immunoglobulin is a monoclonal immunoglobulin.

31. The composition of claim 27, wherein the immunoglobulin is a recombinant immunoglobulin.

32. The composition of claim 27, wherein the immunoglobulin is enriched from pooled human plasma.

33. The composition of claim 27, wherein the concentration of the immunoglobulin is 50±5 g/L.

34. The composition of claim 27, wherein the concentration of the immunoglobulin is less than 50 g/L.

35. The composition of claim 27, wherein the concentration of the immunoglobulin is at least 50 g/L.

36. The composition of claim 35, wherein the concentration of the immunoglobulin is from 50 g/L to 150 g/L.

37. The composition of claim 36, wherein the concentration of the immunoglobulin is 100±10 g/L.

38. The composition of claim 35, wherein the concentration of the immunoglobulin is at least 100 g/L.

39. The composition of claim 38, wherein the concentration of the immunoglobulin is 150±15/L.

40. The composition of claim 35, wherein the concentration of the immunoglobulin is from 150 g/L to 250 g/L.

41. The composition of claim 40, wherein the concentration of the immunoglobulin is 200±20 g/L.

42. The composition of claim 35, wherein the concentration of the immunoglobulin is at least 200 g/L.

43. The composition of claim 27, wherein at least 95% of the protein in the composition is immunoglobulin.

44. The composition of claim 43, wherein at least 95% of the protein in the composition is IgG immunoglobulin.

45. The composition of claim 44, wherein at least 98% of the protein in the composition is IgG immunoglobulin.

46. The composition of claim 27, wherein the composition is stable for at least 6 months when stored at between 28° C. and 32° C.

47. The composition of claim 46, wherein the composition is stable for at least 1 year when stored at between 28° C. and 32° C.

48. The composition of claim 46, wherein the composition is stable for at least 2 year when stored at between 28° C. and 32° C.

49. The composition of claim 27, wherein the composition is stable for at least 1 month when stored at between 38° C. and 42° C.

50. The composition of claim 49, wherein the composition is stable for at least 3 months when stored at between 38° C. and 42° C.

51. The composition of claim 49, wherein the composition is stable for at least 6 months when stored at between 38° C. and 42° C.

52. The composition of claim 27, wherein the composition is stable for at least 1 year when stored at between 28° C. and 32° C.

53. The composition of claim 46, wherein the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is between 0% and 5%.

54. The composition of claim 53, wherein the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is between 0% and 2%.

55. The composition of claim 46, wherein the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is from 0% to 5% and the percentage of immunoglobulin in the monomeric state is from 80% to 100%.

56. The composition of claim 55, wherein the composition is considered stable as long as the percentage of immunoglobulin in the aggregated state is from 0% to 2% and the percentage of immunoglobulin in the monomeric state is from 85% to 100%.

57. The composition of claim 1, wherein the labile therapeutic protein is a coagulation factor.

58. The composition of claim 57, wherein the coagulation factor is selected from the group consisting of Factor VII, Factor VIII, Factor IX, a protein K-dependent coagulation complexand, and von Willebrand Factor (vWF).

59. The composition of claim 57, wherein the coagulation factor is Factor VIII.

60. The composition of claim 59, wherein the pH of the composition is between 6.0 and 7.0.

61. The composition of claim 60, wherein the pH of the composition is 6.5±0.2.

62. The composition of claim 27, wherein the composition retains at least 80% of its Factor VIII activity when stored at a temperature between 2° C. and 8° C. for at least 1 month.

63. The composition of claim 1, wherein the labile protein is stable for less than 3 months in an aqueous formulation containing:

(a) from 0 mM to 50 mM of an alkali metal chloride salt;

(b) an amino acid; and

(c) a pH of from 5.5 to 7.

64. The composition of claim 1, wherein the composition is formulated for subcutaneous and/or intramuscular administration.

65. A method for stabilizing an aqueous composition of a labile therapeutic protein, the method comprising formulating the composition at a pH between 5.5 and 7.0, wherein the formulated composition comprises:

(a) a labile therapeutic protein;

(b) from 75 mM to 200 mM of an alkali metal chloride salt; and

(c) an amino acid.