SALTS AND POLYMORPHS OF CYCLIC BORONIC ACID ESTER DERIVATIVES AND THERAPEUTIC USES THEREOF
Disclosed herein is the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. The crystalline form maybe formulated for treating subjects with bacterial infection. Accordingly, some embodiments relate to compositions and methods of administering the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
Field of the Invention
The present invention relates to salts and polymorphs of cyclic boronic acid ester derivatives, compositions, their use and preparation as therapeutic agents for treating bacterial infection. In particular, the present invention relates to a potassium salt of 2-((3R,6S)-2-hydroxy-3 -(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
Description of the Related Art
Antibiotics have been effective tools in the treatment of infectious diseases during the last half-century. From the development of antibiotic therapy to the late 1980s there was almost complete control over bacterial infections in developed countries. However, in response to the pressure of antibiotic usage, multiple resistance mechanisms have become widespread and are threatening the clinical utility of anti-bacterial therapy. The increase in antibiotic resistant strains has been particularly common in major hospitals and care centers. The consequences of the increase in resistant strains include higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs
Various bacteria have evolved β-lactam deactivating enzymes, namely, β-lactamases, that counter the efficacy of the various β-lactams. β-lactamases can be grouped into 4 classes based on their amino acid sequences, namely, Ambler classes A, B, C, and D. Enzymes in classes A, C, and D include active-site serine β-lactamases, and class B enzymes, which are encountered less frequently, are Zn-dependent. These enzymes catalyze the chemical degradation of β-lactam antibiotics, rendering them inactive. Some β-lactamases can be transferred within and between various bacterial strains and species. The rapid spread of bacterial resistance and the evolution of multi-resistant strains severely limits β-lactam treatment options available.
The increase of class D β-lactamase-expressing bacterium strains such as Acinetobacter baumannii has become an emerging multidrug-resistant threat. A. baumannii strains express A, C, and D class β-lactamases. The class D β-lactamases such as the OXA families are particularly effective at destroying carbapenem type β-lactam antibiotics, e.g., imipenem, the active carbapenems component of Merck's Primaxin® (Montefour, K.; et al. Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert Rev. Anti Infect. Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J. Antimicrob. Agents Chemother. 2000, 40, 428. 2006, 50, 2280; Bou, G. et al, J. Antimicrob. Agents Chemother. 2000, 44, 1556). This has imposed a pressing threat to the effective use of drugs in that category to treat and prevent bacterial infections. Indeed the number of catalogued serine-based β-lactamases has exploded from less than ten in the 1970s to over 300 variants. These issues fostered the development of five “generations” of cephalosporins. When initially released into clinical practice, extended-spectrum cephalosporins resisted hydrolysis by the prevalent class A β-lactamases, TEM-1 and SHV-1. However, the development of resistant strains by the evolution of single amino acid substitutions in TEM-1 and SHV-1 resulted in the emergence of the extended-spectrum β-lactamase (ESBL) phenotype.
New β-lactamases have recently evolved that hydrolyze the carbapenem class of antimicrobials, including imipenem, biapenem, doripenem, meropenem, and ertapenem, as well as other β-lactam antibiotics. These carbapenemases belong to molecular classes A, B, and D. Class A carbapenemases of the KPC-type predominantly in Klebsiella pneumoniae but now also reported in other Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. The KPC carbapenemase was first described in 1996 in North Carolina, but since then has disseminated widely in the US. It has been particularly problematic in the New York City area, where several reports of spread within major hospitals and patient morbidity have been reported. These enzymes have also been recently reported in France, Greece, Sweden, United Kingdom, and an outbreak in Germany has recently been reported. Treatment of resistant strains with carbapenems can be associated with poor outcomes.
Another mechanism of β-lactamase mediated resistance to carbapenems involves combination of permeability or efflux mechanisms combined with hyper production of beta-lactamases. One example is the loss of a porin combined in hyperproduction of ampC beta-lactamase results in resistance to imipenem in Pseudomonas aeruginosa. Efflux pump over expression combined with hyperproduction of the ampC β-lactamase can also result in resistance to a carbapenem such as meropenem.
Because there are three major molecular classes of serine-based β-lactamases, and each of these classes contains significant numbers of β-lactamase variants, inhibition of one or a small number of β-lactamases is unlikely to be of therapeutic value. Legacy β-lactamase inhibitors are largely ineffective against at least Class A carbapenemases, against the chromosomal and plasmid-mediated Class C cephalosporinases and against many of the Class D oxacillinases. Therefore, there is a need for improved β-lactamase inhibitors.
SUMMARY OF THE INVENTIONThe present invention relates to antimicrobial agents and potentiators thereof. Some embodiments include salts, polymorphs, compounds, compositions, pharmaceutical compositions, use and preparation thereof. In particular, come embodiments relate to salts and polymorphs of cyclic boronic acid ester derivatives.
Some embodiments relate to a potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
In some embodiments, the potassium salt is in a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks selected from the group consisting of peaks at approximately 7.3°, 13.9°, 16.9°, 19.1°, 20.8°, and 25.2° 2θ.
Some embodiments include a pharmaceutical composition comprising the potassium salt described herein.
Some embodiments include a pharmaceutical composition prepared by dissolving the potassium salt described herein.
Some embodiments include a method of preventing a bacterial infection, comprising administering to a subject in need thereof, a composition described herein.
Some embodiments include a sterile container, comprising any one of the foregoing composition or any one of the foregoing potassium salt.
Some embodiments include a method of preparing a pharmaceutical composition for administration, comprising reconstituting the contents of any one of the foregoing the sterile container using a pharmaceutically acceptable liquid carrier.
Some embodiments relate to a process of making a crystalline form of a potassium salt of 2-((3R,6S)-2-hydroxy-3 -(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid, comprising combining a purified 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid with a solvent to form an intermediate solution; intermixing a potassium counterion with the intermediate solution; and isolating the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
The present invention relates to salts and polymorphs of cyclic boronic acid ester derivatives and pharmaceutical compositions comprising the same. Some embodiments include uses thereof, including methods of preparation, and methods of treatment. In particular, the present invention relates to polymorphs of a salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. More specifically, the present invention relates to polymorphs of a potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
Compound 1Compound 1 as used herein refers to 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2 oxaborinan-6-yl)acetic acid as shown in the structure below.
Compound 1 can be made by known methods such as the procedures described in US 2012/0040932, which is incorporated by reference in its entirety. More specifically, the skilled artisan given the disclosure in Example 1 of US 2012/0040932 is well equipped to prepare Compound 1.
Compound 1 contains a boronic acid moiety that is chemically stable in solutions having pH values between 2 and 8. The pKa of Compound 1 is measured to be 3.92. When combined with counterions such as potassium at suitable pH, Compound 1 can be converted into a salt.
Some embodiments relate to a pharmaceutically acceptable salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. In some embodiments, the pharmaceutically acceptable salt is a potassium salt. In some embodiments, the pharmaceutically acceptable salt is a calcium salt. In some embodiments, the pharmaceutically acceptable salt is a magnesium salt.
Crystalline Form of Compound 1ACompound 1A as used herein refers to the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. Compound 1A can be made into a pure and stable crystalline form under controlled conditions. The X-ray powder diffraction (PXRD) pattern of Compound 1A is substantially the same as shown in
Compound 1A is in a crystalline form exhibiting an X-ray powder diffraction pattern that includes at least three characteristic peaks selected from the group consisting of peaks at approximately 7.3°, 13.9°, 16.9°, 19.1°, 20.8°, and 25.2° 2θ. In some embodiments, the crystalline form of Compound 1A exhibits an X-ray powder diffraction pattern comprising at least peaks at 7.3°, 13.9°, 16.9°, 19.1°, 20.8°, and 25.2° 2θ. In some embodiments, the crystalline form of Compound 1A exhibits an X-ray powder diffraction pattern comprising at least peaks at approximately 7.3°, 13.9°, 14.6°, 16.9°, 17.9°, 19.1°, 20.8°, 21.2°, 25.2°, and 25.6° 2θ.
As is well understood in the art, because of the experimental variability when X-ray diffraction patterns are measured on different instruments, the peak positions are assumed to be equal if the two theta (2θ) values agree to within 0.2° (i.e., ±0.2°). For example, the United States Pharmacopeia states that if the angular setting of the 10 strongest diffraction peaks agree to within ±0.2° with that of a reference material, and the relative intensities of the peaks do not vary by more than 20%, the identity is confirmed. Accordingly, peak positions within 0.2° of the positions recited herein are assumed to be identical.
Process of making Crystalline Form of Compound 1A
One process for making a crystalline form of Compound 1A can include combining a purified Compound 1 with a solvent to form an intermediate solution; intermixing a potassium ion with the intermediate solution; and isolating the crystalline form of Compound 1A.
The source of potassium ion can vary. In some embodiment, the potassium ion is from potassium hydroxide. In some embodiment, the potassium ion is from potassium t-butoxide.
The solvent used for salt formation can vary depending on the source of the potassium ion and reaction conditions. In some embodiment, the solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, acenitrile, acetone, ethyl acetate, methyl tert-butyl ether, water, and any combinations thereof. In some embodiment, the solvent is acetone or acenitrile. In some embodiment, the solvent is acetone. In some embodiment, the solvent is acenitrile.
Administration and Pharmaceutical CompositionsSome embodiments include pharmaceutical compositions comprising the potassium salt described herein and a pharmaceutically acceptable carrier. Such a composition can be administered to a subject as part of a therapeutic treatment.
Compound 1A described herein can be administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for disease states described herein. Suitable dosage levels may be from about 0.1 mg/kg to about 200 mg/kg or more of body weight, from about 0.25 mg/kg to about 120 mg/kg or more of body weight, from about 0.5 mg/kg or less to about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of body weight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
In some embodiments, the pharmaceutical composition described herein includes a unit dose from 0.01 mg to 10 g of the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. In some embodiments, the pharmaceutical composition described herein includes a unit dose from 0.1 mg to 5 g of the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. In some embodiments, the pharmaceutical composition described herein includes a unit dose from 0.1 mg to 2.5 g of the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. In some embodiments, the pharmaceutical composition described herein includes a unit dose from 1.5 g to 2.5 g of the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. In some embodiments, the pharmaceutical composition described herein includes a unit dose of less than 5 g, less than 4.5 g, less than 4g, less than 3.5 g, less than 3 g, less than 2.5 g of the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid. In some embodiments, the pharmaceutical composition described herein includes a unit dose more than 0.1 mg, more than 0.5 mg, more than 10 mg, more than 50 mg, more than 100 mg, more than 150 mg, more than 200 mg, more than 500 mg, more than 1 g, more than 2 g of the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.
The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference in its entirety.
In addition to the selected compound useful as described above, come embodiments include compositions containing a pharmaceutically-acceptable carrier. The term “pharmaceutically-acceptable carrier”, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances, which are suitable for administration to a mammal. The term “compatible”, as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction, which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration preferably to an animal, preferably mammal being treated.
Some examples of substances, which can serve as pharmaceutically-acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.
The compositions described herein are preferably provided in unit dosage form. As used herein, a “unit dosage form” is a composition containing an amount of a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.
The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).
Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, with a maximum of about 90%, of the compound. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art. suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
Compositions described herein may optionally include other drug actives.
Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar vein, an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.
For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.
The resulting composition may be infused into the patient over a period of time. In various embodiments, the infusion time ranges from 5 minutes to continuous infusion, from 10 minutes to 8 hours, from 30 minutes to 4 hours, and from 1 hour to 3 hours. In one embodiment, the drug is infused over a 3 hour period. The infusion may be repeated at the desired dose interval, which may include, for example, 6 hours, 8 hours, 12 hours, or 24 hours.
The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. Reconstituted concentrated solutions may be further diluted into a parenteral solutions having a volume of from about 25 to about 1000 ml, from about 30 ml to about 500 ml, or from about 50 ml to about 100 ml. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.
The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
Kits for Intravenous AdministrationSome embodiments include a sterile container having the composition described herein. Some embodiments include a sterile container having Compound 1A described herein. Some embodiments include a kit comprising a potassium salt described herein and an additional agent, such as an antimicrobial agent. In one embodiment, both components are provided in a single sterile container. In the case of solids for reconstitution, the agents may be pre-blended and added to the container simultaneously or may be dry-powder filled into the container in two separate steps. In some embodiments, an additional agent is a sterile crystalline product. In other embodiments, the additional agent is a lyophile. Non-limiting examples of agents to aid in lyophilization include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. One embodiment includes non-sterile solids that are irradiated either before or after introduction into the container.
In the case of a liquid, the agents may be dissolved or dispersed in a diluent ready for administration. In another embodiment, the solution or dispersion may be further diluted prior to administration. Some embodiments include providing the liquid in an IV bag. The liquid may be frozen to improve stability.
In one embodiment, the container includes other ingredients such as a pH adjuster, a solubilizing agent, or a dispersing agent. Non-limiting examples of pH adjusters include NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In some embodiments, the liquid carrier is a saline solution.
The molar ratio of Compound 1A described herein to additional agent (e.g., antibacterial agent) may be from about 10:1 to 1:10, 8:1 to 1:8, 5:1 to 1:5, 3:1 to 1:3, 2:1 to 1:2, or about 1:1. In various embodiments the amount of compound described herein may be from 100 mg to 5 g, 500 mg to 2 g, or about 1 g. Similarly, in various embodiments the amount of additional agent may be from 100 mg to 5 g, 500 mg to 2 g, or about 1 g.
In an alternative embodiment, the two components may be provided in separate containers. Each container may include a solid, solution, or dispersion. In such embodiments, the two containers may be provided in a single package or may be provided separately. In one embodiment, the compound or composition described herein is provided as a solution while the additional agent (e.g., antibacterial agent) is provided as a solid ready for reconstitution. In one such embodiment, the solution of the compound or composition described herein is used as the diluent to reconstitute the other agent.
In case of preparing a pharmaceutical composition for administration, the contents of the sterile container can be reconstituted using a pharmaceutically acceptable liquid carrier. In some embodiments, the liquid carrier is a saline solution. In some embodiments, the liquid carrier is a dextrose solution. In some embodiments, the method of administration, comprising administering the reconstituted solution described herein intravenously to a subject.
Methods of TreatmentSome embodiments of the present invention include methods of treating bacterial infections with the compounds and compositions described herein. Some methods include administering a compound, composition, pharmaceutical composition described herein to a subject in need thereof. In some embodiments, a subject can be an animal, e.g., a mammal, a human. In some embodiments, the bacterial infection comprises a bacteria described herein. As will be appreciated from the foregoing, methods of treating a bacterial infection include methods for preventing bacterial infection in a subject at risk thereof.
Further embodiments include administering a combination of compounds to a subject in need thereof. A combination can include a compound, composition, pharmaceutical composition described herein with an additional medicament.
Some embodiments include co-administering a compound, composition, and/or pharmaceutical composition described herein, with an additional medicament. By “co-administration,” it is meant that the two or more agents may be found in the patient's bloodstream at the same time, regardless of when or how they are actually administered. In one embodiment, the agents are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. When combining the agents in a single dosage form, they may be physically mixed (e.g., by co-dissolution or dry mixing) or may form an adduct or be covalently linked such that they split into the two or more active ingredients upon administration to the patient. In another embodiment, the agents are administered sequentially. In one embodiment the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered orally and another being administered i.v.
Examples of additional medicaments include an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent and an anti-allergic agent.
Some embodiments include co-administration of a compound, composition or pharmaceutical composition described herein with an antibacterial agent such as a β-lactam. Examples of such β-lactams include Amoxicillin, Ampicillin (e.g., Pivampicillin, Hetacillin, Bacampicillin, Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (e.g., Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin, Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Tomopenem, Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin, Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone, Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole, Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone, Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef, Cefixime, Ceftazidime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone, Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428, MC-04,546, ME1036, BAL30072, SYN 2416, Ceftiofur, Cefquinome, Cefovecin, Aztreonam, Tigemonam, Carumonam, RWJ-442831, RWJ-333441, and RWJ-333442.
Preferred embodiments include β-lactams such as Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, ME1036, Tomopenem, Razupenem, and Panipenem.
Some embodiments include co-administration of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, wherein the additional agent comprises a monobactam. Examples of monobactams include aztreonam, tigemonam, BAL 30072, SYN 2416 (BAL19764), and carumonam.
Some embodiments include co-administration of the compounds, compositions and/or pharmaceutical compositions described herein with an additional agent, wherein the additional agent comprises a Class A, B, C, or D beta-lactamase inhibitor. An example of a class B beta lactamase inhibitor includes ME1071 (Yoshikazu Ishii et al, “In Vitro Potentiation of Carbapenems with ME1071, a Novel Metallo-β-Lactamase Inhibitor, against Metallo-B-lactamase Producing Pseudomonas aeruginosa Clinical Isolates.” Antimicrob. Agents Chemother. doi:10.1128/AAC.01397-09 (July 2010)). Other examples of beta-lactamase inhibitors administered as an additional agent include clavulanic acid, tazobactam, sulbactam, avibactam (NXL-104), MK-7655, and BAL29880. MK-7655 has the following structure:
The compounds and compositions described herein can be used to treat bacterial infections. Bacterial infections that can be treated with the compounds, compositions and methods described herein can comprise a wide spectrum of bacteria. Example organisms include gram-positive bacteria, gram-negative bacteria, aerobic and anaerobic bacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms.
More examples of bacterial infections include Pseudomonas aeruginosa, Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia, Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, Salmonella typhi, Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Francisella tularensis, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia, Bordetella pertussis, Bordetella parapertussis, Bordetella bronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilus ducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamella catarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella, Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.
The following examples will further describe the present invention, and are used for the purposes of illustration only, and should not be considered as limiting.
EXAMPLES Example 1 Salt Screening Study Step 1. Purification and Characterization of Compound 1Compound 1, 2-((3R, 6 S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid, was found to often contain undesired NaCl salt.
During the purification process, compound 1 was combined with water (15.0 mL) and the suspension was stirred at room temperature for 4 hrs. The solids were isolated using a Buchner funnel and Whitman #1 filter paper. After filtration, the compound was air-dried for 15 hrs. The yield of the procedure was 87% by weight.
After the purification step, the purified compound was analyzed using HPLC, PXRD and TGA. The PXRD pattern of the purified compound 1 is shown in
During the salt-screening step, 60 combinations of seven counterions with nine solvent systems were tested. These combinations were subject to a series of crystallization modes and resulted in approximately 360 screening experiments.
Counterion SelectionCompound 1 has a pKa of 3.92 and was expected to form salts with strong bases. Because of a possible high projected dose (3 g/day) of compound 1, the counterion selection was limited to Class 1 molecules having low toxicity. (Handbook of Pharmaceutical Salts Properties, Selection, and Use P. H. Stahl, C. G. Wermuth, (2002) Wiley-VCH, Weinheim). Table 1 lists seven basic counterions selected for the salt screen study, their pKa values, and the corresponding stoichiometry and dosing strategies.
Nine solvent systems were evaluated in the Salt-screening study. The solvents were selected based on the solubility data accumulated during preceding studies. In addition, solvents represented a diverse set of polarities, dielectric constants, dipole moments, and hydrogen-bond donor/acceptor attributes to promote crystallization of salts. The solvents and rationale for their selection are summarized in Table 2.
The salt-screening experiments were set up by combining 20.0±0.5 mg of Compound 1 with 300-500 μL of the solvent and the counterion in a stoichiometric amount. The screening studies were conducted in two stages.
In Stage 1, the samples involving counterion Nos. 1-6 listed in Table 1 were paired with solvent Nos. 1-6 listed in Table 2, whereas samples involving counterion Nos. 7 and 8 were paired with solvent Nos. 1-5 and 8.
All samples were subject to the following processing steps: 1) Stirring for 48 hrs while maintaining the cycling temperature between 5° C.-40° C.; 2) Stirring for 6 hrs at 40° C.; 3) Stirring for 24 hrs at 20° C.; 4) solvent addition (same solvent in the same amount); 5) Stirring for 72 hrs while maintaining the cycling temperature between 10° C.-30° C.; 6) Stirring for 72 hrs at 5° C.; 7) Solvent addition (the solvent type and amount was adjusted based on the observed solubility and the solvent can be the same solvent previously used, water, or DMSO); 8) Stirring for 24 hrs while maintaining the cycling temperature between 5° C.-30° C.; the solutions obtained from the above steps were 9) cooled to 5° C. and held at 5° C. for 72 hrs; 10) allowed to evaporate at ambient conditions over 3-14 days.
In Stage 2, a few samples that remained undissolved and amorphous in the first stage were 1) subjected to rapid solvent evaporation under vacuum; 2) dissolved in solvent Nos. 7-9 listed in Table 2; 3) cooled to 5° C. and held at 5° C. for 72 hrs; and 4) allowed to evaporate at ambient conditions over 3-7 days.
All samples were inspected visually and by Polarized light microscopy at every step listed above to check any formation of crystalline products. Any crystalline products obtained from these procedures were isolated by vacuum filtration and, where possible, analyzed by FT-Raman. Unique crystalline products were subjected to further analyses by PXRD, DSC, TGA-IR, and HPLC, as necessary.
Results of Salt-Screening StudyA majority of the experiments produced amorphous products, including oils, gums, and powders. Some crystalline screening products underwent partial or complete deliquescence upon isolation, some screening products were mixtures of unreacted components, and some screening products were mixtures of decomposed components. The counterion Nos. 3-8 listed in Table 1 did not yield a pure stable crystalline form of Compound 1A. Only the potassium salt of compound 1 yielded crystalline products. The results of some experiments are summarized in Table 3.
Table 3 only listed 83 examples of the approximately 360 screening experiments performed using various combinations of counterions, solvent systems, and crystallization mode. Most of the screening experiments produced amorphous powders, oils, gums. For example, those experiments that involved calcium and magnesium counterions yielded products that were mixtures of the unreacted substrates. The FT-Raman and PXRD analysis of the products showed that no pure and stable crystalline salt was formed in the experiments involving calcium or magnesium counterions. For another example, when the screening experiments involved the solvent system of THF and Water (95:5 vol %) and a range of counterions (potassium, choline, calcium, and magnesium), the HPLC analysis confirmed significant decomposition present in those products.
Among the approximately 360 screening experiments performed, only the potassium salt Compound 1A in four experiments yielded a pure and stable crystalline form after long-term (>4 days) stirring of the initially amorphous products (gums and oils). The potassium salt was subsequently reproduced at 50 mg and 300 mg scales using seeding, which facilitated crystallization of the several hours of amorphous intermediate phase. The potassium salt may undergo deliquescence when isolated in open air; however, the deliquescence may be significantly reduced and/or eliminated by using the nitrogen blanket. Once a free-flowing powder was isolated, the powder was stable in open-air for at least 7 days.
In addition, only one crystalline form of the potassium salt was observed during the course of the presented study. This single crystalline form also showed that Compound 1A has a low propensity for polymorphism.
Example 2 Preparation of Potassium Salt at 50 mg Scale48.7 mg of Compound 1 was combined with acetone (1.0 mL) in a 2-mL vial containing a stir bar. The suspension was stirred at 40° C. for 10 min and seeded with about 1 mg of potassium salt. 164.0 μL of potassium t-butoxide (1.0eq. of compound 1; 1.0M solution in t-BuOH) was added in five aliquots: 10 μL, 20 μL, 20 μL, 20 μL, 93 μL in every 5 min. Gum was formed upon the counterion addition. The sample was stirred for 15 hrs while the cycling temperature was maintained between 40° C.-45° C., during which the gum changed into a free-flowing suspension. The suspension was equilibrated at 5° C. for 30 min and the solids were isolated on a Buchner funnel under nitrogen blanket and allowed to dry for 30 min. The yield of this preparation procedure was 70% wt.
Example 3 Preparation of Potassium Salt at 300 mg ScaleCompound 1 (302.6 mg) was combined with ACN (15.0 mL) in a 20-mL vial containing a stir bar. The suspension was stirred at 50° C. for 30 min and seeded with about 3 mg of potassium salt. 256.7 μL of potassium hydroxide (0.9 eq. of compound 1; 3.57M aqueous solution) was added in eight aliquots: 20 μL, 20 μL, 20 μL, 20 μL, 20 μL, 50 μL, 50 μL, 56.7 μL in every 15 min. Partial conversion to a gum upon the counterion addition was observed. The suspension was stirred at 50° C. for 60 min, cooled to 5° C. at 0.1° C./min rate (7.5 hrs), and subjected to stirring while the cycling temperature was maintained between 40° C.-45° C. for 10 hrs. The temperature cycle involved holding at 40° C. for 1 hr followed by cooling at 0.5° C./min, and then holding at 5° C. for 2 hrs followed by heating to 40° C. at a maximum rate. The suspension was equilibrated at 5° C. for 2 hrs. The solids were isolated on a Büchner funnel under nitrogen blanket, allowed to dry for 60 min at room temperature and then at 40° C. under vacuum for 3 hrs. The yield of this procedure was 65% wt.
Example 4 Characterization of Potassium SaltThe potassium salt is a crystalline powder, as indicated by PXRD data in
Studies of a possible sodium salt crystalline form were performed using purified compound 1 and amorphous sodium salt of compound 1 as the starting materials and explored diverse crystallization modes, solvents and temperatures.
The studies discovered five crystalline forms of the sodium salt (Groups A-E). Groups A and B were obtained from the screening experiments using compound 1 as the starting material. The PXRD pattern of Group A showed broad peaks indicative of poor crystallinity. The isolated material was found to be sticky and deliquesced readily (<5 minutes) when exposed to ambient conditions. PXRD pattern of Group B showed sharper peaks compared to Group A. The isolated Group B material was free flowing and easy to handle. Thermal analyses of Group B of sodium salt showed this form is a methanol/water solvate which converted to a hydrate on drying at 60° C.
Attempts to prepare Groups A and B using purified compound 1 led to two new crystalline forms of sodium salt (Groups D and E). These forms did not deliquesce when exposed to ambient conditions and were free-flowing solids. However, the DSC data of these two new forms showed broad endotherms below 150° C. indicative of a solvated/hydrated form.
Group C was isolated from a single crystallization experiment using amorphous sodium salt as the input. Group C of sodium salt showed physical properties similar to Group B and was found to be an acetone/water solvate which desolvated on drying at 60° C.
These results showed that the sodium salt of compound 1 is not a desirable crystalline form because of poor crystallinity, complicated polymorphism, poor thermal properties and hygroscopicity. In contrast, as described above, the potassium salt surprisingly demonstrated better crystallinity with a single crystalline form.
Claims
1. A potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
2. The potassium salt of claim 1, wherein the potassium salt is in a crystalline form exhibiting an X-ray powder diffraction pattern comprising at least three characteristic peaks selected from the group consisting of peaks at approximately 7.3°, 13.9°, 16.9°, 19.1°, 20.8°, and 25.2° 2θ.
3. The potassium salt of claim 2, exhibiting an X-ray powder diffraction pattern comprising at least peaks at approximately 7.3, 13.9°, 16.9°, 19.1°, 20.8°, and 25.2° 2θ.
4. The potassium salt of claim 3, exhibiting an X-ray powder diffraction pattern comprising at least peaks at approximately 7.3°, 13.9°, 14.6°, 16.9°, 17.9°, 19.1°, 20.8°, 21.3°, 25.2°, and 25.6° 2θ.
5. The potassium salt of claim 1, wherein said crystalline form has a melting point of 199.0° C.
6. The potassium salt of claim 1 having an X-ray powder diffraction pattern substantially the same as shown in FIG. 1.
7. A pharmaceutical composition comprising the potassium salt of claim 1 and a pharmaceutically acceptable excipient or a pharmaceutically acceptable liquid carrier.
8. (canceled)
9. The pharmaceutical composition of claim 7, further comprising an additional medicament selected from an antibacterial agent, antifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.
10. (canceled)
11. The pharmaceutical composition of claim 10, wherein the additional medicament is a β-lactam antibacterial agent selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.
12. (canceled)
13. (canceled)
14. (canceled)
15. The pharmaceutical composition of claim 7, comprising a unit dose from 0.1 mg to 5 g of the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
16. A method of treating a bacterial infection, comprising administering to a subject in need thereof, a composition according to claim 7.
17. The method of claim 16, further comprising administering an additional medicament selected from all antibacterial agent, aritifungal agent, an antiviral agent, an anti-inflammatory agent, or an anti-allergic agent.
18. (canceled)
19. The method of claim 17, wherein the additional medicament is a β-lactam antibacterial agent selected from Ceftazidime, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem, Panipenem, Aztreonam, Tigemonam, BAL30072, SYN 2416, or Carumonam.
20. (canceled)
21. (canceled)
22. (canceled)
23. The method of claim 16, wherein the subject is a mammal.
24. The method of claim 23, wherein the mammal is a human.
25. (canceled)
26. (canceled)
27. The method of claim 16, comprising administering the composition intravenously or orally to the subject.
28. (canceled)
29. A sterile container, comprising:
- the composition according to claim 7.
30. A sterile container, comprising:
- the potassium salt according to claim 1.
31. A method of preparing a pharmaceutical composition for administration, comprising reconstituting the contents of the sterile container of claim 29 using a pharmaceutically acceptable liquid carrier.
32. The method of any one of claims 31, wherein the liquid carrier is a saline solution or dextrose solution.
33. (canceled)
34. (canceled)
35. A process of making a crystalline form of a potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid, comprising:
- combining a purified 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid with a solvent to form an intermediate solution;
- intermixing a potassium ion with the intermediate solution; and
- isolating the crystalline form of the potassium salt of 2-((3R,6S)-2-hydroxy-3-(2-(thiophen-2-yl)acetamido)-1,2-oxaborinan-6-yl)acetic acid.
36. The process of claim 35, wherein the potassium ion is from potassium hydroxide or potassium t-butoxide.
37. (canceled)
38. The process of claim 35, wherein the solvent is selected from the group consisting of tetrahydrofuran, 1,4-dioxane, acenitrile, acetone, ethyl acetate, methyl tert-butyl ether, water, and any combinations thereof.
39. The process of claim 38, wherein the solvent is acetone or acenitrile.
Type: Application
Filed: Apr 29, 2015
Publication Date: Jun 22, 2017
Inventors: Joanna A. Bis (Cary, NC), Pingyun Chen (Chapel Hill, NC), Senthil Kumar Kusalakumari Sukumar (Raleigh, NC)
Application Number: 15/309,425
