Hydrophobic derivatives of natural biodegradable polysaccharides and uses thereof
Low molecular weight hydrophobic derivatives of non-cyclic α(1→4)glucopyranose polymers and non-reducing polysaccharides are described. The derivates can be used to form matrices in various forms, including body members of implantable articles, coatings, and consumer items, which have desirable properties.
Latest Patents:
The present non-provisional Application claims the benefit of commonly owned provisional Application having Ser. No. 60/782,957, filed on Mar. 15, 2006, and entitled HYDROPHOBIC DERIVATIVES OF NATURAL BIODEGRADABLE POLYSACCHARIDES; and commonly owned provisional Application having Ser. No. 60/900,853, filed on Feb. 10, 2007, and entitled BIODEGRADABLE HYDROPHOBIC POLYSACCHARIDE-BASED DRUG DELIVERY IMPLANTS; which Applications are incorporated herein by reference in their entirety.
TECHNICAL FIELDThe present invention relates to hydrophobic derivatives of natural biodegradable polysaccharides, and articles including these derivatives.
BACKGROUNDPolylactide (PLA) is a synthetic biodegradable thermoplastic derived from lactic acid that has been used extensively in the preparation of a wide variety of items. In particular, PLA has been used to construct biodegradable articles such as bags, containers, diapers and packaging materials. PLA has also been used for in the fabrication of biodegradable medical devices such as sutures that can dissolve in physiological conditions.
Similar to other thermoplastics, PLA can be processed into fibers and films, thermoformed, or injection molded. While PLA provides desirable processing and degradation properties, it suffers from brittleness, hardness, inflexibility, and low melt tension. In order to overcome these undesirable characteristics, PLA is often blended with secondary agents, such as plasticizers, to improve its properties. Many commonly used secondary agents such as plasticizers, however, are not degradable. This presents obstacles for the preparation of PLA-based articles that are intended to be completely degradable.
SUMMARY OF THE INVENTIONGenerally, the present invention relates to hydrophobic derivatives of a natural biodegradable polysaccharide (“hydrophobic polysaccharides”), articles that include these hydrophobic polysaccharides, and methods utilizing these articles.
Generally, the hydrophobic polysaccharides comprise a poly-α(1→4)glucopyranose backbone and have a low molecular weight and a plurality of groups pendent from the backbone that provide the hydrophobic portion. These hydrophobic polysaccharides have been found to be amenable to use in various fabrication processes and also can be used to form articles with desirable properties, such as properties desirable for use in association with implantable medical articles. For example, matrices formed using hydrophobic polysaccharides of the invention demonstrate one more of the following properties, such as compliance, conformability, and/or durability, which provide(s) benefits for in vivo use. These properties can prevent or minimize cracking, delamination, and/or abrasion of the matrix during use. The coating compositions can also be prepared having a high concentration of solids, allowing the formation of a matrix having a high content of a secondary compound, such as a bioactive agent. Coatings for implantable medical articles as well as the body members of implantable medical articles exemplify hydrophobic polysaccharide matrices.
The hydrophobic polysaccharides can be degraded into natural materials, which provide advantages for compatibility of implantable articles. Degradation of the matrix can result in the release of, for example, naturally occurring mono- or disaccharides, such as glucose, which are common serum components. This provides an advantage over matrices formed from polyglycolide-type molecules, which can degrade into products that cause unwanted side effects in the body by virtue of their presence or concentration in vivo.
In one aspect, the invention provides a hydrophobic derivative of a natural biodegradable polysaccharide comprising a non-cyclic poly-α(1→4)glucopyranose backbone and a plurality of groups pendent from the poly-α(1→4)glucopyranose backbone, the groups comprising a hydrocarbon segment having two or more carbon atoms, wherein the hydrophobic derivative has a molecular weight of about 100,000 Da or less.
In another aspect, the invention provides a hydrophobic derivative of a natural biodegradable polysaccharide comprising a non-cyclic poly-α(1→4)glucopyranose backbone; and a plurality of groups pendent from the poly-α(1→4)glucopyranose backbone, wherein the hydrophobic derivative has a molecular weight of about 100,000 Da or less, and a glass transition temperature of 35° C. or greater.
In another aspect, the invention provides a hydrophobic derivative of a natural biodegradable polysaccharide comprising a hydrophilic portion comprising a non-cyclic poly-α(1→4)glucopyranose backbone; a hydrophobic portion comprising a plurality of groups pendent from the poly-α(1→4)glucopyranose backbone, wherein the weight ratio between the hydrophilic portion and the hydrophobic portion in the range of 5:1 to 1:1.25, and wherein the hydrophobic derivative has a molecular weight of about 100,000 Da or less.
In another aspect, the invention provides a hydrophobic derivative of a natural biodegradable polysaccharide comprising a non-cyclic poly-α(1→4)glucopyranose backbone; and a plurality of groups pendent from the poly-α(1→4)glucopyranose backbone, the groups comprising a hydrocarbon segment, wherein at least a portion of the groups comprise a bioactive agent that is cleavable from the poly-α(1→4)glucopyranose backbone, and wherein the hydrophobic derivative has a molecular weight of about 100,000 Da or less.
In another aspect, the invention provides a hydrophobic derivative of a natural biodegradable polysaccharide comprising a polymeric backbone comprising non-reducing disaccharides and a plurality of groups pendent from the polymeric backbone, wherein the hydrophobic derivative has a molecular weight of about 100,000 Da or less. The polymeric backbone can be selected from the group consisting of polytrehalose, polysucrose, and polyalditol.
In another aspect, the invention provides a disposable article formed of a hydrophobic polysaccharide of the invention.
In another aspect, the invention provides coating for an implantable medical article, wherein the coating is formed of a hydrophobic polysaccharide of the invention.
In another aspect, the invention provides an implantable medical article having a body member that is formed of a hydrophobic polysaccharide of the invention.
In another aspect, the invention provides a method for delivering a bioactive agent to a subject comprising the steps of: implanting in a subject at a target location an implantable medical article formed of a hydrophobic polysaccharide of the invention; and allowing the bioactive agent to be released from the implantable medical article to provide a therapeutic effect to the subject.
In another aspect, the invention provides a method for delivering a bioactive agent to a subject comprising the steps of: implanting in a subject at a target location an implantable medical article comprising a coating formed of a hydrophobic polysaccharides of the invention and a bioactive agent; and allowing the bioactive agent to be released from the coating to provide a therapeutic effect to the subject.
The embodiments of the present invention described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can appreciate and understand the principles and practices of the present invention.
All publications and patents mentioned herein are hereby incorporated by reference. The publications and patents disclosed herein are provided solely for their disclosure. Nothing herein is to be construed as an admission that the inventors are not entitled to antedate any publication and/or patent, including any publication and/or patent cited herein.
The invention is generally directed to the hydrophobic derivatives of non-cyclic α(1→4)glucopyranose polymers, articles that are formed using these hydrophobic polysaccharides, and uses of articles formed from these hydrophobic polysaccharides. The invention is also directed to hydrophobic derivatives of polysaccharides formed of non-reducing sugars, such as polyalditol. The hydrophobic polysaccharides have a low molecular weight and are useful for the preparation of polymeric matrices, which can be in a variety of forms, such as coatings or body members of articles.
As used herein, a “hydrophobic derivative” of a non-cyclic α(1→4)glucopyranose polymer refers to a non-cyclic α(1→4)glucopyranose polymer with a hydrophobic portion, wherein the hydrophobic derivative is not soluble in water. In many cases the hydrophobic portion includes a plurality of groups that are pendent from poly α(1→4)glucopyranose backbone and that, together, provide the polymer with the hydrophobic property. The plurality of pendent groups is collectively referred to as the “hydrophobic portion” of the hydrophobic derivative. The hydrophobic derivatives of the invention therefore include a hydrophobic portion and a polysaccharide portion.
The non-cyclic α(1→4)glucopyranose polymer portion includes repeating glucopyranose monomeric units having α(1→4) linkages and is capable of being enzymatically degraded. Exemplary non-cyclic α(1→4)glucopyranose polymer portions include maltodextrin and amylose.
As used herein, “amylose” or “amylose polymer” refers to a linear polymer having repeating glucopyranose units that are joined by α-1,4 linkages. Some amylose polymers can have a very small amount of branching via α-1,6 linkages (about less than 0.5% of the linkages) but still demonstrate the same physical properties as linear (unbranched) amylose polymers do. Generally amylose polymers derived from plant sources have molecular weights of about 1×106 Da or less. Amylopectin, comparatively, is a branched polymer having repeating glucopyranose units that are joined by α-1,4 linkages to form linear portions and the linear portions are linked together via α-1,6 linkages. The branch point linkages are generally greater than 1% of the total linkages and typically 4%-5% of the total linkages. Generally amylopectin derived from plant sources have molecular weights of 1×107 Da or greater.
Amylose can be obtained from, or is present in, a variety of sources. Typically, amylose is obtained from non-animal sources, such as plant sources. In some aspects, a purified preparation of amylose is used as starting material for the preparation of the amylose polymer having a hydrophobic portion. In other aspects, as starting material, amylose can be used in a mixture that includes other polysaccharides.
For example, in some aspects, starch preparations having a high amylose content, purified amylose, synthetically prepared amylose, or enriched amylose preparations can be used in the preparation of a hydrophobic derivative of amylose. In starch sources, amylose is typically present along with amylopectin, which is a branched polysaccharide. If a mixture of amylose and a higher molecular weight precursor is used (such as amylopectin), it is preferred that amylose is present in the composition in an amount greater than the higher molecular weight precursor. For example, in some aspects, starch preparations having high amylose content, purified amylose, synthetically prepared amylose, or enriched amylose preparations can be used in the preparation of a hydrophobic derivative of amylose polymer. In some embodiments the composition includes a mixture of polysaccharides including amylose wherein the amylose content in the mixture of polysaccharides is 50% or greater, 60% or greater, 70% or greater, 80% or greater, or 85% or greater by weight. In other embodiments the composition includes a mixture of polysaccharides including amylose and amylopectin and wherein the amylopectin content in the mixture of polysaccharides is 30% or less, or 15% or less.
The amount of amylopectin present in a starch may also be reduced by treating the starch with amylopectinase, which cleaves α-1,6 linkages resulting in the debranching of amylopectin into amylose.
Steps may be performed before, during, and/or after the process of derivatizing the amylose polymer to provide for a hydrophobic derivative, to enrich the amount of amylose, or to purify the amylose.
Amylose of particular molecular weights can be obtained commercially or can be prepared. For example, synthetic amyloses with an average molecular mass of 70 kDa can be obtained from Nakano Vinegar Co., Ltd. (Aichi, Japan). The decision of using amylose of a particular size range may depend on factors such as the physical characteristics of the composition (e.g., viscosity), the desired rate of degradation of the coating formed from the hydrophobic polysaccharide, and the presence of other optional components in the composition, such as bioactive agents.
Purified or enriched amylose preparations can be obtained commercially or can be prepared using standard biochemical techniques such as chromatography. In some aspects, high-amylose cornstarch can be used to prepare the hydrophobic polysaccharide.
Maltodextrin is typically generated by hydrolyzing a starch slurry with heat-stable α-amylase at temperatures at 85-90° C. until the desired degree of hydrolysis is reached and then inactivating the α-amylase by a second heat treatment. The maltodextrin can be purified by filtration and then spray dried to a final product. Maltodextrins are typically characterized by their dextrose equivalent (DE) value, which is related to the degree of hydrolysis defined as: DE=MW dextrose/number-averaged MW starch hydrolysate X 100. Generally, maltodextrins are considered to have molecular weights that are less than amylose molecules.
A starch preparation that has been totally hydrolyzed to dextrose (glucose) has a DE of 100, whereas starch has a DE of about zero. A DE of greater than 0 but less than 100 characterizes the mean-average molecular weight of a starch hydrolysate, and maltodextrins are considered to have a DE of less than 20. Maltodextrins of various molecular weights, for example, in the range of about 500 Da to 5000 Da are commercially available (for example, from CarboMer, San Diego, Calif.).
In another aspect, the hydrophobic polysaccharide has a polymeric backbone formed of non-reducing disaccharides (natural biodegradable non-reducing polysaccharides). A non-reducing polysaccharide refers to a polymer of non-reducing disaccharides (two monosaccharides linked through their anomeric centers) such as trehalose (α-D-glucopyranosyl α-D-glucopyranoside) and sucrose (β-D-fructofuranosyl α-D-glucopyranoside). An exemplary non-reducing polysaccharide comprises polyalditol which is available from GPC (Muscatine, Iowa). In another aspect, the polysaccharide is a glucopyranosyl polymer, such as a polymer that includes repeating (1→3)O-β-D-glucopyranosyl units. A non-reducing polysaccharide can provide an inert matrix thereby improving the stability of sensitive bioactive agents, such as proteins and enzymes.
To facilitate discussion of the invention, the hydrophobic derivatives of the non-cyclic α(1→4)glucopyranose polymers and non-reducing polysaccharides are generally referred to herein as “hydrophobic polysaccharides.”
In many aspects the polysaccharide portion and the hydrophobic portion comprise the predominant portion of the hydrophobic polysaccharide. In one aspect, the wherein the weight ratio between the hydrophilic portion and the hydrophobic portion in the range of 5:1 to 1:1.25. For example, based on a weight percentage, the polysaccharide portion can be about 25% wt of the hydrophobic polysaccharide or greater, in the range of about 25% to about 75%, in the range of about 30% to about 70%, in the range of about 35% to about 65%, in the range of about 40% to about 60%, or in the range of about 45% to about 55%. Likewise, based on a weight percentage of the overall hydrophobic polysaccharide, the hydrophobic portion can be about 25% wt of the hydrophobic polysaccharide or greater, in the range of about 25% to about 75%, in the range of about 30% to about 70%, in the range of about 35% to about 65%, in the range of about 40% to about 60%, or in the range of about 45% to about 55%. In exemplary aspects, the hydrophobic polysaccharide has approximately 50% of its weight attributable to the polysaccharide portion, and approximately 50% of its weight attributable to its hydrophobic portion.
The hydrophobic polysaccharide has the properties of being insoluble in water. The term for insolubility is a standard term used in the art, and meaning 1 part solute per 10,000 parts or greater solvent. (see, for example, Remington: The Science and Practice of Pharmacy, 20th ed. (2000), Lippincott Williams & Wilkins, Baltimore Md.).
A hydrophobic polysaccharide can be prepared by coupling one or more hydrophobic compound(s) to a natural biodegradable polysaccharide polymer. Methods for preparing hydrophobic polysaccharides are described herein.
The hydrophobic polysaccharides have a molecular weight of 100,000 Da or less. Use of these lower molecular weight derivatives provides matrices having desirable physical properties. In some aspects the hydrophobic polysaccharides have a molecular weight of about 50,000 Da or less, or 25,000 Da or less. Particularly preferred size ranges for the hydrophobic polysaccharides are in the range of about 2,000 Da to about 20,000 Da, or about 4,000 Da to about 10,000 Da.
The molecular weight of the polymer is more precisely defined as “weight average molecular weight” or Mw. Mw is an absolute method of measuring molecular weight and is particularly useful for measuring the molecular weight of a polymer (preparation), such as preparations of hydrophobic polysaccharides. Polymer preparations typically include polymers that individually have minor variations in molecular weight. Polymers are molecules that have a relatively high molecular weight and such minor variations within the polymer preparation do not affect the overall properties of the polymer preparation. The weight average molecular weight (Mw) can be defined by the following formula:
wherein N represents the number of moles of a polymer in the sample with a mass of M, and Σi is the sum of all NiMi (species) in a preparation. The Mw can be measured using common techniques, such as light scattering or ultracentrifugation. Discussion of Mw and other terms used to define the molecular weight of polymer preparations can be found in, for example, Allcock, H. R. and Lampe, F. W. (1990) Contemporary Polymer Chemistry; pg 271.
The addition of hydrophobic portion will generally cause an increase in molecular weight of the polysaccharide from its underivitized, starting molecular weight. The amount increase in molecular weight can depend on one or more factors, including the type of polysaccharide derivatized, the level of derivation, and, for example, the type or types of groups attached to the polysaccharide to provide the hydrophobic portion.
In some aspects, the addition of hydrophobic portion causes an increase in molecular weight of the polysaccharide of about 20% or greater, about 50% or greater, about 75% or greater, about 100% or greater, or about 125%, the increase in relation to the underivitized form of the polysaccharide.
As an example, a maltodextrin having a starting weight of about 3000 Da is derivitized to provide pendent hexanoate groups that are coupled to the polysaccharide via ester linkages to provide a degree of substitution (DS) of about 2.5. This provides a hydrophobic polysaccharide having a theoretical molecular weight of about 6000 Da.
In forming the hydrophobic polysaccharide, and as an example, a compound having a hydrocarbon segment can be covalently coupled to one or more portions of the polysaccharide.
For example, the compound can be coupled to monomeric units along the length of the polysaccharide. This provides a polysaccharide derivative with one or more pendent groups. Each chemical group comprises a hydrocarbon segment. The hydrocarbon segment can constitute all of the pendent chemical group, or the hydrocarbon segment can constitute a portion of the pendent chemical group. For example, a portion of the hydrophobic polysaccharide can have the following structure:
[M]-[L]-[H]
wherein M is a monomeric unit of the polysaccharide, and in the pendent chemical group ([L]-[H]), H is the hydrocarbon segment, and L is a chemical group linking the hydrocarbon segment to the monomeric unit of the polysaccharide.
The pendent group can also include an additional portion that is not a hydrocarbon segment [N] as represented by the following structure:
[M]-[L]-[H]-[N]
A “hydrocarbon segment” herein refers to a group of covalently bonded carbon atoms having the formula (CHn)m, wherein m is 2 or greater, and n is independently 2 or 1. A hydrocarbon segment can include saturated hydrocarbon groups or unsaturated hydrocarbon groups, and examples thereof include alkyl, alkenyl, alkynyl, cyclic alkyl, cyclic alkenyl, aromatic hydrocarbon and aralkyl groups.
The monomeric units of the hydrophobic polysaccharides described herein typically include monomeric units having ring structures with one or more reactive groups. These reactive groups are exemplified by hydroxyl groups, such as the ones that are present on glucopyranose-based monomeric units of amylose and maltodextrin. These hydroxyl groups can be reacted with a compound that includes a hydrocarbon segment and a group that is reactive with the hydroxyl group (a hydroxyl-reactive group).
Examples of hydroxyl reactive groups include acetal, carboxyl, anhydride, acid halide, and the like. These groups can be used to form a hydrolytically cleavable covalent bond between the hydrocarbon segment and the polysaccharide backbone. For example, the method can provide a pendent group having a hydrocarbon segment, the pendent group linked to the polysaccharide backbone with a cleavable ester bond. In these aspects, the synthesized hydrophobic polysaccharide will include chemical linkages that are both enzymatically cleavable (the polymer backbone) and non-enzymatically hydrolytically cleavable (the linkage between pendent group and the polymer backbone).
Other cleavable chemical linkages that can be used to bond the pendent groups to the polysaccharide include peroxyester groups, disulfide groups, and hydrazone groups.
In some cases the hydroxyl reactive groups include those such as isocyanate and epoxy. These groups can be used to form a non-cleavable covalent bond between the pendent group and the polysaccharide backbone. In these aspects, the synthesized hydrophobic polysaccharide includes chemical linkages that are enzymatically cleavable (the polymer backbone).
Other reactive groups, such as carboxyl groups, acetyl groups, or sulphate groups, are present on the ring structure of monomeric units of other natural biodegradable polysaccharides, such as chondrotin or hyaluronic acid. These groups can also be targeted for reaction with a compound having a hydrocarbon segment to be bonded to the polysaccharide backbone.
Various factors can be taken into consideration in the synthesis of the hydrophobic polysaccharide. These factors include the physical and chemical properties of the polysaccharide, including its size, and the number and presence of reactive groups on the polysaccharide and solubility, the physical and chemical properties of the compound that includes the hydrocarbon segment, including its the size and solubility, and the reactivity of the compound with the polysaccharide.
In preparing the hydrophobic polysaccharide any suitable synthesis procedure can be performed. Synthesis can be carried out to provide a desired number of groups with hydrocarbon segments pendent from the polysaccharide backbone. The number and/or density of the pendent groups can be controlled, for example, by controlling the relative concentration of the compound that includes the hydrocarbon segment to the available reactive groups (e.g., hydroxyl groups) on the polysaccharide.
The type and amount of groups having the hydrocarbon segment pendent from the polysaccharide is sufficient for the hydrophobic polysaccharide to be insoluble in water. In order to achieve this, as a general approach, a hydrophobic polysaccharide is obtained or prepared wherein the groups having the hydrocarbon segment pendent from the polysaccharide backbone in an amount in the range of 0.25 (pendent group):1 (polysaccharide monomer) by weight.
To exemplify these levels of derivation, very low molecular weight (less than 10,000 Da) glucopyranose polymers were reacted with compounds having the hydrocarbon segment to provide low molecular weight hydrophobic glucopyranose polymers. In one mode of practice, the natural biodegradable polysaccharide maltodextrin in an amount of 10 g (MW 3000-5000 Da; ˜3 mmols) was dissolved in a suitable solvent, such as tetrahydrofuran. Next, a solution having butyric anhydride in an amount of 18 g (0.11 mols) was added to the maltodextrin solution. The reaction was allowed to proceed, effectively forming pendent butyrate groups on the pyranose rings of the maltodextrin polymer. This level of derivation resulted in a degree of substitution (DS) of butyrate group of the hydroxyl groups on the maltodextrin of about 1.
For maltodextrin and other polysaccharides that include three hydroxyl groups per monomeric unit, on average, one of the three hydroxyl groups per glycopyranose monomeric unit becomes substituted with a butyrate group. A maltodextrin polymer having this level of substitution is referred to herein as maltodextrin-butyrate DS1. As described herein, the DS refers to the average number of reactive groups (including hydroxyl and other reactive groups) per monomeric unit that are substituted with the group having the hydrocarbon segment.
An increase in the DS can be achieved by incrementally increasing the amount of compound that provides the hydrocarbon segment to the polysaccharide. As another example, butyrylated maltodextrin having a DS of 2.5 is prepared by reacting 10 g of maltodextrin (MW 3000-5000 Da; ˜3 mmols) with 0.32 mols butyric anhydride.
In some modes of practice, the invention provides a hydrophobic glucopyranose polymer comprising a DS in the range of about 2-3, comprising pendent linear, branched, or cyclic a C4-C10 groups, and the polymer has a MW in the range of about 2000 to about 20000 Da.
In some modes of practice, the invention provides a hydrophobic glucopyranose polymer comprising a DS in the range of about 2-3, comprising pendent linear, branched, or cyclic C5-C7 groups, and the polymer has a MW in the range of about 2000 to about 20000 Da
The degree of substitution can influence the hydrophobic character of the polysaccharide. In turn, coatings formed from hydrophobic polysaccharides having a substantial amount of groups having the hydrocarbon segments bonded to the polysaccharide backbone (as exemplified by a high DS) are generally more hydrophobic and can be more resistant to degradation. For example, a matrix formed from maltodextrin-butyrate DS1 has a rate of degradation that is faster than a matrix formed from maltodextrin-butyrate DS2.
The type of hydrocarbon segment present in the groups pendent from the polysaccharide backbone can also influence the hydrophobic properties of the polymer. In one aspect, the hydrophobic polysaccharide has pendent groups with hydrocarbon segments being short chain branched alkyl group. Exemplary short chain branched alkyl group are branched C4-C10 groups. The preparation of a hydrophobic polymer with these types of pendent groups is exemplified by the reaction of maltodextrin with valproic acid/anhydride with maltodextrin (MD-val). The reaction can be carried out to provide a relatively lower degree of substitution of the hydroxyl groups, such as is in the range of 0.5-1.5. Although these polysaccharides have a lower degree of substitution, the short chain branched alkyl group imparts considerable hydrophobic properties to the polysaccharide.
Even at these low degrees of substitution the MD-val can form forms matrices that are very compliant and durable. Because of the low degrees of substitution, the pendent groups with the branched C8 segment can be hydrolyzed from the polysaccharide backbone at a relatively fast rate, thereby providing a matrix that can quickly degrade in vivo.
Various synthetic schemes can be used for the preparation of a hydrophobic polysaccharide. In some modes of preparation, pendent polysaccharide hydroxyl groups are reacted with a compound that includes a hydrocarbon segment and a group that is reactive with the hydroxyl groups. This reaction can provide polysaccharide with pendent groups comprising hydrocarbon segments.
In some aspects, the pendent group comprises a hydrocarbon segment that is a linear, branched, or cyclic C2-C18 group. More preferably the hydrocarbon segment comprises a C2-C10, or a C4-C8, linear, branched, or cyclic group. The hydrocarbon segment can be saturated or unsaturated, and can comprise alkyl groups or aromatic groups, respectively. The hydrocarbon segment can be linked to the polysaccharide backbone via a hydrolyzable bond or a non-hydrolyzable bond.
In some aspects the compound having a hydrocarbon segment that is reacted with the polysaccharide backbone is derived from a natural compound. Natural compounds with hydrocarbon segments include fatty acids, fats, oils, waxes, phospholipids, prostaglandins, thromboxanes, leukotrienes, terpenes, steroids, and lipid soluble vitamins.
Exemplary natural compounds with hydrocarbon segments include fatty acids and derivatives thereof, such as fatty acid anhydrides and fatty acid halides. Exemplary fatty acids and anhydrides include acetic, propionic, butyric, isobutyric, valeric, caproic, caprylic, capric, and lauric acids and anhydrides, respectively. The hydroxyl group of a polysaccharide can be reacted with a fatty acid or anhydride to bond the hydrocarbon segment of the compound to the polysaccharide backbone via an ester group.
The hydroxyl group of a polysaccharide can also cause the ring opening of lactones to provide pendent open-chain hydroxy esters. Exemplary lactones that can be reacted with the polysaccharide include caprolactone and glycolides.
Generally, if compounds having large hydrocarbon segments are used for the synthesis of the hydrophobic polysaccharide, a smaller amount of the compound may be needed for its synthesis. For example, as a general rule, if a compound having a hydrocarbon segments with an alkyl chain length of Cx is used to prepare a hydrophobic polysaccharide with a DS of 1, a compound having a hydrocarbon segment with an alkyl chain length of C(x X 2) is reacted in an amount to provide a hydrophobic polysaccharide with a DS of 0.5.
The hydrophobic polysaccharide can also be synthesized having combinations of pendent groups with two or more different hydrocarbon segments, respectively. For example, the hydrophobic polysaccharide can be synthesized using compounds having hydrocarbon segments with different alkyl chain lengths. In one mode of practice, a polysaccharide is reacted with a mixture of two or more fatty acids (or derivatives thereof) selected from the group of acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, caproic acid, caprylic acid, capric acid, and lauric acid to generate the hydrophobic polysaccharide.
In other cases the hydrophobic polysaccharide is synthesized having a non-hydrolyzable bond linking the hydrocarbon segment to the polysaccharide backbone. Exemplary non-hydrolyzable bonds include urethane bonds.
The hydrophobic polysaccharide can also be synthesized so that hydrocarbon segments are individually linked to the polysaccharide backbone via both hydrolyzable and non-hydrolyzable bonds. As another example, a hydrophobic polysaccharide is prepared by reacting a mixture of butyric acid anhydride and butyl isocyanate with maltodextrin. This yields a hydrophobic polysaccharide of maltodextrin with pendent butyric acid groups that are individually covalently bonded to the maltodextrin backbone with hydrolyzable ester linkages and non-hydrolyzable urethane linkages. The degradation of a coating having this type of hydrophobic polysaccharide can occur by loss of the butyrate groups from hydrolysis of the ester linkages. However, a portion of the butyrate groups (the ones that are bonded via the urethane groups) are not removed from the polysaccharide backbone and therefore the polysaccharide can maintain a desired degree of hydrophobicity, prior to enzymatic degradation of the polysaccharide backbone.
In some aspects, the group that is pendent from the polysaccharide backbone has properties of a bioactive agent. In this regard, the coating comprises polysaccharide-coupled bioactive agent. In some aspects, a bioactive agent which has a hydrocarbon segment can be hydrolyzed from the hydrophobic polysaccharide and released from the matrix to provide a therapeutic effect in a subject. One example of a therapeutically useful compound having a hydrocarbon segments is butyric acid, which has been shown to elicit tumor cell differentiation and apoptosis, and is thought to be useful for the treatment of cancer and other blood diseases.
Other illustrative compounds comprising hydrocarbon segments include valproic acid and retinoic acid. These compounds can be coupled to a polysaccharide backbone, and then cleaved from the polysaccharide backbone in a subject. Retinoic acid is known to possess antiproliferative effects and is thought to be useful for treatment of proliferative vitreoretinopathy (PVR). The pendent group that provides a therapeutic effect can also be a natural compound (such as butyric acid, valproic acid, and retinoic acid).
Other illustrative compound that can be coupled to the polysaccharide backbone is a corticosteroid. An exemplary corticosteroid is triamcinolone. One method of coupling triamcinolone to a natural biodegradable polymer is by employing a modification of the method described in Cayanis, E. et al., Generation of an Auto-anti-idiotypic Antibody that Binds to Glucocorticoid Receptor, The Journal of Biol. Chem., 261(11):5094-5103 (1986). Triamcinolone hexanoic acid is prepared by reaction of triamcinolone with ketohexanoic acid; an acid chloride of the resulting triamcinolone hexanoic acid can be formed and then reacted with the polysaccharide, such as maltodextrin or polyalditol, resulting in pendent triamcinolone groups coupled via ester bonds to the polysaccharide.
The hydrophobic polysaccharide can also be synthesized having two or more different pendent groups, wherein at least one of the pendent groups comprises a bioactive agent. The hydrophobic polysaccharide can be synthesized with an amount of a pendent groups comprising a bioactive agent, that when released from the polysaccharide, provides a therapeutic effect to a subject. An example of such a hydrophobic polysaccharide is maltodextrin-caproate-triamcinolone. This hydrophobic polysaccharide can be prepared by reacting a mixture including triamcinolone hexanoic acid and an excess of caproic anhydride (n-hexanoic anhydride) with maltodextrin to provide a derivative with a DS of 2.5.
In some aspects, the group that is pendent from the polysaccharide includes a hydrocarbon segment that is an aromatic group, such as a phenyl group. As one example, o-acetylsalicylic acid is reacted with a polysaccharide such as maltodextrin to provide pendent chemical group having a hydrocarbon segment that is a phenyl group, and a non-hydrocarbon segment that is an acetate group wherein the pendent group is linked to the polysaccharide via an ester bond.
It has been discovered that these hydrophobic polysaccharides can be used to form articles that are wholly or partially degradable. A partially degradable article can be an article that has a biostable portion, such as a biostable body member, and a biodegradable portion, such as a biodegradable coating. The articles of the invention have desirable and beneficial physical properties. For example, the hydrophobic polysaccharides can be used to form biodegradable coatings that demonstrate excellent durability, compliance, and rate of degradation. Furthermore, these coatings offer advantages for the controlled release of bioactive agents, if included in the coating. Advantageously, these articles can be formed without requiring the covalent crosslinking of the polysaccharide polymers.
The hydrophobic polysaccharides of the invention can be used in many applications, including systems and methods wherein the hydrophobic polysaccharide is contacted with a carbohydrase. Interestingly, it has also been discovered some of the hydrophobic polysaccharides can be formed into coatings or articles that have a substantially slow rate of degradation. This is desirable in a variety of applications where it desired that the article (or coating) maintain its integrity for a protracted period of time, such as a period of months to years, but that it eventually degrades. Given this, the hydrophobic polysaccharides have utility in a broad range of applications. Such applications include medical applications, including implantable medical articles and coatings for implantable medical articles for the long-term treatment of various conditions. These hydrophobic polysaccharides can also be used in the preparation of disposable consumer items. In these applications the structural integrity of the item is maintained for a period of use. However, following disposal, the item loses its structural integrity as the hydrophobic polysaccharide degrades.
Generally, the hydrophobic polysaccharide is used to form an article, or a portion of an article, that can be degraded. In some aspects, the article is a disposable consumer item. A disposable consumer item broadly refers to any sort of article that is utilized by an individual and then disposed of after use. Following disposal, the article can be degraded in an appropriate waste environment. For example, the article can be disposed of in a landfill wherein the article is exposed to conditions that promote its degradation. For example, the article is exposed to carbohydrases present in the soil or water. These carbohydrases can be produced from environmental microorganisms and promote the degradation of the article over a period of time.
Examples of disposable consumer items include packaging materials, paper products, tissues, towels, wipes, food containers, beverage containers, utensils, plates, cups, boxes, food wrap, food bags, garbage bags, personal care items, feminine hygiene products, restroom supplies, seat covers, child and infant care products.
In some aspects, the hydrophobic polysaccharide is used to form the body member, or a portion of a body member, of an implantable medical article. In these aspects, a degradable body member, or portion thereof, can provide mechanical properties at the implantation site and can maintain these mechanical properties until they are no longer needed. After a period of time has elapsed, the body member is degraded to an extent that the mechanical properties are no longer provided, and the degraded components of the article are processed by the body.
In some embodiments, the body member of the medical article slowly degrades and transfers stress at the appropriate rate to surrounding tissues as these tissues heal and can accommodate the stress once borne by the body member of the medical article. The medical article can optionally include a coating or a bioactive agent to provide one or more additional functional features, however, these are not required in order for the article to be of use at the treatment site.
A biodegradable stent structure formed from the hydrophobic polysaccharide is an example of a body member of an implantable device. Other body members are exemplified herein.
The article can also comprise fibers, such as microfibers and/or nanofibers that are formed from the hydrophobic polysaccharide. The fibers can be included in or associated with various articles including implantable medical articles and cell culture articles.
In another aspect of the invention, the hydrophobic polysaccharide is used to form a coating on the surface of a medical article. The hydrophobic polysaccharide can be present in one or more coated layers all or a portion of the surface of the device. A “coating” as used herein can include one or more “coated layers”, each coated layer including one or more coating materials. In some cases, the coating can be formed of a single layer of material that includes the hydrophobic polysaccharide, such as hydrophobic amylose or maltodextrin. In other cases, the coating includes more than one coated layer, at least one of the coated layers including the hydrophobic polysaccharide. If more than one layer is present in the coating, the layers can be composed of the same or different materials.
Bioactive agents can also be included in the coating. The bioactive agent can be in the same coated layer as the hydrophobic polysaccharide, or in a different coated layer. The bioactive agent can be released from the coating upon degradation of the coated layer that includes the hydrophobic polysaccharide. Alternatively, or additionally, the coated layer that includes the hydrophobic polysaccharide can modulate bioactive agent release. In this aspect some or no degradation of the coated layer that includes the hydrophobic polysaccharide may occur.
The following list of medical articles is provided to illustrate various medical articles that can be fabricated from the hydrophobic polysaccharide to form the body member of the medical articles. This list of various medical articles also exemplifies various body members that can be provided with a coating that includes the hydrophobic polysaccharide.
These types of articles are typically introduced temporarily or permanently into a mammal for the prophylaxis or treatment of a medical condition. For example, these articles can be introduced subcutaneously, percutaneously or surgically to rest within an organ, tissue, or lumen of an organ, such as arteries, veins, ventricles, or atria of the heart.
Exemplary medical articles include vascular implants and grafts, grafts, surgical devices; synthetic prostheses; vascular prosthesis including endoprosthesis, stent-graft, and endovascular-stent combinations; small diameter grafts, abdominal aortic aneurysm grafts; wound dressings and wound management device; hemostatic barriers; mesh and hernia plugs; patches, including uterine bleeding patches, atrial septic defect (ASD) patches, patent foramen ovale (PFO) patches, ventricular septal defect (VSD) patches, and other generic cardiac patches; ASD, PFO, and VSD closures; percutaneous closure devices, mitral valve repair devices; left atrial appendage filters; valve annuloplasty devices, catheters; central venous access catheters, vascular access catheters, abscess drainage catheters, drug infusion catheters, parenteral feeding catheters, intravenous catheters (e.g., treated with antithrombotic agents), stroke therapy catheters, blood pressure and stent graft catheters; anastomosis devices and anastomotic closures; aneurysm exclusion devices; biosensors; cardiac sensors; birth control devices; breast implants; infection control devices; membranes; tissue scaffolds; tissue-related materials; shunts including cerebral spinal fluid (CSF) shunts, glaucoma drain shunts; dental devices and dental implants; ear devices such as ear drainage tubes, tympanostomy vent tubes; ophthalmic devices; cuffs and cuff portions of devices including drainage tube cuffs, implanted drug infusion tube cuffs, catheter cuff, sewing cuff; spinal and neurological devices; nerve regeneration conduits; neurological catheters; neuropatches; orthopedic devices such as orthopedic joint implants, bone repair/augmentation devices, cartilage repair devices; urological devices and urethral devices such as urological implants, bladder devices, renal devices and hemodialysis devices, colostomy bag attachment devices; biliary drainage products.
In some aspects the hydrophobic polysaccharide is utilized in an ophthalmic article. Compositions including the hydrophobic polysaccharide can be used for the formation of a coating on the surface of an ophthalmic article, in the construction of the body member of the ophthalmic article, or both. The ophthalmic article can be configured for placement at an external or internal site of the eye. In some aspects, the articles can be utilized to deliver a bioactive agent to an anterior segment of the eye (in front of the lens), and/or a posterior segment of the eye (behind the lens). Suitable ophthalmic devices can also be utilized to provide bioactive agent to tissues in proximity to the eye, when desired.
Suitable external articles can be configured for topical administration of bioactive agent. Such external devices can reside on an external surface of the eye, such as the cornea (for example, contact lenses) or bulbar conjunctiva. In some embodiments, suitable external devices can reside in proximity to an external surface of the eye.
Articles configured for placement at an internal site of the eye can reside within any desired area of the eye. In some aspects, the ophthalmic article can be configured for placement at an intraocular site, such as the vitreous. Illustrative intraocular devices include, but are not limited to, those described in U.S. Pat. No. 6,719,750 B2 (“Devices for Intraocular Drug Delivery,” Varner et al.) and U.S. Pat. No. 5,466,233 (“Tack for Intraocular Drug Delivery and Method for Inserting and Removing Same,” Weiner et al.); U.S. Publication Nos. 2005/0019371 A1 (“Controlled Release Bioactive Agent Delivery Device,” Anderson et al.), 2004/0133155 A1 (“Devices for Intraocular Drug Delivery,” Varner et al.), 2005/0059956 A1 (“Devices for Intraocular Drug Delivery,” Varner et al.), and U.S. application Ser. Nos. 11/204,195 (filed Aug. 15, 2005, Anderson et al.), Ser. No. 11/204,271 (filed Aug. 15, 2005, Anderson et al.), Ser. No. 11/203,981 (filed Aug. 15, 2005, Anderson et al.), Ser. No. 11/203,879 (filed Aug. 15, 2005, Anderson et al.), Ser. No. 11/203,931 (filed Aug. 15, 2005, Anderson et al.); and related applications.
In some aspects of the invention, a coating including the hydrophobic polysaccharide is formed on a non-linear intraocular device.
In some aspects, the ophthalmic article can be configured for placement, or can be formed, at a subretinal area within the eye. Illustrative ophthalmic devices for subretinal application include, but are not limited to, those described in U.S. Patent Publication No. 2005/0143363 (“Method for Subretinal Administration of Therapeutics Including Steroids; Method for Localizing Pharmacodynamic Action at the Choroid and the Retina; and Related Methods for Treatment and/or Prevention of Retinal Diseases,” de Juan et al.); U.S. application Ser. No. 11/175,850 (“Methods and Devices for the Treatment of Ocular Conditions,” de Juan et al.); and related applications.
Ophthalmic articles can also be configured for placement within any desired tissues of the eye. For example, ophthalmic devices can be configured for placement at a subconjunctival area of the eye, such as devices positioned extrasclerally but under the conjunctiva, such as glaucoma drainage devices and the like.
A coating that includes the hydrophobic polysaccharide can be formed on the body member of a medical article, including those listed herein, wherein the medical article is formed of a non-biodegradable material. For example, a coating can be formed on a body member of a medical article that is partially or entirely fabricated from a plastic polymer. Plastic polymers include those formed of synthetic polymers, including oligomers, homopolymers, and copolymers resulting from either addition or condensation polymerizations. Examples of suitable addition polymers include, but are not limited to, acrylics such as those polymerized from methyl acrylate, methyl methacrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid, methacrylic acid, glyceryl acrylate, glyceryl methacrylate, methacrylamide, and acrylamide; vinyls such as ethylene, propylene, vinyl chloride, vinyl acetate, vinyl pyrrolidone, vinylidene difluoride, and styrene. Examples of condensation polymers include, but are not limited to, nylons such as polycaprolactam, polylauryl lactam, polyhexamethylene adipamide, and polyhexamethylene dodecanediamide, and also polyurethanes, polycarbonates, polyamides, polysulfones, poly(ethylene terephthalate), polydimethylsiloxanes, and polyetherketone.
Other suitable polymers that can be used to construct the body member include polyamides, polyimides, polyolefins, polystyrenes, polyesters, polycarbonates, polyketones, polyureas, acrylonitrile butadiene, butadiene rubber, chlorinated and chloro-sulfonated polyethylene, chloroprene, EPM, EPDM, PE-EPDM, PP-EPDM, EVOH, epichlorihydrin, isobutylene isoprene, isoprene, polysulfides, silicones, NBR/PVC, styrene butadienes, and vinyl acetate ethylenes, and combinations thereof.
In some cases the coating of the invention is formed on an implantable medical article is partially or entirely fabricated from a degradable polymer. The article can degrade in an aqueous environment, such as by simple hydrolysis, or can be enzymatically degraded.
Examples of classes of synthetic polymers that can be used to form the structure of the article include polyesters, polyamides, polyurethanes, polyorthoesters, polycaprolactone (PCL), polyiminocarbonates, aliphatic carbonates, polyphosphazenes, polyanhydrides, and copolymers thereof. Specific examples of biodegradable materials that can be used in connection with the device of the invention include polylactide, polygylcolide, polydioxanone, poly(lactide-co-glycolide), poly(glycolide-co-polydioxanone), polyanhydrides, poly(glycolide-co-trimethylene carbonate), and poly(glycolide-co-caprolactone). As an example, the hydrophobic polysaccharide can provide a barrier coating to articles fabricated from PLA or copolymers thereof. The coating can shield the article during a portion or all of a desired period of treatment. The coating article can still be fully degradable.
Blends of these polymers with other biodegradable polymers can also be used.
Coatings that include the hydrophobic polysaccharide can also be formed on medical devices that are partially or entirely fabricated from a metal. Although many devices or articles are constructed from substantially all metal materials, such as alloys, some may be constructed from both non-metal and metal materials, where at least a portion of the surface of the device is metal.
Commonly used metals include platinum, gold, or tungsten, as well as other metals such as rhenium, palladium, rhodium, ruthenium, titanium, nickel, and alloys of these metals, such as stainless steel, titanium/nickel, nitinol alloys, cobalt chrome alloys, non-ferrous alloys, and platinum/iridium alloys. One exemplary alloy is MP35. These metals, including other alloys or combinations, can be suitable substrates for a coating composition that includes the hydrophobic polysaccharide.
In some aspects the biodegradable coating is formed on the surface of an erodable implantable medical device formed from of a metal. For example, the biodegradable coating can be formed on a magnesium alloy stent that can be corroded following placement in a subject (see, for example, De Mario, C. et al. (2004) J. Interv. Cardiol., 17(6):391-395, and Heublein, B., et al. (2003) Heart; 89:651-656). The erodable implantable medical device can also include a bioactive agent, if desired.
In aspects where the structure of the implantable medical article is fabricated from a material that is erodable or degradable, an in vivo lifetime of the article can be determined. The biodegradable coatings of the present invention can be applied to the surface of these erodable or degradable articles to prolong their in vivo lifetime. The in vivo lifetime is a period of time starting upon placement of the coated article at a target location, and ending when the coated article is completely degraded at the target location.
Other surfaces that can be coated include those that include human tissue such as bone, cartilage, skin and teeth; or other organic materials such as wood, cellulose, compressed carbon, and rubber. Other contemplated biomaterials include ceramics including, but not limited to, silicon nitride, silicon carbide, zirconia, and alumina, as well as glass, silica, and sapphire. Combinations of ceramics and metals can also be coated.
The hydrophobic polysaccharide can be formed into, or can be present in a coated layer on, an article having a porous structure. In many cases the porous structure of the article is a fabric or has fabric-like qualities. The porous structure can be formed from textiles, which include woven materials, knitted materials, and braided materials. Particularly useful textile materials are woven materials which can be formed using any suitable weave pattern known in the art.
The porous structure can be that of a graft, sheath, cover, patch, sleeve, wrap, casing, and the like, including many of the medical articles described herein. These types of articles can function as the medical article itself or be used in conjunction with another part of a medical article.
Other particular contemplated porous structures include grafts, particularly grafts having textured exterior portions. Examples of textured grafts include those that have velour-textured exteriors, with textured or smooth interiors. Grafts constructed from woven textile products are well known in the art and have been described in numerous documents, for example, U.S. Pat. No. 4,047,252; U.S. Pat. No. 5,178,630; U.S. Pat. No. 5,282,848; and U.S. Pat. No. 5,800,514.
A medical article having a biodegradable coating including the hydrophobic polysaccharide, or a medical article that is formed using the hydrophobic polysaccharide can be prepared by assembling an article having two or more “parts.” These parts can be pieces of a medical article that can be put together to form the article. All or a portion of the part of the medical article can include the hydrophobic polysaccharide. In this regard, the invention also contemplates parts of medical article (for example, not the fully assembled article) that include the hydrophobic polysaccharide.
In one aspect, the invention provides coatings that include a coated layer comprising the hydrophobic polysaccharide, wherein the coating is also capable of releasing one or more bioactive agents.
In one aspect of the invention, a bioactive agent is present in association with a hydrophobic coated layer that includes the hydrophobic polysaccharide. In these aspects, the bioactive agent generally has poor or no solubility in water. Depending on the properties of the hydrophobic layer and the bioactive agent associated with the hydrophobic layer, the coating can demonstrate a particular release mechanism.
In one aspect, the bioactive agent may be released from the coated layer with little or no degradation of the hydrophobic polysaccharide. For example, a coated layer that includes maltodextrin-butyrate having a high degree of substitution (such as in the range of DS 2-DS 3) and a hydrophobic bioactive agent that is not covalently bonded to the maltodextrin-butyrate may release the bioactive agent with little or no degradation of the coating. That is, release of the bioactive agent is primarily driven by diffusion of the bioactive agent from the coated layer.
In other aspect, degradation of the coated layer containing the hydrophobic polysaccharide contributes to release of the bioactive agent. In these aspects, the coated layer is weaker and more susceptible to degradation. For example, the coated layer can be formed from a maltodextrin-butyrate having a lower degree of substitution (such as about DS 1) and that includes a bioactive agent. Degradation of the coated layer can proceed by hydrolysis of the butyrate group and enzymatic degradation of the maltodextrin. Depending on the properties of the bioactive agent, release can occur by degradation of the coated layer; however, diffusion of the bioactive agent from the coated layer may also occur.
The bioactive agent may be covalently bonded to the natural biodegradable polysaccharide. In some aspects the bioactive agent is a group pendent from the hydrophobic polysaccharide, such as a butyrate group. Preferably, if the bioactive agent is covalently bonded, it is cleavable from the polysaccharide. Cleavable chemical linkages that can be used to bond the bioactive agent to the polysaccharide include ester group, peroxyester groups, disulfide groups, and hydrazone groups. Alternatively, the cleavable linking group can be enzymatically cleaved, for example, by proteases or by carbohydrases.
Another aspect relates to the ability of the hydrophobic polysaccharide to control release of a bioactive agent from another portion of the coating. In these aspects the coating includes more than one coated layer of material, wherein a bioactive agent is present in a first coated layer, and second coated layer of material that includes the hydrophobic polysaccharide. The second coated layer is able to control the release of the bioactive agent from the coating.
For example, a first coated layer that includes a polymeric material and a bioactive agent can be formed between the device surface and a second coated layer that includes the hydrophobic polysaccharide. The bioactive agent diffuses from the first coated layer, but the second coated layer controls its release from the surface of the device in a more effective therapeutic profile.
This arrangement of coated materials has been advantageously used to control the release of a hydrophilic bioactive agent from the coating. In one mode of practice, a first coated layer is prepared that includes a synthetic polymer and a hydrophilic bioactive agent. For example, the synthetic polymer can be a non-biodegradable polymer. Exemplary synthetic polymers include poly(alkyl(meth)acrylates) such as poly(butylmethacrylate); secondary polymers can be included in the first coated layer. A hydrophilic bioactive agent is included in the first coated layer. A second coated layer that includes the hydrophobic polysaccharide is formed. The second coated layer can be in direct contact with the first coated layer. Upon implantation, the second coated layer slows the release of the hydrophilic bioactive agent, which is otherwise typically released very rapidly.
The term “bioactive agent,” refers to an inorganic or organic molecule, which can be synthetic or natural, that causes a biological effect when administered in vivo to an animal, including but not limited to birds and mammals, including humans.
A partial list of bioactive agents is provided below. According to embodiments of the present invention, one may choose one or more of the bioactive agents to be included in an article or coating that comprises the hydrophobic polysaccharide. A comprehensive listing of bioactive agents, in addition to information of the water solubility of the bioactive agents, can be found in The Merck Index, Thirteenth Edition, Merck & Co. (2001).
Articles and coatings prepared according to the invention can be used to release bioactive agents falling within one or more of the following classes include, but are not limited to: ACE inhibitors, actin inhibitors, analgesics, anesthetics, anti-hypertensives, anti polymerases, antisecretory agents, anti-AIDS substances, antibiotics, anti-cancer substances, anti-cholinergics, anti-coagulants, anti-convulsants, anti-depressants, anti-emetics, antifungals, anti-glaucoma solutes, antihistamines, antihypertensive agents, anti-inflammatory agents (such as NSAIDs), anti metabolites, antimitotics, antioxidizing agents, anti-parasite and/or anti-Parkinson substances, antiproliferatives (including antiangiogenesis agents), anti-protozoal solutes, anti-psychotic substances, anti-pyretics, antiseptics, anti-spasmodics, antiviral agents, calcium channel blockers, cell response modifiers, chelators, chemotherapeutic agents, dopamine agonists, extracellular matrix components, fibrinolytic agents, free radical scavengers, growth hormone antagonists, hypnotics, immunosuppressive agents, immunotoxins, inhibitors of surface glycoprotein receptors, microtubule inhibitors, miotics, muscle contractants, muscle relaxants, neurotoxins, neurotransmitters, polynucleotides and derivatives thereof, opioids, photodynamic therapy agents, prostaglandins, remodeling inhibitors, statins, steroids, thrombolytic agents, tranquilizers, vasodilators, and vasospasm inhibitors.
Antibiotics are art recognized and are substances which inhibit the growth of or kill microorganisms. Examples of antibiotics include penicillin, tetracycline, chloramphenicol, minocycline, doxycycline, vancomycin, bacitracin, kanamycin, neomycin, gentamycin, erythromycin, cephalosporins, geldanamycin, and analogs thereof. Examples of cephalosporins include cephalothin, cephapirin, cefazolin, cephalexin, cephradine, cefadroxil, cefamandole, cefoxitin, cefaclor, cefuroxime, cefonicid, ceforanide, cefotaxime, moxalactam, ceftizoxime, ceftriaxone, and cefoperazone.
Antiseptics are recognized as substances that prevent or arrest the growth or action of microorganisms, generally in a nonspecific fashion, e.g., by inhibiting their activity or destroying them. Examples of antiseptics include silver sulfadiazine, chlorhexidine, glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenolic compounds, iodophor compounds, quaternary ammonium compounds, and chlorine compounds.
Anti-viral agents are substances capable of destroying or suppressing the replication of viruses. Examples of anti-viral agents include α-methyl-P-adamantane methylamine, hydroxy-ethoxymethylguanine, adamantanamine, 5-iodo-2′-deoxyuridine, trifluorothymidine, interferon, and adenine arabinoside.
Enzyme inhibitors are substances that inhibit an enzymatic reaction. Examples of enzyme inhibitors include edrophonium chloride, N-methylphysostigmine, neostigmine bromide, physostigmine sulfate, tacrine HCl, tacrine, 1-hydroxymaleate, iodotubercidin, p-bromotetramisole, 10-(α-diethylaminopropionyl)-phenothiazine hydrochloride, calmidazolium chloride, hemicholinium-3,3,5-dinitrocatechol, diacylglycerol kinase inhibitor I, diacylglycerol kinase inhibitor II, 3-phenylpropargylamine, N-monomethyl-L-arginine acetate, carbidopa, 3-hydroxybenzylhydrazine HCl, hydralazine HCl, clorgyline HCl, deprenyl HCl, L(−), deprenyl HCl, D(+), hydroxylamine HCl, iproniazid phosphate, 6-MeO-tetrahydro-9H-pyrido-indole, nialamide, pargyline HCl, quinacrine HCl, semicarbazide HCl, tranylcypromine HCl, N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride, 3-isobutyl-1-methylxanthine, papaverine HCl, indomethacin, 2-cyclooctyl-2-hydroxyethylamine hydrochloride, 2,3-dichloro-α-methylbenzylamine (DCMB), 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride, p-aminoglutethimide, p-aminoglutethimide tartrate, R(+), p-aminoglutethimide tartrate, S(−), 3-iodotyrosine, alpha-methyltyrosine, L(−) alpha-methyltyrosine, D L(−), cetazolamide, dichlorphenamide, 6-hydroxy-2-benzothiazolesulfonamide, and allopurinol.
Anti-pyretics are substances capable of relieving or reducing fever. Anti-inflammatory agents are substances capable of counteracting or suppressing inflammation. Examples of such agents include aspirin (salicylic acid), indomethacin, sodium indomethacin trihydrate, salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal, diclofenac, indoprofen and sodium salicylamide. Local anesthetics are substances that have an anesthetic effect in a localized region. Examples of such anesthetics include procaine, lidocaine, tetracaine and dibucaine.
Examples of statins include lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, and superstatin.
Examples of steroids include glucocorticoids such as cortisone, hydrocortisone, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, triamcinolone, beclomethasone, fludrocortisone, and aldosterone; sex steroids such as testostersone, dihydrotestosterone, estradiol, diethylstilbestrol, progesterone, and progestins.
The bioactive agent can be an immunosuppressive agent, for example, rapamycin, ABT-578, cyclosporine, everolimus, mycophenolic acid, sirolimus, tacrolimus, and the like.
In order to prepare a coating on the surface of a body member, or an article formed from the hydrophobic polysaccharide, a composition that includes the hydrophobic polysaccharide can be prepared. The natural biodegradable polysaccharide is dissolved in a suitable solvent and the composition is used in a desired process.
Examples of solvents that can be used to prepare a composition include aromatic compounds such as toluene and xylene, and ethers such as tetrahydrofuran. Other suitable solvents include halogenated alkanes such as methylene chloride and chloroform; and amides such as dimethylformamide (DMF). Combinations of one or more of these or other solvents can also be used. The type of solvent system used can be chosen according to the hydrophobic polysaccharide, and any other optional component present in the composition.
In preparing the article, the concentration of the hydrophobic polysaccharide in a composition can be chosen to provide an article or coating with desired physical and functional properties. In some cases a coating composition, such as one for a spray coating process, can be prepared having the hydrophobic polysaccharide composition at a concentration in the range of about 5 mg/mL to about 500 mg/mL. In one modes of practice the hydrophobic polysaccharide is present in the composition at about 50 mg/mL and the composition is used for coating a surface.
The hydrophobic polysaccharide can be blended with one or more other hydrophobic compounds in a composition for preparation of an article. The other hydrophobic compounds can be hydrophobic polysaccharides. For example, mixtures of hydrophobic polysaccharides of different molecular weights can be blended in a composition and used to prepare an article.
In some aspects, the composition used to form the coating or article can include a radiopacifying agent. The presence of a radiopacifying agent in the formed coating or article can promote detection of the location of a device following implantation.
The composition can also include a bioactive agent, such as one or more of those described herein. The bioactive agent can be present in the composition at a concentration, which allows formation of a coating or an article with therapeutically useful properties. The amount and type of bioactive agent may be chosen based on the type of hydrophobic polysaccharide present in the composition.
Compositions of the invention that include the hydrophobic polysaccharide in an organic solvent can be used to coat the surface of a variety of implantable medical devices. The coating composition (with or without bioactive agent) can be applied to a medical device using standard techniques to cover the entire surface of the device, or a portion of the device surface. If more than one coated layer is applied to a surface, it is typically applied successively. For example, a natural biodegradable polysaccharide coated layer can be formed by, for example, dipping, spraying, bushing, or swabbing the coating material on the article to form a layer, and then drying the coated layer. The process can be repeated to provide a coating having multiple coated layers, wherein at least one layer includes the natural biodegradable polysaccharide. The compositions of the present invention are particularly suitable for use in spray coating processes.
An exemplary spray coating process and apparatus that can be used for coating implantable medical articles using the compositions of the present invention is described in U.S. Patent Publication No. 2004-0062875-A1 (filed Sep. 27, 2002).
A composition that includes the hydrophobic polysaccharide can be spray coated directly onto the surface of a body member of a medical article, or can be spray coated onto a surface that includes one or more coated layers of material previously formed on the body member. The composition may be spray coated onto a coated layer of material that includes a bioactive agent.
Other coated layers can include polymers such as methacrylate, acrylate, alkylacrylate, acrylamide, vinylpyrrolidinone, vinylacetamide, or vinyl formamide polymers. These polymers can also include latent reactive groups, such as photoreactive groups.
In some cases the coated layer that includes the hydrophobic polysaccharide is formed on a base layer. The base layer can serve one or more functions, for example, it can provide an improved surface for the formation of a coated layer that includes the hydrophobic polysaccharide.
Components of the biodegradable coating can be applied to the medical device using standard techniques to cover the entire surface of the device, or a portion of the device surface. As indicated, the components can be applied to the medical device independently or together, for example, in a composition. The coating formed on the device can be a single layer coating, or a multiple layer coating.
In other aspects, the hydrophobic polysaccharide is used to form a medical implant that includes a bioactive agent. The implant may not have any distinct mechanical properties, such as would be apparent with an intravascular prosthesis, but rather provides a mechanism to deliver the bioactive agent to a particular portion of the body. The implant can have a defined structure and size that is appropriate for its use at a desired location in the body.
A medical implant having a defined structure can be formed by any suitable process, including molding, extruding, shaping, cutting, casting, and the like. In forming a medical implant, the concentration of the natural biodegradable polysaccharide may be higher to provide a more structurally rigid implant.
In other aspects, the hydrophobic polysaccharide is used to form a microparticle. The microparticle can also include a bioactive agent, and it can be used to deliver this bioactive agent from a coating on a medical article. Generally, microparticles have a size in the range of 5 nm to 100 μm in diameter, and are spherical or somewhat spherical in shape. Microparticles that include a hydrophobic polysaccharide can be prepared by established techniques, for example, by solvent evaporation (see, for example, Wichert, B. and Rohdewald, P. (1993) J. Microencapsul. 10:195). Bioactive agents can also be incorporated into the microparticles using these techniques and can be formulated to release a desired amount of the agent over a predetermined period of time. The bioactive agent can be released from the biodegradable microparticle upon degradation of the biodegradable microparticle in vivo.
Medical articles formed from the hydrophobic polysaccharide, or that include a biodegradable coating can be treated to sterilize one or more parts of the article, or the entire medical article. Sterilization can take place prior to using the medical article and/or, in some cases, during implantation of the medical article.
In some aspects, the invention provides a method for delivering a bioactive agent from coating or article formed from a hydrophobic polysaccharide. In performing this method, the article is placed in a subject. Upon exposure to body fluid the bioactive agent is released from the coating. The coating can be formulated, as described herein, to release the bioactive agent over a prolonged period of time.
In some cases, depending on the properties of the article or coating formed from the hydrophobic polysaccharide, a carbohydrase can promote the degradation of the biodegradable coating. The carbohydrase that contacts the coating or article can specifically degrade the natural biodegradable polysaccharide. This may occur before, during, or after the release of the bioactive agent. Examples of carbohydrases that can specifically degrade natural biodegradable polysaccharide coatings include α-amylases, such as salivary and pancreatic α-amylases; disaccharidases, such as maltase, lactase and sucrase; trisaccharidases; and glucoamylase (amyloglucosidase).
Serum concentrations for amylase are estimated to be in the range of about 50-100 U per liter, and vitreal concentrations also fall within this range (Varela, R. A., and Bossart, G. D. (2005) J Am Vet Med Assoc 226:88-92).
In some aspects, the carbohydrase can be administered to a subject to increase the local concentration, for example in the serum or the tissue surrounding the implanted device, so that the carbohydrase may promote the degradation of the coating. Exemplary routes for introducing a carbohydrase include local injection, intravenous (IV) routes, and the like. Alternatively, degradation can be promoted by indirectly increasing the concentration of a carbohydrase in the vicinity of the coated article, for example, by a dietary process, or by ingesting or administering a compound that increases the systemic levels of a carbohydrase.
In other cases, the carbohydrase can be provided on a portion of the article. For example the carbohydrase may be eluted from a portion of the article that does not include hydrophobic polysaccharide. In this aspect, as the carbohydrase is released it locally acts upon the coating to cause its degradation and promote the release of the bioactive agent.
The invention will be further described with reference to the following non-limiting Examples.
EXAMPLE 111 g of dried maltodextrin (GPC, Grain Processing Corporation, Muscatine, Iowa) was dissolved in 100 mls of dimethyl sulfoxide with stirring. When the solution was complete, 20 g (0.244 moles, 19.32 mls, Sigma-Aldrich) of 1-methylimidizole followed by 50 g (0.32 moles, 52 mls, Sigma-Aldrich, Milwaukee, Wis.) of butyric anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then quenched with deionized water. The taffy-like material that precipitated from the quenched reaction mixture was placed in 1,000 MWCO dialysis tubing and dialyzed vs. continuous flow deionized water for three days. After this time the solid product was lyophilized. 23.169 g of a white powdery solid was obtained. The theoretical degree of substitution (DS) was 2.5.
EXAMPLE 210 g of dried MD was dissolved in 100 mls of dimethyl sulfoxide with stirring. When the solution was complete, 23.7 g (0.29 moles, 22.9 mls) of 1-methylimidizole followed by 29.34 g (0.29 moles, 27.16 mls) of acetic anhydride (Sigma-Aldrich, Milwaukee, Wis.) were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid was collected via filtration and dried in vacuo. 15.92 g of a yellow powdery solid was obtained. The theoretical DS was 2.5
EXAMPLE 310 g of dried MD was dissolved in 100 mls of dimethyl sulfoxide with stirring. When the solution was complete, 9.49 g (0.11 moles, 9.17 mls) of 1-methylimidizole followed by 18.19 g (0.11 moles, 18.81 mls) of butyric anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid was collected via filtration and dried in vacuo. 16.11 g of a white powdery solid was obtained. The theoretical DS was 1.
EXAMPLE 410 g of dried MD was dissolved in 100 mls of dimethyl sulfoxide with stirring. When the solution was complete, 14.24 g (0.17 moles, 13.76 mls) of 1-methylimidizole followed by 27.32 g (0.17 moles, 28.25 mls) of butyric anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid was collected via filtration and dried in vacuo. 18.95 g of a white powdery solid was obtained. The theoretical DS was 1.5.
EXAMPLE 510 g of dried MD was dissolved in 100 mls of dimethyl sulfoxide with stirring. When the solution was complete, 18.97 g (0.23 moles, 18.33 mls) of 1-methylimidizole followed by 36.39 g (0.23 moles, 37.63 mls) of butyric anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid was collected via filtration and dried in vacuo. 19.78 g of a white powdery solid was obtained. The theoretical DS was 2.
EXAMPLE 610 g of dried polyalditol (GPC, Grain Processing Corporation, Muscatine, Iowa) was dissolved in 100 mls of dimethyl sulfoxide with stirring. When the solution was complete, 28.46 g (0.35 moles, 27.5 mls) of 1-methylimidizole followed by 54.58 g (0.35 moles, 56.44 mls) of butyric anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then quenched with deionized water. The reaction mixture was placed in 1,000 MWCO dialysis tubing and dialyzed vs. continuous flow deionized water for three days. After this time the solution was lyophilized. 11.55 g of a white powdery solid was obtained. The theoretical DS was 2.
EXAMPLE 71 g of dried β-cyclodextrin (Sigma-Aldrich, Milwaukee, Wis.) was dissolved in 10 mls of dimethyl sulfoxide with stirring. When the solution was complete, 5.02 g (0.061 moles, 4.85 mls) of 1-methylimidizole followed by 9.62 g (0.061 moles, 9.95 mls) of butyric anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then quenched with deionized water. The reaction mixture was placed in 1,000 MWCO dialysis tubing and dialyzed vs. continuous flow deionized water for three days. After this time the solution was lyophilized. 234 mg of a white powdery solid was obtained. The theoretical DS was 2.
EXAMPLE 810 g of dried MD was dissolved in 100 mls of dimethyl sulfoxide with stirring. When the solution was complete, 23.7 g (0.29 moles, 22.9 mls) of 1-methylimidizole followed by 37.38 g (0.29 moles, 36.8 mls) of propionoic anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid was collected via filtration and dried in vacuo. 18.49 g of a white powdery solid was obtained. The theoretical DS was 2.5.
EXAMPLE 910 g of dried MD was dissolved in 100 mls of dimethyl sulfoxide with stirring. When the solution was complete, 9.48 g (0.12 moles, 9.16 mls) of 1-methylimidizole followed by 14.95 g (0.12 moles, 14.73 mls) of propionoic anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid was collected via filtration and dried in vacuo. 14.32 g of a white powdery solid was obtained. The theoretical DS was 1.
EXAMPLE 104 g of dried MD was dissolved in 40 mls of dimethyl sulfoxide with stirring. When the solution was complete, 9.48 g (0.12 moles, 9.16 mls) of 1-methylimidizole followed by 24.63 g (0.12 moles, 26.6 mls) of caproic anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid obtained was taffy-like and collected via filtration and dried in vacuo. 7.18 g of a white solid was obtained. The theoretical DS was 2.5.
EXAMPLE 114 g of dried MD was dissolved in 40 mls of dimethyl sulfoxide with stirring. When the solution was complete, 3.79 g (0.046 moles, 3.7 mls) of 1-methylimidizole followed by 9.85 g (0.046 moles, 10.64 mls) of caproic anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid was collected via filtration and dried in vacuo. 9.02 g of a white powdery solid was obtained. The theoretical DS was 1.
EXAMPLE 122.0 g of dried MD was dissolved in 10 mls of dimethyl sulfoxide with stirring. 0.751 g (2.3 mmole) decanoic anhydride was dissolved in 3 ml of chloroform. When the solutions were complete 0.188 g (2.3 mmoles, 0.183 mls) of 1-methylimidizole was added to the DMSO/MD solution followed by the addition of the chloroform/anhydride solution and 7.0 ml DMSO. The reaction was stirred for 1 hour at room temperature. The reaction mixture was placed in 1,000 MWCO dialysis tubing and dialyzed vs. continuous flow deionized water for three days. The dialysis tube and contents were placed in 1 liter of acetone/methanol-50/50 (volume) three times for more than 1 hour for each solvent change. The dialysis tube and contents were then placed in 4 liters of acetone/methanol-50/50 (volume) three times for 1 day for each solvent change. The solid from the dialysis tube was dried in vacuo. 1.69 g of a white solid was obtained. The theoretical DS was 0.1.
EXAMPLE 135.0 g of dried MD was dissolved in 10 mls of dimethyl sulfoxide with stirring. 3.15 g (5.75 mmole) stearic anhydride was dissolved in 3 ml of chloroform. When the solutions were complete 0.472 g (5.75 mmoles, 0.458 mls) of 1-methylimidizole was added to the DMSO/MD solution followed by the addition of the chloroform/anhydride solution and 7.0 ml DMSO. The reaction was stirred for 1 hour at room temperature. The reaction mixture was placed in 1,000 MWCO dialysis tubing and dialyzed vs. continuous flow deionized water for three days. The dialysis tube and contents were placed in 1 liter of acetone/methanol-50/50 (volume) three times for more than 1 hour for each solvent change. The dialysis tube and contents were then placed in 4 liters of acetone/methanol-50/50 (volume) three times for 1 day for each solvent change. The solid from the dialysis tube was dried in vacuo. 6.58 g of a white powdery solid was obtained. The theoretical DS was 0.1.
EXAMPLE 144 g of dried MD was dissolved in 40 mls of dimethyl sulfoxide with stirring. When the solution was complete, 9.48 g (0.12 moles, 9.16 mls) of 1-methylimidizole followed by 24.63 g (0.12 moles, 26.6 mls) of caproic anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid obtained was taffy-like and collected via filtration and dried in vacuo. 7.18 g of a white solid was obtained. The theoretical DS was 2.5.
EXAMPLE 154 g of dried MD was dissolved in 40 mls of dimethyl sulfoxide with stirring. When the solution was complete, 9.48 g (0.12 moles, 9.16 mls) of 1-methylimidizole followed by 24.63 g (0.12 moles, 26.6 mls) of heptanoic anhydride were added with stirring at room temperature. The reaction solution was stirred for one hour and was then slowly add to 750 mls of deionized water in a Waring blender. The precipitated solid was collected via filtration, re-suspended in 1 L of deionized water and stirred for one hour. The solid obtained was taffy-like and collected via filtration and dried in vacuo. 7.18 g of a white solid was obtained. The theoretical DS was 2.5.
EXAMPLE 16Vacuum oven-dried Polyalditol PD60 (4.10 g), N-hydroxysuccinimide (0.38 g), 4-di(methylamino)pyridine (0.39 g), and 2-propylpentanoic acid (9.01 g; valproic acid) were weighed into a 120 mL amber vial. Anhydrous dimethyl sulfoxide, DMSO, (50 mL) was poured into the vial, purged with nitrogen, and placed on a rotary shaker to dissolve. N,N′-diisopropylcarbodiimide, DIC, (9.47 g) was weighed into a 30 mL amber vial and dissolved with 10 mL of anhydrous DMSO. The DIC solution was poured into the 120 mL amber vial and purged with nitrogen gas. A Teflon stir bar was inserted into the 120 mL vial before being capped and placed on a stir plate to stir overnight at room temperature. After overnight stirring, no visible product was seen and the reaction was placed in a 55° C. oven to stir overnight. The reaction formed two layers after heating overnight and was precipitated into 2 L deionized water while stirring. The yellowish/white solid was vacuum-filtered using a water aspirator and rinsed three times with deionized water (100 mL). The solid precipitate was collected and dried in a vacuum oven at 40° C. overnight. The dried solid was organic soluble (tetrahydrofuran, methylene chloride). A 50 mg/mL solution in THF was prepared and tested by dip coating onto a clean Pebax rod giving a uniform, off-white coating.
EXAMPLE 17Vacuum oven-dried Polyalditol PD60 (4.10 g), N-hydroxysuccinimide (0.38 g), 4-di(methylamino)pyridine (0.39 g), and o-acetylsalicylic acid, ASA, (11.26 g) were weighed into a 120 mL amber vial. Anhydrous dimethyl sulfoxide (50 mL) was poured into the vial, purged with nitrogen, and placed on a rotary shaker to dissolve. N,N′-diisopropylcarbodiimide, DIC, (9.47 g) was weighed into a 30 mL amber vial and dissolved with 10 mL of anhydrous DMSO. The DIC solution was poured into the 120 mL amber vial and purged with nitrogen gas. A Teflon stir bar was inserted into the 120 mL vial before being capped and placed on a stir plate to stir overnight at room temperature. After overnight stirring, no visible product was seen and the reaction was placed in a 55° C. oven to stir overnight. The reaction formed a viscous, orange material after heating overnight and was precipitated into 2 L deionized water while stirring. The orange solid was vacuum-filtered using a water aspirator and rinsed once with acetone (25 mL) followed by three times with deionized water (100 mL). The solid precipitate was collected and dried in a vacuum oven at 40° C. overnight. The dried solid was organic soluble (tetrahydrofuran, methylene chloride).
EXAMPLE 18 Release of Lidocaine from Stainless Steel StentsA solution was prepared in 15 mls of THF containing 200 mgs of poly(butylmethacrylate) (PBMA) with an approximate weight average molecular weight of 337 kD, 200 mgs poly (ethylene-co-vinyl acetate) (PEVA) with a vinyl acetate content of 33% (w/w), and 200 mgs lidocaine.
Stainless steel stents were prepared for coating as follows. The stents were cleaned by soaking in a 6% (by volume) solution of ENPREP-160SE (Cat. #2108-100, Enthone-OMI, Inc., West Haven, Conn.) in deionized water for 1 hour. After soaking, the parts were then rinsed several times with deionized water. After rinsing, the stents were soaked for 1 hour at room temperature in 0.5% (by volume) methacryloxypropyltrimethoxy silane (Cat.#M6514, Sigma Aldrich, St. Louis, Mo.) made in a 50% (by volume) solution of deionized water and isopropyl alcohol. The stainless steel wires were allowed to drain and air dry. The dried stents were then placed in a 100° C. oven for 1 hour.
After oven-drying, the stents were placed in a parylene coating reactor (PDS 2010 LABCOTER™ 2, Specialty Coating Systems, Indianapolis, Ind.) and coated with 2 g of Parylene C (Specialty Coating Systems, Indianapolis, Ind.) by following the operating instructions for the LABCOTER™ system. The resulting Parylene C coating was approximately 1-2 μm thickness.
Solutions for coatings were sprayed onto the Parylene C treated stents using an IVEK sprayer (IVEK Dispenser 2000, IVEK Corp., North Springfield, Vt.) mounting a nozzle with a 1.0 mm (0.04 inch) diameter orifice and pressurized at 421.84 g/cm.sup.2 (6 psi). The distance from the nozzle to the stent surface during coating application was 5 to 5.5 cm. A coating application consisted of spraying 40 μL of the coating solution back and forth on the stent for 7 seconds. The spraying process of the coating was repeated until the amount of lidocaine on the stent was estimated to be around 200 micrograms. The coating compositions on the stents were dried by evaporation of solvent, approximately 8-10 hours, at room temperature (approximately 20° C. to 22° C.). After drying, the coated stents were re-weighed. From this weight, the mass of the coating was calculated, which in turn permitted the mass of the coated polymer(s) and lidocaine to be determined.
Three solutions were prepared in THF; each solution was prepared at 50 mg/mL. The three solutions were comprised of maltodextrin-propionate (MD-Prop) (from Example 8), maltodextrin-acetate (MD-Ace) (from Example 2), and maltodextrin-caproate (MD-Cap) (from Example 10). Each of these solutions was coated onto PBMA/PEVA/lidocaine coated stents as described above. The spraying process was repeated until the amount of MD polymer was estimated to be around 500 micrograms.
The Elution Assay utilized herein was as follows. Phosphate buffered saline (PBS, 10 mM phosphate, 150 mM NaCl, pH 7.4, aqueous solution) was pipetted in an amount of 3 mL to 10 mL into an amber vial with a Teflon™ lined cap. A wire or coil treated with the coating composition was immersed into the PBS. A stir bar was placed into the vial and the cap was screwed tightly onto the vial. The PBS was stirred with the use of a stir plate, and the temperature of the PBS was maintained at 37° C. with the use of a water bath. The sampling times were chosen based upon the expected or desired elution rate. At the sampling time point, the stent was removed from the vial and placed into a new vial containing fresh PBS. A UV/VIS spectrophotometer was used to determine the concentration of the drug in the PBS solution that previously contained the stent treated with the coating composition. The cumulative amount of drug eluted versus time was plotted to obtain an elution profile. The elution profiles are illustrated graphically in
1 cm×0.75 cm strips were cut from a sheet of magnesium alloy (96% magnesium, 3% aluminum, 1% zinc; Goodfellow Cambridge Lmtd., Huntington, England). 1000 mg of MD-Cap DS 2.5 (from Example 10) was dissolved in THF at room temperature. Half of the magnesium alloy strips were coated with MD-Cap DS 2.5 by dipping the bottom half of each strip into the polymer solution, removing the strip, allowing the strip to dry, dipping the top half of the strip into the polymer solution, removing the strip and allowing the strip to dry. This procedure was repeated 4 times. Both the coated and uncoated strips were subsequently weighed. Coated and uncoated strips are placed individually into vials and 2 mls of phosphate buffered saline (PBS) pH 7.4 is added to each vial. The vials were sealed and placed in a 37° C. environmental chamber. At various time points the vials were removed from the chamber and the strips visually observed; approximate estimates of the amount of each strip remaining were made and are shown in Table 1.
Triamcinolone acetonide-releasing medical implants were prepared by combining various hydrophobic maltodextrin (MD) polymers with triamcinolone acetonide (TA) in various ratios. In some cases a hydrophilic polymer was added to the hydrophobic MD and TA. Implants were prepared using hydrophobic MDs, TA, and hydrophilic polymers in the amounts as shown in Table 2.
The ingredients were heated and mixed in an extruder (DACA™ Microcompounder; DACA Instruments, Santa Barbara Calif.). Total batch size for an individual preparation was 4 grams. For example 2 g of MD-Hex (DS 2.5)˜3 kDa was mixed with 2 g of triamcinolone acetonide (Pharmacia & Upjohn Company) the preparation of implant sample A. Ingredients were fed in dry (powder of pellet) form to the feed section of the heated extruder. For preparations containing MD-But 2.0 the extruder was heated to a temperature of approximately 150° C. For preparations containing MD-But 2.0 the extruder was heated to a temperature of approximately 150° C. For preparations containing MD-Hex 2.5, MD-Hep 2.5, or if the preparation included a hydrophilic polymer, the extruder was heated to a temperature of approximately 110° C. The extruder heated, mixed, and recirculated the ingredients to create a uniform mixture. The polymeric ingredients melted and blended together, and the TA is uniformly blended into the polymer melt. Processing temperatures did not melt PVP in the PVP-containing mixtures. The ingredients were mixed for an average of about 6 minutes before being extruded. Solvent was not added, so the original polymorphic form of the TA during the extrusion process was maintained. After melting and mixing, the mixture was extruded out of a die and elongated into a cylindrical shape with diameter in the range of about 250 μm to about 650 μm. Other diameters, such in the range of about 100 μm to 1000 μm, can be prepared. Upon cooling and solidification, the resulting cylinders were cut to the desired length, typically 3-6 mm, to create the implant.
Claims
1. A hydrophobic derivative of a natural biodegradable polysaccharide comprising: wherein the hydrophobic derivative has a molecular weight of 100,000 Da or less.
- a non-cyclic poly-α(1→4)glucopyranose backbone; and
- a plurality of groups pendent from the poly-α(1→4)glucopyranose backbone, the groups comprising a hydrocarbon segment comprising two or more carbon atoms;
2. The hydrophobic derivative of claim 1 having a molecular weight 50,000 Da or less.
3. The hydrophobic derivative of claim 2 wherein the hydrophobic derivative has a molecular weight of 25,000 Da or less.
4. The hydrophobic derivative of claim 3 wherein the hydrophobic derivative has a molecular weight in the range of 2000 Da to 20,000 Da.
5. The hydrophobic derivative of claim 4 wherein the hydrophobic derivative has a molecular weight in the range of 4000 Da to 10,000 Da.
6. The hydrophobic derivative of claim 1 wherein the hydrocarbon segment is selected from the group consisting of linear, branched, and cyclic C2-C18 groups.
7. The hydrophobic derivative of claim 6 wherein the hydrocarbon segment is selected from the group consisting of linear, branched, and cyclic C4-C10 groups.
8. The hydrophobic derivative of claim 7 wherein the plurality of groups pendent from the poly-α(1→4)glucopyranose backbone provide a degree of substitution in the range of 2-3.
9. The hydrophobic derivative of claim 7 wherein the hydrocarbon segment is selected from the group consisting of linear, branched, and cyclic C5-C7 groups.
10. The hydrophobic derivative of claim 7 wherein the hydrocarbon segment is selected from the group consisting of branched C4-C8 alkyl groups.
11. The hydrophobic derivative of claim 10 wherein the plurality of groups pendent from the poly-α(1→4)glucopyranose backbone provide a degree of substitution in the range of 0.5-1.5.
12. The hydrophobic derivative of claim 7 wherein the hydrocarbon segment is an aromatic C6 group.
13. The hydrophobic derivative of claim 1 wherein the groups pendent from the poly-α(1→4)glucopyranose backbone are coupled to the backbone via hydrolyzable covalent bonds.
14. The hydrophobic derivative of claim 1 wherein the groups pendent from the poly-α(1 →4)glucopyranose backbone are coupled to the backbone via hydrolyzable ester bonds.
15. A hydrophobic derivative of a natural biodegradable polysaccharide comprising: wherein the hydrophobic derivative has a molecular weight of 100,000 Da or less and a Tg of 35° C. or greater.
- a non-cyclic poly-α(1→4)glucopyranose backbone; and
- a plurality of groups pendent from the poly-α(1→4)glucopyranose backbone,
16. The hydrophobic derivative of claim 15 having a Tg in the range of 40° C. to 65° C.
17. A hydrophobic derivative of a natural biodegradable polysaccharide comprising: wherein the weight ratio between the hydrophilic portion and the hydrophobic portion in the range of 5:1 to 1:1.25, and wherein the hydrophobic derivative has a molecular weight of 100,000 Da or less.
- a hydrophilic portion comprising a non-cyclic poly-α(1→4)glucopyranose backbone; and
- a hydrophobic portion comprising a plurality of groups pendent from the poly-α(1→4)glucopyranose backbone,
18. The hydrophobic derivative of claim 17 wherein the weight ratio between the hydrophilic portion and the hydrophobic portion in the range of 2:1 to 1:1.25
19. The hydrophobic derivative of claim 18 wherein the weight ratio between the hydrophilic portion and the hydrophobic portion in the range of 1:0.75 to 1:1.25
20. The hydrophobic derivative of claim 19 wherein the weight ratio between the hydrophilic portion and the hydrophobic portion in the range of 1:1 to 1:1.25
21. A hydrophobic derivative of a natural biodegradable polysaccharide comprising: wherein the hydrophobic derivative has a molecular weight of 100,000 Da or less.
- a non-cyclic poly-α(1→4)glucopyranose backbone; and
- a plurality of groups pendent from the poly-α(1→4)glucopyranose backbone, the groups comprising a hydrocarbon segment, wherein at least a portion of the groups comprise a bioactive agent that is cleavable from the poly-α(1→4)glucopyranose backbone,
22. The hydrophobic derivative of claim 21 wherein the bioactive agent is an anti-inflammatory agent.
23. The hydrophobic derivative of claim 21 wherein the bioactive agent is an antiproliferative.
24. The hydrophobic derivative of claim 21 wherein the bioactive agent is a steroid.
25. The hydrophobic derivative of claim 21 wherein the bioactive agent comprises a carboxylate group.
26. A hydrophobic derivative of a natural biodegradable polysaccharide comprising: wherein the hydrophobic derivative has a molecular weight of 100,000 Da or less.
- a polymeric backbone comprising non-reducing disaccharides; and
- a plurality of groups pendent from the polymeric backbone,
27. The hydrophobic derivative of claim 26 wherein the polymeric backbone is selected from the group consisting of polytrehalose, polysucrose, and polyalditol.
Type: Application
Filed: Mar 15, 2007
Publication Date: Nov 8, 2007
Applicant:
Inventor: Stephen J. Chudzik (St. Paul, MN)
Application Number: 11/724,553
International Classification: C07H 1/00 (20060101);
