Amphiphilic polysaccharide derivatives

Details Amphiphilic polysaccharide derivatives Amphiphilic polysaccharide derivatives

1999-04-27

2001-06-12

Fonda, Kathleen K. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S054000, C514S057000, C536S021000, C536S017500, C536S056000, C536S092000, C536S095000, C536S122000, C536S123100, C606S228000, C606S231000, C604S890100, C604S891100

Reexamination Certificate

active

06245753

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to polysaccharide derivatives having increased hydrophobicity as compared to the unmodified polysaccharide. More particularly, the invention relates to amphiphilic polysaccharide derivatives, such as amphiphilic heparin derivatives, wherein the bioactivity of the polysaccharide is preserved. Further, the invention relates to methods of making and using such amphiphilic polysaccharide derivatives.
Heparin is a polysaccharide composed of sulfated D-glucosamine and D-glucuronic acid residues. Due to its numerous ionizable sulfate groups, heparin possesses a strong electronegative charge. It is also a relatively strong acid that readily forms water-soluble salts, e.g. heparin sodium. It is found in mast cells and can be extracted from many body organs, particularly those with abundant mast cells. The liver and lungs are especially rich in heparin. The circulating blood contains no heparin except after profound disruption of mast cells. Heparin has many physiological roles, such as blood anticoagulation, inhibition of smooth muscle cell proliferation, and so forth. In particular, heparin is a potent anticoagulant agent that interacts strongly with antithrombin III to prevent the formation of fibrin clots. In vivo, however, applications of heparin are very limited. Because of its hydrophilicity and high negative charge, heparin is not absorbed efficiently from the GI tract, nasal or buccal mucosal layers, and the like. Therefore, the only routes of administration used clinically are intravenous and subcutaneous injections. Moreover, since heparin is soluble in relatively few solvents, it is hard to use for coating surfaces of medical devices or in delivery systems.
To improve the properties of heparin, R. J. Linhardt et al., 83 J. Pharm. Sci. 1034-1039 (1994), coupled lauryl (C
12
) and stearyl (C
18
) groups to single heparin chains, resulting in a derivatized heparin having increased hydrophobicity but with low anticoagulant activity. This result demonstrated that coupling a small linear aliphatic chain to heparin was ineffective in enhancing the hydrophobicity of heparin while preserving activity. Thus, known heparin derivatives have been ineffective in preserving anticoagulation activity.
Rivera et al., Oral Delivery of Heparin in Combination with Sodium N-[8-(2-Hydroxybenzolyl)amino]caprylate: Pharmacological Considerations, 14 Pharm. Res. 1830-1834 (1997), disclosed the possibility of oral delivery of heparin using heparin mixed with sodium N [8-(2-hydroxybenzolyl)amino]caprylate. Dryjski et al., Investigations on Plasma Activity of Low Molecular Weight Heparin after Intravenous and Oral Administrations, 28 Br. J. Clin. Pharma. 188-192 (1989), described the possibility of oral absorption of low molecular weight heparin using enhancers.
Two basic methods have been developed for the formulation of a heparin-releasing system. One method involves binding heparin to a cationic polymer matrix by ionic bonds. The release of heparin is controlled by an ion exchange mechanism. Another method involves dispersed heparin, where heparin is first physically blended with a polymer, and then the release of heparin is controlled by diffusion. The most simple and efficient method for preparing such a heparin device is solvent casting. But a solvent casting method cannot be used for preparing the heparin device since heparin is not dissolved in the organic solvent used for dissolving the polymer. If heparin derivatives could be prepared with increased hydrophobicity while maintaining bioactivity, then the heparin derivatives could be simply immobilized in a polymer matrix by a solvent casting procedure.
In view of the foregoing, it will be appreciated that the development of a hydrophobic heparin derivative or amphiphilic heparin derivative having high bioactivity would be a significant advancement in the art. Such a hydrophobic heparin derivative could be used in a controlled release system, for oral administration, or for surface modification of medical devices for improving biocompatibility. Such a heparin derivative would greatly extend the medical applications of heparin.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to synthesize amphiphilic heparin derivatives having high heparin bioactivity.
It is also an object of the invention to provide a hydrophobic heparin derivative that is soluble in a solvent such as acetone/water, as well as water.
It is another object of the invention to provide heparin derivatives that can be used for a controlled release system to prevent coagulation at a surface.
It is still another object of the invention to provide heparin derivatives that can be absorbed from the GI tract, thereby facilitating oral delivery for preventing blood coagulation.
It is yet another object of the invention to provide heparin derivatives comprising heparin coupled with a bile acid, such as deoxycholic acid or glycocholic acid, or a hydrophobic agent, such as cholesterol, or an alkanoic acid.
These and other objects can be addressed by providing a composition of matter comprising a polysaccharide covalently bonded to a hydrophobic agent. Preferably, the polysaccharide is a member selected from the group consisting of heparin, heparin sodium, sulfonated polysaccharides, cellulose, hydroxymethylcellulose, and hydroxypropylcellulose. An especially preferred polysaccharide is heparin. Preferably, such heparin has a molecular weight of about 200 to 100,000. In a preferred embodiment of the invention, the hydrophobic agent is a member selected from the group consisting of bile acids, sterols, and alkanoic acids. Preferred bile acids include cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, and mixtures thereof. Preferred sterols include cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and mixtures thereof. Preferred alkanoic acids comprise about 4 to 20 carbon atoms, such as butyric acid, valeric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and mixtures thereof. Preferably the polysaccharide and the hydrophobic agent are present in a mole ratio of about 1:1 to 1:1000.
Another aspect of the invention comprises a pharmaceutical composition comprising a pharmaceutically effective amount of (a) a composition of matter comprising a polysaccharide covalently bonded to a hydrophobic agent, and (b) a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier can be an oral drug carrier, sustained release carrier, carrier for parenteral administration, and the like. Preferred sustained release carriers include polymeric matrices such as are well known in the art, including members selected from the group consisting of poly(ethylene oxide)-poly(&egr;-caprolactone) copolymers, polyurethane polymers, silicone polymers, ethylene vinyl acetate polymers, hydrogels, collagen, gelatin, and mixtures thereof, and the like.
Still another aspect of the invention comprises a method for inhibiting blood coagulation on medical devices that come in contact with blood comprising coating the medical device with a pharmaceutical composition comprising a polymeric matrix intimately admixed with a composition of matter comprising heparin covalently bonded to a hydrophobic agent. Typically, the medical device is coated by using a film casting technique such as is well known in the art.


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A. Leone-Bay, et al.; 4-[4-(2-Hydroxybenzoyl)amino]phenyl butyric Acid as a Novel Oral Delivery Agent for Recombinant Human Growth Hormone, 39 J. Med. Chem. 2571-2578 (1996).
R. Altman, et al.; Oral Anticoagulant Treatm

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