Amphiphilic polysaccharide derivatives

• US 6,245,753 B1
• Filed: 04/27/1999
• Issued: 06/12/2001
• Est. Priority Date: 05/28/1998
• Status: Active Grant

• Current Assignee: Mediplex Corporation, Korea
• Original Assignee: Mediplex Corporation, Korea
• Inventors: Lee, Yong-Kyu, Byun, Youngro
• Primary Examiner(s): FONDA, KATHLEEN KAHLER
• Application Number:
  US09/300,173
• Time in Patent Office: 777 Days
• Field of Search: 514/54, 514/56, 514/57, 536/21, 536/17.5, 536/56, 536/92, 536/95, 536/122, 536/123.1, 606/228, 606/231, 604/890.1, 604/891.1
• US Class Current: 514/56
• CPC Class Codes: A61K 31/727 Heparin; Heparan
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: C08B 37/00 Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof cellulose D21; microbiological processes C12P
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/775 Nanosized powder or flake, e.g. nanosized catalyst
• CPC Class Codes: Y10S 977/905 Specially adapted for travel through blood circulatory system
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

Polysaccharides, which are widely used as an anticoagulation drugs, especially heparin, are clinically administered only by intravenous or subcutaneous injection because of their strong hydrophilicity and high negative charge. Amphiphilic heparin derivatives were synthesized by conjugate to bile acids, sterols, and alkanoic acids, respectively. The hydrophobicity of the heparin derivatives depended on the feed mole ratio of heparin to hydrophobic agent. The heparin derivatives were slightly hydrophobic and exhibited good solubility in a water-acetone solvent, as well as water. The heparin derivatives have a high anticoagulant activity. These slightly hydrophobic heparin derivatives can be absorbed in gastric intestinal tract and can be used as oral dosage form. Also, the heparin derivatives can be used for the surface modification to prevent anticoagulation for medical devices such as extracorporeal devices and implanted devices.

Claims

1. A composition of matter comprising a polysaccharide covalently bonded to a hydrophobic agent, wherein said hydrophobic agent is a member selected from the group consisting of sterols, 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.

2. The composition of matter of claim 1 wherein the polysaccharide is a member selected from the group consisting of heparin, heparin sodium, sulfonated polysaccharides, cellulose, hydroxymethylcellulose, and hydroxypropylcellulose.

3. The composition of matter of claim 2 wherein said polysaccharide is heparin.

4. The composition of matter of claim 3 wherein said heparin has a molecular weight of about 200 to 100,000.

5. A composition of matter comprising heparin covalently bonded to a sterol, wherein the sterol is a member composition of matter of claim 3 wherein said hydrophobic agent is selected from the group consisting of cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and mixtures thereof.

6. The composition of matter of claim 1 wherein said polysaccharide and said hydrophobic agent are present in a mole ratio of about 1:

1 to 1;

1000.

16. The composition of matter of claim 1 wherein the hydrophobic agent is deoxycholic acid.

7. A pharmaceutical composition comprising (a) a pharmaceutically effective amount of a composition of matter comprising a polysaccharide covalently bonded to a hydrophobic agent, wherein the hydrophobic agent is a member selected from the group consisting of sterols, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, ursodeoxycholic acid, isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycochenodeoxvcholic acid, dehydrocholic acid, hyocholic acid, hyodeoxycholic acid, and mixtures thereof and (b) a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7 wherein said pharmaceutically acceptable carrier is an oral drug carrier.

9. The pharmaceutical composition of claim 8 wherein said pharmaceutically acceptable carrier is a sustained release carrier.

10. The pharmaceutical composition of claim 9 wherein said sustained release carrier is a polymeric matrix.

11. The pharmaceutical composition of claim 10 wherein said sustained release carrier is a polymeric matrix selected from the group consisting of poly(ethylene oxide)-poly(ε

-caprolactone)copolymers, polyurethane polymers, silicone polymers, ethylene vinyl acetate polymers, hydrogels, collagen, gelatin, and mixtures thereof.

12. The pharmaceutical composition of claim 11 wherein said polymeric matrix is a poly((ethylene oxide)-poly(ε

-caprolactone) copolymer.

13. The pharmaceutical composition of claim 7 wherein said polysaccharide is heparin.

17. The pharmaceutical composition of claim 7 wherein the hydrophobic agent is a sterol selected from the group consisting of cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and mixtures thereof.

18. The pharmaceutical composition of claim 7 wherein the hydrophobic agent is deoxycholic acid.

19. The pharmaceutical composition of claim 13 wherein the hydrophobic agent is a sterol selected from the group consisting of cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and mixtures thereof.

20. The pharmaceutical composition of claim 13 wherein the hydrophobic agent is deoxycholic acid.

14. A method for inhibiting blood coagulation on a medical device that comes in contact with blood comprising coating said 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, wherein the hydrophobic agent is a member selected from the group consisting of sterols, 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.

15. The method of claim 14 wherein said polymeric matrix is a member selected from the group consisting of poly(ethylene oxide)-poly(ε

-caprolactone) copolymers, polyurethane polymers, silicone polymers, ethylene vinyl acetate polymers, hydrogels, collagen, gelatin, and mixtures thereof.

21. The method of claim 14 wherein the hydrophobic agent is a sterol selected from the group consisting of cholestanol, coprostanol, cholesterol, epicholesterol, ergosterol, ergocalciferol, and mixtures thereof.

22. The method of claim 14 wherein the hydrophobic agent is deoxycholic acid.