Water insoluble derivatives of hyaluronic acid

• US 6,030,958 A
• Filed: 08/18/1997
• Issued: 02/29/2000
• Est. Priority Date: 09/18/1987
• Status: Expired due to Fees

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Miller, Robert, Burns, James W.
• Primary Examiner(s): FONDA, KATHLEEN KAHLER
• Application Number:
  US08/914,320
• Time in Patent Office: 925 Days
• Field of Search: 536/84, 536/88, 536/89, 536/98, 536/124, 514/57, 514/54
• US Class Current: 514/57
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: C08B 11/20 Post-etherification treatments of chemical or physical type, e.g. mixed etherification in two steps, including purification
• CPC Class Codes: C08B 33/00 Preparation of derivatives of amylose
• CPC Class Codes: C08B 33/04 Ethers
• 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 37/0063 Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
• CPC Class Codes: C08B 37/0069 Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08L 1/28 Alkyl ethers
• CPC Class Codes: C08L 3/18 Ethers
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

A water insoluble, biocompatible composition that includes the reaction product of a polyanionic polysaccharide and an activating agent.

Claims

1. A method for making a water insoluble biocompatible composition, said method consisting essentially of combining, in an aqueous solution, a polyanionic polysaccharide selected from the group consisting of carboxymethylcellulose and carboxymethylamylose, and a carbodiimide under conditions sufficient to form said composition, wherein the reaction is carried out at a pH below 8.0, and the molar ratio of polysaccharide to carbodiimide is 1 mole of carboxyl groups of polysaccharide to at least about 4 moles of carbodiimide.

2. The method of claim 1 wherein said polyanionic polysaccharide is carboxymethylcellulose.

3. The method of claim 1 wherein said polyanionic polysaccharide is carboxymethylamylose.

4. The method of claim 1 wherein said carbodiimide comprises 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide methiodide.

5. The method of claim 1 wherein said polyanionic polysaccharide is present in a concentration of 0.005-0.1M.

6. The method of claim 5 wherein said polyanionic polysaccharide is present in a concentration of 0.01-0.02M.

7. The method of claim 1 wherein said method is carried out at a pH 3.5-8.0.

8. The method of claim 1 wherein the molar ratio of said polyanionic polysaccharide to said carbodiimide is about 1:

4.

9. A water insoluble composition prepared according to the method of claim 1.

10. The composition of claim 9 wherein said composition is in the form of a gel.

11. The composition of claim 9 wherein said composition is in the form of fibers.

12. The composition of claim 9 wherein said polyanionic polysaccharide is carboxymethylcellulose.

13. The composition of claim 9 wherein said polyanionic polysaccharide is carboxymethylamylose.

14. The composition of claim 9 wherein said carbodiimide comprises 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide methiodide.

15. The composition of claim 9, further comprising a pharmaceutically active substance dispersed within said gel.

16. The composition of claim 15 wherein said pharmaceutically active substance is chosen from the group consisting of proteins, growth factors, enzymes, drugs, biopolymers, and biologically compatible synthetic polymers.

17. The composition of claim 9 wherein said composition is in the form of an adhesion prevention composition.

18. The composition of claim 9 wherein said composition is in the form of a membrane.

19. The composition of claim 9 wherein said composition is in the form of a foam.

20. The composition of claim 9 wherein said composition is in the form of a gel.

21. A method of preventing post-operative adhesions comprising inserting the composition of claim 9 into the locus between tissues to be separated during the healing process following surgery.