Water insoluble derivatives of polyanionic polysaccharides

• US 6,610,669 B1
• Filed: 12/22/1999
• Issued: 08/26/2003
• Est. Priority Date: 09/18/1987
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Miller, Robert J., Calias, Pericles
• Primary Examiner(s): HENLEY III, RAYMOND J
• Application Number:
  US09/469,638
• Time in Patent Office: 1,343 Days
• Field of Search: 536/84, 536/88, 536/89, 536/98, 536/124, 514/54, 514/57
• 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 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• 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 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/042 Polysaccharides
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• 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 2666/02 : Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• 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 gel is prepared by reacting carboxymethylcellulose and a carbodiimide, wherein the reaction is conducted in an aqueous medium containing a water miscible organic solvent, such as a lower alkanol, an alkyl pyrrolidone, DMSO or acetone. The present method permits the reaction to contain higher concentrations of carboxymethycellylose and less carbodiimide than conventional methods.

Claims

1. A method for preparing a water insoluble biocompatible gel comprising reacting a polyanionic polysaccharide with an activating agent in an aqueous solution containing a water miscible organic solvent selected from the group consisting of a lower alkanol and a polar aprotic solvent.

2. The method of claim 1 wherein the polar aprotic solvent is selected from the group consisting of an alkyl pyrrolidones, DMSO and acetone.

3. The method of claim 1 wherein said polyanionic polysaccharide is chosen from the group consisting of hyaluronic acid, carboxymethyl cellulose, carboxymethyl amylose, carboxymethyl chitosan, chondroitin-6-sulfate, dermatin sulfate, heparin, and heparin sulfate.

4. The method of claim 3 wherein said polyanionic polysaccharide is hyaluronic acid.

5. The method of claim 3 wherein said polyanionic polysaccharide is carboxymethyl cellulose.

6. The method of claim 1 wherein said activating agent comprises a carbodiimide.

7. The method of claim 6 wherein said carbodiimide comprises 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide methiodide.

8. The method of claim 1 wherein the solvent is a lower alkanol.

9. The method of claim 8 wherein the solvent is ethanol or isopropanol.

10. The method of claim 2 wherein the solvent is an alkyl pyrrolidone.

11. The method of claim 10 wherein the solvent is N-methyl-2-pyrrolidone.

12. The method of claim 2 wherein the solvent is DMSO.

13. The method of claim 2 wherein the solvent is acetone.

14. The method of claim 1 wherein the concentration of solvent in the solution is in the range of from about 5% to about 80% by weight.

15. The method of claim 1 wherein polyanionic polysaccharide is present in a concentration range of 0.2M to 2.0M.

16. The method of claim 1 wherein said method is carried out at a pH of 4.0 to 5.0.

17. The method of claim 1 wherein the molar ratio of carboxyl groups of said polyanionic polysaccharide to said activating agent is less than about 1:

1.

18. The method of claim 17 wherein the molar ratio of carboxyl groups of said polyanionic polysaccharide to said activating agent is less than about 1:

4.

19. A water insoluble biocompatible gel prepared according to the method of claims 4 or 5.

20. The gel of claim 19 further comprising a pharmaceutically active substance dispersed within said gel.

21. The gel of claim 20 wherein said pharmaceutically active substance is chosen from the group consisting of growth factors, enzymes, drugs, biopolymers, and biologically compatible synthetic polymers.

22. A method of preventing post-operative adhesions comprising inserting, into the locus between tissues to be separated during the healing process following surgery, the water insoluble, biocompatible gel of claim 19.

23. The method of claim 22 wherein the gel is inserted into the locus between tissues using a laparoscopic instrument during a minimally invasive surgical procedure.