Water insoluble derivatives of hyaluronic acid

• US 5,017,229 A
• Filed: 06/25/1990
• Issued: 05/21/1991
• Est. Priority Date: 06/25/1990
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Genzyme Corporation (Sanofi )
• Inventors: Cox, Steven, Burns, James W., Walts, Alan E.
• Primary Examiner(s): Morris, Theodore
• Assistant Examiner(s): Brunsman, David M.
• Application Number:
  US07/543,163
• Time in Patent Office: 330 Days
• Field of Search: 252/315.3, 514/777, 424/7.1, 424/488, 536/4.1, 106/157, 106/162, 106/186, 106/213
• US Class Current: 106/162.2
• CPC Class Codes: A61B 90/00 Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges protective face masks A41D13/11; surgeon's or patient's gowns or dresses A41D13/12; devices for carrying-off, for treatment of, or for carrying-over, body liquids A61M1/00
• 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: A61L 31/042 Polysaccharides
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• 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: 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 that includes the reaction product of hyaluronic acid, a polyanionic polysaccharide, and an activating agent.

Claims

1. A method for making a water insoluble biocompatible gel, said method comprising

combining an aqueous solution of HA at a concentration in the range between 0.4% and 2.6% w/w, a polyanionic polysaccharide, and an activating agent under conditions sufficient to form said gel.

2. The method of claim 1 wherein said polyanionic polysaccharide is chosen from the group consisting of carboxymethylcellulose, carboxymethylamylose, chondroitin-6-sulfate, dermatin sulfate, heparin, and heparin sulfate.

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

4. The method of claim 2 wherein said polyanionic polysaccharide is carboxymethylamylose.

5. The method of claim 1 wherein said HA and said polyanionic polysaccharide are added together, followed by addition of said activating agent.

6. The method of claim 1 wherein said polyanionic polysaccharide is combined with said activating agent, followed by addition of HA.

7. The method of claim 1 wherein said HA is combined with said activating agent, followed by addition of said polyanionic polysaccharide.

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

9. The method of claim 8 wherein said carbodiimide comprises 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide methiodide.

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

11. The method of claim 10 wherein said polyanionic polysaccharide is present in a concentration of 0.01-0.02M.

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

13. The method of claim 1 wherein the molar ratio of said polyanionic polysaccharide to said activating agent is at least 1:

1.

14. The method of claim 13 wherein the molar ratio of said polyanionic polysaccharide to said activating agent is about 1:

4.

15. A water insoluble biocompatible gel prepared according to the method of claim 1.

16. A water insoluble, biocompatible gel comprising the reaction product of HA, a polyanionic polysaccharide, and an activating agent.

17. The gel of claim 16 wherein said activating agent comprises a carbodiimide.

18. The gel of claim 17 wherein said carbodiimide comprises 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide methiodide.

19. The gel of claim 16, further comprising a pharmaceutically active substance dipsersed within said gel.

20. The gel of claim 19 wherein said pharmaceutically active substance is chosen from the group consisting of growth factors, enzymes, drugs, biopolymers, and biologically compatible synthetic polymers.

21. The gel of claim 16 wherein said polyanionic polysaccharide is chosen from the group consisting of carboxymethylcellulose, carboxymethylamylose, chondroitin-6-sulfate, dermatin sulfate, heparin, and heparin sulfate.

22. The gel of claim 21 wherein said polyanionic polysaccharide is carboxymethylcellulose.

23. The gel of claim 21 wherein said polyanionic polysaccharide is carboxymethylamylose.

24. The gel of claim 16 wherein said gel is in the form of an adhesion prevention composition.

25. The gel of claim 24 wherein said composition is in the form of a membrane.