Method for producing double-crosslinked hyaluronate material

• US 20070066816A1
• Filed: 09/13/2006
• Published: 03/22/2007
• Est. Priority Date: 12/31/2002
• Status: Abandoned Application

• Current Assignee: Industrial Technology Research Institute
• Original Assignee: Industrial Technology Research Institute
• Inventors: Chen, Jui-Hsiang, Jan, Shu-Hua, Tsai, Shiao-Wen, Su, Li-Ting, Yang, Chiung-Lin, Chang, Pei-ching
• Application Number:
  US11/519,932
• Publication Number:
  US 20070066816A1
• Time in Patent Office: Days
• US Class Current: 536/53
• 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: D01F 11/00 Chemical after-treatment of artificial filaments or the like during manufacture
• CPC Class Codes: D01F 9/00 Artificial filaments or the like of other substances; Manufacture thereof; Apparatus specially adapted for the manufacture of carbon filaments

Abstract

Disclosed is a method for producing a double-crosslinked hyaluronate material. A hyaluronic acid or a salt thereof is sequentially reacted with an epoxide compound and a carbodiimide compound to produce a more biodegradation-resistant hyaluronate material. The HA acid is preferably reacted with the carbodiimide first, and more preferably in a mixed solvent including water and an organic solvent, such as ketone.

Claims

1. A method for producing double-crosslinked hyaluronate material, consisting essentially of the steps of:

(a) subjecting hyaluronic acid or a salt thereof to a first crosslinking reaction using either an epoxide compound or a carbodiimide compound as a crosslinking agent, and

(b) subjecting the product obtained from step (a) to a second crosslinking reaction using either an epoxide compound as a crosslinking agent if a carbodiimide compound was used as the crosslinking agent in step (a), or using a carbodiimide compound as a crosslinking agent if an epoxide compound was used as the crosslinking agent in step (a), thereby obtaining a double crosslinked hyaluronate material.

2. The method as claimed in claim 1, wherein the epoxide compound is a polyfunctional epoxide compound.

3. The method as claimed in claim 2, wherein the epoxide compound is 1,4-butanediol diglycidyl ether (BDDE), ethylene glycol diglycidyl ether (EGDGE), 1,6-hexanediol diglycigyl ether, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, polytetramethylene glycol digylcidyl ether, neopentyl glycol digylcidyl ether, polyglycerol polyglycidyl ether, diglycerol polyglycidyl ether, glycerol polyglycidyl ether, tri-methylolpropane polyglycidyl ether, pentaerythritol polyglycidyl ether, sorbitol polyglycidyl ether, or a combination thereof.

4. The method as claimed in claim 1, wherein the stoichiometry ratio of hyaluronic acid or a salt thereof to the epoxide compound in the crosslinking reaction is about 1:

50 to 1;

0.05 by crosslinking equivalent.

5. The method as claimed in claim 1, wherein the epoxide compound is in a solution with a concentration of about 0.1 to 30% by weight.

6. The method as claimed in claim 1, wherein the temperature for crosslinking reaction using the epoxide compound as the crosslinking agent is between about 15 and 80°

C.

7. The method as claimed in claim 1, wherein the time for crosslinking reaction with the epoxide compound as the crosslinking agent is between 10 minutes and 12 hours.

8. The method as claimed in claim 1, wherein the carbodiimide compound is 1-methyl-3-(3-dimethyl-aminopropyl)-carbodiimide, 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide, 3-(3-dimethylaminopropyl)-3-ethylcarbodiimide, or a combination thereof.

9. The method as claimed in claim 1, wherein the stoichiometry ratio of hyaluronic acid or a salt thereof to the carbodiimide compound in the crosslinking reaction is about 1:

50 to 1;

0.05 by crosslinking equivalent.

10. The method as claimed in claim 1, wherein the carbodiimide compound is in a solution with a concentration of about 0.1 to 30% by weight.

11. The method as claimed in claim 1, wherein the temperature for crosslinking reaction using the carbodiimide compound as the crosslinking agent is between about 15 and 80°

C.

12. The method as claimed in claim 1, wherein the time for crosslinking reaction using the carbodiimide compound as the crosslinking agent is between 30 minutes and 12 hours.

13. The method as claimed in claim 1, wherein the hyaluronic acid or a salt thereof is contained in a material.

14. The method as claimed in claim 1, wherein, in step (a), the hyaluronic acid or a salt thereof is preformed into a solution, film, membrane, powder, microsphere, fiber, filament, matrix, porous substrate or gel before undergoing the first crosslinking reaction.

15. The method as claimed in claim 14, wherein the film is formed by placing a solution of hyaluronic acid or a salt thereof with a concentration of about 1 to 20% by weight in a mold and drying at a temperature between 25 and 70°

C.

16. The method as claimed in claim 14, wherein the film has a thickness of about 10 to 5000 μ

m.

17. The method as claimed in claim 14, wherein the microsphere is formed by intermittently extruding and dropping a solution of hyaluronic acid or a salt thereof into a coagulant.

18. The method as claimed in claim 14, wherein the microsphere has a diameter of about 0.01 to 2000 μ

m.

19. The method as claimed in claim 14, wherein the fiber is formed by extruding a solution of hyaluronic acid or a salt thereof into a coagulant.

20. The method as claimed in claim 1, wherein, in step (b), the product obtained from step (a) is preformed into a solution, film, membrane, powder, microsphere, fiber, filament, matrix, porous substrate or gel before undergoing the second crosslinking reaction.

21. The method as claimed in claim 20, wherein the film is formed by placing the product obtained from step (a) in a mold and drying at a temperature between 25 and 70°

C.

22. The method as claimed in claim 20, wherein the film has a thickness of about 10 to 5000 μ

m.

23. The method as claimed in claim 20, wherein the microsphere is formed by intermittently extruding and dropping the product obtained from step (a) into a coagulant.

24. The method as claimed in claim 20, wherein the microsphere has a diameter of about 0.01 to 2000 μ

m.

25. The method as claimed in claim 20, wherein the fiber is formed by extruding the product obtained from step (a) into a coagulant.

26. The method as claimed in claim 1, after step (b), further comprising the following step:

(c) washing and drying the double-crosslinked hyaluronate material obtained in step (b).

27. The method as claimed in claim 26, wherein step (c) includes washing and drying at a temperature less than 60°

C.

28. The method as claimed in claim 1, wherein the double-crosslinked hyaluronate material is in the form of solution, film, membrane, powder, microsphere, fiber, filament, matrix, porous substrate or gel.

29. The method as claimed in claim 28, wherein the film has an in vitro hyluronidase degradation of less than 1% by weight.

30. The method as claimed in claim 28, wherein the film has an in vitro hyluronidase degradation of less than 0.5% by weight.

31. The method as claimed in claim 28, wherein the gel has an in vitro hyluronidase degradation of less than 50% by weight.

32. The method as claimed in claim 28, wherein the gel has an in vitro hyluronidase degradation of less than 40% by weight.

33. The method as claimed in claim 1, wherein the first crosslinking reaction uses the carbodiimide compound as a crosslinking agent, and the second crosslinking reaction uses the epoxide compound as a crosslinking agent.

34. The method as claimed in claim 1, wherein the crosslinking reaction is performed in a mixed solvent including an organic solvent and water.

35. The method as claimed in claim 34, wherein the organic solvent comprises acetone.

36. The method as claimed in claim 34, wherein the organic solvent has a higher volume ratio than the water.

37. A double-crosslinked hyaluronate material produced by the method as claimed in claim 1.