Polysaccharide gel composition

• US 5,827,937 A
• Filed: 07/17/1995
• Issued: 10/27/1998
• Est. Priority Date: 07/17/1995
• Status: Expired due to Term

• Current Assignee: Q-Med Aktiebolag (Nestle SA)
• Original Assignee: Q-Med Aktiebolag (Nestle SA)
• Inventors: .ANG.gerup, Bengt
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): White, Everett
• Application Number:
  US08/503,323
• Time in Patent Office: 1,198 Days
• Field of Search: 536/20, 536/21, 536/119, 536/123.1, 536/124, 536/123.12, 514/54, 514/55, 514/56
• US Class Current: 536/123.12
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• 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: C08J 2305/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08J 3/075 Macromolecular gels

Abstract

The present invention provides a process for preparing a cross-linked biocompatible polysaccharide gel composition, which comprises:

forming an aqueous solution of a water soluble, cross-linkable polysaccharide;

initiating a cross-linking of said polysaccharide in the presence of a polyfunctional cross-linking agent therefor;

sterically hindering the cross-linking reaction from being terminated before gelation occurs, an activated poly-saccharide being obtained; and

reintroducing sterically unhindered conditions for said activated polysaccharide so as to continue the cross-linking thereof to a viscoelastic gel. The invention also provides a gel composition obtainable by such a process as well as gel compositions for different medical uses.

Claims

1. A process for preparing a cross-linked biocompatible polysaccharide gel composition, which process comprises the following steps:

(i) forming an aqueous solution of a water soluble, cross-linkable polysaccharide;

(ii) initiating a first cross-linking reaction whereby cross-linking of said polysaccharide is effected using a polyfunctional cross-linking agent therefor;

(iii) sterically hindering the first cross-linking reaction such that it is terminated before gelation occurs, resulting in the production of an activated polysaccharide; and

(iv) performing a second cross-linking reaction after sterically unhindered conditions are reintroduced for said activated polysaccharide to produce a viscoelastic gel.

2. A process according to claim 1, wherein the polysaccharide is selected from the group consisting of glucose amino glucans.

3. A process according to claim 2, wherein said glucose amine glucan comprises hyaluronic acid.

4. A process according to claim 1 wherein the cross-linking agent is selected from the group consisting of aldehydes, epoxides, polyaziridyl compounds, glycidyl ethers and divinyl sulphones.

5. A process according to claim 4, wherein said glycidyl ether comprises 1,4-butanediol diglycidylether.

6. A process according to claim 1, wherein said sterically hindering of the cross-linking reaction comprises diluting the aqueous medium in which the cross-linking reaction is performed, to accomplish a lower concentration of the polysaccharide in said medium.

7. A process according to claim 1, wherein said reintroduction of sterically unhindered conditions comprises evaporating the aqueous medium in which the cross-linking reaction is performed, to accomplish a higher concentration of the polysaccharide in said medium.

8. A process according to claim 1, wherein said reintroduction of sterically unhindered conditions comprises dialysing the aqueous medium in which the cross-linking reaction is performed.

9. A process according to claim 1, wherein the initial cross-linking reaction in the presence of a polyfunctional cross-linking agent is performed at an alkaline pH, ether cross-linking reactions thereby being promoted.

10. The process of claim 9, wherein the cross-linking is effected at a pH above pH 9.

11. A process according to claim 1, wherein the initial cross-linking reaction in the presence of a polyfunctional cross-linking agent is performed at an acidic pH, ester cross-linking reactions thereby being promoted.

12. A process according to claim 1, wherein said sterical hindrance of the cross-linking reaction is accomplished before said cross-linking agent has been consumed.

13. A process according to claim 1, wherein a biologically active substance is enclosed within the cross-linked polysaccharide gel composition during the preparation thereof.

14. A process according to claim 13, wherein said active substance is enclosed within the gel composition by dissolving or dispersing the same in said activated polysaccharide before subjecting last-mentioned polysaccharide to sterically unhindered conditions.

15. A process according to claim 14, wherein said biologically active substance is selected from the group consisting of hormones, cytokines, vaccines, cells and tissue augmenting substances.

16. A process according to claim 13, wherein said biologically active substance is selected from the group consisting of hormones, cytokines, vaccines, cells and tissue augmenting substances.

17. A process according to claim 16, wherein said tissue augmenting substance comprises a polymer selected from the group consisting of collagen, starch, dextranomer, polylactide, poly-β

-hydroxybutyrate and copolymers thereof.

18. A process according to claim 16, wherein said hormone is selected from the group consisting of erytropoeitin and calcitonin.

19. A process according to claim 13, wherein said biologically active substance contains functional groups reactive with the polysaccharide and is enclosed within the gel structure by chemical reaction therewith.

20. A process according to claim 19, wherein said biologically active substance containing functional groups has been prereacted with a cross-linking agent for said polysaccharide.

21. The process of claim 20, wherein the same cross-linking agent is used for said prereaction.

22. The process of claim 13, wherein the cross-linking is effected at a pH ranging from 2 to 6.

23. The process of claim 13, wherein the biologically active substance is introduced at physiological pH and salt concentration conditions.

24. A cross-linked biocompatible polysaccharide gel composition, which is obtainable by cross-linking of a cross-linkable polysaccharide with a polyfunctional cross-linking agent therefor in two steps, the first cross-linking step being terminated before gelation occurs by a sterical hindrance of the cross-linking reaction, and the second cross-linking step being initiated by reintroducing sterically unhindered conditions for said cross-linking reaction to continue the same up to a viscoelastic gel, wherein said gel composition exhibits retained biocompatibility, viscoelasticity and does not swell substantially when placed in contact with water.

25. A cross-linked biocompatible polysaccharide according to claim 24, which comprises a biologically active substance enclosed therein.

26. A composition according to claim 25, which is adapted as a depot preparation.

27. An improved method of medical or prophylactic treatment of a mammal, which comprises administration of a biologically active substance wherein the improvement comprises administering a composition as defined in claim 26 to a mammal in need of such a treatment.

28. The method of claim 27, which comprises treatment of a human being.

29. An improved method of medical or prophylactic treatment of a mammal, which comprises administration of a biologically active substance wherein the improvement comprises administering a composition as defined in claim 25 to a mammal in need of such a treatment.

30. The method of claim 29, which comprises treatment of a human being.

31. A method of treatment or prophylaxis of tissue augmentation in a mammal comprising administering a medical or prophylactic composition comprising a polysaccharide gel composition according to claim 25.

32. The method of claim 31, wherein the mammal is a human being.

33. A medical or prophylactic composition comprising a polysaccharide gel composition according to claim 24.

34. A method of hormone treatment of a mammal which comprises the administration of a medical or prophylactic depot composition comprising a polysaccharide gel composition according to claim 24, which contains a prophylactically or therapeutically effective amount of a hormone.

35. The method of claim 34, wherein the mammal is a human being.