Cross-linked hyaluronic acid grafted with dextran

Patent metadata

Field	Value
Publication number	US-10131718-B2
Application number	US-201515314168-A
Country	US
Kind code	B2
Filing date	May 29, 2015
Priority date	May 29, 2014
Publication date	Nov 20, 2018
Grant date	Nov 20, 2018

Abstract

A hyaluronic acid product is comprising a cross-linked hyaluronic acid and one or more dextran molecules. The hyaluronic acid is cross-linked by ether bonds, and the one or more dextran molecules are covalently grafted to the cross-linked hyaluronic acid.

First claim

The invention claimed is:

1. A hyaluronic acid product comprising a cross-linked hyaluronic acid and one or more dextran molecules, wherein the hyaluronic acid is cross-linked by ether bonds and the one or more dextran molecules are covalently grafted to the cross-linked hyaluronic acid, wherein the dextran molecules are covalently linked to the hyaluronic acid by single end-point attachment via a bi- or polyfunctional linker between the reducing end of dextran and a carboxyl group of hyaluronic acid.

2. A hyaluronic acid product according to claim 1 , wherein the cross-linked hyaluronic acid is in the form of a gel.

3. A hyaluronic acid product according to claim 1 , wherein the cross-linked hyaluronic acid is in the form of gel particles having an average size in the range of 0.01-5 mm.

4. A hyaluronic acid product according to claim 1 , wherein the hyaluronic acid chains are cross-linked to each other via a linker which is derived from a bi- or polyfunctional cross-linking agent.

5. A hyaluronic acid product according to claim 4 , wherein said bi- or polyfunctional cross-linking agent is a bis- or polyepoxide.

6. A hyaluronic acid product according to claim 5 , wherein said bi- or polyfunctional cross-linking agent is a diglycidyl ether.

7. A hyaluronic acid product according to claim 6 , wherein said bi- or polyfunctional cross-linking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene (EGDGE) and ethylene glycol diglycidyl ether (EGDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.

8. A hyaluronic acid product according to claim 7 , wherein said bi- or polyfunctional cross-linking agent is 1,4-butanediol diglycidyl ether (BDDE).

9. A hyaluronic acid product according to claim 1 , wherein the one or more dextran molecules and the disaccharides of the cross-linked hyaluronic acid have a molar ratio of 0.1-99%.

10. A hyaluronic acid product according to claim 1 , wherein the one or more dextran molecules and the disaccharides of the cross-linked hyaluronic acid have a molar ratio of 1-60%.

11. A hyaluronic acid product according to claim 1 , wherein the dextran molecules have an average molecular weight of less than 10 kDa.

12. A hyaluronic acid product according to claim 1 , wherein the dextran molecules have an average molecular weight of less than 5 kDa.

13. A hyaluronic acid product according to claim 1 , wherein the dextran molecule contains a linker having an amino, hydrazide, carbazate, semicarbazide, thiosemicarbazide, thiocarbazate or aminooxy functional group, and wherein the functional group of the linker forms a covalent bond with a carboxyl group of the cross-linked hyaluronic acid.

14. A hyaluronic acid product according to claim 13 , wherein the bi- or polyfunctional linker comprises a diamine or a dihydrazide.

15. A hyaluronic acid product according to claim 1 , wherein the one or more dextran molecules are covalently grafted to the cross-linked hyaluronic acid by amide bonds.

16. A process of preparing a hyaluronic acid product comprising a cross-linked hyaluronic acid and one or more dextran molecules, the process comprising the steps of:
(a) providing a cross-linked hyaluronic acid and one or more functionalized dextran molecules;
(b) covalently grafting one or more functionalized dextran molecules to the cross-linked hyaluronic acid;
wherein the functionalized dextran molecules provided in step (a) are functionalized at the reducing end with a bi- or polyfunctional linker having at least one functional group available for linking the dextran molecules to a carboxyl group of the cross-linked hyaluronic acid.

17. A process according to claim 16 , wherein the cross-linked hyaluronic acid in step (a) is in the form of a gel.

18. A process according to claim 16 , wherein the cross-linked hyaluronic acid in step (a) is in the form of gel particles having an average size in the range of 0.01-5 mm.

19. A process according to claim 16 , wherein the one or more dextran molecules and the disaccharides of the cross-linked hyaluronic acid of the resulting hyaluronic acid product have a molar ratio of 0.1-99%.

20. A process according to claim 16 , wherein the one or more dextran molecules and the disaccharides of the cross-linked hyaluronic acid of the resulting hyaluronic acid product have a molar ratio of 1-60%.

21. A process according to claim 16 , wherein the dextran molecules provided in step (a) have an average molecular weight of less than 10 kDa.

22. A process according to claim 16 , wherein the dextran molecules provided in step (a) have an average molecular weight of less than 5 kDa.

23. A process according to claim 16 , wherein the one or more functionalized dextran molecules of step (a) contain a linker having an amino, hydrazide, carbazate, semicarbazide, thiosemicarbazide, thiocarbazate or aminooxy functional group, and wherein the functional group of the linker forms a covalent bond with a carboxyl group of the cross-linked hyaluronic acid.

24. A process according to claim 23 , wherein the bi- or polyfunctional linker comprises a diamine or a dihydrazide.

25. A process according to claim 16 , wherein the covalent grafting of step (b) involves:
(i) activating the carboxyl groups on the cross-linked hyaluronic acid with a coupling agent to form an activated cross-linked hyaluronic acid; and
(ii) coupling the linker of the one or more functionalized dextran molecules to the carboxyl groups of the activated cross-linked hyaluronic acid.

26. A process according to claim 25 , wherein the activation of the cross-linked hyaluronic acid and the coupling of the dextran molecule to the activated cross-linked hyaluronic acid occur simultaneously in step (b).

27. A process according to claim 25 , wherein the activation of the cross-linked hyaluronic acid occurs prior to and separately from the coupling of the one or more dextran molecules to the activated cross-linked hyaluronic acid in step (b).

28. A process according to claim 25 , wherein the coupling agent is selected from the group consisting of triazine-based coupling agents, carbodiimide coupling agents, imidazolium-derived coupling agents, Oxyma and COMU.

29. A process according to claim 28 , wherein the coupling agent is a triazine-based coupling agent.

30. A process according to claim 29 , wherein the triazine-based coupling agent is selected from the group consisting of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT).

31. A process according to claim 30 , wherein the triazine-based coupling agent is DMTMM.

32. A hyaluronic acid product obtainable by the process according to claim 16 .

33. A hyaluronic acid product according to claim 1 for use as a dermal filler.

Assignees

• Galderma Sa

Inventors

• Karlsson Anders
• Mojarradi Hotan

Classifications

• A61P17/00

  Drugs for dermatological disorders · CPC title

• C08L2203/02

  for biomedical use · CPC title

• C08B37/0072 Primary

  Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates · CPC title

• C08L5/02

  Dextran; Derivatives thereof · CPC title

• C08J3/075

  Macromolecular gels · CPC title