CROSS-LINKING OF LOW-MOLECULAR WEIGHT AND HIGH-MOLECULAR WEIGHT POLYSACCHARIDES, PREPARATION OF INJECTABLE MONOPHASE HYDROGELS, POLYSACCHARIDES AND HYDROGELS OBTAINED

• US 20100226988A1
• Filed: 05/18/2010
• Published: 09/09/2010
• Est. Priority Date: 04/10/2003
• Status: Active Grant

• Current Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Original Assignee: Allergan, Inc. (Canada) (Abbvie Incorporated)
• Inventors: LEBRETON, PIERRE
• Granted Patent: US 8,338,388 B2
• Time in Patent Office: Days
• US Class Current: 424/488
• CPC Class Codes: A61K 31/738 Cross-linked polysaccharides
• 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 27/20 Polysaccharides
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 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: C08J 2305/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08J 3/24 Crosslinking, e.g. vulcanising, of macromolecules mechanical aspects B29C35/00; crosslinking agents C08K
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

A process for the crosslinking of at least one polymer selected from polysaccharides and derivatives thereof, which is carried out in an aqueous solvent by the action of an effective and non-excessive amount of at least one crosslinking agent, characterized in that it is carried out on a mixture containing at least one low-molecular weight polymer and at least one high-molecular weight polymer. A process for the preparation of an injectable monophase hydrogel of at least one crosslinked polymer selected from polysaccharides and derivatives thereof. Crosslinked polymers and injectable monophase hydrogels respectively obtainable by each of said processes.

Claims

1. A cross-linked polymer prepared by a process comprising:

1) forming a mixture of a first hyaluronic acid salt product having a first molecular weight and a second hyaluronic acid salt product having a second molecular weight greater than the first molecular weight, wherein the first hyaluronic acid salt product and the second hyaluronic acid salt product are two separate pre-existing products prior to the forming step; and

2) cross-linking the mixture of step

     1) in an aqueous solvent in the presence of an effective and non-excessive amount of at least one cross-linking agent, such that the degree of cross-linking, defined by the ratio;

100×

(total number of reactive groups in said cross-linking agent/total number of disaccharide units in the first hyaluronic acid salt and second hyaluronic acid salt), is theoretically between 0.5 and 70%.

2. The polymer of claim 1, wherein at least one of the first and second hyaluronic acid salt products is selected from a sodium salt, a potassium salt, and mixtures thereof.

3. The polymer of claim 1, wherein the first hyaluronic acid salt product has a molecular weight of no greater than 9.9×

10⁵ Da; and

the second hyaluronic acid salt product has a molecular weight of at least 10⁶ Da.

4. The polymer of claim 1, wherein the polymer has an intrinsic viscosity of less than 1900 ml/g.

5. The polymer of claim 1, wherein the mixture contains more than 50% by weight of the first hyaluronic acid salt product and less than 50% by weight of the second hyaluronic acid salt product.

6. The polymer of claim 1, wherein the mixture contains about 90% by weight of the first hyaluronic acid salt product and about 10% by weight of the second hyaluronic acid salt product.

7. The polymer of claim 1, wherein the mixture contains more than 70% by weight the first hyaluronic acid salt product and less than 30% by weight of the second hyaluronic acid salt product.

8. The polymer of claim 1, wherein the cross-linking agent is selected from epichlorohydrin, divinyl sulfone, 1,4-bis(2,3-epoxypropoxy) butane, 1,2-bis(2,3-epoxypropoxy)ethylene, 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane, aldehydes, and mixtures thereof.

9. The polymer of claim 8, wherein the aldehydes are selected from formaldehyde, glutaraldehyde, crotonaldehyde, and mixtures thereof.

10. The polymer of claim 1, wherein the cross-linking agent is 1,4-bis(2,3-epoxypropoxy)butane.

11. The polymer of claim 1, wherein the first hyaluronic acid salt product has a molecular weight of between 10⁴ Da and 9.9×

10⁵ Da;

the second hyaluronic acid salt product has a molecular weight of between 1.1×

10⁶ Da and 5×

10⁶ Da; and

the mixture contains more than 50% by weight of the first hyaluronic acid salt product and at least 5% by weight of the second hyaluronic acid salt product.

12. The polymer of claim 1, wherein the second hyaluronic acid salt product has a molecular weight of about 3×

10⁶ Da.

14. The polymer of claim 1, wherein the mixture contains more than 70% by weight of the first hyaluronic acid salt product.

15. An injectable monophase hydrogel prepared by a process comprising:

1) forming a mixture of a first hyaluronic acid salt product having a first molecular weight and a second hyaluronic acid salt product having a second molecular weight greater than the first molecular weight, wherein the first hyaluronic acid salt product and the second hyaluronic acid salt product are two separate pre-existing products prior to the forming step;

2) cross-linking the mixture of step

     1) in an aqueous solvent in the presence of an effective and non-excessive amount of at least one cross-linking agent, such that the degree of cross-linking, defined by the ratio;

100×

(total number of reactive groups in said cross-linking agent/total number of disaccharide units in the first hyaluronic acid salt and second hyaluronic acid salt), is theoretically between 0.5 and 70%; and

3) formulating the cross-linked mixture formed in step

     2), neutralized if necessary, into a solution buffered to a pH of between 6.5 and 7.5.

13. The polymer of claim 17, wherein the first hyaluronic acid salt product has a molecular weight of about 3×

10⁵ Da.

16. The hydrogel of claim 15, wherein the concentration of the cross-linked mixture in the solution is between 20 and 30 mg/g.

17. The hydrogel of claim 15 wherein the mixture contains more than 70% by weight of the first hyaluronic acid salt product.

18. A cross-linked polymer prepared by a process comprising:

cross-linking a polymer mixture comprising a first portion of which is a low-molecular weight polymer and a second portion of which is a high-molecular weight of the same polymer as the first portion, in an aqueous solvent in the presence of an effective and non-excessive amount of at least one cross-linking agent.

19. The polymer of claim 18, wherein the low-molecular weight polymer and high-molecular weight polymer is a hyaluronic acid salt.

20. The polymer of claim 18 wherein the low-molecular weight polymer has a molecular weight of no greater than 9.9×

10⁵ Da; and

the high-molecular weight polymer has a molecular weight of at least 10⁶ Da.

21. The polymer of claim 18 having an intrinsic viscosity of less than 1900 ml/g.

22. The polymer of claim 18, wherein the mixture contains more than 70% by weight of the low-molecular weight polymer and less than 30% by weight of the high-molecular weight polymer.

23. The polymer of claim 22, wherein the degree of cross-linking is theoretically between 4 and 50%.

24. The polymer of claim 18, wherein the mixture contains about 90% by weight of the low-molecular weight polymer and about 10% by weight of the high-molecular weight polymer.

25. The polymer of claim 18, wherein low-molecular weight polymer has a molecular weight of between 10⁴ Da and 9.9×

10⁵ Da, and the high-molecular weight polymer has a molecular weight of between 10⁶ Da and 10⁸ Da.

26. The polymer of claim 25, wherein the high-molecular weight polymer has a molecular weight of between 1.1×

10⁶ Da and 5×

10⁶ Da.

27. The polymer of claim 25 wherein the mixture comprises more than 70% by weight the low-molecular weight polymer and less than 30% by weight of the high-molecular weight polymer.

28. An injectable monophase hydrogel prepared by a process comprising:

a) cross-linking at least one low-molecular weight polymer selected from polysaccharides and derivatives thereof and at least one high-molecular weight polymer selected from polysaccharides and derivatives thereof in an aqueous solvent in the presence of an effective and non-excessive amount of at least one cross-linking agent and

b) formulating the cross-linked mixture formed in step a), neutralized if necessary, into a solution buffered to a pH of between 6.5 and 7.5.

29. The hydrogel of claim 28, wherein the pH is between 7 and 7.4.

30. The hydrogel of claim 28, wherein the pH is between 7.1 and 7.3.

31. The hydrogel of claim 28, wherein the concentration of the cross-linked mixture in the solution is between 10 and 40 mg/g.

32. The hydrogel of claim 28, wherein the concentration of the cross-linked mixture in the solution is between 20 and 30 mg/g.