Cross-linking of low and high molecular weight polysaccharides preparation of injectable monophase hydrogels and polysaccharides and hydrogels thus obtained

• US 7,741,476 B2
• Filed: 04/08/2004
• Issued: 06/22/2010
• Est. Priority Date: 04/10/2003
• Status: Active Grant

• Current Assignee: Allergan Industrie SAS (Abbvie Incorporated)
• Original Assignee: Allergan Industrie SAS (Abbvie Incorporated)
• Inventors: Lebreton, Pierre
• Primary Examiner(s): Jiang; Shaojia Anna
• Assistant Examiner(s): BLAND, LAYLA D
• Application Number:
  US10/552,309
• Publication Number:
  US 20060194758A1
• Time in Patent Office: 2,266 Days
• Field of Search: None
• US Class Current: 536/124
• 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 is also disclosed. Crosslinked polymers and injectable monophase hydrogels, respectively, are obtainable by each of said processes.

Claims

1. Process of preparing a cross-linked polymer 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. Process according to 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. Process according to 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. Process according to claim 1, wherein said mixture has an intrinsic viscosity of less than 1900 ml/g.

5. Process according to claim 1 wherein said 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. Process according to claim 1, wherein said mixture contains at least 5% by weight of the second hyaluronic acid salt product.

7. Process according of claim 1, wherein said cross-linking agent is selected from bifunctional crosslinking agents and mixtures thereof.

8. Process according to claim 1, wherein the degree of cross-linking is theoretically between 4 and 50%.

9. Process for the preparation of an injectable monophase hydrogel of at least one cross-linked hyaluronic acid salt product comprising:

formulating the cross-linked mixture according to claim 1, neutralized if necessary, into a solution buffered to a pH of between 6.5 and 7.5.

10. Process according to claim 1, wherein at least one of the first and second hyaluronic acid salt products is a sodium salt.

11. Process according to 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, the first hyaluronic acid salt product is a sodium salt having a molecular weight of about 3·

10⁵ Da, and the second hyaluronic acid salt product is a sodium salt having a molecular weight of about 3·

10⁶ Da.

12. Process according to claim 1, wherein the first hyaluronic acid salt product has a molecular weight of between 10⁴ Da and 9.9×

10⁵ Da, and the second hyaluronic acid salt product has a molecular weight of between 10⁶ Da and 10⁸ Da.

13. Process according to claim 1, wherein the second hyaluronic acid salt product has a molecular weight of between 1.1×

10⁶ Da and 5×

10⁶ Da.

14. Process according to claim 1, wherein said 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.

15. Process according to claim 1, wherein said 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.

16. Process according to claim 15, wherein said aldehydes are selected from formaldehyde, glutaraldehyde, crotonaldehyde, and mixtures thereof.

17. Process according to claim 1, wherein said cross-linking agent is 1,4-bis(2,3-epoxypropoxy)butane.

18. Process according to claim 9, wherein the pH is between 7 and 7.4.

19. Process according to claim 9, wherein the pH is 7.1 and 7.3.

20. A process according to 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, said 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.

21. The process according to claim 20, wherein the second hyaluronic acid salt product has a molecular weight of about 3×

10⁶ Da.

22. The process according to claim 20, wherein the first hyaluronic acid salt product has a molecular weight of about 3×

10⁵ Da.

23. The process according to claim 20, wherein said mixture contains more than 70% by weight of the first hyaluronic acid salt product.