Cross-linked gels of hyaluronic acid and products containing such gels

• US 4,582,865 A
• Filed: 12/06/1984
• Issued: 04/15/1986
• Est. Priority Date: 12/06/1984
• Status: Expired due to Term

• Current Assignee: Genzyme Biosurgery Corporation (Sanofi )
• Original Assignee: Biomatrix, Inc. (Sanofi )
• Inventors: Balazs, Endre A., Leshchiner, Adolf
• Primary Examiner(s): Griffin, Ronald W.
• Application Number:
  US06/678,895
• Time in Patent Office: 495 Days
• Field of Search: 524/27, 524/29, 536/4.1
• US Class Current: 524/29
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 8/73 Polysaccharides
• CPC Class Codes: A61K 8/731 Cellulose; Quaternized cellulose derivatives
• CPC Class Codes: A61K 8/735 Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• 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: C08L 2666/02 Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

Disclosed are cross-linked gels of hyaluronic acid, alone or mixed with other hydrophilic polymers and containing various substances or covalently bonded low molecular weight substances and processes for preparing them. These products are useful in numerous applications including cosmetic formulations and as drug delivery systems.

Claims

1. A method of preparing a mixed cross-linked gel of hyaluronic acid and at least one other hydrophilic polymer having a functional group capable of reacting with divinyl sulfone, said method comprising subjecting a mixture of sodium hyaluronate and said other hydrophilic polymer in a dilute aqueous alkaline solution at a pH of not less than about 9 to a cross-linking reaction with divinyl sulfone at about 20°

C.

2. A method according to claim 1 wherein the other hydrophilic polymer is a natural or synthetic polysaccharide selected from the group consisting of hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, chondroitin sulfate and heparin, a protein selected from the group consisting of collagen, elastin, albumin, a globulin, keratin sulfate, a sulfated aminoglycosaminolgycan and a synthetic water soluble polymer.

3. A method according to claim 1 wherein sodium hyaluronate has a molecular weight of about 50,000 to about 8×

10⁶.

4. A method according to claim 1 wherein the combined concentration of sodium hyaluronate and the other hydrophilic polymers in the reaction mixture is 1-8% by weight and the sodium hyaluronate comprises from 5-95% of the total.

5. A method according to claim 1 wherein the ratio of the sodium hyaluronate to divinyl sulfone is from 15:

1 to 1;

5 by weight.

6. A method according to claim 1 and further comprising adding an alkali metal chloride, sulfate, phosphate or acetate to the reaction mixture in an amount sufficient to provide up to about 20% by weight concentration in the mixture.

7. A method of preparing a cross-linked gel of hyaluronic acid or a mixed cross-linked gel of hyaluronic acid and at least one other hydrophilic polymer having a functional group capable of reacting with divinyl sulfone, either of which further includes an inert water insoluble substance, said method comprising subjecting sodium hyaluronate or a mixture of sodium hyaluronate and said other hydrophilic polymer in a dilute aqueous alkaline solution at a pH of not less than about 9, to which has been added an inert water insoluble substance to a cross-linking reaction with divinyl sulfone at about 20°

C.

8. A method according to claim 7 wherein the inert water insoluble substance is a hydrocarbon, an oil or fat, a pigment, polyethylene or polytetrafluoro ethylene.

9. A method according to claim 8 wherein the hydrocarbon is petrolatum, the oil or fat is beeswax, coconut oil or lanolin, and the pigment is kaolin, ferric oxide or an insoluble dye.

10. A method according to claim 7 wherein sodium hyaluronate has a molecular weight of about 50,000 to about 8×

10⁶.

11. A method according to claim 7 wherein the concentration of sodium hyaluronate or the mixture of sodium hyaluronate and the other hydrophilic polymer is 1-8% by weight and the inert water insoluble substance is present in an amount of 1-95% by weight based on the total weight of polymers plus inert water insoluble substance.

12. A method according to claim 7 wherein the ratio of the sodium hyaluronate to divinyl sulfone is from 15:

1 to 1;

5 by weight.

13. A method according to claim 7 and further comprising adding an alkali metal chloride, sulfate, phosphate or acetate to the reaction mixture in an amount sufficient to provide up to about 20% by weight concentration in the mixture.

14. A method of preparing a cross-linked gel of hyaluronic acid or a mixed cross-linked gel of hyaluronic acid and at least one other hydrophilic polymer having a functional group capable of reacting with divinyl sulfone, either of which further includes a low molecular weight substance covalently bonded to the macromolecular network, said method comprising subjecting sodium hyaluronate or a mixture of sodium hyaluronate and said other hydrophilic polymer in a dilute aqueous alkaline solution at a pH of not less than about 9, to which has been added a low molecular weight substance having a functional group with active hydrogen atoms reactive to divinyl sulfone to a cross-linking reaction with divinyl sulfone at about 20°

C.

15. A method according to claim 14 wherein the low molecular weight substance is a drug.

16. A method according to claim 14 wherein the low molecular weight substance is a carminic acid.

17. A method according to claim 14 wherein sodium hyaluronate has a molecular weight of about 50,000 to about 8×

10⁶.

18. A method according to claim 14 wherein the concentration of sodium hyaluronate or the mixture of sodium hyaluronate and the other hydrophilic polymer is 1-8% by weight and the low molecular weight substance is present in an amount of 1-95% by weight based on the total weight of polymers plus inert water insoluble substance.

19. A method according to claim 14 wherein the ratio of the sodium hyaluronate to divinyl sulfone is from 15:

1 to 1;

5 by weight.

20. A method according to claim 14 and further comprising adding an alkali metal chloride, sulfate, phosphate or acetate to the reaction mixture in an amount sufficient to provide up to about 20% by weight concentration in the mixture.

21. A mixed cross-linked gel of hyaluronic acid and at least one other hydrophilic polymer having a functional group capable of reacting with divinyl sulfone, wherein the combined concentration of sodium hyaluronate and the other hydrophilic polymer is 1-8% by weight and the sodium hyaluronate comprises from 5-95% of the total.

22. A gel according to claim 21 wherein the other hydrophilic polymer is a natural or synthetic polysaccharide selected from the group consisting of hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, chondroitin sulfate and heparin, a protein selected from the group consisting of collagen, elastin, albumin, a globulin, keratin sulfate, a sulfated aminoglycosaminoglycan and a synthetic water soluble polymer.

23. A cross-linked gel of hyaluronic acid or a mixed cross-linked gel of hyaluronic acid and at least one other hydrophilic polymer having a functional group capable of reacting with divinyl sulfone and further comprising an inert water insoluble substance, wherein the concentration of sodium hyaluronate or the mixture of sodium hyaluronate and the other hydrophilic polymer is 1-8% by weight and the inert water insoluble substance is present in an amount of 1-95% by weight based on the total weight of polymers plus inert water insoluble substance.

24. A gel according to claim 23 wherein the inert water insoluble substance is a hydrocarbon, an oil or fat, a pigment, polyethylene or polytetrafluoroethylene.

25. A gel according to claim 24 wherein the hydrocarbon is petrolatum, the oil or fat is beeswax, coconut oil or lanolin, and the pigment is kaolin, ferric oxide or an insoluble dye.

26. A cross-linked gel of hyaluronic acid or a mixed cross-linked gel of hyaluronic acid and at least one other hydrophilic polymer having a functional group capable of reacting with divinyl sulfone and further comprising a low molecular weight substance covalently bonded to the macromolecular network, wherein the concentration of sodium hyaluronate or the mixture of sodium hyaluronate and the other hydrophilic polymer is 1-8% by weight and the low molecular weight substance is present in an amount of 1-95% by weight based on the total weight of the polymer.

27. A gel according to claim 26 wherein the low molecular weight substance is a drug.

28. A gel according to claim 26 wherein the low molecular weight substance is carminic acid.