Drug delivery systems based on hyaluronans derivatives thereof and their salts and methods of producing same

• US 5,128,326 A
• Filed: 07/23/1990
• Issued: 07/07/1992
• Est. Priority Date: 12/06/1984
• Status: Expired due to Term

• Current Assignee: Genzyme Biosurgery Corporation (Sanofi )
• Original Assignee: Biomatrix, Inc. (Sanofi )
• Inventors: Larsen, Nancy E., Balazs, Endre A., Leshchiner, Adolf
• Primary Examiner(s): GRIFFIN, RONALD
• Application Number:
  US07/559,413
• Time in Patent Office: 715 Days
• Field of Search: 514/54, 514/769, 424/446
• US Class Current: 514/54
• 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 47/61 the organic macromolecular compound being a polysaccharide or a derivative 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: 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: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/7007 Drug-containing films, membranes or sheets A61K9/0041, A61K9/0043, A61K9/006, A61K9/0063 take precedence
• 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 drug delivery systems based on a polymeric component which is soluble or insoluble (cross-linked) hyaluronan or hyaluronan copolymerized with another hydrophilic polymer or hylan and one or more substances having biological or pharmacological activity and methods of preparing same.

Claims

1. A drug delivery system comprising a polymeric component which is an insoluble hyaluronan or a soluble hylan and a selected amount of at least one substance having biological or pharmacological activity and which is controllably releasable from said system so as to effect delivery of a therapeutically effective amount of said substance to a desired site.

2. A drug delivery system in accordance with claim 1 wherein the polymeric component is a soluble hylan and comprises an aqueous hylan solution.

3. A drug delivery system in accordance with claim 2 wherein the substance is dissolved or dispersed in the aqueous solution.

4. A drug delivery system in accordance with claim 2 wherein the solution is a viscoelastic putty.

5. A drug delivery system in accordance with claim 2 wherein the hylan concentration is about 0.05 to 4% by weight.

6. A drug delivery system in accordance with claim 2 in the form of an injectable product.

7. A drug delivery system in accordance with claim 2 in the form of a topical product.

8. A drug delivery system in accordance with claim 7 and comprising eye drops.

9. A drug delivery system in accordance with claim 7 wherein the hylan has a molecular weight of at least about 1×

10⁶ and the concentration of hylan is from about 0.05 to 2% by weight.

10. A drug delivery system in accordance with claim 2 wherein the substance is serotonin.

11. A drug delivery system in accordance with claim 4 wherein the substance is salicylic acid.

12. A method of obtaining a product in accordance with claim 2 comprising dissolving or dispersing the substance in a water or saline solution of hylan.

13. A method of obtaining a product in accordance with claim 2 comprising mixing a solution or dispersion of the substance with a hylan solution.

14. A method of obtaining a product in accordance with claim 4 comprising adding the substance to a solution of hylan and adjusting the pH of the resulting mixture to about 2.5.

15. A drug delivery system in accordance with claim 1 wherein the polymeric component is an insoluble hyaluronan.

16. A drug delivery system in accordance with claim 15 wherein the insoluble hyaluronan is a cross-linked gel of hyaluronan or a cross-linked gel of hyaluronan and at least one other hydrophilic polymer.

17. A drug delivery system in accordance with claim 16 wherein the other hydrophilic polymer is any such polymer having a functional group capable of reacting with divinyl sulfone.

18. A drug delivery system in accordance with claim 17 wherein the other hydrophilic polymer is a natural or synthetic polysaccharide selected from the group consisting of hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, glycosaminoglycans, a protein or glycoprotein selected from the group consisting of collagen, elastin, albumin, a globulin, keratin sulfate, a sulfated aminoglycosaminoglycan and a synthetic water soluble polymer, selected from the group consisting of polyvinyl alcohol and its co-polymers and co-polymers of poly-(hydroxyethyl)methacrylate.

19. A drug delivery system in accordance with claim 16 wherein the insoluble hyaluronan is in the form of a molecular cage and the substance is dispersed within said molecular cage.

20. A drug delivery system in accordance with claim 16 wherein the substance is covalently bonded to the macromolecules of hyaluronan or said at least one other hydrophilic polymer.

21. A drug delivery system in accordance with claim 19 in combination with a support or substrate therefor.

22. The combination in accordance with claim 21 wherein the support or substrate is a polymeric porous sponge, a gauze or a polymeric film.

23. A method of obtaining a product in accordance with claim 16 comprising placing the gel into a solution of the substance and allowing the substance to diffuse into the gel whereby a product having the substance uniformly dispersed therethrough is obtained.

24. A method of obtaining a product in accordance with claim 16 comprising dehydrating the gel and placing the dehydrated gel into a solution of the substance to cause reswelling of the dehydrated gel, said substance being diffused into the gel while the reswelling occurs.

25. A method in accordance with claim 24 wherein dehydrating is effected by treating the gel with a water miscible solvent or by drying.

26. A method in accordance with claim 25 wherein a water miscible solvent is used.

27. A method in accordance with claim 26 wherein the water miscible solvent is ethanol, isopropanol or acetone.

28. A method of obtaining a product in accordance with claim 16 comprising placing a concentrated gel in a solution of said substance and allowing the gel to swell in said solution whereby the substance is diffused into the gel while it is swelling.

29. A drug delivery ststem in accordance with claim 16 wherein when the insoluble hyaluronan is a cross-linked hyaluronan gel and at least one other hydrophilic polymer, the hyaluronan comprises from 5 to 95% by weight of said insoluble hyaluronan.

30. A method of obtaining a product in accordance with claim 20 which comprises subjecting hyaluronan or a mixture of hyaluronan and the other hydrophilic polymer to a cross-linking reaction in the presence of said substance provided that said substance has a chemical group reactive toward the cross-linking agent to thereby cause the formation of covalent bonds between said chemical group and the hyaluronan or the other hydrophilic polymer.

31. A method in accordance with claim 30 wherein the chemical group is hydroxyl, amino or sulfhydryl.

32. A method in accordance with claim 30 wherein said substance is gentamicin.

33. A drug delivery system in accordance with claim 21 and comprising a membrane formed of a gel of hyaluronan containing gentamicin.

34. A drug delivery system in accordance with claim 21 and comprising a membrane formed of a gel of hyaluronan and chondroitin sulfate containing gentamicin.

35. A drug delivery system in accordance with claim 20 and comprising a gel of cross-linked hyaluronan and gentamicin covalently attached thereto.

36. A drug delivery system in accordance with claim 21 and comprising a gel of hyaluronan containing mydriacyl.

37. A drug delivery system in accordance with claim 21 and comprising a porous polymeric sponge, said sponge having a hyaluronan gel immobilized therein together with said substance.

38. A drug delivery system in accordance with claim 37 wherein said substance is serotonin.

39. A drug delivery system in accordance with claim 37 wherein said sponge is formed of a polyurethane.

40. A drug delivery system in accordance with claim 21 and comprising a cotton gauze, said gauze having a hyaluronan gel immobilized therein together with said substance.

41. A drug delivery system in accordance with claim 40 wherein said substance is gentamicin.