Water-insoluble derivatives of hyaluronic acid and their methods of preparation and use

• US 6,013,679 A
• Filed: 12/05/1995
• Issued: 01/11/2000
• Est. Priority Date: 08/01/1989
• Status: Expired due to Fees

• Current Assignee: Anika Research Incorporated, The Research Foundation for The State University of New York (State University of New York)
• Original Assignee: Anika Research Incorporated, The Research Foundation for The State University of New York (State University of New York)
• Inventors: Prestwich, Glenn D., Kuo, Jing-Wen, Swann, David A.
• Primary Examiner(s): CEPERLEY, MARY
• Application Number:
  US08/567,563
• Time in Patent Office: 1,498 Days
• Field of Search: 514/54, 514/777, 424/7.1, 424/488, 424/447, 424/449, 252/315.3, 106/162.2
• US Class Current: 514/777
• 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 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• 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: A61L 15/28 Polysaccharides or their derivatives A61L15/225 takes precedence
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 31/042 Polysaccharides
• 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 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

This invention describes a method for preparing water-insoluble biocompatible gels, films and sponges by reacting hyaluronic acid, or a salt thereof, with a carbodiimide in the absence of a nucleophile or a polyanionic polysaccharide. The water-insoluble gels, films and sponges of this invention may be used as surgical aids to prevent adhesions of body tissues and as drug delivery vehicles.

Claims

1. A method for preparing a water-insoluble biocompatible gel, comprising reacting hyaluronic acid, or a salt thereof, with a carbodiimide to form a water insoluble gel in the absence of a nucleophile and a polyanionic polysaccharide other than the hyaluronic acid of the reaction.

2. The method of claim 1, wherein said carbodiimide is a monocarbodiimide of the formula:

space="preserve" listing-type="equation">R.sup.1 -N═

C═

N--R.sup.2

in which R¹ and R² are each independently selected from the group consisting of hydrocarbyl, substituted-hydrocarbyl, alkoxy, aryloxy, and alkaryloxy.

3. The method of claim 2, wherein said monocarbodiimide is selected from the group consisting of 3-(Dimethylamino) propyl)-3-ethyl-carbodiimide, cyclohexyl-B-(N-methylomorpholino) ethylcarbodiimide p-toluene-sulfonate, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide.

4. The method of claim 1, wherein said carbodiimide is a biscarbodiimide of the formula:

space="preserve" listing-type="equation">R.sup.1 --N═

C═

N--R.sup.2 --N═

C═

N--R.sup.3

in which R¹, R² and R³ are each independently selected from the group consisting of hydrocarbyl, substituted-hydrocarbyl, alkoxy, aryloxy, and alkaryloxy.

5. The method of claim 4, wherein said biscarbodiimide is one of phenylenebis-(ethyl)-carbodiimide and 1,6-hexamethylenebis (ethylcarbodiimide).

6. The method of claim 1, wherein the molar equivalent ratio of said carbodiimide to said hyaluronic acid is at least about 1:

20.

7. The method of claim 1, wherein said method is carried out at a pH in a range of between about 4.0 and about 6.0.

8. The method of claim 1, wherein said hyaluronic acid, or said salt thereof, is in an aqueous mixture having a concentration in a range of between about 0.4% and about 2.6% w/w.

9. The method of claim 1, wherein said hyaluronic acid has a molecular weight of between about 6×

10⁴ and about 1.2×

10⁷ daltons.

10. The method of claim 1, said method further comprising the steps of:

a) precipitating said modified hyaluronic acid;

b) separating said modified hyaluronic acid from the reaction mixture;

c) drying said modified hyaluronic acid; and

d) resuspending said modified hyaluronic acid in water.

11. The method of claim 10, said method further comprising admixing a detectable marker.

12. A water-insoluble biocompatible gel prepared according to the method of claim 1.

13. A water-insoluble biocompatible gel prepared according to the method of claim 10.

14. A method for making a water-insoluble biocompatible film, comprising the steps of:

a) providing the biocompatible gel of claim 13;

b) pouring said gel into a mold; and

c) drying said gel.

15. A water-insoluble biocompatible film prepared according to the method of claim 14.

16. A method for making a water-insoluble biocompatible film, comprising the steps of:

a) providing the biocompatible gel of claim 13; and

b) compressing said gel under conditions that cause water to be discharged from said gel.

17. A water-insoluble biocompatible film prepared according to the method of claim 16.

18. A method of making a water-insoluble biocompatible sponge, comprising the steps of:

a) providing the biocompatible gel of claim 13; and

b) freeze-drying said gel.

19. A water-insoluble biocompatible sponge prepared according to the method of claim 18.