Biocompatible viscoelastic gel slurries, their preparation and use

• US 5,399,351 A
• Filed: 06/24/1993
• Issued: 03/21/1995
• Est. Priority Date: 07/09/1990
• Status: Expired due to Term

• Current Assignee: Genzyme Corporation (Sanofi )
• Original Assignee: Biomatrix, Inc. (Sanofi )
• Inventors: Larsen, Nancy E., Leshchiner, Edward, Leshchiner, Adelva, Balazs, Endre A.
• Primary Examiner(s): Kishore, Gollamudi S.
• Application Number:
  US08/080,629
• Time in Patent Office: 635 Days
• Field of Search: 424/422, 424/423, 424/426, 424/427, 424/428, 424/430, 424/78.08, 424/484, 424/486, 424/488, 252/315.01, 252/315.1, 252/315.3, 514/54, 514/944, 536/55.1-55.3
• US Class Current: 424/422
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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 47/38 Cellulose; Derivatives thereof
• 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 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/042 Polysaccharides
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• 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
• CPC Class Codes: H04B 10/50 Transmitters
• CPC Class Codes: Y10S 530/813 Carrier is a saccharide

Abstract

Disclosed are biocompatible viscoelastic gel slurries formed from a polymeric gel, preferably a hyaluronan or a derivative thereof such as hylan swollen in an aqueous medium and a fluid phase which is an aqueous solution of a polymer which may also but not necessarily be a hyaluronan or derivative thereof. Also disclosed are methods of making such slurries, controlling their rheological properties and the uses thereof.

Claims

1. A method of controlling adhesion formation between tissues of a living body resulting from surgical intervention comprising applying to the affected tissues a biocompatible viscoelastic gel slurry comprising a two phase mixture, a first phase being a particulate biocompatible gel phase, said gel phase comprising a chemically cross-linked glycosaminoglycan, or said glycosaminoglycan chemically co-cross-linked with at least one other polymer selected from the group consisting of polysaccharides and proteins, said gel phase being swollen in a physiologically acceptable aqueous medium and being uniformly distributed in the second phase, said second phase comprising a polymer solution of a water-soluble biocompatible polymer selected from the group consisting of polysaccharides, polyvinylpyrrolidone and poly ethyleneoxide in said physiologically acceptable aqueous medium, and wherein the polymer solution in the two phase mixture constitutes from 0.01 to 99.5% and the gel phase constitutes the remainder and thereafter separating the affected tissues.

2. A method according to claim 1 wherein the glycosaminoglycan chemically co-cross-linked with said at least one other polymer is hyaluronan or hylan.

3. A method according to claim 1 wherein the chemically cross-linked glycosaminoglycan is hyaluronan or hylan.

4. A method according to claim 1 wherein the polymer concentration of the biocompatible gel swollen in the physiologically acceptable aqueous medium is from 0.01 to 30%.

5. A method according to claim 1 wherein the polymer concentration of the polymer solution phase is from 0.01 to 70%.

6. A method of controlling cell movement and attachment to surfaces in a living body by placing a biocompatible viscoelastic gel slurry comprising a two phase mixture, a first phase being a particulate biocompatible gel phase, said gel phase comprising a chemically cross-linked glycosaminoglycan, or said glycosaminoglycan chemically co-cross-linked with at least one other polymer selected from the group consisting of polysaccharides and proteins, said gel phase being swollen in a physiologically acceptable aqueous medium and being uniformly distributed in the second phase, said second phase comprising a polymer solution of a water-soluble biocompatible polymer selected from the group consisting of polysaccharides, polyvinylpyrrolidone and poly ethyleneoxide in said physiologically acceptable aqueous medium, and wherein the polymer solution in the two phase mixture constitutes from 0.01 to 99.5% and the gel phase constitutes the remainder in the space in the body where such control is desired.

7. A method according to claim 6 wherein the glycosaminoglycan chemically co-cross-linked with said at least one other polymer is hyaluronan or hylan.

8. A method according to claim 6 wherein the chemically cross-linked glycosaminoglycan is hyaluronan or hylan.

9. A method according to claim 6 wherein the polymer concentration of the biocompatible gel swollen in the physiologically acceptable aqueous medium is from 0.01 to 30%.

10. A method according to claim 6 wherein the polymer concentration of the polymer solution phase is from 0.01 to 70%.

11. A method for controlled drug delivery which comprises mixing a drug with a biocompatible viscoelastic gel slurry comprising a two phase mixture, a first phase being a particulate biocompatible gel phase, said gel phase comprising a chemically cross-linked glycosaminoglycan, or said glycosaminoglycan chemically co-cross-linked with at least one other polymer selected from the group consisting of polysaccharides and proteins, said gel phase being swollen in a physiologically acceptable aqueous medium and being uniformly distributed in the second phase, said second phase comprising a polymer solution of a water-soluble biocompatible polymer selected from the group consisting of polysaccharides, polyvinylpyrrolidone and poly ethyleneoxide in said physiologically acceptable aqueous medium, and wherein the polymer solution in the two phase mixture constitutes from 0.01 to 99.5% and the gel phase constitutes the remainder and applying the resulting mixture at the site in a living body where said drugs delivery is desired.

12. A method according to claim 11 wherein the glycosaminoglycan chemically co-cross-linked with said at least one other polymer is hyaluronan or hylan.

13. A method according to claim 11 wherein the chemically cross-linked glycosaminoglycan is hyaluronan or hylan.

14. A method according to claim 11 wherein the polymer concentration of the biocompatible gel swollen in the physiologically acceptable aqueous medium is from 0.01 to 30%.

15. A method according to claim 11 wherein the polymer concentration of the polymer solution phase is from 0.01 to 70%.

16. A method for soft tissue augmentation which comprises implanting a drug with a biocompatible viscoelastic gel slurry comprising a two phase mixture, a first phase being a particulate biocompatible gel phase, said gel phase comprising a chemically cross-linked glycosaminoglycan, or said glycosaminoglycan chemically co-cross-linked with at least one other polymer selected from the group consisting of polysaccharides and proteins, said gel phase being swollen in a physiologically acceptable aqueous medium and being uniformly distributed in the second phase, said second phase comprising a polymer solution of a water-soluble biocompatible polymer selected from the group consisting of polysaccharides, polyvinylpyrrolidone and poly ethyleneoxide in said physiologically acceptable aqueous medium, and wherein the polymer solution in the two phase mixture constitutes from 0.01 to 99.5% and the gel phase constitutes the remainder into a part of a living body where such augmentation is desired.

17. A method according to claim 16 wherein the glycosaminoglycan chemically co-cross-linked with said at least one other polymer is hyaluronan or hylan.

18. A method according to claim 16 wherein the chemically cross-linked glycosaminoglycan is hyaluronan or hylan.

19. A method according to claim 16 wherein the polymer concentration of the biocompatible gel swollen in the physiologically acceptable aqueous medium is from 0.01 to 30%.

20. A method according to claim 16 wherein the polymer concentration of the polymer solution phase is from 0.01 to 70%.

21. A method of viscosupplementation for medical purposes which comprises implanting a biocompatible viscoelastic gel slurry comprising a two phase mixture, a first phase being a particulate biocompatible gel phase, said gel phase comprising a chemically cross-linked glycosaminoglycan, or said glycosaminoglycan chemically co-cross-linked with at least one other polymer selected from the group consisting of polysaccharides and proteins, said gel phase being swollen in a physiologically acceptable aqueous medium and being uniformly distributed in the second phase, said second phase comprising a polymer solution of a water-soluble biocompatible polymer selected from the group consisting of polysaccharides, polyvinylpyrrolidone and poly ethyleneoxide in said physiologically acceptable aqueous medium, and wherein the polymer solution in the two phase mixture constitutes from 0.01 to 99.5% and the gel phase constitutes the remainder into a space of a living body where rheological control is desired.

22. A method according to claim 21 wherein the glycosaminoglycan chemically co-cross-linked with said at least one other polymer is hyaluronan or hylan.

23. A method according to claim 21 wherein the chemically cross-linked glycosaminoglycan is hyaluronan or hylan.

24. A method according to claim 21 wherein the polymer concentration of the biocompatible gel swollen in the physiologically acceptable aqueous medium is from 0.01 to 30%.

25. A method according to claim 21 wherein the polymer concentration of the polymer solution phase is from 0.01 to 70%.

26. A method according to claim 21 wherein the space of a living body is a joint space.