Bioactive and biocompatible polyurethane-buthanediol-glycosaminoglycan salt copolymers

• US 8,278,406 B2
• Filed: 04/25/2008
• Issued: 10/02/2012
• Est. Priority Date: 04/27/2007
• Status: Active Grant

• Current Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Original Assignee: Wisconsin Alumni Research Foundation (University of Wisconsin System)
• Inventors: Masters, Kristyn S., Crone, Wendy C., Xu, Fangmin
• Primary Examiner(s): CAIN, EDWARD J
• Application Number:
  US12/110,096
• Publication Number:
  US 20080293906A1
• Time in Patent Office: 1,621 Days
• Field of Search: 527/300, 527/301
• US Class Current: 527/300
• CPC Class Codes: A61K 31/75 of ethene
• 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 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 33/0035 using a polymer with positively charged atoms in the polymeric backbone, e.g. ionenes
• CPC Class Codes: C08B 37/0063 Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
• CPC Class Codes: C08B 37/0069 Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
• 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: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08G 18/10 Prepolymer processes involving reaction of isocyanates or isothiocyanates with compounds having active hydrogen in a first reaction step
• CPC Class Codes: C08G 18/3206 aliphatic
• CPC Class Codes: C08G 18/4854 Polyethers containing oxyalkylene groups having four carbon atoms in the alkylene group
• CPC Class Codes: C08G 18/64 Macromolecular compounds not provided for by groups C08G18/42 - C08G18/63
• CPC Class Codes: C08G 18/6484 Polysaccharides and derivatives thereof
• CPC Class Codes: C08G 18/7657 containing two or more aromatic rings
• CPC Class Codes: C08G 18/7671 containing only one alkylene bisphenyl group
• CPC Class Codes: C08L 75/04 Polyurethanes

Abstract

A bioactive and biocompatible polyurethane-butanediol-glycosaminoglycan copolymer for use in medical implant devices. The biocompatible urethane component being the reaction product of 4,4′-methylene-di-(p-phenyl isocyanate) and poly(tetramethylene oxide)n and further reacted with 1,4-butanediol, wherein n=10 to 40. The bioactive glycosaminoglycan being a salt of hyaluronic acid, such as a cetylpyridinium salt acid having 5 to 10,000 repeating units or a salt of heparin, such as a dimethyldioctadecylammonium salt of heparin has 5 to 65 repeating units or a suitable salt of dermatan sulfate. The weight content of the bioactive glycosaminoglycan is an amount sufficient to render the copolymer bioactive. The copolymers described herein have excellent hemocompatibility and biocompatibility.

Claims

1. A copolymer comprising the polymerization reaction product of a biocompatible polyurethane and a bioactive polysaccharide, wherein the bioactive polysaccharide is incorporated into the polyurethane backbone of the copolymer.

2. The copolymer of claim 1, wherein the bioactive polysaccharide is a bioactive glycosaminoglycan.

3. The copolymer of claim 2, wherein the bioactive glycosaminoglycan is a member selected from the group consisting of a suitable salt of hyaluronic acid, a suitable salt of heparin, and a suitable salt of dermatan sulfate.

4. The copolymer of claim 3, wherein the salt of hyaluronic acid is a member selected from the group consisting of a cetylpyridinium salt and a tetrabutylammonium salt, and wherein the salt of heparin is a dimethyldioctadecylammorium salt.

5. The copolymer of claim 4, wherein the salt of hyaluronic acid has 5 to 10,000 repeating units, and wherein the dimethyldioctadecylammonium salt of heparin has 5 to 65 repeating units.

6. The copolymer of claim 1, wherein the weight content of the bioactive polysaccharide is in the range of about 0.05% to about 30%.

7. The copolymer of claim 6, wherein the high and low range endpoints of the weight content of the bioactive polysaccharide are any combination of members selected from the group consisting of 0.05%, 0.1%, 0.33%, 0.66%, 1.3%, 2.0%, 5.4%, 10%, 20% and 30%.

8. The copolymer of claim 7, comprising the cetylpyridinium salt of hyaluronic acid.

9. The copolymer of claim 7, wherein the biocompatible polyurethane is the reaction product of 4,4′

-methylene-di-(p-phenyl isocyanate) and poly(tetramethylene oxide)_n and further reacted with 1,4-butanediol, and wherein n=10 to 40.

10. The copolymer of claim 8, wherein the biocompatible polyurethane is the reaction product of 4,4′

-methylene-di-(p-phenyl isocyanate) and poly(tetramethylene oxide)_n and further reacted with 1,4-butanediol, and wherein n=10 to 40.

11. The copolymer of claim 6, wherein the biocompatible polyurethane is the reaction product of a suitable isocyanate-containing molecule and a suitable poly(C_2-10 alkylene oxide)_n and further reacted with a suitable C_4-50 diol-containing molecule, wherein n=10 to 40, wherein the C_2-10 alkylene is linear or branched, substituted or un-substituted, and wherein the C_4-50 is linear or branched, substituted or un-substituted.

12. A method of making a bioactive and biocompatible polyurethane-diol-polysaccharide copolymer comprising:

reacting a suitable isocyanate-containing molecule and a suitable poly(C_2-10 alkylene oxide)_n to produce a diisocyanate reactant, and, reacting the diisocyanate reactant with a suitable C_4-50 diol-containing molecule and a bioactive polysaccharide,

wherein n=10 to 40,

wherein the C_2-10 alkylene is linear or branched, substituted or un-substituted, and,

wherein the C_4-50 is linear or branched, substituted or un-substituted.

13. The method of claim 12, wherein the bioactive polysaccharide is a bioactive glycosaminoglycan.

14. The method of claim 13, wherein the glycosaminoglycan is a member selected from the group consisting of a suitable salt of hyaluronic acid, a suitable salt of heparin, and a suitable salt of dermatan sulfate.

15. The method of claim 14, wherein the salt of hyaluronic acid is a member selected from the group consisting of a cetylpyridinium salt and a tetrabutylammonium salt, and wherein the salt of heparin is a dimethyldioctadecylammonium salt.

16. The method of claim 15, wherein the salt of hyaluronic acid has 5 to 10,000 repeating units, and wherein the dimethyldioctadecylammonium salt of heparin has 5 to 65 repeating units.

17. The method of claim 12, wherein the weight content of the bioactive polysaccharide is in the range of about 0.05% to about 30%.

18. The method of claim 17, wherein the high and low range endpoints of the weight content of the bioactive polysaccharide are any combination of members selected from the group consisting of 0.05%, 0.1%, 0.33%, 0.66%, 1.3%, 2.0%, 5.4%, 10%, 20% and 30%.

19. A method of making a bioactive and biocompatible polyurethane-butanediol-glycosaminoglycan salt copolymer comprising:

reacting 4,4′

-methylene-di-(p-phenyl isocyanate) and poly(tetramethylene oxide)_n to produce a diisocyanate reactant, and,

reacting the diisocyanate reactant with 1,4-butanediol and a bioactive glycosaminoglycan salt selected from the group consisting of a suitable salt of hyaluronic acid and a suitable salt of heparin,

wherein n=10 to 40.

20. The method of claim 19, wherein the salt of hyaluronic acid is a member selected from the group consisting of a cetylpyridinium salt and a tetrabutylammonium salt, and wherein the salt of heparin is a dimethyldioctadecylammonium salt.

21. The method of claim 20, wherein the salt of hyaluronic acid has 5 to 10,000 repeating units, and wherein the dimethyldioctadecylammonium salt of heparin has 5 to 65 repeating units.

22. The method of claim 21, comprising the cetylpyridinium salt of hyaluronic acid having 5 to 10,000 repeating units.

23. The method of claim 19, wherein the weight content of the bioactive glycosaminoglycan salt is in the range of about 0.05% to about 30%.

24. The method of claim 23, wherein the high and low range endpoints of the weight content of the bioactive glycosaminoglycan salt are any combination of members selected from the group consisting of 0.05%, 0.1%, 0.33%, 0.66%, 1.3%, 2.0%, 5.4%, 10%, 20% and 30%.