Crosslinked polymer compositions and methods for their use

• US 5,874,500 A
• Filed: 12/18/1996
• Issued: 02/23/1999
• Est. Priority Date: 12/18/1995
• Status: Expired due to Term

• Current Assignee: Angiodevice International GmbH (Angiotech Pharmaceuticals (US), Inc.)
• Original Assignee: Cohesion Technologies Inc. (Angiotech Pharmaceuticals Incorporated)
• Inventors: Rhee, Woonza M., Berg, Richard A., DeLustro, Frank A.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US08/769,806
• Time in Patent Office: 797 Days
• Field of Search: 525/54.1, 525/419, 525/420, 525/425
• US Class Current: 525/54.1
• CPC Class Codes: A61L 2300/232 Monosaccharides, disaccharides, polysaccharides, lipopolysaccharides
• CPC Class Codes: A61L 2300/252 Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
• CPC Class Codes: A61L 2300/606 Coatings
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 31/041 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08G 65/329 with organic compounds
• CPC Class Codes: C08H 1/00 Macromolecular products derived from proteins food proteins A23; glue, gelatine C09H
• CPC Class Codes: C08H 1/06 derived from horn, hoofs, hair, skin or leather
• CPC Class Codes: C08L 5/16 Cyclodextrin; Derivatives thereof
• CPC Class Codes: C08L 71/00 Compositions of polyethers obtained by reactions forming an ether link in the main chain of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: Y10S 623/90 Stent for heart valve
• CPC Class Codes: Y10S 623/901 Method of manufacturing prosthetic device

Abstract

Crosslinked polymer compositions comprise a first synthetic polymer containing multiple nucleophilic groups covalently bound to a second synthetic polymer containing multiple electrophilic groups. The first synthetic polymer is preferably a synthetic polypeptide or a polyethylene glycol that has been modified to contain multiple nucleophilic groups, such as primary amino (--NH₂) or thiol (--SH) groups. The second synthetic polymer may be a hydrophilic or hydrophobic synthetic polymer which contains, or has been derivatized to contain, two or more electrophilic groups, such as succinimidyl groups. The compositions may further comprise other components, such as naturally occurring polysaccharides or proteins (such as glycosaminoglycans or collagen) and/or biologically active agents. Also disclosed are methods for using the crosslinked polymer compositions to effect adhesion between a first surface and a second surface; to effect tissue augmentation; to prevent the formation of surgical adhesions; and to coat a surface of a synthetic implant.

Claims

1. A composition comprising a multi-nucleophilic polyalkylene oxide and a multi-electrophilic polyalkylene oxide, wherein the multi-nucleophilic polyalkylene oxide has m nucleophilic groups and the multi-electrophilic polyalkylene oxide has n electrophilic groups, wherein m and n are each greater than or equal to two, and wherein m+n is greater than or equal to five.

2. The composition of claim 1, wherein n is two, and wherein m is greater than or equal to three.

3. The composition of claim 1, wherein m is two, and wherein n is greater than or equal to three.

4. The composition of claim 2, wherein the multi-nucleophilic polyalkylene oxide is tetrafunctionally activated.

5. The composition of claim 3, wherein the multi-electrophilic polyalkylene oxide is tetrafunctionally activated.

6. The composition of claim 1, wherein both the multi-nucleophilic polyalkylene oxide and the multi-electrophilic polyalkylene oxide are tetrafunctionally activated.

7. The composition of claim 1, wherein the multi-nucleophilic polyalkylene oxide further comprises two or more nucleophilic groups selected from the group consisting of --NH₂, --SH, --H, --PH₂, and --CO--NH--NH₂.

8. The composition of claim 7, wherein the multi-nucleophilic polyalkylene oxide further comprises two or more primary amino groups.

9. The composition of claim 7, wherein the multi-nucleophilic polyalkylene oxide further comprises two or more thiol groups.

10. The composition of claim 1, wherein the multi-nucleophilic polyalkylene oxide is polyethylene glycol or a derivative thereof.

11. The composition of claim 10, wherein the polyethylene glycol further comprises two or more nucleophilic groups selected from the group consisting of a primary amino group and a thiol group.

12. The composition of claim 1, wherein the multi-electrophilic polyalkylene oxide further comprises two or more electrophilic groups selected from the group consisting of --CO₂ N(COCH₂)₂, --CO₂ H, --CHO, --CHOCH₂, --N═

C═

O, --SO₂ CH═

CH₂, --N(COCH)₂, and --S--S--(C₅ H₄ N).

13. The composition of claim 1, wherein the multi-electrophilic polyalkylene oxide further comprises two or more succinimidyl groups.

14. The composition of claim 1, wherein the multi-electrophilic polyalkylene oxide further comprises two or more maleimidyl groups.

15. The composition of claim 1, wherein the multi-electrophilic polyalkylene oxide is a polyethylene glycol or a derivative thereof.

19. The composition of claim 1 further comprising a polysaccharide or a protein.

20. The composition of claim 1 further comprising a polysaccharide, wherein the polysaccharide is a glycosaminoglycan.

21. The composition of claim 20, wherein the glycosaminoglycan is selected from the group consisting of hyaluronic acid, chitin, chondroitin sulfate A, chondroitin sulfate B, chondroitin sulfate C, keratin sulfate, keratosulfate, heparin, and derivatives thereof.

22. The composition of claim 19 further comprising a protein, wherein the protein is collagen or a derivative thereof.

29. The composition of claim 1, wherein the multi-nucleophilic polyalkylene oxide or the multi-electrophilic polyalkylene oxide, or both the multi-nucleophilic polyalkylene oxide and the multi-electrophilic polyalkylene oxide, further comprise(s) a linking group.

30. The composition of claim 1, wherein the multi-nucleophilic polyalkylene oxide is given by the formula:

space="preserve" listing-type="equation">polymer-Q.sup.1 -X.sub.m

and wherein the multi-electrophilic polyalkylene oxide is given by the formula;

space="preserve" listing-type="equation">polymer-Q.sup.2 -Y.sub.n

wherein X is an electrophilic group and Y is a nucleophilic group;

wherein m and n are each 2 to 4;

wherein m+n≦

5;

wherein each of Q¹ and Q² are linking groups selected from the group consisting of --O--(CH₂)_n '"'"'--, --S--(CH₂)_n '"'"'--, --NH--(CH₂)_n '"'"'--, --O₂ C--NH--(CH₂)_n '"'"'--, --O₂ C--(CH₂)_n '"'"'--, --O₂ C--CR¹ H--, and --O--R² --CO--NH;

wherein n'"'"'=1 to 10;

wherein R¹ =--H, --CH₃, or --C₂ H₅ ;

wherein R² =--CH₂ -- or --CO--NH--CH₂ CH₂ --; and

wherein Q¹ and Q² may be the same or different or may be absent.

31. The composition of claim 30, wherein Y is given by the formula:

space="preserve" listing-type="equation">--CO.sub.2 N(COCH.sub.2).sub.2.

32. The composition of claim 30, wherein Y is given by the formula:

space="preserve" listing-type="equation">--N(COCH).sub.2.

33. The composition of claim 1, wherein the multi-nucleophilic polykylene oxide or the multi-electrophilic polyalkylene oxide or both the multi-nucleophilic polyalkylene oxide and the multi-electrophilic polyalkylene oxide further comprise(s) a biodegradable group.

34. The composition of claim 33, wherein the biodegradable group is selected from the group consisting of lactide, glycolide, ε

-caprolactone, poly(α

-hydroxy acid), poly(amino acid) and poly(anhydride).

16. A composition comprising a multi-nucleophilic polyalkylene oxide and a multi-electrophilic polyalkylene oxide, wherein the multi-nucleophilic polyalkylene oxide further comprises at least one prmary amino group and at least one thiol group.

17. A composition comprising a multi-nucleophilic polyalkylene oxide and a multi-electrophilic polyalkylene oxide, wherein the multi-nucleophilic polyalkylene oxide further comprises two or more thiol groups and the multi-electrophilic polyalkylene oxide further comprises two or more electrophilic groups selected from the group consisting of succinimidyl groups and maleimidyl groups.

18. A composition comprising a multi-nucleophilic polyalkylene oxide and a multi-electrophilic polyalkylene oxide, wherein the multi-nucleophilic polyalkylene oxide further comprises two or more nucleophilic groups selected from the group consisting of primary amino groups and thiol groups, and the multi-electrophilic polyalkylene oxide further comprises two or more succinimidyl groups.

23. A composition comprising a first polyethylene glycol comprising two or more thiol groups, and a second polyethylene glycol comprising two or more succinimidyl groups or maleimidyl groups, wherein the sum of the thiol groups and the succinimidyl or maleimidyl groups is at least five.

24. The composition of claim 23 further comprising a protein or a polysaccharide.

25. The composition of claim 24 further comprising a polysaccharide, wherein the polysaccharide is a glycosaminoglycan.

26. The composition of claim 25, wherein the glycosaminoglycan is selected from the group consisting of hyaluronic acid, chitin, chondroitin sulfate A, chondroitin sulfate B, chondroitin sulfate C, keratin sulfate, keratosulfate, heparin, and derivatives thereof.

27. The composition of claim 24 further comprising a protein, wherein the protein is collagen or a derivative thereof.

28. The composition of claim 23, wherein the first polyethylene glycol further comprises four thiol groups and the second polyethylene glycol further comprises four succinimidyl groups.