Adhesive complex coacervates and methods of making and using thereof

Patent metadata

Field	Value
Publication number	US-9272069-B2
Application number	US-86404508-A
Country	US
Kind code	B2
Filing date	Nov 13, 2008
Priority date	Jan 24, 2008
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

Described herein is the synthesis of adhesive complex coacervates. The adhesive complex coacervates are composed of a mixture of one or more polycations, one or more polyanions, and one of more multivalent cations. The polycations and polyanions in the adhesice complex coacervate are crosslinked with one another by covalent bonds upon curing. The adhesive complex coacervates have several desirable features when compared to conventional bioadhesives, which are effective in water-based applicatgions. The adhesive complex coacervates described herein exhibit good interfacial tension in water when applied to a substrate (i.e., they spread over the interface rather than being beaded up). Additionally, the ability of the complex coacervate to crosslink intermolecularly increases the cohesive strength of the adhesive complex coacervate. The adhesive complex coacervates have numerous biological applications as bioadhesives and drug delivery devices. In particular, the adhesive complex coacervates described herein are particularly useful in underwater applications and situations where water is present such as, for example, physiological conditions.

First claim

What is claimed:

1. An adhesive comprising a complex coacervate, wherein the complex coacervate comprises at least one synthetic polycation, at least one synthetic polyanion, and at least one multivalent cation, wherein the synthetic polycation and the synthetic polyanion each comprise at least one crosslinkable group covalently bonded to the synthetic polycation and the synthetic polyanion capable of covalently crosslinking with one another.

2. The coacervate of claim 1 , wherein the polycation comprises a polyamino compound.

3. The coacervate of claim 1 , wherein the polycation comprises a polyacrylate comprising one or more pendant amino groups.

4. The coacervate of claim 1 , wherein the polycation comprises a polyacrylate comprising one or more pendant imidazole groups.

5. The coacervate of claim 1 , wherein the polycation comprises a polymer comprising at least one fragment comprising the formula I

wherein R 1 , R 2 , and R 3 are, independently, hydrogen or an alkyl group, X is oxygen or NR 5 , where R 5 is hydrogen or an alkyl group, and m is from 1 to 10, or the pharmaceutically-acceptable salt thereof.

6. The coacervate of claim 5 , wherein R 1 , R 2 , and R 3 are methyl, X is NH, and m is 2.

7. The coacervate of claim 2 , wherein the polyamino compound comprises from 10 to 90 mole % primary, secondary, or tertiary amino groups.

8. The coacervate of claim 1 , wherein the polyanion comprises one or more sulfate, sulfonate, carboxylate, borate, boronate, phosphonate, or phosphate groups.

9. The coacervate of claim 1 , wherein the polyanion comprises a polyphosphate compound.

10. The coacervate of claim 1 , wherein the polyanion comprises a polyacrylate comprising one or more pendant phosphate groups.

11. The coacervate of claim 1 , wherein the polyanion comprises a polymer comprising at least one fragment comprising the formula II

wherein R 4 is hydrogen or an alkyl group, and n is from 1 to 10, or the pharmaceutically-acceptable salt thereof.

12. The coacervate of claim 11 , wherein R 4 is methyl and n is 2.

13. The coacervate of claim 10 , wherein the polyphosphate compound comprises from 10 to 90 mole % phosphate groups.

14. The coacervate of claim 1 , wherein the polyanion comprises a polyphosphoserine.

15. The coacervate of claim 1 , wherein the multivalent cation comprises one or more transition metal ions or rare earth metals.

16. The coacervate of claim 1 , wherein the multivalent cation comprises one or more divalent cations.

17. The coacervate of claim 1 , wherein the multivalent cation comprises Ca +2 and Mg +2 .

18. The coacervate of claim 1 , wherein the composition is biocompatible and biodegradable.

19. The coacervate of claim 1 , wherein the composition further comprises one or more bioactive agents encapsulated in the complex.

20. The coacervate of claim 1 , wherein the groups capable of crosslinking with one another are the same or different.

21. The coacervate of claim 1 , wherein the crosslinking group on the polycation comprises a nucleophilic group and the crosslinking group on the polyanion comprises an electrophilic group.

22. The coacervate of claim 1 , wherein the crosslinking group on the polycation and polyanion comprises a hydroxyl aromatic compound capable of undergoing oxidation.

23. The coacervate of claim 1 , wherein the crosslinking group on the polyanion comprises a DOPA residue or a catechol residue and the polycation comprises a nucleophilic group capable of reacting with the crosslinking group to form a covalent bond.

24. An adhesive complex coacervate produced by the process comprising
(a) preparing a polyelectrolyte complex comprising admixing at least one synthetic polycation, at least one synthetic polyanion, and at least one multivalent cation, and the synthetic polycation and synthetic polyanion each comprise at least one group capable of covalently crosslinking with each other; and
(b) adjusting the pH of the polyelectrolyte complex, the concentration of the at least one divalent cation, or a combination thereof to produce the adhesive complex coacervate.

25. The coacervate of claim 24 , wherein the coacervate is produced in situ.

26. The coacervate of claim 24 , wherein step (a) is performed at a pH less than 4, and step (b) comprises raising the pH.

27. The coacervate of claim 24 , wherein step (b) comprises raising the pH of the polyelectrolyte complex to a pH of greater than or equal to 7.0.

28. The coacervate of claim 24 , wherein after step (b) further comprises contacting the complex coacervate with an oxidant in order to facilitate the crosslinking between the polycation and polyanion.

29. The coacervate of claim 28 , wherein the oxidant comprises O 2 , NaIO 4 , a peroxide, or a transition metal oxidant.

30. A method for repairing a bone fracture in a subject, comprising contacting the fractured bone with the adhesive complex coacervate of claim 1 and covalently crosslinking the synthetic polycation and synthetic polyanion in the adhesive complex coacervate.

31. The method of claim 30 , wherein the method is in vitro.

32. The method of claim 30 , wherein the method is in vivo.

33. The method of claim 30 , wherein the fracture comprises complete fracture, an incomplete fracture, a linear fracture, a transverse fracture, an oblique fracture, a compression fracture, a spiral fracture, a comminuted fracture, a compacted fracture, or an open fracture.

34. The method of claim 30 , wherein the fracture comprises an intra-articular fracture.

35. The method of claim 30 , wherein the fracture comprises a craniofacial bone fracture.

36. The method of claim 30 , wherein the method comprises adhering a fractured piece of bone to an existing bone.

37. The method of claim 30 , wherein the composition sets within 60 seconds.

38. A method for adhering a metal substrate to a bone of a subject comprising contacting the bone with the composition of claim 1 , applying the metal substrate to the coated bone, and covalently crosslinking the synthetic polycation and synthetic polyanion in the adhesive complex coacervate.

39. A method for adhering a bone-tissue scaffold to a bone of a subject comprising contacting the bone and tissue with the composition of claim 1 , applying the bone-tissue scaffold to the bone and tissue, and covalently crosslinking the synthetic polycation and synthetic polyanion in the adhesive complex coacervate.

40. The method of claim 39 , wherein the tissue comprises cartilage, a ligament, a tendon, a soft tissue, an organ, or synthetic derivative thereof.

41. The method of claim 39 , wherein the scaffold comprises one or more drugs that facilitate growth or repair of the bone and tissue.

42. A method for repairing a crack in a tooth, comprising applying the composition of claim 1 to the crack and covalently crosslinking the synthetic polycation and synthetic polyanion in the adhesive complex coacerv

Assignees

• Stewart Russell
• Shao Hui
• Univ Utah Res Found

Inventors

• Stewart Russell
• Shao Hui

Classifications

• A61L24/043

  Mixtures of macromolecular materials · CPC title

• C08F8/06

  Oxidation · CPC title

• A61L2300/602

  Type of release, e.g. controlled, sustained, slow · CPC title

• C08F2810/30

  leading to the formation or introduction of aliphatic or alicyclic unsaturated groups · CPC title

• C08F8/00

  Chemical modification by after-treatment (graft polymers, block polymers, crosslinking with unsaturated monomers or with polymers C08F251/00 - C08F299/00; of conjugated diene rubbers C08C) · CPC title