Adhesive complex coacervates and methods of making and using thereof

• US 9,272,069 B2
• Filed: 11/13/2008
• Issued: 03/01/2016
• Est. Priority Date: 01/24/2008
• Status: Active Grant

• Current Assignee: University of Utah Research Foundation (State of Utah)
• Original Assignee: University of Utah Research Foundation (State of Utah)
• Inventors: Stewart, Russell, Shao, Hui
• Primary Examiner(s): Salamon, Peter A
• Application Number:
  US12/864,045
• Publication Number:
  US 20100305626A1
• Time in Patent Office: 2,665 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61L 2300/412 Tissue-regenerating or healing or proliferative agents
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 2300/62 Encapsulated active agents, e.g. emulsified droplets
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: C08F 230/02 containing phosphorus
• CPC Class Codes: C08F 2800/10 as molar percentages
• CPC Class Codes: C08F 2810/20 leading to a crosslinking, either explicitly or inherently
• CPC Class Codes: C08F 2810/30 leading to the formation or introduction of aliphatic or alicyclic unsaturated groups
• CPC Class Codes: C08F 8/00 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 Class Codes: C08F 8/06 Oxidation
• CPC Class Codes: C08F 8/10 Acylation
• CPC Class Codes: C09J 133/14 of esters containing halogen, nitrogen, sulfur or oxygen atoms in addition to the carboxy oxygen

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.

Claims

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

6. The coacervate of claim 5, wherein R¹, R², and R³ 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

12. The coacervate of claim 11, wherein R⁴ 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.

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 coacervate.

43. A method for securing a dental implant, comprising applying the composition of claim 1 to an oral substrate, attaching the dental implant to the substrate, and covalently crosslinking the synthetic polycation and synthetic polyanion in the adhesive complex coacervate.

44. The method of claim 43, wherein the dental implant comprises a crown or denture.

45. A method for delivering one or more bioactive agents comprising administering the coacervate of claim 1 to a subject.

46. The coacervate of claim 1, wherein the polycation comprises a polyamino compound and the polyanion comprises a polyphosphate compound.

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 O₂, NaIO₄, a peroxide, or a transition metal oxidant.