Adhesive complex coacervates and methods of making and using thereof

• US 10,517,987 B2
• Filed: 03/12/2018
• Issued: 12/31/2019
• 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 J., Shao, Hui
• Primary Examiner(s): Falkowitz, Anna R
• Application Number:
  US15/918,423
• Publication Number:
  US 20180272027A1
• Time in Patent Office: 659 Days
• CPC Class Codes: A61F 2/2846 Support means for bone substitute or for bone graft implants, e.g. membranes or plates for covering bone defects nets or sleeves applied to surface of endoprostheses A61F2/30907; bone plates A61B17/80; bone regeneration in dental surgery A61C8/0006
• 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 24/0073 with a macromolecular matrix
• 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: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: C08F 220/54 Amides , e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
• CPC Class Codes: C08F 220/56 Acrylamide; Methacrylamide
• 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: C08L 33/26 Homopolymers or copolymers of acrylamide or methacrylamide
• CPC Class Codes: C09D 133/26 Homopolymers or copolymers of acrylamide or methacrylamide
• 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 and their use thereof. The adhesive complex coacervates are composed of a mixture of one or more polycations and one or more polyanions. The polycations and polyanions in the adhesive 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 applications. 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. A liquid adhesive complex coacervate, wherein the complex coacervate comprises at least one polycation and at least one polyanion, and wherein the complex coacervate does not include a multivalent cation.

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

3. The liquid adhesive complex coacervate of claim 1, wherein the polycation comprises a polyacrylate having pendant amino groups.

4. The liquid adhesive complex coacervate of claim 3, wherein the polyacrylate is a homopolymer or copolymer derived from the polymerization of an acrylate monomer comprising an acrylate, a methacrylate, an acrylamide, or any combination thereof.

5. The liquid adhesive complex coacervate of claim 1, wherein the polycation comprises a polyacrylate comprising a primary, secondary, or tertiary amino group, an alkylamino group, a heteroaryl group, or an aromatic group substituted with one or more amino groups, or imidazole groups.

6. The liquid adhesive complex coacervate of claim 1, wherein the polyanion comprises a polymer comprising pendant sulfate, sulfonate, carboxylate, borate, boronate, phosphonate, phosphate groups, or any combination thereof.

7. The liquid adhesive complex coacervate of claim 1, wherein the polyanion comprises a polyphosphate compound.

8. The liquid adhesive complex coacervate of claim 1, wherein the polyanion comprises an inorganic polyphosphate.

9. The liquid adhesive complex coacervate of claim 1, wherein the polyanion comprises a metaphosphate salt.

10. The liquid adhesive complex coacervate of claim 1, wherein the polyanion comprises a polyacrylate comprising pendant phosphate or phosphonate groups.

11. The liquid adhesive complex coacervate of claim 1, wherein the polyanion comprises a naturally-occurring polyphosphate.

12. The liquid adhesive complex coacervate of claim 1, wherein the complex coacervate further comprises a bioactive agent.

13. The liquid adhesive complex coacervate of claim 1, wherein the polycation and polyanion comprises at least one group capable of covalent crosslinking with each other.

14. The liquid adhesive complex coacervate of claim 13, wherein the crosslinking group on the polycation comprises a nucleophilic group and the crosslinking group on the polyanion comprises an electrophilic group.

15. The liquid adhesive complex of claim 13, wherein the crosslinking group on the polycation comprises an electrophilic group and the crosslinking group on the polyanion comprises a nucleophilic group.

16. The liquid adhesive complex coacervate of claim 13, wherein the crosslinking group on the polycation and polyanion comprises an ortho-dihydroxy aromatic group capable of undergoing oxidative crosslinking.

17. The liquid adhesive complex coacervate of claim 13, wherein (1) the crosslinking group on the polyanion comprises a quinone group and the polycation comprises a nucleophilic group capable of reacting with the quinone group to form a covalent bond or (2) the crosslinking group on the polycation comprises a quinone group and the polyanion comprises a nucleophilic group capable of reacting with the quinone group to form a covalent bond.

18. The liquid adhesive complex coacervate of claim 17, wherein the nucleophilic group is a hydroxyl, a thiol group, or a substituted or unsubstituted amino group.

19. The liquid adhesive complex coacervate of claim 13, wherein the crosslinking group on the polyanion and the polycation comprises an actinically crosslinkable group.

20. The liquid adhesive complex coacervate of claim 19, wherein the actinically crosslinkable group comprises an olefinic group.

21. The liquid adhesive complex coacervate of claim 20, wherein the olefinic group comprises an acrylate group, a methacrylate group, an acrylamide group, a methacrylamide group, an allyl group, a vinyl group, a vinylester group, or a styrenyl group.

22. The liquid adhesive complex coacervate of claim 1, wherein the coacervate further comprises an initiator and optionally a co-initiator.

23. The liquid adhesive complex coacervate of claim 22, wherein the initiator comprises (1) one or more of a radical initiator, a thermal initiator, or a photoinitiator, or (2) two or more radical initiators, thermal initiators, or a photoinitiators.

24. The liquid adhesive complex coacervate of claim 23, wherein the photoinitiator and optionally a co-initiator are covalently attached to the polycation and/or polyanion.

25. The liquid adhesive complex coacervate of claim 23, wherein the photoinitiator comprises a water-soluble initiator comprising riboflavin, eosin, eosin y, or rose Bengal.

26. The liquid adhesive complex coacervate of claim 23, wherein the photoinitiator comprises a phosphine oxide, a peroxide, an azide compound, an α

-hydroxyketone, or an α

-aminoketone.

27. A method for inhibiting blood flow in a blood vessel of a subject comprising introducing the liquid adhesive complex coacervate of claim 1 into the vessel.

28. A method for repairing a bone fracture in a subject, comprising contacting the fractured bone with the liquid adhesive complex coacervate of claim 1.

29. A method for adhering a metal substrate to a bone of a subject comprising contacting the bone with the liquid adhesive complex coacervate of claim 1 and applying the metal substrate to the coated bone.

30. A method for adhering a bone-tissue scaffold to a bone of a subject comprising contacting the bone and tissue with the liquid adhesive complex coacervate of claim 1 and applying the bone-tissue scaffold to the bone and tissue.

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

32. A method for repairing a laceration, comprising applying to the laceration the liquid adhesive complex coacervate of claim 1.

33. A method for securing a dental implant, comprising (a) applying to an oral substrate and/or dental implant the liquid complex coacervate of claim 1, and (b) attaching the dental implant to the substrate.