Adhesive complex coacervates and method of making and using thereof

• US 9,913,926 B2
• Filed: 09/14/2012
• Issued: 03/13/2018
• 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:
  US13/617,882
• Publication Number:
  US 20130189313A1
• Time in Patent Office: 2,006 Days
• Field of Search: 424400, 525209, 5147724, 623 2362
• 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. They have numerous biological applications as bioadhesives and drug delivery devices and are particularly useful in underwater applications and situations where water is present such as, for example, physiological conditions.

Claims

1. An adhesive comprising a fluid complex coacervate, wherein the complex coacervate comprises a polyamino compound and a polyphosphate compound, wherein each polyamino compound and polyphosphate compound includes at least one fragment having the formula VII

2. The coacervate of claim 1, wherein the polyphosphate compound comprises a polymer comprising at least one fragment comprising the formula II

3. The coacervate of claim 1, wherein the polyphosphate compound comprises at least one dihydroxyl aromatic group capable of undergoing oxidation, wherein the dihydroxyl aromatic group is covalently attached to the polyphosphate compound.

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

5. The coacervate of claim 1, wherein the coacervate further comprises a stabilized oxidant complex.

6. An adhesive produced by the process comprising

(a) heating an adhesive complex coacervate of claim 1, wherein upon heating the adhesive complex coacervate the coacervate is converted to an insoluble solid;

and

(b) covalently crosslinking the polyphosphate compound and polyamino compound in the insoluble solid to produce the adhesive.

7. An adhesive produced by the process comprising

(a) preparing an adhesive complex coacervate of claim 1;

(b) adjusting the pH of the adhesive complex coacervate to produce an insoluble solid; and

(c) covalently crosslinking the polyamino compound and polyphosphate compound in the insoluble solid to produce the adhesive.

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

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

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

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

12. A method for repairing a corneal laceration in a subject, comprising applying to the laceration the adhesive complex coacervate of claim 1.

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

14. The coacervate of claim 1, wherein the coacervate has a pH greater than or equal to 7.0.

15. The coacervate of claim 1, wherein the coacervate has a pH from 7. 0 to 9.0.

16. The coacervate of claim 1, wherein R² is hydrogen and R³ is an acrylate or methacrylate group.

17. The coacervate of claim 1, wherein R¹ is methyl, R² is hydrogen, R³ is an acrylate or methacrylate group, X is NH, and m is 2.

18. The coacervate of claim 1, wherein the polyamino compound has at least one fragment of the formula I