Adhesive complex coacervates and methods of making and using thereof

• US 8,283,384 B2
• Filed: 07/23/2009
• Issued: 10/09/2012
• 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: Shao, Hui, Stewart, Russell J
• Primary Examiner(s): Singh, Anoop
• Assistant Examiner(s): FALKOWITZ, ANNA R
• Application Number:
  US12/508,280
• Publication Number:
  US 20100120923A1
• Time in Patent Office: 1,174 Days
• Field of Search: 514/772.1, 424/423, 424/490, 525/50, 525/328.2, 525/326.7
• US Class Current: 514/772.1
• 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 biodegradable adhesive complex coacervate comprising at least one biodegradable polycation polyamine and at least one polyanion, wherein the at least one biodegradable polycation polyamine comprises modified gelatin, wherein the modified gelatin is modified with one or more alkylamino groups, heteroaryl groups, or an aromatic group substituted with one or more amino groups and wherein the biodegradable polyamine polycation or polyanion is a synthetic compound, and the polycation and polyanion cross-link with each other to produce said adhesive.

2. The coacervate of claim 1, wherein the biodegradable polyamine comprises gelatin modified with ethylenediamine.

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

4. The coacervate of claim 3, wherein the polyphosphate compound comprises a natural compound or a synthetic analogue.

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

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

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

8. The coacervate of claim 1, wherein the coacervate comprises at least one multivalent cation, and the multivalent cation comprises Ca⁺² and/or Mg⁺².

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

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

12. The coacervate of claim 10, wherein the polycation and polyanion comprises at least one fragment comprising the formula VII

11. An adhesive complex coacervate comprising at least one polycation polyamine, at least one polyanion, and at least one multivalent cation, wherein the at least one biodegradable polycation polyamine comprises modified gelatin, wherein the modified gelatin is modified with one or more alkylamino groups, heteroaryl groups, or an aromatic group substituted with one or more amino groups and the polycation polyamine and polyanion actinically cross-link with each other to produce said adhesive.

13. An adhesive produced by the process comprising:

(a) heating an adhesive complex coacervate comprising at least one polycation polyamine and at least one polyanion, wherein the polycation polyamine comprises modified gelatin, wherein the modified gelatin is modified with one or more alkylamino groups, heteroaryl groups, or an aromatic group substituted with one or more amino groups, wherein the polycation and polyanion crosslinks, wherein upon heating the adhesive complex coacervate the coacervate is converted to an insoluble solid; and

(b) crosslinking the polycation and polyanion in the insoluble solid to produce the adhesive.

14. An adhesive produced by the process comprising

(a) preparing an adhesive complex coacervate comprising admixing at least one polycation polyamine and at least one polyanion, wherein the polycation polyamine comprises modified gelatin, wherein the modified gelatin is modified with one or more alkylamino groups, heteroaryl groups, or an aromatic group substituted with one or more amino groups, and wherein at least one polycation or polyanion is a synthetic compound, and the polycation and polyanion crosslinks with each other;

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

(c) crosslinking the polycation and polyanion in the insoluble solid to produce the adhesive.