In situ solidifying complex coacervates and methods of making and using thereof

• US 10,369,249 B2
• Filed: 01/26/2018
• Issued: 08/06/2019
• Est. Priority Date: 07/14/2014
• 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.
• Primary Examiner(s): Gulledge, Brian
• Application Number:
  US15/880,650
• Publication Number:
  US 20180256776A1
• Time in Patent Office: 557 Days
• Field of Search: None
• CPC Class Codes: A61K 49/0043 Fluorescein, used in vivo
• CPC Class Codes: A61K 49/0054 Macromolecular compounds, i.e. oligomers, polymers, dendrimers
• CPC Class Codes: A61K 49/0073 semi-solid, gel, hydrogel, ointment
• CPC Class Codes: A61L 2300/416 Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
• CPC Class Codes: A61L 2300/44 Radioisotopes, radionuclides
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/02 containing inorganic materials
• CPC Class Codes: A61L 24/043 Mixtures of macromolecular materials
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 24/10 Polypeptides; Proteins A61L24/043 takes precedence
• CPC Class Codes: A61L 24/104 Gelatin
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 2430/36 for embolization or occlusion, e.g. vaso-occlusive compositions or devices
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00
• CPC Class Codes: C09D 5/1668 Vinyl-type polymers

Abstract

Described herein are fluid complex coacervates that produce solid adhesives in situ. Oppositely charged polyelectrolytes were designed to form fluid adhesive complex coacervates at ionic strengths higher than the ionic strength of the application site, but an insoluble adhesive solid or gel at the application site. When the fluid, high ionic strength adhesive complex coacervates are introduced into the lower ionic strength application site, the fluid complex coacervate is converted to a an adhesive solid or gel as the salt concentration in the complex coacervate equilibrates to the application site salt concentration. In one embodiment, the fluid complex coacervates are designed to solidify in situ at physiological ionic strength and have numerous medical applications. In other aspects, the fluid complex coacervates can be used in aqueous environment for non-medical applications.

Claims

1. An adhesive fluid complex coacervate comprising water, at least one polycation, at least one polyanion, and a salt that produces monovalent ions in water, wherein the salt is sodium chloride, and wherein the concentration of the monovalent ions in the adhesive fluid complex coacervate is greater than the concentration of the monovalent ions present at an application site, and wherein the polycation is synthetic polyguanidinyl polymer comprising an acrylate, methacrylate, acrylamide, or methacrylamide backbone and two or more guanidinyl groups pendant to the backbone.

2. The adhesive fluid complex coacervate of claim 1, wherein the concentration of the monovalent ions in the complex coacervate is 1.5 to 10 times greater than the concentration of the monovalent ions at the application site.

3. The adhesive fluid complex coacervate of claim 1, wherein the total positive/negative charge ratio of the polycation to the polyanion is from 4 to 0.25 and the concentration of the monovalent ions in the complex coacervate is from 0.5 M to 2.0 M.

4. The adhesive fluid complex coacervate of claim 1, wherein the adhesive fluid complex coacervate has a pH of 6 to 9.

5. The adhesive fluid complex coacervate of claim 1, wherein the polycation is a synthetic polyguanidinyl polymer comprising a copolymer of a monomer selected from the group consisting of an acrylate, a methacrylate, an acrylamide, a methacrylamide, or any combination thereof and a compound of formula I

6. The adhesive fluid complex coacervate of claim 5, wherein the polycation comprises polymerization product between the compound of formula I and methacrylamide.

7. The adhesive fluid complex coacervate of claim 5, wherein R¹ is methyl, X is NH, m is 3.

8. The adhesive fluid complex coacervate of claim 1, wherein the polyanion comprises a polyphosphate.

9. The adhesive fluid complex coacervate of claim 1, wherein the polyanion is an inorganic polyphosphate or a phosphorylated sugar.

10. The adhesive fluid complex coacervate of claim 1, wherein the polyanion comprises a hexametaphosphate salt.

11. The adhesive fluid complex coacervate of claim 1, wherein the polyanion is inositol hexaphosphate.

12. The adhesive fluid complex coacervate of claim 1, wherein the polyanion comprises phosphate groups and/or phosphonate groups.

13. The adhesive fluid complex coacervate of claim 1, wherein the polyanion comprises a polyacrylate comprising two or more pendant phosphate or phosphonate groups.

14. The adhesive fluid complex coacervate of claim 1, wherein the polyanion is the copolymerization product between a phosphate or phosphonate acrylate and/or phosphate or phosphonate methacrylate with one or more additional polymerizable monomers.

15. The adhesive fluid complex coacervate of claim 1, wherein the adhesive fluid complex coacervate further comprises a contrast agent or a visualization agent.

16. The adhesive fluid complex coacervate of claim 15, wherein the contrast agent comprises tantalum particles, gold particles, or an iodine complex.

17. The adhesive fluid complex coacervate of claim 1, wherein the adhesive fluid complex coacervate further comprises a reinforcing component.

18. The adhesive fluid complex coacervate of claim 17, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, nanoparticles, or microparticles.

19. The adhesive fluid complex coacervate of claim 1, wherein the adhesive fluid coacervate further comprises one or more bioactive agents.

20. The adhesive fluid complex coacervate of claim 19, wherein the bioactive agent comprises an antibiotic, a pain reliever, an immune modulator, a growth factor, an enzyme inhibitor, a hormone, a mediator, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapy agent, a receptor antagonist, a nucleic acid, or any combination thereof.

21. The adhesive fluid complex coacervate of claim 1, wherein the polycation is a synthetic polyguanidino polymer comprising the polymerization product between a monomer selected from the group consisting of an acrylate, a methacrylate, an acrylamide, a methacrylamide, or any combination thereof and a compound of formula I

22. The adhesive fluid complex coacervate of claim 21, wherein the compound of formula I is an HCl salt.

23. The adhesive fluid complex coacervate of claim 1, wherein the application site is within a blood vessel.

24. An adhesive fluid complex coacervate comprising water, at least one polycation, at least one polyanion, and a salt that produces monovalent ions in water, wherein the salt is sodium chloride, and wherein the concentration of the monovalent ions in the adhesive fluid complex coacervate is greater than the concentration of the monovalent ions present at an application site, and wherein the polyanion comprises a hexametaphosphate salt.

25. The adhesive fluid complex coacervate of claim 24, wherein the concentration of the monovalent ions in the complex coacervate is 1.5 to 10 times greater than the concentration of the monovalent ions at the application site.

26. The adhesive fluid complex coacervate of claim 24, wherein the total positive/negative charge ratio of the polycation to the polyanion is from 4 to 0.25 and the concentration of the monovalent ions in the complex coacervate is from 0.5 M to 2.0 M.

27. The adhesive fluid complex coacervate of claim 24, wherein the adhesive fluid complex coacervate has a pH of 6 to 9.

28. The adhesive fluid complex coacervate of claim 24, wherein the polycation comprises a polyamino compound, wherein the polyamino compound comprises a natural polymer or a synthetic polymer having two or more guanidinyl sidechains.

29. The adhesive fluid complex coacervate of claim 24, wherein the polycation comprises a polyacrylate comprising two or more pendant amino groups.

30. The adhesive fluid complex coacervate of claim 29, wherein the amino group comprises an alkylamino group, a heteroaryl group, a guanidinyl group, an imidazole, or an aromatic group substituted with one or more amino groups, a primary amino group, a secondary amino group, tertiary amino group, or a quaternary amine.

31. The adhesive fluid complex coacervate of claim 24, wherein the polycation is a synthetic polyguanidinyl polymer comprising a copolymer of a monomer selected from the group consisting of an acrylate, a methacrylate, an acrylamide, a methacrylamide, or any combination thereof and a compound of formula I

32. The adhesive fluid complex coacervate of claim 31, wherein the polycation comprises polymerization product between the compound of formula I and methacrylamide.

33. The adhesive fluid complex coacervate of claim 31, wherein R¹ is methyl, X is NH, m is 3.

34. The adhesive fluid complex coacervate of claim 24, wherein the adhesive fluid complex coacervate further comprises a contrast agent or a visualization agent.

35. The adhesive fluid complex coacervate of claim 34, wherein the contrast agent comprises tantalum particles, gold particles, or an iodine complex.

36. The adhesive fluid complex coacervate of claim 24, wherein the adhesive fluid complex coacervate further comprises a reinforcing component.

37. The adhesive fluid complex coacervate of claim 36, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, nanoparticles, or microparticles.

38. The adhesive fluid complex coacervate of claim 24, wherein the adhesive fluid coacervate further comprises one or more bioactive agents.

39. The adhesive fluid complex coacervate of claim 38, wherein the bioactive agent comprises an antibiotic, a pain reliever, an immune modulator, a growth factor, an enzyme inhibitor, a hormone, a mediator, a messenger molecule, a cell signaling molecule, a receptor agonist, an oncolytic virus, a chemotherapy agent, a receptor antagonist, a nucleic acid, or any combination thereof.

40. The adhesive fluid complex coacervate of claim 24, wherein the polycation is a synthetic polyguanidino polymer comprising the polymerization product between a monomer selected from the group consisting of an acrylate, a methacrylate, an acrylamide, a methacrylamide, or any combination thereof and a compound of formula I

41. The adhesive fluid complex coacervate of claim 40, wherein the compound of formula I is an HCl salt.

42. The adhesive fluid complex coacervate of claim 24, wherein the application site is within a blood vessel.