In situ solidifying solutions and methods of making and using thereof

• US 10,729,807 B2
• Filed: 06/24/2019
• Issued: 08/04/2020
• 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:
  US16/450,338
• Publication Number:
  US 20190321510A1
• Time in Patent Office: 407 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. A method for reducing or inhibiting blood flow in a blood vessel of a subject comprising introducing into the vessel a solution comprising water, at least one polycation, at least one polyanion, and a concentration of monovalent ions in water sufficient to prevent association of the polycation and polyanion, wherein the concentration of the monovalent ions in the solution is greater than the concentration of the monovalent ions in the blood vessel of the subject, whereupon introduction of the solution into the vessel the solution is converted to a solid in situ within the vessel, and wherein the polycation comprises a natural polymer or a synthetic polymer having two or more quanidinyl sidechains.

2. The method of claim 1, wherein the method reduces or inhibits blood flow to a tumor, an aneurysm, a varicose vein, an arteriovenous malformation, or a bleeding wound.

3. The method of claim 1, wherein the method reinforces the inner wall of a blood vessel in the subject.

4. The method of claim 1, wherein the concentration of the monovalent ions in the solution is 1.5 to 10 times greater than the concentration of the monovalent ions in the blood vessel of the subject.

5. The method of claim 1, wherein the monovalent ions in the solution are sodium ions and chloride ions.

6. The method 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 each monovalent ion in the solution is from 0.5 M to 2.0 M.

7. The method of claim 1, wherein the solution further comprises a salt that produces monovalent ions, wherein the salt is NaCl.

8. The method of claim 1, wherein the solution has a pH of 6 to 9.

9. The method of claim 1, wherein the polycation comprises a polyacrylate comprising two or more pendant quanidinyl groups.

10. The method of claim 1, 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.

11. The method of claim 1, wherein the polycation is a synthetic polyguanidinyl 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

12. The method of claim 11, wherein the polycation comprises polymerization product between the compound of formula I and methacrylamide.

13. The method of claim 11, wherein R¹ is methyl, X is NH, m is 3.

14. The method of claim 1, wherein the polyanion comprises a polyphosphate.

15. The method of claim 1, wherein the polyanion is an inorganic polyphosphate or a phosphorylated sugar.

16. The method of claim 1, wherein the polyanion comprises a hexametaphosphate salt.

17. The method of claim 1, wherein the polyanion is inositol hexaphosphate.

18. The method of claim 1, wherein the polyanion comprises a polyacrylate comprising two or more pendant phosphate groups.

19. The method 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.

20. The method of claim 1, wherein the solution further comprises a contrast agent or a visualization agent.

21. The method of claim 20, wherein the contrast agent comprises tantalum particles, gold particles, or an iodine complex.

22. The method of claim 1, wherein the solution further comprises a reinforcing component.

23. The method of claim 22, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, a nanoparticle, or a microparticle.

24. The method of claim 1, wherein the solution further comprises one or more bioactive agents.

25. The method of claim 24, 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, a chemotherapy agent, a receptor antagonist, a nucleic acid, or any combination thereof.

26. The method 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

27. The method of claim 1, wherein the polycation comprises a synthetic polymer containing one or more guanidinyl sidechains.

28. The method of claim 1, wherein the polycation comprises a synthetic polyguanidinyl polymer having an acrylate or methacrylate backbone and one or more guanidinyl sidechains.

29. The method of claim 1, wherein the polycation comprises a protamine.

30. The method of claim 1, wherein the polycation comprises a protamine, wherein the protamine comprises a crosslinkable gorup.

31. A method for reducing or inhibiting blood flow in a blood vessel of a subject comprising introducing into the vessel a solution comprising water, at least one polycation, at least one polyanion, and a concentration of monovalent ions in water sufficient to prevent association of the polycation and polyanion, wherein the concentration of the monovalent ions in the solution is greater than the concentration of the monovalent ions in the blood vessel of the subject, whereupon introduction of the solution into the vessel the solution is converted to a solid in sity within the vessel, and wherein the polyanion comprises a polyphosphate.

32. The method of claim 31, wherein the polyanion is an inorganic polyphosphate or a phosphorylated sugar.

33. The method of claim 31, wherein the polyanion comprises a hexametaphosphate salt.

34. The method of claim 31, wherein the polyanion is inositol hexaphosphate.

35. The method of claim 31, wherein the polyanion comprises a polyacrylate comprising two or more pendant phosphate groups.