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

• US 9,913,927 B2
• Filed: 07/14/2015
• Issued: 03/13/2018
• 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 M
• Application Number:
  US15/325,885
• Publication Number:
  US 20170157285A1
• Time in Patent Office: 973 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 artificial blood vessels A61L27/507
• 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 the subject comprising introducing into the vessel an adhesive fluid complex coacervate comprising at least one polycation, at least one polyanion, and a monovalent salt, wherein the concentration of the monovalent salt selected from the group consisting of NaCl, KCl, and mixtures thereof in the adhesive fluid complex coacervate is greater than the concentration of the monovalent salt in the blood vessel of the subject, whereupon introduction of the adhesive fluid complex coacervate into the vessel the adhesive fluid complex coacervate is converted to a solid in situ that creates an artificial embolus within the vessel.

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 comprising introducing into the vessel the fluid complex coacervate.

4. The method of claim 1, wherein the concentration of the monovalent salt in the complex coacervate is 1.5 to 10 times greater than the concentration of the monovalent salt in the aqueous environment.

5. The method of claim 1, wherein the monovalent salt in the complex coacervate is NaCl.

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 monovalent salt in the complex coacervate is from 0.5 M to 2.0 M.

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

8. The method of claim 1, 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.

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

10. The method of claim 9, 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.

11. 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.

12. 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

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

14. The method of claim 12, wherein R¹ is methyl, X is NH, m is 3.

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

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

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

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

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

20. 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.

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

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

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

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

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

26. The method of claim 25, 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.

27. 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