# US 10,369,249 B2 · In situ solidifying complex coacervates and methods of making and using thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,369,249 B2 - Document ID: US10369249B2 - Status: Granted - Kind: B2 - Application number: 15/880,650 - Filed: 2018-01-26 - Published: 2018-09-13 - Granted: 2019-08-06 - Earliest claimed: 2014-07-14 - Assignees: University of Utah Research Foundation - Applicants: University of Utah Research Foundation - Inventors: Russell J. Stewart - Web page: https://patentgrep.com/patent/US10369249B2 ## CPC - A61L 24/046: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds (A61L24/043 takes precedence)} - A61K 49/0043: {Fluorescein, used in vivo} - A61K 49/0054: {Macromolecular compounds, i.e. oligomers, polymers, dendrimers} - A61K 49/0073: {semi-solid, gel, hydrogel, ointment} - A61L 24/0015: {Medicaments; Biocides} - A61L 24/0031: {Hydrogels or hydrocolloids} - A61L 24/0042: {Materials resorbable by the body} - A61L 24/02: containing inorganic materials - A61L 24/043: {Mixtures of macromolecular materials} - A61L 24/10: Polypeptides; Proteins {(A61L24/043 takes precedence)} - A61L 24/104: {Gelatin} - C09D 5/1668: {Vinyl-type polymers} - A61L 2300/416: Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus - A61L 2300/44: Radioisotopes, radionuclides - A61L 2430/02: for reconstruction of bones; weight-bearing implants - A61L 2430/36: for embolization or occlusion, e.g. vaso-occlusive compositions or devices - A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C09D: COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR (cosmetics A61K; processes for applying liquids or other fluent materials to surfaces, in general, B05D; staining wood B27K5/02; glazes or vitreous enamels C03C; natural resins, French polish, drying-oils, driers, turpentine, per se, C09F; polishing compositions other than French polish, ski waxes C09G; adhesives or use of materials as adhesives C09J; materials for sealing or packing joints or covers C09K3/10; materials for stopping leaks C09K3/12; processes for the electrolytic or electrophoretic production of coatings C25D) ## 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 ### Claim 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. ### Claim 2 (depends on 1) 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. ### Claim 3 (depends on 1) 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. ### Claim 4 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the adhesive fluid complex coacervate has a pH of 6 to 9. ### Claim 5 (depends on 1) 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 wherein R1 is hydrogen or an alkyl group, X is oxygen or NR5, where R5 is hydrogen or an alkyl group, and m is from 1 to 10, or the pharmaceutically-acceptable salt thereof. ### Claim 6 (depends on 5) The adhesive fluid complex coacervate of claim 5, wherein the polycation comprises polymerization product between the compound of formula I and methacrylamide. ### Claim 7 (depends on 5) The adhesive fluid complex coacervate of claim 5, wherein R1 is methyl, X is NH, m is 3. ### Claim 8 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the polyanion comprises a polyphosphate. ### Claim 9 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the polyanion is an inorganic polyphosphate or a phosphorylated sugar. ### Claim 10 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the polyanion comprises a hexametaphosphate salt. ### Claim 11 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the polyanion is inositol hexaphosphate. ### Claim 12 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the polyanion comprises phosphate groups and/or phosphonate groups. ### Claim 13 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the polyanion comprises a polyacrylate comprising two or more pendant phosphate or phosphonate groups. ### Claim 14 (depends on 1) 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. ### Claim 15 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the adhesive fluid complex coacervate further comprises a contrast agent or a visualization agent. ### Claim 16 (depends on 15) The adhesive fluid complex coacervate of claim 15, wherein the contrast agent comprises tantalum particles, gold particles, or an iodine complex. ### Claim 17 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the adhesive fluid complex coacervate further comprises a reinforcing component. ### Claim 18 (depends on 17) The adhesive fluid complex coacervate of claim 17, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, nanoparticles, or microparticles. ### Claim 19 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the adhesive fluid coacervate further comprises one or more bioactive agents. ### Claim 20 (depends on 19) 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. ### Claim 21 (depends on 1) 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 wherein R1 is hydrogen or an alkyl group, X is oxygen or NR5, where R5 is hydrogen or an alkyl group, and m is 3, or the pharmaceutically-acceptable salt thereof, the polyanion comprises sodium hexametaphosphate, the total positive/negative charge ratio of the polycation solution to the polyanion is from 0.95 to 1.10 and the concentration of NaCl in the adhesive fluid complex coacervate is from 0.5 M to 2.0 M. ### Claim 22 (depends on 21) The adhesive fluid complex coacervate of claim 21, wherein the compound of formula I is an HCl salt. ### Claim 23 (depends on 1) The adhesive fluid complex coacervate of claim 1, wherein the application site is within a blood vessel. ### Claim 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. ### Claim 25 (depends on 24) 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. ### Claim 26 (depends on 24) 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. ### Claim 27 (depends on 24) The adhesive fluid complex coacervate of claim 24, wherein the adhesive fluid complex coacervate has a pH of 6 to 9. ### Claim 28 (depends on 24) 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. ### Claim 29 (depends on 24) The adhesive fluid complex coacervate of claim 24, wherein the polycation comprises a polyacrylate comprising two or more pendant amino groups. ### Claim 30 (depends on 29) 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. ### Claim 31 (depends on 24) 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 wherein R1 is hydrogen or an alkyl group, X is oxygen or NR5, where R5 is hydrogen or an alkyl group, and m is from 1 to 10, or the pharmaceutically-acceptable salt thereof. ### Claim 32 (depends on 31) The adhesive fluid complex coacervate of claim 31, wherein the polycation comprises polymerization product between the compound of formula I and methacrylamide. ### Claim 33 (depends on 31) The adhesive fluid complex coacervate of claim 31, wherein R1 is methyl, X is NH, m is 3. ### Claim 34 (depends on 24) The adhesive fluid complex coacervate of claim 24, wherein the adhesive fluid complex coacervate further comprises a contrast agent or a visualization agent. ### Claim 35 (depends on 34) The adhesive fluid complex coacervate of claim 34, wherein the contrast agent comprises tantalum particles, gold particles, or an iodine complex. ### Claim 36 (depends on 24) The adhesive fluid complex coacervate of claim 24, wherein the adhesive fluid complex coacervate further comprises a reinforcing component. ### Claim 37 (depends on 36) The adhesive fluid complex coacervate of claim 36, wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, nanoparticles, or microparticles. ### Claim 38 (depends on 24) The adhesive fluid complex coacervate of claim 24, wherein the adhesive fluid coacervate further comprises one or more bioactive agents. ### Claim 39 (depends on 38) 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. ### Claim 40 (depends on 24) 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 wherein R1 is hydrogen or an alkyl group, X is oxygen or NR5, where R5 is hydrogen or an alkyl group, and m is 3, or the pharmaceutically-acceptable salt thereof, the polyanion comprises sodium hexametaphosphate, the total positive/negative charge ratio of the polycation solution to the polyanion is from 0.95 to 1.10 and the concentration of NaCl in the adhesive fluid complex coacervate is from 0.5 M to 2.0 M. ### Claim 41 (depends on 40) The adhesive fluid complex coacervate of claim 40, wherein the compound of formula I is an HCl salt. ### Claim 42 (depends on 24) The adhesive fluid complex coacervate of claim 24, wherein the application site is within a blood vessel.