In situ solidifying solutions and methods of making and using thereof
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.
1. An injectable 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 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
wherein R 1 is hydrogen or an alkyl group, X is oxygen or NR 5 , where R 5 is hydrogen or an alkyl group, and m is from 1 to 10, or the pharmaceutically-acceptable salt thereof;
wherein when the injectable solution is introduced into a subject, the injectable solution is converted to a solid in the subject; and
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 injectable solution is from 0.5 M to 2.0 M.
2. The injectable solution of claim 1 , wherein the injectable solution is introduced in a blood vessel of the subject.
3. The injectable solution of claim 1 , wherein the concentration of the monovalent ions in the injectable solution is 1.5 to 10 times greater than the concentration of the monovalent ions within the subject.
4. The injectable solution of claim 1 , wherein the monovalent ions in the injectable solution are sodium ions and chloride ions.
5. The injectable solution of claim 1 , wherein the injectable solution further comprises a salt that produces monovalent ions, wherein the salt is NaCl.
6. The injectable solution of claim 1 , wherein the injectable solution has a pH of 6 to 9.
7. The injectable solution of claim 1 , wherein the polycation comprises polymerization product between the compound of formula I and methacrylamide.
8. The injectable solution of claim 1 , wherein R 1 is methyl, X is NH, m is 3.
9. The injectable solution of claim 1 , wherein the polyanion comprises a polyphosphate.
10. The injectable solution of claim 1 , wherein the polyanion is an inorganic polyphosphate or a phosphorylated sugar.
11. The injectable solution of claim 1 , wherein the polyanion comprises a hexametaphosphate salt.
12. The injectable solution of claim 1 , wherein the polyanion is inositol hexaphosphate.
13. The injectable solution of claim 1 , wherein the polyanion comprises a polyacrylate comprising two or more pendant phosphate groups.
14. The injectable solution 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 injectable solution of claim 1 , wherein the injectable solution further comprises a contrast agent or a visualization agent.
16. The injectable solution of claim 15 , wherein the contrast agent comprises tantalum particles, gold particles, or an iodine complex.
17. The injectable solution of claim 1 , wherein the injectable solution further comprises a reinforcing component.
18. The injectable solution of claim 17 , wherein the reinforcing component comprises natural or synthetic fibers, water-insoluble filler particles, a nanoparticle, or a microparticle.
19. The injectable solution of claim 1 , wherein the injectable solution further comprises one or more bioactive agents.
20. The injectable solution 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, a chemotherapy agent, a receptor antagonist, a nucleic acid, or any combination thereof.
21. The injectable solution of claim 1 , wherein
the polyanion comprises sodium hexametaphosphate,
the total positive/negative charge ratio of the polycation to the polyanion is from 0.95 to 1.10 and
the injectable solution further comprises NaCl, wherein the concentration of sodium ions in the injectable solution is from 0.5 M to 2.0 M and the concentration of the chloride ions in the injectable solution is from 0.5 M to 2.0 M.