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1. (WO2018039318) BIODEGRADABLE POLYMER FORMULATIONS FOR EXTENDED EFFICACY OF BOTULINUM TOXIN
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We claim:

1. A method of formulating polymer microparticles for the controlled release of one or more encapsulated proteins, comprising the steps of:

(a) dissolving protein in an aqueous solution to form a protein solution;

(b) precipitating the protein from the solution to form a precipitant;

(c) optionally washing the precipitant one or more times with a wash solvent to form a solvent-washed precipitant;

(d) mixing or dispersing the precipitant in a solution containing a polymer to form a polymer-protein dispersion; and

(e) preparing polymer microparticles encapsulating the protein from the polymer-protein dispersion.

2. The method of claim 1 step (b) wherein the precipitating agent is selected from the group consisting of L-histidine methyl ester, L-cysteine ethyl ester, Na-(tert-butoxycarbonyl)-L-asparagine, L-proline benzyl ester, N-acetyl-L-tryptophan, gentisic acid, pentetic acid, octanoic acid, zinc chloride, and combinations thereof.

3. The method of claim 1 wherein the precipitating agent is zinc chloride.

4. The method of claim 1 step (c) wherein the wash solvent is selected from the group consisting of acetone, acetonitrile, dioxane, ethanol, 2-methoxy ethyl acetate, methoxy ethanol, ethoxy ethanol, butoxy ethanol, 2-propanol propylene glycol methyl ether, ethanediol, 1 ,2-propanediol, tert-butyl alcohol, diethylene glycol, and combinations thereof.

5. The method of claim 1 step (d) wherein the polymer solvent is selected from the group consisting of benzyl alcohol, n-butyl acetate, chlorobenzene, chloroform, dioxane, dichloromethane, ethyl acetate, ethyl benzoate, ethyl formate, methyl formate, methyl n-propyl ketone, phenethylamine, triacetin, trichloroethylene, and combinations thereof.

6. The method of claim 5 wherein the polymer solvent is a combination of dioxane and dichloromethane or ethyl acetate and dichloromethane.

7. The method of claim 1 wherein the polymer solvent dispersion is formed into microparticles using a micropatterned template.

8. The method of claim 7 wherein the micropatterned template comprises polyvinyl alcohol).

9. The method of claim 1 wherein the microparticles are formed by adding the polymer-protein dispersion to a non-polymer solvent to form an emulsion.

10. The method of claim 9 wherein the non-solvent is an aqueous solvent pre-conditioned with an organic solvent or solvents that dissolve the polymer.

1 1. The method of claim 10 wherein the organic solvent used for preconditioning is dichloromethane.

12. The method of claim 11 wherein the emulsion comprises

dichloromethane in a concentration between 0.1% and 1.3% in an aqueous solution.

13. The method of claim 9 wherein the organic solvent used for preconditioning is ethyl acetate.

14. The method of claim 9 wherein the emulsion comprises ethyl acetate in a concentration between 0.1% and 8.7% in aqueous solution.

15. The method of claim 9 wherein the drug-polymer emulsion is mixed with an overhead stirrer or a high-speed homogenizer.

16. The method of claim 9 wherein the emulsion is an aqueous emulsion containing a dissolution prevention agent selected from the group consisting of L-histidine methyl ester, L-cysteine ethyl ester, Na-(tert-butoxycarbonyl)-L-asparagine, L-proline benzyl ester, N-acetyl-L-tryptophan, gentisic acid, pentetic acid, octanoic acid, or zinc chloride.

17. The method of claim 16 wherein the dissolution prevention agent is zinc chloride.

18. The method of claim 17 wherein the concentration of zinc chloride is between 0.1% to 10% w/v.

19. The method of claim 1 wherein the protein comprises a botulinum toxin selected from the group consisting of botulinum toxin types A, B, C, D, E, F, G, and mixtures thereof.

20. The method of claim 19, wherein the botulinum toxin is a botulinum toxin type A.

21. The method of claim 20, wherein between about 1 unit and about 50,000 units of botulinum toxin A are associated with the microparticles.

22. The method of claim 21, wherein the quantity of the botulinum toxin associated with the microparticles is between about 100 units and about 30,000 units of botulinum toxin A.

23. The method of claim 19, wherein between about 100 units and about 30,000 units of botulinum toxin B are associated with the microparticles.

24. The method of claim 1, wherein the protein comprises a serum albumin protein.

25. The method of claim 1, wherein the polymer is a biodegradable polymer.

26. The method of claim 25, wherein the biodegradable polymer is selected from the group consisting of polylactide, poly(lactide-co-glycolide), polycaprolactone, polyorthoester, poly(ester amide), polyanhydride, poly(p-dioxanone), poly(alkylene oxalate), poly(lactide-co-glycolide)-poly(ethylene glycol) block copolymers, collagens and other proteins, hyaluronic acid and other polysaccharides, nucleic acids, lends and copolymers thereof.

27. The method of claim 26, wherein the polymer is a poly(lactide-co-glycolide) having the lactide:glycolide (L:G) ratio of between about 50:50 and 100: 1, inclusive.

28. The method of claim 27 wherein the polymer is a poly(lactide-co-glycolide) having the L:G ratio of between about 75:25 and 85: 15, inclusive.

29. The method of claim 1, where solvent washing is performed using a solvent selected from the group consisting of acetone, acetonitrile, dioxane, ethanol, 2-methoxy ethyl acetate, methoxy ethanol, ethoxy ethanol, butoxy ethanol, 2-propanol, propylene glycol methyl ether, ethanediol, 1,2-propanediol, tert-butyl alcohol, diethylene glycol, methanol, N-methylpyrrolidone, dimethylacetamide, dimethylformamide,

dimethylsulfoxide, pyridine, tetrahydrofurane, or combinations thereof.

30. The method of claim 1, where solvent washing maintains protein activity and the solvent is selected from the group consisting of acetone, acetonitrile, dioxane, ethanol, 2-methoxy ethyl acetate, methoxy ethanol, ethoxy ethanol, butoxy ethanol, 2-propanol, propylene glycol methyl ether, ethanediol, 1,2-propanediol, tert-butyl alcohol, di ethylene glycol, and combinations thereof.

31. The method of claim 1, where the precipitant is dried by fireeze-drying in the absence of solvent washing or after solvent washing.

32. The method of claim 1 , wherein solvent-washed precipitate is directly mixed with polymer solution.

33. The method of claim 1, further comprising reducing the size of precipitants by dry or wet milling.

34. The method of claim 33, wherein the milling temperature is controlled at the temperature of solidified carbon dioxide or liquid nitrogen.

35. The method of claim 33 comprising wet milling of precipitate mixed with n-butyl acetate, dioxane, dichlomethane, ethyl acetate, or combinations thereof.

36. A pharmaceutical composition, comprising a plurality of polymer microparticles encapsulating protein, formulated according to the method of any one of claims 1-35.

37. The pharmaceutical composition of claim 36 dispersed in a diluent consisting of an aqueous thermosensitive polymer solution.

38. The pharmaceutical composition of claim 37 wherein the aqueous thermosensitive polymer solution transitions between liquid and gel within the range of 4 °C to 40 °C.

39. The pharmaceutical composition of claim 38 wherein the aqueous thermosensitive polymer solution transitions between liquid and gel within the range of 20 °C to 38 °C.

40. The pharmaceutical composition of claim 37 wherein the aqueous thermosensitive polymer is selected from poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide), poly(lactide)-b-poly(ethylene glycol)-b-poly(lactide), poly(lactide-co-caprolactone)-b-poly(ethylene glycol)-b-poly(lactide-co-caprolactone), poly(caprolactone)-b-poly(ethylene glycol)-b-poly(caprolactone), methoxy poly(ethylene glycol)-b-poly(caprolactone), or combinations thereof

41. The pharmaceutical composition of claim 37 wherein the aqueous thermosensitive polymer solution is included at a concentration between 5% and 40% (w/v) in the aqueous solution.

42. The pharmaceutical composition of claim 41 wherein the aqueous thermosensitive polymer solution is added into the aqueous solution to a concentration between 10% and 30% (w/v).

43. The pharmaceutical composition of claim 36 dispersed in a diluent consisting of a gel-forming solution or a gel.

44. The pharmaceutical composition of claim 43 wherein the gel-forming solution is hyaluronic acid and the gel is crosslinked hyaluronic acid.

45. The pharmaceutical composition of claim 36, wherein the protein comprises a botulinum toxin selected from the group consisting of botulinum toxin types A, B, C, D, E, F, G, and mixtures thereof.

46. The pharmaceutical composition of claim 36 further comprising one or more therapeutic, prophylactic, or diagnostic agents.

47. A pharmaceutical composition, comprising a plurality of Zn-precipitated botulinum toxin/albumin, formulated according to the method of claim 1.

48. The pharmaceutical composition of claim 47 dispersed in a diluent consisting of an aqueous thermosensitive polymer solution.

49. The pharmaceutical composition of claim 47 dispersed in a diluent consisting of an aqueous gel.

50. A method of treating one or more diseases, disorders of cosmetic defects comprising administering to a subj ect in need thereof an effective amount of the pharmaceutical composition of claim 36 to reduce or prevent one or more symptoms of a diseases, disorder or cosmetic defects in the subject.

51. The method of claim 50, wherein one or more diseases, disorders or cosmetic defects to be treated is selected from the group consisting of hemorrhagic cystitis, interstitial cystitis/painful bladder syndrome, hemorrhagic cystitis, IC/PBS, hematuria, urinary urgency, supra pubic pain, inflammation, and urinary retention, crossed eyes (strabismus), uncontrolled blinking (blepharospasm), muscle stiffness/spasms, cervical dystonia, torticollis, uncontrollable sweating, undesirable wrinkles, headaches and migraines.