US 11,723,876 B2
Biodegradable polymer formulations for extended efficacy of botulinum toxin
Kinam Park, West Lafayette, IN (US); Yeonhee Yun, West Lafayette, IN (US); Sarah Michelle Skidmore, Lafayette, IN (US); Byung Kook Lee, West Lafayette, IN (US); and John Solomon Garner, West Lafayette, IN (US)
Assigned to SK JOINT VENTURES II, LLC, New York, NY (US)
Filed by SK JOINT VENTURES II, LLC, New York, NY (US)
Filed on Feb. 8, 2021, as Appl. No. 17/170,614.
Application 17/170,614 is a continuation of application No. 15/684,134, filed on Aug. 23, 2017, granted, now 10,925,837.
Claims priority of provisional application 62/380,229, filed on Aug. 26, 2016.
Prior Publication US 2021/0161826 A1, Jun. 3, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 9/50 (2006.01); A61K 47/36 (2006.01); A61K 47/34 (2017.01); A61K 9/00 (2006.01); A61K 9/16 (2006.01); A61K 9/14 (2006.01); A61K 9/51 (2006.01); A61K 38/48 (2006.01); C01G 9/04 (2006.01); C08G 63/08 (2006.01); A61K 9/113 (2006.01)
CPC A61K 9/5031 (2013.01) [A61K 9/0024 (2013.01); A61K 9/143 (2013.01); A61K 9/146 (2013.01); A61K 9/1647 (2013.01); A61K 9/5153 (2013.01); A61K 38/4893 (2013.01); A61K 47/34 (2013.01); A61K 47/36 (2013.01); C01G 9/04 (2013.01); C08G 63/08 (2013.01); A61K 9/0019 (2013.01); A61K 9/113 (2013.01)] 47 Claims
 
1. A method of formulating polymer particles for the controlled release of one or more encapsulated botulinum toxin proteins, comprising the steps of:
(a) dissolving the botulinum toxin protein with a protein bulking agent in an aqueous solution to form a protein solution;
(b) precipitating the protein from the protein solution with a precipitating agent selected from the group consisting of L-histidine methyl ester, L-cysteine ethyl ester, Nα-(tert-butoxycarbonyl)-L-asparagine, L-proline benzyl ester, N-acetyl-L-tryptophan, gentisic acid, pentetic acid, octanoic acid, zinc chloride, and combinations thereof to form a protein precipitate;
(c) washing the protein precipitate one or more times with a wash solvent to form a solvent-washed protein precipitate, wherein the wash solvent is a solvent which retains the toxicity of the botulinum toxin in a mouse lethality test at 48 hours at a dose of 10 units/injection and 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;
(d) mixing or dispersing the solvent-washed protein precipitate in a solution containing a polymer to form a polymer-protein dispersion; and
(e) forming polymer particles having uniformly dispersed therein between about 100 units and about 50,000 units of botulinum toxin protein and bulking agent complexed together with the precipitating agent, wherein the particles release an effective amount of botulinum toxin over a period of weeks.