US 12,251,472 B1
Manufacturing of bupivacaine multivesicular liposomes
Eran Levy, San Diego, CA (US); Jeffrey S. Hall, San Diego, CA (US); and John J. Grigsby, Jr., San Diego, CA (US)
Assigned to Pacira Pharmaceuticals, Inc., San Diego, CA (US)
Filed by Pacira Pharmaceuticals, Inc., San Diego, CA (US)
Filed on Jul. 2, 2024, as Appl. No. 18/762,128.
Claims priority of provisional application 63/649,828, filed on May 20, 2024.
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 9/1277 (2025.01); A61K 31/445 (2006.01)
CPC A61K 9/1277 (2013.01) [A61K 31/445 (2013.01)] 25 Claims
 
1. A process for preparing bupivacaine encapsulated multivesicular liposomes (MVLs), the process comprising:
(a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a water-in-oil first emulsion, wherein the volatile water-immiscible solvent solution comprises at least one phosphatidyl choline, at least one phosphatidyl glycerol, cholesterol, and at least one neutral lipid, and wherein either the first aqueous solution or the solvent solution comprises bupivacaine;
(b) mixing the water-in-oil first emulsion with a second aqueous solution to form a water-in-oil-in-water second emulsion, wherein the second aqueous solution comprises lysine and at least one osmotic agent;
(c) substantially removing the volatile water-immiscible solvent from the water-in-oil-in-water second emulsion by sparging the water-in-oil-in-water second emulsion at a temperature of about 18° C. to about 20° C. to form a first aqueous suspension of bupivacaine encapsulated MVLs having a first volume;
(d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated multivesicular liposomes by a first microfiltration to provide a second aqueous suspension of bupivacaine encapsulated MVLs having a second volume, wherein the first microfiltration feed flow rate is 200 L/min to 400 L/min;
(e) exchanging the second aqueous suspension medium with a saline solution by diafiltration to provide a third aqueous suspension of bupivacaine encapsulated MVLs having a third volume, wherein the diafiltration feed flow rate is 190 L/min to 350 L/min; and
(f) reducing the third volume of the third aqueous suspension by a second microfiltration to provide a final aqueous suspension of bupivacaine encapsulated MVLs having a target concentration of bupivacaine from about 12 mg/mL to about 17 mg/mL;
wherein the final aqueous suspension of bupivacaine encapsulated MVLs has a volume of about 150 L to about 300 L; and
wherein the process has a bupivacaine MVL product yield of at least about 75%.