US 12,280,149 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. 18/762,013.
Claims priority of provisional application 63/649,846, 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)] 29 Claims
OG exemplary drawing
 
1. A process for preparing a batch of 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 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) or a salt thereof, 1,2-dierucoylphosphatidylcholine (DEPC), tricaprylin and cholesterol, 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 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 about 200 L/min to about 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 about 200 L/min to about 350 L/min; and
(f) reducing the third volume of the third aqueous suspension by a second microfiltration to provide a batch of aqueous suspension of bupivacaine encapsulated MVLs having a target concentration of bupivacaine from 12 mg/mL to 17 mg/mL;
wherein the batch has a volume of at least 100 liters to about 300 liters;
wherein the batch has a cumulative percentage release of bupivacaine from 46% to 71% at a 24-hour time point, measured from two to six aliquots of the batch using a rotator-facilitated in vitro release assay for at least 48 hours, after storage of the aliquots at 2° C. to 8° C. for about 12 months from batch manufacture date; and
wherein the rate of change in the cumulative percentage release of bupivacaine at the 24-hour time point is 0.05%/month to 0.5%/month after storage of the aliquots at 2° C. to 8° C. for about 12 months.