US 12,251,468 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. 18/761,898.
Claims priority of provisional application 63/649,846, filed on May 20, 2024.
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 9/127 (2025.01); A61K 31/445 (2006.01)
CPC A61K 9/127 (2013.01) [A61K 31/445 (2013.01)] 29 Claims
 
1. A batch comprising a composition of bupivacaine encapsulated multivesicular liposomes (MVLs), the composition comprising:
bupivacaine residing inside a plurality of internal aqueous chambers of MVLs separated by lipid membranes, wherein the lipid membranes comprise 1,2-dierucoylphosphatidylcholine (DEPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) or a salt thereof, cholesterol, and tricaprylin; and
an aqueous medium in which the bupivacaine encapsulated MVLs are suspended, wherein the aqueous medium also comprises unencapsulated bupivacaine;
the total bupivacaine concentration in the composition is 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 of the batch 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.