US 12,144,890 B2
Manufacturing of bupivacaine multivesicular liposomes
Jeffrey S. Hall, San Diego, CA (US); David J. Turnbull, San Diego, CA (US); John J. Grigsby, Jr., San Diego, CA (US); Soroush M. Ardekani, San Diego, CA (US); and Kathleen D. A. Los, San Diego, CA (US)
Assigned to Pacira Pharmaceuticals, Inc., San Diego, CA (US)
Filed by Pacira Pharmaceuticals, Inc., San Diego, CA (US)
Filed on May 30, 2023, as Appl. No. 18/325,927.
Application 18/325,927 is a continuation of application No. 17/719,716, filed on Apr. 13, 2022.
Application 17/719,716 is a continuation of application No. 17/536,516, filed on Nov. 29, 2021, granted, now 11,304,904.
Application 17/536,516 is a continuation of application No. 17/319,591, filed on May 13, 2021, granted, now 11,185,506, issued on Nov. 30, 2021.
Application 17/319,591 is a continuation of application No. 17/156,400, filed on Jan. 22, 2021, granted, now 11,033,495, issued on Jun. 15, 2021.
Prior Publication US 2023/0301916 A1, Sep. 28, 2023
Int. Cl. A61K 9/127 (2006.01); A61K 31/451 (2006.01); B01D 61/14 (2006.01); B01F 23/41 (2022.01); B01F 23/80 (2022.01); B01F 101/22 (2022.01)
CPC A61K 9/1277 (2013.01) [A61K 31/451 (2013.01); B01D 61/147 (2013.01); B01D 61/1471 (2022.08); B01F 23/4105 (2022.01); B01F 23/808 (2022.01); B01D 2315/10 (2013.01); B01D 2315/16 (2013.01); B01F 23/4144 (2022.01); B01F 23/4145 (2022.01); B01F 2101/22 (2022.01); B01F 2215/044 (2013.01); B01F 2215/0477 (2013.01); B01F 2215/0481 (2013.01)] 30 Claims
OG exemplary drawing
 
1. A composition of bupivacaine encapsulated multivesicular liposomes (MVLs) prepared by a process, the process comprising:
(a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a first water-in-oil emulsion, wherein the volatile water-immiscible solvent solution comprises bupivacaine, 1,2-dierucoylphosphatidylcholine (DEPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG), and at least one neutral lipid;
(b) mixing the first water-in-oil emulsion with a second aqueous solution to form a second water-in-oil-in-water emulsion, wherein the second aqueous solution comprises lysine;
(c) removing the volatile water-immiscible solvent from the second water-in-oil-in-water 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 MVLs by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated MVLs having a second volume;
(e) exchanging the aqueous supernatant of the second aqueous suspension with a saline solution by diafiltration to provide a third aqueous suspension of bupivacaine encapsulated MVLs having a third volume; and
(f) further reducing the third volume of the third aqueous suspension by microfiltration to provide a final aqueous suspension of bupivacaine encapsulated MVLs, and a bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL;
wherein all steps are carried out under aseptic conditions;
wherein the process produces a batch having a volume of about 100 L to about 250 L comprising the composition of bupivacaine encapsulated MVLs,
wherein an erucic acid concentration of the composition is about 99 μm/mL or less when measured after the composition is stored at 25° C. for six months; and
wherein the composition comprise lysine encapsulated in the internal aqueous chambers of the MVLs, and the encapsulated lysine concentration in the composition is at least about 0.03 mg/mL.