Manufacturing of bupivacaine multivesicular liposomes

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.