Manufacturing of bupivacaine multivesicular liposomes

A process for preparing bupivacaine encapsulated multivesicular liposomes (MVLs), the process comprising, 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 bupivacaine, 1, 2-dierucoylphosphatidylcholine (DEPC), 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), cholesterol, and at least one neutral lipid, and wherein a mixing time in step (a) is about 65 minutes to about 75 minutes;
• (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 dextrose, and wherein a mixing time in step (b) is about 60 seconds to about 65 seconds;
• (c) diluting the water-in-oil-in-water second emulsion with additional second aqueous solution to form a diluted water-in-oil-in-water second emulsion;
• (d) removing the volatile water-immiscible solvent from the diluted water-in-oil-in-water second emulsion to form a first aqueous suspension of bupivacaine encapsulated MVLs having a first volume;
• (e) 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;
• (f) 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
• (g) further reducing the third volume of the third aqueous suspension by microfiltration to provide a final bulk aqueous suspension of bupivacaine encapsulated MVLs having a volume of about 100 L to about 250 L, 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.