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US 11,185,506 B1Granted
Manufacturing of bupivacaine multivesicular liposomes
AssigneePacira Pharmaceuticals, Inc.
InventorsJeffrey S. Hall, David J. Turnbull, John J. Grigsby, Jr., Soroush M. Ardekani, Paige N. Davis, Louie D. Garcia, Stephanie M. Kurz, Kathleen D. A. Los
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Abstract
Embodiments of the present application relate to commercial manufacturing processes for making bupivacaine multivesicular liposomes (MVLs) using independently operating dual tangential flow filtration modules.
Claims17
A process for preparing bupivacaine encapsulated multivesicular liposomes in a commercial scale, 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 bupivacaine, at least one amphipathic lipid comprising 1, 2-dierucoylphosphatidylcholine (DEPC), and at least one neutral lipid;
- (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;
- (c) removing the volatile water-immiscible solvent from the water-in-oil-in-water second emulsion to form a first aqueous suspension of bupivacaine encapsulated multivesicular liposomes having a first volume;
- (d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated multivesicular liposomes by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated multivesicular liposomes 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 multivesicular liposomes 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 multivesicular liposomes having a target concentration of bupivacaine from about 11.3 mg/mL to about 17.0 mg/mL;
- wherein all steps are carried out under aseptic conditions;
- wherein the erucic acid concentration in the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes is about 23 μg/mL or less after the final aqueous suspension is stored at 25° C. for one month;
- wherein the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes has a volume of about 150 L to about 250 L;
- and
- wherein the internal pH of the bupivacaine encapsulated multivesicular liposomes in the final aqueous suspension is about 5.5.
9 more elements
Dependencies are inferred from the claim text.