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US 12,151,024 B2Granted
Manufacturing of bupivacaine multivesicular liposomes
AssigneePacira Pharmaceuticals, Inc.
InventorsJeffrey S. Hall, David J. Turnbull, John J. Grigsby, Jr., Soroush M. Ardekani, Kathleen D. A. Los
Life of this patent
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Abstract
Embodiments of the present application relate to compositions bupivacaine multivesicular liposomes (MVLs) prepared by a commercial manufacturing process with large particle diameter span.
Claims54
A composition of bupivacaine encapsulated multivesicular liposomes (MVLs), comprising:
- bupivacaine residing inside a plurality of internal aqueous chambers of the 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), and at least one neutral lipid;
- and
- an aqueous medium in which the bupivacaine encapsulated MVLs are suspended;
- wherein the multivesicular liposomes have an average d90 particle diameter ranging from about 54 μm to about 65 μm, and an average particle diameter span (d90-d10) of at least about 38 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month, and wherein the composition comprises an erucic acid concentration of about 99 μg/mL or less when measured after storage of the composition at 25° C. for six months.
1 more element
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 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 the multivesicular liposomes have an average d90 particle diameter ranging from about 54 μm to about 65 μm and an average particle diameter span (d90-d10) of at least about 38 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month, and wherein the composition comprises an erucic acid concentration of about 99 μg/mL or less when measured after storage of the composition at 25° C. for six months.
5 more elements
Dependencies are inferred from the claim text.