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US 12,296,047 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.
Claims30
A batch comprising 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), cholesterol, and tricaprylin;
- (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 bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL;
- wherein the batch has a volume of 100 L to 250 L;
- wherein the MVLs have an average d90 particle diameter ranging from 54 μm to 65 μm and an average particle diameter span (d90-d10) of 38 μm to 48 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month;
- and
- wherein the erucic acid concentration of the batch is about 105 μg/mL or less when measured after storage of the composition at about 25° C. for six months.
8 more elements
Batches comprising compositions of bupivacaine encapsulated multivesicular liposomes (MVLs) prepared by a process, the process of preparing a batch 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), cholesterol, and tricaprylin;
- (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 bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL;
- wherein each batch has a volume of 100 L to 250 L;
- wherein the MVLs of each batch have an average d90 particle diameter ranging from 54 μm to 65 μm and an average particle diameter span (d90-d10) of 38 μm to 48 m when measured after storage of the composition at 2 to 8° C. for less than 1 month;
- and
- wherein an average erucic acid concentration of three batches prepared by the process is about 105 μg/mL or less when measured after storage of compositions of the batches at about 25° C. for six months.
8 more elements
Dependencies are inferred from the claim text.