Bupivacaine multivesicular liposome formulations and uses thereof
Inventors
Garcia, Louie D. • Ardekani, Soroush M. • Davis, Paige N. • Kurz, Stephanie M. • Leon, Damon A. • Los, Kathleen D. A. • Grigsby, Jr., John J. • Levy, Eran • Simonian, Alisha R.
Assignees
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Publication Number
US-12285419-B2
Publication Date
2025-04-29
Expiration Date
Abstract
Some embodiments of the present application are related to multivesicular liposome formulations comprising high concentration of bupivacaine for the purpose of preventing, treating or ameliorating pain, for example, post-surgical pain for an extended period of time. Processes of making and administering bupivacaine encapsulated multivesicular liposome formulations (BUP-MVLs) and their uses as medicaments are also provided.
Core Innovation
The invention relates to bupivacaine encapsulated multivesicular liposomes (MVLs) in which bupivacaine resides inside a plurality of internal aqueous chambers separated by lipid membranes. The lipid membranes comprise DPPG or a salt thereof, DEPC, cholesterol, and a triglyceride selected from triolein, tricaprylin, and combinations thereof, and the MVLs are suspended in an aqueous medium with buffering agent concentration and osmolality.
The plurality of internal aqueous chambers comprises one or more pH modifying agents and has a pH from about 3.0 to about 6.6. The composition specifies a bupivacaine concentration from about 18 mg/mL to about 40 mg/mL, and in one described formulation the aqueous medium pH is from about 6.5 to about 7.5 while the internal chamber pH is maintained within about 3.5 to about 6.6.
The invention also includes a process for preparing bupivacaine encapsulated MVLs. The process comprises mixing a first aqueous solution with a lipid solution to form a first water-in-oil emulsion, combining the first emulsion with a second aqueous solution to form a second emulsion, substantially removing the organic solvent to form a first aqueous suspension, and exchanging the aqueous supernatant with a third aqueous solution one or more times to provide a final aqueous suspension.
Claims Coverage
The document provides three independent claims covering a bupivacaine-encapsulated MVL composition, a process for preparing the bupivacaine-encapsulated MVLs, and a more specific bupivacaine-encapsulated MVL composition with defined external aqueous medium pH and a defined tricaprylin-to-triolein mass ratio. Across the independent claims, the inventive features focus on internal chamber pH modification, specific lipid membrane components, buffered and controlled osmolality suspension conditions, defined bupivacaine concentration, and MVL preparation involving emulsions, solvent removal, and aqueous supernatant exchange.
Bupivacaine in internal aqueous chambers of MVLs
Bupivacaine resides inside a plurality of internal aqueous chambers of the MVLs separated by lipid membranes, wherein the lipid membranes comprise DPPG or a salt thereof, DEPC, cholesterol, and a triglyceride selected from triolein, tricaprylin, and combinations thereof.
Buffered suspension with defined osmolality and bupivacaine concentration
An aqueous medium in which the bupivacaine encapsulated MVLs are suspended, wherein the aqueous medium comprises at least one buffering agent in a concentration from about 1 mM to about 50 mM, and wherein the osmolality of the aqueous medium is from about 320 mOsm/kg to about 360 mOsm/kg; wherein the bupivacaine concentration in the composition is from about 18 mg/mL to about 40 mg/mL.
Internal chamber pH modification
The plurality of internal aqueous chambers of the MVLs comprises one or more pH modifying agents, and has a pH from about 3.0 to about 6.6.
Water-in-oil emulsion preparation with solvent removal and aqueous supernatant exchange
Mixing a first aqueous solution comprising one or more pH modifying agents with a lipid solution comprising at least one organic solvent, DPPG or a salt thereof, DEPC, cholesterol, and a triglyceride selected from triolein, tricaprylin, and combinations thereof to form a first water-in-oil emulsion, wherein at least one of the first aqueous solution and the lipid solution comprises bupivacaine; combining the first water-in-oil emulsion with a second aqueous solution to form a second emulsion; substantially removing the organic solvent from the second emulsion to form a first aqueous suspension of bupivacaine encapsulated MVLs; and exchanging the aqueous supernatant of the first aqueous suspension with a third aqueous solution one or more times to provide a final aqueous suspension of bupivacaine encapsulated MVLs.
Final suspension constraints
The final aqueous suspension has bupivacaine concentration from about 18 mg/mL to about 40 mg/mL, at least one buffering agent in a concentration from about 1 mM to about 50 mM, and osmolality from about 320 mOsm/kg to about 360 mOsm/kg.
Defined external aqueous medium pH and fixed bupivacaine concentration
Bupivacaine resides inside a plurality of internal aqueous chambers of the MVLs separated by lipid membranes comprising DPPG or a salt thereof, DEPC, cholesterol, tricaprylin and triolein; the aqueous medium comprises one or more buffering agents in a concentration from about 5 mM to about 20 mM, has osmolality from about 320 mOsm/kg to about 360 mOsm/kg, and pH from about 6.5 to about 7.5; the bupivacaine concentration is about 20 mg/mL; and the plurality of internal aqueous chambers comprises phosphoric acid as a pH modifying agent and has a pH from about 3.5 to about 6.6.
Fixed tricaprylin-to-triolein mass ratio
The mass ratio of tricaprylin to triolein in the composition is about 5:1 to about 15:1.
Overall, the claim set ties together a specific MVL lipid membrane composition, a buffered aqueous suspension with defined osmolality, and internal chamber pH modification by pH modifying agents, including phosphoric acid in the more specific composition. The process claim mirrors these constraints by requiring emulsion formation, organic solvent removal, and aqueous supernatant exchange to produce a final aqueous suspension having the specified bupivacaine concentration, buffering agent concentration, and osmolality.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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