Manufacturing of bupivacaine multivesicular liposomes
Inventors
Levy, Eran • Hall, Jeffrey S. • Grigsby, Jr., John J.
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12251472-B1
Publication Date
2025-03-18
Expiration Date
Abstract
Embodiments of the present disclosure relates to commercial manufacturing process of making bupivacaine multivesicular liposomes with improved yield and desired particle size distribution.
Core Innovation
The invention is a process for preparing bupivacaine encapsulated multivesicular liposomes (MVLs) that uses a sequential emulsification scheme and controlled downstream volume reduction. A water-in-oil first emulsion is formed by mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution comprising at least one phosphatidyl choline, at least one phosphatidyl glycerol, cholesterol, and at least one neutral lipid, wherein either the first aqueous solution or the solvent solution comprises bupivacaine. The first emulsion is then mixed with a second aqueous solution to form a water-in-oil-in-water second emulsion containing lysine and at least one osmotic agent.
The process substantially removes the volatile water-immiscible solvent from the water-in-oil-in-water second emulsion by sparging the second emulsion at about 18° C. to about 20° C. to form a first aqueous suspension of bupivacaine encapsulated MVLs having a first volume. The first volume is reduced by a first microfiltration to provide a second aqueous suspension, and the second aqueous suspension medium is exchanged with a saline solution by diafiltration to provide a third aqueous suspension.
The third volume is reduced by a second microfiltration to provide a final aqueous suspension having a target concentration of bupivacaine from about 12 mg/mL to about 17 mg/mL. The process defines overall volume and yield targets for the final aqueous suspension, including a final aqueous suspension volume of about 150 L to about 300 L and a bupivacaine MVL product yield of at least about 75%. The resulting MVLs are further characterized by volume-weighted particle size distribution metrics such as d10, d50, and d90.
Claims Coverage
The independent claim covers a complete manufacturing process for bupivacaine encapsulated MVLs using sequential emulsification, solvent sparging, and a filtration/diafiltration volume-exchange/concentration workflow, while enforcing yield, volume, and concentration targets. Dependent claims narrow or further specify components, operating constraints, filtration system configuration, and particle-size outcomes.
Sequential formation of water-in-oil and water-in-oil-in-water emulsions for bupivacaine MVLs
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 at least one phosphatidyl choline, at least one phosphatidyl glycerol, cholesterol, and at least one neutral lipid, and wherein either the first aqueous solution or the solvent solution comprises bupivacaine; 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 at least one osmotic agent
Solvent removal by sparging at 18° C. to 20° C.
substantially removing the volatile water-immiscible solvent from the water-in-oil-in-water second emulsion by sparging the water-in-oil-in-water second emulsion at a temperature of about 18° C. to about 20° C. to form a first aqueous suspension of bupivacaine encapsulated MVLs having a first volume
Two microfiltrations and diafiltration with saline exchange
reducing the first volume of the first aqueous suspension by a first microfiltration to provide a second aqueous suspension; exchanging the second aqueous suspension medium with a saline solution by diafiltration to provide a third aqueous suspension; and reducing the third volume of the third aqueous suspension by a second microfiltration to provide a final aqueous suspension having a target concentration of bupivacaine from about 12 mg/mL to about 17 mg/mL
Yield and final volume targets for bupivacaine MVLs
the final aqueous suspension of bupivacaine encapsulated MVLs has a volume of about 150 L to about 300 L, and the process has a bupivacaine MVL product yield of at least about 75%
Specified phosphoric acid aqueous and lipid-solvent component choices
the volatile water-immiscible solvent solution comprises bupivacaine and specified lipid/solvent constituents including DPPG (or a salt thereof), DEPC, tricaprylin, and cholesterol
Crossflow filtration system architecture switching between microfiltration and diafiltration modes
steps (d), (e), and (f) are conducted using a crossflow filtration system configured to switch between microfiltration and diafiltration mode, with a plurality of independently operating crossflow modules, each having filter arrays of hollow fiber filters
Particle size distribution constraint on final MVLs
the process yields MVLs having a volume-weighted mean d90 of about 46 μm to about 57 μm
Overall, the claim set covers a bupivacaine MVL manufacturing process that is defined by forming a water-in-oil and then a water-in-oil-in-water emulsion using phosphoric acid, lysine, an osmotic agent, and specified lipid/solvent components, substantially removing solvent by sparging at about 18° C. to about 20° C., applying a first microfiltration, saline diafiltration, and a second microfiltration, and meeting final volume and yield targets, with additional dependent refinements to component selection, crossflow filtration system configuration, and a d90 size distribution range.
Stated Advantages
Increases product yield compared to prior Exparel® scale processes.
Controls particle size distribution during microfiltration and diafiltration.
Reduces particle size distribution span while maintaining yield.
Documented Applications
Pain treatment using the produced bupivacaine encapsulated MVLs (parenteral administration including epidural/perineural/injection modalities as stated).
Interested in licensing this patent?