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-12280149-B1
Publication Date
2025-04-22
Expiration Date
Abstract
Embodiments of the present disclosure relates to a new and improved large scale commercial manufacturing process of making bupivacaine multivesicular liposomes (MVLs). Batches of bupivacaine MVLs prepared by the new process have high yields, improved stabilities, and desired particle size distributions.
Core Innovation
The disclosed invention provides a process for preparing a batch of bupivacaine encapsulated multivesicular liposomes using an aseptic double-emulsion workflow. The process forms a water-in-oil first emulsion by mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution, where the solvent solution comprises DPPG or a salt thereof, DEPC, tricaprylin, and cholesterol, and where either the aqueous or solvent solution comprises bupivacaine.
The emulsion is then mixed 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. The volatile water-immiscible solvent is substantially removed by sparging the second emulsion to form a first aqueous suspension of bupivacaine encapsulated MVLs, which is then processed by first microfiltration and diafiltration to exchange the medium with saline solution.
Finally, the third aqueous suspension volume is reduced by a second microfiltration to provide a batch of aqueous suspension with a target concentration of bupivacaine from 12 mg/mL to 17 mg/mL. The batch volume is at least 100 liters to about 300 liters, and the batch is characterized by cumulative percentage release of bupivacaine from 46% to 71% at a 24-hour time point using a rotator-facilitated in vitro release assay after storage at 2°C to 8°C for about 12 months.
Claims Coverage
The independent claim covers one full emulsion-based preparation process for bupivacaine encapsulated multivesicular liposomes, including first and second emulsion formation, solvent removal by sparging, sequential microfiltration and diafiltration, and a target bupivacaine concentration tied to specified in vitro release performance after about 12 months storage. The inventive features include seven merged process and batch-performance features.
Aqueous phosphoric acid and volatile solvent first emulsion composition
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 solvent solution comprises DPPG or a salt thereof, DEPC, tricaprylin and cholesterol, and wherein either the first aqueous solution or the solvent solution comprises bupivacaine.
Second emulsion with lysine and osmotic agent
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.
Sparging solvent removal from the second emulsion
Substantially removing the volatile water-immiscible solvent from the water-in-oil-in-water second emulsion by sparging to form a first aqueous suspension of bupivacaine encapsulated MVLs having a first volume.
First microfiltration concentration with specified feed flow range
Reducing the first volume of the first aqueous suspension by a first microfiltration to provide a second aqueous suspension of bupivacaine encapsulated MVLs having a second volume, wherein the first microfiltration feed flow rate is about 200 L/min to about 400 L/min.
Diafiltration medium exchange to saline
Exchanging the second aqueous suspension medium with a saline solution by diafiltration to provide a third aqueous suspension of bupivacaine encapsulated MVLs having a third volume, wherein the diafiltration feed flow rate is about 200 L/min to about 350 L/min.
Second microfiltration to target bupivacaine concentration
Reducing the third volume of the third aqueous suspension by a second microfiltration to provide a batch of aqueous suspension of bupivacaine encapsulated MVLs having a target concentration of bupivacaine from 12 mg/mL to 17 mg/mL.
Batch size and storage-stability release performance constraints
The batch has a volume of at least 100 liters to about 300 liters, and after storage at 2°C to 8°C for about 12 months, the batch has a cumulative percentage release of bupivacaine from 46% to 71% at a 24-hour time point and a rate of change in the cumulative percentage release at the 24-hour time point of 0.05%/month to 0.5%/month.
Overall, the independent claim defines an aseptic double-emulsion process with specified first- and second-emulsion compositions, solvent removal by sparging, sequential microfiltration and diafiltration, and batch acceptance characterized by defined in vitro release performance after about 12 months storage at 2°C to 8°C.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
Interested in licensing this patent?