Manufacturing of bupivacaine multivesicular liposomes
Inventors
Levy, Eran • Hall, Jeffrey S. • Grigsby, Jr., John J.
Assignees
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Publication Number
US-12246092-B1
Publication Date
2025-03-11
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 invention relates to a process for preparing a plurality of batches of bupivacaine encapsulated multivesicular liposomes (MVLs). The process includes forming a water-in-oil first emulsion by mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution containing DPPG or a salt thereof, DEPC, tricaprylin, and cholesterol, 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, where the second aqueous solution comprises lysine and at least one osmotic agent.
The process further includes 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. 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 then reduced by a second microfiltration to provide a batch with a target concentration of bupivacaine from 12 mg/mL to 17 mg/mL.
The invention also specifies manufacturing constraints for the plurality of batches and corresponding in vitro release behavior after storage. The plurality of batches are manufactured within a period of six months, with each batch volume about 100 liters to about 300 liters. Each batch is characterized by a cumulative percentage release of bupivacaine at a defined time point after storage of aliquots at 2°C to 8°C for about 12 months, and by an average rate of change of that cumulative release within defined limits.
Claims Coverage
The partial content provides two independent claims and describes the same overall manufacturing process architecture for multiple MVL batches, with inventive features centered on specified emulsion formation components, solvent removal by sparging, sequential microfiltration and diafiltration volume handling to target bupivacaine concentration, and batch-level in vitro release performance constraints after storage, with differing numeric release windows and rate-of-change ranges at 24 hours and 48 hours.
Specified emulsion formation with bupivacaine encapsulation
Mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a water-in-oil first emulsion, where the volatile water-immiscible 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; mixing the water-in-oil first emulsion with a second aqueous solution to form a water-in-oil-in-water second emulsion, where the second aqueous solution comprises lysine and at least one osmotic agent.
Solvent removal by sparging
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.
Sequential microfiltration 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 batch having a target concentration of bupivacaine from 12 mg/mL to 17 mg/mL.
Multiple batch production timing, scale, and concentration-linked release specifications
Manufacturing a plurality of batches according to the process steps, where the plurality of batches are manufactured within a period of six months and each batch has a volume of about 100 liters to about 300 liters; and specifying cumulative percentage release of bupivacaine at a defined time point after storage of aliquots at 2°C to 8°C for about 12 months, together with an average rate of change limit.
24-hour release window and rate-of-change constraints
Each batch has a cumulative percentage release of bupivacaine from 46% to 71% at a 24-hour time point, measured from two to six aliquots using a rotator-facilitated in vitro release assay for at least 48 hours, and an average rate of change in the cumulative percentage release of bupivacaine at the 24-hour time point is 0.05%/month to 0.5%/month after storage.
48-hour release window and rate-of-change constraints
Each batch has a cumulative percentage release of bupivacaine from 60% to 85% at a 48-hour time point, measured from two to six aliquots using a rotator-facilitated in vitro release assay for at least 48 hours, and an average rate of change in the cumulative percentage release of bupivacaine at the 48-hour time point is -0.18%/month to 0.33%/month after storage.
Across both independent claims, the core claimed inventive subject matter is a process for manufacturing a plurality of bupivacaine encapsulated MVL batches using specified emulsion constituents and a lysine and osmotic-agent second aqueous phase, solvent removal by sparging, and sequential microfiltration plus diafiltration and saline exchange to reach a 12 mg/mL to 17 mg/mL target concentration, combined with batch-level in vitro release and average rate-of-change constraints after 12 months of storage at 2°C to 8°C, with the main difference being the release window and rate-of-change limits at 24 hours versus 48 hours.
Stated Advantages
Higher yields and improved IVRA stability trends compared to prior processes.
Documented Applications
Optional pain-treatment methods using the resulting bupivacaine encapsulated MVL compositions.
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