Manufacturing of bupivacaine multivesicular liposomes
Inventors
Levy, Eran • Hall, Jeffrey S. • Grigsby, Jr., John J.
Assignees
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Publication Number
US-12251468-B1
Publication Date
2025-03-18
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 batch comprising a composition of bupivacaine encapsulated multivesicular liposomes (MVLs) where bupivacaine resides inside a plurality of internal aqueous chambers separated by lipid membranes. The lipid membranes comprise 1,2-dierucoylphosphatidylcholine (DEPC) and/or 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) or a salt thereof, together with cholesterol and tricaprylin. The MVLs are suspended in an aqueous medium that also comprises unencapsulated bupivacaine.
The total bupivacaine concentration in the composition is from 12 mg/mL to 17 mg/mL, and the batch has a volume of at least 100 liters to about 300 liters. The batch is defined by rotator-facilitated in vitro release assay results after storage at 2°C to 8°C for about 12 months from batch manufacture date, including cumulative percentage release at 24-hour or 48-hour time points and constrained rates of change at those time points.
The disclosed commercial-scale approach is characterized by improved product yield and stability, including tighter release behavior and constraints on the slope/rate-of-change of cumulative release over storage. The background problem being addressed concerns controlling bupivacaine release behavior and maintaining product stability across storage while improving performance at larger manufacturing scales.
Claims Coverage
The provided material includes two independent claims. Both independent claims define a batch by a specific MVL composition, total bupivacaine concentration, batch volume, and constrained rotator-facilitated in vitro release performance after about 12 months at 2°C to 8°C.
MVL composition with specified lipid membrane components
A batch comprising a composition of bupivacaine encapsulated multivesicular liposomes (MVLs) where bupivacaine resides inside a plurality of internal aqueous chambers separated by lipid membranes, the lipid membranes comprising 1,2-dierucoylphosphatidylcholine (DEPC) and/or 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) or a salt thereof, cholesterol, and tricaprylin.
Aqueous medium containing encapsulated and unencapsulated bupivacaine
An aqueous medium in which the bupivacaine encapsulated MVLs are suspended, wherein the aqueous medium also comprises unencapsulated bupivacaine.
Total bupivacaine concentration and batch volume range
The total bupivacaine concentration in the composition is from 12 mg/mL to 17 mg/mL, and the batch has a volume of at least 100 liters to about 300 liters.
24-hour cumulative release and constrained 24-hour rate of change after storage
The 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 after storage at 2°C to 8°C for about 12 months from batch manufacture date, with a rate of change of 0.05%/month to 0.5%/month.
48-hour cumulative release and constrained 48-hour rate of change after storage
The 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 after storage at 2°C to 8°C for about 12 months from batch manufacture date, with a rate of change of -0.18%/month to 0.33%/month.
Overall, the claims scope is centered on batch compositions of bupivacaine-encapsulated MVLs with DEPC/DPPG (or salts) plus cholesterol and tricaprylin, suspended in an aqueous medium containing both encapsulated and unencapsulated bupivacaine. The batch is limited to specific total bupivacaine concentration and batch volume ranges, and it must meet tightly constrained rotator-facilitated IVRA cumulative release and rate-of-change criteria at either the 24-hour or 48-hour time points after about 12 months storage at 2°C to 8°C.
Stated Advantages
Improved product yield and stability versus prior processes, including flatter slopes/rate-of-change in cumulative release.
Higher yields (average ~82%, up to 14.4K vials) while maintaining tight IVRA release specifications after storage.
Improved stability outcomes associated with particle size distribution effects and tighter cumulative release/rate-of-change constraints.
Documented Applications
Not explicitly described in patent.
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