Manufacturing of bupivacaine multivesicular liposomes
Inventors
Levy, Eran • Hall, Jeffrey S. • Grigsby, Jr., John J.
Assignees
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Publication Number
US-12318483-B1
Publication Date
2025-06-03
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 method of treating or ameliorating pain in a subject by administering a composition of bupivacaine encapsulated multivesicular liposomes (MVLs) from batches with defined composition and performance requirements. The MVLs include bupivacaine residing inside a plurality of internal aqueous chambers separated by lipid membranes, where the lipid membranes comprise 1,2-dierucoylphosphatidylcholine (DEPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) or a salt thereof, cholesterol, and tricaprylin.
The composition further includes an aqueous medium in which the encapsulated MVLs are suspended, and that aqueous medium also comprises unencapsulated bupivacaine. The total bupivacaine concentration is from 12 mg/mL to 17 mg/mL, and the batches are manufactured within a period of six months with each batch volume in a range of 100 liters to 300 liters.
Each batch is characterized by cumulative percentage release of bupivacaine at specified time points measured using a rotator-facilitated in vitro release assay after storage of aliquots at 2°C to 8°C for about 12 months from batch manufacture date. The claimed approach links a pain treatment composition with batch-manufactured MVL formulations and quantified release stability criteria at 24 hours or 48 hours after storage.
Claims Coverage
Two independent claims are provided: a 24-hour release stability version and a 48-hour release stability version. Each independent claim specifies the composition architecture and the quantitative manufacturing and rotator-facilitated in vitro release criteria after storage.
Pain treatment with DEPC/DPPG/cholesterol/tricaprylin MVLs containing encapsulated and unencapsulated bupivacaine with 24-hour release stability
A method of treating or ameliorating pain in a subject in need thereof by administering a composition of bupivacaine encapsulated multivesicular liposomes (MVLs), the composition comprising bupivacaine residing inside a plurality of internal aqueous chambers of MVLs separated by lipid membranes comprising 1,2-dierucoylphosphatidylcholine (DEPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) or a salt thereof, cholesterol, and tricaprylin, and an aqueous medium in which the bupivacaine encapsulated MVLs are suspended wherein the aqueous medium also comprises unencapsulated bupivacaine, wherein the total bupivacaine concentration is from 12 mg/mL to 17 mg/mL, wherein the batches are manufactured within a period of six months and each batch volume is 100 liters to 300 liters, wherein each batch has a cumulative percentage release from 46% to 71% at a 24-hour time point measured using a rotator-facilitated in vitro release assay after storage of aliquots at 2°C to 8°C for about 12 months from batch manufacture date, and wherein an average rate of change in the cumulative percentage release at the 24-hour time point is 0.05%/month to 0.5%/month after storage.
Pain treatment with DEPC/DPPG/cholesterol/tricaprylin MVLs containing encapsulated and unencapsulated bupivacaine with 48-hour release stability
A method of treating or ameliorating pain in a subject in need thereof by administering a composition of bupivacaine encapsulated multivesicular liposomes (MVLs), the composition comprising bupivacaine residing inside a plurality of internal aqueous chambers of MVLs separated by lipid membranes comprising 1,2-dierucoylphosphatidylcholine (DEPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG) or a salt thereof, cholesterol, and tricaprylin, and an aqueous medium in which the bupivacaine encapsulated MVLs are suspended wherein the aqueous medium also comprises unencapsulated bupivacaine, wherein the total bupivacaine concentration is from 12 mg/mL to 17 mg/mL, wherein the batches are manufactured within a period of six months and each batch volume is 100 liters to 300 liters, wherein each batch has a cumulative percentage release from 60% to 85% at a 48-hour time point measured using a rotator-facilitated in vitro release assay after storage of aliquots at 2°C to 8°C for about 12 months from batch manufacture date, and wherein an average rate of change in the cumulative percentage release at the 48-hour time point is -0.18%/month to 0.33%/month after storage.
Together, the independent claims require administering a bupivacaine encapsulated MVL pain treatment composition that includes DEPC, DPPG or its salt, cholesterol, tricaprylin, and an aqueous suspension containing unencapsulated bupivacaine, while also constraining batch manufacturing parameters and defining quantified cumulative release and average rate-of-change criteria at 24 hours or 48 hours after storage.
Stated Advantages
Improved yield (about 82% average) compared with prior processes referenced as 45 L and UK 200 L processes.
Improved IVRA stability trend lines, described as flatter and sometimes slightly upward release-rate behavior.
Potentially extending shelf life.
Documented Applications
Local infiltration into a surgical site for local analgesia.
Regional analgesia via an interscalene brachial plexus nerve block or a femoral nerve block.
Non-limiting administration context for pediatric dosing in subjects 6 to 17 years old.
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