Manufacturing of bupivacaine multivesicular liposomes
Inventors
Hall, Jeffrey S. • Turnbull, David J. • Grigsby, Jr., John J. • Ardekani, Soroush M. • Los, Kathleen D. A.
Assignees
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Publication Number
US-12178909-B1
Publication Date
2024-12-31
Expiration Date
Abstract
Embodiments of the present application relate to batches of bupivacaine multivesicular liposomes (MVLs) prepared by a commercial manufacturing process using independently operating dual tangential flow filtration modules.
Core Innovation
The invention relates to a process for preparing bupivacaine encapsulated multivesicular liposomes (MVLs) under aseptic conditions by forming a water-in-oil first emulsion and converting it to a water-in-oil-in-water second emulsion. The volatile water-immiscible solvent solution comprises bupivacaine, DEPC, DPPG, cholesterol, and at least one neutral lipid, together with a first aqueous solution comprising phosphoric acid, and the second aqueous solution comprises lysine and dextrose.
The process removes the volatile water-immiscible solvent to form an aqueous suspension of bupivacaine encapsulated MVLs, then reduces volume by microfiltration and exchanges the aqueous supernatant with saline solution by diafiltration. The third aqueous suspension is further reduced by microfiltration to provide a final bulk aqueous suspension with a defined volume range and a bupivacaine concentration range.
The disclosed commercial manufacturing approach is supported by examples comparing the described process to an existing commercial process using measurements including erucic acid and lysine/dextrose measurements over incubation/storage.
Claims Coverage
Independent claim clm-00001 defines a full aseptic preparation process with four inventive features: double-emulsion formation, solvent removal, microfiltration/diafiltration volume adjustment, and final bulk suspension parameters. Dependent claims further narrow diafiltration equipment and may add compositional and quality thresholds for stability and erucic acid across batches.
Aseptic double-emulsion formation for bupivacaine encapsulated MVLs
A process comprising mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution comprising bupivacaine, DEPC, DPPG, cholesterol, and at least one neutral lipid to form a water-in-oil first emulsion, then mixing the water-in-oil first emulsion with a second aqueous solution comprising lysine and dextrose to form a water-in-oil-in-water second emulsion, with all steps carried out under aseptic conditions.
Volatile solvent removal to form a bupivacaine encapsulated aqueous suspension
Removing the volatile water-immiscible solvent from the diluted water-in-oil-in-water second emulsion to form an aqueous suspension of bupivacaine encapsulated MVLs.
Microfiltration volume reduction and saline exchange by diafiltration
Reducing the aqueous suspension by microfiltration, exchanging the aqueous supernatant with saline solution by diafiltration, and further reducing the suspension by microfiltration to provide a final bulk aqueous suspension with a volume of about 100 L to about 250 L and a bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL.
Multiple independently operating crossflow modules for diafiltration
The diafiltration step is carried out using a plurality of independently operating crossflow modules, wherein each crossflow module contains at least one filter array made up of a plurality of hollow fiber filters.
The claims center on aseptic double-emulsion creation, solvent removal to generate an aqueous MVL suspension, and downstream microfiltration/diafiltration to reach final bulk volume and bupivacaine concentration, with diafiltration equipment further characterized by independently operating crossflow modules.
Stated Advantages
Increased final product volume.
Improved operability.
Improved stability, including lower lipid hydrolysis and faster/greater pH control.
Higher lysine/dextrose encapsulation.
Documented Applications
Commercial manufacturing of bupivacaine encapsulated multivesicular liposomes (MVLs) (Exparel®-like), including aseptic processing and large-scale tangential flow filtration used to compare batches versus an existing commercial process.
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