Claims for Patent: 12,296,047

Summary for Patent: 12,296,047

Title:	Manufacturing of bupivacaine multivesicular liposomes
Abstract:	Embodiments of the present application relate to compositions bupivacaine multivesicular liposomes (MVLs) prepared by a commercial manufacturing process with large particle diameter span.
Inventor(s):	Jeffrey S. Hall, David J. Turnbull, John J. Grigsby, Jr., Soroush M. Ardekani, Kathleen D. A. Los
Assignee:	Pacira Pharmaceuticals Inc
Application Number:	US18/943,310
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 12,296,047
Patent Claims:	1. A batch comprising a composition of bupivacaine encapsulated multivesicular liposomes (MVLs) prepared by a process, the process comprising: (a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a first water-in-oil emulsion, wherein the volatile water-immiscible solvent solution comprises bupivacaine, 1,2-dierucoylphosphatidylcholine (DEPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG), cholesterol, and tricaprylin; (b) mixing the first water-in-oil emulsion with a second aqueous solution to form a second water-in-oil-in-water emulsion, wherein the second aqueous solution comprises lysine; (c) removing the volatile water-immiscible solvent from the second water-in-oil-in-water emulsion to form a first aqueous suspension of bupivacaine encapsulated MVLs having a first volume; (d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated MVLs by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated MVLs having a second volume; (e) exchanging the aqueous supernatant of the second aqueous suspension with a saline solution by diafiltration to provide a third aqueous suspension of bupivacaine encapsulated MVLs having a third volume; and (f) further reducing the third volume of the third aqueous suspension by microfiltration to provide a final aqueous suspension of bupivacaine encapsulated MVLs having a bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL; wherein the batch has a volume of 100 L to 250 L; wherein the MVLs have an average d90 particle diameter ranging from 54 μm to 65 μm and an average particle diameter span (d90-d10) of 38 μm to 48 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month; and wherein the erucic acid concentration of the batch is about 105 μg/mL or less when measured after storage of the composition at about 25° C. for six months. 2. The batch of claim 1, wherein the average d90 particle diameter of the MVLs is from 54 μm to 58 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month. 3. The batch of claim 1, wherein the average particle diameter span of the MVLs is from m to 48 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month. 4. The batch of claim 1, wherein the erucic acid concentration of the batch is about 99 μg/mL or less when measured after storage of the composition at about 25° C. for six months. 5. The batch of claim 1, wherein the composition of the batch comprises lysine encapsulated in the internal aqueous chambers of the MVLs, and the encapsulated lysine concentration in the composition is about 0.03 mg/mL. 6. The batch of claim 1, wherein the composition of the batch comprises about 5% or less by weight of free bupivacaine. 7. The batch of claim 1, wherein the internal pH of the bupivacaine encapsulated MVLs is about 5.5 when measured after storage of the composition at 2 to 8° C. for up to 9 months. 8. The batch of claim 1, wherein the mixing in step (a) is performed using a mixer at a high shear speed from about 1100 rpm to about 1200 rpm for about 65 to about 75 minutes. 9. The batch of claim 1, wherein the mixing in step (b) is performed using a mixer at a low shear speed from about 450 rpm to about 510 rpm for about 60 to about 65 seconds. 10. The batch of claim 1, wherein the bupivacaine concentration in the composition of the batch is about 13.3 mg/mL. 11. The batch of claim 1, wherein the batch has a volume of about 110 L to about 200 L. 12. A method of treating or ameliorating pain in a subject in need thereof, comprising administering a composition of the batch of claim 1 to the subject. 13. The method of claim 12, wherein the administration is via local infiltration to provide local analgesia. 14. The method of claim 12, wherein the administration is via a nerve block to provide regional analgesia. 15. The method of claim 12, wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration. 16. Batches comprising compositions of bupivacaine encapsulated multivesicular liposomes (MVLs) prepared by a process, the process of preparing a batch comprising: (a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a first water-in-oil emulsion, wherein the volatile water-immiscible solvent solution comprises bupivacaine, 1,2-dierucoylphosphatidylcholine (DEPC), 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG), cholesterol, and tricaprylin; (b) mixing the first water-in-oil emulsion with a second aqueous solution to form a second water-in-oil-in-water emulsion, wherein the second aqueous solution comprises lysine; (c) removing the volatile water-immiscible solvent from the second water-in-oil-in-water emulsion to form a first aqueous suspension of bupivacaine encapsulated MVLs having a first volume; (d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated MVLs by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated MVLs having a second volume; (e) exchanging the aqueous supernatant of the second aqueous suspension with a saline solution by diafiltration to provide a third aqueous suspension of bupivacaine encapsulated MVLs having a third volume; and (f) further reducing the third volume of the third aqueous suspension by microfiltration to provide a final aqueous suspension of bupivacaine encapsulated MVLs having a bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL; wherein each batch has a volume of 100 L to 250 L; wherein the MVLs of each batch have an average d90 particle diameter ranging from 54 μm to 65 μm and an average particle diameter span (d90-d10) of 38 μm to 48 m when measured after storage of the composition at 2 to 8° C. for less than 1 month; and wherein an average erucic acid concentration of three batches prepared by the process is about 105 μg/mL or less when measured after storage of compositions of the batches at about 25° C. for six months. 17. The batches of claim 16, wherein the average d90 particle diameter of the MVLs of each batch is from 54 μm to 58 μm when measured after storage of the composition of the batch at 2 to 8° C. for less than 1 month. 18. The batch of claim 16, wherein the average particle diameter span of the MVLs of each batch is from 40 μm to 48 μm when measured after storage of the composition of the batch at 2 to 8° C. for less than 1 month. 19. The batches of claim 16, wherein the average erucic acid concentration of three batches prepared by the process is about 99 μg/mL or less when measured after storage of the compositions of the batches at about 25° C. for six months. 20. The batches of claim 16, wherein the average erucic acid concentration of three batches prepared by the process is greater than 53 μg/mL when measured after storage of the compositions of the batches at about 25° C. for six months. 21. The batches of claim 19, wherein the average erucic acid concentration of three batches prepared by the process is greater than 53 μg/mL when measured after storage of the compositions of the batches at about 25° C. for six months. 22. The batches of claim 16, wherein the composition of each batch comprises about 5% or less by weight of free bupivacaine. 23. The batches of claim 16, wherein the mixing in step (a) is performed using a mixer at a high shear speed from about 1100 rpm to about 1200 rpm for about 65 to 75 minutes. 24. The batches of claim 16, wherein the mixing in step (b) is performed using a mixer at a low shear speed from about 450 rpm to about 510 rpm for about 60 to 65 seconds. 25. The batches of claim 16, wherein the bupivacaine concentration in the composition of each batch is about 13.3 mg/mL. 26. The batches of claim 16, wherein each batch has a volume of about 110 L to about 200 L. 27. A method of treating or ameliorating pain in a subject in need thereof, comprising administering a composition of a batch of claim 16 to the subject. 28. The method of claim 27, wherein the administration is via local infiltration to provide local analgesia. 29. The method of claim 27, wherein the administration is via a nerve block to provide regional analgesia. 30. The method of claim 27, wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.