Claims for Patent: 11,033,495

Summary for Patent: 11,033,495

Title:	Manufacturing of bupivacaine multivesicular liposomes
Abstract:	Embodiments of the present application relate to commercial manufacturing processes for making bupivacaine multivesicular liposomes (MVLs) using independently operating dual tangential flow filtration modules.
Inventor(s):	Hall; Jeffrey S. (San Diego, CA), Turnbull; David J. (San Diego, CA), Grigsby, Jr.; John J. (San Diego, CA), Ardekani; Soroush M. (San Diego, CA), Davis; Paige N. (San Diego, CA), Garcia; Louie D. (San Diego, CA), Kurz; Stephanie M. (San Diego, CA), Los; Kathleen D. A. (San Diego, CA)
Assignee:	Pacira Pharmaceuticals, Inc. (San Diego, CA)
Application Number:	17/156,400
Patent Claims:	1. A composition of bupivacaine encapsulated multivesicular liposomes (MVLs) prepared by a commercial scale process, the commercial scale process comprising: (a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a water-in-oil first 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), and at least one neutral lipid; (b) mixing the water-in-oil first emulsion with a second aqueous solution to form a water-in-oil-in-water second emulsion, wherein the second aqueous solution comprises lysine and dextrose; (c) removing the volatile water-immiscible solvent from the water-in-oil-in-water second 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 target concentration from about 12.6 mg/mL to about 17.0 mg/mL; wherein all steps are carried out under aseptic conditions; and wherein the erucic acid concentration in the composition is about 23 .mu.g/mL or less after the composition is stored at 25.degree. C. for one month. 2. The composition of claim 1, wherein the composition has a pH of about 7.1 after the composition is stored at 25.degree. C. for one month. 3. The composition of claim 1, wherein the erucic acid concentration in the composition is about 38 .mu.g/mL or less after the composition is stored at 25.degree. C. for two months. 4. The composition of claim 3, wherein the composition has a pH of about 7.1 after the composition is stored at 25.degree. C. for two months. 5. The composition of claim 1, wherein the erucic acid concentration in the composition is about 54 .mu.g/mL or less after the composition is stored at 25.degree. C. for three month. 6. The composition of claim 5, wherein the composition has a pH of about 6.9 after the composition is stored at 25.degree. C. for three months. 7. The composition of claim 1, wherein the erucic acid concentration in the composition is about 99 .mu.g/mL or less after the composition is stored at 25.degree. C. for six months. 8. The composition of claim 7, wherein the composition has a pH of about 6.5 after the composition is stored at 25.degree. C. for six months. 9. The composition of claim 1, wherein the mixing in step (a) is performed using a first mixer at a high shear speed. 10. The composition of claim 9, wherein the high sheer speed is from about 1100 rpm to about 1200 rpm. 11. The composition of claim 10, wherein the high sheer speed is about 1150 rpm. 12. The composition of claim 11, wherein the mixing time in step (a) is about 65 to 75 minutes. 13. The composition of claim 1, wherein the mixing in step (b) is performed using a second mixer at a low shear speed. 14. The composition of claim 13, wherein the low shear speed is from about 450 rpm to about 510 rpm. 15. The composition of claim 14, wherein the low shear speed is about 495 rpm. 16. The composition of claim 15, wherein the mixing time in step (b) is about 60 to 65 seconds. 17. The composition of claim 1, wherein the concentration of bupivacaine in the composition is about 13.3 mg/mL. 18. The composition of claim 1, wherein the d.sub.50 of the multivesicular liposomes in the composition is about 27 .mu.m. 19. The composition of claim 1, wherein the internal pH of the bupivacaine encapsulated MVLs in the composition is about 5.5. 20. A method of providing post surgical pain management in a subject in need thereof, comprising administering a composition of claim 1 to the subject. 21. The method of claim 20, wherein the administration is via local infiltration to a surgical site to provide local analgesia. 22. The method of claim 20, wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.