Manufacturing of bupivacaine multivesicular liposomes
Embodiments of the present application relate to commercial manufacturing processes for making bupivacaine multivesicular liposomes (MVLs) using independently operating dual tangential flow filtration modules.
1. A composition of bupivacaine encapsulated multivesicular liposomes (MVLs), comprising:
bupivacaine residing inside a plurality of internal aqueous chambers of the MVLs separated by lipid membranes, wherein the lipid membranes comprise 1,2-dierucoylphosphatidylcholine (DEPC), 1,2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), and at least one neutral lipid; and
an aqueous medium in which the bupivacaine encapsulated MVLs are suspended;
wherein erucic acid concentration in the composition is about 23 μg/mL or less after the composition is stored at 25° C. for one month.
2. The composition of claim 1 , wherein the composition has an initial pH of about 7.4.
3. The composition of claim 2 , wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for one month.
4. The composition of claim 1 , wherein the erucic acid concentration in the composition is about 38 μg/mL or less after the composition is stored at 25° C. for two months.
5. The composition of claim 4 , wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for two months.
6. The composition of claim 1 , wherein the erucic acid concentration in the composition is about 54 μg/mL or less after the composition is stored at 25° C. for three months.
7. The composition of claim 6 , wherein the composition has a pH of about 6.9 after the composition is stored at 25° C. for three months.
8. The composition of claim 1 , wherein the erucic acid concentration in the composition is about 99 μg/mL or less after the composition is stored at 25° C. for six months.
9. The composition of claim 8 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.
10. The composition of claim 1 , wherein the lipid membranes further comprise cholesterol and tricaprylin.
11. The composition of claim 1 , wherein the plurality of internal aqueous chambers of the MVLs comprise lysine.
12. The composition of claim 1 , wherein the plurality of internal aqueous chambers of the MVLs has an initial pH of about 5.50.
13. The composition of claim 1 , wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL.
14. The composition of claim 13 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
15. The composition of claim 1 , wherein the composition comprises less than 5% by weight unencapsulated bupivacaine.
16. The composition of claim 1 , wherein the d 50 of the multivesicular liposomes in the composition is about 27 μm.
17. The composition of claim 1 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated multivesicular liposomes in the composition is about 35% to 40%.
18. The composition of claim 1 , prepared by a commercial process having a final product volume of about 200 L to about 225 L.
19. A method of treating or ameliorating post surgical pain in a subject in need thereof, comprising administering a composition of claim 1 to the subject.
20. The method of claim 19 , wherein the administration is via local infiltration to a surgical site to provide local analgesia.
21. The method of claim 19 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.
22. The composition of claim 8 , wherein the composition has an initial pH of about 7.4.
23. The composition of claim 8 , wherein the lipid membranes further comprise cholesterol and tricaprylin.
24. The composition of claim 8 , wherein the plurality of internal aqueous chambers of the MVLs comprise lysine.
25. The composition of claim 8 , wherein the plurality of internal aqueous chambers of the MVLs has an initial pH of about 5.50.
26. The composition of claim 8 , wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL.
27. The composition of claim 26 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
28. The composition of claim 8 , wherein the composition comprises less than 5% by weight unencapsulated bupivacaine.
29. The composition of claim 8 , wherein the d 50 of the multivesicular liposomes in the composition is about 27 μm.
30. The composition of claim 8 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated multivesicular liposomes in the composition is about 35% to 40%.
31. The composition of claim 8 , prepared by a commercial process having a final product volume of about 200 L to about 225 L.
32. The method of claim 19 , wherein the composition has an initial pH of about 7.4.
33. The method of claim 19 , wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for one month.
34. The method of claim 19 , wherein the erucic acid concentration in the composition is about 38 μg/mL or less after the composition is stored at 25° C. for two months.
35. The method of claim 34 , wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for two months.
36. The method of claim 19 , wherein the erucic acid concentration in the composition is about 54 μg/mL or less after the composition is stored at 25° C. for three months.
37. The method of claim 36 , wherein the composition has a pH of about 6.9 after the composition is stored at 25° C. for three months.
38. The method of claim 19 , wherein the erucic acid concentration in the composition is about 99 μg/mL or less after the composition is stored at 25° C. for six months.
39. The method of claim 38 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.
40. The method of claim 19 , wherein the lipid membranes further comprise cholesterol and tricaprylin.
41. The method of claim 19 , wherein the plurality of internal aqueous chambers of the MVLs comprise lysine.
42. The method of claim 19 , wherein the plurality of internal aqueous chambers of the MVLs has an initial pH of about 5.50.
43. The method of claim 19 , wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL.
44. The method of claim 43 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
45. The method of claim 19 , wherein the composition comprises less than 5% by weight unencapsulated bupivacaine.
46. The method of claim 19 , wherein the d 50 of the multivesicular liposomes in the composition is about 27 μm.
47. The method of claim 19 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated multivesicular liposomes in the composition is about 35% to 40%.
48. The method of claim 19 , wherein the composition is prepared by a commercial process having a final product volume of about 200 L to about 225 L.
49. The method of claim 38 , wherein the composition has an initial pH of about 7.4.
50. The method of claim 38 , wherein the lipid membranes further comprise cholesterol and tricaprylin.
51. The method of claim 38 , wherein the plurality of internal aqueous chambers of the MVLs comprise lysine.
52. The method of claim 38 , wherein the plurality of internal aqueous chambers of the MVLs has an initial pH of about 5.50.
53. The method of claim 38 , wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL.
54. The method of claim 53 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
55. The method of claim 38 , wherein the composition comprises less than 5% by weight unencapsulated bupivacaine.
56. The method of claim 38 , wherein the d 50 of the multivesicular liposomes in the composition is about 27 μm.
57. The method of claim 38 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated multivesicular liposomes in the composition is about 35% to 40%.
58. The method of claim 38 , wherein the composition is prepared by a commercial process having a final product volume of about 200 L to about 225 L.
59. The method of claim 38 , wherein the administration is via local infiltration to a surgical site to provide local analgesia.
60. The method of claim 38 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.