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 encapsulated MVLs comprising bupivacaine residing inside a plurality of internal aqueous chambers of 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), cholesterol, and at least one neutral lipid, the plurality of internal aqueous chambers of the MVLs also comprise lysine; and
an aqueous medium in which the bupivacaine encapsulated MVLs are suspended, wherein the aqueous medium also comprises unencapsulated bupivacaine;
wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL, wherein an erucic acid concentration in the composition is about 53 μg/mL or less after the composition is stored at 25° C. for three months.
2. The composition of claim 1 , wherein the composition has a pH of about 6.9 after the composition is stored at 25° C. for three months.
3. 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.
4. The composition of claim 3 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.
5. The composition of claim 3 , wherein the at least one neutral lipid in the lipid membranes comprises tricaprylin.
6. The composition of claim 3 , wherein the encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is about 0.03 μg/mL.
7. The composition of claim 3 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
8. The composition of claim 3 , wherein the DEPC and DPPG in the composition is in a mass ratio of about 7:1 to about 10:1.
9. The composition of claim 3 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the composition is about 32% to 44%.
10. The composition of claim 3 , wherein the bupivacaine is in a salt form.
11. The composition of claim 10 , wherein the bupivacaine is in the form of bupivacaine phosphate.
12. The composition of claim 1 , wherein the aqueous medium comprises a saline solution.
13. The composition of claim 3 , wherein the aqueous medium comprises a saline solution.
14. A method of treating or ameliorating pain in a subject in need thereof, comprising administering the composition of claim 3 to the subject.
15. The method of claim 14 , wherein the administration is via local infiltration to a surgical site to provide postsurgical local analgesia.
16. The method of claim 14 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide postsurgical regional analgesia.
17. The method of claim 14 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.
18. The method of claim 14 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.
19. The method of claim 14 , wherein the at least one neutral lipid in the lipid membranes comprises tricaprylin.
20. The method of claim 14 , wherein the encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is about 0.03 μg/mL.
21. The method of claim 14 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
22. The method of claim 14 , wherein the DEPC and DPPG in the composition is in a mass ratio of about 7:1 to about 10:1.
23. The method of claim 14 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the composition is about 32% to 44%.
24. The method of claim 14 , wherein the bupivacaine is in a salt form.
25. The method of claim 24 , wherein the bupivacaine is in the form of bupivacaine phosphate.
26. The method of claim 14 , wherein the aqueous medium comprises a saline solution.
27. The method of claim 21 , wherein the encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is about 0.03 μg/mL.
28. The method of claim 21 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the composition is about 32% to 44%.
29. The method of claim 28 , wherein the bupivacaine is in a salt form.
30. The method of claim 29 , wherein the bupivacaine is in the form of bupivacaine phosphate.
31. The method of claim 30 , wherein the aqueous medium comprises a saline solution.
32. The method of claim 21 , wherein the administration is via local infiltration to a surgical site to provide postsurgical local analgesia.
33. The method of claim 21 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide postsurgical regional analgesia.
34. The method of claim 21 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.