Manufacturing of bupivacaine multivesicular liposomes
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.
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 when measured after the composition is stored at 25° C. for three months, and the erucic acid concentration in the composition is about 99 μg/mL or less when measured after the composition is stored at 25° C. for six months; and
wherein the encapsulated lysine concentration in the composition is at least about 0.03 mg/mL.
2. The composition of claim 1 , wherein the composition has a pH of about 6.9 when measured after the composition is stored at 25° C. for three months.
3. The composition of claim 1 , wherein the composition has a pH of about 6.5 when measured after the composition is stored at 25° C. for six months.
4. The composition of claim 1 , wherein the at least one neutral lipid in the lipid membranes comprises tricaprylin.
5. The composition of claim 1 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
6. The composition of claim 1 , wherein the DEPC and DPPG in the composition is in a mass ratio of about 7:1 to about 10:1.
7. The composition of claim 1 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the composition is about 32% to 44%.
8. The composition of claim 1 , wherein the bupivacaine is in a salt form.
9. The composition of claim 8 , wherein the bupivacaine is in the form of bupivacaine phosphate.
10. The composition of claim 1 , wherein the aqueous medium comprises a saline solution.
11. The composition of claim 1 , wherein the composition comprises 5% or less by weight of unencapsulated bupivacaine.
12. A method of treating or ameliorating pain in a subject in need thereof, comprising administering the composition of claim 1 to the subject.
13. The method of claim 12 , wherein the administration is via local infiltration to a surgical site to provide local analgesia.
14. The method of claim 12 , wherein the administration is via interscalene brachial plexus nerve block or femoral 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. The method of claim 12 , wherein the composition has a pH of about 6.9 when measured after the composition is stored at 25° C. for three months.
17. The method of claim 12 , wherein the composition has a pH of about 6.5 when measured after the composition is stored at 25° C. for six months.
18. The method of claim 12 , wherein the at least one neutral lipid in the lipid membranes comprises tricaprylin.
19. The method of claim 12 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
20. The method of claim 12 , wherein the DEPC and DPPG in the composition is in a mass ratio of about 7:1 to about 10:1.
21. The method of claim 12 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the composition is about 32% to 44%.
22. The method of claim 12 , wherein the bupivacaine is in a salt form.
23. The method of claim 22 , wherein the bupivacaine is in the form of bupivacaine phosphate.
24. The method of claim 12 , wherein the aqueous medium comprises a saline solution.
25. The method of claim 12 , wherein the composition comprises 5% or less by weight of unencapsulated bupivacaine.
26. The composition of claim 1 , wherein the encapsulated lysine concentration in the composition is about 0.03 mg/mL to about 0.08 mg/mL.
27. The composition of claim 26 , wherein the composition comprises 2% or less by weight of unencapsulated bupivacaine.
28. The method of claim 12 , wherein the encapsulated lysine concentration in the composition is about 0.03 mg/mL to about 0.08 mg/mL.
29. The method of claim 28 , wherein the composition comprises 2% or less by weight of unencapsulated bupivacaine.