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, 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 plurality of internal aqueous chambers of the MVLs has a pH of about 5.5;
wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL, 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, and wherein the composition has a shelf life of up to 2 years when stored at 2-8° C.
2. The composition of claim 1 , wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for one month.
3. 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.
4. The composition of claim 3 , wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for two months.
5. 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 month.
6. The composition of claim 5 , wherein the composition has a pH of about 6.9 after the composition is stored at 25° C. for three months.
7. 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.
8. The composition of claim 7 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.
9. The composition of claim 1 , wherein the lipid membranes further comprise cholesterol and tricaprylin.
10. The composition of claim 1 , wherein the encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is about 0.030 μg/mL to about 0.032 μg/mL.
11. The composition of claim 1 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
12. The composition of claim 1 , wherein the composition comprises less than about 5% by weight unencapsulated bupivacaine.
13. The composition of claim 1 , wherein the composition comprises less than about 8% by weight unencapsulated bupivacaine when stored at 2-8° C. for up to 2 years.
14. 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%.
15. The composition of claim 1 , wherein the encapsulated bupivacaine is in a salt form.
16. The composition of claim 15 , wherein the encapsulated bupivacaine is in the form of bupivacaine phosphate.
17. A method of treating or ameliorating pain in a subject in need thereof, comprising administering a composition of claim 1 to the subject.
18. The method of claim 14 , wherein the administration is via local infiltration to a surgical site to provide local analgesia.
19. The method of claim 14 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.
20. The method of claim 14 , wherein the pain is postsurgical pain.