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 residing inside a plurality of internal aqueous chambers of the MVLs separated by lipid membranes, wherein the lipid membranes comprise 1, 2-dierucoylpho sphatidylcholine (DEPC), 1, 2-dip almitoyl-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 an encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is about 0.03 mg/mL to about 0.08 mg/mL, and wherein 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.
2. The composition of claim 1 , wherein the encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is from about 0.030 mg/mL to about 0.032 mg/mL.
3. The composition of claim 2 , wherein the encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is about 0.031 mg/mL.
4. The composition of claim 1 , wherein an encapsulated dextrose concentration in the bupivacaine encapsulated MVLs composition is from about 1.25 mg/mL to about 1.32 mg/mL.
5. The composition of claim 4 , wherein the encapsulated dextrose concentration of the bupivacaine encapsulated MVLs composition is about 1.29 mg/mL.
6. The composition of claim 1 , wherein the internal pH of the bupivacaine encapsulated MVLs is about 5.5.
7. The composition of claim 1 , wherein the composition has an initial external pH of about 7.0 to about 7.4.
8. The composition of claim 1 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin.
9. The composition of claim 1 , wherein the lipid membranes further comprise cholesterol.
10. 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.
11. The composition of claim 10 , 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 5% by weight unencapsulated bupivacaine.
13. The composition of claim 1 , wherein the d 50 of the MVLs in the composition is about 24 μm to about 31 μm.
14. The composition of claim 1 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the composition is about 35% to about 40%.
15. The composition of claim 1 , wherein the DEPC and DPPG in the composition are in a mass ratio of about 7:1 to about 10:1.
16. The composition of claim 1 , wherein the bupivacaine is in a salt form.
17. The composition of claim 16 , wherein the bupivacaine is in the form of bupivacaine phosphate.
18. Batches comprising compositions 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 the batches consistently comprise an encapsulated lysine concentration of about 0.03 mg/mL to about 0.08 mg/mL in the bupivacaine encapsulated MVLs compositions, and wherein the erucic acid concentrations in the compositions of a plurality of batches are about 99 μg/mL or less when measured after the compositions are stored at 25° C. for six months.
19. The batches of claim 18 , wherein encapsulated dextrose concentrations in the bupivacaine encapsulated MVLs compositions of the plurality of batches are from about 1.25 mg/mL to about 1.32 mg/mL.
20. The batches of claim 18 , wherein the internal pH of the bupivacaine encapsulated MVLs is about 5.5.
21. The batches of claim 18 , wherein the compositions of the plurality of batches have an initial external pH of about 7.0 to about 7.4.
22. The batches of claim 18 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin.
23. The batches of claim 18 , wherein the lipid membranes further comprise cholesterol.
24. The batches of claim 18 , wherein the bupivacaine concentrations in the compositions of the plurality of batches are from about 11.3 mg/mL to about 17.0 mg/mL.
25. The batches of claim 18 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the compositions of the plurality of batches is about 35% to about 40%.
26. The batches of claim 1 , wherein the DEPC and DPPG in the compositions of the plurality of batches are in a mass ratio of about 7:1 to about 10:1.
27. A method of treating or ameliorating pain in a subject in need thereof, comprising administering the composition of claim 1 to the subject.
28. The method of claim 27 , wherein the administration is via local infiltration to a surgical site to provide postsurgical local analgesia.
29. The method of claim 27 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide postsurgical regional analgesia.
30. The method of claim 27 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.
31. The composition of claim 1 , wherein the encapsulated lysine concentration in the composition is at least about 5% higher than the encapsulated lysine concentration of a bupivacaine encapsulated MVL product (Exparel®) manufactured by a 45 L commercial process.
32. The composition of claim 31 , wherein the internal pH of the bupivacaine encapsulated MVLs is about 5.5.
33. The composition of claim 31 , wherein the composition has an initial external pH of about 7.0 to about 7.4.
34. The composition of claim 31 , wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL.
35. The composition of claim 31 , wherein the composition comprises less than 5% by weight unencapsulated bupivacaine.
36. A method of treating or ameliorating pain in a subject in need thereof, comprising administering a composition of claim 31 to the subject.
37. The method of claim 36 , wherein the administration is via local infiltration to a surgical site to provide postsurgical local analgesia.
38. The method of claim 36 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide postsurgical regional analgesia.
39. The method of claim 36 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.