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) prepared by a process, the process comprising:
(a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a first water-in-oil emulsion, wherein the volatile water-immiscible solvent solution comprises bupivacaine, 1, 2-dierucoylphosphatidylcholine (DEPC), at least one phosphatidylglycerol, and at least one neutral lipid;
(b) mixing the first water-in-oil emulsion with a second aqueous solution to form a second water-in-oil-in-water emulsion, wherein the second aqueous solution comprises lysine;
(c) removing the volatile water-immiscible solvent from the second water-in-oil-in-water emulsion to form a first aqueous suspension of bupivacaine encapsulated MVLs having a first volume;
(d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated MVLs by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated MVLs having a second volume;
(e) exchanging the aqueous supernatant of the second aqueous suspension with a saline solution by diafiltration to provide a third aqueous suspension of bupivacaine encapsulated MVLs having a third volume; and
(f) further reducing the third volume of the third aqueous suspension by microfiltration to provide a final aqueous suspension of bupivacaine encapsulated MVLs having a bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL;
wherein all steps are carried out under aseptic conditions; and
wherein an erucic acid concentration in the composition is about 99 μg/mL or less after the composition is stored at 25° C. for six months.
2. The composition of claim 1 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.
3. The composition of claim 1 , wherein the mixing in step (a) is performed using a first mixer at a high shear speed.
4. The composition of claim 3 , wherein the high sheer speed is from about 1100 rpm to about 1200 rpm.
5. The composition of claim 4 , wherein the high sheer speed is about 1150 rpm.
6. The composition of claim 4 , wherein a mixing time in step (a) is about 65 to 75 minutes.
7. The composition of claim 1 , wherein the mixing in step (b) is performed using a second mixer at a low shear speed.
8. The composition of claim 7 , wherein the low shear speed is from about 450 rpm to about 510 rpm.
9. The composition of claim 8 , wherein the low shear speed is about 495 rpm.
10. The composition of claim 8 , wherein a mixing time in step (b) is about 60 to 65 seconds.
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 d 50 of the bupivacaine encapsulated MVLs in the composition is about 24 to about 31 μm.
13. The composition of claim 1 , wherein the volatile water-immiscible solvent solution further comprises cholesterol.
14. The composition of claim 13 , wherein the phosphatidylglycerol is 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG).
15. The composition of claim 14 , wherein the neutral lipid is tricaprylin.
16. The composition of claim 1 , wherein an external pH of the composition is about 7.
17. A method of providing local or regional analgesia in a subject in need thereof, comprising administering the composition of claim 1 to the subject.
18. The method of claim 17 , wherein the administration is via local infiltration to a surgical site to provide postsurgical local analgesia.
19. The method of claim 17 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide postsurgical regional analgesia.
20. The method of claim 17 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.
21. The method of claim 17 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.
22. The method of claim 17 , wherein the mixing in step (a) is performed using a first mixer at a high shear speed.
23. The method of claim 22 , wherein the high sheer speed is from about 1100 rpm to about 1200 rpm.
24. The method of claim 23 , wherein the high sheer speed is about 1150 rpm.
25. The method of claim 23 , wherein a mixing time in step (a) is about 65 to 75 minutes.
26. The method of claim 17 , wherein the mixing in step (b) is performed using a second mixer at a low shear speed.
27. The method of claim 26 , wherein the low shear speed is from about 450 rpm to about 510 rpm.
28. The method of claim 27 , wherein the low shear speed is about 495 rpm.
29. The method of claim 27 , wherein a mixing time in step (b) is about 60 to 65 seconds.
30. The method of claim 17 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.
31. The method of claim 17 , wherein the d 50 of the bupivacaine encapsulated MVLs in the composition is about 24 to about 31 μm.
32. The method of claim 17 , wherein the volatile water-immiscible solvent solution further comprises cholesterol.
33. The method of claim 32 , wherein the phosphatidylglycerol is DPPG.
34. The method of claim 33 , wherein the neutral lipid is tricaprylin.
35. The method of claim 17 , wherein an external pH of the composition is about 7.