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 water-in-oil first emulsion, wherein the volatile water-immiscible solvent solution comprises bupivacaine, 1, 2-dierucoylphosphatidylcholine (DEPC), 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), and at least one neutral lipid;
(b) mixing the water-in-oil first emulsion with a second aqueous solution to form a water-in-oil-in-water second emulsion, wherein the second aqueous solution comprises lysine and dextrose;
(c) removing the volatile water-immiscible solvent from the water-in-oil-in-water second 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 volume of the third aqueous suspension by microfiltration to provide a final aqueous suspension of bupivacaine encapsulated MVLs having a target concentration of bupivacaine;
wherein all steps in the process are carried out under aseptic conditions; and
wherein the internal pH of the bupivacaine encapsulated MVLs in the composition is about 5.50.
2. The composition of claim 1 , wherein the encapsulated lysine concentration of the bupivacaine encapsulated MVLs composition is about 0.030 μg/mL to about 0.032 μg/mL.
3. The composition of claim 2 , wherein the encapsulated lysine concentration of the bupivacaine encapsulated MVLs composition is about 0.031 μg/mL.
4. The composition of claim 1 , wherein the encapsulated dextrose concentration of the bupivacaine encapsulated MVLs composition is about 1.25 μg/mL to about 1.32 μg/mL.
5. The composition of claim 4 , wherein the encapsulated dextrose concentration of the bupivacaine encapsulated MVLs composition is about 1.29 μg/mL.
6. The composition of claim 1 , wherein the mixing of step (a) is performed using a first mixer at a high shear speed.
7. The composition of claim 6 , wherein the high sheer speed is from about 1100 rpm to about 1200 rpm.
8. The composition of claim 7 , wherein the high sheer speed is about 1150 rpm.
9. The composition of claim 8 , wherein the mixing of step (a) is performed for about 65 to 75 minutes.
10. The composition of claim 1 , wherein the mixing of step (b) is performed using a second mixer at a low shear speed.
11. The composition of claim 10 , wherein the low shear speed is from about 450 rpm to about 510 rpm.
12. The composition of claim 11 , wherein the low shear speed is about 495 rpm.
13. The composition of claim 12 , wherein the mixing of step (b) is performed for about 60 to 65 seconds.
14. The composition of claim 1 , wherein the target concentration of bupivacaine in the final aqueous suspension is from about 11.3 mg/mL to about 17.0 mg/mL.
15. The composition of claim 1 , wherein the concentration of bupivacaine in the composition is about 13.3 mg/mL.
16. The composition of claim 1 , wherein the d 50 of the multivesicular liposomes in the composition is about 24 μm to about 31 μm, or about 27 μm.
17. The composition of claim 1 , wherein the final aqueous suspension of bupivacaine encapsulated MVLs has a volume of about 200 L to about 225 L.
18. A method of treating or ameliorating pain in a subject in need thereof, comprising administering a composition of claim 1 to the subject.
19. The method of claim 18 , wherein the administration is via local infiltration to a surgical site to provide local analgesia.
20. The method of claim 18 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.
21. The method of claim 18 , wherein the concentration of bupivacaine in the composition is about 13.3 mg/mL.
22. The composition of claim 1 , wherein the composition has a pH of about 7.0 to about 7.4.
23. The composition of claim 1 , wherein the lipid membranes further comprise cholesterol and tricaprylin.
24. 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%.
25. The method of claim 18 , wherein encapsulated lysine concentration of the bupivacaine encapsulated MVLs composition is about 0.030 μg/mL to about 0.032 μg/mL.
26. The method of claim 25 , wherein the encapsulated lysine concentration of the bupivacaine encapsulated MVLs composition is about 0.031 μg/mL.
27. The method of claim 18 , wherein encapsulated dextrose concentration of the bupivacaine encapsulated MVLs composition is about 1.25 μg/mL to about 1.32 μg/mL.
28. The method of claim 27 , wherein the encapsulated dextrose concentration of the bupivacaine encapsulated MVLs composition is about 1.29 μg/mL.
29. The method of claim 18 , wherein the lipid membranes further comprise cholesterol and tricaprylin.
30. The method of claim 18 , wherein the composition has a pH of about 7.0 to about 7.4.
31. The method of claim 18 , wherein the d 50 of the multivesicular liposomes in the composition is about 24 μm to about 31 μm, or about 27 μm.
32. The method of claim 18 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated multivesicular liposomes in the composition is about 35% to 40%.