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 commercial scale process, the commercial scale 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 third volume of the third aqueous suspension by microfiltration to provide a final aqueous suspension of bupivacaine encapsulated MVLs having a target concentration from about 12.6 mg/mL to about 17.0 mg/mL;
wherein all steps are carried out under aseptic conditions; and
wherein the erucic acid concentration in the composition is about 23 μg/mL or less after the composition is stored at 25° C. for one month.
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 mixing in step (a) is performed using a first mixer at a high shear speed.
10. The composition of claim 9 , wherein the high sheer speed is from about 1100 rpm to about 1200 rpm.
11. The composition of claim 10 , wherein the high sheer speed is about 1150 rpm.
12. The composition of claim 11 , wherein the mixing time in step (a) is about 65 to 75 minutes.
13. The composition of claim 1 , wherein the mixing in step (b) is performed using a second mixer at a low shear speed.
14. The composition of claim 13 , wherein the low shear speed is from about 450 rpm to about 510 rpm.
15. The composition of claim 14 , wherein the low shear speed is about 495 rpm.
16. The composition of claim 15 , wherein the mixing time in step (b) is about 60 to 65 seconds.
17. The composition of claim 1 , wherein the concentration of bupivacaine in the composition is about 13.3 mg/mL.
18. The composition of claim 1 , wherein the d 50 of the multivesicular liposomes in the composition is about 27 μm.
19. The composition of claim 1 , wherein the internal pH of the bupivacaine encapsulated MVLs in the composition is about 5.5.
20. A method of providing post surgical pain management in a subject in need thereof, comprising administering a composition of claim 1 to the subject.
21. The method of claim 20 , wherein the administration is via local infiltration to a surgical site to provide local analgesia.
22. The method of claim 20 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.