Manufacturing of bupivacaine multivesicular liposomes

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), 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DPPG), 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, and a bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL;

wherein all steps are carried out under aseptic conditions;

wherein the process produces a batch having a volume of about 100 L to about 250 L comprising the composition of bupivacaine encapsulated MVLs,

wherein an erucic acid concentration of the composition is about 99 μm/mL or less when measured after the composition is stored at 25° C. for six months; and

wherein the composition comprise lysine encapsulated in the internal aqueous chambers of the MVLs, and the encapsulated lysine concentration in the composition is at least about 0.03 mg/mL.

2. The composition of claim 1 , wherein the composition has a pH of about 6.5 when measured 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 from about 1100 rpm to about 1200 rpm.

4. The composition of claim 3 , wherein a mixing time in step (a) is about 65 to 75 minutes.

5. The composition of claim 1 , wherein the mixing in step (b) is performed using a second mixer at a low shear speed from about 450 rpm to about 510 rpm.

6. The composition of claim 5 , wherein a mixing time in step (b) is about 60 to 65 seconds.

7. The composition of claim 1 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.

8. The composition of claim 1 , wherein the volatile water-immiscible solvent solution further comprises cholesterol.

9. The composition of claim 8 , wherein the at least one neutral lipid in the volatile water-immiscible solvent solution is tricaprylin.

10. The composition of claim 1 , wherein the composition has an initial external pH of about 7.

11. The composition of claim 1 , wherein the composition comprises 5% or less by weight of free bupivacaine.

12. A method of providing local or regional analgesia to a subject in need thereof, comprising administering the composition of claim 1 to the subject.

13. The method of claim 12 , wherein the administration is via local infiltration to a surgical site to provide postsurgical local analgesia.

14. The method of claim 12 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide postsurgical regional analgesia.

15. The method of claim 12 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.

16. The method of claim 12 , wherein the composition has a pH of about 6.5 when measured after the composition is stored at 25° C. for six months.

17. The method of claim 12 , wherein the composition has an initial external pH of about 7.

18. The method of claim 12 , wherein the composition comprises 5% or less by weight of free bupivacaine.

19. The method of claim 12 , wherein the mixing in step (a) is performed using a first mixer at a high shear speed from about 1100 rpm to about 1200 rpm.

20. The method of claim 19 , wherein a mixing time in step (a) is about 65 to 75 minutes.

21. The method of claim 12 , wherein the mixing in step (b) is performed using a second mixer at a low shear speed from about 450 rpm to about 510 rpm.

22. The method of claim 21 , wherein a mixing time in step (b) is about 60 to 65 seconds.

23. The composition of claim 4 , wherein the mixing in step (a) is performed at a temperature from about 21° C. to about 23° C. using a blade diameter between about 8 inches to about 10 inches.

24. The composition of claim 6 , wherein the mixing in step (b) is performed at a temperature from about 21° C. to about 23° C. using a blade diameter between about 10 inches to about 15 inches.

25. The composition of claim 7 , wherein the composition comprises 5% or less by weight of free bupivacaine.

26. The composition of claim 25 , wherein the composition comprises 2% or less by weight of free bupivacaine.

27. The method of claim 19 , wherein the mixing in step (a) is performed at a temperature from about 21° C. to about 23° C. using a blade diameter between about 8 inches to about 10 inches.

28. The method of claim 21 , wherein the mixing in step (b) is performed at a temperature from about 21° C. to about 23° C. using a blade diameter between about 10 inches to about 15 inches.

29. The method of claim 12 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.

30. The method of claim 29 , wherein the composition comprises 2% or less by weight of free bupivacaine.