Manufacturing of bupivacaine multivesicular liposomes

Patent metadata

Field	Value
Publication number	US-12144890-B2
Application number	US-202318325927-A
Country	US
Kind code	B2
Filing date	May 30, 2023
Priority date	Jan 22, 2021
Publication date	Nov 19, 2024
Grant date	Nov 19, 2024

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Pacira Pharmaceuticals Inc

Inventors

• Hall Jeffrey S
• Turnbull David J
• Grigsby Jr John J
• Ardekani Soroush M
• Los Kathleen D A

Classifications

• B01D61/1471

  comprising multiple microfiltration steps · CPC title

• B01F2101/22

  Mixing of ingredients for pharmaceutical or medical compositions · CPC title

• B01F23/4145

  Emulsions of oils, e.g. fuel, and water · CPC title

• B01F23/4144

  Multiple emulsions, in particular double emulsions, e.g. water in oil in water; Three-phase emulsions · CPC title

• B01F23/4105

  Methods of emulsifying · CPC title