Manufacturing of bupivacaine multivesicular liposomes

Patent metadata

Field	Value
Publication number	US-12151024-B2
Application number	US-202217840104-A
Country	US
Kind code	B2
Filing date	Jun 14, 2022
Priority date	Jan 22, 2021
Publication date	Nov 26, 2024
Grant date	Nov 26, 2024

Abstract

Embodiments of the present application relate to compositions bupivacaine multivesicular liposomes (MVLs) prepared by a commercial manufacturing process with large particle diameter span.

First claim

What is claimed is:

1. A composition of bupivacaine encapsulated multivesicular liposomes (MVLs), comprising:
bupivacaine residing inside a plurality of internal aqueous chambers of the MVLs separated by lipid membranes, wherein the lipid membranes comprise 1, 2-dierucoylphosphatidylcholine (DEPC), 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), and at least one neutral lipid; and
an aqueous medium in which the bupivacaine encapsulated MVLs are suspended;
wherein the multivesicular liposomes have an average d 90 particle diameter ranging from about 54 μm to about 65 μm, and an average particle diameter span (d 90 -d 10 ) of at least about 38 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month, and wherein the composition comprises an erucic acid concentration of about 99 μg/mL or less when measured after storage of the composition at 25° C. for six months.

2. The composition of claim 1 , wherein the average d 90 particle diameter of the multivesicular liposomes is from about 54 μm to about 58 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month.

3. The composition of claim 1 , wherein the average particle diameter span (d 90 -d 10 ) of the multivesicular liposomes is from about 40 μm to about 48 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month.

4. The composition of claim 1 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin.

5. The composition of claim 1 , wherein the lipid membranes further comprise cholesterol.

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

7. The composition of claim 1 , wherein the bupivacaine is in the form of bupivacaine phosphate.

8. The composition of claim 3 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin.

9. The composition of claim 3 , wherein the lipid membranes further comprise cholesterol.

10. The composition of claim 3 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.

11. The composition of claim 3 , wherein the bupivacaine is in the form of bupivacaine phosphate.

12. A method of treating or ameliorating pain in 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 provide local analgesia, or via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.

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

15. 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 having a volume of about 100 L to about 250 L and a bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL;
wherein the multivesicular liposomes have an average d 90 particle diameter ranging from about 54 μm to about 65 μm and an average particle diameter span (d 90 -d 10 ) of at least about 38 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month, and wherein the composition comprises an erucic acid concentration of about 99 μg/mL or less when measured after storage of the composition at 25° C. for six months.

16. The composition of claim 15 , wherein the average d 90 particle diameter of the multivesicular liposomes is from about 54 μm to about 58 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month.

17. The composition of claim 15 , wherein the multivesicular liposomes have an average particle diameter span from about 40 μm to about 48 μm when measured after storage of the composition at 2 to 8 ° C. for less than 1 month.

18. The composition of claim 15 , wherein the mixing in step (a) is performed using a first mixer at a high shear speed.

19. The composition of claim 18 , wherein the high sheer speed is from about 1100 rpm to about 1200 rpm.

20. The composition of claim 15 , wherein the mixing in step (b) is performed using a second mixer at a low shear speed.

21. The composition of claim 20 , wherein the low shear speed is from about 450 rpm to about 510 rpm.

22. The composition of claim 15 , wherein the at least one neutral lipid in the volatile water-immiscible solvent solution comprises tricaprylin.

23. The composition of claim 15 , wherein the volatile water-immiscible solvent solution further comprise cholesterol.

24. The composition of claim 15 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.

25. The composition of claim 15 , wherein the bupivacaine is in the form of bupivacaine phosphate.

26. A method of treating or ameliorating pain in a subject in need thereof, comprising administering the composition of claim 15 to the subject.

27. The method of claim 26 , wherein the administration is via local infiltration to provide local analgesia, or via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.

28. The method of claim 26 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.

29. The composition of claim 1 , wherein the composition comprises about 8% or less by weight of free bupivacaine.

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

31. The composition of claim 1 , wherein the internal pH of the bupivacaine encapsulated MVLs is about 5.5 when measured after storage of the composition at 2 to 8° C. for up to 9 months.

32. The composition of claim 1 , wherein the composition comprises lysine encapsulated in the internal aqueous chambers of the MVLs, and the encapsulated lysine concentration in the composition is about 0.03 mg/mL.

33. The composition of claim 2 , wherein the average particle diameter span (d 90 -d 10 ) of the multivesicul

Assignees

• Pacira Pharmaceuticals Inc

Inventors

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

Classifications

• B01D61/146

  comprising multiple ultrafiltration 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