Compositions of bupivacaine multivesicular liposomes

Patent metadata

Field	Value
Publication number	US-11426348-B2
Application number	US-202217590636-A
Country	US
Kind code	B2
Filing date	Feb 1, 2022
Priority date	Jan 22, 2021
Publication date	Aug 30, 2022
Grant date	Aug 30, 2022

Abstract

Embodiments of the present application relate to compositions of multivesicular liposomes (MVLs) and commercial manufacturing processes for making bupivacaine MVLs.

First claim

What is claimed is:

1. Batches comprising compositions of bupivacaine 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 batches consistently comprise an erucic acid concentration of less than about 109 μg/mL after the compositions are stored at 25° C. for six months.

2. The batches of claim 1 , wherein the batches comprise the erucic acid concentration of about 99 μg/mL or less after the compositions are stored at 25° C. for six months.

3. The batches of claim 1 , wherein the compositions have an initial pH of about 7.0 to about 7.4.

4. The batches of claim 1 , the compositions have a pH of about 6.5 after the compositions are stored at 25° C. for six months.

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

6. The batches of claim 1 , wherein the lipid membranes further comprise cholesterol.

7. The batches of claim 1 , wherein the plurality of internal aqueous chambers of the MVLs has an initial pH of about 5.50.

8. The batches of claim 1 , wherein the bupivacaine concentration in the compositions is from about 11.3 mg/mL to about 17.0 mg/mL.

9. The batches of claim 8 , wherein the bupivacaine concentration in the compositions is about 13.3 mg/mL.

10. The batches of claim 1 , wherein the compositions comprise less than 5% by weight unencapsulated bupivacaine.

11. The batches of claim 1 , wherein the d 50 of the MVLs in the compositions is about 24 μm to about 31 μm.

12. The batches of claim 1 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the compositions is about 35% to 40%.

13. The batches of claim 1 , wherein the internal aqueous chambers of the MVLs comprise lysine, and the encapsulated lysine concentration in the bupivacaine encapsulated MVLs compositions is about 0.03 mg/mL.

14. The batches of claim 1 , wherein the internal aqueous chambers of the MVLs comprise dextrose, and the encapsulated dextrose concentration in the bupivacaine encapsulated MVLs compositions is about 1.25 mg/mL to about 1.32 mg/mL.

15. The batches of claim 1 , wherein the DEPC and DPPG in the compositions are in a mass ratio of about 7:1 to about 10:1.

16. The batches of claim 1 , wherein the bupivacaine is in a salt form.

17. The batches of claim 16 , wherein the bupivacaine is in the form of bupivacaine phosphate.

18. The batches of claim 1 , wherein the aqueous medium comprises a saline solution.

19. A method of treating or ameliorating pain in a subject in need thereof, comprising administering a composition of claim 1 to the subject.

20. The method of claim 19 , wherein the composition has an initial pH of about 7.0 to about 7.4.

21. The method of claim 19 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.

22. The method of claim 19 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin.

23. The method of claim 19 , wherein the lipid membranes further comprise cholesterol.

24. The method of claim 19 , wherein the plurality of internal aqueous chambers of the MVLs has an initial pH of about 5.50.

25. The method of claim 19 , wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL.

26. The method of claim 25 , wherein the bupivacaine concentration in the composition is about 13.3 mg/mL.

27. The method of claim 19 , wherein the composition comprises less than 5% by weight unencapsulated bupivacaine.

28. The method of claim 19 , wherein the d 50 of the multivesicular liposomes in the composition is about 24 μm to about 31 μm.

29. The method of claim 19 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated multivesicular liposomes in the composition is about 35% to 40%.

30. The method of claim 19 , wherein the internal aqueous chambers of the MVLs comprise lysine, and the encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is about 0.03 mg/mL.

31. The method of claim 19 , wherein the administration is via local infiltration to provide local analgesia.

32. The method of claim 19 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.

33. The batches of claim 2 , wherein the compositions have an initial pH of about 7.0 to about 7.4.

34. The batches of claim 2 , wherein the compositions have a pH of about 6.5 after the compositions are stored at 25° C. for six months.

35. The batches of claim 2 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin.

36. The batches of claim 2 , wherein the lipid membranes further comprise cholesterol.

37. The batches of claim 2 , wherein the bupivacaine concentration in the compositions is from about 11.3 mg/mL to about 17.0 mg/mL.

38. The batches of claim 37 , wherein the bupivacaine concentration in the compositions is about 13.3 mg/mL.

39. The batches of claim 2 , wherein the compositions comprise less than 5% by weight unencapsulated bupivacaine.

40. The batches of claim 2 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the compositions is about 35% to 40%.

41. The batches of claim 2 , wherein the internal aqueous chambers of the MVLs comprise lysine, and the encapsulated lysine concentration in the bupivacaine encapsulated MVLs compositions is about 0.03 mg/mL.

42. The batches of claim 2 , wherein the internal aqueous chambers of the MVLs comprise dextrose, and the encapsulated dextrose concentration in the bupivacaine encapsulated MVLs compositions is about 1.25 mg/mL to about 1.32 mg/mL.

43. The batches of claim 2 , wherein the DEPC and DPPG in the compositions are in a mass ratio of about 7:1 to about 10:1.

44. The batches of claim 2 , wherein the bupivacaine is in the form of bupivacaine phosphate.

45. The batches of claim 2 , wherein the aqueous medium comprises a saline solution.

46. A method of treating or ameliorating pain in a subject in need thereof, comprising administering a composition of claim 2 to the subject.

47. The method of claim 46 , wherein the composition has an initial pH of about 7.0 to about 7.4.

48. The method of claim 46 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.

49. The method of claim 46 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin.

50. The method of claim 46 , wherein the lipid membranes further comprise cholesterol.

51. The method of clai

Assignees

• Pacira Pharmaceuticals Inc

Inventors

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

Classifications

• A61K47/14

  Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters · CPC title

• A61K47/28

  Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid · CPC title

• A61K47/12

  Carboxylic acids; Salts or anhydrides thereof · CPC title

• A61K31/445 Primary

  Non condensed piperidines, e.g. piperocaine · CPC title

• A61K9/127 Primary

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · CPC title