Manufacturing of bupivacaine multivesicular liposomes

Patent metadata

Field	Value
Publication number	US-11819575-B2
Application number	US-202217720166-A
Country	US
Kind code	B2
Filing date	Apr 13, 2022
Priority date	Jan 22, 2021
Publication date	Nov 21, 2023
Grant date	Nov 21, 2023

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), comprising:
bupivacaine residing inside a plurality of internal aqueous chambers of the MVLs separated by lipid membranes, wherein the lipid membranes comprise 1, 2-dierucoylpho sphatidylcholine (DEPC), 1, 2-dip almitoyl-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 an encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is about 0.03 mg/mL to about 0.08 mg/mL, and wherein the erucic acid concentration in the composition is about 99 μg/mL or less when measured after the composition is stored at 25° C. for six months.

2. The composition of claim 1 , wherein the encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is from about 0.030 mg/mL to about 0.032 mg/mL.

3. The composition of claim 2 , wherein the encapsulated lysine concentration in the bupivacaine encapsulated MVLs composition is about 0.031 mg/mL.

4. The composition of claim 1 , wherein an encapsulated dextrose concentration in the bupivacaine encapsulated MVLs composition is from about 1.25 mg/mL to about 1.32 mg/mL.

5. The composition of claim 4 , wherein the encapsulated dextrose concentration of the bupivacaine encapsulated MVLs composition is about 1.29 mg/mL.

6. The composition of claim 1 , wherein the internal pH of the bupivacaine encapsulated MVLs is about 5.5.

7. The composition of claim 1 , wherein the composition has an initial external pH of about 7.0 to about 7.4.

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

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

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

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

12. The composition of claim 1 , wherein the composition comprises less than 5% by weight unencapsulated bupivacaine.

13. The composition of claim 1 , wherein the d 50 of the MVLs in the composition is about 24 μm to about 31 μm.

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

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

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

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

18. Batches comprising compositions 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 batches consistently comprise an encapsulated lysine concentration of about 0.03 mg/mL to about 0.08 mg/mL in the bupivacaine encapsulated MVLs compositions, and wherein the erucic acid concentrations in the compositions of a plurality of batches are about 99 μg/mL or less when measured after the compositions are stored at 25° C. for six months.

19. The batches of claim 18 , wherein encapsulated dextrose concentrations in the bupivacaine encapsulated MVLs compositions of the plurality of batches are from about 1.25 mg/mL to about 1.32 mg/mL.

20. The batches of claim 18 , wherein the internal pH of the bupivacaine encapsulated MVLs is about 5.5.

21. The batches of claim 18 , wherein the compositions of the plurality of batches have an initial external pH of about 7.0 to about 7.4.

22. The batches of claim 18 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin.

23. The batches of claim 18 , wherein the lipid membranes further comprise cholesterol.

24. The batches of claim 18 , wherein the bupivacaine concentrations in the compositions of the plurality of batches are from about 11.3 mg/mL to about 17.0 mg/mL.

25. The batches of claim 18 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the compositions of the plurality of batches is about 35% to about 40%.

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

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

28. The method of claim 27 , wherein the administration is via local infiltration to a surgical site to provide postsurgical local analgesia.

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

30. The method of claim 27 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.

31. The composition of claim 1 , wherein the encapsulated lysine concentration in the composition is at least about 5% higher than the encapsulated lysine concentration of a bupivacaine encapsulated MVL product (Exparel®) manufactured by a 45 L commercial process.

32. The composition of claim 31 , wherein the internal pH of the bupivacaine encapsulated MVLs is about 5.5.

33. The composition of claim 31 , wherein the composition has an initial external pH of about 7.0 to about 7.4.

34. The composition of claim 31 , wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL.

35. The composition of claim 31 , wherein the composition comprises less than 5% by weight unencapsulated bupivacaine.

36. A method of treating or ameliorating pain in a subject in need thereof, comprising administering a composition of claim 31 to the subject.

37. The method of claim 36 , wherein the administration is via local infiltration to a surgical site to provide postsurgical local analgesia.

38. The method of claim 36 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide postsurgical regional analgesia.

39. The method of claim 36 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration.

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

• A61K9/1277 Primary

  Preparation processes; Proliposomes · CPC title

• A61K31/451 Primary

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine · CPC title

• B01D61/146

  comprising multiple ultrafiltration steps · CPC title

• B01D61/147

  Microfiltration · CPC title