Manufacturing of bupivacaine multivesicular liposomes

Patent metadata

Field	Value
Publication number	US-11925706-B2
Application number	US-202318325924-A
Country	US
Kind code	B2
Filing date	May 30, 2023
Priority date	Jan 22, 2021
Publication date	Mar 12, 2024
Grant date	Mar 12, 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), comprising:
bupivacaine encapsulated MVLs comprising bupivacaine residing inside a plurality of internal aqueous chambers of 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), cholesterol, and at least one neutral lipid, the plurality of internal aqueous chambers of the MVLs also comprise lysine; and
an aqueous medium in which the bupivacaine encapsulated MVLs are suspended, wherein the aqueous medium also comprises unencapsulated bupivacaine;
wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL;
wherein an erucic acid concentration in the composition is about 53 μg/mL or less when measured after the composition is stored at 25° C. for three months, and 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; and
wherein 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 6.9 when measured after the composition is stored at 25° C. for three months.

3. 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.

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

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

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

7. The composition of claim 1 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the composition is about 32% to 44%.

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

9. The composition of claim 8 , wherein the bupivacaine is in the form of bupivacaine phosphate.

10. The composition of claim 1 , wherein the aqueous medium comprises a saline solution.

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

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 a surgical site to provide local analgesia.

14. The method of claim 12 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide 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 6.9 when measured after the composition is stored at 25° C. for three months.

17. 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.

18. The method of claim 12 , wherein the at least one neutral lipid in the lipid membranes comprises tricaprylin.

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

20. The method of claim 12 , wherein the DEPC and DPPG in the composition is in a mass ratio of about 7:1 to about 10:1.

21. The method of claim 12 , wherein the percent packed particle volume (% PPV) of the bupivacaine encapsulated MVLs in the composition is about 32% to 44%.

22. The method of claim 12 , wherein the bupivacaine is in a salt form.

23. The method of claim 22 , wherein the bupivacaine is in the form of bupivacaine phosphate.

24. The method of claim 12 , wherein the aqueous medium comprises a saline solution.

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

26. The composition of claim 1 , wherein the encapsulated lysine concentration in the composition is about 0.03 mg/mL to about 0.08 mg/mL.

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

28. The method of claim 12 , wherein the encapsulated lysine concentration in the composition is about 0.03 mg/mL to about 0.08 mg/mL.

29. The method of claim 28 , wherein the composition comprises 2% or less by weight of unencapsulated 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

• 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