Manufacturing of bupivacaine multivesicular liposomes

Patent metadata

Field	Value
Publication number	US-11179336-B1
Application number	US-202117319956-A
Country	US
Kind code	B1
Filing date	May 13, 2021
Priority date	Jan 22, 2021
Publication date	Nov 23, 2021
Grant date	Nov 23, 2021

Abstract

Embodiments of the present application relate to commercial manufacturing processes for making bupivacaine multivesicular liposomes (MVLs) 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-dierucoylphosphatidylcholine (DEPC), 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), 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 plurality of internal aqueous chambers of the MVLs has a pH of about 5.5;
wherein the bupivacaine concentration in the composition is from about 11.3 mg/mL to about 17.0 mg/mL, wherein erucic acid concentration in the composition is about 23 μg/mL or less after the composition is stored at 25° C. for one month, and wherein the composition has a shelf life of up to 2 years when stored at 2-8° C.

2. The composition of claim 1 , wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for one month.

3. The composition of claim 1 , wherein the erucic acid concentration in the composition is about 38 μg/mL or less after the composition is stored at 25° C. for two months.

4. The composition of claim 3 , wherein the composition has a pH of about 7.1 after the composition is stored at 25° C. for two months.

5. The composition of claim 1 , wherein the erucic acid concentration in the composition is about 54 μg/mL or less after the composition is stored at 25° C. for three month.

6. The composition of claim 5 , wherein the composition has a pH of about 6.9 after the composition is stored at 25° C. for three months.

7. The composition of claim 1 , wherein the erucic acid concentration in the composition is about 99 μg/mL or less after the composition is stored at 25° C. for six months.

8. The composition of claim 7 , wherein the composition has a pH of about 6.5 after the composition is stored at 25° C. for six months.

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

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

11. The composition of claim 1 , 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 about 5% by weight unencapsulated bupivacaine.

13. The composition of claim 1 , wherein the composition comprises less than about 8% by weight unencapsulated bupivacaine when stored at 2-8° C. for up to 2 years.

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

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

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

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

18. The method of claim 14 , wherein the administration is via local infiltration to a surgical site to provide local analgesia.

19. The method of claim 14 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide regional analgesia.

20. The method of claim 14 , wherein the pain is postsurgical pain.

Assignees

• Pacira Pharmaceuticals Inc

Inventors

• Hall Jeffrey S
• Turnbull David J
• Grigsby Jr John J
• Ardekani Soroush M
• Davis Paige N
• Garcia Louie D
• Kurz Stephanie M
• Los Kathleen D A

Classifications

• B01D61/1471

  comprising multiple microfiltration steps · CPC title

• B01F23/4144

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

• B01F2101/22

  Mixing of ingredients for pharmaceutical or medical compositions · CPC title

• B01F23/808

  Filtering the mixture · CPC title

• B01F23/4145

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