Manufacturing of bupivacaine multivesicular liposomes

Patent metadata

Field	Value
Publication number	US-2022233446-A1
Application number	US-202117156422-A
Country	US
Kind code	A1
Filing date	Jan 22, 2021
Priority date	Jan 22, 2021
Publication date	Jul 28, 2022
Grant date	—

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

1 . A process for preparing bupivacaine encapsulated multivesicular liposomes in a commercial scale, the process comprising:
(a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a water-in-oil first emulsion, wherein the volatile water-immiscible solvent solution comprises bupivacaine, at least one amphipathic lipid and at least one neutral lipid; (b) mixing the water-in-oil first emulsion with a second aqueous solution to form a water-in-oil-in-water second emulsion; (c) removing the volatile water-immiscible solvent from the water-in-oil-in-water second emulsion to form a first aqueous suspension of bupivacaine encapsulated multivesicular liposomes having a first volume; (d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated multivesicular liposomes by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated multivesicular liposomes 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 multivesicular liposomes 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 multivesicular liposomes having a target concentration of bupivacaine; wherein all steps are carried out under aseptic conditions.

2 . The process of claim 1 , wherein the mixing of step (a) is performed using a mixer at a high shear speed.

3 . The process of claim 1 , wherein the high sheer speed is from about 1100 rpm to about 1200 rpm.

4 . The process of claim 3 , wherein the high sheer speed is about 1150 rpm.

5 . The process of claim 1 , wherein the mixing of step (a) is performed for about 65-75 minutes.

6 . The process of claim 1 , wherein the mixing of step (b) is performed using two mixers at a low shear speed.

7 . The process of claim 6 , wherein the low shear speed is from about 450 rpm to about 510 rpm.

8 . The process of claim 7 , wherein the low shear speed is about 495 rpm.

9 . The process of claim 8 , wherein the mixing of step (b) is performed for about 60 to 65 seconds.

10 . The process of claim 1 , wherein the second aqueous solution comprises lysine and dextrose.

11 . The process of claim 1 , wherein step (e) is performed using two sets of filtration modules, wherein each set of the filtration modules operate independently of the other.

12 . The process of claim 1 , where each set of filtration modules comprise five or more individual hollow fiber filters, wherein each individual hollow fiber filter has a membrane pore size from about 0.1 μm to about 0.2 μm.

13 . The process of claim 1 , wherein the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes has a volume of about 150 L to about 250 L.

14 . The process of claim 13 , wherein the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes has a volume of about 200 L to about 225 L.

15 . The process of claim 1 , wherein the target concentration of bupivacaine is from about 12.6 mg/mL to about 17 mg/mL.

16 . The process of claim 14 , wherein the target concentration of bupivacaine is from about 12.6 mg/mL to about 17 mg/mL.

17 . The process of claim 15 , wherein the target concentration of bupivacaine is about 13.3 mg/mL.

18 . The process of claim 17 , wherein the target concentration of bupivacaine comprises less than 5% unencapsulated bupivacaine.

19 . The process of claim 1 , wherein the d 50 of bupivacaine encapsulated multivesicular liposomes in the final aqueous suspension is about 24 μm to about 31 μm.

20 . The process of claim 19 , wherein the d 50 of bupivacaine encapsulated multivesicular liposomes in the final aqueous suspension is about 27 μm.

21 . The process of claim 1 , wherein the internal pH of the bupivacaine encapsulated multivesicular liposomes in the final aqueous suspension is about 5.5.

22 . The process of claim 1 , wherein the external pH of the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes is about 7.0 to about 7.4.

23 . The process of claim 10 , wherein the encapsulated lysine concentration of bupivacaine multivesicular liposomes in the final aqueous suspension is about 0.03 mg/mL.

24 . The process of claim 1 , wherein final aqueous suspension of bupivacaine encapsulated multivesicular liposomes is suitable for direct human administration.

25 . The process of claim 1 , wherein the percent packed particle volume (% PPV) of the final aqueous suspension of bupivacaine encapsulated multivesicular liposomes is about 35% to 40%.

26 . A composition of bupivacaine encapsulated multivesicular liposomes prepared by the process according to claim 1 .

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

• B01F2215/0481

  Numerical speed values · CPC title

• B01F2215/0477

  Numerical time values · CPC title

• B01F2215/0431

  Numerical size values, e.g. diameter of a hole or conduit, area, volume, length, width, or ratios thereof · CPC title

• B01F33/821

  with consecutive receptacles · CPC title

• B01F2101/22

  Mixing of ingredients for pharmaceutical or medical compositions · CPC title