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EP-4740937-A2 - MANUFACTURING OF BUPIVACAINE MULTIVESICULAR LIPOSOMES

EP4740937A2EP 4740937 A2EP4740937 A2EP 4740937A2EP-4740937-A2

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.

Inventors

  • HALL, JEFFREY S.

Assignees

  • Pacira Pharmaceuticals, Inc.

Dates

Publication Date
20260513
Application Date
20220121

Claims (15)

  1. A composition of bupivacaine encapsulated multivesicular liposomes (MVLs) prepared by a commercial scale process, the commercial scale 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 vola- tile water-immiscible solvent solution comprises bupivacaine, 1, 2-dierucoylphosphatidylcholine (DEPC), 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), 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, wherein the second aqueous solution comprises lysine and dextrose; (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 MVLs having a first volume; (d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated MVLs by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated MVLs 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 MVLs 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 MVLs having a target concentration of bupivacaine from 11.3 mg/mL to 17 mg/ml; wherein all steps are carried out under aseptic conditions; and wherein an erucic acid concentration in the composition is 23 µg/mL or less after the composition is stored at 25° C for one month; and wherein the final aqueous suspension of bupivacaine encapsulated MVLs has a volume of 150 L to 250 L.
  2. The composition of claim 1, wherein the target concentration of bupivacaine is 12.6 mg/mL to 17 mg/ml.
  3. The composition of claim 1 or 2, wherein the composition has a pH of 7.1 after the composition is stored at 25° C for one month.
  4. The composition of any one of claims 1 to 3, wherein the erucic acid concentration in the composition is 38 µg/mL or less after the composition is stored at 25°C for two months.
  5. The composition of claim 4, wherein the composition has a pH of 7.1 after the composition is stored at 25° C for two months.
  6. The composition of any one of claims 1 to 5, wherein the erucic acid concentration in the composition is 54 µg/mL or less after the composition is stored at 25°C for three months.
  7. The composition of claim 6, wherein the composition has a pH of 6.9 after the composition is stored at 25°C for three months.
  8. The composition of any one of claims 1 to 7, wherein the erucic acid concentration in the composition is less than 109 µg/mL, after the composition is stored at 25°C for six months.
  9. The composition of claim 8, wherein the composition has a pH of 6.5 after the composition is stored at 25° C for six months.
  10. The composition of any one of claims 1 to 9, wherein: (a) the mixing in step (a) is performed using a first mixer at a high shear speed, wherein the high shear speed is from 1100 rpm to 1200 rpm; and/or (b) the mixing in step (b) is performed using a second mixer at a low shear speed, wherein the low shear speed is from 450 rpm to 510 rpm.
  11. The composition of any one of claims 1 to 10, wherein the concentration of bupivacaine in the composition is 13.3 mg/mL.
  12. The composition of any one of claims 1 to 11, wherein the d 50 of the multivesicular liposomes in the composition is 24 µm to 31 µm, or 27 µm.
  13. The composition of any one of claims 1 to 12, wherein the internal pH of the bupivacaine encapsulated MVLs in the composition is 5.5.
  14. The composition of any one of claims 1 to 13, wherein the bupivacaine encapsulated MVLs have an internal lysine concentration of at least 0.03 mg/mL.
  15. A composition according to any one of claims 1 to 14 for use in a method of treating or ameliorating pain in a subject.

Description

BACKGROUND Field This disclosure relates generally to commercial manufacturing processes for making bupivacaine multivesicular liposomes using independently operating tangential flow filtration systems. Description of the Related Art Bupivacaine is a versatile drug that has been shown to be efficacious for a wide variety of indications, including: local infiltration, peripheral nerve block, sympathetic nerve block, and epidural and caudal blocks. It may be used in pre-, intra- and post-operative care settings. Bupivacaine encapsulated multivesicular liposomes (Exparel®) has been approved in the US and Europe for use as postsurgical local analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia, providing significant long-lasting pain management across various surgical procedures. Particularly, Exparel® has had great success in the market in part due to the ability to locally administer bupivacaine multivesicular liposomes (MVLs) at the time of surgery and extend the analgesic effects relative to other non-liposomal formulations of bupivacaine. Such extended release properties of bupivacaine MVLs allow patients to control their post-operative pain without or with decreased use of opioids. Given the addictive nature of opioids and the opioid epidemic that has been affecting countries around the world, there is an urgent need for new and improved large scale productions of Exparel® to meet the substantial and growing market demand. SUMMARY Some aspects of the present disclosure relate to a crossflow filtration system comprising: a diafiltration vessel; anda plurality of independently operating crossflow modules, each crossflow module of the plurality of independently operating crossflow modules comprising at least one filter array, each filter array comprising a plurality of hollow fiber filters, wherein each crossflow module of the plurality of independently operating crossflow modules is connected to a retentate conduit, a permeate conduit, and a rotary lobe pump. In some embodiments, the crossflow filtration system may be used in the microfiltration and/or diafiltration step of the commercial process described herein. Some aspects of the present disclosure relate to 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. Some aspects of the present disclosure relate to a composition of bupivacaine encapsulated multivesicular liposomes (MVLs) prepared by a commercial scale process, the commercial scale 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, 1, 2-dierucoylphosphatidylcholine (DEPC), 1, 2-dipalmitoyl-sn-glycero-3 phospho-rac-(1-glycerol) (DPPG), 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 MVLs having a first volume;(d) reducing the first volume of the first aqueous suspension of bupivacaine encapsulated MVLs by microfiltration to provide a second aqueous suspension of bupivacaine encapsulated MVLs 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