	US 12,296,047 B2
	Manufacturing of bupivacaine multivesicular liposomes
Jeffrey S. Hall, San Diego, CA (US); David J. Turnbull, San Diego, CA (US); John J. Grigsby, Jr., San Diego, CA (US); Soroush M. Ardekani, San Diego, CA (US); and Kathleen D. A. Los, San Diego, CA (US)
Assigned to Pacira Pharmaceuticals, Inc., San Diego, CA (US)
Filed by Pacira Pharmaceuticals, Inc., San Diego, CA (US)
Filed on Nov. 11, 2024, as Appl. No. 18/943,310.
Application 18/943,310 is a continuation of application No. 17/840,104, filed on Jun. 14, 2022, granted, now 12,151,024.
Application 17/840,104 is a continuation in part of application No. 17/719,716, filed on Apr. 13, 2022, granted, now 11,819,574, issued on Nov. 21, 2023.
Application 17/719,716 is a continuation of application No. 17/536,516, filed on Nov. 29, 2021, granted, now 11,304,904, issued on Apr. 19, 2022.
Application 17/536,516 is a continuation of application No. 17/319,591, filed on May 13, 2021, granted, now 11,185,506, issued on Nov. 30, 2021.
Application 17/319,591 is a continuation of application No. 17/156,400, filed on Jan. 22, 2021, granted, now 11,033,495, issued on Jun. 15, 2021.
Prior Publication US 2025/0064742 A1, Feb. 27, 2025
Int. Cl. A61K 9/127 (2006.01); A61K 9/1277 (2025.01); A61K 31/451 (2006.01); B01D 61/14 (2006.01); B01F 23/41 (2022.01); B01F 23/80 (2022.01); B01F 101/22 (2022.01)

CPC A61K 9/1277 (2013.01) [A61K 31/451 (2013.01); B01D 61/146 (2022.08); B01D 61/147 (2013.01); B01F 23/4105 (2022.01); B01F 23/808 (2022.01); B01D 2315/10 (2013.01); B01D 2315/16 (2013.01); B01F 23/4144 (2022.01); B01F 23/4145 (2022.01); B01F 2101/22 (2022.01); B01F 2215/044 (2013.01); B01F 2215/0477 (2013.01); B01F 2215/0481 (2013.01)]

30 Claims

1. A batch comprising a composition of bupivacaine encapsulated multivesicular liposomes (MVLs) prepared by a process, the process comprising:

(a) mixing a first aqueous solution comprising phosphoric acid with a volatile water-immiscible solvent solution to form a first water-in-oil 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), cholesterol, and tricaprylin;

(b) mixing the first water-in-oil emulsion with a second aqueous solution to form a second water-in-oil-in-water emulsion, wherein the second aqueous solution comprises lysine;

(c) removing the volatile water-immiscible solvent from the second water-in-oil-in-water 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 bupivacaine concentration from about 11.3 mg/mL to about 17.0 mg/mL;

wherein the batch has a volume of 100 L to 250 L;

wherein the MVLs have an average d₉₀particle diameter ranging from 54 μm to 65 μm and an average particle diameter span (d₉₀-d₁₀) of 38 μm to 48 μm when measured after storage of the composition at 2 to 8° C. for less than 1 month; and

wherein the erucic acid concentration of the batch is about 105 μg/mL or less when measured after storage of the composition at about 25° C. for six months.