Compositions of bupivacaine multivesicular liposomes

Abstract

Embodiments of the present application relate to compositions of multivesicular liposomes (MVLs) and manufacturing processes for making bupivacaine MVLs.

1 .- 22 . (canceled) 
     
     
         23 . A composition of bupivacaine encapsulated multivesicular liposomes (MVLs), prepared by a 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), and at least one neutral lipid;   (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 dextrose;   (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 internal dextrose concentration of the bupivacaine encapsulated MVLs is about 1.25 mg/mL to about 1.32 mg/mL and the percent packed particle volume (% PPV) of the final aqueous suspension of bupivacaine encapsulated MVLs is about 37%.   
     
     
         24 . The composition of  claim 23 , wherein the internal dextrose concentration of the bupivacaine encapsulated MVLs is about 1.29 mg/mL. 
     
     
         25 . The composition of  claim 23 , wherein the mixing in step (a) is performed using a first mixer at a high shear speed. 
     
     
         26 . The composition of  claim 25 , wherein the mixing in step (a) is performed at a high shear speed from about 1100 rpm to about 1200 rpm. 
     
     
         27 . The composition of  claim 23 , wherein the mixing in step (b) is performed using a second mixer at a low shear speed. 
     
     
         28 . The composition of  claim 27 , wherein the mixing in step (b) is performed at a low shear speed from about 450 rpm to about 510 rpm. 
     
     
         29 . The composition of  claim 23 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin. 
     
     
         30 . The composition of  claim 23 , wherein the volatile water-immiscible solvent solution further comprises cholesterol. 
     
     
         31 . The composition of  claim 23 , wherein the bupivacaine concentration in the final aqueous suspension is about 13.3 mg/mL. 
     
     
         32 . The composition of  claim 23 , wherein the bupivacaine is in the form of bupivacaine phosphate. 
     
     
         33 . The composition of  claim 23 , wherein the internal dextrose concentration of the bupivacaine encapsulated MVLs is at least about 5% higher than a bupivacaine encapsulated MVLs product (Exparel) manufactured by a 45 L commercial process. 
     
     
         34 . The composition of  claim 33 , wherein the at least one neutral lipid of the lipid membranes comprises tricaprylin. 
     
     
         35 . The composition of  claim 33 , wherein the volatile water-immiscible solvent solution further comprises cholesterol. 
     
     
         36 . The composition of  claim 33 , wherein the bupivacaine concentration in the final aqueous suspension is about 13.3 mg/mL. 
     
     
         37 . The composition of  claim 33 , wherein the bupivacaine is in the form of bupivacaine phosphate. 
     
     
         38 . A method of treating or ameliorating pain in a subject in need thereof, comprising administering a bupivacaine encapsulated multivesicular liposomes composition of  claim 23  to the subject. 
     
     
         39 . The method of  claim 38 , wherein the administration is via local infiltration to a surgical site to provide postsurgical local analgesia. 
     
     
         40 . The method of  claim 38 , wherein the administration is via interscalene brachial plexus nerve block or femoral nerve block to provide postsurgical regional analgesia. 
     
     
         41 . The method of  claim 38 , wherein the composition has a volume of 10 mL or 20 mL for a single-dose administration. 
     
     
         42 . A method of treating or ameliorating pain in a subject in need thereof, comprising administering a bupivacaine encapsulated multivesicular liposomes composition of  claim 33  to the subject.