Ready-To-Use Carfilzomib Compositions

Abstract

The present invention provides a stable, non-aqueous, ready-to-use parenteral composition comprising: carfilzomib or pharmaceutically acceptable salt thereof, acidifying agent, optionally a surfactant, one or more solvents or co-solvents.

1 . A composition comprising:
 carfilzomib or a pharmaceutically acceptable salt thereof in a range of about 1 mg/mL to about 20 mg/mL;   ethanoic acid, wherein a ratio of the ethanoic acid to the carfilzomib is about 1:1 to about 15:1;   at least one solvent;   optionally a surfactant; and   optionally an anti-oxidant, wherein the composition has pH from about 2 to about 9, wherein the composition is stable, ready to use, and substantially non-aqueous.   
     
     
         2 . The composition according to  claim 1 , wherein the composition is substantially free of cyclodextrin. 
     
     
         3 . The composition according to  claim 1 , wherein the ratio of ethanoic acid to carfilzomib is about 1.5:1 to about 10:1. 
     
     
         4 . The composition according to  claim 1 , wherein the ethanoic acid in the composition is in range equal to or greater than 30 mg/mL to keep the composition stable for at least 24 hours upon dilution. 
     
     
         5 . The composition according to  claim 1 , wherein the at least one solvent comprises at least one of an alcohol, a glycol, glycerol or a derivative thereof, and mixtures thereof. 
     
     
         6 . The composition according to  claim 1 , wherein the surfactant is at least one of a polyoxyethylene sorbitan ester, a polyoxyethylene polyoxypropylene copolymer, a sorbitan ester, lecithin, cremophor, and mixtures thereof. 
     
     
         7 . The composition according to  claim 1 , wherein the anti-oxidant is at least one of monothioglycerol, alpha-tocopherol, L-cysteine, thioglycolic acid, sodium metabisulfite, ascorbic acid, sodium formaldehyde sulfoxylate, sodium bisulfate, butylated hydroxy toluene, butylated hydroxy anisole, or mixtures thereof. 
     
     
         8 . The composition according to  claim 5 , wherein the solvent is a glycol which is at least one of propylene glycol, polyethylene glycol, and mixtures thereof and the alcohol is at least one of ethanol, butanol, t-butanol, and mixtures thereof. 
     
     
         9 . The composition according to  claim 1 , wherein the pH is from about 2 to about 9. 
     
     
         10 . The composition according to  claim 1 , wherein the anti-oxidant is alpha-tocopherol; the surfactant is a polyoxyethylene sorbitan ester; and the solvent is glycerol, propylene glycol, polyethylene glycol, ethanol, butanol, t-butanol, and mixtures thereof. 
     
     
         11 . The composition according to  claim 1 , wherein the composition is ready to dilute; is stable when stored at 25° C., 60% relative humidity for at least 1 month, is clear upon dilution with a physiological solution and is stable when diluted for at least about 24 hours. 
     
     
         12 . The composition of  claim 1 , wherein the composition is substantially free of non-volatile sugar acid. 
     
     
         13 . A method for treating multiple myeloma and related conditions comprising administering the composition according to  claim 1  in a parenteral dosage form. 
     
     
         14 . A composition comprising:
 carfilzomib or a pharmaceutically acceptable salt thereof;   ethanoic acid; and   at least one solvent, wherein the composition is stable when stored at 25° C., 60% relative humidity for at least 1 month and the composition is ready to use and the composition is clear upon dilution with physiological solution and stable for at least about 24 hours.   
     
     
         15 . The composition according to  claim 14 , wherein the carfilzomib or pharmaceutically acceptable salt thereof is in a range of about 1 mg/mL to about 20 mg/mL, wherein a ratio of the ethanoic acid to the carfilzomib is about 1:1 to about 15:1. 
     
     
         16 . The composition according to  claim 14 , wherein the ethanoic acid in the composition is in range equal to or greater than 30 mg/mL to keep the composition stable for at least 24 hours upon dilution. 
     
     
         17 . A method for manufacturing a composition, comprising;
 adding carfilzomib to ethanol to obtain a clear solution; and   adding an acidifying agent including ethanoic acid to adjust a pH of the clear solution in a range from 2 to 9 to form the composition, wherein a ratio of the ethanoic acid to the carfilzomib is about 1:1 to about 15:1.   
     
     
         18 . The method of  claim 17 , wherein adding carfilzomib to ethanol further comprises:
 adding an additional solvent to the clear solution, wherein the additional solvent is at least one of propylene glycol, polyethylene glycol, polysorbate, or sorbitan easters.   
     
     
         19 . The method of  claim 17 , further comprising:
 adding an anti-oxidant to the clear solution, wherein the anti-oxidant is at least one of monothioglycerol, alpha-tocopherol, L-cysteine, thioglycolic acid, sodium metabisulfite, ascorbic acid, sodium formaldehyde sulfoxylate, sodium bisulfate, butylated hydroxy toluene, butylated hydroxy anisole, and mixtures thereof.   
     
     
         20 . The method of  claim 17 , further comprising:
 filtering the composition; and   supplying an inert gas when manufacturing the composition.