Aprepitant Injectable Formulations

Abstract

An aqueous stable and ready-to-use formulation of aprepitant is prepared. Especially preferred formulations comprise a synergistic combination of a co-solvent and a surfactant and may further include a secondary co-solvent. Among other advantages of contemplated formulations, aprepitant is dissolved at high concentrations and remains dissolved and stable, even over prolonged periods of time.

What is claimed is: 
     
         1 . A sterile liquid formulation of aprepitant for injection, comprising:
 an aqueous single phase solvent system comprising water, a primary co-solvent, a surfactant, and a secondary co-solvent;   wherein the primary co-solvent and the surfactant are present in a synergistic ratio with respect to solubilization of aprepitant;   wherein the secondary co-solvent is present in an amount of equal or less than 6 volume % of the water and the primary co-solvent together; and   aprepitant at a concentration of at least 5 mg/ml.   
     
     
         2 . The sterile liquid formulation of  claim 1 , wherein the primary co-solvent is a short-chain alcohol. 
     
     
         3 . The sterile liquid formulation of  claim 2 , wherein the short-chain alcohol is ethanol. 
     
     
         4 . The sterile liquid formulation of  claim 1 , wherein the surfactant is a nonionic surfactant. 
     
     
         5 . The sterile liquid formulation of  claim 4 , wherein the non-ionic surfactant is a polysorbate. 
     
     
         6 . The sterile liquid formulation of  claim 1 , wherein the secondary co-solvent is a short-chain polyethylene glycol or dimethylacetamide. 
     
     
         7 . The sterile liquid formulation of  claim 6 , wherein the secondary co-solvent is a short-chain polyethylene glycol and is present in an amount of equal or less than 3 volume %. 
     
     
         8 . The sterile liquid formulation of  claim 6 , wherein the secondary co-solvent is dimethylacetamide and is present in an amount of equal or less than 1 volume %. 
     
     
         9 . The sterile liquid formulation of  claim 1 , wherein the primary co-solvent is ethanol, the secondary co-solvent is a short-chain polyethylene glycol or dimethylacetamide, and wherein the surfactant is a polysorbate. 
     
     
         10 . The sterile liquid formulation of  claim 1 , wherein the secondary co-solvent is omitted from the sterile liquid formulation. 
     
     
         11 . A kit for preparation of a sterile liquid formulation of aprepitant for injection, the kit comprising:
 (a) a first container that includes a solvent system comprising a primary co-solvent, a surfactant, and an optional secondary co-solvent;   wherein the primary co-solvent and the surfactant are present in a synergistic ratio with respect to solubilization of aprepitant;   wherein the optional secondary co-solvent is present in an amount of equal or less than 30 vol % of the primary co-solvent and the surfactant together;   aprepitant at a concentration of at least 9 mg/ml;   (b) a second container that includes a sterile aqueous diluent in an amount sufficient to dilute the aprepitant to a concentration of at least 5 mg/ml; and   wherein the non-aqueous solvent system and the sterile aqueous diluent are present in an amount such that the aprepitant at the concentration of at least 5 mg/ml is completely soluble and stable in the sterile liquid formulation.   
     
     
         12 . The kit of  claim 11  wherein the primary co-solvent is a short-chain alcohol, and wherein the surfactant is a non-ionic surfactant. 
     
     
         13 . The kit of  claim 11  wherein the secondary co-solvent is a short-chain polyethylene glycol or dimethylacetamide. 
     
     
         14 . The kit of  claim 11  wherein the sterile aqueous diluent is water. 
     
     
         15 . A method of increasing solubility and stability of aprepitant in an aqueous solution, the method comprising:
 preparing an aqueous single phase solvent system comprising water, a primary co-solvent, and a surfactant, wherein the primary co-solvent and the surfactant are present in a synergistic ratio with respect to solubilization of aprepitant;   dissolving aprepitant in a secondary co-solvent to form a concentrated aprepitant solution;   combining the concentrated aprepitant solution with the aqueous single phase solvent system to thereby form an aprepitant formulation with increased solubility and stability for aprepitant.   
     
     
         16 . The method of  claim 15  wherein the primary co-solvent is a short-chain alcohol. 
     
     
         17 . The method of  claim 15  wherein the surfactant is a nonionic surfactant. 
     
     
         18 . The method of  claim 15  wherein the secondary co-solvent is a short-chain polyethylene glycol or dimethylacetamide. 
     
     
         19 . The method of  claim 15  wherein aprepitant formulation contains at least 5 mg/ml aprepitant. 
     
     
         20 . The method of  claim 15  wherein aprepitant in the aprepitant formulation remains in solution for at least one month when stored at 40° C. and 75% relative humidity.