Aprepitant Injectable Formulations
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.
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.