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Publication Number
US-9974793-B2
Publication Date
2018-05-22
Expiration Date
Abstract
Disclosed herein are novel pharmaceutical formulations of aprepitant suitable for parenteral administration including intravenous administration. Also included are formulations including both aprepitant and dexamethasone sodium phosphate. The pharmaceutical formulations are stable oil-in-water emulsions for non-oral treatment of emesis and are particularly useful for treatment of subjects undergoing highly emetogenic cancer chemotherapy.
Core Innovation
The invention relates to a physically stable pharmaceutical composition comprising aprepitant, an emulsifier, an oil, and water, wherein the composition is an emulsion. The disclosure emphasizes maintaining formulation stability while meeting USP <729> droplet size and large fat globule limits for long shelf life.
The formulation is characterized by controlling pH to prevent degradation, using pH-adjusting agents such as sodium oleate and buffers including phosphate, citrate, Tris, carbonate, succinate, maleate, borate, and PBS/PBS-mod. The oil phase, emulsifier, and co-surfactant options include soybean oil, egg yolk lecithin/lecithin/phospholipids, and ethanol, and a tonicity/osmotic agent such as sucrose is described as part of the aqueous phase to improve stability characteristics including freeze-thaw behavior.
The disclosure describes emulsion performance in terms of droplet size using DLS and addresses the presence or absence of crystals over time, including freeze-thaw behavior. Pharmacokinetic results in rats are reported, showing higher initial aprepitant levels from the emulsion versus fosaprepitant solution and bioequivalent exposure by later timepoints, and indicating that dexamethasone co-formulation does not alter aprepitant pharmacokinetics.
Claims Coverage
The partial content includes two independent claims. Each independent claim is centered on a physically stable pharmaceutical emulsion of aprepitant with specified emulsifier:aprepitant and oil:aprepitant wt % ratios; the second claim further fixes specific named components and ratios.
Physically stable emulsion with specified emulsifier and oil ratios
A physically stable pharmaceutical composition comprising aprepitant, an emulsifier, an oil, and water, wherein the ratio of the emulsifier to aprepitant ranges from about 18:1 to 22:1 (wt %:wt %), wherein the ratio of the oil to aprepitant ranges from about 11:1 to 15:1 (wt %:wt %), wherein the composition is an emulsion.
Physically stable emulsion with defined egg yolk lecithin and soybean oil ratios
A physically stable pharmaceutical composition comprising aprepitant, egg yolk lecithin, soybean oil, and water, wherein the ratio of the egg yolk lecithin to aprepitant is 20:1 (wt %:wt %), wherein the ratio of the soybean oil to aprepitant is 13:1 (wt %:wt %), wherein the composition is an emulsion.
Across the independent claims, coverage is directed to physically stable pharmaceutical oil-in-water emulsions containing aprepitant, with emulsion identity and stability being grounded in defined wt % ratios between emulsifier and aprepitant and between oil and aprepitant, with the second independent claim specifying egg yolk lecithin and soybean oil at fixed ratios.
Stated Advantages
Physically stable pharmaceutical emulsion.
Meets USP <729> droplet size and large fat globule limits for long shelf life.
Controlled pH to prevent degradation.
Provides acceptable droplet size as measured by DLS and addresses crystal absence/presence over time and freeze-thaw behavior.
Pharmacokinetic performance shows higher initial aprepitant levels from the emulsion versus fosaprepitant solution, with bioequivalent exposure by later timepoints.
Dexamethasone co-formulation does not alter aprepitant pharmacokinetics.
Documented Applications
Intravenous suitability for aprepitant delivered as a physically and chemically stable oil-in-water emulsion.
Use of the emulsion formulation as co-formulated with dexamethasone sodium phosphate, while maintaining aprepitant pharmacokinetics.
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