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Publication Number
US-10500208-B2
Publication Date
2019-12-10
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 describes stable oil-in-water injectable emulsions comprising aprepitant formulated for intravenous or parenteral administration. The formulations include an oil, an emulsifier, a co-emulsifier that is an alcohol, a tonicity agent, a pH modifier, and water, and the emulsion is physically stable. The emulsion pH ranges from about 7.5 to 9.0.
A key part of the invention is the selection and combination of formulation components to maintain physical stability, including control of droplet size and related physical stability criteria such as USP <729>. The document describes measuring and evaluating particle size and related parameters, including zeta potential and pH, for representative formulations, and it reports physical stability observations under storage conditions, including room temperature and 5°C.
The invention also addresses stability with respect to processing and handling conditions, including freeze-thaw performance and the impact of tonicity agents, including sucrose. In pharmacokinetic assessments in rats, the injectable aprepitant emulsion shows higher initial aprepitant exposure compared with fosaprepitant solution, and the co-delivery with dexamethasone sodium phosphate is described as having a minimal effect on aprepitant pharmacokinetics.
Claims Coverage
The independent claims are directed to an injectable physically stable oil-in-water emulsion composition of aprepitant with defined component categories and a specific pH range. One independent claim defines the core composition; the listed dependent claims refine component selection and quantitative or processing limitations.
Physically stable aprepitant injectable emulsion with defined component categories and pH range
An injectable emulsion comprising aprepitant; 11 wt/wt % to 15 wt/wt % of an emulsifier; an oil; a co-emulsifier which is an alcohol; a tonicity modifier; a pH modifier; and water, wherein the pH of the emulsion ranges from about 7.5 to 9.0, and wherein the emulsion is physically stable.
Oil-to-aprepitant ratio in the injectable emulsion
The emulsion where the oil-to-aprepitant ratio is about 11:1 to 15:1 by weight/weight.
Ethanol as the alcohol co-emulsifier
The emulsion where the alcohol component is ethanol.
Phospholipid emulsifier
The emulsion characterized by using a phospholipid as the emulsifier.
Sodium oleate as the pH modifier
The emulsion where its pH modifier is sodium oleate.
Microfluidization and sterilizing in emulsion preparation
A method for preparing a pharmaceutical emulsion by forming an oil phase from aprepitant, emulsifier, alcohol and oil, forming an aqueous phase from water, a tonicity agent, a pH modifier and optionally a buffer, homogenizing the phases to make a coarse premix, microfluidizing the premix at 10,000–30,000 psi to produce the pharmaceutical emulsion, and sterilizing it.
Overall claim coverage centers on an aprepitant oil-in-water injectable emulsion with an emulsifier content (11–15 wt/wt%), an alcohol co-emulsifier, a tonicity modifier, a pH modifier, and a defined pH range (about 7.5 to 9.0), with physical stability. Additional refinements include specifying oil-to-aprepitant ratio, selecting ethanol as the alcohol co-emulsifier, using a phospholipid emulsifier, selecting sodium oleate as the pH modifier, and defining microfluidization/sterilizing preparation conditions.
Stated Advantages
Physically stable emulsion.
Increased initial aprepitant exposure in rats compared with fosaprepitant solution.
Co-delivery with dexamethasone sodium phosphate with minimal effect on aprepitant pharmacokinetics.
Documented Applications
Intravenous or parenteral administration of an aprepitant injectable emulsion formulation.
Co-delivery with dexamethasone sodium phosphate in an aprepitant injectable emulsion, supported by rat pharmacokinetic evaluation.
Rat pharmacokinetics evaluation in Sprague-Dawley rats, including comparison with fosaprepitant solution.
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