Emulsion formulations of an NK-1 receptor antagonist and uses thereof
Inventors
Ottoboni, Thomas B. • Han, Han
Assignees
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Publication Number
US-10624850-B2
Publication Date
2020-04-21
Expiration Date
Abstract
Disclosed herein are novel pharmaceutical formulations of a neurokinin-1 (NK-1) receptor antagonist suitable for parenteral administration including intravenous administration. Also included are formulations including both the NK-1 receptor antagonist 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 provides stable oil-in-water injectable pharmaceutical emulsions comprising an NK-1 receptor antagonist for parenteral administration. The emulsion formulation includes an emulsifier, an oil, a co-surfactant comprising an alcohol, a tonicity agent, a pH modifier, and water, with the emulsion pH about 7.5 to 9.0 and the ratio of the emulsifier to the NK-1 receptor antagonist about 18:1 to 22:1 (wt/wt %).
The problem addressed is nausea and/or vomiting in subjects who are at risk of or suffering from nausea and/or vomiting, including chemotherapy-induced nausea and vomiting. The emulsion formulation is designed to maintain physical and chemical stability over shelf life, including maintaining a droplet size profile (USP <729>, mean droplet size <500 nm) and controlling creaming and crystal visibility.
In addition to the NK-1 receptor antagonist, the emulsion may be co-formulated with dexamethasone sodium phosphate and/or dexamethasone in the aqueous phase. The document reports that buffer/pH control and formulation choices such as emulsifier-to-oil ratios and specific oil-to-antagonist ratios improve physical and chemical stability, and that dexamethasone in the emulsion does not adversely affect aprepitant pharmacokinetics.
Claims Coverage
The independent claim covers a method for treating a subject by administering a specific injectable NK-1 receptor antagonist emulsion, with key inventive formulation constraints. The independent claim defines the emulsion components and requires specific pH and emulsifier-to-antagonist ratio ranges, while the dependent claims refine the emulsion composition and narrow specific material selections and constraints.
Injectable NK-1 antagonist emulsion with defined component set
The method administers an injectable pharmaceutical emulsion comprising an NK-1 receptor antagonist, 11 wt/wt % to 15 wt/wt % emulsifier, an oil, a co-surfactant comprising an alcohol, a tonicity agent, a pH modifier, and water.
Emulsion pH and emulsifier-to-antagonist ratio constraints for nausea and/or vomiting treatment
The emulsion has a pH ranging from about 7.5 to 9.0 and an emulsifier-to-NK-1 receptor antagonist ratio ranging from about 18:1 to 22:1 (wt/wt %), where the subject is at risk of or is suffering from nausea and/or vomiting.
Overall, the claim coverage centers on administering an injectable oil-in-water NK-1 receptor antagonist emulsion that is constrained by the emulsion component set, a defined pH window (about 7.5 to 9.0), and an emulsifier-to-antagonist ratio window (about 18:1 to 22:1, wt/wt %), for treating subjects at risk of or suffering from nausea and/or vomiting. Dependent refinements further specify particular pH modifier identities and optional co-formulation with dexamethasone sodium phosphate in the aqueous phase.
Stated Advantages
Provides stable physical and chemical formulations over shelf life, including maintaining droplet size profile and limiting instability features such as creaming and crystal visibility.
Reported pharmacokinetic performance in rats showing higher initial exposure and bioequivalence versus fosaprepitant solutions.
Dexamethasone in the emulsion does not adversely affect aprepitant pharmacokinetics.
Documented Applications
Treatment of a subject at risk of or suffering from nausea and/or vomiting by administering the injectable emulsion, including chemotherapy-induced nausea and vomiting (CINV).
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