Emulsion formulations of an NK-1 receptor antagonist and uses thereof

Inventors

Ottoboni, Thomas B. • Han, Han

Assignees

Heron Therapeutics LLC

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 relates to stable oil-in-water injectable pharmaceutical emulsions that include a neurokinase-1 (NK-1) receptor antagonist, an emulsifier, an oil, a co-surfactant, and an aqueous phase. The compositions define a specific emulsifier-to-NK-1 receptor antagonist ratio of about 18:1 to 22:1 (wt/wt %), and are described for intravenous or parenteral administration as physically stable and chemically stable over shelf life.

The emulsions include an oil phase and an aqueous phase configured with tonicity/osmotic agents and pH modifiers/buffers. The oil phase includes the NK-1 receptor antagonist together with an emulsifier such as lecithin and a co-surfactant together with an oil such as soybean oil, and the aqueous phase includes water with tonicity agents and pH modifiers/buffers such as sodium oleate and Tris, PBS, or citrate, to support stability.

Physical stability is reported using USP <729> criteria, including droplet size and PFAT5 limits, and the compositions are described as meeting mean droplet size and PFAT5 targets over shelf life. Chemical stability is described in terms of limited change in drug concentration, and stability studies include freeze-thaw sensitivity tied to sucrose. Pharmacokinetic evidence is described showing that the emulsions support faster/higher early NK-1 exposure versus a fosaprepitant solution, and that dexamethasone is co-released with minimal impact on aprepitant pharmacokinetics.

Claims Coverage

The independent claim covers an injectable pharmaceutical emulsion defined by five formulation components and a constrained emulsifier-to-NK-1 receptor antagonist weight ratio. The described claim set further narrows the emulsion by specifying particular NK-1 receptor antagonists, selecting oil/emulsifier ratios and ethanol limits, and adding dexamethasone sodium phosphate in the aqueous phase.

Claim coverage centers on an injectable oil-in-water emulsion defined by a required emulsifier-to-NK-1 receptor antagonist ratio and additional refinements that specify which NK-1 receptor antagonists may be used, constrain emulsifier-to-oil ratio, limit ethanol content, specify soybean oil, and optionally add dexamethasone sodium phosphate in the aqueous phase.

Stated Advantages

Documented Applications