Methods of use of emulsion formulations of an NK-1 receptor antagonist
Inventors
Ottoboni, Thomas B. • Han, Han
Assignees
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Publication Number
US-11744800-B2
Publication Date
2023-09-05
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 disclosure provides injectable pharmaceutical emulsions comprising aprepitant or a neurokinin-1 (NK-1) receptor antagonist, with egg lecithin or phospholipids as emulsifier and soybean oil or other enumerated oils as the oil component. The emulsion is defined as an oil-in-water formulation and includes ethanol or another alcohol as co-surfactant, sucrose or another osmotic agent, sodium oleate or oleic acid or a salt thereof as pH modifier, and water, with component selection and compositional ratio relationships between emulsifier and NK-1 receptor antagonist.
The disclosure further specifies that the emulsifier-to-NK-1 receptor antagonist ratio is about 18:1 to 22:1 (wt/wt %), including a narrower ratio of about 19:1 to 20:1 for the prevention method. It also states weight-percent ranges for the emulsifier, oil, co-surfactant, osmotic agent, and pH modifier, while listing particular members of each component class. The formulation is presented as a composition-defined injectable emulsion.
The disclosure addresses stability for the injectable emulsions by describing physical and chemical stability criteria using USP <729>, including droplet size, fat globules, and absence of crystals, together with reported particle-size and zeta potential data. It also describes comparative pharmacokinetic findings in rats for an emulsion versus fosaprepitant, including co-delivery timing with dexamethasone, and reports freeze-thaw and storage stability observations.
Claims Coverage
The provided material contains three independent claims. The inventive coverage centers on composition-defining injectable NK-1 receptor antagonist oil-in-water emulsions with defined component selections, defined weight-percent ranges, and an emulsifier-to-antagonist wt/wt ratio constraint of about 18:1 to 22:1, plus a prevention use by intravenous administration.
Injectable pharmaceutical emulsion with constrained egg lecithin to aprepitant ratio
An injectable pharmaceutical emulsion comprising aprepitant, egg lecithin, soybean oil, ethanol, sucrose, sodium oleate, and water, wherein the ratio of the egg lecithin to aprepitant ranges from about 18:1 to 22:1 (wt/wt %).
Injectable pharmaceutical emulsion with enumerated emulsifier, oil, co-surfactant, osmotic agent, and pH modifier
An injectable pharmaceutical emulsion comprising a neurokinin-1 (NK-1) receptor antagonist, about 14 wt/wt % to 15 wt/wt % of an emulsifier selected from egg phospholipids and soy phospholipids, about 9 wt/wt % to 10 wt/wt % of an oil selected from enumerated oils, about 2 wt/wt % to 3 wt/wt % of a co-surfactant comprising an alcohol, about 3 wt/wt % to 8 wt/wt % of an osmotic agent selected from enumerated osmotic agents, about 0.4 wt/wt % to 0.5 wt/wt % of a pH modifier in the form of oleic acid or a salt thereof, and water, wherein the ratio of the emulsifier to NK-1 receptor antagonist ranges from about 18:1 to 22:1 (wt/wt %).
Prevention of post-operative nausea and vomiting by intravenous administration of a defined emulsion
A method for preventing post-operative nausea and vomiting in a subject, comprising intravenously administering an injectable pharmaceutical emulsion comprising aprepitant, about 14 wt/wt % to 15 wt/wt % of egg lecithin, about 9 wt/wt % to 10 wt/wt % of soybean oil, about 2 wt/wt % to 3 wt/wt % of ethanol, about 3 wt/wt % to 8 wt/wt % of sucrose, about 0.4 wt/wt % to 0.5 wt/wt % of sodium oleate, and water, wherein the ratio of the egg lecithin to aprepitant ranges from about 19:1 to 20:1 (wt/wt %).
Across the independent claims, the core claim coverage is directed to injectable oil-in-water emulsions containing an NK-1 receptor antagonist, with defined emulsifier, oil, co-surfactant, osmotic agent, and pH modifier components and with an emulsifier-to-antagonist weight-to-weight ratio constraint centered on about 18:1 to 22:1, plus a prevention method by intravenous administration.
Stated Advantages
Prevention of post-operative nausea and vomiting.
Documented Applications
Preventing post-operative nausea and vomiting in a subject by intravenous administration of an injectable pharmaceutical emulsion comprising aprepitant and specified excipient components.
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