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-12115255-B2
Publication Date
2024-10-15
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 relates to stable oil-in-water injectable emulsions that comprise an NK-1 receptor antagonist, including aprepitant, for parenteral use in treating CINV. The emulsion is formulated with an emulsifier and an oil phase, together with a co-emulsifier that is an alcohol, a tonicity modifier, a pH modifier, and water, where the pH of the emulsion ranges from about 7.5 to 9.0.
The formulations include specific compositional constraints for aprepitant-containing emulsions, including an emulsifier content and defined roles for the oil, alcohol co-emulsifier, tonicity modifier, and pH modifier. In example formulations described in the document, the stability of the emulsion is evaluated against USP <729> droplet size and fat globules, and pH control is used to prevent chemical degradation, including assessment of storage and freeze-thaw stability.
The document describes preparation and performance of crude and fine emulsions using homogenization and sterilizing filtration, and reports resulting emulsion properties such as particle size and pH. It further reports pharmacokinetic comparison in rats, including bioequivalence versus fosaprepitant solution and retention of dexamethasone pharmacokinetics when co-formulated, alongside stability observations at room temperature and at 5°C.
Claims Coverage
The independent claims cover two main formulations for injectable emulsions containing about 0.7–0.8 wt% aprepitant with defined emulsifier/oil/alcohol/co-surfactant/water/pH modifier components, including a constrained emulsion pH range and a constrained emulsifier-to-aprepitant ratio (wt/wt%). Across the independent claims, the core inventive features are the specific component set and quantitative formulation constraints (pH and emulsifier-to-aprepitant ratio).
Injectable emulsion with pH 7.5 to 9.0 using aprepitant plus alcohol co-emulsifier
An injectable emulsion comprising about 0.7–0.8 wt% aprepitant; an emulsifier in an amount of 13 wt/wt% to 20 wt/wt%; 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.
Injectable pharmaceutical emulsion with egg phospholipid emulsifier and emulsifier-to-aprepitant ratio 20:1 to 25:1
An injectable pharmaceutical emulsion comprising about 0.7–0.8 wt% aprepitant; an egg phospholipid emulsifier; an oil; a co-surfactant; water; and a pH modifier, wherein the ratio of the emulsifier to aprepitant is about 20:1 to 25:1 (wt/wt%).
Claim coverage centers on injectable aprepitant-containing oil-in-water emulsions that use an alcohol co-emulsifier plus tonicity and pH modifiers with an emulsion pH about 7.5–9.0, and on an embodiment using an egg phospholipid emulsifier with an emulsifier-to-aprepitant ratio about 20:1–25:1 (wt/wt%).
Stated Advantages
Emulsion stability is evaluated against USP <729> droplet size/fat globules limits.
pH control prevents chemical degradation.
Storage and freeze-thaw stability are assessed as part of emulsion stability.
Rat pharmacokinetics show bioequivalence versus fosaprepitant solution.
When co-formulated, dexamethasone pharmacokinetics remain unchanged.
Documented Applications
Treatment of CINV using parenteral injectable emulsions containing NK-1 receptor antagonists, including aprepitant.
Parenteral use/administration context described for IV or parenteral CINV treatment in connection with aprepitant formulations.
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