Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate
Inventors
Pelletier, Marc F. • Mcguirk, Paul Robert • Farr, George William
Assignees
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Publication Number
US-10894055-B2
Publication Date
2021-01-19
Expiration Date
Abstract
Provided are novel formulations of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate as described below and uses thereof.
Core Innovation
The disclosure relates to a pharmaceutical composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) and one or more Bronsted bases, where the one or more Bronsted bases is a solid. The composition has less than 2% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after one week at room temperature and is suitable for dissolution with an aqueous solution to form an injection.
A kit is provided containing one or more containers with Formula I and one or more Bronsted bases, with less than 5% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after one week at room temperature. The kit embodiments include Bronsted bases having conjugate acid pKa between 6 and 11, Formula I in lyophilized form, and an aqueous solution that is mixed with Formula I to form an injection.
The disclosure also includes a method of administering a pharmaceutically acceptable salt of Formula I by injection to a human. The method comprises mixing Formula I, one or more Bronsted bases, and an aqueous solution to form a composition and administering the composition 24 hours or less after mixture with the aqueous solution, with dependent embodiments directed to cerebral edema, including cytotoxic cerebral edema and cerebral edema associated with stroke and hypoxia.
Claims Coverage
The independent claims cover three main inventive features: a pharmaceutical composition, a kit, and an injection administration method. Across these claims, coverage centers on Formula I with solid Bronsted bases, impurity limits after one week at room temperature, and mixing with an aqueous solution for injection with a 24-hour administration window.
Pharmaceutical composition with solid Bronsted bases and impurity stability
A pharmaceutical composition comprising Formula I and one or more solid Bronsted bases, wherein the composition has less than 2% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after one week at room temperature, and is suitable for dissolution with an aqueous solution to form an injection.
Kit with Formula I, Bronsted bases, and impurity stability
A kit comprising one or more containers with Formula I and one or more Bronsted bases, wherein the kit has less than 5% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after one week at room temperature.
Injection administration within 24 hours after aqueous mixing
A method of administering a pharmaceutically acceptable salt of Formula I by injection to a human, comprising mixing Formula I, one or more Bronsted bases, and an aqueous solution to form a composition and administering the composition 24 hours or less after mixture with the aqueous solution.
The independent claims collectively cover a stable Formula I formulation with solid Bronsted bases, a kit form with an impurity threshold, and an administration method in which the composition is prepared by mixing with an aqueous solution and administered within 24 hours, with dependent claims further narrowing to cerebral edema contexts.
Stated Advantages
Impurity limitation of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after one week at room temperature (<2% for the composition; <5% for the kit).
Suitability for dissolution with an aqueous solution to form an injection.
Timely administration such that the injected composition is administered 24 hours or less after mixture with the aqueous solution.
Documented Applications
Injectable pharmaceutical use for treating edema, including cerebral edema.
Administration in humans with cerebral edema where the edema is associated with stroke-related mechanisms and/or hypoxia causes.
Cerebral edema characterized as cytotoxic cerebral edema.
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