Pharmaceutical compositions and methods of making pharmaceutical compositions comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate
Inventors
Pelletier, Marc F. • Mcguirk, Paul Robert • Farr, George William
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11801254-B2
Publication Date
2023-10-31
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 pharmaceutical compositions comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) and one or more Bronsted bases, wherein the Bronsted bases are an amine and/or a salt thereof. The composition is characterized by a stability-related impurity constraint after one week at room temperature, namely less than 2% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide, with dependent coverage describing a tighter limit of less than 1%.
The disclosed compositions further refine the Bronsted base selection and define a molar ratio between Formula I and the Bronsted base. Specific Bronsted bases include tris(hydroxymethyl)aminomethane, meglumine, diethanolamine, and/or a tris(hydroxymethyl)aminomethane salt, and aqueous solution embodiments have pH between 8 and 8.5, with broader pH ranges around pH 7 to 10.5 also described.
The disclosure further provides formulation scope including dissolution to form an injection, aqueous sterile solution context, and solid-form scope including crystalline, amorphous, and lyophilized material. It also describes reconstitution to provide sterile injectable liquids and intravenous administration contexts, together with a method of making a salt solution by admixing Formula I and an amine and/or a salt thereof.
Claims Coverage
The independent claim coverage centers on one pharmaceutical composition and one method, with Formula I combined with one or more Bronsted bases under a one-week room-temperature impurity/stability constraint. Dependent coverage refines the Bronsted base identity, Formula I/base molar ratios, aqueous pH, conjugate-acid pKa, tighter impurity limits, and the admixing method for salt solution formation.
Formula I with Bronsted base composition under impurity stability constraint
A pharmaceutical composition comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate (Formula I) and one or more Bronsted bases, wherein the Bronsted bases are an amine and/or a salt thereof, and the pharmaceutical composition comprises less than 2% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after one week at room temperature.
Specific Bronsted bases including tris(hydroxymethyl)aminomethane and meglumine
The pharmaceutical composition includes one or more Bronsted bases selected from tris(hydroxymethyl)aminomethane, meglumine, diethanolamine, and/or a tris(hydroxymethyl)aminomethane salt.
Defined Formula I to Bronsted base molar ratio
The pharmaceutical composition is defined by a molar ratio of Formula I to one or more Bronsted bases that is at least 1:2, with additional molar-equivalent relationships described in the partial content.
Tighter impurity limit for the specified hydroxybenzamide
The pharmaceutical composition includes less than 1% N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after one week at room temperature.
Aqueous solution pH range
When dissolved in an aqueous solution, the pharmaceutical composition has a pH between 8 and 8.5, with broader pH ranges around pH 7 to 10.5 also described.
Admixing Formula I with an amine or salt to make a salt solution
The method comprises admixing Formula I and an amine and/or a salt thereof to form the salt solution.
Overall claim coverage combines Formula I with one or more Bronsted bases under defined identity, quantitative relationship, and impurity/stability constraints after one week at room temperature, and includes a method of making a salt solution by admixing Formula I with an amine and/or salt thereof.
Stated Advantages
Maintains low levels of N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide after one week at room temperature, with thresholds of less than 2% and less than 1% in dependent coverage.
Enables aqueous solution formulations with defined pH, including pH between 8 and 8.5.
Provides injection-related formulation embodiments, including dissolution to form an injection and aqueous sterile solution options.
Documented Applications
Pharmaceutical composition embodiments for injection and injection preparation, including dissolution to form an injection and intravenous injection.
Lyophilized formulation with reconstitution into sterile solution.
Sterile solution formats such as syringes, vials, and ampoules.
Disease contexts described for concurrent or sequential co-administration with additional therapeutic agents, including neurological and other diseases, pulmonary edema, fibromyalgia, multiple sclerosis, cerebral edema, stroke, TBI, glioma, meningitis, and acute mountain sickness.
Ocular ischemia, including retinal ischemia and intraocular pressure context.
Cardiovascular ischemia including myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, and myocardial hypoxia.
Sepsis.
Migraine.
Neuromyelitis optica.
Glioblastoma.
Aquaporin-mediated diseases, including AQP2/AQP4 conditions.
Aquaporin-mediated therapeutic use with targets including AQP4 and AQP2 for disease conditions listed in the document, including cerebral/spinal cord/optic nerve/retinal edema, hyponatremia, pulmonary edema, epilepsy, myocardial ischemia/infarction, sepsis, migraines, fibromyalgia, multiple sclerosis, glioblastoma, and neuromyelitis optica.
Administration-ready formulation use, including dissolution to form an injection and aqueous sterile solution options.
Pharmaceutical compositions/kits for aquaporin-mediated disease treatment, including cerebral edema, pulmonary edema, and hyponatremia, using aquaporin inhibitors.
Injectable sterile aqueous solutions for intravenous administration, including IV bolus and IV infusion contexts.
Solid-state forms that can be reconstituted to sterile injectable liquids.
Interested in licensing this patent?