Highly water-soluble salts of a short acting phenylalkylamine calcium channel blocker and uses thereof
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10117848-B2
Publication Date
2018-11-06
Expiration Date
Abstract
The present invention includes surprisingly water-soluble salts of a phenylalkylamine compound that are potent antagonists of L-type calcium channels. Aqueous solutions including salts of the instant invention are formulated for nasal administration and provide a novel therapeutic platform for the treatment of stable angina, migraine, and cardiac arrhythmia, such as paroxysmal supraventricular tachycardia.
Core Innovation
The invention describes compound I as a calcium channel blocker and relates it to aqueous compositions formulated for nasal administration. The compositions comprise a pharmaceutically acceptable salt or free base of compound I, or racemates or enantiomers thereof, dissolved at a concentration between 150 mg/mL and 600 mg/mL, including concentrated aqueous nasal spray formulations.
The disclosure addresses the need to treat paroxysmal supraventricular tachycardia (PSVT), stable angina, migraine, and cardiac arrhythmia, and states that prior oral calcium channel blocker formulations have slow GI absorption and are not suitable for rapid episode relief. It links the nasal approach to limited nasal volume per administration and to highly water-soluble acid-addition salts, including acetic acid/acetate and methanesulfonic acid/methanesulfonate, to achieve therapeutic dosing within nasal dose volume constraints.
The compositions are described as having formulation parameters that support solubility, permeability, and stability while remaining suitable for nasal administration. The disclosure includes water content, pH, drug concentration, excipient and additive selections, EDTA as a chelating agent, optional acids such as acetic acid, methanesulfonic acid, and sulfuric acid, viscosity ranges, and a nasal pump-spray delivery system configuration with unit dosage forms.
Claims Coverage
The independent claims cover four inventive features: a high-concentration aqueous nasal composition of compound I, methods of treating selected diseases by nasal administration of that composition, a specific acetate salt of the S-enantiomer at a defined concentration, and a method of making a nasal solution with acidic acid, EDTA, pH adjustment, and final concentration control.
High-concentration aqueous nasal composition of compound I
An aqueous composition formulated for nasal administration comprising a pharmaceutically acceptable salt or free base of compound I, or a racemate or enantiomer thereof, wherein compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of between 150 mg/mL and 600 mg/mL.
Nasal administration for treating cardiac arrhythmia, stable angina, or migraine
A method of treating a disease selected from the group consisting of cardiac arrhythmia, stable angina, and migraine by nasally administering to a patient in need thereof an aqueous composition comprising a pharmaceutically acceptable salt of compound I, or a racemate or enantiomer thereof, wherein compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of between 150 mg/mL and 600 mg/mL.
Acetate salt of the S-enantiomer at fixed high concentration for nasal use
An aqueous composition formulated for nasal administration comprising the acetate salt of the S-enantiomer of compound I, dissolved in the aqueous composition at a concentration of 350 mg/mL ± 25 mg/mL.
Method of making nasal solution with acidic acid, EDTA, pH adjustment, and final concentration control
A method of making a solution formulated for nasal administration to a patient comprising adding a solution comprising acidic acid to the free base of the S-enantiomer of compound I to form a mixture; adding a solution comprising ethylenediaminetetracetic acid; heating and mechanically stirring the resulting mixture until the S-enantiomer of compound I has fully dispersed within the mixture; adjusting the pH of the mixture to be 4.5 ± 0.1 by adding a solution comprising sulfuric acid; and diluting the mixture such that the final concentration of the S-enantiomer of compound I in solution is 350 mg/mL ± 125 mg/mL.
The claims center on an aqueous nasal formulation where compound I, including a racemate or enantiomer or a pharmaceutically acceptable salt or free base, is dissolved at a defined high concentration for nasal delivery, together with methods of using such compositions to treat cardiac arrhythmia, stable angina, migraine, or PSVT, and a specialized acetate salt of the S-enantiomer at fixed concentration.
Stated Advantages
The limited nasal volume motivates the use of highly water-soluble acid-addition salts so that therapeutic dosing can be achieved in concentrated aqueous nasal spray formulations.
The compositions are described as supporting solubility, permeability, and stability while remaining suitable for nasal administration.
Enables rapid episode relief by nasal aqueous salt formulations rather than slow GI absorption from prior oral formulations.
ECG and PR segment changes are linked to supportive evidence for PSVT termination efficacy.
Supports efficacy via ECG PR-segment prolongation for terminating PSVT, as stated by the disclosure.
Documented Applications
Nasally administered aqueous compositions for treatment of paroxysmal supraventricular tachycardia (PSVT), stable angina, migraine, and cardiac arrhythmia.
Treating a disease selected from cardiac arrhythmia, stable angina, and migraine by nasally administering an aqueous composition of compound I.
Treating PSVT by nasally administering an aqueous composition comprising the acetate salt of the S-enantiomer of compound I.
Interested in licensing this patent?