Methods of administration for highly water-soluble salts of a short acting phenylalkylamine calcium channel blocker
Inventors
Plat, Francis • WIGHT, Douglas
Assignees
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Publication Number
US-12257224-B2
Publication Date
2025-03-25
Expiration Date
Abstract
The present invention is related to methods of treating cardiac arrhythmia, angina, or a migraine in a patient in need thereof, with a therapeutically effective amount of a compound having a structure according to the formula: the method comprising nasally administering to the patient (i) a first dose, and (ii) a second dose of an aqueous composition comprising a pharmaceutically acceptable acetate or methanesulfonate salt of compound I, or a racemate or enantiomer thereof, wherein the acetate or methanesulfonate salt of compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of 350 mg/mL±50 mg/mL, and wherein the second dose of the compound is administered between 5 minutes and 25 minutes after the first dose.
Core Innovation
The invention relates to treating cardiac arrhythmia in a subject in need thereof by nasally administering compound I. The method uses a therapeutically effective amount of compound I, including a racemate or enantiomer thereof, in an aqueous composition comprising a pharmaceutically acceptable acetate or methanesulfonate salt of compound I.
The method comprises administering a first dose and a second dose, where the second dose is administered between 8 minutes and 16 minutes after the first dose. The first dose and the second dose are the same, and each dose comprises between 60 mg and 80 mg of compound I. The aqueous composition dissolves the acetate or methanesulfonate salt of compound I, or the racemate or enantiomer thereof, at a concentration of 350 mg/mL to 150 mg/mL.
The disclosures further describe aqueous composition properties and components, including a pH of 4.5±1.5 and a chelating agent such as EDTA. Additional dependent constraints refine the dosing and formulation parameters while maintaining nasal administration of the aqueous composition containing the specified salt form of compound I.
Claims Coverage
The claim coverage centers on treating cardiac arrhythmia with a two-dose intranasal regimen of an aqueous composition containing a pharmaceutically acceptable acetate or methanesulfonate salt of compound I. The coverage is defined by six inventive features, with dependent claims refining formulation pH and adding chelating agents such as EDTA.
Two-dose intranasal regimen for compound I salt
A method comprising nasally administering a first dose and a second dose of an aqueous composition comprising a pharmaceutically acceptable acetate or methanesulfonate salt of compound I, or a racemate or enantiomer, wherein the second dose is administered between 8 minutes and 16 minutes after the first dose, and wherein the first dose and the second dose are the same.
Specified aqueous salt concentration for compound I
The acetate or methanesulfonate salt of compound I, or the racemate or enantiomer thereof, is dissolved in the aqueous composition at a concentration of 350 mg/mL to 150 mg/mL.
Defined per-dose compound I amount
Each of the first dose and the second dose comprises between 60 mg and 80 mg of compound I.
pH-constrained aqueous composition
The aqueous composition has a pH of 4.5±1.5.
Chelating agent-containing aqueous composition
The aqueous composition further includes a chelating agent.
EDTA-containing aqueous composition
The aqueous composition further comprises EDTA as a chelating agent.
Overall, the claims cover treating cardiac arrhythmia with a two-dose intranasal regimen of an aqueous composition containing a pharmaceutically acceptable acetate or methanesulfonate salt of compound I, with defined salt concentration, a timing window between doses, and defined mg amount per dose. Dependent claims further refine aqueous composition pH and include chelating agents such as EDTA.
Stated Advantages
Maximal ventricular rate reduction within 60 minutes, evaluated using Holter-based endpoints.
Time to nadir and achievement of ventricular rate targets including <100 bpm with specified reduction criteria.
Time to cardioversion into sinus rhythm.
Reduction quantified by area under the heart rate curve over 60 minutes and 360 minutes for mITT.
Second nasal dosing elevates serum levels above single-dose levels for about 60 minutes.
Documented Applications
Use in a Holter-based clinical study evaluating treatment effects on ventricular rate and related electrocardiographic endpoints after nasal administration of compound I.
Use in pharmacokinetic evaluation comparing single versus two nasal doses and assessing serum concentration time profiles.
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