Kits and methods for induction of cardioversion in subjects with atrial arrhythmias
Inventors
Belardinelli, Luiz • Schuler, Carlos • Guzman, Miguel
Assignees
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Publication Number
US-12059414-B2
Publication Date
2024-08-13
Expiration Date
Abstract
Disclosed herein are methods and kits for treating or preventing a heart condition, e.g., cardiac arrhythmia, e.g., atrial arrhythmia, using potassium channel inhibitors and class I antiarrhythmic agents. Also disclosed herein are methods and kits for treating a heart condition via an intravenously, orally, or inhalationally administered fixed-dose combination of a sodium channel blocker and a class I antiarrhythmic agent.
Core Innovation
The invention relates to a pharmaceutical composition that comprises flecainide or a pharmaceutically acceptable salt thereof and ibutilide or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients, diluents, or carriers. The composition is described as a liquid solution and includes ibutilide hemifumarate, with specified concentration ranges and mass/mass ratio ranges for the flecainide and ibutilide components.
The disclosure relates to cardioversion and management of atrial arrhythmias using the flecainide and ibutilide composition. Administration timing is described so that the Tmax of the sodium-channel blocker and the potassium-channel blocker occur closely, and the disclosure discusses electrophysiology in which potassium-channel blockers prolong atrial APD/ERP and slow sodium channel recovery/unbinding, while the sodium-channel blocker counteracts proarrhythmic and QT-prolonging effects of IKr blockers.
The document further includes pharmaceutically acceptable salts and solvate embodiments, including ibutilide hemifumarate and enantiomeric excess embodiments, along with kit and unit-dose concepts. The compositions are described for inhalation, intranasal spray, oral/nasal inhalation, and intravenous administration, and are positioned to address pharmacokinetic and pharmacodynamic behavior such as rapid onset, a target Tmax window, and reduced variability of absorption via inhalation.
Claims Coverage
The independent claim coverage centers on a pharmaceutical composition with two active antiarrhythmics, flecainide and ibutilide, plus pharmaceutically acceptable excipients, diluents, or carriers. The inventive features include the specific drug pairing and quantitative coformulation constraints, with dependent claims narrowing the dosage form, salt form, concentration ranges, and mass-to-mass ratios.
Flecainide and ibutilide combination composition
A pharmaceutical composition comprising flecainide or a pharmaceutically acceptable salt thereof, ibutilide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers.
Liquid solution formulation
The pharmaceutical composition is formulated as a liquid solution.
Flecainide and ibutilide concentration ranges
The pharmaceutical composition contains specified concentration ranges of flecainide or a pharmaceutically acceptable salt and ibutilide or a pharmaceutically acceptable salt.
Flecainide to ibutilide mass-to-mass ratio
The pharmaceutical composition includes flecainide or a pharmaceutically acceptable salt and ibutilide or a pharmaceutically acceptable salt in a mass-to-mass ratio ranging from 60:1 to 240:1.
Flecainide to ibutilide mass-to-mass ratio of about 120:1
The claim specifies a pharmaceutical composition containing flecainide or a pharmaceutically acceptable salt and ibutilide or a pharmaceutically acceptable salt in a mass-to-mass ratio of about 120:1.
Ibutilide hemifumarate salt form
The pharmaceutical composition where the ibutilide or a pharmaceutically acceptable salt is ibutilide hemifumarate.
Overall, the claims coverage is centered on a two-active pharmaceutical composition using flecainide and ibutilide, refined by a liquid-solution dosage form, explicit concentration ranges, quantitative flecainide to ibutilide mass/mass ratio constraints, and a specified ibutilide salt form, ibutilide hemifumarate.
Stated Advantages
Reduced incidence of torsades de pointes (TdP).
Reduced incidence of above-nomogram QT interval.
Reduced hypotension when mean arterial pressure (MAP) is less than 70 mmHg.
Reduced variability of absorption via inhalation.
Rapid onset within a target Tmax window and desirable pharmacokinetic/pharmacodynamic behavior, including QTc outcomes.
Documented Applications
A comparative clinical study use case where subjects receive a sodium channel blocker alone versus a sodium channel blocker plus a potassium channel blocker, with outcomes assessed for TdP incidence, above-nomogram QT interval, and hypotension (MAP <70 mmHg).
Use of the disclosed compositions to address atrial arrhythmias and related patient populations described in the document, including atrial fibrillation variants and atrial flutter variants.
Use within formulations and delivery formats described in the document, including fixed-dose combination embodiments and kit embodiments that include a Mg2+ source alongside the disclosed composition.
Treatment of cardiac arrhythmias, including atrial arrhythmia indications such as atrial fibrillation, paroxysmal atrial fibrillation, persistent atrial fibrillation, and atrial flutter.
Cardioversion and management of atrial arrhythmias.
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