Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration
Inventors
Schuler, Carlos • Narasimhan, Rangachari • Belardinelli, Luiz • MADHAVAPEDDI, Prashanti
Assignees
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Publication Number
US-10441537-B2
Publication Date
2019-10-15
Expiration Date
Abstract
Methods of treating a heart condition include administering by inhalation an effective amount of at least one antiarrhythmic pharmaceutical agent to a patient in need thereof. Nebulized drug product and kits are also contemplated.
Core Innovation
The invention relates to inhalation pharmaceutical compositions comprising a unit dose of an antiarrhythmic agent in a liquid solution, formulated for administration via inhalation to treat atrial arrhythmia in a human subject in need thereof. The antiarrhythmic agent is selected from flecainide, a salt thereof, and a solvate thereof, and the unit dose and concentration ranges are defined for the inhalation formulation.
Pulmonary administration is described as different from intravenous dosing, including dose reduction relative to intravenous dose approaches. The core disclosure links inhalation and pulmonary administration to pharmacokinetic and pharmacodynamic behavior, including a pulsatile pharmacokinetic profile and a brief pharmacodynamic transient comparable to intravenous profiles at reduced dose.
The document further discusses ECG monitoring outcomes, including changes in QRS interval and timing related to QRS measurement, together with pharmacokinetic parameter ranges such as Tmax, Cmax, AUCLast, distribution half-life, and elimination half-life after inhalation. It also reports pharmacokinetic and ECG effects associated with inhalation and pulmonary delivery, and describes ECG-guided self-titration, including use of ECG monitoring and portable/mobile ECG.
Claims Coverage
The provided independent claim scope centers on one inhalation pharmaceutical composition for treating atrial arrhythmia, with quantifiable unit-dose and concentration constraints for an antiarrhythmic agent formulated as a liquid solution for inhalation.
Inhalation antiarrhythmic liquid solution unit dose for atrial arrhythmia
An inhalation pharmaceutical composition comprising a unit dose of an antiarrhythmic agent in a liquid solution that is therapeutically effective for treating atrial arrhythmia in a human subject in need thereof, wherein the antiarrhythmic agent is selected from flecainide, a salt thereof, and a solvate thereof, and wherein the pharmaceutical composition is formulated for administration via inhalation.
Specified unit dose and concentration ranges for inhaled antiarrhythmic
The unit dose of the antiarrhythmic agent is about 50 mg to about 350 mg, and the concentration of the antiarrhythmic agent in the unit dose is about 35 to about 60 mg/mL.
Kit with aerosolization device
A kit comprising the inhalable pharmaceutical composition together with an aerosolization device.
Across the provided independent claim, the claim scope is directed to inhalation delivery of an antiarrhythmic agent in a liquid-solution unit dose for treating atrial arrhythmia in humans, with specified ranges for unit dose and drug concentration, and includes a kit embodiment with an aerosolization device.
Stated Advantages
Rapid pharmacokinetic onset after inhalation, described as a rapid rise within 1–3 min.
Comparable pharmacokinetic profiles between inhalation and intravenous administration, described as dose-proportional Cmax/AUC and similar PK profiles.
Conversion to normal sinus rhythm is accelerated in the described preclinical evidence following intratracheal or pulmonary delivery.
Reduced systemic adverse effects versus intravenous administration is described in the preclinical evidence.
Inhalation delivery produces pharmacokinetics and ECG changes similar to intravenous delivery is described in the preclinical evidence.
Lung spirometry and respiratory safety assessments are described in the clinical evaluation.
Enables rapid cardioversion of atrial arrhythmias by delivering an antiarrhythmic agent preferentially to the left atrium via pulmonary veins and attaining transient, pulsatile coronary exposure.
Reduces systemic exposure afterward compared with oral or intravenous administration.
Avoids or reduces dilution and metabolism and reduces drug-drug interaction and QT/QRS-related risk compared with oral or intravenous administration.
Documented Applications
Phase 1 clinical evaluation of inhaled flecainide acetate versus placebo and comparison with intravenous flecainide, including lung spirometry, respiratory safety assessments, ECG pharmacodynamics, adverse-event summaries, and pharmacokinetic results.
Preclinical porcine and dog evidence for intratracheal or pulmonary delivery of flecainide showing pharmacokinetics and ECG changes similar to intravenous delivery and accelerates conversion to normal sinus rhythm.
Treatment of atrial arrhythmia in a human subject in need thereof, including atrial fibrillation, paroxysmal atrial fibrillation, atrial flutter, supraventricular tachycardia, and paroxysmal supraventricular tachycardia.
Self-diagnosing and titrating therapy with ECG or electro-physiologic endpoints for arrhythmia conversion timing [procedural detail omitted for safety].
Inhalation pulmonary antiarrhythmic therapy targeting transient, pulsatile coronary exposure after delivery to the left atrium via pulmonary veins [procedural detail omitted for safety].
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