Antiarrhythmic formulation
Inventors
HURREY, Michael Laird • Belardinelli, Luiz • MADHAVAPEDDI, Prashanti • Schuler, Carlos
Assignees
Rutgers State University of New Jersey • Incarda Therapeutics Inc
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Publication Number
US-11020384-B2
Publication Date
2021-06-01
Expiration Date
Abstract
Pharmaceutical compositions comprising an antiarrhythmic agent for treatment of a heart condition via inhalation. 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 disclosed.
Core Innovation
The invention provides a pharmaceutical composition in the form of a liquid solution comprising a salt of flecainide, a cyclodextrin, and an acid. The salt of flecainide is at a concentration above 60 mg/mL, the cyclodextrin is present at from about 5% (w/v) to about 50% (w/v), and the acid is present at 2 mM to 10 mM, with a pH above 5.5 when measured at room temperature.
The cyclodextrin is used to enable increased solubility of flecainide salt at high concentration while maintaining a pH above 5.5 and using only low acid levels. The cyclodextrin is optionally hydroxypropyl-b2-cyclodextrin, and the acid is optionally acetic acid.
The invention further includes unit dose and inhalation delivery concepts for acute atrial arrhythmias, including atrial fibrillation, atrial tachycardia, supraventricular tachycardia, and paroxysmal atrial fibrillation. It is presented with inhalation PK/PD concepts that include rapid onset, transient pharmacokinetics/pharmacodynamics, a pulsatile profile described as mimicking intravenous delivery, and reduced systemic plasma levels.
Claims Coverage
The document includes two independent claims covering a high-concentration liquid solution pharmaceutical composition and a unit dose of the same type of liquid solution, with defined component identity, concentration constraints, and a room-temperature pH above 5.5.
High-concentration flecainide salt liquid solution with cyclodextrin and acid at pH above 5.5
A pharmaceutical composition comprising a therapeutically effective amount of a salt of flecainide, a cyclodextrin, and an acid, wherein the composition is in the form of a liquid solution that has the salt of flecainide at a concentration above 60 mg/mL, the cyclodextrin at a concentration of from about 5% (w/v) to about 50% (w/v), the acid at a concentration of 2 mM to 10 mM, and a pH above 5.5 when measured at room temperature.
Unit dose with defined flecainide-salt amount in the high-concentration cyclodextrin/acid liquid solution
A unit dose of a pharmaceutical composition comprising a salt of flecainide, a cyclodextrin, and an acid, wherein the pharmaceutical composition is in the form of a liquid solution that has the salt of flecainide at a concentration above 60 mg/mL, the cyclodextrin at a concentration of from about 5% (w/v) to about 50% (w/v), the acid at a concentration of 2 mM to 10 mM, and a pH above 5.5 when measured at room temperature, and wherein the unit dose comprises from about 50 mg to about 350 mg of the salt of flecainide.
Across both independent claims, the inventive core is the combination of a flecainide salt at high concentration with cyclodextrin and low-molarity acid in a liquid solution having a room-temperature pH above 5.5, with the second independent claim additionally constraining the unit dose to a defined flecainide-salt mass range.
Stated Advantages
Provides therapeutic cardiac exposure with lower systemic plasma levels through an inhalation PK/PD relationship described as mimicking intravenous delivery with a pulsatile profile.
Heart-directed route is described as a treatment rationale.
Reduced drug-drug interactions and side effects are described as advantages.
Reduced burning/stinging.
Easier inhalation.
Improved organoleptic/tolerability.
Enables higher solubility of flecainide salt in a liquid solution at high concentration.
Allows a higher pH and lower acid levels to reduce irritation/cough while maintaining or increasing delivery efficiency.
Supports rapid onset with a transient pharmacokinetics/pharmacodynamics profile described as IV-mimicking.
Describes lower overall plasma exposure compared with oral or IV approaches.
Documented Applications
Inhalation therapy performance evaluation for flecainide acetate using an estimated total lung dose framework and inhalation PK/PD linked to ECG pharmacodynamic endpoints such as QRS and 94QRS.
Treatment context for atrial fibrillation, supraventricular tachycardia, and paroxysmal atrial fibrillation, with eligibility-related dose scaling described relative to intravenous delivery.
Inhalable flecainide acetate solutions formulated with hydroxypropyl-b2-cyclodextrin and acetic acid for improved organoleptic/tolerability during inhalation.
Preclinical pig pulmonary delivery study using flecainide cyclodextrin/acetate formulations, including reported dose-dependent atrial fibrillation conversion and plasma PK outcomes.
Clinical Phase 2 INSTANT (FL-002) study design and reported PK/ECG/adverse event summaries using cyclodextrin/acetic acid inhalation formulations.
Acute treatment of atrial arrhythmias, including atrial fibrillation and atrial tachycardia.
Inhalation delivery via fast pulmonary nebulization, supported by aerosol droplets having mass median aerodynamic diameter (MMAD) less than 10 bcm.
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