Antiarrhythmic formulation
Inventors
HURREY, Michael Laird • Belardinelli, Luiz • MADHAVAPEDDI, Prashanti • Schuler, Carlos
Assignees
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Publication Number
US-11007185-B2
Publication Date
2021-05-18
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 disclosed subject matter provides a kit that includes a pharmaceutical composition comprising a salt of flecainide, a cyclodextrin, and an acid, together with a receptacle and instructions for use of a nebulizer to inhalationally administer the pharmaceutical composition in aerosol to a subject. The inhalational aerosol dose contains from about 50 mg to about 250 mg of the salt of flecainide, and the aerosol droplets have a mass median aerodynamic diameter of less than 10 m. The pharmaceutical composition is provided as a liquid solution with defined concentration ranges for the flecainide salt, cyclodextrin, and acid, and a defined pH window measured at room temperature.
The disclosed inhalational flecainide acetate delivery to the heart is associated with pharmacokinetic/pharmacodynamic behavior that mimics intravenous dosing, including reduced overall systemic exposure while maintaining high, transient cardiac exposure. The disclosed comparison uses ECG pharmacodynamics including maximum QRS change (94QRS) and 94QRSmax/Cmax to compare inhalation versus IV delivery, and identifies relationships among Tmax, Cmax, AUCLast, distribution half-life, and elimination half-life.
The disclosure further includes animal pharmacokinetic/pharmacodynamic and cardioversion studies and inhalation toxicology to support the inhalational approach. It also describes formulation performance and safety considerations related to solubility/precipitation with salts, cyclodextrin solubilization, and viscosity/aerosol considerations, together with clinical context and eligibility factors.
Claims Coverage
The provided content covers one independent claim defining a flecainide-salt/cyclodextrin/acid liquid-solution kit for nebulized inhalational aerosol administration with specific dosing, droplet size, composition concentrations, and a room-temperature pH range. The independent claim includes 2 inventive features.
Nebulizer inhalational flecainide-salt cyclodextrin acid kit
A kit comprising a pharmaceutical composition that includes a salt of flecainide, a cyclodextrin, and an acid, a receptacle containing the pharmaceutical composition, and instructions for use of a nebulizer to inhalationally administer an aerosol dose to a subject, where the dose contains from about 50 mg to about 250 mg of the salt of flecainide and the aerosol droplets have a mass median aerodynamic diameter of less than 10 m.
Liquid solution concentrations and room-temperature pH window
The pharmaceutical composition is a liquid solution that has the flecainide salt at a concentration of from about 65 mg/mL to about 95 mg/mL, the cyclodextrin at a concentration of from about 10% (w/v) to about 30% (w/v), the acid at a concentration of from about 2 mM to about 10 mM, and a pH of from about 5.5 to about 6.5 when measured at room temperature.
The claim coverage centers on a nebulizer-deliverable liquid-solution kit defining the flecainide-salt/cyclodextrin/acid composition, a defined dose range and aerosol droplet size constraint, and specific concentration and room-temperature pH requirements.
Stated Advantages
Improved tolerability.
Reduced systemic exposure compared with oral or IV dosing.
Fast cardioversion and/or return to normal sinus rhythm.
Significantly shortens induced atrial fibrillation (AF) duration versus placebo.
Provides dose-dependent effects on AF dominant frequency and ventricular rate.
Causes conversion to normal sinus rhythm.
Slows AV conduction as indicated by increased atrial depolarization (Pa) and prolonged PR interval.
Inhibition of peak and late INa is described as a rationale for suppressing ectopy and pulmonary vein firing.
A lower acetate formulation is described as providing more persistent Pa prolongation and greater suppression of AF re-induction.
A lower acetate formulation is described as showing reduced gag response.
Reduced overall systemic exposure with high, transient cardiac exposure while inhalationally delivering flecainide in a manner that mimics intravenous dosing behavior.
PK and ECG relationships are described between Cmax and AF-to-sinus rhythm conversion timing.
Documented Applications
Treatment-related objectives for atrial arrhythmia indications, including atrial fibrillation and paroxysmal atrial fibrillation, and related supraventricular tachycardias such as paroxysmal supraventricular tachycardia.
Treatment-related objectives include cardioversion to normal sinus rhythm.
In vivo intratracheal pig studies using flecainide complexed with hydroxypropyl-b2-cyclodextrin (HPb2CD) to assess induced atrial fibrillation outcomes and ECG/physiologic readouts.
A clinical program for an ongoing Phase 2 study (FLE-002, INSTANT) of inhaled flecainide acetate oral inhalation solution, including dosing and safety/ECG/QRS observations, and evaluation of AF-to-sinus rhythm conversion in relation to PK measures such as Cmax.
Inhalational delivery of flecainide to the heart using nebulizer aerosol administration, including assessment using ECG pharmacodynamics (94QRS) in comparison to IV dosing.
Cardioversion studies and cardioversion-related outcomes in the context of atrial arrhythmia models described in the document.
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