Antiarrhythmic formulation

Abstract

To provide pharmaceutical compositions comprising an antiarrhythmic agent for treatment of a heart condition via inhalation, and methods for treatment.SOLUTION: Methods for treating a heart condition include the step for administering by inhalation of an effective amount of at least one antiarrhythmic pharmaceutical agent to a patient in need thereof. Nebulized drug product and kits are also disclosed.SELECTED DRAWING: Figure 23A

Description

[Technical field]

[0001] cross reference

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 881,689, filed August 1, 2019, U.S. Nonprovisional Application No. 16 / 901,909, filed June 15, 2020, and U.S. Nonprovisional Application No. 16 / 901,941, filed June 15, 2020, each of which is incorporated by reference in its entirety into this specification. [Background technology]

[0002]

[0002] Cardiac arrhythmia (also cardiac rhythm disorder) is a term describing any of a large heterogeneous group of conditions in which abnormal electrical activity occurs in the heart. The heart may beat too fast or too slow, and may be regular or irregular.

[0003]

[0003] The treatment of atrial arrhythmias is an area with a high level of unmet clinical need. Many of the drugs currently in use have been on the market since the early 1980s and 1990s and are often inadequate due to either a lack of efficacy or a side effect profile that is often cardiac-related and requires extensive monitoring of the patient.

[0004] What is needed for rapid and safe cardiac defibrillation (a solution to arrhythmias) is: (a) creates little or no risk of ventricular rate acceleration prior to cardioversion; (b) slowing atrioventricular (AV) conduction to allow simultaneous ventricular rate control and cardiac defibrillation; (c) should have little or no effect on prolonging the QRS interval beyond the upper limit of normal (approximately 120 milliseconds) with a low risk of torsades de pointes; and (d) should have little or no negative inotropic effect; they should have only a mild negative chronotropic effect without the risk of severe bradycardia when the patient is returned to sinus rhythm. (e) little or no hypotension. (f) Does not produce adverse events other than those that are mild, transient (i.e., lasting no more than a few minutes), do not require treatment, and have no sequelae. It is treatment.

[0005] None of the currently approved drug products exhibit these properties. The high oral and intravenous (IV) doses required to compensate for absorption, metabolism and dilution result in long-term high blood concentrations that can lead to dangerous adverse cardiac events such as arrhythmia induction, QT prolongation and torsades de pointes. FELDMAN et al., “Analysis of Coronary Response to Various Doses of Intracoronary Nitroglycerin,” Circulation, 66:321-327 (1982); and BARBATO et al., “Adrenergic Receptors in Human Atherosclerotic Coronary Arteries,” Circulation, 111:288-294 (2005). Concomitant conditions also limit the use of ideal drugs in some patients, as is the case with intravenous adenosine. GAGLIONE et al., “Is There Coronary Vasoconstriction after Intracoronary Beta-adrenergic Blockade in Patients with Coronary Artery Disease,” J Am Coll Cardiol, 10:299-310 (1987). Injections of drugs such as verapamil and diltiazem are used to treat patients with close It is a second-line treatment that requires monitoring. NOGUCHI et al., “Effects of Intracoronary Propranolol on Coronary Blood Flow and Regional Myocardial Function in Dogs,” Eur J Pharmacol., 144(2):201-10 (1987); and ZALEWSKI et al., “Myocardial Protection during Transient Coronary Artery Occlusion in Man: Beneficial Effects of Regional Beta-adrenergic Blockade,” Circulation, 73:734-73 (1986).

[0006] Paroxysmal atrial fibrillation (PAF) is a subset of the total atrial fibrillation (AF) population, estimated to be 25-30% of the total AF population. Approximately 2.5 million patients in the United States suffer from AF. The PAF patient population is estimated to be between 900,000 and 1.5 million worldwide.

[0007]

[0007] Paroxysmal supraventricular tachycardia (PSVT) is a type of arrhythmia that affects approximately 500,000-600,000 patients in the United States.

[0008] Ablation techniques, such as RF ablation, are often used to treat arrhythmias. However, ablation is expensive, with costs typically ranging from about $25,000 to $36,000 per procedure. Despite the high cost, ablation may not completely correct the arrhythmia. In many cases, multiple ablation procedures are required to achieve a good therapeutic outcome.

[0008]

[0009] Oral medications, e.g., pills, tend to require high doses and long durations for onset of action. Oral doses of cardiac medications generally tend to be well above 1 mg. Because these patients typically take multiple medications, high doses increase the chance of side effects and drug-drug interactions. Onset times for oral cardiovascular medications tend to be around 60 minutes. Oral antiarrhythmics have been developed primarily for prevention, whereas treatment is administered intravenously.

[0009]

[0010] Intravenous injections usually require a hospital environment to administer the drug, typically involving a visit to the emergency room (ER). These expenses make this treatment more expensive than treatments that allow patients to self-administer the drug. Intravenous injections require a higher dose than is actually required by the heart to compensate for dilution and metabolism. Drugs injected IV pass through the right side of the heart and then the lungs to reach the left side of the heart. The drug remains in the bloodstream at high concentrations, bathing all organs and tissues with this high concentration of drug until it is excreted through the kidneys or other metabolic pathways (e.g., liver). As a result, IV drugs can produce undesirable side effects. Drugs administered via the IV route are significantly diluted in the venous blood volume and lungs before reaching the cardiac circulation.

[0010]

[0011] Injecting drugs directly into the heart is usually a last resort taken by cardiologists as a life-saving measure in emergency situations. The doses of drugs injected directly into the heart in this manner are usually less than their IV and / or oral doses.

[0011]

[0012] In some cases, unplanned surgery is necessary to save the patient's life. Of course, unplanned surgery is expensive and carries high risks for the patient.

[0013] Cardiac arrhythmias are associated with disabling symptoms such as a tightness around the chest, palpitations, fatigue, shortness of breath and in some cases chest pain.

[0012]

[0014] Considering the above, arrhythmias often lead to emergency room (ER) visits where intravenous drugs are administered, may require prolonged hospital stays, and in some cases, unplanned invasive surgery. Pipeline Insights: Antiarrhythmics, Datamonitor (06 / 2006); and TWISS et al., “Efficacy of Calcium Channel Blockers as Maintenance Therapy for Asthma,” British J of Clinical Pharmacology (November 2001). Summary of the Invention [Problem to be solved by the invention]

[0013]

[0015] However, there remains a need for improved compositions and methods for treating cardiac conditions. Accordingly, there also remains a need for methods of making these compositions. [Means for solving the problem]

[0014]

[0016] In some aspects, described herein is a pharmaceutical composition comprising a therapeutically effective amount of a salt of flecainide, the pharmaceutical composition being in the form of a liquid solution having a concentration of the salt of flecainide greater than 60 mg / mL.

[0015]

[0017] In some cases, the pharmaceutical composition further comprises a cyclodextrin. In some cases, the pH of the solution is greater than 5.5 when the pH is measured at room temperature. In some cases, the pH of the solution is about 5.5 to about 6.5 when the pH is measured at room temperature. In some cases, the pharmaceutical composition further comprises a cyclodextrin and the pH of the solution is greater than 5.5 when the pH is measured at room temperature. In some cases, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatized α-cyclodextrin, derivatized β-cyclodextrin, and derivatized γ-cyclodextrin. In some cases, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin The cyclodextrin is selected from the group consisting of cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, and sulfoalkylether-γ-cyclodextrin. In some cases, the cyclodextrin comprises hydroxypropyl-β-cyclodextrin. In some cases, the concentration of the cyclodextrin in the pharmaceutical composition is about 1% (w / v) to about 80% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is about 15% (w / v) to about 25% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is from about 10% (w / v) to about 30% (w / v) of the solution.In some cases, the concentration of the cyclodextrin is at least about 5% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is at least about 10% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is about 20% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is up to about 20% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is about 25% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is up to about 25% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is about 10% (w / v) to about 30% (w / v) of the solution. In some cases, the concentration of the salt of flecainide is up to about 200 mg / mL. In some cases, the concentration of the flecainide salt is about 65 mg / mL to about 130 mg / mL. In some cases, the concentration of the flecainide salt is about 65 mg / mL to about 95 mg / mL. In some cases, the concentration of the flecainide salt is about 70 mg / mL to about 115 mg / mL. In some cases, the concentration of the flecainide salt is about 100 mg / mL. In some cases, the concentration of the flecainide salt is about 75 mg / mL. In some cases, the flecainide salt is selected from the group consisting of flecainide acetate, flecainide hydrochloride, flecainide citrate, flecainide phosphate and flecainide nitrate. In some cases, the flecainide salt comprises flecainide acetate. In some cases, the flecainide salt comprises flecainide hydrochloride.

[0016]

[0018] In some cases, the pharmaceutical composition further comprises an acid. In some cases, the acid is acetic acid, citric acid, nitric acid, hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbic acid, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactic acid, proline acid, glycerol ... The acid is selected from the group consisting of pionic acid, sorbic acid, stearic acid, and succinic acid. In some cases, the concentration of the acid in the pharmaceutical composition is about 2 mM to about 200 mM. In some cases, the concentration of the acid in the pharmaceutical composition is about 2 mM to about 50 mM. In some cases, the concentration of the acid in the pharmaceutical composition is about 2 mM to about 10 mM. In some cases, the concentration of the acid is up to about 50 mM. In some cases, the concentration of the acid is about 20 mM. In some cases, the concentration of the acid is about 5 mM. In some cases, the acid includes acetic acid. In some cases, the concentration of the acetic acid is about 5 mM. In some cases, the acid includes citric acid. In some cases, the concentration of the citric acid is about 5 mM. In some cases, the acid comprises a mixture of acids selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbic acid, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactic acid, propionic acid, sorbic acid, stearic acid and succinic acid. In some cases, the acid comprises a mixture of acids selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid. In some cases, the acid comprises hydrochloric acid.

[0017]

[0019] In some cases, the salt of flecainide includes flecainide acetate and the acid includes acetic acid. In some cases, the pH of the solution is up to about 6.5. In some cases, the pH of the solution is about 5.9. In some cases, the pH of the solution is about 5.5 to about 6.5.

[0018]

[0020] In some cases, the pharmaceutical composition further comprises an artificial sweetener configured to enhance the organoleptic properties of the pharmaceutical composition. In some cases, the artificial sweetener is selected from the group consisting of acesulfame potassium, aspartame, cyclamate, mogroside, saccharin, stevia, sucralose, neotame, mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, and pharma- ceutically acceptable salts thereof. In some cases, the artificial sweetener comprises saccharin. In some cases, the artificial sweetener comprises a salt of saccharin. In some cases, the artificial sweetener comprises sodium saccharin. In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 1% (w / v). In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 1% (w / v). In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 0.05% (w / v). In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 0.01% (w / v).

[0019]

[0021] In some cases, the pharmaceutical composition is formulated for administration by inhalation. In some cases, the pharmaceutical composition is a nebulized solution comprising nebulized droplets having a mass median aerodynamic diameter of less than 10 μm.

[0020]

[0022] In some embodiments, a unit dose of any pharmaceutical composition provided herein comprising about 50 mg to about 350 mg of a salt of flecainide is described herein.

[0023] In some cases, the dosage unit contains about 60 mg to about 150 mg of a salt of flecainide. In some cases, the dosage unit contains about 75 mg to about 125 mg of a salt of flecainide. In some cases, the dosage unit contains about 250 mg to about 350 mg of a salt of flecainide. In some cases, the dosage unit contains about 100 mg to about 250 mg of a salt of flecainide. In some cases, the dosage unit contains about 315 mg of a salt of flecainide. In some cases, the dosage unit contains about 260 mg of a salt of flecainide. In some cases, the dosage unit contains about 230 mg of a salt of flecainide. In some cases, the dosage unit contains about 200 mg of a salt of flecainide.

[0021]

[0024] In some aspects, kits are described herein that include any pharmaceutical composition or any dosage unit described herein and instructions for use of the pharmaceutical composition for treating a cardiac condition. In some cases, the cardiac condition includes atrial fibrillation. In some cases, the atrial fibrillation includes tachycardia. In some cases, the atrial arrhythmia includes supraventricular tachycardia, paroxysmal ... The present invention relates to a method for treating atrial fibrillation comprising administering to a patient a cardiac tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes of persistent and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter or isolated atrial fibrillation. In some cases, the kit further comprises a container containing the pharmaceutical composition. In some cases, the container is selected from the group consisting of a vial, a syringe, a capsule, a blow-fill-seal, a blister, a cartridge and an ampoule.

[0022]

[0025] In some aspects, a system is described herein that includes any pharmaceutical composition and a nebulizer provided herein. In some cases, the system further includes instructions for use of the nebulizer and pharmaceutical composition for the treatment of a cardiac condition. In some cases, the pharmaceutical composition is formulated for administration by the nebulizer, and the nebulizer is selected from the group consisting of a breath-actuated jet nebulizer, a vibrating mesh nebulizer, and an ultrasonic nebulizer. In some cases, the nebulizer is selected from the group consisting of a breath-actuated jet nebulizer, a vibrating mesh nebulizer, and an ultrasonic nebulizer. In some cases, the system further includes instructions for use of the nebulizer and pharmaceutical composition for the treatment of atrial arrhythmia. In some cases, the system further includes instructions for use of the nebulizer to administer a dose of the pharmaceutical composition by aerosol to a subject by inhalation. In some cases, the atrial arrhythmia includes tachycardia. In some cases, the atrial arrhythmia is selected from the group consisting of supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes in sustained and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter or isolated atrial fibrillation. In some cases, the nebulizer is configured to deliver a dose of the pharmaceutical composition in an aerosol, the aerosol of the pharmaceutical composition having droplets with a median aerodynamic diameter of less than 10 μm. In some cases, the nebulizer is a breath-actuated nebulizer. In some cases, the nebulizer is a jet nebulizer. In some cases, the instructions include instructions for using the nebulizer to inhalatively administer a dose of the pharmaceutical composition to a subject in an aerosol, the dose including about 50 mg to about 150 mg of a salt of flecainide. In some cases, the pharmaceutical composition is in the form of a liquid solution having: (i) a salt of flecainide in a concentration of about 65 mg / mL to about 95 mg / mL; (ii) cyclodextrin in a concentration of about 10% (w / v) to about 30% (w / v) of the solution; and (iii) a pH of about 5.5 to about 6.5 when the pH is measured at room temperature. In some cases, the concentration of the salt of flecainide is about 65 mg / mL to about 95 mg / mL. In some cases, the concentration of the salt of flecainide is about 70 mg / mL to about 80 mg / mL.In some cases, the instructions include instructions for using the nebulizer to deliver the pharmaceutical composition in an aerosolized dose containing about 90 mg of a salt of flecainide.In some cases, the instructions include instructions for using the nebulizer to deliver the pharmaceutical composition in an aerosolized dose containing about 120 mg of a salt of flecainide.

[0023]

[0026] In some aspects, a system is described herein that includes a pharmaceutical composition comprising a salt of flecainide, a cyclodextrin, and an acid; a nebulizer configured to deliver the pharmaceutical composition as droplets having a mass median aerodynamic diameter of less than 10 μm; and instructions for use of the nebulizer to deliver the pharmaceutical composition in an aerosolized dose containing about 50 mg to about 250 mg of a salt of flecainide, wherein the pharmaceutical composition is in the form of a liquid solution having (i) a salt of flecainide at a concentration of 65 mg / mL to 100 mg / mL; (ii) a cyclodextrin at a concentration of about 10% (w / v) to about 30% (w / v) of the solution; and (iii) a pH of about 5.5 to about 6.5 when measured at room temperature. In some embodiments, the system further includes a nose clip. The nose clip may be used to obstruct the passage of air through the subject's nose upon inhalation and increase the proportion of the total inhaled dose that is aerosol emitted by the nebulizer. In some embodiments, the dose contains about 150 mg to about 250 mg of a salt of flecainide.In some embodiments, the dose contains about 200 mg of a salt of flecainide.

[0024]

[0027] In some aspects, a method of treating a subject suffering from a cardiac condition comprises administering a compound in the form of a liquid solution. The method described herein comprises administering to a subject a pharmaceutical composition of the present invention by inhalation, wherein the pharmaceutical composition comprises a therapeutically effective amount of a salt of flecainide, and the concentration of the salt of flecainide in the pharmaceutical composition is greater than 60mg / mL.In some cases, the pharmaceutical composition further comprises cyclodextrin.In some cases, the pH of the solution is greater than 5.5 when the pH is measured at room temperature.

[0025]

[0028] In some aspects, a method of treating a human subject suffering from a cardiac condition, comprising administering to the subject by inhalation within about 10 minutes a pharmaceutical composition in the form of a liquid solution, wherein the pharmaceutical composition comprises a therapeutically effective amount of a salt of flecainide, and the administration results in a peak plasma concentration (C) of the salt of flecainide in the subject that is at least 200 ng / mL. max Described herein is a method for producing a peak plasma concentration (C) of a salt of flecainide in a subject that is at least 200 ng / mL. In some cases, the concentration of the salt of flecainide in the pharmaceutical composition is greater than 60 mg / mL of solution. In some cases, the pharmaceutical composition further comprises a cyclodextrin. In some cases, administration of the pharmaceutical composition produces a peak plasma concentration (C) of the salt of flecainide in the subject that is at least 200 ng / mL. max In some cases, administration of the pharmaceutical composition results in a peak plasma concentration (C) of the salt of flecainide in the subject that is at least 250 ng / mL. max ) In some cases, C max is about 250 ng / mL to about 1000 ng / mL. max is about 300 ng / mL to about 700 ng / mL. max is about 400 ng / mL to about 600 ng / mL. In some cases, administration of the pharmaceutical composition occurs within about 10 minutes. In some cases, administration of the pharmaceutical composition occurs within about 5 minutes. In some cases, administration of the pharmaceutical composition occurs by one or two inhalations. In some cases, administration of the pharmaceutical composition occurs by two inhalations separated by a break of about 10 seconds to about 1 minute. In some cases, administration occurs by a nebulizer. In some cases, the nebulizer is a breath-actuated nebulizer. In some cases, the nebulizer is a jet nebulizer. In some cases, the nebulizer is a vibrating mesh nebulizer. In some cases, the nebulizer is an ultrasonic nebulizer.

[0026]

[0029] In some cases, about 50 mg to about 150 mg of a flecainide salt is administered to the subject by inhalation. In some cases, about 75 mg to about 125 mg of a flecainide salt is administered to the subject by inhalation. In some cases, about 250 mg to about 350 mg of a flecainide salt is administered to the subject by inhalation. In some cases, about 150 mg to about 250 mg of a flecainide salt is administered to the subject by inhalation. In some cases, about 90 mg of a flecainide salt is administered to the subject by inhalation. In some cases, about 120 mg of a flecainide salt is administered to the subject by inhalation. In some cases, about 150 mg of a flecainide salt is administered to the subject by inhalation. In some cases, about 200 mg of a flecainide salt is administered to the subject by inhalation. In some cases, the cardiac condition includes atrial arrhythmia. In some cases, the atrial arrhythmia includes tachycardia. In some cases, the atrial arrhythmia is selected from the group consisting of supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes in sustained and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter, or isolated atrial fibrillation. In some cases, the method includes aerosolizing the pharmaceutical composition by forming droplets having a median aerodynamic diameter of less than 10 μm. In some cases, the method includes acute treatment after detection of the atrial arrhythmia. In some cases, the subject has normal sinus rhythm within 10 minutes after administration. In some cases, the subject has normal sinus rhythm within 8 minutes after administration. In some cases, the subject has normal sinus rhythm within 5 minutes after administration. In some cases, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatized α-cyclodextrin, derivatized β-cyclodextrin, and derivatized γ-cyclodextrin. In some cases, the cyclodextrin may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, In some cases, the cyclodextrin is selected from the group consisting of cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin dimaltosyl-β-cyclodextrin, succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, and sulfoalkylether-γ-cyclodextrin. In some cases, the cyclodextrin comprises hydroxypropyl-β-cyclodextrin. In some cases, the concentration of the cyclodextrin in the pharmaceutical composition is about 1% (w / v) to about 80% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is about 15% (w / v) to about 25% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is about 10% (w / v) to about 30% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is at least about 5% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is at least about 10% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is about 20% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is about 22.5% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is up to about 20% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is up to about 25% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is up to about 23% (w / v) of the solution. In some cases, the concentration of the cyclodextrin is up to about 22.5% (w / v) of the solution. In some cases, the concentration of the flecainide salt is up to about 200 mg / mL. In some cases, the concentration of the flecainide salt is from about 65 mg / mL to about 130 mg / mL. In some cases, the concentration of the flecainide salt is from about 65 mg / mL to about 95 mg / mL.In some cases, the concentration of the flecainide salt is about 70 mg / mL to about 115 mg / mL. In some cases, the concentration of the flecainide salt is about 100 mg / mL. In some cases, the concentration of the flecainide salt is about 75 mg / mL. In some cases, the flecainide salt is selected from the group consisting of flecainide acetate, flecainide hydrochloride, flecainide citrate, flecainide phosphate, and flecainide nitrate. In some cases, the flecainide salt comprises flecainide acetate. In some cases, the flecainide salt comprises flecainide hydrochloride. In some cases, the pharmaceutical composition further comprises an acid. In some cases, the acid is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbic acid, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactic acid, propionic acid, sorbic acid, stearic acid, and succinic acid. In some cases, the acid is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, and sulfuric acid. In some cases, the concentration of the acid in the pharmaceutical composition is about 2 mM to about 200 mM. In some cases, the concentration of the acid in the pharmaceutical composition is about 2 mM to about 50 mM. In some cases, the concentration of the acid in the pharmaceutical composition is about 2 mM to about 10 mM. In some cases, the concentration of the acid is up to about 50 mM. In some cases, the concentration of the acid is about 20 mM. In some cases, the concentration of the acid is about 5 mM. In some cases, the acid includes acetic acid. In some cases, the concentration of acetic acid is about 5 mM. In some embodiments, the concentration of citric acid is 3.5 mM. In some cases, the acid comprises a mixture of acids selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, and sulfuric acid. In some cases, the acid comprises hydrochloric acid. In some cases, the salt of flecainide comprises flecainide acetate and the acid comprises acetic acid. In some cases, the pH of the solution is about 4.5 to about 6.5, about 5 to about 6.5, about 5 to about 6.2, or about 5.2 to about 5.9. In some cases, the pH of the solution is up to about 6.5. In some cases, the pH of the solution is about 5.5 to about 6.5. In some cases, the pH of the solution is about 5.9. In some cases, the pH of the solution is about 5.2. In some cases, the salt of flecainide comprises flecainide acetate. In some cases, the pharmaceutical composition further comprises a sweetener.In some cases, the artificial sweetener is acesulfame. carium, aspartame, cyclamate, mogrosides, saccharin, stevia, sucralose, neotame, alcohol neotame, mannitol, so The artificial sweetener is selected from the group consisting of maltitol, xylitol, lactitol, isomalt, maltitol, and pharma- ceutically acceptable salts thereof. In some cases, the artificial sweetener comprises saccharin. In some cases, the artificial sweetener comprises a salt of saccharin. In some cases, the artificial sweetener comprises sodium saccharin. In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 1% (w / v). In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 0.05% (w / v). In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 0.01% (w / v).

[0027]

[0030] In some aspects, disclosed herein is a method of producing a liquid formulation for the treatment of a human subject suffering from a cardiac condition, the method comprising administering to the subject by inhalation a pharmaceutical composition described herein.

[0028]

[0031] In some aspects, disclosed herein is a method of treating a human subject suffering from a cardiac condition, comprising administering to the subject a dosage unit described herein by inhalation. In some cases, the cardiac condition includes atrial fibrillation. In some cases, the atrial fibrillation is recurrent atrial fibrillation. In some cases, the atrial fibrillation is paroxysmal atrial fibrillation. In some cases, the subject has a systolic blood pressure greater than about 90 mmHg. In some cases, the subject has a systolic blood pressure between about 100 mmHg and about 160 mmHg. In some cases, the subject has a ventricular rate of 170 BPM or less. In some cases, the subject has a ventricular rate of about 80 BPM to about 155 BPM. In some cases, the subject is 85 years old or younger. In some cases, the subject is 18 to 85 years old. In some cases, the subject has undergone cardiac ablation more than 3 months prior to administration. In some cases, the subject is receiving an ongoing prescription of oral flecainide or a pharma- ceutically acceptable salt thereof. In some cases, the atrial fibrillation has an onset occurring within about 48 hours prior to administration. In some cases, the atrial fibrillation has an onset occurring within about 1 hour to about 48 hours prior to the treatment prior to administration. In some cases, the subject does not exhibit a condition comprising an abnormal left ventricular ejection fraction within 6 months prior to administration. In some cases, the subject does not exhibit a condition comprising heart failure of class 2 or higher as classified by the New York Heart Association functional classification within 6 months prior to administration. In some cases, the subject does not exhibit a condition comprising myocardial infarction or a history of myocardial infarction. In some cases, the subject does not exhibit a condition comprising hemodynamic instability or cardiac instability. In some cases, the subject does not exhibit a condition comprising an episode of atrial flutter within 6 months prior to administration. In some cases, the subject has not undergone cardiac surgery for a condition within 6 months prior to administration.

[0029]

[0032] In some aspects, disclosed herein is a method of preparing a liquid pharmaceutical composition, comprising combining (a) water; (b) a pH adjusting agent; (c) flecainide or a pharma- ceutically acceptable salt thereof; and (d) cyclodextrin. In some cases, (i) the concentration of flecainide or a pharma- ceutically acceptable salt thereof is about 65 mg / mL to about 95 mg / mL in the pharmaceutical composition, (ii) the concentration of cyclodextrin in the pharmaceutical composition is about 10% (w / v) to about 30% (w / v), and (iii) the pH of the pharmaceutical composition at room temperature is about 5.5 to about 6.5. In some cases, the combining step includes (a) providing water; (b) contacting a portion of the water with flecainide or a pharma- ceutically acceptable salt thereof, cyclodextrin and a pH adjusting agent in a vessel; and (c) adding a next portion of the water to the vessel to provide a pharmaceutical composition, wherein (i) the concentration of flecainide or a pharma- ceutically acceptable salt thereof is about 65 mg / mL to about 95 mg / mL in the pharmaceutical composition, (ii) the concentration of cyclodextrin in the pharmaceutical composition is about 10% (w / v) to about 30% (w / v), and (iii) the pH of the pharmaceutical composition at room temperature is about 5.5 to about 6.5. In some cases, the pH adjusting agent is selected from acetate ions, citrate ions, nitrate ions, The pH adjuster comprises an ion selected from the group consisting of chloride, sulfate, maleate, tartrate, phosphate, aconitate, adipate, ascorbate, benzoate, caprylate, cholic acid, formate, glutamate, lactate, propionate, sorbate, stearate and succinate. In some cases, the pH adjuster is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbate, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactate, propionic acid, sorbic acid, stearic acid and succinic acid. In some cases, the pH adjuster is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid. In some cases, the pH adjuster comprises a mixture of acids selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid. In some cases, the concentration of the pH adjuster in the pharmaceutical composition is about 2 mM to about 50 mM. In some cases, the concentration of the pH adjuster in the pharmaceutical composition is about 2 mM to about 10 mM. In some cases, the pH adjuster comprises acetic acid. In some cases, the concentration of the acetic acid in the pharmaceutical composition is about 5 mM. In some cases, the pH adjuster comprises citric acid. In some cases, the concentration of the citric acid in the pharmaceutical composition is about 5 mM. In some cases, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatized α-cyclodextrin, derivatized β-cyclodextrin, and derivatized γ-cyclodextrin.In some cases, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin The cyclodextrin is selected from the group consisting of dimaltosyl-β-cyclodextrin, succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, and sulfoalkylether-γ-cyclodextrin. In some cases, the cyclodextrin comprises hydroxypropyl-β-cyclodextrin. In some cases, the concentration of the cyclodextrin in the pharmaceutical composition is about 10% (w / v) to about 30% (w / v). In some cases, the method further comprises adding a sweetener. In some cases, the sweetener is selected from the group consisting of acesulfame potassium, aspartame, cyclamate, mogroside, saccharin, stevia, sucralose, neotame, mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, and pharma- ceutically acceptable salts thereof. In some cases, the sweetener comprises saccharin. In some cases, the sweetener comprises a salt of saccharin. In some cases, the sweetener comprises sodium saccharin. In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 1% (w / v). In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 0.05% (w / v). In some cases, the concentration of the sweetener in the pharmaceutical composition is about 0.001% (w / v) to about 0.01% (w / v).In some cases, a pharma- ceutically acceptable salt of flecainide is added. In some cases, the pharma- ceutically acceptable salt of flecainide is selected from the group consisting of flecainide acetate, flecainide hydrochloride, flecainide citrate, flecainide phosphate and flecainide nitrate. In some cases, the pharma- ceutically acceptable salt of flecainide includes flecainide acetate. In some cases, the pharma- cetically acceptable salt of flecainide includes flecainide hydrochloride. In some cases, the method further comprises packaging the pharmaceutical composition in a dosage unit form. In some cases, the method further comprises packaging the pharmaceutical composition in a dosage unit form, the dosage unit form being about 50 mg to about 350 mg of pharma- cetically acceptable. The dosage unit form comprises about 60 mg / mL to about 150 mg of a pharma- ceutically acceptable salt of flecainide. In some cases, the dosage unit form comprises about 75 mg to about 125 mg of a pharma- ceutically acceptable salt of flecainide. In some cases, the dosage unit form comprises about 250 mg to about 350 mg of a pharma- ceutically acceptable salt of flecainide. In some cases, the dosage unit form comprises about 150 mg to about 250 mg of a pharma- ceutically acceptable salt of flecainide. In some cases, the dosage unit form comprises about 90 mg of a pharma- ceutically acceptable salt of flecainide. In some cases, the dosage unit form comprises about 120 mg of a pharma- ceutically acceptable salt of flecainide. In some cases, the dosage unit form comprises about 200 mg of a pharma- ceutically acceptable salt of flecainide. In some cases, the dosage unit form further comprises a container. In some cases, the container is selected from the group consisting of a vial, a syringe, a capsule, a blow-fill-seal, a blister, a cartridge, and an ampoule. Incorporation by Reference

[0033] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0030]

[0034] The novel features of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth exemplary embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings, in which: [Brief description of the drawings]

[0031] [Figure 1]

[0035] FIG. 2 is a schematic diagram showing the complex formation between hydroxypropyl-β-cyclodextrin and flecainide acetate in a representative pharmaceutical formulation. [Diagram 2]

[0036] 1 is a graph outlining the pharmacokinetic profiles of three different flecainide formulations when delivered by intravenous infusion in a porcine model of atrial fibrillation. [Figure 3A]

[0037] FIG. 1 is a graph outlining the pharmacokinetic profile (plasma concentration of flecainide acetate) of two different flecainide formulations when delivered by intratracheal instillation at a dose of 0.75 mg / kg in a porcine model of atrial fibrillation. [Figure 3B]

[0038] FIG. 1 is a graph outlining the pharmacokinetic profile (plasma concentration of flecainide acetate) of two different flecainide formulations when delivered by intratracheal instillation at a dose of 1 mg / kg in a porcine model of atrial fibrillation. [Figure 4A]

[0039] 4A and 4B are graphs outlining the pharmacodynamic profiles (QRS interval duration and atrial depolarization, respectively) of two different flecainide formulations when delivered by intratracheal instillation at a dose of 0.75 mg / kg in a porcine model of atrial fibrillation. [Figure 4B] 4A and 4B are graphs outlining the pharmacodynamic profiles (QRS interval duration and atrial depolarization, respectively) of two different flecainide formulations when delivered by intratracheal instillation at a dose of 0.75 mg / kg in a porcine model of atrial fibrillation. [Figure 4C]

[0040] 4C and 4D are graphs outlining the pharmacodynamic profiles (QRS interval duration and atrial depolarization, respectively) of two different flecainide formulations when delivered by intratracheal instillation at a dose of 1 mg / kg in a porcine model of atrial fibrillation. [Figure 4D] 4C and 4D are graphs outlining the pharmacodynamic profiles (QRS interval duration and atrial depolarization, respectively) of two different flecainide formulations when delivered by intratracheal instillation at a dose of 1 mg / kg in a porcine model of atrial fibrillation. [Diagram 5]

[0041] FIG. 1 is a schematic diagram of the experimental design in Example 9. [Figure 6]

[0042] 1 is a graph outlining the plasma concentrations of flecainide acetate when a representative HPβCD-flecainide formulation is delivered by intratracheal instillation at two different doses in a porcine model of atrial fibrillation. [Figure 7]

[0043] FIG. 1 outlines the duration of atrial fibrillation in a porcine model in response to different treatments. [Figure 8]

[0044] FIG. 1 shows representative examples of AF conversion in a porcine model in response to different treatments. [Figure 9]

[0045] 1 is a graph outlining the dominant frequency during atrial fibrillation in a porcine model in response to different treatments. [Figure 10]

[0046] 1 is a graph outlining ventricular rate in a porcine model in response to different treatments. [Figure 11]

[0047] 1 is two graphs outlining heart rate in a porcine model of atrial fibrillation in response to intratracheal instillation of a representative flecainide formulation at doses of 0.5 mg / kg and 1.0 mg / kg, respectively. [Figure 12]

[0048] 1 is a graph outlining the duration of atrial fibrillation in a porcine model in response to different treatments. [Figure 13]

[0049] 1 is a graph outlining atrial depolarization in a porcine model in response to different treatments. [Figure 14]

[0050] 1 is a graph outlining the PR interval in a porcine model in response to different treatments. [Figure 15]

[0051] 1 is a graph outlining QRS duration in a porcine model in response to different treatments. [Figure 16]

[0052] 1 is a graph outlining the duration of atrial fibrillation when atrial fibrillation is re-induced in a porcine model in response to different treatments. [Figure 17]

[0053] 1 is a graph outlining ventricular rate in a porcine model in response to different treatments. [Figure 18]

[0054] 1 is a graph outlining mean arterial pressure in a porcine model in response to different treatments. [Figure 19]

[0055] 1 is a graph outlining left ventricular contractility in a porcine model in response to different treatments. [Figure 20]

[0056] 1 is a graph outlining the plasma concentrations of flecainide acetate in a porcine model in response to different treatments. [Figure 21]

[0057] 1 is a graph summarizing the magnitude of prolongation of QRS interval duration (ΔQRSmax) in individual human subjects following inhalation of formulations of flecainide as described in Table 19. [Figure 22A]

[0058] FIG. 12 is a graph outlining the peak plasma concentrations (Cmax) of flecainide in individual human subjects following inhalation of flecainide formulations listed in Table 19. The coefficients of variation (%CV) in Cmax values ​​were 111, 83, 67, and 55 for the 60

[65] , 90

[45] , 120

[75] CD, 120

[75] iCD-SAC dose cohorts, respectively. [Figure 22B]

[0059] 1 is a graph summarizing the peak plasma concentrations (Cmax) of flecainide in individual human subjects following inhalation of CD and iCD flecainide formulations as set forth in Table 19. [Figure 22C]

[0060] 1 is a graph summarizing the peak plasma concentrations (Cmax) of flecainide in individual human subjects undergoing cardiac defibrillation following inhalation of CD and iCD flecainide formulations as set forth in Table 19. [Figure 23A]

[0061] 1 is a graph summarizing cardiac defibrillation rates in human subjects as categorized by administered formulation as described in Table 19. [Figure 23B]

[0062] 1 is a graph summarizing cardiac defibrillation rates in human subjects as classified by Cmax of flecainide measured after inhalation of flecainide formulations listed in Table 19. [Figure 23C]

[0063] 1 is a graph summarizing cardiac defibrillation rates in human subjects with ventricular rates of >80 and <155 bpm at screening, as categorized by Cmax of flecainide measured after inhalation of flecainide formulations listed in Table 19. [Figure 23D]

[0064] 1 is a graph outlining cardiac defibrillation rates in human subjects as categorized by observed Cmax (<250 ng / mL or >250 ng / mL) across all dose cohorts. [Figure 24]

[0065] 1 is a graph outlining the time from the end of flecainide inhalation to conversion of atrial fibrillation to normal sinus rhythm in human subjects administered the formulations described in Table 19. [Diagram 25]

[0066] FIG. 14 is a graph summarizing cardiac defibrillation rates in human subjects categorized by subjects with a ventricular rate of <80 bpm at screening and subjects with a ventricular rate of ≧80 and ≦155 bpm at screening, and further categorized by formulation administered (listed in Table 19). [Figure 26]

[0067] Figure 26A is a graph outlining the negative inotropic load of pulmonary and intravenous delivery of flecainide observed in animals. Figure 26B is a graph outlining the correlation between reduced left ventricular contractility (LV dP / dt max) and QRS complex prolongation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032]

[0068] In summary, the present disclosure relates to a novel formulation comprising relatively high concentration of flecainide for treating (e.g. cardiac arrhythmic) cardiac conditions in a subject in need of treatment.In some aspects, a method of treatment is provided herein, comprising administering a novel formulation comprising relatively high concentration of flecainide to treat (e.g. cardiac arrhythmic) cardiac conditions in a subject in need of treatment.

[0033]

[0069] In some embodiments, the pharmaceutical compositions and methods of treatment provided herein are advantageous in providing a fast, effective and safe therapeutic solution for cardiac conditions, such as arrhythmias, e.g., atrial arrhythmias. In some embodiments, the present disclosure relates to inhalation administration of pharmaceutical compositions in the form of solutions comprising salts of flecainide.

[0034]

[0070] In some embodiments, as shown in human subject studies of the pharmacokinetics and pharmacodynamics of inhaled administration of flecainide acetate (e.g., clinical trials FLE-001, FLE-003 (in healthy subjects) and FLE-002 (in patients) sponsored by InCarda Therapeutics, Inc.), the drug mass nebulization rate contributes to the efficiency of inhalation therapy. In some embodiments, it is not expected that a human subject will continuously inhale nebulized drug solution for longer than approximately 4.5 minutes without a break. Long inhalation periods (e.g., longer than 5 minutes) may cause fatigue, inadequate or poor compliance with proper inhalation maneuvers, insufficient delivery of drug to the lungs, and stress in some subjects. In some cases, stress in some subjects, such as stress induced by long inhalation periods or other discomfort, may result in increased sympathetic tone, which may make cardiac cardioversion more difficult.

[0035]

[0071] In some cases, rapid drug mass spray rate minimizes the inhalation time for effective dose. Drug mass spray rate can be strongly influenced by drug concentration in spray solution. In spray products, drug delivery rate can be limited by the device's ability to generate spray cloud with suitable droplet size (e.g., less than 5 microns) for inhalation. On the other hand, if aerosolization rate is too high and cloud is too dense, small spray droplets can coalesce into larger droplets that tend to deposit in mouth and throat and not reach lungs.

[0036]

[0072] In one aspect, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a salt of flecainide, the pharmaceutical composition being in the form of a liquid solution having a concentration of the salt of flecainide greater than 60 mg / mL. In some embodiments, the pharmaceutical composition further comprises a cyclodextrin. In some embodiments, the presence of cyclodextrin is advantageous over the corresponding composition without cyclodextrin. In some embodiments, the pharmaceutical composition further comprises a cyclodextrin, and the pH of the solution is greater than 5.5 when the pH is measured at room temperature. In some embodiments, the pharmaceutical composition further comprises a cyclodextrin, and the pH of the solution is greater than 5.5 when the pH is measured at room temperature. In some embodiments, the presence of the cyclodextrin allows the pH of the solution to be increased without compromising the solubility of the salt of flecainide, compared to a corresponding solution without the cyclodextrin.

[0037]

[0073] In some embodiments, the pharmaceutical composition or formulation provided herein allows for the delivery of more pharma- ceutical active ingredient, such as flecainide, to the subject. In some embodiments, the subject pharmaceutical composition or formulation has an increased flecainide concentration compared to the corresponding flecainide formulation (e.g., an aqueous solution of flecainide acetate with a solubility of about 60 mg / mL). In some cases, the increased flecainide concentration increases the delivery rate when the composition is nebulized and administered by inhalation. In some embodiments, the increased flecainide concentration shortens the inhalation period because a given dose can be delivered at a higher rate compared to the corresponding formulation with a lower concentration of flecainide. The shorter inhalation period can improve the subject's compliance and further increase the delivery efficiency of the drug.

[0038]

[0074] In some embodiments, the pharmaceutical compositions or formulations provided herein reduce harmful coughing in subjects during inhalation, have improved organoleptic properties, and improve the overall patient inhalation experience. In some embodiments, the improved overall inhalation experience leads to better compliance with a complete inhalation program. In some embodiments, more effective drug delivery is achieved when subjects have better inhalation compliance and thus more drug is delivered.

[0039]

[0075] In some embodiments, the subject pharmaceutical compositions or formulations have improved pharmacokinetic or pharmacodynamic parameters, e.g., peak plasma levels (C max) is higher with the subject pharmaceutical compositions compared to a corresponding pharmaceutical composition having a lower concentration of a salt of flecainide. In some embodiments, the C achieved with the subject pharmaceutical compositions max is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 or more times higher than a corresponding pharmaceutical composition having a lower concentration of a salt of flecainide.

[0040]

[0076] In some embodiments, a pharmaceutical composition having a lower concentration of acid or a higher pH, e.g., up to about 10 mM acetic acid, e.g., about 5 mM acetic acid, or a pH of e.g., higher than 5.5, e.g., a pH of 5.9, when the pH is measured at room temperature, has a higher C compared to a corresponding pharmaceutical composition having a higher concentration of acid or a lower pH, e.g., at least about 50 mM acetic acid, e.g., about 90 mM acetic acid, or a pH of e.g., up to 5.5, e.g., a pH of about 5.2, when the pH is measured at room temperature. max In some embodiments, the C achieved with a subject pharmaceutical composition having a low concentration of acid or a high pH. max is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 or more times higher than a corresponding pharmaceutical composition having a higher concentration of acid or a lower pH. In some embodiments, the C achieved with a subject pharmaceutical composition having up to about 10 mM acetic acid, e.g., about 5 mM acetic acid, or a pH greater than 5.5, e.g., a pH of 5.9, when the pH is measured at room temperature. max is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, or 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 or more times higher than a corresponding pharmaceutical composition having an acetic acid concentration of about 90 mM or a pH of about 5.2.

[0041]

[0077] In one aspect of the disclosure, provided herein is a dosage unit of the pharmaceutical composition provided herein. In some embodiments, the dosage unit comprises about 50 mg to about 350 mg of a salt of flecainide. In another aspect, provided herein is a kit comprising a pharmaceutical composition or dosage unit provided herein and instructions for use of the pharmaceutical composition for treating a cardiac condition (e.g., arrhythmia, e.g., atrial arrhythmia).

[0042]

[0078] In one aspect of the present disclosure, a system is provided herein that includes the pharmaceutical composition provided herein and a nebulizer. In some embodiments, the system further includes instructions for use of the nebulizer and pharmaceutical composition for the treatment of a cardiac condition. In some embodiments, the system includes a pharmaceutical composition that includes a salt of flecainide, a cyclodextrin, and an acid; a nebulizer configured to administer the pharmaceutical composition by inhalation as droplets having a mass median aerodynamic diameter of less than 10 μm; and instructions for use of the nebulizer to administer the pharmaceutical composition by inhalation in an aerosolized dose containing about 50 mg to about 150 mg of a salt of flecainide, the pharmaceutical composition being in the form of a liquid solution having (i) a salt of flecainide in a concentration of about 65 mg / mL to about 95 mg / mL, (ii) a cyclodextrin in a concentration of about 10% (w / v) to about 30% (w / v) of the solution, and (iii) a pH of about 5.5 to about 6.5 when the pH is measured at room temperature.

[0043]

[0079] In one aspect of the present disclosure, a method for treating a subject suffering from a cardiac condition is provided.In some embodiments, the method comprises administering to the subject a pharmaceutical composition in the form of a liquid solution by inhalation, the pharmaceutical composition comprises a therapeutically effective amount of a salt of flecainide, and the concentration of the salt of flecainide in the pharmaceutical composition is higher than 60mg / mL.

[0044]

[0080] As used herein, a "cardiac condition" can refer to a condition in which the heart has abnormal function and / or structure, e.g., the heart beats in an irregular rhythm, experiences arrhythmia, atrial fibrillation and / or tachycardia, has myocardial infarction and / or coronary artery disease. As used herein, an "atrial arrhythmia" can refer to an arrhythmia that affects at least one atrium and does not include bradycardia. For example, an atrial arrhythmia can originate in and affect at least one atrium. As used herein, a "tachycardia" can refer to an arrhythmia in which the heart beats too fast. For example, a tachycardia can involve a resting heart rate of more than 100 beats per minute, e.g., greater than 110, greater than 120, or greater than 130 beats per minute. In some cases, the tachycardia can include sinus tachycardia, atrial fibrillation, atrial flutter, AV nodal reentrant tachycardia, accessory pathway-mediated tachycardia, atrial tachycardia, multifocal atrial tachycardia, junctional tachycardia, ventricular tachycardia, supraventricular tachycardia, or any combination thereof.

[0045]

[0081] As used herein, the phrase "cardiac rhythm arrhythmia" can refer to an arrhythmia in which the heart beats irregularly. As used herein, the term "atrial fibrillation" can refer to an abnormal heart rhythm characterized by rapid and irregular beating of the atria. As used herein, the term "cardiac defibrillation" can refer to a process in which an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia is converted to a normal sinus rhythm. Cardiac defibrillation can be induced by electricity, drugs, or both.

[0046]

[0082] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to an "antiarrhythmic agent" can include not only a single active agent but also a combination or mixture of two or more different active agents.

[0047]

[0083] References herein to "one embodiment," "one version," or "one aspect" include one or more such embodiments, versions, or aspects, unless otherwise clear from the context. The present invention may include any of the above-mentioned embodiments or aspects.

[0048]

[0084] As used herein, the term "pharmaceutical acceptable solvate" can refer to a solvate that retains one or more of the biological activities and / or properties of the antiarrhythmic pharmaceutical agent and is not biologically or otherwise undesirable. Examples of pharmaceutical acceptable solvates include, but are not limited to, the antiarrhythmic pharmaceutical agent in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof.

[0049]

[0085] As used herein, the term "salt" is equivalent to the term "pharmaceutical acceptable salt" and can refer to salts that retain one or more of the biological activities and properties of the free acids and bases and are not biologically or otherwise undesirable. Representative examples of pharmaceutical acceptable salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexaphosphate ... These include syn-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenyl acetates, phenyipropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates.

[0050]

[0086] The term "about" in reference to a reference numerical value can include a range of values ​​from that value plus or minus 10%. For example, the amount "about 10" includes the amount from 9 to 11, including the reference numbers 9, 10, and 11. The term "about" in reference to a reference numerical value can also include a range of values ​​from that value plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%.

[0051]

[0087] As used herein, "atrial arrhythmia" can refer to an arrhythmia that affects at least one atrium and does not include bradycardia. For example, an atrial arrhythmia can originate in and affect at least one atrium.

[0052]

[0088] As used herein, "tachycardia" can mean an excessively fast heart rate, e.g., faster than normal, arrhythmia. For example, tachycardia can involve a resting heart rate of more than 100 beats per minute, e.g., greater than 110, greater than 120, or greater than 130 beats per minute.

[0053]

[0089] As used herein, the phrase "cardiac rhythm arrhythmia" can refer to an arrhythmia in which the heart beats irregularly.

[0090] As used herein, the amount of a drug described herein in the coronary circulation of the heart can be measured by extracting a sample from any vascular area in the coronary circulation of the heart (e.g., arteries, veins, including the coronary sinus) by using a cannula. The amount of drug in the sample can then be determined by known means, such as bioanalytical techniques employing analytical instruments, such as LC-MS / MS. Thus, the amount of drug in the blood in the heart can be measured at any particular time.

[0054]

[0091] As used herein, the terms "treating" and "treatment" refer to a disease. "Treatment" of a patient with an active agent provided herein can refer to the prevention of a particular condition, disease, or disorder in susceptible individuals, as well as the treatment of clinically symptomatic individuals.

[0055]

[0092] As used herein, a "nominal amount" can refer to the amount contained in a dosage unit receptacle to be administered.

[0093] As used herein, an "effective amount" can refer to an amount that encompasses both a therapeutically effective amount and a prophylactically effective amount.

[0056]

[0094] As used herein, the "therapeutically effective amount" of an active agent can refer to an amount that is effective to achieve a desired therapeutic result. The therapeutically effective amount of a given active agent can vary with respect to factors such as the type and severity of the disorder or disease being treated, as well as the age, sex and weight of the patient. In some cases, "inhalation" (e.g. "oral inhalation" or "nasal inhalation") refers to the inhalation delivery of a therapeutically effective amount of a pharmaceutical agent contained in one dosage unit receptacle, which may require one or more breaths, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or more breaths in some cases. For example, if the effective amount is 90 mg and each dosage unit receptacle contains 30 mg, the delivery of the effective amount may require 3 inhalations.

[0057]

[0095] Unless otherwise specified, the term "therapeutically effective amount" can include a "prophylactically effective amount," e.g., an amount of an active agent effective to prevent the onset or recurrence of a particular condition, disease or disorder in a susceptible individual.

[0058]

[0096] As used herein, the phrase "minimum effective amount" can mean the minimum amount of a pharmaceutical agent required to achieve an effective dose.

[0097] As used herein, "mass median diameter" or "MMD" can refer to the median diameter of multiple particles, typically in a polydisperse particle population of various particle sizes, for example. MMD values ​​reported herein are determined by laser diffraction (Sympatec Helos, Clausthal-Zellerfeld, Germany), unless the context indicates otherwise. For example, for powders, the sample is added directly to the feed funnel of a Sympatec RODOS dry powder dispersion unit. This can be accomplished manually or by mechanical stirring from the end of a VIBRI vibratory feed element. The sample is dispersed into primary particles by application of pressurized air (2-3 bar) with the intake negative pressure (suction) maximized for a given dispersion pressure. The dispersed particles are probed with a 632.8 nm laser light that intersects the dispersed particle trajectory at right angles. The laser light scattered from the ensemble of particles is imaged onto a concentric array of photomultiplying detector elements using an inverse Fourier lens assembly. The scattered light is acquired with an allotted time of 5 ms. The particle size distribution is back-calculated from the scattered light spatial / intensity distribution using a proprietary algorithm.

[0059]

[0098] As used herein, "geometric diameter" may refer to the diameter of a single particle as determined by microscopy, unless the context indicates otherwise.

[0099] As used herein, "median aerodynamic diameter" or "MMAD" can refer to the median aerodynamic diameter of a plurality of particles, or particles in a typically polydisperse population. "Aerodynamic diameter" can generally be the diameter of a sphere of unit density that has the same settling velocity in air as a powder, and is therefore a useful way to characterize an aerosolized powder or other dispersed particle or particle formulation in terms of its settling behavior. Aerodynamic diameter encompasses the shape, density, and physical size of the particle or particles. As used herein, MMAD refers to ... generally the diameter of a sphere of unit density that has the same settling velocity in air as a powder, and is therefore a useful way to characterize an aerosolized powder or other dispersed particle or particle formulation in terms of its settling behavior. This refers to the median aerodynamic or particle size distribution of aerosolized particles as determined by a particle size distribution test.

[0060]

[0100] By "pharmaceutically acceptable" component is meant a component that is not biologically or otherwise undesirable, e.g., a component can be incorporated into a pharmaceutical formulation of the present disclosure and administered to a patient as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained. When the term "pharmaceutically acceptable" is used to refer to an excipient, this can mean that the component meets the required toxicological and manufacturing testing standards, or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0061]

[0101] As used herein, "P wave" can refer to the wave produced by atrial depolarization of the atria (right and left) and is typically 0.08-0.1 seconds (80-100 ms) in duration.

[0062]

[0102] As used herein, "room temperature" may refer to a temperature between 18°C ​​and 25°C. Cyclodextrin

[0103] In some embodiments of the present disclosure, cyclodextrin is used as a solubility enhancer for salts of flecainide. Cyclodextrin is a cyclic carbohydrate derived from starch. Unmodified cyclodextrins vary by the number of glucopyranose units that are linked together in a cylindrical structure. The parent cyclodextrin contains six, seven or eight glucopyranose units and is referred to as α-, β- and γ-cyclodextrin, respectively. Each cyclodextrin subunit can have secondary hydroxyl groups at positions 2 and 3, and a primary hydroxyl group at position 6. Cyclodextrin can be depicted as a hollow truncated cone with a hydrophilic exterior surface and a hydrophobic interior cavity. In aqueous solutions, these hydrophobic cavities can provide a place for hydrophobic organic compounds that can fit all or part of their structure into these cavities. This process is known as inclusion complexation and can result in an apparent increase in aqueous solubility and stability of the complex drug.

[0063]

[0104] Cyclodextrins in the pharmaceutical compositions provided herein include, but are not limited to, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatized α-cyclodextrin, derivatized β-cyclodextrin, and derivatized γ-cyclodextrin. Non-limiting examples of cyclodextrins that can be used in the subject pharmaceutical compositions include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β ... Examples of cyclodextrins include rutosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin, dimaltosyl-β-cyclodextrin, succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, and sulfoalkylether-γ-cyclodextrin. In some embodiments, the pharmaceutical composition includes hydroxypropyl-β-cyclodextrin (HPβCD). In some embodiments, the pharmaceutical composition includes more than one type of cyclodextrin, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 In some embodiments, the pharmaceutical composition comprises HPβCD and one or more other cyclodextrins, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more other different types of cyclodextrins.

[0064]

[0105] A subject pharmaceutical composition can include cyclodextrin at a concentration of at least about 1% (w / v) of solution, e.g., at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 28%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100% or more (w / v) of solution.In some embodiments, the pharmaceutical composition comprises a cyclodextrin at a concentration of about 1% (w / v) to about 80% (w / v) of the solution, e.g., about 2% (w / v) to about 70% (w / v), about 2% (w / v) to about 60% (w / v), about 2% (w / v) to about 50% (w / v), about 2% (w / v) to about 40% (w / v), about 2% (w / v) to about 30% (w / v), about 2% (w / v) to about 20% (w / v), about 2% (w / v) to about 15% (w / v), about 2 ... v) ~ about 10% (w / v), about 2% (w / v) - about 8% (w / v), about 2% (w / v) - about 5% (w / v), about 5% (w / v) - about 80% (w / v), about 5% (w / v) - about 70% (w / v), about 5% (w / v) - about 60 % (w / v), about 5% (w / v) to about 50% (w / v), about 5% (w / v) to about 40% (w / v), about 5% (w / v) to about 30% (w / v), about 5% (w / v) to about 20% (w / v), about 5% (w / v) to about 15% (w / v), about 5% (w / v) to about 12% (w / v), about 5% (w / v) to about 10% (w / v), about 10% (w / v) to about 60% (w / v), about 10% (w / v) to about 50% (w / v), about 10% (w / v) to about 40% (w / v) ), about 10% (w / v) to about 30% (w / v), about 20% (w / v) to about 30% (w / v), about 10% (w / v) to about 25% (w / v), about 19% (w / v) to about 25% (w / v), about 19.5% (w / v) to about 25% ( about 20% (w / v) to about 25% (w / v), about 20.5% (w / v) to about 25% (w / v), about 21% (w / v) to about 25% (w / v), about 21.5% (w / v) to about 25% (w / v), about 22% (w / v) to about 25% (w / v), about 22.5% (w / v) to about 25% (w / v), about 23% (w / v) to about 25% (w / v), about 10% (w / v) to about 20% (w / v), or about 10% (w / v) to about 15% (w / v).In some embodiments, the pharmaceutical composition comprises cyclodextrin at about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, or ...4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4%, 4 Contains at concentrations of 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 31%, 32%, 33%, 34%, 35%, 38%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% (w / v).

[0065]

[0106] In some embodiments, the concentration of cyclodextrin contributes to the viscosity of the solution, which can reduce the efficiency (or speed) of the solution spraying.For example, in some cases, the higher the concentration of cyclodextrin, the higher the viscosity of the solution.In some cases, the concentration of cyclodextrin in pharmaceutical composition is adjusted so that the viscosity of the solution is not higher than the standard value, for example, about 3.1cP, 3.2cP, 3.3cP, 3.4cP, 3.5cP, 3.6cP, 3.7cP, 3.8cP, 3.9cP, 4.0cP, 4.1cP, 4.2cP, 4.3cP, 4.4cP, 4.5cP, 4.6cP, 4.7cP, 4.8cP, 4.9cP or 5.0cP. In some cases, the concentration of cyclodextrin in the pharmaceutical composition may be up to about 2%, 5%, 8%, 10%, 12%, 15%, 18%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, 31%, 32%, 33%, 34%, 35%, 38%, 40%, 45%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 109, 108, 109, 109, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 109 55%, 60%, 65%, 70%, 75% or 80% (w / v).

[0066]

[0107] In some embodiments, the pharmaceutical composition comprises HPβCD in a concentration of about 20% (w / v) of solution. In some embodiments, the pharmaceutical composition comprises HPβCD in a concentration of about 22.5% (w / v) of solution. In some embodiments, the pharmaceutical composition comprises HPβCD in a concentration of about 20% (w / v) of solution.

[0067] acid

[0108] Some aspects of the present disclosure relate to the use of one or more acids in pharmaceutical compositions. In some cases, the acid enhances the solubility of flecainide. In some cases, flecainide free base has low solubility, for example, in water. In some cases, a certain salt of flecainide has high solubility compared to other salts of flecainide and flecainide free base. For example, flecainide acetate may have high solubility compared to some other flecainide salts, as demonstrated in Example 1. In some cases, the acid is provided in pharmaceutical compositions to provide anion for flecainide salt formation and a sufficiently low pH to ensure the solubility of flecainide salt.

[0068]

[0109] In some cases, a mixture of more than one acid can increase the solubility of flecainide compared to a single acid. In some cases, the pharmaceutical composition includes acetic acid as the single acid. In some cases, the pharmaceutical composition includes citric acid as the single acid. In some cases, the pharmaceutical composition includes a mixture of different acids. In some cases, the pharmaceutical composition includes lactic acid. In some cases, the pharmaceutical composition includes L-(+)-lactic acid. In some cases, the pharmaceutical composition includes D-(-)-lactic acid. In some cases, the pharmaceutical composition includes a mixture of D-(-)-lactic acid and L-(+)-lactic acid, i.e., the pharmaceutical composition includes DL-lactic acid. In some cases, there are equal amounts of D-(-)-lactic acid and L-(+)-lactic acid in the pharmaceutical composition. In some cases, the pharmaceutical composition includes ascorbic acid. Non-limiting examples of acids that may be used in the subject pharmaceutical compositions and methods of treatment include any suitable organic or inorganic acid, such as any GRAS (Generally Regarded as Safe) listed acid, such as acetic acid, aconitic acid, adipic acid, alginic acid, benzoic acid, caprylic acid, citric acid, cholic acid, formic acid, lactic acid (e.g., D-(-)-lactic acid or L-(+)-lactic acid), linoleic acid, malic acid, maleic acid, propionic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid, glutamic acid, hydrochloric acid, phosphoric acid, ascorbic acid, erythorbic acid, sorbic acid, or thiodipropionic acid, or any other acid not listed in the GRAS but that is pharma- ceutically acceptable in the subject pharmaceutical compositions.

[0069]

[0110] In some cases, the pharmaceutical composition comprises a mixture of different acids, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different acids. In some cases, the pharmaceutical composition comprises one of the following: acetic acid and nitric acid; acetic acid and sulfuric acid; acetic acid and citric acid; acetic acid, nitric acid and sulfuric acid; acetic acid, nitric acid and citric acid; acetic acid, citric acid and sulfuric acid; or acetic acid, nitric acid, citric acid and sulfuric acid.

[0070]

[0111] In some embodiments, the pharmaceutical composition has a pH greater than 5.5 when the pH is measured at room temperature, e.g., greater than 5.6, greater than 5.7, greater than 5.8, greater than 5.9, greater than 6.0, greater than 6.1, greater than 6.2, greater than 6.3, greater than 6.4, greater than 6.5, greater than 6.6, greater than 6.7, or greater than 6.8 when the pH is measured at room temperature. In some cases, the pharmaceutical composition is acidic at room temperature, e.g., has a pH of at most 6.9, at most 6.8, at most 6.7, at most 6.6, at most 6.5, at most 6.4, at most 6.3, at most 6.2, at most 6.1, at most 6.0, at most 5.9, at most 5.8, at most 5.7, or at most 5.6 when the pH is measured at room temperature. In some cases, the pharmaceutical composition has a pH of about 5.5 to about 6.5 when the pH is measured at room temperature, e.g., For example, the pharmaceutical composition has a pH of about 5.6 to about 6.4, about 5.7 to about 6.3, about 5.8 to about 6.2, or about 5.9 to about 6.1 when the pH is measured at room temperature. In some cases, the pharmaceutical composition has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, or 6.4 when the pH is measured at room temperature. In some examples, the pharmaceutical composition has a pH of about 5.5 when the pH is measured at room temperature. In some embodiments, the pH of the pharmaceutical composition is titrated with a pH buffer as described herein.

[0071]

[0112] In some embodiments, the concentration of the acid in the pharmaceutical composition is from about 2 mM to about 200 mM, for example, from about 2 mM to about 180 mM, from about 2 mM to about 150 mM, from about 2 mM to about 120 mM, from about 2 mM to about 100 mM, from about 2 mM to about 80 mM, from about 2 mM to about 60 mM, from about 2 mM to about 50 mM, from about 2 mM to about 40 mM, from about 2 mM to about 30 mM, from about 2 mM to about 20 mM, from about 2 mM to about 10 mM, from about 2 mM to about 8 mM, or from about 2 mM to about 50 mM. ~about 6mM, about 5mM to about 200mM, about 5mM to about 150mM, about 5mM to about 120mM, about 5mM to about 100mM, about 5mM to about 80mM, about 5mM to about 60mM, about 5mM to about 50mM, about 5mM to about 40mM, about 5mM to about 30mM, about 5mM to about 20mM, about 5mM to about 10mM, about 5mM to about 8mM, about 10mM to about 200mM, about 10mM to about 150mM, about 10mM to about 120 mM, about 10mM to about 100mM, about 10mM to about 90mM, about 10mM to about 80mM, about 10mM to about 70mM, about 10mM to about 60mM, about 10mM to about 50mM, about 10mM to about 40mM, Approximately 10mM to approximately 30mM, approximately 10mM to approximately 20mM, approximately 20mM to approximately 200mM, approximately 20mM to approximately 150mM, approximately 20mM to approximately 100mM, approximately 20mM to approximately 90mM, approximately 20mM to approximately 80mM, approximately 20 mM to about 70 mM, about 20 mM to about 60 mM, about 20 mM to about 50 mM, about 20 mM to about 40 mM, about 20 mM to about 30 mM, about 40 mM to about 200 mM, about 40 mM to about 150 mM, about 40 mM to about 120 mM, about 40 mM to about 100 mM, about 40 mM to about 90 mM, about 40 mM to about 80 mM, about 40 mM to about 70 mM, about 40 mM to about 60 mM, or about 40 mM to about 50 mM. In some embodiments, the concentration of the acid in the pharmaceutical composition is at most about 200 mM, e.g., at most about 180 mM, at most about 160 mM, at most about 150 mM, at most about 140 mM, at most about 120 mM, at most about 100 mM, at most about 90 mM, at most about 80 mM, at most about 70 mM, at most about 60 mM, at most about 50 mM, at most about 40 mM, at most about 30 mM, at most about 20 mM, at most about 10 mM, at most about 9 mM, at most about 8 mM, at most about 7 mM, at most about 6 mM, at most about 5 mM, at most about 4 mM, at most about 3 mM, at most about 2 mM, or at most about 1 mM.In some embodiments, the concentration of acid in the pharmaceutical composition is about 100 mM, about 90 mM, about 80 mM, about 70 mM, about 60 mM, about 50 mM, about 40 mM, about 30 mM, about 20 mM, about 10 mM, about 9 mM, about 8 mM, about 7 mM, about 6 mM, about 5 mM, about 4 mM, about 3 mM, about 2 mM, or about 1 mM.In some embodiments, the concentration of acid in the pharmaceutical composition is about 20 mM.In some embodiments, the concentration of acid in the pharmaceutical composition is about 5 mM.

[0072]

[0113] Without wishing to be bound by any particular theory, the concentration of acid in pharmaceutical composition may contribute to the pharmaceutical application of the composition. In some embodiments, the concentration of acid, and therefore the pH of the solution, may affect the solubility of flecainide salt in the formulation, thus affecting the concentration of flecainide salt. As discussed above, the concentration of flecainide salt may contribute to the delivery efficiency and speed of the pharmaceutical composition. In some embodiments, the concentration of acid may affect the organoleptic properties of the pharmaceutical composition. For example, the lower the pH of the solution, the more irritating the solution may be to the mouth, nose, pharynx or other parts of the respiratory system, especially the upper respiratory system. The irritation of the solution may induce coughing or other adverse reactions, or reduce the compliance of the subject, thus adversely affecting the delivery efficiency of the pharmaceutical composition.

[0073]

[0114] In some embodiments, the pharmaceutical compositions provided herein do not induce a cough reflex when inhaled by a subject. induces a cough reflex less frequently when inhaled by a subject than a corresponding pharmaceutical composition having a higher concentration of acid or a lower pH, e.g., about 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90%, or 100%, or 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 or more fold less than the corresponding pharmaceutical composition. In some embodiments, a subject receiving an inhaled administration of the pharmaceutical composition reports less severe discomfort when inhaling the composition or has a lower incidence of reporting discomfort when inhaling the composition compared to a corresponding pharmaceutical composition having a higher concentration of acid or a lower pH, e.g., about 10%, 20%, 30%, 50%, 60%, 70%, 80%, 90% or 100%, or 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 or more fold lower than the corresponding pharmaceutical composition.

[0074]

[0115] Without wishing to be bound by a particular theory, the presence of cyclodextrin in pharmaceutical composition may reduce the concentration of acid required to achieve a desired concentration of flecainide salt according to some aspects of the present disclosure. In some embodiments, the presence of cyclodextrin (e.g., HPβCD) increases the solubility of flecainide, for example, by inclusion complex formation that "dissolves" flecainide salt (e.g., flecainide acetate) inside the cavity of cyclodextrin. On the other hand, inclusion complex formation may reduce the reliance of flecainide salt on acid (or low pH) to be dissolved in solution. Thus, as a result, the introduction of cyclodextrin (e.g., HPβCD) may result in a reduction in the concentration of acid in solution, both of which synergistically result in an increase in the concentration of flecainide in solution, improved organoleptic properties, increased delivery speed and improved delivery efficiency.

[0075] Sweeteners and organoleptic properties

[0116] In some embodiments, the pharmaceutical compositions provided herein include a sweetener to improve the organoleptic properties of the composition. The sweetener may be a natural sweetener, such as a specific sugar or an artificial sweetener. Without wishing to be bound by a particular theory, the presence of a sweetener in a pharmaceutical composition may improve the organoleptic properties of the composition. In some cases, the presence of a sweetener in a pharmaceutical composition may improve the compliance of a subject. The presence of a sweetener in a pharmaceutical composition may increase the delivery efficiency of the composition. In some embodiments, the presence of a sweetener in a pharmaceutical composition may enhance the therapeutic effect of the composition.

[0076]

[0117] Non-limiting examples of artificial sweeteners that may be used in the pharmaceutical composition include acesulfame potassium, aspartame, cyclamate, mogrosides, saccharin, stevia, sucralose, neotame, and sugar alcohols (e.g., erythritol, hydrogenated starch hydrolysates, isomalt, lactitol, maltitol, mannitol, sorbitol, and xylitol), such as those used in commercial products such as Sweet n' low powdered sweetener, Truvia powdered sweetener, Equal (aspartame), Stevia powder sachet, Aspen Naturals liquid stevia, Now Better Stevia liquid sweetener, Sweet N' Low liquid sweetener, Quick Sweet: Neotame liquid sweetener, or Splenda powder sachet, or pharma- ceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition comprises saccharin. In some embodiments, the pharmaceutical composition comprises a salt of saccharin. In some embodiments, the pharmaceutical composition comprises sodium saccharin.

[0077]

[0118] Natural sweeteners that may be used in the pharmaceutical composition include, but are not limited to, sucrose, agave, brown sugar, powdered sugar, corn syrup, dextrose, fructose, fruit juice concentrate, glucose, isomerized sugar, honey, invert sugar, lactose, maltose, maltose, maple syrup, molasses, nectar, raw sugar and syrup. Sugars can increase the viscosity of liquid solutions, and therefore in some embodiments, the concentration of any sugar added to the pharmaceutical composition is tightly controlled below a certain threshold.

[0078]

[0119] In some embodiments, the concentration of the sweetener, e.g., artificial sweetener, in the pharmaceutical composition is from about 0.001% (w / v) to about 1% (w / v) of the solution, e.g., 0.002% to 1%, 0.005% to 1%, 0.01% to 1%, 0.02% to 1%, 0.05% to 1%, 0.08% to 1%, 0.1% to 1%, 0.2% to 1%, 0.5% to 1%, 0.8 to 1%, 0.002% to 0.5%, 0.005% to 0.5%, 0.01%-0.5%, 0.02%-0.5%, 0.05%-0.5%, 0.08%-0.5%, 0.1%-0.5%, 0.2%-0.5%, 0.005%-0.1%, 0.01%-0.1%, 0.02%-0.1%, 0.05%-0.1%, 0.08%-0.1%, 0.005%-0.05%, 0.01%-0.05%, or 0.02%-0.05% (w / v). In some embodiments, the concentration of the sweetener, e.g., artificial sweetener, in the pharmaceutical composition is at least about 0.001%, at least about 0.002%, at least about 0.005%, at least about 0.01%, at least about 0.02%, at least about 0.05%, at least about 0.08%, at least about 0.1%, at least about 0.2%, at least about 0.5%, or at least about 0.8, or at least about 1% (w / v) of the solution. In some embodiments, the concentration of sweetener, e.g., artificial sweetener, in the pharmaceutical composition is at most about 0.001%, at most about 0.002%, at most about 0.005%, at most about 0.01%, at most about 0.02%, at most about 0.05%, at most about 0.08%, at most about 0.1%, at most about 0.2%, at most about 0.5%, or at most about 0.8, or at most about 1% (w / v) of the solution.

[0079] Pharmaceutical Compositions, Formulations and Kits

[0120] In one aspect, provided herein is a pharmaceutical composition for the treatment of a cardiac condition, e.g., cardiac arrhythmia, e.g., atrial arrhythmia.

[0080]

[0121] The pharmaceutical composition may comprise a therapeutically effective amount of a salt of flecainide.The therapeutically effective amount of flecainide, when administered by inhalation to a subject in need of treatment, may be effective for treating cardiac conditions, such as cardiac arrhythmia, for example, atrial arrhythmia.In some cases, the therapeutically effective amount of flecainide salt, when administered by inhalation to a subject in need of treatment, is effective for treating atrial arrhythmia by inducing cardiac defibrillation.

[0081]

[0122] In some cases, a pharmaceutical composition comprising a therapeutically effective amount of a salt of flecainide is provided herein. In some embodiments, as described herein, the pharmaceutical composition is in the form of a liquid solution. In some cases, the concentration of flecainide or a salt of flecainide (e.g., flecainide acetate or flecainide hydrochloride) in the pharmaceutical composition or formulation is about 60 mg / mL to about 200 mg / mL, such as 60 mg / mL to 195 mg / mL, 60 mg / mL to 190 mg / mL, 60 mg / mL to 185 mg / mL, 60 mg / mL to 175 mg / mL, 60 mg / mL to 170 mg / mL, 60 mg / mL to 185 ... / mL~165mg / mL, 60mg / mL~160mg / mL, 60mg / mL~155mg / mL, 60mg / mL~150mg / mL, 60mg / mL~145mg / mL, 60mg / mL~ 140mg / mL, 60mg / mL~135mg / mL, 60mg / mL~130mg / mL, 60mg / mL~125mg / mL, 60mg / mL~120mg / mL, 60mg / mL~118mg / mL, 60mg / mL~115mg / mL, 60mg / mL~112mg / mL, 60mg / mL~110mg / mL, 60mg / mL~108mg / mL, 60mg / mL~105mg / mL, 60mg / mL~102mg / mL, 60mg / mL~100mg / mL, 60mg / mL~98mg / mL, 60mg / mL~95mg / mL, 60mg / mL~92mg / mL, 60mg / mL ~90mg / mL, 60mg / mL~88mg / mL, 60mg / mL~85mg / mL, 60mg / mL~82mg / mL, 60mg / mL~80mg / mL, 60mg / mL~78mg / mL, 60mg / mL~75mg / mL, 60mg / mL~72mg / mL, 60mg / mL~70mg / mL, 70mg / mL~195mg / mL, 70mg / mL~190mg / mL, 70mg / mL~ 185mg / mL、70mg / mL~175mg / mL、70mg / mL~170mg / mL、70mg / mL~165mg / mL、70mg / mL~160mg / mL、70mg / mL~155mg / mL、70mg / mL~150mg / mL、70mg / mL~145mg / mL、70mg / mL~140mg / mL、70mg / mL~135mg / mL、70mg / mL~130mg / mL、70mg / mL~125mg / mL、70mg / mL~120mg / mL、70mg / mL~118mg / mL、70mg / mL~115mg / mL、70mg / mL~112mg / mL、70mg / mL~110mg / mL、70mg / mL~108mg / mL、70mg / mL~105mg / mL、70mg / mL~102mg / mL、70mg / mL~100mg / mL、70mg / mL~98mg / mL、70mg / mL~95mg / mL、70mg / mL~92mg / mL、70mg / mL~90mg / mL、70mg / mL~88mg / mL、70mg / mL~85mg / mL、70mg / mL~82mg / mL、70mg / mL~80mg / mL、70mg / mL~78mg / mL、70mg / mL~75mg / mL、80mg / mL~195mg / mL、80mg / mL~190mg / mL、80mg / mL~185mg / mL、80mg / mL~175mg / mL、80mg / mL~170mg / mL、80mg / mL~165mg / mL、80mg / mL~160mg / mL、80mg / mL~155mg / mL、80mg / mL~150mg / mL、80mg / mL~145mg / mL、80mg / mL~140mg / mL、80mg / mL~135mg / mL、80mg / mL~130mg / mL、80mg / mL~125mg / mL、80mg / mL~120mg / mL、80mg / mL~118mg / mL、80mg / mL~115mg / mL、80mg / mL~112mg / mL、80mg / mL~110mg / mL、80mg / mL~108mg / mL、80mg / mL~105mg / mL、80mg / mL~102mg / mL、80mg / mL~100mg / mL、80mg / mL~98mg / mL、80mg / mL~95mg / mL、80mg / mL~92mg / mL、80mg / mL~90mg / mL、80mg / mL~88mg / mL、80mg / mL~85mg / mL、90mg / mL~195mg / mL, 90mg / mL~190mg / mL, 90mg / mL~185mg / mL, 90mg / mL~175mg / mL, 90mg / mL~170mg / mL, 90mg / m L~165mg / mL, 90mg / mL~160mg / mL, 90mg / mL~155mg / mL, 90mg / mL~150mg / mL, 90mg / mL~145mg / mL, 90mg / mL~140mg / mL, 90mg / mL~135mg / mL, 90mg / mL~130mg / mL, 90mg / mL~125mg / mL, 90mg / mL~120mg / mL, 90mg / mL~118mg / mL, 90m g / mL~115mg / mL, 90mg / mL~112mg / mL, 90mg / mL~110mg / mL, 90mg / mL~108mg / mL, 90mg / mL~105mg / mL, 90mg / mL~10 2mg / mL, 90mg / mL~100mg / mL, 90mg / mL~98mg / mL, 90mg / mL~95mg / mL, 100mg / mL~195mg / mL, 100mg / mL~190mg / mL, 100mg / mL~185mg / mL, 100mg / mL~175mg / mL, 100mg / mL~170mg / mL, 100mg / mL~165mg / mL, 100mg / mL~160mg / mL, 10 0mg / mL~155mg / mL, 100mg / mL~150mg / mL, 100mg / mL~145mg / mL, 100mg / mL~140mg / mL, 100mg / mL~135mg / mL, 100m g / mL~130mg / mL, 100mg / mL~125mg / mL, 100mg / mL~120mg / mL, 100mg / mL~118mg / mL, or 100mg / mL~115mg / mL. ,

[0082]

[0123] In some cases, the concentration of flecainide or a salt of flecainide (e.g., flecainide acetate or flecainide hydrochloride) in the pharmaceutical composition or formulation is at least about 115 mg / mL, at least about 112 mg / mL, at least about 110 mg / mL, at least about 109 mg / mL, at least about 108 mg / mL, at least about 107 mg / mL, at least about 106 mg / mL, at least about 105 mg / mL, at least about 104 mg / mL, at least about 106 mg / mL, at least about 104 ... mg / mL, at least about 103 mg / mL, at least about 102 mg / mL, at least about 101 mg / mL, at least about 100 mg / mL, at least about 99 mg / mL, at least about 98 mg / mL, at least about 97 mg / mL, at least about 96 mg / mL, at least about 95 mg / mL, at least about 94 mg / mL, at least about 93 mg / mL, at least about 92 mg / mL, at least about 91 mg / mL, at least about 90 mg / mL, at least about 89 mg / mL, at least about 88 mg / mL, at least about 87 mg / mL, at least about 86 mg / mL, at least about 85 mg / mL, at least about 84 mg / mL, at least about 83 mg / mL, at least about 82 mg / mL L, at least about 81 mg / mL, at least about 80 mg / mL, at least about 79 mg / mL, at least about 78 mg / mL, at least about 77 mg / mL, at least about 76 mg / mL, at least about 75 mg / mL, at least about 74 mg / mL, at least about 73 mg / mL, at least about 72 mg / mL, at least about 71 mg / mL, at least about 70 mg / mL, at least about 69 mg / mL, at least about 68 mg / mL, at least about 67 mg / mL, at least about 66 mg / mL, at least about 65 mg / mL, at least about 64 mg / mL, at least about 63 mg / mL, at least about 62 mg / mL, at least about 61 mg / mL, or at least about 60 mg / mL.

[0083]

[0124] In some cases, the concentration of flecainide or a salt of flecainide (e.g., flecainide acetate or flecainide hydrochloride) in the pharmaceutical composition or formulation is about 195 mg / mL, about 190 mg / mL, about 185 mg / mL, about 175 mg / mL, about 170 mg / mL, about 165 mg / mL, about 160 mg / mL, about 155 mg / mL, about 150 mg / mL, about 145 mg / mL, about 140 mg / mL, about 135mg / mL, approximately 130mg / mL, approximately 125mg / mL, approximately 120mg / mL, approximately 118mg / mL, approximately 115mg / mL, approximately 112mg / mL, approximately 110mg / mL, approximately 109mg / mL, Approximately 108mg / mL, approximately 107mg / mL, approximately 106mg / mL, approximately 105mg / mL, approximately 104mg / mL, approximately 103mg / mL, approximately 102mg / mL, approximately 101mg / mL, approximately 100mg / mL, Approx. 99 mg / mL, approx. 98 mg / mL, approx. 97 mg / mL, approx. 96 mg / mL, approx. 95 mg / mL, approx. 94 mg / mL, approx. 93 mg / mL, approx. 92 mg / mL, approx. 91 mg / mL, approx. 90 mg / mL , about 89 mg / mL, about 88 mg / mL, about 87 mg / mL, about 86 mg / mL, about 85 mg / mL, about 84 mg / mL, about 83 mg / mL, about 82 mg / mL, about 81 mg / mL, about 80 mg / m L, about 79 mg / mL, about 78 mg / mL, about 77 mg / mL, about 76 mg / mL, about 75 mg / mL, about 74 mg / mL, about 73 mg / mL, about 72 mg / mL, about 71 mg / mL, about 70 mg / mL, about 69 mg / mL, about 68 mg / mL, about 67 mg / mL, about 66 mg / mL, about 65 mg / mL, about 64 mg / mL, about 63 mg / mL, about 62 mg / mL, or about 61 mg / mL.

[0084]

[0125] In some cases, the nominal concentration of flecainide or a salt of flecainide (e.g., flecainide acetate or flecainide hydrochloride) in the pharmaceutical composition or formulation is about 125 mM to about 430 mM, e.g., 125 mM to 420 mM, 125 mM to 400 mM, 125 mM to 390 mM, 125 mM to 380 mM, 125 mM to 410 mM, 125 mM to 420 mM, 125 mM to 400 mM, 125 mM to 390 mM, 125 mM to 380 mM, 125 mM to 43 ... ~370mM, 125mM~360mM, 125mM~350mM, 125mM~340mM, 125mM~330mM, 125mM~320mM, 12 5mM~310mM, 125mM~300mM, 125mM~290mM, 125mM~280mM, 125mM~270mM, 125mM~260mM, 125mM~250mM, 125mM~240mM, 125mM~230mM, 125mM~220mM, 125mM~210mM, 125mM~200 mM, 125mM~190mM, 125mM~180mM, 125mM~170mM, 125mM~160mM, 125mM~155mM, 125mM~1 50mM, 125mM~145mM, 125mM~140mM, 125mM~135mM, 125mM~130mM, 140mM~420mM, 140m M~400mM, 140mM~390mM, 140mM~380mM, 140mM~370mM, 140mM~360mM, 140mM~350mM, 14 0mM~340mM、140mM~330mM、140mM~320mM、140mM~310mM、140mM~300mM、140mM~290mM、140mM~280mM、140mM~270mM、140mM~260mM、140mM~250mM、140mM~240mM、140mM~230mM、140mM~220mM、140mM~210mM、140mM~200mM、140mM~190mM、140mM~180mM、140mM~170mM、140mM~160mM、140mM~155mM、140mM~150mM、140mM~145mM、160mM~420mM、160mM~400mM、160mM~390mM、160mM~380mM、160mM~370mM、160mM~360mM、160mM~350mM、160mM~340mM、160mM~330mM、160mM~320mM、160mM~310mM、160mM~300mM、160mM~290mM、160mM~280mM、160mM~270mM、160mM~260mM、160mM~250mM、160mM~240mM、160mM~230mM、160mM~220mM、160mM~210mM、160mM~200mM、160mM~190mM、160mM~180mM、160mM~170mM、180mM~420mM、180mM~400mM、180mM~390mM、180mM~380mM、180mM~370mM、180mM~360mM、180mM~350mM、180mM~340mM、180mM~330mM、180mM~320mM、180mM~310mM、180mM~300mM、180mM~290mM、180mM~280mM、180mM~270mM、180mM~260mM、180mM~250mM、180mM~240mM、180mM~230mM、180mM~220mM、180mM~210mM、180mM~200mM、180mM~190mM、200mM~420mM、200mM~400mM、200mM~390mM、200mM~380mM、200mM~370mM、200mM~360mM、200mM~350mM、200mM~340mM、200mM~330mM、200mM~320mM、200mM~310mM、200mM~300mM、200mM~290mM、200mM to 280mM, 200mM to 270mM, 200mM to 260mM, 200mM to 250mM, 200mM to 240mM, 200mM to 230mM, 200mM to 220mM, or 200mM to 210mM.

[0085]

[0126] In some cases, the nominal concentration of flecainide or a salt of flecainide (e.g., flecainide acetate or flecainide hydrochloride) in the pharmaceutical composition or formulation is at least about 400 mM, at least about 390 mM, at least about 380 mM, at least about 370 mM, at least about 360 mM, at least about 350 mM, at least about 340 mM, at least about 330 mM, at least about 320 mM, at least about 310 mM, at least about 300 mM, at least about 290 mM, at least about 280 mM, at least about 270 mM, at least about 260 mM, at least about 255 mM, M, at least about 250 mM, at least about 245 mM, at least about 240 mM, at least about 235 mM, at least about 230 mM, at least about 225 mM, at least about 220 mM, at least about 215 mM, at least about 210 mM, at least about 200 mM, at least about 190 mM, at least about 180 mM, at least about 170 mM, at least about 160 mM, at least about 155 mM, at least about 150 mM, at least about 145 mM, at least about 140 mM, at least about 135 mM, at least about 130 mM, or at least about 125 mM.

[0086]

[0127] In some cases, the concentration of flecainide or a salt of flecainide (e.g., flecainide acetate or flecainide hydrochloride) in the pharmaceutical composition or formulation is about 420 mM, about 400 mM, about 390 mM, about 380 mM, about 370 mM, about 360 mM, about 350 mM, about 340 mM, about 330 mM, about 320 mM, about 310 mM, about 300 mM, about 290 mM, about 280 mM, about 270 mM, about 260 mM, about 255 mM, about 250 mM, about 245 mM, about 240 mM, about 235 mM, about 230 mM, about 225 mM, about 220 mM, about 215 mM, about 210 mM, about 200 mM, about 190 mM, about 180 mM, about 170 mM, about 160 mM, about 155 mM, about 150 mM, about 145 mM, about 140 mM, about 135 mM, about 130 mM, or about 125 mM.

[0087]

[0128] In some aspects, provided herein are dosage units of the pharmaceutical compositions described herein for the treatment of cardiac conditions, e.g., cardiac arrhythmia, e.g., atrial arrhythmia, via oral or nasal inhalation.

[0088]

[0129] In one variation, a dosage unit of a pharmaceutical composition provided herein comprises at least about 50 mg, e.g., at least about 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 450 mg, 500 mg, or more of flecainide or a flecainide salt, e.g., flecainide acetate or flecainide hydrochloride. The dosage unit of the pharmaceutical composition provided herein may be from about 50 mg to about 500 mg, for example, 50 mg to 60 mg, 50 mg to 70 mg, 50 mg to 80 mg, 50 mg to 90 mg, 50 mg to 100 mg, 50 mg to 110 mg, 50 mg to 120 mg, 50 mg to 130 mg, 50 mg to 140 mg, 50 mg to 150 mg, 50 mg to 160 mg, 50 mg to 170 mg, 50 mg ~180mg, 50mg~190mg, 50mg~200mg, 50mg~210mg, 50mg~220mg, 50mg~230mg, 50mg~240mg, 50mg~250mg, 5 0mg~260mg, 50mg~270mg, 50mg~280mg, 50mg~290mg, 50mg~300mg, 50mg~310mg, 50mg~320mg, 50mg~330mg , 50mg~340mg, 50mg~350mg, 50mg~360mg, 50mg~370mg, 50mg~380mg, 50mg~390mg, 50mg~400mg, 50mg~45 0mg, 50mg~500mg, 80mg~90mg, 80mg~100mg, 80mg~110mg, 80mg~120mg, 80mg~130mg, 80mg~140mg, 80mg~ 150mg, 80mg~160mg, 80mg~170mg, 80mg~180mg, 80mg~190mg, 80mg~200mg, 80mg~210mg, 80mg~220mg, 80 mg~230mg, 80mg~240mg, 80mg~250mg, 80mg~260mg, 80mg~270mg, 80mg~280mg, 80mg~290mg, 80mg~300mg,80mg~310mg、80mg~320mg、80mg~330mg、80mg~340mg、80mg~350mg、80mg~360mg、80mg~370mg、80mg~380mg、80mg~390mg、80mg~400mg、80mg~450mg、80mg~500mg、120mg~140mg、120mg~150mg、120mg~160mg、120mg~170mg、120mg~180mg、120mg~190mg、120mg~200mg、120mg~210mg、120mg~220mg、120mg~230mg、120mg~240mg、120mg~250mg、120mg~260mg、120mg~270mg、120mg~280mg、120mg~290mg、120mg~300mg、120mg~310mg、120mg~320mg、120mg~330mg、120mg~340mg、120mg~350mg、120mg~360mg、120mg~370mg、120mg~380mg、120mg~390mg、120mg~400mg、120mg~450mg、120mg~500mg、150mg~160mg、150mg~170mg、150mg~180mg、150mg~190mg、150mg~200mg、150mg~210mg、150mg~220mg、150mg~230mg、150mg~240mg、150mg~250mg、150mg~260mg、150mg~270mg、150mg~280mg、150mg~290mg、150mg~300mg、150mg~310mg、150mg~320、 mg、150mg~330mg、150mg~340mg、150mg~350mg、150mg~360mg、150mg~370mg、150mg~380mg、150mg~390mg、150mg~400mg、150mg~450mg、150mg~500mg、180mg~200mg、180mg~210mg、180mg~220mg、180mg~230mg、180mg~240mg、180mg~250mg、180mg~260mg、180mg~270mg、180mg~280mg、180mg~290mg、180mg~300mg、180mg~310mg、180mg~320mg、180mg~330mg、180mg~340mg、180mg~350mg、180mg~360mg、180mg~370mg、180mg~380mg、180mg~390mg、180mg~400mg、180mg~450mg、180mg~500mg、200mg~220mg、200mg~230mg、200mg~240mg、200mg~250mg、200mg~260mg、200mg~270mg、200mg~280mg、200mg~290mg、200mg~300mg、200mg~310mg、200mg~320mg、200mg~330mg、200mg~340mg、200mg~350mg、200mg~360mg、200mg~370mg、200mg~380mg、200mg~390mg、200mg~400mg、200mg~450mg、200mg~500mg、220mg~240mg、220mg~250mg、220mg~260mg、220mg~270mg、220mg~280mg、220mg~290mg、220mg~300mg、220mg~310mg、220mg~320mg、220mg~330mg、220mg~340mg、220mg~350mg、220mg~360mg、220mg~370mg、220mg~380mg、220mg~390mg、220mg~400mg、220mg~450mg、220mg~500mg、250mg~260mg、250mg~270mg、250mg~280mg、250mg~290mg、250mg~300mg、250mg~310mg、250mg~320mg、250mg~330mg、250mg~340mg、250mg~350mg、250mg~360mg, 250mg~370mg, 250mg~380mg, 250mg~390mg, 250mg~400mg, 250mg~450mg, 250mg~500 mg, 280mg~260mg, 280mg~270mg, 280mg~280mg, 280mg~290mg, 280mg~300mg, 280mg~310mg, 280mg~3 20mg, 280mg~330mg, 280mg~340mg, 280mg~350mg, 280mg~360mg, 280mg~370mg, 280mg~380mg, 280mg ~390mg, 280mg~400mg, 280mg~450mg, 280mg~500mg, 300mg~320mg, 300mg~330mg, 300mg~340mg, 300 mg~350mg, 300mg~360mg, 300mg~370mg, 300mg~380mg, 300mg~390mg, 300mg~400mg, 300mg~450mg, 300mg~500mg, 320mg~330mg, 320mg~340mg, 320mg~350mg, 320mg~360mg, 320mg~370mg, 320mg~380m g, 320 mg to 390 mg, 320 mg to 400 mg, 320 mg to 450 mg, 320 mg to 500 mg, 340 mg to 360 mg, 340 mg to 370 mg, 340 mg to 380 mg, 340 mg to 390 mg, 340 mg to 400 mg, 340 mg to 450 mg, or 340 mg to 500 mg of flecainide or a flecainide salt.

[0089]

[0130] In one variation, the dosage units provided herein may be about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 450 mg, or about 500 mg of flecainide or a flecainide salt.

[0090]

[0131] In some aspects, the present invention provides a formulation for the treatment of cardiac conditions, such as cardiac arrhythmia, e.g., atrial arrhythmia.The formulation may comprise the pharmaceutical composition provided herein and a pharmaceutically acceptable carrier, excipient, diluent, or any other component suitable for the intended route of administration, such as oral or nasal inhalation.Examples of pharmaceutically acceptable excipients include, but are not limited to, lipids, metal ions, surfactants, amino acids, carbohydrates, buffers, salts, polymers, etc., and combinations thereof.

[0091]

[0132] The pharmaceutical preparation according to one or more embodiments of the present disclosure may comprise a salt of flecainide, and optionally one or more other active ingredients, and optionally one or more pharmaceutically acceptable excipients.For example, the pharmaceutical preparation may comprise particles of flecainide salt without other ingredients added (neat particles), may comprise neat particles of antiarrhythmic pharmaceutical agent together with other particles, and / or may comprise particles containing antiarrhythmic pharmaceutical agent and one or more active ingredients and / or one or more pharmaceutically acceptable excipients.

[0092]

[0133] In one embodiment, the kit for treating cardiac conditions by inhalation is also provided herein.The kit may include one or more pharmaceutical agents, such as salt of flecainide, or some other active agents described herein.In some cases, the kit includes a container for pharmaceutical agents or compositions.In some cases, the kit includes a dosage unit of the pharmaceutical agent discussed above.In some cases, the kit also includes a container / receptacle for containing pharmaceutical agents.

[0093]

[0134] In some cases, the kit includes a separate container / receptacle for containing the pharmaceutical composition described herein. In some cases, the kit includes an aerosolization device for forming an aerosol of the pharmaceutical composition. The aerosolization device may be any device provided herein and used in some cases for inhalation of the pharmaceutical composition. In some cases, the kit includes a nasal spray device provided herein. In some cases, the pharmaceutical composition is present in the kit in the form of an aerosol. In some other cases, the kit includes a single container for containing the pharmaceutical composition. The kit may further include instructions on how to use the kit. The instructions may be presented on a paper sheet in the form of a data sheet, manual, or printed on one or more containers or devices of the kit. Alternatively, the instructions may be provided in electronic form available online, for example on a disk, or by a web link available from the kit. The instructions for use of the kit may include instructions for use of the pharmaceutical composition and the aerosolization device (e.g., a nebulizer) for treating any applicable indication, for example, a cardiac condition, for example, cardiac arrhythmia, for example, atrial arrhythmia. The instructions for using the kit may include instructions for using the pharmaceutical composition for treating atrial fibrillation and the aerosolization device (e.g., nebulizer).In some cases, the kit includes a nose clip.The nose clip may be used to prevent the passage of air through the subject's nose during inhalation, and increase the proportion of the total inhaled dose that is the aerosol emitted by the nebulizer.

[0094]

[0135] Examples of carbohydrates include, but are not limited to, monosaccharides, disaccharides and polysaccharides, such as monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose, disaccharides such as lactose, maltose, sucrose, trehalose, trisaccharides such as raffinose, and other carbohydrates such as starch (hydroxyethyl starch) and maltodextrin.

[0095]

[0136] Non-limiting examples of lipids include phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; polymer chains with lipids such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; sulfonated monosaccharides, disaccharides, and polysaccharides with lipids; fatty acids such as palmitic acid, stearic acid, and oleic acid; cholesterol, cholesterol esters, and cholesterol hemisuccinate.

[0096]

[0137] In some cases, the phospholipid comprises one or more saturated phospholipids such as phosphatidylcholine.Exemplary acyl chain lengths are 16:0 and 18:0 (e.g., palmitoyl and stearoyl).The content of phospholipid can be determined by the activity of active agent, delivery mode, and other factors.

[0097]

[0138] Phospholipids from both natural and synthetic sources can be used in various amounts.When phospholipids are present, the amount is typically sufficient to coat the active agent with at least a single molecular layer of phospholipids.Generally, the content of phospholipids ranges from about 5wt% to about 99.9wt%, for example, from about 20wt% to about 80wt%.

[0098]

[0139] In general, suitable phospholipids may include those that have a gel to liquid crystal phase transition above about 40° C., such as above about 60° C., or above about 80° C. The incorporated phospholipids may be relatively long chain (e.g., C 16 ~C 22Exemplary phospholipids useful in the present disclosure include, but are not limited to, phosphoglycerides such as dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, diarachidoylphosphatidylcholine, dibehenoylphosphatidylcholine, diphosphatidylglycerol, short chain phosphatidylcholine, hydrogenated phosphatidylcholine, E-100-3 (available from Lipoid KG, Ludwigshafen, Germany), long chain saturated phosphatidylethanolamine, long chain saturated phosphatidylserine, long chain saturated phosphatidylglycerol, long chain saturated phosphatidylinositol, phosphatidic acid, phosphatidylinositol, and sphingomyelin.

[0099]

[0140] Examples of metal ions include divalent cations, including, but not limited to, calcium, magnesium, zinc, iron, etc. For example, when phospholipids are used, the pharmaceutical composition may also include polyvalent cations, as disclosed in WO01 / 85136 and WO01 / 85137, which are incorporated herein by reference in their entirety. Polyvalent cations may be used to improve the stability of the pharmaceutical composition at its storage temperature (T m ) at least about 20° C., e.g., at least about 40° C. higher than m As shown, the melting temperature of phospholipids (T m The polyvalent cation may be present in an amount effective to increase the phospholipid concentration. The molar ratio of polyvalent cation to phospholipid may be at least about 0.05:1, such as from about 0.05:1 to about 2.0:1, or from about 0.25:1 to about 1.0:1. An example of a molar ratio of polyvalent cation:phospholipid is about 0.50:1. When the polyvalent cation is calcium, it may be in the form of calcium chloride. Metal ions, such as calcium, are often included with phospholipids, although neither is required.

[0100]

[0141] The pharmaceutical composition may include one or more surfactants. For example, one or more surfactants may be present in the liquid phase, with one or more associated with the solid particles or particles of the composition. "Associated" means that the pharmaceutical composition may incorporate, adsorb, absorb, be coated by, or be formed with the surfactant. Surfactants include, but are not limited to, fluorinated and non-fluorinated compounds, such as saturated and unsaturated lipids, non-ionic detergents, non-ionic block copolymers, ionic surfactants, and combinations thereof. In addition to the above-mentioned surfactants, it should be emphasized that suitable fluorinated surfactants may be used to be compatible with the teachings of this specification and provide the desired preparation.

[0101]

[0142] Examples of non-ionic detergents include, but are not limited to, sorbitan esters including sorbitan trioleate (Span™ 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene(20) sorbitan monolaurate, and polyoxyethylene(20) sorbitan monooleate, oleyl polyoxyethylene(2) ether, stearyl polyoxyethylene(2) ether, lauryl polyoxyethylene(4) ether, glycerol esters, and sucrose esters. Other suitable non-ionic detergents can be readily identified using McCutcheon's Emulsifiers and Detergents (McPublishing Co., Glen Rock, NJ), which is incorporated herein by reference in its entirety.

[0102]

[0143] Examples of block copolymers include, but are not limited to, diblock and triblock copolymers of polyoxyethylene and polyoxypropylene, including poloxamer 188 (Pluronic™ F-68), poloxamer 407 (Pluronic™ F-127) and poloxamer 338. Examples of ionic surfactants include, but are not limited to, sodium sulfosuccinate and fatty acid soaps. Examples of amino acids include, but are not limited to, hydrophobic amino acids. The use of amino acids as pharma- ceutically acceptable excipients is known in the art, as disclosed in WO95 / 31479, WO96 / 32096 and WO96 / 32149, which are incorporated herein by reference in their entireties.

[0103]

[0144] Examples of buffering agents include, but are not limited to, acetate, tris, or citrate. Examples of acids include, but are not limited to, carboxylic acids. Examples of salts include, but are not limited to, sodium chloride, salts of carboxylic acids (e.g., sodium citrate, sodium ascorbate, magnesium gluconate, sodium gluconate, tromethamine hydrochloride, etc.), ammonium carbonate, ammonium acetate, ammonium chloride, etc. Examples of organic solids include, but are not limited to, camphor, etc. The pharmaceutical compositions of one or more embodiments of the present disclosure may also include biocompatible, e.g., biodegradable, polymers, copolymers, or blends or other combinations thereof. In this regard, useful polymers include polylactides, polylactide-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydrides, polylactams, polyvinylpyrrolidones, polysaccharides (dextran, starch, chitin, chitosan, etc.), hyaluronic acid, proteins (albumin, collagen, gelatin, etc.). One of ordinary skill in the art will appreciate that by selecting an appropriate polymer, the delivery efficiency of the composition and / or the stability of the dispersion can be tailored to optimize the effectiveness of the antiarrhythmic pharmaceutical agent.

[0104]

[0145] In the case of solution, the composition may include one or more osmolality adjusters, such as sodium chloride.For example, sodium chloride can be added to the solution to adjust the osmolality of the solution.In one or more embodiments, the aqueous composition essentially consists of the antiarrhythmic pharmaceutical agent, the osmolality adjuster and water.

[0105]

[0146] The solution may also include a buffer or pH adjuster, typically a salt prepared from an organic acid or base. Representative buffers include citric acid, lactic acid, ascorbic acid, gluconic acid, organic acid salts of carboxylic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers. Thus, buffers may include citrates, phosphates, phthalates, and lactates.

[0106]

[0147] In addition to the above-mentioned pharma- ceutically acceptable excipients, other pharma-ceutically acceptable excipients may be added to the pharmaceutical composition to improve particle rigidity, production yield, emitted dose and deposition, shelf life, and patient satisfaction. It may be desirable to improve the acceptance. Such optional pharma- ceutically acceptable excipients include, but are not limited to, colorants, taste masking agents, buffers, hygroscopic agents, antioxidants, and chemical stabilizers. In addition, various pharma-ceutically acceptable excipients can be used to impart structure and morphology to the particulate composition (e.g., latex particulates). In this regard, it is understood that post-production techniques such as selective solvent extraction can be used to remove hardened components.

[0107]

[0148] The pharmaceutical composition of one or more embodiments of the present disclosure may be tasteless.In this regard, a taste masking agent is optionally included in the composition, but in some embodiments, the composition does not include a taste masking agent other than cyclodextrin, and even if it does not include a taste masking agent, it is tasteless.

[0108]

[0149] Pharmaceutical compositions may also include mixtures of pharma- ceutically acceptable excipients, for example, mixtures of carbohydrates and amino acids are within the scope of this disclosure.

[0150] The compositions of one or more embodiments of the present disclosure may take a variety of forms, such as a solution containing a non-aqueous phase such as a propellant (e.g., chlorofluorocarbons, hydrofluoroalkanes), a dry powder, a reconstituted powder, a suspension, or a dispersion.

[0109]

[0151] The solutions of the present disclosure are typically clear. In this regard, many of the antiarrhythmic pharmaceutical agents of the present disclosure are water soluble.

[0152] In some embodiments, the isotonicity of the solution ranges from isotonic to physiological isotonicity, which is the isotonicity of physiological fluids.

[0110]

[0153] In some variations, the pharmaceutical composition is a nebulized aerosol and includes droplets having a mass median diameter of less than about 20 μm, e.g., less than about 10 μm, less than about 7 μm, or less than about 5 μm. The droplets may have a mass median aerodynamic diameter in the range of about 1 μm to about 6 μm, e.g., about 1.5 μm to about 5 μm, or about 2 μm to about 4 μm. If the droplets are too large, a high percentage of the particles will not reach the lungs. If the droplets are too small, a high percentage of the droplets will be exhaled.

[0111]

[0154] The dosage unit of the pharmaceutical composition may be placed in a container. Examples of containers include, but are not limited to, syringes, capsules, blow-fill seals, blisters, vials, ampoules, cartridges, or container closure systems made of metal, polymers (e.g., plastics, elastomers), glass, etc. For example, the vial may be a colorless type I borosilicate glass ISO 4R 6mL vial with a chlorobutyl rubber siliconized stopper and a flip-off aluminum cap with a colored plastic cover. In some embodiments, the vial may be a colorless type I borosilicate glass ISO 6R 10mL vial with a chlorobutyl rubber siliconized stopper and a flip-off aluminum cap with a colored plastic cover.

[0112]

[0155] The container may be inserted into the aerosolization device. The container may be of a suitable shape, size, and material to contain the pharmaceutical composition and provide the pharmaceutical composition in a usable state. For example, the capsule or blister may include a wall comprising a material that does not adversely react with the pharmaceutical composition. Additionally, the wall may comprise a material that allows the capsule to open and the pharmaceutical composition to be aerosolized. In one variation, the wall comprises one or more of gelatin, hydroxypropyl methylcellulose (HPMC), HPMC blended with polyethylene glycol, hydroxypropyl cellulose, agar, aluminum foil, and the like. In one variation, the capsule may include telescopically joined portions, for example, as described in U.S. Pat. No. 4,247,066, which is incorporated herein by reference in its entirety. The size of the capsule may be selected to appropriately contain a dose of the pharmaceutical composition. Sizes generally range from size 5 to size 000, each having an outer diameter of about 4.91 mm. The diameter of the capsule may range from about 11.10 mm to about 26.14 mm, and the volume may range from about 0.10 ml to about 1.37 mL. Suitable capsules are commercially available, for example, from Shionogi Qualicaps Co., Nara, Japan, and Capsugel, Greenwood, SC. ​​After filling, an upper part may be placed over a lower part to form a capsule shape and contain a powder within the capsule, as described in U.S. Patent Nos. 4,846,876 and 6,357,490, and WO00 / 07572, which are incorporated herein by reference in their entireties. After the upper part is placed over the lower part, the capsule may be banded as desired.

[0113]

[0156] In the case of a solution, the amount of the composition in a dosage unit is about 0.5 mL to about 15 mL, for example, 1 mL to 15 mL, 2 mL to 15 mL, 3 mL to 15 mL, 4 mL to 15 mL, 5 mL to 15 mL, 6 mL to 15 mL, 7 mL to 15 mL, 8 mL to 15 mL, 9 mL to 15 mL, 10 mL to 15 mL, 11 mL to 15 mL, 12 mL to 15 mL, 10 mL to 15 mL, 14 mL to 15 mL, 1 mL to 13 mL, 2 mL to 13 mL, 3 mL to 13 mL, 4 mL to 13 mL, 5 mL to 13 mL, 6 mL to 13 mL, 7 mL to 13 mL, 8 mL to The volume may be in the range of 13mL, 9mL to 13mL, 10mL to 13mL, 11mL to 13mL, 12mL to 13mL, 1mL to 10mL, 2mL to 10mL, 3mL to 10mL, 4mL to 10mL, 5mL to 10mL, 6mL to 10mL, 7mL to 10mL, 8mL to 10mL, 9mL to 10mL, 1mL to 8mL, 2mL to 8mL, 3mL to 8mL, 4mL to 8mL, 5mL to 8mL, 6mL to 8mL, 7mL to 8mL, 1mL to 5mL, 2mL to 5mL, 3mL to 5mL, 4mL to 5mL or 1mL to 3mL. In some embodiments, the amount of the composition in a dosage unit is about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 10 mL, about 14 mL, or about 15 mL. In some embodiments, the amount of the composition in a dosage unit is up to about 2 mL, up to about 3 mL, up to about 4 mL, up to about 5 mL, up to about 6 mL, up to about 7 mL, up to about 8 mL, up to about 9 mL, up to about 10 mL, up to about 11 mL, up to about 12 mL, up to about 10 mL, up to about 14 mL, or up to about 15 mL.

[0114]

[0157] The compositions of the present disclosure may be made by any of the various methods and techniques known and available to those of skill in the art.

[0158] For example, a solution of an antiarrhythmic pharmaceutical agent may be made using the following procedure. Typically, the manufacturing equipment is sterilized before use. A portion of the final volume, such as a solvent, for example 70% of water for injection, may be added to a suitable container. Some or all of the other additional pharma- ceutically acceptable carriers or excipients, solubilizers, or additional components of other pharmaceutical compositions (e.g., cyclodextrin, for example HPβCD; for example, acids, for example acetic acid, hydrochloric acid, nitric acid, or citric acid; for example, saccharin, for example sodium saccharin) may be added either before or after the addition of the antiarrhythmic pharmaceutical agent, for example, a flecainide salt, for example, flecainide acetate. The antiarrhythmic pharmaceutical agent, for example, a salt of flecainide, may then be added. The antiarrhythmic pharmaceutical agent may be mixed until dissolved. Additional solvent may be added to make up the final batch volume. The batch may be filtered, for example, through a 0.2 μm filter into a sterile receiving vessel. The fill components may be sterilized before use when filling the batch into vials, for example, 10 mL vials.

[0115]

[0159] By way of example, the above sterilization may include: One glass bottle of 5 liter type and a lid may be placed in an autoclave bag and sterilized using an autoclave at an elevated temperature, for example 121°C for 15 minutes. Similarly, a vial may be placed in a suitable rack, inserted into an autoclave bag and sterilized using an autoclave at an elevated temperature, for example 121°C for 15 minutes. Similarly, a stopper may be placed in an autoclave bag and sterilized using an autoclave at an elevated temperature, for example 121°C for 15 minutes. Prior to sterilization, A sterile filter may be attached to tubing, for example a 2 mm length of 7 mm x 13 mm silicone tubing. The filling line may be prepared by placing it in an autoclave bag and sterilizing it using an autoclave at an elevated temperature, for example 121°C for 15 minutes.

[0116]

[0160] The filtration described above may involve filtration into a laminar flow working area. A receiving bottle and a filter may be placed within the laminar flow working area.

[0161] The above filling may also be done under laminar flow protection. The filling line may be opened and placed into a receiving bottle. The sterile vials and stoppers may be opened under laminar flow protection. Each vial may be filled to a target fill of, for example, 5 g, and stoppered. A flip-off collar may be applied to each vial. The sealed vials may be inspected for vial leakage, proper overseal, and cracks.

[0117]

[0162] The pharmaceutical composition according to one or more embodiments of the present disclosure may contain a combination of an antiarrhythmic pharmaceutical agent (e.g., flecainide salt) and one or more additional active agents, if desired, including, but not limited to, agents that can be delivered through the lungs.

[0118]

[0163] Additional active agents may include, for example, hypnotics and sedatives, psychostimulants, tranquilizers, respiratory agents, anticonvulsants, muscle relaxants, anti-Parkinson's agents (dopamine antagonists), analgesics, anti-inflammatory agents, anti-anxiety agents (anxiolytics), appetite suppressants, anti-migraine agents, muscle contractants, additional anti-infective agents (antivirals, antifungals, vaccines), anti-arthritic agents, antimalarials, antiemetics, anti-epileptic agents, cytokines, growth factors, anti-cancer agents, anti-thrombotic agents, antihypertensive agents, cardiovascular agents, antiarrhythmic agents, antioxidants, anti-asthmatic agents, hormonal agents including contraceptives, sympathomimetics, diuretics, lipid regulating agents, antiandrogens, anthelmintics, anticoagulants, neoplastic agents, antineoplastic agents, hypoglycemic agents, nutritional agents and supplements, growth supplements, antienteritis agents, vaccines, antibodies, diagnostic agents, and imaging agents. The additional active agent, when administered by inhalation, may act locally or systemically.

[0119]

[0164] The additional active agent may fall into one of a number of structural classes, including, but not limited to, small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of eliciting a physiological effect, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like.

[0120]

[0165] Examples of additional active agents suitable for use in the present disclosure include, but are not limited to, calcitonin, amphotericin B, erythropoietin (EPO), factor VIII, factor IX, ceredase, cerezyme, cyclosporine, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-1 receptor, interleukin-2, interleukin-1 receptor antagonist, interleukin-3. , interleukin-4, interleukin-6, luteinizing hormone releasing hormone (LHRH), factor IX, insulin, proinsulin, insulin analogs (e.g., monoacylated insulin as described in U.S. Pat. No. 5,922,675, which is incorporated by reference in its entirety), amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), insulin-like growth factor (IGF), insulinotropin, macrophage colony stimulating factor (M-CSF), nerve growth factor (NGF), tissue growth factor, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factor, parathyroid hormone (PTH), glucagon-like peptides. Thymosin alpha 1, IIb / IIa inhibitors, alpha-1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosphonates, respiratory syncytial virus antibodies, cystic fibrosis transmembrane regulator (CFFR) gene, deoxyribonuclease (DNase), bactericidal / permeability enhancing protein (BPI), anti-CMV antibodies, 13-cis retinoic acid, oleandomycin, troleandomycin, roxithromycin, clarithromycin, daversin, azithromycin fluoroquinolones, such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxacin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin; sine, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, iroxacin, pazufloxacin, clinafloxacin and sitafloxacin, teicoplanin, lampolaninin, mideplanin, colistin, daptomycin, gramicidin, colistimethate, polymyxins such as polymyxin B, capreomycin, bacitracin, penems; penicillins including penicillinase-susceptible agents such as penicillin G, penicillin V, methicillin, penicillinase-resistant agents such as cyclosacillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram-negative microorganism-active agents such as ampicillin, amoxicillin, and hetacillin, cyclosacillin, and galampicillin; antipseudomonal penicillins such as carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins such as cefpodoxime, cefprozil, ceftibuten, ceftizoxime, ceftriaxone, cephalothin, monobactams such as cephapirin, cephalexin, cephaladrin, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cefaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefinetazole, ceftazidime, loracarbef and moxalactam, aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isethiouate, lidocaine, metaproterenol sulfate, dipeptide, Beclomethasone diprepionate, triamcinolone acetaminophen amide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate, and where applicable, analogs, agonists, antagonists, inhibitors, and pharma- ceutically acceptable salt forms of the above. With respect to peptides and proteins, the present disclosure is intended to encompass synthetic, native, glycosylated, non-glycosylated, pegylated forms, and biologically active fragments, derivatives, and analogs thereof.

[0121]

[0166] Additional active agents for use in the present disclosure may further include nucleic acids, such as naked nucleic acid molecules, vectors, related viral particles, plasmid DNA or RNA, or other nucleic acid constructs of a type suitable for transfection or transformation of cells, such as those suitable for gene therapy, including antisense. Additionally, active agents may include live attenuated or killed viruses suitable for use as vaccines. Other useful drugs are listed in the Physician's Desk Reference (latest edition), which is incorporated herein by reference in its entirety. This includes those that are

[0122]

[0167] When a combination of active agents is used, the agents may be provided in combination in a single pharmaceutical composition or individually in separate pharmaceutical compositions. preparation

[0168] In some aspects, the present disclosure provides a method for preparing a liquid pharmaceutical composition comprising an antiarrhythmic pharmaceutical agent. In some cases, the method comprises the steps of: (a) water; (b) a pH adjusting agent; (c) a phlebotomy agent; and (d) a phlebotomy agent. The method includes combining (a) cyclodextrin or a pharma- ceutically acceptable salt thereof; and (d) cyclodextrin. In some cases, the water used to prepare the formulation is sterilized. In some cases, the water used to prepare the formulation is water for injection. In some cases, all of the starting materials are sterilized by established techniques that meet medical standards.

[0123]

[0169] In some cases, the preparation method includes the steps of: (a) providing water; (b) contacting a portion of the water with flecainide or a pharma- ceutically acceptable salt thereof, a cyclodextrin and a pH adjuster in a vessel; and (c) adding a next portion of water to the vessel to provide the pharmaceutical composition.

[0124]

[0170] In some cases, in the compositions prepared by the methods provided herein, the concentration of flecainide or a pharma- ceutically acceptable salt thereof is from about 65 mg / mL to about 95 mg / mL in the pharmaceutical composition, the concentration of cyclodextrin in the pharmaceutical composition is from about 10% (w / v) to about 30% (w / v), and the pH of the pharmaceutical composition at room temperature is from about 5.5 to about 6.5.

[0125]

[0171] In some cases, the pH adjuster comprises an ion selected from the group consisting of acetate, citrate, nitrate, chloride, sulfate, maleate, tartrate, phosphate, aconitate, adipate, ascorbate, benzoate, caprylate, cholate, formate, glutamate, lactate, propionate, sorbate, stearate, and succinate. In some cases, the pH adjuster comprises a pH buffer. In some cases, the pH adjuster comprises an acid or a base. In some cases, the pH adjuster comprises an acid. In some cases, the pH adjuster is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbic acid, benzoic acid, caprylic acid, cholate, formic acid, glutamic acid, lactate, propionic acid, sorbic acid, stearic acid, and succinic acid. In some cases, the pH adjuster is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, and sulfuric acid. In some cases, the pH adjuster comprises a mixture of acids including, but not limited to, acetic acid, citric acid, nitric acid, hydrochloric acid, and sulfuric acid. In some cases, the pH adjuster comprises acetic acid. In some cases, the pH adjuster comprises citric acid.

[0126]

[0172] In some cases, the pH adjuster is added to a concentration of about 2 mM to about 50 mM. In some cases, the pH adjuster is added to a concentration of about 2 mM to about 10 mM. In some cases, the pH adjuster includes acetic acid. In some cases, the concentration of acetic acid in the pharmaceutical composition is about 5 mM. In some cases, the pH adjuster includes citric acid. In some cases, the concentration of citric acid in the pharmaceutical composition is about 5 mM.

[0127]

[0173] In some cases, the preparation method includes adding a cyclodextrin to the solution. In some cases, the cyclodextrin added includes α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatized α-cyclodextrin, derivatized β-cyclodextrin, or derivatized γ-cyclodextrin. In some cases, the cyclodextrin may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin dimaltosyl-β-cyclodextrin, succinyl-β-cyclodextrin, 6A-amino-6A-deoxy- In some cases, the cyclodextrin comprises hydroxypropyl-β-cyclodextrin. In some cases, the concentration of the cyclodextrin in the pharmaceutical composition is about 10% (w / v) to about 30% (w / v).

[0128]

[0174] In some cases, the preparation method includes adding a sweetener to the solution. In some cases, the sweetener is selected from the group consisting of acesulfame potassium, aspartame, cyclamate, mogroside, saccharin, stevia, sucralose, neotame, mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, and pharma- ceutically acceptable salts thereof. In some cases, the sweetener comprises saccharin. In some cases, the sweetener comprises a salt of saccharin. In some cases, the sweetener comprises sodium saccharin. In some cases, the sweetener is added to a concentration of about 0.001% (w / v) to about 1% (w / v). In some cases, the sweetener is added to a concentration of about 0.001% (w / v) to about 0.05% (w / v). In some cases, sweeteners are added to a concentration of about 0.001% (w / v) to about 0.01% (w / v).

[0129]

[0175] In some cases, the preparation method comprises adding a pharmaceutically acceptable salt of flecainide, such as flecainide acetate, flecainide hydrochloride, flecainide citrate, flecainide phosphate or flecainide nitrate.In some cases, the pharmaceutically acceptable salt of flecainide comprises flecainide acetate.In some cases, the pharmaceutically acceptable salt of flecainide comprises flecainide hydrochloride.

[0130]

[0176] In some cases, the preparation method further comprises packaging the pharmaceutical composition in a dosage unit form. For example, the dosage unit form may comprise about 50 mg to about 350 mg of a pharmaceutically acceptable salt of flecainide. For example, the dosage unit form comprises about 60 mg to about 150 mg of a pharmaceutically acceptable salt of flecainide, such as about 75 mg to about 125 mg, about 250 mg to about 350 mg, or about 150 mg to about 250 mg, such as about 90 mg, about 120 mg, or about 200 mg of a pharmaceutically acceptable salt of flecainide.

[0131] Treatment

[0177] The methods, compositions and kits provided herein may include administration of the pharmaceutical composition by inhalation, for example oral or nasal inhalation.

[0132]

[0178] The treatment provided herein may include or be suitable for inhalation, for example oral or nasal inhalation.In some cases, during administration by oral inhalation, pharmaceutical agent is inhaled by patient through mouth and absorbed by lungs.In some cases, during administration by nasal inhalation, pharmaceutical agent is inhaled by patient through nose and absorbed by nasal mucosa and / or lungs.

[0133]

[0179] Inhalation route can avoid liver first metabolism, thus eliminating the fluctuation of dosage.Unlike oral tablets or pills, the metabolic rate of the patient may not be important, because administration is independent of the metabolic system experienced through the digestive tract when the drug is administered via oral route, such as tablets, pills, solutions or suspensions.The rapid absorption of the drug from the nasal mucosa and / or lungs can achieve a rapid onset of action, potentially improving efficacy and / or reducing dosage.

[0134]

[0180] Rapid absorption rates of drugs through the lungs can be achieved because aerosols small enough to penetrate the central and peripheral regions of the lungs provide a large available surface area. The rate and extent of absorption of drugs delivered by inhalation can result in plasma concentration versus time profiles that are comparable to the IV route of administration.

[0135]

[0181] The onset of action may be short. For example, the patient may have normal sinus rhythm within 20 minutes of the start of administration, for example, within 15 minutes, within 10 minutes, or within 5 minutes of the start of administration. In some cases, a rapid onset of action is advantageous because the longer a patient remains in arrhythmia (i.e., atrial fibrillation), the more difficult it is to restore normal sinus rhythm.

[0136]

[0182] In some embodiments, the disclosed methods allow the patient to avoid other therapies, such as ablation and / or electrical cardioversion. In other embodiments, the disclosed methods are used in combination with other therapies, such as before or after electrical cardioversion and / or ablation therapy.

[0137]

[0183] In some aspects of the present disclosure, the composition or formulation of the pharmaceutical composition is administered by inhalation. The pharmaceutical composition may be aerosolized prior to administration or may be presented to the user in the form of an aerosol.

[0138]

[0184] The pharmaceutical composition may be administered using an aerosolization device. The aerosolization device may be a nebulizer, a metered dose inhaler, or a liquid dose infusion device. The aerosolization device may include the extrusion of the pharmaceutical preparation through micron or submicron sized holes, followed by Rayleigh breakup into fine droplets. The pharmaceutical composition may be delivered by a nebulizer as described in WO99 / 16420, the entirety of which is incorporated herein by reference, by a metered dose inhaler as described in WO99 / 16422, by a liquid dose infusion device as described in WO99 / 16421, and by a dry powder inhaler as described in US Published Application Nos. 20020017295 and 20040105820, WO99 / 16419, WO02 / 83220, and US Pat. No. 6,546,929. Thus, the inhaler may include a canister containing particles or particles and a propellant, and the inhaler includes a metered dose valve that communicates with the interior of the canister. The propellant may be a hydrofluoroalkane.

[0139]

[0185] For example, the pharmaceutical formulation may be in a liquid solution and may be administered using a nebulizer, such as those disclosed in PCT WO99 / 16420, the entire disclosure of which is incorporated herein by reference, to provide an aerosolized medicament that can be administered to the pulmonary airways of a patient in need of administration. Nebulizers known in the art are readily available for administration of the claimed formulations. Breath-activated or breath-actuated nebulizers, as well as other types of improvements that have been developed or will be developed, are also contemplated as being compatible with and within the scope of the formulations of the present disclosure.

[0140]

[0186] In some cases, the nebulizer is a breath-activated or breath-actuated nebulizer. In some cases, the nebulizer is a hand-held inhalation device (e.g., AeroEclipse® II Breath Actuated Nebulizer (BAN)). In some cases, the nebulizer has a compressed air source. In some cases, the nebulizer converts the liquid medicament into an aerosol. In some cases, the nebulizer converts the liquid medicament into an aerosol by forcing the pharmaceutical preparation through micron or submicron sized holes. In some cases, the nebulizer converts the liquid medicament into an aerosol so that the liquid medicament can be inhaled into the lungs. In some cases, the nebulizer is a small volume nebulizer. In some cases, the nebulizer is a small volume jet nebulizer. In some cases, the aerosolized medicament is only generated when inhaled by the device. In some cases, the medicament is contained in the cup during breathing or during breaks in the treatment. In some cases, the medicament is contained in the cup until it is ready to be inhaled.

[0141]

[0187] A nebulizer can impart energy to a liquid pharmaceutical formulation to aerosolize the liquid, enabling delivery to the patient's pulmonary system, e.g., the lungs. A nebulizer includes a liquid delivery system, such as a container having a reservoir that contains the liquid pharmaceutical formulation. Liquid pharmaceutical formulations generally include an active agent that is either in solution or suspended within a liquid medium.

[0142]

[0188] In one type of nebulizer that can be used in the subject methods and kits, generally referred to as a jet nebulizer, compressed gas is forced through an orifice in a container. The compressed gas causes liquid to be aspirated through a nozzle, where the aspirated liquid mixes with the flowing gas and forms aerosol droplets. The cloud of droplets may then be administered to the patient's airways.

[0143]

[0189] In another type of nebulizer that can be used with the subject methods and kits, generally referred to as a vibrating mesh nebulizer, energy, such as mechanical energy, causes a mesh to vibrate. This vibration of the mesh aerosolizes the liquid pharmaceutical formulation, producing an aerosol cloud that is administered to the patient's lungs. In another type of nebulizer that can be used with the subject methods and kits, nebulization involves extrusion through micron or submicron sized holes followed by Rayleigh breakup into fine droplets.

[0144]

[0190] Alternatively or additionally, the pharmaceutical formulation may be in liquid form and aerosolized using a nebulizer as described in WO2004 / 071368, which is incorporated herein by reference in its entirety, and U.S. Published Application Nos. 2004 / 0011358 and 2004 / 0035413, both of which are incorporated herein by reference in their entirety.Other examples of nebulizers include, but are not limited to, Aeroneb® Go or Aeroneb® Pro nebulizers available from Aerogen Ltd., Galway, Ireland; PARI eFlow and other PARI nebulizers available from PARI Respiratory Equipment, Inc., Midlothian, Va; Lumiscope® nebulizers 6600 or 6610 available from Lumiscope Company, Inc., East Brunswick, NJ, and Omron NE-U22 available from Omron Healthcare, Inc., Kyoto, Japan. Other examples of nebulizers include devices produced by Medspray (Enschede, The Netherlands).

[0145]

[0191] It has been found that vibrating mesh nebulizers, such as those that do not use compressed gas to form droplets, such as Aeroneb® Pro, provide unexpected improvements in dosing efficiency and consistency. By using a vibrating perforated or non-perforated membrane to generate fine droplets, rather than introducing compressed air, aerosolized pharmaceutical formulations can be introduced without substantially affecting flow characteristics. Furthermore, when using this type of nebulizer, the resulting droplets are introduced at a low speed, which reduces the likelihood of droplets being carried to undesired areas. It has also been found that when using extrusion / Rayleigh jet breakup nebulizers, the resulting droplets are introduced at a low speed, which reduces the likelihood of droplets being carried to undesired areas.

[0146]

[0192] In some cases, the nebulizers usable in the subject methods and kits are of the vibrating mesh type. In some cases, the nebulizers usable in the subject methods and kits are of the pressurized jet type. In some cases, the nebulizers usable in the subject methods and kits are of the extrusion / Rayleigh splitting type. In some cases, the nebulizers are lightweight (up to 60g, up to 100g, up to 200g, up to 250g) and nearly silent. In some cases, the nebulizers have a sound level of less than 35 A-weighted decibels (dBA) at 1 meter. In some cases, the nebulizers have a dosing cup volume of 6 mL. In some cases, the nebulizers are of the axially dispensing type. The nebulizer has a residual volume of less than 0.3 mL. In some cases, the nebulizer produces an average flow rate of 0.4 mL / min. In some cases, the nebulizer produces an average flow rate of 0.5 mL / min. In some cases, the nebulizer produces an average flow rate of 0.6 mL / min. In some cases, the nebulizer produces an average flow rate of 0.7 mL / min. In some cases, the nebulizer produces an average flow rate of 0.8 mL / min. In some cases, the nebulizer produces an average flow rate of 0.9 mL / min. In some cases, the nebulizer produces an average flow rate of 1.0 mL / min. In some cases, the nebulizer produces an average flow rate of 1.1 mL / min. In some cases, the nebulizer produces an average flow rate of 1.2 mL / min. In some cases, the nebulizer produces an average particle size of 3.0 μm MMAD. In some cases, the nebulizer produces an average particle size of 3.0 μm MMAD to 4.0 μm MMAD. In some cases, the nebulizer produces an average particle size of 3.0 μm MMAD. In some cases, the nebulizer produces an average particle size of 3.0 μm MMAD to 5.0 μm MMAD. In some cases, the nebulizer produces an average particle size of 3.0 μm MMAD. In some cases, the nebulizer produces an average particle size of 3.0 μm MMAD to 6.0 μm MMAD.

[0147]

[0193] Yet another type of nebulizer that can be used in the subject methods and kits generates ultrasound to directly vibrate and aerosolize the pharmaceutical formulation.

[0194] The pharmaceutical formulations disclosed herein may also be administered to the lungs of a patient by aerosolization, such as with a metered dose inhaler. The use of such formulations results in excellent dose reproducibility and improved lung deposition, as disclosed in WO99 / 16422, the entirety of which is incorporated herein by reference. Metered dose inhalers (MDIs) known in the art may be utilized to administer the claimed pharmaceutical compositions. It is contemplated that breath-activated or breath-actuated MDIs and pressurized MDIs (pMDIs), including other types of improvements that have been developed or will be developed, are compatible with the formulations of the present disclosure and therefore fall within its scope.

[0148]

[0195] It is understood that the formulation of one or more embodiments of the present disclosure may be used with MDIs and nebulizers, as well as with liquid dose infusion or LDI technology, for example as disclosed in WO99 / 16421, the entirety of which is incorporated herein by reference. Liquid dose infusion involves direct administration of the formulation to the lungs. For LDI, the formulation is preferably used with partial or total liquid ventilation. Furthermore, one or more embodiments of the present disclosure may further include a step of introducing a therapeutically beneficial amount of a physiologically acceptable gas (e.g., nitric oxide or oxygen) into the pharmaceutical microdispersion before, during or after administration.

[0149]

[0196] The pharmaceutical compositions of one or more embodiments of the present disclosure may exhibit improved emitted dose efficiency. Thus, a variety of aerosolization devices and techniques can be used to deliver high doses of the pharmaceutical compositions.

[0150]

[0197] The emitted dose (ED) of the particles of the present disclosure may be greater than about 30%, such as greater than about 40%, greater than about 50%, greater than about 60%, or greater than about 70%.

[0198] The pharmaceutical composition may be administered to a patient as required.For example, the method, kit and composition can be particularly used for treating a subject experiencing a cardiac condition, such as cardiac arrhythmia, such as atrial arrhythmia.In some cases, the subject is administered the treatment described herein when the subject is experiencing atrial arrhythmia.In some cases, the pharmaceutical composition is administered to the subject after the onset of an episode of cardiac arrhythmia.In other cases, the subject is treated during an episode of cardiac arrhythmia.

[0151]

[0199] The dose of antiarrhythmic drug, for example flecainide salt, for example flecainide acetate, may be administered during one inhalation or during multiple inhalations.The increase or decrease in concentration of antiarrhythmic pharmaceutical drug may be reduced by administering pharmaceutical composition more frequently, or may be increased by administering pharmaceutical composition less frequently.Thus, the pharmaceutical composition provided herein may be administered from about 4 times a day to about once a month, for example from about once a day to about once a month. It may be administered about once every two weeks, about once every two days to about once a week, and about once a week.

[0152]

[0200] In some cases, the antiarrhythmic pharmaceutical agent is delivered over two or more inhalations. In some cases, the time between two or more inhalations is about 0.1 to 10 minutes. The antiarrhythmic pharmaceutical agent is administered in less than 60 minutes, less than 50 minutes, less than 40 minutes, less than 30 minutes, less than 20 minutes, less than 15 minutes, less than 10 minutes, less than 7 minutes, less than 5 minutes, less than 3 minutes, less than 2 minutes, or less than 1 minute at the doses described. In some cases, delivery of the required dose of the antiarrhythmic pharmaceutical agent is completed in 1, 2, 3, 4, 5, or 6 inhalations. In some cases, each inhalation is administered for about 0.5, 1, 1.2, 1.5, 1.8, 2, 2.2, 2.5, 2.8, 3, 3.2, 3.5, 3.8, 4, 4.2, 4.5, 4.8, or 5 minutes. In some cases, each inhalation is administered for more than 5 minutes. In some cases, each inhalation is administered for up to 4.5 minutes. In some cases, each inhalation includes at least 60 inhalation breaths, 50 inhalation breaths, 40 inhalation breaths, 30 inhalation breaths, 20 inhalation breaths, 10 inhalation breaths, 8 inhalation breaths, 6 inhalation breaths, 4 inhalation breaths, 3 inhalation breaths, 2 inhalation breaths or 1 inhalation breath. In some cases, each inhalation includes no more than 100 inhalation breaths, 90 inhalation breaths, 80 inhalation breaths, 70 inhalation breaths, 60 inhalation breaths, 50 inhalation breaths, 40 inhalation breaths, 30 inhalation breaths or 20 inhalation breaths. In some cases, the inhalation of the antiarrhythmic pharmaceutical agent is performed by deep lung breathing lasting more than 1, 2, 3 or 4 seconds. In some cases, the inhalation of the antiarrhythmic pharmaceutical agent is performed by deep lung breathing lasting about 1, 2, 3 or 4 seconds.

[0153]

[0201] In some embodiments, during the inhalation delivery of the antiarrhythmic pharmaceutical agent, the subject takes or is instructed to take a break between two inhalations.In such embodiments, the break between two inhalations lasts about 0.1 to 10 minutes, such as 0.2 to 5, 1 to 5, 1.5 to 5, 2 to 5, 3 to 5, 4 to 5, 1 to 1.5, 1 to 2, 1 to 2.5, 1 to 3, 1 to 3.5, 1 to 4, 1.5 to 2, 1.5 to 2.5, or 1.5 to 3 minutes.In some cases, the subject takes or is instructed to take a break of about 1 minute between two inhalations. In some cases, the inhalation pattern for delivery of a single dose proceeds as follows: first inhalation about 4-4.5 minutes, a break of about 1 minute, and a second inhalation about 4-4.5 minutes; first inhalation about 4-4.5 minutes, a break of about 30 seconds, and a second inhalation about 4-4.5 minutes; first inhalation about 4-4.5 minutes, a break of about 1 minute, and a second inhalation about 4-4.5 minutes; second break about 1 minute, and a third inhalation about 4-4.5 minutes; or first inhalation about 4-4.5 minutes, a break of about 30 seconds, and a second inhalation about 4-4.5 minutes; second break about 30 seconds, and a third inhalation about 4-4.5 minutes.

[0154]

[0202] In one variation, the antiarrhythmic drug may be administered daily, in which case the daily dosage of flecainide acetate ranges from about 0.1 mg to about 600 mg, such as from about 0.5 mg to about 500 mg, from about 1 mg to about 400 mg, from about 2 mg to about 300 mg, and from about 3 mg to about 200 mg.

[0155]

[0203] In some cases, the treatment provided herein can be provided to the subject more than once as needed.For example, the present disclosure can include follow-up inhalation if no cardiac defibrillation occurs after first inhalation.In some cases, if no cardiac defibrillation occurs within 30 minutes of first inhalation, follow-up dosage is higher or the same as first dosage.

[0156]

[0204] Medication may be guided by the patient's mood. Additionally or alternatively, medication may be guided using a portable / mobile ECG device. For example, medication may be guided using a Holter monitor.

[0157]

[0205] In another variation, the pharmaceutical composition is administered prophylactically to a subject at risk of developing arrhythmia. For example, a patient with a history of arrhythmia may be administered For this reason, patients may be prophylactically treated with a pharmaceutical composition comprising an antiarrhythmic medicinal agent.

[0158]

[0206] The pharmaceutical compositions may be administered to a patient in any regimen effective for preventing arrhythmia. An exemplary prophylactic regimen includes administering the antiarrhythmic pharmaceutical agent described herein 1 to 21 times per week.

[0159]

[0207] In some cases, the patient who receives the pharmaceutical composition according to the method described herein must meet one or more of the following ECG criteria: no P waves are seen on the ECG; rough fibrillation waves; RR intervals fluctuate; absolutely irregular QRS complexes are present; or ventricular rate is elevated. In some cases, the treatment method disclosed herein includes a step of confirming the patient in an atrial fibrillation episode by ECG. In some cases, the method includes a step of confirming that the patient has the following ECG characteristics before administering the pharmaceutical composition described herein: no P waves are seen on the ECG; rough fibrillation waves; RR intervals fluctuate; absolutely irregular QRS complexes are present; and ventricular rate is elevated. In some cases, the patient who receives the pharmaceutical composition according to the method described herein has a medical history that is ongoing within a predetermined period and makes the patient eligible to safely receive flecainide. In some cases, the patient's current AF episode has a duration of less than 48 hours. In some cases, the total exposure of flecainide that the patient receives within the past 24-hour period does not exceed 320 mg.

[0160]

[0208] The amount of flecainide salt delivered to a subject for treatment of arrhythmia, e.g., atrial arrhythmia, e.g., atrial fibrillation (e.g., the approximate amount of flecainide salt present in the mouthpiece when inhaled by a subject) may be from about 50 mg to about 300 mg, e.g., 50 mg to 60 mg, 50 mg to 70 mg, 50 mg to 80 mg, 50 mg to 90 mg, 50 mg to 100 mg, 50 mg to 110 mg, 50 mg to 120 mg, 50 mg to 130 mg, 50 mg to 140 mg, 50 mg to 150 mg, 50 mg to 160 mg, 50 mg to 170 mg, 50 mg to 180 mg, 50 mg to 190 mg, 50 mg to 200 mg, 50 mg to 210 mg, 50 mg to 220 mg, 50 mg to 230 mg, 50 mg to 240 mg, 50 mg to 250 mg, 50 mg to 260 mg, 50 mg to 270 mg, 50 mg to 280 mg, 50 mg to 290 mg, 50 mg to 300 mg, 50 mg to 310 mg, 50 mg to 320 mg, 50 mg to 330 mg, 50 mg to 340 mg, 50 mg to 350 mg, 50 mg to 360 mg, 50 mg to 370 mg, 50 mg to 380 mg, 50 mg to 390 mg, 50 mg to 400 mg, 50 mg to 410 mg, 50 mg to 420 mg, 50 mg to 430 mg, 50 mg to 440 0mg~190mg, 50mg~200mg, 50mg~210mg, 50mg~220mg, 50mg~230mg, 50mg~240mg, 50mg~250mg, 50mg~260mg, 50mg~270mg, 50mg~280mg, 50mg~290mg, 70mg ~80mg, 70mg~90mg, 70mg~100mg, 70mg~110mg, 70mg~120mg, 70mg~130mg, 70mg~140mg, 70mg~170mg, 70mg~160mg, 70mg~170mg, 70mg~180mg, 70mg~190m g, 70mg~200mg, 70mg~210mg, 70mg~220mg, 70mg~230mg, 70mg~240mg, 70mg~270mg, 70mg~260mg, 70mg~270mg, 70mg~280mg, 70mg~290mg, 70mg~300mg, 8 0mg~90mg, 80mg~100mg, 80mg~110mg, 80mg~120mg, 80mg~130mg, 80mg~140mg, 80mg~150mg, 80mg~160mg, 80mg~170mg, 80mg~180mg, 80mg~190mg, 80mg~ 200mg, 80mg~210mg, 80mg~220mg, 80mg~230mg, 80mg~240mg, 80mg~250mg, 80mg~260mg, 80mg~270mg, 80mg~280mg, 80mg~290mg, 80mg~300mg, 100mg~11 0mg, 100mg~120mg, 100mg~130mg, 100mg~140mg, 100mg~150mg, 100mg~160mg, 100mg~170mg, 100mg~180mg, 100mg~190mg, 100mg~200mg, 100mg~210mg,100mg~220mg, 100mg~230mg, 100mg~240mg, 100mg~250mg, 100mg~260mg, 100mg~270mg, 100mg~280mg, 100mg~290mg, 100mg~3 00mg, 120mg~140mg, 120mg~150mg, 120mg~160mg, 120mg~170mg, 120mg~180mg, 120mg~190mg, 120mg~200mg, 120mg~210mg, 1, 20mg~220mg, 120mg~230mg, 120mg~240mg, 120mg~250mg, 120mg~260mg, 120mg~270mg, 120mg~280mg, 120mg~290 mg, 120mg~300mg, 150mg~160mg, 150mg~170mg, 150mg~180mg, 150mg~190mg, 150mg~200mg, 150mg~210mg, 150mg~ 220mg, 150mg~230mg, 150mg~240mg, 150mg~250mg, 150mg~260mg, 150mg~270mg, 150mg~280mg, 150mg~290mg, 15 0mg~300mg, 180mg~200mg, 180mg~210mg, 180mg~220mg, 180mg~230mg, 180mg~240mg, 180mg~250mg, 180mg~260mg , 180mg~270mg, 180mg~280mg, 180mg~290mg, 180mg~300mg, 200mg~220mg, 200mg~230mg, 200mg~240mg, 200mg~2 50mg, 200mg~260mg, 200mg~270mg, 200mg~280mg, 200mg~290mg, 200mg~300mg, 220mg~240mg, 220mg~250mg, 220m The amount of the compound may be from 250 mg to 260 mg, 220 mg to 270 mg, 220 mg to 280 mg, 220 mg to 290 mg, 220 mg to 300 mg, 250 mg to 260 mg, 250 mg to 270 mg, 250 mg to 280 mg, 250 mg to 290 mg, 250 mg to 300 mg, 280 mg to 260 mg, 280 mg to 270 mg, 280 mg to 280 mg, 280 mg to 290 mg, or 280 mg to 300 mg.

[0161]

[0209] In one variation, the amount of flecainide salt delivered to a subject for treatment of arrhythmia, e.g., atrial arrhythmia, e.g., atrial fibrillation (e.g., the approximate amount of flecainide salt present in the aerosolization device when inhaled by a subject) is at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, at least about 200 mg, at least about 210 mg, at least about 220 mg, at least about 230 mg, at least about 240 mg, at least about 250 mg, at least about 260 mg, at least about 270 mg, at least about 280 mg, or at least about 290 mg.

[0162]

[0210] In one variation, the amount of flecainide salt delivered to a subject for treatment of arrhythmia, e.g., atrial arrhythmia, e.g., atrial fibrillation (e.g., the approximate amount of flecainide salt present in the mouthpiece when inhaled by the subject) is at most about 100 mg, at most about 110 mg, at most about 120 mg, at most about 130 mg, at most about 140 mg, at most about 150 mg, at most about 160 mg, at most about 170 mg, at most about 180 mg, at most about 190 mg, at most about 200 mg, at most about 210 mg, at most about 220 mg, at most about 230 mg, at most about 240 mg, at most about 250 mg, at most about 260 mg, at most about 270 mg, at most about 280 mg, or at most about 290 mg.

[0163]

[0211] In some cases, the amount of flecainide salt delivered to a subject for treatment of arrhythmia, e.g., atrial arrhythmia, e.g., atrial fibrillation (e.g., the approximate amount of flecainide salt present in the mouthpiece when inhaled by a subject) is about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, or about 290 mg.

[0164]

[0212] When the pharmaceutical composition is inhaled by a subject, the pharmaceutical composition is lost along the respiratory pathway. In some embodiments, the estimated total lung dose (eTLD, e.g., a theoretical value that measures the dose of the medicament active ingredient that reaches the lungs, e.g., about 70% of the dose present in the aerosolization device) of flecainide acetate delivered by the methods provided herein is about 40 mg to about 180 mg, e.g., 40 mg to 60 mg, 40 mg to 70 mg, 40 mg to 80 mg, 40 mg to 90 mg, 40 mg to 100 mg, 40 mg to 110 mg, 40 mg to 120 mg, 40 mg to 130 mg, 40 mg to 140 mg, 40 mg to 150 mg, 40 mg to 160 mg, 40 mg to 170 mg, 40 mg to 180 mg, 40 mg to 190 mg, 40 mg to 200 mg, 40 mg to 210 mg, 40 mg to 220 mg, 40 mg to 230 mg, 40 mg to 240 mg, 40 mg to 250 mg, 40 mg to 260 mg, 40 mg to 270 mg, 40 mg to 280 mg, 40 mg to 290 mg, 40 mg to 300 mg, 40 mg to 310 mg, 40 mg to 320 mg, 40 mg to 330 mg, 40 mg to 340 mg, 40 mg to 350 mg, 40 mg to 360 mg, 40 mg to 370 mg, 40 mg to 380 mg, 40 mg to 400 mg, 40 mg to 410 mg, 40 mg to 420 mg, 40 mg to 450 mg, 40 mg to 460 mg, 40 g~160mg, 40mg~170mg, 40mg~180mg, 50mg~60mg, 50mg~70mg, 50mg~80mg, 50mg~90mg, 50mg~100mg, 50mg~110mg, 50mg~120mg, 50mg~130mg, 5 0mg~140mg, 50mg~150mg, 50mg~160mg, 50mg~170mg, 50mg~180mg, 70mg~80mg, 70mg~90mg, 70mg~100mg, 70mg~110mg, 70mg~120mg, 70mg~130m g, 70mg~140mg, 70mg~170mg, 70mg~160mg, 70mg~170mg, 70mg~180mg, 80mg~90mg, 80mg~100mg, 80mg~110mg, 80mg~120mg, 80mg~130mg, 80mg ~140mg, 80mg~150mg, 80mg~160mg, 80mg~170mg, 80mg~180mg, 90mg~100mg, 90mg~110mg, 90mg~120mg, 90mg~130mg, 90mg~140mg, 90mg~150mg , 90mg to 160mg, 90mg to 170mg, 90mg to 180mg, 100mg to 110mg, 100mg to 120mg, 100mg to 130mg, 100mg to 140mg, 100mg to 150mg, 100mg to 160mg, 100mg to 170mg, 100mg to 180mg, 120mg to 140mg, 120mg to 150mg, 120mg to 160mg, 120mg to 170mg, 120mg to 180mg, 150mg to 160mg, 150mg to 170mg or 150mg to 180mg.

[0165]

[0213] In some cases, the eTLD of flecainide acetate delivered by the methods provided herein is at least about 40mg, at least about 60mg, at least about 70mg, at least about 80mg, at least about 90mg, at least about 100mg, at least about 110mg, at least about 120mg, at least about 130mg, at least about 140mg, at least about 150mg, at least about 160mg, or at least about 170mg. In some cases, the eTLD of flecainide acetate delivered by the methods provided herein is up to about 60mg, up to about 70mg, up to about 80mg, up to about 90mg, up to about 100mg, up to about 110mg, up to about 120mg, up to about 130mg, up to about 140mg, up to about 150mg, up to about 160mg, up to about 170mg, or up to about 180mg. In some cases, the eTLD of flecainide acetate delivered by the methods provided herein is about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 160 mg, about 170 mg or about 180 mg.

[0166]

[0214] This method of treatment results in a pulsatile pharmacokinetic profile and transient pharmacodynamic effects that mimic the action of IV. This method delivers a safe and effective high drug concentration to the heart while distribution to the rest of the body dilutes the drug to subtherapeutic levels. This method is the shortest route of delivery to the heart after intracardiac injection. It offers the efficacy and rapid onset of action of IV as well as the convenience of self-administration, such as the "pill-in-the-pocket" technique. Although delivery of drugs by the lungs for systemic action is not novel, it was thought to be ineffective to the heart due to the rapid passage of the drug therethrough. Animal and human PK / PD data in this study demonstrated that drug exposure was greater than other This route of administration indicates that much lower doses are sufficient for therapeutic effect. This method ensures that total plasma drug concentrations are much lower than those achieved by oral / IV, thus minimizing drug-drug interactions and side effects.

[0167]

[0215] In some cases, the T of antiarrhythmic medicinal agents administered by inhalation max may be within about 30 minutes, e.g., within about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 15, 20, 25, or 30 minutes. In some cases, the T of an antiarrhythmic pharmaceutical agent administered by inhalation max In some cases, the T of an antiarrhythmic medicinal agent administered by inhalation is about 5 minutes or less. maxis about 0.1 minutes to about 30 minutes, for example, 0.1 to 0.5, 0.1 to 1, 0.1 to 1.5, 0.1 to 2, 0.1 to 2.5, 0.1 to 3, 0.1 to 3.5, 0.1 to 4, 0.1 to 4.5, 0.1 to 5, 0.1 to 6, 0.1 to 8, 0.1 to 10, 0.1 to 15, 0.1 to 20, 0.1 to 2 5, 0.1~30, 0.2~0.5, 0.2~1, 0.2~1.5, 0.2~2, 0.2~2.5, 0.2~3, 0.2~3.5, 0.2~4, 0.2~4.5, 0.2~5, 0.2~6, 0.2~8, 0.2~10, 0.2~15, 0.2~20, 0.2~25, 0.2~30 , 0.3~0.5, 0.3~1, 0.3~1.5, 0.3~2, 0.3~2.5, 0.3~3, 0.3~3.5, 0.3~4, 0.3~4.5, 0.3~5, 0.3~6, 0.3~8, 0.3~10, 0.3~15, 0.3~20, 0.3~25, 0.3~30, 0.5~1, 0 .5~1.5, 0.5~2, 0.5~2.5, 0.5~3, 0.5~3.5, 0.5~4, 0.5~4.5, 0.5~5, 0.5~6, 0.5~8, 0.5~10, 0.5~15, 0.5~20, 0.5~25, 0.5~30, 1~1.5, 1~2, 1~2.5, 1~3, 1~3 .5, 1~4, 1~4.5, 1~5, 1~6, 1~8, 1~10, 1~15, 1~20, 1~25, 1~30, 1.5~2, 1.5~2.5, 1.5~3, 1.5~3.5, 1.5~4, 1.5~4.5, 1.5~5, 1.5~6, 1.5~8, 1.5~10, 1.5~15, 1 .5~20, 1.5~25, 1.5~30, 2~2.5, 2~3, 2~3.5, 2~4, 2~4.5, 2~5, 2~6, 2~8, 2~10, 2~15, 2~20, 2~25, 2~30, 2.5~3, 2.5~3.5, 2.5~4, 2.5~4.5, 2.5~5, 2.5~6, 2. 5~8, 2.5~10, 2.5~15, 2.5~20, 2.5~25, 2.5~30, 3~3.5, 3~4, 3~4.5, 3~5, 3~6, ​​3~8, 3~10, 3~15, 3~20, 3~25, 3~30, 3.5~4, 3.5~4.5, 3.5~5, 3.5~6, 3.5~8, 3 .5~10, 3.5~15, 3.5~20, 3.5~25, 3.5~30, 4~4.5, 4~5, 4~6, 4~8, 4~10, 4~15, 4~20, 4~25, 4~30, 4.5~5, 4.5~6, 4.5~8, 4.5~10, 4.5~15, 4.5~20, 4.5~25, 4.The range may be 5-30, 5-6, 5-8, 5-10, 5-15, 5-20, 5-25, 5-30, 5.5-6, 5.5-8, 5.5-10, 5.5-15, 5.5-20, 5.5-25, 5.5-30, 6-8, 6-10, 6-15, 6-20, 6-25, 6-30, 8-10, 8-15, 8-20, 8-25, 8-30, 10-15, 10-20, 10-25, 10-30, 15-20, 15-25, 15-30, 20-25, 20-30, or 25-30 minutes. Ranges given in this disclosure may be ranges between two exact values, and in some cases, ranges in this disclosure may refer to ranges between two approximate values. For example, "1-10" may refer to "from 1 to 10" in some cases, but in other cases, "1-10" may refer to "from about 1 to about 10". In some cases, the T of an antiarrhythmic medicinal agent administered by inhalation. max may be 0.01 to 5, 0.02 to 5, 0.03 to 5, 0.04 to 5, 0.05 to 5, 0.06 to 5, 0.07 to 5, 0.08 to 5, 0.09 to 5, 0.12 to 5, 0.14 to 5, 0.15 to 5, 0.16 to 5, 0.18 to 5, 0.2 to 5, 0.24 to 5, 0.26 to 5, 0.28 to 5, 0.3 to 5, 0.35 to 5, 0.4 to 5, 0.5 to 5, 0.6 to 5, 0.7 to 5, 0.8 to 5, 0.9 to 5, or 1 to 5 minutes. In some cases, the T of the antiarrhythmic medicinal agent administered by inhalation may be 0.01 to 5, 0.02 to 5, 0.03 to 5, 0.04 to 5, 0.03 to 5, 0.04 to 5, 0.05 to 5, 0.06 to 5, 0.07 to 5, 0.8 to 5, 0.9 to 5, or 1 to 5 minutes. max The T of an antiarrhythmic medicinal agent administered by inhalation may be about 0.1 to about 3 minutes. max teeth In some cases, the T of an antiarrhythmic medicinal agent administered by inhalation (e.g., flecainide) may be about 0.1 to about 5 minutes. max may be about 0.2 to about 5 minutes. In one or more embodiments, the antiarrhythmic pharmaceutical agent is a Class I, Class II, Class III, or Class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic pharmaceutical agent is a Class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic pharmaceutical agent is flecainide or a pharma- ceutically acceptable salt thereof.

[0168]

[0216] In some cases, T maxis calculated as the time at which the maximum plasma concentration of the antiarrhythmic drug is observed. max T may be calculated as the time to reach maximum plasma concentration after administration of the antiarrhythmic pharmaceutical agent. max T may be calculated as the time to reach maximum plasma concentration after initiation of administration of the antiarrhythmic pharmaceutical agent. max T may be calculated as the time to reach maximum plasma concentration after completion of administration of the antiarrhythmic pharmaceutical agent. max may be calculated from the plasma concentration of the antiarrhythmic drug measured in the left ventricular cavity. max may be calculated from the plasma concentration of the antiarrhythmic drug measured in the pulmonary artery. max may be calculated from the plasma concentration of the antiarrhythmic pharmaceutical agent measured in a vein (e.g., the femoral vein). max may be measured in human PK / PD studies.

[0169]

[0217] As used herein, the term "human PK / PD study" may refer to any environment in which a human subject receives a single dose of an antiarrhythmic agent provided herein and pharmacokinetic (PK) or pharmacodynamic (PD) parameters are measured from the human subject after administration of the antiarrhythmic agent. In some cases, the human PK / PD study provided herein may refer to a clinical trial conducted in a clinic or hospital setting. In some cases, the human PK / PD study may be a single-center or multi-center study. The human PK / PD study may be conducted on healthy human subjects or human cardiovascular patients. In some cases, the patient with cardiovascular disease experiences arrhythmias described herein. In some cases, the human PK / PD study may be a single-dose study, and in other cases, the human PK / PD study may be a multiple-dose (e.g., ascending dose) study.

[0170]

[0218] Pharmacokinetics (PK) as described herein relates to the time course of a therapeutic agent, such as an antiarrhythmic medicinal agent, such as flecainide, in the body. Pharmacodynamics (PD) relates to the relationship between pharmacokinetics and efficacy in vivo. PK / PD parameters correlate therapeutic agent, such as an antiarrhythmic medicinal agent, such as flecainide, with effective activity.

[0171]

[0219] Any standard pharmacokinetic protocol can be used in human PK / PD study to determine the plasma concentration profile in humans after administration of the formulation described herein, for example, an inhalable formulation comprising flecainide, thereby establishing whether the formulation meets the pharmacokinetic criteria described herein. For example, but by no means limiting, a type of randomized single-dose crossover study using a group of healthy human adult subjects can be utilized. The number of subjects can be sufficient to provide adequate control of variability in statistical analysis, typically about 8 or more, for example, about 10, 12, 14, 16, 18, 20 or 25. In certain embodiments, smaller groups can be used. In one embodiment, subjects receive a single dose of the inhalable formulation described herein, for example, an inhalable formulation comprising flecainide, at time zero. Blood samples are collected from each subject before administration and at multiple intervals after administration. Plasma may be separated from the blood sample by centrifugation, and the separated plasma analyzed, for example, by a validated high performance liquid chromatography / tandem mass spectrometry (LC / APCI-MS / MS) procedure, such as that described in Ramu et al., Journal of Chromatography B, 751:49-59 (2001). In other embodiments, data from a single subject is analyzed. These may be collected and used to construct a PK profile, and may show an improved pharmacokinetic profile.

[0172]

[0220] In some cases, the C of antiarrhythmic medicinal agents administered by inhalation maxis about 10 ng / mL to about 5000 ng / mL, for example, about 10 to 30, 10 to 50, 10 to 70, 10 to 80, 10 to 90, 10 to 100, 10 to 110, 10 to 120, 10 to 130, 10 to 140, 10 to 150, 10 to 160, 10 to 170, 10 to 180, 10 to 190, 10 to 200, 10 to 250, 10 to 300, 10 to 350, 10 to 400, 10 to 450, 10 to 500, 10 to 550, 10 to 600, 10 to 650, 10 to 700, 10 to 800, 10 to 900, 10 to 1000, 10 to 1500, 10 to 2000, 10 to 3000, 10~4000, 10~5000, 20~30, 20~50, 20~70, 20~80, 20~90, 20~100, 20~110, 20~120, 20~130, 20~140, 20~150, 20~160, 20~170, 20~180, 20~190, 20~200, 2 0~250, 20~300, 20~350, 20~400, 20~450, 20~500, 20~550, 20~600, 20~650, 20~700, 20~800, 20~900, 20~1000, 20~1500, 20~2000, 20~3000, 20~4000, 20 ~5000, 30~50, 30~70, 30~80, 30~90, 30~100, 30~110, 30~120, 30~130, 30~140, 30~150, 30~160, 30~170, 30~180, 30~190, 30~200, 30~250, 30~300, 30~ 350, 30~400, 30~450, 30~500, 30~550, 30~600, 30~650, 30~700, 30~800, 30~900, 30~1000, 30~1500, 30~2000, 30~3000, 30~4000, 30~5000, 50~70, 50~8 0, 50~90, 50~100, 50~110, 50~120, 50~130, 50~140, 50~150, 50~160, 50~170, 50~180, 50~190, 50~200, 50~250, 50~300, 50~350, 50~400, 50~450, 50~50 0, 50~550, 50~600, 50~650, 50~700, 50~800, 50~900, 50~1000, 50~1500, 50~2000, 50~3000, 50~4000, 50~5000, 70~80, 70~90, 70~100, 70~110, 70~120,70~130、70~140、70~150、70~160、70~170、70~180、70~190、70~200、70~250、70~300、70~350、70~400、70~450、70~500、70~550、70~600、70~650、70~700、70~800、70~900、70~1000、70~1500、70~2000、70~3000、70~4000、70~5000、80~90、80~100、80~110、80~120、80~130、80~140、80~150、80~160、80~170、80~180、80~190、80~200、80~250、80~300、80~350、80~400、80~450、80~500、80~550、80~600、80~650、80~700、80~800、80~900、80~1000、80~1500、80~2000、80~3000、80~4000、80~5000、90~100、90~110、90~120、90~130、90~140、90~150、90~160、90~170、90~180、90~190、90~200、90~250、90~300、90~350、90~400、90~450、90~500、90~550、90~600、90~650、90~700、90~800、90~900、90~1000、90~1500、90~2000、90~3000、90~4000、90~5000、100~110、100~120、100~130、100~140、100~150、100~160、100~170、100~180、100~190、100~200、100~250、100~300、100~350、100~400、100~450、100~500、100~550、100~600、100~650、100~700、100~800、100~900、100~1000、100~1500、100~2000、100~3000、100~4000、100~5000、110~120、110~130、110~140、110~150、110~160、110~170、110~180、110~190、110~200、110~250、110~30、 0、110~350、110~400、110~450、110~500、110~550、110~600、110~650、110~700、110~800、110~900、110~1000、110~1500、110~2000、110~3000、110~4000、110~5000、120~130、120~140、120~150、120~160、120~170、120~180、120~190、120~200、120~250、120~300、120~350、120~400、120~450、120~500、120~550、120~600、120~650、120~700、120~800、120~900、120~1000、120~1500、120~2000、120~3000、120~4000、120~5000、130~140、130~150、130~160、130~170、130~180、130~190、130~200、130~250、130~300、130~350、130~400、130~450、130~500、130~550、130~600、130~650、130~700、130~800、130~900、130~1000、130~1500、130~2000、130~3000、130~4000、130~5000、140~150、140~160、140~170、140~180、140~190、140~200、140~250、140~300、140~350、140~400、140~450、140~500、140~550、140~600、140~650、140~700、140~800、140~900、140~1000、140~1500、140~2000、140~3000、140~4000、140~5000、150~160、150~170、150~180、150~190、150~200、150~250、150~300、150~350、150~400、150~450、150~500、150~550、150~600、150~650、150~700、150~800、150~900、150~1000、150~1500、150~2000、150~3000、150~4000、150~5000、160~170、160~180、160~190、160~200、160~250、160~300、160~350、160~400、160~450、160~500、160~550、160~600、160~650、160~700、160~800、160~900、160~1000、160~1500、160~2000、160~3000、160~4000、160~5000、170~180、170~190、170~200、170~250、170~300、170~350、170~400、170~450、170~500、170~550、170~600、170~650、170~700、170~800、170~900、170~1000、170~1500、170~2000、170~3000、170~4000、170~5000、180~190、180~200、180~250、180~300、180~350、180~400、180~450、180~500、180~550、180~600、180~650、180~700、180~800、180~900、180~1000、180~1500、180~2000、180~3000、180~4000、180~5000、190~200、190~250、190~300、190~350、190~400、190~450、190~500、190~550、190~600、190~650、190~700、190~800、190~900、190~1000、190~1500、190~2000、190~3000、190~4000、190~5000、200~250、200~300、200~350、200~400、200~450、200~500、200~550、200~600、200~650、200~700、200~800、200~900、200~1000、200~1500、200~2000、200~3000、200~4000、200~5000、250~300、250~350、250~400、250~450、250~500、250~550、250~600、250~650、250~700、250~800、250~900、250~1000、250~1500、250~2000、250~3000、250~4000、250~5000、300~350、300~400、300~450、300~500、300~550、300~600、300~650、300~700、300~800、300~900、300~、1000、300~1500、300~2000、300~3000、300~4000、300~5000、350~400、350~450、350~500、350~550、350~600、350~650、350~700、350~800、350~900、350~1000、350~1500、350~2000、350~3000、350~4000、350~5000、400~450、400~500、400~550、400~600、400~650、400~700、400~800、400~900、400~1000、400~1500、400~2000、400~3000、400~4000、400~5000、450~500、450~550、450~600、450~650、450~700、450~800、450~900、450~1000、450~1500、450~2000、450~3000、450~4000、450~5000、500~550、500~600、500~650、500~700、500~800、500~900、500~1000、500~1500、500~2000、500~3000、500~4000、500~5000、550~600、550~650、550~700、550~800、550~900、550~1000、550~1500、550~2000、550~3000、550~4000、550~5000、600~650、600~700、600~800、600~900、600~1000、600~1500、600~2000、600~3000、600~4000、600~5000、650~700、650~800、650~900、650~1000、650~1500、650~2000、650~3000、650~4000、650~5000、700~800、700~900、700~1000、700~1500、700~2000、700~3000、700~4000、700~5000、800~900、800~1000、800~1500、800~2000、800~3000、800~4000、800~5000、900~1000、900~1500、900~2000、900~3000、900~4000、900~5000、1000~1500、1000~2000、1000~3000、1000~4000、1000~5000、In some cases, the C of the antiarrhythmic medicinal agent administered by inhalation may be 1500 to 2000, 1500 to 3000, 1500 to 4000, 1500 to 5000, 2000 to 3000, 2000 to 4000, 2000 to 5000, 3000 to 4000, 3000 to 5000, or 4000 to 5000 ng / mL. max is about 20 The C of the antiarrhythmic pharmaceutical agent administered by inhalation may be from 20 to 500, 30 to 500, 40 to 500, 50 to 500, 60 to 500, 70 to 500, 80 to 500, 90 to 500, 100 to 500, 150 to 500, 200 to 500, or 250 to 500 ng / mL. max In some cases, the C of the antiarrhythmic medicinal agent administered by inhalation may be about 50 to about 500 ng / mL. max The C of the antiarrhythmic medicinal agent administered by inhalation may be about 200 to about 500 ng / mL. max In some cases, the C of the antiarrhythmic medicinal agent administered by inhalation is at least about 200 ng / mL. max is at least about 250 ng / mL. In one or more embodiments, the antiarrhythmic pharmaceutical agent is a Class I, Class II, Class III or Class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic pharmaceutical agent is a Class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic pharmaceutical agent is flecainide or a pharmaceutically acceptable salt thereof.

[0173]

[0221] In some cases, C max may be calculated as the maximum observed plasma concentration of the antiarrhythmic drug. max C may be calculated as the peak plasma concentration achieved by the antiarrhythmic drug following administration of the drug. max may be calculated from the plasma concentration of the antiarrhythmic drug measured in the left ventricular cavity. max may be calculated from the plasma concentration of the antiarrhythmic drug measured in the pulmonary artery. maxmay be calculated from the plasma concentration of the antiarrhythmic drug measured in a vein (e.g., the femoral vein). max may be measured in human PK / PD studies.

[0174]

[0222] In some cases, the AUC of an antiarrhythmic drug administered by inhalation Last teeth, About 100 hours * ng / mL~about 10000hr *ng / mL, e.g. 100-200, 100-300, 100-400, 100-420, 100-440, 100-460, 100-480, 100-500, 100-520, 100-540, 100-560, 100-580, 100-600, 100-620, 100- 640, 100~660, 100~680, 100~700, 100~800, 100~900, 100~1000, 100~1500, 100~2000, 100~3000, 100~3500, 100~4000, 100~4500, 100~5000, 100~5500, 100~6000, 100~6500, 100~7000, 100~8000, 100~9000, 100~10000, 200~300, 200~400, 200~420, 200~440, 200~460, 200~480, 200~500, 200~520, 200~54 0, 200~560, 200~580, 200~600, 200~620, 200~640, 200~660, 200~680, 200~700, 200~800, 200~900, 200~1000, 200~1500, 200~2000, 200~3000, 200~350 0, 200~4000, 200~4500, 200~5000, 200~5500, 200~6000, 200~6500, 200~7000, 200~8000, 200~9000, 200~10000, 300~400, 300~420, 300~440, 300~460, 300~480, 300~500, 300~520, 300~540, 300~560, 300~580, 300~600, 300~620, 300~640, 300~660, 300~680, 300~700, 300~800, 300~900, 300~1000, 300~ 1500, 300~2000, 300~3000, 300~3500, 300~4000, 300~4500, 300~5000, 300~5500, 300~6000, 300~6500, 300~7000, 300~8000, 300~9000, 300~10000, 40 0~420, 400~440, 400~460, 400~480, 400~500, 400~520, 400~540, 400~560, 400~580, 400~600, 400~620, 400~640, 400~660, 400~680, 400~700, 400~800,400~900、400~1000、400~1500、400~2000、400~3000、400~3500、400~4000、400~4500、400~5000、400~5500、400~6000、400~6500、400~7000、400~8000、400~9000、400~10000、420~440、420~460、420~480、420~500、420~520、420~540、420~560、420~580、420~600、420~620、420~640、420~660、420~680、420~700、420~800、420~900、420~1000、420~1500、420~2000、420~3000、420~3500、420~4000、420~4500、420~5000、420~5500、420~6000、420~6500、420~7000、420~8000、420~9000、420~10000、440~460、440~480、440~500、440~520、440~540、440~560、440~580、440~600、440~620、440~640、440~660、440~680、440~700、440~800、440~900、440~1000、440~1500、440~2000、440~3000、440~3500、440~4000、440~4500、440~5000、440~5500、440~6000、440~6500、440~7000、440~8000、440~9000、440~10000、460~480、460~500、460~520、460~540、460~560、460~580、460~600、460~620、460~640、460~660、460~680、460~700、460~800、460~900、460~1000、460~1500、460~2000、460~3000、460~3500、460~4000、460~4500、460~5000、460~5500、460~6000、460~6500、460~7000、460~8000、460~、 9000、460~10000、480~500、480~520、480~540、480~560、480~580、480~600、480~620、480~640、480~660、480~680、480~700、480~800、480~900、480~1000、480~1500、480~2000、480~3000、480~3500、480~4000、480~4500、480~5000、480~5500、480~6000、480~6500、480~7000、480~8000、480~9000、480~10000、500~520、500~540、500~560、500~580、500~600、500~620、500~640、500~660、500~680、500~700、500~800、500~900、500~1000、500~1500、500~2000、500~3000、500~3500、500~4000、500~4500、500~5000、500~5500、500~6000、500~6500、500~7000、500~8000、500~9000、500~10000、520~540、520~560、520~580、520~600、520~620、520~640、520~660、520~680、520~700、520~800、520~900、520~1000、520~1500、520~2000、520~3000、520~3500、520~4000、520~4500、520~5000、520~5500、520~6000、520~6500、520~7000、520~8000、520~9000、520~10000、540~560、540~580、540~600、540~620、540~640、540~660、540~680、540~700、540~800、540~900、540~1000、540~1500、540~2000、540~3000、540~3500、540~4000、540~4500、540~5000、540~5500、540~6000、540~6500、540~7000、540~8000、540~9000、540~10000、560~580、560~600、560~620、560~640、560~660、560~680、560~700、560~800、560~900、560~1000、560~1500、560~2000、560~3000、560~3500、560~4000、560~4500、560~5000、560~5500、560~6000、560~6500、560~7000、560~8000、560~9000、560~10000、580~600、580~620、580~640、580~660、580~680、580~700、580~800、580~900、580~1000、580~1500、580~2000、580~3000、580~3500、580~4000、580~4500、580~5000、580~5500、580~6000、580~6500、580~7000、580~8000、580~9000、580~10000、600~620、600~640、600~660、600~680、600~700、600~800、600~900、600~1000、600~1500、600~2000、600~3000、600~3500、600~4000、600~4500、600~5000、600~5500、600~6000、600~6500、600~7000、600~8000、600~9000、600~10000、620~640、620~660、620~680、620~700、620~800、620~900、620~1000、620~1500、620~2000、620~3000、620~3500、620~4000、620~4500、620~5000、620~5500、620~6000、620~6500、620~7000、620~8000、620~9000、620~10000、640~660、640~680、640~700、640~800、640~900、640~1000、640~1500、640~2000、640~3000、640~3500、640~4000、640~4500、640~5000、640~5500、640~6000、640~6500、640~7000、640~8000、640~9000、640~10000、660~680、660~700、660~800、660~900、660~1000、660~1500、660~2000、660~3000、660~3500、660~4000、660~4500、660~5000、660~5500、660~6000、660~6500、660~7000、660~8000、660~9000、660~10000、680~700、680~800、680~900、680~1000、680~1500、680~2000、680~3000、680~3500、680~4000、680~4500、680~5000、680~5500、680~6000、680~6500、680~7000、680~8000、680~9000、680~10000、700~800、700~900、700~1000、700~1500、700~2000、700~3000、700~3500、700~4000、700~4500、700~5000、700~5500、700~6000、700~6500、700~7000、700~8000、700~9000、700~10000、800~900、800~1000、800~1500、800~2000、800~3000、800~3500、800~4000、800~4500、800~5000、800~5500、800~6000、800~6500、800~7000、800~8000、800~9000、800~10000、900~1000、900~1500、900~2000、900~3000、900~3500、900~4000、900~4500、900~5000、900~5500、900~6000、900~6500、900~7000、900~8000、900~9000、900~10000、1000~1500、1000~2000、1000~3000、1000~3500、1000~4000、1000~4500、1000~5000、1000~5500、1000~6000、1000~6500、1000~7000、1000~8000、1000~9000、1000~10000、1500~2000、1500~3000、1500~3500、1500~4000、1500~4500、1500~5000、1500~5500、1500~6000、1500~6500、1500~7000、1500~8000、1500~9000、1500~10000、2000~3000、2000~3500、2000~4000、2000~4500、2000~5000、2000~5500、2000~6000、2000~6500、2000~7000, 2000~8000, 2000~9000, 2000~10000, 2500~3000, 2500~3500, 2500~4000, 2500~4500, 2500~5000, 2500~5500, 2500~6000, 2500~6500, 2500~7000, 2500~8000, 2500~, 9000, 2500~10000, 3000~3500, 3000~4000, 3000~4500, 3000~5000, 3000~5500, 3000~6000, 3000~6500, 3000~7000, 3000~8000, 3000~9000, 3000~10000, 3500~4000, 3500~4500, 3500~5000, 3500~5500, 3500~ 6000, 3500~6500, 3500~7000, 3500~8000, 3500~9000, 3500~10000, 4000~4500, 4000~5000, 4000~5500, 4000~6000, 4000~6500, 4000~7000, 4000~8000, 4000~9000, 4000~10000, 4500~5000, 4500~5500, 4500~6 000, 4500~6500, 4500~7000, 4500~8000, 4500~9000, 4500~10000, 5000~5500, 5000~6000, 5000~6500, 5000~7000, 5000~8000, 5000~9000, 5000~10000, 5500~6000, 5500~6500, 5500~7000, 5500~8000, 5500~9 000, 5500~10000, 6000~6500, 6000~7000, 6000~8000, 6000~9000, 6000~10000, 6500~7000, 6500~8000, 6500~9000, 6500~10000, 7000~8000, 7000~9000, 7000~10000, 8000~9000, 8000~10000 or 9000~10000hr * In some cases, the AUC of the antiarrhythmic medicinal agent administered by inhalation may be Last Approximately 200 to 2000 hours * ng / mL In some cases, the AUC of the antiarrhythmic medicinal agent administered by inhalation Last Approximately 500 to 800 hours * In some cases, it may be administered by inhalation. AUC of antiarrhythmic drugs administered Last Approximately 400 to 600 hours * ng / mL In one or more embodiments, the antiarrhythmic pharmaceutical agent is a Class I, Class II, Class III, or Class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic pharmaceutical agent is a Class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic pharmaceutical agent is flecainide or a pharma- ceutically acceptable salt thereof.

[0175]

[0223] In some cases, AUC Last may be calculated as the area under the concentration-time curve up to the last measurable concentration. In some cases, AUC Last may be calculated as the total drug exposure over time. In some cases, AUC Last may be calculated from the plasma concentration of the antiarrhythmic drug measured in the left ventricular cavity. Last may be calculated from the plasma concentration of the antiarrhythmic medicinal agent measured in the pulmonary artery. Last may be calculated from the plasma concentration of the antiarrhythmic pharmaceutical agent measured in a vein (e.g., the femoral vein). Last may be measured in human PK / PD studies.

[0176]

[0224] In some cases, the distribution of antiarrhythmic medicinal agents administered by inhalation 1 / 2is about 0.1 minutes to about 15 minutes, for example, about 0.1 to 0.5, 0.1 to 1, 0.1 to 1.5, 0.1 to 2, 0.1 to 2.5, 0.1 to 2.6, 0.1 to 2.7, 0.1 to 2.8, 0.1 to 2.9, 0.1 to 3, 0.1 to 3.1, 0.1 to 3.2, 0.1 to 3.3, 0.1 to 3.4, 0. 1~3.5, 0.1~3.6, 0.1~3.7, 0.1~3.8, 0.1~3.9, 0.1~4, 0.1~4.1, 0.1~4.2, 0.1~4.3, 0.1~4.4, 0.1~4.5, 0.1~5, 0.1~5.5, 0.1~6, 0.1~7, 0.1~8, 0.1~9, 0.1 ~10, 0.1~11, 0.1~12, 0.1~13, 0.1~14, 0.1~15, 0.5~1, 0.5~1.5, 0.5~2, 0.5~2.5, 0.5~2.6, 0.5~2.7, 0.5~2.8, 0.5~2.9, 0.5~3, 0.5~3.1, 0.5~3.2, 0.5~ 3.3, 0.5~3.4, 0.5~3.5, 0.5~3.6, 0.5~3.7, 0.5~3.8, 0.5~3.9, 0.5~4, 0.5~4.1, 0.5~4.2, 0.5~4.3, 0.5~4.4, 0.5~4.5, 0.5~5, 0.5~5.5, 0.5~6, 0.5~7, 0 .5~8, 0.5~9, 0.5~10, 0.5~11, 0.5~12, 0.5~13, 0.5~14, 0.5~15, 1~1.5, 1~2, 1~2.5, 1~2.6, 1~2.7, 1~2.8, 1~2.9, 1~3, 1~3.1, 1~3.2, 1~3.3, 1~3.4, 1~3. 5, 1-3.6, 1-3.7, 1-3.8, 1-3.9, 1-4, 1-4.1, 1-4.2, 1-4.3, 1-4.4, 1-4.5, 1-5, 1-5.5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1.5-2, 1.5 ~2.5, 1.5~2.6, 1.5~2.7, 1.5~2.8, 1.5~2.9, 1.5~3, 1.5~3.1, 1.5~3.2, 1.5~3.3, 1.5~3.4, 1.5~3.5, 1.5~3.6, 1.5~3.7, 1.5~3.8, 1.5~3.9, 1.5~4, 1.5~ 4.1, 1.5-4.2, 1.5-4.3, 1.5-4.4, 1.5-4.5, 1.5-5, 1.5-5.5, 1.5-6, 1.5-7, 1.5-8, 1.5-9, 1.5-10, 1.5-11, 1.5-12, 1.5-13, 1.5-14, 1.5-15, 2-2.5, 2-2.6、2~2.7、2~2.8、2~2.9、2~3、2~3.1、2~3.2、2~3.3、2~3.4、2~3.5、2~3.6、2~3.7、2~3.8、2~3.9、2~4、2~4.1、2~4.2、2~4.3、2~4.4、2~4.5、2~5、2~5.5、2~6、2~7、2~8、2~9、2~10、2~11、2~12、2~13、2~14、2~15、2.5~2.6、2.5~2.7、2.5~2.8、2.5~2.9、2.5~3、2.5~3.1、2.5~3.2、2.5~3.3、2.5~3.4、2.5~3.5、2.5~3.6、2.5~3.7、2.5~3.8、2.5~3.9、2.5~4、2.5~4.1、2.5~4.2、2.5~4.3、2.5~4.4、2.5~4.5、2.5~5、2.5~5.5、2.5~6、2.5~7、2.5~8、2.5~9、. 2.5~10、2.5~11、2.5~12、2.5~13、2.5~14、2.5~15、2.6~2.7、2.6~2.8、2.6~2.9、2.6~3、2.6~3.1、2.6~3.2、2.6~3.3、2.6~3.4、2.6~3.5、2.6~3.6、2.6~3.7、2.6~3.8、2.6~3.9、2.6~4、2.6~4.1、2.6~4.2、2.6~4.3、2.6~4.4、2.6~4.5、2.6~5、2.6~5.5、2.6~6、2.6~7、2.6~8、2.6~9、2.6~10、2.6~11、2.6~12、2.6~13、2.6~14、2.6~15、2.7~2.8、2.7~2.9、2.7~3、2.7~3.1、2.7~3.2、2.7~3.3、2.7~3.4、2.7~3.5、2.7~3.6、2.7~3.7、2.7~3.8、2.7~3.9、2.7~4、2.7~4.1、2.7~4.2、2.7~4.3、2.7~4.4、2.7~4.5、2.7~5、2.7~5.5、2.7~6、2.7~7、2.7~8、2.7~9、2.7~10、2.7~11、2.7~12、2.7~13、2.7~14、2.7~15、2.8~2.9、2.8~3、2.8~3.1、2.8~3.2、2.8~3.3、2.8~3.4、2.8~3.5、2.8~3.6、2.8~3.7、2.8~3.8、2.8~3.9、2.8~4、2.8~4.1、2.8~4.2、2.8~4.3、2.8~4.4、2.8~4.5、2.8~5、2.8~5.5、2.8~6、2.8~7、2.8~8、2.8~9、2.8~10、2.8~11、2.8~12、2.8~13、2.8~14、2.8~15、2.9~3、2.9~3.1、2.9~3.2、2.9~3.3、2.9~3.4、2.9~3.5、2.9~3.6、2.9~3.7、2.9~3.8、2.9~3.9、2.9~4、2.9~4.1、2.9~4.2、2.9~4.3、2.9~4.4、2.9~4.5、2.9~5、2.9~5.5、2.9~6、2.9~7、2.9~8、2.9~9、2.9~10、2.9~11、2.9~12、2.9~13、2.9~14、2.9~15、3~3.1、3~3.2、3~3.3、3~3.4、3~3.5、3~3.6、3~3.7、3~3.8、3~3.9、3~4、3~4.1、3~4.2、3~4.3、3~4.4、3~4.5、3~5、3~5.5、3~6、3~7、3~8、3~9、3~10、3~11、3~12、3~13、3~14、3~15、3.1~3.2、3.1~3.3、3.1~3.4、3.1~3.5、3.1~3.6、3.1~3.7、3.1~3.8、3.1~3.9、3.1~4、3.1~4.1、3.1~4.2、3.1~4.3、3.1~4.4、3.1~4.5、3.1~5、3.1~5.5、3.1~6、3.1~7、3.1~8、3.1~9、3.1~10、3.1~11、3.1~12、3.1~13、3.1~14、3.1~15、3.2~3.3、3.2~3.4、3.2~3.5、3.2~3.6、3.2~3.7、3.2~3.8、3.2~3.9、3.2~4、3.2~4.1、3.2~4.2、3.2~4.3、3.2~4.4、3.2~4.5、3.2~5、3.2~5.5、3.2~6、3.2~7、3.2~8、3.2~9、3.2~10、3.2~11、3.2~12、3.2~13、3.2~14、3.2~15、3.3~3.4、3.3~3.5、3.3~3.6、3.3~3.7、3.3~3.8、3.3~3.9、3.3~4、3.3~4.1、3.3~4.2、3.3~4.3、3.3~4.4、3.3~4.5、3.3~5、3.3~5.5、3.3~6、3.3~7、3.3~8、3.3~9、3.3~10、3.3~11、3.3~12、3.3~13、3.3~14、3.3~15、3.4~3.5、3.4~3.6、3.4~3.7、3.4~3.8、3.4~3.9、3.4~4、3.4~4.1、3.4~4.2、3.4~4.3、3.4~4.4、3.4~4.5、3.4~5、3.4~5.5、3.4~6、3.4~7、3.4~8、3.4~9、3.4~10、3.4~11、3.4~12、3.4~13、3.4~14、3.4~15、3.5~3.6、3.5~3.7、3.5~3.8、3.5~3.9、3.5~4、3.5~4.1、3.5~4.2、3.5~4.3、3.5~4.4、3.5~4.5、3.5~5、3.5~5.5、3.5~6、3.5~7、3.5~8、3.5~9、3.5~10、3.5~11、3.5~12、3.5~13、3.5~14、3.5~15、3.6~3.7、3.6~3.8、3.6~3.9、3.6~4、3.6~4.1、3.6~4.2、3.6~4.3、3.6~4.4、3.6~4.5、3.6~5、3.6~. 5.5、3.6~6、3.6~7、3.6~8、3.6~9、3.6~10、3.6~11、3.6~12、3.6~13、3.6~14、3.6~15、3.7~3.8、3.8~3.9、3.8~4、3.8~4.1、3.8~4.2、3.8~4.3、3.8~4.4、3.8~4.5、3.8~5、3.8~5.5、3.8~6、3.8~7、3.8~8、3.8~9、3.8~10、3.8~11、3.8~12、3.8~13、3.8~14、3.8~15、3.9~4、3.9~4.1、3.9~4.2、3.9~4.3、3.9~4.4、3.9~4.5、3.9~5、3.9~5.5、3.9~6、3.9~7、3.9~8、3.9~9、3.9~10、3.9~11、3.9~12、3.9~13、3.9~14、3.9~15、4~4.1、4~4.2、4~4.3、4~4.4、4~4.5、4~5、4~5.5、4~6、4~7、4~8、4~9、4~10、4~11、4~12、4~13、4~14、4~15、4.1~4.2、4.1~4.3、4.1~4.4、4.1~4.5、4.1~5、4.1~5.5、4.1~6、4.1~7、4.1~8、4.1~9、4.1~10、4.1~11、4.1~12、4.1~13、4.1~14、4.1~15、4.2~4.3、4.2~4.4、4.2~4.5、4.2~5、4.2~5.5、4.2~6、4.2~7、4.2~8、4.2~9、4.2~10、4.2~11、4.2~12、4.2~13、4.2~14、4.2~15、4.3~4.4、4.3~4.5、4.3~5、4.3~5.5、4.3~6、4.3~7、4.3~8、4.3~9、4.3~10、4.3~11、4.3~12、4.3~13、4.3~14、4.3~15、4.4~4.5、4.4~5、4.4~5.5、4.4~6、4.4~7、4.4~8、4.4~9、4.4~10、4.4~11、4.4~12、4.4~13、4.4~14、4.4~15、4.5~5、4.5~5.5、4.5~6、4.5~7、4.5~8、4.5~9、4.5~10、4.5~11、4.5~12、4.5~13、4.5~14、4.5~15、5~5.5、5~6、5~7、5~8、5~9、5~10、5~11、5~12、5~13、5~14、5~15、5.5~6、5.5~7、5.5~8、5.5~9、5.5~10、5.5~11、5.5~12, 5.5~13, 5.5~14, 5.5~15, 6~7, 6~8, 6~9, 6~10, 6~11, 6~12, 6~13, 6~14, 6~15, 7~8, 7~9, 7~10, 7~11, 7~12, 7~13, 7~14, 7~15, 8~9, 8~10, 8~11, 8~12, 8~13, 8~14, In some cases, the distribution of the antiarrhythmic medicinal agent administered by inhalation may be t.8-15, 9-10, 9-11, 9-12, 9-13, 9-14, 9-15, 10-11, 10-12, 10-13, 10-14, 10-15, 11-12, 11-13, 11-14, 11-15, 12-13, 12-14, 12-15, 13-14, 13-15, or 14-15 minutes. 1 / 2 may be about 3 to about 5 minutes. In one or more embodiments, the antiarrhythmic pharmaceutical agent is a Class I, Class II, Class III, or Class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic pharmaceutical agent is a Class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic pharmaceutical agent is flecainide or a pharma- ceutically acceptable salt thereof.

[0177]

[0225] In some cases, the distribution t 1 / 2 may be calculated as the time at which the plasma level of the antiarrhythmic pharmaceutical agent has decreased to half of the equilibrium plasma level due to distribution to tissues throughout the body. 1 / 2 may be calculated as the time it takes for an antiarrhythmic pharmaceutical agent to lose half of its pharmacological activity. 1 / 2 may be calculated from the plasma concentration of the antiarrhythmic drug measured in the left ventricular cavity. 1 / 2 may be calculated from the plasma concentration of the antiarrhythmic drug measured in the pulmonary artery. 1 / 2 may be calculated from the plasma concentration of the antiarrhythmic pharmaceutical agent measured in a vein (e.g., the femoral vein). 1 / 2 may be measured in human PK / PD studies.

[0178]

[0226] In some cases, the elimination of antiarrhythmic medicinal agents administered by inhalation 1 / 2is about 1 hour to about 25 hours, for example, about 1 to 3, 1 to 5, 1 to 7, 1 to 7.5, 1 to 8, 1 to 8. 5、1~8.7、1~8.9、1~9.1、1~9.3、1~9.5、1~9.7、1~9.9、1~10.1、1~10.3、1~10.5、1~10.7、1~10.9、1~11.1、1~11.3、1~11.5、1~11.7、1~11.9、1~12.1、1~12.5、1~13、1~13.5、1~14、1~15、1~16、1~17、1~18、1~19、1~20、1~25、3~5、3~7、3~7.5、3~8、3~8.5、3~8.7、3~8.9、3~9.1、3~9.3、3~9.5、3~9.7、3~9.9、3~10.1、3~10.3、3~10.5、3~10.7、3~10.9、3~11.1、3~11.3、3~11.5、3~11.7、3~11.9、3~12.1、3~12.5、3~13、3~13.5、3~14、3~15、3~16、3~17、3~18、3~19、3~20、3~25、5~7、5~7.5、5~8、5~8.5、5~8.7、5~8.9、5~9.1、5~9.3、5~9.5、5~9.7、5~9.9、5~10.1、5~10.3、5~10.5、5~10.7、5~10.9、5~11.1、5~11.3、5~11.5、5~11.7、5~11.9、5~12.1、5~12.5、5~13、5~13.5、5~14、5~15、5~16、5~17、5~18、5~19、5~20、5~25、7~7.5、7~8、7~8.5、7~8.7、7~8.9、7~9.1、7~9.3、7~9.5、7~9.7、7~9.9、7~10.1、7~10.3、7~10.5、7~10.7、7~10.9、7~11.1、7~11.3、7~11.5、7~11.7、7~11.9、7~12.1、7~12.5、7~13、7~13.5、7~14、7~15、7~16、7~17、7~18、7~19、7~20、7~25、7.5~8、7.5~8.5、7.5~8.7、7.5~8.9、7.5~9.1、7.5~9.3、7.5~9.5、7.5~9.7、7.5~9.9、7.5~10.1、7.5~10.3、7.5~10.5、7.5~10.7、7.5~10.9、7.5~11.1、7.5~11.3、7.5~11.5、7.5~11.7、7.5~11.9、7.5~12.1、7.5~12.5、7.5~13、7.5~13.5、7.5~14、7.5~15、7.5~16、7.5~17、7.5~18、7.5~19、7.5~20、7.5~25、8~8.5、8~8.7、8~8.9、8~9.1、8~9.3、8~9.5、8~9.7、8~9.9、8~10.1、8~10.3、8~10.5、8~10.7、8~10.9、8~11.1、8~11.3、8~11.5、8~11.7、8~11.9、8~12.1、8~12.5、8~13、8~13.5、8~14、8~15、8~16、8~17、8~18、8~19、8~20、8~25、8.5~8.7、8.5~8.9、8.5~9.1、8.5~9.3、8.5~9.5、8.5~9.7、8.5~9.9、8.5~10.1、8.5~10.3、8.5~10.5、8.5~10.7、8.5~10.9、8.5~11.1、8.5~11.3、8.5~11.5、8.5~11.7、8.5~11.9、8.5~12.1、8.5~12.5、8.5~13、8.5~13.5、8.5~14、8.5~15、8.5~16、8.5~17、8.5~18、8.5~19、8.5~20、8.5~25、8.7~8.9、8.7~9.1、8.7~9.3、8.7~9.5、8.7~9.7、8.7~9.9、8.7~10.1、8.7~10.3、8.7~10.5、8.7~10.7、8.7~10.9、8.7~11.1、8.7~11.3、8.7~11.5、8.7~11.7、8.7~11.9、8.7~12.1、8.7~12.5、8.7~13、8.7~13.5、8.7~14、8.7~15、8.7~16、8.7~17、8.7~18、8.7~19、8.7~20、8.7~25、8.9~9.1、8.9~9.3、8.9~9.5、8.9~9.7、8.9~9.9、8.9~10.1、8.9~10.3、8.9~10.5、8.9~10.7、8.9~10.9、8.9~11.1、8.9~11.3、8.9~11.5、8.9~11.7、8.9~11.9、8.9~12.1、8.9~12.5、8.9~13、8.9~13.5、8.9~14、8.9~15、8.9~16、8.9~17、8.9~18、8.9~19、8.9~20、8.9~25、9.1~9.3、9.1~9.5、9.1~9.7、9.1~9.9、9.1~10.1、9.1~10.3、9.1~10.5、9.1~10.7、9.1~10.9、9.1~11.1、9.1~11.3、9.1~11.5、9.1~. 11.7、9.1~11.9、9.1~12.1、9.1~12.5、9.1~13、9.1~13.5、9.1~14、9.1~15、9.1~16、9.1~17、9.1~18、9.1~19、9.1~20、9.1~25、9.3~9.5、9.3~9.7、9.3~9.9、9.3~10.1、9.3~10.3、9.3~10.5、9.3~10.7、9.3~10.9、9.3~11.1、9.3~11.3、9.3~11.5、9.3~11.7、9.3~11.9、9.3~12.1、9.3~12.5、9.3~13、9.3~13.5、9.3~14、9.3~15、9.3~16、9.3~17、9.3~18、9.3~19、9.3~20、9.3~25、9.5~9.7、9.5~9.9、9.5~10.1、9.5~10.3、9.5~10.5、9.5~10.7、9.5~10.9、9.5~11.1、9.5~11.3、9.5~11.5、9.5~11.7、9.5~11.9、9.5~12.1、9.5~12.5、9.5~13、9.5~13.5、9.5~14、9.5~15、9.5~16、9.5~17、9.5~18、9.5~19、9.5~20、9.5~25、9.7~9.9、9.7~10.1、9.7~10.3、9.7~10.5、9.7~10.7、9.7~10.9、9.7~11.1、9.7~11.3、9.7~11.5、9.7~11.7、9.7~11.9、9.7~12.1、9.7~12.5、9.7~13、9.7~13.5、9.7~14、9.7~15、9.7~16、9.7~17、9.7~18、9.7~19、9.7~20、9.7~25、9.9~10.1、9.9~10.3、9.9~10.5、9.9~10.7、9.9~10.9、9.9~11.1、9.9~11.3、9.9~11.5、9.9~11.7、9.9~11.9、9.9~12.1、9.9~12.5、9.9~13、9.9~13.5、9.9~14、9.9~15、9.9~16、9.9~17、9.9~18、9.9~19、9.9~20、9.9~25、10.1~10.3、10.1~10.5、10.1~10.7、10.1~10.9、10.1~11.1、10.1~11.3、10.1~11.5、10.1~11.7、10.1~11.9、10.1~12.1、10.1~12.5、10.1~13、10.1~13.5、10.1~14、10.1~15、10.1~16、10.1~17、10.1~18、10.1~19、10.1~20、10.1~25、10.3~10.5、10.3~10.7、10.3~10.9、10.3~11.1、10.3~11.3、10.3~11.5、10.3~11.7、10.3~11.9、10.3~12.1、10.3~12.5、10.3~13、10.3~13.5、10.3~14、10.3~15、10.3~16、10.3~17、10.3~18、10.3~19、10.3~20、10.3~25、10.5~10.7、10.5~10.9、10.5~11.1、10.5~11.3、10.5~11.5、10.5~11.7、10.5~11.9、10.5~12.1、10.5~12.5、10.5~13、10.5~13.5、10.5~14、10.5~15、10.5~16、10.5~17、10.5~18、10.5~19、10.5~20、10.5~25、10.7~10.9、10.7~11.1、10.7~11.3、10.7~11.5、10.7~11.7、10.7~11.9、10.7~12.1、10.7~12.5、10.7~13、10.7~13.5、10.7~14、10.7~15、10.7~16、10.7~17、10.7~18、10.7~19、10.7~20、10.7~25、10.9~11.1、10.9~11.3、10.9~11.5、10.9~11.7、10.9~11.9、10.9~12.1、10.9~12.5、10.9~13、10.9~13.5、10.9~14、10.9~15、10.9~16、10.9~17、10.9~18、10.9~19、10.9~20、10.9~25、11.1~11.3、11.1~11.5、11.1~11.7、11.1~11.9、11.1~12.1、11.1~12.5、11.1~13、11.1~13.5、11.1~14、11.1~15、11.1~16、11.1~17、11.1~18、11.1~19、11.1~20、11.1~25、11.3~11.5、11.3~11.7、11.3~11.9、11.3~12.1、11.3~12.5、11.3~13、11.3~13.5、11.3~14、11.3~15、11.3~16、11.3~17、11.3~18、11.3~19、11.3-20, 11. .3-25, 11.5-11.7, 11.5-11.9, 11.5-12.1, 11.5-12.5, 11.5-13, 11.5-13.5, 11.5-14, 11.5-15, 11.5-16, 11.5-17, 11.5-18, 11.5-19, 11.5-20, 11.5-25, 11.7-11.9, 11.7-12.1, 11.7-12.5, 11.7-13, 11.7-13.5, 11.7-14, 11.7-15, 11.7-16, 11. 7~17, 11.7~18, 11.7~19, 11.7~20, 11.7~25, 11.9~12.1, 11.9~12.5, 11.9~13, 11.9~13.5, 11.9~14, 11.9~15, 11.9~16, 11.9~17, 11.9~18, 11.9~19, 11.9~20, 11.9~25, 12.1~12.5, 12.1~13, 12.1~13.5, 12.1~14, 12.1~15, 12.1~16, 12.1~17, 12.1~ 18, 12.1-19, 12.1-20, 12.1-25, 12.5-13, 12.5-13.5, 12.5-14, 12.5-15, 12.5-16, 12.5-17, 12.5-18, 12.5-19, 12.5-20, 12.5-25, 13-13.5, 13-14, 13-15, 13-16, 13-17, 13-18, 13-19, 13-20, 13-25, 13.5-14, 13.5-15, 13.5-16, 13.5-17, 13.5-18 , 13.5 to 19, 13.5 to 20, 13.5 to 25, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 25, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 25, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 25, 17 to 18, 17 to 19, 17 to 20, 17 to 25, 18 to 19, 18 to 20, 18 to 25, 19 to 20, 19 to 25, or 20 to 25 hours. 1 / 2may be about 8.5 to about 10.5 hours. In one or more embodiments, the antiarrhythmic pharmaceutical agent is a Class I, Class II, Class III, or Class IV antiarrhythmic agent. In some embodiments, the antiarrhythmic pharmaceutical agent is a Class Ic antiarrhythmic agent. In other embodiments, the antiarrhythmic pharmaceutical agent is flecainide or a pharma- ceutically acceptable salt thereof.

[0179]

[0227] In some cases, emissions 1 / 2 may be calculated as the time at which the plasma level of the antiarrhythmic pharmaceutical agent has decreased to half of the plasma level at equilibrium due to metabolism and excretion. In some cases, the excretion t 1 / 2 may be calculated from the plasma concentration of the antiarrhythmic drug measured in the left ventricular cavity. 1 / 2 may be calculated from the plasma concentration of the antiarrhythmic drug measured in the pulmonary artery. 1 / 2 may be calculated from the plasma concentration of the antiarrhythmic pharmaceutical agent measured in a vein (e.g., the femoral vein). 1 / 2 may be measured in human PK / PD studies.

[0180]

[0228] In some cases, the maximum change in QRS interval duration (ΔQRS) following administration by inhalation of the antiarrhythmic medicinal agent is from about 0.01 msec to about 100 msec, e.g., from about 0.01 to 0.1, 0.01 to 0.5, 0.01 to 1, 0.01 to 1.5, 0.01 to 2, 0.01 to 2.5, 0.01 to 3, 0.01 to 3.5, 0.01 to 4, 0.01 to 4. .5, 0.01~5, 0.01~5.5, 0.01~6, 0.01~8, 0.01~10, 0.01~15, 0.01~20, 0.01~25, 0.01~30, 0.01~40, 0.01~50, 0.01~60, 0.01~70, 0.01~80, 0.01~90, 0.01~100, 0.1~0.5, 0.1~1, 0.1~1 .5, 0.1~2, 0.1~2.5, 0.1~3, 0.1~3.5, 0.1~4, 0.1~4.5, 0.1~5, 0.1~5.5, 0.1~6, 0.1~8, 0.1~10, 0.1~15, 0.1~20, 0.1~25, 0.1~30, 0.1~40, 0.1~50, 0.1~60, 0.1~70, 0.1~80, 0.1~90, 0 .1~100, 0.5~1, 0.5~1.5, 0.5~2, 0.5~2.5, 0.5~3, 0.5~3.5, 0.5~4, 0.5~4.5, 0.5~5, 0.5~5.5, 0.5~6, 0.5~8, 0.5~10, 0.5~15, 0.5~20, 0.5~25, 0.5~30, 0.5~40, 0.5~50, 0.5~60, 0.5~ 70、0.5~80、0.5~90、0.5~100、1~1.5、1~2、1~2.5、1~3、1~3.5、1~4、1~4.5、1~5、1~5.5、1~6、1~8、1~10、1~15、1~20、1~25、1~30、1~40、1~50、1~60、1~70、1~80、1~90、1~100、1.5~2、1.5~2.5、1.5~3、1.5~3.5、1.5~4、1.5~4.5、1.5~5、1.5~5.5、1.5~6、1.5~8、1.5~10、1.5~15、1.5~20、1.5~25、1.5~30、1.5~40、1.5~50、1.5~60、1.5~70、1.5~80、1.5~90、1.5~100、2~2.5、2~3、2~3.5、2~4、2~4.5、2~5、2~5.5、2~6、2~8、2~10、2~15、2~20、2~25、2~30、2~40、2~50、2~60、2~70、2~80、2~90、2~100、2.5~3、2.5~3.5、2.5~4、2.5~4.5、2.5~5、2.5~5.5、2.5~6、2.5~8、2.5~10、2.5~15、2.5~20、2.5~25、2.5~30、2.5~40、2.5~50、2.5~60、2.5~70、2.5~80、2.5~90、2.5~100、3~3.5、3~4、3~4.5、3~5、3~5.5、3~6、3~8、3~10、3~15、3~20、3~25、3~30、3~40、3~50、3~60、3~70、3~80、3~90、3~100、3.5~4、3.5~4.5、3.5~5、3.5~5.5、3.5~6、3.5~8、3.5~10、3.5~15、3.5~3.20、3.5~3.25、3.5~3.30、3.5~40、3.5~50、3.5~60、3.5~70、3.5~80、3.5~90、3.5~100、4~4.5、4~5、4~5.5、4~6、4~8、4~10、4~15、4~20、4~25、4~30、4~40、4~50、4~60、4~70、4~80、4~90、4~100、4.5~5、4.5~5.5、4.5~6、4.5~8、4.5~10、4.5~15、4.5~20、4.5~25、4.5~30、4.5~4.50、4.5~50、4.5~60、4.5~70、4.5~80、4.5~90、4.5~100、5~5.5、5~6、5~8、5~10、5~15、5~20、5~25、5~30、5~40、5~50、5~60、5~70、5~80、5~90、5~100、5.5~6、5.5~8、5.5~10、5.5~15、5.5~20、5.5~25、5.5~30、5.5~40、5.5~50、5.5~60、5.5~70、5.5~80、5.5~90、5.5~100, 6~8, 6~10, 6~15, 6~20, 6~25, 6~30, 6~40, 6~50, 6~60, 6~70, 6~80, 6~90, 6~100, 8~10, 8~15, 8~20, 8~25, 8~30, 8~40, 8~50, 8~60, 8~70, 8~80, 8~90, 8~100, 10~15, 10~20, 10~25, 10~30, 10~40, 10~50, 10~60, 10~70, 10~80, 10~90, 10~100, 15~20, 15~25, 15~30, 15~40, 15~50, 15~60, 15~70, 15~80, 15~90, 15~100, 20~25, 20~30, 20~4 0, 20~50, 20~60, 20~70, 20~80, 20~90, 20~100, 25~30, 25~40, 25~50, 25~60, 25~70, 25~80, 25~90, 25~100, 30~40, 30~50, 30~60, 30~70, 30~80, 30~90, 30~100, 40~50, 4 It may be 0 to 60, 40 to 70, 40 to 80, 40 to 90, 40 to 100, 50 to 60, 50 to 70, 50 to 80, 50 to 90, 50 to 100, 60 to 70, 60 to 80, 60 to 90, 60 to 100, 70 to 80, 70 to 90, 70 to 100, 80 to 90, 80 to 100, or 90 to 100 msec. In some cases, the maximum change in QRS interval duration (ΔQRS) after administration by inhalation of the antiarrhythmic medicinal agent may be about 1 to about 10 msec. In some cases, the maximum change in QRS interval duration (ΔQRS) after administration by inhalation of the antiarrhythmic medicinal agent may be about 5 to about 20 msec. In some cases, ΔQRS may be measured in a human PK / PD study. In the present disclosure, the term "ΔQRS", when not referenced with respect to time after administration of an antiarrhythmic agent, may be used interchangeably with the term "maximum ΔQRS", which means, for example, the maximum change in QRS after administration of an antiarrhythmic agent provided herein. In one or more embodiments, the antiarrhythmic pharmaceutical agent is Class I, Class II, Class III or Class II. In some embodiments, the antiarrhythmic pharmaceutical agent is a class IV antiarrhythmic drug. In other embodiments, the antiarrhythmic pharmaceutical agent is flecainide or a pharmaceutically acceptable salt thereof.

[0181]

[0229] In some cases, the time point at which the QRS interval is measured after administration by inhalation of the antiarrhythmic pharmaceutical agent to determine ΔQRS compared to before administration is about 0.1 minutes to about 450 minutes, for example, about 0.1 to 1, 0.1 to 3, 0.1 to 5, 0.1 to 10, 0.1 to 15, 0.1 to 30, 0.1 to 45, 0.1 to 60, 0.1 to 90, 0.1 to 120, 0.1 to 150, 0.1 to 180, 0.1 to 210, 0.1 to 240, 0.1 to 270, 0.1 to 300, 0.1 to 330, 0.1 to 360, 0.1 to 390, 0.1 to 410, 0.1 to 450, 1 to 3, 1 to 5, 1 to 10, 1 to 1 5, 1~30, 1~45, 1~60, 1~90, 1~120, 1~150, 1~180, 1~210, 1~240, 1~270, 1~300, 1~330, 1~360, 1~390, 1~410, 1~450, 3~5, 3~10, 3~15, 3~30, 3~45, 3~60, 3~ 90, 3~120, 3~150, 3~180, 3~210, 3~240, 3~270, 3~300, 3~330, 3~360, 3~390, 3~410, 3~450, 5~10, 5~15, 5~30, 5~45, 5~60, 5~90, 5~120, 5~150, 5~180, 5~ 210, 5~240, 5~270, 5~300, 5~330, 5~360, 5~390, 5~410, 5~450, 10~15, 10~30, 10~45, 10~60, 10~90, 10~120, 10~150, 10~180, 10~210, 10~240, 10~270, 10~300, 10~330, 10~360, 10~390, 10~410, 10~450, 15~30, 15~45, 15~60, 15~90, 15~120, 15~150, 15~180, 15~210, 15~240, 15~270, 15~300, 15~330, 15~ 360, 15~390, 15~410, 15~450, 30~45, 30~60, 30~90, 30~120, 30~150, 30~180, 30~210, 30~240, 30~270, 30~300, 30~330, 30~360, 30~390, 30~410, 30~45 0, 45~60, 45~90, 45~120, 45~150, 45~180, 45~210, 45~240, 45~270, 45~300, 45~330, 45~360, 45~390, 45~410, 45~450, 60~90, 60~120, 60~150, 60~180,60~210, 60~240, 60~270, 60~300, 60~330, 60~360, 60~390, 60~410, 60~450, 90~120, 90~150, 90~180, 90~210, 90~240, 90~270, 90~300, 90~330, 90~360, 90~390, 90~410, 90~450, 120~150, 120~180, 120~210, 120~240, 120~270, 120~300, 120~330, 120~360, 120~390, 120~410, 120~450, 150~180, 150~210, 150~240, 150~270, 150~300, 150~330, 150~360, 150~390, 150~410, 150~450, 180~210, 180~240, 180~270, 180 ~300, 180~330, 180~360, 180~390, 180~410, 180~450, 210~240, 210~270, 210~300, 210~330, 210~360, 210~390, 210~410, 210~450, 240~270, 240~300, 240~330, 240~360, 240~390, 240~410, 240~450, 270~30 It may be 0, 270 to 330, 270 to 360, 270 to 390, 270 to 410, 270 to 450, 300 to 330, 300 to 360, 300 to 390, 300 to 410, 300 to 450, 330 to 360, 330 to 390, 330 to 410, 330 to 450, 360 to 390, 360 to 410, 360 to 450, 390 to 410, 390 to 450, or 410 to 450 minutes.

[0182]

[0230] The antiarrhythmic activity of a pharmaceutical agent may be correlated with QRS interval duration. In some cases, an antiarrhythmic pharmaceutical agent administered by inhalation may have a similar effect to an intravenous delivery (e.g., intravenous infusion). In some cases, such increased antiarrhythmic activity may be due to a decrease in the maximum ΔQRS C. max For example, for the same C maxFor example, when considering the peak plasma concentration of an antiarrhythmic pharmaceutical agent, inhaled delivery of an antiarrhythmic agent provided herein may have a higher maximum ΔQRS than intravenous delivery of the same agent. In some cases, comparisons may not be made between corresponding doses by two different routes of administration, e.g., inhalation of a first dose of an agent may have a higher maximum ΔQRS than intravenous delivery of the same agent. max (C max1 ) and the first maximum ΔQRS (ΔQRS max1 ), and the intravenous administration of the second dose of the agent may have a second C max (C max2 ) and the second maximum ΔQRS (ΔQRS max2 In some cases, C max1 and C. max2 may be similar. In some cases, C max1 and C. max2 In some examples of the present disclosure, ΔQRS max1 Against C max1 The ratio of ΔQRS max2 Against C max2 Higher, i.e., ΔQRS max1 / C max1 >ΔQRS max2 / C max2 In some cases, ΔQRS max1 / C max1 is ΔQRS max2 / C max2at least 1.1 times, at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.2 times, at least 2.3 times, at least 2.4 times, at least 2.5 times, at least 2.6 times, at least 2.7 times, at least 2.8 times, at least 2.9 times, at least 3.0 times, at least 3.1 times, at least 3.2 times, at least At least 3.3 times, at least 3.4 times, at least 3.5 times, at least 3.6 times, at least 3.7 times, at least 3.8 times, at least 3.9 times, at least 4.0 times, at least 4.2 times, at least 4.4 times, at least 4.6 times, at least 4.8 times, at least 5.0 times, at least 5.5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 12 times, at least 15 times, at least 20 times, at least 25 times, or at least 50 times higher. max1 / C max1 is ΔQRS max2 / C max2 is at least 2-fold higher than that of the antiarrhythmic drug. In one or more embodiments, the antiarrhythmic drug is a class I, class II, class III or class IV antiarrhythmic drug. In some embodiments, the antiarrhythmic drug is a class Ic antiarrhythmic drug. In other embodiments, the antiarrhythmic drug is flecainide or a pharmaceutically acceptable salt thereof.

[0183]

[0231] In some cases, the compositions and methods provided herein provide a reduced negative inotropic load to subjects receiving inhalation delivery of antiarrhythmic pharmaceutical agents, such as flecainide, compared to receiving a corresponding dose of the same agent by a different route (e.g., oral or intravenous delivery). Certain antiarrhythmic drugs may have negative inotropic effects, which may limit their use in rapid cardioversion of new-onset paroxysmal atrial fibrillation (AF). For example, intravenous delivery of flecainide may exert a negative inotropic load on the subject's heart, which may be measured by left ventricular (LV) contractility. In some cases, negative inotropic load may be measured by the area under the curve (AUC) of the curve that describes the magnitude of LV contractility (e.g., measured by dP / dt max) and the time it remains below baseline (e.g., baseline level before drug administration or at rest). In some embodiments, the negative inotropic load of the inhalation delivery of a therapeutically effective dose of an antiarrhythmic pharmaceutical agent by the methods described herein is lower than that of the corresponding therapeutically effective dose of the same agent delivered by a different route (e.g., oral or intravenous delivery). For example, in such embodiments, the negative inotropic load of the inhalation delivery of a therapeutically effective dose of an antiarrhythmic pharmaceutical agent by the methods described herein is up to 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% of that of the corresponding therapeutically effective dose of the same agent delivered by a different route (e.g., oral or intravenous delivery). In some embodiments, the negative inotropic load of the inhalation delivery of a therapeutically effective dose of an antiarrhythmic pharmaceutical agent by the methods described herein is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10% of that of the corresponding therapeutically effective dose of the same agent delivered by a different route (e.g., oral or intravenous delivery). As described herein The negative inotropic load of a therapeutically effective dose of an antiarrhythmic pharmaceutical agent delivered by the disclosed method inhalation is about 30% of that of a corresponding therapeutically effective dose of the same agent delivered by a different route (e.g., oral or intravenous delivery). In such embodiments, the corresponding therapeutically effective dose of an antiarrhythmic pharmaceutical agent delivered by the other route may have a similar conversion rate (percentage of effective conversions of arrhythmias to sinus rhythm) with, for example, a variance of 20% or less than 10% compared to a therapeutically effective inhalation dose of the same agent.

[0184] Indications and Targets

[0232] The cardiac arrhythmias that the methods, compositions and kits provided herein can treat include, but are not limited to, tachycardia, supraventricular tachycardia (SVT), paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (AF), paroxysmal atrial fibrillation (PAF), persistent atrial fibrillation, permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter and isolated atrial fibrillation.In some cases, the methods, compositions and kits provided herein are used to treat subjects suffering from atrial arrhythmias, such as atrial fibrillation.

[0185]

[0233] Thus, the pharmaceutical composition according to some examples of the present disclosure may be used to treat and / or provide prophylaxis for a wide range of patients. The patient suitable for receiving the treatment and / or prophylaxis described herein is any mammalian patient in need of treatment and / or prophylaxis, preferably such mammal is human. Examples of subjects include, but are not limited to, pediatric patients, adult patients, and geriatric patients. In some examples, the composition is intended only for treatment to rapidly resolve symptoms and restore normal sinus rhythm, and is not interpreted as a preventative measure, e.g., if the patient is well, no medication is needed. This allows for an increase in the benefit-risk ratio and overall safety of treatment with sporadic or intermittent dosing, and a focus on reducing disabling symptoms and restoring sinus rhythm only when necessary.

[0186]

[0234] The required dosage and frequency of administration of the antiarrhythmic pharmaceutical agent depends on the composition and the concentration of the antiarrhythmic pharmaceutical agent in the composition. In some cases, the dosage is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of its normal intravenous dosage. In some cases, the dosage is about 5% to about 10%, about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 50% to about 60%, about 60% to about 70%, about 70% to about 80%, about 80% to about 90%, or about 90% to about 95% of the intravenous dosage.

[0187]

[0235] The pharmaceutical compositions disclosed herein may be more effective in subjects with or without certain physiological or demographic factors, such as age, certain hemodynamic criteria, electrophysiological characteristics, and previous treatments in clinical presentation. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure suffers from atrial fibrillation with onset occurring within 48 hours prior to treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure suffers from atrial fibrillation with onset occurring 1 hour to 48 hours prior to treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure suffers from recurrent atrial fibrillation. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure has undergone cardiac ablation 3 months or more prior to treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is receiving an ongoing prescription for an oral antiarrhythmic drug for atrial fibrillation. In some embodiments, the oral antiarrhythmic drug is flecainide or a pharma- ceutically acceptable salt thereof.

[0188]

[0236] In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is over the age of 17. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is up to the age of 85. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is between the ages of 18 and 85.

[0189]

[0237] In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure has a systolic blood pressure of less than 180 mmHg, less than 175 mmHg, less than 170 mmHg, less than 165 mmHg, less than 160 mmHg, less than 155 mmHg, or less than 150 mmHg at the time of treatment. In some cases, when referring to a physiological measurement of a subject, such as blood pressure, e.g., systolic or diastolic blood pressure, or heart rate, e.g., ventricular rate, the term "at the time of treatment" means that the measurement is taken 1 minute to 6 hours prior to treatment, such as 1 minute to 10 minutes, 1 minute to 30 minutes, 1 minute to 60 minutes, 1 minute to 90 minutes, 1 minute to 2 hours, 1 minute to 3 hours, 1 minute to 4 hours, 1 minute to 5 hours, 10 minutes to 30 minutes, 10 minutes to 60 minutes, 30 minutes to 60 minutes, 30 minutes to 90 minutes, 30 minutes to 2 hours, 1 hour to 2 hours, or 2 hours to 3 hours prior to treatment. In some cases, physiological measurements of a subject, such as measurements of systolic blood pressure or ventricular rate, provide the basis for an informed decision as to whether or not the subject should be treated with the subject pharmaceutical compositions and methods. In some embodiments, subjects treated with pharmaceutical compositions of the present disclosure have a systolic blood pressure of greater than 70 mmHg, greater than 75 mmHg, greater than 80 mmHg, greater than 85 mmHg, greater than 90 mmHg, greater than 95 mmHg, greater than 100 mmHg, greater than 105 mmHg, greater than 110 mmHg, greater than 115 mmHg, or greater than 120 mmHg at the time of treatment.

[0190]

[0238] In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure has a blood glucose level of about 60 mmHg to about 180 mmHg, about 65 mmHg to about 180 mmHg, about 70 mmHg to about 180 mmHg, about 75 mmHg to about 180 mmHg, about 80 mmHg to about 180 mmHg, about 85 mmHg to about 180 mmHg, about 90 mmHg to about 180 mmHg, about 95mmHg to 180mmHg, 100mmHg to 180mmHg, 105mmHg to 180mmHg, 110mmHg to 180mmHg, 115mmHg to 180mmHg, 120mmHg to 180mmHg, 70mmHg to 175mmHg, 70mmHg to 170mmHg, 70mmHg to 165mmHg mHg, about 70mmHg to about 160mmHg, about 70mmHg to about 155mmHg, about 70mmHg to about 150mmHg, about 80mmHg to about 165mmHg, about 90m mHg ~ approx. 165mmHg, approx. 100mmHg ~ approx. 165mmHg, approx. 70mmHg ~ approx. 160mmHg, approx. 70mmHg ~ approx. 160mmHg, approx. 75mmHg ~ approx. 160 mmHg, about 80 mmHg to about 160 mmHg, about 85 mmHg to about 160 mmHg, about 90 mmHg to about 160 mmHg, about 95 mmHg to about 160 mmHg, about 100 mmHg to about 160 mmHg, about 70 mmHg to about 155 mmHg, about 75 mmHg to about 155 mmHg, or about 80 mmHg to about 155 mmHg.

[0191]

[0239] In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure has a ventricular rate of at least about 50 BPM, at least about 55 BPM, at least about 60 BPM, at least about 65 BPM, at least about 70 BPM, at least about 75 BPM, at least about 80 BPM, at least about 85 BPM, at least about 90 BPM, at least about 95 BPM, or at least about 100 BPM during treatment. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure has a ventricular rate of about 200 BPM or less, about 190 BPM or less, about 180 BPM or less, about 175 BPM or less, about 170 BPM or less, about 165 BPM or less, about 160 BPM or less, about 155 BPM or less, about 150 BPM or less, about 145 BPM or less, or about 140 BPM or less during treatment.

[0192]

[0240] In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure has a blood glucose level of about 50 BPM to about 200 BPM, 50 BPM to about 180 BPM, about 55 BPM to about 180 BPM, about 60 BPM to about 180 BPM, about 65 BPM to about 180 BPM, about 70 BPM to about 180 BPM, about 75 BPM to about 180 BPM, about 80 BPM to about 180 BPM, about 85 BPM to about 180 BPM, about 95 BPM to about 180 BPM, about 100 BPM to about 180 BPM, about 50 BPM to about 175 BPM, about 50 BPM to about 170 BPM, about 50 BPM to about 165BPM, approximately 50BPM to approximately 160BPM, approximately 50BPM to approximately 155BPM, approximately 70BPM to approximately 175BPM, approximately 70BPM to approximately 170BPM, approximately 70BPM to approximately 165BPM, approximately 70BPM to approximately 160BP M, about 70BPM to about 155BPM, about 75BPM to about 180BPM, about 75BPM to about 175BPM, about 75BPM to about 170BPM, about 75BPM to about 165BPM, about 75BPM to about 160BPM, about 75 BPM to about 155 BPM, about 80 BPM to about 175 BPM, about 80 BPM to about 170 BPM, about 80 BPM to about 165 BPM, about 80 BPM to about 160 BPM, about 80 BPM to about 155 BPM, about 80 BPM to about 150 BPM, about 80 BPM to about 145 BPM, about 85 BPM to about 155 BPM, about 90 BPM to about 155 BPM, about 95 BPM to about 155 BPM, or about 100 BPM to about 155 BPM.

[0193]

[0241] In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure has not been treated with antiarrhythmic drugs or electrical cardioversion since the onset of the episode of atrial arrhythmia for which the pharmaceutical composition is administered. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit acute decompensated heart failure at the time of treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not have heart failure with reduced ejection fraction or a history of it. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not have myocardial ischemia or a history of it. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not have myocardial infarction or a history of it. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure has not exhibited a myocardial infarction (MI) within 3 months prior to administration of the pharmaceutical composition. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit uncorrected severe aortic or mitral stenosis at the time of treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit hypertrophic cardiomyopathy with outflow tract obstruction at the time of treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not have persistent atrial fibrillation or a history of it. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit atrial flutter at the time of treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit an episode of atrial flutter within 6 months prior to treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit abnormal left ventricular ejection fraction at the time of treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit class 2 or higher heart failure according to the New York Heart Association functional classification at the time of treatment.

[0194]

[0242] In some embodiments, subjects treated with the pharmaceutical compositions of the present disclosure are hemodynamically stable, have a systolic blood pressure greater than about 90 mmHg at the time of treatment, have a ventricular rate of about 70 BPM to about 170 BPM, and have no condition or history of conditions including myocardial infarction, myocardial ischemia, atrial stenosis, hypertrophic cardiomyopathy, and heart failure with reduced ejection fraction.

[0195]

[0243] In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not have a history of or have long QT syndrome, conduction disease (e.g., second or third degree heart block, bundle branch block), sick sinus syndrome, Brugada syndrome, torsade de pointes (TdP). In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit, at the time of treatment, the following ECG-related features: QTc interval longer than 480 msec (estimated by Fridericia's formula); QRS duration longer than 105 ms; monomorphic or polymorphic ventricular tachycardia, either sustained or non-sustained; and excessive ventricular premature beats (ventricular extrasystoles) with multifocal PVCs greater than 20 per hour; or a predominantly paced heart rhythm.

[0196]

[0244] In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit severe renal dysfunction, and the subject's eGFR is less than 30 mL / min / 1.73 m2 at the time of treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is not undergoing dialysis at the time of treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit liver function abnormalities at the time of treatment. In some embodiments, the liver function abnormalities are biochemically consistent with liver disease or significant liver abnormalities. In some embodiments, subjects treated with a pharmaceutical composition of the present disclosure do not exhibit uncorrected hypokalemia at the time of treatment. In some embodiments, subjects treated with a pharmaceutical composition of the present disclosure do not exhibit serum potassium below 3.6 mEq / L at the time of treatment.

[0197]

[0245] In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit an established pulmonary disease that requires an inhaled drug during treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not have or have a history of hypersensitivity to flecainide acetate or any of its active metabolites. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is not co-administered with a systemic drug that is an inhibitor of CYP 2D6. In some embodiments, the inhibitor of CYP 2D6 is an antidepressant, a neuroleptic, or an antihistamine. In some embodiments, the inhibitor of CYP 2D6 is propranolol or ritonavir. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is not co-administered with a systemic drug that is a CYP 2D6 inducer. In some embodiments, the CYP 2D6 inducer is phenytoin, phenobarbital, or carbamazepine.

[0198]

[0246] In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure has not been treated with a class I or class II antiarrhythmic drug within 1 week prior to administration of the pharmaceutical composition. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure who has an ongoing episode of atrial fibrillation has not been treated with a class I or class III antiarrhythmic drug since the onset of the ongoing episode. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is administered 320 mg or less of flecainide or a pharma- ceutically acceptable salt thereof per day from any source. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure who has an ongoing episode of atrial fibrillation has not been treated with electrical cardioversion since the onset of the ongoing episode. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure has not been treated with amiodarone within 12 weeks prior to administration of the pharmaceutical composition. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure is not considered at high risk for stroke based on a screening coagulation panel. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit a CHA2DS2-VASc score of 2 or greater.

[0199]

[0247] In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit congenital heart disease at the time of treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit a history of refractory atrial fibrillation that has been pharmacologically or electrically cardioverted. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit atrial fibrillation secondary to electrolyte abnormalities, thyroid disease, or non-cardiovascular causes at the time of treatment. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure does not exhibit syncope at the time of treatment.

[0200]

[0248] In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit a serious or life-threatening medical condition other than cardiac arrhythmia at the time of treatment. In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure does not exhibit an acute pathogenic infection at the time of treatment.

[0201]

[0249] In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure has not exhibited drug or alcohol addiction within 12 months prior to administration of the pharmaceutical composition. In some embodiments, the subject treated with the pharmaceutical composition of the present disclosure has a blood glucose level of 40 Kg / m 2 Does not exhibit a higher body mass index.

[0202]

[0250] In some embodiments, a subject treated with a pharmaceutical composition of the present disclosure is: (i) suffer from atrial fibrillation with onset occurring between 1 and 48 hours prior to the procedure; (ii) had undergone cardiac ablation more than 3 months prior to the procedure, were receiving an ongoing prescription for oral flecainide or a pharma- ceutically acceptable salt thereof, or suffered from recurrent atrial fibrillation; (iii) were between 18 and 85 years of age; (iv) having a systolic blood pressure of about 100 mmHg to about 160 mmHg at the time of treatment; (v) having a ventricular rate of about 80 BPM to about 155 BPM at the time of the procedure; This applies to: (a) abnormal left ventricular ejection fraction within 6 months prior to the procedure; (b) heart failure of class 2 or greater as classified by the New York Heart Association functional classification within 6 months prior to the procedure; (c) myocardial infarction or history of myocardial infarction; (d) hemodynamic or cardiac instability at the time of the procedure; and (e) episode of atrial flutter within 6 months prior to the procedure and the subject has not undergone cardiac surgery for any of the conditions (a)-(e) within 6 months prior to treatment.

[0203] Numbered paragraphs [1] A pharmaceutical composition comprising a therapeutically effective amount of a salt of flecainide, said pharmaceutical composition being in the form of a liquid solution having a concentration of said salt of flecainide greater than 60 mg / mL.

[0204] [2] The pharmaceutical composition described in paragraph [1], further comprising a cyclodextrin. [3] The pharmaceutical composition of paragraph [1] or [2], wherein the pH of the solution is greater than 5.5 at room temperature.

[0205] [4] The pharmaceutical composition of paragraph [1], further comprising a cyclodextrin, wherein the pH of the solution is greater than 5.5 at room temperature. [5] The pharmaceutical composition of paragraph [2] or [4], wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatized α-cyclodextrin, derivatized β-cyclodextrin, and derivatized γ-cyclodextrin.

[0206] [6] The cyclodextrin is, for example, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, or maltotriosyl-γ-cyclodextrin. The pharmaceutical composition of paragraph [2] or [4], wherein the cyclodextrin is selected from the group consisting of dimaltosyl-β-cyclodextrin, succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, and sulfoalkylether-γ-cyclodextrin.

[0207] [7] The pharmaceutical composition of paragraph [2] or [4], wherein the cyclodextrin comprises hydroxypropyl-β-cyclodextrin. [8] The pharmaceutical composition described in paragraph [2] or [4], wherein the concentration of the cyclodextrin in the pharmaceutical composition is from about 1% (w / v) to about 80% (w / v) of the solution.

[0208] [9] The pharmaceutical composition described in paragraphs [2], [4] or [8], wherein the concentration of the cyclodextrin is about 15% (w / v) to about 25% (w / v) of the solution.

[10] The concentration of the cyclodextrin is about 10% (w / v) to about 3 The pharmaceutical composition according to paragraph [2], [4] or [8], wherein the composition is 0% (w / v).

[0209]

[11] The pharmaceutical composition of paragraph [8], wherein the concentration of the cyclodextrin is at least about 5% (w / v) of the solution.

[12] The pharmaceutical composition of paragraph [8], wherein the concentration of the cyclodextrin is at least about 10% (w / v) of the solution.

[0210]

[13] The pharmaceutical composition described in paragraph [8], wherein the concentration of the cyclodextrin is about 20% (w / v) of the solution.

[14] The pharmaceutical composition of paragraph [8], wherein the concentration of the cyclodextrin is at most about 20% (w / v) of the solution.

[0211]

[15] The pharmaceutical composition described in paragraph [8], wherein the concentration of the cyclodextrin is about 25% (w / v) of the solution.

[16] The pharmaceutical composition of paragraph [8], wherein the concentration of the cyclodextrin is at most about 25% (w / v) of the solution.

[0212]

[17] The pharmaceutical composition according to any one of paragraphs [1] to

[16] , wherein the concentration of the salt of flecainide is at most about 200 mg / mL.

[18] The pharmaceutical composition according to any one of paragraphs [1] to

[17] , wherein the concentration of the salt of flecainide is from about 65 mg / mL to about 130 mg / mL.

[0213]

[19] The pharmaceutical composition according to any one of paragraphs [1] to

[18] , wherein the concentration of the salt of flecainide is from about 65 mg / mL to about 95 mg / mL.

[20] The pharmaceutical composition according to any one of paragraphs [1] to

[19] , wherein the concentration of the salt of flecainide is from about 70 mg / mL to about 115 mg / mL.

[0214]

[21] The pharmaceutical composition according to any one of paragraphs [1] to

[20] , wherein the concentration of the salt of flecainide is about 100 mg / mL.

[22] The pharmaceutical composition according to any one of paragraphs [1] to

[21] , wherein the concentration of the salt of flecainide is about 75 mg / mL.

[0215]

[23] The pharmaceutical composition according to any one of paragraphs [1] to

[22] , wherein the salt of flecainide is selected from the group consisting of flecainide acetate, flecainide hydrochloride, flecainide citrate, flecainide phosphate and flecainide nitrate.

[0216]

[24] The pharmaceutical composition according to any one of paragraphs [1] to

[23] , wherein the salt of flecainide comprises flecainide acetate.

[25] The pharmaceutical composition according to any one of paragraphs [1] to

[24] , wherein the salt of flecainide comprises flecainide hydrochloride.

[0217]

[26] The pharmaceutical composition according to any one of paragraphs [1] to

[25] , further comprising an acid.

[27] The pharmaceutical composition according to paragraph

[26] , wherein the acid is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbic acid, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactic acid, propionic acid, sorbic acid, stearic acid and succinic acid.

[0218]

[28] The pharmaceutical composition of paragraph

[26] , wherein the acid is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid.

[29] The pharmaceutical composition described in any one of paragraphs

[0026] to

[28] , wherein the concentration of the acid in the pharmaceutical composition is about 2 mM to about 200 mM.

[0219]

[30] The pharmaceutical composition described in any one of paragraphs

[26] to

[28] , wherein the concentration of the acid in the pharmaceutical composition is about 2 mM to about 50 mM.

[31] The pharmaceutical composition described in any one of paragraphs

[26] to

[28] , wherein the concentration of the acid in the pharmaceutical composition is from about 2 mM to about 10 mM.

[0220]

[32] The pharmaceutical composition of paragraph

[29] , wherein the concentration of the acid is up to about 50 mM.

[33] The pharmaceutical composition of paragraph

[29] , wherein the concentration of the acid is about 20 mM.

[0221]

[34] The pharmaceutical composition of paragraph

[29] , wherein the concentration of the acid is about 5 mM.

[35] The pharmaceutical composition described in any one of paragraphs

[29] to

[32] , wherein the acid comprises acetic acid.

[0222]

[36] The pharmaceutical composition of paragraph

[35] , wherein the concentration of acetic acid is about 5 mM.

[37] The pharmaceutical composition described in any one of paragraphs

[29] to

[32] , wherein the acid comprises citric acid.

[0223]

[38] The pharmaceutical composition of paragraph

[37] , wherein the concentration of citric acid is about 5 mM.

[39] The pharmaceutical composition of paragraph

[26] , wherein the acid comprises a mixture of acids selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbic acid, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactic acid, propionic acid, sorbic acid, stearic acid, and succinic acid.

[0224]

[40] The pharmaceutical composition of paragraph

[26] , wherein the acid comprises a mixture of acids selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid.

[41] The pharmaceutical composition of paragraph

[26] , wherein the acid comprises hydrochloric acid.

[0225]

[42] The pharmaceutical composition according to any one of paragraphs

[26] to

[36] , wherein the salt of flecainide comprises flecainide acetate and the acid comprises acetic acid.

[43] The pharmaceutical composition described in any one of paragraphs [3] to

[42] , wherein the pH of the solution is up to about 6.5.

[0226]

[44] The pharmaceutical composition described in any one of paragraphs [3] to

[42] , wherein the pH of the solution is from about 5.5 to about 6.5.

[45] The pharmaceutical composition described in any one of paragraphs [3] to

[42] , wherein the pH of the solution is about 5.9.

[0227]

[46] The pharmaceutical composition described in any one of paragraphs [1] to

[45] , further comprising a sweetener.

[47] The pharmaceutical composition of paragraph

[46] , wherein the sweetener is selected from the group consisting of acesulfame potassium, aspartame, cyclamate, mogroside, saccharin, stevia, sucralose, neotame, mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol, and pharma- ceutically acceptable salts thereof.

[0228]

[48] ​​The pharmaceutical composition described in paragraph

[46] , wherein the sweetener comprises saccharin.

[49] The pharmaceutical composition described in paragraph

[46] , wherein the sweetener comprises a salt of saccharin.

[50] The pharmaceutical composition described in paragraph

[46] , wherein the sweetener comprises sodium saccharin.

[0229]

[51] The pharmaceutical composition described in any one of paragraphs

[46] to

[50] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 1% (w / v).

[52] The pharmaceutical composition described in any one of paragraphs

[46] to

[50] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 1% (w / v).

[0230]

[53] The pharmaceutical composition described in any one of paragraphs

[46] to

[50] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 0.05% (w / v).

[54] The pharmaceutical composition described in any one of paragraphs

[46] to

[50] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 0.01% (w / v).

[0231]

[55] The pharmaceutical composition of any one of paragraphs [1] to

[54] , formulated for administration by inhalation.

[56] The pharmaceutical composition described in any one of paragraphs [1] to

[55] , which is a spray solution comprising spray droplets having a mass median aerodynamic diameter of less than 10 μm.

[0232]

[57] A dosage unit of the pharmaceutical composition described in any one of paragraphs [1] to

[56] , comprising about 50 mg to about 350 mg of the salt of flecainide.

[58] The dosage unit according to paragraph

[57] , comprising from about 60 mg to about 150 mg of the salt of flecainide.

[0233]

[59] The dosage unit according to paragraph

[57] , comprising from about 75 mg to about 125 mg of the salt of flecainide.

[60] The dosage unit according to paragraph

[57] , comprising about 250 mg to about 350 mg of the salt of flecainide.

[0234]

[61] The dosage unit according to paragraph

[57] , comprising from about 100 mg to about 250 mg of the salt of flecainide.

[62] The dosage unit according to paragraph

[57] , comprising about 90 mg of the salt of flecainide.

[0235]

[63] The dosage unit according to paragraph

[57] , comprising about 120 mg of the salt of flecainide.

[64] The dosage unit according to paragraph

[57] , comprising about 200 mg of the salt of flecainide.

[0236]

[65] A kit comprising the pharmaceutical composition or the dosage unit described in any one of paragraphs [1] to

[64] and instructions for use of the pharmaceutical composition for the treatment of a cardiac condition.

[0237]

[66] The kit of paragraph

[65] , wherein the cardiac condition comprises atrial fibrillation.

[67] The kit of paragraph

[66] , wherein the atrial fibrillation includes tachycardia.

[68] The kit of paragraph

[66] , wherein the atrial arrhythmia is selected from the group consisting of supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes of sustained and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter or isolated atrial fibrillation.

[0238]

[69] The kit described in any one of paragraphs

[65] to

[68] , further comprising a container containing the pharmaceutical composition.

[70] The kit of paragraph

[69] , wherein the container is selected from the group consisting of a vial, a syringe, a capsule, a blow-fill-seal, a blister, a cartridge, and an ampoule.

[0239]

[71] (1)(a) Salts of flecainide, (b) cyclodextrin, and (c) acid a pharmaceutical composition comprising: (2) a receptacle containing the pharmaceutical composition; and (3) Instructions for use of a nebulizer for administering a dose of the pharmaceutical composition by aerosol inhalation to a subject, the dose containing about 50 mg to about 250 mg of the salt of flecainide, and the aerosol of the pharmaceutical composition having droplets with a median aerodynamic diameter of less than 10 μm. A kit comprising: The pharmaceutical composition comprises: (i) the salt of flecainide having a concentration of about 65 mg / mL to about 95 mg / mL; (ii) the cyclodextrin at a concentration of about 10% (w / v) to about 30% (w / v) of the solution; and (iii) a pH of about 5.5 to about 6.5 when measured at room temperature; The kit is in the form of a liquid solution having the formula:

[0240]

[72] The kit of paragraph

[71] , wherein the concentration of the salt of flecainide is about 70 mg / mL to about 80 mg / mL.

[73] The kit according to paragraph

[71] or

[72] , wherein the concentration of the salt of flecainide is about 75 mg / mL.

[0241]

[74] The kit according to any one of paragraphs

[71] to

[73] , wherein the salt of flecainide is selected from the group consisting of flecainide acetate, flecainide hydrochloride, flecainide citrate, flecainide phosphate and flecainide nitrate.

[0242]

[75] The kit described in any one of paragraphs

[71] to

[73] , wherein the salt of flecainide comprises flecainide acetate.

[76] The kit according to any one of paragraphs

[71] to

[75] , wherein the acid is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, ascorbic acid, lactic acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactic acid, propionic acid, sorbic acid, stearic acid and succinic acid.

[0243]

[77] The kit described in any one of paragraphs

[71] to

[75] , wherein the acid comprises acetic acid.

[78] The kit described in any one of paragraphs

[71] to

[75] , wherein the acid comprises citric acid.

[0244]

[79] The kit described in any one of paragraphs

[71] to

[78] , wherein the concentration of the acid in the pharmaceutical composition is about 2 mM to about 10 mM.

[80] The kit described in any one of paragraphs

[71] to

[78] , wherein the concentration of the acid is about 5 mM.

[0245]

[81] The kit described in any one of paragraphs

[71] to

[80] , wherein the pH of the solution is about 5.9 when measured at room temperature.

[82] The cyclodextrin is α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin. The kit according to any one of paragraphs

[71] to

[81] , wherein the cyclodextrin is selected from the group consisting of glyceryl phosphate, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, maltotriosyl-γ-cyclodextrin dimaltosyl-β-cyclodextrin, succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, sulfobutyl ether-γ-cyclodextrin, sulfoalkyl ether-β-cyclodextrin, and sulfoalkyl ether-γ-cyclodextrin.

[0246]

[83] The kit described in any one of paragraphs

[71] to

[81] , wherein the cyclodextrin comprises hydroxypropyl-β-cyclodextrin.

[84] The kit described in any one of paragraphs

[71] to

[83] , wherein the concentration of the cyclodextrin is about 15% (w / v) to about 25% (w / v) of the solution.

[0247]

[85] The kit described in any one of paragraphs

[71] to

[83] , wherein the concentration of the cyclodextrin is about 20% (w / v) of the solution.

[86] The kit described in any one of paragraphs

[71] to

[85] , wherein the pharmaceutical composition further contains an artificial sweetener.

[0248]

[87] The kit described in any one of paragraphs

[71] to

[86] , wherein the dosage contains about 150 mg to about 250 mg of the salt of flecainide.

[88] The kit described in any one of paragraphs

[71] to

[86] , wherein the dose contains about 200 mg of the salt of flecainide.

[0249]

[89] The kit described in any one of paragraphs

[71] to

[88] , further comprising a nebulizer selected from the group consisting of a breath-actuated jet nebulizer, a vibrating mesh nebulizer, and an ultrasonic nebulizer.

[0250]

[90] The kit described in any one of paragraphs

[71] to

[89] , wherein the pharmaceutical composition is formulated for administration by a breath-actuated jet nebulizer, a vibrating mesh nebulizer, or an ultrasonic nebulizer.

[0251]

[91] A system comprising the pharmaceutical composition described in any one of paragraphs [1] to

[70] and a nebulizer.

[92] The system of paragraph

[91] , wherein the pharmaceutical composition is formulated for administration by a nebulizer, and the nebulizer is selected from the group consisting of a breath-actuated jet nebulizer, a vibrating mesh nebulizer, and an ultrasonic nebulizer.

[0252]

[93] The system of paragraph

[91] , wherein the nebulizer is selected from the group consisting of a breath-actuated jet nebulizer, a vibrating mesh nebulizer, and an ultrasonic nebulizer.

[94] The system described in any one of paragraphs

[91] to

[93] , further comprising instructions for use of the nebulizer and the pharmaceutical composition for the treatment of a cardiac condition.

[0253]

[95] The system described in any one of paragraphs

[91] to

[93] , further comprising instructions for use of the nebulizer and the pharmaceutical composition for the treatment of atrial arrhythmia.

[96] The system of paragraph

[95] , wherein the atrial arrhythmia includes tachycardia.

[0254]

[97] The atrial arrhythmia is selected from the group consisting of supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, and paroxysmal atrial fibrillation. The system of paragraph

[95] , wherein the atrium is selected from the group consisting of acute episodes of atrial fibrillation, persistent and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter or isolated atrial fibrillation.

[0255]

[98] The system described in any one of paragraphs

[91] to

[97] , wherein the nebulizer is configured to deliver the pharmaceutical composition as droplets having a mass median aerodynamic diameter of less than 10 μm.

[0256]

[99] The system described in any one of paragraphs

[91] to

[98] , wherein the nebulizer is a breath-actuated nebulizer.

[0100] The system described in any one of paragraphs

[91] to

[98] , wherein the nebulizer is a jet nebulizer.

[0257]

[0101] A system described in any one of paragraphs

[94] to

[0100] , wherein the instructions for use include instructions for using the nebulizer to deliver the pharmaceutical composition in a dosage unit containing from about 60 mg to about 150 mg of the salt of flecainide.

[0258]

[0102] A system described in any one of paragraphs

[94] to

[0100] , wherein the instructions for use include instructions for using the nebulizer to deliver the pharmaceutical composition in a dosage unit containing from about 75 mg to about 125 mg of the salt of flecainide.

[0259]

[0103] A system described in any one of paragraphs

[94] to

[0100] , wherein the instructions for use include instructions for using the nebulizer to deliver the pharmaceutical composition in a dosage unit containing approximately 90 mg of the salt of flecainide.

[0260]

[0104] A system described in any one of paragraphs

[94] to

[0100] , wherein the instructions for use include instructions for using the nebulizer to deliver the pharmaceutical composition in a dosage unit containing approximately 120 mg of the salt of flecainide.

[0261] A pharmaceutical composition comprising a salt of flecainide, a cyclodextrin and an acid; a nebulizer configured to deliver the pharmaceutical composition as droplets having a mass median aerodynamic diameter of less than 10 μm; and Instructions for use of said nebulizer to deliver said pharmaceutical composition in a dosage unit containing from about 50 mg to about 250 mg of said salt of flecainide. A system comprising: The pharmaceutical composition is in the form of a liquid solution having: (i) the salt of flecainide in a concentration of 65 mg / mL to 100 mg / mL; (ii) the cyclodextrin in a concentration of about 10% (w / v) to about 30% (w / v) of the solution; and (iii) a pH of about 5.5 to about 6.5 at room temperature.

[0262]

[0106] A method for treating a subject suffering from a cardiac condition, comprising the step of administering to the subject by inhalation a pharmaceutical composition in the form of a liquid solution, the pharmaceutical composition comprising a therapeutically effective amount of a salt of flecainide, and the concentration of the salt of flecainide in the pharmaceutical composition is greater than 60 mg / mL.

[0263]

[0107] The method according to paragraph

[0106] , wherein the pharmaceutical composition further comprises a cyclodextrin.

[0108] The method according to paragraph

[0106] or

[0107] , wherein the pH of the solution is greater than 5.5 when the pH is measured at room temperature.

[0264] A method of treating a human subject suffering from a cardiac condition, comprising administering a pharmaceutical agent in the form of a liquid solution. A method comprising the step of administering a composition to the subject by inhalation within about 10 minutes, wherein the pharmaceutical composition comprises a therapeutically effective amount of a salt of flecainide, and wherein the administration results in a peak plasma concentration (Cmax) of the salt of flecainide in the subject that is at least 200 ng / mL.

[0265]

[0110] The method described in paragraph

[0109] , wherein the concentration of the flecainide salt in the pharmaceutical composition is greater than 60 mg / mL of the solution.

[0111] The method according to paragraph

[0106] ,

[0109] or

[0110] , wherein the pharmaceutical composition further contains a cyclodextrin.

[0266]

[0112] The method described in any one of paragraphs

[0106] to

[0108] or

[0111] , wherein the administration of the pharmaceutical composition results in a peak plasma concentration (Cmax) of the salt of flecainide in the subject that is at least 200 ng / mL.

[0267]

[0113] The method described in any one of paragraphs

[0106] to

[0112] , wherein the administration of the pharmaceutical composition results in a peak plasma concentration (Cmax) of the salt of flecainide in the subject that is at least 250 ng / mL.

[0268]

[0114] The method described in paragraph

[0113] , wherein the Cmax is about 250 ng / mL to about 1000 ng / mL.

[0115] The method described in paragraph

[0113] , wherein the Cmax is about 300 ng / mL to about 700 ng / mL.

[0269]

[0116] The method described in paragraph

[0113] , wherein the Cmax is about 400 ng / mL to about 600 ng / mL.

[0117] The method described in any one of paragraphs

[0106] to

[0116] , wherein the administration of the pharmaceutical composition is performed within about 10 minutes.

[0270]

[0118] The method described in any one of paragraphs

[0106] to

[0116] , wherein the administration of the pharmaceutical composition is performed within about 5 minutes.

[0119] The method described in any one of paragraphs

[0106] to

[0118] , wherein the administration of the pharmaceutical composition is by one or two inhalations.

[0271]

[0120] The method described in any one of paragraphs

[0106] to

[0118] , wherein the administration of the pharmaceutical composition is performed by two inhalations separated by a break of about 10 seconds to about 1 minute.

[0272]

[0121] The method of any one of paragraphs

[0106] to

[0120] , wherein the administration is performed by a nebulizer.

[0122] The method described in paragraph

[0121] , wherein the nebulizer is a breath-actuated nebulizer.

[0273]

[0123] The method described in paragraph

[0121] , wherein the nebulizer is a jet nebulizer.

[0124] The method described in paragraph

[0121] , wherein the sprayer is a vibrating mesh sprayer.

[0125] The method described in paragraph

[0121] , wherein the nebulizer is an ultrasonic nebulizer.

[0274]

[0126] The method according to any one of paragraphs

[0106] to

[0123] , wherein about 60 mg to about 150 mg of the salt of flecainide is administered to the subject by inhalation.

[0127] The method according to any one of paragraphs

[0106] to

[0123] , wherein about 75 mg to about 125 mg of the salt of flecainide is administered to the subject by inhalation.

[0275]

[0128] The method according to any one of paragraphs

[0106] to

[0125] , wherein about 250 mg to about 350 mg of the salt of flecainide is administered to the subject by inhalation.

[0129] The method according to any one of paragraphs

[0106] to

[0125] , wherein about 100 mg to about 250 mg of the salt of flecainide is administered to the subject by inhalation.

[0276]

[0130] The method described in any one of paragraphs

[0106] to

[0123] , wherein approximately 90 mg of the salt of flecainide is administered to the subject by inhalation.

[0131] The method described in any one of paragraphs

[0106] to

[0123] , wherein approximately 120 mg of the salt of flecainide is administered to the subject by inhalation.

[0277]

[0132] The method described in any one of paragraphs

[0106] to

[0125] , wherein approximately 200 mg of the salt of flecainide is administered to the subject by inhalation.

[0133] The method of any one of paragraphs

[0106] to

[0131] , wherein the cardiac condition includes atrial arrhythmia.

[0278]

[0134] The method described in paragraph

[0133] , wherein the atrial arrhythmia includes tachycardia.

[0135] The method described in paragraph

[0133] , wherein the atrial arrhythmia is selected from the group consisting of supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes of sustained and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter or isolated atrial fibrillation.

[0279]

[0136] A method according to any one of paragraphs

[0106] to

[0135] , comprising a step of aerosolizing the pharmaceutical composition by forming droplets having a median aerodynamic diameter of less than 10 μm.

[0280]

[0137] A method according to any one of paragraphs

[0106] to

[0136] , comprising acute treatment following detection of the atrial arrhythmia.

[0138] A method according to any one of paragraphs

[0106] to

[0137] , wherein the subject has normal sinus rhythm within 10 minutes of the administration.

[0281]

[0139] A method according to any one of paragraphs

[0106] to

[0137] , wherein the subject has normal sinus rhythm within 8 minutes of the administration.

[0140] A method according to any one of paragraphs

[0106] to

[0137] , wherein the subject has normal sinus rhythm within 5 minutes of the administration.

[0282]

[0141] The method according to any one of paragraphs

[0107] to

[0140] , wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatized α-cyclodextrin, derivatized β-cyclodextrin and derivatized γ-cyclodextrin.

[0283]

[0142] The cyclodextrin may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, or maltotriosyl-γ-cyclodextrin. Dimaltosyl-β-cyclodextrin, Succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, Sulfobutylether-β-cyclodextrin, Sulfobutylether-γ-cyclodextrin The method according to any one of paragraphs

[0107] to

[0140] , wherein the cyclodextrin is selected from the group consisting of sulfoalkyl ether-β-cyclodextrin, and sulfoalkyl ether-γ-cyclodextrin.

[0284]

[0143] The method of any one of paragraphs

[0107] to

[0140] , wherein the cyclodextrin comprises hydroxypropyl-β-cyclodextrin.

[0144] The method described in any one of paragraphs

[0107] to

[0143] , wherein the concentration of the cyclodextrin in the pharmaceutical composition is from about 1% (w / v) to about 80% (w / v) of the solution.

[0285]

[0145] The method of any one of paragraphs

[0107] to

[0143] , wherein the concentration of the cyclodextrin is from about 15% (w / v) to about 25% (w / v) of the solution.

[0146] The method according to any one of paragraphs

[0107] to

[0143] , wherein the concentration of the cyclodextrin is from about 10% (w / v) to about 30% (w / v) of the solution.

[0286]

[0147] The method described in paragraph

[0144] , wherein the concentration of the cyclodextrin is at least about 5% (w / v) of the solution.

[0148] The method described in paragraph

[0144] , wherein the concentration of the cyclodextrin is at least about 10% (w / v) of the solution.

[0287]

[0149] The method described in paragraph

[0144] , wherein the concentration of the cyclodextrin is about 20% (w / v) of the solution.

[0150] The method described in paragraph

[0144] , wherein the concentration of the cyclodextrin is at most about 20% (w / v) of the solution.

[0288]

[0151] The method according to any one of paragraphs

[0106] to

[0150] , wherein the concentration of the salt of flecainide is at most about 200 mg / mL.

[0152] The method according to any one of paragraphs

[0106] to

[0150] , wherein the concentration of the salt of flecainide is from about 65 mg / mL to about 130 mg / mL.

[0289]

[0153] The method according to any one of paragraphs

[0106] to

[0150] , wherein the concentration of the salt of flecainide is from about 65 mg / mL to about 95 mg / mL.

[0154] The method according to any one of paragraphs

[0106] to

[0150] , wherein the concentration of the salt of flecainide is from about 70 mg / mL to about 115 mg / mL.

[0290]

[0155] The method according to any one of paragraphs

[0106] to

[0150] , wherein the concentration of the salt of flecainide is about 100 mg / mL.

[0156] The method according to any one of paragraphs

[0106] to

[0150] , wherein the concentration of the salt of flecainide is about 75 mg / mL.

[0291]

[0157] The method according to any one of paragraphs

[0106] to

[0156] , wherein the salt of flecainide is selected from the group consisting of flecainide acetate, flecainide hydrochloride, flecainide citrate, flecainide phosphate and flecainide nitrate.

[0292]

[0158] The method according to any one of paragraphs

[0106] to

[0156] , wherein the salt of flecainide comprises flecainide acetate.

[0159] The method according to any one of paragraphs

[0106] to

[0156] , wherein the salt of flecainide comprises flecainide hydrochloride.

[0293]

[0160] Any of paragraphs

[0106] to

[0159] , wherein the pharmaceutical composition further comprises an acid. The method described in one.

[0161] The method according to paragraph

[0160] , wherein the acid is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbic acid, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactic acid, propionic acid, sorbic acid, stearic acid and succinic acid.

[0294]

[0162] The method according to paragraph

[0160] , wherein the acid is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid.

[0163] The method according to any one of paragraphs

[0160] to

[0162] , wherein the concentration of the acid in the pharmaceutical composition is from about 2 mM to about 200 mM.

[0295]

[0164] The method according to any one of paragraphs

[0160] to

[0162] , wherein the concentration of the acid in the pharmaceutical composition is from about 2 mM to about 50 mM.

[0165] The method according to any one of paragraphs

[0160] to

[0162] , wherein the concentration of the acid in the pharmaceutical composition is from about 2 mM to about 10 mM.

[0296]

[0166] The method described in paragraph

[0163] , wherein the concentration of the acid is up to about 50 mM.

[0167] The method described in paragraph

[0163] , wherein the concentration of the acid is about 20 mM.

[0297]

[0168] The method described in paragraph

[0163] , wherein the concentration of the acid is about 5 mM.

[0169] The method of paragraph

[0163] , wherein the acid comprises acetic acid.

[0170] The method described in paragraph

[0169] , wherein the concentration of acetic acid is about 5 mM.

[0298]

[0171] The method described in paragraph

[0163] , wherein the acid comprises citric acid.

[0172] The method described in paragraph

[0169] , wherein the concentration of citric acid is about 5 mM.

[0173] The method of paragraph

[0160] , wherein the acid comprises a mixture of acids selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbic acid, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactic acid, propionic acid, sorbic acid, stearic acid and succinic acid.

[0299]

[0174] The method of paragraph

[0160] , wherein the acid comprises a mixture of acids selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid.

[0175] The method according to paragraph

[0160] , wherein the acid comprises hydrochloric acid.

[0300]

[0176] The method according to any one of paragraphs

[0160] to

[0170] , wherein the salt of flecainide comprises flecainide acetate and the acid comprises acetic acid.

[0177] The method described in any one of paragraphs

[0108] to

[0176] , wherein the pH of the solution is at most about 6.5.

[0301]

[0178] The method described in any one of paragraphs

[0108] to

[0176] , wherein the pH of the solution is from about 5.5 to about 6.5.

[0179] The method described in any one of paragraphs

[0108] to

[0176] , wherein the pH of the solution is about 5.9.

[0302]

[0180] The method according to any one of paragraphs

[0106] to

[0179] , wherein the salt of flecainide comprises flecainide acetate.

[0181] The method described in any one of paragraphs

[0106] to

[0180] , wherein the pharmaceutical composition further contains a sweetener.

[0303]

[0182] The method described in paragraph

[0181] , wherein the artificial sweetener is selected from the group consisting of acesulfame potassium, aspartame, cyclamate, mogroside, saccharin, stevia, sucralose, neotame, mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol and pharma- ceutically acceptable salts thereof.

[0304]

[0183] The method described in paragraph

[0181] , wherein the sweetener comprises saccharin.

[0184] The method according to paragraph

[0181] , wherein the sweetener comprises a salt of saccharin.

[0185] The method described in paragraph

[0181] , wherein the sweetener comprises sodium saccharin.

[0305]

[0186] The method described in any one of paragraphs

[0181] to

[0185] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 1% (w / v).

[0187] The method described in any one of paragraphs

[0181] to

[0185] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 0.05% (w / v).

[0306]

[0188] The method described in any one of paragraphs

[0181] to

[0185] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 0.01% (w / v).

[0189] A method for treating a human subject suffering from a cardiac condition, comprising the step of administering to the subject by inhalation a pharmaceutical composition described in any one of paragraphs 1 to

[56] .

[0307]

[0190] A method for treating a human subject suffering from a cardiac condition, comprising the step of administering to the subject by inhalation a dosage unit described in any one of paragraphs

[57] to

[64] .

[0308]

[0191] The method of any one of paragraphs

[0106] to

[0190] , wherein the cardiac condition includes atrial fibrillation.

[0192] The method described in paragraph

[0191] , wherein the atrial fibrillation is recurrent atrial fibrillation.

[0309]

[0193] The method described in paragraph

[0191] , wherein the atrial fibrillation is paroxysmal atrial fibrillation.

[0194] The method described in any one of paragraphs

[0106] to

[0193] , wherein the subject has a systolic blood pressure of greater than about 90 mmHg during treatment.

[0310]

[0195] The method described in any one of paragraphs

[0106] to

[0193] , wherein the subject has a systolic blood pressure of about 100 mmHg to about 160 mmHg at the time of treatment.

[0196] A method according to any one of paragraphs

[0106] to

[0195] , wherein the subject has a ventricular rate of 170 BPM or less during treatment.

[0311]

[0197] The method described in any one of paragraphs

[0106] to

[0195] , wherein the subject has a ventricular rate of about 80 BPM to about 155 BPM during treatment.

[0198] The method described in any one of paragraphs

[0106] to

[0197] , wherein the subject is 85 years of age or younger.

[0312]

[0199] The method described in any one of paragraphs

[0106] to

[0197] , wherein the subject is between 18 and 85 years of age.

[0200] A method according to any one of paragraphs

[0106] to

[0199] , wherein the subject has undergone cardiac ablation more than three months prior to the administration.

[0313]

[0201] The method of any one of paragraphs

[0106] to

[0200] , wherein the subject is receiving an ongoing prescription for oral flecainide or a pharma- ceutically acceptable salt thereof.

[0202] The atrial fibrillation has an onset that occurred within about 48 hours prior to the administration. A method according to any one of

[0106] to

[0201] .

[0314]

[0203] A method according to any one of paragraphs

[0106] to

[0201] , wherein the atrial fibrillation has an onset occurring from about 1 hour to about 48 hours prior to the pre-administration treatment.

[0204] The method described in any one of paragraphs

[0106] to

[0203] , wherein the subject does not exhibit a pathology involving an abnormal left ventricular ejection fraction within 6 months prior to the administration.

[0315]

[0205] A method according to any one of paragraphs

[0106] to

[0204] , wherein the subject does not exhibit a pathology including heart failure of class 2 or higher as classified by the New York Heart Association functional classification within 6 months prior to the administration.

[0316]

[0206] The method of any one of paragraphs

[0106] to

[0205] , wherein the subject does not exhibit a pathology including myocardial infarction or a history of myocardial infarction.

[0207] The method described in any one of paragraphs

[0106] to

[0206] , wherein the subject does not exhibit a pathology including hemodynamic instability or cardiac instability.

[0317]

[0208] The method described in any one of paragraphs

[0106] to

[0207] , wherein the subject does not exhibit a pathology including an episode of atrial flutter within 6 months prior to the administration.

[0209] The method described in any one of paragraphs

[0106] to

[0208] , wherein the subject has not undergone cardiac surgery for the condition within 6 months prior to the administration.

[0318] (a) water; (b) pH adjuster; (c) flecainide or a pharma- ceutically acceptable salt thereof; and (d) Cyclodextrin 23. A method of preparing a liquid pharmaceutical composition comprising combining:

[0319]

[0211] (i) the concentration of the flecainide or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is about 65 mg / mL to about 95 mg / mL; (ii) the concentration of the cyclodextrin in the pharmaceutical composition is about 10% (w / v) to about 30% (w / v); (iii) The method according to paragraph

[0210] , wherein the pharmaceutical composition has a pH of about 5.5 to about 6.5 at room temperature.

[0320]

[0212] The combining step comprises: (a) providing said water; (b) contacting a portion of the water with the flecainide or a pharma- ceutically acceptable salt thereof, the cyclodextrin, and the pH adjuster in a vessel; and (c) adding a next portion of the water to the vessel to provide the pharmaceutical composition. Including, (i) the concentration of the flecainide or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is about 65 mg / mL to about 95 mg / mL; (ii) the concentration of the cyclodextrin in the pharmaceutical composition is about 10% (w / v) to about 30% (w / v); (iii) The method according to paragraph

[0210] or paragraph

[0211] , wherein the pharmaceutical composition has a pH of about 5.5 to about 6.5 at room temperature.

[0321]

[0213] The pH adjuster is selected from the group consisting of acetate ion, citrate ion, nitrate ion, chloride ion, sulfate ion, maleate ion, tartrate ion, phosphate ion, and aconitate ion. The method according to any one of paragraphs

[0210] to

[0212] , wherein the ion is selected from the group consisting of adipic acid ions, ascorbic acid ions, benzoic acid ions, caprylic acid ions, cholate ions, formate ions, glutamic acid ions, lactate ions, propionate ions, sorbic acid ions, stearate ions and succinic acid ions.

[0322]

[0214] The method according to any one of paragraphs

[0210] to

[0213] , wherein the pH adjuster is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid, sulfuric acid, maleic acid, tartaric acid, phosphoric acid, aconitic acid, adipic acid, ascorbic acid, benzoic acid, caprylic acid, cholic acid, formic acid, glutamic acid, lactic acid, propionic acid, sorbic acid, stearic acid and succinic acid.

[0323]

[0215] The method according to any one of paragraphs

[0210] to

[0214] , wherein the pH adjuster is selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid.

[0216] The method of any one of paragraphs

[0210] to

[0215] , wherein the pH adjuster comprises a mixture of acids selected from the group consisting of acetic acid, citric acid, nitric acid, hydrochloric acid and sulfuric acid.

[0324]

[0217] The method according to any one of paragraphs

[0210] to

[0216] , wherein the concentration of the pH adjuster in the pharmaceutical composition is from about 2 mM to about 50 mM.

[0218] The method according to any one of paragraphs

[0210] to

[0217] , wherein the concentration of the pH adjuster in the pharmaceutical composition is from about 2 mM to about 10 mM.

[0325]

[0219] The method described in paragraph

[0217] or paragraph

[0218] , wherein the pH adjuster comprises acetic acid.

[0220] The method described in paragraph

[0219] , wherein the concentration of acetic acid in the pharmaceutical composition is about 5 mM.

[0326]

[0221] The method described in paragraph

[0217] or paragraph

[0218] , wherein the pH adjuster comprises citric acid.

[0222] The method described in paragraph

[0221] , wherein the concentration of citric acid in the pharmaceutical composition is about 5 mM.

[0327]

[0223] The method according to any one of paragraphs

[0210] to

[0222] , wherein the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, derivatized α-cyclodextrin, derivatized β-cyclodextrin and derivatized γ-cyclodextrin.

[0328]

[0224] The cyclodextrin may be α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, hydroxyethyl-γ-cyclodextrin, dihydroxypropyl-β-cyclodextrin, glucosyl-α-cyclodextrin, glucosyl-β-cyclodextrin, diglucosyl-β-cyclodextrin, maltosyl-α-cyclodextrin, maltosyl-β-cyclodextrin, maltosyl-γ-cyclodextrin, maltotriosyl-β-cyclodextrin, or maltotriosyl-γ-cyclodextrin. Any of paragraphs

[0210] to

[0223] , which is selected from the group consisting of dimaltosyl-β-cyclodextrin, succinyl-β-cyclodextrin, 6A-amino-6A-deoxy-N-(3-hydroxypropyl)-β-cyclodextrin, sulfobutylether-β-cyclodextrin, sulfobutylether-γ-cyclodextrin, sulfoalkylether-β-cyclodextrin, and sulfoalkylether-γ-cyclodextrin. The method according to any one of the preceding claims.

[0329]

[0225] The method of any one of paragraphs

[0210] to

[0224] , wherein the cyclodextrin comprises hydroxypropyl-β-cyclodextrin.

[0226] The method according to any one of paragraphs

[0211] to

[0225] , wherein the concentration of the cyclodextrin in the pharmaceutical composition is from about 10% (w / v) to about 30% (w / v).

[0330]

[0227] The method described in paragraphs

[0210] to

[0226] further comprising the step of adding a sweetener.

[0228] The method of paragraph

[0227] , wherein the sweetener is selected from the group consisting of acesulfame potassium, aspartame, cyclamate, mogroside, saccharin, stevia, sucralose, neotame, mannitol, sorbitol, xylitol, lactitol, isomalt, maltitol and pharma- ceutically acceptable salts thereof.

[0331]

[0229] The method of paragraph

[0227] , wherein the sweetener comprises saccharin.

[0230] The method of paragraph

[0227] , wherein the sweetener comprises a salt of saccharin.

[0231] The method described in paragraph

[0227] , wherein the sweetener comprises sodium saccharin.

[0332]

[0232] The method described in any one of paragraphs

[0227] to

[0231] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 1% (w / v).

[0233] The method described in any one of paragraphs

[0227] to

[0231] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 0.05% (w / v).

[0333]

[0234] The method according to any one of paragraphs

[0227] to

[0231] , wherein the concentration of the sweetener in the pharmaceutical composition is from about 0.001% (w / v) to about 0.01% (w / v).

[0235] The method according to any one of paragraphs

[0210] to

[0234] , wherein the pharma- ceutically acceptable salt of flecainide is added.

[0334]

[0236] The method according to paragraph

[0235] , wherein the pharma- ceutically acceptable salt of flecainide is selected from the group consisting of flecainide acetate, flecainide hydrochloride, flecainide citrate, flecainide phosphate and flecainide nitrate.

[0335]

[0237] The method according to paragraph

[0235] , wherein the pharma- ceutically acceptable salt of flecainide comprises flecainide acetate.

[0238] The method according to paragraph

[0235] , wherein the pharma- ceutically acceptable salt of flecainide comprises flecainide hydrochloride.

[0336]

[0239] The method of any one of paragraphs

[0210] to

[0238] , further comprising a step of packaging the pharmaceutical composition in a dosage unit form.

[0240] The method described in any one of paragraphs

[0235] to

[0238] , further comprising a step of packaging the pharmaceutical composition in a dosage unit form, the dosage unit form containing from about 50 mg to about 350 mg of the pharma- ceutically acceptable salt of flecainide.

[0337]

[0241] The method according to paragraph

[0240] , wherein the dosage unit form contains from about 60 mg to about 150 mg of the pharma- ceutically acceptable salt of flecainide.

[0242] The method according to paragraph

[0240] , wherein the dosage unit form contains from about 75 mg to about 125 mg of the pharma- ceutically acceptable salt of flecainide.

[0338]

[0243] The dosage unit form comprises about 250 mg to about 350 mg of the pharma- ceutically acceptable The method according to paragraph

[0240] , comprising administering to the patient a salt of flecainide.

[0244] The method according to paragraph

[0240] , wherein the dosage unit form contains from about 150 mg to about 250 mg of the pharma- ceutically acceptable salt of flecainide.

[0339]

[0245] The method according to paragraph

[0240] , wherein the dosage unit form contains about 90 mg of the pharma- ceutically acceptable salt of flecainide.

[0246] The method according to paragraph

[0240] , wherein the dosage unit form contains about 120 mg of the pharma- ceutically acceptable salt of flecainide.

[0340]

[0247] The method according to paragraph

[0240] , wherein the dosage unit form contains about 200 mg of the pharma- ceutically acceptable salt of flecainide.

[0248] The method of any one of paragraphs

[0239] to

[0247] , wherein the dosage unit form further comprises a container.

[0341]

[0249] The method of paragraph

[0248] , wherein the container is selected from the group consisting of a vial, a syringe, a capsule, a blow-fill-seal, a blister, a cartridge and an ampoule. EXAMPLES

[0342]

[0251] The following examples are provided to further illustrate some embodiments of the present disclosure, but are not intended to limit the scope of the disclosure, and it will be understood that by their representative nature, other procedures, methodologies, or techniques known to those skilled in the art may be substituted.

[0343] Example 1 Solubility of Flecainide Salts

[0252] This example illustrates that among the different flecainide salts tested, flecainide acetate had the highest water solubility. This example also illustrates that sodium chloride, which is suggested to be desirable to add to inhalation formulations to reduce the incidence of coughing, can precipitate flecainide free base when added to flecainide solutions.

[0344] In this example, the solubilities of flecainide citrate, flecainide phosphate, flecainide hydrochloride and flecainide nitrate were all compared to that of flecainide acetate. As shown in Table 1, the water solubility of flecainide acetate was at least one order of magnitude higher than the other salts formed. Furthermore, the addition of sodium chloride (e.g., saline) to the formulation results in precipitation from the solution and loss of solubility of flecainide acetate. X-ray powder diffraction (XRPD) analysis confirmed that there was a form conversion when sodium chloride was added into the solution.

[0345] [Table 1]

[0346]

[0254] It should be noted that formulation at a pH below 5.2 may result in undesirable organoleptic properties and risk of toxicity problems. This example suggests that the acetate salt of flecainide is more suitable for pharmaceutical formulations than some of the other salts of flecainide.

[0347] Example 2 Solubility of Flecainide Acetate in the Presence of Cyclodextrin

[0255] This example shows the change in water solubility of flecainide acetate in the presence of different cyclodextrins.

[0348]

[0256] In this example, it was shown that the water solubility of flecainide acetate increases with increasing concentration of various cyclodextrins. Table 2 summarizes the solubility of flecainide acetate as a function of cyclodextrin concentration with 100 mM acetate buffer.

[0349] [Table 2]

[0350]

[0257] In addition, the solubility of flecainide acetate was measured at constant cyclodextrin concentrations (i.e., hydroxypropyl-β-cyclodextrin and β-cyclodextrin) and varying acetate buffer concentrations from 0 to 100 mM, and almost no difference was observed in these solubilities.

[0351]

[0258] The solubility of flecainide free base was compared to flecainide acetate using the same buffer and cyclodextrin concentrations. The concentration of flecainide acetate was found to be nearly six times greater than that of the free base form.

[0352] Example 3 Solubility of Flecainide Acetate in the Presence of Hydroxypropyl-β-Cyclodextrin (HPβCD)

[0259] This example shows that the water solubility of flecainide acetate increases as the concentration of HPβCD in solution increases.

[0353] In this example, the solubility of flecainide acetate in different concentrations of HPβCD (Trappsol® hydroxypropyl-β-cyclodextrin; purchased from CTD Inc.) solutions was tested. The average molecular weight and degree of substitution of the tested HPβCD are 1495 and 6.2, respectively.

[0354] Flecainide acetate (dosage concentration: 100-150 mg / mL) was suspended in HPβCD solutions of different concentrations (0%-180% w / v). The suspensions were then magnetically stirred (1000 r / min) at room temperature for 24 or 48 hours. The suspensions were then subjected to centrifugation at 10000 rpm (3 min) and filtration through 0.45 μm membrane to obtain the supernatant for HPLC solubility test and the remaining solid was analyzed by X-ray powder diffraction (XRPD) assay.

[0355] As shown in Table 3, the solubility of flecainide acetate at 48 h increased linearly with HPβCD concentration in the range of 0% to 40% (w / v), suggesting that complex formation may have occurred (Figure 1). In one experiment, the solubility of flecainide acetate in 40% (w / v) HPβCD solution (48 h) reached 104.7 mg / mL (calculated as free base). In another experiment, the solubility of flecainide acetate in 40% (w / v) HPβCD solution (48 h) reached 108.6 mg / mL (calculated as free base). It was also observed that the solubility of flecainide acetate in HPβCD solution decreased from 60% to 140% (w / v) HPβCD. A maximum solubility of 124.9 mg / mL (calculated as free base) was observed in 180% (w / v) HPβCD solution at a sampling time of 24 h.

[0356]

[0263] In the range of 0% to 40% (w / v) of HPβCD, the complex formation stability constant (K 1:1 ) was determined to be 5.75 by phase solubility plot (Higuchi-Connors phase solubility method).

[0357] [Table 3]

[0358] Example 4 Viscosity of Flecainide Acetate-HPβCD Solutions

[0264] This example shows the effect of HPβCD concentration on solution viscosity. In this and the following examples, the (HP)-β-cyclodextrin used is "Cavitron W7 HP7 PHARMA". The manufacturer (Ashland) specifies that it contains <1.5% beta cyclodextrin (our batch had 1%), and that the molar substitution is between 0.86 and 1.14 (our batch had 1.05). According to the manufacturer's catalog, the typical degree of substitution is 6.0-8.0 with an average MW of approximately 1520.

[0359]

[0266] A Higuchi-Connors phase solubility experiment on the solution adjusted to a pH of 5.2 with NaOH confirmed that the complexation efficiency of HPβCD:flecainide acetate was 0.8, which means that 80% of the HPβCD molecules were complexed with flecainide acetate. As shown in Table 4, the viscosity of the solution increased with the addition of HPβCD. However, aerosol properties were not significantly affected up to at least approximately 22.5% HPβCD. Above this concentration, the aerosol output rate may decrease slightly.

[0360] [Table 4]

[0361] Example 5 Pharmacokinetic and pharmacodynamic studies in a porcine model

[0267] This example shows the bioequivalence and pharmacodynamic equivalence of representative cyclodextrin-containing flecainide acetate formulations compared to the parent flecainide acetate formulation.

[0362] IV infusion

[0268] Studies were conducted in pigs to determine the pharmacokinetics (PK) of the same doses of flecainide delivered by IV infusion.

[0363] In these examples, these solutions (original and novel cyclodextrin-containing formulations) were prepared and compared in a porcine model of atrial fibrillation: (1) 75 mg / mL flecainide acetate, 10% sulfobutylether-β-cyclodextrin, 90 mM acetate, pH 5.2; (2) 75 mg / mL flecainide acetate, 10% hydroxypropyl-β-cyclodextrin, 90 mM acetate, pH 5.2; and (3) 35 mg / mL flecainide acetate, 90 mM acetate buffer, pH 5.2.

[0364]

[0270] In a crossover design study with a 2-hour washout period, the same dose of flecainide was administered to each pig using three solutions.

[0271] As shown in Figure 2, when adjusted to equal doses (1 mg / Kg body weight) and dose infusion rates (10 min), the three solutions appear to result in approximately equal PK profiles in a porcine animal model.

[0365]

[0272] C obtained using sulfobutyl ether-β-cyclodextrin max It was also observed that the PK profile with hydroxypropyl-β-cyclodextrin was lower (about 20%) than that with the original 35 mg / ml flecainide acetate formulation. The PK profile with hydroxypropyl-β-cyclodextrin was more similar to that with the 35 mg / ml acetate buffer formulation (Cmax was 7% higher). The Cmax, distribution and elimination phases were all nearly identical between HPβCD and the original 35 mg / ml flecainide acetate formulation. This suggests that the complexation of flecainide acetate with cyclodextrin is loose and that flecainide dissociates rapidly once delivered into the systemic bloodstream.

[0366] IT drip

[0273] Experiments were conducted in pigs to determine the pharmacokinetics (PK) and pharmacodynamics (PD; QRS interval and duration of atrial depolarization, Pa) of the same dose of flecainide delivered by IV infusion and intratracheal instillation using the two formulations.

[0367] In these examples, these solutions (original and novel cyclodextrin-containing formulations) were prepared and compared in a porcine model of atrial fibrillation: (1) 75 mg / mL flecainide acetate, 10% hydroxypropyl-β-cyclodextrin, 90 mM acetate, pH 5.2; and (2) 35 mg / mL flecainide acetate, 90 mM acetate buffer, pH 5.2.

[0368]

[0275] As shown in Figures 3A-3B and 4A-4D, when adjusted to equal doses (0.75 mg Kg body weight and 1 mg / Kg body weight) and dose infusion rates (10 min), the two solutions appear to result in approximately equal PK and PD profiles in a porcine animal model.

[0369] Example 6 Safety Evaluation of Inhaled Delivery of Flecainide Acetate Formulations

[0276] Five Good Laboratory Practice (GLP)-compliant 14-day repeat-dose inhalation studies were conducted in rats and dogs to evaluate the potential toxicology associated with the FlecIH-101, FlecIH-102 and FlecIH-103 formulations (Table 5).

[0370] [Table 5]

[0371] The results showed that inhaled flecainide produced no new or unusual toxicities associated with inhalation of flecainide compared to commercially available IV and oral flecainide dosage forms. The no observed adverse effect levels (NOAELs) for 14-day repeated dose rat and dog toxicology studies conducted with flecainide acetate in the acetate formulation (FlecIH-101) were 28.7 mg / kg / day (Study 1) and 8.03 mg / kg / day (Study 4), respectively, and 1.0 mg / kg / day (Study 5) in humans. The NOAEL for 14-day repeated-dose rat and dog toxicology studies conducted with flecainide acetate in an acetate formulation containing hydroxypropyl-β-cyclodextrin (Flec-IH-102) was 67.7 mg / kg / day (Study 2) and 9.87 mg / kg / day (Study 5), respectively. A bridging 14-day repeated-dose rat study confirmed that 30 mg / kg / day flecainide acetate was the NOAEL in an acetate formulation containing hydroxypropyl-β-cyclodextrin and sodium saccharin (FlecIH-103, Study 3).

[0372]

[0278] The critical effect identified was high-dose airway outcome in a rat inhalation toxicity study, with mild squamous cell metaplasia in the nose, minimal to mild squamous metaplasia in the larynx, and minimal to mild alveolar macrophage aggregates and neutrophilic infiltrates in the lungs.

[0373] Overall, the results indicate that nose-only exposure of rats to inhaled flecainide acetate at inhaled doses ranging from 28.7 to 147.6 mg / kg resulted in virtually no clinical signs and no effects on body weight, neurobehavioral and clinical pathology parameters. Histopathological changes in the lungs, larynx and nasal turbinates during the dosing period were non-malignant at the lowest dose tested. Thus, the NOAEL was 28.7 mg / kg flecainide by inhalation.

[0374] Inhalation toxicity studies were conducted in dogs. Overall, inhaled flecainide provided for 14 days at doses up to 8.03 mg / kg in Study 4 and 9.87 mg / kg / day in Study 5 (average for both sexes) did not result in any adverse effects in clinical signs, body weight, clinical pathology parameters, pulmonary function parameters or histopathological changes. Electrocardiograms showed small changes in PR interval, QRS interval and HR. Although potentially test substance related, these were non-malignant changes and therefore the NOAEL was considered to be 9.87 mg / kg. Detailed study parameters and results for Study 5 are outlined below.

[0375] Test 5 This example describes a 14-day repeat dose toxicity study by face mask inhalation with 14-day recovery in dogs. The purpose of this study is to evaluate the potential toxicity of aerosolized flecainide from a representative inhalation solution (75 mg / mL flecainide acetate / 10% w / v HPβCD / 90 mM acetate buffer formulation at pH 5.2) after 14 consecutive days of face mask inhalation exposure in beagle dogs (4 dogs / sex / group), and to investigate whether potential effects are reversible after a 14-day recovery period (2 dogs / sex / group), including air and vehicle control groups. The study design is shown in Table 6.

[0376] [Table 6]

[0377] In addition to the aerosol drug concentration, the aerosol particle size distribution was also characterized. The mean particle size MMAD and GSD for the low, medium and high dose groups were 2.38 (1.79), 2.03 (1.87) and 2.08 (1.79) microns, respectively, and 1.74 (1.88) microns for the vehicle control group. The mean flecainide acetate dose delivered was 1.86, 5.08 and 9.88 mg / kg for the low, medium and high dose groups, respectively. Chamber oxygen levels were monitored throughout the exposure. The main test animals were sacrificed on day 15. Recovery animals were sacrificed on day 29 after a 14-day recovery period. Endpoints included clinical observations, body weight, ophthalmology, clinical pathology, urinalysis, gross pathology, histopathology, bioanalysis and toxicokinetic analysis.

[0378] All study dogs survived until scheduled euthanasia without any cases of morbidity or mortality. Body weights showed no treatment-related differences. The most common clinical observation was loose stools, which occurred periodically during the study with similar incidence across sexes and study groups; no clinical observations related to flecainide or vehicle exposure occurred. The only observation related to flecainide exposure was labored breathing during or immediately after exposure, which occurred on days 1 or 7 in some mid- or high-dose animals. On post-study ophthalmic examination, new cataracts (<5% of the lens) were observed in five dogs in the air control (2), low-dose (1), and mid-dose (2) groups, but none in the vehicle control or high-dose animals. Due to their small size, it is possible that these were present but not detected on pre-study examination. Respiratory parameters showed no significant effects of exposure at any dose level or at any time point. All ECGs were considered normal with no abnormalities in rhythm or waveform. Small changes in heart rate, PR interval, and QRS interval were potentially test substance related but were not considered adverse findings.

[0379] Statistically significant clinical chemistry, hematology, and coagulation changes did not occur consistently across sexes or doses during treatment or recovery time points overall and were generally minor in magnitude. On gross examination, tissues were grossly free of abnormalities. Necropsy findings of lung and thymus discoloration were observed in some vehicle and flecainide animals during treatment and recovery periods. Other sporadic and incidental gross observations occurred that were within normal ranges or background levels and were not related to the test article. As expected, minor sporadic and incidental histologic findings occurred in this study. Such findings included cysts and mild infiltrates of various cell types. These were sporadic and / or occurred with a prevalence, character, and severity indistinguishable from controls. Pathological histology attributable to treatment with the test article. There were no histological changes.

[0380] Overall, inhaled flecainide administered for 14 days at doses up to 9.88 mg / kg / day (average for both sexes) did not cause any adverse effects in clinical signs, body weight, clinical pathology parameters, pulmonary function parameters or histopathological changes. Electrocardiograms showed small changes in PR interval, QRS interval and HR. Although possibly related to the test substance, these were non-malignant changes and therefore the NOAEL was considered to be 9.88 mg / kg.

[0381]

[0286] In summary, inhaled flecainide from a representative inhalation solution (75 mg / mL flecainide acetate / 10% w / v HP-β-cyclodextrin / 90 mM acetate buffer formulation at pH 5.2) using a face mask in male and female beagle dogs over 14 consecutive days showed results comparable to those from studies conducted with the original inhalation solution (35 mg / mL flecainide acetate / 90 mM acetate buffer formulation at pH 5.2).

[0382] Example 7 Representative Formulations with ...

Claims

[Claim 1] The invention described in the specification.

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