Kits and methods for induction of cardioversion in subjects with atrial arrhythmias - Patents.com

Abstract

Disclosed herein are methods and kits for treating or preventing cardiac conditions, such as cardiac arrhythmias, such as atrial arrhythmias, using a potassium channel inhibitor and a class I antiarrhythmic agent. Also disclosed herein are methods and kits for treating cardiac conditions with a fixed dose combination of a sodium channel blocker and a class I antiarrhythmic agent administered intravenously, orally, or by inhalation.

Description

[Technical field]

[0001] cross reference

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 127,089, filed December 17, 2020, and U.S. Provisional Application No. 63 / 153,492, filed February 25, 2021, each of which is incorporated by reference in its entirety into this specification. [Background technology]

[0002]

[0002] Atrial fibrillation (AF) is one of the most common sustained cardiac arrhythmias encountered in clinical practice and can lead to complications such as congestive heart failure or thromboembolism. Summary of the Invention

[0003]

[0003] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a sodium channel blocker, ibutilide, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents, or carriers.

[0004]

[0004] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a sodium channel blocker, dofetilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents, or carriers.

[0005]

[0005] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a sodium channel blocker, sotalol or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents, or carriers.

[0006] In some embodiments, the present disclosure provides a method of treating a subject suffering from atrial arrhythmia, comprising administering to the subject: (i) a first amount of a sodium channel blocker, and (ii) a second amount of a potassium channel blocker selected from the group consisting of ibutilide or a pharma- ceutically acceptable salt thereof, dofetilide or a pharma- ceutically acceptable salt thereof, and sotalol or a pharma- ceutically acceptable salt thereof. administering The administration determines whether or not the potassium channel blocker has a t max and a t of said sodium channel blocker in said subject occurring within about 30 minutes of said max Bringing about Thereby, a method for inducing cardioversion of said atrial arrhythmia is provided.

[0007] Incorporation by Reference

[0007] 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. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 illustrates a QT interval nomogram that can be used to assess a subject's risk of Torsades de Pointes (TdP). [Diagram 2]

[0009] FIG. 2 is an exemplary action potential diagram. [Diagram 3]

[0010] FIG. 13: Representative tracings showing the effect of flecainide and ibutilide, alone and in combination, on atrial (left column) and ventricular (right column) action potentials in the canine right atrial preparation. [Figure 4]

[0011] 1 is a chart showing the effect of flecainide, ibutilide, and their combination on atrial and ventricular effective refractory period (ERP) and action potential duration (APD) in a canine right atrial preparation. [Diagram 5]

[0012] FIG. 1 is a chart showing the effect of flecainide, ibutilide and their combination on atrial and ventricular post-repolarization refractoriness (PRR) in a canine right atrial preparation. [Figure 6]

[0013] 1 is a chart showing the percent incidence of atrial fibrillation (AF) in right atrial preparations from dogs treated with flecainide and ibutilide alone and in combination. [Figure 7]

[0014] 1 is an exemplary ECG tracing showing repeatedly induced self-terminating episodes of AF followed by induction of persistent AF (lasting >1 hour). [Figure 8]

[0015] 1 is a chart showing the percentage of experiments in which ACh-induced AF in a canine right atrium preparation was terminated by administration of flecainide and ibutilide alone and in combination. [Figure 9]

[0016] 1 is a chart showing the effects of flecainide (1.5 μM), ibutilide (20 nM), and the combination of flecainide and ibutilide in blunting the effect of ACh-mediated ERP shortening in a canine right atrial preparation. [Figure 10]

[0017] FIG. 13 shows traces showing the effects of ibutilide (B, 50 nM) and flecainide (C, 1.5 μM) and control (A) in canine LV wedge preparations. [Figure 11]

[0018] FIG. 1 shows a chart summarizing the pharmacokinetic profiles of flecainide and ibutilide in animals administered 1 mg / kg flecainide acetate (Treatment A, Group 1), 0.007 mg / lg ibutilide hemifumarate (Treatment A, Group 2), 1 mg / kg flecainide acetate + 0.007 mg / lg ibutilide hemifumarate (Treatment A, Group 3), 2 mg / kg flecainide acetate (Treatment B, Group 1), 0.014 mg / lg ibutilide hemifumarate (Treatment B, Group 2), and 2 mg / kg flecainide acetate + 0.014 mg / lg ibutilide hemifumarate (Treatment B, Group 3). [Figure 12]

[0019] FIG. 1 is a schematic showing the Markov model of Na channel-drug interactions used in the in silico modeling of chemical atrial defibrillation with flecainide and ibutilide. [Figure 13]

[0020] 1 is a chart showing simulated (lines) and experimental (symbols) flecainide-Na channel interactions. [Figure 14]

[0021] Panel A shows simulated atrial cell action potentials and atrial Na currents generated by the Grandi-Bers human atrial cell model described in Example 8, and Panel B shows simulated Na currents during an atrial action potential. [Figure 15]

[0022] FIG. 1 shows simulated action potential adaptation curves illustrating the prolongation of the refractory period, shown as APD90, at various pacing frequencies by flecainide alone or ibutilide alone. [Figure 16]

[0023] FIG. 1 shows simulated action potential adaptation curves at different pacing frequencies with different concentrations of flecainide and ibutilide combinations. [Figure 17]

[0024] FIG. 1 shows ΔERPs in the presence of flecainide, ibutilide, and a combination of flecainide and ibutilide observed in a simulated fiber composed of 165 cells connected by resistors to simulate gap junctions. [Figure 18]

[0025] FIG. 1 shows a simulated self-sustaining model of atrial reentry using a one-dimensional model of 1500 Grandi-Bers simulated cells connected by resistors to simulate gap junctions. [Figure 19]

[0026] FIG. 18 shows simulated action potentials over time for each cell in the ring model shown in FIG. 17 when exposed to various combinations of flecainide and ibutilide, where darkness of the greyscale represents potential (peak / trough = darker) and individual cells are represented by a series of vertically stacked horizontal lines plotted over time, with the vertical axis position of each line indicating the cell's position within the ring. [Figure 20]

[0027] Figure 1 shows simulated action potentials in a one-dimensional model of 340 Grandi-Bers simulated cells in the presence of Ach (0.015 μM) when exposed to various combinations of flecainide and ibutilide, where darkness of the greyscale represents potential (peak / trough = darker) and individual cells are represented by a series of vertically stacked horizontal lines plotted over time, with the vertical axis position of each line indicating the cell's position within the ring. [Figure 21]

[0028] FIG. 1 shows simulated QT / QTc intervals from the modified O'Hara-Rudy model compared with clinical data. [Figure 22]

[0029] FIG. 1 shows the range of APD90 in a population of simulated tissues resulting from application of flecainide and ibutilide alone or in combination. [Figure 23]

[0030] FIG. 1 shows the simulated QT / QTc of the modified O'Hara-Rudy model with ibutilide alone (0.02 μM) or in combination (ibutilide 0.02 μM + flecainide 2.2 μM). [Figure 24]

[0031] FIG. 1 shows APD adaptation curves (solid lines) from a modified O'Hara-Rudy model with or without drug application (control example) constructed from measurements of rate-dependence curves measured as APD90 at steady state for each pacing cycle length (600 ms to 1200 ms). [Diagram 25]

[0032] FIG. 1 shows extended APD adaptation curves constructed from measurements of inverse use-dependence measured as APD90 at steady state for each pacing cycle length (600 ms to 1200 ms) for individual drugs and combinations using the original O'Hara-Rudy human ventricular model. [Figure 26]

[0033] FIG. 1 shows QT / QTc intervals simulated using the original O'Hara-Rudy human ventricular model compared with clinical data. [Figure 27]

[0034] FIG. 1 shows the drug binding burst regime used in the model of flecainide and Na channel interaction utilized in Example 9, part 1, where drug binds to the grey state. [Figure 28]

[0035] FIG. 1 shows a modified Shannon-Bers Markov model formulation of RyR2 flecainide drug-channel interaction. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009]

[0036] In some embodiments, the present disclosure relates to administering a therapeutically effective amount of a sodium channel blocker (or class I antiarrhythmic agent) and a potassium channel blocker as a fixed dose combination to a subject suffering from cardiac arrhythmia. In some embodiments, the cardiac arrhythmia is an atrial arrhythmia, which may include supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, acute episodes in permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter, or isolated atrial fibrillation. In some embodiments, the sodium channel blocker is flecainide and the potassium channel blocker is ibutilide. In some embodiments, the sodium channel blocker is flecainide and the potassium channel blocker is dofetilide. In some embodiments, the sodium channel blocker is flecainide and the potassium channel blocker is sotalol ... 2+ A source of sedatives, such as magnesium sulfate, is administered in combination with a sodium channel blocker and a potassium channel blocker.

[0010] Pharmaceutical agents.

[0037] In some embodiments, the method for treating cardiac arrhythmia, e.g., atrial fibrillation, comprises administering a compound that increases the action potential duration (APD) of atrial myocytes, such as a potassium channel blocker.Non-limiting examples of potassium channel blockers that can be used in the methods and kits provided herein include ibutilide, dofetilide, sotalol, semiritide, methanandamide, anandamide, arachidonamide, A293 (2-(butylsulfonylamino)-N-[(1R)-1-(6-methoxy-3-pyridyl)propyl]-benzamide), bupivacaine, etidocaine, genistein, mepivacaine, phenytoin, quinidine, R-ropivacaine, S-ropivacaine, tetracaine, amiodarone, dronedarone, E-4031, vernakalant, and its pharmaceutically acceptable salts and solvates.

[0011]

[0038] Among them, ibutilide or a pharma- ceutically acceptable salt thereof is a potassium channel blocker that can be used for the purposes of the present disclosure. Ibutilide is N-(4-(4-(ethyl(heptyl)amino)-1-hydroxybutyl)phenyl)methanesulfonamide and has the following structural formula:

[0012] [ka]

[0013]

[0039] Ibutilide inhibits the delayed rectifier potassium current (I Kr) and potentiate the inward depolarization or non-inactivation component of the slow sodium current (e.g., late, persistent or persistent sodium current). In some embodiments, ibutilide is used in the form of a pharmaceutically acceptable salt or solvate, such as ibutilide fumarate (e.g., ibutilide hemifumarate). Ibutilide can be a racemic combination of its two enantiomers R and S. In some embodiments, ibutilide can be a composition in which (R)-ibutilide is in enantiomeric excess over (S)-ibutilide. In some embodiments, ibutilide can be a composition in which (S)-ibutilide is in enantiomeric excess over (R)-ibutilide. In some embodiments, ibutilide can be a composition in which the enantiomeric excess of (S)-ibutilide is at least 90%, such as at least 90, 95, 98, 99, 99.5, or 99.9 percent. In some embodiments, ibutilide can be a composition in which the enantiomeric excess of (R)-ibutilide is at least 90%, such as at least 90, 95, 98, 99, 99.5, or 99.9 percent.

[0014]

[0040] Dofetilide or a pharma- ceutically acceptable salt thereof is a potassium channel blocker belonging to the group of class IIIa antiarrhythmic agents and can be used for the purposes of the present disclosure. Dofetilide is N-(4-(2-(methyl(4-(methylsulfonamido)phenoxy)ethyl)amino)ethyl)phenyl)methanesulfonamide and has the following structural formula:

[0015] [ka]

[0016]

[0041] In some embodiments, dofetilide is used in the form of a pharma- ceutically acceptable salt. Dofetilide can be a racemic combination of its two enantiomers R and S. In some embodiments, dofetilide can be a composition in which (R)-dofetilide is in enantiomeric excess over (S)-dofetilide. In some embodiments, dofetilide can be a composition in which (S)-dofetilide is in enantiomeric excess over (R)-dofetilide. In some embodiments, dofetilide can be a composition in which the enantiomeric excess of (S)-dofetilide is at least 90%, for example at least 90, 95, 98, 99, 99.5 or 99.9 percent. In some embodiments, dofetilide can be a composition in which the enantiomeric excess of (R)-dofetilide is at least 90%, for example at least 90, 95, 98, 99, 99.5, 99.9 percent.

[0017]

[0042] Sotalol or a pharma- ceutical acceptable salt thereof is a potassium channel blocker (i.e., I) belonging to the group of class IIIa antiarrhythmic agents that bind nonselectively to both β1- and β2-adrenergic receptors. kr Sotalol is N-{4-[1-hydroxy-2-(propan-2-ylamino)ethyl]phenyl}methanesulfonamide and has the following structural formula:

[0018] [ka]

[0019]

[0043] The antiarrhythmic effect of sotalol is primarily a class III effect, i.e. kr This is due to the inhibition of β-adrenergic receptor blockade, which results in a prolongation of the action potential duration and effective refractory period of atrial and ventricular cardiomyocytes. In addition, due to its beta-adrenergic receptor blocking activity, sotalol can also reduce the proarrhythmic effects associated with conditions of increased sympathetic drive and / or catecholamines. KrAlthough both inhibitory and beta-adrenergic receptor blocking activities may contribute to the antiarrhythmic effects of sotalol, inhibition of potassium currents and the associated prolongation of the ERP are the primary mechanism underlying the antiarrhythmic action of this drug.

[0020]

[0044] Sotalol may be a racemic combination of its two enantiomers D-(+)-sotalol and L-(-)-sotalol, also known as d,l-sotalol. The L-(-)-enantiomer of sotalol has both beta-blocking (class II) activity and potassium channel blocking (class III) properties. The D-(+)-enantiomer has class III properties similar to those of L-(-)-sotalol. However, the affinity of D-(+)-sotalol for beta-adrenergic receptors is 30-60 times lower than that of L-(-)-sotalol.

[0021]

[0045] In some embodiments, sotalol is used in the form of a pharma- ceutically acceptable salt or solvate, for example, sotalol hydrochloride. In some embodiments, sotalol can be a composition in which D-(+)-sotalol has an enantiomeric excess over L-(-)-sotalol. In some embodiments, sotalol can be a composition in which L-(-)-sotalol has an enantiomeric excess over D-(+)-sotalol. In some embodiments, sotalol can be a composition in which the enantiomeric excess of L-(-)-sotalol is at least 90%, for example at least 90, 95, 98, 99, 99.5 or 99.9 percent. In some embodiments, sotalol can be a composition in which the enantiomeric excess of D-(+)-sotalol is at least 90%, for example at least 90, 95, 98, 99, 99.5, 99.9 percent.

[0022]

[0046] In some embodiments, a potassium channel blocker (e.g., ibutilide) is administered in combination with a sodium channel blocker for the treatment of atrial arrhythmias. Potassium channel blockers can be used to prolong the atrial action potential, shorten the diastolic interval (the period between two successive atrial beats), and induce a corresponding delay in the recovery of sodium channels from inactivation. As a result, these changes can delay the unbinding of sodium channel blockers (e.g., flecainide) from bound sodium channels. For example, flecainide has a long unbinding time (τ off ≒20.5 s), and administration of both potassium and sodium channel blockers may reduce the proportion of sodium channels available for activation. Under these conditions, atrial myocyte excitability can be reduced, terminating atrial arrhythmias.

[0023]

[0047] The sodium channel blocker of the present disclosure may include class Ia, class Ib, class Ic, or class Id antiarrhythmic agents, or their pharmaceutically acceptable salts or solvates.Class Ia antiarrhythmic agents include, but are not limited to, quinidine, procainamide, and disopyramide.Class Ib antiarrhythmic agents include, but are not limited to, lidocaine, tocainide, phenytoin, moricizine, and mexiletine.Class Ic antiarrhythmic agents include, but are not limited to, flecainide, propafenone, and moricizine.Class Id antiarrhythmic agents may be, for example, ranolazine.

[0024]

[0048] Lidocaine, or a pharma- ceutically acceptable salt thereof (e.g., lidocaine hydrochloride), is a sodium channel blocker that belongs to the group of class Ib antiarrhythmic agents and can be used for the purposes of this disclosure. Lidocaine is 12-(diethylamino)-N-(2,6-dimethylphenyl)acetamide and has the following structural formula:

[0025] [ka]

[0026]

[0049] In some embodiments, lidocaine is provided in the pharmaceutical composition of the present disclosure as a pharma- ceutically acceptable salt.The salt of lidocaine can be, for example, magnesium salt, acetate, citrate, nitrate, hydrochloride, sulfate, maleate, tartrate, phosphate, aconitate, adipate, ascorbate, benzoate, caprylate, cholate, formate, glutamate, lactate, propionate, sorbate, stearate or succinate.

[0027]

[0050] Mexiletine or a pharma- ceutically acceptable salt thereof is a sodium channel blocker belonging to the group of class Ib antiarrhythmic agents and can be used for the purposes of this disclosure. Mexiletine is 1-(2,6-dimethylphenoxy)propan-2-amine and has the following structural formula:

[0028] [ka]

[0029]

[0051] In some embodiments, mexiletine is used in the form of a pharma- ceutically acceptable salt or solvate, such as mexiletine hydrochloride. Mexiletine can be a racemic combination of its two enantiomers, R and S. In some embodiments, mexiletine can be a composition in which (R)-mexiletine is in enantiomeric excess over (S)-mexiletine. In some embodiments, mexiletine can be a composition in which (S)-mexiletine is in enantiomeric excess over (R)-mexiletine. In some embodiments, mexiletine can be a composition in which the enantiomeric excess of (S)-mexiletine is at least 90%, e.g., at least 90, 95, 98, 99, 99.5, or 99.9 percent. In some embodiments, mexiletine can be a composition in which the enantiomeric excess of (R)-mexiletine is at least 90%, e.g., at least 90, 95, 98, 99, 99.5, or 99.9 percent.

[0030]

[0052] Flecainide or a pharma- ceutically acceptable salt thereof is a sodium channel blocker belonging to the group of class Ic antiarrhythmic agents and can be used for the purposes of the present disclosure. Flecainide is 1-(2-(2-hydroxy-3-(propylamino)propoxy)phenyl)-3-phenylpropan-1-one and has the following structural formula:

[0031] [ka]

[0032]

[0053] Propafenone or its pharma- ceutically acceptable salt is a sodium channel blocker belonging to the group of class Ic antiarrhythmic drugs and can be used for the purposes of the present disclosure. Propafenone is N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide and has the following structural formula:

[0033] [ka]

[0034]

[0054] In some embodiments, flecainide is used in the form of a pharma- ceutically acceptable salt or solvate, for example, flecainide acetate. Flecainide can be a racemic combination of its two enantiomers R and S. In some embodiments, flecainide can be a composition in which (R)-flecainide is in enantiomeric excess over (S)-flecainide. In some embodiments, flecainide can be a composition in which (S)-flecainide is in enantiomeric excess over (R)-flecainide. In some embodiments, flecainide can be a composition in which the enantiomeric excess of (S)-flecainide is at least 90%, for example at least 90, 95, 98, 99, 99.5 or 99.9 percent. In some embodiments, flecainide can be a composition in which the enantiomeric excess of (R)-flecainide is at least 90%, for example at least 90, 95, 98, 99, 99.5, 99.9 percent.

[0035] Pharmaceutically acceptable salts.

[0055] The present disclosure provides for the use of pharmaceutically acceptable salts of any therapeutic compound described herein.Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts.The acid added to a compound to form an acid addition salt can be an organic acid or an inorganic acid.The base added to a compound to form a base addition salt can be an organic base or an inorganic base.In some embodiments, the pharmaceutically acceptable salt is a metal salt.In some embodiments, the pharmaceutically acceptable salt is an ammonium salt.

[0036]

[0056] Metal salts can result from the addition of inorganic bases to the compounds of the present disclosure. Inorganic bases consist of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, an alkaline earth metal, a transition metal, or a main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0037]

[0057] In some embodiments, the metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.

[0038]

[0058] Ammonium salts can result from the addition of ammonia or an organic amine to the compounds of the present disclosure. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, imidazole or pyrazine.

[0039]

[0059] In some embodiments, the ammonium salt is a triethylamine salt, a trimethylamine salt, a diisopropylamine salt, an ethanolamine salt, a diethanolamine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.

[0040]

[0060] Acid addition salts may result from the addition of an acid to a compound of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid. pantothenic acid, acetic acid, trifluoroacetic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.

[0041]

[0061] In some embodiments, the salt is a hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, gentisate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, pantothenate, acetate, trifluoroacetate, mandelate, cinnamate, aspartate, stearate, palmitate, glycolate, propionate, butyrate, fumarate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate salt.

[0042] Combination therapy.

[0062] Flecainide inhibits the cardiac voltage-dependent sodium channel (Na VFlecainide can exhibit voltage- and use-dependent block of the peak inward sodium current (1.5 subtype) and corresponding inhibition of the transient peak inward sodium current by preferential binding of the inactivated open state of the channel. A feature of the sodium channel blocking activity of flecainide is the slow dissociation rate of the bound drug from its target channel (e.g., up to several seconds). This may result in incomplete recovery of flecainide-bound channels during diastole, resulting in a smaller population of channels available for activation. This feature may make flecainide more effective at reducing myocyte excitability when the frequency of action potentials is high, such as during tachyarrhythmias (e.g., AF). The voltage- and frequency-dependent potency of flecainide for inhibition of peak sodium current can be in the micromolar range of approximately 0.5-2.5 μM, with use-dependent block occurring at concentrations as low as 0.5 mM. In addition to inhibition of the transient peak sodium current, flecainide can also inhibit the slow inactivation component of the sodium current (also referred to as the late or persistent sodium current) with a potency of 3.4 μM. Flecainide also inhibits myocardial sarcoplasmic reticulum Ca 2+ It is capable of inhibiting the release channel (ryanodine receptor RyR2) with a potency of approximately 20 μM.

[0043]

[0063] The prolongation of the atrial effective refractory period (ERP) caused by sodium channel blockers (e.g., flecainide) may be enhanced by the prolongation of the atrial action potential induced by potassium channel inhibitors (e.g., ibutilide, dofetilide, or sotalol). Given that the atrial rate increases during episodes of arrhythmias such as atrial fibrillation, the ERP may be particularly prolonged by flecainide. In some cases, inhibition of sodium channels by sodium channel blockers (e.g., flecainide) can result in delayed reactivation of the channel and prolongation of the atrial ERP during AF, both of which may be further enhanced by the prolongation of the atrial action potential (AP) and ERP by potassium channel blockers such as ibutilide. In some embodiments, the combination of sodium channel blockers and delayed rectifier potassium channel I KrCombinations of inhibitors (eg, flecainide and ibutilide) can produce an overall synergistic electrophysiological effect, eg, a greater than additive overall effect in suppressing AF.

[0044]

[0064] Combination therapy including flecainide and a potassium blocker such as ibutilide or dofetilide can enhance antiarrhythmic efficacy while reducing the risk of both proarrhythmic and hemodynamic adverse events that may be associated with each of the components used in monotherapy. In some embodiments, co-administration of flecainide with a potassium channel blocker (e.g., ibutilide or dofetilide) for acute treatment of recent-onset atrial fibrillation reduces the risk of cardiovascular adverse events compared to potassium channel blocker or flecainide monotherapy. For example, compared to ibutilide monotherapy, co-administration of flecainide with ibutilide can reduce the risk of torsades de pointes (TdP), a polymorphic ventricular tachycardia (VT) that can be observed with ibutilide-promoted QT prolongation. In some embodiments, without wishing to be bound by a particular theory, ibutilide is used to treat late I Na Strengthening I Kr can inhibit the late I phase, thereby prolonging the action potential and QT interval of ventricular cells, whereas flecainide inhibits the late I phase. Na In some embodiments, flecainide exerts an inhibitory effect on ibutilide, dofetilide or sotalol-promoted I and counteracts the QT prolongation. Kr For example, flecainide not only reduces the net inward current in the plateau phase of the action potential, but also reduces the inward current that might otherwise induce the delayed afterdepolarization (DAD) required to initiate TdP. In addition, flecainide, as well as other sodium channel blockers such as mexiletine, ranolazine, and tetrodotoxin, inhibit the I KrBoth the use-dependence of blocker-induced ventricular repolarization and beat-to-beat variability (i.e., APD and QT intervals) can be reduced. Thus, by this action, sodium channel blockers can reduce the "torsades de pointes-inducing" effects of potassium channel blockers such as ibutilide, dofetilide, E-4031, and sotalol (see Wu et al., Circulation 2011).

[0045]

[0065] Ibutilide, dofetilide, or sotalol Kr Inhibition of can also reduce the risk of adverse events associated with the use of flecainide to terminate atrial arrhythmias (e.g., atrial fibrillation). For example, ibutilide, sotalol, or dofetilide can attenuate the decrease in intracellular calcium caused by sodium channel blockers, and reduce the negative inotropic effect and hypotension associated with flecainide. In some embodiments, administration of flecainide induces atrial flutter (AFL) with 1:1 AV transmission, and administration of ibutilide converts flecainide-promoted atrial flutter to sinus rhythm.

[0046]

[0066] Combination therapy including flecainide and sotalol can enhance antiarrhythmic efficacy while reducing the risk of both proarrhythmic and hemodynamic adverse events that may be associated with each of the components used in monotherapy. In some embodiments, co-administration of flecainide and sotalol for acute treatment of recent-onset atrial fibrillation reduces the risk of cardiovascular adverse events compared to sotalol or flecainide monotherapy. For example, co-administration of flecainide and sotalol can reduce the risk of torsades de pointes (TdP), a polymorphic ventricular tachycardia (VT) that can be observed with sotalol-facilitated QT prolongation, compared to sotalol monotherapy. In some embodiments, without wishing to be bound by a particular theory, it is believed that sotalol is an I Kr , thereby prolonging the action potential and QT interval of ventricular cells, whereas flecainide inhibits I NaIn some embodiments, flecainide exerts an inhibitory effect on sotalol-promoted I and counteracts sotalol-promoted QT prolongation. Kr For example, flecainide can reduce the net inward current during the plateau phase of the action potential as well as reduce the inward current that would otherwise elicit the delayed afterdepolarization (DAD) required for the initiation of TdP.

[0047]

[0067] Potassium channel blockers can provide increased half-life or decreased renal clearance. Renal clearance can be measured through standard measures of renal impairment, such as creatinine clearance. For example, severe renal impairment is characterized by a creatinine clearance of less than 20 ml / min. Thus, the dosage of the potassium channel blocker (e.g., ibutilide or dofetilide) can be modified based on the measured creatinine clearance in the subject. In some embodiments, normal creatinine clearance is characterized by a clearance rate of about 80 to about 140 mL / min. In some embodiments, the creatinine clearance is about 80 mL / min to about 140 mL / min. In some embodiments, the creatinine clearance is at least about 80 mL / min. In some embodiments, the creatinine clearance is up to about 140 mL / min. In some embodiments, creatinine clearance is about 80 mL / min to about 85 mL / min, about 80 mL / min to about 90 mL / min, about 80 mL / min to about 95 mL / min, about 80 mL / min to about 100 mL / min, about 80 mL / min to about 105 mL / min, about 80 mL / min to about 110 mL / min, about 80 mL / min to about 115 mL / min, about 80 mL / min to about 120 mL / min, about 80 mL / min to about 125 mL / min, about 80 mL / min to about 130 mL / min, about 80 mL / min to about 140 mL / min, about 85 mL / min to about 90 mL / min, about 85 mL / min to about 95 mL / min, about 85 mL / min to about 100 mL / min, about 85 mL / min to about 105 mL / min, about 85 mL / min to about 110 mL / min / min, about 85mL / min to about 115mL / min, about 85mL / min to about 120mL / min, about 85mL / min to about 125mL / min, about 85mL / min to about 130mL / min, about 85mL / min ~ approx. 140mL / min, approx. 90mL / min ~ approx. 95mL / min, approx. 90mL / min ~ approx. 100mL / min, approx. 90mL / min ~ approx. 105mL / min, approx. 90mL / min ~Approx. 110mL / min, approx. 90mL / min ~ approx. 115mL / min, approx. 90mL / min ~ approx. 120mL / min, approx. 90mL / min ~ approx. 125mL / min, approx. 90mL / min ~ approx. 130 mL / min, about 90mL / min to about 140mL / min, about 95mL / min to about 100mL / min, about 95mL / min to about 105mL / min, about 95mL / min to about 110mL / min,Approximately 95 mL / min ~ approx. 115 mL / min, approx. 95 mL / min ~ approx. 120 mL / min, approx. 95 mL / min ~ approx. 125 mL / min, approx. 95 mL / min ~ approx. 130 mL / min, approx. 95 mL / min min ~ approx. 140 mL / min, approx. 100 mL / min ~ approx. 105 mL / min, approx. 100 mL / min ~ approx. 110 mL / min, approx. 100 mL / min ~ approx. 115 mL / min, approx. 100 mL / min ~ Approx. 120mL / min, approx. 100mL / min ~ approx. 125mL / min, approx. 100mL / min ~ approx. 130mL / min, approx. 100mL / min ~ approx. 140mL / min, approx. 105mL / min ~ approx. 1 10mL / min, approx. 105mL / min ~ approx. 115mL / min, approx. 105mL / min ~ approx. 120mL / min, approx. 105mL / min ~ approx. 125mL / min, approx. 105mL / min ~ approx. 130m L / min, about 105mL / min to about 140mL / min, about 110mL / min to about 115mL / min, about 110mL / min to about 120mL / min, about 110mL / min to about 125mL / min 110mL / min to 130mL / min, 110mL / min to 140mL / min, 115mL / min to 120mL / min, 115mL / min to 125mL / min, approx. 115 mL / min to about 130 mL / min, about 115 mL / min to about 140 mL / min, about 120 mL / min to about 125 mL / min, about 120 mL / min to about 130 mL / min, about 120 mL / min to about 140 mL / min, about 125 mL / min to about 130 mL / min, about 125 mL / min to about 140 mL / min, or about 130 mL / min to about 140 mL / min.

[0048]

[0068] In some embodiments, the potassium channel blocker is C QT prolongation, also known as C This can cause an increase in the normal QT interval. C The value is less than 430ms. C If the QT increases to >430 ms, discontinuation of the potassium channel blocker (e.g., ibutilide or dofetilide) should be considered. C The extension may be greater than about 450 ms, 460 ms or 470 ms.

[0049]

[0069] In some embodiments, the blocked potassium channel reduces the QT CThe creatinine clearance value can be increased and the clearance reduced, where the subject has a reduced creatinine clearance value.

[0050]

[0070] In some embodiments, the sodium channel blocker (e.g., flecainide, mexiletine, or propafenone), the potassium channel blocker (e.g., ibutilide, dofetilide, or sotalol), or the combination of a sodium channel blocker and a potassium channel blocker, is selected from the group consisting of Mg 2+ Administered in combination with a source of Mg 2+ Sources include Mg 2+ and anions, such as sulfate, disulfate, oxide, hydroxide, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, glycinate, threonate, aspartate, acetate, propionate, gluconate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, malate, succinate, suberate, sebacate, stearate, isocyanate, stearate ... In some embodiments, the salts include, but are not limited to, Mg, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene 1-sulfonate, naphthalene 2-sulfonate, and mandelate. 2+The source is magnesium citrate, magnesium aspartate, magnesium threonate, magnesium glycinate, magnesium chloride, magnesium sulfate, magnesium oxide, or magnesium malate. 2+ The source comprises magnesium sulfate or a hydrate thereof. In some embodiments, Mg 2+ Sources include magnesium sulfate heptahydrate.

[0051]

[0071] Mg 2+ Ions are transported through L-type calcium channels (I CaL ) inhibitor, Ca V1.2 In some embodiments, Mg can enhance the voltage-dependent inactivation and stimulated dephosphorylation of the channel. 2+ Ca containing the proximal C-terminal domain V1.2 It acts directly on the channel. Overall, Mg 2+ is the I CaL Although it can promote inhibition of the effect (e.g., I CaL 26% decrease in cAMP-stimulated (e.g., stimulated by beta-adrenergic agonists) I CaL It can also cause a larger reduction (e.g., about 63%) of Mg 2+ The ion is also K + Induce inward rectification of K channels + The outward flow of ions can be prevented.

[0052]

[0072] Mg 2+ Administration of a source of magnesium (e.g., intravenous magnesium sulfate) can be effective in terminating or preventing TdP, including TdP caused by administration of ibutilide, dofetilide, or sotalol. 2+ I reduces the amplitude of early afterdepolarizations (EADs) by decreasing calcium influx (through L-type calcium channels), and thus can suppress EADs that can initiate TdP. CaL and K. + Inhibition of current causes Mg 2+Administration of vasopressin (e.g., IV magnesium sulfate) can slow the ventricular rate and induce cardioversion of atrial fibrillation.

[0053]

[0073] As mentioned above, flecainide is effective in preventing late I Na Inhibition of Mg can counteract the "torsades de pointes-inducing" effects of ibutilide, sotalol, or dofetilide. 2+ The combination of flecainide and Mg 2+ It may be more effective in preventing TdP induced by ibutilide, sotalol or dofetilide than monotherapy. 2+ Administration of the source of flecainide reduces the risk of TdP associated with administration of ibutilide, sotalol or dofetilide without compromising the efficacy of the combination of flecainide and ibutilide, sotalol or dofetilide. Kr Inhibition combined with Mg 2+ By I CaL Weak inhibition of AF can also slow AV nodal conduction (e.g., prevent 1:1 AV transmission) when flecainide converts AF to atrial flutter.

[0054] method.

[0074] One aspect of the present disclosure provides a method of treating a subject suffering from an atrial arrhythmia, comprising administering to the subject (i) a first amount of a sodium channel blocker, and (ii) a second amount of a potassium channel blocker, thereby inducing cardioversion of the atrial arrhythmia.

[0055]

[0075] In some embodiments, the administration reduces the t value of the potassium channel blocker in the subject. max t of a sodium channel blocker in a subject occurring within about 1 hour, about 0.5 hours, about 15 minutes, about 5 minutes, about 3 minutes, about 2 minutes, about 1 minute, or about 30 seconds of max results.

[0056]

[0076] In some embodiments, the administration reduces the t value of the potassium channel blocker in the subject. max t of a sodium channel blocker in a subject occurring within about 1 hour, within about 0.5 hours, within about 15 minutes, within about 5 minutes, within about 3 minutes, within about 2 minutes, within about 1 minute, or within about 30 seconds prior to max results.

[0057]

[0077] In some embodiments, the administration reduces the t value of the potassium channel blocker in the subject. max

[0023] A t of a sodium channel blocker in a subject occurs within about 1 hour, within about 0.5 hours, within about 15 minutes, within about 5 minutes, within about 3 minutes, within about 2 minutes, within about 1 minute, or within about 30 seconds after administration of the sodium channel blocker. max results.

[0058]

[0078] In some embodiments, the subject's QT c is the t max In some embodiments, the subject's QT c is the t max The delay time is about 490 ms, about 495 ms, about 500 ms, about 505 ms, or about 510 ms or less between the

[0059]

[0079] In some embodiments, the potassium channel blocker is I KrIn some embodiments, the potassium channel blocker is an inhibitor. In some embodiments, the potassium channel blocker is ibutilide or a pharma- ceutically acceptable salt thereof. In some embodiments, the potassium channel blocker is dofetilide or a pharma- ceutically acceptable salt thereof. In some embodiments, the potassium channel blocker is sotalol or a pharma- ceutically acceptable salt thereof. In some embodiments, the sodium channel blocker is a class Ib antiarrhythmic agent. In some embodiments, the sodium channel blocker is a class Ic antiarrhythmic agent. In some embodiments, the sodium channel blocker is flecainide or a pharma- ceutically acceptable salt thereof. In some embodiments, the sodium channel blocker is propafenone or a pharma- ceutically acceptable salt thereof.

[0060]

[0080] In some embodiments, the potassium channel blockade also blocks beta adrenergic receptors.

[0081] In some embodiments, the sodium channel blocker is administered to the subject within 90 minutes, 60 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, 3 minutes, 2 minutes, 1 minute, or 30 seconds of administration of the potassium channel blocker to the subject. In some embodiments, the sodium channel blocker is administered to the subject simultaneously with administration of the potassium channel blocker.

[0061]

[0082] In some embodiments, the sodium channel blocker and the potassium channel blocker are administered to multiple experimental subjects in a clinical study.The clinical study can further include a control cohort, which can include subjects administered with the sodium channel blocker without ibutilide, or can include subjects administered with the potassium channel blocker without the sodium channel blocker.In some embodiments, the clinical study can further include a control cohort, which can include subjects administered with the sodium channel blocker without dofetilide, or can include subjects administered with the potassium channel blocker without the sodium channel blocker.In some embodiments, the clinical study can further include a control cohort, which can include subjects administered with the sodium channel blocker without sotalol, or can include subjects administered with the potassium channel blocker without the sodium channel blocker.

[0062]

[0083] In some embodiments, each subject of the plurality of experimental subjects is administered both a first amount of a sodium channel blocker and a second amount of a potassium channel blocker, and each subject of a control cohort is administered the first amount of a sodium channel blocker without the second amount of a potassium channel blocker, or each subject of a control cohort is administered the second amount of a potassium channel blocker without the first amount of a sodium channel blocker.

[0063]

[0084] In some embodiments, the sodium channel blocker and ibutilide or a pharmaceutically acceptable salt thereof are administered simultaneously to multiple experimental subjects. In some embodiments, the sodium channel blocker and dofetilide or a pharmaceutically acceptable salt thereof are administered simultaneously to multiple experimental subjects. In some embodiments, the sodium channel blocker and sotalol or a pharmaceutically acceptable salt thereof are administered simultaneously to multiple experimental subjects. In some embodiments, the sodium channel blocker is administered to each subject of multiple experimental subjects within 90 minutes, 60 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, 3 minutes, 2 minutes, 1 minute, or 30 seconds after the potassium channel blocker is administered to each subject.

[0064]

[0085] The multiple experimental subjects can be, for example, at least 2 subjects, at least about 5 subjects, at least about 10 subjects, at least about 15 subjects, at least about 20 subjects, at least about 30 subjects, at least about 40 subjects, at least about 50 subjects, at least about 100 subjects, or at least about 150 subjects. The multiple experimental subjects may be, for example, at least 2 subjects, at least about 5 subjects, about 2 to about 15 subjects, about 2 to about 20 subjects, about 2 to about 30 subjects, about 2 to about 40 subjects, about 2 to about 50 subjects, about 2 to about 100 subjects, about 2 to about 150 subjects, about 2 to about 300 subjects, about 5 to about 15 subjects, about 5 to about 20 subjects, about 5 to about 30 subjects, about 5 to about 40 subjects, about 5 to about 50 subjects, about 5 to about 100 subjects, about 5 to about 150 subjects, or about 5 to about 300 subjects.

[0065]

[0086] The number of subjects in the control cohort can be, for example, at least about 2 subjects, at least about 5 subjects, at least about 10 subjects, at least about 15 subjects, at least about 20 subjects, at least about 30 subjects, at least about 40 subjects, at least about 50 subjects, at least about 100 subjects, or at least about 150 subjects. The multiple experimental subjects may be, for example, at least 2 subjects, at least about 5 subjects, about 2 to about 15 subjects, about 2 to about 20 subjects, about 2 to about 30 subjects, about 2 to about 40 subjects, about 2 to about 50 subjects, about 2 to about 100 subjects, about 2 to about 150 subjects, about 2 to about 300 subjects, about 5 to about 15 subjects, about 5 to about 20 subjects, about 5 to about 30 subjects, about 5 to about 40 subjects, about 5 to about 50 subjects, about 5 to about 100 subjects, about 5 to about 150 subjects, or about 5 to about 300 subjects.

[0066]

[0087] In some embodiments, the experimental subject is a healthy subject. In some embodiments, the experimental subject suffers from atrial arrhythmia during administration. In some embodiments, the subjects in the control cohort are healthy subjects. In some embodiments, the subjects in the control cohort suffer from atrial arrhythmia during administration. In some embodiments, the experimental subject is a human subject. In some embodiments, the experimental subject is an animal subject. In some embodiments, the experimental subject is a porcine subject. In some embodiments, the experimental subject is a canine subject.

[0067]

[0088] In some embodiments, the t of a sodium channel blocker in multiple experimental subjects max is the t max the occurrence of the above-mentioned occurrences at intervals of about 1 hour, about 30 minutes, about 15 minutes, about 10 minutes, about 5 minutes, about 3 minutes, about 2 minutes, about 1 minute, or about 30 seconds or less.

[0068]

[0089] In some embodiments, the incidence of torsades de pointes (TdP) is reduced in a plurality of experimental subjects as compared to the incidence of TdP in a control cohort. In some embodiments, the incidence of TdP (torsades de pointes) is reduced by at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 35%, or at least about 50% in a plurality of experimental subjects as compared to the incidence of TdP in a control cohort.

[0069]

[0090] In some embodiments, the incidence of QT intervals that exceed the nomogram is reduced in multiple experimental subjects in clinical studies compared to the incidence of QT intervals that exceed the nomogram in control cohorts in clinical studies.The risk of torsades de pointes (TdP) in a subject can be evaluated according to the QT nomogram described in Chan et al.QJM: An International Journal of medicine, Volume 100, Issue 10, October 2007, Pages 609-615, which is incorporated herein by reference in its entirety.In some embodiments, the subject's QT interval is plotted against heart rate in a nomogram according to Figure 1, and if the resulting point exceeds the line of the nomogram (e.g., "exceeds the nomogram"), the subject is considered to be at risk of TdP. In some embodiments, the incidence of QT intervals above the nomogram is reduced by at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 35%, or at least about 50% in multiple experimental subjects compared to the incidence of TdP in a control cohort.

[0070]

[0091] In some embodiments, the incidence of hypotension is reduced in a plurality of experimental subjects in the clinical study, compared to the incidence of hypotension in a control cohort in the clinical study. In some embodiments, hypotension comprises a mean arterial pressure (MAP) of less than 70 mmHg that lasts for at least 5 minutes after administration. In some embodiments, the incidence of hypotension is reduced by at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 35%, or at least about 50% in a plurality of experimental subjects, compared to the incidence of TdP in a control cohort.

[0071]

[0092] In some embodiments, the average magnitude of increase in QTc in multiple experimental subjects with atrial arrhythmia in a clinical study compared to the mean QTc in a control cohort of the clinical study is about 1% or less, about 2% or less, about 3% or less, about 4% or less, about 5% or less, about 10% or less, about 15% or less, about 20% or less, about 30% or less, about 40% or less, or about 50% or less.

[0072]

[0093] Mean QT in the control cohort of the clinical study c QT interval in multiple experimental subjects in a clinical study compared with c The method of any one of embodiments 25-41, wherein the average magnitude of the increase in QT is about 60 ms or less, about 50 ms or less, about 40 ms or less, about 30 ms or less, about 20 ms or less, about 10 ms or less, or about 6 ms or less. c is calculated according to the Fridericia formula.

[0073]

[0094] In some embodiments, the present disclosure provides a method of mitigating a decrease in intracellular calcium in a cell caused by administration of a sodium channel blocker, comprising treating the cell with a potassium channel blocker. In some embodiments, the potassium channel blocker is an I KrIn some embodiments, the potassium channel blocker is an inhibitor. In some embodiments, the potassium channel blocker is ibutilide or a pharma- ceutically acceptable salt thereof. In some embodiments, the potassium channel blocker is dofetilide or a pharma- ceutically acceptable salt thereof. In some embodiments, the potassium channel blocker is sotalol or a pharma- ceutically acceptable salt thereof. In some embodiments, the sodium channel blocker is flecainide or a pharma- ceutically acceptable salt thereof. In some embodiments, the cell is an atrial muscle cell.

[0074]

[0095] In some embodiments, the present disclosure provides a method for reducing the risk of ibutilide-promoted TdP in a subject suffering from atrial arrhythmias undergoing treatment with ibutilide or a pharma- ceutical acceptable salt thereof, comprising co-administering a therapeutically effective amount of flecainide or a pharma- ceutical acceptable salt thereof with ibutilide. In some embodiments, the method comprises administering Mg 2+ The method further comprises the step of co-administering flecainide and ibutilide with the source.

[0075]

[0096] In some embodiments, the present disclosure provides a method for reducing the risk of dofetilide-accelerated TdP in a subject suffering from atrial arrhythmias undergoing treatment with dofetilide or a pharmacologic acceptable salt thereof, comprising co-administering a therapeutically effective amount of flecainide or a pharmacologic acceptable salt thereof with dofetilide. 2+ The method further comprises the step of co-administering flecainide and dofetilide with the source.

[0076]

[0097] In some embodiments, the present disclosure provides a method for reducing the risk of sotalol-accelerated TdP in a subject suffering from atrial arrhythmias receiving treatment with sotalol or a pharmacologic acceptable salt thereof, comprising co-administering a therapeutically effective amount of flecainide or a pharmacologic acceptable salt thereof with sotalol. 2+ The method further comprises the step of co-administering flecainide and sotalol with the source.

[0077]

[0098] In some embodiments, the present disclosure provides a method for reducing the risk of ibutilide-promoted TdP in a subject suffering from atrial arrhythmia receiving treatment with ibutilide or a pharma- ceutical acceptable salt thereof, comprising co-administering a therapeutically effective amount of propafenone, or a pharma- ceutical acceptable salt thereof, with ibutilide. In some embodiments, the method comprises administering Mg 2+ The method further comprises the step of co-administering the source with propafenone and ibutilide.

[0078]

[0099] In some embodiments, the present disclosure provides a method of reducing the risk of dofetilide-promoted TdP in a subject suffering from atrial arrhythmias receiving treatment with dofetilide or a pharma- ceutical acceptable salt thereof, comprising co-administering a therapeutically effective amount of propafenone, or a pharma- ceutical acceptable salt thereof, with dofetilide. 2+ The method further comprises the step of co-administering the source with propafenone and dofetilide.

[0079]

[0100] In some embodiments, the disclosure provides a method of reducing the risk of sotalol-accelerated TdP in a subject suffering from atrial arrhythmias receiving treatment with sotalol or a pharmacologic acceptable salt thereof, comprising co-administering a therapeutically effective amount of propafenone or a pharmacologic acceptable salt thereof with sotalol. 2+ The method further comprises the step of co-administering the source with propafenone and sotalol.

[0080]

[0101] In some embodiments, administering a dose of a sodium channel blocker and a dose of a potassium channel blocker induces cardioversion of an atrial arrhythmia in a subject faster than administering a dose of a sodium channel blocker to a subject without a dose of a potassium channel blocker. In some embodiments, administering a dose of a sodium channel blocker and a dose of a potassium channel blocker induces cardioversion of an atrial arrhythmia in a subject faster than administering a dose of a potassium channel blocker to a subject without a dose of a sodium channel blocker. In some embodiments, a therapeutically effective amount of a sodium channel blocker administered to a subject in parallel or simultaneously with a potassium channel blocker is less than a therapeutically effective amount of a sodium channel blocker administered to a subject when not administered in combination or sequentially with a potassium channel blocker. In some embodiments, a therapeutically effective amount of a potassium channel blocker administered to a subject in parallel or simultaneously with a sodium channel blocker is less than a therapeutically effective amount of a potassium channel blocker administered to a subject when not administered in combination with a sodium channel blocker. In some embodiments, administration of both a potassium channel blocker and a sodium channel blocker reduces the minimum therapeutically effective dose of the potassium channel blocker or the sodium channel blocker by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of the minimum therapeutically effective dose of each when used alone without other agents in the corresponding subject.

[0081]

[0102] In some embodiments, administration of potassium channel blockers and sodium channel blockers can prolong the action potential duration or effective refractory period of atrial myocytes. As used herein, "effective refractory period" may refer to the time during which atrial myocytes cannot respond to a new conduction stimulus and cannot trigger a de novo action potential. Quantitatively, the effective refractory period may be considered as the sum of the durations of phases 0, 1, 2 and 3 of an action potential. Exemplary action potentials with 0, 1, 2, 3 and 4 corresponding to the respective phases are shown in FIG. 2. In some embodiments, administration of potassium channel blockers and sodium channel blockers can prolong the effective refractory period of atrial myocytes by at least 5%, for example, about 5%, about 10%, about 15%, about 20%, about 25%, about 35% or about 40%. In some cases, the prolongation effect is measured as an average before and after administration of potassium channel blockers and sodium channel blockers. For example, the effective refractory period before and after administration can be quantified as an average over a period of at least 2, 4, 6, 8, 10, 12, 15, 18, 20, 22, 25, 28, 30, 35, 40, 45, 50, or 60 minutes, or over a period of at least 10, 20, 30, 40, 50, 60, 80, or 100 muscle cell action potentials. In some embodiments, the average effective refractory period after administration is measured at about 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 20, 22, 25, 28, 30, 35, 40, 45, 50, or 60 minutes after administration.

[0082]

[0103] In some embodiments, administration can prevent the recurrence of atrial arrhythmia for at least 1 hour after administration, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24 hours after administration, or for example, about 1, 2, 3, 4, 5, 6 or 7 days after administration.

[0083]

[0104] In some embodiments, administration does not induce ventricular arrhythmias. As used herein, "ventricular arrhythmias" can include ventricular fibrillation, sustained polymorphic ventricular tachycardia, and sustained monomorphic ventricular tachycardia.

[0084]

[0105] In some embodiments, a subject suffering from atrial arrhythmia is administered a first unit dose of a sodium channel blocker (e.g., flecainide). In some embodiments, a second unit dose comprising a potassium channel blocker (e.g., ibutilide, sotalol, or dofetilide) is administered if the first unit dose does not induce cardioversion in the subject. In some embodiments, the first unit dose or the second unit dose comprises Mg 2+ The device further includes a source.

[0085]

[0106] In some embodiments, a unit dose of a sodium channel blocker is administered to a subject suffering from atrial arrhythmia, and a potassium channel blocker and a Mg 2+ In some of these cases, the unit dose of the sodium channel blocker induces cardioversion in a subject when administered in parallel with a potassium channel blocker and a Mg channel blocker. 2+ If not administered in parallel with a source, it will not induce cardioversion in a subject.

[0086]

[0107] In some embodiments, the subject method and composition are used to treat subjects with arrhythmias, such as atrial arrhythmias, that are unresponsive to sodium channel blocker monotherapy (e.g., flecainide monotherapy).For example, in the average population, there are approximately 30% patients with paroxysmal atrial fibrillation that shows resistance to flecainide monotherapy.In some embodiments, when subjects, for example, are administered sodium channel blocker monotherapy without potassium channel blocker, do not undergo cardioversion from atrial arrhythmias to normal sinus rhythm, subjects suffer from atrial arrhythmias that are unresponsive to sodium channel blocker monotherapy ("sodium channel blocker unresponsive" subjects).

[0087]

[0108] In some embodiments, if a subject does not undergo cardioversion from atrial arrhythmia to normal sinus rhythm when administered flecainide monotherapy, for example, without potassium channel blocker, the subject suffers from atrial arrhythmia that is unresponsive to flecainide monotherapy ("flecainide unresponsive" subject). For example, a subject may be unresponsive to flecainide treatment when flecainide is administered alone orally, by intravenous injection, or by inhalation at a dose that is otherwise therapeutically effective in most patients. For example, an otherwise therapeutically effective oral dose that does not induce cardioversion in a flecainide non-responsive subject may be at least about 25 mg per day, e.g., about 25 mg per day, e.g., about 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, 200 mg per day, 225 mg per day, 250 mg per day, 275 mg per day, 300 mg per day, 325 mg per day, 350 mg per day, 375 mg per day and 400 mg per day. For example, an otherwise therapeutically effective intravenous dose of flecainide that does not induce cardioversion in a flecainide non-responsive subject without a potassium channel blocker may be, for example, at least about 0.1 mg / kg, such as about 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, or 3 mg / kg. In some examples, an otherwise therapeutically effective inhaled dose of flecainide that does not induce cardioversion in a flecainide non-responsive subject without a potassium channel blocker may be, for example, about 0.1 mg to about 100 mg administered over multiple inhalations.

[0088]

[0109] In some embodiments, the potassium channel blocker is Mg 2+ In some embodiments, the potassium channel blocker is administered simultaneously with the Mg 2+ In some embodiments, a subject suffering from cardiac arrhythmia, e.g., atrial arrhythmia, is administered a sodium channel blocker, a potassium channel blocker, and a Mg channel blocker simultaneously.2+ In some embodiments, a first unit dose of a sodium channel blocker, a second unit dose of a potassium channel blocker, and a third unit dose of a Mg channel blocker are administered in parallel or simultaneously. 2+ Provided herein are kits for treating cardiac arrhythmias, eg, atrial arrhythmias, comprising a source.

[0089] Definition.

[0110] As used herein, a "cardiac condition" may 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 heart disease. As used herein, an "atrial arrhythmia" may refer to an arrhythmia that affects at least one atrium, and does not include bradycardia. For example, an atrial arrhythmia may originate from and affect at least one atrium. As used herein, a "tachycardia" may refer to an arrhythmia in which the heart beats too fast. For example, a tachycardia may involve a resting heart rate of more than 100 beats per minute, e.g., more than 110 beats per minute, more than 120 beats per minute, or more than 130 beats per minute. In some embodiments, the tachycardia may 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.

[0090]

[0111] As used herein, the phrase "cardiac arrhythmia" may refer to an arrhythmia in which the heart beats irregularly. As used herein, the term "atrial fibrillation" may refer to an abnormal heart rhythm characterized by rapid and irregular beating of the atria. As used herein, the term "cardioversion" may refer to a process in which an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia is converted to a normal sinus rhythm. Cardioversion can be accomplished by electricity, drugs, or both.

[0091]

[0112] As used herein, the singular forms "a," "an," and "the" can include plural referents 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.

[0092]

[0113] References herein to "one embodiment," "one variation" or "one aspect" may include one or more of such embodiments, variations or aspects, unless otherwise clear from the context.

[0093]

[0114] As used herein, the term "pharmaceutical acceptable solvate" may 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 combined with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine, or combinations thereof.

[0094]

[0115] As used herein, the term "pharmaceutical acceptable salt" may 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. Examples of pharmaceutical acceptable salts include sulfate, disulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, and benzoate. , chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates.

[0095]

[0116] The term "about" in connection with a reference numerical value can include a range of values ​​from that value plus or minus 10%. For example, the amount "about 10" includes amounts from 9 to 11, inclusive of the reference numerical values ​​9, 10, and 11. The term "about" in connection with 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%.

[0096]

[0117] As used herein, the amount of an agent described herein in the "coronary circulation of the heart" can be measured by collecting a blood sample from any vascular region of the coronary circulation of the heart (e.g., arteries, veins, including the coronary sinus) using a catheter or cannula. The amount of agent in the sample can then be determined by known means, such as bioanalytical techniques utilizing analytical instruments such as LC-MS / MS. In this manner, the amount of agent in the blood in the heart can be measured for any particular time.

[0097]

[0118] As used herein, the terms "treat" and "treatment" may refer to restoring sinus rhythm, reducing the severity and / or frequency of symptoms, eliminating symptoms and / or the underlying cause, reducing the likelihood of occurrence of symptoms and / or the underlying cause, and / or repairing damage. Thus, "treating" a patient with an active agent provided herein can include prevention of a particular condition, disease or disorder in susceptible individuals, as well as treatment of clinically symptomatic individuals.

[0098]

[0119] As used herein, "nominal amount" may refer to the amount contained within a unit dose receptacle to be administered.

[0120] As used herein, a "therapeutically effective amount" of an active agent may refer to an amount effective to achieve a desired therapeutic result. The therapeutically effective amount of a given active agent may vary with 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.

[0099]

[0121] In one embodiment, the pharmaceutical composition of the present disclosure is administered by oral inhalation. In some embodiments, "inhalation" (e.g., "oral inhalation" or "nasal inhalation") refers to a period of time that begins when the patient begins inhaling the pharmaceutical composition and ends when the patient stops inhaling the pharmaceutical composition. In some embodiments, the patient is administered the pharmaceutical agent contained in one unit dose receptacle in one inhalation, which in some cases may include inhalation administration by ventilated breathing from a period of, for example, 0.1 to 15 minutes. 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 at the described dose 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. 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 performed 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 performed for longer than 5 minutes. In some cases, each inhalation is performed 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 100 or less 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 with deep lung breaths lasting more than 1, 2, 3, or 4 seconds. In some cases, the inhalation of the antiarrhythmic pharmaceutical agent is performed with deep lung breaths lasting about 1, 2, 3, or 4 seconds.

[0100]

[0122] In some embodiments, during 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 for 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 delivering a single dose is as follows: a first inhalation of about 4-4.5 minutes, a break of about 1 minute, and a second inhalation of about 4-4.5 minutes; a first inhalation of about 4-4.5 minutes, a break of about 30 seconds, and a second inhalation of about 4-4.5 minutes; a first inhalation of about 4-4.5 minutes, a first break of about 1 minute, and a second inhalation of about 4-4.5 minutes; a second break of about 1 minute, and a third inhalation of about 4-4.5 minutes; or a first inhalation of about 4-4.5 minutes, a first break of about 30 seconds, and a second inhalation of about 4-4.5 minutes; a second break of about 30 seconds, and a third inhalation of about 4-4.5 minutes.

[0101]

[0123] In some embodiments, the subject inhales or is instructed to inhale the aerosolized pharmaceutical composition of the present disclosure by ventilating for a certain duration.In some embodiments, after inhaling the pharmaceutical composition for a first duration (e.g., about 3.5 minutes), the subject stops inhaling the aerosolized pharmaceutical composition for another duration, such as a period equivalent to the break defined above (e.g., about 1 minute), and then resumes inhaling the aerosolized pharmaceutical composition for another duration (e.g., about 3.5 minutes).In some embodiments, the subject inhales the aerosolized pharmaceutical composition for 3.5 minutes, stops inhaling the aerosolized pharmaceutical composition for about 1 minute, and then resumes inhaling the aerosolized pharmaceutical composition for another 3.5 minutes.

[0102]

[0124] In some embodiments, a subject inhales the aerosolized pharmaceutical composition of the present disclosure by ventilating. As used herein, "ventilating" may refer to inhalation and exhalation during tidal breathing. For example, ventilating may include inhaling the aerosolized pharmaceutical composition while breathing at a rate of 10-14 breaths per minute.

[0103]

[0125] As used herein, the phrase "minimum effective amount" may refer to the minimum amount of a pharmaceutical agent required to achieve an effective dose.

[0126] As used herein, "mass median diameter" or "MMD" may typically refer to, for example, the median diameter of a plurality of particles in a polydisperse particle population consisting of a range of particle sizes. 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 feeder funnel of a Sympatec RODOS dry powder dispersion unit. This can be achieved manually or by mechanical stirring from the tip of a VIBRI vibratory feeder element. The sample is dispersed into primary particles by application of pressurized air (2-3 bar), and a vacuum reduction (suction) maximized for a given dispersion pressure. The dispersed particles are probed with a 632.8 nm laser beam that intersects the dispersed particle trajectory at right angles. Laser light scattered from the particle ensemble is imaged onto a concentric array of photomultiplier tube detector elements using an inverse Fourier lens assembly. The scattered light is acquired in 5 ms time slices and the particle size distribution is back-calculated from the spatial and intensity distribution of the scattered light using a proprietary algorithm.

[0104]

[0127] As used herein, "geometric diameter" may refer to the diameter of a single particle as determined by microscopic examination, unless the context indicates otherwise.

[0128] As used herein, "mass median aerodynamic diameter" or "MMAD" may refer to the median aerodynamic diameter of a plurality of particles or particles, typically in a polydisperse population. "Aerodynamic diameter" may be the diameter of a unit density sphere that generally 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 the median aerodynamic particle or particle size distribution of aerosolized particles as determined by cascade impaction, unless the context indicates otherwise.

[0105]

[0129] A "pharmaceutically acceptable" ingredient means an ingredient that is not biologically or otherwise undesirable, e.g., an ingredient can be incorporated into a pharmaceutical formulation of the invention and administered to a patient as described herein without causing significant undesirable biological effects or adversely interacting with any of the other ingredients of the formulation in which it is included. When the term "pharmaceutically acceptable" is used to refer to an excipient, it may also mean that the ingredient has met the necessary standards of toxicological and manufacturing testing, or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0106]

[0130] The treatments provided herein may include or be suitable for parenteral injection, oral or nasal administration (e.g., oral or nasal inhalation), or nasal spray administration. As provided herein, the term "oral or nasal administration" may refer to oral inhalation, nasal inhalation, or nasal spray administration. In some embodiments, during administration by oral inhalation, the pharmaceutical agent is inhaled by the patient through the mouth and absorbed by the lungs. In some embodiments, during administration by nasal inhalation, the pharmaceutical agent is inhaled by the patient through the nose and absorbed by the nasal mucosa and / or lungs. In some embodiments, during nasal spray administration, the pharmaceutical agent is sprayed into the patient's nose and then absorbed by the nasal mucosa and / or lungs. In some embodiments, during nasal spray administration, the pharmaceutical agent is passively administered to the patient, e.g., the patient does not actively inhale the sprayed agent. In some embodiments, during nasal spray administration, the pharmaceutical agent is passively and actively administered to the patient, e.g., the agent is sprayed into the nose and then actively inhaled by the patient through the nose, at least in part.

[0107]

[0131] As used herein, "parenteral injection" may refer to administration made using a needle or an indwelling catheter, and may include, for example, intracardiac, intraarterial, intravenous, intramuscular and subcutaneous administration.

[0108]

[0132] As used herein, "QT interval" may refer to the time interval between the beginning of the QRS complex and the end of the subsequent T wave as measured by an electrocardiogram (ECG). The QT interval may vary between subjects due to factors not directly related to disease pathology or drug-related effects, including age, sex, and ventricular rate. In some embodiments, the measurement of the QT interval is based on the Bazett QT interval. c Corrected for heart rate according to =QT / (√RR) (QT c ), where RR is the interval between two successive R waves and QT is the QT interval as defined above. In some embodiments, the measurement of the QT interval is performed using the Fridericia QT c =QT / 3 √RR) and corrected for heart rate (QTc ), where RR is the interval between two successive R waves and QT is the QT interval as defined above. In some embodiments, the measurement of the QT interval is performed using the Framingham QT c Corrected for heart rate according to =QT + 0.154*(1-RR) (QT c RR = QT + 1.75*(HR-60), where HR is the heart rate in beats per minute and QT is as defined above. In some embodiments, the QT interval measurement is corrected for heart rate according to the Hodges formula Hodges[QTc=QT + 1.75*(HR-60), where HR is the heart rate in beats per minute and QT is as defined above. In some embodiments, the QT interval measurement is corrected for heart rate according to the van de Waters QT formula c Corrected for heart rate according to =QT - 0.087(RR - 1000) (QT c ), where RR is the interval between two successive R waves and QT is the QT interval as defined above. In some embodiments, the risk of torsades de pointes (TdP) in a subject is determined by a QT c In some embodiments, the subject's QT interval is evaluated according to the magnitude of the prolongation. c If is greater than 480 msec, the subject is at risk for TdP.

[0109] Route of administration. Oral or nasal inhalation.

[0133] In some embodiments of the present disclosure, a composition or formulation of a pharmaceutical agent, such as a potassium channel blocker, a class I antiarrhythmic agent, or both, is administered by inhalation. The pharmaceutical formulation can be aerosolized prior to administration or presented to the user in the form of an aerosol.

[0110]

[0134] Inhalation or intranasal spray administration routes can avoid first-pass hepatic metabolism and therefore eliminate dosing variability.Unlike oral tablets or pills, administration is independent of the metabolic pathways experienced when a drug is administered orally through the gastrointestinal tract, for example as a tablet, pill, solution or suspension, so the patient's metabolic rate may not be an issue.

[0111]

[0135] Rapid absorption of drugs from the nasal mucosa and / or lungs may achieve a rapid onset of action, potentially improved efficacy, and / or reduced dosage.

[0136] Rapid absorption rate of drugs through the lungs can be achieved due to the large surface area available in the lungs, which allows aerosols small enough to penetrate the central and peripheral regions of the lungs.In the case of nasal delivery or intranasal spray delivery, the nasal mucosa can have a relatively permeable epithelial layer and a highly vascularized subepithelial layer, which can provide direct access of drugs for absorption into the systemic circulation.As a result, the rate and extent of absorption of drugs delivered by oral or nasal administration routes can produce plasma concentration versus time profiles comparable to those of IV administration routes.

[0112]

[0137] The time of onset of action may be short. For example, the patient may have normal sinus rhythm within 20 minutes of initiation of administration, for example within 15 minutes, within 10 minutes, or within 5 minutes of initiation of administration. In some embodiments, a rapid onset of action is advantageous because the longer a patient has arrhythmia, the longer it may take to convert the patient to normal sinus rhythm.

[0113]

[0138] In some embodiments, the disclosed methods allow patients to avoid other therapies, such as ablation and / or electrical cardioversion, hi other embodiments, the methods of the present invention are used in combination with other therapies, such as before or after electrical cardioversion and / or ablation therapy.

[0114]

[0139] The pharmaceutical composition can be administered using an aerosolization device. The aerosolization device can be a nebulizer, a metered dose inhaler, a liquid dose injection device, or a dry powder inhaler. The aerosolization device can include extruding the pharmaceutical preparation through micron or submicron sized holes, followed by Rayleigh breakup into fine droplets. The pharmaceutical composition can be delivered by a nebulizer as described in WO99 / 16420, by a metered dose inhaler as described in WO99 / 16422, by a liquid dose injection 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, which are incorporated herein by reference in their entirety. Thus, the inhaler can 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.

[0115]

[0140] For example, the pharmaceutical formulation may be in a liquid solution and administered with a nebulizer, such as that disclosed in PCT WO99 / 16420, the disclosure of which is incorporated herein by reference in its entirety, to provide an aerosolized medicament that can be administered to the pulmonary airways of a patient in need thereof. Nebulizers known in the art can be readily utilized for administration of the claimed formulations. Breath-driven or breath-actuated nebulizers, as well as other types of improvements that have been developed or are to be developed, are also contemplated as being compatible with and within the scope of the formulations of the present disclosure.

[0116]

[0141] In some embodiments, the nebulizer is a breath-driven or breath-actuated nebulizer. In some embodiments, the nebulizer is a hand-held inhaler device (e.g., AeroEclipse® II Breath Actuated Nebulizer (BAN)). In some embodiments, the nebulizer has a compressed air source. In some embodiments, the nebulizer converts the liquid medicament into an aerosol. In some embodiments, the nebulizer converts the liquid medicament into an aerosol by forcing the pharmaceutical preparation through micron or submicron sized holes. In some embodiments, the nebulizer converts the liquid medicament into an aerosol so that it can be inhaled into the lungs. In some embodiments, the nebulizer is a small volume nebulizer. In some embodiments, the nebulizer is a small volume jet nebulizer. In some embodiments, the aerosolized medicament is only generated when inhaled through the device. In some embodiments, the medicament is contained in the cup between breaths or during breaks in the treatment. In some embodiments, the medicament is contained in the cup until ready for inhalation.

[0117]

[0142] A nebulizer can impart energy to a liquid pharmaceutical formulation to aerosolize the liquid and allow 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 in solution or suspended in a liquid medium.

[0118]

[0143] In one type of nebulizer that can be used in the subject methods and kits, commonly referred to as a jet nebulizer, compressed gas is forced through an orifice in a container. The compressed gas forces liquid out of a nozzle, where it can mix with the flowing gas to form aerosol droplets. The cloud of droplets can then be administered to a patient's respiratory tract.

[0119]

[0144] In another type of nebulizer that can be used in the subject methods and kits, commonly referred to as a vibrating mesh nebulizer, energy, such as mechanical energy, vibrates a mesh. This vibration of the mesh aerosolizes the liquid pharmaceutical formulation, creating an aerosol cloud that is administered to the patient's lungs. In another type of nebulizer that can be used in the subject methods and kits, atomization involves extrusion through micron or submicron sized holes followed by Rayleigh breakup into fine droplets.

[0120]

[0145] 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, Virginia, Lumiscope® Nebulizer 6600 or 6610 available from Lumiscope Company, Inc., East Brunswick, New Jersey, and Omron NE-U22 available from Omron Healthcare Co., Ltd., Kyoto, Japan. Other examples of nebulizers include devices manufactured by Medspray (Enschede, The Netherlands).

[0121]

[0146] It has been found that vibrating mesh nebulizers, such as those that form droplets without compressed gas, 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. In addition, the droplets generated when using this type of nebulizer are introduced at a low velocity, thereby reducing the possibility of the droplets being driven into undesired areas. It has been found that when using extrusion / Rayleigh jet breakup nebulizers, the droplets generated are also introduced at a low velocity, thereby reducing the possibility of the droplets being driven into undesired areas.

[0122]

[0147] In some embodiments, the nebulizers that can be used in the subject methods and kits are of the vibrating mesh type. In some embodiments, the nebulizers that can be used in the subject methods and kits are of the pressurized jet type. In some embodiments, the nebulizers that can be used in the subject methods and kits are of the extrusion / Rayleigh splitting type. In some embodiments, the nebulizers are lightweight (up to 60 g, up to 100 g, up to 200 g, up to 250 g) and nearly silent. In some embodiments, the nebulizers have a sound level of less than 35 A-weighted decibels (dBA) at 1 meter. In some embodiments, the nebulizers have a dosing cup capacity of 6 mL. In some embodiments, the nebulizers have a residual volume of less than 0.3 mL. In some embodiments, the nebulizers produce an average flow rate of 0.4 mL / min. In some embodiments, the nebulizers produce an average flow rate of 0.5 mL / min. In some embodiments, the nebulizers produce an average flow rate of 0.6 mL / min. In some embodiments, the nebulizers produce an average flow rate of 0.7 mL / min. In some embodiments, the nebulizer produces an average flow rate of 0.8 mL / min. In some embodiments, the nebulizer produces an average flow rate of 0.9 mL / min. In some embodiments, the nebulizer produces an average flow rate of 1.0 mL / min. In some embodiments, the nebulizer produces an average flow rate of 1.1 mL / min. In some embodiments, the nebulizer produces an average flow rate of 1.2 mL / min. In some embodiments, the nebulizer produces an average particle size of 3.0 μm MMAD. In some embodiments, the nebulizer produces an average particle size of 3.0 μm MMAD to 4.0 μm MMAD. In some embodiments, the nebulizer produces an average particle size of 3.0 μm MMAD. In some embodiments, the nebulizer produces an average particle size of 3.0 μm MMAD to 5.0 μm MMAD. In some embodiments, the nebulizer produces an average particle size of 3.0 μm MMAD. In some embodiments, the nebulizer produces a mean particle size of between 3.0 μm MMAD and 6.0 μm MMAD.

[0123]

[0148] Yet another type of nebulizer that can be used in the subject methods and kits uses ultrasound to directly vibrate and aerosolize the pharmaceutical formulation.

[0149] Alternatively or additionally, the present disclosure can include a dry powder inhaler.Particular variations of dry powder aerosolization devices are described in U.S. Patent Nos. 4,069,819 and 4,995,385, which are incorporated herein by reference in their entirety.Another useful device having a chamber sized and configured to receive a capsule such that the capsule is perpendicular to the direction of inhalation is described in U.S. Patent No. 3,991,761, which is incorporated herein by reference in its entirety.Also, the capsule can be punctured at both ends by a puncturing mechanism, as described in U.S. Patent Nos. 3,991,761 and 5,619,985, which are incorporated herein by reference in their entirety.In another variation, the chamber can receive a capsule in such a manner that air flows through the capsule, as described, for example, in U.S. Patent Nos. 4,338,931 and 5,619,985, which are incorporated herein by reference in their entirety. In another variation, aerosolization of the pharmaceutical composition can be achieved by pressurized gas flowing through an inlet, for example as described in U.S. Patent Nos. 5,458,135, 5,785,049 and 6,257,233, or by propellants as described in WO00 / 72904 and U.S. Patent No. 4,114,615, which are incorporated herein by reference. These types of dry powder inhalers are commonly referred to as active dry powder inhalers.

[0124]

[0150] Other dry powder inhalers include those available from Boehringer Ingelheim (e.g., Respimat inhaler), Hovione (e.g., FlowCaps inhaler), Plastiape (e.g., Osmohaler inhaler) and MicroDose. The present invention may also utilize condensation aerosol devices available from Alexza, Mountain View, Calif. Yet another useful inhaler is disclosed in WO2008 / 051621, which is incorporated herein by reference in its entirety.

[0125]

[0151] The pharmaceutical formulations disclosed herein can also be administered to the lungs of a patient by aerosolization, such as by 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 can be utilized for administration of the claimed pharmaceutical compositions. Breath-driven or breath-actuated MDIs and pressurized MDIs (pMDIs), including other types of improvements that have been developed or will be developed, are also compatible with the formulations of the present disclosure and are therefore contemplated as being within its scope.

[0126]

[0152] It is understood that, in conjunction with DPIs, MDIs and nebulizers, the formulations of one or more embodiments of the present invention can be used with liquid dose injection or LDI technology, for example, as disclosed in WO99 / 16421, the entirety of which is incorporated herein by reference. Liquid dose injection includes administering the formulation directly to the lungs. For LDI, the formulations are preferably used with partial or total liquid ventilation. Furthermore, one or more embodiments of the present invention may further include introducing a therapeutically beneficial amount of a physiologically acceptable gas (such as nitric oxide or oxygen) into the pharmaceutical microdispersion before, during or after administration.

[0127]

[0153] The pharmaceutical composition of one or more embodiments of the present disclosure may have improved emitted dose efficiency. Thus, a variety of aerosolization devices and techniques can be used to deliver high doses of the pharmaceutical composition.

[0128]

[0154] The emitted dose (ED) of the particles of the invention 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%. Administered by intranasal spray.

[0129]

[0155] In another aspect of the disclosure, the disclosure relates to intranasal spray administration of a pharmaceutical composition for the treatment of a subject suffering from a cardiac condition, such as cardiac arrhythmia, e.g., atrial arrhythmia. A nasal spray device can be used for the purpose of spraying a pharmaceutical formulation in aerosol form into the nasal cavity. A device useful for nasal administration can be a small, rigid bottle to which a metered-dose sprayer is attached. In some embodiments, a metered dose is delivered by drawing the pharmaceutical solution described herein into a chamber of a defined volume, the chamber having an opening dimensioned to aerosolize the aerosol formulation by forming a spray when the liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical agent, e.g., a potassium channel blocker, a class I antiarrhythmic agent, or both. In some embodiments, the chamber is a piston configuration. Such devices are commercially available. Alternatively, a plastic squeeze bottle with an opening or aperture dimensioned to aerosolize the aerosol formulation by forming a spray when squeezed. The opening can be found in the top of the bottle, which is generally tapered to partially fit into the nasal passages for efficient administration of the aerosol formulation. Nasal inhalers can provide a metered amount of an aerosol formulation to administer a measured dose of a drug.

[0130]

[0156] In some embodiments, Aptar / Pfeiffer Unitdose delivery device is used to deliver the disclosed compositions. Other devices that can be used according to the present disclosure include, but are not limited to, those described in Djupesland, Drug Deliv Transl Res. (2013) Feb; 3 (1). In some embodiments, the nasal spray device delivers a volume of about 50 μL, about 60 μL, about 80 μL, about 100 μL, about 150 μL, about 200 μL, about 300 μL, about 400 μL, about 500 μL, about 600 μL, about 700 μL, about 800 μL per spray. In some embodiments, the nasal spray device is configured to deliver the pharmaceutical formulation in more than one spray, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 or even more sprays. Direct product contact parts of the container closure may include containers (glass vials), plungers (stoppers) manufactured using FIOLAX glass by MGLAS or NUOVA OMPI.

[0131]

[0157] The nasal spray device can be intended for use by both medical and non-medical personnel. The device may have one or more features selected from single use, needle-free, ready to use, disposable, and combinations thereof. The device may be configured to administer the disclosed compositions as one spray per nostril. The device may include one or more unit dose containers, each container delivering about one 100 μL spray. In other embodiments, the device may be modified to deliver a volume of about 50 μL to about 800 μL sprays, and may utilize solutions of various concentrations. Any nasal spray device known in the art may be used to deliver the nasal sprays and compositions described herein. In one embodiment, the nasal spray device is an Aptar / Pfeiffer Unitdose device. The nasal sprays provided herein may include a preservative solution having a pH and osmolality suitable for nasal administration. Similarly, the nasal sprays may be prepared as a sterile solution without antimicrobial preservatives.

[0132] Administer intravenously.

[0158] The potassium channel blocker may also be administered by parenteral route, which may include intravenous injection. The intravenous administration of the potassium channel blocker may also be accompanied by the administration of a sodium channel blocker (e.g., flecainide). The sodium channel blocker may be administered before, after, or in parallel with the intravenous administration of the potassium channel blocker. The sodium channel blocker may be administered by inhalation, intravenous injection, or as a tablet, pill, solution, or suspension for oral ingestion. The intravenous administration of the potassium channel blocker in parallel with the administration of the sodium channel blocker may include the administration of a fixed dose combination of the potassium channel blocker and the sodium channel blocker (e.g., ibutilide and flecainide) formulated for intravenous injection.

[0133] Oral route

[0159] The potassium channel blocker may also be administered by oral route. Oral administration may include, but is not limited to, pills, tablets, capsules or syrups. Oral administration of the potassium channel blocker may also be accompanied by administration of a sodium channel blocker (e.g., flecainide). The sodium channel blocker may be administered before, after or in parallel with intravenous administration of the potassium channel blocker. The sodium channel blocker may be administered by inhalation, intravenous injection, or in tablets, pills, solutions or suspensions for oral ingestion. Oral administration of the potassium channel blocker in parallel with administration of the sodium channel blocker may include administration of a fixed dose combination of the potassium channel blocker and the sodium channel blocker (e.g., ibutilide / dofetilide and flecainide) formulated for oral administration.

[0134]

[0160] The potassium channel blocker and the sodium channel blocker can be combined in a single oral administration, such as a tablet. In some embodiments, the tablet comprises a potassium channel blocker and a sodium channel blocker. In some embodiments, the tablet comprises ibutilide and flecainide, flecainide and dofetilide, flecainide and sotalol, mexiletine and sotalol, mexiletine and dofetilide, or mexiletine and ibutilide.

[0135]

[0161] Oral administration (e.g., tablets, capsules, etc.) may be formulated to regulate the release and absorption of the drug upon administration to a subject. Tablets may be formulated, but are not limited to, for timed release, controlled delivery, controlled release, delayed release, long acting, long acting release, modified release, extended release, sustained action, extended release, timed release, immediate release, extended release, or sustained release.

[0136] Dosing regimen.

[0162] The potassium channel blockers provided herein, e.g., Class IIIa antiarrhythmic agents, may be co-administered with another antiarrhythmic therapy, e.g., a sodium channel blocker, which may be, e.g., a Class I antiarrhythmic agent. For example, a patient may self-administer a sodium channel blocker (e.g., flecainide) within minutes (e.g., 5-15 minutes) of self-administering a potassium channel blocker, e.g., ibutilide or dofetilide.

[0137]

[0163] In some embodiments, the administration of the potassium channel blocker is performed in parallel with the administration of the sodium channel blocker, for example, a class I antiarrhythmic agent. For example, an aerosolization device configured to simultaneously deliver two separate drug formulations can be used. In such a device, for example, two drug formulations, including a potassium channel blocker and a class I antiarrhythmic agent, respectively, can be received in two separate receptacles, and the device can form an aerosol containing both of the two formulations, thereby ensuring that the subject inhales the two drugs simultaneously. In another example, a combination pharmaceutical composition is provided that includes two drugs, for example, both a potassium channel blocker and a class I antiarrhythmic agent. In such a case, the combination composition is administered to the subject by intravenous injection, inhalation, or intranasal spray administration, thereby achieving the therapeutic effect of the co-administration of two active agents.

[0138]

[0164] The methods provided herein may include administration of an antiarrhythmic agent, such as a class I antiarrhythmic agent, for induction of cardioversion. The methods provided herein may further include application of electrical current to induce cardioversion. Cardioversion provided herein may include both pharmaceutical and electrical.

[0139]

[0165] The pharmaceutical composition can be administered to a patient as needed.For example, the method, kit and composition may be particularly used in treating a subject experiencing a cardiac condition, such as cardiac arrhythmia, for example, atrial arrhythmia.In some embodiments, the subject is administered the treatment described herein when the subject is experiencing atrial arrhythmia.In some embodiments, the treatment, for example, the combined inhalation therapy with both a potassium channel blocker and a class I antiarrhythmic drug, 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.

[0140]

[0166] In some embodiments, the treatment provided herein is provided to the subject more than once as needed.For example, the present invention may involve follow-up inhalation if cardioversion does not occur after first inhalation.In some cases, if cardioversion does not occur within 30 minutes after first inhalation, follow-up dose is higher, lower or the same as first dose.

[0141]

[0167] Medication can be guided by how the patient feels. Additionally or alternatively, medication can be guided by using a portable / mobile ECG device. For example, medication can be guided by using a wearable device such as a Holter monitor, Apple Watch, AliveCor® KardiaMobile® 6L, QardioCore® ECG, fitbit® charge5 or Oura® Ring.

[0142]

[0168] Mg suitable for the disclosed methods, kits and compositions 2+ The amount of the source may be, for example, about 50 mg to about 3000 mg of Mg. +2 cations, for example, about 50 mg to about 2000 mg, about 100 mg to about 2000 mg, about 200 mg to about 2000 mg, about 300 mg to about 2000 mg, about 500 mg to about 2000 mg, 50 mg to about 1000 mg, about 100 mg to about 1000 mg, about 200 mg to about 1000 mg, about 300 mg to about 1000 mg, or about 500 mg to about 1000 mg of Mg 2+ The disclosed methods, kits and compositions may be suitable for delivering cations to a subject. 2+ The amount of the source can be, for example, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 100 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or about 2000 mg of Mg. 2+ This may be sufficient to deliver the cations to the subject.

[0143]

[0169] The amount of magnesium sulfate for the disclosed methods, kits, and compositions can be, for example, about 1 mg to about 10,000 mg of magnesium sulfate, for example, about 1 mg to about 8000 mg, about 1 mg to about 6000 mg, about 1 mg to about 4000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 1 mg to about 700 mg, about 1 mg to about 600 mg, about 1 mg to about 500 mg, about 5 mg to about 6000 mg, about 5 mg to about 4000 mg, about 5 mg to about 2000 mg, about 5 mg to about 1000 mg, about 1000 mg to about 10 The amount of magnesium sulfate may be in the range of about 2,000 mg, about 2000 mg to about 10,000 mg, about 3000 mg to about 10,000 mg, about 4000 mg to about 10,000 mg, about 5000 mg to about 10,000 mg, about 5 mg to about 700 mg, about 5 mg to about 600 mg, about 5 mg to about 500 mg, about 20 mg to about 6000 mg, about 20 mg to about 4000 mg, about 20 mg to about 2000 mg, about 20 mg to about 1000 mg, about 20 mg to about 700 mg, about 20 mg to about 600 mg, or about 20 mg to about 500 mg. Amounts of magnesium sulfate suitable for the disclosed methods, kits, and compositions can be, for example, about 0.5 g, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, or about 10 g.

[0144]

[0170] Amounts of magnesium sulfate suitable for the disclosed methods, kits, and compositions may be in the range of, for example, about 1 mg per kilogram of body weight of the subject (mg / kg) to about 200 mg / kg, e.g., about 1 mg / kg to about 150 mg / kg, about 1 mg / kg to about 150 mg / kg, about 10 mg / kg to about 150 mg / kg, about 20 mg / kg to about 150 mg / kg, about 50 mg / kg to about 150 mg / kg, about 100 mg / kg to about 150 mg / kg, about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 80 mg / kg, about 1 mg / kg to about 60 mg / kg, about 1 mg / kg to about 40 mg / kg, or about 1 mg / kg to about 20 mg / kg. Amounts of magnesium sulfate suitable for the disclosed methods, kits and compositions can be, for example, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 75 mg / kg, or about 100 mg / kg.

[0145]

[0171] The amount of ibutilide or a pharma- ceutically acceptable salt thereof (e.g., ibutilide fumarate) suitable for the disclosed methods, kits, and compositions is, for example, about 0.002 mg to 100 mg, for example, about 0.002 mg to about 50 mg, about 0.002 mg to about 25 mg, about 0.002 mg to about 15 mg, about 0.002 mg to about 10 mg, about 0.002 mg to about 5 mg, about 0.002 mg to about 2 mg, about 0.002 mg to about 1 mg, about 0.01 mg to about 50 mg, about 0.01 mg to about 25 mg, about 0.01 mg to about 15 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 2 mg, about 0.01 mg to about 1 The dosage may be in the range of about 0.01 mg to about 0.5 mg, about 0.05 mg to about 50 mg, about 0.05 mg to about 25 mg, about 0.05 mg to about 10 mg, about 0.05 mg to about 5 mg, about 0.05 mg to about 1 mg, about 0.05 mg to about 0.5 mg, about 0.05 mg to about 0.1 mg, about 0.01 mg to about 0.5 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 25 mg, about 0.25 mg to about 10 mg, about 0.25 mg to about 5 mg, about 0.25 mg to about 1 mg, about 0.25 mg to about 0.5 mg, or about 0.25 mg to about 0.1 mg of ibutilide or a pharma- ceutically acceptable salt thereof. The amount of ibutilide or a pharma- ceutically acceptable salt thereof suitable for the disclosed methods, kits, and compositions may be, for example, about 0.002 mg, about 0.01 mg, about 0.02 mg, about 0.05 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, or about 2 mg.

[0146]

[0172] An amount of ibutilide or a pharma- ceutically acceptable salt thereof (e.g., ibutilide fumarate) suitable for the disclosed methods, kits, and compositions may be in the range of, for example, about 0.0001 mg (mg / kg) to about 5 mg / kg per kilogram of the subject's body weight, e.g., about 0.001 mg / kg to about 0.25 mg / kg, about 0.005 mg / kg to about 0.25 mg / kg, about 0.01 mg / kg to about 0.25 mg / kg, about 0.1 mg / kg to about 0.25 mg / kg, about 0.001 mg / kg to about 0.2 mg / kg, about 0.001 mg / kg to about 0.1 mg / kg, about 0.001 mg / kg to about 0.05 mg / kg, about 0.001 mg / kg to about 0.01 mg / kg, or about 0.001 mg / kg to about 0.005 mg / kg. The amount of ibutilide or a pharma- ceutically acceptable salt thereof (e.g., ibutilide fumarate) suitable for the disclosed methods, kits, and compositions may be, for example, about 0.0001 mg / kg, about 0.0005 mg / kg, about 0.001 mg / kg, about 0.005 mg / kg, about 0.01, about 0.05 mg / kg, about 0.1 mg / kg, or about 0.2 mg / kg.

[0147]

[0173] The amount of dofetilide or a pharma- ceutically acceptable salt suitable for the disclosed methods, kits, and compositions is, for example, about 0.002 mg to 100 mg, for example, about 0.002 mg to about 50 mg, about 0.002 mg to about 25 mg, about 0.002 mg to about 15 mg, about 0.002 mg to about 10 mg, about 0.002 mg to about 5 mg, about 0.002 mg to about 2 mg, about 0.002 mg to about 1 mg, about 0.01 mg to about 50 mg, about 0.01 mg to about 25 mg, about 0.01 mg to about 15 mg, about 0.01 mg to about 5 mg, about 0.01 mg to about 2 mg, about 0.01 mg to about 1 ...1 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 10 mg, about 0.01 mg to about 10 The dose range may be from about 0.5 mg to about 0.5 mg, from about 0.05 mg to about 50 mg, from about 0.05 mg to about 25 mg, from about 0.05 mg to about 10 mg, from about 0.05 mg to about 5 mg, from about 0.05 mg to about 1 mg, from about 0.05 mg to about 0.5 mg, from about 0.05 mg to about 0.1 mg, from about 0.01 mg to about 0.5 mg, from about 0.25 mg to about 50 mg, from about 0.25 mg to about 25 mg, from about 0.25 mg to about 10 mg, from about 0.25 mg to about 5 mg, from about 0.25 mg to about 1 mg, from about 0.25 mg to about 0.5 mg, or from about 0.25 mg to about 0.1 mg of dofetilide or a pharma- ceutically acceptable salt thereof. The amount of dofetilide or a pharma- ceutically acceptable salt thereof suitable for the disclosed methods, kits, and compositions may be, for example, about 0.002 mg, about 0.01 mg, about 0.02 mg, about 0.05 mg, about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 1.5 mg, or about 2 mg.

[0148]

[0174] The amount of dofetilide or a pharma- ceutically acceptable salt thereof suitable for the disclosed methods, kits, and compositions can be, for example, about 1 μg per kilogram of the subject's body weight (μg / kg) to about 10 μg / kg, for example, about 1 μg / kg to about 2 μg / kg, about 1 μg / kg to about 3 μg / kg, about 1 μg / kg to about 4 μg / kg, about 1 μg / kg to about 5 μg / kg, about 1 μg / kg to about 6 μg / kg, about 1 μg / kg to about 7 μg / kg, about 1 μg / kg to about 8 μg / kg, about 1 μg / kg to about 10 μg / kg, or about 1 μg / kg to about 20 μg / kg. g ~ approx. 9 μg / kg, approx. 1 μg / kg ~ approx. 10 μg / kg, approx. 2 μg / kg ~ approx. 3 μg / kg, approx. 2 μg / kg ~ approx. 4 μg / kg, approx. 2 μg / kg ~ approx. 5 μg / kg, approx. 2 μg / kg ~ approx. kg, about 2μg / kg to about 8μg / kg, about 2μg / kg to about 9μg / kg, about 2μg / kg to about 10μg / kg, about 3μg / kg to about 4μg / kg, about 3μg / kg to about 5μg / kg, about 3μg / kg to about 6μg / kg, about 3μg / kg~about 7μg / kg, about 3μg / kg~about 8μg / kg, about 3μg / kg~about 9μg / kg, about 3μg / kg~about 10μg / kg, about 4μg / kg~about 5μg / kg, about 4μg / kg~about 6μg / kg, about 4μg / kg~about 7μ g / kg, about 4μg / kg to about 8μg / kg, about 4μg / kg to about 9μg / kg, about 4μg / kg to about 10μg / kg, about 5μg / kg to about 6μg / kg, about 5μg / kg to about 7μg / kg, about 5μg / kg to about 8μg / kg, about 5 The range may be from about μg / kg to about 9 μg / kg, from about 5 μg / kg to about 10 μg / kg, from about 6 μg / kg to about 7 μg / kg, from about 6 μg / kg to about 8 μg / kg, from about 6 μg / kg to about 9 μg / kg, from about 6 μg / kg to about 10 μg / kg, from about 7 μg / kg to about 8 μg / kg, from about 7 μg / kg to about 9 μg / kg, from about 7 μg / kg to about 10 μg / kg, from about 8 μg / kg to about 9 μg / kg, from about 8 μg / kg to about 10 μg / kg, or from about 9 μg / kg to about 10 μg / kg. The amount of dofetilide or a pharma- ceutically acceptable salt suitable for the disclosed methods, kits, and compositions may be, for example, about 1 μg / kg, about 2 μg / kg, about 3 μg / kg, about 4 μg / kg, about 5 μg / kg, about 6 μg / kg, about 7 g / kg, about 8 g / kg, about 9 μg / kg, or about 10 μg / kg.

[0149]

[0175] The concentration of dofetilide or a pharma- ceutically acceptable salt thereof suitable for the disclosed methods, kits and compositions may range, for example, from about 1 μg / mL to about 40 μg / mL. In some embodiments, the concentration of dofetilide is from about 1 μg / mL to about 40 μg / mL. In some embodiments, the concentration of dofetilide is at least about 1 μg / mL. In some embodiments, the concentration of dofetilide is up to about 40 μg / mL. In some embodiments, the concentration of dofetilide is from about 1 μg / mL to about 2 μg / mL, from about 1 μg / mL to about 3 μg / mL, from about 1 μg / mL to about 4 μg / mL, from about 1 μg / mL to about 5 μg / mL, from about 1 μg / mL to about 10 μg / mL, from about 1 μg / mL to about 15 μg / mL, from about 1 μg / mL to about 20 μg / mL, from about 1 μg / mL to about 25 μg / mL, from about 1 μg / mL to about 30 μg / mL, from about 1 μg / mL to about 35 μg / mL, from about 1 μg / mL to about 4 0μg / mL, about 2μg / mL to about 3μg / mL, about 2μg / mL to about 4μg / mL, about 2μg / mL to about 5μg / mL, about 2μg / mL to about 10μg / mL, about 2μg / mL to about 15μg / mL, about 2μg / mL to about 2 0μg / mL, approximately 2μg / mL to approximately 25μg / mL, approximately 2μg / mL to approximately 30μg / mL, approximately 2μg / mL to approximately 35μg / mL, approximately 2μg / mL to approximately 40μg / mL, approximately 3μg / mL to approximately 4μg / mL, approximately 3μg / mL to approximately 5μg / mL, about 3μg / mL to about 10μg / mL, about 3μg / mL to about 15μg / mL, about 3μg / mL to about 20μg / mL, about 3μg / mL to about 25μg / mL, about 3μg / mL to about 30μg / mL, about 3μg / mL ~35μg / mL, approximately 3μg / mL~approximately 40μg / mL, approximately 4μg / mL~approximately 5μg / mL, approximately 4μg / mL~approximately 10μg / mL, approximately 4μg / mL~approximately 15μg / mL, approximately 4μg / mL~approximately 20μg / mL, approximately 4μg / m L ~ about 25μg / mL, about 4μg / mL - about 30μg / mL, about 4μg / mL - about 35μg / mL, about 4μg / mL - about 40μg / mL, about 5μg / mL - about 10μg / mL, about 5μg / mL - about 15μg / mL, about 5μ g / mL~about 20μg / mL, about 5μg / mL~about 25μg / mL, about 5μg / mL~about 30μg / mL, about 5μg / mL~about 35μg / mL, about 5μg / mL~about 40μg / mL, about 10μg / mL~about 15μg / mL,Approximately 10μg / mL to approximately 20μg / mL, approximately 10μg / mL to approximately 25μg / mL, approximately 10μg / mL to approximately 30μg / mL, approximately 10μg / mL to approximately 35μg / mL, approximately 10μg / mL to approximately 40μg / mL, approximately 15μg / mL to about 20μg / mL, about 15μg / mL to about 25μg / mL, about 15μg / mL to about 30μg / mL, about 15μg / mL to about 35μg / mL, about 15μg / mL to about 40μg / mL, about 20 μg / mL ~ approx. 25 μg / mL, approx. 20 μg / mL ~ approx. 30 μg / mL, approx. 20 μg / mL ~ approx. 35 μg / mL, approx. 20 μg / mL ~ approx. 40 μg / mL, approx. 25 μg / mL ~ approx. 30 μg / mL, approx. 25 μg / mL ~ approx. g / mL to about 35 μg / mL, about 25 μg / mL to about 40 μg / mL, about 30 μg / mL to about 35 μg / mL, about 30 μg / mL to about 40 μg / mL, or about 35 μg / mL to about 40 μg / mL. ,

[0150]

[0176] The amount of sotalol or a pharma- ceutically acceptable salt suitable for the disclosed methods, kits, and compositions may be, for example, in the range of about 0.002 mg to 200 mg, e.g., about 0.002 mg to about 200 mg. In some embodiments, it is at least about 0.002 mg. In some embodiments, it is up to about 200 mg. In some embodiments, it is about 0.002 mg to about 1 mg, about 0.002 mg to about 5 mg, about 0.002 mg to about 10 mg, about 0.002 mg to about 25 mg, about 0.002 mg to about 50 mg, about 0.002 mg to about 100 mg, about 0.002 mg to about 125 mg, about 0.002 mg to about 150 mg, about 0.002 mg to about 175 mg, about 0.002 mg to about 200 mg, about 1 mg to about 5 mg, about 1 mg to about 10 mg. g, about 1 mg to about 25 mg, about 1 mg to about 50 mg, about 1 mg to about 100 mg, about 1 mg to about 125 mg, about 1 mg to about 150 mg, about 1 mg to about 175 mg, about 1 mg to about 200 mg, about 5 mg to about 10 mg, about 5 mg to about 25 mg, about 5 mg to about 50 mg, about 5 mg to about 100 mg, about 5 mg to about 125 mg, about 5 mg to about 150 mg, about 5 mg to about 175 mg, about 5 mg to about 200 mg, about 10 mg to about 2 5mg, about 10mg to about 50mg, about 10mg to about 100mg, about 10mg to about 125mg, about 10mg to about 150mg, about 10mg to about 175mg, about 10mg to about 200mg, about 25mg to about 50mg , about 25 mg to about 100 mg, about 25 mg to about 125 mg, about 25 mg to about 150 mg, about 25 mg to about 175 mg, about 25 mg to about 200 mg, about 50 mg to about 100 mg, about 50 mg to about 125 mg, about 50 mg to about 150 mg, about 50 mg to about 175 mg, about 50 mg to about 200 mg, about 100 mg to about 125 mg, about 100 mg to about 150 mg, about 100 mg to about 175 mg, about 100 mg to about 200 mg, about 125 mg to about 150 mg, about 125 mg to about 175 mg, about 125 mg to about 200 mg, about 150 mg to about 175 mg, about 150 mg to about 200 mg, or about 175 mg to about 200 mg.

[0151]

[0177] The amount of sotalol or a pharma- ceutically acceptable salt thereof suitable for the disclosed methods, kits, and compositions can be, for example, about 1 μg (mg / kg) to about 10 mg / kg per kilogram of the subject's body weight, e.g., about 1 mg / kg to about 2 mg / kg, about 1 mg / kg to about 3 mg / kg, about 1 mg / kg to about 4 mg / kg, about 1 mg / kg to about 5 mg / kg, about 1 mg / kg to about 6 mg / kg, about 1 mg / kg to about 7 mg / kg, about 1 mg / kg to about 8 mg / kg, about 1 mg / kg to about 9 mg / kg, about 1 mg / kg to about 20 mg / kg, about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 60 mg / kg, about 1 mg / kg to about 70 mg / kg, about 1 mg / kg to about 80 mg / kg, about 1 mg / kg to about 90 mg / kg, about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 120 mg / kg, about 1 mg / kg to about 140 mg / kg, about 1 mg / kg to about 150 mg / kg, about 1 mg / kg to about 160 mg / kg, about 1 mg / kg to about 170 mg / kg, about 1 mg / kg to about 180 mg / kg, about 1 mg / kg to about 190 mg / kg, about 1 mg / kg to about 200 mg / kg, about 1 mg / kg to about 210 mg / kg, about 1 mg / kg to about 220 mg / kg, about 1 mg / kg to about 230 mg / kg, about 1 mg / kg to about 250 mg / kg, about Approximately 9 mg / kg, approximately 1 mg / kg to approximately 10 mg / kg, approximately 2 mg / kg to approximately 3 mg / kg, approximately 2 mg / kg to approximately 4 mg / kg, approximately 2 mg / kg to approximately 5 mg / kg, approximately 2 mg / kg to approximately 6 mg / kg, approximately 2 mg / kg to approximately 7 mg / k g, about 2 mg / kg to about 8 mg / kg, about 2 mg / kg to about 9 mg / kg, about 2 mg / kg to about 10 mg / kg, about 3 mg / kg to about 4 mg / kg, about 3 mg / kg to about 5 mg / kg, about 3 mg / kg to about 6 mg / kg, about 3 mg / kg kg ~ approx. 7 mg / kg, approx. 3 mg / kg ~ approx. 8 mg / kg, approx. 3 mg / kg ~ approx. 9 mg / kg, approx. 3 mg / kg ~ approx. 10 mg / kg, approx. 4 mg / kg ~ approx. 5 mg / kg, approx. 4 mg / kg ~ approx. 6 mg / kg, approx. 4 mg / kg ~ approx. 7 m g / kg, about 4 mg / kg to about 8 mg / kg, about 4 mg / kg to about 9 mg / kg, about 4 mg / kg to about 10 mg / kg, about 5 mg / kg to about 6 mg / kg, about 5 mg / kg to about 7 mg / kg, about 5 mg / kg to about 8 mg / kg, about 5 The amount of sotalol or a pharmacologic acceptable salt suitable for the disclosed methods, kits, and compositions may be, for example, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 ...

[0152]

[0178] The concentration of sotalol or a pharma- ceutically acceptable salt thereof suitable for the disclosed methods, kits, and compositions may range, for example, from about 1 mg / mL to about 40 mg / mL. In some embodiments, the concentration of sotalol is at least about 1 mg / mL. In some embodiments, the concentration of sotalol is up to about 40 mg / mL. In some embodiments, the concentration of sotalol is about 1 mg / mL to about 2 mg / mL, about 1 mg / mL to about 3 mg / mL, about 1 mg / mL to about 4 mg / mL, about 1 mg / mL to about 5 mg / mL, about 1 mg / mL to about 10 mg / mL, about 1 mg / mL to about 15 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 25 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 35 mg / mL, about 1 mg / mL to about 40 mg / mL, about 2 mg / mL ~3 mg / mL, approximately 2 mg / mL ~ approximately 4 mg / mL, approximately 2 mg / mL ~ approximately 5 mg / mL, approximately 2 mg / mL ~ approximately 10 mg / mL, approximately 2 mg / mL ~ approximately 15 mg / mL, approximately 2 mg / mL ~ approximately 20 mg / mL, approximately 2 mg / mL ~ approximately 25 mg / mL, about 2 mg / mL to about 30 mg / mL, about 2 mg / mL to about 35 mg / mL, about 2 mg / mL to about 40 mg / mL, about 3 mg / mL to about 4 mg / mL, about 3 mg / mL to about 5 mg / mL, about 3 mg / mL to about 10 mg / mL, about 3 m g / mL~about 15mg / mL, about 3mg / mL~about 20mg / mL, about 3mg / mL~about 25mg / mL, about 3mg / mL~about 30mg / mL, about 3mg / mL~about 35mg / mL, about 3mg / mL~about 40mg / mL, about 4mg / mL ~5mg / mL, 4mg / mL~10mg / mL, 4mg / mL~15mg / mL, 4mg / mL~20mg / mL, 4mg / mL~25mg / mL, 4mg / mL~30mg / mL, 4mg / mL~35m g / mL, approximately 4 mg / mL to approximately 40 mg / mL, approximately 5 mg / mL to approximately 10 mg / mL, approximately 5 mg / mL to approximately 15 mg / mL, approximately 5 mg / mL to approximately 20 mg / mL, approximately 5 mg / mL to approximately 25 mg / mL, approximately 5 mg / mL to approximately 30 mg / mL , about 5 mg / mL to about 35 mg / mL, about 5 mg / mL to about 40 mg / mL, about 10 mg / mL to about 15 mg / mL, about 10 mg / mL to about 20 mg / mL, about 10 mg / mL to about 25 mg / mL, about 10 mg / mL to about 30 mg / mL,About 10 mg / mL to about 35 mg / mL, about 10 mg / mL to about 40 mg / mL, about 15 mg / mL to about 20 mg / mL, about 15 mg / mL to about 25 mg / mL, about 15 mg / mL to about 30 mg / mL, about 15 mg / mL to about 35 mg / mL, about 15 mg / mL to about 40 mg / mL, about 20 mg / mL to about 25 mg / mL, about 20 mg / mL to about 30 mg / mL, about 20 mg / mL to about 35 mg / mL, about 20 mg / mL to about 40 mg / mL, about 25 mg / mL to about 30 mg / mL, about 25 mg / mL to about 35 mg / mL, about 25 mg / mL to about 40 mg / mL, about 30 mg / mL to about 35 mg / mL, about 30 mg / mL to about 40 mg / mL, or about 35 mg / mL to about 40 mg / mL.

[0153]

[0179] The amount of flecainide or a pharma- ceutically acceptable salt thereof (e.g., flecainide acetate) suitable for the disclosed methods, kits, and compositions may be in the range of, for example, about 1 mg to 400 mg, e.g., about 1 mg to 300 mg, about 5 mg to about 300 mg, about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 140 mg, about 5 mg to about 120 mg, about 5 mg to about 100 mg, about 5 mg to about 80 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, or about 5 mg to about 20 mg. The amount of flecainide or a pharma- ceutically acceptable salt thereof (e.g., flecainide acetate) suitable for the disclosed methods, kits, and compositions may be, for example, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.

[0154]

[0180] An amount of ibutilide or a pharma- ceutically acceptable salt thereof (e.g., ibutilide acetate) suitable for the disclosed methods, kits, and compositions may be, for example, about 0.01 mg (mg / kg) to about 3 mg / kg per kilogram of the subject's body weight, e.g., about 0.05 mg / kg to about 2 mg / kg, about 0.05 mg / kg to about 1.5 mg / kg, about 0.05 mg / kg to about 1 mg / kg, about 0.05 mg / kg to about 0.5 mg / kg, about 0.05 mg / kg to about 0.25 mg / kg, about 0.05 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 2 mg / kg, about 0.1 mg / kg to about 1.5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, or about 0.1 mg / kg to about 0.25 mg / kg. The amount of ibutilide or a pharma- ceutically acceptable salt thereof (e.g., ibutilide acetate) suitable for the disclosed methods, kits, and compositions may be, for example, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.75 mg / kg, about 1 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, or about 2 mg / kg.

[0155]

[0181] The amount of dofetilide or a pharma- ceutically acceptable salt thereof suitable for the disclosed methods, kits, and compositions can be, for example, about 1 μg per kilogram of the subject's body weight (μg / kg) to about 10 μg / kg, for example, about 1 μg / kg to about 2 μg / kg, about 1 μg / kg to about 3 μg / kg, about 1 μg / kg to about 4 μg / kg, about 1 μg / kg to about 5 μg / kg, about 1 μg / kg to about 6 μg / kg, about 1 μg / kg to about 7 μg / kg, about 1 μg / kg to about 8 μg / kg, about 1 μg / kg to about 10 μg / kg, or about 1 μg / kg to about 20 μg / kg. g ~ approx. 9 μg / kg, approx. 1 μg / kg ~ approx. 10 μg / kg, approx. 2 μg / kg ~ approx. 3 μg / kg, approx. 2 μg / kg ~ approx. 4 μg / kg, approx. 2 μg / kg ~ approx. 5 μg / kg, approx. 2 μg / kg ~ approx. 6 μg / kg, approx. 2 μg / kg ~ approx. / kg, about 2μg / kg to about 8μg / kg, about 2μg / kg to about 9μg / kg, about 2μg / kg to about 10μg / kg, about 3μg / kg to about 4μg / kg, about 3μg / kg to about 5μg / kg, about 3μg / kg to about 6μg / kg, about 3μ g / kg~about 7μg / kg, about 3μg / kg~about 8μg / kg, about 3μg / kg~about 9μg / kg, about 3μg / kg~about 10μg / kg, about 4μg / kg~about 5μg / kg, about 4μg / kg~about 6μg / kg, about 4μg / kg~about 7μg / kg, about 4μg / kg to about 8μg / kg, about 4μg / kg to about 9μg / kg, about 4μg / kg to about 10μg / kg, about 5μg / kg to about 6μg / kg, about 5μg / kg to about 7μg / kg, about 5μg / kg to about 8μg / kg, It may be about 5 μg / kg to about 9 μg / kg, about 5 μg / kg to about 10 μg / kg, about 6 μg / kg to about 7 μg / kg, about 6 μg / kg to about 8 μg / kg, about 6 μg / kg to about 9 μg / kg, about 6 μg / kg to about 10 μg / kg, about 7 μg / kg to about 8 μg / kg, about 7 μg / kg to about 9 μg / kg, about 7 μg / kg to about 10 μg / kg, about 8 μg / kg to about 9 μg / kg, about 8 μg / kg to about 10 μg / kg, or about 9 μg / kg to about 10 μg / kg. The amount of dofetilide or a pharma- ceutically acceptable salt suitable for the disclosed methods, kits, and compositions may be, for example, about 1 μg / kg, about 2 μg / kg, about 3 μg / kg, about 4 μg / kg, about 5 μg / kg, about 6 μg / kg, about 7 μg / kg, about 8 μg / kg, about 9 μg / kg, or about 10 μg / kg.

[0156]

[0182] An amount of sotalol or a pharma- ceutically acceptable salt thereof suitable for the disclosed methods, kits, and compositions may be, for example, about 0.01 mg (mg / kg) to about 3 mg / kg per kilogram of the subject's body weight, e.g., about 0.05 mg / kg to about 2 mg / kg, about 0.05 mg / kg to about 1.5 mg / kg, about 0.05 mg / kg to about 1 mg / kg, about 0.05 mg / kg to about 0.5 mg / kg, about 0.05 mg / kg to about 0.25 mg / kg, about 0.05 mg / kg to about 0.1 mg / kg, about 0.1 mg / kg to about 2 mg / kg, about 0.1 mg / kg to about 1.5 mg / kg, about 0.1 mg / kg to about 1 mg / kg, about 0.1 mg / kg to about 0.5 mg / kg, or about 0.1 mg / kg to about 0.25 mg / kg. The amount of sotalol or a pharma- ceutically acceptable salt thereof suitable for the disclosed methods, kits, and compositions may be, for example, about 0.01 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.25 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.75 mg / kg, about 1 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, or about 2 mg / kg.

[0157] Indications and Targeted Use.

[0183] The examples of 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), permanent atrial fibrillation, permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter, and isolated atrial fibrillation.In some embodiments, the methods, compositions and kits provided herein are used to treat subjects suffering from atrial arrhythmias, such as atrial fibrillation.Examples of atrial arrhythmias can include, for example, paroxysmal atrial fibrillation and permanent atrial fibrillation.

[0158]

[0184] Therefore, the pharmaceutical composition according to some examples of the present disclosure can be used to treat a wide range of patients.The patient suitable for receiving the treatment described herein is any mammalian patient in need thereof, and preferably such mammal is human.Examples of subjects include, but are not limited to, pediatric patients, adult patients, and geriatric patients.In some embodiments, the composition is intended only as a treatment for rapid resolution of symptoms and restoration of normal sinus rhythm, and is not interpreted as a prophylactic drug, e.g., when the patient is well, no drug is needed, which can increase the benefit-risk ratio and overall safety of treatment by focusing on sporadic or intermittent dosing, and reducing disabling symptoms and restoring sinus rhythm only when necessary.

[0159]

[0185] 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 embodiments, the inhaled dose is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% of its normal intravenous dose. In some embodiments, the inhaled dose 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 dose.

[0160]

[0186] In some embodiments, the invention includes a fast-acting inhalation product that has a rapid onset of action compared to oral medications. The product is expected to be at least as rapid as intravenous medications. In some embodiments, the amount of at least one antiarrhythmic pharmaceutical agent peaks in the coronary sinus of the heart at a time ranging from 10 seconds to 30 minutes, e.g., 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5 minutes, from the start of administration. In certain embodiments, the electrophysiological effect is observed by electrocardiogram at a time ranging from 10 seconds to 30 minutes, e.g., 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5 minutes, from the start of administration. In some embodiments, a cardiac score from a monitor implementing an arrhythmia detection algorithm indicates a transition from the patient's arrhythmic state to normal sinus rhythm at a time ranging from 10 seconds to 30 minutes, e.g., 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5 minutes, from the start of administration. In some embodiments, the patient's short form-36 quality of life score improves within a time range of 10 seconds to 30 minutes, e.g., 30 seconds to 20 minutes, 1 minute to 10 minutes, 2 minutes to 8 minutes, or 2.5 minutes to 5 minutes, from the start of administration. In certain embodiments, the patient has normal sinus rhythm within 30 minutes, e.g., within 10 minutes, from the start of administration.

[0161]

[0187] Peak concentrations of the pharmaceutical agent can be seen early in time following its delivery according to the present disclosure. In some embodiments, the concentration of potassium channel blocker in the coronary circulation of the heart is about 0.001 mg / L to about 0.1 mg / L, about 0.001 mg / L to about 0.09 mg / L, about 0.001 mg / L to about 0.08 mg / L, about 0.001 mg / L to about 0.07 mg / L, about 0.001 mg / L to about 0.06 mg / L, about 0.001 mg / L to about 0.05 mg / L, about 0.001 mg / L to about 0.04 mg / L, about 0.001 mg / L to about 0.03 mg / L, about 0.001 mg / L to about 0.04 mg / L, about 0.001 mg / L to about 0.05 mg / L, about 0.001 mg / L to about 0.05 mg / L, about 0.001 mg / L to about 0.06 mg / L, about 0.001 mg / L to about 0.05 mg / L, about 0.001 mg / L to about 0.04 mg / L, about 0.001 mg / L to about 0.03 mg / L, about 0.001 mg / L to about 0.05 ... g / L~about 0.02mg / L, about 0.001mg / L~about 0.01mg / L, about 0.001mg / L~about 0.009mg / L, about 0.001mg / L~about 0.008mg / L, about 0.001mg / L~about 0.007mg / L, about 0.001mg / L ~0.006mg / L, approx. 0.001mg / L~0.005mg / L, approx. 0.001mg / L~0.004mg / L, approx. 0.001mg / L~0.003mg / L, approx. 0.001mg / L~0.002mg / L, approx. 0.002mg / L~ Approx. 0.1mg / L, Approx. 0.005mg / L~Approx. 0.1mg / L, Approx. 0.01mg / L~Approx. 0.1mg / L, Approx. 0.02mg / L~Approx. 0.1mg / L, Approx. 0.03mg / L~Approx. 0.1mg / L, Approx. 0.04mg / L~Approx. 0.1mg / L, Approx. 0.05m g / L~about 0.1mg / L, about 0.06mg / L~about 0.1mg / L, about 0.07mg / L~about 0.1mg / L, about 0.08mg / L~about 0.1mg / L, about 0.09mg / L~about 0.1mg / L, about 0.01mg / L~about 0.1mg / L, about 0. In some embodiments, the concentration of the potassium channel blocker in the coronary circulation of the heart is about 0.01 mg / L to about 0.09 mg / L, about 0.01 mg / L to about 0.08 mg / L, about 0.01 mg / L to about 0.07 mg / L, about 0.01 mg / L to about 0.06 mg / L, about 0.01 mg / L to about 0.05 mg / L, about 0.01 mg / L to about 0.04 mg / L, about 0.01 mg / L to about 0.03 mg / L, about 0.01 mg / L to about 0.02 mg / L, about 0.03 mg / L to about 0.09 mg / L, about 0.05 mg / L to about 0.09 mg / L, or about 0.05 mg / L to about 0.08 mg / L. In some embodiments, the concentration of the potassium channel blocker in the coronary circulation of the heart is about 0.01 mg / L to about 0.1 mg / L at 2.5 minutes after administration.

[0162]

[0188] In some embodiments, the peak concentration of the potassium channel blocker in the coronary circulation of the heart is from about 0.001 mg / L to about 0.1 mg / L, e.g., from about 0.001 mg / L to about 0.1 mg / L, from about 0.001 mg / L to about 0.09 mg / L, from about 0.001 mg / L to about 0.08 mg / L, from about 0.001 mg / L to about 0.07 mg / L, from about 0.001 mg / L to about 0.06 mg / L, from about 0.001 mg / L to about 0.05 mg / L, from about 0.001 mg / L to about 0.04 mg / L, from about 0.001 mg / L to about 0.0 3mg / L, about 0.001mg / L to about 0.02mg / L, about 0.001mg / L to about 0.01mg / L, about 0.001mg / L to about 0.009mg / L, about 0.001mg / L to about 0.008mg / L, about 0.001mg / L to about 0.007mg / L, Approx. 0.001 mg / L ~ approx. 0.006 mg / L, approx. 0.001 mg / L ~ approx. 0.005 mg / L, approx. 0.001 mg / L ~ approx. 0.004 mg / L, approx. 0.001 mg / L ~ approx. 0.003 mg / L, approx. 0.001 mg / L ~ approx. 0.002 mg / L, approx. 0.0 02mg / L~approx. 0.1mg / L, approx. 0.005mg / L~approx. 0.1mg / L, approx. 0.01mg / L~approx. 0.1mg / L, approx. 0.02mg / L~approx. 0.1mg / L, approx. 0.03mg / L~approx. 0.1mg / L, approx. 0.04mg / L~approx. 0.1mg / L, approx. 0 .05mg / L~approx. 0.1mg / L, approx. 0.06mg / L~approx. 0.1mg / L, approx. 0.07mg / L~approx. 0.1mg / L, approx. 0.08mg / L~approx. 0.1mg / L, approx. 0.09mg / L~approx. 0.1mg / L, approx. 0.01mg / L~approx. 0.1mg / L, approx. 0 The peak concentration of potassium channel blocker in the coronary circulation of the heart peaks at about 0.01 mg / L to about 0.09 mg / L, about 0.01 mg / L to about 0.08 mg / L, about 0.01 mg / L to about 0.07 mg / L, about 0.01 mg / L to about 0.06 mg / L, about 0.01 mg / L to about 0.05 mg / L, about 0.01 mg / L to about 0.04 mg / L, about 0.01 mg / L to about 0.03 mg / L, about 0.01 mg / L to about 0.02 mg / L, about 0.03 mg / L to about 0.09 mg / L, about 0.05 mg / L to about 0.09 mg / L, or about 0.05 mg / L to about 0.08 mg / L. In some embodiments, the peak concentration of potassium channel blocker in the coronary circulation of the heart peaks at about 0.01 mg / L to about 0.1 mg / L.

[0163] Formulations and kits.

[0189] In one aspect, provided herein is a pharmaceutical composition for the treatment of a cardiac condition, e.g., cardiac arrhythmia, e.g., atrial arrhythmia.

[0164]

[0190] The pharmaceutical composition can include a therapeutically effective amount of potassium channel blocker.The therapeutically effective amount of potassium channel blocker can be effective for treating cardiac conditions, such as cardiac arrhythmia, for example, atrial arrhythmia, when administered to a subject in need thereof by inhalation or nasal spray administration.In some embodiments, the therapeutically effective amount of potassium channel blocker can be effective for treating atrial arrhythmia by inducing cardioversion and slowing AV node conduction when administered to a subject in need thereof by inhalation or nasal spray administration.

[0165]

[0191] In some embodiments, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of a potassium channel blocker and a therapeutically effective amount of an antiarrhythmic agent, such as a class I antiarrhythmic agent. In some embodiments, the therapeutically effective amount of the potassium channel blocker and the therapeutically effective amount of the class I antiarrhythmic agent, when administered by inhalation or intranasal spray administration to a subject in need thereof, are effective in treating atrial arrhythmias by inducing cardioversion and slowing AV nodal conduction.

[0166]

[0192] The potassium channel blocker may be in a liquid solution. In some embodiments, the potassium channel blocker in the pharmaceutical composition is ibutilide or a pharma- ceutically acceptable salt thereof (e.g., ibutilide fumarate), and the concentration of ibutilide or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition or formulation provided herein is about 0.0005 mg / mL to about 5 mg / mL, e.g., about 0.0005 mg / mL to about 2.5 mg / mL, about 0.0005 mg / mL to about 2 mg / mL, about 0.0005 mg / mL to about 1 mg / mL, about 0.0005 mg / mL to about 0.5 mg / mL, about 0.0005 mg / mL to about 0.25 mg / mL, about 0.0005 mg / mL to about 0.2 mg / mL, about 0.0005 mg / mL to about 0.1 ... L ~ approx. 0.05 mg / mL, approx. 0.0005 mg / mL ~ approx. 0.02 mg / mL, approx. 0.0005 mg / mL ~ approx. 0.01 mg / mL, approx. 0.0005 mg / mL ~ approx. 0.0 01mg / mL, about 0.001mg / mL to about 2.5mg / mL, about 0.001mg / mL to about 2mg / mL, about 0.001mg / mL to about 1mg / mL, about 0.001mg / mL to about 0.5 mg / mL, about 0.001 mg / mL to about 0.25 mg / mL, about 0.001 mg / mL to about 0.2 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / mL to about 0.05 mg / mL, about 0.001 mg / mL to about 0.02 mg / mL, or about 0.001 mg / mL to about 0.01 mg / mL. In some embodiments, the potassium channel blocker in the pharmaceutical composition is ibutilide or a pharma- ceutically acceptable salt thereof (e.g., ibutilide fumarate), and the concentration of ibutilide or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions or formulations provided herein is about 0.001 mg / mL, about 0.005 mg / mL, about 0.01 mg / mL, about 0.02 mg / mL, about 0.025 mg / mL, about 0.03 mg / mL, about 0.04 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.75 mg / mL, or about 1 mg / mL.In some embodiments, the potassium channel blocker in the pharmaceutical composition is sotalol or a pharma- ceutically acceptable salt thereof and the concentration of ibutilide or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions or formulations provided herein is about 0.001 mg / mL, about 0.005 mg / mL, about 0.01 mg / mL, about 0.02 mg / mL, about 0.025 mg / mL, about 0.03 mg / mL, about 0.04 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.75 mg / mL, about 1 mg / mL, about 2 mg / mL, or about 5 mg / mL.

[0167]

[0193] Dofetilide or a pharma- ceutically acceptable salt thereof may be in a liquid solution. In some embodiments, the potassium channel blocker in the pharmaceutical composition is dofetilide. The concentration of dofetilide or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions or formulations provided herein is about 1 μg / mL to about 40 μg / mL. In some embodiments, the concentration of dofetilide is at least about 1 μg / mL. In some embodiments, the concentration of dofetilide is up to about 40 μg / mL. In some embodiments, the concentration of dofetilide is from about 1 μg / mL to about 2 μg / mL, from about 1 μg / mL to about 3 μg / mL, from about 1 μg / mL to about 4 μg / mL, from about 1 μg / mL to about 5 μg / mL, from about 1 μg / mL to about 10 μg / mL, from about 1 μg / mL to about 15 μg / mL, from about 1 μg / mL to about 20 μg / mL, from about 1 μg / mL to about 25 μg / mL, from about 1 μg / mL to about 30 μg / mL, from about 1 μg / mL to about 35 μg / mL, or from about 1 μg / mL to about 40 μg / mL. mL ~ approx. 40μg / mL, approx. 2μg / mL ~ approx. 3μg / mL, approx. 2μg / mL ~ approx. 4μg / mL, approx. 2μg / mL ~ approx. 5μg / mL, approx. 2μg / mL ~ approx. 10μg / mL, approx. 2μg / mL ~ approx. 15μg / mL, approx. 2μ g / mL~about 20μg / mL, about 2μg / mL~about 25μg / mL, about 2μg / mL~about 30μg / mL, about 2μg / mL~about 35μg / mL, about 2μg / mL~about 40μg / mL, about 3μg / mL~about 4μg / mL, Approximately 3μg / mL to approximately 5μg / mL, approximately 3μg / mL to approximately 10μg / mL, approximately 3μg / mL to approximately 15μg / mL, approximately 3μg / mL to approximately 20μg / mL, approximately 3μg / mL to approximately 25μg / mL, approximately 3μg / mL to approximately 30μg / mL, about 3μg / mL to about 35μg / mL, about 3μg / mL to about 40μg / mL, about 4μg / mL to about 5μg / mL, about 4μg / mL to about 10μg / mL, about 4μg / mL to about 15μg / mL, about 4μg / mL to about 20μg / mL, about 4μg / mL to about 25μg / mL, about 4μg / mL to about 30μg / mL, about 4μg / mL to about 35μg / mL, about 4μg / mL to about 40μg / mL, about 5μg / mL to about 10μg / mL, about 5μg / mL~about 15μg / mL, about 5μg / mL~about 20μg / mL, about 5μg / mL~about 25μg / mL, about 5μg / mL~about 30μg / mL, about 5μg / mL~about 35μg / mL, about 5μg / mL~about 40μg / mL,Approximately 10μg / mL to approximately 15μg / mL, approximately 10μg / mL to approximately 20μg / mL, approximately 10μg / mL to approximately 25μg / mL, approximately 10μg / mL to approximately 30μg / mL, approximately 10μg / mL to approximately 35μg / mL, approximately 10μg / mL mL~about 40μg / mL, about 15μg / mL~about 20μg / mL, about 15μg / mL~about 25μg / mL, about 15μg / mL~about 30μg / mL, about 15μg / mL~about 35μg / mL, about 15μg / mL~about 40 μg / mL, approximately 20 μg / mL to approximately 25 μg / mL, approximately 20 μg / mL to approximately 30 μg / mL, approximately 20 μg / mL to approximately 35 μg / mL, approximately 20 μg / mL to approximately 40 μg / mL, approximately 25 μg / mL to approximately 30 μg / mL, About 25 μg / mL to about 35 μg / mL, about 25 μg / mL to about 40 μg / mL, about 30 μg / mL to about 35 μg / mL, about 30 μg / mL to about 40 μg / mL, or about 35 μg / mL to about 40 μg / mL. ,

[0168]

[0194] The sodium channel blocker (e.g., flecainide) may be in a liquid solution. In some embodiments, the sodium channel blocker in the pharmaceutical composition or formulation provided herein is flecainide or a pharma- ceutically acceptable salt thereof (e.g., flecainide acetate), and the concentration of flecainide or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition or formulation provided herein is about 1 mg / mL to about 150 mg / mL, e.g., about 1 mg / mL to about 5 mg / mL, about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 5 ... The sodium channel blocker (e.g., flecainide) may be in a liquid solution. In some embodiments, the sodium channel blocker in the pharmaceutical compositions or formulations provided herein is flecainide or a pharma- ceutically acceptable salt thereof (e.g., flecainide acetate), and the concentration of flecainide or a pharma- ceutically acceptable salt thereof in the pharmaceutical compositions or formulations provided herein is about 1 mg / ml, about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 40 mg / ml, about 50 mg / ml, about 75 mg / ml, about 100 mg / ml, about 125 mg / ml, or about 150 mg / ml.

[0169]

[0195] Mg 2+ The source may be in a liquid solution. In some embodiments, the Mg source in the pharmaceutical compositions or formulations provided herein 2+The source of magnesium sulfate is magnesium sulfate, and the concentration of magnesium sulfate in the pharmaceutical composition or formulation provided herein is about 5 mg / mL to about 1000 mg / mL, for example, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 200 mg / mL, about 10 mg / mL to about 300 mg / mL, about 10 mg / mL to about 400 mg / mL, about 10 mg / mL to about 500 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 400 mg / mL, about 100 mg / mL to about 500 mg / mL, about 200 mg / mL to about 500 mg / mL, / mL to about 300 mg / mL, about 200 mg / mL to about 400 mg / mL, about 200 mg / mL to about 500 mg / mL, about 300 mg / mL to about 400 mg / mL, about 300 mg / mL to about 500 mg / mL, about 400 mg / mL to about 500 mg / mL, about 400 mg / mL to about 600 mg / mL, about 5 mg / mL to about 700 mg / mL, about 10 mg / mL to about 700 mg / mL, about 20 mg / mL to about 700 mg / mL, about 100 mg / mL to about 700 mg / mL, about 400 mg / mL to about 700 mg / mL, about 500 mg / mL to about 700 mg / mL. In some embodiments, the Mg concentration in the pharmaceutical composition or formulation provided herein is about 10 mg / mL to about 700 mg / mL. 2+ The source is magnesium sulfate and the concentration of magnesium sulfate in the pharmaceutical compositions or formulations provided herein is about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, about 200 mg / mL, about 300 mg / mL, about 400 mg / mL, about 500 mg / mL, about 600 mg / mL, about 700 mg / mL, about 800 mg / mL, about 900 mg / mL or about 1000 mg / mL.

[0170]

[0196] In some embodiments, ibutilide, sotalol or a pharma- ceutically acceptable salt thereof is co-formulated with flecainide or a pharma- ceutically acceptable salt thereof in a co-formulation. In some embodiments, the mass to mass ratio of flecainide acetate to ibutilide fumarate in the co-formulation is 1 to about 0.005, 1 to about 0.01, 1 to about 0.02, 1 to about 0.03, 1 to about 0.04, 1 to about 0.05, 1 to about 0.06, 1 to about 0.07, 1 to about 0.08, 1 to about 0.09, 1 to about 0.1, 1 to about 0.2, 1 to about 0.3, 1 to about 0.4, 1 to about 0.5, 1.5 to about 0.005, 1.5 to about 0.01, 1.5 to about 0.02, 1.5 to about 0.03, 1.5 to about 0.04, 1.5 to about 0.05, 1.5 ...5, 1.5 to about 0.06, 1 to about 0.07, 1 to about 0.08, It is about 0.05, 1.5 to about 0.06, 1.5 to about 0.07, 1.5 to about 0.08, 1.5 to about 0.09, 1.5 to about 0.1, 1.5 to about 0.2, 1.5 to about 0.3, 1.5 to about 0.4, 1.5 to about 0.5, 2 to about 0.005, 2 to about 0.01, 2 to about 0.02, 2 to about 0.03, 2 to about 0.04, 2 to about 0.05, 2 to about 0.06, 2 to about 0.07, 2 to about 0.08, 2 to about 0.09, 2 to about 0.1, 2 to about 0.2, 2 to about 0.3, 2 to about 0.3, 2 to about 0.4, or 2 to about 0.5.

[0171]

[0197] In some embodiments, dofetilide or a pharma- ceutically acceptable salt thereof is co-formulated with flecainide or a pharma- ceutically acceptable salt thereof in a co-formulation. In some embodiments, the mass-to-mass ratio of flecainide acetate to dofetilide in the co-formulation is about 1,000 to about 4,000. In some embodiments, the mass-to-mass ratio of flecainide acetate to dofetilide in the co-formulation is at least about 1,000. In some embodiments, the mass-to-mass ratio of flecainide acetate to dofetilide in the co-formulation is up to about 4,000. In some embodiments, the mass to mass ratio of flecainide acetate to dofetilide in the co-formulation is about 1,000 to about 1,250, about 1,000 to about 1,500, about 1,000 to about 2,000, about 1,000 to about 2,500, about 1,000 to about 3,000, about 1,000 to about 3,500, about 1,000 to about 4,000, about 1,250 to about 1,500, about 1,250 to about 2,000, about 1,250 to about 2,500, about 1,250 to about 3,000, about 1,250 to about 3,500, about 1,250 to about 4 ,000, about 1,500 to about 2,000, about 1,500 to about 2,500, about 1,500 to about 3,000, about 1,500 to about 3,500, about 1,500 to about 4,000, about 2,000 to about 2,500, about 2,000 to about 3,000, about 2,000 to about 3,500, about 2,000 to about 4,000, about 2,500 to about 3,000, about 2,500 to about 3,500, about 2,500 to about 4,000, about 3,000 to about 3,500, about 3,000 to about 4,000, or about 3,500 to about 4,000.

[0172]

[0198] Another aspect of the present disclosure provides a unit dose of a pharmaceutical composition described herein for the treatment of a cardiac condition, e.g., cardiac arrhythmia, e.g., atrial arrhythmia, by oral or nasal inhalation or intranasal spray administration.

[0173]

[0199] In one aspect, a formulation for the treatment of cardiac conditions, such as cardiac arrhythmia, e.g., atrial arrhythmia, is provided herein. The formulation can include the pharmaceutical composition provided herein and a pharmaceutically acceptable carrier, excipient, diluent, or any other component suitable for the intended route of administration, e.g., oral or nasal inhalation, or nasal spray administration. For example, the pharmaceutical composition can include neat particles of potassium channel blockers and / or antiarrhythmic pharmaceutical agents (e.g., particles containing only potassium channel blockers and / or antiarrhythmic pharmaceutical agents), neat particles of potassium channel blockers and / or sodium channel blockers and other particles, and / or particles containing potassium channel blockers and / or sodium channel blockers and one or more active ingredients and / or one or more pharmaceutically acceptable excipients. 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.

[0174]

[0200] Treatment according to the present disclosure can significantly reduce the variability in absorption typically observed when delivered orally. Due to rapid absorption by the nasal mucosa or lungs, T max The time may be as short as 0.5 to 5 minutes after inhalation.

[0175]

[0201] The antiarrhythmic agent can be administered by any route, including intravenous, intramuscular, transdermal and oral delivery.

[0202] The pharmaceutical formulation according to one or more embodiments of the present disclosure may include one or more potassium channel blockers and sodium channel blockers, and optionally one or more other active ingredients, and optionally one or more pharmaceutically acceptable excipients.For example, the pharmaceutical formulation may include particles of antiarrhythmic pharmaceutical agents without other ingredients added (neat particles), may include neat particles of antiarrhythmic pharmaceutical agents together with other particles, and / or may include particles containing antiarrhythmic pharmaceutical agents and one or more active ingredients and / or one or more pharmaceutically acceptable excipients.

[0176]

[0203] In some cases, the potassium channel blocker is co-formulated with another antiarrhythmic agent (e.g., a sodium channel blocker) as either an inhalation or parenteral injection solution or suspension for the treatment of cardiac arrhythmia.In some cases, the potassium channel blocker and the other antiarrhythmic agent are formulated as separate individual formulations.In some embodiments, the individual formulations are administered to a subject simultaneously.In some embodiments, the individual formulations are combined and optionally diluted with an excipient before administration.

[0177]

[0204] Potassium channel blockers, when co-administered by oral or nasal administration prior to or together with an antiarrhythmic therapy, e.g., a Class Ic antiarrhythmic drug, can achieve one or more of the following results not met by current marketed products: rapid cardioversion of atrial arrhythmias, and, when used in combination with a potassium channel blocker, avoidance of the proarrhythmic effects of the Class Ic inhibitor by reducing the minimum therapeutically effective dose of the Class Ic inhibitor.

[0178]

[0205] In one aspect, a kit for treating cardiac conditions by inhalation or intranasal administration is also provided herein.The kit may include one or more pharmaceutical agents, such as potassium channel blockers, antiarrhythmic agents, or both, or some additional active agents as described herein.In some embodiments, the kit includes a container for the pharmaceutical agent or composition.In some embodiments, the kit includes a unit dose of the pharmaceutical agent discussed above.In some embodiments, the kit also includes a container / receptacle for containing the pharmaceutical agent.

[0179]

[0206] In some embodiments, the kit includes separate containers / receptacles for housing the potassium channel blocker and the class I antiarrhythmic agent. In some embodiments, the kit includes an aerosolization device for forming an aerosol of the pharmaceutical composition. The aerosolization device may be any device provided herein and may be used in some embodiments for inhalation of the pharmaceutical composition. In some embodiments, the kit includes a nasal spray device provided herein. In some embodiments, the pharmaceutical composition is present in the kit in aerosol form. In some other cases, the kit includes a single container for housing the potassium channel blocker and the class I antiarrhythmic agent, e.g., the potassium channel blocker and the class I antiarrhythmic agent are present in one single pharmaceutical composition, e.g., a single solution. The kit may further include instructions on how to use the kit. The instructions may be presented in the form of a data sheet, manual, paper strip, printed on one or more containers or devices of the kit. Alternatively, the instructions may be provided in electronic form available online, e.g., on a disk or by a web link available from the kit.

[0180]

[0207] Examples of carbohydrates include, but are not limited to, monosaccharides, disaccharides and polysaccharides.For example, monosaccharides such as dextrose (anhydrous and monohydrate), galactose, mannitol, D-mannose, sorbitol, sorbose, etc.; disaccharides such as lactose, maltose, sucrose, trehalose, etc.; trisaccharides such as raffinose, etc.; and other carbohydrates such as starch (hydroxyethyl starch), cyclodextrin and maltodextrin.In some embodiments, carbohydrates such as cyclodextrin are used to stabilize or increase the dissolution rate of pharmaceutical agents in liquid solvents, such as water.

[0181]

[0208] Non-limiting examples of lipids include phospholipids, glycolipids, ganglioside GM1, sphingomyelin, phosphatidic acid, cardiolipin; lipids having polymeric chains such as polyethylene glycol, chitin, hyaluronic acid, or polyvinylpyrrolidone; lipids having sulfonated monosaccharides, disaccharides, and polysaccharides, fatty acids such as palmitic acid, stearic acid, and oleic acid, cholesterol, cholesterol esters, and cholesterol hemisuccinate.

[0182]

[0209] In some embodiments, 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).Phospholipid content may be determined by the activity of the active agent, the mode of delivery, and other factors.

[0183]

[0210] 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%.

[0184]

[0211] In general, suitable phospholipids can include those that have a gel to liquid crystal phase transition above about 40° C., e.g., above about 60° C., or above about 80° C. The incorporated phospholipids can be relatively long chain (e.g., C 16 ~C 22) saturated lipids. Exemplary phospholipids useful in the present invention 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.

[0185]

[0212] Examples of metal ions include, but are not limited to, divalent cations including calcium, magnesium, zinc, iron, etc. For example, when phospholipids are used, the pharmaceutical composition can also include polyvalent cations as disclosed in WO01 / 85136 and WO01 / 85137, the entire contents of which are incorporated herein by reference. Polyvalent cations are used to aid in the stability of the pharmaceutical composition at its storage temperature (T m ) is at least about 20° C., e.g., at least about 40° C. greater than T m As shown, the melting point (T m ) may be present in an amount effective to enhance the phospholipid. The molar ratio of polyvalent cation to phospholipid may be at least about 0.05:1, such as about 0.05:2 to about 2.0:1 or about 0.25:2 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 in the phospholipid, but neither is required.

[0186]

[0213] As mentioned above, the pharmaceutical composition can include one or more surfactants. For example, one or more surfactants can be present in the liquid phase with one or more associated with the solid particles or particles of the composition. By "associated" it is meant that the pharmaceutical composition can incorporate, adsorb, absorb, be coated by, or be formed by 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 aforementioned surfactants, it should be emphasized that suitable fluorinated surfactants can be used to fit the teachings of this specification and provide the desired preparation.

[0187]

[0214] Examples of non-ionic detergents include, but are not limited to, sorbitan trioleate (Span™ 85), sorbitan sesquioleate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, and sorbitan esters including 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.

[0188]

[0215] 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.

[0189]

[0216] Examples of ionic surfactants include, but are not limited to, sodium sulfosuccinate and fatty acid soaps.

[0217] 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 entirety.

[0190]

[0218] Examples of buffers include, but are not limited to, Tris or citrate.

[0219] Examples of acids include, but are not limited to, carboxylic acids.

[0191]

[0220] 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, and the like.

[0192]

[0221] Examples of organic solids include, but are not limited to, camphor, and the like.

[0222] The pharmaceutical composition of one or more embodiments of the present invention can also include biocompatible, e.g., biodegradable polymers, copolymers, or blends or other combinations thereof.In this regard, useful polymers include polylactides, polylactides-glycolides, cyclodextrins, polyacrylates, methylcellulose, carboxymethylcellulose, polyvinyl alcohol, polyanhydrides, polylactams, polyvinylpyrrolidones, polysaccharides (e.g., dextran, starch, chitin, chitosan), hyaluronic acid, proteins (e.g., albumin, collagen, gelatin).Those skilled in the art will understand that by selecting the appropriate polymer, the delivery efficiency of the composition and / or the stability of the dispersion can be adjusted to optimize the effectiveness of the antiarrhythmic pharmaceutical agent.

[0193]

[0223] In the case of a solution, the composition may include one or more osmolality adjusting agents, such as sodium chloride. For example, sodium chloride may be added to the solution to adjust the osmolality of the solution. In one or more embodiments, the aqueous composition consists essentially of an antiarrhythmic pharmaceutical agent, an osmolality adjusting agent and water.

[0194]

[0224] The solution may also contain a buffer or pH adjuster, typically a salt prepared from an organic acid or base.Representative buffers include organic acid salts of citric acid, lactic acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffers.Accordingly, buffers include citrate, phosphate, phthalate, and lactate.

[0195]

[0225] In addition to the above pharmaceutically acceptable excipients, it may be desirable to add other pharmaceutically acceptable excipients to the pharmaceutical composition to improve particle rigidity, production yield, emitted dose and deposition, shelf life and patient acceptability. Such optional pharmaceutically acceptable excipients include, but are not limited to, colorants, taste masking agents, buffers, hygroscopic agents, antioxidants and chemical stabilizers. In addition, various pharmaceutically acceptable excipients can be used to impart structure and morphology to the particle composition (e.g., latex particles). In this regard, it is understood that post-production techniques such as selective solvent extraction can be used to remove the rigidifying components.

[0196]

[0226] The pharmaceutical compositions of one or more embodiments of the present invention may be tasteless. In this regard, although a taste-masking agent is optionally included in the composition, the compositions often do not include a taste-masking agent and are tasteless even when they do not include a taste-masking agent.

[0197]

[0227] Pharmaceutical compositions can also include mixtures of pharma- ceutically acceptable excipients, for example, mixtures of carbohydrates and amino acids are within the scope of the present invention.

[0228] The compositions of one or more embodiments of the present invention can 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 dispersion.

[0198]

[0229] Solutions of the present invention are typically clear. In this regard, many of the antiarrhythmic pharmaceutical agents of the present invention are water-soluble.

[0230] In some embodiments, the isotonicity of the solution ranges from isotonic to physiological isotonicity, which is the isotonicity of physiological fluids.

[0199]

[0231] The composition may have a pH in the range of 3.5 to 8.0, for example 4.0 to 7.5 or 4.5 to 7.0, or 5.0 to 6.5.

[0232] For dry powders, the moisture content can be less than about 15 wt%, e.g., less than about 10 wt%, less than about 5 wt%, less than about 2 wt%, less than about 1 wt%, or less than about 0.5 wt%. Such powders are described in WO95 / 24183, WO96 / 32149, WO99 / 16419, WO99 / 16420, and WO99 / 16422, which are incorporated herein by reference in their entireties.

[0200]

[0233] In one variation, the pharmaceutical composition is in the form of inhalable dry powder.Such dry powder can be prepared, for example, by supercritical fluid solution-enhanced dispersion (SEDS), which is described in U.S. Patent Nos. 5,851,453, 6,440,337, 6,576,262, 7,150,766 and 10,798,955, and U.S. Patent Publication Nos. US20060073087A1 and US20020073511A1, each of which is incorporated herein by reference in its entirety.

[0201]

[0234] In another variation, the pharmaceutical composition is in the form of an inhalable dry powder formed by the techniques described in U.S. Patent Publication No. US20180221849A1, and U.S. Patent Nos. 6,620,351, 7,744,923, and 9,233,348, each of which is incorporated by reference herein in its entirety.

[0202]

[0235] In another variation, the pharmaceutical composition is in the form of an inhalable dry powder formed by imprint lithography as described in U.S. Pat. Nos. 10,842,748, 9,214,590, 7,855,046, 8,128,393, and 9,545,737, each of which is incorporated herein by reference in its entirety.

[0203]

[0236] In one variation, the pharmaceutical composition comprises an antiarrhythmic pharmaceutical agent incorporated in a phospholipid matrix. The pharmaceutical composition may comprise a phospholipid matrix in the form of particles incorporating an active agent and being hollow and / or porous microstructures as described in WO99 / 16419, WO99 / 16420, WO99 / 16422, WO01 / 85136 and WO01 / 85137, all of which are incorporated herein by reference. The hollow and / or porous microstructures are useful for delivering antiarrhythmic pharmaceutical agents to the lungs, as the density, size and aerodynamic quality of the hollow and / or porous microstructures facilitate transport to the deep lungs during inhalation by the user. In addition, the phospholipid-based hollow and / or porous microstructures reduce the attractive forces between particles, making the pharmaceutical composition more likely to disaggregate during aerosolization, and improving the flow properties of the pharmaceutical composition, thereby facilitating processing.

[0204]

[0237] In one variation, the pharmaceutical composition has a density of about 1.0 g / cm 3 Less than 0.5g / cm 3 Less than 0.3g / cm 3 Less than 0.2g / cm 3 Less than or about 0.1 g / cm 3The powder is composed of a hollow and / or porous microstructure having a bulk density of less than 10 ...

[0205]

[0238] In some embodiments, the present invention includes particles with a high degree of roughness. For example, the particles can have a roughness of greater than 2, such as greater than 3, or greater than 4, and the roughness can range from 2 to 15, such as from 3 to 10.

[0206]

[0239] In one variation, the pharmaceutical composition is in dry powder form and is contained within a unit dose receptacle that can be inserted into or near an aerosolization device to aerosolize a unit dose of the pharmaceutical composition. This variation is useful in that the dry powder form can be stably stored in the unit dose receptacle for extended periods of time. In some examples, the pharmaceutical composition of one or more embodiments of the present invention can be stable for at least two years. In some variations, refrigeration is not required to achieve stability. In other variations, reduced temperatures, for example 2-8°C, can be used to extend stable storage. In many variations, the storage stability allows for aerosolization with an external power source.

[0207]

[0240] It is understood that the pharmaceutical compositions disclosed herein may include a structural matrix that exhibits, defines, or includes voids, holes, defects, hollows, spaces, interstitial spaces, openings, perforations, or holes.The absolute shape (as opposed to morphology) of the perforated microstructure is generally not important, and any overall configuration that provides the desired properties is contemplated as being within the scope of the present invention.Thus, some embodiments include approximately spherical shapes.However, collapsed, deformed, or crushed particles are also suitable.

[0208]

[0241] In one variation, the antiarrhythmic pharmaceutical agent is incorporated into a matrix that forms discrete particles, and the pharmaceutical composition comprises a plurality of discrete particles. The discrete particles may be sized to be effectively administered and / or available where needed. For example, in the case of an aerosolizable pharmaceutical composition, the particles are of a size that allows the particles to be aerosolized and delivered to the user's respiratory tract during the user's inhalation.

[0209]

[0242] The matrix material may comprise hydrophobic or partially hydrophobic materials.For example, the matrix material may comprise lipids such as phospholipids and / or hydrophobic amino acids such as leucine or trileucine.Examples of phospholipid matrices are described in WO99 / 16419, WO99 / 16420, WO99 / 16422, WO01 / 85136 and WO01 / 85137, as well as U.S. Patent Nos. 5,874,064, 5,855,913, 5,985,309, 6,503,480 and 7,473,433, and U.S. Published Application No. 20040156792, all of which are incorporated herein by reference in their entirety. Examples of hydrophobic amino acid matrices are described in US Pat. Nos. 6,372,258, 6,358,530, and 7,473,433, which are incorporated herein by reference in their entireties.

[0210]

[0243] When phospholipids are utilized as the matrix material, the pharmaceutical composition may also include multivalent cations as disclosed in WO01 / 85136 and WO01 / 85137, which are incorporated herein by reference in their entireties.

[0211]

[0244] According to another embodiment, the release rate of the composition containing the antiarrhythmic pharmaceutical agent is controlled. According to one or more embodiments, the composition of the present invention provides an immediate release of the antiarrhythmic pharmaceutical agent. Alternatively, the composition of other embodiments of the present invention can be provided as a non-homogeneous mixture of active agent incorporated and not incorporated into the matrix material to provide a desired release rate of the antiarrhythmic pharmaceutical agent. According to this embodiment, the antiarrhythmic pharmaceutical agent formulated using the emulsion-based manufacturing process of one or more embodiments of the present invention is useful in immediate release applications when administered to the respiratory tract. The rapid release is promoted by: (a) the high specific surface area of ​​the low density porous powder, (b) the small size of the drug crystals incorporated therein, and (c) the low surface energy of the particles.

[0212]

[0245] Alternatively, it may be desirable to engineer the particle matrix to provide extended release of the active agent. This may be particularly desirable when the active agent is rapidly cleared from the lungs or when sustained release is desired. For example, the nature of the phase behavior of phospholipid molecules is influenced by the nature of their chemical structure and / or the preparation method and drying conditions in the spray-dried feedstock and other compositional components utilized. In the case of spray-drying of an active agent solubilized in small unilamellar vesicles (SUVs) or multilamellar vesicles (MLVs), the active agent is encapsulated in multiple bilayers and released over an extended period of time.

[0213]

[0246] In contrast, spray drying a feedstock consisting of emulsion droplets and dispersed or dissolved active agent according to the teachings herein results in a phospholipid matrix with less long-range order, thereby facilitating rapid release. Without being bound to a particular theory, this is believed to be due in part to the fact that the active agent is never formally encapsulated in the phospholipids, and that the phospholipids are initially present on the surface of the emulsion droplets as a monolayer (not a bilayer as in the case of liposomes). The spray-dried particles prepared by the emulsion-based manufacturing process of one or more embodiments of the present invention often have a high degree of disorder. Spray-dried particles also typically have low surface energy, where values ​​as low as 20 mN / m have been observed for spray-dried DSPC particles (determined by inverse gas chromatography). Small-angle X-ray scattering (SAXS) studies performed with spray-dried phospholipid particles also show a high degree of lipid disorder, with scattering peaks that are smeared and length scales that only extend beyond a few nearest neighbors in some cases.

[0214]

[0247] It should be noted that a matrix with a high gel-to-liquid crystal phase transition temperature is not sufficient in itself to achieve sustained release of an active agent. Having sufficient order in the bilayer structure is also important to achieve sustained release. To promote rapid release, emulsion systems with high porosity (high surface area) and minimal interactions between the drug substance and the phospholipids can be used. The pharmaceutical composition formation process also includes adding other compositional ingredients (e.g., small polymers such as Pluronic F-68, carbohydrates, salts, hydrotropes) to break the bilayer structure.

[0215]

[0248] To achieve sustained release, the incorporation of phospholipids in bilayer form can be used, especially when an active agent is encapsulated therein. In this case, the T mIncreasing the solubility of phospholipids can benefit from the incorporation of divalent counterions or cholesterol. Similarly, increasing the interaction between phospholipids and drug substances through the formation of ion pairs (negatively charged active substance + stearylamine, positively charged active substance + phosphatidylglycerol) tends to slow the dissolution rate. If the active substance is amphiphilic, surfactant / surfactant interactions can also slow the dissolution of the active substance.

[0216]

[0249] Addition of divalent counterions (e.g., calcium or magnesium ions) to long-chain saturated phosphatidylcholine results in an interaction between the negatively charged phosphate moiety of the zwitterionic head and the positively charged metal ion. This leads to the replacement of the water of hydration and condensation of the packing of the lipid heads and acyl chains of the phospholipid. In turn, this increases the Tm of the phospholipid. The reduction in head hydration can have a significant effect on the spreading properties of spray-dried phospholipid particles in contact with water. Fully hydrated phosphatidylcholine molecules diffuse very slowly into dispersed crystals by molecular diffusion through the aqueous phase. The process is initiated when the solubility of the phospholipid in water is very low (approximately 10 for DPPC). -10 mol / L) and is therefore extremely slow. Prior art attempts to overcome this phenomenon include homogenizing the crystals in the presence of phospholipids, where the high shear and radius of curvature of the homogenized crystals facilitates coating of the phospholipids onto the crystals. In contrast, "dry" phospholipid powders according to one or more embodiments of the present invention spread rapidly upon contact with an aqueous phase, thereby coating the dispersed crystals without the need for high energy input.

[0217]

[0250] For example, upon reconstitution, the surface tension of a spray-dried DSPC / Ca mixture at the air / water interface decreases measurably to the equilibrium value (~20 mN / m). In contrast, DSPC liposomes show little decrease in surface tension (~50 mN / m) over a few hours, a decrease that is likely due to the presence of hydrolysis products such as free fatty acids in the phospholipids. Single-tailed fatty acids can diffuse to the air / water interface much faster than the hydrophobic parent compound. Thus, the addition of calcium ions to phosphatidylcholine can facilitate the rapid encapsulation of crystalline drugs more quickly and with lower applied energy.

[0218]

[0251] In another variation, the pharmaceutical composition comprises low density particles achieved by co-spray drying nanocrystals with a perfluorocarbon in water emulsion. The nanocrystals can be formed by precipitation and may range in size, for example, from about 45 μm to about 80 μm. Examples of perfluorocarbons include, but are not limited to, perfluorohexane, perfluorooctyl bromide, perfluorooctyl ethane, perfluorodecalin, and perfluorobutyl ethane.

[0219]

[0252] In accordance with the teachings herein, the particles can be provided in a "dry" state. That is, in one or more embodiments, the particles have a moisture content that allows the powder to remain chemically and physically stable and dispersible during storage at ambient or reduced temperatures. In this regard, there is little or no change in the size, content, purity and aerodynamic particle size distribution of the primary particles.

[0220]

[0253] Thus, the moisture content of the particles is typically less than about 10 wt%, for example less than about 6 wt%, less than about 3 wt%, or less than about 1 wt%. The moisture content is at least partially determined by the composition and controlled by the process conditions utilized, such as inlet temperature, feed concentration, pump speed, and type, concentration, and post-drying of the foaming agent. The reduction in bound water significantly improves the dispersibility and flowability of phospholipid-based powders, leading to the possibility of highly efficient delivery of powdered pulmonary surfactant or particle compositions containing active agents dispersed in phospholipids. The improved dispersibility allows these powders to be effectively delivered using simple passive DPI devices.

[0221]

[0254] Yet another variation of pharmaceutical compositions includes particle compositions that can contain or be partially or completely coated with charged species that extend the residence time at the contact point or enhance the penetration through mucosa. For example, anionic charges are known to promote mucoadhesion, while cationic charges can be used to associate the formed particles with negatively charged bioactive agents such as genetic material. Charges can be imparted by association or incorporation of polyanionic or polycationic materials such as polyacrylic acid, polylysine, polylactic acid, and chitosan.

[0222]

[0255] In some variations, the pharmaceutical composition comprises particles 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 particles can 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 particles are too large, a relatively high percentage of the particles will not reach the lungs. If the particles are too small, a relatively high percentage of the particles may be exhaled.

[0223]

[0256] The unit dose of pharmaceutical composition may be placed in a container.The example of the container includes but is not limited to syringe, capsule, blow-fill seal, blister, vial, ampoule or container closure system made of metal, polymer (e.g., plastic, elastomer), glass, etc.For example, the vial may be a colorless I-type borosilicate glass ISO 6R 10mL vial with a chlorobutyl rubber siliconized stopper and a tear-off aluminum cap with a colored plastic cover.

[0224]

[0257] The container can be inserted into the aerosolization device. The container may be of a shape, size and material suitable for containing the pharmaceutical composition and providing 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 be opened to aerosolize the pharmaceutical composition. 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 comprise telescopic adjacent sections, 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 accommodate a dose of the pharmaceutical composition. Sizes generally range from size 5 to size 000, with outer diameters ranging from about 4.91 mm to 9.97 mm, heights ranging from about 11.10 mm to about 26.14 mm, and volumes ranging from about 0.13 mL to about 1.37 mL, respectively. Suitable capsules are commercially available, for example, from Shionogi Qualicaps Co., Nara Prefecture, Japan, and Capsugel, Greenwood, SC. ​​After filling, the upper part is placed over the lower part to form the capsule shape and contain the 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 optionally be banded.

[0225]

[0258] In the case of a solution, the amount of the composition in a unit dose typically ranges from about 0.5 ml to about 15 ml, for example, from about 2 ml to about 15 ml, from about 3 ml to about 10 ml, from about 4 ml to about 8 ml, or from about 5 ml to about 6 ml.

[0226]

[0259] The compositions of the present invention can be made by any of the various methods and techniques known and available to those of skill in the art.

[0260] For example, a solution of an antiarrhythmic pharmaceutical agent can be made using the following procedure: Typically, the manufacturing equipment is sterilized prior to use. A portion, e.g., 70%, of the final volume of a solvent, e.g., water for injection, can be added to a suitable container. The antiarrhythmic pharmaceutical agent can then be added. The antiarrhythmic pharmaceutical agent can be mixed until dissolved. Additional solvent can be added to make up the final batch volume. The batch can be filtered, e.g., through a 0.2 μm filter, into a sterile receiving container. A filling component can be used to fill the batch into vials, e.g., 10 ml vials, after sterilization.

[0227]

[0261] As an example, the sterilization described above can include the following: 5 liter type 1 glass bottles and lids can be placed in an autoclave bag and sterilized using an autoclave at high temperature, for example, 121°C for 15 minutes. Similarly, vials can be placed in a suitable rack, inserted into an autoclave bag, and sterilized using an autoclave at high temperature, for example, 121°C for 15 minutes. Similarly, stoppers can be placed in an autoclave bag and sterilized using an autoclave at high temperature, for example, 121°C for 15 minutes. Prior to sterilization, a sterile filter can be attached to the tube, for example, a 2 mm length of 7 mm x 13 mm silicone tubing. Filling lines can be prepared by placing them in an autoclave bag and sterilizing using an autoclave at high temperature, for example, 121°C for 15 minutes.

[0228]

[0262] The filtering described above can include filtering into a laminar flow working area. The receiving bottle and filter can be located in the laminar flow working area.

[0263] The above mentioned filling may also be done under laminar flow protection. The filling line may be opened and placed into the receiving bottle. The sterilized vials and stoppers may be opened under laminar flow protection. Each vial may be filled to a target fill amount 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 leaks, correct overseals, and cracks.

[0229]

[0264] In the case of a dry powder, the composition can be formed by spray drying, freeze drying, milling (eg, wet milling, dry milling), and the like.

[0265] As an example, an antiarrhythmic drug can be prepared by lyophilizing the antiarrhythmic drug to form a powder for storage. The powder is then reconstituted prior to use. This technique can be used when the antiarrhythmic drug is unstable in solution.

[0230]

[0266] In some embodiments, the lyophilized powder has an antiarrhythmic agent at about 1 mg / mL to about 150 mg / mL, such as 1 mg / mL to 5 mg / mL, 1 mg / ml to 10 mg / mL, 1 mg / ml to 15 mg / mL, 1 mg / mL to 20 mg / mL, 1 mg / mL to 25 mg / mL, 1 mg / mL to 30 mg / mL, 1 mg / mL to 35 mg / mL, 1 mg / mL to 40 mg / mL, 1 mg / mL to 45 mg / mL, 1 mg / mL to 50 mg / mL, 1 mg / mL to 55 mg / mL, 5 mg / ml to 10 mg / mL, 5 mg / ml to 15 mg / mL, 5 mg / mL to 20 mg / mL, 5 mg / mL to 25 mg / mL, 5 mg / mL to 30 mg / mL, 5 mg / mL to 35 mg / mL, 5 mg / mL to 40 mg / mL, 5 mg / mL to 45 mg / mL, 5 mg / mL to 50 mg / mL, 5 mg / mL to 55 mg / mL, 5 mg / mL to 60 mg / mL; 10 mg / ml to 15 mg / mL, 10 mg / mL to 20 mg / mL, 10 mg / mL to 25 mg / mL, 10 mg / mL to 30 mg / mL, 10 mg / mL to 35 mg / mL, 10 mg / mL to 40 mg / mL, 10 mg / mL to 45 mg / mL, 10 mg / mL to 50 mg / mL, 10 mg / mL to 55 mg / mL, 10 mg / mL to 60 mg / mL, 15 mg / mL to 20 mg / mL, 15 mg / mL to 25 mg / mL, 15 mg / mL to 30 mg / mL, 15 mg / mL to 35 mg / mL, 15 mg / mL to 40 mg / mL, 15 mg / mL to 45 mg / mL, 15 mg / mL to 50 mg / mL, 15 mg / mL to 55 mg / mL, 15 mg / mL to 60 mg / mL, 20 mg / mL to 25 mg / mL, 20 mg / mL to 30 mg / mL, 20 mg / mL to 35 mg / mL, 20 mg / mL to 40 mg / mL, 20 mg / mL to 45 mg / mL, 20 mg / mL to 50 mg / mL, 20 mg / mL to 55 mg / mL, 20 mg / mL to 60 mg / mL, 25 mg / mL to 30 mg / mL, 25 mg / mL to 35 mg / mL, 25 mg / mL to 40 mg / mL, 25 mg / mL to 45 mg / mL, 25 mg / mL to 50 mg / mL, 25 mg / mL to 55 mg / mL, 25 mg / mL to 60 mg / mL, 30 mg / mL to 35 mg / mL, 30 mg / mL to 40 mg / mL, 30 mg / mL to 45 mg / mL, 30 mg / mL to 50 mg / mL,30mg / mL~55mg / mL, 30mg / mL~60mg / mL, 30mg / mL~150mg / mL, 35mg / mL~40mg / mL, 35mg / mL~45mg / mL, 35mg / mL~50mg / mL, 35mg / mL~55mg / mL, 35mg / mL~60mg / mL, 40mg / mL~45mg / mL, 40mg / mL~50mg / mL, 40mg / mL~55mg / mL, 40mg / mL~60mg / mL, 45mg / mL~50mg / mL, 45mg / mL~55mg / mL, 45mg / mL~60mg / mL, 50mg / mL~55mg / mL, 50mg / mL~60mg / mL, 55mg / mL~60 mg / mL, 55mg / mL~65mg / mL, 55mg / mL~70mg / mL, 55mg / mL~75mg / mL, 60mg / mL~65mg / mL, 60mg / mL~70mg / mL, 60mg / mL~7 5mg / mL, 60mg / mL~80mg / mL, 70mg / mL~75mg / mL, 70mg / mL~80mg / mL, 75mg / mL~80mg / mL, 75mg / mL~85mg / mL, 75mg / mL ~90mg / mL, 80mg / mL~85mg / mL, 80mg / mL~90mg / mL, 85mg / mL~90mg / mL, 90mg / mL~100mg / mL, 90mg / mL~110mg / mL, 100m It can be reconstituted in an appropriate solvent to be present at a concentration of 100 mg / mL to 110 mg / mL, 100 mg / mL to 120 mg / mL, 110 mg / mL to 120 mg / mL, 120 mg / mL to 130 mg / mL, 120 mg / mL to 140 mg / mL, 130 mg / mL to 140 mg / mL, 130 mg / mL to 150 mg / mL, 140 mg / mL to 150 mg / mL, or 145 mg / mL to 150 mg / mL.

[0231]

[0267] The solvent of the solution to be lyophilized may comprise water. The solution may be excipient-free. For example, the solution may be cryoprotectant-free.

[0268] In one or more embodiments, an appropriate amount of drug substance (e.g., 120 g per liter of final solution) can be dissolved in about 75% of the total theoretical volume of water for injection, for example under nitrogen bubbling. Dissolution time can be recorded and appearance can be evaluated.

[0232]

[0269] Dilution to final volume with WFI may then be performed. Final volume may be confirmed. Density, pH, endotoxin, bioburden and UV content may be measured both before and after sterile filtration. The moisture content of the lyophilized powder is typically less than about 7 wt%, for example, less than about 5 wt%, less than about 4 wt%, less than about 3 wt%, less than about 2 wt%, or less than about 1 wt%.

[0233]

[0270] The powder can be reconstituted with water by manual agitation in less than about 60 seconds, e.g., less than about 30 seconds, less than about 15 seconds, or less than about 10 seconds, at 25° C. and 1.0 atmosphere pressure. The powder typically has a large specific surface area that facilitates reconstitution. The specific surface area is typically about 5 m 2 / g~about 20m 2 / g, for example, about 8m 2 / g~15m 2 / g, or about 10m 2 / g~12m 2 Upon reconstitution with water, the antiarrhythmic pharmaceutical agent solution typically has a pH in the range of about 2.5 to about 7, for example, about 3 to about 6.

[0234]

[0271] In spray drying, the preparation or feedstock to be spray dried can be any solution, coarse suspension, slurry, colloidal dispersion, or paste that can be atomized using the selected spray drying equipment. For insoluble drugs, the feedstock may include the above suspension. Alternatively, a dilute solution and / or one or more solvents may be utilized in the feedstock. In one or more embodiments, the feedstock includes a colloidal system such as an emulsion, an inverse emulsion, a microemulsion, a multiple emulsion, a particle dispersion, or a slurry.

[0235]

[0272] The pharmaceutical composition useful in one or more embodiments of the present invention may alternatively be formed by lyophilization. Lyophilization is a freeze-drying process that sublimates water from the composition after freezing. The freeze-drying process is often used for biologicals and medicines that are relatively unstable in aqueous solutions, because they can be dried without exposure to high temperatures and then stored in a dry state with fewer stability issues. In relation to one or more embodiments of the present invention, such techniques are particularly suitable for incorporating peptides, proteins, genetic materials and other natural and synthetic macromolecules into pharmaceutical compositions without compromising physiological activity. The freeze-dried cake, which contains a fine foam-like structure, can be micronized using techniques known in the art to provide particles of the desired size.

[0236]

[0273] In some embodiments, the potassium channel blockers and sodium channel blockers can be administered by parenteral injection as a single liquid solution that may contain other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickening agents, preservatives or excipients. Parenteral injections can be formulated for bolus injection or continuous infusion. The pharmaceutical composition may be in a form suitable for parenteral injection as a sterile suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulating agents such as suspending, stabilizing or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form. For example, the compositions described herein can be provided in liquid form and may be formulated in saline-based aqueous solutions of various pHs (5-8) with or without detergents such as 0.01-1% polysorbate-80, or carbohydrate additives such as mannitol, sorbitol or trehalose. Commonly used preservatives include chlorobutanol, m-cresol, benzyl alcohol, phenylethyl alcohol, phenol, methylparaben or propylparaben. Commonly used buffers include histidine, acetate, phosphate, borate or citrate. Commonly used isotonicity adjusting agents include sodium chloride, mannitol and glycerin. Infusion solutions may contain 0-10% dextrose. Suspensions of the active compound can be prepared as oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Suspensions can also contain suitable stabilizers or agents that increase the solubility of the compounds, for example, cyclodextrins or organic solvents, to allow for the preparation of highly concentrated solutions.The organic solvent may include alcohols, such as C1-C4 straight chain alkyl, C3-C4 branched alkyl, ethanol, ethylene glycol, glycerin, 2-hydroxypropanol, propylene glycol, maltitol, sorbitol, xylitol; substituted or unsubstituted aryl and benzyl alcohols. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0237]

[0274] Non-limiting examples of pharma- ceutically acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.

[0238]

[0275] Pharmaceutical compositions according to one or more embodiments of the present invention can optionally include a combination of an antiarrhythmic pharmaceutical agent with one or more additional active agents, including, but not limited to, agents that can be delivered through the lungs.

[0239]

[0276] Additional active agents may include, for example, hypnotics and sedatives, mental stimulants, tranquilizers, respiratory system drugs, anticonvulsants, muscle relaxants, anti-Parkinson's drugs (dopamine antagonists), analgesics, anti-inflammatory drugs, anti-anxiety drugs (anxiolytics), appetite suppressants, anti-migraine drugs, muscle contraction drugs, additional anti-infective drugs (antivirals, antifungals, vaccines), anti-arthritic drugs, antimalarials, antiemetics, anti-epileptic drugs, cytokines, growth factors, anti-cancer drugs, antithrombotic drugs, antihypertensive drugs, cardiovascular drugs, antiarrhythmic drugs, antioxidants, anti-asthmatic drugs, hormonal drugs including contraceptives, sympathomimetics, diuretics, lipid regulating agents, antiandrogens, antiparasitic drugs, anticoagulants, neoplasms, antineoplastic drugs, 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, can act locally or systemically.

[0240]

[0277] 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.

[0241]

[0278] Examples of additional active agents suitable for use in the present invention include 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 herein in its entirety), amylin, C-peptide, somatostatin, somatostatin including octreotide Tatin analogs, 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 peptide 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, daversine, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, leucomycin, miokamycin, rokitamycin, andazithromycin and swinolide A;Fluoroquinolones, such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxacin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin, clinafloxacin and sitafloxacin, teicoplanin, ramoplanin, mideplanin, colistin, daptomycin, gramicidin, colistimethate, polymyxins, e.g. polymyxin B, capreomycin, bacitracin, penems; penicillinase-susceptible drugs, e.g. penicillin G, penicillin V; penicillinase-resistant drugs, e.g. methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, Penicillins, including nafcillin; Gram-negative microbiological active agents, such as ampicillin, amoxicillin and hetacillin, cillin and galampicillin; antipseudomonal penicillins, such as carbenicillin, ticarcillin, azlocillin, mezlocillin and piperacillin; cephalosporins, such as cefpodoxime, cefprozil, ceftibuten, ceftizoxime, ceftriaxone, cephalothin, cephapirin, Cephalexin, cephradine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cefaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefintazole, ceftazidime, loracarbef and moxalactam, monobactams such as aztreonam;and carbapenems, such as imipenem, meropenem, pentamidine isethionate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate, and one or more of the above analogs, agonists, antagonists, inhibitors, and pharma- ceutically acceptable salt forms, where applicable. With respect to peptides and proteins, the invention is intended to encompass synthetic, native, glycosylated, non-glycosylated, pegylated forms, and biologically active fragments, derivatives, and analogs thereof.;

[0242]

[0279] Additional active agents for use in the present invention may further comprise nucleic acids as naked nucleic acid molecules, vectors, associated viral particles, plasmid DNA or RNA, or other nucleic acid constructs suitable for transfection or transformation of cells, for example, suitable for gene therapy, including antisense.Furthermore, active agents may comprise live attenuated viruses or killed viruses suitable for use as vaccines.Other useful drugs include those listed in the Physician's Desk Reference (latest edition), which is incorporated herein by reference in its entirety.

[0243]

[0280] When a combination of active agents is used, the agents may be provided combined in a single pharmaceutical composition or individually in separate pharmaceutical compositions. EXAMPLES

[0244]

[0281] The following examples are provided to further illustrate some embodiments of the invention, but are not intended to limit the scope of the invention, and it will be understood by their exemplary nature that other procedures, methods, or techniques known to those skilled in the art may alternatively be used.

[0245] Example 1: Intravenous administration of ibutilide in a porcine model of paroxysmal atrial fibrillation. Anesthesia and monitoring.

[0282] Normal Yorkshire pigs are pre-anesthetized with Telazol (4.7 mg / kg, intramuscularly) and then further anesthetized using alpha-chloralose (IV bolus of 80 mg / kg, followed by continuous IV infusion of 24 mg / kg / h). The pigs are intubated and ventilated at a constant rate of 12 breaths / min and a tidal volume of 400 ml per beat. Blood samples for measurement of plasma levels of ibutilide and flecainide are taken at the same time points at which pharmacodynamic measurements are performed. Systolic, diastolic and mean arterial pressure (MAP), pulmonary artery pressure (PAP), LV pressure and ECG (e.g., heart rate) are continuously monitored. At specific time points (0, 2, 5, 10, 15, 30, 60 min), pulmonary artery wedge pressure (PWP) using atrial electrocardiogram, LV contractile force (LV dp / dt), ECG intervals (e.g., QRS, PR, QT) and atrial depolarization duration (Pa) are measured.

[0246] Conversion of atrial fibrillation to normal sinus rhythm and pharmacokinetic analysis.

[0283] Cardiac catheters are positioned under fluoroscopic control. Electrograms are recorded from a decapolar electrode catheter positioned in the LV. Mean arterial pressure (MAP) is recorded continuously from the femoral artery sheath. LV blood pressure is continuously monitored from a pigtail catheter. A catheter is introduced into the pericardial space via the right atrial appendage to deliver intrapericardial acetylcholine. Atrial pacing at 160 beats / min is achieved by delivering electrical stimuli to the right atrial catheter electrode. Electrograms are monitored from atrial and ventricular sites.

[0247]

[0284] AF is induced by a 1 mL bolus of 102.5 mM solution of acetylcholine delivered from the pericardial catheter, followed by a saline flush (2 mL). Burst pacing is performed 1 min after intrapericardial administration of ACh with a cycle length of 178 ms. After AF initiation, flushing is performed with 20 mL of saline. The duration of AF is compared starting 2 min after induction of AF, the time point at which an IV dose of ibutilide fumarate is administered. Ibutilide fumarate is administered intravenously into the right jugular vein at 0.1 mg / kg body weight, 1.0 mg / kg body weight, or 5.0 mg / kg body weight. Blood samples are collected in a partially evacuated tube from the jugular catheter. Blood samples are collected before administration of ibutilide fumarate and 0, 2, 5, 10, 15, and 30 min after administration. A washout period of 120 min was allowed between the induction of each episode of AF. Plasma concentrations of ibutilide will be assessed in all blood samples using HPLC / MS-MS and pharmacokinetic and pharmacodynamic parameters will be determined.

[0248]

[0285] The mean ventricular rate for each AF is obtained by averaging six measurements of ventricular rate performed 30 seconds each between IV delivery (sterile water or ibutilide fumarate solution) and conversion of AF to normal sinus rhythm. Contractile force (LV dP / dt) and MAP are recorded during atrial pacing at 160 beats / min before induction of AF and after termination of AF.

[0249] Example 2: Fixed-dose combination matrix study of IV ibutilide and IV flecainide in a porcine model of paroxysmal atrial fibrillation.

[0286] Normal pigs are anesthetized, hemodynamic and ECG parameters are monitored, and AF is induced as in Example 1. Multiple intravenous fixed dose combinations of flecainide acetate and ibutilide fumarate as described in Table 1 are administered and their effects assessed on terminating AF induced according to the procedures outlined in Example 1.

[0250] [Table 1]

[0251] Example 3: Fixed-dose combination matrix study of IV ibutilide and IV flecainide in a porcine model of permanent atrial fibrillation.

[0287] Normal Yorkshire pigs are implanted with single chamber atrial pacemakers. Burst atrial pacing at 42 Hz with a sinus rhythm detection rate of 180 / min is performed for 10 days, whereupon the occurrence of permanent AF is confirmed by ECG measurements. Pigs are anesthetized and hemodynamic and ECG parameters are monitored as in Example 1. The FDCs in Table 1 are administered intravenously into the right jugular vein. Blood samples are collected from the jugular catheter into a partially evacuated tube. Blood samples are collected before administration of ibutilide fumarate and at 0, 2, 5, 10, 15 and 30 minutes after administration. A washout period of 120 minutes is allowed between each dose administration. Plasma concentrations of ibutilide in all blood samples are assessed using HPLC / MS-MS, and pharmacokinetic and pharmacodynamic parameters are determined as in Example 1.

[0252] Example 4: Oral administration of dofetilide in a porcine model of paroxysmal atrial fibrillation. Anesthesia and monitoring.

[0288] Normal Yorkshire pigs are pre-anesthetized with Telazol and then further anesthetized using alpha-chloralose. The pigs are intubated and ventilated at a constant rate of 12 breaths / min and a tidal volume of 400 ml per beat. Blood samples for measurement of plasma levels of dofetilide and flecainide are taken at the same time points at which pharmacodynamic measurements are performed. Systolic, diastolic and mean arterial pressure (MAP), pulmonary artery pressure (PAP), LV pressure and ECG (e.g., heart rate) are continuously monitored. At specific time points (0, 2, 5, 10, 15, 30, 60 min), pulmonary artery wedge pressure (PWP) using atrial electrocardiogram, LV contractile force (LV dp / dt), ECG intervals (e.g., QRS, PR, QT) and atrial depolarization duration (Pa) are measured.

[0253] Conversion of atrial fibrillation to normal sinus rhythm and pharmacokinetic analysis.

[0289] Atrial fibrillation is converted to normal sinus rhythm and pharmacokinetic analysis is performed as described in Example 1.

[0254] Example 5: Fixed-dose combination matrix study of oral tablets in the treatment of paroxysmal atrial fibrillation in a porcine model.

[0290] This study evaluates the treatment of paroxysmal atrial fibrillation in a porcine model by oral administration of tablets containing potassium and sodium channel blockers. Treatment groups are divided to confirm the effect of combination drug tablets: 1) control treatment, 2) dofetilide, 3) sotalol, 4) flecainide, 5) dofetilide + flecainide, 6) sotalol + flecainide, 7) ibutilide and 8) ibutilide + flecainide.

[0255]

[0291] Normal pigs are anesthetized, hemodynamic and ECG parameters are monitored, and AF is induced similarly as described in Example 1. Orally administered tablets consisting of dofetilide or sotalol in combination with flecainide acetate are administered and their effectiveness assessed for terminating AF induced according to the procedures outlined in Example 1.

[0256] Example 6. Fixed-dose combination matrix study of oral tablets in the treatment of permanent atrial fibrillation in a porcine model.

[0292] A single chamber atrial pacemaker is implanted in a normal Yorkshire pig. Burst atrial pacing of 42 Hz is performed for 10 days with a sinus rhythm detection rate of 180 / min, and the occurrence of permanent AF is confirmed by ECG measurement. The pig is anesthetized, and hemodynamic and ECG parameters are monitored as in Example 1.

[0257]

[0293] This study evaluates the treatment of paroxysmal atrial fibrillation in a porcine model by oral administration of tablets containing potassium and sodium channel blockers. Treatment groups are divided to confirm the effect of combination drug tablets: 1) control treatment, 2) dofetilide, 3) sotalol, 4) flecainide, 5) dofetilide + flecainide, and 6) sotalol + flecainide.

[0258]

[0294] Normal pigs are anesthetized, hemodynamic and ECG parameters are monitored, and AF is induced similarly as described in Example 1. Orally administered tablets consisting of ibutilide, dofetilide or sotalol in combination with flecainide acetate are administered and their effectiveness assessed for terminating AF induced according to the procedures outlined in Example 1.

[0259]

[0295] Blood samples are collected from the jugular catheter into a partially evacuated tube. Blood samples are collected before and 0, 2, 5, 10, 15, and 30 minutes after dofetilide administration. A washout period was allowed between each dose administration. Plasma concentrations of dofetilide in all blood samples are assessed using HPLC / MS-MS, and pharmacokinetic and pharmacodynamic parameters are determined as in Example 1.

[0260] Example 7: Efficacy of flecainide and ibutilide in preventing ACh-mediated AF in a canine isolated coronary perfusion model.

[0296] A study was conducted to investigate the effects of flecainide and ibutilide, alone and in combination, on atrial and ventricular electrophysiological parameters, as well as their efficacy in preventing the induction of ACh-mediated AF and in terminating AF once induced, in a canine isolated coronary perfusion model of AF.

[0261] method.

[0297] Experiments were performed using an isolated canine arterial perfusion preparation consisting of the right atrium with the edge of the right ventricle. Hearts were from approximately 1-year-old beagles and were preserved in ice-cold cardioplegia solution for approximately 40 min prior to the experiments.

[0262] Electrophysiological recordings.

[0298] During the experiments, transmembrane action potential (AP) recordings (sampling rate 41 kHz) were obtained from the atria and ventricles using floating glass microelectrodes (10–25 MΩ DC resistance). Pseudo electrocardiograms (ECGs) were recorded using two electrodes consisting of Ag / AgCl half-cells placed 1.0–1.2 cm from the opposing ends of the atrial coronary perfusion preparation in Tyrode's solution bathing the preparation (Figure 1). Effective refractory periods (ERPs) were measured by delivering premature stimuli every 10 basic beats with a pacing cycle length (CL) of 500 ms. Diastolic thresholds of excitation (DTEs) were determined by increasing the stimulation intensity in 0.01 mA steps, starting from 0.1 mA, until a stable 1:1 activation was achieved. Post-repolarization refractoriness (PRR) was noted when the ERP exceeded APD90 in the ventricles and APD70 in the atria. Ventricular ERPs coincide with APD90, and atrial ERPs generally coincide with APD70. The anti-atrial fibrillation (AF) ability of flecainide with or without ibutilide was tested in an acetylcholine (ACh, 0.5 μM)-mediated AF model. AF was induced by a single premature stimulus and / or rapid pacing burst (CL=50-100 ms for 3-10 s).

[0263]

[0299] In another experimental series (series II), the effects of flecainide and ibutilide, alone and in combination, were investigated for their effect in terminating AF after induction with burst pacing. Ventricular electrical activity was monitored for the occurrence of early afterdepolarizations (EADs) and torsades de pointes (TdP).

[0264] solution.

[0300] Stock solutions were made by dissolving dry powders of the test articles in distilled water vehicle. The solutions were stored in a refrigerator and used on the day of the experiment. Dilutions of the stock solutions were performed immediately prior to the experiment. Composition of Tyrode's solution (in mM): NaCl 129, KCl 4, NaH2PO4 0.9, NaHCO3 20, CaCl2 1.8, MgSO4 0.5, Glucose 5.5, Insulin 1 unit / liter, buffered with 95% O2 and 5% CO2, pH=7.4.

[0265] Experiment Series I.

[0301] Electrophysiological measurements were performed on isolated canine arterially perfused right atria with the edge of the right ventricle after at least 20 min of perfusion with each drug concentration defined in Table 2. Electrophysiological measurements were performed at a CL of 500 ms.

[0266] [Table 2]

[0267]

[0302] Figure 3 shows representative traces illustrating the effects of flecainide (Table 2, A, step 2), ibutilide (A, step 5), and the combination of flecainide and ibutilide on atrial (Figure 3, left column) and ventricular (Figure 3, right column) action potentials (B, step 2) (CL = 500 ms).

[0268]

[0303] Figure 4 shows a chart showing the effect of flecainide, ibutilide, and their combination on the effective refractory period (ERP) and action potential duration (APD) of the atria and ventricles. APD70 is shown for the atria and APD90 for the ventricles (ERP generally corresponds to these levels of APD). Pacing CL=500ms.

[0269]

[0304] FIG. 5 shows a chart showing the effect of flecainide (Table 2, A, step 2), ibutilide (A, step 5), and the combination of flecainide and ibutilide on post-repolarization refractoriness (PRR) of the atria and ventricles. In the atria, PRR=ERP minus APD70. In the ventricles, PRR=ERP minus APD90. CL=500ms.

[0270]

[0305] FIG. 6 is a chart showing the percent occurrence of ACh-mediated AF in canine right atrium preparations treated with ibutilide (Table 2, A, step 6), flecainide (A, step 3), and a combination of ibutilide and flecainide (B, step 3). ACh (0.5 μM) was added to the coronary perfusate in the presence of flecainide (1.5 μM), ibutilide (20 nM), or a combination of these agents. Induction of AF was first tested with a single premature beat, and rapid pacing was applied if persistent AF was not induced.

[0271]

[0306] In each preparation, there were multiple episodes of self-terminating AF before the AF became persistent. Self-terminating AF was defined as AF that terminated within 20 seconds (most cases of self-terminating AF terminated within 1-2 seconds). Figure 7 shows an exemplary ECG tracing demonstrating repeatedly induced self-terminating episodes of AF followed by induction of persistent AF (lasting >1 hour).

[0272] Experiment Series II.

[0307] The effects of flecainide and ibutilide, alone and in combination, on the termination of persistent AF were investigated in canine right atria in the experimental groups defined in Table 3. Persistent AF was induced in the presence of ACh (0.5 μM) and the test drugs were added to the coronary perfusate containing ACh (0.5 μM) at the 5th to 8th minutes of AF.

[0273] [Table 3]

[0274]

[0308] FIG. 8 is a chart showing the percentage of preparations in which ACh-induced persistent AF was terminated by administration of flecainide (Table 3, A, step 3), ibutilide (B, step 3), or the combination of flecainide and ibutilide (C, step 3). The combination of flecainide (1.5 μM) and ibutilide (20 nM) terminated persistent AF in all cases (2 of 2 cases) 9 to 17 minutes after exposure to the drug combination. Flecainide alone was ineffective (0 of 2 cases), and ibutilide terminated persistent AF in 1 of 3 test samples. FIG. 9 is a chart showing the effects of flecainide (1.5 μM), ibutilide (20 nM), and the combination of flecainide and ibutilide in blunting the effect of ACh-mediated ERP shortening (C, step 3).

[0275] Experiment Series III.

[0309] A series of experiments was performed using canine left ventricular wedge preparations bathed in 3 mM KCl Tyrode's solution and paced at a CL of 2500 msec to sensitize the preparations to the development of EAD. Drugs were administered in the sequence and concentrations specified in Table 4.

[0276] [Table 4]

[0277]

[0310] Canine left ventricular (LV) wedge preparations were excised from the same hearts used to obtain the right atrium preparations. Given that ibutilide failed to induce EAD and / or TdP under these conditions, the preparations were further sensitized by exposure to ATX-II (10-20 nM) to increase late sodium channel currents, thereby mimicking conditions encountered in the setting of heart failure.

[0278]

[0311] The resulting traces are shown in FIG. 10, where from top to bottom, each panel shows the M (midmyocardial) and Epi (epicardial) action potential (AP) recordings, as well as the corresponding ECG (BCL=2000 msec). Panel A: control. Panel B: recording obtained after 40 min of perfusion with ibutilide (50 nM). Panel C: recording obtained after adding flecainide (1.5 μM, 30 min) to the perfusate. The numbers appearing below the MAP indicate the APD90 values, while the numbers above the ECG recording indicate the values ​​of the QT interval. Ibutilide significantly prolonged the repolarization (QT interval and Tpeak-Tend were dramatically prolonged). The addition of flecainide partially reversed the effect of ibutilide.

[0279] Example 8: Single-dose pharmacokinetic and pharmacodynamic studies in pigs.

[0312] A study was conducted to determine the comparative pharmacokinetic / pharmacodynamic (PK / PD) responses of the test articles (flecainide or ibutilide) when administered to study subjects (Sinclair pigs) by intravenous injection either individually or as a flecainide-ibutilide combination.

[0280]

[0313] Flecainide acetate was given as a 90 nM acetate buffer solution (pH 5.2) for intravenous injection. Ibutilide hemifumarate was given as a 90 nM acetate buffer solution (pH 5.2) for intravenous injection.

[0281]

[0314] The study used nine male Sinclair pigs, aged 3-5 months and weighing 13.5-16 kg at the start of the study.

[0315] After animals were transferred to the study, all animals were randomly assigned to treatment groups according to the study design described below. The study was designed as a crossover design with a minimum of 1 week washout between treatment "A" and treatment "B". Test articles (antiarrhythmic drugs flecainide and ibutilide) were administered as individual or combination doses by intravenous (IV) infusion in a low dose regimen ("A") followed by a higher dose regimen ("B"). Electrocardiograms (EKGs) were performed prior to infusion and within 30 minutes of dose completion for both "A" and "B" treatments. Infusions were performed under sedation and anesthesia was maintained during blood collection after infusion. Blood was collected according to Table 5 below: prior to infusion, mid-infusion, and 0, 2, 4, 6, 8, 10, 15, 30, 45, 60, and 120 minutes after infusion completion for both "A" and "B" treatments.

[0282] [Table 5]

[0283] Test article and vehicle formulations.

[0316] The formulations used in the study are defined in Table 6.

[0284] [Table 6]

[0285] Test article and vehicle administration: intravenous injection.

[0317] All animals were anesthetized for intravenous (IV) infusion of test articles (approximately 10 mL / kg over 10 min) and blood collection according to ACL-2010, Procedures for Injections, Blood Withdrawal, and Dermal Dosing in Swine. Pigs were sedated with target doses of 0.5 mg / kg midazolam and 25 mg / kg ketamine (working doses ranged from 0.5215 to 0.519 mg / kg and 24.83 to 25.33 mg / kg, respectively), except for one animal, which received half the target dose (0.26 mg / kg midazolam and 12.67 mg / kg ketamine) as directed by a veterinarian. Animals were anesthetized with isoflurane (induction 5%, maintenance approximately 0.5 to 3%) by facemask inhalation during injections and blood collection. All anesthesia and monitoring of vital parameters was performed in accordance with ACL-2011. Animal weights and volumes of formulation administered are summarized in Table 7.

[0286] [Table 7]

[0287] Clinical Observations and Survival.

[0318] All animals survived to completion of the study. Animals were clinically observed twice daily continuously per ACL-1974 Receipt, Quarantine and Husbandry of Swine while under anesthesia during, pre- and post-dose dosing until final blood draw per TXP-1532, Pharmacologic and Toxicological Observations of Experimental Animals. Abnormal clinical observations included two animals in the ibutilide treatment group that stopped breathing under anesthesia. One of these animals was during the high dose treatment ("B") and was intubated and provided with oxygen under the direction of veterinary staff. The other was during the low dose treatment (A) and returned to normal breathing without the need for additional support. Both of these abnormal events were determined to be due to anesthesia.

[0288] body weight.

[0319] The mean group weights are shown in Table 8.

[0289] [Table 8]

[0290] Electrocardiogram (EKG).

[0320] All animals underwent electrocardiograms (EKGs) using the EMKA system. EKGs were collected pre-dosing (any time prior to each dose administration) and within 30 min of the completion of each infusion according to TLE-2125, Physiological Data Collection for Large Animals Using the emka PACK4g Acquisition System. ECG waveforms were quantitatively assessed for heart rate (HR) and PR, QRS and QT / QTc intervals using a validated ecgAUTO system (v3.5.5, emka TECHNOLOGIES, Paris, France).

[0291] QTcB(Bazett)=QT / RR(1 / 2) QTcF(Fridericia)=QT / RR(1 / 3) QTcV(Van de Water)=QT-0.087(RR-1000) where RR = time between successive beats measured in milliseconds.

[0292]

[0321] In this study, HR fluctuated at baseline (consistent mean values ​​with treatment A / B in flecainide group 1, fluctuating with treatment B in ibutilide group 2, and strong reduction with treatment B in combination group 3). After infusion, all groups with either treatment A or B experienced a reduction in HR. Prolongation of the PR interval was seen in all groups / treatments after infusion, driven directly by pharmacology and indirectly by the reduction in HR. QT / QTc increased with ibutilide treatment A / B. The increase in QT / QTcV was smaller in the combination group, which was determined to be due to the adverse effect of flecainide.

[0293]

[0322] Baseline normalized post-infusion physiological parameters for Treatment A and Treatment B are shown in Tables 9 and 10, respectively.

[0294] [Table 9]

[0295] [Table 10]

[0296] Bioanalysis.

[0323] Blood samples were collected and placed into K3EDTA blood collection tubes at the time points mentioned above. The tubes were centrifuged, and the plasma was separated and aliquoted into appropriately labeled vials. Samples were stored at -70 to -90°C until transferred for analysis. max were observed at or near the end of the infusion. Furthermore, the test article maintained a dose response between the low and high doses (Treatments A and B). Plasma concentrations of the test article were above the lower limit of quantitation at the 120 minute collection time point.

[0297]

[0324] FIG. 11 shows charts summarizing the pharmacokinetic profiles of flecainide and ibutilide in animals administered 1 mg / kg flecainide acetate (Treatment A, Group 1), 0.007 mg / lg ibutilide hemifumarate (Treatment A, Group 2), 1 mg / kg flecainide acetate + 0.007 mg / lg ibutilide hemifumarate (Treatment A, Group 3), 2 mg / kg flecainide acetate (Treatment B, Group 1), 0.014 mg / lg ibutilide hemifumarate (Treatment B, Group 2), and 2 mg / kg flecainide acetate + 0.014 mg / lg ibutilide hemifumarate (Treatment B, Group 3).

[0298]

[0325] Quantitative values ​​of flecainide and ibutilide in individual animal plasma are shown in Tables 11 and 12, respectively. The following samples were re-extracted and re-analyzed: Treatment A: Sample IDs 2003, 3001, 3002 - all time points (39 samples) Treatment B: Sample IDs 1002, 1003 - 0 min and 50% dose (4 samples)

[0326] Replicate analyses were performed in duplicate and a second sample aliquot not originally analyzed was used. Reanalyses are reported based on the following criteria: if the average result of the initial and reanalyzed samples is within 20% agreement, the original value is maintained. If the average of the initial and reanalyzed samples is outside of 20% agreement, the average of the reanalyzed samples is reported.

[0299] [Table 11]

[0300] [Table 12]

[0301] overview.

[0327] Intravenous administration of test articles (antiarrhythmic drugs flecainide and ibutilide) was evaluated in low-dose (1 mg / kg, 0.007 mg / kg, or both, respectively) and high-dose (2 mg / kg, 0.014 mg / kg, or both, respectively) regimens, and short-term pharmacological responses were assessed by correlating electrocardiograms with circulating blood volume. Electrocardiograms were performed before infusion and within 30 minutes of completion of dosing for both treatments. Blood was collected for bioanalysis before, midway through, and at 0, 2, 4, 6, 8, 10, 15, 30, 45, 60, and 120 minutes after completion of infusion for both treatment groups.

[0302]

[0328] All animals survived to study completion and there were no inconclusive test article clinical observations. max were observed at or near the end of the infusion. Furthermore, the test article maintained a dose response between the low and high doses (Treatments A and B). Plasma concentrations of the test article were above the lower limit of quantitation at the 120 minute collection time point.

[0303] Example 9: In silico modeling of chemical atrial defibrillation with flecainide and ibutilide.

[0329] An in silico study was conducted to determine whether a specific combination of sodium and potassium channel blockers could be utilized to terminate atrial fibrillation. A comprehensive modeling and simulation approach was applied to determine the potential efficacy of flecainide and ibutilide used in combination for chemical cardioversion. A simulated safety study was also performed to analyze the potential safety pharmacological effects of this drug combination on ventricular electrophysiology.

[0304] Part 1 - Effects of flecainide and ibutilide on atrial electrophysiology.

[0330] To describe the interaction between Na channel (Figure 12) and flecainide, a computational framework was formulated by numerical optimization from experimentally obtained rate constants. Figure 12 shows a Markov model of Na channel-drug interaction. Drug-free includes eight states (black top row). Grey lines indicate entry and exit from the drug-bound state, denoted by D+. Some arrows have been omitted for clarity.

[0305]

[0331] The model simulated features including frequency- and use-dependent block, tonic block, and time- and voltage-dependent recovery (Figure 13). Figure 13 shows simulated (lines) and experimental (symbols) flecainide-Na channel interactions. Panel A shows steady-state channel availability, where currents were measured at -10 mV with 10 μM flecainide. Panel B shows dose-dependence of use-dependent block (UDB) from 300 pulses of 25 ms from -100 mV to -10 mV at 5 Hz with the indicated drug doses. Block is the peak current of the last pulse normalized to the first pulse. Panel C shows recovery from UDB after a pulse from -100 mV (25 ms to -10 mV at 25 Hz) with 10 μM flecainide. Panel D shows frequency-dependence of UDB, protocol is the same as that of panel B with 10 μM flecainide. Panel E shows dose-dependence of tonic block (TB). A single depolarizing pulse from -100 mV to -10 mV was evoked. Block is a percentage of the peak current normalized to the drug-free condition.

[0306]

[0332] Using a similar technique, I Kr The blocker ibutilide was modeled using a concentration-response relationship to determine the concentration-dependent I Kr Peak conductance of the channel. Wild-type drug-free Na + and flecainide models were used as previously described in Moreno, JD, et al., Sci Transl med, 2011.3(98):p.98ra83. Models of Na channel and drug interactions, and hERG (Yang, PC, et al., Circ Res, 2020.126(8):p.947-964) and drug interactions were incorporated into the Grandi-Bers atrial human cell model. An example is shown in Figure 14, where panel A shows simulated atrial cell action potentials and atrial Na currents generated by the Grandi-Bers human atrial cell model, and panel B shows simulated Na currents during an atrial AP. Prediction of the effects of flecainide and ibutilide in simulated atrial myocytes (APD 90 ).

[0307]

[0333] When modeled in atrial myocytes, simulations predicted that flecainide alone would show a rate-dependent reduction in atrial action potential excitability, while ibutilide alone would show an inverse use-dependent prolongation of action potential duration (Figure 15). Figure 15 shows the APD at various pacing frequencies with flecainide alone or ibutilide alone. 90 Figure 1 shows simulated action potential adaptation curves showing an extension of the refractory period, indicated as APD. The cell was paced for 1000 beats at each cycle length, and the final APD 90 was recorded.

[0308]

[0334] When flecainide and ibutilide were modeled together in atrial myocytes, the combined effect was non-additive and reduced APD 90 This resulted in changes in both the effect on the effective refractory period as indicated by the change in the slope of the APD adaptation curve shown in FIG. 16 as well as in the morphology of the action potential as indicated by the change in the slope of the APD adaptation curve shown in FIG.

[0309]

[0335] The simulation predicted that flecainide reduced the reverse use-dependent prolongation of action potential duration induced by ibutilide. Furthermore, the simulation proposed three possible ideal drug combinations with low concentrations of ibutilide (important for ventricular safety) for the prolongation of refractory period >20 ms and flattening of the reverse use-dependent curve. These combinations are indicated by stars in Figure 16. Combined flecainide and ibutilide effectively prolonged action potential duration while reducing the reverse use-dependent. In effect, this result indicated that during atrial fibrillation, where the heart rate is rapid, the drug is suitable to extend the refractory period and terminate the arrhythmia. The resulting predicted preferred drug concentrations included 1.0 μM flec + 0.01 μM ibu, 1.5 μM flec + 0.005 μM ibu, and 2.0 μM flec + 0.005 μM ibu.

[0310] Prediction of the effects of flecainide and ibutilide in simulated atrial tissue.

[0336] The possibility that flecainide and ibutilide together exert a synergistic effect on the effective refractory period in connective tissue was explored, showing a synergistic effect resulting from the drug combination. Figure 17 shows the ΔERP observed in a simulated fiber composed of 165 cells connected by resistors simulating gap junctions. Refractory periods were recorded in a 1D fiber upon drug application alone (left bar) or in combination (right bar).

[0311]

[0337] We also developed a simulated self-sustaining model of atrial reentry by constructing a representative of atrial reentry using a one-dimensional model of 1500 Grandi-Bers simulated cells connected by resistors simulating gap junctions. The first cell was stimulated to induce propagation along the fiber. Then, when the voltage at the center of the cell was >-40, both ends of the one-dimensional tissue model were connected to induce unidirectional reentry by continuously propagating around the ring. A schematic of the model used to simulate reentrant atrial arrhythmias is shown in Figure 18. The wavelength (CV=56cm / s×CL=400ms) was set to 22.5cm. The simulated 1500 Grandi-Bers cells were connected in a ring to allow for self-sustaining reentry activity.

[0312]

[0338] Figure 19 shows simulated action potentials in the ring model upon exposure to drug combinations of flecainide and ibutilide, where darkness of the greyscale represents potential (peak / trough = darker) and individual cells are represented by a series of vertically stacked horizontal lines plotted over time, with the vertical axis position of each line indicating the cell position within the ring. The flecainide and ibutilide drug combinations investigated terminated sinus rhythm reentry within 20 seconds. Higher doses of flecainide combined with low doses of ibutilide terminated reentry quickly.

[0313]

[0339] Atrial reentry was also simulated using a one-dimensional model of 340 Grandi-Bers simulated cells in the presence of Ach (0.015 μM) to allow for a self-sustained reentry rhythm at rapid rates (>150 BPM). In these cases, the wavelength was set to 5 cm, since the CL was reduced to 166 ms. As shown in the resulting action potentials depicted in FIG. 20, the lowest doses of flecainide and ibutilide did not terminate reentry before 150 seconds, but higher doses of flecainide combined with low doses of ibutilide rapidly inhibited reentry.

[0314] Part 2: Prediction of the effects of flecainide and ibutilide on simulated ventricular electrophysiology (safety pharmacology).

[0340] A safety pharmacological screening was performed in O'Hara-Rudy human ventricular myocytes for the proarrhythmic effects of flecainide and ibutilide, alone or in combination, by tracking key parameters. Each parameter was tracked in the absence of drug and in the presence of flecainide and ibutilide, alone or in combination. Wild-type drug-free Na+ and flecainide and ibutilide models were incorporated into the O'Hara-Rudy human ventricular cell model with modifications as previously described in Moreno, JD, et al., Sci Transl med, 2011.3(98):p.98ra83.

[0315] Modified ORd model.

[0341] The baseline O'Hara-Rudy model was modified as per Krogh-Madsen, T., et al., Front. Physiol., 2017.8:p.1059. The optimized O'Hara-Rudy model using clinical extended QT data and with physiological boundaries for intracellular calcium and sodium concentrations shows improved predictive power of torsades de pointes risk. The optimized model was tested against known arrhythmogenic and non-arrhythmogenic ion channel blockers and shown to provide improved risk assessment and reduced false positive results that occurred with the original O'Hara-Rudy model (shown in the appendix below). Table 13 shows the modified ionic current conductance in the optimized O'Hara-Rudy model.

[0316] [Table 13]

[0317]

[0342] Table 14 shows the IC of drugs for current inhibition tested in the optimized O'Hara-Rudy model. 50 The range of values ​​is shown. Kr has an EC of 0.4 μM 50 was assigned.

[0318] [Table 14]

[0319]

[0343] The optimized O'Hara-Rudy model accurately reproduces the clinically reported effects of flecainide on heart rate corrected QT intervals in a 4 cm simulation that approximates the size of the human heart. Figure 21 shows the modified ORd simulated QT / QTc intervals compared to clinical data (Hellestrand, K., et al. (1982), Pacing and Clinical Electrophysiology, 5:180-184.). The length of the cable was set to 4 cm in the simulation. The cable was paced for 50 beats at various cycle lengths.

[0320]

[0344] FIG. 22 shows the APD in a population of simulated tissues resulting from application of flecainide and ibutilide alone or in combinations where drug affinity was randomly varied within the experimentally reported range (combination doses predicted to be ideal for eliminating atrial fibrillation in part 1). 90 In each case, I Kr IC of flecainide against 50 1.5 to 3.9 μM, I NaL 3.4 to 44 μM against leukemia, and furthermore, late stage I Na Current range peak I Na A delta of 300 was generated by randomly varying the APD within the range of 0.1%–0.2% of the APD. The cells were paced at 1 Hz for 500 beats. The last beat was taken as the APD. 90 On average, flecainide was predicted to cause APD prolongation. Low doses of ibutilide showed on average a greater APD prolongation, while drug combinations at doses predicted in the experimental setting showed variable output.

[0321]

[0345] Next, I Kr About IC 50 = 3.9 μM, I NaL About IC 50 The optimized ORd model with 0.02 μM was used to simulate the effect of drug combinations on the QT interval. Figure 23 shows the QT / QTc simulated by the modified ORd model with ibutilide alone (0.02 μM) or in combination (ibutilide 0.02 μM + flecainide 2.2 μM).

[0322]

[0346] The effect of adding late Na current blockade on the APD adaptation curve of the modified Ord model was predicted to determine the possibility of eliminating the reverse use-dependence caused by hERG blockade. The model predictions indicate that the addition of a late Na current blocker can be considered as an additional adjunctive therapy during chemical atrial defibrillation to improve safety. Figure 24 shows the APD adaptation curve at steady state for each pacing cycle length (600 ms to 1200 ms). 90Shown are APD adaptation curves (solid lines) with and without drug application (controls) constructed from measurements of rate-dependence curves measured as: additional late Na blockade from 10% to 100% blockade in 10% increments. + The curve with interruption is shown as a dashed line.

[0323] appendix.

[0347] Figure 25 shows the APD response using the original O'Hara-Rudy human ventricular model at steady state for each pacing cycle length (600 ms to 1200 ms) for individual drugs and combinations. 90 1 shows an extended APD adaptation curve constructed from measurements of the inverse use dependence measured as

[0324]

[0348] Figure 26 shows the QT / QTc intervals simulated using the original O'Hara-Rudy human ventricular model compared to clinical data (Hellestrand 1982). The length of the cable was set to 4 cm in the simulation. The cable was paced for 50 beats at various cycle lengths.

[0325] method.

[0349] The flecainide model was used as previously described in Moreno, JD, et al. Sci Transl med, 2011.3(98):p.98ra83., and Yang, PC, et al., J Physiol, 2016.594(3):p.567-93, and included a drug-binding burst regime (drug binding to the grey state shown in Figure 27). The rate constants for the upper (normal mode) state are from Moreno, JD, et al. The burst state affinity of the charged form of flecainide is shown in Figure 27 for the late I Na The affinity of the tonic block of TB I was initially set to the value found by assuming that it was equal to the Kd at -100 mV. The value of Kd was then calculated and used as the initial value for optimization. For example, the affinity of the tonic block of TB I against WT was set to the value found by assuming that the Kd at -100 mV Na,L The affinity of is approximately 3.4 μM. The optimized Kd0 and burst were 0.92 μM. The transition rates are shown in Table 15.

[0326] [Table 15-1]

[0327] [Table 15-2]

[0328] I Kr , I to or I CaL Simulating a shutdown.

[0350] I Kr , I to or I CaL To simulate the inhibitory effect of flecainide on currents, we used the peak conductance, G, of each independent channel. X was reduced in a concentration-dependent manner using a concentration-response relationship with a Hill coefficient of 1 (n=1) as follows:

[0329]

number

[0330] Here, G X,max is the nominal conductance value obtained from each ventricular myocyte model, and IC 50 is the concentration of drug that results in 50% inhibition of the target transmembrane current or intracellular organelle. Table 16 shows the IC 50 Indicates the value.

[0331] [Table 16]

[0332] Flecainide is I K1 Increase the

[0351] G k1 was calculated as follows:

[0333]

number

[0334] Here, flecainide I k1 EC 50 =0.4μM. Ibutilide G Kr . G Kr was calculated as follows:

[0335]

number

[0336] Here, Ibutilide IC 50 =0.018μM. RyR2-flecainide drug-channel interaction.

[0352] The Shannon-Bers Markov model formulation of RyR2 (Shannon, TR, et al., Biophys J, 2004.87(5):p.3351-71) is used to characterize the transitions to and from the open state O, k on =D*[Drug] and k off =D*IC 50,Drug The Markov model is modified to include the drug-bound state DO by: -1 ms -1 It was estimated that.

[0337] Embodiment

[0353] Embodiment 1. A pharmaceutical composition comprising a sodium channel blocker, a potassium channel blocker, and one or more pharma- ceutically acceptable excipients, diluents, or carriers.

[0338]

[0354] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the potassium channel blocker is ibutilide, dofetilide, sotalol, methanandamide, anandamide, ambasilide, arachidonamide, A293 (2-(butylsulfonylamino)-N-[(1R)-1-(6-methoxy-3-pyridyl)propyl]-benzamide), bupivacaine, etidocaine, genistein, mepivacaine, phenytoin, quinidine, R-ropivacaine, sematilide, S-ropivacaine, tetracaine, amiodarone, dronedarone, E-4031, vernakalant, or a pharmaceutically acceptable salt thereof.

[0339]

[0355] Embodiment 3. The pharmaceutical composition of embodiment 1, wherein the potassium channel blocker is a class IIIa antiarrhythmic agent.

[0356] Embodiment 4. The pharmaceutical composition of embodiment 3, wherein the Class IIIa antiarrhythmic agent is ambasilide, amiodarone, dronedarone, dofetilide, ibutilide, sotalol, or vernakalant, or a pharmaceutically acceptable salt thereof.

[0340]

[0357] Embodiment 5. The pharmaceutical composition of embodiment 1, wherein the potassium channel blocker is sotalol or a pharma- ceutical acceptable salt thereof.

[0358] Embodiment 6. The pharmaceutical composition of embodiment 1, wherein the potassium channel blocker is sotalol hydrochloride.

[0341]

[0359] Embodiment 7. The pharmaceutical composition of embodiment 1, wherein the potassium channel blocker is dofetilide or a pharma- ceutically acceptable salt thereof.

[0360] Embodiment 8. The pharmaceutical composition of embodiment 1, wherein the potassium channel blocker is ibutilide or a pharma- ceutically acceptable salt thereof.

[0342]

[0361] Embodiment 9. The pharmaceutical composition of embodiment 1, wherein the potassium channel blocker is ibutilide hemifumarate.

[0362] Embodiment 10. The pharmaceutical composition of any one of embodiments 1-9, wherein the sodium channel blocker is a class Ia antiarrhythmic agent.

[0343]

[0363] Embodiment 11. The pharmaceutical composition of embodiment 10, wherein the class Ia antiarrhythmic agent is quinidine, procainamide or disopyramide, or a pharma- ceutically acceptable salt thereof.

[0344]

[0364] Embodiment 12. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is a class Ib antiarrhythmic agent.

[0365] Embodiment 13. The pharmaceutical composition of embodiment 12, wherein the class Ib antiarrhythmic agent is lidocaine, tocainide, phenytoin, moricizine or mexiletine or a pharma- ceutically acceptable salt thereof.

[0345]

[0366] Embodiment 14. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is lidocaine or a pharma- ceutically acceptable salt thereof.

[0367] Embodiment 15. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is lidocaine hydrochloride.

[0346]

[0368] Embodiment 16. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is mexiletine or a pharma- ceutical acceptable salt thereof.

[0369] Embodiment 17. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is mexiletine hydrochloride.

[0347]

[0370] Embodiment 18. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is a Class Ic antiarrhythmic agent.

[0371] Embodiment 19. The pharmaceutical composition of embodiment 18, wherein the Class Ic antiarrhythmic agent is flecainide or propafenone or a pharma- ceutically acceptable salt thereof.

[0348]

[0372] Embodiment 20. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is flecainide or a pharma- ceutically acceptable salt thereof.

[0373] Embodiment 21. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is flecainide acetate.

[0349]

[0374] Embodiment 22. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is propafenone or a pharma- ceutically acceptable salt thereof.

[0375] Embodiment 23. The pharmaceutical composition of any one of embodiments 1 to 9, wherein the sodium channel blocker is propafenone hydrochloride.

[0350]

[0376] Embodiment 24. Mg 2+ 2. The pharmaceutical composition of embodiment 1, further comprising a source.

[0377] Embodiment 25. The Mg 2+ The pharmaceutical composition of embodiment 24, wherein the source comprises magnesium citrate, magnesium fumarate, magnesium acetate, magnesium aspartate, magnesium threonate, magnesium glycinate, magnesium chloride, magnesium sulfate, magnesium oxide or magnesium malate, or hydrates thereof.

[0351]

[0378] Embodiment 26. The Mg 2+ The pharmaceutical composition of embodiment 24, wherein the source comprises magnesium sulfate or a hydrate thereof.

[0379] Embodiment 27. The Mg 2+ 25. The pharmaceutical composition of embodiment 24, wherein the source comprises magnesium sulfate heptahydrate.

[0352]

[0380] Embodiment 28. The pharmaceutical composition according to embodiment 24, which is in the form of a liquid solution.

[0381] Embodiment 29. A pharmaceutical composition according to any one of embodiments 1, in the form of an inhalable dry powder.

[0353]

[0382] Embodiment 30. The pharmaceutical composition of embodiment 29, wherein the dry powder is a spray-dried powder.

[0383] Embodiment 31. The pharmaceutical composition of embodiment 29, wherein the dry powder is formed by supercritical fluid enhanced dispersion (SEDS).

[0354]

[0384] Embodiment 32. The pharmaceutical composition of embodiment 29, wherein the dry powder is formed by supercritical precipitation.

[0385] Embodiment 33. The pharmaceutical composition of embodiment 29, wherein the dry powder is formed by imprint lithography.

[0355]

[0386] Embodiment 34. The pharmaceutical composition of embodiment 29, wherein the dry powder is formed by lyophilization.

[0387] Embodiment 35. The pharmaceutical composition of embodiment 1, in the form of a liquid solution.

[0356]

[0388] Embodiment 36. The pharmaceutical composition of any one of embodiments 1, 29 or 35, wherein the sodium channel blocker is flecainide or a pharma- ceutically acceptable salt thereof, and the potassium channel blocker is ibutilide or a pharma- ceutically acceptable salt thereof.

[0357]

[0389] Embodiment 37. The pharmaceutical composition of embodiment 36, wherein the mass / mass ratio of said flecainide or a pharma- ceutically acceptable salt thereof to said ibutilide or a pharma- ceutically acceptable salt thereof in said pharmaceutical composition is 60:1 to 240:1.

[0358]

[0390] Embodiment 38. The pharmaceutical composition of embodiment 36, wherein the weight / weight ratio of said flecainide or its pharma- ceutically acceptable salt to said ibutilide or its pharma- ceutically acceptable salt in said pharmaceutical composition is about 120:1.

[0359]

[0391] Embodiment 39. A pharmaceutical composition according to any one of embodiments 35 to 38, comprising about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0392] Embodiment 40. A pharmaceutical composition according to any one of embodiments 35 to 38, comprising about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0360]

[0393] Embodiment 41. A pharmaceutical composition according to any one of embodiments 35 to 38, comprising from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0394] Embodiment 42. A pharmaceutical composition according to any one of embodiments 35 to 38, comprising about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0361]

[0395] Embodiment 43. A pharmaceutical composition according to any one of embodiments 35 to 38, comprising about 75 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0396] Embodiment 44. A pharmaceutical composition according to any one of embodiments 35 to 38, comprising about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0362]

[0397] Embodiment 45. A pharmaceutical composition according to any one of embodiments 35 to 38, comprising about 1 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0398] Embodiment 46. The pharmaceutical composition of embodiment 35, comprising about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.0005 mg / mL to about 5 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

[0363]

[0399] Embodiment 47. The pharmaceutical composition of embodiment 35, comprising about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.0005 mg / mL to about 5 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

[0364]

[0400] Embodiment 48. The pharmaceutical composition of embodiment 35, comprising about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.001 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

[0365]

[0401] Embodiment 49. The pharmaceutical composition of embodiment 35, comprising about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.001 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

[0366]

[0402] Embodiment 50. The pharmaceutical composition of embodiment 28 comprising about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.0005 mg / mL to about 5 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, and about 5 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof.

[0367]

[0403] Embodiment 51. The pharmaceutical composition of embodiment 28, comprising about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.01 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, and about 20 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof.

[0368]

[0404] Embodiment 52. The pharmaceutical composition of embodiment 28, comprising about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.01 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, and about 20 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof.

[0369]

[0405] Embodiment 53. The pharmaceutical composition of embodiment 28, comprising about 75 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.6 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

[0370]

[0406] Embodiment 54. The pharmaceutical composition of embodiment 28, comprising about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.014 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

[0371]

[0407] Embodiment 55. The pharmaceutical composition of embodiment 28, comprising about 1 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.007 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

[0372]

[0408] Embodiment 56. The pharmaceutical composition of any one of embodiments 36-38 and 46-55, wherein the ibutilide or a pharma- ceutically acceptable salt thereof is ibutilide hemifumarate.

[0373]

[0409] Embodiment 57. The pharmaceutical composition of any one of embodiments 1, 29 or 35, wherein the sodium channel blocker is flecainide or a pharma- ceutically acceptable salt thereof, and the potassium channel blocker is dofetilide or a pharma- ceutically acceptable salt thereof.

[0374]

[0410] Embodiment 58. The pharmaceutical composition of embodiment 36, wherein the mass / mass ratio of said flecainide or a pharma- ceutically acceptable salt thereof to said dofetilide or a pharma- ceutically acceptable salt thereof in said pharmaceutical composition is 60:1 to 480:1.

[0375]

[0411] Embodiment 59. The pharmaceutical composition of embodiment 36, wherein the mass / mass ratio of said flecainide or a pharma- ceutically acceptable salt thereof to said dofetilide or a pharma- ceutically acceptable salt thereof in said pharmaceutical composition is about 240:1.

[0376]

[0412] Embodiment 60. A pharmaceutical composition according to any one of embodiments 57 to 59, comprising from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0413] Embodiment 61. A pharmaceutical composition according to any one of embodiments 57 to 59, comprising about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0377]

[0414] Embodiment 62. A pharmaceutical composition according to any one of embodiments 57 to 59, comprising from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0415] Embodiment 63. A pharmaceutical composition according to any one of embodiments 57 to 59, comprising about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0378]

[0416] Embodiment 64. A pharmaceutical composition according to any one of embodiments 57 to 59, comprising about 75 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0417] Embodiment 65. A pharmaceutical composition according to any one of embodiments 57 to 59, comprising about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0379]

[0418] Embodiment 66. A pharmaceutical composition according to any one of embodiments 57 to 59, comprising about 1 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0419] Embodiment 67. The pharmaceutical composition of embodiment 35, comprising about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.0005 mg / mL to about 5 mg / mL of dofetilide or a pharma- ceutically acceptable salt thereof.

[0380]

[0420] Embodiment 68. The pharmaceutical composition of embodiment 35, comprising about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.001 mg / mL to about 1 mg / mL of dofetilide or a pharma- ceutically acceptable salt thereof.

[0381]

[0421] Embodiment 69. The pharmaceutical composition of embodiment 35, comprising about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.0005 mg / mL to about 5 mg / mL of dofetilide or a pharma- ceutically acceptable salt thereof, and about 5 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof.

[0382]

[0422] Embodiment 70. The pharmaceutical composition of embodiment 35, comprising about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.01 mg / mL to about 1 mg / mL of dofetilide or a pharma- ceutically acceptable salt thereof, and about 20 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof.

[0383]

[0423] Embodiment 71. The pharmaceutical composition of any one of embodiments 1, 29 or 35, wherein the sodium channel blocker is flecainide or a pharma- ceutically acceptable salt thereof and the potassium channel blocker is sotalol or a pharma- ceutically acceptable salt thereof.

[0384]

[0424] Embodiment 72. The pharmaceutical composition of embodiment 36, wherein the mass / mass ratio of the flecainide or a pharma- ceutically acceptable salt thereof to the sotalol or a pharma- ceutically acceptable salt thereof in the pharmaceutical composition is 0.5:1 to 2:1.

[0385]

[0425] Embodiment 73. The pharmaceutical composition of embodiment 36, wherein the weight / weight ratio of said flecainide or its pharma- ceutically acceptable salt to said sotalol or its pharma- ceutically acceptable salt in said pharmaceutical composition is about 1:1.

[0386]

[0426] Embodiment 74. A pharmaceutical composition according to any one of embodiments 71 to 73, comprising about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0427] Embodiment 75. A pharmaceutical composition according to any one of embodiments 71 to 73, comprising about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0387]

[0428] Embodiment 76. A pharmaceutical composition according to any one of embodiments 71 to 73, comprising from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0429] Embodiment 77. A pharmaceutical composition according to any one of embodiments 71 to 73, comprising about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0388]

[0430] Embodiment 78. A pharmaceutical composition according to any one of embodiments 71 to 73, comprising about 75 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0431] Embodiment 79. A pharmaceutical composition according to any one of embodiments 71 to 73, comprising about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0389]

[0432] Embodiment 80. A pharmaceutical composition according to any one of embodiments 71 to 73, comprising about 1 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0433] Embodiment 81. The pharmaceutical composition of embodiment 35, comprising from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and from about 0.0005 mg / mL to about 5 mg / mL of sotalol or a pharma- ceutically acceptable salt thereof.

[0390]

[0434] Embodiment 82. The pharmaceutical composition of embodiment 35, comprising about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.01 mg / mL to about 1 mg / mL of sotalol or a pharma- ceutically acceptable salt thereof.

[0391]

[0435] Embodiment 83. The pharmaceutical composition of embodiment 28, comprising about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.0005 mg / mL to about 5 mg / mL of sotalol or a pharma- ceutically acceptable salt thereof, and about 5 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof.

[0392]

[0436] Embodiment 84. The pharmaceutical composition of embodiment 28, comprising about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.01 mg / mL to about 1 mg / mL of sotalol or a pharma- ceutically acceptable salt thereof, and about 20 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof.

[0393]

[0437] Embodiment 85. The pharmaceutical composition of any one of embodiments 71 to 84, wherein the sotalol or a pharma- ceutically acceptable salt thereof is sotalol hydrochloride.

[0438] Embodiment 86. The pharmaceutical composition of any one of embodiments 36 to 84, wherein said flecainide or a pharma- ceutically acceptable salt thereof is flecainide acetate.

[0394]

[0439] Embodiment 87. The pharmaceutical composition of any one of embodiments 36 to 84, wherein said flecainide or a pharma- ceutically acceptable salt thereof is flecainide hydrochloride.

[0440] Embodiment 88. A method for treating a subject suffering from atrial arrhythmia, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1 to 87.

[0395]

[0441] Embodiment 89. A method of treating a subject suffering from atrial arrhythmia, comprising administering to the subject (i) a first amount of a sodium channel blocker, and (ii) a second amount of a potassium channel blocker; wherein said administering reduces the t of said potassium channel blocker in said subject. max and a t of said sodium channel blocker in said subject occurring within an interval of about 30 minutes from max Bringing about thereby inducing cardioversion of said atrial arrhythmia.

[0396]

[0442] Embodiment 90. The incidence of torsades de pointes (TdP) is reduced in a plurality of experimental subjects of said clinical study compared to the incidence of TdP in a control cohort of said clinical study; (i) each subject of said plurality of experimental subjects is administered both said first amount of said sodium channel blocker and said second amount of said potassium channel blocker; (ii) The method of embodiment 89, wherein each subject in the control cohort is administered the first amount of the sodium channel blocker without the second amount of the potassium channel blocker, or each subject in the control cohort is administered the second amount of the potassium channel blocker, or a pharma- ceutically acceptable version thereof, without the first amount of the sodium channel blocker.

[0397]

[0443] Embodiment 91. The method of embodiment 90, wherein the incidence of Torsades de Pointes (TdP) in the plurality of experimental subjects is reduced by at least about 5% compared to the incidence of TdP in the control cohort.

[0398]

[0444] Embodiment 92. The method of embodiment 90, wherein the incidence of Torsades de Pointes (TdP) in the plurality of experimental subjects is reduced by at least about 20% compared to the incidence of TdP in the control cohort.

[0399]

[0445] Embodiment 93. The method of embodiment 90, wherein the incidence of Torsades de Pointes (TdP) in the plurality of experimental subjects is reduced by at least about 35% compared to the incidence of TdP in the control cohort.

[0400]

[0446] Embodiment 94. The method of embodiment 90, wherein the incidence of Torsades de Pointes (TdP) in the plurality of experimental subjects is reduced by at least about 50% compared to the incidence of TdP in the control cohort.

[0401]

[0447] Embodiment 95. The incidence of QT intervals above the nomogram is reduced in a plurality of experimental subjects of said clinical study compared to the incidence of QT intervals above the nomogram in a control cohort of said clinical study; (i) each subject of said plurality of experimental subjects is administered both said first amount of said sodium channel blocker and said second amount of said potassium channel blocker; (ii) The method of any one of embodiments 89-94, wherein each subject in the control cohort is administered the first amount of the sodium channel blocker without the second amount of the potassium channel blocker, or each subject in the control cohort is administered the second amount of the potassium channel blocker without the first amount of the sodium channel blocker.

[0402]

[0448] Embodiment 96. The method of embodiment 95, wherein the incidence of QT intervals above the nomogram in the plurality of experimental subjects is reduced by at least about 5% compared to the incidence of QT intervals above the nomogram in the control cohort.

[0403]

[0449] Embodiment 97. The method of embodiment 95, wherein the incidence of QT intervals above the nomogram in the plurality of experimental subjects is reduced by at least about 20% compared to the incidence of QT intervals above the nomogram in the control cohort.

[0404]

[0450] Embodiment 98. The method of embodiment 95, wherein the incidence of QT intervals above the nomogram in the plurality of experimental subjects is reduced by at least about 35% compared to the incidence of QT intervals above the nomogram in the control cohort.

[0405]

[0451] Embodiment 99. The method of embodiment 95, wherein the incidence of QT intervals above the nomogram in the plurality of experimental subjects is reduced by at least about 50% compared to the incidence of QT intervals above the nomogram in the control cohort.

[0406]

[0452] Embodiment 100. The incidence of hypotension is reduced in a plurality of experimental subjects of said clinical study compared to the incidence of hypotension in a control cohort of said clinical study, (i) each subject of said plurality of experimental subjects is administered both said first amount of said sodium channel blocker and said second amount of said potassium channel blocker; (ii) each subject in the control cohort is administered the first amount of the sodium channel blocker without the second amount of the potassium channel blocker, or each subject in the control cohort is administered the second amount of the potassium channel blocker without the first amount of the sodium channel blocker; The method of any one of embodiments 89-99, wherein said hypotension comprises a mean arterial pressure (MAP) of less than 70 mmHg sustained for at least 5 minutes after said administering.

[0407]

[0453] Embodiment 101. The method of embodiment 100, wherein the incidence of said hypotension in said plurality of experimental subjects is reduced by at least about 5% compared to the incidence of said hypotension in said control cohort of said clinical study.

[0408]

[0454] Embodiment 102. The method of embodiment 100, wherein the incidence of said hypotension in said plurality of experimental subjects is reduced by at least about 20% compared to the incidence of said hypotension in said control cohort of said clinical study.

[0409]

[0455] Embodiment 103. The method of embodiment 100, wherein the incidence of said hypotension in said plurality of experimental subjects is reduced by at least about 35% compared to the incidence of said hypotension in said control cohort of said clinical study.

[0410]

[0456] Embodiment 104. The method of embodiment 100, wherein the incidence of said hypotension in said plurality of experimental subjects is reduced by at least about 50% as compared to the incidence of said hypotension in said control cohort of said clinical study.

[0411]

[0457] 105. Mean QT in a control cohort of a clinical study c In a number of experimental subjects suffering from said atrial arrhythmias in said clinical study, c The average magnitude of the increase is 5% or less, (i) each subject of said plurality of experimental subjects is administered both said first amount of said sodium channel blocker and said second amount of said potassium channel blocker; (ii) The method of any one of embodiments 89-104, wherein each subject in the control cohort is administered the first amount of the sodium channel blocker without the second amount of the potassium channel blocker, or each subject in the control cohort is administered the second amount of the potassium channel blocker without the first amount of the sodium channel blocker.

[0412]

[0458] 106. Mean QT in a control cohort of a clinical study c QT intervals in multiple experimental subjects in the clinical study compared with c The average magnitude of the increase is about 40 ms or less. (i) each subject of said plurality of experimental subjects is administered both said first amount of said sodium channel blocker and said second amount of said potassium channel blocker; (ii) The method of any one of embodiments 89-105, wherein each subject in the control cohort is administered the first amount of the sodium channel blocker without the second amount of the potassium channel blocker, or each subject in the control cohort is administered the second amount of the potassium channel blocker without the first amount of the sodium channel blocker.

[0413]

[0459] Embodiment 107. The QT curve in the plurality of experimental subjects. c 107. The method of embodiment 106, wherein the average magnitude of the increase is about 20 ms or less.

[0460] Embodiment 108. The QT interval in the plurality of experimental subjects c 107. The method of embodiment 106, wherein the average magnitude of the increase is about 10 ms or less.

[0414]

[0461] Embodiment 109. The QT curve in the plurality of experimental subjects. c 107. The method of embodiment 106, wherein the average magnitude of increase is about 6 ms or less.

[0462] Embodiment 110. The QT c But the formula QT c =QT+0.154*(1-RR), where RR is the interval between two successive R waves and QT is the time interval between the start of the QRS complex and the end of the subsequent T wave as measured by an electrocardiogram (ECG).

[0415]

[0463] Embodiment 111. The method of any one of embodiments 90 to 110, wherein the experimental subject is a healthy subject.

[0464] Embodiment 112. The method of any one of embodiments 90 to 110, wherein the experimental subject suffers from atrial arrhythmia during said administration.

[0416]

[0465] Embodiment 113. The method of any one of embodiments 90 to 112, wherein the subjects of the control cohort are healthy subjects.

[0466] Embodiment 114. The method of any one of embodiments 90 to 112, wherein the subjects in the control cohort suffer from atrial arrhythmia during said administration.

[0417]

[0467] Embodiment 115. The method of any one of embodiments 90 to 114, wherein the sodium channel blocker and the potassium channel blocker are administered simultaneously to the multiple experimental subjects.

[0418]

[0468] Embodiment 116. The t of the sodium channel blocker in the plurality of experimental subjects. max the t of the potassium channel blocker in the subject max The method of any one of embodiments 90-115, wherein the steps occur within an interval of about 30 minutes from

[0419]

[0469] Embodiment 117. The t of the sodium channel blocker in the plurality of experimental subjects. max the t of the potassium channel blocker in the subject max The method of any one of embodiments 90-115, wherein the steps occur within an interval of about 15 minutes from

[0420]

[0470] Embodiment 118. The t of the sodium channel blocker in the plurality of experimental subjects. max the t of the potassium channel blocker in the subject max The method of any one of embodiments 90-115, wherein the two or more of the above steps occur within an interval of about 5 minutes or less.

[0421]

[0471] Embodiment 119. The t of the sodium channel blocker in the plurality of experimental subjects. max the t of the potassium channel blocker in the subject max The method of any one of embodiments 90-115, wherein the first and second periods occur within an interval of about 3 minutes or less.

[0422]

[0472] Embodiment 120. The method of any one of embodiments 89 to 119, wherein the atrial arrhythmia is selected from the group consisting of supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, persistent and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter and isolated atrial fibrillation.

[0423]

[0473] Embodiment 121. The method of any one of embodiments 89 to 119, wherein the atrial arrhythmia comprises paroxysmal atrial fibrillation.

[0474] Embodiment 122. The method of any one of embodiments 89 to 119, wherein the atrial arrhythmia comprises permanent atrial fibrillation.

[0424]

[0475] Embodiment 123. The method of any one of embodiments 90 to 119, wherein the experimental subject is a human subject.

[0476] Embodiment 124. The method of any one of embodiments 90 to 123, wherein the sodium channel blocker and the potassium channel blocker are administered intravenously.

[0425]

[0477] Embodiment 125. The method of any one of embodiments 90-123, wherein the sodium channel blocker and the potassium channel blocker are administered orally.

[0478] Embodiment 126. The method of any one of embodiments 90-123, wherein the sodium channel blocker and the potassium channel blocker are administered by oral inhalation.

[0426]

[0479] Embodiment 127. The method of any one of embodiments 89 to 124, wherein the subject is a human subject.

[0480] Embodiment 128. The method of any one of embodiments 89 to 124, wherein the subject suffers from paroxysmal atrial fibrillation unresponsive to monotherapy with the sodium channel blocker.

[0427]

[0481] Embodiment 129. The t of the sodium channel blocker in the subject maxthe t of the potassium channel blocker in the subject max The method of any one of embodiments 89-128, wherein the steps occur within an interval of about 15 minutes from

[0428]

[0482] Embodiment 130. The t of the sodium channel blocker in the subject. max the t of the potassium channel blocker in the subject max The method of any one of embodiments 89-128, wherein the steps occur within an interval of about 5 minutes from

[0429]

[0483] Embodiment 131. The t of the sodium channel blocker in the subject max the t of the potassium channel blocker in the subject max The method of any one of embodiments 89-128, wherein the first and second periods occur within an interval of about 3 minutes or less.

[0430]

[0484] Embodiment 132. The method of any one of embodiments 89-128, wherein the sodium channel blocker is administered within an interval of 15 minutes of administration of the potassium channel blocker.

[0431]

[0485] Embodiment 133. The method of any one of embodiments 89-128, wherein the sodium channel blocker is administered within an interval of 5 minutes of administration of the potassium channel blocker.

[0432]

[0486] Embodiment 134. The method of any one of embodiments 89-128, wherein the sodium channel blocker is administered within an interval of 3 minutes of administration of the potassium channel blocker.

[0433]

[0487] Embodiment 135. The method of any one of embodiments 89 to 134, wherein the sodium channel blocker comprises a Class Ic antiarrhythmic agent.

[0488] Embodiment 136. The method of any one of embodiments 89-134, wherein the sodium channel blocker comprises flecainide or a pharma- ceutically acceptable salt thereof.

[0434]

[0489] Embodiment 137. The method of any one of embodiments 89-134, wherein the sodium channel blocker comprises flecainide acetate.

[0490] Embodiment 138. The method of any one of embodiments 89-134, wherein the sodium channel blocker comprises flecainide hydrochloride.

[0435]

[0491] Embodiment 139. The method of any one of embodiments 136 to 138, wherein the first amount is from about 0.1 mg to about 2 mg per kilogram of the subject.

[0492] Embodiment 140. The method of any one of embodiments 136-138, wherein the first amount is from about 0.1 mg to about 1 mg per kilogram of the subject.

[0436]

[0493] Embodiment 141. The method of any one of embodiments 136-138, wherein the first amount is about 0.5 mg per kilogram of the subject.

[0494] Embodiment 142. The method of any one of embodiments 136-138, wherein the first amount is from about 5 mg to about 300 mg.

[0437]

[0495] Embodiment 143. The method of any one of embodiments 136-138, wherein the first amount is from about 5 mg to about 150 mg.

[0496] Embodiment 144. The method of any one of embodiments 89 to 143, wherein the potassium channel blocker is ibutilide, dofetilide, sotalol, methanandamide, anandamide, ambasilide, arachidonamide, A293 (2-(butylsulfonylamino)-N-[(1R)-1-(6-methoxy-3-pyridyl)propyl]-benzamide), bupivacaine, etidocaine, genistein, mepivacaine, phenytoin, quinidine, R-ropivacaine, sematilide, S-ropivacaine, tetracaine, amiodarone, dronedarone, E-4031, vernakalant, or a pharmaceutically acceptable salt thereof.

[0438]

[0497] Embodiment 145. The method of any one of embodiments 89 to 143, wherein the potassium channel blocker is ibutilide or a pharma- ceutically acceptable salt thereof.

[0498] Embodiment 146. The method of any one of embodiments 89 to 143, wherein said ibutilide or a pharma- ceutically acceptable salt thereof is ibutilide hemifumarate.

[0439]

[0499] Embodiment 147. The method of embodiment 145 or embodiment 146, wherein the second amount is about 0.001 mg to about 0.25 mg per kilogram of the subject.

[0500] Embodiment 148. The method of embodiment 145 or embodiment 146, wherein the second amount is about 0.005 mg to about 0.02 mg per kilogram of the subject.

[0440]

[0501] Embodiment 149. The method of embodiment 145 or embodiment 146, wherein the second amount is from about 0.01 mg to about 15 mg.

[0502] Embodiment 150. The method of embodiment 145 or embodiment 146, wherein the second amount is from about 0.25 mg to about 1 mg.

[0441]

[0503] Embodiment 151. The method of any one of embodiments 89-143, wherein the potassium channel blocker is dofetilide or a pharma- ceutically acceptable salt thereof.

[0504] Embodiment 152. The method of any one of embodiments 89-143, wherein the potassium channel blocker is sotalol or a pharma- ceutically acceptable salt thereof.

[0442]

[0505] Embodiment 153. The method of any one of embodiments 89 to 143, wherein the potassium channel blocker is sotaolol hydrochloride.

[0506] Embodiment 154. The method of any one of embodiments 89 to 153, wherein the sodium channel blocker and the potassium blocker are administered simultaneously to the subject.

[0443]

[0507] Embodiment 155. The method of any one of embodiments 89-134, wherein the sodium channel blocker comprises flecainide or a pharma- ceutically acceptable salt thereof, and the potassium channel blocker comprises ibutilide or a pharma- ceutically acceptable salt thereof.

[0444]

[0508] Embodiment 156. The method of embodiment 155, wherein the sodium channel blocker is co-formulated with the potassium channel blocker in a fixed dose combination.

[0509] Embodiment 157. The method of embodiment 156, wherein the fixed dose combination is a liquid unit dosage form.

[0445]

[0510] Embodiment 158. The method of embodiment 157, wherein the mass / mass ratio of said flecainide or a pharma- ceutically acceptable salt thereof to said ibutilide or a pharma- ceutically acceptable salt thereof in said liquid unit dosage form is from 60:1 to 240:1.

[0446]

[0511] Embodiment 159. The method of embodiment 157, wherein the mass / mass ratio of said flecainide or a pharma- ceutically acceptable salt thereof to said ibutilide or a pharma- ceutically acceptable salt thereof in said liquid unit dosage form is about 120:1.

[0447]

[0512] Embodiment 160. The method according to any one of embodiments 157-159, wherein the liquid unit dosage form contains from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0448]

[0513] Embodiment 161. The method according to any one of embodiments 157-159, wherein the liquid unit dosage form contains from about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0449]

[0514] Embodiment 162. The method according to any one of embodiments 157-159, wherein the liquid unit dosage form contains from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0450]

[0515] Embodiment 163. The method according to any one of embodiments 157-159, wherein the liquid unit dosage form contains from about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0451]

[0516] Embodiment 164. The method according to any one of embodiments 157-159, wherein the liquid unit dosage form contains about 75 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0452]

[0517] Embodiment 165. The method of embodiment 157, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.0005 mg / mL to about 5 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0453]

[0518] Embodiment 166. The method of embodiment 157, wherein the liquid unit dosage form comprises about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.0005 mg / mL to about 5 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0454]

[0519] Embodiment 167. The method of embodiment 157, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.001 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0455]

[0520] Embodiment 168. The method of embodiment 157, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.001 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0456]

[0521] Embodiment 169. The method according to any one of embodiments 155-168, wherein said flecainide or a pharma- ceutically acceptable salt thereof is flecainide acetate and said ibutilide or a pharma- ceutically acceptable salt thereof is ibutilide hemifumarate.

[0457]

[0522] Embodiment 170. The method of any one of embodiments 89-134, wherein the sodium channel blocker comprises flecainide or a pharma- ceutically acceptable salt thereof, and the potassium channel blocker comprises dofetilide or a pharma- ceutically acceptable salt thereof.

[0458]

[0523] Embodiment 171. The method of embodiment 170, wherein the sodium channel blocker is co-formulated with the potassium channel blocker in a fixed dose combination.

[0524] Embodiment 172. The method of embodiment 171, wherein the fixed-dose combination is a liquid unit dosage form.

[0459]

[0525] Embodiment 173. The method of embodiment 172, wherein the mass / mass ratio of the flecainide or a pharma- ceutically acceptable salt thereof to the dofetilide or a pharma- ceutically acceptable salt thereof in the liquid unit dosage form is from 60:1 to 480:1.

[0460]

[0526] Embodiment 174. The method of embodiment 172, wherein the mass / mass ratio of said flecainide or a pharma- ceutically acceptable salt thereof to said dofetilide or a pharma- ceutically acceptable salt thereof in said liquid unit dosage form is about 240:1.

[0461]

[0527] Embodiment 175. The method according to any one of embodiments 172 to 174, wherein the liquid unit dosage form contains from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0462]

[0528] Embodiment 176. The method according to any one of embodiments 172-174, wherein the liquid unit dosage form contains from about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0463]

[0529] Embodiment 177. The method according to any one of embodiments 172-174, wherein the liquid unit dosage form contains from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0464]

[0530] Embodiment 178. The method according to any one of embodiments 172 to 174, wherein the liquid unit dosage form contains from about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0465]

[0531] Embodiment 179. The method according to any one of embodiments 172 to 174, wherein the liquid unit dosage form contains about 75 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0466]

[0532] Embodiment 180. The method of any one of embodiments 172-174, wherein the liquid unit dosage form contains about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0533] Embodiment 181. The method of any one of embodiments 172-174, wherein the liquid unit dosage form contains about 1 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0467]

[0534] Embodiment 182. The method of embodiment 172, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.0005 mg / mL to about 5 mg / mL of dofetilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0468]

[0535] Embodiment 183. The method of embodiment 172, wherein the liquid unit dosage form comprises about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.0005 mg / mL to about 5 mg / mL of dofetilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0469]

[0536] Embodiment 184. The method of embodiment 172, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.001 mg / mL to about 1 mg / mL of dofetilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0470]

[0537] Embodiment 185. The method of embodiment 172, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.001 mg / mL to about 1 mg / mL of dofetilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0471]

[0538] Embodiment 186. The method of any one of embodiments 89-134, wherein the sodium channel blocker comprises flecainide or a pharma- ceutically acceptable salt thereof, and the potassium channel blocker comprises sotalol or a pharma- ceutically acceptable salt thereof.

[0472]

[0539] Embodiment 187. The method of embodiment 186, wherein the sodium channel blocker is co-formulated with the potassium channel blocker in a fixed dose combination.

[0540] Embodiment 188. The method of embodiment 187, wherein the fixed dose combination is a liquid unit dosage form.

[0473]

[0541] Embodiment 189. The method of embodiment 188, wherein the mass / mass ratio of the flecainide or a pharma- ceutically acceptable salt thereof to the sotalol or a pharma- ceutically acceptable salt thereof in the liquid unit dosage form is 0.5:1 to 2:1.

[0474]

[0542] Embodiment 190. The method of embodiment 188, wherein the weight / weight ratio of the flecainide or a pharma- ceutically acceptable salt thereof to the sotalol or a pharma- ceutically acceptable salt thereof in the liquid unit dosage form is about 1:1.

[0475]

[0543] Embodiment 191. The method according to any one of embodiments 188 to 190, wherein the liquid unit dosage form contains from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0476]

[0544] Embodiment 192. The method according to any one of embodiments 188 to 190, wherein the liquid unit dosage form contains from about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0477]

[0545] Embodiment 193. The method of any one of embodiments 188-190, wherein the liquid unit dosage form contains from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0478]

[0546] Embodiment 194. The method according to any one of embodiments 188 to 190, wherein the liquid unit dosage form contains from about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0479]

[0547] Embodiment 195. The method according to any one of embodiments 188-190, wherein the liquid unit dosage form comprises about 75 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0480]

[0548] Embodiment 196. The method of any one of embodiments 188-190, wherein the liquid unit dosage form contains about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0549] Embodiment 197. The method according to any one of embodiments 188 to 190, wherein the liquid unit dosage form comprises about 1 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

[0481]

[0550] Embodiment 198. The method of embodiment 188, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.0005 mg / mL to about 5 mg / mL of sotalol or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0482]

[0551] Embodiment 199. The method of embodiment 188, wherein the liquid unit dosage form comprises about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, about 0.0005 mg / mL to about 5 mg / mL of sotalol or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0483]

[0552] Embodiment 200. The method of embodiment 188, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.001 mg / mL to about 1 mg / mL of sotalol or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0484]

[0553] Embodiment 201. The method of embodiment 188, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.001 mg / mL to about 1 mg / mL of sotalol or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0485]

[0554] Embodiment 202. The method of any one of embodiments 198-201, wherein said flecainide or a pharma- ceutically acceptable salt thereof is flecainide acetate and said sotalol or a pharma- ceutically acceptable salt thereof is sotalol hydrochloride.

[0486]

[0555] Embodiment 203. The method of any one of embodiments 155-202, wherein said flecainide or a pharma- ceutically acceptable salt thereof is flecainide acetate.

[0556] Embodiment 204. A third amount of Mg 2+ The method of any one of embodiments 89-202, further comprising administering a source.

[0487]

[0557] Embodiment 205. The Mg 2+ 205. The method of embodiment 204, wherein the source is administered at an interval of not more than 0.5 hours from the administration of said sodium channel blocker.

[0558] Embodiment 206. The Mg 2+ 205. The method of embodiment 204, wherein the source is administered at an interval of not more than 0.5 hours from the administration of said potassium channel blocker.

[0488]

[0559] Embodiment 207. The third amount is from about 0.2 mg to about 20 mg of Mg per kilogram of the subject. 2+ The method of any one of embodiments 204-206, wherein the amount is sufficient to administer a cation.

[0489]

[0560]

[0023] Embodiment 208. The third amount is about 0.2 g to about 1 g of Mg. 2+ The method of any one of embodiments 204-206, wherein the amount is sufficient to administer a cation.

[0490]

[0561] Embodiment 209. The Mg 2+ The method of any one of embodiments 204-208, wherein the source comprises magnesium citrate, magnesium fumarate, magnesium acetate, magnesium aspartate, magnesium threonate, magnesium glycinate, magnesium chloride, magnesium sulfate, magnesium oxide or magnesium malate, or a hydrate thereof.

[0491]

[0562] Embodiment 210. The Mg 2+ 209. The method of any one of embodiments 204-208, wherein the source comprises magnesium sulfate or a hydrate thereof.

[0563] Embodiment 211. The Mg 2+ The method of any one of embodiments 204 to 208, wherein the source comprises magnesium sulfate heptahydrate.

[0492]

[0564] Embodiment 212. The method of embodiment 210 or embodiment 211, wherein the third amount is from about 1 mg to about 100 mg per kilogram of the subject.

[0565] Embodiment 213 The method of embodiment 210 or embodiment 211, wherein the third amount is from about 1 g to about 10 g.

[0493]

[0566] Embodiment 214. The method of any one of embodiments 89-134, wherein the sodium channel blocker comprises flecainide or a pharma- ceutically acceptable salt thereof, and the potassium channel blocker comprises ibutilide or a pharma- ceutically acceptable salt thereof.

[0494]

[0567] 215. A third amount of Mg 2+ 215. The method of embodiment 214, further comprising administering a source.

[0568] Embodiment 216. The flecainide or a pharma- ceutical acceptable salt thereof, the ibutilide or a pharma- ceutical acceptable salt thereof, and the Mg 2+ The method of embodiment 215, wherein the sources are co-formulated in a fixed dose combination.

[0495]

[0569] Embodiment 217. The method of embodiment 216, wherein the fixed dose combination is a liquid unit dosage form.

[0570] Embodiment 218. The liquid unit dosage form contains from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.0005 mg / mL to about 5 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, from about 1 mg / mL to about 140 mg / mL of Mg. 2+ The method of embodiment 217, comprising a cation and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0496]

[0571] Embodiment 219. The Mg 2+ 218. The method of embodiment 217, wherein the source comprises magnesium sulfate or a hydrate thereof.

[0572] Embodiment 220. The method of embodiment 219, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.0005 mg / mL to about 5 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, from about 5 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0497]

[0573] Embodiment 221. The method of embodiment 219, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.001 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, from about 20 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0498]

[0574] Embodiment 222. The method of embodiment 219, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.0005 mg / mL to about 5 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, from about 5 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0499]

[0575] Embodiment 223. The method of embodiment 219, wherein the liquid unit dosage form comprises from about 1 mg / mL to about 30 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, from about 0.001 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof, from about 20 mg / mL to about 700 mg / mL of magnesium sulfate or a hydrate thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

[0500]

[0576] Embodiment 224. The method of any one of embodiments 214-223, wherein said flecainide or a pharma- ceutically acceptable salt thereof is flecainide acetate.

[0577] Embodiment 225. The method of any one of embodiments 157-213 or 217-224, wherein the liquid unit dosage form is administered intravenously.

[0501]

[0578] Embodiment 226. The t of the potassium channel blocker in the subject. max In the subject's QT cThe method of any one of embodiments 89-225, wherein the time t1 is about 490 ms or less.

[0502]

[0579] Embodiment 227. The t of the potassium channel blocker in the subject. max About 30 minutes before and about 30 minutes after c The method of any one of embodiments 89-225, wherein the time t1 is about 490 ms or less.

[0503]

[0580] Embodiment 228. (i) A first unit dosage form packaged in a first container, said first unit dosage form comprising a sodium channel blocker and one or more pharma- ceutically acceptable excipients, diluents or carriers; and (ii) a second unit dosage form packaged in a second container, said second unit dosage form comprising a potassium channel blocker or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents, or carriers. wherein the first unit dosage form or the second unit dosage form comprises Mg 2+ The kit further comprises a source.

[0504]

[0581] Embodiment 229. The kit of embodiment 228, wherein the potassium channel blocker is sotalol or a pharma- ceutically acceptable salt thereof.

[0582] Embodiment 230. The kit of embodiment 228, wherein the potassium channel blocker is dofetilide or a pharma- ceutically acceptable salt thereof.

[0505]

[0583] Embodiment 231. The kit of embodiment 228, wherein the potassium channel blocker is ibutilide or a pharma- ceutically acceptable salt thereof.

[0584] Embodiment 232. The Mg 2+The kit of embodiment 228, wherein the source comprises magnesium citrate, magnesium fumarate, magnesium acetate, magnesium aspartate, magnesium threonate, magnesium glycinate, magnesium chloride, magnesium sulfate, magnesium oxide or magnesium malate, or hydrates thereof.

[0506]

[0585] Embodiment 233. The kit of embodiment 228, wherein the sodium channel blocker is a class Ic antiarrhythmic agent.

[0586] Embodiment 234. The kit of embodiment 228, wherein the sodium channel blocker is flecainide or a pharma- ceutically acceptable salt thereof.

[0507]

[0587] Embodiment 235. A kit described in any one of embodiments 231 to 234, wherein the first unit dosage form or the second unit dosage form is a lyophilized powder.

[0588] Embodiment 236. The kit of a...

Claims

1. A pharmaceutical composition comprising flecainide or a pharma- ceutically acceptable salt thereof, ibutilide or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients, diluents or carriers.

2. 10. The pharmaceutical composition of claim 1 in the form of an inhalable dry powder.

3. 3. The pharmaceutical composition of claim 2, wherein the dry powder is formed by supercritical fluid enhanced dispersion (SEDS).

4. 3. The pharmaceutical composition of claim 2, wherein the dry powder is formed by supercritical precipitation.

5. 3. The pharmaceutical composition of claim 2, wherein the dry powder is formed by imprint lithography.

6. The pharmaceutical composition of claim 2 , wherein the dry powder is a lyophilized powder.

7. 10. The pharmaceutical composition of claim 1 in the form of a liquid solution.

8. 10. The pharmaceutical composition of claim 1 or 7, comprising about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.0005 mg / mL to about 5 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

9. 10. The pharmaceutical composition of claim 1 or 7, comprising about 1 mg / mL to about 20 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.001 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

10. 10. The pharmaceutical composition of claim 1 or 7, comprising about 50 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.001 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

11. 10. The pharmaceutical composition of claim 1 or 7, comprising about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.001 mg / mL to about 1 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

12. 10. The pharmaceutical composition of claim 1 or 7, comprising about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.014 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

13. 10. The pharmaceutical composition of claim 1 or 7, comprising about 75 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.6 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

14. 10. The pharmaceutical composition of claim 1 or 7, comprising about 1 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof, and about 0.007 mg / mL of ibutilide or a pharma- ceutically acceptable salt thereof.

15. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the mass / mass ratio of said flecainide or said pharma- ceutically acceptable salt thereof to said ibutilide or said pharma- ceutically acceptable salt thereof in said pharmaceutical composition is from 60:1 to 240:

1.

16. 8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the mass / mass ratio of said flecainide or said pharma- ceutically acceptable salt thereof to said ibutilide or said pharma- ceutically acceptable salt thereof in said pharmaceutical composition is about 120:

1.

17. 17. The pharmaceutical composition according to claim 15 or 16, comprising about 1 mg / mL to about 100 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

18. 17. The pharmaceutical composition according to claim 15 or 16, comprising about 1 mg / mL to about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

19. 17. The pharmaceutical composition according to claim 15 or 16, comprising about 2 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

20. 17. The pharmaceutical composition according to claim 15 or 16, comprising about 1 mg / mL of flecainide or a pharma- ceutically acceptable salt thereof.

21. The pharmaceutical composition according to any one of claims 8 and 1 to 20, wherein said flecainide or a pharma- ceutically acceptable salt thereof is flecainide acetate.

22. The pharmaceutical composition according to any one of claims 1 to 20, wherein said flecainide or a pharma- ceutically acceptable salt thereof is flecainide hydrochloride.

23. 23. The pharmaceutical composition according to any one of claims 1 to 22, wherein said ibutilide or a pharma- ceutically acceptable salt thereof is ibutilide fumarate.

24. 23. The pharmaceutical composition according to any one of claims 1 to 22, wherein said ibutilide or a pharma- ceutically acceptable salt thereof is ibutilide hemifumarate.

25. A pharmaceutical composition according to any one of claims 1 to 24 for use in treating atrial arrhythmia in a subject.

26. 26. The method of claim 25, wherein the atrial arrhythmia is selected from the group consisting of supraventricular tachycardia, paroxysmal supraventricular tachycardia, atrial fibrillation, paroxysmal atrial fibrillation, persistent and permanent atrial fibrillation, atrial flutter, paroxysmal atrial flutter and isolated atrial fibrillation.

27. 26. The method of claim 25, wherein the atrial arrhythmia comprises paroxysmal atrial fibrillation.

28. 26. The method of claim 25, wherein the atrial arrhythmia comprises permanent atrial fibrillation.

29. The method of any one of claims 25 to 28, wherein the subject is a human subject.

30. The method according to any one of claims 25 to 28, wherein the subject suffers from paroxysmal atrial fibrillation unresponsive to monotherapy with flecainide or a pharma- ceutically acceptable salt thereof.

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