Compositions containing propafenone and mexiletine and their use

Abstract

A pharmaceutical composition in a fixed-dose combination is described, comprising: a) a dofetilide component; and b) a mexiletine component; wherein the dofetilide component and the mexiletine component are physically separated from each other, and a method for treating or preventing atrial fibrillation or related symptoms in a subject by administering such pharmaceutical composition to a subject in need, and a method for preparing such a fixed-dose combination product.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 115,258, filed November 18, 2020, the disclosure of which is incorporated herein by reference in its entirety. Background of the Invention

[0004] Atrial fibrillation is the most common abnormal heart rhythm, affecting approximately 5.2 million people in the United States and more than 10 million people in China. 1 , 2 33 million people worldwide have been affected. 3 Despite improvements in primary and secondary prevention of coronary artery disease and effective treatments for hypertension and other heart conditions, the prevalence of atrial fibrillation (AF) continues to rise. This increase in AF is likely at least partly due to increased average life expectancy. It is projected that the prevalence of AF in the United States will reach 12.1 million cases by 2023. 4 Atrial fibrillation (AF) increases the risk of stroke, heart failure, and death, especially in older adults. In the United States, approximately 35% of strokes each year are caused by AF.

[0005] One of the important treatments for atrial fibrillation is to restore and maintain a normal heart rhythm. Currently, there are two main treatment methods in clinical practice: (1) drug therapy; and (2) radiofrequency ablation. Both methods have their advantages and disadvantages, and neither is sufficient to eliminate atrial fibrillation.

[0006] Because drug therapy for atrial fibrillation has relatively poor efficacy and a higher incidence of adverse reactions, the recurrence rate of atrial fibrillation is higher when patients receive drug therapy than with radiofrequency ablation. Although dofetilide has been used to treat atrial fibrillation for over 20 years... 5,6 However, among the few antiarrhythmic drugs available on the market, it accounts for only 2% of annual antiarrhythmic drug prescriptions (compared to 45% for another antiarrhythmic drug, amiodarone). 7 Furthermore, dofetilide has not yet been approved for use in Europe and China. The main reasons why clinicians use dofetilide less frequently include its relatively suboptimal efficacy. 8 QT prolongation increases the risk of life-threatening ventricular arrhythmias, specifically torsades de points (TdP). 9 Therefore, the US FDA requires a mandatory 3-day in-hospital loading period; and experience is required when using this drug to avoid or minimize adverse events associated with dofetilide overdose.

[0007] New, effective, and safe methods and pharmaceutical compositions are still needed to treat or prevent atrial fibrillation and its associated symptoms. Specifically, new methods and pharmaceutical compositions are needed to provide more effective prevention and / or treatment of atrial fibrillation to patients in need, while reducing the risk of adverse reactions, such as the incidence of total diastolic fibrillation (TdP).

[0008] As is well known, mexiletine is not only an effective TdP inhibitor that inhibits late sodium currents, but it also synergizes with dofetilide (an antiarrhythmic drug for treating atrial fibrillation), thereby significantly improving the treatment of atrial fibrillation and reducing the risk of ventricular arrhythmias, as described in U.S. Patent No. 9,597,302, the entire contents of which are incorporated herein by reference. It is recommended that the dosage range of dofetilide be expanded when using dofetilide and mexiletine in combination for the treatment of atrial fibrillation (i.e., allowing for the safe administration of higher doses of dofetilide, thereby improving efficacy and the range of treatment), because the two drugs have a synergistic effect in inhibiting atrial fibrillation and reducing the risk of ventricular arrhythmias. This will greatly improve clinicians' ability to treat atrial fibrillation conservatively rather than through invasive procedures such as radiofrequency ablation, as the efficacy and safety of the combined use of dofetilide and mexiletine are significantly improved.

[0009] While combinations of dofetilide and mexiletine can be obtained by mixing these active ingredients with a carrier, it remains unclear how to predict which of these combinations will possess the physicochemical properties that would make the composition suitable for pharmaceutical use. Fixed-dose combination products (FDCs) comprise two or more drugs combined in a fixed proportion into a single or unit dosage form. The terms single dosage form and unit dosage form are used interchangeably herein. Developing a specific fixed-dose combination product (FDC) with a variety of desired pharmaceutical properties of an active pharmaceutical ingredient (API) is often an unpredictable task, such as the selection and manufacture of API and non-API components in this fixed-dose form. If pharmaceutical physical properties, such as hygroscopicity, crystallinity, melting point, solubility, dissolution rate, and stability, present predictable challenges in the case of a single API formulation, these challenges become even more pronounced in the case of a single dosage form with multiple APIs and other components, due to the potential for reactivity between the dosage form's constituent components. Due to the limitations of those skilled in the art in anticipating or successfully predicting these properties and their role in certain aspects of the pharmaceutical industry, there remains a need to find formulations of certain pharmaceutical compounds that make them acceptable pharmaceutical preparations. Drug formulations that deliver two or more APIs simultaneously in a single dosage form are advantageous and desirable because they offer one or more benefits, such as enhanced efficacy, reduced incidence of adverse reactions, pharmacokinetic advantages, improved adherence and compliance by reducing tablet burden, reducing individual drug doses or simplifying treatment courses, reducing the development of drug resistance, and reducing potential costs from packaging to distribution. However, they are difficult to develop because they present several challenges, such as pharmacodynamic mismatch, pharmacokinetic mismatch, chemical incompatibilities, drug interactions, and more nuanced dose titration limitations for individual components. For example, see YK Gupta et al., Fixed-dose drug combinations: Issues and challenges in India, Indian J. Pharmacol. 48(4), 347-49 (2016) (which outlines the general problems of fixed-dose combinations and explores their motivations). Various approaches to achieving multiple API doses in the past have included discrete dosage forms for each API, including in a single package, multiple APIs in a single dosage form, and multiple layers of different APIs in a single compressed tablet. However, the compatibility of various APIs may limit the use of such techniques.

[0010] Furthermore, various excipient components commonly used in pharmaceutical compositions can interact with each other and act differently with APIs, thereby impairing the physical and / or chemical properties of the composition. For example, a filler typically used with one API may perform poorly when used with another API or other excipients in the combination. Therefore, it is becoming increasingly difficult to formulate more than one API into a single formulation without harmfully affecting the properties of a fixed-dose combination. Summary of the Invention

[0011] Generally, this invention relates to pharmaceutical compositions comprising a dofetilide component and a mexiletine component. Generally, this invention also relates to methods of treating or preventing atrial fibrillation using a combination of dofetilide and mexiletine according to various formulations of the invention. Therefore, various embodiments of the invention provide combined dual-active formulations of dofetilide and mexiletine in a single dose unit, which may include immediate-release, sustained-release, and / or modified-release components.

[0012] Various embodiments of the present invention include a unit dosage form of pharmaceutical composition comprising: a) a dofetilide component; and b) a mexiletine component; wherein the dofetilide component and the mexiletine component are contained within a single dosage unit; wherein the dofetilide component comprises an effective amount of the dofetilide active ingredient and one or more pharmaceutically acceptable excipients; wherein the mexiletine component comprises an effective amount of mexiletine and one or more pharmaceutically acceptable excipients; and wherein the dofetilide component and the mexiletine component are physically separated from each other, for example, by coating each API-containing particle with an inert layer and / or incorporating each API into the composition in the form of flakes or particles.

[0013] In various embodiments of the invention, separating the dofetilide component and the mexiletine component from each other may include filling two separate compartments of a multi-compartment drug delivery system (e.g., a multi-compartment capsule), each compartment containing the dofetilide component and the mexiletine component respectively. In various embodiments of the invention, separating the dofetilide component and the mexiletine component from each other may include tableting or other combinations of the dofetilide component and the mexiletine component in solid form with an inert intermediate layer or film. In various embodiments of the invention, separating the dofetilide component and the mexiletine component from each other may include coating one or both of the dofetilide component and the mexiletine component. In various embodiments of the invention, the dofetilide component and the mexiletine component may be in different states (e.g., solid and liquid) and physically separated.

[0014] Embodiments of the present invention include a unit dosage form of pharmaceutical composition comprising: a) a dofetilide component; and b) a mexiletine component; wherein the dofetilide component and the mexiletine component are contained within a capsule; wherein the dofetilide component comprises an effective amount of the active ingredient dofetilide, either alone or in combination with one or more pharmaceutically acceptable excipients; wherein the mexiletine component comprises an effective amount of mexiletine, either alone or in combination with one or more pharmaceutically acceptable excipients; wherein at least one of the dofetilide component and the mexiletine component is compressed and coated with a polymer film.

[0015] Other embodiments of the invention include methods for treating or preventing atrial fibrillation or related symptoms in subjects in need, the methods comprising administering to the subject a pharmaceutical composition according to any formulation described herein.

[0016] In various embodiments, the combined dual-active formulation of dofetilide and mexiletine can be immediate-release, sustained-release, or modified release dose units. In various embodiments, mexiletine can be granulated in a mixture containing various excipients and formulated into tablets, microcapsules, or granules. In various embodiments, mexiletine and / or dofetilide can be in powder, liquid, or suspension form. In various embodiments, dofetilide can be mixed in a mixture containing various excipients and formulated into tablets, microcapsules, or granules. In various embodiments, one or more polymer coatings are layered onto mexiletine tablets or microcapsules. In various embodiments, one or more polymer coatings are layered onto dofetilide tablets or microcapsules. In various embodiments, dofetilide tablets or microcapsules and mexiletine tablets or microcapsules can be contained in capsules. In various embodiments, pharmaceutical compositions containing dofetilide and mexiletine components exhibit uniformity of content and stability. In various embodiments, the combined dual-active formulation of dofetilide and mexiletine does not undergo changes such as browning and color changes.

[0017] Various embodiments of the present invention relate to methods for preparing pharmaceutical compositions comprising effective amounts of dofetilide and mexiletine, as well as various excipients. The examples provided herein illustrate implementations of these methods.

[0018] The amounts of dofetilide and mexiletine included in the embodiments of the present invention are as follows:

[0019] Dofetilide ranged from 0.113 μmol to 5.66 μmol, and mexiletine ranged from 0.139 mmol to 4.64 mmol.

[0020] Dofetilide is available in doses ranging from 50 mcg to 2500 mcg, and mexiletine in the form of mexiletine hydrochloride is available in doses ranging from 30 mg to 1000 mg.

[0021] The dosage of dofetilide is 100 mcg to 600 mcg, and the dosage of mexiletine is 100 mg to 500 mg of mexiletine hydrochloride, for example (a) 125 mcg of dofetilide with 150, 200, 250, 300, 350, 400, 450, or 500 mg of mexiletine hydrochloride, (b) 250 mcg of dofetilide with 150, 200, 250, 300, or 500 mg of mexiletine hydrochloride, (c) 350, 400, 450 or 500 mg mexiletine hydrochloride, (d) 375 mcg dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 mg mexiletine hydrochloride, (e) 500 mcg dofetilide and 150, 200, 250, 300, 350, 400, 450, 500 mg mexiletine hydrochloride;

[0022] 500 mcg dofetilide and 275 mg mexiletine hydrochloride;

[0023] 500 mcg dofetilide and 245 mg mexiletine hydrochloride;

[0024] Dofetilide dosages range from 125 mcg to 500 mcg, and mexiletine dosages range from 160 mg to 280 mg mexiletine hydrochloride, for example, 500 mcg dofetilide and 245, 250, 255, 260, 265, 270, 275, or 280 mg mexiletine hydrochloride; and

[0025] The dosage of dofetilide is 250 mcg or 500 mcg, and the dosage of mexiletine is 165 mg or 245 mg mexiletine hydrochloride.

[0026] Further embodiments of the invention are illustrated by means of a composition wherein dofetilide and mexiletine are each present in any of the aforementioned amounts, and, upon analysis over time, the dofetilide component has impurities that satisfy at least one of the following three characteristics: (a), (b), and (c).

[0027] (a) One month after the preparation of the pharmaceutical composition, the content is below the limit of quantitation at room temperature and below 0.5% at 40°C / 75% relative humidity.

[0028] (b) Two months after the preparation of the pharmaceutical composition, the concentration was below 0.8% at 40°C / 75% relative humidity, and

[0029] (c) Less than 0.3% at room temperature and less than 1% at 40°C / 75% relative humidity three months after preparation of the pharmaceutical composition; and

[0030] Among them, the impurities in the mexiletine component, as analyzed over time, satisfy at least one of the following three characteristics: (d), (e), and (f):

[0031] (d) One month after the preparation of the pharmaceutical composition, the result was below the limit of quantitation at room temperature and 40°C / 75% relative humidity.

[0032] (e) Two months after the preparation of the pharmaceutical composition, the result is below the limit of quantitation under conditions of 40°C / 75% relative humidity, and

[0033] (f) The drug composition was below the limit of quantitation three months after preparation, at room temperature and 40°C / 75% relative humidity.

[0034] Further embodiments of the invention are illustrated by means of a composition wherein dofetilide and mexiletine are each present in any of the aforementioned amounts, and, upon analysis over time, the dofetilide component has impurities that satisfy at least one of the following three characteristics: (a), (b), and (c).

[0035] (a) One month after the preparation of the pharmaceutical composition, the content is below the limit of quantitation at room temperature and below 0.2% at 40°C / 75% relative humidity.

[0036] (b) Two months after the preparation of the pharmaceutical composition, at 40°C / 75% relative humidity, the concentration was below 0.5%, and

[0037] (c) Less than 0.2% at room temperature and less than 0.7% at 40°C / 75% relative humidity three months after the preparation of the pharmaceutical composition; and

[0038] Among them, the impurities in the mexiletine component, as analyzed over time, satisfy at least one of the following three characteristics: (d), (e), and (f):

[0039] (d) One month after the preparation of the pharmaceutical composition, the result was below the limit of quantitation at room temperature and 40°C / 75% relative humidity.

[0040] (e) Two months after the preparation of the pharmaceutical composition, the result is below the limit of quantitation under conditions of 40°C / 75% relative humidity, and

[0041] (f) The drug composition was below the limit of quantitation three months after preparation, at room temperature and 40°C / 75% relative humidity.

[0042] Other aspects, features, and advantages of the invention will become apparent from the following disclosure, including the detailed description of the invention, illustrative embodiments, and appended claims.

[0043] Detailed description of the invention

[0044] Various publications, articles, and patents are referenced or described in the background and throughout this specification; each of these references is incorporated herein by reference in its entirety. Discussions of documents, actions, materials, devices, articles, or the like included in this specification are intended to provide background to the invention. Such discussion is not an admission that any or all of these matters constitute part of the prior art relating to any disclosed or claimed invention.

[0045] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings specified in this specification. All patents, published patent applications, and publications referenced herein are incorporated herein by reference as if fully set forth herein. It must be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly specifies otherwise.

[0046] For example, phrases such as “at least one of [the elements]”, “at least one selected from [the elements] [...]”, and similar terms used throughout the written description and claims are intended to include any of a variety of possibilities, which, unless otherwise stated, include, but are not limited to, selecting only one element from the elements list. For example, “at least one of A and B” is intended to include embodiments referring only to A, embodiments referring only to B, and embodiments referring to both A and B.

[0047] As used herein, unless otherwise stated, the name of a compound may include all possible isomers of the compound (e.g., optical isomers, enantiomers, diastereomers, racemic mixtures, or racemic mixtures), esters, prodrugs, metabolite forms, pharmaceutically acceptable salts, pharmaceutically acceptable esters, pharmaceutically acceptable amides, and protected derivatives.

[0048] As used herein, the term "subject" refers to any animal, preferably a mammal, and most preferably a human, that will be or has been administered a compound or pharmaceutical composition according to embodiments of the present invention. The term "mammal" as used herein includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., more preferably, humans. Preferably, the subject is or has been an observational or experimental subject for the treatment or prevention of atrial fibrillation and related symptoms; more preferably, such a subject is an elderly subject.

[0049] As described in this article, “subjects” are preferably those who need treatment or prevention of atrial fibrillation and related symptoms. Atrial fibrillation is an abnormal heart rhythm characterized by irregular and often rapid beatings that typically lead to poor blood flow throughout the body. During atrial fibrillation, the two upper chambers (atria) of the heart beat erratically and irregularly, uncoordinated with the two lower chambers (ventricles). Symptoms of atrial fibrillation include palpitations, dizziness, lightheadedness, fainting, shortness of breath, chest pain, angina-like chest pain, exercise intolerance, and swelling of the extremities. Although atrial fibrillation episodes can come and go asymptomatic, atrial fibrillation can cause blood clots to form in the heart, which can circulate to other organs and cause blood flow obstruction (ischemia). Subjects with a history of stroke, transient ischemic attack (TIA), hypertension, diabetes, heart failure, rheumatic fever, or a family history of atrial fibrillation may have a higher risk or predisposition to atrial fibrillation or complications associated with a diagnosed atrial fibrillation. Therefore, such subjects may need to prevent atrial fibrillation or are more likely to require treatment for atrial fibrillation.

[0050] This disclosure provides information and a summary of research protocols to determine the pharmacological characteristics of illustrative embodiments of the invention, such as bioavailability, drug-drug interactions, and the effects of factors such as food effects. These protocols can also be used, independently or in combination, with methods known to those skilled in the art to determine other pharmacological characteristics, such as the therapeutically effective amount of the active ingredient. Furthermore, as will be understood by those skilled in the art, a particular dose level for any given subject will depend on a variety of factors, including age, weight, health status, sex, diet, time of administration, route of administration, excretion rate, any other therapeutic agents administered in combination, and the severity of the disease or condition being treated.

[0051] The compositions of the present invention comprise one or more therapeutically active ingredients, their prodrugs, their pharmaceutically acceptable salts, their hydrates, their solvates, and combinations thereof. Specifically, the therapeutically active ingredients in the pharmaceutical compositions of the present invention include dofetilide and mexiletine.

[0052] The term "dofelit" refers to the compound N-[4-(2-{[2-(4-methanesulfonamide phenoxy)ethyl](methyl)amino}ethyl)phenyl]methanesulfonamide, having the structure of formula (I):

[0053]

[0054] In embodiments of the present invention, any prodrug, pharmaceutically acceptable salt, hydrate, solvate, or combination thereof of dofetilide may be conceived as dofetilide, provided that the applicable amount is appropriately converted when administered by weight. Dofetilide is marketed by Pfizer Inc. under the trade name [Brand Name Missing]. Dofetilide is an antiarrhythmic drug that has been marketed for the treatment of atrial fibrillation for over 20 years. 5,6 However, its efficacy is suboptimal. 8 Dofetilide administration can also cause adverse reactions, such as an increased risk of QT interval prolongation, leading to life-threatening ventricular arrhythmias, and TdP triggered by R-on-T extrasystoles via early afterdepolarization (EAD). 12 Although uncommon, many factors, including hypokalemia, female sex, drug interactions, ventricular hypertrophy, and renal insufficiency, can significantly increase the risk of dofetilide-induced TdP. In various embodiments of the invention, dofetilide components with an average particle size (d90) of less than 10 μm can be used.

[0055] The term "mexiletine" refers to either (RS)-1-(2,6-dimethylphenoxy)propyl-2-amine or 2-(2-aminopropoxy)-1,3-xylene, whose hydrochloride form has the structure of formula (II):

[0056]

[0057] In embodiments of the invention, any prodrug or pharmaceutically acceptable salt of mexiletine, including but not limited to mexiletine hydrochloride, hydrates, solvates, or combinations thereof, may be conceivable as mexiletine, provided that the applicable amount is appropriately converted when administered by weight. Mexiletine is a sodium channel blocker that has been used since the early 1970s to treat documented ventricular arrhythmias, such as sustained ventricular tachycardia. 13,14 It can also block INA-L (late sodium current), which has recently proven to be an effective treatment for terminating TdP in acquired LQTS (long QT syndrome), such as LQTS acquired after dofetilide administration. 11 However, mexiletine is generally considered to have a minimal electrophysiological effect in the atria, meaning it lacks atrial selectivity. Therefore, mexiletine is not suitable for the effective treatment of atrial fibrillation. 15 Furthermore, none of the atrial fibrillation patient management guidelines from the American College of Cardiology, the American Heart Association, or the Heart Rhythm Society include Mexiletine. 16 .

[0058] The term “pellet” refers to a formulation with a diameter of approximately 5.0 mm or less that has undergone a compression process, or has been made by layering into sucrose nonpareils or by extrusion followed by optional rounding or other similar known techniques.

[0059] The term "granule" refers to a pharmaceutical formulation in which the components have been mixed together to tightly and uniformly disperse the API in some or all other components and to increase the particle size. Well-known techniques in the pharmaceutical industry include wet or dry granulation.

[0060] The term "tablet" refers to coated or uncoated tablets, single-layer or multi-layer tablets, and any other dosage form that has undergone a compression or compaction process to form solid dosage units. As used herein, "tablet" may include pellets or microplates.

[0061] The terms “milling” or “milled” used in this article refer to the physical breakdown of coarse particles into finer particles by applying mechanical energy.

[0062] The grinding mill suitable for the method of the present invention is, for example, a dry grinding mill capable of grinding materials into ultrafine particles by mechanical impact and / or abrasion, which is referred to as a high-speed stirring mill and an impact mill. Specific examples of grinding mills are cylindrical mills, such as rotary ball mills, vibratory ball mills, tube mills, and rod mills.

[0063] As used herein, the term "excipient" refers to a therapeutically inert, pharmaceutically acceptable component added to a pharmaceutical preparation as a filler or diluent, binder, disintegrant, flow aid or glidant, lubricant or wetting agent, etc. Excipients belonging to these and other categories are well known in pharmaceutical preparations and manufacturing.

[0064] The term “geometric blending” as used in this article refers to the technique of dispersing small amounts of API in incremental proportions with an appropriate amount of diluent, which ensures a uniform distribution of API in the final mixture.

[0065] As used herein, the term "dry mix" refers to mixing dried components, such as in a mixture of APIs, fillers, or other excipients, prior to further use.

[0066] Pharmaceutical compositions according to embodiments of the present invention are formulated for oral administration. Pharmaceutical compositions suitable for oral administration include solid forms such as pellets, tablets, capsules, and hard or soft capsules (each comprising immediate-release, time-release, and sustained-release formulations), as well as lozenges and dispersible powders or granules. Pharmaceutical compositions according to various embodiments of the present invention are formulated into capsules. In various embodiments, hard capsules are used.

[0067] Pharmaceutically acceptable carriers ideally used for preparing solid oral dosage forms include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating or disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. If desired, solid pharmaceutical compositions suitable for oral administration may further include one or more sweeteners, flavoring agents, coloring agents, or preservatives to provide an attractive or palatable formulation.

[0068] The effective amount of the therapeutically active ingredient contained in a dosage form will depend on a variety of factors, such as the patient being treated, the route of administration, and the required delivery dose. An exemplary pharmaceutical composition, as an embodiment of the invention, comprises 50 mcg to 2500 mcg of dofetilide (in the range of 0.113 μmol to 5.66 μmol dofetilide) and 30 mg to 600 mg of mexiletine hydrochloride (in the range of 0.232 mmol to 4.64 mmol mexiletine) per dosage form. In a further embodiment, each dosage form contains 50 mcg to 1000 mcg of dofetilide and 30 mg to 600 mg of mexiletine hydrochloride. In embodiments of the invention, an exemplary effective amount of mexiletine hydrochloride is 50 mg to 1000 mg in some embodiments and 100 mg to 300 mg per dosage form in further embodiments. Examples of effective amounts of mexiletine hydrochloride include, but are not limited to, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg per dosage form. In some embodiments, dofetilide is delivered at 250 mcg or 500 mcg, and mexiletine hydrochloride is delivered at a dose of 165 mg or 245 mg. Based on formulas (I) and (II) given above, those skilled in the art know how to correlate amounts given by mass with amounts given by mole, whether referring to each of dofetilide and mexiletine as free compounds (molar masses of 441.56 g mol, respectively). -1 and 179.26g mol -1 Or in the form of, for example, salt (e.g., molar mass of 215.72 g mol) -1 (Mexiletine hydrochloride). For example, mentioning 0.838 mmol mexiletine includes 150 mg of mexiletine free base and 181 mg of mexiletine hydrochloride.

[0069] Various embodiments of the present invention include a mexiletine component, wherein the mexiletine is granulated in an aqueous suspension having a binder and a microcrystalline cellulose component. Suitable binders include polyvinylpyrrolidone, hydroxypropyl methylcellulose (“HPMC”), and starch. In various embodiments, the binder may comprise a polyvinylpyrrolidone binder. In some embodiments of the present invention, the polyvinylpyrrolidone binder may comprise povidone K29 / 32.

[0070] Various embodiments of the present invention include one or more microcrystalline cellulose components. Microcrystalline cellulose suitable for various embodiments of the present invention includes any pharmaceutically acceptable filler, such as, but not limited to, AVICEL microcrystalline cellulose obtained from many commercial sources. Generally, suitable particle sizes for microcrystalline cellulose components that can be used in various embodiments of the present invention are from about 50 μm to about 180 μm. In some embodiments, the average particle size is from 50 μm to about 100 μm. In various embodiments of the present invention, the mexiletine component is first granulated in a formulation containing the microcrystalline cellulose component and then mixed with another microcrystalline cellulose component and other optional excipients. In some embodiments, microcrystalline cellulose components with different average particle sizes are used. In some embodiments, mexiletine may be granulated together with a microcrystalline cellulose component having a smaller average particle size than the microcrystalline cellulose used in subsequent mixing.

[0071] In various embodiments of the invention, mexiletine components can be prepared by granulating mexiletine in an aqueous suspension of polyvinylpyrrolidone (PVP) with microcrystalline cellulose. In various embodiments of the invention, the particles are dried in an oven and ground, which can be done according to methods known in the art, such as using a Fitzmill mill. In various embodiments of the invention, the ground mexiletine hydrochloride particles can be mixed with microcrystalline cellulose, a flow aid (e.g., silica, or in some embodiments, colloidal silica), and a lubricant (e.g., magnesium stearate).

[0072] In various embodiments of the invention, a mixture of mexiletine hydrochloride can be compressed into microcapsules using a mold, according to methods known in the art. For example, in various embodiments of the invention, a mixture of granular mexiletine can be compressed into tablets or microcapsules. In various embodiments of the invention, the mexiletine microcapsules can be coated with a polyvinyl alcohol (PVA)-based polymer film using any suitable technique (several of which are known in the art). In various embodiments, the polymer film coating may include Opadry film coating obtained from Calcon Corporation (Hallesville, Pennsylvania). In various embodiments, coating can be performed using a pan coater or a fluidized bed coater, according to methods known in the art.

[0073] In various embodiments of the invention, the dofetilide component can be prepared by dry mixing dofetilide with various excipients. In various embodiments of the invention, micronized dofetilide is geometrically mixed with pregelatinized starch, microcrystalline cellulose, silica (in some embodiments, colloidal silica), and magnesium stearate. In various embodiments, the dofetilide mixture can be further compressed into tablets using a mold according to previously established methods. In various embodiments, the dofetilide mixture can be compressed into tablets or pellets.

[0074] In various embodiments of the invention, dofetilide tablets can be coated with polyvinyl alcohol (PVA) using any known technique. In some embodiments, coating can be performed using a pan coater or fluidized bed coater according to methods known in the art. In further embodiments of the invention, coated dofetilide tablets or microcapsules and coated mexiletine hydrochloride tablets or microcapsules are filled into hard capsules. In various embodiments of the invention, dofetilide tablets or microcapsules and mexiletine tablets or microcapsules can be filled into hard capsules.

[0075] Various other embodiments of the invention include methods for treating atrial fibrillation or related symptoms in subjects in need, the methods comprising administering to the subject 100 mcg to 1000 mcg, or higher doses (e.g., up to 1500 mcg) of dofetilide and 100 mg to 1000 mg of mexiletine hydrochloride, in some embodiments, in capsules according to any of the foregoing formulation embodiments. For example, the method may include administering a pharmaceutical composition, such as a capsule, to a subject in need, containing 100-500 mcg, 505-600 mcg, 605-700 mcg, 705-800 mcg, 805-900 mcg, or 905-1000 mcg of dofetilide, and 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg of mexiletine hydrochloride, as well as a pharmaceutically acceptable carrier. The method may also include administering to a subject in need a first pharmaceutical composition, such as a capsule, containing 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of mexiletine hydrochloride and a pharmaceutically acceptable carrier, and a second pharmaceutical composition, such as a capsule, containing 100-500 mcg, 505-600 mcg, 605-700 mcg, 705-800 mcg, 805-900 mcg, or 905-1000 mcg of dofetilide and a pharmaceutically acceptable carrier. Example

[0076] The invention will now be described in further detail with reference to the following specific, non-limiting embodiments. However, those skilled in the art will understand from this disclosure that many modifications can be made to the disclosed specific embodiments without departing from the scope of the invention, and similar or analogous results can still be obtained.

[0077] Example 1:

[0078] Mexiletine hydrochloride was granulated with Avicel PH101 using an aqueous binder solution of povidone K29 / 32. The granules were dried in an oven at 55°C and ground using a FitzMill mill. The ground mexiletine hydrochloride granules were mixed with Avicel PH102, Cab-O-Sil, and magnesium stearate. The mexiletine hydrochloride mixture was compressed into 7 mg microcapsules using a 2.0 mm die. The core microcapsules of mexiletine hydrochloride were then coated with polyvinyl alcohol (PVA)-based omega-3. The formulation of the mexiletine hydrochloride microcapsules is shown in Table 1 below. A dofetilide mixture was prepared by geometrically mixing micronized dofetilide with starch 1500, Avicel PH101, Cab-O-Sil, and magnesium stearate. The dofetilide mixture was compressed into 85 mg tablets using a 5.6 mm die. The formulation of the dofetilide tablets is shown in Table 2. The unit dosage form pharmaceutical composition of this embodiment was prepared by filling OEL hard gelatin capsules with dofetilide tablets containing 500 mcg and mexiletine hydrochloride containing 275 mg of mexiletine hydrochloride, and coated mexiletine hydrochloride microgranules. These capsules have the characteristics of immediate drug release.

[0079] Table 1. Formulation of Mexiletine Hydrochloride Microcapsules 71.4%

[0080]

[0081] Note: (1) Pure water, USP was used in manufacturing but did not appear in the final product.

[0082] Table 2. Dofetilide Tablets, 0.59% – Formulation

[0083]

[0084] The stability of the capsules was tested under accelerated conditions at room temperature and 40°C / 75% relative humidity (“RH”), and the data are shown in Table 3.

[0085] Table 3: Stability of the capsules in Example 1, 500mcg / 275mg

[0086]

[0087] Note: Unless otherwise stated, percentages given when referring to the composition throughout the specification are weight percentages (w / w). The term "QL" stands for limit of quantitation, which is the lowest concentration that can not only be detected but also quantified with specified precision.

[0088] Example 2:

[0089] Mexiletine hydrochloride was granulated with Avicel PH101 using an aqueous binder solution of povidone K29 / 32. The granules were dried in an oven at 55°C and ground using a FitzMill. The ground mexiletine hydrochloride granules were mixed with Avicel PH102, Cab-O-Sil, and magnesium stearate. The mexiletine hydrochloride mixture was compressed into 7 mg microspheres using a 2.0 mm die. The mexiletine hydrochloride core microspheres were then coated with polyvinyl alcohol (PVA)-based omega-3. The formulation of the mexiletine hydrochloride granules is shown in Table 4. A dofetilide mixture was prepared by geometrically mixing micronized dofetilide with starch 1500, Avicel PH101, Cab-O-Sil, and magnesium stearate. The dofetilide mixture was compressed into 85 mg tablets using a 5.6 mm die. The dofetilide core tablets were then coated with polyvinyl alcohol (PVA)-based omega-3. The formulation of the dofetilide tablets is shown in Table 5. The pharmaceutical composition of the unit dosage form of this embodiment was prepared by filling OEL hard gelatin capsules with a content of 500 mcg of dofetilide and 275 mg of mexiletine hydrochloride.

[0090] Table 4: Mexiletine Hydrochloride Microcapsules 71.4% - Formulation

[0091]

[0092]

[0093] Note: (1) Pure water, USP was used in manufacturing but did not appear in the final product.

[0094] Table 5: Dofetilide Tablets, 0.53% – Formulation

[0095]

[0096] Note: (1) Pure water, USP used in manufacturing, but not in the final product.

[0097] The capsules in this embodiment demonstrate the immediate-release properties of dofetilide and mexiletine after one month of storage under initial and accelerated stability conditions at 40°C / 75% relative humidity.

[0098] The stability of the capsules was tested at room temperature and under accelerated conditions of 40°C / 75% relative humidity. The test data are shown in Table 6.

[0099] Table 6: Stability of the capsules in Example 2, 500mcg / 275mg

[0100]

[0101]

[0102] Unknown impurities are expressed using relative retention time (“RRT”). For identified impurities, they should be explicitly mentioned, such as 2,6-DMP (2,6-xylenol), MX-200 (3,9-dimethyl-2,3-dihydro-1,4-benzoxazepine), and MX-300 (2-hydroxy-3-methylbenzaldehyde).

[0103] Comparative Example 1:

[0104] Dry blend of dofetilide and mexiletine granules

[0105] Dry-mixed filled capsules of Comparative Example 1 were prepared by granulating mexiletine hydrochloride using an aqueous binder solution with 0.5 mg hydroxypropyl methylcellulose, HPMC E5 LV, and 31 mg purified water as solvents. The granules were then dried in an oven at 55°C and milled using a Fitzmill mill. Micronized dofetilide was geometrically mixed with 48 mg pregelatinized starch (starch 1500) and 98 mg microcrystalline cellulose (Avicel PH 101). The mexiletine granules and dofetilide mixture were then mixed with 2.2 mg Cab-O- The mixture was prepared with 250 mcg of dofetilide and 275 mg of mexiletine hydrochloride. The mixture was further lubricated with 1.0 mg of magnesium stearate. The resulting mixture was then filled into No. 0 hard gelatin capsules.

[0106] The capsules of Comparative Example 1 exhibit immediate-release properties of dofetilide and mexiletine hydrochloride. Importantly, the micronized dofetilide and optimized geometric mixing process resulted in good uniformity of the content of the mexiletine hydrochloride and dofetilide drug substances (Table C4).

[0107] Table C3. Formulations of Mexiletine Granulation and Dry-Mixed Dofetiate

[0108]

[0109] *The solvent evaporates during the process and will not appear in the final product.

[0110] Table C4. Content uniformity of Comparative Example 1

[0111]

[0112]

[0113] In the context of this invention, impurity analysis was performed according to standard high-performance liquid chromatography (HPLC) and detected using ultraviolet spectroscopy (UV) to identify one or more of the following: mass, relative retention time, and amount (as a relative area percentage), which are provided herein using notations typical of such standard methods. For illustrative commentary on the same subject, see, for example, S. Levin, “High Performance Liquid Chromatography (HPLC) in the pharmaceutical analysis,” Medtechnica (2010), which is incorporated herein by reference (describes HPLC models, HPLC theory, the role of HPLC in pharmaceutical analysis, and specialized HPLC separations). Initial stability of the batch indicated that almost no impurities were detected. However, after one month of storage under accelerated stabilization conditions (40°C / 75% relative humidity), dofetilide-related impurities increased significantly. In particular, oxidative degradation products of dofetilide were formed (dofetilide-related impurity 6). The interaction between mexiletine hydrochloride and dofetilide may contribute to the higher dofetilide impurities. Given that mexiletine hydrochloride is a basic compound and exists in relatively high concentrations (1100 times that of dofetilide), mexiletine hydrochloride can affect the stability of dofetilide.

[0114] In summary, Comparative Example 1 demonstrated the immediate-release characteristics and good content uniformity of dofetilide and mexiletine hydrochloride, but its stability was lower than that of the aforementioned examples due to the increase of impurities over time.

[0115] Table C5. Stability of Comparative Example 1 (0.25 mg / 275 mg)

[0116]

[0117] Example 3:

[0118] A study was conducted, Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 275mg vs. Reference Product Dofetilide capsules 500 mcg (0.5 mg) and mexiletine hydrochloride capsules USP, 250 mg, were administered simultaneously once to healthy male and non-pregnant female volunteers in a fasting state to determine the relative bioavailability of dofetilide and mexiletine from the test products described above. In this study, a difference of 275 mg mexiletine hydrochloride in the test product dofetilide / mexiletine hydrochloride capsules and 250 mg mexiletine hydrochloride in one of the reference products was considered acceptable. This consideration also applies to similar differences in the same API amount in other examples provided herein. Potential participants were subject to selection criteria based on multiple factors, such as age, health habits, BMI, cardiovascular disease, diet, behavioral incompatibility, ability to participate in the entire study, pregnancy and contraception in women and men, blood chemistry, known medical history or presence of certain clinically significant diseases and abnormalities, positive tests for certain diseases or for ingestion / administration / use of specific drugs, congenital deficiencies, allergies and intolerances, and participation in other trials.

[0119] Test and reference products were administered to subjects during the study period under specific time and dietary conditions. Samples from 18 subjects were analyzed in a bioanalytical laboratory. Data from these 18 subjects were included in pharmacokinetic and statistical analyses. Plasma samples were collected every 48 hours following each dosing period to determine the concentrations of dofetilide and mexiletine. Pharmacokinetic parameter C was estimated based on the plasma levels of dofetilide and mexiletine in subjects included in the statistical analysis. max T max AUC t AUC inf T1 / 2 and λ.

[0120] result

[0121] Test product Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 275mg, showed comparison with the reference product. (Dofelithe) capsules 500mcg (0.5mg) showed comparable absorption rate and extent to dofelithe. The AUC of the test / reference (T / R) was measured at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 16, 24, 36, and 48 hours after administration in each study period. t The geometric mean ratio (GMR) of the area under the plasma concentration-time curve starting from time zero is approximately 100%. inf (Area under the plasma concentration-time curve from time 0 to infinity) and C max (maximum observed plasma concentration) and AUC t AUC inf and C maxThe corresponding 90% CI (confidence interval) are all within the FDA's acceptable range of 80.00%-125.00%.

[0122] Test product Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 275mg, showed comparable absorption rate and extent of mexiletine. The reference product, Mexiletine Hydrochloride Capsules USP, 250mg, showed a test / reference (T / R) AUC. t and AUC inf The geometric mean ratio (GMR) is approximately 108%, C max It is 110%, AUC t AUC inf and C max The corresponding 90% CI is within the FDA's acceptable range of 80.00%-125.00%.

[0123] Therefore, it proves the test product Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 275mg vs. Reference Product Dofetilide capsules 500 mcg (0.5 mg) and mexiletine hydrochloride capsules USP, 250 mg had comparable bioavailability in healthy, non-smoking male and non-pregnant female volunteers in a fasting state. Therefore, administration Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 275mg, is equivalent to the combined administration of commercially available dofetilide and mexiletine as separate entities.

[0124] Example 4:

[0125] A study was conducted, Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 245mg Dofetilide capsules 500 mcg (0.5 mg) and mexiletine hydrochloride capsules USP, 250 mg were administered at each time point to healthy male and non-pregnant female volunteers in fasting states to determine the relative bioavailability of dofetilide and mexiletine from the aforementioned test products. Another objective of this study was to evaluate the effects of food (high-fat diet versus fasting) on ​​the fixed-dose combination formulation. Effects of bioavailability of dofetilide / mexiletine hydrochloride capsules, 500 mcg / 245 mg, administered to healthy male and non-pregnant female volunteers. Potential subjects were subject to selection criteria based on multiple factors (e.g., those summarized in Example 3). Test and reference products were administered to subjects during the study period under specific time and dietary conditions. Data from 26 subjects were included in pharmacokinetic and statistical analyses and comparisons under different conditions.

[0126] result

[0127] Test product A ( Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 245mg) showed similar performance to reference product B. (Dofetilide) capsules (500 mcg) provide the equivalent absorption rate and extent of dofetilide. Descriptive statistics (minimum, maximum, median, mean, standard deviation, and coefficient of variation) of all pharmacokinetic parameters for dofetilide and mexiletine are provided for the tested and reference products. AUC t AUC inf and C max The parameters were transformed using a natural logarithm transformation before analysis. For T... 1 / 2 , λ, T max and T lag (If applicable) Unconverted data and AUC t AUC inf and C max Perform ANOVA on the ln-transformed data, and analyze the variance of T. max and T lag (If applicable) Perform the analysis using other nonparametric tests (Wilcoxon test). Calculate the AUC based on LSMEANS and ESTIMATE from the ANOVA. t AUC inf and C max The 90% confidence interval (CI) of the geometric mean is calculated. If food has no effect on the bioavailability of dofetilide and mexiletine, based on ln-transformed data, the 90% confidence interval of the ratio of the geometric mean between fed and fasted treatments should be included in the AUC. t AUC inf and C max Within 80%-125%. AUC of test / reference A / B. t AUC inf and C max The geometric mean ratios (GMRs) were approximately 98%, 98%, and 96%, respectively, and the AUC was... t The corresponding 90% CI falls within the FDA acceptable range of 80%-125%. Test product A ( Dofetilide / Mesiletine Hydrochloride Capsules (500 mcg / 245 mg) showed comparable absorption rate and extent of mesiletine to Reference Product C (Mesiletine Hydrochloride Capsules USP 250 mg). AUC of Test / Reference (A / C) t AUC inf and C max The geometric mean ratios (GMRs) were approximately 97%, 97%, and 97%, respectively, and the AUC was... tThe corresponding 90% CI falls within the FDA acceptable range of 80.00%–125.00%. Therefore, in healthy, non-smoking male and non-pregnant female volunteers under fasting conditions, test product A ( Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 245mg), Reference Product B ( (Dofelith) capsules, 500 mcg) and reference product C (Mexiletine Hydrochloride Capsules USP 250 mg) showed comparable bioavailability. Test product Dofetilide / mexiletine hydrochloride capsules, 500mcg / 245mg, showed comparable absorption rates and extent of dofetilide in both the fed (Product D) and fasting (Product A) states: AUC of Product D / Product A (fed / fasting). t AUC inf and C max The geometric mean ratios (GMRs) were approximately 102%, 101%, and 114%, respectively, corresponding to 90% CIs that fall within the FDA acceptable range of 80.00%–125.00%. (Tested product) Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 245mg, showed comparable absorption rates and extent of mexiletine in both the fed (Product D) and fasting (Product A) states: AUC of Test Product D / Test Product A (fed / fasting). t AUC inf and C max The geometric mean ratios (GMRs) were approximately 97%, 97%, and 92%, respectively. The corresponding 90% CI falls within the FDA acceptable range of 80.00%–125.00%. Therefore, for Dofetilide / mexiletine hydrochloride capsules, 500mcg / 245mg, were administered to healthy, non-smoking male and non-pregnant female volunteers. Food had no effect on the bioavailability of dofetilide / mexiletine. Furthermore, for Dofetilide / Mexiletine Hydrochloride Capsules, 500mcg / 245mg, no drug interactions of the active pharmaceutical ingredient were observed.

[0128] Those skilled in the art will understand that modifications can be made to the above embodiments without departing from their broad inventive concept. Therefore, it should be understood that the invention is not limited to the specific embodiments disclosed, but is intended to cover modifications within the spirit and scope of the invention as defined in the appended claims.

[0129] References

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[0132] -3. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, Gillem RF, Kim YH, McAnulty JH, Jr., Zheng ZJ, Forouzanfar MH, Naghavi M, Mensah GA, Ezzati M, Murray CJ. Global epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129:837-847.

[0133] -4. Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the US adult population. Am J Cardiol 2013; 112:1142-1147.

[0134] -5. Suttorp MJ, Polak PE, van't HA, Rasmussen HS, Dunselman PH, Kingma JH. Efficacy and safety of a new selective class III antiarrhythmic agent Dofetilide in paroxysmal atrial fibrillation or atrial flutter. Am J Cardiol 1992; 69:417-419.

[0135] -6. Rasmussen HS, Allen MJ, Blackburn KJ, Butrous GS, Dalrymple HW. Dofetilide, a novel class III antiarrhythmic agent. J Cardiovasc Pharmacol 1992; 20Suppl 2:S96-105.

[0136] -7. Zimetbaum P. Antiarrhythmic drug therapy for atrial fibrillation. Circulation 2012; 125:381-389.

[0137] -8. Qin D, Leeg G, Alam MB, Rattan R, Munir MB, Patel D, Khattak F, Adelstein E, Jain SK, Saba S. Comparative effectiveness of antiarrhythmic drugs for rhythm control of atrial fibrillation. J Cardiol 2015.

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[0139] -10. Qi D, Yang Z, Robinson VM, Li J, Gao C, Guo D, Kowey PR, Yan G X. Heterogeneous distribution of INa-L determines interregional differences in rate adaptation of repolarization. Heart Rhythm 2015; 12:1295-1303.

[0140] -11. Badri M, Patel A, Patel C, Liu G, Goldstein M, Robinson VM, Li J, Xue X, Yang L, Kowey PR, Yan G X. Mexiletine prevents recurrent torsades de Pointes in Acquired Long QT Syndrome Refractory to Conventional Measures. JACC: Clinical Electrophysiology 2015; 1:315-322.

[0141] -12. Yan GX, Wu Y, Liu T, Wang J, Marinchak RA, Kowey P R. Phase 2 early after depolarization as a trigger of polymorphic ventricular tachycardia in acquired long-QT syndrome: direct evidence from intracellular recordings in the intact left ventricular wall. Circulation 2001; 103:2851-2856.

[0142] -13. Talbot RG, Nimmo J, Julian DG, Clark RA, Neilson JM, Prescott LF. Treatment of ventricular arrhythmias with mexiletine (Ko 1173). Lancet 1973; 2:399-404.

[0143] -14. Campbell NP, Kelly JG, Shanks RG, Chaturvedi NC, Strong JE, Pantridge JF. Mexiletine (Ko 1173) in the management of ventricular dysrhythmias. Lancet 1973; 2:404-407.

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Claims

1. A unit dosage form of pharmaceutical composition comprising: a) Multi-feliate components; and b) Mexiletine components; in, The dofetilide component and the mexiletine component are contained in a single dosage form; The polyfetate component and the mexiletine component are contained within the gelatin capsule; The multifiltrate component comprises a sheet-like dry mixture of micronized multifiltrate, first microcrystalline cellulose, pregelatinized starch, colloidal silica and magnesium stearate, and the multifiltrate component is formulated into tablets; The mexiletine component comprises a granular mixture of mexiletine hydrochloride, polyvinylpyrrolidone binder, and a second microcrystalline cellulose, wherein the granular mixture is further mixed with a third microcrystalline cellulose, colloidal silica, and magnesium stearate, and wherein the granular mixture is formed into microspheres. The component selected from the polyfetate component and the mexiletine component is coated with a polyvinyl alcohol polymer film coating. The unit dosage form has immediate release characteristics; The unit dosage form comprises one of the following (a), (b) or (c) compositions: (a) 500 mcg dofetilide and 275 mg mexiletine hydrochloride, (b) 500 mcg dofetilide and 245 mg mexiletine hydrochloride, (c) 250 mcg dofetilide and 245 mg mexiletine hydrochloride.

2. The pharmaceutical composition according to claim 1, characterized in that, in, The polyvinylpyrrolidone adhesive is polyvinyl ketone, and the mexiletine component comprises a plurality of microspheres, each of the microspheres having an uncoated or coated core. Each of the microspheres contains a mixture of mexiletine hydrochloride and a microsphere excipient; The mexiletine component contains 70 w / w% to 80 w / w% mexiletine hydrochloride, 2 w / w% povidone and 10 w / w% second microcrystalline cellulose; The dofetilide component comprises tablets, the tablets comprising a mixture of dofetilide and tablet excipients, the tablets being uncoated or coated, and the coated or uncoated tablets containing 0.5 w / w% to 0.6 w / w% dofetilide; Wherein, when the microspheres are coated, the coating content of the microspheres is 9.1 w / w% of the coated microspheres. Wherein, when the tablet is coated, the tablet coating is 9.1 w / w of the coated tablet.

3. The pharmaceutical composition according to claim 1, characterized in that, At least one of the two components selected from the said polyfetate component and the said mexiletine component is compressed.

4. The pharmaceutical composition in unit dosage form according to claim 1, characterized in that, Over time analysis, the impurities in the multi-feliate component satisfy at least one of the following three characteristics: (a), (b), and (c): (a) One month after the preparation of the pharmaceutical composition, the content is below the limit of quantitation at room temperature and below 0.5% at 40 °C / 75% relative humidity. (b) Two months after the preparation of the pharmaceutical composition, the content was below 0.8% at 40 °C / 75% relative humidity, and (c) Less than 0.3% at room temperature and less than 1% at 40 °C / 75% relative humidity three months after the preparation of the pharmaceutical composition; and Among them, over time analysis, the impurities in the mexiletine component satisfy at least one of the following three characteristics: (d), (e), and (f): (d) One month after the preparation of the pharmaceutical composition, the result was below the limit of quantitation at room temperature and 40 °C / 75% relative humidity. (e) Two months after the preparation of the pharmaceutical composition, the result is below the limit of quantitation at 40 °C / 75% relative humidity, and (f) The drug composition was below the limit of quantitation three months after preparation, at room temperature and 40 °C / 75% relative humidity.

5. The pharmaceutical composition in unit dosage form according to claim 4, characterized in that, Over time analysis, the impurities in the multi-feliate component satisfy at least one of the following three characteristics: (a), (b), and (c): (a) One month after the preparation of the pharmaceutical composition, the content is below the limit of quantitation at room temperature and below 0.2% at 40 °C / 75% relative humidity. (b) Two months after the preparation of the pharmaceutical composition, the content was below 0.5% at 40 °C / 75% relative humidity, and (c) Less than 0.2% at room temperature and less than 0.7% at 40 °C / 75% relative humidity three months after preparation of the pharmaceutical composition; and Among them, over time analysis, the impurities in the mexiletine component satisfy at least one of the following three characteristics: (d), (e), and (f): (d) One month after the preparation of the pharmaceutical composition, the result was below the limit of quantitation at room temperature and 40 °C / 75% relative humidity. (e) Two months after the preparation of the pharmaceutical composition, the result is below the limit of quantitation at 40 °C / 75% relative humidity, and (f) The drug composition was below the limit of quantitation three months after preparation, at room temperature and 40 °C / 75% relative humidity.

6. Use of the pharmaceutical composition according to claim 1 in the preparation of a medicament for treating or preventing atrial fibrillation or related symptoms.

7. A method for preparing the pharmaceutical composition of claim 1, comprising: Obtain the multi-fetolide component and the mexiletine component, and place the multi-fetolide component and the mexiletine component into a capsule.

8. The method according to claim 7, characterized in that, The placement of the dofetilide component and the mesiletine component within the capsule comprises filling a gelatin capsule with at least one coated dofetilide tablet and at least one uncoated mesiletine microsphere.

9. The method according to claim 7, characterized in that, The placement of the dofetilide component and the mesiletine component within the capsule comprises filling a gelatin capsule with at least one uncoated dofetilide tablet and at least one coated mesiletine microsphere.

10. The method according to claim 8, characterized in that, The preparation of the coated dofetilide tablets includes Micronized dofetiite was geometrically mixed with starch, microcrystalline cellulose, colloidal silica and magnesium stearate to obtain a dofetiite mixture. Compress the dofetilide mixture to obtain dofetilide tablets; and The dofetilide tablets were coated with a polyvinyl alcohol polymer film to obtain coated dofetilide tablets.

11. The method according to claim 9, characterized in that, The preparation of the uncoated dofetilide tablets includes Micronized dofetilide was geometrically mixed with starch, microcrystalline cellulose, colloidal silica, and magnesium stearate to obtain a dofetilide mixture; and The multifiltrate mixture was compressed to obtain uncoated multifiltrate tablets.

12. The method according to claim 8, characterized in that, The preparation of the uncoated mexiletine microspheres includes Mexiletine hydrochloride was granulated using first microcrystalline cellulose and polyvinylpyrrolidone binder to obtain mexiletine granules. The mexiletine granules were dried to obtain dried mexiletine granules. The dry mexiletine particles were ground to obtain ground mexiletine particles; The ground mexiletine particles were mixed with second microcrystalline cellulose, colloidal silica and magnesium stearate to obtain a mexiletine mixture. The mexiletine mixture was compressed to obtain uncoated mexiletine microspheres.

13. The method according to claim 9, characterized in that, The preparation of the coated mexiletine microspheres includes Mexiletine hydrochloride was granulated using first microcrystalline cellulose and polyvinylpyrrolidone binder to obtain mexiletine granules. The mexiletine granules were dried to obtain dried mexiletine granules. The dry mexiletine particles were ground to obtain ground mexiletine particles; The ground mexiletine particles were mixed with second microcrystalline cellulose, colloidal silica and magnesium stearate to obtain a mexiletine mixture. Compress the mexiletine mixture to obtain mexiletine microspheres; and The mexiletine microspheres were coated with a polyvinyl alcohol polymer film to obtain coated mexiletine microspheres.

14. The method according to claim 7, characterized in that, The method of placing the multifeliate component and the mexiletine component into the capsule includes (a) A gelatin capsule filled with at least one coated dofetilide tablet and at least one uncoated mexiletine microsphere. The preparation of the coated dofetilide tablets includes: geometrically mixing micronized dofetilide with starch, microcrystalline cellulose, colloidal silica and magnesium stearate to obtain a dofetilide mixture; Compress the dofetilide mixture to obtain dofetilide tablets; and The dofetilide tablets were coated with a polyvinyl alcohol polymer film to obtain coated dofetilide tablets; and The preparation of the uncoated mexiletine microspheres includes: granulating mexiletine hydrochloride with a first microcrystalline cellulose and a polyvinylpyrrolidone binder to obtain mexiletine particles; The mexiletine granules were dried to obtain dried mexiletine granules. The dry mexiletine particles were ground to obtain ground mexiletine particles; The ground mexiletine particles were mixed with second microcrystalline cellulose, colloidal silica, and magnesium stearate to obtain a mexiletine mixture; and Compress the ground mexiletine particles to obtain uncoated mexiletine microspheres; or (b) Filling gelatin capsules with at least one uncoated dofetilide tablet and at least one coated mexiletine microcapsules. The preparation of the uncoated dofetilide tablets includes: geometrically mixing micronized dofetilide with starch, microcrystalline cellulose, colloidal silica, and magnesium stearate to obtain a dofetilide mixture; and Compress the multifiltrate mixture to obtain uncoated multifiltrate tablets; and The preparation of the coated mexiletine microspheres includes: granulating mexiletine hydrochloride with a first microcrystalline cellulose and a polyvinylpyrrolidone binder to obtain mexiletine particles; The mexiletine granules were dried to obtain dried mexiletine granules. The dry mexiletine particles were ground to obtain ground mexiletine particles; The ground mexiletine particles were mixed with second microcrystalline cellulose, colloidal silica and magnesium stearate to obtain a mexiletine mixture. Compress the mexiletine mixture to obtain mexiletine microspheres; and The mexiletine microspheres were coated with a polyvinyl alcohol polymer film to obtain coated mexiletine microspheres.

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