Compositions containing dofetilide and mexiletine and their use

Abstract

A pharmaceutical composition in a fixed-dose combination is described, which contains a) a dofetilide component; and b) a mexiletine component. The dofetilide component and the mexiletine component are physically separated from each other. Also described are a method for treating or preventing atrial fibrillation or associated symptoms in a subject in need thereof by administering the pharmaceutical composition to the subject, and a method for preparing the fixed-dose combination product.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 115,258, filed on 18 November 2020, the disclosure thereof being incorporated herein by reference in its entirety. [Background technology]

[0002] Atrial fibrillation is the most common arrhythmia, affecting approximately 5.2 million people in the United States and over 10 million in China. 1,2 33 million people worldwide 3 Despite improvements in primary and secondary prevention of coronary artery disease, and effective treatments for hypertension and other heart diseases, the incidence of atrial fibrillation continues to rise. This increase in atrial fibrillation may be at least partially due to the increased average human lifespan. In the United States, the incidence of atrial fibrillation is projected to reach 12.1 million by 2030. 4 Atrial fibrillation increases the risk of stroke, heart failure, and death in patients, especially the elderly. Approximately 35% of all strokes in the United States each year are attributed to atrial fibrillation.

[0003] One of the key treatment approaches for atrial fibrillation is to restore and maintain a normal heartbeat. Currently, there are two main clinical approaches to this treatment: (1) drug therapy and (2) radiofrequency ablation. Both approaches have their advantages and disadvantages, and neither is sufficient to eliminate atrial fibrillation. When treating patients with drug therapy, the effectiveness is relatively poor, resulting in a higher recurrence rate of atrial fibrillation compared to radiofrequency ablation, and drugs used to manage atrial fibrillation have a high incidence of side effects. Dofetilide has been used to treat atrial fibrillation for over 20 years, however 5、6 Its annual prescriptions account for only 2% of the small number of antiarrhythmic drugs available on the market (compared to 45% for another antiarrhythmic drug, amiodarone). 7 Furthermore, dofetilide is not approved in Europe and China. The main reason for the limited use of dofetilide by clinicians is its relatively suboptimal efficacy.8 The risk of QT prolongation leading to a fatal ventricular arrhythmia called Torsades de Pointes (TdP). 9 As a result, a mandatory 3-day in-hospital loading period is required by the U.S. FDA. Experience is required when using this drug, so that adverse events associated with dofetilide overloading into the system are avoided or minimized. There remains a need for novel, effective, and safe methods and pharmaceutical compositions to treat or prevent atrial fibrillation and related symptoms. Specifically, there is a need for novel methods and pharmaceutical compositions that provide more effective prevention and / or treatment of atrial fibrillation to patients in need, while reducing the risk of side effects such as TdP development.

[0004] Mexiletine is not only an effective suppressor of TdP by inhibiting delayed sodium current, but is also known to act synergistically with dofetilide, an antiarrhythmic drug used to treat atrial fibrillation. As a result, it significantly improves the treatment of atrial fibrillation and reduces the risk of ventricular arrhythmias, such as those described in U.S. Patent No. 9,597,302. The entire content of this patent is incorporated herein by reference. The combination of dofetilide and mexiletine suggests that the synergistic effect of both drugs in suppressing atrial fibrillation, as well as the reduction in the risk of ventricular proarrhythmic effects, will expand the dose range of dofetilide in the treatment of atrial fibrillation (i.e., more dofetilide doses can be safely administered, increasing efficacy and broadening the scope of treatment). Since both the efficacy and safety profiles of the combination of dofetilide and mexiletine are significantly improved, it will greatly enhance the ability of clinicians to treat atrial fibrillation using conservative methods rather than invasive means such as radiofrequency ablation. Combinations of dofetilide and mexiletine can be obtained by mixing these active ingredients with a carrier, but it is unclear how to predict which combination will have the physicochemical properties to make a composition suitable for pharmaceutical use. Fixed-dose combination products (FDCs) contain two or more drugs combined in fixed ratios in 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 containing multiple active pharmaceutical ingredients (APIs) and possessing the desired pharmaceutically acceptable properties is often an unpredictable task, for example, regarding the selection of APIs and non-API components in such fixed-dose forms and their manufacturing processes. While physical pharmaceutically acceptable properties such as hygroscopicity, crystallinity, melting point, solubility, dissolution rate, and stability can represent the unpredictability challenges for single API formulations, such challenges become more pronounced for single dosage forms containing multiple APIs and other components due to the reactions that can occur within the dosage form between its constituent components. Because there are limitations to what those skilled in the art can anticipate or successfully predict regarding such properties, and due to the role played in certain aspects of the pharmaceutical industry, there remains a need to find methods for producing certain pharmaceutical compounds that are deemed drug-acceptable. Single-dosage formulations based on the simultaneous administration of two or more APIs are considered advantageous and desirable because they offer one or more benefits, such as synergistic therapeutic effects, reduced incidence of side effects, pharmacokinetic advantages, improved adherence and compliance due to reduced tablet burden, reduced individual drug doses or simplified regimens, decreased tolerance development, and potential cost reductions from packaging to distribution. However, they are considered difficult to develop because they can lead to problems such as pharmacodynamic mismatch, pharmacokinetic mismatch, chemical contraindications, drug interactions, and limitations on the fine titration of individual raw materials.For example, see Y.K. Gupta, et al., Fixed dose drug combinations: Issues and challenges in India, Indian J. Pharmacol. 48(4), 347-49(2016) (generally specifying the issues of fixed dose formulations and the motivation to reduce these issues). So far, various means to achieve multiple API administrations have been to contain the individual dosage forms of each API in a single package, to include multiple APIs in one dosage form, and to include multiple layers of different APIs in a compressed tablet. However, due to the compatibility of various APIs, the use of such techniques may be limited.

[0005] Furthermore, various excipient components commonly used in pharmaceutical compositions may interact with each other and may interact with APIs differently than those that interfere with the physical and / or chemical properties of the formulation. For example, a filler commonly used with one API may not function well with another API or other excipients in the formulation. Therefore, it is becoming increasingly difficult to formulate more than one API in a single dosage form without adversely affecting the properties of the fixed dose formulation.

Summary of the Invention

Problems to be Solved by the Invention

[0006] The present invention generally relates to pharmaceutical compositions containing a dofetilide component and a mexiletine component. The present invention also generally relates to a method of treating or preventing atrial fibrillation using formulations of dofetilide and mexiletine according to various embodiments of the present invention. Accordingly, various embodiments of the present invention provide a dual-activity combined formulation of dofetilide and mexiletine in a single dosage unit, which can include immediate-release, sustained-release and / or release-modulating components.

Means for Solving the Problems

[0007] Various embodiments of the present invention include a pharmaceutical composition in a unit dosage form comprising a) a dofetilide component; and b) a mexiletine component; the dofetilide component and the mexiletine component are contained within a single dosage unit; the dofetilide component comprises an effective amount of the dofetilide active ingredient and one or more pharmaceutically acceptable excipients; the mexiletine component comprises an effective amount of mexiletine and one or more pharmaceutically acceptable excipients; and the dofetilide component and the mexiletine component are physically separated from each other, for example, by an inert layer coating each API-containing particle, and / or by incorporating each API in the form of small tablets or granules into a formulation. In various embodiments of the present invention, the separation of the dofetilide component and the mexiletine component may include filling two separate compartments of a multi-compartment drug delivery system (e.g., a multi-compartment capsule), each containing the dofetilide component and the mexiletine component. In various embodiments of the present invention, the separation of the dofetilide component and the mexiletine component may include tableting or otherwise mixing solid dofetilide and mexiletine components having an inert intervening layer or film. In various embodiments of the present invention, the separation of the dofetilide component and the mexiletine component may include coating one or both of the dofetilide and mexiletine components. In various embodiments of the present invention, the dofetilide component and the mexiletine component may be in different states (e.g., solid and liquid) and can be physically separated. Embodiments of the present invention include a pharmaceutical composition in a unit dosage form comprising a) a dofetilide component; and b) a mexiletine component; the dofetilide component and the mexiletine component are contained within a capsule; the dofetilide component comprises an effective amount of the dofetilide active ingredient alone or with one or more pharmaceutically acceptable excipients; the mexiletine component comprises an effective amount of mexiletine alone or with one or more pharmaceutically acceptable excipients; and at least one of the dofetilide component and the mexiletine component is compressed and coated with a polymer film coating.

[0008] Other embodiments of the present invention include methods for treating or preventing atrial fibrillation or associated symptoms in a target area, the method including administering a pharmaceutical composition described in any of the embodiments of the formulation described herein to a target area. In various embodiments, the dual-activity compound formulation of dofetilide and mexiletine can be in immediate-release, sustained-release, or controlled-release dose units. In various embodiments, mexiletine can be granulated in a blend containing various excipients and formulated into tablets, pellets, 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 blend containing various excipients and formulated into tablets, pellets, or granules. In various embodiments, one or more polymer coatings form a layer on the mexiletine tablets or pellets. In various embodiments, one or more polymer coatings form a layer on the dofetilide tablets or pellets. In various embodiments, dofetilide tablets or pellets and mexiletine tablets or pellets can be contained within capsules. In various embodiments, pharmaceutical compositions containing dofetilide and mexiletine components exhibit uniform content and stability. In various embodiments, the combined formulation of dofetilide and mexiletine with dual activity does not cause changes such as browning and discoloration.

[0009] Various embodiments of the present invention relate to methods for producing pharmaceutical compositions comprising effective amounts of dofetilide and mexiletine together with various excipients. Examples given herein illustrate embodiments of such methods. Embodiments of the present invention include amounts of dofetilide and mexiletine, as indicated by the following amounts. The amounts of dofetilide ranged from 0.113 μmol to 5.66 μmol, and mexiletine ranged from 0.139 mmol to 4.64 mmol. Dofetilide is available in doses ranging from 50 mcg to 2500 mcg, and mexiletine is available in the form of mexiletine hydrochloride from 30 mg to 1000 mg. Mexiletine is a mixture of 100mcg to 600mcg of dofetilide and 100mg to 500mg of mexiletine hydrochloride, for example (a) 125mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500mg of mexiletine hydrochloride, (b) 250mcg of dofetilide and 150, 200, 250, 30 (c) 0, 350, 400, 450 or 500 mg of mexiletine hydrochloride; (d) 375 mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 mg of mexiletine hydrochloride; (c) 500 mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 mg of mexiletine hydrochloride. The medication consists of 500 mcg of dofetilide and 275 mg of mexiletine hydrochloride. The medication consists of 500 mcg of dofetilide and 245 mg of mexiletine hydrochloride. The ingredients are dofetilide in amounts ranging from 125 mcg to 500 mcg, and mexiletine hydrochloride in amounts ranging from 160 mg to 280 mg, for example, 500 mcg of dofetilide and 245, 250, 255, 260, 265, 270, 275, or 280 mg of mexiletine hydrochloride. The medications are dofetilide in amounts of 250 mcg or 500 mcg, and mexiletine hydrochloride in amounts of 165 mg or 245 mg.

[0010] Further embodiments of the present invention include the presence of dofetilide and mexiletine in any of the above amounts, wherein the dofetilide component is as follows: (a), (b), and (c): (a) One month after preparation of the pharmaceutical composition, the concentration was below the limit of quantification at room temperature and below 0.5% under 40°C / 75%RH conditions. (b) Two months after the preparation of the pharmaceutical composition, under 40°C / 75%RH conditions, less than 0.8% (c) After 3 months, the pharmaceutical composition was less than 0.3% at room temperature and less than 1% under 40°C / 75%RH conditions. It satisfies at least one of three characteristics selected from and has impurities that are analyzed over time, The mexiletine component is as follows: (d), (e) and (f): (d) One month after preparation of the pharmaceutical composition, under room temperature and 40°C / 75%RH conditions, the limit of quantification is less than the limit of quantification. (e) Two months after preparation of the pharmaceutical composition, under 40°C / 75%RH conditions, below the limit of quantification. (f) Three months after preparation of the pharmaceutical composition, under room temperature and 40°C / 75%RH conditions, the limit of quantification was less than the limit of quantification. This is represented by a composition that satisfies at least one of three characteristics selected from and has impurities that are analyzed over time. Further embodiments of the present invention include the presence of dofetilide and mexiletine in any of the above amounts, wherein the dofetilide component is as follows: (a), (b), and (c): (a) One month after preparation of the pharmaceutical composition, the concentration was below the limit of quantification at room temperature and below 0.2% under 40°C / 75%RH conditions. (b) Two months after the preparation of the pharmaceutical composition, under 40°C / 75%RH conditions, less than 0.5% (c) After 3 months, the pharmaceutical composition was less than 0.2% at room temperature and less than 0.7% under 40°C / 75%RH conditions. It satisfies at least one of three characteristics selected from and has impurities that are analyzed over time, The mexiletine component is as follows: (d), (e) and (f): (d) One month after preparation of the pharmaceutical composition, under room temperature and 40°C / 75%RH conditions, the limit of quantification is less than the limit of quantification. (e) Two months after preparation of the pharmaceutical composition, under 40°C / 75%RH conditions, below the limit of quantification. (f) Three months after preparation of the pharmaceutical composition, under room temperature and 40°C / 75%RH conditions, the limit of quantification was less than the limit of quantification. This is represented by a composition that satisfies at least one of three characteristics selected from and has impurities that are analyzed over time.

[0011] Other aspects, features, and advantages of the present invention will become apparent from the following disclosure, including modes for carrying out the invention, exemplary embodiments, and appended claims. [Modes for carrying out the invention]

[0012] Various publications, papers, and patents are cited or referenced in the background art and throughout the specification; each of these references is incorporated herein by reference in its entirety. The descriptions of documents, laws, substances, devices, articles, etc. included herein are for the purpose of providing context for the invention. Such descriptions are not endorsed, and any or all of these constitute part of the prior art to any invention disclosed or claimed. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art relating to the present invention. Otherwise, certain terms used herein have the meanings set forth in the specification. All patents, published patent applications and publications referenced herein are incorporated by reference as fully expressed herein. In use herein and in the appended claims, the singular forms "a," "an," and "the" include plural nouns unless otherwise specified in the context.

[0013] Terms such as “at least one [list of elements]” and “at least one [...] selected from the [list of elements]” used throughout the specification and claims, and similar terms, mean to include, but not necessarily to, one of several choices, but unless otherwise indicated, include selection of only one element from the list of elements. For example, “at least one of A and B” means to include embodiments that refer to A only, embodiments that refer to B only, and embodiments that refer to A and B. As used herein, and unless otherwise indicated, the name of a compound may include all possible isomers of that compound (e.g., optical isomers, enantiomers, diastereomers, racemic compounds or racemic mixtures), esters, prodrugs, metabolites, pharmaceutically acceptable salts, pharmaceutically acceptable esters, pharmaceutically acceptable amides, and protected derivatives.

[0014] As used herein, the term “subject” means any animal to which a compound or pharmaceutical composition according to embodiments of the present invention is administered, or is being administered, preferably a mammal, most preferably a human. As used herein, the term “mammal” encompasses any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and more preferably humans. Preferably, the subject is an object requiring treatment or prevention of atrial fibrillation and associated symptoms, or an object of observation or experimentation thereof, and more preferably such a subject is an elderly human. The “subjects” described herein preferably require treatment or prevention of atrial fibrillation and its associated symptoms. Atrial fibrillation is an arrhythmia characterized by an irregular and rapid pulse, generally resulting in poor blood flow to the body. In atrial fibrillation, the two upper chambers of the heart (atria) beat in a disordered and irregular manner, not working in coordination with the two lower chambers of the heart (ventricles). Symptoms of atrial fibrillation include, for example, palpitations, dizziness, confusion, syncope, shortness of breath, chest pain, angina, exercise intolerance, and edema of the extremities. While the onset of atrial fibrillation may come and go without causing symptoms, atrial fibrillation can lead to the formation of blood clots in the heart, which can circulate to other organs and cause obstruction of blood flow (ischemia). Individuals with a history of stroke, transient ischemic attack (TIA), hypertension, diabetes, heart failure, rheumatic fever, or a family history of atrial fibrillation may be at increased risk or prone to developing atrial fibrillation or complications associated with already diagnosed atrial fibrillation. Therefore, such individuals may require prevention of atrial fibrillation or treatment of atrial fibrillation.

[0015] The present disclosure provides information and an outline of a research protocol for elucidating the pharmacological characteristics of exemplary embodiments of the present invention, such as the effects of factors like bioavailability, drug-drug interactions, and diet effects. Such protocols can use methods known to those skilled in the art, either alone or in combination, to determine further pharmacological characteristics, such as a therapeutically effective amount of an active ingredient. Further, as understood by those skilled in the art, the specific dosage levels for any particular subject will depend on various factors, such as age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, any additional therapeutic agents administered concomitantly, and the severity of the disease or condition being treated.

[0016] The composition of the present invention includes one or more therapeutically active ingredients, their prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and combinations. Specifically, the therapeutically active ingredients of the pharmaceutical composition include dofetilide and mexiletine.

[0017] The term "dofetilide" refers to the compound N-[4-(2-{[2-(4-methanesulfonamidophenoxy)ethyl](methyl)amino}ethyl)phenyl]methanesulfonamide having the structure of formula (I):

Chemical formula

[0018] The term "pellet" refers to a formulation having a diameter of approximately 5.0 mm or less, which is produced by a compression process, or by forming layers on a nonpareil, or by extrusion, optionally followed by spheroidization, or other similar known techniques. The term "granules" refers to pharmaceuticals in which raw materials are mixed together to closely and evenly disperse the API (Analytic Cellular Impulse) among some or all of the other raw materials, thereby increasing the particle size. Well-known techniques are available in the pharmaceutical industry, and one can choose between wet or dry granulation. The term “tablet” refers to coated or uncoated tablets, single-layer or multi-layer tablets, and any other dosage forms that undergo a compression or compaction process to form a solid dosage unit. As used herein, “tablet” may also include pellets or miniature tablets. As used herein, the terms “grind” or “grinded” refer to the application of mechanical energy to physically break down coarse particles. The mills usable in this process include, for example, high-speed stirring mills and impact mills, which are drying mills capable of crushing materials into ultrafine particles by mechanical impact and / or grinding. Specific examples of mills include cylindrical mills such as rotary ball mills, vibrating ball mills, tube mills, and rod mills.

[0019] As used herein, the term “excipient” refers to therapeutically inert and pharmaceutically acceptable raw materials added to pharmaceutical formulations to act, for example, as fillers or diluents, binders, disintegrants, flow aids or fluidizers, lubricants, or wetting agents. Excipients classified in these categories and other categories are well known in pharmaceutical formulations and manufacturing. As used herein, the term “geometric blending” refers to the technique of increasing the proportions and completely dispersing a small amount of API with an appropriate amount of diluent, thereby ensuring that the API is uniformly distributed in the final blend. As used herein, the term “dry blend” refers to the mixing of dry raw materials before further use, such as a mixture of APIs, fillers, or other excipients.

[0020] The pharmaceutical compositions according to embodiments of the present invention are prepared for oral administration. Suitable pharmaceutical compositions for oral administration include solid forms such as pills, tablets, caplets, and hard and soft capsules (including immediate-release, sustained-release, and sustained-release formulations, respectively), as well as lozenges and dispersible powders or granules. Pharmaceutical compositions according to various embodiments of the present invention are prepared in capsule form. Hard capsules are used in various embodiments. Preferred pharmaceutically acceptable carriers for the manufacture of 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 agents or disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid, or talc. If desired, the solid pharmaceutical composition suitable for oral administration may further contain one or more sweeteners, flavoring agents, coloring agents, or preservatives to provide an interesting or palatable product. The effective amount of therapeutic active ingredient contained in a dosage form is determined by factors such as the patient receiving treatment, the method of administration, and the desired delivery dose. Exemplary pharmaceutical compositions, such as those in embodiments of the present invention, contain 50 mcg to 2500 mcg of dofetilide (in the range of 0.113 μmol to 5.66 μmol) and 30 mg to 600 mg of mexiletine HCl (in the range of 0.232 mmol to 4.64 mmol) per dosage form. Further embodiments include 50 mcg to 1000 mcg of dofetilide and 30 mg to 600 mg of mexiletine HCl per dosage form. Exemplary effective amounts of mexiletine HCl in embodiments of the present invention are 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 HCl 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 in 250 mcg or 500 mcg doses, and mexiletine HCl is delivered with an active ingredient content of 165 mg or 245 mg. Considering formulas (I) and (II) above, dofetilide and mexiletine (each with a molar mass of 441.56 gmol) are considered as free compounds. -1 and 179.26 gmol -1 Whether related to ) or, for example, salt form (215.72 gmol) -1 Whether it is the molar mass of mexiletine HCl or something else, the method of converting mass to molar is known to those skilled in the art. For example, a reference to 0.838 mmol of mexiletine includes a reference to 150 mg of free mexiletine base and a reference to 181 mg of mexiletine HCl.

[0021] Various embodiments of the present invention include a mexiletine component, which is granulated in an aqueous suspension with a binder and a microcrystalline cellulose component. Suitable binders include polyvinylpyrrolidone, hydroxypropyl methylcellulose ("HPMC"), and starch. In various embodiments, the binder may include a polyvinylpyrrolidone binder. In one embodiment of the present invention, the polyvinylpyrrolidone binder may include povidone K29 / 32. Various embodiments of the present invention include one or more microcrystalline cellulose components. Suitable microcrystalline celluloses for use in various embodiments of the present invention include any pharmaceutically acceptable filler, such as Avicel microcrystalline cellulose, which is available from many commercial sources, but is not limited to these. Generally, suitable particle sizes for microcrystalline cellulose components that can be used in various embodiments of the present invention range from about 50 μm to about 180 μm. In some embodiments, the average particle size ranges from 50 μm to about 100 μm. In various embodiments of the present invention, the mexiletine component is first granulated into a formulation containing a microcrystalline cellulose component, and then blended 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 can be granulated with a microcrystalline cellulose component having a smaller average particle size than the microcrystalline cellulose used in the subsequent blend. In various embodiments of the present invention, the mexiletine component can be prepared by granulating mexiletine with microcrystalline cellulose in an aqueous suspension of polyvinylpyrrolidone (PVP). In various embodiments of the present invention, the granules can be dried in an oven and ground, for example, using a Fitsmill grinder according to methods well known in the art. In various embodiments of the present invention, the ground mexiletine hydrochloride granules can be blended with microcrystalline cellulose, a fluidizing agent such as silicon dioxide, colloidal silica in some embodiments, and a lubricant such as magnesium stearate.

[0022] In various embodiments of the present invention, a mexiletine hydrochloride blend can be compressed into pellets using machinery and equipment known in the art. For example, in various embodiments of the present invention, a granular mexiletine blend can be compressed into tablets or pellets. In various embodiments of the present invention, the mexiletine pellets can be coated with a polyvinyl alcohol (PVA)-based polymer film coating by any suitable technique. Some of these techniques are known in the art. In various embodiments, the polymer film coating can include Opadry film coatings available from Caracon (Harleysville, PA). In various embodiments, the coating can be carried out using a pan coater or a fluidized bed coater by methods known in the art. In various embodiments of the present invention, the dofetilide component can be prepared by dry blending dofetilide with various excipients. In various embodiments of the present invention, pulverized dofetilide is geometrically mixed with pregelatinized starch, microcrystalline cellulose, silicon dioxide (colloidal silica in some embodiments) and magnesium stearate. In various embodiments, the dofetilide blend can be further compressed into tablets using mechanical equipment according to previously established methods. In various embodiments, the dofetilide blend can be compressed into tablets or pellets. In various embodiments of the present invention, dofetilide tablets can be coated with polyvinyl alcohol (PVA) by any known technique. In some embodiments, coating is carried out using a pan coater or fluidized bed coater by methods known in the art. In further embodiments of the present invention, hard capsules are filled with coated dofetilide tablets or pellets and coated mexiletine hydrochloride tablets or pellets. In various embodiments of the present invention, dofetilide tablets or pellets and mexiletine tablets or pellets can be filled into hard capsules.

[0023] Various other embodiments of the present invention include methods for treating atrial fibrillation or associated symptoms in a subject of interest, and in some embodiments include administering to a subject 100 mcg to 1000 mcg or more of dofetilide (e.g., up to 1500 mcg) and 100 mg to 1000 mg of mexiletine hydrochloride in a capsule according to any of the embodiments of the above formulation. For example, this method may include administering to the target subject 100-500 mcg, 505-600 mcg, 605-700 mcg, 705-800 mcg, 805-900 mcg, or 905-1000 mcg of dofetilide, and a pharmaceutical composition such as a capsule containing 100 mg of mexiletine HCl, 200 mg of mexiletine HCl, 300 mg of mexiletine HCl, 400 mg of mexiletine HCl, 500 mg of mexiletine HCl, 600 mg of mexiletine HCl, 700 mg of mexiletine HCl, 800 mg of mexiletine HCl, 900 mg of mexiletine HCl, or 1000 mg of mexiletine HCl, and a pharmaceutically acceptable carrier. This method may also include administering to the subject requiring treatment a first pharmaceutical composition, such as a capsule containing 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of mexiletine HCl 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. [Examples]

[0024] The present invention will be described in further detail below with reference to the specific, non-limiting examples listed below. However, those skilled in the art should consider this disclosure and recognize that many modifications can be made in the specific embodiments disclosed, and that similar or comparable results can be obtained without departing from the scope of the invention. Example 1 Mexiletine hydrochloride was granulated with Avicel PH101 using an aqueous solution of povidone K29 / 32 as a binder. The granules were dried in an oven at 55°C and ground using a Fitsmill pulverizer. The ground mexiletine HCl granules were blended with Avicel PH102, Cab-O-Sil, and magnesium stearate. The mexiletine HCl blend was compressed into 7 mg pellets using a 2.0 mm machine. The mexiletine HCl core pellets were coated with polyvinyl alcohol (PVA)-based Opadry. The composition of the mexiletine HCl pellets is shown in Table 1 below. A dofetilide blend was prepared by geometrically mixing finely ground dofetilide with starch 1500, Avicel PH101, Cab-O-Sil, and magnesium stearate. The dofetilide blend was compressed into 85 mg tablets using a 5.6 mm machine. Table 2 shows the formulation of the dofetilide tablets. The pharmaceutical composition in this example was prepared by filling an 0EL-sized hard gelatin capsule with one dofetilide tablet and a coated mexiletine HCl pellet, with active ingredient contents of 500 mcg and 275 mg, respectively. These capsules exhibited an immediate-release drug profile.

[0025] [Table 1] Note: (1) Purified water and USP are used in the manufacturing process but are not present in the final product. [Table 2]

[0026] The stability of the capsules was tested under accelerated conditions at room temperature and 40°C / 75% relative humidity ("RH"), and the data is shown in Table 3. [Table 3] Note: Throughout this specification, percentages relating to compositions are mass percentages (mass / mass) unless otherwise indicated. The term "QL" is an abbreviation for limit of quantification, the minimum concentration that can be not only detected but also quantified with a specific degree of precision.

[0027] Example 2 Mexiletine HCl was granulated with Avicel PH101 using an aqueous solution of povidone K29 / 32 as a binder. The granules were dried in an oven at 55°C and ground using a Fitsmill. The ground mexiletine HCl granules were blended with Avicel PH102, Cab-O-Sil, and magnesium stearate. The mexiletine HCl blend was compressed into 7 mg pellets using a 2.0 mm machine. The mexiletine HCl core pellets were coated with polyvinyl alcohol (PVA)-based OpaDry. The composition of the mexiletine HCl pellets is shown in Table 4. A dofetilide blend was prepared by geometrically mixing finely ground dofetilide with starch 1500, Avicel PH101, Cab-O-Sil, and magnesium stearate. The dofetilide blend was compressed into 85 mg tablets using a 5.6 mm machine. Dofetilide core tablets were coated with polyvinyl alcohol (PVA)-based OpaDry. The formulation of the dofetilide tablets is shown in Table 5. The active ingredient content of dofetilide and mexiletine HCl was 500 mcg and 275 mg, respectively. The unit dosage form of the pharmaceutical composition according to this example was prepared by filling an 0EL-sized hard gelatin capsule with one coated dofetilide tablet and one coated mexiletine HCl pellet.

[0028] [Table 4] Note: (1) Purified water and USP are used in the manufacturing process but are not present in the final product. [Table 5] Note: (1) Purified water and USP are used in the manufacturing process but are not present in the final product.

[0029] The capsules of this example exhibited immediate release characteristics of dofetilide and mexiletine, both immediately and after storage for one month under accelerated stability conditions of 40°C / 75%RH. The stability of the capsules was tested at room temperature and under accelerated conditions of 40°C / 75%RH, and the test data are shown in Table 6. [Table 6] Unknown impurities are mentioned by relative retention time ("RRT"). Impurities identified by explicit mention, such as 2,6-DMP (2,6-dimethylphenol), MX-200 (3,9-dimethyl-2,3-dihydro-1,4-benzoxazepine), and MX-300 (2-hydroxy-3-methylbenzaldehyde), are also mentioned.

[0030] Comparative Example 1 Dry blend dofetilide with mexiletine granules. Comparative Example 1's dried blend-filled capsules (Table C3) were prepared by granulating mexiletine hydrochloride with an aqueous binder solution containing 0.5 mg of hypromellose (HPMC E5 LV) and 31 mg of purified water as a solvent. The granules were then dried in an oven at 55°C and pulverized using a Fitsmill pulverizer. The pulverized dofetilide was geometrically mixed with 48 mg of pregelatinized starch (Starch 1500) and 98 mg of microcrystalline cellulose (Avicel PH101). The active ingredient content of dofetilide and mexiletine HCl was 250 mcg and 275 mg, respectively, and the mexiletine granules and dofetilide blend were mixed with 2.2 mg of Cab-O-Sil®. This blend was further fluidized with 1.0 mg of magnesium stearate. The resulting blend was then filled into size 0 hard gelatin capsules. The capsules of Comparative Example 1 exhibited rapid-release characteristics for both dofetilide and mexiletine hydrochloride. Importantly, the micronized dofetilide and optimized geometric mixing process resulted in excellent content uniformity for both mexiletine hydrochloride and dofetilide (Table C4).

[0031] [Table 7] * The solvent evaporates during the process and is not present in the final product. [Table 8]

[0032] Impurity analysis relating to the present invention was performed by standard high-performance liquid chromatography (HPLC), and one or more of the mass, relative retention time, and amount (as relative area percentage) of impurities were determined by detection using ultraviolet spectroscopy (UV). Such standard methods are shown herein using typical notation. For a descriptive review of the above, see, for example, S. Levin, “High Performance Liquid Chromatography (HPLC) in the pharmaceutical analysis”, Medtechnica (2010), which is incorporated herein by reference (it describes HPLC modes, HPLC theory, the role of HPLC in drug analysis, and special HPLC separations). Regarding the initial stability of this batch, almost no impurities were detected. However, after storage for one month under accelerated stability conditions (40°C / 75%RH), dofetilide-related impurities increased significantly. In particular, oxidative degradation products of dofetilide (docefetilide-related impurity 6) were formed. The interaction between mexiletine hydrochloride and dofetilide may lead to the formation of more dofetilide impurities. Assuming that mexiletine hydrochloride is a basic compound and presents at relatively high levels (1100 times that of dofetilide), mexiletine hydrochloride may affect the stability of dofetilide. In summary, Comparative Example 1 showed rapid-release properties and excellent content uniformity of dofetilide and mexiletine hydrochloride, but its stability was lower than that shown in the aforementioned examples due to an increase in impurities over time.

[0033] [Table 9]

[0034] Example 3 Under fasting conditions, a study was conducted in healthy male and non-pregnant female volunteers to test the relative bioavailability of dofetilide and mexiletine in the test product FBHRS001® (500mcg / 275mg dofetilide / mexiletine HCl capsules) and the reference product (500mcg (0.5mg) ticosin® (docetilide) capsules and 250mg mexiletine hydrochloride capsules USP) administered simultaneously. The difference between 275mg of mexiletine HCl in the test product's dofetilide / mexiletine HCl capsules and 250mg of mexiletine HCl in one of the reference products was considered acceptable from the perspective of this study. This consideration also applies to similar differences in amounts of the same API in further examples cited herein. Potential participants are determined by selection criteria based on multiple factors, including age, healthy habits, BMI, cardiovascular disease, dietary habits, behavioral incompatibilities, availability to participate in the entire study, pregnancy and contraception practices for women and men, blood chemistry, known medical history or presence of any clinically significant conditions and abnormalities, positive tests, deficiencies, allergies and intolerances to the digestion / administration / use of any condition or specific medication, and participation in other tests. Under specific time and dietary conditions, the test and reference samples were administered to subjects during the study period. Samples from 18 subjects were analyzed in a bioanalysis laboratory. Data from these 18 subjects were included in pharmacokinetic and statistical analyses. After administration in each period, the concentrations of dofetilide and mexiletine in plasma samples collected at 48-hour intervals were measured. The pharmacokinetic parameter C max , T max AUC t AUC inf , T 1 / 2 λ was evaluated based on the plasma levels of dofetilide and mexiletine included in the statistical analysis.

[0035] result The test product, FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 275mg, showed comparable dofetilide absorption rate and degree to the reference product, Ticosin® (docetilide) capsules 500mcg (0.5mg). During each study period, the AUC was measured at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12, 16, 24, 36, and 48 hours after administration. t The geometric mean ratio (GMR) of the test sample / reference sample (T / R) for the area under the plasma concentration-time curve (AUC) was approximately 100%. inf (Area under the plasma concentration-time curve from time zero to infinity), and C max (Maximum plasma concentration), and AUC t AUC inf and C max The corresponding 90% CI (confidence interval) fell within the FDA acceptance range of 80.00% to 125.00%. The test product, FBHRS001 (registered trademark) dofetilide / mexiletine HCl capsules 500mcg / 275mg, showed comparable absorption rate and degree of mexiletine. The reference product, mexiletine hydrochloride capsules USP 250mg, showed a test product / reference product (T / R) geometric mean ratio (GMR) of AUC. t and AUC inf Approximately 108%, C max It showed 110%, and AUC t AUC inf and C max The corresponding 90% CI fell within the FDA's acceptable range of 80.00-125.00%. Therefore, the relative bioavailability of the test product FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 275mg and the reference products Ticosin® (docetilide) capsules 500mcg (0.5mg) and mexiletine hydrochloride capsules USP 250mg were demonstrated in healthy, non-smoking, non-pregnant male and female volunteers under fasting conditions. As a result, administration of FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 275mg was equivalent to simultaneous administration of separately commercial dofetilide and mexiletine.

[0036] Example 4 A study was conducted in healthy male and non-pregnant female volunteers under fasting conditions to test the relative bioavailability of dofetilide and mexiletine in FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 245mg, as well as ticosin® (docetilide) capsules 500mcg and mexiletine hydrochloride capsules USP 250mg administered separately for each period. Another objective of this study was to evaluate the effect of diet on the bioavailability of the fixed-dose combination FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 245mg in healthy male and non-pregnant female volunteers (high-fat diet vs. fasting). Potential subjects were determined by selection criteria based on multiple factors, such as those summarized in Example 3. Subjects were administered the test product and reference product during the study period under specific time and dietary conditions. Data from 26 participants were included in pharmacokinetic and statistical analyses, as well as comparisons under different conditions.

[0037] result Test sample A (FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 245mg) showed comparable dofetilide absorption rate and degree to reference sample B (Ticosin® (docetilide) capsules 500mcg). Descriptive statistics (minimum, maximum, median, mean, standard deviation, and variation) were obtained for all pharmacokinetic parameters of dofetilide and mexiletine in both the test and reference samples. AUC was calculated using natural logarithmic transformation before analysis. t AUC inf and C max The parameters of T were converted. 1 / 2 λ, T max , T lag Unconverted data (if applicable), and AUC t AUC inf and C max An ANOVA was performed on the naturally logarithmic transformed data, and a further nonparametric test (Wilcoxon test) was used to determine the T max and T lag(Where applicable) was analyzed. Based on ANOVA's LSMEANS and ESTIMATE, AUC was calculated. t AUC inf and C max The 90% confidence interval (CI) for the geometric mean ratio was calculated. Regarding the absence of a dietary effect on the bioavailability of dofetilide and mexiletine, the 90% confidence interval for the geometric mean ratio between dietary intake and fasting treatment, based on naturally log-transformed data, is given by AUC. t AUC inf and C max Therefore, it should fall within 80% to 125%. The geometric mean ratio (GMR) of test sample / reference sample A / B is AUC. t AUC inf and C max These figures are approximately 98%, 98%, and 96%, respectively, and AUC t The corresponding 90% CI was within the FDA acceptance range of 80% to 125%. Test sample A (FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 245mg) showed comparable mexiletine absorption rate and degree to reference sample C (mexiletine hydrochloride capsules USP 250mg). The test sample / reference sample (A / C) geometric mean ratio (GMR) was given by AUC. t AUC inf and C max These figures are approximately 97%, 97%, and 97%, respectively, and AUC t The corresponding 90% CI was within the FDA acceptance range of 80.00% to 125.00%. Therefore, relative bioavailability was demonstrated between test product A (FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 245mg), reference product B (Ticosin® (docetilide) capsules 500mcg), and reference product C (mexiletine hydrochloride capsules USP 250mg) in healthy, non-smoking, non-pregnant male and female volunteers under fasting conditions. The test product FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 245mg showed comparable dofetilide absorption rates and levels under both dietary intake (product D) and fasting conditions (product A). The geometric mean ratio (GMR) of test product D / test product A (dietary intake / fasting) was given by AUC. t AUCinf and C max The absorption rates were approximately 102%, 101%, and 114%, respectively, and the corresponding 90% CIs were within the FDA acceptance range of 80.00% to 125.00%. The test product, FBHRS001(registered trademark) dofetilide / mexiletine HCl capsules 500mcg / 245mg, showed comparable mexiletine absorption rates and levels under dietary intake (product D) and fasting conditions (product A). The geometric mean ratio (GMR) of test product D / test product A (dietary intake / fasting) was given by AUC. t AUC inf and C max These figures were approximately 97%, 97%, and 92%, respectively. The corresponding 90% CIs fell within the FDA acceptance range of 80.00% to 125.00%. As a result, in healthy, non-smoking male and non-pregnant female volunteers, dofetilide / mexiletine in FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 245mg did not show any dietary effect on bioavailability. Furthermore, no API-mediated drug interactions were observed with FBHRS001® dofetilide / mexiletine HCl capsules 500mcg / 245mg.

[0038] Those skilled in the art will understand that modifications can be made to the above embodiments without departing from the broader concept of the invention. Accordingly, it will be understood that the present invention is not limited to the detailed embodiments disclosed, but is intended to encompass modifications within the spirit and scope of the invention as defined in the appended claims. Another aspect of the present invention may be as follows: [1] a) dofetilide component; and b) Mexiletine component; A pharmaceutical composition in a unit dosage form containing, The dofetilide component and the mexiletine component are contained in a single dosage form; The dofetilide component comprises an effective amount of dofetilide and a blend of one or more pharmaceutically acceptable excipients of the dofetilide component; The mexiletine component comprises an effective amount of mexiletine and a blend of one or more pharmaceutically acceptable excipients of the mexiletine component; A pharmaceutical composition in which at least one of the two components selected from the dofetilide component and the mexiletine component is coated with a coating. [2] The pharmaceutical composition according to [1], wherein the single dosage form is a capsule. [3] The pharmaceutical composition according to [1] or [2], wherein the effective amount of mexiletine comprises mexiletine hydrochloride. [4] The pharmaceutical composition according to any one of the above [1] to [3], wherein the coating is a polymer film coating. [5] The pharmaceutical composition according to any one of the two components selected from the dofetilide component and the mexiletine component, wherein at least one of them is compressed. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the coating is a polymer film coating and the polymer film coating contains polyvinyl alcohol (PVA). [7] The pharmaceutical composition according to any one of [1] to [6], wherein both the dofetilide component and the mexiletine component are coated. [8] The pharmaceutical composition according to any one of the above [1] to [7], wherein the pharmaceutically acceptable excipients of the one or more dofelitide components include components selected from the group consisting of fluidizers and lubricants. [9] The pharmaceutical composition according to any one of the above [1] to [8], wherein the pharmaceutically acceptable excipients of the one or more dofetilide components include colloidal silica and magnesium stearate.

[10] The pharmaceutical composition according to any one of the claims [1] to [9], wherein the pharmaceutically acceptable excipient of the one or more mexiletine components comprises a component selected from the group consisting of fluidizers and lubricants.

[11] The pharmaceutical composition according to any one of the above [1] to

[10] , wherein the pharmaceutically acceptable excipients of the one or more mexiletine components include colloidal silica and magnesium stearate.

[12] The pharmaceutical composition according to any one of the items [1] to

[11] , wherein both the dofetilide component and the mexiletine component further comprise colloidal silica and magnesium stearate.

[13] The pharmaceutical composition according to any one of the above [1] to

[12] , wherein the blend contained in the dofetilide component is a dry blend.

[14] The pharmaceutical composition according to any one of the above [1] to

[13] , wherein the blend contained in the mexiletine component is a granular blend.

[15] The pharmaceutical composition according to any one of the above [1] to

[14] , wherein the effective amount of dofetilide comprises dofetilide having an average particle size (d90) of less than 10 μm.

[16] The pharmaceutical composition according to any one of [1] to

[15] , wherein the mexiletine component is pelletized and coated with a polyvinyl alcohol polymer film coating.

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

[16] , wherein the mexiletine component comprises a granular blend of mexiletine hydrochloride, a polyvinylpyrrolidone binder, and a second microcrystalline cellulose, the granular blend of mexiletine hydrochloride is further mixed with a third microcrystalline cellulose, colloidal silica, and magnesium stearate, the granular blend is pelletized and coated with a polyvinyl alcohol polymer film coating, and the second microcrystalline cellulose and the third microcrystalline cellulose have different particle sizes.

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

[17] , wherein the second microcrystalline cellulose and the third microcrystalline cellulose have different particle sizes.

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

[18] , wherein the effective amount of dofetilide is 0.113 μmol to 5.66 μmol and the effective amount of mexiletine is 0.139 mmol to 4.64 mmol.

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

[19] , wherein the effective amount of dofetilide is 50 mcg to 2500 mcg, and the effective amount of mexiletine is 30 mg to 1000 mg in the form of mexiletine hydrochloride.

[21] The unit dosage form is an effective amount of dofetilide in an amount of 100 mcg to 600 mcg and an effective amount of mexiletine in an amount of 100 mg to 500 mg of mexiletine hydrochloride, for example (a) 125 mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 mg of mexiletine hydrochloride, (b) 250 mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 A pharmaceutical composition according to any one of the above [1] to

[20] , comprising (c) 375 mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 mg of mexiletine hydrochloride, and (d) 500 mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 mg of mexiletine hydrochloride.

[22] The pharmaceutical composition according to any one of the above items [1] to

[21] , wherein the unit dosage form contains 500 mcg of dofetilide and 275 mg of mexiletine hydrochloride.

[23] The pharmaceutical composition according to any one of the above items [1] to

[21] , wherein the unit dosage form contains 500 mcg of dofetilide and 245 mg of mexiletine hydrochloride.

[24] A pharmaceutical composition according to any one of the claims [1] to

[23] , comprising the effective amount of dofetilide in a unit dosage form of 125 mcg to 550 mcg of dofetilide, and the effective amount of mexiletine in a unit dosage form of 160 mg to 280 mg of mexiletine hydrochloride, for example, 500 mcg of dofetilide and 245, 250, 255, 260, 265, 270, 275 or 280 mg of mexiletine hydrochloride.

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

[24] , comprising the effective amount of dofetilide, in which the unit dosage form is 250 mcg or 500 mcg of dofetilide, and the effective amount of mexiletine, in which the unit dosage form is 165 mg or 245 mg of mexiletine hydrochloride.

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

[25] , wherein the dofetilide component further comprises colloidal silica and magnesium stearate as a tablet-formed dry blend; and the mexiletine component further comprises colloidal silica and magnesium stearate, wherein the mexiletine component having colloidal silica and magnesium stearate is pelletized and coated with a polyvinyl alcohol polymer film coating.

[27] A pharmaceutical composition according to any one of the above [1] to

[24] , wherein the unit dosage form is (a) an effective amount of dofetilide in the form of 250 mcg of dofetilide and an effective amount of mexiletine in the form of 165 mg of mexiletine HCl, or (b) an effective amount of dofetilide in the form of 500 mcg of dofetilide and an effective amount of mexiletine in the form of 245 mg of mexiletine HCl.

[28] a) dofetilide component; and b) Mexiletine component; A pharmaceutical composition in a unit dosage form containing, The dofetilide component and the mexiletine component are contained within the gelatin capsule; The dofetilide component comprises a tabletized dry blend of finely ground dofetilide, primary microcrystalline cellulose, pregelatinized starch, colloidal silica, and magnesium stearate; The mexiletine component comprises a granular blend of mexiletine hydrochloride, a polyvinylpyrrolidone binder, and a second microcrystalline cellulose, the granular blend being further mixed with a third microcrystalline cellulose, colloidal silica, and magnesium stearate, the granular blend being pelletized and coated with a polyvinyl alcohol polymer film coating, the second microcrystalline cellulose having a smaller average particle size than the third microcrystalline cellulose; A pharmaceutical composition comprising the aforementioned unit dosage form containing 100 mcg to 600 mcg of dofetilide and 100 mg to 300 mg of mexiletine hydrochloride.

[29] The pharmaceutical composition according to

[28] , wherein the unit dosage form contains an effective amount of dofetilide in an amount of 125 mcg to 500 mcg of dofetilide and an effective amount of mexiletine in an amount of 160 mg to 280 mg of mexiletine hydrochloride, for example, 500 mcg of dofetilide and 245, 250, 255, 260, 265, 270, 275 or 280 mg of mexiletine hydrochloride.

[30] The pharmaceutical composition according to

[29] , comprising the effective amount of dofetilide, in which the unit dosage form is 250 mcg or 500 mcg of dofetilide, and the effective amount of mexiletine, in which the unit dosage form is 165 mg or 245 mg of mexiletine hydrochloride.

[31] a) dofetilide component; and b) Mexiletine component; A pharmaceutical composition in a unit dosage form containing, A pharmaceutical composition in which the dofetilide component and the mexiletine component are physically separated from each other.

[32] The pharmaceutical composition according to

[31] , wherein the effective amount of dofetilide is 0.113 μmol to 5.66 μmol and the effective amount of mexiletine is 0.139 mmol to 4.64 mmol.

[33] The pharmaceutical composition according to

[31] , wherein the effective amount of dofetilide is 50 mcg to 2500 mcg, and the effective amount of mexiletine is 30 mg to 1000 mg in the form of mexiletine hydrochloride.

[34] The unit dosage form is the effective amount of dofetilide in an amount of 100 mcg to 600 mcg and the effective amount of mexiletine in an amount of mexiletine hydrochloride in an amount of 100 mg to 500 mg, for example (a) 125 mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 mg of mexiletine hydrochloride, (b) 250 mcg of dofetilide and 150, 200, 250, The pharmaceutical composition according to

[33] above, comprising (c) 300, 350, 400, 450 or 500 mg of mexiletine hydrochloride, (d) 375 mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 mg of mexiletine hydrochloride, and (d) 500 mcg of dofetilide and 150, 200, 250, 300, 350, 400, 450 or 500 mg of mexiletine hydrochloride.

[35] The pharmaceutical composition according to

[34] , wherein the unit dosage form contains 500 mcg of dofetilide and 275 mg of mexiletine hydrochloride.

[36] The pharmaceutical composition according to

[35] , wherein the unit dosage form contains 500 mcg of dofetilide and 245 mg of mexiletine hydrochloride.

[37] The pharmaceutical composition according to

[34] , wherein the unit dosage form contains an effective amount of dofetilide in an amount of 125 mcg to 500 mcg of dofetilide and an effective amount of mexiletine in an amount of 160 mg to 280 mg of mexiletine hydrochloride, for example, 500 mcg of dofetilide and 245, 250, 255, 260, 265, 270, 275 or 280 mg of mexiletine hydrochloride.

[38] The pharmaceutical composition according to

[37] , comprising the effective amount of dofetilide, in which the unit dosage form is 250 mcg or 500 mcg of dofetilide, and the effective amount of mexiletine, in which the unit dosage form is 165 mg or 245 mg of mexiletine hydrochloride.

[39] A pharmaceutical composition in a unit dosage form as described in any one of the above items [1] to

[38] , The dofetilide component is as follows (a), (b) and (c): (a) One month after the preparation of the pharmaceutical composition, the concentration is below the limit of quantification at room temperature and below 0.5% under 40°C / 75%RH conditions. (b) Two months after the preparation of the pharmaceutical composition, under 40°C / 75%RH conditions, less than 0.8% (c) The pharmaceutical composition after 3 months, less than 0.3% at room temperature and less than 1% under 40°C / 75%RH conditions; It has impurities that are analyzed over time and satisfy at least one of three characteristics selected from, The mexiletine component is as follows: (d), (e) and (f): (d) One month after the preparation of the pharmaceutical composition, under room temperature and 40°C / 75%RH conditions, the limit of quantification is less than the limit of quantification. (e) Two months after the preparation of the pharmaceutical composition, under conditions of 40°C / 75%RH, the limit of quantification is less than the limit of quantification. (f) Three months after the preparation of the pharmaceutical composition, under room temperature and 40°C / 75%RH conditions, the limit of quantification is less than the limit of quantification. A pharmaceutical composition having impurities that are analyzed over time and satisfy at least one of three characteristics selected from the above.

[40] A pharmaceutical composition in a unit dosage form as described in any one of the above items [1] to

[39] , The dofetilide component is as follows (a), (b) and (c): (a) One month after the preparation of the pharmaceutical composition, the concentration is below the limit of quantification at room temperature and below 0.2% under 40°C / 75%RH conditions. (b) Two months after the preparation of the pharmaceutical composition, under 40°C / 75%RH conditions, less than 0.5% (c) The pharmaceutical composition after 3 months, less than 0.2% at room temperature and less than 0.7% under 40°C / 75%RH conditions; It has impurities that are analyzed over time and satisfy at least one of three characteristics selected from, The mexiletine component is as follows: (d), (e) and (f): (d) One month after the preparation of the pharmaceutical composition, under room temperature and 40°C / 75%RH conditions, the limit of quantification is less than the limit of quantification. (e) Two months after the preparation of the pharmaceutical composition, under conditions of 40°C / 75%RH, the limit of quantification is less than the limit of quantification. (f) Three months after the preparation of the pharmaceutical composition, under room temperature and 40°C / 75%RH conditions, the limit of quantification is less than the limit of quantification. A pharmaceutical composition having impurities that are analyzed over time and satisfy at least one of three characteristics selected from the above.

[41] A method for treating or preventing atrial fibrillation or associated symptoms in a subject requiring treatment, comprising administering a pharmaceutical composition described in any one of items [1] to

[40] above to the subject.

[42] A method for preparing the pharmaceutical composition according to any one of the items [1] to

[40] , comprising obtaining the dofetilide component and the mexiletine component, and housing the dofetilide component and the mexiletine component in a capsule.

[43] The method according to any one of [1] to

[41] , wherein the placement of the dofetilide component and the mexiletine component within the capsule comprises filling a gelatin capsule with at least one coated dofetilide tablet and at least one uncoated mexiletine pellet.

[44] The method according to any one of [1] to

[43] , wherein the placement of the dofetilide component and the mexiletine component within the capsule comprises filling a gelatin capsule with at least one uncoated dofetilide tablet and at least one coated mexiletine pellet.

[45] The manufacture of the coated dofetilide tablets is A dofetilide blend is obtained by geometrically mixing finely powdered dofetilide with starch, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate; The aforementioned dofetilide blend is compressed to obtain dofetilide tablets; The dofetilide tablets are coated with a polyvinyl alcohol-based coating film to obtain coated dofetilide tablets. The method of any one of the above [1] to

[44] , including

[46] The manufacture of the uncoated dofetilide tablets, A dofetilide blend is obtained by geometrically mixing finely powdered dofetilide with starch, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate; The aforementioned dofetilide blend is compressed to obtain uncoated dofetilide tablets, The method described in any one of the above [1] to

[45] , including:

[47] The production of the uncoated mexiletine pellets is To obtain mexiletin granules by granulating mexiletin with microcrystalline cellulose and an aqueous binder; The mexiletine granules are dried to obtain dried mexiletine granules; The dried mexiletine granules are pulverized to obtain pulverized mexiletine granules; The crushed mexiletine granules are compressed to obtain uncoated mexiletine pellets, The method of any one of the above [1] to

[46] , including the method of [1] to

[46] .

[48] ​​The production of the coated mexiletine pellets is To obtain mexiletin granules by granulating mexiletin with microcrystalline cellulose and an aqueous binder; The mexiletine granules are dried to obtain dried mexiletine granules; The dried mexiletine granules are pulverized to obtain pulverized mexiletine granules; The pulverized mexiletine granules are blended with microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate to obtain a mexiletine blend; The mexiletine blend is compressed to obtain mexiletine pellets; The aforementioned mexiletine pellets are coated with a polyvinyl alcohol-based coating film to obtain coated mexiletine pellets. The method of any one of the above [1] to

[47] , including the method of [1] to

[47] .

[0039] [References] TIFF0007880331000012.tif109154 TIFF0007880331000013.tif231156

Claims

1. a) dofetilide component; and b) Mexiletine component; A pharmaceutical composition in a unit dosage form containing, The dofetilide component and the mexiletine component are contained in a single dosage form; The dofetilide component comprises an effective amount of dofetilide and a blend of one or more pharmaceutically acceptable excipients of the dofetilide component; The mexiletine component comprises an effective amount of mexiletine and a blend of one or more pharmaceutically acceptable excipients of the mexiletine component; At least one of the two components selected from the dofetilide component and the mexiletine component is coated, and the unit dosage form has a rapid-release profile with respect to the dofetilide component and the mexiletine component; The unit dosage form has the following composition: (a), (b), or (c): (a) an effective amount of mexiletine equivalent to 500 mcg of dofetilide and 275 mg of mexiletine hydrochloride, (b) an effective amount of mexiletine equivalent to 500 mcg of dofetilide and 245 mg of mexiletine hydrochloride, or (c) an effective amount of mexiletine equivalent to 250 mcg of dofetilide and 245 mg of mexiletine hydrochloride, It contains one of the following: The aforementioned unit dosage form is a capsule; The mexiletine component comprises a plurality of coated or uncoated pellets, each of which has a pellet core and, if coated, a pellet coating; Each of the aforementioned pellet cores comprises a mixture of mexiletine hydrochloride and a pellet excipient. Each of the coated pellet cores is coated with the pellet coating, each of the pellet cores contains 70% to 80% by mass of mexiletine hydrochloride, and each of the pellet cores contains 2% by mass of povidone; The dofetilide component comprises a tablet, the tablet comprises a mixture of dofetilide and a tablet excipient, the tablet is either uncoated or coated with a tablet coating, and the coated or uncoated tablet contains 0.5% to 0.6% by mass of dofetilide; The mixture of mexiletine hydrochloride and pellet excipient is (i) a blend of mexiletine hydrochloride, polyvinylpyrrolidone binder, and primary microcrystalline cellulose, and (ii) a mixture of secondary microcrystalline cellulose, colloidal silica, and magnesium stearate; The pellet coating is a polyvinyl alcohol polymer film coating, and the pellet coating is present in an amount of 9.1% by mass of the coated pellet; The first microcrystalline cellulose and the second microcrystalline cellulose in each of the aforementioned pellets have different particle sizes; A pharmaceutical composition wherein, if the tablet is coated, the tablet coating is a polyvinyl alcohol polymer film coating, and the tablet coating is present in an amount of 9.1% by mass of the coated tablet.

2. The pharmaceutical composition according to claim 1, wherein at least one of the two components selected from the dofetilide component and the mexiletine component is compressed.

3. The pharmaceutical composition according to claim 1, wherein the dofetilide component further comprises colloidal silica and magnesium stearate.

4. A pharmaceutical composition in a unit dosage form as described in claim 1, The dofetilide component is as follows (a), (b), and (c): (a) One month after the preparation of the pharmaceutical composition, the concentration was below the limit of quantification at room temperature and below 0.5% under 40°C / 75% RH conditions. (b) Two months after the preparation of the pharmaceutical composition, under 40°C / 75% RH conditions, less than 0.8% (c) The pharmaceutical composition after three months, less than 0.3% at room temperature and less than 1% under 40°C / 75% RH conditions; Having impurities that are analyzed over time and satisfy at least one of three characteristics selected from, The mexiletine component is as follows: (d), (e) and (f): (d) One month after the preparation of the pharmaceutical composition, under room temperature and 40°C / 75% RH conditions, the amount is below the limit of quantification. (e) Two months after the preparation of the pharmaceutical composition, under 40°C / 75% RH conditions, the amount is below the limit of quantification. (f) Three months after the preparation of the pharmaceutical composition, under room temperature and 40°C / 75% RH conditions, the amount was below the limit of quantification. A pharmaceutical composition having impurities that are analyzed over time and satisfy at least one of three characteristics selected from the above.

5. A pharmaceutical composition in a unit dosage form according to claim 4, The dofetilide component is as follows (a), (b), and (c): (a) One month after the preparation of the pharmaceutical composition, the concentration was below the limit of quantification at room temperature and below 0.2% under 40°C / 75% RH conditions. (b) Two months after the preparation of the pharmaceutical composition, under 40°C / 75% RH conditions, less than 0.5% (c) The pharmaceutical composition after three months, less than 0.2% at room temperature and less than 0.7% under 40°C / 75% RH conditions; Having impurities that are analyzed over time and satisfy at least one of three characteristics selected from, The mexiletine component is as follows: (d), (e) and (f): (d) One month after the preparation of the pharmaceutical composition, under room temperature and 40°C / 75% RH conditions, the amount is below the limit of quantification. (e) Two months after the preparation of the pharmaceutical composition, under 40°C / 75% RH conditions, the amount is below the limit of quantification. (f) Three months after the preparation of the pharmaceutical composition, under room temperature and 40°C / 75% RH conditions, the amount was below the limit of quantification. A pharmaceutical composition having impurities that are analyzed over time and satisfy at least one of three characteristics selected from the above.

6. A pharmaceutical composition according to any one of claims 1 to 5 for treating or preventing atrial fibrillation or associated symptoms in a target area.

7. A method for preparing the pharmaceutical composition according to any one of claims 1 to 5, comprising obtaining the dofetilide component and the mexiletine component, and housing the dofetilide component and the mexiletine component in a capsule.

8. The method according to claim 7, wherein the placement of the dofetilide component and the mexiletine component within the capsule comprises filling a gelatin capsule with at least one coated dofetilide tablet and at least one uncoated mexiletine pellet.

9. The method according to claim 7, wherein the placement of the dofetilide component and the mexiletine component within the capsule comprises filling a gelatin capsule with at least one uncoated dofetilide tablet and at least one coated mexiletine pellet.

10. The manufacturing of the aforementioned coated dofetilide tablets, A dofetilide blend is obtained by geometrically mixing finely ground dofetilide with starch, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate; The aforementioned dofetilide blend is compressed to obtain dofetilide tablets; The dofetilide tablets are coated with a polyvinyl alcohol-based coating film to obtain coated dofetilide tablets. The method according to claim 8, including the method described in claim 8.

11. The manufacture of the aforementioned uncoated dofetilide tablets, A dofetilide blend is obtained by geometrically mixing finely ground dofetilide with starch, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate; The aforementioned dofetilide blend is compressed to obtain uncoated dofetilide tablets, The method according to claim 9, including the method described in claim 9.

12. The production of the aforementioned uncoated mexiletine pellets To obtain mexiletin granules by granulating mexiletin with microcrystalline cellulose and an aqueous binder; The process involves drying the aforementioned mexiletine granules to obtain dried mexiletine granules; The dried mexiletine granules are pulverized to obtain pulverized mexiletine granules; The crushed mexiletine granules are compressed to obtain uncoated mexiletine pellets, The method according to claim 8, including the method described in claim 8.

13. The production of the aforementioned coated mexiletine pellets To obtain mexiletin granules by granulating mexiletin with microcrystalline cellulose and an aqueous binder; The process involves drying the aforementioned mexiletine granules to obtain dried mexiletine granules; The dried mexiletine granules are pulverized to obtain pulverized mexiletine granules; The pulverized mexiletine granules are blended with microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate to obtain a mexiletine blend; The mexiletine blend is compressed to obtain mexiletine pellets; The aforementioned mexiletine pellets are coated with a polyvinyl alcohol-based coating film to obtain coated mexiletine pellets. The method according to claim 9, including the method described in claim 9.

14. A method for preparing the pharmaceutical composition according to claim 6, comprising obtaining the dofetilide component and the mexiletine component, and housing the dofetilide component and the mexiletine component in a capsule, (a) The placement of the dofetilide component and the mexiletine component within the capsule comprises filling a gelatin capsule with at least one coated dofetilide tablet and at least one uncoated mexiletine pellet, The manufacturing of the aforementioned coated dofetilide tablets, A dofetilide blend is obtained by geometrically mixing finely ground dofetilide with starch, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate; The aforementioned dofetilide blend is compressed to obtain dofetilide tablets; The dofetilide tablets are coated with a polyvinyl alcohol-based coating film to obtain coated dofetilide tablets. Includes, The production of the aforementioned uncoated mexiletine pellets To obtain mexiletin granules by granulating mexiletin with microcrystalline cellulose and an aqueous binder; The process involves drying the aforementioned mexiletine granules to obtain dried mexiletine granules; The dried mexiletine granules are pulverized to obtain pulverized mexiletine granules; The crushed mexiletine granules are compressed to obtain uncoated mexiletine pellets, including, or (b) The placement of the dofetilide component and the mexiletine component within the capsule comprises filling a gelatin capsule with at least one uncoated dofetilide tablet and at least one coated mexiletine pellet, The manufacture of the aforementioned uncoated dofetilide tablets, A dofetilide blend is obtained by geometrically mixing finely ground dofetilide with starch, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate; The aforementioned dofetilide blend is compressed to obtain uncoated dofetilide tablets, Includes, The production of the aforementioned coated mexiletine pellets To obtain mexiletin granules by granulating mexiletin with microcrystalline cellulose and an aqueous binder; The process involves drying the aforementioned mexiletine granules to obtain dried mexiletine granules; The dried mexiletine granules are pulverized to obtain pulverized mexiletine granules; The pulverized mexiletine granules are blended with microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate to obtain a mexiletine blend; The mexiletine blend is compressed to obtain mexiletine pellets; The aforementioned mexiletine pellets are coated with a polyvinyl alcohol-based coating film to obtain coated mexiletine pellets. Methods that include...

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