MXPA99004460A - Combination of dofetilida and a blocking of the calculates - Google Patents

Abstract

Pharmaceutical compositions and methods comprising dofetilide and calcium channel blockers, the compositions and procedures useful for the treatment of arrhythmias

Description

COMBINATION OF DOFET1L1DA AND A BLOCKING OF CALCIUM CHANNELS BACKGROUND OF THE INVENTION This invention relates to a pharmaceutical combination of dofetilide and a calcium channel blocker, to kits containing such combinations and to the use of such combinations to treat atrial fibrillation in mammals. Dofetilide is a selective inhibitor of the fast component of the delayed rectifying potassium current that prolongs the duration of the action potential and the effective refractory period in a concentration-dependent manner. Clinical studies have shown that dofetilide is effective in treating patients with atrial arrhythmias, as well as ventricular arrhythmias. In particular, for example, dofetilide has been studied in patients with severe left ventricular dysfunction (Willian M. Bailey et al., Electrophysioloqic and Hemodynamic Effects of Dofetilide in Patients with Severe Left Ventricular Dvsfunction Circulation, 1992, Vol. , part 4, Supplement 1, page 1265) in which it was found that, unlike Class I agents, dofetilide is safe in patients with congestive heart failure. Studies have shown that episodes of atrial fibrillation result in a drastic reduction in the atrial refractory period. This is known as "electrical remodeling" of the atrium and is reversible after conversion of sinus rhythm. Before completing the inversion of the reduced refractory period, the atrium increases the vulnerability to recurrence of atrial fibrillation (AF). However, Tieleman et al., In A Clinical lllustration of Reduction of Electrical Remodeling by the use of Intracellullar Calcium Lowerinq Drugs During AF, NASPE Abstract, Pace, Vol 20, page 1142, No. 368, April 1997 concluded that "patients who use drugs that reduce intracellular calcium during AF seem to experience a lower incidence of AF relapse after cardioversion." This could be explained by a reduction in electrical remodeling of the atrium by preventing intracellular calcium overload. during AF ". In addition, Daoud et al., In Circulation, vol 96, no. 5 September 1997"Effect of verapamil and procainamide on electrical remodeling induced by atrial fibrillation in humans" observed that "previous treatment with the antagonist of the Calcium channels, verapamil, but not with the sodium channel antagonist, procainamide, markedly attenuates the changes induced by acute AF in the electrophysiological properties of the atrium.These data suggest that the calcium load during AF may be less partially responsible for AF-induced electrical remodeling. " Amlodipine is a calcium channel blocker that is widely accepted. It has been approved for the treatment of hypertension. In addition, U.S. Patent No. 5,155,120 describes its use for the treatment of congestive heart failure. Although there are several therapies available for the treatment of atrial fibrillation, the search for new therapies in this field of technique continues.

SUMMARY OF THE INVENTION This invention relates to pharmaceutical compositions comprising dofetilide or a pharmaceutically acceptable salt thereof and a calcium channel blocker and to the use of such compositions for the treatment of arrhythmia, including atrial fibrillation in mammals (e.g., male or female). females) The combinations comprise therapeutically effective amounts of dofetilide and a calcium channel blocker. Another aspect of this invention is a method for treating arrhythmias in a mammal, which comprises administering to a mammal in need of such treatment therapeutically effective amounts of a. dofetilide; and b. a blocker of calcium channels. A procedure Preferred is one in which atrial fibrillation is treated. It is especially preferred that the maintenance of normal sinus rhythm be improved. A particularly preferred method is the inhibition of electrical remodeling of the atrium before conversion to sinus rhythm. A particularly preferred mammal is a male or female human. It is particularly preferred that the human patient have sustained atrial fibrillation. Another preferred aspect of this method is that the calcium channel blocker be administered before administering dodecyde. In another aspect of this procedure, the previous sequential administration is followed by practically simultaneous administration of the calcium channel blocker and dofetilide. Another aspect of this invention is a case comprising: a. in a first unit dose form, a therapeutically effective amount of dofetilide and a pharmaceutically acceptable carrier; b. in a second unit dose form, a therapeutically effective amount of a calcium channel blocker and a pharmaceutically acceptable carrier; and c. means for containing said first and second dosage forms. Another aspect of this invention is a synergistic pharmaceutical composition for improving the maintenance of normal sinus rhythm in a mammal comprising: a. dofetiiida; and b. a blocker of calcium channels; being the amount of dofetilide alone and the amount of the calcium channel blocker only insufficient to achieve the improved maintenance of normal sinus rhythm if administered alone and the combined effect of the amount of dofetilide and the blocker of the major calcium channels that the sum of the maintenance effects of sinus rhythm that can be achieved with the individual amounts of dofetilide and calcium channel blocker; and c. a pharmaceutically acceptable diluent or vehicle. Another additional aspect of this invention is a synergistic procedure for improving the maintenance of normal sinus rhythm in a mammal comprising administering said mammal to. an amount of dofetilide; and b. an amount of a calcium channel blocker being the amount of dofetilide alone and the amount of the calcium channel blocker alone insufficient to achieve the improved maintenance of normal sinus rhythm if administered alone and the combined effect of the amount of dofetilide and calcium channel blocker greater than the sum of the maintenance effects of sinus rhythm that can be achieved with the individual amounts of dofetilide and calcium channel blocker. In each of the above compositions, methods and kits, a preferred amount of dofetilide ranges from about 0.1 mcg / kg / day to about 30 mcg / kg / day and an especially preferred amount of dofetilide ranges from about 1 mcg / kg / day at approximately 15 mcg / kg / day. In each of the above compositions, methods and kits, a preferred amount of calcium channel blocker ranges from about 0.001 mg / kg / day to about 10 mg / kg / day and an especially preferred amount of blood channel blocking agent. Calcium ranges from about 0.01 mg / kg / day to about 5 mg / kg / day. In each of the above compositions, methods and kits, especially preferred calcium channel blockers are amlodipine, nifedipine, isradipine, diltiazem or verapamil or one of its pharmaceutically acceptable salts. In each of the compositions, methods and kits above, particularly preferred calcium channel blockers are amlodipine, nifedipine or isradipine or a pharmaceutically acceptable salt thereof. In each of the above compositions, methods and kits, an especially preferred calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof, in particular its besylate salt. Another aspect of this invention is a method of treating arrhythmias in a mammal, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of amlodipine or a pharmaceutically acceptable salt thereof, in particular, its besylate salt. A preferred method is one in which atrial fibrillation is treated. It is especially preferred that the maintenance of normal sinus rhythm be improved. A particularly preferred method is the inhibition of electrical remodeling of the atrium before conversion to sinus rhythm. An especially preferred mammal is a male or female human. A preferred amount of amlodipine ranges from about 0.001 mg / kg / day to about 10 mg / kg / day and an especially preferred amount of calcium channel blocker ranges from about 0, 01 mg / kg / day at approximately 5 mg / kg / day. The invention makes an important contribution to the field of antiarrhythmic agents through a new treatment regimen: the previous treatment of patients with atrial fibrillation with an appropriate calcium channel blocker before cardioversion (pharmacological or electrical) improves the maintenance of the sinus rhythm in combination with the administration of dofetilide, decreasing the possibility of a premature relapse of atrial fibrillation after cardioversion. This treatment regimen has the additional effect of increasing the conversion rates of dofetilide. The term arrhythmia refers to the conditions in which the normal rhythm of the heart varies, in particular, the sinus rhythm. The term "reduction" is intended to include partial prevention or prevention, which, although greater than that which could be obtained by not taking any drug or taking a placebo, is less than 100%, in addition to practically total prevention. The term "treat", or "treatment" as used herein, includes preventive (eg, prophylactic) and palliative treatment. The term "pharmaceutically acceptable salt" refers to non-toxic anion salts containing anions such as (but not limited to) chloride, bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate, fumarate, oxalate, lactate, tartrate, citrate, besylate, gluconate, methanesulfonate and 4-toluene sulfonate. The expression also refers to salts of non-toxic cations such as (but not limited to) sodium, potassium, calcium, magnesium, ammonium or protonated benzathine (N, N'-dibenzylethylene diamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine (N-methyl-glucamine), benetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol). As used herein, the terms "reaction inert solvent" and "inert solvent" refer to a solvent or mixture of solvents that does not interact with the starting materials, reagents, intermediates or products in a manner that affects adversely the performance of the desired product. The skilled chemist in the art will recognize that certain compounds of this invention will contain one or more atoms that may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and conformational isomers. Such isomers and their mixtures are all included in this invention. The hydrates and solvates of the compounds of this invention are also included. Other features and advantages will be apparent from the specification and appended claims describing the invention.

DETAILED DESCRIPTION OF THE INVENTION As mentioned above, dofetilide is known in the art. In U.S. Patent No. 4,959,366, the disclosure of which is incorporated herein by reference, dofetilide is claimed and its preparation is described. The following description is provided as an aid to the preparation of dofetilide. Dofetilide has the following formula I and can be named as methanesulfonamide, N- [4- [2- [methyl [2- [4- (methylsulfonyl) amino] phenoxy] et] l] amino] phenyl- or β [( p-methanesulfonamidophenethyl) methylamino] methanesulfone-p-phenetidide.

Formula I According to U.S. Patent No. 4,959,366, a solution of 1- (4-amino-phenoxy) -2- [N- (4-aminophenethyl) -N-methylamino] was stirred at room temperature overnight. Ethane (0.75 g) and methanesulfonic anhydride (1.0 g) in dry methylene chloride (50 ml). After evaporation, the resulting oil was partitioned between a 2N aqueous sodium bicarbonate solution and ethyl acetate. After two additional extractions with ethyl acetate, the organic portions were combined, dried over magnesium sulfate, filtered and evaporated. The resulting colorless solid (1.2 g) was crystallized from ethyl acetate / methanol to provide dofetilide. 1- (4-aminophenoxy) -2- [N- (4-aminophenethyl) -N-methylamino] ethane was prepared from a solution of 1- (4-nitrophenoxy) -2- [N-methyl-N- ( 4-Nitrophenethyl) amino] ethane (1.5 g) in ethanol (100 ml). The solution was stirred at room temperature under three atmospheres of hydrogen in the presence of Raney nickel. The reaction mixture was filtered and evaporated to dryness. The residual oil was redissolved in ether, filtered and evaporated to give a yellow solid (1.1 g) which was crystallized from ethyl acetate / petroleum ether at 60-80 ° C to provide the desired product (0, 9 g), pf 73-74 ° C. The starting materials and reagents for the synthesis described above are also readily available or can be synthesized by those skilled in the art using conventional organic synthesis methods. Dofetilide is basic and forms salts with pharmaceutically acceptable anions. Such salts are all within the scope of the present invention and can be prepared by conventional methods. For example, these can be prepared by simply contacting the acidic and basic entities, usually in a stoichiometric ratio in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered by filtration, by precipitation with a non-solvent medium, followed by filtration, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization, as appropriate. Any calcium channel blocker can be used as the second compound (active agent) of this invention. "Blocker of calcium channels" means any compound that blocks the entry of Ca2 + into cells. Alternatively, the term "calcium channel blocker" refers to compounds that block the movement of Ca2 + through the slow or Ca2 + channel and thereby alter the plateau phase of the cardiac action potential. The calcium channels are multisubunit proteins that extend through the membrane that allow the controlled entry of Ca2 + ions into the cells from the extracellular fluid. In summary, depolarization in the atrial tissue is mediated by two ion currents directed towards the interior of the cells. When the transmembrane potential of the cardiac cell reaches the threshold, a rapid entry of Na + occurs. The second input current is caused largely by the movement of Ca2 + into the cell through the slow channel or Ca2 + channel. The entry of Ca2 + contributes to maintain the plateau phase of the cardiac action potential. The most common type of calcium channel is the voltage dependent. In a voltage-dependent channel, the "gate" that allows the entry of Ca2 + ions into cells requires a depolarization to a certain level of the potential difference between the cell that supports the channel and the extracellular medium that bathes the cell . The rate of Ca2 + entry to the cells depends on this potential difference. Many of these calcium channel blockers bind to calcium channels and block, or reduce, the rate of Ca2 + entry to the cells in response to the depolarization of the interior and exterior of the cells. Said inhibition is easily determined by those skilled in the art according to conventional tests. In one assay, the ability of such compounds to inhibit calcium movement within the cells is shown by their efficacy in reducing the response of isolated cardiac tissue to an increase in calcium concentration in vitro. The test is carried out by assembling spiral cut strips of rat aorta with one end fixed and the other attached to a force transducer. The tissue is immersed in a bath of physiological saline containing potassium ions at a concentration of 45 millimolar and does not contain calcium. Calcium chloride is added to the bath with a pipette to provide a final concentration of two millimolar calcium. The change in tension caused by the resulting contraction in the tissue is measured. The bath is emptied and replaced by fresh saline and, after 45 minutes, the test is repeated with the particular compound to be tested present in the saline. The concentration of compound required to reduce the response by 50% is recorded. The blocker of the calcium channels can be of any type and it is most preferable that it be a dihydropyridine. Examples of dihydropyridines include amlodipine, nifedipine, nitrendipine, nicardipine, nimodipine, niludipine, riodipine, felodipine, darodipine, isradipine, lercanidipine and nisoldipine and their pharmaceutically acceptable salts. Other calcium channel blockers include phenylalkylamines (for example verapamil, desmetoxiverapamil, methoxiverapamil), benzothiazepines (for example, diltiazem), diphenylpiperazines, diarylaminopropylamines (bepridyl) and gallopamil and their pharmaceutically acceptable salts. Amlodipine or one of its pharmaceutically acceptable salts (eg, the besylate salt) is preferred. Amlodipine is claimed and described in U.S. Patent No. 4,572,909 and its besylate salt is claimed and described in U.S. Patent No. 4,879,303, the disclosures of which are incorporated herein by reference. Amlodipine besylate is also known as (±) -monobenzenesulfonate of 2 - [(2-aminoethoxy) methyl] A- (2-chlorophenyl) 1,4-dihydro-6-methyl acid 3-ethyl-5-methyl ester -3,5-pyridinedicarboxylic acid. The calcium channel blocking compounds of this invention are readily available or can be readily synthesized by those skilled in the art using conventional organic synthesis methods. Some of the compounds of this invention have asymmetric carbon atoms and are therefore enantiomers or diastereoisomers. The diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods known per se, for example, by chromatography and / or fractional crystallization. The enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (for example an alcohol), separating the diastereoisomers and converting (for example, by hydrolysis) the individual diastereomers into the corresponding pure enantiomers. Such isomers, including diastereomers, enantiomers and mixtures thereof, are all considered part of this invention. Many calcium channel blockers are acidic or basic and form a salt with a pharmaceutically acceptable cation or anion, as appropriate. Such salts are all within the scope of this invention and can be prepared by conventional methods. For example, these may be prepared by simply contacting the acidic and basic entities, usually in a stoichiometric ratio, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. The salts are recovered by filtration, by precipitation with a non-solvent medium, followed by filtration, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization, as appropriate. In addition, when the compounds of this invention form hydrates or solvates, these are also included within the scope of the invention. The utility of the compounds and combinations of the present invention in treating arrhythmias such as atrial fibrillation in mammals (e.g., humans) is demonstrated by the activity of the compounds and combinations of this invention in conventional assays and the clinical protocol described then. Such assays and clinical protocol also provide a means by which the activities of the compounds of this invention can be compared to the activities of other known compounds. The results of these comparisons are useful for determining dose levels in mammals, including humans, for the treatment of such diseases.

PROTOCOL The recurrence rate of atrial fibrillation was analyzed in a group of 264 patients in a phase III study of dofetilide who had undergone cardioversion after sustained atrial fibrillation for a duration of 2 to 26 weeks. Study number 115-120 was a parallel group, randomized, double-blind, placebo-controlled study conducted in several centers. Dofetilide hospitalized patients were administered twice daily (125 mcg, 250 mcg, 500 mcg) or placebo according to a 1: 1: 1: 1 randomized distribution. Patients who had not converted pharmacologically after 5 doses were electrically converted to a sinus rhythm. Those who remained in sinus rhythm for 24 hours after conversion by any means were considered "converted" and were assigned a twelve-month assessment of sinus rhythm maintenance. Patients who had recurrence to axial fibrillation (relapse to atrial fibrillation or flutter with a duration of at least 24 hours) were considered to have had an adverse event that excluded them. The Kaplan-Meier method was used to estimate the probability of maintenance of sinus rhythm over time and was represented graphically. Logarithmic order tests were used to test differences in the maintenance of sinus rhythm between the groups and the risk relationships provided by the Cox proportional hazards model. Patients who completed 12 months without relapse or dropped out for reasons other than atrial fibrillation relapse were considered in the time-event analysis on the day of their last dose of study medication.

The effect of treatment with blockers of calcium channels for previous conversion in the maintenance of sinus rhythm was analyzed. The 264 patients who were converted were analyzed according to their use of the calcium channel blocker instead of according to their treatment group at random. The group of calcium channel blockers consisted of patients (n = 48) who received a calcium channel blocker while undergoing fibrillation in the trial from at least 7 days before the conversion until at least the day before. the conversion. The group without calcium channel blockers is formed by the rest of the converters (n = 216). Both groups consisted of patients from the four randomized treatment groups (3 doses of dofetilide and placebo). The groups were compared by the Kaplan-Meier method, the logarithmic order test stratified by treatment group and the proportional hazard model of Cox with the use of the treatment and the calcium channel blocker. In patients who received calcium channel blocker and randomly treated dofetilide while suffering from atrial fibrillation until conversion, the risk ratio (relative risk) for atrial fibrillation recurrence over a year adjusted for the use of antiarrhythmics (randomized treatment group) compared to those who did not receive calcium channel blocker and only received their treatment with dofetilide at random was 0.77 (95% CI 0.51-1.2). The risk reduction was greater in the first 15 days after cardioversion, as can be seen from the Kaplan-Meier estimates of atrial fibrillation recurrence rates: Recurrence rate (%): [W / typical error] 15 days 30 days 60 days BCC (n = 48) 27.4 [0.057] 38.1 [0.071] 42.6 [0.072] Without BCC (n = 216) 43.0 [0.035] 48.0 [0.035] 52.1 [0.035] Thus, the data demonstrate an improved risk reduction for patients receiving treatment with calcium channel blockers and random treatment with dofetilide, compared to patients who received only random treatment with dofetilide. In addition, the risk reduction is stronger for calcium channel blockers amlodipine, nifedipine, nicardipine or isradipine (and dofetilide), compared to calcium channel blockers verapamil or diltiazem (and dofetilide) [RR = 0.58, (0.29-1.14) p = 0.11]. Therefore, calcium channel blockers have a class-dependent protective effect against electrical remodeling induced by atrial fibrillation. Consequently, pretreatment of patients with atrial fibrillation with an appropriate calcium channel blocker prior to cardioversion (pharmaceutical or electrical) improves the maintenance of sinus rhythm in combination with the administration of dofetilide, decreasing the possibility of premature recurrence of atrial fibrillation after cardioversion. This treatment regimen has the additional effect of increasing the pharmacological conversion rates of dofetilide and decreasing the recurrence rate. The administration of the compounds and combinations of this invention may be by any method that releases such compounds and combinations in the desired tissue (e.g., cardiac tissues). These methods include the oral, parenteral, intraduodenal, and the like. In general, the compounds and combinations of the present invention are administered in single doses (for example once a day) or in several doses. The compounds, combinations and methods of this invention are useful for treating arrhythmia such as atrial fibrillation and for maintaining normal sinus rhythm. Thus, the compounds, combinations and methods of this invention are useful for improving sinus rhythm in patients at risk of a recurrence of atrial fibrillation after cardioversion. In addition, the compounds, combinations and procedures decrease the risk of recurrence of intermittent or paradoxical atrial fibrillation. In general, the compounds and combinations of this invention are administered orally, although parenteral administration (eg, intravenous, intramuscular, subcutaneous or intramedullary) can be used, for example, when oral administration is inadequate for the present object. or when the patient is unable to take the medication. Topical administration may also be indicated, for example, when the patient suffers from gastrointestinal disorders or when the medication is best applied on the surface of a tissue or organ, as determined by the attending physician. Typically, the calcium channel blocker is administered in a conventional mode of administration (e.g., amlodipine is administered once a day) and dofetilide is administered twice daily. Preferably, the patient is pretreated with the calcium channel blocker for a period of about one day to about one year, with the interval from three days to about two weeks being especially preferred, before being converted to normal sinus rhythm. Conversion to normal sinus rhythm is accomplished with the administration of dofetilide (if necessary, with optional electrocardioversion) and the combined administration of the calcium channel blocker for approximately one to fourteen days, followed by treatment with long dofetilide. duration. Optionally, the calcium channel blocker can be continued in the long term. Of course, when the two compounds are administered simultaneously, these can be administered together or at different times during the day. Thus, the two different compounds of this invention can be co-administered simultaneously or sequentially in any order, or a single pharmaceutical composition comprising dofetilide and a calcium channel blocker can be administered in a pharmaceutically acceptable carrier. In any case, the amount and time of administration of the compounds will, of course, depend on the subject being treated, the intensity of the condition, the manner of administration and the criteria of the prescribing physician. A) Yes, due to the variability between patients, the doses indicated above are indicative and the doctor can increase or decrease the doses of the compounds to achieve the treatment (for example, antiarrhythmic effect) that the doctor considers appropriate for the patient. In general, an amount of compound or combination of this invention that is sufficient to obtain the desired maintenance of sinus rhythm is used. In general, an effective dose for the activities of this invention, for example the antiarrhythmic activities of dofetilide, ranges from 0.1 mcg / kg / day to about 30 mcg / kg / day and an especially preferred amount of dofetilide ranges from about 1, 0 mcg / kg / day at approximately 15 mcg / kg / day, with a preferred dose being 15 mcg / kg / day. A quantity of calcium channel blocker of this invention is used which is effective for the activities of this invention, for example, antiarrhythmic activities. Typically, an effective dose for the calcium channel blockers of this invention varies in the range of about 0.001 mg / kg / day to about 10 mg / kg / day in single or divided doses, preferably about 0.1 mg / kg / day at approximately 5 mg / kg / day in single or divided doses. The compounds and combinations of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable carrier or diluent. Thus, the compounds and combinations of this invention can be administered individually or in combination in any conventional oral, parenteral, rectal or transdermal dosage form. For oral administration, a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are used together with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic . In addition, for the purposes of tablet preparation, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful. Solid compositions of a similar type are also used as fillers in hard and soft filled gelatin capsules; Lactose or milk sugar being the preferred materials in this respect, as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol. , glycerol and various combinations thereof. For parenteral administration, solutions in sesame or peanut oil or aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts can be used. Such aqueous solutions can be suitably buffered, if necessary, and the liquid diluent first made isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for the purposes of intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, the sterile aqueous media used can all be obtained easily by conventional techniques well known to those skilled in the art. For the purposes of transdermal administration (eg, topical), dilute sterile aqueous or partially aqueous solutions are prepared (usually in a concentration of about 0.1% to 5%), or others similar to the above parenteral solutions. The methods for preparing the various pharmaceutical compositions with a certain amount of active ingredient are known or will be apparent to those skilled in the art in view of this description. Examples of methods for preparing pharmaceutical compositions can be found in Reminqton's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975). The pharmaceutical compositions according to the present invention may contain 0.1% -95% of the compounds of this invention, preferably 1% -70%. In any case, the composition or formulation to be administered will contain an amount of a compound (s) according to the invention sufficient to treat the disease / disorder of the subject being treated. Since the present invention has an aspect that relates to the treatment of, for example, arrhythmias, by treatment with a combination of active ingredients that can be administered separately, the invention also relates to the combination of pharmaceutical compositions separated into form of case. The kit comprises two separate pharmaceutical compositions: dofetilide and a calcium channel blocker as described above. The case comprises a packaging means for separate compositions such as a divided bottle or a package in a divided sheet. Typically, the kit comprises instructions for administration of the separate components. The case form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or when increasing or decreasing the dosage of the components is desired. individual by the prescribing doctor. An example of such a case is the so-called blister pack.

Blister packs are well known in the packaging industry and are widely used for packaging dosage unit dosage forms (tablets, capsules and the like). The blister packs are generally formed by a sheet of a relatively rigid material covered with a thin sheet of a preferably transparent plastic material. During the packaging process, alveoli are formed in the thin sheet of plastic. The alveoli have the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the alveoli and the sheet of relatively rigid material is sealed to the thin sheet of plastic on the face of the sheet opposite the direction in which the alveoli have been formed. As a result, the tablets or capsules are hermetically sealed in the alveoli between the thin sheet of plastic and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by applying a manual pressure on the cells, by means of which an opening is made in the sheet in the position of the socket. The tablet or capsule can then be extracted through said opening. It may be desirable to provide a memory aid means in the case, for example, in the form of numbers near the tablets or capsules, so that the numbers correspond to the days of the administration schedule in which the tablets should be ingested or specified capsules. Another example of said means of memory aid is a calendar printed on the card, for example, as follows: "First week, Monday, Tuesday, ... etc ... Second week, Monday, Tuesday, ... " and so on. Other variations of memory aids will be apparent. A "daily dose" may be a single tablet or capsule or several tablets or capsules that must be taken on a given day. In addition, a daily dose of the first compound may consist of a tablet or capsule, while a daily dose of the second compound, may consist of several tablets or capsules, or vice versa. The means of memory aid should reflect this.

In another preferred embodiment of the invention, there is provided a dispenser designed to dispense the daily doses one by one in the order of their intended use. Preferably, the dispenser is provided with a means of memory aid, to facilitate compliance with the administration pattern. An example of said memory aid means is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of said memory aid means is a battery-operated microprocessor memory coupled to a liquid crystal display or an audible reminder signal that, for example, displays the date on which the last dose was taken and / or remember when the next dose should be taken. The compounds of this invention, alone or in combination with each other or with other compounds, will generally be administered in a convenient formulation. The following formulation examples are merely illustrative and are not intended to limit the scope of the present invention. In the following formulations, "active ingredient" means a compound (s) of this invention and thus may refer to dofetilide, a calcium channel blocker or a combination of the two.

Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared using the following: Ingredient Quantity (mg / capsule) Active ingredient 0,25-100 Starch, FN 0-650 0-50 starch fluid powder Silicone fluid of 350 centistokes 0-15 A tablet formulation is prepared using the following ingredients: Formulation 2: Tablets Ingredient Amount (mg / tablet) Active ingredient 0,25-100 Microcrystalline cellulose 200 - 650 Silicon dioxide, pyrolysis 10-650 Stearic acid 5-15 The components are mixed and compressed to form tablets. Alternatively, tablets containing 0.25 to 100 mg of active ingredients are prepared as follows: Formulation 3: Tablets Ingredient Quantity (mg / tablet) Active ingredient 0.25 - 100 Starch 45 Microcrystalline cellulose 35 Polyvinylpyrrolidone (as a 10% aqueous solution) 4 Sodium carboxymethyl cellulose 4,5 Magnesium stearate 0.5 Talcum 1 The active ingredients, starch and cellulose are passed through a U.S. No. 45 and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a U.S. No. 14. The granules thus produced are dried at 50 ° to 60 ° C and passed through a U.S. No. 18. Sodium carboxymethyl cellulose, magnesium stearate and talc, previously passed through a U.S. mesh screen, are then added. No. 60, to the granules that, after mixing, are compressed in a tablet machine to produce tablets. Suspensions containing 0.25 to 100 mg of active ingredient are prepared per 5 ml dose as follows: Formulation 4: Suspensions Ingredient Quantity (mg / 5 ml) Active ingredient 0.25 - 100 mg Sodium carboxymethyl cellulose 50 mg Syrup 1, 25 mg Benzoic acid solution 0.10 ml Aroma is.

Coloring is.

Purified water, c.s.p. 5 mi The active ingredients are passed through a mesh screen U.S. No. 45 and mixed with the sodium carboxymethyl cellulose and the syrup to form a smooth paste. The benzoic acid, flavor and coloring solution is diluted with some water and added, with stirring. Sufficient water is then added to produce the necessary volume. An aerosol solution is prepared containing the following ingredients: Formulation 5: Aerosol Ingredient Quantity (% by weight) Active ingredient 0.25 Ethanol 25.75 Propellant 22 (chlorodifluoromethane) 70.00 The active ingredient is mixed with ethanol and the mixture is added to a portion of the propellant 22, cooled to 30 ° C and transferred to a filling device. The necessary quantity is then introduced into a stainless steel container and diluted with the rest of the propellant. The valve units are then adjusted to the container. Prepares as follows suppositories: Formulation 6: Suppositories Ingredient Quantity (mg / suppository) Active ingredient 250 Glycerides of saturated fatty acids 2,000 The active ingredient is passed through a U.S. mesh screen. No. 60 and is suspended in the glycerides of saturated fatty acids, previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of 2 g nominal capacity and allowed to cool. An intravenous formulation is prepared as follows: Formulation 7: Intravenous solution Ingredient Amount Active ingredient 20 mg Isotonic saline solution 1,000 ml The solution of the above ingredients is administered intravenously to a patient at a rate of approximately 1 ml / min.

Claims (32)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition comprising a therapeutically effective amount of: a. dofetilide; b. a blocker of calcium channels; and c. a pharmaceutically acceptable diluent or vehicle.

2. A pharmaceutical composition according to claim 1, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition according to claim 3, wherein the amount of dofetilide ranges from about 0.1 mcg / kg / day to about 30 mcg / kg / day.

4. A pharmaceutical composition according to claim 4, wherein the calcium channel blocker is amlodipine besylate and the amount of amlodipine besylate ranges from about 0.01 mg / kg / day to about 5 mg / kg / day.

5. Use of dofetilide or in combination with a calcium channel blocker for the preparation of a medicament for treating a mammal that has arrhythmias.

6.- Use of a calcium channel blocker in combination with dofetilide for the preparation of a medicine for the treatment of arrhythmias.

7. The use according to claim 5 or 6, wherein the blocker of the calcium channels is amlodipine or one of its pharmaceutically acceptable salts.

8. The use according to claim 7, wherein the medicament obtained provides from about 0.1 mcg / kg / a to about 30 mcg / kg / dofetilide to a mammal per day.

9. The use according to claim 8, wherein the blocker of the calcium channels in the medicament obtained is amlodipine besylate and the medicament provides from about 0.01 mg / kg / a to about 5 mg / kg / of said amlodipine besilate to a mammal per day.

10. The use according to claim 9, wherein the mammal is a human being that has atrial fibrillation and normal sinus rhythm is maintained.

11. The use according to claim 10, wherein the mammal is a human whose electrical remodeling of the atrium is inhibited before conversion to a sinus rhythm.

12. The use according to claim 10, wherein the human previously treated with amlodipine or one of its pharmaceutically acceptable salts, before conversion to a normal sinus rhythm with dofetilide and optional electrocardioversion to produce the inhibition of a recurrence of atrial fibrillation after cardioversion.

13.- A case that includes: a. in a first unit dose form, a therapeutically effective amount of dofetilide and a pharmaceutically acceptable carrier; b. in a second unit dose form, a therapeutically effective amount of a calcium channel blocker and a pharmaceutically acceptable carrier; and c. means for containing said first and second dosage forms.

14. A kit according to claim 13, wherein the calcium channel blocker is amlodipine or one of its pharmaceutically acceptable salts.

15. A kit according to claim 14, wherein the amount of dofetilide ranges from about 0.1 mcg / kg / day to about 30 mcg / kg / day.

16. A kit according to claim 15, wherein the calcium channel blocker is amlodipine besylate and the amount of amlodipine besylate ranges from about 0.01 mg / kg / day to about 5 mg / kg / day .

17. A pharmaceutical composition for treating arrhythmias in a mammal comprising a. an amount of dofetilide; and b. an amount of a calcium channel blocker being the amount of dofetilide alone and the amount of the calcium channel blocker alone insufficient to achieve the improved maintenance of normal sinus rhythm if administered alone and the combined effect of the amount of dofetilide and the calcium channel blocker greater than the sum of the maintenance effects of sinus rhythm that can be achieved with the individual amounts of dofetilide and calcium channel blocker; and c. a pharmaceutically acceptable diluent or vehicle.

18. - A pharmaceutical composition according to claim 17, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition according to claim 18, wherein the amount of dofetilide ranges from about 0.1 mcg / kg / day to about 30 mcg / kg / day.

20. A pharmaceutical composition according to claim 19, wherein the calcium channel blocker is amlodipine besylate and the amount of amlodipine besylate ranges from about 0.01 mg / kg / day to about 5 mg / kg / day.

21.- The use of dofetilide or in combination with a calcium channel blocker for the preparation of a medicine to improve the maintenance of sinus rhythm in a mammal, being the amount of dofetilide alone and the amount of blocking of the channels of only insufficient calcium to achieve improved maintenance of normal sinus rhythm if administered alone and the combined effect of the amount of dofetilide and calcium channel blocker greater than the sum of the sinus rhythm maintenance effects that can be achieved with the individual amounts of dofetilide and of calcium channel blocker.

22. The use according to claim 21, wherein the calcium channel blocker is amlodipine or a pharmaceutically acceptable salt thereof.

23. The use according to claim 22, wherein the medicament obtained provides from about 0.1 mcg / kg / a to about 30 mcg / kg / dofetilide to a mammal per day.

24. The use according to claim 22, wherein the blocker of the calcium channels in the medicament obtained is amlodipine besylate and the medicament provides from about 0.01 mg / kg / a to about 5 mg / kg / of said amlodipine besilate to a mammal per day.

25. The use according to claim 24, wherein the mammal is a human being.

26.- The use of amlodipine or one of its salts pharmaceutically for the production of a medicine to treat arrhythmias in a mammal.

27. The use according to claim 26, wherein the medicament is either and is also useful for treating atrial fibrillation.

28. The use according to claim 26, wherein the medicament is any and is also useful for improving the maintenance of normal sinus rhythm.

29. The use according to claim 26, wherein the medicament is any and is also useful to inhibit remodeling of the atrium before conversion to sinus rhythm.

30. The use according to claim 26, wherein the mammal is a human being.

31. The use according to claim 30, wherein the blocker of the calcium channels in the drug obtained is amlodipine besilate and the medicine obtained provides approximately 0.01 mg / kg / a approximately 5 mg / kg / said amlodipine besylate to said mammal per day.

32. The use according to claim 30, wherein the mammal is a human being previously treated with amlodipine or one of its pharmaceutically acceptable salts, before conversion to a normal sinus rhythm, causing the inhibition of the recurrence of fibrillation headset after cardioversion.