WO2014119989A2 - Pharmaceutical composition comprising an angiotensin ii-receptor antagonist and a calcium channel blocker for the treatment of arterial hypertension - Google Patents

Pharmaceutical composition comprising an angiotensin ii-receptor antagonist and a calcium channel blocker for the treatment of arterial hypertension Download PDF

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WO2014119989A2
WO2014119989A2 PCT/MX2014/000034 MX2014000034W WO2014119989A2 WO 2014119989 A2 WO2014119989 A2 WO 2014119989A2 MX 2014000034 W MX2014000034 W MX 2014000034W WO 2014119989 A2 WO2014119989 A2 WO 2014119989A2
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pharmaceutical composition
pharmaceutically acceptable
combinations
composition according
tablet
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PCT/MX2014/000034
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Spanish (es)
French (fr)
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WO2014119989A3 (en
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Miguel Ángel GARCIA PÉREZ
Gabriel MARCELÍN JIMÉNEZ
Concepción Albina VÁZQUEZ FLORES
Laura Ivonne GALO MOJICA
Alionka Citlalli P. ANGELES MORENO
Octavio CARO RODRÍGUEZ
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Garcia Pérez Miguel Ángel
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel tablet-tablet composition consisting of a combination of at least two active ingredients in two or more phases, one of which is at least one angiotesin II receptor antagonist which is released with zero order and / or order one kinetics without delay time; the other is a calcium channel blocker which is released with zero order kinetics.
  • the application of the composition is for the prophylaxis and / or treatment of arterial hypertension, congestive heart failure, unstable angina pectoris, acute myocardial infarction, diabetic nephropathy and associated disorders.
  • cardiovascular diseases have become the leading cause of death in all the industrialized countries of the world, epidemiological analysis has allowed us to recognize the existence of biological variables called risk factors for cardiovascular disease, which are able to influence the probability of the disease of strokes, coronary heart disease, heart failure or peripheral artery disease (Castells E., 2000).
  • cardiovascular disorders are: arterial hypertension, cardiac arrhythmias, atherosclerosis, angina pectoris, cardiomyopathies, cerebrovascular disorder, heart failure, hyperlipidemias, hypotension, shock, venous thromboembolism, preclampsia, among others.
  • Hypertension is the most important risk factor for cardiovascular diseases and when it is associated with other disorders such as obesity, high cholesterol, alcohol consumption or smoking, the likelihood of suffering a serious cardiac complication increases exponentially.
  • renal, neurological or any other organ or region of the body human (Sat ⁇ n J., 1999). 95% of the hypertension observed in clinical practice do not have one. defined etiology, constitute the so-called essential arterial hypertension (AHT), also called primary or idiopathic, while 5% are due to various causes among which the ones induced by drug use, drug use, disease stand out renovascular, renal failure, pheochromocytoma and hyperaldosteronism (aicas C, 2003).
  • AHT essential arterial hypertension
  • Blood pressure is a continuous variable, therefore there is no cut-off point to define the threshold below which blood pressure values are normal, however, high blood pressure corresponds to a persistent elevation of blood pressure over limits.
  • PAS when its value is greater than or equal to 140 mmHg it is defined as PAS or systolic blood pressure, when its value is greater than or equal to 90 mmHg it is defined as PAD or diastolic blood pressure. (Minsal, 2010).
  • Arterial hypertension is basically characterized by the existence of an endothelial dysfunction, with a break in the balance between other relaxing factors of the blood vessel (nitric oxide-NO, hyperpolarizing factor of the endothelium-EDHF), vasoconstrictor factors (mainly endothelin), decrease in level of the endothelium of prostacyclin-PG12 vasodepressant and relative increase in thromboxane-TXA2 intracellular vasoconstrictor.
  • nitric oxide-NO hyperpolarizing factor of the endothelium-EDHF
  • vasoconstrictor factors mainly endothelin
  • Endothelin very potent local vasoconstrictor factors, about 10 to 100 times more powerful than angiotesin II. It is known that this is a complex system: preproendothelin-proendothelin-ETl.
  • an endothelin converting enzyme acts, forming mainly ET1, but also to a lesser extent, ET2 and ET3. Only ET1 seems to have systemic vasoconstrictor action.
  • ET1 exerts various actions: on vascular tone, renal excretion of sodium and water, and the production of the extracellular matrix.
  • ETl is involved, in an important way, in the process of vascular remodeling and regulation of cell proliferation. It is an extraordinarily potent mitogenic substance that produces hyperplasia and hypertrophy of vascular smooth muscle.
  • the renin-angiotesin-aldosterone system is an extremely complex system, comprising a series of proteins and 4 angiotesins (I, II, III and IV) with their own specific activities.
  • the actions of angiotesin II include: contraction of arterial and venous vascular smooth muscle, stimulation of the synthesis and secretion of aldosterone, release of norepinephrine in sympathetic terminations, modulation of sodium (Na) transport by renal tubular cells, increased oxidative stress by activation of NADH and NADPH dependent oxidases, vasopressin stimulation / ADH, stimulation of the dipsogenic center in the central nervous system, antagonism of the natriuretic-natural atrial peptide system (BNP) and type C (CNP), increased production of endothelin (ET1) and vasoconstrictor prostaglandins (TXA2, PgF2a).
  • BNP natriuretic-natural atrial peptide system
  • CNP type C
  • angiotesin II and aldosterone increase the collagen tissue at the cardiac and vascular level, to inhibit the activity of metalloproteinase (MMP1) that destroys collagen and increase the specific tissue inhibitors of MMP1 (TIMPs).
  • MMP1 metalloproteinase
  • TRIPs specific tissue inhibitors of MMP1
  • FDE endogenous digitalis
  • vasoactive intestinal peptide is intensely vasodilator
  • coherin is vasoconstrictor
  • cholecystokinin is vasodilator
  • substance P is also vasodilator, like bombesin, endorphins and eicosanoids (Wagner P., 2010) .
  • angiotesin-converting enzyme ACEI
  • Angiotesin II receptor antagonists ARA II
  • ACEI angiotesin II receptor antagonists
  • ARA II angiotesin II receptor antagonists
  • angiotesin II receptors include valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan ⁇ and eprosartan, among others.
  • Losartan is the oldest and best evaluated drug in this group, being the only agent of this type approved for the treatment of heart failure. It has proven to be an effective antihypertensive orally, with additional uricosuric activity, has an active metabolite of the order of 10-40 times more potent than losartan, for this reason in patients with chronic hepatopathy may lose effectiveness by hindering their metabolism and decreasing the generation of their active metabolite. Some of its characteristics is that it reaches its maximum plasma concentration in 1 hour and its active metabolite in about 3 to 4 hours, it has an absolute bioavailability of 33%, with a elimination half-life of 2.6 to 9 hours, it joins proteins in a percentage of 98.7% (Cadime, 2000).
  • Losartan when suffering the substantial metabolism of the first step by the cytochrome P-450 enzymes, is metabolized to an active metabolite which is the. 5-carboxylic acid, said metabolite is responsible for most of the effects of Losartan on the angiotensin receptor (Rodr ⁇ guez C, 2002).
  • nifedipine amlodipine, felodipine, verapamil, diltiazem, nitrendipine, nicardipine, isradipine and nisoldipine, among others.
  • Felodipine is an antagonist of the calcium channels of the dihydropyridine group, which has an oral bioavailability of 15%, as a result of intense first-pass metabolism. It has a volume of distribution of 10 L / kg and binds to plasma proteins in a proportion greater than 99%. Almost 100% of the dose is metabolized in the liver, forming inactive metabolites that are mostly eliminated in the urine.
  • the present invention relates to a pharmaceutical composition in the form of a tablet or tablet of two or more phases comprising a first tablet with a release system having a kinetic of zero order and / or of order one without delay time than at less a calcium channel blocking agent; and, a second tablet with a release system that exhibits a zero order kinetics of at least one angiotesin II receptor antagonist agent.
  • Said composition is useful for the treatment of arterial hypertension, congestive heart failure, unstable angina pectoris, acute myocardial infarction, diabetic nephropathy or associated disorders.
  • FIGURE 1 Dissolution profile of 25mg / 5mg Losartan / Felodipine tablets VS 5mg Felodipine tablets.
  • FIGURE 2 Dissolution profile of tablets
  • the present invention relates to a novel pharmaceutical composition in the form of a two-phase tablet-tablet which comprises: a) at least one internal tablet having a zero order kinetics containing at least one calcium channel blocker, its pharmaceutically acceptable salts, derivatives, metabolites, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; b) at least one external tablet with a release system that exhibits zero order and / or order one kinetics without delay time which contains at least one angiotesin II receptor antagonist, its pharmaceutically acceptable salts, derivatives , prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; and optionally c) one or more pharmaceutically acceptable excipients, all of them in an oral administration system.
  • the internal tablet with a release system that has zero order kinetics containing at least one calcium channel blocker was developed in this way in the novel composition object of this invention, taking into account that its usefulness to prevent cardiovascular events in hypertensive patients is proven when they are in a long-acting system compared to those of short-acting that increase the probability of coronary events and mortality and therefore are not used as hypertensive.
  • the external tablet with a release system that presents a kinetic of zero order and / or of order one without delay time which, preferably of order one, was developed in this way in order to perform at least a delivery of at least one angiotesin II receptor antagonist agent and thus obtain a better synergistic effect with the calcium channel blocking agent. Decreasing peripheral vascular resistance, blood pressure and afterload.
  • At least one calcium channel blocking agent is selected from the following group: nifedipine, amlodipine, felodipine, verapamil, diltiazem, nitrendipine, nicardipine, isradipine, nisoldipine, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, same that is contained in the internal tablet within the composition.
  • At least one angiotesin II receptor antagonist agent is selected from the group consisting of valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan, eprosartan, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof.
  • composition described in the present invention its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, are preferably used, but not limited to, a blocker of calcium channels to felodipine.
  • concentration range between 1 mg and 10 mg, more preferably in a range of 3 mg to 7 mg.
  • the angiotesin II receptor antagonist agent that is preferably used, but not limited to, is losartan, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, in a concentration range between 5 mg and 60 mg and more preferably from 17 to 35 mg.
  • the internal tablet of the composition in addition to containing at least one calcium channel blocking agent, may contain one or more excipients.
  • the internal tablet and the external tablet of the The composition may contain at least one pharmaceutically acceptable excipient, which is selected from; alginic acid, crospovidone, ion exchange resins, aluminum silicate, magnesium silicate, microcrystalline cellulose, starch, sodium starch glycol, modified cellulose gum, PVP, sodium dodecyl sulfate corn starch, rice starch, N-vinyl -2- crosslinked pyrrolidone, croscarmellose sodium, formaldehyde-casein, sorbitol, starch, pregentalized starch, corn starch, sucrose, sugar, compressible sugar, isomalt, tragacanth, talcum, trehalose, xylitol, acacia, agar, algic acid, carbonate of calcium, calcium lactate, carbomer, calcium carboxymethylcellulose, myocrystalline
  • the internal tablet of the composition in addition to containing at least one calcium channel blocking agent, is formed by one or more monosaccharides, one or more polyethylene oxides, one or more cellulose derivatives, one or more salts of silica and one or more lubricating agents; and the external tablet of the composition, in addition to containing at least one angiotesin II receptor antagonist agent, is made up of one or more cellulose polymers, one or more silica salts, one or more monosaccharides and one or more agents.
  • lubricants in addition to containing at least one calcium channel blocking agent, is formed by one or more monosaccharides, one or more polyethylene oxides, one or more cellulose derivatives, one or more salts of silica and one or more lubricating agents.
  • the monosaccharides can be fructose, lactose, mannitol, xylol, sorbitol, anhydrous lactose and / or lactose monohydrate and / or combinations thereof;
  • the polyethylene oxides may be selected from polyox N-10, polyox N-80, polyox N12-k, polyox N60-k and / or polyox N-301 or combinations thereof;
  • Cellulose derivatives may be microcrystalline cellulose, sodium carboxymethylcellulose, silicified microcrystalline cellulose, cellulose, hydroxypropylmethyl cellulose, calcium microcrystalline cellulose, hydroxyethyl cellulose, microcrystalline cellulose, calcium microcrystalline cellulose, hydroxypropyl cellulose and / or combinations thereof;
  • the silicon salt can be silicon oxide, calcium silicate, magnesium aluminum silicate, aluminum silicate, magnesium silicate, colloidal silicon dioxide, magnesium aluminum metasilicate, siliconized microcrystalline cellulose, magnesium trisilicate, silicon dioxide and / or colloidal
  • the pharmacokinetics of the active ingredients losartan (A) and felodipine (B) administered independently in a single dose administered orally is the same as the pharmacokinetics of the same co-administered active ingredients (C) in their pharmaceutical form.
  • the pharmacokinetics of the active ingredients losartan (A) and felodipine (B) administered independently in a single dose administered orally is different from the pharmacokinetics of the same co-administered active ingredients (C) in their pharmaceutical form.
  • the study design was developed with 12 healthy volunteers, "longitudinal sexes both, 18 to 55 years of age by cross pattern, randomized, prospective, single - blind, single - center, single - dose under fasting conditions, three sessions , six sequences (ABC, ACB, BAC, BCA, CAB, CBA), seven days of washing between each study session, to determine the pharmacokinetic parameters and bioavailability in fixed doses of losartan, felodipine and losartan-felodipine.
  • the groups were balanced with the same number of volunteers for each sequence.
  • the study was run in darkness, due to the photosensitivity of the felodipine; The medication was administered with 250 mL of 10-hour fasting electrolyte solution; and the volunteers remained in bed for 4 hours or until they could return to the rest of the group, as long as their vital signs were normal.
  • the average values corresponding to the losartan metabolite EXP3174 for the pharmacokinetic parameters were obtained using WinNonLin® software from the individual values of the 12 volunteers after administering the fixed dose of 25 mg losartan from the reference medicine (A) and the tablet-tablet medicine (C) containing the combined dose of 25 mg losartan and 5 mg felodipine: these are shown in the table 4 including the Student t test for the comparison of means without assuming equal variances for considering different formulations with an alpha value of 0-05 for the rejection of the null hypothesis of equality as well as the value of bioavailability from the relationship between the tablet-tablet formulation (C) with respect to the formulation of the reference medicine (A).
  • the The developed composition has an "in vivo" release system that allows intact molecules to pass through the body for a time not less than 2.5 hours for Losartan and not less than 8.5 hours for the metabolite of losartan EXP3174.
  • Table 5 Values of felodipine pharmacokinetic parameters obtained for each of the volunteers who participated in the study.
  • the composition Developed presents an "in vivo" release system that allows intact molecules to pass through the body for a time not less than 12 hours for Felodipine.
  • composition developed from the present invention allows the delivery of the active ingredients losartan and felodipine without manifesting negative interaction that delays or prevents the absorption, metabolism or distribution thereof when administered in combination compared to its pharmacokinetic behavior when administered independently.
  • the tablet-tablet formulation (C) does not alter the pharmacokinetic behavior of the active ingredients, once the composition comprising a) at least one internal tablet having a zero order kinetics containing at least one calcium channel blocker is administered, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; b) at least one external tablet having zero order and / or order one kinetics without delay time containing at least one angiotesin II receptor antagonist, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; and optionally
  • compositions used during the development of the invention are presented below as illustrative, but not limited to, examples:
  • Example 1 Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with order one release kinetics without delay time.
  • Example 2 Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with order one release kinetics without delay time.
  • Example 3 Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with order one release kinetics without delay time.
  • the present compositions have a dissolution profile of the active ingredients such that, as seen in Figure 1, the felodipine begins to release at 2 hours reaching approximately 20 percent dissolved active ingredient and at approximately 10 hours it has dissolved 100 percent of the active substance.
  • the above was compared with a composition in form of tablets, observing that in said composition the dissolution is carried out more quickly at the beginning, however, at 10 hours of the test, it is not possible to dissolve 100 percent felodipine.
  • the dissolution profile of Losartan ( Figure 2), begins to be released in such a way that at 5 minutes, there is 40 percent dissolved losartan reaching approximately 100 percent of active ingredient dissolved at 45 minutes , an equivalent dissolution profile was obtained when compared with a composition in the form of Losartan tablets of 12.5 mg.

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Abstract

The invention concerns a pharmaceutical composition in tablet-tablet form having at least two phases and comprising an inner tablet which has zero order kinetics for at least one calcium channel blocking agent and an outer tablet which has zero order kinetics and/or order one kinetics without a delay time for at least one angiotensin II-receptor antagonist. The composition can be used for the treatment of arterial hypertension, congestive cardiac insufficiency, unstable angina pectoris, acute myocardial infarction, diabetic nephropathy or associated disorders.

Description

COMPOSICIÓN FARMACÉUTICA CON UN ANTAGONISTA DE LOS RECEPTORES DE LA ANGIOTESINA II Y UN BLOQUEADOR DE LOS CANALES DE CALCIO PARA EL TRATAMIENTO DE LA HIPERTENSIÓN PHARMACEUTICAL COMPOSITION WITH AN ANTAGONIST OF THE ANGIOTESINE II RECEIVERS AND A BALLOONER OF CALCIUM CHANNELS FOR THE TREATMENT OF HYPERTENSION
ARTERIAL ARTERIAL
CAMPO DE LA INVENCIÓN FIELD OF THE INVENTION
La presente invención se refiere a una novedosa composición en forma de tableta-tableta conformada por una combinación de al menos dos principios activos en dos o más fases, uno de ellos es al menos un antagonista de los receptores de la angiotesina II el cual es liberado con una cinética de orden cero y/o de orden uno sin tiempo de retardo; el otro es un bloqueador de los canales de calcio el cual es liberado con una cinética de orden cero. La aplicación de la composición es para la profilaxis y/o tratamiento de la hipertensión arterial, insuficiencia cardiaca congestiva, angina de pecho inestable, infarto agudo del miocardio, nefropatia diabética y desórdenes asociados. ANTECEDENTES The present invention relates to a novel tablet-tablet composition consisting of a combination of at least two active ingredients in two or more phases, one of which is at least one angiotesin II receptor antagonist which is released with zero order and / or order one kinetics without delay time; the other is a calcium channel blocker which is released with zero order kinetics. The application of the composition is for the prophylaxis and / or treatment of arterial hypertension, congestive heart failure, unstable angina pectoris, acute myocardial infarction, diabetic nephropathy and associated disorders. BACKGROUND
En la actualidad, . las enfermedades cardiovasculares se han convertido en la primer causa de muerte en todo los países industrializados del mundo, el análisis epidemiológico ha permitido reconocer la existencia de variables biológicas denominadas factores de riesgo de enfermedad cardiovascular, las cuales son capaces de influenciar en la probabilidad del padecimiento de accidentes cerebrovasculares, enfermedad coronaria, insuficiencia cardiaca o arteriopatía periférica (Castells E. ,2000) . Nowadays, . cardiovascular diseases have become the leading cause of death in all the industrialized countries of the world, epidemiological analysis has allowed us to recognize the existence of biological variables called risk factors for cardiovascular disease, which are able to influence the probability of the disease of strokes, coronary heart disease, heart failure or peripheral artery disease (Castells E., 2000).
Entre las principales enfermedades o desórdenes cardiovasculares se encuentran: hipertensión arterial, las arritmias cardiacas, aterosclerosis, angina de pecho, cardiomiopatías, desorden cerebrovascular, falla del corazón, hiperlipidemias, hipotensión, shock, tromboembolismo venoso, preclampsia, entre otros.  Among the main diseases or cardiovascular disorders are: arterial hypertension, cardiac arrhythmias, atherosclerosis, angina pectoris, cardiomyopathies, cerebrovascular disorder, heart failure, hyperlipidemias, hypotension, shock, venous thromboembolism, preclampsia, among others.
La hipertensión arterial es el factor de riesgo más importante de las enfermedades cardiovasculares y cuando se asocia a otros trastornos como la obesidad, el colesterol elevado, el consumo de alcohol o el tabaquismo, se incrementa de manera exponencial la probabilidad de padecer una complicación grave cardíaca, renal, neurológica o de cualquier otro órgano o región del cuerpo humano (Satín J. , 1999). El 95% de las hipertensiones que se observan en la práctica clínica no tienen una. etiología definida, constituyen la llamada hipertensión arterial (HTA) esencial, también denominada primaria o idiopática, mientras que el 5% son debido a diversas causas entre las que destacan por su frecuencia las inducidas por el consumo de drogas, el consumo de fármacos, enfermedad renovascular, falla renal, feocromocitoma e hiperaldosteronismo ( aicas C, 2003). Hypertension is the most important risk factor for cardiovascular diseases and when it is associated with other disorders such as obesity, high cholesterol, alcohol consumption or smoking, the likelihood of suffering a serious cardiac complication increases exponentially. , renal, neurological or any other organ or region of the body human (Satín J., 1999). 95% of the hypertension observed in clinical practice do not have one. defined etiology, constitute the so-called essential arterial hypertension (AHT), also called primary or idiopathic, while 5% are due to various causes among which the ones induced by drug use, drug use, disease stand out renovascular, renal failure, pheochromocytoma and hyperaldosteronism (aicas C, 2003).
La presión arterial es una variable continua, por lo tanto no existe un punto de corte para definir el umbral bajo el cual los valores de la presión arterial son normales, sin embrago, la hipertensión arterial corresponde a una elevación persistente de la presión arterial sobre límites normales, cuando su valor es mayor o igual a 140 mmHg se define como PAS o presión arterial sistólica, cuando su valor es mayor o igual a 90 mmHg se define como PAD o presión arterial diastólica. (Minsal, 2010) .  Blood pressure is a continuous variable, therefore there is no cut-off point to define the threshold below which blood pressure values are normal, however, high blood pressure corresponds to a persistent elevation of blood pressure over limits. normal, when its value is greater than or equal to 140 mmHg it is defined as PAS or systolic blood pressure, when its value is greater than or equal to 90 mmHg it is defined as PAD or diastolic blood pressure. (Minsal, 2010).
La hipertensión arterial se caracteriza básicamente por la existencia de una disfunción endotelial, con ruptura del equilibrio entre otros factores relajantes del vaso sanguíneo (óxido nítrico-NO, factor hiperpolarizante del endotelio-EDHF) , los factores vasoconstrictores (principalmente endotelinas) , disminución a nivel del endotelio de la prostaciclina-PG12 vasodepresora y aumento relativo del tromboxano-TXA2 intracelular vasoconstrictor. Arterial hypertension is basically characterized by the existence of an endothelial dysfunction, with a break in the balance between other relaxing factors of the blood vessel (nitric oxide-NO, hyperpolarizing factor of the endothelium-EDHF), vasoconstrictor factors (mainly endothelin), decrease in level of the endothelium of prostacyclin-PG12 vasodepressant and relative increase in thromboxane-TXA2 intracellular vasoconstrictor.
Algunos de los principales factores que intervienen en la presión arterial son:  Some of the main factors involved in blood pressure are:
Las endotelinas (ETs) , factores vasoconstrictores locales muy potentes, cerca de 10 a 100 veces más poderosos que la angiotesina II. Se sabe que se trata de un sistema complejo: preproendotelina-proendotelina-ETl . A nivel de la proendotelina actúa una enzima convertidora de la endotelina (ECE) , formándose principalmente ET1, pero también en menor proporción, ET2 y ET3. Solo la ET1 parece poseer acción vasoconstrictora sistémica. La ET1 ejerce diversas acciones: sobre el tono vascular, la excreción renal de sodio y agua, y la producción de la matriz extracelular . La ETl está implicada, de modo importante, en el proceso de remodelamiento vascular y de regulación de la proliferación celular. Se trata, de una sustancia mitogénica extraordinariamente potente, que produce hiperplasia e hipertrofia del músculo liso vascular.  Endothelin (ETs), very potent local vasoconstrictor factors, about 10 to 100 times more powerful than angiotesin II. It is known that this is a complex system: preproendothelin-proendothelin-ETl. At the level of proendothelin, an endothelin converting enzyme (ECE) acts, forming mainly ET1, but also to a lesser extent, ET2 and ET3. Only ET1 seems to have systemic vasoconstrictor action. ET1 exerts various actions: on vascular tone, renal excretion of sodium and water, and the production of the extracellular matrix. ETl is involved, in an important way, in the process of vascular remodeling and regulation of cell proliferation. It is an extraordinarily potent mitogenic substance that produces hyperplasia and hypertrophy of vascular smooth muscle.
Por otro lado, el sistema renina-angiotesina- aldosterona (S AA) , se trata de un sistema sumamente complejo, que comprende una serie de proteínas y 4 angiotesinas (I, II, III y IV) con actividades propias y específicas. Las acciones de la angiotesina II incluyen: contracción del músculo liso vascular arterial y venoso, estimulación de la síntesis y secreción de la aldosterona, liberación de noradrenalina en las terminaciones simpáticas, modulación del transporte del sodio (Na) por las células tubulares renales, aumento del estrés oxidativo por activación de oxidasas NADH y NADPH dependientes, estimulación de la vasopresina/ADH, estimulación del centro dipsógeno en el sistema nervioso central, antagonismo del sistema del péptido atrial natriurético-natural (BNP) y tipo C (CNP) , incremento de la producción de endotelina (ET1) y de prostaglandinas vasoconstrictoras (TXA2, PgF2a) . Además la angiotesina II y la aldosterona incrementan el tejido colágeno a nivel cardiaco y vascular, par inhibición de la actividad de la metaloproteinasa (MMP1) que destruye el colágeno e incremento de los inhibidores tisulares específicos de la MMP1 (TIMPs) . El resultado es el incremento del colágeno-3 en el corazón y vasos sanguíneos de los pacientes hipertensos . On the other hand, the renin-angiotesin-aldosterone system (S AA) is an extremely complex system, comprising a series of proteins and 4 angiotesins (I, II, III and IV) with their own specific activities. The actions of angiotesin II include: contraction of arterial and venous vascular smooth muscle, stimulation of the synthesis and secretion of aldosterone, release of norepinephrine in sympathetic terminations, modulation of sodium (Na) transport by renal tubular cells, increased oxidative stress by activation of NADH and NADPH dependent oxidases, vasopressin stimulation / ADH, stimulation of the dipsogenic center in the central nervous system, antagonism of the natriuretic-natural atrial peptide system (BNP) and type C (CNP), increased production of endothelin (ET1) and vasoconstrictor prostaglandins (TXA2, PgF2a). In addition, angiotesin II and aldosterone increase the collagen tissue at the cardiac and vascular level, to inhibit the activity of metalloproteinase (MMP1) that destroys collagen and increase the specific tissue inhibitors of MMP1 (TIMPs). The result is the increase in collagen-3 in the heart and blood vessels of hypertensive patients.
Otro factor es el digitálico endógeno (FDE) , se trata de un factor hormonal, descrito hace varios años, que inhibe la bomba Na-K-Mg-ATPasa, con intensa actividad vasoconstrictora, de acción natriurética. Su efecto natriurético se expresa de modo evidente e importante después de un aporte de sodio por vía oral. Resulta posible establecer un rol fisiopatológico en la hipertensión arterial por incremento de la actividad plasmática del FDE. Another factor is the endogenous digitalis (FDE), it is a hormonal factor, described several years ago, that inhibits the Na-K-Mg-ATPase pump, with intense vasoconstrictor activity, of natriuretic action. Its natriuretic effect is expressed clearly and importantly after a sodium intake by mouth. It is possible to establish a pathophysiological role in the arterial hypertension due to an increase in plasma FDE activity.
Un factor más son las hormonas gastrointestinales del sistema, muchas de estas hormonas, secretadas por diversas células especializadas del aparato digestivo, poseen una intensa acción vascular. Por ejemplo, el péptido intestinal vasoactivo (VIP) es intensamente vasodilatador, la coherina es vasoconstrictora, la colecistokinina (CCK) es vasodilatadora, la sustancia P también vasodilatadora, lo mismo la bombesina, las endorfinas y los eicosanoides (Wagner P. , 2010) .  One more factor is the gastrointestinal hormones of the system, many of these hormones, secreted by various specialized cells of the digestive system, have an intense vascular action. For example, the vasoactive intestinal peptide (VIP) is intensely vasodilator, coherin is vasoconstrictor, cholecystokinin (CCK) is vasodilator, substance P is also vasodilator, like bombesin, endorphins and eicosanoids (Wagner P., 2010) .
Para el tratamiento de la hipertensión arterial se utilizan varios tipos de fármacos entre los que se encuentran: los inhibidores enzima convertidora de angiotesina (IECA) que inhiben la enzima que convierte la angiotesina I en angiotesina II, con el consecuente efecto vasodilatador (hipotensor) ; los antagonistas del receptor de la angiotesina II (ARA II) estos bloquean los receptores AT1 de la angiotesina II, de esta manera interfieren en el sistema renina-angiotesina-aldosterona, con el consecuente efecto vasodilatador, y a diferencia de los IECA, por su mecanismo de acción no aumentan los niveles de bradicinina; los calcioantagonistas o bloqueadores de canales de calcio, estos son potentes antihipertensivos y actúan a nivel de los canales de calcio en músculo liso vascular y músculo cardiaco, los de acción prolongada, son los que tienen probada utilidad y previenen eventos cardiovasculares en pacientes hipertensos, en cambio los de acción corta pueden aumentar la probabilidad de eventos coronarios y mortalidad por lo que no deben ser usados como antihipertensivos; los diuréticos sobre todo los tiazidicos en dosis bajas y especialmente en personas mayores de 55 años; los beta- bloqueadores que muestran ser efectivos en la prevención de eventos coronarios, insuficiencia cardiaca y tienen mayor eficiencia en comparación con otros fármacos en pacientes con un evento coronario reciente aunque provocan aumento de peso e incrementan la incidencia de diabetes. Otros agentes son los antialdosterónicos, los alfa-2 agonistas, los bloqueadores alfa-1 y los inhibidores de la renina (Minsal, 2010) . Several types of drugs are used to treat arterial hypertension, including: angiotesin-converting enzyme (ACEI) inhibitors that inhibit the enzyme that converts angiotesin I to angiotesin II, with the consequent vasodilator (hypotensive) effect; Angiotesin II receptor antagonists (ARA II) these block the AT1 receptors of angiotesin II, thus interfering with the renin-angiotesin-aldosterone system, with the consequent vasodilator effect, and unlike ACEIs, by their mechanism action levels do not increase bradykinin levels; Calcium antagonists or calcium channel blockers, these are potent antihypertensives and act at the level of the Calcium in vascular smooth muscle and cardiac muscle, those of prolonged action, are those that have proven usefulness and prevent cardiovascular events in hypertensive patients, however those of short action can increase the probability of coronary events and mortality so they should not be used as antihypertensives; diuretics especially thiazides in low doses and especially in people over 55 years; beta-blockers that are shown to be effective in preventing coronary events, heart failure and are more efficient compared to other drugs in patients with a recent coronary event although they cause weight gain and increase the incidence of diabetes. Other agents are antialdosteronics, alpha-2 agonists, alpha-1 blockers and renin inhibitors (Minsal, 2010).
Entre los principales fármacos antangonistas de los receptores de la angiotesina II se encuentran: valsartán, telmisartán, losartán, irbesartán, olmesartán, candesartán · y eprosartán, entre otros.  Among the main antagonistic drugs of angiotesin II receptors are: valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan · and eprosartan, among others.
El losartán es el fármaco más antiguo y mejor evaluado de este grupo, siendo el único agente de este tipo aprobado para el tratamiento de la insuficiencia cardiaca. Ha demostrado ser un antihipertensivo efectivo por via oral, con actividad uricosúrica adicional, posee un metabolito activo del orden de 10-40 veces más potente que el losartán, por esta razón en pacientes con hepatopatia crónica puede perder eficacia al dificultarse su metabolismo y disminuir la generación de su metabolito activo. Algunas de sus características es que alcanza su concentración máxima en plasma en 1 hora y su metabolito activo en alrededor de 3 a 4 horas, tiene una biodisponibilidad absoluta de 33%, con una vida media de eliminación de 2.6 a 9 horas, se une a proteínas en un porcentaje de 98.7% (Cadime, 2000). Losartan is the oldest and best evaluated drug in this group, being the only agent of this type approved for the treatment of heart failure. It has proven to be an effective antihypertensive orally, with additional uricosuric activity, has an active metabolite of the order of 10-40 times more potent than losartan, for this reason in patients with chronic hepatopathy may lose effectiveness by hindering their metabolism and decreasing the generation of their active metabolite. Some of its characteristics is that it reaches its maximum plasma concentration in 1 hour and its active metabolite in about 3 to 4 hours, it has an absolute bioavailability of 33%, with a elimination half-life of 2.6 to 9 hours, it joins proteins in a percentage of 98.7% (Cadime, 2000).
El Losartan, al sufrir el metabolismo sustancial del primer paso por las enzimas del citocromo P-450, se metaboliza a un metabolito activo el cual es el. ácido 5- carboxílíco, dicho metabolito es el responsable de la mayoría de los efectos del Losartán en el receptor de angiotensina (Rodríguez C, 2002) .  Losartan, when suffering the substantial metabolism of the first step by the cytochrome P-450 enzymes, is metabolized to an active metabolite which is the. 5-carboxylic acid, said metabolite is responsible for most of the effects of Losartan on the angiotensin receptor (Rodríguez C, 2002).
Por otro lado, entre los principales fármacos calcio- antagonistas o bloqueadores de canales de calcio se encuentran: nifedipino, amlodipino, felodipina, verapamilo, diltiazem, nitrendipino, nicardipino, isradipino y nisoldipino, entre otros.  On the other hand, among the main calcium-antagonist drugs or calcium channel blockers are: nifedipine, amlodipine, felodipine, verapamil, diltiazem, nitrendipine, nicardipine, isradipine and nisoldipine, among others.
La felodipina es un antagonista de los canales de calcio del grupo de las dihidropiridinas, el cual presenta una biodisponibilidad oral del 15%, como consecuencia de un intenso metabolismo de primer paso. Tiene un volumen de distribución de 10 L/kg y se une a las proteínas plasmáticas en una proporción superior al 99%. Prácticamente el 100% de la dosis es metabolizada en el hígado, formando metabolitos inactivos que son eliminados mayoritariamente con la orina. Felodipine is an antagonist of the calcium channels of the dihydropyridine group, which has an oral bioavailability of 15%, as a result of intense first-pass metabolism. It has a volume of distribution of 10 L / kg and binds to plasma proteins in a proportion greater than 99%. Almost 100% of the dose is metabolized in the liver, forming inactive metabolites that are mostly eliminated in the urine.
En el estado de la técnica se encontraron documentos que describen el uso de un antagonista de los receptores de la angiotesina II en un sistema de liberación inmediata en combinación con un bloqueador de los canales de calcio en un sistema de liberación cronoterapuetico para el uso en el tratamiento de hipertensión arterial (MX/a/2009/003489, US 20110281823 y US 20100003332).  Documents describing the use of an angiotesin II receptor antagonist in an immediate release system in combination with a calcium channel blocker in a chronotherapeutic release system for use in the art were found in the prior art. treatment of arterial hypertension (MX / a / 2009/003489, US 20110281823 and US 20100003332).
Los sistemas de liberación comúnmente utilizados en el estado de la técnica para estos fármacos actual son la liberación inmediata, la liberación controlada y la liberación sostenida, estos últimos dos, están diseñados principalmente para prolongar el efecto terapéutico o bien, disminuir los picos de concentración característicos de los sistemas convencionales. Estos sistemas se llevan utilizando varias décadas, aunque siguen apareciendo novedades diseñadas para facilitar la posología o aportar un mejor perfil farmacocinético. OBJETO DE LA INVENCIÓN The release systems commonly used in the state of the art for these current drugs are immediate release, controlled release and sustained release, the latter two, are designed primarily to prolong the therapeutic effect or decrease characteristic concentration peaks. of conventional systems. These systems have been used for several decades, although innovations designed to facilitate dosage or provide a better pharmacokinetic profile continue to appear. OBJECT OF THE INVENTION
La presente invención se refiere a una composición farmacéutica en forma de tableta-tableta de dos o más fases que comprende una primer tableta con un sistema de liberación que presenta una cinética de orden cero y/o de orden uno sin tiempo de retardo que de al menos un agente bloqueador de los canales de calcio; y, una segunda tableta con un sistema de liberación que presenta una cinética de orden cero de al menos un agente antagonista de los receptores de la angiotesina II. Dicha composición es útil para el tratamiento de hipertensión arterial, insuficiencia cardiaca congestiva, angina de pecho inestable, infarto agudo del miocardio, nefropatia diabética o desórdenes asociados. The present invention relates to a pharmaceutical composition in the form of a tablet or tablet of two or more phases comprising a first tablet with a release system having a kinetic of zero order and / or of order one without delay time than at less a calcium channel blocking agent; and, a second tablet with a release system that exhibits a zero order kinetics of at least one angiotesin II receptor antagonist agent. Said composition is useful for the treatment of arterial hypertension, congestive heart failure, unstable angina pectoris, acute myocardial infarction, diabetic nephropathy or associated disorders.
BREVE DESCRIPCIÓN DE LAS FIGURAS BRIEF DESCRIPTION OF THE FIGURES
FIGURA 1. Perfil de disolución de tabletas de Losartán/Felodipino de 25mg/5mg VS tabletas de Felodipino de 5mg. FIGURE 1. Dissolution profile of 25mg / 5mg Losartan / Felodipine tablets VS 5mg Felodipine tablets.
FIGURA 2. Perfil de disolución de tabletas de FIGURE 2. Dissolution profile of tablets
Losartán/Felodipino de 25mg/5mg VS 2 tabletas de Felodipino de 5mg. DESCRIPCIÓN DETALLADA DE LA INVENCIÓN Losartan / Felodipine 25mg / 5mg VS 2 tablets Felodipine 5mg. DETAILED DESCRIPTION OF THE INVENTION
La presente invención se refiere a una novedosa composición farmacéutica en forma de tableta-tableta de dos fases la cual comprende: a) al menos una tableta interna que presenta una cinética de orden cero que contiene al menos un bloqueador de los canales de calcio, sus sales farmacéuticamente aceptables, derivados, metabolitos, profármacos, polimorfos, amorfos o combinaciones de los mismos y/o uno o más excipientes farmacéuticamente aceptables; b) al menos una tableta externa con un sistema de liberación que presenta una cinética de orden cero y/o de orden uno sin tiempo de retardo que que contiene al menos un antagonista de los receptores de la angiotesina II, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos y/o uno o más excipientes farmacéuticamente aceptables; y de manera opcional c) uno o más excipientes farmacéuticamente aceptables, todos ellos en un sistema de administración oral. The present invention relates to a novel pharmaceutical composition in the form of a two-phase tablet-tablet which comprises: a) at least one internal tablet having a zero order kinetics containing at least one calcium channel blocker, its pharmaceutically acceptable salts, derivatives, metabolites, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; b) at least one external tablet with a release system that exhibits zero order and / or order one kinetics without delay time which contains at least one angiotesin II receptor antagonist, its pharmaceutically acceptable salts, derivatives , prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; and optionally c) one or more pharmaceutically acceptable excipients, all of them in an oral administration system.
La tableta interna con un sistema de liberación que presenta una cinética de orden cero que contiene al menos un bloqueador de los canales de calcio se desarrolló de esta forma en la novedosa composición objeto de esta invención, teniendo en cuenta que su utilidad para prevenir eventos cardiovasculares en pacientes hipertensos está probada cuando están en un sistema de acción prolongada en comparación con los de acción corta que aumentan la probabilidad de eventos coronarios y mortalidad por lo cual no son utilizados como hipertensivos . The internal tablet with a release system that has zero order kinetics containing at least one calcium channel blocker was developed in this way in the novel composition object of this invention, taking into account that its usefulness to prevent cardiovascular events in hypertensive patients is proven when they are in a long-acting system compared to those of short-acting that increase the probability of coronary events and mortality and therefore are not used as hypertensive.
Por otra lado, la tableta externa con un sistema de liberación que presenta una cinética de orden cero y/o de orden uno sin tiempo de retardo que, de manera preferentemente de orden uno, fue desarrollada de esta forma con la finalidad de realizar al menos una entrega de al menos un agente antagonista de los receptores de la angiotesina II y de esta manera, obtener un mejor efecto sinérgico con el agente bloqueador de los canales de calcio. Disminuyendo la resistencia vascular periférica, la presión sanguínea y la postcarga. On the other hand, the external tablet with a release system that presents a kinetic of zero order and / or of order one without delay time which, preferably of order one, was developed in this way in order to perform at least a delivery of at least one angiotesin II receptor antagonist agent and thus obtain a better synergistic effect with the calcium channel blocking agent. Decreasing peripheral vascular resistance, blood pressure and afterload.
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Para efectos de la presente invención, se selecciona al menos un agente bloqueador de los canales de calcio del siguiente grupo: nifedipino, amlodipino, felodipino, verapamilo, diltiazem, nitrendipino, nicardipino, isradipino, nisoldipino, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos, mismo que se encuentra contenido en la tableta interna dentro de la composición. En cuanto al ingrediente activo contenido en al menos una tableta externa de la composición, se selecciona al menos un agente antagonista de los receptores de la angiotesina II del grupo que consiste en valsartán, telmisartán, losartán, irbesartán, olmesartán, candesartán, eprosartán , sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos. For purposes of the present invention, at least one calcium channel blocking agent is selected from the following group: nifedipine, amlodipine, felodipine, verapamil, diltiazem, nitrendipine, nicardipine, isradipine, nisoldipine, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, same that is contained in the internal tablet within the composition. As for the active ingredient contained in at least one external tablet of the composition, at least one angiotesin II receptor antagonist agent is selected from the group consisting of valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan, eprosartan, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof.
En la composición descrita en la presente invención se utiliza de manera preferente, más no limitativa, como bloqueador de los cana'les de calcio al felodipino, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos, en un rango de concentración entre 1 mg y 10 mg, más preferentemente en un rango de 3 mg a 7 mg.  In the composition described in the present invention, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, are preferably used, but not limited to, a blocker of calcium channels to felodipine. concentration range between 1 mg and 10 mg, more preferably in a range of 3 mg to 7 mg.
El agente antagonista de los receptores de la angiotesina II que se utiliza de manera preferente, más no limitativa, es el losartán, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos, en un rango de concentración entre 5 mg y 60 mg y más preferentemente de 17 a 35 mg.  The angiotesin II receptor antagonist agent that is preferably used, but not limited to, is losartan, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, in a concentration range between 5 mg and 60 mg and more preferably from 17 to 35 mg.
La tableta interna de la composición, además de contener al menos un agente bloqueador de los canales de calcio puede contener uno o más excipientes, De manera general, la tableta interna y la tableta externa de la composición puede contener al menos un excipiente farmacéuticamente aceptable, el cual se selecciona de; ácido alginico, crospovidona, resinas de intercambio iónico, silicato de aluminio, silicato de magnesio, celulosa microcristalina, almidón, almidón glicolato sódico, goma de celulosa modificada, PVP, dodecil sulfato de sodio almidón de maíz, almidón de arroz, la N-vinil-2- pirrolidona entrecruzada, sodio croscarmeloso, formaldehído-caseina, sorbitol, almidón, almidón pregentalizado, almidón de maiz, sucrosa, azúcar, azúcar compresible, isomaltosa, tragacanto, talco, trehalosa, xilitol, acacia, agar, .acido alginico, carbonato de calcio, lactato de calcio, carbomero, carboximetilcelulosa cálcica, celulosa mic¾ocristalina, celulosa, ceratonia, quitosán, copovidona, dextratos, dextrina, dextrosa, etilcelulosa, gelatina, behenato de glicerio, goma guar, hidroxietil celulosa, hidroximetil celulosa, hidroxipropil celulosa baja-sustitución, hidroxipropil de almidón, hipromelosa, inulina, lactosa monohidratada, silicato de aluminio y magnesio, maltodextrina, metilcelulosa, policarbofil, polidextrosa, oxido de polietileno, polimetacrilatos, povidona, alginato de sodio, almidón, almidón pregelatinizado, sucrosa, polietilenglicol succinato, zein, estearato de calcio, behenato de glicerilo, monoestearato de glicerilo, palmitostearato de glicerilo, ácido laurico, leucina, estearato de magnesio, maltodextrina, aceite mineral, aceite mineral ligero, ácido miristico, ácido palmitico, polietilenglicol, alcohol polivinilico, benzoato de potasio, cloruro de sodio, hialuronato de sodio, lauril sulfato de sodio, estearil fumarato de sodio, ácido esteárico, talco, aceite vegetal hidrogenado, estearato de zinc, ácido adipico, ácido bórico, carbonato de calcio, lactato de calcio, meglumina, fosfato de calcio, ácido citico monohidratado, glicina, ácido maleico, metionina, glutamato monosódico, citrato de potasio, acetato de sodio, borato de sodio, carbonato de sodio, citrato de sodio dihidratado, hidróxido de sodio, fosfato de sodio dibásico, fosfato de sodio monobásico, citrato de potasio, citrato de sodio, hidróxido de sodio, hidróxido de potasio, bicarbonato de sodio, carbonato de sodio, bicarbonato de calcio, carbonato de calcio, bicarbonato de potasio, hidrogenofosfato de disodio, fosfato trisódico, arginina, talco, citrato de acetiltributil, citrato de acetriltrietil, carbonato de calcio, carboximetilcelulosa cálcica, carboximetilcelulosa sódica, acetato de celulosa, acetato ftalato de celulosa, ceresina, alcohol cetilico, quitosan, dietil ftalato, dimetil ftalato, etilcelulosa, gelatina, glucosa líquida, glicerina behenato de glicerilo, palmitostearato de glicerilo ,hidroxietil celulosa, hidroximetil celulosa, hidroxipropil celulosa, hipromelosa, acetato succinato de hipromelosa, hipromelosa ftalato, isomaltosa, maltitol, maltodextrina, metilcelulosa, parafina, poloxamero, polidextrosa, poli LD-ácido láctico, óxido de polietileno, polimetacrilatos, poli (metil vinil éter/anhidrido maleico) acetato, ftalato polivinil propilen glicol, shelac, cloruro de sodio, ácido esteárico, sucrosa, dióxido de titanio, triacetin citrato de tributil, citrato de trietil trioleina, cera de carnauba, cera microcristalina, cera blanca, cera amarilla, xilitol, zein, o combinaciones de los mismos . The internal tablet of the composition, in addition to containing at least one calcium channel blocking agent, may contain one or more excipients. In general, the internal tablet and the external tablet of the The composition may contain at least one pharmaceutically acceptable excipient, which is selected from; alginic acid, crospovidone, ion exchange resins, aluminum silicate, magnesium silicate, microcrystalline cellulose, starch, sodium starch glycol, modified cellulose gum, PVP, sodium dodecyl sulfate corn starch, rice starch, N-vinyl -2- crosslinked pyrrolidone, croscarmellose sodium, formaldehyde-casein, sorbitol, starch, pregentalized starch, corn starch, sucrose, sugar, compressible sugar, isomalt, tragacanth, talcum, trehalose, xylitol, acacia, agar, algic acid, carbonate of calcium, calcium lactate, carbomer, calcium carboxymethylcellulose, myocrystalline cellulose, cellulose, ceratonia, chitosan, copovidone, dextrates, dextrin, dextrose, ethyl cellulose, gelatin, glycerium behenate, guar gum, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxymethyl cellulose substitution, hydroxypropyl starch, hypromellose, inulin, lactose monohydrate, aluminum magnesium silicate, maltodextrin, methylcellulose, p olicarbophil, polydextrose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, starch, pregelatinized starch, sucrose, polyethylene glycol succinate, zein, calcium stearate, glyceryl behenate, glyceryl monostearate, palmitostearate glyceryl, lauric acid, leucine, magnesium stearate, maltodextrin, mineral oil, light mineral oil, myristic acid, palmitic acid, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium chloride, sodium hyaluronate, sodium lauryl sulfate, stearyl fumarate sodium, stearic acid, talc, hydrogenated vegetable oil, zinc stearate, adipic acid, boric acid, calcium carbonate, calcium lactate, meglumine, calcium phosphate, citric acid monohydrate, glycine, maleic acid, methionine, monosodium glutamate, potassium citrate, sodium acetate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate, potassium citrate, sodium citrate, sodium hydroxide, potassium hydroxide , sodium bicarbonate, sodium carbonate, calcium bicarbonate, calcium carbonate, potassium bicarbonate, disodium hydrogen phosphate, trisodium phosphate, arginine, talc, acetyltributyl citrate, acetryltriethyl citrate, calcium carbonate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ceresin, cetyl alcohol, chitosan, diethyl phthalate, dimethyl phthalate, ethylcellulose, gelatin, liquid glucose glyceryl behenate, glyceryl palmitostearate, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, hypromellose phthalate, isomalt, maltitol, maltodextrin, methylcellulose, paraffin, polyethylene, polydextrose, poly LD-lactic acid, polyethylene oxide, polymethyl methacrylate maleic anhydride) acetate, polyvinyl phthalate propylene glycol, shelac, sodium chloride, stearic acid, sucrose, titanium dioxide, triacetin tributyl citrate, triethyl triolein citrate, carnauba wax, microcrystalline wax, white wax, yellow wax, xylitol, zein, or combinations thereof.
De manera preferente, la tableta interna de la composición, además de contener al menos un agente bloqueador de los canales de calcio está conformado por uno o más monosacáridos, uno o más óxidos de polietileno, uno o más derivados de celulosa, una o más sales de silice y uno o más agentes lubricantes; y la tableta externa de la composición, además de contener al menos un agente antagonista de los receptores de la angiotesina II está conformado por uno o más polímeros de celulosa, uno o más sales de silice, uno «o más monosacáridos y uno o más agentes lubricantes.  Preferably, the internal tablet of the composition, in addition to containing at least one calcium channel blocking agent, is formed by one or more monosaccharides, one or more polyethylene oxides, one or more cellulose derivatives, one or more salts of silica and one or more lubricating agents; and the external tablet of the composition, in addition to containing at least one angiotesin II receptor antagonist agent, is made up of one or more cellulose polymers, one or more silica salts, one or more monosaccharides and one or more agents. lubricants
En donde los monosacáridos pueden ser fructosa, lactosa, manitol, xilol, sorbitol, lactosa anhidra y/o lactosa monohidratada y/o combinaciones de los mismos; los óxidos de polietileno pueden ser seleccionados de polyox N-10, polyox N-80, polyox N12-k, polyox N60-k y/o polyox N-301 o combinaciones de los mismos; los derivados de celulosa pueden ser celulosa microcristalina, carboximetilcelulosa de sodio, celulosa microcristalina silicificada, celulosa, hidroxipropilmetilcelulosa, celulosa microcristalina cálcica, hidroxietilcelulosa, celulosa microcristalina, celulosa microcristalina cálcica, hidroxipropilcelulosa y/o combinaciones de los mismos; la sal de silicio puede ser oxido de silicio, silicato de calcio, silicato aluminico magnésico, silicado de aluminio, silicato de magnesio, dióxido de silicio coloidal, metasilicato de aluminio y magnesio, celulosa microcristalina silificada, trisilicato de magnesio, dióxido de silicio y/o dióxido de silicio coloidal o combinaciones de los mismos; y/o el agente lubricante puede ser estearato de calcio, behenato de glicerilo, monoestearato de glicerilo, palmitostearato de glicerilo, ácido laurico, leucina, estearato de magnesio, maltodextrina, aceite mineral, aceite mineral ligero, ácido miristico, ácido palmitico, polietilenglicol, alcohol polivinilico, benzoato de potasio, cloruro de sodio, hialuronato de sodio, lauril sulfato de sodio, estearil fumarato de sodio, ácido esteárico, talco, aceite vegetal hidrogenado, estearato de zinc y/o combinaciones de los mismos. Where the monosaccharides can be fructose, lactose, mannitol, xylol, sorbitol, anhydrous lactose and / or lactose monohydrate and / or combinations thereof; the polyethylene oxides may be selected from polyox N-10, polyox N-80, polyox N12-k, polyox N60-k and / or polyox N-301 or combinations thereof; Cellulose derivatives may be microcrystalline cellulose, sodium carboxymethylcellulose, silicified microcrystalline cellulose, cellulose, hydroxypropylmethyl cellulose, calcium microcrystalline cellulose, hydroxyethyl cellulose, microcrystalline cellulose, calcium microcrystalline cellulose, hydroxypropyl cellulose and / or combinations thereof; The silicon salt can be silicon oxide, calcium silicate, magnesium aluminum silicate, aluminum silicate, magnesium silicate, colloidal silicon dioxide, magnesium aluminum metasilicate, siliconized microcrystalline cellulose, magnesium trisilicate, silicon dioxide and / or colloidal silicon dioxide or combinations thereof; and / or the lubricating agent may be calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, lauric acid, leucine, magnesium stearate, maltodextrin, mineral oil, light mineral oil, myristic acid, palmitic acid, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium chloride, sodium hyaluronate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, oil hydrogenated vegetable, zinc stearate and / or combinations thereof.
Para evaluar la eficacia de este sistema tableta- tableta de dos fases se plantearon dos hipótesis a seguir en el desarrollo de la presente invención las cuales fueron:  To evaluate the effectiveness of this two-phase tablet-tablet system, two hypotheses were proposed to follow in the development of the present invention which were:
Primera: la farmacocinética de los principios activos losartán (A) y felodipino (B) administrados de manera independiente en dosis única administrada por vía oral es igual a la farmacocinética de los mismos principios activos co-administrados (C) en su forma farmacéutica.  First: the pharmacokinetics of the active ingredients losartan (A) and felodipine (B) administered independently in a single dose administered orally is the same as the pharmacokinetics of the same co-administered active ingredients (C) in their pharmaceutical form.
Segunda: la farmacocinética de los principios activos losartán (A) y felodipino (B) administrados de manera independiente en dosis única administrada por vía oral es diferente a la farmacocinética de los mismos principios activos co-administrados (C) en su forma farmacéutica.  Second: the pharmacokinetics of the active ingredients losartan (A) and felodipine (B) administered independently in a single dose administered orally is different from the pharmacokinetics of the same co-administered active ingredients (C) in their pharmaceutical form.
El diseño del estudio fue desarrollado con 12 voluntarios sanos, de «sexos ambos, de 18 a 55 años de edad, mediante modelo cruzado, aleatorio, prospectivo, simple ciego, longitudinal, unicéntrico, de dosis única, en condiciones de ayuno, tres sesiones, seis secuencias (A-B-C, A-C-B, B-A-C, B-C-A, C-A-B, C-B-A) , siete días de lavado entre cada sesión de estudio, para determinar los parámetros farmacocinéticos y la biodisponibilidad en dosis fija de losartán, felodipino y losartán-felodipino. Los grupos fueron balanceados con igual número de voluntarios por cada secuencia. El estudio fue corrido en oscuridad, debido a la fotosensibilidad del felodipino; el medicamento fue administrado con 250 mL de solución electrolítica en ayuno de 10 horas; y los voluntarios permanecieron en cama durante 4 horas o hasta que se pudieran reincorporar al resto del grupo, siempre y cuando sus signos vitales fueran normales. The study design was developed with 12 healthy volunteers, "longitudinal sexes both, 18 to 55 years of age by cross pattern, randomized, prospective, single - blind, single - center, single - dose under fasting conditions, three sessions , six sequences (ABC, ACB, BAC, BCA, CAB, CBA), seven days of washing between each study session, to determine the pharmacokinetic parameters and bioavailability in fixed doses of losartan, felodipine and losartan-felodipine. The groups were balanced with the same number of volunteers for each sequence. The study was run in darkness, due to the photosensitivity of the felodipine; The medication was administered with 250 mL of 10-hour fasting electrolyte solution; and the volunteers remained in bed for 4 hours or until they could return to the rest of the group, as long as their vital signs were normal.
Los resultados obtenidos para los parámetros farmacocinéticos del losartán en cada uno de los voluntarios para el estudio se muestran a continuación: The results obtained for the pharmacokinetic parameters of losartan in each of the volunteers for the study are shown below:
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Tabla 1. Valores de los parámetros farmacocinéticos de losartán obtenidos para cada uno de los voluntarios que participaron en el estudió.  Table 1. Values of losartan pharmacokinetic parameters obtained for each of the volunteers who participated in the study.
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000021_0001
Figure imgf000022_0001
Los valores correspondientes a losartán para los parámetros farmacocinéticos, fueron obtenidos utilizando el software WinNonLin® a partir de los valores individuales de los 12 voluntarios después de administrar la dosis fija de 25 mg de losartán a partir del medicamento de referencia (A) y el medicamento tableta- tableta (C) conteniendo la dosis combinada de 25 mg de losartán y 5 mg de felodipino: estos valores se muestran en la tabla 2 incluyendo la prueba de t-student para la comparación de medias, sin suponer varianzas iguales por considerar diferentes formulaciones con un valor de alfa de 0.05 para el rechazo de la hipótesis nula de igualdad, así como el valor de la biodisponibilidad obtenida a partir de la relación entre la formulación tableta-tableta (C) con respecto a la formulación del medicamento de referencia (A) .  The values corresponding to losartan for the pharmacokinetic parameters were obtained using the WinNonLin® software from the individual values of the 12 volunteers after administering the fixed dose of 25 mg losartan from the reference medicine (A) and the medicine tablet-tablet (C) containing the combined dose of 25 mg losartan and 5 mg felodipine: these values are shown in table 2 including the t-student test for the comparison of means, without assuming equal variances for considering different formulations with an alpha value of 0.05 for the rejection of the null hypothesis of equality, as well as the bioavailability value obtained from the relationship between the tablet-tablet formulation (C) with respect to the formulation of the reference medicine (A ).
Tabla 2. Parámetros farmacocinéticos promedio obtenidos para el losartán con el medicamento de referencia (A) y el medicamento tableta-tableta (C) a partir de los 12 voluntarios que participaron en el estudio. Table 2. Average pharmacokinetic parameters obtained for losartan with the reference medicine (A) and the tablet-tablet medicine (C) a from the 12 volunteers who participated in the study.
Figure imgf000023_0001
Figure imgf000023_0001
Los valores individuales para los parámetros farmacocinéticos del metabolito de losartán EXP3174 correspondientes a la concentración plasmática máxima (Cmax) ; tiempo en que se alcanza el Cmax (Tmax) ; el área bajo la curva del perfil Cp vs t de cero al último tiempo de muestreo (ABCo-t) ; el área bajo la curva del perfil vs t de cero a infinito (ABCo-inf) ; constante de velocidad de la última porción lineal del perfil Cp vs (λζ) ; tiempo de vida media (ti/2) , tiempo medio de residencia de cero al último tiempo de muestreo (TMRo-t) y tiempo medio de residencia de cero a infinito (TMRo-inf) correspondientes de los 12 voluntarios que participaron en el estudio se muestran en la tabla 3; para su obtención se utilizó el software WinNonLin®. Individual values for the pharmacokinetic parameters of the losartan metabolite EXP3174 corresponding to the maximum plasma concentration (Cmax); time in which the Cmax (Tmax) is reached; the area under the curve of the Cp vs t profile from zero to the last sampling time (ABCo-t); the area under the profile curve vs t from zero to infinity (ABCo-inf); velocity constant of the last linear portion of the profile Cp vs (λζ); average life time (ti / 2), average residence time from zero to the last sampling time (TMRo-t) and corresponding average residence time from zero to infinity (TMRo-inf) of the 12 volunteers who participated in the study be show in table 3; WinNonLin® software was used to obtain it.
Tabla 3. Valores de los parámetros farmacocinéticos del metabolito de losartán EXP3174 obtenidos para cada uno de los voluntarios que participaron en el estudio.  Table 3. Values of the pharmacokinetic parameters of the losartan metabolite EXP3174 obtained for each of the volunteers who participated in the study.
Figure imgf000024_0001
Figure imgf000024_0001
Los valores promedio correspondientes al metabolito de losartán EXP3174 para los parámetros farmacocinéticos, fueron obtenidos utilizando el software WinNonLin® a partir de los valores individuales de los 12 voluntarios después de administrar la dosis fija de 25 mg de losartán a partir del medicamento de referencia (A) y el medicamento tableta-tableta (C) conteniendo la dosis combinada de 25 mg de losartán y 5 mg de felodipino: estos se muestran en la tabla 4 incluyendo la prueba t de Students para la comparación de medias sin suponer varianzas iguales por considerar diferentes formulaciones con un valor de alfa de 0-05 para el rechazo de la hipótesis nula de igualdad asi como el valor de la biodisponibilidad a partir de la relación entre la formulación tableta-tableta (C) con respecto a la formulación del medicamento de referencia (A) . The average values corresponding to the losartan metabolite EXP3174 for the pharmacokinetic parameters were obtained using WinNonLin® software from the individual values of the 12 volunteers after administering the fixed dose of 25 mg losartan from the reference medicine (A) and the tablet-tablet medicine (C) containing the combined dose of 25 mg losartan and 5 mg felodipine: these are shown in the table 4 including the Student t test for the comparison of means without assuming equal variances for considering different formulations with an alpha value of 0-05 for the rejection of the null hypothesis of equality as well as the value of bioavailability from the relationship between the tablet-tablet formulation (C) with respect to the formulation of the reference medicine (A).
Tabla 4. Parámetros farmacocinéticos obtenidos para el metabolito de losartán EXP3174 con el medicamento de referencia (A) y el ' medicamento tableta-tableta (C) obtenido de los 12 voluntarios que participaron en el estudio.  Table 4. Pharmacokinetic parameters obtained for the losartan metabolite EXP3174 with the reference medicine (A) and the 'tablet-tablet medicine (C) obtained from the 12 volunteers who participated in the study.
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000025_0001
Figure imgf000026_0001
Los valores individuales para los parámetros farmacocinéticos felodipino correspondientes a la concentración plasmática máxima (Cmax) ; tiempo en que se alcanza el Cmax (Tmax) ; el área bajo la curva del perfil Cp vs t de cero al último tiempo de muestreo (ABCo-t) el área bajo la curva del perfil Cp vs t (λζ); tiempo de vida media (ti/2) , tiempo medio de residencia de cero al último de muestreo (TMRo-t) y tiempo medio de residencia de cero a infinito (TMRo-inf) correspondientes a los 12 voluntarios que participaron en el estudio se muestran en la tabla 5; para su obtención se utilizó el software WinNonLin®.  Individual values for felodipine pharmacokinetic parameters corresponding to the maximum plasma concentration (Cmax); time in which the Cmax (Tmax) is reached; the area under the curve of the profile Cp vs t from zero to the last sampling time (ABCo-t) the area under the curve of the profile Cp vs t (λζ); half-life (ti / 2), average residence time from zero to last sampling (TMRo-t) and average residence time from zero to infinity (TMRo-inf) corresponding to the 12 volunteers who participated in the study were shown in table 5; WinNonLin® software was used to obtain it.
De acuerdo con los resultados del tiempo medio de residencia de cero al último tiempo de muestreo (TMRO-t) y tiempo medio de residencia de cero a infinito (T RO-inf) en los voluntarios, se pbtuvo que, de manera sorprendente, la composición desarrollada presenta un sistema de liberación "in vivo" tal que permite que las moléculas intactas transiten a través del cuerpo por un tiempo no menor a 2.5 horas para Losartán y no menor a 8.5 horas para el metabolito de losartán EXP3174. Tabla 5. Valores de los parámetros farmacocinéticos de felodipino obtenidos para cada uno de los voluntarios que participaron en el estudio. According to the results of the average residence time from zero to the last sampling time (TMRO-t) and average residence time from zero to infinity (T RO-inf) in the volunteers, it was found that, surprisingly, the The developed composition has an "in vivo" release system that allows intact molecules to pass through the body for a time not less than 2.5 hours for Losartan and not less than 8.5 hours for the metabolite of losartan EXP3174. Table 5. Values of felodipine pharmacokinetic parameters obtained for each of the volunteers who participated in the study.
Figure imgf000027_0001
Los valores promedio correspondientes al felodipino para los parámetros farmacocinéticos, fueron obtenidos utilizando el software WinNonLin® a partir de los valores individuales de los 12 voluntarios después de administrar la dosis fija de 5 mg de felodipino a partir del medicamento de referencia (B) y el medicamento tableta- tableta (C) conteniendo la dosis combinada de 25 mg de losartán y 5 mg de felodipino: estos se muestran en la tabla 6 incluyendo la prueba t-student para la comparación de medias sin suponer varianzas iguales, por considerar diferentes formulaciones cort un valor de alfa de 0.05 para el rechazo de la hipótesis nula de igualdad, asi como el valor de la biodisponibilidad obtenida a partir de la relación entre la formulación tableta-tableta (C) con respecto a la formulación (B) .
Figure imgf000027_0001
The average values corresponding to felodipine for the pharmacokinetic parameters were obtained using WinNonLin® software from the individual values of the 12 volunteers after administering the fixed dose of 5 mg of felodipine from the reference medicine (B) and the tablet-tablet medicine (C) containing the combined dose of 25 mg losartan and 5 mg felodipine: these are shown in table 6 including the t-student test for the comparison of means without assuming equal variances, considering different short formulations an alpha value of 0.05 for the rejection of the null hypothesis of equality, as well as the bioavailability value obtained from the relationship between the tablet-tablet formulation (C) with respect to the formulation (B).
Tabla 6. Parámetros farmacocinéticos promedio obtenidos para el felodipino con el medicamento de referencia (B) y el medicamento tableta-tableta obtenido de los 12 voluntarios que participaron en el estudio.  Table 6. Average pharmacokinetic parameters obtained for felodipine with the reference medicine (B) and the tablet-tablet medicine obtained from the 12 volunteers who participated in the study.
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000028_0001
Figure imgf000029_0001
De acuerdo a los resultados del tiempo medio de residencia de cero al último tiempo de muestreo (TMR0-t) y tiempo medio de residencia de cero a infinito (TMRO-inf) en los voluntarios, se obtuvo que, de manera sorprendente, la composición desarrollada presenta un sistema de liberación "in vivo" tal que permite que las moléculas intactas transiten a través del cuerpo por un tiempo no menor a 12 horas para Felodipino.  According to the results of the average residence time from zero to the last sampling time (TMR0-t) and average residence time from zero to infinity (TMRO-inf) in the volunteers, it was obtained that, surprisingly, the composition Developed presents an "in vivo" release system that allows intact molecules to pass through the body for a time not less than 12 hours for Felodipine.
La variabilidad intraindividual e interindividual fue determinada a partir de los datos de Cp vs t para los parámetros farmacocinéticos que reflejan la exposición sistémica al organismo de cada uno de los fármacos presentes en cada formulación: el Cmax y el ABC: los resultados obtenidos a partir del porcentaje del coeficiente de variación (%CV) se muestran en las Tablas 7, 8 y 9. Tabla 7. Resultados obtenidos de la variabilidad del The intraindividual and interindividual variability was determined from the data of Cp vs t for the pharmacokinetic parameters that reflect the systemic exposure to the organism of each of the drugs present in each formulation: Cmax and ABC: the results obtained from Percentage of the coefficient of variation (% CV) are shown in Tables 7, 8 and 9. Table 7. Results obtained from the variability of the
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losartán expresada en %CV.  losartan expressed in% CV.
Figure imgf000030_0001
Figure imgf000030_0001
Tabla 8. Resultados obtenidos de la variabilidad del metabolito de losartán EXP3174 expresada en %CV. Table 8. Results obtained from the metabolite variability of losartan EXP3174 expressed in% CV.
Figure imgf000030_0002
Figure imgf000030_0002
Tabla 9. Resultados obtenidos de la variabilidad del felodipino expresada en %CV.  Table 9. Results obtained from felodipine variability expressed in% CV.
Figure imgf000030_0003
Figure imgf000030_0003
Los resultados farmacocinéticos determinados a partir Modelo Independiente no mostraron diferencias estadísticamente significativas cuando el losartán y el felodipino son administrados de manera independiente y la mezcla de ambos eri dosis fija, provenientes de las formulaciones del medicamento de referencia (A) conteniendo 12.5 mg de losartán (dos tabletas), el medicamento de referencia (B) conteniendo 5 mg de felodipino y el medicamento tableta-tableta (C) conteniendo la combinación fija de 25 mg de losartán con 5 mg de felodipino. The pharmacokinetic results determined from the Independent Model showed no differences. Statistically significant when losartan and felodipine are administered independently and the mixture of both eri fixed dose, coming from the formulations of the reference medicine (A) containing 12.5 mg of losartan (two tablets), the reference medicine (B) containing 5 mg of felodipine and the tablet-tablet medicine (C) containing the fixed combination of 25 mg of losartan with 5 mg of felodipine.
Los resultados farmacocinéticos permiten concluir que la composición desarrollada a partir de la presente invención, permite la entrega de los ingredientes activos losartán y felodipino sin manifestar interacción negativa que retrase o impida la absorción, metabolismo o distribución de los mismos al administrarlos en combinación en comparación con su comportamiento farmacocinético al ser administrados de manera independiente .  The pharmacokinetic results allow to conclude that the composition developed from the present invention, allows the delivery of the active ingredients losartan and felodipine without manifesting negative interaction that delays or prevents the absorption, metabolism or distribution thereof when administered in combination compared to its pharmacokinetic behavior when administered independently.
A la luz de esta invención, al determinar la biodisponibilidad de losartán y felodipino incluyendo el metabolito activo de losartán EXP3174 a partir de la relación de la formulación tableta-tableta (C) con respecto a la formulación de los medicamentos administrados de forma independiente (A) y (B) respectivamente, se obtuvo de manera comprobable que la formulación tableta-tableta (C) no altera el comportamiento farmacocinético de los ingredientes activos, una vez administrada la composición que comprende a) al menos una tableta interna que presenta una cinética de orden cero que contiene al menos un bloqueador de los canales de calcio, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos y/o uno o más excipientes farmacéuticamente aceptables; b) al menos una tableta externa que presenta una cinética de orden cero y/o de orden uno sin tiempo de retardo que contiene al menos un antagonista de los receptores de la angiotesina II, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos y/o uno o más excipientes farmacéuticamente aceptables; y de manera opcional c) uno o más excipientes farmacéuticamente aceptables, todos ellos en un sistema de administración oral. In light of this invention, in determining the bioavailability of losartan and felodipine including the active metabolite of losartan EXP3174 from the ratio of the tablet-tablet formulation (C) with respect to the formulation of the drugs administered independently (A ) and (B) respectively, it was verifiably obtained that the tablet-tablet formulation (C) does not alter the pharmacokinetic behavior of the active ingredients, once the composition comprising a) at least one internal tablet having a zero order kinetics containing at least one calcium channel blocker is administered, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; b) at least one external tablet having zero order and / or order one kinetics without delay time containing at least one angiotesin II receptor antagonist, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; and optionally c) one or more pharmaceutically acceptable excipients, all of them in an oral administration system.
A continuación se presentan a manera de ejemplos ilustrativos, más no limitativos, las composiciones utilizadas durante el desarrollo de la invención:  The compositions used during the development of the invention are presented below as illustrative, but not limited to, examples:
Ejemplo 1: Sistema Tableta-tableta con tableta interna con una cinética de liberación de orden cero y tableta externa con una cinética de liberación de orden uno sin tiempo de retardo.
Figure imgf000033_0002
Example 1: Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with order one release kinetics without delay time.
Figure imgf000033_0002
Ejemplo 2: Sistema Tableta-tableta con tableta interna con una cinética de liberación de orden cero y tableta externa con una cinética de liberación de orden uno sin tiempo de retardo. Example 2: Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with order one release kinetics without delay time.
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000033_0001
Figure imgf000034_0001
Ejemplo 3: Sistema Tableta-tableta con tableta interna con una cinética de liberación de orden cero y tableta externa con una cinética de liberación de orden uno sin tiempo de retardo. Example 3: Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with order one release kinetics without delay time.
Figure imgf000034_0002
Figure imgf000034_0002
Laa presentea composiciones presentan un perfil de disolución de los principios activos tales que, como se observa en la Figura 1, el felodipino empieza a liberarse a las 2 horas alcanzando aproximadamente el 20 por ciento de principio activo disuelto y a las 10 horas se ha disuelto aproximadamente el 100 porciento del principio activo. Lo anterior, fue comparado con una composición en forma de tabletas, observando que en dicha composición la disolución se lleva a cabo de manera más rápida al inicio, sin embargo, a las 10 horas de la prueba, no se logra disolver el 100 por ciento de felodipino. Por otro lado, el perfil de disolución de Losartán (Figura 2) , empieza a liberarse de manera tal que a los 5 minutos, se tiene un 40 por ciento disuelto de losartán alcanzando aproximadamente el 100 por ciento de principio activo disuelto a los 45 minutos, se obtuvo un perfil de disolución equivalente al comparalo con una composición en forma de tabletas de Losartán de 12.5 mg. The present compositions have a dissolution profile of the active ingredients such that, as seen in Figure 1, the felodipine begins to release at 2 hours reaching approximately 20 percent dissolved active ingredient and at approximately 10 hours it has dissolved 100 percent of the active substance. The above was compared with a composition in form of tablets, observing that in said composition the dissolution is carried out more quickly at the beginning, however, at 10 hours of the test, it is not possible to dissolve 100 percent felodipine. On the other hand, the dissolution profile of Losartan (Figure 2), begins to be released in such a way that at 5 minutes, there is 40 percent dissolved losartan reaching approximately 100 percent of active ingredient dissolved at 45 minutes , an equivalent dissolution profile was obtained when compared with a composition in the form of Losartan tablets of 12.5 mg.

Claims

REIVINDICACIONES Habiéndose descrito la invención, se reclama como propiedad lo contenido en las siguientes reivindicaciones: CLAIMS Having described the invention, the content of the following claims is claimed as property:
1. Una composición farmacéutica en forma de dos fases o más la cual comprende: a) al menos una tableta interna que presenta una cinética de orden cero que contiene al menos un bloqueador de los canales de calcio, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos y/o uno o más excipientes farmacéuticamente aceptables; b) al menos una tableta externa que presenta una cinética de orden cero y/o de orden uno sin tiempo de retardo que contiene al menos un antagonista de los receptores de la angiotesina II, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos y/o uno o más excipientes farmacéuticamente aceptables; y de manera opcional c) uno o más excipientes farmacéuticamente aceptables, todos ellos en un sistema de administración oral.  1. A pharmaceutical composition in the form of two or more phases which comprises: a) at least one internal tablet having a zero order kinetics containing at least one calcium channel blocker, its pharmaceutically acceptable salts, derivatives, prodrugs , polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; b) at least one external tablet having zero order and / or order one kinetics without delay time containing at least one angiotesin II receptor antagonist, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; and optionally c) one or more pharmaceutically acceptable excipients, all of them in an oral administration system.
2. Una composición farmacéutica de conformidad con la reivindicación 1, caracterizada porque el fármaco bloqueador de los canales de calcio se selecciona de nifedipino, amlodipino, felodipina, verapamilo, diltiazem, nitrendipino, nicardipino, isradipino, nisoldipino, sus sales farmacéuticamente aceptables, derivados, profármacos, metabolitos, polimorfos, amorfos y/o combinaciones de los mismos. 2. A pharmaceutical composition according to claim 1, characterized in that the calcium channel blocking drug is selected from nifedipine, amlodipine, felodipine, verapamil, diltiazem, nitrendipine, nicardipine, isradipine, nisoldipine, their pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, polymorphs, amorphous and / or combinations thereof.
Una composición farmacéutica de conformidad con las reivindicaciones 1 y 2, caracterizada porque el fármaco bloqueador de los canales de calcio es felodipino, sus sales farmacéuticamente aceptables, derivados, profármacos, metabolitos, polimorfos, amorfos y/o combinaciones de los mismos. A pharmaceutical composition according to claims 1 and 2, characterized in that the calcium channel blocking drug is felodipine, its pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, polymorphs, amorphous and / or combinations thereof.
Una composición farmacéutica de conformidad con la reivindicación 1, caracterizada porque el fármaco antagonista de los receptores de la angiotesina II se selecciona de valsartán, telmisartán, losartán, irbesartán, olmesartán, candesartán, eprosartán y/o sus sales farmacéuticamente, sus sales farmacéuticamente aceptables, derivados, profármacos, metabolitos, polimorfos, amorfos o combinaciones de los mismos. A pharmaceutical composition according to claim 1, characterized in that the angiotesin II receptor antagonist drug is selected from valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan, eprosartan and / or its pharmaceutical salts, its pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, polymorphs, amorphous or combinations thereof.
Una composición farmacéutica de conformidad con las reivindicaciones 1 y 4, caracterizada porque el fármaco antagonista de los receptores de la angiotesina II es losartán, sus sales farmacéuticamente aceptables, derivados, profármacos, metabolitos, polimorfos, amorfos o combinaciones de los mismos. A pharmaceutical composition according to claims 1 and 4, characterized in that the angiotesin II receptor antagonist drug is losartan, its pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, polymorphs, amorphous or combinations thereof.
Una composición farmacéutica de conformidad con las reivindicaciones 1 a 3, caracterizada porque el fármaco bloqueador de los canales de calcio se encuentra en un rango de concentración entre aproximadamente 1 mg a aproximadamente 10 mg, más preferiblemente en un rango de concentración entre aproximadamente 3 mg a aproximadamente 7 mg. A pharmaceutical composition according to claims 1 to 3, characterized in that the calcium channel blocking drug is in a concentration range between about 1 mg to about 10 mg, more preferably in a concentration range between about 3 mg at approximately 7 mg
Una composición farmacéutica de conformidad con las reivindicaciones 1, 4 y 5, caracterizada porque el fármaco antagonista de los receptores de la angiotesina II se encuentra en un rango de concentración entre aproximadamente 5 mg a aproximadamente 60 mg, más preferiblemente en un rango de concentración entre aproximadamente 17 mg a aproximadamente 35 mg. A pharmaceutical composition according to claims 1, 4 and 5, characterized in that the angiotesin II receptor antagonist drug is in a concentration range between about 5 mg to about 60 mg, more preferably in a concentration range between about 17 mg to about 35 mg.
Una composición farmacéutica de conformidad con las reivindicaciones 1 a 7, caracterizada porque la tableta interna que presenta una cinética de orden cero contiene al menos un bloqueador de los canales de calcio, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de- los mismos y/o uno o más monosacáridos y/o uno o más óxidos de polietileno y/o uno o más derivados de celulosa y/o una o más sales de sílice y/o uno o más agentes lubricantes. A pharmaceutical composition according to claims 1 to 7, characterized in that the internal tablet having a zero order kinetics contains at least one calcium channel blocker, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations of - the same and / or one or more monosaccharides and / or one or more polyethylene oxides and / or one or more cellulose derivatives and / or one or more silica salts and / or one or more lubricating agents.
Una composición farmacéutica de conformidad con las reivindicaciones 1 a 7, caracterizada porque la tableta externa que presenta una cinética de orden cero y/o de orden uno sin tiempo de retardo que contiene al menos un antagonista de los receptores de la angiotesina II, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos y/o uno o más polímeros de celulosa y/o uno o más sales de sílice y/o uno o más monosacáridos y/o uno o más agentes lubricantes. A pharmaceutical composition according to claims 1 to 7, characterized in that the external tablet having a zero order and / or order one kinetics without delay time containing at least one angiotesin II receptor antagonist, its salts Pharmaceutically acceptable derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more cellulose polymers and / or one or more silica salts and / or one or more monosaccharides and / or one or more lubricating agents.
Una composición farmacéutica de conformidad con las reivindicaciones 8 y 9, caracterizada porque el monosacárido se selecciona de fructosa, lactosa, manitol, xilol, sorbitol, lactosa anhidra, lactosa monohidratada o combinaciones de los mismos. A pharmaceutical composition according to claims 8 and 9, characterized in that the monosaccharide is selected from fructose, lactose, mannitol, xylol, sorbitol, anhydrous lactose, lactose monohydrate or combinations thereof.
Una composición farmacéutica de conformidad con las reivindicaciones 8 y 9, caracterizada porque el oxido de polietileno se selecciona de polyox N-10, polyox N-80, polyox N12-k, polyox N60-k y/o polyox N-301 o combinaciones de los mismos. A pharmaceutical composition according to claims 8 and 9, characterized in that the polyethylene oxide is selected from polyox N-10, polyox N-80, polyox N12-k, polyox N60-k and / or polyox N-301 or combinations of the same.
Una composición farmacéutica de conformidad con las reivindicaciones 8 y 9, caracterizada porque el derivado de celulosa se selecciona de celulosa microcristalina, - carboximetilcelulosa de sodio, celulosa microcristalina silicificada, celulosa, hidroxipropilmetilcelulosa, celulosa microcristalina cálcica, hidroxietilcelulosa, celulosa microcristalina, celulosa microcristalina cálcica, hidroxipropilcelulosa y/o combinaciones de los mismos . A pharmaceutical composition according to claims 8 and 9, characterized in that the Cellulose derivative is selected from microcrystalline cellulose, - sodium carboxymethyl cellulose, silicified microcrystalline cellulose, cellulose, hydroxypropylmethyl cellulose, calcium microcrystalline cellulose, hydroxyethyl cellulose, microcrystalline cellulose, calcium microcrystalline cellulose, hydroxypropyl cellulose and / or combinations thereof.
Una composición farmacéutica de conformidad con las reivindicaciones 8 y 9, caracterizada porque la sal de silicio se selecciona de oxido de silicio, silicato de calcio, silicato aluminico magnésico, silicado de aluminio, silicato de magnesio, dióxido de silicio coloidal, metasilicato de aluminio y magnesio, celulosa microcristalina silificada, trisilicato de magnesio, dióxido de silicio y/o dióxido de silicio coloidal y/o combinaciones de los mismos . A pharmaceutical composition according to claims 8 and 9, characterized in that the silicon salt is selected from silicon oxide, calcium silicate, magnesium aluminum silicate, aluminum silicate, magnesium silicate, colloidal silicon dioxide, aluminum metasilicate and magnesium, silicified microcrystalline cellulose, magnesium trisilicate, silicon dioxide and / or colloidal silicon dioxide and / or combinations thereof.
Una composición farmacéutica de conformidad con las reivindicaciones 8 y 9, caracterizada porque el agente lubricante se selecciona de estearato de calcio, behenato de glicerilo, monoestearato de glicerilo, palmitostearato de glicerilo, ácido laurico, leucina, estearato de magnesio, maltodextrina, aceite mineral, aceite mineral ligero, ácido mirístico, ácido palmitico, polietilenglicol, alcohol polivinílico, benzoato de potasio, cloruro de sodio, hialuronato de sodio, lauril sulfato de sodio, estearil fumarato de sodio, ácido esteárico, talco, aceite vegetal hidrogenado, estearato de zinc y/o combinaciones de los mismos. A pharmaceutical composition according to claims 8 and 9, characterized in that the lubricating agent is selected from calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, lauric acid, leucine, magnesium stearate, maltodextrin, mineral oil, light mineral oil, myristic acid, palmitic acid, polyethylene glycol, polyvinyl alcohol, potassium benzoate, sodium chloride, sodium hyaluronate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, zinc stearate and / or combinations of the same.
Una composición farmacéutica de conformidad con las reivindicaciones 1 a 14, para su uso en el tratamiento de hipertensión arterial y/o insuficiencia cardiaca congestiva y/o angina de pecho inestable y/o infarto agudo del miocardio y/o nefropatia diabética y/o desórdenes asociados. A pharmaceutical composition according to claims 1 to 14, for use in the treatment of arterial hypertension and / or congestive heart failure and / or unstable angina pectoris and / or acute myocardial infarction and / or diabetic nephropathy and / or disorders Associates
Una composición farmacéutica de dos fases que contiene o más la cual comprende: a) al menos una fase interna que presenta una cinética de orden cero que contiene al menos un bloqueador de los canales de calcio, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos y/o uno o más excipientes farmacéuticamente aceptables; b) al menos una fase externa que presenta una cinética de orden cero y/o de orden uno sin tiempo de retardo que contiene al menos un antagonista de los receptores de la angiotesina II, sus sales farmacéuticamente aceptables, derivados, profármacos, polimorfos, amorfos o combinaciones de los mismos y/o uno o más excipientes farmacéuticamente aceptables; y de manera opcional c) uno o más excipientes farmacéuticamente aceptables, todos ellos en un sistema de administración oral. A two-phase pharmaceutical composition containing or more which comprises: a) at least one internal phase having a zero order kinetics containing at least one calcium channel blocker, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs , amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; b) at least one external phase presenting a zero order and / or one order kinetics without delay time containing at least one angiotesin II receptor antagonist, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more pharmaceutically acceptable excipients; and optionally c) one or more pharmaceutically acceptable excipients, all of them in an oral administration system.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007001067A2 (en) * 2005-06-27 2007-01-04 Daiichi Sankyo Company, Limited Solid dosage form comprising an angiotensin ii receptor antagonist and a calcium channel blocker
WO2007001065A2 (en) * 2005-06-27 2007-01-04 Daiichi Sankyo Company, Limited Method for the preparation of a wet granulated drug product
WO2008044862A1 (en) * 2006-10-10 2008-04-17 Hanall Pharmaceutical Co., Ltd. Combined preparation for the treatment of cardiovascular diseases based on chronotherapy theory
WO2010065492A1 (en) * 2008-12-02 2010-06-10 Sciele Pharma, Inc. Alpha2-adrenergic agonist a calcium channel blocker composition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007001067A2 (en) * 2005-06-27 2007-01-04 Daiichi Sankyo Company, Limited Solid dosage form comprising an angiotensin ii receptor antagonist and a calcium channel blocker
WO2007001065A2 (en) * 2005-06-27 2007-01-04 Daiichi Sankyo Company, Limited Method for the preparation of a wet granulated drug product
WO2008044862A1 (en) * 2006-10-10 2008-04-17 Hanall Pharmaceutical Co., Ltd. Combined preparation for the treatment of cardiovascular diseases based on chronotherapy theory
WO2010065492A1 (en) * 2008-12-02 2010-06-10 Sciele Pharma, Inc. Alpha2-adrenergic agonist a calcium channel blocker composition

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