MX2013001277A - Pharmaceutical composition comprising an angiotensin ii-receptor antagonist and a calcium channel blocker for the treatment of arterial hypertension. - Google Patents

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

PHARMACEUTICAL COMPOSITION WITH AN ANTAGONIST OF ANGIOTHESIN II RECEPTORS AND A BLOCKER OF CALCIUM CHANNELS FOR THE TREATMENT OF BLOOD HYPERTENSION FIELD OF THE INVENTION The present invention relates to a novel composition in the form of a tablet-tablet formed by a combination of at least two active ingredients in two or more phases, one of which is at least one antagonist of angiotesin II receptors which is released with a kinetic of order zero and / or of order one without time of delay; the other is a blocker of the calcium channels 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 Currently, cardiovascular diseases have become the leading cause of death in all the industrialized countries of the world, epidemiological analysis has allowed to recognize the existence of biological variables called risk factors of cardiovascular disease, which are able to ience in the probability of suffering from cerebrovascular accidents, coronary heart disease, heart failure or peripheral arterial disease (Castells E., 2000).

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, preeclampsia, 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 probability of suffering a serious cardiac complication increases exponentially , renal, neurological or any other organ or region of the human body (Satín J., 1999). 95% of the hypertension observed in clinical practice does not have a definite etiology; it is called essential arterial hypertension (AHT), also known as primary or idiopathic hypertension, while 5% are due to various causes, among which are highlighted by its frequency is induced by drug use, drug consumption, renovascular disease, renal failure, pheochromocytoma and hyperaldosteronism (Maicas C, 2003).

Blood pressure is a continuous variable, therefore there is no cut-off point to define the threshold under which the blood pressure values are normal, however, arterial hypertension corresponds to a persistent elevation of blood pressure over limits Normal, when its value is greater than or equal to 140 mmHg is defined as SBP or systolic blood pressure, when its value is greater than or equal to 90 mmHg it is defined as DBP or diastolic blood pressure. (Minsal, 2010).

Hypertension is basically characterized by the existence of endothelial dysfunction, with rupture of the balance between other blood vessel relaxing factors (nitric oxide-NO, endothelial hyper-polarizing factor-EDHF), vasoconstrictor factors (mainly endothelin), decrease in the endothelium of prostacyclin-PG12 vasodepressor and relative increase of intraboxcular thromboxane-TXA2 vasoconstrictor.

Some of the main factors that intervene in blood pressure are: Endothelins (ETs), highly potent local vasoconstrictor factors, about 10 to 100 times more powerful than angiotesin II. It is known that it is a complex system: preproendotelina-proendotelina-ETl. At the level of proendothelin acts an endothelin converting enzyme (ECE), forming mainly ET1, but also to a lesser extent, ET2 and ET3. Only ET1 seems to possess systemic vasoconstrictive action. The ET1 exerts diverse actions: on the vascular tone, the renal excretion of sodium and water, and the production of the extracellular matrix. ET1 is implied, 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 the vascular smooth muscle.

On the other hand, the renin-angiotesin-aldosterone system (SRAA), is an extremely complex system, comprising a series of proteins and 4 angiotesins (I, II, III and IV) with own and specific activities. The actions of angiotesin II include: contraction of arterial and venous vascular smooth muscle, stimulation of aldosterone synthesis and secretion, release of noradrenaline at sympathetic endings, modulation of sodium (Na) transport by renal tubular cells, increase of oxidative stress by activation of NADH and NADPH dependent oxidases, stimulation of vasopressin / ADH, stimulation of the dipsogen center in the central nervous system, antagonism of the natriuretic-natural atrial peptide (BNP) and type C (CNP) system, increase in the production of endothelin (ET1) and vasoconstrictor prostaglandins (TXA2, PgF2oc). In addition, angiotesin II and aldosterone increase collagen tissue at the cardiac and vascular levels, by inhibiting the activity of metalloproteinase (MMP1) that destroys collagen and increases tissue inhibitors specific to MMP1 (TI Ps). The result is the increase of collagen-3 in the heart and blood vessels of hypertensive patients.

Another factor is the endogenous digitalis (EDF), it is a hormonal factor, described several years ago, that inhibits the Na-K-Mg-ATPase pump, with intense vasoconstrictor activity, natriuretic action. Its natriuretic effect is expressed obvious and important way after a sodium intake orally. It is possible to establish a physiopathological role in arterial hypertension by increasing the plasma activity of PDE.

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, vasoactive intestinal peptide (VIP) is intensely vasodilatory, chortenin is vasoconstrictor, cholecystokinin (CCK) is vasodilator, substance P 'is also vasodilator, bombesin, endorphins and eicosanoids are the same (Wagner P., 2010). ).

Several types of drugs are used for the treatment of arterial hypertension, among which are: the angiotensin-converting enzyme inhibitors (ACEI) that inhibit the enzyme that converts angiotesin I into angiotesin II, with the consequent vasodilator effect (hypotensive); Angiotesin II receptor antagonists (ARA II) block the ATI receptors of angiotesin II, thus interfering with the renin-angiotesin-aldosterone system, with the consequent vasodilator effect, and unlike ACE-I, because of their mechanism of action does not increase bradykinin levels; Calcium channel blockers or blockers of calcium channels, these are powerful antihypertensive agents and act at the level of calcium channels in vascular smooth muscle and cardiac muscle, the long-acting ones are those that have proven useful and prevent cardiovascular events in hypertensive patients, in change those of short action can increase the probability of coronary events and mortality reason why they should not be used like antihypertensive; diuretics, especially thiazides in low doses and especially in people over 55 years of age; beta-blockers that are effective in the prevention of 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).

Among the main antagonist drugs of angiotesin II receptors are: 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 been shown to be an effective antihypertensive by oral route, with additional uricosuric activity, it has an active metabolite of the order of 10-40 times more potent than losartan, for this reason in patients with chronic liver disease can lose effectiveness by making their metabolism difficult and decreasing the generation of its 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, has an absolute bioavailability of 33%, with an elimination half-life of 2.6 to 9 hours, joins proteins in a percentage of 98.7% (Cadime, 2000).

Losartan, when suffering the substantial metabolism of the first step by the enzymes of cytochrome P-450, is metabolized to an active metabolite which is 5-carboxylic acid, said metabolite is responsible for most of the effects of Losartan in the Angiotensin receptor (Rodríguez C, 2002).

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.

Felodipine is a calcium channel antagonist of the group of dihydropyridines, which has an oral bioavailability of 15%, as a consequence of an 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%. Virtually 100% of the dose is metabolized in the liver, forming inactive metabolites that are mostly eliminated with urine.

In the state of the art, documents were found describing the use of an angiotensin II receptor antagonist in an immediate release system in combination with a calcium channel blocker in a chronotherapeutic release system for use in the treatment of hypertension (MX / a / 2009/003489, US 20110281823 and US 20100003332).

The delivery 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 the characteristic concentration peaks of the conventional systems. These systems have been used for several decades, although novelties designed to facilitate the posology or provide a better pharmacokinetic profile still appear.

OBJECT OF THE INVENTION The present invention relates to a pharmaceutical composition in the form of a tablet-tablet of two or more phases comprising a first tablet with a release system that presents a kinetic of order zero and / or order one without delay time that of minus a calcium channel blocking agent; and, a second tablet with a delivery system that exhibits a zero-order kinetics of at least one antagonist agent of angiotesin II receptors. Said composition is useful for the treatment of arterial hypertension, congestive heart failure, unstable angina pectoris, acute myocardial infarction, diabetic nephropathy or associated disorders.

BRIEF DESCRIPTION OF THE FIGURES FIGURE 1. Dissolution profile of tablets of Losartan / Felodipine of 25mg / 5mg VS Feldipino tablets of 5mg.

FIGURE 2. Dissolution profile of tablets of Losartan / Felodipine of 25mg / 5mg VS 2 tablets of Felodipine of 5mg.

DETAILED DESCRIPTION OF THE INVENTION 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 delivery system having a zero-order and / or order-of-order kinetics without delay time that contains at least one angiotensin 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 delivery system.

The internal tablet with a release system having zero-order kinetics containing at least one calcium channel blocker was thus developed 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 prolonged action system in comparison with short-acting ones that increase the probability of coronary events and mortality, for which reason they are not used as hypertensive.

On the other hand, the external tablet with a release system that presents a kinetic of order zero and / or of order one without delay time that, preferably of order one, was developed in this way in order to perform at least a delivery of at least one antagonist of the angiotesin II receptors and in this way, obtain a better synergistic effect with the calcium channel blocking agent. Decreasing peripheral vascular resistance, blood pressure and afterload.

For purposes of the present invention, at least one calcium channel blocking agent of the following group is selected: nifedipine, amlodipine, felodipine, verapamil, diltiazem, nitrendipine, nicardipine, isradipine, nisoldipine, their pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations of them, 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 angiotysin II receptor antagonist 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.

In the composition described in the present invention, it is preferable, but not limiting, as a blocker of calcium channels to felodipine, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, in a range of concentration between .1 mg and 10 mg, more preferably in a range of 3 mg to 7 mg.

The angiotysin II receptor antagonist which is used in a preferred but not limitative manner is losartan, its pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof, in a concentration range between 5 and 10. mg and 60 mg and more preferably 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. Generally, the internal tablet and the external tablet of 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 glycolate, modified cellulose gum, PVP, sodium dodecyl sulfate corn starch, rice starch, N-vinyl Cross-linked pyrrolidone, croscarmellose sodium, formaldehyde-casein, sorbitol, starch, pregentalized starch, corn starch, sucrose, sugar, compressible sugar, isomaltose, tragacanth, talc, trehalose, xylitol, acacia, agar, alginic acid, carbonate calcium, calcium lactate, carbomer, calcium carboxymethylcellulose, microcrystalline cellulose, cellulose, ceratonia, chitosan, copovidone, dextrates, dextrin, dextrose, ethylcellulose, gelatin, glyceryl behenate, guar gum, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose low-substitution , starch hydroxypropyl, hypromellose, inulin, lactose monohydrate, aluminum magnesium silicate, maltodextrin, methylcellulose, poly carbofil, polydextrose, polyethylene oxide, polymethacrylates, povidone, sodium alginate, starch, pregelatinized starch, sucrose, polyethylene glycol succinate, zein, calcium stearate, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, lauric acid, leucine, magnesium stearate, maltodextrin, mineral oil, oil light mineral, 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, acid adipic, 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, citrate sodium dihydrate, sodium hydroxide, dibasic sodium phosphate, monobasic sodium phosphate, potassium citrate, sodium citrate, hydroxide sodium, potassium hydroxide, sodium bicarbonate, sodium carbonate, calcium bicarbonate, calcium carbonate, potassium bicarbonate, disodium hydrogen phosphate, trisodium phosphate, arginine, talc, acetyltributyl citrate, acetriltriethyl citrate, carbonate calcium, calcium carboxymethylcellulose, sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ceresin, cetyl alcohol, chitosan, diethyl phthalate, dimethyl phthalate, ethylcellulose, gelatin, liquid glucose, glycerin glyceryl behenate, glyceryl palmitostearate, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, hypromellose phthalate, isomaltose, maltitol, maltodextrin, methylcellulose, paraffin, poloxamer, polydextrose, poly LD-lactic acid, polyethylene oxide, polymethacrylates, poly (methyl vinyl ether / maleic anhydride) ) acetate, polyvinyl propylene glycol phthalate, shelac, sodium chloride, stearic acid, sucrose, titanium dioxide, tributycin tributyl citrate, triethyl triolein citrate, carnauba wax, microcrystalline wax, white wax, yellow wax, xylitol, zein or combinations thereof.

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 antagonist agent of the Angiotesin II receptors is comprised of one or more cellulose polymers, one or more silica salts, one or more monosaccharides and one or more lubricating agents.

Wherein the monosaccharides may be fructose, lactose, mannitol, xylol, sorbitol, anhydrous lactose and / or lactose monohydrate and / or combinations thereof; the polyethylene oxides can be selected from polyox N-10, polyox N-80, polyox N12-k, polyox N60-k and / or polyox N-301 or combinations thereof; the cellulose derivatives may be microcrystalline cellulose, sodium carboxymethylcellulose, silicified microcrystalline cellulose, cellulose, hydroxypropylmethylcellulose, calcium microcrystalline cellulose, hydroxyethylcellulose, microcrystalline cellulose, calcium microcrystalline cellulose, hydroxypropylcellulose and / or combinations thereof; the silicon salt may be silicon oxide, calcium silicate, magnesium aluminum silicate, aluminum silicate, magnesium silicate, colloidal silicon dioxide, aluminum magnesium metasilicate, silicon microcrystalline cellulose, magnesium trisilicate, silicon dioxide and / or colloidal silicon dioxide or combinations thereof; and / or the lubricating agent can 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, hydrogenated vegetable oil, zinc stearate and / or combinations thereof.

To evaluate the effectiveness of this two-phase tablet-tablet system, two hypotheses to be followed in the development of the present invention were proposed, which were: First: the pharmacokinetics of the active substances losartan (A) and felodipine (B) administered independently in a single dose administered orally is equal to the pharmacokinetics of the same co-administered active principles (C) in their pharmaceutical form.

Second: the pharmacokinetics of the active substances losartan (A) and felodipine (B) administered independently in a single dose administered orally is different from the pharmacokinetics of the same co-administered active principles (C) in their pharmaceutical form.

The study design was developed with 12 healthy volunteers, both sexes, from 18 to 55 years of age, by means of a cross-over, randomized, prospective, simple model. blind, longitudinal, unicentric, 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 the bioavailability in a fixed dose of losartan, felodipine and losartan-felodipine.

The groups were balanced with an equal number of volunteers per sequence. The study was run in darkness, due to the photosensitivity of the felodipine; the medication was administered with 250 mL of electrolyte solution in a 10-hour fast; and the volunteers remained in bed for 4 hours or until they could rejoin the rest of the group, as long as their vital signs were normal.

The results obtained for the pharmacokinetic parameters of losartan in each of the volunteers for the study are shown below: Table 1. Values of losartan pharmacokinetic parameters obtained for each of the volunteers who participated in the study Tmax = time in which the Cmax is reached ?? = Slope value of the linear portion of the phase of elimination = average life time of? 3 Vz_F = Distribution volume based on the terminal phase of?.

C1_F = Total purification for extravascular administration = Average residence time 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 losartan 25 mg from the reference medicine (A) and the drug tablet-tablet (C) containing the combined dose of 25 mg of losartan and 5 mg of 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 value of the bioavailability obtained from the relationship between the tablet-tablet formulation (C) with respect to the formulation of the reference medicine Table 2. Average pharmacokinetic parameters obtained for losartan with the reference medicine (A) and the tablet-tablet medicine (C) from the 12 volunteers who participated in the study.

Tmax - time in which the Cmax is reached ?? = Slope value of the linear portion of the phase of elimination Ti / 2 = average life time of? 2 Vz_F = Volume of distribution based on the terminal phase of Xz C1_F = Total purification for extravascular administration TMR = Average residence time 5 The individual values for the pharmacokinetic parameters of the losartan metabolite EXP3174 corresponding to the maximum plasma concentration (Cmax); time when Cmax (Tmax) is reached; the area under 0 profile curve Cp vs t from zero to last sampling time (ABCo-t); the area under the profile curve vs t from zero to infinity (ABCo-inf); constant speed of the last linear portion of the profile Cp vs (??); average life time (ti / 2), average residence time from zero to last sampling time (T R0-t) and average residence time from zero to infinity (TMRo-inf) corresponding to the 12 volunteers who participated in the study are shown in table 3; The inNonLin® software was used to obtain it.

Table 3. Values of the pharmacokinetic parameters of losartan metabolite EXP3174 obtained for each of the 5 volunteers who participated in the study.

Tmax = time in which the Cmax is reached ?, = Slope value of the linear portion of the phase of elimination Ti = average life time of ?? Vz_F = Distribution volume based on the terminal phase of? C1_F = Total purification for extravascular administration TMR = Average residence time The average values corresponding to the metabolite of losartan EXP3174 for the pharmacokinetic parameters were obtained using the WinNonLin® software from the individual values of the 12 volunteers after administering the fixed dose of losartan 25 mg from the reference medicine ( A) and the tablet-tablet drug (C) containing the combined dose of 25 mg of losartan and 5 mg of felodipine: these are shown in table 4, including Student's 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 equality hypothesis. as the value of the bioavailability from the ratio between the tablet-tablet formulation (C) with respect to the formulation of the reference medicine (A).

Table . Pharmacokinetic parameters obtained for the metabolite of losartan EXP3174 with the reference medicine (A) and the tablet-tablet drug (C) obtained from the 12 volunteers who participated in the study.

Tmax = time in which the Cmax is reached ? 2 = Slope value of the linear portion of the phase of elimination Ti = average life time of ?? Vz_F = Volume of distribution based on the terminal phase of C1_F = Total purification for extravascular administration TMR = Average residence time The individual values for . the felodipine pharmacokinetic parameters corresponding to the maximum plasma concentration (Cmax); time when Cmax (Tmax) is reached; the area under the curve of the Cp profile vs t from zero to the last sampling time (ABCo-t); the area under the profile curve Cp vs t (??); mean life time (ti2), mean residence time from zero to last sampling (TMRo-t) and mean residence time from zero to infinity (TMRo-inf) corresponding to the 12 volunteers who participated in the study are shown in Table 5; The WinNonLin® software was used to obtain it.

According to the results of the mean residence time from zero to the last sampling time (TMRO-t) and mean 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 transit through the body for a time not less than 2.5 hours for Losartan and not less than 8.5 hours for the metabolite losartan EXP3174.

Table 5. Values of the felodipine pharmacokinetic parameters obtained for each of the volunteers who participated in the study.

Tmax = time in which the Cmax is reached ?? = Slope value of the linear portion of the phase of elimination Ti = mean life time of? 2 Vz_F = Volume of distribution based on the terminal phase of ?? C1_F = Total purification for extravascular administration TMR = Average residence time The average values corresponding to the felodipine for the pharmacokinetic parameters were obtained using the inNonLin® software from the individual values of the 12 volunteers after administering the fixed dose of 5 5 mg of felodipine from the reference medicine (B) and the tablet-tablet drug (C) containing the combined dose of 25 mg of losartan and 5 mg of felodipine: these are shown in table 6 including the t-student test for the comparison of means without assuming equal variances, for 10 consider different formulations with an alpha value of 0.05 for the rejection of the null hypothesis of equality, as well as the value of the bioavailability obtained from the relationship between the tablet-tablet formulation (C) with respect to the formulation (B ). 15 Table 6. Average pharmacokinetic parameters obtained for the felodipine with the reference medicine (B) and the tablet-tablet medicine obtained from the 12 volunteers who participated in the study.

Tmax = time in which the Cmax is reached ?? = Slope value of the linear portion of the phase of elimination Tl / 2 = average life time of? 2 Vz_F = Distribution volume based on the terminal phase of? 7, C1_F = »Total purification for an extravascular admission TMR = Average residence time According to the results of the mean 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 developed composition presents an "in vivo" release system such that it allows the intact molecules to transit through the body for a time not less than 12 hours for Felodipino.

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: the Cmax and the ABC: the results obtained from the percentage of the variation coefficient (% CV) are shown in Tables 7, 8 and 9.

Table 7. Results obtained from the variability of the rtan expressed in% CV.

Table 8. Results obtained from the variability of losartan metabolite EXP3174 expressed in% CV.

Table 9. Results obtained from the variability of felodipine expressed in% CV.

The pharmacokinetic results determined from the Independent Model did not show statistically significant differences when the losartan and the felodipine are administered independently and the mixture of both in fixed doses, 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 drug (C) containing the fixed combination of 25 mg of losartan with 5 mg of felodipine.

The pharmacokinetic results allow us to conclude that the composition developed from the present invention allows the delivery of the active ingredients losartan and felodipine without manifesting a negative interaction that delays or impedes the absorption, metabolism or distribution thereof when administered in combination in comparison with its pharmacokinetic behavior when administered independently.

In light of this invention, when 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 biocatalyst, 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 exhibiting zero-order and / or order-one kinetics without a delay time containing at least one antagonist of angiotesin II receptors, their 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 delivery system.

The following are presented by way of illustrative examples, but not limiting, the compositions used during the development of the invention: Example 1: Tablet-tablet system with internal tablet with zero order release kinetics and external tablet with a release order kinetics without delay time.

Example 2: Tablet-tablet system with internal tablet with zero-order release kinetics and external tablet with a release order kinetics without delay time.

Example 3: Tablet-tablet system with internal tablet with zero-order release kinetics and external tablet with a release order 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 be released after 2 hours, reaching approximately 20 percent of dissolved active principle and at 10 hours it has dissolved approximately 100 percent of the active substance. The above was compared with a composition in the 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 the 100 percent of felodipino. On the other hand, the dissolution profile of Losartan (Figure 2), begins to be released in such a way that after 5 minutes, there is a 40 percent dissolved losartan reaching approximately 100 percent dissolved active principle at 45 minutes. , an equivalent dissolution profile was obtained when compared to a composition in the form of Losartan tablets of 12.5 mg.

Claims (14)

CLAIMS Having described the invention, the content of the following claims is claimed as property:

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 exhibiting zero-order and / or order-one kinetics without a delay time containing at least one antagonist of angiotesin II receptors, their 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 delivery system.

2. A pharmaceutical composition according to claim 1, characterized in that the calcium channel blocker 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.

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.

A pharmaceutical composition according to claim 1, characterized in that the antagonist drug of angiotesin II receptors is selected from valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan, eprosartan and / or its pharmaceutically acceptable salts, its pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, polymorphs, amorphous or combinations thereof.

A pharmaceutical composition according to claims 1 and 4, characterized in that the antagonist drug of angiotesin II receptors is losartan, its pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, polymorphs, amorphous or combinations thereof.

A pharmaceutical composition according to claims 1 to 3, characterized in that the blocking agent of calcium channels is in a concentration range between about 1 mg to about 10 mg, more preferably in a concentration range between about 3 mg a approximately 7 mg.

A pharmaceutical composition according to claims 1, 4 and 5, characterized in that the antagonist drug of angiotesin II receptors 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.

A pharmaceutical composition according to claims 1 to 7, characterized in that the internal tablet exhibiting zero order kinetics contains at least one calcium channel blocker, pharmaceutically acceptable salts, derivatives, prodrugs, polymorphs, amorphous or combinations thereof. the same and / or one or more monosaccharides and / or one or more oxides of polyethylene and / or one or more cellulose derivatives and / or one or more silica salts and / or one or more lubricating agents.

A pharmaceutical composition according to claims 1 to 7, characterized in that the external tablet exhibiting zero order kinetics and / or of order one without a delay time containing at least one antagonist of angiotesin II receptors, their salts pharmaceutically acceptable, derivatives, prodrugs, polymorphs, amorphous or combinations thereof and / or one or more cellulose polymers and / or one or more salts of silica and / or one or more monosaccharides and / or one or more lubricating agents.

A pharmaceutical composition according to claims 8 and 9, characterized in that the monosaccharide is selected from fructose, lactose, mannitol, xylol, sorbitol, lactose anhydrous, lactose monohydrate or combinations thereof.

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 Nl2-k, polyox N60-ky / or polyox N-301 or combinations of the same.

12. A pharmaceutical composition according to claims 8 and 9, characterized in that the cellulose derivative is selected from microcrystalline cellulose, sodium carboxymethylcellulose, silicified microcrystalline cellulose, cellulose, hydroxypropylmethylcellulose, calcium microcrystalline cellulose, hydroxyethylcellulose, microcrystalline cellulose, calcium microcrystalline cellulose, hydroxypropylcellulose and / or combinations thereof.

13. 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, silicon microcrystalline cellulose, magnesium trisilicate, silicon dioxide and / or colloidal silicon dioxide and / or combinations thereof.

14. 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 thereof. A pharmaceutical composition according to claims 1 to 14, for use in the treatment of hypertension and / or congestive heart failure and / or unstable angina pectoris and / or acute myocardial infarction and / or diabetic nephropathy and / or disorders associates 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 having zero-order and / or order-one kinetics without a delay time containing at least one receptor antagonist of the angiotesin II, 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 delivery system.