MXPA04012380A - Pharmaceutical combination in a novel pharmaceutical form useful for treating arterial hypertension and stable chronic coronary-artery insufficiency. - Google Patents

Abstract

The present invention proposes a stable pharmaceutical association between a granulated betablocker and a calcium channel-antagonist pertaining to the dihydropiridinic class in tablets, said tablets being subsequently coated by a hard gelatine capsule.

Description

PHARMACEUTICAL COMBINATION IN A NEW USEFUL PHARMACEUTICAL FORM IN BLOOD HYPERTENSION AND CORONARY INSUFFICIENCY STABLE CHRONICLE TECHNICAL FIELD The present invention proposes the stable pharmaceutical association between a beta-blocker in the form of granulate and a calcium channel antagonist belonging to the class of dihydropyridines in tablet form, which are coated by a hard gelatin capsule.

BACKGROUND OF THE INVENTION Chronic stable coronary insufficiency, also known as angina pectoris or angina pectoris, is characterized by a sudden and dilacerating pain that manifests itself when there is insufficiency in the arteries responsible for the irrigation of the heart.

The heart, which is one of the vital organs of the body, also grows, works and breathes. For everything, you need to feed. The blood vessels are responsible for bringing to it the regular supply of oxygen and other indispensable "foods". Through two coronary arteries and their branches, the blood then reaches the heart, for irrigation. It acts as a "fuel" that puts the gears of the heart pump into action. That is, it enables the heart to exercise its basic function: it pumps blood for the rest of the body. Therefore, the whole cycle of the circulation of blood through the body depends in large part on the provision of the heart and, therefore, on the proper functioning of the arteries that are responsible for feeding it.

If by chance the coronary arteries are not working well, they do not supply the heart with the required nutrition, which will then react violently. For the organism, within which all this happens, the reaction is recorded in the form of a suffocating and oppressive pain, in the middle of the chest, which is the main characteristic of angina (spasmodic pain) of the chest. Angina pectoris usually manifests itself in special conditions of increased exertion, exaggerated repletion, emotional excitement.

The main root of angina is in the initial problem that triggers the insufficiency. In 95% of cases, the predisposed cause of angina pectoris is arteriesclerosis of the coronary arteries, which is a degenerative process, which results in decreased caliber and narrowing of the internal space of these coronary arteries, which impairs blood flow . All this picture interferes in the irrigation of the myocardium. In this way, because of a greater physical effort, where the heart needs more blood, the vessels are not sufficient to provide their needs. As the heart does not receive the ideal amount of oxygen, stable chronic coronary insufficiency occurs. Thus, the mechanism begins to trigger from the cardiovascular injury.

However, the insufficiency of the arteries that provide the heart may still have other origins. Rheumatic fever, syphilis and aortic valve injuries are examples of alterations that can cause decreased blood flow in the coronary arteries and, thus, constitute a cause of angina. But other causes can appear and contribute to the creation of the painting. For example, in a person with hypertension or diabetes, coronary insufficiency can trigger angina; but if there is no such insufficiency, the alteration does not arise.

To identify angina, in general, the description of the picture by the patient suffices. The physical examination can, occasionally, detect some cardiocirculatory alterations. However, only with an electrocardiogram and a radiograph of the heart can more precise elements be obtained, because the clinical picture itself can cause confusion. For example, deviations from the spine can determine the understanding of some nerve branches and cause pain "in the chest".

In the human body, the heart drives blood to all organs, carrying oxygen from the lungs. This blood is carried by the arteries and returns to the heart through the veins, to lead to the lung where it will be enriched again with oxygen. The resistance to the passage of blood through the arteries is proportional to its total volume, its viscosity and the rigidity of the vessel wall.

Thus, blood pressure is the product of the volume of blood expelled by the heart versus resistance to its passage. Therefore, when measuring blood pressure, which is usually recorded in millimeters of mercury (mmHg), we evaluate a relationship of the amount of blood within the artery and the ability of the artery to accommodate this blood.

In the measurement of blood pressure, the first number that is the highest value, is called "systolic" and corresponds to the pressure of the artery at the time blood was pumped by the heart. The second number, or the lowest number, is called "diastolic" and corresponds to the pressure in the same artery, at the moment when the heart is relaxed, after a contraction. Currently, values higher than 12.0 for systolic pressure, and 8.0 for diastolic pressure, characterize the state of arterial hypertension.

Systemic arterial hypertension that evolves asymptomatically in the great majority of cases, constitutes one of the main causes of death in developed countries, being one of the main risk factors for cardiovascular morbidity. Its prevalence is high, and it is diagnosed in about 15 to 20% of the population in general. In Brazil, there are no global data, but it is estimated that at least 15 to 20% of the population is hypertensive, which corresponds to approximately thirty million people. The prevalence rates in the Brazilian urban adult population in selected studies vary from 22.3 to 43.9%.

The uncontrolled systemic arterial hypertension causes metabolic and hormonal alterations that are responsible for the complications in the so-called white organs, which are: heart, kidneys, brain, retina and blood vessels.

Therapeutics of high blood pressure is currently changing and is due to several reasons. Firstly, it is due to the increase in the number of patients considered high risk, then to the growth of the elderly population, to the increase in the incidence of type II diabetes, which reflects an increase in obesity in industrialized societies and the longer survival of patients with heart attack, stroke, heart failure or kidney failure.

Second, countless randomized and controlled studies have shown conclusive evidence that, in high-risk patients, levels of blood pressure reduction should be considerably lower than those previously advocated.

Despite the clear evidence that hypertension increases the risk of cardiovascular morbidity, the relative ease of diagnosis of hypertension, the availability of several antihypertensive drugs and the evidence of the decrease in cardiovascular morbidity with the regulation of blood pressure, through various classes of antihypertensive drugs and, consequently, they are with their blood pressure controlled.

However, recent studies conducted in Canada, the United States and many other countries show that only 50 to 60% of hypertensive patients know about their disease and only a minority of these is controlled. Therefore, the need for better detection and management of hypertension treatment becomes evident.

Inadequate control of blood pressure can be caused by several factors, including the innumerable physiopathological mechanisms and their heterogeneity among patients, the lack of doctors to assess or modify first-line medications and the patient's adherence to treatment.

The antihypertensive regimen of a single drug, in general, only reaches a physiopathological mechanism that leads to the development, maintenance and arterial progression. The role of a particular pathophysiologic mechanism varies from patient to patient, which probably explains the low response rates of monotherapy. Another reason for the limited efficacy of monotherapy is related to the compensatory increase of other pressor mechanisms, with an attempt to cancel the antihypertensive effects. In addition, arterial hypertension can be associated with other conditions (diabetes mellitus, glucose resistance, obesity, dyslipidemia, etc.) that are risk factors for cardiovascular morbidity. In this way, in addition to controlling blood pressure, antihypertensive drugs must have, at least, a neutral (if not positive) effect in these conditions. In addition, adverse metabolic effects (more commonly in high doses) imbalance the positive effects of lowering blood pressure.

Thus, in the long-term control of arterial hypertension, the adherence of the patient to treatment is a fundamental aspect. This adherence is hindered by social, cognitive and behavioral factors enhanced by the likelihood of adverse reactions with increased doses and by the need for several daily doses that some of the hypotensive drugs need.

Thus, to control blood pressure levels, several studies demonstrate the need for multiple drug use associated with some recommendations for better adherence of the patient to treatment, such as: incentive to changes in lifestyle, educate the patient and the family about the disease, maintain a good doctor-patient relationship and discuss the integration of the daily treatment with the individual.

A fixed combination of drugs provides a greater simplicity of the therapeutic regimen, allowing a reduction in the number of tablets, which is associated with a better adherence of the patient to the treatment. In addition, the price of the fixed combination of drugs is usually lower, when compared to the use of associated drugs in different packages. On the other hand, the association of two drugs separately offers greater flexibility in the assessment process, when compared to a fixed combination. However, that counterbalances the evidence that the more complex the therapeutic regimen, the worse the adherence.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph of Dissolution Percentage vs. Time for amlodipine besilate in 0.01 N HCl Figure 2 is a graph of Dissolution Percentage vs. Time for amlodipine besilate in stopper pH 4.6.

Figure 3 is a graph of Dissolution Percentage vs. Time for amlodipine besilate in stopper pH 6.8.

Figure 4 is a graph of Dissolution Percentage vs. Time for atonolol.

DESCRIPTION OF THE INVENTION The present invention proposes the pharmaceutical association between a calcium channel antagonist, amlodipine, and a beta-blocker, atenolol, useful for controlling blood pressure values, and thus, systemic arterial hypertension, as well as regulating the blood flow in the coronary arteries, reducing the risk of angina pectoris. This association agrees efficacy and lower incidence of adverse effects with fewer daily doses.

Amlodipine is part of the group of calcium channel blockers or blockers, and belongs to the class of dihydropyridines, being the drug that has minor structural changes and, therefore, greater photostability and lower rate of metabolic clearance. Amlodipine, or (2- [2-amino-ethoxyl) methyl] -4 (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine) is highly soluble in water and has the formula Plain structural: Dihydropyridinics inhibit the influx of calcium through the membrane into the cardiac and vascular musculature, promoting relaxation of the smooth vascular musculature. They present lower incidence of myocardial depression and conduction disturbances in comparison to the other calcium antagonists.

The amlodipine is completely and gradually absorbed by the gastrointestinal tract with similar recovery in urine and faeces, which is demonstrated through radioactive assays, when the drug is administered orally or intravenously. It reaches serum peaks between 6 and 9 hours, after oral administration. The bioavailability is from 60 to 65%, being higher among calcium antagonists.

This drug is extensively metabolized, after oral administration. The first step occurs by oxidation of the pyridine analogue with subsequent oxidative deamination of the 2-aminoethoxymethyl side chain or deesterification of the 5-methoxycarbonyl group. Although the initial pathway of metabolism is similar to that of other dihydropyridines, the oxidation rate of amlodipine appears to be lower. The main derivatives of amlodipine are derivatives of pyridine, which are inactive from the point of view of the activity of blocking calcium channels.

Amlodipine presents high ligation with plasma proteins, around 98%, as well as high affinity to tissues, as evidenced by the large volume of distribution, about 21 1 / Kg. This drug shows a slower association and dissociation rate when the vascular and cardiac tissues isolated differentially from the other dihydropyridinics were evaluated.

The hemodynamic analysis of the dose-response curve of amlodipine administered intravenously in patients with left ventricular dysfunction indicates that cumulative doses of 10 to 20 mg promote the reduction of systolic and diastolic blood pressure, as well as the rate of systemic vascular resistance in repose. There is also a significant increase in heart rate and rate. The primary effect of amlodipine in patients with stable angina appears to derive from decreased afterload and increased cardiac performance.

The elimination half-life of amlodipine is 35 to 50 hours, being the longest among calcium antagonists, regardless of whether or not the administered dose is unique. This long half-life allows the use of amlodipine in a single daily dose.

About 60% of the dose of amlodipine is excreted in the urine, being 5 to 10% with the inactive form. The plasma clearance of the drug is 7 ml / min / Kg and it is reduced in elderly people. Fecal excretion is 20 to 25% of the dose, which follows biliary excretion.

Adverse effects to amlodipine may include: edema, flushing, skin rash, flabbiness, fatigue, gynecomastia, in addition to haematological, cardiovascular, gastrointestinal, hepatic, genitourinary, visual, skeletal muscle disorders and adverse metabolic events.

Another active principle used in the present invention is atenolol, or 4- [2-hydroxy-3 [(1-methylethyl) amino] propoxy] benzeneacetamido, which has the following structural organization: Calcium channel blockers, such as amlodipine, promote arterial vasodilation predominantly and predominantly. They are effective antihypertensive drugs and reduce cardiovascular morbidity in elderly people. Beta-blockers, such as atenolol, have as mechanism of action the initial decrease in cardiac output, reduction of renin secretion, readaptation of baroreceptors and decrease in catecholamines at nerve synapses. They are effective in the treatment of arterial hypertension and are also effective in reducing cardiovascular morbidity.

The peak of antihypertensive response with atenolol occurs in 3 to 14 days and the initial response in 3 hours. Its duration of action, after oral ingestion, is 24 hours. Atenolol reaches the peak concentration in 2 to 4 hours. It has bioavailability of 40 to 60%, after oral ingestion and its gastrointestinal absorption is fast and incomplete. Atenolol binds to plasma proteins in less than 5%. Only small amounts penetrate the central nervous system. Its volume of distribution is 50 to 75 liters (intravenous). Its elimination half-life is 6 to 7 hours.

Atenolol is not metabolized in the liver and there is no clinically active metabolite. 40 to 50% of atenolol excretion is renal and 50% of excretion is through faeces. In addition, atenolol is dialyzable.

Adverse events to the consumption of atenolol are the following disturbances: cardiovascular, metabolic, gastrointestinal, genitourinary, respiratory, ophthalmological, muscular, as well as adverse events in the central nervous system.

The practical objectives of the therapeutic combination of atenolol or any of its pharmaceutically acceptable salts, with amlodipine, or any of its pharmaceutically acceptable salts, are to obtain better control of blood flow in the coronary arteries, as well as of blood pressure and / or increase the tolerability of the organism to these disturbances, through the use of lower doses of the existing component. The pharmaceutical association proposed by the present invention of atenolol, or any of its pharmaceutically acceptable salts, with amlodipine, or any of its pharmaceutically acceptable salts, is still the best option in hypertension associated with coronary artery disease or arrhythmias cardiac The prescription, in a single pharmaceutical form, of a beta blocker and a calcium antagonist, is understood, in this invention, as atenolol, or any of its pharmaceutically acceptable salts, with amlodipine, or any of its pharmaceutically acceptable salts, promotes a theoretical and practical advantage of increasing the adherence of the patient, by reducing the number of daily doses and the number of drugs that the patient must carry From the pharmacological point of view, the hemodynamic effects of atenolol, or any of its salts pharmaceutically acceptable, with amlodipine, or any of its pharmaceutically acceptable salts, are complementary, since they act in different mechanisms of arterial hypertension and angina pectoris. In addition, neutralization occurs of the adverse effects that occur with each drug in isolation. As an example, there is a decrease in tachycardia caused by dihydropyridine and peripheral vasoconstriction from the use of beta-blockers.

In addition, they are drugs that present a satisfactory metabolic profile and also reverse or prevent trophic phenomena such as hypertrophy of the left ventricle and vascular hypertrophy. Because they are highly effective drugs such as monotherapy, they have the capacity to protect white organs and have a low incidence of adverse effects.

The association presented by this invention between atenolol, or any of its pharmaceutically acceptable salts, with amlodipine, or any of its pharmaceutically acceptable salts, promotes a greater tolerance when compared to drugs used in isolation, through the following mechanism: Amlodipine reduces the peripheral vasoconstriction caused by atenolol and atenolol reduces the effects of the sympathetic activity of amlodipine.

In addition, the simple association of atenolol with amlodipine in the same galenic formulation is not obvious in the current state of the art, since the association is not stable in the form of tablets. Stability is achieved only when the two active components of the formulation are comprised in a hard gelatinous capsule, wherein the amlodipine, or any of its pharmaceutically acceptable salts, is in the form of tablets and atenolol, or any of its pharmaceutically salts acceptable, is in the form of granulate.

Thus, the ideal pharmacotechnical achieved for the association of the present invention is responsible for the stability of the pharmaceutical combination of those two classes of active principles (amlodipine or any one of its pharmaceutically acceptable salts with atenolol or any of its pharmaceutically acceptable salts). acceptable, which promotes the potential of the mechanism of action of the drug in the body.

In this way, the combination of amlodipine (calcium antagonist) with atenolol (beta-blocker) in a single galenic formulation, that is, hard gelatin capsules, is stable rational and current, because in addition to making the therapy easier, it promotes an increase in efficacy, with a reduction in adverse reactions and in a single daily dose, which evidently increases the patient's adherence to chronic hypotensive treatment and stable chronic coronary insufficiency (angina pectoris).

The present medicament is intended for the prevention and treatment of arterial hypertension and stable coronary insufficiency in a single daily dose and consists of the following composition: from 5 to 20 mg of amlodipine and from 20 to 100 mg of atenolol.

Such an association, formulated according to appropriate pharmaceutical technology, can present, in addition to the active principles mentioned, pharmaceutically acceptable excipients.

Some comparative dissolution methods between tablets and capsules for each active principle are detailed below: Example 1: Amlodipine Besilate: 1. 1 Description and reference of the method.

Condition 1: Apparatus II (blades) Dissolution medium: hydrochloric acid 0.01 N Temperature: 37 ° C + 0.5 Volume: 900 mi Blade speed: 100 rpm Time: 60 minutes According to local methodology Comments: Completed Show yourself in the times: 10, 20, 30, 45 and 60 minutes.

Condition 2: Apparatus II (blades) Dissolution medium: 0.1 N acetate buffer pH 4.6 Temperature: 37 ° C ± 0.5 Volume: 900 ml Blade speed: 100 rpm Time: 60 minutes According to local methodology Observations: Samples were taken at times: 10, 20, 30, 45 and 60 minutes.

Condition 3: Apparatus II (blades) Dissolution medium: Phosphate buffer pH 6.8 Temperature: 37 ° C ± 0.5 Volume: 900 ml Blade speed: 100 rpm Time: 60 minutes According to local methodology Comments: performed in the times: 10, 20, 30, 45 and 60 minutes.

Results of dissolved percentages: Condition 1: TABLE 1 Amlodipine Besilate Capsules: 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes Samples%%%% Dissolution Dissolution Dissolution Dissolution Dissolution 1 85.04 91.16 94.36 96.81 97.26 2 84.49 90.74 94.90 95.37 97.09 3 85.75 91.54 95.54 97.17 97.82 4 85.81 91.87 95.92 97.42 98.75 5 85.49 91.53 95.63 96.78 98.11 6 84.21 91.09 95.21 96.42 97.86 7 86.75 92.53 96.96 98.08 99.07 8 85.47 91.46 95.49 96.71 97.86 85.72 91.84 95.95 97.14 98.24 0 85.82 92.15 96.11 97.14 98.19 1 85.33 91.23 96.19 97.13 98.32 2 85.47 91.57 95.61 96.87 97.99 1 TABLE 2 Amlodipine besylate tablets: 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes Samples% a. 0. Q. g, or Dissolution Dissolution Dissolution Dissolution Dissolution 1 78.30 88.30 91.28 94.86 96.68 2 80.32 88.59 92.37 95.78 96.24 3 80.13 87.45 92.86 95.73 98.08 4 79.85 88.01 93.62 94.59 96.73 5 80.04 89.36 93.15 95.48 97.09 6 79.79 88.79 93.32 96.23 98.13 7 79.56 89.29 92.89 95.42 94.51 78.50 87.19 93.02 95.18 97.02 78.65 86.14 92.76 94.50 96.57 0 79.85 89.65 92.08 94.76 96.63 1 79.52 87.49 93.51 95.78 97.30 2 79.37 87.22 91.98 95.32 96.21 Condition 2: TABLE 3 Amlodipine Besilate Capsules: TABLE 4 Amlodipine besylate tablets: 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes Samples Q. o, o o. * o ~ o o% Dissolution Dissolution Dissolution Dissolution Dissolution 1 70.44 78.73 83.61 84.88 86.15 2 69.91 79.20 84.10 83.89 85.62 3 70.02 78.41 83.27 84.48 86.92 4 71.21 79.06 83.95 85.07 87.13 5 70.68 77.90 82.72 86.85 85.31 6 68.37 77.26 82.04 83.59 85.19 7 69.30 78.83 83.71 84.68 86.56 8 68.95 78.34 83.18 83.94 85.84 69.99 78.81 83.12 84.72 86.17 0 69.11 79.13 84.03 84.92 86.94 1 70.12 79.20 84.12 85.29 87.58 2 71.88 79.29 81.27 85.52 87.29 Condition 3: TABLE 5 Amlodipine Besilate Capsules: 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes Samples Dissolution Dissolution Dissolution Dissolution Dissolution 1 63.58 71.42 76.72 79.95 82.01 2 66.23 72.84 76.46 81.28 79.63 3 62.18 70.36 75.53 79.02 77.91 4 62.54 79.51 76.75 78.19 77.83 5 63.13 71.09 75.96 78.46 78.95 6 62.09 70.29 76.89 79.12 79.35 7 64.37 71.21 76.54 78.34 78.67 8 64.08 80.79 75.78 78.62 78.52 9 65.48 72.27 77.63 79.52 79.64 0 67.24 73.34 78.19 79.53 79.86 1 63.16 71.25 76.35 78.41 79.64 2 62.94 71.32 76.59 79.16 79.86 TABLE 6 Amlodipine Besylate Tablets: 10 minutes 20 minutes 30 minutes 45 minutes 60 minutes Samples o. g, o, * or ¾%? Dissolution Dissolution Dissolution Dissolution Dissolution 1 56.76 67.37 75.58 81.35 83.81 2 58.21 68.51 76.12 81.19 83.61 3 53.95 66.32 75.31 80.63 84.29 4 56.81 67.85 74.18 80.86 82.64 5 55.20 67.13 75.29 80.76 84.15 6 52.99 66.79 74.28 80.37 82.48 7 56.10 67.94 76.37 81.72 84.16 8 57.41 67.81 74.21 80.97 85.62 56.34 66.82 72.33 81.24 82.67 0 57.35 67.14 76.28 80.64 84.15 1 57.39 67.42 75.02 81.72 83.24 2 58.61 65.29 73.38 80.12 82.84 1. 3: Averages and deviations: Condition 1: TABLE 7 Amlodipine Besilate Capsules: % of dissolution% of CV of the average results 10 minutes 85.45 0.77 20 minutes 91.56 0.53 30 minutes 95.66 0.69 45 minutes 96.92 0.66 60 minutes 98.05 0.56 TABLE 8 Amlodipine besylate tablets:% dissolution% CV of the average results 10 minutes 79.49 0.84 20 minutes 88.12 1.20 30 minutes 92.74 0.75 45 minutes 95.30 0.57 60 minutes 96.77 0.97 Condition 2; TABLE 9 Amlodipine Besilate Capsules: % of dissolution% of CV of the average results 10 minutes 77.71 1.40 20 minutes 79.66 1.51 30 minutes 82.50 1.90 45 minutes 83.48 1.62 60 minutes 85.42 1.66 TABLE 10 Amlodipine Besylate Tablets: % of dissolution% of CV of the average results 10 minutes 70.00 1.41 20 minutes 78.68 0.78 30 minutes 83.26 1.06 5 minutes 84.82 1.02 0 minutes 86.39 0.92 Condition 3: TABLE 11 Amlodipine Besilate Capsules: % of dissolution% of CV of the average results 10 minutes 63.92 2.57 20 minutes 72.97 4.77 30 minutes 76.62 0.97 45 minutes 79.13 1.10 60 minutes 79.38 1.44 TABLE 12 Amlodipine besylate tablets: % of dissolution% of CV of the average results 10 minutes 56.43 2.95 20 minutes 67.20 1.26 30 minutes 74.86 1.64 5 minutes 80.96 0.62 0 minutes 83.64 1.10 1.4 Acceptance criteria: So that the averages of the percentages of dissolution obtained in each time can be used in the calculations, the percentage of the coefficient of variation of these results can not be greater than 20% for the initial times (up to 15 minutes) and can not be greater than 10% for the other times.

Condition 1: Capsules vs. Tablets (amlodipine besilate in HC1 0.01 N), see Figure 1"Dissolution Percentage vs. Time" Condition 2: Capsules vs. tablets (amlodipine besylate in stopper pH 4.6), see Figure 2"Dissolution percentage vs. time" Condition 3: Capsules vs. tablets (amlodipine besylate in stopper pH 6.8), see Figure 3"Dissolution percentage vs. time". 1. 5 Calculation of Fs factors: f1 =. { [? t = ln I Rt - Tt |]? / [? t = n Rt]} ? x 100 (III) f2 = 50 x log. { [1 + (1 / n)? t = n (Rt - Tt) 2] ~ 0'5 x 100.}. (IV) Where: n = number of times analyzed Rt =% dissolution of the reference product at time t Tt =% dissolution of another product at time t Observations : 1) so that the dissolution curves are considered similar, the value of fl must be between 0 and 15 and the value of f2 must be between 50 and 100. ) the percentage of dissolution at each time t is the average of the results obtained from the 12 tablets. 1. 6 Results of the calculation of Fs: Condition 1: Capsules 5/25 mg (amlodipine besilate) x 5/25 mg tablets (amlodipine besilate) Fl = 4, 73 F2 = 67.68 Condition 2: Capsules 5/25 mg (amlodipine besilate) x 5/25 mg tablets (amlodipine besilate) Fl = 2.92 F2 = 71.55 Condition 3: Capsules 5/25 mg (amlodipine besilate) x 5/25 mg tablets (amlodipine besilate) Fl = 5.81 F2 = 65.59 Example 2: Atenolol: 2. 1 Description and reference of the method: Apparatus II (blades) Dissolution medium: 0.1 N acetate buffer pH 4.6 Temperature: 37 ° C ± 0.5 Volume: 900 ml Blade speed: 50 rpm Time: 45 minutes According to United States Pharmacopeia Remarks: Samples were taken at times: 10, 15, 20, 30 and 45 minutes. 2. 2 Results of dissolved percentages: TABLE 13 Atenolol capsules 10 minutes 15 minutes 20 minutes 30 minutes 45 minutes Samples o, o, Q. o? or% Dissolution Dissolution Dissolution Dissolution Dissolution 1 73.80 92.74 96.24 98.30 99.36 2 59.19 78.57 100.57 102.50 103.09 3 56.16 j 82.83 90.61 95.28 97.18 4 87.17 98.36 99.02 99.66 100.23 5 65.82 81.57 92.67 98.76 99.74 6 70.24 89.67 95.76 99.37 100.67 7 62.89 80.56 91.82 96.72 99.13 78.59 95.71 98.58 99.85 100.86 84.72 96.65 99.37 100.28 101.21 0 77.52 93.73 96.81 100.87 101.08 1 58.34 79.87 93.73 97.19 98.89 2 61.89 83.67 94.29 98.12 99.07 TABLE 14 Atenolol Tablets 10 minutes 15 minutes 20 minutes 30 minutes 45 minutes Samples%% o or "0 Dissolution Dissolution Dissolution Dissolution Dissolution 1 62.52 79.40 88.91 94.64 96.87 2 64.94 82.46 90.10 96.21 98.64 3 66.23 83.96 93.10 94.49 97.54 4 66.38 84.99 95.71 97.11 98.27 5 62.48 79.57 88.18 95.00 98.26 64.91 82.49 88.92 96.45 97.85 68.94 85.48 94.15 96.51 98.37 60.54 78.70 92.30 98.78 99.18 64.45 80.56 93.58 95.41 97.85 0 61.83 78.25 94.56 96.34 98.19 1 65.49 85.45 91.23 97.34 99.47 2 61.84 79.71 92.51 94.32 96.83 2. 3 Averages and deviations: TABLE 15 Atenolol Capsules % dissolution% CV% of the results 10 minutes 69.69 15.19 15 minutes 87.83 8.38 20 minutes 95.79 3.36 30 minutes 98.91 1.98 45 minutes 100.04 1.50 TABLE 16 Atenolol Tablets % dissolution% CV% of the results 10 minutes 64.21 3.70 20 minutes 81.75 3.33 30 minutes 91.94 2.68 5 minutes 96.05 1.39 0 minutes 98.11 0.82 2. 4 Graphics: See Figure 4"Dissolution Percentage vs. Time". 2. 5 Calculation of Fs factors: f1 =. { [? t = ln I Rt - Tt |]? / [? t = n Rt]} ? x 100 (V) f2 = 50 x log. { [1 + (l / n)? t = n (Rt - Tt) 2] ~ 0'5 x 100.}. (SAW) Where: n = number of times analyzed Rt =% dissolution of the reference product at time t Tt =% dissolution of another product at time t Observations : 1) so that the dissolution curves are considered similar, the value of fl must be between 0 and 15 and the value of f2 must be between 50 and 100. 2) the percentage of dissolution at each time t is the average of the results obtained from the 12 tablets. 1. 6 Results of the calculation of Fs: Condition 1: Capsules 5/25 mg (atenolol) x tablets 5/25 mg (atenolol) Fl = 6.48 F2 = 63.72 Conclusion: In accordance with the results obtained in examples 1 and 2, it can be concluded that the dissolution profiles of the capsules containing amlodipine, or any of its pharmaceutically acceptable salts, in the form of tablets, and atenolol, or any of its pharmaceutically salts acceptable, in the form of granules, are better than the dissolution profiles of the tablets containing the same active ingredients, as verified in examples 1 and 2.

Said conclusion is important because it proves that amlodipine, or any of its pharmaceutically acceptable salts, in the form of tablets, in association with atenolol, or any of its pharmaceutically acceptable salts, with the form of granules, which are involved by a hard gelatin capsule, results in a galenic formulation more stable than the form of tablets containing the same active ingredients, also does not alter the dissolution profiles of drugs in the body.

Claims (12)

1. Pharmaceutical combination in a new pharmaceutical form useful in arterial hypertension and in stable chronic coronary insufficiency, characterized by presenting, as active principles, a calcium channel antagonist and a beta-blocker.

2. Pharmaceutical combination in a new pharmaceutical form useful in arterial hypertension and stable chronic coronary insufficiency, according to claim 1, characterized in that the calcium channel antagonist is amlodipine or any of its pharmaceutically acceptable salts.

3. Pharmaceutical combination in a new pharmaceutical form useful in arterial hypertension and stable chronic coronary insufficiency, according to claims 1 and 2, characterized in that the beta-blocker is atenolol or any of its pharmaceutically acceptable salts.

Pharmaceutical combination in a new pharmaceutical form useful in hypertension and stable chronic coronary insufficiency, according to claims 1 to 3, characterized in that, in addition to the active ingredients, the formulation can also present pharmaceutically acceptable excipients .

Pharmaceutical combination in a new pharmaceutical form useful in arterial hypertension and stable chronic coronary insufficiency, according to claims 1 to 4, characterized by being used in the prevention and treatment of arterial hypertension, as well as coronary insufficiency stable (angina pectoris).

Pharmaceutical combination in a new pharmaceutical form useful in hypertension and stable chronic coronary insufficiency, according to claims 1 to 5, characterized by formulating according to appropriate pharmaceutical technology.

A pharmaceutical combination in a new pharmaceutical form useful in arterial hypertension and in stable chronic coronary insufficiency, according to claims 1 to 6, characterized in that amlodipine, or any of its pharmaceutically acceptable salts, is presented in the form of a tablet.

Pharmaceutical combination in a new pharmaceutical form useful in arterial hypertension and stable chronic coronary insufficiency, according to claims 1 to 7, characterized in that atenolol, or any of its pharmaceutically acceptable salts, is presented in the form of granules.

Pharmaceutical combination in a new pharmaceutical form useful in arterial hypertension and stable chronic coronary insufficiency, according to claims 1 to 8, characterized in that the tablet containing amlodipine, or any of its pharmaceutically acceptable salts, and of the atenolol granulate, or any of its pharmaceutically acceptable salts, are contained within a hard gelatin capsule.

Pharmaceutical combination in a new pharmaceutical form useful in arterial hypertension and stable chronic coronary insufficiency, according to claims 1 to 9, characterized in that the pharmacotechnical used is responsible for the stability of the pharmaceutical association of amlodipine or any of its pharmaceutically acceptable salts with atenolol or any of its pharmaceutically acceptable salts.

11. Pharmaceutical combination in a new pharmaceutical form useful in arterial hypertension and stable chronic coronary insufficiency, according to claims 1 to 10, characterized in that the pharmaceutical form of capsules, containing amlodipine, or any of its pharmaceutically salts acceptable, in the form of a tablet, and atenolol, or any of its pharmaceutically acceptable salts, in the form of granulate, presents better dissolution profiles than in the tablet form, -

12. Pharmaceutical combination in a new pharmaceutical form useful in hypertension and stable chronic coronary insufficiency, according to claims 1 to 11, characterized in that the formulation has the following composition: from 5 to 20 mg of amlodipine or any of its pharmaceutically acceptable salts and from 20 to 100 mg of atenolol or any of its pharmaceutically acceptable salts.