UA122908C2 - Pharmaceutical composition comprising an hmg-coa reductase inhibitor and an eca inhibitor - Google Patents

Abstract

Fixed pharmaceutical compositions comprising an HMG-CoA reductase inhibitor, atorvastatin, and an antihypertensive agent, perindopril, and use of said compositions for the treatment and prevention of cardiovascular diseases and more particularly coronary events in patients with a history of myocardial infarction and/or of revascularization in combination with primary hypo-cholesteraemia or mixed hyperlipidaemia.

Description

The present invention relates to a fixed pharmaceutical composition containing an inhibitor of HMG-

CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase and antihypertensive agent, as well as the use of this composition in the treatment and prevention of cardiovascular diseases.

Technical level

Cardiovascular disease is the leading cause of death in developed and developing countries, accounting for approximately one third of all deaths worldwide. Deaths related to cardiovascular disease are expected to increase to 23.3 million in 2030.

In Europe, cardiovascular disease is the leading cause of premature mortality and disability-adjusted life years for men and women, accounting for nearly 4.1 million deaths per year, or 46,95 of all deaths. Almost 1.8 million of these deaths (20 95 of all deaths) are related to coronary heart disease (CHD). One in six men and one in seven women in Europe will die from a myocardial infarction (MI).

The development of coronary artery disease is caused by the global effect of risk factors that can be eliminated or that cannot be eliminated. These risk factors include hypertension, dyslipidemia, overweight and obesity, diabetes, sedentary lifestyle, smoking, alcohol, more or less high salt intake, family history of hypertension and premature cardiovascular disease, age, gender, and psychological factors such as like anxiety and depression. The coexistence of such risk factors significantly increases morbidity and mortality rates.

People with a history of MI and acute cerebrovascular accident (ACC) have the highest risk of other coronary syndromes and stroke. There is substantial scientific evidence that specific interventions can reduce the risk of other vascular events in patients with MI. In particular, acetylsalicylic acid or aspirin at low doses of 75 to 150 mg is considered the cornerstone of pharmacological prevention of arterial thrombosis.

Stable coronary artery disease associated with dyslipidemia, as well as other risk factors, may increase the risk of cardiovascular disease. Dyslipidemia is a risk factor for cardiovascular diseases that can be eliminated, and this factor is of great importance in their prevention. The greatest attention is paid to the high level

Of total cholesterol (THD) and low-density lipoprotein (LDL), particularly because they can be modified by lifestyle changes and medications.

Primary and secondary prevention clinical trials show that lowering total cholesterol and low-density lipoprotein cholesterol (LDL-C) with statins can prevent cardiovascular disease.

Interestingly, treating a single risk factor can reduce the risk of cardiovascular disease by about 30,905, while treating multiple risk factors can reduce the risk of cardiovascular disease by more than 50,95.

Chronic diseases usually require long-term multifaceted treatment, which increases the risk of non-adherence to the treatment regimen, as well as related concerns about the safety of such treatment. Patients are classified as noncompliant based on the proportion of treatment days with coverage less than 0.80.

Noncompliance is widespread among ambulatory patients with coronary artery disease and is associated with a wide range of adverse effects, including total and cardiovascular mortality, hospitalization for a cardiovascular event, and revascularization procedures. Similarly, discontinuation of low-dose acetylsalicylic acid increases the risk of nonfatal MI or death from coronary heart disease by more than 50–95 in primary care patients with a history of ischemic events.

Noncompliance with treatment was the most common reason for treatment discontinuation.

A meta-analysis of five studies comparing the administration of a fixed combination and individual components was performed. The efficiency of compliance of combined therapy compared to the introduction of individual components was investigated. This meta-analysis evaluated the use of fixed combination therapy in various clinical contexts, including hypertension, heart failure, myocardial infarction, hypercholesterolemia, diabetes, tuberculosis, and human immunodeficiency virus infection. The results of this meta-analysis showed a much better compliance of fixed combinations compared to the introduction of individual components. The compliance rate was improved by 2695 in patients receiving fixed combinations.

The use of polypills for the treatment of secondary cardiovascular diseases has received increased attention and support from the World Health Organization (WHO) and the World Heart Federation (WHF).

It is in this context that the present invention proposes to develop a novel fixed combination comprising a statin and at least one antihypertensive agent selected from an IPF such as perindopril or a diuretic such as indapamide, optionally with another active agent selected from a non-steroidal anti-inflammatory drug (NSAIDs) such as acetylsalicylic acid.

In the prior art, there are a number of documents that describe the relationship between statins, antihypertensive drugs and/or aspirin.

Patent application M/O 99/11259 describes a therapeutic combination containing amlodipine and atorvastatin in the treatment of hypertension, hyperlipidemia, angina, atherosclerosis, and cardiovascular risk management.

UMO patent application 99/11260 describes a combination therapy containing atorvastatin and an antihypertensive agent in the treatment of hypertension, hyperlipidemia, angina pectoris, atherosclerosis, and cardiovascular risk management. These antihypertensive drugs include calcium channel inhibitors, ACE inhibitors, A-II antagonists, diuretics, beta-adrenergic blockers, vasodilators, and alpha-adrenergic blockers.

The two applications do not mention interaction or decomposition problems that may exist within a fixed pharmaceutical composition of two or more active ingredients.

UMO patent application 03/092729 describes a stable pharmaceutical composition that contains a statin in combination with an ACE inhibitor, and that contains at least one stabilizing agent for the statin and at least one stabilizing agent for the ACE inhibitor, and in this composition, the statin and the ACE inhibitor are separated by a layer or a membrane made of a compatible physiologically inert material with a neutral pH.

ACE inhibitors are compounds sensitive to dissolution reactions activated in the presence of acids or bases. Such an application solves the problem of decomposition or dissolution of ACE inhibitors in the presence of statins by developing a stable pharmaceutical composition in which the amount of active ingredients does not change over time, and the active ingredients do not decompose at all or only partially decompose.

Patent application MO 99/47123 describes a pharmaceutical composition that contains

A cholesterol-lowering agent based on a statin and an aspirin to minimize statin:aspirin interactions, in which (i) the statin and aspirin are presented in a single bilayer tablet and in which the aspirin is present in the first layer and the statin in the second layer; or (its) pharmaceutical composition is made in the form of a capsule, which contains aspirin granules and statin granules. This application solves the problem of interactions between active ingredients.

UMO patent application 2011/096665 describes a complex composition for the prevention and treatment of cardiovascular diseases, which contains a) aspirin covered with a barrier of a hydrophobic excipient, and b) an HMG-CoOA reductase inhibitor. This application solves the problem of the instability of HMG-CoA reductase, which is unstable in an acidic environment.

UMO patent application 2012/002919 describes a pharmaceutical composition in the form of a tablet or capsule containing atorvastatin and aspirin, each of these active ingredients can be in the form of tablets, mini-tablets, micro-tablets, microcapsules, granules and/or powder , and such a composition can be used in the prevention or treatment of cardiovascular diseases. Doses of aspirin range from 1 to 500 mg, preferably from 1 to 300 mg, and most preferably from 1 to 150 mg. Doses of atorvastatin are from 1 to 200 mg, preferably from 1 to 150 mg, and most preferably from 1 to 100 mg/dose. The composition according to this application solves the problem of interaction of active ingredients with each other. The described examples are pharmaceutical compositions containing aspirin tablets and atorvastatin granules or aspirin tablets and atorvastatin granules in capsules.

UMO patent application 2012/011882 describes a pharmaceutical composition that contains atorvastatin and aspirin, while each of these active ingredients is in the form of a powder, and such a composition can be used in the prevention or treatment of cardiovascular diseases. The object of this application is to provide a pharmaceutical composition which contains both aspirin and atorvastatin, and which has good bioavailability and which does not exhibit chemical degradation. In addition, atorvastatin in the composition is sufficiently soluble in water.

UMO patent application 2012/081905 describes a pharmaceutical composition for the prevention and treatment of cardiovascular diseases, which contains, on the one hand, an HMG-CoA reductase inhibitor and the main auxiliary agent, and, on the other hand, aspirin covered with an enteric layer. The HMG-CoA reductase inhibitor can be in the form of powder, granules, pellets or mini-tablets, and the aspirin can be in the form of granules, pellets or mini-tablets.

UMO patent application 2012/124973 describes a pharmaceutical composition for the treatment of cardiovascular diseases, which contains atorvastatin in the form of mini-tablets and aspirin in the form of enteric-coated mini-tablets or mini-granules, thus reducing the interaction between the two active ingredients, and while at the same time optimizing the therapeutic effect and stability during storage.

Patent application UMO 03/020243 describes a pharmaceutical composition that can be made in the form of a capsule and that contains an agent that lowers the level of cholesterol and is a statin, PPI, and aspirin, and in which at least one of the components is separated from the other two.

The components can be in the form of pellets or granules. This application describes a pharmaceutical composition which is a multi-layer tablet containing a first layer of lovastatin extended release, a second layer of enalapril extended release, a distribution layer of excipients and an immediate release layer of aspirin. This application also describes a pharmaceutical composition that contains lovastatin granules, enalapril granules and an immediate release aspirin matrix, which are mixed to form a tablet by compression.

Finally, this application describes a pharmaceutical composition in the form of tablets or capsules containing a variety of active ingredients, including lovastatin, enalapril and aspirin, all in an immediate release form, which is obtained by mixing the powders and the mixture is then injected into the capsule.

This application also describes the problem of interaction between different active ingredients in a fixed pharmaceutical composition, as well as possible interactions between active ingredients and excipients. However, different active ingredients have different release profiles.

UMO patent application 2004/080488 describes pharmaceutical compositions containing acetylsalicylic acid, an HMG-CoA reductase inhibitor and, optionally, an antihypertensive drug for the primary prevention of cardiovascular diseases. This application describes examples that include - aspirin, atorvastatin and optionally amlodipine, as well as - aspirin, simvastatin and perindopril.

Patent application MO 2009/118359 describes a pharmaceutical composition in the form of a capsule for

For the prevention of cardiovascular diseases, which contains film-coated tablets of acetylsalicylic acid, film-coated tablets of simvastatin or pravastatin, and film-coated tablets of lisinopril, ramipril, or perindopril. The examples described in this application contain 100 mg of acetylsalicylic acid, 20 mg of simvastatin and ramipril (2.5; 5 or 10 mg) or lisinopril (20 mg).

UMO patent application 2014/195421 describes an oral composition for the treatment of cardiovascular diseases, which contains an HMG-CoA reductase inhibitor, which is a statin, and acetylsalicylic acid, and in which the interaction between the two active ingredients is minimized. In this composition, two active ingredients are made in the form of a covered unit dose.

The oral composition may additionally contain an inhibitor of the renin-angiotensive system, which is, for example, such an ACE inhibitor as perindopril.

The essence of the invention

The proposed invention relates to a fixed pharmaceutical composition containing an HMG-CoA reductase inhibitor and an antihypertensive agent.

In addition, the proposed invention relates to a fixed pharmaceutical composition that contains an HMG-CoA inhibitor and at least one antihypertensive agent selected from an angiotensin-converting enzyme (ACE) inhibitor, a diuretic, and optionally an NSAID.

More specifically, the proposed invention relates to a fixed pharmaceutical composition containing an HMG-CoA inhibitor and an angiotensin-converting enzyme (API) inhibitor, in which: - the HMG-CoA inhibitor is atorvastatin or its addition salt with a pharmaceutically acceptable acid, their hydrates and crystallized forms, and - PPI is perindopril or its additive salt with a pharmaceutically acceptable acid or base, their hydrates and crystallized forms.

In addition, this invention relates to a fixed pharmaceutical composition, which contains, in addition to the HMG-CoOA reductase inhibitor and IPF, another active ingredient selected from: - NSAIDs or - diuretic.

The proposed invention also relates to the use of fixed pharmaceutical compositions in the treatment and prevention of cardiovascular diseases and, in particular, in the prevention of coronary syndromes in patients with a history of myocardial infarction and/or revascularization due to primary hypercholesterolemia or mixed hyperlipidemia.

The HMG-CoA reductase inhibitor that is preferably used is atorvastatin or its addition salt with a pharmaceutically acceptable acid or base, and in particular, its calcium or sodium salt, hydrates and crystalline forms thereof.

A preferably used angiotensin-converting enzyme inhibitor is perindopril or an addition salt thereof with a pharmaceutically acceptable acid or base, and in particular, its tert-butylamine, tosylate or arginine salts, hydrates and crystalline forms thereof.

NSAIDs that are mainly used are acetylsalicylic acid, or aspirin, or its additive salt with a pharmaceutically acceptable acid or base, their hydrates and crystalline forms.

The diuretic that is preferably used is indapamide or its addition salt with a pharmaceutically acceptable acid or base, their hydrates and crystalline forms.

Detailed description of the invention

The proposed invention relates to a fixed pharmaceutical composition containing atorvastatin or its pharmaceutically acceptable salts, hydrates and crystalline forms thereof, and perindopril or its pharmaceutically acceptable salts, hydrates and crystalline forms, as well as to the use of said composition in the prevention and treatment of cardiovascular vascular diseases.

The proposed invention also relates to a fixed pharmaceutical composition, which, in addition to atorvastatin and perindopril, additionally contains acetylsalicylic acid, which is also called aspirin, or its pharmaceutically acceptable salts, hydrates and crystalline forms thereof, as well as the use of said composition in the prevention and treatment of cardio - vascular diseases.

The proposed invention also relates to a fixed pharmaceutical composition, which, in addition to atorvastatin and perindopril, additionally contains indapamide or its pharmaceutically acceptable salts, their hydrates and crystalline forms, as well as the use of the specified composition in the prevention and treatment of cardiovascular diseases.

Cardiovascular diseases more specifically mean the prevention of coronary syndromes in patients with a history of myocardial infarction and/or

For revascularization in cases with primary hypercholesterolemia or mixed hyperlipidemia.

A fixed pharmaceutical composition has the advantage of reducing production costs and, above all, improving treatment compliance for some patients and, as a result, better control of their pathology.

In the proposed invention, a fixed pharmaceutical composition consists of at least two active ingredients, which are 1) atorvastatin and 2) perindopril, which belong to different therapeutic classes and have complementary effects, and therefore have the advantage of affecting several risk factors responsible for cardiovascular -vascular diseases, when using one dose.

In addition, the proposed invention is a fixed pharmaceutical composition that contains at least three active substances that belong to different therapeutic classes and have complementary effects and are as follows: 1) atorvastatin, 2) perindopril and additionally: a) acetylsalicylic acid, or b) indapamide or

The use of these fixed therapeutic combinations: - atorvastatin and perindopril, - atorvastatin and perindopril and acetylsalicylic acid, and - atorvastatin and perindopril "with indapamide is the prevention of coronary syndromes in patients with a history of myocardial infarction and/or revascularization due to primary hypercholesterolemia or mixed hyperlipidemia as replacement therapy in adult patients who are simultaneously controlled by monotherapy with atorvastatin, perindopril and/or active substances a) - d) in the same doses as in the fixed pharmaceutical composition.

The fixed pharmaceutical composition according to this invention is taken once a day in the morning.

Thus, it is possible to simplify medication administration for patients who take medications separately and, as a result, to improve compatibility by reducing the number of tablets.

All of the active ingredients listed above are medicinal products that have received a registration certificate and have been on the market worldwide for many years. All components are well-known active substances with well-established effectiveness and tolerability.

Atorvastatin is part of a group of medicines called HMG-CoA reductase inhibitors or statins. Atorvastatin reduces the concentration of low-density lipoprotein (LDL) and triglycerides in the blood with an increase in the concentration of high-density lipoprotein (HDL). Atorvastatin in the form of calcium salt trihydrate is sold under the name Taiog? or

At? th corresponding pharmaceutical composition is described in the UMO patent application 94/16693.

Atorvastatin is indicated for: - the treatment of hypercholesterolemia in the form of a dietary supplement to reduce high levels of total cholesterol (Chol-3), LDL-cholesterol (LDL-C), apolipoprotein B and triglycerides in patients with primary hypercholesterolemia, including familial hypercholesterolemia or mixed hyperlipidemia, - prevention of cardiac events in patients with a high risk of having the first such cardiovascular event as a supplement to the correction of other risk factors.

Perindopril is an angiotensin-converting enzyme inhibitor into angiotensin HER (angiotensin-converting enzyme ACE). This converting enzyme, or kinase, is an exopeptidase that allows the conversion of angiotensin I to the vasoconstrictor angiotensin II, which causes the breakdown of the vasodilator bradykinin into an inactive heptapeptide.

Perindopril in the form of arginine salt is sold under the name Coversilg? and indicated for: - treatment of arterial hypertension, - reduction of the risk of cardiac manifestations in patients with a history of myocardial infarction and/or revascularization, and - treatment of symptomatic heart failure.

Acetylsalicylic acid is an inhibitor of platelet activation: by blocking platelet cyclooxygenase by acetylation, it inhibits the synthesis of thromboxane A2, a physiological activator substance released by platelets that will play a role in the complications of atheromatous lesions. Acetylsalicylic acid 100 mg is marketed under the name Abzrigip Rgoiesi" and is indicated for: - prevention of secondary cardiovascular and cerebrovascular complications in patients with ischemic atherosclerotic disease (for example, myocardial infarction, stable and unstable angina pectoris, complete or temporary acute cerebrovascular accident of ischemic origin) , - prevention of thromboembolic manifestations after surgery or vascular intervention, and - reduction of graft occlusion after aorto-coronary bypass.

Indapamide is a sulfonamide diuretic, which pharmacologically belongs to thiazide diuretics. Indapamide hemihydrate is sold under the name RiItsdeh? and indicated for the treatment of arterial hypertension.

One of the main risks of fixed pharmaceutical combinations is the results of possible interactions between the various active ingredients that are present in the combination. In addition, the active ingredients may be incompatible with some excipients, which are nevertheless necessary to stabilize one or another of the active ingredients.

The use of acetylsalicylic acid to reduce the risk of myocardial infarction and the use of statins to lower cholesterol and prevent or treat cardiovascular and cerebrovascular diseases are very well supported by the results of laboratory tests. In fact, concomitant use of statins and ASA in patients who have high cholesterol and who are considered to be "at" risk of myocardial infarction is not common. However, the simultaneous use of statins and acetylsalicylic acid requires special precautions to minimize the interaction between these two drugs, since it is well known that HMG-CoA reductase inhibitors are degraded in the presence of acetylsalicylic acid. Interactions include physical and chemical incompatibilities, as well as side effects.

In addition, statins are sensitive to factors such as heat, humidity, low pH, and light.

In particular, atorvastatin is converted into a lactone, which is the result of an intramolecular esterification reaction. The main products that are formed during the decomposition of statins are lactones and oxidation products that reduce the stability of atorvastatin and, accordingly, its half-life.

Atorvastatin is a molecule that is quite easily decomposed and requires the use of a stabilizing agent, which is in the composition of Tapog? is calcium carbonate. Is this song Tapog? described, in particular, in patent EP 0 680 320.

Unexpectedly, by mixing perindopril with atorvastatin to form a mixture based on the Tapoge composition, that is, in the presence of calcium carbonate, the applicant realized that calcium carbonate modifies the human pharmacokinetics of perindopril, which makes it difficult to achieve bioequivalence of the perindopril composition in the fixed combination "perindopril and atorvastatin".

In fact, in a study of the interaction of a fixed combination of "atorvastatin 40 mg and perindopril arginine 10 mg" compared to atorvastatin 40 mg in pure form and perindopril arginine 10 mg in pure form, the applicant showed that Stach (which is the maximum concentration of the product that is present in of blood after administration) of perindopril in bitherapy was modified. god

Atorvastatin (ng/ml) 77201 Atorvastatin Perindopril 00 Atorvastatin 33333000

C Perindopril 01010100 710 Atorvastatin Perindopril 0 | Perindopril 33303031

Thus, the ratio between perindopril administered in a fixed combination of "atgorvastatin and perindopril" and perindopril administered alone is greater than 130 95.

Therefore, it is necessary to separate these two active ingredients physically to obtain a stable fixed pharmaceutical composition of atorvastatin and perindopril.

The present invention solves this problem by developing a fixed pharmaceutical composition in the form of a capsule, which contains minigranules of atorvastatin and minigranules of perindopril.

Aspirin is known to degrade HMG-CoA reductase inhibitors. In a study of the compatibility of different active ingredients, the applicant was able to show that when the 3 active ingredients are separate, no decomposition occurs, including when atorvastatin and perindopril are in the same composition. In contrast, when aspirin is added to a mixture of atorvastatin and perindopril, the active ingredients break down as shown in the table below.

Table A:

Study of the compatibility of the active substances of perindopril atorvastatin hay 2 2531-30 1.6 | 5 yushShshfZzb

Atorvastatin 31733001

Perindopril. 30317000014200001100000013 ее 10010001

Perindopril

Atorvastatin them

Perindopril same 38,881 15,668 5,784

Aspirin

Thus, in a fixed pharmaceutical composition according to the present invention, which contains atorvastatin, perindopril and aspirin, it is necessary to separate aspirin from atorvastatin and perindopril. Thus, the applicant has developed a fixed pharmaceutical composition in the form of a capsule containing atorvastatin minigranules, perindopril minigranules and aspirin enteric-soluble minigranules.

However, in this fixed pharmaceutical composition, the enteric-dissolving aspirin minigranules are not bioequivalent to enteric-dissolving aspirin tablets on the market, as shown by the applicant (see Figure below, treatment 4).

In this study, it can be seen that treatment profile 4 is different from treatment profiles 1-3, thus showing a difference between enteric-dissolving aspirin tablet and enteric-dissolving aspirin minigranules.

and PROFILES OF MIDDLE POINTS: high and low. and what is that What is YN

Time (hours) : : SOY LUYUVANNYAT 0 LUYUVANNYAS 00LUYUVANNYAT WITH S LUYUVANNYAT

Treatment 1: - 1 capsule of atorvastatin calcium minigranules without calcium carbonate - 1 capsule of perindopril arginine minigranules - 1 capsule of enteric-soluble aspirin minigranules

Treatment 2: - 1 capsule of atorvastatin calcium minigranules with calcium carbonate - calcium carbonate mixing process without grinding - 1 capsule of perindopril arginine minigranules - 1 capsule of enteric-soluble aspirin minigranules

Treatment 3: - 1 capsule of atorvastatin calcium minigranules with calcium carbonate - calcium carbonate mixing process without grinding - 1 capsule of perindopril arginine minigranules - 1 capsule of enteric-soluble aspirin minigranules

Treatment 4: - 1 tablet Tapogo - 1 tablet SomegzuF - 1 enteric-dissolving aspirin tablet

The present invention solves the problem by developing a fixed pharmaceutical composition containing atorvastatin, perindopril and aspirin, in which there is no interaction between different active ingredients and no interaction with excipients. Moreover, in this composition, the active ingredients are bioequivalent to the individual compounds sold as individual tablets.

Thus, the present invention provides a fixed pharmaceutical composition in the form of a capsule containing atorvastatin minigranules, perindopril minigranules and aspirin enteric tablets. Thus, this formulation has the advantage of being bioequivalent to a single enteric-dissolving aspirin tablet, with no interaction between the three active ingredients or excipients.

Also, and for the same reasons as above, this invention includes a fixed pharmaceutical composition comprising:

A) minigranules of atorvastatin, minigranules of perindopril and minigranules of indapamide.

All fixed pharmaceutical compositions according to the present invention contain pharmaceutically acceptable salts in combination with one or more pharmaceutically acceptable excipients, their hydrates and their crystalline forms.

In another embodiment of the invention, fixed pharmaceutical compositions are described, which contain atorvastatin and its pharmaceutically acceptable salts and perindopril and its pharmaceutically acceptable salts in combination with one or more pharmaceutically acceptable excipients, their hydrates and crystalline forms, and: - doses of atorvastatin vary from 10 mg to 80 mg expressed as atorvastatin base, or ranging from 10.80 mg to 86.80 mg expressed as atorvastatin calcium trihydrate, and

- doses of perindopril vary from 1.65 mg to 9.512 mg, expressed on the basis of perindopril, or vary from 2.5 mg to 14 mg, expressed as perindropril arginine.

In another embodiment of the invention, fixed pharmaceutical compositions are described, which additionally contain aspirin and its pharmaceutically acceptable salts or amlodipine and its pharmaceutically acceptable salts or indapamide and its pharmaceutically acceptable salts or bisoprolol and its pharmaceutically acceptable salts in combination with one or more pharmaceutically acceptable excipients , their hydrates and their crystalline forms, and: - doses of aspirin are from 75 mg to 150 mg, expressed on the basis of aspirin, - doses of indapamide vary from 0.625 mg to 2.5 mg, expressed on the basis of indapamide

Preferably, in the fixed pharmaceutical compositions according to the present invention, the doses of: - atorvastatin calcium are 10 mg, 20 mg, 40 mg and 80 mg - perindopril arginine are 2.5 mg, 3.5 mg, 5 mg, 7 mg, 10 mg and 14 mg, - aspirin are 75 mg, 100 mg and 150 mg, and - indapamide are 0.625 mg, 1.25 mg, 1.5 mg and 2.5 mg.

Fixed pharmaceutical compositions according to the present invention, which are the most preferred, are represented by pharmaceutical compositions containing: a) 10 mg of atorvastatin calcium and 2.5 mg, 5 mg or 10 mg of perindopril arginine, b) 20 mg of atorvastatin calcium and 2.5 mg , 5 mg or 10 mg of perindopril arginine, c) 40 mg of atorvastatin calcium and 2.5 mg, 5 mg or 10 mg of perindopril arginine.

Fixed pharmaceutical compositions according to the present invention, which are described in a), b) or c) can each additionally contain 75 mg, 100 mg or 150 mg of aspirin.

Fixed pharmaceutical compositions according to the present invention, which are described in a), b) or c) can each additionally contain 1.5 mg or 2.5 mg of indapamide.

Fixed pharmaceutical compositions according to the present invention, which are even more preferred, are pharmaceutical compositions that contain: i) 10 mg of atorvastatin calcium and 5 mg or 10 mg of perindopril arginine, i) 20 mg of atorvastatin calcium and 5 mg or 10 mg of perindopril arginine, iii) 40 mg of atorvastatin calcium and 5 mg or 10 mg of perindopril arginine,

With them) 100 mg of aspirin and a. 20 mg of atorvastatin calcium and 5 mg or 10 mg of perindopril arginine; b. 40 mg of atorvastatin calcium and 5 mg or 10 mg of perindopril arginine, m) 1.25 mg of indapamide, 5 mg of perindopril arginine and 10 mg, 20 mg or 40 mg of atorvastatin calcium, mi) 2.5 mg of indapamide and 10 mg of perindopril arginine and 10 mg, 20 mg or 40 mg of atorvastatin calcium.

The fixed pharmaceutical compositions of the present invention mentioned above all contain one or more pharmaceutically acceptable excipients, their hydrates and their crystalline forms.

In addition to atorvastatin, perindopril, aspirin and indapamide, said pharmaceutical compositions contain one or more excipients or carriers selected from diluents, lubricants, binders, disintegrants, surfactants, enteric coatings, absorbents, dyes, sweeteners, etc.

It is possible to mention, without limitation, an example: - for diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerin, - for lubricants: silicon, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol, - for compounds binding substances: magnesium aluminum silicate, starch, gelatin, tragacanth, cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone, - for disintegrants: agar, starch, alginic acid and its sodium salt, effervescent mixtures, carboxymethylcellulose salts, carboxymethylstarch salts, polyvinylpyrrolidone derivatives.

The dose used depends on the age of the patient, the nature of the disorder and any associated pathology and treatment. It is always 1 tablet/day, but it can be adjusted, in particular, depending on the patient's condition, in order to stabilize the cardiovascular parameters at the correct values.

The following examples illustrate the invention, but do not limit it.

Examples

The method of preparation of pharmaceutical compositions according to the present invention.

In the following examples of the preparation of minigranules according to this invention, 60 methods, known to a specialist in this field of technology, are carried out, respectively.

Example 1: Preparation of atorvastatin minigranules

The calcium salt of atorvastatin and calcium carbonate are mixed in purified water. Then croscarmellose sodium and polysorbate 80 are added. The previously obtained suspension is then sprayed on sugar microgranules to form atorvastatin minigranules.

Table 1

Atorvastatin 20 and 40 mg immediate-release minigranules

Atorvastatin calcium salt 21.64 43.28 based on 20 40

Calcium carbonate 21.64 43.28

Hydroxypropyl cellulose

Polysorbate 80

Croscarmellose sodium 1.915

Sugar microgranules 28.01 56.02 (General Maasai 77777771 Y11180111111111t1vo1

Example 2: Preparation of perindopril minigranules

Perindopril arginine and hydroxypropyldelulose are mixed in purified water. The previously obtained suspension is then sprayed on sugar microgranules to form perindopril minigranules.

Table 2

Perindopril 5 and 10 mg immediate release minigranules

Dosage (mg)

Components 2,145 22,855 45,71 (Total Maasai 77777711 11111301 11111161,

Example 3: Preparation of enteric-dissolving aspirin tablets

The first mixture is formed from acetylsalicylic acid, microcrystalline cellulose and corn starch, then the mixture is sieved for the first time, and then mixed again. In the second stage, microcrystalline cellulose is mixed with anhydrous colloidal silicon and sodium stearyl fumarate, and then the mixture is sieved. Then the first mixture is added, the resulting mixture is mixed and formed into tablets by methods known to a person skilled in the art.

The coating suspension is obtained by mixing talc, Agiamia Ropsiaii, triethyl citrate, a copolymer of methacrylic acid and ethyl acrylate (1:11) and purified water. The tablet is then coated with a coating suspension by methods known to those skilled in the art.

Table C

Enteric-soluble tablet of acetylsalicylic acid 100 mg

Tablet (30303033...

Microcrystalline cellulose

Cornstarch

Sodium stearyl fumarate

Silicon dioxide, colloidal anhydrous 0 01010101

Copolymer of methacrylic acid and ethyl acrylate (1:1) 11.76

Triethyl citrate

Apgiamia Ropsea 36002 Edisoi Ropsea 48 0.003

Example 4: Preparation of indapamide minigranules

Mix indapamide and hypromellose in purified water. The previously obtained suspension is then sprayed on microcrystalline cellulose to form minigranules of indapamide.

Table 4

Minigranules of indapamide immediate release 1.25 and 2.5 mg

Dosage (mg)

Components

Hypromellose, type 2910 0.138 0.276

Microcrystalline cellulose, type SR-305 28.61 57.22 (General Masaid//-/-//777777777111111111111111111111111111301Ї11111116осСсщС

The following capsules were obtained according to this invention.

Example 5: Capsules containing atorvastatin and perindopril

The atorvastatin immediate release minigranules obtained in Example 1 and the perindopril immediate release minigranules obtained in Example 2 are each lubricated by methods known to one skilled in the art. The capsules are then filled with lubricated minigranules by methods known to a person skilled in the art.

Table 5

Compositions of capsules containing atorvastatin and perindopril

Atorvastatin/Perindopril

Draw (M) 20/75 | naked | 405 40/10 components I-

Amount per capsule (mg)

Atorvastatin immediate-release minigranules 801 80 1 160 | 160

Atorvastatin calcium salt 21.64 21.64 43.28 43.28 based on 20 20 40 40

Calcium carbonate 21.64 21.64 43.28 43.28

Hydroxypropyl cellulose

Polysorbate 80

Croscarmellose sodium 1.915 1.915

Sugar microgranules 28.01 28.01 56.02 56.02

Table 5

Compositions of capsules containing atorvastatin and perindopril components I- (Minigranules of perindopril immediate release | 30 | 60 | 30 | 60

Example 6: Capsules containing atorvastatin, perindopril and aspirin

According to the same method as described in Example 5, the capsule is filled with atorvastatin immediate-release minigranules, perindopril immediate-release minigranules, and acetylsalicylic acid enteric tablets, which are obtained by

Example 3.

Table 6

Compositions of capsules containing atorvastatin, perindopril and acetylsalicylic acid

Dosage (mg) Acetylsolicylic acid

Components (minigranules of atorvastatin immediate release.d | 80 | 80 | 160 | 160 based on 20 20 40 40 (minigranules of perindopril immediate release.d | 30 / 60 | 30 | 60

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Example 7: Capsules containing atorvastatin, perindopril and indapamide

The capsules of Example 7 are prepared in the same way as the capsules of Example 5, with the additional addition of immediate-release indapamide minigranules, which are prepared according to Example 4.

Table 7

Compositions containing atorvastatin, perindopril and indapamide

Dosage (mg)

Mini pellets

Shen ze er liberation

Calcium salt 10.82 10.82 21.64 21.64 43.28 43.28 atorvastatin 10 10 20 20 40 40 by base

Perindopril immediate-release minigranules 30 30

Minigranules of indapamide zetinyvytnenya 32060806 ov

Microcrystalline pi i p PNYA POLYA PO KOH

Claims (10)

FORMULA OF THE INVENTION 1. A fixed pharmaceutical composition containing atorvastatin and its pharmaceutically acceptable salts, as well as perindopril and its pharmaceutically acceptable salts in combination with one or more pharmaceutically acceptable excipients, their hydrates, while oatorvastatin and its pharmaceutically acceptable salts and perindopril and its pharmaceutically acceptable acceptable salts are presented in the form of minigranules. 2. Fixed pharmaceutical composition according to claim 1, which additionally contains indapamide and its pharmaceutically acceptable salts in combination with one or more pharmaceutically acceptable excipients, their hydrates. C. A fixed pharmaceutical composition according to claim 1 or 2, which is characterized in that the pharmaceutical composition is a capsule. 4. Fixed pharmaceutical composition according to any of claims 1-3, which is characterized by the fact that indapamide and its pharmaceutically acceptable salts are in the form of minigranules. 5. A fixed pharmaceutical composition according to any one of claims 1-4, which is characterized in that atorvastatin has the calcium form of atorvastatin. 6. Fixed pharmaceutical composition according to any of claims 1-4, which is characterized by the fact that perindopril has the form of perindopril tert-butylamine or perindopril arginine and most preferably has the form of perindopril arginine. 7. A fixed pharmaceutical composition according to any of claims 1-6, which is characterized in that: "doses of atorvastatin vary from 10 to 80 mg, expressed on the basis of atorvastatin, or from 10.80 to 86.80 mg, expressed as atorvastatin calcium trihydrate, "- doses of perindopril vary from 1.65 to 9.512 mg, expressed on the basis of perindopril , or from 2.5 to 14 mg, expressed in the form of perindopril arginine, "- doses of indapamide vary from 0.625 to 2.5 mg, expressed on the basis of indapamide. 8. A fixed pharmaceutical composition according to any one of claims 1-7, which differs in that the doses of: " atorvastatin calcium are 10, 20, 40 and 80 mg, " perindopril arginine are 2.5, 3.5, 5, 7 , 10 and 14 mg, "Indapamide are 0.625, 1.25, 1.5 and 2.5 mg. 9. Use of a fixed pharmaceutical composition according to any of claims 1-8 in the treatment or prevention of cardiovascular diseases. 10. The use of a fixed pharmaceutical composition according to claim 9, which is characterized by the fact that cardiovascular diseases are selected from coronary syndromes in patients with a history of myocardial infarction and/or revascularization due to primary hypercholesterolemia or mixed hyperlipidemia.