Classifications

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  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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  • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
  • A61K31/10—Sulfides; Sulfoxides; Sulfones
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  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
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  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
• • A—HUMAN NECESSITIES
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  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
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  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
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  • A61K31/60—Salicylic acid; Derivatives thereof
  • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
  • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
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  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
  • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
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Definitions

• the present invention relates to a fixed pharmaceutical composition
• a fixed pharmaceutical composition comprising an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase and an antihypertensive agent and the use of said composition for the treatment and prevention of cardiovascular diseases .
• Cardiovascular disease is the leading cause of death in both developed and developing countries, accounting for about one-third of all deaths worldwide. Deaths from cardiovascular disease are expected to increase to 23.3 million in 2030.
• cardiovascular disease is the leading cause of premature mortality and disability-adjusted life expectancy among men and women, causing nearly 4.1 million deaths annually, or 46% of all deaths. death. Nearly 1.8 million of these deaths (20% of all deaths) are due to coronary heart disease (CHD). Every one-sixth of men and one-seventh of women in Europe will die of myocardial infarction (MI).
• CHD coronary heart disease
• Dyslipidemia is a modifiable cardiovascular risk factor of great importance in the prevention of cardiovascular disease.
• High levels of total cholesterol (TC) and low density lipoproteins (LDL) have received the most attention, particularly because they can be modified by lifestyle changes and drug treatments.
• Clinical studies in primary prevention and secondary prevention show that reducing total cholesterol and low density lipoprotein cholesterol (LDL-C) with statins can prevent cardiovascular disease.
• treating a single risk factor can reduce cardiovascular events by about 30%, while treating multiple risk factors can reduce the risk of cardiovascular disease by more than 50%.
• Chronic diseases generally require long-term multi-therapy, which increases the risk of non-adherence to treatment as well as related safety concerns. Patients are classified as non-adherents on the basis of the proportion of treatment days covered less than 0.80. Non-compliance with cardioprotective medication is prevalent in ambulatory patients with coronary artery disease and is associated with a wide range of adverse effects including all-cause cardiovascular mortality, cardiovascular hospitalizations and revascularization procedures. Similarly, discontinuation of low-dose acetylsalicylic acid increases the risk of non-fatal MI or coronary heart disease death by> 50%> in primary care patients with a history of ischemic events. Failure to take medication was the most common reason for stopping treatment.
• a meta-analysis of nine studies was performed comparing the administration of a fixed combination and individual components. The effectiveness of adherence to combination therapy by compared to a therapy of taking individual components was examined. This meta-analysis evaluated the use of fixed combination therapies in various clinical settings, including hypertension, heart failure, myocardial infarction, hypercholesterolemia, diabetes, tuberculosis, and HIV infection. human immunodeficiency. The results of this meta-analysis showed a much better compliance of the fixed combinations with respect to the setting of the separate components. The compliance rate was improved by 26% in patients receiving fixed combinations.
• the present invention proposes to develop a novel fixed combination comprising a statin and at least one antihypertensive drug selected from an IEC such as perindopril or a diuretic such as indapamide with possibly another active ingredient chosen from a non-steroidal anti-inflammatory drug (NSAID) such as acetylsalicylic acid.
• an IEC such as perindopril
• a diuretic such as indapamide
• NSAID non-steroidal anti-inflammatory drug
• the patent application WO 99/11259 describes a therapeutic combination comprising amlodipine and atorvastatin in the treatment of hypertension, hyperlipidemia, angina pectoris, atherosclerosis and the management of risk. heart.
• the patent application WO 99/11260 describes a combination therapy comprising atorvastatin and an antihypertensive agent in the treatment of hypertension, hyperlipidemia, angina pectoris, atherosclerosis and the management of cardiac risk.
• antihypertensives that are mentioned are calcium channel blockers, ACE inhibitors, A-II antagonists, diuretics, beta-adrenergic receptor blockers, vasodilators and alpha-adrenergic receptor blockers.
• Patent Application WO 03/092729 discloses a stable pharmaceutical formulation containing a statin combined with an ACE inhibitor which comprises at least one statin stabilizing agent and at least one ACE inhibitor stabilizing agent and wherein the statin and the ACE inhibitor are separated by a layer or membrane made of a physiologically compatible inert material having a neutral pH value.
• ACE inhibitors are compounds that are sensitive to degradation reactions that are favored in the presence of acids or bases. This application solves the problem of decomposition or degradation of ACE inhibitors in the presence of statins by developing a stable pharmaceutical composition whose quantity of active ingredients does not vary over time and whose active principles do not decompose. or very little.
• Patent application WO 99/47123 discloses a pharmaceutical composition comprising a statin-based cholesterol lowering agent and aspirin in a formulation designed to minimize statin interaction: aspirin, where (i) statin and aspirin are formulated into a single bilayer tablet and where aspirin is present in a first layer and the statin is present in a second layer; or (ii) the pharmaceutical composition is in the form of a capsule containing aspirin granules and statin granules. This request solves the problem of interactions between the active ingredients
• Patent application WO 2011/096665 describes a complex formulation for the prevention and treatment of cardiovascular diseases comprising a) hydrophobic additive coated barrier aspirin and b) an HMG-CoA reductase inhibitor. This application solves the problem of instability of unstable HMG-CoA reductase in an acid medium.
• the patent application WO 2012/002919 describes a pharmaceutical composition in tablet or capsule form comprising atorvastatin and aspirin, each of these active ingredients being in the form of tablets, mini-tablets, micro-tablets, microcapsules, granules, and / or powder and which can be used for the prevention or treatment of cardiovascular diseases.
• Aspirin doses range from 1 to 500 mg, preferably from 1 to 300 mg and more preferably from 1 to 150 mg.
• the doses of atorvastatin are from 1 to 200 mg, preferably from 1 to 150 mg, and more preferably from 1 to 100 mg / dose.
• the formulation according to this application solves the problem of interactions of the active ingredients with each other. Examples which are described are pharmaceutical formulations comprising either aspirin tablets and atorvastatin granules or aspirin tablets and atorvastatin powder in capsules.
• the patent application WO 2012/011882 describes a pharmaceutical composition comprising atorvastatin and aspirin, each of these active ingredients being in powder form and which can be used for the prevention or treatment of cardiovascular diseases.
• the purpose of this application is to provide a pharmaceutical formulation that combines both aspirin and atorvastatin and has good bioavailability and does not exhibit chemical degradation. But also a formulation in which atorvastatin is sufficiently soluble in water.
• the patent application WO 2012/081905 describes a pharmaceutical formulation for the prevention and treatment of cardiovascular diseases which comprises on the one hand an HMG-CoA reductase inhibitor and a basic additive and on the other hand aspirin with a enteric coating layer.
• the HMG-CoA reductase inhibitor can be formulated as a powder, granule, bead or mini-tablet and the aspirin can be formulated as granules, beads or mini-tablets.
• the patent application WO 2012/124973 describes a pharmaceutical composition for the treatment of cardiovascular diseases comprising atorvastatin in the form of mini tablets and aspirin in the form of mini tablets or mini granules having an enteric coating thus reducing the interactions between the two active ingredients while optimizing the therapeutic effect and storage stability.
• the patent application WO 03/020243 describes a pharmaceutical composition that may be in capsule form, comprising a cholesterol lowering agent which is a statin, an IEC and aspirin from which at least one of the components is separated from the other two components. .
• the components may be in the form of beads or granules.
• This application describes a pharmaceutical composition which is a multilayer tablet comprising a first prolonged-release layer of lovastatin, a second extended-release layer enalapril, a separating layer of excipients and an immediate-release layer of aspirin.
• This application also discloses a pharmaceutical composition comprising lovastatin granules, enalapril granules and an immediate-release aspirin matrix which are mixed to form a compressed tablet.
• a pharmaceutical composition in the form of tablets or capsules comprising several active ingredients including lovastatin, enalapril and aspirin, all in immediate release form, which is obtained by mixing the powders which is then put into a capsule.
• This application also addresses the problem of the interactions between the different active principles within a fixed pharmaceutical composition but also the possible interactions between the active ingredients and the excipients. However, the different active ingredients have a different release profile from each other.
• the patent application WO 2004/080488 describes pharmaceutical compositions containing acetylsalicylic acid, an HMG-CoA reductase inhibitor and optionally an antihypertensive agent for the primary prevention of cardiovascular diseases.
• This application describes examples including
• Patent application WO 2009/118359 discloses a pharmaceutical capsule composition for the prevention of cardiovascular diseases which comprises acetylsalicylic acid film-coated tablets, film-coated tablets of simvastatin or pravastatin and film-coated tablets of lisinopril, ramipril or perindopril.
• examples described in this application include 100 mg of acetylsalicylic acid, 20 mg of simvastatin and ramipril (2.5, 5 or 10 mg) or lisinopril (20 mg).
• the patent application WO 2014/195421 describes an oral formulation for the treatment of cardiovascular diseases comprising an HMG-CoA reductase inhibitor which is a statin and acetylsalicylic acid and whose interactions between the two active ingredients are minimized.
• the two active ingredients are in the form of unit dose coated.
• the oral formulation may further contain an inhibitor of the renin-angiotensin system which is an ACE inhibitor such as perindopril for example.
• the present invention relates to a fixed pharmaceutical composition comprising an HMG-CoA reductase inhibitor and an antihypertensive agent.
• the present invention relates to a fixed pharmaceutical composition
• a fixed pharmaceutical composition comprising an HMG-CoA inhibitor and at least one antihypertensive agent selected from an angiotensin converting enzyme (ACE) inhibitor, a diuretic and optionally an NSAID.
• ACE angiotensin converting enzyme
• the present invention relates to a fixed pharmaceutical composition
• a fixed pharmaceutical composition comprising an HMG-CoA inhibitor and an angiotensin converting enzyme (ACE) inhibitor wherein:
• the inhibitor of HMG-CoA is atorvastatin or a pharmaceutically acceptable acid addition salt thereof, their hydrates and crystalline forms, and
• the IEC is perindopril or one of its addition salts with a pharmaceutically acceptable acid or base, their hydrates and crystalline forms.
• the present invention also relates to a fixed pharmaceutical composition comprising, in addition to the HMG-CoA reductase inhibitor and the IEC, another active ingredient chosen from:
• the present invention further relates to the use of these fixed pharmaceutical compositions for the treatment and prevention of cardiovascular diseases and more particularly the prevention of coronary events in patients with a history of myocardial infarction and / or revascularization. in combination with primary hypercholesterolemia or mixed hyperlipidemia.
• the HMG-CoA reductase inhibitor preferentially used is atorvastatin or one of its addition salts with a pharmaceutically acceptable acid or base, and more particularly its calcium or sodium salts, their hydrates and crystalline forms.
• the angiotensin converting enzyme inhibiting agent preferentially used is perindopril or an addition salt thereof with a pharmaceutically acceptable acid or base, and more particularly its tert-butylamine, tosylate or d-butylate salts. arginine, their hydrates and crystalline forms.
• the NSAID preferentially used is acetylsalicylic acid or aspirin or one of its addition salts with a pharmaceutically acceptable acid or base, their
• the diuretic preferably used is indapamide or one of its addition salts with an acid or a pharmaceutically acceptable base, their hydrates and crystalline forms.
• the present invention relates to a fixed pharmaceutical composition
• a fixed pharmaceutical composition comprising atorvastatin or its pharmaceutically acceptable salts, their hydrates and crystalline forms and perindopril or its pharmaceutically acceptable salts, their hydrates and crystalline forms and the use of said composition for the prevention and control of treatment of cardiovascular diseases.
• the present invention also relates to a fixed pharmaceutical composition
• a fixed pharmaceutical composition comprising in addition to atorvastatin and perindopril, acetylsalicylic acid also called aspirin or its pharmaceutically acceptable salts, their hydrates and crystalline forms and the use of said composition for the prevention and the treatment of cardiovascular diseases.
• the present invention also relates to a fixed pharmaceutical composition comprising, in addition to atorvastatin and perindopril, indapamide or its pharmaceutically acceptable salts, their hydrates and crystalline forms and the use of said composition for the prevention and treatment of cardiovascular illnesses.
• Cardiovascular disease is more specifically the prevention of coronary events in patients with a history of myocardial infarction and / or revascularization in combination with primary hypercholesterolemia or mixed hyperlipidemia.
• a pharmaceutical composition fixed to the advantage of allowing both a reduction in manufacturing costs, but above all a better compliance of the treatment on the part of patients and therefore better control of their pathology.
• the fixed pharmaceutical composition of at least two active ingredients which are 1) antitopril and 2) perindopril belonging to different therapeutic classes with complementary effects has the advantage of targeting several risk factors responsible for cardiovascular diseases. in one take.
• the present invention is also a fixed therapeutic combination of at least three active ingredients belonging to different therapeutic classes having complementary effects which are 1) atorvastatin, 2) perindopril as well as:
• the fixed pharmaceutical composition according to the invention is to be taken once a day in the morning.
• Atorvastatin is part of a group of medications called HMG-CoA reductase inhibitors or statins. Atorvastatin reduces low-density lipoprotein (LDL) and triglyceride levels in the blood, while increasing high-density lipoprotein (HDL) concentrations. Atorvastatin in the form of calcium salt trihydrate is marketed under the name Tahor® or Lipitor® and the corresponding pharmaceutical composition is described in patent application WO 94/16693. Atorvastatin is indicated for:
• hypercholesterolemia as a supplement to a diet to reduce elevated total cholesterol (Chol-T), LDL-cholesterol (LDL-C), apo lipoprotein B and triglycerides in patients with primary hypercholesterolemia including familial hypercholesterolemia or mixed hyperlipidemia,
• Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin II (angiotensin converting enzyme ECA).
• This conversion enzyme, or kinase is an exopeptidase that allows the conversion of angiotensin I to vasoconstrictor angiotensin II causing degradation of vasodilator bradykinin to an inactive heptapeptide.
• Perindopril in the form of arginine salt is marketed under the name of Coversyl® and is indicated for:
• Acetylsalicylic acid is an inhibitor of platelet activation: by blocking platelet cyclooxygenase by acetylation, it inhibits the synthesis of thromboxane A2, a physiological activator released by platelets, which plays a role in complications of atheromatous lesions.
• Acetylsalicylic Acid 100 mg is marketed under the name Aspirine Protect® and is indicated for:
• Atheromatous ischemic disease eg myocardial infarction, stable and unstable angina, cerebral, constitutional or transient stroke, of ischemic origin
• Indapamide is a sulfonamide diuretic, pharmacologically related to thiazide diuretics.
• Indapamide hemihydrate is marketed under the name Fludex® and is indicated for the treatment of arterial hypertension.
• the active ingredients may be incompatible with certain excipients which are nevertheless necessary in order to stabilize one or the other of these active principles.
• acetylsalicylic acid to reduce the risk of myocardial infarction and the use of statins to lower cholesterol levels and prevent or treat cardiovascular and cerebrovascular diseases are very well documented. Indeed, it is not unusual that patients with high cholesterol who are considered at risk for "doing" a myocardial infarction take both a statin and acetylsalicylic acid. However, the use of both statins and acetylsalicylic acid requires special precautions to minimize the interactions between these two drugs because, it is well known in the art, that the HMG-CoA inhibitors reductase decompose in the presence of acetylsalicylic acid. Interactions include physical and chemical incompatibilities but also side effects.
• statins are sensitive to factors such as heat, humidity, low pH and light.
• atorvastatin is converted into a lactone which results from an intramolecular esterification reaction.
• the major degradation products that are produced during of the decomposition of statins are lactones and oxidation products which decrease the stability of ⁇ atorvastatme and therefore its half-life.
• Atorvastatin is a molecule that breaks down quite easily and requires the use of a stabilizing agent that in the Tahor® formulation is calcium carbonate. This formulation of Tahor® is described in particular in patent EP 0 680 320.
• the ratio of perindopril administered in the fixed combination "atorvastatin + perindopril" and perindopril administered alone is more than 130%.
• the present invention solves this problem by developing a fixed capsule pharmaceutical composition comprising atorvastatin mini-granules and perindopril mini-granules. It is well known in the prior art that aspirin degrades HMG-CoA reductase inhibitors. In a compatibility study of the different active ingredients, the Applicant has been able to demonstrate that when the 3 active ingredients are alone there is no degradation including, when atorvastatin and perindopril are formulated together. However, when aspirin is added to the mixture "atorvastatin + perindopril" the 3 active ingredients degrade as shown in the table below.
• the fixed pharmaceutical composition according to the invention which comprises atorvastatin, perindopril and aspirin
• atorvastatin a fixed pharmaceutical composition in capsule form
• a fixed pharmaceutical composition in capsule form comprising atorvastatin mini-granules, mini-granules of perindopril and gastro-resistant mini-granules of aspirin.
• the gastro-resistant mini-granules of aspirin are not bioequivalent to the gastro-resistant tablets of aspirin present on the market as demonstrated by the Applicant (see figure below - treatment 4).
• the treatment profile 4 is different from the treatment profiles 1 to 3, thus showing a difference between the gastro-resistant aspirin tablet and the gastro-resistant aspirin mini-granules.
• the present invention solves the problem by developing a fixed pharmaceutical composition comprising atorvastatin, perindopril and aspirin, a composition in which the interactions between the various active ingredients and the interactions with excipients are non-existent.
• the active ingredients are bioequivalent to the individual compounds that are the individual tablets marketed.
• the present invention therefore provides a fixed pharmaceutical capsule composition comprising atorvastatin mini-granules, mini-granules of perindopril and gastro-resistant aspirin tablets.
• This composition therefore has the advantage of being bioequivalent to the gastro-resistant tablet of aspirin alone and not to present interactions between the 3 active ingredients or with the excipients.
• the present invention comprises a fixed pharmaceutical composition comprising:
• All fixed pharmaceutical compositions according to the invention comprise pharmaceutically acceptable salts in combination with one or more pharmaceutically acceptable excipients, their hydrates and their crystalline forms.
• the present invention also extends to fixed pharmaceutical compositions comprising 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 their crystalline forms in which: doses of atorvastatin vary from 10 mg to 80 mg expressed as atorvastatin base or range 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 as perindopril base or range from 2.5 mg to 14 mg expressed as perindopril arginine.
• the present invention also extends to fixed pharmaceutical compositions further comprising 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 in which: doses of aspirin are 75 mg to 150 mg expressed as aspirin base,
• indapamide doses vary from 0.625 mg to 2.5 mg expressed as indapamide base.
• - 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.
• compositions comprising:
• atorvastatin calcium and 2.5 mg, 5 mg or 10 mg perindopril arginine a) 10 mg atorvastatin calcium and 2.5 mg, 5 mg or 10 mg perindopril arginine, b) 20 mg atorvastatin calcium and 2.5 mg, 5 mg or 10 mg perindopril arginine, c) 40 mg atorvastatin calcium and 2.5 mg, 5 mg or 10 mg perindopril arginine.
• the fixed pharmaceutical compositions according to the invention as described in a), b) or c) may each contain in addition to 75 mg, 100 mg or 150 mg of aspirin.
• the fixed pharmaceutical compositions according to the invention as described in a), b) or c) may each additionally contain 1.5 mg or 2.5 mg of indapamide.
• compositions comprising:
• the above-mentioned fixed pharmaceutical compositions according to the invention all comprise one or more pharmaceutically acceptable excipients, their hydrates and their crystalline forms.
• said pharmaceutical compositions contain one or more excipients or vehicles selected from diluents, lubricants, binders, disintegrating agents, surfactants, enteric coatings, absorbents, dyes, sweeteners, etc.
• ⁇ for diluents lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerin,
• ⁇ for lubricants silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol,
• binders magnesium aluminum silicate, starch, gelatin, tragacanth, cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone,
• disintegrants agar, starch, alginic acid and its sodium salt, effervescent mixtures, carboxymethylcellulose salts, carboxymethyl starch salts, polyvinylpyrrolidone derivatives.
• the useful dosage varies according to the age of the patient, the nature of the affection and, pathologies and possibly associated treatments. It is always 1 tablet / day and can be adjusted depending mainly on the patient's condition in order to stabilize cardiovascular parameters at the right values.
• Atorvastatin calcium is mixed with calcium carbonate in purified water. Croscarmellose sodium and polysorbate 80 are then added. The suspension previously obtained is then sprayed on the sugar beads to form atorvastatin mini-granules.
• Perindopril arginine and hydroxypropylcellulose are mixed in purified water. The previously obtained suspension is then sprayed onto the sugar beads to form the mini-granules of perindopril.
• a first mixture is formed with acetylsalicylic acid, microcrystalline cellulose and corn starch which is then sieved a first time and then mixed again.
• the microcrystalline cellulose is mixed with the anhydrous colloidal silica and the sodium stearyl fumarate, which is then sieved.
• We then add the first mixture we The mixture is mixed together and the tablets are formed according to conventional techniques well known to those skilled in the art.
• the coating suspension is obtained by mixing talc, Ariavit Ponceau, triethylcitrate, methacrylic acid-ethyl acrylate copolymer (1: 1) and purified water.
• the tablet is then coated with the coating suspension according to techniques well known to those skilled in the art.
• Indapamide and hypromellose are mixed in purified water. The suspension previously obtained is then sprayed onto the microcrystalline cellulose to form indapamide mini-granules.
• the atorvastatin mini-granules with immediate release obtained according to Example 1 and the immediate-release perindopril mini-granules obtained according to Example 2 are each lubricated according to the techniques well known to those skilled in the art.
• the capsules are then filled with the mini-capsules lubricated according to techniques well known to those skilled in the art.
• Example 6 Capsules Comprising Atorvastatin, Perindopril and Aspirin
• EXAMPLE 7 Capsules Comprising Atorvastatin, Perindopril and Indapamide
• the capsules of Example 7 are obtained in the same manner as the capsules of Example 5, by additionally adding indapamide mini-granules. immediate release obtained according to Example 4.

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