EP3340980A1 - Pharmaceutical composition comprising an hmg-coa reductase inhibitor and an eca inhibitor - Google Patents

Pharmaceutical composition comprising an hmg-coa reductase inhibitor and an eca inhibitor

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Publication number
EP3340980A1
EP3340980A1 EP16763927.7A EP16763927A EP3340980A1 EP 3340980 A1 EP3340980 A1 EP 3340980A1 EP 16763927 A EP16763927 A EP 16763927A EP 3340980 A1 EP3340980 A1 EP 3340980A1
Authority
EP
European Patent Office
Prior art keywords
perindopril
atorvastatin
pharmaceutical composition
aspirin
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP16763927.7A
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German (de)
French (fr)
Inventor
Gilles Fonknechten
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratoires Servier SAS
Original Assignee
Laboratoires Servier SAS
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Filing date
Publication date
Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Publication of EP3340980A1 publication Critical patent/EP3340980A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—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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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2813—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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.

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 hypocholesteraemia or mixed hyperlipidaemia.

Description

COMPOSITION PHARMACEUTIQUE COMPRENANT UN INHIBITEUR DE LA HMG-CoA REDUCTASE ET UN INHIBITEUR ECA  PHARMACEUTICAL COMPOSITION COMPRISING HMG-CoA REDUCTASE INHIBITOR AND ECA INHIBITOR
Domaine technique Technical area
La présente invention concerne une composition pharmaceutique fixe comprenant un inhibiteur de la HMG-CoA (3-hydroxy-3-méthylglutaryl-coenzyme A) réductase et un agent antihypertenseur et, l'utilisation de ladite composition pour le traitement et la prévention de maladies cardiovasculaires. The present invention relates to 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 .
Etat de la technique/contexte de l'invention State of the art / context of the invention
Les maladies cardiovasculaires sont la principale cause de décès dans les pays développés et les pays en voie de développement, ce qui représente environ un tiers de tous les décès dans le monde. Les décès liés aux maladies cardiovasculaires devraient augmenter jusqu'à 23,3 millions en 2030. 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.
En Europe, les maladies cardiovasculaires sont la première cause de mortalité prématurée et de l'espérance de vie corrigée de l'incapacité chez les hommes et les femmes, causant près de 4,1 millions de décès par an, soit 46% de tous les décès. Près de 1,8 millions de ces décès (20% de tous les décès) sont dus à une maladie coronarienne (CHD). Chaque un sixième des hommes et un septième des femmes en Europe vont mourir d'un infarctus du myocarde (IM). In Europe, 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).
Le développement des maladies de l'artère coronaire est dû à l'effet global des facteurs de risque modifiables et non modifiables. Ces facteurs de risque comprennent l'hypertension, la dyslipidémie, le surpoids et l'obésité, le diabète, une vie sédentaire, le tabagisme, l'alcool, une plus ou moins forte consommation de sel, des antécédents familiaux d'hypertension et de maladie cardiovasculaire prématurée, l'âge, le sexe, et les facteurs psychologiques tels que l'anxiété et la dépression. La coexistence de ces facteurs de risque augmente de façon significative la morbidité et les taux de mortalité. Les personnes ayant eues des antécédents d'IM et d'accident vasculaire cérébral (AVC) sont les plus à risque pour d'autres événements coronariens et cérébraux. Il existe des preuves scientifiques considérables que des interventions spécifiques permettent de réduire le risque d'autres événements vasculaires chez les patients ayant un IM. En particulier, l'acide acétylsalicylique ou aspirine, à de faibles doses de 75 à 150 mg, est considéré comme la pierre angulaire de la prévention pharmaco logique de thrombose artérielle. The development of diseases of the coronary artery is due to the global effect of modifiable and non-modifiable risk factors. These risk factors include hypertension, dyslipidemia, overweight and obesity, diabetes, sedentary lifestyle, smoking, alcohol, increased salt intake, a family history of high blood pressure and high blood pressure. premature cardiovascular disease, age, sex, and psychological factors such as anxiety and depression. The coexistence of these risk factors significantly increases morbidity and mortality rates. People with a history of MI and stroke are most at risk for other coronary and cerebral events. There is considerable scientific evidence that specific interventions can reduce the risk 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 the pharmacological prevention of arterial thrombosis.
Les maladies stabilisées de l'artère coronaire associées avec la dyslipidémie, ainsi que d'autres facteurs de risque, peuvent accroître le risque de maladie cardiovasculaire. La dyslipidémie est un facteur de risque cardiovasculaire modifiable d'une grande importance dans la prévention des maladies cardio vasculaires. Le taux élevé de cholestérol total (CT) et les lipoprotéines de basse densité (LDL) ont reçu le plus d'attention, en particulier parce qu'ils peuvent être modifiés par des changements de style de vie et des traitements médicamenteux. Des études cliniques dans la prévention primaire et la prévention secondaire montrent que la réduction de cholestérol total et du cholestérol des lipoprotéines de basse densité (LDL-C) avec des statines peut prévenir les maladies cardio vasculaires. Stabilized diseases of the coronary artery associated with dyslipidemia, as well as other risk factors, may increase the risk of cardiovascular 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.
Fait intéressant, le traitement d'un seul facteur de risque peut réduire les événements cardiovasculaires d'environ 30%, tandis que le traitement des facteurs de risque multiples peut réduire le risque de maladies cardiovasculaires de plus de 50%.  Interestingly, 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%.
Les maladies chroniques nécessitent généralement une multi-thérapie à long terme, ce qui augmente le risque de non-observance du traitement ainsi que les préoccupations de sécurité liées. Les patients sont classés comme non-adhérents sur la base de la proportion de jours de traitement couverts de moins de 0,80. Non-respect de la médication cardioprotective est répandu chez les patients ambulatoires atteints de coronaropathie et est associé à un large éventail d'effets indésirables, y compris toutes causes confondues et la mortalité cardiovasculaire, les hospitalisations cardiovasculaires et les procédures de revascularisation. De même, l'arrêt de la prise d'acide acétylsalicylique à faible dose augmente le risque d'IM non fatal ou décès par maladie coronarienne de près de 50%> chez les patients en soins primaires qui ont des antécédents d'événements ischémiques. Le non-respect de la prise des médicaments était la raison la plus courante pour l'arrêt du traitement. 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.
Une méta-analyse de neuf études a été réalisée comparant l'administration d'une combinaison fixe et des composants individuels. L'efficacité de l'observance d'une thérapie combinée par rapport à une thérapie de prise des composants individuels a été examinée. Cette méta-analyse a évalué l'utilisation des thérapies combinées fixes dans différents contextes cliniques, incluant l'hypertension, l'insuffisance cardiaque, infarctus du myocarde, l'hypercholestérolémie, le diabète, la tuberculose et l'infection par le virus de l'immunodéficience humaine. Les résultats de cette méta-analyse ont montré une bien meilleure observance des combinaisons fixes par rapport à la prise des composants séparés. Le taux d'observance a été amélioré de 26% chez les patients recevant des combinaisons fixes. 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.
L'utilisation de poly-pilule pour le traitement de maladies cardiovasculaires secondaires a reçu une attention croissante ainsi que le soutien de l'Organisation Mondiale de la Santé (OMS) et de la Fédération Mondiale du Cœur (WHF). The use of poly-pill for the treatment of secondary cardiovascular diseases has received increasing attention as well as support from the World Health Organization (WHO) and the World Heart Federation (WHF).
C'est dans ce contexte que la présente invention se propose de développer une nouvelle combinaison fixe comprenant une statine et au moins un antihypertenseur choisi parmi un IEC tel que le périndopril ou un diurétique tel que l'indapamide avec éventuellement un autre principe actif choisi parmi un anti- inflammatoire non-stéroïdien (AINS) tel que l'acide acétylsalicylique. It is in this context that 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.
Dans l'art antérieur il existe un certain nombre de documents qui décrivent des associations entre des statines, des antihypertenseurs et/ou de l'aspirine. In the prior art there are a number of documents which describe associations between statins, antihypertensives and / or aspirin.
La demande de brevet WO 99/11259 décrit une combinaison thérapeutique comprenant de l'amlodipine et de l'atorvastatine dans le traitement de l'hypertension, l'hyperlipidémie, l'angine de poitrine, l'athérosclérose et la prise en charge du risque cardiaque. 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.
La demande de brevet WO 99/11260 décrit une thérapie combinée comprenant l'atorvastatine et un agent antihypertenseur dans le traitement de l'hypertension, l'hyperlipidémie, l'angine de poitrine, l'athérosclérose et la prise en charge du risque cardiaque. Parmi les antihypertenseurs qui sont mentionnés on trouve, les inhibiteurs des canaux calciques, les inhibiteurs ACE, les antagonistes A-II, les diurétiques, les bloqueurs des récepteurs bêta- adrénergique, les vasodilatateurs et les bloqueurs des récepteurs alpha-adrénergiques. Ces deux demandes ne mentionnent aucunement les problèmes d'interactions ou de dégradation qui peuvent exister au sein d'une composition pharmaceutique fixe de deux principes actifs ou plus. 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. Among the antihypertensives that are mentioned are calcium channel blockers, ACE inhibitors, A-II antagonists, diuretics, beta-adrenergic receptor blockers, vasodilators and alpha-adrenergic receptor blockers. These two applications do not mention the problems of interactions or degradation that may exist in a fixed pharmaceutical composition of two or more active ingredients.
La demande de brevet WO 03/092729 décrit une formulation pharmaceutique stable contenant une statine combinée avec un inhibiteur de l'ECA qui comprend au moins un agent stabilisateur de statine et au moins un agent stabilisateur de l'inhibiteur de l'ECA et dans laquelle la statine et l'inhibiteur de l'ECA sont séparés par une couche ou une membrane faite d'un matériau inerte physio logiquement compatible et présentant une valeur de pH neutre. Les inhibiteurs de l'ECA sont des composés qui sont sensibles à des réactions de dégradation qui sont favorisées en présence de d'acides ou de bases. Cette demande résout le problème de la décomposition ou dégradation des inhibiteurs de l'ECA en présence de statines en mettant au point une composition pharmaceutique stable dont la quantité de principes actifs ne varie pas au fil du temps et dont les principes actifs ne se décomposent pas ou très peu. 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.
La demande de brevet WO 99/47123 décrit une composition pharmaceutique comprenant un agent abaissant le cholestérol à base de statine et de l'aspirine dans une formulation conçue pour minimiser l'interaction statine : aspirine, où (i) la statine et l'aspirine sont formulés en un seul comprimé bicouche et où l'aspirine est présente dans une première couche et la statine est présente dans une seconde couche; ou (ii) la composition pharmaceutique est sous la forme d'une capsule contenant des granules d'aspirine et des granules de statine. Cette demande résout le problème d'interactions entre les principes actifs 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
La demande de brevet WO 2011/096665 décrit une formulation complexe pour la prévention et le traitement de maladies cardiovasculaires comprenant a) de l'aspirine revêtue d'une barrière d'un additif hydrophobe et b) un inhibiteur de la HMG-CoA réductase. Cette demande résout le problème de l'instabilité de la HMG-CoA réductase instable en milieu acide. 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.
La demande de brevet WO 2012/002919 décrit une composition pharmaceutique sous forme de comprimé ou de gélule comprenant de l'atorvastatine et de l'aspirine, chacun de ces principes actifs pouvant être sous formes de comprimés, mini-comprimés, micro-comprimés, microcapsules, granule, et/ou poudre et qui peut être utilisée pour la prévention ou le traitement de maladies cardiovasculaires. Les doses d'aspirine varient de 1 à 500 mg, préférentiellement de 1 à 300 mg et plus préférentiellement de 1 à 150 mg. Les doses d'atorvastatine sont de 1 à 200 mg, préférentiellement de 1 à 150 mg, et plus préférentiellement de 1 à 100 mg /dose. La formulation selon cette demande résout le problème des interactions des principes actifs entre eux. Les exemples qui sont décrits sont des formulations pharmaceutiques comprenant soit des comprimés d'aspirine et des granules d'atorvastatine soit des comprimés d'aspirine et de la poudre d'atorvastatine dans des gélules. 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.
La demande de brevet WO 2012/011882 décrit une composition pharmaceutique comprenant de l'atorvastatine et de l'aspirine, chacun de ces principes actifs étant sous forme de poudre et qui peut être utilisée pour la prévention ou le traitement de maladies cardiovasculaires. Le but de cette demande est de fournir une formulation pharmaceutique qui combine à la fois l'aspirine et l'atorvastatine et qui a une bonne biodisponibilité et ne présente pas de dégradation chimique. Mais aussi une formulation dans laquelle l'atorvastatine est suffisamment soluble dans l'eau. 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.
La demande de brevet WO 2012/081905 décrit une formulation pharmaceutique pour la prévention et le traitement de maladies cardiovasculaires qui comprend d'une part un inhibiteur de la HMG-CoA réductase et un additif basique et d'autre part de l'aspirine avec une couche d'enrobage entérique. L'inhibiteur de la HMG-CoA réductase peut être formulé sous forme de poudre, granule, billes ou mini comprimés et l'aspirine peut être formulée sous forme de granules, billes ou mini comprimés. La demande de brevet WO 2012/124973 décrit une composition pharmaceutique pour le traitement de maladies cardiovasculaires comprenant de l'atorvastatine sous forme de mini comprimés et de l'aspirine sous forme de mini comprimés ou de mini granules ayant un enrobage entérique réduisant ainsi les interactions entre les deux principes actifs tout en optimisant l'effet thérapeutique et la stabilité au stockage. La demande de brevet WO 03/020243 décrit une composition pharmaceutique pouvant être sous forme de gélule, comprenant un agent abaissant le taux de cholestérol qui est une statine, un IEC et de l'aspirine dont au moins un des composants est séparée des deux autres. Les composants peuvent se présenter sous formes de billes ou de granules. Cette demande décrit une composition pharmaceutique qui est un comprimé multicouche comprenant une première couche à libération prolongée de lovastatine, une seconde couche à libération prolongée d'enalapril, une couche de séparation formée d'excipients et une couche à libération immédiate d'aspirine. Cette demande décrit aussi une composition pharmaceutique comprenant des granules de lovastatine, des granules d'enalapril et une matrice à libération immédiate d'aspirine qui sont mélangés pour former un comprimé obtenu par compression. Enfin cette demande décrit une composition pharmaceutique sous forme de comprimés ou de gélules comprenant plusieurs principes actifs dont la lovastatine, l'enalapril et l'aspirine, tous sous forme de libération immédiate, qui est obtenue en mélangeant les poudres qui est ensuite mis dans une gélule. 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. Finally this application describes 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.
Cette demande adresse aussi le problème des interactions entre les différents principes actifs au sein d'une composition pharmaceutique fixe mais aussi les éventuelles interactions entre les principes actifs et les excipients. Cependant, les différents principes actifs ont un profil de libération différent les uns des autres. 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.
La demande de brevet WO 2004/080488 décrit des compositions pharmaceutiques contenant de l'acide acétylsalicylique, un inhibiteur HMG-CoA réductase et éventuellement un antihypertenseur pour la prévention primaire de maladies cardiovasculaires. Cette demande décrit des exemples comprenant 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
de l'aspirine, de l'atorvastatine et éventuellement de l'amlodipine et,  aspirin, atorvastatin and possibly amlodipine and,
- de l'aspirine, de la simvastatine et du périndopril.  - aspirin, simvastatin and perindopril.
La demande de brevet WO 2009/118359 décrit une composition pharmaceutique sous forme de gélule pour la prévention des maladies cardiovasculaires qui comprend des comprimés pelliculés d'acide acétylsalicylique, des comprimés pelliculés de simvastatine ou pravastatine et de comprimés pelliculés de lisinopril, ramipril ou périndopril. Les exemples décrits dans cette demande comprennent 100 mg d'acide acétylsalicylique, 20 mg de simvastatine et du ramipril (2,5 ; 5 ou 10 mg ) ou du lisinopril (20 mg). La demande de brevet WO 2014/195421 décrit une formulation orale pour le traitement de maladies cardiovasculaires comprenant un inhibiteur de la HMG-CoA réductase qui est une statine et de l'acide acétylsalicylique et dont les interactions entre les deux principes actifs sont minimisées. Dans cette formulation les deux principes actifs se présentent fous forme de dose unitaire enrobée. La formulation orale peut contenir en outre un inhibiteur du système rénine-angiotensine qui est un inhibiteur de l'ECA comme le périndopril par exemple. Résumé de l'invention 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. In this formulation 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. Summary of the invention
La présente invention concerne une composition pharmaceutique fixe comprenant un inhibiteur de la HMG-CoA réductase et un antihypertenseur. The present invention relates to a fixed pharmaceutical composition comprising an HMG-CoA reductase inhibitor and an antihypertensive agent.
Plus particulièrement, la présente invention concerne une composition pharmaceutique fixe comprenant un inhibiteur de la HMG-CoA et au moins un antihypertenseur choisi parmi un inhibiteur de l'enzyme de conversion de l'angiotensine (IEC), un diurétique et éventuellement un AINS. More particularly, the present invention relates to 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.
Plus particulièrement, la présente invention concerne une composition pharmaceutique fixe comprenant un inhibiteur de la HMG-CoA et un inhibiteur de l'enzyme de conversion de l'angiotensine (IEC) dans laquelle : More particularly, the present invention relates to a fixed pharmaceutical composition comprising an HMG-CoA inhibitor and an angiotensin converting enzyme (ACE) inhibitor wherein:
l'inhibiteur de la HMG-CoA est l'atorvastatine ou un de ses sels d'addition à un acide pharmaceutiquement acceptable, leurs hydrates et formes cristallines, et,  the inhibitor of HMG-CoA is atorvastatin or a pharmaceutically acceptable acid addition salt thereof, their hydrates and crystalline forms, and
- l'IEC est le périndopril ou un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, leurs hydrates et formes cristallines. La présente invention concerne aussi une composition pharmaceutique fixe comprenant en plus de l'inhibiteur de la HMG-CoA réductase et de l'IEC, un autre principe actif choisi parmi :  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:
- un AINS ou,  - an NSAID or,
- un diurétique La présente invention concerne de plus l'utilisation de ces compositions pharmaceutiques fixes pour le traitement et la prévention de maladies cardiovasculaires et plus particulièrement la prévention des événements coronaires chez les patients ayant des antécédents d'infarctus du myocarde et/ou de revascularisation en association avec l'hypercholestérolémie primaire ou hyperlipidémie mixte. L'inhibiteur de la HMG-CoA réductase préférentiellement utilisé est l'atorvastatine ou un de ses sels d'addition à un acide ou a une base pharmaceutiquement acceptable, et plus particulièrement ses sels de calcium ou de sodium, leurs hydrates et formes cristallines. L'agent inhibiteur de l'enzyme de conversion de l'angiotensine préférentiellement utilisé est le périndopril ou un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, et plus particulièrement ses sels de tert-butylamine, tosylate ou d'arginine, leurs hydrates et formes cristallines. L'AINS préférentiellement utilisé est l'acide acétylsalicylique ou aspirine ou un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, leurs hydrates et formes cristallines. 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 hydrates and crystalline forms.
Le diurétique préférentiellement utilisé est l'indapamide ou un de ses sels d'addition à un acide ou a une base pharmaceutiquement acceptable, leurs hydrates et formes cristallines. Description détaillée de l'invention 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. Detailed description of the invention
La présente invention concerne une composition pharmaceutique fixe comprenant l'atorvastatine ou ses sels pharmaceutiquement acceptables, leurs hydrates et formes cristallines et le périndopril ou ses sels pharmaceutiquement acceptables, leurs hydrates et formes cristallines et, l'utilisation de ladite composition pour la prévention et le traitement de maladies cardiovasculaires. The present invention relates to 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.
La présente invention concerne aussi une composition pharmaceutique fixe comprenant en plus de l'atorvastatine et du périndopril, de l'acide acétylsalicylique encore appelé aspirine ou ses sels pharmaceutiquement acceptables, leurs hydrates et formes cristallines et, l'utilisation de ladite composition pour la prévention et le traitement de maladies cardiovasculaires. La présente invention concerne aussi une composition pharmaceutique fixe comprenant en plus de l'atorvastatine et du périndopril, de l'indapamide ou ses sels pharmaceutiquement acceptables, leurs hydrates et formes cristallines et, l'utilisation de ladite composition pour la prévention et le traitement de maladies cardiovasculaires. The present invention also relates to 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.
Par maladies cardiovasculaires on entend plus précisément la prévention des événements coronaires chez les patients ayant des antécédents d'infarctus du myocarde et/ou de revascularisation en association avec l'hypercholestérolémie primaire ou hyperlipidémie mixte. 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.
Une composition pharmaceutique fixe à l'avantage de permettre à la fois une réduction des coûts de fabrication, mais surtout une meilleure observance du traitement de la part des patients et par conséquent un meilleur contrôle de leur pathologie. 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.
Dans la présente invention, la composition pharmaceutique fixe d'au moins deux principes actifs qui sont 1) Patorvastatine et 2) le périndopril appartenant à différentes classes thérapeutiques ayant des effets complémentaires a donc l'avantage de cibler plusieurs facteurs de risque responsables des maladies cardiovasculaires en une seule prise. In the present invention, 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.
La présente invention est aussi une combinaison thérapeutique fixe d'au moins trois principes actifs appartenant à différents classes thérapeutiques ayant des effets complémentaires qui sont 1) l'atorvastatine, 2) le périndopril ainsi que : 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:
a) l'acide acétylsalicylique ou,  a) acetylsalicylic acid or,
b) l'indapamide ou  (b) indapamide or
L'utilisation de ces combinaisons thérapeutiques fixes : The use of these fixed therapeutic combinations:
atorvastatine + périndopril,  atorvastatin + perindopril,
atorvastatine + périndopril + acide acétylsalicylique et,  atorvastatin + perindopril + acetylsalicylic acid and,
atorvastatine + périndopril + indapamide  atorvastatin + perindopril + indapamide
est la prévention des événements coronaires chez les patients ayant des antécédents d'infarctus du myocarde et/ou de revascularisation en association avec une hypercholestérolémie primaire ou une hyperlipidémie mixte en tant que thérapie de substitution chez les patients adultes contrôlés concurremment en monothérapie avec l'atorvastatine, le périndopril et/ou les principes actifs a) à d) aux mêmes doses que celles présentes dans la composition pharmaceutique fixe. is the prevention of coronary events in patients with a history of myocardial infarction and / or revascularization in combination with primary hypercholesterolemia or mixed hyperlipidemia as a replacement therapy in adult patients concurrently controlled as monotherapy with atorvastatin , perindopril and / or the active ingredients a) to d) at the same doses as those present in the fixed pharmaceutical composition.
La composition pharmaceutique fixe selon l'invention est à prendre une fois par jour le matin. The fixed pharmaceutical composition according to the invention is to be taken once a day in the morning.
On peut donc simplifier la prise d'un traitement chez les patients recevant des médicaments séparément et ainsi améliorer l'observance en limitant le nombre de comprimés. Tous les principes actifs précédemment cités sont des médicaments ayant obtenus une autorisation de mise sur le marché et qui sont commercialisés dans le monde entier depuis de nombreuses années. Tous ces composants sont des substances actives bien connues avec une efficacité et une tolérance bien établie. L'atorvastatine fait partie d'un groupe de médicaments appelés inhibiteurs de la HMG-CoA réductase ou statines. L'atorvastatine réduit les concentrations de lipoprotéines de basse densité (LDL) et de triglycérides dans le sang, tout en augmentant les concentrations lipoprotéine de haute densité (HDL). L'atorvastatine sous forme de sel de calcium trihydrate est commercialisée sous le nom de Tahor® ou Lipitor® et la composition pharmaceutique correspondante est décrite dans la demande de brevet WO 94/16693. L'atorvastatine est indiquée pour : It is therefore possible to simplify the treatment of patients receiving drugs separately and thus improve compliance by limiting the number of tablets. All the active ingredients mentioned above are drugs that have been granted marketing authorization and have been marketed worldwide for many years. All these components are well-known active substances with a well-established efficacy and tolerance. 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:
le traitement de l'hypercholestérolémie en complément d'un régime pour réduire les élevées de cholestérol total (Chol-T), de LDL-cholestérol (LDL-C), d'apo lipoprotéine B et de triglycérides chez les patients présentant une hypercholestérolémie primaire incluant l'hypercholestérolémie familiale ou les hyperlipidémies mixtes,  Treatment of 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,
la prévention des événements cardiovasculaires chez les patients ayant un risque élevé de présenter un premier événement cardiovasculaire, en complément de la correction des autres facteurs de risques.  the prevention of cardiovascular events in patients with a high risk of presenting a first cardiovascular event, in addition to the correction of other risk factors.
Le périndopril est un inhibiteur de l'enzyme qui transforme l'angiotensine I en angiotensine II (enzyme de conversion de l'angiotensine ECA). Cette enzyme de conversion, ou kinase, est une exopeptidase qui permet la conversion de l'angiotensine I en angiotensine II vasoconstrictrice provoquant la dégradation de la bradykinine vasodilatatrice en un heptapeptide inactif. Le périndopril sous forme de sel d'arginine est commercialisée sous le nom de Coversyl® et est indiqué pour : 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:
- le traitement de l'hypertension artérielle,  - the treatment of arterial hypertension,
- la réduction du risque d'événements cardiaques chez les patients ayant un antécédent d'infarctus du myocarde et/ou revascularisation et  - reduced risk of cardiac events in patients with a history of myocardial infarction and / or revascularization and
le traitement de l'insuffisance cardiaque symptomatique.  the treatment of symptomatic heart failure.
L'acide acétylsalicylique est un inhibiteur de l'activation plaquettaire : en bloquant par acétylation la cyclo-oxygénase plaquettaire, elle inhibe la synthèse du thromboxane A2, substance activatrice physiologique libérée par les plaquettes, et qui jouerait un rôle dans les complications des lésions athéromateuses. L'acide acétylsalicylique 100 mg est commercialisée sous le nom de Aspirine Protect® et est indiqué pour : 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:
- la prévention des complications secondaires cardiovasculaires et cérébrovasculaires chez les patients présentant une maladie athéromateuse ischémique (par ex. infarctus du myocarde, angor stable et instable, accident vasculaire cérébral, constitué ou transitoire, d'origine ischémique),  - the prevention of secondary cardiovascular and cerebrovascular complications in patients with atheromatous ischemic disease (eg myocardial infarction, stable and unstable angina, cerebral, constitutional or transient stroke, of ischemic origin),
la prévention des événements thromboemboliques après chirurgie ou intervention vasculaire, et  prevention of thromboembolic events after surgery or vascular intervention, and
- la réduction de l'occlusion des greffons après pontage aortocoronaire. L'indapamide est un diurétique sulfamide, apparenté sur le plan pharmaco logique aux diurétiques thiazidiques. L'indapamide hémihydrate est commercialisé sous le nom de Fludex® et est indiqué pour le traitement de l'hypertension artérielle.  - the reduction of graft occlusion after coronary artery bypass grafting. 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.
Un des risques majeurs des combinaisons pharmaceutiques fixes résulte d'une possible interaction entre les différents principes actifs présents dans cette combinaison. De plus, les principes actifs peuvent s'avérer incompatibles avec certains excipients qui sont néanmoins nécessaires afin de stabiliser l'un ou l'autre de ces principes actifs. One of the major risks of fixed pharmaceutical combinations results from a possible interaction between the different active ingredients present in this combination. In addition, 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.
L'utilisation d'acide acétylsalicylique pour réduite le risque d'infarctus du myocarde et l'utilisation de statines pour abaisser le taux cholestérol et prévenir ou traiter les maladies cardiovasculaires et cérébrovasculaires sont très bien documentés. En effet, il n'est pas inhabituel que les patients ayant un taux élevé de cholestérol et qui sont considérés à risques pour « faire » un infarctus du myocarde prennent à la fois une statine et de l'acide acétylsalicylique. Cependant, l'utilisation à la fois de statines et d'acide acétylsalicylique nécessite de prendre des précautions particulières afin de minimiser les interactions entre ces deux médicaments car, il est bien connu de l'art antérieur, que les inhibiteurs de la HMG-CoA réductase se décomposent en présence d'acide acétylsalicylique. Les interactions comprennent les incompatibilités physiques et chimiques mais aussi les effets secondaires. The use of 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.
De plus, les statines sont sensibles à des facteurs tels que la chaleur, l'humidité, pH faible et la lumière. En particulier, l'atorvastatine est transformée en lactone qui résulte d'une réaction d'estérifîcation intramoléculaire. Les produits de dégradation majeurs qui sont produits lors de la décomposition des statines sont les lactones et les produits d'oxydation qui diminuent la stabilité de Γ atorvastatme et de ce fait sa durée de demi-vie. In addition, statins are sensitive to factors such as heat, humidity, low pH and light. In particular, 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 Γ atorvastatme and therefore its half-life.
L'atorvastatine est une molécule qui se décompose assez facilement et nécessite l'utilisation d'un agent stabilisant qui dans la formulation du Tahor® est du carbonate de calcium. Cette formulation du Tahor® est notamment décrite dans le brevet EP 0 680 320. 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.
De manière surprenante, en mélangeant le périndopril avec l'atorvastatine et en formulant le mélange sur la base de la formulation du Tahor® donc, en présence de carbonate de calcium, la Demanderesse s'est rendue compte que le carbonate de calcium modifie la pharmacocinétique humaine du périndopril rendant difficile la bioéquivalence de la formulation de périndopril dans la combinaison fixe « périndopril + atorvastatme ». Surprisingly, by mixing perindopril with atorvastatin and formulating the mixture on the basis of the Tahor® formulation, therefore, in the presence of calcium carbonate, the Applicant has realized that calcium carbonate modifies the pharmacokinetics human perindopril making it difficult to bioequivalence of the formulation of perindopril in the fixed combination "perindopril + atorvastatme".
En effet dans une étude d'interaction de la combinaison fixe « atorvastatme 40 mg + périndopril arginine 10 mg » versus atorvastatme 40 mg seul et périndopril arginine 10 mg seul, la Demanderesse a montré que le Cmax (qui est la concentration maximale de produit présente dans le sang après administration) du périndopril dans la bithérapie était modifié. Indeed, in an interaction study of the fixed combination "atorvastatin 40 mg + perindopril arginine 10 mg" versus atorvastatin 40 mg alone and perindopril arginine 10 mg alone, the Applicant has shown that C max (which is the maximum concentration of product present in the blood after administration) of perindopril in dual therapy was modified.
Ainsi, le rapport entre périndopril administré dans la combinaison fixe « atorvastatme + périndopril » et périndopril administré seul est à plus de 130%. Thus, the ratio of perindopril administered in the fixed combination "atorvastatin + perindopril" and perindopril administered alone is more than 130%.
Il est donc nécessaire de séparer physiquement ces deux principes actifs afin d'obtenir une composition pharmaceutique fixe stable d' atorvastatme et de périndopril. It is therefore necessary to physically separate these two active ingredients in order to obtain a stable fixed pharmaceutical composition of atorvastatin and perindopril.
La présente invention résout ce problème en mettant au point une composition pharmaceutique fixe sous forme de gélule comprenant des mini-granules d' atorvastatme et des mini-granules de périndopril. Il est bien connu de l'art antérieur que l'aspirine dégrade les inhibiteurs de la HMG-CoA réductase. Dans une étude de compatibilité des différents principes actifs, la Demanderesse a pu mettre en évidence que lorsque les 3 principes actifs sont seuls il n'y a pas de dégradation y compris, lorsque l'atorvastatine et le périndopril sont formulés ensemble. En revanche, lorsque l'aspirine est ajoutée au mélange « atorvastatine + périndopril » les 3 principes actifs se dégradent comme le montre le tableau ci -après. 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.
Tableau A : étude de compatibilité des principes actifs Table A: compatibility study of active ingredients
Donc, dans la composition pharmaceutique fixe selon l'invention qui comprend l'atorvastatine, le périndopril et l'aspirine, il est nécessaire de séparer l'aspirine de l'atorvastatine et du périndopril. La Demanderesse a donc mis au point une composition pharmaceutique fixe sous forme de gélule comprenant, des mini-granules d' atorvastatine, des mini-granules de périndopril et des mini-granules gastro -résistantes d'aspirine. Thus, in the fixed pharmaceutical composition according to the invention which comprises atorvastatin, perindopril and aspirin, it is necessary to separate aspirin from atorvastatin and perindopril. The Applicant has therefore developed a fixed pharmaceutical composition in capsule form comprising atorvastatin mini-granules, mini-granules of perindopril and gastro-resistant mini-granules of aspirin.
Cependant dans cette composition pharmaceutique fixe, les mini-granules gastro -résistantes d'aspirine ne sont pas bioéquivalentes aux comprimés gastro -résistants d'aspirine présents sur le marché comme démontré par la Demanderesse (voir figure ci-après - traitement 4). However, in this fixed pharmaceutical composition, 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).
Dans cette étude, on peut voir que le profil du traitement 4 est différent des profils des traitements 1 à 3 montrant ainsi une différence entre le comprimé gastro -résistant d'aspirine et les mini-granules gastro -résistantes d'aspirine. In this study, it can be seen that 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.
Temps (heures)  Time (hours)
1 m  1 m
Traitement 1 : Treatment 1:
• 1 gélule de mini-granules d'atorvastatine calcium sans carbonate de calcium  • 1 capsule of atorvastatin calcium mini granules without calcium carbonate
• 1 gélule de mini-granules de périndopril arginine  • 1 capsule of mini-granules of perindopril arginine
· 1 gélule de mini-granules d'aspirine gastro-résistante  · 1 capsule of gastro-resistant aspirin mini-granules
Traitement 2 :  Treatment 2:
• 1 gélule de mini-granules d'atorvastatine calcium avec carbonate de calcium - procédé de mélange du carbonate de calcium sans broyage  • 1 capsule of atorvastatin calcium mini-granules with calcium carbonate - calcium carbonate blending process without grinding
• 1 gélule de mini-granules de périndopril arginine  • 1 capsule of mini-granules of perindopril arginine
1 gélule de mini-granules d'aspirine gastro-résistante  1 capsule of gastro-resistant aspirin mini-granules
Traitement 3 :  Treatment 3:
• 1 gélule de mini-granules d'atorvastatine calcium avec carbonate de calcium - procédé de mélange du carbonate de calcium avec broyage  • 1 capsule of atorvastatin calcium mini-granules with calcium carbonate - process of mixing calcium carbonate with grinding
• 1 gélule de mini-granules de périndopril arginine  • 1 capsule of mini-granules of perindopril arginine
1 gélule de mini-granules d'aspirine gastro-résistante  1 capsule of gastro-resistant aspirin mini-granules
Traitement 4 :  Treatment 4:
• 1 comprimé de Tahor®  • 1 tablet of Tahor®
• 1 comprimé de Coversyl®  • 1 tablet of Coversyl®
• 1 comprimé d'aspirine gastro -résistant La présente invention trouve la solution au problème en mettant au point une composition pharmaceutique fixe comprenant de l'atorvastatine, du périndopril et de l'aspirine, composition dans laquelle les interactions entre les différents principes actifs et les interactions avec les excipients sont inexistantes. De plus, dans cette composition les principes actifs sont bioéquivalents aux composés individuels que sont les comprimés individuels commercialisés. 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. In addition, in this composition the active ingredients are bioequivalent to the individual compounds that are the individual tablets marketed.
La présente invention propose donc une composition pharmaceutique fixe sous forme de gélule comprenant, des mini-granules d'atorvastatine, des mini-granules de périndopril et des comprimés gastro -résistants d'aspirine. Cette composition a donc l'avantage d'être bioéquivalente au comprimé gastro -résistant d'aspirine seul et de ne pas présenter d'interactions entre les 3 principes actifs ni avec les excipients. 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.
De la même manière et pour les mêmes raisons que citées précédemment, la présente invention comprend une composition pharmaceutique fixe comprenant des : In the same way and for the same reasons as mentioned above, the present invention comprises a fixed pharmaceutical composition comprising:
A) mini-granules d'atorvastatine, des mini-granules de périndopril et des mini-granules d'indapamide.  A) mini granules of atorvastatin, mini-granules of perindopril and mini-granules of indapamide.
Toutes les compositions pharmaceutiques fixes selon l'invention comprennent des sels pharmaceutiquement acceptables en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables, leurs hydrates et leurs formes cristallines. 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.
La présente invention s'étend également aux compositions pharmaceutiques fixes comprenant de l'atorvastatine et ses sels pharmaceutiquement acceptables et, du périndopril et ses sels pharmaceutiquement acceptables en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables, leurs hydrates et leurs formes cristallines dans lesquelles : les doses d'atorvastatine varient de 10 mg à 80 mg exprimées en atorvastatine base ou varient de 10,80 mg à 86,80 mg exprimées en atorvastatine calcium trihydrate et, - les doses de périndopril varient de 1,65 mg à 9,512 mg exprimées en périndopril base ou varient de 2,5 mg à 14 mg exprimées en périndopril arginine. 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.
La présente invention s'étend également aux compositions pharmaceutiques fixes comprenant en outre de l'aspirine et ses sels pharmaceutiquement acceptables, ou de l'amlodipine et ses sels pharmaceutiquement acceptables, ou de l'indapamide et ses sels pharmaceutiquement acceptables, ou du bisoprolol et ses sels pharmaceutiquement acceptables, en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables, leurs hydrates et leurs formes cristallines dans lesquelles : - les doses d'aspirine sont de 75 mg à 150 mg exprimées en aspirine base,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,
- les doses d'indapamide varient de 0,625 mg à 2,5 mg exprimée en indapamide base. doses of indapamide vary from 0.625 mg to 2.5 mg expressed as indapamide base.
De manière préférentielle, dans les compositions pharmaceutiques fixes selon l'invention, les doses : Preferably, in the fixed pharmaceutical compositions according to the invention, the doses:
- d'atorvastatine calcium sont de 10 mg, 20 mg, 40 mg et 80 mg,  - atorvastatin calcium are 10 mg, 20 mg, 40 mg and 80 mg,
- de périndopril arginine sont de 2,5 mg, 3,5 mg, 5 mg, 7 mg, 10 mg et 14 mg,  - Perindopril arginine are 2.5 mg, 3.5 mg, 5 mg, 7 mg, 10 mg and 14 mg,
- d'aspirine sont de 75 mg, 100 mg et 150 mg et,  - Aspirin are 75 mg, 100 mg and 150 mg and,
- d'indapamide sont de 0,625 mg, 1,25 mg, 1,5 mg et 2,5 mg.  Indapamide are 0.625 mg, 1.25 mg, 1.5 mg and 2.5 mg.
Les compositions pharmaceutiques fixes selon l'invention les plus particulièrement préférées sont les compositions pharmaceutiques comprenant : The most particularly preferred fixed pharmaceutical compositions according to the invention are pharmaceutical compositions comprising:
a) 10 mg d'atorvastatine calcium et 2,5 mg, 5 mg ou 10 mg de périndopril arginine, b) 20 mg d'atorvastatine calcium et 2,5 mg, 5 mg ou 10 mg de périndopril arginine, c) 40 mg d'atorvastatine calcium et 2,5 mg, 5 mg ou 10 mg de périndopril 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.
Les compositions pharmaceutiques fixes selon l'invention telle que décrite en a), b) ou c) peuvent contenir chacune en plus de 75 mg, 100 mg ou 150 mg d'aspirine. 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.
Les compositions pharmaceutiques fixes selon l'invention telle que décrite en a), b) ou c) peuvent contenir chacune en plus 1,5 mg ou 2,5 mg d'indapamide. 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.
Les compositions pharmaceutiques fixes selon l'invention encore plus préférentiellement préférées sont les compositions pharmaceutiques comprenant : The still more preferably preferred fixed pharmaceutical compositions according to the invention are pharmaceutical compositions comprising:
i) 10 mg d'atorvastatine calcium et 5 mg ou 10 mg de périndopril arginine,  i) 10 mg of atorvastatin calcium and 5 mg or 10 mg of perindopril arginine,
ii) 20 mg d'atorvastatine calcium et 5 mg ou 10 mg de périndopril arginine,  (ii) 20 mg of atorvastatin calcium and 5 mg or 10 mg of perindopril arginine,
iii) 40 mg d'atorvastatine calcium et 5 mg ou 10 mg de périndopril arginine,  (iii) 40 mg of atorvastatin calcium and 5 mg or 10 mg of perindopril arginine,
iv) 100 mg d'aspirine et  iv) 100 mg of aspirin and
a. 20 mg d'atorvastatine calcium et 5 mg ou 10 mg de périndopril arginine;  at. 20 mg atorvastatin calcium and 5 mg or 10 mg perindopril arginine;
b. 40 mg d'atorvastatine calcium et 5 ou 10 mg de périndopril arginine v) 1,25 mg d'indapamide, 5 mg de périndopril arginine et, 10 mg, 20 mg ou 40 mg d'atorvastatine calcium,  b. 40 mg of atorvastatin calcium and 5 or 10 mg of perindopril arginine v) 1.25 mg of indapamide, 5 mg of perindopril arginine and, 10 mg, 20 mg or 40 mg of atorvastatin calcium,
vi) 2,5 mg d'indapamide et, 10 mg de périndopril arginine et, lOmg, 20 mg ou 40 mg d'atorvastatine calcium. Les compositions pharmaceutiques fixes selon l'invention précédemment mentionnées comprennent toutes un ou plusieurs excipients pharmaceutiquement acceptable, leurs hydrates et leurs formes cristallines. vi) 2.5 mg of indapamide and 10 mg of perindopril arginine and 10 mg, 20 mg or 40 mg of atorvastatin calcium. The above-mentioned fixed pharmaceutical compositions according to the invention all comprise one or more pharmaceutically acceptable excipients, their hydrates and their crystalline forms.
Outre Patorvastatine, le périndopril, l'aspirine et l'indapamide, lesdites compositions pharmaceutiques contiennent un ou plusieurs excipients ou véhicules choisis parmi des diluants, des lubrifiants, des liants, des agents de désintégration, des tensioactifs, des revêtements entériques, des absorbants, des colorants, des édulcorants, etc .. In addition to antitropatin, perindopril, aspirin and indapamide, said pharmaceutical compositions contain one or more excipients or vehicles selected from diluents, lubricants, binders, disintegrating agents, surfactants, enteric coatings, absorbents, dyes, sweeteners, etc.
A titre d'exemple et de manière non limitative, on peut citer : By way of example and in a nonlimiting manner, mention may be made of:
♦ pour les diluants : le lactose, le dextrose, le sucrose, le mannitol, le sorbitol, la cellulose, la glycérine,  ♦ for diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerin,
♦ pour les lubrifiants : la silice, le talc, l'acide stéarique et ses sels de magnésium et de calcium, le polyéthylène glycol,  ♦ for lubricants: silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol,
♦ pour les liants : le silicate d'aluminium et de magnésium, l'amidon, la gélatine, la tragacanthe, la cellulose, la méthylcellulose, l'hydroxypropylcellulose, l'hydroxypropylmethylcellulose, et la polyvinylpyrrolidone,  For the binders: magnesium aluminum silicate, starch, gelatin, tragacanth, cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone,
♦ pour les désintégrants : l'agar, l'amidon, l'acide alginique et son sel de sodium, les mélanges effervescents, les sels de carboxyméthylcellulose, les sels de carboxyméthylamidon, les dérivés de la polyvinylpyrrolidone.  For the disintegrants: agar, starch, alginic acid and its sodium salt, effervescent mixtures, carboxymethylcellulose salts, carboxymethyl starch salts, polyvinylpyrrolidone derivatives.
La posologie utile varie selon l'âge du patient, la nature de l'affection et, les pathologies et traitements éventuellement associés. Elle est toujours de 1 comprimé/jour et peut être ajustée en fonction surtout de l'état du patient afin de stabiliser les paramètres cardiovasculaires aux bonnes valeurs. 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.
Les exemples qui suivent illustrent l'invention et ne la limitent en aucune façon. Exemples Méthode de préparation des compositions pharmaceutiques selon l'invention. The following examples illustrate the invention and do not limit it in any way. Examples Method of preparation of the pharmaceutical compositions according to the invention.
Dans les exemples qui suivent, la préparation des mini-granules selon l'invention se fait selon des techniques bien connues de l'homme du métier Exemple 1 : préparation des mini-granules d'atorvastatine In the examples which follow, the preparation of the mini-granules according to the invention is carried out according to techniques well known to those skilled in the art. Example 1 Preparation of atorvastatin mini-granules
On mélange l'atorvastatine calcium et le carbonate de calcium dans de l'eau purifiée. On rajoute ensuite le sodium croscarmellose et le polysorbate 80. La suspension précédemment obtenue est ensuite pulvérisée sur les billes de sucres pour former les mini-granules d'atorvastatine.  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.
Tableau 1 - Mini-granules d'atorvastatine à libération immédiate de 20 et 40 mg Table 1 - 20 and 40 mg Atorvastatin Immediate Release Granules
Exemple 2 : préparation des mini-granules de périndopril Example 2 Preparation of Mini-Granules of Perindopril
On mélange le périndopril arginine et l'hydroxypropylcellulose dans de l'eau purifiée. La suspension précédemment obtenue est ensuite pulvérisée sur les billes de sucres pour former les mini-granules de périndopril.  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.
Tableau 2 - Mini-granules de périndopril à libération immédiate de 5 et 10 mg Table 2 - 5 and 10 mg Immediate Release Perindopril Mini Granules
Exemple 3 : préparation des comprimés gastro-résistants d'aspirine Example 3 Preparation of gastro-resistant aspirin tablets
On forme un premier mélange avec l'acide acétylsalicylique, la cellulose microcristalline et l'amidon de maïs qui est ensuite tamisé une première fois puis mélangé à nouveau. Dans un second temps, on mélange la cellulose microcristalline avec la silice colloïdale anhydre et le sodium stéarylfumarate qui est ensuite tamisé. On rajoute ensuite le premier mélange, on mélange le tout et on forme les comprimés selon les techniques classiques bien connus de l'homme du métier. A first mixture is formed with acetylsalicylic acid, microcrystalline cellulose and corn starch which is then sieved a first time and then mixed again. In a second step, 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.
La suspension d'enrobage est obtenue en mélangeant le talc, l'Ariavit Ponceau, le triéthylcitrate, le copolymère acide méthacrylique-acrylate d'éthyle (1 : 1) et de l'eau purifiée. Le comprimé est ensuite enrobé avec la suspension d'enrobage selon les techniques bien connues de l'homme du métier.  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.
Tableau 3 - Comprimé gastro-résistant d'acide acétylsalicylique 100 mg Table 3 - Gastro-Resistant Acetylsalicylic Acid Tablet 100 mg
Exemple 4 : préparation des mini-granules d'indapamide Example 4 Preparation of indapamide mini-granules
On mélange l'indapamide et l'hypromellose dans de l'eau purifiée. La suspension précédemment obtenue est ensuite pulvérisée sur la cellulose microcristalline pour former les mini-granules d'indapamide.  Indapamide and hypromellose are mixed in purified water. The suspension previously obtained is then sprayed onto the microcrystalline cellulose to form indapamide mini-granules.
Tableau 4 - Mini-granules de d'indapamide à libération immédiate de 1,25 et 2,5 mg Table 4 - Mini-granules of indapamide immediate release 1.25 and 2.5 mg
Les gélules suivantes ont été préparées selon l'invention Exemple 5 : gélules comprenant de P atorvastatine et du périndopril The following capsules have been prepared according to the invention Example 5 Capsules Comprising P Atorvastatin and Perindopril
Les mini-granules d'atorvastatme à libération immédiate obtenues selon l'exemple 1 et les mini-granules de périndopril à libération immédiate obtenues selon l'exemple 2 sont chacune lubrifiés selon les techniques bien connues de l'homme du métier. Les gélules sont ensuite remplies par les mini-gélules lubrifiées selon les techniques bien connues de l'homme du métier.  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.
Tableau 5 - Compositions des gélules comprenant Γ atorvastatine et le périndopril Table 5 - Capsule compositions comprising Γ atorvastatin and perindopril
Exemple 6 : gélules comprenant de P atorvastatine, du périndopril et de l'aspirine Example 6 Capsules Comprising Atorvastatin, Perindopril and Aspirin
Selon le même procédé que celui de l'exemple 5, on remplit la gélule de mini-granules d'atorvastatme à libération immédiate, de mini-granules de périndopril à libération immédiate et de comprimés gastro -résistants d'acide acétylsalicylique obtenu selon l'exemple 3. Tableau 6 - Compositions des gélules comprenant l'atorvastatine, périndopril et acide acétylsalicylique According to the same method as that of Example 5, the capsule of atorvastatin mini-granules immediate release, mini-granules of perindopril immediate release and gastro-resistant tablets of acetylsalicylic acid obtained according to example 3. Table 6 - Capsule Compositions Comprising Atorvastatin, Perindopril and Acetylsalicylic Acid
Exemple 7 : gélules comprenant de l'atorvastatine, du périndopril et de l'indapamide Les gélules de l'exemple 7 sont obtenues de la même manière que les gélules de l'exemple 5, en rajoutant en plus des mini-granules d'indapamide à libération immédiate obtenues selon l'exemple 4. Tableau 7 - Compositions des gélules comprenant l'atorvastatine, périndopril et indapamide 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. Table 7 - Capsule Compositions Comprising Atorvastatin, Perindopril and Indapamide

Claims

REVENDICATIONS
1. Composition pharmaceutique fixe comprenant de l'atorvastatine et ses sels pharmaceutiquement acceptables et, du périndopril et ses sels pharmaceutiquement acceptables en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables, leurs hydrates et leurs formes cristallines. A fixed pharmaceutical composition 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.
2. Composition pharmaceutique fixe selon la revendication 1 comprenant en outre de l'aspirine et ses sels pharmaceutiquement acceptables, ou de l'indapamide et ses sels pharmaceutiquement acceptables en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables, leurs hydrates et leurs formes cristallines. The fixed pharmaceutical composition according to claim 1 further comprising aspirin and its pharmaceutically acceptable salts, or indapamide and its pharmaceutically acceptable salts in combination with one or more pharmaceutically acceptable excipients, their hydrates and their crystalline forms.
3. Composition pharmaceutique fixe selon l'une des revendications 1 ou 2 dans laquelle la composition pharmaceutique est une gélule. 3. Fixed pharmaceutical composition according to one of claims 1 or 2 wherein the pharmaceutical composition is a capsule.
4. Composition pharmaceutique fixe selon l'une des revendications 1 à 3 dans laquelle : 4. Fixed pharmaceutical composition according to one of claims 1 to 3 wherein:
- l'atorvastatine et ses sels pharmaceutiquement acceptables ou,  atorvastatin and its pharmaceutically acceptable salts or
- le périndopril et ses sels pharmaceutiquement acceptables ou,  perindopril and its pharmaceutically acceptable salts, or
- l'indapamide et ses sels pharmaceutiquement acceptables ou,  indapamide and its pharmaceutically acceptable salts, or
sont chacun sous forme de mini granules.  are each in the form of mini granules.
5. Composition pharmaceutique fixe selon l'une des revendications 2 ou 3 dans laquelle l'aspirine et ses sels pharmaceutiquement acceptables est sous forme de comprimé gastro-résistant. 5. Fixed pharmaceutical composition according to one of claims 2 or 3 wherein the aspirin and its pharmaceutically acceptable salts is in the form of gastro-resistant tablet.
6. Composition pharmaceutique fixe selon l'une des revendications 1 à 5 dans laquelle l'atorvastatine est sous forme d'atorvastatine calcium. 6. Fixed pharmaceutical composition according to one of claims 1 to 5 wherein the atorvastatin is in the form of atorvastatin calcium.
7. Composition pharmaceutique fixe selon l'une des revendications 1 à 5 dans laquelle le périndopril est sous forme de périndopril tert-butylamine ou périndopril arginine et plus préférentiellement sous forme de périndopril arginine. 7. Fixed pharmaceutical composition according to one of claims 1 to 5 wherein the perindopril is in the form of perindopril tert-butylamine or perindopril arginine and more preferably in the form of perindopril arginine.
8. Composition pharmaceutique fixe selon l'une des revendications 1 à 7 dans laquelle - les doses d'atorvastatine varient de 10 mg à 80 mg exprimées en atorvastatine base ou entre 10,80 mg à 86,80 mg exprimées en atorvastatine calcium trihydrate, 8. Fixed pharmaceutical composition according to one of claims 1 to 7 wherein doses of atorvastatin vary from 10 mg to 80 mg expressed as atorvastatin base or between 10.80 mg to 86.80 mg expressed as atorvastatin calcium trihydrate,
- les doses de périndopril varient de 1,65 mg à 9,512 mg exprimées en périndopril base ou entre 2,5 mg à 14 mg exprimées en périndopril arginine,  the doses of perindopril vary from 1.65 mg to 9.512 mg expressed as perindopril base or between 2.5 mg to 14 mg expressed as perindopril arginine,
- les doses d'aspirine sont de 75 mg à 150 mg exprimées en aspirine base,  doses of aspirin are 75 mg to 150 mg expressed as aspirin base,
- les doses d'indapamide varient de 0,625 mg à 2,5 mg exprimées en indapamide base.  the doses of indapamide vary from 0.625 mg to 2.5 mg expressed in indapamide base.
9. Composition pharmaceutique fixe selon l'une des revendications 1 à 8 dans laquelle les doses : 9. Fixed pharmaceutical composition according to one of claims 1 to 8 wherein the doses:
- d'atorvastatine calcium sont de 10 mg, 20 mg, 40 mg et 80 mg,  - atorvastatin calcium are 10 mg, 20 mg, 40 mg and 80 mg,
- de périndopril arginine sont de 2,5 mg, 3,5 mg, 5 mg, 7 mg, 10 mg et 14 mg, - Perindopril arginine are 2.5 mg, 3.5 mg, 5 mg, 7 mg, 10 mg and 14 mg,
- d'aspirine sont de 75 mg, 100 mg et 150 mg, - Aspirin are 75 mg, 100 mg and 150 mg,
- d'indapamide sont de 0,625 mg, 1,25 mg, 1,5 mg et 2,5 mg.  Indapamide are 0.625 mg, 1.25 mg, 1.5 mg and 2.5 mg.
10. Compositions pharmaceutiques fixes selon l'une des revendications 1 à 9 pour leur utilisation dans le traitement ou la prévention de maladies cardiovasculaires. 10. Fixed pharmaceutical compositions according to one of claims 1 to 9 for their use in the treatment or prevention of cardiovascular diseases.
11. Compositions pharmaceutiques fixes selon la revendication 10 caractérisées en ce que les maladies cardiovasculaires sont choisies parmi les événements coronaires chez les patients ayant des antécédents d'infarctus du myocarde et/ou de revascularisation en association avec l'hypercholestérolémie primaire ou hyperlipidémie mixte. 11. Fixed pharmaceutical compositions according to claim 10 characterized in that the cardiovascular diseases are selected from coronary events in patients with a history of myocardial infarction and / or revascularization in combination with primary hypercholesterolemia or mixed hyperlipidemia.
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