WO2017182754A1 - Pharmaceutical composition comprising a beta blocker, a converting enzyme inhibitor and an antihypertensive or an nsaid - Google Patents

Pharmaceutical composition comprising a beta blocker, a converting enzyme inhibitor and an antihypertensive or an nsaid Download PDF

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Publication number
WO2017182754A1
WO2017182754A1 PCT/FR2017/050929 FR2017050929W WO2017182754A1 WO 2017182754 A1 WO2017182754 A1 WO 2017182754A1 FR 2017050929 W FR2017050929 W FR 2017050929W WO 2017182754 A1 WO2017182754 A1 WO 2017182754A1
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Prior art keywords
perindopril
bisoprolol
pharmaceutical composition
pharmaceutically acceptable
amlodipine
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PCT/FR2017/050929
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French (fr)
Inventor
Gilles Fonknechten
Original Assignee
Les Laboratoires Servier
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Filing date
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Priority to CN201780023915.6A priority Critical patent/CN109069438A/en
Priority to BR112018070968A priority patent/BR112018070968A2/en
Priority to EA201892354A priority patent/EA201892354A1/en
Priority to TNP/2018/000344A priority patent/TN2018000344A1/en
Priority to RU2018140193A priority patent/RU2756320C2/en
Priority to UAA201811111A priority patent/UA125511C2/en
Priority to KR1020187033434A priority patent/KR102267965B1/en
Priority to EP17722115.7A priority patent/EP3445342A1/en
Priority to SG11201808848SA priority patent/SG11201808848SA/en
Publication of WO2017182754A1 publication Critical patent/WO2017182754A1/en
Priority to PH12018502155A priority patent/PH12018502155A1/en

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    • 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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • 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
    • A61K31/40—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
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • 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
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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
    • 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
    • A61K9/14—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
    • 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
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K9/2833—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

Definitions

  • the present invention relates to a fixed pharmaceutical composition comprising a betablocker, an angiotensin converting enzyme (ACE) inhibitor and a therapeutic agent, the use of said composition for the treatment and prevention
  • a fixed pharmaceutical composition comprising a betablocker, an angiotensin converting enzyme (ACE) inhibitor, and an angiotensin converting enzyme.
  • therapeutic agent in which:
  • beta-blocker is bisoprolol or one of its addition salts with a pharmaceutically acceptable acid, their hydrates and crystalline forms,
  • the inhibitor of the conversion enzyme is perindopril or one of its addition salts with a pharmaceutically acceptable acid or base, their hydrates and crystalline forms and,
  • the therapeutic agent is chosen from among another antihypertensive agent or a non-steroidal anti-inflammatory agent State of the art / context of the invention
  • Cardiovascular disease is the leading cause of death in both developed and developing countries, accounting for one-third of all deaths, and 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 for both men and women, causing nearly 4.1 million deaths annually, or 46 per cent 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
  • Hypertension and coronary artery disease are major steps in the cardiovascular continuum leading to the development of advanced heart disease. Hypertension is the leading cause of death in the world, causing about 7.5 million deaths (accounting for about 13% of deaths). Coronary artery disease is the most common consequence of hypertension and is the 1st cause of death in Europe. Heart failure is the terminal pathology, a consequence of many heart diseases. The mortality rate is still high with 50% survival at 5 years.
  • Chronic diseases such as cardiovascular disease usually 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.
  • a meta-analysis of nine studies was performed comparing the administration of a fixed combination and individual components. The efficacy of combination therapy versus individual component therapy was examined. This meta-analysis evaluated the use of fixed combination therapies in different clinical settings, including hypertension, heart failure, myocardial infarction, hypercholesterolemia, diabetes, tuberculosis, and human immunodeficiency virus infection. The results of this meta-analysis showed a much better compliance of the fixed combinations with respect to the setting of the separate components. The compliance rate was improved by 26% in patients receiving fixed combinations.
  • betablockers and ACE inhibitors are used alone or in combination as initiation or maintenance treatment for arterial hypertension.
  • beta-blockers are indicated in the plan you (direct action on the heart, improving perfusion in ischemic area) and
  • beta-blockers that are co-prescribed with perindopril are acebutolol, atenolol, bisoprolol, metoprolol and nebivolol.
  • Bisoprolol is the beta-blocker that is most co-prescribed with perindopril followed by atenolol.
  • the perindopril assays are expressed as arginine salt (2.5 mg, 5 mg or 10 mg) or tert-butyl amine salt (2 mg, 4 mg or 8 mg) and the bisoprolol dosages are expressed as a base.
  • the dosage of perindopril arginine salt 5 mg followed by 10 mg is the one most frequently prescribed with bisoprolol 2.5 mg, 5 mg and 10 mg.
  • the present invention proposes to develop a novel fixed combination comprising a betablocker such as bisoprolol, an antihypertensive agent. selected from an IEC such as perindopril and at least one therapeutic agent selected from another antihypertensive or non-steroidal anti-inflammatory drug (NSAID).
  • a betablocker such as bisoprolol
  • an antihypertensive agent selected from an IEC such as perindopril
  • NSAID non-steroidal anti-inflammatory drug
  • the present invention relates to a fixed pharmaceutical composition
  • a betablocker comprising a betablocker, an angiotensin converting enzyme (ACE) inhibitor and at least one therapeutic agent and the use of said composition for the treatment and prevention of cardiovascular diseases and more particularly arterial hypertension or stable coronary disease.
  • ACE angiotensin converting enzyme
  • the present invention relates to a fixed pharmaceutical composition
  • a betablocker an angiotensin converting enzyme (ACE) inhibitor and at least one therapeutic agent wherein:
  • beta-blocker is bisoprolol or one of its addition salts with a pharmaceutically acceptable acid, and more particularly its fumarate salt, their hydrates and crystalline forms,
  • the inhibitor of the conversion enzyme is perindopril or one of its addition salts with an acid or a pharmaceutically acceptable base, and more particularly its tert-butylamine, tosylate or arginine salts, their hydrates and crystalline forms , and
  • the 3 ** TM therapeutic agent which is chosen from:
  • NSAID nonsteroidal anti-inflammatory drug
  • the calcium channel inhibitor preferentially used belongs to the class of dihydropyridines and is amlodipine or one of its addition salts with a pharmaceutically acceptable acid or base, and more particularly its besodium or maleate salts, their hydrates and forms. crystal.
  • 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 NSAID preferentially used is acetylsalicylic acid or aspirin or one of its addition salts with an acid or a pharmaceutically acceptable base, their hydrates and forms crystal.
  • the present invention relates to a fixed pharmaceutical composition
  • a fixed pharmaceutical composition comprising bisoprolol or its pharmaceutically acceptable salts, their hydrates and crystalline forms, perindopril or pharmaceutically acceptable salts thereof, their hydrates and crystalline tons, and a therapeutic agent and the use thereof. of said composition for the treatment or prevention of cardiovascular diseases.
  • the present invention also relates to a fixed pharmaceutical composition
  • a fixed pharmaceutical composition comprising bisoprolol, perindopril and as a therapeutic agent a calcium channel inhibitor which is amlodipine or its pharmaceutically acceptable salts, their hydrates and crystalline forms and the use of said composition for the treatment or prevention of cardiovascular diseases.
  • the present invention also relates to a fixed pharmaceutical composition
  • a fixed pharmaceutical composition comprising bisoprolol, perindopril and as a therapeutic agent a diuretic which is indapamide or its pharmaceutically acceptable salts, their hydrates and crystalline forms and the use of said composition for treatment or prevention of cardiovascular disease.
  • the present invention also relates to a fixed pharmaceutical composition
  • a fixed pharmaceutical composition comprising bisoprolol, perindopril and as a therapeutic agent a non-steroidal anti-inflammatory drug (NSAID) which is acetylsalicylic acid also known as aspirin or pharmaceutically acceptable salts thereof.
  • NSAID non-steroidal anti-inflammatory drug
  • Cardiovascular disease is more specifically the treatment or prevention of arterial hypertension or stable coronary artery disease.
  • Bisoprolol is a betablocker.
  • Bisoprolol has previously been described in French Patent FR 2 367053 or US Pat. No. 4,258,062.
  • Bisoprolol fumarate is a white powder of formula (Ia):
  • Bisoprolol fumarate marketed as Cardensiel®, is indicated for the treatment of stable chronic heart failure with reduced left ventricular systolic function, in addition to angiotensin converting enzyme (ACE) inhibitors and diuretics. possibly digitalis.
  • Cardensiel® is a film-coated tablet that can be broken or not obtained by conventional direct compression.
  • the different dosages available for Cardensiel® are 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg expressed as bisoprolol fumarate with an initial dosage of 1.25 mg once daily then gradually increase to 10 mg which is the maintenance dose. Whatever the dose, the dosage is always one dose per day.
  • Lodoz® (a) The combination of bisoprolol fumarate and hydrochlorothiazide which is marketed as Lodoz ® is indicated for mild to moderate hypertension.
  • Lodoz® is a monolayer film-coated tablet obtained by conventional direct compression.
  • the different dosages available for Lodoz® are:
  • Asabis® The combination of bisoprolol fumarate and acetylsalicylic acid which is marketed as Asabis® is indicated for the treatment of hypertension in patients previously stabilized with the individual components and the treatment of angina in previously stabilized patients with the individual components.
  • Asabis® is a capsule containing bisoprolol fumarate which is either in the form of simple bisoprolol / excipients mixture in the form of granules and acetylsalicylic acid in the form of a film-coated tablet.
  • the different dosages available from Asabis® are:
  • Patent application EP 2 359 815 describes the combination of bisoprolol fumarate and amlodipine besilate and its use for the treatment of hypertension and angina pectoris.
  • the pharmaceutical composition comprising bisoprolol and amlodipine is either a conventional direct compression monolayer tablet or a capsule in which the bisoprolol and amlodipine are in powder form.
  • an angiotensin I converting enzyme (ACE) inhibitor is an angiotensin I converting enzyme (ACE) inhibitor.
  • ACE angiotensin I converting enzyme
  • Perindopril has previously been described in patent EP 0049658.
  • the compounds of the invention may be in the form of addition salts with a base or an inorganic or organic acid. pharmaceutically acceptable.
  • EP 1 403 275, EP 1 420028, EP 1 420029, EP 1 422236, EP 1 603 558 and EP 1 7533 720 describe a method for obtaining perindopril salts, plus specifically tert-butylamine salt.
  • the L-arginine salt of perindopril of formula (IIa) has been described for the first time in European patent EP 1 354873:
  • Perindopril which is marketed under the name of Coversyl® is indicated for the treatment of arterial hypertension, stable coronary artery disease, in particular for the risk of cardiac events in patients with a history of myocardial infarction and / or revascularization. and, heart failure especially for the treatment of symptomatic heart failure.
  • Coversyl® is a film-coated monolayer tablet that can be scored or scored.
  • the different dosages available for Coversyl® are: 2.5 mg, 5 mg, and 10 mg expressed as perindopril arginine or 1.66975 mg / cp 2.5 mg; 3,395 mg / cp 5 mg; 6.790 mg / cp 10 mg expressed as perindopril. Dosage should be patient-specific However, the recommended starting dose is 5 mg daily in a morning dose.
  • Two fixed combinations containing perindopril are currently marketed: Coveram® and Bipreterax®:
  • Coveram® is a monolayer tablet.
  • the different dosages available of Coveram® are:
  • Bipreterax® The combination of perindopril arginine and indapamide which is marketed under the name Bipreterax® is indicated for the treatment of essential hypertension and is also indicated in patients for whom blood pressure is insufficiently controlled by perindopril alone.
  • Bipreterax® is a monolayer film-coated tablet. The different dosages available for Bipreterax® are:
  • Patent EP 1 800 678 describes the combination of ivabradine and perindopril and its use for the treatment of arterial hypertension.
  • Patent application EP 2404600 describes the use of this same combination for the treatment of heart failure.
  • Triplixam® The combination of perindopril arginine, inpadamide and amlodipine besilate which is marketed under the name of Triplixam® is indicated for the treatment of essential hypertension, in substitution, in patients already controlled with the combination of fixed dose perindopril / indapamide and amlodipine, taken simultaneously at the same dosages.
  • Triplixam® is a monolayer tablet. The different dosages available for Triplixam® are:
  • Cosyrel® The combination of perindopril arginine, and bisoprolol fumarate obtained under the name Cosyrel® is indicated for the treatment of hypertension, stable coronary artery disease, or chronic heart failure as a replacement in patients already controlled by perindopril and bisoprolol, taken simultaneously with the same nosologies.
  • Cosyrel® is a bilayer tablet.
  • the different dosages available of Cosyrel® are:
  • 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 therapeutic combination of at least three active ingredients belonging to different therapeutic classes having complementary effects which are 1) bisoprolol, 2) perindopril as well as:
  • the fixed pharmaceutical composition according to the invention is to be taken once a day in the morning.
  • Bisoprolol is a betablocker with a high affinity for beta-1 receptors, without intrinsic sympathomimetic activity or membrane stabilizing effect.
  • Bisoprolol fumarate salt is marketed as Cardensiel® and is indicated for the treatment of stable chronic heart failure with reduced left systolic function, in addition to angiotensin converting enzyme inhibitors and diuretics and possibly digitalis.
  • Perindopril is an inhibitor of the enzyme that converts angiotensin I to angiotensin ⁇ (angiotensin converting enzyme ACE).
  • This conversion enzyme, or kinase is an exopeptidase that allows the conversion of angiotensin I to angiotensin ⁇ vasoconstrictor causing degradation of the vasodilator bradykinin to an inactive heptapeptide.
  • Perindopril in the form of arginine salt is marketed under the name of Coversyl® and is indicated for:
  • Amlodipine is an inhibitor of calcium ion flux belonging to the family of dihydropyridines (slow calcium channel blocker or calcium channel blocker) and inhibits the transmembrane entry of calcium ions into cardiac muscle and vascular smooth muscle.
  • Amlodipine as besilate salt is marketed under the name Amlor® and is indicated for:
  • 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.
  • Acetylsalicylic acid is an inhibitor of platelet activation: by blocking platelet cyclooxygenase by acetylation, it inhibits the synthesis of thromboxane A2, a physiological activating substance released by platelets, which plays a role in the complications of the lesions. atheromatous.
  • Acetylsalicylic acid 100 mg is marketed for example under the name Aspirine Protect® and is indicated for:
  • Atheromatous ischemic disease eg myocardial infarction, stable and unstable angina, cerebral, structural or transient stroke, of ischemic origin
  • the active ingredients may be incompatible with certain excipients which are nevertheless necessary for the formulation of one or other of these active ingredients.
  • This epoxibiso impurity is always present in the starting material.
  • the fixed combination Cosyrel® which contains perindopril and bisoprolol and has just obtained its MA is the only fixed combination of perindopril which is in the form of bilayer tablet. Indeed, whether it is the monolayer tablet obtained by direct compression or the monolayer tablet obtained by wet granulation, the formulations have not given rise to satisfactory results from the point of view of the dosage and / or the stability.
  • a tablet in the form of a bilayer has made it possible to propose a solution to the disadvantages mentioned above.
  • Compatibility analyzes carried out by the Applicant for the various active principles of the present invention have demonstrated Incompatibility when the 3 active ingredients, each in powder form, are mixed. Table A below represents the degradation of the active ingredients in the case of the combination of bisoprolol, perindopril and amlodipine.
  • the present invention solves this problem because the Applicant has developed a fixed pharmaceutical composition in capsule form comprising mini-granules of the various active ingredients or even mini-granules of the various active ingredients and gastro-resistant tablets of aspirin. Indeed, when the 3 active ingredients are in the form of granules there can be interaction between these 3 active ingredients simultaneously insofar as they can not be in contact simultaneously. In the case of the present invention, the contact between the active ingredients can only be 2 to 2, thus avoiding the simultaneous contact between all the active ingredients present in the capsule.
  • the present invention finds the solution to the problem by developing a fixed pharmaceutical composition comprising bisoprolol, perindopril and amlodipine, a composition in which the interactions between the various active ingredients and the interactions with the excipients are non-existent. Moreover, in this composition the The active ingredients are bioequivalent to the individual compounds that are the individual tablets marketed.
  • the present invention provides a fixed capsule pharmaceutical composition
  • a fixed capsule pharmaceutical composition comprising bisoprolol, perindopril and amlodipine and wherein:
  • the bisoprolol is in the form of mini-granules
  • Perindopril is in the form of mini-granules
  • - Amlodipine is in the form of mini-granules.
  • the present invention also comprises a fixed pharmaceutical composition
  • a fixed pharmaceutical composition comprising:
  • the aspirin is in the form of gastric tablets. resistant to achieve therapeutic equivalence compared to the gastro-resistant tablet of aspirin alone.
  • 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 bisoprolol and its pharmaceutically acceptable salts, perindopril and its pharmaceutically acceptable salts and either amlodipine and its pharmaceutically acceptable salts, or indapamide and its pharmaceutically acceptable salts. or either aspirin and its pharmaceutically acceptable salts, in combination with one or more pharmaceutically acceptable excipients, their hydrates and their crystalline forms in which:
  • the doses of bisoprolol vary from 2.10 to 8.50 mg expressed as bisoprolol base or vary from 2.5 mg to 10 mg expressed as bisoprolol fumarate
  • the doses of perindopril vary from 1.65 mg to 9.512 mg expressed as perindopril base or vary from 2.5 mg to 14 mg expressed as perindopril arginine
  • amlodipine vary from 2.5 to 10 mg expressed as amlodipine base or vary from 3.47 mg to 13.89 mg expressed as amlodipine besylate,
  • mdapamide the doses of mdapamide vary from 0.625 mg to 2.5 mg expressed as indapamide base
  • doses of aspirin are 75 mg to 150 mg expressed as aspirin base.
  • perindopril arginine are 2.5 mg, 3.5 mg, 5 mg, 7 mg, 10 mg and 14 mg,
  • - of mdapamide are 0.625 mg, 1.25 mg, 1.5 mg and 2.5 mg and,
  • compositions comprising:
  • 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 carriers selected from diluents, lubricants, binders, disintegrants, 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, carboxymethyl cellulose 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 the cardiovascular parameters at good values.
  • Bisoprolol fumarate and hypromellose are mixed in purified water. The suspension previously obtained is then sprayed onto the microcrystalline cellulose to form the mini-granules of bisoprolol.
  • 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.
  • Indapamide and hypromellose are mixed in purified water. The suspension previously obtained is then sprayed onto the microcrystalline cellulose to form indapamide mini-granules.
  • a first mixture is formed with acetylsalicylic acid, micro-crystalline 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 steaylfumarate which is then sieved.
  • the first mixture is then added, the mixture is mixed and the tablets are formed according to standard 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.
  • the bisprolol mini-granules obtained according to Example 1, the immediate-release mini-granules of perindopril obtained according to Example 2 and the immediate-release mini-granules of amlodipine according to Example 3 are each lubricated according to the well-known techniques. 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 7 Capsules Comprising Bisoprolol, Perindopril and Indapamide
  • the capsule of immediate-release bisoprolol mini-granules according to Example 1 is filled with immediate release mini-granules of perindopril according to Example 2 and mini-granules. indapamide according to Example 4.
  • Example 8 Capsules Comprising Bisoprolol, Perindopril and Aspirin
  • Example 6 the capsule of immediate-release bisoprolol mini-granules according to Example 1 was filled with immediate release mini-granules of perindopril according to Example 2 and gastric tablets. aspirin resistant according to Example 5.

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Abstract

The invention relates to fixed-combination pharmaceutical compositions comprising a beta blocker (bisoprolol), an antihypertensive agent (perindopril) and a 3rd<sp /> therapeutic agent. The invention further relates to the use of said composition for the treatment and prevention of cardiovascular diseases, more particularly hypertension and stable coronary disease.

Description

COMPOSITION PHARMACEUTIQUE COMPRENANT UN BETABLOQUANT, UN INHIBITEUR DE L'ENZYME DE CONVERSION ET  PHARMACEUTICAL COMPOSITION COMPRISING A BETABLOQUANT, A CONVERSION ENZYME INHIBITOR AND
UN ANTIHYPERTENSEUR OU UN AINS  AN ANTIHYPERTENESS OR NSAID
Domaine technique La présente invention concerne une composition pharmaceutique fixe comprenant un bétabloquant, un inhibiteur de l'enzyme de conversion de l'angiotensine (HEC) et un 3*™" agent thérapeutique, l'utilisation de ladite composition pour le traitement et la prévention de maladies cardiovasculaires et plus particulièrement Γ hypertension artérielle et/ou la maladie coronaire stable. Plus particulièrement, la présente invention concerne une composition pharmaceutique fixe comprenant un bétabloquant, un inhibiteur de l'enzyme de conversion de l'angiotensine (IEC) et un 3 agent thérapeutique dans laquelle : Technical Field The present invention relates to a fixed pharmaceutical composition comprising a betablocker, an angiotensin converting enzyme (ACE) inhibitor and a therapeutic agent, the use of said composition for the treatment and prevention In particular, the present invention relates to a fixed pharmaceutical composition comprising a betablocker, an angiotensin converting enzyme (ACE) inhibitor, and an angiotensin converting enzyme. therapeutic agent in which:
- le bétabloquant est le bisoprolol ou un de ses sels d'addition à un acide pharmaceutiquement acceptable, leurs hydrates et formes cristallines,  beta-blocker is bisoprolol or one of its addition salts with a pharmaceutically acceptable acid, their hydrates and crystalline forms,
- l'inhibiteur de l'enzyme de conversion est le périndopril ou un de ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable, leurs hydrates et formes cristallines et,  the inhibitor of the conversion enzyme is perindopril or one of its addition salts with a pharmaceutically acceptable acid or base, their hydrates and crystalline forms and,
- le 3*"* agent thérapeutique est choisi parmi un autre antihypertenseur ou un antiinflammatoire non-stéroïdien. Etat de la technique/contexte de l'invention  the therapeutic agent is chosen from among another antihypertensive agent or a non-steroidal anti-inflammatory agent State of the art / context of the invention
Les maladies cardiovasculaires sont la 1*" cause de mortalité aussi bien dans les pays développés que les pays en voie de développement, ils sont responsables d'un tiers des décès. Les décès liés aux maladies cardiovasculaires devraient augmenter jusqu'à 23,3 millions en 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). Cardiovascular disease is the leading cause of death in both developed and developing countries, accounting for one-third of all deaths, and deaths from cardiovascular disease are expected to increase to 23.3 million. in 2030. In Europe, cardiovascular disease is the leading cause of premature mortality and disability-adjusted life expectancy for both men and women, causing nearly 4.1 million deaths annually, or 46 per cent 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).
L'hypertension et la maladie coronaire sont des étapes majeures du continuum cardiovasculaire aboutissant au développement de maladies cardiaques de stade avancé. L'hypertension est la 1 cause de mortalité dans le monde causant environ 7,5 millions de décès (ce qui représente environ 13% des décès). La maladie coronaire est la conséquence la plus fréquente de l'hypertension et est la 1ère cause de mortalité en Europe. L'insuffisance cardiaque est la pathologie terminale, conséquence de nombreuses maladies cardiaques. Le taux de mortalité reste actuellement encore élevé avec 50% de survie à 5 ans. Hypertension and coronary artery disease are major steps in the cardiovascular continuum leading to the development of advanced heart disease. Hypertension is the leading cause of death in the world, causing about 7.5 million deaths (accounting for about 13% of deaths). Coronary artery disease is the most common consequence of hypertension and is the 1st cause of death in Europe. Heart failure is the terminal pathology, a consequence of many heart diseases. The mortality rate is still high with 50% survival at 5 years.
Par conséquent, une optimisation de la prise en charge et de la stratégie de traitement des patients est nécessaire. Therefore, optimization of management and treatment strategy of patients is necessary.
Les maladies chroniques telles que les maladies cardiovasculaires 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. Chronic diseases such as cardiovascular disease usually 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.
Les associations fixes permettent une simplification du traitement en réduisant le nombre de comprimés quotidien et ont, par conséquent, le potentiel d'améliorer l'adhérence des patients au traitement  Fixed combinations allow for simplification of treatment by reducing the number of tablets daily and, therefore, have the potential to improve patient adherence to 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, lliypercholestérolémie, le diabète, la tuberculose et l'infection par le virus de rimmunodéficience 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 efficacy of combination therapy versus individual component therapy was examined. This meta-analysis evaluated the use of fixed combination therapies in different clinical settings, including hypertension, heart failure, myocardial infarction, hypercholesterolemia, diabetes, tuberculosis, and human immunodeficiency virus infection. The results of this meta-analysis showed a much better compliance of 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 of the World Heart Federation (WHF).
La Société Européenne de Cardiologie (ESC = Européen Society of Cardiology) dans ses directives notamment celles de 2012 et 2013 recommande spécifiquement l'association de bétabloquants et d'IEC pour le traitement et/ou la prévention de l'hypertension artérielle chez les patients insuffisants cardiaques en post-infarctus ou souffrant de fibrillation auriculaire. Plus généralement, les bétabloquants et les IEC peuvent également être utilisés seuls ou en association en traitement d'initiation ou de maintenance de l'hypertension artérielle. The European Society of Cardiology (ESC = European Society of Cardiology) in its directives especially those of 2012 and 2013 specifically recommends the combination of betablockers and ACE inhibitors for the treatment and / or prevention of arterial hypertension in patients with insufficient post-infarction or atrial fibrillation. More generally, betablockers and ACE inhibitors may also be used alone or in combination as initiation or maintenance treatment for arterial hypertension.
Pour le traitement de la maladie coronaire stable, 2 objectifs ont été exprimés à savoir : For the treatment of stable coronary disease, 2 objectives were expressed namely:
a) Amélioration des symptômes et contrôle du rythme cardiaque : les bétabloquants sont indiqués en lte intention (action directe sur le cœur, amélioration de la perfusion dans zone ischemiée) et a) Improvement of symptoms and heart rate control: beta-blockers are indicated in the plan you (direct action on the heart, improving perfusion in ischemic area) and
b) Prévention de l'apparition d'événements cardiovasculaires, en particuliers en cas de pathologie concomitante telle que l'hypertension, l'insuffisance cardiaque ou le diabète.  b) Prevention of the occurrence of cardiovascular events, especially in cases of concomitant pathology such as hypertension, heart failure or diabetes.
Le bisoprolol et le périndopril sont tous deux des principes actifs de médicaments approuvés et commercialisés depuis plusieurs années dans le monde. Leurs profils d'efficacité et de tolérance sont par conséquents bien établis. Les médicaments contenant ces deux principes actifs sont très utilisés dans la pratique médicale et très souvent co-prescrits. En effet, les médicaments en question ont des indications communes, à savoir l'hypertension et la maladie coronaire. Both bisoprolol and perindopril have been active ingredients in approved drugs that have been on the market for several years worldwide. Their efficiency and tolerance profiles are therefore well established. Drugs containing these two active ingredients are widely used in medical practice and very often co-prescribed. Indeed, the drugs in question have common indications, namely hypertension and coronary disease.
De plus, leurs mécanismes d'action sont complémentaires et leurs effets bénéfiques sur la morbi-mortalité dans les maladies cardiovasculaires ont été démontrés dans des essais cliniques à grande échelle (l'étude CIBIS pour le bisoprolol et l'étude EUROPA pour le périndopril). In addition, their mechanisms of action are complementary and their beneficial effects on morbidity and mortality in cardiovascular diseases have been demonstrated in large-scale clinical trials (the CIBIS study for bisoprolol and the EUROPA study for perindopril). .
Parmi les bétabloquants qui sont co-prescrits avec le périndopril on trouve l'acébutolol, l'aténolol, le bisoprolol, le métoprolol et le nébivolol. Le bisoprolol est le bétabloquant qui est le plus co-prescrit avec le périndopril suivi par l'aténolol. Among beta-blockers that are co-prescribed with perindopril are acebutolol, atenolol, bisoprolol, metoprolol and nebivolol. Bisoprolol is the beta-blocker that is most co-prescribed with perindopril followed by atenolol.
Les dosages de périndopril et de bisoprolol les plus co-prescrits dans les deux indications cibles de l'association, à savoir hypertension et maladie coronaire stable, sont indiqués dans le tableau ci-après : The most co-prescribed doses of perindopril and bisoprolol in the two target indications of the combination, hypertension and stable coronary artery disease, are shown in the table below:
Figure imgf000005_0001
Figure imgf000005_0001
Les dosages de périndopril sont exprimés en sel d'arginine (2,5 mg, 5 mg ou 10 mg) ou en sel de tert-butyl aminé (2mg, 4 mg ou 8 mg) et les dosages de bisoprolol sont exprimés en base.  The perindopril assays are expressed as arginine salt (2.5 mg, 5 mg or 10 mg) or tert-butyl amine salt (2 mg, 4 mg or 8 mg) and the bisoprolol dosages are expressed as a base.
Le dosage de périndopril sel d'arginine 5 mg suivi du 10 mg est celui qui est le plus co- prescrit avec le bisoprolol 2,5 mg, 5 mg et 10 mg. The dosage of perindopril arginine salt 5 mg followed by 10 mg is the one most frequently prescribed with bisoprolol 2.5 mg, 5 mg and 10 mg.
Il y a donc un réel besoin d'une composition pharmaceutique fixe comprenant un bétabloquant et un EEC pour son utilisation dans le traitement et la prévention de maladies cardiovasculaires et plus particulièrement le traitement de l'hypertension artérielle et de la maladie coronaire stable. There is therefore a real need for a fixed pharmaceutical composition comprising betablocker and EEC for its use in the treatment and prevention of cardiovascular diseases and more particularly the treatment of arterial hypertension and stable coronary disease.
C'est dans ce contexte que la présente invention se propose de développer une nouvelle combinaison fixe comprenant un bétabloquant tel que le bisoprolol, un antihypertenseur choisi parmi un IEC tel que le périndopril et au moins un 3*** agent thérapeutique choisi parmi un autre antihypertenseur ou un anti-inflammatoire non-stéroïdien (AINS). It is in this context that the present invention proposes to develop a novel fixed combination comprising a betablocker such as bisoprolol, an antihypertensive agent. selected from an IEC such as perindopril and at least one therapeutic agent selected from another antihypertensive or non-steroidal anti-inflammatory drug (NSAID).
Résumé de l'invention Summary of the invention
La présente invention concerne une composition pharmaceutique fixe comprenant un bétabloquant, un inhibiteur de l'enzyme de conversion de l'angiotensine (IEC) et au moins un 3*°* agent thérapeutique et, l'utilisation de ladite composition pour le traitement et la prévention de maladies cardiovasculaires et plus particulièrement l 'hypertension artérielle ou la maladie coronaire stable. The present invention relates to a fixed pharmaceutical composition comprising a betablocker, an angiotensin converting enzyme (ACE) inhibitor and at least one therapeutic agent and the use of said composition for the treatment and prevention of cardiovascular diseases and more particularly arterial hypertension or stable coronary disease.
Plus particulièrement, la présente invention concerne une composition pharmaceutique fixe comprenant un bétabloquant, un inhibiteur de l'enzyme de conversion de l'angiotensine (IEC) et au moins un 3^" agent thérapeutique dans laquelle : More particularly, the present invention relates to a fixed pharmaceutical composition comprising a betablocker, an angiotensin converting enzyme (ACE) inhibitor and at least one therapeutic agent wherein:
- le bétabloquant est le bisoprolol ou un de ses sels d'addition à un acide phannaceutiquement acceptable, et plus particulièrement son sel de fumarate, leurs hydrates et formes cristallines,  beta-blocker is bisoprolol or one of its addition salts with a pharmaceutically acceptable acid, and more particularly its fumarate salt, their hydrates and crystalline forms,
- rinhibiteur de l'enzyme de conversion est le périndopril ou un de ses sels d'addition à un acide ou à une base phannaceutiquement acceptable, et plus particulièrement ses sels de tert-butylamine, tosylate ou d'arginine, leurs hydrates et formes cristallines, et the inhibitor of the conversion enzyme is perindopril or one of its addition salts with an acid or a pharmaceutically acceptable base, and more particularly its tert-butylamine, tosylate or arginine salts, their hydrates and crystalline forms , and
- le 3**™ agent thérapeutique qui est choisi parmi : the 3 ** ™ therapeutic agent which is chosen from:
o un autre antihypertenseur qui est un inhibiteur calcique ou un diurétique ou, o un anti-inflammatoire non-stéroïdien (AINS).  o another antihypertensive agent that is a calcium channel blocker or a diuretic or, o a nonsteroidal anti-inflammatory drug (NSAID).
L'inhibiteur calcique préférentiellement utilisé appartient à la classe des dihydropyridines et est l'amlodipine ou un de ses sels d'addition à un acide ou à une base phannaceutiquement acceptable, et plus particulièrement ses sels de bésilate ou de maléate, leurs hydrates et formes cristallines. Le diurétique préférentiellement utilisé est l'indapamide ou un de ses sels d'addition à un acide ou à une base phannaceutiquement acceptable, leurs hydrates et formes cristallines. The calcium channel inhibitor preferentially used belongs to the class of dihydropyridines and is amlodipine or one of its addition salts with a pharmaceutically acceptable acid or base, and more particularly its besodium or maleate salts, their hydrates and forms. crystal. 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.
L'AINS préférentiellement utilisé est l'acide acétylsalicylique ou aspirine ou un de ses sels d'addition à un acide ou à une base phannaceutiquement acceptable, leurs hydrates et formes cristallines. The NSAID preferentially used is acetylsalicylic acid or aspirin or one of its addition salts with an acid or a pharmaceutically acceptable base, their hydrates and forms crystal.
Description détaillée de l'invention Detailed description of the invention
La présente invention concerne une composition phannaceutique fixe comprenant le bisoprolol ou ses sels phannaceutiquement acceptables, leurs hydrates et formes cristallines, le périndopril ou ses sels phannaceutiquement acceptables, leurs hydrates et tonnes cristallines et, un 3*°* agent thérapeutique et, l'utilisation de ladite composition pour le traitement ou la prévention de maladies cardiovasculaires. The present invention relates to a fixed pharmaceutical composition comprising bisoprolol or its pharmaceutically acceptable salts, their hydrates and crystalline forms, perindopril or pharmaceutically acceptable salts thereof, their hydrates and crystalline tons, and a therapeutic agent and the use thereof. of said composition for the treatment or prevention of cardiovascular diseases.
La présente invention concerne aussi une composition pharmaceutique fixe comprenant le bisoprolol, le périndopril et comme 3*™ agent thérapeutique un inhibiteur du canal calcique qui est l'amlodipine ou ses sels phannaceutiquement acceptables, leurs hydrates et formes cristallines et, l'utilisation de ladite composition pour le traitement ou la prévention de maladies cardiovasculaires . The present invention also relates to a fixed pharmaceutical composition comprising bisoprolol, perindopril and as a therapeutic agent a calcium channel inhibitor which is amlodipine or its pharmaceutically acceptable salts, their hydrates and crystalline forms and the use of said composition for the treatment or prevention of cardiovascular diseases.
La présente invention concerne aussi une composition pharmaceutique fixe comprenant le bisoprolol, le périndopril et comme 3*™ agent thérapeutique un diurétique qui est l'indapamide ou ses sels phannaceutiquement acceptables, leurs hydrates et formes cristallines et, l'utilisation de ladite composition pour le traitement ou la prévention de maladies cardiovasculaires. The present invention also relates to a fixed pharmaceutical composition comprising bisoprolol, perindopril and as a therapeutic agent a diuretic which is indapamide or its pharmaceutically acceptable salts, their hydrates and crystalline forms and the use of said composition for treatment or prevention of cardiovascular disease.
La présente invention concerne aussi une composition pharmaceutique fixe comprenant le bisoprolol, le périndopril et comme 3**°" agent thérapeutique un anti-inflammatoire non- stéroïdien (AINS) qui est l'acide acétylsalicylique encore appelé aspirine ou ses sels phannaceutiquement acceptables, leurs hydrates et formes cristallines et, l'utilisation de ladite composition pour le traitement ou la prévention de maladies. The present invention also relates to a fixed pharmaceutical composition comprising bisoprolol, perindopril and as a therapeutic agent a non-steroidal anti-inflammatory drug (NSAID) which is acetylsalicylic acid also known as aspirin or pharmaceutically acceptable salts thereof. hydrates and crystalline forms and the use of said composition for the treatment or prevention of diseases.
Par maladies cardiovasculaires on entend plus précisément le traitement ou la prévention de rhypertension artérielle ou de la maladie coronaire stable. Le bisoprolol ou (R,S)l-[4-[[2-(l-méthyléthoxy)éthoxy]méthyl]phénoxy]-3-[l- méthyléthyl)amino]-2-propanol, de formule (I) :
Figure imgf000008_0001
Cardiovascular disease is more specifically the treatment or prevention of arterial hypertension or stable coronary artery disease. Bisoprolol or (R, S) 1- [4 - [[2- (1-methylethoxy) ethoxy] methyl] phenoxy] -3- [1-methylethyl) amino] -2-propanol, of formula (I):
Figure imgf000008_0001
est un bétabloquant. Le bisoprolol a été précédemment décrit dans le brevet français FR 2 367053 ou US 4258062. Le bisoprolol fumarate est une poudre blanche de formule (la) : is a betablocker. Bisoprolol has previously been described in French Patent FR 2 367053 or US Pat. No. 4,258,062. Bisoprolol fumarate is a white powder of formula (Ia):
Figure imgf000008_0002
Figure imgf000008_0002
Le bisoprolol fumarate qui est commercialisé sous le nom de Cardensiel® est indiqué dans le traitement de l'insuffisance cardiaque chronique stable avec réduction de la fonction ventriculaire systolique gauche, en complément des inhibiteurs de l'enzyme de conversion (IEC) et des diurétiques et, éventuellement, des digitaliques. Le Cardensiel® est un comprimé pelliculé sécable ou non obtenu par compression directe conventionnelle. Les différents dosages disponibles du Cardensiel® sont 1,25 mg, 2,5 mg, 3,75 mg, 5 mg, 7,5 mg et 10 mg exprimés en bisoprolol fumarate avec une posologie initiale de 1,25 mg une fois par jour puis on augmente progressivement jusqu'à lOmg qui est la dose de maintenance. Quelle que soit la dose, la posologie est toujours de une prise par jour. Bisoprolol fumarate, marketed as Cardensiel®, is indicated for the treatment of stable chronic heart failure with reduced left ventricular systolic function, in addition to angiotensin converting enzyme (ACE) inhibitors and diuretics. possibly digitalis. Cardensiel® is a film-coated tablet that can be broken or not obtained by conventional direct compression. The different dosages available for Cardensiel® are 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg and 10 mg expressed as bisoprolol fumarate with an initial dosage of 1.25 mg once daily then gradually increase to 10 mg which is the maintenance dose. Whatever the dose, the dosage is always one dose per day.
Deux associations fixes contenant du bisoprolol sont actuellement commercialisées : Lodoz® et Asabis® : Two fixed combinations containing bisoprolol are currently marketed: Lodoz® and Asabis®:
(a) L'association du bisoprolol fumarate et de l 'hydrochlorothiazide qui est commercialisée sous le nom de Lodoz® est indiquée pour l'hypertension artérielle légère à modérée. Le Lodoz® est un comprimé pelliculé en monocouche obtenu par compression directe conventionnelle. Les différents dosages disponibles du Lodoz® sont :
Figure imgf000008_0003
(a) The combination of bisoprolol fumarate and hydrochlorothiazide which is marketed as Lodoz ® is indicated for mild to moderate hypertension. Lodoz® is a monolayer film-coated tablet obtained by conventional direct compression. The different dosages available for Lodoz® are:
Figure imgf000008_0003
(b) L'association du bisoprolol fumarate et de l'acide acétylsalicylique qui est commercialisé sous le nom de Asabis® est indiquée pour le traitement de l'hypertension chez les patients préalablement stabilisés avec les composants individuels et, le traitement de l'angine de poitrine chez les patients préalablement stabilisés avec les composants individuels. Asabis® est une gélule contenant du bisoprolol fumarate qui est soit sous forme de simple mélange bisoprolol/excipients soit sous forme de granules et de l'acide acétylsalicylique sous forme de comprimé pelliculé. Les différents dosages disponibles de Asabis® sont : (b) The combination of bisoprolol fumarate and acetylsalicylic acid which is marketed as Asabis® is indicated for the treatment of hypertension in patients previously stabilized with the individual components and the treatment of angina in previously stabilized patients with the individual components. Asabis® is a capsule containing bisoprolol fumarate which is either in the form of simple bisoprolol / excipients mixture in the form of granules and acetylsalicylic acid in the form of a film-coated tablet. The different dosages available from Asabis® are:
Figure imgf000009_0002
Figure imgf000009_0002
La demande de brevet EP 2 359 815 décrit l'association de bisoprolol fumarate et d'amlodipine besilate ainsi que son utilisation pour le traitement de l'hypertension et de l'angine de poitrine. La composition pharmaceutique comprenant le bisoprolol et l'amlodipine est soit un comprimé monocouche obtenu par compression directe conventionnelle soit, une gélule dans laquelle le bisoprolol et l'amlodipine sont sous forme de poudre. Patent application EP 2 359 815 describes the combination of bisoprolol fumarate and amlodipine besilate and its use for the treatment of hypertension and angina pectoris. The pharmaceutical composition comprising bisoprolol and amlodipine is either a conventional direct compression monolayer tablet or a capsule in which the bisoprolol and amlodipine are in powder form.
Le périndopril ou acide (2S)-2-[(lS)-carbémoxybutylamino]-l-oxopropyl (23,3aS,7aS)perhydroindole carboxylique, de formule (II) : Perindopril or (2S) -2 - [(1S) -carbemoxybutylamino] -1-oxopropyl (23,3aS, 7aS) perhydroindole carboxylic acid, of formula (II):
Figure imgf000009_0001
Figure imgf000009_0001
est un inhibiteur de l'enzyme de conversion de l'angiotensine I (IEC). Le périndopril a été précédemment décrit dans le brevet EP 0049658. Dans ce brevet européen, de manière classique, il est mentionné que les composés de l'invention peuvent se présenter sous forme de sels d'addition avec une base ou un acide minéral ou organique pharmaceutiquement acceptable. Les brevets EP 0308 341, EP 1 256 590, EP 1 268424, EP 1 279 665, EP 1 321 471, EP 1 333 026, EP 1 362 864, EP 1 367061, EP 1 367062, EP 1 367063, EP 1 371 659, EP 1 380 590, EP 1 380 591.EP 1 403 275, EP 1 420028, EP 1 420029, EP 1 422236, EP 1 603 558 et EP 1 7533 720 décrivent une méthode d'obtention de sels de périndopril, plus spécifiquement le sel de tert-butylamine. Le sel de L-arginine du périndopril de formule (lia) a été décrit pour la première fois dans le brevet européen EP 1 354873 :
Figure imgf000010_0001
is an angiotensin I converting enzyme (ACE) inhibitor. Perindopril has previously been described in patent EP 0049658. In this European patent, it is conventionally mentioned that the compounds of the invention may be in the form of addition salts with a base or an inorganic or organic acid. pharmaceutically acceptable. The patents EP 0308 341, EP 1 256 590, EP 1 268424, EP 1 279 665, EP 1 321 471, EP 1 333 026, EP 1 362 864, EP 1 367061, EP 1 367062, EP 1 367063 and EP 1 371. 659, EP 1 380 590, EP 1 380 591. EP 1 403 275, EP 1 420028, EP 1 420029, EP 1 422236, EP 1 603 558 and EP 1 7533 720 describe a method for obtaining perindopril salts, plus specifically tert-butylamine salt. The L-arginine salt of perindopril of formula (IIa) has been described for the first time in European patent EP 1 354873:
Figure imgf000010_0001
Les formes cristallines alpha et bêta du sel de ^arginine du périndopril ont été décrites dans les brevets européens EP 1 989 182 et EP 2 016051 respectivement, la forme cristalline delta a été décrite dans le brevet européen EP 2612 850 et la forme cristalline gamma a été décrite dans la demande internationale WO 2009/157018.  The alpha and beta crystalline forms of the arginine salt of perindopril have been described in European patents EP 1 989 182 and EP 2 016051 respectively, the crystalline delta form has been described in European Patent EP 2612 850 and the crystalline form gamma a has been described in international application WO 2009/157018.
Le périndopril qui est commercialisé sous le nom de Coversyl® est indiqué dans le traitement de l'hypertension artérielle, de la maladie coronaire stable notamment pour le risque d'événements cardiaques chez les patients ayant un antécédent d'infarctus du myocarde et/ou revascularisation et, de l'insuffisance cardiaque notamment pour le traitement de l'insuffisance cardiaque symptomatique. Le Coversyl® est un comprimé monocouche pelliculé sécable ou non sécable. Les différents dosages disponibles du Coversyl® sont : 2,5 mg, 5 mg, et 10 mg exprimés en périndopril arginine ou encore 1,6975 mg/cp 2,5 mg; 3,395 mg/cp 5 mg ; 6,790 mg/cp 10 mg exprimé en périndopril. La posologie doit être adaptée au patient Cependant, la dose initiale recommandée est de 5 mg par jour en une prise matinale. Deux associations fixes contenant du périndopril sont actuellement commercialisées : Coveram® et Bipreterax® : Perindopril which is marketed under the name of Coversyl® is indicated for the treatment of arterial hypertension, stable coronary artery disease, in particular for the risk of cardiac events in patients with a history of myocardial infarction and / or revascularization. and, heart failure especially for the treatment of symptomatic heart failure. Coversyl® is a film-coated monolayer tablet that can be scored or scored. The different dosages available for Coversyl® are: 2.5 mg, 5 mg, and 10 mg expressed as perindopril arginine or 1.66975 mg / cp 2.5 mg; 3,395 mg / cp 5 mg; 6.790 mg / cp 10 mg expressed as perindopril. Dosage should be patient-specific However, the recommended starting dose is 5 mg daily in a morning dose. Two fixed combinations containing perindopril are currently marketed: Coveram® and Bipreterax®:
(a) L'association du périndopril arginine et de l'amlodipine besilate qui est commercialisée sous le nom de Coveram® est indiquée pour le traitement de l 'hypertension artérielle essentielle et/ou de la maladie coronaire stable, en substitution, chez les patients déjà contrôlés avec le périndopril et l'amlodipine pris simultanément à la même posologie. Le (a) The combination of perindopril arginine and amlodipine besilate which is marketed as Coveram® is indicated for the treatment of essential hypertension and / or stable coronary artery disease, in patients with already controlled with perindopril and amlodipine taken simultaneously at the same dosage. The
Coveram® est un comprimé monocouche. Les différents dosages disponibles du Coveram® sont : Coveram® is a monolayer tablet. The different dosages available of Coveram® are:
Figure imgf000010_0002
(b) L'association du périndopril arginine et de l'indapamide qui est commercialisée sous le nom de Bipreterax® est indiquée pour le traitement de l'hypertension artérielle essentielle et est aussi indiqué chez les patients pour lesquels la pression artérielle est insuffisamment contrôlée par le périndopril seul. Le Bipreterax® est un comprimé pelliculé monocouche. Les différents dosages disponibles du Bipreterax® sont :
Figure imgf000010_0002
(b) The combination of perindopril arginine and indapamide which is marketed under the name Bipreterax® is indicated for the treatment of essential hypertension and is also indicated in patients for whom blood pressure is insufficiently controlled by perindopril alone. Bipreterax® is a monolayer film-coated tablet. The different dosages available for Bipreterax® are:
Figure imgf000011_0002
Figure imgf000011_0002
Le brevet EP 1 800678 décrit l'association de l'ivabradine et du périndopril ainsi que son utilisation pour le traitement de l'hypertension artérielle. La demande de brevet EP 2404600 décrit l'utilisation de cette même association pour le traitement de l'insuffisance cardiaque.  Patent EP 1 800 678 describes the combination of ivabradine and perindopril and its use for the treatment of arterial hypertension. Patent application EP 2404600 describes the use of this same combination for the treatment of heart failure.
Deux autres associations fixes avec le périndopril qui ont obtenu une autorisation de mise sur le marché (AMM) en Europe sont le Triplixam® et le Cosyrel®. Two other fixed associations with perindopril that have been granted Marketing Authorization (MA) in Europe are Triplixam® and Cosyrel®.
L'association du périndopril arginine, d'inpadamide et de l'amlodipine besilate qui est commercialisé sous le nom de Triplixam® est indiquée pour le traitement de l'hypertension artérielle essentielle, en substitution, chez les patients déjà contrôlée avec l'association à dose fixe périndopril/indapamide et l'amlodipine, pris simultanément aux mêmes posologies. Le Triplixam® est un comprimé monocouche. Les différents dosages disponibles du Triplixam® sont : The combination of perindopril arginine, inpadamide and amlodipine besilate which is marketed under the name of Triplixam® is indicated for the treatment of essential hypertension, in substitution, in patients already controlled with the combination of fixed dose perindopril / indapamide and amlodipine, taken simultaneously at the same dosages. Triplixam® is a monolayer tablet. The different dosages available for Triplixam® are:
Figure imgf000011_0003
Figure imgf000011_0003
Figure imgf000011_0001
Figure imgf000011_0001
L'association du périndopril arginine, et du bisoprolol fumarate qui a obtenu ΓΑΜΜ sous le nom de Cosyrel® est indiquée pour le traitement de l'hypertension, des maladies coronaires stables, ou l'insuffisance cardiaque chronique en substitution chez les patients déjà contrôlée par périndopril et bisoprolol, pris simultanément aux mêmes nosologies. Le Cosyrel® est un comprimé bicouche. Les différents dosages disponibles du Cosyrel® sont : The combination of perindopril arginine, and bisoprolol fumarate obtained under the name Cosyrel® is indicated for the treatment of hypertension, stable coronary artery disease, or chronic heart failure as a replacement in patients already controlled by perindopril and bisoprolol, taken simultaneously with the same nosologies. Cosyrel® is a bilayer tablet. The different dosages available of Cosyrel® are:
Figure imgf000012_0002
Figure imgf000012_0002
Figure imgf000012_0001
Figure imgf000012_0001
A ce jour et à notre connaissance il n'existe aucune composition pharmaceutique fixe associant à la fois un bétabloquant, un IEC et :  To date, and to our knowledge, there is no fixed pharmaceutical composition combining a betablocker, an IEC and:
- un inhibiteur calcique, ou  a calcium channel blocker, or
- un diurétique, ou  - a diuretic, or
- un AINS.  - an NSAID.
C'est donc un réel besoin pour les patients souffrants de maladies cardiovasculaires telles que l'hypertension artérielle ou la maladie coronaire stable de bénéficier d'une telle composition pharmaceutique fixe. It is therefore a real need for patients suffering from cardiovascular diseases such as arterial hypertension or stable coronary disease to benefit from such a fixed pharmaceutical composition.
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 combinaison thérapeutique fixe d'au moins trois principes actifs appartenant à différents classes thérapeutiques ayant des effets complémentaires qui sont 1) le bisoprolol, 2) le périndopril ainsi que : In the present invention, the fixed therapeutic combination of at least three active ingredients belonging to different therapeutic classes having complementary effects which are 1) bisoprolol, 2) perindopril as well as:
a) ramlodipine, ou  a) ramlodipine, or
b) l'indapamide ou  (b) indapamide or
c) l'acide acétylsalicylique  c) acetylsalicylic acid
a donc l'avantage de cibler plusieurs facteurs de risque responsables des maladies cardiovasculaires, en une seule prise. therefore has the advantage of targeting several risk factors responsible for cardiovascular disease, in a single dose.
L'utilisation de ces combinaisons thérapeutiques fixes : The use of these fixed therapeutic combinations:
- bisoprolol + périndopril + amlodipine,  - bisoprolol + perindopril + amlodipine,
- bisoprolol + périndopril + indapamide et - bisoprolol + périndopril + acide acétylsalicylique, - bisoprolol + perindopril + indapamide and - bisoprolol + perindopril + acetylsalicylic acid,
est le traitement ou la prévention de l'hypertension artérielle ou la maladie coronaire stable en tant que thérapie de substitution chez les patients adultes contrôlés concurremment en monothérapie avec le bisoprolol, le périndopril et/ou les principes actifs a) à c) aux mânes doses que celles présentes dans la composition pharmaceutique fixe. is the treatment or prevention of high blood pressure or stable coronary artery disease as a replacement therapy in adult patients concurrently controlled as monotherapy with bisoprolol, perindopril and / or the active ingredients a) to c) at doses than 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. It is therefore possible to simplify the treatment of patients receiving drugs separately and thus improve compliance by limiting the number of tablets.
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. 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.
Le bisoprolol est un bêtabloquant ayant une forte affinité pour les récepteurs bêta-1, sans activité sympathomimétique intrinsèque, ni effet stabilisant de membrane. Le bisoprolol sous forme de sel de fumarate est commercialisé sous le nom de Cardensiel® et est indiqué pour le traitement de l'insuffisance cardiaque chronique stable avec réduction de la fonction systolique gauche, en complément des inhibiteurs de l'enzyme de conversion et des diurétiques et, éventuellement, des digitaliques. Bisoprolol is a betablocker with a high affinity for beta-1 receptors, without intrinsic sympathomimetic activity or membrane stabilizing effect. Bisoprolol fumarate salt is marketed as Cardensiel® and is indicated for the treatment of stable chronic heart failure with reduced left systolic function, in addition to angiotensin converting enzyme inhibitors and diuretics and possibly digitalis.
Le périndopril est un inhibiteur de l'enzyme qui transforme l'angiotensine I en angiotensine Π (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 Π 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 Π (angiotensin converting enzyme ACE). This conversion enzyme, or kinase, is an exopeptidase that allows the conversion of angiotensin I to angiotensin Π vasoconstrictor causing degradation of the 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 rêvas cul arisation et  - the reduction of the risk of cardiac events in patients with a history of myocardial infarction and / or
- le traitement de l'insuffisance cardiaque symptomatique. L'amlodipine est un inhibiteur du flux ionique calcique appartenant à la famille des dihydropyridines (bloqueur du canal calcique lent ou inhibiteur calcique) et inhibe l'entrée transmembranaire des ions calcium dans le muscle cardiaque et le muscle lisse vasculaire. L'amlodipine sous forme de sel de bésilate est commercialisée sous le nom de Amlor® et est indiquée pour : - the treatment of symptomatic heart failure. Amlodipine is an inhibitor of calcium ion flux belonging to the family of dihydropyridines (slow calcium channel blocker or calcium channel blocker) and inhibits the transmembrane entry of calcium ions into cardiac muscle and vascular smooth muscle. Amlodipine as besilate salt is marketed under the name Amlor® and is indicated for:
- l'hypertension,  - hypertension,
- l'angor chronique stable, et  - chronic stable angina, and
- l'angor vasosp astique.  - vasospastic angina.
L'indapamide est un diurétique sulfamide, apparenté sur le plan pharmacologique aux diurétiques thiazidiques. L'indapamide hémihydrate est commercialisé sous le nom de Fludex® et est indiqué pour le traitement de l'hypertension artérielle. 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.
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 acti vatrice physiologique libérée par les plaquettes, et qui jouerait un rôle dans les complications des lésions athéromateuses. L'acide acétylsalicylique 100 mg est commercialisée par exemple 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 activating substance released by platelets, which plays a role in the complications of the lesions. atheromatous. Acetylsalicylic acid 100 mg is marketed for example under the name Aspirine Protect® and is indicated for:
- la prévention des complications secondaires cardiovas cul aires et cérébrovascul aires chez les patients présentant une maladie athéromateuse ischémique (par exemple : 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, structural 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.  - the reduction of graft occlusion after coronary artery bypass grafting.
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 à la formulation de 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 for the formulation of one or other of these active ingredients.
Cependant, un des risques majeurs des combinaisons pharmaceutiques fixes résulte d'une possible interaction entre les différents principes actifs présents dans cette combinaison. En dehors des excipients, lorsque les principes actifs sont formulés seuls, bisoprolol seul, périndopril seul, ou encore le 3*"" agent thérapeutique seul, ils peuvent contenir des impuretés et/ou des produits de dégradation dans les produits de départ mais aussi des impuretés potentielles dans le produit final. Par exemple, une des impuretés organiques qui résulte de la However, one of the major risks of fixed pharmaceutical combinations results from a possible interaction between the various active ingredients present in this combination. Apart from the excipients, when the active ingredients are formulated alone, bisoprolol alone, perindopril alone, or even the 3 "" therapeutic agent alone, they may contain impurities and / or degradation products in the starting materials, but also potential impurities in the final product. For example, one of the organic impurities that results from the
Figure imgf000015_0001
Figure imgf000015_0001
Cette impureté epoxibiso est toujours présente dans le produit de départ.  This epoxibiso impurity is always present in the starting material.
Lorsque trois principes actifs sont présents dans une composition pharmaceutique fixe, en plus des contraintes liées aux principes actifs seuls, il peut y avoir des problèmes de sous- dosages dans la composition finale mais aussi des problèmes de stabilité de ces principes actifs ainsi que l'apparition de nouvelles impuretés en plus des impuretés déjà connues des principes actifs pris isolément When three active ingredients are present in a fixed pharmaceutical composition, in addition to the constraints related to the active principles alone, there may be problems of sub-dosages in the final composition but also problems of stability of these active ingredients as well as appearance of new impurities in addition to the already known impurities of the active ingredients taken in isolation
Toutes les associations fixes de périndopril actuellement sur le marché et Triplixam® qui vient d'obtenir son AMM sont des comprimés monocouches. Aucun problème de sous-dosage des principes actifs ou encore de stabilité ou de formation de nouvelles impuretés des compositions pharmaceutiques fixes n'a été reporté. All fixed perindopril combinations currently on the market and Triplixam® which has just obtained its MA are monolayer tablets. No problem of under-dosage of the active ingredients or of stability or formation of new impurities of the fixed pharmaceutical compositions has been reported.
L'association fixe Cosyrel® qui contient du périndopril et du bisoprolol et qui vient d'obtenir son AMM est la seule association fixe de périndopril qui se présente sous forme de comprimé bicouche. En effet, que ce soit le comprimé monocouche obtenu par compression directe ou que ce soit le comprimé monocouche obtenu par granulation humide, les formulations n'ont pas donné lieu à des résultats satisfaisants d'un point de vue du dosage et/ou de la stabilité. Un comprimé sous forme de bicouche a permis de proposer une solution aux inconvénients précédemment mentionnés. Des analyses de compatibilité effectuées par la Demanderesse pour les différents principes actifs de la présente invention ont pu mettre en évidence Incompatibilité lorsque les 3 principes actifs, chacun sous forme de poudre, sont mélangés. Le Tableau A ci-après représente la dégradation des principes actifs dans le cas de l'association de bisoprolol, périndopril et amlodipine. The fixed combination Cosyrel® which contains perindopril and bisoprolol and has just obtained its MA is the only fixed combination of perindopril which is in the form of bilayer tablet. Indeed, whether it is the monolayer tablet obtained by direct compression or the monolayer tablet obtained by wet granulation, the formulations have not given rise to satisfactory results from the point of view of the dosage and / or the stability. A tablet in the form of a bilayer has made it possible to propose a solution to the disadvantages mentioned above. Compatibility analyzes carried out by the Applicant for the various active principles of the present invention have demonstrated Incompatibility when the 3 active ingredients, each in powder form, are mixed. Table A below represents the degradation of the active ingredients in the case of the combination of bisoprolol, perindopril and amlodipine.
D'après les résultats du tableau A, dans la composition pharmaceutique fixe selon l'invention qui comprend le bisoprolol, le périndopril et Γ amlodipine, il est nécessaire de séparer d'une part le bisoprolol du périndopril et d'autre part, le bisoprolol de Γ amlodipine et le périndopril de l' amlodipine. From the results of Table A, in the fixed pharmaceutical composition according to the invention which comprises bisoprolol, perindopril and amlodipine, it is necessary to separate on the one hand bisoprolol from perindopril and on the other hand, bisoprolol of amlodipine and perindopril of amlodipine.
Figure imgf000016_0001
Figure imgf000016_0001
Pour obtenir une composition pharmaceutique fixe stable comprenant au moins trois principes actifs, il s'avère donc nécessaire de séparer physiquement ces principes actifs. La présente invention résout ce problème car la Demanderesse a mis au point une composition pharmaceutique fixe sous forme de gélule comprenant des mini-granules des différents principes actifs ou encore des mini-granules des différents principes actifs et des comprimés gastro-résistants d'aspirine. En effet, lorsque les 3 principes actifs sont sous formes de granules il ne peut y avoir interaction entre ces 3 principes actifs simultanément dans la mesure où ils ne peuvent pas être en contact simultanément. Dans le cas de la présente invention, le contact entre les principes actifs ne peut se faire que 2 à 2 évitant ainsi le contact simultané entre tous les principes actifs présents dans la gélule.  To obtain a stable fixed pharmaceutical composition comprising at least three active principles, it is therefore necessary to physically separate these active principles. The present invention solves this problem because the Applicant has developed a fixed pharmaceutical composition in capsule form comprising mini-granules of the various active ingredients or even mini-granules of the various active ingredients and gastro-resistant tablets of aspirin. Indeed, when the 3 active ingredients are in the form of granules there can be interaction between these 3 active ingredients simultaneously insofar as they can not be in contact simultaneously. In the case of the present invention, the contact between the active ingredients can only be 2 to 2, thus avoiding the simultaneous contact between all the active ingredients present in the capsule.
La présente invention trouve la solution au problème en mettant au point une composition pharmaceutique fixe comprenant du bisoprolol, du périndopril et de Γ amlodipine, 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 finds the solution to the problem by developing a fixed pharmaceutical composition comprising bisoprolol, perindopril and amlodipine, a composition in which the interactions between the various active ingredients and the interactions with the excipients are non-existent. Moreover, in this composition the The active ingredients are bioequivalent to the individual compounds that are the individual tablets marketed.
Plus particulièrement, la présente invention propose une composition pharmaceutique fixe sous forme de gélule comprenant du bisoprolol, du périndopril et de Famlodipine et dans laquelle : More particularly, the present invention provides a fixed capsule pharmaceutical composition comprising bisoprolol, perindopril and amlodipine and wherein:
- le bisoprolol est sous forme de mini-granules,  the bisoprolol is in the form of mini-granules,
- le périndopril est sous forme de mini-granules et  - Perindopril is in the form of mini-granules and
- l'amlodipine est sous forme de mini-granules.  - Amlodipine is in the form of mini-granules.
De la même manière et pour les mêmes raisons que citées précédemment, la présente invention comprend aussi une composition pharmaceutique fixe comprenant des : In the same way and for the same reasons as mentioned above, the present invention also comprises a fixed pharmaceutical composition comprising:
A) mini-granules de bisoprolol, des mini-granules de périndopril et des mini-granules d'amlodipine,  A) mini-granules of bisoprolol, mini-granules of perindopril and mini-granules of amlodipine,
B) niini-granules de bisoprolol, des mini-granules de périndopril et des comprimés gastro-résistants d'aspirine Dans la composition pharmaceutique fixe comprenant du bisoprolol, du périndopril et de l'aspirine, l'aspirine est sous forme de comprimés gastro-résistantes permettant d'obtenir une équivalence thérapeutique par rapport au comprimé gastro-résistants d'aspirine seul.  B) niini-granules of bisoprolol, mini-granules of perindopril and gastro-resistant tablets of aspirin In the fixed pharmaceutical composition comprising bisoprolol, perindopril and aspirin, the aspirin is in the form of gastric tablets. resistant to achieve therapeutic equivalence compared to the gastro-resistant tablet of aspirin alone.
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 du bisoprolol et ses sels pharmaceutiquement acceptables, du périndopril et ses sels pharmaceutiquement acceptables et soit de l'amlodipine et ses sels pharmaceutiquement acceptables, ou soit de l'indapamide et ses sels pharmaceutiquement acceptables, ou soit de l'aspirine et ses sels pharmaceutiquement acceptables, en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables, leurs hydrates et leurs formes cristallines dans lesquelles : The present invention also extends to fixed pharmaceutical compositions comprising bisoprolol and its pharmaceutically acceptable salts, perindopril and its pharmaceutically acceptable salts and either amlodipine and its pharmaceutically acceptable salts, or indapamide and its pharmaceutically acceptable salts. or either aspirin and its pharmaceutically acceptable salts, in combination with one or more pharmaceutically acceptable excipients, their hydrates and their crystalline forms in which:
- les doses de bisoprolol varient de 2,10 à 8,50 mg exprimées en bisoprolol base ou varient de 2,5 mg à 10 mg exprimées en bisoprolol fumarate, - 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 doses of bisoprolol vary from 2.10 to 8.50 mg expressed as bisoprolol base or vary from 2.5 mg to 10 mg expressed as bisoprolol fumarate, the doses of perindopril vary from 1.65 mg to 9.512 mg expressed as perindopril base or vary from 2.5 mg to 14 mg expressed as perindopril arginine,
- les doses d'amlodipine varient de 2,5 à 10 mg exprimées en amlodipine base ou varient de 3,47 mg à 13,89 mg exprimées en amlodipine bésilate,  doses of amlodipine vary from 2.5 to 10 mg expressed as amlodipine base or vary from 3.47 mg to 13.89 mg expressed as amlodipine besylate,
- les doses d'mdapamide varient de 0,625 mg à 2,5 mg exprimée en indapamide base, the doses of mdapamide vary from 0.625 mg to 2.5 mg expressed as indapamide base,
- 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.
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:
- de bisoprolol fumarate sont de 2,5 mg, 5 mg et 10 mg,  - Bisoprolol fumarate are 2.5 mg, 5 mg and 10 mg,
- de périndopril arginine sont de 2,5 mg, 3,5 mg, 5 mg, 7 mg, lO mg et 14 mg,  perindopril arginine are 2.5 mg, 3.5 mg, 5 mg, 7 mg, 10 mg and 14 mg,
- d'amlodipine bésilate sont de 2,5 mg, 5 mg et 10 mg,  - Amlodipine besylate are 2.5 mg, 5 mg and 10 mg,
- d'mdapamide sont de 0,625 mg, 1,25 mg, 1,5 mg et 2,5 mg et,  - of mdapamide are 0.625 mg, 1.25 mg, 1.5 mg and 2.5 mg and,
- d'aspirine sont de 75 mg, 100 mg et 150 m g,  - Aspirin are 75 mg, 100 mg and 150 m g,
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) 5 mg de bisoprolol fumarate et 5 mg ou 10 mg de périndopril arginine,  a) 5 mg of bisoprolol fumarate and 5 mg or 10 mg of perindopril arginine,
b) 10 mg de bisoprolol fumarate et 5 mg ou 10 mg de périndopril arginine,  (b) 10 mg of bisoprolol fumarate and 5 mg or 10 mg of perindopril arginine,
et chacune en plus comprennent, and each in addition include,
i) soit 5 mg ou 10 mg d'amlodipine bésilate  i) either 5 mg or 10 mg of amlodipine besylate
ii) soit 1,25 mg ou 2,5 mg d'mdapamide,  (ii) either 1.25 mg or 2.5 mg of mdapamide,
iii) soit 100 mg d'aspirine.  iii) 100 mg of aspirin.
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) 5 mg de bisoprolol fumarate, 5 mg de périndopril arginine et,  i) 5 mg of bisoprolol fumarate, 5 mg of perindopril arginine and,
a. soit 5 mg d'amlodipine bésilate,  at. either 5 mg of amlodipine besilate,
b. soit 1,25 mg d'indapamide,  b. 1.25 mg of indapamide,
c. soit 100 mg d'aspirine  vs. 100 mg of aspirin
ii) 5 mg de bisoprolol fumarate, 10 mg de périndopril arginine et,  ii) 5 mg of bisoprolol fumarate, 10 mg of perindopril arginine and,
a. soit 5 mg d'amlodipine bésilate,  at. either 5 mg of amlodipine besilate,
b. soit 2,5 mg d'indapamide,  b. 2.5 mg of indapamide,
c. soit 100 mg d'aspirine iii) 5 mg de bisoprolol fumarate, 10 mg de périndopril arginine et 10 mg d'amlodipine bésilate vs. 100 mg of aspirin iii) 5 mg of bisoprolol fumarate, 10 mg of perindopril arginine and 10 mg of amlodipine besylate
iv) 10 mg de bisoprolol fumarate, 10 mg de périndopril arginine et,  iv) 10 mg of bisoprolol fumarate, 10 mg of perindopril arginine and,
a. soit 10 mg d'amlodipine bésilate,  at. either 10 mg of amlodipine besilate,
b. soit 2,5 mg d'indapamide  b. 2.5 mg of indapamide
c. soit 100 mg d'aspirine  vs. 100 mg of aspirin
v) 10 mg de bisoprolol fumarate, 5 mg de périndopril arginine et,  v) 10 mg of bisoprolol fumarate, 5 mg of perindopril arginine and,
a. soit 1, 25 mg d'indapamide,  at. that is 1.25 mg of indapamide,
b. soit 100 mg d'aspirine. Les compositions pharmaceutiques fixes selon l'invention précédemment mentionnées comprennent toutes un ou plusieurs excipients pharmaceutiquement acceptable, leurs hydrates et leurs formes cristallines.  b. or 100 mg of aspirin. 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 le bisoprolol, le périndopril, l'amlodipine, Tindapamide et l'aspirine, 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 bisoprolol, perindopril, amlodipine, indapamide and aspirin, said pharmaceutical compositions contain one or more excipients or carriers selected from diluents, lubricants, binders, disintegrants, 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, rhydroxypropylcellulose, rhydroxypropylmethylcellulose, 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 carboxyméthyl cellulose, les sels de carboxyméthylamidon, les dérivés de la polyvinylpyrrolidone.  For the disintegrants: agar, starch, alginic acid and its sodium salt, effervescent mixtures, carboxymethyl cellulose 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 the cardiovascular parameters at good values.
Les exemples qui suivent illustrent l'invention et ne la limitent en aucune façon. Exemples The following examples illustrate the invention and do not limit it in any way. Examples
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 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.
Exemple 1 : préparation des mini-granules de bisoprolol Example 1 Preparation of the Mini-Granules of Bisoprolol
On mélange le bisoprolol fumarate et l'hypromellose dans de l'eau purifiée. La suspension précédemment obtenue est ensuite pulvérisée sur la cellulose microcristalline pour former les mini-granules de bisoprolol.  Bisoprolol fumarate and hypromellose are mixed in purified water. The suspension previously obtained is then sprayed onto the microcrystalline cellulose to form the mini-granules of bisoprolol.
Figure imgf000020_0001
Figure imgf000020_0001
Exemple 2 : préparation des mini-granules de périndopril  Example 2 Preparation of Mini-Granules of Perindopril
On mélange le périndopril arginine et rhydroxypropylcellulose 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.
Figure imgf000020_0002
Figure imgf000020_0002
Exemple 3 : préparation des mini-granules d'amlodipine On mélange l'amlodipine bésilate et l'hypromellose dans de l'eau purifiée. La suspension précédemment obtenue est ensuite pulvérisée sur la cellulose micro cristalline pour former les mini-granules d'amlodipine. Example 3 Preparation of Mini-Granules of Amlodipine Amlodipine besylate and hypromellose are mixed in purified water. The previously obtained suspension is then sprayed onto the micro-crystalline cellulose to form amlodipine mini-granules.
Figure imgf000021_0002
Figure imgf000021_0002
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.
Figure imgf000021_0001
Exemple 5 : préparation des comprimés gastro-résistants d'aspirine
Figure imgf000021_0001
Example 5 Preparation of gastro-resistant aspirin tablets
On forme un premier mélange avec l'acide acétylsalicylique, la cellulose micro cristalline 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 stéaiylfumarate 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, micro-crystalline 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 steaylfumarate which is then sieved. The first mixture is then added, the mixture is mixed and the tablets are formed according to standard 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'éthyie (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.
Figure imgf000022_0001
Figure imgf000022_0001
Les gélules suivantes ont été préparées selon l'invention Exemple 6 : gélules comprenant du bisoprolol, du périndopril et de l'amlodlpine  The following capsules were prepared according to the invention. EXAMPLE 6 Capsules Comprising Bisoprolol, Perindopril and Amlodlpine
Les mini-granules bisoprolol obtenues selon l'exemple 1, les mini-granules de périndopril à libération immédiate obtenues selon l'exemple 2 et les mini-granules à libération immédiate d'amlodipine selon l'exemple 3 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 bisprolol mini-granules obtained according to Example 1, the immediate-release mini-granules of perindopril obtained according to Example 2 and the immediate-release mini-granules of amlodipine according to Example 3 are each lubricated according to the well-known techniques. 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.
Figure imgf000022_0002
Figure imgf000022_0002
Figure imgf000023_0001
Figure imgf000023_0001
Exemple 7 : gélules comprenant du bisoprolol, du périndopril et de l'indapamide Example 7 Capsules Comprising Bisoprolol, Perindopril and Indapamide
Selon le même procédé que celui de l'exemple 6, on remplit la gélule de mini-granules de bisoprolol à libération immédiate selon l'exemple 1, de mini-granules de périndopril à libération immédiate selon l'exemple 2 et des mini-granules d'indapamide selon l'exemple 4.  According to the same method as that of Example 6, the capsule of immediate-release bisoprolol mini-granules according to Example 1 is filled with immediate release mini-granules of perindopril according to Example 2 and mini-granules. indapamide according to Example 4.
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000023_0002
Figure imgf000024_0001
Exemple 8 : gélules comprenant bisoprolol, périndopril et aspirine Example 8 Capsules Comprising Bisoprolol, Perindopril and Aspirin
Selon le même procédé que celui de l'exemple 6, on remplit la gélule de mini-granules de bisoprolol à libération immédiate selon l'exemple 1, de mini-granules de périndopril à libération immédiate selon l'exemple 2 et des comprimés gastro-résistant d'aspirine selon l'exemple 5.  According to the same method as that of Example 6, the capsule of immediate-release bisoprolol mini-granules according to Example 1 was filled with immediate release mini-granules of perindopril according to Example 2 and gastric tablets. aspirin resistant according to Example 5.
Tableau 8 - Compositions des gélules comprenant bisoprolol, périndopril et aspirine Table 8 - Capsule Compositions Comprising Bisoprolol, Perindopril and Aspirin
Figure imgf000024_0002
Figure imgf000025_0001
Figure imgf000024_0002
Figure imgf000025_0001

Claims

REVENDICATIONS
1. Composition pharmaceutique fixe comprenant du bisoprolol et ses sels pharmaceutiquement acceptables, du périndopril et ses sels pharmaceutiquement acceptables et soit : A fixed pharmaceutical composition comprising bisoprolol and its pharmaceutically acceptable salts, perindopril and its pharmaceutically acceptable salts and either:
- de l'amlodipine et ses sels pharmaceutiquement acceptables, ou  amlodipine and its pharmaceutically acceptable salts, or
- de l'indapamide et ses sels pharmaceutiquement acceptables, ou  indapamide and its pharmaceutically acceptable salts, or
- de l'acide acétylsalicylique et ses sels pharmaceutiquement acceptables,  acetylsalicylic acid and its pharmaceutically acceptable salts,
en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables, leurs hydrates et leurs formes cristallines.  in combination with one or more pharmaceutically acceptable excipients, their hydrates and their crystalline forms.
2. Composition pharmaceutique fixe selon la revendication 1 dans laquelle la composition pharmaceutique est une gélule. The fixed pharmaceutical composition of claim 1 wherein the pharmaceutical composition is a capsule.
3. Composition pharmaceutique fixe selon Tune des revendications 1 ou 2 dans laquelle : 3. Fixed pharmaceutical composition according to one of claims 1 or 2 wherein:
- le bisoprolol et ses sels pharmaceutiquement acceptables ou,  bisoprolol and its pharmaceutically acceptable salts, or
- le périndopril et ses sels pharmaceutiquement acceptables ou,  perindopril and its pharmaceutically acceptable salts, or
- l'amlodipine et ses sels pharmaceutiquement acceptables ou,  amlodipine 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.
4. Composition pharmaceutique fixe selon l'une des revendications 1 ou 2 dans laquelle l'aspirine et ses sels pharmaceutiquement acceptables est sous forme de comprimé gastrorésistant 4. Fixed pharmaceutical composition according to one of claims 1 or 2 wherein the aspirin and its pharmaceutically acceptable salts is in the form of gastroresistant tablet
5. Composition pharmaceutique fixe selon l'une des revendications 1 à 4 dans laquelle le bisoprolol est sous forme de bisoprolol fumarate. 5. Fixed pharmaceutical composition according to one of claims 1 to 4 wherein the bisoprolol is in the form of bisoprolol fumarate.
6. Composition pharmaceutique fixe selon l'une des revendications 1 à 4 dans laquelle le périndopril est sous forme de périndopril te/ï-butylamine ou périndopril arginine et plus préférentiellement sous forme de périndopril arginine. 6. Fixed pharmaceutical composition according to one of claims 1 to 4 wherein the perindopril is in the form of perindopril te / ï-butylamine or perindopril arginine and more preferably in the form of perindopril arginine.
7. Composition pharmaceutique fixe selon l'une des revendications 1 à 4 dans laquelle l'amlodipine est sous forme d'amlodipine besylate. 7. Fixed pharmaceutical composition according to one of claims 1 to 4 wherein the amlodipine is in the form of amlodipine besylate.
8. Composition pharmaceutique fixe selon l'une des revendications 1 à 7 dans laquelle :8. Fixed pharmaceutical composition according to one of claims 1 to 7 wherein:
- les doses de bisoprolol varient de 2,10 mg à 8,50 mg exprimées en bisoprolol base ou entre 2,5 à 10 mg exprimées en bisoprolol fumarate, the doses of bisoprolol vary from 2.10 mg to 8.50 mg expressed as bisoprolol base or between 2.5 to 10 mg expressed as bisoprolol fumarate,
- 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'amlodipine varient de 2,5 à 10 mg exprimées en amlodipine base ou entre 3,47 mg à 13,89 mg exprimées en amlodipine bésilate,  doses of amlodipine vary from 2.5 to 10 mg expressed as amlodipine base or between 3.47 mg and 13.89 mg expressed as amlodipine besilate,
- 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 as indapamide base,
- 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.
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:
- de bisoprolol fumarate sont de 5 mg et 10 mg,  - Bisoprolol fumarate are 5 mg and 10 mg,
- de périndopril arginine sont de 5 mg et 10 mg,  - Perindopril arginine are 5 mg and 10 mg,
- d'amlodipine sont de 5 mg et 10 mg,  - amlodipine are 5 mg and 10 mg,
- d'indapamide bésilate sont de 1 ,25 mg et 2,5 mg et,  indapamide besilate are 1, 25 mg and 2.5 mg and,
- d'aspirine est de 100 mg.  - Aspirin is 100 mg.
10. Compositions pharmaceutiques fixes selon l'une des revendications 1 à 9 pour leur utilisation dans le traitement ou la prévention de maladies cardio vasculaires . 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 cardiovas cul aires sont choisies parmi l'hypertension artérielle et la maladie coronaire stable. 11. Fixed pharmaceutical compositions according to claim 10, characterized in that the cardiovascular diseases are chosen from arterial hypertension and stable coronary disease.
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