WO2017054787A1 - Composition pharmaceutique comprenant la combinaison de candésartan, d'amlopidine et d'hydrochlorothiazide - Google Patents

Composition pharmaceutique comprenant la combinaison de candésartan, d'amlopidine et d'hydrochlorothiazide Download PDF

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WO2017054787A1
WO2017054787A1 PCT/CZ2016/000110 CZ2016000110W WO2017054787A1 WO 2017054787 A1 WO2017054787 A1 WO 2017054787A1 CZ 2016000110 W CZ2016000110 W CZ 2016000110W WO 2017054787 A1 WO2017054787 A1 WO 2017054787A1
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pharmaceutically acceptable
pharmaceutical composition
acceptable salt
hydrochlorothiazide
candesartan
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PCT/CZ2016/000110
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English (en)
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Praveen Khullar
Kum PRASAD
Kishor KOTHAWADE
Prashant Gupta
Saravanan DEVARAJAN
Santosh Kumar Deolia
Kalsotra SACHIN
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Zentiva, K.S.
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Publication of WO2017054787A1 publication Critical patent/WO2017054787A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/33—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a composition for preventing or treating cardiovascular disorders
  • a composition for preventing or treating cardiovascular disorders comprising the combination of candesartan of formula I, chemically 2-ethoxy-l-( ⁇ 4-[2-(2H-l,2,3,4- tetrazol-5-yl)phenyl]phenyl ⁇ methyl)-lH-l,3-benzodiazoIe-7-carboxylic acid, or a pharmaceutically acceptable salt thereof, with Hydrochlorothiazide of formula II, chemically 6-chloro-l,l-dioxo-3,4- dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide, or a pharmaceutically acceptable salt thereof, and Amlodipine of formula III, chemically 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)- 6-methyl-l,4-dihydro-3,5-pyridine dicarboxylate, or
  • Hypertension can be classified into essential or secondary hypertension, and most (approximately 90 - 95%) of the hypertension belongs to the essential hypertension class. While secondary hypertension is generally treatable by correcting the known causes, essential hypertension, the exact cause of which is not yet elucidated, is generally treated by relaxation therapy, dietary therapy and exercise therapy which are optionally combined with medication. Notable antihypertensive drugs include diuretics, sympatholytic agents and vasodilators. Vasodilators are most widely prescribed antihypertensive drugs, and they are divided into several groups according to their pharmacological action which include ACE (angiotensin converting enzyme) inhibitors, angiotensin II receptor antagonists and calcium channel blockers.
  • ACE angiotensin converting enzyme
  • Diuretic drugs due to their mild hypotensive effects, have long been clinically used as antihypertensive agents.
  • undesirable side effects caused by the use for a long time influences on metabolism, for example, hypokalaemia, hyperuricemia, hyperlipidemia and diabetes mellitus, have been taken up.
  • While calcium antagonists have been used as therapeutic agents of circulatory diseases such as hypertension, cardiac diseases, cerebral apoplexy, nephritis and arteriosclerosis, it has also been known that they tend to cause such undesirable side effects as tachycardia, hypotension, erythroprosopaigia and encephalagia, which are considered to be due to their abrupt vasodilative action.
  • benzimidazole derivatives have an angiotensin II antagonistic activities and are useful for the therapy of circulatory diseases including hypertension, cardiac diseases (cardiac insufficiency, myocardial infarction, etc.), cerebral apoplexy, nephritis and arteriosclerosis.
  • the mechanism of the action is considered that the benzimidazole derivatives inhibit the binding of angiotensin II having a strong vasoconstrictive action to an angiotensin II acceptor.
  • JPA H3(1991)-27362 and JPA H5(1993)-132467 it is disclosed that an imidazole derivative having angiotensin II antagonistic action is administered together with a diuretic agent or a calcium antagonistic agent.
  • WO2008044862 relates to a functional combination preparation comprising a dihydropyridine-based calcium channel blocker such as amlodipine and an ARB (angiotensin-2 receptor blocker) such as losartan.
  • a functional combination preparation comprising a dihydropyridine-based calcium channel blocker such as amlodipine and an ARB (angiotensin-2 receptor blocker) such as losartan.
  • the document relates to chronotherapeutically designed combination formulations for the preparation and treatment of cardiovascular diseases, which are formulated based on xenobiotics and chronotherapy for enabling the two drugs to be chronotherapeutically released, thereby improving the therapeutic activity as compared to the co-administration of each drug in the form of a single tablet, while reducing side effects and maintaining the therapeutic activity as high as possible during the period of time of a day when the risk of a compliance of cardiovascular disease is highest.
  • WO2005070463 relates to a pharmaceutical composition
  • a pharmaceutical composition comprising enantiomerically pure (S)- amlodipine malate, an ARB and optionally other active agents.
  • the document is directed to methods for treating, preventing and managing cardiovascular diseases and disorders and symptoms thereof, using the composition.
  • EP1314425 is directed to medicinal compositions for preventing or treating heart failure and discloses compositions containing a HMG-CoA reductase inhibitor selected from the group consisting of pravastatin, simvastatin, lovastatin, pitavastatin and ZD-4522, an angiotensin II receptor antagonist and optionally a calcium channel blocker.
  • a HMG-CoA reductase inhibitor selected from the group consisting of pravastatin, simvastatin, lovastatin, pitavastatin and ZD-4522, an angiotensin II receptor antagonist and optionally a calcium channel blocker.
  • the Indian patent application 755/MUM/2003 is concerned with a process of making a stable pharmaceutical formulation of tablet comprising an effective amount of (S)-amlodipine besylate salt with pharmaceutically acceptable and compatible (physical and chemical) excipients.
  • a fixed-dose combination product comprising ail three active pharmaceutical ingredients: (i) an angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof, (ii) a calcium channel blocker (CCB) and (iii) a diuretic, preferably comprising candesartan (ARB), amlodipine (CCB) and hydrochlorothiazide (diuretic) in comparison with separate single-dosed products.
  • ARB an angiotensin receptor blocker
  • CCB calcium channel blocker
  • a diuretic preferably comprising candesartan (ARB), amlodipine (CCB) and hydrochlorothiazide (diuretic) in comparison with separate single-dosed products.
  • It is the object of the present invention to provide a composition for preventing or treating cardiovascular disorders comprising the combination of candesartan or a pharmaceutically acceptable salt thereof with hydrochlorothiazide or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt thereof and the method of preparing the same.
  • the object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising: (i) an angiotensin receptor blocker (ARB) or a pharmaceutically acceptable salt thereof, (ii) a calcium channel blocker (CCB) or a pharmaceutically acceptable salt thereof, and (iii) a diuretic or a pharmaceutically acceptable salt thereof.
  • ARB an angiotensin receptor blocker
  • CCB calcium channel blocker
  • a diuretic or a pharmaceutically acceptable salt thereof a pharmaceutically acceptable salt thereof.
  • This invention relates to the pharmaceutical composition, wherein (i) the angiotensin receptor blocker (ARB) is selected from the group consisting of candesartan, losartan, olmesartan, telmisartan, valsartan, irbesartan, azilsartan; (ii) the calcium channel blocker (CCB) is selected from the group consisting of amlodipine, barnidipine, felodipine, nifedipine, lercanidipine, manidipine; and (iii) the diuretic is selected from the group consisting of bumetanide, furosemide, chlorothalidone, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide.
  • ARB angiotensin receptor blocker
  • CCB calcium channel blocker
  • the diuretic is selected from the group consisting of bumetanide, furosemide, chlorothalidone
  • this invention relates pharmaceutical composition, wherein (i) the angiotensin receptor blocker (ARB) is candesartan; (ii) the calcium channel blocker (CCB) is amlodipine; and (iii) the diuretic is hydrochlorothiazide.
  • ARB angiotensin receptor blocker
  • CCB calcium channel blocker
  • the diuretic is hydrochlorothiazide.
  • this invention relates to the pharmaceutical composition which is administered orally, preferably in a form of a tablet. More preferably, a pharmaceutical composition which is administered orally in a form of a bi-layer tablet.
  • this invention relates to a pharmaceutical composition, wherein the first layer comprises candesartan or its pharmaceutically acceptable salt and hydrochlorothiazide and in the second layer comprises amlodipine or its pharmaceutically acceptable salt.
  • this invention relates to pharmaceutical composition, wherein the pharmaceutically acceptable salt of candesartan is candesartan cilexetil and the pharmaceutically acceptable salt of amlodipine is amlodipine besylate.
  • this invention relates to a pharmaceutical composition, wherein candesartan is contained in an amount from 5 to 150 mg, amlodipine is contained in an amount from 1 mg to 50 mg, and hydrochlorothiazide is contained in an amount from 0.5 mg to 30 mg.
  • a pharmaceutical composition wherein candesartan is contained in an amount from 10 to 50 mg, amlodipine is contained in an amount from 5 mg to 35 mg, and hydrochlorothiazide is contained in an amount from 1 mg to 20 mg.
  • a further aspect of the present invention is a method of preparation of the pharmaceutical composition, comprising the step of granulating candesartan or a pharmaceutically acceptable salt thereof along with hydrochlorothiazide or a pharmaceutically acceptable salt thereof to obtain a candesartan and hydrochlorothiazide granule part.
  • the method further comprises the step wherein the candesartan and hydrochlorothiazide granule part with a mixture part comprising amlodipine or a pharmaceutically acceptable salt thereof are mixed together. More preferably the method further comprising the steps: (i) manufacture of layer 1: candesartan or a pharmaceutically acceptable salt thereof and hydrochlorothiazide granules using wet granulation approach; and (II) manufacture of layer 2: amlodipine or a pharmaceutically acceptable salt thereof granules using slugging approach.
  • the pharmaceutically acceptable salt of candesartan is candesartan cilexetil.
  • the pharmaceutically acceptable salt of amlodipine is amlodipine besylate.
  • the invention also relates to a pharmaceutical composition for use in preventing or treating of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental vascular remodeling, myocardial infarction and its sequelae, atherosclerosis, angina (whether unstable or stable), renal insufficiency (diabetic and non-diabetic), heart failure, angina pectoris, diabetes, secondary aldosteronism, primary and secondary pulmonary hypertension, renal failure conditions, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, peripheral vascular disease, Raynaud's disease,
  • the present invention relates to a pharmaceutical composition for use in preventing or treating the appropriate cardiovascular disorders. More preferably the cardiovascular disorders are selected from the group consisting of angina pectoris, hypertension, artery vasospasm, deep vein thrombosis, cardiac hypertrophy, cerebral infarct, congestive heart failure and myocardial infarction.
  • the newly invented triple combination product is surprisingly maintaining the same properties of the original mono or dual combination reference product (Atacand Plus - Candesartan cilexetil and Hydrochlorothiazide tablet) and Esidrix Tablets (Hydrochlorothiazide) - e.g. dissolution rates, stability.
  • the combination formulation prevents an excessive degradation of the mono components and therefore contributes to a better stability of the final triple combination product. Therefore it is not necessary to somehow adjust the storage limits of the triple combination product.
  • a dosage form to be developed that can overcome the difficulties of the prior art and the difficulties found during the manufacturing process. More particularly, there is a need to develop a simple and cost-effective means to manufacture a dosage form which allows easy laboratory testing and that limits the potential of interactions of one API with further APIs or with one or more of the excipients used in the formulation.
  • Fig 1 Dissolution rates of Candesartan cilexetil 32 mg when compared between different reference product combinations and Test Example 1
  • the present invention relates to a pharmaceutical composition for the treatment of cardiovascular disorders, which comprises 2-ethoxy-l-( ⁇ 4-[2-(2H-l,2,3,4-tetrazol-5-yl)phenyl]phenyl ⁇ methyl)-lH-l,3- benzodiazole-7-carboxylic acid (candesartan) or a pharmaceutically acceptable salt thereof in combination with 6-chloro-l,l-dioxo-3,4-dihydro-2H-l,2,4-benzothiadiazine-7-sulfonamide (hydrochlorothiazide, HCTZ) or a pharmaceutically acceptable salt thereof and 3-ethyl 5-methyl 2-[(2- aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate
  • Amiodipine is the generic name for 3-ethyl-5-methyl-2-(2-aminoethoxy-methyl)-4-(2-chlorophenyl)-6- methyl-l,4-dihydro-3,5-pyridine dicarboxylate, and EP Patent Publication No. 89167 discloses various forms of pharmaceutically acceptable salts of amiodipine.
  • the pharmaceutically acceptable salts of amiodipine used in the present invention may be formed using acids which form non-toxic, pharmaceutically acceptable acid addition salts, which include but are not limited to hydrochloride, hydrobromide, sulphate, phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, besylate and camsylate salts and amiodipine is currently available as Norvasc.
  • Candesartan is the generic name for 2-ethoxy-l-( ⁇ 4-[2-(2H-l,2,3,4-tetrazol-5- yl)phenyl]phenyl ⁇ methyl)-lH-l,3-benzodiazole-7-carboxylic acid and it is disclosed in EP0425921, EP0459136 and EP0520423 that benzimidazole derivatives have an angiotensin II antagonistic activities and are useful for the therapy of circulatory diseases including hypertension, cardiac diseases (cardiac insufficiency, myocardial infarction, etc.), cerebral apoplexy, nephritis and arteriosclerosis.
  • Candesartan cilexetil is currently available as Atacand. Accordingly, the preferred pharmaceutically acceptable salt of candesartan that can be used in the present invention is candesartan cilexetil.
  • Hydrochlorothiazide is the generic name for 6-chloro-l,l-dioxo-3,4-dihydro-2H-l,2,4- benzothiadiazine-7-sulfonamide and Hydrochlorothiazide is currently available as Esidrix and Combination of Candesartan cilexetil along with hydrochlorothiazide is currently available as Atacand Plus.
  • the mechanism of the action is considered that the benzimidazole derivatives inhibit the binding of angiotensin II having a strong vasoconstrictive action to an angiotensin II acceptor.
  • JPA H3(1991)-27362 and JPA H5(1993)-132467 it is disclosed that an imidazole derivative having angiotensin II antagonistic action is administered together with a diuretic agent or a calcium antagonistic agent.
  • composition of candesartan or a pharmaceutically acceptable salt thereof with hydrochlorothiazide or a pharmaceutically acceptable salt thereof and amlodipine or a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof can achieve improved preventive or therapeutic effects for cardiovascular disorders, such as angina pectoris, hypertension, artery vasospasm, deep vein, cardiac hypertrophy, cerebral infarct, congestive heart failure and myocardial infarction, as compared with conventional single formulations, while minimizing adverse effects of the single drugs.
  • cardiovascular disorders such as angina pectoris, hypertension, artery vasospasm, deep vein, cardiac hypertrophy, cerebral infarct, congestive heart failure and myocardial infarction
  • composition is prepared as an uncoated bi-layer tablet and manufacturing process comprising the following steps:
  • composition and manufacturing procedure are intended to further illustrate the present invention without limiting its scope.
  • Manufacturing composition and process for candesartan hydrochlorothiazide and amlodipine tablets containing candesartan (as candesartan cilexetil), hydrochlorothiazide (HCTZ), amlodipine besylate (as amlodipine besylate) are provided for illustration.
  • the pharmaceutical composition of the present invention can be prepared by the prescriptions described as follows.
  • qs refers to "Quantum satis” meaning the amount which is necessarily needed. It refers to a specific amount for an ingredient that is necessarily needed to achieve the desired result, but not more. Table 1
  • Lactose (Pharmatose 200 M) 170.60 60.93
  • the ingredients of the candesartan and hydrochlorothiazide mixture part were wet-granulated using PEG and HPC solution and dried to obtain the granule part having the specified amounts of the ingredient.
  • the candesartan and hydrochlorothiazide mixture part was mixed with the ingredients of the amlodipine granules part according to the corresponding amounts, and the resulting mixture was compressed into tablets using a bi-layered tablet press having 32 mg of candesartan (as candesartan cilexetil) and 25 mg of hydrochlorothiazide as the first layer and 13.89 mg of amlodipine (as amlodipine besylate) as the second layer.
  • Example 1 Combined tablet prepared in Example 1 and Reference Products - Atacand (Candesartan cilexetil), Atacand Plus (Candesartan cilexetil and Hydrochlorothiazide Tablet), Esidrix (Hydrochlorothiazide) and Norvasc (Amlodipine besylate) tablets were subjected to drug dissolution testing for comparison purposes. Obtained dissolution rates are shown in Figure 1 and 2.
  • Lactose (Pharmatose 200 M) 85.30 60.93
  • a combined tablet containing 16 mg of candesartan (as candesartan cilexetii), 12.50 mg of hydrochlorothiazide and 6.95 mg of amiodipine (as amiodipine besylate) was prepared by repeating the procedure of example 1.
  • a combined tablet containing 32 mg of candesartan (as candesartan cilexetil), 12.50 mg of hydrochlorothiazide and 13.89 mg of amlodipine (as amlodipine besylate) was prepared by repeating the procedure of example 1.
  • a combined tablet containing 32 mg of candesartan (as candesartan cilexetil), 12.50 mg of hydrochlorothiazide and 6.95 mg of amlodipine (as amlodipine besylate) was prepared by repeating the procedure of example 1.
  • Example I, II and III are shown in Table 6 and stability Results of Example IV and V are shown in Table 7.
  • Ketone Cilexetil 0.210 0.213 0.272 0.186 0.175 0.221 0.199 0.211 0.278
  • Ketone Cilexetil 0.183 0.173 0.206 0.155 0.144 0.198
  • a combined tablet containing 32 mg of candesartan (as candesartan cilexetil), 12.50 mg of hydrochlorothiazide and 13.89 mg of amiodipine (as amiodipine besylate) was prepared by repeating the procedure of example 1.

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Abstract

La présente invention concerne une composition pour la prévention ou le traitement de troubles cardio-vasculaires comprenant une combinaison de candésartan représenté par la formule chimique (I), 2-éthoxy-1-({4-[2-(2H-1,2,3,4-tétrazol-5-yl)phényl]phényl}méthyl)-1H-1,3-benzodiazole-7-acide carboxylique, ou d'un sel pharmaceutiquement acceptable de celui-ci, d'hydrochlorothiazide représenté par la formule chimique (II), 6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide, ou d'un sel pharmaceutiquement acceptable de celui-ci, et d'amlodipine représenté par la formule chimique (III), 3-éthyl-5-méthyl-2-(2-aminoéthoxy-méthyl)-4-(2-chlorophényl)-6-méthyl-1,4-dihydro -3,5-dicarboxylate de pyridine, ou d'un sel pharmaceutiquement acceptable de celui-ci, ainsi qu'un procédé de préparation de cette composition. Le choix de ces agents et leur dosage dans ce schéma de combinaison sont conçus pour améliorer la tolérance par minimisation du risque d'effets secondaires dépendants de la dose, habituellement associés à des agents individuels et qui peuvent être éliminés significativement par le produit à triple combinaison proposé. (Formules (I), (II), (III))
PCT/CZ2016/000110 2015-10-02 2016-09-27 Composition pharmaceutique comprenant la combinaison de candésartan, d'amlopidine et d'hydrochlorothiazide WO2017054787A1 (fr)

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CZ2015-687A CZ2015687A3 (cs) 2015-10-02 2015-10-02 Farmaceutická kompozice obsahující kombinaci kandesartanu, amlodipinu a hydrochlorthiazidu

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WO2020021341A1 (fr) * 2018-07-26 2020-01-30 The George Institute for Global Health Compositions pour le traitement de l'hypertension
WO2022132067A1 (fr) * 2020-12-18 2022-06-23 Santa Farma Ilac Sanayii A.S. Compositions de comprimés bicouches stables
GR1010320B (el) * 2021-08-04 2022-10-11 Win Medica Φαρμακευτικη Ανωνυμη Εταιρεια, Στερεες φαρμακοτεχνικες μορφες ιρβεσαρτανης, υδροχλωροθειαζιδης και αμλοδιπινης
US11478462B2 (en) 2017-01-25 2022-10-25 The George Institute for Global Health Compositions for the treatment of hypertension
WO2023285646A1 (fr) 2021-07-15 2023-01-19 Adamed Pharma S.A Composition pharmaceutique comprenant de l'amlodipine, du candésartan cilexetil et de l'hydrochlorothiazide pour le traitement de l'hypertension

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11478462B2 (en) 2017-01-25 2022-10-25 The George Institute for Global Health Compositions for the treatment of hypertension
US12102623B2 (en) 2017-01-25 2024-10-01 The George Institute for Global Health Compositions for the treatment of hypertension
WO2020021341A1 (fr) * 2018-07-26 2020-01-30 The George Institute for Global Health Compositions pour le traitement de l'hypertension
WO2022132067A1 (fr) * 2020-12-18 2022-06-23 Santa Farma Ilac Sanayii A.S. Compositions de comprimés bicouches stables
WO2023285646A1 (fr) 2021-07-15 2023-01-19 Adamed Pharma S.A Composition pharmaceutique comprenant de l'amlodipine, du candésartan cilexetil et de l'hydrochlorothiazide pour le traitement de l'hypertension
GR1010320B (el) * 2021-08-04 2022-10-11 Win Medica Φαρμακευτικη Ανωνυμη Εταιρεια, Στερεες φαρμακοτεχνικες μορφες ιρβεσαρτανης, υδροχλωροθειαζιδης και αμλοδιπινης

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