EP2575808A1 - Combinaison d'agents antihypertenseurs - Google Patents

Combinaison d'agents antihypertenseurs

Info

Publication number
EP2575808A1
EP2575808A1 EP11729785.3A EP11729785A EP2575808A1 EP 2575808 A1 EP2575808 A1 EP 2575808A1 EP 11729785 A EP11729785 A EP 11729785A EP 2575808 A1 EP2575808 A1 EP 2575808A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
composition according
cellulose
sodium
calcium
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11729785.3A
Other languages
German (de)
English (en)
Inventor
Mahmut Bilgic
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bilgic Mahmut
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP2575808A1 publication Critical patent/EP2575808A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a combination of antihypertensive active agents; methods for preparation of said combination; and use of said combination in the treatment of hypertension, hypertension-related diseases and various cardiovascular diseases.
  • the present invention relates to use of the active agents a) mdapamide which is a diuretic, b) amlodipine which is a calcium channel blocker and c) telmisartan which is an angiotensin receptor antagonist in combination.
  • Indapamide chemical name of which is 4-chloro-N-(2-methylindolyn-l-yl)-3-sulfamoyl- benzamide, was first disclosed in the patent numbered US 3565911. There exist various processes for preparation of the molecule indapamide and pharmaceutical compositions comprising the active agent indapamide in the prior art. It is known that indapamide is indicated in the treatment of hypertension and edema.
  • Amlodipine chemical name of which is 3-ethyl 5-methyl (+/-)-2-[(2-aminoethoxy)methyl]-4- (o-cUorophenyl)-l,4-dmydropyridme-6-memyl-3,5-pyridinedicarboxylate, was disclosed in the patent numbered EP 0089167 in detail.
  • telmisartan The molecule telmisartan, chemical name of which is 4'-[(l,4-dimethyl-2'-propyl[2,6-bi-lH- benzimidazo l]- -yl)meyl]-[l, -biphenyl)-2-carboxylic acid, was disclosed in the patent numbered EP 0502314.
  • telmisartan chemical name of which is 4'-[(l,4-dimethyl-2'-propyl[2,6-bi-lH- benzimidazo l]- -yl)meyl]-[l, -biphenyl)-2-carboxylic acid
  • the present invention relates to combined use of the active agents indapamide (formula I) which is a diuretic; amlodipine (formula II) which is a calcium channel blocker; and telmisartan (formula III) which is an angiotensin receptor antagonist.
  • telmisarta The present invention comprises use of the active agents indapamide, amlodipine and telmisartan in combination. In addition, it also comprises optional use of pharmaceutically acceptable excipients in said composition.
  • the active agents of the combination of the present invention can be in free form or in the forms of pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, different polymorphic forms and amorphous forms of the respective active agents.
  • the active agent amlodipine in the combination of the present invention is preferably in the form of pharmaceutically acceptable salt thereof.
  • besylate salt of amlodipine which can be in the form of besylate, mesylate or maleate salt, is used.
  • the present invention relates to use of said combination in the treatment of hypertension, hypertension-related diseases and various cardiovascular diseases.
  • hypertension-related diseases and various cardiovascular diseases refers to diseases such as acute and/or chronic heart failure, congestive heart failure, left heart failure, hypertrophic cardiomyopathy, arrhythmia, cardiomegalia, atrial fibrillation, embolism, ischemic heart disease, coronary artery disease, myocardial infarction, atherosclerosis, angina, renal failure, angina pectoris, diabetes, secondary aldosteronism, pulmonary hypertension, diabetic nephropathy, scleroderma, glomerulosclerosis, albuminuria, diabetic retinopathy, migraine, peripheral vascular diseases, Raynaud's phenomenon, cognitive disorders, hypertensive encephalopathy, thrombotic glaucoma and stroke.
  • Pharmaceutical compositions comprising the combination of the present invention can be used simultaneously, sequentially or separately.
  • the active agents of the composition of the present invention can be formulated separately so as to be used in a kit form.
  • the present invention relates to administration of said combination in warm blooded animals in the treatment of hypertension, hypertension-related diseases and various cardiovascular diseases.
  • the present invention relating to use of a pharmaceutical composition to be used in the manufacture of an effective drug for the treatment of hypertension, hypertension related diseases and various cardiovascular diseases is characterized by comprising the active agents indapamide, amlodipine and telmisartan.
  • the composition comprising the active agents telmisartan, amlodipine and indapamide can be prepared to be used by the oral route.
  • compositions of the present invention comprises oral dosage forms and their pharmaceutical formulations which optionally comprise pharmaceutically acceptable excipients in addition to the active agents.
  • Oral dosage forms can be in solid dosage forms such as tablet; capsule; enteric coated or modified release tablets; prolonged release tablet; delayed release tablet; fast soluble tablet; effervescent tablet; effervescent granule; fast soluble powder mixture or dry powder mixture for syrup preparation; dragee; orally disintegrating tablet; water soluble tablet; water soluble powder, tablet or granule; film tablet; or liquid dosage forms such as suspension.
  • the amount of active agent in the formulation of the present invention can vary in the range of 0.5% to 95%, preferably in the range of 1% to 90% in proportion to total amount of substances in the pharmaceutical formulation.
  • Dose of the active agent in the pharmaceutical formulation can vary according to the route of administration; patient's age and state of health.
  • one dose of the pharmaceutical composition comprising the present invention can comprise 10-300 mg telmisartan; 2,5-25 mg amlodipine; 0,1-10 mg indapamide.
  • the composition of the present invention is composed of the active agents telmisartan, amlodipine and indapamide. Desired therapeutic action time is obtained by intake of telmisartan and amlodipine once a day. However, this is not possible for indapamide.
  • the inventors considered to formulate the combination in compressed bilayer tablet form in order to equalize action times of the active agents. Antihypertensive action times of the active agents of the composition can be equalized by comprising indapamide, which has shorter hypertensive action time compared with the other active agents in the composition, both in the fast release layer and the constant release layer. More effective compositions have been obtained by formulating the combination of the present invention in compressed bilayer tablet form.
  • the constant release layer comprising indapamide is the innermost layer of the tablet.
  • Fast release layer comprising telmisartan, amlodipine and indapamide, on the other hand, is placed around the constant release layer.
  • tablet forms are obtained such that the coating is the outermost layer of the tablet.
  • polymers can be used in order to provide constant release of indapamide.
  • Polymers ensuring constant release can be selected from, but not limited to, a group comprising cellulose derivatives, particularly hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, methyl hydroxypropyl cellulose, carboxymethyl cellulose, povidone; acrylic acid copolymers or combinations thereof.
  • compositions comprising the combinations of antihypertensive active agents are produced according to conventional techniques optionally with addition of pharmaceutically acceptable excipients.
  • excipients can also be used in addition to the active agents used in each oral formulation.
  • excipients can be components such as at least one binder, lubricant, disintegrant, demulsifying agent, stabilizing agent, flavoring agent, diluent, surfactant and glidant.
  • binders can be selected from, but not limited to, the group comprising starches (such as potato starch, corn starch, wheat starch); sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums (such as acacia); gelatin; cellulose derivatives (such as macrocrystalline cellulose, HPC, HEC, HPMC, carboxymethyl cellulose, methyl cellulose, ethyl cellulose); povidone, polyvinylpyrrolidone, polyethylene glycol; waxes; calcium carbonate; calcium phosphate; alcohols (such as sorbitol, xylitol, mannitol) and water.
  • starches such as potato starch, corn starch, wheat starch
  • sugars such as sucrose, glucose, dextrose, lactose, maltodextrin
  • natural and synthetic gums such as acacia
  • gelatin such as macrocrystalline cellulose, HPC, HEC, HPMC, carboxy
  • Pharmaceutically acceptable lubricant can be selected from, but not limited to, the group comprising stearic acid, stearic acid salts (calcium state, magnesium stearate, etc.), talc, colloidal silica, wax, boric acid, adipic acid, sulfates (sodium sulfate), glycol, fumaric acid, sodium benzoate, DL-leucine, lauryl sulfate (sodium lauryl sulfate, magnesium lauryl sulfate, etc.), silicates, starch derivatives.
  • Pharmaceutically acceptable disintegrants can be selected from, but not limited to, the group comprising cellulose derivatives (low-substituted hydoxypropyl cellulose, carboxymethylcellulose, calciumcarboxymethylcellulose, cross-linked sodium carboxymethyl cellulose) and chemically modified starch/cellulose derivatives (carboxymethyl starch, sodiumcarboxymethyl starch, etc.).
  • compositionsifying agents can be selected from, but not limited to, the group comprising colloidal clay (bentonite, etc.), metal hydroxides (magnesium hydroxide, aluminum hydroxide, etc.), anionic surfactant (sodium lauryl sulfate, calcium stearate, etc.), cationic surfactant or ionic surfactant (polyoxyethylene alkyl ether, fatty acid ester of polyoxyethylene sorbitan or sucrose esters of fatty acids).
  • colloidal clay bentonite, etc.
  • metal hydroxides magnesium hydroxide, aluminum hydroxide, etc.
  • anionic surfactant sodium lauryl sulfate, calcium stearate, etc.
  • cationic surfactant or ionic surfactant polyoxyethylene alkyl ether, fatty acid ester of polyoxyethylene sorbitan or sucrose esters of fatty acids.
  • Stabilizing agent and/or agents can be selected from agents such as antioxidants, chelating agents, alkalinizing agents and photoprotective agents.
  • Antioxidants can be selected from, but not limited to, the group comprising substances such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium sulfite, gallates (such as propyl gallate), tocopherol, citric acid, malic acid, ascorbic acid, acetylsistein, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • gallates such as propyl gallate
  • tocopherol citric acid, malic acid, ascorbic acid, acetylsistein, fumaric acid, lecithin, ascorbyl palmitate, ethylenediamine tetraacetate.
  • Chelating agents can be selected from, but not limited to, the group comprising disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or combinations thereof.
  • Alkalinizing agents can be selected from, but not limited to, alkali metal salts such as sodium carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines, ⁇ , ⁇ '- dibenzylemylenediamine, diemanolamine, ethylenediamine, meglumine, monosodium glutamate, polacryline sodium, sodium alginate.
  • Photoprotective agents can be selected from, but not limited to, a group comprising metal oxides such as titanium oxide, iron oxide or zinc oxide.
  • Pharmaceutically acceptable flavoring agents can be selected from, but not limited to, the group comprising sour cherry flavor, blackberry flavor, grapefruit flavor, grape flavor, pear flavor, orange flavor, apricot flavor or combinations thereof.
  • Pharmaceutically acceptable diluents can be selected from, but not limited to, the group comprising lactose, dry lactose, lactose monohydrate, directly compressed lactose (lactose D.C.), starch, hydrolyzed starch, mannitol, sorbitol, xylitol, dextrose, dextrose monohydrate, dibasic calcium phosphate dihydrate, monobasic calcium, sulfate monohydrate, calcium sulfate dihydrate, amylose, calcium carbonate, glycine, bentonite.
  • compositions can be selected from, but not limited to, the group comprising sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters (polysorbates), polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, sugar esters of fatty acids and glycerides of fatty acids.
  • glidants can be selected from, but not limited to, the group comprising talc, silicone dioxide, magnesium trisilicate, cellulose powder, starch, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfates.
  • solubility modulators such as solubility modulators, sweeteners, coloring agents and coating agents can also be used in the formulation.
  • telmisartan, amlodipine and indapamide are turn into a pharmaceutical composition by conventional methods in the prior art.
  • the homogenous mixture obtained afterwards is dried and shaped as required.
  • Preparation of the bilayer tablet composed of a fast release and a constant release layer comprises the following steps:
  • the constant release layer is prepared.
  • indapamide constitutes 5% of total amount of substances and pharmaceutically acceptable excipients with polymers providing constant release characteristic in addition.
  • Granulation solution is prepared according to methods in the prior art. The granules obtained are dried and sieved. They are mixed so as to provide homogeneity.
  • telmisartan a layer which comprises telmisartan, amlodipine and indapamide surrounding the constant release layer.
  • This layer is prepared according to conventional tablet production methods with the addition of all the active agents and pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises 5% indapamide; 10% amlodipine and 30% telmisartan of total substance amount. Afterwards, the homogenous mixture obtained is dried and shaped as required.
  • Both mixtures prepared are pressed as bilayer tablet by imposing an appropriate compressive force. Firstly, the constant release layer is pressed, then the fast release layer is pressed around it.
  • the tablet is coated with pharmaceutically acceptable coating materials.
  • indapamide there is 2,5% indapamide in proportion to total substance amount of the pharmaceutical formulation in the constant release layer which is the innermost layer of the tablet.
  • polymers such as hydroxypropyl methyl cellulose, microcrystalline cellulose are added.
  • Other excipients are also added into the pharmaceutical composition.
  • Granulation solution is prepared according to methods in the prior art. The granules obtained are dried and then sieved. They are mixed so as to provide homogeneity.
  • the fast release layer surrounding the constant release layer comprises 5% indapamide, 10% amlodipine and 35% telmisartan in proportion to total substance amount of the pharmaceutical formulation.
  • Said active agents are mixed with pharmaceutically acceptable excipients.
  • Granulation solution is prepared according to methods in the prior art. The granules obtained are dried and then sieved. They are mixed so as to provide homogeneity.
  • composition is pressed into tablet form such that the constant release layer is the inner layer while the fast release layer is the outer layer.
  • the tablet is coated with pharmaceutically acceptable coating materials.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une combinaison d'agents actifs antihypertenseurs; des procédés de préparation de cette combinaison; et l'utilisation de cette combinaison dans le traitement de l'hypertension, des maladies liées à l'hypertension et de diverses maladies cardiovasculaires.
EP11729785.3A 2010-05-28 2011-05-27 Combinaison d'agents antihypertenseurs Withdrawn EP2575808A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201004315 2010-05-28
PCT/TR2011/000153 WO2011149438A1 (fr) 2010-05-28 2011-05-27 Combinaison d'agents antihypertenseurs

Publications (1)

Publication Number Publication Date
EP2575808A1 true EP2575808A1 (fr) 2013-04-10

Family

ID=44310842

Family Applications (1)

Application Number Title Priority Date Filing Date
EP11729785.3A Withdrawn EP2575808A1 (fr) 2010-05-28 2011-05-27 Combinaison d'agents antihypertenseurs

Country Status (2)

Country Link
EP (1) EP2575808A1 (fr)
WO (1) WO2011149438A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10322117B2 (en) * 2017-01-25 2019-06-18 The George Institute for Global Health Compositions for the treatment of hypertension
US10369156B2 (en) 2016-11-15 2019-08-06 The George Institute for Global Health Compositions for the treatment of hypertension

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SG11201606689VA (en) 2014-02-13 2016-09-29 Incyte Corp Cyclopropylamines as lsd1 inhibitors
ES2750956T3 (es) 2014-02-13 2020-03-30 Incyte Corp Ciclopropilaminas como inhibidores de LSD1
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
NZ735998A (en) 2015-04-03 2024-08-30 Incyte Holdings Corp Heterocyclic compounds as lsd1 inhibitors
NZ740186A (en) 2015-08-12 2024-07-05 Incyte Holdings Corp Salts of an lsd1 inhibitor
CN107174570B (zh) * 2017-03-09 2019-11-05 苏州东瑞制药有限公司 一种溶出性能稳定的替米沙坦片及其制备方法
CN107375274A (zh) * 2017-07-25 2017-11-24 合肥华方医药科技有限公司 生物利用度提高的吲达帕胺药物组合物
KR102066832B1 (ko) * 2017-11-15 2020-01-16 주식회사 종근당 텔미사르탄 또는 그의 약제학적으로 허용가능한 염을 포함하는 인습성 및 용출률이 향상된 제제
CA3107616A1 (fr) * 2018-07-26 2020-01-30 The George Institute for Global Health Compositions pour le traitement de l'hypertension
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
EP4373474A1 (fr) 2021-07-22 2024-05-29 KRKA, D.D., Novo Mesto Comprimé bicouche comprenant du telmisartan et de l'indapamide
EP4295839A1 (fr) 2022-06-20 2023-12-27 KRKA, d.d., Novo mesto Combinaison de valsartan et d'indapamide

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10369156B2 (en) 2016-11-15 2019-08-06 The George Institute for Global Health Compositions for the treatment of hypertension
US10322117B2 (en) * 2017-01-25 2019-06-18 The George Institute for Global Health Compositions for the treatment of hypertension
US10799487B2 (en) 2017-01-25 2020-10-13 The George Institute for Global Health Compositions for the treatment of hypertension
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

Also Published As

Publication number Publication date
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