EP2575808A1 - Combination of antihypertensive agents - Google Patents

Combination of antihypertensive agents

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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Withdrawn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)
French (fr)
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
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Filing date
Publication date
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Publication of EP2575808A1 publication Critical patent/EP2575808A1/en
Withdrawn legal-status Critical Current

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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.

Abstract

The present invention relates to a combination of a 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.

Description

COMBINATION OF ANTIHYPERTENSIVE AGENTS
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. There exist synthesis methods related with amlodipine and pharmaceutical compositions comprising amlodipine; use of the active agent amlodipine in diseases such as angina, variant angina and hypertension in the prior art.
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. In addition, there exist studies conducted with the molecule telmisartan; synthesis of the molecule telmisartan and pharmaceutical compositions comprising the molecule telmisartan in the prior art. Telmisartan is an active agent indicated in the treatment of hypertension.
Hypertension treatments in which angiotensin receptor antagonists, calcium channel blockers or diuretics are used alone are known in the prior art. However, said monotherapies remain insufficient for most patients.
When the prior art is taken into consideration, there is need for novel pharmaceutical compositions which are used in the treatment of hypertension, hypertension-related diseases and various cardiovascular diseases and yield more effective and certain results compared with existing therapies. The inventors have surprisingly found that combination of the active agents indapamide, amlodipine and telmisartan induces synergistic effect in the treatment of hypertension, hypertension-related diseases and various cardiovascular diseases. The combination of the present invention provides greater therapeutic benefit in comparison with the treatment in which indapamide, amlodipine or telmisartan are used alone or two of these active agents are combined.
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.
In another aspect, 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.
In another aspect, the active agent amlodipine in the combination of the present invention is preferably in the form of pharmaceutically acceptable salt thereof. Preferably, besylate salt of amlodipine, which can be in the form of besylate, mesylate or maleate salt, is used. In another aspect, the present invention relates to use of said combination in the treatment of hypertension, hypertension-related diseases and various cardiovascular diseases.
According to the invention, "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.
In another aspect, the active agents of the composition of the present invention can be formulated separately so as to be used in a kit form.
In the present invention, it has been seen that an effective use is provided by formulating the pharmaceutical composition comprising the combination of the present invention in the same dosage 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. In another aspect, 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. According to present invention, the composition comprising the active agents telmisartan, amlodipine and indapamide can be prepared to be used by the oral route.
Pharmaceutical 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. According to the invention, 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. In another aspect, 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. At this point, 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.
According to the present invention, 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. By imposing sufficient compressive force, tablet forms are obtained such that the coating is the outermost layer of the tablet.
In another aspect, various 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.
Pharmaceutical compositions comprising the combinations of antihypertensive active agents are produced according to conventional techniques optionally with addition of pharmaceutically acceptable excipients.
According to the present invention, pharmaceutically acceptable excipients can also be used in addition to the active agents used in each oral formulation. These excipients can be components such as at least one binder, lubricant, disintegrant, demulsifying agent, stabilizing agent, flavoring agent, diluent, surfactant and glidant.
Pharmaceutically acceptable 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.
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.).
Pharmaceutically acceptable demulsifying 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).
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.
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, Ν,Ν'- 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.
Pharmaceutically acceptable surfactants 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.
Pharmaceutically acceptable 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.
In addition to these, other pharmaceutically acceptable excipients such as solubility modulators, sweeteners, coloring agents and coating agents can also be used in the formulation.
Examples of pharmaceutically acceptable formulations of the present invention are given below. These examples are given to exemplify the present invention, but the invention is not limited to these examples. EXAMPLES EXAMPLE 1:
The active agents 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.
EXAMPLE 2:
Preparation of the bilayer tablet composed of a fast release and a constant release layer comprises the following steps:
- Firstly, the constant release layer is prepared. In the constant release layer, there is only indapamide as the active agent. In the pharmaceutical composition, 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.
- There placed 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.
EXAMPLE 3:
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. In order to provide constant release characteristic to this layer, 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.
- The 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.

Claims

1. A pharmaceutical composition characterized by comprising the active agents telmisartan, amlodipine and indapamide.
2. The pharmaceutical composition according to claim 1 characterized in that the active agents telmisartan, amlodipine and indapamide can be in free form or in the form of pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, different polymorphic forms or amorphous forms of the respective active agents.
3. The pharmaceutical composition according to claim 1 characterized in that the active agent amlodipine is in the form of besylate, mesylate or maleate salt.
4. The pharmaceutical composition according to claim 3 characterized in that the active agent amlodipine is in the form of besylate salt.
5. The pharmaceutical composition according to claim 1 characterized in that said composition comprises pharmaceutically acceptable excipients in addition to the active agents telmisartan, amlodipine and indapamide.
6. The pharmaceutical composition according to claim 1 characterized in that said composition is used in the production of a drug so as to be used in the treatment of diseases such as hypertension, 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.
7. The pharmaceutical composition according to claim 1 characterized in that said composition is used simultaneously, sequentially or separately.
8. The pharmaceutical composition according to claim 1 characterized in that the active agents in said composition are formulated separately so as to be used in a kit form.
9. The pharmaceutical composition according to claim 1 characterized in that said composition is formulated in the same dosage form.
10. The pharmaceutical composition according to claim 1 characterized in that said composition is administered by the oral route.
11. The phannaceutical composition according to claim 1 characterized in that said composition is formulated 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 of 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.
12. The pharmaceutical composition according to claim 1 characterized in that the amount of the active agents varies in the range of 0,5% to 95%, preferably in the range of 1% to 90% in proportion to total substance amount in the pharmaceutical composition.
13. The pharmaceutical composition according to claim 1 characterized in that the amount of telmisartan is in the range of 10-300 mg, the amount of amlodipine is in the range of 2,5-25 mg, the amount of indapamide is in the range of 0,1-10 mg in one dose of the phannaceutical composition.
14. The pharmaceutical composition according to claim 1 characterized in that said composition is formulated in compressed bilayer tablet form.
15. The pharmaceutical composition according to claim 14 characterized in that said tablet is composed of a constant release layer and a fast release layer.
16. The phannaceutical composition according to claim 15 characterized in that the constant release layer comprises the active agent indapamide.
17. The pharmaceutical composition according to claim 15 characterized in that the fast release layer comprises the active agents telmisartan, amlodipine and indapamide.
18. The pharmaceutical composition according to claim 15 characterized in that the active agent indapamide is used together with polymers providing constant release such as 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.
19. The pharmaceutical composition according to claim 15 characterized in that the constant release layer is formulated to be the innermost layer while the fast release layer surrounds the constant release layer.
20. The pharmaceutical composition according to claim 1 characterized in that the active agent combination comprises at least one binder, lubricant, disintegrant, demulsifying agent, stabilizing agent, flavoring agent, diluent, surfactant and glidant as the excipients.
21. The pharmaceutical composition according to claim 20, wherein the binder used in said composition is selected from a 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 microcrystalline 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.
22. The pharmaceutical composition according to claim 20, wherein the lubricant used in said composition is selected from a 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.), silicates, starch derivatives.
23. The pharmaceutical composition according to claim 20, wherein the disintegrant used in said composition is selected from a 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).
24. The pharmaceutical composition according to claim 20, wherein the demulsifying agent used in said composition is selected from a group comprising colloidal clay (bentonite), metal hydroxides (magnesium hydroxide, aluminum hydroxide), anionic surfactant (sodium lauryl sulfate, calcium stearate), cationic surfactant or ionic surfactant (polyoxyethylene alkyl ether, fatty acid ester of polyoxyethylene sorbitan or sucrose esters of fatty acids).
25. The pharmaceutical composition according to claim 20, wherein the stabilizing agent used in said composition is selected from a group comprising agents such as antioxidants, chelating agents, alkalinizing agents and photoprotective agents.
26. The pharmaceutical composition according to claim 25, wherein the antioxidant used in said composition is selected from a 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, ethylenediaminetetraacetate.
27. The pharmaceutical composition according to claim 25, wherein the chelating agent used in said composition is selected from a group comprising disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or combinations thereof.
28. The pharmaceutical composition according to claim 25, wherein the alkalinizing agent used in said composition is selected from a group comprising 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, N,N'-dibenzylemylenediamine, diemanolamine, ethylenediamine, meglumine, monosodium glutamate, polacryline sodium, sodium alginate.
29. The pharmaceutical composition according to claim 25, wherein the photoprotective agents used in said composition are selected from a group comprising metal oxides such as titanium oxide, iron oxide or zinc oxide.
30. The pharmaceutical composition according to claim 20, wherein the flavoring agent used in said composition is selected from a group comprising sour cherry flavor, blackberry flavor, grapefruit flavor, grape flavor, pear flavor, orange flavor, apricot flavor or combinations thereof.
31. The pharmaceutical composition according to claim 20, wherein the diluent used in said composition is selected from a group comprising lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, magnesium aluminamethasilicate or combinations thereof.
32. The pharmaceutical composition according to claim 20, wherein the surfactant used in said composition is selected from a 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.
33. The pharmaceutical composition according to claim 20, wherein the glidant used in said composition is selected from a group comprising talc, silicone dioxide, magnesium trisilicate, cellulose powder, starch, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulfates.
EP11729785.3A 2010-05-28 2011-05-27 Combination of antihypertensive agents Withdrawn EP2575808A1 (en)

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