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WO2010053233A1 - Nouveau sel de zinc de telmisartan et procédé de préparation associé - Google Patents

Nouveau sel de zinc de telmisartan et procédé de préparation associé Download PDF

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Publication number
WO2010053233A1
WO2010053233A1 PCT/KR2009/001139 KR2009001139W WO2010053233A1 WO 2010053233 A1 WO2010053233 A1 WO 2010053233A1 KR 2009001139 W KR2009001139 W KR 2009001139W WO 2010053233 A1 WO2010053233 A1 WO 2010053233A1
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Prior art keywords
telmisartan
zinc
zinc salt
salt
diseases
Prior art date
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Ceased
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PCT/KR2009/001139
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English (en)
Inventor
Hong Woo Lee
Lyn Hean Kang
Choong Leol Yoo
Sung Kwon Kang
Seung Uk Lee
Ho Hyung Ryu
Dong Jin Kim
Min Hyo Ki
Mi Hwa Choi
Yoon Ho Kim
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Chong Kun Dang Corp
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Chong Kun Dang Corp
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Filing date
Publication date
Application filed by Chong Kun Dang Corp filed Critical Chong Kun Dang Corp
Publication of WO2010053233A1 publication Critical patent/WO2010053233A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/06—Zinc compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/20—Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical

Definitions

  • the present invention relates to a telmisartan zinc salt with improved physicochemical properties of the free acid of telmisartan which is an angiotensin II antagonist that is useful for the treatment of hypertensive diseases, and a method for preparing the same.
  • telmisartan The compound 2-[4-[[4-methyl-6-(1-methylbenzoimidazol-2-yl)-2-propylbenzoimidazol-1-yl]methyl]phenyl]benzoic acid (hereinafter, referred to as "telmisartan”) is known from European Patent EP 502 314 B1 and has the following chemical structure:
  • Telmisartan is known to be an angiotensin antagonist, particularly an angiotensin II antagonist which, by virtue of its pharmacological properties, may be used, for example, to treat hypertension and cardiac insufficiency, to treat ischemic peripheral circulatory disorders and myocardial ischaemia, to prevent the progression of cardiac insufficiency after myocardial infarction, and to treat diabetic neuropathy, glaucoma, and the like.
  • Telmisartan was discovered and developed by Boehringer Ingelheim. Under the trademarks MICARDIS R and MICARDISPLUS R (combination with hydrochlorothiazide) the company markets telmisartan in 84 countries around the world, including the USA, Japan and European countries. Telmisartan is a member of the angiotensin II receptor blocker (ARB) class and is being investigated in the most ambitious and far-reaching research programme conducted with an ARB. In the clinical trial programmes ONTARGET, PROTECTION and PROFESS, over 58,000 patients have been enrolled to investigate the cardiovascular protective effects of MICARDIS R .
  • ARB angiotensin II receptor blocker
  • telmisartan The free acid of telmisartan has a very limited solubility. For this reason, in the industrial production of telmisartan, commercially available free acid formulations of telmisartan are prepared by direct contact of telmisartan with a strong alkalizer such as sodium hydroxide. Such a production process is potentially dangerous to human health. In addition, quality reproducibility of the final formulation may vary depending on a period of reaction time. Physicochemical properties of telmisartan in the solid free acid form may also pose difficulties of direct application thereof to the human body, so many researches have been actively conducted to overcome the limited applicability of telmisartan.
  • telmisartan In order to overcome these disadvantages of telmisartan, for example, International Publication Nos. WO 2003/037876 and WO 2006/044754 disclose acid or base addition salts of telmisartan, and telmisartan preparations containing alkali metal excipients.
  • European Patent EP 1 144 386 B1 disclose sodium salts of telmisartan which are intended to overcome the disadvantages of the free acid of telmisartan.
  • telmisartan sodium salt of telmisartan may be an approximate solution to the problems associated with poor physicochemical properties of the free acid of telmisartan such as limited solubility and the like.
  • telmisartan sodium salt as an antihypertensive drug inevitably involves problems in terms of safety.
  • telmisartan magnesium and calcium salts suffer from disadvantages associated with poor properties of pharmaceutically important factors, e.g. high hygroscopicity and low thermal stability, as compared to the free acid form of telmisartan.
  • telmisartan which is of high purity and high quality thus making it suitable for application to a pharmaceutical composition, in conjunction with improvements of formulation-related factors of tablet preparations such as solubility, solid rheology and electrostaticity, including high hygroscopicity and low stability which are disadvantages of telmisartan in the free acid form.
  • Zinc is a metallic chemical element with the symbol Zn, atomic number 30 and atomic weight 65.39. Zinc was recognized as useful mineral since the 1950's. With the revelation that "dwarfism” and “hypogonadism” are due to zinc deficiency, a great deal of interest has been focused on the importance of zinc in human health. In the United States, the recommended intake for zinc was established in the 1970's. In Korea, the recommended dietary allowance (RDA) for zinc was first presented in 1995. Zinc is the ubiquitous mineral which is found in all animal tissues and is involved in epithelial healing or prostate function. In addition, it is known that zinc is essential for dermal or skeletal growth and maintenance and for the synthesis of nucleic acids and proteins.
  • zinc sulfate preparations As examples of pharmaceutical products utilizing these pharmacological actions of zinc, commercially available zinc sulfate preparations may be mentioned.
  • KDRIs Dietary Reference Intakes for Koreans (KDRIs) published by The Korean Nutrition Society in 2005
  • the recommended daily intake of zinc is in the range of 8 to 10 mg for adult males, 7 to 8 mg for adult females, 10 to 11 mg for pregnant women, and 13 mg for lactating women, respectively.
  • the tolerable upper intake level of zinc is 35 mg for both adult males and females. Due to the above-mentioned validated safety of zinc, zinc gluconate, zinc oxide, and the like are used as food additives, whereas zinc stearate and the like are used as pharmaceutical excipients.
  • telmisartan As a result of a variety of extensive and intensive studies and experiments to solve the problems suffered by conventional free acids of telmisartan as discussed before, the inventors of the present invention have developed zinc salts of telmisartan which are pharmaceutically very excellent and are also superior in terms ofsafety.
  • the present invention has been made in view of the above problems, and it is an object of the present invention to provide a novel zinc salt of telmisartan which exhibits excellent pharmaceutical properties and high safety, by improving disadvantages of the free acid of telmisartan that is an angiotensin II antagonist.
  • telmisartan 2-[4-[[4-methyl-6-(1-methylbenzoimidazol-2-yl)-2-propylbenzoimidazol-1-yl]methyl]phenyl]benzoic acid (telmisartan), which is pharmaceutically acceptable and is very useful as a pharmaceutical composition for the prevention or treatment of hypertensive diseases and/or cardiovascular diseases due to improved physicochemical properties of a drug compound and which is represented by Formula 1 below:
  • the telmisartan zinc salt of the present invention is provided in the form of an ionically-bonded salt produced by the combination of two telmisartan molecules into a divalent zinc ion.
  • the telmisartan zinc salt in accordance with the present invention may be prepared directly from telmisartan of Formula 1 per se , or otherwise may be obtained from the conversion of the ready-made telmisartan salt into a desired form.
  • a method for preparing a zinc salt of telmisartan including reacting telmisartan with a zinc compound in the presence of an organic solvent.
  • the preparation of the telmisartan zinc salt includes a) dissolving or suspending the free acid of telmisartan in an organic solvent at a given temperature higher than room temperature; b) dissolving the zinc compound in the organic solvent or adding the zinc compound in the solid form to the solution or suspension of Step a) to obtain a reaction mixture; and c) solidifying the mixture of Step b) under various temperature and solvent conditions, followed by filtration, washing and drying of the resulting solid to prepare a desired zinc salt of telmisartan.
  • Preferred examples of the zinc compound that can be used in the preparation method of the present invention may include zinc hydroxide, zinc acetate, zinc chloride, zinc bromide, zinc iodide, and the like. Although various equivalents of the zinc compound may be used relative to one mole of the telmisartan free acid, an amount of the zinc compound is preferably 0.5 mol or higher.
  • the reaction temperature is in the range of 25°C to 100°C.
  • the salt deposition temperature is preferably in the range of -10°C to 100°C.
  • Preferred examples of the organic solvent that can be used in the preparation method of the present invention may include lower alcohols such as methanol, ethanol, isopropanol and butanol; ethers such as 1,4-dioxane, tetrahydrofuran, diethylether and isopropylether; amides such as dimethylformamide and diethylacetamide ketones such as acetone and methylethylketone; esters such as isopropylacetate; halogenated hydrocarbons such as chloroform and dichloromethane; lower hydrocarbons such as hexane, heptane and octane; dimethylsulfoxide and water. These solvent compounds may be used alone or in any combination thereof.
  • the telmisartan zinc salt of the present invention exhibits significantly improved physicochemical properties of specific volume and electrostaticity of solids in conjunction with high solubility, good stability and non-hygroscopicity, as compared to known telmisartan. Therefore, pharmaceutical compositions containing the telmisartan zinc salt of the present invention can be effectively used for the treatment and prevention ofhypertension-related diseases.
  • telmisartan zinc salt of the present invention even if the patient of interest takes the telmisartan zinc salt of the present invention at a maximum daily dose (80 mg in terms of telmisartan), an amount of the zinc salt to be absorbed into the body is only 5 mg which is below the recommended daily intake of zinc. Further, upon considering the recent report demonstrating that hypertension may be caused due to zinc deficiency (Pediatr. Res. 58(4), 672, 2005), it can be said that the telmisartan zinc salt is therapeutically or prophylactically beneficial for hypertension.
  • the present invention provides a pharmaceutical composition for treatment or prevention of hypertensive diseases and/or cardiovascular diseases, containing a telmisartan zinc salt as an active ingredient and one or more pharmaceutically acceptable carriers.
  • a dose of the telmisartan zinc salt in the composition of the present invention is very variable.
  • an effective daily dose of the telmisartan zinc salt is in the range of about 10 to 100 mg, preferably 20 to 90 mg.
  • the dosage and number of dosages can be easily determined by the attending physician, depending on characteristics of formulations, weight and condition of the subject, administration routes, etc.
  • the term "pharmaceutically acceptable carrier” encompasses any of the standard pharmaceutically accepted carriers which are used in known pharmaceutical formulations such as sterile solutions, tablets, coated tablets and capsules. Typically such carriers contain excipients such as starch, milk, sugar, certain types of clay, gelatin, stearic acid, talc, vegetable fats or oils, gums, glycols, or other known excipients. Such carriers may also include flavor and color additives or other ingredients. Compositions containing such carriers may be formulated by well known conventional methods.
  • Administration of the pharmaceutical composition in accordance with the present invention is by any route including oral, rectal, injection. Most preferred are oral compositions such as tablets, capsules, granules, etc.
  • telmisartan zinc salt for the preparation of a pharmaceutical composition for the treatment or prevention of hypertensive diseases and/or cardiovascular diseases.
  • a method for preventing or treating of hypertensive diseases and/or cardiovascular diseases in comprising administering a therapeutically effective amount of a telmisartan zinc salt to mammal including a human in need of treatment or prevention of hypertensive diseases and/or cardiovascular diseases.
  • the present invention enables high-purity production of a telmisartan zinc salt with no introduction of an additional purification process.
  • the thus-produced telmisartan zinc salt exhibits excellent pharmaceutical properties associated with the solubility, stability and non-hygroscopicity, as well as improvements in physicochemical properties such as specific volume and electrostaticity of solids, which are required for practical commercializationof drug compounds. Therefore, the telmisartan zinc salt of the present invention in combination with a pharmaceutically acceptable carrier can be usefully employed as an active ingredient of antihypertensive drugs or cardio and vascular protective-pharmaceutical compositions.
  • 1 H NMR data given in the following Examples are the values measured using a Bruker UltraShield TM 400 (400 MHz) spectrometer. Unless otherwise specified, all reagents and solvents were purchased from Aldrich and Acros.
  • HPLC conditions used for the measurement of the purity and content of telmisartan zinc saltsin the present invention were the same as those of the telmisartan analysis in the European Pharmacopoeia 6.2.
  • telmisartan and 600 mL of acetone were refluxed at 53°C to prepare a suspension to which 4.4 g of zinc chloride was then added, followed by stirring at that temperature for 2 hours.
  • the reaction mixture was concentrated to 300 mL at 40°C and 50 mbar under reduced pressure, followed by stirring at room temperature for 2 hours to precipitate a white solid.
  • the resulting solid was washed with cold acetone, filtered, and dried under vacuum to obtain a telmisartan zinc salt.
  • telmisartan zinc salt 150 mL of dimethylsulfoxide was added to 30 g of telmisartan, and the mixture was heated with stirring to 50°C until a clear solution was obtained. To the resulting solution was added 4.4 g of zinc chloride, followed by stirring at that temperature for about one hour. The reaction mixture was cooled to room temperature and 600 mL of acetone was added thereto, followed by stirring to precipitate a white solid. The resultingsolid was washed with cold acetone, filtered and dried under vacuum to obtain a telmisartan zinc salt.
  • telmisartan and 600 mL of tetrahydrofuran were refluxed at 65°C to prepare a suspension to which 4.4 g of zinc chloride was then added, followed by stirring at that temperature for 2 hours.
  • the reaction mixture was concentrated to 300 mL at 40°C and 50 mbar under reduced pressure, followed by stirring at room temperature for 2 hours to precipitate a white solid.
  • the resulting solid was washed with cold tetrahydrofuran, filtered, and dried under vacuum to obtain a telmisartan zinc salt.
  • telmisartan and mL of dimethylsulfoxide were mixed and heated with stirring to 50°C until a clear solution was obtained.
  • 4.4 g of zinc chloride was added to the resulting solution, followed by stirring at that temperature for about one hour.
  • the reaction mixture was cooled to room temperature and 300 mL of tetrahydrofuran was added thereto, followed by stirring at 5°C for 2 hours to precipitate a white solid.
  • the resultingsolid was washed with cold tetrahydrofuran, filtered and dried under vacuum to obtain a telmisartan zinc salt.
  • telmisartan sodium salt 30 g was dissolved in 600 mL of ethanol and 2.4 g of sodium hydroxide was added thereto, followed by stirring at room temperature for about 1 hour. Ethanol which was used as a solvent of the reaction mixture was removed by distillationunder reduced pressure. 100 mL of ethanol was added to the resulting solid and the mixture was dissolved under reflux. 500 mL of methyl t-butyl ether was added to the reaction mixture over one hour, and the mixture was cooled to room temperature to precipitate a white solid. The resulting solid was filtered and dried under vacuum to obtain a telmisartan sodium salt.
  • telmisartan magnesium salt 30 g was suspended with stirring in 1500 mL of methanol. 2.4 g of magnesium methoxide was added to the resulting suspension which was then refluxed at a temperature of 60 to 65°C for about 12 hours. The reaction mixture was filtered and methanol was removed by distillation under reduced pressure. The residue was dried under vacuum to obtain a telmisartan magnesium salt.
  • telmisartan calcium salt 30 g was suspended with stirring in 1500 mL of methanol. To the resulting suspension was added 2.4 g of calcium hydroxide, followed by reflux at 60 to 65°C for about 12 hours. The reaction mixture was filtered and methanol was removed by distillationunder reduced pressure. The residue was dried under vacuum to obtain a telmisartan calcium salt.
  • test samples were prepared according to the procedure described in Examples 1 to 4 and Comparative Examples 1 to 3. Purity of the samples was measured by HPLC. The results obtained are given in Table 1 below.
  • the commercially available telmisartan free acid was almost precipitated leaving only about 5% of the original mass, whereas Examples 1 and 3 exhibited significantly improved properties in precipitability, as compared to the free acid form of telmisartan. Therefore, the telmisartan zinc salts of the present invention have superior solubility in aqueous solutions, and very low probability of deposition and consequent precipitation (low precipitability) in an aqueous solution state, which are advantageous for the absorption of drugs.
  • hygroscopicity is a very important factor for practical processing and storage of pharmaceutical products, among various properties required for drug compounds to be used as pharmaceutical raw materials.
  • a telmisartan free acid and individual samples of Examples 1 and 2, and Comparative Examples 1 to 3 were dried under vacuum (P 2 O 5 , for one day or more), and initial water contents of the samples were measured using a Karl Fisher method. Thereafter, amounts of sorbed water were automatically measured at 25°C and relative humidity (RH) of 15, 35, 55, 75 and 95%, respectively, using a hygroscopicity measurement apparatus (Model No. Hydrosorb 1000, manufactured by Quantachrome Instruments). The results obtained are given in Table 3 below.
  • the initial water content was defined as a water content of the test sample which will exhibit no further decrease in weight, after the drying wascontinuously and thoroughly conducted.
  • telmisartan should be managed to have a water content of less than 1% according to the national standards for drug substances published by the Food and Drug Administration (FDA) and telmisartan having the above-specified water content of more than 1% should not be used for pharmaceutical applications
  • the samples of Comparative Examples 1 to 3 were found to have excessively high hygroscopicity which is not acceptable for drug formulations.
  • the telmisartan zinc salts of the present invention have excellent non-hygroscopic properties thus making it not absorb moisture, even when they were exposed to ambient humidity conditions.
  • the samples of Examples 1 and 3 exhibited decreased static electricity (low electrostaticity), as compared to the telmisartan free acid and the samples of Comparative Examples 1 to 3, thus confirming that the compounds of the present invention have excellent processability taking into consideration instrument rubbing that may take place during the preparation of pharmaceutical formulations.
  • telmisartan salts of the present invention have a low specific volume
  • the telmisartan free acid and the samples of Examples 1 and 3, and Comparative Examples 1 to 3 were placed in graduated cylinders. From a vertical height of 10 cm, free fall of the cylinders was repeated 20 times or more such that tapping of the samples was carried out to achieve sufficient compacting of the contents.
  • the specific volume values of test samples were measured before and after tapping. The results obtained are given in Table 6 below.
  • the samples of Examples 1 and 3 When compared with the telmisartan free acid and the samples of Comparative Examples 1 to 3, the samples of Examples 1 and 3 exhibited a noticeable reduction of the specific volume. Powdered drug substances usually have high specific volumes and are therefore designed into suitable dosage forms (tablets or capsules) always after compression molding thereof. Therefore, when the specific volume is large, the pharmaceutical processability of the drug substance becomes very poor.
  • the telmisartan zinc salts of the present invention have excellent physicochemical properties in terms of pharmaceutical processability.
  • the present invention enables high-purity production of a telmisartan zinc salt with no introduction of an additional purification process.
  • the thus-produced telmisartan zinc salt exhibits excellent pharmaceutical properties associated with the solubility, stability and non-hygroscopicity, as well as improvements in physicochemical properties such as specific volume and electrostaticity of solids,which are required for practical commercialization of drug compounds. Therefore, the telmisartan zinc salt of the present invention in combination with a pharmaceutically acceptable carrier can be usefully employed as an active ingredient of antihypertensive drugs or cardio and vascular protective-pharmaceutical compositions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

La présente invention concerne un nouveau sel de zinc d’acide 2-[4-[[4-méthyl-6-(1-méthylbenzoimidazol-2-yl)-2-propylbenzoimidazol-1-yl]méthyl]phényl]benzoïque (telmisartan) et son procédé de préparation. Le sel de zinc de telmisartan de l’invention présente d’excellentes propriétés physicochimiques par comparaison avec le telmisartan et ses sels d’addition d’acides classiques, ainsi qu’une sécurité suffisante en tant que nouveau composé de sel. Par conséquent, le sel de zinc de telmisartan de la présente invention est utile comme composé ayant une activité antagoniste de l’angiotensine II.
PCT/KR2009/001139 2008-11-10 2009-03-06 Nouveau sel de zinc de telmisartan et procédé de préparation associé Ceased WO2010053233A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20080110743 2008-11-10
KR10-2008-0110743 2008-11-10
KR1020080135292A KR100893652B1 (ko) 2008-11-10 2008-12-29 신규한 텔미사르탄 아연염 및 그의 제조방법
KR10-2008-0135292 2008-12-29

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WO2010053233A1 true WO2010053233A1 (fr) 2010-05-14

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050004107A1 (en) * 2003-04-30 2005-01-06 Boehringer Ingelheim International Gmbh Telmisartan sodium salt pharmaceutical formulation
WO2005108375A1 (fr) * 2004-05-11 2005-11-17 Cipla Limited Preparation de telmisartan
KR20050120714A (ko) * 2003-04-15 2005-12-22 상꾜 가부시키가이샤 안구 내 혈관 신생성 질환의 예방 또는 치료를 위한 의약
WO2006050921A2 (fr) * 2004-11-11 2006-05-18 Lek Pharmaceuticals D.D. Preparation de sels de telmisartan avec une solubilite amelioree
WO2007001066A1 (fr) * 2005-06-27 2007-01-04 Daiichi Sankyo Company, Limited Préparation pharmaceutique contenant un antagoniste du récepteur de l'angiotensine ii et un bloqueur du canal calcique

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6737432B2 (en) 2001-10-31 2004-05-18 Boehringer Ingelheim Pharma Kg Crystalline form of telmisartan sodium
DE10301371A1 (de) 2003-01-16 2004-08-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmazeutische Kombination zur Prophylaxe oder Therapie von kardiovaskulären, kardiopulmonalen, pulmonalen oder renalen Krankheiten

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050120714A (ko) * 2003-04-15 2005-12-22 상꾜 가부시키가이샤 안구 내 혈관 신생성 질환의 예방 또는 치료를 위한 의약
US20050004107A1 (en) * 2003-04-30 2005-01-06 Boehringer Ingelheim International Gmbh Telmisartan sodium salt pharmaceutical formulation
WO2005108375A1 (fr) * 2004-05-11 2005-11-17 Cipla Limited Preparation de telmisartan
WO2006050921A2 (fr) * 2004-11-11 2006-05-18 Lek Pharmaceuticals D.D. Preparation de sels de telmisartan avec une solubilite amelioree
WO2007001066A1 (fr) * 2005-06-27 2007-01-04 Daiichi Sankyo Company, Limited Préparation pharmaceutique contenant un antagoniste du récepteur de l'angiotensine ii et un bloqueur du canal calcique

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