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WO1996031234A1 - Compositions de combinaison contenant benazeprile ou benazeprilat et valsartane - Google Patents

Compositions de combinaison contenant benazeprile ou benazeprilat et valsartane Download PDF

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Publication number
WO1996031234A1
WO1996031234A1 PCT/EP1996/001440 EP9601440W WO9631234A1 WO 1996031234 A1 WO1996031234 A1 WO 1996031234A1 EP 9601440 W EP9601440 W EP 9601440W WO 9631234 A1 WO9631234 A1 WO 9631234A1
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WO
WIPO (PCT)
Prior art keywords
active ingredient
composition according
ingredient component
valsartan
benazepril
Prior art date
Application number
PCT/EP1996/001440
Other languages
English (en)
Inventor
Marc De Gasparo
Randy Lee Webb
David Saul Cohen
Original Assignee
Novartis Ag
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 Novartis Ag filed Critical Novartis Ag
Priority to MX9707683A priority Critical patent/MX9707683A/es
Priority to JP8529972A priority patent/JPH11503139A/ja
Priority to SK1338-97A priority patent/SK133897A3/sk
Priority to BR9604818A priority patent/BR9604818A/pt
Priority to EP96910948A priority patent/EP0820302A1/fr
Priority to PL96322529A priority patent/PL322529A1/xx
Priority to AU53990/96A priority patent/AU5399096A/en
Publication of WO1996031234A1 publication Critical patent/WO1996031234A1/fr
Priority to NO974400A priority patent/NO974400D0/no

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • Angiotensinogen a ⁇ 2-macroglycoprotein
  • renin enzyme a ⁇ 2-macroglycoprotein
  • angiotensin I which itself is biologically only very weakly active.
  • the next step in the cascade is the removal of a further two amino acids by the action of the angiotensin-converting enzyme (ACE), bonded mainly in the endothelium, with formation of angiotensin II.
  • ACE angiotensin-converting enzyme
  • ACE-inhibitors The interruption of the enzymatic degradation of angiotensin I to angiotensin II with so-called ACE-inhibitors is a sucessful variant for the regulation of blood pressure and thus also makes available a therapeutic method for the treatment of congestive heart failure.
  • One known representative from among the conventional ACE-inhibitors is the active ingredient 3-[(1 -(ethoxycarbonyl)-3-phenyl-(1 S)-propyl)amino]-2,3,4,5-tetra- hydro-2-oxo-1 H-1-(3S)-benzazepine-1 -acetic acid [benazepril] of formula
  • angiotensin II The vasoconstrictive effects of angiotensin II are produced by its action on the non-striated muscle cells, the stimulation of the formation of the adrenergenic hormones epinephrine and norepinephrine as well as the increase of the activity of the sympathetic nervous system as a result of the formation of norepinephrine.
  • Angiotensin II also has an influence on the electrolytic balance, produces e.g. antinatriuretic and antidiuretic effects in the kidney and thereby promotes the release of, on the one hand, the vasopressin peptide from the pituitary gland and, on the other hand, of aldosterone from the adrenal giomerulosa. All these influences play an important part in the regulation of blood pressure.
  • Angiotensin II interacts with specific receptors on the surface of the target cell. It has been possible to identify receptor subtypes which are termed e.g. AT r and AT 2 -receptors. In recent times great efforts have been made to identify substances that bind to the AT « -receptor. Such active ingredients are often termed angiotensin II antagonists. Because of the inhibition of the AT ⁇ -receptor such antagonists can be used e.g. as anti hypertensives or for the treatment of congestive heart failure.
  • Angiotensin II antagonists are therefore understood to be those active ingredients which bind to the AT receptor subtype. These include compounds having different structural features.
  • the representative selected for the AT* -antagonists is the active ingredient (S)-N- (1 -carboxy-2-methyl-prop-1 -yl)-N-pentanoyl-N-[2'(1 H-tetrazol-5-yl)biphenyl-4-yl- methyljamine [valsaitan] of formula
  • compositions of benazepril and valsaitan are typically acid addition salts.
  • These acid addition salts are formed, for example, with strong inorganic acids, typically mineral acids, such as sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic acids, typically with C C 4 alkanecarboxylic acids which may be substituted, e.g.
  • halogen typically acetic acid, for example with dicarboxylic acids which may be unsaturated, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid, for example with hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid, for example with amino acids, such as aspartic acid or glutaminic acid, or e.g. benzoic acid, or with organic sulfonic acids, for example with C C 4 alkane acid or arylsulfonic acid which may be substituted, e.g.
  • dicarboxylic acids which may be unsaturated, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or terephthalic acid
  • hydroxycarboxylic acids such as ascorbic acid, glycolic acid, lactic acid, malic acid, tart
  • Suitable salts with bases are typically metal salts, such as alkali metal salts or alkaline earth metal salts, typically sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, pi- peridine, pyrrolidine, a mono-, di- or tri-lower alkylamine, typically ethylamine, tert- butylamine, diethylamine, diisopropylamine, triethylamine, tributylamine or dimethylpropylamine, or a mono-, di- or trihydroxy-lower alkylamine, typically mono-, di- or triethanolamine.
  • Corresponding internal salts can also be used.
  • PCT application WO 94/28924 discloses the combination of an ACE-inhibitor with an angiotensin-ll antagonist.
  • Clinical tests of the combination of enalapril (ACE- inhibitor) with losartan (AT* -antagonist) in the indicated doses did not result in any significant synergistic effect of lowered blood pressure at all compared with the lowered blood pressure achieved with enalapril, only an additive effect could be ascertained.
  • Synergistic effect will be understood to occur when the two active ingredients are administered together, be it, for example, together in one combined unit dose form or one after the other or separately in two separate unit dose forms, and when the combined effects of the combination are greater than the algebraic sum of the two individual effects, i.e. when a more than additive effect is achieved.
  • the synergistic effect can be shown experimentally, e.g. by telemetering, as follows:
  • SHR spontaneously hypertensive rats
  • SHRfBR Taconic Farms, Germantown, New York
  • a radiotelemetric device is implanted in the lower abdominal aorta of all test animals at least one month before the experiments.
  • the radio transmitter is fastened to the inner abdominal muscle with a silk seam.
  • the cardiovascular parameters are continuously transmitted via the radio transmitter, allowing data to be collected without disturbing the animals in their cages.
  • the animals are kept in their cages at controlled temperature and atmospheric humidity and at a 12-hourly alternation of light and darkness.
  • the body weights are measured at weekly intervals. Usually groups of five rats are formed.
  • One group of animals receives only valsaitan; another group receives only benazepril; a further group receives a combination of valsaitan and benazepril; the fourth group receives a combination of valsaitan and benazepril which is differently dosed; and a last group, receiving only the vehicle (0.15 N NaOH), is used as control group.
  • Minipumps are used for continuous subcutaneous drug delivery over a 14 day interval.
  • the mean arterial blood pressure and the heart beat are checked by means of a computerised data detection system (Data Sciences Inter., Inc.). The mean arterial blood pressure and the heart beat are measured every 10 minutes for 10 seconds and recorded. The values for each rat are reported as mean values over 24 hours and contain 144 data points per day.
  • the base line for the blood pressure is determined as the average from three consecutive days before the minipump is implanted.
  • the values during the administration of the active ingredients are 24 hour mean values. On the 14th day the minipumps are removed and observation of the effects is continued for 7 days after the administration of the active ingredients is discontinued.
  • Val+Bz valsartan + benazepril
  • a synergistic effect of a combination of valsartan and benazepril in congestive heart failure can be manifested, for example, in an animal model in which congestive heart failure can be induced by atrial pacing.
  • Chronic rapid heart pacing in the pig is a well- accepted model of congestive heart failure.
  • a dose of benazeprilate (0.15 mg/kg/day) or valsartan (2.4 mg/kg/day) is selected to block the Ang I and Ang II pressure response by 50 % without altering resting blood pressure.
  • Chronic rapid pacing and concomitant ACE inhibition reduce the LV and diastolic dimension, significantly improve LV pump function and reduce the levels of circulating catecholamines.
  • Ang II receptor blockade with valsartan improves cardiac output and decreases pulmonary and systemic vascular resistence.
  • combined benazeprilate and valsartan significantly provide further beneficial effects on LV geometry, function and neurohormonal activation including endothelin plasma levels Moreover, such a combination reduces LV wall stress and pulmonary and vascular resistance, important indices of myocardial oxygen consumption and LV afterload, to a greater degree than that of ACE inhibition alone.
  • myocytes ⁇ adrenergic and calcium response when compared to monotherapy with benazeprilate.
  • compositions for the treatment of hypertension, congestive heart failure and renal failure which composition comprises (1) the ACE-inhibitor benazepril or benazeprilat or a pharmaceutically acceptable salt thereof and (2) the AT antagonists valsartan or a pharmaceutically acceptable salt thereof.
  • components (1) and (2) can be present and administered together, one after the other or separately in one combined unit dose form or in two separate unit dose forms.
  • Said pharmaceutical compositions are those for enteral, such as oral, and also rectal or parenteral administration to warm-blooded animals, the pharmacological active ingredient being present on its own or together with the usual pharmaceutical excipients.
  • the pharmaceutical compositions contain, for example, from about 0.1 % to 100 %, preferably from about 1 % to about 80 %, of the active ingredient.
  • Pharmaceutical compositions for enteral or parenteral and also for ocular administration are typically those in unit dose forms, such as dragees, tablets, capsules or suppositories and also ampoules. These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilising methods.
  • compositions for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, to give tablets or dragee cores.
  • Suitable carriers are preferably fillers, typically sugars, such as lactose, saccha ⁇ rose, mannitol or sorbitol, cellulose compositions and/or calcium phosphates, e.g. tricalcium phosphate or calciumhydrogen phosphate, furthermore binders, such as starch paste, typically using e.g.
  • Excipients are primarily flow regulators and lubricants, typically silica gel, talcum, stearic acid or salts thereof, typically magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juice, using, inter alia, concentrated sugar solutions which optionally contain gum arabic, talcum, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose compositions, typically acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate. Colourants or pigments may be added to the tablets or dragee coatings, for example to identify or indicate different doses of active ingredient.
  • compositions for oral administration are dry-filled gelatin capsules as well as soft closed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol.
  • the dry-filled capsules may contain the active ingredient in the form of granules, typically in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talcum or magnesium stearate.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilisers can also be added.
  • Suitable pharmaceutical compositions for rectal administration are typically suppositories consisting of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons and higher alkanols.
  • gelatin rectal capsules containing a combination of the active ingredient with a base substance may also be used.
  • Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • compositions for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, typically a water-soluble salt, and also suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, typically fatty oils, e.g. sesame oil, or synthetic fatty acid esters, typically ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and, optionally, also stabilisers.
  • suitable lipophilic solvents or vehicles typically fatty oils, e.g. sesame oil, or synthetic fatty acid esters, typically ethyl oleate or triglycerides
  • viscosity-increasing substances e.g. sodium carboxymethylcellulose, sorbitol and/or dextran and, optionally, also stabilisers.
  • unit dose forms that can be used for oral administration, typically tablets or capsules.
  • the dose of the active ingredient can depend on various factors, e.g. mode of application, species of warm-blooded animal, age and/or individual state.
  • the estimated normal dose for oral administration to a patient weighing about 75 kg is an approximate dose of the active ingredient component (1) [benazepril or a pharmaceutically acceptable salt therof] of about 5 mg to about 40 mg and of the active ingredient component (2) [valsartan or a pharmaceutically acceptable salt thereof] of about 20 mg to about 160 mg, preferably once or twice a day.
  • the weight ratio of the active ingredient component (1) to the active ingredient component (2) can be, for example, about 1 to 8 and also 1 to 4 or 1 to 2.
  • the novel combination compositions can comprise as active ingredient component (1) preferably about 10 mg to about 40 mg, more preferably 10 mg to about 20 mg and, most preferably, 10 mg.
  • novel combination compositions can comprise as active ingredient component (2) preferably about 20 mg to about 80 mg, more preferably about 40 mg to about 80 and, most preferably, about 40 mg or 80 mg.
  • compositions consisting of benazepril monohydrochloride and valsartan in a unit dose form.
  • the amount of ACE-inhibitor therein is preferably 10 mg and the amount of AT* -antagonist is preferably 40 mg or 80 mg.
  • the active ingredient components (1) and (2) can be obtained together, one after the other or separately in one combined unit dose form or in two separate unit dose forms. They are preferably obtained together in one combined unit dose form.
  • the novel pharmaceutical combination can be used for a method for the treatment of hypertension and congestive heart failure.
  • the method for the treatment of hypertension, congestive heart failure and renal failure comprises administering to a patient in need of such treatment a corresponding pharmaceutical combination composition according to this invention, comprising (1) the ACE-inhibitor benazepril or benazeprilat or a pharmaceutically acceptable salt thereof and (2) the AT* -antagonists valsartan or a pharmaceutically acceptable salt thereof.
  • This invention also relates to the preparation of the novel pharmaceutical combination compositions.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Cardiology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention se rapporte à des compositions de combinaison pharmaceutique pour le traitement de l'hypertension, l'insuffisante cardiaque globale et l'insuffisance rénale, comportant (1) le bénazéprile inhibiteur de ACE de formule (I) ou le bénazéprilat de formule (II) ou un de leurs sels pharmaceutiquement acceptables, et la valsartane antagoniste AT1 de formule (III) ou un de leurs sels pharmaceutiquement acceptables, ainsi que les méthodes de traitement de l'hypertension, de l'insuffisance cardiaque globale et de l'insuffisance rénale.
PCT/EP1996/001440 1995-04-07 1996-04-02 Compositions de combinaison contenant benazeprile ou benazeprilat et valsartane WO1996031234A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
MX9707683A MX9707683A (es) 1995-04-07 1996-04-02 Composiciones de combinacion que contienen benazepril o benazeprilat y valsartan.
JP8529972A JPH11503139A (ja) 1995-04-07 1996-04-02 ベナゼプリルまたはベナゼプリラートおよびバルサルタンを含有する組み合わせ組成物
SK1338-97A SK133897A3 (en) 1995-04-07 1996-04-02 Combination compositions containing benazepril or benazeprilat and valsartan
BR9604818A BR9604818A (pt) 1995-04-07 1996-04-02 Composições de combinação contendo benazepril ou benazeprilat e valsartan
EP96910948A EP0820302A1 (fr) 1995-04-07 1996-04-02 Compositions de combinaison contenant benazeprile ou benazeprilat et valsartane
PL96322529A PL322529A1 (en) 1995-04-07 1996-04-02 Complex compositions containing benazeoprile or benazeprilate and valsartan
AU53990/96A AU5399096A (en) 1995-04-07 1996-04-02 Combination compositions containing benazepril or benazeprilat and valsartan
NO974400A NO974400D0 (no) 1995-04-07 1997-09-23 Kombinasjonspreparater inneholdende benazepril eller benazeprilat og valsartan

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH101295 1995-04-07
CH1012/95 1995-04-07

Publications (1)

Publication Number Publication Date
WO1996031234A1 true WO1996031234A1 (fr) 1996-10-10

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PCT/EP1996/001440 WO1996031234A1 (fr) 1995-04-07 1996-04-02 Compositions de combinaison contenant benazeprile ou benazeprilat et valsartane

Country Status (15)

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EP (1) EP0820302A1 (fr)
JP (1) JPH11503139A (fr)
KR (1) KR19980703647A (fr)
CN (1) CN1181019A (fr)
AU (1) AU5399096A (fr)
BR (1) BR9604818A (fr)
CA (1) CA2214143A1 (fr)
CZ (1) CZ313897A3 (fr)
HU (1) HUP9801593A2 (fr)
MX (1) MX9707683A (fr)
NO (1) NO974400D0 (fr)
PL (1) PL322529A1 (fr)
SK (1) SK133897A3 (fr)
TR (1) TR199701121T1 (fr)
WO (1) WO1996031234A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0835106A1 (fr) * 1995-06-30 1998-04-15 Merck & Co. Inc. Procede de traitement de nephropathies a l'aide d'un inhibiteur de l'ace et d'un antagoniste de l'a ii
WO2002015891A2 (fr) * 2000-08-22 2002-02-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Combinaison pharmaceutique d'antagonistes de l'angiotensine ii et d'inhibiteurs de l'enzyme de conversion de l'angiotensine i
WO2001076573A3 (fr) * 2000-04-12 2003-04-17 Novartis Ag Combinaison de composés organiques
EP1578360A2 (fr) * 2002-08-28 2005-09-28 Curis, Inc. Administration conjointe de morphogenes et d'inhibiteurs de conversion de l'enzyme de l'angiotensine pour le traitement de l'insuffisance renale chronique
EP1671632A1 (fr) * 2000-08-22 2006-06-21 Boehringer Ingelheim Pharma GmbH & Co. KG Combinaison pharmaceutique d'antagonistes de l'angiotensine II et d'inhibiteurs de ACE
US7560446B2 (en) 1999-01-26 2009-07-14 Novartis Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
US8058301B2 (en) * 2002-02-04 2011-11-15 Novartis Ag Salt hydrates
EP2420232A3 (fr) * 2006-10-06 2012-05-02 Boehringer Ingelheim Vetmedica GmbH Antagonistes du récepteur II d'angiotensine pour la prévention ou le traitement des maladies cardiovasculaires chez les chats
US8278339B2 (en) 2000-07-19 2012-10-02 Novartis Ag Valsartan salts
US8871795B2 (en) 2009-05-20 2014-10-28 Boehringer Ingleheim Vetmedica Gmbh Pharmaceutical oral telmisartan solution
WO2015116880A1 (fr) * 2014-01-31 2015-08-06 Janssen Pharmaceutica Nv Procédés de traitement et de prévention de troubles rénaux et de troubles graisseux du foie
US11576894B2 (en) 2009-07-08 2023-02-14 Janssen Pharmaceutica Nv Combination therapy for the treatment of diabetes

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL362252A1 (en) * 2000-12-18 2004-10-18 Novartis Ag Therapeutic combination of amlodipine and benazepril
CN1465712A (zh) * 2002-07-05 2004-01-07 安徽省生物医学研究所 一种预测acei类降压药药效的试剂盒、方法、软件和复方药
CN101869710A (zh) * 2009-04-24 2010-10-27 北京奥萨医药研究中心有限公司 降压药物组合物

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1991017771A1 (fr) * 1990-05-11 1991-11-28 Pfizer Inc. Compositions et procedes therapeutiques synergiques
EP0629408A1 (fr) * 1993-06-16 1994-12-21 LABORATOIRES MERCK, SHARP & DOHME-CHIBRET Combination d'inhibiteurs ACE et d'antagonistes AII

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991017771A1 (fr) * 1990-05-11 1991-11-28 Pfizer Inc. Compositions et procedes therapeutiques synergiques
EP0629408A1 (fr) * 1993-06-16 1994-12-21 LABORATOIRES MERCK, SHARP & DOHME-CHIBRET Combination d'inhibiteurs ACE et d'antagonistes AII

Non-Patent Citations (1)

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Title
BAZIL MK ET AL: "Hemodynamic effects of amlodipine and benazeprilat in spontaneously hypertensive rats.", J CARDIOVASC PHARMACOL, MAR 1993, 21 (3) P405-11, UNITED STATES, XP000578242 *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0835106A4 (fr) * 1995-06-30 1998-09-30 Merck & Co Inc Procede de traitement de nephropathies a l'aide d'un inhibiteur de l'ace et d'un antagoniste de l'a ii
EP0835106A1 (fr) * 1995-06-30 1998-04-15 Merck & Co. Inc. Procede de traitement de nephropathies a l'aide d'un inhibiteur de l'ace et d'un antagoniste de l'a ii
US7560446B2 (en) 1999-01-26 2009-07-14 Novartis Ag Use of angiotensin II receptor antagonists for treating acute myocardial infarction
WO2001076573A3 (fr) * 2000-04-12 2003-04-17 Novartis Ag Combinaison de composés organiques
US9499499B2 (en) 2000-07-19 2016-11-22 Novartis Ag Valsartan salts
US20140073677A1 (en) * 2000-07-19 2014-03-13 Erwin Marti Valsartan salts
US8278339B2 (en) 2000-07-19 2012-10-02 Novartis Ag Valsartan salts
EP1671632A1 (fr) * 2000-08-22 2006-06-21 Boehringer Ingelheim Pharma GmbH & Co. KG Combinaison pharmaceutique d'antagonistes de l'angiotensine II et d'inhibiteurs de ACE
WO2002015891A2 (fr) * 2000-08-22 2002-02-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Combinaison pharmaceutique d'antagonistes de l'angiotensine ii et d'inhibiteurs de l'enzyme de conversion de l'angiotensine i
SG148838A1 (en) * 2000-08-22 2009-01-29 Boehringer Ingelheim Pharma Pharmaceutical combination of angiotensin ii antagonists and ace inhibitors
WO2002015891A3 (fr) * 2000-08-22 2002-06-13 Boehringer Ingelheim Pharma Combinaison pharmaceutique d'antagonistes de l'angiotensine ii et d'inhibiteurs de l'enzyme de conversion de l'angiotensine i
US8058301B2 (en) * 2002-02-04 2011-11-15 Novartis Ag Salt hydrates
US8329919B2 (en) 2002-02-04 2012-12-11 Novartis Ag Salt hydrates
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JPH11503139A (ja) 1999-03-23
SK133897A3 (en) 1998-02-04
AU5399096A (en) 1996-10-23
CN1181019A (zh) 1998-05-06
CA2214143A1 (fr) 1996-10-10
NO974400L (no) 1997-09-23
BR9604818A (pt) 1998-06-09
EP0820302A1 (fr) 1998-01-28
KR19980703647A (ko) 1998-12-05
HUP9801593A2 (hu) 1999-01-28
TR199701121T1 (xx) 1998-03-21
MX9707683A (es) 1997-12-31
PL322529A1 (en) 1998-02-02
CZ313897A3 (cs) 1998-01-14
NO974400D0 (no) 1997-09-23

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