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WO2006034631A1 - Composition comprenant de l’amlodipine et un antagoniste des recepteurs de l’angiotensine ii - Google Patents

Composition comprenant de l’amlodipine et un antagoniste des recepteurs de l’angiotensine ii Download PDF

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Publication number
WO2006034631A1
WO2006034631A1 PCT/CN2005/001544 CN2005001544W WO2006034631A1 WO 2006034631 A1 WO2006034631 A1 WO 2006034631A1 CN 2005001544 W CN2005001544 W CN 2005001544W WO 2006034631 A1 WO2006034631 A1 WO 2006034631A1
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Prior art keywords
amlodipine
angiotensin
composition
pharmaceutically acceptable
irbesartan
Prior art date
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Ceased
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PCT/CN2005/001544
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English (en)
Chinese (zh)
Inventor
Kaihong Yuan
Yunshu Zhou
Piaoyang Sun
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Jiangsu Hengrui Medicine Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
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Publication of WO2006034631A1 publication Critical patent/WO2006034631A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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

  • composition comprising amlodipine and an angiotensin II receptor inhibitor
  • the present invention relates to a pharmaceutical combination of amlodipine or a pharmaceutically acceptable acid addition salt thereof and an angiotensin II receptor inhibitor such as irbesartan or the like and a pharmaceutically acceptable salt thereof, a kit containing the same, and a use thereof
  • the present invention also relates to a compound having an additive and synergistic effect of amlodipine or a pharmaceutically acceptable acid addition salt thereof and an angiotensin receptor inhibitor such as irbesartan or a pharmaceutically acceptable salt thereof.
  • Compounds with additive and synergistic effects can be used to treat individuals with angina, atherosclerosis, mixed hypertension, and hyperlipidemia, as well as individuals, including humans, who have cardiac risk symptoms or signs. Background technique
  • Hypertension is the main cause of coronary heart disease, cerebrovascular disease and renal vascular disease, and it is also the main cause of death and sickness in adults.
  • ACE inhibitors have the following advantages: (1) superior to general vasodilators, When blood pressure drops, heart and kidney blood flow does not decrease. (2) It is superior to calcium antagonists, does not cause water and steel retention, and does not increase heart rate. (3) Better than a-blocker, does not cause orthostatic hypotension. (4) Better than the older generation of antihypertensive drugs, no central role. (5) Better than nitrate drugs, no drug resistance, no liver first pass effect. (6) There is no stopping phenomenon.
  • ACE inhibitors such as non-dose-related irritating dry cough (5% to 20%), fatal angioedema such as pharynx, larynx, respiratory tract, and lung (0.1 to 0.2%).
  • Angll angiotensin receptor antagonists, avoiding the rise of bradykinin, directly blocking the ATI receptor.
  • ATI antagonizes the inhibitor Angll-mediated vasoconstriction, and inhibits Ang II-mediated renal tubular sodium and water reabsorption; inhibits RAS regulation of stress receptor reflexes, increases sensitivity, and inhibits sympathetic excitation Induction of the central and peripheral sympathetic nerves, the difference between ATI antagonists and ACE inhibitors is the blockade of receptor levels, rather than blockade of the ACE pathway.
  • ACE inhibitors are beneficial for blocking Angll, while the increase of bradykinin is not conducive to the production of Angll by chymase;
  • ATI antagonists are beneficial for blocking Angll adverse Angll production, 70% rely on chymase, and 30% rely on ACE.
  • amlodipine an antihypertensive drug, and related dihydropyridine compounds.
  • Amlodipine besylate is disclosed in U.S. Patent 4,879,303, the disclosure of which is incorporated herein by reference.
  • Amlodipine and amlodipine besylate are strong long-acting calcium channel blockers. Therefore, amlodipine, amlodipine besylate and other pharmaceutically acceptable acid addition salts of amlodipine can be used as antihypertensive agents and anti-ischemic drugs.
  • amlodipine and its pharmaceutically acceptable acid addition salts in the treatment of congestive heart failure is also disclosed in U.S. Patent 5,155,120.
  • Amlodipine besylate is currently marketed under the name Norvasc®.
  • Amlodipine has the following structural formula.
  • Atherosclerosis is a condition characterized by irregularly distributed lipid deposits on the intima of arteries, including the coronary arteries, carotid arteries, and peripheral arteries. Deaths caused by atherosclerotic coronary heart disease (hereinafter referred to as "CHD") accounted for 53% of all deaths caused by cardiovascular events. CHD accounts for nearly half of the total annual cost of cardiovascular medicine in the United States (about $500-60 billion) and about 6% of total national medical expenditure. Despite attempts to change secondary risk factors such as smoking, obesity and lack of exercise, as well as treatment of dyslipidemia by changing diet and medication, CHD is still the leading cause of death in the United States.
  • CHD atherosclerotic coronary heart disease
  • Amlodipine can prevent myocardial ischemia in patients with angina pectoris by reducing total peripheral resistance (or afterload), which reduces the heart rate and blood pressure product, thereby reducing the need for myocardial oxygen at any given level of exercise.
  • amlodipine has been shown to block contractions and restore oxygen supply to the heart muscle.
  • amlodipine can increase the oxygen supply to the myocardium by dilating the coronary arteries.
  • Hypertension is often associated with hyperlipidemia and is considered to be a major risk factor for the development of heart disease that ultimately leads to adverse cardiac events. The classification of such risk factors may be due to a common mechanism.
  • patients are generally more compliant with hypertension control than with high blood lipids. Therefore, a single therapy that can treat these conditions simultaneously is beneficial to the patient.
  • Coronary heart disease is a multifactorial disease whose incidence and severity are affected by lipid distribution, the presence of diabetes, and the gender of the patient. The incidence is also affected by smoking and left ventricular hypertrophy (caused by hypertension). In order to significantly reduce the risk of coronary heart disease, it is important to control the entire risk spectrum. For example, attempts to hypertensive intervention have not been shown to completely normalize cardiovascular mortality caused by coronary heart disease. Treatment of patients with or without coronary artery disease with cholesterol synthesis inhibitors reduces the risk of cardiovascular morbidity and mortality.
  • the FraminSham Heart Study (in ongoing prospects for adult males and females) confirms that certain risk factors can be used to anticipate the development of coronary heart disease (see Wilson et al., Am. J. Cardiol 1987, 59). (14): 91G—94G). These factors include age, gender, total cholesterol levels, high-density lipoprotein (HDL) levels, systolic blood pressure, smoking, impaired glucose tolerance, and cardiac enlargement (in ECG, Left ventricular hypertrophy on the echocardiogram or heart enlargement in the chest X-ray). It is easy to program a calculator or computer with a multivariate logic function to calculate the conditional probability of a cardiovascular event. Based on these factors include age, gender, total cholesterol levels, high-density lipoprotein (HDL) levels, systolic blood pressure, smoking, impaired glucose tolerance, and cardiac enlargement (in ECG, Left ventricular hypertrophy on the echocardiogram or heart enlargement in the chest X-ray). It is easy to program a
  • composition A which comprises a pharmaceutically effective amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof, a pharmaceutically effective amount of an angiotensin II receptor inhibitor or The pharmaceutically acceptable salt thereof and the pharmaceutically acceptable carrier, wherein the daily dosage of amlodipine is 0.25-50 mg, preferably 0.5 ⁇ 25 mg per day; irbesartan, telmisartan, valsartan, losartan, candidia
  • the daily dosage of sartan is 0.5-600 mg, preferably 1 ⁇ 300 mg per day.
  • composition AA a pharmaceutical composition of composition A, hereinafter referred to as "composition AA", wherein the angiotensin receptor receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition AA angiotensin receptor receptor inhibitor
  • composition AB a pharmaceutical composition of composition AA, hereinafter referred to as "composition AB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition AB angiotensin II receptor inhibitor
  • the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • sartan losartan
  • candesartan or irbesartan telmisartan
  • valsartan losartan
  • losartan candesartan
  • composition B a pharmaceutical composition of composition AA, hereinafter referred to as "composition B", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, A pharmaceutically acceptable salt of valsartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition B which comprises amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition to include an antihypertensive effect and a hypolipidemic effect in a mammal having hypertension and hyperlipidemia, hereinafter referred to as " Composition B", the effect is greater than the sum of the antihypertensive effect and the hypolipidemic effect achieved by administering the first and second pharmaceutical compositions, respectively, the second pharmaceutical composition containing a certain amount of amlodipine or A pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, the first pharmaceutical composition comprising an amount of an angiotensin II receptor inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent .
  • composition BA a pharmaceutical composition of composition B, hereinafter referred to as "composition BA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition BA angiotensin II receptor inhibitor
  • sartan losartan
  • candesartan or irbesartan telmisartan
  • valsartan losartan
  • candesartan candesartan.
  • composition BB a pharmaceutical composition of composition BA, hereinafter referred to as "composition BB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition BB angiotensin II receptor inhibitor
  • the present invention relates to a pharmaceutical composition of composition BA, wherein said second composition comprises amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an anti-spasmodic effect and a hypolipidemic effect in a mammal having hypertension and hyperlipidemia, hereinafter referred to as "composition" C", the effect is greater than the sum of the antihypertensive effect and the hypolipidemic effect achieved by respectively administering the first and second pharmaceutical compositions, the second pharmaceutical composition containing a certain amount of angiotensin receptor An inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, the first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition CA a pharmaceutical composition of composition C, hereinafter referred to as "composition CA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition CA angiotensin II receptor inhibitor
  • irbesartan telmisartan
  • guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition CB a pharmaceutical composition of composition CA, hereinafter referred to as "composition CB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition CB angiotensin II receptor inhibitor
  • composition CA comprising amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an anti-spasmodic effect and a hypolipidemic effect in a mammal having hypertension and hyperlipidemia, hereinafter referred to as "composition" D", the effect is greater than the antihypertensive effect and the hypolipidemic effect achieved by respectively administering the first or second pharmaceutical composition, the second pharmaceutical composition containing a certain amount of an angiotensin II receptor inhibitor Or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, the first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition D which comprises amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an antihypertensive effect and a hypolipidemic effect in a mammal having hypertension and hyperlipidemia, hereinafter referred to as "composition" E", the effect is greater than the antihypertensive effect and the hypolipidemic effect achieved by respectively administering the first or second pharmaceutical composition, the second pharmaceutical composition containing a certain amount of amlodipine or a pharmaceutically acceptable drug thereof An acid addition salt and a pharmaceutically acceptable carrier or diluent, the first pharmaceutical composition comprising an amount of an angiotensin II receptor inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • composition EA a pharmaceutical composition of composition E, hereinafter referred to as "composition EA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition EA angiotensin II receptor inhibitor
  • the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • sartan losartan
  • candesartan or irbesartan telmisartan
  • valsartan losartan
  • losartan candesartan
  • the invention further relates to a pharmaceutical composition of composition EA, wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, valsartan, losartan, candesartan or A pharmaceutically acceptable salt of irbesartan, telmisartan, valsartan, losartan, candesartan.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an anti-angina effect in a mammal suffering from angina pectoris, hereinafter referred to as "composition F", said effect being greater than the respective administration a sum of the anti-angina effects achieved by the first and second pharmaceutical compositions, the second pharmaceutical composition comprising an amount of an angiotensin receptor inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or dilution
  • the first pharmaceutical composition contains an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition FA a pharmaceutical composition of composition F, hereinafter referred to as "composition FA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition FA angiotensin II receptor inhibitor
  • composition FB a pharmaceutical composition of composition FA, hereinafter referred to as "composition FB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition FB angiotensin II receptor inhibitor
  • composition FA comprising amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the invention further relates to a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an anti-angina effect in a mammal suffering from angina pectoris, hereinafter referred to as "composition G", said effect being greater than separate administration a sum of the anti-angina effects achieved by the first and second pharmaceutical compositions, the second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent
  • the first pharmaceutical composition contains an amount of an angiotensin II receptor inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • composition GA a pharmaceutical composition of composition G, hereinafter referred to as "composition GA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition GA angiotensin II receptor inhibitor
  • irbesartan a pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition GB a pharmaceutical composition of composition GA, hereinafter referred to as "composition GB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition GA hereinafter referred to as "composition GB”
  • the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • sartan losartan
  • candesartan or irbesartan telmisartan
  • valsartan losartan
  • composition GA a pharmaceutical composition of composition GA, wherein said second pharmaceutical composition comprises amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an anti-angina effect in a mammal suffering from angina pectoris, hereinafter referred to as "composition H", said effect being greater than the respective administration
  • composition H an anti-angina effect achieved by the first or second pharmaceutical composition
  • the second pharmaceutical composition comprising an amount of an angiotensin II receptor inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent
  • the first pharmaceutical composition contains an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • the present invention relates to a pharmaceutical composition of composition H comprising amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition for achieving an anti-angina effect in a mammal suffering from angina pectoris, hereinafter referred to as "composition J", said effect being greater than the respective administration An anti-angina effect achieved by the first or second pharmaceutical composition, the second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent,
  • the first pharmaceutical composition contains an amount of an angiotensin II receptor inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • composition JA a pharmaceutical composition of the composition, hereinafter referred to as "composition JA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition JA a pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition JB a pharmaceutical composition of composition JA, hereinafter referred to as "composition JB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, valsartan, A pharmaceutically acceptable salt of losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition to achieve an anti-atherosclerotic effect in a mammal, hereinafter referred to as "composition K", said effect being greater than being administered separately a sum of the anti-atherosclerotic effects achieved by the first and second pharmaceutical compositions, the second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or dilution
  • the first pharmaceutical composition contains an amount of an angiotensin II receptor inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • composition KA a pharmaceutical composition of composition K, hereinafter referred to as "composition KA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition KA a pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition KB a pharmaceutical composition of composition KA, hereinafter referred to as "composition KB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine
  • composition KB a pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition KB a pharmaceutical composition of composition KA, hereinafter referred to as "composition KB", wherein said second pharmaceutical composition comprises amlodipine, amlodipine besylate or other Medicinal amlodipine salt.
  • composition KC a pharmaceutical composition of composition KB, hereinafter referred to as "composition KC”, wherein the anti-atherosclerotic effect is manifested by delaying the development of atherosclerotic plaques.
  • the present invention also relates to a pharmaceutical composition of the composition KC, wherein the development of the atherosclerotic plaque is delayed in the coronary artery.
  • the invention further relates to a composition of composition KC wherein the development of the atherosclerotic plaque is delayed in the carotid artery.
  • the invention further relates to a composition of composition KC wherein the development of the atherosclerotic plaque is delayed in the peripheral arterial system.
  • composition KD a composition of composition KD, hereinafter referred to as "composition KD", Wherein the anti-atherosclerotic effect is manifested as regression of atherosclerotic plaques.
  • the present invention also relates to a composition of the composition KD, wherein the regression of the atherosclerotic plaque occurs in the coronary artery.
  • the present invention also relates to a composition of the composition KD, wherein the regression of the atherosclerotic plaque occurs in the carotid artery.
  • the present invention also relates to a composition of the composition KD, wherein the regression of the atherosclerotic plaque occurs in the peripheral arterial system.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition to achieve an anti-atherosclerotic effect in a mammal, hereinafter referred to as "composition L", said effect being greater than being administered separately a sum of anti-atherosclerotic effects achieved by the first and second pharmaceutical compositions, the second pharmaceutical composition comprising an amount of an angiotensin II receptor inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or A diluent, the first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition L an anti-atherosclerotic effect in a mammal
  • composition LA a composition of composition L, hereinafter referred to as "composition LA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, laksa A pharmaceutically acceptable salt of stan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition LB a composition of composition LA, hereinafter referred to as "composition LB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, laksa A pharmaceutically acceptable salt of stan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition LB a composition of composition LA, hereinafter referred to as "composition LB”, which comprises amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • composition LC a composition of composition LB, hereinafter referred to as "composition LC”, wherein the anti-atherosclerotic effect is manifested by delaying the development of atherosclerotic plaques.
  • the present invention also relates to a composition of the composition LC, wherein the development of the atherosclerotic plaque is delayed in the coronary artery.
  • the invention further relates to a composition of the composition LC wherein the development of the atherosclerotic plaque is delayed in the carotid artery.
  • the invention further relates to a composition of the composition LC wherein the development of the atherosclerotic plaque is delayed in the peripheral arterial system.
  • composition LD a composition of the composition LB, hereinafter referred to as "composition LD", wherein the anti-atherosclerotic effect is manifested as regression of atherosclerotic plaques.
  • the present invention also relates to a composition of the composition LD, wherein the regression of the atherosclerotic plaque occurs in the coronary artery.
  • the present invention also relates to a composition of the composition LD, wherein the regression of the atherosclerotic plaque occurs in the carotid artery.
  • the present invention also relates to a composition of composition LD, wherein said atherosclerosis is hard
  • the regression of plaques occurs in the peripheral arterial system.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition to achieve an anti-atherosclerotic effect in a mammal, hereinafter referred to as "composition M", said effect being greater than being administered separately
  • composition M an anti-atherosclerotic effect achieved by the first or second pharmaceutical composition
  • the second pharmaceutical composition comprising an amount of an angiotensin II receptor inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent
  • the first pharmaceutical composition contains an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent; provided that the angiotensin II receptor inhibitor is not atorvastatin or Its pharmaceutically acceptable salt.
  • composition M comprising amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the present invention also relates to a first pharmaceutical composition for use with a second pharmaceutical composition to achieve an anti-atherosclerotic effect in a mammal, hereinafter referred to as "composition N", said effect being greater than being administered separately
  • composition N an anti-atherosclerotic effect achieved by the first or second pharmaceutical composition
  • the second pharmaceutical composition comprising a certain amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent
  • the first pharmaceutical composition contains an amount of an angiotensin II receptor inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • composition NA a composition of composition N, hereinafter referred to as "composition NA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, laksa A pharmaceutically acceptable salt of stan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • the invention further relates to a composition of composition NA, wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, valsartan, losartan, candesartan or erg A pharmaceutically acceptable salt of besartan, telmisartan, valsartan, losartan, candesartan.
  • the invention further relates to a first pharmaceutical composition for use in conjunction with a second pharmaceutical composition for controlling cardiac risk in a mammal in which a risk of adverse cardiac events occurs, hereinafter referred to as "composition P", said effect a greater than a sum of the controlled cardiac risk effects achieved by administering the first and second pharmaceutical compositions, respectively, the second pharmaceutical composition comprising an amount of an angiotensin II receptor inhibitor or a pharmaceutically acceptable salt thereof A pharmaceutically acceptable carrier or diluent, the first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition PA a composition of composition P, hereinafter referred to as "composition PA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, laksa A pharmaceutically acceptable salt of stan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition PB a composition of the composition PA, hereinafter referred to as "composition PB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, laksa A pharmaceutically acceptable salt of stan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • composition PA comprising amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the invention further relates to use with a second pharmaceutical composition for the risk of adverse cardiac events in the presence of A first pharmaceutical composition for controlling cardiac risk in a dangerous mammal, hereinafter referred to as "composition Q", which is greater than the controlled cardiac risk effect achieved by administering the first and second pharmaceutical compositions, respectively.
  • a second pharmaceutical composition comprising a quantity of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, the first pharmaceutical composition comprising an amount of angiotensin II receptor An inhibitor or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition QA a composition of composition Q, hereinafter referred to as "composition QA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, laksa A pharmaceutically acceptable salt of stan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • the invention relates to a composition of composition QA, wherein the statin is irbesartan, telmisartan, valsartan, losartan, candesartan or irbesartan , pharmaceutically acceptable salts of telmisartan, valsartan, losartan, candesartan.
  • composition QA wherein said second pharmaceutical composition comprises amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the invention further relates to a first pharmaceutical composition for use in conjunction with a second pharmaceutical composition for controlling cardiac risk in a mammal in which a risk of adverse cardiac events occurs, hereinafter referred to as "composition R", said effect An effect of controlling cardiac risk achieved by administering the first or second pharmaceutical composition separately, the second pharmaceutical composition comprising an amount of an angiotensin II receptor inhibitor or a pharmaceutically acceptable salt thereof A pharmaceutically acceptable carrier or diluent, the first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.
  • composition R comprising amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the invention further relates to a first pharmaceutical composition for use in conjunction with a second pharmaceutical composition for controlling cardiac risk in a mammal in which a risk of adverse cardiac events occurs, hereinafter referred to as "composition S", said effect
  • a second pharmaceutical composition comprising a certain amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier, which is greater than the effect of controlling the cardiac risk achieved by administering the first or second pharmaceutical composition, respectively Or a diluent, the first pharmaceutical composition comprising an amount of an angiotensin II receptor inhibitor, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • composition SA a composition of composition S, hereinafter referred to as "composition SA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, laksa A pharmaceutically acceptable salt of stan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • the invention further relates to a composition of the composition SA, wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, valsartan, losartan, candesartan or erg A pharmaceutically acceptable salt of besartan, telmisartan, valsartan, losartan, candesartan.
  • kit A which comprises:
  • an angiotensin II receptor inhibitor or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent in a second unit dosage form
  • c is for a container containing the first and second dosage forms.
  • kit AA a kit of kit A, hereinafter referred to as "kit AA", wherein the angiotensin receptor receptor inhibitor is irbesartan, telmisartan, and laksa Medicinal salts of tantan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, and candesartan
  • kits A wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, valsartan, chlorine A pharmaceutically acceptable salt of sartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • kit AZ contains amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the present invention also relates to a kit of kit A, wherein the therapeutic effect is treatment of hypertension and hyperlipidemia.
  • the invention also relates to a kit of kit A, wherein the therapeutic effect is treatment of angina pectoris.
  • the invention further relates to a kit of kit A, wherein said therapeutic effect is to control cardiac risk.
  • the present invention also relates to a kit of kit A, hereinafter referred to as "kit A", wherein the therapeutic effect is treatment of atherosclerosis.
  • kit AC a kit of kits, hereinafter referred to as "kit AC", wherein the treatment of atherosclerosis delays the development of atherosclerotic plaques.
  • the invention further relates to a kit of kits AC wherein the coronary artery delays the development of atherosclerotic plaques.
  • the invention further relates to a kit of kits AC wherein the carotid artery delays the progression of atherosclerotic plaques.
  • the invention further relates to a kit of kits AC wherein the peripheral arterial system delays the development of atherosclerotic plaques.
  • Kit A kit of AB hereinafter referred to as “kit AD”, wherein the treatment of atherosclerosis causes regression of atherosclerotic plaques.
  • the present invention also relates to a kit for the kit AD, wherein the regression of the atherosclerotic plaque occurs in the coronary artery.
  • the invention further relates to a kit for a kit AD, wherein the regression of the atherosclerotic plaque occurs in the carotid artery.
  • the invention further relates to a kit for a kit AD, wherein the regression of the atherosclerotic plaque occurs in the peripheral arterial system.
  • the present invention also relates to a kit of the kit AZ, hereinafter referred to as "kit AE”, wherein the therapeutic effect is to treat sputum blood pressure and hyperlipidemia.
  • kit AF a kit of the kit AZ, hereinafter referred to as “kit AF”, wherein the therapeutic effect is treatment of angina pectoris.
  • the present invention also relates to a kit of the kit AZ, hereinafter referred to as "kit AG", wherein the therapeutic effect is to control cardiac risk.
  • kit AH a kit of the kit AZ, hereinafter referred to as "kit AH", wherein the therapeutic effect is treatment of atherosclerosis.
  • kit AJ a kit of kit AH, hereinafter referred to as "kit AJ"
  • kit AJ the treatment of atherosclerosis delays the development of atherosclerotic plaque.
  • the present invention also relates to a kit of kit AJ, wherein the coronary artery delays the development of atherosclerotic plaques.
  • the invention further relates to a kit of kit AJ, wherein the carotid artery delays the development of atherosclerotic plaques.
  • the present invention also relates to a kit of kit AJ, wherein the peripheral arterial system delays the development of atherosclerotic plaques.
  • kit AK a kit, hereinafter referred to as "kit AK", wherein the treatment of atherosclerosis causes regression of atherosclerotic plaques.
  • the invention further relates to a kit for a kit AK, wherein the regression of the atherosclerotic plaque occurs in a coronary artery.
  • the invention further relates to a kit for a kit AK, wherein the regression of the atherosclerotic plaque occurs in the carotid artery.
  • the invention also relates to a kit of kits AK, wherein the regression of the atherosclerotic plaque occurs in the peripheral arterial system.
  • the invention also relates to a method of treating a mammal in need of treatment, hereinafter referred to as "Method A", which method comprises administering to said mammal
  • first compound and the second compound can be administered, optionally independently of one another, with a pharmaceutically acceptable carrier or diluent.
  • Method AA a method of Method A, hereinafter referred to as "Method AA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, valsartan, chlorine A pharmaceutically acceptable salt of sartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.
  • the present invention relates to a method of Method AA, hereinafter referred to as "Method AB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, valsartan, losartan, kan Ground sand: pharmaceutically acceptable salt of fdan or irbesartan, telmisartan, valsartan, losartan, and candesartan.
  • method AB a method of method AA, hereinafter referred to as "method AB", wherein Contains amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.
  • the invention further relates to a method of method A, hereinafter referred to as "method AC", wherein said first compound and said second compound are administered simultaneously.
  • the invention further relates to a method of method A, hereinafter referred to as "method AD", wherein said first compound and said second compound are administered sequentially in any order.
  • the present invention also relates to a method of the method, hereinafter referred to as "Method AE", wherein the first compound and the second compound are administered simultaneously.
  • the invention further relates to a method of method AB, hereinafter referred to as "method AF", wherein said first compound and said second compound are administered sequentially in any order.
  • the invention also relates to a method of Method A, hereinafter referred to as "Method AG", wherein the treatment comprises anti-spasmodic blood pressure therapy and anti-hyperlipidemic therapy.
  • the invention further relates to a method of method AE, wherein said treatment comprises antihypertensive therapy and antihyperlipidemic therapy.
  • the invention further relates to a method of the method AP, wherein the treatment comprises antihypertensive treatment and antihyperlipide therapy.
  • the invention also relates to a method of method A, wherein the treatment comprises anti-angina treatment.
  • the invention further relates to a method of method AB, wherein said treatment comprises anti-angina treatment.
  • the invention further relates to a method of method AF, wherein said treatment comprises anti-angina treatment.
  • the invention further relates to a method of method A, wherein said treatment comprises the control of cardiac risk.
  • the invention further relates to a method of method AE, wherein said treatment comprises the control of cardiac risk.
  • the invention also relates to a method of method AF, wherein said treatment comprises control of cardiac risk.
  • the invention also relates to a method of method A, wherein the treatment comprises treatment of anti-atherosclerosis.
  • the invention further relates to a method of method AE, wherein said treatment comprises treatment against atherosclerosis.
  • the invention further relates to a method of method AF, wherein said treatment comprises treatment against atherosclerosis.
  • Amlodipine is a racemic compound due to its asymmetry at the 4-position of the dihydropyridine ring.
  • the R and S enantiomers can be prepared as described by Arrowsmith et al., J. Med. Chem., 1986, 29, 1696. Essentially only the S(-) isomer and the racemic mixture containing the R(+) and S(-) forms have calcium channel blocker activity. (See International Patent Application No. PCT / EP94 / 02697).
  • the calcium channel blocker activity of the R (+) isomer is weak or absent. However, the R(+) isomer is a potent inhibitor of smooth muscle cell migration. Therefore, the R(+) isomer can be used to treat or prevent atherosclerosis.
  • cardiac risk refers to the likelihood that a patient will suffer from future adverse cardiac events such as myocardial infarction, cardiac arrest, heart failure, and cardiac ischemia. Cardiac risk can be described in the Framingham crisis The risk equation is calculated. The term “control of cardiac risk” means that the risk of future adverse cardiac events is greatly reduced.
  • the compounds of the present invention are usually administered in the form of a pharmaceutical composition containing at least one compound of the present invention together with a pharmaceutically acceptable carrier or diluent.
  • the compounds of the invention may be administered alone or together in any conventional oral, parenteral or transdermal dosage form.
  • the pharmaceutical composition for oral administration may be in the form of a solution, suspension, tablet, pill, capsule, powder or the like.
  • Tablets contain various excipients such as sodium citrate, calcium carbonate and calcium phosphate, as well as various disintegrating agents such as starch (preferably potato starch or tapioca starch) and certain complex silicates, as well as binders such as poly Vinyl pyrrolidone, sucrose, gelatin and gum arabic.
  • lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for the preparation of tablets.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules; in this regard, preferred materials also include lactose and high molecular weight polyethylene glycol.
  • preferred materials also include lactose and high molecular weight polyethylene glycol.
  • the compounds of the present invention can be combined with various sweetening, flavoring, coloring, emulsifying and/or suspending agents and diluents such as water. , ethanol, propylene glycol, glycerin and various combinations thereof are mixed.
  • the combination of the present invention may also be administered in the form of a controlled release preparation such as a sustained release or rapid release preparation.
  • a controlled release preparation such as a sustained release or rapid release preparation.
  • the controlled release formulations of the combination of the present invention can be prepared according to methods well known to those skilled in the art. The method of administration can be determined by the attending physician after assessing the condition and needs of the patient.
  • a generally preferred formulation of amlodipine is
  • a solution in castor oil or peanut oil or aqueous propylene glycol, and a sterile aqueous solution of the corresponding water-soluble salt may be employed.
  • the aqueous solution can be suitably buffered and the liquid diluent first adjusted to isotonic with sufficient saline or glucose.
  • these aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injections.
  • the sterile aqueous vehicle used is readily obtained by conventional methods well known to those skilled in the art.
  • composition of the present invention may contain 0.1% to 95% of the compound of the present invention, preferably 1% to 70%.
  • the compositions or formulations for administration should contain a compound of the invention in an amount effective to treat the condition or disease of the patient to be treated.
  • kits contains two different pharmaceutical compositions: amlodipine or a pharmaceutically acceptable acid addition salt thereof; an angiotensin II receptor inhibitor or a pharmaceutically acceptable salt thereof.
  • the kit contains containers for containing different compositions such as separate vials or separate foil pouches, however, it is also possible to include the different compositions in a single, undivided container.
  • a typical kit contains instructions for administering different components.
  • kits are particularly advantageous when adjusting the dosage.
  • the following dosages of the invention, as well as other dosages given are for a typical human patient having a body weight of from about 63 ⁇ 43 ⁇ 4 to about 70 kg.
  • One skilled in the art can readily determine the dosage required for a patient having a body weight outside the range of 65 kg to 70 ks, based on the patient's medical history and the presence of a disease such as diabetes.
  • the dosages given herein and in the appended claims are all daily doses.
  • amlodipine is administered in an amount of from about 0.25 mg to about 50 mg, in accordance with the present invention.
  • the amlodipine is administered at a dose of from about 0.5 mg to about 25 mg.
  • the free base form or other salt forms of amlodipine benzene sulfonate can also be used in the present invention.
  • the calculation of the dosage of the other forms of amlodipine besylate or the free base form or other salt forms can be easily accomplished by simply comparing the molecular weights of the substances involved.
  • the above angiotensin II receptor inhibitor is administered at a dose of irbesartan, usually from about 25 mg to about 600 mg, preferably from about 50 mg to about 300 mg;
  • Telmisartan usually from about 5 mg to about 400 mg, preferably from about 10 mg to about 200 mg;
  • Valsartan is usually from about 10 mg to about 600 mg, preferably from about 20 mg to about 300 mg.
  • Losartan usually from about 5 mg to about 400 mg, preferably from about 10 mg to about 200 mg;
  • Candesartan usually from about 0.5 mg to about 100 mg, preferably from about 1 mg to about 50 mg;
  • Example 1 Therapeutic effect of irbesartan and amlodipine in the treatment of moderate to severe hypertension
  • the selected patients were divided into 2 groups, the first group (Ami 'group) 8 cases, amlodipine 5mg-day, 4 weeks, the second group (Irb + Aml group) 10 cases, irbesartan 150mg and ammonia chloride Level 5mg - once a day, 4 weeks. Six of them were from the first group for continued treatment. In the course of treatment, according to the requirements of the "Recommendation of Evaluation Methods for Clinical Trial of Cardiovascular Drugs", the sitting blood pressure, standing blood pressure, interrogation and observation of adverse reactions are measured every 2 weeks. Blood glucose, blood ester, creatinine, alanine aminotransferase are checked before and after treatment. , potassium, sodium and electrocardiogram.
  • the efficacy standard was evaluated according to the Guidelines for Clinical Research of Cardiovascular System Drugs formulated by the Ministry of Health.
  • the antihypertensive target should reach ⁇ 140/90 13 ⁇ 4, and the rate of achievement of antihypertensive treatment is calculated. This is also a commonly used efficacy index in recent years.
  • Amlodipine alone has a certain effect on the treatment of moderate to severe hypertension.
  • the total effective rate is 65%, but the effective rate is only 25%.
  • the rate of compliance is 12.5%, which can not meet most of the moderate to severe Blood pressure treatment requirements.
  • Test drug irbesartan, white powder. Amlodipine, light yellow powder. Hengrui Pharmaceutical Co., Ltd. Provided.
  • the arterial catheter was made by thermal docking with polyethylene (PE) PE10 and PE50.
  • the catheter is filled with heparinized polyvinylpyrrolidone solution.
  • Spontaneously hypertensive rats were treated with diazepam 5 mg/kg + ketamine hydrochloride 50 mg/kg intraperitoneal injection for anesthesia.
  • the arterial catheter is inserted from the left femoral artery into the lower aortic aorta. Then the gastrostomy tube is intubated. After 2 days of recovery, the arterial catheter was connected to the pressure transducer via a perfusion tee.
  • Each blood pressure signal is converted into a biological signal by a pressure transducer, and the computer collects the compression pressure, diastolic pressure and cardiac interval in real time. After 12 hours of stable connection to the computer system, blood pressure and cardiac interval were recorded as normal controls within one hour. The test drug or blank control solution is then administered via the gastric fistula. Blood pressure and cardiac interval were recorded continuously within 25 hours after administration. Observe the changes in systolic blood pressure, diastolic blood pressure and its volatility and cardiac interval.
  • SBP systolic blood pressure
  • DBP diastolic blood pressure
  • n 10. *p ⁇ 0.05 compared to before administration ** ⁇ 0.01
  • Table 2 show that: irbesartan 50.0mg/kg and irbesartan plus amlodipine 50.0+0.5, 50.0+1.0, 50.0+2.0mg/kg can significantly reduce spontaneous hypertension Systolic blood pressure at 24 hours after administration of rats; amlodipine 2.0 mg/kg and irbesartan and amlodipine 50.0+1.0, 50.0+2.0 mg/kg significantly reduced spontaneously hypertensive rats after administration Diastolic blood pressure at 24 hours. Effects of irbesartan and amlodipine on blood pressure variability at 24 hours after administration in spontaneously hypertensive rats
  • irbesartan 50 mg/kg and 50+0.5 mg/kg had no significant effect on systolic blood pressure and diastolic blood pressure fluctuation at 24 hours after administration in spontaneously hypertensive rats.
  • Table 4 The probability of systolic blood pressure reduction in irbesartan and amlodipine in spontaneously hypertensive rats
  • mice 64 spontaneous spontaneous hypertension, 20-24 weeks old, weighing 200-300g, male and female, provided by the Experimental Animal Center of the Second Military Medical University.
  • Experimental group - group animals (only) dose (mg/kg/d) blank control group 10 0 irbesartan group 12 50. 0 amlodipine group 12 1. 0 irbesartan + amlodipine group 1 10 25. 0+0. 5 irbesartan + amlodipine group 2 10 50. 0+1. 0 irbesartan + amlodipine group 3 10 100. 0+2.
  • Mode of Administration The drug is immersed in the standard feed of the animal according to the daily feed of the animal, and the animal is allowed to consume it by itself.
  • the drug was incorporated into the rat standard feed according to the daily feed amount of the animal, and the animals were allowed to eat by themselves, while the control animals were fed with the standard drug of the drug without the drug. Animals were given free access to water, and the indoor temperature, relative humidity, and illumination time of each group of animals were the same. Four months after treatment, rats in each group were anesthetized with diazepam 5 mg/kg + ketamine 50 mg/kg, and the dorsal position was fixed. The arterial catheter was inserted from the left femoral artery into the lower aorta, while left. Lateral femoral vein cannulation. After 2 days of recovery, the arterial catheter was connected to the pressure transducer via a perfusion tee.
  • Each blood pressure signal is converted into a biological signal by a pressure transducer, and the computer collects the compression and diastolic pressure per log in real time.
  • the rats were incubated for 6 hours after connection with the computer system, and then 5 hours of systolic and diastolic blood pressure were continuously recorded. After the recording, the animals were decapitated and the heart and aorta were taken for pathological examination.
  • the experimental results in Table 1 showed that the systolic and diastolic blood pressures of the spontaneously hypertensive rats in each drug treatment group were significantly lower than those in the control group.
  • Irbesartan (50.0 mg/kg/d), amlodipine (1.0 mg/kg/d), and irbesartan plus amlodipine (25. 0+0.5, 50. 0+1. 0, 100. 0+2.
  • the systolic blood pressure of the treatment group decreased by 14%, 10%, 13%, 18% and 25%, respectively, and the diastolic blood pressure decreased by 12% compared with the control group. 11%, 14%, 20% and 26%. Effects of long-term treatment with irbesartan and amlodipine on organ damage in spontaneously hypertensive rats
  • LVW/BW ratio of left ventricular weight to body weight
  • AW/length ratio of thoracic aorta weight to length.
  • Table 2 The results of Table 2 showed that: compared with the control group, the left ventricular hypertrophy of spontaneously hypertensive rats in each drug treatment group (the index is LVW/BW) And aortic hypertrophy (the indicator is AW / length) were significantly reduced. Irbesartan (50.
  • the liquid was supplied at a rate of 5 g of slurry per minute, and the atomization pressure was 2 bar.
  • the continuous flow of the fluidized pellets was started. After the spraying, the air volume was reduced, and the pellets were dried at 40 ° C for a while under a slight boiling state. After taking out, it was dried in an oven at 40 ° C for 24 hours, and the weight gain was about 18%.

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Abstract

Cette invention concerne une composition pharmaceutique ou un ensemble d’éléments comprenant de l’amlodipine ou un sel pharmaceutiquement acceptable de celle-ci, ainsi qu’un antagoniste des récepteurs de l’angiotensine II, par exemple l’irbesartan ou un sel pharmaceutiquement acceptable de celui-ci. Elle concerne également un procédé de traitement de l’hypertension de la créature ou de l’être humain et des symptômes cardiaques dangereux avec cette composition. La composition possède un effet synergique. La composition peut être utilisée pour le traitement de certaines maladies, notamment l’angor, l’athérosclérose, l’hypertension de forme mixte et l’hyperlipémie.
PCT/CN2005/001544 2004-09-30 2005-09-23 Composition comprenant de l’amlodipine et un antagoniste des recepteurs de l’angiotensine ii Ceased WO2006034631A1 (fr)

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CN117137913A (zh) * 2022-05-31 2023-12-01 深圳信立泰药业股份有限公司 一种ARNi复合物与氨氯地平的复方药物组合物的新应用
CN117137921A (zh) * 2022-05-31 2023-12-01 深圳信立泰药业股份有限公司 一种ARNi复合物的药物组合物的新应用

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CN101433536A (zh) * 2007-11-12 2009-05-20 北京瑞康医药技术有限公司 含有烟酸氨氯地平和沙坦类药物的治疗组合物
CN101564536B (zh) * 2008-04-21 2010-12-15 鲁南制药集团股份有限公司 一种治疗高血压的药物组合物缓控释制剂
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ES2598490T3 (es) 2009-05-20 2017-01-27 Boehringer Ingelheim Vetmedica Gmbh Disolución farmacéutica bebible de telmisartán
CN101966181A (zh) * 2010-07-08 2011-02-09 王丽燕 包含坎地沙坦和氨氯地平的口服固体制剂及其新应用
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WO2011001202A1 (fr) * 2009-06-30 2011-01-06 Sanofi-Aventis Compositions à dose pharmaceutique solide fixe comprenant de l'irbésartan et de l'amlodipine, leur préparation et leur application thérapeutique
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CN117137921A (zh) * 2022-05-31 2023-12-01 深圳信立泰药业股份有限公司 一种ARNi复合物的药物组合物的新应用

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