WO2006034631A1

WO2006034631A1 - Composition comprising amlodipine and angiotensin ii receptor blocker

Info

Publication number: WO2006034631A1
Application number: PCT/CN2005/001544
Authority: WO
Inventors: Kaihong Yuan; Yunshu Zhou; Piaoyang Sun
Original assignee: Jiangsu Hengrui Medicine Co., Ltd.
Priority date: 2004-09-30
Filing date: 2005-09-23
Publication date: 2006-04-06
Also published as: CN100364532C; CN1765362A

Abstract

A pharmaceutical composition or a kit of parts comprising amlodipine or a pharmaceutically acceptable salt thereof and angiotensin II receptor blocker e.g. irbesartan or a pharmaceutically acceptable salt thereof. A method of treatment the creature or human being of hypertension and existing the dangerous symptom of heart with the composition. The effect of the composition is synergism. The use of the composition, for the treatment for the disease selected from angina pectoris, atherosclerosis, mixed type hypertension and hyperlipemia.

Description

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 method of treating a subject suffering from angina pectoris, atherosclerosis, mixed hypertension, and hyperlipidemia, and a subject having cardiac risk symptoms, including a human.

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

According to WTO estimates, about 20% of adults have high blood pressure, and 75% of the confirmed patients have not been effectively treated. The incidence of cardiovascular disease due to death from hypertension is increasing by 50% year by year, and the morbidity rate is also on the rise. The mortality rate remains high. According to domestic clinical statistics, blood pressure drops by 1.20/0.67KPA, preventing about 450,000 deaths from stroke each year. Studies have shown that blood pressure is reduced by 0.67Kpa and cardiovascular risk is reduced by 30%.

With the increase of blood pressure, the risk of stroke and coronary events increases. 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.

The goal of clinical treatment is to use effective drugs to effectively control blood pressure; prevent or damage heart, kidney, brain target organs; reduce cardiovascular mortality and morbidity. Among the commonly used anti-hypertensive drugs in the clinic, the ACE inhibitor developed in the 1980s can be said to be a very effective antihypertensive drug. In pharmacology, 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.

However, there are insurmountable adverse reactions due to 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%). ), which led to the development of angiotensin (Angll) 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.

U.S. Patent 4,572,909, the disclosure of which is incorporated herein by reference in its entirety in And 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. The use of 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.

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. In patients with vasospasm angina, amlodipine has been shown to block contractions and restore oxygen supply to the heart muscle. In addition, 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. In addition, 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

The 5209 men and women who participated in the Framingham study assessed the risk of coronary artery disease during different follow-up periods. During the optional six-year period, modeled incidence rates ranged from less than 1% to over 80%. However, these rates are usually less than 10% and rarely exceed 45% in men and rarely exceed 25% in women. Summary of the invention

The present invention relates to a pharmaceutical composition, hereinafter referred to as "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.

In particular, the present invention relates to a pharmaceutical composition of composition A, hereinafter referred to as "composition AA", wherein the angiotensin receptor receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

In particular, the present invention relates to a pharmaceutical composition of composition AA, hereinafter referred to as "composition AB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

More particularly, the present invention relates to 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.

The invention further relates to a pharmaceutical composition of 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 .

In particular, the present invention relates to a pharmaceutical composition of composition B, hereinafter referred to as "composition BA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

In particular, the present invention relates to a pharmaceutical composition of composition BA, hereinafter referred to as "composition BB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan. More particularly, 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.

In particular, the present invention relates to a pharmaceutical composition of composition C, hereinafter referred to as "composition CA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

In particular, the present invention relates to a pharmaceutical composition of composition CA, hereinafter referred to as "composition CB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

More particularly, the present invention relates to a pharmaceutical composition of 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.

More particularly, the invention relates to a pharmaceutical composition of 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.

In particular, the present invention relates to a pharmaceutical composition of composition E, hereinafter referred to as "composition EA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, 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.

In particular, the present invention relates to a pharmaceutical composition of composition F, hereinafter referred to as "composition FA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

In particular, the present invention relates to a pharmaceutical composition of composition FA, hereinafter referred to as "composition FB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

More particularly, the present invention relates to a pharmaceutical composition of 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.

In particular, the present invention relates to a pharmaceutical composition of composition G, hereinafter referred to as "composition GA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

In particular, the present invention relates to a pharmaceutical composition of composition GA, hereinafter referred to as "composition GB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

More particularly, the invention relates to 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 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.

More particularly, 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.

In particular, the present invention relates to a pharmaceutical composition of the composition, hereinafter referred to as "composition JA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

The present invention also relates to 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.

In particular, the present invention relates to a pharmaceutical composition of composition K, hereinafter referred to as "composition KA", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

In particular, the present invention relates to a pharmaceutical composition of composition KA, hereinafter referred to as "composition KB", wherein the angiotensin II receptor inhibitor is irbesartan, telmisartan, guanidine A pharmaceutically acceptable salt of sartan, losartan, candesartan or irbesartan, telmisartan, valsartan, losartan, candesartan.

More particularly, the present invention relates to 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.

More specifically, the present invention also relates to 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.

More specifically, 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.

More particularly, the present invention also relates to a composition of composition KD, hereinafter referred to as "composition KD", Wherein the anti-atherosclerotic effect is manifested as regression of atherosclerotic plaques.

More specifically, the present invention also relates to a composition of the composition KD, wherein the regression of the atherosclerotic plaque occurs in the coronary artery.

More specifically, the present invention also relates to a composition of the composition KD, wherein the regression of the atherosclerotic plaque occurs in the carotid artery.

More specifically, 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.

In particular, the present invention relates to 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.

In particular, the present invention relates to 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.

More particularly, the present invention relates to a composition of composition LA, hereinafter referred to as "composition LB", which comprises amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt. .

More specifically, the present invention also relates to 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.

More specifically, 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.

More specifically, the present invention also relates to a composition of the composition LB, hereinafter referred to as "composition LD", wherein the anti-atherosclerotic effect is manifested as regression of atherosclerotic plaques.

More specifically, the present invention also relates to a composition of the composition LD, wherein the regression of the atherosclerotic plaque occurs in the coronary artery.

More specifically, the present invention also relates to a composition of the composition LD, wherein the regression of the atherosclerotic plaque occurs in the carotid artery.

More particularly, 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 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.

More particularly, the invention relates to a composition of 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 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.

In particular, the present invention relates to 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.

In particular, the present invention relates to 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.

In particular, the present invention relates to 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.

More particularly, the invention relates to a composition of 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.

In particular, the present invention relates to 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.

In particular, 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.

More particularly, the invention relates to a composition of 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.

More particularly, the invention relates to a composition of 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.

In particular, the present invention relates to 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.

The invention also relates to a kit for achieving a therapeutic effect in a mammal, hereinafter referred to as "kit A", which comprises:

a certain amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof in the first unit dosage form and pharmaceutically acceptable Carrier or diluent;

b. an amount of 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.

In particular, the present invention relates to 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

The present invention also relates to a kit of the kit AA, hereinafter referred to as "kit 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.

More specifically, the present invention relates to a kit of kit AA, hereinafter referred to as "kit AZ", which 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.

The present invention also relates to 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. The present invention also relates to 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.

The present invention also relates to a kit of the kit AZ, hereinafter referred to as "kit AH", wherein the therapeutic effect is treatment of atherosclerosis.

The present invention also relates to a kit of kit AH, hereinafter referred to as "kit AJ", wherein 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.

The present invention also relates to 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

(a) a quantitative first compound, the first compound being amlodipine or a pharmaceutically acceptable acid addition salt thereof;

(b) a quantitative second compound, wherein the second compound is an angiotensin II receptor inhibitor or a pharmaceutically acceptable salt thereof;

Wherein the first compound and the second compound can be administered, optionally independently of one another, with a pharmaceutically acceptable carrier or diluent.

In particular, the present invention relates to 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.

More specifically, the present invention relates to 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. (See International Patent Application No. PCT I EP95 I 00847). For the above reasons, those skilled in the art will select a racemic mixture of the R (de) isomer, the _S (I) isomer or the R (+) isomer and the S (-) isomer for use in the present invention. Compound.

The term "cardiac risk" as used herein 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. Thus, 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. In addition, 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. When required for oral administration with aqueous suspensions and/or elixirs, 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. 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

Norvasc

For parenteral administration, 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. If desired, 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. In this regard, the sterile aqueous vehicle used is readily obtained by conventional methods well known to those skilled in the art.

Methods of preparing various pharmaceutical compositions containing a certain amount of active ingredient are known to those skilled in the art or are apparent. See, for example, Remington's Pharmaceuticai SCienCeS, Mack Publishing Company, Easter, Pa., 15th Ed. (1975).

The pharmaceutical composition of the present invention may contain 0.1% to 95% of the compound of the present invention, preferably 1% to 70%. In any event, 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.

Since the present invention relates to the treatment of diseases using a combination of active ingredients which can be administered separately, the present invention therefore also relates to the incorporation of different pharmaceutical compositions in the form of kits. The kit 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. When different ingredients are preferably administered in different dosage forms (eg oral and parenteral), at different dosing intervals, or when a component of the combination needs to be gradually prescribed by the prescribing physician The form of the kit is 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.

Generally, amlodipine is administered in an amount of from about 0.25 mg to about 50 mg, in accordance with the present invention. Preferably, the amlodipine is administered at a dose of from about 0.5 mg to about 25 mg. Those skilled in the art will appreciate that 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.

Generally, according to the present invention, 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;

Those skilled in the art will appreciate that the free base forms or other salt forms of the above described angiotensin receptor receptors can also be used in the present invention. The calculation of the dosage of the other forms of the angiotensin II receptor inhibitor or the free base form or other salt forms can be easily accomplished by simply comparing the molecular weights of the substances involved. Detailed ways

Example 1 Therapeutic effect of irbesartan and amlodipine in the treatment of moderate to severe hypertension

HOT studies have shown that 70% of hypertensive patients require a combination of drugs to achieve the target value of blood pressure reduction. The seventh report of the American Association for the Prevention, Detection, Assessment and Treatment of Hypertension (JNC 7) states that most hypertensive patients require two or more antihypertensive drugs to achieve the target blood pressure (< 140/90 mmHg= If the blood pressure exceeds the target blood pressure value of 20/10mmHg, two kinds of antihypertensive drugs should be considered as the initial drug. We use angiotensin II receptor t (ATi) blocker irbesartan (Irbesartan) (by Jiangsu Heng Rui Pharmaceutical Co., Ltd.) and calcium antagonist amlodipine (produced by Beijing Secco Pharmaceutical Co., Ltd.) in combination with the treatment of moderate to severe hypertension, initially achieved good results, the summary report is as follows:

I. Materials and methods

According to the diagnostic criteria of the Guidelines for Prevention and Treatment of Hypertension in China, patients with moderate to severe hypertension (SBP 160 and/or DBP 100mmHg) who did not take antihypertensive drugs or discontinued for more than 2 weeks were selected for queuing secondary hypertension, severe heart, liver and kidney. Functional impairment, pregnancy and lactation women, drug allergy.

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. (1) Significant effect: The diastolic blood pressure decreased by ^10 mmHg and decreased to normal or decreased by 20 mmHg or more. (2) Effective: The diastolic blood pressure drops by 3⁄4 lOmmHg, but falls to normal or decreases by 10~19mraHg. (3) Invalid: The above criteria were not met. In addition, according to the "Guidelines for the Prevention and Treatment of Hypertension in China", 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.

Second, the results

1. Amlodipine alone for the treatment of moderate to severe hypertension, systolic blood pressure decreased by 14.2mmHg at 2 weeks, decreased by 19.8mmHg at 4 weeks, and diastolic blood pressure decreased by 11.0 and 12.8mmHg, respectively. The total effective rate was 5/8 and 6/8 at 4 and 4 weeks, respectively. The effective rates were 2/8 and 3/8, respectively, and the blood pressure was up to 1 in 1 and the compliance rate was 1/8.

(See Table 1, Table 3, Table 5 for details).

2. Irbesartan combined with amlodipine in the treatment of moderate to severe hypertension, systolic blood pressure decreased by 28.2 mmHg at 2 weeks, decreased by 33.6 mmHg at 4 weeks, and decreased by 15.6 and 18.3 mmHg at 2 and 4 weeks, respectively. The total effective rate was 8/10 and 9/10 at week and 4 weeks, respectively, and the exchange rate was 6/10 and 7/10 respectively, and the compliance rate was 3/10 and 6/10 at 2 weeks and 4 weeks, respectively. (See Table 2, Table 3, Table 5 for details)

3. The heart rate before and after treatment was 75.8 beats/min and 74.2 beats/min, respectively, with no significant change. No upright hypotension, liver and kidney dysfunction, and other adverse reactions were found. Table 1 Amlodipine antihypertensive effect

After treatment

2W 4W

SBP 165.4±10.3 150.1±16.1 145.5±12.3

DBP 104.3±7.2 93.3±5.1 91.5±5.9

SBP systolic blood pressure DBP diastolic blood pressure unit mmHg (lmmHg=0.1333Kpa) irbesartan, amlodipine combined antihypertensive effect

(n=10) before treatment

2W 4W

SBP 164.2±14.7 136.0±11.5 130.6±11.7

DBP 103.1±6.1 87.5±5.3 84.6±4.8

Blood pressure lowering value SBP (mmHg) DBP (mmHg)

2W 4W 2W 4W

Ami 14.2 19.8 11.0 12.8

Irb+Aml 28.2 33.6 15.6 18.5

Ami amlodipine Irb irbesartan

Table 4 Amlodipine antihypertensive effect

Efficient

Compliance rate, total efficiency, effective effect, effective

2W 5/8 2/8 3/8 1/8

4W 6/8 3/8 3/8 1/8 Table 5 Analysis of the therapeutic effect of irbesartan and amlodipine

Efficient

(n=10) compliance rate

Total efficiency, effective, effective

2W 8/10 6/10 2/10 3/10

4W 9/10 7/10 2/10 6/10 III. Conclusion

Based on preliminary findings

1. 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%. There is only one case of blood pressure compliance, the rate of compliance is 12.5%, which can not meet most of the moderate to severe Blood pressure treatment requirements.

2. Irbesartan combined with amlodipine in the treatment of moderate to severe hypertension, the total effective rate is 90%, the effective rate is 70%, and the compliance rate reaches 30% and 60% at the 2nd and 4th weeks, respectively. Better than amlodipine alone. The combination of irbesartan and amlodipine has the advantages of large depressurization amplitude, fast compliance, and small side effects. It is suitable for the initial treatment of moderate to severe hypertension. Example 2: Combination of irbesartan and amlodipine in blood pressure of spontaneously hypertensive rats

Synergistic effects of blood pressure fluctuations Objective: To observe the synergistic effect of irbesartan and amlodipine on blood pressure and blood pressure fluctuations in spontaneously hypertensive rats.

Test drug: irbesartan, white powder. Amlodipine, light yellow powder. Hengrui Pharmaceutical Co., Ltd. Provided.

Animals: 74 spontaneously hypertensive rats, 20-24 weeks old, weighing 200-300 g, male and female, were provided by the Experimental Animal Center of the Second Military Medical University. Experimental grouping _:

Group animals (only) Dose (mg/kg) Carboxymethylcellulose sodium group (blank control group) 8 0 Amlodipine group 1 8 0.5 Amlodipine group 2 10 1.0 Amlodipine group 3 8 2.0 Urbesha Tan group 10 50.0 irbesartan + amlodipine group 1 10 50.0 + 0.5 irbesartan + amlodipine group 2 10 50.0 + 1.0 irbesartan + amlodipine group 3 10 50.0 + 2.0 mode of administration - Administered through the gastric fistula. Main experimental steps

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. Experimental results:

Table 1 Effect of irbesartan and amlodipine on 24-hour mean blood pressure in spontaneously hypertensive rats

Drug Dose (mg/kg) SBP (mmHg) DBP (mmHg)

Con 179 ±9.0 110± 14.0

Amlo 0.5 171 ± 14.0 105±12.8

Amlo 1.0 169± 11.4* 106 ±9.7

Amlo 2.0 87± 17.2** Irbe 50 161 ±25.2* 107±29.2

Irbe+Amlo 50+0.5 157±27.1** 117±21.1

Irbe+Amlo 50+1.0 156± 17.5** 97± 13.9*

Irbe+Amlo 50+2.0 147±24·3** 96± 19.1*

Note: SBP, systolic blood pressure; DBP, diastolic blood pressure; n=10, compared with the control group, *p<0.05, **p<0.01 The experimental results of Table 1 indicate that amlodipine 1.0, 2.0 mg/kg, Irbesartan 50 mg/kg and irbesartan plus amlodipine 50.0+0.5, 50.0+1.0, 50.0+2.0 mg/kg significantly reduced 24-hour mean systolic blood pressure in spontaneously hypertensive rats; amlodipine 2.0 mg /kg and irbesartan plus amlodipine 50.0 + 1.0, 50.0 + 2.0 mg / kg can significantly reduce the 24-hour mean diastolic blood pressure in spontaneously hypertensive rats. Table 2 Effect of irbesartan and amlodipine on blood pressure at 24 hours after administration in spontaneously hypertensive rats

Drug Dose SBP DBP

(mg/kg) (mmHg) (mmHg)

Before After Before After con 180±13.1 179±11.6 112±19.9 109±14.2

Amlo 0.5 181±12.7 177±14.6 118±11.5 110±12.4

Amlo 1.0 178±11.8 168±18.4 118±8.4 105±15.8

Amlo 2.0 178±10.0 169±28.5 111±7·2 92±18.8*

Irbe 50 171±10.4 148±38.4* 116±9.8 111±44.1

Irbe+Amlo 50+0.5 169±19.5 146±33.3* 119±18.5 97±34.0

Irbe+Amlo 50+1.0 181±16.3 151±20.5** 121±16.0 91±16.1*

Irbe+Amlo 50+2.0 172±14.7 144±28.0** 116±19.0 92±25.5* Note: SBP, systolic blood pressure; DBP, diastolic blood pressure; n=10. *p<0.05 compared to before administration **ρ<0.01 The results of 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

Amlo 1.0 11.4±1.9 10.4±2.5* 10.5±2.5 7.3±3.1*

Amlo 2.0 13.1±2.0 11.9±2.7 9.7±1.3 8.7±1.8

Irbe 50 9.2±1.8 8.9±2.6 7.4±1.13 7.4±3

Irbe+Amlo 50+0.5 8.05±1.8 7.5±2.2 7.2±2.3 6.9±1.9

Irbe+Amlo 50+1.0 9.8±1.9 7.5±1.9* 6.8±0.9 6.0±1.1*

Irbe+Amlo 50+2.0 8.9±2.3 7.3±1.2** 8.2±1.9 6.1±1.4* SBPV, systolic blood pressure fluctuations; DBPV, diastolic blood pressure fluctuations; n=8-10 per group. *p<0.05, **p<0.01 compared with before administration. Table 3 results show: amlodipine 1.0, 2.0 mg/kg and irbesartan plus amlodipine 50+1.0, 50+2.0 Mg/kg significantly reduced systolic blood pressure and diastolic blood pressure fluctuations at 24 hours (25th h) after administration in spontaneously hypertensive rats. However, 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

Drug Dose probability

(mg/kg)

Amlo 0.5 2/8

Amlo 1.0 3/10

Amlo 2.0 5/8

Irbe 50 5/10

Irbe+Amlo 50+0.5 5/10

Irbe+Amlo 50+1.0 8/10

Irbe+Amlo 50+2.0 8/10 Note: A reduction in systolic blood pressure of 20 mmHg is an effective blood pressure reduction at 24 hours after administration compared with the mean systolic pressure one hour before administration. Table 4 lists the percentage of each group of animals that responded effectively to the corresponding drug. According to this percentage, the q values of the three different ratios are obtained by the following formula. q=PA+B/(PA+PB-PAxPB). The results showed that: irbesartan plus amlodipine reduced the systolic blood pressure of spontaneously hypertensive rats by the ratio of 50+1.0 mg/kg (1.23), while the 50+0.5 and 50+2.0 mg/kg groups The q values are 0.833 and 0.985, respectively. The results of the experiment showed that irbesartan plus amlodipine 50+1.0 mg/kg had a significant synergistic antihypertensive effect. Experimental results:

The results of this experiment suggest that the combination of irbesartan and amlodipine at a ratio of 50+1.0 mg/kg has a synergistic effect on reducing systolic blood pressure in spontaneously hypertensive rats.

Animals: 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. 0 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. Main experimental steps

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.

Experimental results: Table 1 Effect of long-term treatment with irbesartan and amlodipine on 24-hour mean blood pressure in spontaneously hypertensive rats

Drug Dose (mg/kg/d n SBP (mmHg) DBP (mmHg)

)

Con 9 184±9· 8 123±9· 2

Irb 50 9 158± 12 ^tt 108± 13**

Ami 1. 0 9 165 ±6. T* 109 ±4. 6**

Irb+Aml 25+0. 5 10 160± 15** 106± 1 wide

Irb+Aml 50+1. 0 8 150 ±7** 98 ±5. 2**

Irb+Aml 100+2. 0 10 138± 12** 91 ±9· 4** Note: SBP, systolic blood pressure; DBP, diastolic blood pressure; compared with the control group, **p<0. 01

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. Omg/kg/d) 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

Drug Dose (mg/kg/ n LVW/BW (mg/kg) AW/length (mg/mm d) )

Con 10 2. 92±0. 30 1. 42±0. 18

Irb 50 12 2. 52±0. 22** 1. 21 ±0. 14**

Ami 1. 0 ' 12 2. 58 ±0. 26** 1. 22±0. 07** Irb+Aml 25+0.5 11 2.64±0.17* 1.19±0.09**

Irb+Aml 50+1.0 10 2.34±0.11** 1.10±0.09**

Irb+Aml 100+2.0 11 2.23±0.20** 1 07±0.11**

Note: LVW/BW, ratio of left ventricular weight to body weight; AW/length, ratio of thoracic aorta weight to length. Compared with the control group, *p<0.05, **p<0.01 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. Omg/kg/d), amlodipine (1.0 mg/kg/d), and irbesartan plus amlodipine (25.0+0.5, 50.0+1.0, 100.0+2.0 mg/d) The LVW/BW of the treatment group was reduced by 14%, 12%, 10%, 20% and 24, respectively, compared with the control group. /. , LVW/BW decreased by 15%, 14%, 16%, 23% and 25%, respectively, compared with the control group. Table 3. Probability of systolic blood pressure in spontaneously hypertensive rats by irbesartan and amlodipine

Dose

Parameter Drug Probability q Value

(mg/kg/d)

Irb 50

SBP Ami 1 P =3/9 q: =1.29

Irb + Aral 50+1 Plrb+Aml ~8/8

DBP Ami 1 P«=4/9 q ⁼ =1.97

Irb + Ami 50+1 Plrb+Aml ~7/8

Irb + Ami 50+1 Plrb+Aml ~6/l0

AW/length Ami 1 P«=l/12 q= :2.54

Irb + Ami 50+1 Plrb+Aml = 6/10 Note: Compared with the blank control group, the systolic blood pressure and diastolic blood pressure of the treatment group were reduced by 20 Hg, which was effective blood pressure reduction. For the organ injury index (LW/BW and AW/BW), 1/5 of the average value of the index in the control group was used as the standard value. Compared with the control group, the decrease value of the index in the treatment group was greater than or equal to the standard value. That is to effectively reduce. Table 3 lists the percentage of the effective response of different indicators of each group of animals to the corresponding drugs and the q value obtained by this percentage. Q-

It shows that synergistic effect is produced after the combination of the two drugs; q 0.85, indicating that the two drugs produce antagonistic effect after combination. The results of the experiment showed that: when irbesartan plus amlodipine was treated at a dose of 50+1.Omg/kg/d for long-term treatment, the q values of systolic blood pressure, diastolic blood pressure, LVW/BW and AW/BW were all obtained. Greater than 1.15. The results of the experiment showed that: irbesartan plus amlodipine was treated at a dose of 50+1.0 mg/kg/d for a long time, which had a synergistic effect on blood pressure reduction and protection of target organ damage. Experimental results: The results of this experiment suggest that: irbesartan and amlodipine at a dose of 50 + 1.0 mg / kg / d for long-term treatment, a synergistic effect on blood pressure control and organ protection in spontaneously hypertensive rats.

Example 3

Amlodipine 2mg

Irbesartan lOOmg

Microcrystalline cellulose 27.5mg

Milk candy monohydrate

Magnesium stearate 0.5mg

~~ 130mg

After the above raw materials and auxiliary materials are uniformly mixed, they are conventionally wet granulated, dried, and tableted. Example 4

Amlodipine 2mg

Irbesartan lOOmg

NaCl 0.9g

Water for injection

~~ 100ml

Take sodium chloride, stir and dissolve with water for injection, then add amlodipine and irbesartan respectively, continue to stir to completely dissolve, add water for injection to the total amount, filter to clear, potting, sterilization, that is . Example 5

Sustained release pellet preparation

Sustained release part of prescription (pill 1)

Pill core prescription

Amlodipine 2g

Irbesartan 100g

Microcrystalline cellulose 15g

Hypromellose 5g

Pure water 200ml

M 1000 tablets coating prescription

25% ethylcellulose aqueous dispersion 184g

Pure water 123g

13⁄4 1000 capsules Microcrystalline cellulose, lactase, amlodipine and irbesartan were pre-pulverized through an 80 mesh sieve, and weighed according to the prescription of the pellet 1 and mixed uniformly. The aqueous solution of hydroxypropylmethylcellulose was used as a binder. Pills, dry at 50~60 °C, choose 20~30 mesh pellets, and set aside. - Prepare and select the pellets, place them in a fluidized bed, use bottom spray, fluidize by hot air suspension, the inlet air temperature is 55 Ό, and adjust the peristaltic pump when the bed temperature is controlled at 30 °C. 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%.

It is to be understood that the invention is not limited to the specific embodiments described herein, and the various modifications and changes may be made without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

Claim

A pharmaceutical composition comprising 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 a pharmaceutically acceptable salt thereof, wherein said blood vessel The angiotensin II receptor inhibitor is selected from the group consisting of irbesartan, telmisartan, valsartan, losartan, and candesartan, wherein the daily dose of amlodipine is 0.25-50 mg, preferably 0.5 to 25 mg per day. _; irbesartan, telmisartan, valsartan, losartan, candesartan daily dosage of 0.5mg ~ 600mg, l ~ 300mg per day is preferably administered.

2. A pharmaceutical composition according to claim 1 wherein said amlodipine is amlodipine, amlodipine besylate or other pharmaceutically acceptable amlodipine salt.

3. The pharmaceutical composition according to claim 2, wherein the angiotensin II receptor inhibitor is irbesartan.

The pharmaceutical composition according to claim 2, wherein said angiotensin II receptor inhibitor is telmisartan.

The pharmaceutical composition according to claim 2, wherein the angiotensin II receptor inhibitor is valsartan.

6. The pharmaceutical composition according to claim 2, wherein the angiotensin II receptor inhibitor is losartan.

7. The pharmaceutical composition according to claim 2, wherein the angiotensin II receptor inhibitor is candesartan.

8. A kit for achieving a therapeutic effect in a mammal, including a human, consisting of - a. a pharmaceutically effective amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof in a first unit dosage form and pharmaceutically acceptable Carrier or diluent;

b. A pharmaceutically effective amount of an angiotensin II receptor inhibitor, or a pharmaceutically acceptable salt thereof, in a second unit dosage form, wherein the angiotensin II receptor inhibitor is selected from the group consisting of irbesartan, tilissa Tan or valsartan.

c for containing the containers in the first and second dosage forms.

9. A kit according to claim 8 wherein said amlodipine is amlodipine besylate.

10. A kit according to claim 9, wherein said angiotensin II receptor inhibitor is irbesartan.

The kit according to claim 9, wherein the angiotensin II receptor inhibitor is telmisartan.

The kit according to claim 9, wherein said angiotensin receptor receptor inhibitor is laksa Tan.

The kit according to claim 9, wherein the angiotensin II receptor inhibitor is losartan.

The kit according to claim 9, wherein the angiotensin II receptor inhibitor is candesartan.

15. Use of a composition according to any of claims 1-7 for the manufacture of a medicament for the treatment of a mammal, including a human hypertension.

16. Use of a composition according to any of claims 1-7 for the manufacture of a medicament for the treatment of mammals, including human hyperlipidemia.

17. Use of a composition according to any of claims 1-7 for the manufacture of a medicament for the treatment of a mammalian condition, including an angina condition.

18. Use of a composition according to any of claims 1 to 7 for the manufacture of a medicament for the treatment of a mammalian atherosclerotic disease.

19. Use of a composition according to any of claims 1 to 7 for the manufacture of a medicament for preventing a heart disease associated with hypertension or hyperlipidemia in a mammal.

20. A composition according to any one of claims 1 to 7, wherein the weight ratio of amlodipine to irbesartan in the composition is from 1:10 to 1:2000.

21. A composition according to any one of claims 1 to 7 wherein the composition has a weight ratio of amlodipine to telmisartan of from 1:1 to 1:1000.

22. A composition according to any of claims 1-7 wherein the weight ratio of amlodipine to valsartan in the composition is 1: 2-1: 2000.

23. A composition according to any of claims 1-7 wherein the weight ratio of amlodipine to losartan in the composition is from 1:1 to 1:1200.

24. A composition according to any of claims 1-7 wherein the composition has a weight ratio of amlodipine to candesartan of from 1:10 to 10:1.

The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is in the form of a tablet, a capsule, an oral solution, an injection, a powder injection, a sustained release agent, a dropping pill, and a granule. Or slow release pellets.