HK1029530B - Combination pharmaceutical form comprising amlodipine and a statin compound - Google Patents

Description

Combination pharmaceutical form comprising amlodipine and a statin compound

no marking

The present invention relates to pharmaceutical combinations of amlodipine or a pharmaceutically acceptable acid addition salt thereof and statins or a pharmaceutically acceptable salt thereof, kits containing said combinations and methods of using said combinations for treating subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and subjects presenting with symptoms of cardiac risk, including humans. The invention also relates to additive and synergistic combinations of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a statin compound or a pharmaceutically acceptable salt thereof, whereby the additive and synergistic combinations are useful in the treatment of subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and subjects presenting symptoms or signs of cardiac risk, including humans.

Background

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by HMG-CoA reductase. Inhibin inhibits HMG-CoA reductase from catalyzing this conversion reaction. Thus, various statins are effective lipid lowering agents. Statins include, for example, simvastatin as disclosed in U.S. Pat. No. 4,444,784 (which is incorporated herein by reference); pravastatin as disclosed in U.S. Pat. No. 4,346,227, which is incorporated herein by reference; cerivastatin as disclosed in U.S. patent 5,502,199 (which is incorporated herein by reference); mevastatin as disclosed in U.S. patent 3,983,140 (which is incorporated herein by reference); vilostatin (velostatin) disclosed in U.S. Pat. No. 4,448,784 and U.S. Pat. No. 4,450,171, both of which are incorporated herein by reference; fluvastatin as disclosed in U.S. Pat. No. 4,739,073, which is incorporated herein by reference; combretadine as disclosed in U.S. patent 4,804,770 (which is incorporated herein by reference); lovastatin as disclosed in U.S. Pat. No. 4,231,938, which is incorporated herein by reference; the pravastatin disclosed in European patent application publication No. 738510A 2 (which is incorporated herein by reference); fluroindolastatin (fluindostatin) disclosed in european patent application publication No. 363934 a1, which is incorporated herein by reference; atorvastatin (atorvastatin) disclosed in U.S. Pat. No. 4,681,893, which is incorporated herein by reference; atorvastatin calcium disclosed in U.S. Pat. No. 5,273,995 (which is incorporated herein by reference); and dihydrocompactin as disclosed in U.S. Pat. No. 4,450,171, which is incorporated herein by reference.

U.S. Pat. No. 4,572,909, which is incorporated herein by reference, discloses amlodipine and related dihydropyridine compounds useful as potent anti-ischemic and anti-hypertensive agents. Amlodipine besylate is disclosed in U.S. patent No. 4,879,303, which is incorporated herein by reference. Amlodipine and amlodipine besylate are strong long-acting calcium channel blockers. Therefore, amlodipine besylate and other pharmaceutically acceptable acid addition salts of amlodipine can be used as antihypertensive agents and anti-ischemic agents. The use of amlodipine and its pharmaceutically acceptable acid addition salts for the treatment of congestive heart failure is also disclosed in U.S. patent No. 5,155,120. Amlodipine benzenesulphonic acidSalt is currently available as Norvasc^The name of (1) is sold. Amlodipine has the following structural formula.

Atherosclerosis is a condition characterized by an irregular distribution of lipid deposits on the intima of arteries, including coronary, carotid and peripheral arteries. Death due to atherosclerotic coronary heart disease (hereinafter "CHD") accounts for 53% of all deaths due to cardiovascular events. CHD accounts for nearly half of the total annual cardiovascular medical costs in the United states (about $500 and 600 billion) and about 6% of the total national medical expenditure. Despite attempts to modify secondary risk factors such as smoking, obesity and lack of exercise, as well as treatment of dyslipidemia (dyslipemia) by modification of diet and drug therapy, CHD remains the leading cause of death in the united states.

High blood cholesterol and high blood lipids are conditions associated with the development of atherosclerosis. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) are known to be effective in lowering plasma cholesterol levels, particularly low density lipoprotein cholesterol (LDL-C) levels in men (Brown and Goldstein, New England journal of Medicine, 1981, 305, 9, 515-. It has now been shown that lowering LDL-C levels can prevent coronary heart disease (see, e.g., the Scandinavian simvastatin survival research group: randomized cholesterol lowering trials in 4444 patients with coronary heart disease: Scandinavian simvastatin survival study (4S), Lancet (Lancet), 1994, 344, 1383-89; shepherd. J. et al, use of pravastatin for prevention of coronary heart disease in men with hypercholesterolemia, New England journal of medicine, 1995, 333, 1301-07).

Angina is a severe chest tightness pain that usually radiates from the precordial region to the left shoulder and arm. Angina pectoris is usually caused by cardiac ischemia and is usually caused by coronary artery disease.

At present, there are great differences in the treatment of symptomatic angina pectoris in various countries. Patients with symptomatic stable angina are often treated in the united states with surgery or PTCA. Patients undergoing PTCA or other surgical procedures for treating angina pectoris are often associated with complications such as restenosis. The restenosis can be manifested as a short-term proliferation of the trauma caused by angioplasty, or as a long-term progression of atherosclerosis in the transplanted vessel and angioplasty segment.

Control of angina symptoms involves the use of a variety of drugs (usually in combinations of two or more) of the following classes: beta-blockers, nitrates, and calcium channel blockers. Most, if not all, patients also require treatment with lipid lowering drugs. The National Cholesterol Education Program (NCEP) identifies patients with coronary artery disease as a special population that requires invasive control of LDL-C elevation.

Amlodipine can prevent myocardial ischemia in exertional angina patients by reducing the total peripheral resistance (or afterload), which can reduce the heart rate-blood pressure product and thus reduce the need for myocardial oxygen at any particular exercise level. Amlodipine has been shown to block contraction and thereby restore myocardial oxygen supply in patients with vasospastic angina. In addition, amlodipine can also increase the oxygen supply to the myocardium by dilating coronary arteries.

Hypertension is often associated with hyperlipidemia and is considered a major risk factor for the development of heart disease that ultimately leads to adverse cardiac events. This classification of risk factors may be due to a common mechanism. In addition, compliance of patients with hypertension control is generally better than compliance with hyperlipidemia. Thus, a monotherapy capable of treating these conditions simultaneously would be advantageous to the patient.

Coronary heart disease is a multifactorial disease whose incidence and severity are influenced by lipid profile, the presence of diabetes, and the gender of the patient. Incidence is also affected by smoking and left ventricular hypertrophy (caused by hypertension), and it is important to control the overall risk profile in order to significantly reduce the risk of coronary heart disease. For example, attempts at hypertension intervention have been shown to fail to completely normalize the cardiovascular mortality caused by coronary heart disease. Treatment of patients with or without coronary artery disease with cholesterol synthesis inhibitors may reduce the risk of cardiovascular morbidity and mortality.

Framingham Heart Study (an ongoing prospective survey of adult males and females) demonstrates that certain risk factors can be used to predict the development of coronary Heart disease (see Wilson et al, J.Cardiol., USA, 1987, 59 (14): 91G-94G). These factors include age, sex, total cholesterol level, High Density Lipoprotein (HDL) level, systolic blood pressure, smoking, glucose tolerance, and cardiac enlargement (left ventricular hypertrophy on an electrocardiogram, echocardiogram, or cardiac enlargement in chest X-ray). The calculator or computer is easily programmed with a multivariate logistic function to be able to calculate the conditional probability of a cardiovascular event. These assessed the risk of coronary artery disease during different follow-up periods based on an assay of 5209 men and women participating in the Framingham survey. The modeled incidence varies from less than 1% to over 80% over an optional six year period. However, these incidences are generally less than 10%, and rarely exceed 45% in men and 25% in women.

Kramsch et al, Journal of Human Hypertension (1995) (supplement No. 1), 53-59, discloses the use of calcium channel blockers, including amlodipine, for the treatment of atherosclerosis. The document also suggests that a combination of amlodipine and a lipid lowering agent may be used to treat atherosclerosis. Tests in humans have shown that calcium channel blockers are beneficial for treating early atherosclerotic lesions (see, e.g., Lichtlen, p.r. et al, delay in angiographic development of coronary artery disease by nifedipine, lancets (Lancet), 1990, 335, 1109-13; Waters, D et al, clinical trials evaluating the effect of calcium channel blockers on development of coronary atherosclerosis, Circulation (Circulation), 1990, 82, 1940-53). U.S.4,681,893 discloses that certain statins, including atorvastatin, are hypolipidemic agents useful in the treatment of atherosclerosis. Jukema et al, supra, 1995 (supplement No. 1), 1-197 disclose that calcium channel blockers may act synergistically with lipid lowering agents (e.g., HMG-Coa reductase inhibitors), particularly pravastatin. Orekhov et al, Cardiovascular drugs and Therapy (Cardiovascular drugs and Therapy), 1997, 11, 350 disclose the use of amlodipine in combination Therapy with lovastatin for the treatment of atherosclerosis.

Summary of The Invention

The present invention relates to a pharmaceutical composition, hereinafter referred to as "composition a", comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof, an amount of statins or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, with the proviso that said statins are not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a pharmaceutical composition of composition a, hereinafter referred to as "composition AA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

In particular, the present invention relates to a pharmaceutical composition of composition AA, hereinafter "composition AB", wherein said statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a pharmaceutical composition of composition AA, hereinafter "composition AB", wherein the statin is simvastatin, pravastatin, mevastatin or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition of the composition AB, which contains amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter referred to as "composition B", for use with a second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, to achieve an antihypertensive effect and a hypolipidemic effect in mammals suffering from hypertension and hyperlipidemia, which is greater than the sum of the antihypertensive effect and the hypolipidemic effect achieved by administering said first and second pharmaceutical compositions separately, said first pharmaceutical composition comprising an amount of statins or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or diluent; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a pharmaceutical composition of composition B, hereinafter referred to as "composition BA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinvastatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin, compactin, or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

In particular, the present invention relates to a pharmaceutical composition of composition BA, hereinafter "composition BB", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a pharmaceutical composition of composition BA, wherein said second composition comprises amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter referred to as "composition C", for use with a second pharmaceutical composition comprising an amount of statins or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, to achieve an antihypertensive effect and a hypolipidemic effect in mammals suffering from hypertension and hyperlipidemia, said effects being greater than the sum of the antihypertensive effect and the hypolipidemic effect achieved by administering said first and second pharmaceutical compositions, respectively; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a pharmaceutical composition of composition C, hereinafter referred to as "composition CA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinvastatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin, compactin, or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

In particular, the present invention relates to a pharmaceutical composition of composition CA, hereinafter referred to as "composition CB", wherein said statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a pharmaceutical composition of composition CA, which comprises amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter referred to as "composition D", for use with a second pharmaceutical composition comprising an amount of statins or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, to achieve an antihypertensive effect and a hypolipidemic effect in mammals suffering from hypertension and hyperlipidemia, which effects are greater than those achieved by administering said first or second pharmaceutical composition, respectively; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

More particularly, the present invention relates to a pharmaceutical composition of composition D, which comprises amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter referred to as "composition E", for use with a second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, to achieve an antihypertensive effect and a hypolipidemic effect in mammals suffering from hypertension and hyperlipidemia, which are greater than those achieved by administering said first or second pharmaceutical composition, respectively, said first pharmaceutical composition comprising an amount of statins or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a pharmaceutical composition of composition E, hereinafter "composition EA", wherein said statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

The invention also relates to a pharmaceutical composition of composition EA, wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition F", for use with a second pharmaceutical composition comprising an amount of statins, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, to achieve an anti-angina effect in a mammal suffering from angina pectoris that is greater than the sum of the anti-angina effects achieved by administering said first and second pharmaceutical compositions separately, said first pharmaceutical composition comprising an amount of amlodipine, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a pharmaceutical composition of composition F, hereinafter referred to as "composition FA", wherein said statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

In particular, the present invention relates to a pharmaceutical composition of composition FA, hereinafter referred to as "composition FB", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a pharmaceutical composition of composition FA comprising amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition G", for use with a second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, to achieve an anti-angina effect in a mammal suffering from angina pectoris that is greater than the sum of the anti-angina effects achieved by administering said first and second pharmaceutical compositions separately, said first pharmaceutical composition comprising an amount of statins or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a pharmaceutical composition of composition G, hereinafter referred to as "composition GA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

In particular, the present invention relates to a pharmaceutical composition of composition GA, hereinafter referred to as "composition GB", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a pharmaceutical composition of composition GA, wherein said second pharmaceutical composition comprises amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter referred to as "composition H", for use with a second pharmaceutical composition comprising an amount of statins, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent, to achieve an anti-angina effect in a mammal suffering from angina pectoris that is greater than the anti-angina effect achieved by administering said first or second pharmaceutical composition, respectively; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

More particularly, the present invention relates to a pharmaceutical composition of composition H, which comprises amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter referred to as "composition J", for use with a second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, to achieve an anti-angina effect in a mammal suffering from angina pectoris that is greater than the anti-angina effect achieved by administering said first or second pharmaceutical composition, respectively, said first pharmaceutical composition comprising an amount of statins or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a pharmaceutical composition of composition J, hereinafter "composition JA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin, compactin, or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

The invention also relates to a pharmaceutical composition of composition JA, hereinafter referred to as "composition JB", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition K", for use with a second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, to achieve an anti-atherosclerotic effect in a mammal that is greater than the sum of the anti-atherosclerotic effects achieved by administering said first and second pharmaceutical compositions separately, said first pharmaceutical composition comprising an amount of statins or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a pharmaceutical composition of composition K, hereinafter referred to as "composition KA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinvastatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

In particular, the present invention relates to a pharmaceutical composition of composition KA, hereinafter referred to as "composition KB", wherein said statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More specifically, the present invention relates to a pharmaceutical composition of composition KA, hereinafter "composition KB", wherein said second pharmaceutical composition comprises amlodipine besylate.

More specifically, the invention also relates to a pharmaceutical composition of composition KB, hereinafter referred to as "composition KC", wherein said anti-atherosclerotic effect is manifested as a delay in the development of atherosclerotic plaques.

More particularly, the invention also relates to a pharmaceutical composition of composition KC, wherein the development of atherosclerotic plaques in the coronary arteries is delayed.

The invention also relates to a composition of composition KC, wherein the development of atherosclerotic plaques is delayed in the carotid arteries.

The invention also relates to a composition of composition KC, wherein the development of atherosclerotic plaques is delayed in the peripheral arterial system.

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

More particularly, the invention also relates to a composition of composition KD wherein the regression of atherosclerotic plaques occurs in coronary arteries.

More particularly, the invention also relates to a composition of composition KD wherein the regression of atherosclerotic plaques occurs in carotid arteries.

More particularly, the invention also relates to a composition of composition KD wherein the regression of atherosclerotic plaques occurs in the peripheral arterial system.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition L", for use with a second pharmaceutical composition comprising an amount of statins, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, to achieve an anti-atherosclerotic effect in a mammal that is greater than the sum of the anti-atherosclerotic effects achieved by administration of said first and second pharmaceutical compositions, respectively, said first pharmaceutical composition comprising an amount of amlodipine, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a composition of composition L, hereinafter "composition LA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

In particular, the present invention relates to a composition of composition LA, hereinafter "composition LB", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a composition of composition LA, hereinafter "composition LB", which comprises amlodipine besylate.

More particularly, the present invention also relates to a composition of composition LB, hereinafter referred to as "composition LC", wherein said anti-atherosclerotic effect is manifested as a delay in the development of atherosclerotic plaques.

More particularly, the invention also relates to a composition of composition LC wherein the development of atherosclerotic plaques in coronary arteries is retarded.

The invention also relates to a composition of composition LC wherein the development of atherosclerotic plaques is delayed in the carotid artery.

The invention also relates to a composition of composition LC wherein the development of atherosclerotic plaques is delayed in the peripheral arterial system.

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

More particularly, the present invention also relates to a composition of composition LD wherein the regression of atherosclerotic plaques occurs in coronary arteries.

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

More particularly, the present invention also relates to a composition of composition LD wherein the regression of atherosclerotic plaques occurs in the peripheral arterial system.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition M", for use with a second pharmaceutical composition comprising an amount of statins, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent, for achieving an anti-atherosclerotic effect in a mammal, said effect being greater than the anti-atherosclerotic effect achieved by administration of said first or second pharmaceutical composition, respectively; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

More particularly, the present invention relates to a composition of composition M, which comprises amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition N", for use with a second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of statins or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, for achieving an anti-atherosclerotic effect in a mammal, which effect is greater than the anti-atherosclerotic effect achieved by administration of said first or second pharmaceutical composition, respectively; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a composition of composition N, hereinafter referred to as "composition NA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

The invention also relates to a composition of composition NA, wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition P", for use with a second pharmaceutical composition comprising an amount of statins, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, for controlling cardiac risk in a mammal at risk of developing an adverse cardiac event, said effect being greater than the sum of the cardiac risk controlling effects achieved by administering said first and second pharmaceutical compositions separately, said first pharmaceutical composition comprising an amount of amlodipine, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a composition of composition P, hereinafter referred to as "composition PA", wherein said statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

In particular, the present invention relates to a composition of composition PA, hereinafter referred to as "composition PB", wherein said statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a composition of composition PA comprising amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition Q", for use with a second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, for controlling cardiac risk in a mammal at risk of developing an adverse cardiac event, said effect being greater than the sum of the cardiac risk controlling effects achieved by administering said first and second pharmaceutical compositions separately, said first pharmaceutical composition comprising an amount of statins or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a composition of composition Q, hereinafter "composition QA", wherein said statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dalvastatin, dihydrocompactin, compactin, or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

In particular, the present invention relates to a composition of composition QA, wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a composition of composition QA wherein said second pharmaceutical composition comprises amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition R", for use with a second pharmaceutical composition comprising an amount of statins, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier or diluent, for controlling cardiac risk in a mammal at risk of developing an adverse cardiac event, said effect being greater than the effect on controlling cardiac risk achieved by administering said first or second pharmaceutical composition, respectively; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

More particularly, the present invention relates to a composition of composition R, which contains amlodipine besylate.

The present invention also relates to a first pharmaceutical composition, hereinafter "composition S", for use with a second pharmaceutical composition comprising an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of statins or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, for controlling cardiac risk in a mammal at risk of developing an adverse cardiac event, said effect being greater than the cardiac risk controlling effect achieved by administering said first or second pharmaceutical composition, respectively; provided that the statin is not atorvastatin or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a composition of composition S, hereinafter referred to as "composition SA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

The invention also relates to a composition of composition SA, wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

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

a. an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;

b. an amount of statin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and

c. a container for containing said first and second dosage forms, with the proviso that said statin is not atorvastatin or a pharmaceutically acceptable acid addition salt thereof.

In particular, the present invention relates to a kit of kit a, hereinafter referred to as "kit AA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

The invention also relates to a kit of kit AA, hereinafter referred to as "kit AB", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a kit of kits AA, hereinafter referred to as "kit AZ", which contains amlodipine besylate.

The invention also relates to a kit of kit a, wherein the therapeutic effect is the treatment of hypertension and hyperlipidemia.

The invention also relates to a kit of kit a, wherein the therapeutic effect is the treatment of angina pectoris.

The invention also relates to a kit of kit a wherein the therapeutic effect is controlling cardiac risk.

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

The invention also relates to a kit of kits AB, hereinafter referred to as "kit AC", wherein the treatment of atherosclerosis is the delay of the development of atherosclerotic plaques.

The invention also relates to a kit of parts AC, wherein the development of atherosclerotic plaques in coronary arteries is delayed.

The invention also relates to a kit of kits AC, wherein the development of atherosclerotic plaques is delayed in the carotid artery.

The invention also relates to a kit of kits AC, wherein the development of atherosclerotic plaques is delayed in the peripheral arterial system.

A kit of parts AB, hereinafter referred to as "kit AD", wherein the treatment of atherosclerosis is causing regression of atherosclerotic plaques.

The invention also relates to a kit of parts AD, wherein the regression of atherosclerotic plaques occurs in coronary arteries.

The invention also relates to a kit of kit AD, wherein the regression of atherosclerotic plaques occurs in the carotid arteries.

The invention also relates to a kit of kit AD, wherein the regression of atherosclerotic plaques occurs in the peripheral arterial system.

The invention also relates to a kit of kit AZ, hereinafter referred to as "kit AE", wherein the therapeutic effect is the treatment of hypertension and hyperlipidemia.

The invention also relates to a kit of kits AZ, hereinafter referred to as "kit AF", wherein the therapeutic effect is the treatment of angina pectoris.

The invention also relates to a kit of kits AZ, hereinafter referred to as "kit AG", wherein the therapeutic effect is the control of cardiac risk.

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

The invention also relates to a kit of kit AH, hereinafter referred to as "kit AJ", wherein the treatment of atherosclerosis is the delay of the development of atherosclerotic plaques.

The invention also relates to a kit of parts AJ, wherein the development of atherosclerotic plaques in coronary arteries is delayed.

The invention also relates to a kit of parts AJ, wherein the development of atherosclerotic plaques is delayed in the carotid artery.

The invention also relates to a kit of parts AJ, wherein the development of atherosclerotic plaques is delayed in the peripheral arterial system.

A kit of kit AH, hereinafter "kit AK", wherein said treatment of atherosclerosis is causing regression of atherosclerotic plaques.

The invention also relates to a kit AK, wherein the regression of atherosclerotic plaques occurs in coronary arteries.

The invention also relates to a kit AK, wherein the regression of atherosclerotic plaques occurs in carotid arteries.

The invention also relates to a kit AK, wherein the regression of atherosclerotic plaques occurs in the peripheral arterial system.

The present invention also relates to a method of treating a mammal in need thereof, hereinafter referred to as "method A", comprising administering to said mammal

(a) An amount of a first compound that is amlodipine or a pharmaceutically acceptable acid addition salt thereof;

(b) an amount of a second compound that is a statin or a pharmaceutically acceptable salt thereof;

wherein said first compound and said second compound may be administered independently of each other, optionally together with a pharmaceutically acceptable carrier or diluent, with the proviso that said statin is not atorvastatin or a pharmaceutically acceptable acid addition salt thereof.

In particular, the present invention relates to one of the methods of method a, hereinafter "method AA", wherein the statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin, compactin, or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin.

The present invention relates to one of the methods of method AA, hereinafter "method AB", wherein said statin is simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, dalvastatin, dihydrocompactin or compactin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin or compactin.

More particularly, the present invention relates to a method of method AA, hereinafter "method AB", which comprises amlodipine besylate.

The invention also relates to a method of method a, hereinafter "method AC", wherein said first compound and said second compound are administered simultaneously.

The invention also relates to a method of method a, hereinafter "method AD", wherein said first compound and said second compound are administered sequentially, in any order.

The invention also relates to a method of method AB, hereinafter "method AE", wherein said first compound and said second compound are administered simultaneously.

The invention also relates to a method of method AB, hereinafter "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 said treatment comprises antihypertensive treatment and antihyperlipidemic treatment.

The invention also relates to a method of AE, wherein the treatment comprises antihypertensive treatment and antihyperlipidemic treatment.

The invention also relates to a method of method AF, wherein said treatment comprises antihypertensive treatment and antihyperlipidemic treatment.

The invention also relates to a method of method a wherein said treatment comprises anti-angina treatment.

The invention also relates to a method of method AE, wherein said treatment comprises anti-angina treatment.

The invention also relates to a method of method AF, wherein the treatment comprises anti-angina treatment.

The invention also relates to a method of method a wherein said treatment comprises cardiac risk control.

The invention also relates to a method of AE, wherein said treatment comprises cardiac risk management.

The invention also relates to a method of treating AF, wherein said treatment comprises cardiac risk management.

The invention also relates to a method of method a wherein said treatment comprises anti-atherosclerotic treatment.

The invention also relates to a method of method AE, wherein said treatment comprises anti-atherosclerotic treatment.

The invention also relates to a method of method AF, wherein said treatment comprises anti-atherosclerotic treatment.

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 in arowsmith et al, journal of medicinal chemistry (j.med. chem.), 1986, 29, 1696. Essentially only the S (-) isomer and racemic mixtures containing the R (+) and S (-) forms have calcium channel blocker activity. (see International patent application No. PCT/EP 94/02697). The calcium channel blocker of the R (+) isomer is either poorly active or inactive. However, the R (+) isomer is a potent inhibitor of smooth muscle cell migration. Thus, the R (+) isomer is useful for treating or preventing atherosclerosis. (see International patent application No. PCT/EP 95/00847). For the reasons stated above, one skilled in the art will select the R (+) isomer, the S (-) isomer or a racemic mixture of the R (+) isomer and the S (-) isomer for use in the compound of the present invention.

The term "cardiac risk" as used herein refers to the likelihood that a patient will suffer from a future adverse cardiac event such as myocardial infarction, cardiac arrest, heart failure, cardiac ischemia. Cardiac risk can be calculated using the Framingham risk equation described. The term "control of cardiac risk" means that the risk of future adverse cardiac events is substantially reduced.

Detailed Description

The compound of the invention comprises two active ingredients: amlodipine or a pharmaceutically acceptable acid addition salt thereof and inhibin or a pharmaceutically acceptable salt thereof. The compound of the invention can also contain a pharmaceutically acceptable carrier or diluent.

Amlodipine is a potent calcium channel blocker and can be used for the treatment of hypertension. Amlodipine can be prepared as described in U.S. patent No. 4,572,909, which is incorporated herein by reference. At present, the Norvasc is adopted^The sold amlodipine besylate salt may be prepared as described in U.S. patent No. 4,879,303, which is incorporated herein by reference. Other pharmaceutically acceptable acid addition salts of amlodipine, amlodipine besylate and amlodipine are strong long-acting calcium channel blockers. Other acid addition salts of amlodipine can be prepared by reacting the free base of amlodipine with a suitable acid. When the salt is a salt of a monovalent acid (e.g., hydrochloride, hydrobromide, p-toluenesulfonate, acetate), a hydrogen salt of a divalent acid (e.g., hydrogen sulfate, hydrogen succinate) or a dihydrogen salt of a trivalent acid (e.g., dihydrogen phosphate, dihydrogen citrate), at leastOne molar equivalent of acid is generally used, with a molar excess of acid. However, when a salt such as a sulfate, hemisuccinate, hydrogen phosphate or phosphate salt is desired, an appropriate and precise stoichiometric amount of acid is typically used. The free base of amlodipine and the acid are usually mixed in a co-solvent that can precipitate the desired salt, or can be isolated by concentration and/or addition of a poor solvent.

Another active ingredient used in the compound of the invention is inhibin. The term "statin" as used in the present specification and claims is an synonym for the terms "3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor" and "HMG-CoA reductase inhibitor". The above three terms may be used interchangeably throughout the specification and claims. As the consent suggests, statins are inhibitors of 3-hydroxy-3-methylglutaryl-coa reductase and are therefore effective in lowering plasma cholesterol levels. Statins and pharmaceutically acceptable salts thereof are particularly useful in lowering low density lipoprotein cholesterol (LDL-C) levels in mammals, particularly humans.

HMG-CoA reductase inhibitors suitable for use in the present invention include, but are not limited to, simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, mevastatin, fluvastatin, pravastatin, dihydrocompactin, compactin, or lovastatin; or a pharmaceutically acceptable salt of simvastatin, pravastatin, rivastatin, mevastatin, fluroinstatin, vilostatin, fluvastatin, pravastatin, dihydrocompactin, compactin or lovastatin. However, it is noted that atorvastatin or a pharmaceutically acceptable salt thereof is not within the scope disclosed herein.

The statins disclosed herein may be prepared according to methods well known to those skilled in the art. In particular, simvastatin can be prepared according to the methods disclosed in U.S. Pat. No. 4,444,784, which is incorporated herein by reference. Pravastatin can be prepared according to the methods disclosed in U.S. Pat. No. 4,346,227, which is incorporated herein by reference. cerivastatin may be prepared according to the methods disclosed in U.S. patent 5,502,199, which is incorporated herein by reference. cerivastatin can also be prepared according to the method disclosed in European patent application publication No. EP 617019. Mevastatin can be prepared according to the methods disclosed in U.S. patent 3,983,140, which is incorporated herein by reference. Vilostatin can be prepared according to the methods disclosed in U.S. patent 4,448,784 and U.S. patent 4,450,171, both of which are incorporated herein by reference. Fluvastatin may be prepared according to the methods disclosed in U.S. Pat. No. 4,739,073, which is incorporated herein by reference. Conpidine can be prepared according to the methods disclosed in U.S. Pat. No. 4,804,770, which is incorporated herein by reference. Lovastatin can be prepared according to the methods disclosed in U.S. Pat. No. 4,231,938, which is incorporated herein by reference. Davastatin may be prepared according to the procedures disclosed in European patent application publication No. 738510A 2, which is incorporated herein by reference. Fluorandantin may be prepared according to the methods disclosed in European patent application publication No. 363934A 1, which is incorporated herein by reference. Dihydrocombretadine may be prepared according to the methods disclosed in U.S. Pat. No. 4,450,171, which is incorporated herein by reference.

It will be appreciated that some of the statins described above contain a free carboxyl group or a free amino group as part of their chemical structure. In addition, certain statins within the scope of the present invention also contain a lactone group, which is present in equilibrium with the free carboxylic acid form. The lactones can be present in the form of carboxylic acids by preparing pharmaceutically acceptable salts of the lactones. Accordingly, the present invention includes pharmaceutically acceptable salts of these carboxylic acids or amino groups. The term "pharmaceutically acceptable salts" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cation salts. "pharmaceutically acceptable cationic salts" are intended to define, but are not limited to, alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), aluminum salts, ammonium salts, salts with organic amines such as benzathine (N, N' -dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benzylamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), and procaine, and the like. The term "pharmaceutically acceptable acid addition salts" is used to define, but is not limited to, hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate, p-toluenesulfonate and the like.

Pharmaceutically acceptable cationic salts of statins containing a free carboxylic acid can be conveniently prepared by reacting the free acid form of the statin with a suitable base (typically 1 equivalent) in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine, and tromethamine. The salt can be isolated by concentration to dryness or by addition of a poor solvent. In many cases, it is preferred to prepare the acid by mixing a solution of the acid with a solution of another cationic salt (sodium or potassium ethylhexanoate, magnesium oleate) and using a solvent that can precipitate the desired cationic salt (e.g., ethyl acetate), or can be isolated by concentration and/or addition of a poor solvent.

Pharmaceutically acceptable acid addition salts of statins containing a free amino group may conveniently be prepared by reacting the free base form of the statin with a suitable acid. When the salt is a salt of a monobasic acid (e.g., hydrochloride, hydrobromide, p-toluenesulfonate, acetate), a hydrogen salt of a dibasic acid (e.g., hydrogen sulfate, hydrogen succinate) or a dihydrogen salt of a tribasic acid (e.g., dihydrogen phosphate, dihydrogen citrate), at least one molar equivalent of the acid is used, usually a one molar excess of the acid is used. However, when a salt such as a sulfate, hemisuccinate, hydrogen phosphate or phosphate salt is desired, an appropriate and precise stoichiometric amount of acid is typically used. The free base and acid are typically mixed in a co-solvent that can precipitate the desired salt, or can be separated by concentration and/or addition of a poor solvent.

Further, amlodipine and pharmaceutically acceptable acid addition salts thereof may also be in the form of a hydrate or solvate. Furthermore, the statins of the invention and pharmaceutically acceptable salts of the statins of the invention may also be in the form of hydrates or solvates. Such hydrates and solvates are also included within the scope of the present invention.

The pharmaceutical compositions and methods of the present invention are useful for treating atherosclerosis, angina pectoris, and conditions characterized by the co-existence of hypertension and hyperlipidemia in mammals, particularly humans. In addition, because these diseases and conditions are closely related to the development of heart disease and adverse cardiac events, these compounds and methods are useful for controlling cardiac risk in patients at risk for developing adverse cardiac conditions and at risk for adverse cardiac events due to their anti-atherosclerotic, anti-angina, anti-hypertensive and anti-hyperlipidemic effects.

The effectiveness of the compounds of the present invention as a pharmaceutical in the treatment of atherosclerosis in mammals (e.g., humans) can be demonstrated by the activity of the compounds of the present invention in the following routine and clinical trials.

Amlodipine and inhibin are administered alone or in combination

Therapeutic effect on atherosclerosis

This study is a prospective randomized assessment of the effect of a combination of amlodipine or a pharmaceutically acceptable salt thereof and statins on the progression/regression of coronary and carotid artery disease. This study was conducted to demonstrate that combinations of amlodipine or a pharmaceutically acceptable acid addition salt thereof and statins are effective in slowing or arresting the progression of Coronary Artery Disease (CAD) or causing regression of existing coronary artery disease in patients identified as having the disease, as evidenced by changes in coronary angiography or carotid ultrasound.

The study was conducted as a double-blind, placebo-controlled trial with a minimum of about 500 subjects, preferably about 780 to about 1200 subjects, using a coronary artery disease angiography file. It is particularly preferred to study about 1200 subjects in this study. Subjects were admitted to the study after meeting the entry criteria described below.

Entry criteria: the subjects admitted to the trial must meet certain criteria. Thus, the subject must be an adult aged 18-80 years of age undergoing clinical coronary angiographyHuman, male or female. When subsequently assessed by Quantitative Coronary Angiography (QCA), the subject may judge that it is unlikely that surgery would require significant focal lesions, e.g. 30% to 50%, in at least one vessel segment (non-PTCA, non-bypass or non-MI vessels) within the next 3 years. The vessel segment to be analyzed must be left undisturbed. Since Percutaneous Transluminal Cardiac Angioplasty (PTCA) intervenes in a vessel segment by insertion of a balloon catheter, a non-PTCA vessel segment is required for analysis. The vessel segment being analyzed must also be unaffected by thrombotic events such as Myocardial Infarction (MI). non-MI vessels are therefore needed. The vessel segment to be analyzed included: left trunk, proximal, middle and distal left anterior descending branch, first and second diagonal branches, proximal and distal left circumflex artery, first or maximum clearance blunt edge, proximal, middle and distal right coronary artery. The subject should have an ejection fraction greater than 30% when or within 3 months prior to receiving a qualified angiogram, as determined by catheterization or radionuclide ventricular angiography or ECHO electrocardiography, provided that no interventional event such as a thrombotic event or surgery such as PTCA has occurred.

Typically, the study is conducted in multiple locations due to the number of patients and physical limitations of the facility. At study entry, subjects received quantitative coronary angiography and type B carotid ultrasonography and evaluated carotid compliance at the designated test centers. Thereby establishing a baseline for each subject. Once admitted to the trial, subjects were randomized to receive amlodipine besylate (10mg) and placebo or statin (the dose depends on the particular statin used, but typically 80mg was used first) and placebo or amlodipine besylate (10mg) and statin (80 mg). It will be appreciated by those skilled in the art that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of statins may also be used in the present invention. Dose calculations for statins and other forms of amlodipine besylate are readily accomplished by simple comparisons of the molecular weights of the materials involved. The amount of amlodipine can be varied as desired. Typically, the subject may start at 10mg and gradually decrease to 5mg, as determined by the clinician. Also, for optimal effect by the subject, the physician may decide to gradually decrease the amount of statin starting from 80 mg. The subject is monitored for 1-3 years, with 3 years generally preferred. Type B carotid ultrasound assessment of atherosclerosis and compliance of carotid arteries at regular intervals throughout the study.

Typically, a suitable interval is 6 months. Evaluation is usually performed with a B-ultrasound apparatus. However, other methods may be used by those skilled in the art to make this assessment. Coronary angiography is performed at the end of the 1-3 year treatment period. Baseline and post-treatment angiograms and interventional carotid ultrasonography B were evaluated to assess the development of new lesions or existing atherosclerotic lesions. A measure of arterial compliance was evaluated to assess changes from baseline and over a 6 month evaluation period.

The first objective of this study was to demonstrate that a combination of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a statin can reduce the development of atherosclerotic lesions in subjects with coronary artery disease when determined by Quantitative Coronary Angiography (QCA). The QCA may determine the pore canals in the lumen of the artery being measured.

The first endpoint of the study was the change in mean diameter of the mean segment of the coronary tree. Thus, the diameter of the arterial segment is measured at multiple locations along the length of the arterial segment. The average diameter of the segment is then determined. After the average segment diameter for a number of segments is determined, the average of all segment means is calculated to obtain the average segment diameter mean. Subjects receiving statin and amlodipine or a pharmaceutically acceptable acid addition salt thereof will have a slower, complete cessation of, or increase in average segmental diameter. These results indicate that the development of atherosclerosis is delayed, the development of atherosclerosis is stopped and atherosclerosis is resolved, respectively.

The second objective of this study was to demonstrate that amlodipine or a pharmaceutically acceptable acid addition salt thereof and statins reduce the rate of progression of atherosclerosis in the carotid artery as measured by the slope of the mean maximum intimal-media thickness measurement (mean maximum) as a function of time for 12 different vessel wall segments, greater than the effect of amlodipine or a pharmaceutically acceptable acid addition salt thereof or statins alone. Subjects receiving statin and amlodipine or a pharmaceutically acceptable acid addition salt thereof have a slower increase in intimal media thickness, stop the increase, or begin to decrease. These results indicate that the development of atherosclerosis is delayed, the development of atherosclerosis is stopped and atherosclerosis is resolved, respectively. In addition, these results can be used to help determine dosage.

The effectiveness of the compounds of the present invention as a medicament in the treatment of angina pectoris in a mammal (e.g., a human) can be confirmed by the activity of the compounds of the present invention in the following routine tests and clinical tests.

Amlodipine and inhibin are administered alone or in combination

Effect for treating angina pectoris

The study is a double-blind, parallel, randomized study demonstrating the efficacy of amlodipine or a pharmaceutically acceptable acid addition salt thereof in combination with statins in the treatment of symptomatic angina.

Entry criteria: the subjects were either male or female between 18-80 years of age, had a typical history of chest pain and were accompanied by one of the following objective evidence of cardiac ischemia: (1) ST elevation in ECG by 1 mm or more; (2) the stress test of the treadmill is positive; (3) new wall motion abnormalities in ultrasound; or (4) coronary angiograms with significant stenosis. Generally, a stenosis of about 30-50% is considered significant.

Each subject is evaluated for about 10 to 32 weeks. At least 10 weeks are typically required to complete the study. Sufficient subjects were used in this screen to ensure that about 200 and 800 subjects, preferably about 400 subjects, were able to complete the study. Subjects were screened for 4 weeks using the following entry criteria. After meeting the screening criteria, the anti-angina drug currently used by the subject is washed out and stabilized on a long-acting nitrate such as nitroglycerin, isosorbide-5-mononitrate, or isosorbide dinitrate. The term "washout" as used in this screen refers to the cessation of the currently used anti-angina drug such that substantially all of the drug is eliminated from the subject. A period of 8 weeks may be used to simultaneously complete the wash-out period and establish the subject on stable administration of the nitrate. Subjects who have angina attacks one or two times per week when long-acting nitrates are administered stably are generally allowed to skip the washout period. After the subject stabilized on nitrate, the subject entered the randomization phase, provided that the subject had sustained angina attacks one or two per week. During the randomization phase, subjects were randomized into one of the four study groups described below. After completion of the washout period, subjects who met the entry criteria were subjected to 24 hours of active Electrocardiogram (ECG) monitoring, such as halt monitoring, exercise stress testing, such as treadmill, and PET (photon emission tomography) scanning to assess myocardial perfusion to establish a baseline for each subject. When performing stress testing, the speed of the treadmill and the grade of the treadmill may be controlled by a technician. The speed of the treadmill and the angle of the tread slope typically increase during the testing period. The time interval between each speed and grade increase is typically determined using a modified Bruce Protocol.

After completion of the baseline determination, subjects were initiated in one of the following four study groups: (1) a placebo; (2) inhibin (about 2.5mg-160 mg); (3) amlodipine besylate (about 2.5mg to about 20 mg); or (4) the amlodipine besylate and the inhibin compound with the dosage. The subjects were then monitored for 2-24 weeks. It will be appreciated by those skilled in the art that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of statins may also be used in the present invention. Dose calculations for statins and other forms of amlodipine besylate are readily accomplished by simple comparisons of the molecular weights of the materials involved.

After the end of the monitoring period, the subjects received the following survey: (1)24 hour active ECG, such as Holter monitoring; (2) exercise stress testing (e.g., treadmill testing using the modified BruceProtocol); (3) myocardial perfusion was assessed with PET scans. Patients still had painful ischemic events and used nitroglycerin on a daily basis. It is often desirable to accurately record the number of angina attacks in a patient over the course of a test. Since patients usually take nitroglycerin to relieve pain or angina pectoris attacks, the number of times patients take nitroglycerin can reasonably and accurately record the number of angina pectoris attacks.

To confirm the efficacy and dosage of the pharmaceutical combination of the invention, the person performing the test can evaluate the subject using the test described. When detected with ECG, successful treatment may reduce the incidence of ischemic events, may allow the subject to exercise on a treadmill for longer periods of time or with greater intensity, or may exercise on a treadmill without pain, or may exhibit better perfusion or less hypoperfusion in PET.

The effectiveness of the compounds of the present invention as a medicament for treating hypertension and hyperlipidemia in mammals (e.g., humans) suffering from a combination of hypertension and hyperlipidemia can be confirmed by the activity of the compounds of the present invention in the following routine tests and clinical trials.

Amlodipine and inhibin are administered alone or in combination for patients suffering from both

Therapeutic effect on patients with hypertension and hyperlipidemia

The study is a double-blind, parallel, randomized study demonstrating the effect of combined administration of amlodipine or a pharmaceutically acceptable acid addition salt thereof and statins in the simultaneous control of hypertension and hyperlipidemia in patients with mild, moderate or severe hypertension and hyperlipidemia.

Each subject is evaluated for 10-20 weeks, preferably 14 weeks. Enough subjects were used in this screen to ensure that approximately 400 and 800 subjects were able to complete the study.

Entry criteria: the subject is aged 18-80 years old with hyperlipemia and hypertensionAdult male or female. The presence of hyperlipidemia can be confirmed by assessing Low Density Lipoprotein (LDL) levels in a subject associated with certain positive risk factors. A subject is considered to have hyperlipidemia requiring drug treatment when the subject's LDL is greater than or equal to 190 if the subject does not have Coronary Heart Disease (CHD) and the positive risk factors are less than two. A subject is considered to have hyperlipidemia requiring drug treatment when the subject's LDL is greater than or equal to 160 if the subject does not have CHD and has two or more positive risk factors. A subject is considered to have hyperlipidemia when the LDL of the subject is greater than or equal to 130 if the subject has CHD.

Positive risk factors include: (1) a male over the age of 45, (2) a female over the age of 55, wherein the female has not undergone Hormone Replacement Therapy (HRT), (3) a family history of early-onset cardiovascular disease, (4) the subject frequently smokes, (5) the subject has diabetes, (6) HDL is below 45, and (7) the subject has hypertension. HDL above 60 is considered a negative risk factor and can offset one of the positive risk factors described above.

Hypertension is indicated when the resting diastolic Blood Pressure (BP) is greater than 90 or the resting systolic BP is greater than 140. All blood pressures were the average of three measurements at 5 minute intervals.

Subjects were screened using the entry criteria described above. When all screening criteria were met, subjects were washed out of the antihypertensive and lipid lowering drugs currently used and were placed on the NCEP ATPII step 1 diet. NCEP ATP II (adult treatment protocol, second revision) the step 1 diet addresses the amount of saturated and unsaturated fats that can be consumed as part of total caloric intake. The term "washout" as used in this screen refers to the cessation of the antihypertensive and lipid lowering agents currently in use such that substantially all of the agent is eliminated from the subject. Newly diagnosed subjects are typically not treated prior to the start of the trial. These subjects also used the NCEPATP II step 1 diet. After a 4-week washout period and a diet stabilization period, subjects were subjected to the following baseline survey: (1) blood pressure and (2) fasting lipid test. Fasting lipid testing determines the baseline lipid level of a subject in the fasted state. Typically, subjects fasted for 12 hours and then lipid levels were determined.

After performing the baseline survey, the subject began receiving one of the following items: (1) fixed dose amlodipine besylate, typically about 2.5-10 mg; (2) a fixed dose of statin, typically about 2.5-160 mg; or (3) the amlodipine besylate and the inhibin compound with the dosage. It will be appreciated by those skilled in the art that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of statins may also be used in the present invention. Dose calculations for statins and other forms of amlodipine besylate are readily accomplished by simple comparisons of the molecular weights of the materials involved. Subjects continued to use these doses for at least 6 weeks, usually no more than 8 weeks. After 6-8 weeks, subjects were returned to the test center to again assess baseline. The blood pressure of the subject at the end of the study was compared to the blood pressure of the subject at the time of entry. Lipid testing measures total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apoB, VLDL (very low density lipoprotein) and other components of the subject's lipid profile. The improvement in the values obtained after treatment relative to the values before treatment indicates the effectiveness of the drug combination.

The effectiveness of the compounds of the present invention as pharmaceuticals in controlling cardiac risk in mammals, such as humans, at risk for adverse cardiac events may be demonstrated by the activity of the compounds of the present invention in the following routine and clinical trials.

Future onset of amlodipine and inhibin administration alone or in combination

Effect of treatment of subjects at risk of cardiovascular events

The study is a double-blind, parallel, randomized study demonstrating the effect of the combined administration of amlodipine or a pharmaceutically acceptable acid addition salt thereof and statins in reducing the calculated total risk for future cardiovascular events in subjects at risk for developing such events. The risk was calculated using the Framingham Risk equation. A subject is considered at risk for a future cardiovascular event if the subject has more than one standard deviation from the mean calculated by the Framingham risk equation. This study was conducted to evaluate the effect of a combination of fixed amlodipine or a pharmaceutically acceptable acid addition salt thereof and statins in controlling cardiovascular risk in patients with mild to moderate hypertension and hyperlipidemia by simultaneously controlling hypertension and hyperlipidemia.

Each subject is evaluated for 10-20 weeks, preferably 14 weeks. Enough subjects were recruited to ensure that about 400 and 800 subjects were able to complete the study.

Entry criteria: the subjects included in the study were adult male or female subjects between 18-80 years of age, with a 5 year risk baseline that was higher than the median for age and gender of the subjects as determined by the Framingham heart study (a prospective study of adult males and females to show which risk factors can be used to predict development of coronary heart disease). Age, sex, systolic and diastolic blood pressure, smoking, the presence of sugar intolerance, the presence of left ventricular hypertrophy, serum cholesterol and high density lipoprotein (LDL) above the Framingham Population standard by more than one standard deviation are all evaluated to determine whether a patient is at risk for an adverse cardiac event. The values of the risk factors are substituted into the Framingham equation and calculated to determine whether the subject is at risk for a future cardiovascular event.

Subjects were screened using the entry criteria described above. When all screening criteria are met, the subjects are washed out of the antihypertensive and lipid lowering agents currently used and any other drugs that may affect the screening results. The patient was then placed on the NCEP ATP II step 1 diet described above. Newly diagnosed subjects are typically not treated prior to the start of the trial. These subjects also used the NCEP ATP II step 1 diet. After a 4-week washout period and a diet stabilization period, subjects were subjected to the following baseline survey: (1) blood pressure; (2) fasting; (3) lipid examination; (4) a glucose tolerance test; (5) an ECG; (6) cardiac ultrasound. These tests were carried out by conventional methods well known to those skilled in the art. ECG and cardiac ultrasound are commonly used to determine the presence or absence of left ventricular hypertrophy.

After the baseline survey was performed, the patient began receiving one of the following items: (1) fixed dose amlodipine besylate (about 2.5-10 mg); (2) a fixed dose of inhibin (about 2.5-160 mg); or (3) the amlodipine besylate and the inhibin compound with the dosage. Patients were asked to continue using these doses and return within 6-8 weeks to re-assess baseline. At this point, the new values are substituted into the Framingham equation to determine whether the subject's risk of a future cardiovascular event is reduced, increased, or unchanged.

The above experiments demonstrate the efficacy of amlodipine or a pharmaceutically acceptable acid addition salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof in the treatment of angina pectoris, atherosclerosis, hypertension associated with hyperlipidemia, cardiac risk control, and also provide a means for comparing the activity between the compounds of the present invention and the activity of other known compounds. The results of these comparisons can be used to determine dosage levels for treating the disease in mammals, including humans.

The following doses, as well as other doses given in the present specification and appended claims, are for a typical human patient weighing from about 65kg to about 70 kg. The person skilled in the art will readily be able to determine the required dosage for a patient weighing outside the range of 65kg to 70kg, based on the patient's history and the diseases present, such as diabetes. The dosages given herein and in the appended claims are daily dosages.

Generally, amlodipine is generally administered in a dose of about 2.5mg to about 20mg in accordance with the present invention. Preferably, amlodipine is administered in a dose of about 5mg to about 10 mg. It will be appreciated by those skilled in the art that the free base form or other salt forms of amlodipine besylate may also be used in the present invention. Calculation of the dosage of the other forms of amlodipine besylate, or the free base form or other salt forms, is readily accomplished by simple comparison of the molecular weights of the materials involved.

Generally, according to the invention, the above statins are administered in the following doses:

simvastatin, typically from about 2.5mg to about 160mg, preferably from about 10mg to about 40 mg;

pravastatin, typically from about 2.5mg to about 160mg, preferably from about 10mg to about 40 mg;

cerivastatin, typically about 25 μ g to about 5mg, preferably about 1mg to about 3.2 mg;

fluvastatin, typically from about 2.5mg to about 160mg, preferably from about 20mg to about 80 mg;

lovastatin, typically about 2.5mg to about 160mg, preferably about 10mg to about 80 mg.

It will be appreciated by those skilled in the art that the free base forms or other salt forms of the statins described above may also be used in the present invention. Calculation of the dosage of the other forms of the statins, or the free base forms or other salt forms, is readily accomplished by simple comparison of the molecular weights of the materials involved.

The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable carrier or diluent. Thus, the compounds of the present 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 solution, suspension, tablet, pill, capsule, powder, etc. Tablets contain various excipients such as sodium citrate, calcium carbonate and calcium phosphate and various disintegrants such as starch (preferably potato or tapioca starch) and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are also generally very useful for the preparation of tablets. Solid compositions of a similar type may also be used as fillings for soft and hard gelatin capsules; preferred materials in this regard also include lactose and high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds of the invention may be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying and/or suspending agents, and with diluents such as water, ethanol, propylene glycol, glycerin, and various combinations thereof.

The compounds of the invention may also be administered in a controlled release formulation such as a sustained or rapid release formulation. The complex controlled release formulations of the present invention may be prepared according to methods well known to those skilled in the art. The method of administration may be determined by the attending physician after assessing the condition and needs of the patient. A generally preferred formulation of amlodipine is Norvasc^。

Parenteral administration may take the form of solutions in castor oil or arachis oil or aqueous propylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts. If desired, the aqueous solution may be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection. In this regard, the sterile aqueous vehicle employed is readily obtained by conventional methods well known to those skilled in the art.

Methods of preparing various pharmaceutical compositions containing certain amounts of active ingredients are known or will be apparent to those skilled in the art. See, for example, Remington's pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15 th edition (1975).

The pharmaceutical compositions of the invention may contain from 0.1% to 95% of a compound of the invention, preferably from 1% to 70%. In any event, the composition or formulation for administration should contain an amount of the compound of the invention effective to treat the condition or disease in the patient to be treated.

Since the invention relates to the treatment of diseases using combinations of active ingredients that can be administered separately, the invention also relates to combining different pharmaceutical compositions in the form of a kit. The kit contains two different pharmaceutical compositions: amlodipine or a pharmaceutically acceptable acid addition salt thereof; inhibin or a pharmaceutically acceptable salt thereof. The kit contains containers for containing the different compositions, such as separate vials or separate foil pouches, however, the different compositions may also be contained in a single, undivided container. A typical kit contains instructions for administration of the different components. The kit form is particularly advantageous when the different components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dosing intervals, or when the dosage of a component of the combination needs to be adjusted incrementally by the prescribing physician.

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

Claims (15)

1. A pharmaceutical composition comprising:

a. a quantity of amlodipine or a pharmaceutically acceptable acid addition salt thereof;

b. an amount of a statin or a pharmaceutically acceptable salt thereof, wherein said statin is selected from fluvastatin, rivastatin, or pravastatin; and

c. a pharmaceutically acceptable carrier or diluent.

2. The pharmaceutical composition of claim 1 comprising amlodipine besylate.

3. The pharmaceutical composition of claim 2, wherein the statin is fluvastatin.

4. The pharmaceutical composition of claim 2, wherein the statin is rivastatin.

5. The pharmaceutical composition of claim 2, wherein the statin is pravastatin.

6. A kit for achieving a therapeutic effect in a mammal, comprising:

a. an amount of amlodipine or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;

b. an amount of a statin or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent, in a second unit dosage form, wherein the statin is selected from fluvastatin, rivastatin, or pravastatin; and

c. a container for containing the first and second dosage forms.

7. The kit of claim 6, wherein said amlodipine is amlodipine besylate.

8. The kit of claim 7, wherein said statin is fluvastatin.

9. The kit of claim 7, wherein said statin is rivastatin.

10. The kit of claim 7, wherein said statin is pravastatin.

11. Use of a composition according to claims 1-5 for the manufacture of a medicament for the treatment of hypertension in a mammal.

12. Use of a composition according to claims 1-5 for the manufacture of a medicament for the treatment of hyperlipidemic conditions in a mammal.

13. Use of a composition according to claims 1-5 for the manufacture of a medicament for the treatment of angina pectoris disorders in a mammal.

14. Use of a composition according to claims 1-5 for the manufacture of a medicament for the treatment of atherosclerotic disorders in a mammal.

15. Use of the composition of claims 1-5 for the manufacture of a medicament for preventing hypertension or hyperlipidemia associated cardiac disorders in a mammal.