HK1049162A - Mutual salt of amlodipine and atorvastatin - Google Patents

Description

Common salts of amlodipine and atorvastatin

The present invention relates to a common salt of amlodipine (amlodipine) and atorvastatin (atorvastatin), pharmaceutical compositions thereof, and methods of using said salt and/or said compositions for treating subjects suffering from angina pectoris, atherosclerosis, and concurrent hypertension and hyperlipidemia, as well as for treating subjects, including humans, exhibiting symptoms of cardiac risk.

Background

The conversion of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) to mevalonate is an earlier rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. Inhibin inhibits HMG-CoA reductase from catalyzing this conversion. Therefore, statins are effective lipid lowering agents.

Atorvastatin calcium disclosed in U.S. Pat. No.5,273,995 (which is incorporated herein by reference) is now identified as Lipitor^Sold, having the formula:atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA. Therefore, atorvastatin calcium is a potent lipid lowering compound. The free carboxylic acid form of atorvastatin exists predominantly as a lactone of the formula:it is disclosed in U.S. Pat. No.4,681,893 (incorporated herein by reference).

Amlodipine and related dihydropyridine compounds are disclosed in U.S. Pat. No.4,572,909 (which is incorporated herein by reference) as potent anti-ischemic and anti-hypertensive agents. U.S. Pat. No.4,879,303, which is incorporated herein by reference, discloses amlodipine besylate (also known as amlodipine besylate). Both amlodipine and amlodipine besylate are effective, long lasting calcium channel blockers. Therefore, amlodipine besylate and other pharmaceutically acceptable acid addition salts of amlodipine are useful as antihypertensive agents and as anti-ischemic agents. Amlodipine and its pharmaceutically acceptable acid addition salts are also disclosed in U.S. patent No.5,155,120 (believed to have utility in the treatment of congestive heart failure). Amlodipine besylate is currently available as Norvasc^And (5) selling. Amlodipine has the following formula:

atherosclerosis is a condition characterized by an irregular distribution of lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries. Atherosclerotic coronary heart disease (hereinafter "CHD") accounts for about 53% of all deaths caused by cardiovascular events. CHD accounts for nearly half of cardiovascular health care expenses (about $ 500-600 billion) in the United states every year, and accounts for about 6% of the national medical expenses every year. Despite attempts to improve secondary risk factors such as, inter alia, smoking, obesity and lack of exercise, and to take dietary improvement and pharmacotherapy to treat dyslipidemia, CHD remains the most common cause of death in the united states.

High levels of blood cholesterol and blood lipids are conditions that are involved in the onset of atherosclerosis. It is well known that inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) are effective in lowering plasma cholesterol levels, particularly low density lipoprotein cholesterol (LDL-C) levels in humans (Brown and Goldstein, New England Journal of medicine, 1981, 305, No.9, 515-517). It has now been demonstrated that lowering LDL-C levels can provide protection against coronary heart disease (see, e.g., the Scandinavian simvastatin survival study: randomized trials of cholesterol lowering in 4444 patients with coronary heart disease: Scandinavian simvastatin survival study (4S), Lancet (Lancet), 1994, 344, 1383-89; and Shepherd, J. et al, prevention of coronary heart disease in people with hypercholesterolemia with pravastatin, journal of New England medicine, 1995, 333, 1301-07).

Angina is a severe contractive pain in the chest that usually radiates from the ostium to the left shoulder and down to the left arm. Angina pectoris is generally due to cardiac ischemia and is usually caused by coronary heart disease.

Currently, the treatment of symptomatic angina pectoris varies from country to country. In the united states, symptomatic, persistent angina is often treated by surgery or PTCA. Patients undergoing PTCA or other surgery aimed at treating angina are often accompanied by complications (e.g., restenosis). This restenosis is manifested either as a short-term proliferative response to angioplasty-induced trauma, or as a long-term progression of the atherosclerotic process in the transplanted vessel and segment of angioplasty.

Symptomatic treatment of angina pectoris involves the use of several drugs, usually combinations of two or more of the following types: beta blockers, nitrates and calcium channel blockers. Most, if not all, of these patients also require treatment with lipid lowering agents. The National Cholesterol Education Program (NCEP) recognizes that patients with coronary artery disease are a special class of patients who require active treatment for elevated LDL-C.

Amlodipine helps prevent myocardial ischemia in patients with exertional angina by reducing the total peripheral resistance or afterload, which reduces the heart rate blood pressure product and thus myocardial oxygen demand at any particular exercise level. In patients with vasospastic angina, amlodipine is shown to prevent contraction and thus restore myocardial oxygen supply. Further, amlodipine has been shown to increase myocardial oxygen supply by dilating coronary arteries.

Hypertension often coexists with hyperlipidemia, which are considered to be the major risk factors for the development of heart disease, ultimately leading to adverse cardiac events. Clustering of such risk factors may be due to a common mechanism. In addition, patients who are amenable to treatment for hypertension are generally better than patients who are amenable to treatment for hyperlipidemia. Therefore, it would be advantageous for a patient to have one therapy to treat both conditions.

Coronary heart disease is a multifactorial disease in which the incidence and severity is influenced by lipid profile, the presence of diabetes, and the sex of the patient. Morbidity is also affected by smoking and left ventricular hypertrophy, which is a secondary symptom to hypertension. To reasonably reduce the risk of coronary heart disease, it is important to control the entire risk range. For example, hypertension intervention trials cannot account for the complete normalization of cardiovascular mortality due to coronary heart disease. Treatment of patients with or without coronary artery disease with cholesterol synthesis inhibitors reduces the risk of cardiovascular morbidity and mortality.

From the Framingham cardiac study, an ongoing and promising study of adult males and females, it has been shown that certain risk factors can be used to predict the progression 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 intolerance, and cardiac dilatation (electrocardiogram, left ventricular hypertrophy as shown on echocardiogram, or chest X-ray showing dilated heart). The calculator and computer are easily programmable using multivariate logarithmic functions, and are then able to calculate the conditional probability of a cardiovascular event. These determinants (based on the experience of 5,209 men and women participating in the Framingham study) estimate the risk of coronary artery disease during different periods of follow-up. The simulated incidence ranged from less than 1% to greater than 80% over a randomly selected six year period. However, these ratios are typically less than 10% and rarely exceed 45% (in men) and 25% (in women).

Kramsch et al, in Journal of Human Hypertension (1995) (supplement 1) 53-59, disclose the use of calcium channel blockers (including amlodipine) in the treatment of atherosclerosis. This document further suggests that a combination of amlodipine and a lipid lowering agent may be used to treat atherosclerosis. Human trials have shown that calcium channel blockers have a beneficial effect in the treatment of early atherosclerotic lesions. (see, for example, Lichtlen, P.R. et al, nifedipine's blocking effect on the angiographic progression of coronary artery disease, lancets, 1990, 335, 1109-13; and Waters, D. et al, clinical trials for the control of the effects of calcium channel blockers on the progression of coronary atherosclerosis, Circulation, 1990, 82, 1940-53). U.S.4,681,893 discloses that certain statins, including atorvastatin, are hypolipidemic agents and, therefore, are useful in the treatment of atherosclerosis. Jukema et al, in cycles 1995 (supplement 1) 1-197, disclose evidence that calcium channel blockers act synergistically in combination with lipid lowering agents, such as 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 with lovastatin in the treatment of atherosclerosis.

Commonly assigned international patent application publication No. wo 99/11259 discloses a pharmaceutical composition comprising a combination of amlodipine and atorvastatin.

Summary of the invention

The present invention relates to a compound which is an atorvastatin salt of amlodipine. It is to be understood that the term "amlodipine salt of atorvastatin" is a synonym for the term "atorvastatin salt of amlodipine". Those terms are used interchangeably in this specification and the appended claims.

The invention particularly relates to atorvastatin salts of amlodipine, which are compounds of formula IThe invention more particularly relates to compounds of formula I wherein the carbon atom in the 4-position of the dihydropyridine ring has the (R) configuration, such as 7- [2- (4-fluoro-phenyl) -5-isopropyl-3-phenyl-4-phenylmethylaminoacyl-pyrrol-1-yl]-3, 5-dihydroxy-heptanoic acid salt with 2- (2-amino-ethoxymethyl) -4(R) - (2-chloro-phenyl) -6-methyl-1, 4-dihydro-pyridine-3, 5-dicarboxylic acid 3-ethyl ester 5-methyl ester.

The invention still more particularly relates to compounds of formula I wherein the carbon atom in the 4-position of the dihydropyridine ring has the (S) configuration, 7- [2- (4-fluoro-phenyl) -5-isopropyl-3-phenyl-4-phenylmethylaminoacyl-pyrrol-1-yl ] -3, 5-dihydroxy-heptanoate with 3-ethyl 5-methyl 2- (2-amino-ethoxymethyl) -4(S) - (2-chloro-phenyl) -6-methyl-1, 4-dihydro-pyridine-3, 5-dicarboxylate.

The invention also relates to pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier, vehicle or diluent.

The invention also relates to a method of treating angina in a mammal suffering from angina which comprises administering to said mammal an angina treating effective amount of a compound of formula I.

The present invention is also directed to a method of treating angina pectoris in a mammal suffering from angina pectoris comprising administering to said mammal an angina pectoris treating effective amount of a pharmaceutical composition comprising the common salt of amlodipine and atorvastatin and a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention also relates to a method of treating hypertension and hyperlipidemia in a mammal suffering from hypertension and hyperlipidemia comprising administering to said mammal a hypertension and hyperlipidemia treating effective amount of a compound of formula I.

The present invention also relates to a method for treating hypertension and hyperlipidemia in a mammal suffering from hypertension and hyperlipidemia, which comprises administering to said mammal a hypertension and hyperlipidemia treating effective amount of a pharmaceutical composition comprising a common salt of amlodipine and atorvastatin together with a pharmaceutically acceptable carrier, vehicle or diluent.

The invention also relates to a method of treating atherosclerosis in a mammal suffering from atherosclerosis comprising administering to said mammal an anti-atherosclerotic effective amount of a compound of formula I. The invention is particularly relevant in those cases: wherein the anti-atherosclerotic effect is manifested by a slowing of atherosclerotic plaque development (including wherein the atherosclerotic plaque formation is slowed in the coronary, carotid or peripheral arterial systems). The invention also specifically relates to those cases: wherein said anti-atherosclerotic effect is manifested by a regression of atherosclerotic plaques (including wherein said regression occurs in the coronary, carotid and/or peripheral arterial systems).

The present invention also relates to a method of treating atherosclerosis in a mammal suffering from atherosclerosis comprising administering to said mammal an anti-atherosclerotic effective amount of a pharmaceutical composition comprising the common salt of amlodipine and atorvastatin together with a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention also relates to a method of controlling cardiac risk in a mammal at risk of suffering an adverse cardiac event comprising administering to said mammal a cardiac risk treating effective amount of a compound of formula I.

The present invention also relates to a method of controlling cardiac risk in a mammal at risk of suffering a detrimental cardiac event comprising administering to said mammal a cardiac risk treating effective amount of a pharmaceutical composition comprising the common salt of amlodipine and atorvastatin together with a pharmaceutically acceptable carrier, vehicle or diluent.

The present invention also relates to pharmaceutical compositions comprising an amount of a compound of formula I and amlodipine or a pharmaceutically acceptable salt thereof (e.g., amlodipine besylate). The invention also relates to methods of treating diseases and conditions in a mammal comprising administering such pharmaceutical compositions to said mammal (e.g., a human). Diseases and conditions that may be treated with such pharmaceutical compositions include: angina pectoris, atherosclerosis, concurrent hypertension and hyperlipidemia, and cardiac risk.

The present invention also relates to pharmaceutical compositions comprising an amount of a compound of formula I and atorvastatin or a pharmaceutically acceptable salt thereof (e.g. the hemicalcium salt of atorvastatin). The invention also relates to methods of treating diseases and conditions in a mammal comprising administering such pharmaceutical compositions to said mammal (e.g., a human). Diseases and conditions that may be treated with such pharmaceutical compositions include: angina pectoris, atherosclerosis, concurrent hypertension and hyperlipidemia, and cardiac risk.

The invention also relates to methods of delivering amlodipine in vivo by administering a compound of formula I to a mammal (e.g., a human).

The invention also relates to methods of delivering atorvastatin in vivo by administering a compound of formula I to a mammal (e.g., a human).

The present invention also relates to a method of treating a mammal comprising administering to said mammal an amount of a compound of formula I and an amount of amlodipine or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating a mammal comprising administering to said mammal an amount of a compound of formula I and an amount of atorvastatin or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating a mammal with amlodipine comprising administering to said mammal a compound of formula I.

The invention also relates to a method of treating a mammal with atorvastatin comprising administering to said mammal a compound of formula I.

Amlodipine is a racemic compound due to the 4-position symmetry of its dihydropyridine ring. The R and S enantiomers can be prepared by the method described by arowsmith et al in journal of medical chemistry (j.med. chem.), 1986, 29, 1696. The calcium channel blocking activity of amlodipine is essentially limited to the S (-) isomer as well as to racemic mixtures containing the R (+) and S (-) forms. (see International patent application No. PCT/EP 94/02697). The R (+) isomer has little or no calcium channel blocking activity. However, the R (+) isomer is a possible inhibitor of smooth muscle cell migration. Therefore, the R (+) isomer is useful for treating or preventing atherosclerosis. (see International patent application No. PCT/EP 95/00847). Based on the above, the skilled person will be able to select the R (+) isomer, the S (-) isomer or a racemic mixture of the R (+) isomer and the S (-) isomer for use in the combination of the present invention.

As used in this specification and the appended claims, the term "cardiac risk" refers to the likelihood that a subject will suffer an adverse cardiac event in the future, e.g., a myocardial infarction, cardiac arrest, heart failure, and/or myocardial ischemia. Cardiac risk was calculated using the Framingham risk equation set forth above. The term "cardiac risk control" means that the risk of a future adverse cardiac event is substantially reduced.

Detailed description of the invention

The common salt of amlodipine and atorvastatin and pharmaceutical compositions thereof of the present invention can be readily prepared as described below and in the examples below.

Specifically, the common salt of atorvastatin and amlodipine is prepared by: the free base of amlodipine is dissolved in a suitable reaction inert solvent and the resulting solution is added to a solution of atorvastatin free acid in a suitable reaction inert solvent. The terms "reaction inert solvent" and "inert solvent" as used herein refer to a solvent or mixture of solvents that does not interact with starting materials, reagents, intermediates or products in a manner that adversely affects the yield of the desired product. Preferred solvents for amlodipine include, but are not limited to: acetone, water/acetone mixtures, alcoholic solvents (e.g., methanol and ethanol). A particularly preferred solvent for amlodipine is a 1: 1 mixture of water and acetone. Preferred solvents for atorvastatin include, but are not limited to: ethyl acetate, toluene, acetone, and alcoholic solvents (e.g., methanol and ethanol). A particularly preferred solvent for atorvastatin is ethyl acetate. The reaction mixture was stirred vigorously at room temperature. Crystallization was achieved by addition of a weakly polar solvent (e.g., toluene (20ml)) to give a common salt of amlodipine and atorvastatin. It will be appreciated by those skilled in the art that amlodipine is a racemic mixture of two enantiomers and that the use of a salt formed from a racemic mixture of amlodipine will result in a diastereomeric mixture of the salts of amlodipine and atorvastatin. Optically pure forms of the salts of amlodipine and atorvastatin can be prepared using the same procedures described above, but replacing the racemic mixture with the (R) -enantiomer of amlodipine or the racemic mixture with the (S) -enantiomer of amlodipine.

Amlodipine can be readily prepared by the methods described in U.S. Pat. No.4,572,909, which is incorporated herein by reference. Amlodipine besylateAcid salt (currently in Norvasc)^Sold) can be prepared as described in U.S. Pat. No.4,879,303, which is incorporated herein by reference. Both amlodipine and amlodipine besylate are effective, long lasting calcium channel blockers.

The R and S enantiomers of amlodipine can be prepared as described in arowsmith et al, journal of medical chemistry, 1986, 29, 1696.

Atorvastatin can be readily prepared by the methods described in U.S. Pat. No.4,681,893, which is incorporated herein by reference. The hemi calcium salt of atorvastatin (currently expressed as Lipitor)^Sold) can be prepared as described in U.S. Pat. No.5,273,995, which is incorporated herein by reference.

Furthermore, the common salt of amlodipine and atorvastatin of the present invention may occur as a hydrate or as a solvate. Both the hydrates and solvates are also within the scope of the present invention.

The common salts, pharmaceutical compositions and methods of the present invention are all suitable for therapeutic use as a medicament, i.e., for the treatment of atherosclerosis, angina pectoris, and conditions characterized by the simultaneous presence of hypertension and hyperlipidemia in a mammal, particularly a human. Furthermore, since these diseases and conditions are closely related to the progression of heart disease and harmful heart conditions, the common salts, pharmaceutical compositions and methods (by virtue of their role as anti-atherosclerotic, anti-angina, anti-hypertensive and anti-hyperlipidemic agents) are useful in controlling cardiac risk.

The utility of the salts and compositions of the invention as therapeutic agents in the treatment of atherosclerosis in mammals, particularly humans, is illustrated by the following general assay and the activity of the compounds of the invention in clinical protocols.

Common salts of amlodipine and atorvastatin

Therapeutic effect on atherosclerosis

This study is a randomized assessment of the expected effect of the combination of amlodipine and the common salt of atorvastatin on the progression/regression of coronary artery disease and carotid artery disease. This study was applied to demonstrate that the common salt of amlodipine and atorvastatin can effectively slow or stop the progression or cause regression of existing Coronary Artery Disease (CAD) in subjects with established disease (as evidenced by angiography of the coronary arteries or ultrasound examination of the carotid arteries).

The study is an angiographic recording of coronary artery disease as a double-blind, placebo-controlled trial on a minimum of about 500 subjects, preferably from about 780 to about 1200 subjects. It is particularly preferred that about 1200 subjects be studied in this study. Subjects were admitted to the study after meeting some of the following entry criteria.

Entry criteria: the subject who is allowed to enter the test must meet some criteria. For example, the subject must be an adult, male or female, 18-80 years of age, for which angiography is clinically indicated. Patients will have significant focal lesions (e.g. 30% to 50%) on angiography, which is judged unlikely to require intervention in the following 3 years, based on the subsequent assessment of the smallest segment (non-PTCA, non-bypassed or non-MI vessels) by Quantitative Coronary Angiography (QCA). The segments required to undergo analysis have not been intervened. Since Percutaneous Transluminal Cardiac Angiography (PTCA) intervenes on segments by inserting balloon catheters, there is a need to analyze non-PTCA segments. It is also required that the segment being analyzed has not undergone a thrombotic event, e.g., a Myocardial Infarction (MI). Therefore, non-MI vessels are needed. The segments to be analyzed include: left general, proximal, medial and distal left anterior descending, first and second oblique branches, proximal and distal left circumflex, first or maximum lumen circumference margin (largest space artery), proximal, medial and distal right coronary artery. Subjects will have an ejection fraction greater than 30%, as determined by catheterization or radionuclide angiography or ECHO cardiography at the time of, or within the first three months of, acceptance of a qualified angiogram, but without an intervening event (e.g., thrombotic event) or procedure (e.g., PTCA).

Typically, the study is conducted in multiple locations due to the number of patients and physical limitations of any one device. Upon entering the study, subjects underwent quantitative coronary angiography at the designated test centers, as well as B-mode carotid ultrasound examination and assessment of carotid compliance. This established a baseline for each subject. Once admitted to the trial, the subjects randomly received amlodipine besylate (10mgs) and either placebo or atorvastatin calcium (10mgs) and either placebo or a common salt of amlodipine and atorvastatin (about 5-160 mgs). All doses given in this protocol are daily doses. The amounts of amlodipine besylate, atorvastatin calcium and the common salts of amlodipine and atorvastatin can be varied as desired. Typically, the subject will initially receive 10mg and the amount will be titrated down to as little as 5mg (at the discretion of the clinician).

The subject is monitored for a period of one to three years, with three years being generally preferred. B-mode carotid ultrasound estimates of carotid atherosclerosis and compliance were performed periodically throughout the study. In general, a time interval of six months is suitable. Typically, this estimation is performed using a B-mode ultrasound machine. However, other methods may be used by those skilled in the art to make this estimate.

Coronary angiography is performed at the end of a one to three year treatment period. The baseline and post-treatment angiograms and interventional B-mode carotid echograms are evaluated for the progression of new lesions or existing atherosclerotic lesions. Arterial compliance was assessed as changes from baseline and changes over a 6 month evaluation period.

The primary objective of this study was to show that the common salt of amlodipine and atorvastatin reduces the progression of atherosclerotic lesions as determined by Quantitative Coronary Angiography (QCA) in subjects with clinical coronary artery disease. QCA measures the patency in the lumen of the artery being measured.

The primary endpoint of this study was the change in mean diameter of the segments of the coronary tree. The diameter of the arterial segment is therefore determined at different locations along the length of that segment. The average diameter of that segment is then determined. After the average segment diameter of many segments is determined, the average of all segment means is determined to obtain an average segment diameter mean. The average segment diameter of subjects taking common salts of amlodipine and atorvastatin will decrease more slowly, will be completely prevented, or will increase. These results reflect respectively: slowing the progression of atherosclerosis, preventing the progression of atherosclerosis and regression of atherosclerosis.

The second objective of this study was to show that the common salt of amlodipine and atorvastatin reduces the rate of progression of atherosclerosis in the carotid arteries as measured by the slope of the maximum intima-media thickness measurement (mean maximum) for 12 individual wall segments as a function of time. The intima-media thickness of subjects taking a common salt of atorvastatin and amlodipine will increase more slowly, will stop increasing or will decrease. These results reflect respectively: slowing the progression of atherosclerosis, preventing the progression of atherosclerosis and regression of atherosclerosis.

The utility of the common salts and compositions of the present invention as pharmaceutical agents for treating angina pectoris in a mammal (e.g., a human) is illustrated by the following general assay and the activity of the compounds of the present invention in a clinical protocol.

Effect of common salts of amlodipine and atorvastatin in the treatment of angina pectoris

The study is a double-blind, parallel, randomized study to show the effect of the common salt of amlodipine and atorvastatin in the treatment of symptomatic angina.

Entry criteria: the subjects were either male or female, aged 18-80 years, and their typical history of chest pain correlated with one of the following objective signs of cardiac ischemia: (1) the stress test segment is elevated about one millimeter or more from the ECG; (2) positive pedal drive mill (pedal) stress test; (3) new wall motion anomalies for ultrasonic waves; or (4) coronary angiograms reflect significant qualifying stenoses. Stenosis of about 30-50% is generally considered significant.

Each subject is evaluated for about 10-32 weeks. It generally takes at least 10 weeks to complete the study. Sufficient subjects were used in this screen to ensure that about 200-800 subjects, preferably about 400 subjects, were evaluated to complete the study. Subjects meeting the above entry criteria were screened in one four week period. After meeting the screening criteria, subjects were washed out of the current antianginal drug and stabilized with a long acting nitrate (e.g., nitroglycerin, isosorbide-5-mononitrate, or isosorbide dinitrate). The term "washout" when used in connection with screening means that the current anti-angina drug is cleared such that substantially all of the drug is removed from the subject. Preferably, a period of 8 weeks is used as the wash-out period and the subject is allowed to establish a stable amount of the nitrate. Subjects who have had one or two episodes of angina per week but who rely on a stable dose of a long-acting nitrate are generally allowed to omit the washout period. After the subjects were stabilized by nitrate, they entered the randomized phase if they continued to angina once or twice a week. In the randomization phase, subjects were randomized into one of the following four study groups. After completion of the washout phase, subjects meeting the entry criteria underwent a 24 hour ambulatory Electrocardiogram (ECG) examination, such as Holter monitoring, exercise stress testing (e.g., foot-driven mill), and assessment of myocardial perfusion using PET (photon emission tomography) scans to establish a baseline for each subject. When performing stress testing, the speed of the pedal-driven mill and the inclination of the pedal-driven mill may be controlled by a mechanic. The speed of the pedal driven mill and the angle of inclination of the pedal driven mill were typically increased during the test. The time interval between each speed and inclination increase is typically determined using modified BruceProtocol.

After completion of the baseline survey, the subjects began one of four studies: (1) a placebo; (2) atorvastatin calcium (about 2.5mg to about 160 mg); (3) amlodipine besylate (about 2.5mg to about 20 mg); or (4) a common salt (about 5-160 mg) of amlodipine and atorvastatin. The subjects were then monitored for 2-24 weeks.

After the end of the monitoring period, the subjects will receive the following survey: (1)24 hour ambulatory ECG, such as Holter monitoring; (2) exercise stress testing (e.g., pedal-driven mills using the modified Bruce Protocol); and (3) assessment of myocardial perfusion using PET scanning. Patients recorded a diary of painful ischemic events and nitroglycerin consumption. It is often necessary to accurately record the number of angina attacks suffered by a patient during the course of a trial. Because patients typically take nitroglycerin to relieve the pain of angina pectoris attacks, the number of times a patient takes nitroglycerin provides a reasonably accurate record of the number of angina pectoris attacks.

To elucidate the effects of the compounds and compositions of the invention, and to determine the dosage of the compounds and compositions of the invention, the person performing the test will use the test to evaluate the subject. Successful treatment will result in fewer ischemic events (by ECG examination), will cause the subject to move longer or with greater intensity on the pedal-driven mill, or move without pain on the pedal-driven mill, or will result in better perfusion or fewer perfusion defects [ as judged by Photon Emission Tomography (PET) ].

The utility of the common salts and compositions of the present invention as a pharmaceutical agent for treating hypertension and hyperlipidemia in a mammal (e.g., a human) suffering from concurrent hypertension and hyperlipidemia is illustrated by the following routine assay and the activity of the compounds of the present invention in a clinical protocol.

Common salts of amlodipine and atorvastatin

For hypertension and hyperlipidemia

Therapeutic Effect of the subjects

The study is a double-blind, parallel, randomized study to show the effect of the common salt of amlodipine and atorvastatin in controlling hypertension and hyperlipidemia in subjects 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 screening to ensure that about 400-800 subjects were evaluated to complete the study.

Entry criteria: the tested persons are all male or female adults with the ages of 18-80, and the adults are suffering from hypertension and hyperlipidemia. The presence of hyperlipidemia is confirmed by assessing the Low Density Lipoprotein (LDL) levels of the subject relative to certain positive risk factors. If the subject does not have Coronary Heart Disease (CHD) and has less than two positive risk factors, then the subject is considered to have hyperlipidemia if the LDL of the subject is greater than or equal to 190. If the subject does not have CHD and has two or more positive risk factors, then the subject is considered to have hyperlipidemia if the LDL of the subject is greater than or equal to 160. If the subject has CHD, then the subject is considered to have hyperlipidemia if the LDL of the subject is greater than or equal to 130.

Positive risk factors include: (1) a male of greater than 45, (2) a female of greater than 55, wherein the female has not undergone Hormone Replacement Therapy (HRT), (3) a family history of pre-existing cardiovascular disease, (4) the subject is currently a smoker, (5) the subject has diabetes, (6) HDL is less than 45, and (7) the subject has hypertension. HDL greater than 60 is considered a negative risk factor and will offset a positive risk factor as described above.

The presence of hypertension is evidenced by a diastolic Blood Pressure (BP) greater than 90 when sedentary or a systolic BP greater than 140 when sedentary. All blood pressures are typically determined as the average of three determinations at five minute intervals.

Screening subjects who meet the above entry criteria. After all screening criteria were met, subjects were washed out of their existing antihypertensive and lipid-lowering drugs and assigned a NCEP ATPIISTEP 1 diet. NCEP ATPII (adult treatment group, second revision) Step 1 diet lists the amount of saturated and unsaturated fat that can be consumed as part of the total energy intake. The term "washout" as used in this protocol means the removal of existing antihypertensive and lipid-lowering agents such that substantially all of the agents are excluded from the subject. Newly diagnosed subjects typically remain untreated until the time of the test. These subjects were also scheduled NCEP ATPII Step 1 diets. After four weeks of washout and food stabilization, subjects underwent the following baseline investigations: (1) blood pressure and (2) fasting lipid screening. Fasting lipid screening determines the baseline lipid levels of the subjects in the fasted state. Typically, subjects eat no food for 12 hours, at which time lipid levels are measured.

After the baseline survey was conducted, the subjects began receiving one of the following: (1) fixed dose amlodipine besylate (typically about 2.5-10 mg); (2) fixed dose of atorvastatin calcium (typically about 10-80 mg); or (3) a common salt (about 5 to 160mgs) of amlodipine and atorvastatin. The subject then remains on these doses for a minimum of six weeks, usually no more than eight weeks. Subjects returned to the test center at the end of 6-8 weeks so that baseline assessments could be repeated. 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 screening 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 utility of the combination.

The utility of the common salts and compositions of the present invention as pharmaceutical agents for controlling cardiac risk in mammals (e.g., humans) at risk for adverse cardiac events is illustrated by the following routine assay and the activity of the compounds of the present invention in clinical protocols.

Common salt pair of amlodipine and atorvastatin

In the risk of future cardiovascular events

Effect of the subjects

The study is a double-blind, parallel-group, randomized study to show the effect of the common salt of amlodipine and atorvastatin in reducing the overall calculated risk of future events in subjects at risk for having future cardiovascular events. The risk is calculated using the Framingham Risk equation. A subject is considered at risk for having a future cardiovascular event if the subject is greater than one standard deviation above the mean calculated by the Framingham risk equation. The study was applied to evaluate the efficiency of the common salt of amlodipine and atorvastatin in controlling cardiovascular risk by controlling hypertension and hyperlipidemia in patients with mild to moderate hypertension and hyperlipidemia.

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

Entry criteria: the subjects included in this study were either male or female adults between 18-80 years of age with a baseline five-year risk that was higher than the mean values determined for the subject's age and gender by the Framingham heart study (an ongoing prospective study of adult males and females that showed that certain risk factors could be used to predict the progression of coronary heart disease). In determining whether a patient is at risk for an adverse cardiac event, all of the following factors are evaluated: age, sex, systolic and diastolic blood pressure, smoking habits, presence or absence of carbohydrate intolerance, presence or absence of left ventricular hypertrophy, serum cholesterol and High Density Lipoprotein (HDL) above one standard deviation of the mean value of Framingham populition. The value of the risk factor is substituted into the Framingham Risk equation and calculated to determine whether the subject is at risk for a future cardiac event.

Screening subjects who meet the above entry criteria. After all screening criteria are met, the patient's existing antihypertensive and lipid-lowering drugs and any other drugs that will affect the screening results are washed out. The patient is then scheduled NCEPATPII Step 1 food as described in the hypertensive and hyperlipidemia screens above. Newly diagnosed subjects typically remain untreated until the time of the test. These subjects were also scheduled NCEP ATPII Step 1 diets. After four weeks of washout and food stabilization, subjects underwent the following baseline investigations: (1) blood pressure; (2) fasting; (3) screening lipid; (4) glucose tolerance test; (5) an ECG; and (6) cardiac ultrasound examinations. These tests are carried out using standard methods well known to those skilled in the art. ECG and cardiac ultrasonography 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: (1) a fixed dose of amlodipine (about 2.5-10 mg); (2) a fixed dose of atorvastatin (about 10-80 mg); or (3) a common salt (about 5 to 160mgs) of amlodipine and atorvastatin. Patients remain receiving these doses and are asked to return within 6-8 weeks so that baseline assessments can be repeated. At this point, the new values are substituted into the Framingham risk equation to determine whether the subject has a lesser, greater, or unchanged risk of a future cardiovascular event.

The above tests illustrate the effects of the common salt of amlodipine and atorvastatin in the treatment of angina pectoris, atherosclerosis, complicated hypertension and hyperlipidemia, and in the control of cardiac risk, and provide a method by which the activities between the compounds of the present invention and other known compounds can be compared. The results of these comparisons are useful in determining dosage levels for treating such diseases in mammals, including humans.

The following dosages, as well as those elsewhere in this specification and in the claims that follow, are suitable for average human subjects having a body weight of from about 65kg to about 70 kg. A skilled physician will be readily able to determine the dosage required for a subject who weighs outside the range of 65kg to 70kg based on the subject's medical history and the disease (e.g., diabetes) present in the subject. The dosages given herein and in the appended claims are daily dosages.

Generally, according to the present invention, the common salt of amlodipine and atorvastatin is administered at a dose of about 2.5mg to about 20 mg.

The common salt of the present invention is typically administered in the form of a pharmaceutical composition comprising the common salt of the present invention together with pharmaceutically acceptable carriers, vehicles and diluents. Thus, the common salts of the present invention may be administered in any conventional oral, parenteral or transdermal dosage form.

For oral administration, the pharmaceutical composition may be in the form of a solution, suspension, tablet, pill, capsule, powder, or the like. A tablet comprising the following components was used: various excipients, for example, sodium citrate, calcium carbonate and calcium phosphate; together with various disintegrants, for example, starch (preferably potato or tapioca starch); and certain complex silicates; and also binders, such as polyvinylpyrrolidone, sucrose, gelatin and acarbol. Additionally, lubricants (e.g., magnesium stearate, sodium lauryl sulfate, and talc) are generally well suited for tableting. Solid ingredients of a similar class are also used as fillers for filled soft and hard gelatin capsules; preferred materials in this regard also include lactose or milk sugar and high molecular weight polyethylene glycols. When an oral aqueous suspension and/or elixir is desired, the compounds of the invention can be combined with: various sweeteners, flavoring agents, coloring agents, emulsifying and/or suspending agents, and such diluents: for example, water, ethanol, propylene glycol, glycerol, and various similar combinations thereof.

The common salts of the present invention may also be administered in a controlled release composition, such as a sustained release formulation or a rapid release formulation. Such controlled release formulations of the common salts of the present invention may be prepared using methods well known to those skilled in the art. Preferred methods of administration will be determined by the attending physician or other skilled artisan upon assessment of the condition and need of the subject.

For parenteral administration, solutions in sesame or peanut oil or aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts. Such aqueous solutions may be suitably buffered if desired, and the liquid diluent should first be 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 medium employed is readily available by standard techniques well known to those skilled in the art.

Methods for preparing various pharmaceutical compositions with certain amounts of active ingredients are known or will be apparent to those skilled in the art in light of this disclosure. See, for example, Remington Pharmaceutical Sciences (Remington's Pharmaceutical Sciences), Mack Publishing Company, Easton, Pa., 19 th edition (1995).

The pharmaceutical composition of the present invention may comprise 0.1% to 95% of the compound of the present invention, preferably 1% to 70%. In any event, the composition administered will comprise an amount of a compound of the invention effective to treat the condition or disease in the subject being treated.

Example 1 common salts of amlodipine and atorvastatin. To a solution of atorvastatin free acid (5.0g, 8.9mM) in ethyl acetate (300ml) was added free base of racemic amlodipine (3.7g, 8.9mM) dissolved (1: 1) in water-acetone (25ml ) or methanol (25ml) at room temperature with vigorous stirring. Crystallization was achieved by addition of a weakly polar solvent (e.g., toluene (20ml)) to give the diastereomeric common salts of amlodipine and atorvastatin.

It is to be understood that the invention is not limited to the particular embodiments described herein, but is capable of various changes and modifications without departing from the spirit and scope of this novel concept as defined by the following claims.

Claims (35)

1. A compound which is an atorvastatin salt of amlodipine.

2. The compound of claim 1 which is

3. The compound of claim 2, wherein the carbon atom at the 4-position of the dihydropyridine ring has the (R) configuration.

4. The compound of claim 2, wherein the carbon atom at the 4-position of the dihydropyridine ring has the (S) configuration.

5. A pharmaceutical composition comprising a compound of claim 1 in association with a pharmaceutically acceptable carrier, vehicle or diluent.

6. A method of treating angina pectoris in a mammal suffering from angina pectoris comprising administering to said mammal an angina pectoris treating effective amount of a compound of claim 1.

7. A method of treating angina pectoris in a mammal suffering from angina pectoris comprising administering to said mammal an angina pectoris treating effective amount of a pharmaceutical composition of claim 5.

8. A method of treating hypertension and hyperlipidemia in a mammal suffering from hypertension and hyperlipidemia comprising administering to said mammal a hypertension and hyperlipidemia treating effective amount of a compound of claim 1.

9. A method of treating hypertension and hyperlipidemia in a mammal suffering from hypertension and hyperlipidemia comprising administering to said mammal a hypertension and hyperlipidemia treating effective amount of the pharmaceutical composition of claim 5.

10. A method of treating atherosclerosis in a mammal suffering from atherosclerosis comprising administering to said mammal an anti-atherosclerotic effective amount of a compound of claim 1.

11. The method of claim 10, wherein said atherosclerosis is manifested by a slowing of the progression of atherosclerotic plaques.

12. The method of claim 10, wherein the atherosclerosis is manifested by regression of atherosclerotic plaques.

13. A method of treating atherosclerosis in a mammal suffering from atherosclerosis comprising administering to said mammal an anti-atherosclerotic effective amount of a pharmaceutical composition of claim 5.

14. A method of controlling cardiac risk in a mammal at risk of suffering an adverse cardiac event comprising administering to said mammal a cardiac risk treating effective amount of a compound of claim 1.

15. A method of controlling cardiac risk in a mammal at risk of suffering an adverse cardiac event comprising administering to said mammal a cardiac risk treating effective amount of the pharmaceutical composition of claim 5.

16. A pharmaceutical composition comprising an amount of the compound of claim 1 and amlodipine or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition of claim 16 comprising amlodipine besylate.

18. A pharmaceutical composition comprising an amount of a compound of claim 1 and atorvastatin or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition of claim 18 comprising the hemicalcium salt of atorvastatin.

20. A method of treating angina pectoris in a mammal suffering from angina pectoris comprising administering to said mammal an effective amount of a pharmaceutical composition of claim 16.

21. A method of treating angina pectoris in a mammal suffering from angina pectoris comprising administering to said mammal an effective amount of a pharmaceutical composition of claim 18.

22. A method of treating atherosclerosis in a mammal comprising administering to said mammal an atherosclerosis treating effective amount of a pharmaceutical composition of claim 16.

23. A method of treating atherosclerosis in a mammal comprising administering to said mammal an atherosclerosis treating effective amount of a pharmaceutical composition of claim 18.

24. A method of controlling cardiac risk in a mammal comprising administering to said mammal a cardiac risk treating effective amount of the pharmaceutical composition of claim 16.

25. A method of controlling cardiac risk in a mammal comprising administering to said mammal a cardiac risk management effective amount of a pharmaceutical composition of claim 18.

26. A method of treating a mammal suffering from hypertension and hyperlipidemia comprising administering to said mammal a hypertension and hyperlipidemia treating effective amount of a pharmaceutical composition of claim 16.

27. A method of treating a mammal suffering from hypertension and hyperlipidemia comprising administering to said mammal a hypertension and hyperlipidemia treating effective amount of a pharmaceutical composition of claim 18.

28. A method of delivering amlodipine in vivo by administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a mammal.

29. The method of claim 28, wherein the mammal is a human.

30. A method of delivering atorvastatin in vivo by administering to a mammal a compound of claim 1 or a pharmaceutically acceptable salt thereof.

31. The method of claim 30, wherein the mammal is a human.

32. A method of treating a mammal comprising administering to said mammal an amount of a compound of claim 1 and an amount of amlodipine or a pharmaceutically acceptable salt thereof.

33. A method of treating a mammal comprising administering to said mammal an amount of a compound of claim 1 and an amount of atorvastatin or a pharmaceutically acceptable salt thereof.

34. A method of treating a mammal with amlodipine comprising administering to said mammal a compound of claim 1.

35. A method of treating a mammal with atorvastatin comprising administering to said mammal a compound of claim 1.