CA2296723A1

CA2296723A1 - Combination therapy comprising atorvastatin and an antihypertensive agent

Info

Publication number: CA2296723A1
Application number: CA002296723A
Authority: CA
Inventors: Robert Andrew Donald Scott
Original assignee: Pfizer Inc
Current assignee: Pfizer Products Inc
Priority date: 1997-08-29
Filing date: 1998-08-11
Publication date: 1999-03-11
Also published as: IL133962A; IL133962A0; BG104075A; GT199800126A; EG24678A; TR200000563T2; MA26536A1; AP9801332A0; US20030199492A1; ZA987839B; UY25155A1; OA11291A; JP2005041875A; EA200000012A1; AP1191A; EP1009400A1; US20020099046A1; CN1268053A; HRP980474A2; ES2234134T3

Abstract

This invention relates to pharmaceutical combinations of atorvastatin or a pharmaceutically acceptable salt thereof and antihypertensive agents, kits containing such combinations and methods of using such combinations to treat subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and to treat subjects presenting with symptoms of cardiac risk, including humans. This invention also relates to additive and synergistic combinations of atorvastatin or a pharmaceutically acceptable salt thereof and antihypertensive agents whereby those synergistic combinations are useful in treating subjects suffering from angina pectoris, atherosclerosis, combined hypertension and hyperlipidemia and those subjects presenting with symptoms of cardiac risk, including humans.

Description

COMBINATION THERAPY COMPRISING ATORVASTATIN AND AN ANTINYPERTENSIVE AGENT
This invention relates to pham~aoeutic~l combinations of atorvastaatin or a pharmaceutically acceptable salt thereof and antihypertensive agents, kits containing such combinations and methods of using such combinatrons to treat subjects suffering from angina pectoris, atherosderosis, combined hypertension and hypertipidemia and to treat subjects presenting with symptoms of cardiac risk, inducting humans. This invention also relates to addtive and synergistic combinations of atorvastatin or a pham3aceutically acceptable sail thereof and antihypertens'rve agents Hrt>ereby those addfive and synergistic combinations are useful in treating subjects suffering from angina pectoris, atherosderosis, combined hypertension and hyperlipidemia and those subjects presenting with symptoms or signs of cardiac risk, including humans.
The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is an early and rate-Umi~r~g step in the cholesterol biosynthetic pathway.
This step is catalyzed by the enzyme HMG-CoA redudase. Statins inhibit HMG.CoA
reducatase from aging this conversion. As such, statins are cdlectively potent lipid lowering agents.
Atorvastatin caldum, disc; used in U.S. Patent No. 5,273,995, which is incorporated herein by reference, is currently sold as Lipitore and has the formula cap Atorvastatin caldum is a selective, competive inhibitor of MG~oA. As such, atorvastatin calcium is a po~M ~pid lowering compound. The free carboxylic aad form of atorvastatin exists predominantly as the ladnne of the formula:

O
Me Me ~~~ OH
O. ~ N
I ~ N H
~F
w and is disclosed in U.S. Patent No. 4,681,893, which is incorporated herein by reference.
Several Basses of compounds are known to have activity as antihypertensive agents. These include caldum channel blodcers, ACE inhibitors, A-II
antagonists, diuretics, beta-adrenergic receptor blodcers, vasodilators and alpha-adrenergic receptor blodcers.
Atherosderosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries.
Atherosderotic coronary heart disease (hereinafter termed 'CHD') accounts for 53%
of ail deaths attributable to a cardiovascular event CHD accounts for nearly one-half (about $50-60 billion) of the total U.S. cardiovascular heaitl~re expendihrres and about 6°~ of the overall national medical bill each year. Despite attempts to modify secondary risk factors such as, inter alia, smoking, obesity and lack of exercise, and treatment of dyslipidemia with dietary modification and drug therapy, CHD
remains the most common cause of death in the United States.
High levels of blood diolesterol and blood lipids are conditions involved in the onset of atherosderosis. It is well known that inhbitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA n~udase) are effective in k~nrering the level of blood plasma cholesterol, espeaally low density lipoprotein cholesterol (LDL-C), in man (Brown and Gokistein, New England Journal of Medidne, 1981, 305, No. 9, 51~. It his now been established that lowering LDL-C levels affords protection from coronary heart disease (see, e.g., The Scandmavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4.444 patients .with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet, 1994, 344, *rB

89; and Shepherd, J. et al., Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia, New England Journal of Medians, 1995, 333, 1301-0~.
Angina pectoris is a severe constricting pain in the chest, often radiating from the preconiium to the left shoulder and down the left arm. Often angina pectoris is due to ischemia of the heart and is usually caused by coronary disease.
Currently the treatrnent of symptomatic angina pectoris varies significantly from country to country. In the U.S., patients iwho present with symptomatic, stable angina pectoris are frequently treated with surgical procedures or PTCA
Patients who undergo PTCA or other surgical procedures designed to treat angina pectoris frequently experience complications such as restenosis. This restenosis may be manifested either as a short term proliferative response to angioplasty-induced trauma or as long term progression of the atherosderotic process in both graft vessels and angioplastied segments.
The symptomatic management of angina pectoris invohres the use of a number of drugs, frequently as a combination of two or more of the following Basses:
beta blodcers, nitrates and calaum channel Mockers. Most, if not all, of these patients require therapy with a lipid lowering agent as well. The National Cholesterol Education Program (NCEP) recognizes patients with existing coronary artery disease as a spedal Bass requiring aggressive management of raised LDL-C.
Amlodipine helps to prevent myocardial isd~emia in patients with exertional angina pectoris by nedudng Total Peripheral Resistance, or aftertoad, which reduces the rate pressure product and thus myocardial oxygen demand at any particular level of exerdse. In patients with vasospastic angina pectoris, amlodipine has been demonstrated to block constriction and thus restore myocardial oxygen supply.
Further, amlodipine has been shown to increase myocarc(ial oxygen supply by dilating the coronary arteries.
Hypertension fnequenHy coexists with hyperfipidemia and both are considered to be major risk factors for developing cardiac disease ultimately resulting in adverse cardiac events. This dustering of risk factors is potentially due to a common mechanism. Further, patient compliance with the management of hypertension is generally better than patient compliance with hyperiipidemia. It would therefore be advantageous for patients to have a single therapy which treats both of these conditions.
Coronary heart disease is a muitifactorial disease in which the inddence and severity are affected by the lipid profile, the presence of diabetes and the sex of the subject. Inadence is also affected by smoking and left ventricular hypertrophy which is secondary to hypertension. To meaningfully reduce the risk of coronary heart disease, it is important to manage the entire risk spectrum. For example, hypertension intervention trials have failed to demor~trate fuU normafrzation in cardiovascular mortality due to coronary heart disease. Treatment with cholesterol synthesis inhibitors in patients with and without coronary artery disease reduces the risk of cardiovascular morbidity and mortality.
The Framingham Heart Study, an ongoing prospective study of adult men and women, has shown that certain risk factors can be used to predict the development of coronary heart disease. (see Wilson et al., Am. J. Cardiol.198T, 59(14):9'! G-94G).
These factors include age, gender, total cholesterol level, high density lipoprotein (HDL) level, systolic blood pressure, dgarette smoking, glucose intolerance and cardiac enlargement (left ventricular hypertrophy on electmcar~diogram, echocardiogram or enlarged heart on diest X-ray). Calculators and computers can easily be programmed using a multivariate logistic function that allows calculation of the conditional probability of cardiovascular events. These determinations, based on experience with 5,209 men and women partidpating in the Framingham study, estimate coronary artery disease risk over variable periods of follow-up.
Modeled inddence rates range from less than 1 % to greater than 80°r6 over an arbitrarily selected six year interval. However, these rates are typically less than 10%
and rarely exceed 45°~ in men and 25% in women.
Kramsch et al., Journal of Human Hypertension (1995) (Suppl. 1), 53-59 discloses the use of caldum channel dockers, inducting amkxfrpine, to treat atherosderosis. That n:fen:noe further suggests that atherosderosis can be treated with a combination of amlodipine and a lipid kywering agent. Human trials have shovm that caldum d~anne) dodkers have benefidal effects in the treatment of early atherosderotic lesions. (see, e.g., Lidttlen, P.R. et al., Retardation of angiographic progression o coronary artery disease by nifedipine, Lancet,1990, 335, 1109-13; and Waters, D. et al., A controlled clinical trial to assess the effect of a caldum channel W0.99/11260 PCT/IB98/01230 _5.
blodcer on the progression of coronary atherosderosis, Circulation, 1990, 82, 53.) U.S. 4,681,893 discloses that certain statins, including atorvastatin, are hypolipidemic agents and as such are useful in treating atherosderosis. Jukema et al., Circulation, 1995 (Suppl.1 ), 1-197disdose that there is evidence that calcium channel blodcers act synergistic a~ combination with lipid towering agents (e.g., HMG-CoA redudase inhibitors), speafically pravastatin. On:khov et al., Cardiovascular Drugs and Therapy,199T,11, 350 disclose the use of amlodipine in combination with lovastatin for the treatment of atherosderosis.

WO, 99/11260 PC'T/IB98/01230 This invention is directed to a pharmaceutical composition, hereinafter termed "Composition A', comprising:
a. an amount of atonrastatin or a pharmaceutically acceptable salt thereof, b. an amount of an antihypertensive agent or a pharmaceutically acceptable salt thereof, and c. a pharmaceutically axeptable carrier or diluent;
provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable aad addition salt thereof.
This invention is particularly directed to a pharmaceutical oomposi~on, hereinafter termed 'Composition AA' of Composition A wherein said antihypertensive agent is a calaum channel blodcer, an ACE inhibitor, an A II antagonist, a diuretic, a beta-adrenergic receptor blodcer, a vasodilator or an alpha-adrenergic receptor blodcer.
This invention is more particularly directed to a pharmaceutical composition, hereinafter tanned 'Composition AB', of Composition AA comprising the hemicalcium salt of atonrastatin.
This invention is still more particularly directed to a pharmaceutical composition, hereinafter termed 'Composition AC', of Composition AB wherein said antihypertensive agent is a calaum channel blodcer, said calaum channel blodcer being verapamil, di~iazem mibefradil, isradipine, laddipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine or felodipine.
This invention is still more particularly din~cted to a pharmaceuti~ai composition of composition AC wherein said calaum channel blodcer is felodipine or nifedipine.
This invention is also more particx~lariy directed to a pharmaceutical composition of Composition AB wherein said antihypertensive agent is an ACE
inhibitor, said ACE inhibitor being benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril,,quinapril or trandolapril.
This invention is also more particularly d'u~eded to a pharmaceutical composition of Composition AB wherein said anhhypertensive agent is an A-11 antagonist, said A II antagonist being losartan, ir~artan or valsartan.

This invention is also more particularly directed to a pharmaceutical composition of Composfion AB wherein said antihypertens'rve agent is a diuretic, said diuretic being amiloride or bendroflumethiazide.
This invention is also more particularly directed to a pharmaceutical composition of Composition AB wherein said antihypertensive agent is a beta-adrenergic receptor blocker, said beta-adrenergic receptor blodcer being carvedilol.
This invention is also more particularly directed to a pharmaceutical composition of Composition AB wherein said antihypertensive agent is an atpha-adrenergic receptor blodcer, said alpha-adrenergic n~ceptor blodcer being doxazosin, prazosin or trimazosin.
This invention is also directed to a first pharmaceutical composition, hereinafter termed 'Composition B', for use with a second pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof, which effect is greater than the sum of the therapeutic effect achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composfion comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composfion comprising an amount of an antiphypertens'rve agent or a pharmaceutically acceptable salt then:of and a pharmaceutically acceptable canier or diluent; provided that said antihypertensive agent is not amlodipine or a phartnaceuticaUy acceptable aid addition salt thereof.
This invention is particulariy directed to a pharmaceutical composition, hereinafter termed 'Composition BA', of Composition B wherein said arttihypertensive agent is a ca~ium channel blodcer, an ACE inhibitor, an A-11 antagonist, a diuretic, a beta-adnenergic nceptor blodcer or an alpha-adrenergic receptor blodcer.
This invention is more particularly d'u~ected to a phannaceuacal composition, hereinafter termed 'Composition BB', of Composition BA wherein said second pharmaceutical composition comprises the hemic~laum salt of atorvastatin.
This invention is stall more partiailarty directed to a pharmaceutical composition, hereinafter tem~ed 'Composition BC', of Composition B8 wherein said antihypertensive agent is a cilium channel blodcer, said calcium channel Mocker being verapamil, diltiazem, mibefradil, isradipine, laddipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine or felodipine.
This invention is still more particulary directed to a pharmaceutical composition of Composition BC wherein said calcium channel blodcer is felodipine or nifedipine.
This invention is still more particularly directed to a pharmaceutical composition of Composfion BB when:in said antihypertensive agent is an ACE
inhibitor, said ACE inhibitor being benazepril, captopril, enalapril, fosinopril, tisinopril, perindopril, quinapril or trandolapril.
This invention is still more particularly directed to a phartnaoeulical composition of Composition BB wherein said antihypertens'rve agent is an A-II
antagonist, said A-II antagonist being losartan, irbesartan or valsartan.
This invenfion is also more particularly directed to a pharmaceutical composition of Composition BB wherein said antihypertensive agent is a diuretic, said diuretic being amiloride or bendrofiumethiazide.
This invention is also more particularly directed to a pharmaceutical composition of Composition BB wherein said antihypertensive agent is a beta-adrenergic receptor Mocker, said beta-adrenergic n~ceptor bkxker being carvedilol.
This invention is also more partiarlariy direcxed to a pharmaceutical composition of Composition BB wherein said antihypertensive agent is an alpha-adrenergic receptor Mocker, said alpha-adrenergic receptor blodcer being doxazosin, prazosin or trimazosin.
This invention is also directed to a first pharmaceutical composfion, hereinafter termed 'Composition C', for use with a second pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof, which effect is greater than the sum of the therapeutic efi~ct achieved by administering said first and second pharmaoeutihcal compositions separately and which second pharmaceutical composition comprises an amount of an arttihypertensive agent or a pharmaceutically acceptable salt then:of and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin agent or a phartnaceutica~y acceptable salt thereof and a pham~aoeudc~tly acceptable carrier or diluer~ provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable aad addition salt thereof.

V1~0,99/11260 PCT/IB98/01230 _g.
This invention is particularly directed to a pharma~cal composition, hereinafter termed 'Composition CA', of Composition C wherein said antihypertensive agent is a calaum channel Mocker, an ACE inhibitor, an A-II
antagonist, a diuretic, a beta-adrenergic receptor blodcer or an alpha-adrenergic receptor blodcer.
This invention is more particularly directed to a pharmaceutical composfion, hereinafter termed "Composition CB', of Composition CA comprising the hemicalcium salt of atorvastatin.
This invention is still more partiarharty directed to a pharmaceutical composition hereinafter termed 'Composition CC', of Composition CB wherein said antihypertensive agent is a calaum channel blodcer, said calcium channel blodcer being verapamil, dittiazem, mibefradil, isradipine, laadipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine or felodipine.
This invention is stall more particularly directed to a pharmaceutical composition of Composfion CC wherein said calaum channel blocker is felodipine or nifedipine.
This invention is also more particularly directed to a pharmaceutical composition of Composition CB wherein said antihypertensive agent is an ACE
inhibitor, said ACE inhibitor being benazeprii, captopril, enalapril, fosinopn'1, lisinopril, perindopr~, quinapril or trandolapril.
This invention is also more partiarlariy directed to a pharmaceutical composition of Composition CB wherein said antihypertensive agent is an A-II
antagonist, said A-II antagonist being losartan, irbesartan or valsartan.
This invention is also more partia~arty directed to a pharmaceutical composition of Composition CB wherein said antihypertensive agent is a diuretic, said diuretic being amiloride or bendroflumethiazide.
This invention is still more particularly directed to a pharmaceutical composfion of Composiflon CB wherein said antihypertensive agent is a beta-adrenergic receptor blodcer, said beta-adrenergic n~ceptor blodcer being carvedilot.
This invention is still more particularly directed to a pharmaceutical composition of Composition CB wherein said antihypertensive agent is an alpha-adrenergic n:oeptor blodcer, said alpha-adrenergic receptor blodcer being doxazosin, prazosin or trimazosin.

WO. 99/11260 PCT/IB98/01230 This invention is also particularly directed to a pharmaceutical composition of Composition B wherein said therapeutic effect is antianginal;
antiatherosGerotic;
antihypertensive and hypolipidemic; or is effective for cardiac risk management.
This invention is particularly directed to a pharmaceutical composition of Composition BB wherein said therapeutic effect is antianginal;
antiatherosclerotic;
antihypertensive and hypolipidemic; or is effective for cardiac risfc management.
This invention is also particularly directed to a pharmaceutical composition of Composition C wherein said therapeutic effect is antianginal;
antiatherosderotic;
antihypertensive and hypolipidemic; or is effective for cardiac risk management.
This invention is also particularly directed to a pharmaceutical composition of Composition CB wherein said therapeutic effect is antianginal;
antiatherosclerotic;
antihypertensive and hypolipidemic; or is effective for cardiac risk management.
This invention is also directed to a first pharmaceutical composition, hereinafter termed 'Composition D', for use with a second pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof, which effect is greater than the therapeutic effect achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of an antihypertensive agent or a pharmaceutically acceptable salt thereof and a pham~aceutically acceptable carrier or diluent, provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable aad addition salt thereof.
This invention is partiariariy directed to a phannaoeuticaf composition, hereinafter termed 'Composition DA', of Composition D wherein said antihypertensive agent is a calcium channel blodcer, an ACE intubitor, an A ll antagonist, a diuretic, a beta-adrenergic receptor blodcer or an alpha-adrenergic receptor blodcer.
This invention is more particularly directed to a pharmaceutical composition, hereinafter~enned'Composition DB', of Composition DA wherein said second pharmaceutical composition comprises the hemicalaum salt of atorvastatin.

WO, 99/11260 PCT1IB98/01230 _11_ This invention is also particularly directed to a pharmaceutical composition of Composition D wherein said therapeutic effect is antianginal;
antiatherosclerotic;
antihypertensive and hypolipidemic; ~ is effective for cardiac risk management This invention is also directed to a pharmaceutical composition of Composition DB wherein said therapeutic effect is antianginal;
antiatherosderotic;
antihypertensive and hypolipidemic; or is effective for cardiac risk management.
This invention is also directed to a first pharmaceutical compositian, hereinafter termed 'Composition E', for use with a second pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof, which effect is greater than the therapeutic effect achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of an antihypertens'rve agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acxeptable sail thereof and a pharmaceutically acceptable carrier or diluent, provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable aad addition salt thereof.
This invention is particularly directed to a pharmaceutical oomposfion, hereinafter termed 'Composition EA', of Composition E wherein said antihypertensive agent is a cafaum channel bk~dcer, an ACE inhibitor, an A-II
antagonist, a diuretic, a beta-adrenergic n~oeptor blocker or an alpha-adrenergic receptor blodcer.
This invention is more particularly directed to a pharmaceutical composition, hereinafter termed 'Composition EB', of Composition EA comprising the hemicalaum salt of atonrastatin.
This invention is also particulariy directed to a pharmaceutical composition of Composition E wherein said therapeutic effect is antianginal;
antiatherosderotic;
antihypertensive and hypolipidemic; or is effective for cardiac risk management.
This invention is also particulariy dm~ded to a pharmaceutical composition of Composition EB wherein said therapeutic effect is antianginal;
antiatherosderotic;
antihypertensive and hypolipidemic; or is effective for cardiac risk management.
This invention is also din:cxed to a kit, hereinafter termed 'ICt A', for achieving a therapeutic effect in a mammal comprising:

WO. 99/11260 PCT/IB98/01230 a. an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or dituent in a first unit dosage form;
b. an amount of an antihypertensive agent or a phannaoeutically axeptable salt thereof and a pharmaceutically acceptable carrier or d~uent in a second unit dosage form; and c. container means for containing said first and second dosage forms, provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable cad addition salt thereof.
This invention is particularly directed to a kit, hereinafter termed 'Kit AA", of Kit A comprising the hemicalaum salt of atorvastatin.
This invention is more particularty directed to a kit, hereinafter termed '1Gt AB", of 1Gt AA wherein said an6hypertens'rve agent is a cataum channel bkx~cer, an ACE inhibitor, an A-II antagonist, a diuretic, a beta-adrenergic nrceptor blodcer or an alpha-adrenergic receptor blodcer.
This invention ~s still more partiarlarly directed to a kit of Kd AB wherein said therapeutic effect is antianginal; antiattlerosclerotic; antihypertensive and hypolipidemic; or is effective for cardiac risk management.
This invention is also directed to a method, hereinafter termed 'Method A", for treating a mammal in need of therapeutic treatment comprising administering to said mammal (a) an amount of a first compound, said fast compound being atorvastatin or a pharmaceutically acceptable salt thereof; and (b) an amount of a second compound, said second compound being an antihypertensive agent or a pharmaceutically acceptable salt thereof;
wherein said first compound and said second compound are each optionally and independently administered together with a pharmaceutically acceptable ~n~ier or diluent, provided that said antihypertensive agent is not amlodipine or a phartnaoeutically arable add addition salt thereof.
This invention is parba~a~yr directed to a method, hereinafter termed 'Method AA', of Method A comprising the hemicaldum salt of atorvastatin.
This invention is more particularly directed to a method, hereinafter termed 'Method AB', of Method AA wherein said antihypertensive agent is a calaum channel WO, 99/11260 PCT/IB98/01230 blocker, an ACE inhibitor, an A-II antagonist, a diuretic, a beta-adrenergic receptor blocker, or an alpha-adrenergic receptor blodcer.
This invention is also particularly directed to a method, hereinafter termed 'Method AC', of Method A wherein said first compound and said second compound are administenrd sequentially in either order.
This invention is also particularly din:~ct~ed to a method, hereinafter termed 'Method AD', of Method A wherein said first compound and said second compound are administend simultaneously.
This invention is still more particularly directed to a method, hereinafter termed 'Method AE', of Method AB wherein said first compound and said second compopund are administend sequentially in eitfier order.
This invention is still more particularly directed to a method, hereinafter termed 'Method AF', of Method AB wherein said first compound and said second compound are administered simultaneously.
This invention is also particularly directed to a method of Method A wherein said therapeutic treatment comprises antihypertensive and antihyperlipidemic treatmertt.
This invention is also particularly directed to a method of Method AE wherein said therapeutic treatment comprises antihypertensive and antihyperiipidemic treatment.
This invention is also partiarlariy ding to a method of Method AF wherein said therapeutic treatment comprises antihypertensive and antihyperlipidemic treatrnent.
This invention is also partiarlarfy directed to a method of Method A wherein said therapeutic trea~r~ent comprises antianginal treatment.
This invention is also partiarlarly directed to a method of Method AE wherein said therapeutic treatment comprises antianginal treatment.
This invention is also particularly dinec~d to a method of Method AF wherein said therapeutic treatment comprises an tianginal treatment.
This invention is also particularly directed to a method of Method A wherein said therapeutic tr~eatrr~nt comprises cardiac risk management.
This invention is also particularly directed to a method of Method AE wherein said therapeutic treatment comprises cardiac risk management This invention is also particularly directed to a method of Method AF wherein said therapeutic treatment comprises cardiac risk management.
This invention is also particularly directed to a method of Method A wherein said therapeutic treatment comprises the treatment of atherosderosis.
This invention is also particularly directed to a method of Method AE wherein said therapeutic treatment comprises the treatment of atherosderosis.
This invention is also particularly directed to a method of Method AF wherein said therapeutic treatrnent comprises the treatment of atherosderosis.
Amlodipine is a racemic compound due to the symmetry at position 4 of the dihydropyridine ring. The R and S enandomers may be prepared as described by Arrowsmith et al., J. Med. Chern., 1986_ Z,Q, 1696. The talcum channel blocking activity of arnlodipine is substantially confined to the S{-) isomer and to the racemic mixture containing the R(+) and S(-) forms. (see International Patent Application Number PCT/EP94/02697). The R(+) isomer has little or no calaum d~annel blocking adwity. However, the R(+) isomer is a potent inhibitor of smooth musde cell migration. Thus, the R(+) isomer is useful in the treatment or prevention of atherosderosis. (see International Patent Application Number PCTIEP95I00847).
Based on the above, a skilled person could choose the R(+) isomer, the S(-) isomer or the racemic mature of the R(+) r and the S(-) isomer for use in the combination of this invention.
Where used herein, the term 'cardiac risk' means the likelihood that a subject will suffer a future adverse cardiac event such as, e.g., myocardial infarction, cardiac arrest, cardiac failure, cardiac ischaemia. Cardiac risk is calculated using the Framingham Risk Equation as set forth above. The term 'cardiac risk management' means that the risk of future adverse cardiac events is substantially reduced.
It will be reoogneed by those skilled in the art that certain of the antihypertensive ager>ts which are used in combination with atorvastatin or a pharmaaretically axeptable salt of atorvastatin contain either an aadic moiety or a basic moiety which may be reacted with either a base to form a cationic salt or an acd to form an acd addtion sa>t, respectively. All of the phamnaceuticalty acceptable salts of the antihypertensive agents disdosed herein are within the scope of the combination of this invention.

WO, 99/11260 PCT/IB98/01230 The pharmaceutical compositions of this invention comprise atorvastatin or a pharmaceutically acxeptabte salt thereof and an antihypertensive agent or a pharmaoe~fi~lly acceptable salt thereof.
Atorvastatin may readily be prepared as described in U.S. Patent No.
4,681,893, which is incorporated herein by reference. The hemicaldum salt of atorvastatin, which is arrrenti~r sold as Lipitor~; may readily be prepared as described in U.S. Patent No. 5,273,995, which is incorporated herein by reference.
The expression 'pharmaoeuti~tyr acceptable salts' indudes both pharmaceutically acceptable acrd addition salts and pharmaceutically acceptable cationic salts. The expression "phamiaceuticalty-acceptable cationic salts" is intended to define but is not limited to such salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., caldum and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N,N'~iibenzylethylenediamine), d~oline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamp~e (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. The expn~sion "pharmaceutically-acceptable add addition salts"
is intended tp define but is not limited to such salts as the hydrochloride, hydrobromide, sulfate,. hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, sucdnate, citrate, methanesulfonate (mesylate) and p-#oluenesulfonate (tosylate) salts.
Besides the hemicalaum salt, other pharmaceutically-acceptable cationic salts of atorvastatin may be headily preQared by reacting the free acrd form of atorvastatin with an appropriate base, usuaAy one equivalent, in a co-solvent.
Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide, calaum hydroxide, benzath'a~e, d~oline, diethanolamine, piperatine and tromethamine. The salt is isolated by concentration to dryness. or by addition of a non-sohrent. In many cases, sags are preferably prepared by mbdng a solution of the add with a solution of a different salt of the canon (sodium or potassium ethylhexanoate, magnesium cleats), and employing a WO, 99/11260 PCT/IB98/01230 ~16-solvent (e.g., ethyl acetate) from the desired cationic salt predpitates, or can be otherwise isolated by concentration and/or addi5on of a non-solvent. The aad addition salts of atorvastatin may be readily prepared by reading the fare base fom~
of atorvastatin with the appropriate add. When the salt is of a monobasic add (e.g., the hydrochloride, the hydrobromide, the p-toluenesutfonate, the acetate), the hydrogen form of a dibasic add (e.g., the hydrogen sulfate, the sucanate) or the dihydrogen form of a tribasic add (e.g., the dihydrogen phosphate, the atrate), at least one molar equivalent and usually a molar excess of the add is employed.
However when such salts as the sulfate, the hemisuccinate, the hydrogen phosphate or the phosphate are desired, the appropriate and exact chemical equivalents of add will generally be used. The free base and the add are usually combined in a co-solvent from which the desired salt predpitates, or can be otherwise isolated by concentration and/or addition of a non-solvent.
The pharmaceutically acceptable aad addition and cationic salts of the antihypertensive agents used in the combination of this invention may be prepared in a manner analogous to that described for the preparation of the pharmaceuticalty acceptable add addition and cationic salts of atorvastatin, but substituting the desired antihypertensive compound for atorvastatin.
The antihypertensive agents which may be used in acoor~dance with this invention are members of different Basses of antihypertensive agents, indufiing caldum channel blodcers {excluding amlodipine and pharmaceutically acceptable add addition salts thereof), ACE ~h~bitors, A-II antagonists, diuretics, beta-adrenergic receptor blodcers, vasodilators and alphaadrenergic receptor blodcers.
Caldum diannel blodcers which are within the scope of this invention include, but are not limited to: bepridil, which may be prepared as disclosed in U.S.
Patent No.

3,962, 238 or U.S. Reissue No. 30,577; dentiazem, which may be prepared as disclosed in U.S. Patent No. 4,567,175; diltiazem, which may be prepared as disclosed in U.S. Patent No. 3,562, fiendifine, which may be prepared as disclosed in U.S. Patent No. 3,262,977; gduopamil, which may be prepared as disclosed in U.S.
Patent No.3,261,859; mibefradtl, which may be prepared as disclosed in U.S.
Patent No. 4,808,605; prenylamine, which may be prepared as disclosed in U.S. Patent No.
3,152,173; semotiadil, which may be prepared as disclosed in U.S. Patent No.

4,786,635; terodiline, which may be prepared as disclosed in U.S. Patent No.

_17_ 3,371,014; verapamil, which may be prepared as disclosed in U.S. Patent No.
3,261,859; aranipine, which may be prepared as disclosed in U.S. Patent No.
4,572,909; bamidipine, which may be Prepared as disclosed in U.S. Patent No.
4,220,649; benidipine, which may be prepared as disd~ed in European Patent Application Publication No. 106,275; cllnidipine, which may be prepared as disclosed in U.S. Patent No. 4,672,068; efonidipine, which may be prepared as disclosed in U.S. Patent No.4,885,284; elgodipine, which may be prepared as disclosed in U.S.
Patent No. 4,952,592; felodipine, which may be pr~epar~ed as disGosed in U.S.
Patent No. 4,264,611; isradipine, which may be prepared as d~sdosed in U.S. Patent No.
4,466,972; lacidipine, which may be prepared as disclosed in U.S. Patent No.
4,801,599; ienranidipine, which may be prepared as disclosed in U.S. Patent No.
4,705,797; manidipine, which may be prepared as disclosed in U.S. Patent No.
4,892,875; nicardipine, which may be prepared as disclosed in U.S. Patent No.
3,985,758; nifedipine, which may be prepared as disclosed in U.S. Patent No.
3,485,847; ru'ivadipine, which may be prepared as disclosed in U.S. Patent No.
4,338,322; nanodipine, which may be prepared as disclosed in U.S. Patent No.
3,799,934; nesoldipme, which may be prepared as d~sdosed in U.S. Patent No.
4,154,839; nitrendipine, which may be prepared as disclosed in U.S. Patent No.
3,799,934; cirmarizine, which may be prepared as disclosed in U.S. Patent No.
2,882,271; flunarizine, which may be prepared as disclosed in U.S. Patent No.
3,773,939; lidoflazine, which may be prepared as disclosed in U.S. Patent No.
3,267,104; lomerQine, which may be prepared as disclosed in U.S. Patent No.
4,663,325; bencydane, which may be prepared as disclosed in Hungarian Patent No.
151,865; etafenone, which may be prepan~i as dsdosed in German Patent No.
1,265,758; and pefieb~ine, which may be prepared as disclosed in British Patent No.
1,025,578. The disclosures of all such U.S. Patents are incorporated herein by reference.
Angio~ensin Converting Enzyme Inhibitors (ACE-Inhibitors) which are within the scope of this invention include, but are not limited to: alaoepril, which may be pnepar~ed as disclosed in U.S. Patent No. 4,248,883; benazepril, which may be prepared as disclosed in U.S. Patent No. 4,410,520; captopril, which may be prepared as d~sdosed in U.S. Patent Nos. 4,046,889 and 4,105,776; ceronapril, which may be prepared as disclosed in U.S. Patent No. 4,452,790; detapril, which Vt~O, 99/11260 PCT/IB98/01230 may be prepared as disclosed in U:S. Patent No. 4,385,051; enalapril, which may be prepared as disclosed in U.S. Patent No. 4,374,829; fosinopril, which may be prepared as disclosed in U.S. Patent No. 4,337,201; imadapril, which may be prepared as disclosed in U.S. Patent No. 4,508,727; lisinopril, which may be prepared as disclosed in U.S. Patent No. 4,555,502; moveltopril, which may be prepared as disclosed in Belgian Patent No. 893,553; pertndopril, which may be prepared as disclosed in U.S. Patent No. 4,508,729; quinapril, which may be prepared as disclosed in U.S. Patent No. 4,344,949; ramipn~, which may be prepared as d~sdosed in U.S. Patent No. 4,587,258; spirapril, which may be prepared as disclosed in U.S.
Patent No. 4,470,972; temocapril, which may be prepared as disclosed in U.S.
Patent No. 4,699,905; and trandolapril, which may be prepared as disclosed in U.S.
Patent No. 4,933,361. The disclosures of all such U.S. patents are incorporated herein by reference.
Angiotensin-II receptor antagonists (A-II antagonists) which are within the scope of this invention include, but are not limited to: candesartan, which may be prepared as disdased in U.S. Patent No. 5,196,444; eprosartan, which may be prepared as disclosed in U.S. Patent No. 5,185,351; irbesartan, which may be prepared as disclosed in U.S. Patent No. 5,270,317; losartan, which may be prepared as disclosed in U.S. Patent No. 5,138,069; and valsartan, which may be prepared as disclosed jn U.S. Patent No. 5,399,578. The disclosures of all such U.S.
patents are incorporated herein by reference.
Beta-adrenergic receptor blodcers (beta- or ~-blodcers) which are within the scope of this invention include, but are not limited to: acebutolol, which may be prepared as disclosed in U.S. Patent No. 3,857,952; alprenolol, which may be prepared as disclosed in Netherlands Patent Application No. 6,605,692;
amosulalol, which may be prepared as disclosed in U.S. Patent No. 4,217,305; arotinolol, which may be prepared as disclosed in U.S. Patent No. 3,932,400; atenolol, which may be prepared as disclosed in U.S. Patent No. 3,663,607 or 3,836,671; befunolol, which may be prepared as disclosed in U.S. Patent No. 3,853,923; betaxolol, which may be prepared as disclosed in U.S. Patent No. 4,252,984; bevantolol, which may be prepared as disclosed in U.S. Patent No. 3,857,981; bisoprolol, which may be prepared as disclosed in U.S. Patent No. 4,171,370; bopindolol, which may be V1r0,99/11260 PCT/IB98/01230 prepared as disclosed in U.S. Patent No. 4,340,541; bucumolol, which may be prepared as disclosed in U.S. Patent No. 3,663,570; bufetolol, which may be prepared as disclosed in U.S. Patent No. 3,723,476; bufuralol, which may be prepared as disclosed in U.S. Patent No. 3,929,836; dunihnlol, which may be prepared as disclosed in U.S. Patent Nos. 3,940,489 and 3,961,071;
buprandolol, which may be prepared as disclosed in U.S. Patent No. 3,309,406; butiridine hydrochloride, which may be prepared as disclosed in Fn~ch Patent No.
1,390,056;
turtofiiolol, which may be prepared as disclosed in U.S. Patent No. 4,252,825;
carazolol, which may be prepared as disclosed in German Patent No. 2,240,599;
carteolol, which may be prepared as disclosed in U.S. Patent No. 3,910,924;
carvediloi, which may be prepared as disclosed in U.S. Patent No. 4,503,067;
celiprolol, which may be prepared as disclosed . in U.S. Patent No. 4,034,009;
cetamolol, which may be prepared as disclosed in U.S. Patent No. 4,059,622;
doranolol, which may be prepared as disclosed in German Patent No. 2,213,044;
dilevatol, which may be prepared as disclosed in Crrfton et al., Journal of Mediclnal Chemistry, 1982. 2~, 670; epanolol, which may be prepared as disclosed in European Patent Publication Ap~icafion No. 41,491;. (d, which may be prepared as disclosed in U.S. Patent No. 4,045,482; labetalol, which may be prepared as disclosed in U.S. Patent No. 4,012,444; levobunolol, which may be prepared as disclosed in U.S. Patent No. 4,4fi3,176; mepindolol, which may be prepared as dtsdosed in Seeman et al., Helv. Ch~nn. Acta, yQU, fig, 241;
metipranolol, which may be prepared as disclosed in Czed~oslovakian Patent Application No. 128,471; metoprolol, which may be prepared as disclosed in U.S.
Patent No. 3,873,600; moproloi, which may be prepared as clsdosed in U.S.
Patent No. 3,501,7691; nadolol, which may be prepared as disclosed in U.S. Patent No.
3,935, 267; nadoxolol, which may be prepared as d'in U.S. Patent No.
3,819,702; r~ebivalol, which may be prepared as disclosed in U.S. Patent No.
4,654,362; niprad'dol, which may be prepared as disclosed in U.S. Patent No.
4,394,382; oxprenolol, which may be prepared as disclosed in British Patent No.
1,077,603; ,perbutclol, which may be prepared as d~sdosed in U.S. Patent No.
3,551,493; pindolol, which may be prepared as d'~sdosed in Swiss Patent Nos.
469,002 and 472,404; practolol, which may be prepared as disclosed in U.S.
Patent W0.99/11260 PCT/IB98/01230 No. 3,408,387; pronethalof, which may be prepared as disclosed in British Patent No.
909,357; propranolol, which may be prepared as disclosed in U.S. Patent Nos.
3,337,628 and 3,520,919; sotalol, which may be prepared as disclosed in Uloth et al., Journal of Medidnal Chemistry, ~, ~, 88; sufinalol, which may be prepared as disclosed in German Patent No. 2,728,641; ta~dol, which may be prepared as disclosed in U.S. Patent Nos. 3,935,259 and 4,038,313; tertatolol, which may be prepared as disclosed in U.S. Patent No. 3,960,891; tilisolol, which may be prepared as disclosed in U.S. Patent No. 4,129,565; timolol, which may be prepared as disclosed in U.S. Patent No. 3,655,663; toGprolol, which may be prepared as disclosed in U.S. Patent No. 3,432,545; and xrbenolol, which may be prepared as disclosed in U.S. Patent No. 4,018,824. The disclosures of al! such U.S.
patents are incorporated herein by reference.
Alpha-adrenergic receptor blodcers (alpha- or a-blodcers) which are within the scope of this invention include, but are not limited to: amosulalol, which may be prepared as disclosed in U.S. Patent No. 4,217,307; arotinolol, which may be prepared as disclosed in U.S. Patent No. 3,932,400; dapiprazole, which may be prepared as disclosed in U.S. Patent No. 4,252,721; doxazosin, which may be prepared as disclosed in U.S. Patent No. 4,188,390; fenspiride, which may be prepared as disclosed in U.S. Patent No. 3,399,192; indoramin, which may be prepared as disclosed in U.S. Patent No. 3,527,761; labetolol, which may be prepared as disclosed above; naftopid~, which may be prepared as disclosed in U.S.
Patent No. 3,997,666; nicergoline, which may be prepared as disclosed in U.S.
Patent No. 3,228,943; prazosin, which may be prepared as disclosed in U.S.
Patent No. 3,511,836; tamsulosin, which may be prepared as disclosed in U.S. Patent No.
4,703,063; tolazoline, which may be prepared as disclosed in U.S. Patent No.
2,161,938; trimazosin, which may be prepared as disclosed in U.S. Patent No.
3,669,968; and yohimbine, which may be isolated from natural sources according to methods v~A known to those sla'lled in the art The disclosures of as such U.S.
patents are,inoorporated herein by reference.
The term 'vasodilator,' where used herein, is meant to include cerebra!
vasodilators, coronary vasodilators and peripheral vasodr'tators. Cerebral vasodilators within the scope of this inver>tion include, but are not Limited to:

W0.99/11260 PCT/IB98/01230 bencydane, which may be prepared as disclosed above; dnnarizine, which may be prepared as disclosed above; citicaline, which may be isolated from natural sources as disclosed in Kennedy et al., Journal of the American Chemical Society, 1955. ~, 250 or synthesized as disclosed in Kennedy, Journal of Biological Chemistry, 1956, ~, 185; cydandelate, which may be prepared as disclosed in U.S. Patent No.
3,663,597; ddonicate, which may be prepared as disclosed in German Patent No.
1, 910,481; diisopropylamine dichloroacetate, which may be prepared as disclosed in British Patent No. 862,248; ebumamonine, which may be prepared as disclosed in Hermann et al., Journal of the American Chemical Soaety, 1979. ~, 1540;
fasudil, which may be prepared as disclosed in U.S. Patent No. 4,678,783; fenoxedil, which may be prepared as disclosed in U.S. Patent No. 3,818,021; flunariane, which may be prepared as disclosed in U.S. Patent No. 3,773,939; ibudilast, which may be prepared as disclosed in U.S. Patent No. 3,850,941; ifenprodil, which may be prepared as disclosed in U.S. Patent No. 3,509,164; lomereine, which may be prepared as disclosed in U.S. Patent No. 4,663,325; nafronyl, which may be prepared as disclosed in U.S. Patent No. 3,334,096; nicametate, which may be prepared as disclosed in B6dce et al., Journal of the American Chemical Society, ~, fig, 1722;
nicergoline, which may be prepared as disclosed above; nimodipine, which may be prepared as d'~sdosed in U.S. Patent No. 3,799,934; papaverine, which may be prepared as reviewed in Goldberg, Chem. Prod. Chem. News, 1954. ~, 371;
pentifylline, which may be prepared as disclosed in German patent No. 860,217;
tinofedrine, which may be prepared as disclosed in U.S. Patent No. 3,563,997;
vincamine, which may be prepared as disclosed in U.S. Patent No. 3,770,724;
vinpocetine, which may be prepared as disclosed in U.S. Patent No. 4,035,750;
and viquidil, which may be prepared as disclosed in U.S. Patent No. 2,500,444. The disclosures of all such U.S. patents are incorporated herein by reference.
Coronary vasodilators within the scope of this irwention include, but are not limited to: amotriphene, which may be prepared as disclosed in U.S. Patent No.
3,010,965; bendazol, which may be prepared as disclosed ~ J. Chem. Soc. 1958, 2426; benfurodil hemisuccinate, which may be prepared as disclosed in U.S.
Patent No. 3,355,463; ber>ziodarone, which may be prepared as disclosed in U.S.
Patent No. 3,012,042; d~loraazine, which may be prepared as d~sdosed in British patent No. 740,932; duoma~ar, which may be prepared as disclosed in U.S. Patent No.

Vt~O, 99/11260 PCT/IB98/01230 3,282,938; dobenfural, which may be prepared as disclosed in British Patent No.
1,160,925; donitrate, which may be prepared from propanediol according to methods well known to those skilled in the art, e.g., see Annalen, 1870, 155, 165;
doricromen, which may be prepared as disclosed in U.S. Patent No. 4,452,811; dilazep, which may be pn:pared as disclosed in U.S. Patent No. 3,532,685; dipyridamole, which may be prepared as disclosed in British Patent No. 807,826; droprenilamine, which may be prepared as disclosed in German Patent No. 2,521,113; efloxate, which may be prepared as disclosed in British Patent Nos. 803,372 and 824,547; erythrityl tetranitrate, which may be prepared by r>itrafion of erythritol acoord'mg to methods well-!mown to those stalled in the art; etafenone, which may be prepared as disclosed in German Patent No. 1,265,758; fendiline, which may be prepared as disclosed in U.S. Patent No. 3,262,977; floredil, which may be prepared as disclosed in German Patent No. 2,020,464; ganglefene, which may be pn:pared as disclosed in U.S.S.R.
Patent No. 115,905; hexestrol, which may be prepared as disclosed in U.S.
Patent No. 2,357,985; hexobendine, which may be prepared as disclosed in U.S. Patent No.
3,267,103; itramin tosylate, which may be prepared as disclosed in Swedish Patent No. 168,308; khellin, which may be prepared as disclosed in Baxter et al., Journal of the Chemical Society,1~,Q, S 30; lidoflazine, which may be prepared as disclosed in U.S. Patent No. 3,267,104; mannitol hexanitrate, which may be prepared by the nitration of mannitol according to methods welNcnown to those skilled in the art;
medibazine, which may be prepared as disclosed in U.S. Patent No. 3,119,826;
rntroglycerin; pentaerythrttol tetrari~trate, which may be prepared by the nitration of pentaerythritol according to methods well-known to those sla'lled in the art;
pentrinitrol, which may be pn:par~ed as d~sdosed in German Patent No. 638,422-3;
pefiexiliine, which may be pr~epan~d as disclosed above; pimefylGne, which may be pnrpared as disclosed in U.S. Patent No. 3,350,400; prenylamine, which may be prepared as disclosed in U.S. Patent No. 3,152,173; propatyl rirtrate, which may be prepared as disclosed in French Patent No. 1,103,113; trapidil, which may be prepared as disclosed in East German Patent No. 55,956; tricromyl, which may be prepared as disclosed in U.S. Patent No. 2,769,015; trimetazidine, which may be prepared as disclosed in U.S. Patent No. 3,262,852; trolnitrate phosphate, which may be prepared by nitration of triethanofamine followed by predpitatlon with phosphoric acid according to methods well-known to those skilled in the art; visnadine, which may be pn:pared as disclosed in U.S. Patent Nos. 2,816,118 and 2,980,699. The disclosures of all suds U.S. patents are incorporated herein by refierence.
Peripheral vasodilators within the scope of this invention include, but an:
not limited to: aluminum r>iccotinate, which may be prepared as disclosed in U.S.
Patent No. 2,970,082; bamethan, whidi may be prepared as disclosed in Comgan et al., Journal of the American Chemical Soaety, 1945. ~Z, 1894; bencydane, which may be pn~pared as disclosed above; betahisstine, which may be prepared as disclosed in Walter et al.; Journal of the American Chemical Sodety, 1941. ~, 2771;
bradykinin, whidi may be prepared as disclosed in Hamburg et al., Arch. Biod~em. Biophys., 1958. ~, 252; brovinramine, which may be prepared as disclosed in U.S. Patent No.
4,146,643; txrfeniode, which may be prepared as disclosed in U.S. Patent No.
3,542,870; buflomedil, which may be pn:pared as disclosed in U.S. Patent No.
3,895,030; butalamine, which may be prepan~i as disclosed in U.S. Patent No.
3,338,899; cetiedit, may be prepared as disclosed in French Patent Nos.
1,460,571; cldonicate, which may be prepared as disclosed in German Patent No.
1,910,481; clnepazide, which may be prepared as disclosed in Belgian Patent No.
730,345; clnnarizine, which may be prepared as disclosed above; cydandelate, which may be prepared as drsdosed above; diisopropylamine dichloroacetate, which may be prepared as disclosed above; eledoisin, which may be pn:pared as d'~sdosed in British Patent No. 984,810; fenoxedil, which may be prepared as disclosed above;
tlunariane, which may be prepared as disclosed above; hepconicate, whicl~ may be prepared as disclosed in U.S. Patent No. 3,384,642; ifenpralil, which may be prepared as disclosed above; iloprost, which may be prepared as disclosed in U.S.
Patent No. 4,692,464; inositol niadnate, which may be prepared as disclosed in Badgett et al., Journal of the American Cherri~cal Soaety, 1947. ~,q, 2907;
isoxsuprine, which may be prepared as disclosed in U.S. Patent No. 3,056,836;
katlidin, which may be prepared as disclosed in Biochem. BioPhys Res. Commun., 1961, 6, 210; kallikr~ein, which may be prepared as disclosed in German Patent No.
1,102,973; moxisylyte, which may be prepared as d'in German Patent No.
905,738; nafronyl, which may be prepared as disclosed above; nicametate, which may be prepared as disebsed above; nicergoline, which may be prepared as disclosed above; nicofuranose, which may be prepared as disclosed in Swiss Patent No. 366,523; nylidrin, which may be prepared as disclosed in U.S. Patent Nos.
2,661,372 and 2,661,373; pentifylline, which may be prepared as disclosed above;
pentoxifylfine, which may be prepared as disclosed in U.S. PateM No.
3,422,107;
piribedil, which may be prepared as disclosed in U.S. Patent No. 3,299,067;
prostaglandin E~, which may be prepared by any of the methods referenced in the Merck Index, Twelfth Edi'tieon, Budaveri, Ed., New Jersey, 1996, p. 1353;
sulodidil, which may be prepared as disclosed in German Patent No. 2,334,404; tolazoline, which may be prepared as disclosed in U.S. Patent No. 2,161,938; and xar>thinol niaclnate, which may be prepared as disclosed in German Patent No. 1,102,750 or Korbonits et al., Acta. Pharm. Hung.,1~$, ~$, 98. The disclosures of all such U.S.
patents are incorporated herein by reference.
The term 'diuretic,' within the scope of this inventor, is meant to include diuretic benzothiadiazine derivatives, diuretic organomercurials, diuretic purines, diuretic steroids, diuretic sulfonamide derivatives, diuretic uraclls and other diuretics such as amanozine, which may be prepared as disclosed in Austrian Patent No.
168,063; amiloride, which may be prepared as disclosed in Belgian Patent No.
639,386; arbutin, which may be prepared as disclosed in Tschitschibat~in, Annalen, 1930. 41~, 303; chlorazanil, which may be prepared as disclosed in Austrian Patent No. 168,063; ethacrynic aad, which may be prepared as disclosed in U.S. Patent No.
3,255,241; etozofin, which may be prepared as disclosed in U.S. Patent No.
3,072,653; hydracarbavne, which may be prepared as disclosed in British Patent No.
856,409; isosorbide, which may be prepared as disclosed in U.S. Patent No.
3,160,641; mannitol; metochalcone, which may be prepared as disclosed in Freudenberg et al., Ber., 1957. ~, 957; muzolimine, which may be pnepar~ed as disclosed in U.S. Patent No. 4,018,890; perhexiline, which may be prepared as disclosed above; tiaynafen, which may be prepared as disclosed in U.S. Patent No.
3,758,506; triamterene which may be prepared as disclosed in U.S. Patent No.
3,081,230; and urea. The disclosures of all suds U.S. pater>tss are incorporated herein by refet~ence.
Diuretic benzothiadiazine derivafrves within the scope of this invention include, but arse not limited to: althiazide, which may be prepared as disclosed in British Patent No. 902,658; bendroflumethiazide, which may be prepared as disclosed in U.S.
Patent No. 3,265,573; benzthiazide, MGlAanus et al., 136th Am. Soc. Meeting V1'O 99/11260 PCT/IB98/01230 (Atlantic City, September 1959), Abstract of papers, pp 13-O;
benrylhydrochlorothia~ide, which may be prepared as disclosed in U.S. Patent No.
3,108,097; buthiazide, which may be prepared as disclosed in British Patent Nos.
861,367 and 885,078; chlorothiaade, which may be prepared as disclosed in U.S.
Patent Nos. 2,809,194 and 2,937,1; d~lorthalidone, which may be ~epared as disclosed in U.S. Patent No. 3,055,904; cydopertthiazide, which may be prepared as disclosed in Belgian Patent No. 587,225; cydothiazide, which may be prepared as disclosed in VVhitehead et al., Journal of Organic Chem~y, ~, ~, 2814;
epithiazide, which may be prepared as disclosed in U.S. Patent No. 3,009,911;
ethiazide, which may be prepared as disclosed in British Patent No. 861,367;
fenquizone, which may be prepared as disclosed in U.S. Patent No. 3,870,720;
indapamide, which may be prepared as disclosed in U.S. Patent No. 3,565,911;
hydrochlorothiazide, which may be pnepar~ed as disclosed in U.S. Patent No.
3,164,588; hydroflumethiaade, which may be prepared as disclosed in U.S.
Patent No. 3,254,076; methydothiazide, whid~ may be prepared as disclosed in Close et al., Journal of the American Chemical Society, 1960. $~, 1132; meticrane, which may be prepared as disclosed in I=rends Patent Nos. AA2790 and 1,365,504; metolazone, which may be prepared as disclosed in U.S. Patent No. 3,360,518; paraflutmde, which may be prepared as disclosed ~ Belgian Patent No. 620,829; potythiazlde, which may be prepand as disclosed in U.S. Patent No. 3,009,911; quinethazone, which may ~ be prepared as disclosed in U.S. Patent No. 2,976,289;
tedothiazide, which may be prepared as disclosed in Close et al., Journal of the American Chemical Soclety, 1960. $Z, 1132; and trichformethiazide, which may be prepared as disloosed in deStevens et al., Experientia, y~Q, ~, 113. The disclosures of all such U.S. patents are incorporated herein by refenenoe.
Diuretic sulfonamide derivatives within the scope of this invention include, but are not limited to: aoetazoiamide, which may be prepared as disclosed in U.S.
Patent No. 2,980,679; ambuside, which may be prepared as disclosed in U.S. Patent No.
3,188,329; azosemide, which may be prepared as disclosed in U.S. Patent No.
3,665,002; bumetanide, Hfiicl~ may be prepared as disclosed in U.S. Patent No.
3,634,583; butazoiamide, ma be Y I~par~ed as disclosed in British Patent No.
769,757; chloraminopt>erramide, which may be prepared as disclosed in U.S.
Patent Nos. 2,809,194, 2,965,655 and 2,965,656; dofenamide, which may be prepared as ~'a.99/11260 PCT/IB98/01230 ..
disclosed in Oiivier, Rec. Trav. Chim., 1918, ~, 307; dopamide, which may be prepared as disclosed in U.S. Patent No. 3,459,756; dorexolone, which may be prepared as disclosed in U.S. Patent No. 3,183,243; disulfamide, which may be prepared as disclosed in British Patent No. 851,287; ethoxotamide, which may be prepared as disclosed in British Patent No. 795,174; furosemide, which may be prepared as disclosed in U.S. Patent No. 3,058,882; mefivside, which may be prepanrd as disclosed in U.S. Patent No. 3,356,692; methazolamide, which may be prepared as disclosed in U.S. Patent No. 2,783,241; piretanide, which may be prepared as disclosed in U.S. Patent No. 4,010,273; torasemide, which may be prepared as disclosed in U.S. Patent No. 4,018,929; tripamide, which may be prepared as disclosed in Japanese Patent No. 73 05,585; and xipamide, which may be prepared' as disclosed in U.S. Patent No. 3,567,777. The disclosures of all such U.S. patents are incorporated herein by reference.
In add'~ion, atorvastatin and pharmaceutically acceptable salts thereof may oxur as hydrates or sohrates. Further, the antihypertensive agents which may be used in accordance with this invention and the pharmaceutically acceptable salts thereof may occur as hydrates or solvates. Said hydrates and solvates are also within the scope of the invention.
the pharmaceutical combinations and methods of this invention are all adapted to therapeutic use as agents in the treatment of atherosderosis, angina pectoris, and a condition characterized by the presence of both hypertens'ron and hyperiipidemia in mammals, particularly humans. Further, since these diseases and conditions are closely related to the development of cardiac disease and adverse cardiac conditions, these combinations and methods, by virtue of their action as antiatherosderotics, antianginals, antihypertensives and antihyperlipidemics, are useful in the management of cardiac risk The utility of the compounds of the present invention as medical agents in the treatment of atherosderosis in mammals (e.g. humans) is demonstrated by the activity of the compounds of this invention in conventional assays and the clinical protocol described below:
'~LQp. on the Treatment Vt~O, 99/11260 PCT/IB98/01230 This study is a prospective randomized evaluation of the effect of a combination of atorvastatin or a pharmaceutically acceptable salt thereof and an antihypertens'rve agent on the progressioNn~ression of coronary and carotid artery disease. The shrdy is used to show that a combination of atorvastatin or a pharmaceutically acceptable salt thereof and an antihypertensive agent is effective in slowing or arresting the progress'ron or causing regression of existing coronary artery disease (CAD) as evidenced by changes in coronary angiography or carotid ultrasound, in subjects with established disease.
This study is an angiographic documentation of coronary artery disease carried out as a double-blind, placebo-controlled trial of a minimum of about subjects and preferably of about 780 to about 1200 subjects. It is especially preferred to study about 1200 subjects in this study. Subjects are admitted into the study after satisfying certain entry criteria set forth below.
~r criteria: Subjects accepted for entry into this trial must satisfy certain criteria. Thus the subject must be an adult, either male or female, aged 18-80 years of age in whom coronary angiography is clinically indicated. Subjects will have angiographic presence of a significant focal lesion such as 30% to 50% on subsequent evaluation by quantitative coronary angiography (QCA) in a minimum of LO one segment (non-PTCA, non-bypassed or non-MI vessel) that is judged not likely to require intervention over the next 3 years. It is required that the segmer>ts undergoing analysis have not been interfered with. Since percutaneous transluminal cardiac angioplasty (PTCA) interteres with segments by the insertion of a balloon catheter, non-PTCA segments are nrquired for analysis. It is also required that the segments to be analyzed have not suffered a thrombotic event, such as a myocardial infarct (MI). Thus the requirement for non-MI vessels. Segments that will be analyzed inducts: left main, proximal, mid and distal left anterior descending, first and second diagonal branch, proximal and distal left arcumflex, first or largest space obtuse marg'mal, proximal, mid and distal right coronary artery. Subjects will have an ejection fraction of greater than 40% determined by catheterization or radionudide ventria~lography or ECHO cardiogram at the time of the qualifying angiogram or within the previous three months of the acceptance of the qualifying angiogram V1r0,99/11260 PCT/IB98/01230 -2&
provided no intervening event such as a thrombotic event or procedure such as PTCA has occurred.
Generally, due to the number of patients and the physical limitations of any one facility, the study is cartied out at mul~ple sites. At entry into the study, subjects undergo quantitative coronary angiography as well as B-mode carotid artery uttrasonography and assessment of carotid arterial compliance at designated testing centers. This establishes baselines for each subject. Once admitted into the test, subjects are randomized to receive an antihypertensive agent or a pharmaoeubcally acceptable salt ther~wf ( the dose is dependent upon the partiarlar antihypertensive agent or salt thereof chosen) and placebo or atorvastatin calaum (80 mss) and placebo or an antihypertens'rve agent or a pharmaceutically acceptable salt then:of (the dose is dependent upon the particular antihypertensive agent or salt thereof chosen) and atorvastatin calcium (80 mss). It will be recognized by a skilled person that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of the statin may be used in this invention.
Calculation of the dosage amount for these other forms of the statinand amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved. The amount of the antihypertensive agent may be varied as required. The amount of the statin will be titrated down from 80 mg if it is determined by the ptlysiaan to be in the best interests of the subject. The subjects are monitored for a one to three year period, generally three years being prefen~ed. B-mode carotid ultrasound assessment of carotid artery atherosclerosis and compliance are performed at regular intervals throughout the study.
Generally, soc month intervals an: suitable. Typically this assessment is performed using B-mode ultrasound equipment. However, a person skilled in the art may use other methods of performing this assessment. Coronary angiography is performed at the conclusion of the one to three year treatment period. The baseline and post-treatrnent angiograms and the intervening ~d artery B-mode uttrasonograms are evaluated for new lesions or progression of e~asting atherosderotic lesions. Arterial compliance measurements are assessed for changes from baseline and over the 6-month ewafuation periods.
The primary objective of this study is to show that the combination of an antihypertensive agent and atorvastatin n:duces the progression of atherosderotic w0,99/11260 PCT/IB98/01230 lesions as measured by quantitative coronary angiography (QCA) in subjects with dinical coronary artery disease. QCA measures the opening in the lumen of the arteries measured.
The primary endpoint of the study is the change in the average mean segment diameter of the coronary artery tree. Thus, the diameter of an arterial segment is measured at various portions along the length of that segment. The average diameter of that segment is then detemnined. After the average segment diameter of many segments has been determined, the average of all segment averages is determined to ar 'rne at the average mean segment diameter. The mean segment diameter of subjects taking atorvastatin or a pharmaceutically acceptable satt thereof and amlodipine or a pharmaceutically acceptable acid addition salt thereof will decline more slowly, will be halted completely, or there will be an increase in the mean segment diameter. These results represent slowed progression of atherosderosis, hatted progression of atherosderosis and regression of atherosderosis, repsectively.
The secondary objective of this study is that the combination of an antihypertensive agent and atorvastatin or a pharmaceutically acceptable salt thereof reduces the rate of progression of atherosderosis in the carotid arteries as measured by the slope of the maximum intimal-medial thickness measurements averaged over 12 separate wall segments (Mean Max) as a function of time, more than does amlodipine or a pharmaceutically acceptable add addition salt thereof or atorvastatin or a pharmaceutically acceptable salt thereof alone. The intimal-medial thickness of subjects taking atorvastatin or a pham>aoeuticalfy acceptable salt thereof and amk~dipine or a pharmaceutically acceptable acid addition salt thereof will increase more slowly, will cease to increase or will decxease. These results represent slowed prorgression of atherosderosis, halted progression of atherosderosis and regression of atherosderosis, resped3vely. Further, these results may be used to fadlitate dosage determinations.
The utility of the compounds of the pn~ent invention as medical agents in the treatment of angina pectoris in mammals (e.g., humans) is demonstrated by the ad;ivity of the compounds of this invention in conventional assays and the dinical protocol described bek~nr:

WO, 99/11260 PCT/IB98/01230 This study is a double blind, parallel arm, randomized study to show the effectiveness of atorvastatin or a pharmaceutically acceptable salt thereof and an antihypertensive agent given in combination in the treatment of symptomatic angina.
Entrv c 'teria: Subjects are males or females between 18 and 80 years of age with a history of typical chest pain assoaated with one of the following objective evidences of carcliac ischemia: (1) stress test segment elevation of about one millimeter or more from the ECG; (2) positive treadmill stress test; (3) new wall motion abnomlality on ultrasound; or (4) coronary angiogram with a significant qualifying stenosis. Generally a stenosis of about 30-50°~ is considered to be signficant.
Each subject is evaluated for about ten to thirty two weeks. At least ten weeks are generally required to complete the study. Sufficient subjects are used in this screen to ensure that about 200 to 800 subjects and preferably about 400 subject are evaluated to complete the study. Subjects are scxeened for compliance with the entry criteria, set forth below, during a four week run in phase. After the screening aiteria are met, subjects are washed out from their current anti-angina) medication and stabilized on a long adi:~g nitrate such as nitroglycerine, isosorbide-5-mononitrate or isosorbide dinitrate. The term "washed out', when used in connection with this screen, means the withdrawal of cun-ent anti-angina) medication so that substantially all of said medication is eliminated from the body of the subject. A
period of eight weeks is preferably allowed for both the wash out period and for the establishment of the subject on stable doses of said nitrate. Subjects having one or two attacks of angina per week while on stable doses of long ailing nitrate are generally permitted to skip the wash out phase. After subjects are stabilized on nitrates, the subjects enter the randomization phase provided the subjects continue to have either one or two angina attacks per week. In the randomization phase, the subjects are,randomly placed into one of the four arms of the study set forth below.
After completing the wash out phase, subjects in compliance with the entry criteria undergo twenty four hour ambulatory etectrocardigram (ECG) such as Hotter monitoring, exercise stress testing such as a treadmill and evaluation of myocardial perfusion using PET (photon emission tomography) scanning to establish a baseline for each subject. When conducting a stress test, the speed of the treadmill and the gradient of the treadmill can be controlled by a techniaan. The speed of the treadmill and the angle of the gradient are generally increased during the test. The time intervals between each speed and gradient increase is generally determined using a modified Bruce Protocol.
After the baseline investigations have been completed, subjects are ini5ated on one of the following four arms of the study: (1 ) placebo; (2) atorvastatin (about 10 mg to about 80 mg); (3) an antihypertensive agent (dose is dependent upon the particular antihypertensive agent chosen); or (4) a combination of the above doses of atorvastatsn and antihypertensive agent together. tt will be recognized by a skiNed person that the free base form or other salt forms of amlodipine besylate or the free base forth or other salt forms of the statin may be used in this invention.
Calculation of the dosage amount for these other forms of the statinand amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the species involved. The subjects are then monitored for two to twenty four weeks.
After the monitoring period has ended, subjects will undergo the following investigations: (1 ) twenty four hour ambulatory ECG, such as Hotter monitoring; (2) exerase stress testing (e.g. treadmill using said modfied Bruce Protocol); and (3) evaiuation~ of myocardial perfusion using PET scanning. Patients keep a diary of painful ischemic events and nitroglycerine consumption. It is generally desirable to have an aerate n3cord of the number of anginal attacks suffered by the patient during the duration of the test. Since a patient generally takes nitroglycerin to ease the pain of an anginal attack, the number of times that the patient administers nitroglycerine provides a reasonably acarraite record of the number of anginal attacks.
To demonstrate the effectiveness and dosage of the drug combination of this invention, the person conducting the test will evaluate the subject using the tests described. Suc~sful treatrnent will yield fewer instances of ischemic events as detected by ECG, will allow the subject to exercise longer or at a higher intensity level on the tnradmill, or to exercise pain on the treadmill, or will yield better perfusion or fewer perfusion defects on ultrasotu~d.

VN0.99/11260 PCT/IB98/01230 The utility of the compounds of the present invention as medical agents in the treatment of hypertension and hyperlipidemia in mammals (e.g., humans) suffering from a combination of hypertension and hyper(ipidemia is demonstrated by the activity of the compounds of this invention in conventional assays and the dinical protocol described below:
L3oth ~,r~rtension and Hyrc~erlioidemia This study is a double blind, parallel arm, randomized study to show the effectiveness of atorvastatin or a pharmaceutically acxeptable salt thereof and an antihypertensive agent given in combination in controlling both hypertension and hyperlipidemia in subjed~s who have mild, moderate, or severe hypertension and hyperlipidemia.
Each subject is evaluated for 10 to 20 weeks and preferably for 14 weeks.
Sufficient subjects are used in this saeen to ensure that about 400 to 800 subjects are evaluated to complete the study.
F;~pr ~t~ert~: Subjects are male or female adults between 18 and 80 years of age having both hyperiipidemia and hypertension. The presence of hyperlipidemia is evidenced by evaluation of the low density lipoprotein (LDL) level of the subject relative to :certain positive risk factors. If the subject has no coronary heart disease (CHD) and has less than two positive risk factors, then the subject is considered to have hyperiipidemia which requires drug therapy if the LDL of the subject is greater than or equal to 190. If the subject has no CHD and has two or more positive risk factors, then the subject is considered to have hyperiipidemia which nrquires dnrg therapy 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 hyperiipidemia if the LDL of the subject is greater than or equal to 130.
Positive risk factors inducts (1 ) male over 45, (2) female over 55 wherein said female is not undergoing hormone replacement therapy (HRT), (3) family history of premature cardiovascular disease, (4) the subject is a current smoker, (5) the subject has diabetes, (6) an HDL of less than 45, and (7~ the subject has hypertension. An HDL of greater than 60 is considered a negative risk factor and will offset one of the above mentioned positive risk factors.

WO. 99/11260 PCT/IB98/01230 The presence of hypertension is evidenced by a sitting diastolic blood pressure (BP) of greater than 90 or s'~ting systolic BP of greater than 140.
All blood pressures are generally determined as the average of three measurements taken five minutes apart.
Subjects are screened for compliance with the entry criteria set forth above.
After all screening criteria are met, subjects are washed out from their current antihypertenslve and lipid lowering medication and are placed on the NCEP ATP
II
Step 1 diet. The NCEP ATP II (adult treatment panel, 2nd revision) Step 1 diet sets forth the amount of saturated and unsaturated fat which can be consumed as a proportion of the total caloric intake. The term 'wvashed out' where used in connection with this screen, means the withdrawal of current an~hypertensive and lipid lowering medication so that substantially all of said medication is eliminated from the body of the subject. Newly diagnosed subjects generally remain untreated until the test begins. These subjects are also placed on the NCEP Step 1 diet. After the four i 5 week wash out and diet stabiiQation period, subjects undergo the following baseline investigations: (1 ) blood pressure and (2) fasting lipid screen. The fas~ng lipid screen determines baseline lipid levels in the fasting state of a subject.
Generally, the subject abstains from food for twelve hours, at which time lipid levels are measun:~d.
After the baseline investigations are performed subjects are started on one of the following: (1 ) a faced dose of an antihypertensive agent, dose dependent upon the particular antihypertenslve agent chosen; (2) a fried dose of atorvastatin, generally about 10 to 84mg; or (3) a combination of the above doses of atorvastatin and an antihypertenslve agent together. It will be recognized by a skilled person that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of the statin may be used it this invention. Calculation of the dosage amount for these other forms of the statinand amlodipine besylate is easily acoomptished by performing a simple ratio relative to the molecx~lar weights of the species involved. Subjects remain on these doses for a minimum of six weeks, and generally for no more than eight weeks. The subjects return to the testing center at the conclusion of the six to eight weeks so that the baseline evaluations can be repeated. The blood pn~sure of the subject at the contusion of the study is compared with the blood pressure of the subject upon entry. The lipid screen VG0.99/11260 PCT/IB98/01230 measures the total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apoB, VLDL (very low density lipoprotein) and other components of the lipid profile of the subject. Improvements in the values obtained after treatment relative to pretreatment values indicate the utif~ty of the drug comf~ination.
The utility of the compounds of the present invention as medical agents in the management of cardiac risk in mammals (e.g., humans) at risk for an adverse cardiac event is demonstrated by the activity of the compounds of this invention in conventional assays and the dinical protocol described bek~ir:
Effects of Atorvastatin and an Antihy~rtensive Aaent. Aloe and in Co!~nbina6on. on Sut?jects at Risk of Future Cardiovascular Events This study is a double blind, parallel arm, randomized study to show the effectiveness of atorvastatin or a pharmaceutically acceptable salt thereof and an antihypertensive agent given in combination in reducing the overall calculated risk of future events in subjects who are at risk for having future cardiovascular events. This risk is calculated by using the Framingham Risk Equation. A subject is considered to be at risk of having a future cardiovascular event if that subject is more than one standard deviation above the mean as calculated by the Framingham Risk Equation.
The study is used to evaluate the efficacy of a fixed combination of atorvastatin or a pharmaceutically acceptable salt thereof and an antihypertensive agent in controlling cardiovascular risk by controlling both hypertension and hyperlipidemia in patients who have both mild to moderate hypertension and hyperlipidemia.
Each subjedas evaluated for 10 to 20 weeks and preferably for 14 weeks.
Suffident subjects are recruited to ensure that about 400 to 800 subjects are evaluated to complete the study.
)iply criteria: Subjects inducted in the study are male or female adult subjects between 18 and 80 years of age with a baseline five year risk which risk is above the median for said subject's age and sex, as defined by the Framingham Heart Study, which is an ongoing prospective study of adult men and women showing that certain risk factors can be used to predict the development of coronary heart disease.
The age, sex, systolic and diastolic blood pressure, smoking habit, presence or absence of carbohydrate a~toleranee, presence or absence of left ventriarlar hypertrophy, senrm cholesterol and high density lipoprotein (HDL) of more than one standard deviation above the none for the Framingham Population are ail evaluated in determining whether a patient is at risk for adverse cardiac event. The values for the risk factors are inserted into the Framingham Risk equation and calculated to determine whether a subject is at risk for a future cardiovascular event.
Subjects are scxeened for compliance with the entry criteria set forth above.
After all screening criteria are met, patients are washed out from their current antihypertensive and lipid lowering medication and any other medication which will impact the results of the screen. The patients are then placed on the NCEP ATP
II
Step 1 diet, as described above. Newly diagnosed subjects generally remain untreated until the test begins. These subjects are also placed on the NCEP
ATP II
Step 1 diet. After the four week wash out and diet stabilization period, subjects undergo the following baseline investigations: (1 ) blood pressun:; (2) fasting; (3) lipid saeen; (4) glucose tolerance test; (5) ECG; and (6) cardiac ultrasound. These tests are carried out using standard procedures well known to persons skilled in the art.
The ECG and the cardiac ultrasound are generally used to measure the presence or absence of left ventricular hypertrophy.
After the baseline investigations are performed patients will be started on one of the following: (1 ) a fixed dose of an antihypertensive agent, dose dependent upon the particular antihypertensive agent chosen; (2) a fixed dose of atorvastatin (about 10 to 80mg); or (3) the combination of the above doses of atorvastatin and an antihypertensive agent. It will be recognized by a skilled person that the free base form or other salt forms of amlodipine besylate or the free base form or other salt forms of the statin may be used in this invention. Calculation of the dosage amount for these other forms of the statinand amlodipine besylate is easily accomplished by performing a simple ratio relative to the molecular weights of the speaes involved.
Patients are kept on these doses and are asked to return in six to eight weeks so that the baseline evaluations can be repeated. At this time the new values are entered into the Framingham Risk equation to determine whether the subject has a lower, greater or no change in the risk of future cardiovascular event.
The above assays demonstrating the effectiveness of amodipine or phartnaceut~cally acceptable acid addition salts thereof and atorvastatin or pharmaceutically acceptable salts thereof in the treatment of angina pectoris, atherosderosis, hypertension and hyperlipidemia together, and the management of cardiac risk, also provide a means whereby the activities of the compounds of this invention can be compared between themselves and with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, inducting humans, for the treatment of such diseases.
The following dosage amounts and other dosage amounts set forth elsewhere in this spedfication and in the appendant daims arse for an average human subject having a weight of about 65 kg to about 70 kg. The skilled practitioner will readily be able to detemnine the dosage amount required for a subject whose weight falls outside the 65 kg to 70 kg range, based upon the medical history of the subject and the presence of diseases, e.g., diabetes, in the subject. All doses set forth herein, and in the appendant daims, are daily doses.
In general, in accordance with this invention, the below-listed antihypertensive agent is administered in the following dosage amounts:
di~iazem, generally about 120 mg to about 480 mg;
verapamil, generally about 20 mg to about 48 mg;
felodipine, generally about 2.5 mg to about 40 mg;
isradipine, generally about 2.5 mg to about 40 mg;
laadipine, generally about 1 mg to about 6 mg;
nicardipine, generally about 32 mg to about 120 mg;
nifedipine, generally about 10 mg to about 120 mg;
nimodipine, generally about 120 mg to about 480 mg;
nisoldipine, generally about 5 mg to about 80 mg;
nitrendipine, generally about 5 mg to about 20 mg;
benazepril, generally about 10 mg to about 80 mg;
captopril, generally about 50 mg to about 150 mg;
enalapril, generally about 5 mg to about 40 mg;
fosinopril, generally about 10 mg to about 80 mg;
lisinopril, generally about 10 mg to about 80 mg;

quinapril, generally about 10 mg to about 80 mg;
losartan, generally about 25 mg to about 100 mg;
valsartan, generally about 40 mg to about 640 mg;
doxazosin, generally about 0.5 mg to about 16 mg;
prazosin, generally about 1 mg to about 40 mg;
trimazosin, generally about 1 mg to about 20 mg; and amiloride, generally about 5 mg to about 20 mg.
It will be recognized by those skilled in the art that dosages for the above antihypertensive compounds must be individualized to each specific subject.
This iindividuafization will depend upon the medical history of the subject and whether the subject is concurrently taking other medications which may or may not intertere or have an adverse effect in combination with the above antihypertensives.
lndividualeation is then achieved by beginning with a low dose of the compound and titrating the amount up until the desired therapeutic effect is achieved.
In general, in accordance with this invention, atorvastatin calcium is generally administered in a dosage of about 2.5 mg to about 160 mg. Preferably, atorvastatin calaum is administered in a dosage of about 10 mg to about 80 mg.
The compounds of the present invention are generally administered in the form of a pharmaceutical composition comprising at least one of the compounds of this invention together with a pharmaceutically acceptable carrier or diluent.
Thus, the compounds of this invention can be administered either individually or together in any conventional oral, parenteral or transdermal dosage form.
For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
Tablets containing various exdpients such as sodium citrate, calaum carbonate and calaum phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acada.
Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Sotid compositions of a similar type are also employed as fillers in soft and hardfilled gelatin capsules;
preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions andlor ef~cirs are rB

desired for oral administration, the compounds of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents andlor suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
The combination of this invention may also be adminstered in a controlled-release dosage formulation such as a slow release or a fast release formulation.
Such controlled release dosage formulations of the combination of this invention may be prepared according to methods well known to those skilled in the art. The method of administration will be determined by the attendant physician after an evaluation of the subject's condition and requirements.
For purposes of parenteral administration, solutions in sesame or peanut oil or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions of the con-esponding water soluble salts. Such aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with suffiaent saline or glucose. These aqueous solutions are espeaally suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art.
Methods of preparing various pharmaceutical compositions with a certain amount of~active ingredient are known, or will be apparent in light of this disdosure, to those skilled in this art. For examples, see Remington's Pharmace~~cal Sue~~o~
Madc Publishing Company, Easter, Pa., 15th Edition (1975).
Pharmaceutical compositions according to the invention may contain 0.1 %
95% of the compounds) of this invention, preferably 1 %-70%. In any event, the composition or formulation to be administered will contain a quantity of a compounds) acxording to the invention in an amount effective to treat the condition or disease of the subject being treated.
Since the present invention relates to the treatment of diseases and condiflons with a combination of active ingredients which may be administered separately,. the invention also relates to combining separate pharmaceutical compositions in kit form. The kit indudes two separate pharmaceutical compositions:
an antihypertensive agent or a pharmaceutically acceptable salt thereof, wherein said antihypertensive agent is not amlodipine or a pharmaceutically acceptable add _3g.

addition salt thereof and atorvastatin or a pharmaceutically acceptable salt thereof.
The kit includes container means for containing the separate composi~ons such as a divided bottle or a divided foil packet. however, the separate compositions may also be contained within a single, undivided container. Typically the kit includes diredtons for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parentera!), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physidan.
It should be understood that the invention is not limited to the particular embodiments described herein, but that various d~anges and modfications may be made without departing from the spirit and scope of this novel concept as defined by the following claims.

Claims

1. A pharmaceutical composition comprising:
a. an amount of atorvastatin or a pharmaceutically acceptable salt thereof;
b. an amount of an antihypertensive agent or a pharmaceutically acceptable salt thereof; and c. a pharmaceutically acceptable carrier or diluent;
provided that said antihypertensive agent is not amiodipine or a pharmaceutically acceptable add addition salt thereof.

2. A pharmaceutical composition of claim 1 wherein said antihypertensive agent is a calcium channel blocker, an ACE inhibitor, an A-ti antagonist, a diuretic, a beta-adrenergic receptor blocker or an alpha-adrenergic receptor blocker.

3. A pharmaceutical composition of claim 2 comprising the hemicalcium salt of atorvastatin.

4. A pharmaceutical composition of claim 3 wherein said antihypertensive agent is a calcium channel blocker, said calcium channel blocker being verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine or felodipine or a pharmaceutically acceptable salt of said calcium channel blocker.

5. A pharmaceutical composition of claim 4 wherein said calcium channel blocker is felodipine, nifedipine or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition of claim 3 wherein said antihypertensive agent is an A-II antagonist, said A-II antagonist being losartan, irbesartan or valsartan or a pharmaceutically acceptable salt of said A-II
antagonist.

7. A pharmaceutical composition of claim 3 wherein said antihypertensive agent is a diuretic, said diuretic being amiloride, bendroflumethiazide or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition of claim 3 wherein said antihypertensive agent is a beta-adrenergic receptor blocker, said beta-adrenergic receptor blocker being carvedilol or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition of claim 3 wherein said antihypertensive agent is an ACE inhibitor, said ACE inhibitor being benazepril, capopril, enalapril, fosinopril, lisinopril, perindopril, quinapril, trandolapril or a pharmaceutically acceptalbe salt thereof.

10. A pharmaceutical composition of claim 3 wherein said antihypertensive agent is an alpha-adrenergic receptor blocker, said alpha-adrenergic receptor blocker being doxazosin, prazosin, trimazosin or a pharmaceutically acceptable salt thereof.

11. A first pharmaceutical composition for use with a second pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof, which effect is greater than the sum of the therapeutic effect achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of an antiphypertensive agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable acid addition salt thereof.

12. A pharmaceutical composition of claim 11 wherein said antihypertensive agent is a calcium channel blocker, an ACE inhibitor, an A-II
antagonist, a diuretic, a beta-adrenergic receptor blocker or an alpha-adrenergic receptor blocker.

13. A pharmaceutical composition of claim 12 wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.

14. A pharmaceutical composition of claim 13 wherein said antihypertensive agent is a calcium channel blocker, said calcium channel blocker being verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine, nifedipine, nimoldipine, nisoldipine, nitrendipine or felodipine.

15. A pharmaceutical composition of claim 14 wherein said calcium channel blocker is felodipine or nifedipine.

16. A pharmaceutical composition of claim 13 wherein said antihypertensive agent is an A-II antagonist, said A-II antagonist being losartan, irbesartan or valsartan.

17. A pharmaceutical composition of claim 13 wherein said antihypertensive agent is a diuretic, said diuretic being amiloride or bendroflumethiazide.

18. A pharmaceutical composition of claim 13 wherein said antihypertensive agent is a beta-adrenergic receptor blocker, said beta-adrenergic receptor blocker being carvedilol.

19. A pharmaceutical composition of claim 13 wherein said antihypertensive agent is an ACE inhibitor, said ACE inhibitor being benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril or trandolapril.

20. A pharmaceutical composition of claim 13 wherein said antihypertensive agent is an alpha-adrenergic receptor blocker, said alpha blocker being doxazosin, prazosin or trimazosin.

21. A first pharmaceutical composition for use with a second pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof, which effect is greater than the sum of the therapeutic effect achieved by administering said first and second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of an antihypertensive agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent; provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable add addition salt thereof.

22. A pharmaceutical composition of claim 21 wherein said antihypertensive agent is a calcium channel blocker, an ACE inhibitor, an A-II
antagonist, a diuretic, a beta-adrenergic receptor blocker or an alpha-adrenergic receptor blocker.

23. A pharmaceutical composition of claim 22 comprising the hemicalcium salt of atorvastatin.

24. A pharmaceutical composition of claim 23 wherein said antihypertensive agent is a calcium channel blocker, said calcium channel blocker being verapamil, diltiazem, mibefradil, isradipine, lacidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine or felodipine.

25. A pharmaceutical composition of claim 24 wherein said calcium channel blocker is felodipine or nifedipine.

26. A pharmaceutical composition of claim 23 wherein said antihypertensive agent is an A II antagonist, said A-II antagonist being losartan irbesartan or valsartan.

27. A pharmaceutical composition of claim 23 wherein said antihypertensive agent is a diuretic, said diuretic being amiloride or bendroflumethiazide.

28. A pharmaceutical composition of claim 23 wherein said antihypertensive agent is a beta-adrenergic receptor blocker, said beta-adrenergic receptor blocker being carvedilol.

29. A pharmaceutical composition of claim 23 wherein said antihypertensive agent is an ACE inhibitor, said ACE inhibitor being benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril, quinapril or trandolapril.

30. A pharmaceutical composition of claim 23 wherein said antihypertensive agent is an alpha-adrenergic receptor blocker, said alpha blocker being doxazosin, prazosin or trimazosin.

31. A pharmaceutical composition of claim 11 wherein said therapeutic effect is antianginal; antiatherosclerotic; antihypertensive and hypolipidemic; or is effective for cardiac risk management.

32. A pharmaceutical composition of claim 13 wherein said therapeutic effect is antianginal; antiatherosclerotic; antihypertensive and hypolipidemic; or is effective for cardiac risk management.

33. A pharmaceutical composition of claim 21 wherein said therapeutic effect is antianginal; antiatherosclerotic; antihypertensive and hypolipidemic; or is effective for cardiac risk management.

34. A pharmaceutical composition of claim 23 wherein said therapeutic effect is antianginal; antiatherosclerotic; antihypertensive and hypolipidemic; or is effective for cardiac risk management.

35. A first pharmaceutical composition for use with a second pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof, which effect is greater than the therapeutic effect achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of an antihypertensive agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable acid addition salt thereof.

36. A pharmaceutical composition of claim 35 wherein said antihypertensive agent is a calcium channel blocker, an ACE inhibitor, an A-II
antagonist, a diuretic, a beta-adrenergic receptor blocker or an alpha-adrenergic receptor blocker.

37. A pharmaceutical composition of claim 36 wherein said second pharmaceutical composition comprises the hemicalcium salt of atorvastatin.

38. A pharmaceutical composition of claim 35 wherein said therapeutic effect is antianginal; antiatherosclerotic; antihypertensive and hypolipidemic; or is effective for cardiac risk management.

39. A pharmaceutical composition of claim 37 wherein said therapeutic effect is antianginal; antiatherosclerotic; antihypertensive and hypolipidemic; or is effective for cardiac risk management.

40. A first pharmaceutical composition for use with a second pharmaceutical composition for achieving a therapeutic effect in a mammal in need thereof, which effect is greater than the therapeutic effect achieved by administering said first or second pharmaceutical compositions separately and which second pharmaceutical composition comprises an amount of an antihypertensive agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, said first pharmaceutical composition comprising an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent, provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable add addition salt thereof.

41. A pharmaceutical composition of claim 40 wherein said antihypertensive agent is a calcium channel blocker, an ACE inhibitor, an A-II
antagonist, a diuretic, a beta-adrenergic receptor blocker or an alpha-adrenergic receptor blocker.

42. A pharmaceutical composition of claim 41 comprising the hemicalcium salt of atorvastatin.

43. A pharmaceutical composition of claim 40 wherein said therapeutic effect is antianginal; antiatherosclerotic; antihypertensive and hypolipidemic; or is effective for cardiac risk management.

44. A pharmaceutical composition of claim 42 wherein said therapeutic effect is antianginal; antiatherosclerotic; antihypertensive and hypolipidemic; or is effective for cardiac risk management.

45. A kit for achieving a therapeutic effect in a mammal comprising:
a. an amount of atorvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a first unit dosage form;
b. an amount of an antihypertensive agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and c. container means for containing said first and second dosage fortes, provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable acid addition salt thereof.

46. A kit of claim 45 comprising the hemicalcium salt of atorvastatin.

47. A method for treating a mammal in need of therapeutic treatment comprising administering to said mammal (a) an amount of a first compound, said first compound being atorvastatin or a pharmaceutically acceptable salt thereof; and (b) an amount of a second compound, said second compound being an antihypertensive agent or a pharmaceutically acceptable salt thereof;

wherein said first compound and said second compound are each optionally and independently administered together with a pharmaceutically acceptable carrier or diluent, provided that said antihypertensive agent is not amlodipine or a pharmaceutically acceptable add addition salt thereof.

48. A method of claim 47 comprising the hemicalcium salt of atorvastatin.

49. A method of claim 47 wherein said therapeutic treatment comprises antihypertensive and antihyperlipidemic treatment.

50. A method of claim 47 wherein said therapeutic treatment comprises antianginal treatment.

51. A method of claim 47 wherein said therapeutic treatment comprises cardiac risk management.

52. A method of claim 47 wherein said therapeutic treatment comprises the treatment of atherosclerosis.