SA98190566B1 - Combinations include amlodipine and atorvastatin - Google Patents

Abstract

Abstract: This invention relates to pharmaceutical combinations of amlodipine, atorvastatin and pharmacologically acceptable salts thereof, and methods of using these combinations for the treatment of patients suffering from angina pectoris, atherosclerosis, high blood pressure and hyperlipidemia, and for the treatment of patients with severe symptoms. On the heart, including the human.

Description

Y atorvastatin and atorvastatin amlodipine Therapeutic combinations including amlodipine Full description Background of the invention Amlodipine from pharmaceutical combinations This invention relates to drug combinations and pharmaceutically acceptable salts thereof; and ways of using these atorvastatin and its salts and conjugates to treat those suffering from angina pectoris; atherosclerosis; And high blood pressure and high levels of fat in the blood united and for the treatment of those who suffer from symptoms dangerous to the heart, including amlodipine 0, including humans. This invention also relates to additional and synergistic combinations of atorvastatin such that these additional and synergistic combinations are useful in the treatment of subjects suffering from angina pectoris; atherosclerosis; united hypertension and hyperlipidemia, and for the treatment of those suffering from serious heart conditions; including human. GENERAL DESCRIPTION OF THE INVENTION TO (HMG-CoA) 3-hydroxy-3-methylglutaryl The conversion of coenzyme A is an early, rate-limited step in the field of cholesterol biosynthesis. This is mevalonate, an enzyme mentioned in 5H117106-00. Statins inhibit reductase, a step catalyzed by an effective fat-reducing enzyme reductase. Jal ge, statins reductase are able to catalyze this conversion. so; The HMG-CoA

Alea vo discovered in US Patent No. 07774495 (Atorvastatin calcium of the formula Lipitor® is incorporated herein by reference; presently sold as 0 9_7 > oH C F 2 so; the HMG-CoA A selective and competitive inhibitor of free carboxylic acid atorvastatin calcium is a potent lipid-lowering compound.Atorvastatin calcium +0 of the formula: lactone is found predominantly in atorvastatin

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. Dihydropyridine and amlodipine compounds were discovered in US Patent No. 452481847 and anti-ischemic agents (US No. 5077964) as effective local anti-anemic agents, effective anti-hypertensive agents. US Patent No. 879,707 reveals; Amlodipine 0 amlodipine besylate (also called amlodipine benzenesulfonate salt) is effective and long-acting. Calcium channel blockers are amlodipine besylate 5 channel blockers and other pharmacologically acceptable acid additive salts. Amlodipine besylate «amlodipine | Thus, the anti-anemic agents pall have use as anti-hypertensive agents amlodipine and its pharmacologically acceptable acid additive salts are in the patent of topical amlodipine. It also reveals 0 that it has a use in the treatment of heart failure. Sold by US Patent No. 055171 Formulation: amlodipine Norvasc® is now known as amlodipine

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CHO | CO,CH,CH, 0 0 Atherosclerosis is a condition characterized by irregularly distributed fatty deposits in the walls of the arteries, including the coronary; Carotid and peripheral arteries. Coronary heart disease (hereinafter denoted yo) accounts for 757 of all deaths due to a cardiovascular event (CHD here in $1 billion) Total care expenditure Te to 50 represents Approximately half (about half) of the blood CHD of cardiovascular health in the United States and about 77 of the total national medical bill each year. Despite attempts to adjust for secondary risk factors such as; consanguineous marriage; smoking; obesity and lack of exercise Treating blood lipid disorders with dietary modifications is the most common cause of death in the United States. © AST CHD Treatment with drugs, however, remains

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¢: High levels of cholesterol and fats in the blood are conditions implicated in the onset of atherosclerosis. Coenzyme inhibitors are known to lower | 3-hydroxy-3-methylglutaryl (HMG-CoA) lowering) is effective in reducing the percentage or level of cholesterol in the blood plasma; especially low-density lipoprotein cholesterol; (LDL.C) in humans (Brown and Goldstein, New England Journal of Medicine, 1981, 305, No. 515-517) ° It is now well established that reducing LDL-C levels offers protection against disease. Coronary artery in the heart. See, for example: The Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet, 1994, 344, 1383-89; and Shepherd. , J.et 1 al., Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia, New England Journal of Medicine, 1995, 333, 1301-07). From the membrane surrounding the heart to the left shoulder and down the left arm. Angina pectoris is often the result of anemia in the heart 1 and the cause is usually coronary artery disease. Treatment for symptomatic angina (Ulla) varies greatly from country to country. in the United States; Patients with symptomatic and stable angina frequently treated with surgical modalities or PTCA Patients treated with PTCA or other surgical modalities designed to treat angina frequently report complications such as restlessness. This yo restenosis may be diagnosed or present as a symptom of either a short-term progressive jab response to the trauma experienced when the vessel graft was performed or the long-term development and progression of sclerosis in both the grafted vessels and the parts to be grafted. Symptomatic treatment of angina involves the use of several medications. Frequently as combinations of two or more of the following categories: beta-nitrate blockers and calcium channel blockers too much” unless ve (JS) These patients require treatment with lipid-lowering agents as well. The National Cholesterol Education Program (NCEP) recognizes All artery disease patients as a special class who need severe and severe treatment for elevated LDL-C AVY

Amlodipine helps prevent localized anemia of the heart muscles (preventing myocardial ischemia) in patients with exertional angina by decreasing total peripheral resistance; or after pregnancy; Which reduces the output pressure ratio and thus the oxygen requirements of the heart muscle at any given limit of exercise. in patients with angina pectoris due to constriction and narrowing of blood vessels; 8001000106 has been shown to block and prevent stenosis and thus restore oxygen supply to the myocardium. Furthermore, amlodipine has been shown to increase the supply of oxygen to the heart muscle by dilating the coronary arteries. High pall pressure is usually associated with high blood lipids and both of them are considered to be one of the "greater risk factors of damage" that lead to heart disease that ultimately leads to the potential 0 to lead to undesirable adverse cardiac events. This group of risk factors is from It may be the result of a common method.Moreover, the patient's compliance with the method of treating high blood pressure is generally better than the patient's compliance with high blood lipids.Therefore, it will be advantageous for patients to take one treatment that treats both of these conditions.The disease of the artery Coronary heart disease is a multifactorial disease in which the incidence ve and severity are affected by profile lipid profile; the presence of diabetes and the person's sex. The incidence of the disease is also affected by smoking and left ventricular hypertrophy of the heart, which is a secondary result of high blood pressure. In order to reduce the risk of coronary artery disease in In the heart sense of the word, it is important to consider the overall risk spectrum, for example, attempts to intervene in hypertension have failed to show that mortality in cardiovascular disease due to coronary artery disease is normal or completely normal. Treatment with cholesterol inhibitors in patients with or without coronary heart disease reduces the risk of morbidity and mortality from cardiovascular disease. The Framingham Heart Study, an advanced prospective study of adult men and women”; have shown that certain risk factors can be used to predict the progression of coronary artery disease Yo. See (Wilson et al., Am.J.Cardiol. 1987, 59(14):91G-94G). These factors include age; sex; total cholesterol level; high-density lipoprotein (HDL) level; blood pressure during lil muscle contraction; cigarette smoking; Glucose intolerance and cardiomegaly

(left ventricular hypertrophy on electrocardiogram; echocardiogram or cardiomegaly on chest X-ray). Computers and computers can be easily programmed using a multivariable symbolic logic related function which enables the calculation of probabilities of the state of cardiovascular events. these accounts; Based on experience by day oY ed and female participants in the Framingham Study assessing coronary artery disease risk at different levels of follow-up. Model incidence rates range from less than 71 to more than 7-year ZA unintentionally selected However, these ratios correspond to less than 701 and rarely more than 7* in men and 5 77 in women. ,0 on the use of a comprehensive calcium channel blocker (camlodipine) for the treatment of atherosclerosis.This reference also suggests that atherosclerosis can be treated by the combination of amlodipine and a lipid-lowering agent.Human trials have shown that calcium channel blockers Beneficial effects in the treatment of early atherosclerotic damage; see eg Lichtlen, P.R. et al., Retardation of angiographic progression o coronary artery disease by nifedipine, Lancet, 1990, 335, 1109-13; and Waters, D. et al. al., Vo Acontrolled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis, Circulation, 1990, 82, 1940-53). Including “atorvastatin” are lipid-lowering agents in the blood and therefore useful in the treatment of atherosclerosis. Circulation, 1995 (Suppl 1), 1-197 x. Jukema et al. reveal that there is evidence that calcium channel blockers act synergistically in combination with lipid-lowering agents (eg; reductase inhibitors). HMG-CoA and especially pravastatin Orekhov et al, Cardivascular Drugs and Therapy, 1997, 11, 350 disclose the use of amlodipine in combination with lovastatin for the treatment of atherosclerosis © Detailed description of the invention The present invention relates to a drug formulation These include: (a) amlodipine or its pharmacologically acceptable acid additive salt; AVY

and "(b) atorvastatin or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier or diluent. According to Gypsum of the invention; (b) is amlodipine besylate or (b) is atorvastatin hemicalcium in a preferred embodiment. In particular, (a) amlodipine besylate © and (b) 5% -atorvastatin hemicalcium Lexie (1) is amlodipine besylate it is typically found in amounts from ¥0 to 0 mg mg; preferably in an amount from ¥ 0 mg to 10 mg When (a) is a pharmacologically acceptable acid addition salt other than camlodipine besylate it is typically found in an amount equal to ¥ 0 mg to yo mg amlodipine besylate Preferably in an amount equal to # mg to 100 mg amlodipine besylate 0 Lexie be (b) catorvastatin it is typically present in an amount of ¥ 0 mg to 100 mg; preferably an amount of 01 mg to 860 mg When (b) is atorvastatin hemicalcium or a pharmaceutically acceptable salt other than catorvastatin hemicalcium it is typically found in an equivalent amount of 8 mg to 100 mg catorvastatin An equivalent amount of 10 is preferred mg to Av mg atorvastatin 0 in a typical embodiment cp) iad (a) amlodipine besylate is present in an amount of 1.0 mg to yo mg or amlodipine or salt acceptable acid addition pharmacologically thereof other than 6 in an equivalent amount of 0.0 mg to 10 mg of amlodipine besylate and (b) atorvastatin is present in an amount of 0.0 mg to 0518 mg i.e. atorvastatin hemicalcium or vo A pharmaceutically acceptable salt other than atorvastatin hemicalcium present in an equivalent amount of 0.¥ mg to 00 mg catorvastatin in the “Junie (a) embodiment amlodipine besylate is present in an amount of ¥ 0 mg to 01 mg or amlodipine or salt with the addition of a pharmaceutically acceptable acid thereof other than 6 equivalents of © mg to 10 mg amlodipine besylate and (b) atorvastatin being present in an amount of 10 mg to Av mg any atorvastatin hemicalcium or a pharmaceutically acceptable salt Yo other than atorvastatin present in the amount of ABS from 01 mg to Av mg atorvastatin We also seek protection for the compositions according to the invention for use as medicines; Especially in AVY

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Treatment of high blood pressure and high blood lipids; heart attack; atherosclerosis and management of cardiac risk; and in the use of these formulations in the preparation of medicaments for the treatment of these conditions. Particularly preferred are formulations of the invention in a form suitable for enteral administration; Such as a tablet or a capsule. Or salt Adding a medically acceptable acid thereof amlodipine Also included in the scope of the invention is the use of 5 or a medically acceptable salt thereof in the preparation of drugs for the treatment of high blood pressure and atorvastatin lipid elevation in the blood; heart attack; Atherosclerosis and dealing with cardiac risk. It is an optically inactive compound due to symmetry at a position; The amlodipine ring has similar molecules and 5 can be prepared as described by dihydropyridine calcium, the amlodipine channel blocker. Arrowsmith et al. J Med.Chem., 1986.29.1696 0 and (5.RH) and the optically inactive mixture containing S(-) formulas is essentially limited to the isomer with hindrance activity R( The +H isomer (PCT/EP94/02697) is an effective inhibitor of cytokinesis with little or no R(H) activity. However, the calcium isomer of the channel is Effective in the treatment or prevention of atherosclerosis (see RH) for smooth muscle. For this reason, the isomer (International Patent Applications No. 00847/2795/0017). Based on the above, a skilled person vo is the isomer amlodipine aud Cus can choose to prepare an isomer from the compounds of the present invention (5). The isomer (5) or the optically inactive mixture of the (+) isomer and the R(H) isomer. The reference here to an anti-atherosclerotic effect involves slowing platelet progression Causing atherosclerosis, especially in the carotid arteries; coronary arteries; or the peripheral arterial system or working on its regression. myocardial death due to blockage in the JO (suffering future adverse cardiac events such as eg artery; myocardial arrest; Heart failure and/or blood failure of the heart muscle (ischemia in the Framingham Risk Equation of the heart muscle). Cardiac risk is calculated using the term “cardiac risk management” meaning that the risk of future adverse cardiac events has been substantially reduced.

AVY q Pharmaceutical formulation thereof J sie or salt addition of acid amlodipine The pharmaceutical formulations of the invention and/or a pharmaceutically acceptable salt thereof include. It may be readily prepared as described in the US patent amlodipine which is sold At the time amlodipine besylate is incorporated herein as a reference. Allg 4077964 the present number as “mm10 may be counted as described in US Patent No. 0 are amlodipine besylate y amlodipine channel blockers which are incorporated herein by reference. +7 effective and long-acting calcium "pharmacologically" intended to specify; But don't limit yourself to; A gia salts The term “phosphate” hydrogen sulfate sulfate chydrobromide < hydrochloride salts such as “citrate” succinate “besylate” acetate “dihydrogen phosphate < hydrogen phosphate 0 and p-toluenesulfonate (tosylate) 0. methanesulfonate(mesylate) can be easily prepared by the reaction of amlodipine form salts with the addition of other acid from

Wis) the free base of it with the appropriate acid. When the salt is from a monobasic acid of hydrogen form “(acetate” p-toluenesulfonate < hydrobromide < hydrochloride acid) dihydrogen or form (succinate < hydrogen sulfate base) (for example, Jl acid) At least one molecular equivalent (citrate “dihydrogen phosphate” tribasic (eg chemisuccinate sulfate) and usually a supermolecular form of the acid is used. However, when salts such as phosphate are desired, appropriate and specific chemical equivalents are generally used. phosphate or Hydrogen phosphate the free base and acid are usually combined into a common solvent from which the desired salt precipitates; or it may otherwise be isolated by concentration and/or by adding a non-solvent. © May be readily prepared as described in US Patent No. atorvastatin which is sold as atorvastatin from hemicalcium salt, which is incorporated herein by reference. 67 It may readily be prepared as described in the present-day Lipitor® US Patent No. 79774406©; which is incorporated herein by reference. The term "Pharmacologically Acceptable Salts" includes both an acceptable acid-adding salt Yo and a pharmacologically acceptable cationic salt. These salts are like alkali metal salts

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“ammonium salts” aluminum salts (magnesium y calcium Jie) the alkali earth metal “choline” benzathine (N,N'-dibenzylethylenediamine) Jia and salts with organic amines “meglumine (N-methylglucamine) “ethylenediamine” diethanolamine «piperazine «diethylamine «benethamine (N-benzylphenethylamine) rocaines tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol) e0 of the term “pharmacologically acceptable acid addition salts” is intended to define, not limit these Salts such as “phosphate < hydrogen sulfate » sulfate < hydrobromide < hydrochloride I » citrate » succinate » acetate » dihydrogen phosphate » hydrogen phosphate

.p-toluenesulfonate(tosylate) and methanesulfonate(mesylate)

1 Other pharmacologically acceptable cationic salts of atorvastatin may easily be prepared by reaction of the free acid form of atorvastatin with an appropriate base; Usually one equivalent in a common solvent. Typical bases are “sodium ethoxide” “sodium methoxide” “sodium hydroxide” “calcium hydroxide” “magnesium hydroxide” “potassium methoxide” “sodium hydride” piperazine “diethanolamine” choline <benzathine and tromethamine isolate salt

ve by concentrating to dryness or by adding a non-solvent. in many cases; It is preferable to prepare the salts by mixing a solution of acid with a solution of a different salt of the cation (eg sodium or (magnesium oleate) «potassium ethylhexanoate» and using a solvent (eg (ethyl acetate) from which the desired cationic salt precipitates. It is also permissible to isolate the salts by concentrating the reaction solution and/or by adding a non-solvent.

7 The acid addition salts of atorvastatin may easily be prepared with the appropriate acid. When the salt is of a monobasic acid <hydrobromide «hydrochloride Mis» (acetate «p-toluenesulfonate] the hydrogen form of a basic SLB acid (eg succinate <hydrogen sulfate or the dihydrogen form of acid tribasic Oa (citrate “dihydrogen phosphate” using at least one molecular equivalent and usually super

chemisuccinate «molecular sulfate of acid. however; When yo salts are desired, appropriate and specific chemical equivalents are generally used. “phosphate or hydrogen phosphate”

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11: The free base and acid usually combine into a common solvent from which the desired salt precipitates; or it may otherwise be isolated by concentration and/or by the addition of a non-solvent. In addition to this “atorvastatin (dl salts) Pharmacologically acceptable acid from it, atorvastatin and medicinally acceptable salts thereof may be present in the form of hydrate or soluble substances. These hydrate 0 and solutes are also included within the scope of the invention. All of the drug combinations and methods of this invention are intended for therapeutic use as agents in the treatment of atherosclerosis; heart attack; a condition characterized by the presence of both high blood pressure and increased blood lipids in mammals; Especially human. more than dia and since these diseases and conditions have close links to heart disease and harmful heart conditions; These unions 0 and ways; Thanks to their work as anti-atherogenic and anti-anginal; antihypertensives (CARL) and antihyperlipidemics; It is useful in controlling heart disease. The usefulness of the compounds of the invention Jal as medicinal agents in the treatment of atherosclerosis in mammals (eg, human) has been demonstrated by the activity of the compounds of the invention in conventional trials and the clinical protocol described below. The effect of catorvastatins amlodipine alone or in combination with cles on the treatment of atherosclerosis This study is a prospective, randomized evaluation of the effect of a combination of atorvastatin 5 amlodipine on progression/regression of coronary and carotid artery disease. The study is used to show that a combination of atorvastatin y amlodipine is effective in slowing or stopping the progression or causing regression of existing coronary artery disease (CAD) as indicated by changes in coronary angiography or carotid ultrasound; in people with the disease. This study is an imaging documentation of the blood vessels of coronary artery disease occurring as a paired trial of unspecified subjects; Tranquilizers under observation for at least about ©5000 people, and it is preferable to study about 7860 to 1701 people. It is especially desirable that we study about 1701 people in this study. Subjects are enrolled in this study after meeting certain entry criteria appended below. Yo Entry Criteria: Persons accepted for entry in this bid must meet certain criteria. Thus »the person must be male or female by default. His age is between ALAA in whom coronary artery angiography is clinically significant. People who will have an AVY damage on an angiogram

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Meaningful focal e.g. 7270 to 7200 on follow-up assessment by quantitative coronary angiography (QCA) with a minimum of one piece (PTCA- ji) non-surpassed or non-necrotizing vessel) where the judgment is not needed to intervene for the next three years. We need not to interfere with the pieces being analyzed. Whereas transcatheter and subcutaneous coronary artery bypass grafting (PTCA) intervenes with resection by balloon catheter implantation; The piece on which PTCA was not performed will be the one required for the experiment. It is also required that the pieces subject to the test should not have been subjected to clotting or thrombosis; Jie occlusal necrosis (MI) Thus was the need for non-occult necrosis vessels. The vertebrae that will be subject to the experiment include: the main north; near; middle; the far north of the anterior descending; the first and second country branches; the far and near lav north; first or largest distal space 0 obtuse: proximal; Central and distal of the right coronary artery. Subjects will have a more constrictive portion of AT that can be determined by catheterization, fluoroscopic imaging of the ventricles, or echocardiography at the time of imaging conditioning or within the 3 months preceding anticipation of sympathetic conditioning provided that there is no dala Jia intervention. or PTCA Jie in general, given the number of patients and the physical limitations of anyone's ability; The study is being conducted at several vo sites. when entering into temptation; Subjects undergo a quantitative coronary angiogram as well as an ultrasound B-case of the carotid artery and determine the compliance of the carotid artery at specific test centers. This proves a rule for each person. Once entered into the experience; Subjects are randomly assigned to receive amlodipine besylate (10 mg) and placebo or A+ (atorvastatin calcium mg) and placebo or 01 (besylate) of amlodipine Av) atorvastatin calcium 0 mg) all subsequent doses in This protocol is for daily doses. Amounts of amlodipine besylate may vary depending on order. Generally, the person will start taking 10 mg and the dose will be titrated until it becomes as low as 10 mg as determined by the doctor. Likewise, the amount of atoravastatin calcium will be titrated from Av mg to less than this as determined by the physician for the benefit of the patient. A skilled person will realize that the free base form or other vo salt forms of 106871816 amlodipine or the free base form of other salt forms of atoravastatin calcium may be used in the invention. Calculating the dosage amount for these forms

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It is easily achieved by making a ratio of amlodipine besylate 5 atoravastatin calcium other than simple to the molecular weights of the species used. Subjects are followed for one to three years; Generally three years is preferred. Evaluation of atherosclerosis in the carotid artery by B-case carotid ultrasound and response was done at regular intervals throughout the study. 0 Generally, intervals of six months are considered appropriate. This evaluation is typically done using a Case-B ultrasound machine; However, a person skilled in the art may use other methods to make this assessment. Angiography is done at the end of the one to three years of treatment. Mainline and post-treatment angiography and interventional sonography B-case evaluated for new damage or progression of existing atherosclerosis. Evaluate 0 arterial response measurements to changes from the mainline and for a six-month evaluation period. Or amlodipine acid salts addition The primary purpose of this study is to demonstrate that a combination of atorvastatin s, or a pharmacologically acceptable salt thereof, reduces the progression of atherosclerosis. It is clinically acceptable in patients with (QCA) measured by quantitative coronary angiography. LS measures the opening in the lumen of measured arteries. QCA is clinical in coronary artery disease. 1 The main objective of this study is to change The average segment diameter of the branches of the coronary artery. Therefore, the diameter of an arterial segment is measured at several segments along that segment. Then it determines the average diameter of that segment. After the average diameter of the piece is determined for many pieces; The average of all segment averages is set to arrive at the average segment diameter. The average segment diameter for people who will decrease more slowly or amlodipine s atorvastatin taking the co-primary drug than 0 will stop completely or there will be an increase in the average segment diameter. These results illustrate the slow progression of sclerosis; sclerosis stopped progressing; regression of sclerosis; In order. Or the addition of amlodipine salt The secondary purpose of this study is to show that the combination of or a pharmaceutically acceptable salt thereof reduces the rate of regression of stiffness in atorvastatin s acid in the carotid arteries as measured by an empirical test. Maximum measurements of the mean thickness of the vessel liner vo side-separated piece (mean maximum) as a function of time; More than 17 with an average of more than or a pharmaceutically acceptable salt of it, atorvastatin, or a pharmaceutically acceptable acid addition salt thereof, or amlodipine

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lonliness. The mean endothelial thickness of subjects taking atorvastatin or its Pharmaceutical Saline Additive and 20010010106 or its Pharmaceutical Saline will increase slowly o ASH will either stop increasing or will decrease. These findings represent a slow progression of atherosclerosis; lea ll halted atherosclerotic progression and regression of atherosclerosis; in the order. The usefulness of the compounds of the present invention as medicinal agents in the treatment of angina pectoris in mammals (eg, human) has been demonstrated by the activity of the compounds of the present invention in routine trials and the clinical protocol described below. catorvastatin s amlodipine ls both alone and in combination clas for the treatment of angina This study is a randomized study; parallel arm undefined double; To demonstrate the effect of a combined prodrug of amlodipine and atorvastatin in the treatment of symptomatic angina. Entry criteria: subjects are men or women between 18 and 80 years of age with a matching history of chest pain associated with one of the target indications of local deficiency or anemia in the heart (ischemia): (1) segment height in stress test in mm or > from an ECG; (1) positive treadmill stress test: a device for producing circular motion ve by stepping on the feet of a wheel or something; (V) new abnormal wall motion appearing in Sonography; or (£) narrowing (AS) evident on the coronary angiogram. Generally a narrowing of about 1-1" 75 is considered significant. Each person is evaluated for about ten to thirty-two weeks. At least ten weeks Generally required to complete the study A sufficient number of subjects is used in this presentation to confirm that approximately 8060 Yee to subjects and preferably about fe subjects were assessed to complete the study Subjects are presented for responding to the above entry criteria during weeks in the holding phase. After completion of presentation criteria, subjects are cleaned off their antianginal drug Jad and fixed on a long-acting nitrate (Jia eg nitroglycerin isosorbide-5-mononitrate or dinitrate 18080:5108). The term "cleans from" is when Yo is used in connection with this offer; It means eliminating the current antianginal medication in order to essentially remove said medication from the person's body. A period of A weeks is preferred to be given for both the elimination period and the stabilization of the person on fixed doses of these nitrate people with one or cnt m

1 Long-acting nitrate allows him to eliminate angina attacks per week while taking doses of nitrate. People generally enter the nitrate elimination phase. After the subjects were fixed on Ala je for randomization on the condition that the subjects still had one or two angina attacks per week. in the random stage; Subjects are randomly placed in one of the four arms of the following experiment statement: After completing the cleaning phase; Subjects who meet the test criteria are subjected to a 0 “Holter electrocardiogram throughout 4 ? Watch clock Monitor ambulatory electrocardigram (ECG) Portable Exercise stress test such as treadmill stress test Evaluation of the saturation of the heart muscle for photon emission) X-fixation (tomography or PET tomography with liquid using a plotter treadmill and treadmill incline do ju main line for each person when attaching a stress test;

SL that can be controlled by the technician. Treadmill speed and inclination angle generally increase 0a 0

Bruce the test. Generally, the time interval between each speed and increment is determined using a modified protocol, after completion of basic checks. Subjects are started on one of the following four study arms: (1) placebo; (¥) atorvastatin calcium (approx. 0.7 mg to about 1,000 mg); (¥) amlodipine besylate eo (approx. 10mg); or (£) a combination of the above doses of atorvastatin s amlodipine Subjects are then followed up for two to twenty-four weeks. A skilled person will recognize that the free base or Jif salt form of amlodipine besylate or The free base form of other salt forms of atoravastatin calcium may be used in the invention. The dosage calculation for these other vy. forms of amlodipine besylate 5 atoravastatin calcium is readily achievable by making a simple ratio of the molecular weights of the species used. After the expiration of the period chal Subjects will undergo the following examinations: (1) a 1-hour “Jit” electrocardiogram; a Jie Holter monitor; (?) an exercise stress test (eg, a treadmill using the modified Bruce protocol). this); and (©) assessment of myocardial fluid saturation using a PET plotter. Patients maintain daily painful ischemia events and nitroglycerin consumption. It is generally preferred to obtain an accurate record of the number of angina episodes experienced by patients during a period the test. Since the patient generally takes nitroglycerin to reduce the pain of an AAD attack, M

The number of times a patient takes nitroglycerin provides a reasonably accurate record of the frequency of angina attacks. To illustrate the effect of the compounds and formulations of the present invention; and for the dosage determination of the compounds and formulations of the present invention; The person taking the test will evaluate the person taking the test using the prescribed tests. A successful treatment will induce a few moments of ischemic events as determined by the electrocardiogram; it will allow the person to exercise for a longer time or at a higher intensity on the treadmill; or to exercise without pain on the treadmill or better liquid saturation will occur or slight defects in liquid saturation as shown on the tomography or X-ray photon emission tomography (PET) Ve usefulness of compounds Compounds of the present invention as agents The medicinal use in the treatment of hypertension and hyperlipidemia in mammals (eg, human) suffering from a combination of hypertension and hyperlipidemia has been demonstrated by the activity of the compounds of this invention in the normal trials and clinical protocol described below. effect of amlodipine and 0TA210772518; Both alone and united together to treat people suffering from each Vo of high blood pressure and increased blood lipids. This study is a randomized study; An unspecified double cplA parallelogram to demonstrate the effect of amlodipine or atorvastatin sy and its approved acid salts in the control of both hypertension and hyperlipidemia in hypertensive subjects. chaps average; or severe hyperlipidemia. 7 Each person is assessed for 10 to 1 week, preferably VE weeks. Sufficient persons are used in this presentation to ensure that approximately 40,860 to 8,060 persons were assessed to complete the study. Entry criteria: Subjects were male or BU 18 to 0” years of age with both hypertension and hyperlipidemia. The presence of an increase in blood lipids inferred by an elevation of the low-density lipoprotein (LDL) limit of a person close to Yo are certain positive risk factors. If the person does not have coronary artery disease (CHD) and has less than two positive risk factors; A person is considered to have hyperlipidemia if the person's LDL is more than or equal to Ve if the person's LDL is

Vv the person does not have coronary artery disease and has two or more positive risk factors” then the person is considered to have hyperlipidemia if the lipoprotein is low density so if the person has coronary artery disease; It considers a person more than or equal to 060 suffers from hyperlipidemia if the LDL of this person is more than

AY or equal to 0 over the age of 00 years where AT (Y) 80 male over the age of (1) Positive risk factors include family history (©) (HRT) This female is not undergoing treatment Replacement of hormones for early disease of the heart and blood vessels; ( ;) The person is a current smoker (0) The person suffers from The person suffers from high blood pressure (V) 5 of 56; Ji HDL Density Je Lipoprotein ) 6) “Sw is considered a negative risk factor and will eliminate one of the high 01 risk factors. 1101 is more than the previously mentioned positive 0. When the muscle relaxes (BP) the presence of a rise in blood pressure is indicated by the presence of pressure Blood Each Ee is measured when the heart muscle contraction is more than a fixed (BP) or a blood pressure of 00. The heart is more than blood pressures in general, with an average of three measurements taken one after the other for five minutes. For responding to the previously mentioned entry criteria When all presentation criteria are met; 1 step A diet that rations the amount of saturated and unsaturated fats that can be consumed 1 step in proportion to the total calories taken. The term "cleaned from" has been used in connection with this Protocol; This means that antihypertensive and ov-reducing medication should be discontinued. This is why all of these drugs are virtually eliminated from the body of the subject. Newly diagnosed people generally remain untreated until testing begins. These subjects are also placed € weeks after treatment off treatment and a stabilization period on the NCEP diet 1 step blood pressure and (?) pic (1) diet; subjects undergo the following mainline examinations : for the percentage of fat during fasting. The picture of fat during fasting determines the limits of the main line of fat in the case of vo at this 17 sad fasting for the subjects of the experiment. Generally, the person is prevented from eating at the time the percentage of fat is measured. M

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After doing the basic tests, people start treatment on one of the following: (1) Fixed dose Fixed dose of (V) mg; generally about 8 to amlodipine besylate of or (?) a combination of the above doses toners to about 10 generally about catorvastatin calcium + together Subjects stay on these doses of atorvastatin calcium y amlodipine for a minimum of weeks Subjects return to the examination center at the end of the six weeks A; generally not for more than to eight weeks for the baseline examinations to be repeated.The skilled person will realize that the base form of the free base form of amlodipine besylate salts or other salt forms of the may be used in the invention.The dosage calculation for this is 20 calcium other than Easily ascertained by amlodipine besylate 5 atoravastatin calcium Other forms of A simple ratio of molecular weights to the species used Compares a person's blood pressure at the end of the study 0 (oI) with the person's blood pressure at entry. Lipid profile measures Cholesterol (VLDL apoB «triglycerides cholesterol» -HDL cholesterol; -LDL low density) and other components of a person's lipid profile. The improvement in the values obtained post-treatment relative to the pre-treatment values implies a benefit of the drug combination. Cardiac activity has been demonstrated by the activity of compounds of this invention in standard trials and the clinical protocol described below. Both alone and in combination in subjects at risk of catorvastatin y amlodipine Effects Nonspecific dual cardiovascular events To clarify the effect of the drug op OA, this study is a randomized study; Parallel Y. In reducing the calculated total risk of events, co-administered atorvastatin y amlodipine with primary co-receptors in subjects at future risk of cardiovascular events. A person is considered to be at risk Framingham calculates this risk using the formula Suffer from cardiovascular events if that person is more than one above Framingham Risk Equation aul 5 uses the mean of the standard deviation as calculated vo risk In the heart bua in atorvastatin s amlodipine study to evaluate the potency of a combined salt of

AVY

and blood vessels by controlling both hypertension and hyperlipidemia in patients with both mild to moderate hypertension and hyperlipidemia. Everyone stays for 01 to yo weeks and preferably VE a week. Enough people signed up to confirm that about 5080 Avs of people were evaluated to complete the study.

Entry criteria: Subjects included in the study were adult males or females between VA and 80 years of age with five years of baseline risk and such risk being above average for the subjects' ages and sexes; As defined by the Framingham Heart Study, an ongoing prospective study of adult men and women showing that certain risk factors can be used to predict the occurrence of coronary heart disease. Age; sex; blood pressure at diastole and systole of the heart;

0 smoking habit; the presence or absence of carbohydrate intolerance; the presence or absence of left ventricular hypertrophy of the heart; Serum cholesterol and high-density lipoprotein (HDL) or more than one standard deviation above normal for a Framingham population were all assessed in determining whether a patient was at risk of adverse cardiac events. The value for risk factors is entered into the Framingham Risk Equation and calculated to determine if the person is at risk of cardiac events

1 and future blood vessels.

Shows people to respond to the input criteria shown previously. After all bid criteria have been met; Patients discontinue their ongoing anti-hypertensive pall and lipid-reducing medication and any other treatment will hinder the results from the presentation. Patients are then placed on the NCEP ATP II step 1 diet as described in Previously Diagnosed Hypertension and Hyperlipidemia. ov. Newly diagnosed people generally remain untreated until testing begins. These subjects are placed ALSO ON THE STEP 1 DIET OF 1] NCEP ATP After weeks of elimination and a steady diet period, subjects undergo the following mainline checks: (1) blood pressure; (?) fasting; (?) lipid profile (£2) Glucose tolerance test (*).

ve telecardiogram is generally used to measure the presence or absence of left ventricular hypertrophy of the heart. After doing the basic tests, patients start taking one of the following: (1) a fixed dose of amlodipine (approximately 0.8 to 10 mg); (¥) a fixed dose of atorvastatin (approximately 1

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Ye A skilled person will understand that the free base form or other salt forms of atorvastatin g amlodipine or (vii) a combination of the above doses of pers J or the amlodipine besylate form may be used in atoravastatin calcium The free base of other salt forms of atoravastatin calcium of the invention.The calculation of the dosage amount for these other forms of atoravastatin calcium is readily accomplished by making a simple ratio of the molecular weights of the species used.amlodipine besylates© Patients are continued on these doses and are told to return in six to eight weeks to return

Framingham Risk Equation Main Line Examinations. At this time the new values enter into the more ill or experiencing a change in the severity of events in the JE to determine whether the person has vascular receptors. Previous trials demonstrate the effect of a combined prodrug of atorvastatin's amlodipine in treatment of angina pectoris; Arteriosclerosis; High blood pressure and increased blood lipids, together with the treatment of heart disease; It also provides averages with which it is possible to compare the activities of the compounds of the invention between themselves and the activities of other known compounds. The results from these comparisons are useful for determining the dose level in mammals; Ley in which the human being; Jie to treat these diseases. vo The following dose quantities and other dose quantities mentioned elsewhere in the specification and in subsequent claims are for an average human weighing from about 0 to about 0 kg. Skilled practitioners will easily be able to determine the amount of dosage required for a person whose weight falls outside the limit of paste to 0kg based on the person's medical history and the presence of diseases; like; sugar in a person. All the doses mentioned here and in the following items; are daily doses. Y. Generals according to this invention; Atorvastatin is given in doses of about 0.5 mg to about 00 mg. Atorvastatin is best given at a dose of about 0 mg to about Av mg. A skilled person will realize the possibility of using the free base form or other salt forms of atorvastatin calcium in this invention. The dosage calculation for these other forms, the free base form, or other salt forms of atorvastatin calcium Ye can easily be done by making a simple ratio of the molecular weights of the species used. Generally applicable to this invention; Amlodipine besylate is given in doses from about ½ mg to about 10 mg. A skilled person will recognize the possibility of using the free base form or the salt forms of AVY

Another form of atorvastatin calcium is in this invention. (Say) It is easy to calculate the dosage amount for these other forms, the free base form, or the other salt forms of amlodipine besylate by making a simple ratio of the molecular weights of the species used. The compounds of the present invention are given in the form of a pharmaceutical formulation that includes the compounds of this invention together together with a pharmacologically acceptable carrier or diluent.Therefore, the compounds of the present invention may be administered in any conventional, non-enteric, or transdermal form.For oral administration a medicinal composition may take the form of solutions;suspensions;tablets;pills;capsules Badra, etc. Tablets containing various catalysts such as sodium citrate phosphate 5 calcium carbonate 20 used with various non-complementary materials such as starch 0 and preferably potato or tapioca starch (a starchy preparation for making sweets) 5 complex silicate Each with binding agents such as gelatin «sucrose «polyvinylpyrrolidine» and acacia.In addition to lubricating agents, sale talc g sodium lauryl sulfate «magnesium stearate Jia, which are very useful for the purposes of making tablets.Solid formulations of similar quality are also used as filling materials in Soft and hard gelatin capsules filled with these substances; Preferred materials in this art also include lactose 0 or higher molecular weight polyethylene glycols Jie. when he desires aqueous suspensions and/or elixirs for oral administration; The compounds of this invention can combine with many local ingredients; flavoring agents; colorants emulsifying agents and/or suspending agents; The same applies to those diluents such as water “glycerine” propylen glycol “ethanol” and many similar compounds thereof. dE of this invention may also be administered in a controlled-release compound such as a slow-release or rapid-release formulation. Such controlled-dose-release formulations of the common prodrugs of this invention may be prepared using methods well known to those skilled in the art. The method for taking the preparation will be determined by the attending physician or other person skilled in the art after assessing the person's condition and needs. The best overall formulation of amlodipine is Norvasc™ vo. The best form of general formulation of atorvastatin is Lipitor™. For parenteral purposes solutions in sesame or peanut oil or in aqueous propylene glycol may be To use; As well as sterile aqueous solutions of soluble salts

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in the corresponding water. It is possible to adjust the pH of such aqueous solutions appropriately, when necessary; The aqueous diluent is first made isotonic with sufficient glucose or salt solution. These aqueous solutions are particularly suitable for intravenous and intramuscular injections; and under the skin and inside the peritoneum in this art; All sterile aqueous media used are easily obtained by titration techniques well known to those skilled in the art. 0 Methods for preparing several drug compositions by means of a given amount of an active ingredient are known; or will. be visible in the light of this content; For those skilled in this art. For example; Look

Remington's Pharmaceutical Sciences, Mack Publishing Company, Easter, Pa., 15th

Edition (1975). of the compound (or 4 ov, pharmaceutical formulations depending on the invention may contain Ve. The combination to be taken will contain any IV = I = 0 compounds) of this invention” preferably containing an amount of a compound (or compounds) according to the invention in an effective quantity to treat the condition or disease of the person being treated

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Claims (1)

YY The claims include: pharmaceutical composition of Bickert-1 1 or its pharmaceutically acceptable salt of addition; amlodipine 0 or its pharmaceutically acceptable salt; and atorvastatin (b) atorvastatin 1 (c) a pharmaceutically acceptable carrier or diluent. According to claim) ¢ where (a) is pharmaceutical composition 7?-1 amlodipine besylate. Y where (b) is 1 According to the claim, pharmaceutical composition 7- Pharmaceutical composition 1 atorvastatin hemicalcium. Calcium extracted from atorvastatin Y 0 Sua oF to 1 laa of any lish pharmaceutical composition 4-Pharmaceutical formulation 1 and (b) is hemicalcium atorvastatin amlodipine besylate .atorvastatin hemicalcium v (1) to 4; Where 1 according to any pharmaceutical composition *- Pharmaceutical composition 01 mg. 01 and is present in an amount of 0.¥ to amlodipine besylate is amlodipine besylate Y to 4; where 1 according to any protective ingredient pharmaceutical composition 1 mg or calcium 061 (b) is atorvastatin 0 present in an amount of 0,¥ mg to or a pharmaceutically acceptable salt atorvastatin hemicalcium halves of atorvastatin 1 present in an equivalent amount of 2 hemicalcium other than halves of atorvastatin ¢ atorvastatin calcium . atorvastatin 061 mg of atorvastatin 061 mg to Y,0 of pros © and 6; where (a) is a lish pharmaceutical composition of 7-pharmaceutical composition 01 mg and (b) 01 present in an amount from *,7 mg to 06 besylate amlodipine besylate Y mg or calcium 01610 present In an amount of 7.5 mg to atorvastatin is atorvastatin 3 or a pharmaceutically acceptable salt other than atorvastatin hemicalcium half of atorvastatin 1 present in an equivalent amount of 0, ¥ mg atorvastatin hemicalcium half of atorvastatin ° atorvastatin .atorvastatin 1001 to 1 mg (1) to 4; Where 1 according to any protective ingredient, pharmaceutical composition +8-pharmaceutical composition, 1 mg. 01, and there is amlodipine besylate in an amount of © mg to amlodipine besylate Y AVY v ¢ 4S 5-1 1 Pharmaceutical composition according to any claim 1 to of where X (b) is atorvastatin 0 present in an amount of 01 mg to Av mg or calcium 1 hemical of atorvastatin hemicalcium or a pharmaceutically acceptable salt other than Ca1 hemical of atorvastatin hemicalcium contained in an Ale° amount of 10 mg to Av mg of atorvastatin (1 and 5); Where A is according to the two claims, pharmaceutical composition, a pharmaceutical composition 1-01 mg and (B) 01 present in an amount from © mg to amlodipine besylate Y is amlodipine besylate mg or calcium hemide Av 10 to 0 mg present in an amount of atorvastatin is atorvastatin v or a pharmaceutically acceptable salt other than atorvastatin hemicalcium of atorvastatin ¢ Av 10 to 0 mg present in an equivalent amount of 0 hemicalcium of atorvastatin ° .atorvastatin mg of atorvastatin 1 -11 1 pharmaceutical composition pursuant to claim 1 where (a) is Y amlodipine or the pharmacologically acceptable acid salt thereof other than amlodipine besylate amlodipine besylate 1 and contained in an equivalent amount of 7.5 mg to 10 mg of amlodipine ¢ besylate. amlodipine besylate -11-1 pharmaceutical composition of claim 7; Where 0 is amlodipine Y or a pharmaceutically acceptable acid addition salt thereof other than amlodipine besylate 1 and is found in an equivalent amount of 7.5 mg to 5 mg of amlodipine ¢ = amlodipine besylate. ( ) According to claim 1- where the pharmaceutical composition is a pharmaceutical composition 1-117 or a salt with the addition of a pharmaceutically acceptable acid thereof other than amlodipine amlodipine 01 mg of amlodipine 01 and is found in an equivalent amount of © mg to amlodipine besylate v .amlodipine besylate £ -14 1 pharmaceutical composition pursuant to claim 4 < where (I) is Y amlodipine or a pharmaceutically acceptable additive salt thereof other than amlodipine besylate 1 6 It is found in an equivalent amount of ½ mg to 10 mg of amlodipine besylate .amlodipine besylate ¢ AVY Yo HS 5-10 1 pharmaceutical composition according to any claim 1 to of where Y is (b) in an equivalent amount of 01 mg to Av mg of atorvastatin (<) where A is present according to claim pharmaceutical composition Pharmaceutical composition 11-1 : atorvastatin mg of atorvastatin Av to 01 mg in an equivalent amount of Y AT to 1 according For any protective ingredient, pharmaceutical composition 45. 1-117 composition (medicament) for use as a drug. Y 18-1 pharmaceutical composition according to claim 117 for use in “treatment of high blood pressure and hyperlipidemia. -19-1 Pharmaceutical composition according to claim VY for use in Y treatment of angina pectoris. -71-1 Pharmaceutical composition pursuant to claim 117 for use in the treatment of atherosclerosis. – “71 1 pharmaceutical composition pursuant to claim 11 for use in ‎Y dealing with cardiac risk. =YY 1 Use of a pharmaceutical composition according to claim 08 in Y to prepare a drug for the treatment of high blood pressure and high blood lipids. 1 ??- Use of a pharmaceutical composition according to element 19 in Y to prepare a drug for the treatment of angina pectoris. 1 740- Using a pharmaceutical composition Li pharmaceutical composition for Claim 01 in Y Prepare a drug for the treatment of atherosclerosis. 1©#?- Use of a pharmaceutical composition pursuant to Claim 71 in Y Preparing a drug to treat a cardiac risk. 1 1 ?- pharmaceutical composition according to any claim 1 to 1? or 0-0 > use a drug composition in accordance with any protective element? to TO where the drug composition is in a form suitable for enteral administration. 717-1 pharmaceutical composition and use in accordance with joa al protection (TY" - where the drug formulation is tablet or capsule form. ANY ¥1 D 1 78- The use of (a) amlodipine or its pharmaceutically acceptable salt and (b) atorvastatin or its medicinally acceptable salt in the preparation of a drug for the treatment of high blood pressure ov and lipid reaction in the blood. Y3—1 Use of (1) amlodipine or its Pharmaceutical Acceptable Acid Additive Salt and (b) Y atorvastatin or its Pharmaceutical Acceptable Salt in preparing a drug for the treatment of angina pectoris. =¥e 1 Use (a) amlodipine or its pharmaceutically acceptable acid addition salt and (b) atorvastatin Y or its medicinally acceptable salt in the preparation of a drug for the treatment of la ll ¥ atherosclerosis. ) amlodipine or its pharmaceutically acceptable salt of addition and (b) atorvastatin Y or its pharmaceutically acceptable salt in the preparation of a drug for the management of cardiac risk. AVY