HK1073784A - Combination dosage form containing a cholesterol-lowering agent, an inhibitor of the renin-angiotensin, and aspirin - Google Patents

Description

Combined dosage form comprising cholesterol-lowering agent, renin-angiotensin inhibitor and aspirin

Technical Field

The present invention relates generally to pharmaceutical formulations for treating patients at high cardiovascular risk, and more particularly to dosage forms combining a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and aspirin.

Background article

Many people are at high risk of suffering from serious to life-threatening cardiovascular events, such as myocardial infarction (heart attack), cardiac arrest, congestive heart failure, stroke, peripheral vascular disease and/or claudication. Risk factors are numerous and widely distributed in the world population. They include smoking, diabetes, hypercholesterolemia (high serum cholesterol), hypertension, angina, systemic lupus erythematosus, pre-morbid heart attack or stroke, hemodialysis, hyper-homocysteine levels, obesity, sedentary lifestyle, receiving organ transplants, and others. Many of these risk factors are mediated through atherosclerosis, which is a major risk factor for cardiovascular events. There is a need for a safe and convenient pharmaceutical formulation that is effective in reducing the risk of cardiovascular events in individuals with these risk factors.

In U.S. patent No. 5,622,985, olukon et al disclose that 3-hydroxy-3-methylglutaryl coenzyme a (hmg coa) reductase inhibitors (cholesterol lowering drugs), particularly pravastatin, when used alone or in combination with Angiotensin Converting Enzyme (ACE) inhibitors, will reduce the risk of a second heart attack in patients with substantially normal cholesterol levels. The combination with ACE inhibitors is optional and no mention is made of HMG CoA reductase inhibitors in combination with other inhibitors of the renin-angiotensin system or with aspirin. Furthermore, prevention of cardiovascular events other than a secondary heart attack is not contemplated.

Similarly, in U.S. patent No. 5,140,012, McGovern et al disclose the use of pravastatin alone or in combination with ACE inhibitors to prevent the onset of restenosis following angioplasty. HMG CoA reductase inhibitors other than pravastatin have not been considered, nor have HMG CoA reductase inhibitors been mentioned in combination with other inhibitors of the renin-angiotensin system or with aspirin. Prevention of cardiovascular disorders other than restenosis following angioplasty is not contemplated.

In U.S. patent nos. 5,461,039 and 5,593,971, tschlar et al disclose the use of cholesterol-lowering drugs, alone or in combination with ACE inhibitors, to inhibit hypertension in normotensive individuals with insulin resistance. There is no mention of cholesterol-lowering drugs in combination with inhibitors of the renin-angiotensin system other than ACE inhibitors or in combination with aspirin. Furthermore, the disclosed methods are limited to insulin resistant normotensive individuals and are not directed to preventing cardiovascular events.

In U.S. statutory invention registration No. H1286, Eisman et al disclose a method of treating peripheral atherosclerotic disease and/or intermittent claudication by administering one or more cholesterol-lowering agents, either by themselves or in combination with an ACE inhibitor, or by administering an ACE inhibitor alone. There is nomention of cholesterol-lowering drugs in combination with inhibitors of the renin-angiotensin system other than ACE inhibitors or in combination with aspirin. Treatment or prevention of cardiovascular disorders other than peripheral atherosclerotic disease and/or intermittent claudication is also not contemplated.

In European patent Specification EP 457,514, Bergey et al disclose the use of cholesterol-lowering agents in combination with ACE inhibitors to prevent, stabilize or regress atherosclerosis. There is no mention of cholesterol-lowering drugs in combination with inhibitors of the renin-angiotensin system other than ACE inhibitors or in combination with aspirin. Nor treatment or prevention of cardiovascular disorders other than atherosclerosis.

In U.S. Pat. No. 6,235,311, Ullah et al disclose the inclusion of hormone Release inhibinPharmaceutical composition of (HMG CoA reductase inhibitor) plus aspirin, optionally containing vitamin B₆、B₁₂Or folic acid, and methods for their use to: lowering serum cholesterol; preventing, inhibiting or treating atherosclerosis; or reducing the risk of and treating cardiovascular events or diseases, coronary artery disease or cerebrovascular disease. This reference does not mention or in any way consider inhibitors of the renin-angiotensin system.

In U.S. patent No. 6,248,729, onglio et al disclose a method for preventing cerebral infarction by administering to a patient a combination of an ADP-receptor blocking antiplatelet agent, an antihypertensive agent (e.g., an angiotensin II antagonist, an ACE inhibitor or an ACE/NEP inhibitor) and optionally aspirin. Pharmaceutical compositions comprising combinations of these agents are also disclosed. However, the disclosed methods and compositions require ADP-receptor blocking antiplatelet drugs (which do not include aspirin), and neither mention nor consider cardiovascular events other than cerebral infarction by Coniglio et al.

In international patent publication WO 01/15674, Schoelkens et al disclose the use of inhibitors of the renin-angiotensin system, optionally together with another antihypertensive agent, cholesterol-lowering agent, diuretic or aspirin, in the prevention of cardiovascular events. Also disclosed are combination products for this purpose, comprising an inhibitor of the renin-angiotensin system and a cholesterol-lowering agent. Further disclosed is the use of an inhibitor of the renin-angiotensin system in combination with another antihypertensive agent or a cholesterol lowering agent or a diuretic or aspirin for the manufacture of a medicament for the prevention of cardiovascular events. The possibility of combining three or more active agents, whether in a method of treating a patient or in the manufacture of a pharmaceutical product, has never been mentioned or considered. Even though specific inhibitors of the renin-angiotensin system, cholesterol lowering agents and aspirin are mentioned, as well as combination therapies involving inhibitors of the renin-angiotensin system and cholesterol lowering agents or aspirin together are mentioned, no consideration is given to combining all three agents in a single dosage form.

Disclosure of the invention

It is therefore a primary object of the present invention to provide a pharmaceutical composition that overcomes the limitations of the formulations and dosage forms described above.

It is an object of the present invention to provide a once-daily orally administered pharmaceutical composition for treating a patient at high cardiovascular risk, said composition comprising a single dosage form comprising a therapeutically effective unit dose of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, aspirin and optionally one or more vitamin B₆、B₁₂And folic acid, plus a pharmaceutically acceptable carrier, wherein each unit dose is a daily dose and at least one active agent is present in dosage units in the dosage form that physically isolate it from other active agents in the dosage form.

It is a further object of the present invention to provide an orally administrable solid dosage form in which at least two drugs are present in dosage units, separate from the other active drugs, and are separated from each other.

It is a further object of the invention to provide an orally administrable solid dosage form in which at least one active agent is present in present release dosage units, e.g., sustained release and/or delayed release dosage units.

It is a further object of the invention to provide such a composition wherein the cholesterol-lowering agent is an HMG CoA reductase inhibitor and the inhibitor of the renin-angiotensin system is an ACE inhibitor or an angiotensin II antagonist.

It is a further object of the present invention to provide such a composition wherein all three vitamin B components are present₆、B₁₂And folic acid is contained therein.

Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.

The present invention provides a once daily oral dosage form comprising a combination of a therapeutically effective unit dose of a cholesterol-lowering drug, a therapeutically effective unit dose of an inhibitor of the renin-angiotensin system and a therapeutically effective unit dose of aspirin, optionally in further combination with at least one vitamin B material, wherein at least one active drug is present in dosage units in the dosage form which are segregated from other active drugs. Preferably, at least two drugs are present in dosage units such that they are separated from other active drugs and they are separated from each other, more preferably at least one active drug is present in controlled release dosage units, e.g. sustained release and/or delayed release dosage units. The invention also provides a method of treating a patient at high cardiovascular risk by administering said dosage form daily. Administration of the dosage forms described herein provides a safe and effective method of reducing the risk of cardiovascular events in such patients, such as the convenient once daily administration of a single oral dosage form containing the aforementioned combination of active agents, wherein any deleterious interactions between the active agents are minimized or eliminated. Such a simple method has a high degree of patient compliance, resulting in considerably improved results. The combination of three or more active ingredients provides the additional advantage that it is possible to reduce the dosage of the active ingredients and increase the safety of the treatment.

In a preferred embodiment, the dosage form of the invention comprises:

from about 10mg to about 120mg, preferably from about 25mg to about 90mg of an HMG CoA reductase inhibitor selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin;

about 1mg to about 60mg, preferably about 15mg to about 45mg of an ACE inhibitor selected from captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril and trandolapril;

about 20mg to 600mg, preferably about 20mg to 150mg, aspirin; and optionally at least one

About 25mg to about 75mg,preferably about 40mg to about 60mg vitamin B₆；

About 0.25mg-2mg, preferably about 0.5mg-1.5mg vitamin B₁₂；

About 0.5mg to about 8mg, preferably about 1.5mg to about 5mg, folic acid;

detailed description of the invention

I. Definition and naming

Before the present invention is described in detail, it is to be understood that this invention is not limited to particular formulations, carriers, etc., as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" or "a pharmacologically active agent" includes a single active agent and also includes combinations of two or more different active agents, reference to "a carrier" includes a single carrier and also includes mixtures of two or more carriers, and the like.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out.

The terms "active agent", "pharmacologically active agent" and "drug" are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological, physiological effect. The main active drugs here are cholesterol-lowering drugs, inhibitors of the renin-angiotensin system and aspirin; other active agents include vitamin B₆、B₁₂And folic acid. The term also includes pharmaceutically acceptable, pharmacologically active derivatives of those active agents specifically mentioned herein, including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs, and the like. When the terms "active agent", "pharmacologically active agent" and "drug" are used, or when an active agent such as an HMG CoA reductase inhibitor or ACE inhibitor is specifically indicated, it is to be understood that applicants intend to includeThe active drug per se and pharmaceutically acceptable, pharmacologically activePharmaceutically active salts, esters, amides, prodrugs, active metabolites, analogs, and the like.

The terms "cholesterol-lowering agent" and "cholesterol-lowering drug" as used herein refer to a pharmacologically active, pharmaceutically acceptable drug that, when administered to a patient suffering from hypercholesterolemia, has the beneficial effect of modulating serum cholesterol levels. More specifically, cholesterol-lowering drugs lower low-density lipoprotein (LDL) cholesterol levels or inhibit oxidation of LDL cholesterol, however, high-density lipoprotein (HDL) serum cholesterol levels may be lowered, remain the same, or be elevated. Preferably, the cholesterol-lowering agent brings serum LDL and HDL cholesterol (more preferably triglyceride levels) to normal or near normal levels.

The term "inhibitor of the renin-angiotensin system" as used herein refers to a pharmacologically active, pharmaceutically acceptable drug which directly or indirectly inhibits the adverse effects of angiotensin, particularly angiotensin II. Including but not limited to: inhibiting the synthesis of angiotensin II, inhibiting the binding of angiotensin II to AT₁On the receptor; or inhibiting renin activity.

"pharmaceutically acceptable", such as by reciting a "pharmaceutically acceptable carrier" or a "pharmaceutically acceptable acid addition salt", herein refers to a material that is not biologically or otherwise undesirable, e.g., the material may be included in a pharmaceutical composition for administration to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other ingredients included in the composition. "pharmacologically active" (or simply "active"), as in a "pharmacologically active" derivative or metabolite, refers to a derivative or metabolite that has the same type of pharmacological activity as the parent compound, and is approximately of equal degree. When the term "pharmaceutically acceptable" is used to refer to derivatives (e.g., salts) of an active agent, it is understood that the compound is also pharmacologically active, i.e., it is therapeutically effective for reducing high cardiovascular risk.

As used herein, "carrier" or "excipient" refers to a conventional pharmaceutically acceptable carrier material suitable for pharmaceutical administration, and includes any material known in the art that is non-toxic and does not interact in a deleterious manner with other components of the pharmaceutical composition or with the drug delivery system.

The term "controlled release" refers to any formulation comprising a drug, the release of which is not immediate; for example, with "controlled release" formulations, oral administration does not result in immediate release of the drug into the absorption pool. The term may be used interchangeably with "non-immediate release" as defined in Remington: the Science and Practice of Pharmacy, eds (Easton, PA: Mack publishing Co., 1995). As discussed therein, immediate and non-immediate release may be defined dynamically by reference to the following equation:

"sink" means a drug solution applied at a specific absorption site, k_r、k_aAnd k_eAre first order rate constantswhich represent (1) release of the drug from the formulation, (2) absorption (3) elimination, respectively. For immediate release dosage forms, the drug release rate constant k_rMuch greater than the absorption constant k_a. For a controlled release formulation, i.e., a formulation of the present invention, the reverse is true, i.e., k_r＜＜k_aThus, the rate of drug release from the dosage form is the rate limiting step in the delivery of the drug to the target area. The term "controlled release" as used herein is intended to include any non-immediate release formulation, including but not limited to sustained release, delayed release, and pulsed release formulations.

The term "sustained release" is used in its conventional sense to refer to a pharmaceutical formulation that releases drug continuously over an extended period of time, preferably, but not necessarily, to produce a substantially constant blood level of drug over a period of time.

The term "delayed release" is used in its conventional sense to refer to a pharmaceutical formulation that has a time delay between the oral pharmaceutical dosage form and its drug release. "delayed release" may or may not include a gradual release of the drug over a period of time, and thus may or may not be "sustained release". Preferred "controlled release" formulations herein are "delayed release" formulations, with particularly preferred "delayed release" formulations being enteric coated compositions.

As used herein, "enteric coating" or "enteric coating" refers to the presence of polymeric materials in the pharmaceutical formulation which increase the resistance of the drug to disintegration in the stomach. Typically, the polymeric material is present as a coating around the drug-containing core, but the polymeric material may also be present in admixture with the drug in the coated formulation.

An "effective" amount or "therapeutically effective amount" of a drug or pharmacologically active agent refers to a nontoxic, but sufficient amount of the drug or agent to provide the desired effect. In the combination therapies of the present invention, an "effective amount" of one of the components of the combination refers to an amount of the compound that is effective to provide the desired effect when used in combination with the other components. The "effective" amount will vary from subject to subject, depending on age and general condition of the individual, the particular active agent, and the like. Therefore, it is not always possible to specify an exact "effective amount". However, an appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.

The term "treatment" as used herein refers to a reduction in the severity and/or frequency of symptoms, elimination of symptoms and/or causes of symptoms, the occurrence of symptoms and/or prevention of their causes of symptoms, amelioration or correction of damage. Thus, for example, "treating" a patient includes preventing a particular condition or adverse physiological event in a susceptible individual, as well as treating an individual with clinical symptoms.

The term "high cardiovascular risk" as used herein refers to an increased risk of developing a cardiovascular event, peripheral vascular disease, coronary heart disease, restenosis, or atherosclerosis in an individual, such risk resulting from a condition, disease, genetic factors, behavior, diet, or other environmental or factors. Environments or factors that contribute to high cardiovascular risk include, but are not limited to: systemic lupus erythematosus, current or previous smoking, diabetes, hemodialysis, receiving organ transplantation, overt coronary artery disease, history of myocardial infarction, history of transient ischemic attacks or strokes, history of peripheral vascular disease, angina, hypertension, hypercholesterolemia, obesity, atherosclerosis, kidney disease, chlamydial infection, Bartonella infection, and obstructive pulmonary disease.

The term "cardiovascular event" as used herein refers to a condition or disease in which the cardiovascular system suddenly develops; it also refers to the sudden worsening of such a condition or disease. Examples of cardiovascular events include, but are not limited to: cardiac arrest, myocardial infarction, ischemia, stroke, worsening of angina pectoris, congestive heart failure.

Active drug:

A. medicine for lowering cholesterol

The present invention employs any effective cholesterol-lowering agent or combination of such agents. Preferred cholesterol lowering agents are HMG CoA reductase inhibitors, bile acid sequestrants, probucol and phenoxy acid (fibric acid) agents. Particularly preferred are HMG CoA reductase inhibitors, especially atorvastatin, cerivistatin, fluindostatin, fluvastatin, lovastatin, mevastatin, pravastatin, simvastatin, and velostatin; the most preferred drugs are lovastatin and pravastatin, particularly pravastatin. Cholesterol-lowering agents are well known in the art and are discussed and reviewed in numerous publications; a useful review is provided by Witztum.J.L., "drugs for use in the treatment of hyperlipidemia", Hardman, J.G., Gilman, A.G., and Limbird, eds. L.E., the pharmacological Basis of Therapeutics, 9 th edition, page 875-897 by Goodman and Gilman (New York: McGraw-Hill, 1996). A brief description of some classes of cholesterol-lowering drugs may be applied below to the present invention.

HMG CoA reductase inhibitors: members of this class of compounds inhibit 3-hydroxy-3-methylglutaryl coenzyme a (hmg coa) reductase. This enzyme catalyzes the conversion of HMGCoA to mevalonate, which is an early and rate-limiting step in cholesterol biosynthesis. Examples of HMG CoA reductase inhibitors that may be used include, but are not limited to, lovastatin (see U.S. Pat. No. 4,231,938), simvastatin (see U.S. Pat. No. 4,444,784), pravastatin (see U.S. Pat. No. 4,346,227), fluvastatin (see U.S. Pat. No. 5,354,772), atorvastatin (see U.S. Pat. No. 5,273,995), cerivistatin (also known as rivastatin (see U.S. Pat. No. 5,177,080), mevastatin (see U.S. Pat. No. 3,883,140), fluindostatin (SandozXU-62-320), simvastatin (also known as synvinolin (see U.S. Pat. No. 4,448,784 and U.S. Pat. No. 4,450,171), and the compounds described and related thereto in the cited references. Some other examples of HMG CoA reductase inhibitors that may be used are provided by, but are not limited to, U.S. Pat. No. 6,264,938 of Table 1, and U.S. Pat. No. 5,622,985, columns 3-6. The present invention encompasses all pharmaceutically acceptable HMG CoA reductase inhibitors. Compounds that inhibit the activity of HMG CoA reductase inhibitors can be readily determined by applying assays well known in the art; see, for example, U.S. Pat. No. 4,231,938 to column 6, and International patent publication WO 84/02131, pages 30-33, for analyses described or referenced herein. The term "HMG CoA reductase inhibitor" is intended to include all pharmaceutically acceptable salts, esters, and lactone forms of the compounds that have HMG CoA reductase inhibitory activity, and thus the use of such salts, esters, and lactone forms is also included within the scope of the present invention.

HMG CoA reductase inhibitors are particularly preferred cholesterol-lowering drugs herein because they tend to exhibit fewer undesirable side effects than other cholesterol-lowering drugs, are more desirable in terms of safety and tolerability, do not require titration, and exhibit one or more beneficial effects in addition to cholesterol-lowering, such as a reduction in bone loss.

Bile acid sequestrant: bile acids secreted into the intestine to aid in lipid digestion and absorption are synthesized in the liver from cholesterol. Typically, about 97% of the bile acids are reabsorbed and reused. If large amounts of bile acids are secreted, the liver must convert more cholesterol to bile acids, lowering serum cholesterol levels, especially LDL cholesterol levels. Although cholesterol biosynthesis is up-regulated in this case, the net effect of increased bile acid synthesis in most individuals is to lower cholesterol, especially LDL cholesterol levels in the serum.

Bile acid sequestrants are resins that are poorly absorbed or other substances that bind and sequester bile acids in the intestine. The sequestered bile acids are then excreted from the feces. Any pharmaceutically acceptable bile acid sequestrant may be used in the practice of the invention. Examples of bile acid sequestrants that may be used in the present invention include, but are not limited to, cholecystamine, colesevelam, resin No. 2 for lipid lowering, poly [ methyl- (3-trimethylaminopropyl) imino-trimethylene dihalide], and those disclosed in U.S. patent No. 6,271,264, international patent publication No. WO 95/34585, and european patent specification EP 0622,078.

Probucol: this compound is an effective lipophilic antioxidant that inhibits the oxidation of LDL cholesterol. Since oxidation of LDL cholesterol is an important, and perhaps essential, factor in the development of atherosclerotic lesions, probucol is useful for the prevention or treatment of atherosclerosis. Although probucol is known to lower serum cholesterol levels, the mechanism of action is not well understood. Probucol is often effective in treating patients who are not responsive to other cholesterol-lowering drugs, such as homozygous familial hypercholesterolemia.

Phenoxy acid derivatives: these compounds, also known as "fibrates", lower triglyceride levels, increase High Density Lipoprotein (HDL) levels, and have variable effects on LDL cholesterol levels in the blood. Examples of phenoxy acid derivatives that can be used in the present invention include, but are not limited to, bezafibrate (bezalip)^TM) Benzclofibrate, binifibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate (Lipidil)^TMLipidil Micro^TM) Gemfibrozil (Lopid)^TM) Nicafibrate, pirfibrate, chlorofibrate,Bis-fibrate and neopolyester (theofibrate).

B. Inhibitors of the renin-angiotensin system

The renin-angiotensin system plays a major role in blood pressure regulation. Renin, an enzyme synthesized, preserved and secreted by the kidney, is effective in increasing blood pressure; normally, its secretion increases when blood pressure is low and decreases when blood pressure is high. Renin functions by acting on angiotensinogen to form decapeptide angiotensin I. Angiotensin I is rapidly converted to octapeptide angiotensin II by Angiotensin Converting Enzyme (ACE). Angiotensin II raises blood pressure through a number of mechanisms including increasing total peripheral resistance (partly by constricting the anterior capillary arteriole and to a lesser extent by constricting the posterior capillary venules; by increasing peripheral noradrenergic neurotransmission; and by acting through the central nervous system), decreasing sodium excretion, but increasing renal potassium excretion, and increasing aldosterone secretion by the adrenal cortex (aldosterone acts to retain sodium and excrete potassium and hydrogen ions). Angiotensin II is also thought to contribute to pathological structural changes in the cardiovascular system, including cardiac hypertrophy (excessive tissue mass), cardiac fibrosis (associated with congestive heart failure and myocardial infarction), and increased thickness of the inner surface of the vessel wall (associated with atherosclerosis).

The most well understood and most widely used are ACE inhibitors which inhibit The conversion of angiotensin I to angiotensin II other drugs which target The renin-angiotensin system are angiotensin II receptor antagonists and renin inhibitors which are discussed briefly below, more information is readily available in The published literature (see, for example, Jackson, E.K and Garrison, J.C. in Hardman, J.G., Gilman, A.G., and Limbird, L.E. eds., Goodman and Gilman's clinical Basis of Therapeutics, 9 th edition, review written by page 733 and 754 (New York: McGraw-Hill)), inhibitors which are preferred and in combination with The renin-angiotensin system inhibitors of The present composition should be understood to reduce blood pressure while ACE inhibitors should be beneficial in patients who suffer from blood plasma levels such as systemic lupus erythematosus, a number of systemic lupus erythematosus (TGF- β).

Angiotensin Converting Enzyme (ACE) inhibitors: as mentioned, ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II. Because angiotensin I has only about 1% of its hypertensive activity, ACE inhibitors are generally effective in lowering blood pressure and reducing other cardiovascular adverse effects caused by angiotensin II. ACE has a number of substrates in addition to angiotensin I, including bradykinin. By interfering with the conversion of bradykinin, ACE inhibitors increase the levels of bradykinin; this mechanism contributes to the action of ACE inhibitors.

Also included in the present invention are ACE/NEP inhibitors, which are ACE inhibitors and also have an inhibitory effect on Neutral Endopeptidase (NEP), which degrades atrial natriuretic peptide. Inhibition of NEP is particularly effective in controlling volume-expanding hypertension.

Many ACE inhibitors have been synthesized. Most of these compounds can be classified into 3 classes according to their chemical structures: (1) mercapto-containing ACE inhibitors including captopril and drugs structurally related to captopril such as fentiapril, perindopril, pivopril, zofenopril and alacepril; (2) bivalent carboxy-containing ACE inhibitors including etopril and drugs structurally related to etopril such as lisinopril, benazepril, quinapril, moexipril, ramipril, spirapril, perindopril, indopril, pentopril, indalapril and cilazapril; (3) phosphorus-containing ACE inhibitors, structurally related to fosinopril. Many ACE inhibitors have evolved to esters and thus have a high degree of oral bioavailability, but themselves have a low potency; they must be converted in vivo into specific potent metabolites.

ACE inhibitors are well known in the art and the use of any ACE inhibitor which is pharmaceutically acceptable, including any of those mentioned in the preceding paragraphs, is encompassed by the present invention, including mixtures thereof and/or pharmaceutically acceptable salts thereof. Examples of other ACE inhibitors that may be used in the practice of the present invention include, but are not limited to, AB-103, ancovenin, benazepril, BRL-36378, BW-A575C, CGS139 13928C, CL242817, CV-5975, Equaten, EU-4865, EU-4867, EU-5476, foroxymetrine, FPL66564, FR-900456, Hoe-065, 15B2, indopril, ketomethyluroids, KRI-1177, KRI-1230, L681176, lisinopril, MCD, MDL-27088, MDL-27467A, mevinpril, MS-41, nicotianamine, pentopril, phenacetin, pivalopril, renothiapril, RG-59RG, RG-6134, RG-207, RGH0399, R00-911, RS-85, RS-51403, RS-5127, RS-44839, RU-268308, RU-2683900, RU-2608, RU-4865, EU-486, MDL-5476, MDL-27467, mevinoprine, MDL-4, and MS-4, SQ-28084, SQ-28370, SQ-28940, SQ-31440, synecor, ulinapril, WF-10129, Wy-44221, Wy-44655, Y23785, YIssum, P-0154, zabipril, Asahi Brewer AB-47, alapriopril, BMS 182657, Asahi Chemical C-111, Asahi Chemical C-112, Dainippon DU-1777, mixanpril, prenyl, fenopril, 1(- (1-carboxy-6- (4-piperidinyl)hexyl) amino) -1-oxopropyl octahydro-indole-2-carboxylic acid, Bioproject BP1.137, Chiesi 1514, Fisonons FPL-66564, ilpril, perindopril, Serverier S-5590, alacepril, enalapril, captopril, cilazapril, fosinopril, etofosinopril, etofovir, enalapril, etopril, enalapril, captopril, fosinopril,

Imidapril, lisinopril, perindopril, quinapril, ramipril, salazine acetate, temocapril, trandolapril, trandolaprilat, ceranapril, moexipril, quinaprilat, and spirapril, all of which are listed in U.S. patent No. 6,248,729.

Preferred ACE inhibitors are captopril, cilazapril, delapril, enalapril, fentiapril, fosinopril, indopril, lisinopril, perindopril, pivopril, quinapril, ramipril, spirapril, trandolapril and zofenopril; particularly preferred are captopril, enalapril, fosinopril, lisinopril, quinapril, ramipril and trandolapril; most preferred is enalapril.

Some examples of ACE/NEP inhibitors useful herein include, but are not limited to, those disclosed in U.S. patent No. 5,508,272, U.S. patent No. 5,362,727, U.S. patent No. 5,366,973, U.S. patent No. 5,225,401, U.S. patent No. 4,722,810, U.S. patent No. 5,223,516, U.S. patent No. 5,552,397, U.S. patent No. 4,749,688, U.S. patent No. 5,504,080, U.S. patent No. 5,612,359, and U.S. patent No. 5,525,723, and european patent applications 0481,522,0534363a2,534,396 and 534,492. Preferred are those designated ACE/NEP inhibitors, as preferred in the above us patents. Particularly preferred are the ACE/NEP inhibitors omapatrilat (disclosed in U.S. Pat. No. 5,508,272) and MDL100240 (disclosed in U.S. Pat. No. 5,430,145).

Angiotensin II receptor antagonists (also known as angiotensin II antagonists): binding of angiotensin II to angiotensin subtype 1 (AT)₁) And subtype 2 (AT)₂) Receptors, as well as some other receptors. All known physiological effects of angiotensin II apparently bind to it and activate AT₁The receptor is involved and is abundantly expressed in tissues affected by angiotensin II. AT₂Receptors are common in some fetal tissues, but rare in adult tissues; until now, its known function has not been discovered. A number of orally active, non-peptide angiotensin II receptor antagonists have been invented. Most of these are aimed AT ATs₁Of receptors, but due to considerations of AT₂Unbalanced activation of receptors, with some newer angiotensin II receptor antagonists targeting AT simultaneously₁And AT₂A receptor. Angiotensin II receptor antagonists are generally highly specific and have little effect on other hormone receptors or ion channels.

Any AT₁Orally active antagonists of the angiotensin II receptor may be used in the present invention. Some examples of angiotensin II receptor antagonists suitable for use herein are saratin (including saratin acetate), candesartan (including candesartan cilexetil), CGP-63170, EMD-66397, KT3-671, LRB/081, valsartan, A-81282, BIBR-363, BIBS-222, BMS-184698, CV11194, EXP-3174, KW-3433, L-161177, L-162154, LR-B/057, LY-235656, PD150304, U-96849, U-97018, UP-275-22. WAY-126227, WK-1492.2K, YM-31472, losartan (including losartan potassium), E-4177, EMD-73495, eprosartan, HN-65021, irbesartan, L-159282, ME-3221, SL-91.0102, tasosartan, telmisartan, UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234, L-162441, L-163007, PD-123177, A81988, BMS-180560, CGP-38560A, CGP-48369, DA-9, DE-3489, DuP-167, EXP-063, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, HR-720, ICI D6888, ICI-D KRne 8731, isoteoline-1177, L-809, L-15825, L-158978, L-5929, and F-D-9, L-159874, LR B087, LY-285434, LY-302289, LY-315995, RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, saprostartan, Salrisartan, Sal B-Sa,sarmesin, WK-1360, X-6803, ZD-6888, ZD-7155, ZD-8731, BIBS39, CI-996, DMP-811, DuP-532, EXP-929, L163017, LY-301875, XH-148, XR-510, zolasartan and PD-123319.

Preferred angiotensin II receptor antagonists include losartan (which is the prototype, and the best known angiotensin II receptor antagonist), irbesartan, eprosartan, candesartan, valsartan, telmisartan, zolasartan, tasosartan. Losartan is particularly preferred.

Renin inhibitors: compounds that inhibit renin activity include: renin antibodies, renin forepart analogs, pepstatin analogs; and the renin substrate angiotensinogen analogue. Since most of these compounds are peptides, they generally have a low oral bioavailability. Non-peptide renin inhibitors are of most interest in the present invention. Preferred renin inhibitors are remikiren (Ro 42-5892), A-72517 and A-74273, with remikiren being most preferred.

C. Aspirin

Aspirin (acetylsalicylic acid), when administered daily at low doses over a long period to patients at risk of cardiovascular events, is very well able to prevent myocardial infarction and stroke due to thrombosis. At least 25% of secondary heart attacks, strokes and cardiovascular deaths can be reduced by daily administration of low doses (approximately 80mg) of aspirin.

Cardiovascular protective activity of aspirinThere appear to be many mechanisms, but in this regard, its antithrombotic, antiplatelet aggregation activity may be of great interest. Aspirin irreversibly acetylates the cyclooxygenase enzyme, rendering it non-functional. Cyclooxygenase is essential for the synthesis of prostanoids (among other compounds), many of them being pro-inflammatory; thrombi A₂It is synthesized by platelets to increase platelet aggregation, eventually forming a thrombus (blood clot); prostacyclin, which has anti-platelet aggregation properties. Cyclooxygenase is synthesized in endothelial cells and not in platelets. Low doses of aspirin neutralize cyclooxygenase selectively in platelets, allowing the sustained synthesis ofcyclooxygenase and prostacyclin in endothelial cells. The net effect is to reduce inflammation and platelet aggregation, thereby reducing thrombus formation in the blood vessel.

Although aspirin is the most preferred aspirin for use in the present invention, other salicylates, including magnesium salicylate, and other anti-platelet aggregation drugs, such as anagrelide, dipyridamole, clopidogrel, and ticlopidine, may also be used herein. Other cyclooxygenase inhibitors, including other non-steroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, sulindac sulfone, flurbipolol, indomethacin, methoprim, meclofenamic acid, and piroxicam may also be used in the present invention.

D. Vitamin B compounds

High serum levels of homocysteine, an amino acid not found in proteins, are highly correlated with atherosclerosis, heart disease, stroke, and peripheral vascular disease. Many studies have shown that oral vitamin B supplementation₆(also known as pyridoxine), vitamin B₁₂(also known as cyanocobalamin) and folic acid (or folate) can be reducedHomocysteine levels and reduces the incidence of atherosclerosis, myocardial infarction and stroke. Folic acid or folate appears to be particularly effective in this regard. Recent investigations have found that approximately 88% of americans ingest less than 400 μ g per day of folic acid, which is recommended to maintain normal homocysteine levels. In the practice of the present invention, folinic acid or folate may be substituted for folic acidFolic acid is preferred, though it is used. Folate salts that can be used include 5-methyltetrahydrofolate (5MeTHF), Tetrahydrofolate (THF), and 5-formyltetrahydrofolate (5 CHOTHF).

E. Derivatives of the same

Any active agent may be used in the form of salts, esters, amides, prodrugs, active metabolites, analogs, and the like, so long as the salt, ester, amide, prodrug, active metabolite, analog is pharmaceutically acceptable and pharmacologically active in the environment in which it is present. Salts, esters, amides, prodrugs, active metabolites, analogs and other active drug derivatives may be formulated using standard procedures known to those skilled in the art of synthetic organic chemistry, as described, for example, in j. Reactions, mechanisms and structures, 4 th edition (New York: Wiley-Interscience, 1992).

For example, acid addition salts are formulated from the free base form of the drug using conventional methods, including the reaction of the free base with the acid. Suitable acids for formulating acid addition salts include organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like; inorganic acid: such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Acid addition salts can be reconverted to the free base by treatment with a suitable base. Conversely, the formulation of base salts of acid moieties which may be present in the active drug may be carried out in the same analogous manner using pharmaceutically acceptable bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine and the like. The preparation of esters involves the conversion of carboxylic acid groups, including RO, by conventional esterification reactions^-Nucleophilic attack of a moiety on the carbonyl carbon. Esterification can also occur by reacting a hydroxyl group with an esterifying reagent, such as an acid chloride. The ester can be reconverted to the free acid, if desired, by applying conventional hydrogenolysis or hydrolysis steps. Amides maybe prepared from esters or they may be prepared from anhydrides or acid chlorides by reaction with ammonia or a lower alkylamine using a suitable amine reactant. Prodrugs and ActivityThe metabolites may also be formulated using techniques known to those skilled in the art or described in the relevant literature. Prodrugs are typically formulated by covalently attaching moieties that yield a moiety of the compound that is therapeutically inactive and only therapeutically active through modification of the individual's metabolic system.

Other derivatives and analogues of the active agents may be formulated using standard techniques known to those skilled in the art of synthetic organic chemistry or may be deduced by reference to the relevant literature. Furthermore, the chiral active agents may be in isomerically pure form, or they may be administered as a racemic mixture of isomers.

Pharmaceutical compositions and dosage forms

When two or more active agents are combined in a single pharmaceutical dosage form, consideration must be given to the interactions that may occur between the active agents, between the active agents and the excipients. This is well within the skill of the technician in the pharmaceutical formulation parking. For example, aspirin is acidic and may react with basic compounds or basic esters, resulting in hydrolysis of the aspirin and/or degradation of other compounds. Aspirin, for example, can react with acid labile compounds, such as pravastatin, to degrade them. The compositions of the present invention thus include pharmaceutical compositions in which two or more active agents are separated from each other in a pharmaceutical dosage form, such as separate flat layers of tablets (e.g., bi-or tri-layer tablets), concentric layers, coated beads or granules (which may be incorporated into compressed tablets or capsules), and/or compounds that may interact with each other by the application of a buffer (see, e.g., U.S. patent No. 6,235,311). Those skilled in the art will also recognize dosage forms in which two or more active agents are physically separated from one another and may be manufactured so that different active agents have different release profiles, for example if one active agent is formulated with an enteric coating, another active agent is formulated with a sustained release matrix, and so forth. Alternatively, non-reactive pharmaceutically active derivatives of one or more potentially interacting compounds may be used, for example, neutral salicylate instead of aspirin.

The present invention provides pharmaceutical dosage forms comprising two or more multiple dosage units which are physically separated from each other, wherein different dosage units may have different release profiles. For example, one or more dosage units may provide immediate release of the active agent (e.g., within about one hour of oral ingestion), one or more dosage units may provide sustained release of the active agent (e.g., wherein the active agent is gradually released over a long period of time), one or more dosage units may provide delayed release of the active agent, wherein the release may or may not be sustained after an initial "delay". Drug release may be "pulsed" in which two or more drug doses are released at separate time intervals.

In one embodiment, the dosage form is a closed, preferably sealed, capsule containing dosage units containing at least two drugs, wherein each dosage unit within the capsule provides or does not provide a different drug release profile. Control of the delayed release dosage unit is achieved by a controlled release polymer coating on the dosage unit or by incorporating the active agent into a controlled release polymer matrix. Each dosage unit may comprise a compressed or molded tablet, wherein each tablet in the capsule provides a different drug release profile. Alternatively, each dosage unit in the capsule may comprise a plurality of beads, granules or microparticles containing the drug. As is known in the art, a "bead" comprising a drug is a bead made with the drug and one or more excipients or polymers. Drug-containing beads can be made by administering the drug to an inert support, such as an inert sugar bead coated with the drug, or by making a "core" that contains both the drug and one or more excipients. Also known as "particles" or "microparticles" containing a drug comprise drug microparticles, which may or may not include one or more additional excipients or polymers. In contrast to drug-containing beads, particles and microparticles do not contain inert support carriers. The granules typically contain drug microparticles and require further processing. Generally, the microparticles are smaller than the granules and are not further processed. While beads, granules and microparticles may be formulated to provide immediate release, beads and granules are typically used to provide delayed release.

In another embodiment, individual dosage units are compressed into a single tablet, which may represent complete but discrete portions (e.g., layers) or may be present as a mixture. Layered tablets, each layer containing a different active agent and/or providing a different release profile, offer a variety of manufacturing advantages. Such tablets may be made by a single step compression, thus eliminating the process operations necessary to formulate coated core dosage forms. Layered tablets also eliminate the attendant steps in processing, as well as the quality control of making two or more different tablets. Furthermore, layers containing only excipients may be interposed between layers containing active agents to prevent possible interactions between the active agents. For tablets containing different dosage units in admixture, drug-containing beads, granules or microparticles having different release profiles (e.g.,immediate and delayed release profiles), and/or beads, granules or microparticles containing different active agents may be compressed together into a single tablet using conventional tableting equipment. In a mixture, there is a random possibility that different active drugs come into contact with each other. However, the protective and/or delayed release coating provided on the particles or other dosage units provides a physical barrier, thus minimizing direct physical contact between the active agents.

In another embodiment, a dosage form of the present invention comprises a coated core-type delivery system wherein the outer layer comprises one active agent, the one or more intermediate layers optionally each comprise one or more additional active agents, and the inner core comprises another active agent, or comprises an inert material. Each layer and/or core also provides a different release profile.

As will be appreciated by those skilled in the art and described in the relevant articles and literature, tablets, beads, granules or microparticles containing a drug can be formulated using a number of methods which provide different modes of drug release. Such methods include, but are not limited to, the following: the drug or drug-containing composition is coated with a suitable coating material, typically although not necessarily a polymeric material; increasing the size of the drug particles; placing the drug in a matrix; the drug complexes are formed with a suitable complexing agent.

Delayed release dosage units and enteric coatings: solid dosage forms, whether tablets or capsules, caplets or microparticles, may be coated to provide delayed release if desired. Dosage forms having a delayed release coating may be manufactured using standard coating procedures and equipment. Such steps are known to those skilled in the art and are disclosed in related articles, such as Remington, supra. Typically, after the solid dosage form is formulated, the delayed release coating composition is applied using a pan coater, airless spray techniques, fluidized bed coating equipment, and the like. The delayed release coating composition comprises a polymeric material such as cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate, dihydroxypropoxy methyl cellulose succinate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, polymers and copolymers formed from acrylic acid, methacrylic acid and/or their esters.

The delayed release dosage unit of any of the embodiments of the present invention may be formulated, for example, by coating the drug or drug-containing composition with a selected coating material. The drug-containing composition may be, for example, a tablet for filling into a capsule, a tablet for use as a core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules for inclusion into a tablet or capsule. Preferred coating materials are composed of bioerodible gradually hydrolysable, gradually water soluble, and/or enzymatically degradable polymers, and preferred delayed release coatings include enteric coating materials.

Enteric coating compositions generally comprise a polymeric material which, upon oral administration of the dosage form to a patient, prevents release of the active agent until it reaches the patient's small intestine. Typically this requires a polymeric material-such as an enteric polymer-to prevent release of the drug in the acidic environment of the stomach, but to dissolve sufficiently in the small intestine to gradually release the active drug therein. The enteric coating material, therefore, should not dissolve in gastrointestinal fluids at pH values below about 4 or5, but should ionize and dissolve at pH values of about 5 or above. Thus, the most effective enteric coating material is a polymeric acid having a pKa in the range of 3 to 5, however, it is contemplated that any material exhibiting the aforementioned pH-dependent solubility characteristics may be employed in the practice of the present invention as an enteric coating to deliver the active agent to the intestinal portion of the gastrointestinal tract. The selection of a particular enteric coating material will depend on the following properties: resistance to dissolution and disintegration in the stomach; impermeability to gastric juice and drugs/carriers/enzymes in the stomach; ability to rapidly dissolve or disintegrate at a target intestinal site; physical and chemical stability upon storage; no toxicity; ease of application as a coating; and economical utility.

Enteric coatings also prevent exposure of the active agent to epithelial and mucosal tissues of the mouth, pharynx, esophagus and stomach, and enzymes associated with these tissues. The enteric coating thus helps protect the active agent and the patient's internal tissues from adverse reactions until the drug is released at the desired site of delivery.

The "amount of coating", or the amount of relative coating material per dosage unit, generally dictates the time interval between ingestion and drug release. The preferred coating weight for a particular coating material can be readily determined by those skilled in the art by evaluating the respective release profiles of tablets, beads and granules formulated with different amounts of the various coating materials. However, generally a suitable coating weight is about 5 wt.% to 50 wt.%.

Suitable enteric coating polymers include, but are not limited to, polymeric gelatin, cellulose butyrate phthalate, cellulose phthalate hydrogen, cellulose propionate phthalate, polyvinyl acetatephthalate (PVAP), Cellulose Acetate Phthalate (CAP), Cellulose Acetate Trimellitate (CAT), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dihydroxypropyl methylcellulose succinate, carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), shellac, zein, and acrylic polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, and/or other vinyl monomers. Preferred panning polymers are acrylic acid, methacrylic acid polymers and copolymers, especially those commercially available under the trade names Eudragit L and Eudragit S, wherein the ratio of free carboxyl groups to ester groups is approximately 1: 1 and 1: 2 respectively, and wherein each copolymer has a (weight average) molecular weight of approximately 135,000 Da.

The coating may and typically does contain plasticizers to prevent the formation of pores and crevices which may lead to the ingress of gastric juices. Suitable plasticizers include, but are not limited to, triethyl citrate (Citroflex 2), triacetin (triacetin), acetyl triethyl citrate (Citroflec a2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. The coating may also contain other coating excipients such as anti-sticking agents, anti-foaming agents, lubricants (e.g., magnesium stearate) and stabilizers (e.g., hydroxypropyl cellulose, acids and bases) which are used to solubilize or disperse the coating material and improve the properties of the coating and the coating product.

Enteric coated dosage forms, whether enteric coated tablets, tablet portions, capsules, granules or beads, can be manufactured using standard enteric coating procedures and equipment. For example, the enteric coating may be applied to the tablets, tablet portions, beads,granules, caplets, or capsules using a coating pan, airless spray technique, fluidized bed coating equipment, and the like. Details regarding the materials, equipment and procedures for formulating coating formulations can be found in Pharmaceutical DosageForms: tablets et al, Lieberman et al (New York: Maccel Dekker, 1989), and Ansel et al, Pharmaceutical document Forms and Drug Delivery System, 6 th edition (Media, PA: Williams&Wilkins, 1995). The thickness of the coating, as mentioned above, must be sufficient to ensure that the oral dosage form remains intact until the desired delivery site in the intestinal tract is reached.

Alternatively, delayed release dosage units may be formulated by dispersing the active agent in a matrix of a suitable material, such as an enteric coating material or other delayed release polymeric material. Hydrophilic polymers and certain fatty compounds are particularly useful for providing a delayed release matrix. Such hydrophilic polymers are composed of polymers or polymers of cellulose, cellulose esters, acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate and vinyl, and enzymatically degradable polymers or copolymers as described above. Fatty compounds useful as matrix materials include, but are not limited to, waxes (e.g., carnauba wax) and triglycerides of stearic acid. Once the active ingredient and matrix material are mixed, the mixture can be compressed into a tablet.

Immediate release dosage unit: the dosage form of the present invention delivers dosage units-e.g., tablets in capsules; a plurality of drug-containing beads, granules or microparticles; one layer of a multilayer tablet; or a layer or core of a coated core dosage form-comprising a therapeutically effective amount of a particular active agent or mixture of active agents, with conventional pharmaceutical excipients. The immediate release dosage unit may or may not be coated with a protective garment. Onepreferred method of formulating an immediate release tablet, e.g. for inclusion in a capsule, is by compression of a drug-containing mixture, e.g. a granulate mixture, using direct mixing, a wet granulation process or a dry granulation process. Immediate release tablets may be molded rather than compressed, starting from a wet material containing a suitable water-soluble lubricant. However, preferred tablets herein are manufactured using compression rather than molding. A preferred method of forming an immediate release drug-containing mixture is to mix the drug microparticles directly with one or more excipients, such as diluents (or fillers), binders, disintegrants, lubricants, glidants, colorants and the like. Beads containing the active agent in immediate release form may also be formulated by any of a number of conventional techniques, typically starting with liquid dispersion. For example, typical methods of formulating drug-containing beads include mixing the active drug with conventional pharmaceutical excipients, such as microcrystalline cellulose, starch, polyvinylpyrrolidone, methylcellulose, talc, metal stearates, silicon dioxide, and the like. The mixture is used to coat bead cores, for example sugar spheres (or so-called "non-pareil") of a size of approximately 20-60 mesh.

Another step in formulating the drug beads is by mixing the drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinylpyrrolidone, talc, magnesium stearate, disintegrants, and the like, extruding the mixture, spheronizing the extrudate, drying and optionally coating to form immediate release beads.

Sustained release dosage forms and dosage units: sustained release formulations provide for prolonged drug release, which may or may not be delayed release. In general, those of ordinary skill in the art recognize that sustained release dosage units are formulated by dispersing the drug into a matrixof gradually bioerodible (hydrolyzable) material, such as an insoluble plastic, hydrophilic polymer or fatty compound, or by coating a solid dosage form containing the drug with such a material. The insoluble plastic matrix is composed of, for example, polyvinyl chloride or polyethylene.

Hydrophilic polymers useful for providing a sustained release coating or matrix of cellulosic polymers include, but are not limited to: cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl cellulose phthalate, cellulose hexahydrophthalate, cellulose acetate hexahydrophthalate and sodium carboxymethyl cellulose; acrylic polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, alkyl acrylates, alkyl methacrylates and the like, such as copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, especially those commercially available under the trade name Eudragit L, and terpolymers of ethyl acrylate, methyl methacrylate and trimethylaminoethylmethacrylic acid chloride (sold under the trade name Eudragit RS) represent preferred examples; vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate phthalate, vinyl acetate crotonic acid copolymer, vinyl-vinyl acetate copolymer, and polyvinyl acetate/polyvinylpyrrolidone mixtures; carbomers, such as hydroxylated ethylene polymers, are referred to as "interpolymers," which are formulated by crosslinking a monoalkenoic acid monomer and a polyalkyl ether of sucrose (available under the trade name Carbopol (r) from b.f. goodrich chemical company); zein and shellac, ammoniated shellac, shellac-acetyl alcohol and shellac n-butyl stearate.

Fatty compounds useful as sustained release matrix materials or sustainedrelease coating materials include, but are not limited to, conventional waxes (e.g., carnauba wax), triglycerides of stearic acid, and hydrogenated oils such as hydrogenated vegetable oils, cottonseed oils, castor oils, rapeseed oils, palm kernel oils, and soybean oils.

Protective coating: any of the dosage forms of the present invention, as well as the dosage units contained therein, may be coated with a protective coating. If a delayed release or sustained release coating is also applied, a protective coating is applied over it. Suitable protective coating materials are known to those of ordinary skill in the art and are described in related articles, such as Remington's, supra. However, typically the protective coating is comprised of a material that acts as a blocking agent surrounding the single dose units, physically separating the different active agents from each other in the dosage form. Suitable coating materials for the sealant typically include resinous materials such as shellac, zein, cellulose acetate phthalate, polyvinyl acetate phthalate or shellac-polyvinyl pyrrolidone combinations. A sealant coating may be applied to the outer surface of an entire dosage form to strengthen the tablet or capsule and improve product stability.

Preparation of the dosage form: the tablets may be manufactured using standard tablet processing procedures and equipment. One method of forming tablets is by direct compression of a powdered, crystalline or granular composition containing the active agent, alone or in combination with one or more carriers, additives and the like. Alternatively to direct compression, tablets may be formulated using a wet-granulation or dry-granulation process. Tablets may also be molded rather than compressed, starting from wet or other easily handled materials; however, compression and granulation techniques are preferred.

In addition to the active drug, tablets for oral administration formulated using the methods of the present invention typically comprise other materials, such as binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, colorants, and the like. The binder gives the tablet its cohesive properties, thus ensuring that the tablet remains intact after compression. Suitable binding materials include, but are not limited to, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, and lactose), polyethylene glycols, waxes, and natural and synthetic gums, such as acacia, sodium alginate, polyvinyl pyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, and the like), and Veegum. The diluent is typically necessary to increase the volume to ultimately provide a full size tablet. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. The use of lubricants to facilitate the manufacture of tablets; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, and stearic acid. Stearate, if present, preferably represents no more than about 2 wt.% of the drug-containing core. Disintegrants are used to facilitate disintegration of the tablet and are typically starches, clays, celluloses, algins, gums or cross-linked polymers. Fillers include materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. Stabilizers are used to inhibit or delay drug degradation reactions, including oxidation reactions as examples. The surfactant may be an anionic, cationic, amphoteric or non-ionic surfactant.

The dosage form may also be a capsule, wherein the composition comprising the activeagent may be in liquid or solid form (including microparticles, such as granules, beads, powder or pellets). Suitable capsules may be hard or soft and are typically made of gelatin, starch or cellulosic materials, gelatin capsules being preferred. The two-piece hard gelatin capsule is preferably sealed, for example with gelatin tape or the like. See, e.g., Remington: the Science and Practice of pharmacy, supra, describes materials and methods for formulating encapsulated pharmaceuticals. If the active composition containing the drug is present in liquid form within the capsule, a liquid carrier is required to solubilize the active drug. The carrier must be compatible with the capsule and all ingredients of the pharmaceutical composition, and must be suitable for ingestion.

In one embodiment, the cholesterol-lowering agent, the inhibitor of the renin-angiotensin system, and the aspirin are all individually contained in separate layers of a multi-layer tablet (the tablet designated herein as "tablet ML 1"). Tablet ML1 may further comprise a layer of excipient, preferably microcrystalline cellulose, between the layers comprising aspirin and the other active agent. In addition, tablet ML1 may include vitamin B₆Vitamin B₁₂And at least one of folic acid. Preferably, a single layer comprises vitamin B₆Vitamin B₁₂And mixtures of folic acid. In a particularly preferred embodiment, the cholesterol-lowering agent, the inhibitor of the renin-angiotensin system and aspirin are each incorporated into respective layers of a multi-layered tablet which is a unit dose adapted for once-daily administration, and further wherein the cholesterol-lowering agent, the inhibitor of the renin-angiotensin system are each in a controlled release dosage unit (e.g., a sustained release and/or delayed release dosage unit) and the aspirin is in an immediate release dosage unit (the tablet designated herein as "tablet ML 2"). In a particularly preferred embodiment, tablet ML2 further comprises a layer comprising vitamin B₆Vitamin B₁₂And folic acid (the tablet is designated herein as "tablet ML 3"). In a highly preferred embodiment, tablet ML3 comprises 80mg of lovageTatin as cholesterol-lowering agent, 40mg of etoposil as inhibitor of renin-angiotensin system, 81mg of aspirin, 50mg of vitamin B₆1mg of vitamin B₁₂And 3mg folic acid.

In another embodiment, wherein the dosage form of the present invention comprises a tablet comprising active agent-containing beads mixed in a matrix, at least one active agent is formulated in the beads and at least one other active agent is formulated in the tablet matrix surrounding the beads. The beads may be uncoated, coated with a protective layer, enteric coated, coated or formulated for sustained release, coated or formulated for delayed release. The matrix may be formulated for immediate release, delayed release or sustained release. In a preferred embodiment, the cholesterol-lowering drug and the inhibitor of the renin-angiotensin system are each separately formulated into a plurality of beads formulated for sustained release, whereas the aspirin is contained in a matrix formulated for immediate release (the tablet designated herein as "tablet B1"). In a particularly preferred embodiment, tablet B1 further comprises a binder in the matrixVitamin B in a mixture of serpentin₆Vitamin B₁₂And folic acid, and each active drug is present in a unit dose suitable for once daily (the tablet is designated herein as "tablet B2"). In a highly preferred embodiment, tablet B2 contains 80mg of lovastatin as the cholesterol-lowering agent, 40mg of etoposide as the inhibitor of the renin-angiotensin system, 81mg of aspirin, 50mg of vitamin B₆1mg of vitamin B₁₂And 3mg folic acid.

In other embodiments, where the dosage form of the present invention comprises a mixed immediate release tablet or capsule, all of the active agents are mixed together as one dosage unit in one immediate release dosage form, being a tablet or capsule. In such embodiments, care is taken to ensure stability and compatibility of the active agent; when required, suitable buffers and other excipients are employed to help ensure the stability and compatibility. In a preferred embodiment, the tablet or capsule contains 80mg of lovageTatin as cholesterol-lowering agent, 40mg of etoposil as inhibitor of renin-angiotensin system, 81mg of aspirin, 50mg of vitamin B₆1mg of vitamin B₁₂And 3mg folic acid. In a particularly preferred embodiment, each of the 6 active agents is individually formulated into a plurality of beads or granules coated with a protective coating that prevents or inhibits chemical interaction between the active agents.

In other embodiments, wherein the dosage form of the present invention comprises coated beads or granules in a tablet or capsule, each active agent is separately formulated into a plurality of beads or granules coated with a protective coating that prevents or inhibits chemical interaction between the active agents and optionally maintains or delays release of the active agents. In a preferred embodiment, the cholesterol-lowering agent and the inhibitor of the renin-angiotensin system are each formulated into coated sustained release beads or granules, or are otherwise formulated, while the aspirin is formulated into coated or otherwise formulated immediate release beads or granules (the tablet or capsule being designated herein as "tablet or capsule CBG 1"). In a particularly preferred embodiment, the tablet or capsule CBG1 further comprises vitamin B₆Vitamin B₁₂And folic acid, each of which is formulated into immediate release beads or granules, and each active drug is present in a unit dose suitable for once daily (the tablet or capsule being designated herein as "tablet or capsule CBG 2"). In a highly preferred embodiment, the tablet or capsule CBG2 contains 80mg lovastatin as the cholesterol-lowering agent, 40mg of etoposide as the inhibitor of the renin-angiotensin system, 81mg of aspirin, 50mg of vitamin B₆1mg of vitamin B₁₂And 3mg folic acid.

In a related embodiment, the capsule, preferably a hard gelatin capsule, is preferably sealed and contains compressed or shaped tablets, beads or granules therein, plus a pharmaceutically acceptable carrier. Each active agent is individually formulated into a plurality of tablets, beads or granules. The tablets, beads or granules may be coated and/or used for immediate release, delayed release or sustained releaseAnd (4) other methods for preparation. The capsule may comprise a mixture of tablets, beads or granules; further, the capsule may comprise a mixture of the dosage units in coated and uncoated form. One preferred dosage form is a hard, sealed, hard gelatin capsule comprising a bile-lowering capsule formulated into a tabletSterol drugs and inhibitors of the renin-angiotensin system, sustained release tablets in bulk, beads or granules in bulk, plus aspirin, vitamin B₆Vitamin B₁₂And folic acid, each formulated into an immediate release mass of tablets, a mass of beads, or a mass of granules.

Effect and administration

The methods and compositions of the present invention are directed to those individuals at high cardiovascular risk, wherein cardiovascular risk includes underlying cardiac arrest, acute or chronic myocardial infarction, coronary heart disease, ischemia, stroke, peripheral vascular disease, claudication, worsening angina, restenosis, and/or atherosclerosis. Individuals with high cardiovascular risk include those with systemic lupus erythematosus, diabetes, angina, overt coronary artery disease, hypertension, hypercholesterolemia, kidney disease, chlamydial infection, Bartonella infection, obstructive pulmonary disease, hemodialysis, a history of organ transplantation, obesity, geriatric, familial cardiac disease, atherosclerosis, stroke, smoking, or a history of myocardial infarction, transient ischemic attacks, stroke, atherosclerosis, or peripheral vascular disease. The pharmaceutical compositions of the present invention may also be administered to a patient suffering from acute Myocardial Infarction (MI) at or shortly after MI. The compositions of the present invention, when administered in this manner, are particularly effective in increasing survival in patients suffering from acute myocardial infarction.

Many individuals at high cardiovascular risk are not treated for this condition, often due to a lack of effective, safe and convenient treatment. For example, women with systemic lupus erythematosus are at high risk of myocardial infarction and stroke, possibly due to an increased propensity for early atherosclerosis, but few treatments are available to reduce this risk. Since this treatment is very long lasting for individuals with high cardiovascular risk, perhaps for the lifetime of the patient, it should be simple and convenient for the patient. When the drug is administered orally once a day, preferably before going to bed, it is found that patients are amenable to long-term treatment in a high proportion. Said invention provides that the combination of the cholesterol-lowering agent, the inhibitor of the renin-angiotensin system, aspirin and optionally vitamin B is contained in a single unit-dose tablet or capsule, which is dosed once a day, preferably before sleep. The described invention therefore addresses a major medical need to provide an effective, safe, simple and convenient method for reducing the incidence of cardiovascular events in individuals at high cardiovascular risk. Such a dosage form provides convenience and simplicity to the patient, thereby improving patient compliance, particularly in patients who have undergone various treatments due to the presence of heart disease or other ailments.

Since three or more active agents are being used together in combination therapy, the potency of each agent and the interplay effects that result from combining them must be considered. These factors have been well within the ordinary clinician's consideration for determining a therapeutically effective or prophylactically effective dose.

Preferred oral dosage forms comprise pharmaceutically effective unit doses of each active agent, wherein the unit doses are suitable for once daily oral administration. The therapeutically effective unit dose of any particular active agent will, of course, depend on the active agent, the needs of the patient and other factors known to the prescribing physician. Those of ordinary skill in the art of pharmaceutical formulation can readily derive appropriate unit doses of the various active agents. However, in general, the therapeutically effective unit dose of each active agent is as follows:

from about 10mg to about 120mg, preferably from about 25mg to about 90mg of an HMG CoA reductase inhibitor selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin;

about 1mg to about 60mg, preferably about 15mg to about 45mg of an ACE inhibitor selected from captopril, etopril, fosinopril, quinapril, ramipril and trandolapril;

about 20mg to 600mg, preferably about 20mg to 150mg, aspirin;

preferably at least one of:

about 25mg to about 75mg, preferably about 40mg to about 60mg vitamin B₆；

About 0.25mg-2mg, preferably about 0.5mg-1.5mg vitamin B₁₂；

About 0.5mg to about 8mg, preferably about 1.5mg to about 5mg folic acid.

In a particularly preferred embodiment, the active ingredients are as follows:

80mg of lovastatin;

40mg of etopril;

81mg of aspirin;

50mg vitamin B₆；

1mg vitamin B₁₂(ii) a And

3mg folic acid.

The formulations of the invention may be administered as long as the patient is at high risk for cardiovascular disease; it is likely that this will be a long time course, possibly for the lifetime of the patient. At least 1-2 weeks of administration is required to obtain minimal benefit. In addition to the preferred formulation designed for daily dosing, a sustained release form of this formulation may also be employed, which may provide for alternate weekly, monthly, etc. dosing.

V. kit

In another embodiment, there is provided a pharmaceutical composition comprising a plurality of oral dosage forms for self-administration; a container means; preferably sealed, carrying the dosage form during storage and prior to use; and guidelines for patient medication. The instructions will typically be written on the package insert, label, and/or other components of the kit, as well as on the oral dosage forms described herein. Each dosage form may be carried separately, for example in a sheet of foil-plastic foil, each dosage form being separated from the others in a single cell or vacuole, or the dosage forms being contained in a single container, for example a plastic bottle. The kits also typically include means for packaging the individual kit components, such as the dosage form, containment device, and instructions for use. Such packets may take the form of cardboard or paper boxes, plastic or foil bags, and the like.

Experimental part

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of pharmaceutical formulation and the like, which are within the skill of the art. Such techniques are explained fully in the literature. In the following examples, efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless otherwise indicated, temperature is in degrees celsius and pressure is atmospheric pressure at or near sea level. All reagents were obtained commercially unless otherwise indicated.

Example 1

A multilayer tablet comprising a layer of sustained release lovastatin, a layer of sustained release etodolapril and a layer comprising immediate release aspirin, vitamin B₆Vitamin B₁₂And folic acid, formulated according to the following table. The ingredients of each layer are mixed separately and then compressed using a suitable layering compressor to produce a layered tablet.

Composition (I)	Mg/sheet
		Layer 1 (sustained Release)
Lovastatin	80.0
		Methocel E4M Premium*	80.0
Microcrystalline cellulose	50.0
		Silicon dioxide	2.0
Magnesium stearate	2.0
		Layer 2 (sustained release)
Etoripril	40.0
		Methocel E4M Premium*	40.0
Microcrystalline cellulose	25.0
		Silicon dioxide	1.0
Magnesium stearate	1.0
		Layer 3 (excipient barrier)
Microcrystalline cellulose	25.0

Layer 4 (immediate release)
		Aspirin	81.0
Vitamin B6	50.0
		Vitamin B12	1.0
Folic acid	3.0
		Microcrystalline cellulose	90.0
Silicon dioxide	2.0
		Magnesium stearate	8.0

Hydroxypropyl methylcellulose is available under the brand name Dow chemical company, Midland, Michigan.

Example 2

Sustained release beads comprising lovastatin and etoposil, tablets of etoposil in a mixed matrix comprising aspirin, vitamin B₆Vitamin B₁₂And folic acid, formulated according to the following.

Composition (I)	Weight (D)
		Sustained release bead 1
Lovastatin	1,000gm
		Hydrogenated castor oil	350gm
Stearic acid	350gm
		Microcrystalline cellulose	300gm
Total of	2,000gm
		Sustained release bead 2
Etoripril	1,000gm
		Hydrogenated castor oil	350gm
Stearic acid	350gm
		Microcrystalline cellulose	300gm
Total of	2,000gm

Immediate release matrix
		Aspirin	810gm
Vitamin B6	500gm
		Vitamin B12	10gm
Folic acid	30gm
		Microcrystalline cellulose	950gm
Silicon dioxide	20gm
		Magnesium stearate	80gm
Total of	2,400gm

The powder components of each bead formulation and matrix layer are mixed separately. To make each bead formulation, purified water (700gm) was added to the powder of the above ingredients, and the mixture was kneaded into a dough and extruded from an extrusion granulator to obtain rod-shaped granules. The granules were then rounded by a pelleter and dried at 55 ℃ for 3 hours. The beads thus formulated were sieved to obtain sustained release beads which passed through a 14 mesh sieve but not a 26 mesh sieve. The sustained release beads and matrix formulation are then mixed, compression molded into tablets. The sustained release beads were mixed with the matrix and then compressed into tablets to make the following composition/tablet:

lovaStatin	80mg
		Etoripril	40mg
Aspirin	81mg
		Vitamin B6	50mg
Vitamin B12	1mg
		Folic acid	3mg

Example 3

Tablets were formulated as in example 2, except that the sustained release beads were coated with an enteric polymer in an aqueous or non-aqueous system. Sustained release beads of lovastatin and etoposide were separately coated. Eudragit L-30D-55 containing 10% -15% diethyl phthalate (w/w) is used in aqueous systems. The coating suspension is formulated to have a solid content of 10% to 30%. To prepare the coating suspension, diethyl phthalate was added to Eudragit L-30D-55 and the contents were stirred untilthe diethyl phthalate was completely dissolved. The resulting suspension is diluted with water to obtain a suspension comprising the desired proportion of solid content. The enteric coated beads are made by applying such an enteric coating suspension and coating the beads, for example by Wurster insertion in a fluid bed system or by spray coating.

Example 4

The tablets or capsules are formulated so that all of the active drug is present in immediate release single dose units. A hard gelatin capsule formulation was formulated according to the following. The following ingredients were used in each capsule:

lovastatin	80mg
		Etoripril	40mg
Aspirin	81mg
		Vitamin B6	50mg
Vitamin B12	1mg
		Folic acid	3mg
Calcium carbonate	50mg
		Magnesium oxide	50mg
Magnesium carbonate	25mg
		Corn starch	25mg
Magnesium stearate	1mg

The powder ingredients are mixed and hermetically encapsulated in hard gelatin capsules. The amount of buffering agent (calcium carbonate, magnesium oxide) can be adjusted as desired to minimize possible interactions between gastrointestinal reactions and the active drug. It will be appreciated that these buffers may be replaced by other suitable buffers if desired.

Example 5

Tablets or capsules are formulated in which all of the active drug is present in the protective-coated or enteric-coated granules or beads, respectively. In hard gelatin capsule dosage forms, each active agent is granulated and coated with cellulose acetate phthalate, e.g., Remington's, supra, according towell-known pharmaceutical procedures. The method as set forth in (1). The active drug appears in each capsule as follows:

pravastatin	40mg
		Ramipril	10mg
Aspirin	81mg
		Vitamin B6	50mg
Vitamin B12	1mg
		Folic acid	3mg

Example 6

Each active agent is formulated separately into coated or uncoated compressed tablets by standard pharmaceutical techniques, and these tablets are then encapsulated in hard gelatin capsules.

Example 7

The capsule formulation of example 1 was applied to a study of double-blind, placebo-controlled 250 (N-250) subjects at high cardiovascular risk. Subjects were divided into 3 groups: group 1 ("general care") (N ═ 100) received regular medical care and once daily placebo capsules; group 2 ("risk-increasing treatment") (N ═ 100) received conventional medical care plus once daily capsules containing 80mg of lovastatin; group 3 ("aggressive risk management") received conventional medical care plus once daily tablets of example 1 d.

Entry principle of the study: all persons older than 18 years of age with Systemic Lupus Erythematosus (SLE), defined as the 1997 revised ACR criteria for SLE, or diagnosed by members of the american college of rheumatology, were also eligible. Record SLE performance/criteria.

The following exclusion principles will apply: liver disease, pregnancy, lactation or reluctance to use acceptable contraception; excess alcohol consumption; with cholestyramine, nicotinic acid or erythromycin; aspirin intolerance; concomitant lithium; diuretics with potassium supplementation or low potassium excretion; concomitant cyclosporin; history of allergy or sensitivity to ACE inhibitors; congestive heart failure; renal artery stenosis; ulceration of the digestive organs during the last 6 months; history of intracranial hemorrhage or brain tumor; bleeding constitutions; history of muscle disease; participate in another investigator drug tested.

The study will last for 5 years. Approximately 10% of the subjects in each of the three groups were given a blood pressure tester and their blood pressures were measured and recorded once a day. Groups 2 and 3 will receive individualized patient education for reducing cardiovascular risk. Subjects in all groups will receive the following laboratory tests:

reference: blood pressure; ANA; a C-reactive protein; an anti-phospholipid antibody; total HDL and LDL cholesterol; CBC;creatine; and (4) potassium. The serum will be preserved.

Three weeks: blood pressure; SGPT; total HDL and LDL cholesterol; CBC; creatine; and (4) potassium. The serum will be preserved (1 red top).

And (4) outlet: blood pressure; total HDL and LDL cholesterol; CBC; creatine. The serum will be preserved (1 red top).

At the completion of the study, it was found that subjects in group 2 experienced fewer cardiovascular events than those in group 1, and subjects in group 3 experienced significantly fewer cardiovascular events than those in group 2.

Claims (31)

1. An orally administrable pharmaceutical dosage form for the treatment of a patient at high cardiovascular risk comprising in combination:

(a) a therapeutically effective daily dose of a cholesterol-lowering agent as a first active agent;

(b) a therapeutically effective daily dose of an inhibitor of the renin-angiotensin system as a second active agent;

(c) a therapeutically effective daily dose of aspirin as a third active agent;

wherein at least one active agent is present in a dosage unit that physically separates one active agent from the other active agent.

2. The dosage form of claim 1, wherein the at least two active agents are present in dosage units that physically separate the at least two active agents and the other active agent and from each other.

3. The dosage form of claim 1, wherein the cholesterol-lowering drug is present in a first dosage unit, the inhibitor of the renin-angiotensin system is present in a second dosage unit, and the aspirin is present in a third dosage unit.

4. The dosage form of claim 3, wherein said dosage form is a capsule, said dosage units each comprising a plurality of beads or particles therein.

5. The dosage form of claim 3, wherein said dosage form is a capsule, and said dosage units each comprise a tablet therein.

6. A dosage form according to claim 3, wherein the dosage form is a compressed tablet, the dosage units each comprising physically separate portions thereof.

7. The dosage form of claim 6, wherein the compressed tablet is a layered tablet, each of the dosage units comprising one layer thereof.

8. A dosage form as claimed in claim 3, wherein the dosage form is a compressed tablet, each dosage unit comprising a plurality of beads or granules in a mixture therein.

9. The dosage form of claim 3, wherein said dosage form is comprised of an inner core coated with at least two concentric layers.

10. The dosage form of claim 9, comprising two concentric layers.

11. The dosage form of claim 10, wherein the inner core is comprised of one of the dosage units and each concentric layer contains one of the dosage units.

12. The dosage form of claim 9, wherein said inner core is comprised of an inert material.

13. The dosage form of claim 12, comprising three concentric layers.

14. The dosage form of claim 13, wherein each concentric layer is comprised of one of the dosage units.

15. The dosage form of any one of claims 2-14, wherein at least one dosage unit is an immediate release dosage unit.

16. The dosage form of any one of claims 2-15, wherein at least one dosage unit is a delayed release dosage unit.

17. The dosage form of any one of claims 2-15, wherein at least one dosage unit is a sustained release dosage unit.

18. The dosage form of any one of claims 1-17, further comprising vitamin B₆Vitamin B₁₂And folic acid.

19. The dosage form of any one of claims 1-18, wherein the cholesterol-lowering agent is selected from the group consisting of HMG CoA reductase inhibitors, bile acid sequestrants, probucol and phenoxy acid agents, and combinations thereof.

20. The dosage form of claim 19, wherein the cholesterol-lowering drug is an HMG CoA reductase inhibitor.

21. The dosage form of claim 20, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, cerivistatin, fluindostatin, fluvastatin, lovastatin, mevastatin, pravastatin, simvastatin, and velostatin.

22. The dosage form of claim 21, wherein the HMG CoA reductase inhibitor is selected from lovastatin and pravastatin.

23. The dosage form of claim 19, wherein the inhibitor of the renin-angiotensin system is selected from the group consisting of an angiotensinogen-converting enzyme (ACE) inhibitor and an angiotensin II antagonist.

24. The dosage form of claim 23, wherein the inhibitor of the renin-angiotensin system is an ACE inhibitor.

25. The dosage form of claim 24, wherein the ACE inhibitor is selected from captopril, cilazapril, delapril, etopril, fentiapril, fosinopril, indopril, lisinopril, perindopril, pivopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril.

26. The dosage form of claim 25, wherein the ACE inhibitor is enalapril.

27. The dosage form of claim 23, wherein the inhibitor of the renin-angiotensin system is an angiotensin II antagonist.

28. The dosage form of claim 20, wherein the first dosage unit comprises about 10mg to about 120mg of an HMGCoA reductase inhibitor selected from the group consisting of atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin, and the second dosage unit comprises about 1mg to about 60mg of an inhibitor of the renin-angiotensin system selected from the group consisting of captopril, etoposil, fosinopril, lisinopril, quinapril, ramipril and trandolapril and zofenopril; the third dosage unit contains approximately 20-600mg of aspirin.

29. The dosage form of claim 28, further comprising at least one of

(a) About 25mg to about 75mg vitamin B₆；

(b) About 0.25mg-2mg vitamin B₁₂；

(c) About 1mg to about 8mg folic acid.

30. A kit for use by a patient at high cardiovascular risk in self-administration of oral dosage forms, the kit comprising a packaging container carrying a plurality of oral dosage forms according to claim 28 or 29 and instructions for pharmaceutical administration.

31. The kit of claim 301 wherein the HMG CoA reductase inhibitor is lovastatin and the inhibitor of the renin-angiotensin system is etoposil.