WO2009010810A2

WO2009010810A2 - Cardiovascular combinations comprising ace and hmg-co-a inhibitors

Info

Publication number: WO2009010810A2
Application number: PCT/IB2006/002614
Authority: WO
Inventors: Eswaran Krishnan Iyer; Rasendra Kumar Jayantilal Jha; Girish Kumar Jain; Abdul Rehman Khan
Original assignee: Wockhardt Limited
Priority date: 2006-08-07
Filing date: 2006-08-07
Publication date: 2009-01-22
Also published as: WO2009010810A3

Abstract

The invention describes new pharmaceutical compositions, their method of manufacture and use of these compositions to be administered as combination therapy for the treatment of cardiovascular and related disorders, in particular a combination of ACE inhibitors or Calcium channel blockers, lipid regulators (HMG-Co-A inhibitors) and platelet aggregation inhibitors.

Description

CARDIOVASCULAR COMBINATIONS COMPRISING ACE and HMG-Co-A INHIBITORS

Reference to Related Applications [0001] This application is a continuation of PCT application No. PCT/IB05/00346 filed February 9, 2005: the entire contents of the aforementioned application being incorporated herein by reference.

Field of the Invention

[0002] The present invention provides pharmaceutical compositions, their method of manufacture and use of these compositions for administration for a combination therapy for the treatment of cardiovascular and related disorders, in particular a combination of ACE inhibitors or Calcium channel blockers, lipid regulators (HMG Co-A inhibitors) and platelet aggregation inhibitors. The combination therapy can also be useful in lowering the risk of cardiovascular disorders. Background of the Invention

[0003] Heart failure is a common cause of death and disability in industrialized nations and is a syndrome commonly encountered in clinical practice. The diagnosis of heart failure carries a risk of mortality comparable to that of the major malignancies. In the past twenty years, advances in understanding the pathophysiology of heart failure and new developments in pharmacotherapy have added substantially to the physician's ability to alleviate the symptoms of this disease and slow the natural progression of underlying myocardial progress. A primary goal in the treatment of heart failure is the alleviation of symptoms, which, may be a direct result of the underlying hemodynamic disorder.

[0004] Hypertension is a common cardiovascular disease. Elevated arterial pressure can cause pathological changes in the vasculature and hypertrophy of the left ventricle of the heart. As a consequence, hypertension, a principal cause of strokes, can lead to disease of the coronary arteries with myocardial infarction or sudden cardiac death, and may be a major contributor to cardiac failure, or renal insufficiency. The risk of cardiovascular disease, disability and death in hypertensive patients is also increased markedly by elevated low-density lipoprotein. The coexistence of hypertension with these risk factors can increase cardiovascular morbidity.

[0005] A chief goal of antihypertensive therapy includes preventing maj or cardiovascular disorders such as myocardial infarction, arrhythmia, angina and the like. Although controlling blood pressure and reducing other known cardiovascular risk factors are pivotal in achieving these goals, additional strategies or a combination therapy are needed to provide optimal protection against cardiovascular disease.

[0006] ACE inhibitors, or angiotensin converting enzyme inhibitors (i.e., Enalapril, Captropril, ramipril, lisinopril, quinapril, and the like) have been reported to reduce peripheral vascular resistance via blockage of the angiotensin converting enzyme. This action reduces the myocardial oxygen consumption, thereby improving cardiac output and moderating left ventricular and vascular hypertrophy. ACE inhibitors are believed to be essential for treatment of Congestive Heart Failure (CHF) due to systolic dysfunction. They also reduce urinary protein excretion and slow the loss of renal function in hypertensive patients with diabetic or non-diabetic progressive renal disease. The effects can be greater than with other antihypertensive drugs that lower the blood pressure by a comparable amount. They have also been shown to have a cardioprotective effect in patients surviving an acute myocardial infarction. They may also prevent myocardial infarctions, strokes, and deaths from cardiovascular causes in patients with coronary artery disease, previous stroke, or peripheral vascular disease.

[0007] Another component of the renin-angiotensin-aldosterone system is bradykinin, a vasoactive peptide metabolized by the same enzyme that converts angiotensin I to angiotensin II. The use of ACE inhibitors to block the breakdown of bradykinin can also promote vasodilation, natriuresis, and may provide a beneficial effect on cardiac remodeling.

[0008] Another important class of antihypertensive drugs is Calcium channel blockers. Calcium channel blockers are reported to act primarily by vasodilation and reduction of peripheral vascular resistance. They are commonly used as agents for hypertension and angina. Some examples of Calcium channel blockers include verapamil, diltiazem, mibefradil, nifedipine, felodipine, amlodipine, nimodipine, nisoldipine, isradipine, bepridil and the like.

[0009] Diltiazem, a commonly prescribed member of the class, is a calcium antagonist that is marketed under the trade name Cardizem^®. The chemical name for diltiazem is (+)cis-3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4- methoxyphenyl)-l ,5-benzothiazepin-4(5H)one. Diltiazem has been reported to be beneficial in the treatment of cardiovascular disorders such as angina, arrhythmias, and hypertension. Diltiazem is believed to produce an antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. It has been reported to produce increases in exercise tolerance.

[0010] The symptomatic treatment for cardiac failure is directed at improving haemodynamic function through the use of drugs that can increase cardiac output and reduce ventricular filling pressures. Therefore, the selected therapy for rapid improvement may include β-adrenergic blockers, rennin-angiotensin inhibitors, calcium channel blockers, and the like. These drugs may be administered either individually or in combination. Combination drug therapies have become common to achieve the dual advantages of dosage reduction and reduced adverse effects.

[0011] Combination therapy can involve multiple doses of multiple medications. A benefit of drug combinations may be the enhanced efficacy, which can lead to widespread use. Some drug combinations may produce synergistic effects that are greater than that predicted by summing the efficacies of the component drugs. In addition, some combinations produce offsetting interactions that weaken side effects of therapy with a single drug. Another potential benefit of a combination therapy concerns the possible _v avoidance of adverse effects. In general, combination therapy has advantages such as (1) increased efficacy, i.e., additive or synergistic effects, (2) reduced adverse events, i.e., low dose strategy, drugs with offsetting actions, (3) enhanced convenience and compliance, (4) prolong duration of action and the like.

[0012] Atherosclerosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries. Atherosclerotic coronary heart disease (hereinafter "CHD") accounts for major deaths attributable to a cardiovascular event. Despite attempts to modify secondary risk factors such as, inter alia, smoking, obesity and lack of exercise, and treatment of dyslipidemia with dietary modification and drug therapy, CHD remains a common cause of death in Western countries. High levels of blood cholesterol and blood lipids are conditions involved at the onset of atherosclerosis. It is generally believed that inhibitors of 3- hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-Co-A reductase) are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C).

[0013] Clinical and pathologic studies show that elevated plasma leyels of total cholesterol, LDL-cholesterol (LDL-C), and apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for developing cardiovascular disease. In heart diseases, atherosclerosis and hypertension are seen in most cases. Statins are reported to exert a major effect, i.e., reduction of low-density lipoprotein (LDL) through a mevalonic acid like moiety that competitively inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co-A reductase) enzyme selectively. Atorvastatin is a selective, competitive inhibitor of HMG-Co-A, the rate-limiting enzyme that converts 3-hydroxy-3-methyl- glutaryl-CoA to mevalonate, a precursor of steroids including cholesterol. Atorvastatin is believed to reduce total-C, LDL-C, and apo B in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin is also reported to reduce VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-I. Atorvastatin can also reduce total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in patients with isolated hypertriglyceridemia.

[0014] Recent studies have demonstrated that lovastatin, simvastatin and pravastatin slow the progression of artherosclerotic lesions in the coronary and carotid arteries. Simvastatin and pravastatin have also been shown to reduce the risk of coronary heart disease events, and in the case of simvastatin a highly significant reduction in the risk of coronary death and total mortality has been reported.

[0015] Individuals with atherosclerosis of their arteries may be prone to develop blood clots in the arteries. Platelets initiate the formation of blood clots by sticking together (clumping), a process called platelet aggregation. Clumps of platelets can be further bound together by a protein (fibrin) formed by clotting factors present in the blood. The clumps of platelets and fibrin make up a blood clot. A blood clot that forms in a coronary artery supplying blood to the muscle of the heart can cause a heart attack, and a blood clot that forms in an artery supplying blood to the brain can cause a stroke.

Antiplatelet agents are medications that block the formation of blood clots by preventing the clumping of platelets. There are three types of antiplatelet agents, aspirin, the thienopyridines, and the glycoprotein Ilb/IIIa inhibitors.

[0016] Aspirin is believed to prevent blood from clotting by inhibiting the enzyme cyclo-oxygenase-1 (COX-I) that produces platelets of thromboxane A-2. In addition to thromboxane A-2, platelets also produce adenosine diphosphate (ADP). When ADP attaches to receptors on the surface of platelets, the platelets can clump. The thienopyridines, for example, ticlopidine and clopidogrel, can block the ADP receptor. Blocking the ADP receptor may prevent ADP from attaching to the receptor and the platelets from clumping.

[0017] Improved treatments for inhibiting platelet aggregation are currently being sought for individuals who are at risk for reocclusion following thrombolytic therapy or angioplasty, transient ischemic attacks and other vaso-occlusive disorders. Therefore, the platelet aggregation inhibitors when administered in combination with HMG-Co-A inhibitors may provide enhanced inhibition of platelet aggregation as compared to administration of either of the agent alone. Another benefit of the combination is that lesser dosage amounts of the platelet aggregation inhibitors may be required to achieve the desired clinical result.

[0018] Angina pectoris is a severe constricting pain in the chest, often radiating from the precordium to the left shoulder and down the left arm. Angina pectoris is often caused by ischemia of the heart and is often caused by coronary disease. The symptomatic management of angina pectoris can involve the use of a number of drugs, frequently as a combination of two or more of the following classes: β-blockers, nitrates and calcium channel blockers. Many patients with angina pectoris also require therapy with a lipid lowering agents or lipid regulating agents as well. Jukema et ah, Circulation, 1995 (Suppl. 1), 1-197, report evidence that calcium channel blockers can act synergistically in combination with lipid lowering agents (e.g., HMG-Co-A reductase inhibitors), specifically pravastatin. Orekhov et ah, Cardiovascular Drugs and Therapy, 1997, 11, 350 reports the use of amlodipine in combination with lovastatin for the treatment of atherosclerosis. '

[0019] Hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease ultimately resulting in adverse cardiac events. This clustering of risk factors is believed to be due to a common mechanism. Further, patient compliance with the management of hypertension is generally better than patient compliance with hyperlipidemia. It would therefore be advantageous to provide patients with a single therapy, which treats both of these conditions.

[0020] A fixed dose administered as a once daily tablet offers dosage convenience and can help with patient compliance. A combination therapy may be used to treat various conditions such as Hypertension with Dyslipidemia and for inhibition of platelet aggregation and for inhibiting the formation of thrombotic occlusions; Hypertension with Dyslipidemia and Diabetic Neuropathy; Angina Pectoris with Dyslipidemia and for inhibition of platelet aggregation and for inhibiting the formation of thrombotic occlusions; and Angina Pectoris with Dyslipidemia and Diabetic Neuropathy and various other related disorders in mammals such as humans. Hence, a combination of ACE inhibitors with platelet aggregation inhibitors and statins as a primary treatment may provide a greater degree of protection and control of these risk factors, improving the vascular and general health of the patient.

[0021] There are reports of combination therapy for the treatment of multiple pathological processes involved in cardiovascular and related diseases in the literature.

[0022] U.S. patent No. 6,677,356 discloses a method for treating hypertension including concurrently administering a combination of a compound selected from the group consisting of pyridoxal-5'-phosphate, pyridoxal, pyridoxamine, a 3'-acylated pyridoxal analogue, and a therapeutic cardiovascular compound selected from the group consisting of an angiotensin converting enzyme (ACE) inhibitor, a calcium channel blocker, a β-adrenergic receptor antagonist, a vasodilator, a diuretic, an α-adrenergic receptor antagonist, a 3'-acylated pyridoxal analogue, an angiotensin II receptor antagonist, an antithrombolytic agent, an antioxidant, and a mixture thereof.

[0023] U.S. patent No. 6,669,955 discloses an orally administrable pharmaceutical composition including combination of cholesterol-lowering agent, an inhibitor of rennin- angiotensin system, aspirin and optionally at least one of vitamin B₆, B₁₂ and folic acid. The active agents are in a unit dose preparation for once daily dosing. The patent states that the composition provides a simple and convenient therapy to reduce the risk of cardiovascular events in individuals who are at elevated cardiovascular risk. The patent also states that the composition is therapeutic for individuals during or immediately following an occurrence of myocardial infarction.

[0024] U.S. Patent No. 6,235,311 discloses pharmaceutical compositions that contain a statin plus aspirin, and optionally containing vitamins B₆, B₁₂ or folic acid, as antioxidants, and methods of use for lowering serum cholesterol, preventing, inhibiting, or treating atherosclerosis or reducing the risk of or treating a cardiovascular event or disease, coronary artery disease or cerebrovascular disease.

[0025] U.S. Patent Application No. 2003/0175344 discloses a formulation including blood pressure lowering agents, each selected from a diuretic, a beta blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, and a calcium channel blocker with an active agent from at least two of the three categories (i) a lipid regulating agent (ii) one piatelet function altering agent and (iii) one serum homocysteine lowering agent. The application also discloses the use and method of treatment for reducing the risk of cardiovascular disease of the active principals by simultaneous, separate or sequential administration of the combination therapy. [0026] U.S. Patent No. 6,251 ,852 discloses a combination therapy and pharmaceutical compositions included of a therapeutically effective amount of a cholesterol reducing agent such as an HMG-Co-A reductase inhibitor in combination with a platelet aggregation inhibitor which said to be useful for inhibiting platelet aggregation, for inhibiting the formation of thrombotic occlusions, and for treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.

[0027] U.S. Patent No. 6,403,571 is a from the same patent family as the '852 patent discussed above and discloses a combination therapy and pharmaceutical compositions included of a therapeutically effective amount of an HMG-Co-A reductase inhibitor in combination with a platelet aggregation inhibitor which is useful for inhibiting platelet aggregation, for inhibiting the formation of thrombotic occlusions, and for treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders. The patent specifically discloses a pharmaceutical composition including a platelet aggregation inhibitor selected from the group consisting of ticlopidine, clopidogrel, and dipyridamole, an HMG-Co-A reductase inhibitor and a pharmaceutically acceptable carrier.

[0028] U.S. Patent No. 6,576,256 discloses methods and compositions said to be useful for reducing the risk of cardiovascular events, in individuals who are at elevated cardiovascular risk, including individuals who have systemic lupus erythematosus. The methods include administering a combination of a cholesterol-lowering agent, such as an HMG Co-A reductase inhibitor; an inhibitor of the rennin-angiotensin system, such as an ACE inhibitor or Angiotensin II antagonists; aspirin; and optionally one or more of vitamin B₆, vitamin Bi₂, and folic acid. The patent discloses pharmaceutical formulations combining all the active agents in unit-dose form for once-daily dosing.

[0029] U.S. Patent No. 6,248,729 discloses a method for preventing a cerebral infarction by administering to a patient a combination of an ADP-receptor blocking antiplatelet drug, an antihypertensive agent (such as an angiotensin II antagonist, an ACE inhibitor, or an ACE/NEP inhibitor), and optionally aspirin. Pharmaceutical compositions including combinations of these agents are also disclosed. The disclosed methods and compositions, however, require an ADP-receptor blocking antiplatelet drug (which does not include aspirin).

[0030] U.S. Patent 4,894,240 discloses a controlled release diltiazem formulation. The '240 patent states that its formulation is suitable for once a day administration. The formulation is prepared from diltiazem beads in which a diltiazem core is enveloped by a multilayer film in which the film is composed of a major component of a water insoluble polymer and a minor component of a water-soluble polymer. Suitable water insoluble polymers include various cellulose esters, polyoxides, polyacrylates, polyethylene, polypropylene, polyurethane, polyvinyl, etc. A proprietary polymer composed of acrylic resins (Eudragit^®), is also specified as being suitable. However, the '240 patent does not disclose a combination therapy using diltiazem.

[0031] US Patent Application 2004/0137054 discloses a pharmaceutical formulation containing statin and ACE inhibitor, being separated by a physiologically inert material. The application discloses the separation of the two drugs in the formulation to provide a stable composition and to prevent the degradation of ACE inhibitors.

[0032] U.S. Patent 5,298,497 discloses the use of a cholesterol-lowering agent, such as pravastatin, alone or in combination with an ACE inhibitor, to prevent or reduce the risk of hypertension in patients having insulin resistance.

[0033] WO Application 2001/76573 discloses the use of a mixture of two components selected from an ATI receptor antagonist with a diuretic, a HMG-Co-A reductase inhibitor and an ACE inhibitor. The combination is said to be suitable for the prevention of cardiovascular diseases.

[0034] U.S. Patent Application No. 2005/0101658 discloses the use of an inhibitor of the rennin-angiotensin system (RAS), optionally together with another antihypertensive drug, a cholesterol-lowering drug, a diuretic, or aspirin, in the prevention of cardiovascular events. The application only discloses a combination product containing an renin-angiotensin inhibitor and a cholesterol-lowering agent or with an antihypertensive agent.

[0035] The physiological effects of antihypertensive agents such as calcium channel blockers, β-adrenergic blockers, angiotensin converting enzyme (ACE) inhibitors or angiotensin II antagonists and diuretics in combination with lipid-regulators and platelet aggregation inhibitors have generally been found to be independent of each other in reducing the risk of cardiovascular disease. At the preferred dosages and in specific pharmaceutical drug delivery form, the use of these agents can provide a reduction in cardiovascular disease. [0036] There can be difficulties in formulating various different classes of drugs that have diverse physicochemical properties and belong to unrelated chemical classes because the different active ingredients and the other excipients require that such a composition remains stable physicochemically and also achieves the desired characteristics "in-vivo " when administered to patients. There may be an incompatibility between the active ingredients themselves, between the excipients and each of the active ingredients, or between the excipients and the combination of active ingredients. These considerations make it important for the formulator to study the details and the ratios of drug to excipients to be used before formulation to provide a physicochemically stable composition, even during storage, to ensure the proper release of the therapeutic ingredients after administration to the patient.

[0037] Accordingly, there is a need for is a need for a combination therapy present invention is directed towards combination therapy that could improve the treatment of cardiovascular disorders through enhanced patient compliance because of ease of administration and a reduced frequency of dosing.

[0038] Hence, there is a need for a combination therapy that could improve the treatment of cardiovascular disorders through enhanced patient compliance because of ease of administration and a reduced frequency of dosing.

Summary of the Invention [0039] The present invention provides a composition including an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor in a single dosage form. The composition is suitable for prophylactic or therapeutic treatment of cardiovascular and related disorders and disorders associated with hypertension, dyslipidemia, diabetic neuropathy, and angina pectoris. The composition is also useful for inhibiting the formation of thrombotic occlusions, and treating, preventing or reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.

[0040] In another embodiment, the present invention provides a pharmaceutical composition and a process for manufacturing a composition including an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor - preferably in a single dosage form.

[0041] In another embodiment, the present invention provides a method for treating cardiovascular and related disorders, including administering to a mammal (e.g., a human) in need of such treatment, a pharmaceutical composition including an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor preferably in a single dosage form.

[0042] In another embodiment, the invention provides a composition in a single dosage form with one or more active agents in extended, modified release or delayed release form and the dosage form is adapted for oral administration.

[0043] In another embodiment, the invention provides a pharmaceutical composition including an ACE inhibitor, an HMG-Co-A inhibitor and a platelet aggregation inhibitor preferably in a single dosage form along with suitable pharmaceutically acceptable excipients thereof. [0044] In another embodiment, the invention provides a composition in the form of an oral formulation including a therapeutically effective amount of an ACE inhibitor or calcium channel blocker, the HMG Co-A inhibitor, the platelet aggregation inhibitor with a pharmaceutically acceptable carrier and optional pharmaceutically acceptable excipients. [0045] In another embodiment, the invention provides a pharmaceutical composition including a calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor preferably in a single dosage form along with suitable pharmaceutically acceptable excipients thereof.

[0046] In another embodiment, the invention provides a composition including calcium channel blocker wherein the calcium channel blocker is in an extended release form. In another embodiment, the invention provides compositions wherein the platelet aggregation inhibitor is in a delayed release form. [0047] In another embodiment, the invention provides an oral composition having at least one of the active agents in extended or modified release form. Preferably, one or more active agent may be in extended or modified release or delayed release form.

[0048] In another embodiment, the invention provides an oral drug delivery system for the combination composition as described herein.

[0049] In another embodiment, the invention provides a delivery system for oral administration including of release in the body of a mammal (e.g., human), a combination composition including an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor preferably in a single dosage form. [0050] In another embodiment, the invention provides an oral delivery system kit including an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor together with suitable excipients thereof.

[0051] In another embodiment, the invention provides a method for using a composition of the invention for the treatment of cardiovascular and related disorders and those associated with hypertension, dyslipidemia, diabetic neuropathy, angina pectoris, for inhibiting platelet aggregation, for inhibiting the formation of thrombotic occlusions, and for treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders. The invention can be formulated such that the components, e.g., a tablet, capsule or kit in any order are consumed within 24 hours after administration of the drugs included in the formulation.

[0052] In another embodiment, the invention provides a pharmaceutical combination composition including an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor preferably in a single dosage form along with suitable pharmaceutically acceptable excipients thereof. The ACE inhibitor may be selected from lisinopril, ramipril, quinapril, enalapril and the like or calcium channel blocker may be selected from verapamil, diltiazem, mibefradil, nifedipine, nisoldipine, isradipine and the like. The HMG-Co-A inhibitor may be selected from Lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, velostatin and the like. The platelet aggregation inhibitor may be selected from aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, sulfipyrazone and the like. [0053] In another embodiment, the invention provides a method for preparing a pharmaceutical dosage form for oral administration including an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor wherein the process comprises blending and granulating, using suitable binders, which may be dissolved (in case of wet granulation) in aqueous or organic solvents or hydro- alcoholic solvents, dried and lubricated. The resultant granules are then compressed as double or triple layer or multilayer using suitable compressing machines. Alternatively, the granules of the said composition can also be prepared using roll compaction, direct compression or fluidized bed granulation techniques. The granules of the instant invention can also be prepared by preparing the granules containing each drug separately and mixing and filling or compressing the granules to provide multilayer tablets or filling capsules with the granular mixture.

[0054] These and other aspects of the invention will be apparent from the accompanying specification. In no event, however, should the above summaries or the terminology employed for the purpose of describing particular embodiments be construed as limitations on the claimed subject matter, which subject matter is defined solely by the attached claims, as may be amended during prosecution. The information below is not admitted to be prior art to the present invention, but is provided solely to assist the understanding of the invention. Detailed Description of the Invention

[0055] As used herein, in this specification and the appended claims, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention belongs. Although any methods, devices and materials similar or equivalent to those described herein may be used in the practice or testing of the invention, the preferred methods, devices and materials are now described. The details of one or more embodiments of the invention are set forth in the description and the examples below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. [0056] As used herein, an "instructional material" includes a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the composition of the invention for its designated use. The instructional material of the kit of the invention may, for example, be affixed to a container which contains the composition or be shipped together with a container which contains the composition. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the composition be used cooperatively by the recipient.

[0057] The terms "treat", "treating" or "treatment" as used herein are used interchangeably and encompasses both prophylaxis, and the treatment of established conditions. "Treating" or "treatment" can also include the management and care of a mammal (e.g., a human patient) for the purpose of combating, the disease conditions referred to herein and can include the administration of a composition according to present invention to prevent the onset of symptoms or complications associated with such conditions.

[0058] The present invention provides a composition including a therapeutically effective amount of an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor in a single dosage form for prophylactic and therapeutic treatment of cardiovascular and related disorders and those associated with hypertension, dyslipidemia, diabetic neuropathy, angina pectoris, for inhibiting platelet aggregation, for inhibiting the formation of thrombotic occlusions, and for treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders.

[0059] Non-limiting examples of ACE inhibitors include ϊisinopril, quinapril, ramipril, captopril, enalapril and the like. Non-limiting examples of calcium channel ^{ blockers include verapamil, diltiazem, nisoldipine, nifedipine, isradipine, mibefradil and the like. Non-limiting examples of HMG Co-A inhibitors include Lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, velostatin and the like. Non-limiting examples of platelet aggregation inhibitors include aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, sulfipyrazone and the like. Preferably, the compositions are in a single dosage form having a suitable carrier and optionally pharmaceutically acceptable excipients.

[0060] As used herein, the term "composition" includes but is not limited to solutions, suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro-tablets, capsules, pellets, including a therapeutically effective amount of the composition of the drugs in a core having a suitable carrier and optionally pharmaceutically acceptable excipients.

[0061] As used herein, the term "therapeutically effective amount" means an amount of the drug, which is capable of eliciting a physiological response in a mammal, e.g., a human patient. More specifically, the term "therapeutically effective amount" means the amount of drug, which is capable of treating cardiovascular and related disorders.

[0062] The term "cardiovascular and related disorders" refers to coronary or cerebrovascular event(s) and disease, including but not limited to myocardial infarction, myocardial ischemia, angina pectoris, congestive heart failure, sudden cardiac death, cerebral infarction, cerebral thrombosis, cerebral ischemia, transient ischemic attacks, and the like.

[0063] The compositions of the present invention comprise a formulation substantially as herein described, and in a deliverable form. Non-limiting examples of deliverable forms include tablets, capsules, elixirs, suspensions, syrups, wafers, and the like. The capsules can include micro-tablets, granules or pellets in a capsule. Typically, the drug delivery form may be a combination tablet, capsule or a kit, substantially as described herein. Suitably, the present invention provides oral compositions comprising at least one an ACE inhibitor or calcium channel blocker, at least one HMG-Co-A inhibitor and at least one platelet aggregation inhibitor with suitable pharmaceutically acceptable excipients thereof.

[0064] The invention includes the use of the active agents in the compositions of the invention or pharmaceutically acceptable salt thereof to prepare a medicament for treating cardiovascular and related disorders in a mammal (e.g., a human). The medicament according to the present invention includes a formulation substantially as herein described, and in particular a capsule, a tablet, micro-tablets, granules or pellets filled in capsule formulation, typically a combination tablet formulation or a kit, substantially as hereinafter further described.

[0065] hi another embodiment, the invention provides a kit comprising a composition including a therapeutically effective amount of an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor, along with instructional material which describes administering the composition comprising the inhibitor to an animal in need of the composition. This should be construed to include other embodiments of kits that are known to those skilled in the art, such as a kit comprising a (preferably sterile) solvent suitable for dissolving or suspending the composition of the invention prior to administering the compound to an animal. Preferably the animal is a human.

[0066] hi another embodiment, the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the agents of the pharmaceutical composition of the invention. The kit comprises a pharmaceutical composition including a therapeutically effective amount of an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor in suitable combinations of the agents. For example, the kit can include three (3) containers each having one pharmaceutical agent; two (2) containers, one container including one agent and the other container including the two remaining agents; or one container including a mixture of all three agents.

[0067] hi a specific embodiment, the kit is provided including two containers, as dual entities (one container having two agents) or triple entities, (with one container having three agents) for treating an animal subject in need of treatment of cardiovascular and related disorders. Preferably, the animal is a human. [0068] The composition of the present invention may be prepared by blending an ACE inhibitor or calcium channel blocker, an HMG-Co-A inhibitor and a platelet aggregation inhibitor using suitable binders that may be dissolved (in case of wet granulation) in aqueous or organic solvents or hydro-alcoholic solvents, and drying, granulating and lubricating the mixture to obtain a granular mixture. The granular mixture may be compressed using suitable double or triple layer compressing machines. Alternatively, the granular mixture may be prepared using roll compaction, direct compression or fluidized bed granulation techniques.

[0069] In another embodiment, granular compositions of the instant invention may be prepared containing each drug separately and blending the granular components to provide a mixture and compressing the granular mixture to provide multi-drug tablets or filling capsules with the granular mixture.

[0070] Alternatively, granular compositions of the instant invention may also be prepared containing a combination of an angiotensin-II antagonist with a diuretic and granules containing the other two drugs prepared separately and blending the granules to provide a granular mixture and compressing the granular mixture to provide multi-drag tablets or filling capsules with the granular mixture, hi a preferred embodiment of the present invention, a combination composition comprises pharmaceutically active agents together with suitable excipients for oral administration. In a preferred embodiment, the present invention provides a composition including the pharmaceutically active agents together with suitable pharmaceutically acceptable excipients for oral administration.

[0071] A preferred ACE inhibitor may be lisinopril, quinapril, ramipril, enalapril, perindopril, captopril and the like. The most preferred ACE inhibitor is lisinopril; or a salt, solvate or derivative thereof.

[0072] A preferred Calcium channel blocker may be verapamil, diltiazem, mibefradil, nifedipine, nisoldipine, isradipine and the like. The most preferred Calcium channel blocker is diltiazem; or a salt, solvate or derivative thereof. Preferably the composition may include of combination of the active agents where diltiazem may be formulated in extended or modified release form.

[0073] A preferred HMG-Co-A inhibitor may be lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, velostatin and the like. The most preferred HMG- Co-A inhibitor is simvastatin or a salt, solvate or derivative thereof.

[0074] A preferred platelet aggregation inhibitor may be aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, sulfipyrazone and the like. The most preferred platelet aggregation inhibitor is aspirin or clopidogrel, a salt, solvate or derivative thereof. Preferably the composition may include of combination of these active agents where aspirin may be formulated in delayed release form.

[0075] In a preferred embodiment of the present invention, aspirin may be formulated as enteric-coated granules as hereinafter described. [0076] In a preferred embodiment of the present invention, diltiazem may be formulated as extended or modified granules as hereinafter described.

[0077] hi a specific embodiment, the present invention provides a tablet formulation including a tablet core or layers having a delayed release or enteric-coated aspirin or a pharmaceutical acceptable salt, or solvate thereof, together with at least one drug each from ACE inhibitor and HMG Co-A inhibitor along with suitable excipients thereof.

[0078] hi another specific embodiment, the present invention provides a tablet formulation including a tablet core or layers having a delayed release or enteric-coated aspirin or a pharmaceutical acceptable salt, or solvate thereof and an extended or modified release diltiazem or a pharmaceutical acceptable salt, or solvate thereof together with an HMG-Co-A inhibitor along with suitable pharmaceutical acceptable excipients thereof.

[0079] Preferably the compositions with the active agents herein are administered orally to a patient. The invention further provides compositions for use in the treatment of cardiovascular and related disorders. Preferably, the patient is a human. [0080] The compositions of the present invention in tablet form can include suitable excipients selected to provide the required properties for pharmaceutical use, such as the required hardness, friability, dissolution, disintegration time and the like. Non-limiting examples of excipients include inert diluents, disintegrating agents, binding agents, lubricating agents, and sweetening agents, flavoring agents, coloring agents and preservatives.

[0081] Suitable diluents that may be employed in a composition of the present invention can be selected based on desired pharmaceutical properties as disclosed herein, such as dissolution, content uniformity, hardness, friability, disintegration time and the like. Non-limiting examples of diluents suitable for practicing the invention can be selected from the group consisting of sodium and calcium carbonate, sodium and calcium phosphate, lactose either present in anhydrous form, hydrated form, or spray dried, and macrocrystalline cellulose, starch and the like. The choice of suitable diluents would be well known to a person having ordinary skill in the art, in order to achieve the desired properties of a pharmaceutical composition according to present invention.

[0082] Suitable binders may also be employed using known methods. Such binders can be selected to provide satisfactory compressibility. Non-limiting examples of binders suitable for practicing the invention include acacia, alginic acid, carbomer, carboxymethyl cellulose sodium, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose and other cellulose derivatives, magnesium aluminum silicate, povidone, pregelatinized starch, sodium alginate, starch, dextrin, gelatin, hydrogenated vegetable oils, polymethacrylates, zein and the like. Other binders known in the art may also be employed.

[0083] The compositions of the present invention may also include pharmaceutically acceptable lubricants and glidants. A person having ordinary skill in the art can select appropriate lubricants and glidants in order to obtain good flow to aid in compression of the tablets.

[0084] Non-limiting examples of lubricants and glidants suitable for practicing the invention include magnesium stearate, calcium stearate, glyceryl behenate, light mineral oil, polyethylene glycol, sodium steryl fumarate, stearic acid, talc, hydrogenated castor oil, calcium silicate, magnesium silicate and colloidal silicon dioxide and the like.

[0085] In another embodiment, the present invention provides a tablet formulation including a tablet core or layers provided with a delayed release or enteric-coated aspirin or a pharmaceutical acceptable salt, or solvate thereof, together with at least one ACE inhibitor and at least one HMG-Co- inhibitor, with suitable excipients thereof.

[0086] In another preferred embodiment, the present invention provides a tablet formulation including a tablet core or layers provided having delayed release or enteric- coated aspirin or a pharmaceutical acceptable salt, or solvate thereof and extended or modified release diltiazem, and an HMG-Co-A inhibitor, with suitable excipients thereof. [0087] The aspirin granules may be coated with conventional enteric-coated polymers in aqueous or non-aqueous systems. These polymers are known in the art and can be selected from the group consisting of methacrylic acid derivatives (for example, Eudragit^® polymers from Rohm Pharma), cellulose acetate phthalate, cellulose acetate maleate, cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate tetrahydrophthalate, shellac, and the like. Plasticizers suitable for use with the enteric-coating polymers are selected from the group consisting of triethyl citrate, diethyl phthalate, tributyl citrate, triacetin, dibutyl phthalate, dibutyl sebicate, and the like. Suitable enteric-coating polymers with one or more plasticizers may be used in aqueous or non-aqueous system to form an enteric-coating on the aspirin granules.

[0088] The diltiazem granules can be prepared by using with conventional hydrophilic or hydrophobic polymers by wet-granulation or fluid bed processor or dry granulation techniques. Alternatively, the diltiazem can be loaded on the sugar spheres or beads with suitable hydrophilic or hydrophobic polymers using aqueous or non-aqueous systems to obtain the desired release rate of the diltiazem after oral administration. Examples of polymers suitable for loading or coating diltiazem onto a sphere of bead can be selected from ethyl cellulose (aqueous dispersion - Sure Release^® from Colorcon Asia Pvt. Limited, Verna, Goa India), methacrylic acid derivatives (for example, Eudragit^® polymers from Rohm Pharma), cellulose acetate phthalate, cellulose acetate maleate, cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate tetrahydrophthalate, hydroxymethyl propyl cellulose, hydropropyl cellulose and other cellulose derivatives, polyvinyl polymers, polyoxyethylene derivatives and the like. Suitable plasticizers may be used with the polymers for coating.

[0089] In addition, the present invention includes a process for preparing a pharmaceutical product, or a pharmaceutical composition, or a medicament substantially as described herein.

[0090] In another specific embodiment, the granular compositions of the present invention include an ACE inhibitor, preferably lisinopril, salts, solvates or derivatives thereof, an HMG-Co-A inhibitor, preferably simvastatin salts, solvates or derivative thereof and a platelet aggregation inhibitor, preferably aspirin (enteric-coated granules); blended and granulated using suitable binders that may be dissolved (in case of wet granulation) in aqueous or organic solvents or hydroalcoholic solvents thereof, dried and lubricated. The granular composition is compressed using suitable double or triple layer compressing machines. Alternatively, the granular composition can also be prepared using roll compaction, direct compression or fluidized bed granulation techniques. The granular composition of the instant invention can also be prepared by preparing the granules containing each drug separately using wet granulation or roll compaction or dry granulation or fluidized bed processor techniques and mixing the granules to provide a granular composition.

[0091] In another specific embodiment, the granular compositions of the present invention include a calcium channel inhibitor, preferably diltiazem, salts, solvates or derivatives thereof (in extended or modified release form), an HMG-Co-A inhibitor, preferably simvastatin, salts, solvates or derivatives thereof, and a platelet aggregation inhibitor, preferably aspirin (enteric-coated granules), prepared using roll compaction, direct compression or fluidized bed granulation techniques. Alternatively, the granular composition can also be prepared using roll compaction, direct compression or fluidized bed granulation techniques. The granular composition of the instant invention can also be prepared by preparing the granules containing each drug separately using wet granulation or roll compaction or dry granulation or fluidized bed processor techniques and mixing the granules to provide a granular composition.

[0092] In another specific embodiment, the granular compositions of the present invention include lisinopril, salt, solvates or derivatives thereof, simvastatin, salts, solvates or derivatives thereof and aspirin (delayed release or enteric-release), prepared by mixing or blending granules including valsartan, enteric-coated aspirin and simvastatin to provide a granular composition and filling a capsule with the granular composition using suitable capsule-filling machine or compressing the granular composition into trilayer tablets. [0093] In another specific embodiment, the granular compositions of the present invention include an diltiazem, salts, solvates or derivatives thereof (extended or modified release), simvastatin, salts, solvates or derivatives thereof and aspirin (delayed release or enteric-release) prepared by mixing or blending the granules or beads (spheres) of diltiazem, granules of enteric-coated aspirin and granules containing simvastatin to provide a granular composition and filling a capsule with the granular composition using suitable capsule-filling machine or compressing the granular composition into trilayer tablets.

[0094] The granular compositions prepared herein can be formed into suitably adapted oral dosage forms such as tablets, pills, capsules by compressing the granular compositions using suitable double or triple layer compressing machines to form tablets and pills or filling capsules with the granular compositions.

[0095] In another embodiment the invention provides a process of preparing a pharmaceutically acceptable oral composition substantially as described herein. The process includes providing a multilayer system for treatment of cardiovascular and related disorders.

[0096] The granular compositions of the invention may be prepared by any granulation process known to those skilled in the art, such as direct compression processes, dry granulation processes, wet granulation processes or fluidized bed processing technology. These processes are suitable for preparing pharmaceutical oral compositions of the present invention. The present invention further provides, therefore, a method of preparing a pharmaceutical composition substantially as described herein, which process may comprise wet granulation or direct compression or dry granulation techniques. [0097] ACE inhibitors or calcium channel blockers, HMG Co-A inhibitors and platelet aggregation inhibitors in combination can be useful for the treatment of cardiovascular and related disorders, hypertension, dyslipidemia, diabetic neuropathy, angina pectoris, for inhibiting platelet aggregation, for inhibiting the formation of thrombotic occlusions, and for treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events, and related vaso-occlusive disorders. The present invention further provides a method for treating a condition prevented, ameliorated or eliminated by administration of these agents in a combined composition, wherein the method includes administering to a mammal (e.g., human patient) suffering from or susceptible to such a condition a therapeutically effectively amount of a formulation of the present invention described herein.

[0098] The tablets/capsules of the invention are orally administered in the amounts necessary to achieve a particular blood level. Once the chosen blood level is achieved, it can be maintained by repeated oral administration of the tablet/capsule at a dose interval of 24 hours, i.e., one tablet/capsule administered daily. Representative therapeutically effective amounts of the respective therapeutic compounds when administered as sole active ingredients are known in the art and may be found in, for example, Physicians' Desk Reference (5th ed., 2002). Once the blood level is achieved, it may be maintained by repeated oral administration of the tablet/capsule at a dose interval of 24 hours, i.e., one tablet/capsule administered daily. An optimum dosage size may be readily determined by a person skilled in the art by observing the therapeutic results achieved, the side effects encountered or by blood serum analysis.

Examples

[0099] The present invention will now be further illustrated by the following examples, which does not limit the scope of the invention in any way. Further different strengths of the formulation may be achieved by proportionately using a dose-weight scale-up or scale-down formula. The selection and concentration of the excipients may also be varied or modified to achieve the desired dissolution profile by a skilled artisan.

Example 1: Lisinopril + Simvastatin + Aspirin DR [00100] Lisinopril Granules

[00101] Procedure:

1. Lisinopril and Dibasic Calcium Phosphate Dihydrate are sifted and mixed together. 2. Povidone, Pregelatinized Starch, Corn starch, Mannitol and Colloidal Silicon

Dioxide are sifted and mixed together. The mixture is added to the mixture from Step 1.

3. The blend from Step 2 is roll compacted using a Roll compactor at a suitable speed to ensure that the compacts of sufficient hardness are formed. The compacts are crushed into granules using a suitable granulator.

4. The blend from step 3 is combined with the extra granular ingredients, i.e., Pregelatinized Starch, Colloidal Silicon Dioxide and Magnesium Stearate and blend well.

Example 2: Aspirin Tablets

[00102] Procedure: 1. Aspirin, MCC, HPMC and a portion of the pregelatinized starch, talc and stearic acid are sifted and mixed together.

2. The blend from Step 1 is roll compacted using a Roll compactor at a suitable speed to ensure that the compacts of sufficient hardness are formed. The compacts are crushed into granules using suitable granulator.

3. The remaining portion of the pregelatinized starch, talc and stearic acid are mixed with the granules from step 2 and compressed into tablets using suitable tooling.

4. The tablets from Step 3 are coated with Opadry clear to provide a seal coat.

5. Eudragit L 30 D 55 is diluted with water and triethyl citrate is added with constant stirring.

6. The seal coated tablets from Step 4 are coated with the Eudragit dispersion prepared in Step 5 to achieve the desired weight build up.

Example 3: Simvastatin Granules

[00103] Procedure:

1. Simvastatin was mixed with Lactose Monohydrate and Butylated Hydroxy Anisole in a rapid mixer - granulator.

2. The remaining Lactose Monohydrate is mixed with the following ingredients; a) Avicel pH - 101 b) Pre Gelatinized Starch c) Ascorbic Acid d) Citric Acid Monohydrate

3. The mixture from Step 1 is combined with the mixture from Step 2.

4. The mixture from Step 3 is granulated with Purified water.

5. The granules from Step 4 are lubricated with crosslmked sodium carboxymethyl cellulose (Ac-D-SoI) and Magnesium Stearate

Combination Composition:

[00104] The granules obtained in Examples 1 and 3 are mixed. The resultant granule composition and Aspirin DR tablets (prepared in Example 2) are filled in a capsule using a suitable capsule-filling machine.

Example 4: Aspirin Granules for Tri-layer Tablets

[00105] Procedure:

1. Aspirin, MCC, HPMC and pregelatinized starch are mixed and sifted together and granulated using water or suitable solvent.

2. The granules are extruded and spheronized to provide beads of 300 - 500 microns.

3. The beads are coated with Opadry clear to provide a seal coat.

4. Eudragit L 30 D 55 is diluted with water and triethyl citrate is added with constant stirring.

5. The seal coated tablets from Step 4 are further coated with the Eudragit dispersion prepared in Step 5 to achieve the desired weight build up.

6. The coated beads are mixed with MCC, PEG, Stearic acid and talc. Combination Composition:

[00106] Granules obtained as in Example 1, 3 & 4 are compressed as a tri-layer tablet. Example IA: Diltiazem XL + Simvastatin + Aspirin DR

[00107] Procedure: Diltiazem Granules

1. Opadry clear is dissolved in water. Diltiazem is added to the solution and stirred until dissolved.

2. The solution from Step 1 is used to form drug layers on sugar spheres using suitable equipment {e.g., a Fluid bed processor). The drug-layered beads are dried.

3. A Surelease (ethylcellulose) dispersion is suitably diluted and is applied to provide a sustained release coating over the drug-layered beads.

4. The coated beads are cured for 24 hrs at room temperature. Example 2A: Aspirin Tablets

[00108] Procedure:

1. Aspirin, MCC, HPMC and a portion of the pregelatinized starch, talc and stearic acid are sifted and mixed together.

2. The mixture from Step 1 is roll compacted using a Roll compactor at a suitable speed to ensure that the compacts of sufficient hardness are formed. The compacts are crushed into granules using suitable granulator.

4. The tablets are coated with Opadry clear to provide a seal coat.

6. The seal coated tablets from Step 4 are further coated with the Eudragit dispersion prepared in Step 5 to achieve the desired weight build up.

Example 3A: Simvastatin Granules

[00109] Procedure:

3. The mixture from Step 1 is combined with the mixture from Step 2.

4. The mixture from Step 3 is granulated with Purified water.

5. The granules from Step 4 are lubricated with crosslinked sodium carboxymethyl cellulose (Ac-D-SoI) and Magnesium Stearate

Combination Composition:

[00110] Beads obtained in Example IA, tablets of example 2A and granules of example 3 A are used to fill capsules using a suitable capsule filling machine.

Example 4A: Aspirin Granules

I Talc I

[00111] Procedure:

1. Aspirin, MCC, HPMC and a portion of the pregelatinized starch, talc and stearic acid are sifted and mixed together and granulated using water or suitable solvent. 2. The granules from step 1 are extruded and spheronized to provide beads of 300 -

500 microns.

3. The beads are coated with Opadry clear to provide a seal coat.

4. Eudragit L 30 D 55 is diluted with water and triethyl citrate is added with constant stirring. 5. Seal coated beads from step 3 are coated with the Eudragit dispersion prepared in

Step 4.

6. The coated beads are mixed with MCC, PEG, Stearic acid & talc. Combination Composition:

[00112] Beads obtained as in Example IA & 4 A granules obtained in example 3 A are filled in a capsule.

[00113] AU references cited herein are expressly incorporated herein by reference in their entirety into this disclosure. Illustrative embodiments of this disclosure are discussed and reference has been made to possible variations within the scope of this disclosure. These and other variations and modifications in the disclosure will be apparent to those skilled in the art without departing from the scope of the disclosure, and it should be understood that this disclosure and the claims shown below are not limited to the illustrative embodiments set forth herein.

Claims

We Claim:

1. An oral pharmaceutical composition comprising:

(a) a therapeutically effective amount of an ACE inhibitor selected from the group consisting of lisinopril, quinapril, enalapril, captopril, perindopril, ramipril, salts, solvates, and derivatives thereof; or a calcium channel blocker selected from the group consisting of verapamil, diltiazem, mibefradil, nifedipine, nisoldipine, isradipine, bepridil, felodipine, nimodipine, salts, solvates, and derivatives thereof;

(b) a therapeutically effective amount of HMG-Co-A inhibitor selected from the group consisting of simvastatin, pravastatin, salts, solvates, and derivatives thereof;

(c) a therapeutically effective amount of platelet aggregation inhibitor selected from the group consisting of aspirin, clopidogrel, ticlopidine, salts, solvates, and derivatives thereof; and a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1, wherein the ACE inhibitor is selected from the group consisting of lisinopril, quinapril, enalapril, captopril, perindopril, ramipril, salts, solvates, and derivatives thereof.

3. The pharmaceutical composition of claim 1 , wherein the calcium channel blocker is selected from the group consisting of verapamil, diltiazem, mibefradil, nifedipine, nisoldipine, isradipine, bepridil, felodipine, nimodipine, salts, solvates, and derivatives thereof.

4. The pharmaceutical composition of claim 3, wherein the calcium channel blocker is diltiazem, a salt, a solvate, or a derivative thereof.

5. The pharmaceutical composition of claim 4, wherein the diltiazem, salt, solvate, or derivative thereof is in an extended or modified release dosage form.

6. The pharmaceutical composition of claim 1, wherein the HMG-Co-A inhibitor is selected from the group consisting of simvastatin, pravastatin, salts, solvates, and derivatives thereof.

7. The pharmaceutical composition of claim 1 , wherein the platelet aggregation inhibitor is selected from the group consisting of clopidogrel, aspirin, ticlopidine, salts, solvates, and derivatives thereof.

8. The pharmaceutical composition of claim 7, wherein the platelet aggregation inhibitor is aspirin, a salt, a solvate, or a derivative thereof

9. The pharmaceutical composition of claim 7, wherein the aspirin, salt, solvate, or derivative thereof is in a delayed release or enteric-coated dosage form.

10. The pharmaceutical composition of claim 1 , wherein the HMG-Co-A inhibitor is selected from the group consisting of simvastatin, pravastatin, a salt, a solvate, or a derivative thereof.

11. The pharmaceutical composition of claim 10, wherein the HMG-Co-A inhibitor is simvastatin, a salt, a solvate, or a derivative thereof.

12. The pharmaceutical composition of claim 1, wherein the ACE inhibitor is selected from the group consisting of lisinopril, quinapril, enalapril, captopril, perindopril, ramipril, salts, solvates, and derivatives thereof.

13. The pharmaceutical composition of claim 11 , wherein the ACE inhibitor is lisinopril, a salt, a solvate, or a derivative thereof.

14. A pharmaceutical composition of any of claims 1-13, wherein the composition is an oral solid dosage form.

15. A pharmaceutical composition of claim 14, wherein the composition is a tablet, granules, pills, a capsule containing granules or micro-tablets, or any combination thereof.

16. A pharmaceutical composition of claim 15, which is a tablet.

17. A pharmaceutical composition of claim 15, which is a capsule.

18. The pharmaceutical composition of claim 1, wherein the composition comprises combination of lisinopril, a salt, a solvate, or a derivative thereof, simvastatin a salt, a solvate, or a derivative thereof, and delayed or enteric-coated aspirin, a salt, a solvate, or a derivative thereof, and a pharmaceutically acceptable carrier.

19. A pharmaceutical composition of claim 1 , wherein the composition comprises combination of simvastatin a salt, a solvate, or a derivative thereof, extended or modified release diltiazem, a salt, a solvate, or a derivative thereof, and delayed or enteric-coated aspirin a salt, a solvate, or a derivative thereof with a pharmaceutically acceptable carrier.

20. A kit containing the pharmaceutical agents of any of claims 1-19, either as dual or triple entities for administration to humans suffering from cardiovascular and related disorders.

21. The pharmaceutical composition of claim 1 , wherein the tablet is prepared by either wet granulation, dry granulation, direct compression or fluidized bed granulation techniques or a suitable combination of these.

22. The pharmaceutical composition of claim 23, wherein the process of preparing the said composition provides a multilayer system for the treatment of cardiovascular and related disorders.

23. A method for preparing the pharmaceutical composition of claim 1 , comprising the steps of:

(a) mixing and blending granules or beads comprising the active agents to form a granular composition; and

(b) filling capsules with the granular or bead composition using a capsule- filling machine or compressing the granular composition to form tablets

24. The method of claim 23, wherein the granular composition is prepared by preparing the granules or beads comprising each drug separately using wet granulation, dry granulation, direct compression, fluidized bed granulation or a suitable combination thereof, and mixing the granules or beads to obtain a granular composition and filling capsules with the granular composition using a capsule-filling machine or compressing the granular composition to form tablets.

25. The method of claim 24, wherein the granular composition is prepared by preparing the granules comprising lisinopril, a salt, a solvate, or a derivative thereof; simvastatin, a salt, a solvate, or a derivative thereof; and delayed release aspirin, a salt, a solvate, or a derivative thereof; using wet granulation, dry granulation, direct compression, fluidized bed granulation techniques or a combination thereof; and mixing the granules or beads to obtain a granular composition and filling capsules with the granular composition using a capsule- filling machine or compressing the granular composition to form tablets.

26. The method of claim 24, wherein the granular composition is prepared by preparing the granules comprising extended or modified release diltiazem, a salt, a solvate, or a derivative thereof; simvastatin, a salt, a solvate, or a derivative thereof; and delayed release aspirin, a salt, a solvate, or a derivative thereof using either wet granulation, dry granulation, direct compression, fluidized bed granulation techniques or a suitable combination thereof; and mixing the granules or beads to obtain a granular composition and filling capsules with the granular composition using a capsule-filling machine or compressing the granular composition to form tablets.

27. A method for prevention or treatment of cardiovascular and related disorders in a subject in need of said treatment, wherein the method comprises administering to the subject a pharmaceutical product or composition according to any of the claims from 1 to 22.

28. Use of the pharmaceutical composition of any of claims 1-22 in the manufacture of a medicament for treating cardiovascular and related disorders.