CARDIOVASCULAR COMBINATIONS USING

RENNIN-ANGIOTENSIN INHIBITORS

Reference to Related Applications

[0001] This application is a continuation of PCT application No. PCT/IB05/00346 filed February 9, 2005, which is 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 angiotensin II antagonists, lipid regulators (HMG CoA inhibitors), platelet aggregation inhibitors and diuretics. 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, maybe 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 the stroke, 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 increases cardiovascular morbidity.

[0005] A chief goal of antihypertensive therapy includes preventing major 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] Angiotensin-II receptor antagonists (or blockers) are a newer class of antihypertensive agents. These drugs are selective for angiotensin II (type 1 receptor); unlike angiotensin-converting enzyme inhibitors, they do not inhibit bradykinin metabolism or enhance prostaglandin synthesis.

[0007] The renin-angiotensin-aldosterone system is believed to play an integral role in the pathophysiology of hypertension because it affects the regulation of fluid volume, electrolyte balance and blood volume. Rennin, an enzyme produced primarily by the juxtaglomerular cells of the kidney, catalyzes the conversion of angiotensinogen into an inactive substance, angiotensin I (A-I). Angiotensin-converting enzyme (ACE) then converts A-I to the physiologically active angiotensin II (A-II), which causes potent vasoconstriction, aldosterone secretion and sympathetic activation. All of these actions can contribute to the development of hypertension. Angiotensin-II receptor antagonists act by binding to specific membrane-bound receptors that displace A-II from its type 1- receptor subtype (AT ₁ ). These drugs therefore function as selective blockers. Representive examples of angiotensin-II antagonists for use in the treatment of hypertension include losartan, valsartan, irbesartan, candesartan and telmisartan.

[0008] 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.

[0009] Combination therapy can involve multiple doses of multiple medications. A benefit of drug combinations may be the enhanced efficacy, which fosters widespread use. Some combinations can produce offsetting interactions that weaken side effects of therapy with a single drug. Another potential benefit of a combination therapy concerns possible avoidance of adverse effects, hi general, combination therapy has advantages such as (1) increased efficacy i.e., additive and 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.

[0010] Diuretic agents (diuretics) are also effective of antihypertensive medications. Treatment with diuretic agents can result in dose-dependent blood pressure reductions because they can inhibit of sodium reabsorption at specific sites in the renal tubules, hi long-term trials, diuretics have been shown to reduce the incidence of stroke, congestive heart failure, coronary artery disease and total mortality from cardiovascular disease. Diuretics reduce the sodium and water-retaining effects of other antihypertensive drugs, and thus, they are a commonly used medication in combination with antihypertensive agents. The most commonly prescribed of the diuretics class are thiazide diuretics. Thiazide diuretics may also relax the muscles in blood vessel walls, making blood flow more easily. Evidence from clinical trials indicates that thiazide diuretics can help decrease death and morbidity from high blood pressure. The most available combinations of diuretics are with ACE inhibitors and angiotensin-II antagonists. Representative commercial combinations include angiotensin-II antagonists with thiazide diuretics viz., losartan and hydrochlorothiazide, cadesartan, and hydrochlorothiazide, valsartan and hydrochlorothiazide, irbesartan and hydrochlorothiazide, and the like. [0011] 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-CoA reductase) are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C). [0012] Clinical and pathologic studies show that elevated plasma levels of total cholesterol (total-C), 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 of the cases. Statins exert their 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-CoA reductase) enzyme selectively. Atorvastatin is a selective, competitive inhibitor of HMG-CoA, the rate-limiting enzyme that converts 3-hydroxy-3-methyl- glutaryl-CoA to mevalonate, a precursor of steroids including cholesterol. It reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous familial hypercholesterolemia (FH), nonfamilial forms of hypercholesterolemia, and mixed dyslipidemia. It also reduces VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-I. It reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL- C, and increases HDL-C in patients with isolated hypertriglyceridemia.

[0013] 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.

[0014] 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 then be further bound together by a protein (fibrin) formed by clotting factors present in the blood. The clumps of platelets and fibrin make up the 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.

[0015] Aspirin is believed to prevent blood from clotting by blocking the production of platelets of thromboxane A-2 by inhibiting the enzyme cyclo-oxygenase-1 (COX-I) that produces 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.

[0016] Improved treatments for inhibiting platelet aggregation are currently being sought for individuals who are at risk for re-occlusion following thrombolytic therapy or angioplasty, transient ischemic attacks and other vaso-occlusive disorders. Therefore, the platelet aggregation inhibitors when administered in combination with HMG-CoA 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.

[0017] 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 involves 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.

[0018] 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.

[0019] A fixed dose administered as a once daily tablet offers dosage convenience and can help with patient compliance. Hence, 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, combination of angiotensin II antagonists (ARBs) and diuretics 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.

[0020] There are reports of combination therapy for the treatment of multiple pathological processes involved in cardiovascular and related diseases in the literature.

[0021] U.S. patent No. 6,677,356 discloses a method for treating hypertension comprising 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.

[0022] U.S. patent No. 6,669,955 discloses an orally administrable pharmaceutical composition comprising combination of cholesterol-lowering agent, an inhibitor of rennin-angiotensin system, aspirin and optionally at least one of vitamin B ₆ , B ₁₂ 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.

[0023] U.S. Patent No. 6,235,311 discloses pharmaceutical compositions that contain a statin plus aspirin, and optionally containing vitamins B ₆ , B ₁₂ or folic acid, as anti- oxidants, 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, fr

[0024] U.S. Patent Application No. 2003/0175344 discloses a formulation comprising 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 platelet 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.

[0025] U.S. Patent No. 6,251,852 discloses a combination therapy and pharmaceutical compositions comprised of a therapeutically effective amount of a cholesterol reducing agent such as an HMG-CoA 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.

[0026] U.S. Patent No. 6,403,571 is a from the same patent family as the '852 patent described above and also discloses a combination therapy and pharmaceutical compositions comprised of a therapeutically effective amount of an HMG-CoA 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 comprising a platelet aggregation inhibitor

selected from the group consisting of ticlopidine, clopidogrel, and dipyridamole, an HMG-CoA reductase inhibitor and a pharmaceutically acceptable carrier.

[0027] 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 CoA 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 B ₆ , vitamin B ₁₂ , and folic acid. The patent discloses pharmaceutical formulations combining all the active agents in unit-dose form for once-daily dosing.

[0028] U.S. Patent No. 6,248,729 disclose 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 comprising 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).

[0029] U.S. Patent No. 5,994,348 discloses a pharmaceutical composition comprising a combination of irbesartan and hydrocholorothiazide (a diuretic agent) with starch or pregelatinized starch as a binder wherein the formulation is free of povidone and poloxamer. The '348 patent specifically discloses the combination of irbesartan and hydrochlorothiazide.

[0030] U.S. Patent No. 6,294,197 discloses a compressed combination dosage form comprising valsartan and hydrochlorothiazide with at least one suitable excipient. The ' 197 patent specifically discloses the combination composition of valsartan and hydrochlorothiazide.

[0031] 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.

[0032] 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. [0033] 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 together 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.

[0034] 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 [0035] The present invention provides a composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor in a single dosage form. The composition is suitable for a combination therapy 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 platelet aggregation, 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. [0036] In another embodiment, the present invention provides a pharmaceutical composition and a process for manufacturing a composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, preferably in a single dosage form.

[0037] In another embodiment, the present invention provides a method for treating cardiovascular and related disorders, comprising administering to a mammal {e.g., a human) in need of such treatment, a pharmaceutical composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, preferably in a single dosage form.

[0038] In another embodiment, the present invention provides a delivery system for oral administration constituting the release in the body of a mammal (e.g., a human), a composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, preferably in a single dosage form.

[0039] hi another embodiment, the present invention provides an oral delivery system kit comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, together with suitable excipients thereof.

[0040] hi another embodiment, the present invention provides a method for using a composition for combination therapy for the treatment of cardiovascular and related disorders and disorders associated with hypertension, dyslipidemia, diabetic neuropathy, angina pectoris, or for inhibiting platelet aggregation, inhibiting the formation of thrombotic occlusions, and treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders. The composition of the invention is formulated such that the components of the tablet, capsule or kit are consumed, in any order, within 24 hours after administration of the drugs of the composition.

[0041] In another embodiment, the present invention provides a method for preparing a pharmaceutical dosage form for oral administration comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA 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 using suitable double or triple layer compressing machines. Alternatively, the granules of the composition can also be prepared using roll compaction, direct compression or fluidized bed granulation technique. The granules of the instant invention can also be prepared containing each drug separately and finally mixing to provide a granular mixture and compressing the granular mixture to provide multilayer tablets or filling capsules with the granular mixture.

[0042] 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.

Detailed Description of the Invention

[0043] As used 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.

[0044] 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.

[0045] The present invention provides a combination therapy comprising therapeutically effective amount of an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor in a single dosage form for prophylactic and therapeutic treatment of cardiovascular and related disorders and disorders 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. [0046] hi another embodiment, the present invention provides a pharmaceutical composition comprising an angiotensin II antagonist, a thiazide diuretic, an HMG CoA inhibitor and a platelet aggregation inhibitor, preferably in a single dosage form, along with suitable pharmaceutically acceptable excipients thereof. Non-limiting examples of angiotensin II antagonists include losartan, valsartan, irbesartan, telmisartan, candesartan and the like. Non-limiting examples of thiazide diuretics include chlorthalidone, hydrochlorothiazide and the like. Non-limiting examples of HMG CoA 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. [0047] In one embodiment, the invention comprises an angiotensin II antagonist selected from losartan, valsartan, irbesartan, telmisartan, candesartan and the like, the thiazide diuretic selected from chlorthalidone, hydrochlorothiazide and the like, the HMG CoA inhibitor selected from lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, velostatin and the like, the platelet aggregation inhibitor selected from aspirin,

clopidogrel, ticlopidine, dipyridamole, ifetroban, sulfipyrazone and the like preferably in a single dosage form, with suitable pharmaceutically acceptable excipients thereof.

[0048] The compositions of the invention having a combination of angiotensin II antagonists, diuretics, HMG CoA inhibitors and platelet aggregation inhibitors are suitable for treating cardiovascular and related disorders and disorders associated with hypertension, dyslipidemia, diabetic neuropathy, and angina pectoris. The compositions are also useful for inhibiting platelet aggregation, inhibiting the formation of thrombotic occlusions, and treating, preventing and reducing the risk of occurrence of cardiovascular and cerebrovascular events and related vaso-occlusive disorders. Thus, the invention provides a method for preventing, ameliorating or eliminating these disorders by administration of a composition of the invention, wherein the method includes administering to a patient (e.g., human) suffering from or susceptible to such a disorder, a therapeutically effectively amount of a composition of the present invention.

[0049] The term "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 human patient for the purpose of combating, the disease conditions as referred to above and can include the administration of a composition according to present invention to prevent the onset of symptoms or complications associated with such conditions. [0050] The term "composition" includes but is not limited to solutions, suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro-tablets, capsules, and pellets, comprising a therapeutically effective amount of the active agents of the composition of the invention in a core with suitable excipients thereof.

[0051] 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.

[0052] 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.

[0053] 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 compositions of the present invention provide an oral composition comprising at least one angiotensin II antagonist, at least one thiazide diuretic, at least one HMG CoA inhibitor and at least one platelet aggregation inhibitor with suitable pharmaceutically acceptable excipients thereof.

[0054] In another embodiment, the invention provides a kit comprising a composition including a therapeutically effective amount of an angiotensin-II antagonist, a therapeutically effective amount of a thiazide diuretic, a therapeutically effective amount of HMG CoA inhibitor, and a therapeutically effective amount of 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.

[0055] In 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 angiotensin-II antagonist, a therapeutically effective amount of a thiazide diuretic, a therapeutically effective amount of HMG CoA inhibitor, and a therapeutically effective amount of platelet aggregation inhibitor in suitable combinations of the agents. For example, the kit can include four (4) containers each having one pharmaceutical agent; three (3) containers, one container including two agents and the other two containers each including one

agent; two (2) containers, one container including one agent and the other container including the three remaining agents, or two (2) containers, with each container including two agents; or one container including a mixture of all four agents.

[0056] hi a specific embodiment, the kit is provided including two containers, as dual entities (each container having two agents) or triple entities, (with one container having three agents and the remaining agent in the other container) for treating an animal subject in need of treatment of cardiovascular and related disorders. Preferably, the animal is a human.

[0057] The composition of the present invention may be prepared by blending an angiotensin II antagonist, a thiazide diuretic, an HMG CoA 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 thereof, 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.

[0058] 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. 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-drug 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.

[0059] A preferred angiotensin II antagonist suitable for practicing the invention is selected from the group consisting of losartan, valsartan, irbesartan, telmisartan, candesartan and the like. A more preferred angiotensin II antagonist is losartan, irbesartan or valsartan; or a salt, solvate or derivative of these angiotensin II antagonists. A

preferred thiazide diuretic is selected from the group consisting of chlorthalidone, hydrochlorothiazide and the like. A more preferred thiazide diuretic is hydrochlorothiazide or a salt, solvate or derivative thereof. A preferred HMG CoA inhibitor is selected from the group consisting of lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, cerivastatin, velostatin and the like. A more preferred HMG CoA inhibitor is simvastatin or ; or a salt, solvate or derivative of these HMG CoA inhibitors. A preferred platelet aggregation inhibitor is selected from the group consisting of aspirin, clopidogrel, ticlopidine, dipyridamole, ifetroban, sulfipyrazone and the like. A more preferred platelet aggregation inhibitor is aspirin or clopidogrel ; or a salt, solvate or derivative of these platelet aggregation inhibitors. Even more preferably, the composition may comprise a combination of these active agents where aspirin may be formulated in delayed release form, such as enteric-coated granules as described herein.

[0060] hi a specific embodiment, the present invention provides, a tablet composition comprising a tablet core or layers provided with a delayed release or enteric-coated aspirin or a pharmaceutical acceptable salt, or solvate thereof, with at least one angiotensin II antagonist, one diuretic and one HMG CoA inhibitor, and suitable excipients.

[0061] hi another specific embodiment, the present invention provides a tablet composition comprising a tablet core or layers having clopidogrel or a pharmaceutical acceptable salt, or solvate thereof, with at least one angiotensin II antagonist, one diuretic and one HMG CoA inhibitor, and suitable excipients.

[0062] 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. [0063] 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.

[0064] 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 or hydrated form, or spray dried, and microcrystalline cellulose, starch and the like. The appropriate choice of diluents would be well known to a person having ordinary skill in the art, in order to achieve the desired pharmaceutical properties of a pharmaceutical composition according to present invention.

[0065] Suitable binders may also be employed using known methods. Such binders should 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.

[0066] 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.

[0067] 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.

[0068] In another embodiment, the present invention provides a tablet composition comprising 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

angiotensin II antagonist, one diuretic, and one HMG CoA inhibitor, with suitable excipients thereof.

[0069] 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 methaacrylic acid derivatives (for example,

Eudragit ^® polymers from Rohm Pharma), cellulose acetate phthalate, cellulose acetate maleate, cellulose acetate succinate, hydroxypropyhnethyl 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.

[0070] hi addition, the present invention includes a process for preparing a pharmaceutical product, or a pharmaceutical composition, or a medicament substantially as described herein.

[0071] In a specific embodiment, the granular compositions of the present invention include an angiotensin II antagonist selected from valsartan, irbesartan, losartan, salts, solvates or derivatives thereof; a thiazide diuretic preferably hydrochlorothiazide, a salt, solvate or derivative thereof; an HMG CoA inhibitor selected from simvastatin, pravastatin, salts, solvates or derivatives thereof; and a platelet aggregation inhibitor selected from aspirin (e.g., enteric-coated granules), clopidogrel, salts, solvates or derivatives thereof; blended and granulated using suitable binders that may be dissolved (in case of wet granulation) in aqueous and/or organic solvents and/or hydroalcoholic solvents thereof, dried and lubricated.

[0072] Alternatively, the granular compositions of the invention can be prepared using roll compaction, direct compression or fluidized bed granulation technique. The compositions can be prepared containing each drug separately using wet granulation or roll compaction or dry granulation or fluidized bed processor techniques and mixing and the granules to obtain granular compositions. Alternatively, granules may be prepared

containing a combination of angiotensin-II antagonist with a diuretic and granules containing the other two drugs separately using wet granulation or roll compaction or dry granulation or fluidized bed processor techniques and mixing the granules to obtain a granular composition with the four agents. [0073] In another embodiment, the present invention provides a composition comprising valsartan, or a salt, solvate or derivative thereof; hydrochlorothiazide, or a salt, solvate or derivative thereof; simvastatin, or a salt, solvate or derivative thereof; and aspirin (delayed release or enteric-release), prepared by forming granules of the valsartan and hydrochlorothiazide, and blending the valsartan and hydrochlorothiazide granules with granules of enteric-coated aspirin, and granules containing simvastatin to form a granular composition.

[0074] hi another embodiment, the present invention provides a composition comprising irbesartan, or a salt, solvate or derivative thereof; hydrochlorothiazide, or a salt, solvate or derivative thereof; pravastatin, or a salt, solvate or derivative thereof; and clopidogrel, or a salt, solvate or derivative thereof; prepared by by forming granules of the irbesartan and hydrochlorothiazide, and blending the irbesartan and hydrochlorothiazide granules with granules containing clopidogrel, and granules containing pravastatin to form a granular composition.

[0075] 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.

[0076] 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.

[0077] The tablets/capsules of the invention are orally administered in the amounts necessary to achieve a particular blood level. 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, Le., 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

[0078] 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 composition 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.

Valsartan + Simvastatin + Aspirin DR+ Hydrochlorothiazide capsules [0079] Example 1: Valsartan and Hydrochlorothiazide Granules

[0080] Procedure:

1. Valsartan, Hydrochlorothiazide, Lactose, Croscarmellose sodium, microcrystalline cellulose (MCC), Aerosil 200 and part of magnesium stearate are mixed.

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

3. The granules from Step 2 are mixed with Magnesium stearate and blended.

Example 2: Aspirin DR

[0081] Procedure:

1. Aspirin, MCC, HPMC and part of the Pregelatinized Starch, Talc and stearic acid are mixed and sifted together.

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

3. The remaining part of Pregelatinized Starch, Talc and stearic acid are mixed with granules of Step 2 and compressed using a suitable tool.

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

5. Eudragit L 30 D 55 is prepared by dilution with water and addition of triethyl citrate under constant stirring.

6. The seal coated tablets are coated with the Eudragit dispersion prepared in step 5 to obtain the desired weight build up.

Example 3: Simvastatin Granules

[0082] Procedure:

1. Simvastatin was mixed with lactose monohydrate and butylated hydroxy anisole in a suitable rapid mixer granulator.

2. The remaining lactose monohydrate is mixed with the following ingredients:

Avicel pH - 101

Pre Gelatinized Starch

Ascorbic Acid

Citric Acid Monohydrate

3. The mixture from Step 1 is mixed geometrically with the mixture from Step 2.

4. The above mixture are granulated with Purified water.

5. The above granules are lubricated with Ac - Di - Sol and Magnesium Stearate

Combination Composition:

[0083] The Granules obtained in Example 1 & 3 are mixed. The resultant granules & Aspirin DR tablets from Example 2 are added to capsules using a suitable capsule-filling machine.

It can also be compressed, as tablet in tablet where Aspirin DR tablets is the core tablet and granules of example 1 & 3 would be coating of the core tablet.

Example 4: Aspirin Granules for Tri-layer Tablets

[0084] Procedure: 1. Aspirin, MCC, HPMC and Pregelatinized Starch are mixed and sifted together. The mixture is granulated using water or suitable solvent.

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

3. The beads are coated with Opadry clear to obtain a seal coat. 4. Eudragit L 30 D 55 is prepared by dilution with water and addition of triethyl citrate under constant stirring.

5. The seal coated beads are coated with the Eudragit dispersion prepared in step 4.

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

Combination Composition:

Granules prepared in Example 1, 3 & 4 are compressed as a tri-layer tablet. Irbesartan + Clopidogrel + Pravastatin + Hydrochlorothiazide

Example 7: Irbesartan and Hydrochlorothiazide Granules

[0085] Procedure:

1. Irbelsartan, Hydrochlorothiazide, Lactose, Croscarmellose sodium, MCC, Aerosil 200 and part of the magnesium stearate are mixed.

2. The mixture from Step 1 is compacted using the 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 granules from step 2 are mixed with Magnesium stearate and blended.

Example 8: Granules of Clopidogrel 75 nig

[0086] Procedure:

1. The Clopidogrel and part of the polyethylene glycol 6000 are co-sifted and mixed.

2. The mixture is transferred to a Fluidized Bed Dryer and heated at 6O ⁰ C (PEG 6000 melts) with fluidization and granulation.

3. The granules are sifted using a suitable sieve.

4. The remaining PEG 6000 (2.12 % or 5 mg) is mixed with the granules obtained from Step 3 to obtain a uniform mixture. The mixture is transferred to a Fluidized Bed Dryer and heated at 60°C with fluidization and granulated.

5. The final granules are dried and sifted using a suitable sieve.

6. Microcrystalline cellulose, Lactose Anhydrous, Crosspovidone and mannitol are sifted and mixed with the granules obtained from Step 5.

7. Talc and colloidal silicon dioxide are sifted and mixed using a suitable blender with the granules from Step 6.

8. The granules from step 7 are blended, sifted and lubricated with hydrogenated castor oil and Glyceryl Behenate, for 2 min.

Example 9: Pravastatin sodium Granules

[0087] Procedure:

1. Pravastatin, Polacrilin potassium and Carboxymethylcellulose calcium are weighed, screened and mixed in suitable blender.

2. Anhydrous lactose, macrocrystalline cellulose and colloidal silicon dioxide (weighed, screened) are added to the mixture from Step 1. The composition is mixed in a suitable blender.

3. Magnesium stearate (weighed, screened) is added to the mixture from Step 2. The composition is mixed in suitable blender.

Example 10: Tablets and Capsules [0088] Using a suitable capsule-filling machine, capsules are prepared using granules obtained in Examples 7, 8, and 9.

[0089] A tri-layer tablet is prepared using the granules obtained in Examples 7, 8, and 9.

[0090] All references cited herein are expressly incorporated herein by reference in their entirety intlOo 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.