FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"Pharmaceutical compositions"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956


(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.



Technical field of the Invention:
The present invention relates to combination of medicaments for their simultaneous, separate or sequential administration for preventing or treating cardiovascular disorders. The present invention also relates to a method of manufacture and use of the same.
Background and prior art of Invention:
Globally, cardiovascular diseases are the number one cause of death and is projected to remain so. An estimated 17.5 million people died from cardiovascular disease in 2005, representing 30 % of all global deaths. Of these deaths, 7.6 million were due to heart attacks and 5.7 million due to stroke. About 80% of these deaths occurred in low- and middle-income countries. If current trends are allowed to continue, by 2015 an estimated 20 million people will die from cardiovascular disease.
Cardiovascular diseases include coronary heart disease (heart attacks), cerebrovascular disease, raised blood pressure (hypertension), peripheral artery disease, rheumatic heart disease, congenital heart disease and heart failure. The major causes of cardiovascular disease are tobacco use, physical inactivity, and an unhealthy diet. The major clinical risk factors for cardiovascular diseases are hypertension, hypercholestromia, hyperhomocysteinemia. The underlying pathophysiology of the clinical risk factors include increase in the risk factors of blood pressure, plasma and serum cholesterol, plasma and serum homocysteine and impair platelet function and coagulation.
Various conventional therapies are currently available for the treatment of cardiovascular diseases but are limited to reduce independent risk factor. The recent approach to treat the cardiovascular diseases is to aim at all the risk factors with the aid of a single formulation wherein this approach suggests the use of combination of drugs, administered simultaneously, separately or sequentially in a single unit dosage form. This approach is also more convenient not only from patient compliance point of view but also from point of view of easy manufacturing than the conventional method of treatment. Many drugs are known for the treatment of cardiovascular diseases such as for example calcium channel blockers, angiotensin II receptor blockers, diuretics, HMG CoA reductase
2

inhibitors, beta blockers, ACE inhibitors, serum homocysteine lowering agent, antiplatelet agents and so on.
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) ,calcium channel blockers, and diuretics with platelet aggregation inhibitors and statins or combination of angiotensin II antagonists (ARBs) ,calcium channel blockers, and diuretics with serum homocysteine lowering agent and statin 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.
Many calcium channel blockers slow down the conduction of electrical activity within the heart, by blocking the calcium channel during the plateau phase of the action potential of the heart. This is known as a negative dromotropic effect. It causes a lowering of the heart rate and may cause heart block which is known as the negative chronotropic effect of calcium channel blockers. The negative chronotropic effects of calcium channel blockers make them a commonly used class of agents in individuals with atrial fibrillation or flutter in whom control of the heart rate is an issue.
Angiotensin-II receptor antagonists (or blockers) are a class of antihypertensive agents which are selective for angiotensin II (type 1 receptor). They block the activation of angiotensin II receptor blocker. Blockade of ATi receptors directly causes vasodilation, reduces secretion of vasopressin, reduces production and secretion of aldosterone, amongst other actions - the combined effect of which is reduction of blood pressure.
3

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 sodium reabsorption at specific sites in the renal tubules. 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.
Beta blockers are a class of drugs used for various indications, but particularly for the management of cardiac arrythmias and cardioprotection after myocardial infarction. (Heart attack)
ACE inhibitors are competitive inhibitors of Angiotensin converting enzyme .They directly block the formation of angiotensin II and reduce the bradykinin level. The net results are reduced vasoconstriction, reduced sodium and water retention and increased vasodilation.
During the past few years, elevated blood levels of homocysteine (a sulfur-containing amino acid) have been linked to increased risk of premature coronary artery disease, stroke, and thromboembolism (venous blood clots), even among people who have normal cholesterol levels. Abnormal homocysteine levels appear to contribute to atherosclerosis in at least three ways: (1) a direct toxic effect that damages the cells lining the inside of the arteries, (2) interference with clotting factors, and (3) oxidation of low-density lipoproteins (LDL). Thus there is a need to administer a homocysteine lowering agent along with other drugs administered for treating cardiovascular diseases.
Most of the combination therapies present to treat the cardiovascular disorders do not include a homocysteine lowering agents and so there is a need to provide a
4

pharmaceutical cornposition that contains a homocysteine lowering agent in addition to other drugs that are used for treating cardiovascular diseases.
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-coeiizyme A reductase (HMG-CoA reductase) are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C). 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.9 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.
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.


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.
While formulating various different classes of drugs that have diverse physicochemical properties and belong to unrelated chemical classes, one can encounter various difficulties 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.
The physiological effects of antihypertensive agents such as calcium channel blockers, [beta]-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.
In the literature, there are reports of combination therapy for the suppression of risk factors involved in cardiovascular and related diseases.


WO 01/76632 discloses a pharmaceutical formulation that contains at least two agents that lower blood pressure such as diuretic, beta blocker, ACE inhibitor, Angiotensin II receptor antagonist, calcium channel blocker in combination with lipid regulating agent, platelet function regulating agent and serum homocysteine lowering agent.
WO200511586 discloses a pharmaceutical oral dosage form comprising therapeutic amounts of a beta adrenergic receptor antagonist, a diuretic, a cholesterol lowering agent, an inhibitor of renin- angiotensin system, and aspirin. However, the said formulation comprises aspirin, an acidic drug which can react with the basic drugs of the other classes in the formulation. To avoid this incompatibility, there is a need to take precautions during manufacturing of this formulation.
Accordingly, there still remains a need for developing a pharmaceutical composition and/or medicament as a single unit dosage form comprising one or more actives being compatible with each other and with suitable excipients. Further, there is a need for a composition and/or medicament that allows ease of manufacture on a large scale. The composition and/or medicament can improve the treatment of cardiovascular disorders through enhanced patient compliance because of ease of administration and a reduced frequency of dosing.
Obj ect of the invention:
An object of the present invention is to provide a novel pharmaceutical composition comprising combination of one or more actives for preventing or treating cardiovascular diseases.
Another object of the present invention is to provide a novel pharmaceutical composition which is stable and avoids the incompatibility problem between one or more actives and the excipients.
Still another object of the present invention is to provide a novel pharmaceutical composition with ease of manufacture.
7

Another object of the present invention is to provide a pharmaceutical composition comprising combination of one or more actives with one or more pharmaceutically acceptable excipients wherein the composition may be administered simultaneously, separately or sequentially.
Yet another object of the present invention is to provide a method to manufacture a pharmaceutical composition comprising combination of one or more actives for prophylaxis and/or treatment of cardiovascular diseases.
Summary of the Invention:
According to one aspect of the present invention, there is a provided a pharmaceutical combination of one or more actives comprising:
i) at least one blood pressure lowering agent or its salts, solvates, tautomers,
derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof ii) at least one lipid regulating agent or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
According to another aspect of the present invention, there is a provided a pharmaceutical composition of one or more actives comprising:
i) at least one blood pressure lowering agent or its salts, solvates, tautomers,
derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof ii) at least one lipid regulating agent or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof and optionally at least one serum homocysteine lowering agent or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof with one or more pharmaceutically acceptable excipients.
According to another aspect of the present invention, there is a provided a pharmaceutical composition of one or more actives comprising:
8

i) at least one blood pressure lowering agent or its salts, solvates, tautomers,
derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof ii) at least one lipid regulating agent or its salts, solvates, tautomers, derivatives,
enantiomers, isomers, hydrates, prodrugs or polymorphs thereof iii) at least one serum homocysteine lowering agent or its salts, solvates,
tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or
polymorphs thereof and optionally at least one antiplatelet agent or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof with one or more pharmaceutically acceptable excipients.
According to another aspect of the present invention, there is a provided a pharmaceutical composition of one or more actives comprising:
i) at least one blood pressure lowering agent or its salts, solvates, tautomers,
derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof
ii) at least one lipid regulating agent or its salts, solvates, tautomers, derivatives,
enantiomers, isomers, hydrates, prodrugs or polymorphs thereof and optionally at least one antiplatelet agent and/or a at least one serum homocysteine lowering agent or their salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof wherein the composition may be administered simultaneously, separately or sequentially.
According to further aspect of the present invention, there is provided a process to manufacture a pharmaceutical composition comprising combinations of the present invention.,
Detailed Description of the Invention:
As discussed herein, the inventors have surprisingly found that the combination of one or more blood pressure lowering agents and one or more lipid regulating agent with one or more pharmaceutically acceptable excipients in a single formulation can treat cardiovascular diseases by alleviating substantially all the risk factors.
9

The blood pressure lowering agents may comprise one or more Calcium channel blockers, angiotensin II receptor blockers, diuretics, beta blockers, angiotensin converting enzyme inhibitors (ACE inhibitors).
The pharmaceutical composition of the present invention comprises combination of one or more blood pressure lowering agents comprising one or more of calcium channel blockers, angiotensin II receptor blockers, diuretics along with one or more lipid regulating agents with one or more pharmaceutically acceptable excipients to treat the risk factors of cardiovascular diseases. Optionally, the composition may comprise one or more of one serum homocysteine lowering agent and one or more antiplatelet agent.
The calcium channel blocker , according to the present invention, may be selected from, but is not limited to, amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine, nitrendipine, nisoldipine and the possible pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof
The angiotensin II receptor blocker, according to the present invention, may be selected from, but is not limited to, valsartan, telmisartan, losartan, irbesartan ,olmesartan, and the possible pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
The diuretics, according to the present invention, may be selected from, but is not limited to, Bendroflumethiazide , Hydroflumethiazide, Hydrochlorothiazide, Chlorothiazide, Polythiazide, Trichlormethiazide, Cyclopenthiazide, Methyclothiazide, Cyclothiazide, Mebutizide and the possible pharmaceutically acceptable salts, pharmaceutically
10

acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
The angiotensin converting enzyme inhibitors (ACE inhibitors), according to present invention, may be selected from, but is not limited to, captopril, Benazepril, alacepril, cilazepril, delapril, enalapril, fosinopril, imidapril, tisinopril, ramipril, perindopril, quinapril, and the possible pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
The beta blocker, according to present invention, may be selected from, but is not limited to, acebutolol, atenolol, betaxolol, esmolol, bisoprolol, metoprolol, nebivolol, amusulalol, landiolol, tilisolol and the possible pharmaceutically acceptable salts, pharmaceutically' acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
The lipid regulating agent, according to present invention, may be selected from, but is not limited to, statins or its salts, solvates, tautomers, derivatives, enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
The statins according to the present invention, may be selected from, but is not limited to, cerivastatin, atorvastatin, lovastatin, simvastatin, rosuvastatin, pravastatin, mevastatin, fluvastatin, rivastatin, pravastatin and the possible pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantibmers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
11

The serum homocysteine lowering agents according to the present invention, may be selected from isoleucine, leucine, valine, or glycine, folic acid and the possible pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
The antiplatelet agent according to present invention is aspirin and the possible pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
The term blood pressure lowering agents, calcium channel blockers, angiotensin II receptor blockers, diuretics , lipid regulating agents , serum homocysteine lowering agents and antiplatelet agents are mentioned in the description as well as the claims in a broad sense to include not only blood pressure lowering agents, calcium channel blockers, angiotensin II receptor blockers, diuretics , lipid regulating agents , serum homocysteine lowering agents and antiplatelet agents per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
According to one embodiment of the present invention, the pharmaceutical composition comprises one or more blood pressure lowering agent selected from calcium channel blocker, Angiotensin II receptor blockers, diuretic and lipid regulating agent selected from statins in the single formulation.
According to another embodiment, the present invention provides a kit comprising a single formulation of calcium channel blocker, Angiotensin II receptor blockers, diuretic
12

; lipid regulating agent selected from statins and a serum homocysteine lowering agent, as a separate formulation.
According to yet another embodiment of the present invention, the pharmaceutical composition comprises one or more blood pressure lowering agent selected from beta blocker, Angiotensin II receptor blockers, diuretic; lipid regulating agent selected from statins alongwith serum homocysteine lowering agent in the single formulation.
According to a further embodiment, the present invention provides a kit comprising a single formulation of beta blocker, Angiotensin II receptor blocker, diuretic; lipid regulating agent selected from statins and serum homocysteine lowering agent and a antiplatelet agent as a separate formulation.
In a preferred embodiment of the present invention, there is provided a pharmaceutical composition comprising Amlodipine, losartan and (Hydrochlorothiazide) HCTZ, Atorvastatin. However, it is known that Amlodipine is highly unstable with many drugs when combined together in composition. Further, Amlodipine shows low dissolution profile when formulated with Losartan and Hydrochlorothiazide. The present invention has overcome this incompatibility by formulating the composition as a trilayered formulation by incorporating Amlodipine in a separate layer than the Losartan and Hydrochlorothiazide layer and atorvastatin in a next layer.
Further, the present invention provides a kit comprising the trilayer tablet of amlodipine, losartan and HCTZ and atorvastatin, with folic acid as a separate tablet. Such a combination is useful for patients who are suffering from cardiovascular disease and have high serum homocysteine level.
In yet another preferred embodiment of the present invention there is provided a pharmaceutical composition comprising atenolol, Losartan and HCTZ, Simvastatin, and folic acid. However, Atenolol shows incompatibility with losartan and
13

Hydrochlorothiazide The present invention has overcome this incompatibility by incorporating the granules of atenolol with the granules of losartan and HCTZ Further, Simvastatin is prone to degradation without citric acid. Simvastatin is stabilised by addition of accidulants selected from acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, phosphoric acid, and tartaric acid.But the addition of acid to Simvastatin increases the bulk of the formulation. So, it cannot be combined with other drugs. The inventors have thus overcome the difficulties mentioned above by formulating the composition as a trilayered formulation comprising one layer of atenolol, losartan and HCTZ another layer of folic acid and next layer of simvastatin.
Further if this combination is given with Aspirin it would be immense use to patients who are at high risk of cardiovascular diseases.But aspirin is prone to degradation when it comes in contact with aqueous solvent. So, it is difficult to formulate with other drugs. Further, aspirin gets degraded in GIT and does not reach in small intestine in non degraded form. So the aspirin tablet needs to be provided separately as an enteric coated tablet.
Thus, the present invention provides a kit comprising trilayer tablet of atenolol, losartan and HCTZ, simvastatin, folic acid and aspirin as a separate tablet.
According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising trilayered tablet comprising Amlodipine , Losartan and Hydrochlorothiazide and simvastatin .
Further, the present invention also provides a kit comprising the trilayer tablet of amlodipine, losartan and HCTZ and simvastatin, with folic acid as a separate tablet. Such a combination is useful for patients who are suffering from cardiovascular disease and have high serum homocysteine level.
14

In yet another preferred embodiment of the present invention there is provided a pharmaceutical composition comprising trilayered tablet comprising a layer of atenolol, losartan and HCTZ, another layer of folic acid and next layer of atorvastatin.
Further, the present invention provides a kit comprising trilayer tablet of atenolol, losartan and HCTZ, atorvastatin, folic acid and aspirin as a separate tablet. Such a combination is useful for patients who are at high risk of cardiovascular diseases.
Thus, the formulations according to the present invention may be administered simultaneously, separately or sequentially in unit solid dosage form suitable for oral administration.
It is further well known in the art that a tablet formulation is the preferred solid dosage form due to its greater stability, less risk of chemical interaction between different medicaments, smaller bulk, accurate dosage, and ease of production.
Solid dosage forms according to the present invention are preferably in the form of tablets but other conventional dosages such as powders, pellets, granules may be present. Alternatively, these tablets, pellets, granules, and the like may be administered directly or may be incorporated in capsule, sachets.
According to a preferred embodiment, the formulation may be administered simultaneously, separately or sequentially in a single unit dosage form wherein both the drugs and excipients are present in a single layer entity (such as a tablet) or by means of multilayer structuring i.e. one or more active with excipients may be present in one or more layers.
Further, the layers of the actives as described in the present invention are interchangeable.
15

The pharmaceutical composition of the present invention may be manufactured using suitable pharmaceutical excipients such as binders, fillers, disintegrants, lubricants, diluents etc.
Suitable binders may include, but are not limited to one or more of calcium phosphate-dibasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and equivalents thereof.
Suitable filler materials may include, but are not limited to silicon dioxide, titanium oxide, alumina, talc, kaolin, powdered cellulose, microcrystalline cellulose, and the like, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, sorbitol, and the like.
Suitable disintegrant materials may include, but are not limited to and are generally starches, clays, celluloses, algins, gums or crosslinked polymers ,one or more of low substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium starch glycollate, crospovidone, croscarmellose sodium, starch, crystalline cellulose, hydroxypropyl starch, and partially pregelatinized starch.
Suitable lubricant materials may include, but are not limited to stearic acid, magnesium stearate, calcium stearate, talc, and hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, colloidal silicon dioxide and equivalents thereof.
Suitable diluents may include, but are not limited to, calcium phosphate-dibasic, calcium sulfate, cellulose-microcrystalline, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and equivalents thereof.
16

Suitable anti-tacking agent may include, but are not limited to talc, stearic acid derivatives, magnesium stearate, glyceryl monostearate, titanium dioxide and the like. Most preferably, purified talc may be used in the formulation.
Alternatively, the pharmaceutical composition according to present invention the formulation may be film coated. Still alternatively, the formulation may be seal coated and further film coated.
The present invention also provides a method of manufacturing the said multilayer tablet.
The ingredients may be formulated into dosage forms according to the invention by conventional methods well known in the art. The said tablet formulation, according to the invention, may conveniently be prepared, for example, by using direct compression or wet or dry granulation processes. In wet granulation, the active ingredient(s) and excipients are blended and then mixed, in the presence of a liquid such as water to form granules. These granules may then be dried, sieved or milled to the desired particle size and compressed into tablets, with other excipients such as lubricants being added before compression.
Accordingly, one of the layer comprising the calcium channel blocker may be mixed with intragranular excipients which includes, but not limited to, diluents, disintegrants and granulated with suitable binder , sieved, sifted and lubricated and dried .The granules may then be compressed into single layer.
Another layer comprising one or more of angiotensin II receptor blocker may be mixed with intragranular excipients which includes, but not limited to, diluents, disintegrants and granulated with suitable binder, sieved, sifted and lubricated and dried. The granules may then be compressed into single layer.
Yet another layer comprising the lipid regulating agent, such as statins, may be mixed with intragranular excipients which includes, but not limited to, diluents, disintegrants
17

and granulated with suitable binder, sieved, sifted and lubricated and dried. The granules may then be compressed into single layer.
Further, another layer comprising combination of angiotensin II receptor blocker, diuretic and beta blocker may be mixed with intragranular excipients which includes, but not limited to, diluents, disintegrants and granulated with suitable binder, sieved, sifted and lubricated and dried. The granules may then be compressed into single layer.
Also, yet another layer comprising the serum homocysteine lowering agent, may be mixed with intragranular excipients which includes, but not limited to, diluents, disintegrants and granulated with suitable binder, sieved, sifted and lubricated and dried. The granules are then compressed into single layer.
According to one embodiment of the present invention, granules of different class of drugs as described hereinforth above may be compressed into multilayer such as trilayered tablet.
The formulation of the serum homocysteine lowering agent may be compressed as a single unit dosage form wherein both the drug and excipients may be present in a single layer entity (such as a tablet).
Alternatively, the formulation of the antiplatelet agent is in a single unit dosage form wherein both the drug and excipients may be present in a single layer entity (such as a tablet).
According to the present invention , the novel pharmaceutical composition comprising one or more blood pressure lowering agent and one or more lipid regulating agent with one or more pharmaceutically acceptable excipients may be administered simultaneously, separately or sequentially with at least one serum homocysteine lowering agent in the form of a kit.
18

Alternatively, according to the present invention, the pharmaceutical composition comprising one or more blood pressure lowering agent, one or more lipid regulating agent and one or more serum homocysteine lowering agent with one or more pharmaceutically acceptable excipients may be administered simultaneously, separately or sequentially with at least one antiplatelet agent in the form of a kit.
The administration of the formulation of the present invention, according to one embodiment is in the form of a kit, which can be easily administered to elderly patients who are at risk at risk of cardiovascular diseases, thus signifying patient compliance.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
1. Formula 1:A. Trilayered tablet

INGREDIENTS QTY (mg /tab)
Amlodipine besylate layer:
Amlodipine besylate 3.46
Microcryatalline cellulose 80.33
Pregelatinized starch 53.00
Corn starch 10.00
Colloidal silicon dioxide 1.50
Ferric oxide 0.20
Magnesium stearate 1.50
Dicalcium Phosphate 50.00
Total 200.00
Losartan potassium and hydrochlorothiazide layer
Losartan potassium 25.00
Hydrochlorothiazide 12.50
Microcrystalline cellulose 116.55
Pregelatinised starch 10.00
19

Croscarmellose sodium 10.00
Lactose monohydrate 75.00
Magnesium stearate 0.75
Sunset yellow FD& C 0.2
Total 250.00
Atorvastatin layer
Atorvastatin 10.84
Mannitol 118.66
Calcium carbonate 2.50
Croscarmellose sodium 10.00
Polyethylene glycol 2.00
Calcium stearate 4.00
Talc 2.00
Total 150.00
B. Folic acid tablet:

INGREDIENTS QTY (mg /tab)
Folic acid 0.88
Sodium starch glycolate 4.00
Microcryatalline cellulose 28.50
Lactose monohydrate 45.52
Magnesium stearate 0.80
Total 80.00
Process:
1, The granules of Amlodipine besylate were prepared with the intra granular
ingredients with the direct compression process.
2. The granules of Losartan and Hydrocholorothiazide were prepared with the intra
granular ingredients with the wet granulation process.
20

3. The granules of Atorvastatin were prepared with the intra granular ingredients with the direct compression process.
4. The granules of step 1, 2, 3 were compressed to form a three layer tablet.
5. The granules of folic acid were prepared with the intra granular ingredients with the wet granulation process.
6. Granules of step 5 were compressed to form a tablet.
Formula 2:
A. Trilayered tablet

INGREDIENTS QTY (mg /tab)
Losartan Potassium ,HCTZ, Atenolol layer
Atenolol 25.00
Sodium starch glycolate 20.00
Hypermellose 1.25
Purified water q.s
Total 46.25
Losartan potassium 25.00
Hydrochlorothiazide 12.50
Microcrystalline cellulose 99.25
Pregelatinised starch 10.00
Lactose monohydrate 56.00
Magnesium stearate 1.00
Total 250.00
Simvastatin layer
Simvastatin 40.00
Lactose monohydrate 263.11
Pregelatinised starch 40.00
Ascorbic acid 10.00
Microcrystalline cellulose 20.00
Ferric oxide 0.20
21

Citric acid monohydrate 5.00
Lactose monohydrate 7.50
Purified water q.s.
Butylated hydroxyl anisole 0.20
Pregelatinised starch 10.00
Magnesium stearate 4.00
Total 400.00
Folic acid layer
Folic acid 0.88
Sodium starch glycolate 10.00
Microcrystalline cellulose 75.00
Lactose monohydrate 112.00
Magnesium stearate 2.00
Total 200.00
B. Aspirin enteric coated tablet

INGREDIENTS QTY(mg/tab)
Aspirin 75.00
Pre gelatinized starch 13.00
Colloidal silicon dioxide 1.00
Stearic acid 0.50
Seal coating
Hypermellose 2.50
Purified water q.s
Total 92.50
Enteric coating
Methacrylic acid copolymer dispersion 4.65
Triethyl citrate 0.63
Titanium dioxide 0.50
22

Talc 1.22
Purified water q.s
Total 99.50
Overcoating
Hypermellose 2.50
Purified water q.s
Total 102.00
1. The granules of losartan potassium, HCTZ and atenolol were prepared with the intra granular ingredients with the wet granulation process.
2. The granules of simvastain were prepared with the intragranular ingredients with the wet granulation process.
3. The granules of folic acid were prepared with the intra granular ingredients with the direct compression process.
4. The granules of step 1, 2, 3 were compressed to form a three layer tablet.
5. The granules of aspirin were prepared with the intra granular ingredients with the direct compression process.
6. Granules of step 5 were compressed to form a tablet and further seal coated and enteric coated.
Formula 3:
A. Trilayered tablet

INGREDIENTS QTY(mg/tab)
Losartan Potassium ,HCTZ, Atenolol layer
Atenolol 25.00
Sodium starch glycolate 20.00
Hypermellose 1.25
Purified water q.s
Total 46.25
Losartan potassium 25.00
Hydrochlorothiazide 12.50
23

Microcrystalline cellulose 99.25
Pregelatinised starch 10.00
Lactose monohydrate 56.00
Magnesium stearate 1.00
Total 250.00
Atorvastatin layer
Atorvastatin 10.84
Mannitol 1158.46
Calcium carbonate 2.50
Ferric oxide 0.20
Croscarmellose sodium 10.00
Polyethylene glycol 2.00
Calcium stearate 4.00
Talc 2.00
Total 150.00
Folic acid layer
Folic acid 0.88
Sodium starch glycolate 10.00
Microcrystalline cellulose 75.00
Lactose monohydrate 112.00
Magnesium stearate 2.00
Total 200.00
C. Aspirin enteric coated tablet

INGREDIENTS QTY(mg/tab)
Aspirin 75.00
Pre gelatinized starch 13.00
Colloidal silicon dioxide 1.00
Stearic acid 0.50
24
•t

Seal coating
Hypermellose 2.50
Purified water q.s
Total 92.50
Enteric coating
Methacrylic acid copolymer dispersion 4.65
Triethyl citrate 0.63
Titanium dioxide 0.50
Talc 1.22
Purified water q.s
Total 99.50
Overcoating
Hypermellose 2.50
Purified water q.s
Total 102.00
1. The granules of losartan potassium, HCTZ and atenolol were prepared with the intra granular ingredients with the wet granulation process.
2. The granules of atorvastatin were prepared with the intragranular ingredients with the direct compression process.
3. The granules of folic acid were prepared with the intra granular ingredients with the wet granulation process.
4. The granules of step 1, 2, 3 were compressed to form a three layer tablet.
5. The granules of aspirin were prepared with the intra granular ingredients with the direct compression process.
6. Granules of step 5 were compressed to form a tablet and further seal coated and enteric coated.
Formula 4:
1. Trilayered tablet
25

INGREDIENTS QTY(mg/tab)
Amlodipine besylate layer:
Amlodipine besylate 3.46
Microcryatalline cellulose 80.33
Pregelatinized starch 53.00
Corn starch 10.00
Colloidal silicon dioxide 1.50
Ferric oxide 0.20
Magnesium stearate 1.50
Dicalcium phosphate 50.00
Total 200.00
Losartan potassium and hydrochlorothiazide layer
Losartan potassium 25.00
Hydrochlorothiazide 12.50
Microcrystalline cellulose 116.55
Pregelatinised starch 10.00
Croscarmellose sodium 10.00
Lactose monohydrate 75.00
Magnesium stearate 0.75
Sunset yellow FD&C 0.2
Total 250.00
Simvastatin layer
Simvastatin 40.00
Lactose monohydrate 263.11
Pregelatinised starch 40.00
Ascorbic acid 10.00
Microcrystalline cellulose 20.00
Ferric oxide 0.20
Citric acid monohydrate 5.00
Lactose monohydrate 7.50
26

Purified water q.s
Butylated hydroxyl anisole 0.200
Pregelatinised starch 10.00
Magnesium stearate 4.00
Total 400.00
C. Folic acid tablet:

INGREDIENTS QTY (mg /tab)
Folic acid 0.88
Sodium starch glycolate 4.00
Microcryatalline cellulose 28.50
Lactose monohydrate 45.52
Magnesium stearate 0.80
Total 80.00
Process:
1. The granules of Amlodipine besylate were prepared with the intra granular ingredients with the direct compression process.
2. The granules of Losartan and Hydrocholorothiazide were prepared with the intra granular ingredients with the wet granulation process.
3. The granules of simvastatin were prepared with the intra granular ingredients with the direct process.
4. The granules of step 1,2,3 were compressed to form a three layer tablet.
5. The granules of folic acid were prepared with the intra granular ingredients with the wet granulation process.
6. Granules of step 5 were compressed to form a tablet.
27

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise.
Dated this 26th day of August 2008

28