NZ621666B2 - Methods for treating cardiovascular disorders - Google Patents

Abstract

Provided is a pharmaceutical dosage form which comprises a fixed dose combination of metoprolol in extended release form with one or more calcium channel blockers, angiotensin II receptor blockers or angiotensin converting enzyme inhibitors and one or more rate controlling excipients wherein the dosage form exhibits a dissolution profile such that 6% or less of metoprolol is released within 1 hour; between 25% to 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after 20 hours, when the release rate is measured in USP Type 2 Dissolution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium. age form exhibits a dissolution profile such that 6% or less of metoprolol is released within 1 hour; between 25% to 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after 20 hours, when the release rate is measured in USP Type 2 Dissolution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium.

Description

METHODS FOR TREATING CARDIOVASCULAR DISORDERS Field Of The Invention The present invention relates to a once-a-day therapeutically synergistic pharmaceutical dosage form for treatment of cardiovascular ers, wherein the dosage form comprises a fixed dose combination of metoprolol in extended release form and one or more calcium channel blocker, angiotensin II receptor r or angiotensin converting enzyme (ACE) inhibitor along with one or more rate lling excipient.

Background Of The Invention ovascular disease or disorder" is intended to mean any cardiovascular disease or disorder known in the art, ing congestive heart failure, complications associated with diabetes mellitus, hyperhomocysteinemia, hypercholesterolemia, atherosclerosis, inflammatory heart disease, valvular heart disease, restenosis, hypertension (e.g. pulmonary hypertension, labile hypertension, idiopathic hypertension, low-renin hypertension, salt-sensitive hypertension, low-renin, salt-sensitive hypertension, thromboembolic pulmonary hypertension; ncy-induced hypertension; renovascular hypertension; hypertension-dependent end-stage renal disease, hypertension associated with cardiovascular surgical procedures, hypertension with left ventricular hypertrophy, and the like), lic dysfunction, coronary artery e, myocardial infarctions, cerebral infarctions, arteriosclerosis, atherogenesis, cerebrovascular disease, angina (including chronic, stable, unstable and variant (Prinzmetal) angina is), aneurysm, ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, vascular or non-vascular complications associated with the use of medical devices, vascular or non-vascular wa|| damage, peripheral vascular e, neointimal hyperplasia ing aneous transluminal coronary angiograph, ar grafting, coronary artery bypass surgery, thromboembolic events, post- angioplasty restenosis, coronary plaque mation, embolism, stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, thrombotic occlusion and reclusion ovascular incidents, and the like.

Many individuals are at an elevated risk of suffering s to life-threatening cardiovascular events, including infarction (heart attack), cardiac arrest, congestive heart e, stroke, peripheral vascular disease and/or claudication. The risk factors are numerous and widespread throughout the world population. They include cigarette smoking, diabetes, hypercholesterolemia (high serum cholesterol), hypertension, angina, ic lupus erythematosus, prior heart attacks or strokes, hemodialysis, hyperhomocysteine levels, obesity, sedentary lifestyle, receiving an organ transplant, atherosclerosis, and others. There is a need for a safe and convenient pharmaceutical formulation that would effectively reduce the risk of incurring a cardiovascular event in individuals who have these risk factors.

The treatments and drugs discovered or known in the art for cardiovascular disease includes but are not limited to beta-blockers, for example, atenolol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, timolol; Alpha blockers, for e, sin, phentolamine, min, phenoxybenzamine, prazosin, terazosin, tolazoline; mixed alpha and beta rs, for example, bucindolol, carvedilol and lol.

Beta-blocker, for example, metoprolol acts by blocking the adrenergic stimulation of the heart and thus reduces the oxygen demand of the cardiac tissue. Apparently, this ns their beneficial effects in angina pectoris and cardioprotective action in myocardial infarction. In addition, beta-blockers normalize blood re in a large proportion of patients with arterial hypertension, which ly is due to an additional action on the control of peripheral resistance to blood-flow.

Metoprolol (Formula I) is a beta1-selective (cardioselective) adrenoreceptor—blocking agent. It is commercially available in two salt forms; one of them is tartrate salt available as sor® tablets and the other is succinate salt available as Toprol®-XL tablets.

The Toprol®-XL tablets contain 23.75 mg, 47.5 mg, 95 mg and 190 mg of metoprolol succinate equivalent to 25 mg, 50 mg, 100 mg and 200 mg of metoprolol te, USP, respectively. Metoprolol is indicated in the ent of hypertension, heart failure and angina pectoris.

WO 30725 Initial therapy with a diuretic or beta-blocker has been the usual first approach for treating cardiovascular disorders. ACE inhibitors, calcium channel blockers and angiotensin receptors blockers are also effective as first-line therapy. The physician is ore required to choose from above classes of agents for l therapy.

Calcium channel blockers play important role in ctile processes of cardiac muscle and vascular smooth muscle by regulating the movement of extracellular calcium ions into these cells through ic ion channels. Calcium channel blockers work by blocking voltage-gated calcium channels (VGCCs) in cardiac muscle and blood vessels.

This decreases ellular calcium leading to a reduction in muscle contraction. In the heart, a decrease in calcium available for each beat results in a decrease in cardiac contractility. ln blood vessels, a decrease in calcium results in less contraction of the vascular smooth muscle and therefore an increase in arterial diameter (CCBs do not work on venous smooth muscle) a enon called vasodilation.

Angiotensin II receptor blockers (ARBs), also known as angiotensin II or antagonists, AT1-receptor antagonists or “sartans”, are a group of drugs which modulate the renin-angiotensin-aldosterone system. Their main uses are in the treatment of ension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart e. Angiotensin II receptor blockers, block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors directly causes lation, reduces secretion of vasopressin, and reduces production and secretion of aldosterone, amongst other actions. The ed effect reduces blood pressure.

ACE inhibitors or ensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension (high blood pressure) and congestive heart e, although they may also be prescribed for cardiac failure, diabetic nephropathy, renal disease, systemic sclerosis, left ventricular hypertrophy and other disorders.

Originally synthesized from compounds found in pit viper venom, they inhibit angiotensin-converting enzyme (ACE), a ent of the blood pressure-regulating renin-angiotensin system.

Angiotensin-converting enzyme inhibitors (ACE inhibitors) reduce the ty of the renin-angiotensin-aldosterone system. One mechanism for ining the blood re is the release of a protein called renin from cells in the kidney (to be specific, the juxtaglomerular apparatus). This produces r protein, angiotensin, which s the adrenal gland to produce erone. This system is activated in response to a fall in blood pressure (hypotension), as well as markers of problems with the salt- water balance of the body, such as decreased sodium concentration in the distal tubule of the kidney, decreased blood volume and stimulation of the kidney by the sympathetic nervous system. In such situations, the kidneys release renin, which acts as an enzyme and cuts off all but the first 10 amino acid residues of angiotensinogen (a protein made in the liver, and which circulates in the blood). These 10 residues are then known as angiotensin I. Angiotensin l is then converted to angiotensin II by angiotensin converting enzyme (ACE).

Angiotensin converting enzyme inhibitors (ACE inhibitors) block the conversion of ensin I to angiotensin II. They, therefore, lower arteriolar resistance and increase venous capacity; increase cardiac output, cardiac index, stroke work, and ; lower scular resistance; and lead to increased natriuresis (excretion of sodium in the urine).

Based on the disease condition and diagnosis, the physicians tend to prescribe a combination of two or more anti-hypertensive drugs to a patient. Such combinations are ed to provide a better control over various cardiovascular diseases. The said combinations can be given as two separate drugs administered separately at same time or at different timings. Several fixed dose combinations of anti-hypertensive drugs are ble in the market. Wherever possible, a fixed dose ation is used by physicians to simplify the dosing regimen. Some of the commercially available cardiovascular drug combinations include Lopressor HCT® rolol and Hydrochlorthiazide); Valturna® (Aliskiren hemifumarate and Valsartan); Exforge HCT® (Amlodipine besylate, Hydrochlorothiazide); Exforge® (Amlodipine besylate and Valsartan); Diovan HCT® (Hydrochlorothiazide and Valsartan); Twynsta® (Amlodipine besylate and Telmisartan); Micardis HCT® chlorothiazide and artan); Hyzaar® (Hydrochlorothiazide and Losartan potassium); Avalide® (Hydrochlorothiazide and lrbesartan); Atacand HCT® (Candesartan cilexetil and Hydrochlorothiazide); Tribenzor® (Amlodipine besylate, Hydrochlorothiazide and Olmesartan medoxomil); Azor® (Amlodipine besylate and olmesartan medoxomil); Benicar HCT® (Hydrochlorothiazide and Olmesartan mil); Vaseretic® pril maleate and Hydrochlorothiazide); Quinaretic® (Hydrochlorothiazide and Quinapril hydrochloride); Accuretic® (Hydrochlorothiazide and Quinapril hydrochloride); Zestoretic® chlorothiazide and Lisinopril); Prinzide® (Hydrochlorothiazide and Lisinopril); Lotrel® ipine besylate and Benazepril hydrochloride); Lotensin HCT® (Benazepril hydrochloride and Hydrochlorothiazide); Capozide® pril and Hydrochlorothiazide); and Tarka® (Trandolapril and Verapamil hydrochloride). However, these fixed dose combinations does not provide ian an option to modulate the dose of drugs within these fixed dose combinations according to need of a patient.

These cardiovascular combinations are also prescribed along with other drugs such as cardioprotectant, platelet aggregation inhibitors, anticoagulants, antipsychotics, etc. This multiple medication administration, complex drug regimen, and frequent dose administration complicates the patient’s compliance. Since cardiovascular disorders are often c disorders, complex drug regimen involving several drugs has a negative impact on patient’s life leading to non-compliance. Most of the patient’s tend to forget dosage regimen quite often. Further, it becomes difficult for the physician to prescribe riate doses of different drugs when used in combination. Moreover, because of the complexity of dosage regimen, it s difficult for the pharmacist to explain the treatment regimen to the patient being treated. Thus, mpliance occurs at all three levels i.e. at ian, pharmacist and t’s level. In order to improve compliance there is a need of an appropriate compliance package, which is self explanatory to patient comprising appropriate fixed dose combinations.

U.S Patent No. 4,572,909 discloses amlodipine; U.S Patent No. 4,446,325 discloses ipine; U.S Patent No. 4,772,596 discloses azelnidipine; U.S Patent No. 4,220,649 discloses barnidipine; U.S Patent No. 4,448,964 ses benidipine; U.S Patent No. ,856,346 discloses clevidipine; U.S Patent No. 4,466,972 discloses isradipine; U.S Patent No. 4,885,284 discloses efonidipine; and U.S Patent No. 4,264,611 ses felodipine.

U.S Patent No. 5,399,578 discloses Valsartan; European Patent No. 0 502 314 discloses Telmisartan; U.S Patent No. 5,138,069 discloses Losartan; U.S Patent No. ,270,317 discloses lrbesartan; U.S Patent No. 5,583,141 and 5,736,555 ses Azilsartan; U.S Patent No. 5,196,444 discloses Candesartan; U.S Patent No. 5,616,599 discloses Olmesartan; and U.S Patent No. 5,185,351 discloses Eprosartan.

U.S Patent No. 829 discloses enalapril; U.S Patent No. 258 discloses ramipril; U.S Patent No. 4,344,949 discloses ril; U.S Patent No. 4,508,729 discloses opril; U.S Patent No. 4,374,829 discloses lisinopril; U.S Patent No. 4,410,520 discloses benazepril; U.S Patent No. 4,508,727 discloses imidapril; U.S Patent No. 4,316,906 discloses zofenopril; U.S Patent Nos. 4,046,889 and 4,105,776 discloses captopril; and U.S Patent No. 201 discloses fosinopril.

Pharmaceutical compositions comprising beta-adrenergic blockers and/or calcium channel blockers are disclosed in ing patent and non-patent literature. e Patent Application No. 101249083 discloses a twice-a-day ned-release matrix preparation containing amlodipine and metoprolol, wherein 25 to 45 percent of the drug is released in a first hour, 45 to 75 percent in a fourth hour, and more than 75 percent in an eighth hour.

PCT Patent Application No. 1999018957 discloses a pharmaceutical combination of atenolol with amlodipine te.

U.S Patent No. 4,942,040 discloses a pharmaceutical preparation giving a controlled and extended release of both a dihydropyridine, e.g. felodipine and a B-adrenoreceptor antagonist, namely metoprolol.

Kumaravelrajan et al., (Lipids in Health and Disease (2011), 10-51) discloses a lled porosity osmotic pump tablet (CPOP) system to deliver Nifedipine (NP) and Metoprolol (MP) in a controlled manner up to 12 hours. The developed osmotic system was effective in the multi-drug therapy of hypertension.

Trenkwalder et al., al of human hypertension, (1995), 9 (2), 837-42) discloses an extended-release (ER) formulation, combining felodipine, 5 mg, and metoprolol, 50 mg.

CTRl/2008/O91/OOO19O discloses a randomised, open-label; parallel group, multicentric study comparing the efficacy and safety of fixed-dose-combinations of Metoprolol XL plus Amlodipine with individual components of the combination.

CTRl/2009/O91/OOO269 discloses a single arm trial assessing the efficacy and tolerability of a dose ation of metoprolol and amlodipine in essential hypertension.

Pharmaceutical itions comprising beta-adrenergic blockers and/or angiotensin II receptor blockers are disclosed in following patent and non-patent ture.

PCT Patent Application No. 201128016 discloses a formulation comprising an immediate-release compartment including drenergic blockers nebivolol and an extended-release compartment including ensin II receptor blockers losartan.

Indian Patent Application No. 2205/MUM/2007 discloses a pharmaceutical combination comprising B1 receptor antagonist nebivolol and angiotensin II receptor blocker telmisartan.

Indian Patent Application No. UM/2008 discloses a pharmaceutical ition of angiotensin II receptor blocker such as losartan potassium and a beta-selective adrenoreceptor blocking agent metoprolol ate in monolithic matrix technology.

CTRl/2010/O91/OO1438 discloses a single arm trial to evaluate the safety and efficacy of fixed dose combination of olmesartan and olol succinate ER in hypertensive patients with cardiovascular disease.

Pharmaceutical compositions comprising beta-adrenergic blockers and/or ACE inhibitors are disclosed in following patent and non-patent literature.

PCT Patent Application No. 2007010501 (‘501) ses a once a day pharmaceutical composition comprising a beta-blocker and ACE tor, n the beta blocker is present in an extended release form and the ACE inhibitor is present in an immediate e form. The composition may exhibit release of metoprolol over a period of 12-13 hours.

U.S Patent Application No. 32879 (879) discloses use of a beta-blocker and an ACE-inhibitor in combination for the treatment of hypertension. The release of drugs from the dosage form may be ed over a period of 12-15 hours and therefore the combination may not provide adequate synergistic effects.

Metoprolol has been classified as a class I substance according to the Biopharmaceutics fication Scheme (BCS), meaning that it is highly soluble and highly permeable. The drug is readily and completely absorbed throughout the whole intestinal tract but is subject to extensive first pass metabolism resulting in incomplete bioavailability (about 50%). Amlodipine besylate, a representative example in class of calcium channel blockers is slightly soluble in water and sparingly soluble in ethanol.

Amlodipine also undergoes extensive first pass metabolism. Thus, formulating a oncea-day dosage form of highly water soluble metoprolol in a fixed dose combination comprising an extended release metoprolol and highly water soluble actives belonging to calcium channel blockers, angiotensin II receptor blockers and ACE inhibitors is a challenging task for a pharmacist.

None of the above mentioned prior arts provides a once-a-day fixed dose formulation comprising an ed release metoprolol with a calcium channel blocker, angiotensin II or blocker or ACE inhibitor, which is safe and has an enhanced therapeutic effect over the existing dual drug therapy. The prior arts disclosing pharmaceutical composition comprising metoprolol in combination with one or more calcium channel blocker, angiotensin II receptor r or ACE inhibitor does not provide a once-a-day dosage form with desired synergistic eutic effect. The combination disclosed in the prior arts also does not address the uniform release and bioavailability related aspects of either of metoprolol, calcium channel r, calcium channel blocker, angiotensin II receptor r or ACE tor when formulated into a once-a-day dosage form. Present inventors developed a matrix dosage form comprising combination of β1 r drugs in combination with calcium channel blocker, angiotensin II receptor blocker or ACE inhibitor. The release profile obtained from matrix tablets was erratic and varied from batch to batch. It was found that due to highly soluble and highly permeable nature of metoprolol, it is difficult to formulate and achieve an extended release once a day formulation in matrix dosage form.

Further, preparing a fixed dose combination comprising an extended release metoprolol was also a major challenge as it was ult to achieve the d therapeutic release of the ation when combined into a single unit dosage form. Therefore, there is an g need for the development of new dosage forms comprising an extended release metoprolol with calcium channel blocker, angiotensin II receptor blocker or ACE inhibitor which are safe and effective.

Summary Of The Invention In one aspect, the t invention provides a pharmaceutical dosage form suitable for once daily administration comprising a fixed dose combination of metoprolol in extended release form, one or more calcium channel blockers, and one or more rate controlling excipients, wherein the dosage form exhibits a dissolution profile such that 6% or less of olol is ed within 1 hour; between 25% to 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after hours, when the release rate is measured in USP Type 2 ution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium.

In another aspect, the present invention provides a pharmaceutical dosage form suitable for once daily stration sing a fixed dose combination of metoprolol in extended release form, one or more angiotensin II receptor blockers, and one or more rate controlling excipients, wherein the dosage form exhibits a dissolution profile such that 6% or less of metoprolol is released within 1 hour; between 25% to 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after 20 hours, when the release rate is measured in USP Type 2 Dissolution tus (paddle, 50 rpm) using 500 ml of pH 6.8 ate buffer at 37°C ± 0.5°C as dissolution medium.

In another aspect, the present invention provides a pharmaceutical dosage form suitable for once daily stration comprising a fixed dose combination of metoprolol in extended release form, one or more ACE inhibitors, and one or more rate controlling excipients, wherein the dosage form exhibits a dissolution profile such that 6% or less of metoprolol is released within 1 hour; between 25% to 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is ed after hours, when the release rate is measured in USP Type 2 Dissolution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium.

In another aspect, the present invention provides a once-a-day pharmaceutical dosage form for treatment of cardiovascular disorders, wherein the dosage form comprises a fixed dose combination of about 25mg to 200mg of metoprolol in extended release form and about 2.5mg to 800mg of one or more m channel blockers.

In another aspect, the present invention es a once-a-day pharmaceutical dosage form for treatment of cardiovascular disorders, n the dosage form comprises a fixed dose combination of about 25mg to 200mg of metoprolol in extended release form and about 20mg to about 800mg of angiotensin II receptor blocker.

In another aspect, the present invention provides a once-a-day pharmaceutical dosage form for treatment of cardiovascular ers, wherein the dosage form ses a fixed dose combination of about 25mg to 200mg of metoprolol in extended release form and about 1mg to about 100mg of ACE inhibitors.

In another , the once-a-day pharmaceutical dosage form for treatment of cardiovascular disorders exhibits immediate release of calcium channel blocker, angiotensin II receptor blocker and ACE inhibitor.

In another , the extended e metoprolol component of the dosage form comprises a water swellable or water insoluble inert core coated with one or more rate controlling excipient.

In another aspect, the water ble core comprises microcrystalline cellulose, hydroxypropyl methylcellulose, starch or mixtures thereof.

In another aspect, the water insoluble inert core comprises silicon dioxide, glass particles, plastic resin particles or mixtures f.

In another aspect, the rate controlling excipient comprises one or more polymeric rate controlling excipients, non-polymeric rate controlling excipients, or mixtures thereof.

In another aspect, the polymeric rate controlling excipient is selected from the group consisting of one or more of cellulose derivatives; polyhydric alcohols; saccharides, gums and derivatives thereof; vinyl derivatives, polymers, copolymers or mixtures thereof; maleic acid mers; polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives; or any combinations thereof and non-polymeric rate controlling ent is selected from the group consisting of fat, wax, fatty acid, fatty acid ester, long chain dric alcohol or their ester or any combinations thereof .

In another aspect, the t invention provides a once-a-day pharmaceutical dosage form for treatment of cardiovascular disorders, wherein the dosage form ses a fixed dose combination of metoprolol in ed e form and an agent ed form one or more calcium channel blockers, one or more angiotensin II receptor blockers and one or more ACE inhibitors along with one or more rate controlling excipients; characterized in that said composition exhibits a dissolution profile such that less than 6% of metoprolol or its salt is released within 1 hour and 25%-50% of metoprolol or its salt is ed within 6 hours and at least 90% of metoprolol is released after 20 hours when the release rate is ed in USP Type 2 Dissolution Apparatus 2 (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C i O.5°C as dissolution medium.

In another aspect, the pharmaceutical composition comprises pharmaceutically acceptable excipients selected from one or more diluent, binder, glidant, solubilizer, ants, disintegrants, colorants, ding agent, thickener or taste masking agent.

In r aspect, the pharmaceutical dosage form is in the form of a tablet, a capsule, granules, a tablet in tablet, tablet/s in capsule, granules in capsule, an orally disintegrating tablet, a bilayer tablet, a trilayer tablet, an in-Iay tablet, or suspension.

In another aspect, the present invention provides a method of treating one or more disorders selected from hypertension, congestive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic pathy, diabetic cardiac myopathy, renal insufficiency, peripheral ar disease, left ventricular hypertrophy, cognitive dysfunction, and chronic heart e, wherein the method comprises administering a once-a-day pharmaceutical dosage form comprising a fixed dose combination of an metoprolol in extended release form and an agent selected form one or more calcium channel blockers, one or more angiotensin II or blockers and one or more ACE inhibitors along with one or more rate controlling excipients to a patient in need of said ent.

Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the pharmaceutically acceptable excipients may include ts, disintegrants, binders, bulking agents, anti-adherents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, stabilizers, vatives, lubricants, glidants, chelating agents, and the like known to the art used either alone or in ation thereof.

Detailed ption Of The Invention The present inventors while working on the development of pharmaceutical composition comprising a fixed dose combination of an extended release olol with calcium channel blockers, angiotensin II receptor blockers, or ACE inhibitors, surprisingly found that the pharmaceutical composition of the present invention provides a table and uniform dissolution profile resulting in eutically effective e of the actives over a period of about 24 hours.

The present invention provides once-a-day fixed dose pharmaceutical composition of an extended release metoprolol and an active agent selected from calcium channel blockers, angiotensin II receptor blockers, and ACE inhibitors. The combinations are not only safe and effective medication for treatment of cardiovascular disease, but are also found to be synergistic with enhanced efficacy. This increased efficacy simplifies the management of cardiovascular es.

The present ors have now developed a safe and effective once-a-day therapeutically synergistic pharmaceutical composition comprising metoprolol in extended release form and an agent selected from one or more calcium channel blockers, one or more angiotensin II receptor blockers, and one or more ACE tors.

From the preliminary studies, inventors have surprisingly found that the combination therapy s in at least 10% improvement in individual’s response when compared to monotherapy.

The term “metoprolol”, as used herein, refers to a metoprolol base, or any pharmaceutically acceptable salt f. In an embodiment, the olol salt is succinate salt or tartrate salt.

In an embodiment, the fixed dosage form comprises metoprolol ate 23.75mg, 47.5mg, 95mg and 190mg equivalent to 25mg, 50mg, 100mg and 200mg of metoprolol tartrate or equivalent to 9.75mg, 19.5mg, 39mg and 78mg of metoprolol base respectively.

The term “calcium channel blocker”, as used herein, refers to calcium channel blocker base, or any pharmaceutically acceptable salt or ester thereof.

The term “angiotensin II receptor blocker”, as used herein, refers to angiotensin II receptor blocker base, or any pharmaceutically acceptable salt or ester thereof.

The term “angiotensin converting enzyme inhibitor” or “ACE tor”, as used herein, refers to angiotensin converting enzyme inhibitor base, or any pharmaceutically acceptable salt or ester thereof.

As used herein, the term "salt" refers to any pharmaceutically acceptable salt (e.g., acid or base) of a compound of the present ion, which upon administration to a t, is capable of providing a compound of this ion or an active metabolite or e thereof. As is known to those of skill in the art, "salts" of the compounds of the t invention may be derived from inorganic or organic acids and bases. es of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalenesulfonic, benzenesulfonic acid, and the like. Other acids, such as oxalic, while not in themselves ceutically able, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Examples of bases include, but are not limited to, alkali metals (e.g., sodium) hydroxides, alkaline earth metals (e.g., magnesium), hydroxides, ammonia, and compounds of formula NW4+, wherein W is C1- 4 alkyl, and the like. Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, cyclopentanepropionate, ethanesulfonate, fumarate, flucoheptanoate, ophosphate, hemisulfate, oate, hexanoate, hydrochloride, romide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, esulfonate, 2—naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, te, undecanoate, and the like.

As used herein, the term "ester" refers to any pharmaceutically acceptable ester of a compound of the present invention, which upon administration to a subject is e of providing a compound of this invention or an active metabolite or residue f.

Representative examples of ester e medoxomil, cilexetil, and the like.

For the purpose of present invention, "once-a-day" means that the composition of the present invention is administered only once over a 24 hour period thereby providing therapeutically beneficial blood levels of the active .

The term "fixed dose combination", as used herein, refers to a combination of two or more separate active agents, combined in a single unit dosage form, in defined doses.

The term “compliance” describes willingness or degree to which a patient correctly follows the prescribed course of treatment.

The term “therapeutically istic”, as used herein, refers to a therapeutic effect achieved by a fixed dose combination treatment that exceeds the l effect achieved by monotherapy associated with the same drugs used in the combination. For example, X is the therapeutic effect obtained by “A” drug and Y is the therapeutic effect obtained by “B” drug on administration, thus when “A” and “B” drugs are given together, then the expected therapeutic effect would be “X+Y” but when the eutic effect achieved by co-administration of both the drugs in a fixed dose combination exceeds “X+Y” i.e. “(X+Y)*Z”, wherein Z is more than 1, the ation is said to be therapeutically istic.

The phrase “inert core,” as used herein, includes core that is water insoluble and non- swellable.

The phrase “insoluble,” as used herein, refers to inert core, which does not dissolve in water.

The phrase “non-swellable,” as used herein, refers to inert core having 20% or less swelling after 24 hours.

The term 'inlayed tablet' or ‘inlay tablet’ as used herein refers to a type of a layered tablet in which instead of the core tablet being completely surrounded by a coating, the top surface is completely exposed.

The term 'inlayed in said layer' is used herein to mean that the tablet of metoprolol may be present at any position in said layer.

The term “bioavailable” as used herein, includes, but is not limited to the rate and extent to which the active agent/s become available to the site of action after administration.

The term "Cmax" is the highest plasma concentration of the drug ed within the dosing interval.

The term "Tmax" is the time period, which elapses after administration of the dosage form at which the plasma concentration of the active agent attains the t plasma concentration within the dosing interval.

WO 30725 The term "AUCOJ' as used , means area under plasma concentration-time curve from drug administration to last observed concentration at time t.

The term "AUCM" as used herein, means area under the plasma tration-time curve extrapolated to infinite time.

The term "mean", when preceding a pharmacokinetic value (e.g. mean Tmax) represents the mean value of the pharmacokinetic value taken from a population of patients or healthy volunteers.

The present invention es once-a-day therapeutically synergistic pharmaceutical dosage form for treatment of cardiovascular ers, wherein the dosage form comprises a fixed dose combination of an extended release metoprolol with an agent ed from one or more calcium channel blockers, one or more angiotensin II receptor blockers and one or more angiotensin converting enzyme inhibitors along with one or more rate controlling excipients.

The calcium channel blockers may be selected from, but not limited to one or more of amlodipine, bepridil, clentiazem, zem, fendiline, gallopamil, mibefradil, prenylamine; semotiadil, terodiline, elgodipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, pine, nisoldipine, nitrendipine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, perhexiline, aranidipine, azelnidipine, ipine, benidipine, cilnidipine, clevidipine, isradipine, efonidipine, felodipine, pranidipineor, and verapamil.

In an embodiment, the calcium l blocker is amlodipine or nifedipine or both. red salt of calcium channel blocker includes amlodipine besylate, bepridil hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, and verapamil hydrochloride.

The angiotensin II receptor blockers may be selected from, but not limited to one or more of Valsartan, artan, Losartan, lrbesartan, Azilsartan, Candesartan, Eprosartan, and Olmesartan.

In an embodiment, the angiotensin II receptor blocker is tan or Olmesartan medoxomil or both.

Preferred salt or ester of angiotensin II receptor blocker includes losartan ium, candesartan cilexetil, olmesartan medoxomil and eprosartan mesylate.

The ACE inhibitors may be selected from, but not limited to one or more of benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, pril, zabicipril, spirapril, pril, perindopril, ramipril, rilat, trandolapril, zofenopril, and quinapril.

In an embodiment, the ACE inhibitors is Lisinopril or Enalapril, or both.

Preferred salt or ester of ACE tor includes, Benazepril hydrochloride, Enalapril maleate, pril sodium, Lisinopril dihydrate, Perindopril ne, and Quinapril hydrochloride.

In an embodiment, when the once-a-day therapeutically synergistic pharmaceutical dosage form of the present invention comprises metoprolol in ed release form and calcium channel blocker, the amount of olol and calcium channel blocker in the dosage form ranges between about 25mg to about 200mg and between about 2.5mg to about 800mg respectively.

In a further embodiment, the once-a-day therapeutically synergistic pharmaceutical dosage form comprises an extended release metoprolol and calcium channel blocker in following combinations: 2012/054257 Meto- prolol Doses of “Calcium Channel Blockers” in combination with Doses Metoprolol In a still further embodiment, the present invention provides a once-a-day therapeutically synergistic unit dosage form comprising a fixed dose combination of 25mg of metoprolol in extended release form with 2.5mg of amlodipine, 25mg of metoprolol in extended e form with 5mg of amlodipine, 50mg of metoprolol in extended release form with 5mg of amlodipine, 50mg of metoprolol in ed release form with 10mg of amlodipine, 100mg of metoprolol in extended release form with 5mg of amlodipine and 100mg of metoprolol in extended release form with 10mg of pine.

In another embodiment, when the once-a-day therapeutically istic pharmaceutical dosage form of the present invention comprises metoprolol in ed release form and angiotensin II receptor r, the amount of metoprolol and angiotensin II receptor blocker in the dosage form ranges between about 25mg to about 200mg and between about 4mg to about 800mg respectively.

In a further embodiment, the once-a-day therapeutically synergistic pharmaceutical dosage form comprises an extended release metoprolol and angiotensin II receptor blocker in following combinations: Doses of “Angiotensin II or Blockers” in combination with Me’EOPFOIOI Metoprolol Doses Lo- Val- Cand lrbe- Olme- Telmi- Epro- sartan sartan e- sartan sartan sartan sartan sanan 20mg 400 mg 20mg 40mg 600 mg 16mg 300mg In a still further embodiment, the t ion provides a once-a-day therapeutically synergistic unit dosage form sing a fixed dose combination of 25mg of metoprolol in extended release form with 80mg of valsartan, 25mg of metoprolol in extended release form with 160mg of valsartan, 50mg of metoprolol in extended release form with 160mg of valsartan, 50mg of metoprolol in extended release form with 320mg of valsartan, 100mg of metoprolol in ed release form with 160mg of valsartan and 100mg of metoprolol in extended release form with 320mg of valsartan.

In another embodiment, when the once-a-day therapeutically synergistic pharmaceutical dosage form of the present invention comprises extended release metoprolol and ACE inhibitor, the amount of metoprolol and ACE inhibitor in the dosage form ranges between about 25mg to about 200mg and between about 1mg to about 100mg respectively.

In a r embodiment, the -day therapeutically synergistic pharmaceutical dosage form comprises an extended release metoprolol and ACE inhibitor in following combinations: Meto- prolol Doses of “ACE inhibitors” in combination with olol doses Bena- Capto- Perin- Rami- Trand- pril olaprll dopril pril 12.5mg 2.5mg 2mg 1mg 4mg 2mg 100mg 20mg 8mg 4mg In a still further embodiment, the present invention provides a once-a-day therapeutically synergistic unit dosage form comprising a fixed dose combination of 25mg of metoprolol in extended e form with 10mg of lisinopril, 25mg of metoprolol in extended release form with 20mg of lisinopril, 50mg of metoprolol in extended release form with 20mg of lisinopril, 50mg of metoprolol in extended release form with 40mg of lisinopril, 100mg of metoprolol in extended release form with 20mg of lisinopril and 100mg of metoprolol in extended release form with 40mg of lisinopril.

In a further embodiment of the present invention, the once-a-day therapeutically synergistic unit dosage form comprises a fixed dose combination of metoprolol in extended e form and active agent selected from one or more calcium channel blockers, one or more ensin II receptor blockers, and one or more ACE inhibitors along with one or more rate controlling excipient, wherein calcium channel blocker, angiotensin II receptor r or ACE inhibitor ts ate release from the unit dosage form.

In a r embodiment, the present invention provides a once-a-day eutically synergistic pharmaceutical dosage form for treatment of cardiovascular disorders comprising a fixed dose combination of metoprolol in extended release form and an active agent selected from one or more calcium channel blockers, one or more angiotensin II receptor blockers, and one or more ACE inhibitors along with one or more rate controlling excipients. The composition comprises an inert core coated with one or more rate controlling ents. Such inert core compositions are sed in PCT Patent Application No. 2007110753 A, and incorporated hereby for reference.

In a further embodiment, the present invention provides a once-a-day therapeutically synergistic ceutical dosage form for treatment of cardiovascular disorders comprising a fixed dose combination of metoprolol in extended release form and an active agent selected from one or more calcium channel blockers, one or more angiotensin II receptor blockers, and one or more ACE inhibitors along with one or more rate controlling excipients, wherein the composition exhibits a dissolution profile such that less than 6% of metoprolol is ed within 1 hour; 25% to 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after 20 hours when the release rate is measured in USP Type 2 Dissolution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C i 05°C as dissolution medium.

As mentioned in several embodiments of the present invention, the rate controlling excipient is polymeric rate lling excipient or non-polymeric rate controlling excipient, or combination thereof.

Suitable polymeric rate controlling excipients are selected from, but not limited to, one or more of ose derivatives; polyhydric ls; saccharides, gums and derivatives thereof; vinyl derivatives, rs, copolymers or mixtures thereof; maleic acid copolymers; polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives; or any ations thereof.

Cellulose derivatives include, but not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl ose, ymethyl cellulose, hydroxypropyl ethylcellulose, ymethylethyl cellulose, carboxyethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose (CMC), methylhydroxyethyl cellulose, methylhydroxypropyl ose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, or combinations thereof.

Polyhydric alcohols include, but are not d to, polyethylene glycol (PEG) or polypropylene glycol; or any combinations thereof.

Saccharides, gums and their derivatives include, but not limited to, dextrin, polydextrin, dextran, pectin and pectin derivatives, alginic acid, sodium te, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin, CMC agar; guar gum, locust bean gum, xanthan gum, karaya gum, tragacanth, carrageenan, acacia gum, arabic gum or gellan gum or the like; or any combinations thereof.

Vinyl derivatives, polymers, copolymers or mixtures thereof include, but not limited to, polyvinyl acetate, polyvinyl alcohol, mixture of polyvinyl e (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w) (Kollidon SR), copolymers of vinyl pyrrolidone, vinyl acetate copolymers, polyvinylpyrrolidone (PVP); or combinations thereof.

Polyalkylene oxides or copolymers thereof include, but not limited to, polyethylene oxide, polypropylene oxide, poly hylene)-poly (oxypropylene) block copolymers (poloxamers) or combinations thereof.

Maleic acid copolymers include, but not limited to, vinylacetate-maleic acid anhydride mer, styrene- maleic acid anhydride copolymer, styrene- maleic acid monoester copolymer, vinylmethylether— maleic acid anhydride copolymer, ethylene-maleic acid anhydride mer, vinylbutyiether- maleic acid anhydride mer, acrylonitrilemethyl acrylate- maleic acid anhydride copolymer, butyl acrylate-styrene-maleic acid anhydride copolymer or the like or any combinations thereof.

Acrylic acid polymers include any suitable polyacrylic acid rs or yvinyl polymers such as those available under the brand name carbopol. Pharmaceutically acceptable acrylic polymer may be include one or more, but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, thyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, ethyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid ide), and yl methacrylate.

Suitable non-polymeric rate controlling excipient includes, but not limited to fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester or any ations f.

Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such , and may also contain hydrocarbons. Waxes employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes, paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes. ic examples include, but are not limited to spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, illa wax, castor wax paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, or mixtures thereof.

Waxes are also yceryl esters, diglyceryl esters, or glyceryl esters (glycerides) and tives and mixtures thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol are substituted by a fatty acid. Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, yl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl lmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl ristate, glyceryl dimyristate, glyceryl trimyhstate, yl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate (compritol), polyglyceryl diisostearate, lauroyl macrogolglycerides (Gelucire), oleoyl macrogolglycerides, stearoyl macrogolglycerides, mixtures of monoglycerides and diglycerides of oleic acid (Peceol), or combinations thereof.

WO 30725 Fatty acids include, but not limited to, enated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, enated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil (Lubritab), hydrogenated cottonseed oil, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, or the like, or mixtures thereof.

Long chain monohydric alcohols include, but not d to, cetyl alcohol, or stearyl alcohol or mixtures thereof.

The water-swellable inert core can comprise hydroxypropyl methylcellulose, microcrystalline cellulose, starch or mixtures thereof.

The insoluble inert core may comprise silicon dioxide, glass particles, c resin particles or es thereof.

The pharmaceutical dosage form of the present invention r comprises other pharmaceutically acceptable excipient selected from the group consisting of diluent, , glidant, solubilizer, stabilizer, ants, disintegrants, cushioning agents, suspending agent, thickening agent, sweetners, ing agent, or plasticizer.

Examples of suitable diluents include, but not limited to one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, or metal carbonate.

Examples of suitable binders include, but not limited to, starch, gums, pregelatinized starch, polyvinyl done (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts.

Suitable lubricants include, but are not limited to, one or more talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, talc and sodium benzoate.

Compositions of the present invention may include a glidant such as, but not d to, colloidal silica, silica gel, precipitated silica, or combinations thereof.

Suitable disintegrant may include, but not limited to, one or more of starch, croscarmellose sodium, crospovidone, and sodium starch glycolate.

The solubilizer may include, but not limited to, one or more surfactant, pH er, complexing agent, or hydrotropic agent.

Suitable surfactants are those known to ordinary skilled in the art and may include, but not limited to, one or more of amphoteric, non-ionic, ic or c surfactants.

Suitable surfactants comprises one or more of sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or r ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, earylic alcohol, terol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40 and the like.

Suitable pH modifiers include, but not limited to, buffers, amino acids or amino acid sugars.

The complexing agents include cyclodextrin class of molecules, such as cyclodextrins containing from six to twelve glucose units, especially, alpha-cyclodextrin, beta- cyclodextrin, gamma-cyclodextrin, or their derivatives, such as hydroxypropyl beta extrins, or mixtures thereof. The complexing agents may also include cyclic amides, hydroxyl benzoic acid derivatives as well as gentistic acid.

Suitable plasticizers include, but are not limited to, one or more of diethyl phthalate, yl citrate, acetyl tributyl citrate, dibutyl phthalate, triacetin, ene glycol, and hylene glycol. 2012/054257 The solvents comprise one or more of dichloromethane, acetone, ethanol, ol, isopropyl alcohol, water or mixture f.

Suitable cushioning agents include, but are not limited to, one or more of PEG, and colloidal n dioxide.

Suitable thickening agents or viscosity modifiers may include, but are not d to, one or more of methylcellulose, ymethylcellulose, microcrystalline cellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, alginate, carageenan, xanthan gum, acacia, tragacanth, locust bean gum, guar gum, carboxypolymethylene, polyvinyl pyrrolidone, polyvinyl alcohol, poloxamer, magnesium aluminum silicate (veegum), bentonite, hectorite, povidone, maltitol, chitosan or combination thereof and the like.

Preservatives may include, but are not limited to, one or more of sodium benzoate, sorbates, such as potassium sorbate, salts of edetate (also known as salts of ethylenediaminetetraacetic acid or EDTA, such as disodium edetate), benzaldionium chloride, parabens and the like.

The formulations of the invention optionally e one or more stabilizing agents to increase the stability and/or compatibility of the suspension when formulated into a dosage form. Suitable izing agents are suspending , flocculating agents, thickening agents, gelling agents, buffering agents, idants, preservatives, antimicrobial agents, and es thereof. Ideally, the agent acts to minimize irreversible ation of suspended particles, and to maintain proper flow characteristics to ease manufacturing processes, e.g., to ensure that the formulation can be y pumped and filled into desired container.

Suitable suspending agents may include, but are not limited to, one or more from cellulose derivatives, clays, natural gums, synthetic gums, or other agents known in the art. Specific suspending agents, by way of example, include microcrystalline cellulose, sodium carboxymethylcellulose, powdered cellulose, ethymethylcellulose, hydroyxypropyl methylcellulose, methylcellulose, ethylcellulose, ethylhydroxy ethylcellulose, hydroxypropyl cellulose, attapulgite, bentonite, hectorite, montmorillonite, silica gel, fumed silicon dioxide, colloidal silicon dioxide, acacia, agar, carrageenan, guar gum, locust bean gum, pectin, sodium alginate, ene glycol alginate, tamarind gum, xanthan gum, carbomer, povidone, sodium starch glycolate, starches, tragacanth, magnesium aluminum silicate, aluminum te, magnesium te, gelatin, rhizin and the like. These suspending agents can further impart different flow properties to the sion. The flow ties of the suspension can be Newtonian, plastic, plastic, thixotropic or combinations thereof. Mixtures of suspending agents may also be used to optimize flow properties and viscosity.

Suitable buffering agents may include, but are not d to, one or more of a bicarbonate salt of a Group IA metal, an alkali earth metal buffering agent, amino acids, an acid salt of an amino acid, an alkali salt of an amino acid, and combinations of any of the foregoing.

Moreover, the composition of the invention optionally include usual auxiliaries known in the art such as saliva stimulating agents like citric acid, lactic acid, malic acid, succinic acid, ascorbic acid, adipic acid, fumaric acid, tartaric acids; cooling sensation agents like maltitol, monomenthyl succinate, ultracool; stabilizers like gums, agar; taste g agents like acrylic polymers, copolymers of acrylates, celluloses, resins; coloring agents like titanium dioxide, natural food colors, dyes suitable for food, drug and cosmetic applications; preservatives like tocopherol, citric acid, butylated hydroxytoluene, butylated yanisole, ascorbic acid, fumaric acid, malic acid, sodium ascorbate or ascorbic acid palmitate or effervescing agents like citric acid, tartaric acid, sodium bicarbonate, sodium carbonate and the like.

The dosage form of the present invention may be in form of a tablet, a capsule, granules, a tablet in tablet, an orally disintegrating , pellets, tablet/s in e, granules/pellets in capsule, a bilayer tablet, a trilayer tablet, an in-lay tablet or suspension.

The tablet-in-tablet dosage form of the invention may be prepared by compressing metoprolol with one or more rate lling excipient to form a core tablet; and compressing one or more calcium l blockers or one or more angiotensin receptor blockers or one or more ACE inhibitors optionally along with one or more pharmaceutically acceptable excipient onto said core tablet to form a compressed outer tablet.

In an embodiment, the tablet-in-tablet dosage form is be prepared by blending metoprolol with rate controlling excipient and other pharmaceutically acceptable excipients. The prepared blend was compressed to form a core tablet. Separately, calcium channel blocker, angiotensin receptor blocker, or ACE inhibitor is d with one or more pharmaceutically acceptable excipients. Some portion of the above blend is placed in die and the core tablet was placed in center of the blend, the remaining blend is filled in die and compressed such that the metoprolol tablet forms inner tablet and calcium channel blocker, angiotensin receptor blocker or ACE inhibitor forms outer tablet.

The once-a-day dosage form of the invention may also be prepared by compressing metoprolol with one or more rate controlling excipient to form a core and an active agent selected from calcium channel r, angiotensin receptor blocker and ACE inhibitor forming outer coating with one or more ceutically acceptable excipients.

In another ment, the once-a-day dosage form is prepared by blending metoprolol with rate controlling excipient and one or more other pharmaceutically acceptable excipients. The ed blend is compressed to form tablets. The formed s then coated with dispersion sing an agent selected from calcium channel blocker, angiotensin receptor blocker and ACE inhibitor, dissolved or dispersed in suitable solvent system along with one or more pharmaceutically acceptable excipient. The outer coating may completely or partially surround the metoprolol .

In another embodiment, the -day dosage form may be prepared by ng two portions with one or more pharmaceutically acceptable excipients followed by compression. First portion may be prepared by coating the inert core with a solution or suspension of metoprolol in a solvent. The olol drug layer is further coated with one or more release-controlling |ayer(s). Second portion may be prepared by coating one or more calcium channel blocker, angiotensin receptor blocker or ACE inhibitor on an inert core, optionally along with one or more rate controlling layers.

In another embodiment, the once-a-day dosage form may be prepared by blending two portions with one or more pharmaceutically acceptable excipients followed by ssion. The first n was prepared by coating the inert core with a dispersion comprising metoprolol, one or more rate lling excipients in a solvent. The coated inner core can further be coated with one or more rate controlling layers or seal coat.

The second portion was prepared by g the inert core with a sion comprising a calcium channel blocker, an angiotensin receptor blocker or an ACE inhibitor in a solvent.

In an embodiment, the once-a-day dosage form may include a tablet comprising an extended release metoprolol with one or more rate controlling excipient, wherein the tablet is inlayed in another layer comprising a calcium channel blocker, an angiotensin receptor blocker, or an ACE inhibitor and optionally other pharmaceutically acceptable excipients.

In a r embodiment, the inlayed dosage form can be prepared by blending metoprolol with rate controlling excipient and other pharmaceutically able excipients. The ed blend was compressed to form a core tablet. One or more agent selected from calcium channel r, angiotensin receptor blocker and ACE inhibitor are separately blended with one or more pharmaceutically acceptable excipients. Some portion of the above blend was placed in die and the core tablet was placed in a way such that the upper surface of metoprolol tablet is completely exposed after compression.

In a further ment, the once-a-day dosage form may be prepared by compressing a first layer comprising an extended e metoprolol along with one or more rate controlling excipients and a second layer comprising one or more calcium channel blocker, angiotensin receptor blocker or ACE inhibitor, one or more pharmaceutically acceptable excipients and, optionally with rate controlling excipient into a bi-layer tablet.

In a r embodiment, the bi-layer dosage form is prepared by blending metoprolol with rate controlling excipient and other pharmaceutically acceptable excipients. The prepared blend was compressed to form a first layer. Onto this first layer a blend comprising calcium channel blocker, angiotensin receptor blocker or ACE inhibitor with one or more pharmaceutically acceptable excipients is compressed to form a bi-layer The present invention further provides a method of treating one or more disorders ed form hypertension, tive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular e, left ventricular hypertrophy, cognitive dysfunction, and chronic heart failure, wherein the method comprises administering a pharmaceutical dosage form of the present invention to a t in need of such treatment.

In r aspect, the present invention provides a method of treating hypertension, wherein the method ses administering a pharmaceutical dosage form of the present invention to a patient in need of such ent.

In an embodiment, a method of treating congestive heart failure comprises administering a pharmaceutical dosage form of the present invention to a patient in need of such ent.

In another embodiment, a method of myocardial infarction comprises administering a ceutical dosage form of the present invention to a patient in need of such treatment.

The examples given below serve to rate embodiments of the present invention.

However they do not intend to limit the scope of present invention.

Example 1: Metoprolol ate ER/ Amlodipine Besylate Tablet Table 1: Metoprolol Succinate ER/ Amlodipine Besylate; Eq 50mg Tartrate/10 mg Micro crystalline cellulose 0.1-20 spheres Seal coat I Ethyl cellulose 0.01-10 Triethyl e 0.001-5 Drug ng Metoprolol Succinate 2—70 Opadry Clear 0.1-20 Extended Release coating Ethyl cellulose 0.1-20 Opadry Clear 0.1-20 Eudragit L30-D55 0.1-20 Extended e coating Triethyl citrate 5 Talc 0.1-20 Seal coat ll Opadry Clear 0.1-20 PEG coating Polyethylene glycol 0.1-20 Amlodipine Besylate 0.1-30 Addition of Drug Prosolv SMCC 90 10-75 (Amlodipine Besylate) Sodium starch glycolate 0.1-20 & Tableting Polyethylene glycol 0.1-20 Sodium Stearyl Fumarate 0.1 -5 Film coating Opadry white 0.1-10 Procedure: Microcrystalline cellulose spheres were given seal coat I of ethyl cellulose. These seal coated s were subjected to Metoprolol succinate layering with a binder in aqueous solvent system. Drug layered pellets were provided with Extended Release coating-l using Ethyl cellulose and opadry. An extended release g-ll of Eudragit was given using Plasticizer, triethyl citrate & talc. Seal l was given to Extended Release coated pellets followed by PEG coating in suitable t system. These PEG coated pellets was blended with the Prosolv, Amlodipine Besylate, Croscarmellose sodium, PEG & Sodium Stearyl Fumarate and compressed into a tablet. An opadry coat was given to core tablets.

Tablets ed from example 1 were subjected to dissolution studies. The s of dissolution studies performed are provided in Table 2.

Table 2: Dissolution profile Dissolution of olol Succinate Method: 500 mL of pH 6.8 ate Method: 500 mL of pH 0.01 N HCI, buffer, USP ll apparatus at 50 rpm Time points (h) % Drug dissolved Time points (min) % Drug dissolved Example 2: Metoprolol Succinate ER/ Amlodipine Besylate Tablet Table 3: Metoprolol Succinate ER/ Amlodipine Besylate; Eq 25mg Tartrate/2.5 mg Stage Ingredients % w/w Micro crystalline cellulose Seal coat I 0.1-20 spheres Ethyl ose yl citrate Drug Layering olol Succinate Extended Release coating Ethyl cellulose Eudragit L30-D55 Extended e coating Triethyl citrate Talc Seal coat ll Opadry Clear Drug Layering Amlodipine Besylate (Amlodipine Besylate) Opadry Clear PEG coating Polyethylene glycol Prosolv SMCC 90 Croscarmellose sodium Tableingt' Polyethylene glycol Sodium Stearyl Fumarate Film coating Opadry white Procedure: Microcrystalline cellulose s was given seal coat I of ethyl cellulose. These seal coated pellets were subjected to Metoprolol succinate layering with a binder in aqueous solvent system. Drug layered pellets were provided with Extended Release g-l using Ethyl cellulose and opadry. An Extended e coating-ll of Eudragit was given using Plasticizer, triethyl citrate & talc. Seal coat-ll was given to Extended Release coated pellets followed by drug layering of pine Besylate and PEG coating in suitable solvent system. These PEG coated pellets was blended with the Prosolv, Croscarmellose , PEG & Sodium Stearyl Fumarate and compressed into tablet.

An opadry coat was given to core tablets.

Tablets obtained from example 2 were subjected to dissolution studies. The results of dissolution studies performed are provided in Table 4.

Table 4: Dissolution profile Dissolution of Metoprolol Succinate Dissolution of Amlodipine Method: 500 mL of pH 6.8 phosphate Method: 500 mL of pH 0.01 N HCI, buffer, USP ll apparatus at 50 rpm USP ll tus at 75 rpm Time points (h) % Drug dissolved Time points (min) % Drug dissolved 84 Example 3: Metoprolol Succinate ER/ pine te Tablet Table 5: Metoprolol Succinate ER/ Amlodipine Besylate; Eq 25mg Tartrate/5 mg “Ingredients % w/w Microcrystallinecellulose spheres 0.1-20 Seal coat I Ethyl cellulose 0.01-10 Triethyl citrate 5 Drug Layering Metoprolol Succinate 2—70 (Metoprolol Succinate) Opadry Clear 0.1-20 Extended Release coating Ethyl cellulose 01-20 -| Opadry Clear 0.1 -20 Eudragit L30_D55 020 Extended e coating Triethyl citrate 0.001-5 Talc 01-20 Seal coat ll Opadry Clear 0.1-20 PEG coating Polyethylene glycol) 0.1-10 Prosolv SMCC 90 10-60 Croscarmellose sodium 0.5-15 Tableting Polyethylene glycol 0.1-10 Sodium Stearyl Fumarate 0.01-5 Drug Layering Amlodipine Besylate 0.1-50 (Amlodipine Besylate) Opadry Clear 0.1-25 Film coating Opadry white 0.1-10 Procedure: Microcrystalline cellulose spheres were given seal coat I of ethyl cellulose. These seal coated pellets were subjected to metoprolol succinate ng with a binder in aqueous solvent system. Drug layered pellets were provided with Extended Release coating-l using Ethyl cellulose and . An Extended Release coating-ll of it was given using cizer, triethyl citrate & talc. Seal coat-ll was given to Extended Release coated pellets followed by PEG coating in le solvent system. These PEG coated pellets was blended with the Prosolv, Croscarmellose sodium, PEG & Sodium Stearyl Fumarate and compressed into tablet. ed metoprolol Succinate core tablets were coated with the Amlodipine Besylate using opadry as a binder. An opadry coat was given to ed coated tablets.

Tablets obtained from e 3 were subjected to dissolution studies. The results of dissolution studies med are provided in Table 6.

Table 6: Dissolution profile Dissolution of Metoprolol Succinate Dissolution of Amlodipine Method: 500 mL of pH 6.8 phosphate Method: 500 mL of pH 0.01 N HCI, buffer, USP ll apparatus at 50 rpm USP ll apparatus at 75 rpm Time points (h) % Drug dissolved Time points (min) % Drug dissolved Example 4: Metoprolol succinate ER/ Valsartan Tablet; Eq 25mg tartrate/160 mg Table 7: Metoprolol succinate ER/ Valsartan Tablet Composition Micro crystalline cellulose 0.1-20 spheres Sea coa| t l Ethyl cellulose 0.01-20 yl citrate 0.001-1 Drug Layering Metoprolol succinate (Metoprolol ate) Opadry Clear 0.1 -1 0 Extended Release Ethyl cellulose 0.1-30 coating -| Opadry Clear 0.1-10 Tabletl ( lnner core ) Eudragit L30-D55 0.1-10 Extended Release - 0.001-5 _ Triethyl e coating -l| Seal coat || Opadry Clear 0.1-10 PEG coating Polyethylene glycol 0.1-10 Prosolv SMCC 90 10-80 Croscarmellose sodium 0.5-15 Blending —- hylene glycol 0.1-10 Sodium Stearyl fumarate 0.01-5 Tablet ll (Outer Granulation Valsartan 5-70 fraction) Micro crystalline cellulose Hypromellose 0.1-20 Silicone dioxide 0.1-10 Magnesium stearate Film coating Opadry white 0140 Procedure: Process involved tab-in-tab technology where core tablet was prepared by using microcrystalline cellulose spheres were given seal coat I of ethyl cellulose. These seal coated pellets were subjected to metoprolol succinate layering with a binder in aqueous solvent . Drug d pellets were provided with Extended Release coating-l using Ethyl cellulose and opadry. An Extended Release coating-ll of Eudragit was given using Plasticizer, triethyl citrate & talc. Seal coat-ll was given to Extended e coated s followed by PEG coating in suitable solvent system. These PEG coated pellets was blended with the Prosolv, Cross carmellose sodium, PEG & Sodium Stearyl fumarate to obtained core tablet. Outer fraction of tab-in-tab was ed by blending Valsartan with Microcrystalline cellulose, Hypromellose, Crospovidone, Silicone dioxide & lubricant, ium stearate. Both blend were used to prepare -tab formulation. Prepared olol succinate/ valsartan tablets were coated with the opadry.

Tablets obtained from example 4 were subjected to dissolution s. The results of dissolution studies performed are ed in Table 8.

Table 8: Dissolution profile Dissolution of Metoprolol succinate Dissolution of Valsartan Method: 500 mL of pH 6.8 phosphate Method: 1000mL of pH 6.8 phosphate buffer, USP ll tus at 50 rpm buffer, USP ll apparatus at 50 rpm Time points (h) % Drug dissolved Time points (min) % Drug dissolved Example 5: Metoprolol succinate ER/ tan Tablet; Eq 25mg Tartrate/80 mg Table 9: Metoprolol succinate ER/ Valsartan Tablet Composition Micro crystalline cellulose 0.1-20 spheres Sea coa| t l Ethyl cellulose 0.01-20 yl citrate 0.001-1 Drug Layering Metoprolol ate (Metoprolol succinate) Opadry Clear 0.1 -1 0 Extended Release Ethyl cellulose 0.1-30 coating -| Opadry Clear 0.1-10 Tabletl ( lnner core ) Eudragit L30-D55 0.1-10 Extended Release - . 0.001-5 _ Triethyl cntrate coating -ll 010 Seal coat || Opadry Clear 0.1-10 PEG coating Polyethylene glycol 0.1-10 Prosolv SMCC 90 10-80 Croscarmellose sodium 0.5-15 Blend'ing Polyethylene glycol 0.1-10 Sodium l fumarate 0.01-5 fraction) Micro crystalline cellulose Hypromellose - Crospovidone - Silicone dioxide - Magnesium stearate - Procedure: Process involved inlay tablet where core tablet was prepared by using microcrystalline cellulose as core which was given seal coat I using suitable solvent system. These seal coated pellets were subjected to metoprolol succinate layering with a binder in aqueous solvent . Drug layered pellets were provided with ed Release coating-l using Ethyl cellulose and opadry in suitable solvent system. An extended e coating-ll of Eudragit was given using Plasticizer, triethyl e & talc. Seal coat-ll was given to Extended Release coating pellets ed by PEG coating in suitable solvent system. These PEG coated pellets was d with the Prosolv, Cross carmellose sodium, PEG & Sodium Stearyl fumarate to obtained core tablet. Outer fraction of inlay tablet was ed by granulation of Valsartan with Microcrystalline ose, Hypromellose, Crospovidone, Silicone dioxide followed by addition of lubricant, Magnesium stearate. Both blends were used to prepare inlay tablets.

Tablets obtained from example 5 were subjected to dissolution studies. The results of dissolution studies performed are provided in Table 10.

Table 10: Dissolution profile Dissolution of Metoprolol succinate Dissolution of Valsartan Method: 500 mL of pH 6.8 phosphate Method: 1000mL of pH 6.8 phosphate buffer, USP ll apparatus at 50 rpm buffer, USP ll apparatus at 50 rpm Time points (h) % Drug ved Time points (min) % Drug dissolved Example 6: Metoprolol ate ER/ Valsartan Capsule; Eq 50mg Tartrate /80 mg Table 11: Metoprolol succinate ER/ Valsartan Tablet Composition Micro lline cellulose O I 1 20 Seal coat I Ethyl cellulose 0.01-20 yl citrate 0.001-1 Drug Layering Metoprolol succinate (Metoprolol succinate) Opadry Clear 0.1-10 Metoprololsuccinate Exent ded Reease| —-Eth| ce uose|| | - ER pellets coating -| Opadry Clear 0.1-10 Eudra it L30-D55 0.1-10 Extended Release —- Trieth lcitrate 0.001-5 coating-.. —- Seal coat || Opadry Clear 0.1-10 Micro crystalline cellulose Valsartan Granules Granulation 0.1-10 Magnesium stearate Procedure: rystalline cellulose spheres was given seal coat I of ethyl cellulose. These seal coated s were subjected to metoprolol succinate layering with a binder in aqueous solvent . Drug layered pellets were ed with Extended Release coating-l using Ethyl cellulose and opadry. An extended release coating-ll of Eudragit was given using Plasticizer, triethyl citrate & talc. Seal coat-ll was given to Extended Release coated pellets followed by Seal coating II to obtained metoprolol succinate ER pellets.

Valsartan granules were prepared by Wet granulation of Valsartan, microcrystalline cellulose & vidone using povidone as binder followed by drying & lubrication with magnesium stearate.

Tablets obtained from example 6 were subjected to dissolution s. The results of dissolution studies performed are provided in Table 12.

Table 12: Dissolution profile Dissolution of Metoprolol succinate Method: 500 mL of pH 6.8 phosphate Method: 1000mL of pH 6.8 ate buffer, USP ll apparatus at 50 rpm Time points (h) Time points (min) % Drug dissolved 2 7 20 85 4 24 3O 94 “um-‘- —“—— ———— —-_—— ———— —“—— Example 7: Metoprolol succinate ER/ Lisinopril ER Capsules Table 13: Metoprolol succinate ER/ Lisinopril ER Capsules; Eq 50mg Tartrate/5 mg Micro crystalline cellulose spheres Seal coat I Ethyl cellulose Triethyl citrate Drug Layering Metoprolol succinate (Metoprolol succinate) Opadry Clear 0.1 -1 O Metoprolol succinate - Extended e Ethyl cellulose 0.1-30 ER pellets coating. -| Opadry Clear 0.1-10 Eudra it 5 0.1-10 ed e—- 0.001-5 _ Triethyl citrate g -l| Seal coat || Opadry Clear 0.1 -10 Micro crystalline cellulose 0.1-10 spheres Drug Layering Lisino ril 0.1-25 Lisinopril pellets (Lisinopril) Procedure: Microcrystalline ose spheres were given seal coat I of ethyl cellulose. These seal coated s were subjected to Metoprolol succinate layering with a binder in aqueous solvent system. Drug layered pellets were ed with Extended Release coating-l using Ethyl cellulose and opadry. An extended release coating of Eudragit was given using Plasticizer, triethyl citrate & talc. Seal coat-ll was given to Extended Release coated-ll pellets followed by seal coat ll & lubrication with talc to obtained metoprolol succinate ER pellets.

WO 30725 To the obtained Lisinopril pellets, microcrystalline cellulose spheres were directly coated with Lisinopril along with opadry as binder. These drug layered s were lubricated with talc and filled with metoprolol ate ER pellets in empty hard gelatin capsule.

Capsules obtained from example 7 were subjected to dissolution studies. The results of dissolution studies performed are provided in Table 14.

Table 14: Dissolution study Dissolution of Metoprolol succinate Dissolution of Lisinopril Method: 500 mL of pH 6.8 phosphate Method: 900mL of 0.1N HCI, USP ll buffer, USP ll apparatus at 50 rpm apparatus at 50 rpm Time points (h) % Drug dissolved Time points (min) % Drug ved Example 8: Metoprolol succinate ER/ Enalapril maleate Tablet Table 15: Metoprolol succinate ER/ Enalapril e Tablet; Eq 50mg Tartrate/10 mg Stage Ingredients %w/w Microcrystallinecellulose spheres 0.1-20 Seal coat I Ethyl cellulose 0.01-20 Triethyl citrate 0.001-5 2012/054257 Drug Layering Metoprolol succinate 2—70 (Metoprolol Succinate) Opadry Clear Extended Release g Ethyl cellulose -l Opadry Clear Eudragit L30-D55 Extended Release coating Triethyl e Talc Seal coat ll Opadry Clear PEG coating Polyethylene glycol ril maleate Lactose Granulation.

Sodium bicarbonate 0.1 -30 Corn starch Prosolv SMCC 90 Pregelatinized starch ng & Tableting Polyethylene glycol Sodium Stearyl Fumarate Film coating Opadry white ure: Microcrystalline ose spheres were given seal coat I of ethyl cellulose. These seal coated pellets were ted to Metoprolol succinate layering with a binder in aqueous solvent system. Drug layered pellets were provided with Extended Release coating-l using Ethyl cellulose and opadry. An Extended Release coating-ll of Eudragit was given using plasticizer, triethyl citrate & talc. Seal coat-ll was given to Extended Release coated pellets followed by PEG coating in suitable solvent system. Separately, Enalapril Maleate was mixed with lactose and treated with sodium bicarbonate. The sodium bicarbonate treated blend was then granulated using starch paste. Metoprolol succinate PEG coated pellets were blended with the Enalapril e granules, Prosolv, Pregelatinized starch, PEG & Sodium Stearyl Fumarate and compressed into a tablet.

An opadry coat was given to the core tablets.

Tablets obtained from example 8 were subjected to dissolution studies. The results of dissolution s performed are provided in Table 16.

Table 16: Dissolution study ——Dissolution of Metoprolol succinate Dissolution of Enalapril e Method: 500 mL of pH 6.8 phosphate Method: 900 mL of pH 6.8 phosphate Time points (h) Time points (min) % Drug dissolved ——-_ “—m- —m-— Example 9: Metoprolol succinate ER/ Enalapril maleate Tablet Table 17: Metoprolol succinate ER/ Enalapril maleate Bilayer ; Eq 100mg Tartrate/10 mg Component Stage Ingredients Layer l((lVletoprolol Microcrystallinecellulose 0-1 20 succinate) spheres Seal coat I Ethyl cellulose 0.01 -20 Triethyl citrate 0.001-5 Drug Layering Metoprolol ate (Metoprolol 0.1-20 . Opadry Clear succmate) Extended Release Ethyl cellulose g -l Opadry Clear 0.1-20 Eudragit L30-D55 0.1-20 Extended e Triethyl citrate 0.001-5 coating -ll Talc 0.1-20 Seal coat ll Opadry Clear 0.1-20 PEG coating hylene glycol 0.1-10 Prosolv SMCC 90 10-80 Croscarmellose sodium 0.5-15 Blending Polyethylene glycol 0.1-10 Sodium Stearyl Fumarate 0.01-5 Enalapril maleate 0.1-25 Lactose 0.1-25 Layer ll Granulation Sodium bicarbonate 0.1-25 (Enalapril Maleate) Starch 0.1-20 Magnesium stearate 0.1-10 Film g Opadry white Procedure: Microcrystalline cellulose s were given seal coat I of ethyl cellulose. These seal coated pellets were subjected to metoprolol succinate layering with a binder in aqueous solvent system. Drug layered s were provided with Extended e coating-l using Ethyl cellulose and opadry. An Extended Release g-ll of Eudragit was given using plasticizer, triethyl citrate & talc. Seal coat-ll was given to Extended Release coated s followed by PEG coating in suitable solvent system. These PEG coated pellets were blended with the Prosolv, Croscarmellose sodium, PEG & Sodium Stearyl Fumarate to obtained layer l blend. Layer ll granules were prepared by treated Enalapril Maleate and lactose with sodium bicarbonate. These treated granules were granulated with starch, dried & lubricated with magnesium te. Both blend were used to prepare two layers of bilayer tablet. Prepared metoprolol Succinate/ Enalapril Maleate bilayer tablets were coated with the opadry.

Tablets obtained from example 9 were subjected to dissolution studies. The results of dissolution studies performed are provided in Table 18.

Table 18: Dissolution study Dissolution of Metoprolol succinate Dissolution of Enalapril maleate Method: 500 mL of pH 6.8 phosphate Method: 900 mL of pH 6.8 phosphate , USP ll apparatus at 50 rpm buffer, USP ll apparatus at 50 rpm.

Time points (h) % Drug dissolved Time points (min) % Drug dissolved Example 10: Clinical Study The study methods involved a multicenter, randomized, placebo-controlled, unbalanced factorial study for lowering the blood pressure. Patients, with confirmed diagnosis of stage II hypertension were eligible to participate in the studies. Patients were ized to one of many treatment : Study 1: Group l were administered extended-release (ER) metoprolol succinate (Eq 25mg Tartrate, Eq 50mg Tartrate, Eq 100mg te), Group II were administered pine besylate , 5mg, 10mg), Group III were administered metoprolol succinate ER/ amlodipine te IR (dosages of present invention).

Study 2: Group I were administered ed-release metoprolol succinate (Eq 25mg tartrate, Eq 50mg tartrate, Eq100mg tartrate), Group II were stered valsartan (40mg, 80mg, 160mg, 320mg), Group III were stered metoprolol succinate ER / Valsartan IR (dosages of present invention).

Study 3: Group I were administered extended-release olol ate (Eq 25mg Tartrate, Eq 50mg Tartrate, Eq 100mg Tartrate), Group II were administered lisinopril (10mg, 20mg, 40mg), Group III were administered extended release of metoprolol succinate / immediate e lisinopril (dosages of present invention).

After one month of therapy non-responder patients were managed with dose-titration or rescue medication.

Treatment groups in all three studies were well balanced at base line and achieved absolute change at one week from the baseline in blood pressure. It was found that at least 10% improvement in blood pressure (systolic blood pressure and diastolic blood pressure) was attained after 3 months treatment using pharmaceutical dosage form of the present invention.

Where the terms “comprise”, “comprises”, “comprised” or “comprising” are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other e, integer, step, component or group thereof.

Claims (22)

The Claims defining the invention are as follows:

1. A pharmaceutical dosage form suitable for once daily administration comprising a fixed dose combination of metoprolol in extended release form, one or more m channel blockers, and one or more rate controlling excipients, wherein the dosage form exhibits a dissolution e such that 6% or less of metoprolol is released within 1 hour; between 25% to 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after 20 hours, when the release rate is measured in USP Type 2 Dissolution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium.

2. The pharmaceutical dosage form according to claim 1, wherein the calcium channel r comprises one or more of amlodipine, aranidipine, azelnidipine, barnidipine, bencyclane, benidipine, bepridil, cilnidipine, clentiazem, ipine, diltiazem, efonidipine, elgodipine, etafenone, felodipine, fendiline, flunarizine, gallopamil, isradipine, lacidipine, lercanidipine, lidoflazine, lomerizine, manidipine, mibefradil, ipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, pranidipine, amine, semotiadil, terodiline, and verapamil.

3. The pharmaceutical dosage form ing to claim 1 or claim 2, wherein the dosage form comprises 25mg to 200mg of olol and 2.5mg to 800mg of the calcium channel r.

4. The pharmaceutical dosage form according to any one of claims 1 to 3, wherein the dosage form exhibits immediate release of the calcium channel blocker.

5. A pharmaceutical dosage form suitable for once daily administration comprising a fixed dose combination of metoprolol in extended release form, one or more angiotensin II receptor blockers, and one or more rate controlling excipients, wherein the dosage form exhibits a dissolution profile such that 6% or less of metoprolol is released within 1 hour; n 25% to 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after 20 hours, when the release rate is measured in USP Type 2 Dissolution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium.

6. The pharmaceutical dosage form according to claim 5, wherein the angiotensin II receptor blocker ses one or more of valsartan, telmisartan, losartan, irbesartan, azilsartan, candesartan, rtan, and olmesartan.

7. The ceutical dosage form according to claim 5 or claim 6, n the dosage form comprises 25mg to 200mg of metoprolol and 20mg to 800mg of the angiotensin II receptor blocker.

8. The pharmaceutical dosage form according to any one of claims 5 to 7, wherein the dosage form exhibits immediate release of the angiotensin II receptor blocker.

9. A pharmaceutical dosage form suitable for once daily stration comprising a fixed dose combination of metoprolol in extended e form, one or more ACE inhibitors, and one or more rate controlling excipients, wherein the dosage form ts a dissolution profile such that 6% or less of metoprolol is released within 1 hour; between 25% to 50% of metoprolol is released within 6 hours and at least 90% of metoprolol is released after 20 hours, when the release rate is measured in USP Type 2 Dissolution Apparatus (paddle, 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37°C ± 0.5°C as dissolution medium.

10.The pharmaceutical dosage form according to claim 9, wherein the ACE inhibitor comprises one or more of benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, rentiapril, pril, spirapril, lisinopril, perindopril, ramipril, spiraprilat, lapril, zofenopril, imidapril, and quinapril.

11.The pharmaceutical dosage form according to claim 9 or claim 10, wherein the dosage form comprises 25mg to 200mg of metoprolol and 1mg to 100mg of the ACE tors.

12.The ceutical dosage form according to any one of claims 9 to 11, wherein the dosage form exhibits immediate release of the ACE inhibitor.

13.The pharmaceutical dosage form according to any one of claims 1 to 12, wherein the dosage form comprises one or more water swellable or water insoluble inert cores coated with one or more rate controlling excipients.

14.The pharmaceutical dosage form according to claim 13, wherein the water swellable core comprises microcrystalline cellulose, hydroxypropyl methylcellulose, starch, or mixtures thereof.

15.The pharmaceutical dosage form according to claim 13, wherein the water insoluble inert core comprises n dioxide, glass les, plastic resin les, or mixtures thereof.

16.The pharmaceutical dosage form according to any one of claims 1 to 15, n the rate controlling ent comprises polymeric rate controlling excipient, non-polymeric rate controlling excipient, or mixtures thereof.

17.The pharmaceutical dosage form according claim 16, wherein the rate controlling excipient ses one or more of cellulose derivatives; polyhydric alcohols; saccharides, gums and derivatives thereof; vinyl derivatives, polymers, copolymers or mixtures thereof; maleic acid copolymers; polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives; fat; wax; fatty acid; fatty acid ester; long chain monohydric l or their ester; or mixtures thereof.

18.The pharmaceutical dosage form according to any one of claims 1 to 12, wherein the dosage form is in the form of a tablet, a capsule, granules, pellets, a tablet in tablet, tablet/s in capsule, granules or pellets in capsule, a bi-layer tablet, a trilayer , and an in-lay tablet.

19.Use of a pharmaceutical dosage form according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment of one or more ers selected from hypertension, congestive heart failure, angina, myocardial infarction, arteriosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renal insufficiency, peripheral vascular disease, left ventricular hypertrophy, cognitive dysfunction and chronic heart failure.

20.Use of a pharmaceutical dosage form according to any one of claims 1 to 18 for the manufacture of a medicament for the treatment of one or more cardiovascular disorders.

21.The pharmaceutical dosage form according to any one of claims 1 to 18, ntially as hereinbefore described with reference to any of the Examples.

22.Use ing to claim 19 or claim 20, substantially as before described with reference to any of the Examples.