USOO9446032B2

(12) United States Patent (10) Patent No.: US 9.446,032 B2 Madhukar Kodgule et al. (45) Date of Patent: Sep. 20, 2016

(54) METHODS FOR TREATING A61K 9/1605; A61 K9/2072; A61 K9/2086; CARDOVASCULAR DISORDERS A61K 9/1652: A61K 9/167: A61 K9/20: A61 K9/2004; A61 K9/2054: A61 K9/48 (75) Inventors: Mandar Madhukar Kodgule, USPC ...... 424/465-489 Aurangabad (IN); Premchand See application file for complete search history. Dalichandji Nakhat, Noida (IN); Amit Gupta, Ahmedabad (IN); Girish (56) References Cited Kumar Jain, Aurangabad (IN) U.S. PATENT DOCUMENTS (73) Assignee: WOCKHARDT LIMITED, Bandra 4.942,040 A * 7/1990 Ragnarsson ...... A61K9/2081 East, Mumbai (IN) 424/459 2005/0032879 A1 2/2005 Okarter et al. (*) Notice: Subject to any disclaimer, the term of this 2008/0233190 A1* 9, 2008 Solomon ...... A61K 9.2072 patent is extended or adjusted under 35 424/467 U.S.C. 154(b) by 94 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 14/240,380 CN 101.249083. A 8, 2008 (22) PCT Filed: Aug. 23, 2012 WO WO2007/O105O1 A2 1, 2007 WO WO 2007O 105O1 A2 * 1, 2007 ...... A61K 9,2081 (86). PCT No.: PCT/B2012/0542.57 WO WO2007/110753 A2 9, 2007 S 371 (c)(1), OTHER PUBLICATIONS (2), (4) Date: May 15, 2014 Efficacy and tolerability of a fixed-dose combination of metoprolol extended releasefamlodipine in patients with mild-to-moderate (87) PCT Pub. No.: WO2013/030725 hypertension: a randomized, parallel-group, multicentre comparison PCT Pub. Date: Mar. 7, 2013 with plus amlodipine. Pareek et al., Clin Drug Investig. 2010:30(2): 123-131. (65) Prior Publication Data A clinical trial to study the effects of two drugs and US 2014/O3O2125 A1 Oct. 9, 2014 metoprolol in patients with high blood pressure and heart disease. Mohan. Clinical Trials Registry—India, Aug. 8, 2011. retrieved on (30) Foreign Application Priority Data Nov. 23, 2012. cited in the application and in the International Search Report. Aug. 26, 2011 (IN) ...... IN2O11MU2395A Aug. 26, 2011 (IN) ...... IN2O11MU2399A * cited by examiner Aug. 27, 2011 (IN) ...... IN2O11MU2411A Primary Examiner — Micah-Paul Young (51) Int. Cl. (74) Attorney, Agent, or Firm — Bio Intellectual Property A6 IK 9/22 (2006.01) Services LLC (Bio IPS); O. (Sam) Zaghmout A6 IK 3/448 (2006.01) A6 IK3I/38 (2006.01) (57) ABSTRACT A6 IK 3/40 (2006.01) There is provided a once-a-day therapeutically synergistic A6 IK 3/4I (2006.01) pharmaceutical dosage form for treatment of cardiovascular A6 IK 45/06 (2006.01) disorders, wherein the dosage form comprises a fixed dose (52) U.S. Cl. combination of metoprolol in extended release form and one CPC ...... A6 IK3I/4418 (2013.01); A61K 3 1/138 or more calcium channel blocker, II receptor (2013.01); A61K 31/40 (2013.01); A61 K3I/41 blocker or angiotensin converting enzyme inhibitor along (2013.01); A61K 45/06 (2013.01) with one or more rate controlling excipient. (58) Field of Classification Search CPC ...... A61K 9/14: A61K 9/141; A61 K9/16; 7 Claims, No Drawings US 9,446,032 B2 1. 2 METHODS FOR TREATING Beta-blocker, for example, metoprolol acts by blocking CARDOVASCULAR DISORDERS the adrenergic stimulation of the heart and thus reduces the oxygen demand of the cardiac tissue. Apparently, this FIELD OF THE INVENTION explains their beneficial effects in angina pectoris and car dioprotective action in myocardial infarction. In addition, The present invention relates to a once-a-day therapeuti beta-blockers normalize blood pressure in a large proportion cally synergistic pharmaceutical dosage form for treatment of patients with arterial hypertension, which probably is due of cardiovascular disorders, wherein the dosage form com to an additional action on the control of peripheral resistance prises a fixed dose combination of metoprolol in extended to blood-flow. release form and one or more calcium channel blocker, 10 Metoprolol (Formula I) is a beta1-selective (cardioselec angiotensin II receptor blocker or angiotensin converting tive) adrenoreceptor-blocking agent. It is commercially enzyme (ACE) inhibitor along with one or more rate con available in two salt forms; one of them is tartrate salt trolling excipient. available as Lopressor(R) tablets and the other is succinate salt available as ToprolR-XL tablets. The ToprolR-XL tab BACKGROUND OF THE INVENTION 15 lets contain 23.75 mg, 47.5 mg, 95 mg and 190 mg of metoprolol Succinate equivalent to 25 mg, 50 mg, 100 mg “Cardiovascular disease or disorder” is intended to mean and 200 mg of metoprolol tartrate, USP, respectively. Meto any cardiovascular disease or disorder known in the art, prolol is indicated in the treatment of hypertension, heart including congestive heart failure, complications associated failure and angina pectoris. with diabetes mellitus, hyperhomocysteinemia, hypercho Initial therapy with a diuretic or beta-blocker has been the lesterolemia, atherosclerosis, inflammatory heart disease, usual first approach for treating cardiovascular disorders. valvular heart disease, restenosis, hypertension (e.g. pulmo ACE inhibitors, calcium channel blockers and angiotensin nary hypertension, labile hypertension, idiopathic hyperten receptors blockers are also effective as first-line therapy. The Sion, low- hypertension, salt-sensitive hypertension, physician is therefore required to choose from above classes low-renin, salt-sensitive hypertension, thromboembolic pull 25 of agents for initial therapy. monary hypertension; pregnancy-induced hypertension; Calcium channel blockers play important role in contrac renovascular hypertension; hypertension-dependent end tile processes of cardiac muscle and vascular Smooth muscle stage renal disease, hypertension associated with cardiovas by regulating the movement of extracellular calcium ions cular Surgical procedures, hypertension with left ventricular into these cells through specific ion channels. Calcium hypertrophy, and the like), diastolic dysfunction, coronary 30 channel blockers work by blocking Voltage-gated calcium artery disease, myocardial infarctions, cerebral infarctions, channels (VGCCs) in cardiac muscle and blood vessels. This arteriosclerosis, atherogenesis, cerebrovascular disease, decreases intracellular calcium leading to a reduction in angina (including chronic, stable, unstable and variant (Prin muscle contraction. In the heart, a decrease in calcium Zmetal) angina pectoris), aneurysm, ischemic heart disease, available for each beat results in a decrease in cardiac cerebral ischemia, myocardial ischemia, thrombosis, platelet 35 contractility. In blood vessels, a decrease in calcium results aggregation, platelet adhesion, Smooth muscle cell prolif in less contraction of the vascular Smooth muscle and eration, Vascular or non-vascular complications associated therefore an increase in arterial diameter (CCBs do not work with the use of medical devices, vascular or non-vascular on venous Smooth muscle) a phenomenon called vasodila wall damage, peripheral vascular disease, neointimal hyper tion. plasia following percutaneous transluminal coronary angio 40 Angiotensin II receptor blockers (ARBs), also known as graph, vascular grafting, coronary artery bypass Surgery, angiotensin II receptor antagonists, ATI-receptor antagonists thromboembolic events, post-angioplasty restenosis, coro or 'sartans', are a group of drugs which modulate the nary plaque inflammation, embolism, stroke, shock, arrhyth renin-angiotensin-aldosterone system. Their main uses are mia, atrial fibrillation or atrial flutter, thrombotic occlusion in the treatment of hypertension (high blood pressure), and reclusion cerebrovascular incidents, and the like. 45 diabetic nephropathy (kidney damage due to diabetes) and Many individuals are at an elevated risk of suffering congestive heart failure. Angiotensin II receptor blockers, serious to life-threatening cardiovascular events, including block the activation of angiotensin II AT1 receptors. Block infarction (heart attack), cardiac arrest, congestive heart ade of AT1 receptors directly causes vasodilation, reduces failure, stroke, peripheral vascular disease and/or claudica secretion of vasopressin, and reduces production and secre tion. The risk factors are numerous and widespread through 50 tion of aldosterone, amongst other actions. The combined out the world population. They include cigarette Smoking, effect reduces blood pressure. diabetes, hypercholesterolemia (high serum cholesterol), ACE inhibitors or angiotensin-converting enzyme inhibi hypertension, angina, Systemic lupus erythematosus, prior tors are a group of drugs used primarily for the treatment of heart attacks or strokes, hemodialysis, hyperhomocysteine hypertension (high blood pressure) and congestive heart levels, obesity, sedentary lifestyle, receiving an organ trans 55 failure, although they may also be prescribed for cardiac plant, atherosclerosis, and others. There is a need for a safe failure, diabetic nephropathy, renal disease, Systemic scle and convenient pharmaceutical formulation that would rosis, left ventricular hypertrophy and other disorders. Origi effectively reduce the risk of incurring a cardiovascular nally synthesized from compounds found in pit viper event in individuals who have these risk factors. Venom, they inhibit angiotensin-converting enzyme (ACE), The treatments and drugs discovered or known in the art 60 a component of the blood pressure-regulating renin-angio for cardiovascular disease includes but are not limited to tensin System. beta-blockers, for example, atenolol, metoprolol, nadolol. Angiotensin-converting enzyme inhibitors (ACE inhibi oXprenolol, pindolol, propranolol, timolol, Alpha blockers, tors) reduce the activity of the renin-angiotensin-aldosterone for example, doxazosin, phentolamine, indoramin, phenoxy system. One mechanism for maintaining the blood pressure benzamine, praZosin, teraZosin, tolaZoline; mixed alpha and 65 is the release of a protein called renin from cells in the beta blockers, for example, bucindolol, carvedilol and kidney (to be specific, the juxtaglomerular apparatus). This labetalol. produces another protein, angiotensin, which signals the US 9,446,032 B2 3 4 adrenal gland to produce aldosterone. This system is acti drugs when used in combination. Moreover, because of the vated in response to a fall in blood pressure (hypotension), complexity of dosage regimen, it becomes difficult for the as well as markers of problems with the salt-water balance pharmacist to explain the treatment regimen to the patient of the body, such as decreased sodium concentration in the being treated. Thus, non-compliance occurs at all three distal tubule of the kidney, decreased blood volume and 5 levels i.e. at physician, pharmacist and patient’s level. In stimulation of the kidney by the sympathetic nervous sys order to improve compliance there is a need of an appro tem. In Such situations, the kidneys release renin, which acts priate compliance package, which is self explanatory to as an enzyme and cuts off all but the first 10 amino acid patient comprising appropriate fixed dose combinations. residues of angiotensinogen (a protein made in the liver, and U.S. Pat. No. 4,572,909 discloses amlodipine; U.S. Pat. which circulates in the blood). These 10 residues are then 10 known as angiotensin I. Angiotensin I is then converted to No. 4,446.325 discloses aranidipine; U.S. Pat. No. 4,772, angiotensin II by angiotensin converting enzyme (ACE). 596 discloses azelnidipine; U.S. Pat. No. 4.220,649 dis Angiotensin converting enzyme inhibitors (ACE inhibi closes barnidipine: U.S. Pat. No. 4,448,964 discloses beni tors) block the conversion of angiotensin I to angiotensin II. dipine: U.S. Pat. No. 5,856,346 discloses clevidipine; U.S. They, therefore, lower arteriolar resistance and increase 15 Pat. No. 4,466.972 discloses isradipine: U.S. Pat. No. 4,885, venous capacity; increase cardiac output, cardiac index, 284 discloses efonidipine; and U.S. Pat. No. 4.264,611 stroke work, and Volume; lower renovascular resistance; and discloses felodipine. lead to increased natriuresis (excretion of Sodium in the U.S. Pat. No. 5,399,578 discloses ; European urine). Patent No. 0 502 314 discloses ; U.S. Pat. No. Based on the disease condition and diagnosis, the physi 5,138,069 discloses Losartan; U.S. Pat. No. 5,270,317 dis cians tend to prescribe a combination of two or more closes ; U.S. Pat. Nos. 5,583,141 and 5,736,555 anti-hypertensive drugs to a patient. Such combinations are discloses ; U.S. Pat. No. 5,196,444 discloses Can expected to provide a better control over various cardiovas desartan; U.S. Pat. No. 5,616,599 discloses Olmesartan; and cular diseases. The said combinations can be given as two U.S. Pat. No. 5,185.351 discloses . separate drugs administered separately at same time or at 25 U.S. Pat. No. 4,374,829 discloses : U.S. Pat. No. different timings. Several fixed dose combinations of anti 4.587.258 discloses : U.S. Pat. No. 4,344,949 dis hypertensive drugs are available in the market. Wherever closes ; U.S. Pat. No. 4,508,729 discloses perindo possible, a fixed dose combination is used by physicians to pril: U.S. Pat. No. 4.374,829 discloses : U.S. Pat. simplify the dosing regimen. Some of the commercially No. 4410,520 discloses : U.S. Pat. No. 4,508,727 available cardiovascular drug combinations include Lopres 30 discloses ; U.S. Pat. No. 4.316,906 discloses sor HCTR (Metoprolol and Hydrochlorthiazide); ValturnaR) ; U.S. Pat. Nos. 4,046,889 and 4,105,776 dis ( hemifumarate and Valsartan): Exforge HCTR) closes ; and U.S. Pat. No. 4,337,201 discloses (Amlodipine besylate, Hydrochlorothiazide); Exforge(R) . (Amlodipine besylate and Valsartan); Diovan HCTR) (Hy Pharmaceutical compositions comprising beta-adrenergic drochlorothiazide and Valsartan): TwynstaR) (Amlodipine 35 blockers and/or calcium channel blockers are disclosed in besylate and Telmisartan); Micardis HCTR) (Hydrochloro following patent and non-patent literature. thiazide and Telmisartan): Hyzaar(R) (Hydrochlorothiazide Chinese Patent Application No. 101249083 discloses a and Losartan potassium): AvalideR (Hydrochlorothiazide twice-a-day Sustained-release matrix preparation containing and Irbesartan); Atacand HCT(R) ( cilexetil and amlodipine and metoprolol, wherein 25 to 45 percent of the Hydrochlorothiazide); Tribenzor R (Amlodipine besylate, 40 drug is released in a first hour, 45 to 75 percent in a fourth Hydrochlorothiazide and Olmesartan medoxomil): Azor R hour, and more than 75 percent in an eighth hour. (Amlodipine besylate and olmesartan medoxomil); Benicar PCT Patent Application No. 1999018957 discloses a HCTR) (Hydrochlorothiazide and Olmesartan medoxomil); pharmaceutical combination of atenolol with amlodipine Vaseretic(R) (Enalapril maleate and Hydrochlorothiazide); besylate. Quinaretic(R) (Hydrochlorothiazide and Quinapril hydro 45 U.S. Pat. No. 4.942,040 discloses a pharmaceutical prepa chloride); Accuretic(R) (Hydrochlorothiazide and Quinapril ration giving a controlled and extended release of both a hydrochloride); Zestoretic(R) (Hydrochlorothiazide and dihydropyridine, e.g. felodipine and a 3-adrenoreceptor Lisinopril); Prinzide(R) (Hydrochlorothiazide and Lisino antagonist, namely metoprolol. pril); Lotrel (R) (Amlodipine besylate and Benazepril hydro Kumaravelrajan et al., (Lipids in Health and Disease chloride); Lotensin HCTR) (Benazepril hydrochloride and 50 (2011), 10-51) discloses a controlled porosity osmotic pump Hydrochlorothiazide); Capozide(R) (Captopril and Hydro tablet (CPOP) system to deliver Nifedipine (NP) and Meto chlorothiazide); and Tarka(R) ( and Verapamil prolol (MP) in a controlled manner up to 12 hours. The hydrochloride). However, these fixed dose combinations developed osmotic system was effective in the multi-drug does not provide physician an option to modulate the dose therapy of hypertension. of drugs within these fixed dose combinations according to 55 Trenkwalder et al., (Journal of human hypertension, need of a patient. (1995), 9 (2), S37-42) discloses an extended-release (ER) These cardiovascular combinations are also prescribed formulation, combining felodipine, 5 mg, and metoprolol. along with other drugs such as cardioprotectant, platelet 50 mg. aggregation inhibitors, anticoagulants, antipsychotics, etc. CTRI/2008/091/000190 discloses a randomised, open This multiple administration, complex drug regi 60 label; parallel group, multicentric study comparing the effi men, and frequent dose administration complicates the cacy and safety of fixed-dose-combinations of Metoprolol patient’s compliance. Since cardiovascular disorders are XL plus Amlodipine with individual components of the often chronic disorders, complex drug regimen involving combination. several drugs has a negative impact on patient’s life leading CTRI/2009/091/000269 discloses a single arm trial to non-compliance. Most of the patient’s tend to forget 65 assessing the efficacy and tolerability of a fixed-dose com dosage regimen quite often. Further, it becomes difficult for bination of metoprolol and amlodipine in essential hyper the physician to prescribe appropriate doses of different tension. US 9,446,032 B2 5 6 Pharmaceutical compositions comprising beta-adrenergic developed a matrix dosage form comprising combination of blockers and/or angiotensin II receptor blockers are dis f blocker drugs in combination with calcium channel closed in following patent and non-patent literature. blocker, angiotensin II receptor blocker or ACE inhibitor. PCT Patent Application No. 201128016 discloses a for The release profile obtained from matrix tablets was erratic mulation comprising an immediate-release compartment 5 and varied from batch to batch. It was found that due to including beta-adrenergic blockers nebivolol and an highly soluble and highly permeable nature of metoprolol, it extended-release compartment including angiotensin II is difficult to formulate and achieve an extended release once receptor blockers losartan. a day formulation in matrix dosage form. Further, preparing Indian Patent Application No. 2205/MUM/2007 discloses a fixed dose combination comprising an extended release a pharmaceutical combination comprising B receptor 10 antagonist nebivolol and angiotensin II receptor blocker metoprolol was also a major challenge as it was difficult to telmisartan. achieve the desired therapeutic release of the combination Indian Patent Application No. 1324/MUM/2008 discloses when combined into a single unit dosage form. Therefore, a pharmaceutical composition of angiotensin II receptor there is an ongoing need for the development of new dosage blocker Such as losartan potassium and a beta-selective 15 forms comprising an extended release metoprolol with cal adrenoreceptor blocking agent metoprolol Succinate in cium channel blocker, angiotensin II receptor blocker or monolithic matrix technology. ACE inhibitor which are safe and effective. CTRI/2010/091/001438 discloses a single arm trial to evaluate the safety and efficacy offixed dose combination of SUMMARY OF THE INVENTION olmesartan and metoprolol Succinate ER in hypertensive patients with cardiovascular disease. In one aspect, the present invention provides a pharma Pharmaceutical compositions comprising beta-adrenergic ceutical dosage form for treatment of cardiovascular disor blockers and/or ACE inhibitors are disclosed in following ders Suitable for once daily administration comprising a patent and non-patent literature. fixed dose combination of metoprolol in extended release PCT Patent Application No. 2007010501 (501) discloses 25 form and one or more calcium channel blockers along with a once a day pharmaceutical composition comprising a one or more rate controlling excipients. beta-blocker and ACE inhibitor, wherein the beta blocker is In another aspect, the present invention provides a phar present in an extended release form and the ACE inhibitor is maceutical dosage form for treatment of cardiovascular present in an immediate release form. The composition may disorders suitable for once daily administration comprising exhibit release of metoprolol over a period of 12-13 hours. 30 a fixed dose combination of metoprolol in extended release U.S Patent Application No. 20050032879 (879) discloses form and one or more one or more angiotensin II receptor use of a beta-blocker and an ACE-inhibitor in combination blockers along with one or more rate controlling excipients. for the treatment of hypertension. The release of drugs from In another aspect, the present invention provides a phar the dosage form may be provided over a period of 12-15 maceutical dosage form for treatment of cardiovascular hours and therefore the combination may not provide 35 disorders suitable for once daily administration comprising adequate synergistic effects. a fixed dose combination of metoprolol in extended release Metoprolol has been classified as a class I substance form and one or more ACE inhibitors along with one or according to the Biopharmaceutics Classification Scheme more rate controlling excipients. (BCS), meaning that it is highly soluble and highly perme In another aspect, the present invention provides a once able. The drug is readily and completely absorbed through 40 a-day pharmaceutical dosage form for treatment of cardio out the whole intestinal tract but is subject to extensive first vascular disorders, wherein the dosage form comprises a pass metabolism resulting in incomplete bioavailability fixed dose combination of about 25 mg to 200 mg of (about 50%). Amlodipine besylate, a representative example metoprolol in extended release form and about 2.5 mg to 800 in class of calcium channel blockers is slightly soluble in mg of one or more calcium channel blockers. water and sparingly soluble in ethanol. Amlodipine also 45 In another aspect, the present invention provides a once undergoes extensive first pass metabolism. Thus, formulat a-day pharmaceutical dosage form for treatment of cardio ing a once-a-day dosage form of highly water soluble vascular disorders, wherein the dosage form comprises a metoprolol in a fixed dose combination comprising an fixed dose combination of about 25 mg to 200 mg of extended release metoprolol and highly water soluble metoprolol in extended release form and about 20 mg to actives belonging to calcium channel blockers, angiotensin 50 about 800 mg of angiotensin II receptor blocker. II receptor blockers and ACE inhibitors is a challenging task In another aspect, the present invention provides a once for a pharmacist. a-day pharmaceutical dosage form for treatment of cardio None of the above mentioned prior arts provides a once vascular disorders, wherein the dosage form comprises a a-day fixed dose formulation comprising an extended release fixed dose combination of about 25 mg to 200 mg of metoprolol with a calcium channel blocker, angiotensin II 55 metoprolol in extended release form and about 1 mg to about receptor blocker or ACE inhibitor, which is safe and has an 100 mg of ACE inhibitors. enhanced therapeutic effect over the existing individual drug In another aspect, the once-a-day pharmaceutical dosage therapy. The prior arts disclosing pharmaceutical composi form for treatment of cardiovascular disorders exhibits tion comprising metoprolol in combination with one or more immediate release of calcium channel blocker, angiotensin II calcium channel blocker, angiotensin II receptor blocker or 60 receptor blocker and ACE inhibitor. ACE inhibitor does not provide a once-a-day dosage form In another aspect, the extended release metoprolol com with desired synergistic therapeutic effect. The combination ponent of the dosage form comprises a water Swellable or disclosed in the prior arts also does not address the uniform water insoluble inert core coated with one or more rate release and bioavailability related aspects of either of meto controlling excipient. prolol, calcium channel blocker, calcium channel blocker, 65 In another aspect, the water Swellable core comprises angiotensin II receptor blocker or ACE inhibitor when microcrystalline cellulose, hydroxypropyl methylcellulose, formulated into a once-a-day dosage form. Present inventors starch or mixtures thereof. US 9,446,032 B2 7 8 In another aspect, the water insoluble inert core comprises combination of an extended release metoprolol with calcium silicon dioxide, glass particles, plastic resin particles or channel blockers, angiotensin II receptor blockers, or ACE mixtures thereof. inhibitors, Surprisingly found that the pharmaceutical com In another aspect, the rate controlling excipient comprises position of the present invention provides a predictable and one or more polymeric rate controlling excipients, non uniform dissolution profile resulting in therapeutically effec polymeric rate controlling excipients, or mixtures thereof. tive release of the actives over a period of about 24 hours. In another aspect, the polymeric rate controlling excipient The present invention provides once-a-day fixed dose is selected from the group consisting of one or more of pharmaceutical composition of an extended release meto cellulose derivatives; polyhydric alcohols; Saccharides, gums and derivatives thereof vinyl derivatives, polymers, prolol and an active agent selected from calcium channel copolymers or mixtures thereof: maleic acid copolymers; blockers, angiotensin II receptor blockers, and ACE inhibi polyalkylene oxides or copolymers thereof, acrylic acid tors. The combinations are not only safe and effective polymers and acrylic acid derivatives; or any combinations medication for treatment of cardiovascular disease, but are thereof and non-polymeric rate controlling excipient is also found to be synergistic with enhanced efficacy. This selected from the group consisting of fat, wax, fatty acid, increased efficacy simplifies the management of cardiovas fatty acid ester, long chain monohydric alcohol or their ester 15 cular diseases. or any combinations thereof. The present inventors have now developed a safe and In another aspect, the present invention provides a once effective once-a-day therapeutically synergistic pharmaceu a-day pharmaceutical dosage form for treatment of cardio tical composition comprising metoprolol in extended release vascular disorders, wherein the dosage form comprises a form and an agent selected from one or more calcium fixed dose combination of metoprolol in extended release channel blockers, one or more angiotensin II receptor block form and an agent selected form one or more calcium ers, and one or more ACE inhibitors. From the preliminary channel blockers, one or more angiotensin II receptor block studies, inventors have surprisingly found that the combi ers and one or more ACE inhibitors along with one or more nation therapy results in at least 10% improvement in rate controlling excipients; characterized in that said com individual’s response when compared to monotherapy. position exhibits a dissolution profile such that less than 6% 25 The term “metoprolol, as used herein, refers to a meto of metoprolol or its salt is released within 1 hour and prolol base, or any pharmaceutically acceptable Salt thereof. 25%-50% of metoprolol or its salt is released within 6 hours and at least 90% of metoprolol is released after 20 hours In an embodiment, the metoprolol salt is Succinate salt or when the release rate is measured in USPType 2 Dissolution tartrate salt. Apparatus 2 (paddle, 50 rpm) using 500 ml of pH 6.8 In an embodiment, the fixed dosage form comprises phosphate buffer at 37° C.-0.5° C. as dissolution medium. 30 metoprolol succinate 23.75 mg, 47.5 mg, 95 mg and 190 mg In another aspect, the pharmaceutical composition com equivalent to 25 mg, 50 mg, 100 mg and 200 mg of prises pharmaceutically acceptable excipients selected from metoprolol tartrate or equivalent to 9.75 mg, 19.5 mg. 39 mg one or more diluent, binder, glidant, Solubilizer, lubricants, and 78 mg of metoprolol base respectively. disintegrants, colorants, Suspending agent, thickener or taste The term "calcium channel blocker', as used herein, masking agent. 35 refers to calcium channel blocker base, or any pharmaceu In another aspect, the pharmaceutical dosage form is in tically acceptable salt or ester thereof. the form of a tablet, a capsule, granules, a tablet in tablet, The term “angiotensin II receptor blocker', as used tablet/s in capsule, granules in capsule, an orally disinte herein, refers to angiotensin II receptor blocker base, or any grating tablet, a bilayer tablet, a trilayer tablet, an in-lay pharmaceutically acceptable salt or ester thereof. tablet, or Suspension. 40 The term “angiotensin converting enzyme inhibitor or In another aspect, the present invention provides a method “ACE inhibitor', as used herein, refers to angiotensin con of treating one or more disorders selected from hyperten verting enzyme inhibitor base, or any pharmaceutically Sion, congestive heart failure, angina, myocardial infarction, acceptable salt or ester thereof. arteriosclerosis, diabetic nephropathy, diabetic cardiac myo As used herein, the term "salt” refers to any pharmaceu pathy, renal insufficiency, peripheral vascular disease, left 45 tically acceptable salt (e.g., acid or base) of a compound of Ventricular hypertrophy, cognitive dysfunction, and chronic the present invention, which upon administration to a Sub heart failure, wherein the method comprises administering a ject, is capable of providing a compound of this invention or once-a-day pharmaceutical dosage form comprising a fixed an active metabolite or residue thereof. As is known to those dose combination of an metoprolol in extended release form of skill in the art, “salts' of the compounds of the present and an agent selected form one or more calcium channel 50 invention may be derived from inorganic or organic acids blockers, one or more angiotensin II receptor blockers and and bases. Examples of acids include, but are not limited to, one or more ACE inhibitors along with one or more rate hydrochloric, hydrobromic, Sulfuric, nitric, perchloric, controlling excipients to a patient in need of said treatment. fumaric, maleic, phosphoric, glycolic, lactic, salicylic, suc Embodiments of the pharmaceutical composition may cinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesul include one or more of the following features. For example, 55 fonic, ethanesulfonic, formic, benzoic, malonic, naphtha the pharmaceutically acceptable excipients may include lene-2-sulfonic, benzenesulfonic acid, and the like. Other diluents, disintegrants, binders, bulking agents, anti-adher acids, Such as Oxalic, while not in themselves pharmaceu ents, anti-oxidants, buffering agents, colorants, flavoring tically acceptable, may be employed in the preparation of agents, coating agents, plasticizers, stabilizers, preserva salts useful as intermediates in obtaining the compounds of tives, lubricants, glidants, chelating agents, and the like 60 the invention and their pharmaceutically acceptable acid known to the art used either alone or in combination thereof. addition salts. Examples of bases include, but are not limited to, alkali metals (e.g., Sodium) hydroxides, alkaline earth DETAILED DESCRIPTION OF THE metals (e.g., magnesium), hydroxides, ammonia, and com INVENTION pounds of formula NW4", wherein W is C alkyl, and the 65 like. Examples of salts include, but are not limited to: The present inventors while working on the development acetate, adipate, alginate, aspartate, benzoate, benzenesul of pharmaceutical composition comprising a fixed dose fonate, bisulfate, butyrate, citrate, camphorate, camphorsul US 9,446,032 B2 9 10 fonate, digluconate, dodecylsulfate, cyclopentanepropi The term “AUCo., as used herein, means area under the onate, ethanesulfonate, fumarate, flucoheptanoate, plasma concentration-time curve extrapolated to infinite glycerophosphate, hemisulfate, heptanoate, hexanoate, time. hydrochloride, hydrobromide, hydroiodide, 2-hydroxy The term “mean', when preceding a pharmacokinetic value (e.g. mean Tmax) represents the mean value of the ethanesulfonate, lactate, maleate, methanesulfonate, 2-naph pharmacokinetic value taken from a population of patients thalenesulfonate, nicotinate, oxalate, palmoate, pectinate, or healthy volunteers. persulfate, phenylpropionate, picrate, pivalate, propionate, The present invention provides once-a-day therapeuti Succinate, tartrate, thiocyanate, tosylate, undecanoate, and 10 cally synergistic pharmaceutical dosage form for treatment the like. of cardiovascular disorders, wherein the dosage form com As used herein, the term “ester refers to any pharma prises a fixed dose combination of an extended release ceutically acceptable ester of a compound of the present metoprolol with an agent selected from one or more calcium invention, which upon administration to a Subject is capable channel blockers, one or more angiotensin II receptor block of providing a compound of this invention or an active 15 ers and one or more angiotensin converting enzyme inhibi metabolite or residue thereof. Representative examples of tors along with one or more rate controlling excipients. ester include medoxomil, cilexetil, and the like. The calcium channel blockers may be selected from, but For the purpose of present invention, “once-a-day means not limited to one or more of amlodipine, bepridil, clenti that the composition of the present invention is administered aZem, diltiazem, fendiline, gallopamil, mibefradil, pre only once over a 24 hour period thereby providing thera nylamine; semotiadil, terodiline. elgodipine, lacidipine, ler peutically beneficial blood levels of the active agents. canidipine, manidipine, nicardipine, nifedipine, nilvadipine, The term “fixed dose combination', as used herein, refers nimodipine, nisoldipine, nitrendipine, flunarizine, lidofla to a combination of two or more separate active agents, Zine, lomerizine, bencyclane, etafenone, perhexyline, arani combined in a single unit dosage form, in defined doses. 25 dipine, azelnidipine, barnidipine, benidipine, cilnidipine, The term “compliance' describes willingness or degree to clevidipine, isradipine, efonidipine, felodipine, pranidipin which a patient correctly follows the prescribed course of eor, and Verapamil. treatment. In an embodiment, the calcium channel blocker is amlo The term “therapeutically synergistic’, as used herein, dipine or nifedipine or both. 30 refers to a therapeutic effect achieved by a fixed dose Preferred salt of calcium channel blocker includes amlo combination treatment that exceeds the optimal effect dipine besylate, bepridil hydrochloride, diltiazem hydro achieved by monotherapy associated with the same drugs chloride, nicardipine hydrochloride, and Verapamil hydro used in the combination. For example, X is the therapeutic chloride. effect obtained by “A” drug and Y is the therapeutic effect obtained by “B” drug on administration, thus when “A” and 35 The angiotensin II receptor blockers may be selected “B” drugs are given together, then the expected therapeutic from, but not limited to one or more of Valsartan, Telmis effect would be “X+Y” but when the therapeutic effect artan, Losartan, Irbesartan, AZilsartan, Candesartan, Epro achieved by co-administration of both the drugs in a fixed Sartan, and Olmesartan. dose combination exceeds “X+Y” i.e. “CX+Y)*Z’, wherein In an embodiment, the angiotensin II receptor blocker is Z is more than 1, the combination is said to be therapeuti 40 Valsartan or Olmesartan medoxomil or both. cally synergistic. Preferred salt or ester of angiotensin II receptor blocker The phrase “inert core,” as used herein, includes core that includes losartan potassium, candesartan cilexetil, olmesar is water insoluble and non-Swellable. tan medoxomil and eprosartan mesylate. The phrase “insoluble,” as used herein, refers to inert 45 The ACE inhibitors may be selected from, but not limited core, which does not dissolve in water. to one or more of benazepril, captopril, , , The phrase “non-swellable,” as used herein, refers to inert enalapril, , fosinopril, , Zabicipril, spi core having 20% or less swelling after 24 hours. rapril, lisinopril, , ramipril, , trandola The term inlayed tablet or inlay tablet as used herein pril. Zofenopril, and quinapril. refers to a type of a layered tablet in which instead of the 50 In an embodiment, the ACE inhibitors is Lisinopril or core tablet being completely Surrounded by a coating, the Enalapril, or both. top surface is completely exposed. Preferred salt or ester of ACE inhibitor includes, The term inlayed in said layer is used herein to mean that Benazepril hydrochloride, Enalapril maleate, Fosinopril the tablet of metoprolol may be present at any position in sodium, Lisinopril dihydrate, Perindopril erbumine, and said layer. 55 Quinapril hydrochloride. The term “bioavailable' as used herein, includes, but is not limited to the rate and extent to which the active agent/s In an embodiment, when the once-a-day therapeutically become available to the site of action after administration. synergistic pharmaceutical dosage form of the present The term “Cmax’ is the highest plasma concentration of invention comprises metoprolol in extended release form the drug attained within the dosing interval. 60 and calcium channel blocker, the amount of metoprolol and The term “Tmax’ is the time period, which elapses after calcium channel blocker in the dosage form ranges between administration of the dosage form at which the plasma about 25 mg to about 200 mg and between about 2.5 mg to concentration of the active agent attains the highest plasma about 800 mg respectively. concentration within the dosing interval. In a further embodiment, the once-a-day therapeutically The term “AUC” as used herein, means area under 65 synergistic pharmaceutical dosage form comprises an plasma concentration-time curve from drug administration extended release metoprolol and calcium channel blocker in to last observed concentration at time t. following combinations: US 9,446,032 B2 12

Metoprolol Doses of "Calcium Channel Blockers in combination with Metoprolol Doses Amlodipine Bepridil Diltiazem Isradipine Nicardipine Nifedipine Verapamil 25 mg 2.5 mg 200 mg 30 mg 5 mg 20 mg 400 mg 40 mg 50 mg 5 mg 300 mg 60 mg 10 mg 30 mg 600 mg 80 mg 100 mg 10 mg 90 mg 800 mg 120 mg 200 mg 120 mg

10 In a still further embodiment, the present invention pro extended release form with 320 mg of Valsartan, 100 mg of vides a once-a-day therapeutically synergistic unit dosage metoprolol in extended release form with 160 mg of val sartan and 100 mg of metoprolol in extended release form form comprising a fixed dose combination of 25 mg of with 320 mg of Valsartan. metoprolol in extended release form with 2.5 mg of amlo In another embodiment, when the once-a-day therapeuti dipine, 25 mg of metoprolol in extended release form with 15 cally synergistic pharmaceutical dosage form of the present invention comprises extended release metoprolol and ACE 5 mg of amlodipine, 50 mg of metoprolol in extended inhibitor, the amount of metoprolol and ACE inhibitor in the release form with 5 mg of amlodipine, 50 mg of metoprolol dosage form ranges between about 25 mg to about 200 mg in extended release form with 10 mg of amlodipine, 100 mg and between about 1 mg to about 100 mg respectively. In a further embodiment, the once-a-day therapeutically of metoprolol in extended release form with 5 mg o f 20 synergistic pharmaceutical dosage form comprises an amlodipine and 100 mg of metoprolol in extended release extended release metoprolol and ACE inhibitor in following form with 10 mg of amlodipine. combinations:

Metoprolol Doses of ACE inhibitors in combination with Metoprolol doses Benazepril Captopril Enalapril Fosinopril Lisinopril Perindopril Ramipril Trandolapril Quinapril 25 mg 5 mg 12.5 mg 2.5 mg 10 mg 2.5 mg 2 mg 1.25 mg 1 mg 5 mg 50 mg 10 mg 25 mg 5 mg 20 mg 5 mg 4 mg 2.5 mg 2 mg 10 mg 100 mg 20 mg 50 mg 10 mg 40 mg 10 mg 8 mg 5 mg 4 mg 20 mg 200 mg 40 mg 100 mg 20 mg 20 mg 10 mg 40 mg 40 mg

In another embodiment, when the once-a-day therapeuti 35 In a still further embodiment, the present invention pro cally synergistic pharmaceutical dosage form of the present vides a once-a-day therapeutically synergistic unit dosage invention comprises metoprolol in extended release form form comprising a fixed dose combination of 25 mg of and angiotensin II receptor blocker, the amount of meto metoprolol in extended release form with 10 mg of lisino prolol and angiotensin II receptor blocker in the dosage form 40 pril, 25 mg of metoprolol in extended release form with 20 ranges between about 25 mg to about 200 mg and between mg of lisinopril, 50 mg of metoprolol in extended release about 4 mg to about 800 mg respectively. form with 20 mg of lisinopril, 50 mg of metoprolol in extended release form with 40 mg of lisinopril, 100 mg of metoprolol in extended release form with 20 mg of lisinopril 45 and 100 mg of metoprolol in extended release form with 40 In a further embodiment, the once-a-day therapeutically mg of lisinopril. synergistic pharmaceutical dosage form comprises an In a further embodiment of the present invention, the extended release metoprolol and angiotensin II receptor once-a-day therapeutically synergistic unit dosage form blocker in following combinations: comprises a fixed dose combination of metoprolol in

Metoprolol Doses of Angiotensin II Receptor Blockers in combination with Metoprolol Doses Losartan Valsartan Candesartan Irbesartan Olmesartan Telmisartan Eprosartan 25 mg 25 mg 40 mg 4 mg 75 mg 5 mg 20 mg 400 mg 50 mg 50 mg 80 mg 8 mg 150 mg 20 mg 40 mg 600 mg 100 mg 100 mg 160 mg 16 mg 300 mg 40 mg 80 mg 800 mg 200 mg 320 mg 32 mg

60 In a still further embodiment, the present invention pro extended release form and active agent selected from one or vides a once-a-day therapeutically synergistic unit dosage more calcium channel blockers, one or more angiotensin II form comprising a fixed dose combination of 25 mg of receptor blockers, and one or more ACE inhibitors along metoprolol in extended release form with 80 mg of Valsar with one or more rate controlling excipient, wherein calcium tan, 25 mg of metoprolol in extended release form with 160 65 channel blocker, angiotensin II receptor blocker or ACE mg of Valsartan, 50 mg of metoprolol in extended release inhibitor exhibits immediate release from the unit dosage form with 160 mg of Valsartan, 50 mg of metoprolol in form. US 9,446,032 B2 13 14 In a further embodiment, the present invention provides a Polyalkylene oxides or copolymers thereof include, but once-a-day therapeutically synergistic pharmaceutical dos not limited to, polyethylene oxide, polypropylene oxide, age form for treatment of cardiovascular disorders compris poly(oxyethylene)-poly (oxypropylene) block copolymers ing a fixed dose combination of metoprolol in extended (poloxamers) or combinations thereof. release form and an active agent selected from one or more Maleic acid copolymers include, but not limited to, viny calcium channel blockers, one or more angiotensin II recep lacetate-maleic acid anhydride copolymer, styrene-maleic tor blockers, and one or more ACE inhibitors along with one acid anhydride copolymer, styrene-maleic acid monoester or more rate controlling excipients. The composition com copolymer, vinylmethylether-maleic acid anhydride copoly prises an inert core coated with one or more rate controlling mer, ethylene-maleic acid anhydride copolymer, vinylbuty 10 lether-maleic acid anhydride copolymer, acrylonitrile excipients. Such inert core compositions are disclosed in methyl acrylate-maleic acid anhydride copolymer, butyl PCT Patent Application No. 2007 110753 A, and incorpo acrylate-styrene-maleic acid anhydride copolymer or the rated hereby for reference. like or any combinations thereof. In a further embodiment, the present invention provides a Acrylic acid polymers include any suitable polyacrylic once-a-day therapeutically synergistic pharmaceutical dos 15 acid polymers or carboxyvinyl polymers such as those age form for treatment of cardiovascular disorders compris available under the brand name carbopol. Pharmaceutically ing a fixed dose combination of metoprolol in extended acceptable acrylic polymer may be include one or more, but release form and an active agent selected from one or more not limited to acrylic acid and methacrylic acid copolymers, calcium channel blockers, one or more angiotensin II recep methyl methacrylate copolymers, ethoxyethyl methacry tor blockers, and one or more ACE inhibitors along with one lates, cynaoethyl methacrylate, aminoalkyl methacrylate or more rate controlling excipients, wherein the composition copolymer, poly(acrylic acid), poly(methacrylic acid), meth exhibits a dissolution profile such that less than 6% of acrylic acid alkylamide copolymer, poly(methyl methacry metoprolol is released within 1 hour; 25% to 50% of late), poly(methacrylic acid) (anhydride), methyl methacry metoprolol is released within 6 hours and at least 90% of late, polymethacrylate, poly(methyl methacrylate), poly metoprolol is released after 20 hours when the release rate 25 (methyl methacrylate) copolymer, polyacrylamide, is measured in USPType 2 Dissolution Apparatus (paddle, aminoalkyl methacrylate copolymer, poly(methacrylic acid 50 rpm) using 500 ml of pH 6.8 phosphate buffer at 37° anhydride), and glycidyl methacrylate. C.+0.5° C. as dissolution medium. Suitable non-polymeric rate controlling excipient As mentioned in several embodiments of the present includes, but not limited to fat, wax, fatty acid, fatty acid invention, the rate controlling excipient is polymeric rate 30 ester, long chain monohydric alcohol or their ester or any controlling excipient or non-polymeric rate controlling combinations thereof. excipient, or combination thereof. Waxes are esters of fatty acids with long chain monohy Suitable polymeric rate controlling excipients are selected dric alcohols. Natural waxes are often mixtures of such from, but not limited to, one or more of cellulose derivatives; esters, and may also contain hydrocarbons. Waxes employed polyhydric alcohols; saccharides, gums and derivatives 35 in the present invention include, but are not limited to, thereof vinyl derivatives, polymers, copolymers or mixtures natural waxes, such as animal waxes, vegetable waxes, and thereof maleic acid copolymers; polyalkylene oxides or petroleum waxes, paraffin waxes, microcrystalline waxes, copolymers thereof; acrylic acid polymers and acrylic acid petrolatum waxes, mineral waxes), and synthetic waxes. derivatives; or any combinations thereof. Specific examples include, but are not limited to spermaceti Cellulose derivatives include, but not limited to, ethyl 40 wax, carnauba wax, Japan wax, bayberry wax, flax wax, cellulose, methylcellulose, hydroxypropylmethylcellulose beeswax, yellow wax, Chinese wax, shellac wax, lanolin (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cel wax, Sugarcane wax, candelilla wax, castor wax paraffin lulose, hydroxymethyl cellulose, hydroxypropyl ethylcellu wax, microcrystalline wax, petrolatum wax, carbowax, and lose, carboxymethylethyl cellulose, carboxyethylcellulose, the like, or mixtures thereof. carboxymethyl hydroxyethylcellulose, hydroxyethyl methyl 45 Waxes are also monoglyceryl esters, diglyceryl esters, or carboxymethyl cellulose, hydroxyethyl methyl cellulose, glyceryl esters (glycerides) and derivatives and mixtures carboxymethyl cellulose (CMC), methyl hydroxyethyl cel thereof formed from a fatty acid having from about 10 to lulose, methylhydroxypropyl cellulose, carboxymethyl Sul about 22 carbon atoms and glycerol, wherein one or more of foethyl cellulose, sodium carboxymethyl cellulose, or com the hydroxyl groups of glycerol are substituted by a fatty binations thereof. 50 acid. Glycerides employed in the present invention include, Polyhydric alcohols include, but are not limited to, poly but are not limited to, glyceryl monostearate, glyceryl dis ethylene glycol (PEG) or polypropylene glycol, or any tearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl combinations thereof. tripalmitate, glyceryl monopalmitate, glyceryl palmitostear Saccharides, gums and their derivatives include, but not ate, glyceryl dilaurate, glyceryl trilaurate, glyceryl mono limited to, dextrin, polydextrin, dextran, pectin and pectin 55 laurate, glyceryl didocosanoate, glyceryl tridocosanoate, derivatives, alginic acid, sodium alginate, polygalacturonic glyceryl monodocosanoate, glyceryl monocaproate, glyc acid, Xylan, arabinoxylan, arabinogalactan, starch, hydroxy eryl dicaproate, glyceryl tricaproate, glyceryl mono propyl Starch, amylose and amylopectin, CMC agar; guar myristate, glyceryl dimyristate, glyceryl trimyhstate, glyc gum, locust bean gum, Xanthan gum, karaya gum, traga eryl monodecenoate, glyceryl didecenoate, glyceryl canth, carrageenan, acacia gum, arabic gum or gellangum or 60 tridecenoate, glyceryl behenate (compritol), polyglyceryl the like; or any combinations thereof. disoStearate, lauroyl macrogolglycerides (Gelucire), oleoyl Vinyl derivatives, polymers, copolymers or mixtures macrogolglycerides, Stearoyl macrogolglycerides, mixtures thereof include, but not limited to, polyvinyl acetate, poly of monoglycerides and diglycerides of oleic acid (Peceol), or vinyl alcohol, mixture of polyvinyl acetate (8 parts w/w) and combinations thereof. polyvinylpyrrolidone (2 parts w/w) (Kollidon SR), copoly 65 Fatty acids include, but not limited to, hydrogenated palm mers of vinyl pyrrolidone, vinyl acetate copolymers, poly kernel oil, hydrogenated peanut oil, hydrogenated palm oil, vinylpyrrolidone (PVP); or combinations thereof. hydrogenated rapeseed oil, hydrogenated rice bran oil, US 9,446,032 B2 15 16 hydrogenated soybean oil, hydrogenated Sunflower oil, The solvents comprise one or more of dichloromethane, hydrogenated castor oil (Lubritab), hydrogenated cottonseed acetone, ethanol, methanol, isopropyl alcohol, water or oil, and mixtures thereof. Other fatty acids include, but are mixture thereof. not limited to, decenoic acid, docosanoic acid, Stearic acid, Suitable cushioning agents include, but are not limited to, palmitic acid, lauric acid, myristic acid, or the like, or one or more of PEG, and colloidal silicon dioxide. mixtures thereof. Suitable thickening agents or viscosity modifiers may Long chain monohydric alcohols include, but not limited include, but are not limited to, one or more of methylcellu to, cetyl alcohol, or stearyl alcohol or mixtures thereof. lose, carboxymethylcellulose, microcrystalline cellulose, The water-swellable inert core can comprise hydroxypro ethylcellulose, hydroxyethylcellulose, hydroxypropylcellu 10 lose, hydroxypropylmethylcellulose, alginate, carageenan, pyl methylcellulose, microcrystalline cellulose, starch or Xanthan gum, acacia, tragacanth, locust bean gum, guar mixtures thereof. gum, carboxypolymethylene, polyvinyl pyrrolidone, poly The water-insoluble inert core may comprise silicon diox vinyl alcohol, poloxamer, magnesium aluminum silicate ide, glass particles, plastic resin particles or mixtures (veegum), bentonite, hectorite, povidone, maltitol, chitosan thereof. 15 or combination thereof and the like. The pharmaceutical dosage form of the present invention Preservatives may include, but are not limited to, one or further comprises other pharmaceutically acceptable excipi more of sodium benzoate, Sorbates, such as potassium ent selected from the group consisting of diluent, binder, Sorbate, salts of edetate (also known as salts of ethylenedi glidant, Solubilizer, stabilizer, lubricants, disintegrants, aminetetraacetic acid or EDTA, such as disodium edetate), cushioning agents, Suspending agent, thickening agent, benzaldionium chloride, parabens and the like. Sweetners, flavoring agent, or plasticizer. The formulations of the invention optionally include one Examples of suitable diluents include, but not limited to or more stabilizing agents to increase the stability and/or one or more of lactose, lactose monohydrate, mannitol, compatibility of the Suspension when formulated into a Sucrose, maltodextrin, dextrin, maltitol, Sorbitol. Xylitol, dosage form. Suitable stabilizing agents are Suspending powdered cellulose, cellulose gum, microcrystalline cellu 25 agents, flocculating agents, thickening agents, gelling lose, starch, calcium phosphate, or metal carbonate. agents, buffering agents, antioxidants, preservatives, antimi Examples of suitable binders include, but not limited to, crobial agents, and mixtures thereof. Ideally, the agent acts starch, gums, pregelatinized starch, polyvinyl prrolidone to minimize irreversible aggregation of Suspended particles, (PVP), copovidone, cellulose derivatives, such as hydroxy and to maintain proper flow characteristics to ease manu propylmethyl cellulose (HPMC), hydroxypropyl cellulose 30 facturing processes, e.g., to ensure that the formulation can (HPC) and carboxymethyl cellulose (CMC) and their salts. be readily pumped and filled into desired container. Suitable lubricants include, but are not limited to, one or Suitable suspending agents may include, but are not more talc, magnesium Stearate, calcium Stearate, polyethyl limited to, one or more from cellulose derivatives, clays, ene glycol, hydrogenated vegetable oils, Stearic acid, sodium natural gums, synthetic gums, or other agents known in the Stearyl fumarate, talc and sodium benzoate. 35 art. Specific Suspending agents, by way of example, include Compositions of the present invention may include a microcrystalline cellulose, sodium carboxymethylcellulose, glidant such as, but not limited to, colloidal silica, silica gel. powdered cellulose, ethymethylcellulose, hydroyxypropyl precipitated silica, or combinations thereof. methylcellulose, methylcellulose, ethylcellulose, ethylhy Suitable disintegrant may include, but not limited to, one droxy ethylcellulose, hydroxypropyl cellulose, attapulgite, or more of starch, croscarmellose sodium, crospovidone, 40 bentonite, hectorite, montmorillonite, silica gel, fumed sili and Sodium starch glycolate. con dioxide, colloidal silicon dioxide, acacia, agar, carra The solubilizer may include, but not limited to, one or geenan, guar gum, locust bean gum, pectin, Sodium alginate, more surfactant, pH modifier, complexing agent, or hydro propylene glycol alginate, tamarind gum, Xanthan gum, tropic agent. carbomer, povidone, Sodium starch glycolate, starches, tra Suitable surfactants are those known to ordinary skilled in 45 gacanth, magnesium aluminum silicate, aluminum silicate, the art and may include, but not limited to, one or more of magnesium silicate, gelatin, glycyrrhizin and the like. These amphoteric, non-ionic, cationic or anionic Surfactants. Suit Suspending agents can further impart different flow proper able Surfactants comprises one or more of sodium lauryl ties to the Suspension. The flow properties of the Suspension Sulfate, monooleate, monolaurate, monopalmitate, monos can be Newtonian, plastic, pseudoplastic, thixotropic or tearate or another ester of polyoxyethylene Sorbitane, 50 combinations thereof. Mixtures of Suspending agents may sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic also be used to optimize flow properties and Viscosity. alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene Suitable buffering agents may include, but are not limited ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, to, one or more of a bicarbonate salt of a Group IA metal, an cremophore RH 40 and the like. alkali earth metal buffering agent, amino acids, an acid salt Suitable pH modifiers include, but not limited to, buffers, 55 of an amino acid, an alkali Salt of an amino acid, and amino acids or amino acid Sugars. combinations of any of the foregoing. The complexing agents include cyclodextrin class of Moreover, the composition of the invention optionally molecules, such as cyclodextrins containing from six to include usual auxiliaries known in the art Such as saliva twelve glucose units, especially, alpha-cyclodextrin, beta stimulating agents like citric acid, lactic acid, malic acid, cyclodextrin, gamma-cyclodextrin, or their derivatives, such 60 Succinic acid, ascorbic acid, adipic acid, fumaric acid, as hydroxypropyl beta cyclodextrins, or mixtures thereof. tartaric acids; cooling sensation agents like maltitol, mono The complexing agents may also include cyclic amides, menthyl Succinate, ultracool; stabilizers like gums, agar, hydroxyl benzoic acid derivatives as well as gentistic acid. taste masking agents like acrylic polymers, copolymers of Suitable plasticizers include, but are not limited to, one or acrylates, celluloses, resins; coloring agents like titanium more of diethyl phthalate, triethyl citrate, acetyl tributyl 65 dioxide, natural food colors, dyes Suitable for food, drug and citrate, dibutyl phthalate, triacetin, propylene glycol, and cosmetic applications; preservatives like alpha-tocopherol, polyethylene glycol. citric acid, butylated hydroxytoluene, butylated hydroxyani US 9,446,032 B2 17 18 sole, ascorbic acid, fumaric acid, malic acid, sodium ascor In an embodiment, the once-a-day dosage form may bate or ascorbic acid palmitate or effervescing agents like include a tablet comprising an extended release metoprolol citric acid, tartaric acid, Sodium bicarbonate, sodium car with one or more rate controlling excipient, wherein the bonate and the like. The dosage form of the present invention may be in form tablet is inlayed in another layer comprising a calcium of a tablet, a capsule, granules, a tablet in tablet, an orally channel blocker, an angiotensin receptor blocker, or an ACE disintegrating tablet, pellets, tablet/s in capsule, granules/ inhibitor and optionally other pharmaceutically acceptable pellets in capsule, a bilayer tablet, a trilayer tablet, an in-lay excipients. tablet or Suspension. The tablet-in-tablet dosage form of the invention may be 10 In a further embodiment, the inlayed dosage form can be prepared by compressing metoprolol with one or more rate prepared by blending metoprolol with rate controlling controlling excipient to form a core tablet, and compressing excipient and other pharmaceutically acceptable excipients. one or more calcium channel blockers or one or more The prepared blend was compressed to form a core tablet. angiotensin receptor blockers or one or more ACE inhibitors optionally along with one or more pharmaceutically accept 15 One or more agent selected from calcium channel blocker, able excipient onto said core tablet to form a compressed angiotensin receptor blocker and ACE inhibitor are sepa outer tablet. rately blended with one or more pharmaceutically accept In an embodiment, the tablet-in-tablet dosage form is be able excipients. Some portion of the above blend was placed prepared by blending metoprolol with rate controlling in die and the core tablet was placed in a way such that the excipient and other pharmaceutically acceptable excipients. upper Surface of metoprolol tablet is completely exposed The prepared blend was compressed to form a core tablet. Separately, calcium channel blocker, angiotensin receptor after compression. blocker, or ACE inhibitor is blended with one or more In a further embodiment, the once-a-day dosage form may pharmaceutically acceptable excipients. Some portion of the 25 be prepared by compressing a first layer comprising an 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 extended release metoprolol along with one or more rate compressed such that the metoprolol tablet forms inner controlling excipients and a second layer comprising one or tablet and calcium channel blocker, angiotensin receptor more calcium channel blocker, angiotensin receptor blocker blocker or ACE inhibitor forms outer tablet. 30 or ACE inhibitor, one or more pharmaceutically acceptable The once-a-day dosage form of the invention may also be prepared by compressing metoprolol with one or more rate excipients and, optionally with rate controlling excipient controlling excipient to form a core and an active agent into a bi-layer tablet. selected from calcium channel blocker, angiotensin receptor In a further embodiment, the bi-layer dosage form is blocker and ACE inhibitor forming outer coating with one or 35 prepared by blending metoprolol with rate controlling more pharmaceutically acceptable excipients. excipient and other pharmaceutically acceptable excipients. In another embodiment, the once-a-day dosage form is The prepared blend was compressed to form a first layer. prepared by blending metoprolol with rate controlling Onto this first layer a blend comprising calcium channel excipient and one or more other pharmaceutically acceptable blocker, angiotensin receptor blocker or ACE inhibitor with excipients. The prepared blend is compressed to form tab 40 lets. The formed tablets then coated with dispersion com one or more pharmaceutically acceptable excipients is com prising an agent selected from calcium channel blocker, pressed to form a bi-layer tablet. angiotensin receptor blocker and ACE inhibitor, dissolved or The present invention further provides a method of treat dispersed in Suitable solvent system along with one or more ing one or more disorders selected form hypertension, pharmaceutically acceptable excipient. The outer coating 45 congestive heart failure, angina, myocardial infarction, arte may completely or partially surround the metoprolol tablet. riosclerosis, diabetic nephropathy, diabetic cardiac myopa In another embodiment, the once-a-day dosage form may thy, renal insufficiency, peripheral vascular disease, left be prepared by blending two portions with one or more Ventricular hypertrophy, cognitive dysfunction, and chronic pharmaceutically acceptable excipients followed by com heart failure, wherein the method comprises administering a pression. First portion may be prepared by coating the inert 50 pharmaceutical dosage form of the present invention to a core with a solution or Suspension of metoprolol in a solvent. patient in need of Such treatment. The metoprolol drug layer is further coated with one or more In another aspect, the present invention provides a method release-controlling layer(s). Second portion may be prepared of treating hypertension, wherein the method comprises by coating one or more calcium channel blocker, angiotensin administering a pharmaceutical dosage form of the present receptor blocker or ACE inhibitor on an inert core, option 55 invention to a patient in need of Such treatment. ally along with one or more rate controlling layers. In an embodiment, a method of treating congestive heart In another embodiment, the once-a-day dosage form may failure comprises administering a pharmaceutical dosage be prepared by blending two portions with one or more form of the present invention to a patient in need of Such pharmaceutically acceptable excipients followed by com treatment. pression. The first portion was prepared by coating the inert 60 core with a dispersion comprising metoprolol, one or more In another embodiment, a method of myocardial infarc rate controlling excipients in a solvent. The coated inner tion comprises administering a pharmaceutical dosage form core can further be coated with one or more rate controlling of the present invention to a patient in need of Such treat layers or seal coat. The second portion was prepared by ment. coating the inert core with a dispersion comprising a calcium 65 The examples given below serve to illustrate embodi channel blocker, an angiotensin receptor blocker or an ACE ments of the present invention. However they do not intend inhibitor in a solvent. to limit the scope of present invention. US 9,446,032 B2

EXAMPLE 1. EXAMPLE 2 Metoprolol Succinate ER/Amlodipine Besylate Metoprolol Succinate ER/Amlodipine Besylate Tablet Tablet 5

TABLE 1. TABLE 3 Metoprolol Succinate ERAmlodipine Besylate: Metoprolol Succinate ERAmlodipine Besylate: Ed 50 mg. Tartrate 10 mg 10 EQ 25 mg. Tartrate/2.5 mg Stage ngredients % Wiw Stage Ingredients % Wiw Seal coat I Micro crystalline cellulose O. 1-2O Seal coat I Micro crystalline cellulose O. 1-2O spheres spheres Ethyl cellulose O.O1-10 Ethyl cellulose O.O1-10 Triethyl citrate O.OO1-5 15 Triethyl citrate O.OO1-5 Drug Layering Metoprolol Succinate 2-70 Drug Layering Metoprolol Succinate 2-70 (Metoprolol Succinate) Opadry Clear O. 1-2O (Metoprolol Succinate) Opadry Clear O. 1-2O Extended Release coating-I Ethyl cellulose O. 1-2O Extended Release coating-I Ethyl cellulose O. 1-2O Opadry Clear O. 1-2O Opadry Clear O. 1-2O Extended Release coating-II Eudragit L30-D55 O. 1-2O Extended Release coating-II Eudragit L30-D55 O. 1-2O Triethyl citrate O.OO1-5 2O Triethyl citrate O.OO1-5 Talc O. 1-2O Talc O. 1-2O Seal coat II Opadry Clear O. 1-2O Seal coat II Opadry Clear O. 1-2O PEG coating Polyethylene glycol O. 1-2O Drug Layering Amlodipine Besylate O. 1-25 Addition of Drug Amlodipine Besylate O.1-30 (Amlodipine Besylate) Opadry Clear 0.1-40 (Amlodipine Besylate) Prosow SMCC 90 10-75 PEG coating Polyethylene glycol O. 1-10 & Tableting Sodium starch glycolate O. 1-2O 25 Tableting Prosoly SMCC 90 10-60 Polyethylene glycol O. 1-2O Croscarmellose sodium O.S-15 Sodium Stearyl Fumarate O. 1-5 Polyethylene glycol O. 1-10 Film coating Opadry white O. 1-10 Sodium Stearyl Fumarate O.O1-5 Film coating Opadry white O. 1-10 Procedure: 30 Microcrystalline cellulose spheres were given seal coat I Procedure: of ethyl cellulose. These seal coated pellets were subjected NTSR lin cells tes N g1Ven S. of to Metoprolol Succinate layering with a binder in aqueous 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 solvent system. Drug layered pellets were provided with Extended Release coating-I using Ethyl cellulose and 35 Extended Release coating-I using Ethyl cellulose and opadry. An extended release coating-II of Eudragit was dry. An Extended Rel ing-II of Eudragi ing Plasticizer, triethvil citrate & talc. Seal coat-II opadry. Xtended Release coating-ll of Eudrag1t was given using Extend dR 1 y d pell f lowed b given using Plasticizer, triethyl citrate & talc. Seal coat-II was given to xten ed Release coated pellets followed by was given to Extended Release coated pellets followed by PEG coating in suitable Solvent system. These PEG coated drug layering of Amlodipine Besylate and PEG coating in pellets was blended with the Prosolv, Amlodipine Besylate, 40 suitable solvent system. These PEG coated pellets was Croscarmellose Sodium, PEG & Sodium Stearyl Fumarate blended with the Prosolv, Croscarmellose sodium, PEG & and compressed into a tablet. An opadry coat was given to Sodium Stearyl Fumarate and compressed into tablet. An core tablets. opadry coat was given to core tablets. Tablets obtained from example 1 were subjected to dis- Tablets obtained from example 2 were subjected to dis solution studies. The results of dissolution studies performed solution studies. The results of dissolution studies performed are provided in Table 2. are provided in Table 4.

TABLE 2 TABLE 4 Dissolution profile 50 Dissolution profile Dissolution of Dissolution of Metoprolol Metoprolol Succinate Dissolution of Amlodipine Succinate Dissolution of Amlodipine Method: 500 mL of Method: 500 mL of Method: 500 mL. Method: 500 mL. pH 6.8 phosphate buffer, pH 0.01N HCl, of pH 6.8 phosphate buffer, of pH 0.01N HCl, USP II apparatus at 50 rpm USP II apparatus at 75 rpm 55 USP II apparatus at 50 rpm USP II apparatus at 75 rpm Time points (h) % Drug dissolved Time points (min) % Drug dissolved Time points (h) % Drug dissolved Time points (min) % Drug dissolved 1 6 10 89 1 6 10 84 2 10 2O 95 2 9 2O 94 4 24 30 96 60 4 25 30 98 6 40 45 97 6 39 45 99 8 53 60 98 8 61 60 99 10 66 10 68 12 75 12 81 16 88 16 92 2O 95 2O 98 24 98 65 24 99 US 9,446,032 B2 21 22 EXAMPLE 3 EXAMPLE 4 Metoprolol Succinate ER/Amlodipine Besylate Tablet Metoprolol Succinate ER/Valsartan Tablet: Eq 25 Mg Tartrate/160 Mg

TABLE 5 TABLE 7 Metoprolol Succinate ERAmlodipine Besylate: Eq 25 ng Tartrate/5 ng Stage ngredients % Wiw 10 Metoprolol Succinate ERValsartan Tablet Composition Seal coat I Microcrystallinecellulose O. 1-2O Component Stage Ingredients % Wiw spheres Ethyl cellulose O.O1-10 Tablet I Seal coat I Micro crystalline O.1-20 Triethyl citrate O.OO1-5 (Inner core) cellulose spheres Drug Layering Metoprolol Succinate 2-70 15 (Metoprolol Succinate) Opadry Clear O. 1-2O Ethyl cellulose O.O1-20 Extended Release coating-I Ethyl cellulose O. 1-2O Triethyl citrate O.OO1 Opadry Clear O. 1-2O Drug Layering Metoprolol Succinate 2-70 Extended Release coating-II Eudragit L30-D55 O. 1-2O (Metoprolol Opadry Clear O.1-10 Triethyl citrate O.OO1-5 Succinate) Talc O. 1-2O Seal coat II Opadry Clear O. 1-2O Extended Release Ethyl cellulose O.1-30 PEG coating Polyethylene glycol) O. 1-10 coating-I Opadry Clear O.1-10 Tableting Prosow SMCC 90 10-60 Extended Release Eudragit L30-D55 O.1-10 Croscarmellose sodium O.S-15 coating-II Triethyl citrate O.OO1-5 Polyethylene glycol O. 1-10 Talc O.1-10 Sodium Stearyl Fumarate O.O1-5 Seal coat II Opadry Clear O.1-10 Drug Layering Amlodipine Besylate O. 1-50 25 (Amlodipine Besylate) Opadry Clear O. 1-25 PEG coating Polyethylene glycol O.1-10 Film coating Opadry white O. 1-10 Blending Prosoly SMCC 90 10-80 Croscarmellose sodium OS-15 Polyethylene glycol O.1-10 Procedure: Microcrystalline cellulose spheres were given seal coat I 30 Sodium Stearyl fumarate O.O1-5 of ethyl cellulose. These seal coated pellets were subjected Tablet II Granulation Walsartan 5-70 to metoprolol Succinate layering with a binder in aqueous (Outer Micro crystalline 5-40 solvent system. Drug layered pellets were provided with fraction) cellulose Extended Release coating-I using Ethyl cellulose and Hypromellose O.1-20 35 Crospovidone O.1-10 opadry. An Extended Release coating-II of Eudragit was Silicone dioxide O.1-10 given using Plasticizer, triethyl citrate & talc. Seal coat-II Magnesium Stearate O. 1-5 was given to Extended Release coated pellets followed by Coating Film coating Opadry white O.1-10 PEG coating in suitable solvent system. These PEG coated pellets was blended with the Prosolv, Croscarmellose 40 sodium, PEG & Sodium Stearyl Fumarate and compressed Procedure: into tablet. Prepared metoprolol Succinate core tablets were coated with the Amlodipine Besylate using opadry as a Process involved tab-in-tab technology where core tablet binder. An opadry coat was given to prepared coated tablets. was prepared by using microcrystalline cellulose spheres Tablets obtained from example 3 were subjected to dis were given seal coat I of ethyl cellulose. These seal coated solution studies. The results of dissolution studies performed 45 are provided in Table 6. pellets were Subjected to metoprolol Succinate layering with a binder in aqueous solvent system. Drug layered pellets TABLE 6 were provided with Extended Release coating-I using Ethyl Dissolution profile 50 cellulose and opadry. An Extended Release coating-II of Eudragit was given using Plasticizer, triethyl citrate & talc. Dissolution of Metoprolol Dissolution of Succinate Amlodipine Seal coat-II was given to Extended Release coated pellets Method: 500 mL. Method: 500 mL. followed by PEG coating in suitable solvent system. These of pH 6.8 phosphate buffer, of pH 0.01N HCl, USP II apparatus at 50 rpm USP II apparatus at 75 rpm 55 PEG coated pellets was blended with the Prosolv, Cross carmellose sodium, PEG & Sodium Stearyl fumarate to Time points (h) % Drug dissolved Time points (min) % Drug dissolved obtained core tablet. Outer fraction of tab-in-tab was pre 1 3 10 91 2 6 2O 98 pared by blending Valsartan with Microcrystalline cellulose, 4 22 30 100 Hypromellose, Crospovidone, Silicone dioxide & lubricant, 6 38 45 100 60 8 61 60 101 Magnesium stearate. Both blend were used to prepare tab 10 67 in-tab formulation. Prepared metoprolol succinate/valsartan 12 77 16 89 tablets were coated with the opadry. 2O 98 24 100 65 Tablets obtained from example 4 were subjected to dis solution studies. The results of dissolution studies performed are provided in Table 8. US 9,446,032 B2 23 24 TABLE 8 fraction of inlay tablet was prepared by granulation of Valsartan with Microcrystalline cellulose, Hypromellose, Dissolution profile Crospovidone, Silicone dioxide followed by addition of Dissolution of Metoprolol Dissolution of lubricant, Magnesium stearate. Both blends were used to Succinate Valsartan prepare inlay tablets. Method: 500 mL. Method: 1000 mL. of pH 6.8 phosphate buffer, of pH 6.8 phosphate buffer, Tablets obtained from example 5 were subjected to dis USP II apparatus at 50 rpm USP II apparatus at 50 rpm solution studies. The results of dissolution studies performed are provided in Table 10. Time points (h) % Drug dissolved Time points (min) % Drug dissolved 10 1 5 10 75 TABLE 10 2 7 2O 86 4 21 30 99 Dissolution profile 6 39 45 99 8 61 60 100 Dissolution of Metoprolol Dissolution of Succinate Valsartan 10 68 15 12 76 Method: 500 mL. Method: 1000 mL. 16 90 of pH 6.8 phosphate buffer, of pH 6.8 phosphate buffer, 2O 98 USP II apparatus at 50 rpm USP II apparatus at 50 rpm 24 98 Time points (h) % Drug dissolved Time points (min) % Drug dissolved 1 4 10 76 2 7 2O 84 EXAMPLE 5 4 22 30 96 6 44 45 98 Metoprolol Succinate ER/Valsartan Tablet: Eq 25 8 61 60 98 Mg Tartrate/80 Mg 10 71 25 12 8O 16 94 2O 99 TABLE 9 24 100 Metoprolol succinate ER/Valsartan Tablet Composition 30 Component Stage Ingredients % Wiw EXAMPLE 6 Tablet I Seal coat I Micro crystalline O.1-20 (Inner core) cellulose spheres Metoprolol Succinate ER/Valsartan Capsule: Eq. 50 Ethyl cellulose O.O1-20 Mg Tartrate/80 Mg Triethyl citrate O.OO1-1 Drug Layering Metoprolol Succinate 2-70 35 (Metoprolol Opadry Clear O.1-10 Succinate) TABLE 11 Extended Release Ethyl cellulose O.1-30 coating-I Opadry Clear O.1-10 Metoprolol Succinate ER/Valsartan Tablet Composition Extended Release Eudragit L30-D55 O.1-10 coating-II Triethyl citrate O.OO1-5 40 Component Stage Ingredients % Wiw Talc O.1-10 Metoprolol Seal coat I Micro crystalline O.1-20 Seal coat II Opadry Clear O.1-10 Succinate cellulose spheres PEG coating Polyethylene glycol O.1-10 ER pellets Ethyl cellulose O.O1-20 Blending Prosow SMCC 90 10-80 Triethyl citrate O.OO1-1 CroScarmellose sodium OS-15 Drug Layering Metoprolol Succinate 2-70 Polyethylene glycol O.1-10 45 (Metoprolol Opadry Clear O.1-10 Sodium Stearyl fumarate O.O1-5 Succinate) Tablet II Granulation Valsartan 5-70 Extended Release Ethyl cellulose O.1-30 (Outer Micro crystalline 5-40 coating-I Opadry Clear O.1-10 fraction) cellulose Extended Release Eudragit L30-D55 O.1-10 Hypromellose O.1-20 coating-II Triethyl citrate O.OO1-5 Crospovidone O.1-10 50 Talc O.1-10 Silicone dioxide O.1-10 Seal coat II Opadry Clear O.1-10 Magnesium Stearate O. 1-5 Lubrication Talc O.OS-5 Valsartan Granulation Valsartan 5-50 Granules Micro crystalline -40 Procedure: cellulose Process involved inlay tablet where core tablet was pre 55 Povidone O.1-10 pared by using microcrystalline cellulose as core which was Crospovidone 1O-SO given seal coat I using Suitable solvent system. These seal Magnesium Stearate -S coated pellets were subjected to metoprolol Succinate lay ering with a binder in aqueous solvent system. Drug layered Procedure: pellets were provided with Extended Release coating-I using 60 Microcrystalline cellulose spheres was given seal coat I of Ethyl cellulose and opadry in suitable solvent system. An ethyl cellulose. These seal coated pellets were subjected to extended release coating-II of Eudragit was given using metoprolol Succinate layering with a binder in aqueous Plasticizer, triethyl citrate & talc. Seal coat-II was given to solvent system. Drug layered pellets were provided with Extended Release coating pellets followed by PEG coating Extended Release coating-I using Ethyl cellulose and in suitable solvent system. These PEG coated pellets was 65 opadry. An extended release coating-II of Eudragit was blended with the Prosolv, Cross carmellose sodium, PEG & given using Plasticizer, triethyl citrate & talc. Seal coat-II Sodium Stearyl fumarate to obtained core tablet. Outer was given to Extended Release coated pellets followed by US 9,446,032 B2 25 26 Seal coating II to obtained metoprolol succinate ER pellets. To the obtained Lisinopril pellets, microcrystalline cellu Valsartan granules were prepared by Wet granulation of lose spheres were directly coated with Lisinopril along with Valsartan, microcrystalline cellulose & Crospovidone using opadry as binder. These drug layered pellets were lubricated povidone as binder followed by drying & lubrication with with talc and filled with metoprolol succinate ER pellets in magnesium Stearate. empty hard gelatin capsule. Tablets obtained from example 6 were subjected to dis Capsules obtained from example 7 were subjected to solution studies. The results of dissolution studies performed dissolution studies. The results of dissolution studies per are provided in Table 12. formed are provided in Table 14.

TABLE 12 10 TABLE 1.4 Dissolution profile Dissolution study Dissolution of Metoprolol Dissolution of Succinate Valsartan Dissolution of Metoprolol Dissolution of Method: 500 mL. Method: 1000 mL. Succinate Lisinopril of pH 6.8 phosphate buffer, of pH 6.8 phosphate buffer, 15 Method: 500 mL. Method: 900 mL. of pH 6.8 phosphate buffer, of 0.1N HCI, USP II USP II apparatus at 50 rpm USP II apparatus at 50 rpm USP II apparatus at 50 rpm apparatus at 50 rpm Time points (h) % Drug dissolved Time points (min) % Drug dissolved Time points (h) % Drug dissolved Time points (min) % Drug dissolved 1 3 10 74 2 7 2O 85 1 4 10 86 4 24 30 94 2 6 2O 98 6 38 45 97 4 2O 30 98 8 60 60 98 6 34 45 99 10 66 8 60 60 99 12 77 10 66 12 76 16 89 25 2O 97 16 89 24 99 2O 97 24 100

EXAMPLE 7 30 EXAMPLE 8 Metoprolol Succinate ER/Lisinopril ER Capsules Metoprolol Succinate ER/Enalapril Maleate Tablet

TABLE 13 35 TABLE 1.5 Metoprolol succinate ER/Lisinopril ER Capsules: Ed 50 mg Tartrate/5 mg Metoprolol Succinate ER/Enalapril maleate Tablet: Eq. 50 mg Tartrate? Component Stage Ingredients % Wiw 10 Ing Metoprolol Seal coat I Micro crystalline O.1-20 Stage ngredients % Wiw Succinate cellulose spheres 40 ER pellets Ethyl cellulose O.O1-20 Seal coat I Microcrystallinecellulose O. 1-2O Triethyl citrate O.OO1 spheres Drug Layering Metoprolol succinate 2-40 Ethyl cellulose O.01-20 (Metoprolol Opadry Clear O.1-10 Triethyl citrate O.OO1-5 Succinate) Drug Layering Metoprolol Succinate 2-70 Extended Release Ethyl cellulose O.1-30 45 (Metoprolol Succinate) Opadry Clear O. 1-2O coating-I Opadry Clear O.1-10 Extended Release coating-I Ethyl cellulose O.1-30 Extended Release Eudragit L30-D55 O.1-10 Opadry Clear O. 1-2O coating-II Triethyl citrate O.OO1-5 Extended Release coating Eudragit L30-D55 O. 1-2O Talc O.1-10 II Triethyl citrate O.OO1-5 Seal coat II Opadry Clear O.1-10 Talc O. 1-2O Seal coat II Opadry Clear O. 1-2O Lubrication Talc O.1-10 50 Lisinopril Drug Layering Micro crystalline O.1-10 PEG coating Polyethylene glycol O. 1-2O pellets (Lisinopril) cellulose spheres Granulation Enalapril maleate O.1-30 Lisinopril O. 1-25 LactOSe -40 Opadry Clear O.1-10 Sodium bicarbonate O.1-30 Talc O.1-10 Corn starch O. 1-10 Lubrication Talc O.O1-5 Blending & Tableting Prosow SMCC 90 10-80 55 Pregelatinized starch O. 1-2O Polyethylene glycol O. 1-2O Procedure: Sodium Stearyl Fumarate O.O1-10 Microcrystalline cellulose spheres were given seal coat I Film coating Opadry white O. 1-10 of ethyl cellulose. These seal coated pellets were subjected to Metoprolol Succinate layering with a binder in aqueous 60 Procedure: solvent system. Drug layered pellets were provided with Microcrystalline cellulose spheres were given seal coat I Extended Release coating-I using Ethyl cellulose and of ethyl cellulose. These seal coated pellets were subjected opadry. An extended release coating of Eudragit was given to Metoprolol Succinate layering with a binder in aqueous using Plasticizer, triethyl citrate & talc. Seal coat-II was solvent system. Drug layered pellets were provided with given to Extended Release coated-II pellets followed by seal 65 Extended Release coating-I using Ethyl cellulose and coat II & lubrication with talc to obtained metoprolol opadry. An Extended Release coating-II of Eudragit was succinate ER pellets. given using plasticizer, triethyl citrate & talc. Seal coat-II US 9,446,032 B2 27 28 was given to Extended Release coated pellets followed by to metoprolol Succinate layering with a binder in aqueous PEG coating in suitable solvent system. Separately, Enal solvent system. Drug layered pellets were provided with april Maleate was mixed with lactose and treated with Extended Release coating-I using Ethyl cellulose and sodium bicarbonate. The sodium bicarbonate treated blend opadry. An Extended Release coating-II of Eudragit was was then granulated using starch paste. Metoprolol Succinate 5 PEG coated pellets were blended with the Enalapril maleate given using plasticizer, triethyl citrate & talc. Seal coat-II granules, Prosolv, Pregelatinized starch, PEG & Sodium was given to Extended Release coated pellets followed by Stearyl Fumarate and compressed into a tablet. An opadry PEG coating in suitable solvent system. These PEG coated coat was given to the core tablets. pellets were blended with the Prosolv, Croscarmellose Tablets obtained from example 8 were subjected to dis sodium, PEG & Sodium Stearyl Fumarate to obtained layer solution studies. The results of dissolution studies performed I blend. Layer II granules were prepared by treated Enalapril are provided in Table 16. Maleate and lactose with sodium bicarbonate. These treated granules were granulated with starch, dried & lubricated TABLE 16 with magnesium Stearate. Both blend were used to prepare 15 two layers of bilayer tablet. Prepared metoprolol Succinate/ Dissolution study Enalapril Maleate bilayer tablets were coated with the Dissolution of Metoprolol Dissolution of Enalapril opadry. Succinate maleate Tablets obtained from example 9 were subjected to dis Method: 500 mL of Method: 900 mL of pH 6.8 phosphate buffer, pH 6.8 phosphate buffer, solution studies. The results of dissolution studies performed USP II apparatus at 50 rpm USP II apparatus at 50 rpm. are provided in Table 18.

Time points (h) % Drug dissolved Time points (min) % Drug dissolved TABLE 1.8 1 6 10 89 2 10 2O 95 Dissolution study 4 24 30 96 25 6 40 45 97 Dissolution of 8 53 60 98 Metoprolol succinate Dissolution of Enalapril maleate 10 66 Method: 500 mL of Method: 900 mL of 12 75 pH 6.8 phosphate buffer, pH 6.8 phosphate buffer, 16 88 USP II apparatus at 50 rpm USP II apparatus at 50 rpm. 2O 95 24 98 30 Time points (h) % Drug dissolved Time points (min) % Drug dissolved 1 3 10 65 2 6 2O 85 4 2O 30 96 EXAMPLE 9 6 25 45 98 35 8 56 60 98 Metoprolol Succinate ER/Enalapril Maleate Tablet 10 63 12 73 16 88 2O 98 TABLE 17 24 99 Metoprolol Succinate ER/Enalapril maleate Bilayer Tablet: Eq. 100 mg 40 Tartrate/10 mg EXAMPLE 10 Component Stage Ingredients % Wiw Layer I Seal coat I Microcrystallinecellulose O.1-20 Clinical Study (Metoprolol spheres 45 Succinate) Ethyl cellulose O.O1-20 Triethyl citrate O.OO1-5 The study methods involved a multicenter, randomized, Drug Layering Metoprolol Succinate 2-70 placebo-controlled, unbalanced factorial study for lowering (Metoprolol Opadry Clear O.1-20 the blood pressure. Patients, with confirmed diagnosis of Succinate) stage II hypertension were eligible to participate in the Extended Release Ethyl cellulose O.1-30 50 coating-I Opadry Clear O.1-20 studies. Patients were randomized to one of many treatment Extended Release Eudragit L30-D55 O.1-20 groups: coating-II Triethyl citrate O.OO1-5 Study 1: Group I were administered extended-release (ER) Talc O.1-20 metoprolol Succinate (Eq 25 mg Tartrate, Eq. 50 mg Seal coat II Opadry Clear O.1-20 PEG coating Polyethylene glycol O.1-10 Tartrate, Eq 100 mg Tartrate), Group II were administered Blending Prosow SMCC 90 10-80 55 amlodipine besylate (2.5 mg, 5 mg, 10 mg), Group III CroScarmellose sodium OS-15 were administered metoprolol succinate ER/amlodipine Polyethylene glycol O.1-10 besylate IR (dosages of present invention). Sodium Stearyl Fumarate O.O1-5 Layer II Granulation Enalapril maleate O. 1-25 Study 2: Group I were administered extended-release meto (Enalapril Lactose O. 1-25 prolol Succinate (Eq 25 mg tartrate, Eq. 50 mg tartrate, Maleate) Sodium bicarbonate O. 1-25 60 Eq100 mg tartrate), Group II were administered Valsartan Starch O.1-20 (40 mg, 80 mg, 160 mg. 320 mg), Group III were Magnesium Stearate O.1-10 administered metoprolol succinate ER/Valsartan IR (dos Coating Film coating Opadry white O.1-10 ages of present invention). Study 3: Group I were administered extended-release meto Procedure: 65 prolol Succinate (Eq.25 mg Tartrate, Eq. 50 mg Tartrate, Eq. Microcrystalline cellulose spheres were given seal coat I 100 mg Tartrate), Group II were administered lisinopril of ethyl cellulose. These seal coated pellets were subjected (10 mg, 20 mg, 40 mg), Group III were administered US 9,446,032 B2 29 30 extended release of metoprolol succinate/immediate able salt thereof, said dosage form exhibiting a dissolution release lisinopril (dosages of present invention). profile such that less than 6% of metoprolol or a pharma After one month of therapy non-responder patients were ceutically acceptable salt thereof is released within 1 hour, managed with dose-titration or rescue medication. between about 25% to about 50% of metoprolol is released Treatment groups in all three studies were well balanced within 6 hours and at least 90% of metoprolol is released at base line and achieved absolute change at one week from within 20 hours when the release rate is measured in USP the baseline in blood pressure. It was found that at least 10% Type 2 Dissolution apparatus in paddle type at 50 rpm using improvement in blood pressure (systolic blood pressure and 500 ml of pH 6.8 phosphate buffer at 37° C. +0.5° C. as diastolic blood pressure) was attained after 3 months treat dissolution medium. ment using pharmaceutical dosage form of the present 10 invention. 4. The pharmaceutical dosage form of claim 3, wherein We claim: the dosage form comprises about 25 mg to about 200 mg of 1. A pharmaceutical dosage form for treatment of cardio metoprolol and about 20 mg to about 800 mg of valsartan or vascular disorders and suitable for once daily administra olmesartan or a pharmaceutically acceptable salt thereof. tion; wherein said dosage form comprising a fixed dose 15 5. A pharmaceutical dosage form for treatment of cardio combination of: a) metoprolol or a pharmaceutically accept Vascular disorders and suitable for once daily administra able salt thereof in extended release form; b) amlodipine or tion, wherein said dosage form comprising a fixed dose a pharmaceutically acceptable salt thereof in immediate combination of: a) metoprolol or a pharmaceutically accept release form and, c) one or more rate controlling polymeric able salt thereof in extended release form; b) enalapril or a or non-polymeric excipients comprising a cellulosic poly pharmaceutically acceptable salt thereof in immediate mers or derivatives thereof and an acrylic acid polymers or release form and, c) one or more rate controlling polymeric derivatives thereof which form a first and a second layers on or non-polymeric excipients, comprising a cellulosic poly metoprolol or a pharmaceutically acceptable salt thereof; mers or derivatives thereof and an acrylic acid polymers or said dosage form exhibiting a dissolution profile such that derivatives thereof which form a first and a second layers on less than 6% of metoprolol or a pharmaceutically acceptable 25 metoprolol or a pharmaceutically acceptable salt thereof, salt thereof is released within 1 hour, between about 25% to said dosage form exhibiting a dissolution profile such that about 50% of metoprolol is released within 6 hours and at less than 6% of metoprolol or a pharmaceutically acceptable least 90% of metoprolol is released within 20 hours when the salt thereof is released within 1 hour, between about 25% to release rate is measured in USP Type 2 Dissolution appa about 50% of metoprolol is released within 6 hours and at ratus in paddle type at 50 rpm using 500 ml of pH 6.8 30 least 90% of metoprolol is released within 20 hours when the phosphate buffer at 37° C. +0.5° C. as dissolution medium. release rate is measured in USP Type 2 Dissolution appa 2. The pharmaceutical dosage form of claim 1, wherein ratus in paddle type at 50 rpm using 500 ml of pH 6.8 the dosage form comprises about 25 mg to about 200 mg of phosphate buffer at 37° C. +0.5° C. as dissolution medium. metoprolol and about 2.5 mg to about 800 mg of amlodipine 6. The pharmaceutical dosage form of claim 5, wherein or a pharmaceutically acceptable salt thereof. 35 the dosage form comprises about 25 mg to about 200 mg of 3. A pharmaceutical dosage form for treatment of cardio metoprolol and about 1 mg to about 100 mg of enalapril or Vascular disorders and suitable for once daily administra a pharmaceutically acceptable salt thereof. tion; wherein said dosage form comprising a fixed dose 7. A method of treating a disorder selected from one or combination of: a) metoprolol or a pharmaceutically accept more of hypertension, congestive heart failure, angina, myo able salt thereof in extended release form; b) valsartan or 40 cardial infarction, arteriosclerosis, diabetic nephropathy, olmesartan or a pharmaceutically acceptable salt thereof in diabetic cardiac myopathy, renal insufficiency, peripheral immediate release form and, c) one or more rate controlling Vascular disease, left ventricular hypertrophy, cognitive dys polymeric or non-polymeric excipients, comprising a cellu function, chronic heart failure, wherein the method com losic polymers or derivatives thereof and an acrylic acid prises administering a pharmaceutical dosage form of claim polymers or derivatives thereof which form a first and a 45 1, 3 or 5 to a patient in need of such treatment. Second layers on metoprolol or a pharmaceutically accept ck ck ck *k ck