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 losartan 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 Olmesartan 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, angiotensin 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-renin 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