US 20090215844A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0215844 A1 Davis et al. (43) Pub. Date: Aug. 27, 2009 (54) COMPOSITIONS COMPRISING NEBVOLOL (60) Provisional application No. 60/577,423, filed on Jun. 4, 2004. (75) Inventors: Eric Davis, Morgantown, WV (US); John O'Donnell, Morgantown, WV (US); Peter Publication Classification Bottini, Morgantown, WV (US) (51) Int. Cl. A63L/353 (2006.01) Correspondence Address: A6II 3/40 (2006.01) FROST BROWN TODD, LLC A6II 3/4I (2006.01) 2200 PNCCENTER, 201 E. FIFTH STREET CINCINNATI, OH 45202 (US) (52) U.S. Cl. .......... 514/381: 514/456; 514/412: 514/423 (73) Assignee: Mylan Laboratories, Inc., Morgantown, WV (US) (57) ABSTRACT (21) Appl. No.: 12/366,866 Nebivolol has been shown to be beneficial in the treatment of cardiovascular diseases such hypertension, congestive heart (22) Filed: Feb. 6, 2009 failure, arterial stiffness and endothelial dysfunction. The present invention features a pharmaceutical composition Related U.S. Application Data comprising nebivolol and at least one other active agent, (62) Division of application No. 1 1/141,235, filed on May wherein the at least one other active agent is a cardiovascular 31, 2005. agent. Patent Application Publication Aug. 27, 2009 Sheet 1 of 4 US 2009/0215844 A1 Figure 1 50 Black Nebivolol (1.0 M) 500 white + tiebivoloi (1.0 (i)} s Black, Untreated S Swhite, untreated . 9 400 S 350. g 300 5 250 O 200 2. Untreated 1.0 Ramipriat Treatment (um) 'p < 0.05 and tip- 0.01 vs preincubation with nei olo alone (n =6) Patent Application Publication Aug. 27, 2009 Sheet 2 of 4 US 2009/0215844 A1 Figure 2 Black Donors + Nebivolol (1.0 iM). d). white ponors + Nebivolol (1.0:1) . c. 2. m2. O. .9 (). C SS: Patent Application Publication Aug. 27, 2009 Sheet 3 of 4 US 2009/0215844 A1 Figure 3 m Ed Black + Nebivolol (1.0...N) at white triebivolol (1.0 iM) 2 Black, Untreated . SS White, treated 9. 9.in. : t CD O O C O 2. 150 'p < 0.05 vs preincubation with nebivolol alone (n = 6) Patent Application Publication Aug. 27, 2009 Sheet 4 of 4 US 2009/0215844 A1 Figure 4 22s a Black Donors : Nebivolol (1.0 AM) white Donors + Nabivolo? (1.04). O 5. 10 Enalapril Treatment (uM) : p < 0.05 vs preincubation with nebivolol alone {=6) US 2009/0215844 A1 Aug. 27, 2009 COMPOSITIONS COMPRISING NEBVOLOL Co-A reductase inhibitors, inotropic agents, rennin inhibi tors, vasodialators, vasopressors, AGE crosslink breakers (advanced glycosylation end-product crosslink breakers, 0001. This application is a divisional of U.S. Non-Provi such as alagebrium, see U.S. Pat. No. 6,458.819), and AGE sional patent application Ser. No. 1 1/141,235, filed May 31, formation inhibitors (advanced glycosylation end-product 2005, which is based on and claims priority from U.S. Pro formation inhibitors, such as pimagedine), and mixtures visional Patent Application Ser. No. 60/577,423, Eric Davis, thereof. In one embodiment, the other cardiovascular agent is John O'Donnell, Peter Bottini, filed Jun. 4, 2004; the disclo an ACE inhibitor or an ARB. In a further embodiment, the sures of both are hereby incorporated by reference in their other cardiovascular agent includes an ACE inhibitor and an entirety. ARB. In a further embodiment, the ACE inhibitor is selected from the group consisting of alacepril, benazepril, captopril, TECHNICAL FIELD ceronapril, cilaZapril, delapril, enalapril, enalaprilat, fosino 0002 This invention relates to compositions comprising pril, imidapril, lisinopril, perindopril, quinapril, ramipril, nebivolol and one or more other active agent. More particu ramiprilat, spirapril, temocapril, trandolapril. In a further larly, this invention relates to compositions comprising nebiv embodiment, the ACE inhibitor is enalapril, ramipril, or rami prilat. In a further embodiment, the other cardiovascular olol and one or more cardiovascular agents for the treatment agent is an ARB Selected from the group consisting of can and/or prevention of cardiovascular diseases. desartan, eprosartan, irbesartan, losartan, Valsartan. BACKGROUND OF THE INVENTION 0007. In a further embodiment, the pharmaceutical com position comprises an amount of nebivolol in the range of 0003 Hypertension is a major health concern in the US. between about 0.125 mg and about 40 mg. In a further Approximately 50 million Americans have elevated blood embodiment, the amount of an ACE inhibitor may be in the pressure defined as a systolic blood pressure (SBP)2140 range of between about 0.5 mg to about 80 mg, and/or the mmHg or a diastolic blood pressure (DBP)290 mmHg. In amount of ARB may be in the range of between about 1 mg addition, individuals with blood pressure of 120/80 mmHg or and about 1200 mg. higher are at increased risk of developing hypertension and 0008. In a further embodiment, the pharmaceutical com are considered to be in a “pre-hypertension' state. Severity of position comprises nebivolol and only one other active agent. hypertension is currently classified by stage, with Stage 1 In a further embodiment, the pharmaceutical composition hypertension spanning blood pressure ranges from 140/90 to comprises nebivolol and only one cardiovascular agent. In a 159/99 mmHg and Stage 2 including blood pressures 2160/ further embodiment, the cardiovascular agent is selected 100 mmHg. from the group consisting of ACE inhibitors (angiotensin II 0004 Onset of hypertension (diastolic alone or in combi converting enzyme inhibitors), ARB's (angiotensin II recep nation with systolic) typically occurs between 25 and 55 tor antagonists), adrenergic blockers, adrenergic agonists, years of age. The risk of developing hypertension increases agents for pheochromocytoma, anti-anginal agents, antiar more dramatically with increasing age. According to the rhythmics, antiplatelet agents, anticoagulants, antihyperten CDC, 68.3% of menaged 65-74 have hypertension in the U.S. sives, antilipemic agents, antidiabetics, antiinflammatory (Health United States, 2003, CDC/National Centerfor Health agents, calcium channel blockers, CETP inhibitors, COX-2 Statistics) and 70.7% of men aged over 75 have hypertension inhibitors, direct thrombin inhibitors, diuretics, endothelin in the U.S. (Health United States, 2003, CDC/National Cen receptor antagonists, HMG Co-A reductase inhibitors, ino ter for Health Statistics). In addition, 73.4% of women aged tropic agents, rennin inhibitors, vasodialators, vasopressors, 65-74 have hypertension in the US (Health United States, AGE crosslink breakers (advanced glycosylation end-prod 2003, CDC/National Center for Health Statistics) and 84.9% uct crosslink breakers, such as alagebrium, see U.S. Pat. No. of women aged over 75 have hypertension in the US (Health 6,458.819), and AGE formation inhibitors (advanced glyco United States, 2003, CDC/National Center for Health Statis Sylation end-product formation inhibitors, such as pimage tics). dine). In a further embodiment, the active agent is an ACE 0005 Pharmaceutical formulations that stimulate, ago inhibitor or and ARB. nize, or potentiate endothelial nitric oxide production, par 0009. In another aspect, the present invention features a ticularly formulations that produce increased nitric oxide lev method of treating a subject for a cardiovascular disorder els in African Americans, are needed. comprising administering to the Subject an effective amount of nebivolol in combination with at least one other cardiovas SUMMARY OF THE INVENTION cular agent. In a further embodiment, the cardiovascular dis 0006. In one aspect, the present invention features a phar order is selected from the group consisting of atherosclerosis, maceutical composition comprising nebivolol and at least one hypertension, diabetes mellitus, hyperhomocysteinemia, other active agent. In a further embodiment, at least one of the heart failure, and renal failure. active agents is a cardiovascular agent. In a further embodi 0010. In another aspect, the present invention features a ment, the at least one cardiovascular agentis selected from the method of preventing a cardiovascular disorder comprising group consisting of ACE inhibitors (angiotensin II converting administration to a subject an effective amount of nebivolol in enzyme inhibitors), ARB's (angiotensin II receptor antago combination with an effective amount of at least one other nists), adrenergic blockers, adrenergic agonists, agents for cardiovascular agent. In a further embodiment, the cardiovas pheochromocytoma, antiarrhythmics, antiplatelet agents, cular disorder is selected from the group consisting of con anticoagulants, antihypertensives, antilipemic agents, gestive heart failure, hypertension, pulmonary hypertension, antidiabetics, antiinflammatory agents, calcium channel myocardial and cerebral infarctions, atherosclerosis, athero blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin genesis, thrombosis, ischemic heart disease, post-angioplasty inhibitors, diuretics, endothelin receptor antagonists, HMG restenosis, coronary artery diseases, renal failure, stable, US 2009/0215844 A1 Aug. 27, 2009 unstable and variant (Prinzmetal) angina, cardiac edema, 0019. The articles “a” and “an are used herein to refer to renal insufficiency, nephrotic edema, hepatic edema, stroke, one or to more than one (i.e., to at least one) of the grammati transient ischemic attacks, cerebrovascular accidents, rest cal object of the article. By way of example, “an element' enosis, controlling blood pressure in hypertension, platelet means one element or more than one element. adhesion, platelet