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 aggregation, Smooth muscle cell prolifera 0020. The phrase “angiotensin converting enzyme inhibi tion, pulmonary edema, and vascular complications associ tor” or ACE inhibitor as used herein refers to a compound ated with the use of medical devices. that inhibits any enzyme from converting angiotensin to any 0011. In another aspect, the present invention features a kit other form. comprising an effective amount of nebivolol in combination 0021. The phrase “angiotensin II receptor antagonist” or with an effective amount of another cardiovascular agent. “ARB refers to a compound that binds to a receptor site on 0012 Even though nebivolol has 3-blocking properties, angiotensin II but does not cause any physiological changes nebivolol is different from other classic f-blockers in that it is unless another receptor ligand is present. highly selective to the B1 adrenergic receptors and also has 0022. The term “antagonist' is art-recognized and refers vasodilating effects related to its effect on endothelial nitric to a compound that binds to a receptor site, but does not cause oxide. It is believed that nebivolol increases the levels of nitric a physiological change unless another receptor ligand is oxide within the vascular endothelium through the L-argin present. ine-nitric oxide pathway and has been shown to improve 0023 The term “bioavailable' is art-recognized and refers endothelial dysfunction and improve compliance of blood to a form of the subject invention that allows for it, or a portion vessels. Nebivolol has also been shown to have antioxidant of the amount administered, to be absorbed by, incorporated characteristics which are favorable to the normal functioning to, or otherwise physiologically available to a subject or of the vascular endothelium. These characteristics make patient to whom it is administered. nebivolol an effective antihypertensive agent with favorable 0024. The phrase “cardiovascular agent' or “cardiovascu effects on the vascular endothelium and cardiovascular sys lar drug” refers to a therapeutic compound that is useful for tem. Nebivolol has been shown to be beneficial in the treat treating or preventing a cardiovascular disease. Non-limiting ment of cardiovascular diseases such as hypertension, con examples of Suitable cardiovascular agents include ACE gestive heart failure, arterial stiffness and endothelial inhibitors (angiotensin II converting enzyme inhibitors), dysfunction. In part, the present invention features a compo ARB's (angiotensin II receptor antagonists), adrenergic sition comprising nebivolol and another cardiovascular agent blockers, adrenergic agonists, agents for pheochromocy that is believed to work via a different mechanism. toma, antianginal agents, antiarrhythmics, antiplatelet 0013 These embodiments of the present invention, other agents, anticoagulants, antihypertensives, antilipemic agents, embodiments, and their features and characteristics, will be antidiabetics, antiinflammatory agents, calcium channel apparent from the description, drawings and claims that fol blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin low. inhibitors, diuretics, endothelin receptor antagonists, HMG Co-A reductase inhibitors, inotropic agents, rennin inhibi BRIEF DESCRIPTION OF THE DRAWINGS tors, vasodialators, vasopressors, AGE crosslink breakers (advanced glycosylation end-product crosslink breakers, 0014 FIG. 1 depicts a comparison of NO release from such as alagebrium, see U.S. Pat. No. 6,458.819), and AGE Black and White donor endothelial cells after chronic treat formation inhibitors (advanced glycosylation end-product ment with ramprilat followed by treatment with nebivolol (1 formation inhibitors. Such as pimagedine), and combinations uM). thereof. 0015 FIG. 2 depicts a comparison of the increase in NO 0025 Cardiovascular disease or disorder refers to any car release from Black and White donor endothelial cells after diovascular disease or disorder known in the art, including, chronic treatment with ramiprilat followed by treatment with but not limited to, wherein the cardiovascular disease is nebivolol (1 uM). selected from the group consisting of congestive heart failure, 0016 FIG. 3 depicts comparison of NO release from hypertension, pulmonary hypertension, myocardial and cere Black and White donor endothelial cells after chronic treat bral infarctions, atherosclerosis, atherogenesis, thrombosis, ment with enalapril followed by treatment with nebivolol (1 ischemic heart disease, post-angioplasty restenosis, coronary uM). artery diseases, renal failure, stable, unstable and variant 0017 FIG. 4 depicts a comparison of the increase in NO (Prinzmetal) angina, cardiac edema, renal insufficiency, release from Black and White donor endothelial cells after nephrotic edema, hepatic edema, stroke, transient ischemic chronic treatment with enalapril followed by treatment with attacks, cerebrovascular accidents, restenosis, controlling nebivolol (1 uM). blood pressure in hypertension, platelet adhesion, platelet aggregation, Smooth muscle cell proliferation, pulmonary DETAILED DESCRIPTION OF THE INVENTION edema, and vascular complications associated with the use of Definitions medical devices. 0026. The term “combination” refers to two or more dif 0018 For convenience, before further description of the ferent active agents which are administered at roughly about present invention, certain terms employed in the specifica the same time (for example, where the active agents are in a tion, examples and appended claims are collected here. These single pharmaceutical preparation) or at different times (for definitions should be read in light of the remainder of the example, one agent is administered to the Subject before the disclosure and understood as by a person of skill in the art. other). Unless defined otherwise, all technical and scientific terms 0027. The terms “drug.” “pharmaceutically active agent.” used herein have the same meaning as commonly understood “bioactive agent,” “therapeutic agent, and “active agent' by a person of ordinary skill in the art. may be used interchangeably and refer to a substance, Such as US 2009/0215844 A1 Aug. 27, 2009 a chemical compound or complex, that has a measurable tives, such as Sodium carboxymethyl cellulose, ethyl cellu beneficial physiological effect on the body, Such as a thera lose and cellulose acetate; (4) powdered tragacanth; (5) malt, peutic effect in treatment of a disease or disorder, when (6) gelatin; (7) talc.; (8) excipients, such as cocoa butter and administered in an effective amount. Further, when these Suppository waxes; (9) oils, such as peanut oil, cottonseed oil, terms are used, or when a particular active agent is specifi safflower oil, sesame oil, olive oil, corn oil and Soybean oil; cally identified by name or category, it is understood that Such (10) glycols, such as propylene glycol, (11) polyols, such as recitation is intended to include the active agent perse, as well glycerin, Sorbitol, mannitol and polyethylene glycol; (12) as pharmaceutically acceptable, pharmacologically active esters, such as ethyl oleate and ethyl laurate; (13) agar, (14) derivatives thereof, or compounds significantly related buffering agents, such as magnesium hydroxide and alumi thereto, including without limitation, salts, pharmaceutically num hydroxide: (15) alginic acid, (16) pyrogen-free water; acceptable salts, N-oxides, prodrugs, active metabolites, iso (17) isotonic saline; (18) IV fluids, including but not limited mers, fragments, analogs, Solvates hydrates, radioisotopes, to Ringer's solution, 5% dextrose in water, and half normal etc. saline; (19) ethyl alcohol; (20) phosphate buffer solutions: 0028. The phrase “effective amount” refers to that amount and (21) other non-toxic compatible Substances employed in of a Substance that produces some desired local or systemic pharmaceutical formulations. effectata reasonable benefit/risk ratio applicable to any treat 0034. The term “prophylactic' or “therapeutic treatment ment. The effective amount of such substance will vary is art-recognized and refers to administration to the host of depending upon the Subject and disease condition being one or more of the Subject compositions. If it is administered treated, the weight and age of the subject, the severity of the prior to clinical manifestation of the unwanted condition disease condition, the manner of administration and the like, (e.g., disease or other unwanted State of the host animal) then which can readily be determined by one of ordinary skill in the treatment is prophylactic, i.e., it protects the host against the art. developing the unwanted condition, whereas if administered 0029) “Endothelial dysfunction” refers to the impaired after manifestation of the unwanted condition, the treatment ability of in any physiological processes carried out by the is therapeutic (i.e., it is intended to diminish, ameliorate or endothelium, in particular, production of nitric oxide regard maintain the existing unwanted condition or side effects less of cause. It may be evaluated by, Such as, for example, therefrom). invasive techniques, such as, for example, coronary artery 0035. The term “structure-activity relationship” or reactivity to acetylcholine or methacholine, and the like, or by “(SAR) is art-recognized and refers to the way in which noninvasive techniques, such as, for example, blood flow altering the molecular structure of a drug or other compound measurements, brachial artery flow dilation using cuffocclu alters its interaction with a receptor, enzyme, nucleic acid or sion of the arm above or below the elbow, brachial artery other target and the like. ultrasonography, imaging techniques, measurement of circu 0036. It will be understood that “substitution' or “substi lating biomarkers. Such as, asymmetric dimethylarginine tuted with includes the implicit proviso that such substitu (ADMA), and the like. For the latter measurement the endot tion is in accordance with permitted valence of the substituted helial-dependent flow-mediated dialation will be lower in atom and the Substituent, and that the Substitution results in a patients diagnosed with an endothelial dysfunction. stable compound, e.g., which does not spontaneously 0030 The phrase “endothelial nitric oxide synthase' or undergo transformation Such as by rearrangement, cycliza “eNOS refers to enzymes that produce nitric oxide tion, elimination, or other reaction. 0031. The phrase “nebivolol composition” refers to a com 0037. The term “substituted” is also contemplated to position comprising nebivolol. Nebivolol is a mixture of d include all permissible Substituents of organic compounds. In and 1 isomers of O.C.'-iminobismethylenebis(5-fluoro-3,4- a broad aspect, the permissible Substituents include acyclic dihydro-2H-1-benzopyran-2-methanol. The composition and cyclic, branched and unbranched, carbocyclic and het may include at least one other cardiovascular agent or at least erocyclic, aromatic and nonaromatic Substituents of organic one pharmaceutically acceptable carrier or both. compounds. Illustrative Substituents include, for example, A "patient,” “subject' or “host may be a human or non those described herein above. The permissible substituents human animal. may be one or more and the same or different for appropriate 0032. The term “pharmaceutically acceptable salts' is art organic compounds. For purposes of this invention, the het recognized and refers to the relatively non-toxic, inorganic eroatoms such as nitrogen may have hydrogen Substituents and organic acid addition salts of compounds, including, for and/or any permissible Substituents of organic compounds example, those contained in compositions of the present described herein which satisfy the valences of the heteroat invention. oms. This invention is not intended to be limited in any 0033. The term “pharmaceutically acceptable carrier is manner by the permissible Substituents of organic com art-recognized and refers to a pharmaceutically-acceptable pounds. material, composition or vehicle. Such as a liquid or Solid 0038. The term “synthetic' is art-recognized and refers to filler, diluent, excipient, Solvent or encapsulating material, production by in vitro chemical or enzymatic synthesis. involved in carrying or transporting any Subject composition 0039. The phrase “therapeutic effect” is art-recognized or component thereof from one organ, or portion of the body, and refers to a local or systemic effect in animals, particularly to another organ, or portion of the body. Each carrier must be mammals, and more particularly humans caused by a phar acceptable in the sense of being compatible with the subject macologically active Substance. The term thus means any composition and its components and not injurious to the Substance intended for use in the diagnosis, cure, mitigation, patient. Some examples of materials which may serve as treatment or prevention of disease or in the enhancement of pharmaceutically acceptable excipients include: (1) Sugars, desirable physical or mental development and/or conditions Such as lactose, glucose and Sucrose; (2) starches, such as in an animal or human. The phrase “therapeutically-effective corn starch and potato starch; (3) cellulose, and its deriva amount’ means that amount of such a Substance that produces US 2009/0215844 A1 Aug. 27, 2009

some desired local or systemic effect at a reasonable benefit/ agent. The amount of each cardiovascular agent present in the risk ratio applicable to any treatment. The therapeutically compositions may vary depending on a number of variables effective amount of such Substance will vary depending upon Such as age, weight, gender, and health related issues. In the Subject and disease condition being treated, the weight general, the dosage of the cardiovascular agents will gener and age of the Subject, the severity of the disease condition, ally be in the range of about 0.01 ng to about 10g per kg body the manner of administration and the like, which can readily weight, specifically in the range of about 1 ng to about 0.1 g be determined by one of ordinary skill in the art. per kg, and more specifically in the range of about 100 ng to 0040. The term “treating is art-recognized and refers to about 10 mg per kg. In another embodiment, the amount of curing as well as ameliorating at least one symptom of any nebivolol in the compositions of the present invention may be condition or disease. anywhere from about 0.125 mg to about 40 mg. In one example, when the other cardiovascular agent is an ACE Nebivolol inhibitor, the amount of the ACE inhibitor may be anywhere from 0.5 mg to about 80 mg. When the other cardiovascular 0041 Nebivolol is a B-receptor blocking drug that is a agent is an ARB, the amount of ARB may be anywhere from mixture of d- and 1-enantiomers, of which d-nebivolol is a about 1 mg to about 1200 mg. The amount of the other highly selective B-receptor antagonist. cardiovascular agent will depend in part on the particular cardiovascular agent used. 0044. In addition to ACE inhibitors and ARBs, additional th OH cardiovascular agents include, but are not limited to adrener ON CH-CH-NH-CH-CH O gic blockers, adrenergic agonists, agents for pheochromocy S toma, antianginal agents, antiarrhythmics, antiplatelet agents, anticoagulants, antihypertensives, antilipemic agents, F F antidiabetics, antiinflammatory agents, calcium channel d-nebivolol blockers, CETP inhibitors, COX-2 inhibitors, direct thrombin pi (pH inhibitors, diuretics, endothelin receptor antagonists, HMG O CH-CH-NH-CH-CH O Co-A reductase inhibitors, inotropic agents, rennin inhibi S S tors, vasodialators, vasopressors, AGE crosslink breakers (advanced glycosylation end-product crosslink breakers, F F such as alagebrium, see U.S. Pat. No. 6,458.819), and AGE l-nebivolol formation inhibitors (advanced glycosylation end-product formation inhibitors, such as pimagedine). Cardiovascular 0042. In addition to its f-receptor blocking properties, agents falling within these general categories are exemplified nebivolol has been shown to cause endothelium-dependent by the following: vasodilation in both normotensive and hypertensive subjects. Angiotensin I Converting Enzymes (ACEs) and Angio Cockcroft J R, Chowienczyk PJ, Brett SE, Chen CP. Dupont tensin II Receptor Antagonists (ARBs) A G. Nueten L. V. Wooding SJ, Ritter J. M., Journal of 0045 Angiotensin II receptor antagonists' (ARBs) are Pharmacology and Experimental Therapeutics. 1995: 274: compounds which interfere with the activity of angiotensin II 1067-1071; Tzemos N, Lim PO, MacDonald T M., Circula by binding to angiotensin II receptors and interfering with its tion, 2001; 104:511-514; Broeders MA, Doevendans PA, activity. Angiotensin I and angiotensin II are synthesized by Bekkers B C, Bronsaer R, Van Gorsel E, Heemskerk J. W. the enzymatic renin-angiotensin pathway. The synthetic pro Egbrink M. G. van Breda E. Reneman RS, van Der Zee R. cess is initiated when the enzyme renin acts on angiotensino Circulation. 2000; 102:677-684. In experimental models, gen, a pseudoglobulin in blood plasma, to produce the nebivolol has been demonstrated to stimulate NO release decapeptide angiotensin I. Angiotensin I is converted by through f3-adrenergic receptor-mediated NO production angiotensin converting enzyme (ACE) to angiotensin II (an and/or ATP efflux with consequent stimulation of P2Y-pu giotensin-1-8 octapeptide). The latter is an active pressor rinoceptor-mediated NO release. Broeders MA, Doevendans Substance which has been implicated as a causative agent in PA, Bekkers BC, Bronsaer R, van Gorsel E, Heemskerk JW, several forms of hypertension in various mammalian species, Egbrink M. G. van Breda E. Reneman RS, van Der Zee R. e.g., humans. Circulation, 2000; 102:677-684; Kalinowski L., DobruckiL 004.6 Angiotensin II receptor antagonists (ARBs) are W. Szczepanska-Konkel M. Jankowski M. Martyniec L. Ang well known and include peptide compounds and non-peptide ielski S, Malinski T., Circulation, 2003: 107:2747-2752. It compounds. Most angiotensin II receptor antagonists are has also been reported that nebivolol inhibits NO synthase slightly modified congeners in which agonist activity is uncoupling and produces systemic antioxidant effects. attenuated by replacement of phenylalanine in position 8 with Mollnau H. Schulz, E. Daiber A, Baldus S, Oelze M. August Some other amino acid; stability can be enhanced by other M. Wendt M. Walter U. Geiger C. Agrawal R. Kleschyov AL, replacements that slow degeneration in vivo. Meinertz T. Thomas Münzel T., Arteriosclerosis, Thrombo 0047. Examples of angiotensin II receptor antagonists sis, and Vascular Biology. 2003; 23:615-621; Troost R. include: peptidic compounds (e.g., Saralasin and related ana Schwedhelm E. Rojczyk S, Tsikas D. Frolich J C., British logs); N-substituted imidazole-2-one (U.S. Pat. No. 5,087, Journal of Clinical Pharmacology, 2000:50:377-379. 634); imidazole acetate derivatives including 2-N-butyl-4- Compositions Comprising Nebivolol chloro-1-(2-chlorobenzile) imidazole-5-acetic acid (see Long et al., J. Pharmacol. Exp. Ther. 247(1), 1-7 (1988)); 0043. In part, the present invention features compositions 4,5,6,7-tetrahydro-1H-imidazo[4,5-cpyridine-6-carboxylic comprising nebivolol and at least one other active agent, acid and analog derivatives (U.S. Pat. No. 4,816.463): N2-tet wherein the at least one other active agent is a cardiovascular razole beta-glucuronide analogs (U.S. Pat. No. 5,085.992); US 2009/0215844 A1 Aug. 27, 2009 substituted pyrroles, pyrazoles, and tryazoles (U.S. Pat. No. hydroxy-3-t-butylaminpropoxy)phthalide. The above 5,081,127); phenol and heterocyclic derivatives such as 1,3- identified compounds can be used as isomeric mixtures, or in imidazoles (U.S. Pat. No. 5,073,566); imidazo-fused 7-mem their respective levorotating or dextrorotating form. ber ring heterocycles (U.S. Pat. No. 5,064,825); peptides (e.g., U.S. Pat. No. 4,772,684); antibodies to angiotensin II Adrenergic Agonists (e.g., U.S. Pat. No. 4.302.386); and aralkyl imidazole com pounds such as biphenyl-methyl Substituted imidazoles (e.g., 0050. Non-limiting examples of adrenergic agonists, both EP 253,310, Jan. 20, 1988); ES8891 (N-morpholinoacetyl-(- C- and B-adrenergic agonists, that may be used in the com 1-naphthyl)-L-alanyl-(4. thiazolyl)-L-alanyl(35.45)-4- positions of the present invention include adrafinil, adrena amino-3-hydroxy-5-cyclo-hexapentanoyl-N-hexylamide, lone, albuterol, amidephrine, apraclonidine, bitolterol, Sankyo Company, Ltd., Tokyo, Japan): SKF 108566 (E-al budralazine, carbuterol, clenbuterol, clonidine, clorprenaline, pha-2-2-butyl-1-(carboxy phenyl)methyl 1H-imidazole-5- clonidine, cyclopentamine, denopamine, detomidine, ylmethylane-2-thiophenepropanoic acid, SmithKline Bee dimetofrine, dioxethedrine, diplivefrin, dopexamine, ephe cham Pharmaceuticals, Pa.); Losartan (DUP753/MK954, drine, epinephrine, etafedrine, ethylnorepinephrine, fenot DuPont Merck Pharmaceutical Company); Remikirin erol, fenoxazoline, formoterol, guanabenz, guanfacine, hexo (RO42-5892. F. Hoffman LaRoche A G); A. Sub.2 agonists prenaline, hydroxyamphetamine, ibopamine, indanazoline, (Marion Merrill Dow) and certain non-peptide heterocycles isoetharine, isometheptene, isoproterenol, mabuterol, (G. D. Searle and Company). Other non-limiting examples of mephentermine, metaproterenol, metaraminol, metazoline, ARBs include candesartan, eprosartan, irbesartan, losartan, methoxamine, methylhexaneamine, methoxyphenamine, and Valsartan. Other ARBs may be identified using standard midodrine, modafinil, moXonidine, naphazoline, norepineph assaying techniques known to one of ordinary skill in the art. rine norfenefrine, octodrine, octopamine, oxyfedrine, 0048 Angiotensin converting enzyme” (ACE) is an oxymetazoline, phenylephrine hydrochloride, phenylpro enzyme which catalyzes the conversion of angiotensin I to panolamine hydrochloride, phenylpropylmethylamine, angiotensin II. ACE inhibitors include amino acids and pholedrine, pirbuterol prenalterol, procaterol, propyl derivatives thereof, peptides, including di- and tri-peptides hexedrine, protokylol, pseudoephedrine, reproterol, rillmeni and antibodies to ACE which intervene in the renin-angio dine, rimiterol, ritodrine, salmeterol, Solterenol, Synephrine, tensin system by inhibiting the activity of ACEthereby reduc talipexole, terbutaline, tetrahydrozoline, tiamenidine, trama ing or eliminating the formation of pressor Substance angio Zoline, tretoquinol, tuaminoheptane, tulobuterol, tymazoline, tensin II. ACE inhibitors have been used medically to treat tyramine, Xamoterol, Xylometazoline, and mixtures thereof. hypertension, congestive heart failure, myocardial infarction and renal disease. Classes of compounds known to be useful Agents for Pheochromocytoma as ACE inhibitors include acylmercapto and mercaptoal kanoyl prolines such as captopril (U.S. Pat. No. 4,105,776) 0051. Include but are not limited to chemotherapeutics. and Zofenopril (U.S. Pat. No. 4.316,906), carboxyalkyl dipeptides such as enalapril (U.S. Pat. No. 4.374,829), lisi Antiangina Agents nopril (U.S. Pat. No. 4.374,829), quinapril (U.S. Pat. No. 4,344.949), ramipril (U.S. Pat. No. 4,587.258), and perin 0.052 Include but are not limited to amlodipine besylate, dopril (U.S. Pat. No. 4,508,729), carboxyalkyl dipeptide amlodipine maleate, betaxolol hydrochloride, bevantolol mimics such as cilazapril (U.S. Pat. No. 4,512.924) and hydrochloride, butoprozine hydrochloride, carvedilol, benazapril (U.S. Pat. No. 4.410,520), phosphinylalkanoyl cinepazet maleate, metoprolol Succinate, molsidomine, prolines such as fosinopril (U.S. Pat. No. 4.337.201) and monatepil maleate, nitrates (including but not limited to glyc trandolopril. Other non-limiting examples of ACE inhibitors eryl trinitrate (GTN, nitroglycerin, Nitro-Bid), isosorbide-5- include, but are not limited to, alacepril, benazepril, captopril, mononitrate (5-ISMN, Ismo), amyl nitrate and nicorandil ceronapril, cilaZapril, delapril, enalapril, enalaprilat, fosino (Icorel)), primidolol, ranolazine hydrochloride, tosifen, Vera pril, imidapril, lisinopril, perindopril, quinapril, ramipril, pamil hydrochloride). ramiprilat, spirapril, temocapril, trandolapril. Antiarrhythmics Adrenergic Blockers 0053 Non-limiting examples of antiarrhythmics that may 0049. Non-limiting examples of adrenergic blockers, both be used in the compositions of the present invention include C- and B-adrenergic blockers, that may be used in the com acebutolol, acecainide, adenosine, ajmaline, alprenolol. positions of the present invention include Beta-adrenergic amiodarone, amoproxan, aprindine, aprotinolol, atenolol. receptor blockers include, but are not limited to, atenolol. azimilide, bevantolol, bidisomide, bretylium tosylate, bucu acebutolol, alprenolol, befunolol, betaxolol, bunitrolol, car molol, butetolol, bunaftine, bunitrolol, bupranolol, butidrine teolol, celiprolol, hydroxalol, indenolol, labetalol, hydrochloride, butobendine, capobenic acid, carazolol, car levobunolol, mepindolol, methypranol, metindol, meto teolol, cifenline, cloranolol, disopyramide, dolfetilide, prolol, metrizoranolol, Oxprenolol, pindolol, propranolol. encainide, esmolol, flecainide, hydroquinidine, ibutilide, practolol, Sotalolnadolol, tiprenolol, tomalolol, timolol. indecainide, indenolol, ipratropium bromide, lidocaine, bupranolol, penbutolol, trimepranol, yohimbine, 2-(3-(1,1- lorajmine, lorcainide, meobentine, mexiletine, moricizine, dimethylethyl)-amino-2-hydroxypropoxy)-3-pyridenecar nadoxolol, nifenaolol, oXprenolol, penbutolol, pentisomide, bonitrilHCl, 1-butylamino-3-(2,5-dichlorophenoxy)-2-pro pilsicainide, pindolol, pirmenol, practolol, prajmaline, panol. 1-isopropylamino-3-(4-(2-cyclopropylmethoxyethyl) procainamide hydrochloride, pronethalol, propafenone, pro phenoxy)-2-propanol, 3-isopropylamino-1-(7-methylindan pranolol, pyrinoline, quinidine, sematilide, Sotalol, talinolol. 4-yloxy)-2-butanol, 2-(3-t-butylamino-2-hydroxy tilisolol, timolol, tocainide, Verapamil. Viquidil, Xibenolol. propylthio)-4-(5-carbamoyl-2-thienyl)thiazol, 7-(2- and mixtures thereof. US 2009/0215844 A1 Aug. 27, 2009

Antiplatelet Agents ester, isosorbide-5-mononitrate, itaZigrel, ketanserin and BM-13.177, lamifiban, lifarizine, molsidomine, nifedipine, 0054 Non-limiting examples of antiplatelet agents that oXagrelate, PGE, platelet activating factorantagonists such as may be used in the compositions of the present invention lexipafant, prostacyclin (PGI. Sub.2), pyrazines, pyridinol car include clopidogrel, dipyridamole, abcixamab, and ticlo bamate, ReoPro (i.e., abciximab), Sulfinpyrazone, synthetic dipine. compounds BN-50727, BN-52021, CV-4151, E-5510, FK-409, GU-7, KB-2796, KBT-3022, KC-404, KF-4939, Anticoagulants OP-41483, TRK-100, TA-3090, TFC-612 and ZK-36374, 0055 Anti-coagulant agents are agents which inhibit the 2,4,5,7-tetrathiaoctane, 2,4,5,7-tetrathiaoctane 2,2-dioxide, coagulation pathway by impacting negatively upon the pro 2,4,5-trithiahexane, theophyllin pentoxifyllin, thromboxane duction, deposition, cleavage and/or activation of factors and thromboxane synthetase inhibitors such as picotamide essential in the formation of a blood clot. Non-limiting and Sulotroban, ticlopidine, tirofiban, trapidiland ticlopidine, examples of anticoagulants (i.e. coagulation-related therapy) trifenagrel, trilinolein, 3-substituted 5,6-bis(4-methoxyphe that may be used in the compositions of the present invention nyl)-1,2,4-triazines, and antibodies to glycoprotein IIb/IIIa as include Aggrenox, Agrylin, Amicar, Anturane, Arixtra, Cou well as those disclosed in U.S. Pat. No. 5,440,020, and anti madin, Fragmin, Heparin Sodium, Lovenox, Mephyton, serotonin drugs, Clopridogrel, Sulfinpyrazone; Aspirin; Miradon, Persantine, Plavix, Pletal, Ticlid, Trental, Warfarin. Dipyridamole; Clofibrate; Pyridinol Carbamate; PGE: Glu Other “anti-coagulant and/or “fibrinolytic' agents include cagon; Antiserotonin drugs; Caffeine; Theophyllin Pentoxi Plasminogen (to plasmin via interactions of prekallikrein, fyllin; Ticlopidine. kininogens, Factors XII, XIIIa, plasminogen proactivator, and tissue plasminogen activatorTPA) Streptokinase; Antihypertensives Urokinase: Anisoylated Plasminogen-Streptokinase Activa 0059 Non-limiting examples of antihypertensives that tor Complex: Pro-Urokinase; (Pro-UK); rTPA (alteplase or may be used in the compositions of the present invention activase: r denotes recombinant); rPro-UK; Abbokinase; include amlodipine, benidipine, benezepril, candesartan, Eminase; Sreptase Anagrelide Hydrochloride; Bivalirudin; captopril, darodipine, dilitazem HCl, diazoxide, doxazosin Dalteparin Sodium; Danaparoid Sodium; Dazoxiben Hydro HCl, enalapril, eposartan, losartan mesylate, felodipine, chloride: Efegatran Sulfate; Enoxaparin Sodium: Ifetroban: fenoldopam, fosenopril, guanabenZ acetate, irbesartan, isra Ifetroban Sodium; Tinzaparin Sodium; retaplase; dipine, lisinopril, mecamylamine, minoxidil, nicardipine Trifenagrel; Warfarin: Dextrans. HCl, nifedipine, nimodipine, nisoldipine, phenoxyben 0056 Still other anti-coagulantagents include, but are not Zamine HCl, prazosin HCl, quinapril, reserpine, teraZosin limited to, Ancrod; Anticoagulant Citrate Dextrose Solution; HCl, telmisartan, and Valsartan. Anticoagulant Citrate Phosphate Dextrose Adenine Solution; Anticoagulant Citrate Phosphate Dextrose Solution; Antico Antilipemic Agents agulant Heparin Solution; Anticoagulant Sodium Citrate Solution: Ardeparin Sodium; Bivalirudin; Bromindione: 0060. Non-limiting examples of antilipemic agents that Dalteparin Sodium; Desirudin; Dicumarol; Heparin Cal may be used in the compositions of the present invention cium; Heparin Sodium; Lyapolate Sodium; Nafamostat include acipimox, aluminum nicotinate, atorvastatin, Mesylate; Phenprocoumon; Tinzaparin Sodium. cholestyramine resin, colestipol, polidexide, beclobrate 0057. Inhibitors of platelet function are agents that impair bezafibrate, ciprofibrate, clinofibrate, clofibrate, clofibric the ability of mature platelets to perform their normal physi acid, etofibrate, fenofibrate, fluvastatin, gemfibrozil, lovasta ological roles (i.e., their normal function). Platelets are nor tin, lysosomal acid lipase, icofibrate, niacin, pirifibrate, prav mally involved in a number of physiological processes Such astatin Sodium, ronifibrate, Simfibrate, theofibrate, simvasta as adhesion, for example, to cellular and non-cellular entities, tin, niceritrol, nicoclonate, nicomol. Oxiniacic acid, etiroXate, aggregation, for example, for the purpose of forming a blood thyopropic acid, thyroxine, acifran, azacosterol, benfluorex, clot, and release of factors such as growth factors (e.g., plate beta-benzalbutyramide, carnitine, chondroitin Sulfate clom let-derived growth factor (PDGF)) and platelet granular com estrone, detaXtran, dextran Sulfate sodium, 5, 8, 11, 14. ponents. One Subcategory of platelet function inhibitors are 17-eicosapentaenoic acid, eritadenine, furazabol, meglutol, inhibitors of platelet aggregation which are compounds melinamide, my tatrienediol, ornithine, gamma-ory Zanol, which reduce or halt the ability of platelets to associate physi pantethine, pentaerythritol tetraacetate, alpha-phenylbutyra cally with themselves or with other cellular and non-cellular mide, pirozadil, probucol, beta-sitosterol, Sultosilic acid (pip components, thereby precluding the ability of a platelet to erazine salt), tiadenol, triparanol, Xenbucin, and mixtures form a thrombus. thereof. 0058 Examples of useful inhibitors of platelet function Antidiabetics includebut are not limited to acadesine, anagrelide (if given at doses exceeding 10 mg/day), anipamil, argatroban, aspirin, 0061 Non-limiting examples of antidiabetics that may be clopidogrel, cyclooxygenase inhibitors such as nonsteroidal used in the compositions of the present invention include anti-inflammatory drugs and the synthetic compound biguanides Such as buformin, metformin, and phenformin; FR-122047, danaparoid sodium, dazoxiben hydrochloride, hormones such as insulin; Sulfonylurea derivatives such as diadenosine 5'5"-P1-P4-tetraphosphate (Ap4A) analogs, acetohexamide, 1-butyl-3-metanily lurea, carbutamide, chlo difibrotide, dilazep dihydrochloride, 1.2- and 1,3-glyceryl rpropamide, glibornuride, gliclazide, glimepiride, glipizide, dinitrate, dipyridamole, dopamine and 3-methoxytyramine, gliquidone, glisoxepid, glyburide, glybuthiazole, glybuzole, efegatran Sulfate, enoxaparin sodium, glucagon, glycoprotein glyhexamide, glymidine, glypinamide, phenbutamide, IIb/IIIa antagonists such as Ro-43-8857 and L-700.462, tolaZamide, tolbutamide, tolcyclamide; HDL agonists; ifetroban, ifetroban Sodium, iloprost, isocarbacyclin methyl PPARY agonists Such as thiazolidinediones Such as pioglita US 2009/0215844 A1 Aug. 27, 2009

Zone, rosiglitaZone, and troglitaZone; and others including macy, Nineteenth Edition, Mack Publishing Company, acarbose, calcium mesoxalate, miglitol, and repaglinide. Eaton, Pa., p. 963 (1995)). Most of the currently available calcium channel blockers, and useful according to the present Antiinflammatory Agents invention, belong to one of three major chemical groups of drugs, the dihydropyridines, such as nifedipine, the phenyl 0062. Non-limiting examples of antiinflammatory agents alkyl amines, such as Verapamil, and the benzothiazepines, that may be used in the compositions of the present invention Such as diltiazem. Non-limiting examples of calcium channel include Alclofenac; Alclometasone Dipropionate; Algestone blockers that may be used in the compositions of the present Acetonide; Alpha Amylase; Amcinafal; Amcinafide; invention include bepridil, clentiazem, diltiazem, fendiline, Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; gallopamil, mibefradil, prenylamine, Semotiadil, terodiline, Anirolac, AnitraZafen; Apazone; Balsalazide Disodium; Verapamil, amlodipine, aranidipine, barnidipine, benidipine, Bendazac. Benoxaprofen; Benzydamine Hydrochloride: cilnidipine, efonidipine, elgodipine, felodipine, isradipine, Bromelains; Broperamole; Budesonide; Carprofen; Ciclo lacidipine, lercanidpine, manidipine, nicardipine, nifedipine, profen; Cintazone; Cliprofen; Clobetasol Propionate; Clobe nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnariz tasone Butyrate; Clopirac; Cloticasone Propionate; ine, flunarizine, lidoflazine, lomerizine, bencyclane, Cormethasone Acetate; Cortodoxone; Deflazacort; Des etafenone, fantofarone, perhexyline, and mixtures thereof. onide; DeSoximetasone; Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone CETP Inhibitors Diacetate; Diflumidone Sodium; Diflunisal; Difluprednate: Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone: 0064. A non-limiting example of a CETP inhibitor that Enlimomab: Enolicam Sodium; Epirizole; Etodolac.; Etofe may be used in the compositions of the present invention namate; Felbinac; Fenamole: Fenbufen, Fenclofenac; Fen includes torcetrapib. clorac; Fendosal: Fenpipalone: Fentiazac.; Flazalone: Fluaza cort; Flufenamic Acid, Flumizole; Flunisolide Acetate; COX-2 Inhibitors Flunixin: Flunixin Meglumine: Fluocortin Butyl; Fluo rometholone Acetate; FluguaZone: Flurbiprofen; Fluretofen; 0065. Non-limiting examples of COX-2 inhibitors that Fluticasone Propionate; Furaprofen; Furobufen; Halcinon may be used in the compositions of the present invention ide; Halobetasol Propionate; Halopredone Acetate; Ibufenac: include compounds according to the following: all of the Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol: compounds and Substances beginning on page 8 of Winokur Ilonidap: Indomethacin; Indomethacin Sodium; Indoprofen; WO99/20110 as members of three distinct structural classes Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxi of selective COX-2 inhibitor compounds, and the compounds cam; Ketoprofen; Lofemizole Hydrochloride; Lomoxicam; and substances which are selective COX-2 inhibitors in Nich Loteprednol Etabonate; Meclofenamate Sodium; Meclofe therger, U.S. Pat. No. 6,136,804, Oct. 24, 2000, entitled namic Acid; Meclorisone Dibutyrate; Mefenamic Acid; "Combination therapy for treating, preventing, or reducing Mesalamine: MeseclaZone; Methylprednisolone Suleptan the risks associated with acute coronary ischemic syndrome ate; Morniflumate; Nabumetone; Naproxen; Naproxen and related conditions', and the compounds and Substances Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgot which are selective COX-2 inhibitors in Isakson et al., PCT ein; Orpanoxin: Oxaprozin: Oxyphenbutazone; Paranyline application WO/09641645 published Dec. 27, 1996, filed as Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone PCT/US 9509905 on Jun. 12, 1995, entitled “Combination of Sodium Glycerate; Pirfenidone: Piroxicam; Piroxicam Cin a Cyclooxygenase-2 Inhibitor and a Leukotriene B4 Receptor namate; Piroxicam Olamine; Pirprofen; Prednazate: Prife Antagonist for the Treatment of Inflammations.” The mean lone: Prodolic Acid; ProquaZone: Proxazole; Proxazole Cit ing of COX-2 inhibitor in this invention shall include the rate; Rimexolone; Romazarit; Salcolex; Salnacedin; compounds and Substances referenced and incorporated into Salsalate: Salycilates; Sanguinarium Chloride: SeclaZone: Winokur WO99/20110 by reference to art therein, the com Sermetacin; Sudoxicam, Sulindac: Suprofen; Talmetacin; pounds and Substances referenced and incorporated into Talniflumate; Talosalate; Tebufelone; Tenidap: Tenidap Nichtberger, U.S. Pat. No. 6,136,804, Oct. 24, 2000, by ref Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine: erence to art therein, and the compounds and Substances Tiopinac; Tixocortol Pivalate: Tolimetin: Tolimetin Sodium; which are COX-2 inhibitors referenced and incorporated into Triclonide; Triflumidate; Zidometacin; Glucocorticoids; Isakson etal, PCT application WO/09641645 published Dec. Zomepirac Sodium. One preferred antiinflammatory agent is 27, 1996, filed as PCT/US 9509905 on Jun. 12, 1995, entitled aspirin. “Combination of a Cyclooxygenase-2 Inhibitor and a Leu kotriene B4 Receptor Antagonist for the Treatment of Inflam Calcium Channel Blockers mations.” The meaning of COX-2 inhibitor in this invention also includes rofecoxib, and celecoxib, marketed as VIOXX 0063 Calcium channel blockers are a chemically diverse and CELEBREX by Merck and Searle/Pfizer respectively. class of compounds having important therapeutic value in the Rofecoxib is discussed in Winokur, WO99/20110 as com control of a variety of diseases including several cardiovas pound 3, on p. 9. Celecoxib is discussed as SC-58635 in the cular disorders, such as hypertension, angina, and cardiac same reference, and in T. Penning, Synthesis and biological arrhythmias (Fleckenstein, Cir. Res. V. 52, (suppl. 1), p. 13-16 evaluation of the 1.5-diarylpyrazole class of cyclooxyge (1983); Fleckenstein, Experimental Facts and Therapeutic nase-2 inhibitors: identification of 4-5-(4-methylphenyl)-3- Prospects, John Wiley, New York (1983); McCall, D., Curr (trifluoromethyl)-1H-pyrozol-1-ylbenzenesulfonamide Pract Cardiol. v. 10, p. 1-11 (1985)). Calcium channel block (SC-58635, celecoxib), J. Med. Chem. Apr. 25, 1997: 40(9): ers are a heterogeneous group of drugs that prevent or slow 1347-56. The meaning of COX-2 inhibitor in this invention the entry of calcium into cells by regulating cellular calcium also includes SC299 referred to as a fluorescent diarylox channels. (Remington, The Science and Practice of Phar azole. C. Lanzo et al., “Fluorescence quenching analysis of the US 2009/0215844 A1 Aug. 27, 2009 association and dissociation of a diarylheterocycle to metone and etodolac. Recognizing that there is overlap cyclooxygenasel-1 and cyclooxygenase-2: dynamic basis of among the selective COX-2 inhibitors set out in this para cycloxygenase-2 selectivity”. Biochemistry May 23, 2000, graph, the intent of the term COX-2 inhibitor is to compre vol.39(20):6228-34, and in J. Talley et al. “4,5-Diaryloxazole hensively include all selective COX-2 inhibitors, selective in inhibitors of cyclooxygenase-2 (COX-2), Med. Res. Rev. the sense of inhibiting COX-2 over COX-1. The inventors add May 1999; 19(3): 199-208. The meaning of COX-2 inhibitor to the class of COX-2 inhibitors useful in the invention the in this invention also includes Valdecoxib, See, “4-5-Methyl drug bearing the name etoricoxib referenced in the Wall 3-phenylisoxazol-1-ylbenzenesulfonamide, Valdecoxib: A Street Journal, Dec. 13, 2000, manufactured by Merck. See, also, Chauret et al., “In vitro metabolism considerations, Potent and Selective Inhibitor of COX-2, J. Med. Chem. including activity testing of metabolites, in the discovery and 2000, Vol. 43: 775-777, and parecoxib, sodium salt or pare selection of the COX-2 inhibitor etoricoxib (MK-0663).” coxib sodium, See, N-(5-methyl-3-phenylixoxazol-4-yl)- Bioorg. Med. Chem. Lett. 11 (8): 1059-62 (Apr. 23, 2001). phenylsulfonylpropanimide, Sodium Salt, Parecoxib Another selective COX-2 inhibitor is DFU 5,5-dimethyl-3- Sodium: A Potent and Selective Inhibitor of COX-2 for (3-fluorophenyl)-4-(4-methylsulphonyl) phenyl-2(5H)-fura Parenteral Administration, J. Med. Chem. 2000, Vol. 43: none referenced in Yergey et al. Drug Metab. Dispos. 29(5): 1661-1663. The meaning of COX-2 inhibitor in this invention 638-44 (May 2001). The inventors also include as a selective also includes the Substitution of the Sulfonamide moiety as a COX-2 inhibitor the flavonoid antioxidant silymarin, and an suitable replacement for the methylsulfonyl moiety. See, J. active ingredient in silymarin, Silybinin, which demonstrated Carteretal, Synthesis and activity of sulfonamide-substituted significant COX-2 inhibition relative to COX-1 inhibition. 4.5-diaryl thiazoles as selective cyclooxygenase-2 inhibi The silymarin also showed protection against depletion of tors.” Bioorg. Med. Chem. Lett Apr. 19, 1999: Vol. 9(8): glutathione peroxidase. Zhao et al. “Significant Inhibition by 1171-74, and compounds referenced in the article “Design the Flavonoid Antioxidant Silymarin against 12-O-tetrace and synthesis of sulfonyl-substituted 4,5-diarylthiazoles as canoylphorbol 13-acetate-caused modulation of antioxidant selective cyclooxygenase-2 inhibitors’, Bioorg. Med. Chem. and inflammatory enzymes, and cyclooxygenase 2 and inter Lett Apr. 19, 1999: Vol. 9(8): 1167-70. The meaning of this leukin-1 alpha expression in SENCAR mouse epidermis: invention includes a COX-2 inhibitor, NS398 referenced in implications in the prevention of stage I tumor promotion.” two articles: Attiga et al., “Inhibitors of Prostaglandin Synthe Mol. Carcinog. December 1999, Vol 26(4):321-33 PMID sis Inhibit Human Prostate Tumor Cell Invasiveness and 10569809. Silymarin has been used to treat liver diseases in Reduce the Release of Matrix Metalloproteinases’, 60 Can Europe. cer Research 4629-4637, Aug. 15, 2000, and in “The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by 0066. A number of the above-identified COX-2 inhibitors blocking Akt activation in human prostate cancer cells inde are prodrugs of selective COX-2 inhibitors, and exert their pendently of Bcl-2. Hsu et al., 275(15) J. Biol. Chem. 11397 action by conversion in vivo to the active and selective COX-2 11403 (2000). The meaning of COX-2 inhibitor in this inven inhibitors. The active and selective COX-2 inhibitors formed tion includes the cyclo-oxygenase-2 selective compounds from the above-identified COX-2 inhibitor prodrugs are referenced in Mitchell et al., “Cyclo-oxygenase-2: pharma described in detail in WO95/00501, published Jan. 5, 1995, cology, physiology, biochemistry and relevance to NSAID WO95/18799, published Jul 13, 1995 and U.S. Pat. No. therapy”, Brit. J. of Pharmacology (1999) vol. 128: 1121 5,474,995, issued Dec. 12, 1995. Given the teachings of U.S. 1132, see especially p. 1126. The meaning of COX-2 inhibi Pat. No. 5,543,297, entitled: “Human cyclooxygenase-2 tor in this invention includes so-called NO-NSAIDs or nitric cDNA and assays for evaluating cyclooxygenase-2 activity.” oxide-releasing-NSAIDs referred to in L. Jackson et al. a person of ordinary skill in the art would be able to determine “COX-2 Selective Nonsteroidal Anti-Inflammatory Drugs: whether an agent is a selective COX-2 inhibitor or a precursor Do They Really Offer Any Advantages?, Drugs, June, 2000 of a COX-2 inhibitor, and therefore part of the present inven vol. 59(6): 1207-1216 and the articles at footnotes 27, and 28. tion. Also included in the meaning of COX-2 inhibitor in this invention includes any substance that selectively inhibits the “Direct Thrombin Inhibitors’ COX-2 isoenzyme over the COX-1 isoenzyme in a ratio of 0067. Nonlimiting examples of direct thrombin inhibitors greater than 10 to 1 and preferably in ratio of at least 40 to 1 include hirudin, hirugen, hirulog, agatroban, PPACK, and as referenced in Winokur WO99/20110, and has one sub thrombinaptamers. stituent having both atoms with free electrons under tradi tional Valence-shell-electron-pair-repulsion theory located Diuretics on a cyclic ring (as in the Sulfylamine portion of celecoxib), and a second Substituent located on a different ring suffi 0068. Non-limiting examples of diuretics that may be used ciently far from said first Substituent to have no significant in the compositions of the present invention include althiaz electron interaction with the first substituent. The second ide, bendroflumethiazide, benzthiazide, buthiazide, chlortha substituent should have an electronegativity within such sub lidone, cyclopenthiazide, cyclothiazide, epithiazide, ethiaz stituent greater than 0.5, or the second substituent should be ide, fenduizone, indapamide, hydroflumethiazide, an atom located on the periphery of the compound selected methyclothiazide, meticrane, metolaZone, paraflutizide, from the group of a halogen F, Cl, Br or I, or a group VI polythiazide, quinethaZone, teclothiazide, trichloromethiaz element, S or O. Thus for purposes of this last included ide, chlormerodrin, meralluride, mercamphamide, mercap meaning of a COX-2 inhibitor, one portion of the COX-2 tomerin Sodium, mercumatilin Sodium, mercurous chloride, inhibitor should be hydrophilic and the other portion lipo mersalyl, acefylline, 7-morpholinomethyl-theophylline, philic. Also included as a COX-2 inhibitor are compounds pamabrom, protheobromine, theobromine, canrenone, olean listed at page 553 in Pharmacotherapy: A Pathophysiologic drin, spironolactone, acetazolamide, ambuside, azosemide, Approach, Depiro et al (McGraw Hill 1999) including nabu bumetanide, butazolamide, clopamide, clrexolone, disulfa US 2009/0215844 A1 Aug. 27, 2009

mide, ethoXZolamide, furosemide, mefruside, methaZola acids and derivatives thereof, peptides and derivatives mide, piretanide, torsemide, tripamide, Xipamide, aminome thereof, and antibodies to renin. Examples of renin inhibitors tradine, amisometradine, amanozine, amiloride, arbutin, that are the subject of United States patents are as follows: chlorazanil, ethacrynic acid, etoZolin, hydracarbazine, isos urea derivatives of peptides (U.S. Pat. No. 5,116,835); amino orbide, mannitol, metochalcone, muZolimine, perhexyline, acids connected by nonpeptide bonds (U.S. Pat. No. 5,114, ticrynafen, triamterene, urea, and mixtures thereof. 937); di- and tri-peptide derivatives (U.S. Pat. No. 5,106, 835); amino acids and derivatives thereof (U.S. Pat. Nos. Endothelin Receptor Antagonists 5,104,869 and 5,095,119); diol sulfonamides and sulfinyls 0069. A non-limiting example of an endothelin receptor (U.S. Pat. No. 5,098,924); modified peptides (U.S. Pat. No. antagonist that may be used in the compositions of the present 5,095,006); peptidyl beta-aminoacyl aminodiol carbamates invention is bosentan. (U.S. Pat. No. 5,089.471); pyrolimidazolones (U.S. Pat. No. 5,075,451); fluorine and chlorine statine or statone containing HMG-CoA Reductase Inhibitor (Statins) peptides (U.S. Pat. No. 5,066,643); peptidyl amino diols 0070 HMG-CoA (3-hydroxy-3-methylglutaryl-coen (U.S. Pat. Nos. 5,063,208 and 4,845,079); N-morpholino Zyme A) reductase is the microsomal enzyme that catalyzes derivatives (U.S. Pat. No. 5,055.466); pepstatin derivatives the rate limiting reaction in cholesterol biosynthesis (HMG (U.S. Pat. No. 4,980,283); N-heterocyclic alcohols (U.S. Pat. CoA6Mevalonate). An HMG-CoA reductase inhibitor inhib No. 4,885.292); monoclonal antibodies to renin (U.S. Pat. its HMG-CoA reductase, and as a result inhibits the synthesis No. 4,780.401); and a variety of other peptides and analogs of cholesterol. A number of HMG-CoA reductase inhibitors thereof (U.S. Pat. Nos. 5,071,837, 5,064,965, 5,063,207, has been used to treat individuals with hypercholesterolemia. 5,036,054, 5,036,053, 5,034,512, and 4,894.437). More recently, HMG-CoA reductase inhibitors have been shown to be beneficial in the treatment of stroke (Endres M, et Vasodilators al., Proc Natl AcadSci USA, 1998, 95:8880-5). 0075 Non-limiting examples of vasodilators that may be 0071. HMG-CoA reductase inhibitors useful for co-ad used in the compositions of the present invention include ministration with the agents of the invention include, but are bencyclane, cinnarizine, citicoline, cyclandelate, ciclonicate, not limited to, simvastatin (U.S. Pat. No. 4,444,784), lovas diisopropylamine dichloroacetate, eburnamonine, fasudil, tatin (U.S. Pat. No. 4,231.938), pravastatin sodium (U.S. Pat. fenoxedil, flunarizine, ibudilast, ifenprodil, isosorbide dini No. 4,346.227), fluvastatin (U.S. Pat. No. 4,739,073), atorv trate, lomerixine, nafronyl, nicametate, nicergoline, nimo astatin (U.S. Pat. No. 5.273.995), cerivastatin, and numerous dipine, papaverine, pentifylline, tinofedrine, Vancamine, Vin others described in U.S. Pat. Nos. 5,622,985; 5,135,935; pocetine, Vicquidil, amotriphene, bendaZol, benfurodil 5,356,896; 4,920,109; 5,286,895; 5,262,435: 5,260,332; hemisuccinate, benziodarone, chloracizine, chromonar, 5,317,031: 5,283.256; 5,256,689; 5,182,298; 5,369,125; clobenfurol, clonitrate, cloricromen, dilaZep, dipyridamole, 5,302,604; 5,166,171: 5,202,327: 5,276,021; 5,196,440; droprenilamine, efloxate, erythrityl tetranitrate, etafenone, 5,091,386; 5,091,378; 4,904,646; 5,385,932; 5,250,435: fendiline, floredil, ganglefence, heart muscle extract, hex 5,132,312; 5,130,306; 5,116,870; 5,112,857; 5,102,911; estrol bis(B-diethylaminoethyl ether), hexobendine, hydrala 5,098,931; 5,081,136; 5,025,000; 5,021,453: 5,017,716; Zine, itramin tosylate khellin, lidoflazine, mannitol hexani 5,001,144; 5,001,128: 4,997,837; 4,996,234: 4,994,494; trate, medibazine, nitroglycerin, isosorbide mononitrate, 4,992,429: 4,970,231: 4,968,693: 4,963,538; 4,957,940; isosorbide dinitrate, and other nitrates, pentaerythritol tet 4,950,675; 4,946,864; 4,946,860: 4,940,800; 4,940,727: ranitrate, pentrinitrol, perhexyline, pimefylline, prenylamine, 4,939,143: 4,929,620: 4,923,861; 4,906,657; 4,906,624 and propatyl nitrate, pyridofylline, trapidil, tricromyl, trimetazi 4,897,402, the disclosures of which patents are incorporated dine, trolnitrate phosphate, Visnadine, aluminum nicotinate, herein by reference. bamethan, bencyclane, betahistine, bradykinin, brovincam 0072 Other non-limiting examples of HMG-CoA reduc ine, bufeniode, buflomedil, butalamine, cetiedil, ciclonicate, tase inhibitors that may be used in the compositions of the cinepazide, cinnarizine, cyclandelate, diisopropylamine present invention include mevastatin, pitavastatin, rosuvasta dichloroacetate, eledoisin, fenoxedil, flunazine, hepronicate, tin, gemcabene, and probucol. ifenprodil, iloprost, inositol niacinate, isoXSuprine, kallidin, Inotropic Agents kallikrein, moxisylyte, nafronyl, nicametate nicergoline, 0073. Non-limiting examples of inotropic agents that may nicofuranose, nicotinyl alcohol, nylidrin, pentifylline, pen be used in the compositions of the present invention include toxifylline, piribedil, prostaglandin E. Suloctidil, tolaZoline, acefylline, acetyldigitoxins, 2-amino-4-picoline, amrinone, Xanthinol niacinate, and mixtures thereof. benfurodil hemisuccinate, bucladesine, camphotamide, con Vasopressors Vallatoxin, cymarin, denopamine, deslanoside, digitalin, digitalis, digitoxin, digoxin, dobutamine, docarpamine, 0076 Non-limiting examples of vasopressors that may be dopamine, dopexamine, enoXimone, erythrophleine, fenal used in the compositions of the present invention include Somine, gitalin, gitoxin, glycocyamine, heptaminol, hydras amezinium methyl Sulfate, angiotensin amide, dimetofrine, tinine, ibopamine, lanatosides, loprinine, milrinone, nerifo dopamine, etifelmin, etillefrin, gepefrine, metaraminol, meth lin, oleandrin, ouabain, oxyfedrine, pimobendan, prenalterol, oxamine, midodrine, norepinephrine, pholedrine, Syneph proscillaridin, resibufogenin, Scillaren, Scillarenin, strophan rine, and mixtures thereof. thin, Sulmazole, theobromine, Vesnarinone, Xamoterol, and Age Crosslink Breakers (Advanced Glycosylation End-Prod mixtures thereof. uct Crosslink Breakers) “Renin Inhibitors’ 0077. Non-limiting examples of AGE crosslink breakers 0074 Renin inhibitors are compounds which interfere that may be used in the compositions of the present invention with the activity of renin. Renin inhibitors include amino include Alagebrium. US 2009/0215844 A1 Aug. 27, 2009

Age Formation Inhibitors (Advanced Glycosylation End 0094 anti-malarials, such as amodiaquine, chloroquine, Product Formation Inhibitors) chlorproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil HCl, pyrimethamine and quinine Sulfate; 0078. Non-limiting examples of AGE formation inhibitors 0095 anti-migraine agents, such as dihydroergotamine that may be used in the compositions of the present invention mesylate, ergotamine tartrate, froVatriptan, methysergide include Pimagedine. maleate, naratriptan HCl, pizotifen maleate, rizatriptan ben Other Actives: Zoate, Sumatriptan Succinate, and Zolmitriptan; 0096 anti-muscarinic agents, such as atropine, benzhexol 0079 Non-limiting examples of other active ingredients HCl, biperiden, ethopropazine HCl, hyoscyamine, mepen that may be combined with these nebivolol compositions Zolate bromide, oxyphencyclimine HCl and tropicamide; include, but are not limited to, the following representative 0097 anti-neoplastic agents and immunosuppressants, classes of compounds, as well as their pharmaceutically Such as aminoglutethimide, amsacrine, azathioprine, acceptable salts, isomers, esters, ethers and other derivatives: bicalutamide, bisantrene, buSulfan, camptothecin, capecitab 0080 analgesics and anti-inflammatory agents, such as ine, chlorambucil, cyclosporin, dacarbazine, aloxiprin, auranofin, azapropaZone, benorylate, capsaicin, 0.098 ellipticine, estramustine, etoposide, irinotecan, celecoxib, diclofenac, diflunisal, etodolac, fenbufen, feno lomustine, melphalan, mercaptopurine, methotrexate, mito profen calcium, flurbiprofen, ibuprofen, indomethacin, keto mycin, mitotane, mitoxantrone, mofetil mycophenolate, profen, ketorolac, leflunomide, meclofenaminc acid, mefe nilutamide, paclitaxel, procarbazine HCl, sirolimus, tacroli namic acid, nabumetone, naproxen, oxaprozin, mus, tamoxifen citrate, teniposide, testolactone, topotecan oxyphenbutaZone, phenylbutaZone, piroxicam, rofecoxib, HCl, and toremifene citrate; Sulindac, tetrahydrocannabinol, tramadol and tromethamine; 0099 anti-protozoal agents, such as atovaquone, ben 0081 antihelminthics, such as albendazole, bephenium Znidazole, clioquinol, decoquinate, diiodohydroxyquinoline, hydroxynaphthoate, cambendazole, dichlorophen, ivermec diloxanide furoate, dinitolmide, furazolidone, metronida tin, mebendazole, oxaminiquine, Oxfendazole, oxantel Zole, nimorazole, nitrofuraZone, ornidazole and tinidazole; embonate, praziquantel, pyrantel embonate and thiabenda 0100 anti-psychotics, such as aripiprazole, clozapine, Zole; Ziprasidone, haloperidol, molindone, loxapine, thioridazine, 0082 anti-asthma agents, such as Zileuton, Zafirlukast, molindone, thiothixene, pimozide, fluphenazine, risperidone terbutaline sulfate, montelukast, and albuterol; mesoridazine, quetiapine, trifluoperazine, chlorprothixene, 0083) anti-bacterial agents, such as alatrofloxacin, chlorpromazine, perphenazine, trifluopromazine, olanzap azithromycin, baclofen, benzathine penicillin, cinoxacin, ine; ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, 0101 anti-thyroid agents, such as carbimazole, paracalci demeclocycline, dirithromycin, doxycycline, tol, and propylthiouracil; 0084 erythromycin, ethionamide, furazolidone, grepa 0102 anti-tussives, such as benzonatate; floxacin, imipenem, levofloxacin, lorefloxacin, moxifloxacin 0103) anxiolytics, sedatives, hypnotics and neuroleptics, HCl, nalidixic acid, nitrofurantoin, norfloxacin, ofloxacin, Such as alprazolam, amylobarbitone, barbitone, bentazepam, rifampicin, rifabutine, rifapentine, sparfloxacin, bromazepam, bromperidol, brotizolam, butobarbitone, car 0085 spiramycin, sulphabenzamide, sulphadoxine, sul bromal, chlordiazepoxide, chlormethiazole, chlorpromazine, phamerazine, chlorprothixene, clonazepam, clobazam, clotiazepam, cloza I0086 ulphacetamide, sulphadiazine, sulphafurazole, sul pine, diazepam, droperidol, ethinamate, flunanisone, fluni phamethoxazole, Sulphapyridine, tetracycline, trimethoprim, trazepam, triflupromazine, flupenthixol decanoate, trovafloxacin, and Vancomycin; fluphenthixol decanoate, flurazepam, gabapentin, haloperi 0087 anti-viral agents, such as abacavir, amprenavir, dol, lorazepam, lormetazepam, medazepam, meprobamate, delavirdine, efavirenz, indinavir, lamivudine, nelfinavir, nevi mesoridazine, methaqualone, methylphenidate, midazolam, rapine, ritonavir, saquinavir, and stavudine; molindone, nitrazepam, 0088 anti-depressants, such as amoxapine, bupropion, 0104 olanzapine, oxazepam, pentobarbitone, perphena citalopram, clomipramine, fluoxetine HCl, maprotiline HCl, Zine pimozide, prochlorperazine, pseudoephedrine, quetiap mianserin HCl, nortriptyline HCl, paroxetine HCl, sertraline ine, risperidone, sertindole, Sulpiride, temazepam, thior HCl, trazodone HCl, trimipramine maleate, and Venlafaxine idazine, triazolam, Zolpidem, and Zopiclone; HC1; 0105 corticosteroids, such as beclomethasone, 0089 anti-epileptics, such as beclamide, carbamazepine, betamethasone, budesonide, cortisone acetate, desoxymetha clonazepam, ethotoin, felbamate, fosphenytoin Sodium, lam Sone, dexamethasone, fludrocortisone acetate, flunisolide, otrigine, methoin, methSuximide, methylphenobarbitone, fluocortolone, fluticasone propionate, hydrocortisone, meth oXcarbazepine, paramethadione, phenacemide, ylprednisolone, prednisolone, prednisone and triamcinolone; 0090 phenobarbitone, phenyloin, phensuximide, primi 0106 anti-parkinsonian agents, such as apomorphine, done, Sulthiame, tiagabine HCl, topiramate, valproic acid, bromocriptine mesylate, lysuride maleate, pramipexole, rop and vigabatrin; inirole HCl, and tolcapone: 0.091 anti-fungal agents, such as amphotericin, butenafine 0107 gastro-intestinal agents, such as bisacodyl, cimeti HCl, butoconazole nitrate, clotrimazole, econazole nitrate, dine, cisapride, diphenoxylate HCl, domperidone, famoti fluconazole, flucytosine, griseofulvin, itraconazole, keto dine, lanosprazole, loperamide, mesalazine, nizatidine, ome conazole, miconazole, natamycin, prazole, ondansetron HCL, rabeprazole sodium, ranitidine 0092 nystatin, Sulconazole nitrate, oxiconazole, erbin HCl and sulphasalazine; afine HCl, terconazole, tioconazole and undecenoic acid; 0.108 keratolytics, such as acetretin, calciprotriene, cal 0093 anti-gout agents, such as allopurinol, probenecid cifediol, calcitriol, cholecalciferol, ergocalciferol, etretinate, and Sulphinpyrazone; retinoids, targretin, and tazarotene; US 2009/0215844 A1 Aug. 27, 2009

0109 lipid regulating agents, such as atorvastatin, beZafi mide, azithromycin, baclofen, bambuterol, bamethan, barbi brate, cerivastatin, ciprofibrate, clofibrate, fenofibrate, fluv tone, barnidipine, basalazide, beclamide, beclobrate, befi astatin, gemfibrozil, pravastatin, probucol, and simvastatin: molol, bemegride, benazepril, bencyclane, bendazac, 0110 muscle relaxants, such as dantrolene sodium and bendazol, bendroflumethiazide, benethamine penicillin, ben tizanidine HCl; exate hydrochloride, benfurodil hemisuccinate, benidipine, 0111 nutritional agents, such as calcitriol, carotenes, benorylate, bentazepam, benzhexyl, benziodarone, ben dihydrotachysterol, essential fatty acids, non-essential fatty Znidazole, benzoctamine, benzodiazepine derivatives, benzo acids, phytonadiol, Vitamin A, vitamin B. Sub.2, vitamin D, diazepine, benzonatate, benzphetamine, benzylmorphine, vitamin E and vitamin K; beperiden, bephenium hydroxynaphthoate, bepridil, betahis 0112 opioid analgesics, such as codeine, dextropro tine, betamethasone, betaxolol, bevantolol, bevonium methyl poxyphene, diamorphine, dihydrocodeine, fentanyl. sulfate, bexarotene, bezadoxifine, bezafibrate, bialamicol, meptazinol, methadone, morphine, nalbuphine and pentaZo biapenem, bicalutamide, bietamiverine, bifonazole, bineda cine; line, binifibrate, biricodar, bisacodyl, bisantrene, bisoprolol, 0113 sex hormones, such as clomiphene citrate, cortisone bitolterol, bopindolol, boswellic acid, bradykinin, bretylium, acetate, danazol, dehydroepiandrosterone, ethynyl estradiol. bromazepam, bromocriptine, bromperidol, brotizolam, finasteride, fludrocortisone, fluoxymesterone, medroX brovincamine, buciclate, bucloxic acid, bucumolol, budrala yprogesterone acetate, megestrol acetate, mestranol, methylt Zine, buieniode, bufetolol, buflomedil, bufuralol, bumet estosterone, norethisterone, norgestrel, oestradiol, conju anide, bunitrolol, bupranolol, buprenorphine, buproprion, gated estrogens, buspirone, buSulfan, butalamine, butarphenol, butaverine, 0114 progesterone, rimexolone, stanozolol, Stilbestrol, butenafine, butenatime, butidrine hydrochloride, butobarbi testosterone and tibolone; tone, butoconazole nitrate, butoconazole, butofilol, butorphe 0115 stimulants, such as amphetamine, dexamphetamine, nol, butropium bromide, cabergoline, calcifediol, calcipot dexfenfluramine, fenfluramine and mazindol; riene, calcitriol, caldibine, cambendazole, camioxirole, 0116 drugs for rheumatoid arthritis such as methotrexate, camo.stat, camposterol, camptothecin, candesartan, candox auranofin, aurothioglucose and gold sodium thiomalate; atril, capecitabine, caprate, capsaicin, captopril, carazolol. 0117 drugs for osteoporosis such as alendronate and ral carbacephems, carbamates, carbameZepine, carbapenems, oxifene; carbarSone, carbatrol, carbenoXolone, carbimazole, carbro 0118 local anesthetics; mal, carbuterol, carisoprodol, carotenes, caroverine, car 0119 anti-herpes drugs such as acyclovir, Valacyclovir teolol, carvedilol, cefaclor, cefazolin, cefbuperazone, and famcyclovir, cefepime, cefoselis, ceftibuten, celcoxib, celecoxib, celip 0120 anti-emetics Such as ondansetron and granisetron; rolol, cephaeline, cephalosporin C, cephalosporins, cepha 0121 Further examples of other active agents which may mycins, cerivastatin, certoparin, cetamolol, cetiedil, cetiriz be suitable for this invention include, without limitation:abe ine, cetraxate, chloracizine, chlorambucil, chlorbetamide, carnil, acamprostate, acavir, acebutolol, aceclofenac, acem chlordantoin, chlordiazepoxide, chlormadinone acetate, etacin, acetaminophen, acetaminosalol, acetanilide, aceto chlormethiazole, chloroquine, chlorothiazide, chlorphe hexamide, acetophenazine maleate, acetophenazine, niramine, chlorphenoxamide, chlorphentermine, chlor acetoxolone, acetoxypregnenolone, acetretin, acrisorcin, proguanil, chlorpromazine, chlorpropamide, chlorprothix acrivastine, acyclovir, adinazolam, adiphenine hydrochlo ene, chlortetracycline, chlorthalidone, cholecalciferol, ride, adrafinil, adrenolone, agatroban, ahnitrine, akatinol, ala chromonar, ciclesonide, ciclonicate, cidofivir, ciglitaZone, trofloxacin, albendazole, albuterol, aldioxa, alendronate, cilansetron, ciloStaZol, cimetidine, cimetropium bromide, alfentanil, alibendol, alitretinoin, allopurinol, allylamines, cinepazet maleate, cinnamedrine, cinnarizine, cinolazepam, allylestrenol, alminoprofen, almotriptan, alosetron, aloX cinoxacin, ciprofibrate, ciprofloxacin, cisapride, cisplatin, iprin, alprazolam, alprenolol, amantadine, ambucetamide, citalopram, citicoline, clarithromycin, clebopride, clemas amidephrine, amidinomycin, amiloride, aminoarylcarboxy tine, clenbuterol, clidanac, clinofibrate, clioquinol, clobazam, lic acid derivatives, aminoglutethimide, aminoglycosides, clobenfurol, clobenzorex, clofazimine, clofibrate, clofibric aminopentamide, aminopromazine, aminorex, amiodarone, acid, cloforex, clomipramine, clonazepam, clonidine, cloni amiphenazole, amiprilose, amisulpride, amitriptyline, trate, clopidogrel, clopirac indomethacin, cloranolol, cloric amlexanoX, amlodipine, amodiaquine, amoSulalol, amotriph romen, clorprenaline, clortermine, clotiazepam,: clotrima ene, amoxapine, amoxicillin, amphecloral, amphetamine, Zole, cloxacillin, clozapine, cmepazide, codeine methyl amphomycin, amphotericin, amplicillin, ampiroxicam, bromide, codeine phosphate, codeine Sulfate, codeine, colloi amprenavir, amrinone, amsacrine, amyl nitrate, amylobarbi dal bismuth Subcitrate, cromafiban, cromolyn, cropropamide, tone, anagestone acetate, anastrozole, andinocillin, andros crotethamide, curcumin, cyclandelate, cyclarbamate, cycla tenediol, androstenediol-17-acetate, androstenediol-17-ben Zocine, cyclexedrine, cyclizine, cyclobenzaprine, cyclodrine, Zoate, androstenediol-3-acetate, androstenediol-3-acetate cyclonium iodide, cyclopentamine, cyclosporin, cypionate, 17-benzoate, androstenedione, androsterone acetate, cyproheptadine, cyproterone acetate, cytarabine, dacarba androsterone benzoate, androsterone propionate, androster Zine, dalfopristine, dantrolene sodium, dapiprazole, dar one, angiotensin, anidulatungin, aniracetam, apaZone, apicy odipine, decanoate, decitabine, decoquinate, dehydroemet cline, apoatropine, apomorphine, apraclonidine, aprepitant, ine, delavirdine, delaviridine, demeclo cycline, denopamine, aprotinin, arbaprostil, ardeparin, aripiprazole, amikacin, aro deramciclone, descitalopram, desipramine, desloratadine, tinolol, arstiinol, arylacetic acid derivatives, arylalkylamines, 3-ketodesogeskel, desomorphine, desoxymethasone, deto arylbutyric acid derivatives, arylcarboxylic acids, arylpipera midine, dexamphetamine, dexanabinol, dexchlorphe Zines, arylpropionic acid derivatives, aspirin, astemizole, niramine, dexfenfluramine, dexmethylphenidate, dexraZOX atenolol, atomoxetine, atorvastatin, atovaquone, atropine, ane, dextroamphetamine Sulfate, dextroamphetamine, auranofin, azapropaZone, azathioprine, azelastine, azetazola dextropropoxyphene, DHEA, diacetate, diamorphine, diaz US 2009/0215844 A1 Aug. 27, 2009 emine, diazepam, diaziquinone, diaZoxide, dibromopropami hydroxymethylprogesterone, hydroxyprogesterone acetate, dine, dichlorophen, diclofenac, dicoumarol, didanosine, hydroxyprogesterone caproate, hydroxyprogesterone, hyme dideoxyadenosine, diethylpropion, difemerine, difenami cromone, hyoscyamine, ibopamine, ibudilast, ibutenac, ibu Zole, diflunisal, digitoxin, digoxin, dihidroergotamine, dihy profen, ibutilide, idoxuridine, ifenprodil, igmesine, iloprost, drocodeine, diLydrocodeinone enol acetate, dihydroergota imatinib, imidapril, imidazoles, imipenem, imipramine, imo mine mesylate, dihydroergotamine, dihydrogesterone, lamine, incadronic acid pergolide, indanazoline, indenolol. dihydromorphine, dihydropyridine derivatives, dihydrostrep indinavir, indomethacin, indoramin, inosinepranobex, inosi tomycin, dihydrotachysterol, dihydroxyaluminum acetylsali tol niacinate, iodoquinol, ipidracine, iproniazid, irbesartan, cylate, diiodohydroxyquinoline, diisopromine, dilaZep, dil irinotecan, irsogladine, isobutyrate, isocaprate esters, isoet evalol, dilitaZem, diloxanide furoate, diloxanide, diltiazem, harine, isometheptene, isoproterenol, isosorbide dinitrate, dimefline, dimenhydrinate, dimethisterone, dimetotrine, isosorbide mononitrate, isosorbide dinitrate, isoxSuprine, dimorpholamine, dinitolmide, dioxaphetyl butyrate, diox isradipine, itasetron, itraconazole, itramintosylate, ivermec ethedrine, diphemethoxidine, diphenhydramine, diphenoxy tin, kallidin, kallikrein, kanamycin, ketamine, ketoconazole, late, diphetarSone, diplivefrin, diponium bromide, dipy ketoprofen, ketorolac, ketotifen, labetalol, lafutidine, lami ridamole, dirithromycin, disopyramide, divalproex sodium, fiban, lamivudine, lamotrigine, lanatoside c. lanSoprazole, dofetilide, domperidone, doneZepil, dopexamine, dopradil, lasofoxifene, leflunomide, leminoprazole, lercanadipine, doSmalfate, doxapram, doxazosin, doxefazepam, doxepin, lesopitron, letrozole, leucovorin, levalbuterol, levallorphan, doxycycline, drofenine, dromostanolone propionate, dromo levetiracetam, levetriacetam, levobunolol, levodopa, levof stanolone, dronabinol, droperidol, droprenilamine, d-threo loxacin, levophacetoperane, levorphanol, lidocaine, lidofla methylphenidate, duloxetine, ebrotidine, eburnamonine, eca zine, lifibrol, limaprost, linezolid, lintitript, liranaftate, lisi bet, ecenofloxacin, econazole nitrate, edavarone, edoxudine, nopril, lisuride, lobeline, lobucavir, lodoxamide, efavirenz, effivarenZ, efloxate, eledoisin, eletriptan, elgo lomefloxacin, lomerizine, lomustine, loperamide, lopinavir, dipine, ellipticine, emepronium bromide, emetine, enalapril, loprazolam, loracarbef, loratadine, lorazepam, lorefloxacin, enanthate, encainide, enlopitat, enoXimone, emprostil, enta lormetazepam, losartan, lovasatain, lovastatin, loxapine Suc capone, epanolol, ephedrine, epinastine, epinephrine, epiru cinate, loxapine, 1-threo methylphenidate, lumiracoxib, bicin, epleronone, eposartan, ergocalciferol, ergoloid mesy lysine acetylsalicylate, lysozyme, lysuride, mabuterol, lates, ergotamine, ertapenum, erythromycin, erytlirityl mafenide, magnesium acetylsalicylate, malgramostin, man tetranitrate, esaprazole, escitalopram, esmolol, esomepra nitol hexanitrate, maprotiline, mazindol, mebendazole, Zole, esonarimod, estazolam, estradiol benzoate, estramus meclizine, meclofenamic acid, mecloxaminepentapiperide, tine, eskiol Succinate, estrone acetate, estrone Sulfate, medazepam.: medibazine, medigoxin, medrogestone, etafedrine, etafenone, ethacrynic acid, ethamivan, ethi medroxyprogesterone acetate, mefenamic acid, mefenorex, namate, ethinyleskadiol 3-acetate, ethinyleskadiol 3-ben mefloquin, mefloquine, megestrol acetate, melengestrol Zoate, ethinylestradiol, ethionamide, ethisterone (17a-ethi acetate, melphalan, mematine, mepenZolate bromide, mep nyltestosterone), ethopropazine, ethotoin, ethoxyphenamine, eridine, mephenoxalone, mephentermine, mepindolol. ethylestrenol, ethylmorphine, ethylnorepinephrine, ethyno mepixanox, meprobamate, meptazinol, mercaptopurine, diol diacetate, etodolac, etofibrate, etoposide, etoricoxib, merropenum, mesalamine, mesalazine, mesoridazine besy etretinate, everolimus, exalamide, examestane, examorelin, late, mesoridazine, metaclazepam, metamfepramone, eZemitibe, falecalcitriol, famciclovir, famotidine, fantofar metampicillin, metaproterenol, metaraminol, methacycline, one, farapenum, fargilitazar, fasudil, felbamate, felodipine, methadone hydrochloride, methadone, methamphetamine, femalamide, fenbuLen, fenbutrazate, fendiline, fenfluramine, methaqualone, methamphetamine, methoin, methotrexate, fenoldopam, fenoprofen, fenoterol, fenoverine, fenoxazo methoxamine, methSuximide, methylhexaneamine, meth line, fenoxedil, fenpiprane, fenproporex, fenspiride, fentanyl. ylphenidate d-threo-methylphenidate, methylphenidate, fexofenadine, flavoxate, flecainide, flopropione, floredil, methylphenobarbitone, methylprednisolone, methysergide, floxuridine, fluconazole, flucytosine, fludarabine, fludiazo metiazinic acid, metizoline, metoclopramide, metolaZone, pam, fludrocortisone, flulenamic acid, flunanisone, flunariz metoprolol, metoxalone, metripranolol, metronidazole, ine, flunisolide, flunitrazepam, fluocortolone, fluoxetine, flu mexiletine, mexilitene, metaxalone, mianserin, mibefradil, penthixol decanoate, fluiphenazine decanoate, fluiphenazine miconazole, midazolam, midodrine, miglitol, milnacipran, enanthate, fluphenazine, fluproduaZone, flurazepam, flurbi milrinone, minoxidil, mirtazapine, misoprostol, mitomycin, profen, fluorogestone acetate, fluticasone propionate, fluvas mitotane, mitoxantrone, mizolastine, modafinil, mofebuta tatin, fluvoxamine, fominoben, formoterol, foScarnet, foscar Zone, mofetil, molindone hydrochloride, molindone, molsi net, fosinopril, fosphenyloin, frovatirptan, fudosteine, domine, monatepil, montelukast, monteplase, moprolol. fumagillin, furazolidone, furazolidone, furfurylmethyl moricizine, morphine hydrochloride, morphine Sulfate, mor amphetamine, furosemide, gabapentin, gabexate, gaboxadol, phine, morpholine Salicylate, mosapramine, moxifloxacin, galanthamine, gallopamil, gammaparin, gaincyclovir, gan moxisylvyte, moxonidine, mycophenolate, nabumetone, glefene, gefarnate, gemcitabine, gemfibrozil, gepirone, ges nadolol, nadoxolol, nadroparin, nafamo.stat, nafronyl, nafto tadene, ghrelin, glatiramer, glaucarubin, glibenclamide, gli pidil, nalbuphine, nalidixic acid, nalmefene, nalorphine, clazide, glimepiride, glipizide, gluconic acid, glutamicacid, naloxone, naltrexone, nandrolone benzoate, nandrolone glyburide, glyceryl trinitrate, glymepiride, granisetron, gre cyclohexanecarboxylate, nandrolone cyclohexane-propi pafloxacin, griseofulvin, guaiaZulene, guanabenz, guanfa onate, nandrolone decanoate, nandrolone furylpropionate, cine, halofankine, haloperidol decanoate, haloperidol, halox nandrolone phenpropionate, naphazoline, naproxen, aZolam, hepronicate, heptanoate, hexobendine, naratriptan, natamycin, nateglinide, nebivalol, nedocromil. hexoprenaline, hydramitrazine, hydrazides, hydro chlorothi nefazodone, nefopam, nelfinavir, nemonapride, neomycin azide, hydrocodone, hydrocortisone, hydromorphone, undecylenate, neomycin, neokofin, nesiritide, n-ethylam hydroxyamphetamine, hydroxymethylprogesterone acetate, phetamine, nevibulol, nevirapine, nexopamil, nicametate, US 2009/0215844 A1 Aug. 27, 2009 13 nicardipine, nicergoline, nicofibrate, nicofuranose, nicomor coxib, rohypnol, rolipram, romoxipride, ronifibrate, ropin phine, nicorandil, nicotinyl alcohol, nicoumalone, nifedipine, irole, ropivacaine, rosaprostol, rosiglitaZone, rosuvastatin, nifenalol, nikethamide, nilutamide, nilvadipine, nimodipine, rotinolol, rotraxate, roXatidine acetate, roXindole, rubitecan, nimorazole, nipradillol, nisoldipine, nitisonone, nitrazepam, salacetamide, salicin, salicylamide, salicylic acid derivatives, nitrofurantoin, nitrofuraZone, nitroglycerin, nizatidine, salmeterol, saquinavir, saquinavir, Scopolamine, secnidazole, norastemizole, norepinephrine, norethynodrel, norfenefrine, Selegiline, Semotiadil, sertindole, Sertraline, Sibutramine, norfloxacin, norgestimate, norgeskel, norgestrienone, sildenafil. SimBibrate, simvastatin, siramesine, Sirolimus, normethadone, normethisterone, normorphine, norpseu sitaxsentan, Sofalcone. Somotiadil, Sorivudine, Sotalol, Soter doophedrine, nortriptyline, novantrone, nylidrin, nystatin, enol, sparfloxacin, spasmolytol, spectinomycin, spiramycin, octamylamine, octodrine, octopamine, ofloxacin, olanzap spizofurone, stavudine, Streptomycin, Succinylsulfathiazole, Sucralfate, Sufentanil, Sulconazole nitrate, Sulfacetamide, Sul ine, olanzapine, olapatadine, olmesartan, olopatidine, olsala fadiazine, Sulfaloxicacid, Sulfarside, Sulfmalol, Sulindac, Zine, omapatrilat, omeprazole, ondasetron, opium, oprevel Suloctidil, Sulphabenzamide, Sulphacetamide, Sulphadiazine, kin, orlistat, ornidazole, ornoprostil, oseltamivir, oxaliplatin, Sulphadoxine, Sulphafurazole, Sulphamerazine, Sulpha oxamniquine, Oxandrolone, Oxantel embonate, oxaprozin, methoxazole, Sulphapyridine, SulphaSalazine, Sulphinpyra oXatomide pemirolast, oxatomide, oxazopam, oXcarba Zone, Sulpiride, Sulthiame, Sultopride, Sulbroponium, Zepine, Oxfendazole, oxiconazole, oxiracetam, oxolinicacid, Sumanirole, Sumahriptan, Sunepihon, Superoxide dismutase, oXprenol, oxycodone, oxyfedrine, oxymetazoline, oxymor Suplatast, Suramin Sodium, Synephrine, tacrine, tacrolimus, phone, oxyphenbutaZone, oxyphencyclimine, oxyprenolol. tacrolimus, tadalafil, talinolol, talipexole, tamoxifen, tamsu oZagrel, paclitaxel, palonosetron, pantoprazole, papaverine, losin, targretin, taZanolast, tazarotene, taZobactum, tecastim paracalcitol, paramethadione, parecoxib, pariprazole, paro eZole, teclozan, tedisamil, tegaserod, telenzepine, telmisar momycin, paroxetine, parsalmide, paZinaclone, pemoline, tan, temazepam, teniposide, teprenone, teraZosin, penbutolol, penciclovir, penicillin G benzathine, penicillin G terbenafine, terbinafine, terbutaline sulfate, terbutaline, ter procaine, penicillin V, penicillins, pentaerythritol tetrani conazole, terfenadine, terodiline, terofenamate, tertatolol. trate.: pentaerythritol tetranitrate, pentapiperide, pentazo testolactone, 4-dihydrotestosterone, tetracyclics, tetracy cine, pentifylline, pentigetide, pentobarbitone, pentorex, pen cline, tetrahydrocannabinol, tehrahydrozoline, thalidomide, toxifylline, pentrinitrol, perbuterol, perenzepine, pergolide, theofibrate, thiabendazole, thiazinecarboxamides, thiocar perhexyline, perindopril erbumine, perospone, perphenazine bamates, thiocarbamizine, thiocarbarSone, thioridazine, thio pimozide, perphenazine, phanquinone, phenacemide, phen thixene, tiagabine, tiamenidine, tianeptine, tiaprofenic acid, acetin, phenazopyridine, phencarbamide, phendimetrazine, tiaramide, ticlopidine, tigloidine, tilisolol, timolol, tinida phenelZine, phenindione, phenmetrazine, phenobarbitone, Zole, tinofedrine, tinzaparin, tioconazole, tipranavir, tira phenoperidine, phenothiazines, phenoxybenzamine, phen paZamine, tirofiban, tiropramide, titanicene, tiZanadine, tiza Suximide, phentermine, phentolamine, phenylsalicylate, phe nidine, tizinadine, tocainide, tolaZamide, tolaZoline, nylacetate, phenylbutaZone, phenylephrinehydrochloride, tolbutamide, tolcapone, tolciclate, tolfenamic acid, toliprolol. phenylpropanolamine hydrochloride, phenylpropanolamine tolteridine, tolterodine, tonaberstat, topiramate, topotecan, hydrochloride, phenylpropyl-methylamine, phenyloin, phlo torasemide, toremifene cibrate, toremifene, to Sufloxacin, tra roglucinol, pholedrine, physostigwine Salicylate, physostig madol, tramaZoline, trandolapril, tranilast, tranylcypromine, mine, phytonadiol, phytosterols, piapenum, picilorex, trapidil, traXanox, traZodone, tretoquinol, triacetin, triamci piclaimilast, picrotoxin, picumast, pifarnine, pilsicainide, nolone, triampterine, triamterene, triazolam, trifluoperazine pimagedine, pimeclone, pimecrolimus, pimethylline, hydrochloride, trifluoperazine, triflupromazine, trihex pimozide, pinaverium bromide, pindolol, pioglitaZone, pip yphenidyl, trimaZosin, trimebutine, trimetazidine, trimetho eracillin, piperazine estrone Sulfate, piperazine derivatives, prim, trimgestone, trimipramine, trimoprostil, trithiozine, piperilate, piracetam, pirbuterol, pirenzepine, piribedil, piri troglitaZone, trolnibrate phosphate, tromethamine, tropicam fibrate, piroxicam, pitavastatin, pizotyline, plaunotol, pola ide, trovafloxacin, troXipide, tuaminoheptane, tulobuterol, prezinc, polybenzarsol, polyestrol phosphate, practolol, pral tymazoline, tyramine, undecanoate, undecanoic acid, urinas nacasan, pramipexole, pranlukast, pravastatin, prazepam, tatin, Valacyclovir, Valdecoxib, Valerate, Valganciclovir, Val praziquantel, prazosin, pregabalin, prenalterol, prenylamine, proic acid, Valsartan, Vancomycin, Vardenafil. Venlafaxine, pridinol, pri?inium bromide, primidone, primipramine, venorelbine, Verapamil, Verapimil, Vidarabine, vigabakin, probenecid, probucol, procainamide, procarbazine, pro Vincamine, Vinpocetine, Viomycin, Vicquidil, Visnadine, Vita caterol, prochlorperazine, proguanil, pronethalol, pro mina derivatives, vitamina, Vitamin b, vitamind, Vitamine, pafenone, propamidine, propatyl nitrate, propentoffyline, Vitamin k, Voglibose, Voriconazole, Xaliproden, Xamoterol, propionate, propiram, propoxyphene, propranolol, propyl Xanthinol niacinate, Xeny tropium bromide, Xibenolol. hexedrine, propylthiouracil, protokylol, protriptyline, proX Ximelagatran, Xylometazoline, yohimbine, Zacopride, azole, pseudoephedrine, purines, pyrantel embonate, pyra Zoles, pyrazolones, pyridofylline, pyrimethamine, Zafirlukast, Zalcitabine, Zaleplon, Zanamivir, Zatebradine, pyrimidines, pyrrolidones, quazepam, quetiapine, quetu Ziconotide, Zidovudine, Zileuton, Zimeldine, Zinc propionate, apine, quinagolide, quinapril, quinestrol, quinfamide, quini Ziprasidone, Zolimidine, Zolmitriptan, Zolpidem, Zonisamide, dine, quinine Sulfate, quinolones, quinupritin, rabalzotan, Zopiclone, and mixtures thereof. rabeprazole Sodium, rabeprazole, racefimine, ramahroban, ramipril, ranitidine, ranolazine, ransoprazole, rasagiline, Formulation rebamipide, refludan, repaglinide, repinotan, repirinast, 0.122 The nebivolol compositions of the present invention reproterol, reserpine, retinoids, ribavirin, rifabutine, rifampi may be administered by various means, depending on their cin, rifapentine, rillmenidine, riluzole, rimantadine, rimiterol, intended use, as is well known in the art. For example, if rioprostil, risperidone, ritanovir, ritapentine, ritipenem, rito compositions of the present invention are to be administered drine, ritonavir, rivastigmine, rizatriptan, rociverine, rofe orally, they may be formulated as tablets, capsules, granules, US 2009/0215844 A1 Aug. 27, 2009 powders, Suspensions or syrups. Alternatively, formulations the compositions may also comprise buffering agents. Solid of the present invention may be administered parenterally as compositions of a similar type may also be employed as fillers injections (intravenous, intramuscular or Subcutaneous), drop in Soft and hard-filled gelatin capsules using Such excipients infusion preparations or Suppositories. For application by the as lactose or milk Sugars, as well as high molecular weight ophthalmic mucous membrane route, compositions of the polyethylene glycols and the like. present invention may be formulated as eyedrops or eye oint I0127. A tablet may be made by compression or molding, ments. These formulations may be prepared by conventional optionally with one or more accessory ingredients. Com means, and, if desired, the compositions may be mixed with pressed tablets may be prepared using binder (for example, any conventional additive, such as an excipient, a binder, a gelatin or hydroxypropylmethyl cellulose), lubricant, inert disintegrating agent, a lubricant, a corrigent, a solubilizing diluent, preservative, disintegrant (for example, sodium agent, a Suspension aid, an emulsifying agent or a coating starch glycolate or cross-linked sodium carboxymethyl cel agent. lulose), Surface-active or dispersing agent. Molded tablets 0123. In formulations of the subject invention, wetting may be made by molding in a Suitable machine a mixture of agents, emulsifiers and lubricants, such as Sodium lauryl Sul the Subject composition moistened with an inert liquid dilu fate and magnesium Stearate, as well as coloring agents, ent. Tablets, and other Solid dosage forms, such as dragees, release agents, coating agents, Sweetening, flavoring and per capsules, pills and granules, may optionally be scored or fuming agents, preservatives and antioxidants may be present prepared with coatings and shells, such as enteric coatings in the formulated agents. and other coatings well known in the pharmaceutical-formu 0.124 Subject compositions may be suitable for oral, lating art. nasal, topical (including buccal and Sublingual), rectal, vagi I0128 Liquid dosage forms for oral administration include nal, aerosol and/or parenteral administration. The formula pharmaceutically acceptable emulsions, microemulsions, tions may conveniently be presented in unit dosage form and Solutions, Suspensions, syrups and elixirs. In addition to the may be prepared by any methods well known in the art of Subject composition, the liquid dosage forms may contain pharmacy. The amount of composition that may be combined inert diluents commonly used in the art, Such as, for example, with a carrier material to produce a single dose vary depend water or other solvents, Solubilizing agents and emulsifiers, ing upon the Subject being treated, and the particular mode of Such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, administration. ethyl acetate, benzyl alcohol, benzyl benzoate, propylene 0.125 Methods of preparing these formulations include glycol. 1,3-butylene glycol, oils (in particular, cottonseed, the step of bringing into association compositions of the groundnut, corn, germ, olive, castor and Sesame oils), glyc present invention with the carrier and, optionally, one or more erol, tetrahydrofuryl alcohol, polyethylene glycols and fatty accessory ingredients. In general, the formulations are pre acid esters of sorbitan, and mixtures thereof. pared by uniformly and intimately bringing into association I0129 Suspensions, in addition to the subject composition, agents with liquid carriers, or finely divided solid carriers, or may contain Suspending agents such as, for example, ethoxy both, and then, if necessary, shaping the product. Formula lated isostearyl alcohols, polyoxyethylene sorbitol and sorbi tions suitable for oral administration may be in the form of tan esters, microcrystalline cellulose, aluminum metahydrox capsules, cachets, pills, tablets, lozenges (using a flavored ide, bentonite, agar-agar and tragacanth, and mixtures basis, usually Sucrose and acacia or tragacanth), powders, thereof. granules, or as a solution or a Suspension in an aqueous or 0.130 Formulations for rectal or vaginal administration non-aqueous liquid, or as an oil-in-water or water-in-oil liq may be presented as a Suppository, which may be prepared by uid emulsion, or as an elixir or syrup, or as pastilles (using an mixing a subject composition with one or more Suitable non inert base. Such as gelatin and glycerin, or Sucrose and aca irritating excipients or carriers comprising, for example, cia), each containing a predetermined amount of a subject cocoa butter, polyethylene glycol, a Suppository wax or a composition thereofas an active ingredient. Compositions of salicylate, and which is solid at room temperature, but liquid the present invention may also be administered as a bolus, at body temperature and, therefore, will melt in the body electuary, or paste. cavity and release the active agent. Formulations which are 0126. In solid dosage forms for oral administration (cap Suitable for vaginal administration also include pessaries, Sules, tablets, pills, dragees, powders, granules and the like), tampons, creams, gels, pastes, foams or spray formulations the Subject composition is mixed with one or more pharma containing Such carriers as are known in the art to be appro ceutically acceptable carriers, such as sodium citrate or dical priate. cium phosphate, and/or any of the following: (1) fillers or I0131 Dosage forms for transdermal administration of a extenders, such as starches, lactose. Sucrose, glucose, manni Subject composition includes powders, sprays, ointments, tol, and/or silicic acid; (2) binders, such as, for example, pastes, creams, lotions, gels, solutions, patches and inhalants. carboxymethylcellulose, alginates, gelatin, polyvinyl pyr The active component may be mixed understerile conditions rolidone, Sucrose and/or acacia; (3) humectants, such as glyc with a pharmaceutically acceptable carrier, and with any pre erol; (4) disintegrating agents, such as agar-agar, calcium servatives, buffers, or propellants which may be required. carbonate, potato or tapioca Starch, alginic acid, certain sili 0.132. The ointments, pastes, creams and gels may contain, cates, and Sodium carbonate; (5) solution retarding agents, in addition to a Subject composition, excipients, such as ani Such as paraffin; (6) absorption accelerators, such as quater mal and vegetable fats, oils, waxes, paraffins, starch, traga nary ammonium compounds; (7) wetting agents, such as, for canth, cellulose derivatives, polyethylene glycols, silicones, example, acetyl alcohol and glycerol monostearate; (8) absor bentonites, silicic acid, talc and Zinc oxide, or mixtures bents, such as kaolin and bentonite clay; (9) lubricants, such thereof. a talc, calcium Stearate, magnesium Stearate, Solid polyethyl 0.133 Powders and sprays may contain, in addition to a ene glycols, sodium lauryl Sulfate, and mixtures thereof, and Subject composition, excipients such as lactose, talc, silicic (10) coloring agents. In the case of capsules, tablets and pills, acid, aluminum hydroxide, calcium silicates and polyamide US 2009/0215844 A1 Aug. 27, 2009

powder, or mixtures of these Substances. Sprays may addi 0142. An effective dose or amount, and any possible tionally contain customary propellants, such as chlorofluoro affects on the timing of administration of the formulation, hydrocarbons and volatile unsubstituted hydrocarbons, such may need to be identified for any particular composition of as butane and propane. the present invention. This may be accomplished by routine 0134 Compositions of the present invention may alterna experiment as described herein, using one or more groups of tively be administered by aerosol. This is accomplished by animals (preferably at least 5 animals per group), or in human preparing an aqueous aerosol, liposomal preparation or Solid trials if appropriate. The effectiveness of any Subject compo particles containing the compound(s). A non-aqueous (e.g., sition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of fluorocarbon propellant) Suspension could be used. Sonic the administration by measuring one or more applicable indi nebulizers may be used because they minimize exposing the ces, and comparing the post-treatment values of these indices agent to shear, which may result in degradation of the com to the values of the same indices prior to treatment. pounds contained in the Subject compositions. 0143. The precise time of administration and amount of 0135) Ordinarily, an aqueous aerosol is made by formulat any particular subject composition that will yield the most ing an aqueous Solution or Suspension of a Subject composi effective treatment in a given patient will depend upon the tion together with conventional pharmaceutically acceptable activity, pharmacokinetics, and bioavailability of a subject carriers and stabilizers. The carriers and stabilizers vary with composition, physiological condition of the patient (includ the requirements of the particular subject composition, but ing age, sex, disease type and stage, general physical condi typically include non-ionic Surfactants (Tweens, Pluronics, or tion, responsiveness to a given dosage and type of medica polyethylene glycol), innocuous proteins like serum albumin, tion), route of administration, and the like. The guidelines Sorbitan esters, oleic acid, lecithin, amino acids such as gly presented herein may be used to optimize the treatment, e.g., cine, buffers, salts, Sugars or Sugar alcohols. Aerosols gener determining the optimum time and/or amount of administra ally are prepared from isotonic Solutions. tion, which will require no more than routine experimentation 0.136 Pharmaceutical compositions of this invention suit consisting of monitoring the Subject and adjusting the dosage able for parenteral administration comprise a Subject compo and/or timing. sition in combination with one or more pharmaceutically 0144. While the subject is being treated, the health of the acceptable sterile isotonic aqueous or non-aqueous Solutions, patient may be monitored by measuring one or more of the dispersions, Suspensions or emulsions, or sterile powders relevant indices at predetermined times during the treatment which may be reconstituted into sterile injectable solutions or period. Treatment, including composition, amounts, times of dispersions just prior to use, which may contain antioxidants, administration and formulation, may be optimized according buffers, bacteriostats, solutes which render the formulation to the results of Such monitoring. The patient may be periodi isotonic with the blood of the intended recipient or suspend cally reevaluated to determine the extent of improvement by ing or thickening agents. measuring the same parameters. Adjustments to the amount 0137 Examples of Suitable aqueous and non-aqueous car (s) of Subject composition administered and possibly to the riers which may be employed in the pharmaceutical compo time of administration may be made based on these reevalu sitions of the invention include water, ethanol, polyols (Such ations. as glycerol, propylene glycol, polyethylene glycol, and the 0145 Treatment may be initiated with smaller dosages like), and Suitable mixtures thereof, vegetable oils, such as which are less than the optimum dose of the compound. olive oil, and injectable organic esters, such as ethyl oleate. Thereafter, the dosage may be increased by Small increments Proper fluidity may be maintained, for example, by the use of until the optimum therapeutic effect is attained. coating materials, such as lecithin, by the maintenance of the 0146 The use of the subject compositions may reduce the required particle size in the case of dispersions, and by the use required dosage for any individual agent contained in the of Surfactants. compositions (e.g., the steroidal anti inflammatory drug) 0138 Pharmaceutical formulations may also be extended because the onset and duration of effect of the different agents or delayed release formulations where the active agents are may be complimentary. released over an extended period of time. 0147 Toxicity and therapeutic efficacy of subject compo sitions may be determined by standard pharmaceutical pro Dosages cedures in cell cultures or experimental animals, e.g., for determining the LDs and the EDso. 0139 Administration of the compositions of the present 0.148. The data obtained from the cell culture assays and invention will be in an amount sufficient to achieve a thera animal studies may be used in formulating a range of dosage peutic effect as recognized by one of ordinary skill in the art. for use in humans. The dosage of any Subject composition lies 0140. The dosage of any compositions of the present preferably within a range of circulating concentrations that invention will vary depending on the symptoms, age and body include the EDs with little or no toxicity. The dosage may weight of the patient, the nature and severity of the disorder to vary within this range depending upon the dosage form be treated or prevented, the route of administration, and the employed and the route of administration utilized. For com form of the subject composition. Any of the subject formula positions of the present invention, the therapeutically effec tions may be administered in a single dose or individed doses. tive dose may be estimated initially from cell culture assays. Dosages for the compositions of the present invention may be 0149. In general, the doses of an active agent will be cho readily determined by techniques known to those of skill in sen by a physician based on the age, physical condition, the art or as taught herein. weight and other factors known in the medical arts. 0141. In certain embodiments, the dosage of the subject compounds will generally be in the range of about 0.01 ng to Efficacy of Treatment about 10 g per kg body weight, specifically in the range of 0150. The efficacy of treatment with the subject composi about 1 ng to about 0.1 g per kg, and more specifically in the tions may be determined in a number of fashions known to range of about 100 ng to about 10 mg per kg. those of skill in the art. US 2009/0215844 A1 Aug. 27, 2009

0151. In one exemplary method, the median rate of growth supplement (ECGS)+10% fetal bovine serum. The decrease in inflammation for treatment with a subject com HUVEC cells were kept in an atmosphere of elevated CO2 position may be compared to other forms of treatment with concentration (5%). Nebivolol was obtained from Mylan the particular cardiovascular agent contained in the Subject Laboratories (Morgantown, W.Va.). composition, or with other cardiovascular agents. The decrease in inflammation for treatment with a subject com 0156 All measurements of endothelial NO release were position as compared to treatment with another method may conducted in Hank's balance solution at 37° C. Cell wells be 10, 25, 50, 75, 100, 150, 200, 300, 400% greater or even were transferred to a Faraday cage and a porphyrinic sensor more. The period of time for observing any Such decrease (diameter 0.5 mm) was positioned at a distance of 5-t2 um may be about 1, 3, 5, 10, 15, 30, 60 or 90 or more hours. The from the surface of the endothelial cells using an inverted comparison may be made against treatment with the particu microscope (Leica Microsystems, Wetzlar, Germany) and a lar cardiovascular agent contained in the Subject composition, computer-assisted micromanipulator. The sensor operated or with other cardiovascular agents, or administration of the with a three-electrode system: nanosensor (working elec same or different agents by a different method, or adminis trode), saturated calomel electrode (reference electrode) and tration as part of a different drug delivery device thana subject platinum wire (counter electrode, 0.5 mm diameter). The composition. The comparison may be made against the same three electrodes were connected to a potentiostat/galvanostat or a different effective dosage of the various agents. PAR273. The baseline was stabilized after about 20 seconds. 0152 Alternatively, a comparison of the different treat The test compounds were injected with a nanoinjector onto ment regimens described above may be based on the effec the surface of the cells following solubilization in buffer. tiveness of the treatment, using standard indices known to Cells were incubated with the test compounds for a 24-hour those of skill in the art. One method of treatment may be 10%, period. The compounds were then washed out of the system 20%, 30%, 50%, 75%, 100%, 150%, 200%, 300% more before being immediately reintroduced in order to evaluate effective, than another method. the consequences of chronic treatment on NO release from 0153. Alternatively, the different treatment regimens may the cells. For additive experiments, cells were incubated with be analyzed by comparing the therapeutic index for each of ACE inhibitor for 24 hours, the inhibitor was washed out of them, with treatment with a Subject composition as compared the system, nebivolol was added and the NO release mea to another regimen having atherapeutic index two, three, five sured. The current proportional to the NO concentration was or seven times that of, or even one, two, three or more orders measured with the sensor, which operated in amperometric of magnitude greater than, treatment with another method mode at a constant potential of 0.63V. Data were acquired using the same or different cardiovascular agents. with the use of an IBM computer with custom software and amperograms (current vs. time curves) were recorded with a Kits Guniry FAS 1 Femtostat (Warminster, Pa.). Maximum release of NO was produced using a calcium agonist (1 LM). By 0154) This invention also provides kits for conveniently increasing cytoplasmic levels of calcium, the ion can bind to and effectively implementing the methods of this invention. calmodulin. The Ca2+-calmodulin complex is a cofactor for Such kits comprise any subject composition, and a means for endothelial NO synthase, along with FAD, FMN, Heme and facilitating compliance with methods of this invention. Such BH4. kits provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the 0157 Nanosensors were prepared from carbon fibers. The correct dosage in the correct manner. The compliance means size of the tip of carbon fiber was reduced from 6 um to less of such kits includes any means which facilitates administer thanum by temperature controlled burning. The sensors were ing the actives according to a method of this invention. Such sensitized to NO by deposition of electrically conductive compliance means include instructions, packaging, and dis polymeric porphyrin and covered with a thin layer of Nafion. pensing means, and combinations thereof. Kit components The porphyrinic microsensor has a response time of 0.1 ms at may be packaged for either manual or partially or wholly a micromolar NO concentration and 10 ms at the detection automated practice of the foregoing methods. In other limit of 1 nM. embodiments involving kits, this invention contemplates a kit 0158. The nanosensor for NO was calibrated using satu including compositions of the present invention, and option rated solution (concentration 1.82 mM verified with the cou ally instructions for their use. lometric method). Linear calibration curves were constructed for each sensor from 5x10-9 to 3x10MNObefore and after EXEMPLIFICATION measurements of cell activity. The concentration-dependent effects of nebivolol and certain ACE-inhibitors on NO releas Example 1 ing capacity were tested using a calcium ionophore (A23 187) that stimulates NO release, independently of G-protein Measurements of NO Release from Human Endothe coupled receptors. The data were presented as the lium meant-SEM for each of the triplicate measurements. The data 0155 All measurements presented were recorded in vitro (calculation and plotting) were transferred to Microcal Origin using a sensitive porphyrinic probe, as previously described. Software (OriginLab Corp., Northampton, Mass.). Malinski T, Taha Z., Nature. 1992: 358:676-678; Malinski T, 0159. The HUVEC preparation is stable over the course of Czuchajowski L., Methods in Nitric Oxide Research. 1996: these experiments with the cells remaining viable in culture 319-339. NO release was measured directly from HUVEC. for >24 hours. Under non-stimulating conditions, basal levels HUVEC cells from Black and White donors were grown in of NO release are very low (<30 nM). Measurement of NO Ham's F12K medium with 2 mM L-glutamine adjusted to release as a function of treatment was conducted in individual contain 1.5 g/L Sodium bicarbonate and Supplemented with endothelial cells. Multiple measurements of NO release can 0.1 mg/ml heparin and 0.03-0.05 mg/ml endothelial cell be conducted on single cells following a brief refractory US 2009/0215844 A1 Aug. 27, 2009

period. For robust statistical analysis, separate cells were used 1-36. (canceled) for each concentration and type of drug used in these analy 37. A composition comprising nebivolol or a pharmaceu SCS. tically acceptable salt thereof, and Valsartan or a pharmaceu (0160. In FIG. 1, the extent of NO release from Black and tically acceptable salt thereof. White donors was measured after chronic treatment with the 38. The composition of claim 37, wherein the nebivolol or ACE inhibitor, ramiprilat, followed by treatment with nebiv pharmaceutically acceptable salt thereof, and Valsartan or pharmaceutically acceptable salt thereof, form a single oral olol (1 uM). At concentrations of 1, 5, and 10 uM ramiprilat, dosage form. there were modest but significant effects in the ability of 39. A method of treating or preventing hypertension in a nebivolol to increase NO release from Black and White donor patient in need thereof, comprising administering to said endothelial cells. The magnitude of the increase is greater in patient an effective amount of nebivolol or a pharmaceuti endothelial cells from Black donors. cally acceptable salt thereof, and Valsartan or a pharmaceuti (0161. In FIG. 3, the extent of NO release from Black and cally acceptable salt thereof. White donors was measured with nebivolol (1 uM) following 40. The method of claim 39, wherein the nebivolol or chronic treatment with the ACE-inhibitor, enalapril. As pharmaceutically acceptable salt thereof, and Valsartan or observed with ramiprilat (above), enalapril significantly pharmaceutically acceptable salt thereof, are orally adminis enhanced the ability of nebivolol to increase NO release at tered. concentrations of 5 and 10 uM and 1, 5 and 10 uM in Black 41. The method of claim 39, wherein the nebivolol or and White donor cells, respectively. The magnitude of the pharmaceutically acceptable salt thereof, and Valsartan or increase is greater in endothelial cells from Blacks than pharmaceutically acceptable salt thereof, are orally adminis Whites (FIG. 4). tered in a single dosage form. 0162 There were significant concentration dependent 42. The method of claim 39, wherein the nebivolol or effects on the ability of nebivolol to enhance NO release from pharmaceutically acceptable salt thereof, and Valsartan or Black and White donor endothelial cells that had been chroni pharmaceutically acceptable salt thereof, are orally adminis cally treated with ACE inhibitors. Additionally, this property tered in separate dosage forms. of the drug appears to work independently off 1-adrenocep 43. A method of treating or preventing cardiovascular dis tor blockade. By promoting a more normal vascular physiol ease in a patient in need thereof, comprising administering to ogy through an NO-dependent pathway, nebivolol treatment said patient an effective amount of nebivolol or a pharmaceu may have better efficacy and fewer side effects as compared to tically acceptable salt thereof, and Valsartan or a pharmaceu agents that only inhibit the sympathetic nervous system. tically acceptable salt thereof. These data further support the hypothesis that nebivolol may 44. The method of claim 43, wherein the nebivolol or have distinct pharmacologic benefits through modulation of pharmaceutically acceptable salt thereof, and Valsartan or endothelial function and NO metabolism. pharmaceutically acceptable salt thereof, are orally adminis tered. INCORPORATION BY REFERENCE 45. The method of claim 43, wherein the nebivolol or 0163 All of the patents and publications cited herein are pharmaceutically acceptable salt thereof, and Valsartan or hereby incorporated by reference. pharmaceutically acceptable salt thereof, are orally adminis tered in a single dosage form. EQUIVALENTS 46. The method of claim 43, wherein the wherein the nebivolol or pharmaceutically acceptable salt thereof, and 0164. Those skilled in the art will recognize, or be able to Valsartan or pharmaceutically acceptable salt thereof, are ascertain using no more than routine experimentation, many orally administered in separate dosage forms. equivalents to the specific embodiments of the invention described herein. c c c c c