FIELD OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising at least one endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor in combination with at least one another active agent optionally with other pharmaceuticalty acceptable excipients useful rn the prophylaxis, treatment and/or amelioration of cardiovascular and other associated disorders such as one or more of coronary artery disease, congestive heart failure, angina, atherosclerosis, hyperlipidemia, diabetes, neurodegenerative disorders or the like The present invention also describes process for preparation of such compositions and method of using such compositions for the prophylaxis, treatment and/or amelioration of cardiovascular and other associated disorders in a subject which comprises the administration of an effective amount of such composition in need thereof
BACKGROUND OF THE INVENTION
Cardiovascular disorders such as Coronary artery disease (CAD) and Congestive heart failure (CHF) are the leading cause of mortality in the developed world, and are associated with substantial morbidity as well Coronary heart disease is a multifactorial disease in which the incidence and severity are affected by the lipid profile, the presence of diabetes and the sex of the subject Typically, the patient with CAD has several concomitant conditions, including hypertension diabetes, and hyperlipidemia, increasing overall risk for poor outcomes and complicating treatment A therapeutic goal for the treatment of such patients is the development of pharmaceutical compositions that can simultaneously target multiple underlying disease processes
Hypertension is a major risk factor for cardiovascular disease and is poorly controlled worldwide Both systolic and diastolic blood pressure (SBP/DBP) has been shown to be related to cardiovascular disease leading to morbidity and mortality Hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease ultimately resulting in adverse cardiac events This clustering of risk factors is potentially due to a common mechanism Further, patient compliance with the management of hypertension is generally better than patient compliance with hyperlipidemia It would therefore be advantageous for patients to have a single therapy which treats both of these conditions
Cardiovascular disorder such as Angina pectoris is a severe constricting pain in the chest, often radiating from the precordium to the left shoulder and down the left arm Often angina pectoris is due to ischemia of the heart and is usually caused by coronary disease The symptomatic
management of angina pectoris involves the use of a number of drugs, frequently as a combination of two or more of the following classes beta-blockers, nitrates and calcium channel blockers Most, if not all, of these patients require therapy with a lipid-lowenng agent as well
Atherosclerosis is a condition characterized by irregularly distributed lipid deposits in the intima of arteries, including coronary, carotid and peripheral arteries It has been demonstrated in animal model that in cardiovascular disorders such as atherosclerosis, the cholesterol content of membranes associated with vascular smooth muscle and macrophage foam cells becomes elevated, resulting in the formation of discrete domains which serve as nucleating sites for the formation of extracellular crystals Preventing crystal formation is an important goal as cholesterol in this state is practically inert and does not respond well to pharmacologic interventions that promote lesion regression In addition, the normal production of NO by the endothelium is critical for maintaining vascular function During atherosclerosis, however, endothelial dysfunction effects a significant reduction in NO production, resulting in increased monocyte and LDL infiltration, loss of smooth muscle cell function and abnormal proliferation, increased oxidative stress, and increased platelet aggregation Pharmacologic interventions that restore endothelial function and NO metabolism have demonstrated benefit in the treatment of various cardiovascular disorders, including coronary artery disease
Many individuals are at an elevated risk of suffering serious to life-threatening cardiovascular events, such as myocardial infarction (heart attack), cardiac arrest, congestive heart failure stroke, peripheral vascular disease and/or claudication The risk factors are numerous and widespread throughout the world population They include cigarette smoking, diabetes hypercholesterolemia (high serum cholesterol), hypertension, angina, systemic lupus erythematosus, prior heart attacks or strokes, hemodialysis, hyperhomocysteine levels, obesity sedentary lifestyle, receiving an organ transplant, atherosclerosis, and others There ts a need for a safe and convenient pharmaceutical formulation that would effectively reduce the risk of incurring a cardiovascular event in individuals who have these risk factors
Endothelm (FT) is a peptide which is composed of 21 amino acids that is synthesized and released by the vascular endothelium Endothelm is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelm (Big ET) This cleavage is caused by an endothelm converting enzyme (ECE) Endothelm exists as three isoforms, ET-1, ET-2 and ET-3 (hereinafter unless otherwise stated endothelm shall mean any or all of the isoforms of endothelm) Endothelm acts on two pharmacologically distinct subtypes of receptors, termed
ET sub A and ET sub B that are expressed on a wide variety of vascular and non-vascular target tells eliciting for example contraction and proliferation of vascular smooth muscle cells and release of nitric oxide from endothelial cells Endothelin is associated with smooth muscle contraction which is involved in the pathogenesis of, inter alia, cardiovascular, cerebrovascular, respiratory and renal pathophysiology It has been shown, among other things, to constrict arteries and veins, increase mean arterial blood pressure decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, stimulate release of atrial natriuretic factor in vitro and in vivo, increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro An agent which suppresses endothelin production, such as an ECE inhibitor or which inhibits the binding of endothelin to an endothelin receptor, such as an endothelin receptor antagonist, antagonizes various physiological effects of endothelin and produces beneficial effects in a variety of therapeutic areas Endothelin receptor antagonists and ECE inhibitors are therefore useful in treating a variety of diseases affected by endothelin A non-exhaustive list of such diseases includes chronic heart failure, myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension, ischemia-repurfusion injury atherosclerosis, coronary and systemic vasospastic disorders, cerebral vasospasm, and subarachnoid hemorrhage and the like
Neutral Endopeptidase (NEP) is a cell surface enzyme that cleaves and inactivates neuropeptides It is well established that the natriuretic peptide system is intimately involved in the control and regulation of blood pressure and plasma volume in the body In humans, this peptide family consists of atrial natriuretic peptide (ANP), brain natriuretic peptide and C-type natriuretic peptide ANP is produced in the atria and its production is stimulated by endothelin arginine vasopressin and catecholamines Atrial wall tension, which can occur as a result of intravascular volume expansion, can also stimulate ANP production The hemodynamic actions of natriuretic peptides within the cardiovascular system occur at many levels and include reducing preload and sympathetic tone, and increasing venous capacitance Natriuretic peptides can also have antimttogenic actions within the cardiovascular tree Natriuretic peptides are degraded by the metallopeptidase neutral endopeptidase enzyme (NEP) Thus NEP inhibitors primarily increase the levels of vasodilatory peptides including atrial natriuretic peptide and brain natriuretic peptide and also increase the half-life of other vasodilator peptides, including bradykimn and adrenomedullin thus enhancing vasodilation, thereby decreasing vascular tone and lowering blood pressure
SLV-306 (Daglutnl) is an orally active inhibitor of neutral endopeptidase (NEP) and endothelin conversion enzyme (ECE) It is a Benzazepme-N-acetic acid derivative which contains an oxo group in alpha position to the nitrogen atom and is substituted in position 3 by a 1-(carboxyalkyl) cyclopentyl-carbonylamino radical, and their salts and biolabile esters fall under the scope of protection of the benzazepine, benzoxazepine and benzothiazepine-N-acetic acid derivatives which contain an oxo group in the alpha position to the nitrogen atom and are substituted in position 3 by a I-(carboxyalkyl) cyclopentyl-carbonylamino radical and have NEP-inhibitory effects on the heart, as described in US patent no 5,677,297 The benzazepine-N-acetic acid compounds specifically SLV-306 used in the present invention are known from EP 0733642, EP 0830863, WO00/48601 and WOO 1/03699, and can be produced by the methods described in said US patent no 5,677,297 SLV-306 is a poorly bio-available drug due to the poor solubility in the gastric fluid Even when this drug is applied in the form of a salt and when they are dissolved in a buffer, it precipitates in the gastric fluid The precipitate formed is very difficult to solubilize again leading to a low overall bioavailability EP 0733642 is related to these compounds and their physiologically acceptable salts as such and to the use of the compound in heart insufficiency FP 0830863 WO00/48601 and WO01/03699 are related to the use of the aforementioned compounds in the improvement of gastrointestinal blood flow, in the treatment of hypertension and in the treatment and prophylaxis of cardiac damages induced by adnamycin and comparable anti-cancer drugs, respectively
PCT publication no WO2004062692 discloses a formulation with enhanced bioavailability consisting of a thermodynamically stable liquid or semisolid solution of the poorly water-soluble biologically active substance i e SLV-306 US publication no 20040186083 describes a method for the prophylaxis or treatment of a pathological condition, the method comprising administering to a subject susceptible to or afflicted with such condition an aldosterone receptor antagonist such as eplerenone and spironolactone and an endothelin receptor antagonist such as bosentan sitaxsentan, darusentan and tezosentan, further comprising administering a third amount of an ECE inhibitor such as SLV-306 US publication no 2004063719 pertains to a method for treating a vascular condition by a combination of at least two agents selected from an antipressor agent (ACE inhibitor an angiotensin-II receptor antagonist, an endothelin antagonist a non-peptidal endothelin antagonist), and an ECE inhibitor, and a sex hormone such as testosterone-1 ike compound PCT publication no WO200124827 describes the use of an endothelin blocker such as SLV-306 in combination with an integrin receptor antagonist such as abciximab for the manufacture of medicaments for the treatment or prevention of diseases PCT publication no W09635453 relates to a composition comprising an endothelin antagonist and/or
an endothelin synthase (ECE) inhibitor, in combination with at least one of a progestin, an estrogen, a cyclooxygenase inhibitor* a nitric oxide (NO) donor and/or an NO substrate
Kramsch et al, Journal of Human Hypertension (1995) Supp 1, 53-59 discloses the use of calcium channel blockers, including amlodipine, to treat atherosclerosis This reference further suggests that atherosclerosis can be treated with a combination of amlodipine and a lipid-lowenng agent Human trials have shown that calcium channel blockers have beneficial effects in the treatment of early atherosclerotic lesions (see, for example, Lichtlen et al, Retardation of angiographic progression of coronary artery disease by nifedipine, Lancet (1990), 335, 1109-13, and Waters et al, A controlled clinical trial to assess the effect of a calcium channel blocker on the progression of coronary atherosclerosis, Circulation (1990), 82, 1940-53) European Patent No 0247633 discloses that certain statins, including atorvastatm, are hypolipidaemic agents and as such are useful in treating atherosclerosis Jukema et al (Circulation (1995) Supp 1, 1-197) discloses that there is evidence that calcium channel blockers act synergistically in combination with lipid-lowermg agents, for example, HMG-CoA reductase inhibitors, specifically pravastatin Orekhov et al (Cardiovascular Drugs and Therapy (1997), 11, 350) discloses the use of amlodipine in combination with lovastatin for the treatment of atherosclerosis
Improved drug therapies for the treatment of subjects suffering from or susceptible to life-threatening cardiovascular and other associated disorders are highly desirable However still there exists a need for a patient compliant, safe and effective compositions that are useful in the management of cardiovascular and other associated disorders
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide pharmaceutical compositions comprising at least one endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor as active agent in combination with at least one another active agent optionally with one or more pharmaceutically acceptable excipients
It is an objective ot the present invention to provide pharmaceutical compositions comprising at least one endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor as active agent in combination with at least one another active agent selected from a group comprising antihypertensives such as calcium channel blockers, ACE Inhibitors, angiotensin antagonists, alpha-adrenergic receptor blockers, beta-adrenergic receptor blockers diuretics, vasodilators, antidiabetics such as biguanide, sulfonylurea or glitazone, lipid lowering
agents such as cholesterol absorption inhibitors, platelet function altering agent such as platelet aggregation inhibitors, serum homocysteine lowering agent and the like or mixtures thereof optionally with one or more pharmaceutically acceptable excipients
It is an objective of the present invention to provide pharmaceutical compositions comprising at least one endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor as active agent in combination with a lipid lowering agent such as ezetimibe, niacin, or policosanol or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof optionally with one or more pharmaceutically acceptable excipients
It is an objective of the present invention to provide pharmaceutical compositions comprising at least one endothelin conversion enzyme (ECE) inhibitor and neutral endopeptidase (NEP) inhibitor which is preferably SLV-306 or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms or mixtures thereof as active agent in combination with at least one another active agent optionally with one or more pharmaceutically acceptable excipients
It is a further objective of the present invention to provide process for the preparation of such pharmaceutical composition, which comprises optionally treating the active agent(s) with one or more pharmaceutically acceptable excipients and formulating into a suitable dosage form
It is yet another objective of the present invention to provide a method of using such composition which comprises administering to a subject in need thereof an effective amount of the composition The compositions of the present invention are useful for the prophylaxis, treatment and/or amelioration of cardiovascular and other associated disorders
It is still further objective of the present invention to provide pharmaceutical compositions useful in the prophylaxis, treatment and/or amelioration of cardiovascular and other associated disorders such as chronic heart failure coronary artery disease congestive heart failure angina atherosclerosis, hyperlipemia, diabetes, myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension, ischemia-reperfusion injury, coronary and systemic vasospastic disorders cerebral vasospasm and subarachnoid hemorrhage hyperglycemia, hyperlipemia metabolic disorders, renal disorders, neurodegenerative disorders, and the like or a combination of such disorders
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes pharmaceutical compositions comprising at least one endothehn conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor as active agent or its pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, conjugate acids, enantiomers, tautomeric forms, prodrugs or mixtures thereof in combination with at least one another active agent optionally with one or more pharmaceutically acceptable excipients
In an embodiment of the present invention, the endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor is selected from but not limited to group comprising CGS 26303, CGS 25462, phosphoramidon, candoxatnl, sinorphan, omapatnlat, FR901533, TMC-66, SM-19712, SLV-306, KC-12615, KC-90095-1-AC, CGS-26303, CGS-30440, CGS-31447, CGS-26670, Sch-54470 or pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, conjugate acids, enantiomers, tautomeric forms prodrugs or mixtures thereof In a preferred embodiment, the endothelin conversion enzyme (ECE) inhibitor and neutral endopeptidase (NEP) inhibitor is SLV-306 (also known as Daglutnl) or its pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, conjugate acids, enanttomers, tautomeric forms, prodrugs or mixtures thereof

In an embodiment, the endothelin conversion enzyme (ECE) and neutral endopeptidase (NEP) inhibitor of the present invention has the general formula (Formula-1)

(Formula Removed)

Wherein
R1 is a selected from the group consisting of (C1-C6) alkoxy (C1-C6) alkyl which may be
substituted by a (C1-C6) alkoxy, phenyi-(C1-C6)-alkyl and phenyloxy-(C1-C6)-alkyl, wherein the
phenyl group may be substituted with (C1-C6) alkyl, (C1-C6) alkoxy or halogen, and naphthyl-
(C1-C6)-alkyl
R2 and R3 are both independently hydrogen or halogen,
R4 is a btolabile ester forming group,
M is hydrogen or a metal ion, preferably a bivalent metal ion, and n is 1 2 or 3
More preferably the endothelin conversion enzyme (ECE) and neutral endopeptidase (NEP) inhibitor is SLV-306 having the formula (Formula-2)
(Formula Removed)
In an embodiment of the present invention, the pharmaceutical compositions comprise endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor preferably SLV-306 in combination with at least one another active agent(s) selected from a group comprising antihypertensives such as calcium channel blockers, ACE Inhibitors, angiotensin antagonists, alpha-adrenergic receptor blockers, beta-adrenergic receptor blockers, diuretics, vasodilators or mixtures thereof, antidiabetics such as biguanide, sulfonylurea or glitazone, lipid lowering agents such as cholesterol absorption inhibitors, platelet function altering agent such as platelet aggregation inhibitors, serum homocysteine lowering agent, and the like or mixtures thereof optionally with one or more pharmaceutically acceptable excipients
In an embodiment of the present invention, the pharmaceutical compositions comprise ECE inhibitor and/or NEP inhibitor preferably SLV-306 in combination with at least one guanidine derivative selected from but not limited to a group comprising bethanidine, debnsoquin, guanabenz, guanadrel, guanethidine, guanfacine, guanoxabenz, guanoxan, hydrazines/phthalazmes such as dihydralazme, endralazine, hydralazine, pheniprazine, pildralazine imidazole derivatives such as clonidine, lofexidine, moxonidine, phentolamine, tiamenidine, or pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers conjugate acids enantiomers, tautomeric forms, prodrugs, or mixtures thereof
In an embodiment, the present invention provides pharmaceutical compositions comprising SLV-306 or its pharmaceutically acceptable salts, esters hydrates, solvates, polymorphs.
isomers conjugate acids, enantiomers, tautomeric forms, prodrugs, or mixtures thereof as active agent in combination with a lipid lowering agent selected from but not limited to a group comprising ezetimibe, niacin, or policosanol or its pharmaceutical^ acceptable salts, polymorphs, solvates, hydrates analogues, enantiomers, tautomeric forms or mixtures thereof optionally with one or more pharmaceutical^ acceptable excipients
Calcium channel blockers within the scope of the present invention include but are not limited to amlodipine, bepndil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil terodilme, verapamil, aranidipine, barnidipine, benidipine, ctlnidipine, efomdipine, elgodipme, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine nimodipine nisoldipine, nitrendipine, cinnanzine, flunanzine, lidoflazine, lomenzine, bencyclane, etafenone or perhexiline or mixtures thereof Angiotensin Converting Enzyme Inhibitors (ACE-Inhibitors) according to the present invention include but are not limited to alacepril, benazepril, captopnl, ceronapnl, delapnl, enalapnl, fosmopnl, lmidapnl, lismopril, moveltipnl permdopril, quinapril, ramipnl, spirapnl, temocapnl or trandolapnl or mixtures thereof Angiotensin-II receptor antagonists (A-Il antagonists) of this invention include but are not limited to candesartan, eprosartan, irbesartan, losartan, or valsartan or mixtures thereof Beta-Blockers which are within the scope of this invention include but are not limited to acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolot, bisoprolol, bopmdolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidnne hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, mpradilol, oxprenolol, penbutolol, pindolol, practolol, pronethalol propranolol, sotalol, sulfinalol talmolol tertatolol, tilisolol, timolol toliproiol or xibenolol or mixtures thereof Alpha-Blockers which are within the scope of the present invention include but are not limited to amosulalol, arotinolol, dapiprazole, doxazosin fenspinde, indoramin, labetolol, naftopidil, nicergoline, prazosin, tamsulosin, tolazoline, tnmazosin or yohimbine, or mixtures thereof
The term vasodilator used herein unless otherwise stated is meant to include cerebral vasodilators, coronary vasodilators or peripheral vasodilators Cerebral vasodilators within the scope of this invention include but are not limited to bencyclane, cinnanzine, citicoline, cyclandelate ciclonicate, dnsopropylamine dichloroacetate, eburnamonme fasudil fenoxedil, flunanzine ibudilast ifenprodil, lomenzine nafronyl, mcametate, nicergoline, nimodipine, papaverine pentifylline tinofedrme vmcamine vinpocetine, or viquidil or mixtures thereof
Coronary vasodilators of this invention include but are not limited to amotnphene, bendazol, benfurodil hemisuccinate benziodarone, chloracizine, chromonar, clobenfural, clonitrate, cloncromen, dilazep, dipyridamole droprenilamme, efloxate, erythntyl tetramtrate, fendiline, floredil, ganglefene, hexestrol bis(P-diethylaminoethyl)ether, hexobendme, ltramin tosylate, khellm, lidoflazme mannitol hexanitrate, medibazine, nitroglycerin, pentaerythntol tetramtrate, pentnnitrol perhexilme, pimefylline, prenylamine propatyl nitrate, trapidil, tricromyl trimetazidine trolnitrate phosphate or visnadine or mixtures thereof Peripheral vasodilators within the scope of this invention include, but are not limited to aluminium nicotinate, bamethan, bencyclane, betahistine, bradykinm, brovincamine, bufeniode, buflomedil, butalamme, cetiedil, ciclomcate cinepazide, cinnanzine cyclandelate dnsopropylamine dichloroacetate eledoisin fenoxedil, flunanzine, hepromcate, ifenprodil, lloprost, inositol niacmate, isoxsuprine, kallidin, kallikrein, moxisylyte, nafronyl, mcametate, mcergoline, nicofuranose, nylidnn, pentifylline, pentoxifylline, pinbedil, prostaglandin E|, suloctidil, tolazohne or xanthmol niacmate or mixtures thereof
The term diuretic according to the present invention includes but is not limited to diuretic benzothiadiazme derivatives, diuretic organomercunals, diuretic purines, diuretic steroids, diuretic sulfonamide derivatives, diuretic uracils and other diuretics such as amanozine, amiloride, arbutm, chlorazaml, ethacrynic acid, etozolin, hydracarbazine, isosorbide, mannitol, metochalcone, muzolimme, perhexilme, ticrynafen, triamterene, theobromine or urea or mixtures thereof Diuretic benzothiadiazme derivatives of the present invention include but are not limited to althiazide, bendroflumethiazide, benzthiazide, benzylhydrochlorothiazide, buthiazide chlorothiazide chlorthalidone cyclopenthiazide, cyclothiazide, epithiazide, ethiazide, fenquizone, indapamide, hydrochliorothiazide, hydroflumethiazide, methyclothiazide, meticrane, metolazone, paraflutizide, polythiazide, quinethazone, teclothiazide, or tnchlormethiazide or mixtures thereof Diuretic sulfonamide derivatives of this invention include but are not limited to acetazolamide, ambuside, azosemide, bumetanide, butazolamide, chloraminophenamide clofenamide, clopamide, clorexolone, 'disulfamide, ethozolamide, furosemide, mefruside methazolamide, piretanide, torsemide, tnpamide or xipamide or mixtures thereof
Anti-diabetic or anti-hyperglycemic agents according to the present invention include but are not limited to biguanides such as metformin, thiazolidinediones such as pioglitazone, rosiglitazone or troglitazone, sulfonylureas such as acetohexamide, chlorpropamide, tolazimide, tolbutamide, gliclazide, glipizide, glyburide, or glimepende, benzoic acid derivatives and glucosidase inhibitors such as acarbose or miglitol or mixtures thereof Preferred lipid lowering agents within
the scope of the present invention include but are not limited to cholesterol absorption inhibitors such as ezetimibe, bile acid sequestrants, probucol, niacin, policosanol, or fibric acid agents, or their pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, conjugate acids, enantiomers, tautomeric forms, prodrugs or mixtures thereof
Platelet function altering agent according to the present invention is selected from but not limited to a group comprising aspirin, ticlopidine, dipyridamole, clopidogrel policosanol, a glycoprotein IIb/IIIa receptor inhibitor, or a non-steroidal anti-inflammatory drug Serum homocysteine lowering agent useful in the present invention is selected from but not limited to a group comprising folic acid, vitamin B6 or vitamin B12 In another embodiment, the composition comprises an ECE and/or NEP inhibitor in combination with an antihistamine active agent such as chlorpheniramine, chlorphenoxamine, or the like or mixtures thereof
In one embodiment the ECE and/or NEP inhibitor can be administered in combination with another antihypertensive or blood pressure regulating agent for the effective prophylaxis, treatment and/or amelioration of hypertension and associated cardiovascular disorder(s) In another embodiment the ECE and/or NEP inhibitor can be administered in combination with a lipid lowering agent or anti-hyperlipidemic agent for the prophylaxis, treatment and/or amelioration of hypertension and associated hyperhpidemia In another embodiment the ECE and/or NEP inhibitor can be administered in combination with antidiabetics, platelet function altering agent and/or serum homocysteine lowering agent or the like or mixtures thereof for the prophylaxis, treatment and/or amelioration of cardiovascular and associated disorders
In one embodiment, a combination comprising ECE and/or NEP inhibitor and an antihypertensive agent is used in the prophylaxis, treatment and/or amelioration of cardiovascular and other associated disorders selected from but not limited to a group comprising chronic heart failure, coronary artery disease, congestive heart failure, angina, atherosclerosis, hyperhpidemia, diabetes, myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension ischemia-reperfusion injury ischaemic heart disease, stroke or transient ischaemic attack, coronary and systemic vasospastic disorders cerebral vasospasm and subarachnoid hemorrhage, aneurysm, angina pectoris, angioneurotic edema, aortrc valve stenosis, arrhythmia, arrhythmogenic right ventricular dysplasia, arteriosclerosis, arteriovenous malformations, atrial fibrillation, Behcet syndrome, bradycardia, cardiac tamponade, cardiomegaty, cardiomyopathy dilated cardiomyopathy hypertrophic cardiomyopathy, restrictive cardiovascular diseases carotid stenosis, cerebral hemorrhage Churg-Strauss syndrome Ebstein's anomaly, Eisenmenger
complex, embolism, endocarditis bacterial fibromuscular dysplasia, heart block, congenital heart diseases congestive heart failure heart valve diseases hematoma, ubdural Hippel-Lindau disease, hyperemia, hypertension, hypertrophy, hypoplastic syndrome, intermittent claudication, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, long QT syndrome, microvascular angina, mitral valve prolapse, moyamoya disease, mucocutaneous lymph node syndrome myocardial infarction myocardial ischemia, myocarditis, pericarditis, peripheral vascular diseases, Phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud disease, Sneddon syndrome, superior vena cava syndrome, tachycardia, Takayasu's arteritis, telangiectasia, hereditary hemorrhagic, temporal arteritis, tetralogy of fallot, thromboangiitis obliterans thrombosis, tricuspid atresia varicose veins vascular diseases, vasculitis, vasosDasm, intracranial ventricular fibrillation, Williams syndrome, Wolff-Parkinson-White syndrome or the like or combinations thereof
In an embodiment, the compositions of the present invention comprising an ECE and/or NEP inhibitor and at least one active agent selected from a group comprising dopamine agonists/COMT inhibitors, anticholinergics, selegiline, deprenyl, NDA antagonists, beta interferons, monoclonal antibodies, glutamate inhibitors, cholmesterase inhibitors such as galantamine, rivastigmine, donepezil or tacrine, glatiramer acetate, mitoxantrone, corticosteroids, muscle relaxants, anticonvulsants such as topiramate, lamotngme, levetiracetam, aldose reductase inhibitors such as thioctic acid, NMDA antagonists, dopamine antagonists or the like or mixtures thereof, are useful for the prophylaxis, treatment and/or amelioration of one or more neurodegenerative disorder such as Parkinson's disease, Alzheimer's disease, multiple sclerosis neuropathies, Huntington's disease, Amyotrophic lateral sclerosis (ALS), or the like
The combinations of the present invention also can be formulated with one or more pharmaceutically acceptable e\cipient(s) in the form of a pharmaceutical composition The excipient(s) may be used as a carrier and must be acceptable in the sense of being compatible with the other ingredients of the composition or must not be deleterious to the recipient The carrier can be a solid or a liquid or both and preferably is formulated with the compound as a unit-dose composition, for example a tablet, which can contain from about 0 05% to 95% by weight of the active compounds Other pharmacologically active agents can also be present, including other compounds useful in the present invention The compositions can be formulated as powders pellets, tablets, capsules, solutions suspensions, emulsions, patches topical preparations, parenterals, etc The pharmaceutical compositions of the invention can be prepared by any of the formulation techniques known to a person skilled in art such as by admixing the components and formulating it into a suitable dosage form, for example, mixing the combination
of an CCE and/or NEP inhibitor and another active agent with pharmaceutically acceptable excipients and compressing the same into a tablet The combinations and compositions of the present invention can be administered by any conventional means available for use in conjunction with pharmaceuticals Oral delivery of the ECE and/or NEP inhibitors, more preferably SI V-306 and at least one active agent useful in the management of cardiovascular and other associated disorders is preferred
Oral delivery of the ECE and/or NEP inhibitor and at least one active agent useful in the prophylaxis, treatment and/or amelioration of cardiovascular and other associated disorders of the present invention can include formulations to provide immediate delivery and/or controlled or prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms Compositions for immediate delivery of active agent(s) include but are not limited to solutions, suspensions, emulsions, fast-dissolving tablets or capsules, disintegrating tablets, Self Microemulsifying Drug Delivery Systems (SMEDDS) or the like Prolonged or sustained delivery formulations include but are not limited to pH independent drug release systems or pH sensitive drug release system based on the changing pH of the small intestine, slow erosion of a tablet or capsule retention in the stomach based on the physical properties of the composition achieved by floatation or bioadhesion of the dosage form to the mucosal lining of the intestinal tract, or enzymatic release of the active drug from the dosage form Dosage forms intended to deliver a fraction of active agent(s) in an immediate release form and the other fraction as a modified release or pulsatile release form as multiple units are also within the scope of the present invention The intended effect is to extend the time period over which the active agent(s) are delivered to the site of action by manipulation of the dosage form such as enteric-coated compositions Suitable polymers for enteric coating include cellulose acetate phthalate, polyvinyl acetate phthalate hydroxypropylmethyl cellulose phthalate and anionic polymers of methacrylic acid and methacrylic acid methyl ester In an embodiment, the composition comprising the combination of the present invention can be formulated into a controlled release system by using a suitable rate controlling polymer such as cellulosic polymers, alginates, methacrylate polymers, gums or the like or the mixtures thereof
Pharmaceutical compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of active ingredients of the present invention, as a powder or granules, as a solution or a suspension in an aqueous or non-aqueous liquid or as an oil-in-water or water-m-oil emulsion Compressed tablets can be prepared by compressing in a suitable machine, the material in a free-flowing form, such
as a powder or granules optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent(s) Molded tablets can be made, for example, by molding the powdered compound in a suitable machine In a preferred embodiment, the compositions of the present invention are formulated as solid oral dosage form compositions possessing good bioavailability comprising one or more alkaline substance and/or surfactants In another preferred embodiment, the solid oral dosage form composition preferably as capsule is formulated as SMEDDS Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water Such compositions may also comprise excipients such as wetting agents emulsifying and suspending agents or sweetening, flavoring, or perfuming agents Pharmaceutical compositions suitable for buccal or sublingual administration include lozenges comprising a compound of the present invention in a flavored base, usually sucrose, and acacia or tragacanth and pastilles comprising the drugs in an inert base such as gelatin and glycerin or sucrose and acacia
In an embodiment of the present invention, the amount of ECE and/or NEP inhibitor and at least one active agent(s) useful in the management of cardiovascular and other associated disorders that can be combined with pharmaceutical ly acceptable excipients to produce a dosage form to be administered varies depending upon the host treated and the particular mode of administration The excipients that can be used for preparation of such compositions are selected from but not limited to diluents, dismtegrants, binders, fillers, bulking agents, anti-adherents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, glidants chelating agents, and the like known to the art used either alone or m combination thereof In an embodiment, the filier(s) used in the present invention is selected from but not limited to a group comprising lactose, mannitol sorbitol, starch, microcrystalline cellulose, xylitol, fructose, sucrose, dextrose, dicalcium phosphate, calcium sulphate and the like or mixtures thereof The dismtegrants used in the present invention include but not limited to starch or its derivatives, partially pregelatinized maize starch croscarmellose sodium sodium starch glycollate and the like used either alone or in combination thereof The lubricants used in the present invention include but not limited to talc magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil and the like used either alone or in combination thereof The tablets may be coated with a material such as glyceryl monostearate glyceryl distearate cellulose acetate phthalate, hydroxypropylcellulose phthalate, polyvinylacetate phthalate, methylmethacrylate polymer, a polymer mixture such as Eudragit®, ccllulosic polymers, carbomcrs, zein, wax or similar material, or any other
dissolvable coat to delay absorption in the gastrointestinal tract Capsules for oral use mclude hard gelatin capsules in which the components are mixed with a solid diluent or soft gelatin capsules wherein the fill material exist as aqueous or hydroalcoholic or oily systems
The compositions of the present invention may be in the form of tablets such as layered or monolithic tablet, mini-tablets such as such as layered or monolithic mini-tablets, capsules, pellets, granules, patches, powders and other dosage forms suitable for oral administration In a preferred embodiment, the composition of the present invention is in the form of layered or monolithic tablets/mini-tablets The composition can be prepared by either direct compression dry compression (slugging) or by granulation In a preferred embodiment of the present invention, the oral composition is prepared by direct compression or compaction granulation The composition prepared by granulation technique is either by aqueous or non-aqueous technique or melt granulation technique The non-aqueous solvent used is selected from a group comprising dehydrated alcohol, isopropyl alcohol, methylene chloride or acetone In an embodiment, the compositions of the present invention are in the form of granules beads or pellets that may be further compacted, compressed, or moulded, or made into capsules The compositions may be coated with a functional coating By the term 'functional coating' it is herein implied that the coating composition comprises a part of the active agent(s) and/or the composition comprises excipients which aid in controlling the rate of release of the active agent(s) and/or the composition comprises additionally another active agent which is different from the active agent present in the core composition The composition may be formulated as layered tablets comprising at least two layers wherein the same active agent is present in all the layers exhibiting different release profiles or one or more additional active agent(s) is present in the layers exhibiting different release profiles The coating composition employed in the present invention may be an aqueous, non-aqueous or a hydro-alcoholic system The solvents used to prepare a non-aqueous coating composition is selected from but not limited to a group comprising dehydrated alcohol, isopropyl alcohol, methylene chloride, acetone or any other solvent known to the art for such use, or mixtures thereof In an embodiment, the compositions of the present invention comprises of at least two fractions wherein one fraction comprises the active agent(s) optionally with one or more pharmaceutical^ acceptable excipients in such quantities so as to provide an immediate release of the active agent(s) and the other fraction comprises the active agent(s) optionally with one or more pharmaceutical ly acceptable excipients in such quantities so as to provide a sustained release of the active agent(s)
In another embodiment of the present invention is provided a process for the preparation of such pharmaceutical composition, which comprises treating the combination of active agents optionally with one or more pharmaceutically acceptable excipients and formulating into a suitable dosage form
It is another embodiment of the present invention to provide a composition comprising a combination of ECE and/or NEP inhibitor and at least one active agent useful in the management of cardiovascular and other associated disorders with increased bioavailability that provides an effective concentration of active agent(s) to obtain the desired therapeutic effect In another embodiment of the present invention, the combination of the ECE and/or NEP inhibitor with at least one active agent may lead to a synergistic effect and/or reduction in the dose required for one or both of the active agent(s) and/or lead to the reduction in the adverse effect associated with the administration of the composition of the present invention
In another embodiment is provided a method of using such composition which comprises administering to a subject in need thereof an effective amount of the composition The compositions of the present invention are useful for the prophylaxis, treatment and/or amelioration of cardiovascular and other associated disorders
In yet another embodiment, the present invention provides the use of the combination comprising an ECE and/or NEP inhibitor with at least one active agent for the manufacture of a medicament for the prevention treatment and/or amelioration of cardiovascular disease and/or for the reduction in the risk of cardiovascular disease and other associated disorders In a further embodiment the cardiovascular and other associated disorders are selected from but not limited to a group comprising chronic heart failure coronary artery disease, congestive heart failure, angina, atherosclerosis, hyperlipidemia, diabetes, myocardial infarction, cardiogenic shock, systemic and pulmonary hypertension ischemia-reperfusion injury, coronary and systemic vasospastic disorders, cerebral vasospasm, and subarachnoid hemorrhage, hyperglycemia, hyperlipidemia, metabolic disorders renal disorders neurodegenerative disorders and the like or a combination of such disorders
The examples given below serve to illustrate embodiments of the present invention However they do not intend to limit the scope of present invention
EXAMPLES
Example-1 Immediate release Tablets
S No Ingredient Quantity (mg/tablet)
1 SLV-306 150 0
2 Atenolol 50 0
3 Sodium bicarbonate 150 0
4 Microcrystalline cellulose 105 0
5 Sodium starch glycollate 20 0
6 Povidone K-30 10 0
7 Magnesium stearate 5 0
8 Sodium starch glycollate 20 0
9 Colloidal silicon dioxide 5 0
10 Magnesium Stearate 5 0 Procedure
i) Sift and mix ingredients 1, 2, 3, 4, 5, 6 & 7
n) Pass the ingredients of step (i) through roller compactor to obtain compacts Pass the
compacts through sieve #16 and retain on sieve #60 to get granules in) Mix the granules of step (n) with ingredients 8, 9 & 10 iv) Compress the granules of step (in) into tablets
Example-2 Extended release Tablets
S No Ingredient Quantity (mg/tablet)
1 SLV-306 calcium 75 0
2 Metformin hydrochloride 500 0
3 Sodium bicarbonate 170 0
4 Hydroxypropyl methylcellulose 90 0
5 Povidone K-90 30 0
6 Croscarmellose Sodium 18 0
7 Magnesium Stearate 9 0
8 Purified talc 4 0
9 Colloidal silicon dioxide 4 0 Procedure
i) Sift and mix ingredients 1 2, 3, 4, 5 & 6
ii) Pass the ingredients of step (i) through roller compactor to obtain compacts Pass the compacts through sieve #16 and retain on sieve #60 to get granules
iii) Mix the granules of step (n) with ingredients 7, 8 & 9
IV) Compress the granules of step (in) into tablets
Example-3 Dual release Capsule
A) Immediate release fraction
S No Ingredient Quantity (mg/capsule)
1 SLV-306 75 0
2 Pohcosanol 40 0
3 Sodium bicarbonate 75 0
4 Sodium starch glycollate 5 0
5 Microcrystallme cellulose 37 0
6 Povidone K-30 5 0
7 Sodium Iauryl sulfate 3 0
8 Magnesium stearate 2 5
9 Sodium starch glycollate 5 0
10 Magnesium stearate 2 5 Procedure
i) Mix ingredients 1 to 8 together and sift through mesh #30 sieve
u) Pass the ingredients of step (i) through roller compactor to obtain compacts Pass the
compacts through sieve #22 and retain on sieve #60 to get granules
in) Mix the granules of step (n) with ingredients 9 & 10
B) Sustained release fraction
S No Ingredient Quantity (mg/capsule)
1 SI V-306 75 0
2 Ezetimibe 10 0
3 Sodium bicarbonate 75 0
4 Methacrylate polymer (Eudragit® LI00-55) 38 0
5 Hydroxypropyl methylceilulose 15 0
6 Povidone K-90 15 0
7 Colloidal silicon dioxide 2 0 Procedure
i) Mix ingredients 1 to 7 together and sift through mesh #30 sieve
ii) Pass the ingredients of step (I) through roller compactor to obtain compacts Pass the compacts through sieve #22 and retain on sieve #60 to get granules
C) Preparation of capsule
Mix the material in step (A) (in) and the material in step (B) (n) and fill into hard gelatin capsule
ExampIe-4 Tablet
S No Ingredient Quantity (mg/tablet)
1 SLV-306 75 0
2 Amlodipine besylate 13 9
3 Lactose 200 0
4 Microcrystalline cellulose 1210
5 Sodium lauryl sulfate 5 0
6 Colloidal silicon dioxide 5 0
7 Sodium bicarbonate 75 1
8 Glyceryl behenate 3 0 Procedure
i) Mix ingredients 1, 2, 3 & 4 and sift through mesh #30 sieve
n) Mix ingredients 5, 6 & 7 and sift through mesh #60 sieve
HI) Mix the material of step (I) with the material of step (n)
iv) Compress the material of step (in) into tablets
Example-5 Tablet
S No Ingredient Quantity (mg/tablet)
1 SLV-306 600 0
2 Eprosartan 100 0
3 Effer soda™ 200 0
4 Croscarmellose sodium 40 0
5 Magnesium stearate 5 0
6 Croscarmellose sodium 40 0
7 Magnesium stearate 10 10
8 Colloidal silicon dioxide 5 0 Procedure
i) Sift and mix ingredients 1, 2, 3, 4 & 5
ii) Pass the ingredients of step (i) through roller compactor to obtain compacts Pass the
compacts through sieve #16 and retain on sieve #60 to get granules
m) Mix the granules of step (n) with ingredients 6 7 & 8 and sift through mesh #40 sieve
iv) Compress the granules of step (in) into tablets
Example-6 Tablet
S No Ingredient Quantity (mg/tablet)
1 SLV-306 150 00
2 Captopnl 12 50
3 Sodium carbonate 200 00
4 Microcrystalline cellulose 187 50
5 Crospovtdone 30 00
6 Povidone K-30 25 00
7 Purified water q s
8 Crospovidone 30 00
9 Magnesium stearate 8 00
10 Colloidal silicon dioxide 4 00
11 Talc 3 00 Procedure
l) Sitt and mix ingredients 1, 2, 3, 4 & 5
n) Dissolve ingredient 6 in 7 and granulate with the mixture of step (I)
in) Dry the granules of step (n) followed by sifting through mesh #20 sieve and blending
with ingredients 8 9, 10 & 11
IV) Compress the material of step (in) into tablets
Example-7 Tablet
S No Ingredient Quantity (mg/tablet)
1 SLV-306 300 0
2 Hydrochlorothiazide 25 0
3 Docusate sodium 10 0
4 Calcium carbonate 250 0
5 Microcrystalline cellulose 147 0
6 Croscarmellose sodium 20 0
7 Starch 35 0
8 Purified water q s
9 Croscarmellose sodium 28 0
10 Magnesium stearate 10 0 Procedure
i) Sift and mix ingredients 1, 2, 3, 4, 5 & 6
u) Granulate the mixture of step (i) with starch mucilage prepared by dispersing ingredient 7

in 8 in) Dry the granules of step (u) followed by sifting and blending with ingredients 9 & 10 iv) Compress the material of step (in) into tablets
Example-8 Tablet
S No Ingredient Quantity (mg/tablet)
1 SLV-306 300 0
2 Amilonde 5 0
3 Docusate sodium 10 0
4 Calcium carbonate 250 0
5 Microcrystalline cellulose 147 0
6 Croscarmellose sodium 20 0
7 Starch 35 0
8 Purified water q s
9 Croscarmellose sodium 28 0
10 Magnesium stearate 10 0 Procedure
i) Sift and mix ingredients 1,2, 3,4 5&6
n) Granulate the mixture of step (i) with starch mucilage prepared by dispersing ingredient 7
in 8 in) Dry the granules of step (n) followed by sifting and blending with ingredients 9 & 10 iv) Compress the material of step (in) into tablets
Example-9 Sustained release Bilayered tablet
A) Immediate release layer
S No Ingredient Quantity (mg/tablet)
1 SLV-306 300 0
2 Crospovidone 15 0
3 Sodium lauryl sulfate 5 0
4 Starch 3 0
5 Purified water q s
6 Crospovidone 15 0
7 Magnesium stearate 7 0
8 Colloidal silicon dioxide 3 0 Procedure
i) Mix ingredients I, 2 & 3
ii) Granulate the mixture of step (i) with starch mucilage prepared from ingredients 4 & 5
iii) Dry the granules sift and blend with ingredients 6, 7 & 8
B) Extended release layer
S No Ingredient Quantity (mg/tablet)
1 Metformin hydrochloride 500 0
2 Povidone K-90 60 0
3 Methacrylic polymer 90 0
4 Microcrystalline cellulose 30 0
5 Povidone K-30 70 0
6 Purified water q s
7 Microcrystalline cellulose 310
8 Talc 6 0
9 Colloidal silicon dioxide 3 0 Procedure
i) Mix ingredients 1, 2, 3 & 4
n) Dissolve ingredient 5 in 6 and granulate with the mixture of step (i)
in) Dry the granules, sift and blend with ingredients 7, 8 & 9
C) Preparation of bilayered tablet
Compress the granules of step (A) (in) and step (B) (in) into bilayered tablet
Example-10 Tablet in tablet
A) Preparation of mini-tablets
S No Ingredient Quantity (mg/tablet)
1 Captopnl 12 50
2 Microcrystalline cellulose 48 0
3 Crospovidone 2 0
4 Starch 4 0
5 Purified water q s
6 Crospovidone 2 0
7 Purified talc 4 0
8 Stearic acid 1 0 Procedure
i) Sift and mix ingredients 1, 2 & 3
ii) Dissolve ingredient 4 in 5 to form the binder solution
iii) Granulate the ingredients of step (i) with the binder solution of step (n)
iv) Dry the granules of step (iii) and mix with ingredients 6, 7 & 8 v) Compress the granules of step (iv) to obtain mini-tablets
B) Preparation of tablet in tablet
S No Ingredient Quantity (mg/tablet)
1 SLV-306 75 0
2 Calcium carbonate 300 0
3 Microcrystalline cellulose 155 0
4 Crospovidone 20 0
5 Povidone K-30 18 0
6 Purified water q s
7 Crospovidone 6 0
8 Microcrystalline cellulose 6 0
9 Magnesium stearate 6 0 Procedure
i) Sift and mix ingredients 1, 2 3&4
u) Dissolve ingredient 5 in 6 to form the binder solution in) Granulate the ingredients of step (i) with the binder solution of step (n) iv) Dry the granules of step (in) and mix with ingredients 7, 8 & 9
v) Compress the mini-tablets of step (A) (v) with the granules of step (B) (iv) to obtain tablet in tablet
C) Coating of tablet in tablet
S No Ingredient Quantity (mg/tablet)
1 Opadry® yellow 25 0
2 Purified water q s Procedure
i) Dissolve Opadry® yellow in sufficient quantity of water
n) Coat the tablet in tablet of step (B) (v) with the coating solution of step (C) (i)
Example-11 Tablet in tablet
A) Preparation of mini-tablet
S No Ingredient Quantity (mg/tablet)
1 Policosanol 40 0
2 Ezetimibe 10 0
3 Microcrystalline cellulose 12 0
4 Lactose 9 2
5 Sodium starch glycollate 1 6
6 Starch 4 0
7 Purified water q s
8 Sodium starch glycollate 1 6
9 Magnesium stearate 0 8
10 Talc 0 8 Procedure
i) Sift and mix ingredients 1, 2, 3 4 & 5
ii) Dissolve ingredient 6 in 7 to form the binder solution
iii) Granulate the ingredients of step (i) with the binder solution of step (n)
iv) Dry the granules of step (in) and mix with ingredients 8, 9 & 10
v) Compress the granules of step (iv) to obtain mini-tablets
B) Coating of mini-tablets
S No Ingredient Quantity (mg/tablet)
1 Opadry® white 3 0
2 Purified water q s Procedure
i) Dissolve Opadry® white in sufficient quantity of water
u) Coat the mini-tablets in step (A) (v) with the coating solution of step (B) (i)
C) Preparation of granules to be filled into Capsule
S No Ingredient Quantity (mg/capsule)
1 SLV-306 300 0
2 Sodium bicarbonate 398 0
3 Microcrystallme cellulose 45 0
4 Sodium starch glycollate 30 0
5 Magnesium stearate 9 0
6 Talc 4 5
7 Microcrystallme cellulose 4 5 Procedure
i) Sift and mix ingredients 1 2 3 & 4
ii) Slug the ingredients of step (i) to obtain slugs of desired hardness followed by breaking
of the slugs and passing of the slugs through #16 mesh to obtain granules iii) Mix the granules of step (n) with ingredients 5, 6 and 7
D) Preparation of Capsule
Hill the coated mini-tablets of step (B) (n) and the granules of step (C) (in) into a hard gelatin capsule
Example-12 Tablet in tablet
A) Preparation of mini-tablets
S No Ingredient Quantity (mg/tablet)
1 Amlodipine besylate 13 90
2 Lactose 44 3
3 Crospovidone 1 2
4 Magnesium stearate 0 6 Procedure
i) Mix ingredients 1, 2, 3 & 4 and sift through mesh #30 sieve
ii) Compress the material of step (n) to obtain mini-tablets
B) Preparation of tablet in tablet
s No Ingredient Quantity (mg/tablet)
1 SLV-306 600 0
2 Sodium carbonate 250 0
3 Sodium lauryl sulfate 15 0
4 Croscarmellose sodium 40 0
5 Microcrystailine cellulose 40 0
6 Croscarmellose sodium 40 0
7 Magnesium stearate 10 0
8 Colloidal silicon dioxide 10 0 Procedure
i) Sift and mix ingredients I 2 3, 4 & 5
ii) Slug the ingredients of step (i) to obtain slugs of desired hardness followed by breaking
of the slugs and passing of the slugs through #16 mesh to obtain granules iii) Mix the granules of step (u) with ingredients 6, 7 & 8 iv) Compress the mini-tablets of step (A) (ii) with the granules of step (B) (iii) to obtain
tablet in tablet
Example-13 Beads
S No Ingredient Quantity (mg/capsule)
1 SLV-306 300 0
2 Aspirin 75 0
3 Sodium bicarbonate 125 0
4 Croscarmellose sodium 10 0
5 Povidone K-30 20 0
6 Gelatin 5 0
7 Talc 5 0
8 Microcrystalline celluose 30 0
9 Purified water q s
10 Sucrose 60 0
11 Hydroxypropyl methylcellulose 5 0
12 Polysorbate 80 5 0 Procedure
i) Mix ingredients 1,2 3, 4, 7 & 8 and sift through mesh #40 sieve
ii) Dissolve ingredients 5, 6, 11 & 12 in 9 to form the binder solution
iii) Take mesh #40 sieve passed ingredient 10 as nucleus and sprinkle binder solution to
sufficiently wet the sugar beads iv) Dust the powder of step (i) over the sugar beads of step (in) Repeat this process until
whole powder is converted into beads v) Fill the beads of step (iv) into a suitable size hard gelatin capsule
Example-14 Soft gelatin capsule, SMEDDS
S No Ingredient Quantity (mg/capsule)
1 SLV-306 calcium 150 0
2 Clopidogrel 37 5
3 Propylene glycol 150 0
4 Polyglycerol oleic ester (Plurol Oleique® CC 497) 30 0
5 Polyoxyl 40 hydrogenated castor oil 310 0 Procedure
i) Disperse ingredients 1 & 2 in ingredient 3 with continuous stirring to obtain a
homogeneous dispersion n) Mix ingredients 4 & 5 together to obtain a homogeneous dispersion in) Add material of step (i) to the material of step (n) with continuous stirring to obtain the fill material iv) Encapsulate the fill material into gelatin sheath to form soft gelatin capsule
Example-15 Oral suspension
S No Ingredient Quantity (mg/lOOml)
1 SLV-306 150 0
2 Lamotrigme 500 0
3 Selegiline hydrochloride 5 0
4 Sodium carboxymethylcellulose 50 0
5 Sorbitol solution (70% w/v) 80 0
6 Citric acid monohydrate 1 5
7 Sodium benzoate 1 0
8 Purified water qs to 100 ml Procedure
i) Mix ingredients 1, 2 & 3 together and sift through mesh #30 sieve
ii) Dissolve ingredients 5, 6 & 7 in ingredient 8 to obtain a homogeneous dispersion and
disperse ingredient 4 in it
iii) Add the material of step (i) with continuous stirring to the material of step (n) to obtain a
homogeneous suspension
Example-16 Oral liquid
S No Ingredient Quantity (mg/lOOml)
1 SI V-306 200 00
2 Niacin 1000 00
3 Folic acid 5 00
4 Ethyl cellulose 60 00
5 Ethyl alcohol 1 25
6 Citric acid monohydrate I 25
7 Sodium citrate 0 50
8 Glycerin 40 00
9 Povidone K-30 3 00
10 Propylene glycol 30 00

11 Saccharine sodium 0 50
12 Sodium chloride 0 50
13 Purified water qs to 100 00 ml Procedure
i) Mix ingredients 1 2 & 3 together and sift through mesh #30 sieve
u) Dissolve 4 in 5 and disperse mixture of step (I) into it Evaporate the solvent and pass the
dried material through mesh #30 sieve in) Dissolve ingredients 6789 10 ll&12in ingredient 13 to obtain a homogeneous dispersion
iv) Add the material of step (n) with continuous stirring to the material of step (in) to obtain a homogeneous dispersion
Example-17 Injection
S No Ingredient Quantity/5ml
1 Polyethylene glycol 1 50 ml
2 Propylene glycol 1 25 ml
3 Glycine Buffer pH 11 3 1 75 ml
4 SLV-306 2 50 mg
5 Phentolamine mesylate 5 00 mg
6 Sodium hydroxide (NaOH) solution 4 0% w/v 0 50 ml Procedure
i) Take specified quantity of Polyethylene glycol into a vessel
ii) Add Propylene glycol to step (i) with continuous stirring using mechanical stirrer
iii) Add about half the quantity of the Glycine Buffer pH 11 3 to the material of step (n) with
continuous stirring to form a homogeneous mixture iv) Pass weighed amount of SLV-306 and Phentolamine mesylate through #60 sieve and add
to the material of step (in) with continuous stirring v) Add specified quantity of NaOH 4 0% solution to the material of step (iv) with
continuous stirring to form a homogeneous solution vi) Mix the solution of step (v) for about 30 minutes by continuous stirring vn) Add remaining quantity of Glycine Buffer pH 11 3 to the material of step (vi) to make up
the volume viii) Mix the solution of step (vn) by continuous stirring
ix) Adjust the final pH to 10 0 by adding NaOH 4 0% w/v solution to the solution of step (vni)
x) Mix the solution of step (tx) by continuous stirring.

We claim:
1. A pharmaceutical composition comprising at least one endothelin conversion enzyme (ECE) inhibitor and/or neutral endopeptidase (NEP) inhibitor selected from a group comprising COS 26303, COS 25462, phosphoramidon, candoxatril, sinorphan, omapatrilat, FR901533, TMC-66, SM-19712, SLV-306, KC-12615, KC-90095-I-AC, CGS-26303, CGS-30440, CGS-31447, CGS-26670, Sch-54470, or pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, conjugate acids, enantiomers, tautomeric forms, prodrugs or mixtures thereof as active agent in combination with at least one another active agent optionally with one or more pharmaceutically acceptable excipients.
2. A composition according to claim 1, wherein the endothelin conversion enzyme (ECE) inhibitor and neutral endopeptidase (NEP) inhibitor is SLV-306 or its pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, isomers, conjugate acids, enantiomers, tautomeric forms, prodrugs or mixtures thereof, wherein the SLV-306 has the following formula:
(Formula Removed)
3. A composition according to any of the claims t-2, wherein the another active agent(s) is an antihypertensive selected from a group comprising calcium channel blockers, ACE Inhibitors, alpha-adrenergic receptor blockers, beta-adrenergic receptor blockers, diuretics, cerebral vasodilator, coronary vasodilator, peripheral vasodilator or mixtures thereof.
4. A composition according to claim 3, wherein the calcium channel blocker is selected from a group comprising amiodipine, bepridil, clentiazem, diltiazem, fendiiine, gallopamil, mibefradil, prenylamine, semotiadil, terodiiine, verapamil, aranidipine, barnidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine,
nisoldipine, nitrendipine, cinnarizine, flunarizine, iidoflazine, iomerizine, bencyclane, etafenone, perhexiline or mixtures thereof.
5. A composition according to claim 3, wherein the ACE Inhibitor is selected from a group comprising alacepril, benazepril, captopril, ceronapril, delapril, enalapril, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril or mixtures thereof.
6. A composition according to claim 3, wherein the alpha-adrenergic receptor blocker is selected from a group comprising amosulalol, arotinolol, dapiprazole, doxazosin, fenspiride, indoramin, labetolol, naftopidil, nicergoline, prazosin, tamsulosin, tolazoline, trimazosin, yohimbine or mixtures thereof.
7. A composition according to claim 3, wherein the beta-adrenergic receptor blocker is selected from a group comprising acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolot, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nipradilol, oxprenolol, penbutolot, pindolol, practolol, pronethalol, propranolol, sotalol, sulfmalol, talinolol, tertatolol, tilisolol, timolol, toliprolol, xibenolol or mixtures thereof.
8. A composition according to claim 3, wherein the diuretic is selected from a group comprising benzothiadiazine derivatives, diuretic organomercurials, diuretic purines, diuretic steroids, diuretic sulfonamide derivatives, diuretic uracils, amanozine, amiloride, arbutin, chlorazanil, ethacrynic acid, etozolin, hydracarbazine, isosorbide, mannitol, metochalcone, muzolimine, perhexiline, ticrynafen, triamterene, theobromine, urea or mixtures thereof.

9. A composition according to claim 3, wherein the cerebral vasodilator is selected from a group comprising bencyclane, cinnarizine, citicoline, cyclandelate, ciclonicate, diisopropylamine dichloroacetate, eburnamonine, fasudil, fenoxedil, flunarizine, ibudilasl, ifenprodil, Iomerizine, nafronyl, nicametate, nicergoline, nimodipine, papaverine, pentifylline, tinofedrine, vincamine, vinpocetine, viquidii or mixtures thereof.
10. A composition according to claim 3, wherein the coronary vasodilator is selected from a group comprising amotriphene, bendazol, benfurodil hemtsuccinate, benziodarone, chloracizine, chromonar, clobenfural, clonitrate, cloricromen, dilazep, dipyridamole, droprenilamine, efloxate, erythrityl tetranitrate, fendiline, floredil, ganglefene, hexestrol bis(p-diethylaminoethyl)ether, hexobendine, itramin tosylate. khellin, Iidoflazine,
mannitol hexanitrate, medibazine, nitroglycerin, pentaerythritol tetranitrate, pentrinitrol, perhexiiine, pimefyiiine, prenylamine, propatyl nitrate, trapidtl, tricromyl, trimetazidine, troinilrate phosphate, visnadine or mixtures thereof.
11. A composition according to claim 3, wherein the peripheral vasodilator is selected from a group comprising aluminium nicotinate, bamethan, bencyclane, betahistine, bradykinin, brovincamine, bufeniode, buflomedil, butalamine, cetiedii, ciclonicate, cinepazide, cinnarizine, cyclandelate, diisopropylamine dichloroacetate, eledoisin, fenoxedil, flunarizine, hepronicate, ifenprodil, iloprost, inositol niacinate, isoxsuprine, kallidin, katlikrein, moxisylyte, nafronyl, nicametate, nicergoline, nicofuranose, nylidrin, pentifylline, pentoxifylline, piribedil, prostaglandin E|, suloctidil, tolazoline, xanthinol niacinate or mixtures thereof.
12. A composition according to any of the claims 1-2, wherein the another active agent(s) is an antidiabetic selected from a group comprising biguanides, thiazolidinediones, sulfonylureas, benzoic acid derivatives, glucosidase inhibitors or mixtures thereof.
13. A composition according to any of the claims 1-2, wherein the another active agent(s) is a platelet function altering agent selected from a group comprising aspirin, ticlopidine, dipyridamole, clopidogrel, a glycoprotein IIb/IIIa receptor inhibitor, a non-steroidal antiinflammatory drug, policosanol or mixtures thereof..
14. A composition according to any of the claims 1-2, wherein the another active agent(s) is a serum homocysteine lowering agent selected from a group comprising folic acid, vitamin B6, vitamin B12 or mixtures thereof.
15. A composition according to any of the claims i-2, wherein the another active agent is a lipid lowering agent selected from a group comprising ezetimibe, niacin, or policosanol or its pharmaceutically acceptable salts, polymorphs, solvates, hydrates, analogues, enantiomers, tautomeric forms, or mixtures thereof.
16. A composition according to any of the claims 1-2, wherein the another active agent is a guanidine derivative selected from the group comprising bethanidine, debrisoquin, guanabenz, guanadrel, guanethidine, guanfacine, guanoxabenz, guanoxan or mixtures thereof.

17. A composition according to any of the claims 1-2, wherein the another active agent is a hydrazine or phthalazine selected from the group comprising dihydralazine, endralazine, hydralazine, pheniprazine, pildralazine or mixtures thereof.
18. A composition according to any of the claims 1-2, wherein the another active agent is an imidazole derivative selected from the group comprising clonidine, lofexidine, moxonidine, phentolamine, tiamenidine or mixtures thereof.
19. A composition according to claim 1, wherein the pharmaceuticalty acceptable excipients are selected from a group comprising diluents, disintegrants, binders, filters, bulking agents, anti-adherents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, organic solvents, stabilizers, preservatives, lubricants, glidants. chelating agents, either alone or in combination thereof.
20. A composition according to any of the claims 1-19, which is formulated to provide immediate delivery and/or controlled or prolonged delivery of the active agent(s).
21. A process for the preparation pharmaceutical composition according to claim 1, which comprises treating the combination of active agents optionally with one or more other pharmaceutically acceptable excipients and formulating into a suitable dosage form.
22. The pharmaceutical composition and process for the preparation of a pharmaceutical composition substantially as herein described and illustrated by the examples.