Compositions for treating vascular diseases characterized by nitric oxide insufficiency

Abstract

The invention provides methods of treating a cardiovascular disease comprising administering a sustained release formulation of hydralazine hydrochloride and at least one of isosorbide dinitrate and/or isosorbide mononitrate in therapeutically effective dosage of each of the aforementioned compounds.

1 . A method of treating a cardiovascular disease in a patient comprising administering to the patient a sustained release oral formulation comprising biodegradable microparticles and/or nanoparticles having dispersed therein a therapeutically effective amount of hydralazine hydrochloride, wherein the hydralazine hydrochloride is present in an amount of about 30 milligrams to about 400 milligrams per day, and at least one of isosorbide dinitrate and isosorbide mononitrate, wherein the isosorbide dinitrate is present in an amount of about 5 milligrams per day to about 200 milligrams per day. 
   
   
       2 . The method of  claim 1 , wherein the cardiovascular disease is congestive heart failure, hypertension, pulmonary hypertension, myocardial and cerebral infarctions, atherosclerosis, atherogenesis, thrombosis, ischemic heart disease, post-angioplasty restenosis, coronary artery diseases, renal failure, stable, unstable and variant (Prinzmetal) angina, cardiac edema, renal insufficiency, nephrotic edema, hepatic edema, stroke, transient ischemic attacks, cerebrovascular accidents, restenosis, controlling blood pressure in hypertension, platelet adhesion, platelet aggregation, smooth muscle cell proliferation, vascular complications associated with the use of medical devices, wounds associated with the use of medical devices, pulmonary thromboembolism, cerebral thromboembolism, thrombophlebitis, thrombocytopenia or bleeding disorders. 
   
   
       3 . The method of  claim 2 , wherein the cardiovascular disease is congestive heart failure, hypertension, restenosis or atherosclerosis. 
   
   
       4 . The sustained release oral formulation of  claim 1 , further comprising a pharmaceutically acceptable carrier. 
   
   
       5 . The sustained release oral formulation of  claim 1 , wherein the hydralazine hydrochloride is present in an amount of about 50 milligrams to about 300 milligrams per day. 
   
   
       6 . The sustained release oral formulation of  claim 1 , wherein the isosorbide dinitrate is present in an amount of about 20 milligrams per day to about 160 milligrams per day. 
   
   
       7 . The sustained release oral formulation of  claim 1 , wherein the isosorbide mononitrate is present in an amount of about 5 milligrams per day to about 120 milligrams per day. 
   
   
       8 . The sustained release oral formulation of  claim 7 , wherein the isosorbide mononitrate is present in an amount of about 15 milligrams per day to about 100 milligrams per day. 
   
   
       9 . The sustained release oral formulation of  claim 1 , wherein the sustained release oral formulation is a solid dose, a liquid dose or a suspension. 
   
   
       10 . The sustained release oral formulation of  claim 9 , wherein the solid dose is a sustained-release tablet or a sustained release capsule. 
   
   
       11 . The sustained release oral formulation of  claim 1 , further comprising at least one nitrosated angiotensin-converting enzyme inhibitor, nitrosated beta-adrenergic blocker, nitrosated calcium channel blocker, nitrosated endothelin antagonist and nitrosated angiotensin II receptor antagonist, nitrosated renin inhibitor, or a mixture thereof 
   
   
       12 . The sustained release oral formulation of  claim 1 , further comprising at least one compound used to treat cardiovascular diseases, or a pharmaceutically acceptable salt thereof. 
   
   
       13 . The sustained release oral formulation of  claim 12 , wherein the at least one compound used to treat cardiovascular diseases is an angiotensin-converting enzyme inhibitor, a beta-adrenergic blocker, a cholesterol reducer, a calcium channel blocker, an angiotensin II receptor antagonist, an endothelin antagonist, a renin inhibitor, or a mixture thereof. 
   
   
       14 . The method of  claim 1 , comprising administering to the patient a sustained release oral formulation comprising biodegradable microparticles and/or nanoparticles having dispersed therein a therapeutically effective amount of hydralazine hydrochloride, wherein the hydralazine hydrochloride is present in an amount of about 30 milligrams to about 400 milligrams per day, and isosorbide dinitrate, wherein the isosorbide dinitrate is present in an amount of about 5 milligrams per day to about 200 milligrams per day. 
   
   
       15 . The method of  claim 14 , comprising administering to the patient a sustained release oral formulation comprising biodegradable microparticles and/or nanoparticles having dispersed therein a therapeutically effective amount of hydralazine hydrochloride, wherein the hydralazine hydrochloride is present in an amount of about 50 milligrams to about 300 milligrams per day, and isosorbide dinitrate, wherein the isosorbide dinitrate is present in an amount of about 20 milligrams per day to about 160 milligrams per day.