Compositions and methods of treating pulmonary hypertension

Abstract

Provided are formulations comprising therapeutically effective amounts of ambrisentan or a pharmaceutically acceptable salt thereof and tadalafil or a pharmaceutically acceptable salt thereof and methods of treating and/or preventing pulmonary hypertension by administration of the formulations.

1 . A combination therapy comprising:
 a therapeutically effective amount of a selective type-A endothelin receptor antagonist (ERA) selected from the group consisting of ambrisentan, sitaxsentan and pharmaceutically acceptable salts thereof, and   a therapeutically effective amount of a phosphodiesterase type 5 (PDE5) inhibitor selected from the group consisting of sildenafil, tadalafil, vardenafil and pharmaceutically acceptable salts thereof,   wherein the weight ratio of the selective type-A ERA and the PDE5 inhibitor is in a range from about 1:1 to about 1:10.   
     
     
         2 . The combination therapy of  claim 1 , wherein the selective type-A ERA is ambrisentan or a salt thereof, and the PDE5 inhibitor is tadalafil or a salt thereof. 
     
     
         3 . The combination therapy of  claim 2 , wherein the weight ratio of the selective type-A ERA and the PDE5 inhibitor is in a range from about 1:2 to about 1:5. 
     
     
         4 . The combination therapy of  claim 1 , wherein the selective type-A ERA and the PDE5 inhibitor are formulated separately. 
     
     
         5 . The combination therapy of  claim 1 , wherein the selective type-A ERA and the PDE5 inhibitor are formulated in a single dosage form. 
     
     
         6 . The combination therapy of  claim 1 , which is formulated for parenteral administration. 
     
     
         7 . The combination therapy of  claim 1 , which is formulated for oral administration. 
     
     
         8 . The combination therapy of  claim 1 , wherein the combination therapy is in tablet form or capsule form. 
     
     
         9 . The combination therapy of  claim 2 , wherein the amount of ambrisentan or a salt thereof is from about 1 mg to about 100 mg daily. 
     
     
         10 . The combination therapy of  claim 2 , wherein the amount of ambrisentan or a salt thereof is from about 2 mg to about 20 mg daily. 
     
     
         11 . The combination therapy of  claim 2 , wherein the amount of tadalafil or salt thereof administered is from about 5 mg to about 500 mg daily. 
     
     
         12 . The combination therapy of  claim 2 , wherein the amount of tadalafil or salt thereof administered is from about 10 mg to about 100 mg daily. 
     
     
         13 . The combination therapy of  claim 1 , wherein the combination therapy consists essentially of:
 a therapeutically effective amount of a selective type-A endothelin receptor antagonist (ERA) selected from the group consisting of ambrisentan, sitaxsentan and pharmaceutically acceptable salts thereof, and   a therapeutically effective amount of a phosphodiesterase type 5 (PDE5) inhibitor selected from the group consisting of sildenafil, tadalafil, vardenafil and pharmaceutically acceptable salts thereof,   wherein the weight ratio of the selective type-A ERA and the PDE5 inhibitor is in a range from about 1:1 to about 1:10.   
     
     
         14 . The combination therapy of  claim 1 , further comprising a third active agent comprising at least one drug selected from the group consisting of prostanoids, PDE5 inhibitors other than tadalafil, endothelin receptor antagonists other than ambrisentan, calcium channel blockers, diuretics, anticoagulants, oxygen and combinations thereof. 
     
     
         15 . A method for treating pulmonary hypertension in a patient comprising administering to the patient a therapeutic amount of a selective type-A ERA selected from the group consisting of ambrisentan, sitaxsentan and pharmaceutically acceptable salts thereof in combination with a therapeutically effective amount of a PDE5 inhibitor selected from the group consisting of sildenafil, tadalafil, vardenafil and pharmaceutically acceptable salts thereof, wherein the weight ratio of the selective type-A ERA and the PDE5 inhibitor is in a range from about 1:1 to about 1:10. 
     
     
         16 . The method of  claim 15 , wherein the selective type-A ERA is ambrisentan or a salt thereof, and the PDE5 inhibitor is tadalafil or a salt thereof. 
     
     
         17 . The method of  claim 15 , wherein the weight ratio of the selective type-A ERA and the PDE5 inhibitor is in a range from about 1:2 to about 1:5. 
     
     
         18 . The method of  claim 15 , wherein the selective type-A ERA and the PDE5 inhibitor are administered in a sequential manner. 
     
     
         19 . The method of  claim 15 , wherein the selective type-A ERA and the PDE5 inhibitor are administered at the same time. 
     
     
         20 . The method of  claim 15 , wherein the selective type-A ERA and the PDE5 inhibitor are administered orally or parenterally. 
     
     
         21 . The method of  claim 16 , wherein the ambrisentan or salt thereof and the tadalafil or salt thereof are administered as a combined dosage unit. 
     
     
         22 . The method of  claim 21 , wherein the combined dosage unit is a tablet or a capsule. 
     
     
         23 . The method of  claim 16 , wherein the amount of ambrisentan or salt thereof administered is from about 1 mg to about 100 mg daily. 
     
     
         24 . The method of  claim 23 , wherein the amount of ambrisentan or salt thereof administered is from about 2 mg to about 20 mg daily. 
     
     
         25 . The method of  claim 16 , wherein the amount of tadalafil or salt thereof administered is from about 5 mg to about 500 mg daily. 
     
     
         26 . The method of  claim 25 , wherein the amount of tadalafil or salt thereof administered is from about 10 mg to about 100 mg daily. 
     
     
         27 . The method of  claim 15 , wherein the selective type-A ERA and the PDE5 inhibitor are administered once daily. 
     
     
         28 . The method of  claim 15 , wherein the pulmonary hypertension comprises pulmonary arterial hypertension (PAH). 
     
     
         29 . The method of  claim 15 , wherein the PAH comprises idiopathic PAH, familial PAH or PAH associated with another disease or condition. 
     
     
         30 . The method of  claim 15 , wherein the PAH at baseline is of WHO Class II, III or IV. 
     
     
         31 . A method for inhibiting endothelin-induced vasoconstriction in a patient comprising administering to the patient a therapeutic amount of ambrisentan or a salt thereof in combination with tadalafil or a salt thereof, wherein the weight ratio of the amount of the ambrisentan or salt thereof and the amount of the tadalafil or salt thereof is in a range from about 1:1 to about 1:10. 
     
     
         32 . A method for treating a disease in a patient comprising administering to the patient a therapeutic amount of ambrisentan or a salt thereof in combination with tadalafil or a salt thereof, wherein the disease is selected from the group consisting of hypertension, pulmonary hypertension, myocardial infarction, angina pectoris, acute kidney failure, renal insufficiency, cerebral vasospasms, cerebral ischemia, subarachnoid hemorrhages, asthma, atherosclerosis, intravascular coagulation, restenosis after angioplasty, hypertension caused by ischemia or intoxication, kidney failure caused by ischemia or intoxication, Raynaud's syndrome and asthmatic airway condition, and wherein the weight ratio of the amount of the ambrisentan or salt thereof and the amount of the tadalafil or salt thereof is in a range from about 1:1 to about 1:10.