Combination therapy of angiotensin converting enzyme inhibitor and side-effect-reduced amount of aldosterone antagonist for treatment of cardiovascular disease

Abstract

Combinations of an ACE inhibitor and an aldosterone receptor antagonist are described for use in treatment of circulatory disorders. Of particular interest are therapies using captopril or enalapril co-administered with a low-dose of spironolactone. This co-therapy would be particularly useful to treat or prevent the progression of congestive heart failure while avoiding or reducing aldosterone-antagonist-induced side effects such as hyperkalemia.

What is claimed is:  
     
         1 . A combination comprising a therapeutically-effective amount of an angiotensin converting enzyme inhibitor and an aldosterone receptor antagonist, said aldosterone receptor antagonist being present in an amount which is therapeutically effective to antagonize a physiological effect of aldosterone but which amount is not sufficient for said aldosterone receptor antagonist to cause a substantial diurectic effect.  
     
     
         2 . The combination of  claim 1  wherein said aldosterone receptor antagonist is a spirolactone-type compound.  
     
     
         3 . The combination of  claim 2  wherein said spirolactone-type compound is spironolactone.  
     
     
         4 . The combination of  claim 1  wherein angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat, spirapril, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril, Marion Merrell Dow MDL-100240, perindoprilat and Servier S-5590.  
     
     
         5 . The combination of  claim 4  wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril.  
     
     
         6 . The combination of  claim 1  further characterized by said angiotensin converting enzyme inhibitor and said aldosterone receptor antagonist being present in said combination in a weight ratio range from about 0.1-to-one to about twenty-five-to-one of said angiotensin converting enzyme inhibitor to said aldosterone receptor antagonist.  
     
     
         7 . The combination of  claim 6  wherein said weight ratio range is from about 0.5-to-one to about fifteen-to-one.  
     
     
         8 . The combination of  claim 7  wherein said weight ratio range is from about 0.5-to-one to about five-to-one.  
     
     
         9 . A co-therapy for treating a cardiovascular disorder in a subject afflicted with or susceptible to multiple cardiovascular disorders, wherein said co-therapy comprises administering a therapeutically-effective amount of an angiotensin converting enzyme inhibitor and administering an aldosterone receptor antagonist in an amount therapeutically effective to antagonize aldosterone but insufficient to cause substantial diuretic effect.  
     
     
         10 . The co-therapy of  claim 9  wherein said subject is afflicted with or susceptible to hypertension and said subject further requires avoidance of the incidence of hyperkalemia.  
     
     
         11 . The co-therapy of  claim 10  wherein said subject is further susceptible to congestive heart failure.  
     
     
         12 . The co-therapy of  claim 10  wherein said subject is further susceptible to ventricular hypertrophy.  
     
     
         13 . The co-therapy of  claim 10  further characterized by administering said angiotensin converting enzyme inhibitor and said aldosterone receptor antagonist in a sequential manner.  
     
     
         14 . The co-therapy of  claim 10  further characterized by administering said angiotensin converting enzyme inhibitor and said aldosterone receptor antagonist in a substantially simultaneous manner.  
     
     
         15 . The co-therapy of  claim 9  wherein said aldosterone receptor antagonist is a spirolactone-type compound.  
     
     
         16 . The co-therapy of  claim 15  wherein said spirolactone-type compound is spironolactone.  
     
     
         17 . The co-therapy of  claim 9  wherein said amgiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat, spirapril, Bioproject BP1.137, Chiesi CHF 1514, Fisons FPL-66564, idrapril, Marion Merrell Dow MDL-100240, perindoprilat and Servier S-5590.  
     
     
         18 . The co-therapy of  claim 17  wherein said angiotensin converting enzyme inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril.  
     
     
         19 . The co-therapy of  claim 9  further characterized by said angiotensin converting enzyme inhibitor and said aldosterone receptor antagonist being used in said co-therapy in a weight ratio range from about 0.1-to-one to about twenty-five-to-one of said angiotensin converting enzyme inhibitor to said aldosterone receptor antagonist.  
     
     
         20 . The co-therapy of  claim 19  wherein said weight ratio range is from about 0.5-to-one to about fifteen-to-one.  
     
     
         21 . The co-therapy of  claim 20  wherein said weight ratio range is from about 0.5-to-one to about five-to-one.  
     
     
         22 . The co-therapy of  claim 9  wherein said angiotensin converting enzyme inhibitor is captopril, in a daily dose range from about 30 mg to about 80 mg per dose, or is enalapril in a dose range from about 5 mg to about 25 mg per dose.  
     
     
         23 . The co-therapy of  claim 22  wherein said aldosterone receptor antagonist is spironolactone in a daily dose range from about 1 mg to about 23 mg per dose.  
     
     
         24 . The co-therapy of  claim 23  wherein said spironolactone daily dose is in a range from about 5 mg to about 20 mg.  
     
     
         25 . The co-therapy of  claim 23  wherein said spironolactone daily dose is in a range from about 5 mg to about 15 mg.  
     
     
         26 . A pharmaceutically-acceptable dosage form comprising one or more excipients and a fixed combination consisting of two cardiovascular drug components, wherein said first drug component is an ACE inhibitor and said second component is spironolactone, wherein said first and second components are present in the dosage form in a weight ratio of said-first-component-to-said-component in a range from about 0.1-to-one to about 25-to-one.  
     
     
         27 . The dosage form of  claim 26  wherein said weight ratio range is 0.5-to-one to about 15-to-one.  
     
     
         28 . The dosage form of  claim 27  wherein said ACE inhibitor is selected from the group consisting of alacepril, benazepril, captopril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril, perindopril, quinapril, ramipril, saralasin acetate, temocapril, trandolapril, ceranapril, moexipril, quinaprilat and spirapril.  
     
     
         29 . The dosage form of  claim 28  wherein said ACE inhibitor is enalapril.  
     
     
         30 . The dosage form of  claim 29  wherein enalapril is present in an amount selected from a range from about 5 mg to about 20 mg and spironolactone is present in an amount selected from a range from about 5 mg to about 22.5 mg.