Enalapril formulations

Abstract

Provided herein are stable enalapril oral liquid formulations. Also provided herein are methods of using enalapril oral liquid formulations for the treatment of certain diseases including hypertension, heart failure and asymptomatic left ventricular dysfunction.

What is claimed is: 
     
         1 . A stable oral liquid formulation, consisting essentially of:
 (i) about 1 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;   (ii) a sweetener,   (iii) a preservative, wherein the preservative comprises
 (a) sodium benzoate, wherein the sodium benzoate is present in the oral liquid formulation at about 1 mg/ml; or 
 (b) a paraben or a mixture of parabens, wherein the paraben or the mixture of parabens is present in the oral liquid formulation at about 0.1 mg/ml to about 2 mg/ml; 
   (iv) optionally a buffer comprising citric acid and sodium citrate, wherein the buffer is present in the oral liquid formulation between about 5 mM and about 20 mM;   (v) water; and   (vi) optionally a flavoring agent;   wherein the formulation is stable at about 5±3° C. for at least 12 months; and   wherein the stable oral liquid formulation has about 95% w/w or greater of the initial enalapril amount and about 5% w/w or less total impurity or related substances at the end of the given storage period.   
     
     
         2 . The stable oral liquid formulation of  claim 1 , wherein the formulation is stable at about 5±3° C. for at least 18 months. 
     
     
         3 . The stable oral liquid formulation of  claim 1 , wherein the formulation is stable at about 5±3° C. for at least 24 months. 
     
     
         4 . The stable oral liquid formulation of  claim 1 , wherein the formulation has a pH of less than about 4. 
     
     
         5 . The stable oral liquid formulation of  claim 1 , wherein the formulation has a pH of less than about 3.5. 
     
     
         6 . The stable oral liquid formulation of  claim 1 , wherein the sweetener is sucralose. 
     
     
         7 . The stable oral liquid formulation of  claim 6 , wherein the sucralose is present in about 0.5 mg/ml to about 0.9 mg/ml in the oral liquid formulation. 
     
     
         8 . The stable oral liquid formulation of  claim 6 , wherein the sucralose is present at about 8% w/w to about 18% w/w of the solids in the oral liquid formulation. 
     
     
         9 . The stable oral liquid formulation of  claim 1 , comprising a flavoring agent. 
     
     
         10 . The stable oral liquid formulation of  claim 1 , wherein the paraben or the mixture of parabens is a mixture of parabens. 
     
     
         11 . The stable oral liquid formulation of  claim 1 , wherein the paraben or the mixture of parabens is methylparaben, ethylparaben, propylparaben, butylparaben, salts thereof, or a combination thereof. 
     
     
         12 . The stable oral liquid formulation of  claim 1 , wherein the mixture of parabens comprises methylparaben and propylparaben. 
     
     
         13 . The stable oral liquid formulation of  claim 1 , wherein the paraben or the mixture of parabens is present at about 0.1 mg/ml to about 0.5 mg/ml in the oral liquid formulation. 
     
     
         14 . The stable oral liquid formulation of  claim 1 , wherein the paraben or the mixture of parabens is present at about 0.5 mg/ml in the oral liquid formulation. 
     
     
         15 . The stable oral liquid formulation of  claim 1 , wherein the citric acid is present at about 2 to about 3.5 mg/ml in the oral liquid formulation. 
     
     
         16 . The stable oral liquid formulation of  claim 1 , wherein the citric acid is present at about 10% w/w to about 50% w/w of the solids in the oral liquid formulation. 
     
     
         17 . The stable oral liquid formulation of  claim 1 , wherein the sodium citrate is present at about 0.1 to about 0.8 mg/ml in the oral liquid formulation. 
     
     
         18 . The stable oral liquid formulation of  claim 1 , wherein the sodium citrate is present at about 1% w/w to about 15% w/w of the solids in the oral liquid formulation. 
     
     
         19 . The stable oral liquid formulation of  claim 1 , consisting essentially of:
 (i) about 1 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;   (ii) a sweetener, wherein the sweetener is sucralose and is present at about 8% w/w to about 18% w/w of the solids in the oral liquid formulation;   (iii) a preservative, wherein the preservative comprises a mixture of parabens, wherein the mixture of parabens comprises methylparaben and propylparaben, and wherein the mixture of parabens is present in the oral liquid formulation at about 0.5 mg/ml;   (iv) a buffer comprising citric acid and sodium citrate, wherein the citric acid is present at about 10% w/w to about 50% w/w of the solids in the oral liquid formulation and the sodium citrate is present at about 1% w/w to about 15% w/w of the solids in the oral liquid formulation;   (v) water; and   (vi) optionally a flavoring agent.