Enalapril compositions

Abstract

Provided herein are stable enalapril powder compositions for oral liquid formulation. 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 pharmaceutical powder for an oral liquid formulation, the powder comprising:
 (a) about 1 to about 30% (w/w) enalapril or a pharmaceutically acceptable salt thereof, and   (b) about 60 to about 99% (w/w) mannitol,   wherein, when the powder is reconstituted into an oral liquid, the liquid is homogenous and stable for at least 12 weeks at about 25-40° C. and about 55-80% relative humidity.   
     
     
         2 . The pharmaceutical powder of  claim 1 , wherein the enalapril is enalapril maleate. 
     
     
         3 . The pharmaceutical powder of  claim 1 , wherein the powder is reconstituted in water for the oral liquid. 
     
     
         4 . The pharmaceutical powder of  claim 1 , wherein the powder is reconstituted in a syrup for the oral liquid. 
     
     
         5 . The pharmaceutical powder of  claim 1 , wherein the powder further comprises a pharmaceutically acceptable excipient. 
     
     
         6 . The pharmaceutical powder of  claim 5 , wherein the pharmaceutically acceptable excipient is a sweetener, flavoring agent or preservative. 
     
     
         7 . The pharmaceutical powder of  claim 5 , wherein the pharmaceutically acceptable excipient is a sweetener. 
     
     
         8 . The pharmaceutical powder of  claim 1 , wherein the enalapril or pharmaceutically acceptable salt thereof is about 12 to about 15% (w/w). 
     
     
         9 . The pharmaceutical powder of  claim 1 , wherein the mannitol is about 80 to 85% (w/w). 
     
     
         10 . The pharmaceutical powder of  claim 1 , wherein the powder is stable for at least 180 days at about 25-40° C. and about 55-80% relative humidity. 
     
     
         11 . A pharmaceutical oral liquid formulation, the liquid formulation comprising
 (a) about 0.5 to about 5 mg/mL enalapril or a pharmaceutically acceptable salt thereof,   (b) about 3 to about 10 mg/mL mannitol, and   (c) a sweetener;   
       wherein, the liquid is homogenous and stable for at least 12 weeks at about 25-40° C. and about 55-80% relative humidity. 
     
     
         12 . The oral liquid formulation of  claim 11 , wherein the enalapril is enalapril maleate. 
     
     
         13 . The oral liquid formulation of  claim 11 , wherein the liquid formulation comprises about 1 mg/mL enalapril. 
     
     
         14 . The oral liquid formulation of  claim 11 , wherein the liquid formulation comprises about 5 mg/mL mannitol. 
     
     
         15 . The oral liquid formulation of  claim 11 , wherein the liquid formulation comprises about 6 mg/mL mannitol. 
     
     
         16 . The oral liquid formulation of  claim 11 , wherein the sweetener is sorbitol. 
     
     
         17 . The oral liquid formulation of  claim 11 , wherein the liquid formulation comprises an additional pharmaceutically acceptable excipient. 
     
     
         18 . The oral liquid formulation of  claim 11 , wherein the pharmaceutically acceptable excipient is a flavoring agent or preservative. 
     
     
         19 . The oral liquid formulation of  claim 11 , wherein the liquid formulation comprises water as the liquid vehicle. 
     
     
         20 . The oral liquid formulation of  claim 11 , wherein the liquid formulation comprises a syrup as the liquid vehicle. 
     
     
         21 . A pharmaceutical powder for an oral liquid formulation, the powder comprising:
 (a) about 1 to about 30% (w/w) enalapril or a pharmaceutically acceptable salt thereof,   (b) about 60 to about 99% (w/w) mannitol, and   (c) about 0.5 to about 2% (w/w) colloidal silicon dioxide,   wherein, when the powder is reconstituted into an oral liquid, the liquid is homogenous and stable for at least 12 weeks at about 25-40° C. and about 55-80% relative humidity.   
     
     
         22 . The pharmaceutical powder of  claim 21 , wherein the enalapril or pharmaceutically acceptable salt thereof is enalapril maleate. 
     
     
         23 . The pharmaceutical powder of  claim 21 , wherein the powder is reconstituted in water for the oral liquid. 
     
     
         24 . The pharmaceutical powder of  claim 21 , wherein the powder is reconstituted in syrup for the oral liquid. 
     
     
         25 . The pharmaceutical powder of  claim 21 , wherein the powder further comprises a pharmaceutically acceptable excipient. 
     
     
         26 . The pharmaceutical powder of  claim 25 , wherein the pharmaceutically acceptable excipient is a sweetener, flavoring agent or preservative. 
     
     
         27 . The pharmaceutical powder of  claim 25 , wherein the pharmaceutically acceptable excipient is a sweetener. 
     
     
         28 . The pharmaceutical powder of  claim 21 , wherein the enalapril or pharmaceutically acceptable salt thereof is about 12 to about 15% (w/w). 
     
     
         29 . The pharmaceutical powder of  claim 21 , wherein the mannitol is about 80 to 85% (w/w). 
     
     
         30 . The pharmaceutical powder of  claim 21 , wherein the silicon dioxide is about 1% (w/w). 
     
     
         31 . The pharmaceutical powder of  claim 21 , wherein the enalapril or pharmaceutically acceptable salt thereof is about 14% (w/w), the mannitol is about 85% (w/w) and the silicon dioxide is about 1% (w/w). 
     
     
         32 . The pharmaceutical powder of  claim 21 , wherein the powder is stable for at least 180 days at about 25-40° C. and about 55-80% relative humidity. 
     
     
         33 . A pharmaceutical oral liquid formulation, the liquid formulation comprising
 (a) about 0.5 to about 5 mg/mL enalapril or a pharmaceutically acceptable salt thereof,   (b) about 3 to about 10 mg/mL mannitol,   (c) about 0.03 to about 0.13 mg/mL colloidal silicon dioxide, and   (d) a sweetener;   
       wherein, the liquid is homogenous and stable for at least 12 weeks at about 25-40° C. and about 55-80% relative humidity. 
     
     
         34 . The oral liquid formulation of  claim 33 , wherein the enalapril is enalapril maleate. 
     
     
         35 . The oral liquid formulation of  claim 33 , wherein the liquid formulation comprises about 1 mg/mL enalapril. 
     
     
         36 . The oral liquid formulation of  claim 33 , wherein the liquid formulation comprises about 5 mg/mL mannitol. 
     
     
         37 . The oral liquid formulation of  claim 33 , wherein the liquid formulation comprises about 6 mg/mL mannitol. 
     
     
         38 . The oral liquid formulation of  claim 33 , wherein the liquid formulation comprises about 0.07 mg/mL colloidal silicon dioxide. 
     
     
         39 . The oral liquid formulation of  claim 33 , wherein the sweetener is sorbitol. 
     
     
         40 . The oral liquid formulation of  claim 33 , wherein the liquid formulation comprises an additional pharmaceutically acceptable excipient. 
     
     
         41 . The oral liquid formulation of  claim 33 , wherein the pharmaceutically acceptable excipient is a flavoring agent or preservative. 
     
     
         42 . The oral liquid formulation of  claim 33 , wherein the liquid formulation comprises water as the liquid vehicle. 
     
     
         43 . The oral liquid formulation of  claim 33 , wherein the liquid formulation comprises a syrup as the liquid vehicle. 
     
     
         44 . A pharmaceutical powder for an oral liquid formulation, the powder comprising:
 (a) about 1 to about 30% (w/w) enalapril or a pharmaceutically acceptable salt thereof,   (b) about 60 to about 99% (w/w) mannitol, and   (c) about 0.5 to about 2% (w/w) colloidal silicon dioxide,   wherein, when the powder is reconstituted into an oral liquid, the liquid maintains no more than 5% total impurities for at least 12 weeks at about 25-40° C. and about 55-80% relative humidity.   
     
     
         45 . The pharmaceutical powder of  claim 44 , wherein the liquid maintains no more than 2.5% total impurities for at least 12 weeks. 
     
     
         46 . The pharmaceutical powder of  claim 44 , wherein the liquid maintains no more than 2.5% enalaprilat for at least 12 weeks. 
     
     
         47 . The pharmaceutical powder of  claim 44 , wherein the liquid maintains no more than 2.5% diketopiperazine for at least 12 weeks. 
     
     
         48 . A pharmaceutical oral liquid formulation, the liquid formulation comprising
 (a) about 1 mg/ml enalapril or a pharmaceutically acceptable salt thereof,   (b) about 6 mg/ml mannitol,   (c) about 0.07 mg/ml colloidal silicon dioxide, and   (d) a sweetener,   wherein, when the liquid formulation is stored at up to 12 weeks at ambient or refrigerated conditions after reconstitution, the liquid formulation provides an 80-125% C max  of 58 ng/mL enalapril following oral administration at a 10 mg enalapril dosage.   
     
     
         49 . The pharmaceutical oral liquid formulation of  claim 48 , wherein, when the liquid formulation is stored at up to 12 weeks at ambient or refrigerated conditions, the liquid formulation provides an 80-125% C max  of 41 ng/mL enalaprilat following oral administration at a 10 mg enalapril dosage. 
     
     
         50 . A pharmaceutical oral liquid formulation, the liquid formulation comprising
 (a) about 1 mg/ml enalapril or a pharmaceutically acceptable salt thereof,   (b) about 6 mg/ml mannitol,   (c) about 0.07 mg/ml colloidal silicon dioxide, and   (d) a sweetener,   wherein, when the liquid formulation is stored at up to 12 weeks at ambient or refrigerated conditions, the liquid formulation provides an 80-125% AUC inf  of 102.6 h*ng/mL enalapril following oral administration at a 10 mg enalapril dosage.   
     
     
         51 . The pharmaceutical oral liquid formulation of  claim 50 , wherein, when the liquid formulation is stored at up to 12 weeks at ambient or refrigerated conditions, the liquid formulation provides an 80-125% AUC inf  of 405.3 h*ng/mL enalaprilat following oral administration at a 10 mg enalapril dosage. 
     
     
         52 . A pharmaceutical oral liquid formulation, the liquid formulation comprising
 (a) about 1 mg/ml enalapril or a pharmaceutically acceptable salt thereof,   (b) about 6 mg/ml mannitol,   (c) about 0.07 mg/ml colloidal silicon dioxide, and   (d) a sweetener,   wherein, when the liquid formulation is stored at up to 12 weeks at ambient or refrigerated conditions, the liquid formulation provides an 80-125 Tmax of 0.87 h for enalapril following oral administration at a 10 mg enalapril dosage.   
     
     
         53 . The pharmaceutical oral liquid formulation of  claim 50 , wherein, when the liquid formulation is stored at up to 12 weeks at ambient or refrigerated conditions, the liquid formulation provides an 80-125 Tmax of 3.45 h for enalaprilat following oral administration at a 10 mg enalapril dosage. 
     
     
         54 . A process for preparing a stable and homogeneous oral liquid formulation comprising enalapril, mannitol and colloidal silicon dioxide, the process which comprises the steps of:
 (i) providing an uniform powder comprising about 10 to about 20% (w/w) enalapril or a pharmaceutically acceptable salt thereof, about 60 to about 90% (w/w) mannitol, and about 0.5 to about 1% (w/w) colloidal silicon dioxide in a bottle;   (ii) adding an amount of sweetener in liquid syrup form;   (iii) shaking the liquid formulation for at least 10 seconds;   (iv) adding a second amount of sweetener in liquid syrup form;   (v) shaking the liquid formulation for at least 10 seconds; and   (vi) allowing the formulation in the bottle to stand for at least one hour to allow bubble dissipation.   
     
     
         55 . A pharmaceutical powder for an oral liquid formulation, the powder comprising:
 (a) about 14% (w/w) enalapril or a pharmaceutically acceptable salt thereof,   (b) about 85% (w/w) mannitol, and   (c) about 1% (w/w) colloidal silicon dioxide,   wherein, when the powder is reconstituted into an oral liquid, the liquid is homogenous and stable for at least 12 weeks at about 25±5° C. and 55±10% relative humidity.   
     
     
         56 . The pharmaceutical powder of  claim 55 , wherein the enalapril or pharmaceutically acceptable salt thereof is enalapril maleate. 
     
     
         57 . The pharmaceutical powder of  claim 55 , wherein the powder is reconstituted in water for the oral liquid. 
     
     
         58 . The pharmaceutical powder of  claim 55 , wherein the powder is reconstituted in syrup for the oral liquid. 
     
     
         59 . The pharmaceutical powder of  claim 55 , wherein the powder further comprises a pharmaceutically acceptable excipient. 
     
     
         60 . The pharmaceutical powder of  claim 59 , wherein the pharmaceutically acceptable excipient is a sweetener, flavoring agent or preservative. 
     
     
         61 . The pharmaceutical powder of  claim 59 , wherein the pharmaceutically acceptable excipient is a sweetener. 
     
     
         62 . The pharmaceutical powder of  claim 61 , wherein the sweetener is a solid. 
     
     
         63 . The pharmaceutical powder of  claim 61 , wherein the sweetener is a liquid. 
     
     
         64 . The pharmaceutical powder of  claim 55 , wherein the powder is stable for at least six months at ambient, accelerated or refrigerated conditions. 
     
     
         65 . The pharmaceutical powder of  claim 55 , wherein the liquid comprises
 (a) about 1 mg/ml enalapril or a pharmaceutically acceptable salt thereof,   (b) about 6 mg/ml mannitol, and   (c) about 0.07 mg/ml colloidal silicon dioxide.   
     
     
         66 . The pharmaceutical powder of  claim 65 , wherein the liquid further comprises a pharmaceutically acceptable excipient. 
     
     
         67 . The pharmaceutical powder of  claim 65 , wherein the pharmaceutically acceptable excipient is a sweetener, flavoring agent or preservative. 
     
     
         68 . The pharmaceutical powder of  claim 65 , wherein the pharmaceutically acceptable excipient is a sweetener. 
     
     
         69 . The pharmaceutical powder of  claim 68 , wherein the sweetener is a syrup. 
     
     
         70 . The pharmaceutical powder of  claim 55 , wherein the powder comprises about 150 mg enalapril, about 890 mg mannitol and 10 mg colloidal silicon dioxide. 
     
     
         71 . A method of treating hypertension in a subject comprising administering to that subject a therapeutically effective amount of an enalapril oral liquid formulation, the enalapril oral liquid formulation reconstituted from a pharmaceutical powder comprising:
 (a) about 14% (w/w) enalapril or a pharmaceutically acceptable salt thereof,   (b) about 85% (w/w) mannitol, and   (c) about 1% (w/w) colloidal silicon dioxide,   wherein, when the powder is reconstituted into an oral liquid, the liquid is homogenous and stable for at least 12 weeks at about 25±5° C. and 60±10% relative humidity.   
     
     
         72 . The method of  claim 72 , wherein the hypertension is primary (essential) hypertension. 
     
     
         73 . The method of  claim 72 , wherein the hypertension is secondary hypertension. 
     
     
         74 . The method of  claim 72 , wherein the subject has blood pressure values are greater than or equal to 140/90 mm Hg. 
     
     
         75 . The method of  claim 72 , wherein the subject is an adult. 
     
     
         76 . The method of  claim 72 , wherein the subject elderly. 
     
     
         77 . The method of  claim 72 , wherein the subject is a child. 
     
     
         78 . The method of  claim 72 , wherein the enalapril or pharmaceutically acceptable salt thereof is enalapril maleate. 
     
     
         79 . The method of  claim 72 , wherein the powder is reconstituted in water for the oral liquid. 
     
     
         80 . The method of  claim 72 , wherein the powder is reconstituted in syrup for the oral liquid. 
     
     
         81 . The method of  claim 72 , wherein the powder further comprises a pharmaceutically acceptable excipient. 
     
     
         82 . The method of  claim 81 , wherein the pharmaceutically acceptable excipient is a sweetener, flavoring agent or preservative. 
     
     
         83 . The method of  claim 81 , wherein the pharmaceutically acceptable excipient is a sweetener. 
     
     
         84 . The method of  claim 83 , wherein the sweetener is a solid. 
     
     
         85 . The method of  claim 72 , wherein the powder is stable for at least six months at ambient, accelerated or refrigerated conditions. 
     
     
         86 . The method of  claim 72 , wherein the liquid comprises
 (a) about 1 mg/ml enalapril or a pharmaceutically acceptable salt thereof,   (b) about 6 mg/ml mannitol, and   (c) about 0.07 mg/ml colloidal silicon dioxide.   
     
     
         87 . The method of  claim 86 , wherein the liquid further comprises a pharmaceutically acceptable excipient. 
     
     
         88 . The method of  claim 87 , wherein the pharmaceutically acceptable excipient is a sweetener, flavoring agent or preservative. 
     
     
         89 . The method of  claim 87 , wherein the pharmaceutically acceptable excipient is a sweetener. 
     
     
         90 . The method of  claim 72 , wherein the powder comprises about 150 mg enalapril, about 890 mg mannitol and 10 mg colloidal silicon dioxide. 
     
     
         91 . The method of  claim 86 , wherein the enalapril oral liquid is administered to the subject at a daily dosage from about 0.01 to about 1.0 mg/kg per body weight. 
     
     
         92 . The method of  claim 86 , wherein the enalapril oral liquid is administered to the subject at a daily dosage of about 5 mg enalapril. 
     
     
         93 . The method of  claim 86 , wherein the enalapril oral liquid is administered to the subject at a daily dosage of about 40 mg enalapril. 
     
     
         94 . The method of  claim 72 , wherein the enalapril oral liquid is administered to the subject in a fasted state. 
     
     
         95 . The method of  claim 72 , wherein the enalapril oral liquid is administered to the subject in a fed state. 
     
     
         96 . The method of  claim 72 , wherein the enalapril oral liquid further administered in combination with an agent selected from the group consisting of diuretics, beta blockers, alpha blockers, mixed alpha and beta blockers, calcium channel blockers, angiotensin II receptor antagonists, ACE inhibitors, aldosterone antagonists and alpha-2 agonists. 
     
     
         97 . A method of treating prehypertension in a subject comprising administering to that subject a therapeutically effective amount of an enalapril oral liquid formulation, the enalapril oral liquid formulation reconstituted from a pharmaceutical powder comprising:
 (a) about 14% (w/w) enalapril or a pharmaceutically acceptable salt thereof,   (b) about 85% (w/w) mannitol, and   (c) about 1% (w/w) colloidal silicon dioxide,   wherein, when the powder is reconstituted into an oral liquid, the liquid is homogenous and stable for at least 12 weeks at about 25±5° C. and 60±10% relative humidity.   
     
     
         98 . The method of  claim 97 , wherein the subject has blood pressure values of about 120-139/80-89 mm Hg. 
     
     
         99 . A method of treating heart failure in a subject comprising administering to that subject a therapeutically effective amount of an enalapril oral liquid formulation, the enalapril oral liquid formulation reconstituted from a pharmaceutical powder comprising:
 (a) about 14% (w/w) enalapril or a pharmaceutically acceptable salt thereof,   (b) about 85% (w/w) mannitol, and   (c) about 1% (w/w) colloidal silicon dioxide,   wherein, when the powder is reconstituted into an oral liquid, the liquid is homogenous and stable for at least 12 weeks at about 25±5° C. and 60±10% relative humidity.   
     
     
         100 . A method of treating left ventricular dysfunction in a subject comprising administering to that subject a therapeutically effective amount of an enalapril oral liquid formulation, the enalapril oral liquid formulation reconstituted from a pharmaceutical powder comprising:
 (a) about 14% (w/w) enalapril or a pharmaceutically acceptable salt thereof,   (b) about 85% (w/w) mannitol, and   (c) about 1% (w/w) colloidal silicon dioxide,   wherein, when the powder is reconstituted into an oral liquid, the liquid is homogenous and stable for at least 12 weeks at about 25±5° C. and 60±10% relative humidity.