Enalapril compositions
Inventors
Rajewski, Lian G. • Rajewski, Roger A. • Haslam, John L. • Heppert, Kathleen • Beckloff, Michael C. • Segrave, Frank • Mauro, Robert • Colabuono, Peter
Assignees
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Publication Number
US-9968553-B1
Publication Date
2018-05-15
Expiration Date
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.
Core Innovation
The invention relates to stable enalapril powder compositions that are reconstituted into homogeneous, stable oral liquid formulations. The powder includes enalapril or a pharmaceutically acceptable salt, a stability agent, and colloidal silicon dioxide, and the reconstituted oral liquid is described as homogeneous and stable for at least 12 weeks at about 25±15°C and 55±10% relative humidity.
The disclosed powder formulations use enalapril with stability agents such as mannitol and optionally colloidal silicon dioxide. Stability of the powder and/or the reconstituted liquid is described with impurity limits and homogeneity observations after storage under ambient, accelerated, and refrigerated conditions, and embodiments are described where the powder remains stable for at least six months across those storage condition categories.
The invention also includes reconstitution into an oral liquid formulation and describes outcomes such as homogeneity and stability of the resulting oral liquid. The document reports kinetic equivalence after storage and provides a clinical bioavailability comparison between an oral liquid reconstituted from the powder and Vasotec® tablets, including fasted and fed conditions with reported pharmacokinetic parameters and exposure relationships.
Claims Coverage
The partial content identifies four independent claims, each directed to administering a reconstitutable pharmaceutical powder to treat a specific cardiovascular condition, where the powder consists essentially of enalapril or a pharmaceutically acceptable salt thereof together with a stability agent and colloidal silicon dioxide, and where the reconstituted oral liquid is homogeneous and stable for at least 12 weeks under defined storage conditions. The independent claims differ by the treatment indication and, in dependent claim members, by specific narrowing criteria such as salt form, subject blood-pressure ranges, and selected stability agents.
Reconstitutable enalapril powder forming stable homogeneous oral liquid
A method comprising administering a pharmaceutical powder reconstituted into an oral liquid, where the powder consists essentially of enalapril or a pharmaceutically acceptable salt thereof, a stability agent, and colloidal silicon dioxide, and the reconstituted liquid is homogeneous and stable for at least 12 weeks at about 25±15°C and 55±10% relative humidity.
Enalapril stability formulation with mannitol and colloidal silicon dioxide
A method of treating hypertension or prehypertension comprising administering a pharmaceutical powder reconstituted into an oral liquid, where the powder consists essentially of enalapril or a pharmaceutically acceptable salt thereof, mannitol, and colloidal silicon dioxide, and the reconstituted liquid is homogeneous and stable for at least 12 weeks at about 25±15°C and 55±10% relative humidity.
Reconstitutable enalapril powder for heart failure or left ventricular dysfunction
A method of treating heart failure or left ventricular dysfunction comprising administering a pharmaceutical powder reconstituted into an oral liquid, where the powder consists essentially of enalapril or a pharmaceutically acceptable salt thereof, a stability agent, and colloidal silicon dioxide, and the reconstituted liquid is homogeneous and stable for at least 12 weeks at about 25±15°C and 55±10% relative humidity.
Enalapril-mannitol colloidal silicon dioxide powder for heart failure or left ventricular dysfunction
A method of treating heart failure or left ventricular dysfunction comprising administering a pharmaceutical powder reconstituted into an oral liquid, where the powder consists essentially of enalapril or a pharmaceutically acceptable salt thereof, mannitol, and colloidal silicon dioxide, and the reconstituted liquid is homogeneous and stable for at least 12 weeks at about 25±15°C and 55±10% relative humidity.
Across the identified independent claims, the claimed coverage centers on administering a reconstitutable pharmaceutical powder that forms a homogeneous and stable oral liquid, with the powder essentially containing enalapril or a pharmaceutically acceptable salt, a stability agent including embodiments with mannitol, and colloidal silicon dioxide, and with stability of the reconstituted liquid for at least 12 weeks at about 25±15°C and 55±10% relative humidity. The independent claims allocate the treatment indication between hypertension/prehypertension and heart failure/left ventricular dysfunction.
Stated Advantages
Reconstituted oral liquid homogeneity and stability for at least 12 weeks at about 25±15°C and 55±10% relative humidity.
Reconstituted oral liquid stability described as remaining stable for at least six months under ambient, accelerated or refrigerated conditions.
Stable powder and/or reconstituted liquid stability is described with impurity limits and kinetic equivalence after storage.
Bioavailability comparison is described between an oral liquid reconstituted from the powder and Vasotec® tablets under fasted and fed conditions with acceptable exposure relationships.
Documented Applications
Treating hypertension or prehypertension in a subject by administering an enalapril-containing pharmaceutical powder reconstituted into an oral liquid.
Treating heart failure or left ventricular dysfunction in a subject by administering an enalapril-containing pharmaceutical powder reconstituted into an oral liquid.
Clinical bioavailability use: comparing pharmacokinetic parameters of an oral liquid reconstituted from the powder versus Vasotec® tablets under fasted and fed conditions.
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