Enalapril formulations
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.
1. A stable oral liquid formulation, consisting essentially of:
(i) about 0.6 to about 1.2 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;
(ii) a preservative, wherein the preservative is sodium benzoate, ascorbic acid, ascorbyl palmitate, BHA, BHT, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, benzoic acid, potassium sorbate, vanillin, a paraben, or a mixture of parabens; and
(iii) water;
wherein the formulation optionally comprises a buffer to maintain the pH about 4.5 or below, a sweetener, a flavoring agent, or any combination thereof;
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 , comprising a sweetener.
3. The stable oral liquid formulation of claim 1 , comprising a buffer, wherein the buffer comprises a citrate, a phosphate, a citrate/phosphate, an acetate, a glycinate, an amino acid, or a tartrate buffer.
4. The stable oral liquid formulation of claim 3 , wherein the buffer is present at a concentration of about 10 mM to about 20 mM.
5. The stable oral liquid formulation of claim 3 , wherein the buffer maintains the pH between about 3 and about 4.
6. The stable oral liquid formulation of claim 1 , comprising about 1.0 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof.
7. The stable oral liquid formulation of claim 1 , wherein the enalapril or a pharmaceutically acceptable salt or solvate thereof is enalapril maleate.
8. The stable oral liquid formulation of claim 1 , wherein the preservative is sodium benzoate, ascorbic acid, ascorbyl palmitate, BHA, BHT, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, benzoic acid, potassium sorbate, or vanillin.
9. The stable oral liquid formulation of claim 1 , wherein the preservative is sodium benzoate.
10. The stable oral liquid formulation of claim 1 , wherein the preservative is present at about 0.1 mg/ml to about 2 mg/ml in the oral liquid formulation.
11. The stable oral liquid formulation of claim 1 , wherein the preservative is present at about 0.1 mg/ml to about 0.5 mg/ml in the oral liquid formulation.
12. The stable oral liquid formulation of claim 1 , wherein the formulation is stable at about 5±3° C. for at least 18 months.
13. A stable oral liquid formulation, consisting essentially of:
(i) about 0.6 to about 1.2 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;
(ii) a preservative, wherein the preservative is sodium benzoate, ascorbic acid, ascorbyl palmitate, BHA, BHT, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, benzoic acid, potassium sorbate, vanillin, a paraben, or a mixture of parabens; and
(iii) water;
wherein the formulation optionally comprises a buffer that is present in the formulation at a concentration of up to 20 mM, a sweetener, a flavoring agent, or any combination thereof;
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.
14. The stable oral liquid formulation of claim 13 , comprising a sweetener.
15. The stable oral liquid formulation of claim 13 , comprising a buffer, wherein the buffer comprises a citrate, a phosphate, a citrate/phosphate, an acetate, a glycinate, an amino acid, or a tartrate buffer.
16. The stable oral liquid formulation of claim 15 , wherein the buffer maintains the pH about 4.5 or below.
17. The stable oral liquid formulation of claim 13 , wherein the enalapril or a pharmaceutically acceptable salt or solvate thereof is enalapril maleate.
18. The stable oral liquid formulation of claim 13 , wherein the preservative is sodium benzoate.
19. The stable oral liquid formulation of claim 13 , wherein the preservative is paraben or a mixture of parabens.
20. The stable oral liquid formulation of claim 13 , wherein the preservative is present at about 0.1 mg/ml to about 2 mg/ml in the oral liquid formulation.
21. The stable oral liquid formulation of claim 15 , wherein the buffer is present in the formulation at a concentration of about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, or about 20 mM.
22. The stable oral liquid formulation of claim 13 , wherein the formulation is stable at about 5±3° C. for at least 18 months.
23. The stable oral liquid formulation of claim 3 , wherein the buffer is present at a concentration of about 5 mM to about 20 mM.