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 buffer to maintain the pH about 4.5 or below, wherein the buffer concentration is about 5 mM to about 20 mM;
(iii) a preservative, wherein the preservative is a paraben or a mixture of parabens; and
(iv) water;
wherein the formulation optionally comprises a sweetener, a flavoring agent, or both;
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 flavoring agent.
4. The stable oral liquid formulation of claim 1 , wherein the buffer comprises a citrate, a phosphate, a citrate/phosphate, an acetate, a glycinate, an amino acid, or a tartrate buffer.
5. The stable oral liquid formulation of claim 1 , wherein the buffer concentration is about 10 mM to about 20 mM.
6. The stable oral liquid formulation of claim 1 , wherein the buffer maintains the pH between about 3 and about 4.
7. The stable oral liquid formulation of claim 1 , wherein the buffer maintains the pH at about 3.3.
8. The stable oral liquid formulation of claim 1 , comprising about 1.0 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof.
9. The stable oral liquid formulation of claim 1 , wherein the enalapril or a pharmaceutically acceptable salt or solvate thereof is enalapril maleate.
10. The stable oral liquid formulation of claim 1 , wherein the preservative 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 preservative is a mixture of 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 2 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 1.6 mg/ml to about 2 mg/ml in the oral liquid formulation.
15. 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.
16. The stable oral liquid formulation of claim 1 , wherein the paraben or the mixture of parabens is present at about 2% w/w to about 30% w/w of the solids in the oral liquid formulation.
17. The stable oral liquid formulation of claim 1 , wherein the formulation is stable at about 5±3° C. for at least 18 months.
18. The stable oral liquid formulation of claim 1 , wherein the formulation is stable at about 5±3° C. for at least 24 months.
19. 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 buffer to maintain the pH about 4.5 or below, wherein the buffer concentration is about 5 mM to about 20 mM;
(iii) a preservative, wherein the preservative is methylparaben, ethylparaben, propylparaben, butylparaben, or a combination thereof; and
(iv) water;
wherein the formulation optionally comprises a sweetener, a flavoring agent, or both;
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.
20. The stable oral liquid formulation of claim 19 , wherein the buffer comprises a citrate, a phosphate, a citrate/phosphate, an acetate, a glycinate, an amino acid, or a tartrate buffer.
21. The stable oral liquid formulation of claim 19 , wherein the buffer concentration is about 10 mM to about 20 mM.
22. The stable oral liquid formulation of claim 19 , wherein the buffer maintains the pH between about 3 and about 4.
23. The stable oral liquid formulation of claim 19 , wherein the buffer maintains the pH at about 3.3.
24. The stable oral liquid formulation of claim 19 , comprising about 1.0 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof.
25. The stable oral liquid formulation of claim 19 , wherein the enalapril or a pharmaceutically acceptable salt or solvate thereof is enalapril maleate.
26. The stable oral liquid formulation of claim 19 , wherein the preservative is a mixture of parabens that are selected from methylparaben, ethylparaben, propylparaben, and butylparaben.
27. The stable oral liquid formulation of claim 19 , wherein the preservative is present at about 0.1 mg/ml to about 2 mg/ml in the oral liquid formulation.
28. The stable oral liquid formulation of claim 19 , wherein the preservative is present at about 1.6 mg/ml to about 2 mg/ml in the oral liquid formulation.
29. The stable oral liquid formulation of claim 19 , wherein the preservative is present at about 0.1 mg/ml to about 0.5 mg/ml in the oral liquid formulation.
30. 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 buffer to maintain the pH about 4.5 or below;
(iii) a preservative, wherein the preservative is methylparaben, ethylparaben, propylparaben, butylparaben, or a combination thereof; and
(iv) water;
wherein the formulation optionally comprises a sweetener, a flavoring agent, or both;
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.