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) about 1 mg/ml of a preservative that is sodium benzoate; 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 2 , wherein the sweetener is sucralose.
4. The stable oral liquid formulation of claim 1 , comprising a flavoring agent.
5. The stable oral liquid formulation of claim 1 , wherein the buffer comprises a citrate, a phosphate, a citrate/phosphate, an acetate, a glycinate, or a tartrate buffer.
6. The stable oral liquid formulation of claim 1 , wherein the buffer comprises citric acid and sodium citrate.
7. The stable oral liquid formulation of claim 6 , wherein the citric acid and/or the sodium citrate is anhydrous, monohydrate or dihydrate.
8. The stable oral liquid formulation of claim 1 , wherein the buffer concentration is about 10 mM to about 20 mM.
9. The stable oral liquid formulation of claim 1 , wherein the buffer maintains the pH between about 3 and about 4.
10. The stable oral liquid formulation of claim 1 , wherein the buffer maintains the pH at about 3.3.
11. The stable oral liquid formulation of claim 1 , wherein the formulation is stable at about 5±3° C. for at least 18 months.
12. The stable oral liquid formulation of claim 1 , wherein the formulation is stable at about 5±3° C. for at least 24 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 buffer to maintain the pH about 4.5 or below, wherein the buffer concentration is about 5 mM to about 20 mM;
(iii) about 1 mg/ml of a preservative that is sodium benzoate; and
(iv) water;
wherein the formulation comprises a sweetener and 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.
14. A stable oral liquid formulation, comprising consisting essentially of:
(i) about 10% to about 25% (w/w of solids) 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) about 19% (w/w of solids) of a preservative that is sodium benzoate; 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.
15. The stable oral liquid formulation of claim 14 , comprising a sweetener.
16. The stable oral liquid formulation of claim 15 , wherein the sweetener is sucralose.
17. The stable oral liquid formulation of claim 14 , comprising a flavoring agent.
18. The stable oral liquid formulation of claim 14 , wherein the buffer comprises a citrate, a phosphate, a citrate/phosphate, an acetate, a glycinate, an amino acid, or a tartrate buffer.
19. The stable oral liquid formulation of claim 14 , wherein the buffer comprises citric acid and sodium citrate.
20. The stable oral liquid formulation of claim 19 , wherein the citric acid and/or the sodium citrate is anhydrous, monohydrate or dihydrate.
21. The stable oral liquid formulation of claim 14 , wherein the buffer concentration is about 10 mM to about 20 mM.
22. The stable oral liquid formulation of claim 14 , wherein the buffer maintains the pH between about 3 and about 3.5.
23. The stable oral liquid formulation of claim 14 , wherein the buffer maintains the pH at about 3.3.
24. The stable oral liquid formulation of claim 14 , wherein the formulation is stable at about 5±3° C. for at least 18 months.
25. The stable oral liquid formulation of claim 14 , wherein the formulation is stable at about 5±3° C. for at least 24 months.
26. 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 citrate buffer to maintain the pH about 4.5 or below comprising citric acid and sodium citrate;
(iii) about 1 mg/ml of a preservative that is sodium benzoate; 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.
27. The stable oral liquid formulation of claim 26 , wherein the citric acid and/or the sodium citrate is anhydrous, monohydrate or dihydrate.
28. The stable oral liquid formulation of claim 1 , comprising about 1.0 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof.
29. The stable oral liquid formulation of claim 1 , wherein the enalapril or a pharmaceutically acceptable salt or solvate thereof is enalapril maleate.
30. The stable oral liquid formulation of claim 1 , wherein the buffer comprises a buffer selected from a citrate, a phosphate, a citrate/phosphate, an acetate, a tartrate, a lactate, a glycinate, and an amino acid buffer.