Claims for Patent: 9,808,442

Summary for Patent: 9,808,442

Title:	Enalapril formulations
Abstract:	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.
Inventor(s):	Mosher; Gerold L. (Kansas City, MO), Miles; David W. (Kansas City, MO)
Assignee:	SILVERGATE PHARMACEUTICALS, INC. (Greenwood Village, CO)
Application Number:	15/613,622
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,808,442
Patent Claims:	1. A method of treating hypertension in a subject comprising administering to that subject a therapeutically effective amount of a stable oral liquid formulation comprising: (i) about 1 mg/ml enalapril maleate; (ii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; (iii) about 1 mg/ml of a preservative that is sodium benzoate; and (iv) water; wherein the pH of the stable oral liquid formulation is less than about 3.5; wherein the stable oral liquid formulation is stable at about 5.+-.3.degree. C. for at least 12 months; and wherein the stable oral liquid formulation has about 95% or greater of the initial enalapril amount and about 5% w/w or less total impurities or related substances at the end of the given storage period. 2. The method of claim 1, wherein the stable oral liquid formulation further comprises a flavoring agent. 3. The method of claim 1, wherein the stable oral liquid formulation further comprises about 0.70 mg/ml of a sweetener that is sucralose. 4. The method of claim 1, wherein the pH is between about 3 and about 3.5. 5. The method of claim 1, wherein the pH is about 3.3. 6. The method of claim 1, wherein the citrate concentration in the buffer is about 5 mM to about 20 mM. 7. The method of claim 1, wherein the citrate concentration in the buffer is about 10 mM. 8. The method of claim 1, wherein the stable oral liquid formulation is stable at about 5.+-.3.degree. C. for at least 18 months. 9. The method of claim 1, wherein the stable oral liquid formulation is stable at about 5.+-.3.degree. C. for at least 24 months. 10. The method of claim 1, wherein the stable oral liquid formulation does not contain mannitol or silicon dioxide. 11. The method of claim 1, wherein the hypertension is primary (essential) hypertension. 12. The method of claim 1, wherein the hypertension is secondary hypertension. 13. The method of claim 1, wherein the subject has blood pressure values greater than or equal to 140/90 mmm Hg. 14. The method of claim 1, wherein the subject is elderly or a child. 15. The method of claim 1, wherein the stable oral liquid formulation is 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. 16. A method of treating heart failure in a subject comprising administering to that subject a therapeutically effective amount of a stable oral liquid formulation comprising: (i) about 1 mg/ml enalapril maleate; (ii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; and (iii) about 1 mg/ml of a preservative that is sodium benzoate; and (iv) water; wherein the pH of the stable oral liquid formulation is less than about 3.5; wherein the stable oral liquid formulation is stable at about 5.+-.3.degree. C. for at least 12 months; and wherein the stable oral liquid formulation has about 95% or greater of the initial enalapril amount and about 5% w/w or less total impurities or related substances at the end of the given storage period. 17. The method of claim 16, wherein the stable oral liquid formulation further comprises about 0.70 mg/ml of a sweetener that is sucralose. 18. The method of claim 16, wherein the pH is between about 3 and about 3.5. 19. The method of claim 16, wherein the pH is between about 3.3. 20. The method of claim 16, wherein the citrate concentration in the buffer is about 5 mM to about 20 mM. 21. The method of claim 16, wherein the stable oral liquid formulation is stable at about 5.+-.3.degree. C. for at least 24 months. 22. The method of claim 16, wherein the stable oral liquid formulation does not contain mannitol or silicon dioxide. 23. The method of claim 16, wherein the heart failure is congestive heart failure. 24. A method of treating left ventricular dysfunction in a subject comprising administering to that subject a therapeutically effective amount of a stable oral liquid formulation comprising: (i) about 1 mg/ml enalapril maleate; (ii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate; and (iii) about 1 mg/ml of a preservative that is sodium benzoate; and (iv) water; wherein the pH of the stable oral liquid formulation is less than about 3.5; wherein the stable oral liquid formulation is stable at about 5.+-.3.degree. C. for at least 12 months; and wherein the stable oral liquid formulation has about 95% or greater of the initial enalapril amount and about 5% w/w or less total impurities or related substances at the end of the given storage period. 25. The method of claim 24, wherein the stable oral liquid formulation further comprises about 0.70 mg/ml of a sweetener that is sucralose. 26. The method of claim 24, wherein the pH is between about 3 and about 3.5. 27. The method of claim 24, wherein the pH is between about 3.3. 28. The method of claim 24, wherein the citrate concentration in the buffer is about 5 mM to about 20 mM. 29. The method of claim 24, wherein the stable oral liquid formulation is stable at about 5.+-.3.degree. C. for at least 24 months. 30. The method of claim 24, wherein the stable oral liquid formulation does not contain mannitol or silicon dioxide.