Enalapril formulations

• US 10,154,987 B2
• Filed: 06/08/2018
• Issued: 12/18/2018
• Est. Priority Date: 03/18/2016
• Status: Active Grant

• Current Assignee: Azurity Pharmaceuticals, Inc.
• Original Assignee: Silvergate Pharmaceuticals Inc (Azurity Pharmaceuticals, Inc.)
• Inventors: Mosher, Gerold L., Miles, David W.
• Primary Examiner(s): Lundgren, Jeffrey S
• Assistant Examiner(s): Springer, Stephanie K
• Application Number:
  US16/003,994
• Publication Number:
  US 20180289669A1
• Time in Patent Office: 193 Days
• Field of Search: None
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006

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.

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, the stable oral liquid formulation comprising:

(i) about 0.6 to about 1.2 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;

(ii) a buffer comprising about 0.8 to about 3.5 mg/ml citric acid and about 0.1 to about 0.8 mg/ml sodium citrate;

(iii) about 0.7 to about 1.2 mg/ml sodium benzoate; and

(iv) water;

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 method of claim 1 further comprising about 0.5 to about 0.9 mg/ml sucralose.

3. The method of claim 1, wherein the formulation does not contain mannitol or silicon dioxide.

4. The method of claim 1, wherein the pH of the stable oral liquid formulation is between about 3 and about 3.5.

5. The method of claim 1, wherein the pH of the stable oral liquid formulation is about 3.3.

6. The method of claim 1, wherein the formulation is stable at about 5±

3°

C. for at least 18 months.

7. The method of claim 1, wherein the formulation is stable at about 5±

3°

C. for at least 24 months.

8. The method of claim 1, wherein the hypertension is primary (essential) hypertension.

9. The method of claim 1, wherein the hypertension is secondary hypertension.

10. The method of claim 1, wherein the subject has blood pressure values greater than or equal to 140/90 mmm Hg.

11. The method of claim 1, wherein the subject is elderly or a child.

12. 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.

13. A method of treating hypertension in a subject comprising administering to that subject a therapeutically effective amount of a stable oral liquid formulation, the stable oral liquid formulation comprising:

(i) about 10% to about 25% (w/w of solids) enalapril or a pharmaceutically acceptable salt or solvate thereof;

(ii) a buffer comprising about 17% to about 47% (w/w of solids) citric acid and about 1% to about 11% (w/w of solids) sodium citrate;

(iii) about 3% to about 25% (w/w of solids) sodium benzoate; and

(iv) water;

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 method of claim 13 further comprising about 8% to about 18% (w/w of solids) sucralose.

15. The method of claim 13, wherein the formulation does not contain mannitol or silicon dioxide.

16. The method of claim 13, wherein the pH of the stable oral liquid formulation is between about 3 and about 3.5.

17. The method of claim 13, wherein the formulation is stable at about 5±

3°

C. for at least 24 months.

18. A method of treating heart failure in a subject comprising administering to that subject a therapeutically effective amount of a stable oral liquid formulation, the stable oral liquid formulation comprising:

(i) about 0.6 to about 1.2 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;

(ii) a buffer comprising about 0.8 to about 3.5 mg/ml citric acid and about 0.1 to about 0.8 mg/ml sodium citrate;

(iii) about 0.7 to about 1.2 mg/ml sodium benzoate; and

(iv) water;

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.

19. The method of claim 18 further comprising about 0.5 to about 0.9 mg/ml sucralose.

20. The method of claim 18, wherein the formulation does not contain mannitol or silicon dioxide.

21. The method of claim 18, wherein the pH of the stable oral liquid formulation is between about 3 and about 3.5.

22. The method of claim 18, wherein the pH of the stable oral liquid formulation is about 3.3.

23. The method of claim 18, wherein the formulation is stable at about 5±

3°

C. for at least 24 months.

24. The method of claim 18, wherein the heart failure is congestive heart failure.

25. 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, the stable oral liquid formulation comprising:

(i) about 0.6 to about 1.2 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;

(ii) a buffer comprising about 0.8 to about 3.5 mg/ml citric acid and about 0.1 to about 0.8 mg/ml sodium citrate;

(iii) about 0.7 to about 1.2 mg/ml sodium benzoate; and

(iv) water;

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.

26. The method of claim 25 further comprising about 0.5 to about 0.9 mg/ml sucralose.

27. The method of claim 25, wherein the formulation does not contain mannitol or silicon dioxide.

28. The method of claim 25, wherein the pH of the stable oral liquid formulation is between about 3 and about 3.5.

29. The method of claim 25, wherein the pH of the stable oral liquid formulation is about 3.3.

30. The method of claim 25, wherein the formulation is stable at about 5±

3°

C. for at least 24 months.