Enalapril formulations

• US 11,040,023 B2
• Filed: 01/15/2021
• Issued: 06/22/2021
• 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): Rao, Savitha M
• Application Number:
  US17/150,587
• Publication Number:
  US 20210137882A1
• Time in Patent Office: 158 Days
• 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 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 sweetener;

(iii) a preservative, wherein the preservative comprises sodium benzoate, a paraben or a mixture of parabens;

(iv) water; and

(v) optionally 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.

2. The stable oral liquid formulation of claim 1, wherein the formulation is stable at about 5±

3°

C. for at least 18 months.

3. The stable oral liquid formulation of claim 1, wherein the formulation is stable at about 5±

3°

C. for at least 24 months.

4. The stable oral liquid formulation of claim 1, wherein the formulation maintains a pH between about 3 and about 4 for at least 3 months at about 5±

3°

C.

5. The stable oral liquid formulation of claim 1, wherein the formulation maintains a pH between about 3 and about 4 for at least 12 months at about 5±

3°

C.

6. The stable oral liquid formulation of claim 1, wherein the sweetener is sucralose.

7. The stable oral liquid formulation of claim 6, wherein the sucralose is present in about 0.5 mg/ml to about 0.9 mg/ml in the oral liquid formulation.

8. The stable oral liquid formulation of claim 1, wherein the sweetener is saccharin or a salt thereof.

9. The stable oral liquid formulation of claim 8, wherein the saccharin or a salt thereof is present at about 2 mg/ml in the oral liquid formulation.

10. The stable oral liquid formulation of claim 1, comprising a flavoring agent.

11. The stable oral liquid formulation of claim 1, wherein the enalapril or a pharmaceutically acceptable salt or solvate thereof functions as a buffer.

12. The stable oral liquid formulation of claim 1, wherein the enalapril or a pharmaceutically acceptable salt or solvate thereof is present at about 1.0 mg/ml in the oral liquid formulation.

13. The stable oral liquid formulation of claim 1, wherein the preservative is a mixture of parabens.

14. 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.

15. The stable oral liquid formulation of claim 1, wherein the mixture of parabens comprises methylparaben and propylparaben.

16. 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.

17. The stable oral liquid formulation of claim 1, wherein the preservative comprises sodium benzoate.

18. The stable oral liquid formulation of claim 17, wherein the sodium benzoate is present at about 0.2 mg/ml to about 1.2 mg/ml in the oral liquid formulation.

19. The stable oral liquid formulation of claim 1, consisting essentially of:

(i) about 1.0 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;

(ii) a sweetener that is sucralose or sodium saccharin;

(iii) a preservative, wherein the preservative comprises a mixture of parabens that is present at about 0.1 mg/ml to about 2 mg/ml in the oral liquid formulation;

(iv) water; and

(v) optionally a flavoring agent.

20. The stable oral liquid formulation of claim 1, consisting essentially of:

(i) about 1.0 mg/ml enalapril or a pharmaceutically acceptable salt or solvate thereof;

(ii) a sweetener that is sucralose or sodium saccharin;

(iii) a preservative, wherein the preservative comprises sodium benzoate that is present at about 0.2 mg/ml to about 1.2 mg/ml in the oral liquid formulation;

(iv) water; and

(v) optionally a flavoring agent.