Enalapril formulations

• US 9,669,008 B1
• Filed: 03/25/2016
• Issued: 06/06/2017
• 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:
  US15/081,603
• Time in Patent Office: 438 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 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 formulation is less than about 3.5; and

wherein the formulation is stable at about 5±

3°

C. for at least 12 months;

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 formulation of claim 1, further comprising a flavoring agent.

3. The formulation of claim 1, wherein the pH is between about 3 and about 3.5.

4. The formulation of claim 3, wherein the pH is about 3.3.

5. The formulation of claim 1, wherein the citrate concentration in the buffer is about 5 mM to about 20 mM.

6. The formulation of claim 5, wherein the citrate concentration in the buffer is about 10 mM.

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

3°

C. for at least 18 months.

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

3°

C. for at least 24 months.

9. The formulation of claim 1, wherein the formulation does not contain mannitol.

10. The formulation of claim 1, wherein the formulation does not contain silicon dioxide.

19. The stable oral liquid formulation of claim 1, further comprising about 0.70 mg/ml of a sweetener that is sucralose.

11. A stable oral liquid formulation, comprising:

(i) about 19.3% (w/w of solids) enalapril maleate;

(ii) a buffer comprising about 35.2% (w/w of solids) citric acid and about 2.9% (w/w of solids) sodium citrate dihydrate;

(iii) about 19.3% (w/w of solids) of a preservative that is sodium benzoate; and

(iv) water;

wherein the pH of the formulation is less than about 3.5; and

wherein the formulation is stable at about 5±

3°

C. for at least 12 months;

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.

12. The formulation of claim 11, further comprising a flavoring agent.

13. The formulation of claim 11, wherein the pH is between about 3 and about 3.5.

14. The formulation of claim 13, wherein the pH is about 3.3.

15. The formulation of claim 11, wherein the citrate concentration in the buffer is about 5 mM to about 20 mM.

16. The formulation of claim 15, wherein the citrate concentration in the buffer is about 10 mM.

17. The formulation of claim 11, wherein the formulation is stable at about 5±

3°

C. for at least 24 months.

20. The stable oral liquid formulation of claim 11, further comprising about 13.5% (w/w of solids) of a sweetener that is sucralose.

18. A stable oral liquid formulation, consisting essentially of:

(i) about 1 mg/ml enalapril maleate;

(ii) about 0.70 mg/ml of a sweetener that is sucralose;

(iii) a buffer comprising about 1.82 mg/ml citric acid and about 0.15 mg/ml sodium citrate dihydrate;

(iv) about 1 mg/ml of a preservative that is sodium benzoate;

(v) a flavoring agent; and

(vi) water;

wherein the pH of the formulation is less than about 3.5 adjusted by sodium hydroxide or hydrochloric acid if needed; and

wherein the formulation is stable at about 5±

3°

C. for at least 12 months;

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.