Lisinopril formulations

• US 9,814,751 B2
• Filed: 04/10/2017
• Issued: 11/14/2017
• Est. Priority Date: 10/30/2015
• 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): Basquill, Sean M
• Application Number:
  US15/483,691
• Publication Number:
  US 20170209523A1
• Time in Patent Office: 218 Days
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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 lisinopril oral liquid formulations. Also provided herein are methods of using lisinopril oral liquid formulations for the treatment of certain diseases including hypertension, heart failure and acute myocardial infarction.

Claims

1. A stable oral liquid formulation, comprising:

(i) about 1 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof;

(ii) a sweetener selected from the group consisting of xylitol, mannitol, sucralose, saccharin, and pharmaceutically acceptable salts thereof;

(iii) a buffer comprising citric acid and sodium citrate;

(iv) a preservative selected from the group consisting of sodium benzoate, benzoic acid, sorbic acid, methylparaben, propylparaben, and pharmaceutically acceptable salts thereof; and

(v) water;

provided that when the preservative is a paraben, then the sweetener is not xylitol or mannitol; and

wherein the formulation is stable at about 25±

5°

C. for at least 6 months.

2. The formulation of claim 1, wherein the lisinopril is lisinopril dihydrate.

3. The formulation of claim 1, wherein the pH is between about 4 and about 5.2.

4. The formulation of claim 1, wherein the pH is about 4.9.

5. The formulation of claim 1, wherein the pH is about 5.2.

6. The formulation of claim 1, wherein the formulation is stable at about 25±

5°

C. for at least 12 months.

7. The formulation of claim 1, wherein the formulation is stable at about 25±

5°

C. for at least 18 months.

8. The formulation of claim 1, wherein the formulation is stable at about 25±

5°

C. for at least 24 months.

9. The formulation of claim 1, wherein the buffer concentration is from about 5 to about 50 mM.

10. The formulation of claim 1, wherein the buffer concentration is about 10 mM.

11. The formulation of claim 1, wherein the sweetener is xylitol.

12. The formulation of claim 11, wherein the amount of xylitol is about 140 to about 160 mg/ml.

13. The formulation of claim 1, wherein the sweetener is sucralose.

14. The formulation of claim 13, wherein the amount of sweetener is about 0.5 to about 3 mg/ml.

15. The formulation of claim 1, wherein the preservative is sodium benzoate.

16. The formulation of claim 1, wherein the amount of the preservative is about 0.5 to about 1.2 mg/ml.

17. The formulation of claim 1, wherein the preservative is methylparaben or propylparaben or salts thereof.

18. The formulation of claim 17, wherein the amount of the paraben is about 0.1 to about 2 mg/ml.

19. A stable oral liquid formulation, comprising:

(i) about 0.8 to about 1.2 mg/ml lisinopril or a pharmaceutically acceptable salt or solvate thereof;

(ii) about 140 to about 160 mg/ml xylitol;

(iii) a buffer comprising about 0.5 to about 1.2 mg/ml citric acid and about 1.2 to about 1.7 mg/ml sodium citrate;

(iv) about 0.5 to about 1.2 mg/ml sodium benzoate; and

(v) water;

wherein the pH of the formulation is between about 4 and about 5, and wherein the formulation is stable at about 25±

5°

C. for at least 12 months.

20. A stable oral liquid formulation, comprising:

(i) about 0.5 to about 1% (w/w of solids) lisinopril or a pharmaceutically acceptable salt or solvate thereof;

(ii) about 95 to about 98% (w/w of solids) of a sweetener that is xylitol;

(iii) a buffer comprising about 0.3 to about 0.7% (w/w of solids) citric acid and about 0.7 to about 1.3% (w/w of solids) sodium citrate;

(iv) about 0.4 to about 1.2% (w/w of solids) of a preservative that is sodium benzoate; and

(v) water;

wherein the pH of the formulation is between about 4 and about 5; and

wherein the formulation is stable at about 25±

5°

C. for at least 12 months.