Levothyroxine liquid formulations

• US 9,782,376 B1
• Filed: 12/01/2016
• Issued: 10/10/2017
• Est. Priority Date: 12/01/2016
• Status: Active Grant

• Current Assignee: Fresenius KABI USA LLC (Fresenius SE & Co. KGaA)
• Original Assignee: Fresenius KABI USA LLC (Fresenius SE & Co. KGaA)
• Inventors: Usayapant, Arunya, Ibrahim, Basma M.
• Primary Examiner(s): Hui, San-Ming
• Application Number:
  US15/366,864
• Time in Patent Office: 313 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 33/18 Iodine; Compounds thereof
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00

Abstract

The present invention is directed to a liquid formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof. The formulation of the present invention includes tromethamine, sodium iodide, and water and has a pH of about 9.0 to about 11.5. The liquid formulation according to the invention is stable and ready-to-use.

Claims

1. A liquid formulation comprising

levothyroxine or a pharmaceutically acceptable salt thereof;

about 1 mg/mL to about 50 mg/mL of tromethamine;

about 10 mcg/mL to about 500 mcg/mL of sodium iodide; and

water;

wherein the formulation has a pH of about 9.0 to about 11.5, and wherein the formulation is stable for at least 12 months at 25±

2°

C.

2. The formulation of claim 1, wherein levothyroxine or a pharmaceutically acceptable salt thereof is levothyroxine sodium.

3. The formulation of claim 2, wherein levothyroxine sodium is present at a concentration of from about 20 mcg/mL to about 100 mcg/mL.

4. The formulation of claim 3, wherein levothyroxine sodium is present at a concentration of about 20 mcg/mL, about 40 mcg/mL, or about 100 mcg/mL.

5. The formulation of claim 1, wherein tromethamine is present at a concentration of about 5 mg/mL to about 20 mg/mL.

6. The formulation of claim 5, wherein tromethamine is present at a concentration of about 10 mg/mL.

7. The formulation of claim 1, wherein sodium iodide is present at a concentration of about 100 mcg/mL to about 300 mcg/mL.

8. The formulation of claim 7, wherein sodium iodide is present at a concentration of about 140 mcg/mL.

9. The formulation of claim 1, further comprising an isotonicity adjuster.

10. The formulation of claim 9, wherein the isotonicity adjuster is sodium chloride.

11. The formulation of claim 1, further comprising a pH adjuster.

12. The formulation of claim 11, wherein the pH adjuster is selected from the group consisting of hydrochloric acid, sodium hydroxide and combinations thereof.

13. The formulation of claim 1, wherein the formulation has a pH of from about 9.8 to about 10.8.

14. The formulation of claim 1, wherein the formulation contains not more than 1.0% liothyronine (T3).

15. The formulation of claim 1, wherein the formulation contains not more than 2.5% total impurities.

16. The formulation of claim 1, wherein the formulation is a ready-to-use formulation contained within a flint colored molded glass vial.

17. The formulation of claim 1, wherein the formulation is stable for at least 18 months at 25±

2°

C.

18. A liquid formulation comprising

(a) levothyroxine or a pharmaceutically acceptable salt thereof in a concentration of about 20 mcg/mL to about 100 mcg/mL;

(b) tromethamine in a concentration of about 5 mg/mL to about 20 mg/mL;

(c) sodium iodide in a concentration of about 100 mcg/mL to about 300 mcg/mL;

(c) sodium chloride; and

(d) water;

wherein the formulation has a pH of about 9.8 to about 10.8, and wherein the formulation is stable for at least 12 months at 25±

2°

C.

19. The formulation of claim 18, wherein levothyroxine or a pharmaceutically acceptable salt thereof is levothyroxine sodium.

20. The formulation of claim 18, wherein the formulation contains not more than 1.0% liothyronine (T3).

21. The formulation of claim 18, wherein the formulation contains not more than 2.5% total impurities.

22. The formulation of claim 18, wherein the formulation is a ready-to-use formulation contained within a flint colored molded glass vial.

23. The formulation of claim 18, wherein the formulation is stable for at least 18 months at 25±

2°

C.

24. A liquid formulation comprising

(a) levothyroxine sodium in a concentration of about 20 mcg/mL to about 100 mcg/mL;

(b) tromethamine in a concentration of about 10 mg/mL;

(c) sodium iodide in a concentration of about 140 mcg/mL;

(c) sodium chloride; and

(d) water;

wherein the formulation has a pH of about 9.8 to about 10.8, and wherein the formulation is stable for at least 12 months at 25±

2°

C.

25. The formulation of claim 24, wherein the formulation is a ready-to-use formulation comprising levothyroxine sodium in a concentration of about 20 mcg/mL in a volume of about 5 mL and is contained within a flint colored molded glass vial.

26. The formulation of claim 25, wherein the formulation is stable for at least 18 months at 25±

2°

C.

27. The formulation of claim 24, wherein the formulation is a ready-to-use formulation comprising levothyroxine sodium in a concentration of about 40 mcg/mL in a volume of about 5 mL and is contained within a flint colored molded glass vial.

28. The formulation of claim 27, wherein the formulation is stable for at least 18 months at 25±

2°

C.

29. The formulation of claim 24, wherein the formulation is a ready-to-use formulation comprising levothyroxine sodium in a concentration of about 100 mcg/mL in a volume of about 5 mL and is contained within a flint colored molded glass vial.

30. The formulation of claim 29, wherein the formulation is stable for at least 18 months at 25±

2°

C.