Levothyroxine liquid formulations

• US 10,398,669 B2
• Filed: 09/11/2017
• Issued: 09/03/2019
• 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 R
• Application Number:
  US15/700,258
• Publication Number:
  US 20180153838A1
• Time in Patent Office: 722 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;

a stabilizing agent comprising tromethamine;

not more than 2% liothyronine (T3); and

water;

wherein the formulation retains at least about 95% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for 12 months at 25±

2°

C., and retains at least about 95% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for 2 months at 40±

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 5 mcg/mL to about 500 mcg/mL.

4. The formulation of claim 1, wherein the tromethamine is present at a concentration of about 1 mg/mL to about 50 mg/mL.

5. The formulation of claim 1, wherein the stabilizing agent comprises a salt of iodine.

6. The formulation of claim 5, wherein the salt of iodine is sodium iodide or potassium iodide.

7. The formulation of claim 6, wherein the salt of iodine is sodium iodide which is present at a concentration of about 10 mcg/mL to about 500 mcg/mL.

8. The formulation of claim 1, wherein the formulation has a pH of from about 9.0 to about 11.5.

9. The formulation of claim 8, wherein the formulation has a pH of from about 9.8 to about 10.8.

10. The formulation of claim 1, wherein the formulation contains not more than 1.5% liothyronine (T3).

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

12. The formulation of claim 1, wherein the formulation contains not more than 5.0% total impurities.

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

14. The formulation of claim 1, wherein the formulation retains at least about 90% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for at least 18 months at 25±

2°

C.

15. The formulation of claim 1, wherein the formulation retains at least about 90% of the initial concentration of levothyroxine or pharmaceutically acceptable salt thereof after storage for at least 24 months at 25±

2°

C.

16. The formulation of claim 1, wherein the formulation does not contain a buffer.

17. The formulation of claim 1, wherein the formulation is a ready-to-use formulation contained within a vial, ampoule, cartridge, syringe, or bag.