Levothyroxine formulations

• US 9,006,289 B2
• Filed: 08/29/2012
• Issued: 04/14/2015
• Est. Priority Date: 08/30/2011
• Status: Active Grant

• Current Assignee: Fresenius KABI USA LLC (Fresenius SE & Co. KGaA)
• Original Assignee: Fresenius KABI USA LLC (Fresenius SE & Co. KGaA)
• Inventors: Jiang, Zhi-Qiang, Usayapant, Arunya, Monen, George
• Primary Examiner(s): MCMILLIAN, KARA RENITA
• Application Number:
  US13/597,884
• Publication Number:
  US 20130053445A1
• Time in Patent Office: 958 Days
• US Class Current: 514/567
• CPC Class Codes: A61K 31/197 the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid carnitine A61K31/205
• 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 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• 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 9/0019 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 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00

Abstract

A levothyroxine composition includes levothyroxine sodium and mannitol. The composition is a solid. The composition may include from 100 to 500 micrograms levothyroxine sodium and from 1 to 5 milligrams mannitol. The composition may include from 100 to 200 micrograms levothyroxine sodium, and the mass ratio of mannitol to levothyroxine sodium in the composition may be at most 40:1. The composition may include about 500 micrograms levothyroxine sodium, and the mass ratio of mannitol to levothyroxine sodium in the composition may be at most 10:1.

Claims

1. A composition, comprising:

about 100 or about 200 micrograms of levothyroxine sodium;

a phosphate buffer; and

from 2 to 4 milligrams of mannitol,

where the composition is a lyophilized solid.

2. The composition of claim 1, where the amount of levothyroxine sodium is about 100 micrograms and the amount of mannitol is about 3 milligrams.

3. The composition of claim 1, where the amount of levothyroxine sodium is about 200 micrograms and the amount of mannitol is about 3 milligrams.

4. The composition of claim 2, where the phosphate buffer is dibasic sodium phosphate in an amount from 400 to 600 micrograms.

5. The composition of claim 4, where the composition is formed by

forming a liquid mixture by combining

the levothyroxine sodium,

the mannitol,

dibasic sodium phosphate, and

a solvent comprising water;

and

lyophilizing the liquid mixture.

6. The composition of claim 1, where when the composition is stored at 25 °

C., at most 0.20% of the levothyroxine sodium is converted to liothyronine over a period of 12 months.

7. The composition of claim 1, where when the composition is stored at 40 °

C., at most 0.20% of the levothyroxine sodium is converted to liothyronine over a period of 3 months.

8. The composition of claim 4, where when the composition is stored at 25 °

C., at most 0.20% of the levothyroxine sodium is converted to liothyronine over a period of 12 months.

9. The composition of claim 3, where the phosphate buffer is dibasic sodium phosphate in an amount from 400 to 600 micrograms.

10. The composition of claim 9, where the composition is formed by

forming a liquid mixture by combining

the levothyroxine sodium,

the mannitol,

dibasic sodium phosphate, and

a solvent comprising water;

and

lyophilizing the liquid mixture.

11. The composition of claim 4, where when the composition is stored at 40 °

C., at most 0.20% of the levothyroxine sodium is converted to liothyronine over a period of 3 months.

12. The composition of claim 9, where when the composition is stored at 25 °

C., at most 0.20% of the levothyroxine sodium is converted to liothyronine over a period of 12 months.

13. The composition of claim 9, where when the composition is stored at 40 °

C., at most 0.20% of the levothyroxine sodium is converted to liothyronine over a period of 3 months.

14. A composition, comprising:

about 500 micrograms of levothyroxine sodium;

a phosphate buffer; and

from 2 to 4 milligrams of mannitol,

where the composition is a lyophilized solid.

15. The composition of claim 14, where the amount of mannitol is about 3 milligrams.

16. The composition of claim 15, where the phosphate buffer is dibasic sodium phosphate in an amount from 400 to 600 micrograms.

17. The composition of claim 16, where the composition is formed by

forming a liquid mixture by combining

the levothyroxine sodium,

the mannitol,

dibasic sodium phosphate, and

a solvent comprising water;

and

lyophilizing the liquid mixture.

18. The composition of claim 14, where when the composition is stored at 25 °

C., at most 0.15% of the levothyroxine sodium is converted to liothyronine over a period of 12 months.

19. The composition of claim 16, where when the composition is stored at 25 °

C., at most 0.15% of the levothyroxine sodium is converted to liothyronine over a period of 12 months.

20. The composition of claim 16, where when the composition is stored at 40 °

C., at most 0.15% of the levothyroxine sodium is converted to liothyronine over a period of 3 months.

21. The composition of claim 14, where when the composition is stored at 40 °

C., at most 0.15% of the levothyroxine sodium is converted to liothyronine over a period of 3 months.