Controlled absorption of admixed thyroid hormone formulations

• US 20040152783A1
• Filed: 11/05/2003
• Published: 08/05/2004
• Est. Priority Date: 11/05/2002
• Status: Abandoned Application

• Current Assignee: Shire LLC (Shire plc)
• Original Assignee: Shire LLC (Shire plc)
• Inventors: Piccariello, Thomas, Moncrief, James Scott, Olon, Lawrence Peter, Boerth, Nancy Johnston
• Application Number:
  US10/701,173
• Publication Number:
  US 20040152783A1
• Time in Patent Office: Days
• US Class Current: 514/567
• 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: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Abstract

The invention relates to admixtures of the thyroid hormones and derivatives thereof. These admixtures, particularly L-thyroxine (T4) and liothyronine (T3), produce steady state or near steady state serum levels of T3. When admixed in the appropriate ratio of T4 to T3, blood levels of T3 hormone are maintained at a steady state for an extended period of time independent of the need for control release excipients. The change in the kinetics of T3 absorption is controlled by the addition of T4 to T3.

Claims

1. A pharmaceutical composition comprising levothyroxine (T4) or a derivative thereof and liothyronine (T3) or a derivative thereof in an admixture, wherein said admixture of T4 to T3 has a ratio which creates in vivo liothyronine serum levels at steady state or near steady state for an extended period of time.

2. A pharmaceutical composition comprising levothyroxine (T4) or a derivative thereof and liothyronine (T3) or a derivative thereof in an admixture wherein said admixture ratio of T4 to T3 is less than 1.

4. The pharmaceutical composition of claim 2 wherein said admixture ratio is below 0.75:

1.

5. The pharmaceutical composition of claim 2 wherein said admixture ratio is below 0.5:

1.

6. The pharmaceutical composition of claim 2 that delivers a peak total liothyronine serum concentration that is less than the peak total liothyronine concentration resulting from an equivalent dose of liothyronine alone.

7. The pharmaceutical composition of claim 2 that results in bioavailability of liothyronine equal to or nearly equal to an equivalent amount of liothyronine administered alone.

8. The pharmaceutical composition of claim 2 that prevents or reduces spiking of liothyronine serum levels.

9. The pharmaceutical composition of claim 2 wherein levothyroxine and liothyronine derivatives are separately selected from salt forms, esterified derivatives, amide linked derivatives, or combinations thereof.

10. The pharmaceutical composition of claim 2, wherein said admixture is covalently linked to one or more amino acid residues.

11. The pharmaceutical composition of claim 2, wherein said admixture is combined with at least one other control release agent.

12. The pharmaceutical composition of claims 2 in a form suitable for oral administration.

13. The pharmaceutical composition of claim 2 in a form suitable for nasal administration.

14. The pharmaceutical composition of claim 2 in a form suitable as a skin patch.

3. A pharmaceutical composition comprising levothyroxine (T4) or a derivative thereof and liothyronine (T3) or a derivative thereof in an admixture, wherein said admixture ratio of T4 to T3 is above 4.

15. A method of creating a steady state liothyronine concentration in vivo comprising administering an admixture of liothyronine or derivatives thereof and levothyroxine or derivatives thereof wherein said steady state is modulated by a ratio of levothyroxine to liothyronine and does not require other control release agents.

16. The method of claim 15 wherein the steady state or near steady state level of liothyronine concentration is supplemented with a control release agent in the formulation.

17. The method of claim 15 wherein said admixture is covalently linked to one or more amino acid residues.

18. A method of increasing the bioavailability of T4 and/or T3 comprising administering an admixture of liothyronine or derivatives thereof and levothyroxine or derivatives in a ratio of T4:

T3 which is above 4;

1 or below 1;

1.

19. A method for treating a condition requiring the modulation of T3 and/or T4 comprising administering levothyroxine (T4) or a derivative thereof and liothyronine (T3) or a derivative thereof in a ratio of T4:

T3 which is above 4;

1 or below 1;

1.

20. The method of claim 19, wherein said admixture has a ratio of less than 1:

1 and greater than 0.05;

1.

21. The method of claim 19, wherein said admixture is administered orally or through a skin patch.

22. The method of claim 19, wherein said condition is hypothyroidism, subclinical hypothyroidism, hyperthyroidism, depression, obesity, congestive heart failure, or a mood disorder.