Liquid pharmaceutical compositions comprising thyroid hormones

• US 6,706,255 B2
• Filed: 09/13/2002
• Issued: 03/16/2004
• Est. Priority Date: 02/01/1994
• Status: Expired due to Fees

• Current Assignee: Abbott GmbH & Company KG (Abbott Laboratories Incorporated)
• Original Assignee: Abbott GmbH & Company KG (Abbott Laboratories Incorporated)
• Inventors: Khan, Karrar Ahmad, Hague, John Neville, Smith, Alan, Dickinson, Jeffrey
• Primary Examiner(s): Huang, Evelyn Mei
• Application Number:
  US10/243,555
• Publication Number:
  US 20030130351A1
• Time in Patent Office: 550 Days
• Field of Search: 424/43, 424/45, 424/568, 424/400, 514/567
• US Class Current: 424/43
• CPC Class Codes: A61K 31/195 having an amino group
• 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 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays

Abstract

Liquid pharmaceutical compositions comprising at least one thyroid hormone, ethanol, a pH adjusting agent, and water are disclosed. The compositions may be delivered by a metered dosage delivery system such as an aerosol or pump-action spray, and are useful in the treatment of disorders associated with an impairment of thyroid hormone function in animals including human beings.

Claims

1. A metered dosage delivery system comprising a stable liquid oral dosage pharmaceutical composition, wherein the composition comprises at least one thyroid hormone;

from about 40% to about 96% of ethanol by volume;

a pH adjusting agent so that the measured pH of the composition is from about 9 to about 12, and from about 4% to about 50% water by volume.

2. The metered dosage delivery system of claim 1, wherein the thyroid hormone is selected from the group consisting of:

L-3, 5, 3′

, 5′

-tetraiodothyronine (levothyroxine or LT4);

L-3, 5, 3′

-triiodothyronine (liothronine or LT3);

L-3, 3′

, 5′

-triiodothyronine (LrT3);

L-3, 5-diiodothyronine (LT2);

pharmaceutically acceptable salts thereof; and

mixtures thereof.

3. The metered dosage delivery system of claim 1, wherein the ethanol is present in an amount from about 50% to about 80% by volume of the composition.

4. The metered dosage delivery system of claim 1, further comprising from a trace amount to about 5% by mass of the composition of a pharmaceutically acceptable sequestrating agent.

5. The metered dosage delivery system of claim 1, further comprising from a trace amount to about 5% by mass of the composition of a pharmaceutically acceptable anti-oxidant.

7. The metered dosage delivery system of claim 2, wherein the thyroid hormone is L-3, 5, 3′

, 5′

-tetraiodothyronine (levothyroxine or LT4), or a pharmaceutically acceptable salt thereof.

8. The metered dosage delivery system of claim 2, wherein the thyroid hormone is L-3, 5, 3′

-triiodothyronine (liothyronine or LT3), or a pharmaceutically acceptable salt thereof.

9. The metered dosage delivery system of claim 2, wherein the thyroid hormone is L-3, 3′

, 5′

-triiodothyronine (LrT3);

or a pharmaceutically acceptable salt thereof.

10. The metered dosage delivery system of claim 2, wherein the thyroid hormone is L-3, 5-diiodothyronine (LT2), or a pharmaceutically acceptable salt thereof.

11. The metered dosage delivery system of claim 1, wherein the fraction of thyroid hormone remaining after storage at 25°

C. in air for 6 months is at least 0.90.

12. The metered dosage delivery system of claim 1, wherein the fraction of thyroid hormone remaining after storage at 25°

C. under nitrogen for 6 months is at least 0.95.

6. A method for preparing a metered dosage delivery system comprising filling the delivery system with a stable liquid oral dosage pharmaceutical composition, wherein the composition comprises at least one thyroid hormone;

from about 40% to about 96% of ethanol by volume;

a pH adjusting agent so that the measured pH of the composition is from about 9 to about 12; and

from about 4% to about 50% water by volume;

whereby a metered dosage delivery system is prepared.

13. The method of claim 6, wherein the thyroid hormone is selected from the group consisting of:

L-3, 5, 3′

, 5′

-tetraiodothyronine (levothyroxine or LT4)

L-3, 5, 3′

-triiodothyronine (liothronine or LT3);

L-3, 3′

, 5′

-triiodothyronine (LrT3);

L-3, 5-diiodothyronine (LT2);

pharmaceutically acceptable salts thereof; and

mixtures thereof.

14. The method of claim 6, wherein the thyroid hormone is L-3, 5, 3′

, 5′

-tetraiodothyronine (levothyroxine or LT4), or a pharmaceutically acceptable salt thereof.

15. The method of claim 6, wherein the thyroid hormone is L-3, 5, 3′

-triiodothyronine (liothyronine or LT3), or a pharmaceutically acceptable salt thereof.

16. The method of claim 6, wherein the thyroid hormone is L-3, 3′

, 5′

-triiodothyronine (LrT3);

or a pharmaceutically acceptable salt thereof.

17. The metered dosage delivery system of claim 6, wherein the thyroid hormone is L-3, 5-diiodothyronine (LT2), or a pharmaceutically acceptable salt thereof.

18. The method of claim 6, wherein the ethanol is present in an amount from about 50% to about 80% by volume of the composition.

19. The method of claim 6, wherein the composition is from a trace amount to about 5% by mass of the composition of a pharmaceutically acceptable sequestrating agent.

20. The method of claim 6, wherein the composition further comprises from a trace amount to about 5% by mass of the composition of a pharmaceutically acceptable anti-oxidant.

21. The method of claim 6, wherein the fraction of thyroid hormone remaining after storage at 25°

C. in air for 6 months is at least 0.90.

22. The method of claim 6, wherein the fraction of thyroid hormone remaining after storage at 25°

C. under nitrogen for 6 months is at least 0.95.