Liquid pharmaceutical compositions comprising thyroid hormones

• US 6,458,842 B1
• Filed: 07/31/1996
• Issued: 10/01/2002
• Est. Priority Date: 02/01/1994
• Status: Expired due to Fees

• Current Assignee: Knoll Pharmaceutical Company (Abbvie Incorporated)
• Original Assignee: Knoll AG (BASF SE)
• Inventors: Smith, Alan, Dickinson, Jeffrey, Khan, Karrar Ahmad, Hague, John Neville
• Primary Examiner(s): Huang, Evelyn Mei
• Application Number:
  US08/682,779
• Time in Patent Office: 2,253 Days
• Field of Search: 514/567, 424/568
• US Class Current: 514/567
• 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

There is disclosed a liquid pharmaceutical composition comprising a therapeutic agent which comprises: one or more thyroid hormone or hormones; from about 40% to about 96% 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; which has utility in the treatment of disorders associated with an impairment of the thyroid hormone function in animals including human beings. The liquid composition may be delivered by a metered dosage delivery system such as an aerosol or pump-action spray.

Claims

1. A stable liquid oral dosage pharmaceutical composition, said composition comprising at least one thyroid hormone selected from the group consisting of L-3,5,3′

,5′

-tetraiodothyronine (levothyroxine or LT4), L-3,5,3′

-triiodothyronine (liothyronine or LT3), L-3,3′

,5′

-triiodothyronine (LrT3), L-3,5-diiodothyrone (LT2), pharmaceutically acceptable salts thereof, and mixtures thereof;

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. A composition as defined in claim 1, in which the ethanol is present in an amount from about 50% to about 80% by volume of the composition.

3. A composition as defined in claim 1, which further comprises from a trace amount to about 5% by mass of the composition of a pharmaceutically acceptable sequestrating agent.

4. A composition as defined in claim 1, which further comprises from a trace amount to about 5% by mass of the composition of a pharmaceutically acceptable anti-oxidant.

5. A method of treating a disorder associated with an impairment of the thyroid hormone function in a mammal, which method comprises administration to a mammal in need of such treatment a therapeutically effective amount of the stable liquid oral dosage pharmaceutical composition defined in claim 1.

6. A method of preparing a stable oral liquid dosage pharmaceutical composition as defined claim 1, which method comprises combining the thyroid hormone with from about 40% to about 96% of ethanol by volume;

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

then adjusting the pH of the resulting solution to a pH of from about 9 to about 12.

7. A method as defined in claim 6, in which the ethanol is added to the composition in an amount from about 50% to about 80% by volume of the composition.

8. A method as defined in claim 7, which further comprises adding to the composition from a trace amount to about 5% by mass of the composition of a pharmaceutically acceptable sequestrating agent.

9. A method as defined in claim 6, which further comprises adding to the composition from a trace amount to about 5% by mass of the composition of a pharmaceutically acceptable anti-oxidant.

10. A composition as defined in claim 1, wherein the fraction of the initial thyroid hormone concentration in the composition remaining after storage of the composition at 25°

C. in air for 6 months is at least 0.94.

11. A composition as defined in claim 1, wherein the fraction of the initial thyroid hormone concentration remaining after storage of the composition at 25°

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

12. A composition as defined in claim 1, wherein the thyroid hormone is L-3,5,3′

,5′

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

13. A composition as defined in claim 1, wherein the thyroid hormone is L-3,5,3′

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

14. A composition as defined in claim 1, wherein the thyroid hormone is L-3,3′

,5′

-triiodothyronine (LrT3) or a pharmaceutically acceptable salt thereof.

15. A composition as defined in claim 1, wherein the thyroid hormone is L-3,5-diiodothyronine (LT2) or a pharmaceutically acceptable salt thereof.

16. A method as defined claim 6, wherein the thyroid hormone is L-3,5,3′

,5′

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

17. A method as defined in claim 6, wherein the thyroid hormone is L-3,5,3′

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

18. A method as defined in claim 6, wherein the thyroid hormone is L-3,3′

,5′

-triiodothyronine (LrT3) or a pharmaceutically acceptable salt thereof.

19. A method as defined in claim 6, wherein the thyroid hormone is L-3,5-diiodothyronine (LT2) or a pharmaceutically acceptable salt thereof.

20. A method as defined in claim 5, wherein the mammal is a human.