Liquid pharmaceutical compositions comprising thyroid hormones

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.

What is claimed:  
     
         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.  
     
     
         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.  
     
     
         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.  
     
     
         13 . The method of  claim 7 , 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 7 , 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 7 , wherein the thyroid hormone is L-3,5,3′-triiodothyronine (liothyronine or LT3), or a pharmaceutically acceptable salt thereof.  
     
     
         16 . The method of  claim 7 , 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 7 , wherein the thyroid hormone is L-3,5-diiodothyronine (LT2), or a pharmaceutically acceptable salt thereof.  
     
     
         18 . The method of  claim 7 , wherein the ethanol is present in an amount from about 50% to about 80% by volume of the composition.  
     
     
         19 . The method of  claim 7 , 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 7 , 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 7 , 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 7 , wherein the fraction of thyroid hormone remaining after storage at 25° C. under nitrogen for 6 months is at least 0.95.