3,5,3'-triiodothyronine sulfate as thyromimetic agent and pharmaceutical formulations thereof

Abstract

The invention regards the use of triiodothyronine sulfate, commonly named T 3 S, as a medicament having thyromimetic activity for the treatment of pathologies due to organic deficiency of triiodothyronine (T 3 ), as such or in association with thyroxine (T 4 ), and pharmaceutical formulations for oral administration thereof.

1 . A solid oral dosage composition comprising T 3 S as the active principle, in a quantity ranging from 1 to 1000 μg and further comprising diluents, glidants or lubricants and disintegrants. 
     
     
         2 . The solid dosage of  claim 1  wherein T 3 S comprises 2.5 to 500 μg. 
     
     
         3 . The solid dosage of  claim 2  wherein T 3 S comprises 5-250 μg. 
     
     
         4 . The solid dosage of  claim 2  further comprising 5-800 μg T 4  (thyroxine). 
     
     
         5 . The solid dosage of  claim 1  wherein said diluent is selected in the group consisting of: cellulose and derivatives thereof, kaolin, starch and derivatives thereof and alkaline inorganic salts. 
     
     
         6 . The solid dosage of  claim 5  wherein the cellulose derivative is selected from the group consisting of: microcrystalline cellulose or salts thereof, powdered cellulose, silicified microcrystalline cellulose, cellulose acetate or salts thereof, and ethyl cellulose or salts thereof. 
     
     
         7 . The solid dosage of  claim 5  wherein the alkaline inorganic salt is selected in the group consisting of: tri-sodium phosphate, tri-calcium phosphate, calcium sulphate, and calcium or magnesium carbonate. 
     
     
         8 . The solid dosage of  claim 1  wherein the disintegrant is selected in the group consisting of: corn starch, croscarmellose or salts thereof, crospovidone or salts thereof, polymethacrylates and maltodextrin or salts thereof. 
     
     
         9 . The solid dosage of  claim 8  wherein the disintegrant is croscarmellose or salts thereof. 
     
     
         10 . The solid dosage of  claim 1  wherein the lubricant is selected from the group consisting of: silicates, including hydrate silicon dioxide, hydrate colloidal silica; magnesium stearate; zinc stearate; and talc. 
     
     
         11 . The solid dosage of  claim 1  wherein the glidant is selected in the group consisting of: glycerol dibehenate, tri-basic calcium phosphate, starch derivatives, talc, magnesium stearate and zinc stearate. 
     
     
         12 . The solid dosage of  claim 11  wherein the glidant is glycerol dibehenate or tribasic calcium phosphate. 
     
     
         13 . The solid dosage of  claim 1  in the form of a tablet. 
     
     
         14 . The solid dosage composition of  claim 1 , comprising calcium carbonate, glycerol dibehenate, croscarmellose sodium salt, hydrate colloidal silica, magnesium stearate and microcrystalline cellulose. 
     
     
         15 . The solid dosage form of any one of  claims 1  or  4  which comprises: 
       
         
           
                 
                 
               
                     
                     
                 
                     
                   Amount per 80-150 mg Tablet 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   Calcium carbonate 
                   20-40 mg, preferably 25-35 mg, 
                 
                     
                     
                   more preferably 30 mg 
                 
                     
                   Glycerol dibehenate 
                   2-15 mg, preferably 4-8 mg, 
                 
                     
                     
                   more preferably 5 mg 
                 
                     
                   Croscarmellose sodium salt 
                   1-10 mg, preferably 2-6 mg, 
                 
                     
                     
                   more preferably 3.5 mg 
                 
                     
                   Hydrate colloidal silica 
                   0.1-5 mg, preferably 0.5-4, 
                 
                     
                     
                   more preferably 2 mg 
                 
                     
                   Magnesium stearate 
                   0.01-2 mg, preferably 0.1-1 mg, 
                 
                     
                     
                   more preferably 0.5 mg 
                 
                     
                   Microcrystalline cellulose 
                   Up to 110 mg 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         16 . A non radioactive immunoassay for T 3 S quantitation comprising a non radioactive T 3 S-conjugate. 
     
     
         17 . The immunoassay of  claim 16  wherein the non radioactive conjugate is T 3 S-biotin. 
     
     
         18 . The immunoassay of  claim 17  wherein the immunoassay is a competitive ELISA. 
     
     
         19 . The immunoassay of  claim 16  wherein the non radioactive conjugate is a T 3 S conjugate comprising the compound of Formula I as a Lanthanide chelating agent 
       
         
           
           
               
               
           
         
       
     
     
         20 . The immunoassay of  claim 16  comprising a DELFIA® assay. 
     
     
         21 . A kit comprising a container for a non radioactive immunoassay according to  claim 16  and a container for a solid oral dosage composition comprising T 3 S as the active principle, in a quantity ranging from 1 to 1000 μg and further comprising diluents, glidants or lubricants and disintegrants. 
     
     
         22 . A kit comprising a container for a solid oral dosage composition according to any one of  claims 2  or  4  and, optionally, a container for a non-radioactive immunoassay for T 3 S quantitation comprising a non radioactive T 3 S-conjugate. 
     
     
         23 . A therapeutic or prophylactic treatment method for a hypothyroid condition due to total thyroid hormone depletion before  131 I radiotherapy comprising administering a thyroidectomised patient T 3 S as the sole thyroid hormone replacement up to 5 days before radioactive isotope administration. 
     
     
         24 . The therapeutic treatment method of  claim 23  wherein said hypothyroid condition is selected form the group consisting of: asthenia, fatigue, skin dryness, somnolence, speech fluency impairment, cold intolerance, weight gain and memory to deficit. 
     
     
         25 . A therapeutic treatment method for a hypothyroid condition comprising administering a composition according to any one of  claims 1 ,  4 ,  13  or  14 . 
     
     
         26 . The therapeutic treatment method of  claim 25  wherein said hypothyroid condition is selected form the group consisting of: asthenia, fatigue, skin dryness, somnolence, speech fluency impairment, cold intolerance, weight gain and memory deficit. 
     
     
         27 . The solid dosage of  claim 1  administered as a daily dose.