Preparation of controlled release granules of TA-5707F using enteric polymers and ethylcellulose, and their in vivo...

Two types of multiple controlled release dosage forms, hydroxypropylmethyl cellulose acetyl succinate (HPMC-AS) coated granules and double layer coated granules with HPMC-AS and ethyl cellulose (EC), were prepared for the newly developed antihistaminergic drug, TA-5707F, using a centrifugal fluidizing granulator. The in vitro dissolution rate of TA-5707F in the second fluid from the former granules could be altered by changing the grade (HPMC-AS-M, AS-H, AS-V) or coating amount. However, the plasma concentration determined in fasted dogs was not markedly affected by the HPMC-AS grades. From the granules coated with 30% (w/w) AS-V (the polymer with the highest pH required for dissolution), little TA-5707F was released into the second fluid, but a fairly high plasma concentration was detected although a constant plasma level was not maintained in the fasted dogs. The dissolution rates from the double layer coated granules were changed by the coating percent of EC. The plasma concentration of TA-5707F in dogs correlated well with the in vitro dissolution rate and was not markedly affected by food. Thus, two kinds of double layer coated granules (coated 0.75% EC and 1% EC) were administered to humans, and showed sustained-releasing plasma profiles; that is, the plasma concentration increased gradually and reached a Cmax 5 and 8 h after administration, respectively. The amount of urinary excretion of TA-5707F and its metabolite was 70% of the dose. This value was almost equal to that of the rapid release tablet. In dogs the in vivo absorption rate was similar to the in vitro dissolution rate, but in humans it was only about half.