In Vitro/in Vivo Evaluation of Two Series of TA-5707F Controlled Release Matrix Tablets Prepared with Hydroxypropyl Methyl Cellulose Derivatives with Entero-Soluble or Gel-Formation Properties

Abstract

Two series of matrix tablets for the newly developed anti-histaminergic drug, TA-5707F, were prepared : one series with an entero-soluble polymer, hydroxypropylmethylcellulose acetyl succinate (HPMC-AS), and one series with a hydrophilic gel-forming polymer, hydroxypropylmethylcellulose (HPMC). In the JP dissolution test of HPMC-AS tablets, as the soluble-pH of HPMC-AS was increased, the dissolution of the drug in the JP XII second fluid (pH 6.8) was increasingly delayed, and the duration time of the constant plasma level in fasted dogs was increased. However, the absorption of TA-5707F in fed dogs was markedly diminished. In the JP dissolution test, the HPMC tablets showed a zero order dissolution profile, being the same in both the JP first (pH 1.2) and the JP second fluids. The H-2 tablet, containing HPMC 60SH-4000 and lactose, showed a constant plasma level in fasted dogs. However, this tablet was disintegrated by the ingestion of food. The H-3 tablet containing a lot of HPMC 60SH-4000, but not lactose, showed insufficient duration in fasted dogs, but its plasma profile was less affected by food, and the propantheline bromide pretreatment extended the constant plasma level in dogs. Thus, the H-3 tablets were considered promising for human use. Then, H-2 and H-3 tablets were administered to humans ; however, the plasma concentration profiles did not show sufficient duration time for either tablet. TA-5707F was considered to have been released slowly in human gastro-intestinal (GI) tract due to more moderate GI mobility.