Prediction of in vivo drug release behavior of controlled-release multiple-unit dosage forms in dogs using a flow-through type dissolution test method

Abstract

A newly designed flow-through type dissolution test method (FT method) was applied to predict in vivo drug release behaviors in dogs of controlled-release multiple unit dosage forms. The in vivo drug release behaviors were directly observed by measuring the residual amount of drugs in preparations recovered from the gastrointestinal (GI) tract after oral administration. Theophylline (TP), acetaminophen (AA), and phenylpropanolamine hydrochloride (PPA), which have different solubility, were used as model drugs. In vivo drug release behaviors in the gastrointestinal (GI) tract of dogs were similar to the results of the Wagner–Nelson method. In vivo release behaviors of TP and AA, until 2 h after administration, were well correlated to in vitro behaviors obtained by the paddle method at 100 rpm. However, the in vivo release rates of TP and AA were gradually decreased because of a lack of fluid in the lower region of the GI tract, their poor solubility, the difference of the release rates, and so on. Non-sink conditions, which would reflect TP and AA release in the lower region of the GI tract, were obtained by the FT method at a cell volume of 0.5 ml and a flow rate of 0.37 ml/h (TP), 0.48 ml/h (AA), respectively. The in vitro release profiles obtained by the FT method combining sink and non-sink conditions were similar to their in vivo profiles. On the other hand, in the case of PPA, the in vivo release profiles were considerably similar to the in vitro ones obtained by both the paddle method and the FT method. In conclusion, the FT method combining sink and non-sink conditions will give a good in vitro/in vivo correlation regarding release behavior for controlled-release multiple unit dosage forms.