A Cubic-Phase Oral Drug Delivery System for Controlled Release of AG337

Abstract

AG337 is a novel thymidylate synthase inhibitor possessing potent antitumorogenic activity which was designed using protein structure-based techniques. It is currently undergoing clinical trials as both N and oral formulations. Based on AG337′s short in vivo half-life, an oral controlled-release formulation is desired. The feasibility of using cubic liquid crystalline phases formed from monoolein for controlled release of AG337 has been investigated in this study. AG337 (m.p. = 298®C) was triturated with glycerol and then dissolved in monoolein using mild heat. The resulting gel was liquified by further heating to 65®C, then cooled to RT to yield a clear viscous solution. Samples of the formulation were exposed to water for up to 48 hr at 25®C. Thermal analysis of this system was undertaken in order to determine the effect of hydration state on the liquid crystalline structure. The differential scanning colorimetry (DSC) profile of samples not exposed to water showed no distinct endo- or exothermic transitions. However, samples exposed to water exhibited multiple endothermic transitions from 80° to 120°C. These data demonstrate a thermal response to time-dependent water uptake in the formulation as might occur in vivo after oral dosing, due to changes in physical properties of the system. In vitro release rates of AG337 from this formulation were evaluated.