Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan; Institute of Pharmaceutical Technology, Goethe University Frankfurt am Main, Max-von-Laue Straße 9, D-60438 Frankfurt am Main, Germany.
Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan.
Eur J Pharm Sci. 2019 Jul 1;135:83-90. doi: 10.1016/j.ejps.2019.05.013. Epub 2019 May 22.
The aim of this research was to develop an in silico modeling and simulation approach to predict the oral performance of a poorly soluble drug candidate, T2CP, formulated as an amorphous solid dispersion and an amorphous powder. The dissolution and precipitation profiles of T2CP of the two amorphous formulations were evaluated in biorelevant media using USP 2 paddle apparatus. Three equations, the Noyes-Whitney equation for dissolution and separate equations describing nucleation and crystal growth, were fitted simultaneously to the in vitro profiles to estimate the dissolution and precipitation parameters for each formulation. The in silico prediction model for the amorphous formulations was designed using STELLA Professional software and the simulated profiles were compared with the observed plasma profiles in dogs. The STELLA model was able to describe the complex characteristics of in vitro dissolution and precipitation of the amorphous formulations well. The predicted plasma concentration profiles using the estimated dissolution and precipitation parameters of the two amorphous formulations were close to the profiles observed in dogs. This research paves the way for further application of biorelevant in vitro methods in combination with in silico tools to mechanistically forecast the in vivo performance of enhanced formulations.
本研究旨在开发一种计算机模拟和仿真方法，以预测作为无定形固体分散体和无定形粉末的难溶性药物候选物 T2CP 的口服性能。使用 USP 2 桨式仪器在生物相关介质中评估了两种无定形制剂的 T2CP 的溶解和沉淀曲线。同时拟合了三个方程，即溶解的 Noyes-Whitney 方程和分别描述成核和晶体生长的方程，以估算每种制剂的溶解和沉淀参数。使用 STELLA Professional 软件设计了无定形制剂的计算机预测模型，并将模拟曲线与犬体内的观察到的血浆曲线进行比较。STELLA 模型能够很好地描述无定形制剂体外溶解和沉淀的复杂特征。使用两种无定形制剂的估计溶解和沉淀参数预测的血浆浓度曲线与犬体内观察到的曲线非常接近。这项研究为进一步将生物相关的体外方法与计算机工具相结合，以机械地预测增强制剂的体内性能铺平了道路。
