Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; LEO Pharma, A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark; LEO Pharma, A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
Int J Pharm. 2021 Dec 15;610:121174. doi: 10.1016/j.ijpharm.2021.121174. Epub 2021 Oct 13.
Amorphous solid dispersion (ASD) is emerging as a useful formulation strategy to increase the bioavailability of active pharmaceutical ingredients with poor solubility. In vitro dissolution testing under non-sink conditions has often been used to evaluate the ability of ASDs to generate and maintain supersaturation to predict the in vivo performance. However, such a single compartment dissolution setup can fail to predict the oral bioavailability, due to an interdependence between precipitation and permeation. Hence, the use of two compartment dissolution-permeation setups is emerging. In this study, three ASDs containing fenofibrate as model drug substance were developed using Soluplus®, and Hypromellose Acetate Succinate in two different grades (high and low), respectively. The aim was to compare the use of a small-scale in vitro non-sink dissolution setup and a small-scale in vitro dissolution-permeation setup to predict the in vivo oral exposure of the ASDs in rats. The maximum concentration (C) and area under curve (AUC) obtained in the in vitro studies were used to predict the in vivo rank order of the formulations. The results showed that the two in vitro studies resulted in the same rank order based on both C and AUC. Interestingly, C resulted in a better in vitro/in vivo correlation than the in vitro AUC, and based on the in vitro C, the in vivo rank order was predicted.
无定形固体分散体（ASD）作为一种提高生物利用度的有效方法，已逐渐受到关注，特别是对于那些溶解度较差的活性药物成分。在非饱和条件下进行体外溶解试验，通常用于评估 ASD 产生和维持过饱和状态的能力，以预测体内性能。然而，由于沉淀和渗透之间的相互依存关系，这种单一隔室溶解设置可能无法预测口服生物利用度。因此，使用双隔室溶解-渗透设置的方法正在出现。在这项研究中，使用 Soluplus®和两种不同等级（高和低）的羟丙甲纤维素醋酸琥珀酸酯（Hypromellose Acetate Succinate），分别开发了三种含有非诺贝特作为模型药物的 ASD。目的是比较使用小型非饱和体外溶解装置和小型体外溶解-渗透装置来预测 ASD 在大鼠体内的口服暴露。在体外研究中获得的最大浓度（C）和曲线下面积（AUC）用于预测制剂的体内排序。结果表明，这两种体外研究基于 C 和 AUC 得出了相同的排序。有趣的是，C 与体外 AUC 相比，具有更好的体外/体内相关性，并且基于体外 C，预测了体内排序。
