基于双载体分子间强相互作用的固体分散体构建及其抑制无定形药物相分离机制研究

固体分散体存储过程中易发生无定形药物相分离，导致药物口服吸收降低，成为限制该体系广泛应用的瓶颈问题。项目组近期发现，采用与药物无相互作用的两种载体分别制备固体分散体，存储过程中两体系均发生相分离；将两载体联用，相分离得到有效抑制（IJP，2020）。推测是两载体分子间产生强相互作用，形成三维物理网络结构，阻碍药物分子运动，抑制相分离。在此基础上，本课题提出构建基于“双载体分子间强相互作用”的固体分散体，通过载体分子间强相互作用抑制药物相分离。拟选择分子间相互作用各异的双载体制备固体分散体，监测药物相分离，探明双载体对药物相分离的抑制作用；研究载药量、双载体化学结构及相对比例对药物相分离速率的影响，揭示处方因素的调控机制；分析“双载体分子间相互作用-药物分子运动-药物相分离速率”的相关性，阐明双载体抑制药物相分离的机制。本课题提出的策略对药物化学结构无要求，为抑制无定形药物相分离提供新思路。

Phase separation of the amorphous drug tends to occur during the storage of solid dispersions, leading to decreased oral absorption, which has been a bottleneck problem restricting the wide application of solid dispersions. In our recent work, two binary solid dispersions of cinnarizine were prepared using two carriers, respectively, and no molecular interactions exited between cinnarizine and each of the carriers. Phase separation was noticed for both solid dispersions. When using two carriers together, it was surprisingly found that phase separation of amorphous drug was inhibited effectively (IJP, 2020). We speculated that the strong molecular interactions between carriers caused the formation of physical network between carriers with a three dimensional structure. Then, the physical network depressed the mobility of drug molecules, leading to inhibited phase separation. According to our work, we propose to construct solid dispersions based on the strong molecular interactions between binary carriers to inhibit the phase separation of amorphous drug. Binary carriers with different extents of molecular interactions will be chosen to prepare solid dispersions. The inhibitory effect of binary carriers on phase separation of amorphous drug will be investigated by monitoring the phase separation of amorphous drug over time. The effect of drug loading, type and ratio of carriers on the rate of phase separation of amorphous drug will be investigated to clarify the formulation optimization. The correlations among the molecular interactions between binary carriers, the mobility of drug molecules and the rate of phase separation of amorphous drug will be discussed to investigate the mechanism of inhibited phase separation of amorphous drug by the binary carriers. This work may provide new insight into the strategies of inhibiting the phase separation of amorphous drug in solid dispersions, no matter the chemical structures of the drug.