Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy , University of Helsinki , FI-00014 , Finland.
Biohybrid Materials, Department of Bioproducts and Biosystems , Aalto University , FI-00076 , Finland.
Biomacromolecules. 2018 Oct 8;19(10):3983-3993. doi: 10.1021/acs.biomac.8b00931. Epub 2018 Sep 12.
Pharmaceutical nanosuspensions are formed when drug crystals are suspended in aqueous media in the presence of stabilizers. This technology offers a convenient way to enhance the dissolution of poorly water-soluble drug compounds. The stabilizers exert their action through electrostatic or steric interactions, however, the molecular requirements of stabilizing agents have not been studied extensively. Here, four structurally related amphiphilic Janus-dendrimers were synthesized and screened to determine the roles of different macromolecular domains on the stabilization of drug crystals. Physical interaction and nanomilling experiments have substantiated that Janus-dendrimers with fourth generation hydrophilic dendrons were superior to third generation analogues and Poloxamer 188 in stabilizing indomethacin suspensions. Contact angle and surface plasmon resonance measurements support the hypothesis that Janus-dendrimers bind to indomethacin surfaces via hydrophobic interactions and that the number of hydrophobic alkyl tails determines the adsorption kinetics of the Janus-dendrimers. The results showed that amphiphilic Janus-dendrimers adsorb onto drug particles and thus can be used to provide steric stabilization against aggregation and recrystallization. The modular synthetic route for new amphiphilic Janus-dendrimers offers, thus, for the first time a versatile platform for stable general-use stabilizing agents of drug suspensions.
药物纳米混悬剂是在存在稳定剂的情况下将药物晶体悬浮在水介质中形成的。这项技术为提高水中溶解度差的药物化合物的溶解提供了一种便利的方法。稳定剂通过静电或空间相互作用发挥作用，然而，稳定剂的分子要求尚未得到广泛研究。在这里，合成了四种结构相关的两亲性 Janus 树状大分子，并对其进行了筛选，以确定不同大分子结构域对药物晶体稳定化的作用。物理相互作用和纳米研磨实验证实，具有第四代亲水树枝状大分子的 Janus 树状大分子在稳定吲哚美辛混悬剂方面优于第三代类似物和泊洛沙姆 188。接触角和表面等离子体共振测量支持这样的假设，即 Janus 树状大分子通过疏水相互作用结合到吲哚美辛表面上，并且疏水性烷基尾的数量决定了 Janus 树状大分子的吸附动力学。结果表明，两亲性 Janus 树状大分子吸附在药物颗粒上，因此可用于提供对抗聚集和重结晶的空间稳定化。因此，新型两亲性 Janus 树状大分子的模块化合成途径首次为药物混悬剂的通用稳定化剂提供了一个通用的平台。
