Department of Industrial and Molecular Pharmaceutics, College of Pharmacy, Purdue University, West Lafayette, Indiana 47907, United States.
Mol Pharm. 2024 Oct 7;21(10):5285-5296. doi: 10.1021/acs.molpharmaceut.4c00711. Epub 2024 Sep 18.
Praziquantel (PZQ) is the treatment of choice for schistosomiasis, which affects more than 250 million people globally. Commercial tablets contain the crystalline racemic compound (-PZQ) which limits drug dissolution and oral bioavailability and can lead to unwanted side effects and poor patient compliance due to the presence of the -enantiomer. While many approaches have been explored for improving PZQ's dissolution and oral bioavailability, studies focusing on investigating its release from amorphous solid dispersions (ASDs) have been limited. In this work, nucleation induction time experiments were performed to identify suitable polymers for preparing ASDs using -PZQ and -PZQ, the therapeutically active enantiomer. Cellulose-based polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS, MF grade) and hydroxypropyl methylcellulose (HPMC, E5 LV grade), were the best crystallization inhibitors for -PZQ in aqueous media and were selected for ASD preparation using solvent evaporation (SE) and hot-melt extrusion (HME). ASDs prepared experimentally were subjected to X-ray powder diffraction to verify their amorphous nature and a selected number of ASDs were monitored and found to remain physically stable following several months of storage under accelerated-stability testing conditions. SE HPMCAS-MF ASDs of -PZQ and -PZQ showed faster release than HPMC E5 LV ASDs and maintained good performance with an increase in drug loading (DL). HME ASDs of -PZQ formulated using HPMCAS-MF exhibited slightly enhanced release compared to that of SE ASDs. SE HPMCAS-MF ASDs showed a maximum release increase of the order of 6 times compared to generic and branded (Biltricide) PZQ tablets. More importantly, SE -PZQ ASDs with HPMCAS-MF released the drug as effectively as -PZQ or better, depending on the DL used. These findings have significant implications for the development of commercial PZQ formulations comprised solely of the -enantiomer, which can result in mitigation of the biopharmaceutical and compliance issues associated with current commercial tablets.
吡喹酮（PZQ）是治疗血吸虫病的首选药物，全球有超过 2.5 亿人受到感染。商业片剂含有晶态外消旋化合物（-PZQ），这限制了药物的溶解和口服生物利用度，并可能导致不必要的副作用和患者用药依从性差，因为存在 -对映异构体。虽然已经探索了许多方法来提高 PZQ 的溶解和口服生物利用度，但专注于研究其从无定形固体分散体（ASD）中释放的研究有限。在这项工作中，进行了成核诱导时间实验，以确定使用-PZQ 和治疗有效对映异构体 -PZQ 制备 ASD 的合适聚合物。基于纤维素的聚合物，羟丙基甲基纤维素乙酸琥珀酸酯（HPMCAS，MF 级）和羟丙基甲基纤维素（HPMC，E5 LV 级），是在水性介质中对-PZQ 最好的结晶抑制剂，并被选为溶剂蒸发（SE）和热熔挤出（HME）制备 ASD 的聚合物。通过 X 射线粉末衍射对实验制备的 ASD 进行了验证，以证明其无定形性质，并对选定数量的 ASD 进行了监测，发现它们在加速稳定性测试条件下储存数月后仍保持物理稳定性。-PZQ 和 -PZQ 的 SE HPMCAS-MF ASD 比 HPMC E5 LV ASD 释放更快，并在增加药物载药量（DL）时保持良好的性能。使用 HPMCAS-MF 配制的 -PZQ 的 HME ASD 与 SE ASD 相比，释放略有增强。SE HPMCAS-MF ASD 与普通和品牌（Biltricide）PZQ 片剂相比，最大释放增加了约 6 倍。更重要的是，使用 HPMCAS-MF 的 SE -PZQ ASD 释放药物的效果与 -PZQ 或更好，具体取决于使用的 DL。这些发现对开发仅由 -对映异构体组成的商业 PZQ 制剂具有重要意义，这可以减轻与当前商业片剂相关的生物制药和合规问题。
