Abstract：
Increasing attention is being afforded to understanding the bidirectional relationship that exists between oral drugs and the gut microbiota. Often overlooked, however, is the impact that pharmaceutical excipients exert on the gut microbiota. Subsequently, in this study, we contrasted the pharmacokinetic performance and gut microbiota interactions between two commonly employed formulations for poorly soluble compounds, namely 1) an amorphous solid dispersion (ASD) stabilised by poly(vinyl pyrrolidone) K-30, and 2) a lipid nanoemulsion (LNE) comprised of medium chain glycerides and lecithin. The poorly soluble antipsychotic, lurasidone, was formulated with ASD and LNE due to its rate-limiting dissolution, poor oral bioavailability, and significant food effect. Both the ASD and LNE were shown to facilitate lurasidone supersaturation within in vitro dissolution studies simulating the gastrointestinal environment. This translated into profound improvements in oral pharmacokinetics in rats, with the ASD and LNE exerting comparable ∼ 2.5-fold improvements in lurasidone bioavailability, compared to the pure drug. The oral formulations imparted contrasting effects on the gut microbiota, with the LNE depleting the richness and abundance of the microbial ecosystem, as evidenced through reductions in alpha diversity (Chao1 index) and operational taxonomical units (OTUs). In contrast, the ASD exerted a \'gut neutral\' effect, whereby a mild enrichment of alpha diversity and OTUs was observed. Importantly, this suggests that ASDs are effective solubility-enhancing formulations that can be used without comprising the integrity of the gut microbiota - an integral consideration in the treatment of mental health disorders, such as schizophrenia, due to the role of the gut microbiota in regulating mood and cognition.
摘要：
越来越多的注意力被给予理解口服药物和肠道微生物群之间存在的双向关系。经常被忽视，然而,是药物赋形剂对肠道微生物群的影响。随后，在这项研究中，我们对比了难溶性化合物的两种常用制剂之间的药代动力学性能和肠道微生物群相互作用，即1)由聚(乙烯基吡咯烷酮)K-30稳定的无定形固体分散体(ASD),和2)由中链甘油酯和卵磷脂组成的脂质纳米乳液(LNE)。溶解性差的抗精神病药，Lurasidone,由于其限速溶出而与ASD和LNE一起配制，口服生物利用度差，和显著的食物效果。在模拟胃肠道环境的体外溶出研究中，ASD和LNE均显示出促进鲁拉西酮过饱和。这转化为大鼠口服药物动力学的深刻改善，ASD和LNE在lurasidone生物利用度方面发挥了相当的~2.5倍的改善，与纯药物相比。口服制剂对肠道微生物群具有对比作用，随着LNE耗尽微生物生态系统的丰富性和丰度，这通过α多样性(Chao1指数)和操作分类单位(OTU)的减少得到了证明。相比之下,ASD发挥了“肠道中性”效应，由此观察到α多样性和OTU的轻度富集。重要的是,这表明ASD是有效的溶解度增强制剂，可以在不包含肠道微生物群完整性的情况下使用-这是治疗精神健康障碍的不可或缺的考虑因素。比如精神分裂症，由于肠道菌群在调节情绪和认知方面的作用。
