目的 采用网络药理学方法探讨栀子豉汤治疗失眠的作用机制；基于质量源于设计（quality by design，QbD）理念，构建并验证栀子豉汤提取工艺的设计空间。方法 通过TCMSP、PharmMapper、Drugbank、GeneCards、Therapeutic Target Database、OMIM等数据库获取栀子豉汤的成分和对应靶点；利用STRING、DAVID数据库和分子对接技术对栀子豉汤治疗失眠的潜在靶点进行分析。以栀子豉汤提取物中的栀子苷、京尼平龙胆双糖苷、大豆苷元、染料木素的提取率及干膏得率作为关键质量属性（critical quality attributes，CQAs），Plackett-Burman设计筛选关键工艺参数（critical process parameters，CPPs），Box-Behnken实验对CPPs进行优化，并构建栀子豉汤提取工艺的设计空间。结果 栀子豉汤的主要活性成分栀子苷、京尼平龙胆双糖苷、大豆苷元、染料木素等，通过作用于白细胞介素-1β（interleukin-1β，IL-1β）、白细胞介素-6（interleukin- 6，IL-6）、雌激素受体1（estrogen receptor 1，ESR1）、一氧化氮合酶3（nitric oxide synthase 3，NOS3）等核心靶点，参与调节神经活性配体-受体相互作用（neuroactive ligand-receptor interaction）、γ-氨基丁酸能突触（GABAergic synapse）、TNF因子信号通路（TNF signaling pathway）等信号通路发挥治疗失眠的作用。栀子豉汤提取工艺的设计空间范围为溶剂用量8～11倍、提取时间为30～84 min，提取次数为1～2次。结论 栀子豉汤可能通过多成分-多靶点-多通路治疗失眠。基于QbD理念建立的栀子豉汤提取工艺设计空间，稳健可靠，可为其制剂的工艺开发提供参考。

Objective In the present study, we applied network pharmacology to explore the molecular mechanism of Zhizichi Decoction (ZD) in insomnia treatment. To establish and validate the design space for the extraction process of ZD based on the concept of quality by design (QbD). Methods Firstly, the components and corresponding targets of ZD were obtained from TCMSP, PharmMapper, Drugbank, GeneCards, Therapeutic Target Database and OMIM databases. Then, STRING, DAVID database and molecular docking technology were used to analyze potential targets of ZD in the treatment of insomnia. With the extraction yield of geniposide, genipin-1-β-D-gentiobioside, daidzein, genistein and dry extract yield as critical quality attributes (CQAs). Subsequently, the Placket-Burman experiment design was used to select the critical process parameters (CPPs). The Box-Behnken experiment design was used to optimize the extraction process, and the design space of the ZD extraction process was established. Results The main active components of ZD, such as geniposide, genipin-1-β-D-gentiobioside, daidzein and genistein, through acting on the core targets of interleukin-1β (IL-1β), interleukin-6 (IL-6), estrogen receptor 1 (ESR1), nitric oxide synthase 3 (NOS3), and involved in the regulation of neuroactive ligand-receptor interaction, GABAergic synapse, TNF signaling pathway, thereby treating insomnia. The design space of extraction technology of ZD was as follows: The amount of solvent was 8—11 times, the extraction time was 30—84 min, and the number of extraction was 1—2 times. Conclusion ZD may treat insomnia through multiple components, multiple targets and multiple pathways. The design space of extraction process of ZD based on QbD concept was robust and reliable, which would provide reference for the process development of its formulations.

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国家自然科学基金项目(81803561);四川省科技计划项目(2020YJ04087);四川省中医药管理局科研专项课题(2021MS189);成都市金牛区医学会科研课题(JNKY2021-06);成都大学附属医院院级课题(Y2021006);成都市医学科研课题(2021070);龙泉驿英才计划C类创新人才计划;四川省科技厅农业科技成果转化资金项目(22NZZH0031)