目的 在不改变儿科中药羚珠散抗惊厥药效的前提下，基于溶剂挥发法的粒子设计技术对羚珠散进行制剂改良，提高其流动性和均一性，降低其Hg元素的暴露量，保证其用药安全性。方法 借助粒子设计技术对羚珠散进行制剂改良，制备并表征“朱砂-琥珀”复合粒子，通过构建幼龄大鼠惊厥模型，对比羚珠散及其改良制剂的抗惊厥效果，探讨两者的体内药动学行为，分析其体内过程和安全性。结果 以复合粒子与琥珀表面润湿性差异最小的各比例参数水平为优化目标对复合粒子进行工艺优化，得到最优制备工艺为溶剂体积250 mL，超声20 min，转速15 r/min。复合粒子表征结果表明，粒子设计羚珠散（后简称为粒子设计散）为结构均一的粒子，其流动性和均匀性均优于物理混合物，且溶剂挥发法改变了朱砂和琥珀的表面形貌，使得其形成了全新的微观结构。溶剂残留实验结果表明，样品中不存在二氯甲烷残留。药效实验结果表明，羚珠散组、粒子设计散组可显著延长惊厥潜伏期（P＜0.05、0.01），缩短惊厥持续时间（P＜0.001），显著降低酰化刺激蛋白（acylated stimulatory protein，ASP）含量，且对肝肾没有明显的毒性作用。药动学结果表明粒子设计散中Hg元素的AUC_0～t、C_max是羚珠散的0.80、0.66倍，一定程度上降低了Hg元素的暴露量。另外，粒子设计散的胆酸和猪去氧胆酸的药时曲线与羚珠散的基本一致，均表现出先吸收后降低的趋势。结论 粒子设计技术成功改善了儿科中药羚珠散的流动性和均一性，并在一定程度上降低了Hg元素的溶出，且羚珠散及其粒子设计散均表现出良好的抗惊厥效果。粒子设计散相较于传统羚珠散而言，能够保障在不影响有效成分胆酸和猪去氧胆酸的体内药动学行为的前提下，一定程度上降低制剂中Hg元素的暴露量，从而提升该制剂的安全性，保障儿童的用药安全。

Objective Without compromising the anticonvulsant efficacy of pediatric medicine Lingzhu Powder (LP, 羚珠散), this study employed particle design technology based on solvent evaporation to improve the formulation of LP. The aim was to enhance its flowability and uniformity, reduce the exposure to mercury (Hg) element, and ensure its safety for use. Methods In this study, particle design technology was used to improve the formulation of LP by preparing and characterizing “Cinnabar-Amber” composite particles. Using a juvenile rat convulsion model, the anticonvulsant effects of LP and its improved formulation were compared. The pharmacokinetic behavior of both formulations in vivo was explored, and their in vivo processes and safety were analyzed. Results Based on the objective of minimizing the wettability difference between composite particles and amber surfaces across various parameter ratios, the process was optimized. The optimal preparation parameters were determined as follows: solvent volume of 250 mL, ultrasonic treatment for 20 min, and stirring speed of 15 r/min. The optimized composite particles exhibited uniform structure, improved flowability, and better homogeneity compared to physical mixtures. The solvent evaporation method altered the surface morphology of cinnabar and amber, creating a novel microstructure. No dichloromethane residue was detected in the samples. Both LP and the particle-designed formulation significantly prolonged the latency to convulsion (P < 0.05, 0.01), shortened the duration of convulsion (P < 0.001), and reduced Acylated stimulatory protein (ASP) content without causing significant toxicity to the liver or kidneys. Pharmacokinetic results showed that the area under the curve (AUC) and maximum concentration (C_max) of Hg in the particle-designed formulation were 0.80 and 0.66 times those of the original LP, respectively, indicating reduced exposure to Hg. The pharmacokinetic profiles of bile acid and hyodeoxycholic acid in both formulations were similar, showing an initial increase followed by a decrease. Conclusion Particle design technology successfully improved the flowability and uniformity of pediatric medicine LP and to some extent reduced the leaching of elemental Hg. Both the original and optimized formulations demonstrated good anticonvulsant effects. The particle-designed formulation, while maintaining the pharmacokinetic behavior of the active components bile acid and hyodeoxycholic acid, reduced Hg exposure the preparation to a certain extent, thereby enhancing the safety of the formulation for pediatric use.

R283.6

国家重点研发计划中药现代化专项（2018YFC1706900）；江苏省科技成果转化专项资金（BA2020077）