[关键词]
[摘要]
目的 基于质量源于设计(quality by design,QbD)理念优化制备葛根总黄酮-甘草酸纳米粉体(Pueraria total flavonoids-glycyrrhizic acid nanopowder,PG-NP),并对其进行质量评价。方法 采用超声破碎-高压均质法制备PG-NP混悬液。以PG-NP混悬液的粒径、多分散指数(polydispersity index,PDI)和ζ电位作为关键质量属性,应用鱼骨图筛选风险因素。采用Plackett-Burman设计试验筛选关键工艺参数(critical process parameters,CCPs),在此基础上结合Box-Behnken设计优化PG-NP混悬液的处方配比,应用单因素试验确定PG-NP中冻干保护剂含量。对优化后的PG-NP进行扫描电子显微镜(scanning electron microscope,SEM)、X射线衍射仪(X ray diffraction,XRD)、差示量热扫描仪(differential scanning calorimetry,DSC)表征,并考察PG-NP中葛根素体外溶出性能。结果 PG-NP的最优制备工艺和处方配比:药辅比为17.5∶1、甘草酸用量为0.13%、搅拌转速为470r/min、均质压力为128.3MPa、甘露醇用量为5%。优化后PG-NP粒径为(228.00±7.80)nm,PDI为0.29±0.05,ζ电位为(-23.10±0.93)mV。PG-NP为具有针棒状晶型的淡黄色粉末,且其体外溶出性能较原料药有明显提高。结论 采用QbD理念优化的PG-NP制备工艺简单易行,处方设计合理,质量可控,可有效改善难溶性成分的溶出。
[Key word]
[Abstract]
Objective To optimize Pueraria total flavonoids nanopowder-glycyrrhizic acid nanopowder (PG-NP) based on concept of quality by design (QbD) and evaluate their quality.Methods PG-NP suspension was prepared by ultrasonic crushing and high pressure homogenization method. A fishbone diagram was used to evaluate risk factors that could affect the particle size, polydispersity index (PDI) and ζ potential of PG-NP suspensions as critical quality attributes. A Plackett-Burman experimental design was used to screen the key process parameters, based on which the prescription ratio of the PG-NP suspension was optimized in conjunction with the Box-Behnken Design, then a single factor test was used to determine the content of lyoprotectant in PG-NP. The scanning electron microscope (SEM), X ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to characterize the optimized PGNP, and the in vitro dissolution properties of puerarin in PG-NP were investigated.Results The optimum preparation process and formulation ratio of PG-NP were as follows: the adjuvant ratio was 17.5:1; the content of glycyrrhizin acid was 0.13%; the stirring speed was 470 r/min; the homogenizing pressure was 1 283 MPa, and the content of mannitol was 5 %. The particle size of the optimized PG-NP was (228.00 ±7.80) nm, the PDI was 0.29 ±0.05, and the ζ potential was (-23.10 ±0.93) mV. PG-NP was light yellow powder with needle-rod crystal form, and in vitro dissolution performance was significantly improved compared with the PDI.Conclusion In this study, the preparation process of PG-NP optimized by the QbD concept was simple and feasible, the formula design was reasonable, and the quality was controllable, which can effectively improve the dissolution of poorly soluble components.
[中图分类号]
R283.6
[基金项目]
安徽省高校自然科学研究重点项目(KJ2021A0538);安徽省高校自然科学研究重点项目(KJ2021A0541);安徽中医药大学药学院研究生培养基金(21pyjj05);安徽中医药大学高层次人才支持计划基金(2022rczd003)