目的 通过质量源于设计（quality by design，QbD）理论制备大黄素固体脂质纳米粒（emodin solid lipid nanoparticle，Emo-SLN）。方法 利用鱼骨法和使用故障模式、影响和危害性分析（failure mode and effects criticality analysis，FMECA）方法筛选出关键质量属性（critical quality attributes，CQAs）、关键物料属性（critical material attributes，CMAs）以及关键工艺参数（critical process parameters，CPPs），并采用熔融-乳化法制备固体脂质纳米粒，用Box-Behnken设计（Box-Behnken design，BBD）优化制剂。结果 确定CMAs为脂质、表面活性剂、药脂比；CPPs为超声功率；CQAs为粒径、ζ电位、包封率、载药量、体外释放率。通过BBD优化制剂，测得其CMAs：脂质单辛酸丙二醇酯（Capryol^TM 90），表面活性剂聚氧乙烯氢化蓖麻油（Cremophor^® RH40），药脂比1∶170；CPPs：超声功率216 W；CQAs：粒径（138.900±1.143）nm，ζ电位（−21.90±0.50）mV，包封率（98.28±1.43）%、载药量（0.23±0.01）%、体外释放表现为在48 h内累积释放率达80%，具有缓释特性。结论 该项目利用QbD成功制备质量符合CQAs要求的Emo-SLN，提高其生物利用度，从而促进其临床应用。

Objective To prepare emodin loaded into solid lipid nanoparticles (Emo-SLN) based on the concept of quality by design (QbD). Methods Critical quality attributes (CQAs), critical material attributes (CMAs), and critical process parameters (CPPs) were screened using a fish bone diagram and failure mode and effects criticality analysis (FEMCA). Subsequently, the Emo-SLN were developed using the melt-emulsification method and optimized by Box-Behnken design (BBD). Results The CMAs were identified as lipid, surfactant, and drug-lipid ratio. The CPP was the ultrasound power. The CQAs included particle size, encapsulation rate, drug loading, and in vitro release. The formulation was optimized by BBD. Capryol^TM 90 (lipid) was selected as the final composition along with Cremophor^® RH40 as the surfactant component at a drug-lipid ratio of 1:170. The ultrasound power was 216 W. The particle size of CQAs was (138.900 ± 1.143) nm, with a ζ potential of (−21.90 ± 0.50) mV and an encapsulation rate of (98.28 ± 1.43)%. Additionally, the drug loading was found to be (0.23 ± 0.01)%, and in vitro release demonstrated sustained release characteristics with cumulative release reaching up to 80% within 48 h. Conclusion Emo-SLN meeting the requirements of CQAs was successfully prepared using QbD, which improved its bioavailability for its enhanced clinical application.

福建省科技厅面上基金（2020J01630）；福建省科技创新联合资金项目（2019Y9010）