基于质量源于设计(QbD)制备大黄素固体脂质纳米粒

Preparation of solid lipid nanoparticles loaded with emodin based on quality by design principles

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(CapryolTM90),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.CapryolTM 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 aζpotential 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.