星点设计-效应面法优化pH值依赖型岩黄连碱口服结肠靶向纳米粒

Optimization of pH-dependent dehydrocavidine oral colon-targeting nanoparticles by central composite design-response surface methodology

目的采用星点设计-效应面法(central composite design-response surface methodology,CCD-RSM)优化pH值依赖型岩黄连碱口服结肠靶向纳米粒(dehydrocavidine-chitosan/pectin-nanoparticles,DC-CS/PT-NPs)制备工艺,并对其进行质量表征及体外释放行为评价。方法采用离子凝胶法制备DC-CS/PT-NPs,以粒径、PDI、ζ电位、包封率、载药量作为评价指标,采用单因素考察和CCD-RSM优化DC-CS/PT-NPs制备工艺。通过透射电子显微镜(transmission electron microscope,TEM)、扫描电子显微镜(scanning electron microscope,SEM)、傅里叶红外光谱(Fourier transform infrared spectroscopy,FTIR)、差示扫描量热法(differential scanning calorimetry,DSC)和X射线衍射法(X-ray diffraction,XRD)对DC-CS/PT-NPs进行表征,并进行体外释放性能评价。结果最佳处方为壳聚糖质量浓度为1.5 mg/mL,果胶质量浓度为1.5 mg/mL,TPP质量浓度为2.0 mg/mL,壳聚糖pH值为5.0。DC-CS/PT-NPs包封率为(61.64±1.77)%,载药量为(8.05±0.18)%,粒径为(418.65±4.92)nm,ζ电位为(−14.14±0.22)mV。DC-CS/PT-NPs呈均匀的球形或类球形;制备成纳米粒后,药物的晶型发生了改变;体外释药结果表明,DC-CS/PT-NPs在人工胃液中2 h仅释放24.35%,在人工小肠液中4 h累积释放率<40%,在人工结肠液中10 h累积释放率>85%。结论CCD-RSM所建立的模型可用于DC-CS/PT-NPs处方优化,DC-CS/PTNPs具有良好的体外结肠释药特征。

Objective To optimize the formulation of pH-dependent dehydrocavidine-chitosan/pectin-nanoparticles(DC-CS/PT-NPs)by central composite design-response surface methodology(CCD-RSM),and to conduct its quality characterization and evaluate its release behavior in vitro.Methods DC-CS/PT-NPs was prepared by ionotropic gelation method.Particle size,PDI,ζpotential,encapsulation rate and drug loading were used as evaluation indexes,and the preparation process of DC-CS/PT-NPs was optimized by single factor investigation and CCD-RSM.DC-CS/PT-NPs were characterized by transmission electron microscopy(TEM),scanning electron microscopy(SEM),Fourier infrared spectroscopy(FT-IR),differential scanning calorimetry(DSC)and X-ray diffraction(XRD),and their release properties were evaluated in vitro.Results The optimal prescription is chitosan concentration of 1.5 mg/mL,pectin concentration of 1.5 mg/mL,TPP concentration of 2.0 mg/mL,and chitosan pH of 5.0.The encapsulation rate of DC-CS/PTNPs was(61.64±1.77)%,the drug loading was(8.05±0.18)%,the particle size was(418.65±4.92)nm,and theζpotential was(−14.14±0.22)mV.DC-CS/PT-NPs are uniformly spherical or quasi-spherical;The crystalline form of the drug was changed after the preparation of nanoparticles.The results of drug release in vitro showed that only 24.35%of DC-CS/PT-NPs were released in artificial gastric fluid for 2 h,and the cumulative release rate was less than 40%in artificial intestinal fluid for 4 h and more than 85%in artificial colonic fluid for 10 h.Conclusion The model established by CCD-RSM can be used to optimize the formulation of DC-CS/PT-NPs,which has good characteristic of colonic drug release in vitro.