多颗粒体系在伊曲康唑增溶中的应用与表征

Application and characterization of multiparticle system for solubilization of itraconazole

关键词:  伊曲康唑  多颗粒体系  增溶  星点设计-响应面法  体外溶出

Key words:  itraconazole  multiparticle system  solubilization  central composite design and response surface methodology  dissolution in vitro

摘要:

目的 为了解决伊曲康唑的难溶性问题，提高其体外溶出度，为伊曲康唑多颗粒体系进一步工业化放大生产提供参考。方法 采用流化床底喷包衣工艺，制备伊曲康唑多颗粒体系微丸，将伊曲康唑与羟丙甲纤维素溶于有机溶剂后喷载于蔗糖丸芯表面，在微丸表面形成固体分散体。采用单因素法考察流化床底喷包衣制备参数。采用星点设计-响应面法，以溶出度、上药效率及粘连率为响应值，对伊曲康唑多颗粒体系的药物载体质量比和丸芯增重进行优化。制备样品对优化后处方进行验证，通过扫描电子显微镜观察伊曲康唑多颗粒体系的镜下层级结构，运用差示扫描量热法(DSC)及X-射线粉末衍射法(XRD)对伊曲康唑多颗粒体系微丸中的固体分散体进行表征，并通过对比伊曲康唑微丸和物理混合物在0.1 N HCl溶出介质中的溶出曲线，对其增溶效果进行验证。结果 单因素法确定流化床底喷包衣参数，泵液速度为3.0~5.0 mL?min-1，雾化压力为1.5 Bar，进风量为110 m3?h-1，物料温度为35 ℃；根据星点设计-响应面法拟合优化后处方的药物载体质量比为1：1.5，丸芯增重为75%，此时各响应值达到期望值。根据扫描电子显微镜结果可知伊曲康唑多颗粒体系微丸直径约为900 μm，微丸的蔗糖丸芯直径约为570 μm，上药后载药层厚度约为110 μm，包封层厚度约为11 μm。通过DSC与XRD结果可知伊曲康唑多颗粒体系微丸中伊曲康唑形成了均匀的固体分散体，为无定形。在0.1 N HCl溶出介质中，第90 min多颗粒体系溶出度约为物理混合物的10倍，增溶效果显著。结论 将伊曲康唑制成多颗粒体系微丸，形成固体分散体，可以显著改善伊曲康唑的体外溶出度。

Abstract:

OBJECTIVE To solve the problem of insolubility of itraconazole, to improve its dissolution in vitro, and to provide a reference for further industrial scale-up of the itraconazole multiparticle system. METHODS Itraconazole multiparticle system pellets were dissolved in an organic solvent and prepared in a fluidized bed by bottom spraying. Itraconazole and hydroxypropyl methylcellulose were sprayed onto the surface of the sucrose pellet core to form a uniform solid dispersion. The preparation parameters of the fluidized bed bottom spray coating were investigated by single factor method. The mass ratio of drug to carrier and core weight gain of the itraconazole multiparticle system were optimized by central composite design and response surface methodology with dissolution rate, application efficiency and adhesion rate as response values. Samples were prepared to verify the optimized prescription, the microscopic hierarchical structure of the itraconazole multiparticle system was observed by scanning electron microscope, and the solid dispersion in the itraconazole multiparticle system pellets was characterized by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The dissolution curves of itraconazole pellets and the physical mixture in 0.1 N HCl dissolution medium were compared to verify the solubilization effect. RESULTS Single factor method was used to determine the bottom spray coating parameters of the fluidized bed. The pumping speed was set as 3.0~5.0 mL?min-1, the atomization pressure was set as 1.5 Bar, the inlet air volume was set as 110 m3?h-1, and the material temperature was set as 35 ℃. According to the central composite design and response surface methodology, the mass ratio of drug to carrier of the optimized prescription was 1:1.5 and the core weight of the pill was 75%, and the response values reached the expected value. The result of scanning electron microscopy showed that the diameter of the itraconazole multiparticle system pellet was about 900 μm, the diameter of the sucrose pellet core was about 570 μm, the thickness of the drug loading layer was about 110 μm, and the thickness of encapsulation layer was about 11 μm. The results of DSC and XRD showed that itraconazole formed a uniform solid dispersion in the itraconazole multiparticle system pellets, which was amorphous. In the dissolution medium of 0.1 N HCl, the dissolution rate of the multiparticle system after 90 min was about 10 times that of the physical mixture, which showed that the solubilization effect was remarkable. CONCLUSIONS The dissolution of itraconazole in vitro can be significantly improved by processing itraconazole into pellets with multiparticle system and forming solid dispersion.