逆向工程在伊曲康唑胶囊仿制中的应用  

Application of reverse engineering in the imitation of itraconazole capsules

作　　者：陈俞丞 许铭志 肖婷玉 胡欣 林华庆[1] CHEN Yucheng;XU Mingzhi;XIAO Tingyu;HU Xin;LIN Huaqing(Key Labroratory of Advanced Drug Delivery Systems of Guangdong Province,Guangdong Pharmaceutical University,Guangzhou 510006,China)

机构地区：[1]广东药科大学广东省药物新剂型重点实验室,广东广州510006

出　　处：《沈阳药科大学学报》2025年第3期222-231,共10页Journal of Shenyang Pharmaceutical University

摘　　要：目的对伊曲康唑胶囊参比制剂进行逆向工程研究,为该制剂的仿制研究提供参考。方法从多个维度对参比制剂进行逆向研究。观察参比制剂在水中的静态崩解现象,作为后续自制制剂表征考察的初步参考条件。专利调研获取专利处方信息,通过分子量检测、黏度测试等对其所用辅料型号进行确认,并通过钠石灰的化学反应确定空心胶囊壳的材料。采用扫描电子显微镜(section scanning electron,SEM)对参比制剂的制备工艺和层级结构进行研究。采用差示扫描量热法(differential scanning calorimetry,DSC)、X射线衍射法(X-ray diffraction,XRD)和拉曼光谱法对参比制剂进行晶型分析。在此逆向工程的基础上制备自制样品,通过晶型表征和在4种介质中的体外溶出试验,对比自制制剂与参比制剂的相似性。结果参比制剂中所用的外隔离层包衣材料、黏合剂和空心胶囊壳分别为聚乙二醇20000、羟丙甲纤维素E5和0号明胶空心胶囊壳。根据扫描电子显微镜结果可知参比制剂微丸直径约为920μm,微丸的蔗糖丸芯直径约为610μm,上药后载药层厚度约为130μm,外隔离层厚度约为11μm。参比制剂与自制制剂中原料药晶型均为无定形。参比制剂的制备工艺为流化床底喷包衣法,自制制剂与参比制剂在体外4种介质中溶出曲线相似,相似因子f_(2)均在50以上。结论逆向工程研究为伊曲康唑胶囊的仿制研究提供了参比制剂的静态崩解、处方组成、层级结构、制备工艺、晶型的信息,在此基础上制备的伊曲康唑胶囊与参比制剂在体外4种介质中溶出行为与溶出曲线均相似。Objective To investigate the reverse engineering of the reference preparation of itraconazole capsules in order to provide a reference for imitation research of the preparation.Methods The reference preparation was studied from multiple dimensions,including observing its static disintegration in water,conducting patent research to obtain patent prescription information,and studying its preparation technology and hierarchical structure through scanning electron microscopy(SEM).The crystal form of the reference preparation was analyzed using differential scanning calorimetry(DSC),X-ray diffraction(XRD)and Raman spectroscopy.Self-made samples were prepared based on reverse engineering,and their similarity to the reference preparation was compared through crystal characterization and in vitro dissolution tests in four media.Results The type of adhesive hypromellose used in the reference preparation was determined to be E5 and the type of polyethylene glycol used in the reference preparation was determined to be polyethylene glycol 20000.Scanning electron microscopy results showed that the diameter of the reference preparation pellet was about 920μm,the diameter of the sucrose pellet core of the pellet was about 610μm,the thickness of the drug loading layer was about 130μm,and the thickness of the outer isolation layer was about 11μm.The crystal type of the raw material in the reference preparation and the self-made preparation was found to be amorphous.The preparation process of the reference preparation was fluidized bed bottom spray coating method.The dissolution curves of the self-made preparation and the reference preparation were similar in vitro,with similarity factors f_(2) above 50 in all four media.Conclusion The reverse engineering study provides valuable information for the imitation study of itraconazole capsules,including static disintegration,prescription composition,hierarchical structure,preparation process,and crystal shape.The dissolution behavior of the prepared itraconazole capsules is similar

关 键 词：伊曲康唑 胶囊 参比制剂 逆向工程 体外溶出 

分 类 号：R94[医药卫生—药剂学]