逆向工程在尼群地平片仿制中的应用  

Application of reverse engineering in the imitation of nitrendipine tablets

作　　者：杨俊 温美强 杨广雪 陈果 程刚[1] YANG Jun;WEN Meiqiang;YANG Guangxue;CHEN Guo;CHENG Gang(School of Pharmacy,Shenyang Pharmaceutical University,Shenyang 110016,China)

机构地区：[1]沈阳药科大学药学院,辽宁沈阳110016

出　　处：《沈阳药科大学学报》2022年第12期1409-1420,共12页Journal of Shenyang Pharmaceutical University

摘　　要：目的 采用逆向工程方法对尼群地平片参比制剂进行研究,为尼群地平片的仿制提供方法和依据。方法 采用重量比法、HPLC法、碘显色法和亚甲基蓝-比色法对参比制剂进行逆向研究。在偏光显微镜下观察参比制剂,采用激光粒度仪测定参比制剂原料药(active pharmaceutical ingredients, API)粒径。采用差示扫描量热法(DSC)、X射线衍射法(XRD)、红外光谱法(IR)和拉曼光谱法对参比制剂原料药晶型进行分析。采用扫描电子显微镜对参比制剂的制备工艺进行研究。制备自制尼群地平片,采用体外溶出试验对自制制剂与参比制剂溶出曲线的相似性进行比较。结果 参比制剂中,一水乳糖、聚维酮(povidone, PVP)、玉米淀粉和十二烷基硫酸钠(sodium dodecyl sulfate, SDS)含量分别为19.2%、7.1%、33.5%和1.23%左右,玉米淀粉与微晶纤维素(microcrystalline cellulose, MCC)比例约为1.3∶1。参比制剂中原辅料粒径均较小,原料药经过微粉化处理,D50约为2.2μm,玉米淀粉和微晶纤维素D50分别为20μm、55μm左右。参比制剂原料药晶型为Ⅰ型。参比制剂的制备工艺为湿法制粒。自制制剂与参比制剂在四种介质中溶出曲线相似,f_(2)相似因子均在60以上。结论 为尼群地平片的仿制提供了参比制剂的处方组成、原辅料粒径、原料药晶型和制备工艺信息,在此基础上制备的尼群地平片与参比制剂在四种介质中溶出曲线均相似。Objective To study the reference preparation of nitrendipine tablets using reverse research methods, and to provide methods and basis for the imitation of nitrendipine tablets.Methods The reference preparation was studied reversely by weight ratio method, HPLC method, iodine coloration method and methylene blue colorimetric method.The reference preparation was observed by the polarized microscope, and the particle size of API in the reference preparation was determined by the laser particle size analyzer.The crystal form of API in the reference preparation was analyzed by differential scanning calorimetry(DSC),X-ray diffraction(XRD),infrared spectroscopy(IR) and raman spectroscopy.Scanning electron microscopy was used to study the manufacturing process of reference preparation.Nitrendipine tablets were prepared and the similarity of dissolution curves between the self-made preparation and the reference preparation were compared by in vitro dissolution test.Results The amount of lactose monohydrate, povidone(PVP),corn starch and sodium dodecyl sulfate(SDS) were about 19.2%,7.1%,33.5%,1.23% in the reference preparation respectively.The ratio of corn starch and microcrystalline cellulose(MCC) was about 1.3∶1.The particle sizes of API and excipients in the reference preparation were small, API was micronized with D50 of 2.2 μm, D50 of corn starch and microcrystalline cellulose were about 20 μm and 55 μm, respectively.The crystal form of API in the reference preparation was form I.The manufacturing process was wet granulation.The dissolution curves of the self-made preparation and the reference preparation were similar in the four media, and the f_(2)similarity factors were all above 60.Conclusion This study provides the information of formulation, particle size of API and excipients, crystal form of API and manufacturing process of the reference preparation for the imitation of nitrendipine tablets.The dissolution curves of nitrendipine tablets prepared on this basis are similar to those of the reference prepara

关 键 词：尼群地平 逆向工程 辅料含量测定 粒径 晶型 制备工艺 仿制药一致性评价 

分 类 号：R94[医药卫生—药剂学]