逆向工程在咖啡因片制剂开发中的应用

Application of reverse engineering in the development of caffeine tablets

目的采用逆向工程技术对咖啡因片原研制剂Good Sense Stay Awake®进行处方及工艺剖析,为咖啡因片仿制药的开发提供指导。方法首先通过文献调研获取原研制剂的处方信息;使用示差折光检测高效液相色谱法和重量分析法对处方组成进行定量解析;使用拉曼成像技术对原辅料粒径进行分析;使用光学显微镜和X线粉末衍射技术分别对活性药用成分(API)晶癖和晶型进行表征;并通过崩解现象确定原研制剂的制备工艺;最后使用吗啉试剂对包材进行鉴别。按确定的处方及工艺制备3批样品,与原研制剂进行质量对比。结果通过对原研制剂的逆向工程分析,确定原研制剂的处方组成为:葡萄糖、微晶纤维素、预胶化淀粉、麦芽糊精、硬脂酸镁、胶态二氧化硅和黄色色淀,其中葡萄糖含量32%,微晶纤维素含量<23%;原研制剂的原料药晶癖与晶型与自制制剂一致;咖啡因、微晶纤维素、葡萄糖、麦芽糊精和预胶化淀粉的平均粒径分别约为206、112、172和61μm;制备工艺为粉末直接压片法;包材为聚氯乙烯-铝箔。根据原研制剂解析结果制备的3批自制制剂与原研制剂质量一致。结论通过对原研制剂开展逆向工程,成功制备了与Good Sense Stay Awake®质量一致的咖啡因片,为逆向工程在仿制药开发及一致性评价中的应用提供了可参考的思路。

Objective The reverse engineering technology was used to analyze the prescription and process of Good Sense Stay Awake®,the reference listed drug of caffeine tablets,in order to provide guidance for the development of generic caffeine tablets.Methods Firstly,the prescription information of the reference listed drug was obtained by literature research.Then,quantitative analysis of the composition of the prescription was achieved by the high-performance liquid chromatography with a crystal refractive in⁃dex detection and the gravimetric analysis method;the particle size of raw and auxiliary materials was analyzed by Raman imaging technology;the crystal habit and crystal form of active pharmaceutical ingredient(API)were characterized by the optical microscope and X-ray powder diffraction technology,respectively;the preparation process of reference listed drug was determined by disintegra⁃tion method;and finally,the package material was identified by the morpholine reagent.Moreover,three batches of samples were pre⁃pared according to the determined prescription and process,and the quality was compared with the reference listed drug.Results By the reverse engineering analysis of the reference listed drug,the prescription composition of the reference listed drug was determined to be composed of glucose,microcrystalline cellulose,pregelatinized starch,maltodextrin,magnesium stearate,colloidal silica and yellow lake,in which the glucose content was 32%and the microcrystalline cellulose content was<23%.The API crystal form of the reference listed drug was consistent with that of the self-made preparation.The average particle size of caffeine,microcrystalline cellu⁃lose,glucose,maltodextrin and pregelatinized starch was approximately 206,112,172 and 61μm,respectively.The tablet prepara⁃tion process was the direct compression method,and the packaging material was polyvinyl chloride aluminum foil.The quality of the three batches of home-made preparations was the same as that of the reference listed drug.Conclusion Caffeine tablets with the same quality as Good Sense Stay Awake®were successfully prepared by reverse engineering of the reference listed drug,which provides a reference for the application of reverse engineering in the generic drug development and consistency evaluation.