目的: 通过测定国产盐酸地芬尼多片和原研制剂的有关物质和溶出度, 评价国产仿制制剂与原研制剂的质量一致性。方法: 参照《中华人民共和国药典》2015 年版方法进行溶出试验, 用pH 1. 2 盐酸溶液、pH 4. 0 醋酸盐溶液、pH 6. 8 磷酸盐溶液、水4 种溶出介质测定溶出曲线, 分析国产制剂与原研制剂的溶出曲线相似性。借助GastroplusTM 软件结合体外溶出试验结果, 建立盐酸地芬尼多片体内外相关性模型。使用HPLC 法测定有关物质, 以0. 5% 三乙胺（有磷酸调pH 至4. 0）-甲醇（44∶56）为流动相, 测定原研制剂、3批仿制制剂及盐酸地芬尼多原料的已知杂质和未知杂质。结果: 国产仿制制剂的体外溶出行为与原研不相似, 软件分析结果显示体外溶出曲线与软件模拟的体内行为不相符, 体外溶出度测定方法不能反应体内溶出吸收过程。国产仿制制剂中除已知的降解杂质烯化合物来源于原料外, 其他杂质主要来源于辅料, 已知杂质和未知杂质含量均与原研制剂相当。结论: 国产盐酸地芬尼多片工艺水平有待提高, 溶出一致性评价方法有待进一步研究。
Objective: To evaluate the quality consistency of generic preparation and reference preparation by measuring the related substances and dissolution of domestic difenidol hydrochloride tablets and reference preparation. Methods: The dissolution test was carried out according to the method in Chinese Pharmacopoeia （2015）. The dissolution curves were determined using four dissolution mediums of（pH 1. 2 hydrochloric acid solution, pH 4. 0 acetate solution, pH 6. 8 phosphate solution and water）, and the similarity of dissolution curves between domestic preparation and reference preparation was analyzed. With the help of gastroplustm software and based on in vitro dissolution test results, the correlation model of difenidol hydrochloride tablets in vivo and in vitro was established. HPLC method was used to determine the related substances, with the mobile phase of 0. 5% triethylamine（pH adjusted to 4. 0 with phosphoric acid）-methanol（44: 56）, the known impurities and unknown impurities of the reference preparation, 3 batches of generic preparations and the raw materials of difenidol hydrochloride was tested. Rusults: The in vitro dissolution behavior of the domestic generic preparations is not similar to that of the reference preparation. The software analysis results show that the in vitro dissolution curve does not match the in vivo behavior. The in vitro dissolution determination method could not reflect the in vivo dissolution and absorption process. In the domestic generic preparations, the known degradation impurity alkene compound is derived from raw materials, while other impurities were mainly derived from excipient materials. The contents of known impurities and unknown impurities were equivalent to those of the reference preparation. Conclusion: The technology level of domestic difenidol hydrochloride tablets needs to be improved, and the dissolution consistency evaluation method needs to be further studied。
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