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目的:采用法定检验方法与探索性研究方法相结合评价国产利福平口服制剂的质量现状及存在问题。方法:按照2010年度国家评价性抽验计划总体要求,采用现行标准对抽验样品进行法定检验;建立或完善了用于探索性研究的多个方法:采用添加原料识别辅料的方法,建立了口服制剂中利福平晶型判别的粉末X-衍射法,对国内外胶囊所用原料进行测定;目测法观察胶囊内容物的颜色,考察其与晶型的关系;建立判定利福平胶囊制剂所用原料晶型的近红外定性模型;采用HPLC-UV-ESI-IT-MSn联用技术,借助MatLab分析软件,对药典色谱条件下色谱图中主要色谱峰进行结构认定,并采用SPSS软件对上述数据进行统计分析;采用斑马鱼模型对比利福平及其部分有关物质对斑马鱼胚胎发育的毒性;分别采用常压干燥、减压干燥和卡氏法测定不同处方胶囊中的水分含量。结果:法定检验:检验226批利福平口服制剂,222批合格,合格率为98.2%,4批不合格项目均为干燥失重;探索性研究:国内胶囊和片剂所用利福平原料均为I型,国外主要为Ⅱ型,部分为I型;胶囊内容物所用原料为I型的呈鲜红色,Ⅱ型的呈暗红色,与粉末X-衍射结果一致;从有关物质检出的类型、个数和检出量结果显示,国产利福平胶囊在杂质谱层面上均优于进口利福平胶囊;6种利福霉素类化合物的斑马鱼胚胎致死作用由强及弱依次为:利福霉素S-钠盐>利福霉素SV>3-甲酰利福霉素SV>醌式利福平>利福平>>N-氧化利福平,其毒性类型主要与其母环结构有关,毒性大小与其3位取代基结构相关;采用原料直接灌装的胶囊,3种水分测定方法测得的数据无显著性差异,但辅料较多的胶囊,卡氏法测定结果明显高于干燥失重法的结果。结论:目前国产利福平口服制剂的制剂工艺较为稳定,总体质量较好,胶囊杂质水平总体优于国外产品;个别企业也存在违规现象,需加强自我约束;现行利福平口服制剂质量标准存在缺陷,有待完善。
OBJECTIVE: To evaluate the quality status and existing problems of domestic rifampin oral preparations by statutory test and exploratory research methods. Methods: In accordance with the general requirements of the National Evaluation Evaluation Plan for 2010, the statutory testing of sampling samples was carried out according to the current standards. A number of methods for exploratory research were established or perfected: the method of adding raw materials to identify excipients was used to establish the oral preparation Determination of rifampin by powder X-ray diffraction method for the determination of raw materials used in capsules at home and abroad; visual observation of the contents of the capsule color, investigate its relationship with the crystal form; The structure of the main chromatographic peaks in the chromatographic conditions of Pharmacopoeia was identified by using the software of HPLC-UV-ESI-IT-MSn with MatLab analysis software, and the data were statistically analyzed by SPSS software The zebrafish model was used to compare the toxicity of rifampicin and its related substances to the zebrafish embryo development. The moisture content in different prescription capsules was determined by atmospheric drying, vacuum drying and card’s method respectively. Results: Statutory test: 226 Rifampicin oral preparations were tested, 222 batches passed the pass rate of 98.2%, 4 batches of unqualified items are dry weight loss; exploratory research: the domestic capsules and tablets rifampicin raw materials are Type I, the main foreign type Ⅱ, part of the type I; capsule content of the material used for the type I was bright red, type Ⅱ was dark red, and powder X-ray diffraction results consistent; detected from the type of substance, The results showed that domestic rifampicin capsules were superior to imported rifampicin capsules at impurity spectrum level. The lethal effects of 6 rifamycins on zebrafish embryos were: Fomomycin S-Sodium salt> Rifamycin SV> 3-Formylifamycin SV> Quinoid Rifampicin> Rifampicin> N-rifampicin, its toxicity type mainly associated with its parent ring structure The toxicities were related to the structure of the three substituents. There was no significant difference between the three kinds of water samples measured by the direct filling of raw materials capsules, but the capsules with more auxiliary materials were significantly higher than the dry The result of the weightlessness method. Conclusion: The preparation technology of rifampicin oral preparation at present is relatively stable, the overall quality is better and the level of capsule impurities is better than that of foreign products. Individual enterprises also have irregularities and need to strengthen self-restraint. The existing quality standards of rifampicin oral preparation Defects, to be perfect.