国产利福平口服制剂质量评价

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 of domestic rifampicin for oral preparation and existing problems. Methods: According to the general requirements of national assessment programs in 2010,use statutory testing methods to examine samples;Establish or improve some methods for the exploratory research:(1) Recognition by adding raw materials used to establish a method for the identification of rifampicin crystalline in oral dosage by powder X-diffraction.Determined the raw materials used for foreign and domestic capsules;capsule contents were observed by visual color to find the contact with rifampicin crystalline;Established the model to identify rifampicin crystal rapidly by near-infrared;(2)Using HPLC-UV-ESI-IT-MSⁿ technology and MatLab analysis software,to identified the structural of main peaks under the chromatographic conditions carried out in Chinese Pharmacopeia 2010.These data were stated by using SPSS software;(3) Using zebrafish model to compare the toxicity of zebrafish embryos of rifampicin and related substances;(4) Using ambient drying,decompression drying and karl fischer titration to determine the moisture content of the capsules. Results: Using statutory testing methods,in 226 batch of samples,224 batch of qualified ( 98.2% ),4 groups ( 1.8% ) failed,Loss on drying as the main causes of failure;Using the exploratory research:(1) Rifampicin raw materials used in domestic capsules are I type,mainly foreign were Ⅱ type,part I type;domestic tablets was I type also.Capsule contents were observed by visual color,I type was bright red,Ⅱ type was dark red;and the results is same of the results from powder X-diffraction;(2)Also referring to the relevant literature,the structure and fragmentation pattern of rifampicin and related impurities were presumed which were based on mass spectrometry results;(3)Comparison the toxicity of zebrafish embryos of rifampicin and related substances showed that,although rifamycins can cause abnormal embryonic development of the individual,but its main role is for the early embryonic death.The order of the embryonic lethal action of six rifamycins is that:S-sodium salt of rifamycin> rifamycin SV> 3 - formyl rifamycin SV> quinone rifampicin> rifampicin>> N- oxidation of rifampicin.Its toxicity mainly related to the parent ring structure,toxicity is related of the structure at C3 substituent;(4)Three methods for measurement of water showed no significant difference,which using raw materials to fill the capsule directly,but t the results of karl fischer titration was significantly higher than the results of weight loss results which the accessories is more. Conclusions: At present the most products quality of domestic rifampicin for oral preparation can meet the current standards,there are still in some problems in few enterprises,such as Loss on drying exceeded,weight uniform uneven and content assayed lowly and so on.Exploratory search suggests that existing standards is in deficiencies,and need to improve standard immediately.