【作者】 冷静；

【导师】 傅超美； 万方； 林大胜； 杨华蓉；

【作者基本信息】 成都中医药大学 ， 中药学， 2009， 博士

【摘要】 三七通舒胶囊是2003年国家批准的原Ⅱ类中药新药,其生产技术先进,药效成分清楚,作用机理明确,具有以药品的形式走向欧盟的潜力,该产品欧盟药品注册的国际合作研究已获得“十一五”国家科技支撑计划项目的支持。目前,三七通舒胶囊与欧盟药品注册要求还存在一定差距,本论文为三七通舒肠溶微丸(胶囊型)的研究,重点对工艺和质量控制的关键瓶颈技术进行研究,建立了更为完善的工艺质量控制标准,为该产品走向欧盟打下坚实的基础,同时为中药的国际化研究起到了示范作用。通过对三七三醇皂苷(PTS)原料药理化性质研究,重点明确了有效成分易被胃酸破坏、吸湿性强和粘性大等影响微丸成型的理化性质。以微丸成型特性及物理学表征参数为指标,对微丸制剂处方(尤其是成丸关键辅料)和制备工艺进行了系统深入的研究,确定最佳处方为PTS120g、微晶纤维素90g、淀粉90g、PVPK306.0g；确定了采用流化床法切喷方式制备微丸和包衣的最佳工艺参数；多批小试工艺验证及三批中试研究表明,确定制剂处方科学合理,工艺条件和工艺参数稳定可控,适宜工业化大生产。按照欧盟药品注册技术要求,通过系统研究,建立了较为完善的PTS原料药及三七通舒肠溶微丸(胶囊型)质量标准体系。重点对三七、PTS和制剂中的重金属、农药残留和有机残留检测方法进行了深入研究,采用微波消解技术和原子吸收光谱法,对镉、铜等8种重金属进行测定并制定了限度指标；采用顶空气相色谱法,对有机氯类、有机磷类及除虫菊酯类等31种农药和苯、甲苯等11种大孔吸附树脂残留溶剂进行了检测并制定了限度标准；以人参皂苷Rg1、人参皂苷Re、三七皂苷R1为评价指标,对三七通舒肠溶微丸(胶囊型)在犬体内药代动力学进行了初步研究,结果表明与原剂型在体内吸收过程相同,生物利用度相当；通过深入研究,建立了同时适用于三七药材、PTS原料药和三七通舒肠溶微丸(胶囊型)的指纹图谱标准,以指纹图谱技术进行了原药材、中间体和成品的相关性评价,实现了全程监控,保证了物质群的稳定性。更多还原

【Abstract】 This project is a research on Sanqi TongShu Intestinal Solution pellets (capsule-type), It emphasized the study of technique and quality control which refers to the registration process in EU, and solved the key technologic problem of TCM when marketing toward to EU, In the hope of setting a model for traditional Chinese medicine to head for EU in the form of drug.Through the systematic study of the PTS raw materials, this project solved the formation difficulties which included that the active ingredients were easy to be destroyed by gastric acid, strong hygroscopic and high viscosity. We made them into intestinal micropill to improve the bioavailability, and also increased the effectiveness and safety.Firstly, this project took forming characteristics and Physical parameters as indicators, combined with new technique and new pharmaceutical excipients, studied deeply and systematically on the preparation technique and preparation formula of micro-pill, especially the key excipients of pills forming. Determined the best technological parameters for making pellets by Tangential spray mode of Fluidized bed and coating. The formula was PTS120g、cellulose microcrystallisate90g,starch90g,PVPK306.0g;8%PVPK30 ethanol solution (alcohol concentration is 50%(w/w)) used as cementing agent to make pill, used Acryl-EZE(?) as enterosoluble coating. Three pilot trials demonstrated that the preparation process was stable, feasible and Suitable for industrial mass production.Then, established the quality standard systerm of PTS raw materials and SanQiTongShu Intestinal Solution pellets (capsule-type) which meet the EU’s Drug Standard. Stressed on the strictly safety control of the raw herb, extractive and preparation, also investigated the detection of heavy metal, pesticide residue deeply. detected eight kinds of heave metal (Cd, Cu, Fe.et al.). and made the limit indicators by Microwave Digestion and Atomic Absorption spectometry. used trithion as internal standard to detect thirty-one kinds of pesticide (organochlorine, orgnaophosphorus, pytethrin. et al..), detected eleven kinds of solvent residue of macroporous adsorptive resins(benzene and methyl benzene. et al.), and made limit standards by Headspace Gas Chromatography. Aslo used ginsenoside-RgⅠ, ginsenoside-Re and Notoginsenoside-RⅠas evaluating indicators, probed into the pharmacokinetic in dogs of the active ingredients of SanQiTongShu Intestinal Solution pellets (capsule-type)。Finally, through the research of finger printing, established common technology and method for the quality (efficacy) evaluating of the Panax Notoginseng-PTS raw materials SanQiTongShu Intestinal Solution pellets (capsule-type), monitor the whole process of preparation from raw material, intermediate to finished product by finger printing to guarantee the stability and homogenicity of the finished preparation. This project laid a good technique foundation of the access of Sanqi Tongshu intestinal pellets (Capsule-Type) to the EU market.更多还原