采用“化学、药效与毒理”三结合方法筛选优化抗关节炎中药复方青附蠲痹汤的最佳制备工艺（英文）

Combinative Approaches of Chemistry, Pharmacology and Toxicology for the Optimal Pharmaceutical Preparation of an Anti-arthritic Chinese Medicine Formulation QFJBT

目的青附蠲痹汤由附子、青风藤、黄芪、白芍、牡丹皮组成,化裁于张仲景《金匮要略》之乌头汤,临床应用治疗风湿及关节炎疾病多年,疗效确切。我们拟筛选确定青附蠲痹汤抗类风湿关节炎(RA)的最佳组方配伍,建立其最优制备工艺,从而将其研发为一种治疗RA的创新中药新药。方法对青附蠲痹汤不同工艺路线制备的产物,采用方中各药味有效成分含量控制、抗炎镇痛药效评价以及急性毒性研究结合的方法,筛选确定青附蠲痹汤的最佳组方配伍和制剂工艺。结果根据生物活性成分含量最高、抗炎镇痛活性最强和安全性最好的标准,建立了青附蠲痹汤中试生产的优化和规范的制药和加工工艺。通过高效液相色谱(HLPC)对青附蠲痹汤中试产品的质量分析表明,三批青附蠲痹汤的色谱指纹图谱基本一致,4种特征标记物和生物活性标记物的含量相对一致。常规的毒理学研究表明青附蠲痹汤具有良好的安全性,雌雄大鼠单次最大耐受剂量为33.63g/kg,相当于临床剂量的346倍。在慢性毒性研究中,结果显示,青附蠲痹汤剂量分别为3.89、6.80和9.72 g/kg(分别相当于临床等效剂量的40、70和100倍)对大鼠血液学参数和血液生化参数无影响。在重复给予青附蠲痹汤三个月后,动物无死亡情况和特异性的毒性反应。结论通过建立严格的工艺控制,对青附蠲痹汤生产优化和规范的制药和加工工艺成功地进行了筛选和确定。

Objective Qing Fu Juan Bi Tang(QFJBT)is an anti-arthritic Chinese medicine formula consisting of five herbs:Aconiti Lateralis Radix Praeparata(Fu Zi,附子),Sinomenii Caulis(Qing Feng Teng,青风藤),Astragali Radix(Huang Qi,黄芪),Paeoniae Radix Alba(Bai Shao,白芍)and Moutan Cortex(Mu Dan Pi,牡丹皮),which have well-established histories of use for treatment of rheumatic and arthritic diseases.We intended to establish the optimized and standardized pharmaceutical procedures and manufacturing processes for the pilot production of QFJBT to develop it as a novel botanical drug product for treatment of rheumatoid arthritis(RA).Methods The combinative approaches of chemical assessment,toxicological and pharmacological evaluation were explored to define the pharmaceutical preparation of QFJBT.Results The optimized and standardized pharmaceutical procedures and manufacturing processes for the pilot production of QFJBT were established in terms of greatest chemical contents of bioactive constituents,potent anti-inflammatory and antinociceptive activities,and favorable safety profile.Quality analysis of the pilot product of QFJBT by high-performance liquid chromatography(HPLC)demonstrated that the chromatographic fingerprint profiles of three batches of QFJBT were basically identical and the contents of four characteristic and bioactive markers were relatively consistent.General toxicological studies showed a favorable safety profile of QFJBT.The maximum tolerated single dose of QFJBT was determined in both sexes of rats to be 33.63 g/kg body weight which is equivalent to 346 times of clinical dose.In the chronic oral toxicity study,the results of laboratory investigation showed that QFJBT at doses of 3.89,6.80 and 9.72 g/kg body weight(equivalent to 40,70 and 100-fold clinical doses,respectively)caused no changes in all hematological parameters and blood biochemical parameters of rats.No mortality or specific toxic responses were observed in animals after three months of repeated dosing with QFJBT.Conclusion The optimized and standardized pharmaceutical and manufacturing processes for the production of QFJBT have been successfully screened and identified through established rigorous in-process controls.