2个高难度仿制药的药学及人体试验研究文献综述

 2023-02-26 11:02

摘 要：1984年Hatch-Waxman法案颁布，从而加快仿制药上市来鼓励药品的价格竞争，同时该法案极大地简化了仿制药审批程序，申请人仅需向FDA提交简略新药申请（Abbreviated New Drug Application，ANDA）。

至关重要的仿制药的安全性和有效性体现在仿制药必须与原研药药学等效和生物等效（Bioequivalence，BE），药学等效主要是通过对比自制产品和参比制剂在体外的溶出实验来体现，而生物等效则主要是通过对比自制产品和参比制剂在人体内的药动学指标来体现。

体外溶出采用相似因子(f2)法比较, 自制产品和参比制剂在不同溶出介质下的2条溶出曲线相似因子(f2)数值不小于50,可认为自制产品和参比制剂具有相似性。

目前，国内外最常用的BE评价方法是药动学方法，即采用生物利用度（Bioavailability，BA）指标进行BE评价。

通过统计学手段，得到自制产品和参比制剂的AUC或Cmax几何均值比值的90%置信区间(Confidence Interval，CI)，一般认为90% CI落在80.00%～125.00%范围内，则表示达到生物等效。

本课题拟开展2个高难度仿制药的药学和人体试验研究，都属于精神类疾病治疗药物，1个是治疗抑郁症的帕罗西汀肠溶缓释片，另1个是治疗帕金森病的罗匹尼罗缓释片。

目前，据调查帕罗西汀肠溶缓释片无国产药品上市，而罗匹尼罗缓释片在国内也仅有GSK原研进口，并无国产药品上市。

对原研制剂剖析后，这2个品种都属于高难度仿制药，随着中国物质生活水平的提高，精神文明健康需求越来越高，在中国帕金森疾病和抑郁症治疗药物市场将非常有前景。

本课题覆盖从仿制药处方开发到人体临床试验的注册申报前制剂开发过程，重点工作在人体试验开展阶段，结合和运用所学知识于医药企业具体仿制药产品开发，锻炼和加强了对仿制药开发整个流程的理解，也充分熟悉了在印度开展生物等效试验开展涉及的具体工作内容。

关键词：高难度仿制药；双层片；多层片；缓控释；体外溶出；生物等效Pharmaceutical and Clinical Studies of Two Generic Products with High Technical BarrierDu Linghui 1(Hanlin College, Nanjing University of Chinese Medicine, Taizhou 225300)AbstractThe Hatch-Waxman act was enacted in 1984, which made it possible for generic companies to get simplified procedures of regulatory approval for drugs by filing an Abbreviated New Drug Application (ANDA) to US FDA, and encouraged the manufacture and price competition of generic drugs among the pharmaceutical industry and established the modern system of government generic drug regulation in the United States. The critical facts of safety and effectiveness of generic drugs are reflected in the studies that generic products must be pharmacologically equivalent and bioequivalent (BE) to the reference listed drug (RLD). Pharmaceutically equivalence mainly can be approached through the comparison of in vitro dissolution profile between generic products and RLD, while bioequivalence mainly can be addressed by comparing the pharmacokinetic (PK) profile between generic products and RLD through in vivo clinical trial. In in vitro dissolution test, the similarity factor (f2) method was used to comparison. The similarity factor (f2) values of the dissolution curves between generic products and RLD are not less than 50, suggesting that they are pharmacologically equivalent. Currently, the most commonly used method for BE evaluation internationally is based on pharmacokinetic profile of both generic products and RLD. Bioavailability (BA) index is adopted for BE evaluation and the 90% Confidence Interval (CI) of the geometric mean ratio of AUC or Cmax of both test products and RLD are obtained by statistical analysis. It is generally suggested that the 90% CI must fall within the range of 80.00% ~ 125.00%, indicating bioequivalence. For this study, pharmaceutical and clinical studies of two generic products with high technical barrier have been conducting and the results will be discussed. Both RLDs are marketed products for the treatment of mental diseases. One is paroxetine enteric-coated sustained-release tablets for depression, and the other is ropinirole sustained-release tablets for Parkinsons disease. However, according to the references, paroxetine enteric-coated sustained-release tablets are not listed in China, while ropinirole sustained-release tablets are only imported by GSK in China, and there are no domestic drugs on the market. Based on previous investigation, both drugs show high technical barrier for formulation development. With the improvement of Chinas living standard, the demand for spiritual civilization and health is enlarged, resulting in very promising drug market for mental diseases.This study will cover major parts of the entire process for generic product development from formulation development to BE study. It enables an undergraduate to utilize and transfer university knowledge to practice and exercise and strengthen the understanding of the generic drug development entire process. It will benefits deeply for rich experience on how to conduct a BE study in Inida.Key words Generic drugs with high technical barrier, Bi-layer tablets, Tri-layer tablets, Controlled release, In vitro dissolution test, Bioequivalence study1仿制药预BE法规1.1 FDA仿制药部（OGD）美国食品及药物管理局（FDA）9个组成部门之一的药物审评和研究中心（CDER）负责审评药品的安全性、有效性和质量。

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