目的: 以阿立哌唑口崩片为对象,采用计算机模型与平行人工膜渗透模型,建立科学、高效的一致性评价体外研究方法,为难溶性药物制剂中关键工艺参数筛选提供方法和数据支持。方法: 建立阿立哌唑口崩片在不同pH介质中的体外溶出曲线测定方法;使用GastroplusTM软件建立阿立哌唑口崩片的计算机模型,模拟药物体内释放曲线,与体外溶出曲线的进行相关性分析,确定生理相关性较好的溶出曲线测定方法;采用计算机模型参数灵敏度分析的结果,设计仿制制剂的粒径范围,制备不同粒径的仿制制剂与参比制剂的体外溶出曲线进行比较,确定粒径范围;采用平行人工膜渗透模型对各仿制制剂与参比制剂进行模拟生物等效性预测,考察粒径变化对药物体内吸收的影响,并通过临床试验结果验证生物等效性预测结论。结果: 阿立哌唑为pH依赖的难溶性药物;阿立哌唑口崩片在pH 1.2、pH 4.0和pH 4.5介质中的溶出曲线不尽相同,pH 1.2介质中溶出最快,pH 4.5介质中溶出最慢;pH 4.5介质的溶出曲线方法体内外相关性最高(Y=0.005 3X2+0.404 1X-0.068 5,r=0.998 7);各仿制制剂与参比制剂的溶出曲线均相似(f2>50);且采用该粒径范围内的仿制制剂中的1批进行临床试验,结果显示,与参比制剂为生物等效。结论: 本文采用计算机模拟结合平行人工膜渗透模型的体外研究方法,建立了体内外相关性较好的溶出曲线方法,并成功指导药物的粒径筛选,确定了工艺参数中药物粒径范围。该方法快速、有效的为仿制药处方工艺筛选提供数据支撑;缩短了仿制药研发的耗时、降低了成本、提高了生物等效性试验成功率。
Objective: To establish a in vitro research method for consistency evaluation of aripiprazole oral disintegrating tablets by using computer modelling and parallel artificial membrane permeation model, to provide methods and data support for the screening of key process parameters in poorly-soluble drug preparations. Methods: In vitro dissolution methods for aripiprazole oral collapsing tablets was established. The model for in vivo absorption of aripiprazole oral collapsing tablets was established using GastroplusTM software. The in vitro/in vivo correlation of the dissolution methods was analyzed to find the physiological correlated dissolution method. The particle size range of the generic product was designed via the parameter sensitivity analysis of computer modelling. The dissolution curves of the generics product with different particle sizes and the reference preparation were compared to determine the particle size range. Parallel artificial membrane permeability assay was conducted to simulate the bioequivalence between the generic products and the reference product, thus to investigate the relationship between the particle size and the in vivo absorption of the drug. Bioequivalence prediction was validated through clinical trial results. Results: Aripiprazole is a poorly-soluble drug and shows a pH-relevant solubility. The dissolution profiles of aripiprazole oral collapsing tablets were different in pH 1.2, pH 4.0 and pH 4.5 media, with the fastest dissolution in pH 1.2 medium and the slowest dissolution in pH 4.5 medium. The dissolution in pH 4.5 medium showed the highest correlation coefficient with the simulated in vivo release curve (Y=0.005 3X2+0.404 1X-0.068 5, r=0.998 7). The dissolution curves of generic products meet the similarity requirement with the reference product(f2>50). A batch of generic products within the particle size range was used for clinical trials, and the results showed that it was bioequivalent with the reference product. Conclusion: A dissolution method with high in vitro and in vivo correlation was established by computer modelling combined with parallel artificial membrane permeation. This method successfully guided the drug particle size screening, and determined the drug particle size range in the process parameters. This method provides data support for the screening of generic drug prescription process quickly and effectively. It reduces the time spent in the research and development of generic products, reduces the cost and improves the success rate of bioequivalence of generic products.
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