摘要
目的:利用计算机模拟软件建立并验证阿莫西林在人体内的生理药动学(physiologically based pharmacokinetic,PBPK)模型,用于阿莫西林胶囊溶出度方法的评价研究。方法:通过溶出特征曲线优化,建立并优化PBPK模型。结果:通过模型计算阿莫西林胶囊(规格:500 mg)药时曲线对比人口服实测药时曲线计算结果的准确性,相关药动学参数计算结果:R2=0. 997,F%=68. 669,Cmax=7 123. 4 ng·mL-1,Tmax=1. 8 h,AUC0~inf=25 550 ng·h·mL-1,AUC0~t=24 470 ng·h·mL-1和Cmax Liver=1 101. 4 ng·mL-1。结论:基于该PBPK模型,以去卷积分算法模拟计算出阿莫西林胶囊在人体内的释放曲线,与现行版《中华人民共和国药典》和《美国药典》中阿莫西林胶囊溶出度限度进行比较与评价,证明上述药典中各溶出度限度均高于制剂体内累计吸收量要求。现行方法是基于阿莫西林胶囊制剂的不同处方,用于进行工艺控制,保证制剂生产一致性的指标,目的在于降低制剂工艺对产品质量波动的影响风险,而非紧密关联体内有效性水平的限度指标。
Objective:To establish and verify the physiologically based pharmacokinetic(PBPK)model of amoxicillin in human body by computer simulation software for evaluating the dissolution methods of amoxicillin capsules.Methods:Through optimization of dissolution characteristic curve,the PBPK model was established and verified.The accuracy of the physiologically based pharmacokinetic model was assessed by comparing the model calculated drug concentration-time curves of 500 mg amoxicillin capsules with the measured ones in human.Results:The correlation coefficient(R2)was 0.997,and the calculation results of the relevant pharmacokinetic parameters were as follows:F%=68.669,Cmax=7 123.4 ng·mL-1,Tmax=1.8 h,AUC0~inf=25 550 ng·h·mL-1,AUC0~t=24 470 ng·h·mL-1,Cmax Liver=1 101.4 ng·mL-1.Conclusion:Based on the calculated results of the PBPK model,the cumulative dissolution curve and absorption curve of amoxicillin capsules in human body were simulated by the convolution/deconvolution integral algorithm,and compared with the current edition of Chinese Pharmacopoeia.By comparing and evaluating the dissolution limits of amoxicillin capsules in the US Pharmacopoeia,it is proved that the dissolution limits in the above-mentioned pharmacopoeia are all higher than the cumulative absorption requirements for the preparation and are determined based on the different formulations of amoxicillin capsules.The index are used for process control to ensure the consistency of preparation production aiming at reducing the risk that the preparation process affect the consistency of product quality,which are not closely related to the level of effectiveness in vivo.
作者
王晨
胡昌勤
许明哲
WANG Chen;HU Chang-qin;XU Ming-zhe(National Institutes for Food and Drug Control,Beijing 102629,China)
出处
《中国新药杂志》
CAS
CSCD
北大核心
2019年第18期2268-2273,共6页
Chinese Journal of New Drugs
基金
国家“重大新药创制”科技重大专项资助项目(2017ZX09101001)
关键词
阿莫西林胶囊
生理药动学模型
溶出度
计算机模拟
一致性评价
amoxicillin capsules
the physiologically based pharmacokinetic model
dissolution
the computer simulation
conformance assessment
