生理药动学模型结合体外相似性溶出实验预测国产口服苯唑西林钠溶出行为差异影响以及工艺合理性

Prediction of the difference in dissolution behavior of domestic oral oxacillin sodium and process rationality by physiological pharmacokinetic model combined with in vitro similarity dissolution test

目的:预测国产不同口服苯唑西林钠体外溶出行为差异对质量与疗效的影响,并分析工艺合理性。方法:采用体外相似性溶出实验分析制剂的体外溶出差异,采用Gastroplus软件建立生理药动学模型(PBPK),利用威布尔函数,拟合体内释放曲线;通过与实测体外溶出曲线的比较研究,预测制剂的溶出差异对体内药动学的影响,并分析工艺的合理性。结果:胶囊的Cmax预测结果在90%~110%范围内,体外溶出量(Q)在30 min内达到80%以上,不影响其体内药动学行为;糖衣片Cmax预测结果在90%~110%范围外,其体外溶出量(Q)在30 min内低于80%,一定程度影响体内药动学行为。结论:目前国产苯唑西林钠胶囊质量优于糖衣片,糖衣、片芯的崩解释放是影响糖衣片体外溶出以及体内吸收的关键因素,与包衣工艺、辅料质量密切相关,是影响其质量与疗效的关键质量属性,其工艺合理性有待进一步研究。

Objective:To predict the effect of in vitro dissolution behavior of oxacillin sodium on its quality and efficacy,and analyze the process rationality.Methods:In vitro similarity dissolution test was used to analyze the dissolution difference of the preparation.Physiologically based pharmacokinetic model(PBPK)was established by Gastroplus software,and release curve was fitted by Weibull function.The influence of the drug preparations on in vivo pharmacokinetics was predicted by the in vitro dissolution study,and the rationality of the production process was analyzed.Results:the Cmaxof the capsule ranged 90%to 110%,and the dissolution in vitro(Q)was more than 80%within 30 minutes,which did not affect its pharmacokinetic behavior in vivo.The Cmaxof sugar-coated tablets failed to range 90%to 110%.The dissolution in vitro(Q)was less than 80%in 30 minutes,indicating that it influenced pharmacokinetic behavior in vivo to a certain extent.Conclusion:At present,the quality of domestic oxacillin sodium capsules is better than sugar-coated tablets.The key factors affecting the dissolution and absorption of sugar-coated tablets in vitro are the disintegration and release of tablet of coating and core.They are closely related to sugar-coated process and excipient quality,as the important factors,affecting the quality and efficacy of sugar-coated tablets.The rationality deserves to be studied further.