基于非线性混合效应模型的雪上一枝蒿凝胶剂药物释放动力学研究

Study on release kinetics for gel of Aconitum brachypodum based on nonlinear mixed effect model

目的:建立基于非线性混合效应模型(nonlinear mixed effect model,NLMEM)的雪上一枝蒿凝胶剂的药物释放动力学(release kinetic,RK)分析方法,以合理评价药物释放过程和阐释释放机制。方法:以含有随机效应的非溶蚀药物体系零级动力学模型为基础模型,采用SAS软件的PROC NLMIXED,对影响药物释放的固定效应及随机效应因素逐个进行分析,建立RK最终典型模型;采用蒙特卡罗(Monte Carlo)方法,从原始数据集中随机抽取10个训练子集分别建立RK模型,计算相对应的预测均方根误差和平均相对误差,评价模型稳定性和预测精度。结果:制剂突释效应F0对RK模型有极显著影响;组方因素中carbopol 940用量对固有释放速率常数k0及浓度梯度变化常数a有极显著影响且依据用量范围呈不同变化;不同组方的k0及a随机效应因素影响显著;所得RK最终模型经交叉验证稳定、有效、可靠。结论:基于非线性混合效应模型所建立的药物释放动力学分析方法,可以较好地评价药物释放过程和阐释释放机制。

Objective： To establish the analytical method for the release kinetic（ RK） of Aconitum Brachypodum gel based on the nonlinear mixed effect model（ NLMEM）,in order to rationally evaluate the drug release process and explain the release mechanism. Method： The zero-order kinetic model containing for non-corroded drug system with the random effect was taken as the base model. The fixed effect and random effect factors impacting the drug release were analyzed by PROC NLMIXED of SAS to establish the final typical model. Subsequently,10 training subsets were randomly extracted from the primary data to respectively their RK models,calculate the corresponding predicted root-mean-square error and average relative error,and evaluate the model stability and prediction accuracy. Result： The burst effect F0 had a very significant effect on the RK model. Among the component factors,carbopol 940showed an obvious effect on the inherence release speed constant k0and the concentration gradient change constant a,with different variations on the basis of dosage range. The random effect factors of k0 and a had a significant impact. The final RK model was proved to be stable,effective and reliable in the cross validation. Conclusion： The drug release kinetic analysis method could be used to rationally evaluate the drug release process and explain the release mechanisms.