四种药物的经皮渗透性能预测

Predictive Skin Permeation of Ethinylestradiol, α-Asarone, Finasteride and Risperidone

关键词:  QSPR模型  经皮给药  预测  疏水性  分子量  经皮渗透系数

Key words:  QSPR models  transdermal drug delivery  prediction  hydrophobicity  molecular weight  skin permeability coefficient

摘要:

目的利用QSPR模型预测药物的经皮渗透性，并检验模型的准确性和适用性。方法以炔雌醇、α-细辛醚、非那甾胺和利培酮为模型药物，Potts-Guy，Cronin，Moss，Morrimoto，Kitagawa，Magnusson和Lien-Gao构建的七个数学等式为QSPR模型，用药物的理化参数计算药物经皮渗透速率的预测值；同时采用离体人皮，在透皮扩散池中进行饱和药物溶液的体外经皮渗透实验。高效液相色谱法测定接受液中的药物浓度，计算药物的最大稳态经皮渗透速率。并将利用模型得到的理论预测值与实验所得的实际经皮渗透数值进行比较和分析，确定最适预测模型。结果采用7种预测模型所得到的理论预测值相对于实验值均在95%可信区间内，具有统计学意义。模型之间的准确度有很大差异，采用疏水性和相对分子质量为参数的模型拟合效果最好，根据均方根误差RMSE（Root Mean Square of Error )，预测的准确性程度依次为Potts-Guy > Cronin > Kitagawa，Morimoto，Magnusson > Moss，Lien-Gao。结论QSPR模型能很好地预测药物的经皮渗透，Potts-Guy预测的准确性最佳。

Abstract:

OBJECTIVE To predict drug skin permeability by using QSPR models, and verify the applicability and veracity of the models for skin percutaneous penetration.METHODS Four drugs:ethinylestradiol, α-asarone,finasteride and risperidone were employed as model drugs, and Potts-Guy, Cronin,Moss, Morimoto, Kitagawa, Magnusson and Lien-Gao equations were selected as QSPR models. Combined drug physical-chemical parameters with QSPR models, the skin percutaneous data were calculated. The penetration experiments in vitro were also carried out on modified Franz-Diffusion Cells, using aqueous drug solutions at saturate solubility, through excised human skin. Samples were withdrawn from the receptor phase at specified time points and the concentrations were determined by HLPC, the maximum steady penetration rates were calculated. Comparing the predictive datas with experimental ones, the most appropriate model was determined. RESULTS The log Jmax for four drugs were superimposed with the 95%CI predicted by the related seven models. It is of statistic meaning. Models utilizing descriptors of hydrophobicity and molecular weight have better prediction,according to RMSE, the accuracy of models follows as Potts-Guy>Cronin>Kitagawa,Morimoto>Magnusson>Moss,Lien-Gao.CONCLUSION QSPR models can well predict skin penetration, and Potts-Guy model has the best prediction ability.