药物与辅料相互作用差异与结构特征的相关性研究

Study on the correlation between the difference of drugs and excipients interaction and their structural characteristics

目的:探索药物的结构特征参数在预测药物与辅料相互作用中的规律。方法:采用两室渗透模型测定不同性质的21种药物的透膜速度,考察辅料对药物渗透的阻滞作用。通过计算药物的分子大小、电荷和形状相关的特征参数,考察药物特征参数与辅料相互作用的相关性。结果:根据12 h时9种辅料对21个药物渗透速度的影响,得到辅料对药物的阻滞率,将药物分为5类。第1类药物的阻滞率小于-25%,辅料表现出加速渗透作用;第2类药物对辅料不敏感,此类药物除非极性可及表面积(ASA_P)与偶极矩(dipole)参数外都与其他药物存在显著差异(Z=-0.704、-0.503,P=0.534、0.669);第3类药物对表面活性剂敏感,此类药物的重原子数量(a_heavy)、分子范德华体积(vol)、正电荷可及表面积(ASA+)参数的差异显著(Z=-1.965、-2.211、-2.111,P=0.047、0.024、0.035);第4类对表面活性剂和崩解剂敏感,此类药物参数的差异不显著;第5类药物对多类辅料敏感,此类药物的负电荷可及表面积(ASA-)、ASA_P、dipole等参数的差异显著(Z=-2.836、-2.611、-2.462,P=0.003、0.007、0.012)。结论:分子大小、极性、形状指标能够较好预测药物与辅料相互作用关系。

Objective:To explore the regularity of the structural characteristic parameters of drugs in predicting the relationship between drugs and excipients.Methods:The two-compartment penetrating detection devices were used to determine the permeation rate of 21 drugs with different properties,and the blocking effect of excipients on drug permeation was investigated.By calculating the characteristic parameters related to the molecular size,charge and shape of drugs,the correlation between the characteristic parameters of the drug and the interaction of excipients was investigated.Results:According to the influence of 9 excipients on the penetration rate of 21 drugs at 12 h,the blocking rate of excipients on drugs was obtained,and the drugs were divided into five categories.The blocking rate of the first class of drugs was less than-25%,and the excipients showed accelerated permeation.The second class of drugs were not sensitive to excipients,and these drugs were significantly different from other drugs except ASA_P and dipole(Z=-0.704,-0.503;P=0.534,0.669).The third class of drugs were sensitive to surfactants,and the parameters of a_heavy,vol and ASA+of these drugs were significantly different(Z=-1.965,-2.211,-2.111;P=0.047,0.024,0.035).The fourth class were sensitive to surfactants and disintegrants,and the parameters of these drugs were not significantly different.The fifth class of drugs were sensitive to many kinds of excipients,and the parameters of ASA-,ASA_P,dipole of drugs had significant differences(Z=-2.836,-2.611,-2.462;P=0.003,0.007,0.012).Conclusion:The molecular size,polarity,and shape index can better predict the interaction with drugs and excipients.