Sloan Kenneth B, Wasdo Scott
Department of Medicinal Chemistry, P.O. Box 100485, University of Florida, Gainesville, Florida 32610, USA.
Med Res Rev. 2003 Nov;23(6):763-93. doi: 10.1002/med.10048.
It has been shown for homologous series of prodrugs that those members who were the more water soluble ones gave the greatest enhancement in topical delivery of the parent drug and not the more lipophilic ones. However, until recently models for topical delivery and equations to predict topical delivery focused only on lipid solubility (S(LIPID)) or partition coefficient (K(OCT:AQ)) and molecular volume (or molecular weight, MW) as parameters. Now several equations (transformed Potts-Guy or Series/Parallel) have been developed which include aqueous solubility (SAQ) as a parameter for predicting flux through skin. Experimental fluxes, solubilities, and MW from seven series of prodrugs have been fit to the transformed Potts-Guy equation to give coefficients for log solubility in isopropyl myristate (log SIPM) and log solubility in water (log SAQ) (0.53 and 0.47, respectively) which show, for parent drugs delivered by prodrugs from IPM in vitro through hairless mouse skin, that water solubility is almost as important as lipid solubility. When the transformed Potts-Guy equation was fit to data for the delivery of NSAID from mineral oil (MO) in vivo through human skin, the coefficients were 0.72 log SMO and 0.28 log SAQ. When the transformed Potts-Guy equation was fit to data for the delivery of their parent drugs by three series of prodrugs from water in vitro through hairless mouse skin the coefficients were 0.66 log S(IPM) and 0.34 log SAQ. Numerous recent examples are also given where more water-soluble members of homologous series of prodrugs give higher flux values from water vehicles in vitro through human skin than the more lipid soluble ones.
对于前药的同系物系列，已表明那些水溶性更高的成员在母体药物的局部递送中产生的增强作用最大，而不是亲脂性更高的成员。然而，直到最近，局部递送模型和预测局部递送的方程式仅将脂溶性（S(LIPID)）或分配系数（K(OCT:AQ)）以及分子体积（或分子量，MW）作为参数。现在已经开发了几个方程式（变换后的Potts-Guy或串联/并联），其中包括水溶性（SAQ）作为预测透过皮肤通量的参数。来自七个前药系列的实验通量、溶解度和MW已拟合到变换后的Potts-Guy方程式中，以给出肉豆蔻酸异丙酯中的对数溶解度（log SIPM）和水中的对数溶解度（log SAQ）的系数（分别为0.53和0.47），这表明，对于前药在体外通过无毛小鼠皮肤从IPM递送的母体药物，水溶性几乎与脂溶性一样重要。当将变换后的Potts-Guy方程式拟合到NSAID在体内通过人皮肤从矿物油（MO）递送的数据时，系数为0.72 log SMO和0.28 log SAQ。当将变换后的Potts-Guy方程式拟合到三个前药系列在体外通过无毛小鼠皮肤从水中递送其母体药物的数据时，系数为0.66 log S(IPM)和0.34 log SAQ。最近还给出了许多例子，其中前药同系物系列中水溶性更高的成员在体外从水性载体通过人皮肤的通量值比脂溶性更高的成员更高。
