Designing for topical delivery: prodrugs can make the difference.

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.