Evaluation of alkyloxycarbonyloxymethyl (AOCOM) ethers as novel prodrugs of phenols for topical delivery: AOCOM prodrugs of acetaminophen

The maximum fluxes of a series of alkyloxycarbonyloxymethyl (AOCOM) ethers of acetaminophen (APAP) through hairless mouse skin from isopropyl myristate, IPM (JMMIPM) were measured. The JMMIPM, solubilities in IPM (SIPM), water (SAQ) and pH 4.0 buffer (S4.0) and molecular weights MW were then fitted to the Roberts–Sloan (RS) equation: log JM = x + y log SLIPID + (1 − y) log SAQ − zMW. Only one of the prodrugs gave an improvement in the flux obtained by APAP itself. The general lack of improvement in flux seems to be due to the fact that there was no improvement in the SAQ values of the AOCOM derivatives compared to APAP. When the n = 5 members of the AOCOM series were added to the n = 66 database of JMMIPM to give n = 71 and fitted to the RS equation where SLIPID was SIPM, the following coefficients were obtained: x = −0.562, y = 0.501, z = 0.00248, r2 = 0.923. These results demonstrate the importance of improving SAQ for prodrugs to improve their solubilities in the skin and hence the flux of the parent drug. The RS equation, which is derived directly from Fick's law, explains this dependence of flux on SAQ.