Overcoming the nail barrier: A systematic investigation of ungual chemical penetration enhancement

This study investigated the in vitro nail permeability of penetrants of varying lipophilicity-caffeine (CF. log P -0.07), methylparaben (MP, log P 1.96) and terbinafine (TBF, log P 3.3) and the effect of 2 novel penetration enhancers (PEs), thioglycolic acid (TA) and urea hydrogen peroxide (urea H2O2) on their permeation. Studies were conducted using full thickness human nail clippings and ChubTur (R) diffusion cells and penetrants were applied as saturated solutions. The rank order of steady-state penetrant flux through nails without PE application (MP > CF > TBF) suggested a greater sensitivity to penetrant molecular weight rather than log P. TA increased the flux of CF and MP similar to 4- and similar to 2-fold, respectively, whilst urea H2O2 proved ineffective at enhancing permeability. The sequential application of TA followed by urea H2O2 increased TBF and CF flux (similar to 19- and similar to 4-fold, respectively) but reversing the application order of the PEs was only mildly effective at increasing just MP flux (similar to 2-fold). Both nail PEs are likely to function via disruption of keratin disulphide bonds and the associated formation of pores that provide more 'open' drug transport channels. Effects of the PEs were penetrant specific, but the use of a reducing agent (TA) followed by an oxidising agent (urea H2O2) dramatically improved human nail penetration. (C) 2008 Elsevier B.V. All rights reserved.