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

Abstract

This study investigated the in vitro nail permeability of penetrants of varying lipophilicity-caffeine (CF, logP -0.07), methylparaben (MP, logP 1.96) and terbinafine (TBF, logP 3.3) and the effect of 2 novel penetration enhancers (PEs), thioglycolic acid (TA) and urea hydrogen peroxide (urea H(2)O(2)) 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 logP. TA increased the flux of CF and MP approximately 4- and approximately 2-fold, respectively, whilst urea H(2)O(2) proved ineffective at enhancing permeability. The sequential application of TA followed by urea H(2)O(2) increased TBF and CF flux ( approximately 19- and approximately 4-fold, respectively) but reversing the application order of the PEs was only mildly effective at increasing just MP flux ( approximately 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 H(2)O(2)) dramatically improved human nail penetration.

Novel nail penetration enhancer containing vesicles “nPEVs” for treatment of onychomycosis

“…In addition, transcutol was reported to increase the permeation through bovine hooves membrane which is structurally similar to the human nails, through the induction of conformational changes in the keratin structure (Shivakumar et al, 2012). The chosen nail penetration enhancers (N-acetyl-L-cysteine, thiourea and thioglycolic acid) were reported to increase the flux across the nail plate through reduction of disulphide linkages in the keratin of the nail, associated with pore formation and consequent swelling and softening of the nail plate, leading to reduction of nail barrier integrity (Brown et al, 2009;Nogueiras-Nieto et al, 2013;Palliyil et al, 2013;Miron et al, 2014). Ethanol was reported to be a nail uptake enhancer as well (Gupta & Paquet, 2013).…”

Free radical facilitated damage of ungual keratin

“…Clean, dry 3 mm 2 nail sections (cleaned as per the nail swelling experiments), were clamped and held in place between receiver and donor chambers of pre-calibrated ChubTur ® permeation cells, details of which are published in earlier work [10,11].…”

“…Cells were rejected if total DPM at 1 h was on average more than 20 % higher than the mean of the other cells that had undergone the same pre-treatment or if the total DPM at 20 h was on average more than 40 % higher than the mean of the other cells that had undergone the same pre-treatment. These values were used as it would not be expected for nail drug permeation variability to exceed 20 % after 1 h or 40 % after 20 h when a varied nail sample pool is utilised [10,11].…”

“…Several compounds including cysteine, dithiothreitol, thioglycolic acid (TA) and urea hydrogen peroxide (urea H 2 O 2 ) are known to diminish the barrier properties of the nail [10,11]. Of these compounds, those that have a thiol group attached and hence reducing properties, are generally applied under conditions where the thiol moiety is ionised.…”

“…Despite their current applications in the hair care industry, TA and urea H 2 O 2 are not employed commercially to enhance permeation into the human nail even though previous research has demonstrated their ability to manipulate ungual keratin [10,11,16]. The nail poses a rigid barrier that displays a higher density compared to other similar tissues such as the hair and skin, therefore prior to utilising these agents in chronic clinical testing a detailed understanding of their interaction with ungual constituents is required.…”