An investigation of how fungal infection influences drug penetration through onychomycosis patient's nail plates

Abstract

The treatment of onychomycosis remains problematic even though there are several potent antifungal agents available for patient use. The aim of this investigation was to understand whether the structural modifications that arise when a patient's nail become infected plates influences the permeation of drugs into the nail following topical application. It was hoped that through improving understanding of the nail barrier in the diseased state, the development of more effective topical treatments for onychomycosis could be facilitated. The permeation of three compounds with differing hydrophobicities, caffeine, terbinafine and amorolfine (clogD at pH 7.4 of -0.55, 3.72 and 4.49 respectively), was assessed across both healthy and onychomycosis infected, full thickness, human nail plate sections. Transonychial water loss (TOWL) measurements performed on the healthy and diseased nails supported previous observations that the nail behaves like a porous barrier given the lack of correlation between TOWL values with the thicker, diseased nails. The flux of the more hydrophilic caffeine was twofold greater across diseased in comparison with the healthy nails, whilst the hydrophobic molecules terbinafine and amorolfine showed no statistically significant change in their nail penetration rates. Caffeine flux across the nail was found to correlate with the TOWL measurements, though no correlation existed for the more hydrophobic drugs. These data supported the notion that the nail pores, opened up by the infection, facilitated the passage of hydrophilic molecules, whilst the keratin binding of hydrophobic molecules meant that their transport through the nail plate was unchanged. Therefore, in order to exploit the structural changes induced by nail fungal infection it would be beneficial to develop a small molecular weight, hydrophilic antifungal agent, which exhibits low levels of keratin binding.

Keywords: Barrier; Fungal; Nail; Onychomycosis; Topical drug delivery.

Graphical abstract

Fig. 1

Permeation profiles of caffeine across healthy (●) and diseased (▴) nail samples. Data are shown as the mean ± SD.

Fig. 2

Permeation profiles of terbinafine across healthy (●) and diseased (▴) nail samples. Data are shown as the mean ± SD.

Fig. 3

Permeation profiles of amorolfine across healthy (●) and diseased (▴) nail samples. Data are shown as the mean ± SD.

Fig. 4

TOWL plotted against thickness for both healthy and diseased nails.

Fig. 5

Drug fluxes from the permeation data for caffeine, amorolfine and terbinafine across healthy and diseased nails plotted against nail thickness.

Fig. 6

Drug fluxes from the permeation data for caffeine, terbinafine and amorolfine across healthy and diseased nails plotted against nail TOWL value.