Lateral drug diffusion in human nails

Abstract

The main objective of the current work is to demonstrate the process of passive lateral diffusion in the human nail plate and its effect on the passive transungual permeation of antifungal drug ciclopirox olamine (CPO). A water soluble dye, methyl red sodium salt (MR) was used to visualize the process of lateral diffusion using a novel suspended nail experiment. The decline in concentration of CPO correlates with that of concentration of MR from the proximal to the distal end of the nail in suspended nail study. Three toenails each were trimmed to 5 mm × 5 mm (25 mm(2)), 7 mm × 7 mm (49 mm(2)), and 9 mm × 9 mm (81 mm(2)) to study the extent and effect of lateral diffusion of the CPO on its in vitro transungual permeation. The permeation flux of CPO decreased as the surface area of the toenail increased. There was a positive correlation between the concentrations of CPO and MR in the area of application and in the peripheral area of the toenails of the three surface areas, confirming the findings in the suspended nail experiment. Profound lateral diffusion of CPO was demonstrated and shown to reduce the in vitro passive transungual drug permeation and prolong the lag-time in human toenails. The study data implies that during passive in vitro transungual permeation experiments, the peripheral nail around the area of drug application has to be kept to a minimum, in order to get reliable data which mimics the in vivo situation.

Fig. 1

Theoretical representation of lateral diffusion of drug molecules in human nails. The horizontal and the vertical arrows denote the lateral movement of the molecules and the transungual diffusion, respectively

Fig. 2

Schematic of the suspended nail experiment to show lateral movement of CPO in human nails

Fig. 3

a Neoprene nail adapters (PermeGear) with an orifice diameter of 3 mm. b Franz diffusion cell with nail adapter

Fig. 4

Sectioning the nails after the transungual permeation with section “a” under the orifice and peripheral sections “b”, “c” and “d” around the orifice

Fig. 5

a Cadaver toenail showing the color gradient of MR from proximal to distal end. b Decline in concentration (μg/mg nail) of CPO from the proximal to the distal end c Correlation between the concentrations of CPO and MR salt in the suspended nail

Fig. 6

a Transungual permeation of CPO through the three sizes of human toenails. b Concentration of CPO in the area of application (a) and subsequent peripheral nail sections (b, c, d) in each of the three sizes of the nails after the transungual permeation study. c Correlation between the log concentrations of CPO and MR in the nail sections (a, b, c, d) after transungual permeation study

Fig. 7

a Correlation between the permeation flux value and the ratio (A _o /A _n). b The ideal cylinder formed under the orifice during passive transungual permeation in absence of lateral diffusion. c The pyramid formed due to lateral diffusion of the drug molecules around the area of drug application. d Correlation between permeation flux and the concentration in the nail around the area of application