Visualization of the mechanism(s) of drug transport and delivery into and through the nail

Abstract

Topical treatment of nail disorders such as onychomycosis and nail psoriasis is desirable to avoid systemic adverse effects and drug-drug interactions. However, the architecture and composition of the nail plate pose a great challenge to the permeation of topically applied drugs. To improve the efficiency of drug permeation into and through the nail, on-going optimization of topical nail formulations is necessary. Presently, to assess drug uptake into the nail post-application of a formulation requires a destructive extraction technique, which provides no detail about the precise localization of the penetrant nor the time course of chemical permeation, and until now, the basic information about the mechanism of drug penetration remains unclear.

The principal aim of this thesis was to demonstrate the novel application of nondestructive imaging techniques, including laser scanning confocal microscopy (LSCM), two-photon fluorescence (TPF) and stimulated Raman scattering (SRS) to study topical nail delivery. The potential use of a number of formulation strategies was investigated based on the insight provided by the imaging tools, including (a) using polymeric particulate-based systems as drug reservoirs, (b) enhancing drug delivery using physical (microneedles) and chemical (penetration enhancers) methods, and (c) development of a thermoresponsive lacquer for topical nail treatment.

SRS microscopy has been successfully used to characterize the concentration-dependent uptake of solvents into the nail. LSCM and TPF imaging have permitted direct visualization of the ‘fate’ of fluorescently-labelled nanoparticles, which remained only at the nail surface and within microneedle-created pores, from which the release of the entrapped model ‘actives’ into the nail occurred. The delivery of an antifungal drug from a sub-micron particle suspension into the nail has also been demonstrated. Increased nail hydration and pre-treatment with penetration enhancer prior to microneedle-poration improved drug permeation. In addition, a thermoreversible hydrogel has been shown to provide continuous release and delivery of model actives into the nail. This aqueous based lacquer offers an attractive, organic solvent-free, topical nail delivery system with good feasibility and practicability. Finally, intercellular and transcellular penetration pathways were also identified for hydrophilic and lipophilic models, respectively.

Overall, this thesis has provided useful information on the underpinning scientific rationale of the application of different formulation strategies for topical nail delivery upon which further development and optimization might be based.

Date of Award	27 Feb 2015
Original language	English
Awarding Institution	University of Bath
Supervisor	Begona Delgado-Charro (Supervisor), Gareth Price (Supervisor) & Richard Guy (Supervisor)