A fundamental study to determine the difference in barrier properties of healthy and diseased nail in order to facilitate drug delivery

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Nail disorders affect up to 10% of the population and range from innocuous discoloration of the nail plate, commonly seen in smokers, to chronic infections, which can be very painful and disfiguring for the sufferer. Nail infections are especially serious for immunocompromised patients and diabetics where they can cause major complications such as limb amputation. There are many highly effective compounds available to treat infections found in the nail but, the ungual keratin represents a highly effective barrier against absorption following topical drug administration, and therefore, the delivery of therapeutic agents to the site of action i.e. within the nail plate and the nail bed, represents a significant challenge. At present, topical treatments used for nail disorders such as fungal infections or psoriasis require long term application, hence patient compliance is often poor and relapse common. The treatments for nail disorders fall into three general categories; the first involves the surgical /chemical removal of all or part of the affected nail to expose the site of infection, which can then be treated topically. The second method of treatment is the oral administration of an appropriate drug and the third is topical drug administration. Although, at present, nail removal and oral administration are the most effective, the pain associated with nail removal and side-effects and potential drug interactions associated with oral drug therapy result in the direct application of a therapeutic agent to the nail plate being most popular with clinicians and patients. Two topical treatments are currently licensed for onychomycosis, Penlac marketed by Dermik in the USA, approved in late 1999 with reported sales of $142 million in 2003 and Loceryl available in Europe with sales of greater than $100 million in the same year). Topical treatments do not carry the risks of serious side effects (such as hepatotoxicity) associated with systemic antifungals and are less painful than treatments involving full or partial nail removal. However, the topical products currently marketed to treat onychomycosis have reported cure rates as low as 24% . Research has suggested the inefficiency of topical onychomycosis treatment is linked to the low penetration of the therapeutic into the nail, as some formulations only deliver 0.2% of their applied dose to the target site. To be effective, the drug must be able to penetrate the nail plate in sufficient quantities, to achieve an efficacious dose within the nail bed something that remains to be achieved with the current marketed products. One of the major reasons for this is that the nail is a more effective barrier to chemical permeation even compared to skin and the complete lack of fundamental understanding of structural properties of this barrier are preventing the effective design of drugs/formulations that can be used at this topical site. As such the aim of this study is to investigate the properties of healthy and onychomycotic nail plates, including their permeability to drugs. Such knowledge will be critical to identify new targets for enhancement strategies to improve the poor drug permeability of this biological barrier and further the ultimate goal of successfully treating onychomycosis topically.