Unique Challenges of Transungual Drug Delivery to Treat Onychomycosis
Tage Ramakrishna, Chief Medical Officer Valeant Pharmaceuticals North America, LLC

This article discusses challenges treating a common nail disease, onychomycosis, by transungual antifungal delivery.

The only approved topical agent is a nail lacquer that has modest efficacy. Despite the unmet need, formulating antifungals to achieve optimal transungual delivery of active drug to the infection site has led to disappointing clinical results. Factors include both poor nail penetration and limited potency of the active drug. Given that systemic treatments are the most effective option, irrespective of disease severity, there remains an unmet need to develop efficient topical formulations. We discuss some of the important aspects to consider in such a development programme and critical success factors. New formulations are in development that may address these concerns.

Human nails may be affected by a number of diseases. These range from relatively harmless conditions such as pigmentation in heavy smokers to more painful and devastating conditions, where the nail may be dystrophied, hypertrophied, inflamed or infected. This may result in emotional and psychological impact.

The most common nail diseases are onychomycosis and nail psorisis. Onychomycosis is a progressive fungal infection of the nail bed, matrix or plate that leads to destruction and deformity of the toenails, and less frequently fingernails. It represents up to 50 per cent of all nail disorders (studies suggest that 48 per cent of the population may be affected by age 70), is most commonly associated with tinea pedis, and has been reported as very distressing to patients. Nails infected with onychomycosis look ugly, discolored and thickened, often causing disability and pain, which in turn may affect a person’s well-being and self-esteem. Onychomycosis is difficult to treat because it is chronic, hard to eradicate and tends to relapse.

Dermatophytes are the key organism associated with onychomycosis. They serve an important evolutionary role in breaking down keratin, hence their association with the toenail environment.

The human nail plate is a sophisticated structure [Figure 1], despite its appearance. It protects the nail bed (the part directly under the nail plate filled with blood vessels), and it protects the nail matrix (the part at the proximal ventral surface of the nail responsible for the cell’s proliferation and nail growth). Although thin, the nail plate has 80-90 layers of dead, keratinised cells linked by desmosomal junctions and intercellular links.

Transungual delivery of an effective antifungal would seem ideal for the successful treatment of onychomycosis. However, the applied active drug must first permeate through the nail plate and reach the nail bed and nail matrix in sufficient concentration to eradicate the infection. Although studies conducted on human skin have elucidated its structure, functions, and its permeability for some substances, much less is known about skin derivate, the nail, and the properties of nail keratin (which constitutes 90 per cent of total nail plate mass).

Until recently, formulating antifungals to achieve optimal transungual delivery of active drug has led to disappointing clinical results in onychomycosis. Poor nail penetration is the main factor limiting their effectiveness. As a result, transungual drug delivery is usually reserved for the mildest disease, for use in combination with systemic therapy, for patients who cannot tolerate oral therapy (or where it is contraindicated), or for preventing relapse. There remains an unmet need to develop an efficient topical formulation to extend the utility of transungual delivery in the treatment of onychomycosis.

Factors Influencing Transungual Drug Delivery
Besides the characteristics of the nail plate (eg, thickness, presence of disease, level of nail plate hydration, presence of an intact dorsal layer), other factors influence transungual permeation [Table 1]. It is well recognised that penetration of a drug into the nail is affected by its physicochemical properties (eg, size, shape, charge, and hydrophobicity), formulation (nature of the vehicle and drug concentration), its contact time with the nail plate, presence of penetration enhancers, and interactions between the drug and the membrane.

Presence of nail disease can alter the properties of nail plate. The thicker the nail is, the more difficult it will be for drugs to reach the nail bed. With increasing hydration rate an increase in drug permeability can be observed. The dorsal layer of the nail plate is the main barrier to drug permeation. Many techniques have been used to remove or damage the dorsal nail layer, not only to influence the main permeability barrier, but also to reduce the thickness of the nail plate. Molecular size of diffusing molecule has been shown to have an inverse relationship with permeation into the nail plate and the degree of ionization of a diffusing molecule plays an important role in permeation through the human nail plate. Nail permeability of an ionic drug is significantly lower than that of a nonionic drug suggesting that the decrease in permeability was caused by a decrease in diffusivity due to ion hydration.

The formulation can influence drug delivery through the human nail plate through many aspects such as hydration of the nail plate, drug solubility, contact time between formulation and the nail plate, and ability to interact with nail constituents. Aqueous based formulations are suitable for increasing the hydration rate of the nail plate, leading to higher permeability of the nail. Yet, in practice, aqueous based formulations are less suitable than lipophilic vehicles, due to their easy removal from the nail plate and short term contact with the nail surface. Lipophilic vehicles such as lacquers leave a hydrophobic film on the nail surface which limits transonychial water loss and at the same time, after the evaporation of the solvent, cause higher concentration of the drug in the film than from original applied formulations.

Ciclopirox 8 per cent nail lacquer is the first topical product approved in the US to treat onychomycosis. It consists of ethyl acetate and isopropanol solvents which evaporate upon application and leave a thin film of the drug on the nail plate. The concentration of the drug in the film increases from 8 to 34.8 per cent. Thus the lacquer formulation improves the drug contact with the nail plate and the concentration gradient across the nail, which is important for passive diffusion of the drug. However, in controlled trials, the mycological cure rate reported with ciclopirox 8 per cent nail lacquer was reported as 29-36 per cent, suggesting other factors may be more important to obtain efficacy. Studies have shown that the concentration of ciclopirox was not such an important factor as the nature of the vehicle, and that antifungal drug delivery can be altered with formulation and delivery enhancers.

Strategies to Enhance Transungual Drug Delivery
There are a number of physical techniques, often applied prior to applying drug, such as removal of the dorsal nail layer by filing or microporation (which leads to an improvement of the drug permeability coefficient), use of acid for surface etching of the nail, and application of electric current (iontophoresis). In addition, chemical enhancers can break the physical and chemical bonds responsible for the stability of nail keratin, and penetration enhancers can improve permeation [Table 2].

Drug partitioning into the healthy and infected toenail, drug-keratin binding, lateral diffusion, drug-epidermal binding and formulation components all may play a role in achieving optimum drug penetration and permeation through the nail. As mentioned previously, the two key factors that affect the accumulation and activity of drug in the nail following transungual delivery are: (1) the physicochemical properties of the drug need to be favorable for absorption through the nail matrix, and (2) the binding of drug to keratin reducing the availability of free active drug.

A recent approach has been to reformulate approved drugs to increase the efficiency of drug delivery into the nail folds, the nail bed and nail plate. Antifungal drugs are known to possess a high binding affinity to keratin that could have a deleterious effect on their efficacy by reducing the availability of free drug. For example, terbinafine, approved as a systemic treatment for onychomycosis, is 98.9 per cent keratin-bound and has shown limited success in treating onychomycosis when delivered transungually.

The degree of drug-keratin binding is not necessarily a disadvantage as it can result in high drug concentrations and persistence in the nail, perhaps forming a drug “reservoir” in the nail plate. However, the rate at which drug is subsequently released from the keratin and delivered into the nail bed must be sufficient to compensate for any loss due to binding, metabolism and clearance of drug from the nail bed. In addition, keratin binding may also decrease drug penetration to the deeper nail layers even with repeated application, because keratin-bound drug does not contribute to a concentration gradient that would otherwise increase drug penetration. Keratin binding and the rate of drug release are both important considerations in any formulation development programme.

First Steps in Developing a Transungual Solution: Choose an Effective Antifungal
To stand a chance of eradicating the infection resulting in onychomycosis, the antifungal must have high potency against the relevant pathogens. Onychomycosis is typically caused by dermatophyte fungi (mainly Trichophyton rubrum) in up to 90 per cent of cases, and can also be due to yeasts (mainly Candida albicans) or molds (mainly Scopulariopsis brevicaulis). With the growing emergence of nondermatophyte infections and mixed infections in onychomycosis, an antifungal with broad spectrum activity is becoming increasingly important. Valeant is among several companies in the process of developing new antifungal treatments for onychomycosis.

Developing an Optimal Transungual Solution
As this decade advances, the broad goal has been to develop stable non-lacquer formulations for antifungal drugs to provide optimal transungual delivery. As products from Valeant and other companies become available, it will soon become clear whether health care providers and patients prefer this approach. It is our hope that this approach will provide advancement over current treatments, and address a significant unmet need for patients.