Activity of TDT 067 (Terbinafine in Transfersome) against Agents of Onychomycosis, as Determined by Minimum Inhibitory and Fungicidal Concentrations

Authors: Mahmoud Ghannoum, Nancy Isham, Jacqueline Herbert, William Henry, and Sam Yurdakul

Publication Year: 2011

PMID: 26833478

Onychomycosis is a common fungal disease that is responsible for up to 50% of nail disorders (13). This disease affects 3 to 23% of the population in the United States and Europe (13, 28), with higher prevalence (>20%) among older people and diabetic patients (23, 25). Other predisposing factors include immunosuppression, poor peripheral circulation, nail trauma, and tinea pedis (31). The incidence of onychomycosis is likely to increase due to a growing elderly population and the spread of human immunodeficiency virus infection/AIDS.

The majority of nail infections (90 to 95%) are caused by dermatophytes (Trichophyton rubrum, T. mentagrophytes, or Epidermophyton floccosum), with the remainder being caused by yeasts (Candida spp.) and nondermatophyte molds (11). Though a few dermatophyte species are endemic to certain areas and absent altogether in others, most dermatophytoses worldwide are caused by only a half-dozen species (1). This distribution is constantly changing, however, due to increased population migration and events such as mass tourism and international sports activities which serve to disseminate less-common species. The most common dermatophyte isolated in the United States, Canada, Mexico, and Europe is T. rubrum, followed in frequency by T. mentagrophytes and E. floccosum (17, 33, 29). An analysis of the dermatophytes isolated in the British Isles over the last 3 decades indicated that T. rubrum and T. mentagrophytes together comprised up to 90% of all foot infections (3), whereas the incidence of E. floccosum infection was dramatically reduced. However, E. floccosum is more prevalent in other areas of the world and has recently been reported from 17% of the onychomycosis infections in the Middle East area (34).

Treatment of onychomycosis has improved considerably over the past decade as a result of the introduction of oral terbinafine and itraconazole, with terbinafine being regarded generally as the more effective of the two agents (10, 30). In spite of the encouraging mycological cure rates shown after treatment with these antifungal agents (30), many nail infections are notoriously difficult to cure, with rates of recurrence of 11.9% and 33.7% being reported for terbinafine and itraconazole, respectively, after long-term follow-up (26). Moreover, oral therapy has the inherent disadvantages of drug-drug interactions and systemic adverse effects (e.g., liver toxicity) (18, 21), which are serious concerns, given the non-life-threatening nature of onychomycosis.

Although the use of topical agents avoids the systemic effects of oral therapy, those available for the treatment of onychomycosis (e.g., tioconazole, amorolfine, and ciclopirox) have limited efficacy. For example, the 28% formulation of tioconazole was reported to have a cure rate of only 20 to 22% (19). A multicenter study of 456 patients demonstrated a 54% clinical response rate for amorolfine nail lacquer; however, patients in this study had no nail bed involvement (27). Ciclopirox, the only FDA-approved topical agent for the treatment of onychomycosis in the United States, achieves drug concentrations in the nail considerably higher than the MIC of ciclopirox for dermatophytes (5). However, poor clinical cure rates have been reported in United States-based studies (<10% complete cure) (16). Combination therapy involving topical and oral antifungals has recently been introduced. For instance, amorolfine hydrochloride 5% nail lacquer and oral terbinafine was shown to be more effective than oral terbinafine alone for the treatment of onychomycosis (2), although a similar study with oral terbinafine and either ciclopirox or amorolfine failed to demonstrate a significant increase in efficacy over that of oral terbinafine alone (20).

The underlying reason for the poor clinical outcomes reported with topical preparations for the treatment of onychomycosis is their inability to penetrate the nail plate and reach the nail bed where the causative fungi reside (24). Different approaches have been investigated to optimize drug penetration through the nail plate, and these include use of (i) potent drugs to ensure that effective drug concentrations are achieved at the site of action, (ii) drugs with optimal physicochemical properties for permeation into the nail plate, (iii) penetration enhancers to facilitate ungual drug permeation, and (iv) appropriate formulations that can aid ungual drug uptake, are easy to use, and stay in contact with nail plates, releasing drugs continuously over long periods of time (24). There has been inconsistency in the results of such studies, and more research is needed in this area (24).

TDT 067 is a novel carrier-based dosage form (liquid spray) of 15 mg/ml of terbinafine in Transfersome (developed by Targeted Delivery Technologies Ltd.) that has been developed to deliver terbinafine to the nail plate, nail bed, and surrounding tissues to treat onychomycosis. The Transfersome carrier vesicles are responsive, composite lipid aggregates that are highly deformable and have high surface hydrophilicity. Thus, the strong transport-driving water gradient acts on the vesicles to pull them into pores and into tissue. Transfersomes activate hydrophilic pathways through the skin, ensuring a high level of deep, local drug accumulation, unlike conventional topical products (6).

This study compared the in vitro antifungal activity of TDT 067 with those of naked terbinafine (terbinafine not in Transfersome vesicles) and a commercially available terbinafine (1%) spray against dermatophytes known to cause onychomycosis, as measured by MIC and minimum fungicidal concentration (MFC).

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