Evaluation of the Morphological Effects of TDT 067 (Terbinafine in Transfersome) and Conventional Terbinafine on Dermatophyte Hyphae In Vitro and In Vivo

Authors: M. Ghannoum, N. Isham, W. Henry, H.-A. Kroon, and S. Yurdakul

Publication Year: 2012

PMID: 22354309

Onychomycosis is a common fungal disease of the nail, with an overall estimated prevalence of 10 to 20% (13). Predisposing factors include increasing age, immunosuppression, poor peripheral circulation, diabetes mellitus, nail trauma, tinea manuum, and tinea pedis (11, 24, 26, 29). Dermatophytes are the major cause of nail infection, with the most frequently detected dermatophyte species being Trichophyton rubrum (91%) and Trichophyton mentagrophytes (7.7%) (7, 9, 28). The treatment of onychomycosis has improved considerably following the introduction of the oral antifungals terbinafine and itraconazole (21). However, drug-drug interactions and hepatotoxicity have been associated with these oral antifungals (1, 15, 20), and there are still a proportion of patients who do not achieve efficacy (25). Elderly patients are at increased risk of onychomycosis (26). As the elderly are often receiving multiple medications, topical treatment, which avoids the potential for drug interactions and systemic effects, may be preferred by physicians and patients. Topical agents approved for the treatment of mild to moderate fungal nail infection without matrix involvement include formulations based on ciclopirox or amorolfine. However, the rates of efficacy reported for these formulations are generally low (5), and this is considered to be due to poor penetration of the antifungals through the nail (18). Consequently, there is still a need for new topical treatments which can penetrate the nail sufficiently for antifungal activity at the site of infection in the nail bed.

TDT 067 (15 mg/ml terbinafine in Transfersome) is a carrier-based dosage form of terbinafine that has been formulated for topical delivery of terbinafine to the nail plate, nail bed, and surrounding tissue to treat onychomycosis. Transfersome is an ultradeformable lipid vesicle consisting of a phospholipid bilayer. The inclusion of the membrane-softening agent Tween 80 facilitates the deformability of the Transfersome, allowing it to pass intact through the intercellular spaces in the skin. The vesicles have high surface hydrophilicity, and their movement across the skin is driven by the transcutaneous water gradient, resulting in delivery of high levels of drug to subdermal tissue (3).

In vitro experiments have demonstrated that TDT 067 has potent inhibitory and cidal activity against dermatophytes and has enhanced antifungal activity compared to that of conventional terbinafine preparations (10). The excipients of TDT 067 are widely used in pharmaceutical and cosmetic products for topical application, and clinical studies involving more than 2,000 patients with different diseases have shown that Transfersome preparations are well tolerated (2, 16, 22). Furthermore, in two phase II clinical studies of TDT 067 in patients with onychomycosis, treatment was well tolerated, and most patients did not experience application site reactions (6, 27). Systemic exposure to TDT 067 was negligible in both studies, and there were no clinically relevant hepatic laboratory abnormalities reported (6, 27).

In this study, we investigated the mechanisms underlying the in vitro activity of TDT 067 by comparing the effects of TDT 067 and conventional terbinafine on the morphology of T. rubrum (the predominant cause of onychomycosis) in vitro using different microscopic tools, including white-light microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Additionally, the in vivo effects of TDT 067 on the morphology of fungi present in subungual debris collected from subjects with onychomycosis enrolled in a phase II clinical trial and treated with TDT 067 were examined by white-light microscopy and TEM and compared with effects on fungi present in nail samples from untreated patients.

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