A novel nanoemulsion technology has intrinsic antifungal activity and can be formulated with terbinafine HCl.
As recently demonstrated in a large phase 2 study conducted by NanoBio, the nanoemulsion technology (NB-00X, NanoBio Corp.) has shown significant antifungal activity following topical application. In addition, it has demonstrated unique pharmacokinetics behavior and can be used to enhance delivery of other antifungal agents.
In vitro skin studies demonstrate that the nanoemulsion, with and without a second antifungal agent, is capable of penetrating down into the epidermis and dermis and diffusing laterally from the dosing area. When formulated with terbinafine HCl, levels of terbinafine found in the epidermis and dermis, at sites over 1 cm away from the dosing area, far exceeded those achieved using a commercially available over-the-counter terbinafine cream.
"This formulation is novel in that it does not attempt to reach the site of infection through the nail, but rather through application to the surrounding skin. It can penetrate down into the dermis through the pores and then diffuse laterally to reach the nail bed," says Susan Ciotti, Ph.D., director of formulation, research & development, NanoBio.
"These in vitro studies indicate an opportunity to leverage the intrinsic permeation and antimicrobial characteristics of the nanoemulsion technology, in combination with its ability to enhance delivery of other agents, as a means of treating diseases like onychomycosis topically," says David Peralta, chief operating officer, NanoBio.
Oil and water
The nanoemulsion is an oil-in-water emulsion consisting of nanometer-sized droplets (average droplet size of 200 nm) stabilized by surfactant. Cetylpyridinium chloride, a cationic surfactant that resides at the interface of the oil-and-water droplet in the nanoemulsion, has known antimicrobial effects.
In vitro studies have demonstrated that the nanoemulsion has fungicidal activity against all dermatophytes common in onychomycosis. When combined with terbinafine, the nanoemulsion solubilizes the terbinafine, resulting in a highly stable structure.
The diffusion characteristics of the nanoemulsion combined with terbinafine versus the commercially available 1 percent terbinafine cream (Lamisil AT, Novartis) were investigated using excised human cadaver skin in a modified diffusion apparatus.
At 24 hours post application, residual formulation was removed, and HPLC assays were performed to determine levels of terbinafine in the epidermis and dermis at the dosing area and at sites in tissue outside the dosing area obtained via a punch biopsy.
"Based on the design of this apparatus, terbinafine would only be measured in the punch biopsy tissue if it had permeated into the skin underlying the application site and diffused laterally into the nondosing area," Dr. Ciotti says.
With application of the nanoemulsion formulation incorporating terbinafine, the concentrations of terbinafine in the epidermis and dermis at the dosing area were 14- and 27-fold higher than those achieved with the commercially available terbinafine cream.
At the most distal site tested (>1 cm from the dosing area), the achieved concentrations of terbinafine in the epidermis and dermis were 310-fold and 118 times higher, respectively, using the nanoemulsion formulation compared with the conventional terbinafine cream.
Going forward, it is expected that further studies will be conducted by NanoBio incorporating antifungal agents in the nanoemulsion, given the exciting potential it has shown for treating diseases such as onychomycosis.
"Over 1,000 patients have been treated with the nanoemulsion itself, and there has been no evidence of irritation or other local adverse events," Dr. Ciotti says.