(542b) Enhanced Delivery to Skin Using Novel Terbinafine Ionic Liquids

The delivery of drugs into and across the skin is non-invasive, painless, and well-accepted, and it represents an attractive alternative to oral and parenteral delivery. The skin is the largest organ of the human body, and it acts as a protective barrier against pathogens and other foreign substances. Skin is composed of several layers, including stratum corneum, viable epidermis and dermis. The outermost layer, i.e., stratum corneum, is usually the rate-limiting barrier for drug delivery to skin, in which solute (i.e., drug) transport across this layer is primarily via passive diffusion. Drug delivery to skin remains limited to a small number of drugs, because the stratum corneum has been shown to prevent skin penetration of most hydrophilic and large molecular weight drugs. In this study, we examined the enhancement of drug delivery to skin using novel room-temperature ionic liquids (RTILs) synthesized from an active pharmaceutical ingredient (API) with antifungal activity.

Ionic liquids (ILs) are organic salts that are composed entirely by ions. Many possible cation-anion combinations, where an active pharmaceutical ingredient (API) is one of the ions, can produce ILs with improved biological activity. Specifically, RTILs are very attractive candidates for drug delivery to skin, since there is no need for solvent to dissolve the API, and they can produce a liquid formulation containing 50% API on a molar basis at room temperature. In addition, the use of RTILs can take advantage of some of their enhanced physical and chemical properties that enable improved solubility, stability, bioavailability and provide an alternative route to deliver drugs to the skin.

Here, we demonstrate the enhanced transdermal delivery of terbinafine using RTIL formulations. We report the synthesis, characterization, and evaluation of novel RTILs with antifungal activity. These RTILs incorporated the API terbinafine in combination with inactive ingredients safely used in other pharmaceutical formulations as counterions. These RTILs are being developed to treat skin fungal infections, and to reduce the side effects often encountered with other delivery routes. They were synthesized through a salt metathesis reaction, and their physicochemical properties (i.e., MW, density, viscosity, log P, water solubility) were measured. Ex-vivo drug permeability experiments were performed using pig ear skin, as well as in-vivo drug permeability experiments using rodents. The drug permeability experimental results from the RTIL formulations showed a significant enhancement in skin permeability of up to two orders of magnitude when compared to the commercial topical formulation of terbinafine. In addition, our studies showed higher amounts of drug remaining in the skin layers when compared to the commercial formulation. In-vitro antifungal activity experiments in four different fungal strains of medical significance confirmed that the RTIL formulations remained active. We can conclude that terbinafine can be formulated as an RTIL with dramatically enhanced skin permeability and strong antifungal efficacy that has promise as a novel RTIL-formulated drug for transdermal delivery of terbinafine.