Trans-ungual Delivery of AR-12, a Novel Antifungal Drug
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`A. S. Kushwaha 1, P. Sharma 1, C. Rappleye 2, A. Zukiwski 3, S. Proniuk 3, S. N. Murthy 1
`1 University of Mississippi, 2 Ohio State University, 3 Arno Therapeutics
`Purpose
`With the growing prevalence of onychomycosis, there is also growing need for more potent and safer drugs for improving the success
`rate of topical therapy of onychomycosis. The novel antifungal drug AR-12 was found to be highly potent against T.rubrum and
`T.tonsurans, the fungal organisms predominantly responsible for causing onychomycosis. The objective of this project was to
`investigate the inherent ability of AR-12 to penetrate into and across the human nail plate. The second objective was to explore
`suitable permeability enhancers to improve the trans-ungual delivery of AR-12.
`Methods
`In vitro permeation studies of AR-12 was performed across the human cadaver nail plates using Franz diffusion cells. Donor and
`receiver compartments were filled with 0.5 ml of 5% w/v alcoholic drug solution and 5 ml of ethanol and phosphate buffer saline
`mixture ( l: l) respectively. Samples (200 µI) from the receiver compartments were withdrawn at different time points and the amount
`drug was analyzed by HPLC. TranScreen-N method was followed to screen the potential permeability enhancers. Then, In vitro
`transport studies of AR-12 with leading enhancers were performed for 7 days.
`Results
`The amount of drug permeated across the nail plate after one week was 0.82±0.l l ng/cm2
`• The amount of drug retained in active
`diffusion area of the nail plate was ,...,().42±0.02 µg/mg .. TranScreen-N clearly showed that PEG-400 could be a potential enhancer of
`trans-ungual delivery of AR-12. Furthermore, in vitro permeation studies of AR-12 in presence of 100/o PEG-400 resulted in 6 folds
`more enhancement in trnas-ungual drug transport compared to control solution. The drug load in the nail plate was found to be 2 folds
`more in presence of l 0% PEG-400.
`Conclusion
`AR-12 is a promising novel antifungal for the treatment of onychomycosis. AR-12 has been found to penetrate across the nail plate in
`significant amounts which can be further improved with the use of appropriate permeation enhancer like PEG-400.
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1075 - Page 1 of 1