Hot-melt extruded drug delivery systems for onychomycosis and other fungal infections

Onychomycosis is a fungal infection of the fingernails or toenails. It causes the nails to thicken, discolor, disfigure and split. Historic treatment of these infections has had limited success rate. Human nail was treated with chemical penetration enhancers, bioadhesives and surface modifiers and investigated using Atomic Force Microscopy, Scanning Electron Microscopy and Optical Microscopy for the assessment of treatment modalities for onychomycosis. These techniques provided both qualitative and semi-quantitative information for the evaluation of nail morphology as it pertains to drug delivery. The dorsal surface morphology changed quite dramatically, when subjected to surface modifiers, tartaric acid (TTA) and phosphoric acid gel. It was also found that higher concentrations and longer exposure times were more effective in modifying the surface of the nail. Hot-melt extrusion technology (HME) was used to prepare thin films containing model drugs ketoconazole or itraconazole. Killion extruder (Model---KLB 100) and Randcastle Microtruder (RCP 0250) were used to extrude thin polymer films. The extruded films were investigated for solid-state characteristics, moisture absorption, bioadhesivity, mechanical properties, release characteristics, permeability studies and physical and chemical stability of the drug within the HME films. The effect of molecular weight of hydroxypropyl cellulose on the drug release properties was also studied. Data from these studies have indicated that nail samples treated with an 'etchant' demonstrated a significant increase in both film bioadhesion and drug permeation compared to the control (non-etched). Addition of TTA within the film formulations significantly influenced the bioadhesion and mechanical properties tested. Force-deflection profiles obtained from nail adhesion experiments indicate that the surface-active nature of TTA containing films was demonstrated to provide better surface modification to the human nail. The hydroxypropyl cellulose (HPC) film containing TTA exhibited a lower tensile strength and a higher percent elongation than those films without TTA. TGA data collected at two-week interval, measured higher moisture content for the TTA-incorporated films than the films without TTA. DSC, SEM and XRD techniques demonstrated that melt cooled mixtures of the drug and the two polymers were amorphous. HPLC studies indicated that the theoretical post-extrusion content of ketoconazole remaining in the six film batches ranged from 90.3% (+/-2.2) to 102.4% (+/-9.0) for up to 6 months and from 83.9% (+/-3.6) to 91.6% (+/-3.0) for up to 12 months. The dissolution rate of itraconazole from HPC matrices was found to decrease with an increase in polymer molecular weight. When the release data was fitted to three models, first-order, square root, and zero-order, to describe the drug release kinetics from the matrices. The results of these studies are encouraging for the future design and formulation of novel drug delivery systems.