Amorphous Compositions Using Concentration Enhancing Polymers for Improved Bioavailability of Itraconazole

Amorphous engineered particle compositions of itraconazole (ITZ) and potential concentration enhancing polymers, cellulose acetate phthalate (CAP) and polyvinyl acetate phthalate (PVAP), were produced by ultra-rapid freezing to investigate the effect of these polymers on the bioavailability of ITZ solid dispersions. X-ray diffraction analyses of engineered particle compositions were shown to be amorphous. Modulated differential scanning calorimetry demonstrated that ITZ:CAP engineered particle compositions exhibited a strong correlation with the Gordon-Taylor relationship while ITZ:PVAP formulations exhibited positive deviations from predicted values attributed to hydrogen bonding interactions between the drug and polymer. Energy dispersive spectroscopy mapping demonstrated that the drug was homogenously distributed within all compositions, supporting the miscibility of the drug with the polymers. Scanning electron microscopy imaging of the particles demonstrated that the material existed in two general forms, discrete particles of approximately 5 mu m and larger aggregates in excess of 30 mu m, with engineered particle compositions having approximately 15 times higher measured specific surfaces areas compared to micronized ITZ. In vitro supersaturated dissolution results showed that all compositions provided significantly lower levels of supersaturation in acidic media and greater extents of supersaturation in neutral media compared to Sporanox pellets. ITZ: CAP formulations provided the greatest degree and extent of supersaturation in neutral media. Dissolution data were fitted to an exponential relationship based on a simplified model of particle growth, allowing for the determination of drug half-life in solution for evaluation of stabilization behavior. 1:2 ITZ:CAP showed superior in vitro performance compared to all other engineered particle compositions and was selected for in vivo testing. Although not fully elucidated, data indicated that the stabilization mechanism was due to interactions between the drug and polymer, primarily attributed to steric hindrance resulting from the molecular weight of the polymer chain and chemical composition of the polymer backbone relative to position of hydrogen bonding sites. In vivo testing conducted in Sprague-Dawley rats (n = 6) demonstrated a significant improvement in oral bioavailability from the 1:2 ITZ:CAP (AUC = 4,516 1,949 ng.h/mL) compared to the Sporanox pellets (AUC = 2,132 1 1,273 ng.h/mL) (p <= 0.05). Additionally, the more rapid onset of action indicated superior targeting of the upper small intestines, and the prolonged half-life suggested the utility of CAP to maintain supersaturated concentrations, in vivo. These results demonstrated that amorphous compositions of ITZ and enteric concentration enhancing polymers provided improved bioavailability due to enhanced intestinal targeting and increased durations of supersaturation.