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ABSTRACT: 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 mum and larger aggregates in excess of 30 mum, 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 +/- 1,273 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.
Molecular Pharmaceutics 10/2008; · 4.78 Impact Factor
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ABSTRACT: Previous attempts to improve the dissolution and absorption properties of itraconazole (ITZ) through advanced formulation design have focused only on release in acidic media; however, recent reports indicate that absorption occurs primarily in the proximal small intestine. This suggests that enhancing supersaturation of ITZ in neutral aqueous environments is essential for improving absorption. The aim of this study was to evaluate different polymeric stabilizers with either immediate release (IR) (Methocel E5, Methocel E50, Kollidon 12, and Kollidon 90) or enteric release (EUDRAGIT L 100-55, HP-55, and HP-55S) properties to determine the chemical and physical attributes of the polymeric stabilizers that promote supersaturation of ITZ in neutral media. Each amorphous composition was produced by hot-melt extrusion and characterized by differential scanning calorimetry. Dissolution testing by a supersaturated acidic-to-neutral pH change method was conducted on each composition. Testing of IR compositions revealed that Methocel was a superior stabilizer compared with Kollidon owing to stronger intermolecular interaction with ITZ molecules in solution. Increasing the molecular weight of polymers was found to promote ITZ supersaturation and was most likely attributable to increased solution viscosity resulting in retention of ITZ molecules in an enthalpically favored association with the polymer for extended durations. Of the enteric polymeric stabilizers, EUDRAGIT L 100-55 was found to be superior to both HP-55 grades because of its greater permeability to acid that allowed for improved hydration of ITZ in the acid phase as well as a greater number of free hydroxyl groups on the polymer backbone that presumably helped to stabilize ITZ in solution. The Methoceltrade mark E50 and EUDRAGIT L 100-55 formulations were evaluated for in vivo drug absorption in male Sprague-Dawley rats and were found to produce a threefold greater ITZ absorption over our previously reported IR formulations. The results of this study confirmed the hypothesis that supersaturation of ITZ following an acidic-to-neutral pH transition in vitro correlates directly to in vivo absorption.
Drug Development and Industrial Pharmacy 07/2008; 34(8):890-902. · 1.49 Impact Factor
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ABSTRACT: To investigate the use of Carbopol 974P as a stabilizing agent for supersaturated levels of itraconazole (ITZ) in neutral pH aqueous media and the resultant effects on oral absorption of ITZ.
Carbopol 974P was incorporated into an EUDRAGIT L 100-55 carrier matrix at concentrations of 20% and 40% based on polymer weight with the aim of prolonging supersaturated ITZ release from the enteric matrix. Amorphous solid dispersions of ITZ in EUDRAGIT L 100-55 containing either 20% or 40% Carbopol 974P were produced by hot-melt extrusion (HME). Solid state analysis of these compositions was performed using differential scanning calorimetry and qualitative energy dispersive X-ray spectroscopy. Dissolution analysis was conducted using a pH change method. Oral absorption of ITZ was evaluated in male Sprague-Dawley rats.
Solid state analysis demonstrated that the extruded compositions were entirely amorphous and homogenous with respect to drug distribution in the polymer matrix. Dissolution analysis revealed that the addition of Carbopol 974P to the EUDRAGIT L 100-55 carrier system functioned to prolong the release of supersaturated levels of ITZ from the EUDRAGIT L 100-55 matrix following an acidic-to-neutral pH transition. In vivo evaluation of ITZ absorption revealed that the addition of Carbopol 974P substantially reduced the absorption variability seen with the EUDRAGIT L 100-55 carrier system. In addition, the 20% Carbopol 974P formulation exhibited a five-fold improvement in absorption over our initially reported ITZ particulate dispersion compositions that limited supersaturation of ITZ primarily to the stomach.
The results of this study strongly suggest that substantial improvements in oral antifungal therapy with ITZ can be achieved via intestinal targeting and polymeric stabilization of supersaturation.
Pharmaceutical Research 03/2008; 25(6):1450-9. · 4.09 Impact Factor
