Targeted Intestinal Delivery of Supersaturated Itraconazole for Improved Oral Absorption

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.