Ternary Amorphous Solid Dispersions Containing a High-Viscosity Polymer and Mesoporous Silica Enhance Dissolution Performance†.

ABSTRACT

The aim of this study was to evaluate the benefits of a ternary amorphous solid dispersion (ASD) that was designed as an immediate-release tablet with a high drug load (e.g., 40% w/w) to produce heightened maintenance of drug supersaturation during dissolution testing, which will be henceforth referred to as the "maintenance ability". Ternary ASD granules were produced by hot melt extrusion (HME) and were comprised of itraconazole (ITZ) 50%, hypromellose (HPMC) 20%, and mesoporous silica (XDP) 30%, where amorphous ITZ incorporated into HPMC was efficiently absorbed in XDP pores. The ternary ASD granules containing a high-viscosity HPMC (AF4M) produced a significantly heightened maintenance ability of drug supersaturation in neutral pH dissolution media in which crystalline ITZ solubility is below 1 µg/mL. The final tablet formulation contained 80% w/w of the ASD granules (40% w/w ITZ), had an acceptable size, and exhibited both sufficient tablet hardness and disintegration. The dissolution behavior of the ternary ASD tablet exhibited a supersaturation maintenance ability similar to that of the ASD granules. Under neutral conditions, the ternary ASD tablet showed immediate and higher ITZ release compared with the binary ASD tablets, and this phenomenon could be explained by the difference in ITZ/AF4M particle size in the tablet. In high-resolution scanning electron microscopy (SEM), it was observed that ITZ and AF4M in the ternary formulation could easily form nano-sized particles (<1 µm) during the absorption process into/onto XDP pores prepared by HME, which contributed to the immediate ITZ release from the ternary ASD tablet under neutral pH conditions. Therefore, the ternary ASD containing high-viscosity HPMC and mesoporous silica prepared by HME made it possible to design a high ASD content, small-size tablet with an ideal dissolution profile in biorelevant media, and we expect that this technology can be applied for continuous HME ASD manufacturing.