含高粘度聚合物和介孔二氧化硅的三元非晶固体分散体增强了溶解性能
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.
Masataka Hanada，Scott V. Jermain，Stephen A. Thompson，Hirosuke Furuta，Mamoru Fukuda和Robert O. Williams III
摩尔。药剂学2020年xxxx年xxx月xxx日
出版日期:2020年12月8日
https://doi.org/10.1021/acs.molpharmaceut.0c00811
关键字:非晶态固体分散、热熔挤出、介孔二氧化硅(Syloid XDP 3050.)、HPMC (亲和醇HPMC HME 15LV，Affinisol HPMC HME 100LV，亲和醇HPMC HME 4M)、伊曲康唑(ITZ)、乳糖水合物(Inhalac 230.)、交联淀粉钠(KICCOLATE)