Integrated gastric to intestinal pH-shift dissolution and permeation testing can predict the marked oral absorption enhancement of an itraconazole-carboxymethyl ethylcellulose amorphous solid dispersion.

In this study, we aimed to investigate correlation of oral absorption and dissolution-permeation behaviors carboxymethyl ethylcellulose (CMEC)-based amorphous solid dispersion (ASD) for itraconazole (ITZ). Amorphization of ITZ and formation of the ASDs through ball milling were confirmed by powder X-ray diffraction, thermal and spectroscopic analyses, using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as an additional carrier. ITZ rapidly dissolved in pH 1.2 medium; however, this was suppressed by ASD formation. The dissolution of ITZ in pH 6.8 medium was <0.2 μg/mL, which was improved by ASD formation. The ASD of ITZ-CMEC (3:7) especially enhanced dissolution to >15-fold that of HPMCAS-based ASDs. The drug-rich colloids generated and grew in the supersaturated solution, but they were effectively inhibited by CMEC. In the oral administration of the ASDs to rat, CMEC resulted in 2-fold higher area under the plasma concentration curve than HPMCAS. Additional dissolution studies combined with gastric, intestinal, and permeated compartments were performed. Both ASDs showed similar dissolution profiles in the simulated gastric fluid followed by reduction and re-dissolution in the fasted state gastrointestinal fluid. Approximately 2- and 1.5-fold higher dissolution and permeation by CMEC compared to HPMCAS was confirmed, respectively, reflecting oral absorption. Therefore, we conclude that CMEC is one of the best ASD carriers, and the oral absorption performances could be understood from the dissolution-permeation performances through both the gastric and intestinal phases.