Formulation and in vivo human bioavailability of dissolving tablets containing a self-nanoemulsifying itraconazole solid dispersion without precipitation in simulated gastrointestinal fluid

To investigate the performance of a solid-state self-nanoemulsifying system with no precipitation in gastric and intestinal fluid, itraconazole (ITZ) was selected as a model drug because of its practically insoluble nature in intestinal fluid. A self-nanoemulsifying ITZ solid dispersion (SNESD) system was prepared as follows: (1) establishment of self-nanoemulsifying composition via the hot melting method, (2) solidification with fumed silicon dioxide (Aerosil 300) via adsorption to prepare SNESD and (3) preparation of a directly compressible tablet containing SNESD. This SNESD was easily formulated in the form of a dissolving tablet and provided a favourable nanoemulsifying microenvironment with no precipitation in the testing media. The SNESD and SNESD-loaded tablet displayed highly enhanced dissolution via nanomisation (266.8 nm and 258.3 nm at 60 min and 120 min, respectively), whereas the drug alone or a reference ITZ Sporanox® capsule displayed very low dissolution and precipitated immediately in intestinal fluid. Drug precipitation in intestinal fluid may affect the in vivo performance of poorly soluble weakly basic drugs and was estimated according to the crystal growth theory. The superdisintegrant and surfactant in the formulation of the tablet were very crucial to the dissolution of the SNESD-loaded tablet. The drug contents and dissolution rates of the SNESD-loaded tablets were also stable during storage in terms of dissolution and drug content. The SNESD-loaded tablet displayed significantly increased oral bioavailability in healthy human volunteers compared with the reference Sporanox® capsule. The current solid-state SNESD-loaded tablet could provide an alternative to liquid-based emulsifying preparations for various poorly water-soluble drugs without precipitation in testing media.

Graphical abstractAn immediate or sustained release tablet containing self-nanoemulsifying solid dispersion (SNESD) of itraconazole showed a continuous dissolution with no precipitation when the simulated gastric fluid (SGF) was switched to simulated intestinal fluid (SIF).Figure optionsDownload full-size imageDownload high-quality image (138 K)Download as PowerPoint slide