Nanocrystal solid dispersion of fuzapladib free acid with improved oral bioavailability

This study aimed to develop an oral nanocrystal solid dispersion (nCSD) of fuzapladib (FZP) with enhanced absorbability for the treatment of acute pancreatitis (AP). The hydration properties of crystalline FZP free acid (crystalline FZP) and FZP sodium salt (FZP/Na) were assessed to select a stable crystal form. The nCSD of FZP free acid (nCSD/FZP) was prepared using a multi‐inlet vortex mixer and evaluated in terms of physicochemical and pharmacokinetic properties. The results of X‐ray powder diffraction analysis indicated that crystalline FZP was stable as an anhydrate, while FZP/Na was converted to its monohydrate at water activity of above 0.2. The nanocrystals in nCSD/FZP were dispersed in hydroxy propyl cellulose‐SSL, and their mean particle size were 160 nm with uniform spherical shape. In dissolution testing, nCSD/FZP exhibited rapid dissolution compared with crystalline FZP and reached a saturated concentration of FZP within initial 30 min. After oral administration (2 mg‐FZP/kg) to rats, the maximum plasma concentration and bioavailability were 7.3‐ and 5.2‐fold higher for nCSD/FZP than crystalline FZP, respectively, due to improved dissolution by nanosization. In conclusion, nCSD/FZP may be a novel oral dosage form with enhanced absorbability facilitating potent therapeutic effects of FZP for the treatment of AP in animals. Fuzapladib free acid (FZP) was stable as an anhydrate, and nanocrystal solid dispersion of FZP (nCSD/FZP) exhibited a marked increase in dissolution rate compared with crystalline FZP. Oral bioavailability of nCSD/FZP in rats was 5.2‐fold higher than that of crystalline FZP, due to improved dissolution by nanosization.