Nanocrystal solid dispersion of fuzapladib free acid with improved oral bioavailability

Abstract

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. K E Y W O R D Sfuzapladib, hydration property, multi-inlet vortex mixer, nanocrystal solid dispersion, oral bioavailability | INTRODUCTIONFuzapladib (FZP) prevents inflammatory cells from entering inflammatory sites by inhibiting cell adhesion to the vascular endothelial cells (Imamura et al., 2003;Shikama et al., 1999;Yamauchi et al., 1999;Yotsuya et al., 1999), and it was recently approved as a novel drug for the treatment of acute pancreatitis (AP) in dogs.Despite its attractive therapeutic effects against AP, BRENDA TM , a commercially available formulation of FZP, shows rapid elimination after intravenous administration, possibly resulting in limited clinical outcomes with only a single dose. Therefore, the dose frequency of BRENDA TM to dogs is set as once daily for 5 days to ensure therapeutic effects against AP. The commercial formulation of FZP has another limitation for clinical use. There are some concerns regarding the chemical and physical stability of FZP in solution, so it is necessary to dissolve freeze-dried powder just before use. There are clinical needs for a solid formulation of FZP with ease of administration. FZP free acid (SH-683) itself is a poorly water-soluble compound with pK a of 5.1 (Figure S1), so it shows pH-dependent solubility: 20 μg/ml in pH 1-4, 27 μg/ml in pH 5, 65 μg/ml in pH 6, and 280 μg/ml in pH 7 (Figure S2). Therefore, dissolution behavior should be improved when developing a solid formulation of FZP.