Development of selumetinib–loaded solid dispersion based on low molecular weight methylcellulose for the enhanced solubility, stability, dissolution, and bioavailability

Abstract

The poor water solubility and bioavailability of selumetinib sulfate (SEL) limit its clinical potential as a promising anticancer drug. The aim of this study was to develop a solid dispersion (SD) of SEL as a new formulation strategy. Methylcellulose 4 cP (MC 4 cP) and Soluplus® were selected as SD carriers for their high solubility of SEL (>1400 μg/mL at pH 1.2). Furthermore, the low molecular weight MC 4 cP was effective in the solubilization of SEL due to its specific molecular affinity and interaction with SEL. The SDs of SEL/MC 4 cP and SEL/Soluplus® were prepared using the spray drying method. All the SDs demonstrated the transformation of crystalline SEL into amorphous form with particle size of <20 μm, in scanning electron microscopy, powder X–ray diffraction, and differential scanning calorimetry. The optimized F3 (SEL/MC 4 cP = 1/10, w/w) exhibited more than twice the dissolution rate of SEL (100.15 ± 1.81 %) at pH 1.2 and 60 min compared with the raw SEL (45.13 ± 2.13 %) and F4 (SEL/Soluplus® = 1/5, w/w) (42.44 ± 1.43 %). F3 showed stable amorphous form without any recrystallization of SEL for 6 months at 40 °C. Furthermore, F3 enhanced oral absorption (1.96–fold in Cmax and 1.69–fold in AUCinf) in rats compared with the raw SEL suspension group, and this improvement was further supported by its nearly 100 % absolute bioavailability. In conclusion, F3 suggested in this work was a potential novel SD formulation for SEL, offering enhanced solubility, dissolution, physical stability, and bioavailability.