Enhanced oral bioavailability and diminished food effect of lurasidone hydrochloride nanosuspensions prepared by facile nanoprecipitation based on dilution

The aim of this study was to improve the oral bioavailability and diminish the food effect of a poorly soluble drug with pH-dependent solubility, lurasidone hydrochloride (LH), by fabricating its nanosuspensions using a facile nanoprecipitation method. Upon dilution with water, LH dissolved in pH 4 solution formed growing cores and aggregated into nanoparticles, due to the maximum solubility of LH at pH 4. Compared with the batches prepared with other stabilizers, the LH nanosuspensions (LH-NS) stabilized by HPMC E50 were found more stable and had a smaller particle size. A Box-Behnken design (BBD) was used to optimize the critical process and formulation parameters. Then the optimized LH-NS were lyophilized with 1% (w/v) mannitol for long-term stability. According to differential scanning calorimetry and X-ray diffraction analysis, the nanocrystals were still in crystalline state after the preparation procedure. Good physical stability was observed for nanoparticles kept for 6 months at 25 and 40 degrees C/75% RH. The in vitro dissolution rate of LH was significantly increased by reducing the particle size. The in vivo test demonstrated that the C-max and AUC(0-24) h values of nanocrystals in fasted rats were approximately 2.08-fold and 239-fold greater than that of raw drug, respectively. Besides, there was no significant difference in the oral bioavailability of nanoparticles between fasting and feeding. This nanoprecipitation technique is a promising method with a facile process and avoidance of toxic organic solvents and undesired byproducts for oral delivery of poorly soluble drugs with pH-dependent solubility. (C) 2017 Elsevier B.V. All rights reserved.