Hydroxypropyl cellulose-based lyospheres accelerate dissolution of aprepitant combined with its supersaturation for...

Spray freeze-drying (SFD) leads to a free-flowing lyophilized powder, providing new therapeutic options. In this work, non-aqueous SFD particles are produced with dimethyl sulfoxide as a spray solvent for obtaining amorphous solid dispersions (ASDs) for oral administration of a poorly water-soluble drug, aprepitant. The SFD process was conducted with the low viscosity hydroxypropyl cellulose grades HPC-SSL or HPC-UL to achieve rapidly dissolving aprepitant powder. Besides different HPC grades, varying solid contents (5 and 10 %) and drug-excipient ratios (20/80, 40/60 and 100/0) were explored and compared to film casted ASDs and analysed regarding particle morphology and characteristics, storage stability, in vitro dissolution and in vivo pharmacokinetic studies in rats. Median particle size of the powder formulations ranged between 300 and 500 µm, increasing HPC content led to amorphous formulations, that remained amorphous for 12 months of storage at 25 °C. Dissolution at pH 1.2 revealed supersaturation across all SFD samples with concentration values twofold and fourfold the saturation concentration for 40/60 and 20/80 drug-excipient ratios respectively. After oral administration to rats, t_max, c_max and AUC varied between 2.5-4 h, 1.04-1.24 µg/ml and 5.4-8.1 µg*h/ml respectively. Pharmacokinetic parameters were not affected by HPC grade, but indicate a possible relationship between a decrease of geometric particle density and an increase in bioavailability. Low viscosity HPC grades proved to be suitable excipients for the use in non-aqueous SFD to produce amorphous, rapidly dissolving, low density powders.