Immediate release of poorly soluble drugs from starch-based pellets prepared via extrusion/spheronisation.

摘要

The aim of this study was to evaluate modified starch (high-amylose, crystalline and resistant starch) as the main excipient for immediate-release pellets containing poorly soluble drugs (hydrochlorothiazide and piroxicam) and prepared via extrusion/spheronisation. The bioavailability of pellets (containing 50 mg hydrochlorothiazide) was determined after oral administration to 6 dogs. A 2(4)-factorial design with central point was used to evaluate the influence of hydrochlorothiazide (10% and 50%, w/w), HPMC (binder, 4% and 7%, w/w), sorbitol (0% and 10%, w/w) and water (granulation liquid, low and high level) on pellet yield, size (Feret mean diameter) and sphericity (aspect ratio and two-dimensional shape factor, eR). Optimal granulation liquid content depended on drug and sorbitol level in the formulation. All factors except sorbitol content, as well as the interactions between drug concentration and binder level and between drug and water level, were significant (P<0.05) for pellet yield, while a significant curvature (P<0.05) suggested non-linearity of the response plots. The model was not significant for pellet shape, while hydrochlorothiazide and water level as well as their interaction were significant (P<0.05) for pellet size. Pellet friability, disintegration, residual water content and in-vitro drug release were determined. Pellets containing 2.5% (w/w) piroxicam were also evaluated. For both model drugs, pellets with a high yield (>90%), acceptable sphericity (AR<1.2) and low friability (<0.01%) were obtained. Due to pellet disintegration, fast dissolution of both hydrochlorothiazide and piroxicam was achieved: >80% drug released in 30 min. The bioavailability (AUC0-->24 h, Cmax and tmax) of hydrochlorothiazide pellets in dogs was not significantly different from fast-disintegrating immediate-release hydrochlorothiazide tablets (P>0.05).