Dry state microcrystals stabilized by an HPMC film to improve the bioavailability of andrographolide

The main purpose of this study was to improve the in-vitro dissolution and the in-vivo bioavailability of a poorly water-soluble drug, andrographolide (ADG).

A wet-milled suspension was prepared using a Lab basket mill in the presence of a hydrophilic carrier solution and then it was layered on to MCC beads with a fluidized bed coater to obtain solidified pellets. Optical microscopy, particle size distribution investigation, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were used to characterize the wet-milled suspension. In addition, the ADG pellets were subjected to investigations involving scanning electron microscopy (SEM), as well as dissolution, accelerated stability and bioavailability measurements.

The particle size was significantly reduced (from 31.6 μm to 2.17 μm), however, the ADG in suspension retained its crystallinity as shown by the results of the DSC and PXRD investigations. The dissolution of the new pellets and commercial dripping pills was 95.6% and 48%, respectively, in pure water over 60 min. After a 6 month accelerated test (40°C and RH 75%), although the initial dissolution rate declined slightly, the overall dissolution of the new pellets within 60 min was almost as high as the freshly prepared pellets. In the in-vivo evaluation, the Cmax (87.54 ± 54.82 μg/L) and AUC(0-t) of the new pellets (495.86 ± 281.05 μg/Lh) were clearly higher than those of the dripping pills (30.88 ± 12.02 μg/L, 301.07 ± 133.85 μg/Lh), while the Tmax of the test preparation was shorter than that of the reference (1.38 h vs 3.29 h).

These results showed that the new core-shell structured pellets consisting of ADG microcrystalline particles and stabilized by HPMC alone, markedly improved the dissolution and bioavailability of andrographolide.