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

Objective: 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). Methods: 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. Results: The particle size was significantly reduced (from 31.6 mu m to 2.17 mu m), 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 degrees 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 C-max (87.54 +/- 54.82 mu g/L) and AUC((0-t)) of the new pellets (495.86 +/- 281.05 mu g/L h) were clearly higher than those of the dripping pills (30.88 +/- 12.02 mu g/L, 301.07 +/- 133.85 mu g/L h), while the T-max of the test preparation was shorter than that of the reference (1.38 h vs 3.29 h). Conclusion: 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. (C) 2015 Elsevier B.V. All rights reserved.