To enhance dissolution and improve oral bioavailability of the poorly water-soluble drug (andrographolide, ADP), using a natural triterpenoid glucoside (glycyrrhizin, GLC) as stabilizer, the ADP nanocrystals (ADP-NC) were prepared in water by homogenization method and converted into ADP nanocrystals-agglomerated particles (nanocomposite microparticles, ADP-NP) using spray-drying. Different types of matrix formers from glucoside (GLC), polyol (mannitol), disaccharide (lactose), polysaccharide (maltodextrin), and polymer (PVPK30) were systematically investigated their effects on particles properties of ADP-NP. And the acceptable ADP-NP was further characterized for oral bioavailability. The results demonstrated that ADP-NC with particles size of 476 +/- 22 nm and span of 2.134 +/- 0.016 were successfully prepared. The ADP-NP containing 100% ratio of GLC possessed a higher yield (60.47%), more excellent redispersibility (1.06) and flowability (HR 1.16), compared to those containing mannitol, lactose, PVPK30 and maltodextrin as matrix formers. These were related with the glass transition property of mannitol, lactose, PVPK30 and maltodextrin. The DSC and XRD analysis demonstrated that the mannitol, lactose, PVPK30 and maltodextrin were amorphous state presented in ADP-NP, but the crystal state of ADP and GLC remained unchanged during the preparation. The ADP-NP containing GLC showed the fast dissolution rate and significantly improved the bioavailability (794.338 +/- 229.259 mu g/L.h) of ADP. This study demonstrated the feasibility of nanocomposite microparticles strategy to improve the oral bioavailability of poorly soluble ADP, and GLC can be an alternative matrix former of ADP-NP, which could prevent from irreversible agglomerates of ADP-NC during spray-drying. (C) 2017 Elsevier B.V. All rights reserved.