Extensive improvement of oral bioavailability of mebendazole, a brick dust, by polymer-containing SNEDDS preparation: Disruption of high crystallinity by utilizing its counter ion

Poorly water-soluble and poorly lipid-soluble drugs are called as “brick dust” and it is very hard for them to be formulated as some dosage form which can provide an effective bioavailability after oral administration. Mebendazole (MBZ), an anti-helminthic drug having anti-cancer properties, is one of the brick dusts and its poor bioavailability has been well known. The strategy of the current study was to improve the oral absorption of MBZ by SNEDDS formulation prepared by utilizing an MBZ-counter ion complex, of which the formation would disrupt the high crystallinity of MBZ. Among five different counter ions examined, (+)-10-camphorsulfonic acid (CSA), 2-naphthalene-sulfonic acid (NSA) and p-toluenesulfonic acid (TSA) largely improved MBZ solubility in the SNEDDS vehicle by forming the complex with MBZ. The solid state of these complexes, MBZ-CSA, MBZ-NSA and MBZ-TSA, was suggested to be amorphous by XRPD and DSC. SNEDDS formulations of the three complexes extensively improved MBZ dissolution under gastric and intestinal luminal conditions, compared with MBZ crystalline powder. However, since the dissolved concentrations of MBZ were time-dependently decreased so much by precipitation, we tried to maintain the high dissolution property by applying some polymer for SNEDDS preparation of MBZ-CSA which provided the highest solubility in the SNEDDS vehicle. Among ten different polymers examined, HPMCP-50 successfully maintained the high dissolution property of MBZ-CSA SNEDDS under both gastric and intestinal luminal conditions. In the in vivo oral administration study, SNEDDS preparations for the three MBZ complexes significantly improved MBZ absorption compared with MBZ crystalline powder, but 2% HPMCP-50-containing SNEDDS of MBZ-CSA provided further improvement of MBZ absorption, resulting in around 10-fold of crystalline powder in AUC.