Analysis of discrepancy in SNEDDS performance for a "brick dust" mebendazole between in-vitro and in-vivo estimation

Oral absorption of mebendazole (MBZ), a brick dust, was successfully improved 10 times by dosing 2% HPMCP-50 SNEDDS of MBZ co-amorphized with (+)-10-camphorsulufonic acid (CSA) (MBZ-CSA), compared with crystal powders in our previous study. However, an in-vitro non-sink dissolution study with pH3.9 acetate buffer or FaSSIF (conventional method) revealed that 2% HPMCP-50 SNEDDS of MBZ-CSA improved the dissolution of MBZ over 440 times compared to the crystal. In the current study, we assessed the reason for the large discrepancy in SNEDDS performance between in-vitro and in-vivo estimations using several novel in-vitro methods. The Sequential Gastro-Intestinal Exposure (SGIE) method, reflecting the transit from the stomach to the small intestine (GI-transit), revealed MBZ precipitation higher than that in the conventional method using FaSSIF. The Egg phosphatidylcholine-Monolayer-CHCl₃ Partition (EMCP) method, reflecting the absorption process, also indicated MBZ precipitation at early time periods greater than the conventional method. The SGIE-EMCP method, reflecting both GI-transit and subsequent absorption processes, indicated the highest precipitation of MBZ and MBZ transfer to the CHCl₃ phase less than the EMCP method. The SGIE-EMCP method also indicated that 2% HPMCP-50 SNEDDS transferred MBZ to the CHCl₃ phase significantly larger than SNEDDS without the polymer, which coincided with the in-vivo tendency.