When interactions between bile salts and cyclodextrin cause a negative food effect: Dynamic dissolution/permeation studies with itraconazole (Sporanox®) and biomimetic media

The marketed oral solution of itraconazole (Sporanox®) contains 40 % (259.2 mM) of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The obvious role of HP-β-CD is to solubilize itraconazole and to overcome its poor aqueous solubility that restricts its absorption. In this study, we investigated biorelevance by in vitro the influence of biomimetic media (containing bile salts and phospholipids) on the predicted itraconazole absorption from the commercial HP-β-CD-based Sporanox® solution. We performed phase-solubility studies of itraconazole and dynamic 2-step-dissolution/permeation studies using a biomimetic artificial barrier, Sporanox® solution, and fasted state simulated intestinal fluid (FaSSIF_V1). Both FaSSIF_V1 and HP-β-CD increased the apparent solubility of itraconazole when used individually. In combination, their solubility-enhancing effect did not result additive probably due to the competition of bile salts with itraconazole for the hydrophobic cavity of HP-β-CD. Our combined dissolution/permeation experiments indicated the occurrence of a transient supersaturation from Sporanox® upon two-step dissolution. Through systematic variation of bile salt concentrations in the biomimetic media, it was observed that the extent and duration of supersaturation depend on the concentration of bile salts: supersaturation was rather stable in the absence of bile salts and phospholipids. The higher the bile salt concentration, the faster the collapse of the transient supersaturation occurred, an effect which is nicely mirrored by reduced in vitro permeation across the barrier. This is an indication of a negative food effect, which in fact had earlier been observed in clinical studies for Sporanox® solution. In essence, we could demonstrate that in vitro two-stage dissolution/permeation experiments using an artificial barrier and selected biomimetic media may predict the negative effects of cyclodextrin-based drug formulations like Sporanox® Oral solution and, at the same time, provide a deeper mechanistic insight.