Interpreting permeability as a function of free drug fraction: The case studies of cyclodextrins and liposomes

Solubilization with lipidic nanocarriers and cyclodextrins are two of the most applied strategies to achieve better oral bioavailability of BCS class II/IV compounds, i.e., with poor water solubility. However, improving drug’s apparent solubility by nanocarrier-based enabling formulations does not always translate into enhanced bioavailability1. The aim of this work was to verify if the free drug fraction CD, i.e., the amount of drug not loaded into the nanocarriers, could be the decisive parameter for the prediction of drug permeation in vitro. We studied hydroxypropyl-β-cyclodextrin (HP-β-CD) and phosphatidylcholine liposomes formulations of three chemically diverse compounds (atenolol, ketoprofen and hydrocortisone) in different conditions (pH 2 and pH 7.4) by i. localized UV-spectroscopy to measure CD a unique level of accuracy and ii. with the state-of-the-art PermeaPad® assay to measure the rate of drug formulations. In conclusion, we proved that the free drug fraction (CD) of enabling formulations is the decisive parameter to interpret/ predict drug absorption tendency in in vitro and, most likely, in vivo. However, this is true only when the complex drug-carrier is not permeable/ very poorly permeable through biomimetic /biological barriers.