LAUSR

The purpose of this work was to investigate the use of the dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO) in oral solubility- enabling formulations for anionic lipophilic drugs, aiming to guide optional formulation design, and maximize oral bioavailability. We have studied the solubility, the permeability, and their interplay, using the low solubility non-steroidal anti-inflammatory drug mefenamic acid as a model drug. Then, we studied the biorelevant solubility enhancement of mefenamic acid from EPO-based formulations throughout the gastrointestinal tract (GIT), using the pH-dilution dissolution method. EPO allowed profound and linear solubility increase of mefenamic acid, from 10 µg/mL without EPO to 9.41 mg/mL in the presence of 7.5% EPO (∼940-fold; 37 °C); however, concomitant decrease of the drug permeability was obtained, both in-vitro and in- vivo in rats, indicating a solubility-permeability tradeoff. In the absence of excipient, the unstirred water layer (UWL) adjacent to the GI membrane was found to hinder the permeability of the drug; accounting for this UWL effect and revealing the true membrane permeability allowed good prediction of the solubility-permeability tradeoff as a function of EPO level using direct relationship between the increased solubility afforded by a given EPO level and the consequent decreased permeability. Biorelevant dissolution studies revealed that EPO levels of 0.05% and 0.1% were insufficient to dissolve mefenamic acid dose during the entire dissolution time course, while 0.5% and 1% EPO allowed complete solubility with no drug precipitation. In conclusion, EPO may serve as a potent solubility-enabling excipient for BCS Class II/IV acidic drugs, however it should be used carefully; it is prudent to use the minimal EPO amounts just sufficient to dissolve the drug dose throughout the GIT, and not more than that. Excess amounts of EPO provide no solubility gain and cause further permeability loss, jeopardizing the overall success of the formulation. This work may help the formulator to hit the optimal solubility-permeability balance, maximizing the oral bioavailability afforded by the formulation.