Comparison of in vitro screening methods for evaluating the effects of pharmaceutical excipients on membrane permeability.

ABSTRACT

The effects of pharmaceutical excipients on intestinal drug absorption have been highlighted and careful excipient selection is required to develop biologically equivalent formulations. This study aimed to evaluate the effects of excipients on drug permeability and compare the characteristics of in vitro screening methods. Three in vitro models, the commercial precoated parallel artificial membrane permeability assay (PAMPA), PermeaPadTM, and Caco-2 monolayer, were used to evaluate the effects of 14 excipients on the permeability of several drugs with different biopharmaceutical classification system classes. Concentration-dependent effects were analyzed to distinguish non-specific effects. The permeability of low-permeability drugs was increased by excipients such as hydroxypropyl cellulose and povidone K30 in the precoated PAMPA model, whereas PermeaPadTM maintained membrane integrity at higher concentrations. Conversely, croscarmellose sodium and sodium lauryl sulfate (SLS) decreased the permeability of highly permeable drugs in both precoated PAMPA and PermeaPadTM assays in a concentration-dependent manner. In Caco-2 monolayer assays, most excipients showed minimal effects on drug permeability. However, SLS significantly reduces the permeability of highly permeable drugs at concentrations above the critical micelle concentration, thereby compromising the integrity of the cell monolayer. Our results suggested that most of excipients, except SLS, did not affect the membrane permeation of drugs at clinically used concentrations. The pre-coated PAMPA model demonstrated high sensitivity to excipient effects, making it suitable for conservative evaluation. The PermeaPadTM and Caco-2 models allowed assessment at higher excipient concentrations, with PermeaPadTM being particularly useful for excipients that cause toxicity in Caco-2 cells.