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

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), PermeaPad^TM, 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.

Highlights

• Commercial precoated PAMPA is the most sensitive system for evaluating excipient effects.
• PermeaPad^TM is applicable to highly cytotoxic excipients owing to its high tolerance to excipient concentrations.
• Caco-2 is a robust cell line that can be used to evaluate excipients at relatively high concentrations.
• Most evaluated excipients did not affect drug membrane permeation at clinically used concentrations.

The permeability of low-permeability drugs was increased by excipients such as hydroxypropyl cellulose and povidone K30 in the precoated PAMPA model, whereas PermeaPad^TM 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 PermeaPad^TM 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 PermeaPad^TM and Caco-2 models allowed assessment at higher excipient concentrations, with PermeaPad^TM being particularly useful for excipients that cause toxicity in Caco-2 cells.

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Materials

The Corning® BioCoat® precoated PAMPA plate system (precoated PAMPA) was purchased from Corning (Glendale, AZ, USA). PermeaPadTM plates were purchased from Phabioc GmbH (Espelkamp, Germany). (±)-propranolol hydrochloride, lucifer yellow CH dipotassium salt (LY), D-(−)-mannitol, lactose monohydrate, corn starch, povidone K30, hydroxypropylcellulose (HPC), croscarmellose sodium (CMS), hydroxypropyl methylcellulose (HPMC), and polysorbate 80 were purchased from FUJIFILM Wako Pure Chemical.

Tokio Morita, Hiroyuki Yoshida, Naomi Tomita, Yoji Sato, Comparison of in vitro screening methods for evaluating the effects of pharmaceutical excipients on membrane permeability, International Journal of Pharmaceutics, 2024, 124727, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124727.

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