When administered orally, the bioavailability of drugs is strongly influenced by their aqueous solubility and permeability. Although solubility-enabling excipients can improve the aqueous solubility of lipophilic drugs, their simultaneous effect on the apparent permeability can be often overlooked. Recently, we demonstrated that the aqueous dissolution of poorly aqueous soluble benznidazole (BNZ) was improved by γ-CD complexation, but the potential impact of γ-CD complexation on the permeability of BNZ remained unexplored. Therefore, the aim of this work was to study the relationship between the aqueous solubility and apparent permeability of BNZ:γ-CD-based formulations, employing both non-cell-based parallel artificial membrane permeability assay (PAMPA) and cell-based (Caco-2 and mucus-producing Caco-2/HT29-MTX co-culture cell model) permeability models. The increase in BNZ aqueous solubility was directly proportional to the γ-CD concentration (from 185 µg mL-1 up to 320 µg mL-1 when 20 mM γ-CD was used in the formulation) and resulted in an increased apparent permeability, though in some cases a decrease was observed. Specifically, in the Caco-2/HT29-MTX cell model an increase in aqueous solubility did not always result in the increase of apparent permeability, with higher γ-CD concentrations leading to a decrease in apparent permeability Papp values down to 3.248 × 10-5 cm s-1 at γ-CD concentration of 30 mM (from 5.164 × 10-5 cm s-1 for 15 mM γ-CD) despite a continuing increase in solubility. Overall, the solubility enhancement of BNZ by γ-CD complexation had different effects on its permeability depending on the permeability model employed, and these effects should be taken into consideration when using solubility-enabling excipients.
Keywords: Apparent permeability; Aqueous solubility; Benznidazole; Non-cell based/cell-based models; Solubility-permeability relationship; γ-CD complexation.
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