Exploring the Impact of Surfactant Type and Digestion: Highly Digestible Surfactants Improve Oral Bioavailability of Nilotinib

Abstract

The scientific rationale for selection of the surfactant type during oral formulation development requires an in-depth understanding of the interplay between surfactant characteristics and biopharmaceutical factors. Currently, however, there is a lack of comprehensive knowledge of how surfactant properties, such as hydrophilic-lipophilic balance (HLB), digestibility, and fatty acid (FA) chain length, translate into <i>in vivo</i> performance. In the present study, the relationship between surfactant properties, <i>in vitro</i> characteristics, and <i>in vivo</i> bioavailability was systematically evaluated. An <i>in vitro</i> lipolysis model was used to study the digestibility of a variety of nonionic surfactants. Eight surfactants and one surfactant mixture were selected for further analysis using the model poorly water-soluble drug nilotinib. <i>In vitro</i> lipolysis of all nilotinib formulations was performed, followed by an <i>in vivo</i> pharmacokinetic evaluation in rats. The <i>in vitro</i> lipolysis studies showed that medium-chain FA-based surfactants were more readily digested compared to long-chain surfactants. The <i>in vivo</i> study demonstrated that a Tween 20 formulation significantly enhanced the absolute bioavailability of nilotinib up to 5.2-fold relative to an aqueous suspension. In general, surfactants that were highly digestible <i>in vitro</i> tended to display higher bioavailability of nilotinib <i>in vivo</i>. The bioavailability may additionally be related to the FA chain length of digestible surfactants with an improved exposure in the case of medium-chain FA-based surfactants. There was no apparent relationship between the HLB value of surfactants and the <i>in vivo</i> bioavailability of nilotinib. The impact of this study's findings suggests that when designing surfactant-based formulations to enhance oral bioavailability of the poorly water-soluble drug nilotinib, highly digestible, medium chain-based surfactants are preferred. Additionally, for low-permeability drugs such as nilotinib, which is subject to efflux by intestinal P-glycoprotein, the biopharmaceutical effects of surfactants merit further consideration.