Exploring the impact of surfactant type and digestion: Highly digestible surfactants improve oral bioavailability of nilotinib

Koehl, Niklas J.; Holm, René; Kuentz, Martin; Jannin, Vincent; Griffin, Brendan T.

Access to this article is restricted until 12 months after publication by request of the publisher.. Restriction lift date: 2021-07-10

Exploring the impact of surfactant type and digestion: Highly digestible surfactants improve oral bioavailability of nilotinib

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dc.check.date	2021-07-10
dc.check.info	Access to this article is restricted until 12 months after publication by request of the publisher.	en
dc.contributor.author	Koehl, Niklas J.
dc.contributor.author	Holm, René
dc.contributor.author	Kuentz, Martin
dc.contributor.author	Jannin, Vincent
dc.contributor.author	Griffin, Brendan T.
dc.contributor.funder	Horizon 2020	en
dc.date.accessioned	2020-10-19T09:48:23Z
dc.date.available	2020-10-19T09:48:23Z
dc.date.issued	2020-07-10
dc.date.updated	2020-10-15T10:00:23Z
dc.description.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 in vivo performance. In the present study, the relationship between surfactant properties, in vitro characteristics, and in vivo bioavailability was systematically evaluated. An in vitro 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. In vitro lipolysis of all nilotinib formulations was performed, followed by an in vivo pharmacokinetic evaluation in rats. The in vitro lipolysis studies showed that medium-chain FA-based surfactants were more readily digested compared to long-chain surfactants. The in vivo 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 in vitro tended to display higher bioavailability of nilotinib in vivo. 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 in vivo 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.	en
dc.description.status	Peer reviewed	en
dc.description.version	Accepted Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Koehl, N. J., Holm, R., Kuentz, M., Jannin, V. and Griffin, B. T. (2020) 'Exploring the impact of surfactant type and digestion: Highly digestible surfactants improve oral bioavailability of nilotinib', Molecular Pharmaceutics, 17(9), pp. 3202-3213. doi: 10.1021/acs.molpharmaceut.0c00305	en
dc.identifier.doi	10.1021/acs.molpharmaceut.0c00305	en
dc.identifier.eissn	1543-8392
dc.identifier.endpage	3213	en
dc.identifier.issn	1543-8384
dc.identifier.issued	9	en
dc.identifier.journaltitle	Molecular Pharmaceutics	en
dc.identifier.startpage	3202	en
dc.identifier.uri	https://hdl.handle.net/10468/10661
dc.identifier.volume	17	en
dc.language.iso	en	en
dc.publisher	ACS Publications	en
dc.relation.project	info:eu-repo/grantAgreement/EC/H2020::MSCA-ITN-ETN/674909/EU/Pharmaceutical Education And Research with Regulatory Links: Innovative drug development strategies and regulatory tools tailored to facilitate earlier access to medicines/PEARRL	en
dc.rights	© 2020, American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in Molecular Pharmaceutics, after technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.0c00305	en
dc.subject	Digestibility	en
dc.subject	Lipolysis	en
dc.subject	Nilotinib	en
dc.subject	Poorly water-soluble drugs	en
dc.subject	Surfactants	en
dc.subject	Suspension	en
dc.title	Exploring the impact of surfactant type and digestion: Highly digestible surfactants improve oral bioavailability of nilotinib	en
dc.type	Article (peer-reviewed)	en