Kuentz, Martin

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Martin
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Kuentz, Martin

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2019 - 20202
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Autor:in: Koehl, Niklas × Thema: nilotinib ×

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  • Vorschaubild nicht verfügbar
    Publikation
    Exploring the Impact of Surfactant Type and Digestion: Highly Digestible Surfactants Improve Oral Bioavailability of Nilotinib
    (American Chemical Society, 08.09.2020) Koehl, Niklas; Kuentz, Martin [in: Molecular Pharmaceutics]
    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.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    New Insights into Using Lipid Based Suspensions for 'Brick Dust' Molecules: Case Study of Nilotinib
    (Springer, 22.02.2019) Koehl, Niklas; Kuentz, Martin [in: Pharmaceutical Research]
    PurposeLipid suspensions have been shown to be a suitablebio-enabling formulation approach for highly lipophilic or‘grease ball’drug molecules, but studies on‘brick dust’drugsare lacking. This study explored the utility of lipid suspensionsfor enhancing oral bioavailability of the rather hydrophobicdrug nilotinibin vivoin rats.MethodsFour lipid suspensions were developed containinglong chain triglycerides, medium chain triglyceride, longchain monoglycerides and medium chain monoglyceridesandin vivobioavailability was compared to an aqueous suspen-sion. Additionally,in vitrolipolysis and wettability tests wereconducted.ResultsNilotinib lipid suspensions did not show a bioavail-ability increase compared to an aqueous suspension. The bio-availability was lower for triglyceride suspensions, relative toboth monoglyceride and an aqueous suspension. The longchain monoglyceride displayed a significantly higher bioavail-ability relative to triglycerides.In vitrolipolysis results suggestedentrapment of nilotinib crystals within poorly dispersible tri-glycerides, leading to slower nilotinib release and absorption.This was further supported by higher wettability of nilotinibby lipids.ConclusionMonoglycerides improved oral bioavailability ofnilotinib in rats, relative to triglycerides. For‘brick dust’drugsformulated as lipid suspensions, poorly dispersible formula-tions may delay the release of drug crystals from the formula-tion leading to reduced absorption.
    01A - Beitrag in wissenschaftlicher Zeitschrift