Reprinted from: Publication of this reprint collection is supported by paid advertising SLAS Technology 27 (2022) 161–171 Contents lists available at ScienceDirect SLAS Technology journal homepage: www.elsevier.com/locate/slast Comparison Between Franz Diffusion Cell and a novel Micro-physiological System for In Vitro Penetration Assay Using Different Skin Models Ilaria Pulsoni a,# , Markus Lubda b,# , Maurizio Aiello a,c , Arianna Fedi c , Monica Marzagalli a , Joerg von Hagen b , Silvia Scaglione a,c,∗ a React4life Srl, Genoa, Italy bMerck KGaA, Darmstadt, Germany c CNR –National Research Council of Italy, Genova, Italy a r t i c l e i n f o Keywords: Drug delivery caffeine penetration in vitro diffusion system skin model a b s t r a c t In vitro diffusive models are an important tool to screen the penetration ability of active ingredients in various formulations. A reliable assessment of skin penetration enhancing properties, mechanism of action of carrier systems, and an estimation of a bioavailability are essential for transdermal delivery. Given the importance of testing the penetration kinetics of different compounds across the skin barrier, several in vitro models have been developedThe aim of this study was to compare the Franz Diffusion Cell (FDC) with a novel fluid-dynamic platform (MIVO) by evaluating penetration ability of caffeine, a widely used reference substance, and LIP1, a testing molecule having the same molecular weight but a different lipophilicity in the two diffusion chamber systems. A 0.7% caffeine or LIP1 formulation in either water or propylene glycol (PG) containing oleic acid (OA) was topically applied on the Strat-M® membrane or pig ear skin, according to the infinite-dose experimental condition (780 ul/cm2 ). The profile of the penetration kinetics was determined by quantify the amount of molecule absorbed at different time-points (1, 2, 4, 6, 8 hours), by means of HPLC analysis. Both diffusive systems show a similar trend for caffeine and LIP1 penetration kinetics. The Strat-M® skin model shows a lower barrier function than the pig skin biopsies, whereby the PGOA vehicle exhibits a higher penetration, enhancing the effect for both diffusive chambers and skin surrogates. Most interestingly, MIVO diffusive system better predicts the lipophilic molecules (i.e. LIP1) permeation through highly physiological fluid flows resembled below the skin models. Introduction The skin tissue is an effective barrier, representing a fundamental interface between the human body and the external environment. Based on its chemical-physical features, it forms a protective layer against harmful environmental influences such as ultra-violet light, microorganisms, pollutants and environmental toxins, pesticides, or other chemical drugs. Moreover, skin regulates temperature and homeostasis of the body, particularly by limiting the loss of water [1]. Dermal absorption assays are routinely adopted to predict risks from skin exposure to chemicals, but also to demonstrate benefits after topic application of cosmetics, medical device or therapeutic active ingredient. In this context, the Organization for Economic Co-operation and Development (OECD) and the United States Environmental Protection Agency have produced guidelines for the in vitro and in vivo assessment of percutaneous absorption [2], that establishes the passage of ∗ Corresponding author: Silvia Scaglione, React4life Srl, Via Greto di Cornigliano 6/R, 16152 Genoa (Italy) E-mail address: s.scaglione@react4life.com (S. Scaglione). # These authors contributed equally to this work. compounds across the skin. This process is basically divided in three steps [3]: i) penetration, which consists of the entry of the chemical compound into the stratum corneum, build up by an intracellular lipid matrix of mainly ceramides, cholesterol and free fatty acids [4,5]; ii), permeation , namely the gradual passage of the substance through the subsequent layers, which are both functionally and anatomically distinct from the stratum corneum; iii) the uptake t into lymphatic and blood vessels [5-8]. Interestingly, according to the skin absorption outcome, the classification of these testing compounds may range from cosmetics to “medical devices made of substances”, that need to be absorbed in order to achieve their intended action [9-11]. Therefore, there is increasing demand for reliable and reproducible in vitro and ex vivo skin absorption methods that accelerate the chemicals testing and the measurement of their absorption percentage. In the last two decades, the European Union and national legislations have stipulated that animal experiments should be avoided whenever scienhttps://doi.org/10.1016/j.slast.2021.12.006 2472-6303/© 2021 The Author(s). Published by Elsevier Inc. on behalf of Society for Laboratory Automation and Screening. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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