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1 Introduction…………………………………………………………………….…….…1 University of Huddersfield Repository Finch, Catherine Vanessa Chemical modification of skin mimic systems Original Citation Finch, Catherine Vanessa (2017) Chemical modification of skin mimic systems. Post-Doctoral thesis, The University of Huddersfield. This version is available at http://eprints.hud.ac.uk/id/eprint/34645/ The University Repository is a digital collection of the research output of the University, available on Open Access. Copyright and Moral Rights for the items on this site are retained by the individual author and/or other copyright owners. Users may access full items free of charge; copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational or not-for-profit purposes without prior permission or charge, provided: • The authors, title and full bibliographic details is credited in any copy; • A hyperlink and/or URL is included for the original metadata page; and • The content is not changed in any way. For more information, including our policy and submission procedure, please contact the Repository Team at: [email protected]. http://eprints.hud.ac.uk/ CHEMICAL MODIFICATION OF SKIN MIMIC SYSTEMS CATHERINE VANESSA FINCH A thesis submitted to the University of Huddersfield in partial fulfilment of the requirements for the degree of Doctor of Philosophy The University of Huddersfield December 2017 Copyright statement i. The author of this thesis (including any appendices and/or schedules to this thesis) owns any copyright in it (the “Copyright”) and s/he has given The University of Huddersfield the right to use such copyright for any administrative, promotional, educational and/or teaching purposes. ii. Copies of this thesis, either in full or in extracts, may be made only in accordance with the regulations of the University Library. Details of these regulations may be obtained from the Librarian. This page must form part of any such copies made. iii. The ownership of any patents, designs, trademarks and any and all other intellectual property rights except for the Copyright (the “Intellectual Property Rights”) and any reproductions of copyright works, for example graphs and tables (“Reproductions”), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property Rights and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property Rights and/or Reproductions. I Abstract This thesis investigates the effect of various physical and chemical surface modification methods on the permeation of topically applied pharmaceutical compounds through poly(dimethylsiloxane) (PDMS), a polymer frequently employed as a model barrier in in vitro skin permeation studies. Such studies are essential for safety, risk assessment, and quality control purposes, in addition to assisting in the design and development of efficacious topically applied medicines. The commercial availability, legal status, ease of handling, and the reproducibility of the permeation data associated with polymeric skin mimics renders them an attractive alternative to biological tissue. However, over-predictions of percutaneous absorption observed following the use of such membranes are a significant disadvantage when attempting to obtain quantitative toxicological data. Accordingly, the aims of the work presented in this thesis were to both reduce the permeability of PDMS to pharmaceutical compounds, and to increase correlation between permeation data obtained using the synthetic substitute and data obtained similarly using suitable biological tissue. Primarily, the potential of an air plasma pre-treatment to produce a lamellae-type structure in PDMS, endeavouring to more accurately model the architectural, physical, and chemical properties of the human stratum corneum, was investigated. Reductions in the permeability coefficient of up to 54.4 % were observed, rendering the modified system promising. Correlation analysis revealed an increase in correlation between the data collected using the modified synthetic substitute (R2 = 0.86) and a self- collated library of literature-derived epidermal tissue permeability data, relating to eighteen compounds and spanning a range of typical penetrants, compared to similar analysis using data obtained using the native substitute ( R2 = 0.75), suggesting an increase in the predictive capability. It was hypothesised that an N2 plasma treatment may provide suitable surface functional groups on the PDMS substrate, namely amine groups, for the covalent attachment of biomolecules via an N,N'- dicylohexylcarbodiimide (DCC) coupling reaction, enabling the production of a skin mimic displaying enhanced biorelevance. Therefore, the effect of an N2 plasma pre-treatment on the permeation of a subset of the eighteen compounds investigated. It was found that the N2 plasma pre-treatment was advantageous in terms of offering a greater reduction in permeability, since longer treatment times could be employed i.e. reductions of up to 61.8 % were observed. However, significant surface oxidation was still observed, with only a marginal increase in nitrogen containing functionalities compared with the air plasma analogue i.e. 0.31 %. Furthermore, the treatment did not offer any additional increase in correlation between epidermal-derived data than previously observed. Further chemical methods of biomolecule attachment were pursued for use in the development of a lipid- proteinaceous bilayer model, initiated in both cases by surface amination using an alkoxysilane. This was followed by a DCC coupling to an amino acid in the former approach, and use of a glutaraldehyde II linker molecule to attach the same amino acid, namely lysine, in the latter approach. In either case, no further reductions in the permeation of the pharmaceutical compounds tested were observed, with respect to that through plasma treated PDMS. In summary, the air plasma treatment of PDMS was found to be a promising approach to simultaneously reducing the permeability of a silicone skin mimic and increasing correlation with data obtained in similar studies employing biological tissue. Further, the covalent coupling of biomolecules to the surface of PDMS following surface amine group generation, via both plasma and wet chemical methods, appeared not to compromise the integrity the PDMS membranes relating to such applications, rendering the techniques compatible with the production of biorelevant semi-synthetic skin mimics. III Dedication This thesis is dedicated to my Mum, Dad, and Lorna. Everything that I have achieved is because of you. IV Acknowledgements I would firstly like to thank my supervisors, Dr Laura Waters and Dr Karl Hemming, for all of their help and guidance throughout my PhD, and without whom completion would not have been possible. I would further like to thank Dr Laura Waters for her unconditional support, for being an inspirational woman in science, and for the multitude of opportunities that you have provided me. I would like to thank every member the research group for sharing their wealth of knowledge, including the fantastic undergraduate students I have had the opportunity to work with; Faiza and Maria, you made my second year of study not only productive, but enjoyable. I would also like to thank the technical staff in the School of Applied Sciences for being an endless source of knowledge and assistance. I would personally like to thank Dr Richard Hughes for being a fantastic laboratory neighbour, and for not requesting to be relocated. I would also like to thank Dr Deborah Hammond at the Kroto Research Institute for allowing me access to a plethora of resources to support my professional development. To all my friends in the organic and inorganic chemistry research groups, thank you for always being insightful, kind, and hilarious. Finally, to my best friends, Scarlett and James, I owe you everything for your unfaltering love and support, and for making the last three years a truly enjoyable time to reflect upon. I will not list everything that you have done for me here, instead I promise to spend the next ten years returning all the favours, hopefully closer to the equator. V Table of Contents Chapter 1 Introduction…………………………………………………………………….…….…1 1.1 Topical and Transdermal Drug Delivery……………………………………………….…….1 1.2 The Structure of Human Skin……………………………………………………….……….1 1.3 Surpassing the Barrier………………………………………………………………………..4 1.4 In Vitro Determination of Percutaneous Absorption………………………………….……...5 1.5 Properties of the Permeant……………………………………………………………….….10 1.6 Modelling Transdermal Absorption………………………………………………………...13 1.6.1 Human Tissue………………………………………………………………………....13 1.6.2 Animal Tissue………………………………………………………………………...14 1.6.3 Alternative Models…………………………………………...………………….........16 1.6.3.1 Cell Culture Models…………………………………………………………….17 1.6.3.2 Quantitative Structure - Permeability Relationships…………...……….……....17 1.6.3.3 Parallel Artificial Membrane Permeability Assay (PAMPA)……...…….….….20 1.6.3.4 Strat-M®…………………………………………………………………….….21 1.6.3.5 Poly(dimethylsiloxane)…………………………………………………………23 1.7 Modification of Poly(dimethylsiloxane)……………………………………………………28 1.7.1 Properties of Poly(dimethylsiloxane)……………………………………….………...28 1.7.2 Dynamic Modification………………………………………………………………..30 1.7.3 Surface Oxidation……………………………………………………….…………….31 1.7.4 Covalent Attachment……………………………………………………….………….33
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