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Human Hemicornea Model for Drug Transport Testing and Screening of Excipients

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Human Hemicornea Model for Drug Transport Testing and Screening of Excipients Human Hemicornea Model for Drug Transport Testing and Screening of Excipients Von der Fakultät für Lebenswissenschaften der Technischen Universität Carolo-Wilhelmina zu Braunschweig zur Erlangung des Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) genehmigte D i s s e r t a t i o n Von Gustavo Adolfo Guzman Castro aus Cartagena / Kolumbien 1. Referent: PD Dr. Stephan Reichl 2. Referentin: Professorin Dr. Christel Müller-Goymann eingereicht am: 13.12.2016 mündliche Prüfung (Disputation) am: 05.09.2017 Druckjahr 2017 3 Vorveröffentlichungen der Dissertation Teilergebnisse aus dieser Arbeit wurden mit Genehmigung der Fakultät für Lebenswissenschaften, vertreten durch den Mentor der Arbeit, in folgenden Beiträgen vorab veröffentlicht: Publikationen Hahne M, Zorn-Kruppa M, Guzman G, Brandner JM, Haltner-Ukomado E, Wätzig H, Reichl S (2012) Prevalidation of a human cornea construct as an alternative to animal corneas for in vitro drug absorption studies J Pharm Sci 101(8):2976-2988 Tagungsbeiträge Guzman G, Haltner-Ukomado E (2010) Evaluation of culture conditions of two human corneal cell lines employed for the establishment of a new corneal model to assay drug permeability. DPhG Jahrestagung 2011, 04.10 - 06.10.2011, Braunschweig, Germany (poster presentation) Guzman G, Reichl S, Bock U, Haltner-Ukomado E (2011) Cell culture model of human cornea for evaluation of transcorneal drug transport. 13. Bad Herrenalber Transporter- und Barriere-Tage, 30.05 - 01.06.2011, Bad Herrenalb, Germany (poster presentation) Guzman G, Reichl S, Haltner-Ukomado E (2012) Influence of the Ca2+, osmolarities and buffer solutions at different pH on the human cornea constructs during permeability assays. Controlled Release Society (CRS) Germany Local Chapter Meeting 2012, 29.03 - 30.03.2012, Würzburg, Germany (poster presentation) Guzman G, Reichl S, Bock U, Haltner-Ukomado E (2012) Intrinsic passive diffusion of molecular markers and active compounds through a serum-free Hemicornea model. 9th International Conference and Workshop on Biological Barriers – in vitro and in silico Tools for Drug Delivery and Nanosafety Research, 29.02 - 09.03.2012 Saarland University Saarbrücken, Germany (poster presentation) Guzman G, Reichl S, Bock U, Haltner-Ukomado E (2012) Optimization of human cornea constructs for a rapid characterization of pharmaceutical preparations, excipients and chemical compounds. Altern Lab Anim 2012, 40: A1-A80 presented at EUSAAT 2012 (14th Annual Congress of EUSAAT) and Linz 2012 (17th European Congress on Alternatives to Animal Testing), 04.09 - 06.9.2012, Linz/Austria (poster presentation) 4 Guzman G, Reichl S, Haltner-Ukomado E (2012) 3D Hemicornea constructs for in vitro drug absorption studies - prevalidation and characterization of the model. 14. Bad Herrenalber Transporter- und Barriere-Tage, 14.05 - 16.05.2012, Bad Herrenalb, Germany (oral presentation) Guzman G, Reichl S, Bock U, Haltner-Ukomado E (2012) Characterization of a human cornea constructs for a rapid screening of preservatives and evaluation of their effect during permeability assays to reduce animal testing. Altern Lab Anim 2012, 40: A1-A80 presented at EUSAAT 2012 (14th Annual Congress of EUSAAT) and Linz 2012 (17th European Congress on Alternatives to Animal Testing), 04.09 - 06.09.2012, Linz/Austria (oral presentation) 5 Este trabajo se lo dedico a mi familia. 6 A little more persistence, a little more effort, and what seemed hopeless failure may turn to glorious success. Elbert Hubbard Acknowledgments This doctoral thesis was carried out from October 2009 to September 2014 at Across Barriers GmbH under the academic supervision of: PD Dr. Stephan Reichl I would like to express my gratitude to PD Dr. Stephan Reichl for giving me the opportunity to work in his research group as external Ph.D. student. I am also grateful for his kind supervision, fruitful suggestions and comments. My sincere thanks are also to Prof. Dr. C. C. Müller-Goymann at the Institut für Pharmazeutische Technologie der Technische Universität Carolo-Wilhelmina zu Braunschweig for the second evaluation of this work. The German Federal Ministry of Education and Research (grant no. 0315504C) and Across Barriers GmbH is acknowledged for the financial support of this investigation. I am eternally grateful to God Almighty for giving me strength and perseverance to succeed during this time. Christina Bickelmann is thanked for the friendly, important contributions and technical support. Sabine Gröbner (Head of Quality Assurance by Across Barriers GmbH) is thanked by her scientific contributions as well as by verification of results. I am grateful to my work colleagues who helped me during this time. I am grateful to my family, who supported me even from the long distance. I am grateful to my father, mother who made possible that my dreams came true and to my brother for being my biggest reference. My special thanks to my wife for supporting me with her love. 3 Table of contents Table of contents 1. Introduction ............................................................................................................. 1 2. Literature review ..................................................................................................... 3 2.1. Anatomy of the eye ..................................................................................................... 3 2.1.1. Anterior compartment ............................................................................................... 3 2.1.2. Posterior compartment ............................................................................................. 3 2.2. Cornea ........................................................................................................................ 4 2.2.1. Corneal epithelium .................................................................................................... 4 2.2.2. Bowman's layer ........................................................................................................ 5 2.2.3. Stroma ...................................................................................................................... 5 2.2.4. Descemet’s membrane ............................................................................................. 6 2.2.5. Corneal endothelium ................................................................................................. 6 2.3. Cell culture models ..................................................................................................... 7 2.3.1. Primary cell cultures ................................................................................................. 7 2.3.2. Immortalized corneal cells ........................................................................................ 9 2.3.3. Organotypic cell culture models .............................................................................. 12 2.3.4. Three-dimensional corneal models ......................................................................... 13 2.4. Ocular drug absorption ............................................................................................. 16 2.4.1. Corneal absorption route ........................................................................................ 16 2.4.2. Non-corneal absorption route ................................................................................. 17 2.4.3. Formulation parameters .......................................................................................... 17 2.4.3.1 pH ........................................................................................................................... 17 2.4.3.2 Osmolality ............................................................................................................... 20 2.4.3.3 EDTA and calcium .................................................................................................. 20 2.4.4. Preservatives .......................................................................................................... 21 3. Materials and Methods ......................................................................................... 23 3.1. Materials ................................................................................................................... 23 3.1.1. Immortalized human cell lines ................................................................................. 23 3.1.2. Permeation markers and substances ...................................................................... 23 3.1.2.1 Permeation markers for the prevalidation of the HC construct ................................ 23 3.1.2.2 Ophthalmic drugs for the prevalidation of the HC construct .................................... 23 3.1.2.3 Other relevant substances ...................................................................................... 24 I Table of contents 3.1.3. Cell culture medium and equipment ........................................................................ 25 3.1.4. Preparation of solutions for cell cultures ................................................................. 25 3.1.5. Preparation of buffer solutions ................................................................................ 25 3.2. Methods .................................................................................................................... 26 3.2.1. Cultivation of corneal cells: HCE-T and HCK cell lines ............................................ 26 3.2.1.1 Cell culture method provided by TUBS for the HCE-T cell line ...............................
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