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Injectable Drug Delivery Systems for Steroids

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Injectable Drug Delivery Systems for Steroids Injectable drug delivery systems for steroids Dissertation zur Erlangung des akademischen Grades des Doktors der Naturwissenschaften (Dr. rer. nat.) eingereicht im Fachbereich Biologie, Chemie, Pharmazie der Freien Universität Berlin vorgelegt von Stefanie Nippe aus Lübben März 2014 1. Gutachter: Professor Dr. R. Bodmeier 2. Gutachter: Privatdozent Dr. H. Kranz Disputation am 16.10.2014 II To my family III Danksagung Die vorliegende Arbeit wurde unter der Leitung von Herrn Professor Dr. Roland Bodmeier vom Institut für Pharmazie der Freien Universität Berlin sowie in der Abteilung Early Development der Bayer HealthCare AG angefertigt und vor Ort von Herrn Dr. Sascha General betreut. Mein besonderer Dank gilt meinem Doktorvater Herrn Prof. Dr. Roland Bodmeier für seine fachliche Betreuung und sein entgegengebrachtes Vertrauen, während der Zeit meiner wissenschaftlichen Arbeit. Herrn Priv-doz. Dr. Heiko Kranz danke ich ganz herzlich für die Bereitschaft die vorliegende Arbeit zu begutachten. Meinem Mentor Herrn Dr. Sascha General danke ich für die Bereitstellung meines Promotionsthemas, die Initiierung interdisziplinärer Zusammenarbeiten sowie die überlassene Freiheit zur Gestaltung der Arbeit. Bei Herrn Dr. Stefan Bracht möchte ich mich für die Möglichkeit zur Anfertigung dieser Dissertation sowie die finanzielle Unterstützung bedanken. Der Abteilung Analytical Development Physical Chemistry danke ich für die Möglichkeit zur Durchführung der umfangreichen Partikelgrößenuntersuchungen. Mein besonderer Dank gilt Herrn Sven Wegner für die hervorragende Einführung in die Messmethoden und seine Hilfsbereitschaft. Dr. Oliver-Martin Fischer und Dr. Andrea Rotgeri sowie der früheren Abteilung Nonclinical Pharmacokinetics, insbesondere Dr. Cornelia Preuße, danke ich herzlich für die Durchführung der in vivo Studien. Besonders bedanken möchte ich mich bei Andreas Eckermann für die gute Zusammenarbeit und Unterstützung. Ein herzlicher Dank geht auch an die Abteilung Pharmaceutical Technology Packaging für die Unterstützung bei den Versuchen zur Applizierbarkeit. Insbesondere bedanken möchte ich mich bei Torsten Wollenberg für die Hilfe bei der Interpretation der Ergebnisse. Meinen Kollegen der ehemaligen Abteilungen Early Development and Drug Delivery Systems sowie Early Development danke ich für die stetige Unterstützung bei allen technische Fragestellungen. Besonders danken möchte ich Markus Hafke , Thomas Trill und Stephan Elze für die Einführung in zahlreiche Analytikmethoden sowie in die Polymerpartikelherstellung. Ganz herzlich danken möchte ich der Firma Intendis für die Möglichkeit zur Durchführung der Rheologiestudien sowie die Einführung in die komplexe Messmethodik. Der Abteilung Analytical Development Project Laboratory II danke ich für die Möglichkeit der Durchführung der HPLC/FD Untersuchungen. IV Meinen Kollegen der IVIVC Gruppe der Hexal AG danke ich für ihr Verständnis sowie für die Möglichkeit flexibel Zeit für die Fertigstellung der Arbeit zu bekommen. Besonders bedanken möchte ich mich bei Jörg Nink und Dr. Markus Wiedmann für die intensive und konstruktive Durchsicht der Arbeit. Den Mitdoktoranden der Bayer HealthCare AG danke für die schöne Zeit in Labor, den Mittagspausen und nach Feierabend. Ganz herzlich danke ich Dr. Annett Richter für das kritische Korrekturlesen der Arbeit sowie die vielen hilfreichen und aufmunternden Anmerkungen. Ein großes Dankeschön geht auch an Julia, Jens, Nicole, Martin, Lisa und Christine für die schönen, ablenkenden Feierabende, die vielen aufbauenden Worte und ihr Verständnis. Mein größter Dank gilt meinen Eltern und meiner Schwester für ihre unermüdliche Unterstützung in allen Lebenslagen. V Table of Contents Abbreviations ............................................................................................................................ VIII CHAPTER 1 Introduction............................................................................................................. 1 1.1 Injectable drug delivery systems ............................................................................................ 2 1.1.1 General aspects ............................................................................................................. 2 1.1.2 Conventional versus controlled-release injectable drug delivery systems ................... 4 1.2 S.c. and i.m. injectable drug delivery systems for lipophilic APIs ........................................ 5 1.2.1 Oil-based solutions as well as aqueous and oil-based microcrystal suspensions (MCSs) .......................................................................................................................... 5 1.2.2 Organogels ................................................................................................................. 10 1.2.3 Biodegradable polymeric particulate systems – Poly(n-butyl-2-cyanoacrylate) (PBCA) and poly(D,L-lactid-co-glycolide) (PLGA) particle .................................... 15 1.3 Combined drug delivery ...................................................................................................... 24 1.4 S.c. and i.m. injectable drug delivery systems for steroids .................................................. 24 1.4.1 General aspects ........................................................................................................... 24 1.4.2 Parenteral s.c. and i.m. injectable contraceptives ....................................................... 24 1.4.3 The steroidal model APIs DRSP, EE, and ZK28 ........................................................ 29 1.4.4 Summary ..................................................................................................................... 30 1.5 Objectives ............................................................................................................................. 31 References .................................................................................................................................. 32 CHAPTER 2 Parenteral oil-based drospirenone microcrystal suspensions - Evaluation of physicochemical stability and influence of stabilising agents ............................ 43 Abstract ...................................................................................................................................... 44 Graphical Abstract ...................................................................................................................... 45 1. Introduction ........................................................................................................................... 46 2. Materials and methods .......................................................................................................... 47 3. Results and discussion ........................................................................................................... 51 4. Conclusion ............................................................................................................................. 58 References .................................................................................................................................. 60 VI CHAPTER 3 Investigation of injectable drospirenone organogels with regard to their rheology and comparison to non-stabilized oil-based drospirenone suspensions ............................................................................................................. 62 Abstract ...................................................................................................................................... 63 1. Introduction ........................................................................................................................... 64 2. Materials and methods .......................................................................................................... 64 3. Results and discussion ........................................................................................................... 69 4. Conclusion ............................................................................................................................. 80 5. Supplement ............................................................................................................................. 81 References .................................................................................................................................. 82 CHAPTER 4 Evaluation of the in vitro release and pharmacokinetics of parenteral injectable formulations for steroids ..................................................................... 84 Abstract ...................................................................................................................................... 85 Graphical Abstract ...................................................................................................................... 86 1. Introduction ........................................................................................................................... 87 2. Materials and methods .......................................................................................................... 88 3. Results ................................................................................................................................... 94 4. Discussion ........................................................................................................................... 104 5. Conclusion ..........................................................................................................................
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