Scale-up of liposome manufacturing [Elektronische Ressource] : combining high pressure liposome extrusion with drying technologies / Michael Wiggenhorn

Michael Wiggenhorn

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• Gesundheit

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2007
• Nombre de lectures: 36
• Langue: English
• Poids de l'ouvrage: 9 Mo

Extrait

Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München




Scale-Up of Liposome Manufacturing:
Combining High Pressure Liposome Extrusion
with Drying Technologies








Michael Wiggenhorn
aus Kranenburg


Juli 2007






































Erklärung

Diese Dissertation wurde im Sinne von § 13 Abs. 3 bzw. 4 der Promotionsordnung vom
29. Januar 1998 von Herrn Prof. Dr. Gerhard Winter betreut.





Ehrenwörtliche Versicherung

Diese Dissertation wurde selbstständig, ohne unerlaubte Hilfe erarbeitet.


München, am 05. Juli 2007









(Michael Wigenhorn)






Dissertation eingereicht am 05. Juli 2007
1. Gutachter: Prof. Dr. Gerhard Winter
2. Gutach Wolfgang Frieß
Mündliche Prüfung am 30. Juli 2007 Acknowledgements

The presented thesis has been investigated and written at the Department of Pharmacy,
Pharmaceutical Technology and Biopharmaceutics at the Ludwig-Maximilians-University
(LMU) in Munich (Bavaria) under the supervision of Prof. Dr. Gerhard Winter.

First of all, I want to express my greatest gratitude to Prof. Dr. Gerhard Winter, who
welcomed me with an open mind and provided me the opportunity to further strengthen my
research education in his working group. I am very thankful for his outstanding professional
and enthusiastic guidance and for giving me the freedom required for the success of this
scientific project. Through all phases I always had the feeling to be in good hands with an
overall encouragement. Thanks for this!

Prof. Dr. Wolfgang Frieß, I not only want to say thank you for taking over the co-referee, but
particularly for being the second scientific and personal advisor in the last years. The
outstanding collaboration between him and Prof. Dr. Winter made practical-working and
sharing of ideas to a tremendous resource of knowledge for me. I am very pleased about
being part of it.

Many thanks go to Prof. Dr. Geoffrey Lee, form the Department of Pharmaceutical
Technology at the Friedrich-Alexander University in Erlangen-Nuernberg, at first for the
possibility to use his technical equipment for several times, and also for joining my defence
and being part of the oral examination commission.

I deeply appreciate the MediGene AG (Martinsried) for the initiation of this interesting
project and the friendly financial support over the last 2 ½ year. Especially, I would like to
thank Dr. Heinrich Haas for the supervision of this project from MediGene side and for the
many fruitful discussions, numerous inspirations and the freedom to operate in many
technical fields. Also, I like to say gratefully thank you to Dr. Klaus Drexler for managing the
whole project from the real beginning. Thank you to Dr. Andreas Geissler for the successful
collaboration in the patent field.
The other colleagues from MediGene AG in Martinsried and in Neuried, a special
acknowledgement belongs to you all, for the assistance in the production and many
analytical considerations. It was a pleasure for me to work with you in this straightforward
collaboration, which simplified practical things. All of you should be mentioned Armin Bareth,
Dr. Brita Schulze, Christina Fingerhut, Dr. Frank Zettl, Dr. Gabriela Kosuthova, Dr. Harald
Meissner, Jürgen Seifert, Melanie Reiter, Dr. Michael Rankl, Ursula Fattler, Tawanda
Muzorewa, Dr. Georg Belke-Louis and all the colleagues who contributed directly or indirectly
to this thesis. Part of this work was done at Delft University of Technology (The Netherlands) at the
Process and Energy Department of Prof. Dr. P. J. Jansens and Prof. Dr. G. J. Witkamp. Thank
you very much for providing the possibility and the access to the equipment.
Without my friends from FeyeCon B.V. (Weesp, The Netherlands) the supercritical part of
the work would not have been feasible at all. Therefore, my deep thankfulness belongs to
you all. Especially to Hubert Pellikaan, who was directly dedicated form the very beginning
and Dr. Bas Vermeulen for the assistance at the apparatus. Dr. Andréanne Bouchard for the
interesting discussions and the “Separex” considerations. Dr. Vanesa Fernández Cid and
Dr. Gerard Hofland for discussions and the careful correction, as well as Dr. Geert Woerlee
who supported the project.

From the Department of Pharmaceutical Chemistry at the LMU in Munich, I would like to
thank Dr. Holger Lerche for the collaboration with the installation of the Static Headspace
Gas Chromatography.

Also I want to appreciate the friendship over the last years to my former lab-colleagues
Patricia Plath and Ahmed Youssef and close to the next door Jan Zillies and Klaus Zwiorek.
Many thanks go to all other (former-) colleagues and friends from the research groups of
Prof. Winter and Prof. Frieß. Especially, to Cornelius, Fritz, Gabi, Dr. Gerhard Simon, Kathrin,
Matthias, Richard, Sandra, Silke, Stefan, Tim and Roland. For their quick proof reading I
want to thank Lars Schiefelbein and Frank Schaubhut. Two students should be mentioned as
well Andrea and Sarah you did a good job.

I would like to thank all my friends at home, in the Netherlands and here in Munich for their
friendship and encouragement during the last years. Achim, Christiane, Christoph, Gerrit,
Guido, Graham, Hildegard, Jens, Jörg, Jürgen, Kathrin, Ludger, Peter, Petra, Prashant,
Roman, Sascha, Simon, Volker, Wouter, and all other.

Finally, and most important I want to appreciate my family and especially my parents for
their dedicative encouragement over the last 10 years of studying. My brother Thomas with
Kerstin, my sister Elisabeth with Ludger (Simon, Johannes and let´s see) and finally my
sister Maria, thank you for being a part of me.

Andrea, you and your love are the best things I will take from Munich. Thanks for being
around me and the help for my work, especially in the last month with proof-reading of the
thesis.
















































































For my parents / Für meine Eltern TABLE OF CONTENTS

Chapter 1
Introduction and Objective of the Thesis

1. INTRODUCTION.................................................................................................2
2. LIPOSOMAL PREPARATION ..................................................................................3
3. LIPOSOMAL FORMULATIONS CONTAINING PACLITAXEL ..........................................5
4. STABILIZING OF LIPOSOMAL FORMULATIO ...........................................................6
5. OBJECTIVE OF THE THESIS .................................................................................8
6. REFERENCES .....................................................................................................12


Chapter 2
Optimizing the Freeze-Drying Process of Liposomal Paclitaxel Formulation

1. INTRODUCTION...............................................................................................16
2. MATERIAL AND METHODS .................................................................................18
2.1 Liposome Preparation........................................................................................18
2.2 Freeze-Drying Method.......................................................................................18
2.3 Lipid Analysis...................................................................................................19
2.4 Paclitaxel Analysis............................................................................................19
2.5 Residual Moisture.............................................................................................19
2.6 Differential Scanning Calorimetry Analysis............................................................19
2.7 Analysis of Cake Morphology..............................................................................20
2.8 Size Measurements of Liposomes........................................................................20
2.9 Residual Ethanol Content...................................................................................20
3. RESULTS AND DISCUSSION21
3.1 Freeze-Drying Method with Modified Cake Geometry.......................................