Lipidic implants for pharmaceutical proteins [Elektronische Ressource] : mechanisms of release and development of extruded devices / vorgelegt von Sandra Herrmann

Sandra Herrmann

Sujets

• Gesundheit

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2007
• Nombre de lectures: 19
• Langue: English
• Poids de l'ouvrage: 8 Mo

Extrait

Lipidic Implants for Pharmaceutical Proteins:
Mechanisms of Release and Development of
Extruded Devices



Dissertation



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





vorgelegt von
Sandra Herrmann
aus Bernburg


München 2007
Erklärung

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

Ehrenwörtliche Versicherung

Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet.




München, den 26.06.2007




……………………………………
Sandra Herrmann





Dissertation eingereicht am: 28.06.2007

1. Gutachter: Prof. Dr. G. Winter
2. Gutachter: Prof. Dr. J. Siepmann

Mündliche Prüfung am: 26.07.2007 ACHKNOWLEDGEMENTS

The present thesis was written at the Department of Pharmacy, Pharmaceutical
Technology and Biopharmaceutics at the Ludwig-Maximilians-University in Munich
under the supervision of Prof. Dr. Gerhard Winter.

First of all, I want to express my deepest appreciation to my supervisor Prof. Dr.
Gerhard Winter for the possibility to join his research group. Especially, I would like to
thank him for his professional guidance and his scientific support. I always felt
inspired and encouraged. Furthermore, I am very grateful to him for the great
opportunities to present my work at congresses all over the world and in particular I
want to thank him for making possible my research stay in Lille.

I am also deeply grateful to Prof. Dr. Jürgen Siepmann for the excellent cooperation
and the scientific input and advice concerning the mathematical analysis of the
release data. Moreover, I want to express my gratitude to Dr. Florence Siepmann for
performing the mathematical modelling. Thanks to the whole research team in Lille
for the warm welcome and the very pleasant stay. I really enjoyed this collaboration
and my time in Lille. For the financial support allowing this collaboration, I want
acknowledge the “Bayerisch-Französisches Hochschulzentrum (BFHZ)”.

Special thanks to Dr. Silke Mohl for introducing me to lipidic depot devices and for
the guidance over the first year. Above all, I would like to thank Silke for her
friendship. My thanks are extended to Dr. Friedrich Gruber for rendering every
assistance und support.

Many thanks to all the colleagues from the research group of Prof. Dr. Winter and
Prof. Dr. Frieß who shared the time in Munich with me for the cooperative and
convenient atmosphere. I especially like to thank Stefan Gottschalk, Andrea Hawe,
Tim Serno, Michael Wiggenhorn, Kathrin Mathis and Ahmed Youssef for all the
support and the numerous discussions.

Furthermore, I would like to acknowledge Christian Minke, from the Department of
Chemistry and Biochemistry, LMU Munich, Germany, for conducting the scanning electron microscopy measurements. Wolfgang Wünschheim, also at Department of
Chemistry and Biochemistry, is acknowledged for the practical introduction to wide
angle X-ray scattering.

Thanks are extended to Roche Diagnostics GmbH, Penzberg, Germany for the
donation of rh-interferon α-2a as well as to Sasol GmH, Witten, Germany for
providing various lipids.

Thanks are also extended to Prof. Dr. F. Bracher, Prof. Dr. F. Paintner, Prof. Dr. W.
Frieß, and Dr. C. Culmsee for serving as members of my thesis advisor committee.

I would also like to thank my parents, my sister Constanze, my brother Lutz, and my
grandparents for their constant support. Marek, thanks a lot for your love and the
encouragement you gave me over the last years.

Finally, I want to thank Dr. Friedrich Gruber and Tim Serno for the proof-reading of
this thesis. TABLE OF CONTENTS
Chapter I: General introduction............................................................................... 1
1. Overview on approved controlled release systems for pharmaceutical peptides .....4
2. Concerns associated with the use of PLA/PLGA as matrix formers ...........................6
2.1. Protein instability during manufacturing of PLA/PLGA microparticles .........................6
2.1.1. Protein loading – emulsion technique ......................................................................6
2.1.2. Protein loading – suspension technique...................................................................7
2.2. Protein instability during release from PLA/PLGA matrices.........................................9
3. Alternative matrix materials...........................................................................................11
3.1. Controlled release systems based on hydrogels .......................................................11
3.2. ms based on lipidic materials ..............................................11
3.2.1. Lipid microparticles.................................................................................................13
3.2.2. Subtypes of lipid based microparticles...................................................................14
3.2.3. Lipidic implants.......................................................................................................15
3.3. Lipids as matrix material – advantages and concerns ...............................................18
3.3.1. Possible advantages of lipidic matrices..................................................................18
3.3.2. Possible problems associated with the use of lipids ..............................................20
4. Implants – a closer look at alternative manufacturing possibilities ..........................23
4.1. Compression moulding ..............................................................................................23
4.2. Solvent casting...........................................................................................................23
4.3. Extrusion....................................................................................................................24
4.3.1. Ram extrusion ........................................................................................................24
4.3.2. Screw extruder .......................................................................................................26
4.4. Stability issues during implant manufacturing............................................................27
4.4.1. Elevated temperatures ...........................................................................................28
4.4.2. Elevated pressures.................................................................................................29
5. General mechanism of protein release and mathematical modelling .......................31
5.1. Protein release from non-degradable matrices..........................................................31
5.2. Drug release from degradable matrices.....................................................................33
5.3. Introduction to mathematical modelling34
5.3.1. Diffusion controlled systems...................................................................................35
5.3.2. Swelling controlled release.....................................................................................41
5.3.3. Erosion controlled release......................................................................................43

Chapter II: Aim of the thesis.................................................................................. 47 Chapter III: Materials and methods ....................................................................... 48
1. Materials ..........................................................................................................................48
1.1. Proteins48
1.1.2. Recombinant interferon α-2a (IFN- α) .....................................................................48
1.1.3. Hen egg white lysozyme ........................................................................................48
1.2. Lipids..........................................................................................................................48
1.2.1. Triglycerides...........................................................................................................48
1.2.2. Chemicals and reagents.........................................................................................50
2. Methods ...........................................................................................................................51
2.1. Preparation of lipidic controlled release devices........................................................51
2.1.1. Lyophilisation of IFN- α ...........................................................................................51
2.1.2. Manufacturing of implants by compression............................................................51
2.1.3. Manufacturing of implants by ram extrusion...........................................................52
2.1.4. Manufacturing of implants by twin screw extrusion................................................5