Comb polymers for biomedical application obtained by grafting biodegradable polyester chains onto hydrophilic polyol backbones [Elektronische Ressource] / vorgelegt von Armin Breitenbach

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Comb polymers for biomedical applicationobtained by grafting biodegradable polyester chainsonto hydrophilic polyol backbonesDissertationzurErlangung des Doktorgradesder Naturwissenschaften(Dr. rer. nat.)demFachbereich Pharmazieder Philipps-Universität Marburgvorgelegt vonArmin Breitenbachaus Siegen/Nordrhein-WestfalenMarburg/Lahn 2000Vom Fachbereich Pharmazieder Philipps-Universität Marburg als Dissertation am22. März 2000 angenommen.Erstgutachter Prof. Dr. T. KisselZweitgutachter Prof. Dr. R. MatuschDrittgutachter Prof. Dr. H. JungingerTag der mündlichen Prüfung am 05. April 2000meiner Mutterin tiefer Zuneigung,Liebe und Dankbarkeit2AcknowledgementsThis work was created at suggestion and supervision ofProf. Dr. Thomas Kisselat the Department of Pharmaceutics and Biopharmacy of the Philipps-Universityof Marburg. I wish to express my appreciation and sincere gratitude for thecontinuous support, guidance and encouragement he has given me throughoutthis work.I cannot refrain from especially thanking my colleagues Dr. Tobias Jung and Dr.Walter Kamm for their friendship, inspiring discussions and stimulatingcooperation, leading to a most pleasant postgraduate time, in particular in the'Turmlabor'. I wish to thank Prof. Dr. E. Kaiserling for his support andcooperation.

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Comb polymers for biomedical application
obtained by grafting biodegradable polyester chains
onto hydrophilic polyol backbones
Dissertation
zur
Erlangung des Doktorgrades
der Naturwissenschaften
(Dr. rer. nat.)
dem
Fachbereich Pharmazie
der Philipps-Universität Marburg
vorgelegt von
Armin Breitenbach
aus Siegen/Nordrhein-Westfalen
Marburg/Lahn 2000Vom Fachbereich Pharmazie
der Philipps-Universität Marburg als Dissertation am
22. März 2000 angenommen.
Erstgutachter Prof. Dr. T. Kissel
Zweitgutachter Prof. Dr. R. Matusch
Drittgutachter Prof. Dr. H. Junginger
Tag der mündlichen Prüfung am 05. April 2000meiner Mutter
in tiefer Zuneigung,
Liebe und Dankbarkeit2
Acknowledgements
This work was created at suggestion and supervision of
Prof. Dr. Thomas Kissel
at the Department of Pharmaceutics and Biopharmacy of the Philipps-University
of Marburg. I wish to express my appreciation and sincere gratitude for the
continuous support, guidance and encouragement he has given me throughout
this work.
I cannot refrain from especially thanking my colleagues Dr. Tobias Jung and Dr.
Walter Kamm for their friendship, inspiring discussions and stimulating
cooperation, leading to a most pleasant postgraduate time, in particular in the
'Turmlabor'. I wish to thank Prof. Dr. E. Kaiserling for his support and
cooperation.
Further, I like to thank all colleagues and staff members, University departments
and companies, namely former Hoechst AG, Schwarz Pharma AG, Boehringer
Mannheim, Chiron-Behring and Aventis.
Financial support of the German Research Counsil (Deutsche Forschungs-
gemeinschaft) and Schwarz Pharma AG is gratefully acknowledged.3
Contents
List of publications 7
List of presentations 9
Chapter 1
1.1 Background and Scope 12
1.2 Summary 17
1.3 Einleitung und Problemstellung 22
1.4 Zusammenfassung 28
1.5 References 34
Chapter 2: Biodegradable comb polyesters: part I: Synthesis,
characterization and structural analysis of poly(lactic acid) and
poly(lactic-co-glycolic acid) grafted onto water-soluble
poly(vinyl alcohol) as backbone
2.1 Abstract 37
2.2 Introduction 38
2.3 Experimental Section 40
2.4 Results and Discussion 45
2.5 Conclusions 61
2.6 Acknowledgements 62
2.7 References 624
Chapter 3: Branched biodegradable polyesters for parenteral drug
delivery systems
3.1 Abstract 64
3.2 Introduction 65
3.3 Materials and Methods 67
3.4 Results and Discussion 69
3.5 Conclusions 82
3.6 References 82
Chapter 4: Biodegradable comb polyesters part II: Erosion and release
properties of poly(vinyl alcohol)-g-poly(lactic-co-glycolic acid)
4.1 Abstract 85
4.2 Introduction 86
4.3 Experimental 88
4.4 Results and Discussion 91
4.5 Conclusions 112
4.6 Acknowledgements 113
4.7 References 113
Chapter 5: Biodegradable comb polyesters, part III: Protein release from
microspheres prepared from poly(vinyl alcohol)-graft-
poly(D,L-lactic-co-glycolic acid)
5.1 Abstract 115
5.2 Introduction 116
5.3 Materials and Methods 1185
5.4 Results and Discussion 125
5.5 Conclusions 142
5.6 References 143
Chapter 6: Biodegradable semi-crystalline comb polyesters influence the
microsphere production by means of a supercritical fluid
extraction technique (ASES)
6.1 Abstract 145
6.2 Introduction 146
6.3 Materials and Methods 148
6.4 Results and Discussion 152
6.5 Conclusions 167
6.6 Acknowledgements 167
6.7 References 167
Chapter 7: Biodegradable comb polyesters containing polyelectrolyte
backbones: A feasible carrier for the preparation of
nanoparticles with defined surface structure and bioadhesive
properties
7.1 Abstract 171
7.2 Introduction 172
7.3 Materials and Methods 174
7.4 Results and Discussion 180
7.5 Conclusions 200
7.6 References 2016
7.7 Outlook: Biodegradation 204
Chapter 8: Self-assembling colloidal carriers for drug delivery: complexes
of proteins with water-soluble polyesters obtained by brush-like
grafting poly(lactic-co-glycolic acid) onto polyelectrolyte
backbones
8.1 Abstract 207
8.2 Introduction 208
8.3 Materials and Methods 209
8.4 Results and Discussion 217
8.5 Conclusions 239
8.6 Acknowledgements 239
8.7 References 240
List of abbreviations 243
Curriculum Vitae 2467
List of Publications
• A. Breitenbach, T. Jung, W. Kamm, T. Kissel, Neue pharmazeutische
Zubereitung, enthaltend kolloidale Polymer-Wirkstoff-Assoziate, insbe-
sondere auch für mucosale Wirkstoffverabreichung, German Patent
Application AZ 19839515.9 (1998).
• A. Breitenbach and T. Kissel, Biodegradable comb polyesters: part I
Synthesis, characterization and structural analysis of poly(lactide) and
poly(lactide-co-glycolide) grafted onto watersoluble poly(vinyl alcohol) as
backbone, Polymer 39(14) (1998) 3261-3271.
• A. Breitenbach, Y. Li and T. Kissel, Branched biodegradable polyesters for
parenteral drug delivery systems, J. Controlled Release 64 (2000) 167-178.
• A. Breitenbach, K. F. Pistel and T. Kissel, Biodegradable comb polyesters
part II: Erosion and release properties of poly(vinyl alcohol)-g-poly(lactic-
co-glycolic acid), Polymer 41(13) (2000) 4781-4792.
• K. F. Pistel, A. Breitenbach, R. Zange and T. Kissel, Biodegradable comb
polyesters part III: Protein release from microspheres prepared from
poly(vinyl alcohol)-graft-poly(D,L-lactic-co-glycolic acid), J. Micro-
encapsulation (2000) submitted.
• A. Breitenbach, D. Mohr and T. Kissel, Biodegradable semi-crystalline comb
polyesters influence the microsphere production by means of a supercritical
fluid extraction technique (ASES), J. Controlled Release 63 (2000) 53-68.8
• A. Breitenbach, T. Jung, W. Kamm and T. Kissel, Biodegradable comb
polyesters containing polyelectrolyte backbones: A novel polymeric
approach for the preparation of nanoparticles with defined surface structure
and bioadhesive properties, Biomaterials (1999) submitted.
• W. Kamm, T. Jung, A. Breitenbach, U. Vogel, J.C. Xiao, E. Kaiserling and
T. Kissel, Novel negatively charged nanoparticles for oral protein delivery:
Intestinal bioadhesion, Uptake and Cytotoxicity, BBA (2000) submitted.
• T. Jung, A. Breitenbach and T. Kissel, Sulfobutylated poly(vinyl alcohol)-
graft-poly(lactide-co-glycolide) facilitate the preparation of small negatively
charged biodegradable nanospheres for protein delivery, J. Controlled
Release (2000) accepted.
• T. Jung, W. Kamm, A. Breitenbach, J. C. Xiao, E. Kaiserling and T. Kissel,
Biodegradable nanoparticles for oral delivery of peptides: Is there a role for
polymers to affect mucosal uptake?, Eur. J. Pharm. Biopharm. 50 (2000)
accepted.
• A. Breitenbach, T. Jung, W. Kamm and T.Kissel, Self-assembling colloidal
carriers for drug delivery: complexes of proteins with water-soluble olyesters
obtained by brush-like grafting poly(lactic-co-glycolic acid) onto
polyelectrolyte backbones, Biomaterials (2000) submitted.