Polymeric micelles and dendritic amphiphiles for the anticancer drug sagopilone [Elektronische Ressource] : solubilization, formulation development, and toxicity assessment / vorgelegt von Annett Richter

Sgsij

Sujets

• Biologie

Informations

• Publié par: philipps-universitat_marburg
• Publié le: 01 janvier 2010
• Nombre de lectures: 14
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Polymeric Micelles and Dendritic Amphiphiles
for the Anticancer Drug Sagopilone:
Solubilization, Formulation Development,
and Toxicity Assessment






Dissertation
zur
Erlangung des Doktorgrades
der Naturwissenschaften
(Dr. rer. nat.)




dem Fachbereich Pharmazie
der Philipps-Universität Marburg
vorgelegt von


Annett Richter

aus Leisnig





Marburg/Lahn 2010







































Vom Fachbereich Pharmazie der Philipps-Universität Marburg als Dissertation
am 18.05.2010 angenommen.


Erstgutachter: Prof. Dr. Thomas Kissel

Zweitgutachter: Prof. Dr. Rainer Haag


Tag der mündlichen Prüfung am 19.05.2010
II
Die vorliegende Arbeit entstand unter der Leitung von

Herrn Prof. Dr. Thomas Kissel

am Institut für Pharmazeutische Technologie und Biopharmazie
der Philipps-Universität Marburg

und in enger Zusammenarbeit mit der Pharmazeutischen Technologie
der Bayer Schering Pharma AG Berlin.
III








Selbstzufriedenheit ist der Sargdeckel jeden Fortschritts.
Philip Rosenthal











Für meine Familie
in Liebe und Dankbarkeit

IV Table of Contents
Chapter 1
Introduction ......................................................................................................... 1
1. Solubilization with regard to anticancer drugs for parenteral application ..................... 2
2. Limitations of current cancer therapy .......................................................................... 12
3. Novel formulations to address limitations ................................................................... 17
4. Objectives of this work ................................................................................................ 26
References ............................................................................................................................ 28
Chapter 2
Solubilization of Sagopilone, a poorly water-soluble anticancer drug, using
polymeric micelles for parenteral delivery ..................................................... 33
Abstract ................................................................................................................................ 34
1. Introduction.................................................................................................................. 35
2. Materials and methods.................................................................................................38
3. Results.......................................................................................................................... 43
4. Discussion.................................................................................................................... 54
5. Conclusion.. 61
References....... 62
Chapter 3
Polymeric micelles for parenteral delivery of Sagopilone: Physicochemical
characterization, novel formulation approaches and their toxicity
assessment in vitro as well as in vivo ................................................................ 66
Abstract ................................................................................................................................ 67
1. Introduction.................................................................................................................. 68
2. Materials and methods.................................................................................................72
3. Results and discussion..................................................................................................77
4. Conclusion.................................................................................................................... 93
References ............................................................................................................................ 94
V
Chapter 4
Non-ionic dendritic glycerol-based amphiphiles: Novel excipients for the
solubilization of poorly water-soluble anticancer drug Sagopilone ............. 97
Abstract ................................................................................................................................ 98
1. Introduction.................................................................................................................. 99
2. Materials and methods...............................................................................................103
3. Results and discussion................................................................................................108
4. Conclusion.................................................................................................................. 117
References .......................................................................................................................... 118
Chapter 5
Summary and Perspectives/ Zusammenfassung und Ausblick ..................120
Summary ............................................................................................................................ 121
Perspectives........................................................................................................................ 123
Zusammenfassung.............................................................................................................. 125
Ausblick ............................................................................................................................. 128
Appendices .......................................................................................................130
Abbreviations ..................................................................................................................... 131
List of Publications............................................................................................................. 133
Curriculum Vitae................................................................................................................ 135
Danksagung........................................................................................................................ 136

VI


CHAPTER 1


INTRODUCTION
1 Chapter 1
1. Solubilization with regard to anticancer drugs for parenteral application
1.1 Solubilization – some remarks
Successful drug development is a complex process from discovery and evaluation through
pharmaceutical and clinical development to production and commercialization. Current drug
discovery of new active pharmaceutical ingredients (APIs) displays an optimized selection
process with regard to pharmacodynamic properties, mainly receptor/ target affinity and
selectivity, using methods such as high throughput screening (HTS), combinatorial chemistry,
and molecular genetics. However, the APIs selected by these methods are preferably
lipophilic comprising poor to negligible water solubility. To date, approximately 40 % of the
new drug compounds are considered poorly water-soluble [1]. In other words,
“The more active a compound, the less water-soluble”. Thus, solubilization represents one
of the major challenges in drug development.
Solubilization is the process of making a compound soluble as well as enhancing its solubility
using different techniques such as the use of cosolvents, complexing agents, or surfactants.
It is a mandatory requirement to enable the therapeutic use of poorly water-soluble drugs.
Almost every phase of the drug development process is faced by solubility hurdles. At the
very early stages of development poorly water-soluble compounds are usually dissolved in
organic solvents such as dimethyl sulfoxide or ethanol and further diluted with an appropriate
buffer to test their activity and efficacy in vitro. Subsequent in vivo testing both at discovery
and preclinical stages requires early formulations [1]. At this phase, solutions and suspensions
are the preferred dosage forms for the discovery as well as the preclinical leads whereas the
latter may also be formulated using novel formulations such as nano-suspensions or lipid-
based formulations [1]. Formulation development for use in clinical development represents
the next hurdle, probably the most challenging one. Excipients used for this application have
to be approved or generally regarded as safe by the authorities (GRAS status). Whereas oral
2 Introduction
applicability offers a relatively broad range of approved excipients and dosage forms,
parenteral application distinctly limits the choice of available solubilizers and the
concentrations to be used.
According to the OECD Guideline for Testing of Chemicals No. 105 the term
‘water solubility’ is defined as the saturation mass concentration of a substance in water
at a given temperature [2]. It is determined using a column elution or a flask method for