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Solubility and permeability as in vitro predictors for in vivo performance of fenofibrate IR solid dosage forms [Elektronische Ressource] / Philipp Buch

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Solubility and permeability asin vitro predictors for in vivo performance offenofibrate IR solid dosage formsDissertationzur Erlangung des Grades„Doktor der Naturwissenschaften“im Promotionsfach Pharmazieam Fachbereich Chemie, Pharmazie und Geowissenschaftender Johannes Gutenberg-Universitätin MainzPhilipp Buchgeb. in Frankfurt am MainMainz, den 02.06.2010D77 (Mainzer Dissertation)Dekan:1. Berichterstatter:2. Berichterstatter:Tag der mündlichen Prüfung: 25.06.2010Die vorliegende Arbeit wurde in der Zeit von April 2005 bis März 2010 an der JohannesGutenberg-Universität in Mainz durchgeführt.Für meine ElternDanksagungTable of contentsTable of contentsAbbreviations ..................................................................................................................... 111. Introduction into absorption models ......................................................................... 131.1 The gastrointestinal tract ........................................................................................ 141.1.1 The intestinal epithelium ................................................................................. 141.1.2 Factors affecting gastrointestinal absorption ................................................... 151.1.2.1 Intestinal transit rate .................................................................................... 151.1.2.2 Ial pH ..................................................................................

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Published 01 January 2010
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Solubility and permeability as
in vitro predictors for in vivo performance of
fenofibrate IR solid dosage forms
Dissertation
zur Erlangung des Grades
„Doktor der Naturwissenschaften“
im Promotionsfach Pharmazie
am Fachbereich Chemie, Pharmazie und Geowissenschaften
der Johannes Gutenberg-Universität
in Mainz
Philipp Buch
geb. in Frankfurt am Main
Mainz, den 02.06.2010D77 (Mainzer Dissertation)
Dekan:
1. Berichterstatter:
2. Berichterstatter:
Tag der mündlichen Prüfung: 25.06.2010Die vorliegende Arbeit wurde in der Zeit von April 2005 bis März 2010 an der Johannes
Gutenberg-Universität in Mainz durchgeführt.Für meine ElternDanksagungTable of contents
Table of contents
Abbreviations ..................................................................................................................... 11
1. Introduction into absorption models ......................................................................... 13
1.1 The gastrointestinal tract ........................................................................................ 14
1.1.1 The intestinal epithelium ................................................................................. 14
1.1.2 Factors affecting gastrointestinal absorption ................................................... 15
1.1.2.1 Intestinal transit rate .................................................................................... 15
1.1.2.2 Ial pH ................................................................................................ 15
1.1.2.3 Intestinal fluid volume ......................................... 16
1.1.2.4 Bile and the effect of food ............................................................................ 17
1.2 In vitro models to study oral absorption .................................................................. 18
1.2.1 Dissolution - predicting the effect of food ........................................................ 18
1.2.2 Permeation ..................................................................................................... 21
1.2.3 Rationale for the connection of dissolution and permeation ............................ 22
1.3 Combination of dissolution and permeation models ............................................... 23
1.3.1 First attempts to combine dissolution and permeation ..................................... 23
1.3.2 Closed dissolution/Caco-2 systems................................................................. 24
1.3.2.1 Dissolution/Caco-2 system by Ginski et al. .................................................. 24
1.3.2.2 Dissolution/Caco-2 system by Kataoka et al. ............................................... 25
1.3.3 Open dissolution/Caco-2 systems ................................................................... 27
1.3.3.1 Dissolution/Caco-2 system by Miyazaki et al. .............................................. 27
1.3.3.2 Dissolution/Caco-2 system by Motz et al. .................................................... 28
1.3.4 Dissolution/permeation systems - alternatives to Caco-2 ................................ 30
1.3.4.1 Dissolution/hollow fiber system by Blanquet et al. ....................................... 30
1.3.4.2 Dissolution/everted intestine system by Kale et al. ...................................... 32
1.3.5 The D/P system by Kataoka et al. as method of choice................................... 33
1.4 In vitro/in vivo correlations ...................................................................................... 34
1.4.1 When is an in vitro/in vivo correlation likely? ................................................... 35
1.5 Fenofibrate as model compound for drugs that are affected by the effect of food ... 36
1.5.1 Fenofibrate formulations ................................................................................. 37
1.5.2 Several aspects of improving the bioavailability of poorly soluble drugs .......... 38
1.5.3 Possible adjustments of dissolution and permeation methods......................... 39
1.6 Aims of the thesis ................................................................................................... 40
2. IVIVC in oral absorption for fenofibrate immediate release tablets using a
dissolution/permeation system .................................................................................. 41
2.1 Abstract.................................................................................................................. 41
2.2 Introduction ............................. 42
2.3 Materials and methods .................................................. 44
2.4 Results and discussion .......................................................................................... 49
2.5 Conclusion ............................................................................................................. 54
2.6 Acknowledgments .................................................................................................. 54
9Table of contents
3. IVIVR in oral absorption for fenofibrate immediate release tablets using
dissolution and dissolution permeation methods .................................................... 55
3.1 Abstract.................................................................................................................. 55
3.2 Introduction ............................................................................................................ 56
3.3 Materials and methods ........................................................................................... 58
3.4 Investigations and results ..... 64
3.5 Discussion ............................................................................................................. 69
3.6 Conclusion ............................................................................................................. 71
3.7 Acknowledgments ................... 71
4. IVIVC for fenofibrate immediate release tablets using solubility and permeability
as in vitro predictors for pharmacokinetics .............................................................. 73
4.1 Abstract.................................................................................................................. 73
4.2 Introduction ............................................................................................................ 74
4.3 Materials and methods ........................................................................................... 76
4.4 Results ................................................................................................................... 81
4.5 Discussion ............................................................................................................. 90
4.6 Conclusion ............................................................................................................. 92
5. Liposome formation from bile salt-lipid micelles in the digestion and drug
delivery model FaSSIF estimated by combined time-resolved neutron andmod
dynamic light scattering ............................................................................................. 93
5.1 Abstract.................................................................................................................. 93
5.2 Introduction ............................................................................................................ 94
5.3 Materials and methods ........................................................................................... 96
5.4 Results ................................................................................................................. 102
5.5 Discussion ........................................................................................................... 111
5.6 Acknowledgments ................. 115
Discussion ........................................................................................................................ 117
Summary .......................................................................................................................... 123
References........................................................................................................................ 125
A. Appendix .................................................................................................................... 133
A.1 Illustration of the observed surfactant-FaSSIF interactions .............................. 133mod
A.2 Two human in vivo studies with fenofibrate IR tablet formulations ........................ 134
A.3 Surface tension measurements ............................................................................ 136
A.4 Time-resolved small-angle neutron scattering measurements .............................. 137
Publications and poster presentations .......................................................................... 139
Curriculum vitae ............................................................................................................... 141
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