Sustained release formulations for compounds underlying intestinal drug efflux [Elektronische Ressource] / Daniel Wagner

Daniel Wagner

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• Publié par: johannes_gutenberg-universitat_mainz
• Publié le: 01 janvier 2003
• Nombre de lectures: 11
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Adieu, dit le renard. Voici mon secret. Il est très simple:
On ne voit qu'avec le coeur. L'essentiel est invisible pour les yeux.
Antoine de Saint-Exupery (Le Petit Prince)

Der Mensch sieht, was vor Augen ist, Gott aber sieht das Herz an.
Die Bibel (Jahreslosung 2003, 1. Samuel 16, 7) Sustained-Release Formulations
for Compounds Underlying
Intestinal Drug Efflux



Dissertation zur Erlangung des Grades
„Doktor der Naturwissenschaften“

am Fachbereich Chemie und Pharmazie
der Johannes Gutenberg-Universität
in Mainz



Daniel Wagner
geb. in Bad Marienberg (Westerwald)


Mainz 2003













Jahr der mündlichen Prüfung: 2003 Table of contents
Table of contents ……………………………………………………..............I – VII


Abbreviations …………… ................................................................................. 1


Chapter I: Introduction and aims of the doctoral thesis.............................. 5

I.1 The phenomenon of intestinal drug efflux 7
I.2 Carriers involved in intestinal drug efflux 9
I.2.1 The intestinal efflux pump P-glycoprotein 10
I.2.2 Other transporters involved in intestinal drug efflux 12
I.3 Models for the investigation of intestinal drug absorption and absorption sites 15
I.4 Regional differences in drug absorption 19
I.5 Sources of regional differences in drug absorption 20
I.5.1 Passive diffusion 21
I.5.2 Paracellular absorption 21
I.5.3 Active transport processes 22
I.6 Consequences for dosage form design 24
I.6.1 Gastroretentive dosage forms 24
I.6.2 Drug delivery to the small intestine 25
I.6.3 Targeted colon delivery 26
I.6.4 Dosage form design for drugs undergoing intestinal drug efflux 28
I.7 Aim of the thesis 31
I.8 Talinolol as model compound for drugs that are subject to intestinal drug
efflux 34


Chapter II: Effective permeabilities of talinolol in different regions of
the rat intestine .......................................................................... 41

II.1 Introduction 41
II.1.2 Dose-dependence of talinolol bioavailability 42
II.1.3 Intestinal perfusion studies in rats 45
I Table of contents
II.2 Materials and methods 47
II.2.1 Materials 47
II.2.2 Animals 47
II.2.3 Instrumentation 47
II.2.4 Quantitative analysis of talinolol from intestinal perfusate solutions 48
II.2.5 Perfusion of rat small and large intestine 48
II.2.6 Net water absorption / secretion during perfusion 49
II.2.7 Intestinal permeability 50
II.2.8 Experimental determination of carrier-mediated and passive components
of drug permeability 50
II.2.9 Theoretical model describing the concentration-dependence of flux and
permeability across membranes for substrates undergoing passive
absorption and Michaelis-Menten type carrier-mediated secretion 51

II.3 Results 55
II.3.1 Analysis of talinolol from perfusate samples 55
II.3.2 Influence of co-administration of P-gp inhibitors on intestinal permeability
of talinolol 59
II.3.3 Estimation of parameters for passive and carrier-mediated membrane
permeability 61

II.4 Discussion and conclusions 63


Chapter III: Development of peroral talinolol controlled-release
dosage forms.............................................................................. 67

III.1 Introduction 67
III.1.1 The need of a controlled-release dosage form for talinolol 70
III.1.2 Technological aspects 71
III.1.3 Properties of excipients used in the formulation of sustained-release
dosage forms for talinolol 73
III.1.3.1 Eudragit polymers 73
® III.1.3.2 Ethocel (Ph. Eur., USP/NF, JPE) 78
II Table of contents
III.2 Materials and methods 79
III.2.1 Chemicals and other materials 79
III.2.2 Preparation of sustained-release matrix granules 79
III.2.3 Preparation of coated sustained-release granules 80
III.2.4 Preparation of sustained-release matrix tablets 81
III.2.5 Pharmaceutical characterization 82
III.2.5.1 Dissolution 82
III.2.5.1.1 Assays 83
III.2.5.1.2 Dissolution media 84
III.2.5.1.3 Stability of talinolol in dissolution media 86
III.2.5.2 Uniformity of mass and content 88
III.2.5.3 Size of tablets 88
III.2.5.4 Crushing strength 89
III.2.5.5 Friability 89
III.2.6 Statistical analysis of dissolution data 90

III.3 Results and discussion 91
III.3.1 Granules and hard gelatin capsules 91
III.3.1.1 Determination of the appropriate capsule size based on bulk density
measurements 91
III.3.1.2 Talinolol granule formulations 94
® III.3.1.2.1 Granule formulation with Eudragit RSPO, calcium hydrogen
phosphate and magnesium stearate 94
® III.3.1.2.2 Granule formulation with Eudragit RSPO and Eudragit RS 12.5 95
® III.3.1.2.3 Granule formulation with Eudragit RSPO, corn starch and
gelatin 97
® III.3.1.2.4 Granules coated with Eudragit L 12.5 100
III.3.1.2.5 Granule formulation with ethylcellulose 102
III.3.2 Influence of the pH on talinolol dissolution 106
III.3.2.1 Dissolution study with capsules containing pure talinolol dry
substance 106
III.3.2.2 Dissolution study with talinolol immediate-release tablets 108
III.3.2.3 Dissolution study with tablets formulated with talinolol and corn
starch 109
III Table of contents
III.3.3 Final discussion on hard gelatin capsule preparations 111
III.3.4 Matrix tablets 113
III.3.4.1 Powder losses during the manufacturing process of matrix tablets 113
III.3.4.2 Parameters with potential influence on the drug release from matrix
tablets 115
III.3.4.2.1 Compression force 115
III.3.4.2.2 Compression time 118
III.3.4.2.3 Rotational speed of the paddles in the dissolution apparatus 119
® ® III.3.4.3 Matrix tablets formulated with Eudragit RSPO, Eudragit S 100,
® ®Eudragit RLPO and Ethocel 121
® III.3.4.4 Matrix tablets formulated with Eudragit S 100 and corn starch 124
III.3.4.5 Influence of pore formers on the dissolution of talinolol matrix tablets 125
® III.3.4.6 Matrix tablets formulated with a combination of Eudragit RSPO and
®Eudragit S 100 130
® III.3.4.7 Matrix tablets formulated with Eudragit L 100-55 132
® III.3.4.8 Matrix tablets formulated with Eudragit L 100-55 and different pore
formers 136
III.3.4.8.1 Corn starch 136
III.3.4.8.2 Polyethylene glycol 4000 140
III.3.4.8.3 Glucose 140
III.3.4.8.4 Mannitol 141
III.3.4.9 Considerations on the appropriate talinolol dose per tablet 145
III.3.4.10 Talinolol matrix tablets with a drug content of 100 mg 147
III.3.4.11 Formulation optimization of talinolol matrix tablets with a drug
content of 100 mg 152
III.3.4.12 Summary of talinolol matrix formulations 157
III.3.4.13 Pharmaceutical characterization of talinolol sustained-release
®tablets formulated with 40 % Eudragit L 100-55 and 20 % mannitol 158
III.3.4.13.1 Tablet thickness 159
III.3.4.13.2 Uniformity of mass 160
III.3.4.13.3 Crushing strength 161
III.3.4.14 Final discussion on matrix tablets 163

III.4 Conclusions 169
IV Table of contents
Chapter IV: Considerations on in vitro dissolution test methods.......... 172

IV.1 Introduction 172

IV.2 Materials and methods 174
IV.2.1 Chemicals and other materials 174
IV.2.2 Solubility studies 174
IV.2.3 Preparation of controlled-release dosage forms 175
IV.2.4 Dissolution studies 175
IV.2.5 Preparation of talinolol crystal forms 176
IV.2.6 Light microscopy 176
IV.2.7 Fourier Transform Infrared Spectroscopy (FT-IR) 176
IV.2.8 Differential Scanning Calorimetry (DSC) 177
IV.2.9 X-Ray Powder Diffraction (XRPD) 177

IV.3 Results 178
IV.3.1 Solubility in aqueous media 178
IV.3.2 Dissolution 182
IV.3.3 Crystal structures 187
IV.3.4 Fourier Transform Infrared Spectroscopy 189
IV.3.5 Differential Scanning Calorimetry 190
IV.3.6 X-Ray Powder Diffraction 192

IV.4 Discussion and conclusions 193


Chapter V: In silico evaluation of talinolol sustained-release tablets.... 196

V.1 Introduction 196

V.2 Materials and methods 199
V.2.1 Computer hardware and software 199
V.2.2 Input parameters for simulations of talinolol IR and CR dosage forms 199
V.2.2.1 Compound properties 199
V Table of contents
V.2.2.2 Phy