La lecture en ligne est gratuite
Le téléchargement nécessite un accès à la bibliothèque YouScribe
Tout savoir sur nos offres
Télécharger Lire

Paediatric formulations of L-arginine for the use in urea cycle disorders [Elektronische Ressource] / vorgelegt von Qaed Abdul Hussein

De
193 pages
Paediatric formulations of L-arginine for the use in urea cycle disorders Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Qaed Abdul Hussein aus Baghdad Düsseldorf, September 2009 aus dem Institut für Pharmazeutische Technologie und Biopharmazie der Heinrich-Heine Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: Prof. Dr. J. Breitkreutz Koreferent: Prof. Dr. P. Kleinebudde Tag der mündlichen Prüfung: 15.09.2009 Index IAbbreviations VIA Introduction and aim of the study 1 1. Introduction 1 2. Aim of the study 4B General Part 51. Therapeutic uses of L-Arginine 52.
Voir plus Voir moins






Paediatric formulations of L-arginine for the
use in urea cycle disorders






Inaugural-Dissertation


zur Erlangung des Doktorgrades
der Mathematisch-Naturwissenschaftlichen Fakultät
der Heinrich-Heine-Universität Düsseldorf


vorgelegt von

Qaed Abdul Hussein

aus Baghdad





Düsseldorf, September 2009




aus dem Institut für Pharmazeutische Technologie und Biopharmazie
der Heinrich-Heine Universität Düsseldorf





















Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät
der Heinrich-Heine-Universität Düsseldorf




Referent: Prof. Dr. J. Breitkreutz
Koreferent: Prof. Dr. P. Kleinebudde

Tag der mündlichen Prüfung: 15.09.2009







Index I
Abbreviations VI
A Introduction and aim of the study 1
1. Introduction 1
2. Aim of the study 4
B General Part 5
1. Therapeutic uses of L-Arginine 5
2. Transduction mechanisms and types of taste 11
2.1 Bitter taste 11
2.2 Sweet taste 12
2.3 Salt taste 12
2.4 Acid taste 13
2.5 Umami taste 13
2.6 Fat taste 13
2.7 Water 14
3. Taste masking technologies 14
3.1 Taste masking with flavours, sweeteners, and amino acids 14
3.2 Taste masking with lipophilic vehicles 17
3.2.1 Lipids 17
3.2.2 Lecithin and lecithin-like substances 17
3.3 Taste masking by physical barriers 17
3.3.1 Carbohydrates 18
3.3.2 Zeolites 18
3.4 Taste masking by inclusion complexation 18
3.5 Taste masking by ion-exchange resins 19
4. Taste masking assessment 19
4.1 In vivo approaches for taste assessment 19
4.1.1 Human taste panel studies 19
4.1.2 Animal preference tests 21
4.1.3 Electrophysiological methods 21



I 4.2 In vitro approaches for taste assessment 21
4.2.1 In vitro drug release studies 22
4.2.2 In vitro assay methods 22
4.3 Biomimetic taste sensing systems 23
4.3.1 Lipid membrane taste sensors 25
4.3.2 The taste-sensing systems SA401 and SA402 25
4.3.3 Astree electronic tongue 25
4.3.4 Ion-sensitive field effect transistors 26
4.3.5 Voltammetric sensors 27
4.3.6 Alternative electronic tongue 27
C Results and Discussion 28
1. L-arginine HCL 10% solution 28
1.1 Introduction 28
1.2 Formulation development 30
1.3 Taste masking of L-arginine in solution 33
1.4 First preformulation study 35
1.5 Second preformulation study 41
1.6 Long-term stability study 46
1.7 In-use stability test 50
1.8 Conclusion 53
2. Multiparticulate formulations 54
2.1 Extrusion/spheronisation process 54
2.1.1 Introduction 54
2.2 Wet Extrusion 56
2.2.1 MCC and HPMC 56
2.3 Solid Lipid Extrusion 58
2.3.1 Formulation variation 60
2.3.2 Process parameters 61
2.3.3 Spheronization 63
2.3.4 Pellet shape, size and size distribution 67



II 2.4 L-arginine free base dissolution 70
2.4.1 Dissolution media and process parameter 70
2.4.2 Self-coating of the lipid pellets 75
2.4.5 Stability of lipid pellets 82
2.4.6 Conclusion 94
3. Taste assessment 96
3.1 Taste analysis of different solution formulations 96
3.2 Taste analysis of primary formulations 97
3.2.1 Insent taste sensing system SA402B 98
3.3 Effects of pH and ionic strength on the taste assessment 104
3.4 Taste analysis of 10% L-arginine HCL formulations 114
3.4.1 Insent taste sensing system SA402B 114
3.4.2 Human taste panel 117
3.4.3 Correlation taste panel to electronic tongue data 118
3.5 Conclusion 120
D Summary 121
E Zusammenfassung 124
F Experimental Part 127
1. Materials 127
1.1 L-arginine 127
1.1.1 Characterization of L-arginine 127
1.1.1.1 Physical properties 127
1.1.1.1.1 X-Ray Powder Diffraction Pattern 127
1.1.1.1.2 Particle Morphology 128
1.1.1.1.3 Thermal Methods of Analysis 129
1.1.1.1.3.1 Melting Behaviour 129
1.1.1.1.3.2 Differential Scanning Calorimetry 129
1.1.1.1.4 Hygroscopicity 129
1.1.1.1.5 Solubility characteristics 129
1.1.1.1.6 Ionization Constants 130



III 1.1.1.1.7 Spectroscopy 130 1.1.1.1.7.1 Vibrational Spectroscopy 130
1.1.1.1.7.2 Nuclear Magnetic Resonance Spectrometry 131
1 1.1.1.1.7.2.1 H-NMR Spectrum 131
13 1.1.1.1.7.2.2 C-NMR Spectrum 132
1.1.1.1.8 Micrometric Properties 134
1.1.1.1.8.1 Bulk and Tapped Densities 134
1.1.1.1.8.2 Powder Flowability 134
1.1.1.2 Methods of Analysis 135
1.1.1.2.1 Compendial Tests 135
1.1.1.2.1.1 European Pharmacopoeia 135
1.1.1.2.1.2 United states Pharmacopoeia 136
1.1.1.2.2 Elemental Analysis 136
1.1.1.2.3 Titrimetric Analysis 137
1.2 Lipid qualities 137
1.3 Other substances 137
2. Methods 139
2.1 Solution preparation 139
2.1.1 Manufacturing 139
2.1.2 Storage stability 139
2.2 Solution characterisation 139
2.2.1 HPLC-UV (DAD) 139
2.2.1.1 Precision 1412.1.2 Accuracy 142
2.2.1.3 Linearity 144
2.2.1.4 Limit of detection and limit of quantification 144
2.2.1.5 Specificity 147
2.2.1.5.1 Chromatograms 147
2.2.1.5.2 Stress tests 151
2.2.2 Physical and chemical evaluation 154



IV 2.2.3 Osmolarity measurement 154
2.2.4 pH-Measurement 154
2.2.5 Conductivity measurement 155
2.2.6 Uniformity of mass of delivered doses from multidose containers 155
2.2.7 Human Taste panel 155
2.2.8 Insent taste sensing system SA402B 155
2.3 Pellet production 160
2.3.1 Sieving 160
2.3.2 Blending of raw materials 160
2.3.3 Extrusion 161
2.3.3.1 Wet extrusion 161
2.3.3.2 Lipid extrusion 161
2.3.3.3 Evaluation of extrudates and pellets 162
2.3.4 Spheronization 162
2.4 Pellet Characterisation 163
2.4.1 Yield 163
2.4.2 Pellet shape, size and size distribution 163
2.4.3 Helium pycnometry density 164
2.4.4 Mercury porosimeter density 164
2.4.5 Porosity 165
2.4.6 Storage stability studies 165
2.4.7 Invitro drug dissolution studies 165
2.4.8 Differential scanning calorimetry 166
2.4.9 Pellet preparation 166
2.4.10 Scanning electron microscopy 167
2.4.11 Raman spectroscopy 167
G Bibliography 168
H Acknowledgements 182





V Abbreviations
A Projected pellet surface
AC Adenylyl cyclise
ADRAC Adverse Drug Reactions Advisory Committee
API Active pharmaceutical ingredient
AR Aspect ratio
ARTG Australian register of therapeutic goods
ASIC Acid-sensing ion channel

cAMP Cyclic adenosine monophosphate
cNMP Cyclic nucleotide monophosphate
cps Cycle per second

d Day
d Pellet diameter
d Dimensionless diameterd
d Equivalent diameter eq
d Median of all equivalent diameters eq50
d Maximum Feret diameter max
d Feret-diameter perpendicular to the maximum Feret diameter 90°
DSC Differential Scanning Calorimetry

EMEA European Medicines Agency
+ENaC Epithelial-type Na channel
EU European Union

FDA Food and Drug Administration
FET Field effect transistor
GMP Guanosine 5-monophosphate
GPCR G-protein-coupled receptor
g Gram


VI h Hours
HCL Hydrochloric acid
HLB Hydrophilic lipophilic balance
HPMC Hypromellose, Hydroxypropyl methylcellulose
HPLC High performance liquid chromatography

ICH International conference on harmonisation
IMP Inosine-5-monophosphate
IP3 phate

kg Kilogram
kV Kilovolt

L Litre

M Molar
mA Milli Ampere
MCC Microcrystalline cellulose
MDEG1 Mammalian degenerin-1 channel
mEq Milli equivalent
mg Milligram
mGluR Metabotropic glutamate receptor
mL Millilitre
mm Millimeter
mmol Millimole
mM Millimolar
min Minutes
mRNA Messenger ribonucleic acid
MRA Multiple regression analysis
MSG Monosodium glutamate
MVDA Multivariate data analysis
2 m square meter

VII n Number of measurements
NAGS N-acetyl glutamate synthase

P p-value of statistic (lack of fit)
p.a. Pro analysis
PCA Principal component analysis
PDE Phosphodiesterase
Ph.Eur. European Pharmacopeia
PLC Phospholipase C
PLS Partial least squares analysis
PROP 6-N-propyl-2-thiouracil

RH relative humidity
rpm turns per minute
2 R Coefficient of determination

SD Standard deviation

TGA Therapeutic Good Administration
TRC Taste receptor cell

UCDs Urea cycle disorders
US United States
USP United States Pharmacopeia
UV Ultraviolet

WHO World Health Organisation

X Median 50
x Quantile Number
Porosity
2D Two dimension
μmol Micro milli mole
μm Micrometer
μL Microlitre
μg Microgram

VIII
0

Un pour Un
Permettre à tous d'accéder à la lecture
Pour chaque accès à la bibliothèque, YouScribe donne un accès à une personne dans le besoin