Systematic {devolopment [development] of formulations suitable for pulmonary applications by nebulisation [Elektronische Ressource] / presented by Antonio Raposo

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DISSERTATION SUBMITTED TO THE COMBINED FACULTIES FOR THE NATURAL SCIENCES AND FOR MATHEMATICS OF THE RUPERTO-CAROLA UNIVERSITY OF HEIDELBERG, GERMANY FOR THE DEGREE OF DOCTOR OF NATURAL SCIENCES PRESENTED BY ANTONIO RAPOSO, LIC. PHARM. BORN IN BARREIRO, PORTUGAL ORAL-EXAMINATION: 19.JUNE.2006 SYSTEMATIC DEVOLOPMENT OF FORMULATIONS SUITABLE FOR PULMONARY APPLICATIONS BY NEBULISATION Referees: Prof. Dr. Gert Fricker Priv. Doz. Dr. Ulrich Massing The following work was conducted at University of Heidelberg, Faculty of Biosciences, Institute for Pharmacy and Molecular Biotechnology, Dep. Pharmaceutical Technology and Pharmacology in cooperation with PARI GmbH Starnberg. First of all, I would like to thank Herrn Prof. Dr. Fricker for taking me as a doctorate student at his institute; Herrn Dr. Keller, director of the Aerosol Research Institute-PARI GmbH, for allowing me to perform the necessary experimental work at the PARI GmbH laboratories. To Herrn Dr. Bultmann, I would like personally to thank him for the guidance and advices given during this work. His encouragement, technical and editorial advice, suggestions, discussions and supervision were an invaluable support to complete this work. I am also very grateful to all my fellow colleagues at the Aerosol Research Institute-PARI GmbH for their assistance and companionship throughout my stay at PARI GmbH.

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DISSERTATION
SUBMITTED TO THE
COMBINED FACULTIES FOR THE NATURAL SCIENCES AND FOR MATHEMATICS
OF THE RUPERTO-CAROLA UNIVERSITY OF HEIDELBERG, GERMANY
FOR THE DEGREE OF
DOCTOR OF NATURAL SCIENCES
PRESENTED BY
ANTONIO RAPOSO, LIC. PHARM.
BORN IN BARREIRO, PORTUGAL
ORAL-EXAMINATION: 19.JUNE.2006










SYSTEMATIC DEVOLOPMENT OF FORMULATIONS
SUITABLE FOR PULMONARY APPLICATIONS
BY NEBULISATION
Referees: Prof. Dr. Gert Fricker
Priv. Doz. Dr. Ulrich Massing
The following work was conducted at University of Heidelberg, Faculty of Biosciences,
Institute for Pharmacy and Molecular Biotechnology, Dep. Pharmaceutical Technology and
Pharmacology in cooperation with PARI GmbH Starnberg.
First of all, I would like to thank Herrn Prof. Dr. Fricker for taking me as a doctorate student
at his institute; Herrn Dr. Keller, director of the Aerosol Research Institute-PARI GmbH, for
allowing me to perform the necessary experimental work at the PARI GmbH laboratories.
To Herrn Dr. Bultmann, I would like personally to thank him for the guidance and advices
given during this work. His encouragement, technical and editorial advice, suggestions,
discussions and supervision were an invaluable support to complete this work.
I am also very grateful to all my fellow colleagues at the Aerosol Research Institute-PARI
GmbH for their assistance and companionship throughout my stay at PARI GmbH. This work
would not have been possible without the support and encouragement of each and every one
of them.
In particular, I would like to thank Dr. Frank Lintz for the motivation and support given to me
during his stay at PARI GmbH.
I would also like to thank very much my colleagues Dr. Albert Bucholski, Uwe Schuschnig
and Andreas Balcke for their support with GC-MS/HPLC-UV and for the endless discussions
about analytics.
My special thanks go out also to Elke Walther and Simone von Opolski for the endless
patience and support given to me during the experimental part of this work.
I would like also to give a special thanks to Gerhard Lang for all his consideration and also
for introducing me to the "Bayrische Kultur".
Finally, I would like to thank my family for their support during my student life, and for their
patience and encouragement while have being separated for many years.



Table of Contents
1 SUMMARY (ENGLISH/GERMAN VERSION) 1
2 INTRODUCTION 3
2.1 The Inhalative Therapy 3
2.2 Respiratory System 6
2.3 Barriers present in the lungs 9
2.3.1 Pulmonary Surfactant 9
2.3.2 Epithelial Surface Fluid 9
2.3.3 Epithelium 9
2.3.4 Interstitium 10
2.3.5 Vascular endothelium 10
2.4 Factors Affecting Deposition of Particles 13
2.5 Mechanisms of Particle Deposition in the Airways 13
2.6 Influence of Particle Size 15
2.7 Lung Permeability 15
2.8 Clearance of Inhaled Particles from the Respiratory Tract 15
2.8.1 Mucociliary clearance 16
2.8.2 Alveolar clearance 16
2.9 Mechanism of absorption 16
2.9.1 Small molecule drug absorption 17
2.9.1.1 Mechanism of small molecule absorption 17
2.9.1.1.1 Active Transport 17
2.9.1.1.2 Slow Absorption of Inhaled Small Molecules 18
2.9.2 Hydrophobic versus Hydrophilic small molecules 18
Subchapter references 21
2.10 Technological Problems 24
2.10.1 Nebulisers 24
2.10.1.1 Jet nebulisers 24
2.10.1.2 Ultrasonic nebulisers 26
2.10.2 Metered Dose Inhalers 29
2.10.3 Dry powders inhalers 33
Subchapter conclusion 37
Subchapter references 37
2.11 eFlow Electronic Inhaler 38
2.12 Vibrating Membrane Principle 40
I Subchapter references 47
3 WORK OBJECTIVES 49
4 CYCLODEXTRINS 51
4.1 Physicochemical Properties of Cyclodextrins 52
4.2 Cyclodextrin-Guest Complexation 54
4.2.1 Overall Inclusion Complex Stability Constant 54
4.2.2 Mechanism of Inclusion Constant 54
4.3 Evaluating Complex Formation 59
4.4 Self-association of cyclodextrin complexes 63
4.5 Pharmacokinetics of the Drug/Cyclodextrin Complexes 65
4.5.1 Competitive displacement 66
4.5.2 Dilution 66
4.5.3 Protein binding 66
4.5.4 Drug uptake into tissue 67
4.6 Benefits of Complexation 68
4.6.1 Improvement in solubility, dissolution and bioavailability 68
4.6.2 Reduction of Unpleasant Side Effects and Bitter Taste 68
4.6.3 Improvements in Drug Stability 68
4.6.4 Reduction in Volatility 69
4.7 Use of Cyclodextrins as Drug Carriers 69
4.8 Toxicological Considerations 70
4.9 Pulmonary Administration of Cyclodextrins 71
Chapter references 71
5 MATERIALS AND METHODS 76
5.1 Materials 76
5.2 Physicochemical Properties of the Drugs Substances 79
5.2.1 Cyclosporin A 79
5.2.1.1 Physicochemical properties of cyclosporin A 80
5.2.2 Azithromycin 80
5.2.2.1 Physicochemical properties of azithromycin 80
5.2.3 Pentoxifylline 81
5.2.3.1 Physicochemical properties of pentoxifylline 82
5.2.4 Budesonide 82
5.2.4.1 Physicochemical properties of budesonide 82
5.3 Methods 83
5.3.1 Analytical Methods 83
5.3.1.1 Particle size and zeta potential determination 83
5.3.1.2 Scanning electron microscopy 84
II


5.3.1.3 Determination of the Cyclosporin, Azithromycin, Budesonide and Pentoxifylline content
85
5.3.1.4 Viscosity determination 86
5.3.1.5 Surface tension determination 87
5.3.1.6 Water content determination 88
5.3.1.7 Lyophilization 89
5.3.1.8 Nebulisation parameters determination 90
5.3.1.9 Taste masking determination 92
5.3.2 Preparation Methods 92
5.3.2.1 Preparation methods for the azithromycin formulations 92
5.3.2.1.1 Initial preparation method the azithromycin/CD formulations 92
5.3.2.1.2 Final preparation method for the azithromycin/CD formulations 93
5.3.2.2 Preparation method for the ethylated- -cyclodextrin nanospheres 93
5.3.2.3 Preparation method for the - -cyclodextrin nanospheres loaded with cyclosporin A 93
5.3.2.4 Optimisation of preparation method for the -cyclodextrin nanospheres loaded with
cyclosporin A 94
5.3.2.5 Preparation method for the -cyclodextrin nanospheres loaded with azithromycin 94
5.3.2.6 Preparation method for the Pentoxifylline formulations 95
5.3.2.7 Preparation method for the Budesonide formulations 95
Subchapter references 95
6 RESULTS 96
6.1 Determination of the nebulisation parameters of the eflow 96
Subchapter conclusion 102
6.2 Solutions 103
6.2.1 Cyclosporin A Cyclodextrin Formulations 103
6.2.1.1 Introduction 103
6.2.1.2 Methods 104
6.2.1.2.1 The Higuchi Connors method and its variants 104
6.2.1.2.2 Preparation method of the CSA/CD lyophilizate 104
6.2.1.3 Results 105
6.2.1.3.1 Phase solubility tests between CSA and several cyclodextrins 105
6.2.1.4 Influence of the cavity size on the solubility of Cyclosporin A 107
6.2.1.4.1 Influence of several excipients on the complexing ability of cyclodextrins 108
6.2.1.4.2 Influence of temperature on the solubility of CSA 112
6.2.1.4.3 Influence of pH on the solubility of CSA 119
6.2.1.4.4 Influence of sodium acetate on the solubility of CSA 120
6.2.1.4.5 Influence of several parameters on the ascorbic acid complexation 122
6.2.1.4.6 Physicochemical properties of the cyclosporin A/cyclodextrin formulations 133
6.2.1.4.7 Determination of the humidity content of the lyophilizate 136
6.2.1.4.8 Lyophilization of the Cyclosporin A/Cyclodextrin Formulation 137
6.2.1.4.9 Physicochemical properties and nebulisation parameters of cyclosporin/cyclodextrin
lyophilizates 139
6.2.1.4.10 Stability trials 140
6.2.1.4.10.1 Stability trial of a lyophilized cyclosporin A/cyclodextrin formulation 143
Subchapter conclusions 143
6.2.2 Azithromycin/Cyclodextrin Formulations 146
6.2.2.1 Influence of several excipients on the solubility of azithromycin 146
6.2.2.2 Influence of sodium acetate and citric acid on the solubility of azithromycin 148
6.2.2.3 Influence of pH on the solubility of azithromycin 150
III 6.2.2.4 Influence of lactic acid, nicotine amide and vitamin E acetate on the solubility of
azithromycin 152
6.2.2.5 Influence on the solubility of azithromycin of a formulation containing ascorbic acid, 2-
HP- -cyclodextrin 155
6.2.2.5.1 Influence of equilibrium time on the solubility of azithromycin 156
6.2.2.5.2 Influence of temperature on the solubility of azithromycin 157
6.2.2.5.3 Influence of pH on the solubility of azithromycin 157
6.2.2.5.4 Influence of 2-HP- -CD concentrations on the solubility of azithromycin 158
6.2.2.5.5 Influence of sodium ascorbate concentrations on the solubility of azithromycin 159
6.2.2.6 Nebulization trials 161
6.2.2.7 Lyophilization of the Azithromycin/Cyclodextrin Formulation 162
6.2.2.8 Stability Batches 164
Subchapter conclusion 166
6.2.3 Pentoxifylline 167 169
6.2.4 Budesonide 170
Subchapter conclusion 173
Chapter references 173
6.3 SUSPENSIONS 175
6.3.1 Methods of preparation 176
6.3.1.1 Preparation of cyclodextrin nanospheres loaded with insoluble drugs 176
6.3.1.1.1 Cyclosporin A/Cyclodextrin and Azithromycin/Cyclodextrin suspensions 176
6.3.1.2 Cyclosporin A Suspensions 176
6.3.1.3 Azithromycin Suspensions 187
Chapter conclusion 190
Chapter references 190
7 SYSTEMATIC FORMULATION DEVELOPMENT 192
7.1 Theoretical approach 192
7.1.1 Measures (Excipients and Procedures) 195
7.1.2 Monographs 201
7.1.3 Rules 201
7.1.3.1.1 Rules for the Solubility problem 201
7.1.3.1.2 Rules for the Viscosity problem 203
7.1.3.1.3 Rules for the Surface Tension problem 203
7.1.3.1.4 Rules for the Osmolarity problem 204
7.1.3.1.5 Rules for the Total Output Rate problem 204
7.1.3.1.6 Rules for the Particle Size problem 205
7.1.3.1.7 Rules for the pH problem 206
7.1.3.1.8 Rules for the Volume problem 206
7.1.3.1.9 Rules for the Taste problem 207
7.1.3.1.10 Rules for the Stability problem 207
7.1.3.1.11 Rules for the back steps 208
7.1.3.1.12 Rules for the prognosis of formulation properties 209
7.1.3.1.13 Rules for the quantity of excipients 210
7.2 Implementation 210
7.2.1 Knowledge base 219
IV


7.2.2 Output 231
Subchapter conclusion 232
8 DISCUSSION 233
9 CONCLUSION 236
10 OUTLOOK 237
11 GLOSSARY 238
12 SYMBOLS AND ABBREVIATION (ALPHABETIC ORDER) 240
13 APPENDIX 241
13.1 Appendix 1 (The problem with propellants) 241
13.2 Appendix 2: Lecithin (properties and experimental data) 241
13.2.1 Physical and Chemical Properties of Lecithin 241
13.2.2 Stability and Degradation of Lecithin 243
Chapter references 246
13.3 Appendix 3: Description of Test A 247
13.3.1 Description of Test A 247
13.4 Appendix 4: Properties of used substances 248
14 INDEX 291
V