Transmucosal Nasal Drug Delivery: Systemic Bioavailability of ...

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Index 1 Index Abbreviations ..................................................................................................................1 Summary..........................................................................................................................3 Background and objectives............................................................................................7 THEORETICAL SECTION 1 Nasal drug delivery 1.1 Topical and systemic bioavailability of nasally applied drugs............................................ 11 1.2 Transmucosal nasal drug delivery ..................................................................................... 12 1.3 Challenges in transmucosal nasal drug delivery ............................................................... 14 1.4 Nose to brain-transport ...................................................................................................... 15 2 Impact of anatomy and physiology on transmucosal nasal drug delivery 2.1 Anatomy and physiology of the nose................................................................................. 17 2.2 Nasal mucosa and mucociliary clearance.......................................................................... 18 2.3 Drug metabolism in the nasal mucosa............................................................................... 21 2.4 Common cold and seasonal allergic rhinitis ...................................................................... 22 3 Midazolam 3.1 Physicochemical characterization...................................................................................... 23 3.2 Pharmacological effects, metabolism and elimination ....................................................... 24 3.3 Undesirable effects ............................................................................................................ 26 3.4 Midazolam delivery ............................................................................................................ 27 4 Compounding of nasal midazolam preparations 4.1 Regulatory requirements for nasal preparations (Ph. Eur. 5.5) ......................................... 31 4.2 Excipients for nasal midazolam preparations .................................................................... 31 4.3 Cyclodextrins...................................................................................................................... 33 4.4 Chitosan hydrochloride ...................................................................................................... 39 Katja Suter-Zimmermann Page I University of Basel, 2008
Index EXPERIMENTAL SECTION 5 Project I: Development of preparations for transmucosal nasal midazolam delivery 5.1 Introduction ........................................................................................................................ 45 5.2 Materials and methods....................................................................................................... 46 5.3 Results ............................................................................................................................... 49 5.4 Discussion.......................................................................................................................... 55 5.5 Conclusions ....................................................................................................................... 59 6 Project II: Pharmacokinetic of transmucosal nasal delivered midazolam – impact of adjuvants 6.1 Introduction ........................................................................................................................ 61 6.2 Methods ............................................................................................................................. 62 6.3 Results ............................................................................................................................... 65 6.4 Discussion.......................................................................................................................... 79 6.5 Conclusions ....................................................................................................................... 81 7 Project III: Transmucosal nasal delivery of low-dose midazolam – evaluation of two preparations for procedural anxiolysis 7.1 Introduction ........................................................................................................................ 83 7.2 Methods ............................................................................................................................. 83 7.3 Results ............................................................................................................................... 87 7.4 Discussion.......................................................................................................................... 92 7.5 Conclusions ....................................................................................................................... 95 8 Overall discussion......................................................................................................97 9 Final conclusions .....................................................................................................101 10 Appendix 10.1 Theoretical section ....................................................................................................... 105 10.2 Project I ........................................................................................................................ 106 10.3 Project II ....................................................................................................................... 127 10.4 Project III ...................................................................................................................... 163 11 References.............................................................................................................177 12 Curriculum vitae ....................................................................................................187 Katja Suter-Zimmermann Page II University of Basel, 2008
Page 1: TRANSMUCOSAL NASAL DRUG DELIVERY Sy
Page 5: Acknowledgments At the Hospital Pha
Page 11 and 12: Summary Summary Transmucosal nasal
Page 13: Summary Project III: In this random
Page 17: THEORETICAL SECTION
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8 Overall discussion pharmacokineti
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8 Overall discussion considered as
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Appendix
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10 Appendix 10.2 Project I 10.2.1 R
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10 Appendix 10.2.4 Specification: M
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10 Appendix 10.2.6 Specification: C
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10 Appendix Katja Suter-Zimmermann
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10 Appendix 10.2.9 Specification: C
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10 Appendix 10.3.2 Case report form
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10 Appendix Frequency 10.3.5 Intens
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10 Appendix 10.3.7 Serumconcentrati
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10 Appendix Identification midazola
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10 Appendix 10.3.8 Midazolam serum
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10 Appendix 10.3.10 Nasal delivery
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10 Appendix 10.4.3 Flowchart: multi
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11 References 11 References Abrams,
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11 References Erjefalt, J.S., I. Er
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11 References Irie, T. and K. Uekam
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11 References Malinovsky, J.M., C.
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11 References Scheepers, M., B. Sch
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12 Curriculum vitae 12 Curriculum v
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