FREE ELECTRONIC LIBRARY - Abstract, dissertation, book

Pages:   || 2 | 3 | 4 | 5 |   ...   | 17 |

«Pharmacokinetics and Pharmacodynamics of Nasally Applied Esketamine Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie ...»

-- [ Page 1 ] --


Pharmacokinetics and Pharmacodynamics of

Nasally Applied Esketamine



Erlangung der Würde eines Doktors der Philosophie

vorgelegt der

Philosophisch-Naturwissenschaftlichen Fakultät

der Universität Basel


Christoph Bitter

aus Straubing, Deutschland

Basel, 2011

Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch

Dieses Werk ist unter dem Vertrag „Creative Commons Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 2.5 Schweiz“ lizenziert. Die vollständige Lizenz kann unter creativecommons.org/licences/by-nc-nd/2.5/ch eingesehen werden.

Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 2.5 Schweiz

Sie dürfen:

das Werk vervielfältigen, verbreiten und öffentlich zugänglich machen

Zu den folgenden Bedingungen:

Namensnennung. Sie müssen den Namen des Autors/Rechteinhabers in der von ihm festgelegten Weise nennen (wodurch aber nicht der Eindruck entstehen darf, Sie oder die Nutzung des Werkes durch Sie würden entlohnt).

Keine kommerzielle Nutzung. Dieses Werk darf nicht für kommerzielle Zwecke verwendet werden.

Keine Bearbeitung. Dieses Werk darf nicht bearbeitet oder in anderer Weise verändert werden.

Im Falle einer Verbreitung müssen Sie anderen die Lizenzbedingungen, unter welche dieses Werk fällt, • mitteilen. Am Einfachsten ist es, einen Link auf diese Seite einzubinden.

Jede der vorgenannten Bedingungen kann aufgehoben werden, sofern Sie die Einwilligung des • Rechteinhabers dazu erhalten.

Diese Lizenz lässt die Urheberpersönlichkeitsrechte unberührt.

• Die gesetzlichen Schranken des Urheberrechts bleiben hiervon unberührt.

Die Commons Deed ist eine Zusammenfassung des Lizenzvertrags in allgemeinverständlicher Sprache:



Die Commons Deed ist kein Lizenzvertrag. Sie ist lediglich ein Referenztext, der den zugrundeliegenden Lizenzvertrag übersichtlich und in allgemeinverständlicher Sprache wiedergibt. Die Deed selbst entfaltet keine juristische Wirkung und erscheint im eigentlichen Lizenzvertrag nicht. Creative Commons ist keine Rechtsanwaltsgesellschaft und leistet keine Rechtsberatung. Die Weitergabe und Verlinkung des Commons Deeds führt zu keinem Mandatsverhältnis.

Quelle: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/ Datum: 3.4.2009 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. phil. Christian Surber Prof. Dr. phil. Georgios Imanidis Prof. Dr. phil. Christoph Meier

–  –  –

Acknowledgments The present thesis was accomplished at the Hospital Pharmacy of the University Hospital Basel (UHBS), Switzerland from 2006 to 2010. I would like to thank everyone who supported me in realizing my projects.

I am deeply grateful to my supervisor Prof. Dr. phil. II Christian Surber, former head of the Hospital Pharmacy (UHBS), now Head of Research and Development, Director, Spirig Pharma AG (Egerkingen, Switzerland), for giving me the opportunity to perform my thesis in the interdisciplinary and fascinating research area of transmucosal nasal drug delivery. I very much appreciated his enthusiasm, his trust, the motivating discussions and his filling my backpack for the future in many ways.

To Prof. Dr. Georgios Imanidis, University of Applied Sciences Northwestern Switzerland FHNW, Basel, I want to express my sincere thanks for welcoming me in his Membrane Transport Group, for the interesting discussions, and for accepting the co-report of this thesis. Further thanks go to Prof. Dr. Christoph R. Meier, Head of Basel Pharmacoepidemiology Unit and Hospital Pharmacy (UHBS), for presenting my thesis to the faculty.

Many thanks go to the team of the Rohstofflabor (Spirig Pharma AG, Egerkingen), enabling determination of viscosity under GMP conditions, and to Dipl. Ing. (FH) Christian Kassecker (Ingenieurbüro Christian Kassecker, Munich, Germany), for generously providing the software for viscosity analytics.

I would like to thank Prof. Dr. Antje Welge-Lüssen, Department of Otorhinolaryngology (UHBS) for the opportunity to perform the FNA-study, for her clinical contributions and the fruitful inputs. Many thanks go to Patrick Berger, Anklin AG, Binningen, for uncomplicatedly providing the light source and a fluorescence filter system.

I highly appreciated the cooperation with the Clinical Research Center (CRC) of the University Hospital Basel during the Eskena-study. My sincere thanks go to Dr. Manuel Haschke, head of CRC, for his clinical contributions, his professional support, his patience, and for imparting his expertise. Special thanks go to Dr. Oliver Bandschapp, Department of Anesthesiology (UHBS) for performing the pain test and the memorable teamwork during the second part of the Eskena-study.

I would like to thank Dr. Marcel Bruggisser, Claudia Bläsi, and Luisa Baselgia for their help during the study. Further thanks go to PD Dr. Matthias E. Liechti, clinical pharmacology & toxicology (UHBS) for his assistance in choosing appropriate psychometric questionnaires. I am thankful to Dr. Thomas Briellmann, Dr. Franz Dussy, and Cornelia Hambach Stäubli, Institute of Legal Medicine, Basel, for performing the serum analyses of esketamine and ketamine.

Acknowledgments Many thanks go to Prof. Dr. Wolfgang Ummenhofer and to Dr. Wilhelm Ruppen, Department of Anesthesiology (UHBS) for enabling the performance of the pain test and the interesting discussions.

I am thankful to Dr. Thomas Zumbrunn and Dr. Thomas Fabbro, study coordination center (UHBS) for statistical analyses, and to Judith Moosburner for help with figures of the theoretical section.

Special thanks go to my colleagues Dr. Meike Timmermann, Verena Figueiredo, Dr. Miriam Reiser, Alfred Reichert, and Martin Stalder for their support and motivation.

I am thankful to Dipl. Ing. (FH) Dr. Franz Stierstorfer for his clinical expertise and proof reading of my manuscript with attention to details.

Heartfelt thanks go to Dr. Katja Suter-Zimmermann for introducing me to the topic of transmucosal nasal drug delivery and sharing her expert knowledge with me.

The most cordial thanks go to my family for their respect, encouragement, and intense support.

Index Index Abbreviations


Background and objectives


1 Transmucosal nasal drug delivery

1.1 Transmucosal nasal drug delivery

1.2 Trends in Transmucosal nasal drug delivery

2 Impact of anatomy and physiology on transmucosal nasal drug delivery

2.1 Functions of the nose

2.2 Anatomy of the nose

2.3 Nasal mucus and mucociliary clearance

2.4 Ways of transmucosal absorption

2.5 In vitro – in vivo correlation in transmucosal nasal drug delivery

3 Challenges in nasal drug delivery

4 Drug – vehicle – device: triad of nasal drug delivery

5 Esketamine

5.1 Physicochemical characterization

5.2 Pharmacologic effects and indications

5.3 Side effects

5.4 Esketamine delivery

6 Absorption enhancer in transmucosal nasal drug delivery

6.1 Prolonged residence time – mucoadhesion and in situ gelling

6.2 Permeation enhancement

6.3 Poloxamer 407

6.4 Chitosanhydrochloride

–  –  –


7 Project I: Development and Characterization of the Nasal Study Medication

7.1 Introduction

7.2 Materials and methods

7.3 Results

7.4 Discussion

7.5 Conclusion

8 Project II: Mucociliary Transport Time and Maximal Application Volume of Vehicles for Transmucosal Nasal Drug Delivery in Healthy Volunteers (FNA-study)

8.1 Introduction

8.2 Subjects and methods

8.3 Results

8.4 Discussion

8.5 Conclusion

9 Project III: Impact of Absorption Enhancer on Pharmacokinetics of Nasally Applied Esketamine in Healthy Volunteers (Eskena-study part I)

9.1 Introduction

9.2 Subjects and methods

9.3 Results

9.4 Discussion

9.5 Conclusion

10 Project IV: Intranasal, Intramuscular, and Intravenous Applied Esketamine:

Determination of Pharmacokinetics, Analgesic Effects, and Psychic Side Effects in Healthy Volunteers (Eskena-study part II)

10.1 Introduction

10.2 Subjects and methods

10.3 Results

10.4 Discussion

10.5 Conclusion

11 Final conclusions and perspectives

12 Appendix

12.1 Project I

12.2 Project III and IV

13 References

14 Curriculum vitae

–  –  –

Summary The aim of this thesis was the in vivo investigation of the bioavailability of nasal esketamine formulations which were developed considering the strategies of enhancing the permeation and prolonging the residence time on the nasal mucosa as absorption site.

Nasal application of esketamine has the potential to be a needle-free and time-saving application mode for emergency situations and a convenient and painless application mode for chronic pain situations allowing self-application by patients. Transmucosally absorbed esketamine circumvents its extensive hepatic first-pass metabolism after oral application. Only moderate absorption of esketamine via the nasal mucosa is reported. Therefore, nasal esketamine formulations providing a substantial bioavailability need to be developed.

In Project I different formulations for transmucosal nasal delivery of esketamine were developed.

Mucoadhesive properties and the maximal nasally applicable volume of these vehicles were investigated in healthy volunteers by observation of the mucociliary transport time (MCTT) of fluorescence labelled vehicles (Project II). The impact of the vehicle on the bioavailability of esketamine in healthy volunteers was investigated in Project III. The nasal esketamine formulation resulting in the highest bioavailability was selected for further investigation in Project IV.

Pharmacokinetics and pharmacodynamics (analgesic effects upon electrically evoked pain) of the selected nasal esketamine formulation were tested in comparison to i.m. and i.v. applied esketamine in healthy volunteers (Project IV).

Project I: Nasal esketamine formulations with the absorption enhancer chitosan and poloxamer (alone and in combination) were developed, which allow administering 20mg esketamine base by each one spray application of 100µl per nostril. An aqueous esketamine solution served as comparator formulation. Stability of the esketamine formulations during the shelf life of 6 months and sufficient microbiological quality as a prerequisite for clinical investigations (Project III and IV) were verified. Four corresponding formulations with fluoresceine-natrium instead of esketaminehydrochloride were developed for investigating the mucoadhesive characteristics of the vehicles and the maximal nasal application volume to prevent immediately swallowing (Project II).

Project II: The usage of an endoscopic fluorescence-filter system facilitates practical in vivo determination of MCTT of the developed fluoresceine-natrium labeled nasal vehicles in healthy volunteers (FNA-study). The vehicle with chitosan showed due to its mucoadhesive characteristics a significant longer MCTT and allows application of 200µl per nostril without immediate run-off problems. A poloxamer containing thermogelling formulation with the same viscosity and osmolality as the formulation containing chitosan showed no prolonged MCTT. Not the viscosity but the character of the excipient has greater influence on the MCTT. The combination of chitosan and poloxamer showed a statistically significant prolongation of MCTT compared to the comparator formulation. The prolongation of the MCTT was less pronounced for the combination of chitosan Christoph Bitter Page 3 of 202 University of Basel, 2010 Summary and poloxamer than for chitosan alone. The effect of an initially slower clearance of the vehicle on the bioavailability of the incorporated drug has to be elucidated in a pharmacokinetic trial.

Project III: The impact of vehicles with the excipients chitosan and poloxamer (alone and in combination) on the pharmacokinetics of nasally applied esketamine was assessed in healthy volunteers (Eskena-study, part I). An aqueous esketamine solution served as comparator formulation. Nasal compatibility and side effects of the different formulations were determined.

None of the formulations was bioequivalent according to AUC and cmax of the others tested according to current EMEA-guidelines. The impact of the vehicle was overall statistically significant for AUC and tmax. The vehicle with the mucoadhesive and permeation enhancing excipient chitosan was exclusively transmucosal absorbed and had a statistically significant impact (increase) on the AUC. The combination of poloxamer and chitosan had a statistically significant impact (reduction) on tmax, but not chitosan or poloxamer alone. The thermogelling vehicle with poloxamer was not statistically significant different from the comparator formulation according to pharmacokinetic parameters.

As the fluoresceine labeled vehicles for assessing MCTT do not consider the effects of esketamine on the mucosa, they are similar but not equal to the tested nasal esketamine formulations. The median of the MCTT of the comparator formulation, the formulation with chitosan and poloxamer, and the formulation with chitosan was analog with the mean of the bioavailability of the corresponding formulations with esketamine. This indicates that the prolonged mucosal residence time of the formulation with chitosan might be a reason for the higher bioavailability of this formulation. This hint has to be investigated in further clinical trials.

Pages:   || 2 | 3 | 4 | 5 |   ...   | 17 |

Similar works:

«BECAUSE IT FEELS GOOD A Hedonistic Theory of Intrinsic Value Ole Martin Moen Doctoral Dissertation in Philosophy Faculty of Humanities University of Oslo, Norway December 2012 Because It Feels Good: A Hedonistic Theory of Intrinsic Value © Ole Martin Moen Exceptions: Pages 53–72 © Springer Pages 135 – 170 © Reason Papers Word count: 72,200 To my parents, for letting me think for myself Intense, long, certain, speedy, fruitful, pure— Such marks in pleasures and pains endure Such...»

«Placing Refuge: Shell Mounds and the Archaeology of Colonial Encounters in the San Francisco Bay Area, California By Tsim Duncan Schneider A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Anthropology in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Kent G. Lightfoot, Chair Associate Professor Junko Habu Professor Margaret W. Conkey Professor Kerwin Klein Spring 2010 Placing Refuge:...»

«Behavioral and Neural Effects of Reasoning Training by Allyson Mackey A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Neuroscience in the Graduate Division of the University of California, Berkeley Committee: Professor Silvia A. Bunge, Ph.D. (Chair) Professor Robert T. Knight, M.D. Professor Sonia J. Bishop, Ph.D. Professor Susan I. Stone, Ph.D. Fall 2012 Abstract Behavioral and Neural Effects of Reasoning Training by Allyson Mackey...»

«Mary Corwin Herring, Ph.D. Department of Curriculum and Instruction Division University of Northern Iowa 159a Schindler Education Center Cedar Falls, IA 50614-0606 Phone: (319) 273-2368 E-mail: mary.herring@uni.edu EDUCATION Doctor of Philosophy, Curriculum and Instruction: Instructional Technology Iowa State University, Ames, IA 1997 Master of Science, Education: Physical Education North Dakota State University, Fargo, ND 1989 Bachelor of Science, Physical Education North Dakota State...»

«|Philosophical Writings Vol. 41 No.1| A Defense of Causal Creationism in Fiction David Sackris SUNY Buffalo In this paper I seek defend the view that fictional characters are author-created abstract entities against objections offered by Stuart Brock in his paper “The Creationist Fiction: The Case against Creationism about Fictional Characters.” I argue that his objections fall far short of his goal of showing that if philosophers want to believe in fictional characters as Abstract...»

«DIPLOMARBEIT Titel der Diplomarbeit Frühe Johannesschüsseln Verfasser Georg Geml angestrebter akademischer Grad Magister der Philosophie (Mag. phil.) Wien, im August 2009 A 315 Studienkennzahl lt. Studienblatt: Kunstgeschichte Studienrichtung lt. Studienblatt: Univ.-Prof. Dr. Michael Viktor Schwarz Betreuerin / Betreuer: ii DANKSAGUNG Ich danke folgenden Personen für die Unterstützung: meinen Eltern Renate und Norbert Geml, Mag. Ursula Arendt, Mag. Ann Katrin Bäumler, Mag. Veronika Decker,...»

«Title of the program* Materiality–Corporeity–Movement Updated Version Applicant, Principal Investigator Univ.Doz.Mag.Dr.phil. Arno BOEHLER (University of Vienna, Department of Philosophy, 40 % self application) Co-Applicants Univ.Prof.MMag.Dr. Susanne GRANZER, partner 1 (Lecture-Performances) (University of Music and Performing Arts Vienna, Max Reinhardt Seminar) Univ.Doz.Dr. Krassimira KRUSCHKOVA, partner 2 (Lecture-Performance Archive) (Director of the Theory Department at Tanzquartier...»

«©Copyright 2009 Deborah A. Turner Conceptualizing Oral Documents Deborah A. Turner A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington Program Authorized to Offer Degree: Information School. University of Washington Graduate School This is to certify that I have examined this copy of a doctoral dissertation by Deborah A. Turner and have found that it is complete and satisfactory in all respects, and that any and...»

«Proceedings of the Electroacoustic Music Studies NetworkConference Electroacoustic Music Beyond Performance, Berlin, June 2014 www.ems-network.org How to Think Sound in Itself? Towards a Materialist Dialectic of Sound Luc Döbereiner luc.doebereiner@gmail.com Abstract This paper develops an ontological-aesthetic perspective on sound that draws primarily on the works of the philosophers Alain Badiou, Slavoj Žižek, and Karen Barad. The basic starting point is here, how to think sound in itself,...»

«NMR Studies of MRI Contrast Agents and Cementitous Materials by Zihui Peng A Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Approved November 2013 by the Graduate Supervisory Committee: Robert Marzke, Chair Sandwip Dey Narayanan Neithalath Ralph Chamberlin Martha McCartney ARIZONA STATE UNIVERSITY December 2013 ABSTRACT Nuclear magnetic resonance (NMR) is an important phenomenon involving nuclear magnetic moments in magnetic field, which...»

«Event-based Multi-document Summarization Lu´ Carlos dos Santos Marujo ıs CMU-LTI-15-010 Language Technologies Institute Dep. of Computer Science and Engineering School of Computer Science Instituto Superior T´cnico e Carnegie Mellon University University of Lisbon 5000 Forbes Ave., PA 15213 Av. Rovisco Pais, 1, 1049-001 Lisbon United States of America Portugal Thesis Advisers: Prof. Jaime Carbonell, Carnegie Mellon University Prof. Anatole Gershman, Carnegie Mellon University Prof. David...»

«ÖKOLOGISCHE WELTBILDER IN DEN WERKEN ADALBERT STIFTERS EINHEITSERFAHRUNG UND HERRSCHAFTSWILLE by EVA SATTELMAYER A thesis submitted to the Department of German In conformity with the requirements for the degree of Doctor of Philosophy Queen’s University Kingston, Ontario, Canada July, 2010 Copyright © Eva Sattelmayer, 2010 Abstract It is an undeniable fact that Adalbert Stifter paid detailed attention to his natural surroundings. Yet in the 1980s and 90s Stifter research focused on the...»

<<  HOME   |    CONTACTS
2016 www.abstract.xlibx.info - Free e-library - Abstract, dissertation, book

Materials of this site are available for review, all rights belong to their respective owners.
If you do not agree with the fact that your material is placed on this site, please, email us, we will within 1-2 business days delete him.