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

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TRANSMUCOSAL NASAL DRUG DELIVERY

Pharmacokinetics and Pharmacodynamics of

Nasally Applied Esketamine

Inauguraldissertation

zur

Erlangung der Würde eines Doktors der Philosophie

vorgelegt der

Philosophisch-Naturwissenschaftlichen Fakultät

der Universität Basel

von

Christoph Bitter

aus Straubing, Deutschland

Basel, 2011

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

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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

Summary

Background and objectives

THEORETICAL SECTION

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

–  –  –

EXPERIMENTAL SECTION

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.



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