Cannabinoids delivery systems based on supramolecular inclusion complexes and polymeric nanocapsules for treatment of neuropathic pain Fanny Astruc-Diaz To cite this version: Fanny Astruc-Diaz. Cannabinoids delivery systems based on supramolecular inclusion complexes and polymeric nanocapsules for treatment of neuropathic pain. Human health and pathology. Université Claude Bernard - Lyon I, 2012. English. NNT : 2012LYO10099. tel-00935588 HAL Id: tel-00935588 https://tel.archives-ouvertes.fr/tel-00935588 Submitted on 23 Jan 2014 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. N° d’ordre : 99-2012 Année 2012 THESE DE L‘UNIVERSITE DE LYON Délivrée par L’UNIVERSITE CLAUDE BERNARD LYON 1 ECOLE DOCTORALE DE CHIMIE DIPLOME DE DOCTORAT (arrêté du 7 août 2006) soutenue publiquement le 9 Juillet 2012 par Mme. ASTRUC-DIAZ Fanny CANNABINOIDS DELIVERY SYSTEMS BASED ON SUPRAMOLECULAR INCLUSION COMPLEXES AND POLYMERIC NANOCAPSULES FOR TREATMENT OF NEUROPATHIC PAIN Jury Mme. DUCKI Sylvie Rapporteur M. VIERLING Pierre Rapporteur M. DUTASTA Jean-Pierre Examinateur M. PAROLA Stéphane Directeur de thèse M. THOMPSON Charles Examinateur - 1 - | Page gÉ `tààxÉ tÇw `tå|Åx? gÉ c{|Ä|ÑÑx? - 2 - | Page ACKNOWLEGEMENTS I would like to give my sincere gratitude to my advisor, Dr. Stephane Parola, for his confidence and for giving me the opportunity of conducting this Ph.D research. I wish to give my profoundness appreciation to Dr. Philippe Diaz for his excellence guidance, patience, caring and time to complete this work. I would like to thank Dr. Charles Thompson for generously giving me the time and the support to achieve this project. I would also like to thank my Jury members for their time to review my dissertation. I am appreciative of the help I've received from my colleagues at the University of Montana, Steven McDaniel for the cyclodextrin molecular modeling, Dr. James Driver for conducting the nanocapsules morphological studies, Dr. Christopher Palmer for his guidance with the use of the GC-MS, Dr. Ravil Petrov for his help and practical experience in the laboratory, and Dr. Nicolas Guilloteau and Dr. Yamina Belabassi for their warm words of encouragement. I am also appreciative for my co-workers at MD Anderson Cancer Center and Dr. Mohamed Naguib for giving me the opportunity to work in his laboratory, Dr. Gabriel Lopez-Berestein for teaching me how to make non ionic liposomes and Dr. Pablo Vivas-Mejia for his help preparing them. I would like to give my gratitude to Dr. Jon Nagy and Ryan Holly for hosting me in their laboratory and assisting me with particle sizing studies. Finally, I would like to thank my friend, Agnes, and my family, my mum and my sister Melanie for their unconditional trust and support through all this difficult and rewarding experience, and my dad who passed away before the completion of this thesis. I am gratefuI to my parents in law, Nelly and Mario for their gentleness and their help taking care of my sons while I was busy preparing my seminar. I would also like to thank my sons for their love and patience even when I was frustrated and not available for them. Most of all, I would like to thank my husband who loved me when I deserved it the least but when I needed the most. - 3 - | Page TABLE OF CONTENTS LIST OF ABBREVIATIONS.……………….………………………………………..- 10 - INTRODUCTION AND OBJECTIVES.…………………………………………...- 15 - CHAPTER I: BIBLIOGRAPHY.………………………………………..……….......- 17 - 1. Cannabis. .......................................................................................................... - 17 - 2. Endocannabinoid system. .................................................................................. - 18 - 3. Cannabinoid receptors. ..................................................................................... - 20 - 4. Endocannabinoids.............................................................................................. - 21 - 5. Enzymes. ........................................................................................................... - 23 - 6. Cannabinoid receptor-mediated intracellular signal pathways. .......................... - 26 - 7. Interactions of cannabinoids with some other receptor systems. ....................... - 28 - 8. Drug of abuse..................................................................................................... - 30 - 9. Therapeutic cannabinoid derivatives on the market. .......................................... - 31 - 10. Phytocannabinoids. ............................................................................................ - 32 - 11. Pain. ................................................................................................................... - 34 - 11.1. Physiological pain............................................................................................ - 34 - 11.2. Neuropathic pain. ............................................................................................ - 37 - 12. CB2 receptors: a target for Neuropathic Pain treatment? .................................. - 42 - 13 References. ........................................................................................................ - 44 - CHAPTER II EARLY FORMULATION AND ENABLING DRUG DELIVERY SYSTEMS DESIGN.............................................................................................. - 62 - 1 Introduction. ................................................................................................ ……- 62 - 1.2 Cyclodextrins. .................................................................................................. - 65 - 1.2.1 Cyclodextrins and complexation. ............................................................................... - 67 - 1.3 Liposomes. ...................................................................................................... - 78 - 1.4 Micelles. .......................................................................................................... - 82 - - 4 - | Page 1.5 Oral Self-Emulsifying Drug Delivery System (SEDDS). ……………………….- 87 - 2 Development of enabling Drug Delivery Systems for the in vivo administration of a series of lipophilic synthetic cannabinoids. ......................................................... - 89 - 2.1 MDA7. ............................................................................................................. - 91 - 2.2 MDA7 physico-chemical properties. ................................................................ - 91 - 2.3 In vitro characterization of MDA7. ................................................................... - 92 - 2.4 Enabling Drug Delivery System design and development. .............................. - 94 - 2.4.1 Preformulation studies. .............................................................................................. - 95 - 2.4.2 MDA7 enabling DDS design and development. ................................................... - 97 - 2.5 In vivo characterization of MDA7. .................................................................. - 130 - 2.5.1 Pharmacokinetic study. ................................................................................... - 130 - 2.5.2 Influence of the DDS selected on MDA7 in vivo efficacy. .................................... - 132 - 2.5.3 Effect of MDA7 administered intraperitoneally on models of nociception in rats. ….- 135 - 2.5.4 Effects of MDA7 on tactile allodynia in the spinal nerve ligation model of neuropathic pain. ……………………………………………………………………………………….- 136 - 2.5.5 Effects of MDA7 on tactile allodynia in a paclitaxel-induced neuropathic pain model. …………………………………………………………………………………………… - 139 - 2.5.6 Open-field chamber testing...................................................................................... - 140 - 2.6 Other cannabinoids evaluated in vivo............................................................ - 141 - 3 Summary and Conclusion. ............................................................................... - 144 - 4 References. ...................................................................................................... - 146 - CHAPTER III CATIONIC POLYMERIC NANOCAPSULES.…......………- 159 - 1 Review. ............................................................................................................ - 159 - 1.1 Structure of drug-loaded nanoparticles. ........................................................ - 159 - 2 Applications of drug-loaded polymeric nanoparticles. ...................................... - 160 - 3 Nanoparticles uptake in cells............................................................................ - 161 - 4 Drug-loaded nanoparticles composition and bioadhesion. ............................... - 161 - 5 Methods of preparation of polymeric drug-loaded nanoparticles. ..................... - 162 - 6 Nanoprecipitation of preformed polymer. ......................................................... - 163 - - 5 - | Page 7 Nanoparticles and oral delivery. ....................................................................... - 164 - 8 Concepts