PERFORMANCE TESTING OF MEDICATED CHEWING GUMS WITH THE GOAL OF ESTABLISHING IN VITRO IN VIVO CORRELATION Dissertation zur Erlangung des Grades „Doktor der Naturwissenschaften“ im Promotionsfach Pharmazie am Fachbereich Chemie, Pharmazie und Geowissenschaften der Johannes Gutenberg-Universität in Mainz Jayachandar Gajendran (geb. in Chennai, Indien) Mainz, den 2016 Dekan: 1. Berichterstatter: 2. Berichterstatter: Tag der mündlichen Prüfung: 10.01. 2017 D77 Dissertation Universität Mainz II DECLARATION I hereby declare that the dissertation titled “Performance testing of medicated chewing gums with the goal of establishing in vitro - in vivo correlation” is the result of my own research work and includes nothing which is the outcome of work done in collaboration. Where other sources of information have been used, they have been acknowledged. No portion of work contained in this dissertation has been submitted in support of any application for any other degree or qualification. Jayachandar Gajendran III IV Dedicated to My Family V VI CONTENTS ACKNOWLEDEMENTS ................................................................................................ IX LIST OF FIGURES ......................................................................................................... XI LIST OF TABLES....................................................................................................... XVII LIST OF ABBREVIATIONS ........................................................................................ XIX 1 Introduction ..................................................................................................................1 1.1 Introduction to buccal drug delivery .........................................................................1 1.2 Drug delivery within the oral cavity..........................................................................5 1.3 Dosage form taxonomy .......................................................................................... 11 1.4 Manufacturing process ........................................................................................... 15 1.5 Quality evaluation of chewing gum formulations .................................................... 17 1.6 In vitro in vivo correlation ...................................................................................... 23 2 Aims of the thesis ........................................................................................................ 29 2.1 Aims of the thesis and dissertation outline .............................................................. 29 3 Materials ..................................................................................................................... 31 3.1 Selection of drug products for the study .................................................................. 31 3.2 Physicochemical properties of marketed chewing gum formulations....................... 32 3.3 Reagents and chemical substances .......................................................................... 40 3.4 Reference standard substances ................................................................................ 42 3.5 Analytical instruments and laboratory supplies ....................................................... 43 4 Methods ....................................................................................................................... 45 4.1 Scientific rationale for in vitro drug release determination ...................................... 45 4.2 Current status of drug release/dissolution testing apparatus ..................................... 46 4.3 Apparatus for release testing of MCGs ................................................................... 47 4.4 Preparation of buffer solutions ................................................................................ 52 4.5 Method of pharmaceutical analysis for gum formulations ....................................... 54 4.6 Stability testing procedure ...................................................................................... 56 4.7 Method of solubility investigations ......................................................................... 56 4.8 Assay and content uniformity testing ...................................................................... 57 4.9 In vitro drug release testing .................................................................................... 58 4.10 Chew-out study ...................................................................................................... 63 4.11 Formulation of nicotine chewing gums by direct compression technique ................ 64 4.12 Coating and micro-encapsulation of DRC ............................................................... 71 4.13 Design of Experiments (DoE) ................................................................................. 75 4.14 Fourier transform infra-red analysis ........................................................................ 78 VII 4.15 Manufacturing of nicotine chewing gums by direct compression ............................ 79 4.16 Method of data evaluation and interpretation .......................................................... 83 4.17 Methods of in vivo data evaluation ......................................................................... 88 5 Results ......................................................................................................................... 91 5.1 HPLC data analyses for model drug substances ...................................................... 91 5.2 Feasibility study results .......................................................................................... 96 5.3 In vitro in vivo correlation .................................................................................... 144 5.4 Formulation development of nicotine gum by direct compression (DC) ................ 164 6 General discussion .................................................................................................... 215 6.1 Product performance testing ................................................................................. 215 6.2 Verification of in vitro test methodology .............................................................. 217 6.3 Formulation development ..................................................................................... 218 7 Abstract ..................................................................................................................... 221 8 Zusammenfassung .................................................................................................... 223 9 Bibliography.............................................................................................................. 225 10 Appendix ................................................................................................................... 237 VIII ACKNOWLEDEMENTS IX X LIST OF FIGURES Figure 1-1. Cross section through oral mucosa..............................................................................3 Figure 1-2. Flow of saliva (mL/min) .............................................................................................4 Figure 1-3. Summary of factors affecting drug release from chewing gum formulations.............. 10 Figure 1-4. Figure showing the force measured on a chewing machine during the simulation of chewing action to test the release of actives from medicated gums ............................ 21 Figure 1-5. Schematic overview of the steps involved for establishing IVIVC ............................ 24 Figure 1-6. Figure showing the typical plasma concentration time curve along with the elimination curve and fraction absorbed/dissolution curve ........................................................... 26 Figure 3-1. Chemical structure of nicotine .................................................................................. 33 Figure 3-2. Chemical structure of nicotine hydrogen tartrate ....................................................... 34 Figure 3-3. Chemical structure of nicotine polacrilex resin ......................................................... 34 Figure 3-4. Chemical structure of caffeine .................................................................................. 35 Figure 3-5. Chemical structure of dimenhydrinate ...................................................................... 36 Figure 4-1. “Home depot” apparatus developed by Phast for compression of chewing gums ....... 48 Figure 4-2. Apparatus A for the drug release testing of medicated chewing gums ....................... 49 Figure 4-3. Apparatus B for the drug release testing of medicated chewing gums........................ 50 Figure 4-4. Un-mounted parts of the chewing apparatus ............................................................. 51 Figure 4-5. Chewing gums of uniform surface area after pressed with “Home Depot” method .... 59 Figure 4-6. Conventional dissolution tests with MCGs ............................................................... 59 Figure 4-7. Schematic representation of the in vivo chew out model vs. the classical BA model .. 63 Figure 4-8. Release of nicotine from a commercially available gum and a directly compressed chewing gum formulation ......................................................................................... 65 Figure 4-9. Release of nicotine from directly compressed chewing gum formulation................... 66 Figure 4-10. Structure of Eudragit RS 100 ...................................................................................