Development and Evaluation of a Medicated Chewing Gum Containing Sceletium Tortuosum
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Development and evaluation of a medicated chewing gum containing Sceletium tortuosum S van der Walt 22197214 Dissertation submitted in fulfilment of the requirements for the degree Masters of Science in Pharmaceutics at the Potchefstroom Campus of the North-West University Supervisor: Dr J Viljoen Co-Supervisor: Prof S Hamman April 2016 ACKNOWLEDGEMENTS First and above all, I praise God, the almighty for providing me this opportunity and granting me the capability to proceed successfully. This thesis appears in its current form due to the assistance and guidance of several people. I would therefore like to offer my sincere thanks to all of them. Dr Joe Viljoen, my supervisor, thank you for accepting me as a M.Sc. student. The numerous hours, warm encouragement, thoughtful guidance, critical comments and correction of the thesis are appreciated immensely. The door of Dr Viljoen’s office was always open whenever I had a question about my research or writing. She consistently allowed this paper to be my own work but steered me in the right direction whenever she thought I needed it. It was a privilege to be able to work under your supervision. To Prof Sias Hamman, my co-supervisor, thank you for your time, tremendous help and support during the completion of this study. Your passion for research shows in your wide field of knowledge in the pharmaceutical industry. Your openness and ability to help others to the best of your knowledge makes you a remarkable researcher. I also want to thank the North-West University for awarding me the NWU Masters bursary, and Prof Alvaro Viljoen, for providing us with the S. tortuosum plant material. A special word of sincere gratitude to Prof Eugene Olivier from the Tshwane University of Technology. Thank you so much for letting me use your facilities and apparatus; and also assisting me during the dissolution studies. Dr Weiyang Chen, thank you for assisting with the UPLC analysis, as well as Dr Tiedt who helped me with obtaining SEM microscopic images of the highest quality. I want to express my gratitude and deepest appreciation to my father, Prof Kobus van der Walt for always motivating me to strive for more and to seize every opportunity in life. To my loving mother, Ina van der Walt, thank you for your support and motivation throughout the completion of this study. Thank you to the rest of my family and friends, especially Herman and Lize Redelinghuis, and Izak and Anna-mart van der Walt. My family’s unfailing support and continuous encouragement throughout my years of study and through the process of researching and writing this thesis are mostly appreciated. This accomplishment would not have been possible without them. I am truly blessed. i TABLE OF CONTENTS ACKNOWLEDGEMENTS i TABLE OF CONTENTS ii LIST OF FIGURES vii LIST OF TABLES x ABSTRACT xiii UITTREKSEL xv CHAPTER 1 INTRODUCTION, PROBLEM STATEMENT, AIM AND OBJECTIVES 1.1 Introduction 1 1.1.1 Sceletium tortuosum 1 1.1.2 Medicated chewing gum 2 1.1.3 SeDeM Expert Diagram System 3 1.2 Research problem 4 1.3 Aims and objectives 5 CHAPTER 2 LITERATURE STUDY 2.1 Introduction 7 2.2 The medicinal plant “Sceletium tortuosum” 8 2.2.1 History and location 8 ii 2.2.2 Mechanism of pharmacological action and uses 9 2.2.2.1 Serotonin reuptake inhibition 9 2.2.2.2 Phosphodiesterase (PDE4) enzyme inhibition 10 2.2.3 Previous studies conducted 11 2.2.4 In vivo studies: safety and toxicology 13 2.2.5 Products currently on the market 15 2.2.5.1 Elev 8® tablets 15 2.2.5.2 Sceletium tortuosum herbs 16 2.2.5.3 Sceletium tortuosum vegecaps 16 2.2.5.4 Sceletium tortuosum raw refined powder, capsules and oral spray 17 2.2.5.5 A variety of Sceletium tortuosum products 17 2.3 Medicated chewing gum 18 2.3.1 Introduction 18 2.3.2 Methods of production of medicated chewing gum 22 2.3.2.1 Fusion 22 2.3.2.2 Cooling, grinding and tableting 23 2.3.2.3 Direct compression 24 2.3.3 Release of medication from medicated chewing gum formulations and absorption through the oral epithelium 25 2.3.4 Evaluation of medicated chewing gums 30 2.4 SeDeM Expert Diagram System 33 2.4.1 Introduction 33 2.4.2 Parameters examined by the SeDeM method 34 iii 2.4.3 Acceptable limits for the SeDeM indices 38 2.4.4 Application of the SeDeM Expert Diagram System 38 2.5 Summary 40 CHAPTER 3 MATERIALS AND METHODS 3.1 Introduction 42 3.2 Materials 42 3.3 Preparation and characterisation of Sceletium tortuosum extracts 43 3.4 Powder evaluation as per SeDeM Expert Diagram System 45 3.4.1 Dimensional factor 46 3.4.2 Compressibility factor 47 3.4.3 Flowability/powder flow properties 47 3.4.4 Lubricity/stability factor 48 3.4.5 Lubricity/dosage factor 49 3.4.6 Determination of acceptable limit values for each parameter 49 3.4.7 Calculating the amount of excipient required to adjust a deficient parameter 50 3.5 Formulation of medicated chewing gum 51 3.5.1 Factorial design 51 3.5.2 Preparation of powder mixtures and medicated chewing gum 52 3.6 Evaluation of medicated chewing gums 52 3.6.1 Morphology 52 3.6.2 Mass variation 53 iv 3.6.3 Crushing strength, diameter, thickness and tensile strength 53 3.6.4 Friability 53 3.6.5 Dissolution 53 3.6.5.1 Preparation of artificial saliva 55 3.6.5.2 Ultra Performance Liquid Chromatographic analysis of artificial saliva samples 55 3.6.6 Statistical analysis of data 56 CHAPTER 4 RESULTS AND DISCUSSION 4.1 Introduction 57 4.2 Yield and chemical characterisation of Sceletium tortuosum extract 57 4.3 Evaluation of the powder characteristics 61 4.3.1 Introduction 61 4.3.2 Powder flow properties of Sceletium tortuosum extract powder and the Health In Gum base powders 62 4.3.3 Evaluation of Sceletium tortuosum extract powder as per SeDeM Expert Diagram System 66 4.3.4 Evaluation of Health in Gum base powders as per SeDeM Expert Diagram System 69 4.3.5 Comparing SeDeM diagrams of the Sceletium tortuosum extract powder and the Health In Gum base powders 78 4.3.6 Preparation and characterisation of medicated chewing gum powder mixtures 81 4.3.6.1 Evaluation of the flow properties of medicated chewing gum powder mixtures 82 v 4.3.6.2 Evaluation of medicated chewing gum powder mixtures as per SeDeM Expert Diagram System 84 4.4 Formulation of medicated chewing gums 93 4.4.1 Morphology 94 4.4.2 Evaluation of the physical properties of the different medicated chewing gum units 96 4.4.3 In-vitro dissolution studies 99 4.5 Conclusion 102 CHAPTER 5 SUMMARY AND FUTURE PROSPECTS 5.1 Summary 107 5.2 Future prospects 109 REFERENCES 110 ANNEXURE A: Cafosa®’s HIG bases, their characteristics and evaluations 122 ANNEXURE B: Handling procedure of Cafosa®’s HIG bases 129 ANNEXURE C: Particle size analysis for homogeneity index parameter 133 ANNEXURE D: Malvern® Mastersizer-2000 particle size analysis 154 vi LIST OF FIGURES Figure 1.1: Illustration of the SeDeM diagram with 12 parameters 4 Figure 2.1: Elev8® tablets in their original packaging 15 Figure 2.2: Dried Sceletium tortuosum plant material purchasable in South Africa 16 Figure 2.3: Sceletium tortuosum vegecaps in original packaging 16 Figure 2.4: Sceletium tortuosum raw refined plant material powder, capsules and oral spray 17 Figure 2.5: Sceletium tortuosum products as advertised 17 Figure 2.6: A schematic representation of (A) Transcellular diffusion and (B) Paracellular diffusion across the oral cavity mucosal epithelium 26 Figure 2.7: Schematic representation of the outer vestibule cavity 27 Figure 2.8: Schematic representation of the different layers of buccal mucosa 28 Figure 2.9: Schematic representation of the parotid, sub-maxillary and sublingual salivary glands 29 Figure 2.10: Construction of the European Pharmacopoeia apparatus (compendial) for testing the dissolution of chewing gum 31 Figure 2.11: A drawing of a non-compendial chewing apparatus for dissolution studies of medicated chewing gums with six chewing modules 32 Figure 2.12: Illustration of a single chewing module 33 Figure 2.13: A representation of a dodecagon shape diagram based on the twelve parameters of the SeDeM Expert Diagram System 37 Figure 3.1: Schematic representation of a Chewing Gum Tesing DRT-6 apparatus 54 Figure 4.1: Photograph of Sceletium tortuosum extract powder 58 vii Figure 4.2: (A) UPLC chromatogram and (B) MS chromatogram of the Sceletium tortuosum extract 60 Figure 4.3: (a) SEM micrograph of Sceletium tortuosum extract powder at a 95X magnification; and (b) SEM micrograph of Sceletium tortuosum extract powder at a 95X magnification including random size measurements of individual particles 64 Figure 4.4: SEM micrographs of Health In Gum 01 base powder displayed in row (a); Health In Gum 03 base powder in row (b); and Health In Gum 04 base powder in row (c). SEM micrographs of the random size measurements of individual particles of the different bases are displayed in column (i) and (ii) at a magnification of 95X 65 Figure 4.5: SeDeM diagram for Sceletium tortuosum extract powder 67 Figure 4.6: SeDeM diagrams for (a) Health In Gum 01 base powder; (b) Health In Gum 03 base powder; and (c) Health In Gum 04 base powder 71 Figure 4.7: Superimposed SeDeM diagrams of Sceletium tortuosum extract powder (yellow) with (a) Health In Gum 01 (green); (b) Health In Gum 03 (blue); and (c) Health In Gum 04 (purple).