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Formulation and Assessment of Taste Masked Combination Therapies for the Treatment of Paediatric Tuberculosis

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Formulation and Assessment of Taste Masked Combination Therapies for the Treatment of Paediatric Tuberculosis UCL SCHOOL OF PHARMACY Formulation and Assessment of Taste Masked Combination Therapies for the Treatment of Paediatric Tuberculosis Alison Keating Thesis submitted in accordance with the requirements of UCL School of Pharmacy for the degree of Doctor of Philosophy September 2017 UCL School of Pharmacy 29 – 39 Brunswick Square, London, WC1N 1AX. Declaration DECLARATION I, Alison Keating, confirm that the work presented in this thesis is my own. This work was conducted at University College London School of Pharmacy from May 2014 to September 2017 under the supervision of Professor Duncan Craig, Dr. Catherine Tuleu and Dr. Claire Forbes. Wherever collaborative work is described every effort is made to indicate this clearly. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. _________________________________ _______________ Alison Keating Date 2 For Mam and Dad 3 Imíonn an tuirse, ach fanann an tairbhe 4 Abstract ABSTRACT Tuberculosis is a major global health problem, which ranks alongside HIV as a leading cause of death worldwide. Adherence to tuberculosis treatment regimens is quite low, particularly in paediatric patients, and the aversive taste of these medicines is often cited as a major reason for this. In the first part of this thesis, the taste of these four drugs was assessed using both a human taste panel and the rodent Brief Access Taste Aversion (BATA) model. Human EC50 (i.e. the concentration of drug which elicits 50% of the maximum taste response) values were determined for each drug and the BATA model was identified as being useful for the assessment of formulations containing isoniazid, rifampicin and ethambutol. The ability of an in vitro technique, the Insent TS-5000Z electronic tongue, to detect and assess the taste of isoniazid, rifampicin, pyrazinamide and ethambutol dihydrochloride was investigated. The best correlation between human responses and electronic tongue responses was observed for ethambutol dihydrochloride. The latter half of this thesis focused on the use of hot melt extrusion (HME) as a processing technique to develop taste masked polymeric formulations of isoniazid and rifampicin and a fixed dose combination containing both isoniazid and rifampicin. A fixed dose combination (FDC) formulation containing 20% w/w isoniazid and 30% w/w rifampicin was produced using Eudragit E-PO as a carrier. The extrudate was milled and incorporated into a dispersible tablet. The weight uniformity, thickness, hardness, disintigration time and content uniformity of the tablets were investigated and found to conform to the specifications for solid dosage forms. The dispersible tablet was found to effectively mask the taste of the drugs when dispersed in water with the drug release remaining below the human EC50 value for each drug. 5 Impact Statement IMPACT STATEMENT This thesis focuses on the development of a taste-masked fixed dose combination for the treatment of paediatric tuberculosis. In the initial part of this work the taste of isoniazid, rifampicin, pyrazinamide and ethambutol dihydrochloride (the four first line drugs used for the treatment of paediatric tuberculosis) was assessed using a human taste panel. This allowed for EC50 values, i.e. the concentration of drug which elicits half the maximum taste response, to be determined. This is the first time the bitterness levels of these drugs have been quantified in a human panel. The data obtained from this study will be extremely useful to future researchers working on paediatric formulations of these drugs. Patient adherence to tuberculosis treatment regimens is quite low, and the poor palatability of currently available formulations is cited as a key factor in this. A greater understanding of the taste of these drugs will allow for more palatable formulations to be developed which in turn will lead to greater patient adherence and improved treatment outcomes. Two non-human taste assessment techniques were also investigated i.e. the rodent brief access taste aversion (BATA) model and the electronic tongue. The comparison of the results from the BATA experiments to the human panel have been helpful in the ongoing validation of this model and suggest that the BATA model will be useful for taste assessment of formulations containing isoniazid, rifampicin and ethambutol dihydrochloride. The ability of the electronic tongue to both detect and assess the taste of these drugs was investigated. Ethambutol dihydrochloride was the only drug to exhibit a linear response which correlated well with human taste responses indicating that this is the only drug of the four assessed which can be effectively assessed using the electronic tongue. This data will also help to contribute to the validation of the electronic tongue and help researchers determine when this technique should be used. In the latter parts of this thesis hot melt extrusion was demonstrated to be useful for the production of taste-masked formulations of isoniazid and a fixed dose combination containing isoniazid and rifampicin. These results help to validate the usage of hot melt extrusion as a taste-masking technique. This may encourage future researchers both in academia and industry to use this technique for taste masking of other drugs which may lead to development of more effectively taste-masked formulations which should help to improve patient adherence to drug regimens, particularly in the paediatric population. 6 Acknowledgements ACKNOWLEDGEMENTS First and foremost, I must thank my supervisors Prof. Duncan Craig, Prof. Catherine Tuleu, Dr. Min Zhao and Dr. Claire Forbes for their help, support and guidance over the course of this project. I genuinely could not have gotten this far without their help. Specifically, I must thank Duncan for his help with the formulation aspects of my project and for his constant reassurance that I was doing better than I thought! I am also indebted to Catherine for her guidance regarding the taste assessment/paediatric aspects of my project. When I started my Ph.D. I never thought that I would get to carry out a human taste study and it certainly would not have been possible without her help. The early stages of my project would have been significantly harder without the guidance and support Min gave me and I am thankful for all the time she devoted to me. Finally, my thanks must go to Claire for her guidance in this project and the insights into industrial pharmacy she has given me. I would like to thank the members of the CDT Management Group: Prof. Steve Brocchini, Prof. Simon Gaisford, Dr. Gareth Williams, Sarah Marks and Claudia Matz for their help and organisation throughout the course of my studies. I am also extremely grateful to the CDT, the EPSRC and Pfizer for funding this project. To all members of the Craig/Barker research group past and present: Bahijja, Fatima, Fauzi, Hend, Essam, Goh, Awis, Stefania, Antony, Sean, Nazgol, Kelvin, Joachim, Francis and Poornima, without you I never would have laughed so much or eaten so much cake during my Ph.D.! I will always remember our mad lunch conversations and the industrial quantities of sugar we consumed. I would also like to thank Dr. Susan Barker for all the tea, sympathy and advice (for both my research and my life!) over the years. To all the members of the Paediatric and Geriatric research group past and present: Mine, Felipe, Jessica, Sara, Yucheng, Sejal, Smita, Abeer, Maria and Haitham thank you for all your help and support. I’m particularly going to miss our trips to EuPFI! My fellow 2013 CDT cohort students Felipe and Pierfrancesco, I really don’t know where the last four years went but I’m glad we all made it. Thanks for keeping me sane! Special mention as well to Alex Clout (who I couldn’t fit into any of the other categories), I’m going to miss our tea breaks. Finally, I must thank my family. To the ‘London branches’: Tom and Angela Keating, Rob, Annette and all the McEneaneys and Albert and Fiona Plattner who have looked out for me and let me eat them out of house and home for the last four years. Thanks so much for 7 Acknowledgements everything you have done and for helping to ease the homesickness! My grandparents Heinz and Eileen and my Aunty Steffi thank you so much for all your help and encouragement throughout my life and particularly during my Ph.D. studies. Most importantly I must thank my parents Veronica and Ed without whom none of this would have been possible. Their incredible love, encouragement, patience and support (both financial and emotional!) has allowed me to follow my dreams and become the person I am today. 8 Publications and Communications PUBLICATIONS AND COMMUNICATIONS Publications: Alison Keating, Jessica Soto, Catherine Tuleu, Claire Forbes, Min Zhao, Duncan Craig. Solid State Characterisation and Taste Masking Efficiency Evaluation of Polymer Based Extrudates of Isoniazid for Paediatric Administration. International Journal of Pharmaceutics, 2017. https://doi.org/10.1016/j.ijpharm.2017.07.008 Oral Presentations: Playing Hide and Seek with Isoniazid – Masking the Taste, Minimising Changes to Dissolution Performance. 8th EuPFI Conference: Formulating Better Medicines for Children, 2016, Lisbon, Portugal. In Vivo Taste Assessment of Four Commonly Used Anti-Tuberculosis Drugs. UCL PhD Research Day, 2017, London, United Kingdom. In Vivo Taste Assessment of Anti-Tuberculosis Drugs – Applications for Paediatric Formulation Development. CDT Targeted Therapeutics Colloquium, 2017, London, United Kingdom. Posters: Alison Keating, Wendy A. Knight. Liposome Size Reduction by Wet Bead Milling. GlaxoSmithKline Crystallisation Science Day, 2014, Stevenage, United Kingdom. Alison Keating, Duncan Craig, Catherine Tuleu, Barry Aldous, Claire Forbes, Min Zhao. Solid state characterization and in vitro taste masking efficiency evaluation of polymer-based extrudates of isoniazid. UCL PhD Research Day, 2015, London, United Kingdom. Alison Keating, Duncan Craig, Catherine Tuleu, Barry Aldous, Claire Forbes, Min Zhao.
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