University of Huddersfield Repository Bahl, Paul Development of Medicated Chewing Gum Formulations for the Delivery of a Poorly Soluble Drug Original Citation Bahl, Paul (2015) Development of Medicated Chewing Gum Formulations for the Delivery of a Poorly Soluble Drug. Doctoral thesis, University of Huddersfield. This version is available at http://eprints.hud.ac.uk/id/eprint/25435/ The University Repository is a digital collection of the research output of the University, available on Open Access. Copyright and Moral Rights for the items on this site are retained by the individual author and/or other copyright owners. Users may access full items free of charge; copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational or not-for-profit purposes without prior permission or charge, provided: • The authors, title and full bibliographic details is credited in any copy; • A hyperlink and/or URL is included for the original metadata page; and • The content is not changed in any way. For more information, including our policy and submission procedure, please contact the Repository Team at: [email protected]. http://eprints.hud.ac.uk/ DEVELOPMENT OF MEDICATED CHEWING GUM FORMULATIONS FOR THE DELIVERY OF A POORLY SOLUBLE DRUG PAUL BAHL A thesis submitted to the University of Huddersfield in partial fulfilment of the requirements for the degree of Doctor of Philosophy The University of Huddersfield in collaboration with Revolymer® 2015 1 I can do all things through Christ who strengthens me... Philippians IV.XIII 2 Copyright statement i. The author of this thesis (including any appendices and/or schedules to this thesis) owns any copyright in it (the “Copyright”) and s/he has given The University of Huddersfield the right to use such copyright for any administrative, promotional, educational and/or teaching purposes. ii. Copies of this thesis, either in full or in extracts, may be made only in accordance with the regulations of the University Library. Details of these regulations may be obtained from the Librarian. This page must form part of any such copies made. iii. The ownership of any patents, designs, trademarks and any and all other intellectual property rights except for the Copyright (the “Intellectual Property Rights”) and any reproductions of copyright works, for example graphs and tables (“Reproductions”), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property Rights and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property Rights and/or Reproductions 3 Dedications and Acknowledgements I would like to dedicate this thesis to my beautiful mother; Kamla Masih Bahl whose continued love, faith, prayers and words of inspiration kept me strong throughout the process and pushed me to succeed. I would like to acknowledge the patience and support of all my family and friends (including my brother Ranjeev, sister Neelam, twin brother Robert and my loyal dog Samson) who have all supported me through my sacrifices. I would like to express my sincere appreciation for the guidance and support of my research supervisors Prof. Barbara Conway and Dr. Vicky Osborne whose expertise, understanding and patience helped me in my academic journey. I also wish to thank my colleagues in the laboratory who supported me in the experimental phases (particularly the technicians), all my university colleagues and all the staff at Revolymer® who showed me support. Lastly I would like to acknowledge the support of the EPSRC and Revolymer® which made it possible for me to complete this work. 4 Abstract The concept of chewing gum for medical purposes provides discrete, convenient administration, the potential for buccal absorption and the avoidance of first pass metabolism or gastrointestinal degradation. This work contributes to the limited information available on the release of poorly soluble drugs from medicated chewing gum formulations. Lansoprazole was chosen as a model drug due to its poor solubility and instability (under acidic conditions), thus a chewing gum formulation would be of particular benefit avoiding gastrointestinal degradation. The solubility and stability of lansoprazole in artificial saliva was found to be dependent on the pH of the solution. An increase in pH caused an increase in solubility with a significant increase between pH 9 and pH 10. At pH 6, concentrations decreased over time confirming the acid instability of lansoprazole. The use of cyclodextrins as solubilisers and stabilisers for lansoprazole were investigated; complexed lansoprazole (with Mβ-CD, 1:1) resulted in a 9 fold increase in solubility compared to free lansoprazole and remained stable at pH 6. Chewing gum formulations incorporating lansoprazole were prepared and the following excipients were investigated: Revolymer‟s® hydrophilic polymer Rev7, buffering excipients and complexed lansoprazole (with Mβ-CD, 1:1). Drug diffusion from gum surfaces was found to be limited, highlighting the need for effective mastication to ensure the timely release of the drug. In vitro release was evaluated using the EP approved masticator. Various parameters were investigated including: the type of dissolution medium, pH, chew rate and sampling and replacement volumes. Significant differences in release after 30 minutes mastication were found for gums containing Rev7 and potassium carbonate (both of which contributed to increasing the hydrophilic capacity of the gum). These gums were also softer than other formulations due to a plasticising effect on the gum base elastomer resulting in softer, less cohesive gums. Complexation was not found to have an impact on in vitro drug release from gums. The study also assessed the buccal absorption of free lansoprazole and complexed lansoprazole (with Mβ-CD, 1:1) using porcine buccal mucosae. The highest partitioning coefficient was observed for free lansoprazole at pH 6.8 due to a lower ionised fraction in combination with a lower molecular weight. Complexed lansoprazole had the highest drug flux but also had the paradoxical effect of decreasing the permeability coefficient. Overall the study contributed to increasing the understanding of factors governing the release of a poorly soluble and unstable API, lansoprazole, from a medicated chewing gum formulation. The optimised formulation would contain lansoprazole, 8 % Rev7 and potassium carbonate to provide the maximum release of drug from the gum and also facilitate buccal absorption. 5 Table of Contents Chapter One: Introduction .......................................................................................... 20 1.1 Oral drug delivery route ................................................................................................... 21 1.1.1 Drug absorption through the oral mucosa ............................................................... 21 1.2 History of chewing gums ................................................................................................. 22 1.3 Chewing gum as a drug delivery system .......................................................................... 23 1.4 Formulation of medicated chewing gums ........................................................................ 24 1.4.1 Conventional/ kettle fusion manufacturing method ................................................ 25 1.4.2 Direct compression method ..................................................................................... 26 1.4.3 Composition of chewing gums ................................................................................ 27 1.5 Additional health benefits with respect to chewing gum ................................................. 28 1.6 Examples of medicated chewing gums ............................................................................ 29 1.6.1 Nicotine replacement gums ..................................................................................... 30 1.6.1.1 Taste masking using buffering excipients ....................................................... 32 1.7 Controlling release from chewing gums .......................................................................... 32 1.7.1 In vitro release from chewing gums ........................................................................ 34 1.7.2 Drug release and absorption from chewing gums ................................................... 35 1.8 Rev7 polymer in chewing gum formulations ................................................................... 37 1.8.1 Structural chemistry of Rev7 polymer ..................................................................... 38 1.8.2 Revolymer® gum base composition ........................................................................ 39 1.9 Lansoprazole .................................................................................................................... 39 1.9.1 Pathophysiology of ulcers ....................................................................................... 42 1.9.2 Epidemiology, prevalence and indications of ulcers ............................................... 42 1.9.3 Mechanism of action of lansoprazole ...................................................................... 43 1.9.4 Pharmacokinetics of lansoprazole ........................................................................... 44 1.9.5 Side effects of