Formulation of Novel Buccal Mucosal Drug Delivery Systems for Nicotine Replacement Therapy (Nrt)

FORMULATION OF NOVEL BUCCAL MUCOSAL DRUG DELIVERY SYSTEMS FOR NICOTINE REPLACEMENT THERAPY (NRT). OBINNA CHIKWADO OKEKE A thesis submitted in partial fulfilment of the requirements of the University of Greenwich for the Degree of Doctor of Philosophy January 2017 DECLARATION “I certify that this work has not been accepted in substance for any degree, and is not concurrently being submitted for any purpose. I also declare that this work is the result of my own investigations except where otherwise identified by references and that I have not plagiarised another’s work”. Mr. Obinna C. Okeke (Candidate) Dr J.S. Boateng (First supervisor) i ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my supervisor, Dr Joshua Boateng, for his enormous support, encouragement and general guidance throughout my research. His constant support and encouragement has led me to believe in myself and give out my best. I also appreciate the University of Greenwich for providing the facilities and student support within this period. I would like to acknowledge Dr Ian Slipper for all SEM and XRPD techniques as well as Devyani Amin for HPLC analysis. Thanks to all University staff for supporting my program. I also want to extend my deepest gratitude to my family. Their support and encouragement have led me to the person I am today. I am grateful to Dr Sam and Samantha Owusu-Ware and family for their support. Finally, to all my roommates, officemates, library IT and assistance team, project students under my supervision and fellow postgraduate students, I want to say I big thank you for your support. ii ABSTRACT Hydroxypropylmethylcellulose (HPMC) and sodium alginate (SA) were used in the formulation of composite wafers and films for potential nicotine (NIC) replacement therapy via the buccal mucosa route. Composite blank (BK), drug loaded (DL) HPMC-SA films (optimized with 2% w/v plasticizer) and wafers (optimized by freeze drying; annealing) were formulated. Further, nicotine stabilisation using MAS (magnesium aluminium silicate) in optimised composite HPMC-SA films and wafers were undertaken. Formulation characterisation was performed using texture analyser (TA) (mechanical and mucoadhesion properties), scanning electron microscopy (SEM) (surface and internal morphology), X-ray diffractometry (XRD) (physical form), attenuated total reflectance – Fourier transform infrared (ATR-FTIR) spectroscopy (physical interactions), thermo gravimetric analysis (TGA), differential scanning calorimetry (DSC), (thermal profiles) and high-performance liquid chromatography (HPLC) (drug loading efficiency and release). NIC stabilisation was required due to challenges of volatility and oxidative degradation associated with NIC especially for films (<35% drug loading efficiency). The incorporation of magnesium aluminium silicate (MAS) (optimum concentration; 0.25% w/v) was therefore necessary to stabilise NIC in HPMC-SA composite wafers and films. Optimized wafers and films (HPMC-SA, 1.25:0.75% w/v) were selected based on the physicochemical properties including drug loading efficiency of wafers and films (>90% NIC). The optimized formulations were used to demonstrate the effect of constituents of simulated saliva (SS) in mucoadhesion, hydration and swelling, and release of NIC, which was further compared with commercially available NiQuitin® strips. In comparison with NiQuitin® strips, optimized wafers and films containing MAS demonstrated NIC stability and a slower release from a mucoadhesive system suitable for targeted buccal drug delivery. Finally, wafers demonstrated a higher permeation flux (140.5547.55g/cm2/hr) than films (42.315.22g/cm2/hr), and can be considered safe (≥ 70% viable cells). iii CONTENTS DECLARATION ............................................................................................................ i ACKNOWLEDGEMENTS ........................................................................................... ii ABSTRACT ................................................................................................................. iii CONTENTS .................................................................................................................. iv FIGURES .................................................................................................................... xiv TABLES ...................................................................................................................... xx ABBREVIATIONS ................................................................................................... xxii CHAPTER 1: GENERAL INTRODUCTION AND LITERATURE REVIEW .......... 1 1.1 Overview .......................................................................................................... 1 Impacts of smoking .................................................................................... 3 1.2 Pharmaceutical drug delivery systems and dosage forms ................................ 5 Solid dosage forms ..................................................................................... 6 Liquid dosage forms ................................................................................... 8 Semi-solid dosage forms ............................................................................ 8 1.3 Routes of administration .................................................................................. 9 Oral route.................................................................................................... 9 Rectal route ................................................................................................ 9 Parenteral routes ....................................................................................... 10 Respiratory route ...................................................................................... 10 Topical routes ........................................................................................... 11 iv Transmucosal routes ................................................................................. 12 1.4 Oral transmucosal routes ................................................................................ 12 The anatomy and physiology of the oral mucosa ..................................... 13 Drug absorption via the oral mucosa........................................................ 16 Advantages of buccal drug delivery ......................................................... 18 Influence of physiological factors on drug absorption ............................. 19 1.5 Bioadhesion / mucoadhesion .......................................................................... 20 Theories of mucoadhesion ....................................................................... 20 Mucoadhesive mechanisms ...................................................................... 21 Factors affecting mucoadhesion ............................................................... 22 Mucoadhesive polymers ........................................................................... 25 Ideal characteristics of a buccal mucoadhesive polymer ......................... 26 1.6 NIC delivery ................................................................................................... 26 Chemical profile of NIC ........................................................................... 27 Pharmacokinetics of NIC ......................................................................... 27 1.7 NIC replacement therapy (NRT) .................................................................... 31 Transdermal patch .................................................................................... 32 Oral NRT .................................................................................................. 32 Electronic NIC delivery systems (ENDS) ................................................ 34 1.8 Proposed novel buccal delivery system for NRT ........................................... 35 1.9 Polymers used ................................................................................................ 36 v Hydroxypropylmethylcellulose (HPMC) ................................................. 36 Sodium alginate ........................................................................................ 37 1.10 Formulation techniques .............................................................................. 42 Solvent casting ....................................................................................... 42 Lyophilisation/freeze drying .................................................................. 43 1.11 Aim and objectives ..................................................................................... 43 CHAPTER 2: PREPARATION AND CHARACTERISATION OF HPMC AND SODIUM ALGINATE (SA) BASED BUCCAL FILMS AND WAFERS ............................. 45 2.1 Introduction .................................................................................................... 45 2.2 Materials and methods ................................................................................... 47 Materials ................................................................................................... 47 Preparation of composite films ................................................................ 47 Preparation of composite wafers .............................................................. 47 Texture analysis (TA)............................................................................... 50 SEM analysis ...........................................................................................

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