`
`MUCOADHESIVE FILMS FOR
`
`DRUG THERAPY
`
`Veh'sha Ann Perumat
`
`(BSc (UDW) Hons (UKZN), SA}
`
`Submitted in part futftlment of the requirements for the degree of Master
`
`of Medical Science [Pharmaceutical Sciences) at the School of
`
`Pharmacy and Pharmacology at the University of KwaZulu-Natal
`
`4
`i‘.’
`u"
`rrk
`
`‘M
`
`Supervisor: Associate Professor Thirumata Govender
`
`Co—supervisor: Mr Dhamend Lutchman
`
`Date submitted: January 2007
`
`Mylan v. MonoSol
`Mylan V. MonoSol
`IPR2017-00200
`IPR2017-00200
`MonoSol Ex. 2009
`MonoSol Ex. 2009
`
`Page 1
`Page 1
`
`
`
`“Consult not your fears but your hopes and dreams,
`
`Thlnk not about your frustrations but about your unfulfilled polenllal,
`
`Concern yourself not with what you tried and falled in,
`
`But with whol ll ls slill possible for you lo do."
`
`- Pope John xxxm -
`
`Page 2
`Page 2
`
`
`
`In loving memory of my grandmothei
`
`Theresa Rebecca Peters
`
`Page 3
`Page 3
`
`
`
`ACKNOWLEDGEMENT-S
`
`Wow! i cannot believe it has been three years since I embarked on this
`Masters journey, and am now at the very end. What an exciting,
`rewarding and memorable three years it has been. I have met so
`many accommodating, supportive and inspiring individuals, who have
`all contributed, in some way, to making my j'ourney pleasurable and
`hassle-free.
`I therefore extend my sincere gratitude to the following
`individuals:
`
`To my supervisor, Professor T. Govender: Dearest Thiru, WOW! You are
`undoubtedly one of the most amazing people I have ever met. Your
`zest for life and research is absolutely inspirational.
`I could not have
`wished for a better supervisor/coach (both professionally and
`personally}. Your contributions, expertise and insight have been of
`tremendous value to me and for the successful completion of this
`thesis. Thank you for embarking on this journey with me. A special
`message to Vinesh, Thank you for taking time from your hectic life to
`assist with the digital pictures and graphics. They have certainly
`enhanced my thesis.
`
`To Dhamend, co-supervisor of my project, i am really glad that I had
`the opportunity to work with you. You are such an awe-inspiring
`person. i am very grateful to you, for spending many hours in the lab
`with me, troubleshooting and enduring the awful smell of mucin. You
`certainly brought life to the lab. I was very fortunate to have had a
`hands-on co~supervisor. Thank you for your invaluable assistance and i
`look forward to working with you again.
`
`To Professor Viness Pillay, Wits University, thank you for sharing your
`knowledge on numerous aspects of my work and especially for
`providing training and assistance with the textural analyser.
`
`To Danny (AlUi and Darrell (lT), you guys are my saving grace. Without
`your constant, prompt assistance, my research would have come to a
`screeching halt. Thank you for always attending to my queries so
`efficiently.
`
`To Harry Schimanski, StableMicroSystems, UK, thank you for providing
`assistance and support
`for
`the textural analyser from across the
`hemisphere. Your contributions and on-line coaching were of extreme
`value to my research. You are a remarkable person.
`
`To the three musketeers (Ashmitha, Sue and Llewi), although we spent
`a short period together, you guys were excellent mentors in the lab.
`Ashmitha, thank you for keeping in touch and for always providing
`assistance. You are a genuine friend.
`
`
`
`Page 4
`Page 4
`
`
`
`
`
`To Les (Leslie Snipes} and Aasha, you guys are the reason i am still
`sane. Thank you for spending time with me and for always bringing
`laughter and fun to the lab. Les, you certainly are the cog that keeps
`the wheels turning,
`thank you for always attending to my needs
`(equipment, stationery, claims. lab, food], you are a great guy. Aash,
`you represent for me the beauty and charm every women should
`possess, thank you for your support and assistance and for being a
`great friend. Continue being the diva you arel!
`
`Kogi and Irene, thank you for believing in me and for encouraging me
`to embark on a masters degree in pharmacy, you two are the reason I
`am so content with my academic life and research in particular.
`
`Sugen (B-guy) and Vishnu [Dirty Harry], what would life and this
`institution be like without your ironical remarks? You guys have been
`there for me since my first day at UDW.
`I really don‘t know what I
`would have done without your
`friendship. Thank you for always
`assisting with everything I request. Hope you guys remain “cool by the
`pool'.
`
`To the staff of the School of Pharmacy, Prof Essack, Prof Dangor,
`Chunderika, Sarah, Zandile, Sazi. Ashen, Frasia, Fathima, Kamsala.
`
`Thavi, Karen, Vassie, Elizabeth, Gouda, Leeanne and Vishal, thank you
`for your concern, kind words and encouragement.
`
`To my parents, thank you for your guidance and unwavering support
`through out my endeavors. especially during masters and for providing
`a stable, sound and happy environment that was always conducive
`
`to learning.
`
`To my sisters, what are sisters for? Vanessa we have been through
`masters together and let me say, it has been a pleasure to have you
`share my pain. Thank you for your support. Special thanks to my little
`sister, Lee-Anne, for being ever obliging to do the terrible tasks in the
`lab, you are a gem. I will forever remember your facial expression the
`first time you smelled mucin. Hope you enjoyed our days in the lab as
`much as l did.
`
`Last but certainly not least, to my husband Sendelyn, Thank you for
`your support, for lending an ear and for providing a shoulder to cry on
`when lab work was at its lowest. Thank you also for your constant,
`watchful eye on my progress in masters and especially for always
`encouraging me to produce my best.
`i am also very grateful for the
`many weekends and after—hours on weekdays that you spent with me
`in the lab as completion of this thesis would not have been possible
`without those crucial extra hours of lab work.
`
`'ii
`
`Page 5
`Page 5
`
`
`
`
`
`RESEARCH OUTPUT
`
`The following posters were presented from data generated in this
`study:
`
`international:
`
`> Perumal, VA, Lutchman, D and Govender, T, Development of a
`Silicone Molded Compartmentalised Tray: An Approach to
`Enhance Drug Uniformity in the Preparation of Polymeric Films,
`AAPS Annual Meeting and Exposition, San Antonio, Texas, USA,
`29 October—02 November 2006.
`
`Local:
`
`> Perumal, VA, Lutchman, D and Govender, T, Development of a
`Silicone Molded Compartmentalised Tray: An Approach to
`Enhance Drug Uniformity in the Preparation of Polymeric Films,
`4*“
`International Conference
`on
`Pharmaceutical
`and
`
`Pharmacological Sciences, Vanderbiljpark, Gauteng, SA, 20-23
`September 2006.
`
`> Perumal, VA, Lutchman, D and Govender, T, Identification of
`
`of
`Preparation
`the
`for
`Parameters
`Process
`Optimal
`Multipolymeric Monolayered Films, 26‘h Annual Conference of
`the Academy of Pharmaceutical Sciences, Port Elizabeth, SA, 29
`September-O2 October 2005.
`
`iii
`
`Page 6
`Page 6
`
`
`
`ABSTRACT
`
`The use of the oral cavity membranes as sites of drug administration
`has been a topic of increasing interest
`for the past decade. The
`buccal route, in particular, offers several advantages over the per oral
`route and may prove to be a viable alternative to other routes for
`drug delivery, as it bypasses hepatic first pass metabolism, thereby
`improving the systemic bioavailability of the administered drug. A
`controlled drug release formulation may further enhance the
`therapeutic efficacy of a buccal drug delivery system. Propranolol HCI
`(PHCI), a non-selective B-blocker,
`primarily advocated in
`the
`treatment of hypertension. has a short half-life l3 - 6 hours) and is also
`subiected to extensive hepatic first—pass metabolism following oral
`administration,
`resulting in a low oral bioavailabitiiy,
`therefore
`rendering it an ideal candidate for buccal drug delivery. For optimal
`controlled release and mucoadhesivity of a buccal delivery system
`containing PHCl,
`the blending of polymers and drug of opposing
`solubilities may be required for the formation of monolayered films. The
`aim of
`this study was therefore to formulate and characterise
`multipolymeric monolayered mucoadhesive films containing drug and
`polymer/s of opposing solubilities for the buccal delivery of PHCI.
`
`the formation of monolayered
`First, preparation parameters for
`multipolymeric films (MMFs) and homopolymeric PHCl films comprising
`drug and polymer/s of opposing solubilities, Le. Chitosan (CHI) and
`Polle,L-lactide—co-glycolide)
`(PLGA) by an emulsification/casting/
`solvent evaporation method were investigated. MMFs could be
`prepared at all homogenisation speeds (6000, 9000, 12000, 15000 rpm)
`and times (i, 5,
`i5, 25 minutes]. The films showed micromatrices
`embedded in the film matrix due to the inclusion of the PLGA polymer.
`Increased homogenisation speed and time resulted in a reduction in
`the size of
`the micromatrices. Phase separation occurred at
`temperatures below 20 °C. Emulsifiers employed in
`the study
`(Polyivinylalcohot)
`(PVA) and Tween 80®} adversely affected the
`morphology and appearance of the film and were therefore not
`considered feasible for inclusion in the formulation. The preparation
`parameters identified for emulsification without phase separation and
`the subsequent generation of monolayered films, without phase
`separation during solvent evaporation and drying, were emulsification
`at 20 °C and homogenisation at 9500 rpm for is minutes.
`
`and a
`investigations
`preliminary
`through
`discovered
`lt was
`comprehensive literature search that
`the conventional
`film casting
`method of
`film preparation suffered from poor drug content
`uniformity. To address this problem of non—uniformity, a specially
`designed silicone-molded tray {SMTl for film casting was prepared and
`evaluated in terms of enhancing drug content uniformity. These
`
`Page 7
`Page 7
`
` w
`
`
`
`the SMT with tetlon-coated perspex
`investigations confirmed that
`inserts provided a reproducible method for the preparation of both
`homopolymeric and multipolymeric (including drug and polymers of
`similar and opposing solubilities) films that met drug content uniformity
`requirements (assay values were within 92-107.5%) and also reduced
`the variability in mucoadhesivity (p=O.2922). drug release (f2 values =
`92.76, 90.99 and 86.06) and film thickness for all three trays.
`
`The final phase of this study involved the identification of a suitable
`polymeric blend for the preparation of MMFs comprising hydrophilic
`and hydrophobic polymers for the controlled buccal delivery of PHCI
`and subsequent characterisation of
`these films
`in terms of
`their
`physicochemical/mechanical
`properties.
`Initial
`investigations
`of
`different polymers for the formation of homopolymeric films showed
`that the combination of drug and polymer/s of opposing ionic states
`was not possible due to complexation. PHCl
`film formation as
`homopolymeric films was achievable with hydrophilic polymers,
`Hydroxypropylmethylcellulose (HPMC) and CHT, and hydrophobic
`polymers, Ethylcellulose (EC) and Eudragit® RSlOO lEUDlOO). It was also
`found that combining PHCI, a hydrophilic drug, with a hydrophilic
`polymer (CHT or HPMC) failed to retard drug release l> 80% at 1 hour),
`whilst the release of PHCl from a hemopolymeric film comprising a
`hydrophobic polymer {EC or EUDlOO) was retarded. A PHCl:EUDiOO
`(i :10) film provided controlled release but was too retarded (< 67% at
`8 hours) for the purposes of this study. Hence, the polymeric content of
`the formulation was altered by the addition of a hydrophilic polymer
`CHI,
`to
`obtain
`the
`desired
`controlled
`release
`profile.
`A
`PHCi:EUDIOO:CHT (i:lO:O.5) polymeric blend (MMF) was found to be
`suitable for the controlled release of PHCI and was reproducible in
`terms of drug content uniformity (p=0.i964t, drug release it; values =
`83.18; 82.03 and 71.19) and mucoadhesivity lp=0.997i). Drug release
`followed Higuchi's square-root model
`(r2=0.9426}. Scanning electron
`microscopy revealed that the addition of CHT to the PHCleUDlOO
`(i :lO) film formulation rendered it more textured. which contributed to
`the faster drug release observed with the PHCI:EUDiOO:CHT (1:10:05)
`MMF. Swelling and erosion studies indicated that maximal swelling of
`the films occurred after 1 hour and 28.26% of the film eroded during
`the 8 hour test period. The system also demonstrated acceptable
`mucoadhesivity and mechanical properties. The surface pH of the
`films also remained constant at neutral pH throughout the study.
`
`this
`The data obtained in this study confirmed the potential of
`multipolymeric monolayered film system as a promising candidate for
`the controlled buccal delivery of PHCl.
`
`Key words: Films; Buccal; Multipolymeric; Mucoadhesive; Controlled drug
`release: Propranolol HCI
`
` V
`
`Page 8
`Page 8
`
`
`
`LIST OF ABBREVIATIONS
`
`Analysis of variance
`Area under the curve
`
`Chitosan
`
`Chlorhexidine
`
`Carboxymeihyicellulose
`Coefficient of variation
`
`Ethylceliutose
`Eudragit
`Glycyrrhizic acid
`HydrophiIe-lipophile balance
`Hydroxypropylcellulose
`Hydroxypropylmethylcellulose
`Lidocaine hydrochloride
`Methylcellulose
`Maximum detachment force
`
`Multlpolymeric monolayered film
`Sodium Alginate
`Poly(acrylic acid)
`Polyalkyleneoxide—maleic acid
`Phosphate buffered saline
`Polycarbophil
`Polycaprolactone
`Polyethylene Glycol
`Poly(ethylene oxide)
`Poiy(DL-lac’ride-co-glycolidel
`Poiy(vinyl alcohol)
`Polyviniypyrroiidone
`Revolutions per minute
`Sodium carboxyme’rhylcellulose
`Standard deviation
`
`Scanning electron microscopy
`Silicone molded tray
`Teflon coated perspex tray
`Textural profile analysis
`Ultraviolet
`
`ANOVA
`
`AUC
`
`CHT
`Chx
`
`CMC
`
`CV
`
`EC
`
`EUD
`
`GL
`
`HLB
`
`HPC
`
`HPMC
`
`LDC
`
`MC
`
`MDF
`
`MMF
`
`No Alginate
`PAA
`
`PAOMA
`
`PBS
`PC
`
`PCL
`
`PEG
`
`PEO
`
`PLGA
`PVA
`
`PVP
`
`rpm
`SCMC
`SD
`
`SEM
`SMT
`
`TCPT
`TPA
`
`UV
`
`
`
`vi
`
`Page 9
`Page 9
`
`
`
`TABLE OF CONTENTS
`
`ACKNOWLEDGEMENTS .................................................................................. i
`
`RESEARCH OUTPUT ....................................................................................... iii
`
`ABSTRACT ..................................................................................................... iv
`
`LIST OF ABBREVIATIONS ............................................................................... Vi
`
`TABLE OF CONTENTS
`
`viI
`
`LIST OFFIGURES xii
`
`LIST OF TABLES ............................................................................................ xiv
`
`CHAPTER ONE
`
`MOTIVATION FOR AND AIM OF STUDY
`
`Tobie of Contenfs
`
`1.1 MOTIVATION FOR STUDY ........................................................................ 2
`
`L2 AIM AND OBJECTIVES OF THE STUDY ................................................... 10
`
`1.3 REFERENCES ........................................................................................... II
`
`
`
`Vii
`
`Page 10
`Page 10
`
`
`
`CHAPTER TWO
`
`THEORETICAL CONCEPTS OF CONTROLLED RELEASE MUCOADHESIVE
`
`DRUG DELIVERY VIA THE ORAL MUCOSA
`
`Table of C ontents
`
`2.1 INTRODUCTION ..................................................................................... 19
`
`2.2 THE ORAL CAVITY .................................................................................. 19
`
`2.2.1 introduction .................................................................................... 19
`
`2.2.2 Overview of the Oral Mucosa ...................................................... 2i
`
`2.2.3 Advantages of Drug Delivery via the Oral Mucosa ................... 23
`
`2.2.4 Limitations of Drug Delivery via the Oral Mucosa ...................... 24
`
`2.3 FUNDAMENTAL ASPECTS OF MUCOADHESION ................................... 25
`
`2.3. 7 Concepts of Mucoadhesion ........................................................ 25
`
`2.3.2 Overview of Mucoadhesive Polymers ......................................... 28
`
`2.3.3 Factors Affecting Mucoadhesive Properties .............................. 32
`
`2.4 CONTROLLED DRUG DELIVERY ............................................................. 37
`
`2.4.l Concept of Controlled Release ................................................... 37
`
`2.4.2 Benefits of Controlled Drug Delivery ............................................ 39
`
`2.4.3 Types of Controlled Release Drug Delivery Systems ................... 40
`
`2.5 BUCCAL DRUG DELIVERY ...................................................................... 41
`
`2.5.1 Candidate Drugs and Disease States ......................................... 41
`
`2.5.2 Design of Buccal Dosage Forms
`
`.................................. 42
`
`2.5.3 Characteristics of a Buccal Delivery System ............................... 43
`
`2.5.4 Types of Buccal Delivery Systems ................................................. 44
`
`2.6 FILMS ...................................................................................................... 49
`
`2.6. I Methods of Film Preparation ........................................................ 49
`
`2.6.2 Characterisation of Films .............................................................. 55
`
`2.7. CONCLUSION ....................................................................................... 61
`
`2.8 REFERENCES ........................................................................................... 62
`
`viii
`
`Page 11
`Page 11
`
`
`
`CHAPTER TH REE
`
`IDENTIFICATION OF OPTIMAL PARAMETERS FOR THE PREPARATION OF
`
`MONOLAYERED FILMS WITH DRUG AND POLYMER/S OF OPPOSING
`
`SOLUBILITIES
`
`Table of Confenfs
`
`3.1 INTRODUCTION AND AIM ..................................................................... 77
`
`3.2 MATERIALS AND METHODS ................................................................... 78
`
`3.2.} Maferials ......................................................................................... 78
`
`3.2.2 Methods .......................................................................................... 79
`
`3.3 RESULTS AND DISCUSSION .................................................................... 82
`
`3.3. I Effecf of Homogenisofion Speed and Time ................................ 82
`
`3.3.2 Effect of Temperafure ................................................................... 87
`
`3.3.3 EffeCIL of EmuIsifiers ........................................................................ 87
`
`3.3.4 Summary of Parameters for rhe Preparation of Monolayered
`Mulffpolymen'c Films with Drug and Polymers of Opposing Solubilifies
`.................................................................................................................. 88
`
`3.3.5 Confirmafion of Parameters for he Preparoh'on of
`Monotayered Homopolymen'c Films with Drug and Polymer of
`Opposing Solubilifles .............................................................................. 89
`
`3.4 CONCLUSIONS ...................................................................................... 91
`
`3.5 REFERENCES ........................................................................................... 93
`
`1x
`
`Page 12
`Page 12
`
`
`
`
`
`CHAPTER FOUR
`
`ENHANCING DRUG CONTENT UNIFORMITY IN POLYMERIC FILMS
`
`Table of Contents
`
`4.1 INTRODUCTION ANDA|M96
`
`4.2 MATERIALS ANDMETHODS 102
`
`4.2.1 Mafen‘als ....................................................................................... 102
`
`4.2.2 Methods ........................................................................................ 103
`
`4.3 RESULTS AND DISCUSSION .................................................................. 114
`
`4.3.1 C alibrah'on Curves for Drug Quantification .............................. 1 14
`
`4.3.2 Development of Trays for Enhancing Drug Unlformlry in Fllms 118
`
`4.3.3 Reproduciblllfy Sludy................................................................... 121
`
`4.3.4 Applicability of The SMT wilh Teflon Coated Perspex lnserls lo
`Mulllpolymen'c Films wilh Drug and Polymers of Similar and Opposing
`Solubllilles .............................................................................................. 124
`
`4.4 CONCLUSIONS .................................................................................... 127
`
`4.5 REFERENCES ......................................................................................... 129
`
`x
`
`Page 13
`Page 13
`
`
`
`CHAPTER FIVE
`
`FORMULATION AND PRELIMINARY CHARCTERISATION OF MMFS FOR
`
`BUCCAL DELIVERY OF PHCI
`
`Table of Contents
`
`5.1 INTRODUCTION ANDAIM 134
`
`5.2 MATERIALS ANDMETHODS 135
`
`5.2.1 Materials ......................................................................... I35
`
`5.2.2 Methods ........................................................................... I35
`
`5.3 RESULTS AND DISCUSSION .................................................................. 141
`
`5.3.1 Selection of Polymers torincorporation into MMFs................ I4}
`
`5.3.2 Optimising the Film for Controlled Release and
`Mucoadhesivity ........................................................................ I46
`
`5.3.3 Reproducibility Study ......................................................... I52
`
`5.3.4 Characterisation of the identified Suitable Formulation ......... I53
`
`5.4 CONCLUSIONS .................................................................................... 165
`
`5.5 REFERENCES ......................................................................................... 168
`
`CHAPTER SIX
`
`GENERAL CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE STUDIES
`
`Table of Contents
`
`6.1 GENERAL CONCLUSIONS ................................................................... 172
`
`6.2 RECOMMENDATIONS FOR FUTURE STUDIES ....................................... I76
`
`APPENDICIES .............................................................................. I79
`
`
`xi
`Page 14
`Page 14
`
`
`
`LIST OF FiGU RES
`
`NUMBER
`20
`Figure 2.l
`Buccal route of administration avoiding
`presystemic elimination of drug
`
`
`
`Figure 2.2
`
`Schematic representation of mucous
`(alglycoprotein chain (bl glycoprotein tetramer
`
`Figure 2.3
`
`Figure 2.4
`
`Figure 3.1
`
`
`
`Drug levels vs time profile depicting differences
`between zero order controlled release, first order
`controlled release and release from a
`
`conventional dosage form
`
`Schematic representation of buccal dosage form
`design
`
`Schematic presentation of the preparation
`process for MMFS
`
`Figure 4.1
`
`Picture of a teflon coated perspex tray
`
`
`
`27
`
`38
`
`43
`
`8‘?
`
`103
`
`Figure 4.2
`
`Pictures of a TCPT with a removable chamber
`
`104
`
`system [at separate components and (b)
`chambers inserted into TC PT
`
`Figure 4.3
`
`Pictures of the SMT (a) without inserts and (b) with
`teflon-coated perspex inserts.
`
`Figure 4.4
`
`Figure 4.5
`
`Figure 4.6
`
`Figure 4.7
`
`Figure 5.1A
`
`Figure 5.1 B
`
`Figure 5.2A
`
`
`
`
`
`A typical detachment profile (Force-Distance
`curve)
`
`Calibration curve of PHCI in H20/Ethanol
`
`Calibration curve of PHCl in PBS pH 6.8
`
`Reproducibility of in vitro drug release profiles
`
`Drug release profiles for homopolymeric HPMC
`films containing PHCI
`
`
`
`Drug release profiles for homopolymeric CHT films
`containing PHCI
`
`Drug release profiles for homopolymeric EC film
`containing PHCI
`
`105
`
`113
`
`114
`
`115
`
`123
`
`143
`
`145
`
`143
`
`
`
`xii
`
`Page 15
`Page 15
`
`
`
`
`
`
`
`Figure 5.23
`
`Figure 5.3A
`
`Figure 5.38
`
`Figure 5.4
`
`Figure 5.5
`
`Figure 5.6
`
`Figure 5.7A
`
`Figure 5.7B
`
`
`
`
`
`
`
`
` Figure 5.8
`Surface pH changes of the optimised MMF
`
`
`Drug release profiles for homopolymeric EUDlOO
`films con’raining PHCl
`
`Drug release profiles of EUDlOO+HPMC films
`prepared oi various raiios
`
`Drug release profiles of EUDl OO+CHT films
`prepared al various ralios
`
`Reproducibiliiy of in vllro drug release profiles
`
`Higuchi square-moi of lime plol for PHCl release
`from PHCi:EUDiOO:CHT (1:10:05) MMFS
`
`Correlation of swelling and erosion profiles of
`MMFs containing PHCl
`
`A rypical siress—sirain profile for lhe PHCleUDlOO
`(1:10) homopolymeric film
`
`A iypical siress—sirain profile for the
`PHCl:EUDiOO:CHT (l:lO:O.5) MMF
`
`MS
`
`M8
`
`148
`
`l62
`
`l53
`
`155
`
`156
`
`
`
`
`
`xiii
`
`Page 16
`Page 16
`
`
`
`Table 4.8
`
`Table 4.9
`
`Table 4.lO
`
`Table 5.]
`
`Table 5.2
`
`Table 5.3
`
`Table 5.4
`
`Tobie 5.5
`
`Table 5.6
`
`Table 5.7
`
`Table 5.8
`
`Table 5.9
`
`
`
`
`
`Summary of results for characterisation studies for
`reproducibility studies (SMT with inserts)
`
`Assay values of homopoiymeric and
`multipolymeric films prepared in the TC PT and SMT
`with inserts
`
`from films
`release profiles
`Summary of PHCI
`prepared in the TCF’T and SMT with inserts
`
`Ratios and amounts of drug and polymer used for
`the preparation of homopoiymeric films
`
`125
`
`126
`
`T36
`
`Ratio and amounts of CHT and HPMC added to
`
`T37
`
`1:10 PHC|:EUDiOO formulation
`
`
`
`Data obtained for mucoadhesion measurements
`
`
`
`Characteristics of several polymers investigated
`for incorporation into film formulations
`
`Summary of results for characterisation studies for
`difterent ratios of MMFs
`
`the homopoiymeric
`Photographic illustration of
`PHCizEUDlOO (ile) film and PHCleUDi002CHT
`(1:10:05) MMF
`
`Summary of results for characterisation studies for
`reproducibility studies
`for
`the
`suitable MMF
`formulation
`
`The effect of dissolution on film morphology
`
`Summary of mechanical test results for
`PHCl:EUDlOO {1:10) homopoiymeric films and
`PHCI:EUDTOO:CHT {1:10:05} MMFs
`
`141
`
`T47
`
`150
`
`151
`
`152
`
`l58
`
`lol
`
`
`
`XV
`
`Page 17
`Page 17
`
`
`
`Chapter One:
`
`Motivation for and Aim of Sfudy
`
`CHAPTER ONE
`
`MOTlVATlON FOR AND AIM OF STUDY
`
`Table of C ontenfs
`
`1.] MOTIVATION FOR STUDY ........................................................................ 2
`
`12 AIM AND OBJECTIVES OF YHE STUDY ................................................... 10
`
`1.3 REFERENCES ........................................................................................... 11
`
`
`
`]
`
`Page 18
`Page 18
`
`
`
`
`Chapter One:
`
`Motivation for and Aim of Study
`
`1.1 MOTIVATION FOR STUDY
`
`Among the various routes of drug delivery, the oral route is perhaps
`
`the most preferred by patients and clinicians alike. However, perorai
`
`administration
`
`of
`
`drugs has disadvantages
`
`that
`
`prohibit
`
`the
`
`administration of certain classes of drugs, eg. peptides and proteins,
`
`and also compromises the bioavailability of other classes of drugs such
`
`as antihypertensives. Consequently, other absorptive mucosa such as
`
`the nasal; vaginal: rectal; ocular and oral linings, are considered as
`
`potential sites of drug administration (Shojaei et al., 2001). The use of
`
`the oral cavity membranes as sites of drug administration has been
`
`the topic of increasing interest for the past decade, It
`
`is well known
`
`that the absorption of therapeutic compounds from the oral mucosa
`
`provides a direct entry of the drug into the systemic circulation,
`
`thereby avoiding tirst~pass hepatic metabolism and gastrointestinal
`
`drug degradation, both of which are associated with peroral
`
`administration (Remunan~Lopez et al., 1998: Kurosaki and Kimura, 2000;
`
`Varshosaz and Dehghan, 2002; Hao and Heng, 2003, Langoth et al.,
`
`2003, Akbari et al., 2004}.
`
`in addition to systemic therapy,
`
`the
`
`oramucosal route can also be used for the delivery of drugs for
`
`localised therapy in the mouth for oral
`
`infections, e.g. periodontitis
`
`(Deasy et al., 1989: Schwach-Abdellaoui et al., 2001; Perugini et al.,
`
`2003; Jones et al., 2004; Periali et al., 2004). Drugs administered via the
`
`oral mucosa! route can therefore otter superior therapeutic outcomes
`
`for drugs that benefit from the circumvention of hepatic first—pass
`
`metabolism and also those for localised therapy.
`
`One such route is the buccal route, which has been investigated for
`
`both local and systemic delivery of therapeutic agents llshida et al.,
`
`1981; Rathbone, 1991: Cassidy et al., 1993: Guo, t994: McQuinn et al.,
`
`1995; Han et al., 1999). Drugs administered via the buccal route: (l)
`
`achieve higher plasma concentrations by avoidance of both the
`
`Page 19
`Page 19
`
`
`
`
`Chapter One:
`Motivation for and Aim of Study
`
`intro—alimentary canal and hepatic first-pass metabolism (Hussain et
`
`al,
`
`l987),
`
`(2) have improved systemic bioavaitability (Bond, 1988:
`
`Huupponen et al., l995), and [3) have improved absorption, as this is
`
`not affected by variations in the gastric emptying rate or the presence
`
`of food (Kaus et al., 1999; Senel and Hincal, 200)). The buccal route
`
`also offers a series of other advantages such as good accessibility,
`
`robustness of the epithelium, facile removal of the dosage form in the
`
`case of need, relatively low enzymatic activity, possibility of elimination
`
`of the administered dosage form from the buccal area by natural
`
`clearance mechanisms and satisfactory patient acceptance and
`
`compliance (McElnay,
`
`i990: Rathbone et all, 1994: Chidambaram
`
`and Srivatsava,
`
`i995; Burgalassi et al., 1996: Khanna et al., 1998;
`
`Shoiaei, 1998; Lee et al., 2000; Varshosaz and Dehgha, 2002; Langoth
`
`et al., 2003; Geresh et al., 2004). Classes of drugs that may benefit from
`
`buccal delivery include hypoglycaemics
`
`(llango et al.,
`
`1997).
`
`antiretrovirals [Xiang et al., 2002), antibiotics (Jones et al., 2000) and
`
`antihypertensives (Guyot and Fawaz, 2000).
`
`Since the buccal route may prove to be a viable alternative to other
`
`routes for drug delivery, attempts have been made to formulate
`
`various buccal delivery systems, which included tablets (All et al., 1998:
`
`Perioli et al., 2004; Munasur et al., 2006 ), films (Kohda et al., 1997;
`
`Remunan- Lopez et al., 1998), disks (Parodi et al., 1996; Ali et al., 2002),
`
`strips (flango et al.,
`
`l997), patches (Wong et al., 1999; Nafee et al.,
`
`2003) and gels (Shin et al., 2000).
`
`An important aspect for buccal drug delivery systems is
`
`that of
`
`controlled drug release, as controlled drug delivery systems provide a
`
`continuous delivery of drugs at predictable and reproducible kinetics
`
`for a pre-determined period, The potential advantages of
`
`this
`
`concept are: minimisation of drug related side effects
`
`(due to
`
`controlled therapeutic blood levels instead of oscillating blood levels)
`
`3
`
`Page 20
`Page 20
`
`
`
`
`Chapter One:
`
`Motivation for and Aim of Study
`
`and improved patient compliance {due to reduced frequency of
`
`dosing) {Jantzen and Robinson,
`
`l996). Therefore, administration of
`
`drugs via the buccal route together with controlled drug release will
`
`optimise drug therapy Controlled drug delivery is acquired by
`
`combining a polymer, natural or synthetic, with an active ingredient in
`
`such a way that the active ingredient is released from the material in a
`
`predesigned manner. Hence controlled release is ultimately achieved
`
`by the ludicious selection of polymers.
`
`Another important property essential
`
`for drug delivery systems for
`
`administration via the oral mucosal route is retention on the mucosae,
`
`i.e. mucoadhesivity, brought about by the use of polymers such as
`
`chitosan
`
`(Senel
`
`et
`
`al.,
`
`2000;
`
`Perugini
`
`et
`
`at,
`
`2003},
`
`hydroxypropylmethylcellulose
`
`(HPMC)
`
`(Ali et at,
`
`2002),
`
`sodium
`
`carboxymethylcellulose (SCMCl (Wong et at, 1999} and poly (acrylic
`
`acid)
`
`(PAAJ
`
`(Shojaei et at, 2000). Mucoadhesive polymers interact
`
`with and adhere to mucin molecules in the mucus lining and are thus
`
`retained on the surface epithelium for extended periods of time
`
`(Ahuja et
`
`al.,
`
`1997}. Mucoadhesive polymers have attracted
`
`considerable attention for controlled drug delivery, as prolonged
`
`residence time of the delivery system at the site of action leads to
`
`increased contact to the absorbing mucosa, thereby resulting in a
`
`steep concentration gradient which favours drug absorption as well as
`
`localisation in
`
`specific
`
`regions
`
`to improve and enhance the
`
`bioavailability of the drug lLueBen et at, 1994). Therefore maximising
`
`mucoadhesivity, especially for controlled drug delivery, remains an
`
`important goal in oral mucosal delivery.
`
`The selection of optimal polymers in a drug delivery system remains the
`
`pivotal goal in the formulation of controlled release buccal delivery
`
`systems for enhancing mucoadhesivity and obtaining controlled drug
`
`release
`
`profiles. The
`
`literature
`
`has
`
`revealed that,
`
`thus
`
`far,
`
`
`
`Page 21
`Page 21
`
`
`
`
`Chapter One:
`
`Motivation for and Aim of Study
`
`mucoadhesive
`
`systems
`
`have
`
`been
`
`formulated
`
`using mainly
`
`homopolymeric systems (Woolfson et at, 1998: Guyot and Fawaz.
`
`2000; Eouani et at, 2001). With homopolymeric systems one may find
`
`that a polymer such as chitosan, which has been shown to display
`
`excellent mucoadhesivity,
`
`is nevertheless unable to prolong drug
`
`release, while a polymer such as poly lactide-co~glycoiide (PLGA) is
`
`not a good mucoadhesive but
`
`ideal
`
`for prolonging drug release
`
`lSeneI et al., 2000; Perugini et al, 2003). Thus, for suitable therapeutic
`
`outcomes, these two properties need to be optimised in a delivery
`
`system to achieve prolonged retention time as well as specified
`
`release kinetics such as zero—order.
`
`More recently, researchers have been focusing on the blending of
`
`polymers to provide improved mucoadhesion and drug release, For
`
`example. patches and films formulated with chitosan blends with
`
`hydrophilic polymers were superior as compared to chitosan alone in
`
`terms of dissolution, improved comfort and reduced irritation, ease of
`
`processing and improved film flexibility {Khoo et ai., 2003). Hence
`
`