FORMULATION AND EVALUATION OF PEDIATRIC

CARBAMAZEPINE SUSTAINED RELEASE ORAL

JELLY

BY

SAEID MEZAIL MAWAZI

A thesis submitted in fulfilment of the requirement for

the degree of Master in Pharmaceutical Sciences

(Pharmaceutical Technology)

Kulliyyah of Pharmacy

International Islamic University Malaysia

JANUARY 2018

ii

ABSTRACT

Once daily epilepsy carbamazepine (CBZ) medication oral jelly for pediatrics was

prepared and evaluated. The available marketed CBZ pediatric dosage form is CBZ

suspension only which is not sustained release medication. Therefore, developing new

CBZ sustained release oral jelly can play an important role to handle the following

issues; (1) suitable dosage form for easy swallowing (2) reducing the multiple daily

doses to one daily dose for patient convenience. This work consists of three parts, first

one is to prepare CBZ sustained release microparticles, the second part is to

incorporate the microparticles in alginate beads and the final one is to suspend the

beads in oral jelly. The microparticles prepared by solvent evaporation method

utilizing EC as sustained release polymer. Microparticles were evaluated for particle

size, encapsulation efficiency (EE), in vitro release test, differential scanning

calorimetry (DSC), attenuated total reflection–fourier transform infrared spectroscopy

(ATR-FTIR), and high-pressure liquid chromatography (HPLC). CBZ release from

microparticles was achieved and compared to the release of CBZ sustained release

tablets of 200 mg stated in United States Pharmacopoeia (USP). The beads fabricated

by crosslinking of sodium alginate with calcium chloride solution utilizing

electrospray. CBZ beads were tested for the size, morphology, in vitro drug release

and HPLC. In vitro release study results of CBZ from the beads showed the same

release of CBZ in microparticles. Finally, the CBZ oral jelly prepared using an iota

carrageenan gelling agent and evaluated for the dissolution test, syneresis, rheology,

drug content uniformity, viscosity, physical appearance, and stability. CBZ loaded

microparticle size ranged from 131 to 186 μm. The highest EE was 96% for MP2 and

the lowest one was 74% for MP9. The cumulative release percentage of CBZ at 24 h

was ranged from 49% in MP1and 89% in MP10. CBZ bead results showed bead size

of 1.4 mm for B2 and 3.5 mm for B4 with same EE of CBZ loaded microparticles.

The release of CBZ from its beads was almost equal for all prepared bead

formulations. In vitro drug release of CBZ was done firstly in the same conditions of

dissolution test of CBZ beads and CBZ microparticles to ensure that there was no

change in the release of CBZ when fabricated in iota carrageenan jelly. Secondly,

comparison dissolution test study was carried out between CBZ oral jelly and

Tegretol® XR 200 mg tablets and similarity factor was calculated to ensure that the

CBZ jelly matching to the guidelines. Stable and homogenize CBZ oral jelly was

obtained with the release similarity factor (F2) of 76 between CBZ oral jelly and

Tegretol® XR 200 mg tablets under the same release conditions. The release of CBZ

from the jelly found to be 94.11% from the original concentration after 24 hours. This

study developed a new CBZ dosage form for pediatric patients with sustained release

property and could be used as main and alternative treatment for pediatric epilepsy

patients.

iii

خلاصة البحث

بسببببدم تببببدو ءببببارب مازب زذو اب تبببب لبط ءا زطتالبببب ير زذدصبببببب ذزبينبببب بببب ار بببب اب تبببب لبط زطبينبب ءا زطتالبب ير زذدصبببب زذببن لوببد زا هامببم مااز ل تبب تببزل زذوببب تببد ز بب زببللبب

زلجببببل زذ ات ببب ذبببدازب زذو اب تببب لبط ( ءقا ببب تبببدم 2( شبببو تزجبببب جدهبببد هسبببا تبببد ت ا ببب زذداببب )1)زطتا بب م تببد تببدا جبببل زا جبتبب ازهببدا ه بب هسببا زاببالدزو زذببدازب اببازب ذا بببه زا ز بببزرقط ذبب لببنز ز بببال زا زذد بب هاوبباا تببد ز بب زجبب:زب اء سبب الببب زلجبب:ب زطا تا بب بب زذو اب تبب لبط

زذببببدازب بدصبببببب زلجبببب:ب زذببببب ت لببببا ء ا بببب هد دبببب تاببببل شببببو هد دبببب تابهبببب بببب ا ءا بببب د بهببببب زذو اببببب ت:بط زةابهبببب زذلبببب ا بببببز زلج بببب زذلببببامهاو ازلجبببب:ب زط بببب لببببا ذاما بببب بببببز زلج بببب زذلبببامهاو لبببزو زذو ازج ببب ا ببب زلجببب:ب زطا البببا هد دببب زذو اب تببب لبط زةابهببب زذلببب ا ببب ا

ب ابببالدزو زطهب هببب ابببا اال دببباذ ب هسببب تد تابببل ت ا ببب بهبببب زذبببدازب ب ابببالدزو ببهقببب ءدلببب ز بببنهمبدصبب ءق م ار ب هد دب زذو اب تب لبط زذلب ا ب ا ب ابالدزو ر ب بهبب زذبدازب ر ب ينب با زذا ا ببب ر ببب هيبببم زحد دببب ر ببب شبببو زحد دببب ز سبببط زحببببزا زذاين ببباب زذ ببب زذمببب

زطشبببم بببا زح ببببزب زجابببب باببب ءلمج ر ببب زحد دببب زةابهببب ذبببدازب ذينلببب زذسبببازء ار ببب ب ببب تا بم ز لباير تا ابب 222زذو اب تب لبط ءص بقب ج بدز تب ر ب بهبب زذبدازب تبد زاببزير زذو اب تب لبط

مابااا زطماهبب زطتبهوببب ببا بينب. زذيربببات بب بببز زلج ب زذلببامهاو بب ا ب اببالدزو ءق بب ءب طلج ببا زذلببامهاو اببا زذو ذسبب او ااازهببد تببد ببهبب ءوبباهد بببز بباد بين بب زذاالهبب زذوابببب

ء بببمم ابببا زذو ذسببب او ااازهبببد تببب زذلبببامها زلج د بببا ز لابببا تببب هد دببب زذو اب تببب لبط زةابهببب زذل ا بز زلج د ا زذلامهاو ز اوابب ببا ابد ر لبا ذ بواا ز,ب اجب هي اب ر ب بهبب

اب تبب لبط تببد لببنا زذوبببز زاط ب تببد هد دبب زطهب هبب اببا اال ب بب ر بب زذ بب زذمبب ذينلبب زذوزذسبببازء باببب ءلمج ر ببب بهبببب زذو اب تببب لبط تبببد ببببز زطلج د بببا ببببا تص بقببب ذالصببباا زذسببب بق تبببد

بز زلج د بببببا زذا بببب دبببب هبببببد تاببببل زا ز,صببببباا زذب ب بببب ن ء ببببب بهببببب زذو اب تببببب لبط ز بببب ب ء ا ينببببب بوببببزذلببامهاو ز,صبباا زط بب ا تببد لببنز ز بببال ء بب د ءما بب بببز زذلببامهاو زلج ببا مز بب لببزو زطهاءبب ازج ا ه ءق م لزو زطهاء ازج ا زاط بين ب ز,بازير زلجبه ب ب بنز ز بزو ر ب رلب

ذ:اجبببب ز ببببزو ر بببب بهببببب ز بببب ب تببببد ز ببببزو ز بببب ب ز,بببب:ا ر بببب ز يراببببب ز,بببب اجب ذااببببزو ر بببب اد ا زذ زذم ذينل زذسازء زذو اب ت لبط تد ز زو از ز ز

iv

APPROVAL PAGE

I certify that I have supervised and read this study and that in my opinion, it conforms

to acceptable standards of scholarly presentation and is fully adequate, in scope and

quality, as a thesis for the degree of Master in Pharmaceutical Sciences

(Pharmaceutical Technology).

…………………………………

Abd Almonem Doolaanea

Supervisor

…………………………………

Hazrina Ab Hadi

Co-Supervisor

I certify that I have read this study and that in my opinion it conforms to acceptable

standards of scholarly presentation and is fully adequate, in scope and quality, as a

thesis for the degree of Master in Pharmaceutical Sciences (Pharmaceutical

Technology).

…………………………………

Bappaditya Chatterjee

Internal Examiner

…………………………………

Haliza Katas

External Examiner

This thesis was submitted to the Department of Pharmaceutical Technology and is

accepted as a fulfilment of the requirement for the degree of Master in Pharmaceutical

Sciences (Pharmaceutical Technology).

…………………………………

Mohd. Rushdi

Head, Department of

Pharmaceutical Technology

This thesis was submitted to the Kulliyyah of Pharmacy and is accepted as a

fulfilment of the requirement for the degree of Master in Pharmaceutical Sciences

(Pharmaceutical Technology).

…………………………………

Juliana Bt. Md. Jaffri

Dean, Kulliyyah of Pharmacy

v

DECLARATION

I hereby declare that this thesis is the result of my own investigations, except where

otherwise stated. I also declare that it has not been previously or concurrently

submitted as a whole for any other degrees at IIUM or other institutions.

Saeid Mezail Mawazi

Signature…………..……….……. Date ……..........................

vi

INTERNATIONAL ISLAMIC UNIVERSITY MALAYSIA

DECLARATION OF COPYRIGHT AND AFFIRMATION OF

FAIR USE OF UNPUBLISHED RESEARCH

FORMULATION AND EVALUATION OF PEDIATRIC

CARBAMAZEPINE SUSTAINED RELEASE ORAL JELLY

I declare that the copyright holder of this thesis is Saeid Mezail Mawazi

Copyright ©2018 by Saeid Mezail Mawazi. All rights reserved.

No part of this unpublished research may be reproduced, stored in a retrieval

system, or transmitted, in any form or by any means, electronic, mechanical,

photocopying, recording or otherwise without prior written permission of the

copyright holder except as provided below

1. Any material contained in or derived from this unpublished research may

only be used by others in their writing with due acknowledgement.

2. IIUM or its library will have the right to make and transmit copies (print or

electronic) for institutional and academic purpose.

3. The IIUM library will have the right to make, store in a retrieval system and

supply copies of this unpublished research if requested by other universities

and research libraries.

By signing this form, I acknowledged that I have read and understand the IIUM

Intellectual Property Right and Commercialization policy.

Affirmed by Saeid Mezail Mawazi

……..……..…………… …………………..

Signature Date

vii

ACKNOWLEDGEMENTS

I would like to express my sincerest gratitude to my supervisor, Asst. Prof. Dr. Abd

Almonem Doolaanea for giving me the opportunity to work on such a significant and

interesting project. Without his invaluable support, guidance, and encouragement, this

journey would not have been possible. I greatly appreciate his continuous faith in my

abilities which has truly enabled me to expand my horizons.

I would like to thank my second advisor, Asst. Prof. Dr. Hazrina Ab Hadi for

accommodating my own interests and for her understanding my patience for my

research and giving me support for what I have done.

My wholehearted thanks to all my lab-mates Samah Hamed, Hamzeh Alkhatib,

Mohammad Nasrin Bin Abdul Rahman, Luqman Muizzuddin Bin Mohd Rosli, Mohd.

Fakhrul Radzi Bin Mamat, Irda Haslinda Binti Hassan, all PG Office members and

Pharmaceutical Technology Department members for their invaluable help, advice

and information. I would like to thank all my close friends, who always stood by my

side.

Finally, I would like to give my special thanks to my family members for their

unconditional love and support and my father in law Dr. Mazin Najeeb for his advice

and support. I would like to dedicate my thesis to my wife, Halah, for always letting

my dreams come true.

viii

TABLE OF CONTENTS

Abstract .......................................................................................................................... ii Abstract in Arabic ......................................................................................................... iii Approval page ............................................................................................................... iv

Declaration ..................................................................................................................... v Declaration of copyright and affirmation of fair use of unpublished research ............. vi Acknowledgements ...................................................................................................... vii Table of Contents ........................................................................................................ viii List of Tables ............................................................................................................... xii

List of Figures ............................................................................................................. xiii List of Abbreviation ..................................................................................................... xv List of Symbols ........................................................................................................... xvi

CHAPTER ONE: INTRODUCTION ........................................................................ 1 Introduction ................................................................................................................... 1

1.1 Background .................................................................................................. 1 1.2 Problem Statement ....................................................................................... 3

1.3 Hypothesis .................................................................................................... 4 1.4 Objective ...................................................................................................... 4

1.5 Study Design ................................................................................................ 4

CHAPTER TWO: LITERATURE REVIEW ........................................................... 6 2.1 Introduction .................................................................................................. 6 2.2 Pharmacological development of pediatric population ................................ 6

2.2.1 Absorption .......................................................................................... 7

2.2.1.1 Oral .......................................................................................... 7 2.2.1.2 Buccal ...................................................................................... 7

2.2.1.3 Topical ..................................................................................... 7 2.2.1.4 Intramuscular ........................................................................... 8 2.2.1.5 Pulmonary ................................................................................ 8 2.2.1.6 Rectal ....................................................................................... 8

2.2.1.7 Nasal ........................................................................................ 8 2.2.1.8 Distribution .............................................................................. 8

2.2.1.9 Body Water/Fat ....................................................................... 9 2.2.1.10 Protein Binding ...................................................................... 9

2.2.2 Metabolism ......................................................................................... 9 2.2.3 Renal Elimination............................................................................. 10

2.3 Pediatric Preparations ................................................................................ 10

2.4 Sustained Release Formulations ................................................................ 12 2.5 Oral Jelly as a Dosage Forms ..................................................................... 14 2.6 Carbamazepine ........................................................................................... 16 2.7 Microencapsulation .................................................................................... 19 2.8 Polymers and Gelling Agents .................................................................... 20

2.8.1 Ethyl Cellulose ................................................................................. 21 2.8.2 Sodium Alginate .............................................................................. 23

2.9 Alginate Beads ........................................................................................... 23

ix

2.10 Electrospray Technique............................................................................ 25

CHAPTER THREE: CARBAMAZEPINE MICROPARTICLES ....................... 26 3.1 Introduction ................................................................................................ 26

3.2 Materials and Methods ............................................................................... 28 3.2.1 Materials ........................................................................................... 28 3.2.2 Preparation of CBZ Microparticles .................................................. 28

3.2.2.1 Preparation of Aqueous Phase ............................................... 28 3.2.2.2 Preparation of Organic Phase ................................................ 28

3.2.2.3 Preparation of the Primary Emulsion .................................... 29 3.2.3 Particle Size Determination ............................................................. 29 3.2.4 Encapsulation Efficiency (EE) ......................................................... 30 3.2.5 In Vitro Drug Release....................................................................... 30

3.2.6 Validation of UV-Vis Method ......................................................... 31 3.2.6.1 Solution Preparation .............................................................. 31 3.2.6.2 Spectrophotometric Method Validation ................................ 31

3.2.6.3 Specificity and Solution Stability .......................................... 32 3.2.6.4 Linearity ................................................................................ 32 3.2.6.5 Accuracy ................................................................................ 32 3.2.6.6 Precision ................................................................................ 33

3.2.7 DSC Analysis ................................................................................... 33 3.2.8 ATR-FTIR Analysis ......................................................................... 34 3.2.9 HPLC Analysis ................................................................................ 34

3.2.10 Morphology Study ......................................................................... 34

3.2.11 Experimental Design and Statistical Analysis ............................... 35 3.3 Results ........................................................................................................ 36

3.3.1 Particle Size ...................................................................................... 36

3.3.2 Encapsulation Efficiency ................................................................. 38 3.3.3 In Vitro Drug Release ...................................................................... 39 3.3.4 Method Validation ........................................................................... 43

3.3.4.1 Specificity .............................................................................. 43 3.3.4.2 Solution Stability ................................................................... 44

3.3.4.3 Linearity ................................................................................ 45 3.3.4.4 Accuracy ................................................................................ 46

3.3.4.5 Precision ................................................................................ 47 3.3.5 DSC Analysis ................................................................................... 48

3.3.6 HPLC ............................................................................................... 50 3.3.7 FTIR ................................................................................................. 52 3.3.8 Morphological Studies ..................................................................... 53

3.4 Discussion .................................................................................................. 54 3.5 Conclusion ................................................................................................. 61

CHAPTER FOUR: CARBAMAZEPINE BEADS ................................................. 62 4.1 Introduction ................................................................................................ 62 4.2 Materials and Methods ............................................................................... 65

4.2.1 Materials ........................................................................................... 65 4.2.2 Design of Experiment ...................................................................... 65

4.2.3 Preparation of Sodium Alginate Solution ........................................ 65

4.2.4 Preparation of Calcium Chloride Solution ....................................... 66

x

4.2.5 Preparation of Beads ........................................................................ 66

4.2.6 Characterization of the Beads .......................................................... 67 4.2.6.1 Bead Size ............................................................................... 67

4.2.6.2 Surface Morphology Study .................................................... 67 4.2.6.3 Encapsulation Efficiency ....................................................... 68 4.2.6.4 In Vitro Drug Release ............................................................ 68 4.2.6.5 Interaction Study by HPLC ................................................... 68

4.3 Results ........................................................................................................ 69

4.3.1 Bead Size .......................................................................................... 69 4.3.2 Morphology Study ........................................................................... 70 4.3.3 EE ..................................................................................................... 71 4.3.4 In Vitro Drug Release ...................................................................... 72

4.3.5 HPLC Analysis ................................................................................ 73 4.4 Discussion .................................................................................................. 75 4.5 Conclusion ................................................................................................. 78

CHAPTER FIVE: PEDIATRICS CARBAMAZEPINE ORAL JELLY ............. 79 5.1 Introduction ................................................................................................ 79 5.2 Material and Methods ................................................................................ 81

5.2.1 Material ............................................................................................ 81

5.2.2 Design of Experiment ...................................................................... 81 5.2.3 Preparation of Carbamazepine Jelly................................................. 81 5.2.4 Characterization of CBZ Oral Jelly.................................................. 82

5.2.4.1 Syneresis ................................................................................ 82

5.2.4.2 Rheology ................................................................................ 83 5.2.4.3 Homogeneity Test ................................................................. 83 5.2.4.4 In vitro Drug Release ............................................................. 84

5.2.4.5 Viscosity ................................................................................ 85 5.2.4.6 Physical Appearance ............................................................. 85 5.2.4.7 HPLC Analysis ...................................................................... 85

5.2.4.8 Stability Study ....................................................................... 85 5.3 Results ........................................................................................................ 87

5.3.1 Syneresis .......................................................................................... 87 5.3.2 Rheology .......................................................................................... 87

5.3.3 Homogeneity Test ............................................................................ 89 5.3.4 In vitro Drug Release ....................................................................... 90

5.3.5 Physical Appearance ........................................................................ 91 5.3.6 HPLC Analysis ................................................................................ 91 5.3.7 Stability Study .................................................................................. 92

5.4 Discussion .................................................................................................. 92 5.5 Conclusion ................................................................................................. 96

CHAPTER SIX: GENERAL CONCLUSION ........................................................ 97

REFERENCES ......................................................................................................... 101

APPENDIX I: PARTICLE SIZE DISTRIBUTION OF MP1-MP16

FORMULATIONS GRAPHS ................................................................................. 113

xi

APPENDIX II: FTIR SPECTRUM OF MP1-MP16 FORMULATIONS .......... 121

APPENDIX III: RESEARCH OUTPUT ............................................................... 129

xii

LIST OF TABLES

Table No. Page No.

‎3.1 Release profile requirement of CBZ as USP 31

‎3.2 Factorial design of prepared CBZ-loaded microparticles 35

‎3.3 Results of EE, particle size, span, and % release of CBZ from

microparticles formulations after 24 hours (n = 3) 36

‎3.4 Solution stability of CBZ in water, where A286 means absorbance

reading at 286 nm wavelength 45

‎3.5 Accuracy study of CBZ spiked at different concentrations 47

‎3.6 Results of a precision study of CBZ at 100% concentration level. 48

‎3.7 Degree crystallinity of CBZ 50

‎4.1 Factorial design of prepared CBZ-beads formulations. 67

‎4.2 Results of bead size, EE and the % release of CBZ for 24 h

for B1-B8 Formulations (n = 3) 69

‎5.1 J1 to J8 formulation of syneresis study 82

‎5.2 Results of syneresis test of J1-J8 formulations 87

‎5.3 Results of rheology study of iota carrageenan jelly 88

‎5.4 Homogeneity test results 89

‎5.5 Release of CBZ from the jelly in water dissolution medium 90

‎5.6 Dissolution test and similarity factor of Tegretol XR tablets

and CBZ-oral jelly (n=3) 90

‎5.7 Stability study results 92

xiii

LIST OF FIGURES

Figure No. Page No.

‎2.1 Carbamazepine Structure 16

‎3.1 Effect of A (EC), B (PVA), C (solvent), D (homogenization speed)

and E (homogenization time) factors on particle size for

MP1-MP8 formulations 37

‎3.2 Effect of A (EC), B (PVA), C (solvent), D (homogenization time)

and C (homogenization speed) factors on particle size for

MP9-MP16 formulations 37

‎3.3 Effect of A (EC), B (PVA), C (solvent), D (homogenization time)

and E (homogenization speed) factors on EE for MP1-MP8

formulations 38

‎3.4 Effect of A (EC), B (PVA), C (solvent), D (homogenization time)

and E (homogenization speed) factors on EE for MP9-MP16

formulations 39

‎3.5 Effect of A (EC), B (PVA), C (solvent), D (homogenization time)

and E (homogenization speed) factors on % Release Profile for 24

h

of MP1-MP8 formulations 40

‎3.6 Effect of A (EC), B (PVA), C (solvent), D (homogenization time)

and E (homogenization speed) factors on % release profile for 24 h

of MP9-MP16 formulations 41

‎3.7 Release of CBZ from MP1-MP8 formulations for 24 h (n = 3) 41

‎3.8 Release of CBZ from MP9-MP16 formulations for 24 h (n = 3) 42

‎3.9 Effect of A (EC), B (PVA), C (solvent), D (homogenizing speed)

and E (homogenization time) factors on % release profile for 24 h

of MP9-MP16 42

‎3.10 Release profile comparison between MP12 and CBZ only (control)

for 24 h 43

‎3.11 UV-spectrum of CBZ, EC, and PVA 44

‎3.12 Linearity of CBZ 46

3.13 DSC thermogram of formulated microparticles, EC and CBZ. 49

‎3.14 HPLC chromatograms for standard CBZ, microparticles and blank 51

xiv

‎3.15 FTIR of MP1-MP16 formulations 52

‎3.16 FTIR results of CBZ, EC and CBZ-microparticles (MP12) 53

‎3.17 Morphology of CBZ microparticles viewed under stereomicroscope

connected to Nikon lens 53

‎4.1 Normal plot of the effect of different factors on formulated bead size 70

4.2 Main effect plot of different factors on the size of the formulated

beads 70

‎4.3 Morphology of CBZ-bead a (B5), b (B4), c (B1), and d (B2)

formulations 71

‎4.4 Effect plot of different factors on EE of prepared beads formulations 72

‎4.5 Release profile of CBZ from beads formulations 73

4.6 Normal plot of the effect of different factors on CBZ dissolution

beads for 24 h 73

‎4.7 HPLC chromatogram of CBZ-standard and CBZ-beads 74

‎5.1 Rheology model of iota-carrageenan jelly 2.5% without beads 88

‎5.2 Rheology model of CBZ jelly 89

‎5.3 HPLC test of stability study for CBZ standard and CBZ-jelly 91

xv

LIST OF ABBREVIATION

CBZ Carbamazepine

EC Ethylcellulose

MR Modified release

EA Ethyl acetate

PVA Polyvinyl alcohol

EE Encapsulation efficiency

DT Dissolution test

PS Particle size

EMA European medicines agency

CHMP Committee for medicinal products for human use

MR Modified release

DSC Differential scanning calorimetry

HPLC High-pressure liquid chromatography

FTIR Fourier transform infrared spectroscopy

MP Microparticles

B Beads

J jelly

BBB Blood-brain barrier

WHO World health organization

HPMC Hydroxypropylmethylcellulose

SF Sphericity Factor

F2 Similarity Factor

HCl Hydrochloric acid

GIT Gastro-intestinal tract

FDA Food and drug administrative

USP United states pharmacopoeia

xvi

LIST OF SYMBOLS

® Trade name

° degree

p P value

µ micro

Σ Sigma

1

CHAPTER ONE

INTRODUCTION

1.1 BACKGROUND

Pharmaceutical dosage forms for pediatrics must be appropriate in relation to their

age. Pediatrics below 6 years generally cannot have solid dosage forms by oral route

unlike liquid and semi-solid dosage forms. According to European Medicines Agency

(EMA) Committee for Medicinal Products for Human Use (CHMP), there is a number

of important considerations to be noted when manufacturing a new dosage form for

pediatrics and as following (Committee, 2006):

1. Minimizing the frequency of dosage.

2. Minimizing non-toxic excipients.

3. Reliable, easy, convenient administration.

4. Should be inexpensive and available commercially.

5. Should be easily prepared, elegant and stable.

6. One dosage form suits all or a full of a range of pediatrics.

EMA (CHMP) mentioned that modified release (MR) preparations can be

helpful for child patients who may need to have medication when they are at school or

in the night. In oral modified release medications, single dose daily formulations can

be advantageous for compliance. While MR injections can minimize significantly the

frequency of the dose but the pain must be avoided. Transdermal formulations can

also prolong the effect of the drug with simple use but the skin permeability level will

be different with age developmental changes and this issue must be taken in the

consideration when preparing such a dosage form. MR formulations should meet the

2

requirements of the dose for a different range of ages.In the MR solid preparations, the

dosage requirements can be achieved by using specified formulations like prolonged

release granules with known dose per granule. Liquid MR dosage forms ingredients

are dissolved in or be bound to very small particles like pellets or resin particles. MR

oral suspensions contain pellets or small particles and size of that particles and pellets

is limited and child patient must not chew it(Committee, 2006).

Epilepsy is one of a brain function disorders characterized mostly by frequent

and unpredictable obstruction of the function of the normal brain, known as epileptic

seizures. It’s the abnormality of a sudden electrical activity (Fisher et al., 2005). This

disorder is affecting about 70,000,000 worldwide of different ages in 2014 (Ali &

Nabi, 2014). Different reasons were reported to know the causes behind epilepsy

syndrome such as the zone of the brain involved, genetic reasons, age etc. (Berg,

Levy, Testa, & Shinnar, 1999). There are many types of epilepsy syndrome like;

Juvenile absence epilepsy, Angelman syndrome, childhood absence epilepsy, Doose

syndrome, Dravet syndrome, epilepsy on infancy with migrating focal seizures,

epilepsy with myoclonic absence, frontal lobe epilepsy, epilepsy with generalized

tonic-clonic seizers alone, hypothalamic hamartoma, lafora progressive myoclonus

epilepsy, PCDH19 epilepsy, and reflex epilepsy etc.(Kramer et al., 1998; U. Lee, Kim,

& Jung, 2006).

CBZ is an anticonvulsant drug used to treat focal seizures, trigeminal,

neuralgia, and bipolar disorder. The site of absorption of CBZ is the gastrointestinal

tract (GIT) but it has faster absorption on a full stomach than an empty stomach. CBZ

is a white or white-yellowish particles, bitter in taste, insoluble in water. CBZ shows

its anticonvulsant or antiepileptic effect by inhibiting voltage-dependent sodium

channel, thus it blocks sustained repetitive firing in individual neurons. It seems to

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give no help in GABA-mediated inhibition (Catterall, 2014). Diplopia, headache,

dizziness, nausea and vomiting are the common side effects of CBZ while the rare

side effects of CBZ includes erythema multiform, Stevens-Johnson syndrome,

Reversible mild leucopenia, blood dyscrasias and toxic hepatitis (Perucca & Gilliam,

2012).

Jellies can be defined as "a semisolid system consisting of either suspension

made up of gelling agent molecules interpenetrated by a liquid" (Jones, Swarbrick, &

Boylan, 2002). Medicated jellies more reasonable for pediatric, many studies have

suggested that the using of oral semi-solid dosage forms are preferred for dysphagic,

children and geriatric patients because of their formulation's nature as semi-solid

preparations (Yutaka Inoue & Kanamotoa, 2015). Oral jelly is a fundamental solution

to dysphagia patients, and also is frequently prescribed for geriatrics (Prakash et al.,

2014).

1.2 PROBLEM STATEMENT

Despite the availability of sustained release formulations of carbamazepine, these

formulations are not designed for pediatric patients. Pediatric patients with epilepsy

need to take carbamazepine suspension divided into two or four times a day for long

duration (Wolters Kluwer Health, 2017). There are no available marketed sustained

release dosage forms to be used for pediatrics. The available dosage form is only

(carbamazepine suspension) giving no options for those patients or their caregivers.

Providing sustained release formulation of CBZ may help pediatrics in administering

the drug with more convenience. The new sustained release dosage form should be

flexible in dosing (mg drug per body weight) and suitable for pediatrics of different

ages. For these reasons, chewable tablets and dispersible tablets may not achieve the

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desired criteria. Instead, oral jellies that appeared as new dosage form might be a

potential candidate.

1.3 HYPOTHESIS

CBZ can be prepared for pediatric-suitable sustained release jelly formulation. The

formulated oral jelly has similar release profile as the reference.

1.4 OBJECTIVE

General objective:

To formulate CBZ in sustained release oral jelly formulation, suitable for pediatric

use.

Specific objectives:

1. To fabricate sustained release CBZ microparticles by a solvent evaporation

method using ethylcellulose polymer.

2. To characterize CBZ loaded microparticles for their particle size,

encapsulating efficiency, in vitro drug release, morphology study, HPLC, ATR-FTIR,

and DSC.

3. To load CBZ microparticles in alginate beads and characterize it for beads

size, morphology study, encapsulation efficiency, in vitro drug release, and HPLC.

4. To suspend the beads in the jelly vehicle and characterize it for the syneresis,

rheology, homogeneity test, in vitro drug release, and stability study.

1.5 STUDY DESIGN

This project is divided into three main parts: first, is the fabrication of CBZ-loaded

microparticles using EC as encapsulating polymer. These microparticles are optimized

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to have sustained release profile similar to the commercially approved sustained

release CBZ tablets. Since microparticle may have grittiness feeling in the mouth

when taken orally, they were entrapped in alginate beads. Alginate beads have better

mouth feeling, jelly texture and biocompatible. Hence, the second part is the

preparation of alginate beads containing CBZ microparticles. The beads are designed

so that they have minimal effect on the release profile of the microparticles. Finally, is

the preparation of jelly base to suspend alginate beads. The jelly acts as a vehicle to

suspend the beads, preventing them from settling down and giving pediatric-friendly

texture to be administered. Similarly, the jelly was optimized to have minimal effect

on the release of CBZ from the microparticle. Therefore, the final dosage form will

have same release profile of the microparticles, which is like the commercially

available CBZ tablets.

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CHAPTER TWO

LITERATURE REVIEW

2.1 INTRODUCTION

Developing a new dosage form is a real challenge to the pharmaceutical researchers,

especially when the dosage form targets pediatric population. Pediatrics differ from

adults in the type of dosage forms and the doses of the medications which considered

to be constant in the adults and depended on the body weight for pediatrics. There are

a differences in the pharmacodynamic and pharmacokinetic properties as the

pediatrics have grown and organ developing stage (Estabrook, Bouxsein, Pitluck, &

Davis, 2000).

There are different age groups named according to pediatrics developmental

stages of their population (Committee, 2006) like:

Pre- newborn infants.

Newborn infants aged (from 0 to 27) days.

Infants and toddlers aged (1-23) months.

Children aged (from 2 to 11) years.

Adolescents aged (12-16 or 18) years.

2.2 PHARMACOLOGICAL DEVELOPMENT OF PEDIATRIC

POPULATION

Children are growing and many physiological and pharmacological changes occurred

during their life. Understanding those changes can give an idea to handle and

manufacture the suitable medications. A brief summary is explained for absorption,

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distribution, metabolism and renal elimination in pediatrics to understand the best way

of bioavailability of any medication prescribed for their use and as follows

(Committee, 2006):

2.2.1 Absorption

The different site of drug absorption of children can be explained by the following

discussion:

2.2.1.1 Oral

In the neonatal stage, gastric pH is high with increasing of gastric emptying, therefore

the rate of absorption for drugs administered orally is faster in older pediatrics than

neonates and infants (Heimann, 1980).

2.2.1.2 Buccal

The permeability of mucosa considered to be higher in pediatrics than adults

(Committee, 2006).

2.2.1.3 Topical

Pediatrics have large surface area compared to adults, therefore percutaneous

absorption is more. Topical substances have potential absorption through the skin of

pediatrics o reach blood circulation and body tissues and may cause toxicity (for

example, adrenal suppression with topical corticosteroids). Epidermis layer in

childhood is more perfused and hydrated than adults and stratum corneum is thinner

(Committee, 2006; Monsour, Rabinovitch, & Dean, 1999).

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2.2.1.4 Intramuscular

Due to the rich supply of blood capillaries in infants than older pediatrics and adults,

the absorption will be greater in infants (Simons, Roberts, Gu, & Simons, 1998).

2.2.1.5 Pulmonary

Absorption through lungs mucosa can be useful but drugs administered locally are

well absorbed in pediatrics but may produce systemic side effects (Committee, 2006).

2.2.1.6 Rectal

Suppositories can be used for infants and can give good absorption but they will be an

issue for older pediatrics (Maeda, Nakano, Aoyama, Matsumoto, & Fujito, 2016).

2.2.1.7 Nasal

Intranasal is a useful route of administration for pediatrics and can be considered as

good absorption route and more preferred for pediatrics than injection but irritation or

―a runny nose‖ and pain may be produced by formulations. Nasal mucosa secretion

can also influence the absorption (Maggio, 2016).

2.2.1.8 Distribution

Age-related changes can be found in body composition especially protein binding and

the transport mechanism. In infancy blood-brain barrier (BBB) is considered as

immature part of their body (Allegaert, Velde, & Anker, 2014).