Development of novel formulations for mucosal delivery of protein ...

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University of Greenwich School of Science Department of Pharmaceutical, Chemical and Environmental Sciences Development of Novel Formulations for Mucosal Delivery of Protein Based Drugs By Isaac Ayensu {BPharm, MSc (Pharmaceutical Analysis and quality control)} Supervised by: Dr. Joshua Boateng Prof. John Mitchell Thesis report presented in partial fulfilment of the requirement for the award of Doctor of Philosophy. October, 2012
DECLARATION “I certify that this work has not been accepted in substance for any degree, and is not concurrently being submitted for any degree other than that of Pharmaceutical sciences being studied at the University of Greenwich. 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 the work of others”. ………………………… ……………………………… ISAAC AYENSU (STUDENT) DR. JOSHUA BOATENG (SUPERVISOR) DATEμ…………………. DATEμ…………………….....
Page 1: Greenwich Academic Literature Archi
Page 5 and 6: ABBREVIATIONS ATR-FT-IR (attenuated
Page 7 and 8: CONTENTS DECLARATION ..............
Page 9 and 10: CHAPTER TWO .......................
Page 11 and 12: CHAPTER FOUR ......................
Page 13 and 14: TABLES Table 1.1: Relationship of i
Page 15 and 16: FIGURES Figure 1.1: Molecular model
Page 17 and 18: [Accessed; 24/05/2012]. ...........
Page 19 and 20: Figure 4.2: In-vitro mucoadhesion m
Page 21 and 22: CHAPTER ONE INTRODUCTION AND LITERA
Page 23 and 24: freezing rate at the start of a lyo
Page 25 and 26: aggregates may lead to an immunogen
Page 27 and 28: Figure 1.1: Molecular model of seru
Page 29 and 30: One of the greatest milestones in m
Page 31 and 32: limited success. INS released in a
Page 33 and 34: composition of the delivery system
Page 35 and 36: ioavailability of proteins using pe
Page 37 and 38: 1.3.3.2 Factors affecting mucoadhes
Page 39 and 40: Human salivary glands secrete 1000-
Page 41 and 42: 1.4.2 The nasal route Nasal protein
Page 43 and 44: 1.4.3 The pulmonary route The lungs
Page 45 and 46: and enzymes from foods and beverage
Page 47 and 48: (Veuillez et al., 2001; Nagai, 1986
Page 49 and 50: 1.6.1 Chitosan Chitosan together wi
Page 51 and 52: 1.6.3 Chitosan derivatives The exce
Page 53 and 54:
with increasing amounts of immobili
Page 55 and 56:
1.6.6.3 Thiolated chitosans as matr
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stability studies among others can
Page 59 and 60:
the product matrix, the vacuum of t
Page 61 and 62:
an oven at an appropriate temperatu
Page 63 and 64:
Several analytical procedures have
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transmitting crystal with a high re
Page 67 and 68:
1.8.4.2 Powder diffraction Powder X
Page 69 and 70:
1.8.5.1 Interpreting DSC thermogram
Page 71 and 72:
(absorption in the range 260 to 320
Page 73 and 74:
Figure 1.26: Representation of SEM.
Page 75 and 76:
CHAPTER TWO FORMULATION DEVELOPMENT
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have recommended annealing time of
Page 79 and 80:
Figure 2.1: Chemical structure of c
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model proteins for buccal delivery.
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microemulsion formulation containin
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Table 2.2: Details of consumables u
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chitosan was stirred continuously f
Page 89 and 90:
Table 2.5: Lyophilisation cycles wi
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a b c d Figure 2.6: Photographs of
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simple one step coupling reaction i
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2.3.5 Lyophilisation The primary dr
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The foremost implication of these f
Page 99 and 100:
3.2 Materials and methods 3.2.1 Mat
Page 101 and 102:
were analysed with Agilent Chemstat
Page 103 and 104:
previously tarred 70 µl aluminium
Page 105 and 106:
3.2.13.2 Assay of BSA and INS conte
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A H1 (GluNAc) H3 -H6 NAc H2 (GluNH
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V o V e Intensity ElutionTime (min)
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c c r er % Transmittance 110 90 70
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during the xerogel preparation proc
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and without APR respectively. The r
Page 117 and 118:
3.3.7 Physical stability of BSA and
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15 Circular dichroism (mdeg) 10 5 0
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Since no product melt-back was obse
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0.8 Absorbance ratio 595/450 0.7 0.
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A B Dialysed chitosan-BSA 100 µm 1
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High magnification SEM micrograph o
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BSA content (%) 100.0 80.0 60.0 40.
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conditions leads to protein hydroly
Page 133 and 134:
3.4 Conclusions Analytical characte
Page 135 and 136:
CHAPTER FOUR HYDRATION CAPACITY AND
Page 137 and 138:
4.2.2.1 Effect of formulation proce
Page 139 and 140:
substrate in order to select the op
Page 141 and 142:
Table 4.3 Hydration capacity of xer
Page 143 and 144:
4.3.2.1 Factors affecting mucoadhes
Page 145 and 146:
impacted on the mucoadhesive proper
Page 147 and 148:
and TG-chitosan xerogels. The chito
Page 149 and 150:
PAF (N) TWA (mJ) Cohesiveness (mm)
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Annealed TG-chitosan xerogel simila
Page 153 and 154:
that each model makes assumptions t
Page 155 and 156:
independent difference and similari
Page 157 and 158:
elease profiles plotted. Blank cont
Page 159 and 160:
the second phase of the release pro
Page 161 and 162:
100 Cummulative BSA Release (%) 80
Page 163 and 164:
controlled drug release has been de
Page 165 and 166:
Cummulative INS release (%) 100 80
Page 167 and 168:
that of non-annealed dialysed chito
Page 169 and 170:
Table 5.5: Release parameters obtai
Page 171 and 172:
The effect of formulation processes
Page 173 and 174:
Table 5.9: Model independent differ
Page 175 and 176:
CHAPTER SIX PERMEATION STUDIES USIN
Page 177 and 178:
6.2 Materials and Methods 6.2.1 Mat
Page 179 and 180:
Permeation studies were conducted f
Page 181 and 182:
fold increase in transport of BSA f
Page 183 and 184:
Cumulative INS permeated (g/cm 2 )
Page 185 and 186:
Average percentage viability was pl
Page 187 and 188:
5.5 A TG-chitosan-INS permeation (E
Page 189 and 190:
CHAPTER SEVEN SUMMARY CONCLUSIONS A
Page 191 and 192:
was observed for dialysed and annea
Page 193 and 194:
2. The long-term stability evaluati
Page 195 and 196:
drug delivery systems via the bucca
Page 197 and 198:
33. Bunte, H., Drooge, D.J., Ottjes
Page 199 and 200:
56. Engles, L. 2005. Review and app
Page 201 and 202:
(chitooligosaccharide derivatives)
Page 203 and 204:
of single-point mutants of an amylo
Page 205 and 206:
121. Koschier, F., Kostrubsky, V.,
Page 207 and 208:
142. Liu, W., Wang, D.Q., Nail, S.
Page 209 and 210:
160. Modi, P., Mihic, M. And Lewin,
Page 211 and 212:
180. Pastore, A., Piemonte, F., Loc
Page 213 and 214:
204. Robinson, J., R. 1990. Rationa
Page 215 and 216:
224. Silva, C.A., Nobre, T.M., Pavi
Page 217 and 218:
245. Tamburic, S., Graig, D.Q.M. 19
Page 219 and 220:
265. Wang W. 2000. Lyophilisation a
Page 221 and 222:
285. Zor, T., Selinger, Z. 1996. Li
Page 223 and 224:
APPENDIX B: Manuscripts in preparat
Page 225 and 226:
2. Accepted abstract for podium and
Page 227 and 228:
4. Abstract # 43 awarded podium and
Page 229 and 230:
6. Published abstract M1144 (2011).
Page 231:
8. Published abstract W1470 (2010).
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