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

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Table 5.5: Release parameters obtained from fitting experimental drug dissolution (release) data to different kinetic equations for TG-chitosan xerogels loaded with BSA containing GSH using Franz-type diffusion cell. .............................................................................................. 149 Table 5.6: Release parameters obtained from fitting experimental drug dissolution (release) data to different kinetic equations for TG-chitosan xerogels loaded with INS and BSA containing different EIs. ......................................................................................................... 150 Table 5.7: Model independent difference (f 1 ) and similarity (f 2 ) factors for release profiles of BSA (determining the effect of membrane dialysis, annealing and thiolation on formulations) with annealed/dialysed chitosan-BSA and annealed TG-Chitosan-BSA xerogels as reference (R j ) formulations. .................................................................................................................... 151 Table 5.8: Model independent difference (f 1 ) and similarity (f 2 ) factors for release profiles of BSA (determining the effect of EI concentration on release) with TG-Chitosan-BSA and TG- Chitosan-GSH-BSA (5 %) xerogels as reference (R j ) formulations. ..................................... 152 Table 5.9: Model independent difference (f 1 ) and similarity (f 2 ) factors for release profiles of INS and BSA (determining the effect of different EIs on release) with TG-Chitosan-INS xerogels and TG-Chitosan-APR-INS (5 %) as reference (R j ) formulations. ......................... 153 Table 6.1: Details of materials used in permeation studies ................................................... 157 Table 6.2 Optimised drug loaded xerogels used for permeability studies ............................. 159 Table 6.3: Permeation parameters of xerogels from EpiOral TM buccal construct ................. 161 Table 6.4: Permeation parameters of xerogels from sheep buccal tissue .............................. 166
FIGURES Figure 1.1: Molecular model of serum albumin. Available at [Accessed; 25/04/12] ............................ 7 Figure 1.2: Structure and amino acid sequence of INS; (i) Sequence of human insulin with the A chain above and the B chain beneath. Cysteines forming disulphide linkages are indicated with bars. (ii) Ribbon model of INS. The A-chain is indicated in red, and the B- chain with blue. Disulphide bridges are shown by gold spheres (sulphur atoms); pairings are indicated in black boxes. Black spheres show C carbons of the residues (Adapted from T- state protomer; Protein Data bank access ion code 4 INS; Baker et al., 1988, cited in Hua et al., 2011). .................................................................................................................................... 9 Figure 1.3: A schematic diagram showing clinical and potential protein delivery routes Abbreviation: absorption enhancers (AE) enzyme inhibitors (EI) and electroporation (EP), Adapted from Agu et al., 2001. ................................................................................................ 12 Figure 1.4: Schematic diagram showing the mechanism of enzyme inhibition. Available at [Accessed; 20/03/2011] ........ 14 Figure 1.5: Mechanism of dosage form and mucosal layer interaction (Carvalho et al., 2010) .................................................................................................................................................. 16 Figure 1.6: A simplified model of a large secreted mucin. Available at [Accessed; 08/08/2011]. ......................... 19 Figure 1.7: (a) Cartoon representation of the buccal mucosa (b) cross-section of the buccal mucosa structure. Available at < www.cedars sinai.edu/Patients/Programs and-Se..website.> [Accessed; 13/08/2010] ............................................................................................................ 25 Figure 1.8: Buccal delivery of insulin from Generex Oral-lyn. Available at [Accessed; 26/05/2011] .................... 26 Figure 1.9: Mechanism of protein transport across epithelial cell layers. (Yu et al., 2009) ... 27 Figure 1.10: Mucoadhesive drug delivery system via the buccal mucosa. Available at [Accessed; 20/05/2011] .. 28 Figure 1.11: Chemical structure of chitosan. Available at [Accessed; 20/05/2011] .................... 29 Figure 1.12: Synthesis of chitosan thioglycolic acid (TG-chitosan) (Ayensu et al., 2012a) ... 32 Figure 1.13: Thiolated chitosan moieties (a) chitosan cysteine (b) chitosan thioglycolic acid and (c) chitosan-4-thiobutylamidine (Roldo et al., 2004) ........................................................ 32 Figure 1.14: A schematic diagram showing the formation of disulphide linkages between thiomer and mucin. Adapted from Kast & Bernkop-Schnürch. 2001. ..................................... 33
Page 1 and 2: Greenwich Academic Literature Archi
Page 3 and 4: DECLARATION “I certify that this
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: TABLES Table 1.1: Relationship of i
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
Page 57 and 58: 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
Page 65 and 66:
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
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(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
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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
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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
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3.2 Materials and methods 3.2.1 Mat
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were analysed with Agilent Chemstat
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previously tarred 70 µl aluminium
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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
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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
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3.4 Conclusions Analytical characte
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CHAPTER FOUR HYDRATION CAPACITY AND
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4.2.2.1 Effect of formulation proce
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substrate in order to select the op
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Table 4.3 Hydration capacity of xer
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4.3.2.1 Factors affecting mucoadhes
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impacted on the mucoadhesive proper
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and TG-chitosan xerogels. The chito
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PAF (N) TWA (mJ) Cohesiveness (mm)
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Annealed TG-chitosan xerogel simila
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that each model makes assumptions t
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independent difference and similari
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elease profiles plotted. Blank cont
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the second phase of the release pro
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100 Cummulative BSA Release (%) 80
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controlled drug release has been de
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Cummulative INS release (%) 100 80
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that of non-annealed dialysed chito
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Table 5.5: Release parameters obtai
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The effect of formulation processes
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Table 5.9: Model independent differ
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CHAPTER SIX PERMEATION STUDIES USIN
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6.2 Materials and Methods 6.2.1 Mat
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Permeation studies were conducted f
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fold increase in transport of BSA f
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Cumulative INS permeated (g/cm 2 )
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Average percentage viability was pl
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5.5 A TG-chitosan-INS permeation (E
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CHAPTER SEVEN SUMMARY CONCLUSIONS A
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was observed for dialysed and annea
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2. The long-term stability evaluati
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drug delivery systems via the bucca
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33. Bunte, H., Drooge, D.J., Ottjes
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56. Engles, L. 2005. Review and app
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(chitooligosaccharide derivatives)
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of single-point mutants of an amylo
Page 205 and 206:
121. Koschier, F., Kostrubsky, V.,
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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
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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
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285. Zor, T., Selinger, Z. 1996. Li
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APPENDIX B: Manuscripts in preparat
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2. Accepted abstract for podium and
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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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