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

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Table 1.3 Marketed/under development protein oral delivery technology by companies. Adapted from Park et al., 2011. Company System Product name Outcomes for absorption Marketed/under development products Emisphere Carrier molecules Eligen ® Increase membrane permeability Calcitonin, Insulin, Growth hormone, parathyroid hormone Altus Protein crystallization CLEC ® Stable against proteolysis and selfaggregation Calcitonin, other polypeptides, lipases, esterases and proteases BioSante Calcium BioOral Protect proteins from acidic Insulin and vaccines phosphate nanoparticles degradation and improve membrane permeability NOBEX/Biocon Amphiphilic oligomers HIM2 Resist enzyme digestion and increase membrane permeation Insulin, enkephalin, calcitonin, parathyroid hormone Appolo Life Science Nanoparticles Oradel Protect proteins from enzyme Insulin and TNF blocker digestion in the stomach and facilitates transport in the intestine Eli-Lilly Oral formulation AI-401 Protect protein from enzyme Insulin digestion Provalis PLC Lipid-based Macrulin Protect proteins from proteolysis Insulin, salmon calcitonin microemulsion and enhance protein absorption in GIT Abbreviation: CLEC, Cross-Linked Enzyme Crystal; HIM”, hexyl-insulin monoconjugate; TNF, tissue necrosis factor.
1.4.3 The pulmonary route The lungs with a large surface area of approximately 140 m 2 and very thin alveolar epithelium (approximately 300 million) allows the passage of 5 L of blood per minute (Cázares-Delgadillo et al., 2011) leading to rapid drug absorption in addition to avoiding firstpass metabolism. Furthermore, the metabolic enzymatic activities and pathways in the lungs differ from those observed in the GIT, making the pulmonary administration of various peptides and proteins very promising (Agu et al., 2001). However, full optimization of pulmonary delivery systems requires addressing critical issues relating to particle size characteristics, obtaining good encapsulation efficiency, preventing protein degradation and predictable drug release. In addition, inhaled peptides may not be suitable for all patients with smokers or asthmatics requiring lower (Himmelmann et al., 2003) or higher (Henry et al., 2003) doses respectively. Furthermore, to achieve a similar glycaemic effect, patients receiving pulmonary INS may require a dose approximately 20 times that of subcutaneous injection (Gale, 2001) which might lead to breathing difficulties and variability in dosing regimen for different categories of patients (Lassmann-Vague & Raccah 2006). 1.4.4 The ocular route Drug administration via the ocular route is much easier than injection with comparable systemic absorption rates. Drug absorption also by-passes the first-pass gastrointestinal and liver effects, resulting in increased bioavailability of peptides and other drugs. The eye tissues are much less likely to develop immunological responses compared with other tissues with prolonged safety (3 months) of use and no ocular side effects upon daily administration of INS eye drops (Chiou, 1994). Chitosan and chitosan derivatives have been developed as drug delivery systems for ocular delivery (Fuente et al., 2010, cited in Khutoryanskiy, 2011). The major drawback is the need for developing delivery systems that are compatible with the conjunctival, corneal and iris tissues with a prolonged residence time. These might raise issues with local tissue irritation, however the use of eye-drops which is rapidly eliminated seem better than an eye devices which must release the drug in a controlled manner. 1.4.5 Vaginal and rectal routes The vaginal and rectal mucosal cavities offer potential alternative routes to attain systemic delivery. Although most of the products in the marketplace are designed for local mucosal administration, a few target systemic delivery. Valenta et al., (2001) used a thiolated 23
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 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: 1.4.2 The nasal route Nasal protein
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
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
Page 77 and 78: have recommended annealing time of
Page 79 and 80: Figure 2.1: Chemical structure of c
Page 81 and 82: model proteins for buccal delivery.
Page 83 and 84: microemulsion formulation containin
Page 85 and 86: Table 2.2: Details of consumables u
Page 87 and 88: chitosan was stirred continuously f
Page 89 and 90: Table 2.5: Lyophilisation cycles wi
Page 91 and 92: a b c d Figure 2.6: Photographs of
Page 93 and 94:
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
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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
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224. Silva, C.A., Nobre, T.M., Pavi
Page 217 and 218:
245. Tamburic, S., Graig, D.Q.M. 19
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265. Wang W. 2000. Lyophilisation a
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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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