Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.571461
Title: Development of novel formulations for mucosal delivery of protein based drugs
Author: Ayensu, Isaac
Awarding Body: University of Greenwich
Current Institution: University of Greenwich
Date of Award: 2012
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Abstract:
Stable mucoadhesive lyophilised chitosan and thiolated chitosan xerogels have been developed for potential delivery of proteins via the buccal mucosa. Membrane dialysis to eliminate sodium acetate (NaAc) and annealing during lyophilisation cycle (developed by differential scanning calorimetry; DSC) were critical for obtaining optimised porous xerogels. Based on characteristic performance and structural integrity, xerogels containing 10 % (per polymer weight) each of plasticizer (glycerol) and cryoprotectant (D-mannitol) were loaded with bovine serum albumin (BSA) and insulin (INS) as model drugs for further development. The optimised xerogels were loaded with enzyme inhibitor (EI) and permeation enhancer (PE) to enhance permeability of the buccal mucosa and backed with impervious ethylcellulose (EC) laminate to ensure unidirectional release. Characterisation of xerogels using 1HNMR and ATR-FT-IR spectroscopy confirmed the functional groups in chitosan and TG-chitosan. The amount of thiol groups on TG-chitosan was quantified by Ellman’s reaction with polymer molecular weight monitoring by gel permeation chromatography (GPC). The stability of the secondary structures of BSA and INS were by ATR-FT-IR and circular dichroism (CD) while xerogel crystallinity was examined by XRPD. SEM micrographs showed highly porous xerogels due to annealing which allowed for high drug loading and hydration capacities of the dialysed and annealed xerogels which also exhibited optimal moisture content for maintaining protein stability. Disulphide bond formation in thiolated xerogels however limited the hydration capacity. Storage at 25 °C/ 60 % RH for six months led to protein instability while storage at 5 °C maintained protein stability. 2% mucin concentration was found optimum for mucoadhesion studies of the chitosan based xerogels. EI (glutathione; GSH and aprotinin; APR) effect on mucoadhesion was concentration dependent and inhibitor specific. In vitro BSA release profiles from annealed xerogels were similar and significantly higher than non-annealed xerogels but were not affected by thiolation. Crystalline NaAc in the undialysed xerogel led to a three-fold reduction in BSA release. Significant reductions in BSA and INS release were also observed with the addition of EIs to TG-chitosan-BSA and TG-chitosan-INS xerogel respectively. The drug dissolution data from xerogels fitted best with model dependent First order, Hixson-Crowell and Korsmeyer-Peppas equations. Permeation studies’ using EpiOralTM showed 12- to 14-fold increase in BSA permeation but was reduced by GSH for both BSA and INS loaded xerogels. APR containing xerogel enhanced INS permeation through sheep buccal membrane and demonstrated a good linear correlation with EpiOralTM. These results demonstrate the potential application of lyophilised chitosan and thiolated chitosan xerogels for buccal mucosa delivery of proteins with improved mucoadhesion, penetration enhancing and enzyme inhibition characteristics.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.571461  DOI: Not available
Keywords: QD Chemistry
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