Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.771134
Title: Mucoadhesive emulsions for the delivery of therapeutic agents
Author: Edwards, Stephanie Ellen
ISNI:       0000 0004 7656 614X
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Abstract:
Mucus lines the moist cavities in the body and acts as a barrier for these surfaces, protecting the underlying cells against the external environment but also unfortunately hindering the permeation of drugs and delivery systems. As the rate of diffusion across this barrier is low, the development of drug delivery systems that can increase retention time at the mucosal interface would be beneficial. Mucus is highly rich in cysteine groups, which have been targeted recently for a new generation of mucoadhesive thiol-functional polymers, able to form disulphide bonds with cysteine rich areas. The aim of this study was to synthesise thiol-functional branched copolymers to stabilise oil-in-water emulsions and test their potential as mucoadhesive therapeutic drug delivery systems. Atom-transfer radical polymerisation was used to synthesise amphiphilic linear and branched copolymers of oligo (ethylene glycol) monomethyl ether methacrylate, with a hydrophobic initiator, dodecyl a-bromoisobutyryl bromide, for testing as polymeric surfactants for oil-in-water macroemulsions and nanoemulsions. Branched polymer architecture was determined to be critical for the formation of successful and stable emulsions. The number of hydrophobic chain ends which can be substituted with hydrophilic functionality, while retaining emulsion stabilisation was evaluated by co-initiating branched copolymerisations with a poly(ethylene glycol)-derived initiator. Systematic reduction of hydrophobic chain ends showed that a minimum of 25 mole percent were necessary to retain emulsion stability. Mucoadhesive functionality was incorporated into the branched copolymers via a xanthate based initiator which contains a masked thiol group. The polymers were then deprotected post-polymerisation to reveal thiol groups at varying concentrations, and used as surfactants to successfully generate functional macroemulsions and nanoemulsions. Mucoadhesive properties of the thiol functionalised emulsions were tested using a novel flow through model which determined that an increase in mole percentage of thiol chain ends did lead to an increase in nanoemulsion adherence to biosimilar mucus. Ex vivo multiple particle tracking, using porcine intestinal mucus confirmed that an increase in thiol chain ends was critical to the mucoadhesive behaviour, where 42 % of particles tracked from a non-thiol functional nanoemulsion were highly diffusive and an increase to 90 mole percent thiol chain ends drastically reduced the amount of diffusive particles to 6 %. The potential of using the mucoadhesive emulsions for ophthalmic treatments utilising mucus content within the tear film was investigated. Cytotoxicity of nanoemulsions was evaluated against mucus secreting human conjunctival epithelial cells and human corneal epithelial cells, and determined to be non-toxic below 9.1 v/v % concentration of emulsion diluted in culture media. Nanoemulsions were also successfully loaded with two common drugs for ophthalmic treatments, amphotericin B and cyclosporin A at doses matching commercial topically dosed products. Overall the potential for thiol-functional macroemulsions and nanoemulsions to have mucoadhesive characteristics has been demonstrated, and the number of thiol chain ends critical to the level of adhesion determined.
Supervisor: Rannard, Steve Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.771134  DOI:
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