Most marketed formulations for treating anterior ocular conditions are topical, with conventional eyedrops representing the most utilized modality. However, due to the natural clearance mechanisms of the eye, less than 5% of an applied dose remains bioavailable following administration. To overcome the shortcomings associated with conventional eyedrops, a series of enzymatically degradable, mucoadhesive thermogels were developed. Thermogels can be applied as a solution, like a conventional eyedrops, but gel against the heat of eye. To avoid obstructing vision, these thermogels were designed to be instilled within the inferior fornix of the eye. In these studies, the base thermogelling polymer (pNAM) was crosslinked with the natural polymer chitosan. Not only does crosslinking strengthen the typically weak thermogels, but chitosan can be enzymatically degraded by lysozyme, the highest concentration protein found in tear fluid. Therefore, the developed thermogels can be applied to the inferior fornix and degrade over multiple days. A limitation of applying materials to the inferior fornix is they tend to be poorly retained. To anchor the developed thermogels within the inferior fornix, the mucoadhesive properties were tailored based on the chitosan utilized as well as the inclusion of a disulfide monomer capable of covalently bonding with the natural mucosal layer covering the surface of the eye. The disulfide bridging monomer could be further conjugated with therapeutic components which were released as a function of mucosal interaction. Conjugates investigated included cysteamine for treating cystinosis, n-acetyl cysteine for treating dry eye, the adhesion peptide RGDC as a model peptide/protein, and polyethylene glycol for modulating material properties. The release of the drugs Ketotifen Fumarate, for treating allergic conjunctivitis, and atropine, for treating myopia, were also investigated. The safety of the developed thermogels were studied both in vivo and extensively in vitro utilizing both rat and rabbit models. / Dissertation / Doctor of Philosophy (PhD) / Topical eyedrops are the most utilized treatment option for the vast majority of ocular diseases. However, eyedrops are largely ineffective with less than 5% of an applied dose reaching the desired cite of action. Therefore, eyedrops need to be frequently reapplied. To overcome these limitations, an eyedrop was developed which can be applied as a liquid but gels against the heat of the eye. This gel allows for prolonged drug release over multiple days, greatly increasing drug efficacy as well as patient comfort and compliance. To prevent obstructing vision, these gels can be applied under the lower eyelid. To keep these gels retained under the lower eyelid, they were designed to anchor to the natural mucus layer which covers the surface of eye. The developed eyedrops represent a significant advancement in ocular care; bettering the convenience, comfort, and effectiveness for patients of a topical formulation compared to traditional eyedrops.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/28253 |
| Date | January 2023 |
| Creators | Ross, Mitchell |
| Contributors | Sheardown, Heather, Chemical Engineering |
| Source Sets | McMaster University |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0021 seconds