Electrospinning nanofiber insert for anterior ocular drug delivery for cataract treatment : A thesis submitted in partial fulfilment of the requirements for the Degree of Doctor of Philosophy at Lincoln University

Abstract

The eye is a complex visual aid (for human and animals) which gathers visual information from the surrounding physical environment. The more common vision threatening diseases that affect both anterior/posterior segment (age related macular degeneration, cataract, keratitis, glaucoma, diabetic retinopathy, retinoblastoma, allergic conjunctivitis, and ocular trauma) is a massive social and economic burden especially for less developed countries. Drug delivery to any tissue is a challenge, eye is not an exception. Barriers to ocular drug delivery are both physiological, anatomical, static, and dynamic. The current cost-effective cataract treatment option involves surgical removal of opaque or cataractous lens and replicated with artificial intraocular lens followed with topical application of corticosteroid eye drops as post-operative management. Whilst current topical drugs are easy to apply their bioavailability is impeded due to various barriers prevailing in the eye which put a strain on the cost and the duration of recovery. This has led researchers to the path of finding alternative methods of ocular drug delivery which more recently has led to the use of nanotechnology. Nanotechnology research that can transport and deliver active ingredient (AI) safely to site of action has gained importance in recent years. Ocular drug delivery with nanotechnology though can overcome some of the challenges but does have some limitations, like patient compliance and irritation. These limitations have been addressed by researchers across the globe by reducing drug particle size, using less irritable polymers and excipients, but with limited success. The research presented in this thesis approached this problem using nanofiber technology to develop solid ocular insert that would allow sustained drug delivery. Caffeine, a model drug, was used to determine the kinetics of bioactive release. Nanofiber membranes fabricated as mono-, two- or three-layered using two polymers, poly (ethylene) oxide (PEO) and poly ε-caprolactone (PCL) and analysed for physical characteristics of fiber (mat thickness, water contact angle, tensile properties, SEM) and drug release. Results from this study shows that the thickness of mat can be increased by having additional layer (average of 46% for two- and 54% for three-layered) compared to monolayer but it is not proportionate to the extra amount of polymer. For water contact angle the results achieved for various iterations were on par with the property of the polymer, hydrophobicity (>80°) and hydrophilicity (<50°). The tensile properties (only for mono- and three-layered formulation), puncture strength and elongation at break there was no differences between the formulations for elongation at break but for puncture strength, the force required was almost double for three-layered formulation compared to control monolayer. However, it was a challenge to measure the tensile property for monolayer formulation with PEO polymer. Mucoadhesion evaluated for only three-layered nanofiber formulations containing PEO and PCL polymer shows that the force required to detach the mat from mucin tablet (used as test material) was almost double compared to the monolayer control formulations. Surface morphology (SEM) of the nanofiber mat shows heterogenous fiber diameter distribution irrespective of the polymer and number of layers. The caffeine release from monolayer was almost immediate (within 5 min) for the formulations with PEO polymer (>50%) compared to PCL polymer wherein the same release % was noticed 1h after the initiation of the experiment. The drug release from two-layered formulation was reduced by 50% when the drug was incorporated in the first layer and the second layer acted as a barrier. Unlike the two-layered formulation, same results could not be achieved from a three-layered formulation when the drug was incorporated in the third layer, there was average >70% drug released after 1h. Surface morphology of mono- and three-layered formulations exhibited the presence of caffeine crystalline structures on the surface of the fiber which probably has attributed to immediate burst release of the drug when in contact with the aqueous solution. The results from this study elucidate that mucoadhesion onto the cornea surface can be enhanced by incorporating a hydrophilic polymer into the formulation which would probably help in the retention and increase the bioavailability of the drug to the target site in the eye. The results also shows that burst release can be mitigated and sustained release achieved when there is a barrier layer to the drug as shown in the two-layered formulation where the drug release was reduced by 50% by having a barrier layer with only the hydrophobic polymer. This formulation show promise for bioactive delivery but will require further exploration and refining.