LAUSR

Keratitis is a severe, sight threatening condition caused by microbial infection. Eyedrops are the standard delivery medium for treating these disorders; however, blinking, elevated tear production and nasolacrimal drainage eliminates much of the instilled dose within a few seconds, meaning they must be applied repeatedly for prolonged periods and, depending on the causative microorganism, poor patient responses. The present study aimed to probe alternative delivery systems for the more effective delivery of chlorhexidine to treat keratitis based upon drug-loaded hydrogel contact lenses and β-cyclodextrin (β-CD), whilst also determining the effect of constant irrigation with simulated tear fluid (STF). Chlorhexidine digluconate (as 0.2 and 2.0% solution, β-CD inclusion complexes and loaded hydrogel contact lenses) were applied to enucleated porcine eyes as single or multiple 10 µL doses, or as drug loaded contact lenses, with and without β-CD. The corneas were then excised and drug extracted followed by quantification using HPLC. The effect of constant irrigation by STF was evaluated to test the effect of increased tear production on corneal delivery. Potential antimicrobial activity of delivered drug was also assessed. Results showed that drug-loaded contact lenses delivered the greatest amount of chlorhexidine over a 24 h period, whilst the eyedrop solution comparator delivered the least, in line with Fick's first law. The β-CD significantly enhanced chlorhexidine delivery to the cornea from eyedrop solution, although contact lenses loaded with chlorhexidine-β-CD failed to enhance delivery. β-CD within the hydrogel matrix impeded drug release. Constant irrigation with STF significantly reduced the amount of drug delivered to the cornea in all cases. Chlorhexidine retained antimicrobial activity in all delivery methods. Hydrogel contact lenses loaded with chlorhexidine deliver significantly higher levels to the cornea compared to eyedrops, either multiple hourly doses or a single dose. They also offer reduced application, in particular to a non-ulcerated corneal infection. Finally, the importance of fully accounting for tear production, especially in keratitis where tear production rate is elevated, in in vitro ocular delivery experiments was highlighted.