A Composite System Based upon Hydroxypropyl Cyclodextrins and Soft Hydrogel Contact Lenses for the Delivery of Therapeutic Doses of Econazole to the Cornea, In Vitro

Abstract

Fungal keratitis, a disease in which the cornea becomes inflamed due to an invasive fungal infection, remains difficult to treat due in part to limited choices of available treatments. Topical eye drops are first-line treatment, but can be ineffective as low levels of drug reach the target site due to precorneal losses and the impenetrability of the cornea. The aim of this study was to determine the corneal delivery of econazole using a novel topical enhancement approach using a composite delivery system based upon cyclodextrins and soft hydrogel contact lenses. Excess econazole nitrate was added to hydroxypropyl-α-cyclodextrin (HP-α-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) solutions, and the solubility determined using HPLC. Proprietary soft hydrogel contact lenses were then impregnated with saturated solutions and applied to freshly enucleated porcine eyeballs. Econazole nitrate ‘eye drops’ at the same concentrations served as the control. After 6 h, the corneas were excised and drug-extracted, prior to quantification using HPLC. Molecular dynamic simulations were performed to examine econazole–HP-β-CD inclusion complexation and dissociation. The minimum inhibitory concentration (MIC) of econazole was determined against four fungal species associated with keratitis, and these data were then related to the amount of drug delivered to the cornea, using an average corneal volume of 0.19 mL. The solubility of econazole increased greatly in the presence of HP-β-CD and more so with HP-α-CD (p < 0.001), with ratios >> 2. Hydrogel contact lenses delivered ×2.8 more drug across the corneas in comparison to eye drops alone, and ×5 more drug delivered to the cornea when cyclodextrin was present. Molecular graphics demonstrated dynamic econazole release, which would create transient enhanced drug concentration at the cornea surface. The solution-only drops achieved the least satisfactory result, producing sub-MIC levels with factors of ×0.81 for both Fusarium semitectum and Fusarium solani and ×0.40 for both Scolecobasidium tshawytschae and Bipolaris hawaiiensis. All other treatments delivered econazole at > MIC for all four fungal species. The efficacies of the delivery platforms evaluated were ranked: HP-α-CD contact lens > HP-β-CD contact lens > contact lens = HP-α-CD drops > HP-β-CD drops > solution-only drops. In summary, the results in this study have demonstrated that a composite drug delivery system based upon econazole–HP-β-CD inclusion complexes loaded into contact lenses can achieve significantly greater corneal drug delivery with the potential for improved clinical responses.

Contact lens as an emerging platform for ophthalmic drug delivery: A systematic review

“…In a set of control experiments conducted by eye scientist, β-CD significantly enhanced the delivery of chlorhexidine eye drops to the cornea; however, contact lenses loaded with chlorhexidine β-CD failed to enhance the delivery of chlorhexidine to the cornea, probably because β-CD in the hydrogel matrix hindered drug release. A substantial increase in econazole solubility and a further increase in corneal drug concentration were observed when CD-based contact lenses were used to deliver econazole, further demonstrating that CD-based contact lenses are promising drug delivery systems [69] . Li et al.…”

Therapeutic applications of contact lens-based drug delivery systems in ophthalmic diseases

“…In summary, in addition to the above methods, free radical polymerization, drug polymer film/coating, β-cyclodextrin, and artificial intelligence sensors are also effective in improving drug loading and prolonging drug release time, and have been applied in drug-loaded contact lenses (García-Fernández et al., 2013 ; Phan et al., 2014a ; Aouak et al., 2019 ; Hewitt et al., 2020 ; Li et al., 2020 ; Liu et al., 2020 ; Pillai et al., 2020 ; Zhao et al., 2021a , 2021b ; Wong et al., 2022 ).…”

Smart molecules in ophthalmology: Hydrogels as responsive systems for ophthalmic applications

“…[81] Wong and colleagues proposed a novel method for enhancing econazole topical delivery by combining excess econazole to cyclodextrin solutions and subsequently immersing soft hydrogel contact lenses in the solutions. [82] In this model, cyclodextrin serves to sequester cholesterol present at the corneal surface, thereby improving the permeability of econazole. Results from the study highlighted that the combination of cyclodextrin and hydrogel contact lenses have a 5� more drug released compared to the hydrogel alone.…”

“…However, these methods often come across challenges such as limited permeability across the hydrophilic stroma layer or rapid nasolacrimal drainage [81] . Wong and colleagues proposed a novel method for enhancing econazole topical delivery by combining excess econazole to cyclodextrin solutions and subsequently immersing soft hydrogel contact lenses in the solutions [82] . In this model, cyclodextrin serves to sequester cholesterol present at the corneal surface, thereby improving the permeability of econazole.…”