Steroid-eluting contact lenses for corneal and intraocular inflammation

Abstract

Ocular inflammation is one of the leading causes of blindness worldwide, and steroids in topical ophthalmic solutions (e.g. dexamethasone eye drops) are the mainstay of therapy for ocular inflammation. For many non-infectious ocular inflammatory diseases, such as uveitis, eye drops are administered as often as once every hour. The high frequency of administration coupled with the side effects of eye drops leads to poor adherence for patients. Drug-eluting contact lenses have long been sought as a potentially superior alternative for sustained ocular drug delivery; but loading sufficient drug into contact lenses and control the release of the drug is still a challenge. A dexamethasone releasing contact lens (Dex-Lens) was previously developed by encapsulating a dexamethasone-polymer film within the periphery of a hydrogel-based contact lens. Here, we demonstrate safety and efficacy of the Dex-Lens in rabbit models in the treatment of anterior ocular inflammation. The Dex-Lens delivered drug for 7 days in vivo (rabbit model). In an ocular irritation study (Draize test) with Dex-Lens extracts, no adverse events were observed in normal rabbit eyes. Dex-Lenses effectively inhibited suture-induced corneal neovascularization and inflammation for 7 days and lipopolysaccharide-induced anterior uveitis for 5 days. The efficacy of Dex-Lenses was similar to that of hourly-administered dexamethasone eye drops. In the corneal neovascularization study, substantial corneal edema was observed in rabbit eyes that received no treatment and those that wore a vehicle lens as compared to rabbit eyes that wore the Dex-Lens. Throughout these studies, Dex-Lenses were well tolerated and did not exhibit signs of toxicity. Dexamethasone-eluting contact lenses may be an option for the treatment of ocular inflammation and a platform for ocular drug delivery. STATEMENT OF SIGNIFICANCE: Inflammation of the eye can happen either on the ocular surface (i.e. the cornea) or inside the eye, both of which can result in loss of vision or even blindness. Ocular inflammation is normally treated by steroid eye drops. Depending on the type and severity of inflammation, patients may have to take drops every hour for days at a time. Such severe dosing regimen can lead to patients missing doses. Also, more than 95% drug in an eye drop never goes inside the eye. Here we present a contact lens that release a steroid (dexamethasone) for seven days at a time. It is much more efficient than eye drops and a significant improvement since once worn, the patient will avoid missing doses.

Keywords: Anterior uveitis; Contact lens; Corneal neovascularization; Dexamethasone; Drug delivery; Inflammation.

Fig. 1:

A) Schematic of Dexamethasone contact lens (Dex-Lens) that illustrates the drug-polymer film completely encapsulated within the periphery of the contact lens. B) Ocular Coherence Tomography (OCT) cross-section of Dex-Lens demonstrates the drug-polymer film within the contact lens hydrogel.

Fig. 2:

Dexamethasone concentration in the aqueous humor of rabbits after 3 sets of hourly dexamethasone 0.1% drops (left) and during 7 days of dexamethasone contact lens (Dex-Lens) wear (right). At most time points, the dexamethasone levels were significantly higher with a Dex-Lens than dexamethasone drops (n = 4 per time point). Data are mean ± standard deviation. p -values as compared to hourly drops by student t-test.

Fig. 3:

A) Photograph of sutures that were placed along the superior and inferior cornea to induce cornea neovascularization (CNV). B) Representative red free slit-lamp photographs from the four study groups 7 days after suture placement. The CNV invasion area was demarcated by a yellow line traced using ImageJ. C) The CNV invasion area on Days 5 and 7, which was calculated from the tracings generated by two masked cornea specialists (n = 6 per group). Dexamethasone drops (Dex Drops) and dexamethasone contact lens (Dex-Lens) had significantly less CNV invasion area compared to eyes that received no treatment or the vehicle lens. Data are mean ± standard deviation. P-values on day 7 as compared to no treatment on day 7 (Tukey’s HSD post hoc test).

Fig. 4:

Corneas from various treatments were harvested 7 days after suture placement and cut in two halves for flow cytometry and real-time PCR. A) Single-cell suspensions of cornea were stained with anti-CD45 antibodies and flow cytometry was performed. A) Representative flow cytometry dot plot and histograms showing the gating strategies and frequencies of CD45+ cells (% in cornea) in different groups. B) Quantification of CD45+ cell frequencies (% in cornea) in indicated groups. (C) Bar chart showing VEGF-A and VEGFR-2 mRNA expression (normalized to GAPDH) in different groups as quantified by real-time PCR. Data are mean ± standard deviation. P-values as compared to no treatment (Tukey’s HSD post hoc test) (n = 6 per group).

Fig.5:

A) Representative corneal OCT images for different treatment groups on day 0 and day 7. Dexamethasone contact lens (Dex-Lens) resulted in less of an increase in cornea thickness as the vehicle lens. B) Box plots of percentage change in central corneal thickness after 7 days of suture and treatment initiation. The red plus is outlier as calculated by MATLAB (n = 6 per group). Data are mean ± standard deviation. P-values as compared to no treatment (multiple comparison using Tukey’s HSD post hoc test).

Fig. 6:

Determination of safety of dexamethasone contact lens (Dex-Lens). A) NEI corneal fluorescein staining scores at Day 7 after suture placement. No significant staining was observed. B) Intraocular pressure (IOP) measurements on Day 0 and Day 7 after suture placement (n = 6 per group). Data are mean ± standard deviation. No significant difference was observed between various groups (Multiple Comparison using Tukey’s HSD post hoc test).

Fig. 7:

In vivo efficacy for treatment of induced anterior uveitis. Aqueous humor protein concentration after endotoxin (lipopolysaccharide) injection into the aqueous humor followed by treatment with: 1) sterile 0.9% saline for 5 days, 2) 0.1% dexamethasone drops (Dex Drops) for 5 days, or 3) dexamethasone-eluting contact lenses (Dex-Lens) worn for 5 days (n = 5 per group). The aqueous humor protein concentration shows that the Dex-Lens was effective in inhibiting anterior uveitis over 5 days. Data are mean ± standard deviation. P-values are compared to baseline (or between treatments if indicated) using Student t-test.