Contact Lenses Loaded with Melatonin Analogs: A Promising Therapeutic Tool against Dry Eye Disease

Abstract

Melatonin analogs topically administered evoke a potent tear secretagogue effect in rabbits. This route of drug administration requires high drug concentration and frequent dosing due to its reduced ocular surface retention. Therefore, contact lenses (CLs) have emerged as an alternative drug-delivery system that prolongs drug retention in the cornea, improving its therapeutic performance. This study explores the in vitro ability of five commercially available hydrogel CLs to act as a delivery system for melatonin analogs and the in vivo secretagogue effect of melatonin analog-loaded CLs. We soaked CLs with melatonin or melatonin analog solutions (1 mM) for 12 h. Spectroscopic assays showed that IIK7-loaded CLs led to the inadequate delivery of this compound. Conventional hydrogel lenses loaded with agomelatine released more agomelatine than silicone ones (16-33% more). In contrast, the CLs of silicone materials are more effective as a delivery system of 5-MCA-NAT than CLs of conventional materials (24-29%). The adaptation of CLs loaded with agomelatine or 5-MCA-NAT in rabbits triggered a higher tear secretion than the corresponding eye drops (78% and 59% more, respectively). These data suggest that CLs preloaded with melatonin analogs could be an adequate strategy to combat aqueous tear deficient dry eye disease.

Keywords: 5-methoxycarbonylamino-N-cetyltryptamine; agomelatine; contact lenses; drug delivery; dry eye.

Figure 1

The IIK7 release from CLs previously soaked with IIK7 solution (1 mL, 1 mM) for 12 h to a saline solution (1 mL) over 60 min. Concentration (μM) values are presented as mean ± S.D of n = 9 lenses per material. The blue color shows the release from CH CLs. The ochre color shows the release from SH CLs.

Figure 2

The melatonin release from CLs previously soaked with melatonin solution (1 mL, 1 mM) for 12 h to a saline solution (1 mL) over 180 min. Concentration (μM) values are presented as the mean ± S.D of n = 9 lenses per material. The blue color shows the release from CH CLs. The ochre color shows the release from SH CLs.

Figure 3

The agomelatine release from CLs previously soaked with agomelatine solution (1 mL, 1 mM) for 12 h to a saline solution (1 mL) over 540 min, with a change in the saline medium at 300 min. Concentration (μM) values are presented as mean ± S.D of n = 9 lenses per material. The blue color shows the release from CH CLs. The ochre color shows the release from SH CLs.

Figure 4

The 5-MCA-NAT release from CLs previously soaked with the 5-MCA-NAT solution (1 mL, 1 mM) for 12 h to a saline solution (1 mL) over 540 min, with a change in the saline medium at 300 min. The concentration (μM) values are presented as the mean ± S.D of n = 9 lenses per material. The blue color shows the release from CH CLs. The ochre color shows the release from SH CLs.

Figure 5

The agomelatine absorption by the CLs soaked with agomelatine solution (1 mL, 1 mM) over 300 min. The concentration (μM) values are presented as the mean ± S.D of n = 3 lenses per material. The blue color shows the release from CH CLs. The ochre color shows the release from SH CLs.

Figure 6

The 5-MCA-NAT absorption by CLs soaked with 5-MCA-NAT solution (1 mL, 1 mM) over 300 min. The concentration (μM) values are presented as the mean ± S.D of n = 3 lenses per material. The blue color shows the release from CH CLs. The ochre color shows the release from SH CLs.

Figure 7

The effect of agomelatine released from CLs and administered topically in tear secretion. The P-HEMA lenses were preloaded with agomelatine 100 μM for 12 h and 10 μL of agomelatine 100 μM was administered topically on rabbit eyes. Tear secretion was evaluated over 240 min (for CLs experiments) and over 180 min (for topical experiments), versus the basal tear secretion and tear secretion after topical application of a saline solution containing 1% DMSO, respectively (100% tear secretion). Tear secretion values (%) are presented as the mean ± S.E.M. of n = 12 lenses and n = 24 rabbit eyes.

Figure 8

The effect of 5-MCA-NAT released from CLs and administered topically in tear secretion. Stenfilcon A lenses were preloaded with 5-MCA-NAT 250 μM for 12 h and 10 μL of 5-MCA-NAT 250 μM was administered topically on the rabbit eyes. Tear secretion was evaluated over 240 min (for CLs experiments) and over 180 min (for topical experiments) versus the basal tear secretion and tear secretion after the topical application of a saline solution containing 1% DMSO, respectively (100% tear secretion). The tear secretion values (%) are presented as mean ± S.E.M. of n = 12 lenses and n = 24 rabbit eyes.