Dry eye disease can have a significant impact on successful contact lens wear. Issues with dryness or contact lens discomfort are frequently cited reasons for patients stopping contact lens wear, impacting both short- and long-term wear retention (Kojima, 2018). There are several pharmaceutical and nonpharmaceutical treatments available for the management of dry eye disease, with actions spanning from improving the wettability and stability of the tear film to reducing inflammation of the ocular surface. There has also been interest in the potential application of contact lenses to deliver therapeutic agents to the eye (Hui, 2017). This article will focus on studies that specifically looked at the developments in the delivery of agents for the management of dry eye from contact lenses.

Cyclosporine Delivery

Cyclosporine is a calcineurin inhibitor that affects the activity of T-cells, reducing inflammation by preventing their activation and their release of proinflammatory cytokines (Utine et al, 2010). On the eye, the drug increases tear production in patients who have dry eye, which is presumed to be caused by inflammation (Boboridis and Konstas, 2018). In patients who have self-reported contact lens-related dryness, use of cyclosporine twice a day can increase their contact lens wear time and decrease their use of rewetting drops (Hom, 2006).

Ocular preparations of cyclosporine are usually formulated as emulsions due to the hydrophobicity of the molecule (Utine et al, 2010). The hydrophobic properties of the molecule can be illustrated when different contact lens materials are investigated for their cyclosporine uptake and release properties. Conventional, non-silicone hydrogel materials such as etafilcon A, which have relatively more hydrophilic properties and charged surfaces, can sustain release in vitro of cyclosporine for approximately one day (Peng and Chauhan, 2011). In contrast, silicone hydrogel materials such as balafilcon A or lotrafilcon B, which have relatively more hydrophobic properties, are able to sustain release profiles of upwards of two weeks, even without any modifications to aid drug delivery, presumably due to greater drug-material interactions (Peng and Chauhan, 2011).

Interestingly, the incorporation of microemulsions or surfactant technology into the polymerization mixture of conventional hydroxyethyl methacrylate (HEMA)-based hydrogels can increase cyclosporine loading and extend drug release time (Kapoor and Chauhan, 2008). Brij-97, a surfactant, significantly increases the solubility of cyclosporine in aqueous solutions and the mixture remains optically clear if mixed into the polymerization mixture of conventional HEMA materials (Kapoor and Chauhan, 2008). The impact of this surfactant significantly decreases the rate at which cyclosporine is released from model HEMA materials, extending release out to 20 days compared to only six or seven days for the unmodified materials in this study (Kapoor and Chauhan, 2008).

Additionally, other techniques can also be used to bind hydrophobic drugs to carrier materials. A supercritical fluid technique can facilitate the binding of cyclosporine to a carrier molecule without the use of organic solvents and is performed at low temperatures, preventing any denaturation of the drug (Choi et al, 2019). When this technique is paired with contact lenses and tested in a benzalkonium chloride rabbit model of dry eye, higher mean tear volumes and tear breakup time are observed compared to eyes treated with cyclosporine eye drops alone (Choi et al, 2019). Commercially available contact lenses have also been modified with the addition of vitamin E as a diffusion barrier for cyclosporine, potentially leading to tailored release rates over longer periods of time compared to unmodified materials (Peng and Chauhan, 2011).

Delivery of Tear Film Enhancers and Secretagogues

There are multiple nonpharmaceutical agents that have been investigated for their interactions and release from contact lenses or model contact lens materials. Agents that are incorporated into artificial tears to improve comfort of the ocular surface—including hyaluronic acid (HA), hydroxypropyl methylcellulose (HPMC), and polyvinylpyrrolidone (PVP)—have all been investigated and reported for delivery from contact lenses, with various successes and/or engineering complexities (Yañez et al, 2008; Ali and Byrne, 2009; White et al, 2011; Maulvi et al, 2017).

For the delivery of HA, one of the challenges is that at high concentrations the molecule in solution is optically opaque (Maulvi et al, 2017). Researchers have attempted to overcome this through a modified cast molding process, where a ring of highly concentrated HA can be incorporated into the material while leaving a central clear zone for viewing while the contact lens is worn (Maulvi et al, 2017).

Pharmacokinetic studies of these contact lenses on the eyes of rabbits showed significant levels of HA in the tear fluid for at least 15 days (Maulvi et al, 2017). The ability of these lenses to provide HA and thus help heal the ocular surface was also demonstrated in a benzalkonium chloride (BAK)-induced rabbit model of dry eye; wearing HA-incorporated contact lenses significantly improved fluorescein staining over time compared to control lenses without HA (Maulvi et al, 2017).

HPMC is a rewetting agent, and studies have utilized a “molecular imprinting” process to tailor and extend release from model contact lens materials (White et al, 2011). In molecular imprinting, a molecular “memory” is created within a polymer through incorporation of the target molecule or a closely related one in the presence of cross-linkers to create size, shape, and functional group-specific complementary sites on a molecular level within the final polymer (White et al, 2011).

Applying this technique to silicone hydrogel polymers to interact specifically with HPMC gave upwards of 60 days of HPMC release, observed under simulated physiological flow rates within the laboratory (White et al, 2011). PVP has also been directly included in the polymerization mixture in the manufacture of HEMA lenses, leading to a slow release over several days, with greater concentrations of PVP or larger molecules of PVP leading to lower measurements of friction on the lens surface (Yañez et al, 2008).

There has also been interest in dinucleotides in the treatment and management of dry eye, including diquafosol (Up4U) and diadenosine tetraphosphate (Ap4A), both of which increase tear production and mucin secretion through P2Y2 receptors (Dominguez-Godinez, 2013; Dominguez-Godinez, 2018). When these agents are soaked into commercially available contact lenses, they induce tear production above baseline levels for upwards of six hours in rabbits, as measured by Schirmer test strips, while application of eye drops increased tear secretion for only 90 minutes (Dominguez-Godinez, 2013; Dominguez-Godinez, 2018).

Conclusions

Clearly, there is promising research investigating the potential of contact lenses to help manage dry eye, from pharmaceutical to nonpharmaceutical agents that can aid the tear film and ocular surface. The ultimate application of such devices, should they reach the market, will depend on how they are targeted and marketed.

One can envision that some nonpharmaceutical interventions may be used not only for dry eye patients but for all contact lens wearers to improve comfort and lens wear retention. Indeed, examples exist of commercially available materials that are already releasing comfort agents, such as commercially available nelfilcon A lenses that release HPMC and polyethylene glycol when worn (Phan et al, 2018).

For pharmaceutical treatment with these contact lenses, the lens wear schedule, and thus the required drug release parameters, become more important and impact the material engineering needed. A daily disposable wear modality with a contact lens that delivers a dry eye drug, similar to the anti-allergy lens already on the market, may be most appropriate for this purpose if it is to be successful commercially (Pall et al, 2019). CLS

The author would like to thank associate professor Michele Madigan for her helpful comments in the development of this article.

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