The evolution of tear substitutes

In an ongoing effort to ameliorate the discomfort and blurred vision that stems from dry eye, tear substitutes have undergone numerous improvements to enhance their efficacy and safety to the ocular surface.

As we learn more about the changes of the ocular surface in disease, so have we improved the effectiveness of tear replacements.

Assess dry eye from a systemic standpoint

Generations of tear substitutes

First generation tears were simply a saline-based, isotonic or hypotonic solution with preservatives, notably benzalkonium chloride (BAK). Although these tear substitutes did not blur vision, they were short acting and needed frequent re-application.

Second generation tears added natural and synthetic polymers (methylcellulose derivatives) and synthetic polymers (e.g., polyvinyl alcohol, povidone, polysorbate-80, HP guar) with gentler preservatives or preservative-free products. These agents are of thicker viscosity or a gel-forming nature and afford higher retention times. Often, the trade-off for this improvement can be short-term blur.

Third generation tears are considered those that incorporate hyaluronic acid (HA). Hyaluronic acid is found naturally in the human body, mainly in connective tissue, but also in vitreous body and synovial fluid and in the tear fluid of the eye. Sodium hyaluronate (sodium salt of hyaluronic acid) has water-retaining properties and reduces the shear forces of the blink. It is highly effective at entrapping water and preventing evaporation prolonging beneficial effects. Hyaluronic acid, with its natural bio-adhesive properties, provides longer hydration. Sodium hyaluronate also seems to have protective effects on the corneal epithelium.¹

Considered fourth generations tears because of the addition of lipid oil-in-water nanoemulsions, these most advanced tear replacements address the evaporation concern of other tear replacements. Artificial tears with a lipid component are presumed to replenish the lipid layer. They have been shown to have a long residence time in the tear film, reduce the tear evaporation rate, improve the signs and symptoms of dry eye, improve the structure of the lipid layer, and to improve diagnostic test results, particularly the Schirmer score and tear break-up time.²

Creating artificial tears

The process of developing a lipid-containing artificial tear can be hampered by many factors, including the combination of immiscible (unmixable) liquids, instability, irregular spreading, effects on visual acuity, and light scattering. There have been varying degrees of success at producing lipid-containing artificial tears in the past, the first being TearGard (Bio Products Ophthalmics Inc.) in 1983, which was successful in protecting the integrity of the tear film and providing relief for dry eye patients.³

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An emulsion is a mixture of two or more liquids that are normally unblendable; common examples of emulsions are milk, mayonnaise, and paint. In tear replacements, oil and water nanoemulsions reduce tear evaporation without blurring while providing surface hydration. Nanoemulsions also improve ocular bioavailability of lipophilic or poorly water-soluble drugs. Generally emulsions need “surface active agents,” or surfactants to stabilize them. The most common surfactant agents create a negatively charged (anionic) preparation.

NovaSorb, the delivery system in RetaineMGD (OCuSOFT) (currently the only marketed cationic lipid emulsion lubricating therapeutic) is a unique oil-in-water nanoemulsion that carries a positive (cationic) charge that delivers ingredients through the electrostatic attraction between positively charged droplets and the negatively charged ocular surface.⁴ Electrostatic interaction increases the lubricants dwell time (residence time), intuitively enhancing bioactivity. In addition, the nanosize of the oil droplets creates an increased contact surface with the ocular surface cells. RetaineMGD is preservative-free, supplied in single-use vials.

Other lipid tear replacements include Refresh Optive Advanced (Allergan), Systane Balance (Alcon), Tears Again Liposome Spray (OCuSOFT) and recently re-released SootheXP (Bausch + Lomb). The first marketed ophthalmic emulsion drug product was Restasis (Allergan), a preservative-free anionic emulsion of cyclosporine A (CsA) at 0.05 percent. Interestingly, Allergan’s preservative-free Refresh Endura, discontinued in 2009, was a castor oil-in-water emulsion. 

It is an exciting time for clinicians and patients as our knowledge and experience in ocular surface disease is tested and refined. New diagnostic technologies can help us analyze and define ocular surface disease and guide our new and sophisticated therapeutic choices for our patients.

References

1. Choy EP, Cho P, Benzie IF, et al. Investigation of corneal effect of different types of artificial tears in simulated dry eye condition using a novel porcine dry eye model (pDEM). Cornea. 2006 Dec;25(10):1200-4.

2. Lee SY, Tong L. Lipid-containing lubricants for dry eye: a systematic review. Optom Vis Sci. 2012 Nov;89(11):1654–61.

3. Silverman JJ. The first three-layered tear substitute. Contacto. 1983;27:19–22.

4. Lallemand F, Daull P, Benita Set al. Successfully improving ocular drug delivery using the cationic nanoemulsion, NovaSorb. J Drug Deliv. 2012;2012:604204.