OVERVIEW OF NEW DRY EYE PRODUCTS

FOR MANY YEARS, there were only two options for managing dry eye syndrome: either put more moisture into the eye, or prevent the moisture already present from evaporating too quickly. Ophthalmic lubricating solutions, more commonly known as artificial tears, have remained the mainstay of dry eye therapy since their introduction in the 1940s.¹ Freeman introduced the first silicone punctal plug in 1975,² and other devices to prevent surface evaporation (e.g. Moist Eye moisture panels from EagleVision) have joined the ranks over the years, but these modalities have never been able to supplant artificial tear therapy from its #1 position.

A cursory review of an online health product service (www.drugstore.com) reveals over 50 distinct items when the term "artificial tears" is entered in the search engine! With so many products to choose from, it can be frustrating and intimidating for both patients and practitioners to know which option to select. The following is a review of some of the more recent products introduced for therapy of dry eye syndrome.

Trends in Artificial Tears

Despite their popularity and success, two significant difficulties still exist with artificial tears. The biggest issue is duration of action; patients frequently report only fleeting relief (on the order of five to 10 minutes) after instillation of many tear supplements. Also of concern is the addition of preservatives in many artificial tears, which can be a significant source of toxicity, particularly when these preparations are used frequently. Therefore, manufacturers have begun producing thicker, more viscous agents that increase corneal contact time without blurring vision. Examples of such products include Refresh Liquigel (Allergan), GenTeal Gel (Novartis), TheraTears Liquid Gel (Advanced Vision Research), and Systane (Alcon). Also, manufacturers have introduced several preservative-free solutions and "disappearing preservatives" to address the issue of toxicity. Virtually every line of dry eye products includes a preservative-free version (e.g., Tears Naturale PF, Hypotears PF, etc.), but only three product lines contain preservatives that break down soon after instillation. These include: GenTeal (Novartis, preserved with GenAqua, or sodium perborate), Tears Again (Cynacon/Ocusoft, preserved with Dissipate), and Refresh Tears (Allergan, preserved with Purite).

Nature's Tears

In mid-2002, a small company based in Oregon launched a unique product that has captured the interest of many exhibit hall attendees. Nature's Tears (Bio-Logic Aqua Technologies) is described by the manufacturer as an all natural moisturizing mist for the eyes consisting simply of tissue culture grade water with no preservatives or propellants. Rather than being instilled as a drop, Nature's Tears is sprayed toward the eyes from a distance of 12 to 18 inches. The premise? Artificial tears flood the ocular surface, washing away the lipid and mucin layers and depleting normal enzymes, claims the manufacturer. However, Nature's Tears mist allows for replenishing of the aqueous component without disturbing the other tear layers. This is an intriguing theory, and the product possesses a significant novelty factor. However, there is a lack of significant prospective studies demonstrating that this product is any more effective than other artificial tear supplements.

Endura

In the summer of 1999, the FDA Ophthalmic Drugs Subcommittee advisory panel unanimously recommended not to approve Allergan's formulation of topical cyclosporine for the treatment of keratoconjunctivitis sicca. One of the reasons cited was that the solution vehicle showed very similar efficacy to the drug itself, and hence there was no significant difference between the controls and the study group. Undaunted, Allergan decided to manufacture this unique vehicle, an emulsion of castor oil and lubricants in an aqueous solution, and market it directly to the public as an over-the-counter product. In the fall of 2002, Refresh Endura was launched.

According to Allergan, Endura is the first lubricant eye drop for dry eye that treats all three layers of the tear film. It is preservative-free and packaged in single-use, disposable vials. Controlled clinical trials with Endura showed enhanced fluorescein tear break-up time, as well as diminished symptoms of dryness and irritation in patients using the solution two to four times daily over 90 days. Clinical practice has shown it to be an excellent and well-tolerated solution, particularly suited for patients with lipid deficiencies secondary to meibomian gland dysfunction.

Systane

In early 2003, Alcon introduced a unique artificial tear product. Systane, which utilizes the demulcent technology of hydroxypropyl (HP) guar, increases in viscosity after contacting the ocular surface. This change is based on pH value. Systane is a liquid in the bottle at a pH of 7.0, but when placed in the eye (which has a pH of ~7.4), a chemical reaction occurs. HP guar binds to the ocular surface and simultaneously crosslinks with borate ions in the solution, forming a network with a gel-like consistency. The result is a more viscous ocular lubricant that, according to Alcon, provides extended relief of dry eye symptoms and generates a protective coating on the ocular surface. In theory, this coating serves as a temporary corneal bandage, allowing the epithelial cells to heal and reestablish healthy microvilli and a normal glycocalyx.

In a randomized, controlled clinical trial, dry eye patients receiving Systane four times daily for six weeks showed a statistically significant reduction in surface staining, dryness and foreign-body sensation, as well as increased tear break up time.^3,4 Mild blurring for 30 seconds after instillation was the most significant adverse effect. Personal experience with Systane has shown it to be an outstanding choice for patients with moderate to severe dry eye who are not ameliorated with normal viscosity tear solutions. It is also excellent for managing minor corneal trauma or exposure keratopathy.

Restasis

In December 2002, the FDA approved Restasis (0.05% cyclosporine ophthalmic emulsion) for the treatment of keratoconjunctivitis sicca, making it the first commercially available pharmaceutical therapeutic agent for the treatment of dry eye. This topical solution is classified as an immunomodulatory agent by the manufacturer (Allergan), and is approved "for patients with keratoconjunctivitis sicca...whose tear production is presumed to be suppressed due to ocular inflammation."

In clinical studies, Restasis was shown to ameliorate symptoms in up to 44% of patients and improve basal tear production (as demonstrated by Schirmer testing) in up to 59% of patients after six months of treatment.⁵ Additionally, a reduction in conjunctival T-lymphocyte infiltration was noted after six months of cyclosporine therapy.⁶

Allergan heralds Restasis as the first drug proven to effectively treat a cause of dry eye disease, rather than only temporarily alleviate symptoms. But although this product has yielded good results in clinical trials, practitioners have been somewhat reluctant to actively prescribe Restasis for several reasons. First, many are confused as to precisely which dry eye patients will benefit from this therapy. Second, ocular burning has been reported as an adverse event in up to 17% of individuals utilizing the drug.⁵ Third, the time frame of six months may seem irrationally long for some practitioners and patients to observe improvement in the disease course (even though many patients experience improvement after only a few weeks). Finally, the retail cost of Restasis is somewhat expensive as compared to conventional therapy, on the order of $80 to $100 per month. While these issues cannot be ignored, the fact remains that Restasis may offer great potential benefit to many of our patients. Practitioners need to remain open minded and personally evaluate this product on at least a few patients before reaching the conclusion that it is too slow, too uncomfortable or too expensive. Restasis is prescribed on a bid basis.

Therapies on the Horizon

More products remain under investigation for the treatment of dry eye syndrome. Diquafosol tetrasodium, a topical agent referred to as INS365 Ophthalmic by Inspire Pharmaceuticals, has been shown to activate P2Y2 receptors in the mucosal cells of the palpebral conjunctiva.^7,8 These receptors are believed to regulate a variety of cellular responses.

When used topically on the ocular surface, INS365 has been shown to pull salt, water and mucin from conjunctival cells, effectively creating an artificial tear comprised of purely endogenous components.⁷ Inspire Pharmaceuticals filed a new drug application for INS365 in June 2003, and received an approvable letter from the FDA on December 22, 2003. A launch of this product is anticipated sometime in 2004.

Still in clinical trials is 15(S)-HETE (15-hydroxyeicosatetraenoic acid) from Alcon Laboratories. Like INS365, this product is best described as a secretagogue, in that it induces secretions from bodily tissues. Specifically, when instilled in the eye, 15(S)-HETE stimulates production of the glycoprotein Muc1.⁹ Muc1 is an important component of the tear mucin layer; enhancement of this element may help to alleviate corneal injury and restore corneal integrity in dry eye patients.