Numerous artificial tear products are on the market, and most originate from the common pool of ingredients provided by what's known as the ophthalmic monograph, differing only in their combinations and amounts. This monograph is the list of pre-approved ingredients and concentration ranges that the U.S. Food and Drug Administration recognizes as safe and effective for use in over-the-counter ophthalmic drugs. It includes several categories of ingredients, as well as regulations regarding statements allowed in the labeling of products made from these ingredients. In this article, we'll take a look at the evolution of dry-eye management and discuss the categories of ingredients included in the monograph and how they act in artificial tears.

Background
Artificial tears are a mainstay in the management of dry-eye symptoms. They can also help prevent the onset of ocular surface damage. These artificial tears have been designed to lower tear-film osmolarity, and minimize cell death and ocular drying, while also relieving the discomfort associated with dry eye.¹

Dry-eye syndrome affects approximately 12 percent of the population.² There are many causes of dry eye, ranging from aqueous deficiency, mucin deficiency and lipid deficiency to other conditional and environmental forms of the disease. Symptoms can arise when tear film isn't adequate, in quantity or quality, to protect the epithelial cells of the eye.¹ This decrease in tear secretions or their ability to be retained on the eye often manifests itself in the form of burning, redness, blurred vision, grittiness, foreign body sensation, tearing and overall ocular discomfort.

Dry eye wasn't always thought of as an ocular disorder by itself. There is very little information available today regarding past attempts at addressing dry eye, due to the assumption that dry eye was just a symptom of other ocular or systemic conditions. Beginning in the time of Hippocrates, dry eye was addressed with lubricating mixtures made of goose fat and warm water.³ Egg albumin, derived from egg whites, and salves (thick emollient-like substances) were also used to soothe and relieve dry-eye symptoms.⁴ Even today, we often hear patients describe natural remedies they've devised to soothe the discomfort associated with dry eye.

Frank J. Holly, PhD, along with Michael Lemp, MD, made some of the earliest discoveries about the cause of dry eye. Dr. Holly recognized the cause of the dry spots was local non-wetting as opposed to local drying. Furthermore, he emphasized the need for mucin and water as well as lipid and protein interaction in tear stability. Following the early findings of Drs. Lemp and Holly, and by building on their initial understanding of dry eye, researchers have pursued several approaches to artificial tears. This has allowed companies to introduce many commercial products.

The Ophthalmic OTC Monograph
Most artificial tear drops strive for the same goals: consistency, comfort and an interaction with the ocular surface intended to ease discomfort and promote protection of the ocular surface. Dry-eye researchers have been able to achieve these goals in a variety of ways in developing the broad range of artificial tears available today. Most often, ingredients can be selected from the ophthalmic over-the-counter monograph for use in differing amounts. The following categories appear on the monograph.

• Astringents. One ingredient is categorized as an ophthalmic astringent on the monograph, zinc sulfate 0.25%. An astringent is used in OTC products such as Clear Eyes ACR (Abbott Labs) to help clear mucous from the ocular surface. This product claims to use an astringent to eliminate buildup of mucous on the eye that can occur with exposure to debris such as pollen, dust and smoke.

The astringent property of zinc sulfate is also put to use in Visine A.C. (Pfizer), with the purpose of relieving the burning, itching and discomfort due to airborne irritants. Such drops can offer temporary relief of mild, nonspecific ocular discomfort. If the cause can be pinpointed to a specific condition, such as discomfort due to ocular allergy, a wiser choice of medication would be a topical multi-action ophthalmic product whose mechanisms specifically combat the molecular actions causing the allergy.

Agents in the Ophthalmic Monograph
Astringents	Demulcents	Emollients	Hypertonicity Agents	Vasoconstrictors
Zinc sulfate 0.25%	Cellulose derivatives:     Carboxymethylcellulose sodium 0.2- 2.5%     Hydroxyethyl cellulose 0.2 -2.5%     Hydroxypropyl  methylcellulose 0.2-2.5%     Methylcellulose 0.2-2.5%     Dextran 70, 0.1%*     Gelatin 0.01% Polyols, liquid:     Glycerin 0.2-1%     Polyethylene glycol 300, 0.2-1%     Polyethylene glycol 400, 0.2-1%     Polysorbate 80, 0.2-1%     Polyvinyl alcohol, 0.1-4% Povidone 0.1-2%	Lanolin preparations:     Anhydrous lanolin  1-10%*     Lanolin 1-10%* Oleaginous ingredients: Light mineral oil   </= 50 Mineral oil  </=   50%*  Paraffin </= 5%* Petrolatum </=  100%  White petrolatum </=  100% White wax </=  5% Yellow wax </=  5%	Sodium chloride 2-5%	Ephedrine hydrochloride, 0.123% Naphazoline hydrochloride 0.01-0.03% Phenylephrine hydrochloride 0.08-0.2% Tetrahydrozoline hydrochloride 0.01-0.05%
* denotes further specifications for use of this agent (i.e., when used it must be with another agent in a particular category)

• Demulcents. These are typically included in an ophthalmic solution to provide proper consistency, viscosity, comfort and moisturization. They dominate our discussion of ingredients, as they are an integral part of most artificial tear solutions.

One of the most common demulcents in currently available artificial tears, hydroxypropyl methycellulose (HPMC), (e.g., Genteal [Novartis] and Tears Naturale [Alcon]) functions as a viscosity-increasing agent. Another HPMC-based product is in a new drop developed by AST (Advanced Surface Technology Inc., Billerica, MA), which has a mid-range viscosity. HPMC can also act in combination with other demulcents, for example, in combination with dextran and glycerin, to form the active ingredient TriSorb, an ingredient in Tears Naturale.

Other tear products, such as Refresh Endura (Allergan), use similar combinations like glycerin and polysorbate to achieve a lubricating component. Whether they're used in combination or singly, companies add these water-soluble polymers in order to lubricate and moisturize the surface of the eye. Most have a surface tension close to natural tears and are therefore able to offer corneal lubrication and minimal tear-film disruption, while possibly also reducing evaporation.

Another popular demulcent in artificial tears is carboxymethylcellulose (CMC), which is used in Allergan's Refresh Tears. Like HPMC, it is a cellulose derivative, and its viscous properties can serve to help artificial tears remain on the surface of the eye for an extended period of time. This can have the effect of increasing tear-film breakup time and, consequently, increasing the amount of time that the ocular surface remains protected.⁵

A variation in concentration of an ingredient such as CMC or HPMC can have significant effects on the consistency of a drop. One example is the artificial tear Refresh Liquigel 1.0%; its higher concentration of CMC gives the drop both liquid and gel-like properties.⁶

Alcon's Systane contains the additive HP-Guar along with the active ingredient, HPMC. Researchers  have shown HP-Guar aids in the drop's ability to manage dry eye by having the HP-Guar polymer molecules bind to the surface of the damaged epithelial cells. On the surface of the eye, the pH-dependent HP-Guar molecules then form a cross-linked network in conjunction with borate ions. Through this process, a gelatinous layer, or scaffold, is formed, merging with the natural tear film to retain more moisture and develop a temporary protective bandage over the eye. This temporary covering appears to allow the repair or replacement of damaged cells to take place in a protected environment.

Povidone K 30, a polyvinyl pyrrolidone polymer, and polyvinyl alcohol (PVA) are hydrophilic, less viscous polymers in the demulcent category. As a non-irritating solubility enhancer, povidone is the active ingredient in tear substitutes indicated for minor irritations and minor dry-eye symptoms.⁵ Murine Tears and Murine Tears Plus (Abbott Labs) contain a combination of povidone and PVA in order to provide soothing relief from dryness.

Beyond artificial tears, other eyedrops also employ such comfort enhancing and lubricating ingredients in a broader range of ophthalmic products currently on the market. For example, loteprednol etabonate (Alrex), an ophthalmic corticosteroid that's used for severe forms of allergy such as vernal keratoconjunctivitis, atopic keratoconjunctivitis, or seasonal allergic conjunctivitis that is unresponsive to other therapies, contains the demulcent povidone. The new formulation of olopatadine (0.2%), currently under review by the FDA, contains povidone, as well. Povidone also serves as the active ingredient in Bausch & Lomb's Renu Lubrication and Rewetting drops, a multipurpose solution used by contact-lens wearers.

These demulcents are essential to artificial tear solutions because of their ability to interact with the ocular surface. Tear mucin is one of the natural components involved in the formation of the tear film and hydration of the corneal epithelial cells that prevent the ocular surface from drying.⁷ In order to mimic the conjunctival mucin, the long, chain-like structures of active-ingredient polymers attach at many points to the corneal surface. The multiple attachments allow for formation of a new surface with different wetting properties.⁸ The surface active and absorptive properties of polymers like HPMC, CMC, povidone and polyvinyl alcohol allow for this mimicking of a new hydrophilic surface, which is facilitated by the spreading action of the lids.⁹ CMC, like HPMC, has a long residency time while also having strong mucoadhesive groups that promote adhesion to the epithelium. CMC's negative charge also mimics the attraction forces of natural mucin. PVA is of lower viscosity but has the ability to lower surface tension, thus enhancing tear-film forming properties and stability.

• Emollients. Lanolin preparations and oleaginous ingredients make up this category. Such oils provide lubrication and are intended to be soothing. They're most often found in formulations on the "heavier" end of the spectrum, such as ointments to be placed in the eye overnight. For example, Refresh PM (Allergan) uses both mineral oil and white petrolatum, while others such as Akwa Tears Ointment and Tears Renewed Ointment (Akorn) use similar emollient compositions.

Other categories, such as hypertonicity agents and vasoconstrictors, are less applicable to the construction of artificial tears. Typically, hypertonic solutions are used in cases of corneal edema, and vasoconstrictors are sometimes employed in more general OTC solutions that include redness reduction among their capabilities. Neither of these categories plays a significant role in most artificial tear solutions.

The broad spectrum of artificial tears available is, to date, the most widely used method for the management of dry-eye symptoms. With so many individuals being affected by this disease, artificial tears have become necessary for relieving their discomfort and dryness. Each tear solution differs from the next, originating from specifically designed combinations of monograph ingredients. In various ways, all attempt to mimic natural tears while protecting the ocular surface and improving patient comfort. The barely tested waters of prescription dry-eye agents are sure to be explored soon by newer formulations, as well.
With the development of so many successful tear substitutes, as well as the potential for new ideas to come in the form of prescription treatments, we can only hope that we're moving closer to a substantive treatment for dry eye. 

Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Ms. Kumar and Ms. Sleeper are research associates at Ophthalmic Research Associates.  

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