Mark B. Abelson, MD, and Susan Washburn North Andover, Mass.

Several pharmaceutical ad campaigns encourage the elderly to inform their pharmacists about all of the medications they’re currently taking in order to avoid harmful drug interactions. This is good advice for ophthalmologists and their patients, as well.

No physician wants to prescribe an ocular medication that, though effective, would cause adverse effects over time due to its preservative. That scenario can occur, however, if an ophthalmologist doesn’t pay close attention to a medication’s ingredients and possible adverse effects. Knowing exactly what’s contained in even the most common ophthalmic preparations, and how these different ingredients could potentially act separately or in combination in a particular patient, are keys to treating ophthalmic disease successfully.

In this month’s article, we’ll look at preservatives commonly used in ocular preparations, primarily artificial tears, and situations where there may be risk to the patient.

What’s Inside the Bottle
An ocular medication is much more than the active drug, and its other components may present difficulties for some patients. This is especially true for patients who overuse their artificial tear products, use multiple ocular medications, suffer chronic eye diseases like dry eye or glaucoma, or require post-surgery dosing of medication.

Ocular medications are composed of unique mixtures of the active drug, a preservative, the drug delivery system, viscosity-increasing agents, buffers and stabilizers, and a vehicle by which all the above ingredients are “carried.” Of these, it’s the preservative that’s most often been considered the culprit in damaging the corneal epithelium leading to disruption of the glycocalyx, when drops are used beyond the recommended dosing. This sequence leaves the epithelium unable to keep the tear film in place and can lead to ocular surface disease.  Research on this speculation, however, has been scarce.

Preservatives’ Benefits
Most ophthalmic products use preservatives. In fact, the U.S. Food and Drug Administration and the U.S. Pharmacopoeia mandate the use of preservatives for all multidose topical ophthalmic medications. Preservatives provide antimicrobial activity in the container and prolong shelf life by preventing the decomposition of the active drug. Research has shown that preservatives are necessary in multidose containers, because bacterial contamination occurs with the use of the drug at least twice daily for one or two weeks.¹

The FDA uses the Preservative Effectiveness Test as a minimum standard of preservative performance. In the PET, technicians prepare a standard concentration of common bacteria, such as Escherichia coli, Pseudomonas aeruginosa and Staphlyococcus aureus, and test it against each preservative. The inoculated tubes are incubated at 20 or 25 degrees Celsius for four weeks, with weekly examinations. After the completion of the PET, a preservative is considered effective if it reduces the bacterial concentration to 0.1 percent or less of the initial concentration after two weeks and keeps the concentration of yeasts and molds at or below their original concentration for the remaining two weeks.¹ 

Preservatives in Artificial Tears
Previous generations of artificial tears contained more toxic preservatives, such as thimerosal, which was found to cause sensitization and lead to drug-induced allergic conjunctivitis in some patients. Current products are preserved with less toxic agents like benzalkonium chloride (BAK) and disodium EDTA. Even

At left, a scanning electron micrograph of rabbit corneal epithelium after mild dosing with 0.02% benzalkonium chloride. After exaggerated dosing with 0.02% BAK (right), there is an increase in epithelial holes, a loss of peripheral microvilli and a noticeable wrinkling of surface cells.

newer agents are now available with a form of preservative that either dissipates or changes to water upon contact with the tear film. Here’s a look at the characteristics of today’s preservatives and how they work.

Ocular preservatives are divided into two types: chemical and oxidative. Chemical preservatives alter cell membrane permeability and lyse cytoplasmic contents. Oxidative preservatives are able to penetrate cell membranes and interfere with a cell’s functions.

Common chemical preservatives found in ophthalmic preparations are BAK, chlorobutanol and sorbate. Sodium perborate, stabilized oxychloro complex (SOC), and Polyquad are newer proprietary preservatives that may be safer to the corneal epithelium. Of these, BAK is still the most prevalent, and its cytotoxicity is well-documented.

One study reported the possibility of damage from a wide range of preservatives. The research, conducted at the Department of Ophthalmology, Ambroise Pare Hospital, University of Paris V, in Boulogne, France, compared the toxic side effects of various preservatives on the ocular surface of the rat, paying special attention to inflammatory infiltrates.

Thirty-five brown Norway rats were divided into seven groups of five each. For one month, they received bilateral drops of either 0.01% cetrimonium chloride, 0.01% BAK, 0.01% benzododecinium bromide, 0.004% thimerosal, 0.05% methyl parahydroxybenzoate or phosphate-buffered saline. The last group remained untreated. Study results showed that all preservative-treated eyes consistently showed corneal and conjunctival damage, but no difference was found among the five tested drugs.²

 • Benzalkonium chloride. BAK is a quaternary ammonium compound that’s often used in conjunction with disodium EDTA. It’s a chemical detergent preservative that’s chemically stable, doesn’t degrade easily, even at high temperatures, and is very effective and fast-acting against many microorganisms. BAK acts upon microorganisms by altering cell membrane permeability and lysing cytoplasmic contents. It’s also been shown to increase the corneal penetration of some drugs by causing a separation of the epithelium.

BAK has been the gold standard of preservatives for years, and is the most common antimicrobial preservative currently used in topical multiuse ophthalmic solutions. Reports have shown that BAK can accumulate in ocular tissue, however, and can cause different types of cell death with frequent dosing.

It’s thought that patients at greatest risk for BAK-induced adverse effects are those suffering from dry-eye syndrome. Because of the lack of natural tears in these patients, the BAK in each eye drop is not as diluted as it would be in a patient with normal tear formation. This may damage the corneal epithelium, contributing to ocular surface disease. These patients may also overdose (use more than six drops per day), which increases the likelihood of BAK-induced adverse effects.

Another French study, this one from 1999, investigated the action of BAK on epithelial conjunctival cells in vitro. Cell exposure to 0.1% and 0.05% BAK induced cell lysis immediately after treatment. All cells treated with 0.01% BAK died within 24 hours. The study’s results suggest that BAK induces cell growth arrest and death at a concentration as low as 0.0001 percent.³

At concentrations and dosing used clinically, however, BAK doesn’t appear to have significant adverse effects unless its frequency of use exceeds four to six times daily.4 This becomes a concern when patients use other drops on top of chronic medications, such as glaucoma drops. It’s important to recall that preservatives themselves are bactericidal.

Additionally, patients with soft contact lenses must remove their lenses for 5 minutes to prevent the absorption of the medication into the lens.⁵

Clearly, BAK is a wonderful, safe preservative, since it’s been used for years. It’s important to note, however, that we need to be careful with its use in patients who are using several medications, are overdosing or have a history of severe corneal damage.

 • Sorbate (sorbic acid). Sorbic acid is thought to work in the following way. Acid molecules can pass through the plasma membrane, dissociate in the cytoplasm, release protons and inhibit growth via acidification. This may activate energetically inefficient intracellular activities, such as energy dependent ion pumps, wasting the cell’s energy stores.

Sorbate may have limited antimicrobial activity, and it isn’t able to eradicate many organisms on its own. While adverse reactions appear to be infrequent, a reaction consisting of punctate keratitis may rarely result from the use of sorbate. Still, sorbic acid preserved products are commonly promoted for sensitive eyes and for contact lenses wearers.⁶ 

 • Chlorobutanol. This is an alcohol-based preservative used in artificial tears and as the active ingredient in certain sedatives and anesthetics. It has a wide range of antimicrobial action. It works by disorganizing the lipid structure of the cell membrane, increasing the permeability of the cell. In one double-blind cross-over study, however, chlorobutanol 0.5% in artificial tears was shown to cause irritation in over half of the subjects.⁷

• Polyquad. Polyquaternium-1 (Polyquad) is a polymeric quaternary ammonium antimicrobial preservative. It’s found in contact lens solutions and the artificial tear product Tears Naturale II (Alcon). Polyquad has been proven to have less of an effect on corneal epithelial cells than BAK. One rabbit study showed that Polyquad produces a lesser uptake of dye into the cornea than BAK and only superficial epithelial damage compared to BAK.⁸ 
 
• Sodium perborate. This is one of the first oxidative preservatives developed, and it works by oxidizing cell walls or membranes and disrupting cellular function. When combined with water, sodium perborate is converted to hydrogen peroxide, allowing low levels of this preservative to be effective at destroying microbes. Also, it’s unique in the fact that, when it makes contact with the tear film and/or ocular tissue, it changes into simple oxygen and water. Genteal (Novartis Ophthalmics), an ocular lubricant, is currently the only product containing sodium perborate. 
 
• Stabilized oxychloro complex (Purite). This is another oxidative preservative first introduced several years ago. The sodium chlorite found in SOC has been used since the mid-1940s in water purification. It’s also used in toothpaste, mouthwash and some antacids.

SOC has a wide spectrum of antimicrobial activity and has been shown to destroy the fungus Aspergillus niger, one of the most difficult organisms to kill.

Keratitis characteristic of medicamentosa. Note the staining over the entire cornea.

SOC was found to be safe and well-tolerated when dosed frequently, according to a 62-patient study in which patients dosed an SOC-based preservative four to eight times daily for a four-week period.⁹  Allergan’s Refresh Tears and, more recently, its Alphagan-P both contain Purite.

Sodium perborate and Purite offer attractive options as multidose drugs for patients who either require more than six doses per day (as some dry-eye patients do), or for those who use more than one drop to treat concomitant diseases (e.g., glaucoma and dry eye).

Non-preserved Drugs
Preservative-free drugs may eliminate the risk of toxic side effects, which can make them attractive treatment options. For example, in a 1992 study conducted to assess the corneal epithelial toxic effects of preservative-free tear preparations, researchers used scanning electron microscopy to evaluate the corneal epithelium of rabbit eyes after the administration of two preservative-free ocular lubricants. The two preservative-free preparations were shown to be non-toxic to the corneal epithelium in both the mild- and exaggerated-use protocols. The epithelial changes observed were no different from those seen in control eyes. The study supported the belief that preservative-free preparations are safe to use in patients, especially with frequent dosing.¹

Non-preserved artificial tears have an extra advantage over preserved ones: They may be the best choice for patients immediately following eye surgery, due to the increased viscosity and pH buffering. Some non-preserved artificial tears include: Refresh Plus and Celluvisc (Allergan); Bion Tears and Tears Naturale Free (Alcon); Ocucoat PF and Moisture Eyes (Bausch & Lomb); Hypotears PF (CIBA Vision); Preservative Free Visine Tears (Pfizer); and TheraTears (Advanced Vision Research).

Though preservative-free drugs may avoid some toxic side effects, they have disadvantages. While it’s true that a preservative may be the cause of an allergic reaction, it’s difficult to determine if the problem is caused by the preservative, the drug, the drug delivery system or the buffers and stabilizers.

Non-preserved preparations may still hold some risk, therefore.
Non-preserved drugs are only available in unit-dose vials, which may be more difficult for a patient to use correctly, affecting compliance. Poor compliance may hinder a non-preserved drug’s effectiveness, even if it’s  more comfortable to use. This can be especially important when it’s used concomitantly with multidose glaucoma medications, for which compliance is vital. Unit-dose vials are also more expensive than multidose containers.

In addition, patients with advanced rheumatoid arthritis may find it difficult to squeeze the drops from the single-use vials. They may be tempted, then, to use the vial for more than one application.

In the future, manufacturers may reformulate existing products with less-toxic preservatives, offer less concentrated forms of current preservatives or develop new ones. At present, despite the numerous glaucoma medications and artificial tears on the market, none is risk free. The ophthalmologist must assess the risk to patients.

For the patient who uses an artificial tear product intermittently or as indicated, his concerns may be few. But, for the individual with some combination of glaucoma, dry eye, ocular infection, allergy and decreased corneal sensitivity, the choice of product is more important. Comfort of use and compliance are factors to be considered in prescribing specific products, as is the length of treatment and the patient’s regimen of ophthalmic agents. Physicians must select the treatments that maximize ocular health while minimizing damage.  

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. Washburn is an associate at Ophthalmic Research Associates.

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