Preservative toxicity in eye drops refers to the toxicity caused by preservatives in eye drops, mainly benzalkonium chloride (BAK), on the corneal and conjunctival epithelium. It is clinically important in patients who use multiple eye drops long term, especially those using several glaucoma medications.
About 70% of commercially available eye drops contain BAK. Because patients with glaucoma often need long-term use of multiple eye drops, ocular surface disease (OSD) is common. It is said that about 50–60% of patients with glaucoma have OSD10), and more than about 60% of patients using three or more BAK-containing eye drops show SPK2). Long-term BAK use has also been reported to affect postoperative outcomes after glaucoma filtering surgery5).
There are several preservatives used in eye drops, and their toxicity differs.
| Preservative | Features | Typical products |
|---|---|---|
| BAK (benzalkonium chloride) | Most commonly used. Concentration-dependent epithelial toxicity | Many glaucoma and antibacterial eye drops |
| Polyquad® | Less toxic than BAK | Travatan® |
| SoftZIA® (zinc-based preservation system) | Low toxicity. Next-generation preservative system | Some glaucoma eye drops |
| Preservative-free (PF) | Safest. Unit-dose forms, etc. | Mucosta UD®,Tapros® PF |
Preservatives are needed to prevent microbial contamination of eye drops after opening. Without preservatives, bacteria and fungi can grow within a few days after opening and raise the risk of infectious eye disease. However, because preservatives themselves are toxic to the ocular surface, balancing the risks and benefits is important during long-term use.
In injuries caused by BAK-containing eye drops, the following subjective symptoms appear.
Punctate superficial keratitis
Fluorescein staining: Positive punctate staining mainly in the lower cornea is a characteristic finding of BAK toxicity.
Distribution: A distribution mainly in the lower cornea, consistent with a flow pattern from the inferior fornix.
Goblet cell damage
Decreased goblet cell density: Can be quantitatively evaluated by conjunctival impression cytology.
Functional impact: Secretion of mucins such as MUC5AC decreases, shortening tear film stability (BUT).
Conjunctival changes
Conjunctival redness and papillary response: Mainly in the inferior fornix. Inflammatory changes caused by chronic irritation.
Fibrosis: Long-term, chronic exposure to BAK can cause scarring of the subconjunctival tissue.
Other findings
Delayed corneal epithelial healing: Barrier function decreases due to disruption of epithelial tight junctions.
Worsening of MGD: Because of BAK’s surfactant effect, the tear film lipid layer becomes unstable, and meibomian gland dysfunction (MGD) worsens.
It is possible. Eye drops containing BAK can cause a stinging or burning sensation right after instillation. If the irritation is only temporary, it is usually less concerning, but if there is persistent stinging, dryness, or a gritty feeling, it is advisable to ask an eye doctor about switching to a preservative-free formulation.
BAK is a cationic surfactant and exerts toxicity on the ocular surface through the following mechanisms1).
The relationship between BAK concentration and epithelial toxicity is shown below.
| BAK concentration | Degree of toxicity | Typical eye drops |
|---|---|---|
| 0.005% or less | Relatively low (effects with long-term use) | Timolol eye drops (some), brimonidine |
| 0.0075–0.01% | Moderate risk of epithelial damage | Dorzolamide, some timolol |
| 0.02% | Clear risk of epithelial damage | Latanoprost eye drops |
The following factors increase BAK toxicity3).
It can be reduced. BAK (benzalkonium chloride) is the most commonly used preservative in eye drops, and its toxicity to the corneal epithelium has been confirmed. With long-term use, switching to preservative-free formulations or BAK-free formulations (such as those containing Polyquad) is desirable. The benefit of switching is especially great for patients with dry eye and for those using three or more eye drops long term.
If preservative toxicity is suspected, assess it comprehensively with the following tests and history-taking.
| Examination | Purpose / findings |
|---|---|
| Fluorescein staining | Detection of SPK. Inferior-predominant punctate staining of the cornea is characteristic of BAK toxicity |
| BUT (tear break-up time) | BUT is shortened due to mucin deficiency caused by a decrease in goblet cells |
| Rose Bengal / lissamine green staining | Stains damaged epithelial cells and cells without a mucin coat |
| Schirmer test | Assessment of tear secretion (evaluation of associated OSD) |
| Conjunctival impression cytology | Allows quantitative assessment of goblet cell density |
| In vivo confocal microscopy | Evaluates fine structural changes in the corneal epithelium, corneal nerves, and conjunctiva |
In the history, be sure to confirm the type and number of eye drops being used, whether they contain BAK, and the length of use. It is also important to check whether the timing of symptom onset matches the start or change of the eye drops.
The most important measure in managing BAK toxicity is switching to preservative-free (PF) formulations.
| Formulation type | Typical products (examples) | Features |
|---|---|---|
| Unit-dose type (single-use) | ムコスタUD® 0.2%,ジクアスUD® 3%,ヒアレインミニ® 0.1%/0.3% | Use up each unit after opening. No preservative needed for long-term storage |
| Multidose PF type (with built-in filter) | Cosopt® Mini combination eye drops (PF) | Sterile container structure for repeated use |
| BAK-free alternative preservative formulation | Travatan® (contains Polyquad) | Uses an alternative preservative with lower toxicity than BAK |
| BAK-free formulation with the same active ingredient | Tapros® PF (tafluprost 0.0015%) | Alternative to latanoprost. Insurance-covered for ocular hypertension and glaucoma |
Switching to alternative PF glaucoma eye drops has been reported to significantly improve objective indicators of ocular surface damage (SPK, BUT, and goblet cell density)7, 8).
Using combination eye drops (formulations that combine 2 to 3 ingredients in one bottle) is effective in reducing total BAK exposure9).
For patients scheduled for glaucoma filtering surgery (trabeculectomy or tube shunt surgery), switching to a BAK-free formulation about 2 to 4 weeks before surgery may reduce conjunctival inflammation and improve surgical outcomes5). It is also useful to assess goblet cell density with preoperative conjunctival impression cytology.
If dry eye is caused or worsened by BAK toxicity, add the following treatments.
Combining multiple measures is effective. First, switching to combination eye drops can reduce the number of instillations and lower total exposure to BAK. Next, discuss switching to preservative-free (PF) formulations with your ophthalmologist. Nasolacrimal occlusion after instillation is also effective and can reduce intraocular and systemic absorption of BAK. If dry eye symptoms are present, using mucin-secretion-promoting eye drops such as diquafosol ophthalmic solution (Diquas UD®) or rebamipide ophthalmic solution (Mucosta UD®) together is also effective9).
Glaucoma requires lifelong eye drop use, and the effects of BAK toxicity are a major concern in this area. The following summarizes the BAK content and alternative formulations of major eye drops.
| Drug | BAK concentration | BAK-free alternative formulation |
|---|---|---|
| Latanoprost eye drops 0.005% | 0.02% (high concentration) | Tafluprost 0.0015% (Tapros® PF) |
| Timolol eye drops 0.25%/0.5% | 0.005–0.01% | Timoptol® XE (gel formulation), PF timolol |
| Dorzolamide hydrochloride ophthalmic solution 1% | 0.0075% | Dorzolamide/timolol preservative-free combination formulation (Cosopt Mini®) |
| Brimonidine tartrate ophthalmic solution 0.1% | 0.005% | BAK-free formulation (varies by product) |
| Travatan® | Contains Polyquad (BAK-free) | It is itself a BAK alternative formulation |
| Ripasudil hydrochloride ophthalmic solution 0.4% (Glanatec®) | Contains BAK | No BAK-free alternative available at present |
BAK toxicity is concentration-dependent, and latanoprost (0.02%) carries the highest risk6). When using multiple BAK-containing eye drops, the issue is not the total BAK concentration across the drugs, but repeated exposure of the ocular surface from each drop. Tafluprost (Tapros® PF) has the same intraocular pressure-lowering effect as latanoprost while being BAK-free, and studies in both animals and clinical trials have shown that its impact on the ocular surface is significantly lower6, 7).
Unlike BAK, Polyquad is a polymeric cationic surfactant. Because it has a large molecular weight and low corneal permeability, its epithelial toxicity is low. In vitro studies have also confirmed that its toxicity to ocular surface epithelial cells is significantly lower than BAK8).
Research is also progressing toward eliminating the need for eye drops themselves.
For the long-term effects of BAK on the ocular surface, studies using in vivo confocal microscopy have reported a decrease in corneal nerve density. This finding suggests that BAK toxicity affects not only the corneal epithelium but also the corneal nervous system, and further evaluation is needed, including its association with neuropathic pain11). In addition, more evidence is needed on the relationship between long-term BAK use and bleb scarring after glaucoma filtering surgery, including optimizing the preoperative BAK washout period.
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