Preservatives are antimicrobial substances added to multi-dose ophthalmic eye drops. They maintain sterility after opening and extend the shelf life. Since the 1970s, regulatory authorities including the US FDA, United States Pharmacopeia (USP), and European Pharmacopoeia (EP) have required the addition of preservatives in multi-dose eye drops.
Preservatives are broadly classified into two categories.
Among all ophthalmic preservatives, BAK is the most widely used, being present in approximately 70% of eye drops. However, its toxic effects on the ocular surface, especially with chronic and long-term use, are a concern 2).
BAK has a broad antimicrobial spectrum (gram-positive bacteria, gram-negative bacteria, fungi, Acanthamoeba), high water solubility, and excellent stability, making formulation easy. Additionally, it disrupts the hydrophobic barrier of the corneal epithelium, promoting transcorneal drug penetration and enhancing intraocular drug delivery. These multifaceted advantages explain why it is used in over 70% of eye drops.
Subjective symptoms of ocular surface damage caused by long-term use of BAK-containing eye drops range from subtle to severe.
BAK exhibits concentration-dependent cytotoxicity to corneal epithelial cells, conjunctival epithelial cells, and meibomian gland epithelial cells 2). Clinically, the following findings are observed.
The cumulative burden of BAK exposure (number of medications used, BAK concentration, daily instillation frequency, treatment duration) correlates with the prevalence, severity, and reduced quality of life of ocular surface disease. Particular caution is needed in patients using multiple glaucoma medications long-term 4).
Advantages of BAK
Broad-spectrum antimicrobial activity: effective against Gram-positive and Gram-negative bacteria, fungi, and Acanthamoeba.
Enhanced drug penetration: disrupts the hydrophobic barrier of the corneal epithelium, increasing intraocular penetration of the active drug.
High stability: highly water-soluble and easy to formulate.
Disadvantages of BAK
Ocular surface toxicity: exhibits cytotoxicity to corneal epithelium, conjunctival epithelium, and meibomian gland epithelium 2).
Tear film instability: exacerbates dry eye by reducing goblet cells and disrupting the lipid layer.
Impact on filtration surgery: long-term use may reduce the success rate of glaucoma surgery 4).
| Preservative | Concentration | Classification |
|---|---|---|
| BAK | 0.003–0.02% | Surfactant type |
| Polyquaternium-1 (PQ-1) | 0.001% | Surfactant type |
| Purite (SOC) | — | Oxidative type |
| SofZia | — | Ion-buffered type |
| Sodium perborate | — | Oxidative type |
Polyquaternium-1 (PQ-1) is a quaternary ammonium compound similar to BAK, but with approximately 27 times the molecular weight of BAK and is primarily hydrophilic 3). Due to its large molecular size and lack of hydrophobic regions, it is difficult for it to penetrate mammalian cells, and it is considered to have lower cytotoxicity compared to BAK. It is used in contact lens care products and some artificial tears.
Stabilized oxychloro complex (SOC) is an oxidative preservative containing a mixture of chlorite, chlorate, and chlorine dioxide 3). When applied to the ocular surface, it is converted into tear components such as sodium ions, chloride ions, oxygen, and water. Because mammalian cells have antioxidants and catalase, the toxicity of Purite is low.
SofZia is an ionic buffer preservative containing boric acid, sorbitol, propylene glycol, and zinc. It rapidly degrades upon contact with cations on the ocular surface, resulting in lower cytotoxicity compared to BAK. It is used in Travatan Z (travoprost 0.004%).
Sodium perborate is an oxidative preservative that exerts its bactericidal effect by combining with water to form hydrogen peroxide 3). On the ocular surface, it is rapidly broken down into oxygen and water by catalase. It has significantly lower toxicity to corneal and conjunctival cells compared to BAK.
In vitro and animal studies have shown that Polyquad, Purite, SofZia, and sodium perborate all have lower cytotoxicity than BAK. However, for Polyquad, there are no randomized controlled trials (RCTs) comparing it to BAK, and in vitro studies have reported potential toxicity such as reduced cell viability and NF-kB activation. The level of evidence is limited, and further verification is needed.
| BAK Toxicity | Dry Eye |
|---|---|
| Characteristic staining limited to the cornea | Staining of conjunctiva only or both cornea and conjunctiva |
| Related to history of eye drop use | Related to environmental factors and aging |
| Improves upon discontinuation of causative eye drops | Improves with tear supplementation and environmental adjustments |
If damage due to preservatives is suspected, try switching to eye drops that do not contain BAK. If punctate keratitis disappears within about two weeks after the change, it is highly likely that BAK was the cause.
The following strategies are useful for reducing the cumulative burden of BAK exposure.
Switching from BAK-containing formulations to those using alternative preservatives (Polyquad, Purite, SofZia) has been reported to improve OSDI scores, TBUT, and corneal staining. In Japan, BAK-free eye drops include boric acid combination types, filter types, and unit-dose (UD) types.
Boric Acid Combination Type
Features: Boric acid has only bacteriostatic action, so other additives are used in combination.
Product examples: Used in several BAK-free glaucoma eye drops.
Filter Type and Unit-Dose Type
Filter type: Prevents bacterial entry using PF containers or NP containers. May be difficult to use for patients with weak grip strength.
Unit-dose type: Single-use disposable to ensure sterility. There are cost-related challenges.
Preservative-free products prevent ocular surface toxicity and improve tolerability. In severe dry eye, neurotrophic keratitis, and limbal stem cell deficiency, the use of preserved eye drops should be minimized.
Multi-dose preservative-free bottles such as ABAK (with antimicrobial membrane, maintains sterility for 3 months after opening) and COMOD (with check valve, maintains sterility for 6 months after opening) have been developed.
The European Glaucoma Society (EGS) guidelines recommend avoiding preservatives and using the lowest possible concentration in patients intolerant to preservatives or requiring long-term treatment 4). Options to reduce OSD include using BAK-free formulations, reducing instillation frequency with fixed combinations, using preservative-free artificial tears, and early laser or surgical intervention 4).
Not necessarily. A systematic review of 323 patients reported no statistically significant difference in outcomes between preservative-free and preserved artificial tears. However, there was a trend favoring preservative-free formulations for subjective symptoms. Preservative-free formulations also have limitations such as cost, difficulty of use, and contamination risk, and are not suitable for all patients.
BAK is a quaternary ammonium compound with both hydrophilic and hydrophobic properties. The same mechanism that destroys microbial cell wall lipids to kill bacteria also damages human ocular surface cells 2).
The toxic threshold of BAK is estimated at 0.005%, which is much lower than the concentrations in many commercially available eye drops (0.003–0.02%). Even at concentrations hundreds of times more diluted than the maximum allowed in cosmetics under EU regulations (0.1%), human corneal, conjunctival, and meibomian gland epithelial cells die within 18 hours in vitro 2).
BAK causes ocular surface damage through the following multiple mechanisms 2).
BAK has high retention in ocular tissues. In rabbit experiments, BAK was detected in ocular tissues for up to 168 hours (7 days) after a single instillation of 0.01% BAK 2). This long half-life contributes to cumulative toxicity.
In addition to BAK, formaldehyde-releasing compounds (such as DMDM hydantoin, quaternium-15, and imidazolidinyl urea) found in cosmetics and eye care products are toxic to the ocular surface 2). Even at concentrations 740 to 2000 times lower than the EU regulatory limit (0.2%) or the CIR recommended limit (0.074%), they have been reported to be toxic to human corneal, conjunctival, and meibomian gland epithelial cells 2).
Marini et al. conducted a prospective multicenter RCT comparing preservative-free bepotastine 1.5% (BB-PF) and BAK-preserved olopatadine 0.2% (OL-BAK) in 97 patients with allergic conjunctivitis 1).
After 60 days of treatment, impression cytology (Nelson classification) showed that the BB-PF group had a 2.0 times higher probability of having normal conjunctival epithelium compared to the OL-BAK group (OR=2.00; 95% CI 1.19–3.34; p=0.010) 1). While normal conjunctiva decreased by 27.4% in the OL-BAK group, an improvement of 20.5% was observed in the BB-PF group 1).
This study demonstrates that even 60 days of BAK exposure can cause histological changes in the conjunctival epithelium, supporting the need for caution regarding preservative toxicity even with short-term use 1).
Conjunctival impression cytology (CIC) is useful. The Nelson classification evaluates the presence of goblet cells and epithelial metaplasia in four grades (0 to III). Grades 0–I are normal, while grades II–III indicate loss of goblet cells and squamous metaplasia, considered abnormal 1). It is used to detect conjunctival damage caused by BAK-preserved eye drops.
