Preservatives in Topical Ophthalmic Medications: Historical and Clinical Perspectives

P. David Freeman; Malik Y. Kahook

Disclosures

Expert Rev Ophthalmol. 2009;4(1):59-64. 

In This Article

Historical & Practical Review of Benzalkonium Chloride

Benzalkonium chloride is a detergent and quaternary ammonium compound with a broad range of antimicrobial activity. It was first introduced as a germicide in the 1910s and became more widely used in the 1940s ( Box 1 ).[7] In the ophthalmic industry, BAK was first used in the 1940s as a means to preserve hard contact lens solutions. Since then, BAK has been used in nearly all classes of ophthalmic solutions, from antiglaucoma medicines to over-the-counter artificial tear solutions.

Benzalkonium chloride is the most frequently used preservative in ophthalmic solutions today,[8] and its concentration in glaucoma formulations ranges from 0.004 to 0.02%. The reasons for the frequent use of BAK as a preservative includes its extreme efficacy in combating microbial contamination of bottles, its ability to break cell–cell junctions in the corneal epithelium, thus allowing for antimicrobial and antihypertensive drops to enter the anterior chamber, as well as familiarity among those formulating ophthalmic preparations in industry. While the efficacy of BAK is well known, there is a multitude of published studies that document the detrimental effects of BAK.[9–13] Benzalkonium is known to induce necrosis (at concentrations of 0.05–0.1%) and cellular apoptosis (at concentrations of 0.01%) by way of disturbing the cellular membrane in bacterial cells.[10] However, human ocular surface cells can also absorb this detergent, and effects on ocular surface cells are similar to those seen in bacterial cells. The effects of the detergent are cumulative and become more severe with more concentrated and frequent exposures.[10] Breakdown of the corneal epithelium and increased permeability of the cornea as a result of BAK toxicity is well documented.[11] Higher concentrations of BAK (as can be induced through repeated exposure and subsequent accumulation of BAK in ocular surface tissues) can reduce tear break-up time by causing disruption of the lipid component of the tear film and hence causes tear-film instability.[12] This is especially problematic in glaucoma patients, as they inherently have a decreased rate of basal tear turnover.[14] In one study, it has been shown that ocular cells repeatedly exposed to BAK can overexpress the cell marker Apo 2.7, which has been implicated in apoptosis.[13]

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