Preservatives in eyedrops: The good, the bad and the ugly☆
Introduction
In the recent past, a large body of evidence from experimental and clinical studies has accumulated showing that the long-term use of topical drugs may induce major and frequent ocular surface changes. Many clinical manifestations associated with low-grade chronic inflammation have been described in patients receiving antiglaucoma treatments for long periods of time. Glaucoma treatment may cause chronic inflammation or aggravate a concomitant ocular surface disease. In clinical practice, glaucoma treatment often lasts for decades. Patients may present preexisting ocular surface impairment, such as dry eye, meibomian gland dysfunction, or chronic allergy, and are very frequently treated with two or more topical ophthalmic formulations. These findings explain that clinical practice apparently often does not fit the safety profiles of drugs tested in clinical trials for short periods of time, alone, and only in patients without active ocular surface disorders.
The need for sterility in multidose eye drops requires the inclusion of an antimicrobial preservative in these solutions, most frequently the quaternary ammonium benzalkonium chloride (BAK). In some patients – on long-term treatments – allergic or inflammatory reactions are experienced, including redness, stinging, burning, irritation, eye dryness, or less frequently, conjunctivitis or corneal damage. Many studies indicate a direct correlation between the presence of preservatives and the symptoms experienced during antiglaucoma therapy. In a recent large-scale European observational study (Jaenen et al., 2007), involving 9658 patients, all recorded symptoms and signs were significantly more frequent in patients taking preserved medications compared with those taking preservative-free formulations. Most effects observed in glaucoma patients are therefore more likely to be due to the preservative than the active ingredients, since toxicity of the preservatives has been well documented experimentally, as has the harmlessness of most active compounds when unpreserved. BAK toxicity for eye structures has been reported since the 1940s (Swan, 1944) and many studies in experimental or cell models have consistently and reliably shown its toxic effects (Baudouin et al., 2008, Baudouin, 2008). Conversely, BAK is a hapten causing relatively few short-term allergic reactions and appears in clinical trials as an effective and safe agent, especially when compared to mercury derivatives or chlorhexidine, formerly used in ophthalmic preparations. Nevertheless, given that the main characteristic of a toxic compound is that it exerts time- and dose-dependent effects, these effects are most likely to occur late, with poor specificity in its manifestations, when delayed, mild, or interacting with other ocular disorders. Moreover, in most cases, the severity of glaucoma as a sight-threatening disease makes dry eye sensation or chronic ocular irritation a comparatively very mild caveat regarding the benefit of glaucoma treatment. However, ocular surface manifestations deeply impact the quality of life and may influence patient compliance, in addition to a variety of long-term consequences for the eye. This review is aimed at reviewing the long-term ocular surface side effects of topical treatments, focusing on BAK toxicity and its potential harmfulness in ophthalmic preparations.
Section snippets
Regulatory aspects
The Pharmacopoeia recommends that eye drops must contain an antimicrobial agent (preservative) to avoid or to limit microbial proliferation after opening the bottle, which could induce a risk of potentially severe eye infection as well as the alteration of the formulation. Eye drops are contaminated essentially by the hands when handling the bottle or by contact of the tip touching the eyelids, lashes, conjunctiva, or tears. There is also a risk of cross-transmission when the same eye drops are
Efficacy as a preservative
BAK was mainly used for its apparently good safety/efficacy profile. This compound is weakly allergenic and has a high rate of antimicrobial properties. In a study illustrating the potent antimicrobial properties of BAK, Charnock showed that among five preservatives, benzalkonium chloride/EDTA, parabens, chlorobutanol, silver chloride complex, and the Purite-stabilized oxychloro complex, only BAK/EDTA satisfied the major criteria for antimicrobial preservation for all the test microorganisms.
Allergic reactions
The symptoms of conjunctival allergy (congestion, tearing, photophobia, burning and stinging sensations) induced by the instillation of preserved eyedrops are various. Simple conjunctival congestion or papillary conjunctivitis may be observed with or without eczema, the worst reaction being patent giant papillary conjunctivitis. In certain cases, a severe type IV allergic reaction may develop. Allergic manifestations are often spectacular (Fig. 2), occurring a few days after treatment
Prospective studies
Only very few prospective studies have addressed the question of the deleterious role of the preservative, in part because of the current lack of preservative-free compounds and to a large extent because a normal ocular surface will experience weak toxic effects after a short duration of treatment, especially with a monotherapy, that is at a low BAK exposure rate. Nevertheless, in healthy volunteers Ishibashi et al. demonstrated that preserved timolol caused significantly higher tear film
Chemical characteristics of BAK
Benzalkonium chloride (BAK) is a bactericidal cationic tensioactive compound used as preservative in various medical preparations in concentrations ranging from 0.004% to 0.025% in eye drops. BAK is a mixture of alkyl benzyl dimethyl ammonium chlorides with several analogs varying in the length of the aliphatic alkyl chain. In commercial preparations, the aliphatic alkyl chains possess lengths of 12, 14 and 16 carbon atoms (Gardner and Girard, 2000). At low concentrations, BAK in aqueous
Experimental data in animal models
Chemicals, cosmetics, and pharmaceuticals have to be assessed for their irritancy potential and risk to the human eye. However, the only method accepted worldwide by regulatory authorities for the assessment of acute eye irritation potential is the Draize rabbit test (Draize et al., 1944), which has been criticized by animal welfare advocates and whose relevance, validity, and precision have been challenged because of the variability and low predictiveness of the human response (Curren and
Dry eye and ocular surface diseases
BAK is a well-known irritant in dermatological and allergological investigations, but it is rarely recognized as the main allergen responsible for contact dermatitis (Uter et al., 2008). However, by truly allergenic mechanisms or as a cofactor and an irritant compound it may cause or enhance various clinical manifestations at the ocular surface level, such as allergic or nonallergenic blepharitis, meibomian gland dysfunction, chronic conjunctival inflammation, or tear film instability. Through
Eliminating the preservative
Considerable efforts have been made in the recent past by the pharmaceutical industry to develop new antiglaucomatous compounds that would bring about efficacy, safety, and compliance. As BAK toxicity is mainly dose-dependent, reducing the number of instillations has improved ocular tolerance. Long-acting preparations of timolol and prostaglandins are given once a day, mathematically reducing the amount of BAK in contact with the eye by 50%. The same has occurred for various fixed combinations
Conclusion
Over more than two decades, a huge number of animal and in vitro studies, using a considerable variety of models, cells, and tissues, have demonstrated that BAK may cause or enhance harmful consequences on the eye structures of the anterior segment, including the tear film, cornea, conjunctiva, and even trabecular meshwork. Despite these consistent and solid data, and warnings coming from observational surveys and individual case series, BAK is still used as the main preservative in eye drops
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Financial disclosure: Christophe Baudouin is consultant for or has received research grants from: Alcon, Allergan, MSD, Pfizer, Santen and Théa. The other authors have benefitted from research grants from the same companies.