Review article
Ocular tolerance of preservatives and alternatives

https://doi.org/10.1016/S0939-6411(01)00246-6Get rights and content

Abstract

Eye drops are multiple dosage forms protected against microbial contamination by means of preservatives. However, the ocular tolerance of these chemicals can vary and this may result in adverse toxic or allergic reactions. This overview presents the pharmacopoeial requirements for the preservation of eye drops, the factors affecting ocular tolerance as well as the adverse external ocular effects induced by preservatives. The alternatives to the use of preservatives are also discussed, including the recent progress in eye drops packaging.

Introduction

Topical ophthalmic medications sometimes may cause toxic or allergic reactions resulting in iatrogenic ocular disease [1]. Toxic reactions relate to the direct chemical irritation of tissue whereas allergic reactions imply sensitization and induction of ocular inflammatory processes by the patient's immune system [2]. These adverse external ocular effects of ophthalmic therapy are due to the topically applied drug, or the excipients present in the preparation. Preservatives are among the excipients currently used in ophthalmic preparations.

These substances are chemicals that are meant to prevent microbial spoilage of pharmaceutical preparations [3]. The term ‘preservative’ should be reserved for these substances in order to avoid confusion with the term ‘stabilizing agents’ that designates chemicals intended to protect against physical–chemical degradation like oxidation. For instance, sodium (meta)bisulfite and ascorbic acid are antioxidants, and hence stabilizing agents.

The addition of preservatives to eye drops, artificial tears, or contact lens solutions aims at destroying microorganisms (bactericidal effect) or at least preventing their growth (bacteriostatic effect) [4], [5]. Indeed, this contamination may cause a physicochemical deterioration of the ophthalmic solutions or a risk of (additional) infection for the patient's eye. The infection of the weakened eye can have serious consequences leading even to ocular perforations [6]. In addition to these serious diseases, the deterioration of the contaminated ophthalmic solutions may alter their efficacy, thus vitiating any beneficial effects on the primary disease and compromising the success of the medical treatment [7]. Such a contamination may occur during the preparation of the medications or during their instillation in the patient's eye [8], [9]. During manufacture, the main sources of contamination are the raw materials (especially water), the air, the personnel, and the packing material [10]. During their use, the contamination of the dropper tips or even the solutions inside the bottle can result from physical contact with microbe-harboring surfaces like fingers, eyelashes, etc. [11]. This microbial contamination of eye drops is a significant risk factor of several complications like bacterial keratitis.

Historically it was not until the middle of the 1960s when severe eye injuries were detected in Sweden, caused by eye ointments contaminated with Pseudomonas aeruginosa, that the use of preservatives in ophthalmic preparations was required by regulatory authorities in Europe and in the USA [10], [12].

Ideally, a preservative should provide numerous qualities like broad antimicrobial activity, chemical/thermal stability, compatibility with the container and other compounds present as well as innocuousness towards ocular tissues [13], [14], [15]. Unfortunately none of the preservatives has all the required qualities so as to be used universally for any ophthalmic preparation. Indeed preservatives that kill or damage growing microbial cells may also be toxic to growing cells of the ocular tissues. When selecting a preservative for an ophthalmic formulation, the following considerations must be taken into account [16]: (a) irritation potential, (b) pH range for maximal antimicrobial activity, (c) compatibility with other ingredients, (d) synergism or antagonism in antimicrobial activity, and (e) processing conditions such as heat or packaging.

This paper reviews ocular cytotoxic or allergic effects caused by preservatives. It focuses on the validity of the use of preservatives in ophthalmic solutions and the risks associated with their use. A discussion of the alternatives to preservatives closes the review.

Section snippets

Classification of preservatives

The main ophthalmic preservatives can be classified according to their chemical type. Table 1 gives an overview of these preservatives, their main synonyms and usual concentrations. The antimicrobial spectrum, the incompatibility with other drugs or excipients, the thermostability as well as the optimal pH for the antimicrobial activity and chemical stability are also mentioned in Table 1.

Pharmacopoeial requirements for preservation of ophthalmic preparations

Pharmacopoeias prescribe the ophthalmic preparations to be prepared and packaged so that sterility is assured at the time of first use and maintained during use (Table 2). The preservatives are intended to prevent the microbial spoilage of ophthalmic preparations packaged in multidose containers. However, since they may be irritating to the ocular tissues, the use of preservative is not recommended or is even excluded in certain cases: when ophthalmic solutions are used in surgical procedures,

Ocular tolerance tests for preservatives

Ocular tolerance can be defined as the ability of ocular tissues to bear a given dose of a chemical without showing evidence of intoxication. The assessment of the ocular tolerance of eye drops is not required by pharmacopoeias but by governmental regulatory bodies like the FDA or OECD, which have published guidelines for eye irritation procedures [29], [30]. The following methods are used to assess the effects of preservatives on the eye.

Adverse external ocular effects induced by preservatives

Problems caused by preservatives topically applied on the eye are reviewed below according to the affected ocular structure, starting with the outermost ocular part, the conjunctiva, and ending with the crystalline lens. Comments on allergy induced by preservatives are made and problems associated with preserved care solutions for contact lenses are outlined.

Alternatives to irritant preservatives

Alternatives to the use of irritant preservatives exist and include the development of better tolerated preservatives and special packaging devices.

Conclusion

The prevention of infectious diseases is certainly preferable to their treatment. The use of preservatives is the easiest way to prevent microbial spoilage of ophthalmic medications. However, ophthalmic preservatives are a double-edged sword. Indeed, they constitute a necessary compromise between what is legally required and necessary, and what is microbiologically efficacious on the one hand and possibly toxic on the other [51]. In other words, preservatives are meant to destroy microorganisms

Acknowledgements

We express our sincere thanks to Dr Marston at the School of Pharmacy, Lausanne, Switzerland, for his contribution in correcting the English language of this paper.

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