Allergy to Ophthalmic Preservatives

Jison Hong; Leonard Bielory

Disclosures

Curr Opin Allergy Clin Immunol. 2009;9(5):447-453. 

In This Article

Chlorobutanol and Phenylethanol

Chlorobutanol is an alcohol that acts by increasing lipid solubility, and its antimicrobial activity is based on its ability to cross the bacterial lipid layer. Chlorobutanol is a widely used, very effective preservative in many pharmaceuticals and cosmetic products, for example, injections, ointments, products for eyes, ears and nose, dental preparations, etc. It has antibacterial and antifungal properties. Chlorobutanol is typically used at a concentration of 0.5% where it lends long-term stability to multi-ingredient formulations.

Phenylethanol is an antimicrobial, antiseptic, and disinfectant, which is used also as an aromatic essence and preservative in pharmaceutics and perfumery.

Animal Studies

Two drops of a chlorobutanol-containing or BAC-containing artificial tear were instilled into the right eye of six rabbits. At the same time six control animals received no eyedrops. The central region of the corneal epithelium was quantitatively assessed using a computer system. There were up to 5% exfoliating cells evident at the ocular surface in treated rabbits but with no difference between the two products. Controls had no cell exfoliation (<0.5%). The distribution of surface areas of the squamous cells in the treated eyes was shifted to slightly larger values than in the controls after use of the chlorobutanol-containing product but the number of epithelial cell craters/cell was unchanged from that of the controls. Cell surface areas were shifted to significantly smaller values than controls after use of the BAC-containing product and there were much fewer epithelial cell craters/cell. The results reveal differences in the effects of preservative-containing artificial tears on the squamous cells of the corneal epithelium in a clinically relevant situation.[25]

Human Studies

Human in-vitro studies have been reported by Tripathi and Tripathi[26] who evaluated the cytotoxicty of BAC and chlorobutanol by exposing primary cultures of human corneal epithelial cells to a single dose of each preservative. Control and experimental cultures were analyzed by continuous time-lapse videomicrographic recordings as well as by sequential phase-contrast microscopy. Both BAC at a concentration of 0.01% and chlorobutanol at 0.5% caused immediate cessation of normal cytokinesis and mitotic activity, and epithelial cells degenerated within 2 and 8 h, respectively. A more recent version of this experiment demonstrated that the survival of corneal and conjunctival epithelia in culture with preservatives polysorbate and benzalkonium were highly cytotoxic with cell survival decreasing to 20% at the concentration estimated in commercial ophthalmic solutions as compared with 80% survival of cells exposed to chlorobutanol.[27] Although there have been limited human in-vivo studies that demonstrate any immediate reactivity through an IgE-mast cell mediated mechanism, Garcia-Medina et al.[28] describes a case of a woman who presented with intense ocular pruritus and conjunctival hyperemia with each instillation of Cloircusi fluotest (Alcon, El Masnou, Spain), containing chlorobutanol. Skin tests were all negative. Chlorobutanol was presumed as the reagent through elimination and positive conjunctival provocation test with purified chlorobutanol confirmed the hypothesis.[28]

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