Introduction

Eye-drop preparations, high in phosphate, may cause severe corneal calcification when used on a damaged ocular surface [1–4]. Daly et al. reported rapid corneal calcification in chemically injured eyes after irrigation with phosphate-buffered saline [2]. Similar irreversible deposits were described after ocular surface disease and frequent use of phosphate-buffered hyaluronic acid artificial tears [3], and after amniotic membrane transplantation with phosphate-rich lubrication [4].

Different corticoid compounds are presently used for the topical treatment of chemical burns, postoperative tissue injury, ocular surface disease and inflammatory conditions [5]. Affected eyes may develop corneal epithelial defects, and thus become susceptible to corneal calcification when exposed to phosphate-rich preparations.

There is only a small amount of information on the phosphate content of topical preparations [6] since buffers are regarded as additives. In preparations containing corticoid-phosphates, small amounts (<0.1 mmol/l) of free phosphate anions may be due to ester hydrolysis. Phosphorylated corticoids are popular with manufacturers, since they allow preparation of a clear solution [5].

Our study investigates the amount of phosphate contained in ophthalmic corticoid preparations. This information should help to prevent sight-threatening corneal calcification.

Materials and methods

All the ophthalmic drop preparations that contain corticoids and that are listed in the “Rote Liste 2007” (Rote Liste Service GmbH, Frankfurt/Main, Editio Cantor Verlag, Aulendorf, Germany) and the “Arzneimittelkompendium der Schweiz 2007” (Documed AG, Basel, Switzerland) were included in this study. When the preparations were available in multidose and unit dose containers, the samples were taken from the preservative-free formulation. For technical reasons, gel preparations were not included. The quantification of the phosphate was performed with the molybdate method on a Modular P autoanalyzer (Roche Diagnostics, Basel, Switzerland) [7]. The precision of these measurements was guaranteed by the inclusion of standardised phosphate solutions as controls. The day-to-day coefficient of variation was 1.7%. The results were compared to the physiological concentrations published elsewhere [7, 8].

Results

The phosphate concentrations of the ocular therapeutics that were studied are given in Table 1. The preparations are listed in alphabetical order and in groups of active drugs. The steroid compound of the therapeutic is shown in the second column.

Table 1 Phosphate concentration in commercially available preparations that contain corticoids (German and Swiss market)
Full size table

Eighteen of 38 corticoid preparations (47%) had a phosphate concentration above physiological levels (>1.45 mmol/l). The concentration varied greatly and ranged from less than 0.1 to 62.6 mmol/l. Medications with betamethasone sodium phosphate showed phosphate concentrations from 18.3 to 35.5 mmol/l, dexamethasone from less than 0.1 to 17.6 mmol/l, dexamethasone sodium phosphate from <0.1 to 62.6 mmol/l, fluorometholone from <0.1 to 22.5 mmol/l, and prednisolone acetate from <0.1 to 0.5 mmol/l.

Discussion

Ophthalmic preparations with corticoids may contain high concentrations of free phosphate. Several medications with phosphorylated corticoids were, however, very low in free phosphate ion (Table 1). This indicates that in corticoid eye drops, as in other ophthalmic preparations [9, 10], the total amount of free phosphate ion is primarily determined by the choice of the buffers, and that phosphate ester bounds resist hydrolysis.

In ophthalmic preparations, the vehicle is an agent other than the active drug or preservative. It is added to a formulation to provide proper tonicity, buffering, and viscosity to complement drug action [11]. Its buffering system may consist of acetic, boric and hydrochloric acid, and of potassium or sodium bicarbonate, borate, phosphate and citrate [11]. Phosphates are presently widely used in ophthalmic preparations due to their high buffering capacity around pH 7.4.

Phosphate buffers, however, play a role in the process of inadvertent corneal calcification [1–4, 12]. Calcification occurs when calcium cations and phosphate anions interact within the tissue to form insoluble crystals. In the cornea, deposition typically occurs as hydroxylapatite Ca5(PO4)3OH [2, 3]. Deposition can be observed as a spectrum of clinical findings, ranging from subtle superficial changes to massive calcification of the entire cornea with visual loss.

“Boundary conditions” for the onset of corneal calcification, particularly a critical concentration of phosphate anions, cannot be defined at present. In an animal model, rapid corneal calcification developed after chemical injury, combined with a large epithelial defect, an alkaline pH, when the eyes were irrigated with Isogutt (Dr. Winzer Pharma GmbH, Germany) [1]. In this formulation, a phosphate concentration of 148 mol/l was measured [6].

The amount of phosphate ion delivered to the ocular surface by ophthalmic corticoid formulations may appear minor when compared to the treatment of chemical injuries or epithelial defects with artificial tears [3, 9]. It has to be borne in mind, however, that the ion product of calcium cations and phosphate anions in aqueous humour, tears and interstitial fluids is, even under physiological conditions, close to their solubility product. A minor increase of one of the components may therefore push this system towards precipitation. Furthermore, corticoids are often used in severely damaged eyes that are prone to the complication of calcification. The high phosphate concentration of some steroid preparations may therefore trigger the process of crystallisation. We do recommend that steroid preparations with physiological phosphate concentrations are used in order to reduce the risk of corneal calcification, particularly when frequent application is required.