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Clinical Ophthalmology Volume 7, 2013 - Issue
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Review

Development of a non-settling gel formulation of 0.5% loteprednol etabonate for anti-inflammatory use as an ophthalmic drop

Martin J Coffey1 Pharmaceutical Product Development, Bausch and Lomb, Inc, Rochester, NY, USACorrespondence[email protected]
,
Heleen H DeCory2 Global Medical Affairs, Pharmaceuticals, Bausch and Lomb, Inc, Rochester, NY, USA
&
Stephen S Lane3 Associated Eye Care, Stillwater, MN, USA
Pages 299-312 | Published online: 13 Feb 2013

Figures & data

Table 1 Physical properties and composition of normal tear fluidCitation11,Citation13–Citation16

Figure 1 Molecular structure of loteprednol etabonate and metabolism of loteprednol etabonate to inactive metabolites.

Notes: Loteprednol etabonate has an ester function at C-20 position and is metabolized by esterases to Δ1-cortienic acid etabonate and then to Δ1-cortienic acid. Both metabolites lack glucocorticoid activity.
Figure 1 Molecular structure of loteprednol etabonate and metabolism of loteprednol etabonate to inactive metabolites.

Table 2 Comparison of 0.5% loteprednol etabonate suspension and gel formulations

Figure 2 Viscosity of loteprednol etabonate 0.5% gel as a function of applied shear stress.

Notes: The viscosity is much higher at low shear, as indicated by the logarithmic y-axis. The yield stress for the gel is about 4 Pa. Below the yield stress, the gel does not flow, and hence, viscosity cannot be measured. At high shear, the formulation has sufficiently low viscosity (<100 cps) that it can be delivered as a drop. Data was obtained using a controlled-stress rheometer (TA Instruments AR2000 with firmware version 7.20; TA Instruments, New Castle, DE, USA) with a vaned-rotor and cup. A steady-state flow experiment was performed by scanning the shear rate from 1000 s−1 to 1 × 10−5 s−1 (log scale, 10 points/decade) at 25°C. Steady state equilibrium was defined as three consecutive measurements within the tolerance window of 2%. The sample period was 10 seconds, and the maximum time point was set to 5 minutes. Data were collected using Rheology Advantage software V5.7.13 (TA Instruments). The yield value for the formulation was determined by fitting the steady-state flow data to the Herschel-Bulkley equation.
Figure 2 Viscosity of loteprednol etabonate 0.5% gel as a function of applied shear stress.

Figure 3 Delivery of LE 0.5% suspension and LE 0.5% gel from the dropper bottle.

Notes: Both formulations were delivered as an eyedrop to a glass plate (held at a 45 degree angle). After delivery, the gel formulation immediately regained its gel structure and remained where it was delivered. In contrast, the suspension formulation flowed away from the administration point. Photograph taken immediately after administering the drop of LE 0.5% suspension and approximately 1 minute after administering the drop of LE 0.5% gel.
Abbreviation: LE, loteprednol etabonate.
Figure 3 Delivery of LE 0.5% suspension and LE 0.5% gel from the dropper bottle.

Figure 4 Sedimentation of LE 0.5% suspension and LE 0.5% gel formulations under 120× g at 1000 rpm (116–145× g) for 24 hours using a LUMiSizer dispersion analyzer (LUM GmbH, Berlin, Germany).

Notes: LE particles settled out of suspension within 20 minutes from the suspension formulation while remaining suspended in the gel formulation. Even when the LE 0.5% gel formulation was placed above additional placebo vehicle (clear), LE particles did not migrate under centrifugation.
Abbreviation: LE, loteprednol etabonate.
Figure 4 Sedimentation of LE 0.5% suspension and LE 0.5% gel formulations under 120× g at 1000 rpm (116–145× g) for 24 hours using a LUMiSizer dispersion analyzer (LUM GmbH, Berlin, Germany).

Figure 5 Drop weight (A), amount of dose delivered per drop (B), and resulting drop potency (C) of a representative lot of LE 0.5% gel.

Notes: Data represent the mean ± standard deviation for three test bottles, with six individual drops expressed per bottle. Bottles that were shaken were inverted ten times in rapid succession immediately prior to drop expression.
Abbreviation: LE, loteprednol etabonate.
Figure 5 Drop weight (A), amount of dose delivered per drop (B), and resulting drop potency (C) of a representative lot of LE 0.5% gel.

Figure 6 Viscosity of loteprednol etabonate gel 0.5%, suspension 0.5%, and ointment 0.5% at low shear rates before (A) and after (B) dilution with simulated tear fluid (3:1 dilution with Hank’s Balanced Salt Solution).

Notes: For a fluid being sheared between two surfaces, moving relative to each other, the shear rate is the relative velocity over the distance between the two surfaces (velocity/distance) and, hence, has units of seconds−1.
Figure 6 Viscosity of loteprednol etabonate gel 0.5%, suspension 0.5%, and ointment 0.5% at low shear rates before (A) and after (B) dilution with simulated tear fluid (3:1 dilution with Hank’s Balanced Salt Solution).

Table 3 Complete resolution of ACC and grade 0 (no) pain – day 8 and day 15 (ITT populations)Citation60,Citation61

Table 4 Drug-related ocular treatment emergent adverse events occurring at an incidence of ≥1% (safety populations)Citation60,Citation61

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