Purpose: The purpose of this research was to develop an appropriate release rate method for the release of loteprednol etabonate suspended in an ophthalmic solution. Our objective was to develop a method that is discriminatory and reproducible. Loteprednol etabonate ophthalmic suspension 0.5% (w/v) is used to treat redness and itching of the eyes caused by allergies, infection, and eye surgery.
Developing a release rate test for a suspension can be challenging due to multiple physicochemical processes involved such as the diffusion of dissolved particles into the receiving medium and dissolution of undissolved particles in the matrix followed by diffusion. Often the rate limiting factor is the dissolution of undissolved particles into the matrix. The research conducted was intended to overcome that challenge to develop a release rate method for loteprednol etabonate ophthalmic suspension.
Methods: In vitro release testing using the Vertical Diffusion Cells (VDC) thru a Nylon 0.45 µm membrane with surface of exposure of 1.00 cm2 using ethanol: 50 mM phosphate buffer at pH 7.2, 70:30 (v/v) as the receiving medium (total cell volume 8 mL) were used to explore the possibility of achieving discriminatory and reproducible release rates of the suspension. Though the conditions used for VDC demonstrated reproducible release rates with average relative standard deviation (RSD) of 6% (typically less than 20% RSD is acceptable), these conditions were not discriminatory between differing strengths of loteprednol etabonate in suspension when using the statistical Wilcoxon Mann/Whitney Rank Sum Test (90% confidence interval). As an alternative apparatus, the use of immersion cells was explored using the same receiving media previously used with the VDC. Using these conditions with immersion cells, we were able to develop a discriminatory method when compared using the Wilcoxon Mann/ Whitney Rank Sum Test with a linear release rate with an average correlation coefficient of 0.997 for all vessels, though with high variation of 40% average RSD. The variation is probably due to the low percent of loteprednol released as a suspension initially maintaining contact with the membrane and then settling to the bottom of the immersion cell as time progressed.
Results: The immersion cell apparatus displayed a potential for developing a validatable In Vitro Release Test for loteprednol etabonate in ophthalmic suspension. Acceptable discrimination between differing dose strengths when compared using the Wilcoxon Mann/ Whitney Rank Sum Test and the correlation coefficient between the square root of time and the amount released over the duration of the test was greater than 0.970, resulting in a linear release
Conclusion: The high variability is probably due to insufficient contact between the membrane and the dosage form and very low amount of the active released at the end of the test. Future studies can be performed to optimize the apparatus parameters to increase the percent of applied dose released and thus improve variability.