Evaluating critical quality attributes and novel drug release testing of difluprednate nanoemulsions

Ophthalmic emulsions are considered complex drug products due to their unique product characteristics, presence of multiple phases as aqueous, swollen micellar and oil phases resulting in a complex drug release pattern. FDA recommends in vivo pharmacokinetic or clinical end point study; or in vitro comparative physicochemical characterization study to demonstrate similarity between the reference and generic products. Purpose of the current investigation is to develop a comprehensive biowaiver approach to assess performance of the nanoemullsions of difluprednate through testing their critical quality attributes (CQA). CQA of the Q1/Q2 formulations such as viscosity, pH, globule size distribution, drug distribution in different phases of emulsion, and in vitro release were tested. Drug and surfactant distribution in various phases was analyzed using UPLC following phase separation by ultracentrifugation. In vitro drug release testing (IVRT) was performed using Franz diffusion and microdialysis methods. Microdialysis method was developed and validated by studying the drug release from Q1/Q2 formulations compared to that of the reference product. Of the two IVRT methods used in the current study, the conventional Franz diffusion cell method served as quality control dissolution method with about 80 % drug release in ≅ 2.5 h, differentiating the drug release profiles between the micelle, emulsions of different globule size distribution. In contrast, microdialysis served as a biorelevant method that can be used to test the drug release as early as 2 min with reproducibility and discriminatory ability. It is likely that the above biowaiver approach using a series of product characterization tests and microdialysis as a bio-relevant IVRT method support the industry in generic product development and in establishing in vitro bioequivalence of complex ophthalmic products.