Evaluating drug distribution and release in ophthalmic emulsions: Impact of release conditions

The purpose of this study is to investigate the process of drug distribution and mechanism of drug release of ophthalmic emulsions in the context of factors associated with the drug release. Cyclosporine and difluprednate emulsions were chosen as model systems. A kinetic method was used to quantitatively evaluate the drug distribution within a simplified biphasic (emulsion) system. The impacts of release associated factors were investigated, including the amount of sodium dodecyl sulfate (SDS), ethanol, and ionic strength in the release medium as well as the temperature. SDS and ethanol were found to significantly enhance both rate and extent of drug diffusion from oil to aqueous phase for both cyclosporine and difluprednate emulsions. The ionic strength was found to decrease the rate and extent of cyclosporine transfer from oil to aqueous phase but had little impact on the transfer of difluprednate between phases. Diffusion of cyclosporine to aqueous phase exhibited a decreasing trend with increasing temperature due to its atypical temperature dependent solubility in water. Based on our previous method to investigate the impact of formulation variables on drug diffusion and the findings in the current study, a biphasic release model for emulsions is proposed and discussed. Lastly, the underlying relationship of three key quality attributes (i.e., globule size distribution, drug distribution, and release characteristics) and their effect on product quality and performance were discussed. This study provides a fundamental insight into the drug distribution and release in complex emulsion systems. It also elucidates the critical variables for the development of in vitro release method to support regulatory assessment of ophthalmic emulsions and formulation development.