Category: Formulation and Quality
Purpose: Establishing bioequivalence (BE) of ophthalmic emulsions in the absence of in vivo data can be challenging. The objective of this study is to understand the underlying mechanism and process of drug distribution and release in the context of formulation and (release) environment-associated variables that are important for BE assessment.
Methods: A novel kinetic method for determining drug partitioning was used to quantitatively evaluate the rate and extent of drug distribution within a simplified biphasic system (Figure 1). The experimental setup consisted of a dissolution work station providing agitation control, in-situ UV fiber optics for real time concentration analysis and a circulating water bath for temperature control. Cyclosporine and difluprednate were used as the model drugs. The formulation-variables included the amount of polysorbate 80, glycerin, and carbomer copolymer as well as the oil-aqueous interfacial area. The investigated (release) environment-associated variables were concentrations of sodium dodecyl sulfate (SDS) and ethanol, ionic strength, temperature, and agitation rate.
Results: Polysorbate 80, SDS, and ethanol were found to greatly enhance both the rate and the extent of the drug distribution from oil to aqueous phase. Figure 2 shows the biphasic diffusion rate constants determined by the kinetic method with respect to the concentrations of polysorbate 80. Glycerin was found to slightly reduce the rate and extent of drug distribution of cyclosporine into the aqueous phase. Carbomer slowed down the drug diffusion into the oil phase and shifted the equilibrium drug distribution towards the aqueous phase. Increasing agitation rate led to accelerated drug diffusion between two phases but without changing the equilibrium drug distribution. Ionic strength was found to reduce the rate of cyclosporine diffusion towards aqueous phase by lowering the solubilizing capacity of micelles. Increasing temperature increased the diffusion of difluprednate into the aqueous phase but not of the cyclosporine. Furthermore, increase in the interfacial area significantly increased the rate of drug diffusion but had negligible effect on the extent of drug distribution. It is noteworthy that the experimental setup utilized a flat interface rather than an interface with curvature, which may have slightly underestimated the influence of globule size on equilibrium drug distribution.
Conclusion: The findings of this study provided insight into the drug distribution and diffusion in complex ophthalmic emulsions and could serve as tools to assist with formulation design as well as development of in vitro methods to determine the product sameness to support BE assessment of ophthalmic emulsions.
Disclaimer: This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.
Yixuan Dong– Visiting Associate, US Food and Drug Administration, Silver Spring, Maryland
Leanna Hengst– Contractor, FDA/CDER/OTR/DPQR, Silver Spring, Maryland
Robert Hunt– US Food and Drug Administration, Silver Spring, Maryland
Deval Patel– ORISE Fellow, US Food and Drug Administration, Silver Spring, Maryland
Anh Vo– Silver Spring, Maryland
Stephanie Choi– Chemist, US Food and Drug Administration, Silver Spring, Maryland
Muhammad Ashraf– Supervisory Chemist, US Food and Drug Administration, Silver Spring, Maryland
Celia Cruz– Division Director, FDA/CDER/OPQ/OTR/DPQR, Silver Spring, Maryland