Comparison of Particle Size and Dispersion State among Commercial Cyclosporine Formulations and Their Effects on Pharmacokinetics in Rats

Abstract

Generic versions of Neoral, a microemulsion capsule formulation of cyclosporine, have been approved worldwide. However, there are concerns about the quality and efficacy of the generics due to the formulation specificity and differences in inactive ingredients among products. In this study, we measured the physicochemical properties of both the innovator and the generic formulations, and compared their bioavailability in rats. When the capsule contents were dispersed in water, the absorbance (600 nm wavelength) of generic products was higher than that of the innovator. Whereas the dispersion solution of the innovator in Fed State Simulated Intestinal Fluid was nearly clear, that of all the generics became white and turbid. The mean diameter of the microemulsion (or emulsion) formed in water by the generics was 39.7, 57.7, 64.5, and 74.8 nm, all of which were larger than that of the innovator (26.4 nm). Although the T(max) of the generics tended to be long relative to that of the innovator, there were no significant differences between the innovator and generics with regard to maximum blood concentration (C(max)) or area under the curve (AUC). These results suggest that the physicochemical differences between the innovator and the generics will not have a significant effect on C(max) or AUC, which is necessary to ensure bioequivalence.