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.

Limustin®, a non‐innovator tacrolimus formulation, yields reduced drug exposure in pediatric renal transplant recipients

“…It has been reported that certain non‐innovator immunosuppressive products used in several countries do not exhibit equivalent pharmaceutical properties with regard to innovator products . Such formulations should not be considered as generics.…”

Influence of filtering on the effective concentration and sterility of a 2% cyclosporine ophthalmic solution: a quality improvement perspective

“…Aggregation size is generally smaller than crystallization size; therefore, the results of (A) and (I) could be attributed to aggregation rather than crystallization. Moreover, in past study, the particle size of Sandimmun ® formulation dispersed in water was measured, and it was reported that the mean particle size was approximately 1400 nm [ 26 ]. This finding is likely because of aggregation, which could also be attributed to results (A) and (I), although the cause of occurrence of aggregation could not be determined in this study.…”

Effect of Absorption Behavior of Solubilizers on Drug Dissolution in the Gastrointestinal Tract: Evaluation Based on In Vivo Luminal Concentration–Time Profile of Cilostazol, a Poorly Soluble Drug, and Solubilizers

“…17 This may be due to different types of solubilizers that are generally used in original and generic products. 6,7,19 Although in vitro dissolution test is routinely used to confirm the possibility of human bioequivalence, the actual impact of absorption behavior of solubilizers on drug dissolution cannot be detected by the in vitro tools and might be one of the reasons for the difficulty to develop bioequivalent oral products of BCS class II drugs.…”

“…30 However, it is well known that particle size and dispersion state of microemulsion are greatly influenced by the concentration of oil, solvents, and/or surfactants in the dispersed medium. 19 The bio-inequivalence of commercial microemulsion capsules of cyclosporine, a BCS class II drug, has been reported. 19,[34][35][36] Because these products contain different solvents and surfactants, 19 the different absorption behavior of these components may have led to the bioinequivalence of the cyclosporine products.…”

“…17 It has been often discussed to extend BCS-based biowaiver using comparative in vitro dissolution testing to BCS class II drugs. 6,7,10,19,20 However, because different types of solubilizers used in original oral products are generally used for the development of generics of poorly soluble drugs, 6,7,19 understanding the reasons for the erratic effect of solubilizers on the intestinal dissolution and absorption of drugs is imperative to develop bioequivalent oral products.…”