Balancing Release and Permeation Rates in Cyclosporine Amorphous Solid Dispersions

Abstract

The solubility advantage of an amorphous drug can be realized only when it releases at a sufficiently rapid rate from its amorphous solid dispersion (ASD). Herein, we evaluated the impact of a plasticizer, glyceryl tributyrate (GTB), on the release of a poorly soluble drug with a high glass transition temperature (Tg). Cyclosporine has a Tg of 124 °C and was formulated as an ASD with hydroxypropyl methylcellulose acetate succinate (HPMCAS). Binary and ternary ASDs were prepared using solvent evaporation, their Tgs were measured using differential scanning calorimetry, and surface area normalized release rates were determined. The drug-rich phase formed above the amorphous solubility was characterized for composition and size. Drug flux following release from the ASD was measured across Caco-2 cell monolayers. Cyclosporine released at a substantially faster rate from ternary ASDs containing GTB as compared to the corresponding binary ASD. This improvement was attributed to a decrease in Tg upon plasticization due to GTB increasing molecular mobility. Addition of GTB, however, reduced the amorphous solubility of cyclosporine resulting in a decrease in the transport rate across the Caco-2 cell monolayer. These observations may have implications for drug absorption. Ultimately, it is expected that the in vivo performance of these ternary ASDs would be determined by the interplay between the enhanced release rate and the decreased permeation rate of the drug.