Addressing the Release and Permeation Challenges of High-T_g Drugs in Amorphous Solid Dispersions

The goal of the current study was to assess the release rate of model high glass transition temperature (T_g) drugs from amorphous solid dispersions (ASDs) as a function of drug loading, and then to evaluate the permeation rate of the resultant solutions using Caco-2 cells. Ivacaftor and ARV-825 were selected as model drugs and were formulated as ASDs with hydroxypropyl methylcellulose acetate succinate (HPMCAS). Release was found to be very slow or not detectable at higher drug loadings. Dramatically improved release was observed upon addition of 10 wt % glyceryl tributyrate to the ASDs, which reduced T_g. Nanosized drug-rich amorphous droplets, generated upon dissolution of ivacaftor ASDs, enhanced the Caco-2 membrane permeation rate, likely by partitioning into the unstirred water layer (UWL) at the surface of the membrane and reducing the concentration gradient across the UWL. The extent of improvement was correlated with the size of droplets: smaller droplets resulted in faster permeation rates. Addition of glyceryl tributyrate, while increasing the release rate, decreased the permeation rate due to formation of larger droplets. In conclusion, the addition of a plasticizer to an ASD containing a high T_g drug led to an improvement in release rate but increased the size of drug-rich nanodroplets produced via the release process with unknown potential implications for in vivo performance.