Developing Multi-Component Solid Formulation Strategies for PROTAC Dissolution Enhancement.

Abstract

PROTACs are an emerging class of beyond-rule-of-5 molecular drugs currently under clinical investigation for the treatment of malignant diseases and are capable of degrading previously "undruggable" protein targets. They are poorly crystallizable due to their structure, consisting of two ligands joined chemically by a flexible linker, yet the inherent insolubility of their amorphous phases hinders their development into sufficiently bioavailable medicines. Formulation approaches to improve the dissolution properties of PROTACs are required as a result, but research in this area is made even more challenging by the scarcity of available samples. In this work, amorphous solid dispersion (ASD) formulations of four cereblon-recruiting PROTACs 'AZ1-4' using hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a polymer excipient are described. ASDs of AZ1 show up to a 2-fold increase in drug supersaturation compared to the pure amorphous API, observed up to a drug loading of 20% w/w. Preparing the ASDs by slurry conversion offers greater solubility enhancement over those prepared by solvent evaporation and maintains the dissolution advantage up to a higher drug load. Positive deviations from theoretical T_g values coupled with a lack of spectral evidence of drug-polymer hydrogen-bond interactions suggest that the ASDs may differ from ideal mixtures via predominantly dispersive drug-polymer interactions. ASDs that provide a dissolution enhancement were stored at elevated temperature and humidity for one month and showed no sign of plasticization or loss of physical stability. Coamorphous formulations using low-molecular-weight excipients, by contrast, showed no dissolution advantage despite evidence of drug-coformer hydrogen-bonding interactions. This work demonstrates that ASDs may be an effective strategy for improving PROTAC bioavailability and producing commercializable solid forms for oral administration despite the lack of well-behaved solid phases of PROTACs. It also highlights the need for a deeper understanding of how to develop successful formulation approaches for bRo5 compounds.