Developing Multi-Component Solid Formulation Strategies for PROTAC Dissolution Enhancement

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Medicinal Chemistry

Background:

• Proteolysis Targeting Chimeras (PROTACs) are novel therapeutics for cancer, but their poor solubility and amorphous nature limit bioavailability.
• Developing oral formulations for PROTACs is challenging due to their physicochemical properties and limited sample availability.

Purpose of the Study:

• To investigate amorphous solid dispersions (ASDs) using hydroxypropyl methylcellulose acetate succinate (HPMCAS) to enhance the dissolution and bioavailability of PROTACs.
• To compare formulation strategies, including slurry conversion versus solvent evaporation, and evaluate physical stability.

Main Methods:

• Preparation of ASDs of four cereblon-recruiting PROTACs (AZ1-4) with HPMCAS.
• Characterization of ASDs, including drug loading, supersaturation, physical stability (Tg, DSC, FTIR), and dissolution testing.
• Comparison with coamorphous formulations and pure amorphous active pharmaceutical ingredients (APIs).

Main Results:

• ASDs of AZ1 demonstrated up to a 2-fold increase in drug supersaturation compared to the pure amorphous API.
• Slurry-prepared ASDs exhibited greater solubility enhancement and maintained advantages at higher drug loadings than solvent-evaporated ASDs.
• ASDs showed good physical stability under accelerated conditions, unlike coamorphous formulations which lacked dissolution benefits.

Conclusions:

• ASDs are a viable strategy for improving PROTAC oral bioavailability and creating commercializable solid forms.
• Formulation by slurry conversion is superior to solvent evaporation for enhancing PROTAC solubility.
• Further research is needed to optimize formulation approaches for beyond-rule-of-5 (bRo5) compounds like PROTACs.