PROTAC Enabling Formulation In Vivo: Implications of the Polymeric Carrier Eudragit E PO

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery
• Pharmacokinetics

Background:

• Proteolysis targeting chimeras (PROTACs) offer novel therapeutic strategies for "undruggable" targets.
• PROTACs often exhibit poor solubility and bioavailability, necessitating advanced formulation approaches.
• Enabling formulations for PROTACs in pharmacokinetic studies remain underexplored.

Purpose of the Study:

• To evaluate the in vivo pharmacokinetic performance of an amorphous spray-dried dispersion (SDD) of a model PROTAC (MS4078) with Eudragit PO (EPO).
• To investigate the in vitro supersaturation and precipitation behavior of the SDD and solution formulations under physiological conditions.
• To elucidate the role of bile salts and phospholipids in the performance of PROTAC formulations.

Main Methods:

• Development of amorphous spray-dried dispersions (SDDs) of MS4078 and EPO.
• In vivo pharmacokinetic study in mice comparing SDD and solution formulations.
• In vitro two-stage precipitation assay using media mimicking physiological conditions with varying bile salt and phospholipid concentrations.

Main Results:

• Both SDD and solution formulations exhibited unexpectedly low in vivo exposure.
• In vitro, the solution vehicle acted as a solubility enhancer.
• The SDD showed complex dissolution profiles dependent on bile salt and phospholipid concentrations, indicating interactions and phase separation involving EPO, bile salts, and phospholipids.

Conclusions:

• The in vitro performance of PROTAC formulations, particularly those containing EPO, is significantly influenced by interactions with bile salts and phospholipids.
• These interactions can lead to phase separation, affecting PROTAC solubilization and stabilization.
• Findings highlight the importance of considering physiological lipid and bile salt concentrations when designing PROTAC formulations and pharmacokinetic studies.