ASDs of PROTACs: Spray-dried solid dispersions as enabling formulations

Area of Science:

• Pharmaceutical Science
• Drug Delivery
• Medicinal Chemistry

Background:

• Proteolysis targeting chimeras (PROTACs) offer a novel therapeutic strategy by enabling targeted protein degradation.
• Poor solubility and dissolution rates of PROTACs hinder their clinical application and limit drug delivery options.
• Addressing the solubility challenge is crucial for unlocking the full potential of PROTAC technology.

Purpose of the Study:

• To investigate the efficacy of amorphous solid dispersions (ASDs) in improving the dissolution performance of a model PROTAC.
• To evaluate spray-dried ASDs containing a PROTAC and various polymers for pharmaceutical applications.
• To understand the underlying mechanisms responsible for enhanced PROTAC solubility in ASD formulations.

Main Methods:

• Spray drying of a model PROTAC with different polymers to create amorphous solid dispersions (ASDs).
• Characterization of formulations for purity, solid state properties, and dissolution performance.
• Stability assessment of the manufactured PROTAC-loaded ASDs under controlled conditions.

Main Results:

• ASDs demonstrated a significant increase in supersaturation compared to physical mixtures, even when the PROTAC was already amorphous.
• The superiority of ASDs was attributed to the homogeneous, molecular distribution of the active pharmaceutical ingredient (API) within the polymer matrix.
• Improved wettability of formulations containing Soluplus further contributed to enhanced dissolution compared to physical mixtures.
• Manufactured formulations exhibited stability for at least 8 weeks when protected from light and humidity.

Conclusions:

• Amorphous solid dispersions (ASDs) represent a viable and effective drug delivery strategy for overcoming the solubility limitations of PROTACs.
• The molecularly dispersed state within ASDs, coupled with improved wettability, is key to enhancing PROTAC dissolution and supersaturation.
• Spray-dried ASDs offer a promising approach for developing more effective therapeutics targeting previously undruggable targets.