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Summary

Developing oral proteolysis targeting chimeras (PROTACs) requires overcoming challenges in solubility and permeability. This review proposes an early quality target product profile framework and evaluates formulation strategies to improve oral PROTAC delivery.

Keywords:
Amorphous solid dispersionClinical bridgingEnabling formulationsLipid-based formulationsPROTACsSolubility and supersaturation

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Area of Science:

  • Pharmaceutical Sciences
  • Drug Delivery
  • Medicinal Chemistry

Background:

  • Proteolysis targeting chimeras (PROTACs) present significant oral developability challenges due to their physicochemical properties (high molecular weight, polarity, lipophilicity).
  • These properties often place PROTACs outside conventional drug-likeness criteria, leading to poor solubility, inconsistent supersaturation, and uncertain permeability (BCS Class II/IV).
  • These limitations hinder oral absorption, systemic exposure, and early-stage developability assessments, including physiologically based biopharmaceutics modeling (PBBM).

Purpose of the Study:

  • To propose an early, flexible quality target product profile (eQTPP) framework to guide formulation selection for oral PROTACs.
  • To review and evaluate clinically deployable enabling formulation strategies for overcoming PROTAC developability challenges.
  • To provide pragmatic decision frameworks integrating characterization, testing, and modeling for successful oral PROTAC development.

Main Methods:

  • Literature review of enabling formulation strategies for oral drug delivery.
  • Evaluation of solubilization approaches (co-solvents, surfactants, cyclodextrins), lipid-based formulations, and amorphous solid dispersions.
  • Consideration of clinical translation factors including fed/fasted state, acid-reducing agents, and PBBM-informed bridging.

Main Results:

  • Solubilization approaches offer increased concentrations but face precipitation and poor solid form translation.
  • Lipid-based formulations can improve solubilization and permeability but have drug loading and stability challenges.
  • Amorphous solid dispersions provide enhanced dissolution and supersaturation but may exhibit in vitro-in vivo disconnects.

Conclusions:

  • Successful oral PROTAC development necessitates a phase-appropriate formulation strategy addressing the primary absorption bottleneck.
  • An integrated approach combining physicochemical characterization, biorelevant testing, and PBBM is crucial for informed formulation selection.
  • The proposed eQTPP framework and decision-making tools aim to minimize development risks and support clinical translation of oral PROTACs.