Amorphous solid dispersions and lipid-based formulations advance oral delivery for poorly water-soluble drugs, including macrocyclic peptides

The development of new small-molecule drugs and biologics is frequently hampered by their limited aqueous solubility, posing a significant challenge for achieving effective oral delivery. Traditional formulation approaches often fall short, leading to poor bioavailability and inconsistent therapeutic outcomes. This gap is particularly pronounced for complex molecules like macrocyclic peptides and proteolysis-targeting chimeras, which often exhibit high lipophilicity or large molecular weights alongside poor solubility. Addressing this requires innovative formulation strategies that can enhance dissolution rates and maintain drug concentrations in the gastrointestinal tract, ultimately improving absorption and patient access to these promising therapeutics.

This review synthesizes the evolution and mechanistic understanding of amorphous solid dispersions (ASDs) and lipid-based formulations (LBFs) as leading strategies for enhancing the oral bioavailability of poorly water-soluble drugs. It examines the distinct applications and common underlying principles of these formulation types, particularly focusing on supersaturation generation and maintenance. The authors explore the expanding formulation design space, noting how the distinctions between these solubility enhancement technologies are blurring, and discuss future evolutionary paths necessary to address the oral delivery of even more challenging molecules, such as proteolysis-targeting chimeras and macrocyclic peptides.

Contemporary drug candidates increasingly exhibit limited aqueous solubility, making oral delivery challenging. Amorphous solid dispersions (ASDs) and lipid-based formulations (LBFs) have emerged as primary strategies to overcome these solubility and dissolution rate limitations. There is a clear trend towards using ASD formulations for drug candidates with high melting points, while LBFs are increasingly favored for extremely lipophilic molecules. Mechanistic assessments reveal a surprising commonality between LBF and ASD enhancement pathways: supersaturation generation and its subsequent maintenance are likely key to achieving optimized in vivo performance for both formulation types. This suggests a convergent understanding of their efficacy. The expanding formulation design space is progressively blurring the distinction between these two solubility enhancement technologies. This ongoing evolution is deemed necessary to effectively address the oral delivery challenges posed by even more complex molecules, including proteolysis-targeting chimeras and macrocyclic peptides. This review highlights that continued innovation in formulation design is crucial for future drug development.

Supersaturation generation and maintenance are likely key to obtaining optimized in vivo performance for both ASDs and LBFs, despite their distinct compositions.