The expanding role of formulations to enable oral delivery of poorly water-soluble drugs

Abstract

Contemporary small-molecule drug candidates increasingly have limited aqueous solubility, rendering oral delivery challenging. Amorphous solid dispersions (ASDs) and lipid-based formulations (LBFs) have evolved as leading formulation approaches to mitigate solubility and dissolution rate limitations. There is an increasing trend towards ASD formulations for drug candidates with high melting points and LBFs for extremely lipophilic molecules. Mechanistic assessment of LBF and ASD enhancement pathways reveals a surprising amount of commonality, notably that supersaturation generation and maintenance are likely key to obtaining optimized in vivo performance for both formulation types. An expanding formulation design space is blurring the distinction between these solubility enhancement technologies and further evolution in this direction is likely necessary to address the oral delivery of even more challenging molecules, such as proteolysis-targeting chimeras and macrocyclic peptides.

Introduction

Orally delivering drugs with poor aqueous solubility has long been a challenge in pharmaceutical development owing to their limited dissolution in the gastrointestinal tract and consequent low absorption1. Various formulation approaches have been developed to address these challenges, including the generation of metastable solid-state forms, salt formation, nanosizing, complexation, lipid-based formulations (LBFs) and amorphous solid dispersions (ASDs)2,3,4,5,6,7. Among these, ASDs and LBFs have emerged as the most widely utilized and generally applicable strategies for enhancing the oral delivery of poorly water-soluble drugs (Box 1), particularly when salt or co-crystal formation is not possible8,9,10.

A contemporary definition of ASDs is that they consist of a miscible amorphous blend of the drug and a suitable polymer, which is further formulated into a tablet or capsule, with improved release of the drug upon contact with aqueous fluids, such as in the gastrointestinal tract (Fig. 1). More than 50 ASD products have been developed, including the antiviral drug ledipasvir, the anticancer drug vemurafenib and the recently approved non-opioid analgesic suzetrigine (Table 1).

Fig. 1: Composition of ASDs and LBFs, and key kinetic processes underpinning drug absorption from these formulations. Amorphous solid dispersions (ASDs) are usually made by spray drying (SD) or hot melt extrusion (HME). Two types of ASD formulation exist: those that remain monolithic and release drug by erosion resulting from polymer dissolution, and those that disintegrate. In both cases, ASDs release drug into solution at a higher concentration than can be achieved with a crystalline drug (thereby generating supersaturation). Lipid-based formulations (LBFs) undergo dispersion/emulsification driven by gastrointestinal motility, forming oil-in-water emulsions containing solubilized drug. These species are modified by digestion and interaction with bile salt micelles to form a range of mixed colloidal species containing bile salts, lysophospholipid and formulation digestion products, as well as the drug. Both ASDs and LBFs can generate drug-rich nanodroplets through the process of liquid–liquid phase separation (LLPS) if the amorphous drug solubility is exceeded. ASDs and LBFs thus similarly lead to the rapid formation of free drug (that is, molecularly dispersed drug in solution), the key species that is ultimately absorbed. If this free drug is supersaturated, it may crystallize, in which case redissolution is typically slow and limited by the crystal lattice. For LBFs, the free drug exists in rapid equilibrium with the drug in a range of colloidal species. Amorphous nanodroplets, generated from either ASDs or LBFs, can persist for minutes to hours without crystallizing or forming a macroscopic precipitate. Further, they exist in equilibrium with free drug and replenish the free drug concentration following absorption or dilution. For both ASDs and LBFs, optimal performance is expected by generating sustained supersaturation and avoiding crystallization. The presence of polymers in ASDs and after deliberate addition to LBFs typically serves to inhibit crystallization. Free drug diffuses into the unstirred water layer adjacent to the membrane and is absorbed (most commonly) by passive transport across the lipid bilayer. If permeation is rapid relative to the diffusion across the unstirred water layer, a concentration gradient can evolve. Diffusion of colloidal species, including micelles and drug-rich nanodroplets, across the unstirred water layer can also occur, albeit at a slower rate than that of free drug, increasing the local free drug concentration at the membrane surface via rapid equilibrium with the solution phase.

Conversely, LBFs usually rely on dissolving the drug in a liquid mixture comprising some combination of oils, surfactants and co-solvent, and filling this mixture into a capsule. Subsequent dispersion of the capsule contents into aqueous media effectively bypasses the dissolution step of a conventional solid oral dosage form (Fig. 1). Notable examples of LBFs include those for several HIV protease inhibitors, the immunosuppressant cyclosporine and, more recently, for crinecerfont and the lipophilic prodrug testosterone undecanoate (Table 2). LBFs can also be used as suspensions, either as a simple carrier for non-dissolution rate-limited drugs or to enhance the bioavailability of poorly water-soluble drugs such as progesterone11. This Perspective will not address lipid suspension formulations in detail, but examples of commercial products are listed in the footnote to Table 2.

The commercialization frequency of LBF versus ASD products has evolved over time (Fig. 2). LBFs predominate for drugs with low melting points (for which ASDs offer little advantage), as well as for products commercialized before 2010. Subsequently, ASDs dominate the landscape, indicating that this formulation type may be more suited to contemporary drug molecules with high melting points that have low solubility in oils, which could otherwise necessitate a higher pill burden for patients, depending on the drug dose. However, for many drugs, the final formulation selection may reflect formulator (and/or organizational) preference and experience rather than specific constraints arising from drug properties.

Despite their apparent differences, both approaches share the fundamental principle of enhancing in vivo drug release by converting the drug into a non-crystalline state that is dissolved or highly dispersed in functional excipients. This process facilitates efficient drug release and absorption in the gastrointestinal tract compared with crystalline solid forms, for which removal of a drug molecule from the crystalline lattice is rate-limiting. Supersaturation is often achievable with ASDs and LBFs, affording higher intestinal solution concentrations relative to crystalline drug and thereby driving absorption by enhancing flux across epithelial cell membranes in the gastrointestinal tract. Importantly, the selection of appropriate ASD polymers or LBF components broadens the applicability of these technologies to a wide range of chemically diverse drug candidates.

The requirement for enabling oral formulations is growing due to the increasing molecular complexity, melting points and hydrophobicity of new therapeutic modalities that are intended for oral administration12,13,14. These trends are driven by advancements in the understanding of how to modulate targets that have historically proven refractory to classical small-molecule drugs. Thus, non-traditional small molecules such as proteolysis-targeting chimeras (PROTACs)15,16, molecular chameleons17 and cyclic peptides18, which fall into the beyond-rule-of-5 (bRo5) space, are increasingly being employed to better access and modulate cellular targets, in particular targets with shallow and poorly defined interaction interfaces, as well as protein–protein interactions. Greater molecular complexity also originates in response to design strategies to improve potency and achieve the desired extent of selectivity.

Formulation and drug delivery technologies play a critical role in optimizing the solubility, stability and bioavailability of such modern drug candidates19. For instance, therapeutic modalities such as PROTACs often have high molecular weights, significant lipophilicity and limited intestinal cell permeability, necessitating specialized formulations to achieve adequate oral bioavailability20,21,22. Similarly, other bRo5 molecules, including peptides (such as the glucagon-like peptide 1 (GLP-1) agonist semaglutide), frequently suffer from poor membrane permeability and/or solubility, likewise demanding advanced formulation strategies23,24. Additional therapeutically important emerging classes of drugs affected by poor solubility include non-peptide GLP-1 receptor agonists25 and non-opioid analgesics26. Traditional approaches involving chemical modification of the drug molecule are often infeasible for these emerging therapeutic modalities due to inherent constraints associated with binding site interactions, further underscoring the critical role of formulation technologies.

This Perspective explores the growing significance of specialized formulations, specifically ASDs and LBFs, in addressing bioavailability challenges resulting from low solubility and in facilitating the development and delivery of innovative medicines. An overview of the design of ASDs and LBFs is provided, followed by examination of the underlying mechanisms by which bioavailability is enhanced. Preclinical and clinical formulations as well as commercialization considerations are discussed. The application of novel formulations to emerging challenges with new therapeutic classes such as oral GLP-1 receptor agonists, PROTACs and macrocyclic peptides is highlighted.

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Excipients mentioned in the article: povidones, polysorbates, HPMCAS, PVPVA, HPC

Ueda, K., Porter, C.J.H., Goodwin, A. et al. The expanding role of formulations to enable oral delivery of poorly water-soluble drugs. Nat Rev Drug Discov (2026). https://doi.org/10.1038/s41573-026-01407-5