From creams to complex molecules: The evolving science of topical delivery

Central to this field is the barrier function of the stratum corneum. This outermost layer of the skin consists of corneocytes embedded in a highly organized lipid matrix composed primarily of ceramides, cholesterol, and free fatty acids. This “brick-and-mortar” structure is highly effective at both limiting water loss and the penetration of exogenous compounds. As a result, passive diffusion across intact skin is restricted to molecules with specific physicochemical properties.

One of the most widely cited principles in topical delivery is the “500 Dalton Rule”, which states that compounds larger than approximately 500 Daltons (Da) rarely penetrate intact human skin by passive diffusion. In practice, this constrains effective passive delivery to small, moderately lipophilic molecules with limited hydrogen bonding capacity. While not absolute, the rule remains a useful benchmark for understanding the inherent selectivity of the skin barrier and the challenges associated with delivering larger or more complex therapeutics.

To overcome these limitations, advances in formulation science have focused on modifying drug-skin interactions and enhancing transport across the barrier. Strategies include lipid-based carriers such as liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs), as well as nano- and micro-emulsions, vesicular systems, hydrogels, and chemical penetration enhancers. These technologies aim to improve drug solubilization, alter partitioning into the stratum corneum, and enhance diffusion through intercellular lipid pathways.

More recently, artificial intelligence and machine learning approaches are being applied to topical formulation development, enabling prediction of skin permeability, optimization of formulation composition, and identification of novel delivery systems beyond traditional trial-and-error approaches. As these methods evolve, they offer the potential to accelerate development and uncover previously inaccessible formulation design spaces.

In parallel, physical delivery technologies have emerged to bypass or transiently disrupt the barrier. Approaches such as microneedles, electroporation, iontophoresis, and thermal ablation create transient pathways that enable delivery of larger and more hydrophilic molecules, including peptides, proteins, and nucleic acids. These strategies are expanding the scope of topical delivery beyond traditional small molecules toward more complex biologic therapeutics.

While current technologies work well for many conventional drugs, the next frontier presents a greater challenge. Increasingly, pharmaceutical research is focusing on large and complex molecules, including peptides, proteins, and nucleic acids. These biologically active molecules offer the possibility of targeting disease pathways with greater specificity than traditional small molecules.

However, their physical properties make them difficult to deliver through the skin. Large molecular size, hydrophilicity, and structural instability all limit their ability to cross the stratum corneum. Even when employing advanced delivery strategies, such as microneedles, electroporation, or novel carrier systems, predicting how these molecules interact with human skin remains a complex task.

This shift towards more sophisticated delivery technologies makes predicting transport across human skin increasingly challenging and difficult to replicate in simplified in vitro models and simplified skin systems. As delivery technologies become more complex, understanding how molecules are transported across intact, functional skin tissue becomes crucial for predicting, efficacy, dosing and safety.

Alongside scientific progress, regulatory frameworks have evolved to evaluate how topical and transdermal products behave within the body. Regulators assess not only safety and efficacy, but also the site of action of the active ingredient. Some products are designed to act locally within the skin, as in dermatological treatments or cosmetics. Others are intended to deliver drugs systemically via transdermal absorption.