Skin Barrier-Informed Topical and Transdermal Drug Delivery: Excipient-Driven Strategies, Vehicle Transformation, and Translational Challenges

Abstract

Topical and transdermal dosage forms can localize therapy or provide controlled systemic exposure, but translation is limited by the selective stratum corneum (SC) barrier and post-application changes in formulation. Existing reviews often address individual enhancers or carriers without integrating drug properties, vehicle microstructure, post-application transformation, quality of evidence, and product development constraints.

This review fills that gap by comparing passive formulations, chemical permeation enhancers, vesicular and lipid-based carriers, supersaturating systems, and physical barrier bypass technologies within a skin barrier-informed framework. Increased permeation alone does not establish translational value. Passive delivery remains most feasible for potent, moderately lipophilic small molecules.

Chemical enhancers are scalable but limited by irritation and drug-dependent compatibility; nanocarriers may improve solubilization and cutaneous deposition but often lack human confirmation; and physical methods broaden delivery to macromolecules while adding device, manufacturing, usability, and regulatory burdens. Solvent evaporation, residual film composition, supersaturation, precipitation, and drug–vehicle affinity further determine the effective post-application driving force. Accordingly, we propose an evidence-ranked framework linking payload properties and target compartment to mechanism, safety, clinical readiness, and regulatory complexity. It distinguishes mechanistic promise from clinically demonstrated delivery and identifies the evidence needed to advance reproducible topical and transdermal products.

Introduction

Topical and transdermal dosage forms provide noninvasive routes for local or systemic therapy and offer patient-friendly alternatives to oral or injectable administration [1,2,3]. For systemic therapy, transdermal delivery can avoid gastrointestinal degradation and hepatic first-pass metabolism. Its clinical value is demonstrated by locally acting dermatologic products and transdermal systems used for cardiovascular, analgesic, hormonal, neurological, and smoking cessation therapies [4,5,6]. Nevertheless, the commercial success of passive transdermal delivery remains restricted to a relatively narrow physicochemical space. Most marketed drugs are potent, chemically stable small molecules with molecular weights below approximately 500 Da, moderate lipophilicity, and daily dose requirements compatible with the limited delivery area and flux of a transdermal system [7,8]. The principal barrier is the stratum corneum (SC), in which protein-rich corneocytes are surrounded by an ordered intercellular lipid matrix. Large, extensively ionized, or highly hydrophilic molecules generally partition poorly into this barrier, whereas excessively lipophilic compounds may be retained within the SC rather than reaching the viable epidermis, dermis, or systemic circulation [4,5,6,7,8]. Delivery therefore depends on more than the nominal drug concentration. Drug solubility in the vehicle, free drug fraction, saturation state, partitioning into SC lipids, diffusivity, target tissue depth, and skin condition collectively determine whether a formulation provides adequate local deposition or systemic exposure.

A further challenge is the fact that topical and transdermal formulations are not compositionally static after application. Volatile solvents may evaporate, water may be absorbed or lost, emulsion phases may redistribute, and the residual film may become progressively enriched in nonvolatile excipients. These transformations can increase drug thermodynamic activity and temporarily enhance permeation, but they may also induce crystallization, reduce molecular mobility, alter occlusion, or increase irritation [9,10,11,12]. Consequently, formulation performance cannot be reliably predicted from the composition in the container alone; the applied and transformed states must also be considered. Formulation strategies can modify this drug–vehicle–skin relationship through different mechanisms. Conventional vehicles and excipients regulate solubilization, drug release, residence time, and deposition within the intended skin compartment [13,14,15]. Vesicular and lipid-based carriers can improve the apparent solubility of poorly water-soluble drugs, protect unstable compounds, and promote epidermal or follicular targeting [16,17]. Chemical permeation enhancers (CPEs) alter SC lipids, keratin interactions, or drug partitioning, whereas microneedles (MNs), iontophoresis, electroporation, ultrasound, and thermal or laser-based approaches physically bypass or transiently perturb the skin barrier [18,19,20]. However, enhanced delivery may be accompanied by irritation, barrier damage, formulation metastability, device dependence, dose loading limitations, manufacturing complexity, or regulatory uncertainty.

Although these technologies have been extensively reviewed, the literature remains fragmented. Previous reviews have generally focused on skin barrier biology, conventional dosage forms, individual excipient classes, nanocarrier systems, or specific physical enhancement technologies as separate topics. However, research has not yet adequately addressed a unified, cross-platform framework that connects barrier mechanism, excipient function, thermodynamic activity, and post-application vehicle transformation with target tissue requirements, payload properties, strength of evidence, safety, manufacturability, and translational readiness. This distinction is important because many studies demonstrate increased permeation using synthetic membranes, excised animal skin, or short-duration laboratory models, whereas substantially fewer have established reproducible delivery in human skin, clinical benefit, repeated use tolerability, long-term stability, scalable production, or regulatory feasibility [21,22]. An experimental increase in flux therefore does not necessarily indicate that a formulation is clinically or commercially viable. Accordingly, this review has four specific objectives. First, it defines the biological, physicochemical, and formulation determinants governing local skin deposition and systemic transdermal transport. Second, it compares conventional vehicles, excipient-based approaches, vesicular and lipid-based carriers, and physical enhancement technologies according to their mechanisms, suitable payloads, expected benefits, safety trade-offs, and principal failure modes. Third, it critically distinguishes evidence derived from in vitro, ex vivo, animal, human pharmacokinetic, clinical, regulatory, and commercial sources and identifies areas in which findings are consistent, controversial, or conflicting. Fourth, it integrates these dimensions into a strategy selection and translational readiness framework that distinguishes clinically established approaches from technologies approaching translation and those that remain primarily experimental (Figure 1). The purpose is not to identify a universally superior delivery platform but to clarify the evidence and design criteria required to match a delivery strategy to a defined drug, target compartment, and intended product profile.

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Sapkota, B.; Phuyal, S.; Bamjan, A.D.; Cho, S.-S.; Shim, J.-H.; Park, J.W.; Subedi, L. Skin Barrier-Informed Topical and Transdermal Drug Delivery: Excipient-Driven Strategies, Vehicle Transformation, and Translational Challenges. Pharmaceutics 2026, 18, 1069. https://doi.org/10.3390/pharmaceutics18091069