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

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.