Transdermal permeation of drugs targeted to deep tissues: the case of NSAIDs

Oral and parenteral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is effective but often limited by systemic adverse effects. Transdermal delivery has emerged as a promising alternative, offering local action with reduced systemic exposure. However, attaining therapeutic concentrations in deep tissues, such as synovial joints, remains challenging due to the presence of skin and tissue barriers. This review summarizes current knowledge on the mechanisms of transdermal permeation and the strategies developed to optimize NSAID delivery to musculoskeletal tissues. Emphasis is given to chemical enhancers, nanostructured carriers, and physical methods, which can synergistically improve permeation and local retention. While evidence supports the potential of these approaches to enhance joint bioavailability and minimize systemic risks, further clinical studies are required to establish their therapeutic relevance. Overall, combining advanced formulations with permeation-enhancing techniques represents a promising path toward safer and more effective transdermal therapies for inflammatory joint disorders.