Challenges in formulating transdermal systems for treating chronic skin infections

Chronic skin infections, such as those caused by bacteria, viruses, and fungi compromise the skin's physical barrier, allowing microbial incursion, biofilm formation, and weakened immune response. This microbial assault disrupts skin hydration, and pH and induces inflammation, making it difficult for drug formulations to penetrate and manage the infection effectively. Traditional therapeutic strategies face hurdles like poor drug retention, systemic side effects, and antimicrobial resistance. Transdermal drug delivery systems (TDDS), on the other hand, offer localized and regulated drug release, decreasing systemic toxicity and improving bioavailability. However, physiological barriers, primarily the stratum corneum, limit the drug's capability to penetrate the deeper layers of the skin and necessitate the usage of permeation enhancers and advanced formulation techniques. Physicochemical barriers of the drug, including high molecular weight, lipophilicity, and solubility, also hamper transdermal drug absorption. Additionally, issues related to drug stability, release kinetics, and adhesive matrices affect drug retention, controlled release, and therapeutic efficacy in the infected skin, which might be compromised due to ulceration, hyperkeratosis, or excessive irritation. Novel strategies such as nanocarrier-based TDDS including liposomes, nanoparticles, and microneedles potentially improve drug permeation and bioavailability while treating chronic skin infections. Nevertheless, the challenges remain in adjusting the compatibility of the drug formulations with the infected skin, while maintaining its effectiveness. This review is a comprehensive look at the physiological and formulation challenges in TDDS for managing chronic skin infections. More real-world evidence is required to further refine TDDS formulations for improved permeation, stability, and clinical efficacy against chronic skin infections.