The largest organ of the human body, the skin, consists of three primary layers: the epidermis, dermis, and subcutaneous tissue. It serves as a crucial protective barrier, maintaining homeostasis by regulating water and electrolyte balance while preventing the entry of harmful microorganisms [1, 2, 3]. However, this barrier function is significantly compromised in chronic skin infections, leading to increased susceptibility to microbial invasion and excessive transdermal loss of essential nutrients [4]. Chronic skin infections, including bacterial (e.g. Staphylococcus aureus, Pseudomonas aeruginosa), viral (e.g. herpes simplex), and fungal (e.g. dermatophytosis, candidiasis) infections, as well as persistent wounds such as diabetic ulcers, pose a significant challenge due to biofilm-mediated resistance and impaired immune responses [5]. Infected skin often exhibits altered hydration levels, pH imbalance, and inflammatory mediators, further influencing drug penetration [6,7]. Traditional management methods such as the use of systemic and topical antimicrobials are often limited by factors such as insufficient drug penetration, systemic toxicity, and the development of antimicrobial resistance [5,8]. Transdermal drug delivery systems (TDDS) have been recognized as a solution to these challenges by providing localized and regulated drug release while reducing the risk of systemic toxicity [5,9]. TDDS bypasses hepatic first-pass metabolism, enhancing bioavailability and ensuring sustained drug release, in contrast to traditional systemic administration. Additionally, TDDS reduces systemic side effects, improves patient compliance, and can be discontinued quickly if required [7,10]. Over the years, TDDS has evolved through four generations, each devised to incapacitate the barrier characteristics of the stratum corneum (SC) and enhance therapeutic efficacy [11,12]. The first-generation TDDS, using passive diffusion, was suitable for small lipophilic molecules such as nitroglycerin and clonidine but not appropriate for hydrophilic or drugs possessing larger molecular weights [13]. The second-generation TDDS formulations included chemical permeation enhancers, iontophoresis, and ultrasound, which improved the drug permeation capabilities of micromolecules such as fentanyl, but not that of macromolecules [14, 15, 16]. The third-generation incorporated techniques such as microneedles and electroporation, which temporarily permeated the SC to facilitate improved permeation of larger molecules such as insulin and vaccines [17,18]. The most recent fourth generation employs nanocarriers such as liposomes, niosomes, and solid lipid nanoparticles (SLNs), significantly improving drug stability, bioavailability, and controlled release for dermatological conditions [7,12]. These advantages have contributed to the increased adoption of TDDS, with more than 70% of patients and physicians prefer transdermal formulations for dermatological conditions, including antifungal and antibacterial agents like amphotericin B and mupirocin [7,10]. Despite its advantages, the clinical application of TDDS remains challenging due to limited drug permeation, inadequate tissue retention, and formulation stability issues. The SC acts as a major barrier, restricting the diffusion of hydrophilic and high-molecular-weight drugs. Physicochemical properties such as molecular weight, solubility, and partition coefficient, along with physiological factors like skin hydration, vascularization, and genetic variability, significantly influence transdermal drug absorption and overall treatment outcomes.

The benefits of transdermal therapy against chronic skin infections can clinically be introduced only when a well-conceived formulation has been developed that incorporates components such as matrix formers containing the drug (drug-in-adhesives), excipients, permeation enhancers, rate controlling membrane, backing membrane that does not allow the drug to permeate and temporary release liner to attain optimal functional TDDS system, overcoming the potential challenges. Nanocarrier-based delivery systems(e.g. nanoparticles, nano-lipids, nanoemulsions, and nanocrystals) present a promising way to promote transdermal delivery with local effects over extended periods for drugs such as terbinafine and acyclovir [7,19].

This review details the challenges associated with formulating TDDS for the treatment of chronic skin infections (Figure 1). It provides insights into the physiobiological and physicochemical factors affecting transdermal drug permeation, the current drawbacks of the TDDS, as well as future formulation strategies for enhancing drug delivery efficiency. By discussing these crucial aspects, this review aims to drive future research efforts in optimizing TDDS against chronic dermatological infections.