Development of a dual-frequency sonophoresis for enhanced skin permeability and efficient drug delivery

Effective transdermal drug delivery has long been a research focus, constrained by the skin's selective permeability, which limits the passage of drugs larger than 500 Daltons. Sonophoresis, employing low-frequency ultrasound waves, enhances skin permeability through transient cavitation, but its application faces two significant challenges: delivering large molecules and reducing prolonged treatment durations. This study introduces a novel dual-frequency sonophoresis designed to address these limitations. Through the integration of high-frequency ultrasound with low-frequency waves, a synergistic effect was generated, enhancing transient cavitation process. In few studies on dual-frequency systems, there has been challenges of large system size and long treatment duration. In our novel proposed system, the size was reduced by utilizing a piezoelectric disc operating at high frequency, and through a precise positioning relative to low-frequency ultrasonic horn, the synergistic effect was maximized, thus the treatment time was reduced. Initial tests employed single-frequency setup on aluminum foil, utilizing a two-level experimental design to maximize transient cavitation effects. The resulting optimal operating conditions were then applied to the dual-frequency system. Subsequent experiments were carried out on both aluminum foil and ex vivo guinea pig skin samples. It was observed that integration of high- and low- frequency ultrasound resulted in a remarkable 51-fold increase in skin permeation. Meanwhile, the penetration time was significantly reduced to four minutes in comparison with twenty minutes using single-frequency system. The obtained results highlighted the potential of our newly proposed dual-frequency sonophoresis to improve transdermal drug delivery efficiency by enhancing molecule transfer rates and minimizing treatment durations.