Ultrasonic Transdermal Delivery System with Acid-Base Neutralization-Generated CO₂ Microbubble Cavitation

Transdermal delivery systems provide a convenient noninvasive approach for drug administration through the skin, and they have been widely developed for in-home health care. The stratum corneum of the skin surface limits drug penetration, but ultrasound (US)-stimulated microbubble (MB) cavitation can enhance skin permeability to promote transdermal drug penetration. However, the specific materials and complex fabrication of MBs influence the scope of application in transdermal delivery systems. Hence, we studied the mixture of citric acid and NaHCO₃ agents to generate shell-free CO₂-MBs by acid-base neutralization effect. The generation rate of CO₂-MBs was 36.3 ± 10 MBs/s and the mean size was 110 ± 14 μm under US sonication (3.1 MHz, 0.5 W/cm², 50% duty cycle, 1 min). The penetration of Evans blue and FITC-conjugated hyaluronic acid in rat abdominal skin by CO₂-MB cavitation improved 2.4 ± 0.3 and 2.1 ± 0.1 fold, respectively. The penetration depth of Evans blue (27.1 ± 5.1 μm) reached the epidermal layer, providing the potential for inducing transcutaneous immunization. Therefore, we proposed a simple and self-operating ultrasonic transdermal delivery system with CO₂-MB cavitation to improve drug penetration for in-home health care development.