Transdermal delivery of macromolecule using sonophoresis with cavitation seed: In-vivo study

Sonophoresis which utilizes ultrasound for transdermal drug delivery (TDD), can increase the skin permeability and improve the efficiency of drug delivery to various drugs. In addition, the addition of microbubbles in sonophoresis accelerate and increase an efficiency of drug delivery. The cavitation induced by sonophoresis with microbubbles on the skin surface may cause disordering of the lipid bilayers and the formation of aqueous channels. However, commercial microbubble such as ultrasound contrast agents (UCA) have limitation for sonophoresis, because mixed microbubbles is uniformly positioned in water based solution, not on skin surface. Accordingly, we hypothesized that if the most of engineered microbubbles can be located on the skin surface, cavitation effect will be maximized for TDD. We propose an advanced concept microbubble specialized in sonophoresis as an alternative cavitation seed, which can be sank near skin surface by gravity. We manufactured the cavitation seed specialized in sonophoresis which consist of liquid phase perfluorohexane core. In order to make sure possibility of macromolecules delivery using sonophoresis with cavitation seed, we performed in vivo experiment using 150kDa of FITC-labeled dextran (FD). The delivered fluorescent into the skin was quantitatively analyzed by an optical imaging system and confocal microscope. In the results, FITC-labeled dextran, 150 kDa, was delivered to 600 μm depth under the skin, and average total flux in ROI was increased 6.4 fold in sonophoresis with cavitation seed group more than diffusion groups. In conclusion, simultaneous application of ultrasound and cavitation seed for TDD demonstrated high efficiency of TDD and possibility of macromolecule delivery into the skin. We confidently believe this technology has the potential in various fields related with TDD.