Sonophoresis with ultrasound contrast agents in transdermal drug delivery: In vivo experimental study

Abstract

Sonophoresis for transdermal drug delivery(TDD) generally uses relatively low frequency ultrasound (e.g., <;100 kHz). The main mechanism of sonophoresis is related to cavitation of bubbles trapped between ultrasound transducer and skin. Thus, enhancement of cavitation can lead to effective TDD. In this presentation, the efficacy of TDD with ultrasound contrast agent(UCA) was tested by animal experiments. FITC(Fluorescein isothiocyanate) Dextran(the concentration of 1g/80ml, molecular weight of 4k, 20k, 150k) with 0.1% UCA was used as the drug to be delivered through the skin. Two type of UCAs, Sonovue® and Definity®, were used in the experiments at 2.47 MHz and 1.12 MHz, respectively, according to their resonance frequency. Ultrasound is applied on the back of rat whose hair is removed. One spot was always reserved for the control experiment and the other spot was used for three different conditional experiments. The first condition was ultrasound at two different frequencies without UCA, the second condition was 1.12 MHz ultrasound with Definity®, and the third condition was 2.24 MHz ultrasound with Sonovue®, respectively. A pulse of 10 msec with 1% duty cycle was used at the acoustic pressure of 1 MPa for 30 minutes in all the experiments. The efficacy of sonophoresis with 0.1% UCAs was quantitatively analyzed with optical imaging system (IVIS® Spectrum) which was used to count photons emitted from fluorescein at the wavelength of 520nm. Histological analysis of the rat skin exposed to sonophoresis was performed to assess the safety. Application of ultrasound without UCA increases the photon count approximately 20.8% , 13.6%, 17.4% at 1.12 MHz and 6.3%, 22.5%, 22.3% at 2.47 MHz for three different Dextran of 4k , 20k , 150k , respectively. With UCA presence, the increments of photon counts were approximately 53.6%, 47.3%, 47.8% at 1.12 MHz and 48.9%, 50.8%, 44.4% at 2.47 MHz for the same three Dextran, respectively. According to the histological analysis, no damage to the tissue. Sonophoresis for TDD was safely and more effectively conducted with the aid of UCA, even though cavitation is a stochastic event. Optimization of ultrasound parameters such as intensity, duty cycle, concentration of UCA is expected to enhance sonophoresis. We believe sonophoresis with UCA has broad applications for various skin diseases.