Exploitation of sub-micron cavitation nuclei to enhance ultrasound-mediated transdermal transport and penetration of vaccines.

Inertial cavitation mediated by ultrasound has been previously shown to enable skin permeabilisation for transdermal drug and vaccine delivery, by sequentially applying the ultrasound then the therapeutic in liquid form on the skin surface. Using a novel hydrogel dosage form, we demonstrate that the use of sub-micron gas-stabilising polymeric nanoparticles (nanocups) to sustain and promote cavitation activity during simultaneous application of both drug and vaccine results in a significant enhancement of both the dose and penetration of a model vaccine, Ovalbumin (OVA), to depths of 500µm into porcine skin. The nanocups themselves exceeded the penetration depth of the vaccine (up to 700µm) due to their small size and capacity to 'self-propel'. In vivo murine studies indicated that nanocup-assisted ultrasound transdermal vaccination achieved significantly (p<0.05) higher delivery doses without visible skin damage compared to the use of a chemical penetration enhancer. Transdermal OVA doses of up to 1µg were achieved in a single 90-second treatment, which was sufficient to trigger an antigen-specific immune response. Furthermore, ultrasound-assisted vaccine delivery in the presence of nanocups demonstrated substantially higher specific anti-OVA IgG antibody levels compared to other transdermal methods. Further optimisation can lead to a viable, safe and non-invasive delivery platform for vaccines with potential use in a primary care setting or personalized self-vaccination at home.

Cavitation-enhanced delivery of insulin in agar and porcine models of human skin.

Ultrasound-assisted transdermal insulin delivery offers a less painful and less invasive alternative to subcutaneous insulin injections. However, ultrasound-based drug delivery, otherwise known as sonophoresis, is a highly variable phenomenon, in part dependent on cavitation. The aim of the current work is to investigate the role of cavitation in transdermal insulin delivery. Fluorescently stained, soluble Actrapid insulin was placed on the surface of human skin-mimicking materials subjected to 265 kHz, 10% duty cycle focused ultrasound. A confocally and coaxially aligned 5 MHz broadband ultrasound transducer was used to detect cavitation. Two different skin models were used. The first model, 3% agar hydrogel, was insonated with a range of pressures (0.25-1.40 MPa peak rarefactional focal pressure-PRFP), with and without cavitation nuclei embedded within the agar at a concentration of 0.05% w/v. The second, porcine skin was insonated at 1.00 and 1.40 MPa PRFP. In both models, fluorescence measurements were used to determine penetration depth and concentration of delivered insulin. Results show that in agar gel, both insulin penetration depth and concentration only increased significantly in the presence of inertial cavitation, with up to a 40% enhancement. In porcine skin the amount of fluorescent insulin was higher in the epidermis of those samples that were exposed to ultrasound compared to the control samples, but there was no significant increase in penetration distance. The results underline the importance of instigating and monitoring inertial cavitation during transdermal insulin delivery.

Exploitation of acoustic cavitation-induced microstreaming to enhance molecular transport.

Ultrasound (US) exposure of soft tissues, such as the skin, has been shown to increase permeability, enhancing the passage of drug molecules via passive processes such as diffusion. However, US regimes have not been exploited to enhance active convective transport of drug molecules from a donor layer, such as a gel, into another medium. A layered tissue-mimicking material (TMM) was used as a model for a drug donor layer and underlying soft tissue to test penetration of agents in response to a range of US parameters. Influence of agent molecular mass (3-2000 kDa), US frequency (0.256/1.1 MHz) and US pressure (0-10 MPa) on transport was characterised. Agents of four different molecular sizes were embedded within the TMM with or without cavitation nuclei (CN) and US applied to achieve inertial cavitation. Post-insonation, samples were analysed to determine the concentration and penetration distance of agent transported. US exposure substantially enhanced transport. At both US frequencies, enhancement of transport was significantly higher (p < 0.05) above the cavitation threshold, and CN reduced the pressure at which cavitation, and therefore transport, was achieved. Acoustic cavitation activity and related phenomena was the predominant transport mechanism, and addition of CN significantly enhanced transport within a range of clinically applicable acoustic pressures. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci.