Using Ultrasound Waves to Enhance Skin’s Permeability to Drugs

This technology could pave the way for noninvasive drug delivery or needle-free vaccinations, according to the researchers.

“This could be used for topical drugs such as steroids--cortisol, for example--systemic drugs and proteins such as insulin, as well as antigens for vaccination, among many other things,” said Carl Schoellhammer, a Massachusetts Institute of Technology (MIT; Cambridge, MA, USA) graduate student in chemical engineering and one of the lead authors of a recent article on the new system.

Ultrasound can boost skin permeability by lightly wearing away the top layer of the skin, an effect that is transient and pain-free. In an article published online August 22, 2012, in the Journal of Controlled Release, the researchers found that applying two separate beams of ultrasound waves--one of low frequency and one of high frequency--can consistently boost permeability across a region of skin more quickly than using a single beam of ultrasound waves.

Senior authors of the paper are Dr. Daniel Blankschtein, a professor of chemical engineering at MIT, and Dr. Robert Langer, another professor at MIT. When ultrasound waves travel through a fluid, they create tiny bubbles that move haphazardly. Once the bubbles reach a specific size, they become unstable and implode. Surrounding fluid flows into the empty space, generating high-speed “microjets” of fluid that generate microscopic abrasions on the skin. In this instance, the fluid could be water or a liquid containing the drug to be delivered.

Recently, researchers working to enhance transdermal drug delivery have focused on low-frequency ultrasound, because the high-frequency waves do not have enough energy to make the bubbles pop. However, those systems usually produce abrasions in scattered, random spots across the treated area.

In the new study, the MIT investigators discovered that by incorporating high and low frequencies offers better results. The high-frequency ultrasound waves generate additional bubbles, which are popped by the low-frequency waves. The high-frequency ultrasound waves also limit the lateral movement of the bubbles, keeping them contained in the desired treatment area, and creating more uniform abrasion, according to Dr. Schoellhammer.

“It’s a very innovative way to improve the technology, increasing the amount of drug that can be delivered through the skin and expanding the types of drugs that could be delivered this way,” said Dr. Samir Mitragotri, a professor of chemical engineering at the University of California at Santa Barbara, who was not part of the research team.

The researchers assessed their new approach using pig skin and found that it boosted permeability much more than a single-frequency system. First, they delivered the ultrasound waves, and then applied either glucose or inulin (a carbohydrate) to the treated skin. Glucose was absorbed 10 times better, and inulin four times better. “We think we can increase the enhancement of delivery even more by tweaking a few other things,” Dr. Schoellhammer stated.

Such a system could be used to deliver any type of drug that is currently given by capsule, potentially increasing the dosage that can be administered. It could also be used to deliver drugs for skin disorders such as acne or psoriasis, or to enhance the activity of transdermal patches already in use, such as nicotine patches.

Ultrasound transdermal drug delivery could also offer a noninvasive way for diabetics to control their blood sugar levels, through short- or long-term delivery of insulin, according to the scientists. Following ultrasound treatment, improved permeability can last up to 24 hours, allowing for delivery of insulin or other drugs over an extended period of time.

These devices also hold potential for administering vaccines, according to the researchers. It has already been shown that injections into the skin can induce the type of immune response necessary for immunization, so vaccination by skin patch could be a needle-free, pain-free way to deliver vaccines. This would be particularly helpful in developing countries, because the training required to administer such patches would be less intensive than that needed to give injections. The researchers are now examining this line of research.

They are also working on a prototype for a handheld ultrasound device, and on ways to boost skin permeability even more. Safety tests in animals would be needed before human tests can begin. The US Food and Drug Administration (FDA) has earlier approved single-frequency ultrasound transdermal systems based on Drs. Langer and Blankschtein’s research, so the researchers are hopeful that the improved system will also pass the safety tests.

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Massachusetts Institute of Technology