In a pinch: drug delivery through the skin

Singaporean scientists have shown that bringing together two magnets, so that they pinch and apply pressure to a fold of skin, leads to short-term changes in the skin barrier and specifically the formation of ‘micropores’ underneath its surface. Measuring about 3 µm in area, these micropores allow drugs applied on the surface of the skin to diffuse through it more easily.

The study was conducted by researchers from Nanyang Technological University, Singapore (NTU Singapore) and the Agency for Science, Technology and Research (A*STAR). It has been published in the journal Science Advances.

“Our research project was first inspired by the traditional Chinese medicine ‘tuina’ therapy, where physicians rub and apply pressure on skin and muscle tissue and apply a topical ointment,” explained lead author Dr Daniel Lio, who did the research as part of his doctoral thesis at NTU and is now working at A*STAR’s Enterprise Group.

Going a step further, the joint team tested the delivery of insulin through the skin of mice using the new method. Experimental results showed that nanoparticles and insulin were effectively delivered through the skin of mice at molecular masses up to 20,000 daltons. This mass is 40 times the largest currently reported in the scientific literature for transdermal drug delivery (ie, via patches), which is 500 daltons.

The amount of drug delivered via the temporal pressure method was also comparable to the amount delivered by a microneedle patch — dozens of needles smaller than the width of a human hair made from biocompatible compounds, commonly used to deliver small amounts of drugs through the skin over time.

Compared to conventional injection where the skin has to be penetrated and there is a risk of a hypoglycaemia effect — when the injected insulin acts too fast and the patient gets dizzy — the new method is able to slowly deliver drugs over time without breaking the skin, thus causing less pain.

The team also found that with their method, cells in the skin layer (epidermis) were observed to have an increase in the number of ‘gap junctions’ and a reduction in ‘tight junctions’. These junctions control the amount of molecules being delivered between the cells: if there is an increased expression of gap junctions, more molecules can be delivered across the cell barrier, while tight junctions restrict the extracellular movement of molecules.

In animal experiments, two magnets were used to apply pressure on the mouse dorsal skin for 1 or 5 min, depending on how fast the drug delivery is needed. The team hypothesised that 1 min would be sufficient for drugs that need to be delivered more slowly or in smaller doses, while more micropores — and therefore more time — would be required for drugs to be delivered faster.

After the magnets were removed, the drug was topically applied like a cream; 12 hours later, the skin was imaged with fluorescent microscopy to see to what extent the drug had penetrated through the skin. The team compared three types of skin: skin that received pressure treatment, skin which had not and skin which had drugs delivered through microneedles.

Skin that received pressure treatment had similar amounts of drug delivered through the skin to that found with a microneedle patch, while skin that did not receive the pressure treatment had significantly less drug delivered. Micropores were also observed to disappear a day after they were formed, which suggests that the skin cells have filled up the gaps.

NTU Professor David Laurence Becker said the method could alleviate the need for diabetes patients to inject insulin multiple times daily using conventional needles and syringes.

“Patients who have to inject drugs daily, such as insulin, are constantly asking whether there is another way to deliver their medicines that doesn’t involve hurting or penetrating the skin,” Prof Becker said. “Our new findings hold promise for them and we hope that we can refine this method so that one day it may be possible to deliver enough drugs through the skin via a patch and to rid them of their daily injections.”

The researchers have since filed a patent for their pressure device, which looks like a vice-like clamp for the skin, through NTU’s innovation and enterprise company, NTUitive. They are also currently carrying out further experiments to refine the drug delivery mechanism.

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