SINGAPORE—Nanyang Technological University, Singapore (NTU) and the Agency for Science, Technology and Research (A*STAR) have showed that applying “temporal pressure” to the skin of mice can create a new way to deliver drugs.
In a paper published in Science Advances, the researchers demonstrated that bringing together two magnets so that they pinch and apply pressure to a fold of skin led to short-term changes in the skin barrier—and specifically the formation of “micropores” underneath its surface. Tests showed that these micropores enabled drugs applied on the surface of the skin to diffuse through it more easily. Six times greater quantity of drug diffused through the skin of mice with the micropores, compared to the skin of mice not receiving the treatment.
The researchers believe that while conventional needles and microneedle injections damage the skin, the use of pressure on skin could pave the way towards painless transdermal delivery of drugs such as insulin. The project was inspired by the traditional Chinese medicine “tuina” therapy, in which physicians rub and apply pressure on skin and muscle tissue and apply a topical ointment, said the lead author of the paper, Dr. Daniel Lio. Lio conducted this research as part of his doctoral thesis at NTU’s School of Chemical and Biomedical Engineering, Interdisciplinary Graduate Program.
According to the paper, transdermal drug delivery (TDD) offers “a convenient and patient-friendly way for the treatment of both local disorders and diseases of other organs. It allows drugs to bypass the first pass metabolism while providing sustained and controlled delivery.” While TDD uses chemical, physical or biochemical enhancers to cross the skin barrier, existing platforms require high doses of chemical enhancers or sophisticated equipment, use fragile biomolecules, or are limited to certain types of drugs.
The researchers developed a methodology based on temporal pressure to enhance the penetration of all kinds of drugs, from small molecules to proteins and nanoparticles (up to 500 nm). By creating micropores on the epidermal layer through a temporal pressure treatment, the researchers achieved elevated expression of gap junctions and reduced expression of occluding tight junctions. They claimed that a 1-minute treatment of 0.28-MPa enables nanoparticles (up to 500 nm) and macromolecules (up to 20 kDa) to reach a depth of 430-μm into the dermal layer. For example, the delivery of insulin through topical application after the pressure treatment yields up to an 80-percent drop in blood glucose in diabetic mice.
Experimental results revealed that nanoparticles and insulin were effectively delivered through the skin of mice at molecular masses up to 20,000 daltons. That amount is 40 times the largest currently reported in the scientific literature for transdermal drug delivery via patches, which is 500 daltons. The amount of drug delivered via the temporal pressure method was comparable to the amount delivered by a microneedle patch 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 hypoglycemia, the new method can slowly deliver drugs over time without breaking the skin, thus causing less pain.
Experiments determined that 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. An increased expression of gap junctions enables the delivery of more molecules across the cell barrier, while tight junctions restrict the extracellular movement of molecules.
In the animal experiments, the researchers used two magnets to apply pressure on the mouse dorsal skin for one or five minutes, depending on how fast the drug delivery needed to be, before removing the magnets and applying the drug topically.
The researchers determined that when drugs need to be delivered more slowly or in smaller doses, one minute would be sufficient. For drugs that need to be delivered faster, more micropores would be needed, and five minutes would be needed. After drugs were left in the mice for 12 hours, the skin was imaged with fluorescent microscopy to see to what extent the drug had penetrated through the skin.
Prof. David Laurence Becker from NTU Lee Kong Chian School of Medicine and Skin Research Institute of Singapore summarized, “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. 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.”
