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Skin scan offers new insight into drug transport

A technique that can follow the progress of topical drugs as they penetrate skin could help to improve formulations, avoid drug wastage and reduce the risk of overdoses.

The laser spectroscopy method, known as coherent Raman scattering (CRS) microscopy, quickly yields information about the mechanism of drug transport, and how the formulation of topical medicines changes after they are applied. “That sort of information is not available by any other technique,” said Richard Guy of the University of Bath, speaking at the 9th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology in Lisbon, Portugal, on 3 April 2014.

Medicinal creams or gels are most often used to treat skin diseases or local inflammation, but it is a tough route for a drug to take. “The skin is a barrier, and it has not evolved for drug delivery,” said Professor Guy.

Drugs typically move slowly through the skin — particularly those that are lipophilic or have a large molecular weight — resulting in poor penetration. In many cases, just 1 per cent of the dose actually penetrates the skin. “We’re throwing away a lot of drug,” said Professor Guy. “And a drug which is exquisitely potent, but has no flux across the skin, is no use at all.”

Conventional techniques to assess topical drug uptake include monitoring physiological effects such as vasoconstriction, measuring bloodstream concentrations or taking biopsies. But these methods may not be relevant to the site of action of some drugs, and can be labour intensive.

CRS offers a quicker, less invasive alternative. It involves shooting pulses of infrared light at the skin to excite chemical bonds in the drug molecules, the excipient and the surrounding tissue, each of which has a set of characteristic vibrational frequencies. Light scattered from the molecules and captured by a confocal microscope reveals the distribution of each compound at different levels through the skin, to a depth of about 60µm.

Getting under my skin

Professor Guy’s team has tested the technique on topical drugs such as ketoprofen and ibuprofen, which are typically delivered in a gel containing ethanol and propylene glycol. In tests on mouse and pig skin, they found that propylene glycol travels through the skin much more quickly than the drug, partly by zooming through hair shafts.

With less propylene glycol remaining at the surface, the concentration of the drug rises and it crashes out as a solid. CRS showed that crystals of drug form on the surface within 30 minutes of application, and the stranded ingredients can no longer enter the skin. “You’re left with a residual film of the drug,” Professor Guy told PJ Online. “People have suggested that before, but this is the first time it has been seen.”

These sorts of studies could help to develop better formulations. “What’s not typically done is to think about making that residual film efficient at continuing drug delivery,” said Professor Guy. It could also help to minimise the wide variation in the amounts of drugs absorbed from topical creams and gels, which poses a risk of overdose if the treatments are used regularly.

And it could also address the possible risk of others coming into contact with the residual drug film. Testosterone gels, for example, are used to treat impotency, and “if lots is left in a film, and then you transfer that by touch from one person to another, that could be a problem,” said Professor Guy.

Growing interest

Professor Guy’s team uses complex kit that covers a tabletop, so it is not ready for routine use yet. But JenLab, a company headquartered in Saarbrücken, Germany, sells a similar Raman scattering instrument for in vivo applications and also uses the technique in contract research.

Martin Weinigel, a research and development engineer at JenLab, told PJ Online that there is a growing interest from pharmaceutical companies in using this technique. “The big goal is to investigate the penetration of these substances in skin,” he said. “It’s not usually easy to investigate the penetration pathway.”

Raman scattering can also be used as a diagnostic technique, he added. “We’ve already applied it to investigate several skin diseases,” Mr Weinigel said.

Citation: The Pharmaceutical Journal DOI: 10.1211/PJ.2014.11137068

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