With an increasing number of large-molecule drugs on the market, painless needle-free drug delivery is an attractive goal. For small molecules, such as nicotine or contraceptive hormones, delivery through the skin is widely used, but this method depends on a limited number of approved chemical penetration enhancers (CPEs) to help therapeutics permeate skin.

The use of CPEs is a convenient way to overcome the skin barrier, but when used at the concentrations necessary for penetration, these molecules are also potent irritants. In a recent issue of Proceedings of the National Academy of Sciences, Mitragotri and colleagues identify design principles for the use of CPEs, finding that it is possible to separate beneficial penetration properties from irritation.

Skin, the largest organ of the human body, possesses very low permeability to the movement of foreign molecules across it because of the hierarchical structure of the stratum corneum (SC), a lipid-rich matrix with embedded corneocyte cells. Although more than 350 molecules have been identified that perturb the SC barrier to facilitate molecular delivery, safety concerns relating to the health of the skin membrane remains the bottleneck for their use in the development of transdermal therapies.

Using Fourier transform infrared spectroscopy, the authors showed that existing CPEs perturb the skin barrier via extraction or fluidization of the lipid bilayers. By contrast, the irritation response correlated with the denaturation of SC proteins. Of the 10 diverse chemical functionalities analysed, two classes emerged. In the first class, the enhancement ratio (ER; measurement of potency) increased proportionally with the irritation potential (IP; measurement of toxicity). In the second class, the ER did not show a good correlation with the IP. Using 35 molecular parameters that contributed to the ER/IP ratio, the authors defined a descriptor for the overall quality of a CPE. These studies reveal fundamental constraints in optimizing the balance between potency and safety.

However, using the structural understanding gained from previous experiments, the authors used in silico screening followed by in vitro testing to identify a number of improved CPEs. They selected the best CPEs from the 10 different chemical classes and mutated them to generate variants. A significant number of the mutants were better fluidizers. The lead candidate, stearyl methacrylate, was tested in vitro, and yielded a predicted ER/IP value of about 12, which is substantially higher than the commonly used oleic acid with a value of 3.8.

With further safety testing, these second-generation molecules could broaden the repertoire of CPEs available for transdermal applications in the future.