Skin patches are widely used for combating nicotine addiction or delivering contraceptive hormones, but few drugs are delivered in this way because not many approved chemicals are available to help therapeutics permeate skin. An approach for rapidly screening and identifying combinations of chemicals that can penetrate the skin could make medicine by patch, rather than needle or pill, more common. In the February issue of Nature Biotechnology, Samir Mitragotri and colleagues describe a large-scale screen that can find rare combinations of chemicals capable of transporting medicines across the skin, while minimizing irritation.

Skin, the largest organ of the human body, possesses very low permeability to the movement of foreign molecules across it, due to the hierarchical structure of the stratum corneum, a lipid-rich matrix with embedded corneocyte cells. Although the use of chemical penetration enhancers (CPEs) is a convenient way to overcome the stratum corneum barrier, only a few CPEs studied up to now induce therapeutic enhancement of drug transport; and when used at the concentrations necessary for penetration, the molecules are also potent irritants. However, two chemicals are better than one because each can act on a different layer of the skin, allowing smaller doses to be used.

The search for new families of potent and safe synergistic combinations of permeation enhancers (SCOPE) involved a number of individual enhancers chosen from older and newer CPEs. Eight distinct categories were represented, including anionic and cationic surfactants, fatty acids and esters, and azone-like compounds. SCOPE formulations are mixtures of known CPEs that show high potency on contact with the stratum corneum but a relative lack of irritation in the epidermis because of the differential retention of components in the stratum corneum. The discovery of these mixtures was enabled by an experimental tool that screens using measurements of skin conductivity — in vitro skin impedance guided high-throughput (INSIGHT) screening — which tested more than 5,000 putative synergistic mixtures using porcine skin as a model. INSIGHT is more than 100-fold more efficient than current tools. The leading hits from INSIGHT were evaluated in vitro for irritation potential; mixtures with high potency and low irritation potential were then tested for flux enhancement using candidate drugs, before in vivo testing for bioavailability and safety.

Two formulations were particularly good, specifically N-lauroyl sarcosine:sorbitan monolaurate 20 (NLS:S20) and sodium laureth sulphate:phenyl piperazine (SLA:PP). Both formulations increased the flux of macromolecules, such as leutinizing hormone releasing hormone and heparin, in vitro by 50- to 100-fold. The SLA:PP formulation also delivered leuprolide acetate to hairless rats without causing skin irritation, confirming the feasibility of using penetration enhancers for systemic delivery of macromolecules from a transdermal patch.