A Multi-scale Model of Drug Delivery Through the Skin

Medicinal patches applied to the skin are an attractive route for drug delivery since they can release medicine slowly into the bloodstream and avoid being metabolized by the digestive system. Yet only a handful of medications have ever made it to market in patch form, largely because the stratum corneum, the skin’s top layer, acts as a barrier. A new multi-scale computational model describing how chemicals move through that layer could help change that, opening the door to development of patches for a wider variety of drugs. The work was published in the June 2009 Annals of Biomedical Engineering.


Only a very  small number of  transdermal drugs  have made it to market.“We believe that by separating the contributions from different levels of scale, the model can provide better insight about the barrier properties of the skin,” says Jee Rim, PhD, a postdoctoral researcher at the University of California, Los Angeles, who did the research in collaboration with pharmaceutical company Alza while he was at Stanford.


Rim’s model began on the micro level, with a molecular dynamics simulation of how a drug molecule diffuses along the middle of lipid bilayers like those in the stratum corneum. Since the lipid bilayers actually weave around impermeable cells called corneocytes, the next step was to consider the path the drug must take to avoid these cells and modify the diffusion coefficient (determined by the molecular dynamics simulations) to account for the behavior. The final step zoomed out to an even larger scale, modeling the effects of boundaries between the patch, the stratum corneum, and the rest of the epidermis.


“One of the insights gained from the study is that the stratum corneum acts as a regulating layer,” says Rim. The slow journey of molecules through the lipid labyrinth seems to be the main reason drugs delivered via patch keep such a stable concentration in the blood.


Experiments with cadaver skin showed similar diffusion parameters to the ones calculated by the model. Drugs moved somewhat slower through the skin samples than the model, which the authors think may be due to water content. “[A future goal] is to consider the effect of water more carefully,” says Rim. Other areas to pursue include studying in more detail how penetration enhancers, like oleic acid, enhance diffusion.


“This is a good example of how you can take calculations from a molecular level up into a more macro level and apply them to a practical drug delivery problem,” says Gerald Kasting, PhD, of the University of Cincinnati. He cautions that the model uses assumptions about the stratum corneum that have been challenged—including the idea that the corneocytes are impermeable to drugs, and that the lipid bilayers contain enough cross-connections that they can be treated as isotropic. Despite those criticisms, he says, “I think this is a wave of the future. As we remove some of the limiting assumptions made in the analysis, some very useful results are going to emerge.”

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