A translational approach to predicting small molecule drug permeation through microneedle-treated skin

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PROJECT SUMMARY / ABSTRACT Transdermal drug delivery has many benefits including ease of product application for patients and more consistent plasma drug concentrations compared to oral or IV dosing. However, many active pharmaceutical ingredients (APIs) do not meet the strict physicochemical properties needed to permeate through the hydrophobic outer skin layer. For APIs that cannot adequately absorb through skin, microneedles (MNs) temporarily increase skin permeability through formation of epidermal micropores. There are two major routes of API transport to consider with MN treatment: micropores (a hydrophilic environment), and intact skin around the micropores (a hydrophobic environment). Effects of API properties and formulation are well understood for delivery through intact skin, but they need to be systematically considered for MN delivery because of the introduction of the second parallel transport pathway (micropores). In vivo micropore closure time and human skin characteristics also impact API delivery with MNs, and these variables cannot be well simulated in vitro. The long-term goal of this work is to improve API delivery and treatment options for a wide range of health conditions through development of innovative MN dosage forms. The goal for the next 5 years is to determine significant in vitro and in vivo factors impacting absorption of small molecule APIs through MN-treated skin. We will use in vitro permeation tests and in vivo pharmacokinetics studies (in animals and humans) to answer key questions about how API properties, formulation, and in vivo skin characteristics impact permeability and flux through micropore vs. intact skin pathways. The main physicochemical characteristics we will initially investigate include ionization/charge, logP, and pKa. Permeation will be examined in vitro under heated vs non-heated conditions (heat can synergistically enhance skin API permeation), and MN properties (length, number) will be examined for effects on permeation. This will give a mechanistic understanding of the API and MN properties having the greatest impact on micropore permeation. Pharmacokinetics studies in guinea pigs will be completed so that in vivo factors impacting permeation can be assessed and compared to in vitro predictions. A second major area of study will involve pharmacokinetics studies in healthy human subjects. We will enroll a cohort of subjects >50 years of age, along with younger (<50 yrs) control subjects so we can 1) correlate age-related micropore closure estimates with API absorption, and 2) study age-related skin changes on MN API delivery. The combined in vitro and in vivo studies will maintain the high clinical relevance of the work. We expect to identify key physicochemical properties and increase our understanding of structure-permeability relationships and biological aspects impacting API permeability with MNs. This will generate fundamental knowledge that can result in direct clinical applications and supports the NIGMS mission in the areas of drug delivery, absorption, transport, and kinetics.