K. Yamamoto, A. Klossek, R. Schulz, T. Ohigashi, M. Weigand, R. Flesch, S. Ahlberg, F. Rancan, A. Vogt, U. Blume-Peytavi, P. Schrade, S. Bachmann, R. Haag, E. Fleige, M. Giulbudagian, M. Calderon, J. Lademann, S. Hedtrich, M. Schäfer-Korting, N. Kosugi, R. Netz and Eckart Ruehl
Physical Chemistry, Institute for Chemistry and Biochemistry, Freie Universitaet Berlin, Berlin, Germany
Topical drug delivery into skin probed by label-free spectromicroscopy is reported. The role of drug formulations and polymeric nanocarriers is evaluated regarding their penetration into deeper skin layers. Selective and high resolution detection (spatial resolution: <100 nm) of drugs and drug nanocarriers is accomplished by X-ray microscopy [1-3]. We report on recent results on the penetration of the anti-inflammatory drugs dexamethasone and tacrolimus that are topically applied to ex vivo human and murine skin samples as well as reconstructed human skin models. Drug solutions, formulations, as well as drugcontaining nanocarriers (core-multishell nanocarriers and pNIPAM-nanogels) have been investigated regarding their skin penetration, reflecting temporal and local changes in drug distributions as a function of depth. Nanocarriers can only penetrate the stratum corneum to the tight junction barrier. High spatial resolution studies permit to approach a molecular understanding of the penetration processes. These studies also allow us to determine the role of nanocarriers altering drug penetration properties. In the case of nanogels they also facilitate drug penetration into corneocytes. In addition, damage to the barriers is investigated, which is either induced by mechanical impact (tape-stripping) or by inflammatory skin diseases (oxazolone-induced psoriasis in murine skin). The experimental results are modeled by the diffusion of drugs using Fokker-Planck equation . This provides evidence for a diffusion and free energy barrier that controls the drug transport via the stratum corneum into the viable epidermis. Complimentary results from stimulated Raman microscopy are briefly reported allowing us to derive 3-dimensional maps of the compounds under study. Focus of these studies was put on the distribution of lipids and proteins [5, 6]. It is shown that proteins and lipids are affected by drug delivery processes depending on the drug formulation penetrating the skin samples.
Financial support by German Research Foundation and SFB 1112 is gratefully acknowledged.
Keywords: Drug delivery, spectromicroscopy, skin, label-free detection.
 K. Yamamoto et al., Anal. Chem. 61, 6173-6179 (2015).
 K. Yamamoto et al., J. Control. Release 242, 64 (2016).
 K. Yamamoto et al., Eur. J. Pharm. Biopharm, accepted (2017). DOI: 10.1016/j.ejpb.2016.12.005
 R. Schulz et al., Proc. Nat. Acad. Sci. 114, 3631 (2017).
 M. Giulbudagian et al., J. Control. Release 243, 323 (2016).
 A. Klossek et al., Eur. J. Pharm. Biopharm, accepted (2017). DOI: 10.1016/j.ejpb.2016.11.001