Influence of the skin barrier on the penetration of topically-applied dexamethasone probed by soft X-ray spectromicroscopy

Yamamoto, Kenji; Klossek, A.; Flesch, R.; Rancan, Fiorenza; Weigand, Markus; Bykova, Iuliia; Bechtel, Michael; Vogt, Annika; Blume-Peytavi, Ulrike; Schrade, Petra; Bachmann, S.; Hedtrich, Sarah; Schäfer‐Korting, Monika; Rühl, E.

doi:10.1016/j.ejpb.2016.12.005

Cited by 19 publications

(54 citation statements)

References 46 publications

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“…The cells of the SC, the corneocytes, are embedded in a structured, multilamellar lipid matrix consisting mainly of ceramides, cholesterol, and free fatty acids [50]. Our results confirm that the barrier function of the skin is decisive for the penetration kinetics of active substances [51,52]; the penetration time contributes only to a small part.…”

Section: Discussionsupporting

confidence: 68%

Nanocrystals for Improved Drug Delivery of Dexamethasone in Skin Investigated by EPR Spectroscopy

et al. 2020

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Nanocrystals represent an improvement over the traditional nanocarriers for dermal application, providing the advantages of 100% drug loading, a large surface area, increased adhesion, and the potential for hair follicle targeting. To investigate their advantage for drug delivery, compared to a base cream formulation, dexamethasone (Dx), a synthetic glucocorticoid frequently used for the treatment of inflammatory skin diseases, was covalently linked with the paramagnetic probe 3-(carboxy)-2,2,5,5-tetramethyl-1-pyrrolidinyloxy (PCA) to DxPCA. To investigate the penetration efficiency between these two vehicles, electron paramagnetic resonance (EPR) spectroscopy was used, which allows the quantification of a spin-labeled drug in different skin layers and the monitoring of the drug release. The penetration behavior in excised healthy and barrier-disrupted porcine skin was monitored by EPR, and subsequently analyzed using a numerical diffusion model. As a result, diffusion constants and free energy values in the different layers of the skin were identified for both formulations. Dx-nanocrystals showed a significantly increased drug amount that penetrated into viable epidermis and dermis of intact (factor 3) and barrier-disrupted skin (factor 2.1) compared to the base cream formulation. Furthermore, the observed fast delivery of the spin-labeled drug into the skin (80% DxPCA within 30 min) and a successive release from the aggregate unit into the viable tissue makes these nanocrystals very attractive for clinical applications.

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Section: Discussionsupporting

confidence: 68%

Nanocrystals for Improved Drug Delivery of Dexamethasone in Skin Investigated by EPR Spectroscopy

et al. 2020

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“…The quantity ln (I/I 0 ) is also called differential absorption, probing the relative change of the transmitted radiation through the sample. Most of dexamethasone is found in the stratum corneum and there specifically in the lipid lamellae between the corneocytes, as follows from high resolution studies [12]. A characteristic minimum in local drug concentration is found near the stratum granulosum, indicating that tight junctions are a further barrier for drug penetration [14], as was analyzed in detail by a transport model [13].…”

Section: Introductionmentioning

confidence: 90%

“…After treatment, the samples were cut into 1 mm x 2 mm pieces and were fixed in 2.5% glutaraldehyde (30 min at room temperature and overnight at 4 ºC). Subsequently, the samples were embedded using the standard protocol also applied in previous works [11,12,15]. Briefly, the samples were post-fixed by 1% OsO 4 and 0.8% K 4 [Fe(CN) 6 ] in 0.1 M cacodylate buffer.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, the penetration of the lipophilic drug dexamethasone by scanning X-ray microscopy was reported [11][12][13]. These studies yielded quantitatively systematic findings at different penetration times, so that the amount of drug in different skin layers was determined.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, stratum corneum removal by repeated tape stripping yielded an enhanced drug penetration behavior, which is due to the thinned stratum corneum. As a result, the drug penetrated in shorter time into deeper skin layers [12]. In addition, the drug transport was modified by core-multishell nanocarriers, which transport dexamethasone more slowly through the stratum corneum and release the drug in the lower part of this top skin layer [15].…”

Section: Introductionmentioning

confidence: 99%

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Soft X-ray microscopy for probing of topical tacrolimus delivery via micelles

Yamamoto

Klossek

Fuchs³

et al. 2019

European Journal of Pharmaceutics and Biopharmaceutics

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The penetration of topically applied tacrolimus formulated in micelles into murine skin is reported, measured by X-ray microscopy. Tacrolimus and micelles are probed for the first time by this high spatial resolution technique by element-selective excitation in the C 1s-and O 1s-regimes. This method allows selective detection of the distribution and penetration depth of drugs and carrier molecules into biologic tissues. It is observed that small, but distinct quantities of the drug and micelles, acting as a drug carrier, penetrate the stratum corneum. A comparison is made with the paraffin-based commercial tacrolimus ointment Protopic ® , where local drug concentrations show to be low. A slight increase in local drug concentration in the stratum corneum is observed, if tacrolimus is formulated in micelles, as compared to Protopic ® . This underscores the importance of the drug formulations for effective drug delivery. Time-resolved penetration shows presence of drug in the stratum corneum 100 min after formulation application, with penetration to deeper skin layers at 1000 min. High resolution micrographs give indications for a penetration pathway along the lipid membranes between corneocytes, but also suggest that the compound may penetrate corneocytes.

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How Qualification of 3D Disease Models Cuts the Gordian Knot in Preclinical Drug Development

Schäfer‐Korting

Zoschke

2020

Handbook of Experimental Pharmacology

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Influence of the skin barrier on the penetration of topically-applied dexamethasone probed by soft X-ray spectromicroscopy

Cited by 19 publications

References 46 publications

Nanocrystals for Improved Drug Delivery of Dexamethasone in Skin Investigated by EPR Spectroscopy

Nanocrystals for Improved Drug Delivery of Dexamethasone in Skin Investigated by EPR Spectroscopy

Soft X-ray microscopy for probing of topical tacrolimus delivery via micelles

How Qualification of 3D Disease Models Cuts the Gordian Knot in Preclinical Drug Development

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