Abstract
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.
Highlights
The stratum corneum (SC) represents the greatest challenge for the penetration of active substances into the viable skin
The electron paramagnetic resonance (EPR) spectra of both vehicles are visually similar (Figure 1A). These spectra are a superposition of an intense central line and a weak, typical three-line spectrum of a nitroxide in solution (DxPCA in water shown in Figure 1B for reference)
The strong and approximately 10 G broad central line arises from spin–spin coupling between the densely packed DxPCA molecules within the nanocrystal formulation and the presence of DxPCA aggregates within the base cream
Summary
The stratum corneum (SC) represents the greatest challenge for the penetration of active substances into the viable skin. It is composed of 10 to 20 cell layers of coherent, coreless corneocytes, which are embedded in a lipid-enriched intercellular space, where ceramides, free fatty acids, and cholesterol constitute the main part, forming bilayer structures of 4 to 5 nm thickness. The topical application of drugs incorporated into a cream formulation is the most frequently used form of therapy for the treatment of skin diseases [3]. The efficiency of direct penetration of the lipid-rich SC is crucially determined by the exact properties of the diffusing drug, since it has been shown that the chemical structure affects solute interactions with lipid bilayers [6]
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