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

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.

Particle Diffusivity and Free-Energy Profiles in Hydrogels from Time-Resolved Penetration Data

“…Extending a previously introduced method ( 29 , 30 , 31 ), spatially resolved diffusivity and free-energy profiles are estimated from experimentally measured concentration profiles. Numerical profiles are computed by discretizing the entire experimental setup from the glass bottom of the substrate to the air-water interface ( z bot to − z top in Fig.…”

“…We investigate the filtering function of hydrogels by theoretical analysis of time-resolved concentration profiles of the labeled dextran molecules as they penetrate into the hydrogel. The employed numerical method allows for simultaneous extraction of free-energy and diffusivity profiles from relative concentration profiles at different times and is a significant extension of earlier methods ( 29 , 30 , 31 ) because it does not require absolute concentration profiles but works with relative, i.e., arbitrarily normalized, concentrations. This is a crucial advantage because often fluorescence intensity profiles are subject to significant perturbation due to, e.g., laser light intensity fluctuations or fluorescence dye bleaching over the course of the experiment, and using relative concentrations makes the often-difficult conversion of measured intensity data into absolute particle concentrations obsolete.…”

Efficacy and Safety of Azelaic Acid Nanocrystal-Loaded In Situ Hydrogel in the Treatment of Acne Vulgaris

“…Previous research has shown that nanocrystals improve dermal bioavailability by increasing penetration through the skin. Due to the increased surface area of the nanocrystals, the dissolution rate increases, making it possible to maintain a large concentration gradient between the formulation and the skin, and thus forcing diffusion of the drug into the skin [ 12 , 13 , 14 ].…”

Hyaluronic Acid—Dexamethasone Nanoparticles for Local Adjunct Therapy of Lung Inflammation

“…Dexamethasone (DEX) is a synthetic glucocorticoid used in a wide range of diseases [ 1 , 2 , 3 , 4 ], particularly when related with lung, from occlusive airway conditions such as asthma [ 5 ] to maturation of foetus lung [ 6 ]. Recent studies report that DEX can be profitably applied to the treatment of acute respiratory distress syndrome [ 7 ] and could reduce deaths among patients with serious cases of COVID-19.…”

“…The formulation of DEX in nano-carriers could improve the delivery of this insoluble drug to the targeted epithelial tissue. Different types of nanotechnologies have been developed, including the conjugation of DEX with a polymeric chain or a lipidic structure [ 12 , 13 , 14 , 15 , 16 , 17 ], as well as its encapsulation in solid nanoparticles, its inclusion in a solid matrix or its formulation as a small crystal evenly coated with a polymer [ 3 , 10 , 18 ]. In particular, formulations where DEX is hosted in a controlled crystalline solid core of a nanostructure show both improved solubility with respect to raw dexamethasone and an increased residence time as compared to its water-soluble analogous, dexamethasone-phosphate.…”