Biodegradable calcium carbonate carriers for the topical delivery of clobetasol propionate.

Inflammatory dermatoses represent a global problem with increasing prevalence and recurrence among the world population. Topical glucocorticoids (GCs) are the most commonly used anti-inflammatory drugs in dermatology due to a wide range of their therapeutic actions, which, however, have numerous local and systemic side effects. Hence, there is a growing need to create new delivery systems for GCs, ensuring the drug localization in the pathological site, thus increasing the effectiveness of therapy and lowering the risk of side effects. Here, we propose a novel topical particulate formulation for the GC clobetasol propionate (CP), based on the use of porous calcium carbonate (CaCO3) carriers in the vaterite crystalline form. The designed carriers contain a substantially higher CP amount than conventional dosage forms used in clinics (4.5% w/w vs. 0.05% w/w) and displayed a good biocompatibility and effective cellular uptake when studied in fibroblasts in vitro. Hair follicles represent an important reservoir for the GC accumulation in skin and house the targets for its action. In this study, we demonstrated successful delivery of the CP-loaded carriers (CP-CaCO3) into the hair follicles of rats in vivo using optical coherent tomography (OCT). Importantly, the OCT monitoring revealed the gradual intrafollicular degradation of the carriers within 168 h with the most abundant follicle filling occurring within the first 48 h. Biodegradability makes the proposed system especially promising when searching for new CP formulations with improved safety and release profile. Our findings evidenced the great potential of the CaCO3 carriers in improving the dermal bioavailability of this poorly water-soluble GC.

In vivo skin optical clearing efficacy quantification of clinically compatible agents using line-field confocal optical coherence tomography.

Significance: The clinical use of optical methods for in vivo skin imaging is limited by skin strong scattering properties, which reduce image contrast and probing depth. The efficiency of optical methods can be improved by optical clearing (OC). However, for the use of OC agents (OCAs) in a clinical setting, compliance with acceptable non-toxic concentrations is required. Aim: OC of in vivo human skin, combined with physical and chemical methods to enhance skin permeability to OCAs, was performed to determine the clearing-effectiveness of biocompatible OCAs using line-field confocal optical coherence tomography (LC-OCT) imaging. Approach: Nine types of OCAs mixtures were used in association with dermabrasion and sonophoresis for OC protocol on three volunteers hand skin. From 3D images obtained every 5 min for 40 min, the intensity and contrast parameters were extracted to assess their changes during the clearing process and evaluate each OCAs mixture's clearing efficacy. Results: The LC-OCT images average intensity and contrast increased over the entire skin depth with all OCAs. The best image contrast and intensity improvement was observed using the polyethylene glycol, oleic acid, and propylene glycol mixture. Conclusions: Complex OCAs featuring reduced component concentrations that meet drug regulation-established biocompatibility requirements were developed and proved to induce significant skin tissues clearing. By allowing deeper observations and higher contrast, such OCAs in combination with physical and chemical permeation enhancers may improve LC-OCT diagnostic efficacy.

Impact of optical clearing on ex vivo human skin optical properties characterized by spatially resolved multimodal spectroscopy.

A spatially resolved multimodal spectroscopic device was used on a two-layered "hybrid" model made of ex vivo skin and fluorescent gel to investigate the effect of skin optical clearing on the depth sensitivity of optical spectroscopy. Time kinetics of fluorescence and diffuse reflectance spectra were acquired in four experimental conditions: with optical clearing agent (OCA) 1 made of polyethylene glycol 400 (PEG-400), propylene glycol and sucrose; with OCA 2 made of PEG-400 and dimethyl sulfoxide (DMSO); with saline solution as control and a "dry" condition. An increase in the gel fluorescence back reflected intensity was measured after optical clearing. Effect of OCA 2 turned out to be stronger than that of OCA 1, possibly due to DMSO impact on the stratum corneum keratin conformation. Complementary experimental results showed increased light transmittance through the skin and confirmed that the improvement in the depth sensitivity of the multimodal spectroscopic approach is related not only to the dehydration and refractive indices matching due to optical clearing, but also to the mechanical compression of tissues caused by the application of the spectroscopic probe.

Optimized skin optical clearing for optical coherence tomography monitoring of encapsulated drug delivery through the hair follicles.

Hair follicles (HF) represent a drug delivery reservoir for improved treatment of skin disorders. Although various particulate systems play an important role in HF-targeting, their optical monitoring in skin is challenging due to strong light scattering. Optical clearing is an effective approach allowing the increasing of particle detection depth in skin. The enhancement of optical probing depth (OPD) and optical detection depth (ODD) of particle localization using optical coherence tomography (OCT) was evaluated under application of various optical clearing agents (OCAs) together with skin permeability enhancers ex vivo in rats. Efficient OPD increasing was demonstrated for all investigated OCAs. However, skin dehydration under action of hyperosmotic agents led to the worsening of OCT-contrast in dermis decreasing the ODD. Lipophilic agents provided optical clearing of epidermis without its dehydration. The highest ODD was obtained at application of a PEG-400/oleic acid mixture. This OCA was tested in vivo showing beneficial ODD and OPD enhancement.

Carbon determination in carbon-manganese steels under atmospheric conditions by Laser-Induced Breakdown Spectroscopy.

The most sensitive lines of carbon, used nowadays for its determination in steels by laser-induced-breakdown spectroscopy (LIBS), are at vacuum UV and, thereby, LIBS potential is significantly reduced. We suggested the use of the C I 833.51 nm line for carbon determination in low-alloy steels (c(C)~0.186-1.33 wt.%) in air. Double-pulse LIBS with the collinear scheme was performed for maximal enhancement of a carbon emission signal without substantial complication of experimental setup. Since this line is strongly broadened in laser plasma, it overlapped with the closest iron lines greatly. We implemented a PCR method for the construction of a multivariate calibration model under spectral interferences. The model provided a RMSECV = 0.045 wt.%. The predicted carbon content in the rail templet was in an agreement with the reference value obtained by a combustion analyzer within the relative error of 6%.

Automatic identification of emission lines in laser-induced plasma by correlation of model and experimental spectra.

We have applied an algorithm to automatically identify emission lines in laser-induced breakdown spectrometry (LIBS). A Q-switched Nd:YAG laser at 355 nm was used to ablate a high-alloy stainless steel sample. The algorithm was implemented by three parts: simulation of the set of spectra corresponding to different temperature (T) and electron density (N(e)), searching the best correlated pair of a model spectrum and an experimental one, and attributing the peaks with certain lines. In order to construct the model spectra, we used the parameters of atomic and ionic lines, levels, the mechanisms of the broadening of spectral lines, and the selected parameters of the spectrograph. The highest correlation coefficient between the model and the experimental spectrum was 0.943 for T = 0.675 eV and lg(N(e)) = 16.7 cm(-3). More than 40 emission lines were labeled automatically in the spectral region 393.34-413.04 nm.