Fungal infections are the fourth common cause of infection affecting around 50 million populations across the globe. Dermatophytes contribute to the majority of superficial fungal infections. Clotrimazole (CTZ), an imidazole derivative is widely preferred for the treatment of topical fungal infections. Conventional topical formulations enable effective penetration of CTZ into the stratum corneum, however, its low solubility results in poor dermal bioavailability, and variable drug levels limit the efficacy. The aim was to increase dermal bioavailability and sustain drug release, thereby potentially enhancing drug retention and reducing its side effects. This work evaluated the CTZ loaded solid lipid nanoparticles (SLN) consisting of precirol and polysorbate-80 developed using high pressure homogenization and optimized with QbD approach. Prior to release studies, CTZ-SLNs were characterized by different analytical techniques. The laser diffractometry and field emission scanning electron microscopy indicated that SLNs were spherical in shape with mean diameter of 450 ± 3.45 nm. DSC and XRD results revealed that the drug remained molecularly dispersed in the lipid matrix. The CTZ-SLNs showed no physicochemical instability during 6 months of storage at different temperatures. Further, the Carbopol with its pseudoplastic behavior showed a crucial role in forming homogenous and stable network for imbibing the CTZ-SLN dispersion for effective retention in skin. As examined, in-vitro drug release was sustained up to 24 h while ex-vivo skin retention and drug permeation studies showed the highest accumulation and lowest permeation with nanogel in comparison to pure drug and Candid® cream. Further, the in-vivo antifungal efficacy of nanogel suggested once-a-day application for 10 days, supported by histopathological analysis for complete eradication infection. In summary, the findings suggest, that nanogel-loaded with CTZ-SLNs has great potential for the management of fungal infections caused by Candida albicans.

Winlevi® (clascoterone) topical cream (1%, w/w) was approved by the U.S. FDA for the treatment of acne vulgaris in patients 12 years of age and older. The active ingredient, clascoterone, is not stable in physiological solutions and can hydrolyze to cortexolone at body temperature. Instability of clascoterone poses a significant challenge in accurately assessing the rate and extent of clascoterone permeation in vitro. Therefore, the purpose of this study was to develop an in vitro skin permeation test (IVPT) method, and a robust analytical method, that can minimize hydrolyzation of clascoterone during the study for quantification of clascoterone. Two IVPT methods, using either vertical diffusion cells or flow-through cells, were developed and compared to evaluate in vitro permeation of clascoterone from Winlevi. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to monitor the level of clascoterone and cortexolone in the IVPT samples. The analytical method features a 2-min high-throughput analysis with good linearity, selectivity, and showed a lower limit of quantitation (LLOQ) of 0.5 ng/mL for both clascoterone and cortexolone. The in vitro skin permeation of clascoterone and cortexolone was observed as early as 2 h in both IVPT methods. A substantive amount of clascoterone was found to hydrolyze to cortexolone when using the vertical static diffusion cells with aliquot sampling. Conversely, degradation of clascoterone was significantly minimized when using the flow-through diffusion cells with fractional sampling. The data enhanced our understanding of in vitro permeation of clascoterone following topical application of the Winlevi topical cream, 1% and underscores the importance of IVPT method development and optimization during product development.

Trazodone is a triazolpyridine derivative approved for the treatment of depression, and currently marketed as oral formulations. The transdermal administration of this drug could reduce side effects, related to peak plasma concentration, and improve patient adherence due to a reduced administration frequency. The aims of this work were: (a) the evaluation of the effect of pH vehicle and permeation enhancers on trazodone permeability across porcine skin ex-vivo; (b) the development and optimization of a transdermal drug delivery system containing trazodone hydrochloride. From the results obtained, it was found that the effect of pH of the vehicle on the permeation of trazodone across the skin is quite complex, because it influences both solubility and partitioning and that the presence of fatty acids in the vehicle has a notable effect on permeation (the enhancement factor obtained was approx. 100). For both the fatty acid selected (oleic and lauric) a parabolic relationship between the transdermal flux and the concentration was found, with an optimum activity in the range 2-3 %. In the second part of the work, different patches were prepared and tested ex-vivo. Overall, the results obtained seem to highlight that drug loading, rather than the components of the adhesive matrix, plays the most relevant role for the permeation of trazodone. The addition of lauric acid, which produced a considerable enhancement in solution, was not effective when included in the patch. The obtained data are promising although probably not clinically relevant for the treatment of depression, but might be interesting for the treatment of insomnia and anxiety disorder, which require much lower doses.

Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.

The in vitro permeation testing (IVPT) of topical products is performed across the human cadaver skin, which is stored frozen for a prolonged duration. The cryo-preservation technique is not economical and is a cumbersome process. Moreover, prolonged skin preservation in a frozen state and frequent freeze-thawing are known to affect the integrity of the skin barrier. Therefore, lyophilization was explored as an alternative to protect the skin tissue from microbial contamination and degeneration. Notably, the project\'s objective was to investigate the impact of the freeze-drying process on the skin\'s barrier properties. The morphometrics of the lyophilized skin were measured. Histological studies did not reveal any notable changes in the organization and intactness of the layers due to the freeze-drying process. The biophysical attributes of the skin, such as transepidermal water evaporation rate and transepidermal electrical resistivity (TEER), were not significantly different between the control skin (not subjected to the freeze-drying process) and the freeze-dried skin (FDS). The permeability of caffeine, a hydrophilic model permeant, and nicotine, a lipophilic model permeant, were consistent across the control and the FDS. It is evident from the studies that the lyophilization process did not significantly impact the barrier properties and permeability of the skin.

Aim: Insulin therapy require self-administration of subcutaneous injection leading to painful and inconvenient drug therapy. The aim is to fabricate nanoemulsion (NE) based insulin loaded microneedles with improved bioavailability and patient compliance. Materials & methods: Different ratios of polyvinyl alcohol and polyvinylpyrrolidone as polymers were prepared through micro-molding technique for microneedles. Characterization of were performed using scanning electron microscope, differential scanning calorimetry, Fourier-transform infrared spectroscopy and circular dichroism. Mechanical strength, hygroscopicity and pain perception of these microneedles were also evaluated. In vitro release, permeation and in vivo PK/PD study of NE-based microneedles were conducted. Results: NE-based microneedles of insulin have improved bioavailability and quick response. Conclusion: Microneedles loaded with insulin can be effectively delivered insulin transdermally to treat diabetes with increased convenience and patient compliance.
[Box: see text].

Hydrogen diffusion and uptake in nickel Alloy 625 under cathodic protection potential (-1050 mVAg/AgCl) and temperature (10 °C) were studied using electrochemical permeation tests. It is the first time hydrogen permeation of nickel alloy at a temperature lower than room temperature was investigated. The results revealed that the effective diffusivity of hydrogen D eff at -1050 mVAg/AgCl varied from 1.81 to 2.86 × 10-15 m2/s across the temperature range of 10-23 °C. The effective subsurface hydrogen concentration C s u b was influenced by both the applied temperature and overpotential. Particularly, the change in C sub at 10 °C is dependent on the hydrogen absorption efficiency affected by the surface coverage fraction of hydrogen. Furthermore, the hydrogen fugacity on the sample surface f H 2 , the applied overpotential, and the temperature have been successfully cross correlated to interpret hydrogen evolution and adsorption. It was demonstrated that f H 2 primarily changed with the applied overpotential, while the temperature affected the gradient of f H 2 during the potential increment. The current study provides valuable insights for industries, assisting in the prediction of hydrogen absorption and hydrogen-assisted failures in subsea nickel alloy components.

Nose-to-brain delivery (NTBD) offering potential benefits for treating Alzheimer\'s disease. In previous research, insulin dry powder (IDP) formulation for NTBD was developed, exhibiting favorable stability. This study aims to conduct in vitro and ex vivo assessment of release, permeation, mucoadhesion and histopathology, as well as an in vivo biodistribution study to produce IDP for NTBD and evaluate brain biodistribution. Spray-freeze-dried IDP formulations with varying weight ratios of trehalose-to-inulin were produced and analyzed. The release study was carried out in PBS with a pH of 5.8 stirred at 50 rpm and maintained at 37 °C ± 0.5 °C. Goat nasal mucosa was used for ex vivo permeation and mucoadhesion testing under similar conditions. An ex vivo histopathological examination and an in vivo study using enzyme-linked immunosorbent assay, were also performed. The IDP dissolution study demonstrated complete release of all IDPs within 120 min. The permeation study indicated that steady-state conditions were observed between 30 and 240 min. The mucoadhesion study unveiled that IDP F5 exhibited the fastest mucoadhesion time and the least force required within the fastest time of 43.60 ± 2.57 s. The histopathological study confirmed that none of the tested IDPs induced irritation in the nasal mucosa. Furthermore, the biodistribution study demonstrated the absence of detectable insulin in the plasma, while IDP F3 exhibited the highest deposited concentration of insulin within both the olfactory bulb and the whole brain. The extensive evaluation of the IDP formulations through in vitro, ex vivo, and in vivo studies implies their strength non-invasive NTBD. IDP F3, with a 1:1 wt ratio of trehalose to inulin, exhibited favorable brain biodistribution outcomes and was recommended for further investigation and development in the context of NTBD.

Corneal blindness can be treated by keratoplasty but a lack of readily available corneal donor tissue for this procedure remains a challenge. Cryopreservation can facilitate the long-term storage of tissue but effective protocols for cryopreserving cornea have yet to be developed. Mathematical modelling can guide protocol design, but previously used models are not comprehensive. A comprehensive model should describe the tissue\'s shrink-swell response and the cryoprotectant concentration throughout the tissue during cryoprotectant loading. Such a model exists for articular cartilage based on a biomechanical triphasic approach. We explored the applicability of this model for describing cryoprotectant permeation in porcine corneas by fitting it to experimental data for the permeation of dimethyl sulfoxide into porcine corneoscleral discs. The model provided as good of a fit for corneoscleral discs data as it did for articular cartilage data, presenting promise for its use in the design of cryopreservation protocols for corneas.

Hydrogen atoms can enter into metallic materials through penetration and diffusion, leading to the degradation of the mechanical properties of the materials, and the application of hydrogen barrier coatings is an effective means to alleviate this problem. Zirconia coatings (ZrO2) have been widely studied as a common hydrogen barrier coating, but zirconia undergoes a crystalline transition with temperature change, which can lead to volumetric changes in the coating and thus cause problems such as cracking and peeling of the coating. In this work, ZrO2 coating was prepared on a Q235 matrix using a sol-gel method, while yttria-stabilized zirconia (YSZ) coatings with different contents of rare earth elements were prepared in order to alleviate a series of problems caused by the crystal form transformation of ZrO2. The coating performances were evaluated by the electrochemical hydrogen penetration test, pencil hardness test, scratch test, and high-temperature oxidation test. The results show that yttrium can improve the stability of the high-temperature phase of ZrO2, alleviating the cracking problem of the coating due to the volume change triggered by the crystalline transition; improve the consistency of the coating; and refine the grain size of the oxide. The performance of YSZ coating was strongly influenced by the yttria doping mass, and the coating with 10 wt% yttria doping had the best hydrogen barrier performance, the best antioxidant performance, and the largest adhesion. Compared with the matrix, the steady-state hydrogen current density of the YSZ coating decreased by 72.3%, the antioxidant performance was improved by 65.8%, and the ZrO2 coating hardness and adhesion levels were B and 4B, respectively, while YSZ coating hardness and adhesion were upgraded to 2H and 5B. With the further increase in yttrium doping mass, the hardness of the coating continued to improve, but the defects of the coating increased, resulting in a decrease in the hydrogen barrier performance, antioxidant performance, and adhesion. In this work, the various performances of ZrO2 coating were significantly improved by doping with the rare earth element, which provides a reference for further development and application of oxide coatings.