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Topical therapy remains a critical component in the management of immune­mediated inflammatory dermatoses such as psoriasis and atopic dermatitis. In this field, macrolactam immunomodulators, including calcineurin and mammalian target of rapamycin inhibitors, can offer steroid­free therapeutic alternatives. Despite their potential for skin­selective treatment compared with topical corticosteroids, the physicochemical properties of these compounds, such as high lipophilicity and large molecular size, do not meet the criteria for efficient penetration into the skin, especially with conventional topical vehicles. Thus, more sophisticated approaches are needed to address the pharmacokinetic limitations of traditional formulations. In this regard, interest has increasingly focused on nanoparticulate systems to optimize penetration kinetics and enhance the efficacy and safety of topical calcineurin and mTOR inhibitors in inflamed skin. Several types of nanovectors have been explored as topical carriers to deliver tacrolimus in both psoriatic and atopic skin, while preclinical data on nanocarrier­based delivery of topical sirolimus in inflamed skin are also emerging. Given the promising preliminary outcomes and the complexities of drug delivery across inflamed skin, further research is required to translate these nanotherapeutics into clinical settings for inflammatory skin diseases. The present review outlined the dermatokinetic profiles of topical calcineurin and mTOR inhibitors, particularly tacrolimus, pimecrolimus and sirolimus, focusing on their penetration kinetics in psoriatic and atopic skin. It also summarizes the potential anti­inflammatory benefits of topical sirolimus and explores novel preclinical studies investigating dermally applied nanovehicles to evaluate and optimize the skin delivery, efficacy and safety of these 'hard­to­formulate' macromolecules in the context of psoriasis and atopic dermatitis.

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Furanoids are a class of contaminants prevalent in both airborne and occupational environments, with potential health implications through inhalation, oral ingestion, and skin penetration. Given their diminutive molecular size, there is a presumption that furanoids can readily permeate the skin. To systematically explore this presumption, we investigated the skin absorption and toxicity of a series of furans (furfuryl alcohol, furfuryl acetate, furfural, methyl 2-furoate, and 5-methylfurfural) using in silico, in vitro, and in vivo models. The in vitro permeation test (IVPT) from neat and aqueous suspension (5 mM) of furans demonstrated a facile absorption through pig and nude mouse skins. The lipophilicity of furans significantly influenced skin deposition, with higher lipophilicity displaying greater deposition. However, an opposing trend emerged in the receptor compartment accumulation. In barrier-defective skin simulating atopic dermatitis (AD) and psoriasis, enhanced deposition occurred with more hydrophilic furans but not with the more lipophilic ones. In the cell-based study, furanoids induced the proliferation of keratinocytes and skin fibroblasts except for the compounds with the aldehyde group (furfural and 5-methylfurfural). Both furfuryl acetate and 5-methylfurfural activated keratinocytes via the overexpression of COX-2 and PGE2 by 1.5‒2-fold. This stimulation involved the mitogen-activated protein kinase (MAPK) signaling pathway. For the in vivo mouse skin treatment, we selected furfuryl acetate (hydrophilic) and 5-methylfurfural (lipophilic). Both furans showed different patterns of skin lesions, where repeated application of furfuryl acetate caused epidermal hyperplasia and scaling, while 5-methylfurfural predominantly evoked skin inflammation and barrier disintegration. Toxicokinetics analysis revealed a higher plasma concentration of topically applied furfuryl acetate than that of the 5-methylfurfural (5.04 versus 2.34 nmol/ml), resulting in the mild injury of furfuryl acetate-treated peripheral organs. Conversely, no notable adverse effects on organs were observed for the 5-methylfurfural. This study established the relationship between cutaneous absorption and the toxicity of furans following skin exposure.

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A number of baby wipe formulations contain 2-phenoxyethanol (PE) as a preservative and cetylpyridinium chloride (CPC) as a surfactant with antimicrobial activity. Previously, we reported the skin absorption of PE in porcine skin and human skin in vitro. In the present work, the permeation of PE from preparations with CPC and without CPC was investigated in human skin in vivo. The studies were conducted using Confocal Raman Spectroscopy (CRS) and tape stripping (TS) methods. The CRS studies showed that the area under the curve (AUC) of PE for the formulation with and without CPC were not significantly different (p > 0.05). The TS data indicated no significant difference in the amounts of PE recovered from tapes 1-6 for the preparation with and without CPC (p > 0.05). When comparing the in vitro and in vivo data, a correlation was observed between the cumulative amount of PE permeated through human skin in vitro at 24 h and the AUC as measured by CRS (r2 = 0.97). In addition, the cumulative amount of PE permeated through human skin in vitro at 24 h was found to correlate with the amount of PE recovered from tape 1 to 6 in vivo (r2 = 0.95). Both CRS and TS techniques demonstrated limitations in assessing the distribution of PE and CPC in the skin in vivo, primarily attributed to the Raman signal intensities of compounds under investigation and the variability in the amount of SC collected by TS. Despite the limitations of CRS and TS, the results from the present study add further insights to the in vitro permeation data. Additionally, the findings of the present study encourage the further development and application of CRS for non-invasive evaluation of topical skin formulations in vivo.

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BACKGROUND: Anti-aging products are widely used, but the desire for safe and more efficient anti-aging products continues to increase. Dissolving microneedle patches (MNPs) have provided a more efficient transdermal drug delivery solution. MNP is a promising candidate for developing better anti-aging products. OBJECTIVE: To develop a more efficient anti-aging MNP product, we fabricated a dual anti-wrinkle microneedle patch (named DA-MNP) using droplet extension (DEN®) technology and evaluated its skin puncture ability, safety, and efficacy through clinical studies. METHODS: A DA-MNP comprising hyaluronic acid (HA) polymer backbone, acetyl octapeptide-3, and L-ascorbic acid 2-glucoside and sodium cyclic lysophosphatidic acid was fabricated using DEN® technology. Placebo MNPs comprising only HA were also fabricated. Twenty-four healthy subjects were enrolled in this comparative clinical study. The DA-MNP or placebo MNP was separately applied to the left and right eyes of subjects for overnight. Assessments, including wrinkle improvement, trans-epidermal water loss (TEWL), eye lifting and adverse effects were evaluated at each scheduled visit day for 28 days. RESULTS: The DA-MNP showed mechanical strength enough for puncturing the stratum corneum. Compared to placebo MNP group, the DA-MNP treated group showed an effective eye wrinkles improvement and better anti-aging of skin, with reduced TEWL, enhanced skin elasticity and lifting, and no adverse effects. CONCLUSION: The present study demonstrated that the fabricated DA-MNP exhibited fast acting on deep wrinkles and enhanced anti-aging efficacy, with no skin safety concern. Thus, this DA-MNP may serve as a new transdermal delivery solution for skin wrinkling and aging.

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Bisphenol S (BPS) was introduced in many industrial and commercial applications as a presumed safer alternative to bisphenol A. However, concerns have been raised surrounding skin absorption and potential persistence of BPS and its related toxic effects in humans. A previous study revealed the likelihood of a reservoir building up in exposed skin. Here, we studied the interactions of BPS solubilized in acetone, ultrapure water, or artificial sebum with freshly excised human skin samples. In vitro tests were performed in static Franz diffusion cells, to explore reservoir and occlusion effects, absorption and metabolism. Most BPS passed through the skin without metabolization - <10% was recovered as glucuronide or sulfate conjugates. Importantly, a substantial amount of BPS persisted in the skin, especially in the stratum corneum. This reservoir could lead to prolonged diffusion into the body after surface cleaning. Occlusion, that may occur with protective clothing, amplified BPS absorption up to six-fold. These findings have implications for occupational settings, highlighting the persistence of BPS contamination even after washing the skin's surface and the need to ensure protective equipment is correctly maintained and used.

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Various cytochrome P450 enzymes (CYPs) that contribute to drug metabolism are expressed in the skin. However, variation among individuals in CYP expression profiles is not well-understood.To investigate CYPs related to the metabolism of transdermal preparations in Japan, multiple skin tissue specimens of individuals of Japanese descent were prepared, and the mRNA expression levels of CYP1A2, CYP3A4, and CYP3A5 were measured. Associations between the expression patterns of these CYPs and body mass index (BMI) were also investigated.There were considerable individual differences in epidermal CYP1A2 mRNA expression levels, and CYP1A2 showed a weak positive correlation with CYP3A4 mRNA expression levels. In contrast to previous results for other organs, epidermal CYP3A4 mRNA expression levels showed a weak positive correlation with BMI.CYP3A4 in the epidermis may have been locally enhanced as a defence mechanism against xenobiotics in response to impaired barrier function. These differences in mRNA expression in the skin may affect the transdermal absorption of drugs, such as lidocaine and fentanyl, which are metabolised by multiple overlapping CYPs.Our study provides new insights into drug metabolism in the skin. These results are valuable for predicting drug effects and transdermal drug transfer rates in Japanese patients.

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In vitro absorption through human skin is a critical component in the safety assessment of chemicals, crop protection products, consumer healthcare products and cosmetics. A barrier integrity assay is used to identify skin samples which are potentially damaged. A retrospective analysis of 9978 electrical resistance (ER) measurements generated in a single laboratory (DTL) over a 15-year period was performed. Skin absorption experiments were performed using two model penetrants, testosterone and sucrose, utilising no ER acceptance criteria, and the results assessed. Using a barrier integrity test, to remove potentially damaged samples, was offset against one that can be used to remove intact skin samples with a poorer barrier function (i.e. false positives). The previously identified barrier integrity limit (10 kΩ for a 2.54 cm2 diffusion cell; Davies et al., 2004) was demonstrated to identify half of all samples tested, many of which would be false positive samples. This retrospective analysis identified 5.0 kΩ (17.5th percentile) as an acceptance criterion for a 2.54 cm2 diffusion cell, whilst not considerably changing results generated in skin absorption studies. This was confirmed from the cumulative absorption of the model penetrants tested. Using this limit would, therefore, provide suitable skin samples for regulatory skin absorption studies.

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Atopic dermatitis (AD) is one of the most common skin autoimmune diseases needing continuous anti-inflammatory management. Pterostilbene is reported to exhibit anti-inflammatory activity with higher bioavailability and stability than its parent compound, resveratrol. In this study, a series of synthetic pterostilbene analogs were designed by the hybridization of pterostilbene with chalcones or benzoyl chloride. Seventeen analogs derived from pterostilbene were synthesized with differences in the positions of hydroxyl, methoxyl, or fluoro moieties. These compounds were screened by the inhibitory effect on the overexpressed Th2-associated cytokines/chemokines in the activated human keratinocytes (HaCaT). The anti-IL-5 and anti-CCL5 activity of these compounds led to the identification of three effective compounds: 3a ((E)- 4-(3,5-dimethoxystyryl)phenyl benzoate), 3d ((E)- 4-(3,5-dimethoxystyryl)phenyl 2-methoxybenzoate), and 3g ((E)- 4-(3,5-dimethoxystyryl)phenyl 2-fluorobenzoate). These benzoyl pterostilbenes also significantly decreased Th1/Th17-associated proinflammatory mediators in the activated macrophages (differentiated THP-1). The result showed that the conditioned medium of benzoyl pterostilbene-treated macrophages reduced the phosphorylated STAT3 in the keratinocytes, indicating the blockade of crosstalk between resident and immune cells. Compounds 3d and 3g generally showed greater skin absorption than 3a. The flux of 3g across barrier-defective skins mimicking the AD skin was 3-fold higher than that of across intact skin. The dinitrochlorobenzene (DNCB)-induced AD mouse model manifested that topical delivery with 3g improved the pathological signs through inhibiting cytokines/chemokines (IL-5, TNF-α, CCL17, and CCL22) and macrophage recruitment. The epidermal thickness was reduced from 76 to 55 µm after topical 3g delivery. The therapeutic activity of 3g was comparable to that of tacrolimus (TAC) used as a positive control. The benzoyl pterostilbenes attenuated the inflammation via the MAPK and c-Jun signaling. Furthermore, this study provided experimental evidence of benzoyl pterostilbene analogs for therapeutic potential on AD.

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Filaggrin (FLG), a skin barrier protein, is associated with higher dermal uptake of some chemicals in carriers of loss-of-function (null) mutations. This study investigates FLG mutations and systemic effects following dermal exposure to chemicals. Individuals (n = 23 FLG null, n = 31 FLG wt) were simultaneously exposed to pyrimethanil, pyrene, oxybenzone, and nickel ions for 4 h. Pre- and post-exposure, 25-hydroxyvitamin D3 (25(OH)D3, LC-MS/MS) and 92 inflammation-related proteins (proximity-extension assay) were measured. FLG null carriers exhibited significantly higher 25(OH)D3 concentrations than wt carriers, both pre- and post-exposure. Eleven proteins differed in abundance post- vs pre-exposure among FLG null carriers, and 22 proteins among wt carriers (three proteins overlapped). Twelve proteins showed median differences (post- vs pre-exposure) between FLG null and wt carriers. Overall, FLG null carriers showed an increase, while FLG wt carriers showed a decrease in inflammation-related proteins. These findings suggest FLG-dependent differences in susceptibility to systemic effects following simultaneous dermal chemical exposure.

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The number of modeling and simulation applications, including physiologically based pharmacokinetic (PBPK) models, physiologically based biopharmaceutics modeling (PBBM), and empirical models, has been constantly increasing along with the regulatory acceptance of these methodologies. While aiming at minimizing unnecessary human testing, these methodologies are used today to support the development and approval of novel drug products and generics. Modeling approaches are leveraged today for assessing drug-drug interaction, informing dose adjustments in renally or hepatically impaired patients, perform dose selection in pediatrics and pregnant women and diseased populations, and conduct biopharmaceutics-related assessments such as establish clinically relevant specifications for drug products and achieve quality assurance throughout the product life cycle. In the generics space, PBPK analyses are utilized toward virtual bioequivalence assessments within the scope of alternative bioequivalence approaches, product-specific guidance development, and food effect assessments among others. Case studies highlighting the evolving and expanding role of modeling and simulation approaches within the biopharmaceutics space were presented at the symposium titled "Model Informed Drug Development (MIDD): Role in Dose Selection, Vulnerable Populations, and Biowaivers - Chemical Entities" and Prologue "PBPK/PBBM to inform the Bioequivalence Safe Space, Food Effects, and pH-mediated DDIs" at the American Association of Pharmaceutical Scientists (AAPS) PharmSci 360 Annual Meeting in Boston, MA, on October 16-19, 2022, and are summarized here.

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Photodynamic therapy (PDT) using methylene blue (MB) as a photosensitizer has emerged as an alternative treatment for skin cancers, such as squamous cell carcinoma (SCC). To increase the cutaneous penetration of the drug, some strategies are used, such as the association of nanocarriers and physical methods. Thus, herein we address the development of nanoparticles based on poly-Ɛ-caprolactone (PCL), optimized with the Box-Behnken factorial design, for topical application of MB associated with sonophoresis. The MB-nanoparticles were developed using the double emulsification-solvent evaporation technique and the optimized formulation resulted in an average size of 156.93 ± 8.27 nm, a polydispersion index of 0.11 ± 0.05, encapsulation efficiency of 94.22 ± 2.19% and zeta potential of -10.08 ± 1.12 mV. Morphological evaluation by scanning electron microscopy showed spherical nanoparticles. In vitro release studies show an initial burst compatible with the first-order mathematical model. The nanoparticle showed satisfactory generation of reactive oxygen species. The MTT assay was used to assess cytotoxicity and IC50; values of 79.84; 40.46; 22.37; 9.90 µM were obtained, respectively, for the MB-solution and the MB-nanoparticle without and with light irradiation after 2 h of incubation. Analysis using confocal microscopy showed high cellular uptake for the MB-nanoparticle. With regard to skin penetration, a higher concentration of MB was observed in the epidermis + dermis, corresponding to 9.81, 5.27 µg/cm2 in passive penetration and 24.31 and 23.81 µg/cm2 after sonophoresis, for solution-MB and nanoparticle-MB, respectively. To the best of our knowledge, this is the first report of MB encapsulation in PCL nanoparticles for application in skin cancer using PDT.

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There is an increase of application of Nickel in the form of nanoparticles (NiNPs) in several fields including modern metallurgy, bioengineering, and medicine. Such growth of the areas of application is actually accompanied with an increase of exposure to Nickel, thus an intensification of the negative effects, the most frequent being the allergic contact dermatitis. Indeed, due to their smaller size, and therefore their higher surface area, NiNPs can release more Ni ions compared to bulk material, that can penetrate and permeate through the skin. To reduce the Ni cutaneous penetration, barrier creams (BC) are applied on the skin surface. There is little information, however, on the efficiency of such commercial protective creams on decreasing Ni cutaneous penetration. For this reason, the objective of the current study was to investigate the protective role of one commercially available formulation for Ni (Nik-L-Block™ containing a chelating agent) and one moisturizing cream (Ceramol 311 basic cream without chelating agent), following exposure to NiNPs, using in vitro Franz cells, as well as the cytotoxicity of NiNPs in primary human dermal fibroblasts was studied. Our results demonstrated that although both tested formulations can decrease Ni accumulation in the skin (4.13 ± 1.74 µg/cm2 for Nik-L-Block™ and 7.14 ± 1.46 µg/cm2 for Ceramol 311 basic cream); there are significant differences between the two creams (p = 0.004). Based on the experimental evidence, we therefore conclude that the composition of such formulations has an imperative role for dermal uptake of Ni. Finally, NiNPs showed no cytotoxic effect on cultured human dermal fibroblasts after 24 and 72 h.

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The influence of hydrophilic surfactants acting on the membrane elasticity of liposomes on the skin absorption of vitamin C is investigated. The purpose of encapsulation inside cationic liposomes is to improve the skin delivery of vitamin C. The properties of elastic liposomes (ELs) are compared to that of conventional liposomes (CLs). ELs are formed by the addition of the "edge activator" Polysorbate 80 to the CLs composed of soybean lecithin, cationic lipid DOTAP (1,2-dioleoyl-3-trimethylammoniopropane chloride), and cholesterol. The liposomes are characterized by dynamic light scattering and electron microscopy. No toxicity is detected in human keratinocyte cells. Evidences of Polysorbate 80 incorporation into liposome bilayers and of the higher flexibility of ELs are given by isothermal titration calorimetry and pore edge tension measurements in giant unilamellar vesicles. The presence of a positive charge in the liposomal membrane increases the encapsulation efficacy by approximately 30% for both CLs and ELs. Skin absorption of vitamin C from CLs, ELs and a control aqueous solution measured in Franz cells shows a high delivery of vitamin C into each skin layer and the acceptor fluid from both liposome types. These results suggest that another mechanism drives skin diffusion, involving interactions between cationic lipids and vitamin C depending on the skin pH.

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The role of inorganic nanoparticles in our society is increasing every day, from its use in sunscreens to their introduction in analytical laboratories, pharmacy, medicine, agricultural and other uses. Therefore, in order to establish precautions as well as correct handling of this type of material by operators, it is important to determine the ability of these compounds to travel through the different layers of the skin and to study their possible toxicological effects. In this sense, several authors have studied the ability of inorganic nanoparticles to penetrate the skin barrier by diverse methodologies in in vivo and in vitro modes. In the first case, most of the studies have been performed with animal skins that can imitate the human one (porcine, mouse and guinea pigs, among others), although human skin from surgery have been also explored. However, the use of animals is a common model that should be avoided in the following years due to ethical issues. In this sense, the use of in vitro methodologies is also usually selected to study the dermal absorption of nanoparticles through the skin. Nevertheless, most of the studies are performed with authentic animal skins, instead of the use of synthetic skins that imitate the permeability of our skin system, which has been scarcely studied. In addition, most of the literature is focused in achieving high-transdermal uptake to use nanoparticles (not only inorganic) as carriers for drugs, but little efforts have been done in the study of their inherent percutaneous absorption and toxicity. For these reasons, this review covers the current state-of-the-art of dermal absorption of inorganic nanoparticles in skin and their possible toxicity taking into account that people can be in contact with these nanomaterials in daily life, work or other places. In this sense, the observed results showed that the nanoparticles rarely reach the blood circulatory system, and no big toxicological effects were commonly found when in vivo and actual skin was used. In addition, similar results were found when synthetic skins were used, demonstrating the possibility of avoiding animals in these studies. In any case, more studies covering the dermal absorption of nanoparticles should be performed to have a better understanding of how nanoparticles can affect our health.

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OBJECTIVES: We aimed to characterize polycyclic aromatic hydrocarbons (PAHs) in the breathing zone and on the skin of wildland firefighters and to assess their contribution to urinary 1-hydroxypyrene (1-HP) over repeated firefighting rotations. We asked if improved skin hygiene or discretionary use of an N95 mask would reduce absorption. METHODS: In collaboration with wildfire services of two Canadian provinces, Alberta and British Columbia (BC), we recruited wildland firefighters from crews willing to be followed up over successive rotations and to be randomly assigned to normal practice, enhanced skin hygiene (ESH), or ESH plus discretionary use of an N95 mask. We collected spot urine samples at the beginning and end of up to four rotations/firefighter. On designated fire days, as close as possible to the end of rotation, we collected skin wipes from the hands, throat, and chest at the beginning and end of the fire day and, in BC, start of fire-day urine samples. Volunteers carried air monitoring pumps. Participants completed questionnaires at the beginning and end of rotations. Exposure since the start of the fire season was estimated from fire service records. Urinary 1-HP was analyzed by LC-MS-MS. Analysis of 21 PAHs on skin wipes and 27 PAHs from air sampling was done by GC-MS-MS. Statistical analysis used a linear mixed effects model. RESULTS: Firefighters in Alberta were recruited from five helitack crews and two unit crews, and in BC from two unit crews with 80 firefighters providing data overall. The fire season in BC was very active with five monitored fire days. In Alberta, with more crews, there were only seven fire days. Overall, log 1-HP/creatinine (ng/g) increased significantly from the start (N = 145) to end of rotation (N = 136). Only three PAHs (naphthalene, phenanthrene, and pyrene) were found on >20% of skin wipes. PAHs from 40 air monitoring pumps included 10 PAHs detected on cassette filters (particles) and 5 on sorbent tubes (vapor phase). A principal component extracted from air monitoring data represented respiratory exposure and total PAH from skin wipes summarized skin exposure. Both routes contributed to the end of rotation urinary 1-HP. The ESH intervention was not demonstrated to effect absorption. Allocation of an N95 mask was associated with lower 1-HP when modeling respiratory exposure (ß = -0.62, 95% CI -1.15 to -0.10: P = 0.021). End of rotation 1-HP was related to 1-HP at the start of the next rotation (ß = 0.25, 95% CI 0.12 to 0.39: P < 0.001). CONCLUSIONS: Exposures to PAHs during firefighting were significant, with samples exceeding the American Conference of Governmental Industrial Hygienists Biological Exposure Index for 1-HP suggesting a need for control of exposure. PAH exposure accumulated during the rotation and was not fully eliminated during the break between rotations. Both respiratory and skin exposures contributed to 1-HP. While improved skin hygiene may potentially reduce dermal absorption, that was not demonstrated here. In contrast, those allocated to discretionary use of an N95 mask had reduced 1-HP excretion. Wildland firefighters in North America do not use respiratory protection, but the results of this study support more effective interventions to reduce respiratory exposure.

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BACKGROUND: Numerous formulations have been utilized in the cosmetic and pharmaceutical industries to effectively deliver bioactive ingredients. METHODS: We selected a well-known liposomal formulation of bilayer lipid vesicles composed of ceramide NP. Ethosomes contain hydrophilic vanillic acid or lipophilic α-bisabolol, and their physicochemical properties were evaluated. Vanillic acid is encapsulated in the aqueous core while α-bisabolol is engaged with the lipid phase. The formulation was prepared by the high-pressure homogenization method at 800 bar for 5 min. The particle size, polydispersity index and zeta potential of the ethosome dispersion were analyzed by dynamic light scattering. In order to measure the skin absorption efficiency from artificial skin, an in vitro assay was performed using the Franz diffusion cell method for 24 hours. In addition, ultracentrifuges for encapsulation efficiency, dialysis membranes for active ingredient release, and low-temperature transmission electron microscopy (TEM) to evaluate the morphology of vesicles were utilized. RESULTS: The particle size of the ethosome containing ceramide NP and vanillic acid was in the range of 80 ~ 130 nm, whereas the particle size of the ethosome containing ceramide NP and α-bisabolol was 150 ~ 170 nm. In the vanillic acid-containing ethosome, increasing the amount of ceramide NP decreased the particle size, whereas the size of the α-bisabolol ethosome did not change. The stability of the prepared ethosome did not change significantly for 4 weeks at 25°C, 4°C, and 45°C. The skin absorption efficiency of ceramide NP and vanillic acid-containing ethosome was increased by about 15% compared to the control group, whereas the ethosome containing α-bisabolol and ceramide NP showed slightly higher skin absorption efficiency than the control group. In addition, encapsulation efficiency evaluation, active ingredient release measurement and cryo-TEM were taken. CONCLUSION AND PERSPECTIVE: Based on the results of these studies, we suggest that ethosome formulations containing ceramide NP can be widely used in the cosmetic industry together with other cosmetic formulations.

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Transdermal drug administration is an elegant method to overcome various side effects of oral or parenteral drug administration. Nevertheless, due to an effective skin barrier, which is provided by the stratum corneum, transdermal drug delivery is sometimes very slow and ineffective. Thus, the effect of a medical device (DERMADROP TDA) for transdermal penetration of drugs in conjunction with a special vehicle emulsion on percutaneous permeation of several substances (with different physicochemical properties) was investigated in Franz-type diffusion cells with porcine skin over 28 h. This medical device disperses pharmaceutical agents via oxygen flow through an application system, which is used in conjunction with specially developed vehicle substances. Substance permeation of various substances with different physicochemical properties (diclofenac, enrofloxacin, flufenamic acid, indomethacin, and salicylic acid) was examined after application with a pipette and with the medical device. Therefore, acceptor media samples were collected up to 28 h after drug administration. Drug concentration in the acceptor medium was determined via high-performance liquid chromatography. Enhanced permeation was observed for diclofenac, enrofloxacin, flufenamic acid, indomethacin, and salicylic acid after oxygen-based administration. This correlates negatively with the molecular weight. Thus, drug administration can effectively be enhanced by a medical device using oxygen.

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Cyclodipeptides (CDPs) or diketopiperazines (DKPs) are often found in nature and in foodstuff and beverages and have attracted great interest for their bioactivities, biocompatibility, and biodegradability. In the laboratory, they can be prepared by green procedures, such as microwave-assisted cyclization of linear dipeptides in water, as performed in this study. In particular, five CDPs were prepared and characterized by a variety of methods, including NMR and ESI-MS spectroscopies and single-crystal X-ray diffraction (XRD), and their cytocompatibility and anti-aging activity was tested in vitro, as well as their ability to penetrate the different layers of the skin. Although their mechanism of action remains to be elucidated, this proof-of-concept study lays the basis for their future use in anti-age cosmetic applications.

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Paraquat is a non-selective contact herbicide that is absorbed through the digestive tract and skin and can cause multiple organ damage. The toxicokinetics of paraquat poisoning in specific patients are rarely reported. Case 1 was a 76-year-old man who intermittently immersed his perineum in diluted paraquat solution for 3 consecutive days because of eczema of the perineal skin. On admission, the patient's scrotal skin was severely corroded and his blood paraquat concentration was 0.5 µg/mL. He developed severe kidney and lung damage after admission and died on Day 6 of admission. Case 2 was a 23-year-old woman who ingested paraquat during gestational week 36. Her initial blood paraquat concentration was 0.81 µg/mL. The patient refused hemoperfusion and a cesarean section. She birthed a baby girl 83 hours after ingesting paraquat. Paraquat concentrations in postnatal maternal blood, fetal blood, umbilical cord blood, and amniotic fluid were 0.19 µg/mL, 0.23 µg/mL, 0.20 µg/mL, and 0.47 µg/mL, respectively. The baby died within hours of birth and the mother died of refractory respiratory failure 2 days after delivery. This paper provides clues about paraquat toxicokinetics in specific patient types and indicates that paraquat can be absorbed through the scrotal skin and the placental barrier.

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Percutaneous occupational exposure to industrial toxicants can be assessed in vitro on excised human or animal skins. Numerous factors can significantly influence skin permeation of chemicals and the flux determination. Among them, the vehicle used to solubilize the solid substances is a tricky key step. A "realistic surrogate" that closely matches the exposure scenario is recommended in first intention. When direct transposition of occupational exposure conditions to in vitro experiments is impossible, it is recommended that the vehicle used does not affect the skin barrier (in particular in terms of structural integrity, composition, or enzymatic activity). Indeed, any such effect could alter the percutaneous absorption of substances in a number of ways, as we will see. Potential effects are described for five monophasic vehicles, including the three most frequently used: water, ethanol, acetone; and two that are more rarely used, but are realistic: artificial sebum and artificial sweat. Finally, we discuss a number of criteria to be verified and the associated tests that should be performed when choosing the most appropriate vehicle, keeping in mind that, in the context of occupational exposure, the scientific quality of the percutaneous absorption data provided, and how they are interpreted, may have long-range consequences. From the narrative review presented, we also identify and discuss important factors to consider in future updates of the OECD guidelines for in vitro skin absorption experiments.

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