Search Results (81)

Some propylene glycol ethers (PGEs) have been associated with reproductive toxicity. Ethoxypropanol (PGEE) and propoxypropanol (PGPE) are two common PGEs found in many commercial products. Although skin exposure is frequent when handling such products, no studies have investigated their skin absorption. Neat or aqueous concentrations of PGEs were applied with different concentrations on previously frozen human skin according to OECD guidelines. We also explored the use of frozen skin for skin irritation screening. Our results show that both PGEs readily permeate human skin (permeation coefficients: Kp_PGEE = 0.0005–0.002 cm/h; Kp_PGPE = 0.0002–0.002 cm/h; rates: J_PGEE = 447.5–1075.2 µg/cm²/h; J_PGPE = 193.9–826.1 µg/cm²/h; and time lag: 2–5 h). The permeability rate was four times greater for PGPE diluted in water compared to neat, and double for PGEE. Increasing the water content increased PGEE skin permeation but had no effect on PGPE. Cleaning products contain 1–5% PGEs, and water-based paints 10–50%, thus increasing the potential for skin uptake in consumers. Our skin irritation results were inconsistent, so we conclude that skin irritation cannot be assessed with previously frozen human skin. Future studies should assess the irritation using fresh skin and investigate the risk of health effects from PGEs exposures. Full article

Background/Objectives: Raynaud’s phenomenon (RP) is characterized by an exaggerated vasoconstrictive response of small blood vessels in the fingers and toes to cold or stress. Oral therapy with tadalafil (TDL), a phosphodiesterase-5 inhibitor, is limited by systemic side effects and reduced patient compliance. This study aimed to develop and evaluate a TDL-loaded nanoemulgel for transdermal delivery as a non-invasive treatment alternative for cold-induced vasoconstriction. Methods: TDL-loaded nanoemulsions were prepared using the aqueous titration method with cinnamon oil as the oil phase and Cremophor RH40 and Transcutol as the surfactant–cosurfactant system. The optimized nanoemulsion was incorporated into a carbopol-based gel to form a nanoemulgel. The formulation was characterized for droplet size, morphology, thermodynamic stability, rheological properties, in vitro drug release, skin permeation, and pharmacokinetic behavior. Infrared thermography was employed to assess in vivo efficacy in cold-induced vasoconstriction models. Results: The optimized TDL nanoemulsion exhibited a spherical morphology, a nanoscale droplet size, and an enhanced transdermal flux. The resulting nanoemulgel displayed suitable physicochemical and rheological properties for topical application, a short lag time (0.7 h), and a high permeability coefficient (Kp = 3.59 × 10⁻² cm/h). Thermal imaging showed significant vasodilation comparable to standard 0.2% nitroglycerin ointment. Pharmacokinetic studies indicated improved transdermal absorption with a higher C_max (2.13 µg/mL), a prolonged half-life (t_1/2 = 16.12 h), and an increased AUC_0–24 compared to an oral nanosuspension (p < 0.001). Conclusions: The developed TDL nanoemulgel demonstrated effective transdermal delivery and significant potential as a patient-friendly therapeutic approach for Raynaud’s phenomenon, offering an alternative to conventional oral therapy. Full article

Understanding the permeation of drugs through the intercellular lipid matrix of the stratum corneum layer of skin is crucial for effective transdermal delivery. Molecular dynamics simulations can provide molecular insights into the permeation process. In this study, we developed a new atomistic model representing the multilamellar arrangement of lipids in the stratum corneum intercellular space for permeation studies. The model was built using ceramides in extended conformation as the backbone along with free fatty acids and cholesterol. The properties of the equilibrated model were in agreement with the neutron scattering data and hydration behavior previously reported in the literature. The permeability of molecules, such as water, benzene and estradiol, and the molecular mechanism of action of permeation enhancers, such as eucalyptol and limonene, were evaluated using the model. The new model can be reliably used for studying the permeation of small molecules and for gaining mechanistic insights into the action of permeation enhancers. Full article

In the early stages of offshore low-permeability oil field development, it is crucial to ascertain the productivity of production wells to select high-production, high-quality reservoirs, which affects the design of the development plan. Therefore, accurate evaluation of well productivity is essential. Drill Stem Testing (DST) is the only way to obtain the true productivity of offshore reservoirs, but conducting DST in offshore oilfields is extremely costly. This article introduces a novel productivity evaluation method for horizontal wells in offshore low-permeability reservoirs based on an improved theoretical model, which relieves the limitations of traditional methods. Firstly, a new horizontal well productivity evaluation theoretical model is derived, with the consideration of the effects of the threshold pressure gradient, stress sensitivity, skin factor, and formation heterogeneity on fluid flow in low-permeability reservoirs. Then, the productivity profiles are classified based on differences in the permeability distribution of horizontal well sections. Thirdly, the productivity evaluation equation is modified by calculating correction coefficients to maximize the model’s accuracy. Based on the overdetermined equation concepts and existing DST productivity data, the derived correction coefficients in this paper are x₁ = 3.3182, x₂ = 0.7720, and x₃ = 1.0327. Finally, the proposed method is successfully applied in an offshore low-permeability reservoir with nine horizontal wells, increasing the productivity evaluation accuracy from 65.80% to 96.82% compared with the traditional Production Index (PI) method. This technology provides a novel approach to evaluating the productivity of horizontal wells in offshore low-permeability reservoirs. Full article

Productivity prediction has always been an important part of reservoir development, and tight reservoirs need accurate and efficient productivity prediction models. Due to the complexity of the tight oil reservoir, the data obtained by the detection instrument need to extract data features at a deeper level. Using the Pearson correlation coefficient and partial correlation coefficient to analyze the main control of productivity factors, eight characteristic parameters of volume coefficient, water saturation, density, effective thickness, skin factor, shale content, porosity, and effective permeability were obtained, and the specific oil production index was used as the target parameter. Two sample structures of pure static parameters and dynamic and static parameters (shale content, effective permeability, porosity, water saturation, and density as dynamic parameters, volume coefficient, skin factor, and effective thickness as static parameters) were created, and corresponding model structures (BP (Backpropagation), neural network model, and LSTM-BP (Long Short-Term Memory Backpropagation) neural network model) were designed to compare the prediction effects of models under different sample structures. The mean absolute error, root mean square error, mean relative percentage error, and coefficient of determination were used to evaluate the model results. The LSTM-BP neural network was used to predict the production capacity of the test set. The results showed that the average absolute error was 0.07, the root mean square error was 0.10, the average absolute percentage error was 21%, and the coefficient of determination was 0.97. Using wells in the WZ area for testing, the LSTM-BP model’s predictions are evenly distributed on both sides of the 45° line, separating the predicted values from actual values, with errors from the line being relatively small. In contrast, the BP model and analytical method are unable to achieve such an even distribution around the line. Experiments show that the LSTM-BP neural network model can effectively extract dynamic parameter features and has a stronger generalization ability. Full article

For efficient heating and cooling applications, minimum wall shear stress and maximum heat transfer rate are desired. The current study optimized the local skin friction coefficient and Nusselt number in Al₂O₃-Cu/water hybrid nanofluid flow over a permeable shrinking rotating disk. First, the governing equations and boundary conditions are solved numerically using the bvp4c solver in MATLAB. Von Kármán’s transformations are used to reduce the partial differential equations into solvable non-linear ordinary differential equations. The augmentation of the mass transfer parameter is found to reduce the local skin friction coefficient and Nusselt number. Higher values of these physical quantities of interest are observed in the injection case than in the suction case. Meanwhile, the increase in the magnitude of the shrinking parameter improved and reduced the local skin friction coefficient and Nusselt number, respectively. Then, response surface methodology (RSM) is conducted to understand the interactive impacts of the controlling parameters in optimizing the physical quantities of interest. With a desirability of 66%, the local skin friction coefficient and Nusselt number are optimized at 1.528780016 and 0.888353037 when the shrinking parameter ($\lambda$) and mass transfer parameter ($S$) are −0.8 and −0.6, respectively. Full article

Porous medium models are commonly used in Computational Fluid Dynamics (CFD) to simulate flow through permeable screens of various types. However, the setup of these models is often limited to replicating a pressure drop in cases where fluid inflow is orthogonal to the screen. In this work, a porous medium formulation that employs a non-diagonal Forchheimer tensor is presented. This formulation is capable of reproducing both the pressure drop and flow deflection under varying inflow angles for complex screen geometries. A general method to determine the porous model coefficients valid for both diagonal and non-diagonal Forchheimer tensors is proposed. The coefficients are calculated using a nonlinear least-squares optimisation based on an analytical solution of a special case of the Navier–Stokes equations. The applicability of the proposed method is evaluated in four different scenarios supplemented by local CFD simulations of permeable screens: wire mesh, perforated screens, air louvers, and expanded mesh panels. The practical application of this method is demonstrated in the modelling of windbreaks and permeable double-skin facades, which typically employ the aforementioned types of porous screens. Full article

This research presents the efficacy of polymeric microneedles in improving the transdermal permeation of methotrexate across human skin. These microneedles were fabricated from PLGA Expansorb^® 50-2A and 50-8A and subjected to comprehensive characterization via scanning electron microscopy, Fourier-transform infrared spectroscopy, and mechanical analysis. We developed and assessed a methotrexate hydrogel for physicochemical and rheological properties. Dye binding, histological examinations, and assessments of skin integrity demonstrated the effective microporation of the skin by PLGA microneedles. We measured the dimensions of microchannels in the skin using scanning electron microscopy, pore uniformity analysis, and confocal microscopy. The skin permeation and disposition of methotrexate were researched in vitro. PLGA 50-8A microneedles appeared significantly longer, sharper, and more mechanically uniform than PLGA 50-2A needles. PLGA 50-8A needles generated substantially more microchannels, as well as deeper, larger, and more uniform channels in the skin than PLGA 50-2A needles. Microneedle insertion substantially reduced skin electrical resistance, accompanied by an elevation in transepidermal water loss values. PLGA 50-8A microneedle treatment provided a significantly higher cumulative delivery, flux, diffusion coefficient, permeability coefficient, and predicted steady-state plasma concentration; however, there was a shorter lag time than for PLGA 50-2A needles, base-treated, and untreated groups (p < 0.05). Conclusively, skin microporation using polymeric microneedles significantly improved the transdermal delivery of methotrexate. Full article

During the development of condensate gas reservoirs, the phenomenon of retrograde condensation seriously affects the production of gas wells. The skin factor caused by retrograde condensation pollution is the key to measuring the consequent decrease in production. In this study, a multiphase flow model and a calculation model of retrograde condensate damage are first constructed through a dynamic simulation of the phase behavior characteristics in condensate gas reservoirs using the skin coefficient, and these models are then creatively coupled to quantitatively evaluate retrograde condensation pollution. The coupled model is solved using a numerical method, which is followed by an analysis of the effects of the selected formation and engineering parameters on the condensate saturation distribution and pollution skin coefficient. The model is verified using actual test data. The results of the curves show that gas–liquid two-phase permeability has an obvious effect on well production. When the phase permeability curve changes from the first to the third type, the skin coefficient increases from 3.36 to 26.6, and the condensate precipitation range also increases significantly. The distribution of the pollution skin coefficient also changes significantly as a result of variations in the formation and dew point pressures, well production, and formation permeability. The average error between the calculated skin of the model and the actual test skin is 3.87%, which meets the requirements for engineering calculations. These results have certain significance for guiding well test designs and the evaluation of condensate gas well productivity. Full article

In this study, we synthesized a family of novel ionic liquids (ILs) with meglumine (MGM) as cations and tartaric acid (TA), azelaic acid (AA), geranic acid (GA), and capric acid (CPA) as anions, using pharmaceutical additives via simple acid–base neutralization reactions. The successful synthesis was validated by attenuated total reflection–Fourier transform infrared (ATR-FTIR) and powder X-ray diffraction (PXRD). Thermal analysis using differential scanning calorimetry confirmed the glass transition temperature of MGM-ILs to be within the range of −43.4 °C–−13.8 °C. We investigated the solubilization of 15 drugs with varying pKa and partition coefficient (log P) values using these ILs and performed a comparative analysis. Furthermore, we present MGM-IL as a new skin permeation enhancer for the drug model flurbiprofen (FRP). We confirmed that AA/MGM-IL improves the skin permeation of FRP through hairless mouse skin. Moreover, AA/MGM-IL enhanced drug skin permeability by affecting keratin rather than stratum corneum lipids, as confirmed by ATR-FTIR. To conclude, MGM-ILs exhibited potential as drug solubilizer and skin permeation enhancers of drugs. Full article

The skin’s protective mechanisms, in some cases, are not able to counteract the destructive effects induced by UV radiations, resulting in dermatological diseases, as well as skin aging. Nutlin-3, a potent drug with antiproliferative activity in keratinocytes, can block UV-induced apoptosis by activation of p53. In the present investigation, ethosomes and transethosomes were designed as delivery systems for nutlin-3, with the aim to protect the skin against UV damage. Vesicle size distribution was evaluated by photon correlation spectroscopy and morphology was investigated by cryogenic transmission electron microscopy, while nutlin-3 entrapment capacity was evaluated by ultrafiltration and HPLC. The in vitro diffusion kinetic of nutlin-3 from ethosomes and transethosomes was studied by Franz cell. Moreover, the efficiency of ethosomes and transethosomes in delivering nutlin-3 and its protective role were evaluated in ex vivo skin explants exposed to UV radiations. The results indicate that ethosomes and transethosomes efficaciously entrapped nutlin-3 (0.3% w/w). The ethosome vesicles were spherical and oligolamellar, with a 224 nm mean diameter, while in transethosome the presence of polysorbate 80 resulted in unilamellar vesicles with a 146 nm mean diameter. The fastest nutlin-3 kinetic was detected in the case of transethosomes, with permeability coefficients 7.4-fold higher, with respect to ethosomes and diffusion values 250-fold higher, with respect to the drug in solution. Ex vivo data suggest a better efficacy of transethosomes to promote nutlin-3 delivery within the skin, with respect to ethosomes. Indeed, nutlin-3 loaded transethosomes could prevent UV effect on cutaneous metalloproteinase activation and cell proliferative response. Full article

The permeability of the oral or nasal mucosa is higher than that of the skin. Mucosa permeability depends mainly on the thickness and keratinization degree of the tissues. Their permeability barrier is conditioned by the presence of certain lipids. This work has the main aim of reinforcing the barrier effect of oral mucosa with a series of formulations to reduce permeation. Transmembrane water loss of different formulations was evaluated, and three of them were selected to be tested on the sublingual mucosa permeation of drugs. Caffeine, ibuprofen, dexamethasone, and ivermectin were applied on porcine skin, mucosa, and modified mucosa in order to compare the effectiveness of the formulations. A similar permeation profile was obtained in the different membranes: caffeine > ibuprofen~dexamethasone > ivermectin. The most efficient formulation was a liposomal formulation composed of lipids that are present in the skin stratum corneum. Impermeability provided by this formulation was notable mainly for the low-molecular-weight compounds, decreasing their permeability coefficient by between 40 and 80%. The reinforcement of the barrier function of mucosa provides a reduction or prevention of the permeation of different actives, which could be extrapolated to toxic compounds such as viruses, contaminants, toxins, etc. Full article

Inflammation, being a typical response to vascular tissue alterations, induces variations in tissue oxygen diffusion pressure. Diabetic microangiopathy, an inflammatory process, is characterized by an increase in vascular flow at rest, reduced venous and arteriolar responses, and increased capillary permeability, resulting in oedema development, decreased transcutaneous oxygen pressure, and increased transcutaneous carbon dioxide pressure. This phenomenon potentially hampers ulcer healing. Although the figure-of-eight method has proven to be a reliable, valid, quick, and efficient test for assessing foot and ankle measurements in patients with oedema and compromised skin integrity, it has not been studied in patients with diabetic foot. The aim of this study was to determine and compare the intra- and inter-observer variabilities of the figure-of-eight method in patients with diabetic foot. A prospective observational and cross-sectional study was undertaken, involving sixty-one subjects from a specialized Diabetic Foot Unit. Three investigators with varying levels of experience independently measured the subjects to assess both intra-observer and inter-observer variability. The evaluation was conducted using the Intraclass Correlation Coefficient (ICC). In the statistical analysis, an ICC of 0.93, adjusted using a 95% confidence interval (CI), was obtained for inter-observer reliability ICC, indicating excellent reliability among observers. Furthermore, an ICC of 0.98 with a 95% CI was obtained for the intra-observer reliability analysis, indicating excellent reliability. The results support using this test during the clinical management of oedema in patients with diabetic foot. The absence of an objective, fast, and readily available diagnostic method for oedema in diabetic foot patients in clinical practice might pose a limitation. Subsequent research should tackle this issue and explore the correlation between ankle perimeter measurements and other clinical outcomes in diabetic foot patients, including wound healing and quality of life. Full article

This research presents novel ibuprofen derivatives in the form of alkyl ester salts of L-amino acids with potential analgesic, anti-inflammatory, and antipyretic properties for potential use in transdermal therapeutic systems. New derivatives of (RS)-2-[4-(2-methylpropyl)phenyl]propionic acid were synthesized using hydrochlorides of alkyl esters (ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and pentyl) of L-glutamine. These were further transformed into alkyl esters of L-amino acid ibuprofenates through neutralization and protonation reactions. Characterization involved spectroscopic methods, including nuclear magnetic resonance and Fourier-transform infrared spectroscopy. Various physicochemical properties were investigated, such as UV–Vis spectroscopy, polarimetric analysis, thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction, water solubility, octanol/water partition coefficient, and permeability through pig skin using Franz diffusion cells. The research confirmed the ionic structure of the obtained hydrochlorides of alkyl esters of L-amino acids and ibuprofenates of alkyl esters of L-glutamic acid. It revealed significant correlations between ester chain length and thermal stability, crystallinity, phase transition temperatures, lipophilicity, water solubility, skin permeability, and skin accumulation of these compounds. Compared to the parent ibuprofen, the synthesized derivatives exhibited higher water solubility, lower lipophilicity, and enhanced skin permeability. This study introduces promising ibuprofen derivatives with improved physicochemical properties, highlighting their potential for transdermal therapeutic applications. The findings shed light on the structure–activity relationships of these derivatives, offering insights into their enhanced solubility and skin permeation, which could lead to more effective topical treatments for pain and inflammation. Full article

The administration of therapeutic drugs through dermal routes, such as creams and ointments, has emerged as an increasingly popular alternative to traditional delivery methods, such as tablets and injections. In the context of drug development, it is crucial to identify the optimal doses and delivery routes that ensure successful outcomes. Physiologically based pharmacokinetic (PBPK) models have been proposed to simulate drug delivery and optimize drug formulations, but the calibration of these models is challenging due to the multitude of variables involved and limited experimental data. One significant research gap that this article addresses is the need for more efficient and accurate methods for calibrating PBPK models for dermal drug delivery. This manuscript presents a novel approach and an integrated dermal drug delivery model to address this gap that leverages virtual in vitro release (IVRT) and permeation (IVPT) testing data to optimize mechanistic models. The proposed approach was demonstrated through a study involving Desoximetasone cream and ointment formulations, where the release kinetics and permeation profiles of Desoximetasone were determined experimentally, and a computational model was created to simulate the results. The experimental studies showed that, even though the cumulative permeation of Desoximetasone at the end of the permeation study was comparable, there was a significant difference seen in the lag time in the permeation of Desoximetasone between the cream and ointment. Additionally, there was a significant difference seen in the amount of Desoximetasone permeated through human cadaver skin at early time points when the cream and ointment were compared. The computational model was optimized and validated, suggesting that this approach has the potential to bridge the existing research gap by improving the accuracy and efficiency of drug development processes. The model results show a good fit between the experimental data and model predictions. During the model optimization process, it became evident that there was variability in both the permeability and the partition coefficient within the stratum corneum. This variability had a significant and noteworthy influence on the overall performance of the model, especially when it came to its capacity to differentiate between cream and ointment formulations. Leveraging virtual models significantly aids the comprehension of drug release and permeation, mitigating the demanding data requirements. The use of virtual IVRT and IVPT data can accelerate the calibration of PBPK models, streamline the selection of the appropriate doses, and optimize drug delivery. Moreover, this novel approach could potentially reduce the time and resources involved in drug development, thus making it more cost-effective and efficient. Full article