Permeation Data Research Articles

Emulgel Containing Metronidazole and Clindamycin for the Treatment of Rosacea

Rosacea is a common skin condition with quite a relevance. It currently affects at least 10% of the European population at some point after the age of 30. It is a chronic disorder that mainly affects the skin on the face and is characterized by outbreaks and remissions. Under normal circumstances, the skin face presents a wide range of commensal organisms, such as Staphylococcus epidermidis or Demodex folliculorum, but dysbiosis of the skin flora plays a relevant role in inflammatory processes and the development of the disease. Metronidazole (MD) is one of the main treatments indicated to reduce redness on the cheeks, nose, chin, or forehead and also to treat flushing, erythema, pimples, and other symptoms due in part to its anti-inflammatory action. On the other hand, clindamycin (CM) is another antibiotic used for rosacea, especially for its action against anaerobic and Gram-positive bacteria. Background/Objectives: This study aimed to develop an emulgel formulation that includes MD and CM, using excipients with non-comedogenic and non-irritating properties. Methods: The formulation was characterised physiochemically, rheological measurements were made, and short-term stability studies were carried out. In vitro release, permeation studies, toxicity an in vitro inflammation model were evaluated in a HaCaT cell model. To determine the interaction between the antibiotics, the minimum inhibitory concentration was determined separately and together using the broth microdilution method. To determine the formulation’s antimicrobial activity, an agar diffusion method was used. Results: The MD-CM-gel droplet size was measured by laser diffraction and the diameter obtained was less than 2.68 ± 0.18 µm in 50% of the particles. Suitable results was observed for the short-term stability. Release and permeation data revealed sustained drug release and adequate permeation through human skin. Non-toxicity was detected and the MD showed an anti-inflammatory effect with non-interference of CM. Also, there is no antagonism between the two antibiotics and the MD-CM-gel shows better results when compared to the formulations with the antibiotics separately and to commercial formulations. Conclusions: It is suggested that, following detailed preclinical and clinical studies, MD-CM-gel could be considered as an alternative for treating rosacea.

Reservoir Fluid Properties From Cuttings: An Innovative Synergy of Gel Permeation Chromatography and Data Analytics

Reservoir Fluid Properties From Cuttings: An Innovative Synergy of Gel Permeation Chromatography and Data Analytics

H2 Production Efficiency in PEM Water Electrolysis Cells – Evaluating the Effect of the Electrode-Electrolyte Interface on O2 and H2 Crossover

PEM water electrolyzers (PEMWEs) are a promising candidate to store fluctuating renewable energy due to their wide current density operating regime. This flexibility is a significant advantage compared to alkaline water electrolysis. However, this flexibility in current density is also a challenge to fully understand local and interfacial effects at different operating conditions minding the different scales that have to be considered in PEMWEs – from the nanometer-sized ionomer thin film to millimeter-sized channel structures for water supply and gas removal.Gas crossover is a big challenge in PEMWEs. It does not just limit the operating regime due to possible formation of explosive gas mixtures on the anode side. 1 It also contributes significantly to the overall efficiency of the system by causing some hydrogen that was produced by the electrical energy input to not reach the cathode exhaust. Crossover hydrogen is lost to the anode exhaust and crossover oxygen chemically recombines with hydrogen, which is therewith also lost when considering the overall hydrogen production efficiency. 2 Compared to PEM fuel cells, gas crossover characteristics in PEMWEs under operation are diverging more from steady-state permeation data. 1, 3 This can be caused by operation dependent two-phase flow characteristics of liquid water and gaseous product. While the anode is actively flushed with liquid water as reactant supply, the cathode of a PEMWE also experiences two-phase operation; either due to being flushed with water additionally or caused by the significant electro-osmotic drag at high current densities leading to water droplet formation in the cathode catalyst layer. The exact environment of the electrode-electrolyte interface will dictate the crossover behavior at different operating points but it is not well understood.In this study we shed some light on the effect of the interfacial two-phase characteristics on the gas crossover behavior at different operating conditions. Hydrogen and oxygen steady-state permeation over PEMWE membranes is studied using a mass spectrometer at different single- and two-phase flow conditions that can be decoupled from the electrochemical gas production and electro-osmotic drag effects due to active hydrogen and oxygen gas supply. By a thorough parameter variation we are able to distinguish solubility, diffusivity and fugacity effects on the overall permeability of the active gases. We show that common pure gas-phase measurements lead to gas permeabilities that show a severalfold difference compared to the results from the two-phase measurements.By comparing such steady-state permeation with gas crossover characteristics at different operating points a better understanding of the electrode-electrolyte interface composition during PEMWE full cell operation can be achieved. While the exact interfacial characteristics depend on the catalyst layer and transport media structure, this experimental data shall serve as a starting point for revisiting the tuning of structural parameters in order to achieve PEMWEs with improved hydrogen production efficiencies. Such dynamic effects will be important in large-scale cells where the two-phase characteristics can change along the cell, additionally. Bernt, M.; Schröter, J.; Möckl, M.; Gasteiger, H. A., Analysis of Gas Permeation Phenomena in a PEM Water Electrolyzer Operated at High Pressure and High Current Density. J. Electrochem. Soc. 2020, 167.Schalenbach, M.; Carmo, M.; Fritz, D. L.; Mergel, J.; Stolten, D., Pressurized PEM water electrolysis: Efficiency and gas crossover. Int. J. Hydrogen Energy 2013, 38, 14921-14933.Trinke, P.; Haug, P.; Brauns, J.; Bensmann, B.; Hanke-Rauschenbach, R.; Turek, T., Hydrogen Crossover in PEM and Alkaline Water Electrolysis: Mechanisms, Direct Comparison and Mitigation Strategies. J. Electrochem. Soc. 2018, 165, F502-F513.

Analyzing multicomponent permeation and coupling effects in pervaporation of Acetone-Butanol-Ethanol solutions using Maxwell-Stefan based modeling

The state-of-the-art research in pervaporation lacks a comprehensive understanding of the selective membrane permeation in real and multicomponent mixtures, a factor critical for its widespread commercial adoption. This work elucidates the contribution of various interaction effects, known as coupling phenomena, on the pervaporation of multicomponent Acetone-Butanol-Ethanol (ABE) solutions through a commercial PDMS membrane. Maxwell-Stefan (MS) diffusion formulations, combined with the UNIQUAC thermodynamic model, mostly restricted in literature to binary solutions permeating through a polymer membrane, are extended to multicomponent feed solutions. The thermodynamic correction factor [Γ] and correlation [B]−1 matrices are analyzed to resolve coupling into its thermodynamic and kinetic (diffusive) constituents.A generalized and explicit analytical derivation for calculation of [Γ] by UNIQUAC model is proposed, allowing estimation for any number of permeants. Subsequently, a significant inhibitory coupling of the component fluxes to the driving forces of its accompanying penetrants is revealed. In addition to the non-ideality arising from diagonal elements Γii, the substantial negative off-diagonal elements Γij in the thermodynamic correction matrices anticipate a decline in effective driving forces, butanol fluxes and permeation selectivity as we transition from binary butanol-water to multicomponent ABE mixtures.Following this, a detailed hit-and-trial based strategy is implemented to evaluate the relevance of membrane plasticization, cluster formation and interspecies frictional interactions towards the MS self and cross diffusivities within the [B]−1 matrix. Existing semi-empirical expressions for self-diffusivities in binary alcohol-water systems incorporating plasticization and clustering constants are reformulated and compared for their ability to accurately describe fluxes in binary and ternary ABE solutions. Furthermore, the optimal model fit was found to be insensitive to variation in MS cross-diffusivities. This suggests that the contribution of correlation effects may be neglected altogether, provided the expressions for self-diffusivities are adequately tailored for membrane plasticization and clustering. Notably, while only butanol clustering suffices for binary mixtures, additional aggregates involving butanol-water, water-water, and butanol-acetone/ethanol are suggested to play a crucial role in steering diffusivities in ternary solutions.Consequently, the proposed models exhibit exceptional agreement with experimental data, achieving R2 values of approximately 0.96, 0.95, and 0.98 for butanol flux in binary butanol-water and ternary solutions containing acetone and ethanol, respectively. Besides providing a more cohesive fit to the overall experimental permeation data, the usefulness of this approach lies in significantly simplifying model computations, thus easing the potential modeling of even more complex mixtures.

In vivo permeation of 2-phenoxyethanol in human skin

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.

Development and evaluation of methotrexate-loaded nanoemulsion formulation for topical treatment of psoriasis.

Psoriasis is a chronic inflammatory disease that is becoming widespread and is associated with many kinds of additional severe diseases. The present study aimed to develop a methotrexate-loaded almond oil-based nanoemulsion formulation (MTX NE) for topical administration. The drug-loaded nanoemulsion formulation was prepared by high shear homogenization technique. The formulation's stability, as well as other physical and chemical characteristics, including entrapment effectiveness, drug release kinetics, skin permeability, skin irritation, and in vivo evaluation of the optimized formulation, was assessed. Additionally, imiquimod-induced psoriasis in rats was employed to investigate the efficacy of MTX NE against skin disorders. The MTX NE formulation was developed with a particle size of 18.74 ± 9.748nm, a polydispersity index (PDI) of 0.198 ± 0.01, and an average entrapment efficiency of 79.65 ± 3.84%. The release kinetics model estimates 81.08% drug release at pH 5.5 after 24h. The major layers of the skin, the epidermis, and dermis were successfully fluidized by the optimized MTX NE formulation, as shown by FTIR results, most likely enhancing drug retention and permeability. However, since Tween 80 and PEG 400 are well-known penetration enhancers, their application greatly accelerates these effects. Permeation data indicate that after 24h, methotrexate was released from the nano-emulsion at 76.83 ± 4.98g/cm2 with a flux rate of 2.385 ± 0.61µg/cm2/h. The in vivo study conducted on rabbit skin showed that the enhanced skin penetration of the prepared MTX-loaded nanoemulsion formulation does not cause any structural modifications in the inter-cellular lipid layers of the stratum corneum. Rabbits used in the in vivo anti-psoriatic investigation demonstrated that MTX NE produced a 95% reduction in PASI. The pharmacokinetic profile revealed that the Cmax, Tmax, and t1/2 values were 8.63µg/mL, 12.5h, and 17.77 ± 2.21h, respectively. These findings suggest that the formulation MTX NE is effective in treating psoriasis and may reduce psoriasis symptoms.

Observations on the Tritiated Water and TEWL Skin Integrity Tests: Relevance to In Vitro Permeation Testing (IVPT).

The in vitro permeation test (IVPT) using ex vivo human skin is a sensitive and robust model system that has been vital in elucidating the fundamental parameters surrounding the absorption of both therapeutic agents and industrial chemicals through skin. FDA and OECD IVPT Guidances recommend that each skin section selected for study should be screened prior to use to ensure that the stratum corneum integrity is retained. Three methods are currently considered acceptable: 1) transepidermal water loss (TEWL), 2) electrical resistance, and 3) tritiated water (3H2O) absorption. A retrospective analysis of data from the authors' laboratory has been performed with the objective of addressing a number of questions regarding the 3H2O and TEWL integrity tests, and the population attributes of a large database consisting of 17,330 individual skin sections obtained from 459 skin donors. The applicability and usefulness of these tests, when compared to companion permeation data obtained from 25 topical drug products, has also been examined. Both integrity tests found water permeability to be equal in White and Hispanic races but higher than in Blacks, 3H2O being more discriminating than TEWL. Male skin is more permeable than female and there is a slight decrease in permeability with advancing age in both groups. Correlation between 3H2O absorption and drug absorption revealed a minimal relationship between the two in most cases, the Pearson correlation coefficient ranging from -0.417 to 0.953. Additionally, drug outliers were not always identified with a failing integrity test. The results call for a critical reexamination of the value of the 3H2O integrity test, and by extension, TEWL, for use in IVPT studies.

Hydrogen isotope transport parameters in materials for tritium extraction systems. Focus on the low pressure

This work aims to fill a gap in the H transport database for niobium and vanadium, materials proposed for the fabrication of tritium extraction systems. The permeability, key parameter for this application, has not been properly determined in niobium so far. Values are given for H2 and D2 permeability in two different Nb samples from different suppliers but with similar microstructure from ∼300 °C to 500 °C and tested with loading pressures from 20 mbar to 500 mbar:ϕ(Nb/H2)[mol·m−1·s−1·Pa−0.5]=4.49·exp(−19,258T)ϕ(Nb/D2)[mol·m−1·s−1·Pa−0.5]=1.31·exp(−19,332T)For vanadium, new measurements for material from different suppliers and with very different microstructure allow to confirm values for the permeability recently published (in contrast to the traditionally accepted values indirectly derived from solubility and diffusivity). In this work, the following expression is given for deuterium:ϕ(V/D2)[mol·m−1·s−1·Pa−0.5]=1.31·exp(−11,603T)There are very few documented attempts to measure surface rate constants for either of the two materials under consideration. These parameters are especially important and define the permeation process under certain conditions, in particular at low pressures. Hydrogen and deuterium permeation data in Nb and V has been therefore obtained in a wide range of pressures, with special focus in the low pressure region, the role of the microstructure being also evaluated. Surface rate constants σk1 and σk2, which are fundamental parameters for the modelling of H isotope transport through the materials, have been determined in vanadium and niobium with different surface finishes, this factor resulting determinant of the result.

Construction and analysis of a detailed new database for gas separation membranes

The countless possibilities associated with the design of new materials for the Membrane Gas Separation Process highlight the need for the creation of databases, that are great tools to guide design choices. The scientific literature is poor in providing detailed information on gas separation membranes. This work aimed to present a heterogeneous and detailed database, which encompasses various types of membranes and permeating gases. In addition, its construction was presented in a transparent manner (ensuring its suitability and safe use) and an analysis of the mined attributes was performed. A database with 1672 records was built with more than 280 different membranes. In total, 29 attributes were collected from 42 different bibliographic references. A wide range of values was mined for most of the attributes. Permeation data for 11 gases were collected and five major types of membranes are present: polymer, zeolite, MMM, CMS, MOF, and ceramic. Most of the attributes had an insignificant linear correlation with gas permeability (including film thickness, pore size, temperature, and pressure), indicating a complex and contextually specific relationship. Total Pore Volume, Micropore Volume, and BET Area attributes were the morphological attributes that are most linearly correlated with gas permeability and can be good performance indicators for membranes, regardless of the material type. It is expected that the results presented will be useful to guide decision-making in the steps of designing new membranes for gas separation in a big picture context.

Disposable Nitrile Glove Resistance to Limonene: Dextrous Robot Hand Versus ASTM F739 Comparison.

The current technique to assess glove resistance to chemicals for worker protection relies on challenging a flat, 2.54 cm diameter glove piece at or near room temperature. This does not simulate a donned whole glove near the skin temperature subjected to work activity forces. Four different types of disposable nonpowdered unlined/unsupported nitrile gloves in triplicate were measured for thickness, porosity, and for the acrylonitrile content (A) of the challenge and collection sides. Limonene permeation at 35 °C through a whole glove on a clenching and nonclenching dextrous robot hand and with the standard ASTM F739 technique were facilitated by taking samples from the collection sides for GC-MS analysis. The standardized breakthrough time (SBT) when permeation reached 100 ng/cm2/min and the steady state permeation rate (SSPR) depended on A, thickness, and porosity. Only the thinnest glove (Lavender) showed statistically significant (p ≤ 0.05) increased average SSPR for the clenching hand relative to the nonclenching hand and for the ASTM technique. The ASTM test data for the three thickest gloves were not statistically different from those of the robot hand, but differed from the manufacturer's. More research with different chemicals and higher clenching forces is needed. Clenching forces can enhance the permeation. Workers wearing ultrathin disposable nitrile gloves have a higher potential for chemical penetration/permeation. Company glove permeation data obtained near room temperature may have a longer SBT and lower SSPR than in practice. Double gloving may be advisible in emergencies and for unknown chemicals when no appropriate thicker Chemical Protective glove is available.

Laser Powder Bed Fusion Printing of CoCrFeMnNi High Entropy Alloy: Processing, Microstructure, and Mechanical Properties

Equiatomic CoCrFeMnNi high entropy alloy (HEA) powder was processed by laser powder bed fusion (LPBF) additive manufacturing (AM). The properties of the spherical pre-alloyed CoCrFeMnNi powder were characterized and its processability using LPBF AM was systematically investigated through the volumetric energy density (VED) based on the surface roughness, defects (micro-cracks and porosity) and densification. After optimization, LPBF processing at a VED of 104 J/mm3 achieved highly dense and crack-free vertical and horizontal test specimens with a porosity fraction lower than 0.01% and micro-pores having a mean size of, respectively, 25.9 μm and 13.4 μm, as determined from X-ray micro-computed tomography (μCT) inspection. Scanning electron microscope (SEM) analysis of the as-built (AB) CoCrFeMnNi processed at a VED of 104 J/mm3 showed a heterogeneous solidification microstructure, consisting of columnar grains with a cellular subgrain structure, and electron backscattered diffraction (EBSD) revealed a crystallographic texture mainly along the < 100 > direction. Post treatment with hot isostatic pressing (HIP) was effective in closing the remnant micro-pores in the bulk volume of the AB CoCrFeMnNi. Also, the cellular sub-grain structure in the AB CoCrFeMnNi completely disappeared after HIP and the resulting microstructure consisted of recrystallized equiaxed grains with annealing twins. The room temperature tensile response was anisotropic for AB CoCrFeMnNi with horizontally built specimens exhibiting higher strength and fracture strains (global and local) compared to vertically built ones; HIP reduced the anisotropy in the tensile properties and led to similar tensile strength with elongation values that were ~ 50% higher than in the AB condition. The HIPed CoCrFeMnNi also displayed higher Charpy impact toughness and absorbed energy at both room and liquid nitrogen temperatures compared to the AB material. Examination of the fracture surfaces after tensile and Charpy impact testing revealed ductile features with characteristic dimpled appearance and pointed to the important role of the remnant micro-pores on failure in the AB CoCrFeMnNi. Tribological assessments pointed to the superior low-stress abrasion resistance of AB and HIPed CoCrFeMnNi compared to 316L stainless steel (SS), which was included in this study to reinforce the analysis. SEM observations revealed that scratching and micro-fracture are the dominant wear mechanisms for the CoCrFeMnNi HEA, whereas ploughing and cutting parallel to the abrasive flow direction are the dominant mechanisms for 316L SS. To the authors’ knowledge, this study is the first to evaluate and report the low-stress abrasion resistance of any high entropy alloy. To understand the corrosion behavior, polarization curves of AB and HIPed CoCrFeMnNi were measured in 3.5 wt% NaCl and 1N H2SO4 solutions, and the results were compared to those of 316L SS. The findings indicate that AB and HIPed CoCrFeMnNi outperform 316L SS in a chloride-containing environment, but not in an acid-containing environment. Additionally, observations of hydrogen permeability revealed that AB CoCrFeMnNi permeates a lower volume of hydrogen atoms (by ~ 5 times) compared to 316L SS, despite its higher (by nearly 3 times) diffusion coefficient. Electrochemical hydrogen permeation data showed that the concentration of atomic hydrogen in the sub-surface of AB and HIPed CoCrFeMnNi was, respectively, about 32 and 26 times lower than in 316L SS. This study provides important material–structure–property data and indicates a promising outlook for LPBF of the CoCrFeMnNi HEA with high-performance.

Machine learning-based discovery of molecular descriptors that control polymer gas permeation

While machine learning has found increasing use in predicting the properties of polymeric materials with only a knowledge of chain architecture, determining the molecular factors underpinning properties (“interpretable AI”) has remained less well explored. We show that encoding chain chemistry in commonly employed formats, e.g., binary-valued fingerprints, leads to uniqueness issues during the hashing process to save storage space. This is because the hashing algorithm can map several chemical moieties into the same bit. These issues carry over into the ML algorithms, especially for “inverse” design and interpretable AI, and cannot be avoided by changing the length of the fingerprint. Using MACCS key featurizations of monomer repeats resolves some of these issues, and we show that a few substructures consistently appear in top features for maximizing permeability across several gases and ML models. These are carbon–carbon double bonds (as in polyacetylenes) especially when they are associated with methyl groups (found in branching architectures). These results, derived from the limited data set of ∼500 polymers with experimental gas permeation data, are in agreement with physical insight and thus provide a robust foundation which could further enable study of these material classes through detailed experiments and simulations.

In Silico Study on the Contribution of the Follicular Route to Dermal Permeability of Small Molecules

PurposeThis study investigates in silico the contribution of the hair follicle to the overall dermal permeability of small molecules, as published experimental work provides inconclusive information on whether the follicular route favours the permeation of hydrophobic or hydrophilic permeants.MethodA study is conducted varying physico-chemical parameters of permeants such as lipophilicity, molecular weight and protein binding. The simulated data is compared to published experimental data to discuss how those properties can modulate the contribution of the hair follicle to the overall dermal permeation.ResultsThe results indicate that the contribution of the follicular route to dermal permeation can range from negligible to notable depending on the combination of lipophilic/hydrophilic properties of the substance filling the follicular route and the permeant.ConclusionCharacterisation of the substance filling the follicular route is required for analysing the experimental data of dermal permeation of small molecules, as changes between in vivo and in vitro due to handling of samples and cessation of vital functions can modify the contribution of the follicular route to overall dermal permeation, hence hindering data interpretation.

Impact of Concentration Polarization Phenomena on Gas Separation Processes with High-Performance Zeolite Membranes: Experiments vs. Simulations.

Polarization phenomena play a key role in membrane separation processes but remain largely unexplored for gas separations, where the mass transfer resistance is most often limited to the membrane. This assumption, which is commonly used today for the simulation of membrane gas separations, has to be reconsidered when high-performance materials, showing a very high permeance and/or selectivity, are used. In this study, a series of steady-state separation performances experimentally obtained on CO2/CH4 mixtures with a zeolite membrane are compared to the predictions of a dedicated 1D approach, recently derived and validated through CFD simulations. Polarization effects are shown to generate a significant negative impact on the separation performances, both in terms of the productivity and separation efficiency. The 1D model predictions, based on pure gas permeance data and without any adjustable parameters, are in very good agreement with the experimental data. This fast and efficient modeling approach can easily be implemented in simulation or process synthesis programs for the rigorous evaluation of membrane gas separation processes, when high-performance materials are used.

MUP-PCL-TEO-PVA Bilayer Nanofiber Scaffold Incorporated with Mupirocin and Thyme Essential Oil for Synergistic Activity Against Bacterial Wound Infections.

Electrospinning process was used for constructing the bilayer nanofibers scaffold using drug and oil&#x0D; containing polymeric emulsion for synergistic activity against bacterial wound infections. The&#x0D; characterization was done for morphology, chemical composition, thermal behaviour, porosity,&#x0D; swelling ratio, drug release, in vitro permeation, ex vivo studies, and antimicrobial activity. In vitro&#x0D; drug permeation study, exhibited initial rapid release of MUP upto 53% in the first 6 hrs and&#x0D; following a slower sustained release achieving 92.17% drug release in 72 hours whereas TEO showed&#x0D; release in 10 hrs with initial burst release followed by sustained release achieving 85.45% release. The&#x0D; ex vivo skin permeation data revealed greater permeability compared to conventional films.&#x0D; Antibacterial activity of the bilayer nanofiber scaffold was found to be greater than that of single layer&#x0D; MUP and TEO scaffold as zone of inhibition of MUP-PCL-TEO-PVA bilayer scaffold was greater&#x0D; which indicates the synergistic activity of MUP and TEO.

New Formulation-Microporation Combination Approaches to Delivering Ciclopirox across Human Nails.

Topical treatments for onychomycosis are of interest to those seeking to avoid systemic drug interactions and to improve systemic safety. This work aimed to develop aqueous-based, simple, and cost-effective vehicles that provide high solubility for ciclopirox and enable the delivery of an active through channels created by nail microporation. Following solubility tests, aqueous gels and thermogels based on hydroxypropylmethylcellulose and poloxamer 407, respectively, were loaded with 8% and 16% ciclopirox. Their performance was then compared to the marketed lacquer Micolamina® in in vitro release tests with artificial membranes and in in vitro permeation tests with human nail clippings with and without poration. Finally, a microbiological assay compared the best gel formulations and the reference product. Little correlation was observed between the in vitro release and the permeation data, and the drug release was highly membrane-dependent. Ciclopirox nail retention in single-dose, porated nails tests was larger than in daily-dosing, non-porated nail conditions. The series of new gel and thermogel vehicles delivered ciclopirox more effectively than Micolamina® in single-dose, porated nail experiments. The inhibition of Trichophyton rubrum activity was significantly increased with microporated nails when the gel formulations were applied but not with Micolamina®. Overall, the results suggest that the new vehicles could be successfully combined with nail microporation to improve the drug delivery and efficacy of topical antifungal medication while reducing the dosing frequency, facilitating patients' adherence.

Development of an In Vitro secondary transfer model for testosterone gel to elucidate protocols of safe contact.

Testosterone gels applied to skin carry a risk of secondary transfer to non-patients , leading to development of symptoms such as precocious purberty. Currently, there is a lack of&amp;nbsp;in vitro&amp;nbsp;data available to inform guidance over safe contact parameters. A secondary transfer model using porcine skin to model primary (patient) skin and secondary (contact) skin was employed, with testosterone permeation and distribution analysis after 24 hours. Primary skin saw increasing amounts of unabsorbed testosterone and a reduction in delivery to the skin during at later contact times. Secondary skin saw a reduction in unabsorbed testosterone and delivery with later contact times. Permeation data mirrored the distribution data. These differences could be explained by changes in the formulation on the skin surface after application.

Microemulgel-based Hydrogel of Diclofenac Sodium using Lipidium sativum as a Gelling Agent

Aim was to prepare hydrogel containing diclofenac sodium using Lipidium sativum as a gelling agent within a micro emulsion-based system. The oil phase consisted of soybean oil, while surfactants, namely Span 80 and Tween 20, were employed in the formulation. Absolute ethanol was used as a co-surfactant and were characterized by a phase diagram. The in-vitro permeation information is derived from the Franz diffusion. Different microemulsion was designed by screening of various components by performing pseudo-ternary phase diagram and then a solubility study. From this psudo-ternary phase diagram was constructed. In-vitro permeation data was screened from these results the topical delivery of diclofenac sodium microemulsion was clearly confirmed as being by means of w/o microemulsion systems. The optimized formulation of the microemulsion consist of soya bean oil 1.25 mL, span:Tween 20 : 2.5 mL, ethanol 1-mL, water 0.2 mL, L. sativum mucilage and it is compared with the marketed preparation. So, the micro emulsion-based hydrogel of diclofenac using L. sativum mucilage can be used as a gelling agent for a topical drug delivery system.

A Synthetic Model of the Mucosa for Oral Penetration Studies.

The main objective of this study is the evaluation of the use of a synthetic membrane, Nuclepore, as a model for permeation studies through sublingual mucosa. The permeability of two types of membranes, porcine sublingual oral mucosa and a synthetic Nuclepore membrane, to water was compared. Moreover, the water permeability of membranes modified with waterproofing formulations was measured to study their ability to protect against the penetration of viruses, toxins, etc. A relatively high correlation (R2 0.88) was obtained between the transmucosal water loss (TMWL) values of the artificial membrane and the mucosa. These results support the possible use of this synthetic membrane in the screening of the water permeability of formulations. In addition, studies of the permeation of different actives, drugs, and biocides through the two membranes were carried out, and these results were compared with their skin permeation data. The synthetic membrane does not seem to discern between compounds in terms of permeability. However, the permeation of caffeine through intact or modified membranes incorporating waterproofing formulations presents similar permeation profiles through the synthetic membrane and mucosa. The results from these assays should lend support to the use of this synthetic membrane when screening formulations to be applied in oral penetration studies.

Development and validation of PAMPA-BBB QSAR model to predict brain penetration potential of novel drug candidates.

Efficiently circumventing the blood-brain barrier (BBB) poses a major hurdle in the development of drugs that target the central nervous system. Although there are several methods to determine BBB permeability of small molecules, the Parallel Artificial Membrane Permeability Assay (PAMPA) is one of the most common assays in drug discovery due to its robust and high-throughput nature. Drug discovery is a long and costly venture, thus, any advances to streamline this process are beneficial. In this study, ∼2,000 compounds from over 60 NCATS projects were screened in the PAMPA-BBB assay to develop a quantitative structure-activity relationship model to predict BBB permeability of small molecules. After analyzing both state-of-the-art and latest machine learning methods, we found that random forest based on RDKit descriptors as additional features provided the best training balanced accuracy (0.70 ± 0.015) and a message-passing variant of graph convolutional neural network that uses RDKit descriptors provided the highest balanced accuracy (0.72) on a prospective validation set. Finally, we correlated in vitro PAMPA-BBB data with in vivo brain permeation data in rodents to observe a categorical correlation of 77%, suggesting that models developed using data from PAMPA-BBB can forecast in vivo brain permeability. Given that majority of prior research has relied on in vitro or in vivo data for assessing BBB permeability, our model, developed using the largest PAMPA-BBB dataset to date, offers an orthogonal means to estimate BBB permeability of small molecules. We deposited a subset of our data into PubChem bioassay database (AID: 1845228) and deployed the best performing model on the NCATS Open Data ADME portal (https://opendata.ncats.nih.gov/adme/). These initiatives were undertaken with the aim of providing valuable resources for the drug discovery community.