Development of a tadalafil transdermal formulation and evaluation of its ability to in vitro transdermal permeate using Strat-M® membrane.

Tadalafil (TDF) has low water solubility, high intestinal permeability and belongs to the Biopharmaceutics Classification System (BCS) Class II. Due to high intestinal permeability, only oral administration (tablets) and oral thin film formulations have been developed. Therefore, it is necessary to develop various formulations, such as external formulations and transdermal absorption formulations requested by patients. The purpose of this study is to improve the solubility and skin permeability of TDF, and to develop a novel transdermal formulation with secured stability over time. The research strategy is to determine solvents that will improve TDF solubility and to screen substances that will enhance TDF permeability. Skin penetration tests were simulated by using a Strat-M® membrane in Franz diffusion cell systems. The optimal formulation (F1, consisting of TDF/HDTMA-Br at a ratio of 1:10 [weight/weight] in DPG) observed the highest permeability compared to all formulations in PBS (pH 7.4). Changes in thermal property of F1 formulation was observed and maintained its stability over 12 months including drug content (µg/mL), appearance, pH, and permeation (µg/cm2). In conclusion, DPG played a supported role in improving both TDF solubilization and permeability, whereas HDTMA-Br played a key role in enhancing permeability. It is thought that these results will be supplemented in the future to conduct research and experiments on humans.

Febuxostat solubilization and stabilization approach using solid dispersion method: Synergistic effect of dicalcium phosphate dehydrate and chitosan.

Drug solubilization studies are continuously being conducted. Febuxostat (FBX) has a low solubility in water. This study aims to develop a stable FBX-solid dispersion (SD) formulation using a solvent evaporation method. The solubilization strategy of FBX is to develope an optimal FBX-SD formulation by selecting a solubilizer and carrier through the screening method. The final selected solubilizer, macrogol 15 hydroxystearate and polyoxyl 15 hydroxystearate (Kolliphor® HS-15), is widely used in the pharmaceutical industry as a nonionic solubilizing and emulsifying agent and has low toxicity. Especially when commonly used in developing lipophilic drug formulations, it dissolves well in water and ethyl alcohol. The optimal composition ratio of the formulation (SD4) was FBX:HS-15®:granular dicalcium phosphate dehydrate (DCP-D): A synthetic magnesium aluminometasilicate (Neusilin®UFL2):chitosan = 1:3:3:1:1 (w/w) and showed 3.0-, 2.3-, and 1.1-fold higher dissolution (%) of FBX compared to that of the Feburic tab® in pH 1.2 media, distilled water (DW), and pH 6.8 buffer, respectively. Also, in vitro release and in vitro permeability in SD4 formulation showed higher than that of Feburic tab®. Based on its stability over 6 months, it was confirmed that chitosan acted as a stabilizer. Moreover, due to weak intermolecular interactions, FBX in the SD4 formulation was considered to exist in a mixed state of amorphous and crystalline FBX. In conclusion, the improved dissolution (%) and stability of FBX in SD4 formulation were secured through the synergistic effect of excipients.

Development and evaluation of febuxostat solid dispersion through screening method.

Febuxostat (Febux) is a BCS II drug and has a very low solubility. In order to overcome this shortcoming, the purpose of study is to increase the in vitro dissolution (%) and drug release (%) of Febux by using a screening method. The Febux-SD formulation was prepared by screening solubilizers, pH agents, and carriers using with a solvent evaporation method. The novel Febux SD formulation was successfully developed. The dissolution (%) of Febux of optimal formulation (SD3) was higher than that of Feburic® tab in pH 1.2, distilled water (DW), and pH 6.8 buffer by 6.3-, 2.6-, and 1.1-fold, respectively, at 60 min. The in vitro drug release (%) and permeability (µg/cm2) of SD3 formulation were improved compared to those of Feburic® tab in the pH shifting method and PBS (7.4), respectively. The SD3 formulation was well maintained the stability for 6 months, and that of physicochemical properties were altered. In conclusion, the Febux solubilization study with meglumine was first attempted and successfully performed. Through the improved dissolution (%) of Febux, high bioavailability of SD3 formulation is expected in animal and human studies.

Development and evaluation of niacinamide transdermal formulation by artificial membrane permeability.

Despite many efforts to improve the transdermal permeability of drugs, most of them are blocked by the skin barrier. Niacinamide (NAC) is a Biopharmaceutics Classification System class I drug with high aqueous solubility and intestinal permeability. Due to the high solubility and intestinal permeability of NAC, the development of new formulations is insufficient as transdermal, injection etc. Thus, this study aimed to develop the novel NAC formulation with improved skin permeability and secured stability. The NAC formulation approach is to first select a solvent that improves skin permeability, and then select a second penetration enhancer to determine the final formulation. All formulations were evaluated for skin permeability using an artificial membrane (Strat-M®). The optimal formulation (non-ionic formulations (NF1) consisted of NAC/Tween®80 = 1:1 wt ratio in dipropylene glycol [DPG]) showed the highest permeability in all formulations in PBS buffer (pH 7.4). The thermal properties of NF1 were altered. Moreover, NF1 maintained a stable drug content, appearance, and pH value for 12 months. In conclusion, DPG had an excellent effect in increasing the NAC permeation, and Tween®80 played a boosting role. Through this study, an innovative NAC formulation was developed, and good results are expected for human transdermal research.

Shear behavior of single cast-in anchor simulating characteristics of bridge bearing anchor.

A bridge bearing anchor transmits various loads of a superstructure to a substructure. Most anchors are generally designed without consideration of characteristics such as concrete pedestal, grout bedding, and anchor socket. This study investigated the shear behavior of anchors in accordance with the edge distance, embedment depth, compressive strength of concrete, and height of the concrete pedestal in order to simulate the practical characteristics of the bridge bearing anchors. The actual shear capacity of the anchor differs from the shear strengths calculated by the ACI 318 and EN 1992-4; especially, the importance of the embedment depth is underestimated in these codes. An increase in the height of the concrete pedestal has a negative effect on the shear capacity because of the stress concentration. The grout is fractured prior to the occurrence of local damages in concrete, resulting in a secondary moment. As a result, the effect of the level arm is observed. An equation, which can predict the relative cracking degree of concrete, is proposed by analyzing the displacement of grout and concrete. High strain occurs in the stirrups close to the anchor, and the behavior of the strain is more influenced by the embedment depth than the edge distance. The comparison of obtained and analytically evaluated failure loads by calculations according to EN 1992-4, Schmid model and Sharma model was conducted to consider the effect of supplementary reinforcement. Finally, the design equation of concrete breakout strength is modified to predict the more precise shear resistance of a bridge bearing anchor.

Interspersing CeOx Clusters to the Pt-TiO2 Interfaces for Catalytic Promotion of TiO2-Supported Pt Nanoparticles.

We propose an interface-engineered oxide-supported Pt nanoparticle-based catalyst with improved low-temperature activity toward CO oxidation. By wet-impregnating 1 wt % Ce on TiO2, we synthesized hybrid oxide support of CeOx-TiO2, in which dense CeOx clusters formed on the surface of TiO2. Then, the Pt/CeOx-TiO2 catalyst was synthesized by impregnating 2 wt % Pt on the CeOx-TiO2 supporting oxide. Pt-CeOx-TiO2 triphase interfaces were eventually formed upon impregnation of Pt on CeOx-TiO2. The Pt-CeOx-TiO2 interfaces open up the interface-mediated Mars-van Krevelen CO oxidation pathway, thus providing additional interfacial reaction sites for CO oxidation. Consequently, the specific reaction rate of Pt/CeOx-TiO2 for CO oxidation was increased by 3.2 times compared with that of Pt/TiO2 at 140 °C. Our results demonstrate a widely applicable and straightforward method of catalytic activation of the interfaces between metal nanoparticles and supporting oxides, which enabled fine-tuning of the catalytic performance of oxide-supported metal nanoparticle classes of heterogeneous catalysts.

High Device Performances and Noise Characteristics of AlGaN/GaN HEMTs Using In Situ SiCN and SiN Cap Layer.

We fabricated and characterized AlGaN/GaN high-electron mobility transistors (HEMTs) with a nano-sized in situ cap layer (one is a silicon carbon nitride (SiCN) layer, and the other is a silicon nitride (SiN) layer) comparing to the conventional device without an in situ cap layer. The pulse characteristics and noise behaviors for two devices with in situ cap layers are much superior to those of the reference device without a cap layer, which means that the in situ cap layer effectively passivates the AlGaN surface. On the other hand, the device with an in situ SiCN cap layer showed the excellent device characteristics and noise performances compared to the other devices because of the reduced positive ionic charges and enhanced surface morphology caused by carbon (C) surfactant atoms during the growth of the SiCN cap layer. These results indicate that the AlGaN/GaN HEMT with the in situ SiCN cap layer is very promising for the next high-power device by replacing the conventional HEMT.

Shielding Effectiveness and Impact Resistance of Concrete Walls Strengthened by High-Strength High-Ductility Concrete.

Following the fourth Industrial Revolution, electronic and data-based technology is becoming increasingly developed. However, current research on enhancing electromagnetic interference (EMI) shielding and the physical protection performance of structures incorporating these technologies is insufficient. Therefore, in this study aiming for the improvement of EMI shielding and structural performance of structures, twelve concrete walls were fabricated and tested to determine their shielding effectiveness and drop-weight impact resistance. Concrete walls strengthened by three thickness types of high-strength, high-ductility concrete (HSDC) have been considered. The test results showed that the shielding effectiveness with strengthening thickness increased by approximately 35.6-46.2%. Specimens strengthened by more than 40% and 10% of the strengthening area ratio of single- and double-layer, respectively, exhibited more than 20 dB of shielding effectiveness. Moreover, the relationship between the damaged area ratio and shielding effectiveness was evaluated by means of the drop-weight impact test. The structural performance and EMI shielding effectiveness improved as the HSDC thickness increased.

Mechanical and Electrical Characteristics of Lightweight Aggregate Concrete Reinforced with Steel Fibers.

There is increased interest in applying electromagnetic (EM) shielding to prevent EM interference, which destroys electronic circuits. The EM shielding's performance is closely related to the electrical conductivity and can be improved by incorporating conductive materials. The weight of a structure can be reduced by incorporating lightweight aggregates and replacing the steel rebars with CFRP rebars. In this study, the effects of lightweight coarse aggregate and CFRP rebars on the mechanical and electrical characteristics of concrete were investigated, considering the steel fibers' incorporation. The lightweight coarse aggregates decreased the density and strength of concrete and increased the electrical conductivity of the concrete, owing to its metallic contents. The steel fibers further increased the electrical conductivity of the lightweight aggregate concrete. These components improved the EM shielding performance, and the steel fibers showed the best performance by increasing shielding effectiveness by at least 23 dB. The CFRP rebars behaved similarly to steel rebars because of their carbon fiber content. When no steel fiber was mixed, the shielding effectiveness increased by approximately 2.8 times with reduced spacing of CFRP rebars. This study demonstrates that lightweight aggregate concrete reinforced with steel fibers exhibits superior mechanical and electrical characteristics for concrete and construction industries.

Building-Information-Modeling Based Approach to Simulate Strategic Location of Shelter in Place and Its Strengthening Method.

It is important to consider establishing a shelter in place (SIP) using existing facilities to prepare for unpredictable and no-notice disasters. In this study, we evaluate the building-information-modeling (BIM)-based approach to simulate the strategic location of SIP and its strengthening method. BIM software was used to model a light rail station and analyze the elements of the facility that can affect the evacuation time to reach the SIP. The purpose of this study was to understand the effects of structural standards on the design of SIPs using a direct simulation. The differences between domestic and overseas standards were analyzed. An analysis was carried out to evaluate whether national specifications are satisfactory. As the proposed evacuation method is based on a rational human behavior analysis through a direct simulation, it was going to be a safer and faster route of evacuation in the case of physical terror attack situations for existing infrastructure, Furthermore, the SIP design is considered where reinforcement of the SIP structure is necessary. Three types of reinforcing were considered. Here, the use of high-strength, high-ductility concrete proved to be an effective method to improve the impact resistance of reinforced concrete walls and recommended for strengthening reinforced concrete members.

Development and evaluation of pseudoephedrine hydrochloride abuse-deterrent formulations using thermal modified rice starch.

There is a continued global effort to prevent the spread of prescription drug abuse. In particular, chemical structure of pseudoephedrine hydrochloride (PSE), an over-the-counter medication, is very similar to that of methamphetamine (MET). The aim of this study was to develop abuse-deterrent formulations (ADF) of PSE by using thermal modified starch (TMR). PSE is a water-soluble drug, but it is intended to inhibit extraction from the extraction medium in excess tablets. Starch-based formulations were successfully developed using cross-linking agent and lipid. The extraction (%) of PSE from TMR7-L5 formulation (equivalent to 5 tablets) were 75.3% in DW, 2.7% in ethyl alcohol, and 63.0% in 40% ethyl alcohol (v/v) at 60 °C for 30 min. Moreover, TMR7-L5 formulation delayed drug release compared to the commercial product in in vitro release. In conclusion, the development of ADFs using a starch-based formulation shows novelty and has potential to prevent drug abuse.

Evaluation on the Microstructure and Durability of High-Strength Concrete Containing Electric Arc Furnace Oxidizing Slag.

The application of electric arc furnace oxidizing slag (EAS) in high strength concrete (HSC) as the cementitious material is investigated in this study. The microstructure and mechanical properties of HSC with four different replacement ratios of EAS were evaluated and HSC with two replacement ratios of ground granulated blast furnace slag (GBS) was used for performance comparison. The results show that the HSC with EAS replacement ratios smaller than 15% undergo similar hydration processes and result in a similar final product when compared with those of NC-NN. Increases in EAS replacement ratio cause a reduction in Ca(OH)2 content; this, in turn, leads to an increase in porosity and a reduction in compressive strength. In terms of shrinkage behavior under free conditions, mixtures with increasing replacement ratios of cementitious materials saw increasing shrinkage, with the HSC containing EAS being similar to the other specimens. The mixtures containing EAS saw a quite gradual decrease in their freezing and thawing resistance properties as the number of freeze-thaw cycles they underwent increased. However, the efficacy of HSC with less than 15% of EAS is similar to GBS; hence, EAS could replace cement in concrete for certain applications, which would lead to more environmental benefits.

Direct Growth of Highly Conductive Large-Area Stretchable Graphene.

The direct synthesis of inherently defect-free, large-area graphene on flexible substrates is a key technology for soft electronic devices. In the present work, in situ plasma-assisted thermal chemical vapor deposition is implemented in order to synthesize 4 in. diameter high-quality graphene directly on 10 nm thick Ti-buffered substrates at 100 °C. The in situ synthesized monolayer graphene displays outstanding stretching properties coupled with low sheet resistance. Further improved mechanical and electronic performances are achieved by the in situ multi-stacking of graphene. The four-layered graphene multi-stack is shown to display an ultralow resistance of ≈6 Ω sq-1, which is consistently maintained during the harsh repeat stretching tests and is assisted by self-p-doping under ambient conditions. Graphene-field effect transistors fabricated on polydimethylsiloxane substrates reveal an unprecedented hole mobility of ≈21 000 cm2 V-1 s-1 at a gate voltage of -4 V, irrespective of the channel length, which is consistently maintained during the repeat stretching test of 5000 cycles at 140% parallel strain.

Development of a naftopidil-chitosan-based fumaric acid solid dispersion to improve the dissolution rate and stability of naftopidil.

Naftopidil (NAF), an α1-adrenoceptor antagonist, is administered as a treatment for benign prostatic hyperplasia; however, according to the Biopharmaceutical Classification System (BCS IV), it is a poorly-soluble drug that exhibits poor permeability. We aimed to increase the dissolution (%) of NAF by adding chitosan to a polymer-free formulation. Compared to the formulation prepared using Flivas®, at 60 min, the solid dispersion (SD) formulation containing NAF, fumaric acid, chitosan, and US2® in a 1:1:2:1 weight ratio improved the dissolution (%) of NAF in distilled water, pH 1.2 media, pH 4.0 and pH 6.8 buffers by 27.2-, 1.2-, 1.1- and 6.5-fold, respectively. The physicochemical properties of the SD1 formulation were also found to be altered, including its thermal properties, crystal intensity, and chemical interaction. As a result, the hydrogen bonding that occurs between NAF and fumaric acid was identified as a major factor in the increase in NAF dissolution (%). Further, chitosan was observed to contribute to the stability of NAF and SD1, which was assessed over a 3-month period. To our knowledge, this is the first study to employ a polymer-free system to improve the solubilization of NAF.

Solubilization of tadalafil using a tartaric acid and chitosan-based multi-system.

Solubilization studies of tadalafil (TDF) have recently improved the dissolution (%) using weak acids and bases in our group. However, the weak acid formulations have a low dissolution (%) of TDF as limitation. Thus, the purpose of this study was to improve the dissolution (%) of TDF over 90% in distilled water (DW) by weak acid-chitosan based multi-system. The SD formulation (SD11: TDF, tartaric acid, chitosan, Aerosil®200, and PVP/VA S-630 in a 1:2:1:1:2 weight ratio) showed higher dissolution (%) of TDF by 5.0-, 6.0-, and 5.8-fold at 60 min than that of Cialis® in DW and pH 1.2 and pH 6.8 buffers, respectively. The physical properties of the SD11 formulation were changed. Moreover, the SD11 formulation maintained stability for 3 months. In conclusion, the solubilization of TDF using chitosan was successfully performed for the first time.

Therapeutic effects of celecoxib polymeric systems in rat models of inflammation and adjuvant-induced rheumatoid arthritis.

The incidence of rheumatoid arthritis (RA), an autoimmune inflammatory disease, is rapidly increasing in aging societies. In the current study, celecoxib (CXB) micelles were developed to improve the oral absorption and anti-inflammatory effects of CXB in cell studies and λ-carrageenan rat models, and to enhance the therapeutic effects of CXB on RA in complete Freund's adjuvant (CFA)-induced RA rat models. Moreover, CXB micelles and previously developed solid dispersion (SD6) formulations were evaluated. The physical properties of optimal CXB micelles (M3), such as crystallinity, thermal properties, and intramolecular interactions, were altered. Compared with the commercial product (Celebrex®), the M3 and SD6 formulations showed significantly improved anti-inflammatory effects in terms of nitric oxide reduction, 1.5-fold and 2.2-fold, respectively, at the cellular level. The relative bioavailability (BA) of the M3 and SD6 formulations was also significantly improved as oral bioavailability (167.2% and 219.8% respectively), compared with that of Celebrex®. In particular, M3 and SD6 significantly reduced inflammation and edema volume relative to Celebrex® in CFA-induced RA rat models. Moreover, both M3 and SD6 effectively suppressed CFA-induced pro-inflammatory cytokines (TNF-α and IL-1ß) in rat splenic tissues. In conclusion, polymeric systems improved the solubility, relative BA (%) and anti-inflammatory effects of CXB. Thus, CXB polymeric systems show potential as therapeutic agents against inflammation and RA and may need to be tested at the clinical level.

Aldehyde-alcohol dehydrogenase undergoes structural transition to form extended spirosomes for substrate channeling.

Aldehyde-alcohol dehydrogenase (AdhE) is an enzyme responsible for converting acetyl-CoA to ethanol via acetaldehyde using NADH. AdhE is composed of two catalytic domains of aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH), and forms a spirosome architecture critical for AdhE activity. Here, we present the atomic resolution (3.43 Å) cryo-EM structure of AdhE spirosomes in an extended conformation. The cryo-EM structure shows that AdhE spirosomes undergo a structural transition from compact to extended forms, which may result from cofactor binding. This transition leads to access to a substrate channel between ALDH and ADH active sites. Furthermore, prevention of this structural transition by crosslinking hampers the activity of AdhE, suggesting that the structural transition is important for AdhE activity. This work provides a mechanistic understanding of the regulation mechanisms of AdhE activity via structural transition, and a platform to modulate AdhE activity for developing antibiotics and for facilitating biofuel production.

Effects of Steelmaking Slag and Moisture on Electrical Properties of Concrete.

Strain sensors can indicate the conditions of concrete structures, but these sensors are only capable of measuring local behaviors of materials. To solve this problem, researchers have introduced conductive materials that can monitor the overall behavior of concrete structures. Steelmaking slag, which contains large amounts of iron oxide (Fe2O3), is conductive, and researchers have considered the addition of this material to improve concrete monitoring. In this study, mechanical and electrical properties of concrete containing steelmaking slag as a binder were evaluated. As the incorporation of steelmaking slag increased, the setting times were delayed, but the compressive strengths were similar within the replacement ratio of 15%. It was found that the addition of steelmaking slag with Fe2O3, the main ingredient of magnetite (Fe3O4), improved the electrical resistivity, piezoresistivity, and sensitivity of the concrete. Drying of the concretes resulted in an increase in electrical resistance and fractional change in resistivity (FCR). Expansion of steelmaking slag, due to contacting of free CaO and moisture under repeated loads, resulted in cracks in the concrete and affected the gauge factor (GF). This study demonstrates the possibility that the addition of steelmaking slag as a binder may provide an economical and environmentally-friendly solution to concrete strain monitoring.

Design and evaluation of the anticancer activity of paclitaxel-loaded anisotropic-poly(lactic-co-glycolic acid) nanoparticles with PEGylated chitosan surface modifications.

This study aimed to evaluate the anticancer activity of paclitaxel-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PNPs) based on their shapes and surface modifications in breast cancer cells. We hypothesized that anisotropic-PNPs (AT-PNPs) with PEGylated chitosan (CP) surface modifications and high aspect ratios exhibit higher anticancer activity than PNPs and AT-PNPs with CP surface modifications and low aspect ratios. Six types of PNPs and AT-PNPs with different shapes and surface modifications were successfully prepared. The cellular uptake and cytotoxicity of the AT-PNPs were higher than those of the PNPs, while the cellular uptake and cytotoxicity of the PNPs and AT-PNPs with CP were higher than those of the uncoated PNPs and AT-PNPs. Moreover, all the particles remained stable for 4 months. In conclusion, this study primarily described the preparation of CP-AT-PNPs, and the CP-AT-PNPs2 developed herein are expected to demonstrate promising anticancer effects in animal experiments and clinical studies.

Correlation of α/γ-Fe2O3 nanoparticles with the toxicity of particulate matter originating from subway tunnels in Seoul stations, Korea.

According to the increasing concern about particulate matter (PM) pollution at subway systems, particularly its potentially severe effects on human health, this study investigated the constituents, characteristics, and toxicity of PM collected at underground subway stations in Seoul, Korea. It was found that α/γ-Fe2O3 NPs, which are considered as thermal products derived from the brake-wheel-rail interface, were the main components of PM (57.6% and 48% of PM10 and PM2.5, respectively). In addition, hydrothermally synthesized α/γ-Fe2O3 NPs, proposing to possess similar properties to those of Fe2O3 contained in PM, were used to investigate the correlation of these oxides with PM toxicity. In particular, the synthesized γ-Fe2O3 NPs induced a negligibly toxic, while the synthesized α-Fe2O3 NPs and PM showed remarkably toxic effects on HeLa cells and zebrafish embryos, specifically in reducing cell proliferation to 85% and 72% survival, causing high apoptosis of 29.8% and 29.3%, and inhibiting the development of embryos up to 60% and 8% after prolonged exposure, respectively. It is considered that α-Fe2O3 NPs were primarily responsible for the harmful effects of PM, resulting in significant damage to DNA due to their capacity of producing high reactive oxygen species (ROS) and, thus, deleterious effects on the human body.