Study on the Effect of Pharmaceutical Excipient PEG400 on the Pharmacokinetics of Baicalin in Cells Based on MRP2, MRP3, and BCRP Efflux Transporters.

Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can directly or indirectly influence the disposition process of active drugs in vivo, thereby affecting the bioavailability of drugs. In order to reveal the pharmacokinetic effect of PEG400 on baicalin in hepatocytes and its mechanism, the present study first started with the effect of PEG400 on the metabolic disposition of baicalin at the hepatocyte level, and then the effect of PEG400 on the protein expression of baicalin-related transporters (BCRP, MRP2, and MRP3) was investigated by using western blot; the effect of MDCKII-BCRP, MDCKII-BCRP, MRP2, and MRP3 was investigated by using MDCKII-BCRP, MDCKII-MRP2, and MDCKII-MRP3 cell monolayer models, and membrane vesicles overexpressing specific transporter proteins (BCRP, MRP2, and MRP3), combined with the exocytosis of transporter-specific inhibitors, were used to study the effects of PEG400 on the transporters in order to explore the possible mechanisms of its action. The results demonstrated that PEG400 significantly influenced the concentration of baicalin in hepatocytes, and the AUC0-t of baicalin increased from 75.96 ± 2.57 µg·h/mL to 106.94 ± 2.22 µg·h/mL, 111.97 ± 3.98 µg·h/mL, and 130.42 ± 5.26 µg·h/mL (p ˂ 0.05). Furthermore, the efflux rate of baicalin was significantly reduced in the vesicular transport assay and the MDCKII cell model transport assay, which indicated that PEG400 had a significant inhibitory effect on the corresponding transporters. In conclusion, PEG400 can improve the bioavailability of baicalin to some extent by affecting the efflux transporters and thus the metabolic disposition of baicalin in the liver.

Design and evaluation of curcumin-loaded poloxamer hydrogels as injectable depot formulations.

Poloxamer hydrogels are of interest as injectable depot delivery systems. However, their use for delivering hydrophobic drugs, such as curcumin, is limited due to poor loading capacity. Here, we evaluated the influence of incorporating hydrophobic medium chain triglycerides (MCT) or amphiphilic polyethylene glycol 400 (PEG400) on the physicochemical properties, drug loading, and in vitro compatibility of a curcumin-loaded poloxamer hydrogel. Poloxamer 407 and 188 hydrogel formulations (16:6 w/w) were prepared and MCT and PEG400 (saturated with curcumin) were added to these systems, either alone or in combination, up to a 10 % w/w additive solvent load. Formulation viscoelasticity, gelation behaviour, injectability, morphology and release profiles were assessed. The cytocompatibility of the formulations was also assessed on dermal fibroblasts (HDFn). Both additives increased curcumin loading into the formulation. Addition of MCT to the hydrogel significantly increased its gelation speed, while PEG400 had a less profound impact. Both additive solvents increased the force required to inject the formulation. PEG400 containing systems were single phase, whereas MCT addition created emulsion systems. All formulations released âˆ¼20-30 % of their loaded curcumin in a sustained fashion over 24 h. The modified hydrogel systems showed good biocompatibility on cells when administering up to ∼100-150 µM curcumin into the culture. This study addresses a key limitation in loading hydrophobic drugs into hydrogels and provides a strategy to enhance drug loading and performance of hydrogels by integrating additives such as MCT and PEG400 into the systems.

Detrimental Impacts of Pharmaceutical Excipient PEG400 on Gut Microbiota and Metabolome in Healthy Mice.

Polyethylene glycol 400 (PEG400) is a widely used pharmaceutical excipient in the field of medicine. It not only enhances the dispersion stability of the main drug but also facilitates the absorption of multiple drugs. Our previous study found that the long-term application of PEG400 as an adjuvant in traditional Chinese medicine preparations resulted in wasting and weight loss in animals, which aroused our concern. In this study, 16S rRNA high-throughput sequencing technology was used to analyze the diversity of gut microbiota, and LC-MS/MS Q-Exactive Orbtriap metabolomics technology was used to analyze the effect of PEG400 on the metabolome of healthy mice, combined with intestinal pathological analysis, aiming to investigate the effects of PEG400 on healthy mice. These results showed that PEG400 significantly altered the structure of gut microbiota, reduced the richness and diversity of intestinal flora, greatly increased the abundance of Akkermansia muciniphila (A. muciniphila), increased the proportion of Bacteroidetes to Firmicutes, and reduced the abundance of many beneficial bacteria. Moreover, PEG400 changed the characteristics of fecal metabolome in mice and induced disorders in lipid and energy metabolism, thus leading to diarrhea, weight loss, and intestinal inflammation in mice. Collectively, these findings provide new evidence for the potential effect of PEG400 ingestion on a healthy host.

Insights into the formulation properties, biocompatibility, and permeability of poorly water-soluble methoxyflavones with PEG400 and propylene glycol.

Herein, thermal and non-thermal techniques were used to elucidate the putative physical and chemical interactions between poorly water-soluble Kaempferia methoxyflavones and PEG400/propylene glycol. Additionally, the biocompatibility of methoxyflavone-glycol solutions was evaluated using Caco-2 cells whereas the absorptive transport was investigated by measuring the apparent permeability coefficient (P app) of the methoxyflavones and transepithelial electrical resistance (TEER) of the Caco-2 cell monolayer. Data from differential scanning calorimetry, Fourier-transform infrared (FTIR), and proton nuclear magnetic resonance (1H NMR) spectroscopic analysis revealed physico-chemical compatibility between the three methoxyflavones and PEG400/propylene glycol. Furthermore, PEG400 and propylene glycol solutions of the methoxyflavones were shown to be compatible with Caco-2 cells at pharmacologically effective concentrations. In vitro transport studies across the Caco-2 cell monolayer revealed high P app values of 24.07 × 10-6 to 19.63 × 10-6 cm s-1 for PEG400 solutions of the methoxyflavones. The TEER values of the Caco-2 cell monolayers indicated that the increased drug transport was partly due to increased tight junction openings, but without compromising the epithelial barrier integrity. The good pharmaceutical and biocompatibility profiles, as well as improved transport of the methoxyflavones in PEG400 and propylene glycol solutions, are suggestive of the worthiness of this approach for further consideration pertaining to the development of these drugs into oral liquid dosage forms.

Glycol 400 assisted preparation of high contact surface TiO2/GO nanocomposites for photocatalytic degradation rhodamine B.

TiO2/graphene oxide (GO) nanocomposites with high contact interface were prepared with glycol 400 (PEG400) served as dispersant. This nanocomposite exhibits improved photocatalytic efficiency in contrast with the nanocomposite prepared without PEG400. In this work, the photocatalytic performance was investigated by observing the degradation rate of Rhodamine B (RhB). And it is found that the mass ratios of GO in nanocomposites plays an important role. When the mass ratio of GO reached 45%, the photocatalytic performance of the nanocomposites reached the highest, which is ∼72%. Moreover, the photocatalytic mechanism was studied through theoretical calculations, which can be summarized as follows: (1) the presence of GO decreases the band gap of TiO2nanoparticles. (2) GO inhibits the the recombination of photogenerated electron-hole pair. (3) GO improves the adsorption capacity of TiO2nanoparticles for RhB. This work promoted the application of TiO2/GO nanocomposites in wastewater treatment.

Experiments on the Electrical Conductivity of PEG 400 Nanocolloids Enhanced with Two Oxide Nanoparticles.

This paper aims to provide some insights into the pH and electrical conductivity of two classes of nanocolloids with PEG 400 as the base fluid. Thus, nanoparticles of two oxides-MgO and TiO2-were added to the base fluid in 5 mass concentrations in the range 0.25-2.5 %wt. The stability was evaluated in terms of pH at ambient temperature, while the electrical conductivity was discussed at both ambient temperature and up to 333.15 K. The electrical conductivity of PEG 400 was previously discussed by this group, while the behavior of the new nanocolloids was debated in terms of the state of the art. More precisely, the influence of MgO increases electrical conductivity, and an enhancement of up to 48% for 0.25% MgO was found, while the influence of TiO2 nanoparticles was found to be in similar ranges. In conclusion, electrical conductivity varies with temperature and the addition of nanoparticles to the base fluid, although the mechanisms that are driving the nanoparticle type and concentration influence are not yet entirely assumed in the available literature.

Multiscale Spectral Analysis on Lysozyme Aqueous Solutions in the Presence of PolyEthyleneGlycol.

Infrared spectroscopy measurements were performed on Lysozyme aqueous solutions also in the presence of PolyEthylene Glycol (PEG 400) as a function of an increasing temperature from T = 27 °C to 90 °C, and, successively in sequence, by decreasing temperatures from T = 90 °C to 27 °C. Data were analyzed by evaluating the spectral difference with respect to the initial spectrum collected at 27 °C. This procedure allows to quantitatively evaluate the thermal restraint related to the thermal scan from T = 27 °C to 90 °C, as well as to introduce a spectral resilience concerning the entire increasing and decreasing thermal paths which allow to highlight the bioprotectant effectiveness of low molecular weight PEG. In particular, the main purpose of the present work is to highlight the effects of a thermal treatment on a mixture of Lysozyme/water and of Lysozyme/water/PEG 400 during an increasing temperature scan, and then after a successive decreasing temperature scan, in order to highlight the bioprotectant role of PEG 400. On that score, an evaluation of the spectral distances of the registered spectra as a function of increasing and decreasing temperatures has been performed and analyzed.

Hydroxypropylation of Polyphenol-Rich Alkaline Extracts from Pinus radiata Bark and Their Physicochemical Properties.

Pinus radiata bark is a rich source of polyphenols, which are mainly composed of proanthocyanidins. This study aimed to utilize P. radiata bark as a polyol source for bio-foam production in the future. Polyphenol-rich alkaline extracts (AEs) from P. radiata bark were prepared by mild alkaline treatment and then derivatized with propylene oxide (PO). Hydroxypropylated alkaline extracts (HAEs) with varying molar substitutions (MS 0.4-8.0) were characterized by FT-IR, NMR, GPC, TGA, and DSC. The hydroxyl value and solubility in commercial polyols were also determined. The molecular weights of the acetylated HAEs (Ac-HAEs) were found to be 4000 to 4900 Da. Analyses of FT-IR of HAEs and 1H NMR of Ac-HAEs indicated that the aromatic hydroxyl groups were hydroxypropylated and showed an increase in aliphatic hydroxyl group content. The glass transition temperature (Tg) of AE and HAEs were 58 to 60 °C, showing little difference. The hydroxyl value increased as the hydroxypropylation proceeded. Although salts were produced upon neutralization after hydroxypropylation, HAEs still showed suitable solubility in polyether and polyester polyols; HAEs dissolved well in polyether polyol, PEG#400, and solubility reached about 50% (w/w). This indicated that neutralized HAEs could be directly applied to bio-foam production even without removing salts.

Solubility and Thermodynamic Properties of Febuxostat in Various (PEG 400 + Water) Mixtures.

The solubility of the poorly soluble medicine febuxostat (FXT) (3) in various {polyethylene glycol 400 (PEG 400) (1) + water (H2O) (2)} mixtures has been examined at 298.2-318.2 K and 101.1 kPa. FXT solubility was measured using an isothermal method and correlated with "van't Hoff, Apelblat, Buchowski-Ksiazczak λh, Yalkowsky-Roseman, Jouyban-Acree, and Jouyban-Acree-van't Hoff models". FXT mole fraction solubility was enhanced via an increase in temperature and PEG 400 mass fraction in {(PEG 400 (1) + H2O (2)} mixtures. Neat PEG 400 showed the highest mole fraction solubility of FXT (3.11 × 10-2 at 318.2 K), while neat H2O had the lowest (1.91 × 10-7 at 298.2 K). The overall error value was less than 6.0% for each computational model, indicating good correlations. Based on the positive values of apparent standard enthalpies (46.72-70.30 kJ mol-1) and apparent standard entropies (106.4-118.5 J mol-1 K-1), the dissolution of FXT was "endothermic and entropy-driven" in all {PEG 400 (1) + H2O (2)} mixtures examined. The main mechanism for FXT solvation in {PEG 400 (1) + H2O (2)} mixtures was discovered to be an enthalpy-driven process. In comparison to FXT-H2O, FXT-PEG 400 showed the strongest molecular interactions. In conclusion, these results suggested that PEG 400 has considerable potential for solubilizing a poorly soluble FXT in H2O.

Automated grindstone chemistry: a simple and facile way for PEG-assisted stoichiometry-controlled halogenation of phenols and anilines using N-halosuccinimides.

A simple electrical mortar-pestle was used for the development of a green and facile mechanochemical route for the catalyst-free halogenation of phenols and anilines via liquid-assisted grinding using PEG-400 as the grinding auxiliary. A series of mono-, di-, and tri-halogenated phenols and anilines was synthesized in good to excellent yields within 10-15 min in a chemoselective manner by controlling the stoichiometry of N-halosuccinimides (NXS, X = Br, I, and Cl). It was observed that PEG-400 plays a key role in controlling the reactivity of the substrates and to afford better regioselectivity. Almost exclusive para-selectivity was observed for the aromatic substrates with free o- and p-positions for mono- and dihalogenations. As known, the decarboxylation (or desulfonation) was observed in the case of salicylic acids and anthranilic acids (or sulfanilic acids) leading to 2,4,6-trihalogenated products when 3 equiv of NXS was used. Simple instrumentation, metal-free approach, cost-effectiveness, atom economy, short reaction time, and mild reaction conditions are a few noticeable merits of this environmentally sustainable mechanochemical protocol.

Syntheses, Molecular Docking and Biological Evaluation of 2-(2- hydrazinyl)thiazoles as Potential Antioxidant, Anti-Inflammatory and Significant Anticancer Agents.

BACKGROUND: Recently, researchers have worked on the development of new methods for the synthesis of bioactive heterocycles using polyethylene glycol as a green solvent. In this context, we report the synthesized 2-(2-hydrazinyl) thiazoles for their in vitro antioxidant, in vitro anti-inflammatory and in vitro anti-cancer activities. OBJECTIVE: The objective of the study was to develop novel antioxidant, anti-inflammatory and anti-cancer drugs. METHODS: At the outset, the condensation of substituted acetophenones 1, thiosemicarbazide 2, and α-haloketones 3 was carried out using PEG-400 (20 mL) in the presence of 5 mol% glacial acetic acid to afford thiosemicarbazones intermediate. Furthermore, these thiosemicarbazones were reacted with α-haloketones 3 to obtain appropriate 2-(2-hydrazinyl) thiazoles. The synthesized compounds were in vitro tested for their antioxidant, anti-inflammatory, and anti-cancer activity. RESULTS: In vitro evaluation report showed that nearly all molecules possessed potential antioxidant activity against 2,2-Diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), superoxide radical (SOR) and hydrogen peroxide (H2O2) radical scavenging activity. Most 2-(2-hydrazinyl) thiazoles derivatives have shown potential anti-inflammatory activity as compared to diclofenac sodium as a reference standard. 2-(2-Hydrazinyl) thiazoles derivatives showed significant anticancer activity for human leukemia cell line K-562 compared to adriamycin as a reference standard. CONCLUSION: All tested compounds showed potential 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and nitric oxide (NO) radical scavenging activity. Among the tested series, 4b, 4d and 4e exhibited good hydrogen peroxide and 4b, 4e, 4f and 4g showed excellent superoxide radical scavenging activity. In addition, the 4b, 4e and 4g compounds revealed potent in vitro anti-inflammatory activity against standard diclofenac sodium drug. 2-(2-Hydrazinyl) thiazole derivatives, such as 4c and 4d, showed significant anticancer activity against human leukemia cell line K-562. Thus, these molecules provide an interesting template for the design and development of new antioxidant, anti-inflammatory, and anti-cancer agents.

Estimating thermodynamic equilibrium solubility and solute-solvent interactions of niclosamide in eight mono-solvents at different temperatures.

Niclosamide is an FDA-approved oral anthelmintic drug currently being repurposed for COVID-19 infection. Its interesting applicability in multiple therapeutic indications has sparked interest in this drug/ scaffold. Despite its therapeutic use for several years, its detailed solubility information from Chemistry Manufacturing & Controls perspective is unavailable. Thus, the present study is intended to determine the mole fraction solubility of niclosamide in commonly used solvents and cosolvents at a temperature range of 298.15-323.15 K. The polymorphic changes from crystalline to monohydrate forms post-equilibration in various solvents were observed. The maximum mole fraction solubility of niclosamide at 323.15 K is 1.103 × 10-3 in PEG400, followed by PEG200 (5.272 × 10-4), 1-butanol (3.047 × 10-4), 2-propanol (2.42 × 10-4), ethanol (1.66 × 10-4), DMSO (1.52 × 10-4), methanol (7.78 × 10-5) and water (3.27 × 10-7). The molecular electrostatic potential showed a linear correlation with the solubility. PEG400 has higher electrostatic potential, and H-bond acceptor count, which forms a hydrogen bond with phenolic -OH of niclosamide and thus enhances its solubility. This data is valuable for the drug discovery and development teams working on the medicinal chemistry and process chemistry of this scaffold.

1,5-Benzothiazepine Derivatives: Green Synthesis, In Silico and In Vitro Evaluation as Anticancer Agents.

Considering the importance of benzothiazepine pharmacophore, an attempt was carried out to synthesize novel 1,5-benzothiazepine derivatives using polyethylene glycol-400 (PEG-400)-mediated pathways. Initially, different chalcones were synthesized and then subjected to a cyclization step with benzothiazepine in the presence of bleaching clay and PEG-400. PEG-400-mediated synthesis resulted in a yield of more than 95% in less than an hour of reaction time. Synthesized compounds 2a-2j were investigated for their in vitro cytotoxic activity. Moreover, the same compounds were subjected to systematic in silico screening for the identification of target proteins such as human adenosine kinase, glycogen synthase kinase-3ß, and human mitogen-activated protein kinase 1. The compounds showed promising results in cytotoxicity assays; among the tested compounds, 2c showed the most potent cytotoxic activity in the liver cancer cell line Hep G-2, with an IC50 of 3.29 ± 0.15 µM, whereas the standard drug IC50 was 4.68 ± 0.17 µM. In the prostate cancer cell line DU-145, the compounds displayed IC50 ranges of 15.42 ± 0.16 to 41.34 ± 0.12 µM, while the standard drug had an IC50 of 21.96 ± 0.15 µM. In terms of structural insights, the halogenated phenyl substitution on the second position of benzothiazepine was found to significantly improve the biological activity. This characteristic feature is supported by the binding patterns on the selected target proteins in docking simulations. In this study, 1,5-benzothiazepines have been identified as potential anticancer agents which can be further exploited for the development of more potent derivatives.

Fabrication and Evaluation of Transdermal Delivery of Carbamazepine Dissolving Microneedles.

This project aims to prepare hydrogel microneedle patches (MNs) as a painless method to deliver carbamazepine transdermally. This can be used as a sustained release system that offers the advantages of lower gastrointestinal side effects and avoids the first-pass metabolism of the drug. MNs were composed of two medicated layers, a microneedle layer and a base layer. MNs were fabricated using polyvinyl alcohol with or without polyvinylpyrrolidone Kollidon 30 as a matrix polymer and in the presence of selected solubilizing agent (polyethylene glycol 400, Tween 80, or α-tocopherol polyethylene glycol). Freezing-thawing cycle was evaluated as one of the processing parameters that may affect the drug release. The MNs were evaluated for their weight variation, base thickness, and content uniformity. The physicochemical compatibility between carbamazepine and the polymers was estimated by Fourier transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and X-ray powder diffraction. Evaluation for the in vitro release studies and ex vivo permeation studies was performed. The prepared MNs were flexible, clear, and uniform in weight, base thickness, and drug content. Physicochemical characterizations showed that carbamazepine was amorphous in most of the MNs. In vitro release and ex vivo permeation studies of carbamazepine were significantly higher for MNs containing a combination of 1:1 w/w of PEG 400 and Tween 80 as solubilizing agents where the release was extended over 96 h, with the release of 85.2% and 59.6% permeation percentage compared to other MNs. A significant effect of the freezing-thawing cycle on the release profile of the drug was observed. The hydrogel MNs are shown to be stable under the studied storage conditions.

The Role of Common Solvents against Pseudomonas aeruginosa-Induced Pathogenicity in a Murine Burn Site Infection Model.

Dimethyl sulfoxide (DMSO) and polyethylene glycols (PEGs) are frequently used as potent excipients in pharmaceutical formulations. However, these agents also have an interesting antimicrobial and anti-inflammatory profile that could interfere with the efficacy testing of anti-infective compounds when the latter are solubilized in DMSO or PEGs. Here, we demonstrate the antimicrobial and anti-inflammatory effects of DMSO-PEG400 in a murine Pseudomonas aeruginosa infection model, aiming to draw attention to the appropriate selection of solvents for difficult-to-solubilize anti-infectives. IMPORTANCE Our study demonstrates the antimicrobial and anti-inflammatory effects of the combination of DMSO and PEG400 against Pseudomonas aeruginosa in vitro and in vivo in a murine infection model of heightened intestinal permeability. The aim of this study is to draw attention to the appropriate selection of solvents for difficult-to-solubilize anti-infective compounds, to avoid interference with the assay or system tested. This is an extremely important consideration, since potential antimicrobial and anti-inflammatory effects of the solvent vehicle are detrimental to research studies on the efficacy of new anti-infective agents, given that the vehicle effect can mask the effect of the tested compounds. Our results can therefore be of great value to the scientific community, as they can guide researchers in the future to avoid this significant pitfall that can cost substantial amounts of money and valuable time during investigations of the effects of novel, difficult-to-solubilize antimicrobial compounds.

Nonaqueous Polyethylene Glycol as a Safer Alternative to Ethanolic Propolis Extracts with Comparable Antioxidant and Antimicrobial Activity.

We compared the chemical composition, antioxidant and antimicrobial activity of two propolis extracts: one obtained with nonaqueous polyethylene glycol, PEG 400 (PgEP), and the other obtained with ethanol (EEP). We analyzed the total phenolic content (TPC) and the concentrations of ten markers of propolis antioxidant activity with HPLC-UV: caffeic acid, p-coumaric acid, trans-ferulic acid, trans-cinnamic acid, kaempferol, apigenin, pinocembrin, chrysin, CAPE, and galangin. Antioxidant activity was tested using DPPH and FRAP assay, and antimicrobial activity was assessed through minimum inhibitory concentrations (MICs) and minimum biofilm eradication concentration (MBEC) determination. Maceration gave the yield of propolis of 25.2 ± 0.08% in EEP, and 21.5 ± 0.24% in PgEP. All ten markers of antioxidant activity were found in both extracts, with all marker concentrations, except kaempferol, higher in EEP. There was no significant difference between the TPC and antioxidant activity of the PgEP and the EEP extract; TPC of PgEP was 16.78 ± 0.23 mg/mL, while EEP had TPC of 15.92 ± 0.78 mg/mL. Both extracts had antimicrobial activity against most investigated pathogens and Staphylococcus aureus, Acinetobacter baumannii, and Escherichia coli biofilms. EEP was more effective against all tested susceptible pathogens, except E. coli, possibly due to higher content of kaempferol in PgEP relative to other polyphenols. Nonaqueous PEG 400 could be used for propolis extraction. It gives extracts with comparable concentrations of antioxidants and has a good antioxidant and antimicrobial activity. It is a safe excipient, convenient for pediatric and veterinary formulations.

Application of Quality by Design to the robust preparation of a liposomal GLA formulation by DELOS-susp method.

Fabry disease is a lysosomal storage disease arising from a deficiency of the enzyme α-galactosidase A (GLA). The enzyme deficiency results in an accumulation of glycolipids, which over time, leads to cardiovascular, cerebrovascular, and renal disease, ultimately leading to death in the fourth or fifth decade of life. Currently, lysosomal storage disorders are treated by enzyme replacement therapy (ERT) through the direct administration of the missing enzyme to the patients. In view of their advantages as drug delivery systems, liposomes are increasingly being researched and utilized in the pharmaceutical, food and cosmetic industries, but one of the main barriers to market is their scalability. Depressurization of an Expanded Liquid Organic Solution into aqueous solution (DELOS-susp) is a compressed fluid-based method that allows the reproducible and scalable production of nanovesicular systems with remarkable physicochemical characteristics, in terms of homogeneity, morphology, and particle size. The objective of this work was to optimize and reach a suitable formulation for in vivo preclinical studies by implementing a Quality by Design (QbD) approach, a methodology recommended by the FDA and the EMA to develop robust drug manufacturing and control methods, to the preparation of α-galactosidase-loaded nanoliposomes (nanoGLA) for the treatment of Fabry disease. Through a risk analysis and a Design of Experiments (DoE), we obtained the Design Space in which GLA concentration and lipid concentration were found as critical parameters for achieving a stable nanoformulation. This Design Space allowed the optimization of the process to produce a nanoformulation suitable for in vivo preclinical testing.

Acetaminophen and tramadol hydrochloride-loaded soft gelatin capsule: preparation, dissolution and pharmacokinetics in beagle dogs.

The objective of this study was to develop a novel acetaminophen and tramadol hydrochloride-loaded soft capsule (ATSC) with enhanced bioavailability of tramadol. The ATSC was manufactured in a pilot-scale batch size with the capsule contents composed of tramadol, acetaminophen, PEG 400 and Capmul MCM at a weight ratio of 37.5:325:177.5:30. Moreover, its dissolution, stability and pharmacokinetics in beagle dogs were carried out compared to commercial tablet. The dissolved amounts of acetaminophen from the ATSC and commercial tablet were not significantly different. However, compared to the latter, the former had significantly higher dissolution rate of tramadol at the initial times. In beagle dogs, the ATSC provided no significant difference in plasma concentrations and AUC of acetaminophen than did the commercial tablet; however, it significantly improved those of tramadol compared to the other, indicating the enhanced oral bioavailability of tramadol. Compared to the commercial tablet, the ATSC had a larger AUC value for tramadol (55.27 ± 11.06 vs. 92.62 ± 21.52 h·ng/ml). In the accelerated long-term stability, the ATSC offered higher than 96% drug content of acetaminophen and tramadol, suggesting that it was stable for at least six months. Therefore, this ATSC would be a recommendable candidate with enhanced oral bioavailability and excellent stability.

Investigation of Effect of Polyethylene Glycol 400 on Pharmacokinetics and Anti-inflammatory Effect of Baicalin Based on UPLC-MS/MS and Molecular Docking Techniques / 中国实验方剂学杂志

Objective:To investigate the effects of polyethylene glycol 400 （PEG400） on the pharmacokinetics and anti-inflammatory effect of baicalin， and to preliminarily explore the anti-inflammatory effects of baicalin and its main metabolite baicalein 6-<italic>O</italic>-<italic>β</italic>-<italic>D</italic>-glucuronide （B6G） by molecular docking. Method:Rats were randomly divided into two groups with water and PEG400 as the dissolving matrix， and rats were administrated the equal dose of baicalin aqueous solution （baicalin+water group） and baicalin PEG400 solution （baicalin+PEG400 group）. After the plasma samples were processed at different time periods， the concentrations of baicalin and B6G in rat plasma were determined by ultra performance liquid chromatography-tandem mass spectrometry （UPLC-MS/MS）， and pharmacokinetic parameters were processed by DAS 3.2.2 software. Mice were randomly divided into a blank group （normal saline， 20 mL·kg^-1）， aspirin group （dose of 0.2 g·kg^-1）， baicalin/baicalin+PEG400 high and low dose （3.0， 1.5 g·kg^-1） groups， after continuous administration for 7 days， the mouse ear swelling and foot swelling models were established， and the swelling degree and swelling inhibition rate were calculated. Result:The pharmacokinetic study showed that compared with baicalin+water group， the plasma concentrations of baicalin and B6G increased after administration of baicalin PEG400 solution， and the area under the curve （AUC_0-<italic>_t</italic>） increased by 2.36， 1.97 times， and the peak concentration （<italic>C</italic>_max） increased by 2.12， 1.65 times， respectively. The results of mouse ear and foot swelling inflammation models showed that the anti-inflammatory effect was enhanced after intragastric administration of baicalin PEG400 solution. In addition， molecular docking results showed that baicalin and B6G could site bind to multiple target proteins ［tumor necrosis factor （TNF）-<italic>α</italic>， interleukin （IL）-6， IL-1<italic>β</italic>， prostaglandin E₂ （PGE₂） and nuclear transcription factor-<italic>κ</italic>B （NF-<italic>κ</italic>B）］ with higher affinity， which was superior to the positive drug aspirin. Conclusion:PEG400 can increase the plasma concentration of baicalin and its main metabolite B6G， and enhance the anti-inflammatory effect. Baicalin and B6G can form strong hydrogen bonds with various inflammatory factors and of nuclear transcription factors， it is speculated that baicalin and B6G jointly play an anti-inflammatory role.

Enamel Deproteinization: Will It Save The Shear Bond Strength For The Sake Of Preventing White Spot Lesions? / Desproteinização do esmalte: salvará a resistência ao cisalhamento para prevenir lesões de manchas brancas?

Objective: This study attempted to investigate the effect of enamel deproteinization using citric acid, PEG 400 and NaOCL on the shear bond strength of orthodontic brackets to enamel using nano-silver modified resin for the prevention of white spot lesions. Material and Methods: 68 premolars were used in the study; nano-silver modified adhesive resin was used to bond orthodontic brackets to the enamel. Specimens were divided into 4 groups according to the applied surface treatment before bonding. Group I (control): acid etching with 37% phosphoric acid. Group II: deproteinization using 5.25% sodium hypochlorite (NaOCl) before acid etching. Group III:deproteinization using 10% citric acid before acid etching. Group IV:deproteinization using 5% polyethylene glycol (PEG 400) before acid etching. The specimens were then thermo- cycled for 6000 cycles. They were examined for surface roughness, shear bond strength and using electron microscope. Results: In both surface roughness and shear bond strength tests, Group III (citric acid) showed the highest values, followed by Group II (sodium hypochlorite); (p < 0.001). The least values were shown for Groups I (control) and IV (PEG 400), with no statistically significant difference between them (p = 0.948). SEM revealed etching pattern type 1 and 2 in the citric acid group while PEG 400 showed shallower micro- porosities. Conclusions: Deproteinization of enamel using either NaOCl or citric acid increased the bond strength of nano-sliver modified resin to enamel, with citric acid showing greater increase in bond strength. Deproteinization using PEG 400 did not increase the bond strength. (AU)

Objetivo: Este estudo buscou investigar o efeito da desproteinização do esmalte utilizando ácido cítrico, PEG 400 e NaOCl na resistência ao cisalhamento de braquetes ortodônticos ao esmalte usando resina modificada com nanoprata para a prevenção de lesões de manchas brancas. Material e Métodos: 68 pré-molares foram usados no estudo; resina adesiva modificada com nanoprata foi usada para colar os braquetes ortodônticos ao esmalte. Os corpos-de-prova foram divididos em 4 grupos de acordo com o tratamento de superfície aplicado antes da colagem. Grupo I (controle): condicionamento ácido com ácido fosfórico a 37%. Grupo II: desproteinização com hipoclorito de sódio a 5,25% (NaOCl) antes do condicionamento ácido. Grupo III: desproteinização com ácido cítrico a 10% antes do condicionamento ácido. Grupo IV: desproteinização com polietilenoglicol 5% (PEG 400) antes do condicionamento ácido. As amostras foram então termocicladas por 6.000 ciclos. Eles foram examinados quanto à rugosidade da superfície, resistência ao cisalhamento e usando microscópio eletrônico. Resultados: Nos testes de rugosidade superficial e resistência ao cisalhamento, o Grupo III (ácido cítrico) apresentou os maiores valores, seguido do Grupo II (hipoclorito de sódio); (p <0,001). Os menores valores foram apresentados para os Grupos I (controle) e IV (PEG 400), sem diferença estatisticamente significativa entre eles (p = 0,948). A microscopia eletrônica revelou padrão de ataque tipo 1 e 2 no grupo de ácido cítrico, enquanto PEG 400 mostrou microporosidades mais rasas. Conclusões: A desproteinização do esmalte com NaOCl ou ácido cítrico aumentou a força de união da resina modificada com nanoprata ao esmalte, com o ácido cítrico apresentando maior aumento na força de união. A desproteinização usando PEG 400 não aumentou a resistência de união. (AU)