Development of taste-masking microcapsules containing azithromycin by fluid bed coating for powder for suspension and in vivo evaluation.

This research aims to develop bitter taste-masking microcapsules containing azithromycin (AZI) by a simpler and familiar method, fluid-bed coating technology, in comparison with Zithromax®. Cores of microcapsules, AZI microparticles, were prepared by fluid-bed granulation, then taste-masking polymer was covered on by fluid-bed coating technique. Eudragit L100, Eudragit RL100, and ethyl cellulose in single and combined with Eudragit L100 and Eudragit E100 were used as taste-masking polymers. The obtained microcapsules were characterised by taste-masking ability, in vitro release, SEM, coating thickness, and coating efficiency. Combination of ethyl cellulose and Eudragit E100 (3:1) in coating thickness of 45.13 ± 2.12% w/w prevents AZI release from microcapsules below bitter taste threshold (1.78 ± 1.17 µg/ml). Bioavailability of powders containing AZI microcapsules and pH modulators (50 mg Na3PO4 and 35 mg Mg(OH)2) was not significantly different from the reference product (Zithromax®, Pfizer, New York, NY) in the rabbit model (p > 0.05). These results support the possibility of developing a generic product containing AZI.

Synergistic effect of miscible cellulose-based microparticles and pH modulators on the bioavailability of a weakly basic drug and its metabolites.

This study aimed to evaluate the miscibility of cellulose derivatives to improve the release rate and stability of microparticles containing the weakly basic drug itraconazole (ITZ). We also investigated the effect of some organic acids on the microenvironmental pH (pHm) and the release rate of ITZ from the cellulose-based microparticles. The synergistic effect of cellulose-based microparticles and pHm modulators on the bioavailability of ITZ compared with the reference product was investigated in a rabbit model. Differential scanning calorimetry and Fourier-transform infrared spectroscopy (FTIR) analysis showed that ITZ, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose phthalate were miscible at a ratio of 1.5:3:1 (w/w/w), and the stability of the microparticles was maintained for 6 months under accelerated conditions. In addition, X-ray diffraction, FTIR, and scanning electron microscopy were used to characterize the properties of the microparticles. Through the titration technique and determination of pHm, the combination of fumaric acid and maleic acid (1:2, w/w) was found to be the most effective pHm modulator for microparticles. The integration of cellulose-based microparticles and pHm modulators showed a synergistic effect on the flux and relative bioavailability of ITZ and its active metabolite OH-ITZ (182.60 % and 217.67 %, respectively) when compared with the reference product.

Green Analytical Method for Simultaneous Determination of Glucosamine and Calcium in Dietary Supplements by Capillary Electrophoresis with Capacitively Coupled Contactless Conductivity Detection.

The need for analytical methods that are fast, affordable, and ecologically friendly is expanding. Because of its low solvent consumption, minimal waste production, and speedy analysis, capillary electrophoresis is considered a "green" choice among analytical separation methods. With these "green" features, we have utilized the capillary electrophoresis method with capacitively coupled contactless conductivity detection (CE-C4D) to simultaneously determine glucosamine and Ca2+ in dietary supplements. The CE analysis was performed in fused silica capillaries (50 µm inner diameter, 40 cm total length, 30 cm effective length), and the analytical time was around 5 min. After optimization, the CE conditions for selective determination of glucosamine and Ca2+ were obtained, including a 10 mM tris (hydroxymethyl) aminomethane/acetic acid (Tris/Ace) buffer of pH 5.0 as the background electrolyte; separation voltage of 20 kV; and hydrodynamic injection (siphoning) at 25 cm height for 30 s. The method illustrated good linearity over the concentration range of 5.00 to 200 mg/L of for glucosamine (R 2 = 0.9994) and 1.00 to 100 mg/L for Ca2+ (R 2 = 0.9994). Under the optimum conditions, the detection limit of glucosamine was 1.00 mg/L, while that of Ca2+ was 0.05 mg/L. The validated method successfully analyzed glucosamine and Ca2+ in seven dietary supplement samples. The measured concentrations were generally in line with the values of label claims and with cross-checking data from reference methods (HPLC and ICP-OES).

Integration of lornoxicam nanocrystals into hydroxypropyl methylcellulose-based sustained release matrix to form a novel biphasic release system.

The study aims to (a) enhance the solubility of a poorly soluble drug by optimization of nanocrystal formulation using the top-down approach and (b) modify the release profile of this drug, which exhibits a short elimination half-life, by the integration of a fast-release phase containing the optimized nanocrystals and a sustained-release phase in a compression-coated tablet. Nanocrystals of the model drug (lornoxicam; LNX) was prepared by simultaneous application of jet-milling and ball-milling techniques. Investigation of the precipitation inhibition capacity, thermal property, and interaction of different polymers with the drug revealed polyvinyl pyrrolidone K30 (PVP) as the most effective stabilizer for nanocrystals. The immediate-release layer containing the optimized nanocrystals (size of 279.5 ± 11.25 nm and polydispersity index of 0.204 ± 0.01) was then compressed on a zero-order sustained-release matrix core using different derivatives of hydroxypropyl methylcellulose (HPMC). Application of the Design of Experiment approach (DoE) was applied to optimize the formulation of tablet. Analysis of drug concentration in dog plasma by liquid chromatography-tandem mass spectrometry demonstrated an improvement in the release behavior of LNX from the optimal compression-coated tablet integrating a HPMC-based sustained release matrix core and a PVP-stabilized lornoxicam nanocrystals coating layer compared to the reference product.

Heterocyclic amines detected in cooked meats and fishes from street markets and restaurants in the city of Hanoi, Vietnam: A Pilot local field investigation findings in 2020.

Background: Street food has been a typical culinary feature of many countries. These foods, mainly, meats and fish, were often fried, and grilled with varied marinade and preparation. However, foods that contain a lot of protein after processing at high temperatures always have many risks, including cancer risks of which heterocyclic aromatic amines (HAAs) have been one of the typical compounds. However, there is a lack of data on HAAs in low- and medium-income countries to date. Objective: The aim was to examine the concentration of HAAs including 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP); 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx); and 2-Amino-9H-pyrido[2,3-b]indole (AαC) in cooked meat and fish samples. Methods: Three standards including PhIP, MeIQx, AαC, and three isotopically labeled internal standards PhIP-d3, MeIQx-d3, and AαC-15N3 were purchased from Toronto Research Chemicals, Inc. (Toronto, Canada). Formic acid, HPLC-grade methanol, acetonitrile, water, sodium chloride, and magnesium sulfate were supplied by Sigma-Aldrich (St. Louis, MO, USA). We collected cooked meat and fish samples from street markets and restaurants in the area of Cau Giay district, Hanoi, Vietnam in 2020. The collected samples were prepared for LC-MS/MS analysis. Results: Among 23 selected samples of cooked beef, fish, chicken, and pork, we have detected PhIP(ng/g) in 9 samples (the mean 2.68, standard deviation 2.41, median 2.40, minimum 0.33, and maximum 7.19); and AαC(ng/g) in 6 samples (the mean 0.74, standard deviation 0.75, median 0.45, minimum 0.12, and maximum 1.90); and MeIQx(ng/g) was not detected in all samples. Three grilled pork samples were positive with AαC at a concentration of 0.75-1.95 ng/g. Five fish samples have been detected to contain PhIP at the concentration of mean of 3.17; the standard deviation of 1.47, and the median of 3.90 ng/g. Two fried chickens have been detected to contain PhIP at the concentration of 0.41 and 7.19 ng/g. Conclusions: We detected a considerable amount of PhIP concentration in the collected fried fish and other fried meat samples and AαC in grilled and fried pork, beef, and chicken samples. The findings warrant further measuring more compounds of the HAA group and extending the number of real samples, as well as types of samples for example cooked meats, fish, fried eggs, tofu, and other cooked food receipts by regions in Vietnam.

Effect of surfactant on the in vitro dissolution and the oral bioavailability of a weakly basic drug from an amorphous solid dispersion.

This study aimed to investigate the effect of a surfactant on the liquid-liquid phase separation, dissolution, diffusion, and the oral bioavailability of a weakly basic drug (l-tetrahydropalmatine; l-THP) from an amorphous solid dispersion (ASD). The carrier used in the ASD was optimized by the application of casting film, solvent shift, and pH shift methods. The interaction between the optimized carrier (HPMCP) and l-THP was then evaluated by Fourier transform-infrared spectroscopy and powder X-ray diffraction. The impact of the surfactant on ASD prepared by the spray-drying method was evaluated by both in vitro and in vivo studies. The results of in vitro studies, including liquid-liquid phase separation, drug diffusion, and pH-shift dissolution, indicated that the addition of a surfactant at a certain concentration below critical micelle concentration to ASD caused the precipitation of and a reduction in the membrane diffusion of l-THP in pH 6.8. This observation was confirmed in an in vivo study in which the drug concentration of l-THP in rabbit plasma was determined by the LC-MS/MS analysis method. Then the absolute and relative bioavailability of l-THP was calculated from the obtained pharmacokinetic parameters. Specifically, the addition of 1.5% surfactant (Poloxamer 188) to the binary ASD decreased the relative bioavailability of l-THP by approximately 2.4 times compared with the original binary ASD. Besides, the study proved that l-THP had low absolute bioavailability (around 1.24%), and the application of binary ASD was meaningful in enhancing the oral bioavailability of l-THP by around 334.77% compared to the raw material. The study is expected to provide a better understanding of how different dosage forms influence the bioavailability of l-THP, thereby allowing the selection of the optimal approach for this weakly basic drug.

Rapid Screening and Quantitative Determination of Illegal Phosphodiesterase Type 5 Inhibitors (PDE-5i) in Herbal Dietary Supplements.

Phosphodiesterase type 5 inhibitors (PDE-5i) are the first-line medication for oral erectile dysfunction, which are used according to the prescription of doctors. However, these substances have been found illegally in supplementary foods. The quality and safety of dietary supplements for enhancing male sexual performance have been questioned, raising the need for continual development of analytical methods. Liquid chromatography coupled with high-resolution mass spectrometry has become one of the most effective methods to identify and measure PDE-5i concentration. In this research, we focused on (i) developing and validating an effective screening and quantitation method for more than 53 PDE-5i in ingredients and supplementary products using LC-Q-Exactive after a simple sample extraction and (ii) assessing PDE-5i content in natural-based supplementary products available in Vietnam market. The extraction method used a small amount of organic solvent, which makes it more environmentally friendly (greener). The developed method has a limit of detection of 0.4 mg/kg, a limit of quantitation of 1.2 mg/kg, recoveries from 80 to 110%, and repeatability lower than 15%. Ninety-two herbal supplementary foods and ingredients used for enhancement of male sexual performance available in Vietnamese markets were collected. Fourteen PDE-5i including conventional and novel analogous were detected and measured in eighteen food supplements and two formulation ingredient samples.

Antibiotic and antiparasitic residues in surface water of urban rivers in the Red River Delta (Hanoi, Vietnam): concentrations, profiles, source estimation, and risk assessment.

Antibiotic residues and antimicrobial resistance in surface water are issues of global concern, especially in developing countries. In this study, the occurrence of seven antibiotics and one antiparasitic agent was determined in surface water samples collected from four rivers running through Hanoi urban area in the Red River Delta, northern Vietnam. The pharmaceuticals in water samples were analyzed by solid-phase extraction combined with liquid chromatography-tandem mass spectrometry method. The concentrations of pharmaceuticals in our samples ranged from 3050 to 16,700 (median 7800) ng/L, which were generally higher than levels found in river water from many other locations in the world. Amoxicillin, oxfendazole, and lincomycin were the most dominant and frequently detected compounds (detection rate 100%), which together accounted for 76 ± 14% of total concentrations. Sulfacetamide and sulfamethoxazole were detected at moderate concentrations in more than two-thirds of the analyzed samples. The remaining antibiotics (i.e., azithromycin, ciprofloxacin, and ofloxacin) were found at lower detection frequency and concentrations. Antibiotic concentrations in the water samples were not significantly different between the investigated rivers. Meanwhile, levels of pharmaceuticals in the samples collected in February 2020 were higher than those found in the remaining samples, largely due to the sharp decrease in sulfamethoxazole and azithromycin concentrations of the samples collected in March and April. Considerable ecological risks of antibiotics in surface water were estimated for some compounds such as amoxicillin, ciprofloxacin, and ofloxacin.

LC-MS/MS Method for Rapid Quantification of Progesterone in Rabbit Plasma and Its Application in a Pharmacokinetic Study of the Transdermal Formulation.

A rapid and effective method using QuEChERS-based sample preparation procedure and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis has been developed and validated to determine progesterone in rabbit plasma. The analyte was extracted from plasma by acetonitrile with phase partitioning by a mixture of magnesium sulfate and sodium chloride. The supernatant was then directly injected into LC-MS/MS in a positive electrospray ionization mode and quantified using progesterone-d9 as the internal standard. The method linearity was in the range from 1 ng/mL (LOQ) to 200 ng/mL. Method recovery was from 86.0% to 103%, and repeatability was lower than 5.5%. The plasma sample was stable for 12 weeks stored at 18 ± 2°C. This method was applied to quantify progesterone in rabbit plasma in a pharmacokinetic study of two transdermal formulations: a reference drug and a eutectic-hydrogel system. The data indicate that the eutectic-hydrogel system's bioavailability was 1.5 times better than that of the reference drug, and the transdermal system is a potential drug delivery system for progesterone.

Isolation and characterization of N-hydroxyethyl dithio-desethyl carbodenafil from a health supplement.

A new phosphodiesterase type-5 inhibitor (PDE-5i) with thiocarbonyl and thiolactam skeleton has been identified. The unknown compound has very similar properties like dithio-desmethyl carbodenafil, which was detected alongside during the screening process. It has been isolated by a semi-preparative high performance liquid chromatography tandem ultra-violet detector (HPLC-UV). The purified compound has been characterized using Fourier-transform infrared spectroscopy (FTIR), high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance spectroscopy (NMR). It is named as N-hydroxyethyl dithio-desethyl carbodenafil due to attachment of a hydroxyethyl group to the heterocyclic nitrogen of dithio-desethyl carbodenafil.

Formulation and biopharmaceutical evaluation of supersaturatable self-nanoemulsifying drug delivery systems containing silymarin.

The first objective of this study was to optimize a supersaturatable self-nanoemulsifying drug delivery system (S-SNEDDS) containing silymarin through the investigation of the single and synergistic effect of either SNEDDS or a precipitation inhibitor on dissolution efficiency (DE) of silymarin. The bioavailability and hepatoprotective activity of S-SNEDDS were then compared to those of a branded product (Legalon®, Meda). SNEDDS containing silymarin was developed by titration technique, and Poloxamer 407 was selected as the optimal precipitation inhibitor by using casting film and solvent-shift method. The interaction of silybin (the major active constituent of silymarin) and the polymer was then determined by differential scanning calorimetry, powder X-ray diffractometry (PXRD), Fourier transforms infrared spectroscopy and 1H NMR analysis. The combination of two techniques including SNEDDS and addition of 10% of Poloxamer 407 remarkably increased DE4h (88.28%) compared to the reference product (6.41%). The relative bioavailability of S-SNEDDS versus Legalon® was about 760%. The hepatoprotective activity of S-SNEDDS in CCl4-induced mice was also superior to the commercial product in declining both the levels of serum transaminases (ALT, AST) and lipid peroxidation as well as glutathione and superoxide dismutase (SOD) activities under tested doses calculated as silybin (10, 25 and 50 mg/kg). These biopharmaceutical and pharmacological advantages of S-SNEDDS indicated prospects in the development of a novel product that offers lower strength of silymarin while enhancing therapeutic outcomes.

Formulation and biopharmaceutical evaluation of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets.

The objective of this study was to prepare and evaluate some physiochemical and biopharmaceutical properties of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets. In the first stage of the study, the bitter taste masking microparticles were prepared by solvent evaporation and spray drying method. When compared to the bitter threshold (32.43µg/ml) of azithromycin (AZI), the microparticles using AZI:Eudragit L100=1:4 and having a size distribution of 45-212µm did significantly mask the bitter taste of AZI. Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance spectroscopy (1H NMR) proved that the taste masking of microparticles resulted from the intermolecular interaction of the amine group in AZI and the carbonyl group in Eudragit L100. Differential scanning calorimeter (DSC) analysis was used to display the amorphous state of AZI in microparticles. Images obtaining from optical microscopy and scanning electron microscopy (SEM) indicated the existence of microparticles in regular cube shape with many layers. In the second stage, dispersible tablets containing microparticles (DTs-MP) were prepared by direct compression technique. Stability study was conducted to screen pH modulators for DTs-MP, and a combination of alkali agents (CaCO3:NaH2PO4, 2:1) was added into DTs-MP to create microenvironment pH of 5.0-6.0 for the tablets. The disintegration time of optimum DTs-MP was 53±5.29s and strongly depended on the kinds of lubricant and diluent. The pharmacokinetic study in the rabbit model using liquid chromatography tandem mass spectrometry showed that the mean relative bioavailability (AUC) and mean maximum concentration (Cmax) of DTs-MP were improved by 2.19 and 2.02 times, respectively, compared to the reference product (Zithromax®, Pfizer).

Development of solidified self-microemulsifying drug delivery systems containing l-tetrahydropalmatine: Design of experiment approach and bioavailability comparison.

The study first aimed to apply a design of experiment (DoE) approach to investigate the influences of excipients on the properties of liquid self-microemulsifying drug delivery system (SMEDDS) and SMEDDS loaded in the pellet (pellet-SMEDDS) containing l-tetrahydropalmatine (l-THP). Another aim of the study was to compare the bioavailability of l-THP suspension, liquid SMEDDS and pellet-SMEDDS in the rabbit model. By using Central Composite Face design (CCF), the optimum ratio of Capryol 90, and Smix `(Cremophor RH 40: Transcutol HP) in the formulation of SMEDDS was determined. This optimum SMEDDS was absorbed on the solid carrier (Avicel or Aerosil) for the preparation of pellet-SMEDDS by extrusion and spheronization method. The ANOVA table indicated that Avicel was more effective than Aerosil, the traditional solid carrier, in both terms of preservation of dissolution rate of l-THP from the original SMEDDS and pelletization yield. Results obtained from scanning electron microscopy (SEM) indicated that the existence of liquid SMEDDS droplets on the surface of pellet-SMEDDS was due to the absorption on Avicel. The powder X-ray diffractometry proved the amorphous state of l-THP in pellet-SMEDDS. Pharmacokinetic study in the rabbit model using liquid chromatography tandem mass spectrometry showed that the SMEDDS improved the oral bioavailability of l-THP by 198.63% compared to l-THP suspension. Besides, pharmacokinetics study also proved that the mean relative bioavailability (AUC) and mean maximum concentration (Cmax) of pellet-SMEDDS were not significantly different from the original liquid SMEDDS (p > 0.05).