•Effects of ion-pairing agent and counter ion on peak capacity were investigated.•The system configuration was fine-tuned to enhance resolving power.•ACN in IP-RPLC provides better chromatographic ...resolution than MeOH.•Column comparison was conducted at the kinetic performance limit (1000 bar).•Sub-minute separation and high-resolution analysis with coupled columns are demonstrated.
A generic performance comparison strategy has been developed to evaluate the impact of mobile-phase additives (ion-pairing agent / counter ion systems), distinct stationary phases on resulting resolving power, and MS detectability of oligonucleotides and their critical impurities in gradient IP-RPLC. Stationary-phase considerations included particle type (core-shell vs. fully porous particles), particle diameter, and pore size. Separations were carried out at 60°C to optimize mass transfer (C-term). The incorporation of an active column preheater mitigated thermal mismatches, leading to narrower peaks and overcoming peak splitting. Acetonitrile as organic modifier outweighed methanol in terms of peak-capacity generation and yielded a 30% lower back pressure. Performance screening experiments were conducted varying ion-pairing agents and counter ions, while adjusting gradient span achieved an equivalent effective retention window. Hexafluoromethylisopropanol yielded superior chromatographic resolution, whereas hexafluoroisopropanol yielded significantly higher MS detection sensitivity. The 1.7 µm core-shell particle columns with 100 Å pores provided maximum resolving power for small (15–35 mers) oligonucleotides. Sub-min analysis for 15–35 polyT ladders was achieved operating a 50 mm long column at the kinetic performance limits. High-resolution separations between a 21-mer modified RNA sequence oligonucleotides and its related (shortmer and phosphodiester) impurities and complementary strand were obtained using a coupled column set-up with a total length of 450 mm.
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.
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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.
N-Hydroxyethyl dithio-desethyl carbodenafil.
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•Adulterated health supplement with dithio-desmethyl carbodenafil and an unknown compound.•Elucidation of N-hydroxyethyl dithio-desethyl ...carbodenafil by FTIR, HRMS and NMR.•Direct bonding of a hydroxyethyl group to the heterocyclic nitrogen of dithio-desethyl carbodenafil.
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.
A capsaicin cream was formulated by optimizing the rheological stability, the release behavior of the drug, and the pharmacological effect.
This study aimed to: (a) apply the Design of Experiment ...approach to study the rheological stability and release behaviors of a drug (capsaicin) from a formulated oil-in-water cream and (b) investigate the skin irritation and anti-inflammatory and analgesic effects of the optimized cream.
The cream prepared by the emulsification method was optimized using the central composite design, and then the pharmacological effect in experimental animals was determined using Complete Freund's adjuvant (CFA).
The effects of a permeation enhancer (X1), Vaseline (X2), and surfactants (X3) on the fluctuation of the ratio of the viscous modulus (G ') to elastic modulus (G') (tan δ) after three cycles of cooling-heating (10-40°C), flux, and skin deposition of capsaicin after 8 h on mouse skin were statistically analyzed and optimized. The final obtained CAP-cream did not cause irritation in the rabbit model and produced comparable anti-inflammatory and analgesic effects to the reference product (Voltaren® emulgel).
This study successfully integrated the DoE approach, rheological science, and pharmacological studies to develop a stable and highly effective semi-solid product containing capsaicin.
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.
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.
This paper presents a comparison of the three distinctive well-known control techniques, including Linear Quadratic Regulator (for short, LQR), Sliding Mode Control (for short, SMC), and Fuzzy Logic ...Control (for short, FLC). Each controller is in a different control category; LQR is an optimal controller employed in both linear and nonlinear systems, SMC is a nonlinear controller commonly applied in a nonlinear system, and the Fuzzy controller is the intelligent controller which can be archived by user’s experiment or other learning techniques. Beside the three main controllers for stabilizing at the equilibrium point, the swing-up controller is designed based on energy-based method to bring the system at the initial position close to the equilibrium points. Finally, the performance and the validity of the three methods are verified through both simulation and experimental results.
The publication presents the results of the exposure assessment within the framework of a joint Russian-Vietnamese study aimed at children’s health risk assessment associated with the N-nitrosamines ...contamination in food. People who permanently cared for children aged from six months to three years were questioned in two urbanized areas of Vietnam and Russia – in the cities of Hanoi (n=481) and Perm (n=183). It is shown that the structure of food consumption among children up to three years differs significantly. Children’s nutrition in Russia is includes a lot of dry soluble cereals and canned meat/vegetables. The most common product in children's nutrition in Vietnam has no analogues in Russia: it is purchased cereals prepared in specialized stores. Canned foods and dry soluble cereals are also included in the diet of children in Vietnam, but the share of consumers and consumption volumes for them are significantly lower than in Russia. Thus, in the age group of 6–12 months, the share of consumers in Russia is 53 %, in Vietnam – 21 %, the median distribution of average daily consumption in Russia is 152 grams, in Vietnam – 28 grams. Taking into account the share of consumers, as well as the volume and frequency of consumption, we determined the priority products for the children’s health risk assessment associated with the N-nitrosamines contamination in food. They are canned meat and dry soluble cereals in Russia; grilled meat and sausages; in Vietnam.
Abstract BACKGROUND Advanced pediatric solid tumors, including central nervous system (CNS) tumors with PDGFRA and/or KIT mutations/amplifications are aggressive diseases with limited treatment ...options. KIT alterations occur in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. No KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC50<2 nM), and PDGFRA activation-loop (D842V) mutants (half-maximal inhibitory concentration IC50=0.24 nM). Cellular IC50 of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios, 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved in the USA and Europe to treat adults with indolent systemic mastocytosis, in the USA for adults with advanced systemic mastocytosis (AdvSM), and in Europe for adults with AdvSM after ≥1 prior systemic therapy. Avapritinib is also approved to treat adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA and PDGFRA D842V mutations in Europe. METHODS ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib (once daily, administered in continuous 28-day cycles) in pediatric patients aged 2 to <18 years with relapsed/refractory solid tumors that harbor PDGFRA and/or KIT mutations/amplifications or patients with diffuse midline glioma H3K27-altered (DMG-H3K27a). Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.
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