Hyaluronic Acid Derivative Effect on Niosomal Coating and Interaction with Cellular Mimetic Membranes

Hyaluronic acid (HA) is one of the most used biopolymers in the development of drug delivery systems, due to its biocompatibility, biodegradability, non-immunogenicity and intrinsic-targeting properties. HA specifically binds to CD44; this property combined to the EPR effect could provide an option for reinforced active tumor targeting by nanocarriers, improving drug uptake by the cancer cells via the HA-CD44 receptor-mediated endocytosis pathway. Moreover, HA can be easily chemically modified to tailor its physico-chemical properties in view of specific applications. The derivatization with cholesterol confers to HA an amphiphilic character, and then the ability of anchoring to niosomes. HA-Chol was then used to coat Span^® or Tween^® niosomes providing them with an intrinsic targeting shell. The nanocarrier physico-chemical properties were analyzed in terms of hydrodynamic diameter, ζ-potential, and bilayer structural features to evaluate the difference between naked and HA-coated niosomes. Niosomes stability was evaluated over time and in bovine serum. Moreover, interaction properties of HA-coated nanovesicles with model membranes, namely liposomes, were studied, to obtain insights on their interaction behavior with biological membranes in future experiments. The obtained coated systems showed good chemical physical features and represent a good opportunity to carry out active targeting strategies.     

Identification of the Impurities in Bopu Powder® and Sangrovit® by LC-MS Combined with a Screening Method

Bopu powder^® and Sangrovit^® were developed from Macleaya cordata and are widely used in agriculture and animal husbandry, but their impurities have been rarely reported in the literature. Impurity analysis is of great importance to the quality and safety of veterinary drugs. In this study, high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS) combined with a screening method was used to screen and characterize the impurities in Bopu powder^® and Sangrovit^®. A total of 58 impurities were screened from Bopu powder^® and Sangrovit^® using the screening strategies, of which 39 were identified by their accurate m/z value, characteristic MS/MS data, and fragmentation pathways of references. This established method was used for impurity analysis for the first time and proved to be a useful and rapid tool to screen and identify the impurities of Bopu powder^® and Sangrovit^®, especially for those at trace levels in a complex sample. In addition, this study marks the first comprehensive research into impurities in these two products and has great significance for the systematic detection of impurities in other plant-derived drugs.     

Understanding the Impact of Key Wine Components on the Use of a Non-Swelling Ion-Exchange Resin for Wine Protein Fining Treatment

The impact of key classes of compounds found in wine on protein removal by the ion-exchange resin, Macro-Prep^® High S, was examined by adsorption isotherm experiments. A model wine system, which contained a prototypical protein Bovine Serum Albumin (BSA), was used. We systematically changed concentrations of individual chemical components to generate and compare adsorption isotherm plots and to quantify adsorption affinity or capacity parameters of Macro-Prep^® High S ion-exchange resin. The pH (hydronium ion concentration), ethanol concentration, and prototypical phenolics and polysaccharide compounds are known to impact interactions with proteins and thus could alter the adsorption affinity and capacity of Macro-Prep^® High S ion-exchange resin. At low equilibrium protein concentrations (< ~0.3 (g BSA)/L) and at high equilibrium protein concentrations in model wines at various pH, the adsorption behavior followed the Langmuir isotherm, most likely due to the resin acting as a monolayer adsorbent. The resulting range of BSA capacity was between 0.15–0.18 (g BSA)/(g Macro-Prep^® High S resin). With the addition of ethanol, catechin, caffeic acid, and polysaccharides, the protein adsorption behavior was observed to differ at higher equilibrium protein concentrations (> ~0.3 (g BSA)/L), likely as a result of Macro-Prep^® acting as an unrestricted multilayer adsorbent at these conditions. These data can be used to inform the design and scale-up of ion-exchange columns for removing proteins from wines.     

In Vivo and In Vitro Assays Evaluating the Biological Activity of Taurine,Glucose and Energetic Beverages

Taurine is one of the main ingredients used in energy drinks which are highly consumed in adolescents for their sugary taste and stimulating effect. With energy drinks becoming a worldwide phenomenon, the biological effects of these beverages must be evaluated in order to fully comprehend the potential impact of these products on the health due to the fact nutrition is closely related to science since the population consumes food to prevent certain diseases. Therefore, the aim of this study was to evaluate the biological effects of taurine, glucose, classic Red Bull^® and sugar-free Red Bull^® in order to check the food safety and the nutraceutical potential of these compounds, characterising different endpoints: (i) Toxicology, antitoxicology, genotoxicology and life expectancy assays were performed in the Drosophila melanogaster model organism; (ii) The in vitro chemopreventive activity of testing compounds was determined by assessing their cytotoxicity, the proapoptotic DNA-damage capability to induce internucleosomal fragmentation, the strand breaks activity and the modulator role on the methylation status of genomic repetitive sequences of HL-60 promyelocytic cells. Whereas none tested compounds showed toxic or genotoxic effect, all tested compounds exerted antitoxic and antigenotoxic activity in Drosophila. Glucose, classic Red Bull^® and sugar-free Red Bull^® were cytotoxic in HL-60 cell line. Classic Red Bull^® induced DNA internucleosomal fragmentation although none of them exhibited DNA damage on human leukaemia cells. In conclusion, the tested compounds are safe on Drosophila melanogaster and classic Red Bull^® could overall possess nutraceutical potential in the in vivo and in vitro model used in this study. Besides, taurine could holistically be one of the bioactive compounds responsible for the biological activity of classic Red Bull^®.     

Solubility Determination of c-Met Inhibitor in Solvent Mixtures and Mathematical Modeling to Develop Nanosuspension Formulation

The solubility and dissolution thermodynamics of new c-Met inhibitor, ABN401, were determined in eleven solvents and Transcutol^® HP–water mixture (TWM) from 298.15 to 318.15 K. The experimental solubilities were validated using five mathematical models, namely modified Apelblat, van’t Hoff, Buchowski–Ksiazaczak λh, Yalkowsky, and Jouyban–Acree van’t Hoff models. The experimental results were correlated and utilized further to investigate the feasibility of nanosuspension formation using liquid anti-solvent precipitation. Thermodynamic solubility of ABN401 increased significantly with the increase in temperature and maximum solubility was obtained with Transcutol^® HP while low solubility in was obtained water. An activity coefficient study indicated that high molecular interaction was observed in ABN401–Transcutol^® HP (THP). The solubility increased proportionately as the mole fraction of Transcutol^® HP increased in TWM, which was also supported by a solvent effect study. The result suggested endothermic and entropy-driven dissolution. Based on the solubility, nanosuspension was designed with Transcutol^® HP as solvent, and water as anti-solvent. The mean particle size of nanosuspension decreased to 43.05 nm when the mole fraction of ABN401 in THP, and mole fraction of ABN401 in TWM mixture were decreased to 0.04 and 0.1. The ultrasonicated nanosuspension appeared to give comparatively higher dissolution than micronized nanosuspension and provide a candidate formulation for in vivo purposes.     

Solid Lipid Nanoparticles Administering Antioxidant Grape Seed-Derived Polyphenol Compounds: A Potential Application in Aquaculture

The supply of nutrients, such as antioxidant agents, to fish cells still represents a challenge in aquaculture. In this context, we investigated solid lipid nanoparticles (SLN) composed of a combination of Gelucire^® 50/13 and Precirol^® ATO5 to administer a grape seed extract (GSE) mixture containing several antioxidant compounds. The combination of the two lipids for the SLN formation resulted in colloids exhibiting mean particle sizes in the range 139–283 nm and zeta potential values in the range +25.6–43.4 mV. Raman spectra and X-ray diffraction evidenced structural differences between the free GSE and GSE-loaded SLN, leading to the conclusion that GSE alters the structure of the lipid nanocarriers. From a biological viewpoint, cell lines from gilthead seabream and European sea bass were exposed to different concentrations of GSE-SLN for 24 h. In general, at appropriate concentrations, GSE-SLN increased the viability of the fish cells. Furthermore, regarding the gene expression in those cells, the expression of antioxidant genes was upregulated, whereas the expression of hsp70 and other genes related to the cytoskeleton was downregulated. Hence, an SLN formulation containing Gelucire^® 50/13/Precirol^® ATO5 and GSE may represent a compelling platform for improving the viability and antioxidant properties of fish cells.     

Drug Discovery of Nucleos(t)ide Antiviral Agents: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Birthday

Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogues, namely tenofovir disoproxil fumarate (Viread^®) and tenofovir alafenamide (Vemlidy^®) against HIV and HBV infections and adefovir dipivoxil (Hepsera^®) against HBV infections; (ii) two thymidine nucleoside analogues, namely brivudine (Zostex^®) against HSV-1 and VZV infections and stavudine (Zerit^®) against HIV infections; (iii) two guanosine analogues, namely valacyclovir (Valtrex^®, Zelitrex^®) against HSV and VZV and rabacfosadine (Tanovea^®-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analogue, namely cidofovir (Vistide^®) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clinical use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogues supports their development to treat or prevent current and emerging infectious diseases worldwide.     

In Vitro Analyses of Spinach-Derived Opioid Peptides,Rubiscolins: Receptor Selectivity and Intracellular Activities through G Protein- and β-Arrestin-Mediated Pathways

Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKey^TM assay, cADDis^® cAMP assay, and PathHunter^® β-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKey^TM assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis^® cAMP and PathHunter^® β-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects.     

Key Factor Study for Generic Long-Acting PLGA Microspheres Based on a Reverse Engineering of Vivitrol®

The FDA (U.S. Food and Drug Administration) has approved only a negligible number of poly(lactide-co-glycolide) (PLGA)-based microsphere formulations, indicating the difficulty in developing a PLGA microsphere. A thorough understanding of microsphere formulations is essential to meet the challenge of developing innovative or generic microspheres. In this study, the key factors, especially the key process factors of the marketed PLGA microspheres, were revealed for the first time via a reverse engineering study on Vivitrol^® and verified by the development of a generic naltrexone-loaded microsphere (GNM). Qualitative and quantitative similarity with Vivitrol^®, in terms of inactive ingredients, was accomplished by the determination of PLGA. Physicochemical characterization of Vivitrol^® helped to identify the critical process parameters in each manufacturing step. After being prepared according to the process parameters revealed by reverse engineering, the GNM demonstrated similarity to Vivitrol^® in terms of quality attributes and in vitro release (f₂ = 65.3). The research on the development of bioequivalent microspheres based on the similar technology of Vivitrol^® will benefit the development of other generic or innovative microspheres.     

Quality-by-Design-Based Development of n-Propyl-Gallate-Loaded Hyaluronic-Acid-Coated Liposomes for Intranasal Administration

The present study aimed to develop n-propyl gallate (PG)-encapsulated liposomes through a novel direct pouring method using the quality-by-design (QbD) approach. A further aim was to coat liposomes with hyaluronic acid (HA) to improve the stability of the formulation in nasal mucosa. The QbD method was used for the determination of critical quality attributes in the formulation of PG-loaded liposomes coated with HA. The optimized formulation was determined by applying the Box–Behnken design to investigate the effect of composition and process variables on particle size, polydispersity index (PDI), and zeta potential. Physiochemical characterization, in vitro release, and permeability tests, as well as accelerated stability studies, were performed with the optimized liposomal formulation. The optimized formulation resulted in 90 ± 3.6% encapsulation efficiency, 167.9 ± 3.5 nm average hydrodynamic diameter, 0.129 ± 0.002 PDI, and −33.9 ± 4.5 zeta potential. Coated liposomes showed significantly improved properties in 24 h in an in vitro release test (>60%), in vitro permeability measurement (420 μg/cm²) within 60 min, and also in accelerated stability studies compared to uncoated liposomes. A hydrogen-peroxide-scavenging assay showed improved stability of PG-containing liposomes. It can be concluded that the optimization of PG-encapsulated liposomes coated with HA has great potential for targeting several brain diseases.     

Evaluation of Efficiency of Polymerization,Surface Roughness,Porosity and Adaptation of Flowable and Sculptable Bulk Fill Composite Resins

A new category of commercial bulk fill composite resins (CRs) enables the placement of 4-mm-thick layers as an alternative to the traditional time-consuming incremental technique. The purpose of the present study was to compare the efficiency of the polymerization, adaptation and porosity of two high-viscosity ‘sculptable’ bulk fill CRs (Filtek™ Bulk Fill (3M™ ESPE, St. Paul, MN, USA) and Tetric EvoCeram^® Bulk Fill (Ivoclar Vivadent AG, Schwan, Liechtenstein)) and two low-viscosity ‘flowable’ bulk fill CRs (SureFil^® SDR™ flow (Dentsply Sirona, Charlotte, NC, USA) and Tetric EvoFlow^® Bulk Fill (Ivoclar Vivadent AG, Schaan, Liechtenstein)). Cylindrical samples of the bulk fill CRs (4 mm height × 10 mm diameter) were analyzed by Fourier-transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). Additionally, occlusal cavities were prepared in twelve extracted human molars and restored with the bulk fill CRs (n = 3 for each CR). The adaptation and porosity of the bulk fill CRs were evaluated by X-ray microcomputed tomography (µCT) with a 3D morphometric analysis, and the adaptation was also analyzed by scanning electron microscopy (SEM) on longitudinal vestibulo-oral sections of the restored teeth. The AFM analysis demonstrated that the surface roughness of the SureFil^® SDR™ flow was higher than that of the Tetric EvoFlow^® Bulk Fill and that the surface roughness of Filtek™ Bulk Fill was higher than that of Tetric EvoCeram^® Bulk Fill. µCT and SEM confirmed that the flowable bulk fill CRs had excellent adaptation to the cavity walls. The 3D morphometric analysis showed the highest and lowest degrees of porosity in Filtek™ Bulk Fill and Tetric EvoFlow^® Bulk Fill, respectively. In general, the flowable bulk fill CRs exhibited better adaptation, a higher efficiency of polymerization and lower porosity than the sculptable materials.     

Pristine and Modified Porous Membranes for Zinc Slurry–Air Flow Battery

The membrane is a crucial component of Zn slurry–air flow battery since it provides ionic conductivity between the electrodes while avoiding the mixing of the two compartments. Herein, six commercial membranes (Cellophane™ 350PØØ, Zirfon^®, Fumatech^® PBI, Celgard^® 3501, 3401 and 5550) were first characterized in terms of electrolyte uptake, ion conductivity and zincate ion crossover, and tested in Zn slurry–air flow battery. The peak power density of the battery employing the membranes was found to depend on the in-situ cell resistance. Among them, the cell using Celgard^® 3501 membrane, with in-situ area resistance of 2 Ω cm² at room temperature displayed the highest peak power density (90 mW cm⁻²). However, due to the porous nature of most of these membranes, a significant crossover of zincate ions was observed. To address this issue, an ion-selective ionomer containing modified poly(phenylene oxide) (PPO) and N-spirocyclic quaternary ammonium monomer was coated on a Celgard^® 3501 membrane and crosslinked via UV irradiation (PPO-3.45 + 3501). Moreover, commercial FAA-3 solutions (FAA, Fumatech) were coated for comparison purpose. The successful impregnation of the membrane with the anion-exchange polymers was confirmed by SEM, FTIR and Hg porosimetry. The PPO-3.45 + 3501 membrane exhibited 18 times lower zincate ions crossover compared to that of the pristine membrane (5.2 × 10⁻¹³ vs. 9.2 × 10⁻¹² m² s⁻¹). With low zincate ions crossover and a peak power density of 66 mW cm⁻², the prepared membrane is a suitable candidate for rechargeable Zn slurry–air flow batteries.     

Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177® (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction

Interleukin-1β (IL-1β), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177^® (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.4 mm), and reduced function (LV ejection fraction < 40%) to a diet that was enriched with OLT1177^® admixed with the chow in the diet at 3.75 g/kg (Group 1 [n = 10]) or 7.5 g/kg (Group 2 [n = 9]), or a standard diet as the no-treatment control group (Group 3 [n = 10]) for 9 weeks. We measured the cardiac function and contractile reserve with an isoproterenol challenge, and the diastolic function with cardiac catheterization at 10 weeks following the MI surgery. When compared with the control (Group 3), the mice treated with OLT1177 (Group 1 and 2) showed significantly greater preservation of their contractile reserve (the percent increase in the left ventricular ejection fraction [LVEF] after the isoproterenol challenge was +33 ± 11% and +40 ± 6% vs. +9 ± 7% in the standard diet; p < 0.05 and p < 0.005 for Group 1 and 2, respectively) and of diastolic function measured as the lower left ventricular end-diastolic pressure (3.2 ± 0.5 mmHg or 4.5 ± 0.5 mmHg vs. 10.0 ± 1.6 mmHg; p < 0.005 and p < 0.009 respectively). No differences were noted between the resting LVEF of the MI groups. These effects were independent of the effects on the ventricular remodeling after MI. NLRP3 inflammasome inhibition with OLT1177^® can preserve β-adrenergic responsiveness and prevent left ventricular diastolic dysfunction in a large non-reperfused anterior MI mouse model. OLT1177^® could therefore be used to prevent the development of heart failure in patients with ischemic cardiomyopathy.     

Amorphous Form of Carvedilol Phosphate—The Case of Divergent Properties

The amorphous form of carvedilol phosphate (CVD) was obtained as a result of grinding. The identity of the obtained amorphous form was confirmed by powder X-ray diffraction (PXRD), different scanning calorimetry (DSC), and FT-IR spectroscopy. The process was optimized in order to obtain the appropriate efficiency and time. The crystalline form of CVD was used as the reference standard. Solid dispersions of crystalline and amorphous CVD forms with hydrophilic polymers (hydroxypropyl-β-cyclodextrin, Pluronic^® F-127, and Soluplus^®) were obtained. Their solubility at pH 1.2 and 6.8 was carried out, as well as their permeation through a model system of biological membranes suitable for the gastrointestinal tract (PAMPA-GIT) was established. The influence of selected polymers on CVD properties was defined for the amorphous form regarding the crystalline form of CVD. As a result of grinding (four milling cycles lasting 15 min with 5 min breaks), amorphous CVD was obtained. Its presence was confirmed by the “halo effect” on the diffraction patterns, the disappearance of the peak at 160.5 °C in the thermograms, and the changes in position/disappearance of many characteristic bands on the FT-IR spectra. As a result of changes in the CVD structure, its lower solubility at pH 1.2 and pH 6.8 was noted. While the amorphous dispersions of CVD, especially with Pluronic^® F-127, achieved better solubility than combinations of crystalline forms with excipients. Using the PAMPA-GIT model, amorphous CVD was assessed as high permeable (Papp > 1 × 10⁻⁶ cm/s), similarly with its amorphous dispersions with excipients (hydroxypropyl-β-cyclodextrin, Pluronic^® F-127, and Soluplus^®), although in their cases, the values of apparent constants permeability were decreased.     

VOCs Are Relevant Biomarkers of Elicitor-Induced Defences in Grapevine

Grapevine is susceptible to fungal diseases generally controlled by numerous chemical fungicides. Elicitors of plant defence are a way of reducing the use of these chemicals, but still provide inconsistent efficiency. Easy-to-analyse markers of grapevine responses to elicitors are needed to determine the best conditions for their efficiency and position them in protection strategies. We previously reported that the elicitor sulphated laminarin induced the emission of volatile organic compounds (VOCs) by grapevine leaves. The present study was conducted to characterise and compare VOC emissions in response to other elicitors. Bastid^® was first used to test the conditions of VOC collection and analysis. Using SBSE-GC-MS, we detected several VOCs, including the sesquiterpene α-farnesene, in a time-dependent manner. This was correlated with the induction of farnesene synthase gene expression, in parallel with stilbene synthesis (another defence response), and associated to resistance against downy mildew. The other elicitors (Redeli^®, Romeo^®, Bion^®, chitosan, and an oligogalacturonide) induced VOC emission, but with qualitative and quantitative differences. VOC emission thus constitutes a response of grapevine to elicitors of various chemical structures. Therefore, VOC analysis is relevant for studying the impact of environmental factors on grapevine defence responses and optimising the performance of elicitors in vineyards.     

Development,Characterization, and Immunomodulatory Evaluation of Carvacrol-loaded Nanoemulsion

Carvacrol (CV) is an essential oil with numerous therapeutic properties, including immunomodulatory activity. However, this effect has not been studied in nanoemulsion systems. The objective of this study was to develop an innovative carvacrol-loaded nanoemulsion (CVNE) for immunomodulatory action. The developed CVNE comprised of 5% w/w oily phase (medium chain triglycerides + CV), 2% w/w surfactants (Tween 80^®/Span 80^®), and 93% w/w water, and was produced by ultrasonication. Dynamic light scattering over 90 days was used to characterize CVNE. Cytotoxic activity and quantification of cytokines were evaluated in peripheral blood mononuclear cell (PBMC) culture supernatants. CVNE achieved a drug loading of 4.29 mg/mL, droplet size of 165.70 ± 0.46 nm, polydispersity index of 0.14 ± 0.03, zeta potential of −10.25 ± 0.52 mV, and good stability for 90 days. CVNE showed no cytotoxicity at concentrations up to 200 µM in PBMCs. CV diminished the production of IL-2 in the PBMC supernatant. However, CVNE reduced the levels of the pro-inflammatory cytokines IL-2, IL-17, and IFN-γ at 50 µM. In conclusion, a stable CVNE was produced, which improved the CV immunomodulatory activity in PBMCs.     

Biochemical Studies in Perfundates and Homogenates of Isolated Porcine Kidneys after Flushing with Zinc or Zinc–Prolactin Modified Preservation Solution Using a Static Cold Storage Technique

Zinc is an effective anti-inflammatory and antioxidant trace element. The aim of this study was to analyse the protective effect of zinc and zinc–prolactin systems as additives of preservation solutions in the prevention of nephron damage caused during ischemia. The study used a model for storing isolated porcine kidneys in Biolasol^®. The solution was modified with the addition of Zn at a dose of 1 µg/L and Zn: 1 µg/L with prolactin (PRL): 0.1 µg/L. After 2 h and 48 h of storage, the levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, sodium, potassium, creatinine and total protein were determined. Zinc added to the Biolasol^® composition at a dose of 1 µg/L showed minor effectiveness in the protection of nephrons. In turn, Zn²⁺ added to Biolasol + PRL (PRL: 0.1 µg/L) acted as a prolactin inhibitor. We do not recommend the addition of Zn(II) (1 µg/L) and Zn(II) (1 µg/L) + PRL (0.1 µg/L) to the Biolasol solution.     

Preparation of Co-Processed Excipients for Controlled-Release of Drugs Assembled with Solid Lipid Nanoparticles and Direct Compression Materials

The purpose of the study was to develop a novel, directly compressible, co-processed excipient capable of providing a controlled-release drug system for the pharmaceutical industry. A co-processed powder was formed by adsorption of solid lipid nanoparticles (SLN) as a controlled-release film onto a functional excipient, in this case, dicalcium phosphate dihydrate (DPD), for direct compression (Di-Tab^®). The co-processed excipient has advantages: easy to implement; solvent-free; industrial scaling-up; good rheological and compressibility properties; and the capability to form an inert platform. Six different batches of Di-Tab^®:SLN weight ratios were prepared (4:0.6, 3:0.6, 2:0.6, 1:0.6, 0.5:0.6, and 0.25:0.6). BCS class III ranitidine hydrochloride was selected as a drug model to evaluate the mixture’s controlled-release capabilities. The co-processed excipients were characterized in terms of powder rheology and dissolution rate. The best Di-Tab^®:SLN ratio proved to be 2:0.6, as it showed high functionality with good flow and compressibility properties (Carr Index = 16 ± 1, Hausner Index = 1.19 ± 0.04). This ratio could control release for up to 8 h, so it fits the ideal profile calculated based on biopharmaceutical data. The compressed systems obtained using this powder mixture behave as a matrix platform in which Fickian diffusion governs the release. The Higuchi model can explain their behavior.     

Synthesis of Tailored Perfluoro Unsaturated Monomers for Potential Applications in Proton Exchange Membrane Preparation

The aim of the present work is the synthesis and characterization of new perfluorinated monomers bearing, similarly to Nafion^®, acidic groups for proton transport for potential and future applications in proton exchange membrane (PEM) fuel cells. To this end, we focused our attention on the synthesis of various molecules with (i) sufficient volatility to be used in vacuum polymerization techniques (e.g., PECVD)), (ii) sulfonic, phosphonic, or carboxylic acid functionalities for proton transport capacity of the resulting membrane, (iii) both aliphatic and aromatic perfluorinated tags to diversify the membrane polarity with respect to Nafion^®, and (iv) a double bond to facilitate the polymerization under vacuum giving a preferential way for the chain growth of the polymer. A retrosynthetic approach persuaded us to attempt three main synthetic strategies: (a) organometallic Heck-type cross-coupling, (b) nucleophilic displacement, and (c) Wittig–Horner reaction (carbanion approach). Preliminary results on the plasma deposition of a polymeric film are also presented. The variation of plasma conditions allowed us to point out that the film prepared in the mildest settings (20 W) shows the maximum monomer retention in its structure. In this condition, plasma polymerization likely occurs mainly by rupture of the π bond in the monomer molecule.     

A fast,sensitive determination of doxorubicin in rat plasma by solid-phase extraction and reversed-phase ion-pair chromatography

A very selective method is described for the determination of doxorubicin in rat plasma. Doxorubicin is extracted from the plasma on a pretreated octadecyl silane column and eluted with phosphate buffer pH 2.6/methanol (25/75, v/v) containing sodium 1-heptanesulfonate as ion-pairing agent. The extraction procedure is suitable for samples which contain doxorubicin encapsulated in liposomes if Triton X-100 is added. A portion of the evaporated eluate is used for high-performance reversed-phase chromatography with the same eluent and a fluorescence detector. Daunorubicin is used as internal standard. Extraction of doxorubicin from plasma is quantitative. The calibration graph is linear for 0.2-100 μg l^?1 doxorubicin with a limit of detection of 0.2 μg l^?1 for 0.5 ml of plasma. The relative standard error of estimate of the calibration was typically 3%.