Successful Dendrimer and Liposome-Based Strategies to Solubilize an Antiproliferative Pyrazole Otherwise Not Clinically Applicable

Water-soluble formulations of the pyrazole derivative 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), which were proven to have in vitro antiproliferative effects on different cancer cell lines, were prepared by two diverse nanotechnological approaches. Importantly, without using harmful organic solvents or additives potentially toxic to humans, CR232 was firstly entrapped in a biodegradable fifth-generation dendrimer containing lysine (G5K). CR232-G5K nanoparticles (CR232-G5K NPs) were obtained with high loading (DL%) and encapsulation efficiency (EE%), which showed a complex but quantitative release profile governed by Weibull kinetics. Secondly, starting from hydrogenated soy phosphatidylcholine and cholesterol, we prepared biocompatible CR232-loaded liposomes (CR232-SUVs), which displayed DL% and EE% values increasing with the increase in the lipids/CR232 ratio initially adopted and showed a constant prolonged release profile ruled by zero-order kinetics. When relevant, attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM) and dynamic light scattering (DLS) experiments, as well as potentiometric titrations completed the characterization of the prepared NPs. CR232-G5K NPs were 2311-fold more water-soluble than the pristine CR232, and the CR232-SUVs with the highest DL% were 1764-fold more soluble than the untreated CR232, thus establishing the success of both our strategies.

Exploration of Neusilin® US2 as an Acceptable Filler in HPMC Matrix Systems—Comparison of Pharmacopoeial and Dynamic Biorelevant Dissolution Study

Modern pharmaceutical technology still seeks new excipients and investigates the further use in already known ones. An example is magnesium aluminometasilicate Neusilin® US2 (NEU), a commonly used inert filler with unique properties that are usable in various pharmaceutical fields of interest. We aimed to explore its application in hypromellose matrix systems (HPMC content 10–30%) compared to the traditionally used microcrystalline cellulose (MCC) PH 102. The properties of powder mixtures and directly compressed tablets containing individual fillers NEU or MCC, or their blend with ratios of 1.5:1, 1:1, and 0.5:1 were investigated. Besides the routine pharmaceutical testing, we have enriched the matrices’ evaluation with a biorelevant dynamic dissolution study and advanced statistical analysis. Under the USP apparatus 2 dissolution test, NEU, individually, did not provide advantages compared to MCC. The primary limitations were the burst effect increase followed by faster drug release at the 10–20% HPMC concentrations. However, the biorelevant dynamic dissolution study did not confirm these findings and showed similarities in dissolution profiles. It indicates the limitations of pharmacopoeial methods in matrix tablet development. Surprisingly, the NEU/MCC blend matrices at the same HPMC concentration showed technologically advantageous properties. Besides improved flowability, tablet hardness, and a positive impact on the in vitro drug dissolution profile toward zero-order kinetics, the USP 2 dissolution data of the samples N75M50 and N50M50 showed a similarity to those obtained from the dynamic biorelevant apparatus with multi-compartment structure. This finding demonstrates the more predictable in vivo behaviour of the developed matrix systems in human organisms.

Chrysin-Loaded Microemulsion: Formulation Design, Evaluation and Antihyperalgesic Activity in Mice

Chrysin is a bioactive flavonoid found in pollens, passion flowers, honey, royal jelly, and propolis, which is commonly used as an ingredient in natural food supplements and is primarily responsible for their pharmacological properties. A transparent chrysin-loaded microemulsion (CS-ME) prepared through a ternary phase diagram was evaluated for use as an antihyperalgesic formulation. It was formulated with 40% Labrasol® (surfactant), 5% isopropyl myristate (oil phase) and 55% water (aqueous phase) and classified as an oil-in-water (O/W) microsized system (74.4 ± 15.8 nm). Its negative Zeta potential (−16.1 ± 1.9 mV) was confirmed by polarized light microscopy and dynamic light scattering analysis. In vitro studies in Franz-type static diffusion cells showed that chrysin release from CS-ME followed zero-order kinetics. Oral administration of CS-ME in mice resulted in a statistically significantly reduction (p < 0.05) in carrageenan-induced mechanical hyperalgesia compared to the control group. Treatment with CS-ME also showed anti-inflammatory activity by significantly decreasing the TNF-α level (p < 0.01) and increasing that of IL-10 (p < 0.05) compared to the control group. These results suggest that the proposed microsystem is a promising vector for the release of chrysin, being able to improve its capacity to modulate inflammatory and nociceptive responses.

Kinetics and mechanisms of catalyzed dual-E (antithetic) controllers

Homeostasis plays a central role in our understanding how cells and organisms are able to oppose environmental disturbances and thereby maintain an internal stability. During the last two decades there has been an increased interest in using control engineering methods, especially integral control, in the analysis and design of homeostatic networks. Several reaction kinetic mechanisms have been discovered which lead to integral control. In two of them integral control is achieved, either by the removal of a single control species E by zero-order kinetics ("single-E controllers"), or by the removal of two control species by second-order kinetics ("antithetic or dual-E control"). In this paper we show results when the control species E 1 and E 2 in antithetic control are removed enzymatically by ping-pong or ternary-complex mechanisms. Our findings show that enzyme-catalyzed dual-E controllers can work in two control modes. In one mode, one of the two control species is active, but requires zero-order kinetics in its removal. In the other mode, both controller species are active and both are removed enzymatically. Conditions for the two control modes are put forward and biochemical examples with the structure of enzyme-catalyzed dual-E controllers are discussed.

Evaluation of Kinetic Pseudo-Order in the Photocatalytic Degradation of Ofloxacin

Ofloxacin is a highly efficient and widely used antibiotic drug. It is classified as a refractory pollutant due to its poor biodegradability. Consequently, it is commonly found in water sources, requiring efficient methods for its removal. Advanced oxidation processes (AOPs) offer efficient alternatives since those yield complete degradation not achieved in adsorption or membrane processes. Previous studies suggest ofloxacin degradation follows a pseudo-first or -second order processes, whereas for full removal of refractory pollutants—lower pseudo-orders are required. Monitoring the actual “pseudo-order” degradation kinetics of ofloxacin is needed to evaluate any proposed AOP process. This study presents a simple procedure to evaluate pseudo-orders of AOPs. Photolysis of 20 μM ofloxacin solutions follow pseudo-zero order kinetics, with half-life times (t1/2) of approx. 60 min. TiO2 heterogenous catalysts have been shown to have no influence at low concentrations (0.2 mg L−1), but a significant reduction of half-life time (t1/2 = 20 min) and increase in pseudo-order (0.8) is measured at 2.0 mg L−1. Similar results are obtained with homogenous catalysis by 2.0 mg L−1 H2O2. The combination of H2O2 and TiO2 catalysts shows additional reduction in half-time life with increase in the pseudo-order to 1.2. The conclusions are (1) heterogenous and homogenous photocatalysis can effectively degrade ofloxacin, (2) combined photocatalysis yields higher pseudo-order, being less prone to achieve full removal, and (3) analysis of specific pseudo-orders in AOPs of refractory pollutants helps to further elucidate the efficiency of the processes.

Evaluation of Kinetic Pseudo-Order in the Photocatalytic Degradation of Oflaxicin

Ofloxacin is a highly efficient and widely used antibiotic drug. It is classified as a refractory pollutant due to its poor biodegradability. Consequently, it is commonly found in water sources, requiring efficient methods for its removal. Advanced Oxidation Processes (AOPs) offer efficient alternatives since those yield complete degradation not achieved in adsorption or membrane processes. Previous studies suggest ofloxacin degradation follows a pseudo-first or -second order processes, whereas for full removal of refractory pollutants &ndash; lower pseudo-orders are required. Monitoring the actual &ldquo;pseudo-order&rdquo; degradation kinetics of ofloxacin is needed to evaluate any proposed AOP process. This study presents a simple procedure to evaluate pseudo-orders of AOPs. Photolysis of 20 mM ofloxacin solutions follow pseudo-zero order kinetics, with half-life times (t1/2) of approx. 60 min. TiO2 heterogenous catalyst show to have no influence at low concentration (0.2 mg L-1) but a significant reduction of half-life time (t1/2 = 20 min) and increase in pseudo-order (0.8) is measured at 2.0 mg L-1. Similar results are obtained with homogenous catalysis by 2.0 mg L-1 H2O2. The combination of H2O2 and TiO2 catalysts shows additional reduction in half-time life with increase in the pseudo-order to 1.2. The conclusions are (1) heterogenous and homogenous photocatalysis can effectively degrade ofloxacin, (2) combined photocatalysis yields higher pseudo-order, being less prone to achieve full removal, (3) analysis of specific pseudo-orders in AOPs of refractory pollutants helps to further elucidate the efficiency of the processes.

Formulation and Evaluation of colon targeted drug Delivery of Diloxanide furoate Tablets using pH Dependent Polymers

Diloxanide Furoate is a Dichloroacetamide derivative utilized for the treatment of various protozoal infections like amoebiasis. Colon targeted tablets were designed using pH sensitive polymers like Eudragit S100, Eudragit L 100,Cellulose acetate phthallate at different concentrations. All the matrix,compression coated formulations showed the desired physicochemical properties as per the official limits. The drug release studies were performed according to the USP paddle method by using 0.1N HCL for 2 hours, pH 7.4 phosphate buffer for 3 hours and pH 6.8 phosphate buffer upto 18 hours. A better controlled drug release was shown for Eudragit L 100. Based on the comparative drug release studies among different Formulations F9 with Eudragit L 100 polymer showed better control drug release. The release kinetics for the Optimised Formulation F9 was calculated and “r2” value was more for Zero order kinetics i.e.,0.970 indicating that the formulation doesnot depend upon its concentration and from the Korsmeyer peppas model the diffusion exponent value “n” is > 1 indicating that it follows super case II transport mechanism. The accelerated stability studies conducted for optimised formulation F9 for 3 months have no significant variation.

DOPA Homeostasis by Dopamine: A Control-Theoretic View

Dopamine (DA) is an important signal mediator in the brain as well as in the periphery. The term “dopamine homeostasis” occasionally found in the literature refers to the fact that abnormal DA levels can be associated with a variety of neuropsychiatric disorders. An analysis of the negative feedback inhibition of tyrosine hydroxylase (TH) by DA indicates, with support from the experimental data, that the TH-DA negative feedback loop has developed to exhibit 3,4-dihydroxyphenylalanine (DOPA) homeostasis by using DA as a derepression regulator. DA levels generally decline when DOPA is removed, for example, by increased oxidative stress. Robust DOPA regulation by DA further implies that maximum vesicular DA levels are established, which appear necessary for a reliable translation of neural activity into a corresponding chemical transmitter signal. An uncontrolled continuous rise (windup) in DA occurs when Levodopa treatment exceeds a critical dose. Increased oxidative stress leads to the successive breakdown of DOPA homeostasis and to a corresponding reduction in DA levels. To keep DOPA regulation robust, the vesicular DA loading requires close to zero-order kinetics combined with a sufficiently high compensatory flux provided by TH. The protection of DOPA and DA due to a channeling complex is discussed.

Gelatin Methacryloyl Hydrogels for the Localized Delivery of Cefazolin

The tuneability of hydrogels renders them promising candidates for local drug delivery to prevent and treat local surgical site infection (SSI) while avoiding the systemic side-effects of intravenous antibiotic injections. Here, we present a newly developed gelatin methacryloyl (GelMA)-based hydrogel drug delivery system (GelMA-DDS) to locally deliver the broad-spectrum antibiotic cefazolin for SSI prophylaxis and treatment. Antibiotic doses from 3 µg to 90 µg were loaded in photocrosslinked GelMA hydrogel discs with 5 to 15% w/v polymer concentration and drug encapsulation efficiencies, mechanical properties, crosslinking and release kinetics, as well as bacterial growth inhibition were assessed. Our results demonstrate that all GelMA groups supported excellent drug encapsulation efficiencies of up to 99%. Mechanical properties of the GelMA-DDS were highly tuneable and unaffected by the loading of small to medium doses of cefazolin. The diffusive and the proteolytic in vitro drug delivery of all investigated cefazolin doses was characterized by a burst release, and the delivered cefazolin amount was directly proportional to the encapsulated dose. Accelerated enzymatic degradation of the GelMA-DDS followed zero-order kinetics and was dependent on both the cefazolin dose and GelMA concentration (3–13 h). Finally, we demonstrate that cefazolin delivered from GelMA induced a dose-dependent antibacterial efficacy against S. aureus, in both a broth and a diffusive assay. The cefazolin-loaded GelMA-DDS presented here provides a highly tuneable and easy-to-use local delivery system for the prophylaxis and treatment of SSI.

Simulated Modelling, Design, and Performance Evaluation of a Pilot-Scale Trickling Filter System for Removal of Carbonaceous Pollutants from Domestic Wastewater

The aim of the present study is to assess the wastewater treatment efficiency of a low-cost pilot-scale trickling filter (TF) system under a prevailing temperature range of 12 °C–38 °C. Operational data (both influent and effluent) for 330 days were collected from the pilot-scale TF for various physicochemical and biological parameters. Average percentage reductions were observed in the ranges of 52–72, 51–73, 61–81, and 74–89% for BOD5, COD, TDS, and TSS, respectively, for the whole year except the winter season, where a 74–88% reduction was observed only for TSS, whilst BOD5, COD, and TDS demonstrated reductions in the ranges of 13–50, 13–49, and 23–61%, respectively. Furthermore, reductions of about 43–55% and 57–86% in fecal coliform count were observed after the 1st and 6th day of treatment, respectively, throughout study period. Moreover, the pilot-scale TF model was based on zero-order kinetics calibrated at 20 °C using experimental BOD5 data obtained in the month of October to calculate the k20 value, which was further validated to determine the kt value for each BOD5 experimental setup. The model resulted in more accurate measurements of the pilot-scale TF and could help to improve its ability to handle different types of wastewater in the future.