Increase In Mean Residence Time Research Articles

Enhanced ophthalmic bioavailability and stability of atropine sulfate via sustained release particles using polystyrene sulfonate resin

Atropine sulfate (ATS) eye drops at low concentrations constitute a limited selection for myopia treatment, with challenges such as low ophthalmic bioavailability and inadequate stability. This study proposes a novel strategy by synthesizing ophthalmic sodium polystyrene sulfonate resin (SPSR) characterized by a spherical shape and uniform size for cationic exchange with ATS. The formulation of ATS@SPSR suspension eye drops incorporates xanthan gum and hydroxypropyl methylcellulose (HPMC) as suspending agents. In vitro studies demonstrated that ATS@SPSR suspension eye drops exhibited sustained release characteristics, and tropic acid, its degradation product, remained undetected for 30 days at 40 °C. The ATS levels in the tear fluids and aqueous humor of New Zealand rabbits indicated a significant increase in mean residence time (MRT) and area under the drug concentration–time curve (AUC0-12h) for ATS@SPSR suspension eye drops compared to conventional ATS eye drops. Moreover, safety assessment confirmed the non-irritating nature of ATS@SPSR suspension eye drops in rabbit eyes. In conclusion, the cation-responsive sustained-release ATS@SPSR suspension eye drops enhanced the bioavailability and stability of ATS, offering a promising avenue for myopia treatment.

Folic acid-conjugated long circulating co-encapsulated atorvastatin and quercetin solid lipid nanoparticles: pharmacokinetics and biodistribution in rats.

Background: Solid lipid nanoparticles (SLNs) have emerged as effective carriers for the simultaneous delivery of two drugs. Moreover, the surface modification of SLNs enhances their targetability and minimizes side effects, rendering them a promising and dynamic strategy for addressing various life-threatening diseases. The assessment of pharmacokinetic parameters is a critical aspect of this approach. In the present study, we report the development and validation of an LC-MS/MS-based bioanalytical method for the quantification of Atorvastatin (ATR) and Quercetin (QUER) encapsulated in folic acid-modified SLNs as a drug delivery system to estimate their pharmacokinetics and tissue distribution. Method: FA-SLNs were synthesized by amide linkage formation (carbodiimide reaction) and tested for their haemocompatibility. Further, an LC-MS/MS method was developed on a C18 (3 × 100 mm, 2.7 μm) column using 0.1% v/v formic acid in water and acetonitrile as the mobile phase with a 0.3 mL min-1 flow rate. For detection, analytes were ionized using an electron spray ionization (ESI) source in multiple reaction monitoring (MRM) mode. MRM for the ATR (559.0 → 440.2) m/z and IS (482.1 → 257.8) m/z in positive polarity, and QUER (301.9 → 151.0) m/z in negative polarity were optimized. Results: Pharmacokinetics studies demonstrated an increase in the half-lives of ATR and QUER of about 6.4-fold and 5.7-fold, respectively, from FA-SLN compared to pure drugs. Further, the active targeting facilitated by FA conjugation showed increased mean residence time (MRT) and decreased clearance time, resulting in long circulation time without the enhanced retention of drugs in the tissues of rats. These findings underscore the potential of FA-modified ATR and QUER-loaded SLNs as an advanced drug delivery strategy in improving the therapeutic outcomes.

Enhancing anti-cancer potential by delivering synergistic drug combinations via phenylboronic acid modified PLGA nanoparticles through ferroptosis-based therapy

In this study, we investigated the potential of the sorafenib (SOR) and simvastatin (SIM) combination to induce ferroptosis-mediated cancer therapy. To enhance targeted drug delivery, we encapsulated the SOR + SIM combination within 4-carboxy phenylboronic acid (CPBA) modified PLGA nanoparticles (CPBA-PLGA(SOR + SIM)-NPs). The developed CPBA-PLGA(SOR + SIM)-NPs exhibited a spherical shape with a size of 213.1 ± 10.9 nm, a PDI of 0.22 ± 0.03, and a Z-potential of −22.9 ± 3.2 mV. Notably, these nanoparticles displayed faster drug release at acidic pH compared to physiological pH. In cellular experiments, CPBA-PLGA(SOR + SIM)-NPs demonstrated remarkable improvements, leading to a 2.51, 2.69, and 2.61-fold decrease in IC50 compared to SOR alone, and a 7.50, 16.71, and 5.11-fold decrease in IC50 compared to SIM alone in MDA-MB-231, A549, and HeLa cells, respectively. Furthermore, CPBA-PLGA(SOR + SIM)-NPs triggered a reduction in glutathione (GSH) levels, an increase in malondialdehyde (MDA) levels, and mitochondrial membrane depolarization in all three cell lines. Pharmacokinetic evaluation revealed a 2.50- and 2.63-fold increase in AUC0-∞, as well as a 1.53- and 2.46-fold increase in mean residence time (MRT) for SOR and SIM, respectively, compared to the free drug groups. Notably, the CPBA-PLGA(SOR + SIM)-NPs group exhibited significant reduction in tumor volume, approximately 9.17, 2.45, and 1.63-fold lower than the control, SOR + SIM, and PLGA(SOR + SIM)-NPs groups, respectively. Histological examination and biomarker analysis showed no significant differences compared to the control group, suggesting the biocompatibility of the developed particles for in-vivo applications. Altogether, our findings demonstrate that CPBA-PLGA(SOR + SIM)-NPs hold tremendous potential as an efficient drug delivery system for inducing ferroptosis, providing a promising therapeutic option for cancer treatment.

Preparation, Characterization and Evaluation of Flavonolignan Silymarin Effervescent Floating Matrix Tablets for Enhanced Oral Bioavailability.

The convenient and highly compliant route for the delivery of active pharmaceutical ingredients is the tablet. A versatile platform of tablets is available for the delivery of therapeutic agents to the gastrointestinal tract. This study aimed to prepare gastro retentive drug delivery floating tablets of silymarin to improve its oral bioavailability and solubility. Hydroxypropyl methylcellulose (HPMCK4M and HPMCK15), Carbopol 934p and sodium bicarbonate were used as a matrix, floating enhancer and gas generating agent, respectively. The prepared tablets were evaluated for physicochemical parameters such as hardness, weight variation, friability, floating properties (floating lag time, total floating time), drug content, stability study, in vitro drug release, in vivo floating behavior and in vivo pharmacokinetics. The drug-polymer interaction was studied by Differential Scanning Calorimetry (DSC) thermal analysis and Fourier transform infrared (FTIR). The floating lag time of the formulation was within the prescribed limit (<2 min). The formulation showed good matrix integrity and retarded the release of drug for >12 h. The dissolution can be described by zero-order kinetics (r2 = 0.979), with anomalous diffusion as the release mechanism (n = 0.65). An in vivo pharmacokinetic study showed that Cmax and AUC were increased by up to two times in comparison with the conventional dosage form. An in vivo imaging study showed that the tablet was present in the stomach for 12 h. It can be concluded from this study that the combined matrix system containing hydrophobic and hydrophilic polymers min imized the burst release of the drug from the tablet and achieved a drug release by zero-order kinetics, which is practically difficult with only a hydrophilic matrix. An in vivo pharmacokinetic study elaborated that the bioavailability and solubility of silymarin were improved with an increased mean residence time.

The Other Mechanisms by Which the Rht Genes Improve the Harvest Index of Wheat.

Uncovering the mechanism that underlies the relationship between crop height and grain yield would potentially inform the strategies for improving wheat with optimal height. The aim of the research reported here was to identify the attributes able to produce wheat yield increases in Rht genotypes without further straw-shortening. Attention was given to examination in a controlled environment the question of the mechanistic foundation that determined the relationship between wheat height and yield in lines (Rht-B1b, Rht-D1b, Rht-B1c, Rht-D1c) compared to wild types in Mercia background. In addition to height reduction, this research revealed three other mechanisms by which the Rht genes may also improve the Harvest Index (HI) of wheat: (i) low Specific Leaf Area (SLA), (ii) increased Mean Residence Time (MRT) of Nitrogen (N), and (iii) increased grain number on spike.

PLGA-modified Syloid®-based microparticles for the ocular delivery of terconazole: in-vitro and in-vivo investigations

The eye is an invulnerable organ with intrinsic anatomical and physiological barriers, hindering the development of a pioneer ocular formulation. The aim of this work was to develop an efficient ocular delivery system that can augment the ocular bioavailability of the antifungal drug, terconazole. Mesoporous silica microparticles, Syloid® 244 FP were utilized as the carrier system for terconazole. Preliminary studies were carried out using different drug:Syloid® weight ratios. The optimum weight ratio was mixed with various concentrations (30 and 60%w/w) of poly (lactic-co-glycolic acid) (PLGA), ester or acid-capped and with different monomers-ratio (50:50 and 75:25) using the nano-spray dryer. Results revealed the superiority of drug:Syloid® weight ratio of 1:2 in terms of yield percentage (Y%), SPAN and drug content percentage (DC%). Furthermore, incorporation of PLGA with lower glycolic acid monomer-ratio significantly increased Y%. In contrast, increasing the glycolic acid monomer-ratio resulted in higher DC% and release efficiency percentage (RE%). Additionally, doubling PLGA concentration significantly reduced Y%, DC%, drug loading percentage (DL%) and RE%. Applying desirability function in terms of increasing DC%, DL% besides RE% and decreasing SPAN, the selected formulation was chosen for DSC, XRD and SEM investigations. Results confirmed the successful loading of amorphized terconazole on PLGA-modified Syloid® microparticles. Moreover, pharmacokinetic studies for the chosen formulation on male Albino rabbits’ eyes revealed a 2, 6.7 and 25.3-fold increase in mean residence time, Cmax and AUC0–24-values, respectively, compared to the drug suspension. PLGA-modified Syloid® microparticles represent a potential option to augment the bioavailability of ocular drugs.

An in vivo pharmacokinetic study of metformin microparticles as an oral sustained release formulation in rabbits

BackgroundMetformin hydrochloride is a biguanide derivative that has been widely used to treat type 2 diabetes in humans. In veterinary medicine, metformin has shown increasing potential for diabetes treatment in different species, such as equids, dogs, cats and rabbits. It is highly hydrophilic, with incomplete gastrointestinal absorption and very large variability in absolute bioavailability between species, ranging from 4% in equids to 60% in humans. Metformin also shows a short half-life of approximately 2 h in dogs, cats, horses and humans. The objectives of this study were to evaluate a poly (lactic acid) (PLA) metformin microparticle formulation to test in rabbits and conduct a pharmacokinetics study of intravenous (SIV) and oral solution (SPO) metformin administration and oral PLA microparticle (SPLA) administration to rabbits to evaluate the improvement in the metformin pharmacokinetics profile.ResultsMetformin-loaded PLA microparticles were characterized by a spherical shape and high encapsulation efficiency. The results from Fourier transform infrared (FTIR) spectroscopy suggested the presence of interactions between metformin and PLA. X-Ray diffraction (XRD) analysis corroborated the results from the differential scanning calorimetry (DSC) studies, showing that metformin is present in an amorphous state within the microparticles. Physicochemical characterization suggested that PLA and metformin hydrochloride interacted within the microparticles via hydrogen bonding interactions. The pharmacokinetic study in rabbits showed sustained-release characteristics from the prepared microparticles with a delay in the time needed to reach the maximum concentration (Tmax), decreased Cmax and bioavailability, and increased mean residence time (MRT) and half-life compared to the pure drug solution.ConclusionsMetformin-loaded PLA microparticles showed optimal and beneficial properties in terms of their physicochemical characteristics, making them suitable for use in an in vivo pharmacokinetic study. The pharmacokinetic parameters of the metformin microparticles from the in vivo study showed a shorter Tmax, longer MRT and half-life, decreased Cmax and the prolonged/sustained release expected for metformin. However, the unexpected decrease in bioavailability of metformin from the microparticles with respect to the oral solution should be evaluated for microparticle and dose design in future works, especially before being tested in other animal species in veterinary medicine.

A comparative outlook on pharmacokinetics and antimalarial studies of artemether and lumefantrine-loaded microneedle patches and a dry suspension containing nanosponges

Artemether and lumefantrine are World Health Organization (WHO) approved combinational therapy for antimalarial action, which exhibits low aqueous solubility and poor oral bioavailability. The present work intended to perform the comparative antimalarial and pharmacokinetic studies for newly designed combinational formulations using carriers such as dry suspension containing nanosponges (ADS) and microneedles (AMN). The nanosponges required for formulation ADS were prepared using the solvent evaporation method, whereas AMN by solvent casting method. The antimalarial test (percentage inhibition test) revealed that formulations showed significant activity towards chloroquine-resistant strain (RKL-9) in comparison to sensitive strain (MRC-2). Rane's test showed that formulations ADS and AMN increased the mean survival time of mice in contrast with the untreated groups. The pharmacokinetic study revealed that the formulation ADS demonstrated similar kinetic profile with increased mean residence time (MRT) of actives, in comparison with marketed preparation (Riamet). However, formulation AMN showed lesser Cmax and AUC but increased MRT, which demonstrated the prolonged presence of actives in the systemic circulation. Thus, the results of antimalarial and pharmacokinetic studies revealed the excellent action of formulations ADS and AMN towards resistant strains and tremendous potential of formulation ADS in escalating the oral bioavailability of actives with improved efficacy, respectively.

Biodistribution, pharmacokinetics and toxicity evaluation of mannosylated gelatin nanoparticles of linezolid for anti-tubercular therapy

ABSTRACT The present study explores the therapeutic potential of gelatin nanoparticles as a carrier for the delivery of linezolid, a repurposed drug for the treatment of Mycobactrium tuberculosis. However, it has significant issues of large dose and toxicity. To overcome this problem, linezolid loaded mannosylated gelatin nanoparticles were prepared for specific targeting to alveolar macrophages. The system was characterised for in-vitro , ex-vivo and in-vivo pharmacokinetics, biodistribution and toxicity studies to evaluate the safety and efficacy of the formulation. The method resulted in small-sized (197–298 nm) nanoparticles with a low polydispersity index (0.127–0.148) and higher drug entrapment (51–56%). The formulation was capable of sustained drug release with a significant increase in mean residence time and the half-life. The system is capable of reducing the dose, dosing frequency, and toxic adverse effects, which ultimately improves patient compliance and, therefore, a promising approach for the effective management of tuberculosis.

Dual drug delivery of cyclodextrin cross-linked artemether and lumefantrine nanosponges for synergistic action using 23 full factorial designs

To improve the physicochemical properties of artemether and lumefantrine, cyclodextrin-based carriers like nanoparticle, microcomplex, nanosponges, etc. play a significant role in the development of dosage forms. The current study focused on the formulation of cyclodextrin-based artemether and lumefantrine-loaded nanosponges to improve the solubility and stability of actives with controlled-release profile. Nanosponges were synthesized using solvent evaporation method and statistically optimized using 23 full factorial designs. Nanosponges showed mean particle size of 316.4 ± 8.5 nm and % entrapment efficiencies of 70.6 ± 1.5 % and 88.3 ± 2.5 % for artemether and lumefantrine, respectively. SEM and TEM analysis revealed the spherical structure of nanosponges with porous surfaces. In-vitro release study of nanosponges showed controlled-release of actives till 24 h. In-vitro antimalarial study showed significant action of nanosponges towards RKL-9 strains in comparison to MRC-2 strains. The pharmacokinetic study of nanosponges showed that the parameters (Cmax and AUC) were under the acceptable limits with increased mean residence time of actives in the blood circulation. The data of stability study demonstrated that nanosponges were stable at 40 °C for 3 months. Thus, hyper-cross-linked cyclodextrin nanosponges advance as a novel nanocarrier system for controlled-release formulations of BCS class II and IV drugs.

Superhydrophobic Substrates for Ultrahigh Encapsulation of Hydrophilic Drug into Controlled-Release Polyelectrolyte Complex Beads: Statistical Optimization and In Vivo Evaluation.

In this work, ultrahigh drug-loaded chitosan (Ch)/K-carrageenan (Kc) polyelectrolyte complex (PEC) beads were formed in situ by cross-linking in a glutaraldehyde-saturated atmosphere and were prepared on superhydrophobic substrates fabricated by spraying glass surfaces with ready-made spray for domestic use (NeverWet®). Verapamil hydrochloride (VP), a highly hydrophilic drug with a short biological half-life, was incorporated into a series of Ch-based and/or Ch/Kc-PEC-based beads to control its release profile in vivo. The formulation of VP-loaded beads was optimized using stepwise statistical designs based on a prespecified criterion. Several characteristics of the prepared beads, such as entrapment efficiency (EE%), in vitro drug release, swelling ratio, size and surface microstructure as well as molecular interactions between the drug and formulation ingredients, were investigated. In vivo pharmacokinetic (PK) studies were carried out using the rabbit model to study the ability of the optimized VP-loaded beads to control the absorption rate of VP. Results revealed that the prepared superhydrophobic substrates were able to fabricate VP-loaded beads with extremely high EE exceeding 90% w/w compared to only 27.80% when using conventional ionotropic gelation technique. PK results showed that the rate of VP absorption was well controlled following oral administration of the optimized beads to six rabbits compared to a marketed VP immediate release (IR) tablet, as evidenced by a 2.2-fold increase in mean residence time (MRT) and 5.24-fold extension in half value duration (HVD) over the marketed product without any observed reduction in the relative oral bioavailability.

Theoretical consideration of the properties of intestinal flow models on route-dependent drug removal: Segregated Flow (SFM) vs. Traditional (TM).

The intestine is endowed with a plethora of enzymes and transporters and regulates the flow of substrate to the liver. Physiologically-based pharmacokinetic models have surfaced to describe intestinal removal. The traditional model (TM) describes the intestinal flow as a whole perfusing the entire tissue that contains the intestinal transporters and enzymes. The segregated flow model (SFM) describes that only a fraction (fQ <0.2) of the intestinal blood flow perfuses the enterocyte region where the intestinal enzymes and transporters are housed, rendering a lower drug distribution/intestinal clearance when drug enters via the circulation than from the gut lumen. As shown by simulations, a higher intestinal clearance and extraction ratio (EI,iv ) exists for the TM than for SFM after iv dosing. By contrast, the EI,po after po dosing is higher for the SFM, due to the smaller volume of distribution for the enterocyte region and a lower flow rate that result in increased mean residence time and higher drug extraction. Under MBI (mechanism-based inhibition), the AUCR,po after oral bolus is the highest for drug when inhibitor is given orally, with SFM>TM. Competitive inhibition of intestinal enzymes leads to higher liver metabolism; again, when both drug and inhibitor are given orally, changes in the SFM>TM. However, less definitive patterns result with inhibition of both intestinal and liver enzymes. In conclusion, differences exist for EI and drug-drug interaction (DDI) between the TM and SFM. The fractional intestinal blood flow (fQ ) is a key factor affecting different extents of intestinal/liver metabolism of the drug after oral as well as intravenous administration.

A factor VIII–nanobody fusion protein forming an ultrastable complex with VWF: effect on clearance and antibody formation

AbstractVon Willebrand factor (VWF) modulates factor VIII (FVIII) clearance and the anti-FVIII immune response. Despite the high affinity that defines the FVIII/VWF interaction, association/dissociation kinetics dictates 2% to 5% FVIII being present as free protein. To avoid free FVIII when studying the FVIII-VWF complex in vivo, we designed a FVIII-nanobody fusion protein, with the nanobody part being directed against VWF. This fusion protein, designated FVIII-KB013bv, had a 25-fold higher affinity compared with B-domainless FVIII (BDD-FVIII) for VWF. In vitro analysis revealed full cofactor activity in 1-stage clotting and chromogenic assays (activity/antigen ratio 1.0 ± 0.3 and 1.1 ± 0.3, respectively). In vivo, FVIII-013bv displayed a twofold increased mean residence time compared with BDD-FVIII (3.0 hours vs 1.6 hours). In a tail clip–bleeding assay performed 24 hours after FVIII infusion, blood loss was significantly reduced in mice receiving FVIII-KB013bv vs BDD-FVIII (15 ± 7 μL vs 194 ± 146 μL; P = .0043). Unexpectedly, when examining anti-FVIII antibody formation in FVIII-deficient mice, the immune-response toward FVIII-KB013bv was significantly reduced compared with BDD-FVIII (1/8 vs 14/16 mice produced anti-FVIII antibodies after treatment with FVIII-KB013bv and BDD-FVIII, respectively). Our data show that a stabilized interaction between FVIII and VWF is associated with a prolonged survival of FVIII and a reduced immune response against FVIII.

Azadirachita indica gum based sildenafil citrate mucoadhesive microspheres – Design and optimization

The current research involved design and optimization of Sildenafil citrate loaded oral mucoadhesive multiparticulate system, to prolong residence time and enhance bioavailability of the drug. The microspheres were prepared by ionotropic gelation method using ‘Azadirachta Indica’ as a mucoadhesive polymer employing 32 factorial design. Microspheres were discrete, spherical, free flowing and the absence of drug-excipient interactions was confirmed by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD) studies. The drug release followed Fickian diffusion mechanism with zero order release kinetics. Optimization of the responses was carried out using numerical desirability and graphical approaches. In vivo pharmacokinetic studies in rabbits demonstrated an increase in mean residence time by 75% and relative bio-availability by 1.5 times. Ex vivo wash off test and radiographic studies in rabbits confirmed the adherence of the microspheres to the GI mucous layer which were retained for an extended period of time. The developed formulation can be a viable alternative to the conventional dosage forms of thrice a day dosing in pulmonary arterial hypertension. The research signified the potential of ‘Azadirachta Indica’ as a mucoadhesive polymer in the design of oral controlled drug delivery systems.

Impact of solid carriers and spray drying on pre/post-compression properties, dissolution rate and bioavailability of solid self-nanoemulsifying drug delivery system loaded with simvastatin

In the present study, different solid self-nanoemulsifying drug delivery system (S-SNEDDS) was formulated by using porous hydrophilic and hydrophobic carriers to improve the dissolution rate and bioavailability of simvastatin (SIM). The prepared liquid-SNEDDS composed of Labrafil M 1944 CS/ Tween-80/ Ethanol (20% / 53.33%/26.67% v/v) with 0.1% SIM, resulted droplet size of 40.69 nm. The hydrophobic carriers used were Aerosil-200, Syloid 244FP, Syloid XDP 3150, Magnesium stearate, Micro Crystalline Cellulose PH102 and lactose and hydrophilic carriers used were Poly vinyl alcohol, Sodium carboxy methyl cellulose and hydroxypropyl-β-cyclodextrin. These S-SNEDDS were characterized through micromeritic, biopharmaceutical studies and stability studies. The spray dried S-SNEDDS prepared by using Aerosil 200 as hydrophobic carrier provided nanoemulsions with unchanged droplet size and drug release when subjected at different stress conditions such as thermodynamic stress and freeze thaw cycles. In vitro dissolution studies revealed that the L-SNEDDS and S-SNEDDS of Aerosil 200 were found to be remarkably superior over the unprocessed SIM and marketed SIM. Scanning electron microscope, Differential scanning calorimeter and Powder X-Ray Diffraction revealed crystalline SIM was present in a changed amorphous state in the SNEDDS formulations prepared with Aerosil 200 as carrier. Further, pharmacokinetic study carried out on rats revealed 0.5 h increase in time for maximal concentration (Tmax), 3.75 folds increase in maximal concentration (Cmax), 1.22 h increase in mean residence time, 1.54 folds increase in area under curve (AUC0-t), 2.10 folds increase in AUC0-∞ and 3.28 folds increase in bioavailability confirms that the developed S-SNEDDS were superior than that of marketed formulation. Hence, it can be safely concluded that Aerosil 200 based S-SNEDDS were able to provide improvement in dissolution rate and oral bioavailability of SIM.

Biological reactor retrofitting using CFD-ASM modelling

In recent years, the interest in modelling activated sludge (AS) systems by means of Computational Fluid Dynamics (CFD) techniques has significantly increased. This work shows a successful case study combining CFD hydrodynamics and biokinetic modelling. The hydrodynamics is analysed by using the Reynolds-averaged Navier-Stokes equation for incompressible non-Newtonian fluids and SST turbulence model. Biokinetics has been included in the CFD as transport equations with source and sink terms defined by the Activated Sludge Model n°1 (ASM1). Furthermore, a strategy for reducing the computational cost while maintaining accuracy of the results of these calculations has been proposed. This strategy is based on a two-step solver configuration and the definition of a variable timestep scheme. The resulting CFD-ASM approach permits a proper evaluation of denitrification in the anoxic tanks as well as the reproduction of nitrate and readily biodegradable substrate distributions. To demonstrate the strength of the proposed CFD-ASM, it has been used to evaluate the operation of a full-scale AS system and optimize its performance through changes in the biological reactor anoxic zone. The original configuration has been retrofitted and modified after detecting intrinsic defects in the fluid behaviour within the tank. This study has been assessed by analysing hydrodynamics in detail and validating the simulation results with tracer tests and flow velocity measurements. Substantial variations on the Residence Time Distribution have been confirmed when modifying the internal elements of the tank configuration: the wall-bushing and the stirrer positioning. As a result of this work, an influential short circuiting was corrected improving hydrodynamics and increasing mean residence time, all favouring denitrification efficiency. Outcomes of this study show the benefit of CFD when applied to AS tanks.

Impact of Hydrodynamic Reconfiguration with Baffles on Treatment Performance in Waste Stabilisation Ponds: A Full-Scale Experiment

Wastewater infrastructure is expensive to build and maintain, and there is a need to focus on improving and modernising existing infrastructure before large capital investments are made to service future population needs. Waste stabilisation ponds (WSPs) are used worldwide for the treatment of wastewater, but their performance is significantly affected by poor hydraulic control. Hydraulic reconfiguration of ponds is a possible solution to this problem, whereby the flow is controlled and short-circuiting is reduced. There is evidence to suggest that this approach has the potential to increase treatment performance, however in the absence of full-scale validation it is difficult to generalise this to a wide range of sites. For example, there is no consensus on the best baffle configuration to optimise hydraulic performance. The main objective of this study was to conduct a full-scale experiment of baffles in a WSP, and to investigate their impact on hydraulic performance. To achieve this objective, the approach combined high-resolution pond bathymetry and 2D hydrodynamic modelling, assessed with hydraulic indices, to determine the optimal baffle configuration for the site; it was shown that three baffles perpendicular to the inflow provided the greatest increase (up to 24%) in mean residence time. This configuration was then implemented in a working WSP. The effects of the baffles on the pond were then assessed using a combination of field tracer testing, revealing an increase in mean residence time of at least 20%, and further hydrodynamic modelling. Through the addition of wind data into the hydrodynamic model, it is shown that baffles not only improve the flow, but also attenuate the effect of wind on pond hydraulics. While the conclusions of this study are site-specific, the implementation of site-specific solutions is important for progress towards optimal pond design. The approach developed here is easily transferrable for use on other sites, and will enhance our ability to plan, design and operate WSP systems in the future.

Novel cremochylomicrons for improved oral bioavailability of the antineoplastic phytomedicine berberine chloride: Optimization and pharmacokinetics

Berberine chloride (BER) is an antineoplastic phytomedicine that combat non-Hodgkin lymphoma. BER suffers from low oral bioavailability due to p-glycoprotein efflux and first-pass metabolism. Lymphatic drug targeting recently gained a profound attention due to circumventing hepatic first-pass metabolism and targeting lymph diseases. Therefore, novel BER-loaded cremochylomicrons were elaborated to mitigate BER drawbacks and enhance its lymphatic targeting and bioavailability. Optimized cremochylomicron was prepared with 2.5%w/v Cremophor El and 12.5% w/w berberine content. Promising in vitro characteristics (particle size = 175.6 nm and entrapment efficiency = 95.5%) were obtained. Lyophilized system showed high colloidal stability over 6 months. In addition in vivo pharmacokinetics study demonstrated significant enhancement (>2fold) in the rate and extent of absorption in cremochylomicron over free BER. Moreover, cremochylomicrons demonstrated in significant increase in mean residence time and volume of distribution with decreased intestinal drug clearance as a result of efflux inhibition. In another avenue, a significant reduction in BER absorption (43%) in presence of cycloheximide inhibitor was obtained confirming the lymphatic targeting ability of cremochylomicrons. In conclusion, berberine-loaded cremochylomicron could be considered as a promising nanoplatform for targeting lymphatic system and improving BER oral bioavailability with lower dose and side effects.

PHARMACOKINETIC STUDY OF MATRIX MEMBRANE MODERATED TRANSDERMAL SYSTEM OF BOSENTAN MONOHYDRATE

Objective: The objective of the present research work is to carry out the pharmacokinetic studies of optimized matrix membrane moderatedtransdermal patch of bosentan monohydrate.Materials and Methods: The matrix membrane moderated transdermal system was formulated using HPMC, HPMC K4M and E RLPO. In vitrodiffusion studies were carried out using modified Franz diffusion cell and for the optimized transdermal patch, pharmacokinetic studies were carriedout using New Zealand male rabbits. Plasma samples were quantified using high-performance liquid chromatography.Results: The in vitro diffusion studies revealed that formulation F3 with HPMC K4M and E RLPO had controlled release up to 28 hrs, and a maximumof 95.02±2.68% drug was released. The release kinetics followed mixed order non-Fickian diffusion. The pharmacokinetic studies of the optimizedpatch revealed controlled release up to 45 hrs where a 2.2-fold increase in area under curve (AUC) and 3.8 times increase in mean residence time(MRT) were observed compared to oral route. The results were appeared to be significant at p≤0.05. The variation in half-life was found to be notstatistically significant when compared between oral and transdermal routes.Conclusion: The pharmacokinetic results concluded that the matrix membrane moderated transdermal system with extended AUC and MRT canenhance the bioavailability of bosentan monohydrate by minimizing the drug-related side effects in oral route.

Sub-Acute Exposure of Fenvalerate in Buffalo Calves:Toxicokinetic Evaluation

The effect of sub-acute fenvalerate administration on its toxicokinetics was studied in male buffalo calves. Four healthy male buffalo calves were administered fenvalerate orally (@ 1 mg.kg -1 .day -1 ) for 21 consecutive days. On day one, blood samples were collected for upto 48 h post administration for toxicokinetic study. The calves were then drenched at the same dose rate for 21 days and sampling was repeated on 21 st day for toxicokinetic analysis. Concentrations of fenvalerate in the serum samples were analysed using gas chromatography (GC) and toxicokinetic parameters were calculated as per the non compartmental analysis. Significantly reduced distribution at steady state (0.11 L.kg -1 Vs 0.19 L.kg -1 ) on 21 st day of continuous exposure compared to day one, clearly indicated limited distribution of the pesticide in various body fluids and tissues upon repeated administration. There was improved persistence of toxicant in the body upon sub-acute exposure as shown by significant increase in area under curve (AUC=156.4 Vs 69.1 μg.h.ml -1 ) after sub-acute administration. This fact was further supported by increased mean residence time (MRT=16.7 h Vs 12.6 h) of the pesticide. There was significant increase in the elimination half life (11.6 h Vs 8.74h) of the toxicant on day 21 compared to that observed on day 1, which was further underlined by a significant decrease in its clearance (0.006 Vs 0.015 L.kg -1 .h -1 ). Sub-acute exposure of fenvalerate at the proposed dose rate resulted in limited tissue distribution, augmented persistence and slow elimination from the body of animals. This altered toxicokinetics of fenvalerate upon subacute exposure might be due to its effect on organs of metabolism and/elimination, thereby posing increased risk of toxicity in buffalo calves.