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We aimed to understand the impact of the interplay between bile salts and cyclodextrins on the dissolution-permeation of poorly soluble drug compounds with a moderate-strong binding constant to cyclodextrin. Phase diagrams were prepared on the chosen model compound albendazole in phosphate buffer, fasted state simulated intestinal fluid (FaSSIF), and a modified fed state simulated intestinal fluid (FeSSIFmod) with (2-hydroxypropyl)-beta-cyclodextrin (HP-β-CD) concentrations of up to 10 % (m/m). Then we investigated the dissolution/permeation interplay of albendazole dissolved/suspended in the different media through a biomimetic barrier on a 96-well in vitro model. The apparent solubility of albendazole was enhanced by HP-β-CD and FaSSIF/FeSSIFmod separately. However, when albendazole was dissolved in HP-β-CD and biomimetic media together, the solubility was significantly lower than the predicted additive solubility from the solubilizing effects. It is postulated that this is due to the sodium taurocholate from the biomimetic media displacing albendazole from the hydrophobic cavity of HP-β-CD. In the permeation experiments, the highest permeation was observed at cyclodextrin concentrations able to solubilize close to the total dose of albendazole without a major surplus of solubilization capacity. Furthermore, an over-proportional permeation enhancement was observed when both, cyclodextrin and biomimetic media were present. These results indicate that the interplay between bile salts and cyclodextrins can enhance the free (molecularly dissolved) fraction of drug in solution to a greater extent than could be obtained with one of the solubilizing components alone. In conclusion, at carefully selected cyclodextrin-concentrations in combination with biomimetic media, obviously, a transient supersaturation is induced, which is made responsible for the observed major permeation enhancement.

In order to achieve a high sample throughput, permeation experiments are often carried out using 96-well sandwich plates. Even though agitation is regarded as important, permeation studies in 96-well format are often carried out without agitation since orbital shaking, the most common agitation method for 96-well plates, has been reported to create difficulties (e.g., well-to-well cross-talk), and high cost and low availability limits the use of other agitation techniques (e.g., magnetic stirring). This study investigates how orbital shaking and magnetic stirring affect the apparent permeability of model compounds with different water-solubilities (methylene blue, carbamazepine, and albendazole) using a novel 96-well sandwich plate comprising a cellulose-hydrate membrane (PermeaPlain (R) plate). Orbital shaking was found less efficient than magnetic stirring in terms of homogeneously distributing a small volume of dye within the donor compartment. Furthermore, in terms of achieving maximum trans-barrier flux, magnetic stirring was found a more effective agitation method than orbital shaking. Obviously, with orbital shaking the medium in the bottom compartment of the sandwich plates never was mixed in-phase. The impact of insufficient mixing on permeation was found strongest with the most lipophilic compound, which correlates with literature reports that the contribution of the unstirred water layer towards the overall resistance of the barrier is most expressed in case of lipophilic drugs. Finally, it was tested how different liquid volumes in the bottom compartment of the plates affect the well-to-well cross-talk during permeation experiments under orbital shaking. This study revealed that 250-300 mu L should be used in the bottom compartment of the sandwich plates to reduce well-to-well cross-talk when using orbital shaking for agitation. (C) 2021 Published by Elsevier Inc. on behalf of American Pharmacists Association.

The amount and composition of organic carbon are major controls on water quality and ecological processes in streams. In this study we explored the fate of the quantity of dissolved organic carbon (DOC) and the composition of dissolved organic matter (DOM) in an agricultural hillslope - stream network system. We conducted our study in the 66 ha HOAL (Hydrological Open Air Laboratory) in Lower Austria. We measured DOC of the soil eluates from different land use units, water samples from the stream and from seven tributaries, and estimated DOM components by fluorescent spectrophotometry and PARAFAC analyses. Soil DOC shows the highest concentrations in summer, but DOC concentrations in the tributaries are lower in summer than in winter by between 19% and 31%. DOM composition of the soil eluate differs between land use units. The forest site exhibits the largest fractions of humic-like fluorophores and less labile DOM. DOM composition in the tributaries is, in addition to DOC, controlled by soil moisture. We estimated the DOC import from the tributaries into the stream as 125 kg during base flow conditions in the period February to December 2017 and the instream DOC production as 38 kg, considering mass balance and exchange with groundwater. Six out of seven DOM components have a positive net production along the stream, only aliphatic DOM with low molecular weight is consumed (65 % of its input). These findings suggest that agricultural land use increases DOC input into streams and alters their DOM quality. Instream processes modify DOM quality over short distances.

Water taps can be a reservoir for microorganisms and pose a risk for contamination and infection. In this work, water samples from different common taps were examined to determine the influence of certain parameters on the microbial load of drinking water. Methods: Four different types of taps were installed along the same water pipe. Over a period of six months, water samples were taken at specific intervals and analyzed for their colony-forming units (CFU/mL) and for the presence of the water pathogens Pseudomonas aeruginosa and Legionella pneumophilia. Two different flushing configurations were investigated: Setup A: the same flush intervals for all taps once a day to determine differences based on type, size and mode of operation. Experimental setup B: different flush cycles for manual and electronic taps to investigate the effects of water stagnation in the tap and whether electronic taps with automatic flushes improve water quality. Results: No Legionella pneumophilia and Pseudomonas aeruginosa were found during the study period. The size of the tap has a great influence on the number of CFU/mL—a maximum of 330 CFU/mL was found in the smallest tap and 1080 CFU/mL in the largest tap, with a significant difference. Stagnation in the tap leads to a significantly higher number of CFU/mL. The results of this work can be used as a basis for the development of innovative taps. There are many possibilities in terms of materials, tap size and intelligent action algorithms—such as automatic flushing—to maintain the quality of our drinking water in a resource-saving way.

For oral drug delivery the stability of liposomes against intestinal bile salts is of key importance. Here, asymmetric flow field-flow fractionation (AF4) coupled to multi-angle laser light scattering (MALLS) and a differential refractive index (dRI) detector was employed to monitor structural re-arrangement of liposomes upon exposure to the model bile salt taurocholate. For comparison, a conventional stability assay was employed using a hydrophilic marker and size exclusion chromatography (SEC) to separate released from liposome-entrapped dye. Calcein-containing liposomes with and without cholesterol were compared in terms of their in vitro stability upon exposure to bile salts by separating liposomes from co-existing colloidal species emerging after stress test using AF4/MALLS/dRI. Dynamic light scattering (DLS) was utilized in parallel. Our AF4/MALLS/dRI results suggested that exposure of egg-phospholipid liposomes to bile salts at physiological concentrations led to the formation of two new species of colloidal associates, likely (mixed) micelles. Subjecting cholesterol-containing liposomes to the same bile media did not lead to any new colloidal structures, indicating increased stability of these liposomes. Our SEC-based release assay largely confirmed these findings, indicating that AF4/MALLS/dRI is a suitable technique for prediction of in vitro oral stability of liposomal formulations. Moreover, the powerful AF4/MALLS/dRI technique appears promising to improve the understanding of the underlying mechanisms during bile salt-induced liposomal breakdown.

As numerous new drug candidates are poorly water soluble, enabling formulations are needed to increase their bioavailability for oral administration. Nanoparticles are a conceptually simple, yet resource consuming strategy for increasing drug dissolution rate, as predicting in vivo oral absorption using in vitro dissolution remains difficult. The objective of this study was to obtain insight into nanoparticle characteristics and performance utilizing an in vitro combined dissolution/permeation setup. Two examples of poorly soluble drugs were examined (cinnarizine and fenofibrate). Nanosuspensions were produced by top-down wet bead milling using dual asymmetric centrifugation, obtaining particle diameters of approx. 300 nm. DSC and XRPD studies indicated that nanocrystals of both drugs were present with retained crystallinity, however with some disturbances. Equilibrium solubility studies showed no significant increase in drug solubility over the nanoparticles, as compared to the raw APIs. Combined dissolution/permeation experiments revealed significantly increased dissolution rates for both compounds compared to the raw APIs. However, there were substantial differences between the dissolution curves of the nanoparticles as fenofibrate exhibited supersaturation followed by precipitation, whereas cinnarizine did not exhibit any supersaturation, but instead a shift towards faster dissolution rate. Permeation rates were found significantly increased for both nanosuspensions when compared to the raw APIs, indicating a direct implication that formulation strategies are needed, be it stabilization of supersaturation by precipitation inhibition and/or dissolution rate enhancement. This study indicates that in vitro dissolution/ permeation studies can be employed to better understand the oral absorption enhancement of nanocrystal formulations.

The marketed oral solution of itraconazole (Sporanox®) contains 40 % (259.2 mM) of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The obvious role of HP-β-CD is to solubilize itraconazole and to overcome its poor aqueous solubility that restricts its absorption. In this study, we investigated biorelevance by in vitro the influence of biomimetic media (containing bile salts and phospholipids) on the predicted itraconazole absorption from the commercial HP-β-CD-based Sporanox® solution. We performed phase-solubility studies of itraconazole and dynamic 2-step-dissolution/permeation studies using a biomimetic artificial barrier, Sporanox® solution, and fasted state simulated intestinal fluid (FaSSIF_V1). Both FaSSIF_V1 and HP-β-CD increased the apparent solubility of itraconazole when used individually. In combination, their solubility-enhancing effect did not result additive probably due to the competition of bile salts with itraconazole for the hydrophobic cavity of HP-β-CD. Our combined dissolution/permeation experiments indicated the occurrence of a transient supersaturation from Sporanox® upon two-step dissolution. Through systematic variation of bile salt concentrations in the biomimetic media, it was observed that the extent and duration of supersaturation depend on the concentration of bile salts: supersaturation was rather stable in the absence of bile salts and phospholipids. The higher the bile salt concentration, the faster the collapse of the transient supersaturation occurred, an effect which is nicely mirrored by reduced in vitro permeation across the barrier. This is an indication of a negative food effect, which in fact had earlier been observed in clinical studies for Sporanox® solution. In essence, we could demonstrate that in vitro two-stage dissolution/permeation experiments using an artificial barrier and selected biomimetic media may predict the negative effects of cyclodextrin-based drug formulations like Sporanox® Oral solution and, at the same time, provide a deeper mechanistic insight.

Fosamprenavir is a phosphate ester prodrug that, upon dissolution, is cleaved to the poorly soluble yet readily absorbable parent drug amprenavir. In this study, a novel cell-free in vitro setup with quasi-continuous monitoring of the dynamic dissolution/bio-conversion/permeation of fosamprenavir was designed and tested. It consists of side-by-side diffusion cells, where the donor and acceptor compartments are separated by the biomimetic barrier PermeaPad®, and sampling from the donor compartment is accomplished via a microdialysis probe. Externally added bovine alkaline phosphatase induced bioconversion in the donor compartment. Microdialysis sampling allowed to follow the enzymatic conversion of fosamprenavir to amprenavir by the bovine alkaline phosphatase in an (almost) real-time manner eliminating the need to remove or inactivate the enzyme. Biomimetic conversion rates in the setup were established by adding appropriate amounts of the alkaline phosphatase. A substantial (6.5-fold) and persistent supersaturation of amprenavir was observed due to bioconversion at lower (500 µM) concentrations, resulting in a substantially increased flux across the biomimetic barrier, nicely reflecting the situation in vivo. At conditions with an almost 10-fold higher dose than the usual human dose, some replicates showed premature precipitation and collapse of supersaturation, while others did not. In conclusion, the proposed novel tool appears very promising in gaining an in-depth mechanistic understanding of the bioconversion/permeation interplay, including transient supersaturation of phosphate-ester prodrugs like fosamprenavir.

Many new drug entities are poorly water- soluble and thus require solubility- enhancing formulations to ensure sufficient bioavailability. On the other hand, it is more and more accepted that not all "dissolved" states of a drug contribute equally to enhanced absorption, i.e. an increase in apparent solubility does not necessarily go in parallel with an increase in molecularly dissolved drug, the latter being regarded as the key driving force for absorption. Our study aimed to provide time- resolved information on the dissolution, supersaturation, and precipitation behavior of molecularly dissolved drug as released from an amorphous solid dispersion and a surfactant- containing crystalline suspension of Posaconazole (PCZ), a weakly basic and poorly water-soluble drug. Thereby, we aimed to gain a deeper mechanistic understanding of enabling formulation principles and possibly establish a dynamic biopharmaceutical assessment tool for molecularly dissolved drug released from enabling formulations. A two-staged dissolution test, with media transition from simulated gastric fluid (SGF) to fasted state simulated intestinal fluid (FaSSIF), was performed with three alternative sampling approaches in parallel: the classical bench centrifugation approach was used to assess total dissolved concentrations, while a nanofiltration method and a microdialysis setup were tested for their ability to discriminate molecularly and colloid-associated drug concentrations over time. For comparison, a single- stage dissolution setup was performed, where a marketed PCZ suspension was dispersed in biomimetic media with increasing amounts of solubilizing agents to understand their effect on the concentration of molecularly dissolved drug. It was demonstrated that the microdialysis setup allowed to follow the molecularly dissolved drug concentration in a time- resolved manner during the single- and two-stage dissolution tests with marginal delays. Interestingly, the PCZ concentrations measured by the nanofiltration approach differed from both, the molecularly dissolved (assessed by microdialysis) and apparently dissolved (assessed by centrifuge) PCZ concentrations, indicating that nanofiltration may allow to differentiate between different colloid- associated (apparently) dissolved drug species. Moreover, it was shown that the release of the molecularly dissolved drug from an amorphous solid dispersion did not correlate at all with the results obtained by the centrifugation method: While this conventional sampling revealed a classical spring and parachute concentration/ time- profile with a high degree of (apparent) supersaturation, the concentration of molecularly dissolved drug (assessed by the microdialysis setup) indicated an initial short decline of PCZ concentration, followed by a prolonged (moderate) molecular supersaturation. This observation may give rise to a re- thinking of the current mechanistic understanding of how amorphous solid dispersions enhance oral bioavailability. In essence, the current study provides data which indicate a benefit of both the microdialysis sampling and nanofiltration approaches for the in vitro biopharmaceutical assessment of enabling drug formulations.

Limitations of the anticancer drug product Taxotere® have encouraged researchers to entrap the active ingredient docetaxel (DTX) into nanocarriers such as liposomes. However, until now no DTX-liposome formulation has reached the clinic. Hence, in the present study, different Soy-PC based DTX-liposome formulations were screened in an attempt to identify lipid-compositions with promising DTX-entrapment (DTX-EE). Various other quality attributes, such as vesicle size and morphology, poly dispersity index (PDI), zeta potential (ZP), stability and in vitro drug release were also investigated. In an initial study, the inclusion of charged lipids within the liposome bilayer was observed to have a positive effect on DTX-EE. Thus, cationic DOTAP (1,2-Dioleoyl-3-trimethylammonium-propane) and anionic DMPG (1,2-Dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol) lipids were selected for further investigations. With anionic DMPG, only a temporary rise in EE was gained with ≥ 20% (w/w) DMPG in Soy-PC lipid-based liposomes, whereas a concentration-dependent increase in EE was observed with cationic DOTAP. A DTX-EE > 95% was obtained with only 5% (w/w) DOTAP in Soy-PC, while neutral liposomes formed from Soy-PC alone, gave 41.5% DTX-EE. In the stability study, a DOTAP concentration > 10% (w/w) in Soy-PC was found to facilitate a stable DTX-EE > 90% after 12 weeks storage. The positive effect of cationic lipids on the EE was confirmed when replacing cholesterol (CHOL), initially shown to suppress DTX-entrapment, with cationic 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]Cholesterol (DC-CHOL). Here, DTX-EE was improved from 29.8% to 92.0% (w/w) with 10% (w/w) CHOL and DC-CHOL in Soy-PC, respectively. Finally, PEGylation of DOTAP-liposomes with DSPE-PEG2000 and DSPE-PEG750 reduced the DTX-EE relative to DOTAP-liposome with no PEGylation. As with the DMPG-liposomes, a temporarily raised affinity between DTX and liposomes was obtained with anionic DSPE-PEGylation of Soy-PC liposomes, however, this effect was not maintained after 4 weeks storage. However, in a dialysis set-up, cationic DOTAP-liposomes released DTX to a higher extent than PEGylated liposomes. Thus, the optimal formulation with regard to storage stability and in vivo performance need to be investigated further, applying conditions that are closer to mimic the in vivo-situation. Applying the Dual Asymmetric Centrifugation (DAC) method in liposome production appears favourable due to its good reproducibility. The observed increase in DTX entrapment with cationic lipids or PEGylation appears scalable into pilot manufacturing scale.

Denkmalgerechte Umnutzungen von Kirchen und Kapellen, auch ohne gottesdienstliche Nutzung, sind in einer säkularen Gesellschaft möglich und wünschenswert. Die Fülle an Möglichkeiten - aber auch an technischen Herausforderungen - ist groß. Durch sorgfältige Planung können zahlreiche Konzepte umgesetzt werden. Abgesehen von Wohnnutzungen, die aufgrund haustechnischer und bauklimatischer Rahmenbedingungen die stärksten Eingriffe fordern, sind alle im Beitrag präsentierten Objektbeispiele nach wie vor für die Öffentlichkeit nutzbar. So empfiehlt der Beitrag, gemäß der alten Weisheit, als generelles Fazit: "Die Kirche im Dorf lassen" und eine neue Nutzung für die Öffentlichkeit finden! Die Möglichkeiten sind vielfältig! Auch und gerade die säkulare Gesellschaft braucht solche besonderen Orte, die den Menschen über die Erfahrungen und Zwänge des Alltäglichen erheben. Als Beispiele sind aufgeführt: die Michaelskapelle in Iphofen, der Zehnthof in Nordheim am Main, die Pfarrkirche Wörth am Main, die Laurentiuskirche in Collenberg-Reistenhausen, die Pfarrkirche Wenigumstadt sowie die Kirche St. Wendelin in Eichenberg. Diese Metadaten wurden zur Verfügung gestellt von der Literaturdatenbank RSWB®plus

ZusammenfassungMit über 45 % Flächenanteil stellt die Landwirtschaft die dominante Landnutzungsform in Niederösterreich dar. Durch landwirtschaftliche Nutzung werden große Mengen an gelöstem organischem Material in Bäche eingebracht. Dieses organische Material führt zu einer Veränderung von Gewässerprozessen und beeinträchtigt den ökologischen Zustand der Gewässer. Das Ziel dieser Studie war es, die Auswirkungen verschiedener Bewirtschaftungspraktiken auf die Menge und die Qualität des gelösten organischen Materials in Fließgewässern zu untersuchen und die Folgen dieser Einträge auf den aquatischen Kohlenstoffumsatz und den Sauerstoffverbrauch abzuklären.Im Sommer 2017 und 2018 wurden Wasserproben aus Bächen mit unterschiedlicher Umlandnutzung, Kläranlagenabflüssen und der Donau in Niederösterreich entnommen und die Konzentrationen an gelöstem organischem Kohlenstoff (DOC) und Nährstoffen analysiert. Weiters wurde in kontrollierten Laborversuchen untersucht, wie sich Extrakte aus unterschiedlichen organischen Quellen, wie Wald- und Ackerboden, Blättern und Gülle, auf die mikrobielle Atmung in Bachsedimenten auswirken. Im Rahmen von Perkolationsversuchen analysierten wir die Auswirkungen von Düngung auf die Konzentrationen von organischem Material im Porenwasser unterschiedlicher Bodentypen.Die Freilanderhebungen zeigen, dass die Konzentrationen an gelöstem organischen Kohlenstoff und Nährstoffen mit zunehmender Nutzung des Umlands durch Landwirtschaft oder Siedlungen ansteigen. Zudem kam es zu einer Anreicherung an labilen organischen Stoffen, was auf eine Belastung durch Mikroorganismen und auf erhöhte mikrobielle Umsatzraten in den Gewässern hindeutet. In den Laborversuchen führten manche DOC-Quellen, wie z. B. Gülle- oder Kuhfladenextrakt, zu einer signifikanten Erhöhung des bakteriellen Sauerstoffverbrauchs. Leicht verfügbare Kohlenstoffquellen haben somit das Potenzial, den Sauerstoffverbrauch in Gewässern zu stimulieren, wobei deren Wirkung sowohl von der Menge und Art der Kohlenstoffquelle als auch von der Beschaffenheit und der stofflichen Vorbelastung der Sedimente abhängt. In den Perkolationsversuchen führte eine nitratbasierende Düngung, unabhängig von der Art des Düngers (mineralisch oder organisch) zu einer Reduktion der DOC-Konzentrationen im Sickerwasser. Der Grund für diese Reduktion könnte in einer Stimulation der Mineralisierung von organischem Material im Boden durch das eingebrachte Nitrat liegen. Unsere Studie weist auf die Bedeutung einer ausreichend langen Bodenpassage hin, um Fließgewässer in landwirtschaftlichen Regionen vor dem Eintrag von labilem organischen Kohlenstoff zu schützen. Das ist gerade im Hinblick auf eine prognostizierte Anhäufung von Trockenheit und Starkregenereignissen in der Zukunft wichtig, die zu einem verstärkten Eintrag von Bodenmaterial in Oberflächengewässer führen kann.

In this paper, we developed a sensitive and simple electrochemical method for the rapid detection of Escherichia coli in water samples. The general principle of the assay utilizes the enzyme $\beta $ -D-glucuronidase. This enzyme was induced by adding methyl- $\beta $ -D-glucuronide sodium salt and its activity promoted the cleavage of 8-hydroxyquinoline glucuronide to the electroactive compound 8-hydroxyquinoline. This cleavage product was further oxidized on the working electrode of a potentiostat using cyclic voltammetry. The obtained current output signal in a specific voltage range (400 to 600 mV) indicated enzyme activity and subsequently was an evidence for E. coli cells in the sample. For our experiment, we designed a low-cost potentiostat and show an evaluation of this instrument. First, the $\beta $ -D-glucuronidase assay was tested with various concentrations of enzyme solutions before living E. coli cells were investigated. Our presented method allowed a clear and a sensitive identification of 1 colony-forming unit of E. coli without any interference from other investigated bacterial strains. Comprising only few working steps (filtration, incubation, and voltammetric analysis), the method allowed incorporation into an automated prototype that delivered results similar to those obtained from samples treated in laboratory.

We investigated the ultrastructural pattern of colloidal phases in human duodenal fluids. Aspirates were collected from three volunteers in both fasted and fed nutritional states. Analysis methods comprised the combination of asymmetric flow field-flow fractionation (AF4) and multi-angle laser light scattering (MALLS). Furthermore, dynamic light scattering (DLS) and diffusion-ordered NMR spectroscopy (DOSY-NMR) were employed as alternative analytical approaches for comparison. By AF4/MALLS, up to four, and in some cases up to five distinct co-existing fractions could be differentiated in the sub-micron size-range, which, in accordance with a previous study (Elvang et al., 2018), may be assigned to three main types, namely small bile salt micelles, intermediate size mixed bile salt/phospholipid micelles and large phospholipid aggregates / vesicles. Although more or less the same colloidal phases were found to co-exist in all aspirates, their prevalence was found to vary, both over time and between the three individual human volunteers. Any uniform changes of patterns of colloidal phases over time, however, could not be identified. On the other hand, prevalence of specific colloidal phases was identified for aspirates of individual volunteers, which correlated reasonably well with the prevalence of certain lipid species in their molecular composition. It remains to be investigated whether such prevalence of specific colloidal phases influences drug solubilizing capacity as well as drug absorption. If so, this may help to better understand the substantial inter-individual variability seen in many drug absorption profiles.

The majority of new drug entities exhibits poor water solubility and therefore enabling formulations are often needed to ensure sufficient in vivo bioavailability upon oral administration. Several in vitro tools have been proposed for biopredictive screening of such drug formulations to facilitate formulation development. Among these, combined dissolution/permeation (D/P) assays have gained increasing interest in recent years, since they are presumed to better predict the absorption behavior as compared to single-compartment dissolution assays. Moreover, especially for supersaturating formulations, it has been demonstrated that the presence of an absorption sink better mimics the intraluminal supersaturation performance. The present study aimed to investigate the biopredictive abilities of two in vitro D/P setups to predict intestinal supersaturation and systemic absorption of supersaturable systems. Experiments were performed with a µFLUX™ and PermeaLoop™ apparatus, respectively, which differ primarily in their volume-to-area ratios between donor compartment and membrane as well as in the type of biomimetic barrier. A two-stage dissolution protocol was adopted to mimic the transit from acidic stomach to more neutral intestinal fluids using biomimetic media. Three formulations of the weakly basic compound Posaconazole (PCZ), namely an acidified and a neutral suspension and an amorphous solid dispersion (ASD) tablet, were tested. Under the present conditions, and for the specific set of formulations studied here, PermeaLoop™ showed a better biopredictive ability for intestinal supersaturation and systemic absorption for the three formulations than the µFLUX™ D/P setup. Interestingly, minor modifications of the two-stage D/P protocol in terms of medium transfer rates from simulated gastric fluid (SGF) to fasted state simulated intestinal fluid (FaSSIF) had a substantial impact particularly on the permeation of the crystalline PCZ suspension ("acidified suspension"). The ASD tablet was less sensitive to gradual medium changes than the crystalline PCZ suspensions. The current study confirms the usefulness of D/P assays for formulation ranking of weakly basic compounds and supersaturating formulations.

The absorption of orally administered drug products is a complex, dynamic process, dependant on a range of biopharmaceutical properties; notably the aqueous solubility of a molecule, stability within the gastrointestinal tract (GIT) and permeability. From a regulatory perspective, the concept of high intestinal permeability is intrinsically linked to the fraction of the oral dose absorbed. The relationship between permeability and the extent of absorption means that experimental models of permeability have regularly been used as a surrogate measure to estimate the fraction absorbed. Accurate assessment of a molecule's intestinal permeability is of critical importance during the pharmaceutical development process of oral drug products, and the current review provides a critique of in vivo, in vitro and ex vivo approaches. The usefulness of in silico models to predict drug permeability is also discussed and an overview of solvent systems used in permeability assessments is provided. Studies of drug absorption in humans are an indirect indicator of intestinal permeability, but both in vitro and ex vivo tools provide initial screening approaches and are important tools for assessment of permeability in drug development. Continued refinement of the accuracy of in silico approaches and their validation with human in vivo data will facilitate more efficient characterisation of permeability earlier in the drug development process and will provide useful inputs for integrated, end-to-end absorption modelling. European Commission Horizon 2020 Science Foundation Ireland CÚRAM Centre for Medical Devices AMBER Centre for Advanced Materials and BioEngineering Research

Powerline communication (PLC) is a versatile method that uses existing infrastructure such as power cables for data transmission. This makes PLC an alternative and cost-effective technology for the transmission of sensor and actuator data by making dual use of the power line and avoiding the need for other communication solutions, such as wireless radio frequency communication. A PLC modem using DSSS (direct sequence spread spectrum) for reliable LIN-bus based data transmission has been developed for automotive applications. Due to the almost complete system implementation in a low power microcontroller, the component cost could be radically reduced which is a necessary requirement for automotive applications. For performance evaluation the DSSS modem was compared to two commercial PLC systems. The DSSS and one of the commercial PLC systems were designed as a direct conversion receiver, the other commercial module uses a superheterodyne architecture. The performance of the systems was tested under the influence of narrowband interference and additive Gaussian noise added to the transmission channel. It was found that the performance of the DSSS modem against singleton interference is better than that of commercial PLC transceivers by at least the processing gain. The performance of the DSSS modem was at least 6 dB better than the other modules tested under the influence of the additive white Gaussian noise on the transmission channel at data rates of 19.2 kB/s

Phospholipids are amphiphilic lipids with versatile properties making them promising excipients for enabling formulations for oral drug delivery. Unfortunately, systematic studies on how phospholipid type and content affect oral absorption are rare. Often, only one phospholipid type is used for the formulation development and only one formulation, optimized according to in vitro parameters, is included in oral bioavailability studies. Using this approach, it is unclear if a certain in vitro parameter is predictive for the in vivo performance. In this study, a labor-saving in vitro permeation screening method was combined with a pharmacokinetic study in rats to for the first time systematically compare two types of phospholipid-based solid dispersions. The dispersions contained the drug celecoxib and monoacyl or diacyl phosphatidylcholine at different drug-to-phospholipid ratios. The in vitro screening revealed: 1) none of the formulations with high phospholipid content increased permeation, 2) phospholipid content was negatively correlated with permeation, and 3) mono and diacyl-phosphatidylcholine formulations performed equally. The pharmacokinetic study revealed: 1) At low phospholipid content absorption was enhanced, 2) phospholipid content was negatively correlated with absorption, and 3) monoacyl and diacyl phosphatidylcholine formulations performed equally. Apart from the reference (suspension), the in vitro permeation screening thus predicted the formulations in vivo performance.

In the present work the surface modification of a carbon screen-printed electrode by electrochemical polymerization of toluidine blue (TB) for determination of tyramine is described. The electrochemical polymerization of the electrode with TB was done by cyclic voltammetry at a scan rate of 50 mV/s and a potential sweep between ‒0.7 V and 1.0 V in the presence of 0.5 mM TB in an electrolyte solution. At each cycle, the polymer film started to deposit on the carbon screen-printed electrode which was repeated 20 times. For parameter optimization the electrochemical behavior of the modified electrode was analyzed by amperometric methods such as cyclic voltammetry (CV) and differential pulse voltammetry (DPV). A phosphate buffer solution (PBS) was used as an electrolyte for all the amperometric experiments. The electrochemically modified poly-TB-coated carbon-screen-printed electrode showed an oxidation peak potential of tyramine at 0.67 V. The unmodified carbon-screen-printed electrode showed the tyramine oxidation peak potential at 0.9 V. Based on the voltammetric results, it was found that the poly-TB-modified carbon-screen-printed electrode showed higher sensitivity (1.78 µA nM−1 cm−2) than a bare carbon-screen-printed electrode toward tyramine detection. Tyramine in 0.1 M PBS (pH 7.4) was analyzed by cyclic voltammetry from the potential of ‒0.7 to 1.0 V at a scan rate of 50 mV/s. The poly-TB-modified carbon-screen-printed electrode exhibited a linear response between catalytic peak current and tyramine concentration from 0.02 µM to 270.5 µM with a lower detection limit of 0.007 µM (S/N = 3).

The aim of this rat study was to investigate the effect of liquid intake on the oral bioavailability of an amorphous solid dispersion (ASD) containing the poorly water-soluble compound ABT-869. To this end, an ASD was prepared by hot-melt extrusion and administered in form of powder in an open gelatin capsule. The study consisted of three arms: (1) administration of the ASD without any liquid, (2) administration of the ASD with 1.5 mL of water, and (3) administration of a suspension of crystalline drug in water. Administration of the ASD without water resulted in a 4-fold higher exposure as compared to the suspension of crystalline drug. When administered together with water, the in vivo performance of the ASD was dramatically affected and not superior to that of the suspension of crystalline drug. The observed phenomena could not be explained mechanistically, but may be related to the following effects: (I) a faster dissolution in a larger volume of fluid and subsequent precipitation, (II) a change in gastrointestinal transit time that caused a mismatch between dissolution rate and absorption rate, and/or (III) a difference in the mucosal adherence/distribution pattern caused by the gelatin capsule. It remains to be investigated whether the phenomena observed in this study are exceptionally pronounced or even unique for this particular formulation. Yet, our findings emphasize that the amount of liquid co-administered with oral enabling formulations can have an impact on the bioavailability. The administration regime used in animal studies should therefore be considered carefully.

Supersaturated lipid-based drug delivery systems have recently been investigated for oral administration for a variety of lipophilic drugs and have shown either equivalent or superior oral bioavailability compared to conventional non-supersaturated lipid-based drug delivery systems. The aim of the present work was to explore supersaturated versus non-supersaturated lipid-based systems at equivalent lipid doses, on in vivo bioavailability in rats and on in vitro permeation across a biomimetic Permeapad

PURPOSE: Here, first experiences with a prototype tool for high throughput (passive) permeability profiling, a 96-well plate comprising the Permeapad® membrane, are reported. The permeabilities of a set of drugs were determined and compared to published measures of oral absorption, such as human fraction absorbed (Fa) and in vitro permeability values obtained using other tools. METHODS: The tool consists of a 96-well bottom and screen plate with the artificial, phospholipid-based barrier (Permeapad®) mounted between the plates' lower and upper compartments. The permeability of 14 model compounds including high- and low-absorption drugs, cationic, anionic, zwitterionic and neutral molecules, was determined by quantifying the compounds' transport over time, deriving the steady-state flux from the linear part of the cumulative curves and calculating the apparent permeability (Papp). The membrane structure was investigated in a high-resolution digital light microscope. RESULTS: The Permeapad® 96-well plate was found suited to distinguish high and low absorption drugs and yielded a hyperbolic correlation to Fa. The Papp values obtained were congruent with those determined with in-house prepared Permeapad® in the Franz cell set-up. Furthermore, good to excellent correlations were seen with Caco-2 permeability (R2 = 0.70) and PAMPA permeability (R2 = 0.89). Microscopic investigation of the Permeapad® barrier revealed the formation of phospholipid vesicles and myelin figures in aqueous environment. CONCLUSION: The Permeapad® 96-well plate permeation set-up is a promising new tool for rapid and reproducible passive permeability profiling.