Search

This work revisits the changing release behavior of indomethacin(IND)-copovidone amorphous solid dispersions (ASDs) when increasing their drug load (DL). While showing congruent release behavior at DL 0.1, ASDs with DLs of 0.3 and higher show incongruent release finally resulting in a complete loss of release. To study and explain this phenomenon, we modeled the release kinetics of these ASDs and looked into their phase behavior both experimentally and theoretically. We applied a diffusion model to accurately describe experimental release profiles for congruent release, incongruent release as well as for loss of release. Predicted concentration profiles for IND, copovidone, and water within the ASD revealed the formation of an ASD layer that almost exclusively contains amorphous IND. Our phase-diagram predictions and experimental data explain this phenomenon by water-induced phase separation in those parts of the ASD which did absorb water from the dissolution medium. Whereas the evolving copovidone-rich phase dissolved, the IND-rich phase remained undissolved and formed a super-hydrophobic cover of the remaining inner core of the ASD, thus finally completely preventing its dissolution. Higher DLs promote phase separation. This leads to the counterintuitive effect that the higher the DL, the lower the absolute amount of IND released. While the ASD containing 6 mg IND (DL 0.1) released 6 mg IND, the one containing 42 mg IND (DL 0.7) released only 1 mg IND. The theoretical approach applied in this work is for the first time able to quantitatively predict that reducing DL or tablet size could be used to overcome this problem., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Anomalous water-sorption kinetics in amorphous solid dispersions (ASDs) are caused by the slow swelling of the polymer. In this work, we used a diffusion-relaxation model with the Williams-Landel-Ferry (WLF) equation and the Arrhenius equation to predict the anomalous water-sorption kinetics in ASDs of poly(vinyl-pyrrolidone)- co -vinyl-acetate (PVPVA) and indomethacin (IND) at 25 °C. These predictions were based on the viscosities of pure PVPVA and pure IND, as well as on the water-sorption kinetics in pure PVPVA. The diffusion-relaxation model was able to predict the different types of anomalous behavior leading to a qualitative and quantitative agreement with the experimental data. Predictions and experiments indicated more pronounced anomalous two-stage water-sorption behavior in the ASDs than in pure PVPVA. This was caused by a higher viscosity of glassy ASD-water mixtures compared to glassy PVPVA-water mixtures at the same distance from their glass transition temperature. These results suggest that this ASD swells more slowly than the polymer it is composed of. The modeling approach applied in this work can be used in the future for predicting diffusion-controlled release behavior or swelling-controlled release behavior of ASDs., Competing Interests: The authors declare no conflict of interest.

Water decreases the stability of amorphous solid dispersions (ASDs) and water sorption is, therefore, unwanted during ASD storage. This work suggests a methodology to predict the water-sorption isotherms and the water-sorption kinetics in amorphous pharmaceutical formulations like ASDs. We verified the validity of the proposed methodology by measuring and predicting the water-sorption curves in ASD films of polyvinylpyrrolidone-based polymers and of indomethacin. This way, the extent and the rate of water sorption in ASDs were predicted for drug loads of 0.2 and 0.5 as well as in the humidity range from 0 to 0.9 RH at 25 °C. The water-sorption isotherms and the water-sorption kinetics in the ASDs were predicted only based on the water-sorption isotherms and water-sorption kinetics in the neat polymer on the one hand and in the neat active pharmaceutical ingredient (API) on the other hand. The accurate prediction of water-sorption isotherms was ensured by combining the Perturbed-Chain Statistical Association Theory (PC-SAFT) with the Non-Equilibrium Thermodynamics of Glassy Polymers (NET-GP) approach. Water-sorption kinetics were predicted using Maxwell-Stefan diffusion coefficients of water in the ASDs.

Polyvinylpyrrolidone (PVP)-based polymers are excellent stabilizers for food supplements and pharmaceutical ingredients. However, they are highly hygroscopic. This study measured and modeled the water-sorption isotherms and water-sorption kinetics in thin PVP and PVP-co-vinyl acetate (PVPVA) films. The water sorption was measured at 25 °C from 0 to 0.9 RH, which comprised glassy and rubbery states of the polymer-water system. The sorption behavior of glassy polymers differs from that in the rubbery state. The perturbed-chain statistical associating fluid theory (PC-SAFT) accurately describes the water-sorption isotherms for rubbery polymers, whereas it was combined with the non-equilibrium thermodynamics of glassy polymers (NET-GP) approach to describe the water-sorption in the glassy polymers. Combined NET-GP and PC-SAFT modeling showed excellent agreement with the experimental data. Furthermore, the transitions between the PC-SAFT modeling with and without NET-GP were in reasonable agreement with the glass transition of the polymer-water systems. Furthermore, we obtained Fickian water diffusion coefficients in PVP and in PVPVA from the measured water-sorption kinetics over a broad range of humidities. Maxwell-Stefan and Fickian water diffusion coefficients yielded a non-monotonous water concentration dependency that could be described using the free-volume theory combined with PC-SAFT and NET-GP for calculating the free volume.

The amorphous state of an active pharmaceutical ingredient (API) enhances its water solubility compared to its crystalline state. However, it is well known that amorphous substances can absorb significant amounts of water therewith inducing API recrystallization. This work explores methods to obtain reliable information about water sorption in amorphous APIs and its modeling. Experimental water-sorption curves over a broad humidity range were obtained by measuring the mass increase of well-defined films of amorphous APIs. Water-sorption isotherms modeled using perturbed-chain statistical associating fluid theory (PC-SAFT) showed better accordance with the experimental data than those obtained using the Flory-Huggins model. Crank's diffusion equation was used to describe the water-sorption kinetics providing Fickian diffusion coefficients of water in indomethacin and in ritonavir. Stefan-Maxwell diffusion coefficients were obtained by converting Fickian diffusion coefficients using water activity coefficients obtained from PC-SAFT. Finally, the free-volume theory was applied to explain the persistent water concentration dependency of the Stefan-Maxwell diffusion coefficients.

Novel coronavirus disease 2019 (COVID-19) is a highly infectious, rapidly spreading viral disease and has emerged as a public health emergency of international concern. As of this time, there are no specific antiviral therapies available for the treatment of COVID-19. However, it is possible that some existing drugs, usually used for other conditions, may have some benefits. Statins have been widely reported to exert antiviral activity against many enveloped viruses by inhibiting the cholesterol biosynthesis pathway. Cholesterol likewise contributes to the coronavirus's life cycle, including viral entry, fusion and budding. In addition, statins have been ascribed beneficial anti-inflammatory, immunomodulatory effects and promote haemodynamic stability. Therefore, statins, which are cholesterol-lowering drugs with anti-inflammatory, immunomodulatory and antiviral properties, may play a role in SARS-CoV-2 therapy. The aim of the present minireview was to delineate the potential beneficial therapeutic effects of statins in treating SARS-CoV-2 infections. Nevertheless, large, randomised trials are needed to confirm the beneficial effects and safety profile of the statins in patients with SARS-CoV-2., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Descriptors play an important role in point cloud registration. The current state-of-the-art resorts to the high regression capability of deep learning. However, recent deep learning-based descriptors require different levels of annotation and selection of patches, which make the model hard to migrate to new scenarios. In this work, we learn local registration descriptors for point clouds in a self-supervised manner. In each iteration of the training, the input of the network is merely one unlabeled point cloud. Thus, the whole training requires no manual annotation and manual selection of patches. In addition, we propose to involve keypoint sampling into the pipeline, which further improves the performance of our model. Our experiments demonstrate the capability of our self-supervised local descriptor to achieve even better performance than the supervised model, while being easier to train and requiring no data labeling.

Mapping and localization of mobile robots in an unknown environment are essential for most high-level operations like autonomous navigation or exploration. This paper presents a novel approach for combining estimated trajectories, namely curvefusion. The robot used in the experiments is equipped with a horizontally mounted 2D profiler, a constantly spinning 3D laser scanner and a GPS module. The proposed algorithm first combines trajectories from different sensors to optimize poses of the planar three degrees of freedom (DoF) trajectory, which is then fed into continuous-time simultaneous localization and mapping (SLAM) to further improve the trajectory. While state-of-the-art multi-sensor fusion methods mainly focus on probabilistic methods, our approach instead adopts a deformation-based method to optimize poses. To this end, a similarity metric for curved shapes is introduced into the robotics community to fuse the estimated trajectories. Additionally, a shape-based point correspondence estimation method is applied to the multi-sensor time calibration. Experiments show that the proposed fusion method can achieve relatively better accuracy, even if the error of the trajectory before fusion is large, which demonstrates that our method can still maintain a certain degree of accuracy in an environment where typical pose estimation methods have poor performance. In addition, the proposed time-calibration method also achieves high accuracy in estimating point correspondences.

The pathologic and molecular substrate of people diagnosed with cognitive deficits and movement disturbance may not occur exclusively in the context of a brain region, but it may be expressed in another part of body such as muscle. A large body of research has demonstrated that slow motor performance is associated with cognitive impairment in elderly people. The interdependence between motor dysfunction and cognition decline is still not fully understood. Although several factors have been suggested to give a plausible explanation, β-amyloid (Aβ) and τ-protein aggregation is a common feature of a number of neurodegenerative disorders which are characterized by both motor and cognitive impairment, and it is assumed that the aggregation process plays a central role in the pathogenesis of cognitive impairment and motor dysfunction in Alzheimer's disease. The purpose of the present review is to provide an overview of the available evidence that can help to better elucidate the pathophysiological mechanisms underlying the relationship between cognitive and movement disturbances by focusing on Aβ and τ-protein.

The natural chlorophyll degradation results in noncolored chlorophyll catabolites (NCCs), but there are controversies if these are the final products. The formation and degradation of NCCs during soybean seed ( Glycine max L. Merrill) maturation and two drying temperatures were investigated. Soybean was harvested at six maturation stages. The effect of postharvest drying at 40 and 60 degrees C on the NCC formation was analyzed by high-performance liquid chromatography (HPLC), and results were expressed as areas under the curve. All samples contained fractions with an absorption maximum at 320 nm, typical for NCC. The amounts of NCC increased until 114 days after planting and were significantly lower in advanced maturation stages. These results indicate that the NCC in soybeans might not be the final products of chlorophyll degradation. Their reduction in advanced maturation stages may be due to further metabolization. Heating soybeans at 40 and 60 degrees C promoted unnatural chlorophyll degradation and impaired the formation of NCC.

The human intestinal microbiota is necessary for the production of enterolignans from the dietary lignan secoisolariciresinol diglucoside (SDG). However, little is known about the bacteria that contribute to SDG conversion. Therefore, we aimed at describing the occurrence and activity of SDG metabolising bacteria. The data showed differences in conversion efficiency between SDG deglycosylating species, but SDG was completely deglycosylated within 20 h by five of six strains. The strain Clostridium sp. SDG-Mt85-3Db showed the highest initial rate of SDG deglycosylation. Furthermore, we found that Bacteroides distasonis and B. fragilis made up 0.5% and 3.3% of total faecal bacteria, respectively. However, Clostridium sp. SDG-Mt85-3Db was detected within the dominant microbiota of only two out of 20 faecal samples. Bacteria involved in the demethylation step of SDG conversion also demethylated a variety of compounds other than SDG. In particular, Peptostreptococcus productus demethylated the lignans pinoresinol, lariciresinol and matairesinol. Finally, Eggerthella lenta catalysed the reduction of pinoresinol and lariciresinol to secoisolariciresinol.