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A reliable in vitro system can support and guide the development of subcutaneous (SC) drug products. Although several in vitro systems have been developed, they have some limitations, which may hinder them from getting more engaged in SC drug product development. This study sought to develop a novel in vitro system, namely, E mulator of S ub C utaneous A bsorption and R elease (ESCAR), to better emulate the in vivo SC environment and predict the fate of drugs in SC delivery. ESCAR was designed using computer-aided design (CAD) software and fabricated using the three-dimensional (3D) printing technique. ESCAR has a design of two acceptor chambers representing the blood uptake pathway and the lymphatic uptake pathway, respectively, although only the blood uptake pathway was investigated for small molecules in this study. Via conducting a DoE factor screening study using acetaminophen solution, the relationship of the output (drug release from the "SC" chamber to the "blood circulation" chamber) and the input parameters could be modeled using a variety of methods, including polynomial equations, machine learning methods, and Monte Carlo simulation-based methods. The results suggested that the hyaluronic acid (HA) concentration was a critical parameter, whereas the influence of the injection volume and injection position was not substantial. An in vitro-in vivo correlation (IVIVC) study was developed using griseofulvin suspension to explore the feasibility of applying ESCAR in formulation development and bioequivalence studies. The developed LEVEL A IVIVC model demonstrated that the in vivo PK profile could be correlated with the in vitro release profile. Therefore, using this model, for new formulations, only in vitro studies need to be conducted in ESCAR, and in vivo studies might be waived. In conclusion, ESCAR had important implications for research and development and quality control of SC drug products. Future work would be focused on further optimizing ESCAR and expanding its applications via assessing more types of molecules and formulations.

Multiple advanced formulations and drug delivery systems (DDSs) have been developed to deliver protein-based biotherapeutics via the subcutaneous (SC) route. These formulations/DDSs include high-concentration solution, co-formulation of two or more proteins, large volume injection, protein cluster/complex, suspension, nanoparticle, microparticle, and hydrogel. These advanced systems provide clinical benefits related to efficacy and safety, but meanwhile, have more complicated formulations and manufacturing processes compared to conventional solution formulations. To develop a fit-for-purpose formulation/DDS for SC delivery, scientists need to consider multiple factors, such as the primary indication, targeted site, immunogenicity, compatibility, biopharmaceutics, patient compliance, etc. Next, they need to develop appropriate formulation (s) and manufacturing processes using the QbD principle and have a control strategy. This paper aims to provide a comprehensive review of advanced formulations/DDSs recently developed for SC delivery of proteins, as well as some knowledge gaps and potential strategies to narrow them through future research., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Our judgement of certain facial characteristics such as emotion, attractiveness or age, is affected by context. Faces that are flanked by younger faces, for example, are perceived as being younger, whereas faces flanked by older faces are perceived as being older. Here, we investigated whether contextual effects in age perception are moderated by own age effects. On each trial, a target face was presented on the screen, which was flanked by two faces. Flanker faces were either identical to the target face, were 10 years younger or 10 years older than the target face. We asked 40 older (64-69 years) and 43 younger adults (24-29) to estimate the age of the target face. Our results replicated previous studies and showed that context affects age estimation of faces flanked by target faces of different ages. These context effects were more pronounced for younger compared to older flankers but present across both tested age groups. An own-age advantage was observed for older adults for unflanked faces who had larger estimation errors for younger faces compared to older faces and younger adults. Flanker effects, however, were not moderated by own-age effects. It is likely that the increased effect of younger flankers is due to mechanisms related to perceptual averaging., (© 2022. The Author(s).)

This study aimed to examine the locus of age of acquisition (AoA) and word frequency (WF) effects in Chinese spoken picture naming, using a picture-word interference task. We conducted four experiments manipulating the properties of picture names (AoA in Experiments 1 and 2, while controlling WF; and WF in Experiments 3 and 4, while controlling AoA), and the relations between distractors and targets (semantic or phonological relatedness). Both Experiments 1 and 2 demonstrated AoA effects in picture naming; pictures of early acquired concepts were named faster than those acquired later. There was an interaction between AoA and semantic relatedness, but not between AoA and phonological relatedness, suggesting localisation of AoA effects at the stage of lexical access in picture naming. Experiments 3 and 4 demonstrated WF effects: pictures of high-frequency concepts were named faster than those of low-frequency concepts. WF interacted with both phonological and semantic relatedness, suggesting localisation of WF effects at multiple levels of picture naming, including lexical access and phonological encoding. Our findings show that AoA and WF effects exist in Chinese spoken word production and may arise at related processes of lexical selection., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Visual attention can be allocated to locations or objects, leading to enhanced processing of information at the specific location (space-based effects) or specific object (object-based effects). Previous studies have observed object-based effects to be smaller and less robust than space-based effects, with large individual differences in their temporal occurrence. Studies on space- and object-based effects are often based on a two-rectangle paradigm in which targets appear at cued locations more often than uncued locations. It is, however, unclear whether and how the target's spatial probability affects the temporal occurrence of these effects. In three experiments with different cue validities (80%, 50% and 33%), we systematically changed the interval between the cue and the target from 50 to 600 ms. On a group level and for individuals, we examined how cue validity affects the occurrence of object- and space-based effects. We observed that the magnitude and the prevalence of space-based effects heavily decreased with reduced cue validity. Object-based effects became even more sparse and turned increasingly negative with decreasing cue validity, representing a different-object rather than a same-object advantage. These findings indicate that changes in cue-validity affect both space- and object-based effects, but it does not account for the low prevalence and magnitude of object-based effects.

Background: The daily cycling of plant physiological processes is speculated to arise from the coordinated rhythms of gene expression. However, the dynamics of diurnal 3D genome architecture and their potential functions underlying the rhythmic gene expression remain unclear., Results: Here, we reveal the genome-wide rhythmic occupancy of RNA polymerase II (RNAPII), which precedes mRNA accumulation by approximately 2 h. Rhythmic RNAPII binding dynamically correlates with RNAPII-mediated chromatin architecture remodeling at the genomic level of chromatin interactions, spatial clusters, and chromatin connectivity maps, which are associated with the circadian rhythm of gene expression. Rhythmically expressed genes within the same peak phases of expression are preferentially tethered by RNAPII for coordinated transcription. RNAPII-associated chromatin spatial clusters (CSCs) show high plasticity during the circadian cycle, and rhythmically expressed genes in the morning phase and non-rhythmically expressed genes in the evening phase tend to be enriched in RNAPII-associated CSCs to orchestrate expression. Core circadian clock genes are associated with RNAPII-mediated highly connected chromatin connectivity networks in the morning in contrast to the scattered, sporadic spatial chromatin connectivity in the evening; this indicates that they are transcribed within physical proximity to each other during the AM circadian window and are located in discrete "transcriptional factory" foci in the evening, linking chromatin architecture to coordinated transcription outputs., Conclusion: Our findings uncover fundamental diurnal genome folding principles in plants and reveal a distinct higher-order chromosome organization that is crucial for coordinating diurnal dynamics of transcriptional regulation., (© 2022. The Author(s).)

This review comprehensively summarizes the application of machine learning in solid oral dosage form development over the past three decades. In both academia and industry, machine learning is increasingly applied for multiple preformulation/formulation and process development studies. Further, this review provides the authors' perspectives on how pharmaceutical scientists can use machine learning for right projects and in right ways; some key ingredients include (1) the determination of inputs, outputs, and objectives; (2) the generation of a database containing high-quality data; (3) the development of machine learning models based on dataset training and model optimization; (4) the application of trained models in making predictions for new samples. It is expected by the authors and others that machine learning will promisingly play a more important role in tomorrow's projects for solid oral dosage form development., Competing Interests: Declaration of Competing Interest Authors do not have any conflict of interest., (Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The objective of this work was to investigate the influence of tablet location along the bottom of a USP apparatus II vessel on polymer erosion and drug release of surface-erodible sustained-release tablets using computational simulation methods. Computational fluid dynamics (CFD) methods were performed to simulate the velocity distribution. A mathematical model was developed to describe polymer erosion and tablet deformation according to the mass transfer coefficient. Numerical analysis was used to simulate drug release controlled by drug diffusion and polymer erosion. The results indicated that tablets located at the off-center position deformed faster than the tablets located at the center position. However, tablet location had no profound impact on drug release rate since all drug release profiles were "similar" according to the f 2 similarity values which were above 50. Hence, our simulation supported that the USP apparatus II was a reliable and robust device for the dissolution testing of surface-erodible sustained-release tablets.

Purpose: One knowledge gap related to subcutaneous (SC) delivery is unpredictable and variable bioavailability. This study was aimed to develop machine learning methods to predict whether mAb's bioavailability was ≥70% or below, without completely knowing the mechanism and causality between inputs and outputs., Methods: A database of mAb SC products was built. The model training and validation were accomplished based on this database and a set of the inputs (product properties) were mapped to the output (bioavailability) using different machine learning algorithms. Dimensionality reduction was undertaken using principal component analysis (PCA)., Results: The bioavailability of the mAb products being investigated varied from 35% to 90%. The tree-based methods, including random forest (RF), Adaptive Boost (AdaBoost), and decision tree (DT) presented the best predictability and generalization power on bioavailability classification. The models based on Multi-layer perceptron (MLP), Gaussian Naïve Bayes (GaussianNB), and k nearest neighbor (kNN) algorithms also provided acceptable prediction accuracy., Conclusion: Machine learning could be a potential tool to predict mAb's bioavailability. Since all input features were acquired using theoretical calculations and predictions rather than experiments, the models may be particularly applicable to some early-stage research activities such as mAb molecule triage, design/optimization, mutant screening, molecule selection, and formulation design.

The objective of this study was to evaluate the transdermal efficiency of iodide microemulsion in treating iodine deficiency using rats as an animal model. Animals were fed either iodine-deficient diet (20 μg/kg iodide) or control diet (200 μg/kg iodide) over a 17-month period. At month 14, iodide microemulsion was applied topically in iodine-deficient group and physiological evaluations of thyroid gland functions were characterized by monitoring the thyroid hormones (T3, T4), thyroid-stimulating hormone (TSH), iodide ion excretion in urine, and the overall rat body weights in both groups. Moreover, morphological evaluations of thyroid gland before and after treatment were performed by ultrasound imaging and through histological assessment. Prior to microemulsion treatment, the levels of T3, T4, and TSH in iodine-deficient group were statistically significant as compared to that in the control group. The levels of T3 and T4 increased while TSH level decreased significantly in iodine-deficient group within the first 4 weeks of treatment. After treatment, iodide concentration in urine increased significantly. There was no statistical difference in weight between the two groups. Ultrasound imaging and histological evaluations showed evidence of hyperplasia in iodine-deficient group. Topical iodide microemulsion has shown a promising potential as a novel delivery system to treat iodine deficiency.