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Traditional methods of producing Xiaochaihu (XCH) capsules, a traditional Chinese medicine, are time-consuming, costly, and labor-intensive, which is not conductive to modernizing TCM. To address the challenges, new fluid-bed granulation and drying processes with water as the binder were developed and optimized guided by the principles of Quality by Design (QbD) in this study. Ishikawa diagram was applied to conduct a preliminary risk assessment, followed by 6-factor definitive screening design (DSD) serving as a QbD statistical tool to develop and optimize the new processes. Multiple potential factors and interactions were studied with a small number of experiments using the DSD. This study identified critical process parameters (CPPs), established quadratic regression models to reveal CPP-critical quality attributes (CQAs) connections within the DSD framework, and defined a dependable design space. Processes conducted by parameter combinations in the design space produced qualified granules with production yield and raw material utilization higher than 90% and moisture content lower than 4%. Furthermore, quantitative analysis of baicalin of all the granules ensured qualified contents of active pharmaceutical ingredient. The newly developed processes for XCH capsules, with advantages of shorter time, environmental friendliness, and decreased cost, exemplify the effective application of QbD and design of experiments (DoE) methodologies in the modernization of TCM manufacturing processes., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The potential harms and benefits of e-cigarettes, or electronic nicotine delivery systems (ENDS), have received significant attention from public health and regulatory communities. Such products may provide a reduced risk means of nicotine delivery for combustible cigarette smokers while being inappropriately appealing to nicotine naive youth. Numerous authors have examined the chemical complexity of aerosols from various open- and closed-system ENDS. This body of literature is reviewed here, with the risks of ENDS aerosol exposure among users evaluated with a margin of exposure (MoE) approach for two non-carcinogens (methylglyoxal, butyraldehyde) and a cancer risk analysis for the carcinogen N-nitrosonornicotine (NNN). We identified 96 relevant papers, including 17, 13, and 5 reporting data for methylglyoxal, butyraldehyde, and NNN, respectively. Using low-end (minimum aerosol concentration, low ENDS use) and high-end (maximum aerosol concentration, high ENDS use) assumptions, estimated doses for methylglyoxal (1.78 × 10 -3 -135 μg/kg-bw/day) and butyraldehyde (1.9 × 10 -4 -66.54 μg/kg-bw/day) corresponded to MoEs of 227-17,200,000 and 271-280,000,000, respectively, using identified points of departure (PoDs). Doses of 9.90 × 10 -6 -1.99 × 10 -4  μg/kg-bw/day NNN corresponded to 1.4-28 surplus cancers per 100,000 ENDS users, relative to a NNN-attributable surplus of 7440 per 100,000 cigarette smokers. It was concluded that methylglyoxal and butyraldehyde in ENDS aerosols, while not innocuous, did not present a significant risk of irritant effects among ENDS users. The carcinogenic risks of NNN in ENDS aerosols were reduced, but not eliminated, relative to concentrations reported in combustible cigarette smoke., (© 2024 John Wiley & Sons Ltd.)

The objective of this study was to evaluate the effect of standardized ileal digestible (SID) tryptophan (Trp) and lysine (Lys) levels on eating and sleeping behavior and the respective feed intake of barrows. Sixty-four pigs, averaging 15.00 ± 1.63 kg of initial body weight, were used and distributed in a randomized blocks design, in a 4 × 4 factorial scheme, consisting of four levels of SID Trp (0.155, 0.185, 0.215, 0.245%) and four levels of SID Lys (0.972, 1.112, 1.252, and 1.392%). Behavior evaluation was performed by an instantaneous sampling using 10-min intervals during 24 h, at each 7 days (days 7, 14, and 21), and each day was divided into four times of 6 h each one (08:30–14:20, 14:30–20:20, 20:30–02:20, and 02:30–08:20 h), during all the experimental period, yielding a total of 3 × 24 h behavior recordings (72 h) × 6 10-min intervals, totalizing 432 observations per animal. Data were analyzed by classifying behavior into eating or sleeping. All these behaviors were measured in order to obtain the estimated frequency of the eating and sleeping behaviors. Changes were observed (P<0.05) for all the behavioral parameters during the starting phase. SID Trp and SID Lys showed an interactive positive effect on the estimated frequency of eating behavior, and mainly SID Trp increased the estimated frequency of the sleeping behavior of starting pigs in the nocturnal time. Pig diets with increasing levels of SID Trp and SID Lys until 0.245 and 1.392%, respectively, increased the average daily feed intake, and the interaction of the amino acids increased the estimated frequency of eating behavior during all the starting phase, and mainly the increasing levels of SID Trp increased the estimated frequency of sleeping behavior of pigs from the middle to the end of the starting phase, from 2:30 to 8:20 h. [ABSTRACT FROM AUTHOR]

Lipid peroxidation, the most aggressive reaction in food, results in the formation of reactive organic compounds that detrimentally impact food sensory qualities and consumers' health. While controlled lipid peroxidation can enhance flavors and appearance in certain foods, secondary peroxidation products lead to sensory deterioration in a variety of products, such as oils, alcoholic beverages, and meat. This publication reviews the use of modern analytical techniques for detecting and quantifying carbonyl compounds, i.e., secondary lipid peroxidation products. The paper focuses specifically on microextraction-based methods: dispersive liquid-liquid microextraction (DLLME), solid-phase microextraction (SPME), and gas-diffusion microextraction (GDME). These techniques offer efficient and sensitive approaches to extracting and quantifying lipid oxidation products and contribute to the understanding of oxidative deterioration in various food products. The review outlines recent advancements, challenges, and limitations in these microextraction techniques, as well as emphasizes the potential for further innovation and improvement in the field of food analysis. [ABSTRACT FROM AUTHOR]

Purpose: Despite their effects on human health, the link between smokeless tobacco (ST) consumption and asthma severity in asthmatic patients is still unknown. Thus, the present study aims to complete the lack of information by investigating the aggravation of inflammation, aggravation of asthma, oxidative stress and cytotoxicity induced by ST in asthmatic patients. Methods: The study recruited 80 male volunteers residing in Annaba town, Algeria, divided into four groups by using a questionnaire, each group consisting of 20 male volunteers. Herein, biochemical parameters, hematological parameters, C-reactive protein (CRP), total IgE, interleukin-5 (IL-5), nitric oxide and oxidative stress were measured. Results: The obtained results showed that ST clearly enhanced lung inflammation and aggravation of asthma through total IgE, IL-5 and CRP increased production. In addition, ST was found to intensify oxidative stress via increased lipid peroxidation and decreased reduced glutathione (GSH) levels. Likewise, the biochemical and hematological parameters results showed that ST causes damage and inflammation to tissues. Conclusion: Therefore, our study reveals that ST obviously enhances allergic inflammation in patients suffering from asthma. [ABSTRACT FROM AUTHOR]

Introduction Based on our preliminary 11C-nicotine positron emission tomography (PET) imaging studies in humans, we speculated that greater deposition of nicotine in the respiratory tract from electronic cigarettes compared to combustible cigarettes could result from the alkaline pH of typical aerosol-producing electronic cigarette liquids (e-liquids). To address this hypothesis, we assessed the effect of e-liquid pH on the retention of nicotine in vitro using 11C-nicotine, PET, and a human respiratory tract model of nicotine deposition. Aims and Methods A single 2-second 35-mL puff was delivered to a human respiratory tract cast from a 2.8-Ohm cartomizer at 4.1 volts. Immediately after the puff, a 2-second 700-mL air wash-in volume was administered. E-liquids (glycerol and propylene glycol 50/50 vol/vol) containing 24 mg/mL nicotine were mixed with 11C-nicotine. Deposition (retention) of nicotine was assessed using a GE Discovery MI DR PET/CT scanner. Eight e-liquids with different pH values (range 5.3–9.6) were investigated. All experiments were performed at room temperature and at a relative humidity of 70%–80%. Results Retention of nicotine in the respiratory tract cast was pH dependent and the pH-sensitive component of the retention was well described by a sigmoid curve. In total, 50% of the maximal pH-dependent effect was observed at pH 8.0, which is close to the pKa2 of nicotine. Conclusions The retention of nicotine in the respiratory tract conducting airways is dependent on the e-liquid pH. Lowering the e-liquid pH reduces retention of nicotine. Nonetheless, reduction of the pH below 7 has little effect, consistent with the pKa2 of protonated nicotine. Implications Similar to combustible cigarettes, the retention of nicotine in the human respiratory tract from consumption of electronic cigarettes may have some health consequences and affect nicotine dependence. Here we demonstrated that the retention of nicotine in the respiratory tract is dependent on the e-liquid pH, and lowering pH reduces retention of nicotine in conducting airways of the respiratory tract. Therefore, e-cigarettes with low pH values would result in reduced respiratory tract nicotine exposure and faster delivery of nicotine to the central nervous system (CNS). The latter can be associated with e-cigarette abuse liability and the effectiveness of e-cigarettes as substitutes for combustible cigarettes. [ABSTRACT FROM AUTHOR]

It seems necessary to understand the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), with its entering bronchoalveolar and brain cells, which have a high concentration of angiotensin-converting enzyme 2 (ACE2). Although the virus infects healthy people, the rate of infection and mortality is higher and significant in vulnerable people, such as drug users and addicts who have acute and chronic respiratory disease. It also places a heavy economic burden on families and societies around the world. Thus, researchers are aiming to provide prevention and treatment strategies to people at risk. The purpose of the present study was to collect studies on the rate of infection with coronavirus in people who abuse drugs. Besides, the role of the ACE2 receptor as a key factor in coronavirus infectivity in these people was investigated. Our narrative review on the relationship between COVID-19 and opioid abuse and smoking, with consideration of ACE2's role, contains original and human studies. According to the results of the current study, those who smoke or are dependent on opioids are much more likely to experience COVID-19-related respiratory side effects or even pass away. [ABSTRACT FROM AUTHOR]

Patients with heart failure (HF) often have multiple chronic conditions and are at increased risk for severe disease and mortality when infected by SARS-CoV-2, the virus that causes COVID-19. Furthermore, disparities in outcomes with COVID-19 have been associated with both racial/ethnic identity but also social determinants of health. Among older, urban-dwelling, minority patients with HF, we sought to characterize medical and non-medical factors associated with SARS-CoV-2 infection. Patients with HF living in Boston and New York City over 60 years of age participating in the Screening for Cardiac Amyloidosis with Nuclear Imaging (SCAN-MP) study between 12/1/2019 and 10/15/2021 (n = 180) were tested for nucleocapsid antibodies to SARS-CoV-2 and queried for symptomatic infection with PCR verification. Baseline testing included the Kansas City Cardiomyopathy Questionnaire (KCCQ), assessment of health literacy, biochemical, functional capacity, echocardiography, and a novel survey tool that determined living conditions, perceived risk of infection, and attitudes towards COVID-19 mitigation. The association of infection with prevalent socio-economic conditions was assessed by the area deprivation index (ADI). There were 50 overall cases of SARS-CoV-2 infection (28%) including 40 demonstrating antibodies to SARS-CoV-2 (indicative of prior infection) and 10 positive PCR tests. There was no overlap between these groups. The first documented case from New York City indicated infection prior to January 17, 2020. Among active smokers, none tested positive for prior SARS-CoV-2 infection (0 (0%) vs. 20 (15%), p = 0.004) vs. non-smokers. Cases were more likely to be taking ACE-inhibitors/ARBs compared to non-cases (78% vs 62%, p = 0.04). Over a mean follow-up of 9.6 months, there were 6 total deaths (3.3%) all unrelated to COVID-19. Death and hospitalizations (n = 84) were not associated with incident (PCR tested) or prior (antibody) SARS-CoV-2 infection. There was no difference in age, co-morbidities, living conditions, attitudes toward mitigation, health literacy, or ADI between those with and without infection. SARS-CoV-2 infection was common among older, minority patients with HF living in New York City and Boston, with evidence of infection documented in early January 2020. Health literacy and ADI were not associated with infection, and there was no increased mortality or hospitalizations among those infected with SARS-CoV-2. [ABSTRACT FROM AUTHOR]

This study investigated the effects of maternal nutrition on the plasma metabolome of Nellore bulls in the rearing and finishing phases, and metabolic differences between these phases. For this study, three nutritional approaches were used in 126 cows during pregnancy: NP—(control) mineral supplementation; PP—protein-energy supplementation in the final third; and FP—protein-energy supplementation during the entire pregnancy. We collected blood samples from male offspring in the rearing (450 ± 28 days old) and finishing phases (660 ± 28 days old). The blood was processed, and from plasma samples, we performed the targeted metabolome analysis (AbsoluteIDQ® p180 Kit). Multiple linear regression, principal component analysis (PCA), repeated measures analysis over time, and an enrichment analysis were performed. PCA showed an overlap of treatments and time clusters in the analyses. We identified significant metabolites among the treatments (rearing phase = six metabolites; finishing phase = three metabolites) and over time (21 metabolites). No significant metabolic pathways were found in the finishing phase, however, we found significant pathways in the rearing phase (Arginine biosynthesis and Histidine metabolism). Thus, prenatal nutrition impacted on plasma metabolome of bulls during the rearing and finishing phase and the different production stages showed an effect on the metabolic levels of bulls. [ABSTRACT FROM AUTHOR]

Propofol is widely used as a short-acting intravenous anaesthetic for the induction and maintenance of anaesthetic sedation. The application of propofol is expanding due to its advantages and the increasing demand for painless diagnosis and treatment. However, accumulating clinical and experimental evidence has shown that propofol can potentially be abused and is prone to causing addiction. To further understand the underlying mechanism of propofol addiction, our review places emphasis on explaining the roles of the mesolimbic, noradrenergic, and nitrergic systems in propofol addiction. We have focused on the role of the gamma-aminobutyric acid, glucocorticoid, N-methyl-D-aspartic acid, adenosine A2A, and corticotropin-releasing factor receptors in the mesolimbic system in forming and maintaining propofol addiction. Furthermore,wehave attempted to clarify the relationship between the dopaminergic pathway, extracellular signal-regulated kinase signalling pathway, and the ventral tegmental area-nucleus accumbens circuit in the mesolimbic system. [ABSTRACT FROM AUTHOR]

Microorganisms adapt to environmental conditions as a survival strategy for different interactions with the environment. The adaptive capacity of fungi allows them to cause disease at various sites of infection in humans. In this study, we propose digital images as responses of a complete factorial 23. Furthermore, we compared two experimental approaches: the experimental design (3D) and the checkerboard assay (2D) to know the influence of pH, glucose, and fluconazole concentration on different strains of the genus Candida. The digital images obtained from the factorial 23 were used as input in the PCA-ANOVA to analyze the results of this experimental design. pH modification in the culture medium modifies the susceptibility in some species less adapted to this type of modification. For the first time, to the best of our knowledge, digital images were used as input to PCA-ANOVA to obtain information on Candida spp.. Therefore, a higher concentration of antifungals is needed to inhibit the same strain at a lower pH. In short, we present an alternative with less use of reagents and time. In addition, the use of digital images allows obtaining information about fungal susceptibility with three or more factors. [ABSTRACT FROM AUTHOR]

The present study aims to search for a nano-delivery system that enables access of antimicrobial compounds to the targeting site of the microbial pathogens. To achieve this obiective, the antimicrobial compounds extracted from the local isolate Streptomyces rimosus were loaded on chitosan (CS) and calcium phosphate (CaP) nanoparticles (NPs) to facilitate drug delivery to some species of bacteria (Escherichia coli ATCC25922, Staphylococcus aureus ATCC25923 and Bacillus cereus ATCC6633) and the yeast Candida albicans ATCC10231. The best incubation period for the production of antifungal and antibacterial compounds, pH, temperature, carbon sources and nitrogen sources were around the third day, 7.0, 30°C, starch and potassium nitrate, respectively. The extracted compounds were identified using gas chromatography-mass spectrometry (GC-MS) analysis which revealed to the identification of nine antimicrobial organic acids. The prepared NPs were characterized using transmission electron microscopy (TEM) and Zeta potential analyser. Results showed those chitosan nanoparticles (CSNPs) were spherical shaped NPs with an average size ≈22 ± 2 nm. The CSNPs loaded with the antimicrobial molecule's diameter was ranged from 55 upto 100 nm. Calcium phosphates nanoparticles (CaPNPs) were also spherical shaped NPs with diameter range from 70 to 95 nm. Loading of antimicrobial compounds onto CaPNPs made them appeared in rod shape with width varying from 14 to 27 nm and length from 274 to 397 nm. The synthesized NPs showed negative values confirming their high dispersity and long-term stability. The tested strains were resistant to solo NPs; but the loaded NPs with the extracted antimicrobial compounds, particularly the CaPNPs, augmented the potency of the isolated antimicrobial compounds, with emergence of differential antimicrobial activity. The activity of the NPs-bound antimicrobial compounds was more evident against bacteria than fungi, Grampositive bacteria than Gram-negative bacteria and against B. cereus than S. aureus. [ABSTRACT FROM AUTHOR]

Cigarette smoking is a risk factor associated with different diseases, claiming millions of lives annually. Smoking status has been studied for a long time and proved to be a major cause of smokers' decreased immunity. In the present pandemic COVID-19 disease, there was an unclear belief about the effect of smoking on patients with COVID-19. Therefore, the current cross-sectional study aimed to evaluate the effect of cigarette smoking on the sequelae of COVID-19. This cross-sectional study involved 200 COVID-19 patients (114 males and 86 females) aged 13-77 years. A number of 87 patients were smokers, and the rest of them were non-smokers. All patients underwent a comprehensive laboratory assessment and diagnosis by full medical history by the physicians. The results indicated a significant difference (P<0.001) between smokers and non-smokers in terms of hypertension, anticoagulant, steroid therapy, pulmonary lesion, oxygen saturation, and duration of disease. As an overall conclusion, it can be stated that COVID-19 is less severe in smokers and they require less intensive treatment. [ABSTRACT FROM AUTHOR]

Introduction: It is unclear whether smokers are more vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to evaluate the association between smoking and the risk of SARS-CoV-2 infection.Methods: A matched case-control study was conducted using a large nationwide database. The case group included patients with SARS-CoV-2 infection confirmed by the Korea Centers for Disease Control and Prevention, and the control group was randomly sampled from the general Korean population in the National Health Insurance Service database by matching sex, age, and region of residence. Conditional logistic regression models were used to investigate whether the risk of infection with SARS-CoV-2 was affected by smoking status.Results: A total of 4,167 patients with SARS-CoV-2 infection and 20,937 matched controls were enrolled. The proportion of ex-smokers and current smokers was 26.6% of the total participants. In multivariate analysis, smoking was not associated with an increased risk of SARS-CoV-2 infection (odds ratio [OR] = 0.56, confidence interval [CI] = 0.50-0.62). When ex-smokers and current smokers were analysed separately, similar results were obtained (current smoker OR = 0.33, CI = 0.28-0.38; ex-smoker OR = 0.81, CI = 0.72-0.91).Conclusions: This study showed that smoking may not be associated with an increased risk of SARS-CoV-2 infection. Smoking tends to lower the risk of SARS-CoV-2 infection; however, these findings should be interpreted with caution.Implications: It is unclear whether smokers are more vulnerable to coronavirus disease 2019. In this large nationwide study in South Korea, smoking tended to lower the risk of infection with severe acute respiratory syndrome coronavirus 2. However, these findings should be interpreted with caution, and further confirmatory studies are required. [ABSTRACT FROM AUTHOR]

A practice-based approach for the scale-up of fluid bed granulation in the context of drug product development is presented and evaluated in this work in the context of clinical drug product manufacturing development. The approach is based on the use of a scale-independent parameter, the evaporation energy to drying capacity ratio (EE/DC), and a process model. The EE/DC ratio is used to quantify, in one scale-independent parameter, the combined effect of the most impacting process parameters and to identify the spray rates to be used at different scales to achieve similar granule moisture rate of change. The process model is used to de-risk scale-up, by allowing the consideration of equipment differences across scales and process dynamics, which are aspects not accounted for by the EE/DC ratio. This approach was tested by scaling up the fluid bed granulation process of two formulations, one placebo and one active, from laboratory to pilot scales. This work showed how it was possible to use a simple scale-up approach coupled with a process model to achieve right first-time scale-up of a fluid bed granulation process and show how a placebo formulation could be used instead of active material, first to define the process at laboratory scale and then to de-risk the scale-up, by identifying scale-dependent differences. [ABSTRACT FROM AUTHOR]

Introduction. In our previous study, it has been confirmed that formaldehyde (FA) not only inhibits the proliferative activity, but also causes DNA-protein crosslinks (DPCs) formation in bone marrow mesenchymal stem cells (BMSCs). The purpose of this study was to detect the protective effect of astragalus polysaccharide (APS) against the cytotoxicity and genotoxicity of BMSCs exposed to FA, and to explore potential molecular mechanisms of APS activity. Material and methods. Human BMSCs were cultured in vitro and randomly divided into control cells (Ctrl group), FA-treated cells (FA group, 120 μmol/L), and cells incubated with FA and increasing concentrations (40, 100, or 400 μg/mL) of APS (FA + APS groups). Cytotoxicity was measured by MTT assay. DNA strand breakage, DNA-protein crosslinks (DPCs), and micronucleus formation were respectively detected by comet assay, KCl-SDS precipitation assay, and micronucleus assay. The mRNA and protein expression level of xeroderma pigmentosum group A (XPA), xeroderma pigmentosum group C (XPC), excision repair cross-complementation group 1 (ERCC1), replication protein A1 (RPA1), and replication protein A2 (RPA2) were all detected by qRT-PCR and Western Blot. Results. Compared with the FA group, the cytotoxicity, DNA strand breakage, DPCs, and micronucleus levels were decreased significantly in FA + APS groups (P < 0.01). Meanwhile, the mRNA and protein expression of XPA, XPC, ERCC1, RPA1, and RPA2 were up-regulated significantly in the FA + APS groups (P < 0.05) with the most prominent effect of the 100 μg/mL APS. Conclusions. Our results suggest that APS can protect the cytotoxicity and genotoxicity of human BMSCs induced by FA. The mechanism may be associated with up-regulated expression of XPA, XPC, ERCC1, RPA1, and RPA2 in the nucleotide excision repair (NER) pathway which promotes DNA damage repair. [ABSTRACT FROM AUTHOR]

Continuous or frequent ingestion of fried foods containing cytotoxic/mutagenic/genotoxic lipid oxidation products (LOPs) may present significant human health risks; such toxins are generated in thermally stressed polyunsaturated fatty acid (PUFA)-rich culinary frying oils (CFOs) during standard frying practices. Since monounsaturated and saturated fatty acids (MUFAs and SFAs, respectively) are much less susceptible to peroxidation than PUFAs, in this study CFOs of differential unsaturated fatty acid contents were exposed to laboratory-simulated shallow-frying episodes (LSSFEs). Firstly, we present a case study exploring the time-dependent generation of aldehydic LOPs in CFO products undergoing LSSFEs, which was then used to evaluate the relative potential health risks posed by them, and also to provide suitable recommendations concerning their safety when used for frying purposes. Sunflower, rapeseed, extra-virgin olive and coconut oils underwent LSSFEs at 180 °C: Samples were collected at 0–90 min time-points (n = 6 replicates per oil). Aldehydes therein were determined by high-resolution 1H NMR analysis at 400 and 600 MHz operating frequencies. For one of the first times, CFO LOP analysis was also performed on a non-stationary 60 MHz benchtop NMR spectrometer. 1H NMR analysis confirmed the thermally promoted, time-dependent production of a wide range of aldehydic LOPs in CFOs. As expected, the highest levels of these toxins were produced in PUFA-rich sunflower oil, with lower concentrations formed in MUFA-rich canola and extra-virgin olive oils; in view of its very high SFA content, only very low levels of selected aldehyde classes were generated in coconut oil during LSSFEs. Secondly, 1H NMR results acquired are discussed with regard to the suitability and validity of alternative, albeit routinely employed, spectrophotometric methods for evaluating the peroxidation status of CFOs and lipid-containing foods. Thirdly, an updated mini-review of the toxicological properties of and intake limits for LOPs, and deleterious health effects posed by their ingestion, is provided. In conclusion, exposure of PUFA-rich CFOs to high-temperature frying practices generates very high concentrations of aldehydic LOP toxins from thermally promoted, O2-powered, recycling peroxidation processes; these toxins penetrate into and hence are 'carried' by fried foods available for human consumption. Such toxins have the capacity to contribute towards the development and progression of non-communicable chronic diseases (NCDs) if cumulatively ingested by humans. [ABSTRACT FROM AUTHOR]

A pioneer in the study of the effect of light on plant development, Wilhelm Pfeffer (1845–1920), outlined both modes of plant development in darkness and in light– today known as skoto- and photo- morphogenesis, respectively. By exploring the current understanding of these pathways in Arabidopsis, we speculate on the possible mechanisms of cell and organ elongation in darkness. We present a thought experiment, which highlights the need for a yet unknown (hidden) external signal, we call aleph (ℵ), and its possible sensor "etioreceptor". Here we propose for the first time that this system is required for growth and developmental patterning to continue in localized spacetime under minimal growth environments, particularly in the absence of light. If true, this mechanism may have played a fundamental role in organism's survival during Darwinian (adaptive) evolution ("survival of the fittest"). We present our working model whereby the hidden signal acting through its etioreceptor, increases auxin biosynthesis to facilitate organ expansion, and suggest a function for this system in the auxin biosynthesis pathway. [ABSTRACT FROM AUTHOR]

Objectives: Ritonavir is an antiretroviral agent which belongs to Biopharmaceutical Classification System (BCS) II having poor water solubility. The purpose of this study was to design Self-Nano Emulsifying Drug Delivery System (SNEDDS) for a poorly water-soluble anti-retroviral drug-Ritonavir by implementing Quality by Design (QbD). Methods: In a DoE based development, Mixture design was used for the development and simultaneous optimization of the Ritonavir-SNEDDS. Droplet size (nm), Emulsification time (seconds), Polydispersity Index (PDI) and % Transmittance were the various responses selected for the study. Labrafil® M 1944 CS (oil), Tween 80 (surfactant) and PEG 6000 (cosurfactant) are the independent variables considered in the design. Eight formulations were prepared and tested for model fit. The simultaneous optimization of formulation was done by the Global desirability function approach obtained through Prediction profiler. Results: The developed optimal Ritonavir -SNEDDS through QbD approach resulted in a robust and sustainable method for improving the oral bioavailability of Ritonavir and confirmed by the characterisation studies- droplet size (264.7 nm), emulsification time (46.1 sec), PDI (0.415) and % transmittance (94.8). Conclusion: The results conclude the potentiality of SNEDDS formulation to improve Ritonavir oral bioavailability under the QbD framework. [ABSTRACT FROM AUTHOR]

Aim: The therapeutic utility of many poorly water-soluble drugs are severely restricted for their bioavailability. The present study was aimed to development of self-micro emulsifying drug delivery (SMEDDS) system for a poorly water soluble anti-retroviral drug - Darunavir by the application of Quality by Design (QbD) to increase its bioavailability. Methodology: Extreme Vertices Mixture Design (EVMD), based on its utility and the applicability to the formulation problem in hand was selected for the study. The different responses selected for this design were drug release in 15 min (%), drug loading (mg/ml), emulsification time (seconds) and droplet size (nm). The factors or the independent variables considered in the design are oil, surfactant and cosurfactant. Ten different formulations were prepared and evaluated to check the model fit. The optimization and model verification were done by conducting experimental runs. Results: The studies revealed that application of EVMD and development of the formulation in a QbD framework resulted in a robust and sustainable method for improving the bioavailability of the drug as evidenced by the characterization studies of optimized batch In vitro drug release in 15 min (92.43%), drug loading (98.95 mg/ml), emulsification time (31.5 sec) and droplet size (222.2 nm). The Transmission electron micrographs (TEM) obtained for optimized formulation showed a uniform spherical morphology. Conclusion: The development of hard to achieve formulation techniques like SMEDDS involving BCS class 2 and 4 drugs can be sustainably achieved with minimal time and resources, matching regulatory requirements can be attained by the application of EVMD, under QbD framework. [ABSTRACT FROM AUTHOR]

The pharmaceutical tablet manufacturing process (PTMP) via wet granulation holds a critical position in pharmaceutical industry. The interest in integrating mechanistic process modeling into the pharmaceutical development has been increased because simulation model is a prerequisite for process design, analysis, control, and optimization. So the simulation modeling for PTMP via wet granulation is very necessary and significant. This study aims at proposing a simulation modeling framework for PTMP via spray fluidized bed granulation (SFBG), which is one of the most widely used wet granulation techniques in pharmaceutical industry. For SFBG, a simulation model that simultaneously involves the influences of operating variables and material attributes on average particle size (APS) is firstly developed, and then a drying model to determine the particle moisture content is introduced to be coupled with the established model predicting APS. For PTMP, considering the important effect of porosity on tablet qualities, a model describing the changes in tablet porosity is developed based on a promoted form of the Heckel equation, and then several recognized models that are all related to porosity are introduced or constructed to calculate important tablet quality indexes. The feasibility and effectiveness of the developed simulation models are validated by performing a computational experimental study to explore the scientific understanding of process and process quality control. [ABSTRACT FROM AUTHOR]

The particles with a narrow size distribution are proper products in a fluid bed granulation and coating. As well, the process efficiency is one of the most important parameters, and the wall deposition of sprayed liquid reduces it. The modality of spray volume distribution is a key parameter in the definition of particle size distribution and process efficiency. This work is done in two steps: In the first step, an experimental study on spray characteristics including spray flux distribution, spray cone angle, and discharge coefficient is conducted. Based on the experimental data, the curves of liquid volume flux versus nozzle pressure and height are obtained. The results indicate that the flux distribution changes significantly with even small pressure and height changes. In the second step, the granulation process is carried out in a semi-industrial conical fluid bed, and the particles size distribution curves and the deposited mass on the bed wall are obtained. The results show that the precise determination of the spray flux distribution is an appropriate way to predict the well-advised nozzle pressure/height in order to achieve the narrow particle size distribution and high efficiency of the process. [ABSTRACT FROM AUTHOR]

Tryptophan (Trp) is an amino acid and an essential component of the human diet. It plays a crucial role in many metabolic functions. Clinicians can use Trp levels in the course of diagnosing various metabolic disorders and the symptoms associated with those diseases. Furthermore, supplementation with this amino acid is considered in the treatment of depression and sleep disorders, mainly due to the Trp relationship with the synthesis of serotonin (5-HT) and melatonin. It is also used in helping to resolve cognitive disorders, anxiety, or neurodegenerative diseases. Reduced secretion of serotonin is associated with autism spectrum disorder, obesity, anorexia and bulimia nervosa, and other diseases presenting peripherals symptoms. The literature strongly suggests that Trp has a significant role in the correct functionality of the brain-gut axis and immunology. This information leads to the consideration of Trp as an essential dietary component due to its role in the serotonin pathway. A reduced availability of Trp in diet and nutraceutical supplementation should be considered with greater concern than one might expect. This paper constitutes a review of the more salient aspects gleaned from the current knowledge base about the role of Trp in diseases, associated nutritional disorders, and food science, in general. [ABSTRACT FROM AUTHOR]

The exhaustion of fossil fuel resources has instigated a necessity to find new alternatives like biofuels, for heat and power generation. Biofuels are usually generated from the thermal conversion of densified biomass material. Densification systems convert biomass into pellets, and consist of three phases: pre-pelletization, pelletization, and post- pelletization. This article provides an overview of available biomass densification techniques. A detailed discussion has been provided to emphasize the effect of raw material properties on the pellet’s durability and bulk density. A quality parameter (Q) has been proposed to evaluate the quality of pellets considering the factors involved in pellet characterization. Particularly, accounting for pellet compression rather than tensile forces were found to be better when quantifying the pellet quality parameter Q. A discussion regarding the binding mechanisms, types of binders used, and their effect on the pellet’s durability is provided, in addition to the pelletization process by itself with the main parameters that affect its operation. The post-pelletization processes were presented, focusing on three thermal conversion techniques: gasification, pyrolysis, and combustion. A comparison between these techniques has been provided, in addition to recommendations regarding pros and cons of each one. Finally, the environmental footprints of densification systems have been reviewed. [ABSTRACT FROM AUTHOR]

FA (formaldehyde) and ACR (acrolein) are common pollutants in environment, which often occur together in air. So, adverse health effects may not only result from their individual toxicity but also from the combined toxicity. While often studied alone, combination effects of these pollutants are inconclusive. Here, we examined the combined cytotoxicity and genotoxicity of FA and ACR on A549 cells based on CCK-8 assay, comet assay, and cytokinesis-block micronuclei assay. FA and ACR mixtures showed significant cytotoxicity and genotoxicity even at NOECs (no observed effect concentrations). Moreover, FA and ACR administrated jointly at doses from NOECs to sub-cytotoxic concentrations demonstrated significant interactions in cytotoxicity, DNA strand breaks, and chromosome damage. Co-exposure to FA and ACR significantly showed a lower responses on DNA strand break and chromosome damage than those expected for additivity, while an opposite result was obtained on cytotoxicity. Taken together, these results indicated that there was significant interactions on cytotoxicity and genotoxicity for FA and ACR, and prolonged exposure to mixtures of FA and ACR below sub-cytotoxic concentrations can produce a serious threat in human’s health. [ABSTRACT FROM AUTHOR]

The objective of this study was to improve the disintegration and dissolution characteristics of a highly water-soluble tablet matrix by altering the manufacturing process. A high disintegration time along with high dependence of the disintegration time on tablet hardness was observed for a high drug loading (70% w/w) API when formulated using a high-shear wet granulation (HSWG) process. Keeping the formulation composition mostly constant, a fluid-bed granulation (FBG) process was explored as an alternate granulation method using a 2(4−1) fractional factorial design with two center points. FBG batches (10 batches) were manufactured using varying disingtegrant amount, spray rate, inlet temperature (T) and atomization air pressure. The resultant final blend particle size was affected significantly by spray rate (p = .0009), inlet T (p = .0062), atomization air pressure (p = .0134) and the interaction effect between inlet T*spray rate (p = .0241). The compactibility of the final blend was affected significantly by disintegrant amount (p < .0001), atomization air pressure (p = .0013) and spray rate (p = .05). It was observed that the fluid-bed batches gave significantly lower disintegration times than the HSWG batches, and mercury intrusion porosimetry data revealed that this was caused by the higher internal pore structure of tablets manufactured using the FBG batches. [ABSTRACT FROM AUTHOR]

Nanosized single crystal orthorhombic Bi2WO6 was synthesized by a hydrothermal method and used as a sorbent for vortex assisted solid phase extraction of lead(II). The crystal and molecular structure of the sorbent was examined using XRD, Raman, SEM and SEM-EDX analysis. Various parameters affecting extraction efficiency were optimized by using multivariate design. The effect of diverse ions on the extraction also was studied. Lead was quantified by flame atomic absorption spectrometry (FAAS). The recoveries of lead(II) from spiked samples (at a typical spiking level of 200-400 ng⋅mL-1) are >95%. Other figures of merit includes (a) a detection limit of 6 ng⋅mL-1, (b) a preconcentration factor of 50, (c) a relative standard deviation of 1.6%, and (d) and adsorption capacity of 6.6 mg⋅g-1. The procedure was successfully applied to accurate determination of lead in (spiked) pomegranate and water samples. [ABSTRACT FROM AUTHOR]

In roll compaction, the specific compaction force, the gap width and the roll speed are the most important settings as they have a high impact in the products obtained. However the mechanical properties of the mixture being compacted are also critical. For this reason, a multilevel full factorial design including these parameters as factors plus three repetitions of the center point was performed for microcrystalline cellulose, mannitol and five binary mixtures (15, 30, 50, 70 and 85% MCC). These two reference excipients were chosen in order to investigate the plastic/brittle behavior of mixtures for the roll compaction process. These materials were roll compacted in a 3-W-Polygran®250/50/3 (Gerteis) and the ribbons obtained were collected and milled into granules which were characterized regarding granule size distribution. After statistical evaluation, it was found that the most critical factors affecting the D10, D50, D90 and the fines fraction from the granules were the gap width and the specific compaction force, as well as the proportion of MCC together with its quadratic effect and the interaction between force and proportion of MCC. The microhardness of the ribbons from the center point as well as the D10, D50, D90 and the fines fraction from the granules produced at these same conditions were characterized. In all the cases, the proportion of MCC, i.e. the composition of the mixture, showed also an important effect on these properties measured. In this sense, the percolation theory was applied in order to study further the importance of the plastic/brittle ratio by calculating the percolation threshold or the limit over which the behavior of the system changes. This resulted in values of 34% for theHU(expression of microhardness), 27% and 28% for the D10 and fines, respectively (percolation of MCC) and 84% and 85% for the D50 and D90, respectively (percolation of mannitol). [ABSTRACT FROM PUBLISHER]

Laws and treaties compel countries to inform the public about harmful chemicals (constituents) in cigarette smoke. To encourage relevant research by behavioral scientists, we provide a primer on cigarette smoke toxicology and summarize research on how the public thinks about cigarette smoke chemicals. We systematically searched PubMed in July 2016 and reviewed citations from included articles. Four central findings emerged across 46 articles that met inclusion criteria. First, people were familiar with very few chemicals in cigarette smoke. Second, people knew little about cigarette additives, assumed harmful chemicals are added during manufacturing, and perceived cigarettes without additives to be less harmful. Third, people wanted more information about constituents. Finally, well-presented chemical information increased knowledge and awareness and may change behavior. This research area is in urgent need of behavioral science. Future research should investigate whether educating the public about these chemicals increases risk perceptions and quitting. [ABSTRACT FROM AUTHOR]

The purpose of this study was the development of novel, fast disintegrating, effervescent pellets by employing the direct pelletization technique as a single step process. In line with the Quality by Design (QbD) regulatory framework, statistical experimental design was extensively applied to correlate significant formulation and process variables with the critical quality attributes of the product. Pellets were studied with regards to sphericity, size and size distribution. In contrast to the existing multiparticulate platforms, this development integrated only water-soluble excipients to facilitate the multifunctional use of the final dosage form. The application of a screening fractional factorial design augmented to a full factorial design set the roadmap for the rational selection of the composition and process parameters, revealing in parallel the positive contribution of the powder feeder on the CQAs, when the critical process and formulation factors were properly adjusted. The response surface methodology was exploited for the final process optimization phase, which allowed the construction of appropriate mathematical models connecting the input variables and the CQAs under study. The implementation of the desirability function, lead to the optimum formulation and process settings for the production of pellets with narrow size distribution and geometric mean diameter of approximately 800 μm. In conclusion, using a lean approach supported by design of experiments (DoE) techniques within the QbD framework, a novel multifunctional formulation platform has been developed. [ABSTRACT FROM AUTHOR]

Objective:Mucociliary clearance sustains a baseline functionality and an “on demand” capability to upregulate clearance upon irritant exposure involving mucus hypersecretion and accelerated ciliary beat frequency (CBF) modulated by nitric oxide (NO). This study characterized these elements as well as cellular and exogenous NO concentrations subsequent to a single exposure to tobacco smoke (TS) or e-cigarette vapor (EV) on cultured human airway epithelium. Materials and methods:Air–liquid interface (ALI) airway epithelial cultures per nonsmoking human subjects were subjected to single TS or EV exposures. Measures of ciliary function and secretion were performed and cellular and exogenous NO concentrations under control and experimental conditions were assessed. Results:Both TS and EV exposures resulted similar patterns of decline in CBF within 1 min of the completion of exposure followed by a gradual return often exceeding baseline within 1 h. Post-exposure examination of exposed cultures suggested morphologic differences in secretory function relative to controls. The relative NO concentrations of TS and EV chamber air were sharply different with EV NO being only slightly elevated relative to cellular NO production. Discussion and conclusions:Epithelial remodeling and mucociliary dysfunction have been clearly associated with TS exposure. However, information contrasting epithelial structure/function following a single acute TS or EV exposure is limited. This study demonstrates a similar pattern of epithelial response to acute TS or EV exposure. Inasmuch as NO may contribute to an inflammatory milieu and generation of toxic metabolites, it is plausible that recurrent exposures over time may be contributory to chronic pathologies. [ABSTRACT FROM AUTHOR]

ABSTRACT Hexanal is a major component of indoor air pollutants and is a kind of aldehydes; it has adverse effects on human health. We performed an in vivo inhalation study and transcriptomic analysis to determine the mode of toxic actions in response to hexanal. Fischer 344 rats of both sexes were exposed by inhalation to hexanal aerosol for 4 h day−1, 5 days week−1 for 4 weeks at 0, 600, 1000, and 1500 ppm. Throughout our microarray-based genome-wide expression analysis, we identified 56 differentially expressed genes in three doses of hexanal; among these genes, 11 genes showed dose-dependent expression patterns (10 downregulated and 1 upregulated, 1.5-fold, p < 0.05). Through a comparative toxicogenomics database (CTD) analysis of 11 genes, we determined that five genes ( CCL12, DDIT4, KLF2, CEBPD, and ADH6) are linked to diverse disease categories such as cancer, respiratory tract disease, and immune system disease. These diseases were previously known for being induced by volatile organic compounds (VOCs). Our data demonstrated that the hexanal-induced dose-dependent altered genes could be valuable quantitative biomarkers to predict hexanal exposure and to perform relative risk assessments, including pulmonary toxicity. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 382-396, 2017. [ABSTRACT FROM AUTHOR]

ABSTRACT In previous studies, we have investigated the relationships between environmental chemicals and health risk based on omics analysis and identified significant biomarkers. Our current findings indicate that hexanal may be an important toxicant of the pulmonary system in epigenetic insights. MicroRNA (miRNA) is an important indicator of biomedical risk assessment and target identification. Hexanal is highly detectable in the exhaled breath of patients with chronic obstructive pulmonary disease (COPD) and chronic inflammatory lung disease. In this study, we aimed to identify hexanal-characterized miRNA-mRNA correlations involved in lung toxicity. Microarray analysis identified 56 miRNAs that commonly changed their expression more than 1.3-fold in three doses (600, 1000, and 1500 ppm) within hexanal-exposed Fischer 344 rats by inhalation, and 226 genes were predicted to be target genes of miRNAs through TargetScan analysis. By integrating analyses of miRNA and mRNA expression profiles, we identified one anti-correlated target gene ( Chga; chromogranin A; parathyroid secretory protein 1). Comparative toxicogenomics database (CTD) analysis of this gene showed that Chga is involved with several disease categories such as cancer, respiratory tract disease, nervous system disease, and cardiovascular disease. Further research is necessary to elucidate the mechanisms of hexanal-responsive toxicologic pathways at the molecular level. This study concludes that our integrated approach to miRNA and mRNA enables us to identify molecular events in disease development induced by hexanal in an in vivo rat model. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1909-1921, 2016. [ABSTRACT FROM AUTHOR]

The present study aimed to develop lipid–polymer hybrid nanoparticles (LPNs) for the combined pulmonary delivery of isoniazid (INH) and ciprofloxacin hydrochloride (CIP HCl). Drug-loaded LPNs were prepared by the double-emulsification solvent evaporation method using the three-factor three-level Box–Behnken design. The optimized formulation had a size of 111.81 ± 1.2 nm, PDI of 0.189 ± 1.4, and PDE of 63.64 ± 2.12% for INH-loaded LPN, and a size of 172.23 ± 2.31 nm, PDI of 0.169 ± 1.23, and PDE of 68.49 ± 2.54% for CIP HCl-loaded LPN. Drug release was found to be sustained and controlled at lower pH and followed the Peppas model. Thein vitrouptake study in alveolar macrophage (AM) showed that uptake of the drugs was increased significantly if administered in the form of LPN. The stability study proved the applications of adding PLGA in LPN as the polymeric core, which leads to a much more stable product as compared to other novel drug delivery systems. Spray drying was done to produce an inhalable, dry, powdered form of drug-loaded LPN. The spray-dried (SD) powder was equally capable of producing nano-aggregates having morphology, density, flowability and reconstitutibility in the range ideal for inhaled drug delivery. The nano aggregates produced by spray drying manifested their aerosolization efficiency in terms of the higher emitted dose and fine particle fraction with lower mass median aerodynamic diameter. Thein vivostudy using pharmacokinetic and pharmacodynamic approaches revealed that maximum internalization efficiency was achieved by delivering LPN in SD powdered forms by pulmonary route. [ABSTRACT FROM AUTHOR]

Atomisation of an aqueous solution for tablet film coating is a complex process with multiple factors determining droplet formation and properties. The importance of droplet size for an efficient process and a high quality final product has been noted in the literature, with smaller droplets reported to produce smoother, more homogenous coatings whilst simultaneously avoiding the risk of damage through over-wetting of the tablet core. In this work the effect of droplet size on tablet film coat characteristics was investigated using X-ray microcomputed tomography (XμCT) and confocal laser scanning microscopy (CLSM). A quality by design approach utilising design of experiments (DOE) was used to optimise the conditions necessary for production of droplets at a small (20 μm) and large (70 μm) droplet size. Droplet size distribution was measured using real-time laser diffraction and the volume median diameter taken as a response. DOE yielded information on the relationship three critical process parameters: pump rate, atomisation pressure and coating-polymer concentration, had upon droplet size. The model generated was robust, scoring highly for model fit (R2 = 0.977), predictability (Q2 = 0.837), validity and reproducibility. Modelling confirmed that all parameters had either a linear or quadratic effect on droplet size and revealed an interaction between pump rate and atomisation pressure. Fluidised bed coating of tablet cores was performed with either small or large droplets followed by CLSM and XμCT imaging. Addition of commonly used contrast materials to the coating solution improved visualisation of the coating by XμCT, showing the coat as a discrete section of the overall tablet. Imaging provided qualitative and quantitative evidence revealing that smaller droplets formed thinner, more uniform and less porous film coats. [ABSTRACT FROM AUTHOR]

Using forward genetics, we revealed that the signal peptide peptidase (SPP) SppA, an aspartyl protease involved in regulated intramembrane proteolysis (RIP), is essential for hypoxia adaptation in Aspergillus nidulans, as well as hypoxia-sensitive mutant alleles of a sterol regulatory element-binding protein (SREBP) srbA and the Dsc ubiquitin E3 ligase complex dscA-E. Both null and dead activity [D337A] mutants of sppA failed to grow in hypoxia, and the growth defect of Δ sppA was complemented by nuclear SrbA-N381 expression. Additionally, SppA interacted with SrbA in the endoplasmic reticulum, where SppA localized in normoxia and hypoxia. Expression of the truncated SrbA-N414 covering the SrbA sequence prior to the second transmembrane region rescued the growth of Δ dscA but not of Δ sppA in hypoxia. Unlike Δ dscA and Δ dscA;Δ sppA double mutants, in which SrbA cleavage was blocked, the molecular weight of cleaved SrbA increased in Δ sppA compared to the control strain in immunoblot analyses. Overall, our data demonstrate the sequential cleavage of SrbA by Dsc-linked proteolysis followed by SppA, proposing a new model of RIP for SREBP cleavage in fungal hypoxia adaptation. Furthermore, the function of SppA in hypoxia adaptation was consistent in Aspergillus fumigatus, suggesting the potential roles of SppA in fungal pathogenesis. [ABSTRACT FROM AUTHOR]

This study for the first time demonstrates combined application of mixture experimental design and artificial neural networks (ANNs) in the solid dispersions (SDs) development. Ternary carbamazepine–Soluplus®–poloxamer 188 SDs were prepared by solvent casting method to improve carbamazepine dissolution rate. The influence of the composition of prepared SDs on carbamazepine dissolution rate was evaluated usingd-optimal mixture experimental design and multilayer perceptron ANNs. Physicochemical characterization proved the presence of the most stable carbamazepine polymorph III within the SD matrix. Ternary carbamazepine–Soluplus®–poloxamer 188 SDs significantly improved carbamazepine dissolution rate compared to pure drug. Models developed by ANNs and mixture experimental design well described the relationship between proportions of SD components and percentage of carbamazepine released after 10 (Q10) and 20 (Q20) min, wherein ANN model exhibit better predictability on test data set. Proportions of carbamazepine and poloxamer 188 exhibited the highest influence on carbamazepine release rate. The highest carbamazepine release rate was observed for SDs with the lowest proportions of carbamazepine and the highest proportions of poloxamer 188. ANNs and mixture experimental design can be used as powerful data modeling tools in the systematic development of SDs. Taking into account advantages and disadvantages of both techniques, their combined application should be encouraged. [ABSTRACT FROM AUTHOR]

High-shear wet granulation is a complex process that in turn makes scale-up a challenging task. Scale-up of high-shear wet granulation process has been studied extensively in the past with various different methodologies being proposed in the literature. This review article discusses existing scale-up principles and categorizes the various approaches into two main scale-up strategies – parameter-based and attribute-based. With the advent of quality by design (QbD) principle in drug product development process, an increased emphasis toward the latter approach may be needed to ensure product robustness. In practice, a combination of both scale-up strategies is often utilized. In a QbD paradigm, there is also a need for an increased fundamental and mechanistic understanding of the process. This can be achieved either by increased experimentation that comes at higher costs, or by using modeling techniques, that are also discussed as part of this review. [ABSTRACT FROM AUTHOR]

Polyvinyl alcohol (PVAL) has not been investigated in a binary formulation as a concentration-enhancing polymer owing to its high melting point/high viscosity and poor organic solubility. Due to the unique attributes of the KinetiSol® dispersing (KSD) technology, PVAL has been enabled for this application and it is the aim of this paper to investigate various grades for improvement of the solubility and bioavailability of poorly water soluble active pharmaceutical ingredients. Solid amorphous dispersions were created with the model drug, itraconazole (ITZ), at a selected drug loading of 20%. Polymer grades were chosen with variation in molecular weight and degree of hydroxylation to determine the effects on performance. Differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, size exclusion chromatography, and dissolution testing were used to characterize the amorphous dispersions. An in vivo pharmacokinetic study in rats was also conducted to compare the selected formulation to current market formulations of ITZ. The 4-88 grade of PVAL was determined to be effective at enhancing solubility and bioavailability of itraconazole. [ABSTRACT FROM AUTHOR]

The KinetiSol® Dispersing (KSD) technology has enabled the investigation into the use of polyvinyl alcohol (PVAL) as a concentration enhancing polymer for amorphous solid dispersions. Our previous study revealed that the 88% hydrolyzed grade of PVAL was optimal for itraconazole (ITZ) amorphous compositions with regard to solid-state properties, non-sink dissolution performance, and bioavailability enhancement. The current study investigates the influence of molecular weight for the 88% hydrolyzed grades of PVAL on the properties of KSD processed ITZ:PVAL amorphous dispersions. Specifically, molecular weights in the processable range of 4 to 18 mPa · s were evaluated and the 4-88 grade provided the highest AUC dissolution profile. Amorphous dispersions at 10, 20, 30, 40, and 50% ITZ drug loads in PVAL 4-88 were also compared by dissolution performance. Analytical tools of diffusion-ordered spectroscopy and Fourier transform infrared spectroscopy were employed to understand the interaction between drug and polymer. Finally, results from a 30-month stability test of a 30% drug loaded ITZ:PVAL 4-88 composition shows that stable amorphous dispersions can be achieved. Thus, this newly enabled polymer carrier can be considered a viable option for pharmaceutical formulation development for solubility enhancement. [ABSTRACT FROM AUTHOR]

Roller compaction is the most commonly employed dry granulation process in the pharmaceutical industry. While this process is increasingly used as an alternative to wet granulation, there are no parameter sets or system of equations to quickly scale up or transfer a formulation between two pieces of equipment. In this work, dimensionless variable was examined as a method to transfer the operating parameters of a formulation between two different pieces of equipment. This work was completed to establish the ground work for the development of a dimensionless relationship relating the operating parameters of the equipment to the porosity of the ribbon. The working hypothesis was three-fold, namely (i) that ribbons of the same porosity made with different equipment will have similar properties, (ii) that it is possible to establish an objective relationship between ribbon porosity and a combination of operating parameters and raw material attributes and (iii) that by expressing such parameter combination as a dimensionless variable, it will be possible to use the same relationship for different pieces of roller compaction equipment. The dimensionless variable RP/RS*HFS*True Density*D2was found to correlate well with the ribbon porosity for the formulations and equipment used in these experiments. Depending on the formulation, the average difference in ribbon porosity between the two units varied between 0.012 and 0.024. [ABSTRACT FROM PUBLISHER]

Context: Niacin (vitamin B3) is a micronized active pharmaceutical ingredient (API) with poor flow properties making the production of high-dose sustained-release tablets by direct compression a challenge. Objective: We evaluated various wet granulation processes as a simple and efficient approach to obtain high-dose (500 and 1000 mg) niacin sustained-release lipid matrix tablets. Materials and methods: A high melting-point lipid (Compritol® 888 ATO) was used as the sustained-release agent. Tablets were prepared by various wet granulation techniques, with different process parameters and binder concentrations to identify the optimal process conditions. Results: A binder (PVP) was needed to increase particle bonding and tablet strength. Process parameters, such as spray rate and quantity of liquid, had only a slight impact on the properties of the granules and resultant tablets, in the presence of low binder concentrations. Increasing binder concentration improved granule wetting, resulting in significant granule growth and improved flow properties. Sustained-release over 12 h was observed for all the compacted granules, irrespective of the drug dose. The sustained-release kinetics for 1000 mg niacin matrix tablets with Compritol 888 produced with the identified optimal parameters were similar to those for the market reference product, Niaspan® FCT 1000 mg. The tablets were stable for up to six months when stored at 25 and 40 °C. Conclusions: Wet granulation with Compritol 888 presents an effective approach to improve material flow and compressibility. High-dose lipid matrix tablets with sustained release profiles can be successfully produced. [ABSTRACT FROM AUTHOR]

Objective: While previous research has demonstrated roller compaction operating parameters strongly influence the properties of the final product, a greater emphasis might be placed on the raw material attributes of the formulation. There were two main objectives to this study. First, to assess the effects of different process variables on the properties of the obtained ribbons and downstream granules produced from the rolled compacted ribbons. Second, was to establish if models obtained with formulations of one active pharmaceutical ingredient (API) could predict the properties of similar formulations in terms of the excipients used, but with a different API. Materials and methods: Tolmetin and acetaminophen, chosen for their different compaction properties, were roller compacted on Fitzpatrick roller compactor using the same formulation. Models created using tolmetin and tested using acetaminophen. The physical properties of the blends, ribbon, granule and tablet were characterized. Multivariate analysis using partial least squares was used to analyze all data. Results: Multivariate models showed that the operating parameters and raw material attributes were essential in the prediction of ribbon porosity and post-milled particle size. The post compacted ribbon and granule attributes also significantly contributed to the prediction of the tablet tensile strength. Conclusions: Models derived using tolmetin could reasonably predict the ribbon porosity of a second API. After further processing, the post-milled ribbon and granules properties, rather than the physical attributes of the formulation were needed to predict downstream tablet properties. An understanding of the percolation threshold of the formulation significantly improved the predictive ability of the models. [ABSTRACT FROM AUTHOR]