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It has been shown that dry coating cohesive active pharmaceutical ingredients (APIs) with nano-silica can improve packing and flow of their blends, facilitating high speed direct ...compression tableting. This paper examines the broader scope and generality of previous work by examining three fine APIs; micronized Acetaminophen (mAPAP), coarse Acetaminophen (cAPAP) and micronized Ibuprofen (mIBU), and considers dry coating with both hydrophobic or hydrophilic nano-silica to examine the effect not only on packing density and flow of their blends, but also dissolution and tensile strength of their tablets. The impact of the excipient size on blend and tablet properties are also investigated, indicating blend flow is most improved when matching API particle size with excipient particle size. In all cases where the API is dry coated, the blend packing and flow improve, so as to suggest such high drug loaded blends could enable direct compression. Using dry coated API along with finer excipients in blends lead to improved hardness of the corresponding tablets. Interestingly, dissolution profiles show dry coated API tablets generally have faster dissolution rates, regardless of silica hydrophilicity, suggesting API powder deagglomeration via nano-silica coating plays a crucial role. The most significant conclusion is that, although there are differences in properties of blends that depend on the API, hydrophobic or hydrophilic nano-silica coating, as well as large or fine excipients, in all cases, dry coating of APIs significantly improves the possibility of using the specific blend at high drug loading in direct compression tableting.
Plasma concentration of vitamin D3 metabolite 25‐hydroxyvitamin D3 (25(OH)D3) is variable among individuals. The objective of this study is to establish an accurate model for 25(OH)D3 ...pharmacokinetics (PKs) to support selection of a suitable dose regimen for an individual. We collated vitamin D3 and 25(OH)D3 plasma PK data from reported clinical trials and developed a physiologically‐based pharmacokinetic (PBPK) model to appropriately recapitulate training data. Model predictions were then qualified with 25(OH)D3 plasma PKs under vitamin D3 and 25(OH)D3 dose regimens distinct from training data. From data exploration, we observed the increase in plasma 25(OH)D3 after repeated dosing was negatively correlated with 25(OH)D3 baseline levels. Our final model included a first‐order vitamin D3 absorption, a first‐order vitamin D3 metabolism, and a nonlinear 25(OH)D3 elimination function. This structure explained the apparent paradox. Remarkably, the model accurately predicted plasma 25(OH)D3 following repeated dosing up to 1250 μg/d in the test set. It also made sensible predictions for large single vitamin D3 doses up to 50,000 μg in the test set. Model predicts 10 μg/d regimen may be ineffective for achieving sufficiency (plasma 25(OH)D3 ≥ 75 nmol/L) for a severely deficient individual (baseline 25(OH)D3 = 10 nmol/L), and it might take the same person over 200 days to reach sufficiency at 20 μg/d dose. We propose to personalize vitamin D3 supplementation protocol with this PBPK model. It would require measuring 25(OH)D3 baseline levels, which is not routinely performed under the current UK public health advice.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Vitamin D PK exhibits substantial inter‐individual variability. Different officially recommended daily doses are confusing.
WHAT QUESTION DID THIS STUDY ADDRESS?
Is the UK’s recommended 10 µg daily dose sufficient? Should everyone be given same dose?
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
Our model accurately predicts plasma 25(OH)D under daily oral administration of vitamin D3. The 10 µg daily vitamin D3 dose is insufficient for prophylaxis (plasma 25(OH)D at 75 nmol/L).
HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?
Combining blood test to measure 25(OH)D baseline with this PBPK model will help inform dosage selection and select follow‐up date to improve effectiveness of Hypovitaminosis D treatment.
Content uniformity of low dose blends with fine active pharmaceutical ingredients (API) is adversely impacted due to API agglomeration caused by high powder cohesion. Dry coating using high-intensity ...vibratory mixing is employed to reduce API cohesion and granular Bond number as well as agglomeration as predicted by contact models, hence improve blend content uniformity (CU). Micronized acetaminophen (mAPAP) (~10μm), a model API, was dry coated with nano-silica R972P (20nm), and mixed with Avicel 102. The amount of silica was varied from 0 to 2.74wt%, corresponding to theoretical surface area coverage (SAC) from 0 to 100% respectively. Bulk density, unconfined yield strength, and dispersive surface energy results indicated dry coating with 0.27 to 1.0wt% silica was adequate for API property enhancement; further corroborated by improved CU for 5wt% API blends. Excellent CU was achieved for 3, 5 and 10wt% API loaded blends, where 30min of mixing was found to be acceptable for all three. The CU with dry coated mAPAP was significantly lower and within the acceptable range as compared to control blends without silica, as well as those with silica added during blending. Sieving of mAPAP illustrated the reduction in mAPAP agglomeration, necessary for improved CU after dry coating, corroborating model based predictions. Compared to theoretical predictions, actual CU was higher unless API agglomerate size distribution obtained via sieving was taken into account. Overall, cohesion reduction by dry coating is shown as a promising approach for improving content uniformity of cohesive API blends.
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Polycyclic aromatic hydrocarbons (PAHs) have attracted an increasing concern in China's megacities. However, rare information is available on the spatial and seasonal variations of inhalation cancer ...risk (ICR) due to PAH exposure and their relations to specific sources. In this study, year-round PM2.5 samples were collected from 2013 to 2014 by high-volume samplers at four sites (one urban, two rural and one roadside station) in Guangzhou in the highly industrialized and densely populated Pearl River Delta (PRD) region and analyzed for 26 polycyclic aromatic hydrocarbons (PAHs) together with molecular tracers including levoglucosan, hopanes and elemental carbon. Higher molecular weight PAHs (5-ring or above) accounted for 64.3–87.5% of total PAHs. Estimated annual averages of benzo(a)pyrene-equivalent carcinogenic potency (BaPeq) were 1.37, 2.31 and 1.56 ng/m3 at urban SZ, rural JL and rural WQS, respectively, much higher than that at the roadside station YJ in an urban street canyon. ICR of PAHs in wintertime reached 2.2 × 10−4, nearly 3 times that in summer; and cancer risk of PAHs was surprisingly higher at the rural site than at other sites. Source contributions by positive matrix factorization (PMF) in the aid of molecular tracers revealed that overall coal combustion and biomass burning altogether contributed 73.8% of total PAHs and 85.2% of BaPeq, and particularly in winter biomass burning became the most significant source of total PAHs and BaPeq (51.8% and 52.5%), followed by coal combustion (32.0% and 39.1%) and vehicle emission (16.2% and 8.4%). The findings of this work suggest that even in China's megacities like Guangzhou, limiting biomass burning may benefit PAHs pollution control and cancer risk reduction.
•Higher BaPeq and PAH-related cancer risk in rural than in urban areas.•Coal combustion and biomass burning contributed most to PAHs and BaPeq.•Vehicle emission only explained ∼15% of ambient PM2.5-bound BaPeq.•Biomass burning contributed most to BaPeq in winter even at urban roadside.
In China diesel vehicles dominate the primary emission of particulate matters from on-road vehicles, and they might also contribute substantially to the formation of secondary organic aerosols (SOA). ...In this study tailpipe exhaust of three typical in-use diesel vehicles under warm idling conditions was introduced directly into an indoor smog chamber with a 30m3 Teflon reactor to characterize primary emissions and SOA formation during photo-oxidation. The emission factors of primary organic aerosol (POA) and black carbon (BC) for the three types of Chinese diesel vehicles ranged 0.18–0.91 and 0.15–0.51gkg-fuel−1, respectively; and the SOA production factors ranged 0.50–1.8gkg-fuel−1 and SOA/POA ratios ranged 0.7–3.7 with an average of 2.2. The fuel-based POA emission factors and SOA production factors from this study for idling diesel vehicle exhaust were 1–3 orders of magnitude higher than those reported in previous studies for idling gasoline vehicle exhaust. The emission factors for total particle numbers were 0.65–4.0×1015particleskg-fuel−1, and particles with diameters less than 50nm dominated in total particle numbers. Traditional C2-C12 precursor non-methane hydrocarbons (NMHCs) could only explain less than 3% of the SOA formed during aging and contribution from other precursors including intermediate volatile organic compounds (IVOC) needs further investigation.
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•Primary and secondary OA of diesel exhaust characterized with a smog chamber.•Much higher primary and secondary OA from diesel vehicles than gasoline ones•Higher diesel vehicle primary emission and secondary production of OA in China•Traditional precursor VOCs explained less than 3% SOA formed during aging.•Particle number emission factors of 0.65–4.0×1015#kg-fuel−1 for diesel vehicles
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•Monte Carlo method is used to investigate properties of nanoparticle agglomerates.•Incorporating interaction energies shows material dependence of fractal dimension.•Agglomerate ...porosity increases with increasing agglomerate mass, reaching a plateau.•The mechanical strength of agglomerates is assessed using three different models.•Crystalline and amorphous structures within agglomerates have been identified.
By accounting for realistic interparticle interaction energy of fine dry nanoparticles, an off-lattice Monte Carlo (MC) simulation approach is used to gain insight into such properties of agglomerates of nanoparticles with primary sizes ranging from 10nm to 100nm. This novel numerical approach allows for assessment of the mechanical properties and morphological features of the agglomerates. An interesting outcome is that the fractal dimension depends on the material properties represented via interaction energy. The agglomerate porosity increases with increasing agglomerate mass and may approach unity. With increasing Hamaker constant and fixed particle size, the agglomerates are characterized by a lower fractal dimension, higher packing porosity, higher mechanical strength, larger agglomeration size, and lower crystalline fraction. For a fixed Hamaker constant, agglomerates of the smaller primary particles exhibit a more compact packing structure, higher mechanical strength, smaller agglomerate size, and higher crystalline fraction. The local structure analysis indicates that for a fixed Hamaker constant, there are more particles in crystalline structure within the agglomerates constituted by the smaller primary particles. Likewise, for a fixed primary particle size, a lower Hamaker constant allows particles to configure into more stable agglomerate structures, thus providing useful insights into agglomerate morphology.
Glyoxal and methylglyoxal, the two smallest yet most abundant dicarbonyls, play vital roles in forming secondary organic aerosols (SOA) in the ambient air. The direct sources for glyoxal and ...methylglyoxal from vehicles are still unclear because of only a few investigations in the USA. Here we carried out tests in the Zhujiang tunnel in urban Guangzhou in south China to obtain emission factors (EFs) of glyoxal and methylglyoxal for on-road vehicles. Measured EFs for glyoxal and methylglyoxal averaged 1.18 ± 0.43 and 0.52 ± 0.26 mg km−1 veh−1, and were about 6.6 and 2.3 times those measured in the Tuscarora Mountain Tunnel in 1999 (Grosjean et al., 2001), respectively. Multiple linear regressions further resolved glyoxal EFs of 1.64 ± 1.03, 0.10 ± 3.49 and 0.58 ± 2.37 mg km−1 and methylglyoxal EFs of 0.17 ± 0.33, 1.68 ± 1.20 and 0.70 ± 0.66 mg km−1, respectively, for gasoline, diesel and liquefied petroleum gas (LPG) vehicles. The fuel-based EFs for glyoxal and methylglyoxal were estimated to be 28.1 and 2.9 mg kg−1 for gasoline vehicles, and 1.5 and 26.3 mg kg−1 for diesel vehicles, respectively. Based on available SOA yields, SOA formed from vehicle-emitted glyoxal and methylglyoxal could attain 25–50% of that formed from vehicle-emitted toluene. With the EFs from this study, the vehicle emission of the two dicarbonyls in China and in the world were roughly estimated. Either the CO-tracer-based or the fuel-based global estimates are below 0.1 Tg a−1 and therefore vehicle emission could be negligible in their global total sources, yet they might play vital roles in urban areas in forming SOA, particularly in the early chemical evolution of vehicle exhausts in the ambient.
•Road vehicle emission factors for glyoxal and methylglyoxal were obtained by tunnel tests.•Vehicle glyoxal and methylglyoxal EFs in China were compared with those in the US.•Mileage-based and fuel-based EFs were resolved by multiple linear regressions.•Vehicle emissions of glyoxal and methylglyoxal in China and in the world were estimated.
Numerous studies have examined the impact of the built environment on mental health, yet there remains an underexplored area concerning how microenvironments within educational buildings affect ...students’ mental well-being from a physical environment standpoint. This paper fills this gap by utilizing data from 440 valid questionnaires to develop regression models that assess students’ perceptions of physical environment factors in college teaching buildings and their impact on anxiety likelihood. This study examined the physical environment of the teaching building’s interior, courtyard, and semi-outdoor areas. Findings indicate that students’ perceptions of specific physical environment factors—such as classroom ventilation (p < 0.01, OR = 0.330), lighting (p < 0.01, OR = 0.444), noise conditions (p < 0.01, OR = 0.415), courtyard thermal comfort (p < 0.01, OR = 0.504), and the views from semi-outdoor areas (p < 0.01, OR = 2.779)—significantly influence the likelihood of experiencing anxiety. Optimal physical conditions are linked to reduced student anxiety. The suitability of the physical environment of teaching buildings is interrelated, and it is urgently necessary to address issues related to unsuitable lighting in window areas of classrooms, as well as problems with ventilation, lighting, and noise caused by the corridor layout within teaching buildings. These insights are crucial for the design and renovation of academic buildings to enhance students’ mental well-being.
A mathematical model based on heat and mass transfer processes in the porous wick of electronic cigarettes was established to describe the atomization of e-liquids according to max liquid ...temperature, vaporization rate and thermal efficiency in a single puff. Dominant capillary-evaporation effects were defined in the model to account for the effects of electrical power, e-liquid composition and porosity of the wick material on atomization and energy transmission processes. Liquid temperature, vaporization rate, and thermal efficiency were predicted using the mathematical model in 64 groups, varying with electrical power, e-liquid composition and wick porosity. Experimental studies were carried out using a scaled-model test bench to validate the model's prediction. A higher PG/VG ratio in the e-liquid promoted energy transfer for vaporization, and the e-liquid temperature was comparatively reduced at a relatively high power, which was helpful to avoid atomizer overheating. Compared with the other factors, wick porosity affected the thermal efficiency more significantly. The vaporization rate increased with a higher wick porosity in a certain range. The modelling results suggested that a greater wick porosity and a higher PG ratio in e-liquids helped to improve the overall thermal efficiency.
Therapeutic angiogenesis via gene delivery is promising for tissue survival and regeneration after injury or ischemia. A stable, safe and efficient gene vector is essential for successful ...angiogenesis. We have demonstrated that our newly developed lipopolysaccharide-amine nanopolymersomes (LNPs) have higher than 95% transfection efficiency when delivering pEGFP into mesenchymal stem cells (MSCs). To explore their clinical potential in therapeutic angiogenesis, in this study, we studied their toxicity, storage stability, protection ability to genes and efficacy to deliver therapeutic genes of pVEGF in MSCs and zebrafish. The results show that LNPs can condense pVEGF to form pVEGF-loaded nanopolymersomes (VNPs), and protect pVEGF against DNase digestion in 6 h. Both LNPs and VNPs have low toxicity to MSCs, erythrocytes and zebrafish embryos. LNPs are stable at 4 °C for at least two years with unchanged size and transfection efficiency. MSCs transfected by VNPs continuously synthesize VEGF for at least four days under control, with a peak (21.25 ng ml(-1)) ∼35-fold greater than that for the untreated group. VNPs induce significant and dose-dependent angiogenesis in zebrafish without causing death, deformity or delay in growth and development, and the induced maximal vessel area of subintestinal vessel plexus is 2.5-fold higher than that for the untreated group. Our study suggests that VNP has high potential in therapeutic angiogenesis.
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