Biological artificial fluid-induced non-lamellar phases in glyceryl monooleate: the kinetics pathway and its digestive process by bile salts

Background: The cubic (Q_II) phase is a promising sustained-release system. However, its rigid gel-like propensity is highly viscous, which makes it difficult to handle in pharmaceutical applications. To circumvent this problem, a less viscous lamellar (L_α) phase that could spontaneously transform to Q_II phase by the introduction of water or biological artificial fluid can be used. However, the kinetics pathway of phase transition, susceptibility to digestive processes and impact of the transition on drug release are not yet well understood.

Method: We investigated various biological artificial fluid-induced L_α to inverse Q_II phase transition over time in glyceryl monooleate (GMO) by water penetration scan and light polarizing microscopy. To reveal the structure stability, fluorescence spectroscopy studies were conducted using pyrene as a probe. Furthermore, the release mechanism of pyrene as a lipophilic drug model in the spontaneously formed Q_II was investigated.

Result: Although hexagonal (H_II) mesophases occurred when phosphate buffered saline (PBS) 7.4, 0.1?M HCl or sodium taurocholate (NaTC) solutions were introduced to GMO at room temperature, they disappear with the exception of 0.1?M HCl at 37?°C. Compared with 25?°C, L_α to Q_II phase transition was in a faster rate as almost completely transforms were observed after 2?h post-immersion. The spontaneously formed mesophases were stable over 24?h immersions in PBS or pancreatic lipase solutions as proven by the extremely low fluorescence signal, however they were digestible by bile salts. This result indicated that digestion by bile salts was the major pathway instead of digestion by lipases. Moreover, pyrene fluorescence spectroscopy confirmed that the digestion by bile salts induced the formation of GMO–bile salt mixed micelles whose performance depended on the bile salt concentrations. This dependence influenced the drug release from the spontaneously formed Q_II phase.

Conclusion: All the results concluded that temperature, pH and ionic strength tendencies for the formation of non-lamellar structures greatly influenced the self-assembly process, thereby affecting the final mesophase structure. The results of this study are important to understand the lamellar to non-lamellar lipid-phase transitions and their possible pharmaceutical applications.     

离子注入射程分布的计算机模拟系统

介绍了自主开发的基于输运理论和蒙特卡罗方法的计算离子注入射程分布的软件集成系统JTU -PRII(JiaotongUniversity -ProjectRangeIonImplantation) ,该系统整体上具有通用性、高效性和实用性 .通用性即 :该系统具有注入离子参数库和注入零件材料库的生成和调用功能 ,能计算各种注入条件下 ,包括各种注入离子 ,各种成分和形状的靶材 ,不同注入能量、注入剂量和注入角度时注入离子在靶材中的分布 ;高效性即 :由于在关键步骤中用数值拟合公式代替了数值迭代求解 ,用固定飞行路程代替随机路程 ,使计算效率大大提高 ,计算速度大大加快 ;实用性即 :由于考虑了溅射效应和靶材成分在注入过程中的动态变化 ,加之蒙特卡罗方法的固有特性 ,使计算的前提假设更接近实际 ,计算结果更加准确 .与其它著名的同类软件 ,如TRIM和SASAMAL相比 ,该软件系统界面美观 ,操作便捷 ,能动态显示中间计算结果和注入过程曲线的变化 ,可调用、计算、比较、注释、拷贝和打印各条成分分布曲线 ,计算结果与实验结果吻合得也很好 .     

Effect of Different Bile Salts on the Relative Hypoglycemia of Witepsol W35 Suppositories Containing Insulin in Diabetic Beagle Dogs

Insulin suppositories were formulated using Witepsol W35 as a base to investigate the effect of various bile salts/acids on the plasma glucose concentration of diabetic beagle dogs. Comparison of the effect of these formulations was made with that produced by insulin subcutaneous injections. Of the bile salts/acids studied, incorporation of 100 mg of deoxycholic acid (DCA), sodium cholate (NaC), or sodium deoxycholate (NaDC) with insulin (10 U/Kg) showed that suppositories containing NaDC produced the highest area under the curve (AUC) and relative hypoglycemia (RH) of 290 ± 83 mg%h and 28% ± 8.1%, respectively. To study the optimum amount of NaDC in insulin suppositories to produce the highest RH, 50-200 mg/suppository were used, and we found that 150 mg NaDC produced 35% ± 13% RH. We also studied the influence of different doses of insulin (5-20 U/kg) in the presence of NaDC (100 mg). It was found that increase of the insulin dose was accompanied by an increase in AUC and maximum reduction in plasma glucose level C_max. A combination of NaDC (100 mg) and NaC (50 mg) produced an AUC of 252 ± 13 mg% h and an RH of 49% ± 2.6%, which were higher than produced by either of its individual components (NaC 50 mg or NaDC 100 mg) when used alone or when compared with an equivalent amount of NaDC (150 mg). When the effect of sodium taurocholate (NaTC) and sodium taurodeoxycholate (NaTDC) was studied, it was found that an insulin suppository containing 100 mg of either NaTC or NaTDC produced an RH equivalent to that produced previously with a mixture of NaDC (100 mg) and NaC (50 mg). On the other hand, NaC (50 mg) did not improve the hypoglycemic effect of NaTC any further. In conclusion, a relative hypoglycemia of about 50% can be reached using insulin suppositories containing Witepsol W35 as a base and NaDC plus NaC (100 mg plus 50 mg, respectively), NaTDC (100 mg), or NaTC (100 mg) as rectal absorption enhancers of insulin. A desirable hypoglycemia, expressed as C_max, and/or AUC can be reached by adjusting the insulin dose in the formulation according to the degree of hyperglycemia.     

Development and in vitro/in vivo evaluation of HPMC/chitosan gel containing simvastatin loaded self-assembled nanomicelles as a potent wound healing agent

The aim of this study was to develop hydroxypropyl methyl cellulose (HPMC)/chitosan gel containing polymeric micelles loaded with simvastatin (Sim) and evaluates its wound healing properties in rats. An irregular full factorial design was employed to evaluate the effects of various formulation variables including polymer/drug ratio, hydration temperature, hydration time, and organic solvent type on the physicochemical characteristics of pluronic F127-cholesterol nanomicelles prepared using the film hydration method. Among single studied factors, solvent type had the most impact on the amount of drug loading and zeta potential. Particle size and release efficiency was more affected by hydration temperature. The optimized formulation suggested by desirability of 93.5% was prepared using 1?mg of Sim, 10?mg of copolymer, dichloromethane as the organic solvent, hydration time of 45?min and hydration temperature of 25?°C. The release of the drug from nanomicelles was found to be biphasic and showed a rapid release in the first stage followed by a sustained release for 96?h. The gel-contained nanomicelles exhibited pseudo-plastic flow and more sustained drug release profile compared to nanomicelles. In excision wound model on normal rats, the wound closure of the group treated by Sim loaded micelles-gel was superior to other groups. Taken together, Sim loaded micelles-gel may represent a novel topical formulation for wound healing.     

The influence of the electron energy distribution on the low pressure chlorine discharge

A global (volume averaged) model of a chlorine discharge is applied to explore the effect of the electron energy distribution on the plasma parameters such as particle densities and reaction rates. The effective electron temperature increases, the densities of charged particles decrease and the total reaction rate for the creation of Cl⁻ decreases as the electron energy distribution function is varied from approximately bi-Maxwellian to Maxwellian to Druyvesteyn distribution, while the applied power is kept fixed. The relative contribution of electron impact dissociation to the creation of the neutral Cl atom increases significantly as the electron energy distribution is varied from approximately bi-Maxwellian to Maxwellian to Druyvesteyn distribution, while the loss processes for Cl are nearly independent of the electron energy distribution.     

Application of mixture experimental design to simvastatin apparent solubility predictions in the microemulsifion formed by self-microemulsifying

Self-microemulsifying drug delivery systems (SMEDDS) are useful to improve the bioavailability of poorly water-soluble drugs by increasing their apparent solubility through solubilization. However, very few studies, to date, have systematically examined the level of drug apparent solubility in o/w microemulsion formed by self-microemulsifying. In this study, a mixture experimental design was used to simulate the influence of the compositions on simvastatin apparent solubility quantitatively through an empirical model. The reduced cubic polynomial equation successfully modeled the evolution of simvastatin apparent solubility. The results were presented using an analysis of response surface showing a scale of possible simvastatin apparent solubility between 0.0024 ∼ 29.0 mg/mL. Moreover, this technique showed that simvastatin apparent solubility was mainly influenced by microemulsion concentration and, suggested that the drug would precipitate in the gastrointestinal tract due to dilution by gastrointestinal fluids. Furthermore, the model would help us design the formulation to maximize the drug apparent solubility and avoid precipitation of the drug.     

硅橡胶膜中的溶胀行为及分配系数

采用自制的硅橡胶(PDMS)膜，研究了两组分混合溶剂在硅橡胶膜中的溶胀行为及分配系数．比较了溶胀率的实验值和理论值，考查了溶胀液平衡浓度与硅橡胶膜的溶胀率和分配系数的关系，以及溶胀液平衡温度与分配系数的关系．     

The influence of variable operating conditions upon the general multi-modal Weibull distribution

For the design spectrum prediction that should be realized within the expected service life, the influence of variable loading conditions is of paramount importance. Further, the results of the measurements must be properly extrapolated and the scatter of loading spectra has to be determined to assure reliable service life prediction. To model load ranges, a general multi-modal Weibull distribution function has recently been proposed. Until now it has been verified only for fixed operating conditions. The scope of this article is to prove that the same distribution model holds for the case of variable operating conditions, too. The influence of variable operating conditions upon the distribution function is demonstrated by a few examples attained by analysing loads acting upon a structure of a fork-lift.     

Effect of particle size distribution on hydrodynamics of pneumatic conveying system based on CPFD simulation

The effect of particle size distribution on the hydrodynamics of dilute-phase pneumatic conveying system was analyzed using computational particle fluid dynamics (CPFD) simulation. The influence of a simulation parameter, i.e., correction factor of drag coefficient (k), on the hydrodynamics of pneumatic conveying system was determined via CPFD simulation. When results of simulation were compared with experimental data of previous studies, the average error of pressure drop per length predicted by the CPFD approach with the correction factor was below 4.4%. Saltation velocity and the pressure drop per unit length declined as the drag force coefficient increased. Simulation results also revealed that the pressure drop per length and the saltation velocity were decreased when the fine powder fraction in the particle size distribution was increased, although the width of particle size distribution was widened, and the standard deviation was increased. Finally, the Relative Standard Deviation (RSD) of pressure drop per length was measured and compared with median diameter (d₅₀), Sauter mean diameter, geometric mean diameter, and arithmetic mean diameter. The RSD of the Sauter mean diameter was 5.8%, approximately twice less than the RSD value of d₅₀ commonly used in pneumatic conveying.     

The influence of deuterium exposures on subsequent outgassing rate of an UHV system

The accuracy of results in experiments where a well-processed UHV system is exposed to hydrogen depends on the hydrogen absorption rate and kinetics of subsequent spontaneous release from the system itself. In experiments to date, the sensitivity required to detect very low rates has been achieved only when tritium has been used as a tracer gas. Unfortunately, tritiated water from the surface prevails among released gas species which is not expected for well-outgassed surfaces. In the present studies, UHV system behaviour at 303 K during three deuterium exposures of duration 92 and 72 h at an initial pressure of 1 mbar was explored. The rate of decrease of pressure was constant during the whole of these periods as monitored by non-ionizing vacuum gauges. It corresponded to an effective sticking probability of the order of 1×10^-12 and resulted in absorption of 5×10¹⁴ D atoms/cm². The release kinetics were observed for several days starting immediately after deuterium had been pumped from the system. Initially, the deuterium release rate exceeded the background hydrogen outgassing by more than three orders of magnitude. These results demonstrate that extremely high sensitivity for deuterium absorption and release can be achieved with a precise pressure measuring technique otherwise attributed exclusively to tritium scintillation methods.     

纤维分布均匀性对T300/BMP316复合材料层压板力学性能的影响

采用三点弯曲法和数字化冲击仪, 研究了纤维分布均匀性对T300/BMP316复合材料弯曲和冲击性能的影响, 用有限元方法分析了纤维分布不均匀复合材料弯曲变形时的应力分布, 提出了用纤维分布效应系数R来评价纤维分布不匀复合材料的性能。结果表明, 纤维分布不均使T300/BMP316复合材料的弯曲性能和冲击性能强烈地受到纤维分布方式和载荷方向的影响, 纤维分布效应系数R反映了纤维分布与性能的关系。      

Preparation of emulsifying wax/glyceryl monooleate nanoparticles and evaluation as a delivery system for repurposing simvastatin in bone regeneration

Simvastatin (Sim) is a widely known drug in the treatment of hyperlipidemia, which has attracted so much attention in bone regeneration due to its potential osteoanabolic effect. However, repurposing of Sim in bone regeneration will require suitable delivery systems that can negate undesirable off-target/side effects. In this study, we have investigated a new lipid nanoparticle (NP) platform that was fabricated using a binary blend of emulsifying wax (Ewax) and glyceryl monooleate (GMO). Using the binary matrix materials, NPs loaded with Sim (0–500?µg/mL) were prepared and showed an average particle size of about 150?nm. NP size stability was dependent on Sim concentration loaded in NPs. The suitability of NPs prepared with the binary matrix materials in Sim delivery for potential application in bone regeneration was supported by biocompatibility in pre-osteoclastic and pre-osteoblastic cells. Additional data demonstrated that biofunctional Sim was released from NPs that facilitated differentiation of osteoblasts (cells that form bones) while inhibiting differentiation of osteoclasts (cells that resorb bones). The overall work demonstrated the preparation of NPs from Ewax/GMO blends and characterization to ascertain potential suitability in Sim delivery for bone regeneration. Additional studies on osteoblast and osteoclast functions are warranted to fully evaluate the efficacy of Sim-loaded Ewax/GMO NPs using in-vitro and in-vivo approaches.     

生长工艺对生长室内温度分布影响的数值模拟

为给实验研究晶体生长工艺提供必要的理论指导,以氢气和氧气的燃烧为基础,研究了焰熔法生长金红石单晶体过程中生长室内的温度分布特征,分析了H_2和O_2流量、喷嘴尺寸对温度分布的影响.研究表明:适合金红石单晶体生长的最佳燃烧器为内O_2、中H_2和外O_2的三管结构;随着H_2流量增加,生长室轴心线上和径向温度逐渐增大,H_2流量增加2 L/min,中心最高温度平均升高160℃,位置向下移动约2.5 mm;随着内、外O_2流量增加,生长室轴心线上和径向温度逐渐降低,与内O_2的影响相比,外O_2对中心温度影响较小,而对径向温度的影响较大;随着内O_2喷嘴孔径的增加,生长室轴心线上最高温度逐渐增大,而位置逐渐向喷嘴方向移动,而外O_2和H_2喷嘴孔径对轴心线上最高温度的影响非常小.     

送风速度对室内气流分布影响的数值模拟

以某一典型的空调房间为研究目标,利用计算流体动力学（CFD）,研究在低温送风条件下,室内气流组织的分布状况。通过建立合理的数学模型进行数值模拟,运用试验手段验证了模拟结果的可靠性,得到几种送风速度下的室内气流速度场与温度场的计算结果,经过分析,确定该空调室的送风速度范围为（0．2—3）m／s,最佳值为2m／s。     

In vitro/in silico approach in the development of simvastatin-loaded self-microemulsifying drug delivery systems

Objective: The aims of this study were to formulate simvastatin (SV)-loaded self-microemulsifying drug delivery systems (SMEDDS), and explore the potential of these drug delivery systems to improve SV solubility, and also to identify the optimal place in the gastrointestinal (GI) tract for the release of SV using coupled in vitro/in silico approach.

Significance: In comparison to other published results, this study considered the extensive pre-systemic clearance of SV, which could significantly decrease its systemic and hepatic bioavailability if SV is delivered into the small intestine.

Methods: SV-loaded SMEDDS were formulated using various proportions of oils (PEG 300 oleic glycerides, propylene glycol monocaprylate, propylene glycol monolaurate), surfactant (PEG 400 caprylic/capric glycerides) and cosurfactant (polysorbate 80) and subjected to characterization, and physiologically-based pharmacokinetic (PBPK) modeling.

Results: According to the in vitro results, the selected SMEDDS consisted of 10.0% PEG 300 oleic glycerides, 67.5% PEG 400 caprylic/capric glycerides, and 22.5% polysorbate 80. The use of acid-resistant capsules filled with SV-loaded SMEDDS was found helpful in protecting the drug against early degradation in proximal parts of the GI tract, however, in silico simulations indicated that pH-controlled drug release system that dissolve in the distal parts of the intestine might further improve SV bioavailability (up to 7.20%).

Conclusion: The obtained results suggested that combined strategy for the improvement of SV bioavailability should comprise solubility enhancement and delayed drug release. The developed SV-specific PBPK model could potentially be used to assess the influence of formulation factors on drug absorption and disposition when developing SV oral dosage forms.     

概括分布的数学特征

重点讨论概括分布的数学特征——导出了概括分布的数学期望、方差、偏度、峰度及其概率 ,得到了概括分布的数学特征与分布参数的关系 ,以说明概括分布密度函数的形状特点     

The influence of methane/argon plasma composition on the formation of the hydrogenated amorphous carbon films

The quality of the a-C:H films was particularly correlated with the mixed ratio of methane/argon plasma. For a constant supply of energy and flowing rate, the optical emission from H_α intensity linearly increased with the addition of methane in argon plasma, while that from intensities of radiation of diatmoic radicals (CH^?and C₂^?) exponentially decreased. For the a-C:H films, the added methane in argon plasma tended to raise the quantity of hydrogenated carbon or sp³ C-H structure, which exponentially decreased the nano-hardness and friction coefficient of the films. In contrast, the electric resistance of the films enlarged dramatically with the increase of the methane content in argon plasma. It is therefore advantageous to balance the mechanical properties and electrical resistance of the a-C:H film by adjusting plasma composition in the course of the film-growing process.     

纳米TiO2对不同材料超滤膜结构与性能的影响

选用聚醚酮(PEK)、聚醚砜(PES)、酚酞聚醚砜(PES-C)3种不同的高分子材料,用浸没沉淀相转化法制备了一系列不同纳米TiO2含量的纳米TiO2复合膜,并通过扫描电子显微镜(SEM),X射线能谱仪(EDS),水接触角测试及超滤实验考察了纳米TiO2对膜的结构及性能的影响.结果表明,纳米TiO2与高分子超滤膜的复合显著改善了膜的亲水性.在截留率较高且基本保持不变的情况下,3种超滤膜的纯水通量和BSA溶液通量都得到了不同程度的提高.而由EDS分析可知,经过一定的时间,膜表面的TiO2会部分脱落,TiO2粒子与膜表面结合的稳定性问题不容忽视.在选用的3种材料中,TiO2粒子与PES-C膜表面结合较为牢固,且复合后BSA溶液通量的增幅最大,通量衰减较小,具有更好的膜结构和性能.     

Mapping the barriers of AI implementations in the public distribution system: The Indian experience

With increasing digitization, private organizations have started adopting modern technology to improve the effectiveness and transparency of their system. In countries like India, where most public services are under government control, technology adoption is nascent due to various obstacles. The study considered artificial intelligence (AI) the most popular technology and identified 18 critical adoption barriers in India's public distribution systems (PDS). The study is further extended to find the contextual relationship among barriers using interpretative structural modeling (ISM) and prioritize them using the analytical network process (ANP) method. The study identifies lack of trust in technology, lack of AI literacy, and political issues as significant barriers to AI adoption in PDS. The hybrid methodology used in this study proposed five different strategies for effective and smooth implementation of AI in PDS, which would help the policymaker plan the same.