Lyophilized insulin nanoparticles prepared from quaternized N-aryl derivatives of chitosan as a new strategy for oral delivery of insulin: in vitro,ex vivo and in vivo characterizations

Objective: The purpose of this research was the development, in vitro, ex vivo and in vivo characterization of lyophilized insulin nanoparticles prepared from quaternized N-aryl derivatives of chitosan.

Methods: Insulin nanoparticles were prepared from methylated N-(4-N,N-dimethylaminobenzyl), methylated N-(4 pyridinyl) and methylated N-(benzyl). Insulin nanoparticles containing non-modified chitosan and also trimethyl chiotsan (TMC) were also prepared as control. The effects of the freeze-drying process on physico-chemical properties of nanoparticles were investigated. The release of insulin from the nanoparticles was studied in vitro. The mechanism of the release of insulin from different types of nanoparticles was determined using curve fitting. The secondary structure of the insulin released from the nanoparticles was analyzed using circular dichroism and the cell cytotoxicity of nanoparticles on a Caco-2 cell line was determined. Ex vivo studies were performed on excised rat jejunum using Frantz diffusion cells. In vivo studies were performed on diabetic male Wistar rats and blood glucose level and insulin serum concentration were determined.

Results: Optimized nanoparticles with proper physico-chemical properties were obtained. The lyophilization process was found to cause a decrease in zeta potential and an increase in PdI as well as and a decrease in entrapment efficiency (EE%) and loading efficiency (LE%) but conservation in size of nanoparticles. Atomic force microscopy (AFM) images showed non-aggregated, stable and spherical to sub-spherical nanoparticles. The in vitro release study revealed higher release rates for lyophilized compared to non-lyophilized nanoparticles. Cytotoxicity studies on Caco-2 cells revealed no significant cytotoxicity for prepared nanoparticles after 3-h post-incubation but did show the concentration-dependent cytotoxicity after 24?h. The percentage of cumulative insulin determined from ex vivo studies was significantly higher in nanoparticles prepared from quaternized aromatic derivatives of chitosan. In vivo data showed significantly higher insulin intestinal absorption in nanoparticles prepared from methylated N-(4-N, N-dimethylaminobenzyl) chitosan nanoparticles compared to trimethyl chitosan.

Conclusion: These data obtained demonstrated that as the result of optimized physico-chemical properties, drug release rate, cytotoxicity profile, ex vivo permeation enhancement and increased in vivo absorption, nanoparticles prepared from N-aryl derivatives of chitosan can be considered as valuable method for the oral delivery of insulin.     

Design,characterization and ex vivo evaluation of chitosan film integrating of insulin nanoparticles composed of thiolated chitosan derivative for buccal delivery of insulin

The purpose of this study is to optimize and characterize of chitosan buccal film for delivery of insulin nanoparticles that were prepared from thiolated dimethyl ethyl chitosan (DMEC-Cys). Insulin nanoparticles composed of chitosan and dimethyl ethyl chitosan (DMEC) were also prepared as control groups. The release of insulin from nanoparticles was studied in vitro in phosphate buffer solution (PBS) pH 7.4. Optimization of chitosan buccal films has been carried out by central composite design (CCD) response surface methodology. Independent variables were different amounts of chitosan and glycerol as mucoadhesive polymer and plasticizer, respectively. Tensile strength and bioadhesion force were considered as dependent variables. Ex vivo study was performed on excised rabbit buccal mucosa. Optimized insulin nanoparticles were obtained with acceptable physicochemical properties. In vitro release profile of insulin nanoparticles revealed that the highest solubility of nanoparticles in aqueous media is related to DMEC-Cys nanoparticles. CCD showed that optimized buccal film containing 4% chitosan and 10% glycerol has 5.81?kg/mm² tensile strength and 2.47?N bioadhesion forces. Results of ex vivo study demonstrated that permeation of insulin nanoparticles through rabbit buccal mucosa is 17.1, 67.89 and 97.18% for chitosan, DMEC and DMEC-Cys nanoparticles, respectively. Thus, this study suggests that DMEC-Cys can act as a potential enhancer for buccal delivery of insulin.     

Optimization of Short Load Forecasting in Electricity Market of Iran Using Artificial Neural Networks

Accurate short-term load forecasting (STLF) is one of the essential requirements for power systems. In this paper, two different seasonal artificial neural networks (ANNs) are designed and compared in terms of model complexity, robustness, and forecasting accuracy. Furthermore, the performance of ANN partitioning is evaluated. The first model is a daily forecasting model which is used for forecasting hourly load of the next day. The second model is composed of 24 sub-networks which are used for forecasting hourly load of the next day. In fact, the second model is partitioning of the first model. Time, temperature, and historical loads are taken as inputs for ANN models. The neural network models are based on feed-forward back propagation which are trained and tested using data from electricity market of Iran during 2003 to 2005. Results show a good correlation between actual data and ANN outcomes. Moreover, it is shown that the first designed model consisting of single ANN is more appropriate than the second model consisting of 24 distinct ANNs. Finally ANN results are compared to conventional regression models. It is observed that in most cases ANN models are superior to regression models in terms of mean absolute percentage error (MAPE).     

Electro-optic investigation of the surface trapping efficiency in n-alkanethiol SAM passivated GaAs(001)

The electro-optic characteristics of the semi-insulating and n(+)-type GaAs(001) surfaces passivated with n-alkanethiol self-assembled monolayers were investigated using Kelvin probe surface photovoltage (SPV) and photoluminescence (PL) techniques. Referencing the equilibrium surface barrier height established in an earlier report, SPV measurements demonstrated a significant (>100 mV) increase in the non-equilibrium band-bending potential observed under low-level photo-injection. Modeling of the SPV accounts for these observations in terms of a large (>10(4)) decrease in the hole/electron ratio of surface carrier capture cross-sections, which is suggested to result from the electrostatic potential of the interfacial dipole layer formed upon thiol chemisorption. The cross-section effects are verified in the high-injection regime based on carrier transport modeling of the PL enhancement manifested as a reduction of the surface recombination velocity.     

Traffic differentiation support in vehicular delay-tolerant networks

Vehicular Delay-Tolerant Networking (VDTN) is a Delay-Tolerant Network (DTN) based architecture concept for transit networks, where vehicles movement and their bundle relaying service is opportunistically exploited to enable non-real time applications, under environments prone to connectivity disruptions, network partitions and potentially long delays. In VDTNs, network resources may be limited, for instance due to physical constraints of the network nodes. In order to be able to prioritize applications traffic according to its requirements in such constrained scenarios, traffic differentiation mechanisms must be introduced at the VDTN architecture. This work considers a priority classes of service (CoS) model and investigates how different buffer management strategies can be combined with drop and scheduling policies, to provide strict priority based services, or to provide custom allocation of network resources. The efficiency and tradeoffs of these proposals is evaluated through extensive simulation.     

Ductile crack growth and constraint in pipelines subject to combined loadings

An important failure mode of offshore pipelines is ductile fracture of the pipe wall triggered by a hypothetical welding defect. In this study, pipelines having an external part-through semi-circumferential crack of various sizes, subject to combined internal pressure and inelastic bending are considered. This is done to assess the response of pipelines during both their installation and operational conditions. Detailed 3D nonlinear finite element (FE) models of pipelines are developed. A row of elements ahead of the initial crack front are modeled using a voided plasticity material model, which enables simulation of crack growth and the subsequent fracture failure mode (denoted by the critical curvature, κ_crit). After discussing the typical response characteristics of such pipelines, the FE model is used to parametrically investigate the influence of varying pipe and crack dimensions, and also the internal pressure levels, on κ_crit. In the second part of this paper, the crack tip constraint ahead of a growing crack in such pipes is evaluated and systematically compared to the crack tip constraint of both the traditionally used deeply cracked Single Edge Notch Bend (SENB) specimens and the constraint-matched Single Edge Notch Tensile (SENT) specimens. This is achieved by comparing the crack resistance curves (R-curves) along with stress triaxiality and equivalent plastic strain fields evaluated ahead of a growing crack of the three systems. The results present grounds for justification of usage of SENT specimens in fracture assessment of such pipes as an alternative to the traditional overly conservative SENB specimens.     

Removal of cyanide in aqueous solution by oxidation with hydrogen peroxide in presence of copper-impregnated activated carbon

This work is devoted to the removal of free cyanide from aqueous solution by oxidation with hydrogen peroxide H₂O₂ catalyzed by copper-impregnated activated carbon. Effects of initial molar ratio [H₂O₂]₀/[CN⁻]₀, copper-impregnated activated carbon amount, pH and the temperature on cyanide removal have been investigated.The presence of copper-impregnated activated carbon has increased the reaction rate showing thus a catalytic activity. The rate of cyanides removal increases with the raise of the initial molar ratio [H₂O₂]₀/[CN⁻]0 and decreases with the increase in the pH from 8 to 12. The increase in the copper-impregnated activated carbon amount from 1.5 to 10 g/L in reaction solution has a beneficial effect. Beyond this value, the impact of activated carbon amount is not anymore significant. The temperature does not have a significant effect between 20 and 35 °C. The four successive times re-use of catalyst shows a good stability. The kinetics of cyanide removal has been found to be of pseudo-second-order with respect to cyanide and the rate constants have been determined. This process seems very interesting because the rate of cyanides removal is very fast, the reaction does not use soluble metal catalyst and it consumes only hydrogen peroxide as chemical product.     

On the grain boundary internal friction peak of α-brasses

A conventional Ke pendulum was used to investigate the temperature dependence of internal friction for thoroughly annealed samples of Cu-30% Zn. The relaxation peak observed at 330° C at a frequency of vibration 0.60 Hz was attributed to grain boundary diffusion. The energy activating the process amounted to 1.84 eV and characterized the activation energy for self diffusion in copper. The relaxation strength showed strain amplitude dependence, however, the activation energy and peak temperature did not show any amplitude dependence. The effect of solute atom concentration, cold work and vacancies was also tested.     

Fair and Reasonable Markup (FaRM) Pricing Model

The Fair and Reasonable Markup (FaRM) is the smallest markup that satisfies the Required Rate of Return (RRR) of the contractor for the particular (or at least the general risk‐class of) project at hand. The model is based on reasonable and easily‐accessible information, and will result in a Minimum Acceptable Price (MAP). The firm cannot accept the project at a price below this MAP without diminishing the “equityholders' wealth.” A modified version of the FaRM Pricing Model for certain contracts under which home‐office overhead expenses must be recovered through FaRM is also presented. Once the FaRM Pricing Model has been implemented, contractors can make more intelligent pricing decisions. Instead of using a subjective markup, which may ignore the cash‐flow differences of various jobs, contractors using FaRM Pricing Model can bid lower on projects which are more attractive and become more competitive while satisfying their RRR. This should result in lower costs to owners. Conversely, by bidding higher on the less‐attractive jobs, contractors will still maintain their RRR should they obtain the contract.     

Large-scale simulations of crack–void and void–void plasticity in metallic fcc crystals under high strain rates

We have simulated the failure of three-dimensional fcc solids containing voids under mode one tension using molecular dynamics, simple interatomic potentials and a system comprising 15 million atoms. When a linear brittle crack front approaches a void, the void acts to impede the progress of the front by causing dislocation emission, thereby rendering the system ductile. When two voids are alone in the system, failure is via ductility with, first, dislocation loops being emitted from the void surfaces and, then, these loops interacting with one another to form.