Process and formulation variables of pregabalin microspheres prepared by w/o/o double emulsion solvent diffusion method and their clinical application by animal modeling studies

Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. In conventional therapy recommended dose for pregabalin is 75?mg twice daily or 50?mg three times a day, with maximum dosage of 600?mg/d. To achieve maximum therapeutic effect with a low risk of adverse effects and to reduce often drug dosing, modified release preparations; such as microspheres might be helpful. However, most of the microencapsulation techniques have been used for lipophilic drugs, since hydrophilic drugs like pregabalin, showed low-loading efficiency and rapid dissolution of compounds into the aqueous continous phase. The purpose of this study was to improve loading efficiency of a water-soluble drug and modulate release profiles, and to test the efficiency of the prepared microspheres with the help of animal modeling studies. Pregabalin is a water soluble drug, and it was encapsulated within anionic acrylic resin (Eudragit S 100) microspheres by water in oil in oil (w/o/o) double emulsion solvent diffusion method. Dichloromethane and corn oil were chosen primary and secondary oil phases, respectively. The presence of internal water phase was necessary to form stable emulsion droplets and it accelerated the hardening of microspheres. Tween 80 and Span 80 were used as surfactants to stabilize the water and corn oil phases, respectively. The optimum concentration of Tween 80 was 0.25% (v/v) and Span 80 was 0.02% (v/v). The volume of the continous phase was affected the size of the microspheres. As the volume of the continous phase increased, the size of microspheres decreased. All microsphere formulations were evaluated with the help of in vitro characterization parameters. Microsphere formulations (P1–P5) exhibited entrapment efficiency ranged between 57.00?±?0.72 and 69.70?±?0.49%; yield ranged between 80.95?±?1.21 and 93.05?±?1.42%; and mean particle size were between 136.09?±?2.57 and 279.09?±?1.97?µm. Pregabalin microspheres having better results among all formulations (Table 3) were chosen for further studies such as differential scanning calorimetry, Fourier transform infrared analysis and dissolution studies. In the last step, the best pregabalin microsphere formulation (P3) was chosen for in vivo animal studies. The pregabalin-loaded microspheres (P3) and conventional pregabalin capsules were applied orally in rats for three days, resulted in clinical improvement of cold allodynia, an indicator of peripheral neuropathy. This result when evaluated together with the serum pregabalin levels and in vitro release studies suggests that the pregabalin microspheres prepared with w/o/o double emulsion solvent diffusion method can be an alternative form for neuropathic pain therapy. Conclusively, a drug delivery system successfully developed that showed modified release up to 10?h and could be potentially useful to overcome the frequent dosing problems associated with pregabalin conventional dosage form.     

Highly sensitive tin oxide hollow microspheres and nanosheets to ethanol gas prepared by hydrothermal method

In this study, we synthesized tetragonal-phase SnO2 with a variety of well-crystallized morphologies as solid microspheres, hollow microspheres and mixture of hollow microspheres and nanosheets via the hydrothermal method. The synthesized samples were characterized with XRD, SEM, and BET. SnO2 hollow microsphere structures have been hydrothermally synthesized by using urea and SnCl2 as raw materials. With the addition of cetyltrimethylammonium bromide (CTAB), nanostructures with morphologies of hollow microspheres and nanosheets were obtained. Also, when CTAB was added in the reaction solution without urea, SnO2 microsphere with a solid interior composed of nanoparticles were obtained. A possible formation mechanism of these samples was briefly discussed. The gas sensing properties of sensors based on these samples were investigated. The result revealed that sample with morphology of hollow microsphere and nanosheet calcined at 600 degrees C showed the highest sensitivity to ethanol due to the special morphology and absence of SnO phase.     

Preparation and characterisation of nanoparticles containing ketoprofen and acrylic polymers prepared by emulsion solvent evaporation method

We have prepared polymeric drug nanoparticles by oil in water (O/W) emulsion solvent evaporation method. We used acetone as solvent for polymer and water as non-solvent. The purpose of this study is to use the emulsion solvent evaporation method in order to prepare nanoparticles and to investigate the effects of the various processing parameters to the characteristics of the nanoparticles. In this research, we use two different forms of acrylic polymers, Eudragit E100 and Eudragit RS. It was found that the size of the nanoparticles depends on different parameters such as the polymer concentration in the organic solvent, surfactant concentration and the volume ratio of oil and water phases. The morphology structure is investigated by transmission electron microscope (TEM). TEM images confirmed that the nanoparticles produced were spherical in shape and the successfully prepared nanoparticles with size 80?nm. The size distribution is measured by laser dynamic light scattering. The size distribution of the nanoparticles was found in the range from 50 to 150?nm. Investigation of Fourier transform infrared spectroscopy indicated the absence of the interactions between the drug and polymer. X-ray diffraction patterns of nanoparticles containing ketoprofen, Eudragit E100 and Eudragit RS showed the amorphous structure.     

正交试验优化脉冲磁场-电沉积Ni-TiN复合镀层工艺研究

为改善钻井泥浆泵活塞的耐磨性能,采用脉冲磁场-电沉积方法在40Cr试件表面制备Ni-TiN复合镀层。利用磨损试验机、电子分析天平、扫描电镜、正交试验法研究并优化Ni-TiN复合镀层的制备工艺参数。结果表明,当磁场强度为0.5T时,Ni-TiN复合镀层的磨损量到达最小值0.72 mg,当阴极电流密度和占空比分别为2.2A/dm2和50%时,Ni-TiN复合镀层的磨损量达到最小值6.4 mg。脉冲磁场-电沉积Ni-TiN复合镀层的最佳工艺参数为磁场强度0.5T,电流密度2.2A/dm2,占空比40%。     

Effect of cerium addition on phase transformation and microstructure of cordierite ceramics prepared by sol-gel method

Low-temperature sintering of cordierite ceramic depends on the phase transformation into cordierite and the properties depend on its microstructure. In the present work, the effect of cerium on the phase transformation and microstructure of cordierite ceramics prepared by sol-gel method is studied by X-ray diffraction (XRD), differential thermal analysis (DTA) and scanning electron microscopy (SEM) in order to lower the sintering temperature and improve the properties of cordierite ceramic with the addition of cerium. It is observed that the cerium addition obviously lowers the crystallization temperature of -cordierite while slightly raises that of -cordierite. The lowest temperature for cordierite transformation, which approaches the crystallization temperature of -cordierite, is achieved in the sample containing 4 wt% of cerium, implying a possibility to lower the sintering temperature of cordierite ceramics. The Ce-contained ceramics show a biphasic microstructure that is dependent on sintering temperature. Sintered below 1300°C, a cordierite-CeO₂ microstructure is present; while sintered at the temperature above 1300°C, appears a cordierite-glass microstructure, of which the amount of glass phase is limited to a small extent. Since the addition of 4 wt% cerium to this MgO-Al₂O₃-SiO₂ system substantially enhances the densification of cordierite ceramics and lowers the sintering temperature to the level of around 1000°C, it makes the ceramics suitable for such applications, where the low-temperature sintering is required, as the substrates for electronic circuit and the catalytic supports (with oxygen storage capacity) for cleaning of automotive exhaust emissions.     

乳化交联法制备壳聚糖微球粘连原因分析

乳化交联法是制备壳聚糖微球常用的工艺，但在制备过程中，常出现微球产物粘连的现象。分析了搅拌速度、油水体积比、表面活性剂添加量和交联剂用量等影响微球粘连的因素，优化出了分散性好，粒度均匀的壳聚糖微球制备工艺参数。结果表明，搅拌速度〉350r／min，油水体积比〉2．5，表面活性剂span80用量为水相的20％时，可获得分散性好的壳聚糖微球，微球的粒径可以控制在1～5μm之间。     

Evaluation and characterization of nanostructure hydroxyapatite powder prepared by simple sol-gel method

Many attempts have been focused on preparing of synthetic hydroxyapatite (HA), which closely resembles bone apatite and exhibits excellent osteoconductivity. Low temperature formation and fusion of the apatite crystals have been the main contributions of the sol-gel process in comparison with conventional methods for HA powder synthesis. This paper describes the synthesis of nano-HA particles via a sol-gel method. Nanocrystalline powder of hydroxyapatite (HA) was prepared using Ca(NO₃)₂·4H₂O and P₂O₅ by a simple sol-gel approach. X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used for characterization and evaluation of the phase composition, morphology and particle size of products. The presence of amorphous and crystalline phases in the as-dried gel precursor was confirmed by the evaluating technique. Single phase of HA was also identified in the heat treated powder by XRD patterns. SEM and TEM evaluations showed that the obtained powder after heat treatment at 600 °C was agglomerated and composed of nanocrystalline (25-28 nm) HA particles. Increasing the sintering temperature and time could cause decomposition of HA into β-tricalcium phosphate and calcium oxide. The prepared nanocrystalline HA is able to improve the contact reaction and the stability at the artificial/natural bone interface for medical applications.     

Evaluation of rapidly disintegrating tablets prepared by a direct compression method

To make rapidly disintegrating tablets with sufficient mechanical integrity as well as a pleasant taste, microcrystalline cellulose (MCC), Tablettose (TT), and cross-linked sodium carboxymethyl cellulose (Ac-di-sol) or erythritol (ET) were formulated. Tablets were made by a direct compression method [1]. Tablet properties such as porosity, tensile strength, and disintegration time were determined. The tensile strength and disintegration time were selected as response variables, tablet porosity and parameters representing the characteristics of formulation were selected as controlling factors, and their relation was determined by the polynomial regression method. Response surface plots and contour plots of tablet tensile strength and disintegration time were also constructed. The optimum combination of tablet porosity and formulation was obtained by superimposing the contour diagrams of tablet tensile strength and disintegration time. Rapidly disintegrating tablets with durable structure and desirable taste could be prepared within the obtained optimum region.     

Investigation for the amorphous state of ER-34122, a dual 5-lipoxygenase/cyclooxygenase inhibitor with poor aqueous solubility,in HPMC solid dispersion prepared by the solvent evaporation method

ER-34122, a poorly water-soluble dual 5-lipoxygenase/cyclooxygenase inhibitor, exists as a crystalline form. According to an Oak Ridge thermal ellipsoid plot drawing, carbonyl oxygen O (5) makes an intermolecular hydrogen bond with the hydrogen bonded to N (3) in the crystal structure. The FTIR and the solid-state ¹³C NMR spectra suggest that the network is spread out in the amorphous state and the hydrogen bonding gets weaker than that in the crystalline phase, because the carbonyl signals significantly shift in both spectra. When amorphous ER-34122 was heated, crystallization occurred at around 140°C. Similar crystallization happened in the solid dispersion; however, the degree of crystallization was much lower than that observed in the pure amorphous material. Also, the DSC thermogram of the solid dispersion did not show any exothermic peaks implying crystallization. The heat of fusion (ΔH_f) determined in the pure amorphous material was nearly equal to that for the crystalline form, whereas the ΔH_f value obtained in the solid dispersion was less than a third of them. These data prove that crystallization of the amorphous form is dramatically restrained in the solid dispersion system. The carbonyl wavenumber shifts in the FTIR spectra indicate that the average hydrogen bond in the solid dispersion is lower than that in the pure amorphous material. Therefore, HPMC will suppress formation of the intermolecular network observed in ER-34122 crystal and preserve the amorphous state, which is thermodynamically less stable, in the solid dispersed system.     

An engineering method for complex structural optimization involving both size and topology design variables

This work presents an engineering method for optimizing structures made of bars, beams, plates, or a combination of those components. Corresponding problems involve both continuous (size) and discrete (topology) variables. Using a branched multipoint approximate function, which involves such mixed variables, a series of sequential approximate problems are constructed to make the primal problem explicit. To solve the approximate problems, genetic algorithm (GA) is utilized to optimize discrete variables, and when calculating individual fitness values in GA, a second-level approximate problem only involving retained continuous variables is built to optimize continuous variables. The solution to the second-level approximate problem can be easily obtained with dual methods. Structural analyses are only needed before improving the branched approximate functions in the iteration cycles. The method aims at optimal design of discrete structures consisting of bars, beams, plates, or other components. Numerical examples are given to illustrate its effectiveness, including frame topology optimization, layout optimization of stiffeners modeled with beams or shells, concurrent layout optimization of beam and shell components, and an application in a microsatellite structure. Optimization results show that the number of structural analyses is dramatically decreased when compared with pure GA while even comparable to pure sizing optimization.     

The effect of Si addition on the microstructure and magnetic properties of Permalloy prepared by mechanical alloying method

In this paper, we report the preparation of nanostructured (Ni₅₀Fe₅₀)_100?xSi_x and (Ni₈₀Fe₂₀)_100?xSi_x powders prepared by the mechanical alloying method. Elemental maps using scanning electron microscopy as well as X-ray diffraction results showed that iron and silicon dissolved in the nickel lattice homogeneously and formed a face-centered cubic γ-(Ni (Fe–Si)) uniform solid solution after milling for 24 h. By increasing Si content up to 20 at.%, estimated crystallite sizes for Ni₅₀Fe₅₀ and Ni₈₀Fe₂₀ alloys were reduced from ～35 and 46 nm to ～9 and 17 nm, respectively. Up to 5 at.% Si, microstrain decreased due to dynamic and static recovery which were prevailing mechanisms due to high work hardening rate of powders. By increasing the Si content, saturation magnetization decreased and different rates of grain refinement resulted in dissimilar behavior of coercivity for two compositions. The maximum saturation magnetization (～156 emu/g) and minimum coercivity (～10 Oe) were achieved for the Ni₅₀Fe₅₀ and (Ni₅₀Fe₅₀)₈₀Si₂₀ alloys, respectively.     

Velocity field level-set method for topological shape optimization using freely distributed design variables

The velocity field level-set topological shape optimization method combines the implicit representation in the standard level-set method and the capabilities of general mathematical programming algorithms in handling multiple constraints and additional design variables. The key concept is to construct the normal velocity field using basis functions and the velocity design variables at specified points (referred to as velocity knots) in the entire design domain. In this study, the velocity design variables are decoupled from the level-set grid points. Making use of this property, we can adaptively change the arrangement of the velocity knots as the structural boundary evolves. This provides more design freedom in the optimization and allows for a significant reduction in the number of design variables. Several numerical examples in two- and three-dimensional design domains are presented to demonstrate the robustness and efficiency of the proposed method. We also show that changing the number of velocity knots may implicitly exert certain control on topological complexity and length scale.     

Development of hollow microspheres as floating controlled-release systems for cardiovascular drugs: preparation and release characteristics

Hollow microspheres of cellulose acetate loaded with four cardiovascular drugs (nifedipine [NFD], nicardapine hydrochloride [NCD], verapamil hydrochloride [VRP], and dipyridamole [DIP]) were prepared by a novel solvent diffusion-evaporation method. The oil-in-water emulsion prepared in an aqueous solution of 0.05% poly(vinyl alcohol) medium with ethyl acetate, a water-soluble and less toxic solvent, was used as the dispersing solvent. The yield of the microspheres was up to 80%. The microspheres had smooth surfaces, with free-flowing and good-packing properties. Scanning electron microscopy (SEM) confirmed their hollow structures, with sizes in the range 489-350 μm. The microspheres tended to float over the gastric media for more than 12 h. The drug loaded in hollow microspheres was in an amorphous state, as confirmed by differential scanning microscopy (DSC). The release of the drugs was controlled for more than 8 h. The release kinetics followed different transport mechanisms depending on the nature of the drug molecules.     

Evaluation of photocatalysis of Au supported ZnO prepared by the spray pyrolysis method

Environmental pollution by organic dyes used in industry is a serious problem in developing countries. Environmentally friendly treatment methods are being studied because conventional methods require chemical or additional decomposition treatment. In particular, oxidation via a photocatalyst is a promising alternative due to its chemical and physical stabilities and low cost. However, electron-hole recombination limits the photocatalytic activity in semiconductor photocatalysts such as ZnO and TiO₂. This study investigates control of electron-hole recombination of the photocatalyst by loading Au on ZnO (Au/ZnO). Using the Ultrasonic Spray Pyrolysis (USP) method, Au/ZnO particle generation is easily achieved under various conditions. XRD analysis confirms the crystal peaks of ZnO and Au. The EDX mapping and STEM images of the particles show that the Au crystals are well dispersed in the inner and outer portions of ZnO. The photocatalytic decomposition rate of organic dye (Rhodamine-B) is faster than that of ZnO in all Au/ZnO particles, and the best photocatalytic activity occurs in particles with 0.1 mass% Au supported on ZnO particles. In addition, optimal photolysis activity occurs in 100 mL of 5 mg/L RhB aqueous solution and 10 mg dose of Au/ZnO particles.     

Effect of addition of polymeric species with ether moieties on porous structure of silica prepared by sol-gel method

The authors have investigated the effect of the addition of polymeric species (polyethyleneglycol, polypropyleneglycol and polytetramethyleneoxide) containing ether moieties in their main chain on the silica porous structure yielded via the sol-gel method. The obtained silica porous structures were characterized by nitrogen adsorption/desorption and SEM. Introducing those polymeric species apparently enhanced the pore formation. The enhancement is more noticeable for higher concentrations of the polymeric species, distributed from the microporous to mesoporous regions. The pore diameter at which the pore enhancement is induced by adding the polymeric species reduces with the fraction of ether moiety. Adding the polymeric species prior to the onset of the hydrolysis of tetraethylorthosilicate (TEOS) was necessary for the enhancement in the mesoporous region to takes place. The pore enhancement was more outstanding when HCL was used as the catalyst for the hydrolysis of the alkoxide than NH₃. The mutual affinity between the added polymeric and silica species is considered as an important factor of the pore generation in the micro- and meso-porous regions.     

PEG-PLA nanoparticles prepared by emulsion solvent diffusion using oil-soluble and water-soluble PEG-PLA

Poly(ethylene glycol)-block-polylactide (PEG-PLA) nanoparticles were prepared through the oil-in-water (O/W, ethyl acetate/water) emulsion technique using oil-soluble PEG-PLA in the presence of water-soluble PEG-PLA as a surfactant. The particle diameter decreased with increasing water-soluble PEG-PLA concentration, the smallest averaged diameter was 75 nm. From these results, it was found that water-soluble PEG-PLA acted as a surfactant which prevents further coalescence of droplets. In addition, the particles diameter decreased with increasing hydrophile-lipophile balance of oil-soluble PEG-PLA in the absence of water-soluble PEG-PLA. In contrast, the particle diameter was constant in the presence of water-soluble PEG-PLA. Therefore, the capability of water-soluble PEG-PLA as a surfactant was more excellent than that of oil-soluble PEG-PLA.     

3,3,3-三氟丙基三甲氧基硅烷的合成研究

以3,3,3-三氟丙基三氯硅烷和甲醇为原料,采用溶剂法合成3,3,3-三氟丙基三甲氧基硅烷,讨论了氮气流速、反应温度、原料配比、溶剂种类、滴加方式等因素对产物收率的影响.并用GC-MS对产物进行了分析.通过实验得出该反应较优的反应条件为:用正己烷作溶剂,N2流速为100mL/min,3,3,3-三氟丙基三氯硅烷和甲醇的摩尔比为1∶3.1,反应温度在70℃左右,3,3,3-三氟丙基三甲氧基硅的产率可达89.4%.     

喷雾干燥制备P(MMA-BA)中空微球及其对苯酚的吸附性能研究

采用种子乳液聚合法合成聚甲基丙烯酸甲酯-丙烯酸丁酯(P(MMA-BA))乳液,再将乳液进行喷雾干燥制备了壳层由纳米粒子构成且具有中空形貌的单孔高分子微球。研究了微球形成机理,并着重探讨了预聚物用量、硬软单体配比m(MMA)∶m(BA)、交联剂用量对微球形貌、比表面积的影响。结果表明,当条件为乳液浓度2%,进口温度125℃,出口温度50℃,进料量250mL/h,预聚物用量为2%(质量分数),硬软单体比m(MMA)∶m(BA)约为7∶3,交联剂用量为10%～20%(质量分数)时,能够形成形状规整的中空微球,用BET法测得其比表面积约为28.8259m2/g。考察了中空微球对低浓度苯酚溶液的吸附性能,结果表明,微球对苯酚的最大吸附量可达7.8568mg/g;微球用量较少时,单位质量微球吸附的苯酚量较大;微球中硬单体比例越高,所得微球比表面积越大,对苯酚的吸附量越高。     

Evaluation of the enhanced oral effect of omapatrilat-monolein nanoparticles prepared by the emulsification-diffusion method

In the present study, the emulsification-diffusion method was optimized in order to obtain omapatrilat/monolein-nanoparticles (omapatrilat/MO-nanoparticles). The antihypertensive effect of omapatrilat/MO-nanoparticles in spontaneously hypertensive rats (SHR) after oral administration was evaluated. The results indicated that the variables involved in the process did not have an influence on particle size, and that the former is directly determined by the amphiphilic properties of MO. When SHR were orally treated with omapatrilat/MO-nanoparticles, blood pressure was significantly reduced and completely normalized after three days. This effect was markedly higher than that observed with omapatrilat suspensions. The effect of omapatrilat/MO-nanoparticles can be attributed to: (i) The molecular dispersion of the drug into the lipophilic domain of monolein's bicontinuous phase; (ii) the adhesive properties of the nanodispersion on the gastrointestinal mucosa; (iii) the high surface area of the dispersion; (iv) the intraluminal interaction between MO, the mixed micelles arising from the digestive process, and omapatrilat; and (v) the well-known absorption-promoting properties of lipids, and in particular, of MO. MO-nanoparticles can be an interesting system to increase the oral bioavailability of drugs.