Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion

Abstract

Context: Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs.

Objective: Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI.

Methods: The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor.

Results: This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600?nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior in vitro inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles.

Conclusions: The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.     

Preparation of PLGA nanoparticles using TPGS in the spontaneous emulsification solvent diffusion method

D-alpha-tocopheryl poly (ethylene glycol) 1000 succinate (TPGS) is a widely used form of vitamin E that has been used as a solubilizer, an emulsifier and as a vehicle for drug delivery formulations. In this study, poly lactide-co-glycolide (PLGA) nanoparticles were prepared by spontaneous emulsification solvent diffusion (SESD) method. TPGS as an emulsifier and further as a matrix material blended with PLGA was used to enhance the encapsulation efficiency and improve the drug release profile of nanoparticles. Rifampicin and estradiol valerate were used as model drugs with different water solubility. The effect of formulation parameters such as drug/polymer ratio, oil phase combination, volume and surfactant content was evaluated. The surface morphology and size of the nanoparticles were studied by scanning electron microscopy (SEM) and laser light scattering. Drug encapsulation efficiency and in vitro drug release profiles of nanoparticles were determined using high performance liquid chromatography (HPLC). The nanoparticles prepared in this study were spherical with size range of 150–250?nm. It was shown that TPGS was a good emulsifier for producing nanoparticles of hydrophobic drugs and improving the encapsulation efficiency and drug loading and drug release profile of nanoparticles. However, the drug loading efficiency of rifampicin, a slightly water-soluble molecule, was significantly lower than that of estradiol valerate, a water insoluble molecule.     

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.     

Synthesis and characterization of ZnO/MgO solids prepared by deposition of preformed colloidal ZnO nanoparticles

The ZnO/MgO solids were prepared by colloidal technique which involves the deposition of preformed colloidal ZnO nanoparticles on magnesia. The morphology of ZnO nanoparticles was investigated by transmission electron microscopy and UV-Vis absorption and diffuse reflectance spectroscopy. We found a good agreement between the average radius and the particle size distribution of the ZnO nanoparticles obtained by both methods. It was shown the ability to control the size of the supported ZnO nanoparticles (3.8-4.4nm) by varying pH of the colloidal solution.     

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.     

Catalytic synthesis of carbon nanofibers and nanotubes by the pyrolysis of acetylene with iron nanoparticles prepared using a hydrogen-arc plasma method

Carbon nanofibers (CNFs) and carbon nanotubes (CNTs) were synthesized at different temperatures by the catalytic pyrolysis of acetylene with iron nanoparticles prepared using a hydrogen-arc plasma method. The obtained carbon nanomaterials were characterized by transmission electron microscopy and field-emission scanning electron microscopy. An iron nanoparticle was always located at the tip of CNFs or CNTs, whose diameter was approximately identical with the diameter of the iron nanoparticle. The structures of the products were closely related to the reaction temperature, and could be changed from fibers to tubes by simply increasing the temperature. CNFs were obtained at the reaction temperature of 550-650 °C. When the reaction temperature was increased to 710-800 °C, CNTs were obtained.     

Self-assembly of colloidal crystals from polystyrene emulsion at elevated temperature by dip-drawing method

The self-assembly of colloidal crystal arrays from polystyrene (PS) sphere emulsion at elevated temperature by dip-drawing method was investigated. The dependence of effective sphere transfer in the meniscus of emulsion on temperature was discussed. The results show that the assembled arrays formed at 50 °C have fewer defects than those at room temperature. The elevated emulsion temperature during the ordered arrangement of colloidal crystals causes quicker solvent evaporation, hence quicker sphere transfer. However, exceeding solvent flux and crystal growth induced by over high temperatures result in more fracture lines displayed in arrays. At 50 °C, the effective sphere transfer by the solvent flux to the array edge can also be enhanced by increasing the PS volume fraction of emulsion, which obviously reduces fracture lines on the surface of multilayer.     

乳液法制备中间相炭微球的研究

为制备高性能中间相炭微球(MesocarbonMicrobeads,简称MCMB),选用三种不同中间相含量的石油渣油沥青为原料(中间相体积含量:PP185%,PP290%,PP3100%),采用乳液法制备中间相沥青微球(MesophasePitchMi crobeads,简称MPMB),再经预氧化和炭化处理,制得圆整度好、收率高、球径分布窄的中间相炭微球。利用扫描电子显微镜(SEM)考察了MPMB的微观形貌,同时还利用激光粒度分析仪测定了MPMB的粒度分布。研究了乳液法制备MPMB的影响因素,研究结果表明:(1)耐高温硅油适宜作为乳液法的导热分散介质;(2)不同中间相含量的沥青制备微球时有其适宜的处理温度和时间(PP1:320℃,30min;PP2:330℃,30min;PP3:355℃,30min),且制得的微球收率(收率:PP1相似文献   

Effect of annealing on the morphology and properties of ZnS:Mn nanoparticles/PVP nanofibers

As one kind of new optoelectronic materials, ZnS:Mn nanoparticles/PVP composite nanofibers are prepared by the electrospinning technique successfully. SEM, XRD, FT-IR spectroscopy, photoluminescence and TEM measurements are employed in the study. By the method of annealing, the effect on the morphology and properties of the composite nanofibers is studied. After annealing treatment, the separating state of the nanofibers is improved obviously, ZnS:Mn nanoparticles are well dispersed in the nanofiber, the PL peak originated from ⁴T₁→⁶A₁ transition of Mn ions shifts from 605 nm to 599 nm. The existence of orange emission peaks confirms that ZnS:Mn nanoparticles are formed in the fibers.     

Synthesis and characterization of ZnO nanoparticles prepared in gelatin media

Zinc oxide nanoparticles (ZnO-NPs) were synthesized via the sol-gel method in gelatin media. Long-chain gelatin compounds were utilized to terminate the growth of ZnO-NPs and to stabilize them. The ZnO-NPs were characterized by a number of techniques, such as X-ray diffraction analysis (XRD), Fourier transform infrared spectroscopy (FTIR), and high-magnification transmission electron microscopy (TEM). The ZnO-NPs calcined at different temperatures exhibited a hexagonal (wurtzite) structure with sizes from 30 to 60 nm. The influence of the calcination temperature on the morphology of ZnO-NPs was also investigated. The results showed that gelatin is an interesting material that can be used as a stabilizer in the sol-gel technique for preparing small ZnO-NPs.     

Preparation and characterization of CdSe nanoparticles in the presence of Triocytlphosphine as solvent and capping agent

Triocytlphosphine (TOP)-capped CdSe nanoparticles (NPs) have been successfully prepared by the one-pot solution growth method at 240 °C under argon atmosphere. In particular, The TOP used in this process as the single coordinating solvent is favorable for probing capping mechanism of CdSe NPs surface. The growth process and characterization of CdSe NPs were determined by photoluminescence (PL) spectroscopy, X-ray diffraction (XRD), Transmission electron microscopy (TEM), Ultraviolet-visible (UV-Vis) spectroscopy and Fourier transform infrared spectroscopy (FTIR). Results demonstrated the TOP-capped CdSe NPs to be well dispersed and uniform in shape and the diameter of the particle was confined within 8 nm. PL measurement showed the near band-edge luminescence of the final product.     

Paclitaxel-loaded lipid nanoparticles prepared by solvent injection or ultrasound emulsification

Lipid nanoparticles were fabricated as an injectable carrier system for paclitaxel. The components for the lipid matrix were based on phospholipids, and sucrose fatty acid ester was used as an emulsifier. Formulation prepared with solvent injection has a slightly larger particle size (187.6 nm) than the formulation (147.7 nm) prepared with ultrasound emulsification. Differential scanning calorimetry results indicated that paclitaxel entrapped in the lipid nanoparticles existed in an amorphous state in the lipid matrix. In vitro drug release was rather slow; only 12.5-16.5% of the drug released from the formulations within 14 days. Lipid nanoparticles demonstrated their potential as a promising pharmaceutical formulation of paclitaxel.     

Carbon nanotubes with hydrophilic surfaces produced by a wet-mechanochemical reaction with potassium hydroxide using ethanol as solvent

Multi-walled carbon nanotubes (MWCNTs) were treated by a simple wet-mechanochemical reaction with potassium hydroxide using ethanol as solvent to enhance their dispersibility. Fourier transmission infrared spectroscopy measurements show that the non-reactive surfaces of MWCNTs were modified directly by multiple hydroxyl groups. The products, defined as MWCNTols, are highly soluble in water and other polar solvents. Different microstructures of linear, swirl, and ring shapes have been observed in MWCNTol sheets. The formation mechanism has been investigated and MWCNTol length was proposed as the key factor affecting the observed microstructures.     

Optimization of the emulsification and solvent displacement method for the preparation of solid lipid nanoparticles

Objective: The essential aim of this article is to prepare solid lipid nanoparticles (SLNs) by emulsification and solvent displacement method and to determine the best process conditions to obtain submicron particles. Methods: The emulsification and solvent displacement method is a modification of the well-known emulsification–diffusion method, but without dilution of the system. The extraction of the partially water-miscible solvent from the emulsion globules is carried out under reduced pressure, which causes the diffusion of the solvent toward the external phase, with subsequent lipid aggregation in particles whose size will depend on the process conditions. The critical variables affecting the process, such as stirring rate, the proportion of phases in the emulsion, and the amount of stabilizer and lipid, were evaluated and optimized. Results: By this method, it was possible to obtain a high yield of solids in the dispersion for the lipids evaluated (Compritol^® ATO 888, Geleol^®, Gelucire^® 44/14, and stearic acid). SLNs of up to ～20 mg/mL were obtained for all lipids evaluated. A marked reduction in size, between 500 and 2500 rpm, was seen, and a transition from micro- to nanometric size was observed. The smaller particle sizes obtained were 113 nm for Compritol^® ATO 888, 70 nm for Gelucire^® 44/14, 210 nm for Geleol^®, and 527 nm for stearic acid, using a rotor–stator homogenizer (Ultra-Turrax^®) at 16,000 rpm. The best phase ratio (organic/aqueous) was 1 : 2. Conclusions: The process proposed in this study is a new alternative to prepare SLNs with technological potential.     

Mechanical performance of styrene-butadiene-rubber filled with carbon nanoparticles prepared by mechanical mixing

Reinforcement of styrene-butadiene-rubber (SBR) was investigated using two different carbon blacks (CBs) with similar particle sizes, including highly structured CB and conventional CB, as well as multi-walled carbon nanotube (MWCNT) prepared by mechanical mixing. The attempts were made to examine reinforcing mechanism of these two different classes of carbon nanoparticles. Scanning electron microscopy and electrical conductivity measurement were used to investigate morphology. Tensile, cyclic tensile and stress relaxation analyses were performed. A modified Halpin-Tsai model based on the concept of an equivalent composite particle, consisting of rubber bound, occluded rubber and nanoparticle, was proposed. It was found that properties of CB filled SBR are significantly dominated by rubber shell and occluded rubber in which molecular mobility is strictly restricted. At low strains, these rubber constituents can contribute in hydrodynamic effects, leading to higher elastic modulus. However, at higher strains, they contribute in stress hardening resulting in higher elongation at break and higher tensile strength. These elastomeric regions can also influence stress relaxation behaviors of CB filled rubber. For SBR/MWCNT, the extremely great inherent mechanical properties of nanotube along with its big aspect ratio were postulated to be responsible for the reinforcement while their interfacial interaction was not so efficient.     

Injectable sustained release PLA microparticles prepared by solvent evaporation-media milling technology

The objective of this study was to develop agomelatine (AGM) intramuscular sustained release PLA microparticles by using solvent evaporation combined with wet milling technology. The final preparation had a regular and homogeneous particle size of approximately 35?µm, as measured by laser diffraction particle size analysis and scanning electron microscopy (SEM). The drug was confirmed to be within the carrier in an amorphous state through differential scanning calorimetry (DSC) and power X-ray diffraction (PXRD) experiments. Additionally, Fourier transform infrared spectroscopy (FT-IR) analysis was applied to confirm that there was hydrogen bonding between the drug and polymer at the molecular level. In vitro release experiments indicated that the drug could achieve long-term sustained release over the period of one month, with only a 3.07% burst release, due to the involvement of the polymer and removal of drug adsorbed on the surface during the wet grinding process. The dominant release mechanism was considered to be diffusion of the drugs in the initial period. Following this, with the hydrolysis of PLA to form a colloidal viscous layer, drug release is due to the combined effect of diffusion and erosion of the polymer matrix. Additionally, drug release behavior is closely related to the degradation mechanism of the polymer carrier. The results suggest that AGM could be developed as a potential delivery system for long-acting intramuscular administration with extensive application prospects.     

Ag diffusion in ZnS thin films prepared by spray pyrolysis

ZnS thin films were deposited by spray pyrolysis method on glass substrates. Diffusion of Ag in ZnS thin films was performed in the temperature range 80-400 °C under a nitrogen atmosphere. The diffusion of Ag is determined with XRF, and the obtained concentration profile allows to calculate the diffusion coefficient. The temperature dependence of Ag diffusion coefficient is determined by the equation D = 8 × 10^− 9 exp(− 0.10 eV / kT). It was found that the as-grown undoped high resistive n-type ZnS thin films were converted to the p-type upon Ag doping with a slight increase in resistivity only by rapid thermal annealing at 400 °C in N₂ atmosphere. In addition, the band gap of the p-type film was decreased as compared with the undoped sample annealed under the same conditions. The results were attributed to the migration of Ag atoms in polycrystalline ZnS films by means of both along intergrain surfaces and intragrain accompanied by interaction with native point defect.     

Preparation of one-dimensional TiO2 nanoparticles within polymer fiber matrices by electrospinning

One-dimensional TiO₂ nanoparticles within polyvinylpyrrolidone (PVP) fiber matrices were prepared via coupling sol-gel method and electrospinning. TEM analysis indicated that TiO₂ nanoparticles chain was in the middle of PVP fiber and dispersed linearly along the fiber direction, which originated from the effect of polarization and orientation caused by high electric field. With the increase of the concentration of sol-gel precursor in the electrospinning solution, the diameter of nanoparticles in resulting fibers decreased from 60 to 13 nm. This composite nanomaterial will have potential applications in photoluminescent (PL), electroluminescent (EL) and non-linear optical devices, flat panel displays, photocathodes for solar and so on.     

Effect of mixed solvent on the morphologies of nanostructured Bi2S3 prepared by solvothermal synthesis

Different morphologies of nanostructured bismuth sulfide (Bi₂S₃) including nanotubes and nanorods have been prepared by solvothermal synthesis at a low temperature of 120 °C for 12 h using various mixed solvents as the reaction medium and urea as the mineralizer. X-ray diffraction analysis showed that all the as-prepared Bi₂S₃ samples are orthorhombic phase. Transmission electron microscopy analysis showed that the morphologies of the nanostructures are mainly related to the viscosity and surface tension of the mixed solvent used in the solvothermal synthesis.