Pulmonary administration route has been recognized as a potential alternative to intravenous (i.v.) administration for peptide delivery. Nanocomposite particles composed with biodegradable polymeric nanoparticle and sugar alcohol were designed for pulmonary peptide delivery. Aqueous suspension of poly (lactic acid-co-glycolic acid) (PLGA) nanospheres (ca. 250nm in diameter) with insulin was prepared by the emulsion solvent diffusion method in water. The composite particles of resultant nanospheres were prepared by a spray drying fluidized bed granulator (Agglomaster®) . The obtained nanosphere composite particles were the agglomerates of spherical small matrix particles of nanosphere and mannitol (c.a. 4μm in diameter). In vitro inhalation property was evaluated with a cascade impactor. The composite particles showed better inhalation performance than the freeze-dried nanosphere by themselves. In vivo experiment, PLGA nanosphere was rapidly cleared from lung after intratracheal (i.t.) administration. Modification of the nanosphere surface with chitosan prolonged the residence time at the deposited site compared to the unmodified nanospheres. Dry powder inhalation system of chitosan-modified PLGA nanosphere composite with insulin can significantly improve the pharmacological action compared to the solution i.v. or i.t. administered. The relative pharmacological availability to subcutaneous injection was found to be 78%.
We have developed a new technology to prepare nanoparticle-containing composite microspheres using a 4-fluid nozzle spray drier in single step. An ethanol/sodium carbonate solution of pranlukast hydrate (PLH) and an aqueous solution of mannitol (MAN) were simultaneously supplied through different liquid channels of a 4-fluid nozzle spray drier (Fujisaki Electric, Tokushima, Japan) and then spray-dried to obtain composite microspheres containing PLH nanoparticles with PLH/MAN ratios of 1:4, and 1:10. Rifampicin (RFP) -MAN microspheres were also prepared in a manner similar to PLH. In vitro aerosol properties of the PLH powder and PLH-MAN and RFP-MAN composite microspheres were evaluated using a cascade impactor. The PLH-MAN composite microspheres with the PLH/MAN ratios of 1:4 and 1:10 were also administrated intratracheally to Sprague Dawley male rats. The residual percent of RFP in lung tissue was studied. The PLH/MAN microspheres were approximately 3μm in diameter and the PLH nanoparticles with diameters of 200-600nm could be prepared in the microspheres. However, the diameter of PLH nanoparticles varied with the PLH/MAN ratio. The pulmonary absorption was markedly higher for the PLH-MAN composite microspheres (100-fold increase in the AUC/dose) compared to the oral administration of PLH powder. The residual percentage of RFP in the lung with the intratracheal administration was significantly higher than that with the oral or intravenous administration during the initial stage, but RFP rapidly disappeared from the lung tissue and could not be observed four hours after the administration. Plasma concentration also rapidly decreased. Particulate design of RFP remaining in the lung and targeting the alveolar macrophage is required for more effective inhalation therapy of tuberculosis.
Chitosan-pCMV-Luc complex powders as a pulmonary gene delivery system were prepared by dispersing aqueous pCMV-Luc/mannitol solutions with or without chitosan in a supercritical carbon dioxide (CO2) /ethanol admixture. The addition of chitosan suppressed the degradation of pCMV-Luc during the supercritical CO2 process. The chitosan-pCMV-Luc powders increased the luciferase activity in mouse lung compared with pCMV-Luc powders without chitosan or pCMV-Luc solutions with or without chitosan after pulmonary administration. The chitosan-pCMV-Luc powder of N/P ratio=5 increased the luciferase activity 27 times that of the pCMV-Luc solution. These results suggest that gene powder with chitosan is a useful pulmonary gene delivery system. Next, the obtained gene powders and gene solutions were placed in stability chambers at 25 or 40°C for 4 weeks. The integrity and transfection potency of the gene were examined by electrophoresis and in vivo pulmonary transfection study in mice. The decrease in the supercoiled and open circular DNA in the powders during storage was much slower than that in solutions. The powders had higher transfection potency than the solutions containing the same amount of DNA. Chitosan improved the stability of DNA in powders. Thus, a gene powder with a cationic vector is a promising ready-to-use formulation for inhalation therapy of pulmonary diseases.
Dispersion performance of Dry Powder Inhaler (DPI) depends largely upon the inhalation patterns of patients. Slight increase in pressure drop of DPI markedly reduces the peak flow rate of inspired air, however, the dispersion performance of DPI is not significantly affected by the change in DPI flow resistance under the simulated inspiration pattern because the total energy available for the particle dispersion with the DPI is almost the same. Furthermore, Andersen Sampler which is commonly used for the evaluation of dispersion performance of DPI is not suitable for this purpose because the dispersion of drug particles takes place in the sampler with almost the same extent as that of DPI. Therefore, it is important to evaluate the dispersion performance of DPI under the simulated inspiration pattern with the DPI using a particle sizer without particle dispersion in the instrument.
The present paper demonstrates the effectiveness of pressure swing granulation (PSG) for dry powder inhalation (DPI) . The popular formulation powders blending fine model drug powder (d50=2μm) with coarse lactose particles were successfully agglomerated into spherical soft granules with PSG. The effects of both lactose particles size and concentration on the product properties and their dispersion characteristics were investigated. In order to enhance the ability of forming PSG granules without reducing the lactose particle size, lactose particles surface morphology was modified with a ball-mill. By this modification, lactose particles of about 8.8μm in mean diameter were successfully agglomerated without binders over the full range of mixing ratio with the model drug particles. For developing a new particle design with a novel formulation of DPI that is suitable especially for very dilute drug concentration, PSG was also applied to the coating of PSG granules from surface modified lactose particles with fine model drug powder. The PSG granules size distribution and strength as well as the dispersibility of the drug particles for DPI were found to be satisfactory for the practical use. Since the excellent dispersion property of PSG granules for inhalation was obtained by containing the surface-modified lactose, PSG method opens up fresh possibilities for producing dry powder for inhalation.
Carbonaceous components in fine particles less than 2.5μm in diameter (PM2.5) in urban areas are of great concern because of health effects and environmental impact. In this study, water-soluble inorganic ions, organic carbon (OC) , elemental carbon (EC) , and levoglucosan emitted from biomass burning were measured in the fine particle (PM2.5) during the early winter at Saitama. The most abundant component of PM2.5 was organics (or OC) , followed by EC, NO3- and SO42-. Levoglucosan showed high concentrations in the sampling period which ranged from 139 to 2,900 ng/m3 (average 1,140 ng/m3) as 12h average and accounted for 1∼5.4% (average 4%) of OC and 0.2∼3.3% (average 1.9%) of total carbon (TC) . Science levoglucosan occupied a large portion of TC in particles though was a single organic compound, we estimated that the TC concentration observed in this study was associated with large contribution by the biomass burning.
Behavior of particle in a glow discharge plasma was evaluated. Transient charging of a particle suspended in a glow discharge plasma was estimated by solving the orbital motion limit model equation, which includes the correlation between the surface charge induced by ion and electron fluxes and the surface electric potential. The glow discharge plasma was described by continuous plasma model, which employs the conservation equations for electron and ion. The trajectories of particle in the plasma were obtained by solving the equation of motion for the charged particle in the plasma field, which takes into account the external forces of fluid drag force, gravitational force, electrostatic force and ion drag force. Calculation results showed the particles are effectively trapped in the boundary region between plasma bulk and sheath. Larger particles are more stably trapped than smaller ones, since the larger particles undertake the electrostatic force and ion drag force more effectively.
A multipurpose finite element solver for partial differential equation (PDE) , which implements adaptive mesh refinement and automatic time step control, is used for solving condensation equation. Instead of empirically determining the mesh and time-step sizes, the sophisticated PDE solver automatically determines the optimum values in the simulation of the condensational growth. The adaptive diffusion coefficient, which depends on the size distribution, stabilizes the calculation without numerically diffusing the shape of the size distribution. The adaptive mesh refinement and automatic time step control realize the accurate calculation of the size distribution and the conservation of the total particle number. Even when the simulated distribution becomes extremely sharp, it gives a result close to the analytical solution. The numerical solutions are accurate enough to be used as the exact ones, which cannot be solved analytically under realistic condition. Since some multipurpose solvers for PDE have been available in scientific modeling and engineering education, these sophisticated and easy-to-use solvers are expected to be actively used in aerosol modeling and education.
Air contaminants emitted from printers in an office, such as volatile organic compounds (VOCs) , particles, and ozone, have become a serious issue in relation to the health effects. In the present work, the particles emitted from various printers (an ink-jet printer, three monochrome laser printers and a color laser printer) in the size range of submicrometer or smaller were characterized by measuring the emission rate, the size distribution and the charge distribution. The stability of emitted particles in dry air was also studied by introducing them into a diffusion dryer. As a result, it was found that the total particle emission rate from the ink-jet printer was in the order of 106 particles per sheet during printing, while that from monochrome laser printers was in the order of 107 during printing and the same concentration of particles were measured when a sheet of paper was passed through the printer without printing. Most of the particles were smaller than 0.1μm, indicating that they are not directly derived from the toner or main ink droplets. The stability test showed that the particles emitted during printing are composed of nonvolatile species and water.
Field tests were conducted to evaluate the PM2.5 sizing performance of preseparators for the NILU filter holder system. The PM2.5 mass concentrations measured by a TEOM with the preseparator was higher by 9% than those measured by another TEOM with a United States Environmental Protection Agency reference inlet for PM2.5 on average. This overestimation was probably due to the re-suspension of large particles. Another field test on the chemical composition of particles showed that daily concentrations of sulfate and ammonium in PM2.5 measured by a denuded filter-pack sampling system with the preseparator well corresponded to those obtained by a low-pressure cascade impactor, the reference method. The re-suspension seemed to affect the PM2.5 nitrate concentration, but it was difficult to estimate because the nitrate concentration by the cascade impactor was likely influenced by the artifact. The re-suspension can be avoided by cascading the preseparators.