Aerosol inhalation delivery of cefazolin in mice: Pharmacokinetic measurements and antibacterial effect.

Aerosol inhalation delivery of cefazolin, a broad-spectrum first-generation cephalosporin antibiotic, was investigated. Inhalation system based on ultrasonic nebulizer was developed for the generation of dry cefazolin aerosol within mean particle diameter range 0.5-3.0 µm and mass concentration 0.01-3 µg/cm3. Pharmacokinetic measurements were carried out for the aerosolized form of cefazolin delivered in mice using nose-only chamber. Cefazolin concentrations in blood serum and in the lungs of mice were measured as a function of time by means of high performance liquid chromatography. Body-delivered dose depending on particle size, concentration and inhalation time as well as other pharmacokinetic parameters were determined. The antibacterial effect of aerosolized cefazolin was assessed through the aerosol inhalation treatment of mice infected with Klebsiella pneumoniae. Survival rate for infected mice after the treatment with cefazolin aerosol demonstrated high antibacterial efficiency of the inhalation delivery of cefazolin in comparison with intraperitoneal delivery.

Excipient-free isoniazid aerosol administration in mice: Evaporation-nucleation particle generation, pulmonary delivery and body distribution.

Excipient-free isoniazid aerosol formation and pulmonary delivery in mice are studied. An evaporation-nucleation route is used for the generation of isoniazid aerosol. Particle diameters and number concentrations are measured with an aerosol spectrometer consisting of a diffusion battery, condensation chamber, and photoelectric counter. The pulmonary delivery of isoniazid particles is studied in both nose-only (NO) and whole-body (WB) inhalation chambers for the particle mean diameter and number concentration to be 600 nm and 6 × 106 cm-3, respectively. It is found that the rate of drug systemic absorption in the WB chamber is 27% higher than that for the NO one because of an additional consumption of drug orally from the fur in the WB chamber. The particle deposition efficiency ε in the mouse respiratory tract is measured as a function of mean diameter. The quantity ε is equal to 0.7 for the particle diameter d = 10 nm and decreases to 0.2 with the diameter increasing to 300 nm, and then, at d > 300 nm the deposition efficiency increases with diameter to 0.5 at d = 2000 nm. The bioavailability of the aerosol form of isoniazid (72 ±â€¯10%) is very close to that for the per-oral form (61 ±â€¯10%).

Experimental study of homogeneous nucleation from the bismuth supersaturated vapor: evaluation of the surface tension of critical nucleus.

The homogeneous nucleation of bismuth supersaturated vapor is studied in a laminar flow quartz tube nucleation chamber. The concentration, size, and morphology of outcoming aerosol particles are analyzed by a transmission electron microscope (TEM) and an automatic diffusion battery (ADB). The wall deposit morphology is studied by scanning electron microscopy. The rate of wall deposition is measured by the light absorption technique and direct weighting of the wall deposits. The confines of the nucleation region are determined in the "supersaturation cut-off" measurements inserting a metal grid into the nucleation zone and monitoring the outlet aerosol concentration response. Using the above experimental techniques, the nucleation rate, supersaturation, and nucleation temperature are measured. The surface tension of the critical nucleus and the radius of the surface of tension are determined from the measured nucleation parameters. To this aim an analytical formula for the nucleation rate is used, derived from author's previous papers based on the Gibbs formula for the work of formation of critical nucleus and the translation-rotation correction. A more accurate approach is also applied to determine the surface tension of critical drop from the experimentally measured bismuth mass flow, temperature profiles, ADB, and TEM data solving an inverse problem by numerical simulation. The simulation of the vapor to particles conversion is carried out in the framework of the explicit finite difference scheme accounting the nucleation, vapor to particles and vapor to wall deposition, and particle to wall deposition, coagulation. The nucleation rate is determined from simulations to be in the range of 10(9)-10(11) cm(-3) s(-1) for the supersaturation of Bi(2) dimers being 10(17)-10(7) and the nucleation temperature 330-570 K, respectively. The surface tension σ(S) of the bismuth critical nucleus is found to be in the range of 455-487 mN/m for the radius of the surface of tension from 0.36 to 0.48 nm. The function σ(S) changes weakly with the radius of critical nucleus. The value of σ(S) is from 14% to 24% higher than the surface tension of a flat surface.

Translation-rotation correction factor in the theory of homogeneous nucleation.

An analytical formula for the correction factor which is to multiply the classical expression for the nucleation rate to account the translation and rotation of the critical nucleus is proposed. The formula is based on the Reiss approach considering the contribution from the clusters translational degrees of freedom, Frenkel's kinetic theory of liquids, and Kusaka's theory. Using this formula we determined the correction factor for argon vapor-to-liquid phase nucleation for the temperature range 80-110 K. These evaluations are in a good agreement with the correction factor calculated numerically by Kusaka (2006). Basing on the Gibbs theory of capillarity it is also shown that for the case of ideal gas-to-liquid nucleation the exponent in the classical formula for the rate of nucleation is strictly equal to the reversible work of drop formation.

Evaluation of surface tension and Tolman length as a function of droplet radius from experimental nucleation rate and supersaturation ratio: metal vapor homogeneous nucleation.

Zinc and silver vapor homogeneous nucleations are studied experimentally at the temperature from 600 to 725 and 870 K, respectively, in a laminar flow diffusion chamber with Ar as a carrier gas at atmospheric pressure. The size, shape, and concentration of aerosol particles outcoming the diffusion chamber are analyzed by a transmission electron microscope and an automatic diffusion battery. The wall deposit is studied by a scanning electron microscope (SEM). Using SEM data the nucleation rate for both Zn and Ag is estimated as 10(10) cm(-3) s(-1). The dependence of critical supersaturation on temperature for Zn and Ag measured in this paper as well as Li, Na, Cs, Ag, Mg, and Hg measured elsewhere is analyzed. To this aim the classical nucleation theory is extended by the dependence of surface tension on the nucleus radius. The preexponent in the formula for the vapor nucleation rate is derived using the formula for the work of formation of noncritical embryo [obtained by Nishioka and Kusaka [J. Chem. Phys. 96, 5370 (1992)] and later by Debenedetti and Reiss [J. Chem. Phys. 108, 5498 (1998)]] and Reiss replacement factor. Using this preexponent and the Gibbs formula for the work of formation of critical nucleus the dependence of surface tension on the radius R(S) of the surface of tension is evaluated from the nucleation data for above-mentioned metals. For the alkali metals and Ag the surface tension was determined to be a strong function of R(S). For the bivalent metals (Zn, Hg, and Mg) the surface tension was independent of radius in the experimental range. A new formula for the Tolman length delta as a function of surface tension and radius R(S) is derived by integration of Gibbs-Tolman-Koenig equation assuming that delta is a monotonic function of radius. The formula derived is more correct than the Tolman formula and convenient for the elaboration of experimental data. Using this formula the values of delta are determined as a function of R(S) from the experimental nucleation data. It is determined that all the metals considered are characterized by strong dependence of delta on radius; for the bivalent metals delta changes sign.