Aerosol Inhalation Delivery of Ag Nanoparticles in Mice: Pharmacokinetics and Antibacterial Action.

The aerosol inhalation delivery of composite particles consisting of Ag nanoparticles enveloped by polyvinylpyrrolidone was investigated in experiments with mice. An ultrasonic nebulizing system was created for the generation of aerosols with a mean diameter and mass concentration of 700 ± 50 nm and 65 ± 5 mg/m3, respectively. The mass fraction of Ag in the composite particles was α = 0.061. The aerosol delivery was performed in a whole-body chamber with an exposition time of 20 min. Pharmacokinetic measurements were taken and the silver concentrations in the blood and lungs of the mice were measured as a function of time after exposition by means of electrothermal (graphite furnace) atomic absorption spectrometry. The inhalation dose and other pharmacokinetic parameters were determined. The antibacterial effect of aerosolized silver was assessed for mice infected with Klebsiella pneumoniae 82 and Staphylococcus aureus ATCC 25953. The survival rate of the infected mice after the aerosol exposure demonstrated the high antibacterial efficiency of Ag nanoparticles after inhalation delivery.

Studies of the Specific Activity of Aerosolized Isoniazid against Tuberculosis in a Mouse Model.

The aerosol inhalation delivery of isoniazid in mice was investigated, and the specific activity of the aerosol form of isoniazid was studied with the mouse model of tuberculosis infection, the M. tuberculosis H37Rv strain. Aerosol delivery was performed using a laminar-flow horizontal nucleation chamber. The inhalation dose was measured in real-time mode using a diffusion aerosol spectrometer. The mean particle diameter was 0.6 ± 0.03 µm, and the inhalation dose was 5-9 mg/kg. Pharmacokinetic measurements were carried out in nose-only and whole-body chambers. Isoniazid concentration in blood serum and its mass in the lungs were measured as a function of time using high-performance liquid chromatography. Studies of the specific activity of aerosolized isoniazid reveal that treatment with the aerosol lead to the complete recovery of the experimental tuberculosis infection as early as after 28 days after the start of inhalation treatment, while in the animals from the group receiving isoniazid per-orally, sole revivable tuberculosis mycobacteria were detected. Histologic examinations show that only a few macrophagal (nonspecific) granulomas without mycobacteria were detected in the spleen after per-oral and aerosol treatment, the number of granulomas on the 28th day being three times smaller in the latter case. The results show that the developed technique of isoniazid aerosol inhalation may have clinical potential.

Aerosol Inhalation Delivery of Ceftriaxone in Mice: Generation Procedure, Pharmacokinetics, and Therapeutic Outcome.

Aerosol inhalation delivery of ceftriaxone in mice was investigated. An ultrasonic nebulizer within the ranges of mean particle diameter 0.5-1.5 µm and mass concentration 0.01-0.6 µg/cm3 was used in inhalation experiments. Pharmacokinetic measurements were carried out using a nose-only chamber. Ceftriaxone concentration in blood serum and its mass in the lungs of mice were measured as a function of time using high-performance liquid chromatography. The body-delivered dose was within the range 3-5 mg/kg. The antibacterial effect of aerosolized ceftriaxone was investigated for mice infected with Klebsiella pneumoniae 82 and Staphylococcus aureus ATCC 25 953. The survival rate for infected mice after the treatment with ceftriaxone aerosol revealed the high antibacterial efficiency of this kind of treatment.

Aerosol Inhalation Delivery of Triazavirin in Mice: Outlooks for Advanced Therapy Against Novel Viral Infections.

Under pandemic-caused emergency, evaluation of the potential of existing antiviral drugs for the treatment of COVID-19 is relevant. Triazavirin, an antiviral drug developed in Russia for per-oral administration, is involved in clinical trials against SARS-CoV-2 coronavirus. This virus has affinity to epithelial cells in respiratory tract, so drug delivery directly in lungs may enhance therapeutic effect and reduce side effects for stomach, liver, kidneys. We elaborated ultrasonic method of triazavirin aerosol generation and investigated the inhalation delivery of this drug in mice. Mean particle size and number concentration of aerosol used in inhalation experiments are 560 nm and 4 × 105 cm-3, respectively. Aerosol mass concentration is 1.6 × 10-4 mg/cm3. Inhalation for 20 min in a nose-only chamber resulted in 2 mg/kg body delivered dose and 2.6 µg/mL triazavirin concentration in blood plasma. Elimination rate constant determined in aerosol administration experiments was ke = 0.077 min-1, which agrees with the value measured after intravenous delivery, but per-oral administration resulted in considerably lower apparent elimination rate constant of pseudo-first order, probably due to non-linear dependence of absorption rate on triazavirin concentration in gastrointestinal tract. The bioavailability of triazavirin aerosol is found to be 85%, which is about four times higher than for per-oral administration.

Supramolecular Complex of Ibuprofen with Larch Polysaccharide Arabinogalactan: Studies on Bioavailability and Pharmacokinetics.

BACKGROUND AND OBJECTIVES: In the present work, pharmacological and pharmacokinetic properties of the supramolecular complex of non-steroid anti-inflammatory drug ibuprofen (IBU) with natural polysaccharide arabinogalactan (AG) were studied. The main goals of such complexation were the increase of ibuprofen's bioavailability and decrease its effective dose after oral administration. METHODS: The complex with mass ratio as IBU:AG 1:10 was obtained by mechanochemical synthesis and characterized by water solubility, electron microscopy, differential scanning calorimetry, X-ray powder diffraction analysis and 1H-nuclear magnetic resonance spectroscopy. Different animal models of pain and inflammation was used to investigate IBU:AG biological effects. Plasma concentration of IBU and its pharmacokinetic parameters were evaluated after oral introduction. RESULTS: It was found that ibuprofen's effective analgesic and anti-inflammatory dose decreased twofold after its introduction as a complex with AG. The reason of this difference is due to the increase of ibuprofen concentration in rats' plasma: C max of IBU at doses of 20 and 40 mg/kg was found as 0.088 and 0.132 µg/ml, whereas C max of IBU in the complex form was 0.103 and 0.160 µg/ml, respectively. CONCLUSIONS: Thus, we have shown that complexation of the IBU with AG results in its bioavailability increase, reduction of the effective dose and should decrease toxic side effects.

Analgesic effect from Ibuprofen nanoparticles inhaled by male mice.

BACKGROUND: Aerosol lung administration is a convenient way to deliver water-insoluble or poorly soluble drugs, provided that small-sized particles are generated. Here, for the outbred male mice, we show that the pulmonary administration of ibuprofen nanoparticles requires a dose that is three to five orders of magnitude less than that for the orally delivered particles at the same analgesic effect. METHOD: The aerosol evaporation-condensation generator consisted of a horizontal cylindrical quartz tube with an outer heater. Argon flow was supplied to the inlet and aerosol was formed at the outlet. The particle mean diameter and number concentration varied from 10 to 100 nm and 10(3)-10(7) cm(-)3, respectively. The analgesic action and side pulmonary effects caused by the inhalation of ibuprofen nanoparticles were investigated. RESULTS: The chemical composition of aerosol particles was shown to be identical with the maternal drug. Using the nose-only exposure chambers, the mice lung deposition efficiency was evaluated as a function of the particle diameter. CONCLUSIONS: The dose-dependent analgesic effect of aerosolized ibuprofen was studied in comparison with the oral treatment. It was found that the dose for aerosol treatment is three to five orders of magnitude less than that required for oral treatment at the same analgesic effect. Accompanying effects were moderate venous hyperemia and some emphysematous signs.

Anti-inflammatory effect from indomethacin nanoparticles inhaled by male mice.

The respiratory system provides entry for drug nanoparticles to cure systemic diseases. The modern devices that are available on the market of therapeutic aerosol delivery systems have a number of disadvantages. There remains a need for an alternative means that is low cost, convenient, and capable of producing small-sized particles. On the other hand, one-third of the modern drugs are poorly water soluble. Many currently available injectable formulations of such drugs can cause side effects that originate from detergents and other agents used for their solubilization. The aerosol lung administration may by a good way for delivery of the water-insoluble drugs. We present here a new way for the generation of drug nanoparticles suitable for many water insoluble substances based on the evaporation-condensation route. In this paper the indomethacin nanoaerosol formation was studied and its anti-inflammatory effect to the outbred male mice was examined. The evaporation-condensation aerosol generator consisted of a horizontal cylindrical quartz tube with an outer heater. Argon flow was supplied to the inlet and the aerosol was formed at the outlet. The particle mean diameter and number concentration were varied in the ranges 3 to 200 nm and 10(3) to 10(7) cm(-3), respectively. The liquid chromatography and X-ray diffraction methods have shown the nanoparticles consist of the amorphous phase indomethacin. The aerosol lung administration experiments were carried out in the whole-body exposure chamber. Both the lung deposited dose and the particle deposition efficiency were determined as a function of the mean particle diameter for mice being housed into the nose-only exposure chambers. The anti-inflammatory action and side pulmonary effects caused by the inhalation of indomethacin nanoparticles were investigated. It was found that the aerosol administration was much more effective than the peroral treatment. The aerosol route required a therapeutic dose six orders of magnitude less than that for peroral administration.

Water as a clustering agent in photolysis and photonucleation of benzaldehyde vapor.

The role of water vapor in benzaldehyde photolysis and photonucleation is investigated experimentally as well as with the help of semiempirical estimation of reaction intermediates. It is shown that water molecules act as a clustering agent that brings together two benzaldehyde molecules. This mechanism may explain the experimental observation of glyoxal formation during photolysis in humid carrier gas even in the presence of oxygen, the dependence of the concentrations of glyoxal and diphenyl on water-vapor concentration, and some other unusual facts concerning minor products detected in the experiment.