Liposomal carrier systems have emerged as a promising technology for pulmonary drug delivery. This study focuses on two selected liposomal systems, namely, dipalmitoylphosphatidylcholine stabilized by phosphatidic acid and cholesterol (DPPC-PA-Chol) and dipalmitoylphosphatidylcholine stabilized by polyethylene glycol and cholesterol (DPPC-PEG-Chol). First, the research investigates the stability of these liposomal systems during the atomization process using different kinds of nebulizers (air-jet, vibrating mesh, and ultrasonic). The study further explores the aerodynamic particle size distribution of the aerosol generated by the nebulizers. The nebulizer that demonstrated optimal stability and particle size was selected for more detailed investigation, including Andersen cascade impactor measurements, an assessment of the influence of flow rate and breathing profiles on aerosol particle size, and an in vitro deposition study on a realistic replica of the upper airways. The most suitable combination of a nebulizer and liposomal system was DPPC-PA-Chol nebulized by a Pari LC Sprint Star in terms of stability and particle size. The influence of the inspiration flow rate on the particle size was not very strong but was not negligible either (decrease of Dv50 by 1.34 μm with the flow rate increase from 8 to 60 L/min). A similar effect was observed for realistic transient inhalation. According to the in vitro deposition measurement, approximately 90% and 70% of the aerosol penetrated downstream of the trachea using the stationary flow rate and the realistic breathing profile, respectively. These data provide an image of the potential applicability of liposomal carrier systems for nebulizer therapy. Regional lung drug deposition is patient-specific; therefore, deposition results might vary for different airway geometries. However, deposition measurement with realistic boundary conditions (airway geometry, breathing profile) brings a more realistic image of the drug delivery by the selected technology. Our results show how much data from cascade impactor testing or estimates from the fine fraction concept differ from those of a more realistic case.
- MeSH
- 1,2-dipalmitoylfosfatidylcholin MeSH
- aerosoly MeSH
- aplikace inhalační MeSH
- bronchodilatancia * MeSH
- cholesterol MeSH
- design vybavení MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- liposomy MeSH
- nebulizátory a vaporizátory MeSH
- trachea * MeSH
- velikost částic MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
This contribution is focused on the preparation of a liposomal drug delivery system of erlotinib resisting the nebulization process that could be used for local treatment of non-small-cell lung cancer. Liposomes with different compositions were formulated to reveal their influence on the encapsulation efficiency of erlotinib. An encapsulation efficiency higher than 98 % was achieved for all vesicles containing phosphatidic acid (d ≈ 100 nm, ζ = - 43 mV) even in the presence of polyethylene glycol (d ≈ 150 nm, ζ = - 17 mV) which decreased this value in all other formulas. The three most promising formulations were nebulized by two air-jet and two vibrating mesh nebulizers, and the aerosol deposition in lungs was calculated by tools of computational fluid and particle mechanics. According to the numerical simulations and measurements of liposomal stability, air-jet nebulizers generated larger portion of the aerosol able to penetrate deeper into the lungs, but the delivery is likely to be more efficient when the formulation is administered by Aerogen Solo vibrating mesh nebulizer because of a higher portion of intact vesicles after the nebulization. The leakage of encapsulated drug from liposomes nebulized by this nebulizer was lower than 2 % for all chosen vesicles.
- MeSH
- aplikace inhalační MeSH
- bronchodilatancia MeSH
- erlotinib MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- liposomy MeSH
- nádory plic * MeSH
- nebulizátory a vaporizátory MeSH
- nemalobuněčný karcinom plic * MeSH
- plíce MeSH
- respirační aerosoly a kapénky MeSH
- velikost částic MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In this study, three different molecules (cholesterol, phosphatidic acid, and polyethylene glycol) were used for the stabilization of liposomes during the nebulization process. The purpose of this article is to answer the question of whether the change in the composition of liposomes affected the parameters of generated aerosol and whether the nebulization process affected observed properties of liposomes. Firstly, liposomes with different composition were prepared and their properties were checked by dynamic and electrophoretic light scattering. The membrane properties were measured by fluorescence spectroscopy - especially generalized polarization (Laurdan) and anisotropy (Diphenylhexatriene). The same characteristic of liposomes was measured after the nebulization by vibrating mesh nebulizer. Cholesterol was capable of liposome stabilization because of increased membrane fluidity. The membrane properties of the outer and inner parts were not influenced by the nebulization process. Electrostatic stabilization was successful for the lowest concentration of phosphatidic acid, but after the nebulization process the hydration of the membrane outer part was changed. Higher amount of PEG needs to be added for successful steric stabilization. The nebulization process of the two lowest concentrations of PEG slightly influenced immobilized water and the rigidity of inner part of the membrane (especially around the phase transition temperature).
- MeSH
- aerosoly MeSH
- chirurgické síťky * MeSH
- liposomy * MeSH
- nebulizátory a vaporizátory MeSH
- velikost částic MeSH
- Publikační typ
- časopisecké články MeSH
Controlled pulmonary drug delivery systems employing non-spherical particles as drug carriers attract considerable attention nowadays. Such anisotropic morphologies may travel deeper into the lung airways, thus enabling the efficient accumulation of therapeutic compounds at the point of interest and subsequently their sustained release. This study focuses on the fabrication of electrospun superparamagnetic polymer-based biodegradable microrods consisting of poly(l-lactide) (PLLA), polyethylene oxide (PEO) and oleic acid-coated magnetite nanoparticles (OA·Fe3O4). The production of magnetite-free (0% wt. OA·Fe3O4) and magnetite-loaded (50% and 70% wt. Fe3O4) microrods was realized upon subjecting the as-prepared electrospun fibers to UV irradiation, followed by sonication. Moreover, drug-loaded microrods were fabricated incorporating methyl 4-hydroxybenzoate (MHB) as a model pharmaceutical compound and the drug release profile from both, the drug-loaded membranes and the corresponding microrods was investigated in aqueous media. In addition, the magnetic properties of the produced materials were exploited for remote induction of hyperthermia under AC magnetic field, while the possibility to reduce transport losses and enhance the targeted delivery to lower airways by manipulation of the airborne microrods by DC magnetic field was also demonstrated.
Medical aerosols are key elements of current chronic obstructive pulmonary disease (COPD) therapy. Therapeutic effects are conditioned by the delivery of the right amount of medication to the right place within the airways, that is, to the drug receptors. Deposition of the inhaled drugs is sensitive to the breathing pattern of the patients which is also connected with the patient's disease severity. The objective of this work was to measure the realistic inhalation profiles of mild, moderate, and severe COPD patients, simulate the deposition patterns of Symbicort® Turbuhaler® dry powder drug and compare them to similar patterns of healthy control subjects. For this purpose, a stochastic airway deposition model has been applied. Our results revealed that the amount of drug depositing within the lungs correlated with the degree of disease severity. While drug deposition fraction in the lungs of mild COPD patients compared with that of healthy subjects (28% versus 31%), lung deposition fraction characteristic of severe COPD patients was lower by a factor of almost two (about 17%). Deposition fraction of moderate COPD patients was in-between (23%). This implies that for the same inhaler dosage severe COPD patients receive a significantly lower lung dose, although, they would need more.
- Publikační typ
- časopisecké články MeSH
Recent developments in the prediction of local aerosol deposition in human lungs are driven by the fast development of computational simulations. Although such simulations provide results in unbeatable resolution, significant differences among distinct methods of calculation emphasize the need for highly precise experimental data in order to specify boundary conditions and for validation purposes. This paper reviews and critically evaluates available methods for the measurement of single and disperse two-phase flows for the study of respiratory airflow and deposition of inhaled particles, performed both in vivo and in replicas of airways. Limitations and possibilities associated with the experimental methods are discussed and aspects of the computational calculations that can be validated are indicated. The review classifies the methods into following categories: 1) point-wise and planar methods for velocimetry in the airways, 2) classic methods for the measurement of the regional distribution of inhaled particles, 3) standard medical imaging methods applicable to the measurement of the regional aerosol distribution and 4) emerging and nonconventional methods. All methods are described, applications in human airways studies are illustrated, and recommendations for the most useful applications of each method are given.
- MeSH
- absorpce v dýchacích cestách MeSH
- aerosoly chemie MeSH
- aplikace inhalační MeSH
- biologické modely MeSH
- farmaceutická chemie metody MeSH
- hydrodynamika MeSH
- laryngální masky * MeSH
- lékové transportní systémy metody MeSH
- lidé MeSH
- nebulizátory a vaporizátory MeSH
- permeabilita MeSH
- plíce účinky léků MeSH
- počítačová simulace * MeSH
- prášky, zásypy, pudry chemie MeSH
- velikost částic MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Inhalation of aerosols generated by electronic cigarettes leads to deposition of multiple chemical compounds in the human airways. In this work, an experimental method to determine regional deposition of multicomponent aerosols in an in vitro segmented, realistic human lung geometry was developed and applied to two aerosols, i.e. a monodisperse glycerol aerosol and a multicomponent aerosol. The method comprised the following steps: (1) lung cast model preparation, (2) aerosol generation and exposure, (3) extraction of deposited mass, (4) chemical quantification and (5) data processing. The method showed good agreement with literature data for the deposition efficiency when using a monodisperse glycerol aerosol, with a mass median aerodynamic diameter (MMAD) of 2.3 μm and a constant flow rate of 15 L/min. The highest deposition surface density rate was observed in the bifurcation segments, indicating inertial impaction deposition. The experimental method was also applied to the deposition of a nebulized multicomponent aerosol with a MMAD of 0.50 μm and a constant flow rate of 15 L/min. The deposited amounts of glycerol, propylene glycol and nicotine were quantified. The three analyzed compounds showed similar deposition patterns and fractions as for the monodisperse glycerol aerosol, indicating that the compounds most likely deposited as parts of the same droplets. The developed method can be used to determine regional deposition for multicomponent aerosols, provided that the compounds are of low volatility. The generated data can be used to validate aerosol deposition simulations and to gain insight in deposition of electronic cigarette aerosols in human airways.
In this article, the results of numerical simulations using computational fluid dynamics (CFD) and a comparison with experiments performed with phase Doppler anemometry are presented. The simulations and experiments were conducted in a realistic model of the human airways, which comprised the throat, trachea and tracheobronchial tree up to the fourth generation. A full inspiration/expiration breathing cycle was used with tidal volumes 0.5 and 1 L, which correspond to a sedentary regime and deep breath, respectively. The length of the entire breathing cycle was 4 s, with inspiration and expiration each lasting 2 s. As a boundary condition for the CFD simulations, experimentally obtained flow rate distribution in 10 terminal airways was used with zero pressure resistance at the throat inlet. CCM+ CFD code (Adapco) was used with an SST k-ω low-Reynolds Number RANS model. The total number of polyhedral control volumes was 2.6 million with a time step of 0.001 s. Comparisons were made at several points in eight cross sections selected according to experiments in the trachea and the left and right bronchi. The results agree well with experiments involving the oscillation (temporal relocation) of flow structures in the majority of the cross sections and individual local positions. Velocity field simulation in several cross sections shows a very unstable flow field, which originates in the tracheal laryngeal jet and propagates far downstream with the formation of separation zones in both left and right airways. The RANS simulation agrees with the experiments in almost all the cross sections and shows unstable local flow structures and a quantitatively acceptable solution for the time-averaged flow field.
- MeSH
- biologické modely * MeSH
- biomechanika MeSH
- bronchy fyziologie MeSH
- časové faktory MeSH
- dýchání * MeSH
- lidé MeSH
- numerická analýza pomocí počítače * MeSH
- plicní ventilace fyziologie MeSH
- trachea fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Researchers have been studying aerosol transport in human lungs for some decades. The overall lung deposition can be predicted with sufficient precision nowadays. However, the prediction of local deposition remains an unsolved problem. Numerical modeling of aerosol transport can provide detailed data with such precision and spatial resolution which were unavailable in the past. Yet, the necessary validation of numerical results represents a difficult task, as the experimental data in a sufficient spatial resolution are hardly available. This article introduces a method based on positron emission tomography, which allows acquisition of detailed experimental data on local aerosol deposition in a realistic model of human lungs. The method utilizes the Condensation Monodisperse Aerosol Generator modified for a safe production of radioactive aerosol particles and a special measuring rig. The scanning of the model is performed on a positron emission tomography-computed tomography scanner. The evaluation of aerosol deposition is based on a volume radioactivity analysis in a specialized, yet publicly available software. The reliability of the method was tested and its first results are discussed in the article. The measurements performed using the presented method can serve for validation of numerical simulations, since the presented lung model digital geometry is available.
- MeSH
- aerosoly aplikace a dávkování farmakokinetika MeSH
- biologické modely * MeSH
- bronchy metabolismus MeSH
- lékové transportní systémy MeSH
- lidé MeSH
- pozitronová emisní tomografie metody MeSH
- trachea metabolismus MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Numerous models of human lungs with various levels of idealization have been reported in the literature; consequently, results acquired using these models are difficult to compare to in vivo measurements. We have developed a set of model components based on realistic geometries, which permits the analysis of the effects of subsequent model simplification. A realistic digital upper airway geometry except for the lack of an oral cavity has been created which proved suitable both for computational fluid dynamics (CFD) simulations and for the fabrication of physical models. Subsequently, an oral cavity was added to the tracheobronchial geometry. The airway geometry including the oral cavity was adjusted to enable fabrication of a semi-realistic model. Five physical models were created based on these three digital geometries. Two optically transparent models, one with and one without the oral cavity, were constructed for flow velocity measurements, two realistic segmented models, one with and one without the oral cavity, were constructed for particle deposition measurements, and a semi-realistic model with glass cylindrical airways was developed for optical measurements of flow velocity and in situ particle size measurements. One-dimensional phase doppler anemometry measurements were made and compared to the CFD calculations for this model and good agreement was obtained.
