Comparative study of the inhalation parameters of COPD patients through NEXThaler® and Ellipta® dry powder inhalers.

The deposition of dry powder aerosol drugs depends on the inhalation parameters of the patients through the inhaler. These data are not directly measured in clinical practice. Their prediction based on the routinely measured spirometric data could help in choosing the appropriate device and optimizing the therapy. The aim of this study was to perform inhalation experiments to find correlations between inhalation parameters of COPD patients through two DPI devices and their native spirometric data, gender, age and disease severity. Another goal was to establish relationships between peak inspiratory flows through NEXThaler® and Ellipta® inhalers and their statistical determinants. Breathing parameters of 113 COPD patients were measured by normal spirometry and while inhaling through the two DPIs. Statistical analysis of the measured data was performed. The average values of peak inspiratory flow through the devices (PIFdev) were 68.4 L/min and 78.0 L/min for NEXThaler® and Ellipta®, respectively. PIFdev values were significantly higher for males than for females, but differences upon age, BMI and disease severity group were not significant. PIFdev values correlated best with their native spirometric counterparts (PIF) and linear relationships between them were revealed. Current results may be used in the future to predict the success of inhalation of COPD patients through DPI devices, which may help in the inhaler choice. By choosing the appropriate device-drug pair for each patient the lung dose can be increased and the efficiency of the therapy improved. Further results of the clinical study will be the subject of a next publication.

A Novel Combined Dry Powder Inhaler Comprising Nanosized Ketoprofen-Embedded Mannitol-Coated Microparticles for Pulmonary Inflammations: Development, In Vitro-In Silico Characterization, and Cell Line Evaluation.

Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 µm (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4-4.5 µm), fine particle fraction (56-71%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations.

Process development of inhalation powders containing simvastatin loaded liposomes using spray drying technology.

The development of an inhalation powder (IP) for cancer therapy is desired to improve the therapeutic response and patient compliance. The latest studies highlighted that statins, a class of drugs used in hypercholesterolemia, can have anticancer and antiinflammatory properties. Therefore, the aim of the study was to develop an IP containing liposomes loaded with simvastatin using spray drying technology, as well as to investigate the influence of formulation factors on the quality attributes of the IP by means of experimental design. Results highlighted that the composition of liposomes, namely type of phospholipid and cholesterol concentration, highly influences the quality attributes of IP, and the use of optimal concentrations of excipients, i.e. D-mannitol and L-leucine, is essential to preserve the characteristics of liposomes throughout the spray drying process. The in vitro characterization of the optimal IP formulation revealed that the total percentage of released drug is higher from the IP formulation compared to the powder of active substance (53.38 vs. 42.76%) over a period of six hours, and 39.67% of dry particles have a size less than 5 µm, making them suitable for inhalation. As a conclusion, spray drying technology can be effectively used in the development and preparation of IP containing liposomes.

The effect of lung emptying before the inhalation of aerosol drugs on drug deposition in the respiratory system.

The amount of drug depositing in the airways depends, among others, on the inhalation manoeuvre and breathing parameters. The objective of this study was to quantify the effect of lung emptying before the inhalation of drugs on the lung doses. Thirty healthy adults were recruited. Their breathing profiles were recorded while inhaling through six different emptied DPI devices without breathe-out and after comfortable or forced exhalation. The corresponding emitted doses and aerosol size distributions were derived from the literature. The Stochastic Lung Model was used to estimate the deposited doses. In general, forceful exhalation caused increased flow rate and inhaled air volume. Increased flow rate led to the increase of the average lung dose for drugs with positive lung dose-flow rate correlation (e.g. Symbicort®: relative increase of 6.7%, Bufomix®: relative increase of 9.2%). For drugs with negative correlation of lung dose with flow rate (all the studied drugs except the above two) lung emptying caused increased (Foster® by 2.7%), almost unchanged (Seebri®, Relvar®, Bretaris®) and also decreased (Onbrez® by 6.6%) average lung dose. It is worth noting that there were significant inter-individual differences, and lung dose of each drug could be increased by a number of subjects. In conclusion, the change of lung dose depends on the degree of lung emptying, but it is also inhaler and drug specific. Forceful exhalation can help in increasing the lung dose only if the above specificities are taken into account.

Effectiveness and quality of life in lung cancer, pre-, post- and perioperative rehabilitation - A review.

Functional conditions like lung function and exercise capacity are important limiting factors of chest surgery in lung cancer with co-morbidities (chronic obstructive pulmonary disease (COPD) and other chronic respiratory diseases). Pulmonary rehabilitation has a favourable effect on the cardiovascular system, metabolism, respiratory and peripheral muscles and lung mechanics. Our aim was to assess the role of pre-, post- and peri-operative pulmonary rehabilitation in lung cancer in this review. We sought to size up the importance of pulmonary rehabilitation in patients undergoing surgery with or without (neo)adjuvant treatment, radiotherapy, chemotherapy, chemoradiotherapy, major physiological impairments and complications. Searches were performed in PubMed and ClinicalTrials.gov databases using the terms "exercise", "rehabilitation", "small cell lung cancer", "non-small cell lung cancer", "exercise capacity", "chest surgery" and "quality of life" from inception to February 7th, 2022. Pulmonary rehabilitation has been recognized as an effective intervention to reduce lung cancer related symptoms and improve the pulmonary function, lung mechanics, chest kinematics, respiratory- and peripheral muscle function, physical activity and quality of life (QoL) of the patients. In conclusion, this review shows positive, highly encouraging and effective results of pulmonary rehabilitation in terms of the patients' lung function, functional mobility and quality of life. The tools for complex pulmonary rehabilitation have evolved considerably over the past two decades, thus this research has been conducted on a variety of studies about this subject and serves as a synthesis of the systematic and meta-analytic reviews.

Modeling of pulmonary deposition of agents of open and fixed dose triple combination therapies through two different low-resistance inhalers in COPD: a pilot study.

Introduction: Inhalation therapy is a cornerstone of treating patients with chronic obstructive pulmonary disease (COPD). Inhaler devices might influence the effectiveness of inhalation therapy. We aimed to model and compare the deposition of acting agents of an open and a fixed dose combination (FDC) triple therapy and examine their repeatability. Methods: We recruited control subjects (Controls, n = 17) and patients with stable COPD (S-COPD, n = 13) and those during an acute exacerbation (AE-COPD, n = 12). Standard spirometry was followed by through-device inhalation maneuvers using a pressurized metered dose inhaler (pMDI) and a soft mist inhaler (SMI) to calculate deposition of fixed dose and open triple combination therapies by numerical modeling. Through-device inspiratory vital capacity (IVCd) and peak inspiratory flow (PIFd), as well as inhalation time (tin) and breath hold time (tbh) were used to calculate pulmonary (PD) and extrathoracic deposition (ETD) values. Deposition was calculated from two different inhalation maneuvers. Results: There was no difference in forced expiratory volume in 1 s (FEV1) between patients (S-COPD: 42 ± 5% vs. AE-COPD: 35 ± 5% predicted). Spiriva® Respimat® showed significantly higher PD and lower ETD values in all COPD patients and Controls compared with the two pMDIs. For Foster® pMDI and Trimbow® pMDI similar PD were observed in Controls, while ETD between Controls and AE-COPD patients did significantly differ. There was no difference between COPD groups regarding the repeatability of calculated deposition values. Ranking the different inhalers by differences between the two deposition values calculated from separate maneuvers, Respimat® produced the smallest inter-measurement differences for PD. Discussion: Our study is the first to model and compare PD using pMDIs and an SMI as triple combination in COPD. In conclusion, switching from FDC to open triple therapy in cases when adherence to devices is maintanined may contribute to better therapeutic effectiveness in individual cases using low resistance inhalers.

Firework smoke: Impacts on urban air quality and deposition in the human respiratory system.

Particle number concentrations and size distributions resulting from the firework displays held in Budapest, Hungary every year on St. Stephen's Day were studied over a period of seven years. In the year most impacted, the total particle number concentration reached its peak measured level of 369 × 103 cm-3 5 min after the end of the display, and returned to the pre-event state within 45 min. The fireworks increased hourly mean concentrations by a factor of 5-6, whereas the concentrations in the diameter range of 100-1000 nm, in which the magnitude of the increase was the greatest, were elevated by a factor of 20-25. An extra particle size mode at 203 nm was manifested in the size distributions as result of the fireworks. The PM10 mass concentrations at peak firework influence and as 1-h mean increased 123 and 58 times, respectively, relative to the concentration before the display. The smoke was characterised by a relatively short overall atmospheric residence time of 25 min. Spatiotemporal dispersion simulations revealed that there were substantial vertical and horizontal concentration gradients in the firework plume. The affected area made up a large part of the city. Not only the spectators of the display at the venue and nearby areas, but the population located further away downwind of the displays and more distant, large and populous urban quarters were affected by the plume and its fallout. The fireworks increased the deposition rate in the respiratory system of females by a factor of 4, as a conservative estimate. The largest surface density deposition rates were seen in the segmental and sub-segmental bronchi, which represents an excessive risk to health. Compared to adults, children were more susceptible to exposure, with the maximum surface density deposition rates in their case being three times those of adults in the trachea.

The effect of exhalation before the inhalation of dry powder aerosol drugs on the breathing parameters, emitted doses and aerosol size distributions.

Airway deposition of aerosol drugs is highly dependent on the breathing manoeuvre of the patients. Though incorrect exhalation before the inhalation of the drug is one of the most common mistakes, its effect on the rest of the manoeuvre and on the airway deposition distribution of aerosol drugs is not explored in the open literature. The aim of the present work was to conduct inhalation experiments using six dry powder inhalers in order to quantify the effect of the degree of lung emptying on the inhalation time, inhaled volume and peak inhalation flow. Another goal of the research was to determine the effect of the exhalation on the aerodynamic properties of the drugs emitted by the same inhalers. According to the measurements, deep exhalation before drug inhalation increased the volume of the inhaled air and the average and maximum values of the inhalation flow rate, but the extent of the increase was patient and inhaler specific. For different inhalers, the mean value of the relative increase in peak inhalation flow due to forceful exhalation was between 15.3 and 38.4% (min: Easyhaler®, max: Breezhaler®), compared to the case of normal (tidal) exhalation before the drug inhalation. The relative increase in the inhaled volume was between 36.4 and 57.1% (min: NEXThaler®, max: Turbuhaler®). By the same token, forceful exhalation resulted in higher emitted doses and smaller emitted particles, depending on the individual breathing ability of the patient, the inhalation device and the drug metered in it. The relative increase in the emitted dose varied between 0.2 and 8.0% (min: Foster® NEXThaler®, max: Bufomix® Easyhaler®), while the relative enhancement of fine particle dose ranged between 1.9 and 30.8% (min: Foster® NEXThaler®, max: Symbicort® Turbuhaler®), depending on the inhaler. All these effects and parameter values point toward higher airway doses due to forceful exhalation before the inhalation of the drug. At the same time, the present findings highlight the necessity of proper patient education on the importance of lung emptying, but also the importance of patient-specific inhaler-drug pair choice in the future.

Do we really target the receptors? Deposition and co-deposition of ICS-LABA fixed combination drugs.

Fixed dose combinations of aerosolized bronchodilators and steroids are routinely used in current asthma and COPD management. As spatial distribution of their receptors within the human airways is different, it is a challenging task to deliver the right drug component to the right receptor. The aim of this work was to apply numerical methods to analyse the airway deposition distribution of two inhalation corticosteroid (ICS) - long-acting beta-agonist (LABA) combination drugs in comparison with the distribution of the corresponding receptors. Our results revealed that different combination drugs exhibit different co-deposition patterns depending on the aerodynamic properties of their components. While ICS and LABA components of Symbicort® Turbuhaler® had similar deposition efficiencies in the same airway generation throughout the whole respiratory tract, the steroid component of Relvar® Ellipta® had up to 25% higher deposition than its bronchodilator component in the large bronchi and up to 40% lower deposition in the deeper airways. Present results highlight the need for extensive research to elucidate whether each drug component should deposit according to its receptor distribution or similar deposition distribution patterns of the components should be attained to benefit from the synergistic effects documented in the open literature. Once this aspect clarified, the next step will be to tailor the aerodynamic properties of each component of combination drugs to yield the desired deposition distribution in the lungs.

Modeling of nursing care-associated airborne transmission of SARS-CoV-2 in a real-world hospital setting.

Respiratory transmission of SARS-CoV-2 from one older patient to another by airborne mechanisms in hospital and nursing home settings represents an important health challenge during the COVID-19 pandemic. However, the factors that influence the concentration of respiratory droplets and aerosols that potentially contribute to hospital- and nursing care-associated transmission of SARS-CoV-2 are not well understood. To assess the effect of health care professional (HCP) and patient activity on size and concentration of airborne particles, an optical particle counter was placed (for 24 h) in the head position of an empty bed in the hospital room of a patient admitted from the nursing home with confirmed COVID-19. The type and duration of the activity, as well as the number of HCPs providing patient care, were recorded. Concentration changes associated with specific activities were determined, and airway deposition modeling was performed using these data. Thirty-one activities were recorded, and six representative ones were selected for deposition modeling, including patient's activities (coughing, movements, etc.), diagnostic and therapeutic interventions (e.g., diagnostic tests and drug administration), as well as nursing patient care (e.g., bedding and hygiene). The increase in particle concentration of all sizes was sensitive to the type of activity. Increases in supermicron particle concentration were associated with the number of HCPs (r = 0.66; p < 0.05) and the duration of activity (r = 0.82; p < 0.05), while submicron particles increased with all activities, mainly during the daytime. Based on simulations, the number of particles deposited in unit time was the highest in the acinar region, while deposition density rate (number/cm2/min) was the highest in the upper airways. In conclusion, even short periods of HCP-patient interaction and minimal patient activity in a hospital room or nursing home bedroom may significantly increase the concentration of submicron particles mainly depositing in the acinar regions, while mainly nursing activities increase the concentration of supermicron particles depositing in larger airways of the adjacent bed patient. Our data emphasize the need for effective interventions to limit hospital- and nursing care-associated transmission of SARS-CoV-2 and other respiratory pathogens (including viral pathogens, such as rhinoviruses, respiratory syncytial virus, influenza virus, parainfluenza virus and adenoviruses, and bacterial and fungal pathogens).

Effects of hygroscopic growth of ambient urban aerosol particles on their modelled regional and local deposition in healthy and COPD-compromised human respiratory system.

Total, regional and local deposition fractions of urban-type aerosol particles with diameters of 50, 75, 110 and 145 nm were modelled and studied in their dry state and after their hygroscopic growth using a Stochastic Lung Model and a Computational Fluid and Particle Dynamics method. Healthy subjects and patients with severe chronic obstructive pulmonary disease (COPD) were considered. The hygroscopic growth factors (HGFs) adopted were determined experimentally and represent a real urban-type environment. The hygroscopic growth of particles resulted in decrease of the deposition fractions in all major parts of the healthy respiratory system and the extent of the deposited fractions was rising monotonically with particle size. In the extrathoracic (ET) region, the relative decrease was between 7% and 13%. In the lungs the deposition decreased by 11-16%. The decrease of deposition fraction due to hygroscopic growth was more accentuated in the conductive airways (up to 25%) and less pronounced towards the terminal airways. The spatial distribution of the deposited particles remained highly inhomogeneous with some areas containing thousands times more particles than the average number of particles per unit surface area. For COPD patients, the hygroscopic growth produced similar deposition alterations in the ET region than for healthy subjects. In the conductive airways, however, the particle growth caused a substantial relative decrease in the deposition fractions. In contrast, the relative depositions of hygroscopic particles increased in the acinar region.

Effects of Spaceflight on Human Skin.

During both short- and long-duration spaceflight, several health problems can occur, including those of the skin. Astronauts in space and after returning to earth experience erythematous, burning, itchy, dry, sensitive, and thinning skin. Other skin problems, such as infections, abrasions, lacerations, delayed wound healing, and accelerated skin aging, are also common. Human skin is an ecosystem composed of a wide range of habitats for bacteria, fungi, and viruses called microbiome, which not only show a strong skin site-specific preference but also serve as microbial fingerprints that are highly unique to individuals. These human skin-associated microorganisms make a substantial contribution to the microbial ecosystems that inhabit the closed environments in space. On the other hand, human skin microbiome is also subject to change during spaceflight, which may lead to skin infections or the flare up of skin diseases. This review highlights some of the interactions between the space environment and the skin.

Formulation and In Vitro and In Silico Characterization of "Nano-in-Micro" Dry Powder Inhalers Containing Meloxicam.

Pulmonary delivery has high bioavailability, a large surface area for absorption, and limited drug degradation. Particle engineering is important to develop inhalable formulations to improve the therapeutic effect. In our work, the poorly water-soluble meloxicam (MX) was used as an active ingredient, which could be useful for the treatment of non-small cell lung cancer, cystic fibrosis, and chronic obstructive pulmonary disease. We aimed to produce inhalable "nano-in-micro" dry powder inhalers (DPIs) containing MX and additives (poly-vinyl-alcohol, leucine). We targeted the respiratory zone with the microcomposites and reached a higher drug concentration with the nanonized active ingredient. We did the following investigations: particle size analysis, morphology, density, interparticular interactions, crystallinity, in vitro dissolution, in vitro permeability, in vitro aerodynamics (Andersen cascade impactor), and in silico aerodynamics (stochastic lung model). We worked out a preparation method by combining wet milling and spray-drying. We produced spherical, 3-4 µm sized particles built up by MX nanoparticles. The increased surface area and amorphization improved the dissolution and diffusion of the MX. The formulations showed appropriate aerodynamical properties: 1.5-2.4 µm MMAD and 72-76% fine particle fraction (FPF) values. The in silico measurements proved the deposition in the deeper airways. The samples were suitable for the treatment of local lung diseases.

Health effects of cigarettes, electronic cigarettes and waterpipes / A cigaretta, az elektromos cigaretta és a vízipipa egészségre gyakorolt hatása.

Összefoglaló. A dohányzás káros hatásainak vizsgálata hosszú ideje az orvostudomány egyik legintenzívebben kutatott területe. A nagy tudományos érdeklodésnek köszönhetoen ma már meggyozo evidenciák állnak rendelkezésre a hagyományos cigaretta használatának számos negatív hatásáról. Ezzel ellentétben a sokkal késobb bevezetett helyettesíto termékek veszélyeirol lényegesen kevesebbet tudunk. E körbe tartozik a manapság egyre népszerubb elektromos cigaretta is, amelyre egyre több, egészségügyi kockázatot felméro munka fókuszál. Ugyanakkor a több évszázados múltra visszatekinto és a világ bizonyos helyein sokáig népszeru vízipipa érdekes esetnek számít, mivel használóinak száma a nyugati világban az utóbbi idoben megugrott, de az emberre gyakorolt hatása számos ponton még vita tárgyát képezi. A jelen munka célja, hogy a hazai és a nemzetközi szakirodalom alapján feltérképezze a hagyományos cigaretta, az elektromos cigaretta és a vízipipa fontosabb egészségügyi hatásait, és rámutasson azokra a kapcsolódó területekre, ahol további kutatások szükségesek. A szakirodalmi áttekintés során a különbözo publikációs adatbázisokban fellelheto tudományos cikkeket elemeztük. A megvizsgált szakirodalom alapján a tartós dohányzásnak bizonyítottan a szív-ér rendszert és a légzorendszert károsító hatása van, de növekvo számú bizonyíték utal a neurológiai káros hatásokra és a gasztroenterológiai hatásokra is. Ugyanakkor az elektromos cigaretta és a vízipipa esetében a bizonyított akut hatások mellett a hosszú távú hatásokat illetoen további intenzív kutatásokra van szükség. Az elektromos cigaretta és a vízipipa esetében a hosszú távú hatások kapcsán a meggyozo evidencia hiánya semmiképpen nem jelenti azt, hogy ezen termékeket kockázatmentesnek kellene tekinteni, sot a pulmonológusoknak és a döntéshozóknak mindent meg kell tenniük annak érdekében, hogy valamennyi dohánytermék törvényi szabályozása azok használatának visszaszorítását célozza. A kérdés fontosságának a COVID-19-pandémia különös aktualitást ad. Orv Hetil. 2021; 162(3): 83-90. Summary. Revealing the health effects associated with smoking has been in the focus of intense research for decades. Due to these research efforts, there is a convincing evidence regarding the negative effects of conventional cigarettes. However, much less is known about the replacement products such as electronic cigarettes. Moreover, the effects of waterpipes are also not fully explored, in spite of their long history. The scope of the present work is to survey the open literature to map the knowledge related to the health effects of conventional cigarettes, e-cigarettes and waterpipes. The analysis of the related scientific literature was performed based on papers retrieved in large publication repositories. Based on the reviewed literature, long-term smoking has demonstrated adverse effects on the respiratory as well as the heart and circulatory systems. In addition, the correlation between cigarette smoking and some gastroenterological and neurological diseases is also increasingly evident. By the same token, though the acute effects of e-cigarette and waterpipe are well documented, the protracted effects are still to be explored. The lack of pertinent information regarding the late effects of e-cigarette and hookah does not imply that there is no health risk associated with their consumption. On the contrary, in addition to the regular antismoke measures, pulmonologists and policy makers should do everything to lower the consumption of these alternative products. Orv Hetil. 2021; 162(3): 83-90.

Ultrafine urban particle measurements in Budapest and their airway deposition distribution calculation.

OBJECTIVES: The aim of this study was to provide particle number and mass deposition rates of submicron particles in the human airways as inputs for toxicology and other areas of aerosol science. METHODS: Scanning Mobility Particle Spectrometer was used to measure the number concentrations and size distributions of the ultrafine urban particles during summer and winter in Budapest. The Stochastic Lung Model (SLM) was applied to calculate number and mass deposition rates of the inhaled particles in different anatomical regions of the airways. RESULTS: Our calculations revealed that for the selected days in summer and winter with PM10 values below the health limit 4.7 and 18.4 billion particles deposited in the bronchial region of the lungs. The deposition in the acinar region of the lung was even higher, 8.3 billion particles for the summer day, and 33.8 billion particles for winter day. CONCLUSIONS: Our results clearly demonstrate that large daily numbers of urban UFPs are deposited in the respiratory tract, which may play a key role in the health effects of particulate matter (PM) inhalation. Present results, connecting the ambient exposure parameters with the local burden of the airway epithelium, can be useful inputs of in vitro cell culture experiments. By the combination of urban UFP monitoring and numerical modeling of particle deposition with toxicological studies, the health risks of urban aerosols could be better assessed. The use of UFP data in addition to PM10 and PM2.5 in the epidemiological studies would also be indicated.

Aerodynamic properties and in silico deposition of isoniazid loaded chitosan/thiolated chitosan and hyaluronic acid hybrid nanoplex DPIs as a potential TB treatment.

Existing therapies yield low drug encapsulation or accumulation in the lungs, hence the site-specific drug delivery remains the challenge for tuberculosis. Lately, dry powder inhalers (DPIs) are showing promising drug deposition in the deeper lung tissues. Biocompatible polymers with the ability to naturally recognize and bind to the surface receptors of alveolar macrophages, the reservoir of the causative organism, were selected. DPIs comprised of chitosan (CS)/thiolated chitosan (TC) in conjugation with Hyaluronic acid (HA) were synthesized loaded with isoniazid (INH) by using the Design of Experiment (DoE) approach. Nanosuspensions were prepared by ionic gelation method using cross-linker, sodium-tripolyphosphate (TPP) and were optimized by using Box-Behnken 3-level screening design and later freeze-dried to obtain nanopowders. Physico-chemical compatibility of nanoplex systems was investigated using in-vitro characterization techniques. In-vitro release and permeation studies were correlated in terms of the pattern of drug content dissolved over time. In addition, the cytotoxicity studies on A549 cells demonstrated the safety profile of the nanoplexes. Moreover, in-silico studies and aerodynamic profiles verify the suitability of DPIs for further in-vivo tuberculosis therapeutics. DoE analyses affirmed the lack of linearity in the model for the certain response of studied parameters in a holistic way, which was not possible else ways.

The effect of oral and nasal breathing on the deposition of inhaled particles in upper and tracheobronchial airways.

The inhalation route has a substantial influence on the fate of inhaled particles. An outbreak of infectious diseases such as COVID-19, influenza or tuberculosis depends on the site of deposition of the inhaled pathogens. But the knowledge of respiratory deposition is important also for occupational safety or targeted delivery of inhaled pharmaceuticals. Simulations utilizing computational fluid dynamics are becoming available to a wide spectrum of users and they can undoubtedly bring detailed predictions of regional deposition of particles. However, if those simulations are to be trusted, they must be validated by experimental data. This article presents simulations and experiments performed on a geometry of airways which is available to other users and thus those results can be used for intercomparison between different research groups. In particular, three hypotheses were tested. First: Oral breathing and combined breathing are equivalent in terms of particle deposition in TB airways, as the pressure resistance of the nasal cavity is so high that the inhaled aerosol flows mostly through the oral cavity in both cases. Second: The influence of the inhalation route (nasal, oral or combined) on the regional distribution of the deposited particles downstream of the trachea is negligible. Third: Simulations can accurately and credibly predict deposition hotspots. The maximum spatial resolution of predicted deposition achievable by current methods was searched for. The simulations were performed using large-eddy simulation, the flow measurements were done by laser Doppler anemometry and the deposition has been measured by positron emission tomography in a realistic replica of human airways. Limitations and sources of uncertainties of the experimental methods were identified. The results confirmed that the high-pressure resistance of the nasal cavity leads to practically identical velocity profiles, even above the glottis for the mouth, and combined mouth and nose breathing. The distribution of deposited particles downstream of the trachea was not influenced by the inhalation route. The carina of the first bifurcation was not among the main deposition hotspots regardless of the inhalation route or flow rate. On the other hand, the deposition hotspots were identified by both CFD and experiments in the second bifurcation in both lungs, and to a lesser extent also in both the third bifurcations in the left lung.

Simulation of the effect of mucociliary clearance on the bronchial distribution of inhaled radon progenies and related cellular damage using a new deposition and clearance model for the lung.

Most of the current dosimetry models of inhaled short-lived radon decay products assume uniform activity distributions along the bronchial airways. In reality, however, both deposition and clearance patterns of inhaled radon progenies are highly inhomogeneous. Consequently, a new deposition-clearance model has been developed that accounts for such inhomogeneities and applied together with biophysical models of cell death and cell transformation. The scope of this study was to apply this model which is based on computational fluid and particle dynamics methods, in an effort to reveal the effect of mucociliary clearance on the bronchial distribution of deposited radon progenies. Furthermore, the influence of mucociliary clearance on the spatial distribution of biological damage due to alpha-decay of the deposited radon progenies was also studied. The results obtained demonstrate that both deposition and clearance of inhaled radon progenies are highly non-uniform within a human airway bifurcation unit. Due to the topology of the carinal ridge, a slow clearance zone emerged in this region, which is the location where most of the radio-aerosols deposit. In spite of the slow mucus movement in this zone, the initial degree of inhomogeneity of the activity due to the nonuniform deposition decreased by a factor of about 3 by considering the effect of mucociliary clearance. In the peak of the airway bifurcation, the computed cell death and cell transformation probabilities were lower when considering deposition and clearance simultaneously, compared to the case when only deposition was considered. However, cellular damage remained clustered.

Numerical simulation of the effect of inhalation parameters, gender, age and disease severity on the lung deposition of dry powder aerosol drugs emitted by Turbuhaler®, Breezhaler® and Genuair® in COPD patients.

The effect of breathing parameters on the airway deposition of the inhaled aerosols with known size was intensively studied in the literature. However, in the case of dry powder aerosol drugs both the quantity and quality of the particles emitted by the inhaler and inhaled by the patients is a complex function of the patient's breathing parameters, which in turn depend also on the disease severity and current status of the patient. The aim of this study was to evaluate the impact of breathing parameters, gender, age, symptoms and exacerbation history related disease severity (GOLD groups) of chronic obstructive pulmonary disease (COPD) patients on the lung dose of four different drugs emitted by three DPIs (dry powder inhalers). Breathing profiles of 47 COPD patients were recorded while they inhaled through Turbuhaler®, Breezhaler® and Genuair® inhalers. Patient specific emitted doses and particle size distributions were determined for Symbicort® Turbuhaler®, Onbrez® Breezhaler®, Seebri® Breezhaler® and Bretaris® Genuair® aerosol drugs. Airway deposition was quantified by a validated whole respiratory tract particle deposition model. Correlation analysis of the lung doses with breathing parameters through the devices and with standard spirometric parameters was performed. The effects of gender, age and degree of disease severity (GOLD groups) on the lung doses were also studied by statistical analysis. Mean values and distributions of the deposited lung doses proved to be both drug and device specific, yielding 24.2 (±7.8), 22.6 (±3.6), 34.2 (±4.8) and 23.9 (±5.4) % values for Symbicort®, Onbrez®, Seebri® and Bretaris®, respectively. Drugs with flow rate sensitive emitted dose and emitted particle size distribution exhibited higher intersubject variability of the lung doses. The degree of correlation of lung doses with breathing parameters through the devices was also drug specific. Correlation with flow rate was the strongest for Symbicort® Turbuhaler®. Longer breath-hold increased the lung dose of all the studied drugs. Correlations of lung dose with standard spirometric parameters was generally weaker than its correlation with the parameters measured when inhaling through the devices. Men had higher lung deposition than women, younger patients had higher deposition than older ones and patients with less severe disease higher doses than those with more severe COPD, but the differences were statistically significant only upon gender and only in case of Symbicort® and Seebri®. Patients with better inhalation parameters are likely to have higher lung deposition when inhaling a drug with emitted dose and particle size distribution sensitive to the inhalation flow rate. At the same time, patients with lower lung capacity show better deposition results when inhaling from inhalers emitting a more constant amount of drug and particles with more stable aerodynamic characteristics. A more powerful inhalation significantly increases the lung dose for the drug emitted by Turbuhaler®, while long breath-hold is likely to yield significantly higher deposition for drugs emitted by Breezhaler® and Genuair®. Lung doses of two different drugs dispensed in the same inhaler can be significantly different.

Development of an Innovative, Carrier-Based Dry Powder Inhalation Formulation Containing Spray-Dried Meloxicam Potassium to Improve the In Vitro and In Silico Aerodynamic Properties.

Most of the marketed dry powder inhalation (DPI) products are traditional, carrier-based formulations with low drug concentrations deposited in the lung. However, due to their advantageous properties, their development has become justified. In our present work, we developed an innovative, carrier-based DPI system, which is an interactive physical blend of a surface-modified carrier and a spray-dried drug with suitable shape and size for pulmonary application. Meloxicam potassium, a nonsteroidal anti-inflammatory drug (NSAID), was used as an active ingredient due to its local anti-inflammatory effect and ability to decrease the progression of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). The results of the in vitro and in silico investigations showed high lung deposition in the case of this new formulation, confirming that the interparticle interactions were changed favorably.