Lung Deposition Research Articles

Nebulization of emergency medications in the south German rescue service

HintergrundIn der Notfallmedizin ist die Durchführung der inhalativen Therapie auch durch Rettungsfachpersonal vorgesehen. Standard Operating Procedures (SOP) und Handlungsempfehlungen zum Einsatz sind nicht bundeseinheitlich und liegen im Falle der Vernebelung von Notfallmedikamenten nicht in allen Bundesländern und Rettungsdienstbereichen vor. Es existieren auch keine Empfehlungen, welcher Verneblertyp genutzt werden soll. Die Medikamentendepositionsraten von Jet- und Mesh-Verneblern unterscheiden sich aber erheblich; klinisch ist die Verwendung von Mesh-Systemen mit einem besseren Patienten-Outcome assoziiert.Ziel der ArbeitDie vorliegende Umfrage sollte die Praxis des Vernebelns von Notfallmedikamenten im süddeutschen Rettungsdienst evaluieren. Ein besonderes Augenmerk wurde auf den eingesetzten Verneblertyp sowie den Einfluss von SOP und Handlungsempfehlungen auf die Anwendung gelegt.Material und MethodenInsgesamt 4800 in Baden-Württemberg, Bayern und Rheinland-Pfalz tätige Notfallsanitäter*innen und Rettungsassistent*innen erhielten insgesamt 17 Fragen zur Durchführung der Medikamentenvernebelung in ihrer alltäglichen Praxis.ErgebnisseDer Jet-Vernebler ist mit Abstand der am häufigsten eingesetzte Verneblertyp. Die Depositionsraten sowohl des Jet- als auch des Mesh-Verneblers werden deutlich überschätzt. Nur 67,3 % aller Befragten vernebelten im Rahmen von SOP oder Handlungsempfehlungen. Das Vorhandensein dieser war allerdings maßgeblich für den Einsatz der Vernebelung ohne Beisein eines*er Notarzt*ärztin und die gefühlte Sicherheit beim Vernebeln.DiskussionDer flächendeckende Einsatz von Mesh-Verneblern könnte die Therapie von Notfallpatient*innen homogenisieren und möglicherweise das Outcome verbessern. SOP und Handlungsempfehlungen zur Anwendung von Vernebelung in der Notfallsituation könnten die inhalative Therapie verbessern und homogenisieren.Zusatzmaterial onlineDie Online-Version dieses Beitrags (10.1007/s00101-021-00992-x) enthält den der Studie zugrunde liegenden Fragebogen.Beitrag und Zusatzmaterial stehen Ihnen auf www.springermedizin.de zur Verfügung. Bitte geben Sie dort den Beitragstitel in die Suche ein, das Zusatzmaterial finden Sie beim Beitrag unter „Ergänzende Inhalte“.

Spray-dried lactose-leucine microparticles for pulmonary delivery of antimycobacterial nanopharmaceuticals

Pulmonary delivery of nanocarriers for novel antimycobacterial compounds is challenging because the aerodynamic properties of nanomaterials are sub-optimal for such purposes. Here, we report the development of dry powder formulations for nanocarriers containing benzothiazinone 043 (BTZ) or levofloxacin (LVX), respectively. The intricacy is to generate dry powder aerosols with adequate aerodynamic properties while maintaining both nanostructural integrity and compound activity until reaching the deeper lung compartments. Microparticles (MPs) were prepared using vibrating mesh spray drying with lactose and leucine as approved excipients for oral inhalation drug products. MP morphologies and sizes were measured using various biophysical techniques including determination of geometric and aerodynamic mean sizes, X-ray diffraction, and confocal and focused ion beam scanning electron microscopy. Differences in the nanocarriers’ characteristics influenced the MPs’ sizes and shapes, their aerodynamic properties, and, hence, also the fraction available for lung deposition. Spay-dried powders of a BTZ nanosuspension, BTZ-loaded silica nanoparticles (NPs), and LVX-loaded liposomes showed promising respirable fractions, in contrast to zirconyl hydrogen phosphate nanocontainers. While the colloidal stability of silica NPs was improved after spray drying, MPs encapsulating either BTZ nanosuspensions or LVX-loaded liposomes showed the highest respirable fractions and active pharmaceutical ingredient loads. Importantly, for the BTZ nanosuspension, biocompatibility and in vitro uptake by a macrophage model cell line were improved even further after spray drying.Graphical abstract

Cylindrical Microparticles Composed of Mesoporous Silica Nanoparticles for the Targeted Delivery of a Small Molecule and a Macromolecular Drug to the Lungs: Exemplified with Curcumin and siRNA.

The transport of macromolecular drugs such as oligonucleotides into the lungs has become increasingly relevant in recent years due to their high potency. However, the chemical structure of this group of drugs poses a hurdle to their delivery, caused by the negative charge, membrane impermeability and instability. For example, siRNA to reduce tumour necrosis factor alpha (TNF-α) secretion to reduce inflammatory signals has been successfully delivered by inhalation. In order to increase the effect of the treatment, a co-transport of another anti-inflammatory ingredient was applied. Combining curcumin-loaded mesoporous silica nanoparticles in nanostructured cylindrical microparticles stabilized by the layer-by-layer technique using polyanionic siRNA against TNF-α was used for demonstration. This system showed aerodynamic properties suited for lung deposition (mass median aerodynamic diameter of 2.85 ± 0.44 µm). Furthermore, these inhalable carriers showed no acute in vitro toxicity tested in both alveolar epithelial cells and macrophages up to 48 h incubation. Ultimately, TNF-α release was significantly reduced by the particles, showing an improved activity co-delivering both drugs using such a drug-delivery system for specific inhibition of TNF-α in the lungs.

Physiological Factors Affecting Lung Deposition

Ventilation and mechanics of breathing are an integral part of respiratory physiology that directly affect aerosol transport and deposition in the lung. Although natural breathing pattern varies widely among individuals, breathing pattern is controllable, and by using an appropriate breathing pattern, aerosol deposition can be substantially modified for desired purposes. Effects of breathing pattern have been investigated under carefully controlled inhalation conditions covering a wide range of tidal volumes (VT) and breathing frequencies (f) or respiratory times (T = 1/f). The studies have shown that lung deposition can increase or decrease as much as two times by changing the breathing pattern. Specific functional relationships have been found between lung deposition and breathing pattern parameters such that lung deposition can be estimated for any given breathing pattern. Both VT and T have shown strong effects on lung deposition, but their influence is variable depending on particle size, particularly, ultrafine vs. micron-sized particles. VT is more influential than T for micron-sized particles whereas VT and T are equally influential for ultrafine particles. Although effects of lung morphology are difficult to study systematically, comparison between normals and patients with obstructive airway disease has shown that lung deposition is closely related with the degree of airways obstruction and can be 2-3 times greater in patients with obstructive airway disease compared to normals. Thus, breathing pattern and the status of airways obstruction should be carefully considered in designing aerosol delivery and estimating deposition dose.

Quantifying Uncertainty in the Residence Time of the Drug and Carrier Particles in a Dry Powder Inhaler

Abstract Dry powder inhalers (DPI), used as a means for pulmonary drug delivery, typically contain a combination of active pharmaceutical ingredients (API) and significantly larger carrier particles. The microsized drug particles—which have a strong propensity to aggregate and poor aerosolization performance—are mixed with significantly large carrier particles that cannot penetrate the mouth-throat region to deagglomerate and entrain the smaller API particles in the inhaled airflow. Therefore, a DPI's performance depends on the carrier-API combination particles' entrainment and the time and thoroughness of the individual API particles' deagglomeration from the carrier particles. Since DPI particle transport is significantly affected by particle-particle interactions, particle sizes and shapes present significant challenges to computational fluid dynamics (CFD) modelers to model regional lung deposition from a DPI. We employed the Particle-In-Cell method for studying the transport/deposition and the agglomeration and deagglomeration for DPI carrier and API particles in the present work. The proposed development will leverage CFD-PIC and sensitivity analysis capabilities from the Department of Energy laboratories: Multiphase Flow Interface Flow Exchange and Dakota UQ software. A data-driven framework is used to obtain the reliable low order statics of the particle's residence time in the inhaler. The framework is further used to study the effect of drug particle density, carrier particle density and size, fluidizing agent density and velocity, and some numerical parameters on the particles' residence time in the inhaler.

A triple combination 'nano'dry powder inhaler for tuberculosis: in vitro and in vivo pulmonary characterization.

Inhalation route of drug delivery is the most favorable for pulmonary infections wherein direct drug delivery is desired to the lungs. Tuberculosis is one such infection suffering from poor therapeutic efficacy because of low patient compliance due to high drug dosing and lengthy treatment protocols. The current research work was undertaken to develop a dry powder inhaler (DPI) for administration of three first-line antitubercular antibiotics directly to the lungs to improve the treatment rates. Nanoformulations of isoniazid, pyrazinamide, and rifampicin were prepared, spray-dried to obtain a dry powder system, and blended with inhalation grade lactose to develop the DPI. The DPI was evaluated for its flow properties, pulmonary deposition, dissolution profile, and stability. The DPI possessed excellent flow properties with a fine particle fraction of 45% and a mass median aerodynamic diameter of approximately 5µm indicating satisfactory lung deposition. In vitro drug release exhibited a sustained release of the formulations. In vivo studies showed a prolonged deposition in the lung at elevated concentrations compared to oral therapy. Stability studies proved that the formulation remainedstable at accelerated and long-term stability conditions. The DPI could complement the existing oral therapy in enhancing the therapeutic efficacy in patients.

Rapid and Deep versus Normal Breathing in Salbutamol Inhalation Effectiveness; a Letter to Editor.

Metered dose Inhalers (MDIs) are widely used in the management of patients with asthma and choronoc obstractyive polmunary disease (COPD). Studies comparing the efficacy of inhalers versus nebulizers have shown no significant difference (1, 2). Good inhaler technique is essential to improve patient compliance and control of symptom, and diminish side effects. The usual technique is to use 5 tidal breaths. The Global Initiative for Asthma guidelines suggest that patients can take a slow and single breath to inhale the drug or do tidal breathing. The total lung deposition of an inhaled treatment is strongly affected by the speed of inhalation.

Occupational exposure to particulate matter during blackboard teaching and its deposition in the airways of human lungs.

This study aims to estimate the teachers' exposure to particulate matter (PM) during a chalk and talk class considering various exposure conditions and to determine the deposition pattern of PM in human airways. The study was carried out in three steps, viz., questionnaire survey, exposure measurement, and dosage calculation. Exposure to chalk dust during teaching was measured for 40 teachers in terms of PM of different size range (PM 10, PM 2.5, and PM 1) while using different brands of chalks. Deposition in lungs was determined using Multiple Path Dosimetry model for four subject categories, viz., adult men, elderly men, adult women, and elderly women. The average exposure during teaching activity was 498, 85, and 30µg/m3 of PM 10, PM 2.5, and PM 1, respectively. Chalks which are made of calcium carbonate with high density of packing emitted lesser PM 10. Results showed no significant difference in the exposure to PM by teachers while writing at different relative heights of the board. The highest total deposition of PM in lung was observed for elderly women. The deposited mass per unit area was the highest for adult women in all the three sizes of PM. This study showed that there was no significant difference in exposure to PM while using normal and dustless chalks. The exposure level suggests that there is a strong need to either shift to smart classes or to improve the technology in chalk production in such a way that it produces less dust and limit the exposure to teaching professionals.

Stability and In Vitro Aerodynamic Studies of Inhalation Powders Containing Ciprofloxacin Hydrochloride Applying Different DPI Capsule Types.

In the case of capsule-based dry powder inhalation systems (DPIs), the selection of the appropriate capsule is important. The use of gelatin, gelatin-PEG, and HPMC capsules has become widespread in marketed capsule-based DPIs. We aimed to perform a stability test according to the ICH guideline in the above-mentioned three capsule types. The results of the novel combined formulated microcomposite were more favorable than those of the carrier-free formulation for all capsule types. The use of HPMC capsules results in the greatest stability and thus the best in vitro aerodynamic results for both DPI powders after six months. This can be explained by the fact that the residual solvent content (RSC) of the capsules differs. Under the applied conditions the RSC of the HPMC capsule decreased the least and remained within the optimal range, thus becoming less fragmented, which was reflected in the RSC, structure and morphology of the particles, as well as in the in vitro aerodynamic results (there was a difference of approximately 10% in the lung deposition results). During pharmaceutical dosage form developments, emphasis should be placed in the case of DPIs on determining which capsule type will be used for specific formulations.

Growth differentiation factor 15 activates macrophages and fibroblasts

Lung fibrosis is a devastating disease characterized by fibroblast accumulation and extracellular matrix deposition in lungs, and bleomycin-induced lung fibrosis is the most widely used experimental model. We found that mRNA expression of growth differentiation factor 15 (GDF15) was elevated in the lungs of bleomycin-treated mice by using comprehensive gene analysis. The protein levels of GDF15 also increased in lung tissue, brochoalveolar lavage fluid and plasma acquired from bleomycin-treated mice compared with those from saline-treated mice. Although GDF15 is believed to be associated with stress responses, the role of GDF15 in lung fibrosis is still unknown. Histological analysis with senescence-associated β-galactosidase staining and anti-p16INK4a antibody showed cellular senescence of alveolar epithelial cells and macrophages in bleomycin-induced fibrotic lungs. From immunohistochemical staining using anti-GDF15 antibody and increased mRNA expression of GDF15 in bleomycin-induced senescent A549 cells, GDF15 appears to be produced from alveolar epithelial cells undergoing bleomycin-induced cellular senescence. Macrophages are broadly classified as M1 phenotype with inflammatory effects and M2 phenotype with anti-inflammatory effects. GDF15 augmented interleukin-4/interleukin-13-induced mRNA expression of M2 markers including arginase 1 and chitinase-like 3. On the other hand, it is known that myofibroblasts that produce extracellular matrix in lung fibrosis are increased by activation of fibroblasts. GDF15 also increased in protein expression of α-smooth muscle actin (a myofibroblast marker) through ALK5-Smad2/3 pathway in WI-38 lung fibroblasts. These results suggested that GDF15 secreted from senescent alveolar epithelial cells acts as a profibrotic factor through activations of M2 macrophages and fibroblasts. This provides that GDF15 could be an attractive therapeutic target for treatment and a predictor of progression of lung fibrosis.

Repurposing Bedaquiline for Effective Non-Small Cell Lung Cancer (NSCLC) Therapy as Inhalable Cyclodextrin-Based Molecular Inclusion Complexes.

There is growing evidence that repurposed drugs demonstrate excellent efficacy against many cancers, while facilitating accelerated drug development process. In this study, bedaquiline (BDQ), an FDA approved anti-mycobacterial agent, was repurposed and an inhalable cyclodextrin complex formulation was developed to explore its anti-cancer activity in non-small cell lung cancer (NSCLC). A sulfobutyl ether derivative of β-cyclodextrin (SBE-β-CD) was selected based on phase solubility studies and molecular modeling to prepare an inclusion complex of BDQ and cyclodextrin. Aqueous solubility of BDQ was increased by 2.8 × 103-fold after complexation with SBE-β-CD, as compared to its intrinsic solubility. Solid-state characterization studies confirmed the successful incorporation of BDQ in the SBE-β-CD cavity. In vitro lung deposition study results demonstrated excellent inhalable properties (mass median aerodynamic diameter: 2.9 ± 0.6 µm (<5 µm) and fine particle fraction: 83.3 ± 3.8%) of BDQ-CD complex. Accelerated stability studies showed BDQ-CD complex to be stable up to 3 weeks. From cytotoxicity studies, a slight enhancement in the anti-cancer efficacy was observed with BDQ-cyclodextrin complex, compared to BDQ alone in H1299 cell line. The IC50 values for BDQ and BDQ-CD complex were found to be ~40 µM in case of H1299 cell line at 72 h, whereas BDQ/BDQ-CD were not found to be cytotoxic up to concentrations of 50 µM in A549 cell line. Taken together, BDQ-CD complex offers a promising inhalation strategy with efficient lung deposition and cytotoxicity for NSCLC treatment.

Elucidating the Effect of Fine Lactose Ratio on the Rheological Properties and Aerodynamic Behavior of Dry Powder for Inhalation.

Dry powder inhaler (DPI) is recognized as the first choice for lung diseases' treatment. However, it lacks a universal way for DPI formulation development. Fine lactose is commonly added in DPIs to improve delivery performance; however, the fine ratio-dependent mechanism is unclear. Therefore, the objective of this study is to explore the influence of fine lactose ratio on DPI powder properties and aerodynamic behavior, and the fine lactose ratio-dependent mechanism involved during powder fluidization and lung deposition. Here salbutamol sulfate was used as a model drug, Lactohale® 206 as coarse carrier, and Lactohale® 300 as fine component; the mixtures were prepared at 1% drug content, with fine content up to 20%. It was shown that with the fine addition, flowability of the mixtures was improved, interaction among particles was increased, and the presence of fines could help to improve DPI's aerosolization performance. When the fines added were less than 3%, the "active site" hypothesis played a leading role. When the added fines were over 3% but less than 10%, fluidization enhancement mechanism was more important. After the added fines reaching 10%, aggregate mechanism started to dominate. However, FPF cannot be further increased once the fines reached 20%. Moreover, the correlations between FPF and dynamic powder parameters were verified in ternary mixtures, and cohesion had a greater impact on FPF than that of flowability. In conclusion, adding lactose fines is an effective way to improve lung deposition of DPI, with the concrete mechanism lactose fine ratio dependent.

Investigation of sorafenib tosylate loaded liposomal dry powder inhaler for the treatment of non-small cell lung cancer

The present hypothesis was to identify the potential of sorafenib tosylate (ST) loaded liposomal dry powder inhaler (ST-LDPI) for targeting non-small cell lung cancer (NSCLC). ST-LDPI was obtained by spray drying the ST loaded liposomes, evaluated for physicochemical properties and in vitro lung deposition by Andersen Cascade Impactor (ACI). Optimized liposomal formulation showed the particle size, zeta potential, encapsulation efficiency and drug content of 111.15 ± 1.03 nm, −29.87 ± 0.56 mV, 93.13 ± 1.11% and 84.47 ± 1.28%, respectively. Furthermore, ST-LDPI exhibited low density and good flowability. FESEM confirmed the spherical nature of particles with mean size of 3.15 ± 0.51 μm. The DSC and FTIR spectra revealed complete encapsulation of ST. Further, the PXRD showed reduced crystallinity ST. In vitro deposition demonstrated the fine particle fraction of 83.7 ± 0.09%, recovery of 95.43 ± 0.03%, mean mass aerodynamic diameter 3.15 ± 0.2 µm, geometric standard deviation 1.78 ± 0.15 µm and 85 ± 0.1% dispersibility. The In vitro drug release revealed biphasic release pattern, burst release in the first 6 h followed by sustained release up to 72 h. Hence this novel approach could be a targeted delivery of ST to the NSCLC treatment.

Differences between cigarette smoking and biomass smoke exposure: An in silico comparative assessment of particulate deposition in the lungs

Cigarette smoking and biomass smoke are the two main environmental risk factors of chronic obstructive pulmonary disease (COPD) worldwide. However, it remains unclear why these exposures result in two different disease phenotypes. In this study, we assessed the lung deposition from biomass and cigarette smoke exposures and examined whether differences due to inherently different particle size distributions and inhalation conditions may contribute to the differences between biomass- and tobacco-related COPD phenotypes. Using high-fidelity three-dimensional computational fluid-particle dynamics in a representative upper airway geometry, coupled to one-dimensional models of the lower airways, we computed total deposited doses and examined regional deposition patterns based on exposure data from a randomized control trial in Peru and from the literature for biomass and mainstream cigarette smoke, respectively. Our results showed that intrathoracic deposition was higher in cigarette smoking, with 36.8% of inhaled biomass smoke particles and 57.7% of cigarette smoke particles depositing in the intrathoracic airways. We observed higher fractions of cigarette smoke particles in the last few airway generations, which could explain why cigarette smoking is associated with more emphysema than biomass smoke exposure. Mean daily deposited dose was two orders of magnitude higher in cigarette smoking. Lobar distributions of the deposited dose also differed, with the left lower and right upper lobes receiving the highest doses of biomass and cigarette smoke particles, respectively. Our findings suggest that the differences between biomass- and tobacco-related COPD could, at least in part, be due to differences in total and regional lung deposition of biomass and cigarette smoke.

Physicochemical analysis techniques specialized in surface characterization of inhalable dry powders

Dry powder inhaler (DPI) formulations are highly efficient in pulmonary drug delivery because devices for their delivery are portable and aerosolization does not require a propellant. The performance of DPIs depends on various physical properties of particles for their manufacture, including aerodynamic diameter, density, particle shape, surface composition, morphology, roughness, and energy. Among these, particle surface properties are the most important factors in determining the interparticulate interactions, which affect the aerosolization efficiency, physicochemical stability, and subsequent in vivo lung deposition efficiency. For a better understanding of the correlation between surface properties and the performance of DPI, there is the need to perform surface characterization of the DPI. This review focuses on analysis of the technology used in the design of DPIs. Thus, the surface crystallinity and polymorphism, surface energy, surface roughness, and changes in solid-state properties of the particles used in DPI formulation will be determined. The commonly used solid-state techniques may not be appropriate for the characterization of DPIs because their detection is mainly limited to the fine changes in physicochemical surface properties such as partial amorphous contents generated on the drug particle surface. Thus, sophisticated technologies with higher detection limits and superior spatial resolutions are required for in-depth characterization. Data obtained from surface analytical techniques can lead to an in-depth understanding of inhalable dry powder at the particle surface. This can provide unique predictive insights into rationally designing inhalable particles with optimal surface properties to provide optimal aerosolization performance for a given DPI formulation.

Inhalable Jojoba Oil Dry Nanoemulsion Powders for the Treatment of Lipopolysaccharide- or H2O2-Induced Acute Lung Injury

Jojoba (Simmondsia chinensis (Link) C.K. Schneid) is a dioecious plant in desert and semi-desert areas, e.g., the Ismailia Desert in Egypt. Jojoba oil (JJBO) is a natural slight yellow oil with the functions of skin barrier repairing and wound healing, which is dermally applied as a traditional medication or cosmetic in the Middle East. The objective of this study was to prepare JJBO dry nanoemulsion powders (JNDs) and investigate their anti-acute lung injury effects. JJBO nanoemulsions (JNEs) were prepared and then lyophilized to JNDs and the properties and simulated lung deposition were measured. Rat acute lung injury (ALI) models were established after intratracheal (i.t.) administration of lipopolysaccharide (LPS) or hydrogen peroxide (H2O2). JNDs and dexamethasone (DXM) solutions were also i.t. administered to the rats. The pathological states of lung tissues were checked. Inflammatory and oxidative factors in the lung tissues were determined using ELISA methods. NF-κB p65 and caspase-3 were measured with a Western blotting method and an immunohistochemical method, respectively. JNDs had an appropriate mass median aerodynamic diameter (MMAD) of 4.17 µm and a fine particle fraction (FPF) of 39.11%. JNDs showed higher anti-inflammatory effect on LPS-induced ALI than DXM with a decrease in total protein content and down-regulation of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and NF-κB p65. JNDs also showed higher anti-inflammatory and anti-oxidation effect on H2O2-induced ALI than DXM with elimination of reactive oxygen species (ROS), increasing of superoxide dismutase (SOD), decrease in of lipid peroxide malondialdehyde (MDA) and glutathione (GSH), and inhibition of caspase-3 expression. Moreover, i.t. JNDs attenuated bleeding and infiltrations of the inflammatory cells in the two ALI models. JNDs are a promising natural oil-contained inhalable medication for the treatment of LPS- or H2O2-induced ALI.

Essentials for aerosol delivery to term and pre-term infants.

Effectively delivering pharmaceutical aerosols to the lungs of preterm and term infants represents a considerable technical challenge. Small infants are obligatory nose breathers, they have small airways, low tidal volumes and rapid respiration rates. It is ethically unacceptable to investigate aerosol deposition in vivo in newborns due to ethical concerns about the radiation exposure involved in imaging studies and drug delivery and blood draws in pharmacokinetics studies. The purpose of the work reported in this article was thus to report the use of modeling to develop an understanding of the regional deposition of aerosols in neonates and to build a theoretical basis for choosing an optimum aerosol size to maximize delivery and minimize variability. Recent data on aerosol deposition in the nasal airways of newborn term and preterm infants was coupled to an established, scalable, lung deposition model to investigate the effects of age, aerosol size and ventilation on regional airway deposition. In the term newborn infant lung deposition ranged from 25% to 35% depending on Geometric Standard Deviations (GSDs). Intrasubject variability was minimized for aerosols with larger GSD. However, mean lung deposition is reduced with increasing GSD. A compromise between maximum lung deposition and increased intersubject variability appears to be in the region of GSDs of 1.75. In the 30-week GA preterm infant lung deposition is slightly higher than in the term infant despite smaller airways and lower tidal volumes. This is likely due to the lower inhaled flow rates that are concomitant with lower lung volumes. Finally, when aerosol delivery is directly to the trachea, as it would be if delivered via an endotracheal tube there is a monotonic increase in lung deposition with increasing aerosol size with peripheral deposition peaking at 2 to 3 µm. However, practical limitations of aerosol transport through endotracheal tubes, limiting delivered aerosol size, likely caps lung deposition at around 30% to 30% of the delivered dose.

Lung Deposition and Inspiratory Flow Rate in Patients with Chronic Obstructive Pulmonary Disease Using Different Inhalation Devices: A Systematic Literature Review and Expert Opinion.

BackgroundOur aim was to describe: 1) lung deposition and inspiratory flow rate; 2) main characteristics of inhaler devices in chronic obstructive pulmonary disease (COPD).MethodsA systematic literature review (SLR) was conducted to analyze the features and results of inhaler devices in COPD patients. These devices included pressurized metered-dose inhalers (pMDIs), dry powder inhalers (DPIs), and a soft mist inhaler (SMI). Inclusion and exclusion criteria were established, as well as search strategies (Medline, Embase, and the Cochrane Library up to April 2019). In vitro and in vivo studies were included. Two reviewers selected articles, collected and analyzed data independently. Narrative searches complemented the SLR. We discussed the results of the reviews in a nominal group meeting and agreed on various general principles and recommendations.ResultsThe SLR included 71 articles, some were of low–moderate quality, and there was great variability regarding populations and outcomes. Lung deposition rates varied across devices: 8%–53% for pMDIs, 7%-69% for DPIs, and 39%–67% for the SMI. The aerosol exit velocity was high with pMDIs (more than 3 m/s), while it is much slower (0.84–0.72 m/s) with the SMI. In general, pMDIs produce large-sized particles (1.22–8 μm), DPIs produce medium-sized particles (1.8–4.8 µm), and 60% of the particles reach an aerodynamic diameter <5 μm with the SMI. All inhalation devices reach central and peripheral lung regions, but the SMI distribution pattern might be better compared with pMDIs. DPIs’ intrinsic resistance is higher than that of pMDIs and SMI, which are relatively similar and low. Depending on the DPI, the minimum flow inspiratory rate required was 30 L/min. pMDIs and SMI did not require a high inspiratory flow rate.ConclusionLung deposition and inspiratory flow rate are key factors when selecting an inhalation device in COPD patients.

Effect of different accessory devices on the dose delivered from pressurised metred-dose inhalers.

Improved aerosol delivery of bronchodilators to chronic obstructive pulmonary disease (COPD) subjects is a cornerstone in the treatment approach. Drug delivery and response are improved with the use of accessory devices [spacers and valved holding chambers (VHCs)] with metred-dose inhalers (pMDIs). However, different accessory devices are available in the market with different properties that could affect aerosol delivery. Thus, this study aimed to assess the relative lung deposition and systemic bioavailability and compare bronchodilator response of salbutamol delivered using different accessory devices attached to pMDIs. Twelve healthy subjects and twelve COPD subjects inhaled 300 μg salbutamol (3 pMDI puffs) using five different accessory devices with either masks or mouthpieces (Able, Aerochamber plus flow Vu, Dolphin chamber, Tipshaler spacer, and modified Drink bottle spacer). Urine samples were collected thirty minutes post-dosing and cumulatively for the next twenty-four hours, to determine and compare the relative lung deposition [0-0.5 hour excretion of urinary salbutamol (USAL0.5)] and systemic bioavailability [0.5-24hours excretion of urinary salbutamol (USAL24)] of salbutamol from the selected accessory devices. Also, the difference between pre and post-inhalation forced expiratory volume in one second (ΔFEV1 %) of predicted was determined for each accessory device. Urinary excretion of salbutamol (both USAL0.5 and USAL24 samples) in COPD subjects was significantly (P<.05) lower than in healthy subjects for all accessory devices. USAL0.5 and USAL24 in non-antistatic spacers (modified Drink bottle spacer and Dolphin chamber spacers) were significantly lower (P<.05) than that for antistatic spacers (Aerochamber plus flow Vu, Able and Tips-haler). No significant difference in USAL0.5 and USAL24 was observed between facemasks and mouthpieces. There was a significant difference (P<.05) in ΔFEV1 % of predicted values between COPD subjects and healthy subjects. However, within the COPD group and the healthy group there was no significant difference in ΔFEV1 % of predicted values between all accessory devices or between with mouthpiece or with a mask. COPD subjects had lower aerosol delivered compared with healthy subjects. Anti-static accessory devices delivered a higher amount of aerosol compared with non-antistatic accessory devices. Even though the presence of a significant difference in aerosol delivery between non-antistatic and antistatic accessory devices no significant difference was found in the ΔFEV1 % between all accessory devices.

Controlled Pulmonary Delivery of Carrier-Free Budesonide Dry Powder by Atomic Layer Deposition.

Ideal controlled pulmonary drug delivery systems provide sustained release by retarding lung clearance mechanisms and efficient lung deposition to maintain therapeutic concentrations over prolonged time. Here, we use atomic layer deposition (ALD) to simultaneously tailor the release and aerosolization properties of inhaled drug particles without the need for lactose carrier. In particular, we deposit uniform nanoscale oxide ceramic films, such as Al2O3, TiO2, and SiO2, on micronized budesonide particles, a common active pharmaceutical ingredient for the treatment of respiratory diseases. In vitro dissolution and ex vivo isolated perfused rat lung tests demonstrate dramatically slowed release with increasing nanofilm thickness, regardless of the nature of the material. Ex situ transmission electron microscopy at various stages during dissolution unravels mostly intact nanofilms, suggesting that the release mechanism mainly involves the transport of dissolution media through the ALD films. Furthermore, in vitro aerosolization testing by fast screening impactor shows a ∼2-fold increase in fine particle fraction (FPF) for each ALD-coated budesonide formulation after 10 ALD process cycles, also applying very low patient inspiratory pressures. The higher FPFs after the ALD process are attributed to the reduction in the interparticle force arising from the ceramic surfaces, as evidenced by atomic force microscopy measurements. Finally, cell viability, cytokine release, and tissue morphology analyses verify a safe and efficacious use of ALD-coated budesonide particles at the cellular level. Therefore, surface nanoengineering by ALD is highly promising in providing the next generation of inhaled formulations with tailored characteristics of drug release and lung deposition, thereby enhancing controlled pulmonary delivery opportunities.