Impact of Nebulization on the Physicochemical Properties of Polymer-Lipid Hybrid Nanoparticles for Pulmonary Drug Delivery.

Nanoparticles (NPs) have shown significant potential for pulmonary administration of therapeutics for the treatment of chronic lung diseases in a localized and sustained manner. Nebulization is a suitable method of NP delivery, particularly in patients whose ability to breathe is impaired due to lung diseases. However, there are limited studies evaluating the physicochemical properties of NPs after they are passed through a nebulizer. High shear stress generated during nebulization could potentially affect the surface properties of NPs, resulting in the loss of encapsulated drugs and alteration in the release kinetics. Herein, we thoroughly examined the physicochemical properties as well as the therapeutic effectiveness of Infasurf lung surfactant (IFS)-coated PLGA NPs previously developed by us after passing through a commercial Aeroneb® vibrating-mesh nebulizer. Nebulization did not alter the size, surface charge, IFS coating and bi-phasic release pattern exhibited by the NPs. However, there was a temporary reduction in the initial release of encapsulated therapeutics in the nebulized compared to non-nebulized NPs. This underscores the importance of evaluating the drug release kinetics of NPs using the inhalation method of choice to ensure suitability for the intended medical application. The cellular uptake studies demonstrated that both nebulized and non-nebulized NPs were less readily taken up by alveolar macrophages compared to lung cancer cells, confirming the IFS coating retention. Overall, nebulization did not significantly compromise the physicochemical properties as well as therapeutic efficacy of the prepared nanotherapeutics.

Preliminary bronchodilator dose effect on aerosol-delivery through different nebulizers in noninvasively ventilated COPD patients.

Objectives: This study aimed to evaluate the effect of a preliminary bronchodilator dose on the aerosol-d elivery by different nebulizers in noninvasively ventilated chronic obstructive pulmonary disease (COPD) patients. Method: COPD patients were randomized to receive study doses of 800 µg beclomethasone dipropionate (BPD) nebulized by either a vibrating mesh nebulizer (VMN) or a jet nebulizer (JN) connected to MinimHal spacer device. On a different day, the nebulized dose of beclomethasone was given to each patient by the same aerosol generator with and without preceded two puffs (100 µg each) of salbutamol delivered by a pressurized-metered dose inhaler. Urinary BPD and its metabolites in 30 min post-inhalation samples and pooled up to 24 h post-inhalation were measured. On day 2, ex-vivo studies were performed with BPD collected on filters before reaching patients which were eluted from filters and analyzed to estimate the total emitted dose.Results: The highest urinary excretion amounts of BPD and its metabolites 30 min and 24 h post-inhalation were identified with pMDI + VMN compared with other regimens(p < 0.001). The amounts of BPD and its metabolites excreted 30 min post inhalation had approximately doubled with pMDI + JN compared with JN delivery (p < 0.05). No significant effect was found in the ex-vivo study results except between VMN and JN with a significant superiority of the VMN (p < 0.001).Conclusion: Using a preliminary bronchodilator dose before drug nebulization significantly increased the effective lung dose of the nebulized drug with both VMNs and JNs. However, adding a preliminary bronchodilator dose increased the 24 hr cumulative urinary amount of the drug representing higher systemic delivery of the drug, which in turn could result in higher systemic side effects.

Utility of Three Nebulizers in Investigating the Infectivity of Airborne Viruses.

Laboratory-generated bioaerosols are widely used in aerobiology studies of viruses; however, few comparisons of alternative nebulizers exist. We compared aerosol production and virus survival for a Collison nebulizer, vibrating mesh nebulizer (VMN), and hydraulic spray atomizer (HSA). We also measured the dry size distribution of the aerosols produced and calculated the droplet sizes before evaporation and the dry size distribution from normal saline solution. Dry count median diameters of 0.11, 0.22, and 0.30 µm were found for normal saline from the Collison nebulizer, VMN, and HSA, respectively. The volume median diameters were 0.323, 1.70, and 1.30 µm, respectively. The effect of nebulization on the viability of two influenza A viruses (IAVs) (H1N1 and H3N2) and human rhinovirus 16 (HRV-16) was assessed by nebulization into an SKC BioSampler. The HSA had the least impact on surviving fractions (SFs) of H1N1 and H3N2 (89% ± 3% and 94% ± 2%, respectively), followed by the Collison nebulizer (83% ± 1% and 82% ± 2%, respectively). The VMN yielded SFs of 78% ± 2% and 76% ± 2%, respectively. Conversely, for HRV-16, the VMN produced higher SFs (87% ± 8%). Our findings indicate that there were no statistical differences between SFs of the viruses nebulized by these nebulizers. However, VMN produced higher aerosol concentrations within the airborne size range, making it more suitable where high aerosol mass production is required. IMPORTANCE Viral respiratory tract infections cause millions of lost days of work and physician visits globally, accounting for significant morbidity and mortality. Respiratory droplets and droplet nuclei from infected hosts are the potential carriers of such viruses within indoor environments. Laboratory-generated bioaerosols are applied in understanding the transmission and infection of viruses, modeling the physiological aspects of bioaerosol generation in a controlled environment. However, little comparative characterization exists for nebulizers used in infectious disease aerobiology, including Collison nebulizer, vibrating mesh nebulizer, and hydraulic spray atomizer. This study characterized the physical features of aerosols generated by laboratory nebulizers and their performance in producing aerosols at a size relevant to airborne transmission used in infectious disease aerobiology. We also determined the impact of nebulization mechanisms of these nebulizers on the viability of human respiratory viruses, including IAV H1N1, IAV H3N2, and HRV-16.

Effect of functional principle, delivery technique, and connection used on aerosol delivery from different nebulizers: An in-vitro study.

OBJECTIVE: Nebulizers can be divided according to their functional principle into jet, ultrasonic and vibrating mesh nebulizers with intermittent or continuous aerosol delivery and may be used with many different adapters and connections and all can influence their efficiency. The aim of the present work was to evaluate the effect functional principle, delivery technique, and connection used on aerosol delivered from four different nebulizers. METHODS: Four nebulizers were used in the study; three of them were jet nebulizers (JNs; AeroEclipse, NebuTech, En ful Kit) and one of them was Aerogen Solo vibrating mesh nebulizers (VMN). AeroEclipse and NebuTech are intermittent output nebulizers, while the rest are continuous output nebulizers. Aerogen Solo was used with either a standard T-piece or Aerogen Ultra holding chamber, and En ful Kit was used with a standard T-piece or Circulaire II holding chamber. 2 ml of salbutamol was nebulized to determine the total emitted dose (TED) and aerodynamic droplet characteristics of the emitted aerosol from the 6 different sets (4 nebulizers with T-piece and 2 holding chambers). RESULTS: The mean ± SD TED from VMN was significantly higher than all the JNs (p < 0.05). Aerogen Ultra with VMN did not show a significant effect on TED compare to T-piece, but it significantly increased (p < 0.05) fine particle dose (FPD; 3091.5 ± 189.4 µg) and fine particle fraction (FPF; 72.7 ± 3.6%). However, the Circulaire II with En ful Kit had significantly higher TED, FPD, and FPF compared to T-piece (p < 0.05). Intermittent JNs (AeroEclipse and NebuTech) had significantly higher TED (p < 0.05) compared to the continuous JNs (En ful Kit) with no significant effect on the other parameters studied. AeroEclipse had the highest MMAD and Aerogen Solo Ultra has the lowest in MMAD. CONCLUSIONS: The functional principle, delivery technique, and connection used had a significant effect on aerosol delivered from nebulizers. VMNs are significantly better than JNs. Intermittent delivery has significantly better TED than continuous delivery. Holding chamber with both VMNs and JNs improved aerosol delivery compared to standard T-piece.

A narrative review on trans-nasal pulmonary aerosol delivery.

The use of trans-nasal pulmonary aerosol delivery via high-flow nasal cannula (HFNC) has expanded in recent years. However, various factors influencing aerosol delivery in this setting have not been precisely defined, and no consensus has emerged regarding the optimal techniques for aerosol delivery with HFNC. Based on a comprehensive literature search, we reviewed studies that assessed trans-nasal pulmonary aerosol delivery with HFNC by in vitro experiments, and in vivo, by radiolabeled, pharmacokinetic and pharmacodynamic studies. In these investigations, the type of nebulizer employed and its placement, carrier gas, the relationship between gas flow and patient's inspiratory flow, aerosol delivery strategies (intermittent unit dose vs continuous administration by infusion pump), and open vs closed mouth breathing influenced aerosol delivery. The objective of this review was to provide rational recommendations for optimizing aerosol delivery with HFNC in various clinical settings.

Size distribution of salbutamol/ipratropium aerosols produced by different nebulizers in the absence and presence of heat and humidification.

BACKGROUND: Few studies have evaluated the size distribution of inhaled and exhaled aerosolized drugs, or the effect of heated humidification on particle size and lung deposition. The present study evaluated these aspects of bronchodilator (salbutamol/ipratropium) delivery using a lung model in the absence and presence of heat and humidification. METHODS: We positioned filters to collect and measure the initial drug, inhaled drug, and exhaled drug. Particle size distribution was evaluated using an 8-stage Marple personal cascade impactor with 0.2-µm polycarbonate filters. RESULTS: A greater inhaled drug mass was delivered using a vibrating mesh nebulizer (VMN) than by using a small volume nebulizer (SVN), when heated humidifiers were not employed. When heated and humidified medical gas was used, there was no significant difference between the inhaled drug mass delivered by the VMN and that delivered by the SVN. A significantly greater mass of inhaled 1.55-µm drug particles was produced by the VMN than with the SVN, under heated and humidified conditions. However, the mass median aerodynamic diameters (MMADs) of the aerosolized drug produced by the SVN and VMN did not differ significantly under the same conditions. CONCLUSIONS: The VMN produced more fine particles of salbutamol/ipratropium, and the drug particle size clearly increased in the presence of heat and humidification.

SPECT-CT Comparison of Lung Deposition using a System combining a Vibrating-mesh Nebulizer with a Valved Holding Chamber and a Conventional Jet Nebulizer: a Randomized Cross-over Study.

PURPOSE: To compare in vivo the total and regional pulmonary deposition of aerosol particles generated by a new system combining a vibrating-mesh nebulizer with a specific valved holding chamber and constant-output jet nebulizer connected to a corrugated tube. METHODS: Cross-over study comparing aerosol delivery to the lungs using two nebulizers in 6 healthy male subjects: a vibrating-mesh nebulizer combined with a valved holding chamber (Aerogen Ultra®, Aerogen Ltd., Galway, Ireland) and a jet nebulizer connected to a corrugated tube (Opti-Mist Plus Nebulizer®, ConvaTec, Bridgewater, NJ). Nebulizers were filled with diethylenetriaminepentaacetic acid labelled with technetium-99 m (99mTc-DTPA, 2 mCi/4 mL). Pulmonary deposition of 99mTc-DTPA was measured by single-photon emission computed tomography combined with a low dose CT-scan (SPECT-CT). RESULTS: Pulmonary aerosol deposition from SPECT-CT analysis was six times increased with the vibrating-mesh nebulizer as compared to the jet nebulizer (34.1 ± 6.0% versus 5.2 ± 1.1%, p < 0.001). However, aerosol penetration expressed as the three-dimensional normalized ratio of the outer and the inner regions of the lungs was similar between both nebulizers. CONCLUSIONS: This study demonstrated the high superiority of the new system combining a vibrating-mesh nebulizer with a valved holding chamber to deliver nebulized particles into the lungs as comparted to a constant-output jet nebulizer with a corrugated tube.

Systematic aging of degradable nanosuspension ameliorates vibrating-mesh nebulizer performance.

CONTEXT: The process of vibrating-mesh nebulization is affected by sample physicochemical properties. Exemplary, electrolyte supplementation of diverse formulations facilitated the delivery of adequate aerosols for deep lung deposition. OBJECTIVE: This study addressed the impact of storage conditions of poly(lactide-co-glycolide) nanosuspension on aerosol properties when nebulized by the eFlow®rapid. MATERIALS AND METHODS: First, purified nanosuspensions were supplemented with electrolytes (i.e. sodium chloride, lactic and glycolic acid). Second, the degradable nanoparticles (NP) were incubated at different temperatures (i.e. 4, 22 and 36 °C) for up to two weeks. The effect of formulation supplementation and storage on aerosol characteristics was studied by laser diffraction and correlated with the sample conductivity. RESULTS AND DISCUSSION: Nebulization of purified nanosuspensions resulted in droplet diameters of >7.0 µm. However, electrolyte supplementation and storage, which led to an increase in sample conductivity (>10-20 µS/cm), were capable of providing smaller droplet diameters during vibrating-mesh nebulization (≤5.0 µm). No relevant change of NP properties (i.e. size, morphology, remaining mass and molecular weight of the employed polymer) was observed when incubated at 22 °C for two weeks. CONCLUSION: Sample aging is an alternative to electrolyte supplementation in order to ameliorate the aerosol characteristics of degradable NP formulations when nebulized by vibrating-mesh technology.

Effect of Interrupting Heated Humidification on Nebulized Drug Delivery Efficiency, Temperature, and Absolute Humidity During Mechanical Ventilation: A Multi-Lab In Vitro Study.

Introduction: During mechanical ventilation (MV), inspired gases require heat and humidification. However, such conditions may be associated with reduced aerosol delivery efficiency. The practice of turning off heated humidification before nebulization and the impact of nebulization on humidity in a dry ventilator circuit remain topics of debate. This study aimed to assess the effect of turning off heated humidification on inhaled dose and humidity with nebulizer use during adult MV. Methods: A bronchodilator (albuterol) and two antibiotics (Colistimethate sodium and Amikacin sulfate) were nebulized with a vibrating mesh nebulizer placed at the humidifier inlet and in the inspiratory limb at the Y-piece. Additionally, albuterol was nebulized using a jet nebulizer in both placements. Aerosol particle size distribution was determined through a cascade impactor. Absolute humidity (AH) and temperature of inspired gases were determined with anemometer/hygrometers before, during, and after nebulization, before, during, and up to 60 minutes after interrupting active humidification. Aerosol collected on a filter distal to the endotracheal tube and on impactor stages were eluted and assayed by spectrophotometry. Results: The inhaled dose was greater when both nebulizers were placed at the humidifier inlet than the inspiratory limb at the Y-piece. Irrespective of the nebulizer types and placements, the inhaled dose either decreased or showed no significant change after the humidifier was turned off. The aerosol particle size ranged from 1.1 to 2.7 µm. With interruption of active humidification, humidity of inspired gas quickly dropped below recommended levels, and nebulization in dry ventilator circuit produced an AH between 10 and 20 mgH2O/L, lower than the recommended minimum of 30 mgH2O/L. Conclusion: Interrupting active humidification during MV before nebulization did not improve aerosol delivery efficiency for bronchodilator or antibiotics, but did reduce humidity below recommended levels.

Bronchodilator Efficacy of High-Flow Nasal Cannula in COPD: Vibrating Mesh Nebulizer Versus Jet Nebulizer.

BACKGROUND: Jet nebulizers are commonly used for bronchodilator therapy in COPD. High-flow nasal cannula with vibrating mesh nebulizer (HFNC-VMN) is a recently developed system; however, few studies have compared the efficacy of bronchodilator administration via HFNC-VMN to jet nebulizer in stable COPD. This study aimed to compare the effect of salbutamol administered via HFNC-VMN versus jet nebulizer on airway and lung function in subjects with stable COPD. METHODS: This randomized non-inferiority crossover physiologic study enrolled subjects with stable COPD. Salbutamol was nebulized via HFNC-VMN or jet nebulizer in random order with a 4-h washout period between crossover sequences. Spirometry, lung volume, and impulse oscillometry were performed at baseline and after each intervention. The primary outcome was change in FEV1 from baseline. Secondary outcomes included changes in other respiratory-related parameters and nebulization time compared between the 2 devices. RESULTS: Seventeen subjects were enrolled. HFNC-VMN and jet nebulizer both significantly improved FEV1 from baseline (P = .005 and P = .002, respectively). The difference between respiratory resistance at 5 Hz and 20 Hz significantly decreased after HFNC-VMN compared to baseline (P = .02), while no significant change was observed after jet nebulizer (P = .056). Area of reactance and resonant frequency of reactance were both significantly decreased (P = .035 and P = .03, respectively), and respiratory reactance at 5 Hz significantly increased (P = .02) in the HFNC-VMN group compared to baseline indicating improved lung mechanics, with no significant changes with the jet nebulizer. HFNC-VMN had a shorter nebulization time (6 [5-9] min vs 20 [16-22] min, respectively, P < .001). CONCLUSIONS: Bronchodilator therapy via HFNC-VMN was not inferior to jet nebulizer for subjects with stable COPD and can significantly improve airway oscillometry mechanics and decrease nebulization time compared to jet nebulizer.

The Effects of Inspiratory Flows, Inspiratory Pause, and Suction Catheter on Aerosol Drug Delivery with Vibrating Mesh Nebulizers During Mechanical Ventilation.

Background: Some experts recommend specific ventilator settings during nebulization for mechanically ventilated patients, such as inspiratory pause, high inspiratory to expiratory ratio, and so on. However, it is unclear whether those settings improve aerosol delivery. Thus, we aimed to evaluate the impact of ventilator settings on aerosol delivery during mechanical ventilation (MV). Methods: Salbutamol (5.0 mg/2.5 mL) was nebulized by a vibrating mesh nebulizer (VMN) in an adult MV model. VMN was placed at the inlet of humidifier and 15 cm away from the Y-piece of the inspiratory limb. Eight scenarios with different ventilator settings were compared with endotracheal tube (ETT) connecting 15 cm from the Y-piece, including tidal volumes of 6-8 mL/kg, respiratory rates of 12-20 breaths/min, inspiratory time of 1.0-2.5 seconds, inspiratory pause of 0-0.3 seconds, and bias flow of 3.5 L/min. In-line suction catheter was utilized in two scenarios. Delivered drug distal to the ETT was collected by a filter, and drug was assayed by an ultraviolet spectrophotometry (276 nm). Results: Compared to the use of inspiratory pause, the inhaled dose without inspiratory pause was either higher or similar across all ventilation settings. Inhaled dose was negatively correlated with inspiratory flow with VMN placed at 15 cm away from the Y-piece (rs = -0.68, p < 0.001) and at the inlet of humidifier (rs = -0.83, p < 0.001). The utilization of in-line suction catheter reduced inhaled dose, regardless of the ventilator settings and nebulizer placements. Conclusions: When VMN was placed at the inlet of humidifier, directly connecting the Y-piece to ETT without a suction catheter improved aerosol delivery. In this configuration, the inhaled dose increased as the inspiratory flow decreased, inspiratory pause had either no or a negative impact on aerosol delivery. The inhaled dose was greater with VMN placed at the inlet of humidifier than 15 cm away the Y-piece.

Aerosol Delivery to Simulated Spontaneously Breathing Tracheostomized Adult Model With and Without Humidification.

BACKGROUND: Optimal aerosol delivery methods for spontaneously breathing patients with a tracheostomy remain unclear. Thus, we aimed to assess the impact of nebulizer placement, flow settings, and interfaces on aerosol delivery by using a vibrating mesh nebulizer and a jet nebulizer in line with unheated humidification. METHODS: An 8.0-mm tracheostomy tube was connected to the lung model that simulates adult breathing parameters via a collecting filter. Albuterol sulfate (2.5 mg/3 mL) was administered via a vibrating mesh nebulizer and a jet nebulizer, which was placed in line with unheated humidification provided by a large-volume nebulizer, with FIO2 set at 0.28, with gas flows of 2 L/min versus 6 L/min. Nebulizers were placed in line distal and proximal to the lung model by using a tracheostomy collar and a T-piece. Conventional nebulization was tested using a vibrating mesh nebulizer and a jet nebulizer directly connected to the tracheostomy tube bypassing the humidification device. The drug was eluted from the collecting filter and assayed with ultraviolet spectrophotometry (276 nm). RESULTS: During in-line nebulizer placement with unheated humidification, the inhaled dose was 2-4 times higher with a gas flow of 2 L/min than 6 L/min, regardless of nebulizer type, placement, or interface (all P < .05). At 6 L/min, the inhaled dose was higher with proximal than distal placement when using both interfaces, but, at 2 L/min, the inhaled dose was lower with proximal placement. With a jet nebulizer, the tracheostomy collar generated a higher inhaled dose at proximal placement compared with the T-piece, whereas the T-piece resulted in a higher inhaled dose than the tracheostomy collar with distal placement, regardless of the flow settings. Compared with conventional nebulization using a vibrating mesh nebulizer, an in-line vibrating mesh nebulizer with a large-volume nebulizer at 2 L/min had a similar inhaled dose, regardless of nebulizer placement and interface. In contrast, the in-line jet nebulizer was influenced by both placement and interface. CONCLUSIONS: Aerosol delivery with an in-line vibrating mesh nebulizer and jet nebulizer with unheated humidification was affected by nebulizer placement, interface, and gas flow settings.

Aerosol Delivery Efficiency With High-Flow Nasal Cannula Therapy in Neonatal, Pediatric, and Adult Nasal Upper-Airway and Lung Models.

BACKGROUND: High-flow nasal cannula (HFNC) systems employ different methods to provide aerosol to patients. This study compared delivery efficiency, particle size, and regional deposition of aerosolized bronchodilators during HFNC in neonatal, pediatric, and adult upper-airway and lung models between a proximal aerosol adapter and distal aerosol circuit chamber. METHODS: A filter was connected to the upper airway to a spontaneously breathing lung model. Albuterol was nebulized using the aerosol adapter and circuit at different clinical flow settings. The aerosol mass deposited in the upper airway and lung was quantified. Particle size was measured with a laser diffractometer. Regional deposition was assessed with a gamma camera at each nebulizer location and patient model with minimum flow settings. RESULTS: Inhaled lung doses ranged from 0.2-0.8% for neonates, 0.2-2.2% for the small child, and 0.5-5.2% for the adult models. Neonatal inhaled lung doses were not different between the aerosol circuit and adapter, but the aerosol circuit showed marginally greater lung doses in the pediatric and adult patient models. Impacted aerosols and condensation in the non-heated HFNC and aerosol delivery components contributed to the dispersion of coarse liquid droplets, high deposition (11-44%), and occlusion of the supine neonatal upper airway. In contrast, the upright pediatric and adult upper-airway models had minimal deposition (0.3-7.0%) and high fugitive losses (∼24%) from liquid droplets leaking out of the nose. The high impactive losses in the aerosol adapter (56%) were better contained than in the aerosol circuit, resulting in less cannula sputter (5% vs 22%), fewer fugitive losses (18% vs 24%), and smaller inhaled aerosols (5 µm vs 13 µm). CONCLUSIONS: The inhaled lung dose was low (1-5%) during HFNC. Approaches that streamline aerosol delivery are needed to provide safe and effective therapy to patients receiving aerosolized medications with this HFNC system.

Aerosolized Pulmonary Delivery of mRNA Constructs Attenuates Severity of Escherichia coli Pneumonia in the Rat.

Acute respiratory distress syndrome (ARDS), a rapid onset inflammatory lung disease with no effective specific therapy, typically has pathogenic etiology termed pneumonia. In previous studies nuclear factor-κB (NF-κB) inhibitor α super-repressor (IκBα-SR) and extracellular superoxide dismutase 3 (SOD3) reduced pneumonia severity when prophylactically delivered by viral vector. In this study, mRNA coding for green fluorescent protein, IκBα-SR, or SOD3 was complexed with cationic lipid, passed through a vibrating mesh nebulizer, and delivered to cell culture or directly to rats undergoing Escherichia coli pneumonia. Injury level was then assessed at 48 h. In vitro, expression was observed as early as 4 h in lung epithelial cells. IκBα-SR and wild-type IκBα mRNAs attenuated inflammatory markers, while SOD3 mRNA induced protective and antioxidant effects. In rat E. coli pneumonia, IκBα-SR mRNA reduced arterial carbon dioxide (pCO2) and reduced lung wet/dry ratio. SOD3 mRNA improved static lung compliance and alveolar-arterial oxygen gradient (AaDO2) and decreased bronchoalveolar lavage (BAL) bacteria load. White cell infiltration and inflammatory cytokine concentrations in BAL and serum were reduced by both mRNA treatments compared to scrambled mRNA controls. These findings indicate nebulized mRNA therapeutics are a promising approach to ARDS therapy, with rapid expression of protein and observable amelioration of pneumonia symptoms.

Influence of Physicochemical Properties of Budesonide Micro-Suspensions on Their Expected Lung Delivery Using a Vibrating Mesh Nebulizer.

The efficiency of lung drug delivery of nebulized drugs is governed by aerosol quality, which depends both on the aerosolization process itself but also on the properties of aerosol precursors. This paper determines physicochemical properties of four analogous micro-suspensions of a micronized steroid (budesonide, BUD) and seeks relationships between these properties and the quality of the aerosol emitted from a vibrating mesh nebulizer (VMN). Despite the same BUD content in all tested pharmaceutical products, their physicochemical characteristics (liquid surface tension, viscosity, electric conductivity, BUD crystal size, suspension stability, etc.) are not identical. The differences have a weak influence on droplet size distribution in the mists emitted from the VMN and on theoretical (calculated) regional aerosol deposition in the respiratory system but, simultaneously, there is an influence on the amount of BUD converted by the nebulizer to aerosol available for inhalation. It is demonstrated that the maximum inhaled BUD dose is below 80-90% of the label dose, depending on the nebulized formulation. It shows that nebulization of BUD suspensions in VMN is sensitive to minor dissimilarities among analogous (generic) pharmaceutics. The potential clinical relevance of these findings is discussed.

Not all nebulizers are created equal: Considerations in choosing a nebulizer for aerosol delivery during mechanical ventilation.

INTRODUCTION: Aerosol therapy is commonly prescribed in the mechanically ventilated patient. Jet nebulizers (JN) and vibrating mesh nebulizers (VMN) are the most common nebulizer types, however, despite VMN's well established superior performance, JN use remains the most commonly used of the two. In this review, we describe the key differentiators between nebulizer types and how considered selection of nebulizer type may enable successful therapy and the optimization of drug/device combination products. AREAS COVERED: Following a review of the published literature up to February 2023, the current state of the art in relation to JN and VMN is discussed under the headings of in vitro performance of nebulizers during mechanical ventilation, respective compatibility with formulations for inhalation, clinical trials making use of VMN during mechanical ventilation, distribution of nebulized aerosol throughout the lung, measuring the respective performance of nebulizers in the patient and non-drug delivery considerations in nebulizer choice. EXPERT OPINION: Whether for standard care, or the development of drug/device combination products, the choice of nebulizer type should not be made without consideration of the unique needs of the combination of each of drug, disease and patient types, as well as target site for deposition, and healthcare professional and patient safety.

Nebulizers effectiveness on pulmonary delivery of alpha-1 antitrypsin.

The nebulization of alpha-1 antitrypsin (AAT) for its administration to the lung could be an interesting alternative to parenteral infusion for patients suffering from AAT genetic deficiency (AATD). In the case of protein therapeutics, the effect of the nebulization mode and rate on protein conformation and activity must be carefully considered. In this paper two types of nebulizers, i.e., a jet and a mesh vibrating system, were used to nebulize a commercial preparation of AAT for infusion and compared. The aerosolization performance, in terms of mass distribution, respirable fraction, and drug delivery efficiency, as well as the activity and aggregation state of AAT upon in vitro nebulization were investigated. The two nebulizers demonstrated equivalent aerosolization performances, but the mesh nebulizer provided a higher efficiency in the delivery of the dose. The activity of the protein was acceptably preserved by both nebulizers and no aggregation or changes in its conformation were identified. This suggests that nebulization of AAT represents a suitable administration strategy ready to be translated to the clinical practice for delivering the protein directly to the lungs in AATD patients, either as a support therapy to parenteral administration or for subjects with a precocious diagnosis, to prevent the onset of pulmonary symptoms.

Comparison of clinical outcomes following delivery of budesonide by both vibrating mesh nebulizer and jet nebulizer in premature infants with bronchopulmonary dysplasia.

Background: This study aimed to compare the efficacy of budesonide inhalation suspension administered via a vibrating mesh nebulizer vs. a jet nebulizer in the treatment of premature infants with bronchopulmonary dysplasia (BPD) undergoing high-frequency oscillatory ventilation (HFOV). Methods: Between July 2020 and July 2022, we retrospectively analyzed the medical records of 36 preterm infants diagnosed with BPD who underwent HFOV. Based on the nebulizer type used, infants were categorized into the vibrating mesh nebulizer group (VMN group) or the jet nebulizer group (JN group). Post-nebulization outcomes, such as the duration of mechanical ventilation, length of stay in the neonatal intensive care unit (NICU), ventilator-associated parameters, and arterial blood gas metrics, were compared between the two groups. Treatment-associated complications were also documented. Results: No significant differences were noted between the VMN and JN groups in terms of mechanical ventilation duration (p = 0.519), NICU length of stay (p = 0.112), ventilator-associated parameters, or complications (p = 0.700). However, after 2 weeks of treatment, the oxygenation index (p = 0.012) and arterial partial pressure of carbon dioxide (p = 0.006) were more favorable in the VMN group compared to the JN group. Conclusion: Among premature infants with BPD on HFOV, for administration of budesonide inhalation suspension resulted in an improved oxygenation index and reduced arterial partial pressure of carbon dioxide when compared to a jet nebulizer, indicating superior therapeutic efficacy.

The Use of an Inspiration-Synchronized Vibrating Mesh Nebulizer for Prolonged Inhalative Iloprost Administration in Mechanically Ventilated Patients-An In Vitro Model.

Mechanically ventilated patients suffering from acute respiratory distress syndrome (ARDS) frequently receive aerosolized iloprost. Because of prostacyclin's short half-life, prolonged inhalative administration might improve its clinical efficacy. But, this is technically challenging. A solution might be the use of inspiration-synchronized vibrating mesh nebulizers (VMNsyn), which achieve high drug deposition rates while showing prolonged nebulization times. However, there are no data comparing prolonged to bolus iloprost nebulization using a continuous vibrating mesh nebulizer (VMNcont) and investigating the effects of different ventilation modes on inspiration-synchronized nebulization. Therefore, in an in vitro model of mechanically ventilated adults, a VMNsyn and a VMNcont were compared in volume-controlled (VC-CMV) and pressure-controlled continuous mandatory ventilation (PC-CMV) regarding iloprost deposition rate and nebulization time. During VC-CMV, the deposition rate of the VMNsyn was comparable to the rate obtained with the VMNcont, but 10.9% lower during PC-CMV. The aerosol output of the VMNsyn during both ventilation modes was significantly lower compared to the VMNcont, leading to a 7.5 times longer nebulization time during VC-CMV and only to a 4.2 times longer nebulization time during PC-CMV. Inspiration-synchronized nebulization during VC-CMV mode therefore seems to be the most suitable for prolonged inhalative iloprost administration in mechanically ventilated patients.

Response to Bronchodilators Administered via Different Nebulizers in Patients With COPD Exacerbation.

BACKGROUND: The recommended treatment of COPD exacerbations includes administration of short-acting bronchodilators that act to reverse bronchoconstriction, restore lung volumes, and relieve breathlessness. In vitro studies demonstrate vibrating mesh nebulizers (VMNs) provide greater drug delivery to the airway compared to standard small-volume nebulizers (SVNs). We examined whether the physiological and symptom response to nebulized bronchodilators during a COPD exacerbation differed between these 2 modes of bronchodilator delivery. METHODS: Subjects hospitalized with a COPD exacerbation participated in a comparative clinical effectiveness study of 2 methods of nebulization. Using block randomization, 32 participants in this open-label trial were administered salbutamol 2.5 mg/ipratropium bromide 0.5 mg via vibrating mesh (VMN group, n = 16) or small-volume jet nebulizer (SVN group, n = 16) on one occasion. Spirometry, body plethysmography, and impulse oscillometry were performed and Borg breathlessness scores recorded pre bronchodilator and at 1 h post bronchodilator. RESULTS: Baseline demographics were comparable between groups. Mean FEV1 was 48% predicted. Significant changes in lung volumes and airway impedance were seen in both groups. Inspiratory capacity (IC) increased by 0.27 ± 0.20 L and 0.21 ± 0.20 L in the VMN and SVN group, respectively, between group difference P = .40. FVC increased in the VMN group by 0.41 ± 0.40 L compared to 0.19 ± 0.20 L with SVN, between group difference P = .053; and residual volume (RV) decreased by 0.36 ± 0.80 L and 0.16 ± 0.50 L in the VMN and SVN group, respectively, between group difference P = .41. The VMN group had a significant reduction in Borg breathlessness score, P = .034. CONCLUSIONS: Greater improvement in symptoms, and larger absolute change in FVC, was observed in response to equivalent doses of standard bronchodilators administered by VMN, compared to SVN, but no substantial difference in change in IC.