Performance Comparisons of Jet and Mesh Nebulizers Using Different Interfaces in Simulated Spontaneously Breathing Adults and Children

Background: Different types of nebulizers and interfaces are used for the treatment of adults and children with pulmonary diseases. The purpose of this study was to determine the efficiency of a mesh nebulizer (MN) with a proprietary adapter and a jet nebulizer (JN) under different configurations in adult and pediatric models of spontaneous breathing. We hypothesize that delivery efficiency of JN and MN will differ depending on the interface used during aerosol therapy in simulated spontaneously breathing adult and pediatric models. While we expect that aerosol delivery with JN will be less efficient than MN, we also hypothesize that lung deposition obtained with the adult lung model will be more than that with the pediatric lung model in all conditions tested in this study. Methods: A lung model using a teaching manikin connected to a sinusoidal pump via a collecting filter at the level of the bronchi simulating a spontaneously breathing adult (Vt 500 mL, RR 15 bpm, I:E ratio 1:2) or pediatric patient (Vt 150 mL, RR 25 bpm, I:E ratio 1:2). Albuterol sulfate (2.5 mg/3 mL) was aerosolized with JN (Mistymax 10, Airlife) or MN (Aerogen Solo®, Aerogen) with the Adapter (Aerogen Solo® Adapter, Aerogen Ltd, Galway, Ireland) using mouthpiece, aerosol mask, and valved-mask in adults and the dragon mask, aerosol mask, and valved-mask in pediatrics (n=3). The Adapter, specifically designed for MN, was attached to all the interfaces used in this study with supplemental oxygen of 2 lpm, and in addition, the MP was tested with no additional flow in the adult model. The JN was driven with 10 lpm based on the manufacturer\u27s label. Drug was eluted from the filter and analyzed via spectrophotometry. Descriptive statistics, dependent t-test and one-way analysis of variance were used for data analysis. Significant level was set at 0.05. Results: In adults, delivery efficiency of JN with the valved mask was significantly greater than that with the aerosol mask (p=0.01). Aerosol delivery of JN with the mouthpiece was not statistically significant from the valved mask (p=0.123) and the aerosol mask (p=0.193). Drug delivery with MN with mouthpiece (15.42±1.4%) and valved-mask (15.15±1.1%) was greater than the open aerosol mask (7.54±0.39%; p=0.0001) in the adult lung model. With no flow mouthpiece delivery increased\u3e2 fold (34.9±3.1%; p=.0001) compared to use of 2 lpm of flow. Using the JN with the pediatric model deposition with valved-mask (5.3±0.8%), dragon mask (4.7±0.9%), and aerosol mask (4.1±0.3%) were similar (p\u3e0.05); while drug delivery with MN via valved-mask (11.1±0.7%) was greater than the dragon mask (6.44±0.3%; p=0.002) and aerosol mask (4.6±0.4%; p=0.002), and the dragon mask was more efficient than the open aerosol mask (p=0.009) Conclusion: The type of nebulizer and interface used for aerosol therapy affects delivery efficiency in these simulated spontaneously breathing adult and pediatric models. Drug delivery was greatest with the valved-mouthpiece and mask with JN and MN, while the standard aerosol mask was least efficient in these simulated spontaneously breathing adult and pediatric lung models. Delivery efficiency of JN was less than MN in all conditions tested in this study except in the aerosol mask. Lung deposition obtained with the adult lung model was more than that with the pediatric lung model

Effective nebulization of interferon-γ using a novel vibrating mesh.

BACKGROUND: Interferon gamma (IFN-γ) is a clinically relevant immunomodulatory cytokine that has demonstrated significant potential in the treatment and management of respiratory diseases such as tuberculosis and pulmonary fibrosis. As with all large biomolecules, clinical translation is dependent on effective delivery to the disease site and delivery of IFN-γ as an aerosol offers a logical means of drug targeting. Effective localization is often hampered by instability and a lack of safe and efficient delivery systems. The present study sought to determine how effectively IFN-γ can be nebulized using two types of vibrating mesh nebulizer, each with differing mesh architectures, and to investigate the comparative efficiency of delivery of therapeutically active IFN-γ to the lungs. METHODS: Nebulization of IFN-γ was carried out using two different Aerogen vibrating mesh technologies with differing mesh architectures. These technologies represent both a standard commercially available mesh type (Aerogen Solo®) and a new iteration mesh (Photo-defined aperture plate (PDAP®). Extensive aerosol studies (aerosol output and droplet analysis, non-invasive and invasive aerosol therapy) were conducted in line with regulatory requirements and characterization of the stability and bioactivity of the IFN-γ post-nebulization was confirmed using SDS-PAGE and stimulation of Human C-X-C motif chemokine 10 (CXCL 10) also known as IFN-γ-induced protein 10KDa (IP 10) expression from THP-1 derived macrophages (THP-1 cells). RESULTS: Aerosol characterization studies indicated that a significant and reproducible dose of aerosolized IFN-γ can be delivered using both vibrating mesh technologies. Nebulization using both devices resulted in an emitted dose of at least 93% (100% dose minus residual volume) for IFN-γ. Characterization of aerosolized IFN-γ indicated that the PDAP was capable of generating droplets with a significantly lower mass median aerodynamic diameter (MMAD) with values of 2.79 ± 0.29 μm and 4.39 ± 0.25 μm for the PDAP and Solo respectively. The volume median diameters (VMD) of aerosolized IFN-γ corroborated this with VMDs of 2.33 ± 0.02 μm for the PDAP and 4.30 ± 0.02 μm for the Solo. SDS-PAGE gels indicated that IFN-γ remains stable after nebulization by both devices and this was confirmed by bioactivity studies using a THP-1 cell model in which an alveolar macrophage response to IFN-γ was determined. IFN-γ nebulized by the PDAP and Solo devices had no significant effect on the key inflammatory biomarker cytokine IP-10 release from this model in comparison to non-nebulized controls. Here we demonstrate that it is possible to combine IFN-γ with vibrating mesh nebulizer devices and facilitate effective aerosolisation with minimal impact on IFN-γ structure or bioactivity. CONCLUSIONS: It is possible to nebulize IFN-γ effectively with vibrating mesh nebulizer devices without compromising its stability. The PDAP allows for generation of IFN-γ aerosols with improved aerodynamic properties thereby increasing its potential efficiency for lower respiratory tract deposition over current technology, whilst maintaining the integrity and bioactivity of IFN-γ. This delivery modality therefore offers a rational means of facilitating the clinical translation of inhaled IFN-γ

Mucociliary and long-term particle clearance in airways of patients with immotile cilia

Spherical monodisperse ferromagnetic iron oxide particles of 1.9 μm geometric and 4.2 μm aerodynamic diameter were inhaled by seven patients with primary ciliary dyskinesia (PCD) using the shallow bolus technique, and compared to 13 healthy non-smokers (NS) from a previous study. The bolus penetration front depth was limiting to the phase1 dead space volume. In PCD patients deposition was 58+/-8 % after 8 s breath holding time. Particle retention was measured by the magnetopneumographic method over a period of nine months. Particle clearance from the airways showed a fast and a slow phase. In PCD patients airway clearance was retarded and prolonged, 42+/-12 % followed the fast phase with a mean half time of 16.8+/-8.6 hours. The remaining fraction was cleared slowly with a half time of 121+/-25 days. In healthy NS 49+/-9 % of particles were cleared in the fast phase with a mean half time of 3.0+/-1.6 hours, characteristic of an intact mucociliary clearance. There was no difference in the slow clearance phase between PCD patients and healthy NS. Despite non-functioning cilia the effectiveness of airway clearance in PCD patients is comparable to healthy NS, with a prolonged kinetics of one week, which may primarily reflect the effectiveness of cough clearance. This prolonged airway clearance allows longer residence times of bacteria and viruses in the airways and may be one reason for increased frequency of infections in PCD patients