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

Inhaled Bronchodilator Administration During Mechanical Ventilation: How to Optimize It, and For Which Clinical Benefit?

articl

In vitro comparison of five nebulizers during noninvasive ventilation: Analysis of inhaled and lost doses

Background: Few studies on performance comparison of nebulizer systems coupled with a single-limb circuit bilevel ventilator are available. Most of these data compared the aerosol drug delivery for only two different systems. Using an adult lung bench model of noninvasive ventilation, we compared inhaled and lost doses of three nebulizer systems coupled with a single-limb circuit bilevel ventilator, as well as the influence of the nebulizer position. Method: Three vibrating mesh nebulizers (Aeroneb® Pro, Aeroneb® Solo, and NIVO®), one jet nebulizer (Sidestream®), and one ultrasonic nebulizer (Servo Ultra Nebulizer 145®) coupled with a bilevel ventilator were tested. They were charged with amikacin solution (500mg/4mL) and operated at two different positions: before and after the exhalation port (starting from the lung). The inhaled dose, the expiratory wasted dose, and the estimated lost dose were assessed by the residual gravimetric method. Results: The doses varied widely among the nebulizer types and position. When the nebulizer was positioned before the exhalation port, the vibrating mesh nebulizer delivered the highest inhaled dose (p<0.001), the jet nebulizer the highest expiratory wasted dose (p<0.001), and the ultrasonic device the highest total lost dose (p<0.001). When the nebulizer was positioned after the exhalation port, the vibrating mesh nebulizers delivered the highest inhaled (p<0.001) and expiratory wasted doses (p<0.001), and the ultrasonic device the highest total lost dose (p<0.001). The most efficient nebulizers were NIVO and Aeroneb Solo when placed before the exhalation port. Conclusions: In a single-limb circuit bilevel ventilator, vibrating mesh nebulizers positioned between the exhalation port and lung model are more efficient for drug delivery compared with jet or ultrasonic nebulizers. In this position, the improved efficiency of vibrating mesh nebulizers was due to an increase in the inhaled dose and a reduction in the exhaled wasted dose compared with placement between the ventilator and the expiratory port. Because of the high total lost dose, the ultrasonic device should not be recommended. Nebulizer placement before the exhalation port increased the inhaled dose and decreased the expiratory wasted dose, except for the jet nebulizer