Nebulized Therapies in COPD: Past, Present, and the Future

Figures & data

Figure 1 The adult lung with dimensions and generations of the airways with predicted aerosol deposition.

Notes: Reprinted from European Journal of Pharmaceutical Sciences, Vol 49/edition number 5, Nahar K, Gupta N, Gauvin R, et al., In vitro, in vivo and ex vivo models for studying particle deposition and drug absorption of inhaled pharmaceuticals, Pages No.805–818, Copyright (2013), with permission from Elsevier.¹⁶
Abbreviation: BSM, bronchial smooth muscle.

Table 1 Characteristics, Advantages, and Disadvantages of Nebulizers with Novel Technologies

Nebulizer Type	Characteristics	Advantages	Disadvantages	Examples
Breath-enhanced JN	Air flows through the jet resulting in aerosolization of the drug solution; powered by compressor The additional room air carried into the nebulizer during inhalation causes aerosolization Drug solution cools during nebulization Expired air vented outside of the device Available as tabletop and portable models	Drug delivery during inhalation only, thus less drug wastage Easy to use and quiet	Sufficient flow required to initiate drug delivery Not ventilator-enabled More expensive versus conventional JNs and ultrasonic nebulizers	1. PARI LC^® Sprint NebuTech HDN^® SideStream Plus^®
Breath-actuated JN	Air flows through the tube resulting in aerosolization of the drug solution; powered by compressor Aerosolization is triggered by patient inhalation Available as tabletop and portable models	1. Same as breath-enhanced JN	1. Same as breath-enhanced JN	1. AeroEclipse^® II BAN
Mesh nebulizer	Piezoelectric crystals vibrate a mesh plate resulting in aerosolization Very fine droplets No significant change in temperature of the solution during nebulization Lower residual drug in chamber versus JNs	Fast, quiet, portable, and easy to use Self-contained power source Particle size optimized for specific medications More efficient when compared other nebulizers	Expensive Hard to clean Medication dosage requires adjusting Incompatible with viscous liquids or liquids that crystallize on drying	AKITA2^®APIXNEB eFlow^®rapid Micro Air^® NE-U22

Note: Data from these studies.^37,38

Abbreviations: BAN, breath-actuated nebulizer; JN, jet nebulizer

Figure 2 Examples of novel marketed nebulizers. Examples of the different types of commercially available nebulizers that incorporate newer aerosol generating technologies. PARI LC^® Sprint (PARI, USA⁸³); SideStream Plus^® (Philips, USA⁸⁴); AeroEclipse^® II (Monaghan Medical Corporation, USA⁸⁵); Micro Air^® NE-U22 (Omron Healthcare, USA⁸⁶); AKITA2^® APIXNEB (PARI Pharma GmbH, Germany⁸⁷).

Table 2 Efficacy and Safety of Nebulized LAMAs – Glycopyrrolate and Revefenacin

Reference	Treatments and Duration	FEV1 (LS Mean Change from Baseline)	AE Incidence (%)	SAE Incidence (%)
Kerwin, 2017^Citation53 (GOLDEN 3; NCT2347761)	GLY 25 µg GLY 50 µg PBO 12 weeks	GLY 25 µg: 105 mL; P<0.0001 GLY 50 µg: 126 mL; P<0.0001	GLY 25 µg: 39.6 GLY 50 µg: 48.2 PBO: 52.3	4.6^a
Kerwin, 2017^Citation53 (GOLDEN 4; NCT2347774)	GLY 25 µg GLY 50 µg PBO 12 weeks	GLY 25 µg: 84 mL; P<0.0001 GLY 50 µg: 82 mL; P<0.0001	GLY 25 µg: 47.2 GLY 50 µg: 53.3 PBO: 52.4	4.2^a
Ferguson, 2017^Citation54 (GOLDEN 5; NCT2276222)	GLY 50 µg TIO 18 µg 48 weeks	GLY 50 µg: 102 mL^b TIO 18 µg: 93 mL	GLY 50 µg: 69.4 TIO 18 µg: 67.0	GLY 50 µg: 12.3 TIO 18 µg: 10.5
Ferguson, 2019^Citation55 (Study 0126; NCT2459080)	REV 175 µg REV 88 µg PBO 12 weeks	REV 175 µg: 146 mL; P<0.0001 REV 88 µg: 79.2 mL; P<0.0003	REV 175 µg: 51.0 REV 88 µg: 51.9 PBO: 51.7	REV 175 µg: 5.1 REV 88 µg: 4.7 PBO: 6.7
Ferguson, 2019^Citation55 (Study 0127; NCT2512510)	REV 175 µg REV 88 µg PBO 12 weeks	REV 175 µg: 147 mL; P<0.0001 REV 88 µg: 160.5 mL; P<0.0001	REV 175 µg: 51.8 REV 88 µg: 56.6 PBO: 46.9	REV 175 µg: 2.5 REV 88 µg: 5.4 PBO: 3.3
Donohue, 2019^Citation56,Citation57 (Study 0128; NCT2518139)	REV 175 µg REV 88 µg TIO 18 µg 52 weeks	REV 175 µg: 52.3 mL; P<0.0003 REV 88 µg: 48.8 mL; P<0.0003 TIO 18 µg: 91.5 mL; P<0.0003	REV 175 µg: 72.2 REV 88 µg: 74.7 TIO 18 µg: 77.2	REV 175 µg: 12.8 REV 88 µg: 15.9 TIO 18 µg: 16.3
Mahler, 2019^Citation33 (Study 0149; NCT3095456)	REV 175 µg TIO 18 µg 28 days	REV 175 µg: 57.9 mL^c TIO 18 µg: 40.9 mL	REV 175 µg: 11.7 TIO 18 µg: 37.5	REV 175 µg: 0 TIO 18 µg: 1
Siler, 2019^Citation58 (Study 0167)	REV 175 µg/FOR 20 µg PBO/FOR 20 µg 42 days	REV 175 µg/FOR 20 µg (seq): 157.1 mL REV 175 µg/FOR 20 µg (combo): 115.6 mL	REV 175 µg/FOR 20 µg (seq): 4.8 PBO/FOR 20 µg (seq): 11.9 REV 175 µg/FOR 20 µg (combo): 8.1 PBO/FOR 20 µg (combo): 10.9	NR

Notes: ^aThe overall percentage of patients who experienced an SAE: ^bThe FEV₁ changes between GLY and TIO were not significant: ^cThe FEV₁ changes between REV and TIO were not significant.

Abbreviations: AE, adverse event; Combo, combined; FEV₁, forced expiratory volume in 1 second; FOR, formoterol; GLY, glycopyrrolate; LS, least squares; NR, none reported; PBO, placebo; REV, revefenacin; SAE, serious AE; Seq, sequential; TIO, tiotropium.

NaharK, GuptaN, GauvinR, et al. In vitro, in vivo and ex vivo models for studying particle deposition and drug absorption of inhaled pharmaceuticals. Eur J Pharm Sci. 2013;49(5):805–818. doi:10.1016/j.ejps.2013.06.00423797056

 PubMed Web of Science ®Google Scholar

AriA. Jet, ultrasonic, and mesh nebulizers: an evaluation of nebulizers for better clinical outcomes. Eurasian J Pulmonol. 2014;16:1–7. doi:10.5152/ejp.2014.00087

 Google Scholar

IbrahimM, VermaR, Garcia-ContrerasL. Inhalation drug delivery devices: technology update. Med Devices (Auckl). 2015;8:131–139. doi:10.2147/MDER.S4888825709510

 PubMedGoogle Scholar

PARI. Available from: https://pariorder.com. Accessed 76, 2020.

 Google Scholar

Philips. SideStream Plus: Reusable nebulizer. Available from: https://www.usa.philips.com/healthcare/product/HC0077830/sidestream-plus-reusable-nebulizer. Accessed 76, 2020.

 Google Scholar

Monaghan. Aeroeclipse® XL ban with Ombra® Compressor. Available from: https://www.monaghanmed.com/Aeroeclipse-XL-Ban-with-Ombra-Compressor/#1540799872824-7b01c579-2e33628f-29b55344-99b1. Accessed 76, 2020.

 Google Scholar

Omron. Portable MicroAir® Nebulizer. Available from: https://omronhealthcare.com/products/microair-nebulizer-neu22v. Accessed 76, 2020.

 Google Scholar

Akita® Jet. Available from: http://www.akita-jet.com. Accessed 76, 2020.

 Google Scholar

KerwinE, DonohueJ, GoodinT, TosielloR, WheelerA, FergusonG. Efficacy and safety of glycopyrrolate/eFlow® CS (nebulized glycopyrrolate) in moderate-to-very-severe COPD: results from the glycopyrrolate for obstructive lung disease via electronic nebulizer (GOLDEN) 3 and 4 randomized controlled trials. Respir Med. 2017;132:238–250. doi:10.1016/j.rmed.2017.07.01128838685

 PubMed Web of Science ®Google Scholar

FergusonG, GoodinT, TosielloR, WheelerA, KerwinE. Long-term safety of glycopyrrolate/eFlow® CS in moderate-to-very-severe COPD: results from the Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer (GOLDEN) 5 randomized study. Respir Med. 2017;132:251–260. doi:10.1016/j.rmed.2017.08.02028919143

 PubMed Web of Science ®Google Scholar

FergusonG, FeldmanG, PudiK, et al. Improvements in lung function with nebulized revefenacin in the treatment of patients with moderate to very severe COPD: results from two replicate phase III clinical trials. Chronic Obstr Pulm Dis. 2019;6(2):154–165. doi:10.15326/jcopdf.6.2.2018.015230974049

 PubMed Web of Science ®Google Scholar

DonohueJ, KerwinE, SethiS, et al. Maintained therapeutic effect of revefenacin over 52 weeks in moderate to very severe chronic obstructive pulmonary disease (COPD). Respir Res. 2019;20(1):241. doi:10.1186/s12931-019-1187-731666076

 PubMed Web of Science ®Google Scholar

DonohueJ, KerwinE, SethiS, et al. Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease. Respir Med. 2019;153:38–43. doi:10.1016/j.rmed.2019.05.01031150963

 PubMed Web of Science ®Google Scholar

MahlerD, OharJ, BarnesC, MoranE, PendyalaS, CraterG. Nebulized versus dry powder long-acting muscarinic antagonist bronchodilators in patients with COPD and suboptimal peak inspiratory flow rate. Chronic Obstr Pulm Dis. 2019;6:4.

 Web of Science ®Google Scholar

SilerTM, MoranEJ, BarnesCN, CraterGD. Safety and efficacy of revefenacin and formoterol in sequence and combination via a standard jet nebulizer in patients with chronic obstructive pulmonary disease: a phase 3b, randomized, 42-day study. Chronic Obstr Pulm Dis. 2020;7(2):99–106. doi:10.15326/jcopdf.7.2.2019.015432324981

 PubMed Web of Science ®Google Scholar