A review of nebulized drug delivery in COPD

Figures & data

Table 1 Initial pharmacologic management of COPD*

GOLD patient category	First choice	Alternative choice	Other possible treatments#
A: low risk, less symptoms	SAMA prn or SABA prn	LAMA or LABA or SABA and SAMA	Theophylline
B: low risk, more symptoms	LAMA or LABA	LAMA and LABA	SABA and/or SAMA; theophylline
C: high risk, less symptoms	ICS + LABA or LAMA	LAMA and LABA or LAMA and PDE-4 inhibitor or LABA and PDE-4 inhibitor	SABA and/or SAMA; theophylline
D: high risk, more symptoms	ICS + LABA and/or LAMA	ICS and LABA and LAMA or ICS and LABA and PDE-4 inhibitor or LAMA and LABA or LAMA and PDE-4 inhibitor	Carbocysteine; SABA and/or SAMA; theophylline

Notes:

* Medications are not listed in order of preference.

# Medications in this column can be used alone or in combination with other options in the first and second columns. Reprinted with permission of the American Thoracic Society. Copyright © 2016. Vestbo J, Hurd SS, Agusti AG, et al. 2013. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 187(4):347–365.⁹⁷ The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Abbreviations: GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; PDE-4, phosphodiesterase-4; prn, as needed; SABA, short-acting β₂-agonist; SAMA, short-acting muscarinic antagonist.

Table 2 Advantages and disadvantages of aerosolized formulations

Inhalation device	Advantages	Disadvantages
DPI	Breath-actuated devices	Requires patient to generate moderate to high inspiratory flowa
	Convenient Portable Rapid medication delivery	Elderly patients and those with hyperinflation and flattened diaphragms may have difficulty achieving adequate inspiratory flow
	Single- and multidose devices Counter indicates remaining doses	Can result in high pharyngeal and central airway deposition, which can lead to adverse events
pMDI	Multiple dosing (≥100 doses/canister)	Multiple steps involved Requires adequate patient coordination to synchronize inhalation with pMDI actuationb
	Short administration time	High pharyngeal deposition, which can lead to adverse events
	Convenient	Only 10%–20% of dose deposited in lungs from suspension MDIsc
	Portable	While the addition of spacer eliminates the need to coordinate inhalation and reduces oropharyngeal deposition, spacers are bulky and require cleaning
SMI	Multiple dosing (1 month’s supply)	Multiple steps involved
	High lung deposition	Not breath actuated
	Portable No propellants Slow-velocity aerosol generated Aerosol persists for 1.5 seconds, increasing ease of synchronizing inhalation with actuation	Not available in most countries
Jet nebulizer	Easy for patients to use	Limited portability
	Requires minimal cognitive ability	Device preparation required
	Does not require hand-breath coordination, manual dexterity, or hand strength	Lengthy administration time Daily cleaning required Not all medications are available in this format May not readily aerosolize drug suspensions
High-efficiency vibrating mesh nebulizer	Portable	High cost
	Quiet	Device preparation required
	Short administration times	Daily cleaning required Not all medications are available in this format May not readily aerosolize drug suspensions Optimal doses need to be defined by additional studies to avoid overdosing

Notes:

a Not all DPIs are high-resistance inhalers, but even the low-resistance inhalers (eg, Breezhaler^®; Novartis, Basel, Switzerland), require a relatively high inspiratory flow compared with higher resistance devices to generate a comparable pressure drop across the resistance of the device in order to de-agglomerate the powder and generate an effective aerosol.⁹⁸

b Breath-actuated MDIs address this concern and are available in some countries.

c Higher (~50%) deposition occurs with solution HFA MDIs (eg, beclomethasone HFA and flunisolide HFA).

Abbreviations: DPI, dry powder inhaler; HFA, hydrofluoroalkane; MDI, metered dose inhaler; pMDI, pressurized metered dose inhaler; SMI, slow mist inhaler.

Figure 1 Examples of commercially available nebulizers that incorporate newer aerosol generating technologies.

Notes: Akita^® Jet (Courtesy of Ventura, UK) and the I-neb^® (Courtesy of Philips Healthcare, USA) employ AAD technology to deliver and monitor nebulizer treatments. Trek^® S (Courtesy of PARI, USA; Trek^® S is a trademark of PARI Gmbh and its affiliates) is a portable jet nebulizer. MicroAir^® NE-U22 (Courtesy of Omron, USA) and the eFlow^® (Courtesy of PARI, USA; eFlow^® is a trademark of PARI Gmbh and its affiliates) are vibrating mesh aerosol nebulizers. Respimat^® is a high-efficiency soft mist inhaler (Reproduced with permission from Boehringer Ingelheim Pharmaceuticals, Inc. Respimat^® is a trademark of and/or used under license from Boehringer Ingelheim International GmbH or its affiliated companies. Materials may also be subject to copyright protection). Aeroneb^® Go (Courtesy of Philips Healthcare) is an ultrasonic nebulizer. All of these devices are approved for use in the US.
Abbreviation: AAD, adaptive aerosol delivery.

Figure 2 AAD technology used in the Akita^® and I-neb^® nebulizers.

Notes: During the first three breaths, AAD calculates when to pulse the aerosol. In subsequent breaths, AAD pulses aerosol during the first 50%–80% of inspiration (blue shade). Republished with permission of Respiratory Care: the official science journal of the American Association for Respiratory Care, from New Aerosol Delivery Devices for Cystic Fibrosis, KC Kesser and DE Geller, volume 54, edition 6, 2009; permission conveyed through Copyright Clearance Center, Inc.¹⁰⁵
Abbreviation: AAD, adaptive aerosol delivery.

Table 3 Nebulized medications commonly used for patients with COPD

Compound	Nebulizer system	Trough FEV1 (L) improvement*	Rescue medication use reduction	Remarks
LABA#
Arformoterol tartrate^Citation40	Jet or VM	0.051¶	Yes	BID; less frequent exacerbations of COPD than placebo
Formoterol fumarate^Citation99	Jet or VM	0.143¶	Yes	BID; no tachyphylaxis during 12 weeks of regular dosing
Olodaterol hydrochloride^Citation100	SMI†	0.275**	Yes	QD
LAMA#
Tiotropium bromide^Citation101	SMI	0.232**	Yes	QD; noninferior to tiotropium 18 mg HandiHaler^®
LABA–LAMA#
Tiotropium bromide–olodaterol hydrochloride^Citation62	SMI	0.068II	Yes	QD; additive bronchodilation without increasing side effects; less rescue medication vs components alone
SABA‡
Albuterol sulfate^Citation102	Jet or VM	NR	NA	prn rescue drug; requires 2–4 daily doses if used as maintenance treatment
Levalbuterol hydrochloride^Citation103	Jet or VM	NR	NA	prn rescue drug
SAMA‡
Ipratropium bromide^Citation68	Jet or VM	NR	NA	Indicated as a bronchodilator for maintenance treatment of bronchospasm associated with COPD
SABA–SAMAI
Albuterol–ipratropium^Citation69	Jet or VM	NR	NA	Improved FEV1 response vs components alone
Albuterol–ipratropium^Citation70	SMI	NR	NA	Provides better bronchodilation than either therapy alone without increasing side effects

Notes:

* Treatment differences (vs placebo) in trough FEV₁ change from baseline.

# Indicated for long-term, maintenance treatment of bronchospasm.

‡ Indicated for the treatment of acute exacerbations.

I Indicated for the treatment of acute exacerbations in patients requiring more than one bronchodilator.

¶ P<0.05;

** P<0.0001 vs placebo.

† Soft mist inhaler (Respimat^®) is not a nebulizer, but has some similar performance characteristics.

II P<0.05 vs single agents used alone.

Abbreviations: BID, twice daily; FEV₁, forced expiratory volume in 1 second; LABA, long-acting β₂-agonist; LAMA, long-acting muscarinic antagonist; NA, not applicable; NR, not reported; prn, as needed; QD, once daily; SABA, short-acting β₂-agonist; SAMA, short-acting muscarinic antagonist; SMI, soft mist inhaler; VM, vibrating mesh.

Table 4 Nebulized therapies in clinical development for the treatment of COPD

Development compound	Chemical name	Nebulizer system	Trough FEV1 (L) improvement*	Rescue medication use reduction	Stage of development
LAMA#
SUN-101	Glycopyrrolate bromide	eFlow^®‡	0.1184I,^Citation73	NR	Phase 3^Citation75–Citation77
TD-4208	Revefenacin (proposed international nonproprietary name)	Jet or VM	0.187I,^Citation104	Yes	Phase 3^Citation83–Citation85

Notes:

* Treatment differences (vs placebo) in trough FEV₁ change from baseline.

# Long-term, maintenance treatment of bronchospasm.

‡ eFlow^® utilizes a vibrating mesh aerosol generator.

I P<0.001.

Abbreviations: FEV₁, forced expiratory volume in 1 second; LAMA, long-acting muscarinic antagonist; NR, not reported; VM, vibrating mesh.

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