Elsevier

The Lancet

Volume 377, Issue 9770, 19–25 March 2011, Pages 1032-1045
The Lancet

Review
Aerosol drug delivery: developments in device design and clinical use

https://doi.org/10.1016/S0140-6736(10)60926-9Get rights and content

Summary

Aerosolised drugs are prescribed for use in a range of inhaler devices and systems. Delivering drugs by inhalation requires a formulation that can be successfully aerosolised and a delivery system that produces a useful aerosol of the drug; the particles or droplets need to be of sufficient size and mass to be carried to the distal lung or deposited on proximal airways to give rise to a therapeutic effect. Patients and caregivers must use and maintain these aerosol drug delivery devices correctly. In recent years, several technical innovations have led to aerosol drug delivery devices with efficient drug delivery and with novel features that take into account factors such as dose tracking, portability, materials of manufacture, breath actuation, the interface with the patient, combination therapies, and systemic delivery. These changes have improved performance in all four categories of devices: metered dose inhalers, spacers and holding chambers, dry powder inhalers, and nebulisers. Additionally, several therapies usually given by injection are now prescribed as aerosols for use in a range of drug delivery devices. In this Review, we discuss recent developments in the design and clinical use of aerosol devices over the past 10–15 years with an emphasis on the treatment of respiratory disorders.

Introduction

In recent years, increased interest in the scientific basis of aerosol therapy has given rise to a growth in technology that makes use of the inherent advantages of the inhaled route of drug administration for the treatment of both pulmonary and non-pulmonary diseases. A key advantage of this route is that it enables delivery of low doses of an aerosolised drug to its site of action for a localised effect (ie, directly to airway surfaces), which leads to a rapid clinical response with few systemic side-effects, particularly for aerosolised β-agonist therapy.1 Drug delivery to the systemic circulation via the distal lung results in rapid absorption of the drug from this large surface area. However, when inhaled drugs are administered for effects on the airway (eg, inhaled corticosteroids), systemic absorption of the drug can give rise to unwanted side-effects.

Aerosol deposition in the lung is affected by several factors, including the aerosol-generating system, particle size distribution of the inhaled aerosol, inhalation pattern (eg, flow rate, volume, breath-holding time), oral or nasal inhalation, properties of the inhaled carrier gas (eg, carbon dioxide, heliox [a gas mixture of helium and oxygen]), airflow obstruction, and type and severity of lung disease. The distribution of target sites and local pharmacokinetics of the drug also affect clinical response. The association between drug deposition and therapeutic response led to development of aerosol drug delivery devices that have pulmonary deposition fractions of 40–50% of the nominal dose compared with the low levels of 10–15% of the nominal dose that were achieved in the past.2 Particular inhalation patterns of specific disease states could be applied to simulate device performance under certain conditions. This simulation would enable adjustments to be made to the device to not only maximise lung aerosol deposition but also to increase the precision and consistency of aerosol drug delivery.3 Compared with previous devices, the increased efficiency of the newer aerosol drug delivery devices means that similar efficacy can be achieved with a lower nominal drug dose.

In clinical practice, pressurised metered-dose inhalers (pMDIs) used with or without a spacer device, dry powder inhalers (DPIs), and nebulisers are used for aerosol delivery. In a 2005 systematic review, the authors concluded that these aerosol drug delivery devices were equally efficacious provided that they were used appropriately.4 In most, but not all the trials reviewed, the investigators tested single dose strengths of β agonists in different devices. These doses were often designed to approximate the plateau of the dose-response curve, thereby limiting the ability to differentiate between devices. Only a few of these studies compared the bronchodilator responses to a range of β-agonist doses. Since publication of that systematic review, several new devices have been marketed for clinical use and new clinical uses for inhaled therapies have emerged. Comparative trials now tend to be designed as cumulative dose-response studies or single doses over a therapeutic range.5

New developments in inhaler technology can take 8–10 years, and recent approaches have focused on incorporating the following features: improvement of aerosol dispersion and production of particles within the extra-fine size range needed for deep lung targeting; development of methods to reduce effort required for inhalation; and improvement of delivery efficiency while maintaining portability and ease of use of the inhaler. With generic and subsequent market entry products becoming increasingly available, in-vitro and in-vivo studies are needed to establish bioequivalence with trademarked products.6 Some of the regulatory requirements for generics have changed in recent years, particularly for DPI generic products. For example, the appearance of the generic DPI device could be different to the originally marketed device while necessarily providing the same dose of drug to the mouth as the original and also providing aerosol characteristics that are the same.7 Some generic DPIs have different dose strengths and different numbers of doses to the original. These products might have obtained approval as new drug products or as subsequent market entry products; the availability of the same drug in different formats can lead to confusion for clinicians prescribing and patients adhering to a treatment plan. In this Review we highlight new developments in aerosol technology and novel therapeutic uses that have emerged in recent years to help improve awareness among clinicians.

Section snippets

Measuring aerosol drug delivery

The inhaled route can deliver a sufficient amount of the drug to airway surfaces throughout the lung to give rise to a clinical response, although dose delivery is dependent on the adequate use of an appropriate administered drug dose and effective inhaler use. In patients with airway narrowing owing to oedema, increased secretions, or smooth muscle constriction, the distribution of inhaled aerosol is non-uniform, with increased concentrations deposited in areas of airway narrowing.8 The amount

Pressurised metered-dose inhalers

pMDIs are portable, convenient, multi-dose devices that use a propellant under pressure to generate a metered dose of an aerosol through an atomisation nozzle.19 Worldwide, pMDIs are the most widely used inhalation devices for the treatment of asthma and chronic obstructive pulmonary disease. Chlorofluorocarbon-propelled pMDIs were routinely prescribed for several decades, but in accordance with the Montreal Protocol of 1987,20 chlorofluorocarbon propellants are being replaced by

Spacers and holding chambers

Spacer devices are categorised as add-on devices, extension devices, or holding chambers and they improve efficacy by providing more reliable delivery of pMDI drugs to patients who have difficulty in coordinating inhalation with pMDI actuation.

Spacer devices have three basic designs—the open tube, the reservoir or holding chamber, and the reverse-flow design, in which the pMDI, placed close to the mouth, is fired in the direction away from the patient. Adding a one-way valve creates a holding

Dry powder inhalers

Several new, innovative DPIs are available for the treatment of asthma and chronic obstructive pulmonary disease57 (figure 4B) and for delivery of a range of other drugs such as proteins, peptides, and vaccines.58 The challenge is to combine suitable powder formulations with DPI designs that generate small particle aerosols.59, 60 Use of DPIs is expected to increase with the phasing out of chlorofluorocarbon production along with increased availability of drug powders and development of novel

Nebulisers

Nebulisers are devices that convert a liquid in solution or suspension into small droplets.

Targeting aerosol delivery in the lung

The ability to target drugs to specific sites of disease is a major unmet need of aerosol therapy.

Heliox

Heliox (a gas mixture of 80% helium and 20% oxygen), which has one-third the density of air, results in more peripheral deposition of inhaled aerosol particles than does air, especially in the presence of airway constriction. In children with airway obstruction, the rate of aerosol deposition is enhanced while breathing heliox compared with breathing oxygen.104

When heliox, rather than air or comparable mixtures of oxygen and air, is the driving gas in a ventilator circuit, aerosolised drug

Aerosol delivery during mechanical ventilation

Drug delivery to patients on mechanical ventilation is complicated by the presence of an artificial airway. The major factors that affect the efficiency of drug delivery during mechanical ventilation include: the position of the patient, the aerosol generator and its configuration in the ventilator circuit, aerosol particle size, synchronisation of aerosol generation with inspiratory airflow from the ventilator, conditions in the ventilator circuit, and ventilatory measurements. Dhand and Guntur

Vaccines

Flumist (MedImmune, Gaithersburg, MD, USA), a live attenuated influenza vaccine given by nasal spray,110 and other inhaled spray-dried formulations containing whole inactivated virus or split subunit vaccine, could be used for influenza prevention.111 In the early 1990s, about 4 million children were immunised against measles with the Classical Mexican Device—a home-built system that incorporated a jet nebuliser from IPI Medical Products (Chicago, IL, USA). Aerosolised vaccine against measles

Device selection

The appropriateness of a device for a patient in a given clinical situation depends on several factors. The following questions should be asked before making a selection. In what devices is the drug being prescribed available and how do these different devices compare in terms of ease of use, performance, clinical efficacy, and safety? Is the device likely to be available for several years? Do the published works support the advertised in-vitro performance information of reliable and

Conclusions

In the past 10–15 years, several innovative developments have advanced the field of inhaler design. There are many choices in all device categories that incorporate features providing efficient aerosol delivery to treat various lung and systemic diseases. Attempts to improve topical delivery to selective areas of the lung or new approaches to access the distal lung for systemic therapy are continually being investigated and they have the potential to provide more advanced aerosol drug delivery

Search strategy and selection criteria

We identified references for this Review by searches of PubMed with the following search terms: “aerosol drug delivery devices”, “aerosol properties/characterization”, “inhalers (MDIs, spacers, dry powder inhalers)”, “aerosol formulations (pressurized, powder, liquid admixtures)”, “HFA and CFC propellants”, “metered-dose inhalers and dose counters”, “generic inhalers”, “nebulizers (pneumatic, vibrating mesh, micropump)”, “breath-actuated inhalers”, “adaptive aerosol delivery”, “aerosol

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