Review 1032 www.thelancet.com Vol 377 March 19, 2011 Lancet 2011; 377: 1032–45 Published Online November 1, 2010 DOI:10.1016/S0140- 6736(10)60926-9 Firestone Institute of Respiratory Health, St Joseph’s Healthcare, and Department of Medicine, McMaster University, Hamilton, ON, Canada (Prof M B Dolovich PEng); and Division of Pulmonary, Critical Care and Environmental Medicine, Department of Internal Medicine, University of Missouri, Columbia, MO, USA (Prof R Dhand MD) Correspondence to: Prof Myrna B Dolovich, Firestone Institute of Respiratory Health, St Joseph’s Healthcare, 50 Charlton Avenue E, Room JT2135, Hamilton, ON L8N 4A6, Canada mdolovic@mcmaster.ca Aerosol drug delivery: developments in device design and clinical use Myrna B Dolovich, Rajiv Dhand 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 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 therapy/inhalation therapy (bronchodilators, corticosteroids, anticholinergics)”, “aerosol therapy/vaccines/gene therapy”, “nanoparticles and inhalation”, “inhalers and nanoformulations”, “aerosol therapy and magnetic particles”, “aerosol therapy and lung deposition”, “aerosol therapy and pediatric respiratory disease”, “aerosol therapy and asthma, chronic obstructive pulmonary disease, cystic fibrosis and other respiratory diseases”, “clinical trials (aerosol delivery and clinical response, dose response)”, “aerosol therapy and mechanical ventilation/artificial respiration”, “aerosol therapy and non-invasive ventilation”, “Heliox therapy”, and “aerosol therapy and pulmonary hypertension” from January, 2000, to August, 2009. Papers published between 2004 and 2009 were given priority, but we also included papers from the early published works on aerosols that described major findings that are still pertinent today. Relevant review papers and their references were cited on the basis of their relevance. Only papers published in the English language were reviewed. Both authors are actively involved in original research in aerosol drug delivery and clinical use of therapeutic aerosols and have extensive databases for the material covered in this manuscript.