Abstract
To the Editor:
Total and regional airway deposition of orally inhaled drugs is determined by the complex interaction of numerous patient- and inhaler-related factors. Particle size (aerodynamic diameter) is considered to be the most important of the aerosol-related factors(1–3); however, the medical literature lacks standard nomenclature to distinguish aerosol particle sizes. There are clear differences in particle behavior and deposition according to size, and hence we believe a strong rationale for clearly denoting the aerosol particle size of orally inhaled, therapeutic aerosols, both in product descriptions and as part of the design and reporting of research in this area.
Orally inhaled medications for asthma and chronic obstructive pulmonary disease (COPD) generally fall into two particle size categories, namely, mass median aerodynamic diameter (MMAD) of <2 μm and MMAD of 2–5 μm.(2,4) Most aerosols prescribed in clinical practice are polydisperse, namely, with geometric standard deviation (GSD) ≥1.22; the majority have GSDs from 2 to 3.(2) Regional lung deposition varies according to aerosol particle MMAD as well as GSD. In general, particles >6 μm deposit preferentially in the oropharynx, those 2–6 μm in the central airways, and those <2 μm in the peripheral small airways and alveoli.(1,3)
Terms in the medical literature that have been used to describe the smaller size category of particles (MMAD ∼1 μm) include extrafine, ultrafine, very fine, and small. Terms that have been used to describe the larger size category of particles (2–5 μm) include coarse, standard, and large.(4)
Currently the only well-established term regarding aerosol particle size is the “fine-particle” dose, defined by the most recent European Respiratory Society/International Society for Aerosols in Medicine (ERS/ISAM) Task Force Report on the delivery of pharmaceutical aerosols as the mass of particles <5 μm in size within the total emitted dose.(2) In addition, experts in the field of medical aerosols have used the terms coarse, fine, and extrafine to describe particle sizes of >5 μm, <5 μm, and <1 μm, respectively,(3) and of >4.7 μm, <4.7 μm, and <1.1 μm, respectively.(5)
We propose the terms “coarse,” “fine,” and “extrafine” to differentiate orally inhaled medical aerosols with particle MMADs of >5 μm, 2.1–5 μm, and <2.1 μm, respectively (Table 1). Extending the designation of extrafine up to MMAD <2.1 μm (rather than just to MMAD 1–1.1 μm previously cited(3,5)) is consistent with the stage 5 cut-point of the Anderson cascade impactor. Moreover, this cut-point is intended to include available(2,4) (and potential future) products with MMAD in the 1.0–2.0 μm range, showing high lung deposition. Thus, the terms “extrafine-particle dose” would denote the mass of particles <2.1 μm in size within the total emitted dose and “coarse-particle dose,” the mass of particles >5 μm in size within the total emitted dose.
DPI, dry powder inhaler; ERS/ISAM, European Respiratory Society/International Society for Aerosols in Medicine; HFA-BDP, hydrofluoroalkane-beclomethasone dipropionate; MMAD, mass median aerodynamic diameter; pMDI, pressurized metered-dose inhaler.
In conclusion, although we acknowledge the variety of factors associated with lung deposition, the strong influence of particle size on the effectiveness of inhaled treatments for asthma and COPD is an important area of research and warrants a common language to denote aerosol particle size. We propose harmonizing the nomenclature with use of the terms extrafine and fine to denote the two common particle size categories of orally inhaled, therapeutic aerosols and coarse for aerosols with MMAD >5 μm. In addition, we encourage the routine reporting of particle size, together with measurement technique, in published studies as well as in prescribing information for orally inhaled therapeutic aerosols.
Footnotes
Acknowledgments
The authors thank the other members of the Small Airways Study Group of the Respiratory Effectiveness Group who participated in discussions about nomenclature for therapeutic aerosol particle size: Dirkje Postma (University of Groningen, Department of Pulmonary Medicine and Tuberculosis, University Medical Center Groningen, the Netherlands, retired), Theresa Guilbert (Cincinnati Children's Hospital and Medical Center, Cincinnati, OH), Jonathan Grigg (Blizard Institute, Queen Mary University London, London, UK), and Wanda Phipatanakul (Boston Children's Hospital and Harvard Medical School, Boston, MA). They also thank Alison Chisholm of the Respiratory Effectiveness Group for moderating the steering committee meetings at which particle size nomenclature was discussed.
Disclaimer
Author Disclosure Statement
E.V.H. is a consultant to the Observational and Pragmatic Research Institute, Pte., Ltd. (Singapore), which has conducted paid research on behalf of several pharmaceutical companies that market inhaled products, including Aerocrine, AKL Research and Development, Ltd., Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp, Novartis, Orion, Takeda, Teva Pharmaceuticals, and Zentiva, a Sanofi company. She has received payment for writing and editorial support to Merck.
D.B.P. has board membership with Aerocrine, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals; consultancy agreements with Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Mylan, Mundipharma, Napp, Novartis, Pfizer, Teva Pharmaceuticals, and Theravance; grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute, Pte., Ltd.) from Aerocrine, AKL Research and Development, Ltd., AstraZeneca, Boehringer Ingelheim, British Lung Foundation, Chiesi, Mylan, Mundipharma, Napp, Novartis, Pfizer, Respiratory Effectiveness Group, Teva Pharmaceuticals, Theravance, United Kingdom National Health Service, Zentiva; payment for lectures/speaking engagements from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Mylan, Merck, Mundipharma, Novartis, Pfizer, Skyepharma, and Teva Pharmaceuticals; payment for article preparation from Mundipharma and Teva Pharmaceuticals; payment for the development of educational materials from Mundipharma and Novartis; payment for travel/accommodation/meeting expenses from Aerocrine, AstraZeneca, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva Pharmaceuticals; funding for patient enrolment or completion of research from Chiesi, Novartis, Teva Pharmaceuticals, and Zentiva; stock/stock options from AKL Research and Development Ltd that produces phytopharmaceuticals; owns 74% of the social enterprise Optimum Patient Care, Ltd. (Australia, Singapore, and United Kingdom), and 74% of Observational and Pragmatic Research Institute, Pte., Ltd. (Singapore); and is peer reviewer for grant committees of the Efficacy and Mechanism Evaluation program, and Health Technology Assessment.
H.C. has no shares in any pharmaceutical companies. He has received sponsorship to carry out studies, together with Board Membership, consultant agreements and honoraria for presentation, from several pharmaceutical companies that market inhaled products. These include Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Innovata Biomed, Meda, Napp Pharmaceuticals, Mundipharma, NorPharma, Norvartis, Orion, Sanofi, Teva, Truddell Medical International, UCB, and Zentiva. Research sponsorship has also been received from grant awarding bodies (EPSRC and MRC). He is the owner of Inhalation Consultancy, Ltd.
R.J.M. has done consultancy work and/or received travel support and/or honoraria for attendance at advisory boards for Teva, AstraZeneca, MedImmune, and Merck; received research grants from MedImmune and the NHLBI; and received royalties from UpToDate.
E.I. reports having received over the past 3 years consulting fees from 4D Pharma, Entrinsic, Health Solutions, GlaxoSmithKline, Merck, Sanafi, AstraZeneca, Bird Rock Bio, Cowen & Co., Novartis, Nuvelution Pharmaceutical, Philips Respironics, Regeneron Pharmaceuticals, TEVA Specialty Pharmaceuticals, and Vitaeris, Inc.; fees for expert testimony from Crammer, Bishop & O'Brien, Fox Rothschild, Danaher Lagnese, McCormick, Fitzpatrick, Kasper & Burchard, and Ryan Ryan Deluca LLP; travel grant support from Research in Real Life (RiRL), TEVA Specialty Pharmaceuticals; Royalties from UpToDate; Deputy Editor fees from the American Thoracic Society; DSMB Member for Novartis with no compensation; and having grant support paid to his Institution from Genentech, Sanofi, and the NIH.
W.M.C.v.A. is a member of Medical Advisory Board of AstraZeneca.
A.P. has received grants, personal fees, and travel expenses reimbursement from Chiesi Farmaceutici, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Pfizer, Takeda, Mundipharma, Menarini, Sanofi, Zambon, and TEVA.
O.S.U. reports grants from AstraZeneca, personal fees from Boehringer Ingelheim, grants and personal fees from Chiesi, personal fees from Aerocrine, grants from GlaxoSmithKline, personal fees from Napp, personal fees from Mundipharma, personal fees from Sandoz, grants from Prosonix, personal fees from Takeda, personal fees from Zentiva, and grants from Edmond Pharma. He is a recipient of a United Kingdom National Institute for Health Research (NIHR) Career Development Fellowship and supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.
N.R. has received over the past 3 years (1) fees for speaking, organizing education, participation in advisory boards or consulting from 3M, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, MSD-Chibret, Mundipharma, Novartis, Pfizer, Sanofi, Sandoz, Teva, Zambon and (
) research grants from Novartis, Boehringer Ingelheim, and Pfizer.