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Nebulized Mannitol, Particle Distribution, and Cough in Idiopathic Pulmonary Fibrosis.

Authors
  • Kanth, Pooja M1
  • Alaienia, Caesar2
  • Smaldone, Gerald C3
  • 1 Pulmonary, Critical Care and Sleep Division, Department of Medicine, Health Sciences Center, Stony Brook, New York.
  • 2 School of Pharmacy and Pharmaceutical Sciences, Stony Brook, New York.
  • 3 Pulmonary, Critical Care and Sleep Division, Department of Medicine, Health Sciences Center, Stony Brook, New York. [email protected]
Type
Published Article
Journal
Respiratory care
Publication Date
Nov 01, 2018
Volume
63
Issue
11
Pages
1407–1412
Identifiers
DOI: 10.4187/respcare.06153
PMID: 30154129
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Inhaled interferon, a potential treatment for idiopathic pulmonary fibrosis, must be formulated with mannitol, which can cause bronchospasm and cough. Coughing during drug inhalation can be affected by many factors, but some factors are fixed by the needs of the formulation and inflammatory disease in the airways. A component of the cough response may be related to sites of deposition, particularly upper and central airways. If deposition sites are important, then manipulating the particle distribution of the aerosol may mitigate coughing. To design a therapeutic formulation and delivery system for formulations that contain mannitol, we tested the effect of particle distribution on cough during mannitol inhalation in volunteers with idiopathic pulmonary fibrosis. A solution of mannitol was formulated to match requirements for future interferon formulations (40 mg/mL, 220 mOsm/L). Mannitol aerosols were generated by using different nebulizers providing particle distributions that were expected to vary upper airway deposition. The nebulizer fill volume was adjusted to correct for differences in nebulizer efficiency with a target inhaled mass of 20 mg. Particle distributions were measured by cascade impaction (mass median aerodynamic diameters, 1.2 and 6.5 μm). Seven subjects with idiopathic pulmonary fibrosis participated in the study. To maximize deposition, the subjects were trained to inhale slowly and deeply (6 s inspiration). Spirometry was measured before and after inhalation. The study was carried out on separate days (day 1: 1.2 μm; day 2: 6.5 μm), and the pattern of coughing was observed. Coughing was often spontaneous and provoked by spirometry. When inhaling the 1.2-μm distribution, no subject coughed during inhalation. Six of the seven subjects coughed when inhaling the 6.5-μm particles. Spirometry was unaffected. In subjects with idiopathic pulmonary fibrosis, nebulized mannitol can cause coughing. Modifying the aerosol distribution prevents coughing during mannitol inhalation. Mannitol aerosols can be inhaled safely without bronchospasm. These data serve to inform future formulation and/or device combinations for planned interferon therapy. Copyright © 2018 by Daedalus Enterprises.

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