Pulmonary, Critical Care and Sleep Division, Department of Medicine, Health Sciences Center, Stony Brook, New York.
School of Pharmacy and Pharmaceutical Sciences, Stony Brook, New York.
Respir Care. 2018 Nov;63(11):1407-1412. doi: 10.4187/respcare.06153. Epub 2018 Aug 28.
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.
吸入型干扰素是特发性肺纤维化的一种潜在治疗方法，必须与甘露醇联合使用，而甘露醇可能会引起支气管痉挛和咳嗽。药物吸入时的咳嗽会受到许多因素的影响，但有些因素受到制剂和气道炎症的需要所固定。咳嗽反应的一个组成部分可能与沉积部位有关，特别是上气道和中央气道。如果沉积部位很重要，那么改变气溶胶的颗粒分布可能会减轻咳嗽。为了设计一种含有甘露醇的治疗制剂和输送系统，我们测试了颗粒分布对特发性肺纤维化志愿者吸入甘露醇时咳嗽的影响。
将甘露醇制成与未来干扰素制剂（40mg/ml，220mOsm/L）要求匹配的制剂。使用不同的雾化器生成甘露醇气溶胶，预计这些雾化器的颗粒分布会改变上气道的沉积。通过级联撞击（质量中值空气动力学直径，1.2μm 和 6.5μm）测量雾化器填充体积以校正不同雾化器效率的差异，目标吸入质量为 20mg。7 名特发性肺纤维化患者参与了这项研究。为了最大限度地提高沉积量，训练患者缓慢而深地吸气（6s 吸气）。吸入前后进行肺活量测定。该研究在不同的日子进行（第 1 天：1.2μm；第 2 天：6.5μm），并观察咳嗽模式。
咳嗽通常是自发的，也可以由肺活量测定引起。当吸入 1.2μm 分布时，没有受试者在吸入时咳嗽。7 名受试者中有 6 名在吸入 6.5μm 颗粒时咳嗽。肺活量测定不受影响。
在特发性肺纤维化患者中，雾化甘露醇可引起咳嗽。改变气溶胶分布可防止甘露醇吸入时咳嗽。可以安全吸入甘露醇气溶胶而不会引起支气管痉挛。这些数据为计划中的干扰素治疗提供了未来制剂和/或设备组合的信息。
