Pneuma Respiratory, Boone, NC, USA.
Harvard University, Boston, MA, USA.
Pulm Pharmacol Ther. 2018 Dec;53:27-32. doi: 10.1016/j.pupt.2018.08.007. Epub 2018 Sep 7.
Delivery of inhaled respiratory medications have been associated with variable delivery of drug due to errors in device operations and have not been designed to monitor true delivery of medication. A fully digital breath-activated inhaled (DBAI) delivery platform has been developed with integrated firmware and software to address these limitations.
the device was designed to produce similar aerosol particle output to a marketed albuterol MDI and to the albuterol/ipratropium combination in a soft mist inhaler (SMI). Cascade impactor studies were conducted to demonstrate comparable aerodynamic particle size distribution (APSD) metrics. Efficacy was evaluated by pharmacodynamic studies involving spirometry in two separate protocols with adult subjects having COPD (albuterol DBAI vs. albuterol MDI - Study A, albuterol/ipratropium DBAI single arm - Study B).
The total emitted doses (TED) were 81.9 ± 10.3, 109.3 ± 15.0 and 121.9 ± 7.0 μg/actuation for the DBAI, SMI and MDI respectively, and the fine (respirable) particle doses (FPD) were 56.2 ± 6.0, 61.7 ± 5.5 and 79.4 ± 2.7 μg/actuation. MMADs for albuterol sulfate were 1.93 ± 0.11, 1.75 ± 0.19, and 2.65 ± 0.05 μm for the DBAI, Respimat soft mist inhaler (SMI) and MDI respectively. The corresponding GSDs were 1.96 ± 0.16, 2.79 ± 0.25, and 1.48 ± 0.02 μm. The corresponding respirable fractions were 68.7 ± 3.2%, 57.3 ± 10.5%, and 65.2 ± 2.4%. Spirometric study A enrolled 23 subjects (age 64 ± 7.3 years, 39% male, FEV 45 ± 14% predicted). Study B enrolled 23 subjects (age 65 ± 8.6 years, 43% male, FEV 47 ± 10% predicted). For Study A, FEV at 20 min post-dose improved by 120 (167) mL (p = 0.002) for the DBAI device and 109 (183) mL (p = 0.008) for the MDI device (p = 0.86 for between group differences). For Study B, FEV (20 min post-dose) improved by 216 (126) mL (p < 0.001).
The DBAI generated highly respirable aerosols containing albuterol sulfate that were similar to the MDI and SMI in respirable fraction but lower in dose. Subsequent pharmacodynamic studies delivering albuterol sulfate alone and in combination with ipratropium bromide confirmed similar responses for the DBAI compared with the other inhalers, which could possibly be related to a response ceiling. The DBAI breath-activated capability combined with the ability to monitor actual delivery of medication may improve effectiveness by overcoming patient miscoordination.
由于设备操作中的错误，吸入式呼吸药物的输送与药物的实际输送存在差异，且并未设计用于监测药物的实际输送情况。为了解决这些限制，我们开发了一种完全数字化的呼吸激活吸入（DBAI）输送平台，具有集成的固件和软件。
该设备的设计目的是产生与市售沙丁胺醇 MDI 相似的气溶胶颗粒输出，以及软雾吸入器（SMI）中的沙丁胺醇/异丙托铵组合。通过级联冲击器研究证明了相当的空气动力学粒径分布（APSD）指标。药效学评估通过两项独立的成年 COPD 患者（沙丁胺醇 DBAI 与沙丁胺醇 MDI-研究 A，沙丁胺醇/异丙托铵 DBAI 单臂-研究 B）的呼吸动力学研究进行。
DBAI、SMI 和 MDI 的总发射剂量（TED）分别为 81.9±10.3、109.3±15.0 和 121.9±7.0 μg/次，细颗粒剂量（FPD）分别为 56.2±6.0、61.7±5.5 和 79.4±2.7 μg/次。硫酸沙丁胺醇的 MMAD 分别为 1.93±0.11、1.75±0.19 和 2.65±0.05μm，DBAI、Respimat 软雾吸入器（SMI）和 MDI 的相应 GSD 分别为 1.96±0.16、2.79±0.25 和 1.48±0.02μm。相应的可吸入部分分别为 68.7±3.2%、57.3±10.5%和 65.2±2.4%。研究 A 纳入了 23 名受试者（年龄 64±7.3 岁，39%为男性，FEV 45±14%预测值）。研究 B 纳入了 23 名受试者（年龄 65±8.6 岁，43%为男性，FEV 47±10%预测值）。对于研究 A，DBAI 装置的 20 分钟后 FEV 改善了 120（167）mL（p=0.002），MDI 装置的 FEV 改善了 109（183）mL（p=0.008）（组间差异无统计学意义）。对于研究 B，FEV（20 分钟后）改善了 216（126）mL（p<0.001）。
DBAI 产生的高度可吸入的硫酸沙丁胺醇气溶胶与 MDI 和 SMI 相似，但可吸入部分较低，但剂量较低。随后的药效学研究表明，与其他吸入器相比，DBAI 单独和联合使用异丙托溴铵输送硫酸沙丁胺醇时，均可获得相似的反应，这可能与反应上限有关。DBAI 的呼吸激活功能与监测药物实际输送的能力相结合，通过克服患者的不协调，可以提高治疗效果。
