Acute Local Tolerability of Acidic Aqueous Vehicles Delivered via Respimat® Soft Mist™ Inhaler in Hyperreactive Asthma Patients

Abstract

Background:Acidic inhalers can be associated with increased adverse reactions. Objectives: This study aimed to determine the acute local tolerability of acidic aqueous placebo formulations delivered via Respimat® Soft Mist™ Inhaler (SMI) and placebo chlorofluorocarbon metered dose inhaler (CFC-MDI).Methods: A single-dose (four inhalations), randomized, double-blind within Respimat SMI device, four-way crossover study in asthma patients with documented bronchial hyperresponsiveness was used. Patients received acidic placebo solutions [pH 2.7, 3.4 or 7.0 (neutral)], delivered via Respimat SMI or placebo CFC-MDI. The primary endpoint was the largest decrease in forced expiratory volume in 1 s (FEV₁) from baseline to 0–30 min after dosing. Secondary endpoints included spirometry, paradoxical bronchoconstriction (defined as a fall in FEV₁ ≧15% below baseline within 30 min of dosing), cough episodes and adverse events.Results: Thirty-two patients were included in the per-protocol population (mean age 27 years, 62.5% males). The mean percentage decrease in FEV₁ was comparable between treatment groups: –1.6% (Respimat SMI pH 2.7), –1.8% (Respimat SMI pH 7.0), –1.9% (CFC-MDI), and –2.3% (Respimat SMI pH 3.4); no patient experienced paradoxical bronchoconstriction. The mean number of cough episodes was significantly lower in the Respimat SMI pH 2.7 group versus CFC-MDI (p = 0.0165). No patient used rescue medication. Only 3 patients experienced at least one adverse event. Conclusions: The Respimat SMI pH 2.7 placebo solution does not induce adverse events in these patients. Compared with the CFC-MDI placebo suspension, Respimat SMI is a well-tolerated inhaled medication delivery system that can accommodate medication formulations with a wide range of pH solutions.

Lack of paradoxical bronchoconstriction after administration of tiotropium via Respimat® Soft Mist™ Inhaler in COPD

“…In spite of this, our analysis shows that administration-related bronchoconstriction is uncommon when tiotropium is administered via Respimat ® SMI for 48 weeks in COPD patients. Our finding is consistent with results of studies in hyperreactive asthma patients who were given four inhalations of a placebo equivalent of the tiotropium formulation from Respimat ® SMI (twice the usual tiotropium dose) 17,18…”

“…In pooled analyses of studies in which a range of short-acting bronchodilators were given as single and repeated doses from Respimat ® SMI to asthma and COPD patients, no bronchospasm was recorded and levels of paradoxical bronchoconstriction were very low 15,16. In asthma patients with documented hyperreactivity, four inhalations of a placebo equivalent of the tiotropium formulation (the usual dose for COPD is only two inhalations) did not produce paradoxical bronchoconstriction and was associated with less cough than a placebo chlorofluorocarbon (CFC)-pMDI,17 supporting results of an earlier study that showed no difference in the degree of fall in FEV 1 between placebo aqueous or ethanolic inhalations and normal saline (all delivered via Respimat ® SMI) 18…”

The function and performance of aqueous aerosol devices for inhalation therapy

“…Inhalation solutions of tiotropium have been shown to be safe in asthma patients, but an increased risk of mortality has been reported for patients with COPD using Respimat ® . The high efficiency of this device also allows for the delivery of acidic solutions with pH values as low as 2.7, as well as ethanolic solutions, to be safely delivered to asthma patients without causing adverse events . The flexibility of this platform has allowed the use of a novel β 2 ‐agonist solution (olodaterol) in a hydroalcoholic mixture to be evaluated for pulmonary delivery .…”

“…[131] The high efficiency of this device also allows for the delivery of acidic solutions with pH values as low as 2.7, as well as ethanolic solutions, to be safely delivered to asthma patients without causing adverse events. [132,133] The flexibility of this platform has allowed the use of a novel b 2 -agonist solution (olodaterol) in a hydroalcoholic mixture to be evaluated for pulmonary delivery. [134] Due to its capacity to produce submicron droplets, Respimat â has been employed to investigate the concept of the enhanced excipient growth approach.…”