Lung Deposition Using the Respimat^® Soft Mist™ Inhaler Mono and Fixed-Dose Combination Therapies: An In Vitro/In Silico Analysis

Abstract

Tiotropium and olodaterol are mainstay treatments for chronic obstructive pulmonary disease (COPD) and yield important clinical improvements, especially when used in fixed-dose combination. Whilst previous studies have shown consistent delivery of tiotropium to the lungs with the Respimat^® inhaler, no such study has been carried out for olodaterol or the components of their fixed-dose combination (TIO/OLO). Combining in vitro and in silico models, we measured the amount of drug retained in the mouth–throat area, entering the trachea and reaching the lung periphery. We applied a hybrid deposition model that considered the experimentally determined output of an Alberta throat model (in vitro – dose to lung) combined with a computational fluid dynamic model of the lungs (in silico). Regardless of the COPD breathing pattern, ≥50% of the nominal dose of either tiotropium, olodaterol, or TIO and OLO in the fixed-dose combination reached the lung. Of the dose reaching the lungs, greater than 50% is deposited in the lung periphery (from generation 8 onwards). Our study demonstrated that aerosol delivery via the Respimat inhaler achieved high deposition deep into the lung periphery with all formulations evaluated.

Keywords:

• In vitro—in vivo correlation
• throat model
• simulation
• tiotropium
• olodaterol
• COPD
• drug delivery

Acknowledgments

We thank Prof. Warren Finlay for a prototype of his idealized throat model (now available at Copley Scientific Limited, Nottingham, UK). Dr. Ralf Kröger (ANSYS Germany) was consulted regarding the CFD calculations.

Data availability statement

The data used and analyzed during the current study are available from the corresponding author on reasonable request.

Declaration of interest

AMC’s research for her PhD thesis was funded by Boehringer Ingelheim. HW is an employee of Boehringer Ingelheim and has patent WO2004024340A1-Blockiervorrichtung für ein Sperrspannwerk. PL has received consulting fees from Boehringer Ingelheim. MD completed an internship with Boehringer Ingelheim at the time of this work. TV has received consulting and presentation fees from Boehringer Ingelheim.

Additional information

Funding

This study was supported by Boehringer Ingelheim. Editorial assistance with writing this manuscript was provided by Ishmam Nawar of MediTech Media, funded by Boehringer Ingelheim.