A review of the development of Respimat® Soft Mist™ Inhaler

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Abstract

Respimat® Soft Mist™ Inhaler (SMI) is a new generation inhaler from Boehringer Ingelheim developed for use with respiratory drugs. The device functions by forcing a metered dose of drug solution through a unique and precisely engineered nozzle (the uniblock), producing two fine jets of liquid that converge at a pre-set angle. The collision of these two jets generates the soft mist. The soft mist contains a high fine particle fraction of approximately 65 to 80%. This is higher than aerosol clouds from conventional portable inhaler devices, such as pressurised metered dose inhalers (pMDIs) and dry powder inhalers (DPIs). In addition, the relatively long generation time of the aerosol cloud (approximately 1.5 s) facilitates co-ordination of inhalation and actuation – a major problem with pMDIs. These features, together with the slow velocity of the soft mist, result in larger amounts of the drug reaching the lungs and less being deposited in the oropharynx compared with either pMDIs or DPIs. Generation of the soft mist from Respimat® SMI is purely mechanical, so propellants are not necessary. The innovative design of Respimat® SMI, using water-based drug formulations, ensures patients receive consistent and reliable doses of the drug with each actuation. The device was initially tested in scintigraphic lung deposition studies and produced encouraging results when compared with the chlorofluorocarbon-based pMDI (CFC-MDI). Subsequent clinical studies have confirmed that Respimat® SMI is effective and safe in delivering bronchodilators to patients with asthma or chronic obstructive pulmonary disease.

Introduction

Inhalation therapy has led to considerable improvements in the treatment of obstructive airways diseases, such as asthma and chronic obstructive pulmonary disease (COPD). As the drug is delivered directly to its site of action, a low dose can be used to produce a therapeutic response and, consequently, side effects are minimised. Additionally, inhaled drug delivery circumvents the limitations imposed by first-pass hepatic metabolism and fast absorption results in an onset of action that is more rapid than that achieved by oral administration.

The efficacy of an inhaled drug is largely dependent on the amount of the drug deposited in the lungs and its topographical anatomical distribution; this is influenced by various interacting factors, including the characteristics of the aerosol, the type of delivery device used, the mode of inhalation and the architecture of the airways (Ganderton, 1997, Pavia, 1997). The characteristics of the aerosol will affect the amount of drug reaching the lung. The method by which fine particles are produced for pulmonary delivery and the size distribution of these particles significantly affects drug deposition within the airways (Newman, 1984, Pavia, 1997). It may be possible to deliver drugs more precisely by using aerosols with a defined particle size distribution; for example, particles with a diameter of 2–5 μm are generally deposited in the smaller bronchioles and peripheral airways (Ariyananda et al., 1996). Larger particles tend to be deposited in the upper airways, whereas those smaller than 2 μm are, to a large extent, breathed in and out of the alveoli with minimal actual deposition (Pavia, 1997, Ariyananda et al., 1996, Matthys, 1990); small particles that do manage to deposit in the alveoli may be rapidly absorbed and exert no pharmacodynamic effect (Pritchard, 2001). A study by Zanen et al. found that the optimal particle size for β2 agonist and anticholinergic aerosols in patients with severe airflow obstruction was approximately 3 μm (Zanen et al., 1996). More recently, the effects of bronchodilator particle size on airway drug deposition in asthmatic patients was studied (Usmani et al., 2003). Monodisperse salbutamol aerosols of 1.5, 3 and 6 μm in size were inhaled and lung function changes were determined; the 3 and 6 μm aerosols were significantly more effective bronchodilators than the 1.5 μm aerosol.

Several types of portable devices are currently available for the delivery of drugs by inhalation; these include the chlorofluorocarbon (CFC) and hydrofluoroalkane (HFA) pressurised metered dose inhalers (pMDIs), and the dry powder inhalers (DPIs). The CFC-MDI has been the cornerstone of asthma and COPD maintenance therapy for many years. However, many patients experience problems in using CFC-MDIs and do not obtain optimal therapeutic benefit from their medication (Giraud and Roche, 2002). The limitations of the pMDI, and the move to eliminate CFC propellants for environmental reasons, have accelerated the development of alternative inhaler devices. Inherent in the development of these new devices has been a determination to improve on known device deficiencies (Steed et al., 1997).

Respimat® Soft Mist Inhaler (SMI) is a new generation inhaler that uses mechanical power from a spring rather than liquid-gas propellant to generate an aerosol cloud suitable for inhalation. This article reviews the development of Respimat® SMI and describes how the latest advances in aerosol technology have been used in order to improve upon existing inhaler performance.

Section snippets

Respimat® SMI

Respimat® SMI is a new generation, propellant-free, multi-dose inhaler developed by Boehringer Ingelheim. The term ‘soft mist’ is used to describe both the mechanism of aerosol generation and the qualities of the aerosol cloud. Respimat® SMI does not belong to any of the existing categories of inhaler device and represents an innovative approach to patient-oriented inhalation therapy.

Conclusions

The performance of the inhaler device is critical for optimal drug delivery, lung deposition and subsequent clinical effects. Respimat® SMI represents an innovative approach to inhalation therapy; this propellant-free, multi-dose inhaler generates an inhalable aerosol cloud (the soft mist) with superior properties to those produced by existing devices, such as pMDIs and DPIs.

The soft mist generated by Respimat® SMI is produced by the collision of two jets of liquid forced through a specially

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