Apart from particle size distribution, spray velocity is one of the most important aerosol characteristics that influence lung deposition of inhaled drugs. The time period over which the aerosol is released (spray duration) is also important for coordination of inhalation. Respimat Soft Mist Inhaler (SMI) is a new generation, propellant-free inhaler that delivers drug to the lung much more efficiently than pressurised metered dose inhalers (pMDIs). The objective of this study was to compare the velocity and spray duration of aerosol clouds produced by Respimat SMI with those from a variety of chlorofluorocarbon (CFC) and hydrofluoroalkane (HFA) pMDIs. All inhalers contained solutions or suspensions of bronchodilators. A videorecording method was used to determine the aerosol velocity. For spray duration, the time for generation of the Soft Mist by Respimat SMI was initially determined using three different methods (videorecording [techniques A and B], laser light diffraction and rotating disc). Videorecording was then used to compare the spray duration of Respimat SMI with those from the other inhalers. The Soft Mist produced by Respimat SMI moved much more slowly and had a more prolonged duration than aerosol clouds from pMDIs (mean velocity at a 10-cm distance from the nozzle: Respimat SMI, 0.8 m/sec; pMDIs, 2.0-8.4 m/sec; mean duration: Respimat SMI, 1.5 sec; pMDIs, 0.15-0.36 sec). These characteristics should result in improved lung and reduced oropharyngeal deposition, and are likely to simplify coordination of inhaler actuation and inhalation compared with pMDIs.

The HandiHaler is a dry powder breath activated inhaler system developed for inhalation therapy for patients with airway disease. Its operation is based on the evacuation of powder from a pierced capsule. We sought to document the inspiratory flow rates attained by patients inspiring through the HandiHaler with various degrees of airflow limitation. Subjects with stable chronic obstructive pulmonary disease (COPD) were the study's population. An in vitro study of fine particle dose was conducted using an Andersen Cascade Impactor to assess medication delivery at low inspiratory flow rates. Subsequently, an in vivo study was conducted to determine inspiratory flow rates in patients with COPD as measured through a pneumotach with a custom coupler device with and without the HandiHaler. Patients were classified into three approximately equal groups of spirometric severity ranging from mild (46-65% predicted normal forced expiratory volume in 1 sec [FEV1]), to moderate (28-45%) to severe (< or = 27%). The in vitro study indicated delivery of medication at flow rates as low as 20 L/min. Twenty-six men completed the in vivo study (age 66.9 +/- 10.9 years, FEV1 = 1.02 +/- 0.45 l.). The median peak inspiratory flow rates attained in the mild (n = 8), moderate (n = 10), and severe (n = 8) categories were 45, 45.6, and 35.4 L/min respectively. The minimum peak inspiratory flow rates in the three groups were 28.2, 21.6 and 20.4 L/min. The HandiHaler device effectively delivers particles to the lung over a wide range of airflow limitation in patients with COPD.

A new cascade impactor has been designed specifically for pharmaceutical inhaler testing. This impactor, called the Next Generation Pharmaceutical Impactor (NGI), has seven stages and is intended to operate at any inlet flow rate between 30 and 100 L/min. It spans a cut size (D50) range from 0.54-microm to 11.7-microm aerodynamic diameter at 30 L/min and 0.24 microm to 6.12 microm at 100 L/min. The aerodynamics of the impactor follow established scientific principles, giving confident particle size fractionation behavior over the design flow range. The NGI has several features to enhance its utility for inhaler testing. One such feature is that particles are deposited on collection cups that are held in a tray. This tray is removed from the impactor as a single unit, facilitating quick sample turn-around times if multiple trays are used. For accomplishing drug recovery, the user can add up to approximately 40 mL of an appropriate solvent directly to the cups. Another unique feature is a micro-orifice collector (MOC) that captures in a collection cup extremely small particles normally collected on the final filter in other impactors. The particles captured in the MOC cup can be analyzed in the same manner as the particles collected in the other impactor stage cups. The user-friendly features and the aerodynamic design principles together provide an impactor well suited to the needs of the inhaler testing community.

The EU Regulation on Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) demands the implementation of alternative methods for analyzing the hazardous effects of chemicals including particulate formulations. In the field of inhalation toxicology, a variety of in vitro models have been developed for such studies. To simulate the in vivo situation, an adequate exposure device is necessary for the direct exposure of cultivated lung cells at the air-liquid interface (ALI). The CULTEX RFS fulfills these requirements and has been optimized for the exposure of cells to atomized suspensions, gases, and volatile compounds as well as micro- and nanosized particles. This study provides information on the construction and functional aspects of the exposure device. By using the Computational Fluid Dynamics (CFD) analysis, the technical design was optimized to realize a stable, reproducible, and homogeneous deposition of particles. The efficiency of the exposure procedure is demonstrated by exposing A549 cells dose dependently to lactose monohydrate, copper(II) sulfate, copper(II) oxide, and micro- and nanoparticles. All copper compounds induced cytotoxic effects, most pronounced for soluble copper(II) sulfate. Micro- and nanosized copper(II) oxide also showed a dose-dependent decrease in the cell viability, whereby the nanosized particles decreased the metabolic activity of the cells more severely.

In the field of inhalation toxicology, progress in the development of in vitro methods and efficient exposure strategies now offers the implementation of cellular-based systems. These can be used to analyze the hazardous potency of airborne substances like gases, particles, and complex mixtures (combustion products). In addition, the regulatory authorities require the integration of such approaches to reduce or replace animal experiments. Although the animal experiment currently still has to provide the last proof of the toxicological potency and classification of a certain compound, in vitro testing is gaining more and more importance in toxicological considerations. This paper gives a brief characterization of the CULTEX® Radial Flow System exposure device, which allows the exposure of cultivated cells as well as bacteria under reproducible and stable conditions for studying cellular and genotoxic effects after the exposure at the air–liquid or air–agar interface, respectively. A commercial bronchial epithelial cell line (16HBE14o-) as well as Salmonella typhimurium tester strains were exposed to smoke of different research and commercial available cigarettes. A dose-dependent reduction of cell viability was found in the case of 16HBE14o- cells; S. typhimurium responded with a dose-dependent induction of revertants. The promising results recommend the integration of cellular studies in the field of inhalation toxicology and their regulatory acceptance by advancing appropriate validation studies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00216-011-5163-4) contains supplementary material, which is available to authorized users.