RESEARCH PAPER Inhalation Performance of Physically Mixed Dry Powders Evaluated with a Simple Simulator for Human Inspiratory Flow Patterns Daiki Hira & Tomoyuki Okuda & Daisuke Kito & Kazunori Ishizeki & Toyoko Okada & Hirokazu Okamoto Received: 17 April 2010 / Accepted: 7 July 2010 / Published online: 14 July 2010 # Springer Science+Business Media, LLC 2010 ABSTRACT Purpose To construct a simple simulator reproducing human inspiratory flow patterns and use it to evaluate the inhalation performance of active ingredient particle-carrier particle sys- tems (physically mixed dry powders). Methods Inspiratory flow patterns were collected and ana- lyzed using a flow recorder. The simulator was constructed using an airtight container, a valve, and a connecting tube. Several of the patterns reproduced by the simulator were compared with those recorded. In addition, the influence of inspiratory flow on the inhalation performance of physically mixed dry powders composed of salbutamol sulfate (SS) and coarse lactose monohydrate was investigated using a twin- stage liquid impinger (TSLI) equipped with the simulator. Results Human inspiratory flow patterns could be character- ized by three parameters: inspiratory flow volume (area under the flow rate-time curve (AUC)), flow increase rate (FIR), and peak flow rate (PFR). The patterns could be reproduced using the simulator. Testing with the simulator in vitro revealed that PFR, but not FIR or AUC, greatly affected the inhalation performance of physically mixed dry powders. Conclusions The simulator is simple to construct and can schematically reproduce human inspiratory flow patterns. Testing with a TSLI and the simulator is useful to evaluate dry powder formulations for clinical application. KEY WORDS dry powder inhaler . inhaler testing . inspiratory flow pattern . physically mixed dry powders . twin-stage liquid impinger (TSLI) INTRODUCTION Inhalation therapy plays an important role in the treatment of not only local respiratory diseases, including asthma (1,2), but also systemic diseases (3,4). Therefore, many attempts have been made to enhance its therapeutic effects (5–8). In the local treatment of respiratory diseases, inhalation therapy is most effective at low drug doses, which can attenuate systemic side effects, since inhaled drugs are delivered directly to target sites (9,10). Among the three major delivery systems for inhalation—nebulizers, metered-dose inhalers (pMDIs), and dry powder inhalers (DPIs)—DPIs have several advantages, such as good portability, low cost, and no propellants. Furthermore, the handling of DPIs is easier than that of pMDIs because of breath-actuated passive aerosolization (11). For effective pulmonary deposition after inhalation, in general, the optimal aerodynamic diameter of drug particles is less than 6 μm(12,13). However, micronized drug particles tend to be highly cohesive and poorly flowable, leading to low performance. To solve these problems, large carrier particles, such as coarse lactose monohydrate, have been mixed with micronized active pharmaceutical ingredient (API) particles to prevent coherence: such preparations are known as physically mixed dry powder formulations (14,15). The micronized API particles and large carrier particles are expected to form an ordered mixture in an inhalation device, which is easily emitted from the device after inhalation, followed by the release of API particles from the mixture. However, it is often difficult for micronized D. Hira : T. Okuda : D. Kito : H. Okamoto (*) Faculty of Pharmacy, Meijo University 150 Yagotoyama Tempaku-ku, Nagoya 468-8503, Japan e-mail: okamotoh@meijo-u.ac.jp K. Ishizeki : T. Okada Hitachi Automotive Systems, Ltd. 1671-1 Kasukawa-cho Isesaki, Gumma 372-0023, Japan Pharm Res (2010) 27:2131–2140 DOI 10.1007/s11095-010-0215-6