0.06 0.05 ) l /gm0.04 µ ( . c n oC 0.03 e n o s ica 0.02 t u l F 0.01 0.00 Nanoscale Res Lett (2009) 4:254–261 Fig. 3 Effect of dosing technique on plasma concentration Effect of Dosing Technique on Plasma Concentration 259 1 mg/kg IN 1 mg/kg IT 1 mg/kg Aersol 5 mg/kg Aersol 1mg/kg Aersol 5 mg/kg Aersol BANG BANG PARI LC PARI LC Table 1 PARI LC Nebulizer MADD via Impactor for Nanosuspen- sion on Different Dose Range Formulation Concentration (mg/mL) 21.74 4.35 2.44 0.43 0.04 Duration (min) 2.0 4.0 4.0 8.0 8.0 MMAD (lm) 3.6 4.1 3.5 3.9 3.4 Average 3.7 ± 0.3 surprise. During the inhalation of an aerosolized drug, assuming if all the drug particles travel at a constant velocity, the large particles carry a higher momentum due to its increased mass. The higher momentum makes it difﬁcult for these particles to negotiate the sharp turns in the anatomy of the nasal cavity and the transition to the upper airway. Thus, these larger particles tend to impact the inside of the nasal cavity or the back of the throat [27–29]. On the other hand, the smaller particles can change their trajectory with relatively increased ease, and can reach the lower parts of the airways [30]. Inside the deep lungs, the drug deposition is due to many factors which include Brownian motion, sedimentation due to gravity, and random impaction [31, 32]. Based on the number of nanoparticles found in each aggregate post nebulization, it is hypothesized that after nebulization, resulting aggregates from regular size particles were too large for inhalation. Due to the larger particle size used (particle size D50 to D90 1.6–2.9 lm), an aggregate with n [ 4 will result in a particle with D50 [ 5 lm which is considered too large for inhalation. When particles are larger than 5 lm, majority of the particles are trapped in the nasal cavity and upper airways, and only a small percentage will actually reach the deep lung [33]. The majority of the ﬂuticasone will then be deposited in the oral/nasal cavity and then swallowed. Because ﬂuticasone is known to have very low oral absorption, low plasma exposure was expected. Based on the observation, it is concluded that regular size ﬂuticasone suspension is not suitable for aerosol delivery. No further studies were con- ducted with regular size ﬂuticasone. The robustness of the delivery system was further tested in vivo. In this experiment, the impact of system ﬂow rate on performance was further investigated. The ﬂow rates tested for this study were 0, 2, and 5 L/min to cover the extreme cases, and the dose was set at 1 mg/kg. In general, our system was very robust. Using our delivery system, the lung depositions were not statistically signiﬁcant, even under the extreme challenge. At a ﬂow rate 0, 2, and 5 L/min, the lung depositions were 2.3, 1.1, and 2.4 lg/g, respectively (Fig. 4). Furthermore, the plasma concentra- tion was about 0.01 lg/mL for all the groups (Fig. 5). If IT delivery is considered to be 100% on target delivery, the lung exposure via aerosol delivery is approximately 30%. In a clinical setting, the typical fraction delivered to lung is believed to be between 10 and 40% [9]. The amount of ﬂuticasone deposited in the lung via nanosuspension aer- osol delivery falls within the clinical range with low Effect of System Flow on Lung Deposition 4.000 3.500 µg 3.000 ion 2.500 t iso 2.000 eD1.500 p ng 1.000 u L 0.500 0.000 0 L / Min 5 L / Min 2 L / Min System Flow Fig. 4 Effect of system ﬂow on lung deposition (PARI LC) 123