Emitted Dose and Lung Deposition from Certain Inhalation Device

Research Abstract

The main aim was to compare the efficiency of three different spacers with that of jet nebulizer through the measurement of in-vitro characteristics and the emitted dose of these inhalation devices in non-invasive ventilation (NIV) conditions and to use a urinary pharmacokinetic method to determine the relative lung and systemic bioavailability of inhaled salbutamol in NIV Chronic Obstructive Pulmonary disease (COPD) patients through the usage of high performance liquid chromatography (HPLC) with ultraviolet (UV) detector. Finally, a correlation between the in-vitro and in-vivo studies was conducted. Two new, accurate and sensitive HPLC methods for the determination of salbutamol in aqueous and urine samples were developed and validated. Salbutamol was extracted using solid phase extraction with bambeterol hydrochloride as internal standard. The accuracy, precision, lower limit of detection and recovery for both methods were within recognized limits. The in-vitro dose emission characteristics of salbutamol sulphate were measured using an Anderson Cascade Impactor (ACI) at a flow of 15 L/min. The total emitted dose (TED) and particle size distribution of salbutamol sulphate were determined with different spacers (AeroChamber MV, AeroChamber Vent and AeroChamber Mini spacers) and the jet nebulizer. The Mass median aerodynamic diameter (MMAD) of the spacers was the smallest (p=0.001) compared to that of the jet nebulizer. The TED deposited on the inhalation filter of the spacers used was about one third of that of the jet nebulizer. However the nominal dose placed into the nebulizer was about seven times that placed in the spacer. That resulted in an average of TED% from the spacer that was 2.5 fold that of the jet nebulizer. Twelve NIV COPD patients (6 females) with mean (SD) age and weight of 63.1(9.4) years, 70.3(8.5) kg respectively were included in this study. One dose of 1200 μg salbutamol in 12 puffs of salbutamol MDI attached to one of the previously described three spacers fitted from one side to the continuous positive airway pressure (CPAP) as non-invasive ventilator and the other side was sealed to the facemask of the patient and amounts of urinary salbutamol excreted 0.5 and 24 hour post dosing were measured. The mean (SD) salbutamol excreted in 30 minute period after the start inhalation of the study dose from the AeroChamber MV, the AeroChamber Vent and the AeroChamber Mini spacers were 54.29(23.68), 44.42(21.55) and 50.42(23.27) μg, respectively and the mean (SD) 24 hours urinary excretion were 295.93 (176.37), 353.55 (131.23) and 363.82(162) μg, respectively. This urinary pharmacokinetic method to identity relative lung and systemic bioavailability between three spacer devices was easy to perform and is a useful and simple in-vivo method to compare the drug delivering efficiency of different spacers in patients receiving non-invasive ventilation. Data mining technology based on artificial neural networks and genetic algorithms were used to model the in-vitro inhalation process, predict and optimize bioavailability from the inhaled doses delivered by MDI using three different spacers in NIV. The modeling of the data indicated that the in-vitro performance of the MDI-spacer systems was dependent mainly on FPD, FPF, MMAD and to lesser extent on the spacer type. The ex-vivo model indicated that the amount of salbutamol collected on the face mask filter was directly affected by FPF and inversely affected by total emitted dose (TED; In-vitro inhalation filter). The in-vivo model (24 h Q) depended directly on the increasing levels of both FPF and TED. Also the female patients showed higher 0.5 h and 24 h Q values than males, whilst spacer type AeroChamber VC demonstrated higher in-vitro TED and resulted also in higher 24 h Q in-vivo values.

Research Keywords

Salbutamol, pressurized metered dose inhaler, Spacer, Non-invasive ventilation, urine, mass median aerodynamic diameter, fine particle dose, fine particle fraction, relative lung bioavailability