Title : The effect of the inhalation manoeuvre parameters on the indacaterol drug deposition from OnbrezBreezhaler® dry powder inhaler.
Abstract:
Dry powder inhalers (DPIs) have been traditionally developed based on in-vitro testing with a square-wave airflow profile as described in the Pharmacopoeia (USP, 2014). Several studies showed that the Pharmacopoeial flow profile is a poor approximation to reality in some important aspects. For example, humans are not able to replicate the square wave generated by a vacuum pump; nor can the majority of patients achieve the pharmacopoeia-recommended inhalation parameters for the change in the pressure inside the inhalation channel of the inhaler or the inhaled volume (Azouz et al., 2015). Breathing simulators, machines designed to generate and apply an inhalation and/or exhalation profile that mimics that of a human subject, are becoming an increasingly routine part of orally inhaled product (OIP) testing. The breathing simulators have opened up opportunities to improve the clinical relevance of in vitro OIP testing techniques. Recently, researchers are starting to use real patient’s inhalation profile (IP) measured during real-life use when an individual uses an inhaler (Olsson et al., 2013). The IP is subsequently replayed through the inhaler in-situ (Olsson et al., 2013) in order to fully scope DPIs product performance (Olsson et al 2010). This ex-vivo method, using a patient inhalation profile instead of the vacuum pump, provides information on the total emitted dose (TED) and particle size distribution (which includes the mass median aerodynamic diameter [MMAD] and the geometric standard deviation [GSD]) that the patient would have inhaled (Chrystyn et al., 2015). The IP generated by the IP recorder has a bell-shape but they differ from patient to patient in terms of the acceleration rate (ACIM), maximum inhalation flow (MIF) and inhaled volume (Vin) (Chrystyn, 2003; Chrystyn 2006; Azouz et al., 2015) depending on patient’s lung capacity and disease state. These parameters have been mentioned to affect the clinical effectiveness of the inhaled aerosol, but which one of these parameters is the most important it’s still unclear. This study was designed to assess the effect of Vin and ACIM on the aerodynamic characteristics of indacaterol dose emission from Onbrez Breezhaler® using a fixed MIF of 85L/min. The profiles were generated when patients with different chronic obstructive pulmonary disease (COPD) severity aged 55- 79 with a mean age of 66 inhales through an empty (Placebo) Onbrez Breezhaler® inhaler device. The patients have read the patient information leaflet (PIL) and they were also trained how to use the inhaler device according to the manufacturer recommendations as described in the PIL. The profiles were recorded when patients inhale as fast as they can through the inhaler. For this study, 9 inhalation profiles were used to assess the effect of each inspiratory parameter on the aerodynamic characteristics of indacaterol emitted dose. Breezhaler is a low resistance device characterized by its low intrinsic resistance value of 0.07 cm H2O (½)/L/min(Pavkov et al., 2010), thus patients were able to achieve a high flow rate through the device with a mean MIF of 88 L/min. The inhalation manoeuvre parameters generated by patient inhalation such as acceleration rate, MIF, and Vin have been shown to affect drug delivery to the lungs (Laube et al., 2011). Three different Vins (1, 2 and 3L) and three ACIM were used (2, 4 and 8 L/s2) at a fixed MIF of 85L/min (figure 1). The inhalation time was either increased or decreased to achieve the desired Vin. The ACIM was modified by increasing the steepness of the slope, whereas the MIF was the one generated by the patient. The experimental set-up was adapted to connect the breath simulator (BRS) with Andersen cascade impactor (ACI) via the mixing inlet, through which a supplementary air flow was introduced to achieve 0 L/min at the mouth piece, the ACI was assembled to be used at 90 L/min flow rate (Olsson et al., 2013; Nadarassan et al., 2010).
