Effect of Inhalation Manoeuvre Parameters In-Vitro and Ex-Vivo on the Dose Emission and the Aerodynamic Characteristics of Formoterol and Indacaterol from Marketed Dry Powder Inhalers

Dry powder inhalers (DPIs) are breath actuated devices relying on the inhalation effort generated by the patients during the inhalation manoeuvre to de-aggregate and disperse the powder formulation and release the dose for lung deposition. The aerodynamic dose emission characteristics vary among patients depending on the maximum inhalation flow (MIF), the inhalation volume (Vin) and the initial acceleration of the inhalation manoeuvre (ACIM). The compendial method for in-vitro testing of DPIs uses a vacuum pump to represent the patient’s inhalation manoeuvre. Furthermore, the pharmacopoeia recommended the use of a MIF corresponding to 4 kPa pressure drop with a Vin of 4 L. The vacuum pump square wave profile cannot be replicated by humans, and it is by no mean representing the actual patient’s inhalation manoeuvre. Additionally, most of the patients and even healthy volunteer are unable to achieve the pharmacopoeia recommended inhalation parameters of MIF and Vin when inhaling through different DPIs. In this thesis, a wide range of MIFs and Vins were used to investigate the dose emission and aerodynamic characteristics of formoterol and indacaterol using the in-vitro methodology. Furthermore, an ex-vivo methodology using COPD patients’ inhalation profiles and simulated patients’ inhalation profiles was used instead of a vacuum pump to study the performance of the indacaterol Breezhaler®. The aim of the study was to initially investigate the effect of MIF and Vin on the dose emission and the aerodynamic dose emission of indacaterol (Onbrez Breezhaler® and formoterol (Aerolizer® and Easyhaler®) over a MIF range of 28.3, 60, 90 and 120 L/min and a Vin range of 0.5, 0.75, 1, 1.5 and 2 L. Secondly, to assess the effect of all three inspiratory parameters MIF, Vin and ACIM on the aerodynamic dose emission of indacaterol Breezhaler® using the ex-vivo methodology with both COPD patients’ inhalation profiles and simulated patient’s inhalation profiles. The formoterol dose emitted after the first inhalation (ED1) from the Aerolizer® significantly increased (p < 0.05) with increasing the III MIF and the Vin. Conversely, the dose emitted after the second inhalation (ED2) and the residual amount (RA) decreased significantly (p < 0.05) with increasing the MIF and Vin. The ED1 and RA (% of the nominal dose) at low MIF of 28.3 L/min and Vin 0.5 L were 45.91%, 34%. At high MIF 120 L/min and a Vin of 2 L, the ED1 and RA were 70.75%, 22.91%. The formoterol dose emission from Easyhaler® showed that increasing the Vin and MIF resulted in a significant (p < 0.05) increase in the total emitted dose (TED), the fine particle dose (FPD) and a significant decrease in the Mass median aerodynamic diameter (MMAD) over a MIF range of 28.3, 60 and 90 L/min with a Vin range of 240, 750, 1500, 2000 mL. The increase in the Vin above 750 mL showed no improvement in the aerodynamic characteristics of formoterol from Easyhaler®. Similarly, the dose emission of indacaterol from Breezhaler® showed that the ED1 significantly increased (p < 0.05) with increasing the MIF, while both the ED2 and RA decreased. At a low MIF of 28.3 L/min and a Vin of 0.5 L, the ED1 and RA (% of the nominal dose) were 66.5% and 20.4%. In contrast, at a high MIF of 120 L/min and a Vin of 2 L, the ED1 and RA were 95.2% and 4.1% respectively. The dose strength study of indacaterol 150 μg and 300 μg showed that despite the difference observed in the carrier particle size, size distribution (SEM) and drug to carrier ratio yet both formulations produced a good drug content uniformity with a % CV < 1.8% and 100% dose recovery. The results of the dose emission and the aerodynamic characteristics followed the same trend for both dose strengths. The increase in the MIF and Vin resulted in an improvement in the aerodynamic characteristics of both formulations. The Breezhaler® device was able to generate particles within the extrafine range (≤ 3 μm) when a MIF of 60 L/min and above was used. Secondly, the performance of 150μg indacaterol Breezhaler® was evaluated using an ex-vivo method with COPD patients’ inhalation profiles. The results showed the importance of increasing the MIF on the dose emission characteristics of indacaterol dose emitted from Onbrez Breezhaler®. At a low MIF of 28.3 L/min, the TED and FPD were 92.0 μg ± 4.2 and IV 28.7 μg ±1.6 while at a high MIF of 87.8 L/min the TED and FPD were 125.1 μg ± 1.4 and 45.6 μg ± 0.8. The impact of the Vin and ACIM was difficult to be determined using COPD patients’ profiles. Therefore, simulated inhalation profiles (changing one parameter at a time) were used to identify the extent of each parameter. The results of the study showed that increasing both the Vin and the ACIM showed an impact on the dose emission characteristics of indacaterol. An increase in the Vin from 1 L to 3 L resulted in an increase in the TED and FPD with less impact on the MMAD. Similarly, increasing the ACIM from 2 L/s2 to 8 L/s2 increased the TED, FPD and more observed effect of the MMAD than the Vin. The results of in-vitro studies showed that a MIF of 30 L/min and a Vin of 750 mL were sufficient to de-aggregate the formoterol dose from a reservoir based Easyhaler®. The dose emission from capsule based inhalers Breezhaler® and Aerolizer® require a higher MIF > 60 L/min and patients are recommended to inhale twice in order to empty the capsule especially those with limited lung capacity. The use of an ex-vivo methodology is important for identifying the effect of all inhalation manoeuvre parameters. Although the MIF is the dominant factor in the dose emission from DPIs, increasing both ACIM and Vin resulted in an improvement in the aerodynamic characteristics of indacaterol Breezhaler® that explains the recommendations of forceful, deep and prolonged inhalation manoeuvre for patients using DPIs

Study of the Emitted Dose After Two Separate Inhalations at Different Inhalation Flow Rates and Volumes and an Assessment of Aerodynamic Characteristics of Indacaterol Onbrez Breezhaler® 150 and 300 μg

Onbrez Breezhaler® is a low-resistance capsule-based device that was developed to deliver indacaterol maleate. The study was designed to investigate the effects of both maximum flow rate (MIF) and inhalation volume (Vin) on the dose emission of indacaterol 150 and 300 μg dose strengths after one and two inhalations using dose unit sampling apparatus (DUSA) as well as to study the aerodynamic characteristics of indacaterol Breezhaler® using the Andersen cascade impactor (ACI) at a different set of MIF and Vin. Indacaterol 150 and 300 μg contain equal amounts of lactose per carrier. However, 150 μg has the smallest carrier size. The particle size distribution (PSD) of indacaterol DPI formulations 150 and 300 μg showed that the density of fine particles increased with the increase of the primary pressure. For both strengths (150 μg and 300 μg), ED1 increased and ED2 decreased when the inhalation flow rate and inhaled volume increased. The reduction in ED1 and subsequent increase in ED2 was such that when the Vin is greater than 1 L, then 60 L/min could be regarded as the minimum MIF. The Breezhaler was effective in producing respirable particles with an MMAD ≤5 μm irrespective of the inhalation flow rate, but the mass fraction of particles with an aerodynamic diameter <3 μm is more pronounced between 60 and 90 L/min. The dose emission of indacaterol was comparable for both dose strengths 150 and 300 μg. These in vitro results suggest that a minimum MIF of 60 L/min is required during routine use of Onbrez Breezhaler®, and confirm the good practice to make two separate inhalations from the same dose