The effect of inspiratory parameters after two separate inhalations on the dose emission of theophylline from low and high resistance dry powder inhalers.

The dose emission from DPIs can be affected by the inspiratory parameters achieved by the patient as well as the device in-use. Conventional in-vitro dose emission methodology was used, but instead of using inhalation volume (Vin) of 2 or 4 L and peak inhalation flow (PIF) corresponding to 4 kPa, a range of PIFs (28.3, 60, 90 and 120 L min-1) and Vins (0.5, 0.75, 1, 1.5, 2, and 4 L) were used. The formulation was composed of spray dried Theophylline as a model drug with Lactohale® α lactose monohydrate carrier. The formulation was aerosolised using two DPIs; a low resistance Breezhaler® and high resistance Handihaler®. The formulation showed a consistent dose content uniformity with a Coefficient of Variation (CV) of 1.70%. The drug distribution on the surface of the carrier was obvious from the SE micrographs with some drug particles lodged into lactose crevices. The dose emission after the first inhalation (ED1) and total emitted dose (TED) of theophylline increased with PIF and Vin, irrespective of the inhaler device. However, the dose delivered was superior for the Handihaler® compared to Breezhaler®. Drug retention in the capsule and device was high at low PIFs and Vins and reduced after the second inhalation. Therefore, our study supports the recommendations for patients who cannot achieve sufficient PIF and Vin to inhale twice for each dose to ensure the better clinical outcome.

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.

Use of inspiratory profiles from patients with chronic obstructive pulmonary disease (COPD) to investigate drug delivery uniformity and aerodynamic dose emission of indacaterol from a capsule based dry powder inhaler.

Most patients using dry powder inhalers (DPIs) are unable to achieve the inhalation parameters recommended for pharmacopoeial in-vitro dose emission testing. The dose emission characteristics of indacaterol Breezhaler (IB) have been measured using COPD patients' inhalation profiles (IPs) when using IB and replayed in-vitro using a breath simulator attached to an Andersen Cascade Impactor. The peak inhalation flow (PIF) of the profiles ranged from 28.3 to 87.8 L/min and inhaled volumes (Vin) from 0.7 to 3 L. The indacaterol total emitted doses (TED), fine particle dose (FPD) and mass median aerodynamic diameter (MMAD) were measured. TED varied between 61% to 83% of the 150 µg nominal dose, the FPD was found to vary between 19% and 30% and the MMAD from 3.7 µm to 2.3 µm with the increase of the profiles' PIF and Vin. The mean (SD) values were 113.4(8.9) µg, 39.7(5.0) µg and 2.7(0.5) µm, respectively. The quantity and the quality of the emitted dose from the indacaterol Breezhaler® are dependent on the capability of a patient generating an optimal inhalation profile. Therefore, when using the IB patients should be encouraged to inhale as fast as they can from the start of their inhalation and for as long as possible.

Real-life budesonide and formoterol dose emission from the medium and high strength fixed dosed combinations in a Spiromax® dry powder inhaler using inhalation profiles from patients with chronic obstructive pulmonary disease.

Dry powder inhalers (DPIs) are passive devices used to administer inhaled medication for the management of asthma and chronic obstructive pulmonary disease (COPD). DPIs require patients to generate a sufficient internal turbulent airflow force during each inhalation to deaggregate the powdered drug formulation into an emitted dose containing particles with the greatest likelihood of lung deposition. This internal force is generated by the interaction between the user's inhalation flow and the resistance of the DPI. Traditional compendial in vitro methods of measuring dose emission use a vacuum pump to simulate inhalation. We have adapted this in vitro method by replacing the square wave inhalation profile generated by a vacuum pump with the inhalation profiles of patients using an empty DPI. This method enables accurate assessment of the actual dose they would have inhaled. In the present study, real-life inhalation profiles were selected from 15 patients with COPD who inhaled through an empty placebo Spiromax® DPI. Ex vivo dose emissions were measured for the medium (emitted dose of 160 µg/4.5 µg) and high-strength (320 µg/9 µg) budesonide/formoterol formulations from the Spiromax DPI. These profiles were used to investigate the effect of the primary inhalation parameter-peak inhalation flow (PIF). Some profiles were modified to isolate other inhalation parameters (namely, inhaled volume [Vin] and acceleration rate of the inhalation maneuver [ACIM]). Both the medium-strength and high-strength DuoResp Spiromax displayed flow-dependent dose emission. When the PIF of a patient's inhalation maneuver increased from 26.8 L/min to 69.7 L/min, there was a significant (p < 0.05) effect on the dose-emission characteristics of the medium-strength and high-strength DuoResp Spiromax. At each PIF, an increase in Vin from approximately 500 mL to 2000 mL had no effect on the dose-emission characteristics of either strength. However, at each Vin there was a significant (p < 0.05) effect on the dose-emission characteristics as PIF increased. The effect of ACIM on the dose-emission characteristics was small. The ex vivo methodology used in this study provides a practical approach to identify the actual dose a patient might inhale during routine real-life use of the DuoResp Spiromax.

Effect of maximum inhalation flow and inhaled volume on formoterol drug deposition in-vitro from an Easyhaler® dry powder inhaler.

Most patients using dry powder inhalers (DPIs) do not achieve the inhalation parameters recommended for pharmacopoeial in-vitro dose emission testing. The dose emission characteristics of formoterol from an Easyhaler® have been measured using the Andersen Cascade Impactor (ACI) with a maximum inhalation flow (MIF) of 28.3, 60 and 90L/min and inhaled volumes (Vin) of 240, 750, 1500 and 2000mL. The total emitted dose (TED) was significantly higher at 90L/min (p<0.05), but the difference in the TED between low (28.3L/min) and high (90L/min) flow rate was significantly reduced by increasing the Vin. The fine particle dose (FPD) was higher (p<0.05) at 90L/min for all Vin values compared to 28.3 and 60L/min. Similarly the mass median aerodynamic diameter (MMAD) was smaller at 90L/min across all Vin values. Dose emission characteristics were lower at 240mL for both MIFs. The results for 240mL could be due to an insufficient Vin pulled through the ACI or incomplete emptying of the dose metering cup. This study shows that the FPD, %FPF and MMAD were not significantly affected by the vin≥750mL and that an inhaled volume as low as 750mL could be used with the ACI.