Effect of Dry Powder Inhaler Resistance on the Inspiratory Flow Rates and Volumes of Cystic Fibrosis Patients of Six Years and Older

Abstract

Several inhaled drugs for use by cystic fibrosis (CF) patients are formulated for nebulizer use only. This therapy is time consuming and includes the risk of contamination of the nebulizers. Dry powder inhalers (DPI) can be an attractive alternative for CF drugs. Inhaled flow rate and volume, and the device resistance are important determinants for optimal dispersion of drug from a DPI. It is important to understand how these variables interact in the CF population in order to properly design a new DPI formulation targeted for these patients. The objective of this study was to assess the inspiratory variables of a representative population of CF subjects 6 years and older with varying degrees of lung disease while inhaling through resistances that simulate DPI devices. Ninety-six stable CF patients were enrolled, ages 6-54 years, FEV(1) 19-126% predicted. Subjects inhaled forcefully through four different resistances (0.019, 0.024, 0.038, and 0.048 kP(0.5)/LPM, respectively), while inspiratory time (IT(DPI)), peak inspiratory flow (PIF(DPI)), and volumes (V(DPI)) were measured. For any resistance, inspired V(DPI) increased with the older age groups; PIF(DPI) was similar between adults and adolescents but lower in the children. Subjects with lower FEV(1) had lower V(DPI) and PIF(DPI). As resistance increased, PIF(DPI) decreased, IT(DPI) increased, with no significant change in V(DPI). At the lowest resistance mean PIF(DPI) was 105 LPM (range 45-163) for all patients; 112 LPM (range 75-163) in adults; and 89 LPM (45-126) in children. Mean inspired V(DPI) was 1.75 L for all patients; 2.2 L (0.8-3.7) in adults; and 1.2 L (0.5-1.8) in children. At the lowest resistance a minimal flow rate of 30, 45, and 60 LPM was attained in 100%, 99%, and 96% of all patients. Volumes of 1.0, 1.5, and 2.0 L were attained by 85%, 57%, and 30% of the patients. At the highest resistance mean PIF(DPI) was 52 LPM (range 26-70) for all patients; 55 LPM (40-70) in adults; and 47 LPM (26-62) in children. Mean inspired V(DPI) was 1.5 L in all patients; 1.9 L (0.9-3.5) in adults and 1.1 L (0.5-2.3) in children. At the highest resistance, a minimal flow rate of 30, 45, and 60 LPM was attained in 99%, 80%, and 22% of all patients. Volumes of 1, 1.5, and 2 L were attained in 84%, 45%, and 23% of the patients. We defined ranges for inspiratory variables in a diverse CF population for a range of device resistances that bracket those of current DPIs. The recorded inspiratory patterns can be used on the bench to design and test new dry powder formulations and devices to target the largest proportion of the CF population.

Tobramycin Inhalation Powder in Cystic Fibrosis Patients: Response by Age Group

“…This may be counterintuitive since the youngest, sickest children should have the most difficulty generating the required flow and volume necessary to ensure the aerosol reaches the lower airways. Tiddens et al 23 investigated this concept in a study in which inspiratory profiles of CF subjects of varying ages and disease severities were recorded using several resistors to simulate the representative resistance of a dry powder inhaler. By reproducing the inspiratory profiles representative of the T-326 inhaler in vitro with a breath simulator, researchers demonstrated that even a low inspired flow of 30 L/min and volume of 0.6 L could empty 14 and to the low-to-medium resistance of the T-326 inhaler.…”

Devices for Dry Powder Drug Delivery to the Lung

“…One advantage of utilizing a patient's inspiratory airflow as the main source of energy is that such devices are breath actuated; this inherently avoids the need to synchronize the actuation and inspiration maneuver by the patient. The downside of this approach is that devices currently available show a device-specific airflow resistance, and this often demands a relatively high inspiratory effort (31) which might be a hurdle for patient populations suffering from obstructive airway diseases such as asthma or COPD, the elderly, or very young (32). The extent of lung deposition is also dependent on the individual patient's inspiratory flow rate causing a potential difference in the dose effectively delivered due to this variability (33).…”

Inhaled antibiotics: dry or wet?

“…TIP has an MMAD ,4 mm and a grain size distribution of 1.7-2.7 mm [50]. The low-resistance inhaler allows the patient to generate a wide range of inspiratory flows [51]. In a controlled laboratory setting, it was shown that almost all CF patients of 6 years and older were able to generate flows of o30 L?min -1 .…”

“…Unfortunately, as discussed, high inspiratory flows increase oropharyngeal deposition and can reduce lung deposition, especially in the small airways. To empty all drug from the TIP capsule, an inspiratory volume of 1 L is sufficient to release all dry powder [51]. Most patients of 6 years and older were able to inhale a volume of o1 L [51].…”

“…To empty all drug from the TIP capsule, an inspiratory volume of 1 L is sufficient to release all dry powder [51]. Most patients of 6 years and older were able to inhale a volume of o1 L [51]. However, to ensure that all drug is released from the capsule, it is recommended to repeat the inhalation manoeuvre twice for each capsule.…”