Effect of Flow Rate on Emitted Aerodynamic Particle Size Distribution from a Dry Powder Inhaler (DPI) Delivering a Short Acting Beta2 Agonist as Monotherapy

BACKGROUND

Short-acting beta2 agonist (SABA) monotherapy is typically required to provide as needed short term relief of bronchoconstriction. The salbutamol EasyHaler^† DPI has recently become available in the UK as an alternative to delivery by pressurized metered-dose inhaler. Our study evaluated delivery from this DPI at different inhalation flow rates.

PURPOSE

To explore the effect of three different fixed inhalation flow rates from 15 to 60 L/min, focusing on metrics derived from the aerodynamic particle size distributions (APSDs) determined by NGI cascade impactor. The chosen metrics represented the total mass of salbutamol, the mass of salbutamol sized as fine particles (<4.46 μm) aerodynamic diameter and the corresponding coarse mass fraction.

MATERIALS & METHODS

The performance of salbutamol Easyhaler^† DPIs was assessed by Next Generation Impactor (NGI) and pre-separator in accordance with the methodology described in Chapter of the United States Pharmacopeia.

TEST METHODOLOGY

n = 5 replicate measurements at each condition Laboratory temperature was in the range 21-22°C; relative humidity between 41 and 42% Reference measurements at 60 L/min deemed likely to represent optimal use • Identical with the highest flow rate undertaken by Vidgren et al.¹ in an initial evaluation of this inhaler design • Sampling at fixed flow rates of 15, and 30 L/min, mimicking sub-optimal inhalation. Salbutamol was recovered quantitatively from: • mouthpiece of inhaler • interior surfaces of the induction port and pre-separator • each surfactant-coated cup of the NGI • micro-orifice collector (MOC).

RESULTS

Table 1 is a summary of the key salbutamol mass-based measures at each flow rate.

The demarcation between fine and coarse mass fraction was set at 4.46 μm aerodynamic diameter, based on the cut-point of NGI stage 2 at the reference flow rate of 60 L/min. Values at the lower flow rates of 30 L/ min and 15 L/min were determined through interpolation based upon this value. FPM<4.46μm was calculated as the product of TM and FPF<4.46μm.

DISCUSSION

The chosen reference flowrate of 60 L/min is close to 55 L/min reported by Turpeinen et al. ² as corresponding to a 4 kPa pressure drop across the Easyhaler^† DPI delivering a salmeterol/fluticasone propionate combination, that has a moderate airflow resistance of 0.036 (kPa)1/2 min L-1.³ In the present study, the mean value of FPM4.46µm increased only slightly from 51.8% at 60 L/min to 55.1% at 30 L/min and further to 65.9% at 15 L/min (Table 1). These observations point to a loss of performance in terms of delivering potentially respirable particles at both lower flowrates than at the reference condition, a situation also observed by Vidgren et al.¹

CLINICAL IMPLICATIONS

In clinical use, it is recognized that many patients will have the physiological capability to generate inspiratory flow rates close to 60 L/min. However, some will not achieve this target, particularly those at the extreme age range of potential users and those of all ages with severe obstructive disease,⁵ and others who may lack the cognitive ability to consistently generate close to the required flow rate range (known to be very dependent on the suitability of the training and learning of the patient⁶).

CONCLUSION

We have highlighted a steep decline in performance of one DPI product registered for the delivery of a SABA at sub-optimal flow rates. Although monotherapy by SABA is not a first line recommendation for asthma management,⁴ it is still commonly used to manage increased symptoms. It would therefore be extremely beneficial to see results from clinical research undertaken to evaluate whether asthma patients undergoing exacerbations (especially severe) can achieve adequate relief of symptoms using such a DPI device.