In-VitroIntra- and Inter-Inhaler Flow Rate-Dependent Dosage Emission from a Combination of Budesonide and Eformoterol in a Dry Powder Inhaler

Abstract

Some dry powder inhalers have profound inhalation flow rate-dependent dosage emission, and it has been suggested that there are links between the in vitro emitted dose, total lung deposition, and subsequent clinical response. We have measured the in vitro dosage delivery for a combination of budesonide and eformoterol in a new version of the Turbuhaler. At inhalation flow rates of 30, 60, and 90 Lmin(-1), the total dose emission for 10 separate inhalations from each of six inhalers was determined. The aerodynamic characteristics of the emitted dose using inhalation flow rates of 28.3 and 60 Lmin(-1) were measured using the Andersen Cascade Impactor. The mean (SD) emitted dose for budesonide, at 30, 60, and 90 Lmin(-1), was 37.5%(18.2%), 64.4%(16.6%), and 107.4%(36.0%) (of the nominal emitted dose), respectively, and for eformoterol were 38.0%(20.3%), 65.0%(16.8%), and 104.9%(36.2%) (of the nominal emitted dose), respectively. Variability of dose emission characteristics from each inhaler and between inhalers at each flow rate was found. The aerodynamic particle size characterization of the emitted dose at flow rates of 28.3 and 60 Lmin(-1) revealed a mean fine particle dose for budesonide of 11.9% and 28.6% of the nominal emitted dose, respectively, and similarly 10.0% and 26.3% for eformoterol. At 28.3 Lmin(-1), the majority of the emitted dose (54.8% for budesonide and 64.5% for eformoterol) was deposited in the throat and preseparator of the Andersen Cascade Impactor. The mass median aerodynamic diameters for budesonide and eformoterol at 28.3 Lmin(-1) were 3.2 and 3.6 microm, respectively, and similarly at 60 Lmin(-1) were 2.4 and 2.5 microm. The modified Turbuhaler containing a budesonide and eformoterol combined formulation shows intra- and inter-inhaler flow-dependent dosage emission. The clinical significance of the in vitro dose-dependent properties should be investigated.

Equivalência farmacêutica da formulação combinada de budesonida e formoterol em cápsula única com dispositivo inalador de pó

“…The authors emphasized the importance of flow rate in drug discharge from the inhaler. (12) In the present study, the delivered fine particle fraction of budesonide and formoterol was 45% and 56%, respectively, when using the Aerocaps® inhaler at a standard flow rate of 90 L/min, compared with 54% and 52%, Brazilian Journal of Pulmonology (10) showed the clinical efficacy of budesonide alone and of the budesonide/formoterol combination contained in a test formulation. To date, there have been no clinical studies directly comparing the ingredients of a test formulation with those of a reference formulation.…”

“…In the study of the Turbuhaler® inhaler, the fine particle fraction was found to be 11.9% and 28.6% of the labeled dose at flow rates of 28.3 L/m and 60 L/m, respectively, confirming that the emitted dose from the inhaler is dependent on patient inhalation flow rates. (12) Radiolabeling has also been employed to study the regional deposition of inhaled particles. A study of mannitol labeled with 99m technetiumdiethylenetriamine pentaacetic acid was conducted in which the Aerolizer® inhaler was used.…”

Budesonide/Formoterol Easyhaler®: Performance Under Simulated Real-Life Conditions

“…In another in vitro study using clinically relevant patient air flow rates, a slight flow-dependent increase in FPD was found for both budesonide and formoterol for both the devices [3]. In contrast, the Turbuhaler has earlier been reported being a highly air flow-dependent device [8,30]. That conclusion may have partially been drawn from performance characteristics with low air flows, e.g.…”

“…It has been previously shown that with clinically relevant flow rates, delivered doses (DD) and fine particle doses (FPD) are rather independent of flow rates with the budesonide/formoterol Easyhaler and budesonide/formoterol Turbuhaler [3], although in vitro flow-dependent properties of, e.g., the Turbuhaler have been reported [8]. However, the inspiratory effort may vary considerably from one patient to another and, thereby, potentially affecting the clinical efficacy of the product.…”

Aerodynamic deposition of combination dry powder inhaler formulations in vitro: A comparison of three impactors

“…While some DPI devices (e.g. Turbuhaler) have been shown to produce large differences in the emitted dose and FPF as a function of change in the flow rate (Tarsin et al, 2004(Tarsin et al, , 2006, the Accuhaler device is thought to produce less variation in emitted dose and FPF values upon increasing the flow rate between 30 and 90 L min −1 (Prime et al, 1999). In the present study, relatively small, but significant, differences were observed in emitted dose and FPF of both drugs when the flow rate was increased from 30 to Q (∼70) L min −1 but the differences were product and impactor dependent.…”