In vitro dose comparison of Respimat® inhaler with dry powder inhalers for COPD maintenance therapy

Abstract

Background: Combining in vitro mouth-throat deposition measurements, cascade impactor data and computational fluid dynamics (CFD) simulations, four different inhalers were compared which are indicated for chronic obstructive pulmonary disease (COPD) treatment.

Methods: The Respimat inhaler, the Breezhaler, the Genuair, and the Ellipta were coupled to the idealized Alberta throat model. The modeled dose to the lung (mDTL) was collected downstream of the Alberta throat model using either a filter or a next generation impactor (NGI). Idealized breathing patterns from COPD patient groups - moderate and very severe COPD - were applied. Theoretical lung deposition patterns were assessed by an individual path model.

Results and conclusion: For the Respimat the mDTL was found to be 59% (SD 5%) for the moderate COPD breathing pattern and 67% (SD 5%) for very severe COPD breathing pattern. The percentages refer to nominal dose (ND) in vitro. This is in the range of 44%-63% in vivo in COPD patients who display large individual variability. Breezhaler showed a mDTL of 43% (SD 2%) for moderate disease simulation and 51% (SD 2%) for very severe simulation. The corresponding results for Genuair are mDTL of 32% (SD 2%) for moderate and 42% (SD 1%) for very severe disease. Ellipta vilanterol particles showed a mDTL of 49% (SD 3%) for moderate and 55% (SD 2%) for very severe disease simulation, and Ellipta fluticasone particles showed a mDTL of 33% (SD 3%) and 41% (SD 2%), respectively for the two breathing patterns. Based on the throat output and average flows of the different inhalers, CFD simulations were performed. Laminar and turbulent steady flow calculations indicated that deposition occurs mainly in the small airways. In summary, Respimat showed the lowest amount of particles depositing in the mouth-throat model and the highest amount reaching all regions of the simulation lung model.

Keywords: CFD; NGI; Respimat; inhalation; lung deposition; throat model.

Figure 1

Air flow characteristics of marketed inhalers. Notes: (A) Flow resistance of the inhalers (n=3 replicates) in the context of other marketed products. Respimat has the lowest resistance of 0.04 Sqrt(mbar) min/L, followed by Breezhaler, 0.06 Sqrt(mbar) min/L; Genuair, 0.1 Sqrt(mbar) min/L; and Ellipta, 0.1 Sqrt(mbar) min/L. P is the pressure at specified flow and Sqrt() is the square root of the contents included in brackets. (B) Linear regressions of the square root of the pressure drop as a function of the flow rate for different inhalers. The indicated slope equals to the flow resistance. Using SI units, for Respimat a resistance of 22,300 Sqrt(Pa) s/m³ was found, for Breezhaler 36,200 Sqrt(Pa) s/m³. Genuair and Ellipta showed the same flow resistance of 58,400 Sqrt(Pa) s/m³. Regression coefficients are provided and rounded to 1.00 with the exception of Genuair, where a moving part inside modifies the flow resistance at about 40 L/min.

Figure 2

Impactor measurement. Notes: Setup consisting of Alberta throat model, mixing inlet, lung simulator, and NGI. For aqueous aerosol (Respimat) the feed air was humidified (RH >95%) in order to avoid artificial particle shrinking inside the impactor. For dry powders, ambient nonhumidified air was used, which had a relative humidity of 40%–50%. Abbreviations: ASL, active servo lung; NGI, next generation impactor; RH, relative humidity.

Figure 3

Filter measurement. Notes: Setup consisting of Alberta throat model, lung simulator and filter for the collection of the modeled dose to the lung. The tilt provided the horizontal operation required for the Genuair inhaler. Abbreviation: ASL, active servo lung.

Figure 4

Inhalation flow profiles. Notes: The profiles in full (Respimat, spontaneous inspiration), dotted (Breezhaler, forced inspiration), and broken thick lines (Genuair and Ellipta, forced inspiration) were used in this study and represent fit curves to average inhalation profiles of patients with the indicated severity of disease and taking into account the different flow resistances of the devices and the breathing modes. Reproduced with permission from Respiratory Drug Delivery 2006, Virginia Commonwealth University and RDD Online. Abbreviation: COPD, chronic obstructive pulmonary disease.

Figure 5

Cumulative lung volume of the air ducts in the present simulation model, of the theoretical calculated volume and of the volume provided by Finlay including alveoles as a function of the airway generation. Note: Reprinted from The mechanics of inhaled pharmaceutical aerosols, Finlay WH, Copyright (2001), with permission from Elsevier.

Figure 6

Visual appearance of the computer mesh used for the CFD calculation. Notes: (A) Mesh of the constructed single path model at the first generation, (B) at the 22nd and 23rd generation, and (C) mesh at the outlet of the 23rd generation.

Figure 7

Modeled dose to the lung determined using the NGI setup (applied for very severe COPD breathing pattern) and the filter setup (for moderate COPD breathing pattern). Notes: Blue, tiotropium (Respimat); red, glycopyrronium (Breezhaler); yellow, aclidinium (Genuair); green, vilanterol (Ellipta); and purple, fluticasone (Ellipta). Abbreviations: COPD, chronic obstructive pulmonary disease; ND, nominal dose; NGI, next generation impactor.

Figure 8

Particle deposition results of CFD simulations and receptor densities. Notes: (A) Laminar flow, (B) turbulent flow, and (C) densities of M1 and M3 muscarinic receptors. Blue, density not known; red, high density; green, low to medium density; yellow, medium to high density. Total modeled particle mass to the lung: Respimat droplets 7.9 mg (including water as a solvent), Breezhaler API particles 0.03 mg, Genuair API particles 0.16 mg, Ellipta vilanterol particles 0.12 mg, Ellipta fluticasone particles 0.37 mg. Abbreviations: API, active pharmaceutical ingredient; CFD, computational fluid dynamics.

Figure 9

CFD simulation results, (A) laminar model, (B) turbulent model. Notes: Simulated mass deposited in the whole lung as % of ND, Respimat, Breezhaler, Genuair, Ellipta vilanterol, and Ellipta fluticasone. Abbreviations: CFD, computational fluid dynamics; ND, nominal dose.