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

Figures & data

Table 1 Respimat inhaler, Breezhaler, Genuair, and Ellipta

	Respimat	Breezhaler	Genuair	Ellipta
Inhaler (sketches)
Batches obtained for this study	204950, 205369	S0009, S0007	F4, F3	R659388, R659402
Active ingredient	Tiotropium	Glycopyrronium	Aclidinium	Fluticasone furoate/vilanterol
Daily delivered dose	5 μg (in 2 puffs)	44 μg	2×322 μg	92/22 μg
Nominal dose	2.5 μg	50 μg	322 μg	92/22 μg
Other ingredients	Benzalkonium chloride, EDTA, water, HCl	Lactose monohydrate, magnesium stearate	Lactose monohydrate	Lactose monohydrate, magnesium stearate
Indication	COPD, asthma	COPD	COPD	COPD, asthma
Common side effects (may affect up to 1 in 10 people) according to patient leaflet	Dry mouth	Dry mouth, difficulty sleeping, runny or stuffy nose, sneezing, sore throat, diarrhea or stomach ache	Headache, sinusitis, nasopharyngitis, cough, diarrhea	Headache, common cold, sore, fungal infection, bronchitis, pain/irritation/infection of nose/throat, flu, itchy, runny or blocked nose, cough, voice disorders, bone weakening, stomach pain, back pain, fever, joint pain
Manufacturer	Boehringer Ingelheim	Novartis	Almirall	GlaxoSmithKline
Market authorization	2007 (Spiriva Respimat COPD)^Citation41 2014 (Spiriva Respimat, asthma)^Citation42	2012^Citation43	2013^Citation44	2013 Relvar Ellipta^Citation45 2013 Anoro Ellipta^Citation46 2014 Incruse Ellipta^Citation47
Dosage	1× daily 2 puffs	1× daily	2× daily	1× daily
Handling in daily use (not first initiation, only main handling steps)	Turn the base, open cap, exhale, press the dose release button while taking a slow, deep breath, close cap	Open the inhaler, insert a capsule, pierce the capsule, exhale, inhale rapidly and deeply, repeat if there is still powder in the capsule	First press the green dose release button, exhale, then inhale strongly and deeply, control if the green control window turns red (if it is not, repeat inhalation)	Open the inhaler by sliding down the cover, exhale, inhale, close the inhaler

Note: Summary of the administration and possible side effects according to patient leaflets.

Abbreviations: COPD, chronic obstructive pulmonary disease; EDTA, ethylenediaminetetraacetic acid.

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.⁵
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.¹

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.

Table 2 Results of all filter and NGI measurements

	Respimat	Breezhaler	Genuair	Ellipta vil	Ellipta flu
Moderate, COPD
Inhaler (%ND)	2.5	6.0	4.2	NA	NA
SD	0.7	0.2	0.2	NA	NA
Throat (%ND)	34.0	40.2	61.2	40.9	56.5
SD	5.9	0.6	1.9	3.5	1.4
mDTL (%ND)	59.2	42.5*	31.8*	48.8*	33.2*
SD	4.9	1.7	2.2	2.7	2.8
DD (%ND)	93.1	82.7	93.0	89.7	89.7
SD	3.3	2.2	3.2	2.4	1.5
Very severe, COPD
Inhaler (%ND)	2.7	7.8	3.6	NA	NA
SD	1.5	1.1	0.2	NA	NA
Throat (%ND)	27.2	31.3	63.0	50.5	53.4
SD	8.7	2.9	1.6	2.3	2.4
mDTL (%ND)	67.4	51.1*	41.9*	55.0*	40.7*
SD	4.6	2.0	1.4	1.8	1.5
DD (%ND)	94.7	82.4	104.9	105.5	94.1
SD	4.1	2.2	1.2	2.8	1.1
FPF (%ND)	44.7	43.1	36.2	39.5	23.8
SD	6.1	2.4	1.6	1.9	1.7
MMAD (μm)	3.7	2.5	2.4	1.8	3.2
SD	0.5	0.1	0.03	0.1	0.2

Notes: n=3 repetitions.

* Indicative for significantly different mDTL of very severe vs moderate COPD inhalation.

Abbreviations: DD, delivered dose; COPD, chronic obstructive pulmonary disease; FPF, fine particle fraction; MMAD, mass median aerodynamic diameter; NA, not available; ND, nominal dose; NGI, next generation impactor; mDTL, modeled dose to the lung; SD, standard deviation.

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.

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