Folie 1 - Respimat

®
Respimat
TM
Mist
Comparing
Soft
Inhaler and DPI Aerosol Deposition
by Combined In Vitro Measurements and CFD Simulations
Anna-Maria Ciciliani1, Herbert Wachtel2, and Peter Langguth1
1Institute
of Pharmacy and Biochemistry, J Gutenberg University, Mainz, Germany
2Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany
Spiriva®
Respimat®
INTRODUCTION
The comparison of drug delivery to the lungs may be performed with development tools,
e.g. throat and lung models. They range from in vitro models [1] as well as computational
models (extending approximately to the 15th generation) [2] to combinations thereof e.g.
comparing a MDI (metered dose inhaler) and a DPI (dry powder inhaler) [3]. Combining
in vitro throat deposition data with an in silico lung deposition simulation resulted in the
present single-path lung model extending to the 23rd generation (alveolar region). The
model is applied to the Spiriva® Respimat® Soft MistTM Inhaler which is compared with
two new DPI’s. All three inhalers contain muscarinic receptor antagonists as active
ingredients. This investigation is motivated by the question, “Does device design result in
significant differences in inhaler performance and particle deposition site in the throat
and lung regions”. The limitations of in vitro and in silico studies are discussed.
Seebri®
Breezhaler®
Eklira®
Genuair®
Inhaler
Active ingredient:
dDD (daily
Delivered Dose):
ND (Nominal
Dose):
Tiotropium
Glycopyrronium
Aclidinium
5µg (in 2 puffs)
44µg
2x 322µg
2.5µg
50µg
322µg
Table 1. Respimat, Breezhaler, and Genuair. Doses according to patient leaflets.
RESULTS
EXPERIMENTS AND METHODS
In vitro deposition testing
In vitro throat deposition (Alberta throat,
Figure 1) and particle size were obtained in
a previous study [4]. Inspiratory flow rates of
COPD (chronic obstructive pulmonary
disease) patients were simulated taking into
account the different flow resistances of the
inhalers [5], see Fig. 4, right and ‘spontaneous’ inhalation for the active Respimat®
and ‘forced’ inhalation for the dry powder
inhalers.
The in vitro results [4] showed for the breathing patterns of COPD patients that the in
vitro-Dose to the Lung (DTL) is higher with Respimat (67 +/- 5 %ND) than with Breezhaler
(51 +/- 2 %ND) and Genuair (42 +/- 1%ND). At the outlet of the throat model we found
different Fine Particle Fractions (FPF’s) of particles with a mass median aerodynamic
Figure 1. Top: In vitro throat model
Down: In silico lung model with
muscarinic M1 and M3 receptor density
(RD) according to [6], image from [7]
Gen 1
Gen 21
Gen 21
Gen 15-23:
outflow
Respimat:
Average flow
55 L/min
Breezhaler:
Average flow
74 L/min
We thank Prof. Warren Finlay for providing data of the idealized throat geometry. Ralf
Kröger (Ansys, Darmstadt, Germany) provided consulting services concerning the CFD
simulation. Financial support was provided by Boehringer Ingelheim.
Figure 5. Summary result of the combined in vitro and CFD study, values given as
%ND for turbulent flow. Experimental data is given for throat deposition and Dose to
the Lung. CFD simulation data presenting groupings of the following airway
generations: Trachea-G4, G5-G14, G15-20, G21-alveoli. The percentages do not
sum up to 100% exactly due to inhaler deposition and drug recovery being below or
above 100% of the ND in the in vitro experiments.
Genuair:
Average flow
38 L/min
Figure 3. Particle deposition results of laminar CFD simulation for Respimat,
Breezhaler, and Genuair (from left to right). Flow defined at the trachea.
6
10000
cum. volume Simulation [cm³]
1000
cum. volume calculated [cm³]
cum. volume Finlay [cm³]
100
Turbohaler
Ellipta
Genuair
Diskus
Breezhaler
Respimat
5
4
3
2
1
0
10
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Generation
Figure 2. Meshing of single-path lung geometry. Dimensions are based on Finlay’s
findings [1] who refers to Raabe et al. [8] and Haefeli-Bleuer [9]. Angles were taken
from Raabe et al. [6]. Alveolar volume is considered using boundary conditions. Gen
denotes the generation of branch.
The advantage of this combined in vitro and in silico model is the elimination of patient
variability. This facilitates the investigation of inhaler features for technical optimization
and comparison but on the other hand not all aspects of the formulation and handling are
considered. More important, effects of the patient’s disease (bronchoconstriction,
reduced or even blocked air exchange in parts of the lung, fate of drug particles after
deposition, clearance) are not assessed. In conclusion, these methods are very useful to
guide inhaler and medical development as an additional tool, but they cannot address
questions on safety and efficacy which require clinical trials.
REFERENCES
Inspiratory Effort (kPa)
yellow: average
to high RD
CONCLUSION
Gen 1
Volume [cm³]
green: average RD
Test inhalers
Spiriva® Respimat® (Boehringer Ingelheim,
Germany), a Soft MistTM Inhaler that
contains an aqueous solution was compared
to Seebri® Breezhaler® (Novartis Pharma
GmbH, Germany), a capsule based dry
powder inhaler, and Eklira® Genuair®
(Almirall Sofotec, Spain), a multidose
reservoir dry powder inhaler. The inhalers
are shown in Table 1.
To sum up, the in vitro and in silico results of Respimat show the lowest throat deposition
and the highest deposition in the whole lung model and in the different lung generations
when compared to Breezhaler and Genuair.
ACKNOWLEDGEMENTS
Trachea
blue: unknown RD
red: high RD
diameter (MMAD) smaller than 5 µm, expressed as percentage of Nominal Dose (ND):
Respimat showed a FPF of 44 +/- 6 %ND, Breezhaler a FPF of 43 +/- 2 %ND, and
Genuair a FPF of 36 +/- 2 %ND. The MMAD’s were 3.7 +/- 0.5 µm, 2.5 +/- 0.1 µm, and
2.4 +/- 0.03 µm, respectively.
The deposition pattern in the 23 generations of the in silico lung model was very similar
for Respimat and Breezhaler, but Respimat delivered more particle mass (%ND) to the
lungs as a whole and to the different lung regions in our model. Genuair had the lowest
overall deposition, especially in the first 14 generations (Figure 3).
For turbulent flow, there is more deposition in the region from trachea to generation 14
but less in generation 15 to 23 compared to the laminar flow simulation. This is valid for
all three inhaler aerosols (Figure 5).
Figure 4 shows the simulated lung volume of the in silico model and the inspiratory effort
needed for inspiring through different inhalers.
0
50
100
Flow Rate achieved (L/min)
Figure 4. Left: Cumulative lung volume of the simulation model. The model was
adjusted so that it fits the volume suggested by Finlay et al. (log. representation)
Right: Pressure drop (inspiratory effort) versus the Flow Rate achieved with
different inhalers.
DISCUSSION
In this study an idealized in vitro throat model was combined with a computational CFD
deposition model. This approach provided a valuable tool for comparing inhaler
performance concerning particle deposition.
Modelling the complex lung geometry and the resulting flow inside the model faces a
series of challenges:
• The dimensions of the airways of different generations are highly diverse and require
adapted meshing. Flow profiles may vary and depend on training of the patients.
• Many models are limited to generation 15 because at higher generations the volume
is increased by alveoli . The geometry of their connection to the small airways is
complex. In our model, the volume was simulated by boundary conditions.
• The choice of turbulence models and of dedicated wall treatments influences the
results. Only particle deposition is calculated. Dissolution, drug transport and
biological features of the lung tissue are not considered in the present model.
The present model cannot account for patient variability and therefore the need for
clinical studies is unchanged in order to provide data on efficacy and safety.
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