1. The Aerosol Drug Management Improvement Team
ADMIT
Slide Deck 2018

2. Part 3
Pulmonary Aerosol Delivery
Nicolas Roche

3. Pulmonary aerosol delivery
Where are the targets?
Localisation of drug receptors
How can lung deposition be assessed?
What are the factors that influence aerosol deposition?
Lung disease and deposition
Patient’s skills and behaviour

4. Pulmonary aerosol delivery
Where are the targets?
Localisation of drug receptors
How can lung deposition be assessed?
What are the factors that influence aerosol deposition?
Lung disease and deposition
Patient’s skills and behavior

5. Located throughout the airways and lung
Pulmonary aerosol delivery
Inflammation and glucocorticoid receptors
Adcock AJRCCM 1996
airways and lung
Located throughout the airways and lung
Muscarinic receptors
Mak & Barnes, ARRD 1990
Beta2 adrenoreceptors
Ikeda BJP 2012

6. Inflammation and glucocorticoid receptors (GR) are located throughout the airways and lung
GR: Airways
GR: Lung
Adcock AJRCCM 1996

7. Beta2 adrenoreceptors are located throughout the airways and lung
Ikeda BJP 2012

8. Muscarinic receptors are located throughout the airways and lung
Ikeda BJP 2012

9. Pulmonary aerosol delivery
Where are the targets?
Localization of drug receptors
How can lung deposition be assessed?
Patient’s skills and behavior
Lung disease and deposition
What are the factors that influence aerosol deposition?

10. Methods to assess lung deposition
Inference
From particle size distribution (modelling)
In vivo measurements
Direct visualisation = scintigraphy
Indirect assessment = charcoal-block method (dosage of pharmacological agents or metabolites in blood or urine)
In vitro modeling from in vivo measurements
Functional respiratory imaging
Using computational fluid dynamics

11. Deposition vs particle size: «basic» physics
Carvalho Int J Pharm 2011

12. Anatomy plays a role: need for complex mathematical modeling
Fernandez Tena , Arch Bronchoneumol 2012

13. (99mtechnetium or 131iodine)
Scintigraphy
2-dimensional (planar)
low-energy
gamma emitters
(99mtechnetium or 131iodine)
3-dimensional
SPECT =
single-photon
emission computed tomography
PET =
positron-emission
tomography
high-energy positron emitters

14. Volume change Resistance change CT-scan-derived modeling basis
Functional respiratory imaging (FRI) – using Computational Fluid Dynamics to assess treatment effect
Volume
change
Resistance
change
CT-scan-derived
modeling basis
Dr. Ir. Jan De Backer, CEO FluiDA

15. Functional respiratory imaging (FRI) – using Computational Fluid Dynamics (CFD) to assess deposition
Step 1
CT scan of patient’s lungs captured to develop 3D patient-specific anatomical models1
Inhaler characteristics such as fine particle fraction, mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD), and plume velocity are incorporated into the CFD model1
Step 2
0.5
1.0
1.5
2.0
3.5
100 80 60 40 20
Flow (L/min)
Time (s)
2.5
3.0
30 L/min
57 L/min
47 L/min
Inhalation factors such as flow rate profile and duration are entered into the algorithm1
Step 3
Deposition modeled with CFD1
Step 4
CFD, computational fluid dynamics; CT, computed tomography 1. FLUIDDA nv, Kontich, Belgium

16. Computational Fluid Dynamics (CFD) vs in vivo scintigraphy
Vinchurkar Inhal Toxicol 2012

17. Pulmonary aerosol delivery
Where are the targets?
Localization of drug receptors
How can lung deposition be assessed?
Patient’s skills and behaviour
Lung disease and deposition
What are the factors that influence aerosol deposition?

18. Factors influencing aerosol deposition
Device
(internal resistance…)
Content
(pharmacological agents,
excipients, propellants)
Inhalation technique
Adherence
Preference
Adequate particle size (MMAD) & respirable dose/fine particle fraction
Appropriate treatment delivery
MDIs and BAIs propel the content into the airways
With DPIs, inhalation is the only propellant
Haughney J et al. Respir Med 2010;104:1237–45;
Papi A et al. Eur Respir J 2011;37:982–5

19. Determinants of lung deposition: the patient
Manipulation
Preparation of inhalation
Dose preparation
Actuation
Exhalation to Functional Residual Capacity
Inhalation manoeuvre/ profile
Preparation of inhalation
Volume (high
Flow
slow (4-5 sec, 30 L/min for MDIs,
quick for DPIs
Shape (sharp vs progressive)
Breath-holding > 4 sec
Airways
Airways anatomy
Oropharynx, larynx
Lower respiratory tract
Airflow obstruction

20. Determinants of lung deposition: the device and its content
Particle chemical characteristics
Particle size distribution
Aerodynamic diameter
Fine particle fraction (<5µm)
Plume characteristics (MDI, soft mist inhaler)
Speed
Temperature
Inspiratory flow required to deaggregate the formulation (DPI) ,
Depends on technological characteristics including internal resistance

21. Deposition versus particle size
Fine particle fraction
Respirable mass
Based on data from a mathematical model
Adapted from Pritchard JN. J Aerosol Med 2001; 14(Suppl 1):S19–26
1. Mitchell JP, Nagel MW. KONA 2004;22:32–65

22. Deposition versus particle size
No influence of disease/airflow obstruction when delivering ultra-fine particles
Mean FEV1:
43% (COPD)-70%(asthma)
N=8 per group
De Backer JAMPDD 2010

23. In vitro mean fine particle mass
Flow dependency varies between DPIs 30 20 10
In vitro mean fine particle mass
(% label claim)
DPI A
DPI B
16%
21% 6%
18%
Flow rate 28.3 L/min
Flow rate 60 L/min
Taylor A et al. Int J Clin Pract. 2005;59:7–12