The important of inhalers device
in asthma management?
นายแพทย์ธีระศักดิ์ แก้วอมตวงศ์
หน่วยโรคระบบการหายใจและเวชบาบัดวิกฤต
ภาควิชาอายุรศาสตร์ โรงพยาบาลรามาธิบดี
Respiratory pharmacology

Inhaled drug administrations are widely used in
pulmonary medicine

Asthma
COPD
Bronchiectasis
Cystic fibrosis

Drugs available for respiratory care







Anti-inflammation: corticosteroids
Anti-infective agents : antibiotics, antifungal
Bronchodilators : β adrenergic agonist and muscarinic receptor antagonist
Mucoregulator : Dornase alpha
Medication for asthma and COPD
Asthma
COPD
Anti-inflammatory drugs
-Corticosteroids
-Anti-leukotriene
-Cromone
-Theophylline
Bronchodilators
-Short and long acting β2-agonits
-Short and long acting anticholinergic
-Theophylline
Bronchodilator
-Short and long acting β2-agonits
-Short acting anticholinergic
Anti-inflammatory drugs
-corticosteroid
ICS/LABA combination
ICS/LABA combination
Anti-immunoglobulin E
Mucolytic drugs
Antibiotic s
Vaccination
Advantages of inhaled therapy






Providing local effect of medications that
optimizes the desired therapeutic effects
Requiring the lower dose
Preferred characteristics
Fast onset of action
Low systemic bioavailability
Less side effects than orally or intravenously administered drugs
American Association of Respiratory Care Aerosol Consensus Statement . Respir Care 1991
Pulmonary drug delivery
Lewis RA, Fleming JS. Br J Dis Chest 1985; 79(4):361-367.
Respiratory drugs
Development of inhalers
The effectiveness of aerosol



The effectiveness of an aerosol
is dependent on how much of
the medication actually reaches
the small peripheral airways of
the lungs
In vitro : Fine particle fraction
(FPF)
In vivo: camera scintigraphy
Burton G. Respiratory Care. A guide to clinical practice 1992
Airway anatomy (tree) Wiebel
Upper & lower respiratory tract
Conducting & gas exchange
Airway generation and flow relationship
Lung deposition of drugs
Factors affecting lung deposition




Particle size
Speed of inspiration (inspiratory flow)
Integrity of airway
Proper inhaled device technique
Particle dynamics in respiratory tract



Impact
Sedimentation
Diffusion
Impaction
Sedimentation
Diffusion
Physical mechanism of drug movement &
deposition
Speed of inspiration (Ideal speed or flow is 30-60 L/min)
•High flow facilitate central impaction but low flow facilitate sedimentation of particle
Diffusion (< 0.5 µm)
high speed movement
and short haul exhaled
Sedimentation
(0.5-5 µm)
Impact (> 5 µm)
at upper airway and high flow rate
Fine-particle fraction (FPF)

Fine-particle fraction (FPF) is percentage of the
aerosol between 1–5 μm that deposits in the lung
Mean aerodynamic diameter (MMAD)
Deposit of particles by size
Particles > 8 µm are deposited in the oropharynx (90% absorbed)
Particles with size 5-8 µm are deposited in the large airways
Particles with size 2-5 µm are deposited in tracheobronchial region
Particles with size 1-2 µm are deposited in the alveolar region
Particles with size < 1 µm are passed expiration
Rau JL Jr. Respiratory care pharmacology. 2002
MMAD and GSD



Mass Median Aerodynamic Diameter (MMAD) is
defined as the diameter at which 50% of the
particles by mass are larger and 50% are smaller
Geometric Standard Deviation (GSD) is a measure
of the spread of an aerodynamic particle size
distribution. Typically calculated as follows:
GSD = (d84/d16)1/2
d84 and d16 represent the diameters at which 84% and 16% of the aerosol mass are
contained, respectively, in diameters less than these diameters.
Particle size distribution
(Histogram)
Particle size distribution
MMAD =1 µm
Histogram of particle size
distribution
Histogram of logarithmic
particle size distribution
MMAD (d50)
MMAD =1 µm
MMAD =5 µm means ?

The calculated aerodynamic diameter that divides the
particles of an aerosol in half, based on the weight of the
particles.
By weight, 50% of the particles will be larger than the MMAD and 50% of the particles
will be smaller than the MMAD.

MMAD of 5 μm =?
50 % of the total sample mass will be present in particles having diameters less than 5
μm, and that 50 % of the total sample mass will be present in particles having an
diameter larger than 5 μm.
Lung deposition and MMAD
Leach C et al. Particle size of inhaled corticosteroids: Does it matter? J Allergy Clin Immunol 2009
Inhaler devices

Metered-dose inhaler (MDIs)

Conventional pressurized inhaler
Activated by pressurized inhaler inspiration

Dry-powder inhaler (DPI)


Single dose
Multi-dose

Nebulizers



Jet
Ultrasonic
pMDI and plum mechanism
HFA and CFC propellant pMDI
CFC pMDI
HFA pMDI
HFA improve lung deposition
MDI with spacing device or VHC
การใช้ยาสูดร่ วมกับ Spacer

ชนิดของ spacer แบ่งเป็ น
Aerosol Cloud Enhancer (ACE)
Volumetric spacer
Aerochamber (VHC) vs Ventahaler
Aerochamber plus
Ventahaler
1) a 145-mL rigid cylinder made
of polyester
(Trudell Medical, London, ON)
2) Adapter that makes it compatible
with most pMDIs
3) Is available with a mouthpiece
or a mask
1) An elliptical-shaped device
made of rigid, transparent plastic
2) Capacity of 750 Ml
3) Designed to fit GlaxoSmithKline
Products Not fit all pMDIs.
Spacer decrease orapharyngeal
deposition
Build in dose counter
MDI and spacer use
Types of dry powder inhaler (DPI)
Single dose dry powder (SD-DPI)
Handihaler
Breezhaler
Multi-dose dry powder (MD-DPI)
Accuhaler
Turbuhaler
Basic design & functional elements (DPI)



Powder formulation
Dose mechanism containing (measuring)
Powder de-agglomeration principle
(Dispersing powder into inhaled air stream)

Inhaler mouthpiece
Powder formulation

Active drug particles with 1-5 µm are extremely
adhesive
Drug stick together or surface of inhaler
Excipients (micronized or agglomerate)
Adhesive mixture (α lactose monohydrate)

The detach of active drug from carriers



Powder formulation
100 µm
Adhesive mixture
100 µm
Nuclear conglomerate
The carrier molecules of excipient
1) Similar size to drugs (micronized)
2) Large size than drug (carrier)
500 µm
Spherical pellet type
Micronized drug and carrier particles
Active drug 3-5 µM
Large carrier lactose particle
500 µM
Active drug 3-5 µM
Micronized lactose
molecule
Adhesive and removal force balance


The Fine Particle Fraction
As a result of the balance between separate
force (from de-agglomeration) and adhesive
force (drug-carrier interaction)
Basic design & functional elements (DPI)



Powder formulation
Dose mechanism containing (measuring)
Powder de-agglomeration principle
(Dispersing powder into inhaled air stream)

Inhaler mouthpiece
Dose measuring system
De-agglomeration principles DPI
Multi-dose dried powder
Dose mechanism containing
(measuring)
Dose mechanism containing
(measuring)
DPI Inhaler performance

Inspiratory flow performance
‘Intrinsic resistance of device’


Patients inspiratory flow ability
Humidity and moister exposure
Inpiratory flow range of DPI

Flow dependence DPI
Turbuhaler

Flow independent DPI
Accuhaler
Flow rate and FPF from inhalers
Intrinsic resistance of DPI
(kPa0.5/min/L)
Inhalers and airflow resistance
120
Flow rate (L/min)
100
80
60
40
2.2  10-2 kPa1/2 L-1 min
2.7  10-2 kPa1/2 L-1 min
3.4  10-2 kPa1/2 L-1 min
5.1  10-2 kPa1/2 L-1 min
Breezhaler
Diskus
Turbuhaler
Handihaler
20
0
0
2
4
6
Inspiratory effort (kPa)
8
10
Singh D et al. ATS 2010 (poster)
Factors affect adhesion de-agglomeration
Drug:
-Type of drug
Carrier:
-Surface properties
-Bulk properties
-Conditioning
-Stability (aging)
-Size of distribution
-Conditioning
-Play-load on carrier
Mixing:
-Type of mixer
-Mixing time
-Batch size
Mixing:
-Type of mixer
-Homogeneity
-Conditioning
Inhalation test:
-Type of inhaler
-Inhalation manouvor
-Test system
Fine particle fraction
De Boer Ah Int J Pharm 2003
Tubuhaler as flow dependent
Necessary inspiratory
flow rate (L/m)
Drug deposition in
lungs (%)
Drug deposition in
oropharyns
35
14.8  3.3
66.6 8.0
60
27.7 4.5
57.3 13.0
Dolovich M. AJRCCM 1988;137:A433.
Scheme of the major variable and interaction in DPI performance
DPI design
-powder formulation
-dose system
-dose de-agglomeration principle
Performance
-Dose entrainment
Airflow resistance
+
Inhalation effort
Flow maneuvers
-peak flow rate
-flow increase rate
-inhalation time
Patient factors
-instruction
-clinical parameters
-age, gender, training
-smoker, nonsmokers
-Fine particle fraction
-Lung deposition
Accuhaler use
Turbuhaler use
Recommended age for inhalation therapy
SVN with mask
SVN with mouthpiece
pMDI with holding chamber/spacer and mask
pMDI with holding chamber/spacer
Dry-powder inhaler
Metered-dose inhaler
Breath-actuated MDI (e.g., Autohaler™)
Breath-actuated nebulizers
≤3 years
 3 years
< 4 years
 4 years
≥ 4 years
≥ 5 years
≥ 5 years
≥ 5 years
Rau JL Jr. Respiratory care pharmacology. 2002
Turbuhaler® is fully effecitve at flow rate ≥
30L/min at patients aged ≥ 6 years of age
FEV1 (% of predicted)
1 mg terbutaline*
90
80
Mean PIF of
Turbuhaler
(L/min)
60
31
70
22
13
60
0
0
0.5
1
2
3
4
Time after medication (hours)
0.25 mg terbutaline via Turbuhaler®
Pederson S, et al. Arch Dis Child 1990; 65: 308-310
5
30 min after administration
of 1mg terbutaline via
Nebuhaler treatment.
Turbuhaler® is clinically effecitve at both
standard & low inspiratory flow rate
similar level of bronchodilation & FEV1
FEV1 (litres)
4.0
Standard inhalation
conditions at peak
inspiratory flow of
83.9L/min
Low inspiratory flow
rate (30L/min)
through entire
inhalation
3.5
3.0
0
0.25
0.5
1
Terbutaline (mg)
Meijer RJ, et al. Thorax 1996; 51: 433-434
2
4
Higher proportion fine particle dose and lung
deposition leads to better efficacy
% of
metered 40
dose
(L) 0.25 mg
terbutaline
pMDI
30
3.0
Turbuhaler
20
10
0
2.5
Fine
particle
dose
Lung deposition
Borgström L, et al. Am J Respir Crit Care Med 1996; 153: 1636-1640
FEV1
0
Turbuhaler gives better central lung
deposition as same as pMDI with spacer
®
38%
12%
(Central lung
deposition 11%)
26%
Thorsson L, et al. Int J Pharmaceut 1998; 168: 119-127
(Central lung
deposition 11%)
Lung deposition of budesonide is greater than
that of fluticasone via Diskus or pMDI
1000
Lung deposition
800
budesonide
turbuhaler
36%
600
400
200
0
Thorsson L, et al. Br J Clin Pharmacol 2001; 52: 529-538
fluticasone
pMDI
20%
fluticasone
Diskus
12%
BUD/FOR turbuhaler delivers higher % of
fine particle dose on both BUD & FORM
Fine particle dose
(% of labeled dose)
MMAD (µm)
BUD/FOR
Turbuhaler
Budesonide
63
2.2
Formoterol
55
2.4
SAL/FLU Disku
Fluticasone
22
4.4
Salmeterol
22
4.4
MMAD = mass median aerodynamic diameter
Granlund KM, et al. Eur Respir J 2000; 16 (suppl. 31): 455s
Higher % of fine particle dose with BUD/FOR
turbuhaler even at low inspiratory flow
35
(% of label claim)
Fine particle dose
30
25
20
15
10
5
0
BUD/FOR Turbuhaler,
budesonide
Inspiratory flow at 40 L/min.
Asking L, et al. J Aerosol M 2001; 14: 502
SAL/FLU Diskus,
fluticasone
Inspiratory flow at 49 L/min.
% fine particle mass at low flow rates in young
asthmatic children is also higher with turbuhaler
35
30
25
20
15
10
5
0
BUD/FOR Turbuhaler
80/4.5 µg
(LABA component)
Gustafsson PM, et al. Am J Respir Crit Care Med 2003; 167: A117
SAL/FLU Diskus
50/100 µg
(LABA component)
Fine particle size of BUD via Turbuhaler is consistent
at all strengths; & higher than FP via Diskus
budesonide
fluticasone
60
(% of labelled dose)
Fine particle dose
50
40
30
20
10
0
80/100
160/250
320/500
Nominal dose of budesonide / fluticasone (µg)
Lipniunas et al , 2002
Lipniunas P, et al. Eur Respir J 2002; 20 (suppl. 38): 541s
Turbuhaler®
Spiral channels
• The air enters through air
inlets and passes through
desiccant store to keep
humidity out
Dose counter
Air inlets
Desiccant store
Air inlets
Turning grip
Diskus®
• The device should be
discarded after removal from
the moisture-protective foil
overwrap pouch
• Diskus® itself does NOT
contain desiccant
Aluminum blisters may fail to protect against
humidity in DiskusTM
25
Serevent® DiskusTM, 50 µg/dose
25°C/60%RH*
Fine particle dose
% of label claim
20
40°C/75%RH*
15
10
5
0
0
1
2
3
4
5
6
7
Months storage
Asking L, et al. J Aerosol Med 1999; 12 (No 3): 204
*RH – relative humidity
in vivo lung deposition of budesonide via
Turbuhaler is higher even when the inhaler is
stored under hot & humid condition (40°/75%)
Relative lung deposition
1.0
0.5
0
Budesonide viaTurbuhaler
Borgström L, et al. Am J Respir Crit Care Med 2003; 167(suppl. 7): A896
Fluticasone via Diskus
Fine particle dose via Turbuhaler at 40°/75% over
3 months is higher
Proportion of initial value (%)
120
Fine particle dose
Turbuhaler®
100
Diskus™
80
Delivered dose
Turbuhaler®
60
Diskus™
40
20
0
Initial value
Borgström and Lipniunas, 2003
3 months
Lipniunas P, et al. Eur Respir J 2003; 22 (suppl. 45): 237s
Drug deposition from various inhalers
Rau JL Jr. Respiratory care pharmacology. 2002
Hand function in elderly and device
Age related physical change
Potential effects of inhalation technique
in elderly
Advantages and disadvantages
Advantages
Disadvantages
pMDI
-Quick to use
-compact and portable
-multi-dose
-Difficult inhalation technique
-propellant required
-High oropharyngeal deposition
pMDI +Space (VHC)
-Practical advantages as p MDI
-Easier to use effectively than p MDI
-Reduced oro-pharyngeal deposition
-More bulky than p MDI
-Propellant required
-Susceptible to effect of static charge
DPI
-Practical advantages similar to p MDI
(Multidose/multiple single dose)
-No propellant needed
-Inspiratory flow-actuated
-Easy to use than p MDI
-Usually more costly than p MDI
-Some may be moisture sensitive
-Inspiratory flow-driven (potential problem
of low inspiratory force)
Treatment include medication
Physical communication
Symptoms and side effect
Disease history
HRQL and functionality
Treatment history
Expectation
Direct consumer advising
Satisfaction with medication
Other influence on expectation
Other influence on satisfaction