The important of inhalers device in asthma management?
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ว�กฤตภาคว�ชาอาย&รศัาสตร� โรงพยาบาล
รามาธี�บดิ์
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 19
30s
1956
1960
s
1959
1971
1980
1988
1989
1989
1995
2001
Com
pres
sed-
air n
ebul
izer
Med
ihal
er®
(firs
t MDI)
Ultras
onic n
ebul
izer
Spin
hale
r® (fi
rst D
PI)
Brea
th- a
ctua
ted
MDI
Diskh
aler
® R
otad
isk
®
( DPI
) Tu
rbuh
aler
® (D
PI)
Auto
hale
r ®
Brea
th- a
ctua
ted
MDI
Disku
s ®
(DPI
)
Novol
izer
®
(D
PI)
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
Diffusion
Sedimentati
on
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
Sedimentation (0.5-5 µm)
Impact (> 5 µm) at upper airway and high flow rate
Diffusion (< 0.5 µm) high speed movement and short haul exhaled
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
Histogram of particle size distribution
Histogram of logarithmic particle size distribution
MMAD =1 µm
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 pMDIHFA and CFC propellant pMDI
HFA pMDICFC pMDI
HFA improve lung deposition HFA improve lung deposition
MDI with spacing device or VHC
การใช�ยาส(ดิ์ร�วมก บ Spacer
ชน�ดิ์ของ spacer แบ�งเป็+น
Aerosol Cloud Enhancer (ACE) Volumetric spacer
Aerochamber (VHC) vs Ventahaler
Aerochamber plus Ventahaler
1) a 145-mL rigid cylinder madeof polyester (Trudell Medical, London, ON)2) Adapter that makes it compatiblewith most pMDIs3) Is available with a mouthpieceor a mask
1) An elliptical-shaped devicemade of rigid, transparent plastic 2) Capacity of 750 Ml 3) Designed to fit GlaxoSmithKlineProducts 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)
Multi-dose dry powder (MD-DPI)
Handihaler Breezhaler
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
Adhesive mixture Nuclear conglomerate Spherical pellet type
100 µm 100 µm 500 µm
The carrier molecules of excipient 1)Similar size to drugs (micronized) 2)Large size than drug (carrier)
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
sis
0
20
40
60
80
100
120
0 2 4 6 8 10
Inspiratory effort (kPa)
Flo
w r
ate
(L/m
in)
Breezhaler 2.2 10-2 kPa1/2 L-1 minDiskus 2.7 10-2 kPa1/2 L-1 minTurbuhaler 3.4 10-2 kPa1/2 L-1 minHandihaler 5.1 10-2 kPa1/2 L-1 min
Increasingtan
rece
Singh D et al. ATS 2010 (poster)
Factors affect adhesion de-agglomeration
Drug: -Type of drug-Size of distribution -Conditioning-Play-load on carrier
Carrier: -Surface properties -Bulk properties -Conditioning-Stability (aging)
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.
DPI design -powder formulation -dose system -dose de-agglomeration principle
Airflow resistance
Inhalation effort
Patient factors -instruction -clinical parameters -age, gender, training -smoker, nonsmokers
Flow maneuvers -peak flow rate -flow increase rate -inhalation time
Performance-Dose entrainment -Fine particle fraction -Lung deposition
+
Scheme of the major variable and interaction in DPI performance
Accuhaler use
Turbuhaler use
Recommended age for inhalation therapy
SVN with maskSVN with mouthpiecepMDI with holding chamber/spacer and maskpMDI with holding chamber/spacerDry-powder inhalerMetered-dose inhalerBreath-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
Time after medication (hours)
FEV1 (% of predicted)
1 mg terbutaline*90
80
70
60
00 0.5 1 2 3 4 5
0.25 mg terbutaline via Turbuhaler®
Mean PIF ofTurbuhaler(L/min)
13
22
31
60
30 min after administrationof 1mg terbutaline viaNebuhaler treatment.
Turbuhaler® is fully effecitve at flow rate ≥ 30L/min at patients aged ≥ 6 years of age
Pederson S, et al. Arch Dis Child 1990; 65: 308-310
4.0
0
FEV
1 (lit
res)
3.5
3.0
Terbutaline (mg)
0.25 0.5 1 2 4
Standard inhalation conditions at peak inspiratory flow of 83.9L/min
Low inspiratory flow rate (30L/min) through entire inhalation
Turbuhaler® is clinically effecitve at both standard & low inspiratory flow ratesimilar level of bronchodilation & FEV1
Meijer RJ, et al. Thorax 1996; 51: 433-434
0
% of metered dose
0
10
20
30
(L)
2.5
3.0
pMDI
Turbuhaler
40
Borgström L, et al. Am J Respir Crit Care Med 1996; 153: 1636-1640
Fineparticle
dose
Lung deposition
FEV1
Higher proportion fine particle dose and lung deposition leads to better efficacy
0.25 mgterbutaline
Turbuhaler gives better central lung deposition as same as pMDI with spacer
®
Thorsson L, et al. Int J Pharmaceut 1998; 168: 119-127
12% (Central lung deposition 11%)
26% (Central lung deposition 11%)
38%
Lung deposition of budesonide is greater than that of fluticasone via Diskus or pMDILung deposition of budesonide is greater than that of fluticasone via Diskus or pMDI
Thorsson L, et al. Br J Clin Pharmacol 2001; 52: 529-538
1000
800
600
400
200
0
Lung d
eposi
tion
budesonideturbuhaler
36%
fluticasoneDiskus12%
fluticasonepMDI20%
Fine particle dose (% of labeled dose)
MMAD (µm)
BUD/FOR Turbuhaler
SAL/FLU Disku
Budesonide
Fluticasone
Formoterol
Salmeterol
2.2
2.4
4.4
4.4
63
55
22
22
Granlund KM, et al. Eur Respir J 2000; 16 (suppl. 31): 455s
MMAD = mass median aerodynamic diameter
BUD/FOR turbuhaler delivers higher % of fine particle dose on both BUD & FORM
Asking L, et al. J Aerosol M 2001; 14: 502
0
5
10
15
20
25
30
35
Fine p
art
icle
dose
(% o
f la
bel cl
aim
)
Inspiratory flow at 40 L/min.
SAL/FLU Diskus, fluticasone
BUD/FOR Turbuhaler,budesonide
Inspiratory flow at 49 L/min.
Higher % of fine particle dose with BUD/FOR turbuhaler even at low inspiratory flow
Gustafsson PM, et al. Am J Respir Crit Care Med 2003; 167: A117
Fine particle dose(% of label claim)
% fine particle mass at low flow rates in young asthmatic children is also higher with turbuhaler
0
5
10
15
20
25
30
35
SAL/FLU Diskus 50/100 µg
(LABA component)
BUD/FOR Turbuhaler 80/4.5 µg
(LABA component)
Lipniunas et al , 2002
80/100
Fin
e p
art
icle
dose
(% o
f la
belle
d d
ose
)
160/250 320/500
Nominal dose of budesonide / fluticasone (µg)
budesonide
fluticasone
0
10
20
30
40
50
60
Fine particle size of BUD via Turbuhaler is consistent at all strengths; & higher than FP via Diskus
Lipniunas P, et al. Eur Respir J 2002; 20 (suppl. 38): 541s
Spiral channels
Turning gripDesiccant store
Air inlets
Dose counter
Turbuhaler®
•The air enters through air inlets and passes through desiccant store to keep humidity out
Air inlets
Diskus®
•The device should be discarded after removal from the moisture-protective foil overwrap pouch
•Diskus® itself does NOT contain desiccant
Asking L, et al. J Aerosol Med 1999; 12 (No 3): 204
25°C/60%RH*
40°C/75%RH*
0
5
10
15
20
25
0 1 2 3 4 5 6 7
Months storage
Fin
e p
art
icle
dose
% o
f la
bel cl
aim
Serevent® DiskusTM, 50 µg/dose
*RH – relative humidity
Aluminum blisters may fail to protect against humidity in DiskusTM
1.0
Budesonide viaTurbuhaler
Rela
tive lung d
eposi
tion
0.5
0Fluticasone via Diskus
in vivo lung deposition of budesonide via Turbuhaler is higher even when the inhaler is stored under hot & humid condition (40°/75%)
Borgström L, et al. Am J Respir Crit Care Med 2003; 167(suppl. 7): A896
Borgström and Lipniunas, 2003
Initial value
Pro
port
ion o
f in
itia
l valu
e (
%)
3 months
Turbuhaler®
Diskus™
Delivered dose
Fine particle dose120
100
80
60
40
20
0
Turbuhaler®
Diskus™
Fine particle dose via Turbuhaler at 40°/75% over 3 months is higher
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 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
Symptoms and side effect
HRQL and functionality
Expectation
Satisfaction with medication
Other influence on satisfaction
Physical communication
Disease history
Treatment history
Direct consumer advising
Other influence on expectation