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