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Inhaler Devices

Dr. Dane EDIGER

Uludağ University School of Medicine

Departement of Allergy

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Inhalation Devices

Aim

To make aerosol from the drugs solution or solid particles

1-Metered dose inhaler

2-Dry powder inhaler

3-Nebulizer

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Definition of an aerosol

• Aero air

• Sol solution

• Liquid or solid suspensions into gas medium

• Particles which are sufficiently small so as to remain airborne for a considerable period of time

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• Lower aerosol size • Upper aerosol size

.0,001 µm 0,01 µm 0,1 µm 1 µm 10 µm 100 µm =0,1 mm

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History of Inhaled Therapy

• China, India, Middle-east

• Hippokrattes

• Galenos

• 4000 years ago: the smoke of ephedra sinica was used to asthma therpy

• Smoke of Atropa belladona, Datura stramonium

• Sulphur, arsenic, menthol, timol, eucaliptus

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Modern age

• Metered dose inhaler 1956 Medihaler

• Dry powder inhaler 1960

• Multidose dry powder inhaler 1970

• 440 million boxes aerosols per year are manufactured in the world

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Why Inhalation Therapy?

• Targeted delivery of medication to the lungs

• Rapid onset of action• Smaller doses• Less systemic and GI adverse effects• Relatively comfortable

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Oropharynx absorbtion

Lung absorbtion

Vena porta

Hepatic inactivation

Gastrointestinal

absorbtion

SYSTEMIC CIRCULATION

Urine eliminationfirst pass effect

PHARMACOKINETICS OF INHALED PHARMACOKINETICS OF INHALED DRUGSDRUGS

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Adverse EffectsLOCAL SYSTEMIC

INH KS Candidiasis

Dysphonia

Adrenal suppression Growth retardation (large doses)

INH B2 AGONIST

Sympathetic stimulation- tremor

Tachicardia

Hypokalemia

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Deposition of particles

> 5 µ impaction

1-5 µ sedimentation

< 1 µ like gas

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Hypothesis from available data

11 – 5 – 5 Upper / central Upper / central airwaysairways

Clinical Clinical effecteffect

Subsequent Subsequent absorption absorption from lungfrom lung

< < 11Peripheral Peripheral

airways / alveoliairways / alveoli

Some local Some local clinical clinical effecteffect

High High systemic systemic

absorptionabsorption

> 5> 5

Particle size Particle size (microns)(microns)

Regional Regional depositiondeposition

EfficacyEfficacy SafetySafety

Mouth / Mouth / oesophageal oesophageal

regionregion

No clinical No clinical effecteffect

Absorption Absorption from GI from GI tract if tract if

swallowedswallowed

> 5> 5

Particle size Particle size (microns)(microns)

Regional Regional depositiondeposition

EfficacyEfficacy SafetySafety

Mouth / Mouth / oesophageal oesophageal

regionregion

No clinical No clinical effecteffect

Absorption Absorption from GI from GI tract if tract if

swallowedswallowed

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Lung deposition of drug

• Particle – size – shape – particle density – solid or liquid phase

• Type of inhalation device

• Tecknique• Airway obstruction• Drug molecule

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4 Types of Inhaler Devices

• MDI/ DPI

• Small volumes • Ready for use• Stable obstructive

disease

• Jet /Ultrasound nebulizer

• High fill volume > 1 ml• Preparation required• Severe respiratory

insufficiency (asthma attack, COPD exac., CF)

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Pressured Metered Dose Inhalers (pMDI)

• Canister • Small reservoir• Metering reservoir• After pressure

valve drug sprays• Aerosol

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Metered Dose Inhalers (pMDI)• Canister

– Propellent gas (liquid under pressure)

• Drug– Dissolved or solid microparticules

into the gas

• Surfaktant– Physical stabilisation– Prevent clustering– Decreas valv friction

• Drug layer is surface of liquid propellent because more lightweight, it must be rinced before use

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Propellant Chloro fluoro carbon (CFC)

– CFC (freon gas)– CFC not flammable– Vapouring after spray– Particules continue

movement

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Propellant Hydro fluoro alcan (HFA)

– Not include chloride – Not disturbe Ozone layer– İt influence on global heating

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• Rapid application

• Handling

• Multidose

MDI advantages

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• Hand-breathe coordinations

• İneffective use in poor ventilated patiens

• Oropharyngeal deposition and local side effects

• Not include dosimeter

MDI Disadvantages

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Hand-breathe coordinations Autohaler

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MDI spacer

Decrease of oropharyngeal deposition

Proposing inhaled CS

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MDI spacer

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Not include dosimeter

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Chest. 2002;121:871-876

The SmartMist was 100% accurate, The Doser CT was 94.3% and MDILog was 90.1%

All three devices are sufficiently accurate to monitor adherence in most clinical settings

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• Cold freon effect

• Oropharyngeal irritation, cough and bronchospasm

• Harmfull for ozone layer

• Cardiac arrhytmia

• Less effective in cold climate

Freon (CFC)

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MDI with HFA (CFC-free)

• Evohaler• Salbutamol • Flutikazon

• BDP

• Levalbuterol

• Budesonide Formoterol

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Therapeutic Ratio of Hydrofluoroalkane and Chlorofluorocarbon Formulations of

Fluticasone Propionate

Fowler SJ., Chest, 2002

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Dry powder inhaler (DPI)

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Classification of Dry Powder Inhalers, Based on Design and Function

Single-Dose DevicesAerolizer formoterol capsule singleHandiHaler tiotropium capsule singleMultiple Unit-Dose DevicesDiskhaler fluticasone blister cassette zanamivir blister cassetteMultiple-Dose DevicesTurbuhaler budesonide reservoir 200Turbuhaler budesonide/formoterol reservoir 120Diskus salmeterol blister strip 60Diskus salmeterol/fluticasone blister strip 60

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Dry powder inhaler (DPI) Multi doses

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Lung depostion form a budesonide Turbohalermeasured by gamma scintigraphy

Borgstrom et al Eur Respir J 1994;7:69-73

30L/min 60L/min Inspiration Rate

Total lung deposition(% of inhaled dose)

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FAST vs SLOW INHALATION USING 500mcg TERBUTALINE via A TURBOHALER

Newman et al Int J Pharm 1991

60L/min 30L/min

LUNG DEPOSITION(% OF THE DOSE)

FEV1, MMFR & PEFR

FOR FAST > SLOW

BUT N.S.

(n=10 ASTHMATICS)

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Dry powder inhaler (DPI) single dose

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Device dependent factors Device

• pMDI: • Portability, Treatment time, Drug

preparation, Reproducibility, Coordination, Actuation, Drug availability, Holding chamber, Propellant

• DPI:• Breath-actuation, Coordination, Portability,

Treatment time, Dose counters, Flow requirement, Drug availability, Resistance, Costs.

• Aerosol• Particle size, Velocity, Physico-chemical

characteristics

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Patient dependent factors

Age• co-operation• compliance• airway anatomy• breathing patterns

Disease

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Dose to the lungs

MDIsCiclesonide 52%Fluticasone 16%Budesonide 5-12%BDP HFA MDI 51%

DPIsDifferent flow ratesBudesonide Turbuhaler 17-39%Budesonide Novolizer 19-32%Budesonide Airmax 28-30%

One flow rateBudesonide Clickhaler 27%Fluticasone Diskus 13%

Lung Deposition of ICS

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TOTAL LUNG DEPOSITION AND DISTRIBUTION OF TERBUTALINE IN THE LUNG FOLLOWING INHALATION USING A TURBOHALER AND MDI

TOTAL LUNGCENTRAL ZONE

INTERMEDIATE ZONE

PERIPHERAL ZONE

% D

EP

OS

ITIO

N

Borgstrom & Newman Int J Pharm 1993;97:47-53

MDI TURBOHALER

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Mean intra-subject variability% coefficient of

variability

0

50

60

20

40

Volumatic

31.8%

Aswania O et al. J Aerosol Med 2004; 17(3): 231-8.

Easi-Breathe Accuhaler Turbohaler Evohaler pMDI

Device

10

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35.9%40.4%

42.4%

52.0%

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•a review looking systematically at the clinical effectiveness and cost-effectiveness of inhaler devices in asthma and COPD

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• Only randomized controlled trials (RCT) • (394 trials- years 1982 to 2001) assessing

– inhaled corticosteroid, – B2-agonist– anticholinergic agents delivered by

• MDI,• MDI with a spacer/holding chamber,• nebulizer, • DPI

• Only 59 (primarily those that tested B2-agonists) proved to have usable data

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Summaries and Results

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Results

• None of the pooled meta-analyses showed a significant difference between devices in any

efficacy outcome in any patient group for each of the clinical settings that was investigated

• The adverse effects that were reported were minimal and were related to the increased drug dose that was delivered

• Each of the delivery devices provided similar outcomes in patients using the correct technique for inhalation

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B2 agonist ED /ICU

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Aerosol Delivery of Short-Acting B2-Agonists in the Hospital Emergency dept

• SABA in the ED: nebulizer = MDIs with spacer– improving pulmonary function – reducing symptoms of acute asthma – in both adult and paediatric patients (quality of evidence: good).

• SABA in the ED: DPI = nebulizer = MDIs with spacer – in adults – data is inadequate (quality of evidence: low)

• Heart rate in the ED : nebulizer > MDIs with spacer (quality of evidence: good)

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Recommendations

• 1. Both the nebulizer and MDI with spacer are appropriate for the SABA in the ED – Quality of evidence: good– net benefit: substantial– strength of recommendation: A

• 2. Data for DPIs are limited– Quality of evidence: low– net benefit: none– strength of recommendation: I

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The appropriate selection of a particular device in this setting

– the patient’s ability to use the device correctly– the preferences of the patient for the device– the availability of the drug/device combination– the compatibility between the drug and the delivery device– the lack of time or skills to properly instruct the patient in the use

of the device or to monitor the appropriate use– the cost of the therapy– the potential of reimbursement

– Quality of evidence: low– net benefit: substantial– Strength of recommendation: B

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Aerosol Delivery of SABA in theInpatient Hospital Setting

• SABA in the inpatient: nebulizer = MDI with spacer – pulmonary function response (quality of evidence: good)

• Recommendations:• 1. Both nebulizers and MDIs with spacer are appropriate for

use in the inpatient setting– Quality of evidence: good– Net benefit: substantial– strength of recommendation: A

• 2. Data for DPIs are limited– Quality of evidence: low– net benefit: none– strength of recommendation: I

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Aerosol Delivery of SABA for Asthma in theOutpatient Setting

• SABA in the adult and paediatric outpatient: MDI = DPI – pulmonary function responses– symptom scores– heart rate– (quality of evidence: good)

• SABA in the outpatient: MDI =MDI with spacer – pulmonary function responses (quality of evidence: low)

• Data for nebulizers are limited– (quality of evidence: low)

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Recommendations

• 1. Both the MDI with or without spacer and DPI are appropriate for the SABA in outpatient

– Quality of evidence: good– net benefit: substantial– strength of recommendation: A

• 2. Data for DPIs are limited– Quality of evidence: low– net benefit: none– strength of recommendation: I

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Inhaled Corticosteroids for Asthma

• Same dose of the same corticosteroid for adult patients with asthma in the outpatient: DPI or MDI with spacer – Pulmonary function response– symptom scores (quality of evidence: good)

• Patient preference: DPI > MDI with spacer – 2 studies (quality of evidence: good).

• Data for incidence of oral candidiasis ??– (quality of evidence: low)

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Recommendations

• 1. Both the MDI with spacer and DPI are appropriate for the inhaled KS in outpatient

– Quality of evidence: good– net benefit: substantial– strength of recommendation: A

• 2. Data for DPIs are limited– Quality of evidence: low– net benefit: none– strength of recommendation: I

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Inhaled B2-Agonists and Anticholinergic Agents for COPD• Inhaled B2-Agonists and Anticholinergic in

the outpatient of COPD: MDIs with or without spacer = DPI = nebulizer – pulmonary function responses (quality of

evidence: good)

• Heart rate : albuterol by nebulizer > MDI – (quality of evidence: good)

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Recommendations:

• MDI, with or without spacer, nebulizer, and DPI are all appropriate for the delivery of inhaled B2- agonist and anticholinergic agents for the treatment of COPD in the outpatient– Quality of evidence: good– net benefit: substantial– strength of recommendation: A

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• Cihazların göreceli etkinlikleri birini diğerine tercih etmek için yeterli bir üstünlük sağlamamakta

• Bu durum hastaya özel cihazı belirlemenin bir sorun olmadığı anlamına da gelmemektedir

• Tüm bu çalışmalar bu cihazları iyi kullanabilen hastalarda yapılmıştır

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IDEAL INHALER

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Respimat

Newman SP J Aerosol Med 1999

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VENTAİRA

Uniform dispersion of medication delivered by Ventaira Pharmaceutical’s device.

Non-uniform dispersion of medication delivered by dry powder inhaler (DPI)

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• Kuru toz inhaler

DirectHaler TM Pulmonary