1. Inhaler Devices Dr. Dane EDIGER Uludağ University School of Medicine
Departement of Allergy

2. Inhalation Devices Aim
To make aerosol from the drugs solution or solid particles
1-Metered dose inhaler
2-Dry powder inhaler
3-Nebulizer

3. 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

4. . Lower aerosol size Upper aerosol size
0,001 µm ,01 µm 0,1 µm 1 µm 10 µm 100 µm =0,1 mm

5. 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

6. 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

7. Why Inhalation Therapy?
Targeted delivery of medication to the lungs
Rapid onset of action
Smaller doses
Less systemic and GI adverse effects
Relatively comfortable
Obstrüktif havayolu hastalıklarının tedavisinde en etkili ve güvenli yoldur
İnhaler kısa etkili B2 agonistle aynı etkiyi oluşturmak için gereken oral formun dozu kat fazladır
İnhaler kısa etkili B2 agonistle oluşan serum ilaç düzeyi oral formla alınana göre 100 kat daha düşüktür
Oral yolla verilen ilaçlarda GİS intoleransı ve sistemik yan etki riski daha yüksektir
İnhaler kısa etkili B2 agonist etkisi 15 dak da, oral formun etkisi 1-2 saatte ortaya çıkar
With COPHIT the future of the inhaler is bright. can be investigated computationally, permitting evaluation of 'what if' scenarios. Investigate the effect of changing device dimensions, or the impact of a spacer on efficacy of drug delivery.

8. PHARMACOKINETICS OF INHALED DRUGS
Oropharynx absorbtion
Lung absorbtion
Gastrointestinal
absorbtion
İnh KS ler lipidde eridikleri için oral emilebilirler, Beta 2 agonistler ise akcaiğer dokusunda emilmektedirler.
Figure 1 shows that following inhalation some of the emitted dose is deposited into the lungs and the remainder impacts in the oropharyngeal area followed by swallowing (1,2). The inhaled dose is then delivered into the systemic circulation following absorption from the lungs and gastro-intestinal tract. A fraction of the dose is eliminated by muco-ciliary clearance followed by swallowing. Bronchodilators, corticosteroids and antibiotics deposited into the lungs will provide a local therapeutic effect. Other drugs can be formulated such that they are deposited into the alveolar area for good systemic delivery. These drugs can be delivered using the pulmonary route to provide their systemic effect when only the injection route is available because of problems with gastro-intestinal administration. When drug is delivered to the systemic circulation the body identifies it as an unwanted visitor and therefore removes the drug. This removal is either by excretion of the unchanged drug in the urine or metabolism to a more water soluble (and usually inactive) derivative that can be removed by the renal route. The renal route is the major pathway to remove either unchanged or metabolised drug but there are other pathways (eg. bile). Drug that is swallowed but not absorbed is eliminated in the faeces.
SYSTEMIC CIRCULATION
Vena porta
Hepatic inactivation
Urine elimination
first pass effect

9. Adverse Effects LOCAL SYSTEMIC INH KS INH B2 AGONIST Candidiasis
Dysphonia
Adrenal suppression Growth retardation (large doses)
INH B2 AGONIST
Sympathetic stimulation- tremor
Tachicardia
Hypokalemia

10. Deposition of particles
> 5 µ impaction
1-5 µ sedimentation
< 1 µ like gas

11. Hypothesis from available data
> 5
Particle size (microns)
Regional deposition
Efficacy
Safety
Mouth / oesophageal region
No clinical effect
Absorption from GI tract if swallowed
> 5
Particle size (microns)
Regional deposition
Efficacy
Safety
Mouth / oesophageal region
No clinical effect
Absorption from GI tract if swallowed
1 – 5
Upper / central airways
Clinical effect
Subsequent absorption from lung
< 1
Peripheral airways / alveoli
Some local clinical effect
High systemic absorption

12. Lung deposition of drug
Particle
size
shape
particle density
solid or liquid phase
Type of inhalation device
Tecknique
Airway obstruction
Drug molecule

13. 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)

14. Pressured Metered Dose Inhalers (pMDI)
Canister
Small reservoir
Metering reservoir
After pressure valve drug sprays
Aerosol

15. 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

16. Propellant Chloro fluoro carbon (CFC)
CFC (freon gas)
CFC not flammable
Vapouring after spray
Particules continue movement

17. Propellant Hydro fluoro alcan (HFA)
Not include chloride
Not disturbe Ozone layer
İt influence on global heating
Salbutamol, salmeterol ve flutikazon için itici gaz farklılık yaratmazken BDP için HFA içeren ÖDİ CFC içeren daha küçük tanecikli ve daha az lokal yan etkili bulunmuştur

18. MDI advantages
Rapid application
Handling
Multidose

19. MDI Disadvantages Hand-breathe coordinations
İneffective use in poor ventilated patiens
Oropharyngeal deposition and local side effects
Not include dosimeter
Yanlış kullanım oranı % Eğitime rağmen %20 kalıyor

20. Hand-breathe coordinations Autohaler

21. MDI spacer
Decrease of oropharyngeal deposition
Proposing inhaled CS

22. MDI spacer

23. Not include dosimeter

24. Chest. 2002;121:
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

25. Freon (CFC) Cold freon effect
Oropharyngeal irritation, cough and bronchospasm
Harmfull for ozone layer
Cardiac arrhytmia
Less effective in cold climate

26. MDI with HFA (CFC-free)
Evohaler
Salbutamol
Flutikazon
BDP
Levalbuterol
Budesonide Formoterol

27. Therapeutic Ratio of Hydrofluoroalkane and Chlorofluorocarbon Formulations of Fluticasone Propionate
Fowler SJ., Chest, 2002

28. Dry powder inhaler (DPI)

29. Classification of Dry Powder Inhalers, Based on Design and Function
Single-Dose Devices
Aerolizer formoterol capsule single
HandiHaler tiotropium capsule single
Multiple Unit-Dose Devices
Diskhaler fluticasone blister cassette
zanamivir blister cassette
Multiple-Dose Devices
Turbuhaler budesonide reservoir 200
Turbuhaler budesonide/formoterol reservoir 120
Diskus salmeterol blister strip 60
Diskus salmeterol/fluticasone blister strip 60

30. Dry powder inhaler (DPI) Multi doses

31. Lung depostion form a budesonide Turbohaler
measured by gamma scintigraphy
Borgstrom et al Eur Respir J 1994;7:69-73
Total lung deposition
(% of inhaled dose)
30L/min L/min
Inspiration Rate

32. FAST vs SLOW INHALATION USING 500mcg TERBUTALINE via A TURBOHALER
(n=10 ASTHMATICS)
FEV1, MMFR & PEFR
FOR FAST > SLOW
BUT N.S.
LUNG DEPOSITION
(% OF THE DOSE)
60L/min L/min
Newman et al Int J Pharm 1991

33. Dry powder inhaler (DPI) single dose

34. Device dependent factors
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

35. Patient dependent factors
Age
co-operation
compliance
airway anatomy
breathing patterns
Disease

36. Lung Deposition of ICS Dose to the lungs MDIs DPIs Ciclesonide 52%
Fluticasone 16%
Budesonide %
BDP HFA MDI 51%
DPIs
Different flow rates
Budesonide Turbuhaler 17-39%
Budesonide Novolizer 19-32%
Budesonide Airmax 28-30%
One flow rate
Budesonide Clickhaler 27%
Fluticasone Diskus 13%

37. TOTAL LUNG DEPOSITION AND DISTRIBUTION OF TERBUTALINE IN THE LUNG FOLLOWING INHALATION USING A TURBOHALER AND MDI
CENTRAL ZONE
INTERMEDIATE ZONE
PERIPHERAL ZONE
TOTAL LUNG
% DEPOSITION
MDI TURBOHALER
Borgstrom & Newman Int J Pharm 1993;97:47-53

38. Mean intra-subject variability
% coefficient of variability 60
52.0% 50
42.4%
40.4% 40
35.9%
31.8% 30 20 10
Volumatic
Easi-Breathe
Accuhaler
Turbohaler
Evohaler pMDI
Device
Aswania O et al. J Aerosol Med 2004; 17(3):

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

40. 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

41. Type 1 Trials: Device Performance Under Conditions of Actual Clinical Use
example
1-To compare the effect of a B2-agonist agent delivered by nebulizer, DPI, and/or MDI in patients presenting to the emergency dept. with acute asthma
improvement in lung function
oxygenation
hospital admission rate
To compare the effect of inhaled corticosteroids delivered by different devices over a period of weeks
daily asthma symptoms,
B2-agonist use
daily peak flow measurement

42. Type 2 Trials: Device Performance in the Clinical Laboratory Setting
To compare drug delivery to the lungs and the clinical response to drugs administered by different devices under carefully controlled clinical laboratory conditions
To establish dose-response curves for each of the devices
To estimate differences in the clinical potency of the devices (relative potency or potency ratio) and a confidence interval
The results; “1 actuation (or µg of drug) delivered from ‘device A’ is equivalent to ‘X’ number of actuations (or µg) delivered from ‘device B.’

43. Summaries and Results

44. 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

45. B2 agonist ED /ICU

46. 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)

47. 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

48. 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

49. Aerosol Delivery of SABA in the Inpatient 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

50. Aerosol Delivery of SABA for Asthma in the Outpatient 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)

51. 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

52. 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)

53. 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

54. 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)

55. 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

56. 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

57. IDEAL INHALER

58. Respimat
Newman SP J Aerosol Med 1999

59. VENTAİRA
Non-uniform dispersion of medication delivered by dry powder inhaler (DPI)
Uniform dispersion of medication delivered by Ventaira Pharmaceutical’s device.

60. DirectHaler TM Pulmonary
Kuru toz inhaler