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Aerosol
Overview
• Introduction
• Definition and types of aerosols
• Definitions for Commonly Used Terms in
Aerosol Delivery
• Fac...
Introduction
• Inhaled therapy was the primary route for
administering β2-agonists, anticholinergics, and
corticosteroids ...
Definition and Types of Aerosols
• An aerosol is a two-phase system defined
as a dispersion or suspension of solid
particl...
Middleton 8th edition
Definitions for Commonly Used
Terms in Aerosol Delivery
• The prediction of deposition efficiency and
therapeutic effect b...
Middleton 8th edition
Factors affect Aerosol Deposition
1. Physical factors; particle diameter, FPF
2. Ventilatory factors; inspiratory volume,
...
Physical factor: Particle size distribution
• Aerosol diameter determined site of lung
deposition, distribution of the dru...
• Impaction: particle inertia, particles >5 μm
• Sedimentation: particles 0.5 - 5 μm
• Diffusion: brownian motion, particl...
Correlation between aerosol particle
size and whole-lung deposition
Small MMADs and high FPFs to enhance delivery
of drug ...
Ventilatory factors:
inspiratory flow rate and breath hold
• Airflow directly influences impaction of
particles onto airwa...
Ventilatory factors:
inspiratory flow rate and breath hold
• Maximum deposition in the pulmonary
region for particles appr...
• Altering particle size while maintaining inspiratory
flow at slow (30-60 L/min) rates on albuterol
aerosol distribution ...
• Total lung deposition (TLD) was greater with the 1.5 μm
aerosol (56%) than with the 6 μm aerosol (46%) (P <0.01)
• Perip...
Ventilatory factors
• Larger particles produced greater
bronchodilation measured using forced
expiratory volume in 1 secon...
Anatomic factors
• A reduction in airway caliber, as from disease,
alters the airflow pattern in the lung and affects
the ...
Aerosol Drug Delivery Devices
• Nebulizers for liquid formulations
– Jet Nebulizers
– Ultrasonic Nebulizers
• New-generation nebulizers
– Breath-Actuate...
Jet Nebulizers
• Use compressed air/oxygen to break up a thin
film or jet of fluid into droplets suitable for
inhalation
•...
Jet Nebulizers
• 30-40% of the nominal dose is trapped in the
nebulizer, and more than 60% of the ED wasted
to the atmosph...
Jet Nebulizers
• The rate of evaporation depends on the volume
of fluid placed in the reservoir
– Volume of 3-5 mL longer ...
Ultrasonic Nebulizers
• Vibrated at a high frequency to create waves on
the liquid overlying the crystal
• Above 1 MHz, pr...
Ultrasonic Nebulizers
• The temperature can rise 10-15°C over a 10-
minute treatment period, which may adversely
affect he...
Breath-Actuated Nebulizers
• generate aerosol only during
inspiration
New-generation nebulizers
Soft Mist Inhalers
• uses ...
Vibrating Mesh Devices: Passive
• generate aerosol only during
inspiration
Vibrating Mesh Devices: Active
• vibrates at a ...
Middleton 8th edition
Pressurized metered-dose inhalers
• Most commonly used
• Portable, compact, and relatively easy to
use
• Uniform dose
Pressurized metered-dose inhalers
• As a result of the Montreal Protocol in 1989,
transition from chlorofluorocarbon (CFC)...
HFA plume is softer, not as narrow, not travel
as far as the CFC propellant
HFA albuterol
CFC albuterol
Middleton 8th edit...
Pressurized metered-dose inhalers
Middleton 8th edition
Pressurized metered-dose inhalers
• For most albuterol HFA pMDIs, the reduction in
dose is still an issue when the pMDI is...
Pressurized metered-dose inhalers
Middleton 8th edition
Breath-Actuated pMDIs
• Improve lung deposition over that achievable
with pMDIs alone
• Autohaler automatically actuates a...
pMDIs and Spacers and
Valved Holding Chambers
• Easy to use: reduces the need for patients
to coordinate inhalation
• Impr...
pMDIs and Spacers and
Valved Holding Chambers
Reservoir chamber with a valve:
• allows the aerosol to be
held in the chamb...
• Volumes for the various devices range 15-750 mL
• Any size of spacer but lower volume (<350 ml) is
more advantageous in ...
Spacers
• Pre-school children
• Inhaled glucocorticosteroids with a low first pass
metabolism in all age groups
• Who cann...
Mask should cover nose
and mouth
Middleton 8th edition
Dry powder inhalers
• Some dispense individual doses of drug from
punctured gelatin capsules such as the Aerolizer
(Novart...
Dry powder inhalers
• Aerosols of dry powder are created by directing
air through an aliquot of loose powder
• Hold the dr...
Dry powder inhalers
• The specific resistance of a DPI device affects
the maximal inspiratory flow rate (IFR)
• High resis...
Middleton 8th edition
β2-agonists
NB MDI DPI Oral
Salbutamol Ventolin Ventolin
Evohaler
Ventodisk
Buventol
Ventolin
Terbutaline Bricanyl Bricany...
β2-agonists
NB MDI DPI Oral
Salbutamol Ventolin
(2.5mg/2.5ml)
Ventolin
Evohaler
(100 mcg/dose,
200 dose)
Ventodisk
Buvento...
Inhaled β2-agonists
• Short-acting (SABAs): duration 3-4 hr
– Salbutamol, terbutaline
• Long-acting (LABAs): duration 12-2...
LABAs
• Salmeterol: developed from salbutamol,
modified to attach the drug molecule near the
β2-receptor by extending its ...
Intracellular signaling after activation of
the β2-receptor by a β2-agonist
• β2-agonists + the receptor’s G protein trime...
Ventolin MDI, DPI
Bricanyl DPIFenoterol MDI
Procaterol DPI
Salmeterol MDI, DPI
Formoterol DPI
Combined β2-agonists
β2-
agonists
Steroid NB MDI DPI
Salmeterol Fluticasone - Seretide
evohaler
Seretide
accuhaler
Formote...
Combined β2-agonists
Drugs MDI DPI
Salmeterol +
Fluticasone
Seretide evohaler
25/50, 25/125, 25/250 mg,
120 dose
Seretide ...
Seretide MDI, DPI Symbicort DPI
Budesonide MDI, DPI
Beclomin
MDI
Flixotide MDI, DPI
Combined β2-agonists
β2-agonists Anticholinergic NB MDI DPI
Ipratropium
bromide
Atrovent Atrovent -
Salbutamol Ipratopium
...
Iprotopium MDI Salbutamol + Iprotopium MDI
Fenoterol + Iprotopium MDI
Dry powder inhalers
• Humid environment decreas emitted dose
• Store DPIs in a cool, dry environment
• Mostly require carr...
• Oropharyngeal doses comparable with pMDI
without an add-on device
• Deposition in the lungs varies from 12- 32%
• Simila...
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Aerosols

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Aerosols

Presented by Sirapassorn Sornphiphatphong, MD

Published in: Health & Medicine
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Aerosols

  1. 1. Aerosol
  2. 2. Overview • Introduction • Definition and types of aerosols • Definitions for Commonly Used Terms in Aerosol Delivery • Factors affect Aerosol Deposition • Aerosol Drug Delivery Devices
  3. 3. Introduction • Inhaled therapy was the primary route for administering β2-agonists, anticholinergics, and corticosteroids in asthma and COPD • Challenging due to – Drug formulation properties – Particle size distribution – Delivery system – Inhalation technique
  4. 4. Definition and Types of Aerosols • An aerosol is a two-phase system defined as a dispersion or suspension of solid particles or liquid droplets in a gaseous medium (air, oxygen, heliox)
  5. 5. Middleton 8th edition
  6. 6. Definitions for Commonly Used Terms in Aerosol Delivery • The prediction of deposition efficiency and therapeutic effect based on – Traditionally: mass median aerodynamic diameter (MMAD) – More recently: fine particle fraction (FPF)
  7. 7. Middleton 8th edition
  8. 8. Factors affect Aerosol Deposition 1. Physical factors; particle diameter, FPF 2. Ventilatory factors; inspiratory volume, inspiratory flow rate, breath-hold time, breathing rate, and nose versus mouth breathing 3. Anatomic factors; airway caliber and distortion due to disease 4. Patient-related factors; technique, complicance
  9. 9. Physical factor: Particle size distribution • Aerosol diameter determined site of lung deposition, distribution of the drug within the lung; deposition efficiency • Sizes for environmental and occupational aerosols diameter range from 0.001 μm (nanoparticles) to 1000 μm (supercoarse) • Therapeutic aerosols targeted to the lower respiratory tract are 0.5 μm - 10 μm in diameter
  10. 10. • Impaction: particle inertia, particles >5 μm • Sedimentation: particles 0.5 - 5 μm • Diffusion: brownian motion, particles <1 μm Deposition of particles in the lung Total curve represents the sum of tracheobronchial and pulmonary values Middleton 8th edition
  11. 11. Correlation between aerosol particle size and whole-lung deposition Small MMADs and high FPFs to enhance delivery of drug to the lungs of patients with airway disease Middleton 8th edition
  12. 12. Ventilatory factors: inspiratory flow rate and breath hold • Airflow directly influences impaction of particles onto airway walls • Particle <5 μm – low flow rate to minimize impaction in the larger conducting airways – prolonged breath hold will allow greater time for sedimentation and diffusion to occur in the peripheral airways
  13. 13. Ventilatory factors: inspiratory flow rate and breath hold • Maximum deposition in the pulmonary region for particles approximately 3 μm in size • At 0.5 μm, <5% deposited in the lung (maximal deposition in respiratory bronchioles)
  14. 14. • Altering particle size while maintaining inspiratory flow at slow (30-60 L/min) rates on albuterol aerosol distribution within the lungs of a patient with asthma • MMAD of 1.5 μm, 3 μm, and 6 μm Middleton 8th edition
  15. 15. • Total lung deposition (TLD) was greater with the 1.5 μm aerosol (56%) than with the 6 μm aerosol (46%) (P <0.01) • Peripheral region deposition was significantly greater with smaller particles; 1.5 μm (25%) > 3 μm (17%) > 6 μm (10%) (P <0.001) Middleton 8th edition
  16. 16. Ventilatory factors • Larger particles produced greater bronchodilation measured using forced expiratory volume in 1 second (FEV1): • 6 μm > 3 μm > 1.5 μm • At 15 μg doses (484 ± 183, 420 ± 121, 337 ± 169) • At 30-μg doses (551 ± 221, 457 ± 200, 347 ± 172) These results suggest that regional targeting of inhaled β2-agonist to the proximal airways may be more important than distal alveolar deposition for bronchodilation
  17. 17. Anatomic factors • A reduction in airway caliber, as from disease, alters the airflow pattern in the lung and affects the distribution of inhaled aerosol Middleton 8th edition
  18. 18. Aerosol Drug Delivery Devices
  19. 19. • Nebulizers for liquid formulations – Jet Nebulizers – Ultrasonic Nebulizers • New-generation nebulizers – Breath-Actuated Nebulizers – Breath-Enhanced Nebulizers – Vibrating Mesh Devices: Passive – Vibrating Mesh Devices: Active – Soft Mist Inhalers • Pressurized metered-dose inhalers – Breath-Actuated pMDIs – pMDIs and Spacers and Valved Holding Chambers • Dry powder inhalers Aerosol Drug Delivery Devices
  20. 20. Jet Nebulizers • Use compressed air/oxygen to break up a thin film or jet of fluid into droplets suitable for inhalation • Venturi effect
  21. 21. Jet Nebulizers • 30-40% of the nominal dose is trapped in the nebulizer, and more than 60% of the ED wasted to the atmosphere during exhalation • <10% of the nebulizer contents to the patient • MMAD of jet nebulizers used for therapy should be between 2 and 4 μm • Low cost • Little patient effort
  22. 22. Jet Nebulizers • The rate of evaporation depends on the volume of fluid placed in the reservoir – Volume of 3-5 mL longer treatment time compared with the 2 mL • Typical treatment times: 5-15 min • At the end of nebulization, when no further aerosol is produced, 0.5-1.5 mL of solution is left in the reservoir; dead volume
  23. 23. Ultrasonic Nebulizers • Vibrated at a high frequency to create waves on the liquid overlying the crystal • Above 1 MHz, producing aerosols with MMADs 2-12 μm that is 2-3 times higher than with most jet nebulizers
  24. 24. Ultrasonic Nebulizers • The temperature can rise 10-15°C over a 10- minute treatment period, which may adversely affect heat-sensitive components of formulations • Ultrasonic nebulizers also are not suitable for nebulizing suspensions
  25. 25. Breath-Actuated Nebulizers • generate aerosol only during inspiration New-generation nebulizers Soft Mist Inhalers • uses mechanical energy to create an aerosol with a low-velocity spray • aerosol ranges 2.2-5.5 μm MMD Middleton 8th edition
  26. 26. Vibrating Mesh Devices: Passive • generate aerosol only during inspiration Vibrating Mesh Devices: Active • vibrates at a high frequency • high FPFs and very low dead volumes • battery-operated Middleton 8th edition
  27. 27. Middleton 8th edition
  28. 28. Pressurized metered-dose inhalers • Most commonly used • Portable, compact, and relatively easy to use • Uniform dose
  29. 29. Pressurized metered-dose inhalers • As a result of the Montreal Protocol in 1989, transition from chlorofluorocarbon (CFC) propellant pMDIs to HFA (hydrofluoroalkane) propellant pMDIs • HFA is medically safe, nontoxic, co-solved with corticosteroids • Lung deposition averages 7-30%
  30. 30. HFA plume is softer, not as narrow, not travel as far as the CFC propellant HFA albuterol CFC albuterol Middleton 8th edition
  31. 31. Pressurized metered-dose inhalers Middleton 8th edition
  32. 32. Pressurized metered-dose inhalers • For most albuterol HFA pMDIs, the reduction in dose is still an issue when the pMDI is first used, and priming is required Middleton 8th edition
  33. 33. Pressurized metered-dose inhalers Middleton 8th edition
  34. 34. Breath-Actuated pMDIs • Improve lung deposition over that achievable with pMDIs alone • Autohaler automatically actuates at inspiratory flow rates of approximately 30 L/min • Easibreathe actuates at 20 L/min
  35. 35. pMDIs and Spacers and Valved Holding Chambers • Easy to use: reduces the need for patients to coordinate inhalation • Improve drug targeting: retaining the large particles that would normally be deposited in the oropharynx • Can be used with a face mask
  36. 36. pMDIs and Spacers and Valved Holding Chambers Reservoir chamber with a valve: • allows the aerosol to be held in the chamber until the patient inhales Open tube For reverse-flow devices • pMDI is removed from its actuator mouthpiece and placed proximally, adjacent to, or in the mouthpiece • With reverse flow, the pMDI is fired in the direction away from the patient Middleton 8th edition
  37. 37. • Volumes for the various devices range 15-750 mL • Any size of spacer but lower volume (<350 ml) is more advantageous in very young children • Electrostatic charge on the plastic spacers decrease drug output • Metallic-coated device, nonelectrostatic plastic, or washing the plastic device periodically with deionizing detergent Middleton 8th edition
  38. 38. Spacers • Pre-school children • Inhaled glucocorticosteroids with a low first pass metabolism in all age groups • Who cannot use pMDIs or DPIs
  39. 39. Mask should cover nose and mouth
  40. 40. Middleton 8th edition
  41. 41. Dry powder inhalers • Some dispense individual doses of drug from punctured gelatin capsules such as the Aerolizer (Novartis Pharmaceuticals, United States) and HandiHaler (Boehringer Ingelheim, Germany) • A tape system containing multiple sealed, single doses in a blister (Diskus, Glaxo, United Kingdom) • Turbuhaler (Astra Draco, Sweden) is an example of a multidose reservoir powder system
  42. 42. Dry powder inhalers • Aerosols of dry powder are created by directing air through an aliquot of loose powder • Hold the drug powder in bulk in a reservoir • breath-actuated, the need to synchronize inhalation with actuation is eliminated • Dependent on the creation of turbulent flow in the inhaler • The peak inspiratory flow rate to dispense powder is 30 - 60 L/min
  43. 43. Dry powder inhalers • The specific resistance of a DPI device affects the maximal inspiratory flow rate (IFR) • High resistance – Decreases the ability to draw air through the inhaler – Proper inhalation produce greater FPF and increase delivery of drug to the lower respiratory tract • The clinical significance of this is not known
  44. 44. Middleton 8th edition
  45. 45. β2-agonists NB MDI DPI Oral Salbutamol Ventolin Ventolin Evohaler Ventodisk Buventol Ventolin Terbutaline Bricanyl Bricanyl Bricanyl Bricanyl Fenoterol Berotec Berotec - Berotec Salmeterol - Serevent Serevent - Formoterol - - Oxis - Procaterol - Meptin - Meptin Bambuterol - - - Bambec
  46. 46. β2-agonists NB MDI DPI Oral Salbutamol Ventolin (2.5mg/2.5ml) Ventolin Evohaler (100 mcg/dose, 200 dose) Ventodisk Buventol Ventolin (2 mg, 2mg/5ml) Terbutaline - - - Bricanyl (2.5 mg) Fenoterol Berotec Berotec - Berotec Salmeterol - Serevent Serevent - Formoterol - - Oxis - Procaterol - - Meptin Meptin (50 mcg) Bambuterol - - - Bambec (10 mg)
  47. 47. Inhaled β2-agonists • Short-acting (SABAs): duration 3-4 hr – Salbutamol, terbutaline • Long-acting (LABAs): duration 12-24 hr duration of activity – Salmeterol, formoterol • Ultra-long-acting (ultra-LABAs): duration at least 24 hr – Indacaterol
  48. 48. LABAs • Salmeterol: developed from salbutamol, modified to attach the drug molecule near the β2-receptor by extending its aliphatic side-chain • Formoterol – Initially as an oral β2-agonist and its long duration of activity when inhaled was discovered serendipitously – Duration depended on route of administration
  49. 49. Intracellular signaling after activation of the β2-receptor by a β2-agonist • β2-agonists + the receptor’s G protein trimer; Gs • Gs disassociates into a Ga subunit and a β/γ dimer • Ga binds to and activates adenylyl cyclase → increased cAMP • cAMP activates protein kinase A (PKA) • PKA – phosphorylates myosin light chain kinase (MLCK) → airway smooth muscle relax – Rho kinases (ROCK), which are needed for contraction, also are targeted • activates some transduction pathways – sodium-hydrogen exchanger regulatory protein – couples directly to potassium channels linked to relaxation of airway smooth muscle
  50. 50. Ventolin MDI, DPI Bricanyl DPIFenoterol MDI
  51. 51. Procaterol DPI Salmeterol MDI, DPI Formoterol DPI
  52. 52. Combined β2-agonists β2- agonists Steroid NB MDI DPI Salmeterol Fluticasone - Seretide evohaler Seretide accuhaler Formoterol Budesonide - - Symbicort - Fluticasone - Flixotide Flixotide - Budesonide Pulmicort Pulmicort / Inflammide Pulmicort - Beclomethasone - Beclomin +
  53. 53. Combined β2-agonists Drugs MDI DPI Salmeterol + Fluticasone Seretide evohaler 25/50, 25/125, 25/250 mg, 120 dose Seretide accuhaler 50/100, 50/250 mcg/dose, 60 dose Formoterol + Budesonide - Symbicort 80/4.5, 300/9, 60 dose 160/4.5, 120 dose Fluticasone Flixotide evohaler 50, 125, 250 mcg/dose, 120 dose Flixotide accuhaler 100, 250 mg Budesonide Pulmicort 100, 200 mcg/dose, 100 dose Pulmicort easyhaler, turbuhaler, swinghaler Beclomethasone Beclomethasone 50,100, 200, 250 mcg/dose Beclomethasone Easyhaler
  54. 54. Seretide MDI, DPI Symbicort DPI
  55. 55. Budesonide MDI, DPI Beclomin MDI Flixotide MDI, DPI
  56. 56. Combined β2-agonists β2-agonists Anticholinergic NB MDI DPI Ipratropium bromide Atrovent Atrovent - Salbutamol Ipratopium bromide Combivent Combivent - Fenoterol Ipratopium bromide Berodual Berodual -
  57. 57. Iprotopium MDI Salbutamol + Iprotopium MDI Fenoterol + Iprotopium MDI
  58. 58. Dry powder inhalers • Humid environment decreas emitted dose • Store DPIs in a cool, dry environment • Mostly require carrier substance including lactose and glucose • The particle size of dry powder: 1-2 μm • Size of the lactose/glucose particles: 20-65 μm and mostly deposits in the oropharynx
  59. 59. • Oropharyngeal doses comparable with pMDI without an add-on device • Deposition in the lungs varies from 12- 32% • Similar to or slightly better than those observed with pMDI

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