Aerosols

Question 1

Advantages of pulmonary route

Answer 1

Direct lung targeting, minimise dose and adverse effects
Non invasive
Rapid onset of action
Avoid GI tract (stability at low pH, presence of enzymes, food effects etc.)
Avoid first pass metabolism in liver
P450 enzymes in lungs <1% of that in liver
Large SA and blood supply for drug absorption
Most devices are portable

Question 2

Disadvantages of pulmonary route

Answer 2

Correct technique of inhaler usage is important for efficient delivery
Disease state (e.g. lung infection) →increase volume of mucus or compromised inhalation effort → affect deposition and absorption
Local / throat irritation possible
Stability of aerosols
Generally lower delivery efficiency

Question 3

Respiratory Tract

Answer 3

Airway bifurcates to form smaller airways
From the trachea to the alveoli:
1. Airway diameter decreases
2. Cross sectional area increases

Question 4

Site of deposition

Answer 4

Site of deposition of the inhaled particles within the respiratory tract directly affects clinical outcomes
Particles deposit at:
Back of throat → swallowed
Bronchioles → local treatment
Alveoli → systemic absorption
Design dosage form to allow particles to reach the target site within the respiratory tract
Site of deposition is largely dependent on particle size

Question 5

Particle Size - Aerodynamic diameter

Answer 5

Aerodynamic (Equivalent) Diameter (da, AED)
* The diameter of a sphere with unit density that has the same sedimentation rate in air (or aerodynamic behaviour)
* Particles having the same aerodynamic diameter may have different dimensions and shapes
* Particle size in aerosol is usually polydisperse

Question 6

Deposition mechanisms

Answer 6

Inertia impaction
Sedimentation
Diffusion

Question 7

Inertia impaction

Answer 7

• Particles > 5μm tend to deposit in the upper airways by inertia impaction
  
  • Particle carried by a gas stream has its own momentum
  • At bifurcation, airstream changes direction/velocity
  • Two possibilities:
    
    1. Particle follows the changing airstream
    2. Particle follows its own momentum and impacts on the airways’ walls
       Momentum = mv (mass x velocity)

Question 8

Sedimentation

Answer 8

• Particles between 1 to 5 μm tend to deposit in the lower airways by sedimentation
  
  • Particles suspended in a fluid are subjected to vertical gravitational force
    Sedimentation rate is predicted by Stoke’s law

Question 9

Diffusion

Answer 9

• Random movement of particles through a fluid (Brownian motion)
  
  • Rate is inversely proportional to particle size
    Diffusion is the major deposition mechanism for particles < 1 μm

Question 10

Size effect of particle deposition

Answer 10

• > 5 μm → deposit in upper airways or extra-thoracic region (mainly by inertia impaction)
  • 1 – 5 μm → deposit in lower airways (predominantly by sedimentation)
    ○ 2 – 5 μm deposit in large and conducting airways
    ○ 1 – 2 μm deposit in the alveoli
    < 1 μm → exhaled (minimal deposition)

Question 11

Other factors affecting particle deposition

Answer 11

Shape
Density
Humidity
Breathing pattern

Question 12

How does shape affect particle deposition

Answer 12

• Elongated particles (e.g. long thin fibres) have small aerodynamic diameters → easily deposit in alveoli
  Potential issues with powder flow

Question 13

How does density affect particle deposition

Answer 13

• Porous or hollow particles have lower density
  
  • Aerodynamic diameters of low-density particles can be much smaller than the geometric diameters

Question 14

How does humidity affect particle deposition?

Answer 14

Hydrophilic particles → adsorbed moisture layer → increases effective particle size → deposition at higher regions of the respiratory tract

Question 15

How does breathing pattern affect deposition

Answer 15

• Increase inhaled volume → increase deposition in lower respiratory tract
  
  • Reduce flow rate → reduce deposition in upper respiratory tract by inertia impaction
    Breath holding → increase deposition by sedimentation and diffusion

Question 16

Conditions for optimal deposition

Answer 16

1. Deep breath (deeper penetration to small airways)
   
   2. Slow inspiration (reduces impaction in oropharynx)
   3. Breath holding (allows sedimentation/diffusion)

Question 17

Inhaler devices

Answer 17

• Pressured Metered-Dose Inhalers (pMDIs)
  
  • Dry-Powder Inhalers (DPIs)
  • Nebulisers
    Soft Mist™ Inhalers

Question 18

pMDIs (Pressurised Metered-Dose Inhalers) Major Components

Answer 18

• Container (aluminium, glass, tin-plated steel)
  
  • Actuator
  • Metering valve (measures 25-100 μL per dose)
  • Drug
  • Propellant
    Excipients

Question 19

Mechanism of pMDIs

Answer 19

• Drug dissolved or suspended in propellants (liquified under pressure)
  
  • Upon actuation → content is exposed to atmospheric conditions
  • Rapid evaporation of propellant → formation of droplets → drug deposition in respiratory tract
  • Final droplet size depends on:
    ○ Original particle size
    ○ Rate of propellant evaporation
    Spray orifice diameter