Respiratory Drug Delivery

Question 1

List some advantages that pulmonary drug delivery has over IV/IM/SC administration.

Answer 1

• IV, IM, SC injections are…
  
  • Expensive
  • Requires sterile manufacture and administration
  • Painful and therefore less well tolerated
  • Risk of infection at injection site
  • Requires trained personnel for administration
  • Risk of needle stick injuries
  • Waste disposal costs

Question 2

What is a limititation of drug apsorption regarding the respiratory epithelium of the human alveoli?

Answer 2

Despite its thin epithelium, the alveoli only has about 0.07 um of fluid. Limited amount of fluid may impact on the dissolution of the dissolution of the drug.

Question 3

Describe the biochemical and physical defence for the pulmonary system

Answer 3

• Biochemical Defence
  
  • ​Phase I and II enzymes present in lungs (CYP450)
  • Resident proteases
    
    • ​contributes to xenobiotic metabolism, oxidation
• Physical Defence
  
  • ​Cough reflex - physical and chemical triggers
  • Bifurcations and branching restricts access

Question 4

What are some pharmacokinetic considerations of the epithelial lining fluid of the pulmonary system?

Answer 4

• Slightly acidic
  
  • Need to consider pKa of drug
    
    • ​ionied/unionised = dissolution? = permeability?
• Small volume
  
  • ​Generally between 12-25mL
    
    • ​Could restrict dissolution of drug
• Thickness
  
  • ​5-10 um & 50-80 nm in alveoli
    
    • ​Should allow easier diffusion in alveoli

Question 5

List EIGHT therapeutic advantages of pulmonary drug delivery

Answer 5

1. Large surface area (~150 m²)
2. Thin epithelial barrier (< 0.2 um)
3. Absence of extremes of pH and metabolism
4. No hepatic first pass metabolism
5. Rich blood supply
6. Rapid delivery into systemic circulation
7. Target delivery and minimize systemic exposure
8. Reduced total dose compared to oral delivery

Question 6

“Absorption rate at the pulmonary epithelial cell is MW dependent.” True or False. Discuss.

Answer 6

• True
• Increase size = Slower rate of absorption

Question 7

What is the absorption mode for:

1. Small hydrophobic
2. Large hydrophilic
3. Peptides/Proteins

Answer 7

1. Small hydrophobic
   
   1. = passive diffusion
2. Large hydrophilic
   
   1. = specific transporters or tight junctions
3. Peptides/Proteins
   
   1. = transcellular/paracellular?

Question 8

Where is the optimal absorption site for most macromolecules in the pulmonary system? Why is IgG not absorbed here?

Answer 8

The distal airways immediately before the terminal alveoli.

IgG is optimally absorbed in larger airways via receptor-mediated transcytosis

Question 9

What is the ideal particle size for an aerosol delivery to the alveoli?

Answer 9

• 1 - 5 um
  
  • Any lower and the particle may be exhaled out with air
  • Any higher and the particle may be deposited elsewhere

Question 10

What are the three ways particle deposition can occur? And how can size, density, time, and flow rate influce these ways?

Answer 10

1. Sedimentation
   
   1. ​increase with size
   2. increase with density
   3. increase with time
   4. independent of flow rate
2. Inertial impaction
   
   1. ​increase with size
   2. increase with density
   3. independent of time
   4. increase with flow rate
3. Diffusion
   
   1. ​decrease with size
   2. independent of density
   3. increase with time
   4. independent of flow rate

Question 11

Briefly describe a Metered Dose Inhaler, and include its benefits.

Answer 11

• Drug dissolved or suspended in a propellant under pressure
• Advantages:
  
  • inexpensive
  • quick
  • convenient
  • can be combined with a spacer

Question 12

What are some advantages and disadvantages of spacers?

Answer 12

• ​Advantages
  
  • _​_20% more effective than MDI
  • Reduces deposition in mouth and throat
• Disadvantage
  
  • _​_The performance can be affected by:
    
    • ​Electrostatic charge
    • Shape
    • Material

Question 13

List FOUR advantages of a Dry Powder Inhaler (DPI) over pMDI.

Answer 13

1. Drug stability
   (most asthma drugs have poor propellant solubility)
2. Ease of handling
3. Greater range of dosages possible
4. Reduced risk of microbiological contamination

Question 14

Compare Jet nebulizers to Ultrasonic nebulisers.

Answer 14

• Jet nebulisers
  
  • Simple to use
  • BUT:
    
    • dose administration takes longer
    • equiment is larger
• Ultrasonic nebulisers
  
  • ​Generate higher output rates
  • BUT:
    
    • ​particle size is larger
    • generates heat in the sample chamber
    • more expensive
    • fragile

Question 15

List reasons why a Dry Powder Inhaler for Oxytocin is more beneficial than the Injectable Oxytocin as treatment of Post-Partum Haemorrhage (PPH)

Answer 15

• Dry powdered inhalers:
  
  • Heat stable formulation
  • Easy to administer
  • Remove risk of blood-borne virus transmission
  • Improve access for isolated communities
  • Cost effective
• Injectable Oxytocin
  
  • ​Cold-chain storage
  • Needle and syringe
  • Access to medical personnel
  • Inapprpriate use
  • Quality of product