Pulmonary Delivery and Aerosols

Question 1

Why is pulmonary drug delivery important?

Answer 1

• important for the treatment and prophylaxis of airway disease such as bronchial asthma and cystic fibrosis

Question 2

What uses does pulmonary drug delivery have?

Answer 2

• rapid onset of activity
• smaller doses can be administered locally compared to oral and parenteral routes
• reduces systemic side effects
• reduces drug costs
• useful where a drug is poorly absorbed orally e.g. sodium cromoglicate
• useful where a drug is metabolised rapidly e.g. isoprenaline

Question 3

Advantages and disadvantages of local drug delivery to the lungs?

Answer 3

Adv

• rapid onset of action
• reduction in systemic side effects
• drug delivered directly to target organ
• non-invasive delivery
• lower doses needed for optimal effect

Disadv

• throat irritation possible
• not all drug is delivered- some lost/ low efficiency of delivery
• difficult breath coordination and manual handling of the device
• corticosteroid use can suppress immune response

Question 4

What examples of diseases are treated via local delivery to the lungs?

Answer 4

• asthma
• COPD
• cystic fibrosis
• pulmonary hypertension
• lung infections

Question 5

Advantages and disadvantages of systemic delivery to the lungs

Answer 5

Adv

• non- invasive drug delivery
• circumvents first pass effect
• very rapid onset of action
• good for biopharmaceuticals

Disadv

• more expensive than oral route
• difficulty with handling and coordination
• some patients may have difficulty breathing through the device
• low efficiency of delivery
• may need low/ exact doses/ special devices

Question 6

Examples of conditions where it uses systemic delivery?

Answer 6

• CNS stimulation
• general anaesthesia
• diabetes
• pain & migraine
• appetite suppression
• biopharmaceuticals

Question 7

List the upper airways of the respiratory tract.

Answer 7

• frontal sinus
• spheroidal sinus
• middle turbinate
• inferior turbinate
• nasopharynx
• oropharynx
• larynx

Question 8

List the central/ conducting airways

Answer 8

• trachea
• main bronchus
• large subsegmental bronchus
• small bronchus
• bronchiole

Question 9

Respiratory/ peripheral/ pulmonary airways (AV)

Answer 9

• terminal bronchiole
• respiratory bronchiole
• alveolar ducts and sacs

Question 10

What is an aerosol?

Answer 10

A two phase system of solid particles or liquid droplets dispersed in air/ gaseous phase, having sufficiently small size to display considerable stability as a suspension.

They are used to deliver drugs to the airways.

Question 11

Describe how a drug enters the respiratory tract

Answer 11

• 90 degree sharp curve in the throat
• If particles are too big, may result in a high deposition in the mouth and trachea
• Big particles will not be able to enter the bronchioles and reach the site of action and so will impact on the trachea instead.
- There’s also a high amount of mucus which will remove the drug to the back of the throat where it may be swallowed again
• In asthma, want drug particles to be delivered to the bronchioles not to the alveoli

Question 12

What other types of lungs are there?

Answer 12

Need to remember that we are not only dealing with healthy adult lungs

• asthmatic bronchiole have thick walls and increased secretion of mucus producing a lower air flow
  • Emphysema patients have weakened and collapsed air sacs with excess mucus
  • Children’s lungs are much smaller than adults so particle sizes should be smaller (children are still using adult inhalers) only 1-3 microns of powder will be deposited in children’s lungs compared to 3-5microns in adults
  • Many organs are affected by cystic fibrosis; airways become thick and sticky with mucus which blocks it

Question 13

What decreases airflow?

Answer 13

1% decrease in diameter = 4% increase in resistance

• Airflow in the lung decreases with increasing branching: airflow is much lower when you’re sleepy
• Airflow in the lungs is affected by disease

Question 14

What should you remind patients who are prescribed corticosteroids?

Answer 14

When patients are prescribed corticosteroids, recommend to the patient to use the inhaler with a spacer or rinse mouth/ throat with water to ensure all drug particles are removed from the mouth/throat.

As steroids suppress the immune system and can cause fungal infections.

Question 15

List the 4 methods of particle deposition.

Answer 15

1) Impaction
2) Sedmentation
3) Electrostatic deposition
4) Diffusion

Question 16

Describe how inertial impaction works.

Answer 16

 Dependent on particles momentum/size, position of particle in the airstream of the parent branch, angle of bifurcation °θ
 Impaction is of significance for the largest particles moving at the highest speed in the RT
 10micron particles have 50% impaction, reduced likelihood of impaction on reduced particle size

Question 17

Describe how sedimentation works.

Answer 17

Particles suspended in a gas are subject to the vertical gravitational force
Is the dominant mechanism for particles depositing in the lower airways
 Important for particles 0.5microns < daero < 5 microns (2microns have 55% chance

Question 18

Describe how diffusion works

Answer 18

 Dominant mechanism for particles <0.5 microns
 The smaller the particles, the more they deposit via diffusion in the peripheral lung and alveolar space

Brownian diffusion in stagnant air of lower airways.

• Collision and bombardment of small particles by molecules in RT produce brownian motion, resultant movement of particles from high to low concentrations causes them to move from the aerosol cloud to airway walls.

Question 19

What are other minor mechanisms for deposition?

Answer 19

• Interception for elongated particles- fibres physically catch onto airway walls
• Charge reflection for charged particles
  (electrostatic charge on a particle induces an opposing charge on walls of RT, resulting in attraction between particles and walls)

Question 20

What is the aerodynamic diameter?

Answer 20

Most fundamentally important physical property of an aerosol for inhalation

da= dg (p^0.5)

da is the physical diameter of a unit density sphere which settles through air with a velocity equal to the particle in question.

Question 21

What are the 5 factors influencing lung deposition?

Answer 21

1) Particle size
2) Particle size distribution
3) Particle density
4) Particle shape
5) Particle hygroscopicity

Question 22

Particle size in central airways and alveoli

Answer 22

MMAD values 3-5 microns have highest deposition in central airways

MMAD values 1-3 microns have the highest deposition in alveoli

Question 23

Particle size distribution in central airways and alveoli

Answer 23

Aerosolised particles with a log-normal distribution will show a greater number of larger particles depositing in the central airways

Monodisperse systems of the correct particle size show a higher deposition in the alveoli.

use particle separation techniques to increase alveolar deposition.

Question 24

Particle density

Answer 24

Higher the density, higher the MMAD, better deposition in central airways

Lower density, lower MMAD, increased alveolar deposition

Question 25

Particle shape

Answer 25

Spherical powders- MMAD 3-10 microns deposit in the central airways.

Non-spherical, irregular particles show poorer flow properties, higher MMAD, higher deposition in central airways

Spherical powders- MMAD 1-3microns deposit in the alveolar region

Long, thin, fibrous particles (>3 microns) will deposit selectively in the alveoli

Question 26

Particle hygroscopicity

Answer 26

High hygroscopic growth rate of particle size, increase in MMAD during lung transit and earlier deposition. Favours deposition in central airways.

Use of a non-hygroscopic, poorly soluble version of the drug or excipient reduces hygroscopic growth during transit.
Favours alveolar deposition.

Question 27

What happens to the drug once it deposits in the lung?

Answer 27

• In large conducting airways (trachea, throat), if drug is poorly soluble, it sticks to the mucus
• Cilia hairs on the epithelial cells remove particles to the back of the mouth to be swallowed and coughed out

If drug is soluble in the mucus:

• needs to pass through layers to get to smooth muscle
• Soluble particle may pass into small conducting airway (terminal bronchioles)
• Consists of one layer of cuboidal epithelial cells, airways surface liquid
• layer of lining is 100nm
• Particles can pass through thin layers easier in small conducting airway to get to the smooth muscle
• in gaseous exchange region- there is no airway surface liquid so particles can be easily exchanged- 100-200 nm

Question 28

What happens to the drug once it is deposited in the upper airways?

Answer 28

1) Mucociliary escalator (local drug conc decreases)

• If drug is non-soluble, it will be stuck in the mucus.
• Epithelial cells with their hairs will remove it from the system
• Lungs are ensuring there are no pathogenic particles

2) Drug dissolution
If drug is soluble, it passes through the layers so local drug concentration is high

Question 29

What happens to the drug once it deposits in the alveolar region?

Answer 29

4) Macrophage clearance (dec in local drug conc)
3) Translocation (dec in local drug conc)

Particle dissolves in small crystals of drug. Some particles will reach blood circulation- translocation.
But macrophages will phagocytose the particles.