Pulmonary Route of Administration

Question 1

Where are particles >1µm likely to deposit?

Answer 1

Upper airways

- Enough momentum and mass for impaction and sedimentation

Question 2

Where are particles which are <0.5µm likely to deposit?

Answer 2

Lower airways (alveoli)
- Brownian diffusion

Question 3

Where are particles 0.5-1 µm likely to deposit?

Answer 3

Nowhere, exhaled out

• Brownian diffusion only significant for particles <0.5µm there no lower airway deposition
• <1µm therefore not enough mass and momentum to deposit in upper airways via impaction and sedimentation

Question 4

Which deposition is directly proportional to particle size?

Answer 4

Impaction and sedimentation

Question 5

Which particle size is deposition by impaction and sedimentation most significant for?

Answer 5

> 1µm

Question 6

Which particle size is deposition by diffusion most significant for?

Answer 6

< 0.5µm

Question 7

When does impaction occur?

Answer 7

When a particle with sufficient momentum doesn’t change direction with airflow in a curved airway and impacts on the wall.

Question 8

What is gravitational sedimentation?

Answer 8

• Particles fall under the effect of gravity
• Significant between breaths
• Increase residence time (travel slowly) and decreased breathing rate increases sedimentation
• Increased by holding breath

Question 9

What are the factors affecting particle deposition in dry powder products?

Answer 9

Particle:
Diameter
Density
Shape
Charge
Surface chemistry

Question 10

What are the factors affecting particle deposition in liquid aerosols?

Answer 10

Velocity
Propellant type
Droplet size distribution

Question 11

Where are large particles more likely to be deposited?

Answer 11

In the upper airways

Question 12

Define inertia

Answer 12

Property of a particle to resist changes in velocity

Question 13

When does inertial impaction occur?

Answer 13

When the forward momentum of a particle renders it unable to follow the airflow in a curved airway so that it impacts on the wall

Question 14

Do sub-micron particles have less or more inertia?

Answer 14

They have less - they are less likely to impact in the upper or lower airways

Question 15

What is electrostatic interaction?

Answer 15

Charge on particles induces the opposite charge on the airway wall
Accelerates particles into the wall
Rare

Question 16

What are sprays useful for?

Answer 16

Targeting upper respiratory tract

Used in hay fever medication (antihistamines), treatment of sinusitis (steroids), and in decongestants

Question 17

Do DPIs need a solvent propellant?

Answer 17

No - the dry powder is sheared and released when a patient inhales.

Thus no environmental issues.

Question 18

Where is a drug deposited in the upper airway likely to be absorbed?

Answer 18

GI tract - cilia move particles to the throat where they are swallowed so they can be absorbed in the GI

Question 19

What can be used to enhance solubility in pMDIs?

Answer 19

• Co-solvents e.g. ethanol
• Inverse micelles
• Liposomes

Enhances solubility of surfactant propellants

Question 20

How can pMDI suspensions be stabilised?

Answer 20

Surfactants (lecithin, oleic acid)

They adsorb to particles and prevent agglomeration (steric barrier)

Question 21

How can the valve be lubricated with in pMDIs?

Answer 21

Surfactants

Question 22

What can be used to mask taste of pMDIs?

Answer 22

Menthol

Question 23

What is used as an anti-oxidant in pDMIs?

Answer 23

Ascorbic acid

Question 24

Give an example of a preservative used in pDMIs?

Answer 24

Phenylethanol

Benzalkonium chloride

Question 25

What kind of inhalers are needed for small airway diseases?

Answer 25

Super fine particle inhalers

Question 26

What are the particle sizes produced by superfine particle inhalers?

Answer 26

Ultrafine <100nm) | Extra fine <1µm

Question 27

What 2 factors contribute to most of a dose not being deposited in the lung?

Answer 27

Impaction and sedimentation

Question 28

What are the benefits of using smaller particles in small airways disease states?

Answer 28

- Show good efficacy - Reduce daily dose of ICS - Achieve greater asthma control and QoL - Improved therapeutic window

Question 29

What are nebulisers used for?

Answer 29

Severe conditions where traditional inhalers can't be used (hospitals and ambulatory care) Allow for administration of higher doses

Question 30

Describe the process by which an traditional (air jet) nebuliser releases the drug

Answer 30

Compressed air/oxygen exits a narrow office at high velocity. This creates a negative pressure which draws up liquid from the capillary. where it is aerosolised. Droplet formed are >40µm. Larger particles are removed via impaction on a bend. These particles return to the reservoir.

Question 31

Describe the process by which an ultrasonic nebuliser releases the drug

Answer 31

Aerosol is created using Piezoelectric crystals. Piezoelectric transducers vibrating at 1-3MHz focus ultrasound waves in liquid. Intense agitation at focus disperse the liquid to create an aerosol.

Question 32

Describe the process by which a vibrating mesh ultrasonic nebuliser releases the drug

Answer 32

Alternating current causes Piezo crystals to expand and contract rapidly. This pulls the mesh into the liquid and then thrusts it forward. Mono-dispersed superfine droplets are ejected with every forward thrust of the mesh. Almost all the liquid is converted to an aerosol for inhalation

Question 33

How can you decrease the aerodynamic diameter for DPIs?

Answer 33

↓ geometric size ↓ density ↑ shape factor (more asymmetric, needle-like)

Question 34

What is the aerodynamic diameter?

Answer 34

Describes dynamic (moving) behaviour of a particle, relating gravitational settling and inertial impaction Key in determining the location and the extent deposition. Efficient alveolar delivery of particles with aerodynamic diameters of 1 – 5 µm.

Question 35

Which methods are used for micronisation of drugs for DPIs?

Answer 35

``` Sieved (200 µm) Jet mill (2 µm) Pin mill Ball mill CO2 spray crystallized (1 µm) ```

Question 36

What are the local benefits of pulmonary administration?

Answer 36

- Rapid action - Avoids 1st pass metabolism - Avoids GI degradation - Lower doses needed (less ADRs) - Accurate dose adjustment (ideal for PRN medicine) - Small volumes (25 - 100ml) - Tamperproof container - Drug protected from air and moisture

Question 37

Inhalation is used as an alternative RoA if...

Answer 37

- Need to avoid variable pharmacokinetics shown when drug is given orally - To treat acute or breakthrough pain - Want to avoid chemical/physical interactions with other medication - If formulation degraded in GIT

Question 38

What is the upper respiratory tract?

Answer 38

Buccal, sub-lingual and nasal cavities Pharynx Upper larynx (above the vocal cords)

Question 39

What is the lower respiratory tract?

Answer 39

Trachea Bronchioles Bronchi Alveolar ducts

Question 40

Describe the physiology of the lower respiratory tract

Answer 40

Trachea branches to primary and then secondary bronchi then to bronchioles which terminate in the alveoli ``` Diameters: - Trachea - 2cm Large diameter allows large particles to travel through - Bronchioles - ≤ 1mm - Terminal bronchioles - ~ 0.5mm ```

Question 41

Describe the physiology of alveoli

Answer 41

300 million alveoli per lung 70 m2 surface area Large surface area for gas exchange and drug absorption

Question 42

What affects the extent and location of deposition of dry powder particles?

Answer 42

Diameter, density, shape, charge, chemical characteristics

Question 43

What respiratory tract features affect deposition of particles?

Answer 43

Lung capacity Geometry of respiratory tract Breathing pattern (frequency, tidal vol) Disease

Question 44

What is brownian diffusion?

Answer 44

Random collision of particle with airway wall Significant only for particles < 0.5 µm Allows deposition to lower airways

Question 45

What is needed for electrostatic interaction to take place?

Answer 45

Particle needs to be travelling slowly and to be near the wall

Question 46

Describe interception

Answer 46

Particle size similar to airway diameter Only significant for particles which are asymmetric and needle-like Become intertwined as a collection

Question 47

Which deposition is inversely proportional to particle size?

Answer 47

Diffusion

Question 48

Describe traditional delivery devices

Answer 48

- Deposition achieved impaction and sedimentation - Aerosols produces particles with size <10 µm (typically 2 – 8µm) - 80-90% of dose not deposited - Large losses to GI absorption (degraded by GI enzymes, side effects)

Question 49

How do sprays work?

Answer 49

- Electronic actuators give a more controlled dispersion (minimises GIT deposition - reduced ADRs) - Bidirectional flow - The act of blowing shuts off the back of the nasal cavity and prevents disposition into the mouth

Question 50

What are small airways diseases?

Answer 50

COPD, Chronic Asthma Inadequately treated using traditional inhalers due to small airways (<2mm diameter). Most particles generated in traditional pMDIs and DPIs deposit in the wider upper airways (by sedimentation and impaction). The smaller (0.5 – 1 mm) particles delivered by the traditional inhalers deposit poorly, most are exhaled.

Question 51

How do super fine particle inhalers work?

Answer 51

``` Use hydrofluoroalkanes (HFAs) propellant Produce very small aerosol particles (ultra- and extra-fine particles) which are more likely to be deposited by diffusion. Less exhaled or swallowed so required smaller dose required ```

Question 52

What is the limitation of nebulisers?

Answer 52

Cumbersome and inefficient | Deliver only ~13% of nebulised drug

Question 53

In what solvent is the drug dispersed in in nebulisers?

Answer 53

Polar solvents (usually H2O)

Question 54

Describe passive DPIs.

Answer 54

- Commercially-available. - Require quick, strong and deep inhalation. - Small drug particles adhered to larger carrier particles. - Separated by sheer forces with large particles. - Large particles deposited in the oropharynx - Smaller particles going down to the lower airways

Question 55

Describe active DPIs.

Answer 55

In development | Use an internal power source to aerosolise the powder

Question 56

Give an example of a carrier used in DPIs.

Answer 56

Lactose Not always used - drug crystals may be used e.g in Pulmicort (budenoside), Turbuhaler (AZ)

Question 57

What are the factors that affect aerodynamic diameter?

Answer 57

- Geometric size (actual size) - Density (mass/volume) - Aerodynamic diameter (related to particle falling speed) - Shape factor - P0 = 1

Question 58

What values does the shape factor take?

Answer 58

X = 1 for spheres More asymmetric shapes, X is more than 1 Dividing by a larger number which reduces the aerodynamic diameter