Pulmonary Route of Administration Flashcards
Where are >5µm particles likely to deposit?
Upper airways
Where are 1-5µm particles likely to deposit?
Lower airways
Where are <1µm particles likely to deposit?
Pulmonary alveoli
What happens to 500nm particles?
Phagocytosis by alveolar macrophages
What is directly proportional to particle size?
Deposition by impaction and sedimentation
Which particle size is deposition by impaction and sedimentation most effective for?
> 1µm
Which particle size is deposition by impaction and sedimentation least effective for?
Small particles <1µm
When does impaction occur?
When a particle with sufficient momentum doesn’t change direction with airflow in a curved airway and impacts on the wall.
What is sedimentation by gravity related to?
Residence time in an airway and its terminal settling velocity, it is increased by holding breath.
By which mechanism do particle sizes <1m deposit?
Diffusional deposition. It is inversely related to particle size.
Inhalation is used as an alternative RoA if…
- there is chemical or physical interaction with other concurrent medicine
- a drug exhibits variable / erratic pharmacokinetics upon oral administration
- there is breakdown in GI tract
What are the factors affecting particle deposition in dry powder products?
Diameter
Density
Shape
Charge
What are the factors affecting particle deposition in liquid aerosols?
Velocity
Propellant
Particle size
Size distribution
Where are large particles more likely to be deposited?
In the upper airways
Define inertia
Property of a particle to resist changes in velocity
When does inertial impaction occur?
When particle inertia / momentum makes a particle unable to change direction with flow
Do sub-micron particles have less or more inertia?
They have less - they are less likely to impact in the upper or lower airways
When is Brownian motion significant?
In the deposition of small particles affected b inertia and gravity
What is the impact of electrostatic interaction?
Charge on particles induces the opposite charge on the lung wall and accelerates particles in its proximity
What are sprays useful for?
Targeting upper respiratory tract
Do DPIs need a solvent propellant?
No - they dry powder fluidises when a patient inhales.
Where is a drug deposited in the upper airway likely to be absorbed?
GI tract - cilia move particles to the throat where they are swallowed so they can be absorbed in the GI
How does Optinose exhibit bidirectional flow?
Uses the connecting pathway opening between nostrils for a dose to enter by one nostril and leave by the other nostril, this allowed small particles to penetrate to the true nasal mucosa at the back of the nose
What can be used to enhance solubility in pMDIs?
- Co-solvents e.g. ethanol
It is a pressure modifier and enhances solubility of surfactant propellants - Inverse micelles / liposomes
What can be used to improve wettability of pDMIs?
Surfactants - they finely divide active ingredients / excipients
How can pMDI suspensions be stabilised?
Surface active agents (lecithin)
- they adsorb to particles and act as a steric barrier to agglomeration
How can the valve be lubricated in pMDIs?
Surfactants / simple lubricating oi
- minimises friction
What can be used to mask taste of pMDIs?
Menthol
What is used as an anti-oxidant in pDMIs?
Ascorbic acid
Give an example of a preservative used in pDMIs?
Benzalkonium chloride
What kind of inhalers are needed for small airway disease?
Super fine particle inhalers
What are the particle sizes used in SAD?
Ultrafine <100nm)
Extra fine <1µm
What 2 factors contribute to most of a dose not being deposited in the lung?
Impaction and sedimentation
What are the benefits of using smaller particles in disease states?
- show good efficacy
- reduce daily dose of ICS
- achieve greater asthma control
- improved therapeutic window
What are nebulisers used for?
Conditions where traditional inhalers would be inappropriate
To avoid banned and pressurised gases
Describe the process by which an air jet nebuliser releases the drug
Compressed air/oxygen exits a narrow office at high velocity
When are is forced through, negative pressure at the exit draws up liquid from a tube
Liquid is drawn up in fragments into an aerosol with droplet sizes >40µm
Larger particles are removed, a bend allows them to impact and return to a reservoir
Describe the process by which an air ultrasonic nebuliser releases the drug
There is no need for compressed gas
Aerosol is created using Piezoelectric crystals
Piezoelectric transducers vibrating at 1-3MHz are shaped to focus ultrasound waves within the liquid
Intense agitation at focus - conical fountain above liquid - dispersed to create an aerosol
Larger aerosol particles are removed by impaction
Describe the process by which a vibrating mesh ultrasonic nebuliser releases the drug
By process of Piezo crystals expanding and contracting, this is driven by alternating voltage, the mesh is pulled back into the liquid and then thrown forward
Near mono-disperse fine droplets are ejected with every forward thrust of the mesh
Almost all the liquid is converted to an aerosol for inhalation
What are the ideal particle properties for DPIs?
↓ size
↓ density
↑ shape factor
How does hygroscopic growth affect aerosolisation and lung deposition?
Leads to irreversible aggregation, altered adhesive and cohesive properties and increase in particle size
Which methods are used for micronisation?
Jet mill
Pin mill
Ball mill
How does super-critical fluid particle engineering micronise DPI active ingredients?
Solvent - lead to rapid expansion
Anti-solvents - solution enhanced dispersion
How are excipients beneficial in DPI formulation?
Improve dispensing
Improve metering
Reduce cohesion by occupying high energy sites of micronised particles
Why are excipients limited in DPI formulation?
The lung has low buffering capacity and can be easily irritated
