Pulmonary Route of Administration Flashcards
Where are particles >1µm likely to deposit?
Upper airways
- Enough momentum and mass for impaction and sedimentation
Where are particles which are <0.5µm likely to deposit?
Lower airways (alveoli) - Brownian diffusion
Where are particles 0.5-1 µm likely to deposit?
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
Which deposition is directly proportional to particle size?
Impaction and sedimentation
Which particle size is deposition by impaction and sedimentation most significant for?
> 1µm
Which particle size is deposition by diffusion most significant for?
< 0.5µm
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 gravitational sedimentation?
- 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
What are the factors affecting particle deposition in dry powder products?
Particle: Diameter Density Shape Charge Surface chemistry
What are the factors affecting particle deposition in liquid aerosols?
Velocity
Propellant type
Droplet 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 the forward momentum of a particle renders it unable to follow the airflow in a curved airway so that it impacts on the wall
Do sub-micron particles have less or more inertia?
They have less - they are less likely to impact in the upper or lower airways
What is electrostatic interaction?
Charge on particles induces the opposite charge on the airway wall
Accelerates particles into the wall
Rare
What are sprays useful for?
Targeting upper respiratory tract
Used in hay fever medication (antihistamines), treatment of sinusitis (steroids), and in decongestants
Do DPIs need a solvent propellant?
No - the dry powder is sheared and released when a patient inhales.
Thus no environmental issues.
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
What can be used to enhance solubility in pMDIs?
- Co-solvents e.g. ethanol
- Inverse micelles
- Liposomes
Enhances solubility of surfactant propellants
How can pMDI suspensions be stabilised?
Surfactants (lecithin, oleic acid)
They adsorb to particles and prevent agglomeration (steric barrier)
How can the valve be lubricated with in pMDIs?
Surfactants
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?
Phenylethanol
Benzalkonium chloride
What kind of inhalers are needed for small airway diseases?
Super fine particle inhalers
What are the particle sizes produced by superfine particle inhalers?
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 small airways disease states?
- Show good efficacy
- Reduce daily dose of ICS
- Achieve greater asthma control and QoL
- Improved therapeutic window
What are nebulisers used for?
Severe conditions where traditional inhalers can’t be used (hospitals and ambulatory care)
Allow for administration of higher doses
Describe the process by which an traditional (air jet) nebuliser releases the drug
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.
Describe the process by which an ultrasonic nebuliser releases the drug
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.
Describe the process by which a vibrating mesh ultrasonic nebuliser releases the drug
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
How can you decrease the aerodynamic diameter for DPIs?
↓ geometric size
↓ density
↑ shape factor (more asymmetric, needle-like)
What is the aerodynamic diameter?
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.
Which methods are used for micronisation of drugs for DPIs?
Sieved (200 µm) Jet mill (2 µm) Pin mill Ball mill CO2 spray crystallized (1 µm)
What are the local benefits of pulmonary administration?
- 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
Inhalation is used as an alternative RoA if…
- 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
What is the upper respiratory tract?
Buccal, sub-lingual and nasal cavities
Pharynx
Upper larynx (above the vocal cords)
What is the lower respiratory tract?
Trachea
Bronchioles
Bronchi
Alveolar ducts
Describe the physiology of the lower respiratory tract
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
Describe the physiology of alveoli
300 million alveoli per lung
70 m2 surface area
Large surface area for gas exchange and drug absorption
What affects the extent and location of deposition of dry powder particles?
Diameter, density, shape, charge, chemical characteristics
What respiratory tract features affect deposition of particles?
Lung capacity
Geometry of respiratory tract
Breathing pattern (frequency, tidal vol)
Disease
What is brownian diffusion?
Random collision of particle with airway wall
Significant only for particles < 0.5 µm
Allows deposition to lower airways
What is needed for electrostatic interaction to take place?
Particle needs to be travelling slowly and to be near the wall
Describe interception
Particle size similar to airway diameter
Only significant for particles which are asymmetric and needle-like
Become intertwined as a collection
Which deposition is inversely proportional to particle size?
Diffusion
Describe traditional delivery devices
- 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)
How do sprays work?
- 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
What are small airways diseases?
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.
How do super fine particle inhalers work?
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
What is the limitation of nebulisers?
Cumbersome and inefficient
Deliver only ~13% of nebulised drug
In what solvent is the drug dispersed in in nebulisers?
Polar solvents (usually H2O)
Describe passive DPIs.
- 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
Describe active DPIs.
In development
Use an internal power source to aerosolise the powder
Give an example of a carrier used in DPIs.
Lactose
Not always used - drug crystals may be used
e.g in Pulmicort (budenoside), Turbuhaler (AZ)
What are the factors that affect aerodynamic diameter?
- Geometric size (actual size)
- Density (mass/volume)
- Aerodynamic diameter (related to particle falling speed)
- Shape factor
- P0 = 1
What values does the shape factor take?
X = 1 for spheres
More asymmetric shapes, X is more than 1
Dividing by a larger number which reduces the aerodynamic diameter
