Christy (Pulmonary drug delivery) Flashcards
Benefits of inhaled drugs
Act quickly
Smaller doses are required
Non-invasive
Relatively confortable
100% bioavailability- no 1st pass metabolism
Go directly into the lungs
Systemically absorbed
Complication of inhaled drugs
Disease state- COPD, asthma.
Drug formulation- need repeated exact microgram doses.
Patient anatomy and overcoming natural defences- ciliated globular epithelium carries anything that goes into the lungs out of the lungs. Drug must go down 90 degree turn. Alveolar macrophages can take them up and stop them from going to site of action. Airways get increasingly narrower.
How to deliver drugs to the lungs
Drug must be presented as an aerosol. This is a 2 phase system consisting of
- particles (either a solid or liquid-why users must shake inhalers before use)
- gas (usually air)
The product needs to be able to generate an aerosol and the particles must be the right size.
Inhalation products are therefore usually:
- a formulation containing drug
- a delivery device
There are 3 main options for achieving an aerosol:
- drug in propellant cloud (pMDI)
- powder dispersed in air (DPI)
- fine droplets in air (nebuliser)
Where should aerosol particles be deposited?
The aerosol must penetrate to smaller airways to be effective for local action or systemic absorption so particle size is a crucial factor in pulmonary drug delivery.
Particles with a size of more than 10um will be deposited in the oropharynx, a size of more than 5um are deposited in the central airways, and those with a size of less than 5um will be deposited in the peripheral (distal) airways.
Particulate drug delivery
Only a portion of the drug dose emitted from an aerosol product will deposit in the airways. Pharmaceutical aerosols are polydisperse meaning them emit a range of particle sizes.
The most important size fraction of this range is known as the Respirable fraction.
This is the mass of drug emitted from the inhaler which is in the size where lung deposition is possible (<5um)
Mechanisms of lung deposition
3 possible mechanisms
1. Inertial impaction
2. Sedimentation
3. Diffusion
Inertial impaction
- There are many branches within the lungs.
- Both mass (size) and velocity affect the likelihood of a particle impacting on a surface.
- Heavier particles have inertia so are not easily deflected by airstream flow change. If the velocity is too high the particle won’t go round bends.
- In distal lung, area across total airway increases greatly so velocity falls. This means impaction is less likely but particles sediment. Impaction can be minimised by slowing the velocity of particles i.e. slow inspiration.
Sedimentation
- Particles fall under gravity. The larger ones sediment faster and smaller particles sediment slower.
- Airway diameter is narrower in distal lung so less distance to fall
- Therefore, the major source of drug deposition in distal airways is by sedimentation.
- Holding your breath allows time for sedimentation
Diffusion
- Deposition by random movement. Predominantly small particles (<0.5um).
- Occurs in periphery of lung- bronchioles and alveoli
Clearance of inhaled particles
Mucociliary clearance in ciliated airways.
Insoluble particles in alveoli are engulfed by macrophages.
May dissolve/absorbed depending on drug polarity.
Factors affecting particle deposition
- Airway calibre
- Airways are constricted in asthmatics and there may be mucus
- Impaction is more likely to occur before particles reach peripheral airways
- Advise patients to be upright when taking inhaler - Speed of inspiration
- With MDIs, pressure expels particles at high speed.
To avoid large velocity patients should breathe in slowly - Patient co-ordination
- When using an inhaler patient needs to coordinate breathing and actuating product
- This can be difficult in some patient groups
- Poor coordination can lead to firing the aerosol before breathing, and breathing in too quickly.
- Should breathe in slowly just before actuation, then hold breath - Particle size
- Important size range for pulmonary deposition is 2-5um
- Some material may aggregate (larger particles) - Formulation
- Nebulisers
- pMDIs
- DPIs
Nebulisers
A device to be used in conjunction with a simple solution or suspension.
Function is to produce an aerosol in the form of a cloud or mist.
The droplets are aqueous solution of the drug.
The mist is slow moving.
Solutions are often sterile and single use.
It is much less portable than other inhalers.
Delivers a high dose and large volume of drug solution.
Normal breathing and avoid coordination problems.
3 types: jet, ultrasonic, vibrating mesh.
pMDIs
Most common form of inhaled drug delivery system.
2 formulation types- drug in solution or suspension in a volatile propellant.
Excipients:
- Propellants
- Surfactant- helps keep suspension stable (patients shake inhaler before use), lubricates moving parts of valve
- Co-solvent- helps dissolve drug, helps dissolve surfactant, manipulate density
Need to minimise solubility of the drug.
Use salt form to reduce particle growth.
Can deliver drug directly to airways.
Suitable for nasal, sublingual, skin.
Minimum contamination of product.
Generally good stability.
Easy to control dose.
Portable.
Expensive.
Pressurised.
Subject to incorrect use (cap not removed, not shaking, inversion, quick inhalation, lack of coordination).
Can use spacers to improve dosing. Spacers allow for velocity reduction and evaporation meaning the potential respirable size fraction is increased and there is reduced deposition at back of the mouth.
Can also use reservoirs which are large volume spacers. They have a one way valve preventing patient exhaling. They reduce the need for patient coordination and the particles stay suspended over several breaths. they are effective but not practical to carry around.
DPIs
Drug dispersed into lungs from a dry powder formulation.
Contain no propellant and particles are dispersed by patient inhalation instead.
The device needs to:
- protect powder from environment until needed
- dispense a precise dose
- liberate drug via airflow
- potential for multi-dose
Need to have correct particle size for inhalation and good flow properties (non-cohesive particles) to give the correct dosage.
A thin coating is applied to reduce cohesiveness.
Need careful selection of solid state form of drug- some drugs have more than one crystalline shape which changes the dosage (polymorphic forms).
Often a greater dose is needed than with MDI- more polydisperse.
Respirable dose depends on patents inspiration rate (low rates produce a lower extent of deaggregation). Can make it unsuitable for some patients e.g. infants, elderly and severe asthmatics
