Pulmonary Drug Delivery: Deposition Flashcards
What is deposition dependent on?
- physiochemical characteristics of the drug
- formulation
- delivery device
- patient factors
What is the most imporant physiochemical factor of the drug?
aerodynamic diameter
diameter of a unit density sphere which settles with the same velocity as the particle in question
depends on size, shape and density
What disperse system is required?
monodisperse
GSD = 1
Where would the following sizes of particles be deposited?
> 10mcm
5-10mcm
2-5mcm
0.5-2mcm
? 0.5mcm
< 0.1mcm
> 10mcm - throat
5-10mcm - upper airways
2-5mcm - lower airways
0.5-2mcm - alveloar region
? 0.5mcm exhaled without deposition
< 0.1mcm - alveolar region
Why is a smaller particle size required for salbutamol?
more than 90% of alpha 2 receptors are located in the pulmonary region
this is where salbutamol acts
Why is beclomethasone more benificial when evenly distributed throughout the lung?
beclomethasone is a bronchodilators inhaled steroid
inflammatory cells, such as lymphocytes and macrophages are present throughout the airways as well as the alveolar region
What are the five mechanisms of deposition?
- inertial impaction
- gravitational sedimentation
- Brownian diffusion
- interception
- electrostatic attraction
Describe inertial impaction.
- particle carried in aerosol stream has its own momentum (mass x velocity)
- when stream meets obstacle or bend, direction of gas flow changes
- inertial force of particle resists change in direction
- particles continue in original direction of motion (larger particles more likely to)
What are the consequences of inertial impaction?
- occurs in upper respiratory tract
- tends to be large particles (>5mcm)
- particles swallowed - limited contribution to therapuetic effect
What is gravitational sedimentation?
sedimentation due to gravitational force
rate determined by stokes law - directly proportional to particle density and diameter2
occurs in bronchi, bronchioles, alveolar region
What is Brownian diffusion?
- particles smaller than 0.5mcm too small to be deposited by impaction or sedimentation during normal breathing
- particles bombarded by surrounding molecules in respiratory tract
- results in movement of particles to low conc areas (eg airway walls)
smaller = more diffusion
What is interception?
- occurs when dimensions of particle are similar to diameter of airways it is passing through
- particle edge makes contact with airway surface and particle becomes trapped
- unimportant for spherical particles
What is electrostatic attraction?
- charged particles formed during generation of aerosol
- induce opposite charge on the wall of the airways
- attraction between opposite charges = increased deposition
What are barriers to absorption?
- hydrophilic drugs are poorly absorbed through pores
- rate of absorption of hydrophobic drugs depends on partition coefficient - logP
- formulation will accept absorption: solutions absorbed quicker than suspensions
physiological:
- mucus layer on surface of lungs
- mucociliary escalator
- macrophage and other cells
- alveolar epithilium
- enzymes
Describe the mucus layer
- thin layer of mucus covers wall of respiratory tract
- first barrier after deposition
- composition and thickness vary along the length of the respiratory effect
- consists mainly of water, mucin (GP), carbohydrate, lipid, surfactant
Describe the mucociliary escalator.
- self cleansing through cilia and mucus
- coordinated movement of cilia propels mucus and material towards pharynx where its swallowed
- 1L of mucus cleared every 24 hours
Describe the marcophages and other cells
- macrophages wander throughout lung - can ingest particles and release peroxides
- granulocytes migrate to airways - phagocytose material and release proteases
- lymphocytes - phagocytotic, sensitise lung to future dose
Describe the alveolar epithelium
- composed of type I and II cells
- transport across epithelium by
- intracellular tight injuctions
- membrane pores
- vesicles
Describe the enzymes
- metabolic barrier present in every region of lung
- phase I: oxidation, reduction and hydrolysis
- phase II: conjugation reactions
How does environmental humidity affect deposition?
- humidity higher in lungs
- condensation of water onto particle occurs as particle moves to high humidity
- water soluble particles grow in size
How does solvent evaporation affect deposition?
- propellant associated with aerosol droplets results in mean emitted size > 40mcm
- may have insufficient time for propellant evaporation
How does chemical composition affect deposition?
pMDI drug suspensions may exhibit physical instability
- flocculation
- bulk separation
- irreverisble aggregation
- crystal growth due to temp cycling (Otswald ripening)
= increased particle size
How does aerosol velocity affect deposition?
- larger particles cant change direction
- large proportion deposits at back of the mouth due to inertial impaction
How does respiratory tract physiology affect deposition?
- gender
- age
- body size
- ethnic group
- pathophysiology
How does a spacer device improve deposition for pMDI?
- reduces initial droplet velocity
- permits propellant evaporation
- removes need for coordination between actuation and inhalation
What is a breath actuated pMDI device?
device fires at the correct point of patients inspiratory cycle
What can you do about breathing pattern to improve deposition?
- increased inhaled volume = greater peripheral distribution of particles
- increased inhalation flow rate = increased deposition in larger airways
- breath holding after inhalation = enhanced deposition by sedimentation and diffusion
rapid inhalation leads to deposition by impaction at the back of the throat
slow, deep inhalation followed by breath-hold
What is gamma scintigraphy?
measures deposition in ling, oropharynx and stomach
What are the four main devices used for assessment of deposition?
- Andersen cascade impactor (ACI)
- multi stage liquid impinger
- next generation pharmaceutical impactor
- single stage glass impinger
