Download Drug administration via the lung

Administration of Drugs via the Lung
lung is an efficient organ for the transport of
gases
• large surface area
• high permeability of the alveolar epithelium
• rich blood supply
• no first pass effects
• Lung anatomy
Series of dividing passageways
Two different surfaces: airways
(trachea, bronchi, bronchioles)
airsacs and alveoli
Respiratory epithelium
• Continuous sheet of cells lining the luminal
surface of the airways
•
Cells of the airways epithelium are
different from alveolar epithelium
Airway epithelium: basal cells, ciliated
cells, goblet cells, Clara cells)
Alveolar epithelium: Type I and Type II
• Epithelium of conducting zone (airway) is
lined by ciliated cells and is covered by
mucous
• Mucous three functions:
protects the epithelium from getting
dehydrated
saturation of the inhaled air
airway protection: coordinated beating of the
cilia
Epithelium of the alveolar region: no mucous, no
ciliated cells, lung surfactant (alveolar lining
fluid)
• Type I cells: principle cell type lining the alveoli,
high surface area, gas exchange takes place
• Type II cells: smaller surface area, synthesis and
secretion of lung surfactant, differentiation into
Type I cells upon cell injury
• Alveolar macrophages: clearance of inhaled
particles, cellular defence
• Metabolism in the lung: Phase I and
Phase II
• Particle inhalation: particle velocity, and
SIZE
• Optimum particle size for airway
penetration: 3-5 µm
Parameters determining particle
deposition in the deep lung
Different biophysical parameters determine regional
drug deposition in the human lungs:
• Aerodynamic particle behaviour (e.g. size, density,
hygroscopicity, shape, electrical charge)
• Breathing pattern of the patients (e.g. flow rate,
ventilation volume, end-inspiratory breathholding)
• Airway anatomy and morphometry of the patient
Air enters from Nose or Mouth
Extrathoracis
region
Passes through
Nasopharynx or Oropharynx
Through the Larynx
Into the Trachea
Tracheobronchial
region
Into the left and right Bronchi
Bronchi further branches into
Bronchioles
Alveolar
region
Terminates into a
Cluster of Alveoli
• The aerodynamic particle diameter is the
diameter of a sphere with a density of 1 g/cm3 that
has the same aerodynamic behaviour as the
particle which shall be characterized
• For a water droplet, the geometric and
aerodynamic particle diameter is identical. In
contrast, large porous particles have a much
smaller aerodynamic particle diameter than their
geometric diameter.
Aerodynamic particle behaviour
• Particles in the ambient air are transported
by different physical mechanisms. The
relevant mechanisms for therapeutic
aerosols are diffusion by Brownian motion
(particles in the size range of ≤0.5 μm),
sedimentation by the gravitational force
(particles in the size range of ≥0.5 μm) and
impaction (size range ≥ 3 μm).
• Diffusion (Brownian motion)
Particle losses by diffusion are based on the
Brownian motion. An aerosol particle which is
suspended in a gas is moved by collisions with
gas molecules. This leads to an irregular and
unoriented movement of particles, which can
cause a contact with an airway wall.
• The probability that a particle will be deposited in
the lungs by diffusion
a. increases with decreasing particle size.
b. increases with increasing residence time
Deposition by diffusion is only relevant for aerosol
particles with a diameter≪0.5 μm
• Sedimentation
Deposition by sedimentation is caused by
the gravitational force of the earth.
The probability that a particle will be
deposited by sedimentation in the lungs is
dependent on the particle diameter and
the residence time of the particle in the
airways
The probability of particle deposition
by sedimentation:
• increases with increasing particle size and
increasing residence time of the particle in
the lungs.
• increases with decreasing size of airspaces.
It is higher in the alveoli than in the bronchi.
• Impaction
Impaction is caused by the inertia of aerosol
particles.
Small particles with an aerodynamic diameter
less than 0.5 μm are able to follow the
streamlines of moving air almost ideally.
In contrast, larger particles (diameters 3 μm
and larger) display inertia and tend to fly
straight ahead.
• The mechanism of particle impaction leads to
deposition in the extrathoracic (nose, larynx) but
also in the intrathoracic (trachea, bronchi) airways
The probability that a particle is deposited by
impaction:
• increases with increasing inertia of the particle
• increases with higher air velocity in the airways
• increases when the angle of the airway bifurcation
• increases and when the airway diameters are
smaller
• increases with the number of airway bifurcations
that the particle has to pass
• Breathing pattern of patients
The upper human airways have anatomical
structures that efficiently serve as a filter
for inhaled natural non-gaseous pollutants.
A fast inhalation leads to an enhanced
deposition by impaction in the larynx and
in the nose and thus prevents particle
penetration into the deep lungs
Absorption of drugs via the lung
• Lipophilicity, specialized mechanisms,
tight junctions
• Upper airways: limited abs due to mucous
layer, thick cells
• Lower airways: lung surfactant, thinner
and broader cells
Barriers to drug absorption
• The geometry of the airways
• Mucociliary clearance
• Macrophage clearance
• Pulmonary metabolism
Drugs administered to the lung
• Localized disease states: bronchodilators,
anti-inflammatory agents, mucolytics,
antiviral agents, anticancerous agents,
phospholipid-protein mixtures for
surfactant replacement
• Systemic drug administration
Delivery systems
• Pressurized metered dose inhalers (MDI)
• Dry powder inhalers (DPI)
• Nebulizers
Device Criteria
• Aerosol generation in the size range of
0.5-5.0um
• Reproducible dosing
• Chemical and physical stability
• Patient’s convenience
Metered Dose Inhalers (MDI)
• The Older generation of Aerosol devices
• Five main components: container,
metering valve, liquid propellant with
excipients, candidate drug and actuator
• Propellant: severs as energy source and a
dispersion medium for the drug
• Traditional propellants are CFC mixtures
which are ch.ct by: low toxicity, high
chemical stability and compatibility
• Surfactant
• Drug: dissolved or suspended
• Container: integral part of formulation.
Metering valve and actuator
• General feature of an aerosol product
• Dosing: 50ug-5.0 mg
• Volume delivered upon actuation: 25-100
ul
• Time of delivery: 10-200 msec
• Velocity of actuated dose: 30 m/sec
Drawbacks of MDI
• High velocity of the actuated dose
• Poor hand lung synchronization
Introduction of spacers
• Dry Powder inhalers (DPI)
Major advantages over MDI
Breath actuated
Suitable for biopharmaceuticals
Large doses delivery is possible
• Nebulizers
Delivery of large doses of the drug
No synchronization is required
Two major types: air jet and ultrasonic
Breathing flow rate
• Breathing flow rates directly affect the
aerosol transport/deposition.
• Based on the activity of an individual, the
inhalation flow rates are roughly classified
as: slow breathing (15 l/min), normal
breathing (30 l/min) and heavy breathing
(60 l/min).