2. 2
Pulmonary Drug Delivery
Anatomy and Physiology of the
Respiratory System
Advantages of Pulmonary Delivery
Lung epithelium at different sites within
the lungs
Pulmonary absorptive surfaces
Systemic delivery of:
Small hydrophobic drugs
Small hydrophilic drugs
Macromolecules drugs
Pulmonary Drug Delivery Devices
3. 3
Anatomy and Physiology of the
Respiratory System
The human respiratory system is divided into
upper and lower respiratory tracts
The upper respiratory system consists of the
nose, nasal cavities, nasopharynx, and
oropharynx
The lower respiratory tract consists of the
larynx, trachea, bronchi, and alveoli, which
are composed of respiratory tissues
The left and right lungs are unequal in size.
The right lung is composed of three lobes:
the superior, middle, and inferior lobes. The
smaller left lung has two lobes
5. 5
Anatomy and Physiology of the
Respiratory System
The nasopharynx is a passageway from the
nose to the oral pharynx
The larynx controls the airflow to the lungs
and aids in phonation
The larynx leads into the cartilaginous and
fibromuscular tube, the trachea, which
bifurcates into the right and left bronchi
The bronchi, in turn, divide into bronchioles
and finally into alveoli
6. 6
Anatomy and Physiology of the
Respiratory System
The respiratory tree can be differentiated into
the conducting zone and the respiratory
zone.
The conducting zone consists of the bronchi,
which are lined by ciliated cells secreting
mucus and terminal bronchioles.
The respiratory zone is composed of
respiratory bronchioles, alveolar ducts, atria,
and alveoli
8. 8
Anatomy and Physiology of the
Respiratory System
The epithelium in the conducting zone gets
thinner as it changes from pseudostratified
columnar to columnar epithelium and finally
to cuboidal epithelium in the terminal
bronchioles
The upper part of the conducting zone (from
the trachea to the bronchi) consists of ciliated
and goblet cells (which secrete mucus)
These cells are absent in the bronchioles.
Alveoli are covered predominantly with a
monolayer of squamous epithelial cells (type
I cells) overlying a thin basal lamina
9. 9
Anatomy and Physiology of the
Respiratory System
Cuboidal type II cells present at the junctions
of alveoli secrete a fluid containing a surfactant
(dipalmitoylphosphatidylcholine), apoproteins,
and calcium ions
The lungs are covered extensively by a vast
network of blood vessels, and almost all the
blood in circulation flows through the lungs.
Deoxygenated blood is supplied to the lungs by
the pulmonary artery
The pulmonary veins are similar to the arteries
in branching, and their tissue structure is
similar to that of systemic circulation. The total
blood volume of the lungs is about 450 mL,
which is about 10 percent of total body blood
volume
12. 12
Advantages of Pulmonary Delivery of
Drugs To Treat Respiratory Disease
Deliver high drug concentrations directly to the
disease site
Minimizes risk of systemic side effects
Rapid clinical response
Bypass the barriers to therapeutic efficacy, such
as poor gastrointestinal absorption and first-pass
metabolism in the liver
Achieve a similar or superior therapeutic effect at
a fraction of the systemic dose, (for example, oral
salbutamol 2–4 mg is therapeutically equivalent
to 100–200 μg by metered dose inhaler)
13. 13
Advantages of Pulmonary Delivery of
Drugs To Treat Systemic Disease
A non-invasive, needle-free delivery system
Suitable for a wide range of substances from
small molecules to very large proteins
Enormous absorptive surface area (140 m2)
and a highly permeable membrane (0.2–0.7
μm thickness) in the alveolar region
Large molecules with very low absorption
rates can be absorbed in significant
quantities; the slow mucociliary clearance in
the lung periphery results in prolonged
residency in the lung
14. 14
Advantages of Pulmonary Delivery of
Drugs To Treat Systemic Disease
A less harsh, low enzymatic environment
Avoids first-pass metabolism
Reproducible absorption kinetics
Pulmonary delivery is independent of dietary
complications, extracellular enzymes, and
inter-patient metabolic differences that affect
gastrointestinal absorption
15. 15
Pulmonary absorptive surfaces
The airways (the trachea, bronchi and
bronchioles) are composed of a gradually
thinning columnar epithelium populated by
many mucus and ciliated cells that
collectively form the mucociliary escalator
The airways bifurcate roughly 16–17 times
before the alveoli are reached
Inhaled insoluble particles that deposit in the
airways are efficiently swept up and out of
the lungs in moving patches of mucus, and
for those deposited in the deepest airways
this can be over a time period of about 24
hour
16. 16
Pulmonary absorptive surfaces
The monolayer that makes up the alveolar
epithelium is completely different. The tall
columnar mucus and cilia cells are replaced
primarily (>95% of surface) by the very broad
and extremely thin (<0.1 µm in places) type 1
cells
Distributed in the corners of the alveolar sacs
are also the progenitor cells for the type 1 cells
and the producers of lung surfactant, the type
2 cells
The air-side surface of each of the 500 million
alveoli in human lungs is routinely 'patrolled' by
12–14 alveolar macrophages, which engulf and
try to digest any insoluble particles that deposit
in the alveoli
17. 17
Pulmonary absorptive surfaces
An excess of 90% of alveolar macrophages
are located at or near alveolar septal
junctional zones
Insoluble, non-digestible particles that
deposit in the alveoli can reside in the lungs
for years, usually sequestered within
macrophages
Molecules such as insulin are formulated
either as liquids or in highly water-soluble
aerosol particles that dissolve rapidly in the
lungs and thereby largely avoid macrophage
degradation
18. 18
Pulmonary absorptive surfaces
Protein therapeutics that are taken up by
macrophages can be rapidly destroyed in the
lysosomal 'guts' of the phagocytic cells
19. 19
The effect of particle size on the deposition of aerosol
particles in the human respiratory tract following a slow
inhalation and a 5-second breath hold
Mouth and throat
Alveolar region
Airways
20. 20
Systemic delivery of small
hydrophobic molecules
Small, mildly hydrophobic molecules can show
extremely rapid absorption kinetics from the
lungs
However, as hydrophobicity increases, molecules
can become too insoluble for rapid absorption and
can persist in the lungs for hours, days or weeks
Typical drug molecules with log octanol–water
partition coefficients greater than 1 can be
expected to be absorbed, with absorption half-
lives (the time it takes half of the molecules
deposited into the lungs to disappear from the
tissue) of approximately 1 minute or so;
decreasing the log octanol–water partition
coefficient to –1 or lower can increase the half-life
to around 60 minutes
21. 21
Systemic delivery of small
hydrophobic molecules
Examples of rapidly absorbed inhaled hydrophobic
drugs include nicotine, 9-tetrahydrocannabinol
(THC), morphine and fentanyl
22. 22
Inhaled morphine (dose = 8.8 mg)
compared with intravenous injection
(dose = 4 mg) in human volunteers
23. 23
Systemic delivery of small
hydrophilic molecules
In general, neutral or negatively charged
hydrophilic small molecules are absorbed
rapidly and with high bioavailabilities from
the lungs
This class of molecules has an average
absorption half-life of about 60 minutes, in
contrast to some of the lipophilic molecules
that are absorbed in seconds to minutes
25. 25
Systemic delivery of
macromolecules
The use of the lungs for the delivery of
peptides and proteins, which otherwise must
be injected, is one of the most exciting new
areas in pulmonary delivery
For reasons that are not completely
understood, the lungs provide higher
bioavailabilities for macromolecules than any
other non-invasive route of delivery
However, unlike the situation with small
molecules, for which lung metabolism is
minimal, enzymatic hydrolysis of small
natural peptides can be very high unless they
are chemically engineered (blocked) to inhibit
peptidases
26. 26
Systemic delivery of
macromolecules
Small natural peptides make poor drugs by
any route of delivery because of peptidase
sensitivity, whereas blocked peptides show
high pulmonary bioavailabilities
As molecular mass increases and peptides
become proteins with greater tertiary and
quaternary structure, peptidase hydrolysis is
inhibited or even eliminated and
bioavailabilities of natural proteins can be
high
Insulin can be considered to be a large
peptide (or small protein), with enough size
to avoid much of the metabolism seen with
smaller peptides
27. 27
Systemic delivery of
macromolecules
The rate of macromolecule absorption is
primarily dictated by size — the larger the
size the slower the absorption
Molecules such as insulin, growth hormone
and many cytokines typically peak in blood
following aerosol inhalation in 30–90
minutes, whereas smaller blocked peptides
can be absorbed faster
After a 15-year development effort, inhaled
human insulin (IHI) applied regularly at meal
time has been approved both in the US and
the European Union for the treatment of
adults with diabetes (Exubera)
28. 28
Systemic delivery of
macromolecules
Conjugation of molecules such as interferons,
follicle stimulating hormone (FSH) and
erythropoietin (EPO) to the constant (Fc) region
of antibodies has been shown to prolong the
systemic duration
Interestingly, the optimal pulmonary site of
absorption of these conjugates seems to be the
conducting airways, in contrast to the major
site for insulin, which is in the deep lung
The airways are enriched with antibody
transcytosis receptor mechanisms. Fc
conjugates of proteins have serum half-lives >1
day and are believed to be absorbed with high
bioavailabilities (20–50%) from the lungs
30. 30
Dry Powder Inhalation (DPI)
Devices
DPIs are used to treat respiratory diseases
such as asthma and COPD, systemic
disorders such as diabetes, cancer,
neurological diseases (including pain), and
other pulmonary diseases such as cystic
fibrosis and pulmonary infectious diseases
Devices requiring the patient's inspiration
effort to aerosolize the powder aliquot are
called passive devices because as they do not
provide an internal energy source
Active devices provide different kinds of
energy for aerosolization: kinetic energy by a
loaded spring and compressed air or electric
energy by a battery
31. 31
Dry Powder Inhalation (DPI)
Devices
Most DPIs contain micronized drug blended
with larger carrier particles, which prevents
aggregation and promotes flow
33. 33
The Pressurized Metered-Dose
Inhalation (pMDI) Device
The pressurized metered-dose inhalation
(pMDI) device was introduced to deliver asthma
medications in a convenient and reliable multi-
dose presentation
The key components of the pMDI device are:
container, propellants, formulation, metering
valve, and actuator
The pMDI container must withstand high
pressure generated by the propellant. Stainless
steel has been used as a pMDI container
material. Aluminum is now preferred because,
compared to glass, it is lighter, more compact,
less fragile, and light-proof
34. 34
The Pressurized Metered-Dose
Inhalation (pMDI) Device
Coatings on the internal container surfaces
may be useful to prevent adhesion of drug
particles and chemical degradation of drug
Propellants in pMDIs are liquefied,
compressed gases that are in the gaseous
phase at atmospheric pressure but form
liquids when compressed
They are required to be nontoxic,
nonflammable, compatible with drugs
formulated either as suspensions or
solutions, and to have appropriate boiling
points and densities
36. 36
Nebulizers
A nebulizer is a device used to administer
medication to patient in the form of a mist inhaled
into the lungs
It is commonly used in treating cystic fibrosis,
asthma, and other respiratory diseases
There are two basic types of nebulizers:
The jet nebulizer functions by the Bernoulli principle by
which compressed gas (air or oxygen) passes through
a narrow orifice, creating an area of low pressure at
the outlet of the adjacent liquid feed tube. This results
in the drug solution being drawn up from the fluid
reservoir and shattering into droplets in the gas
stream
The ultrasonic nebulizer uses a piezoelectric crystal,
vibrating at a high frequency (usually 1–3 MHz), to
generate a fountain of liquid in the nebulizer chamber;
the higher the frequency, the smaller the droplets
produced
