Pulmonary Drug Delivery

Dr Mohammad Issa

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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

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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
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Anatomy and Physiology of the
Respiratory System

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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

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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

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Anatomy and Physiology of the
Respiratory System

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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

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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 9
Comparison of the lung epithelium
at different sites within the lungs

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Types of epithelium

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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)
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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
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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

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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
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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 16
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

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Pulmonary absorptive surfaces
 Protein therapeutics that are taken up by
macrophages can be rapidly destroyed in the
lysosomal 'guts' of the phagocytic cells

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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

Alveolar region
Mouth and throat

Airways

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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
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Systemic delivery of small
hydrophobic molecules
 Examples of rapidly absorbed inhaled hydrophobic
drugs include nicotine, 9-tetrahydrocannabinol
(THC), morphine and fentanyl

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Inhaled morphine (dose = 8.8 mg)
compared with intravenous injection
(dose = 4 mg) in human volunteers

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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

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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 25
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 26
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)
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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
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Pulmonary Drug Delivery Devices
 Dry Powder Inhalation (DPI) Devices

 The Pressurized Metered-Dose Inhalation

(pMDI) Device

 Nebulizers

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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 30
Dry Powder Inhalation (DPI)
Devices
 Most DPIs contain micronized drug blended
with larger carrier particles, which prevents
aggregation and promotes flow

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Principle of dry powder inhaler
design

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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
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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

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The Pressurized Metered-Dose
Inhalation (pMDI) Device

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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 36
produced
Jet nebulizer

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Ultrasonic nebulizer

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