Pulmonary Drug Delivery

Dr Mohammad Issa

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

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

Anatomy and Physiology of the

Respiratory System

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

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 24 mg is therapeutically equivalent to
100200 g 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 (0.20.7 m
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 1617 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 m 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 1214
alveolar macrophages, which engulf and try to digest
any insoluble particles that deposit in the alveoli

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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 octanolwater

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 octanolwater
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

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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

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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 3090 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 (2050%) 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

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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 13 MHz), to
generate a fountain of liquid in the nebulizer chamber; the
higher the frequency, the smaller the droplets produced

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Jet nebulizer

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Ultrasonic nebulizer

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