DRUG DELIVERY TO LUNGS
Physiology of respiratory system
Disorders of lungs
Strategies in pulmonary delivery
Challenges in pulmonary delivery
Approaches in pulmonary delivery
Control delivery of drugs to lungs
Interactions of excipients
Methods of aerosol analysis
Recent and future development
Pulmonary route possesses many advantages
over other routes of administration for the
treatment of specific disease states, particularly
lung associated large protein molecules which
degrade in the gastrointestinal conditions and are
eliminated by the ﬁrst pass metabolism in the liver
can be delivered via the pulmonary route if
deposited, in the respiratory zone of the
Devices used to deliver drug by pulmonary route
area based on one of three platforms pressurized
metered dose inhaler, nebulizer and dry powder.
Anatomy and physiology of the respiratory
Respiratory system of man consists
Upper respiratory tract:
Consists of nose, nasal passages, para nasal
sinuses, mouth, eustachian tube, the pharynx to the
esophagus, the larynx and trachea
Lower respiratory tract:
Consists of lungs (both air passage ways and
Lower respiratory tract
Human lung comprises of left and right lung, are
divided into slightly unequal proportions
Each lung is supplied by a major branch of the
The tissue substance of a lung includes air
passages, alveoli, blood vessels, connective tissues,
Pulmonary blood supply:
The total surface area of the alveolar capillary is
60-80sqm and capillary blood volume is 100-200
This large surface area permits rapid absorption
and removal of any substance that penetrate the
alveoli capillary membrane.
Thus they produce good sink conditions for drug
Lungs are highly permeable to water, lipophilic
materials and most gases.
And Hydrophilic substances with large molecular
size and ionic species have limited permeability.
The alveolar type-1 cells with their tight junctions
limit the penetration of molecules with a diameter
less than 1.2 nm.
The normal alveolar epithelium is almost
impermeable to protein and small solutes.
In contrast, micro vascular endothelium has
better permeation for substances over a large
range of molecular weight.
Advantages of pulmonary drug delivery:
Non invasive method .
Effective drug targeting to the lungs for relatively
common tract diseases such as asthma,
emphysema and chronic bronchitis.
Provides very rapid onset of action avoid
gastrointestinal tract problems such as poor
solubility, low bioavailability, gut irritability,
unwanted metabolites, food effects and dosing
Pulmonary drug delivery having very negligible
Strategies of pulmonary delivery:
Lung deposition and particle size:
Deposition of drug/aerosol in the airways
depends on four factors.
The physico chemical properties of drug
The delivery/liberative device
The patient (breathing pattern and clinical
The breathing parameters, such as breathing
frequency and tidal volumes also play a key role
in deposition of particles in lungs.
Lung deposition Occurs mainly by 3
mechanisms. They are
Where a bifurcation occurs in the respiratory
tract, the air stream changes direction and
particles within the air stream having, sufficiently
high momentum, will impact on the airway walls
rather than follow the changing air stream.
Particles > 5µm and particularly > 10µm
are deposited by this mechanism.
As the remaining small particles move on to the
central lung, the air velocity gradually decreases
too much lower values and the force of gravity
Particles 1-5 um are deposited.
Thus, gravitational sedimentation of an Inhaled
particle is dependent on its size and density in
addition to its residence time in the airways.
The finest particles enter the periphery of the lung
where they can contact with the walls of the
airways as the result of Brownian motion (particle
Particles smaller than 0.5 um are deposited. The
Drug absorption via the lung:
Major physiological factors that affect pulmonary
Mucociliary transport in the airways that
constantly drains fluid and solid particle (bacteria)
in a counter current flow to the oral cavity.
The epithelial cells in the alveoli are covered by a
thin layer of so called epithelial lining fluid. This
fluid is in turn is covered by a monolayer of lung
The epithelial cell layer forms the major barrier to
absorption of drug molecule.
After passing the alveolar epithelium, the
molecule enters the interstitium being part of the
extra cellular space in side the tissue.
Finally, for passage into the blood the molecule
have to pass the endothelial membrane of the
capillaries, separating the interstitial space from
Macrophages can also form a functional barrier for some
particular drug substances during pulmonary absorption.
For an efficient pulmonary absorption process, the alveolar
membrane seems to be an optimal absorption site for a
In contrast to the airways, there is hardly any Muco ciliary
clearance from the alveoli.
The alveolar membrane forms the largest surface area in
The area of the alveoli is 43-102 m2, which is large in
comparison to the surface area of the airways which have
cumulative area of about 2.5 m2.
The alveolar epithelium is thinner and leakier than
Challenges in pulmonary drug delivery:
Low efficiency of inhalation system:
Efficiency of presently available inhalation systems
has generally too low which is important challenge in
pulmonary drug delivery.
Optimum aerosol particle size is very important for
deep lung delivery. Optimum particle size for deep
lung deposition is 1‐5 mm. Aerosol system should
have to produce optimum size particles because they
are too small, they will be exhaled. If the particles are
too large, they affects on the oropharynx and larynx.
Less drug mass per puff:
To get adequate effect with the pulmonary drug
delivery practical delivery of many drug which
require milligram doses but with most existing
systems, the total amount of drug per puff delivered
Poor formulation stability for drug:
Most traditional small molecule asthma drugs are
crystalline and, in the case of corticosteroids,
relatively moisture resistant in the dry state.
They are also rather stable in liquids as
compared to most macromolecules, which are
unstable in the liquid state, amorphous, And
highly moisture sensitive in the dry state.
Improper dosing reproducibility.
Following are reason for Poor dosing
reproducibility like worsening of diseases’,
problem in device, unstability of formulation. To
get maximum dose reproducibility patient
education play important role.
Meter dose inhalers:
In MDIs, drug is either dissolved or suspended in
a liquid propellant mixture together with other
excipients, including surfactants, lubricants for the
valve mechanism and co solvents By this MDIS a
predetermined dose is released as a spray on
actuation metering valve.
Spacers and breath actuated MDIs:
Spacers are positioned between the MDIs and
the patient. The dose from an MDI is discharged
directly into the reservoir prior to the inhalation.
Disadvantage of spacers is they may
cumbersome. The breath actuated device
overcomes the coordination problem of
conventional MDI without adding bulk to the
device. However a substantial inspiratory flow
rate is required for its operation.
Dry powder inhalers (DPIs):
Dry powder systems are occasionally prepared
from the pure drug substance.
More frequently blend with lactose are prepared.
The lactose blends consist of respirable drug
particles and large (50-150) exicipient particles.
The excipient is included as diluents to aid in
dispensing the drug and as a fluidizing agent to
Current challenges facing the development of
these systems for macromolecules include
moisture control, efficient powder manufacturing,
reproducible powder filling, unit dose packaging
and development of efficient reliable aerosol
A) Flex haler B) Diskus
C) Disc haler
D) Hand haler E) Aerolizer
Precautions of DPI:
Keep your dry powder inhaler in a dry place at
Never place the DPI in water.
Never shake or breathe into the DPI.
Never use a spacer device with your DPI.
Unlike other inhaled medications, you may not
taste, smell, or feel the dry powder. This
experience may be different from what you are
used to. As long as you are following the
directions, you will get your full dose of
If you are using a corticosteroid medication, rinse
your mouth and gargle after using the DPI. Do not
Nebulizers are among the oldest devices used for
delivery of therapeutic agents.
These formulations are conforms to sterile
The mechanism of delivery is either air blast or air
jet and ultrasonic systems.
Droplet delivery from an air blast nebulizer is
governed by the surface tension, density and
viscosity of the fluid.
Current challenges facing the development of
liquid systems for macromolecules are
formulation stability, unit dose packing, high
payload delivery and development of efficient
Ultra sonic nebulizer:
How to use nebulizer:
Assemble the nebulizer according to its
instructions. These are the basic steps:
Connect the hose to an air compressor.
Fill the medicine cup with your prescription.
Attach the hose and mouthpiece to the medicine
Place the mouthpiece in your mouth. Breathe
through your mouth until all the medicine is used.
(Often this takes about 10 - 15 minutes). Some
people use a nose clip to help them breathe only
through the mouth. Others prefer to use a mask.
Wash the medicine cup and mouthpiece with
water, and air-dry until your next treatment.
Controlled delivery of drugs to lungs:
Sustained release from a therapeutic aerosol can
prolong the residence of an administered drug in the
airways or alveolar region, minimize the risk of
adverse effects by decreasing its systemic absorption
rate, and increase patient compliance by reducing
A sustained-release formulation must avoid the
clearance mechanisms of the lung, the mucociliary
escalator of the conducting airways and macrophages
in the alveolar region.
Liposomes, as a pulmonary drug delivery vehicle,
have been studied for years and used as a means of
delivering phospholipids to the alveolar surface for
treatment of neonatal respiratory distress syndrome.
More recently, they have been investigated as a
vehicle for sustained-release therapy in the treatment
of lung disease, gene therapy and as a method of
Large porous particles:
A new type of aerosol formulation is the large
porous hollow particles, called Pulmospheres.
They have low particle densities, excellent
dispersibility and can be used in both MDI and
DPI delivery systems.
These particles can be prepared using polymeric
or no polymeric excipients, by solvent
evaporation and spray-drying techniques.
Pulmospheres are made of phosphatidylcholine,
the primary component of human lung surfactant.
It has also been shown that Pulmospheres can
increase systemic bioavailability of certain drugs
Deep-lung delivery of therapeutic proteins:
For many years, medical science has been looking for
an alternative to injections for the delivery of
Due principally to their size, these molecules, mostly
proteins and peptides, cannot naturally and efficiently
pass through the skin or nasal membranes without
the use of penetration enhancers, such as detergents
or electrical impulses.
If administered orally, they are digested or degraded
before they reach the blood stream.
Therefore, oral, transdermal and nasal routes of
delivery are inefficient for these molecules.
In contrast, research has shown that many of those
same molecules are absorbed naturally and quickly
into the bloodstream if they are delivered to the deep
The body absorbs peptides and proteins into the
blood stream by a natural process known as
Transcytosis, which occurs deep in the lung.
Transcytosis allows drug molecules to move
across an impermeable cell membrane without
creating holes in the cells and destroying the
barrier. The process is performed by trillions of
tiny membrane bubbles, or transcytotic vesicles.
Small molecules and peptides are also thought
to be absorbed through the lung surface by an
analogous process called para cellular transport.
Both transcytosis and paracellular transport are
sophisticated cell processes mediated by
complex cell machinery.
The result of these two processes is a noninvasive means of delivering proteins and
peptides to the bloodstream with relatively high
bioavailability and without the use of penetration
Because the molecules are delivered rapidly into
the bloodstream, there is a much more rapid
onset of action than with any other non-i.V.
Methods of aerosol size analysis:
The regional distribution of aerosols in the airways
can be measured directly using gamma scintigraphy,
by radiolabelling droplets or particles, usually with the
short half-life gamma emitter technetium 99m
(99mTc). However, more commonly in vitro
measurements of aerosol size are used to predict
The principal methods that have been employed
characterization of aerosols are :
Time of flight
Phase doppler technique
Applications pulmonary drug delivery:
Pulmonary delivery could also be used for
delivery of vaccines.
Inhaled vaccines may be used to prevent
influenza, pneumonia, tuberculosis, measles,
cytomegalovirus, asthma, and mucosal-entry
diseases such as sexually transmitted diseases
Pulmonary delivery could also replace some oral
drugs due to the much faster onset of action with
improved absorption and avoidance of first pass
losses with delivery through the GI tract.
pulmonary delivery of macromolecule drugs like
protiens and peptides.
XOPENEX® (levalbuterol HCl) Inhalation Solution
ALVESCO® (ciclesonide) Inhalation Aerosol
OMNARIS® (ciclesonide) Nasal Spray
ZETONNA™ (ciclesonide) Nasal Aerosol
BROVANA® (arformoterol tartrate) Inhalation Solution
As more efficient pulmonary delivery devices and
sophisticated formulations become available,
physicians and health professions will have a
choice of a wide variety of device and formulation
combinations that will target specific cells or
regions of the lung, avoid the lung's clearance
mechanisms and be retained within the lung for
longer periods. The more efficient, user-friendly
delivery devices may allow for smaller total
deliverable doses, decrease unwanted sideeffects and increase clinical effectiveness and
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