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F
or last 4000 years it is known that inhaled
therapy for treatment of lung diseases
is superior to oral therapy. However,
making an ideal inhaler has been excessively
challenging mainly because of difficulty in
achieving appropriate particle size required for
lung deposition and making a safe medication
that does not lead to bronchoconstriction or
large systemic absorption. Invention of hundreds
of inhalers over last 4000 years has led to the
effective and safe inhalers of present day. India
is fortunate to have the widest range of inhaled
products available at cheaper costs compared to
rest of the world. Unfortunately, many patients
having obstructive lung diseases still continue to
rely on oral therapy or use inhalers incorrectly.
The major reasons are inadequate knowledge
and awareness of the prescribing physician,
lack of adequate patient education and cost
of inhalers. This issue of Respimirror covers
some excellent articles discussing clinically
important issues related to inhalation therapy.
Compared to oral therapy, delivery of drugs by
inhalation leads to rapid and direct deposition of
the drugs into the airways which allows high local
drug concentrations and limits systemic toxicity.
Hence, inhaled aerosol therapies administered
mainly through dry powder inhalers (DPI),
metered dose inhalers (MDI) and nebulizers are
the mainstay of treatment of obstructive lung
diseases. However, in order to have adequate
therapeutic efficacy patients must be able to use
the proposed device effectively. Studies have
shown that improper inhalation technique and
Drug Launcher
Dr. Rahul Kodgule, CRF
“We contend that no remedy, or
combination of remedies, however potent,
whether allopathically or homeopathically
administered through the medium of the
stomach has ever nor can ever cure a single case
of asthma. For the reason that they do not reach
the seat of the disease, their principal force is
spent upon the general system, and long before
they find their way to the lungs, their power
is lost.”
- Charles Broadbent, 1862
poor drug compliance are important causes of
loss of symptom control in asthma. A reduction
of 25% (due to poor compliance or improper
inhaler technique) in the time of usage of inhaled
steroids doubles the rate of hospitalization for
asthma. Poor compliance with treatment is the
most important cause (responsible for 61%) of
deaths due to asthma. Hence, educating the
patient about the disease, the importance of
treatment compliance and ensuring proper
inhaler technique are the cornerstones of
successful management of obstructive lung
Nitin Vanjare, CRF
A
vians are adapted to fly at great heights
and for longer durations. e.g. the Amur
Falcon can fly from Nagaland to South Africa
over a two months period, including a nonstop
flight for 3½ days over the Arabian sea. How
do they manage to do this, so efficiently? The answer is their
efficient and unique respiratory system. Their lungs are small
and rigid, they do not have a diaphragm but a network of air
sacs instead, no alveoli are present gas exchange occurs in air
capillaries. The respiratory system takes up about one fifth of its
body weight and the presence of air sacs makes the bird light
in weight and makes flying an easier task. The air sacs act as
bellows, which help in moving air in and out of the respiratory
system due to the pressure changes in the air sacs. In birds,
the air travels through the lungs in one direction (unidirectional)
unlike humans where the air travels in and out of the lungs by
the same pathway (bidirectional flow). Respiratory system of
birds is more efficient compared to humans i.e.more oxygen is
transferred with each breath. Along with oxygen the toxins in
air also get transferred more efficiently in the system. This is
one of the possible reason why Teflon fumes are toxic to birds
but not to humans at the same concentration.
diseases. A complete prescription for asthma
or COPD does not end by signing over it but
has to end by proper choice and training of
inhalers.
Choosing a right inhaler for the patient is
like finding a matrimonial match. All the forms
of inhaled therapy have equivalent efficacy and
hence, patient preference plays an important
role in choosing the inhaler. However, all the
aerosol inhalation devices have their own
strengths and limitations.
Dry powder inhalers (DPI) are the easiest for
the patients to understand and use, and consume
least time to train. Being breath-actuated,
DPIs lead to a more reliable drug delivery
with minimal training. Inhalation technique
mainly involves fast inhalation right from the
beginning and complete inhalation. However,
proper use of a DPI requires the patients to have
adequate inspiratory flow rates (>30 L/min)
which can be measured using an inspiratory
flow meter/in-check dial. Patients with very
severe obstruction and children below 5 years
of age may not be able to generate adequate
inspiratory flows to effectively use the DPI.
Metered dose inhalers (MDI) can be used by
patients with any severity of disease. Inhalation
technique mainly involves slow and complete
inhalation followed by a breath-hold of about 10
seconds. Effective use of MDIs requires proper
coordination during actuation and inhalation.
Hence, many patients fail to use the device
effectively. Another important problem with
>>Continued on page 8
Breathing in Birds
Fig : It takes two full inhalation-exhalation cycles for a specific volume
of air (blue) to pass through bird lungs.
Adapted from Bretz and Schmidt-Nielson, 1972
|Volume IV, Issue I, January 2014|RespiMirror 1
History of inhalation therapy
I
Ancient chinese treatment for asthma
nhalation route is the safest, fastest and
most effective way to administer drugs in
patients suffering with asthma and chronic
obstructive pulmonary disease (COPD), and
should be the method of choice in these
patients.” These are guidelines stated by the
Global Initiative for Asthma (GINA) and the
Global Initiative for Chronic Obstructive Lung
Disease (GOLD). And yet, several years before
these guidelines were even thought about, the
inhalation route of therapy existed.
Inhalation therapy in ancient times:
Roman Bath
It is interesting to learn how inhalation
therapy actually evolved to what we know
of it today. The very first traces of inhalation
therapy were seen in China in 2600 BC.
Inhaling fumes of Ma Huang was the prevalent
treatment then for asthma. It is now known
that Ma Huang actually contains ephedrine, a
potent bronchodilator. Around the same time,
ancient India practiced the inhalation of fumes
from burning Datura Stramonium and hemp, a
potent anti-cholinergic (scopolamine). As early
Dr. Komalkirti Apte, CRF
fumes to relieve asthma symptoms was strongly
advocated in 1802 which led to the invention
of asthma cigarettes. These were in use until
recently (1985).
However, the first concept of a device for
inhalational route of therapy was conceptualized
in 1654 by the English physician Christopher
Bennet. It bore a striking resemblance to the
Turbohaler® in markets today. A little over a
century later (1764), another English physician,
Philip Stern stated the use of inhalation route
of treatment for lung ailments. In the next
decade, English physician, John Mudge described
his invention of an inhaler to be used for the
treatment of a catarrhous cough using opium
vapors. The concept of this inhaler was to add
opium extract to boiling water in a pewter
tankard with a lid and a mouthpiece or vent
through which the patient would inhale the
vapors. The early 1800s brought in easier
ways to advocate inhalation therapy. Cavallo
suggested the use of a teapot for holding the
boiling liquid and the subsequent fumes and the
Ancient Inhaler
Ancient Greek treatment for asthma: inhalation of fumes
Asthma Cigarettes
made with rolled
‘dhatura’ leaves
2
RespiMirror|Volume IV, Issue I, January 2014|
as 1554 BC, ancient Egyptian Ebers papyrus
has shown evidence of inhalation of vapors of
black henbane (hyoscyamine), again a potent
anti-cholinergic. Roman Baths, natural hot water
springs in England, were a site of treatment for
several centuries since 836 BC. Geothermal
energy in the area heated the percolated rain
water to high temperatures. This heated water
would surface through fissures and faults in
the surrounding limestone along with fumes
infused with various minerals and chemicals.
Patients with respiratory complaints as well
as arthritic complaints benefitted immensely
from bathing at these hot springs.
Hippocrates (460-377 BC), in ancient Greece,
advocated the inhalation of vapors of herbs and
resins boiled with vinegar and oils through a
tube. Almost 10 centuries later, Rhazes (c850 AD
– c923 AD), a physician in Baghdad, advocated
the inhalation of arsenic vapors for medical
treatment. At the end of the 12th century (1190
AD), a Spanish physician Maimonides wrote
the first book on the treatment of asthma which
included inhalation of vapors generated from
herbs thrown into a fire.
The invention of inhaler devices:
The ancient Indian practice of burning
of Datura Stramonium and inhalation of the
spout for inhaling the vapors. This seemed to
be the inspiration for the subsequent Nelson’s
inhaler in 1865.
Pressurized metered dose inhalers:
The first powdered or pressurized inhaler was
invented by a French physician Sales-Girons in
1858. It involved the use of a holding chamber
which housed the liquid medication. A pump
handle mechanism similar to a bicycle pump
propelled the liquid medication through an
atomizer based upon the force of use.
A similar technique was used in the rubber
bulb vaporizer. The glass top is removed to
add the drops of medication into the rubber
bulb. After re-arranging the instrument, the
rubber bulb is squeezed to vaporize the liquid
medication for use through the inhalational
route.
The inhalational route of therapy gained
worldwide acceptance post a medical treatise
from the American physician Charles Broadbent
which stated that “the soothing and quieting
effects of these vapors is brought immediately to
act upon the parts locally irritated and diseases,
by gentle inhalation of the vapor from a bottle
arranged expressly for the purpose”.
In 1926, Erik Rotheim, a Norwegian engineer,
came up with a spray can which would effectively
>>Continued on page 3
>>Continued from page 2
English physician Christopher Bennet and his
drawing of an inhaler.
deliver liquids in an aerosolized manner. He
used this technique primarily for spraying
insecticides in farms. Philip Meshberg developed
a special valve called as the Meshberg valve.
This valve emitted a fixed dose of aerosol at
every actuation. This technology was then
used in hair spray cans and perfume sprays.
A young 13 years old, Ms. Susie Mason, a
known asthmatic used the rubber bulb vaporizer
in that era. Invariably, she would break the
apparatus very often prompting her father
to buy a new vaporizer every week. She had
observed her mother use hair sprays which
was made of metal and had the Meshberg
valve. In frustration, after having broken her
umpteenth vaporizer, she retorted to her father
to put her medicine in the metal and valved
spray can which her mum used for her hair.
This spearheaded the revolution in inhalation
therapy. Her father was a chemist with Riker
industries, now 3M Pharmaceuticals. Inspired by
his daughter’s demand, Mason along with Charles
Thiel, developed the first cold fill pressurized
metered dose device (pMDI). They used an
old cola bottle, a Meshberg valve and Freon
from an old refrigerator as the propellant. This
device was then used for the first time as an
inhaler device for the drug Vitamin C. By 1956,
isoprenaline and adrenalin were approved for
use through the pMDI and were marketed as
Medihaler-iso and Medihaler-epi respectively.
Dry powder devices:
The first dry powder inhaler was patented
in 1864 by an English physician Newton. He
had then observed that the powder to be
used in this manner needed to be very finely
pulverized and kept dry at all times. Today,
we know that these are the prerequisites of all
dry powder inhalers. Frederick Roe patented
another dry powder device called the Carbolic
Smoke Ball. This could be refilled at repeated
intervals. Soon dry powder devices were also
patented. The first to arrive in the market were
rotahalers (single dose) and diskhalers (multi
dose). The single dose inhalers evolved from
every pharmaceutical company. Today there is
a wide range of single dose dry powder inhalers
such as revolizer, handihaler, lupihaler, redihaler
and many more. Complications of recharging English physician John Mudge and his pewter
for every dose were tackled by inventing a tankard inhaler which contained hot medicated water
device which could store a certain number
of doses. This brought about a revolution in
dry powder inhalers. These newer devices
were called multi dose inhalers and today we
have a large variety of multi dose dry powder
inhalers such as accuhaler, easyhaler, novolizer,
turbohaler, multihaler and more.
Nebulizers:
Nebulizer therapy also initiated in the
early 1860’s. The story of the hot springs is
what brought about a revolution in nebulizer
therapy. As mentioned previously, patients with
respiratory and arthritic complaints benefitted
immensely from the fumes emitted at the
hot springs. Some patients however could
not reach the hot springs due to their disease
conditions. This is when people then began
to transport the water from the hot springs to
the patient. A pump would infuse the chemical
and minerals into the water before the patient
would inhale the steam. German physician,
Siegle patented the steam spray which used the
Venturi principle to atomize liquid medication.
This was the first form nebulization. The effect
of the droplet size on the lung penetration was
noticed in 1878. Today, we have come a long
way to understand the correct droplet size for
effective nebulization.
Inhalation therapy has come a long way in
the past centuries. Newer and improved devices
are being invented and would be in the public
domain soon. This has drastically improved
patient outcomes in the field of obstructive
airway diseases.
First pMDI
Carbolic Smoke Ball
First Nebulizer
|Volume IV, Issue I, January 2014|RespiMirror 3
DO DOCTORS KNOW HOW TO USE INHALERS CORRECTLY? Dr. Sneha Limaye, CRF
D
espite the great benefits offered by the
wide range of aerosol therapy available
in country, a huge percentage (more
than 70%) of Asthma & COPD patients are
never prescribed inhaled medications. A major
reason for this can be attributed to the fact that
many doctors themselves are unaware of the
correct inhaler techniques. Inefficient inhaler
technique is a common problem resulting in
poor drug delivery, decreased disease control,
non adherence and increased inhaler use
ultimately resulting in shifting the patient back
to oral therapy for control and management
of symptoms.
Chest Research Foundation conducted
a study amongst qualified and in-training
doctors and nurses from a tertiary care
teaching hospital in Pune to understand their
knowledge, skill and perceptions about inhaler
use. The study group consisted of 100 final
year MBBS students, 100 Interns, 50 PostGraduate Students (Medicine, Pediatrics and
Chest), 107 qualified nurses and 53 qualified
physiotherapists. Every participant was given a
placebo inhaler and requested to demonstrate
the technique of using a pMDI and scoring was
done to see if every step was followed properly.
A questionnaire was used to understand their
perceptions about inhaler use. In a shocking
revelation, about 50% of the doctors, nurses
and physiotherapist believed that inhalers
were addictive. It was more worrying to learn
that less than 1 percent of the entire study
population (doctors and nurses) knew how
to use an inhaler correctly. The best were the
postgraduate students of respiratory medicine.
9% of them knew how to use inhalers correctly.
If majority of the doctors believe that
inhalers are addictive and less than 1% know
how to use a pMDI correctly, one can only
imagine what must be happening in clinical
practice. Doctors need to be educated about
how to use inhalers correctly and their
importance in the management of asthma
STEPS FOR MDI USE
and COPD. Many doctors complain time
of constraints due to busy OPD and patient
care and despite understanding the need
for communication and patient training on
devices, are not able to devote enough time
to explain the correct techniques. The most
feasible solution for this is train your nurse
or hire and train an educator for your clinic/
hospital. Any of the existing staff members can
also be identified and trained by the doctor in
correct use of inhalers and devices. Once the
doctor has written a prescription, the nurse/
educator can spend the required amount of
time in training the patient on the prescribed
inhaler device and also counsel the patient to
dispel the myths associated with inhaler use.
STEPS FOR DPI USE
1. Remove protective cap and shake the inhaler
1. Prepare the inhaler before usage
2. Hold inhaler upright
2. Keep inhaler horizontal
3. Exhale to residual volume
3. Exhale to residual volume
4. Place mouthpiece between lips and teeth
4. Place mouthpiece between lips and teeth
5. Inhale slowly and simultaneously activate the canister
5. Inhale forcefully and deeply
6. Continue slow and deep inhalation
6. Take the inhaler out of the mouth
7. Hold breath for 5-10 Sec
7. Hold breath for 5 s
Practical Updates for
Respiratory PGs via Web
16th Purview
Announcement
Topic:
Systemic Manifistations
of COPD
Date :15th March 2014
Time : 5 to 7.30 pm
15th Purview on Obstructive Sleep Apnoea, CRF, Pune, 4th Jan 2014
4
RespiMirror|Volume IV, Issue I, January 2014|
log on to www.crfindia.com
to attend this webcast
O
Types of Inhaler Devices Ms. Monika Chopda, CRF
ne of the biggest advancements in the
management of Obstructive Airways
Diseases has been the delivery via the
aerosol route. This has revolutionised the way
asthma and COPD are treated. One of the
earliest inhaler devices to be introduced was the
nebulizer. Subsequently the dry powder inhalers
and metered dose inhalers were developed,
and more recently the small volume nebulizers
have been introduced to deliver drugs directly
to the airways.
There are at least 65 different types of inhaler
devices that are available through which one
can deliver at least 20 different types of drugs
including short, long and very long acting betaagonists, anticholinergics and steroids for the
treatment of asthma and COPD. This route of
delivery is also used to administer antibiotics
to the lungs as well as insulin, other hormones
and anaesthetics.
The principle 4 types of inhalation devices
that are widely used are:
1. Metered dose inhalers ( MDI)
2. Dry powered inhalers (DPI)
3. Small volume Nebulizers
4.Nebulizers
1. Metered dose inhalers (MDI):
This is the most widely available and used
inhalation device for the treatment of OAD’s. It
contains propellants, surfactants, solvents, ethyl
alcohol & the active drug. The active drug is
either in a solution or suspension under pressure.
On activation, the metered valve dispenses a
fixed volume of the suspension or solution.
MDI’s contain between 100-200 doses that
can last for one to several months. MDI’s are
small, easy to carry and relatively cheap (cost
per dose) than other inhaler devices.
Facts of inhalers
1) Speed : The speed with which plume comes
out after activation is 160km/h. One needs to
co-ordinate inhalation with actuation, which
not many people can do effectively.
2) Temperature of plume: The temperature
at which the drug comes out from pMDI after
actuation is -20°C. If you put your finger you will
feel the temp -20 degrees. When the plume comes
Pressurized MDI
Physical
Components
Metal Can
Elastomers
Valve
Actuator
Formulation
Drug
Substance
Propellants
Surfactants/
Co-solvents
Canister
Plastic
Mouthpiece
Metering
Valve
Spray
Orifice
out it has a temp of 0°C. This low temperature
is the reason for Cold Freon effect of pMDI’s.
This temperature may cause bronchospasm in
some patients leading to sudden cough after
taking inhaler.
3) Propellant: The Propellant are the most
important parts of the inhaler. One of the
most commonly used propellants over the
years has been chlorofluro carbon or CFC. It
is also used in whole host of other industries.
In the 1980’s it was realized that because of the
widespread use of CFC’s, there was an Ozone
hole formed in the Stratosphere. This is because
CFC’s deplete ozone and the ozone layer in
the stratosphere protects us against the UV
radiation from the sun. As a result, a resolution
was made that CFC’s will be phased out from
all the industries including inhaler industry.
It is nowadays mandatory to manufacture all
MDI’s with a non CFC propellant.
Now use of CFC has been actually shown
to be harmful to the earth because it can cause
Ozone hole in the Stratosphere. Because of
this all CFC propellants are replaced with non
CFC propellants. One of the newer non CFC
propellants used is HydroFluoroAlkane (HFA).
Many of you may have started using inhalers
with the HFA propellant.
There are three important points one should
know while shifting a patient from CFC inhaler
to HFA inhaler.
Advantages of HFA over CFC
1) Different taste: HFA MDI’s contain a small
amount of ethanol. Adding ethanol changes
the active properties of meter dose inhaler like
the taste of the inhaler, speed of the plume etc.
There are chances that patient may complain
that the new HFA inhaler tastes different. Plume
will tests sour & the speed with which plume
comes out is much slower in HFA propellant as
compare to CFC because of ethanol contained
in it.
2) Plume is warmer (less cold Freon effect):
The plume from HFA inhaler is warmer
as compare to the plume from CFC inhaler.
Due to this patient feels less cold Freon effect
with HFA inhaler as compare to inhaler with
CFC propellant.
(1, 2 are the important differences patients
will notice when the inhaler is changed from
CFC to HFA propellant).
3) After 12 wks change the HFA inhaler: It is
also important to know that all HFA propellants
need to be stored at 0-4degre before they
are dispensed. Once it is dispensed at room
temperature they should be ideally used within
12 weeks because their shelf life remains only
for that period of 12 weeks. After 12 weeks it
is wise to change the inhaler.
Speed with an MDI needs to be inhaled:
It is important to appreciate the fact that
while using pMDI the inhalation should be
slow & deep.
How to overcome co-ordination problem?
To overcome the co-ordination problem
& to improve deposition different types of
accessory devices and advanced inhalers are
developed like Spacer, Neohaler, and Breath
activated MDI’s.
a. Spacer: Many patients can’t coordinate
actuation with inhalation so there is need of
an accessory device called as a spacer. Spacers
|Volume IV, Issue I, January 2014|RespiMirror 5
make aerosol inhalers easier to use and more
effective. Spacer traps the medicine inside, so
patients don’t have to worry about pressing
the inhaler and breathing in at exactly the
same time. There are two types of spacer, a
large and small volume. The material of the
spacer can be static or non-static. Now-a-day’s
non-static inhalers are widely used. On page 9,
Dr. Monica discusses this in detail.
b. Neohaler: It has a small spacer like chamber
at the bottom which actually reduces the speed
of the drug that comes out.
c. Breathe Activated MDI’s: Recently breathe
activated inhaler devices has been introduced
to overcome the problems of co-ordination.
These are called as Breath activated metered
dose inhaler. The patient needs to activate the
device by pulling the red tag upwards & when
patient start inhaling; device automatically
releases single dose of the drug. So there is
no question of bringing up co-ordination with
this device.
medication solution is forced through it, two
fine jets of liquid are produced. The two jets
of liquid converge at an optimised angle, and
the impact of these converging jets generates
the soft mist. This mist is extremely fine (the
majority of the droplets fall into the fine particle
fraction of 5.8 µm average). It moves slowly,
which is the basis for many of its potential
benefits. It has high lung deposition with the
Soft Mist Inhaler
Mouthpiece
Uniblock
Dose-release
button
Capillary tube
Upper housing
2. Dry Powder Inhaler (DPI):
DPI is a device used for generation of
aerosol powder by the patient’s inspiratory
effort. First DPI used was with penicillin to
treat pneumonia a way back. Now whole host
of DPI’s are available. In the DPI’s the drug is
mixed with a powder, usually lactose, and then
it is packed in gelatin capsules. After breaking
or piercing the capsule releases the power. Then
patient needs to breathe in rapidly. Due to the
air currents generated by the patient’s breath,
the drug particles get deaggregated and are
carried into the lungs along with the inspired
air. DPI is available in unit dose & multidose.
Dry Powder Inhaler
Hole for
inserting
rotacap
Mouthpiece
Tin
Rota Chamber
DPI has unique advantages over PMDI:
• DPI’s doesn’t require coordination after
activation,
• DPI’s doesn’t contain CFC so it is
environmental friendly
• Many people find it is very easy to use
The only problem with DPIs is that patient
needs to generate sufficient energy to suck this
drug into the airways. Patient needs to inhale
with more force to bring the drug out. Particles
in powder are aggregated; the only way they
will deaggregate in smaller size is by the force
inspiratory efforts.
3. Small Volume Nebulizers:
Small Volume Nebulizers (Soft Mist Inhaler)
has a unique delivery mechanism, which is
propellant-free and delivers a metered dosage
of medication as a fine mist. It is the nozzle
system that provides the Soft Mist. When the
6
RespiMirror|Volume IV, Issue I, January 2014|
Transparent base
Spring
Cartridge
associated reduced oropharyngeal deposition
and no requirement for forceful inspiration.
Due to the very low velocity of the mist, the
Soft Mist Inhaler in fact has higher efficiency
compared to a conventional MDI.
4. Nebulizer:
Nebulizers use oxygen, compressed air or
ultrasonic power to break up medical solutions
and suspensions into small aerosol droplets that
can be directly inhaled from the mouthpiece
of the device. The definition of an aerosol is a
“mixture of gas and liquid particles,” and the
best example of a naturally occurring aerosol
is mist, formed when small vaporized water
particles mixed with hot ambient air are cooled
down and condense into a fine cloud of visible
airborne water droplets.
The liquid drug to be nebulized is put in the
nebulization chamber, which is then attached
to the compressor with the help of a connecting
tube. A mask or a mouthpiece is then attached
to the chamber to aid inhalation. The mist thus
generated is inhaled by the patient either through
the mouth using a mouthpiece or through the
nose, using a face mask.
The first “powered” or pressurized inhaler
was invented in France by Sales-Girons in 1858.
This device used pressure to atomize the liquid
medication. The pump handle is operated like
a bicycle pump. When the pump is pulled up, it
draws liquid from the reservoir, and upon the
force of the user’s hand, the liquid is pressurized
through an atomizer, to be sprayed out for
inhalation near the user’s mouth.
In 1864, the first steam-driven nebulizer
was invented in Germany. This inhaler was
known as “Siegle’s steam spray inhaler”. The first
electrical nebulizer was invented in the 1930s
and was called a Pneumostat. In 1964, a new
type of electronic nebulizer was introduced:
the “ultrasonic wave nebulizer”.
Types of Nebulizers:
a. Large volume Nebulizers
Large volume nebulizers are used to turn
liquid in to the mist so that it can be inhaled
or to deliver the mist required to moisturise
the patient’s airways in the patients with thick,
tenacious secretions, with any of the following
indications:
a) Administration of pentamidine to patients
with HIV, pneumocystosis, and complications
of organ transplants
b)Bronchiectasis
c) Cystic fibrosis
d) Tracheobronchial stent
e)Tracheostomy
A large volume nebulizer and related
compressor are considered experimental and
investigational for all other indications because
their effectiveness for indications other than
the ones listed above has not been established.
b. Jet nebulizer
The most commonly used nebulizers are Jet
nebulizers, which are also called “atomizers”.
They use compressed air to generate a fine mist.
Jet nebulizers are commonly used for patients
in hospitals who have difficulty using inhalers,
such as in serious cases of respiratory disease,
or severe asthma attacks. The main advantage
of the jet nebulizer is its low operational cost.
The noise (often 60dB during use) and heavy
weight are however still the biggest drawbacks
of the jet nebulizer.
c. Ultrasonic Nebulizers
Ultrasonic wave nebulizers were invented
in 1964 as a new more portable nebulizer. An
ultrasonic nebulizer does not use compressed
air; instead, an ultrasonic nebulizer uses high
frequency vibrations to aerosolize the medication
into a very fine mist. Since ultrasonic nebulizers
don’t compress air, they operate very quietly,
tend to be much smaller in size, and can fit
in nearly any container. The only drawback
is medication restrictions because heat is
transferred to the medication
Which is a better device?
There are so many different types of inhaler
devices available. From an efficacy point of
view all of them are similar. They all produce
the same effect. If patients can not generate
sufficient inspiratory flow then DPI will be
less helpful similarly if co-ordination is not
good only MDI will be less effective so pMDI
can be used with spacer. Now a day’s one good
replacement to MDI plus spacer is use of breathactivated meter dose inhaler.
Pooled meta-analysis of 394 clinical trials
between the years 1982 – 2001, showed that there
is no significant difference between devices in
efficacy outcome & in patient group for each
of the clinical settings that were investigated.
Both study groups showed similar adverse
event profile.
Let the patient decide which inhaler to be
used because 1) if a patient does not like the
inhaler device or is unable to use it correctly, it
is useless. 2) A preferred device that is taken by
the patient and is effective represents a better
value for money.
How inhalers are made?
Introduction
Pharmaceutical aerosols have been playing
an important role in the health and well being
of millions of people throughout the world for
many years. The origin of inhaled therapies
can be traced back 4000 years ago to India,
where people smoked the leaves of the Atropa
belladonna plant to suppress cough. In the 19th
and early 20th centuries, asthmatics smoked
asthma cigarettes that contained stramonium
powder mixed with tobacco to treat the symptoms
of their disease1. People suffering from chronic
obstructive pulmonary disease (COPD) or other
lung conditions often take their medications
through inhaled drug delivery systems.
Administration of drugs by the pulmonary
route is technically challenging due to high
oral deposition and variations in inhalation
technique which can affect the quantity of drug
delivered to the lungs. Therefore, there have been
considerable efforts to provide more efficient
and reproducible aerosol systems through
improved drug delivery devices and through
better formulations that disperse more readily
during inhalation.
Formulation Design
Metered dose inhaler formulation
The pressurized Metered Dose Inhaler
(pMDI) consists of a pressurized canister inside
an actuator. Drugs in pMDIs take the form of
either particulate suspensions or solutions. The
pMDI comprises several components each of
which is important to the success of the whole
device as shown in Fig 1.
Fig. 1. Schematic of typical pressurized Metered-dose inhaler.
Invited article by
Ms. Geena Malhotra, Ms. Pragati Rege, Cipla
process. The most useful technique to reduce
particle size is by Jet milling (or air-attrition
milling). The pMDIs are formulated with
chlorofluorocarbons (CFCs) propellants along
with micronised active ingredients but current
global regulations require pharmaceutical
aerosols to be reformulated to contain
non-ozone-depleting propellants. The two
current alternatives to CFC propellants for
pharmaceutical aerosols are hydrofluorocarbon
(HFC) 134a (also known as hydrofluoroalkane
(HFA) 134a or 1,1,1,2- tetrafluoroethane),
and HFC-227ea (HFA-227a or 1,1,1,2,3,3,3heptafluoropropane)2.
Advantages:
• Small size, portable, unobtrusive
• Quick to use
• More than 100 doses available
• Pressurization of contents protects against
moisture and bacteria
Disadvantages:
• Require propellants
• Drug delivery highly dependent on good
inhaler technique
• Possible to get no drug in lungs with bad
inhaler technique
• Most products have low lung deposition
• Most products have high oropharyngeal
deposition
Dry powder inhaler formulation
Development of Dry Powder Inhalation
Formulation (DPI) is of a particular challenge, as
it involves the preparation of a formulation and
the selection of a device for aerosol dispersion
(Martin et al Respiratory care; September 2005;
Vol 50;No 9). DPIs were designed to eliminate
the co-ordination difficulties associated with
the MDI ( Labiris et al. Br J Clin Pharmacol.56,
600–612).DPI medications are taken in the
form of a dry powder, using a dry powder
inhaler, which is also a handheld device. A
DPI delivers medication to the lungs as you
inhale through it. It doesn’t contain propellants
or other ingredients. There is a wide range of
DPI devices in the market, from single-dose
devices loaded by the patient (e.g. Rotahaler)
to multiunit dose devices (e.g. Diskus, MultiHaler) or reservoir-type (bulk powder) systems
(e.g. Turbuhaler).
Most DPI formulations consist of micronized
active ingredient (particles below 5 micron
process by jet milling) blended with larger carrier
particles (preferably Lactose), which enhance
flow, reduce aggregation, and aid in dispersion.
A combination of intrinsic physicochemical
properties of lactose with active ingredient
such as particle size, shape, surface area, and
morphology affects the forces of interaction
and aerodynamic properties, which in turn
determine fluidization, dispersion, delivery
to the lungs, and deposition in the peripheral
airways.
When a DPI is actuated, the formulation
is fluidized and enters the patient’s airways.
Under the influence of inspiratory airflow,
the drug particles separate from the carrier
particles and are carried deep into the lungs,
while the larger carrier particles impact on
the oropharyngeal surfaces and are cleared.
Advantages of the Dry Powder Inhaler
• Environmental sustainability, propellant-
free design
• Requires less patient coordination required
Disadvantages of the Dry Powder Inhaler
• Deposition efficiency dependent on patient’s
inspiratory airflow
• Potential for dose uniformity problems
• Development and manufacture more
complex/expensive
Assessment of drug delivery
The inhalation aerosol formulations are
characterized to find out its physicochemical
properties with the suitable analytical method.
Crystallanity of the micronised active
ingredient drug particles is examined by
X-ray diffraction and by Differential Scanning
Colorimetry. Particle size and its distribution
are measured with laser diffraction techniques.
Fig. 2. Principle of dry powder inhaler design.
These key components are:
• API (micronized Active Ingredient)
• Surfactant, bulking agent & Co-solvent
(Optional)
• Propellant (CFC’s, HFA134a/HFA227)
• Container
• Metering valve
• Actuator
The quality of pMDI & DPI could be
influenced by a variety of factors associated
with these components, of which particle size of
the micronized active ingredient is a key factor,
because particles below 5 microns are required
for lung deposition. To create particles in the
expected size range of below 5 micron diameter,
the active ingredient undergoes micronization
Powder Reservoir
(e.g. Turbuhaler)
Blister disk
(e.g. Rotadisk)
Passive
Active
Blister strip
(e.g. Diskus)
Capsule
(e.g. Rotahaler)
Formulation
Metering
Dispersion
Passive/Active
Oropharyngeal Deposition
Pulmonary Delivery
|Volume IV, Issue I, January 2014|RespiMirror 7
Particle morphology is measured by scanning
electron microscopy. Water content in the blend
is measured by using Automatic Karl-Fischer
Titrator. Dosage unit sampling apparatus
(DUSA) is used for sampling and testing of
dry powder inhaler. Drug content and solubility
is analyzed with LC-MS, HPLC, UV or other
suitable system. Bulk density, Tap density, and
Carr’s index have to be determined to evaluate
powder flowability(Kumaresan Pharma Times
- Vol. 44, No.10, October 2012).
Conclusion:
Fig. 3. Anderson Cascade Impactor - Simulation of the
Human Respiratory System
Does drug deposition affect clinical decision making?
P
Inhalation is the preferable way of drug
delivery to the respiratory tract for the
treatment of respiratory disease. The choice
of inhaler device is most important in the
treatment of asthma and COPD.
Dr. Rahul Kodgule, CRF
hysicians are often confronted with marketing
efforts from pharmaceutical companies
claiming better drug delivery through their device.
Almost all the dry powder inhalers (DPI) and
metered dose inhalers (MDI) deliver about 5-25%
or even more drug into the lungs if used properly.
The question often arises whether an inhaler
delivering 25% drug into the lungs is better than
the inhaler delivering only 10% (note: deposition
in lung means deposition below vocal cords).
Hundreds of studies and dozens of meta-analyses
have clearly found that the differences in devices
or particle deposition do not affect symptoms, lung
function and exacerbation/hospitalization risk.
Most of the studies, comparing several devices
having different percent particle deposition in
the lung and when used to deliver same dose
of bronchodilator, found that the improvement
in symptoms and lung function is same with
any of the device. As a result differences in the
amount of drug deposition are presently irrelevant.
Hence, choosing an inhaler with better lung
deposition is not as important.
What matters to some extent, is the distribution
of deposition of drug particles in the lungs. Larger
particles are deposited in the upper respiratory
tract and larger airways while smallest ones
reach the lower airways and alveoli. Large and
mid-sized airways have larger smooth muscle
mass and are more amenable to bronchodilator
effects. Hence, targeting larger airways with
bronchodilators having larger aerodynamic
diameter (size) may be a useful strategy. It is
shown that as the aerodynamic diameter of the
bronchodilator particle increases (maximum up
to 10µg) the bronchodilator response increases.
Most of the available inhaled bronchodilators
have similar sized particles and hence there is
hardly anything to choose from.
However, the opposite is true with
corticosteroids. The predominant sites of
inflammation in asthma and majorly in
COPD are peripheral airways and alveoli.
Hence, it is important to achieve delivery of
anti-inflammatory drugs in this region. Antiinflammatory molecules of smaller sizes like
Ciclesonide and Beclomethasone can reach
peripheral lung. In addition smaller molecules
are likely to have lesser deposition in upper
respiratory tract leading to lesser systemic
absorption. However, smaller molecules also
get absorbed from the lung in to the systemic
circulation leading to systemic effects. Ciclesonide
is a pro-drug which gets activated only in the
lung and is rapidly eliminated from systemic
circulation. This means ciclesonide is likely to
be more effective and safe. However, at present
there are no well designed clinical trials published
that suggest Ciclesonide or Beclomethasone
lead to better clinical improvements or are safer
than other corticosteroids.
In nutshell, inhaler devices are not major
determinants of clinical outcomes in patients.
Rather, what is known to be most important
determinant of clinical outcomes is proper
technique of inhaler use and good compliance
with inhaled drugs. It has repeatedly been shown
that poor inhaler technique leads to lack of
control in asthma or poor bronchodilation in
COPD. Hence, it is important that the right
device is chosen for each patient, the patient
should like and understand the device usage,
the patient should be effectively able to use the
device and the patient should remember the
inhalation technique over a period of time.
Drug Launcher
their use. However, nebulizer use demands only
normal tidal breathing and is highly convenient
for use in the hospitals. Nebulizers are also
least efficient as most of the drug coming out
is either lost to the atmosphere or is retained
in the nebulizer while only a modest amount
(2-4%) reaches lung. During emergencies drugs
can be administered with an MDI or DPI in
one minute while a nebulizer may take 5-15
minutes for drug administration.
another problem which is further compounded
by confusion of using several inhalers. This
has led to the development of combination
inhalers. Combination of rapid and long-acting
bronchodilator with inhaled steroid in a single
inhaler for asthma and combinations of longacting beta-agonist, long-acting anti-muscarinic
and anti-inflammatory drug for COPD are
now available. Using combination inhalers has
not only been shown to increase therapeutic
efficacy, but also improves compliance with
therapy.
Developing novel and more effective drugs
for asthma and COPD appears to be difficult
at present. However, a lot of research is taking
place to improve the delivery of available drugs
to the lungs. Development of newer devices for
drug delivery holds promise for better clinical
outcomes in these diseases. All the efforts
towards developing effective and safe drugs
and delivery systems need to be complimented
by motivated efforts by the physicians toward
improved drug and inhaler acceptance and
compliance.
>>Continued from page 1
the use of MDIs is that the patients do not know
when the inhaler got emptied. Hence, MDIs
with dose-counters should be preferred. During
actuation of an MDI pressurized propellant
expands and evaporates out of the device. This
accelerates the drug particles to high speeds
(around 33 m/s) and leads to cooling of these
particles to temperatures below freezing point.
These particles then hit the back of the throat
and prematurely stop inhalation causing a
“Cold Freon” effect. Use of a spacer along with
the MDI prevents the problems related to
co-ordination and Cold Freon. In addition, use
of spacer also reduces drug deposition in the
mouth and hence, any adverse effects related
to oral deposition.
Use of nebulizers should be reserved for inhospital management. An important problem
with at-home use of nebulizers is infection of
the device and clogging of the system leading
to inefficient drug delivery. Nebulizers are also
bulky, expensive and dependent on power for
8
RespiMirror|Volume IV, Issue I, January 2014|
Hence, the inhaler devices should be
chosen smartly and patients must be trained
efficiently. Compliance with inhaler therapy is
SPACERS: USEFUL DEVICES FOR INHALATION THERAPY
I
nhaled medications delivered in aerosol
form is widely prescribed for the treatment
of Obstructive Airways Diseases, both
Asthma and COPD. The Pressurized Metered
Dose Inhaler (pMDI) has emerged as one of
the most useful devices amongst all the inhaled
drug delivery systems and is popular due to
its convenience, portability and efficiency.
However it comes with its own drawbacks,
the most important ones being the need
for actuation inhalation coordination, high
oropharyngeal deposition and cold-freon
effect.
Scientists realized that these issues could be
overcome by introducing devices which will
slow down or space the aerosol dispersion
between the patient and the pMDI. Numerous
pMDI accessory tubes, cylinder drums and air
chambers have been developed to overcome
this drug delivery deficiency.
Advantages of using a spacer are:
1. Spacers act as holding chambers for the
drug once it is actuated thus eliminating the
need for actuation inhalation coordination
by the patient. The patient can inhale after
a delay of a few seconds (not more than
10 seconds).
2. Because of this, spacers are extremely useful
for patients of the pediatric as well as
geriatric age groups for whom even a dry
powder inhaler is a challenge to take.
3. Spacers reduce the aerosol velocity as well as
the particle size of the aerosol thus
decreasing the oropharyngeal impaction
of the drug and reducing the complications
of oropharyngeal candidiasis, dysphonia
and cold freon effect.
4. Spacers create a more natural respirable
flow. By maneuvering medicine past the
upper airways spacers help pMDI’s deliver
more medicine to the lungs.
5. Spacers have been found to be as effective as
nebulizers in controlling an acute
exacerbation of Asthma.
The modern day spacer which is a valved
holding chamber made of non-static material
and is transparent has actually gone through
several levels of development. Spacers were first
developed by Newman et al in 1981 described
as extension chambers or holding chambers
that decreased oropharyngeal deposition.
These spacers were made of various materials
including plastic and metal and came in
various shapes like accessory tubes, cylinder
drums, collapsible bags and air chambers.
The holding chambers were of large volumes
between 600 to 800 ml. The most widely used
shapes and material were cylindrical and
plastic respectively. It was later observed that
the movement of inhaler-generated aerosols
is significantly influenced by electrostatic
charge on the particles and on the adjacent
surfaces. Spacers and valved holding chambers
used with pressurized metered dose inhalers
were shown to have electrostatic charge
which increases variability in the amount of
medication available for inhalation, and hence
inconsistent medication delivery. Conditioning
the device by washing it with a conductive
surfactant (detergent) or by deposition of
the drug particles on the surface were some
of the earlier methods to combat the loss of
drug due to electrostatic charge till scientists
came up with the newer non static material
which allowed for lesser drug deposition on
the walls of the holding chambers. It was
once again Newman et al who showed that
the deposition of aerosol in the whole lung is
improved by using a pear shaped spacer rather
than a tubular spacer. Valves were added to
spacers to ensure one way flow of the inhaled
air. This is important because otherwise, the
aerosol particles will absorb moisture from the
exhaled air, become heavier and settle down,
thus becoming unavailable for inhalation.
Thus features of the modern day spacer are
as follows:
Important practical notes:
•
•
•
•
Spacers of one company should be used
only for pMDIs of the same company to
avoid issues of leakage of drug due to
improper fitting of the spacer to the pMDI.
If two doses are advised using a spacer, the
doses should be actuated separately with
a gap of 1 minute between the two doses.
A spacer should be prescribed even
for adults when high doses of inhaled
corticosteroids are to be administered.
For children less than 3 years, the spacer
should be used along with a baby mask. The
mask should be held in place for at least one
Dr. Monica Barne, CRF
minute and the child may breathe normally
• When using with a mask, ensure that the
child generates sufficient peak inspiratory
flow rate to open the valve during
inhalation.
• In case a child cannot generate sufficient
inspiratory flow, the spacer may be tilted
upwards slightly so that the valve opens
up by gravity and the drug is made available
for inhalation. In this case, the spacer would
then behave like a non valved spacer.
• Children older than 3 years and who can
generate sufficient inspiratory flow rate,
may hold the mouthpiece in his/her mouth
directly without using the mask.
• In resource limited and economically
challenged settings doctors are tempted to
advise the patients to use homemade
spacers with the help of plastic/thermacol
cups or empty plastic bottles cut into
half. When considering the various feature
that have been incorporated to develop a
most efficient spacer, one may realize how
inadequate a plastic bottle may be to be
used as a spacer. One should always insist
on a proper spacer.
• A child should never be given a pMDI
without a spacer and only with a mask.
Not only will the drug made available for
inhalation be reduced but most of the
drug will get deposited on the face and
in the eyes resulting in complications like
thinning and bruising of facial skin as well
as ocular complications of steroids.
Care and maintenance of spacer devices:
It is very important to clean the spacers
regularly not only to ensure maintenance of
the zero-static coating but also because in
some recent studies spacers have been shown
to culture Methicillin Resistant Staphylococcal
Aureus Bacteria.
|Volume IV, Issue I, January 2014|RespiMirror 9
•
•
•
•
•
•
Spacers should be washed under running
tap water once every week.
No detergents or warm water to be used
as they will destroy the electrostatic coating
of the spacer.
After washing, the spacer should be shaken
to remove any excess water.
Leave it for air drying indoors.
Never should the spacer be wiped dry as
this also destroys the non-static coat.
The spacer should be changed every
6 months
Never do this
CRF Programme Calendar
Oman Doctors’ Spirometry Workshop,
CRF, 12th December 2013
CRF Programme
Place
Date
ICONIC
Pune
1st & 2nd February 14
ROAD
Jalgaon
15th Feb 2014
Spirometry Simplified
Dubai
28th February 14
Spirometry Simplified
Muscat
1st March 14
OAD
Muscat
2nd March 14
CASPER
Dubai
14th March 14
Purview
CRF, Pune
15th March 14
Advanced PFT
Workshop
CRF, Pune
15th & 16th March 14
For more details mail to [email protected]
- CRF’s training programmes -
- To read the previous issues of Respimirror visit www.crfindia.com -
Chest Research Foundation
Marigold Premises, Survey No 15,
Kalyaninagar, Pune 411014, Maharashtra, INDIA.
Phone: +91 20 27035361/66208053
Fax: : +91 20 27035371. Website: www.crfindia.com
NOTE : FOR PRIVATE CIRCULATION ONLY.
10
For your feedback / queries write to [email protected]
Do you want to conduct a training programme in your city? Please write to
Mrs. Monika Chopda at [email protected]
Edited by : Mrs. Monika Chopda Published by : Chest Research Foundation, Pune n Printed by : Bookmark Publications, Pune
RespiMirror|Volume IV, Issue I, January 2014|