2. CONTENT
• Introduction
• Human Respiratory System
• Aerosols
• Advantages
• Disadvantages
• Components of Aerosols
• Types of Aerosol systems
• Three commonly used clinical Aerosols
• Manufacturing
• Evaluation
• Application
• Newer Development
• Conclusion
• Reference
3. Introduction
The respiratory tract is one of the oldest routes used for the
administration of drugs. Over the past decades inhalation therapy has
established itself as a valuable tool in the local therapy of pulmonary
diseases such as asthma or COPD. An inhalation therapy that is effective
and safe depends not only on a pharmacologically active molecule, but
also on a delivery system and its application. This type of drug
application in the therapy of these diseases is a clear form of targeted
drug delivery. Delivery of drugs directly to their site of action reduces
the dose needed to produce a pharmacological effect.
4. Human Respiratory System
The human respiratory system is a complicated organ system of
very close structure-function relationships.
The system consist of regions -
The conducting airways
The respiratory region
5. AEROSOLS
Aerosol preparations are stable dispersions or suspensions of solid
material and liquid droplets in a gaseous medium. They are the
dosage forms containing therapeutically active ingredients that are
packaged under pressure in a sealed container.
The drugs, delivery by aerosols is deposited in the airways by:
gravitational sedimentation, inertial impaction, and diffusion.
Mostly larger drug particles are deposited by first two mechanisms
in the airways, while the smaller particles get their way into the
peripheral region of the lungs by following diffusion.
6. Advantages of Aerosols
The dose needed to produce a pharmacological effect can be
reduced.
Low concentrations in the systemic circulation are associated with
reduced systemic side-effects.
Rapid onset of action.
Avoidance of gastrointestinal upset.
Avoidance of intestinal and hepatic first-pass metabolism.
A dose can be removed with out contamination of materials.
Easy and convenience of application.
The medication can be delivered directly to the affected area in
desired form (localized action).
7. Disadvantages of Aerosols
• Delivery devices are required to target drugs to the airways and
these devices may be inefficient.
• Various factors affect the reproducibility of drug delivery to the
lungs, including physiological and pharmaceutical variables.
• Drug absorption may be limited by the physical barrier of the
mucus layer and the interactions of drugs with mucus.
• Mucociliary clearance reduces the retention time of drugs within
the lungs.
• They are expensive.
9. Propellants
Propellants are responsible for performing the essential function of
expelling the material from the container by supplying the
necessary pressure within the aerosol system. They are liquefied or
compounded gases having vapor pressures exceeding employed to
obtain the necessary delivery and spray characteristics of the
aerosol.
The commonly used propellants in aerosol systems are
hydrocarbons, especially the fluorochloro derivatives of methane
and ethane, the butanes and pentanes and compressed gases are
used.
10. Applications Name of propellant
For oral and inhalation
Chloro fluoro carbons
Di-chloro di-fluro methane (propellant 12)
Trichloromonofluoromethane (propellant 11)
Di-chloro tetra-fluro ethane (propellant 114)
Topical preparation Propane, Butane, Isobutane
Compound gases Nitrogen, Carbon dioxide, Nitrous oxide
Types of Propellant
11. Containers
Aerosol containers are usually made up of metal, glass, plastic, or
combination of these materials. The containers must be so designed
that they provide the maximum in pressure safety and impact
resistance.
A. Metals
I. Tinplated steel
II. Aluminium
III. Stainless steel
B. Glass
I. Uncoated glass
II. Plastic coated glass
C. Plastic
12. Valves and Actuator
Valves
The valve regulates the flow of the active ingredients and
propellant from the container and determines the spray
characteristics of the aerosol. It must be manufactured from
materials which are inert to the contents of the aerosol. The
commonly used materials are rubber, plastic, aluminum and
stainless steel. It can deliver the content of the container in the
desired form of spray, foam, etc.
13. Actuator
The actuator or adaptor which is fitted to the aerosol valve stem is
a device which on depression or any other required movement
opens the valve and directs the spray to the desired area. The
design of the actuator which incorporates an orifice of varying size
and shape and expansion chamber is very important in influencing
the physical characteristics of the spray or foam, particularly in the
case of inhalation aerosols, where the active ingredients must be
delivered in the proper particle size range.
14. Product concentrate
The product concentrate is the active drug combined with
additional ingredients or co-solvents required to make a stable
and efficacious product. The concentrate can be a solution,
suspension, emulsion, semisolid or powder.
15. Types of Aerosol systems
1. Solution system or two phase system
The two phase system is the simplest system. Here the product
concentrate is dissolved or dispersed in liquefied propellant and
solvents creating a homogenous system. The propellants exist in
both the liquefied phase and the vapor phase. When the aerosol
valve is actuated, some liquefied propellant and solvent
containing the product concentrate is emitted from the container.
These aerosols are designed to produce a fine mist or wet spray
by taking advantage of the large expansion of the propellant when
it enters room temperature and atmospheric pressure. The two
phase system is commonly used to formulate aerosols for
inhalation or nasal application.
16. 2. Water based system or three phase system
A three phase system (i.e., a heterogeneous system) is made up a
layer of water immiscible liquid propellant, a layer of propellant
immiscible liquid (usually water) which contains the product
concentrate, and the vapor phase. This type of system is used when
the formulation requires the presence of a liquid phase that is not
propellant miscible. When the aerosol valve is actuated, the
pressure of the vapor phase causes the liquid phase to rise in the
dip tube and be expelled from the container. If the product is to
maintain the liquefied gas reservoir, the dip tube must not extend
beyond the aqueous phase.
18. Three commonly used clinical Aerosols
1. Nebulizers
2. Metered–dose Inhaler (MDI)
3. Dry-powder inhaler (DPI)
19. Nebulizer
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- It 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- It uses a piezoelectric crystal, vibrating at a
high frequency (usually 1–3 MHz), to generate a fountain of liquid in
the nebulizer chamber; the higher the frequency, the smaller the
droplets produced.
21. Metered–dose Inhaler (MDI)
Metered dose inhalers are the most commonly used devices for
generation of aerosol. They consist of a micronized form of the drug
in a propellant under pressure with surfactants to prevent clumping
of drug crystals. Lubricants for the valve mechanism and other
solvents are the other constituents. When the device is actuated,
the propellant gets exposed to atmospheric pressure, which leads
to aerosolisation of the drug. As it travels through the air, the
aerosol warms up leading to evaporation of the propellant that
reduces the particle size to the desirable range. The fraction of drug
to the airways ranges from 5 percent to 15 percent.
22. Dry-powder inhaler (DPI)
Dry powder inhalers (DPI) consist of pharmacologically active
powder as an aggregate of fine micronized particles in an inhalation
chamber. These aggregates are converted into an aerosol by
inspiratory airflow through the inhaler generated by the patient.
Lack of requirement of propellant is an advantage of DPIs over
MDIs. The fraction of the drug delivered to the site of action by a
DPI varies from 9% to 30% and varies among different commercially
available products. In a DPI, the aerosol needs to be generated from
the powder formulation by patient’s own
effort.
23. Dry powder inhalers are of two types-
• Unit-Dose Devices
Single dose powder inhalers are devices in which a powder containing
capsule is placed in a holder. The capsule is opened within the device
and the powder is inhaled.
• Multi-dose Devices
This device is truly a metered-dose powder delivery system. The drug
is contained within a storage reservoir and can be dispensed into the
dosing chamber by a simple back and forth twisting action on the base
of the unit.
25. Manufacturing
1. Cold fill process
In the cold fill process, both the product concentrate and the
propellant must be cooled to temperatures between 30°C to 60°C
where they will remain liquefied. The cooling system may be a mixture
of dry ice and acetone or an elaborate refrigeration system. The
chilled product concentrate is quantitatively added to the equally cold
aerosol container and then the liquefied gas is added. The heavy
vapors of the cold liquid propellant will generally displace the air
present in the container. When filling is complete, the valve assembly
is inserted into the container and crimped into place. The container is
then passed through a water bath of about 55°C to check for leaks or
distortion in the container.
26. 2. Pressure fill process
Pressure filling is carried out essentially at room temperature. The
product concentrate is placed in the container, the valve assembly is
inserted and crimped into place, and then the liquefied gas, under
pressure, is added through the valve. The entrapped air in the
package might be ignored if it does not interfere with the stability
of the product, or it may be evacuated prior to or during filling.
After the filling operation is complete, the valve is tested for proper
function. This spray testing also rids the dip tube of pure propellant
prior to consumer use. Pressure filling is used for most
pharmaceutical aerosols. It has the advantage that there is less
danger of moisture contamination of the product and also less
propellant is lost in the process.
27. Evaluation
1. Flame Projection
The aerosol product is sprayed to an open flame for about 4
seconds and the extension of the flame is measured with the help
of a ruler, which is expressed as cm.
2. Spray Testing
Determination of spray patterns involves the impingement of
sprays on a piece of paper that has been treated with dye-talc
mixture. The particles that strike the paper cause the dye to go into
solution and to be absorbed onto the paper. It gives a record of the
spray pattern.
3. Moisture Content
Karl Fischer method or gas chromatography method has also been
used for determination of moisture content of aerosol. Moisture
content is expressed as %.
28. 4. Net Contents
The tared cans, placed onto the filling line are reweighed, and the
difference in weight is equal to the net contents. The other method
is a destructive method and consists of weighing a full container
and then dispensing the contents. The contents are then weighed.
The difference in weight gives the amount of contents present in
the container.
5. Foam Stability
The life of a foam ranges from a few seconds for quick breaking
foam to one hour or more depending on the formulation. The
methods which are used to determine the foam stability includes
visual evaluation, time for a given mass to penetrate the foam, time
for a given rod that is inserted into the foam to fall and rotational
viscometer.
29. 6. Vapor Pressure
The vapor pressure can be determined by pressure gauge. Variation
in pressure indicates the presence of air in headspace. A can
punctuating device is also available for accurately measuring vapor
pressure. The unit of this test is expressed as psig.
7. Density
It is determined by hydrometer or a pycnometer. For this test a
pressure tube is fitted with metal fingers and Hoke valve, which
allow for the introduction of liquids under pressure. The
hydrometer is placed into the glass pressure tube. Sufficient sample
is introduced through the valve to cause the hydrometer to rise half
way up the length of the tube. The density can be read directly. The
density is generally expressed as g/ml.
31. Newer Development
Dr Reddy's launches 'Dose Counter Inhalers' in India Friday, April 16, 2010
Dr Reddy's Laboratories (DRL) has launched an innovation in the
metered dose inhaler (MDI) space with launch of 'Dose Counter
Inhalers (DCI) for the first time in India. This the first MDI in India that
gives patients an advance indication of when the inhaler is going to be
empty. DCI is a new drug delivery device with a single device having 120
metered doses. There is a window in the inhaler that changes color
from green to red. Green indicates the inhaler is full and red indicates
the inhaler is empty. Half green and half red in the window indicate it's
time to change the inhaler.
32. Conclusion
Pulmonary drug delivery is an important research area which
impacts the treatment of illnesses including asthma, chronic
obstructive pulmonary disease and various diseases. Inhalation
gives the most direct access to drug target. In the treatment of
obstructive respiratory diseases, pulmonary delivery can minimize
systemic side effects, provide rapid response and minimize the
required dose since the drug is delivered directly to the conducting
zone of the lungs. So pulmonary drug delivery is best route of
administration as compare to other routes.
33. Reference
1. Clark AR. Medical aerosol inhalers.Past, present and future. Aerosol
Sci Technol. 1995;22:374–391.
2. John J. Sciarra, Christopher J. Sciarra, Aerosols. In: Alfonso R.
Geearo, editor. Remington: Science and practice of pharmacy,
second edition.vol-1.New York: Lippincott Williams and Wilkins
publication; 2001.p.963-979.
3. Loyd V. Allen, Jr. Nicholas G. Popovich, Howard C. Ansel; Aerosols,
2005;681:426-438.
4. Sunitha et al “Drug Delivery and its Development for Pulmonary
System” International Journal of Pharmaceutical, Chemical and
Biological Sciences(1)1,2011, pp.66-82.
5. Karhale A.A.et al “Pulmonary Drug Delivery system” International
journal of PharmTech Research(4)1,2012 ,pp.293-305.