therapeutic aerosols

1. DR. D.Y.PATIL COLLEGE OF PHARMACY, AKURDI, PUNE
PRESENTED BY:
Miss. Harshala N. Dhende
First year M.pharm
Sem-II
(Dept. of Pharmaceutics)
GUIDED BY:
Prof. Dr. SHILPA P. CHAUDHARI
21/04/2017

2. CONTENTS…….
 INTRODUCTION
 ANATOMY OF RESPIRATORY TRACT
 WHAT IS AEROSOL
 WORKING
 COMPONENTS
 TYPES OF AEROSOL SYSTEM
 DRUG DELIVERY DEVICES
 MECHANISM OF DRUG DEPOSITION
 MANUFACTURING OF AEROSOL
 ADVANTAGES
 DISADAVNTAGES
 REFERENCES
2

3. Introduction…..
 Pulmonary drug delivery system is found to have wide range of
application in treatment of illness as well as in the research field due
to its beneficial effect over other dosage form .
 Aerosol therapy has been employed in the treatment of respiratory
disorders for a long time. It was used during the time of Hippocrates
and Ealen and continued to be used in India, China and the Middle
East for several centuries. It is now the treatment of choice for
obstructive airway diseases.
 Aerosols are mainly ued to treat the diseases like Asthma and
Chronic Obstructive Pulmonary Disorder(COPD).
3

4. • Localized delivery of drugs to the respiratory tract has become an
increasingly important and effective therapeutic method for
treating a variety of pulmonary disorders, including asthma,
bronchitis, and cystic fibrosis.
• Several studies have demonstrated the clinical advantage of
inhalation aerosols over systemic therapy for the treatment of
lung disorders.
• The efficacy of a therapeutic aerosol is mainly determined by the
amount of drug reaching the target site.
• Numerous systems are available to deliver aerosols to the lungs.
These include jet and ultrasonic nebulizers, pro- pellant-driven
metered-dose inhalers (pMDIs, pressurized canister), and dry
powder inhalers (DPIs).
4

5. The respiratory tract is divided into the upper
airways and lower airways. The upper airways or upper
respiratory tract includes the nose and nasal
passages, paranasal sinuses, the pharynx, and the portion of
the larynx above the vocal folds (cords).
The lower airways or lower respiratory tract includes the
portion of the larynx below the vocal
folds, trachea, bronchi and bronchioles. The lungs can be
included in the lower respiratory tract or as separate entity
and include the respiratory bronchioles, alveolar
ducts, alveolar sacs, and alveoli.
The respiratory tract can also be divided into a conducting
zone and a respiratory zone, based on the distinction of
transporting gases versus exchanging them.
From the bronchi, the dividing tubes become progressively
smaller with an estimated 20 to 23 divisions before ending at
an alveolus[
Anatomy of Respiratory Tract
5
Fig 1.

6. What is an Aerosol?
“The aerosol container is considered as pressurized
package in which the therapeutically active drug is
dissolved or suspended in compressed or liquefied
gas.”
The delivery of therapeutically active drug in the form of
spray or foam or solid stream is dependent on the
ability of the liquefied compressed gas.
It is also know as canister/ pressure package/
pressurized package.
6

7.  In mid 1950 therapeutic aerosol was introduced in
market.
 pharmaceutical therapeutic aerosol represent the
complex dosage form which will allow delivery of
therapeutically active medicament to the respiratory
tract.
 It provide high drug concentration in broncho-alveolar
fluid and other lung parts.
7

8. Working of therapeutic Aerosol…
 In aerosol the liquified gas propellant /propellant mixture and
product concentrate is sealed within an aerosol container.
Equilibrium is quickly established between the propellant that
remain liquified and the propellant which vapourise and
occupies the upper portion of the container .
 The equilibrium which is developed, developes pressure against
the wall of the container.
 This pressure is responsible for the actuation of aerosol valve. It
forces the liquid phase upto the dip tube through the orifice of
the valve and the contents will release into the atmosphere.
8

9.  As the propellant release in the air it expands and evaporates
because of the drop down in the pressure which leaves the
product concentrate as the airborne liquid droplet or dry particle
depending upon the formulation type.
9
fig. 2. Cross section sketches of contents and operation of a typical
two phase system

10.  Many studies have demonstrated that drug distribution and
deposition along the respiratory tract depends on several
factors:
(1) characteristics of the inhaled formulation (particle
diameter, size distribution, shape, electrical charge, density,
and hygroscopicity)
(2) anatomy of the respiratory tract, and
(3) breathing patterns, such as frequency, tidal volume,
and flow.
 The ideal site of deposition along the airways for drugs
intended for local delivery is not well understood.
 Because the location of autonomic receptors varies within the
respiratory tract, successful therapy may depend on targeting
specific receptor sites in the lung with different types of drugs.
10

11. Components of Aerosol…
 The delivery of components of aerosols depends on its
valve assembly, containers and actuators as well as on
the propellant. The two components of aerosols are
product concentrate and propellant.
 The product concentrate contains the the
therapeutically active ingredients.
 The propellant having vapour pressure greater than
atmospheric pressure at 40 is responsible for the
development of proper pressure in the container to
expel the product concentrate in the desired form like
spray, mist, solid , foam , stream etc.
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12.  Propellant can also act as the solvent or vehicle for the
product concentrate. Thus aerosol components are
classified as,
Aerosol
Product
concentratePropellant
Container
Actuator
Valve
12

13.  Propellant:
The development of pressure within the
container by the propellant causes the opening of the
valve which expels the product by atomization or foam
formation.
Types of propellant used:
depending on the route of administration and the use
,the propellant can be classified
Table no: 1 types of propellant
Application Name of propellant
For oral inhalation Fluorinated hydrocarbons
Di-chloro di-fluro methane
Topical preparation Propane , butane, isobutane
Compound gases Nitrogen , carbondioxide
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14. container
 Withstand a pressure as high as 140 to 180 psig (pounds per sq. inch gauge)
at 1300 F
 A. Metal
1. Tinplated steel
(a) Side-seam (three pieces)
(b) Two-piece or drawn
(c) Tin free steel
2. Aluminum
(a) Two-piece
(b) One-piece (extruded or drawn)
14

15.  3. Stainless steel
B. Glass
1. Uncoated glass
2. Plastic coated glass
VALVE
1. Actuator
2. Ferrule or mount cap
3. Valve body or housing
4. Stem
5. Gasket
6. Spring
7. Dip tube
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16.  TYPES OF ACTUATOR
 Actuators:
• Specially designed button placed on the valve system, helps in
easy opening and closing of the valve.
• Directs the spray to the desired area.
- Spray Actuators
- Foam Actuators
- Solid Stream Actuators
- Special Actuators
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17.  Ferrule/ mounting cup
• Attach the valve in proper position in container.
• Coated with epoxy resin.
 Valve body / housing
• Made of nylon/ delrin
• Connect dip tube, stem & actuator
• Determines rate of delivery
 Stem
• It is made of nylon /delrin /s.steel
• One or more orifice (0.013 to 0.030 inch)
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18. Gasket
 It is made of Buna –N, Neoprene rubber
Spring
 Hold the gasket in its place
 Made of stainless steel
Dip tube
 Made of poly propylene material / poly ethylene
 Inner diameter 0.120 –0.125 inch for less viscous
 Viscous product - 0.195 inch.
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19. TYPES OF AEROSOL
SYSTEM
Types of Aerosol
system
Solution system
or two phase
system
Water based
system or three
phased system
Suspension or
dispersion
system
Foam system
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20. Two phase system
 Contains both vapor & liquid.
 Drug soluble in propellant – no co-solvent.
 Propellant 12 – single or mixture.
 In mixture – propellant with vapor pressure less than
propellant 12 , vapor pressure reduction, bigger sized
aerosol particles.
 E.g. propellant 12/11(30:70), propellant 12/114(45:55)
20

21. Three phase system
 Contains water phase, vapor phase and the propellant.
 Water immiscible with propellant – solubility increased by
adding,
- Co – solvent (ethanol)
- Surfactants (0.5% - 2.0%) – non polar ( esters of oleic
acid, palmitic acid, stearic acid)
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22. Suspension system
 Using suspending agent.
 Oral inhalation aerosols.
 Active ingredients dispersed in propellant or mixture
 Physical stability by,
- Control of moisture content
- Active ingredients with minimum solubility.
- Initial particle size < 5 microns
- Propellant density
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23. Foam system
 Consists of aq. or non aq. vehicles, propellant & surfactants.
 Four types ,
 Aqueous stable foams
 Non aqueous stable forms
 Quick breaking forms
 Thermal forms
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24.  Aqueous stable foams
- Propellant 3-4%
- Dry spray is produced
- Propellant – internal phase
- Steroidal antibiotics
 Non aqueous stable foams
- Emulsifying agent - glycol
 Quick breaking foams
- Propellant – external phase
- Topical application
- Cationic, anionic, non ionic surfactants
 Thermal foams
- Delivered as foam on application of heat
- Shaving creams
24

25. Drug Delivery Devices
Nebulizers
Metered Dose inhaler
Dry powder inhaler
Standard
inhaler
Spacer
and
breath
activated
ultrasonic
pneumatic
Patient
driven
Power
assisted
25

26. Drug delivery devices….
Metered dose
inhaler
Dry powder inhaler
Nebulizer
26

27. Propellant-Driven Metered-Dose Inhalers
 pMDIs are the most frequently prescribed aerosol delivery system because
they are effective and convenient for a large proportion of patients.
 The fundamental components of pMDIs are an actuator, a metering valve,
and a pressurized container that holds the micronized drug sus- pension or
solution, propellant, and surfactant.
 The high vapor pressure propellant supplies the energy for disper- sion in
these delivery systems.
 The limitations of these devices are ,
(1) poor coordination between actuation and inhalation by some patients,and
(2) the release of aerosol particles as large particles at a very high velocity (100
km/h).
 This results in a high oropharyngeal impaction of particles, with
approximately 80% of the dose depositing in the oropharynx and only 10%
in the pulmonary air- ways.
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28. Dry powder inhalers
• DPIs are the most recent development in respiratory therapy. The
majority of these devices are breath-activated inhalers that rely on the
patient’s inspiratory flow to deaggregate and deliver the drug for
inhalation, thereby eliminating the requirement of inhalation
coordination in- herent in pMDI use.
• However, with DPIs there is the need to generate at least moderate
inspiratory flow in order to accomplish effective drug delivery.
• The drug in a DPI is in the form of a finely milled powder in large
aggregates, either alone or in combination with some carrier substance,
commonly lactose.
• There are two types,
1. Patient driven
2. Power assisted
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29.  Nebulization is of increasing interest because it offers opportunities
for novel techniques as well as providing a potential means of
administration for aqueous formula- tions of biomolecules.
 The most frequently used methods of nebulization are the air jet
and ultrasonic devices. The air jet nebulizer produces a stream of
high air velocity that causes liquid to spray as a mist.
 Ultrasonic nebulizers utilize high frequencies to convert liquid into a
fine mist. A wide range of droplet size distributions are produced by
both types of generators, depending on the brand, the operating
conditions, and the composition of the liquid being nebulized.
 Nebulizers produce smaller droplets than do pMDIs, and these
smaller droplets penetrate more easily to the small airways.
Nebulizers
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30. Mechanisms of Drug Deposition
 Drugs for inhalation therapy are administered in aerosol form. The
ability of the aerosolized drug to reach the peripheral airways is a
prerequisite for efficacy. Herein lies the fundamental problem of
inhalation therapy, as the anatomy and physiology of the respiratory
tract have evolved to prevent the entry of particulate matter.
 The mechanisms by which particles deposit in the respiratory tract
include,
1. impaction (inertial deposition),
2. sedimentation (gravitational deposition),
3. brownian diffusion,
4. interception,
5. electrostatic precipitation.
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31. 1. Impaction :
Impaction occurs when a particle’s momentum prevents it from changing
course in an area where there is a change in the direction of bulk air flow. It is
the main deposition mechanism in the upper airways, and at or near bronchial
branching points. The probability of impaction increases with increasing air
velocity, breathing frequency, and particle size .
2. Sedimentation:
Sedimentation results when the gravitational force acting on a particle
overcomes the total force of the air resistance. Inspired particles will then fall
out of the air stream at a constant rate. This is an important mechanism in small
airways having low air velocity. The probability of sedimentation is proportional
to residence time in the airway and to particle size, and decreases with in-
creasing breathing rate.
3. Diffusion
The collision of gas molecules with small aerosol particles exerts discrete
non uniform pressures at the particles’ surfaces, resulting in random brownian
motion. Thus, even in the absence of gravity, a particle in still air moves in a
“random walk”. The effectiveness of brownian motion in depositing particles is
inversely proportional to particle diameters of those particles
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32. Factors Controlling Respiratory Drug Deposition
The factors that control drug deposition are ,
(1) characteristics of the inhaled particles, such as size,
distribution, shape, electrical charge, density, and
hygroscopicity,
(2) anatomy of the respiratory tract, and
(3) breathing patterns such as, frequency, tidal volume, and
flow.
Of these factors, aerosol particle size and size distribution
are the most influential on aerosol deposition.
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33. Particle size characteristic….
 The size of the particles is a critical factor affecting the site
of their deposition, since it determines operating
mechanisms and extent of penetration into the lungs.
 Aerosol size is often expressed in terms of aerodynamic
diameter (Dae). The aerodynamic diameter is defined as the
equivalent diameter of a spherical particle of unit density
having the same settling velocity from an air stream as the
particle Thus, particles that have higher than unit density
will have actual diameters smaller than their Dae.
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34.  Conversely, particles with smaller than unit density
will have geometric diameters larger than their Dae.
 Aerosol size distributions may be characterized as
practically monodisperse (uniform sizes, geometric
standard deviation of , 1.2) or polydisperse
(nonuniform sizes, geometric stan- dard deviation $
1.2).
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35. PRESSURE FILLING
APPARATUS.
MANUFACTURING OF THERAPEUTICAL
AEROSOLS
COLD FILLING
APPARATUS
35

36. QUALITY CONTROL
TESTS
It Includes the testing of :
» Propellants
» Valves, Actuator, Dip Tubes
» Containers
» Weight Checking
» Leak Testing
» Spray Testing
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37. Evaluation Tests:
A. Flammability & combustibility:
1.Flash point
2.Flame Projection
B. Physicochemical characteristics:
1.Vapour pressure
2.Density
3.Moisture content
4.Identification of Propellants
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38. C. Performance
1. Aerosol valve discharge rate
2. Spray pattern
3. Dosage with metered valves
4. Net contents
5. Foam stability
6. Particle size determination
D. Biological testing
1.Therapeutic activity
2.Toxicity studies
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39. ADVANTAGES:
 Convinience, speed and ease of administration.
 Avoidance of personal contact with medicament.
 Useful for both systemic and local effect.
 Hepatic first pass avoided.
 Controlled and uniform dose delivered by metered valve.
 Absence of air in the container prevent oxidation of the drug.
 Dose can be removed without contamination of remaining material.
 Directly delivered to the affected area in a desired form
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40. DISADVANTAGE
 Costly.
 Difficulty in disposal.
 Difficulty in formulation.
 Q.C testing is complicated.
 Cannot be subjected to heat.
 There may be propellant toxicity when inhalation
therapy last for a long period
 Some propellant (CFC) cause environment problem.
40

41. Marketed therapeutic aerosol products
BRAND NAME DRUG USE
Flovent Diskus fluticasone Asthama
Advair Fluticasone and
Salmeterol
Asthma
Aerobid Flunisolide Asthma
Qvar Beclomethasone Asthma
Proventil Albuterol Bronchospasm
Flovent Diskus
Advair
41

42. Conclusion:
 Pharmaceutical Aerosol is a noninvasive pulmonary drug
delivery system which is considered to be the one of the best
method as compared to other route of administration.
 Its advantages over other route enhances its wide range of
application in treatment of illness like Asthma and Chronic
obstructive pulmonary disease(COPD) etc.
 Some of its advantages include directly targeting the drug at the
site of action , avoidance of first pass metabolism, rapid action.
 Hence, pulmonary route of administration can be successfull in
the research field in the future.
42

43. References:
 Leon Lachman, H.A. Liberman, The Theory and Practice Of
Industrial Pharmacy”, 3rd edition, Varghese Publishing House,
1991, page no. 589-618.
 Remington’s “The Theory and Practice Of Pharmacy”, 21st
edition ,Volume 1 ,page no 504-508.
 Sandra Suarez and Anthony J Hickey, “Drug Properties
Affecting Aerosol Behavior”,IRJP JUNE 2000 ,volume 4, page
no. 652–666
 Lahkar Sunita, A review on: Pharmaceutical Aerosol , IRJP
2012, volune 3,page no. 68-75
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