Pulmonary Drug Delivery System Page 1

Assignment On
Pulmonary Drug Delivery System (MDIs and DPIs)



Submitted By
1. Md. Mahamudul Hossain 5. Jannat Ara Haque
ID: 123-007-062 ID: 123-043-062
2. Arfia Chowdhury 6. Shuvankar Biswas
ID: 123-008-062 ID: 123-045-062
3. Jakaria Sheak 7. Jannatul Ferdous
ID: 123-028-062 ID: 123-044-062
4. Mohammed Nasir Uddin 8. Momo Ashrafi
ID: 123-032-062 ID: 131-009-062


Semester: Summer, 2013


Course Name: Applied Pharmaceutics & Pharmaceutical Technology

Course Code: MPP-6101


Submission Date: 07, December, 2013



Submitted To
Md. Istiak Ahamed
Lecturer
Department of Pharmacy
Primeasia University

Pulmonary Drug Delivery System Page 2



Content Page No.
Introduction ................................................................................................................ 3
Pulmonary Drug Delivery System ............................................................................. 3
Pulmonary System ..................................................................................................... 3
Physiology of Route of Administration .................................................................... 4
Applications of Pulmonary Route ............................................................................. 6
Mechanism of Action ................................................................................................ 6
Mechanism of Drug Absorption ............................................................................... 7
Pulmonary Drug Delivery ......................................................................................... 7
Methods of Inhalation delivery ................................................................................. 8
Factors Affecting Pulmonary Drug Delivery ........................................................... 11
Advantages of Pulmonary Drug Delivery ................................................................ 14
Limitations of Pulmonary Drug Delivery .................................................................. 14
Some Example of Pulmonary Drug Marketed in Bangladesh .................................. 15
Conclusion ................................................................................................................ 16
Reference ................................................................................................................... 16




Pulmonary Drug Delivery System Page 3

Pulmonary Drug Delivery System (MDIs and DPIs)
Advantages and Limitations of DDS
Physiology of Route of Administration
Factors Affecting the Drug Absorption
Examples of Some Delivery System (Market Preparations)
Introduction
Pulmonary route was use to treatment of different respiratory diseases from the last decade. The
inhalation therapies involved the use of leaves from plants, vapors from aromatic plants, balsams, and
myhrr. Through, around the turn of the 19th century, with the invention of liquid nebulizers, these
newer treatments developed into valid pharmaceutical therapies. In the 1920 s adrenaline can
introduce as a nebulizer solution, in 1925 nebulizer porcine insulin was use in investigational studies
in diabetes, and in 1945 pulmonary delivery of the newly revealed penicillin was investigate. Steroids
had been introduced in between 1950s for the treatment of asthma and nebulizers were enjoy widely
use. In 1956 the pressured metered dose inhaler (pMDI) was placed, over the last 5 decades, helped
by the advances in molecule design and drug discovery the pMDI was raised to become the major
stay for the asthma treatment. It may found that certain drugs taken by pulmonary route are readily
absorbed by the alveolar region direct in to blood circulation. Pulmonary route having many
advantages over other routes of supervision for the treatment of particular disease states, specifically
lung associated bigger protein molecules may degrade into the gastrointestinal situation and are
excreted through the first pass metabolism into the liver which can be transferred through the
pulmonary route if deposited in the respiratory passage of the lungs. (1)
Pulmonary Drug Delivery System
Pulmonary drug delivery describes various systems, devices, formulations & method of delivery of
drugs to the lung for the treatment of diseases of the respiratory tract. For systemic delivery via the
drug, once the drug is administered they readily pass into the blood stream without the need of any
enhancers. (2)
Pulmonary System
The human pulmonary system is a complicated organ system of very close structurefunction
relationships.
The pulmonary system consists of two regions-
1. The conducting air way region
2. Respiratory regions
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The airway is further divided into many folds: nasal cavity and the associated sinuses, and the
nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles. The respiratory region consists
of respiratory bronchioles, alveolar ducts, and alveolar sacs (3)
Physiology of Route of Administration
1) Lung regions
The respiratory tract starts at the nose and terminates deep in the lung at an alveolar sac. There are a
number of schemes for categorizing the various regions of the respiratory tract (4).
2) Nasopharyngeal region
This is also referred to as the upper airways, which involves the respiratory airways from the nose
down to the larynx.
3) Tracheo-bronchial region
This is also referred to as the central or conducting airways, which starts at the larynx and
extends via the trachea, bronchi, and bronchioles and ends at the terminal bronchioles.
4) Alveolar region
This is also referred to as the respiratory airways, peripheral airways or pulmonary region,
Comprising the respiratory bronchioles, alveolar ducts and alveoli. The term pulmonary can be
misleading since some authors use it with reference to the whole lung, while others control its use to
the alveolar region. In this chapter pulmonary refers to the whole lung. The use of upper respiratory
tract (i.e. NP plus trachea) and lower respiratory tract is also common place.


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Fig: Different regions of the human pulmonary system
Pulmonary epithelium
The lung contains more than 40 different cell types, of which more than six line the airways. The
diversity of pulmonary epithelia can be illustrated by examining its structure at three principal levels.
The bronchi
These are lined predominantly with ciliated and goblet cells. Some serous cells, brush cells and Clara
cells are also present with few Kulchitsky cells.
The bronchioles
These are primarily lined with ciliated cuboidal cells. The frequency of goblet and serous cells
decreases with progression along the airways while the number of Clara cells increases.
The alveolar region
T his is devoid of mucus and has a much flatter epithelium, which becomes the simple squamous
type, 0.10.5 m thick. Two principal epithelial cell types are present:
Type-I Pneumocytes: Thin cells offering a very short airways-blood path length for the diffusion
of gases and drug molecules. Type-I pneumocytes occupy about 93% of the surface area of the
alveolar sacs, despite being only half as abundant as type-II cells.
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Type-II Pneumocytes: Cuboidal cells that store and secrete pulmonary surfactant. Alveolar
macrophages account for ~3% of cells in the alveolar region. These phagocytic cells scavenge and
transport particulate matter to the lymph nodes and the mucociliary escalator.
Ciliated Cells
In the trachea bronchial region, a high proportion of the epithelial cells are ciliated such that there is a
near complete covering of the central airways by cilia. Towards the periphery of the tracheobronchial
region, the cilia are less abundant and are absent in the alveolar region. The ciliated cells each have
about 200 cilia with numerous interspersed microvilli, of about 12 m in length. The cilia are hair-
like projections about 0.25 m in diameter and 5 m in length. They are submersed in an epithelial
lining fluid, secreted mainly from the serous cells in the sub-mucosal glands. The tips of the cilia
project through the epithelial lining fluid into a layer of mucus secreted from goblet cells. The cilia
beat in an planned fashion to propel mucus along the airways to the throat (4).
Applications of Pulmonary Route
Applications of pulmonary route consists-
Anti-asthamatic drugs
Anti neoplastic drugs
Anti diabetic drugs (insulin treatment)
Anti viral drugs COPD
Anti tubercular drugs
Anti migraine (Ergotamine)
Pulmonary arterial hypertension (iloprost)
In acute lung injury (Prostaglandin E) (5)

Mechanism of Action
As the end organ for the treatment of local diseases or as the route of administration for systemic
therapies, the lung is a very attractive target for drug delivery. It provides direct access to disease in
the treatment of respiratory diseases, while providing an enormous surface area and a relatively low
enzymatic, controlled environment for systemic absorption of medications. As a major port of entry,
the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the
body. Airway geometry, humidity, mucociliary clearance and alveolar macrophages play a vital role
in maintaining the sterility of the lung and consequently are barriers to the therapeutic effectiveness
of inhaled medications.
Inhalation of drugs for the treatment of local diseases such as asthma, chronic obstructive pulmonary
disease (COPD), cystic fibrosis, and chronic bronchitis, has been commonplace for many years.
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The therapeutic effect of aerosolized therapies is dependent upon the dose deposited and its
distribution within the lung. The influence of the latter on the effectiveness of inhaled therapies is less
clear. Ruffin and colleagues demonstrated that a small dose of histamine aerosol deposited
predominantly in the large conducting (central) airways was as effective in increasing airway
obstruction as an 11-fold greater dose of histamine aerosol deposited diffusely, suggesting that the
receptors for histamine reside mainly in the large airways and that surface concentration of a drug
affects response.
Since particle size affects the lung deposition of an aerosol, it also can influence the clinical
effectiveness of a drug. Johnson and colleagues showed that the bronchodilation response to
cumulative doses of ipratropium bromide delivered either as a 3.3-m or 7.7-m aerosol was
identical, whereas the response to salbutamol was significantly greater with the finer (3.3 m)
aerosol, suggesting targeting drug aerosol to the location of their receptors in the lung does influence
its effectiveness. (6)
Mechanism of Drug Absorption
Drug diffusion occurs through alveoli.
Absorption through aqueous pores by carrier mediated transport.
Phagocytosis of insoluble particles allow absorption of compounds with low lipophilicity &
or high molecular weight (2).
Pulmonary Drug Delivery
The drugs can be administered by pulmonary route utilizing two techniques:
Aerosol inhalation (also used in intranasal applications) and
Intratracheal instillation.
By applying aerosol technique, we could achieve more uniform distribution with greater extent of
penetration into the peripheral or the alveolar region of the lung, but this costs more and also faced
with difficulty in measuring the exact dose inside the lungs. In contrary to this, instillation process is
much simple, not expensive and has non-uniform distribution of drugs (7).
Inhaleables
Advanced technology for pulmonary delivery is expanding a category of drugs called Inhaleables
defined as respiratory & systemic therapies administered simply by inhaling (2).
Aerosols
Aerosol preparations are stable suspensions of solid material & liquid droplets in a gaseous medium.
The drug delivery by aerosols is deposited in the airways by: Gravitational sedimentation Diffusion
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The term atomizer is used for a device that generates an aerosol & may be powdered by
electrically/mechanically.
A dose can be removed without contamination of remaining material. The medication can be
delivered directly to the affected area in a desired form such as spray or stable form. Irritation
produced by mechanical application of topical medication is reduced or eliminated. Minimum
contamination. Maximum stability (2).
Formulation of aerosol
Aerosol product essentially consists of two components: Product concentrate Propellant Product
concentrate consist of active ingredients or mixture of active ingredients. Other necessary agents such
as solvents, antioxidants & Surfactants (2).
Intratracheal Inhalation
This technique delivers a small amount of solution into the lungs by syringe. This route provides a
rapid and quantifiable method of drug delivery to the lungs. The drug deposition is localized and
uneven and only small absorptive area is used for the absorption from deposition.
Methods of Inhalation delivery
There are three commonly used methods of Inhalation delivery-
A. MeteredDose Inhaler (MDI) and
B. Dry-Powder Inhaler (DPI)
C. Jet or Ultrasonic Nebulizers
The metereddose inhalers are most frequently used aerosol delivery system. The dry-powder-
inhalers are designed to deliver drug/excipients powder to the lungs (2).
A. Metered Dose Inhalers (MDIs)
Metered dose inhalers (MDIs) are a device that helps to deliver a specific amount of medication to
the lungs. It is commonly used to treat asthma, chronic obstructive pulmonary disease (COPD). It is
composed of 4 essential components.
1. The base formulation- drug, propellant, excipients.
2. The container.
3. Metering valve.
4. The actuator (mouth piece).

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Fig: Metered-dose inhalers
Propellant
Propellant Single or blend of various propellants are used. It is selected to give the desired vapour
pressure, solubility & particle size. Propellants can be with active ingredients in many different ways
producing products with varying characteristics. Depending on the type of aerosol system utilized,
the pharmaceutical aerosol may be dispensed as fine mist, wet spray & semi-solid or solid.
Commonly CFC propellants are used because of their low pulmonary toxicity, high chemical stability
and purity and compatibility, Non-inflammable. But now a days the CFC propellants are replaced
with Hydrofluoroalkanes (HFAs) as these CFC cause the ozone depletion effect. Examples:
trichlorofluromethane dichlorodifluoromethane 1.2.dichlorotetrafluromethane (2).
Surfactants
These are added to maintain the drug in dispersed state & promote stability of formulation. It is also
lubricates the valve. Examples: oleic acid, sorbitol.
Containers & valve
Usually the container is made up of aluminum or glass. Glass containers are normally plastic coated
or laminated to enhance their ability to ensure internal pressures of high magnitude.
Metering valves
These are designed to release a fixed volume of product during each actuation. Usually valves
volumes range from 25 to 100 ml although larger volumes are available.
B. Dry Powder Inhalers
This device dispenses a powder in a stream of inspired air. These are environmentally friend since
they do not require CFC propellants for drug dispersion. Self medication is possible (2).
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Fig.: Dry Powder Inhalers
Types of Dry Powder Inhaler
Two types of dry powder inhaler
1. Passive dry powder inhaler Ex: Disc Inhaler, Easy haler
2. Active dry powder inhaler Ex: spiors, prohaler.
Advantages
Advantages Product and formulation stability High drug volume delivery per puff low susceptibility
to microbial growth Applicable to both soluble and insoluble drugs Self medication is possible
Disadvantages
Hygroscopic powders have chances to particle growth. Accurate dose is required.
C. Nebulizer
Nebulizer Nebulizers are those that aerosolize aqueous solutions of water-soluble drugs 0r
suspensions & solvent-water based solutions of water- insoluble substances. Nebulizer have been
successfully employed for drug delivery to the lung. It is also used for local drug delivery to trachea
for local anesthesia (2).
There are two types of Nebulizer
1. Pneumatic Nebulizer : It derives from pressurized gas source ex:- jet or hydro dynamic
2. Electrical Nebulizer : It operates from an electric source ex:-ultra sonic Nebulizer


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Factors Affecting Pulmonary Drug Delivery
1) Mechanisms of particle deposition in the airways
Effective resistance mechanisms may have involved may reduces the burden of external particles
enter the airways, and clearing those it may achieve something in being stored. Therapeutic aerosols
are two-phase colloidal systems in that the drug is contained in a dispersed phase they may have a
solid, liquid or combination of the two, based on the method and formulation of aerosol generation.
Evidently for effective therapy, the drug must have obtain able to the lung in aerosol droplets or
particles that deposit in the specific lung region and in sufficient quantity to be effective. The
respiratory resistance mechanisms of mucociliary clearance and phagocytosis by macrophages may
act upon insoluble particles. Aerosol particle dissolution they may slow and the drug may then
subsequently to be subject to enzymatic deprivation before it reaches to its specific site of
pharmacological action. Aerosols for pulmonary drug delivery are transported from the mouth (5).
2) Inertial impaction
This is the main deposition mechanism for particles >1 m in the upper tracheo-bronchial regions. A
particle having a large momentum it may not able to follow the altering direction of the inspired air
as it transferred the bifurcations and it will show result to collide with the airway walls as it continues
on its original course.
Description of particle deposition mechanisms at an airway branching site 5 Impaction it mainly
occurs near the bifurcations, certainly the impaction of particles from tobacco smoke on the
bifurcations may be one cause why these sites are often the foci for lung tumors. The prospect of
inertial impaction will be dependents upon particle momentum, thus particles with higher densities or
larger diameter and those travelling in airstreams of higher velocity will show superior impaction.
3) Sedimentation
By the settling under gravity the particles may deposited. It becomes highly important for particles
that reach airways where the airstream velocity is relatively low, e.g. the bronchioles and alveolar
region. The fraction of particles depositing by this mechanism it may dependent upon the time the
particles use in these regions.
4) Brownian diffusion
This is of minor significance for particles >1 m. Particles smaller than this size are displaced by a
sequentially bombardment of gas molecules, which may results in particle collision with the airway
walls. The chances of particle deposition by diffusion increases with the particle size decreases.
Brownian diffusion is also more common in regions where airflow is very low or absent, e.g. in the
alveoli. Another method of deposition, that of interception, is of important for fibers but it may not
for drug delivery. Generally:-
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Particles bigger than 10 m will have impact in the upper airways and are rapidly removed by
swallowing, coughing and mucociliary processes.
The particles in the size range 0.55 m may break away from impaction in the upper airways and
may deposit by sedimentation and impaction in the lower TB and A regions. If the aerosol particle
size is between the 3 and 5 m then deposition it mainly occur in the TB region. If the particles are
smaller than the 3 m then appreciable deposition in the A region is likely to occur.

A. PHYSIOLOGICAL FACTORS AFFECTING PARTICLE DEPOSITION IN THE AIRWAYS

1) Lung morphology
Each successful production of the tracheobronchial tree produces airways of falling diameter and
length. Every bifurcation results in an increase possibility for impaction and the decrease in airway
diameter is associated with a smaller displacement necessary a particle to make contact with a
surface.
2) Inspiratory flow rate
When the inspiratory flow rate increases they enhance deposition by impaction in the first few
generations of the TB region. The increase in flow not only increase particle momentum but also
result in an increase in turbulence, mostly in the larynx and trachea, which itself will enhance
impaction in the proximal tracheo-bronchial region.
3) Co-ordination of aerosol generation with inspiration
The energy of aerosol particles generated from pressurized metered dose inhalers (p MDIs, is largely
govern by the pMDI formulation rather than the subjects IFR. pMDI aerosol droplets will be
travelling at velocities of 2,5003,000 cm s1. A failure to co-ordinate actuation of the p-MDI during
the early on phase of the inspiratory plan will result in near total particle impaction in the
oropharnygeal area.
4) Tidal volume
An increased IFR will usually be connected with an enlarge in the volume of air inhaled in one
breath, the tidal volume. Obviously an increase in tidal volume will result in penetration of aerosol
particles deeper into the TB and A regions and a better chance for deposition inside these regions.
5) Breath holding
Increasing the time between the end of inspiration and the start of exhalation increase the time for
sedimentation to occur. Breath-holding is normally used to optimize pulmonary drug delivery.

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6) Disease states
Bronchial obstruction as seen in different pulmonary disorders may associated with the larger local
airflows and turbulence and this will result in localized deposition in the larger airways of the
trachea-bronchial region. The bronchoconstriction of asthma has a more influence on exhalation than
inhalation and thus deposition by sedimentation may be superior than normal.

B. PHARMACEUTICAL FACTORS AFFECTING AEROSOL DEPOSITION

1) Aerosol velocity
The aerosols formed by nebulizers and dry powder inhalers (DPIs) are transported into the lung by
entrainment on inspired air. In difference, pMDIs generate aerosol droplets with velocities greater
than the inspiratory airflow and therefore the aerosol will have a greater affinity to impact in the
oropharyngeal region.
2) Size
Marketable devices do not lead to monodispersed particles and frequently the size distribution is
extensive and the particles may show varying shapes. Consequently a number of terms are used to
adequately characterize an aerosol sample:- The geometric standard deviation (GSD) is defined as the
size ratio at 84.2% on the cumulative frequency curve to the median diameter. This assumes that the
sharing of particle sizes is Lognormal. A monodisperse, i.e. ideal aerosol, has a GSD of 1, although in
practice an aerosol with a GSD of <1.22 is describe as monodisperse while those aerosols with a
GSD >1.22 are referred to as polydispersed or heterodispersed.
3) Shape
Particles which are non-spherical will have at smallest amount one physical dimension which is
superior than the aerodynamic diameter. Ecological fibers 50 m in length can reach the A region
because they align with the inspired airflow. Such materials then impact in the airways by a
procedure of interception with the airway walls.
4) Density
Particles having densities less than 1 g cm3 (unit density) may have a mean physical diameter larger
than the aerodynamic limit. Most micronized drugs for inhalation will contain particle densities
around 1, although materials created by freeze-drying or spraydrying methods are likely to be
appreciably less dense.
5) Physical stability
Therapeutic aerosols are often inherently actually unstable since they have a high concentration of
particles and their close immediacy may lead to mutual repulsion or other inter-particulate reactions.
Aerosol particles generate by DPIs may be hygroscopic and, during their passageway throughout the
Pulmonary Drug Delivery System Page 14

high humidity environments of the airways, may enlarge in size and thus have a greater chance of
being prematurely deposited. It be supposed to not be assumed, however, that the uptake of water
vapor will always occur.
6) Pulmonary delivery devices
Current inhalation devices are separated into three different categories, the refinement of the
nebulizer and the evolution of two types of compact portable devices, dry powder inhaler (DPI) and
metered-dose inhaler (MDI) (5).
Advantages of Pulmonary Drug Delivery
1) It is needle free pulmonary delivery.
2) It requires small and fraction of oral dose.
3) Low concentration in the systemic circulation is associated with reduced systemic side effects.
4) It furnish very rapid onset of action similar to I.V.route (2).
5) Avoidance of gastrointestinal upset
6) Degradation of drug by liver is avoided in pulmonary drug delivery (8)
7) It supplies drugs into the blood stream directly.
8) It provides a non-invasive method of drugs delivery.
Limitations of Pulmonary Drug Delivery
1) Oropharyngeal deposition gives local side effect.
2) Patient may have difficulty using the pulmonary drug devices correctly
3) Drug absorption may be limited by the physical barrier of the mucus layer.
4) Various factors affect the reproducibility on drug delivery on the lungs, including
physiological and pharmaceutical barrier.
5) The lungs are not only accessible surface for drug delivery complex but also delivery devices
are required to target drug delivery (9).
6) Poor patient compliance.
7) It can provide irritant activity.
8) Aerosol can increase bronco constriction.
9) High cost of manufacturing (2).


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Some Example of Pulmonary Drug Marketed in Bangladesh
SL.
No.
Generic Name Brand Name Company Indication Dose
1 Salbutamol
Azmasol
Inhaler
Beximco
Pharmaceuticals
ltd
Bronchodilator 100mcg/puff
2 Levosalbutamol
Levoster
Inhaler
Square
Pharmaceuticals
ltd
Bronchodilator 50mcg/puff
3
Salmetrol
Xinafoate
Salmate Inhaler
Square
Pharmaceuticals
ltd
Bronchodilator 25mcg/puff
4 Ipratropium Iprexl Inhaler
Square
Pharmaceuticals
ltd
Bronchodilator 20mcg/puff
5 Tiotropium Norven Inhaler
Square
Pharmaceuticals
ltd
Bronchodilator 18mcg/puff
6 Beclomethasone
Beclomin
Inhaler
Square
Pharmaceuticals
ltd
Steroid 100mcg/puff
7 Fluticasone
Seretide
Inhaler
GSk
Pharmaceuticals
ltd
Steroid 250mcg/puff
8 Budesonide
Aeronid
Inhaler
Beximco
Pharmaceuticals
ltd.
Steroid 100mcg/puff
9
Sodium
Chromoglycate
Intal 5 Inhaler
Sanofi Aventis
Pharmaceuticals
ltd
Mast Cell
Stabilizer
5mg
10 Formoterol Efo Inhaler
Square
Pharmaceuticals
ltd
Bronchodilator 12mcg/Capsule
Pulmonary Drug Delivery System Page 16

Conclusion
As discussed in this review, the pulmonary drug delivery field is truly one of the mostly popular areas
in todays applied pharmaceutical research and its development. Certainly, still at this time, the more
information is collected the more related question marks are surfacing covering the area of lung
physiology and diseases, lung deposition, intelligent inhalation devices, delivery of
biopharmaceuticals. Absorption enhancement, controlled drug release in the lung and, last but not
least. As more efficient pulmonary drug delivery devices and sophisticated formulations become may
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 lungs
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 side-
effects and increase clinical effectiveness and patient compliance. Some of the key determinants for
successful dispersion of pharmaceutical powders suitable for inhalation are reviewed with an
emphasis on the practical significance.
Reference
1. Derek I.D., & Jesse Z., Review on dry powder platform for pulmonary drug
delivery.,Particuology., 2008, 225238.
2. http://www.authorstream.com/Presentation/NAGESHVANKADARA-1395362-pulmonary-
drug-delivery-sysytem/
3. Critical Reviewsin Therapeutic Drug Carrier Systems 14(4): 395-453, 1997.
4. Remingtons Pharmaceutical science, vol-1., 1990,18, 863-864.
5. Karhale Ashish A. Chaudhari Hiralal S., Ughade Prajkta L.,Baviskar Dheeraj T., Jain Dinesh
K;Int.J.PharmTech Res.2012,4(1)
6. Maryam A, Sheikh A. Alcohol based pressurized metered dose inhalers for use in asthma: a
descriptive study. Prim Care Respir J 2008; 17(2): 111-113
7. International Pharmaceutcial Aerosol Consortium, 1997. Ensuring patient care- the role of the
HFC MDI.
8. Banker G.S. and Rhodes T. R., Modern Pharmaceutics, Marcel Dekker, 4, 529-586.
9. Cole R.B. & Mackay A.D., Concepts of pulmonary physiology.,In Essentials of respiratory
disease, New York, Churchill Livingstone, 1990, 3, 4960.