The document presents information on targeting drugs to the lungs for pulmonary drug delivery. It begins with an introduction and overview of lung anatomy. It then discusses the advantages and disadvantages of pulmonary drug delivery, mechanisms of particle deposition in the airways, and various systems used to target the lungs including microspheres, liposomes, nanoparticles, and dendrimers. The document provides details on different dosage forms for pulmonary delivery such as metered dose inhalers, dry powder inhalers, and nebulizers. It concludes with examples of marketed pulmonary drug products.

1. PRESENTED BY:
G.ANUSHA
M.PHARMACY
(PHARMACEUTICS)
CPS,IST,JNTUH
12/18/2013
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2.  Introduction
 Anatomy
of lungs
 Advantages and disadvantages
 Mechanism of particle deposition in the
airways
 Different systems used to target lungs
 Different dosage forms
 Marketed products
 References
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3.  There
is a continuing need for development of
new treatments for lung disease.
 Basic scientific investigations are identifying
novel targets for the development of new
approaches to therapy of a range of
respiratory conditions.
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4. The large surface area, good vascularization,
immense capacity for solute exchange and ultrathinness of the alveolar epithelium are unique
features of the lung that can facilitate systemic
delivery via pulmonary administration of
peptides and proteins.
 Physical and biochemical barriers, lack of
optimal dosage forms and delivery devices limit
the systemic delivery of biotherapeutic agents
by inhalation.

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5. 






Anatomy and Physiology of the Respiratory
System…:
Respiratory system of man consists
Upper Respiratory Tract: Consists of nose, nasal
passages, paranasal sinuses, mouth, eustachian tube,
the pharynx to the oesophagus, the laryinx and
trachea
Lower Respiratory Tract: Consists of lungs (both air
passage ways and respiratory units)
Lower Respiratory Tract:
The Lung Human lung comprises of left and right
lung, are divided into slightly unequal proportions.
Each lung is supplied by a major branch of the
bronchial tree.
The tissue substance of a lung includes air passages,
alveoli, blood vessels, connective tissues, lymphatic
vessels and nerves
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8. Improve efficiency.
 Reduced unwanted systemic side effects.
 Large surface area for absorption.
 Thin alveolar epithelium permitting rapid
absorption.
 Absence of first pass metabolism.
 Rapid onset of action.
 High availability.
 It requires small and fraction of oral dose and
low concentration in the systemic circulation is
associated with reduced systemic side effects.

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9. Oropharyngeal deposition gives local side effect.
 Patient may have difficulty using the pulmonary
drug devices correctly
 Drug absorption may be limited by the physical
barrier of the mucus layer.
 Various factors affect the reproducibility on drug
delivery on the lungs, including physiological and
pharmaceutical barrier.
 The lungs are not only accessible surface for
drug delivery complex but also delivery devices
are required to target drug delivery

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10. Deposition of drug/aerosol in the airways depends on
four factors:
i.
The physico- chemical properties of drug
ii.
The formulation
iii.
The delivery device
iv. The patient (breathing pattern and clinical status)


The particle size of aerosol is usually standardized by
calculation of its “ aerodynamic diameter ” to deliver
particles to different areas of lung.
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11. DEFINITION:
The aero dynamic diameter of a particle is the
diameter of a unit density sphere (1 gm/cm 3 )
having the same terminal settling velocity (in still air)
as the particle under consideration. It is derived from
stoke’s law
D a = ( ρ p / ρ 0 ) 1/2 D g
where,
ρ p is the particle density, ρ 0 is the standard particle
density (1 gm/cm 3 )
D g is the geometric diameter of the particle
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13. Lung deposition: - Occurs mainly by 3 mechanisms
1) inertial impaction :
 Where a bifurcation occurs in the respiratory tract,
the air stream changes direction and particles with in
the air stream having, sufficiently high momentum,
will impact on the airway walls rather than follow the
changing air stream
 Particles > 5 µ m and particularly > 10 µ m are
deposited by this mechanism
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14. 2) Gravitational sedimentation:
 As the remaining small particles move on to the central
lung the air velocity gradually decreases to much lower
values and the force of gravity becomes important
 Particles 1-5 um are deposited
 From stoke’s law particles settling under gravity will
attain constant terminal settling velocity
S Ut = ρ gd 2 /18 ŋ
 Thus, gravitational sedimentation of an Inhaled particle is
dependent on its size and density in addition to its
residence time in the airways
3) Brownian motion :
 The finest particles enter the periphery of the lung where
they can contact with the walls of the airways as the result
of Brownian motion (particle diffusion)
 smaller than 0.5 um are deposited The particle diffusion is
inversly proportional to particle size.
 Other methods include interception and electrostatic
attraction
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16. Controlled drug delivery to lungs:
 Microsphere
 Dendrimer
 Liposome
 Nanoparticles
 Gene delivery using polymeric nano-carriers
 Peptide-Mediated delivery
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17. LIPOSOMES:





Liposome can also be produced with a wide range of size
and will incorporate both hydrophilic and lipophilic drugs.
The drug carrying capacity, release rate and deposition of
liposome in the lungs is dependent upon lipid composition,
size, and charge and drug/lipid ratio.
Most liposomal carrier–drug systems have been investigated
in aqueous systems using nebulisation.
DPI liposomal formulations have been produced by
lyophilisation followed by milling or spray drying.
Encapsulation of drugs in liposome delivered to the lungs
results in increased residence time
and/or a decrease in
toxic side effects.
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18. Microparticles:
Microparticles are hollow spherical particles in which drugs
encapsulated.
 Microparticle are in the 0.1–500μm range. Microparticles
are physically and chemically more stable than liposomes ,
allowing higher loading of drugs.
 synthetic polymers - polylactic acid (PLA)
-polylactic -co-glycolic acid
 Natural polymers - albumin, gelatin, chitosan and dextran
 Coating can be used to alter the properties in vivo. Such as
mucoadhesive polymers - chitosan and
hydroxypropylcellulose increase the residence time of
peptide drug carriers in the lungs.
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19. 
Micelles:

Micelles: Drugs can be trapped in the core of a
micelle and transported at concentrations even
greater than their intrinsic water solubility. A
hydrophilic shell can form around the micelle,
effectively protecting the contents.
The advantages of polymeric micelles include better
stability than surfactant micelles,
ability to solubilize an adequate amount of
hydrophobic drugs, prolonged circulation times in
vivo, and capability to accumulate in the target
organs.

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20. 
Nanoparticles:
Nanoparticles used for dispersed liquid droplet dosage forms
such as metered dose inhalers and nebulizers, and dry
powder formulations.
 constituted of polymers or lipids and drugs bound either at
the surface of the particles or encapsulated into the
vector.
 Traditional techniques such as spray drying and grinding,
and more recent advances in supercritical fluid extraction,
precipitation, and solvent extraction have been employed
to produce nanoparticle formulations for pulmonary
delivery
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21. Solid lipid nanoparticles (SLN): Three possible
loadings of drugs can be envisaged:
( i ) Dispersion of drugs into the particle;
(ii) core-membrane model containing a membrane
improved with the drug;
(iii) core-membrane model containing a core improved
with the drug.
 In vitro release studies have showed that an
encapsulated drug into solid lipid nanoparticles can
diffuse during a period of time ranging from 5 to 7
weeks.
 Drugs like prednisolone , diazepam and camptotecin
have been incorporated into SLN for pulmonary
applications.

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22. 



Dendrimers are polymers, which have hyperbranched
structures, with layered architectures.
Dendrimers are globular repeatedly branched
macromolecules that exhibit controlled patterns of
branching with multiple arms extending from a
central core.
They are used in drug delivery and imaging at a size
typically ranging from 10 to 100 nm in diameter.
Encapsulation of therapeutic agents, particularly
peptide therapeutics.
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23. Microspheres :

Microspheres Both targeted and sustained drug release
Hydrophilic and lipophilic drugs can be entrapped or incorporated

Albumin microspheres: These are biodegradable colloidal
particles that can be prepared by either physical denaturation or
chemical cross-linking of albumin droplets. The coating of
albumin MS with surfactants could decrease the interaction with
mucus layer and possibly increase the deposition in the lower
airways Particle size range between 1.94 ± 1.47 and 3.42 ±1.51
μm have been prepared using a high-speed homogenization and
heat denaturation process. Poly ( glycolide and/or lactide )

(PGL) microspheres: These are prepared by the polymerization
of lactide and/or glycolide monomers via polyester linkages, the
hydrolysis of which will result in the breakdown of the polymers
to produce non-toxic substances.
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24.  Metered
 Dry
dose inhalers
powder inhalers
 Nebulizers.
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25.  Metered
dose inhalers…:
In MDIs, drug is either dissolved or suspended in
a liquid propellent mixture together with other
excipients, including surfactants, lubricants for
the valve mechanism and cosolvents
 A predetermined dose is released as a spray on
actuatation metering valve After actuating the
canister, expansion of the propellent when
exposed to atmospheric pressure aerosolizes the
drug.
 This active process consumes heat and thus cools
both aerosol and canister
 As it travels through the air, the aerosol warms
and the propellent evaporates, reducing the
particle size to the desirable range
 The high speed gas flow helps to break up the
liquid into a fine spray of droplets

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26. 1)
Containers: Aluminium container with a capacity of
10-30ml
2) Propellents:
 Chloro Fluoro Carbons (CFCs): Trichlorofluoro
methane (CFC-11), dichloro difluro methane (CFC-12)
and dichloro tetrafluro methane (CFC-114)
 Hydrofluoro Alkanes(HFAs) :Trifluro Monofluro Ethane
(HFA-134a) & Hectafluoro Propane (HFA-227)
 These are poor solvents for the surfactants.
 Ethonal is used to dissolve the surfactants
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27. 





Metering valve:
Reproducible delivery of small volume (25-100 μ
l) of product
Metering valve in MDIs are used in the inverted
position
Depression of the valve stem allows the
contents of the metering chamber to be
discharged through the orifice in the valve stem
and made available to the patient
After actuation the metering chamber refills
with liquid from the bulk and is ready to
dispense the next dose
To prevent undesirable layering of medication
the canister should be shaken between each puff
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28. 





Spacers
and
breath
actuated MDIs:
Spacers are positioned
between the MDIs and the
patient
The dose from an MDI is
discharged directly into
the reservoir prior to the
inhalation
Disadvantage of spacers is
they may cumbersome
The
breath
actuated
device overcomes the
coordination problem of
conventional MDI with out
adding bulk to the device
However a substantial
inspiratory flow rate is
required for its operation
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29.  Types






of medicines are available as MDIs,
including:
bronchodilators (ProAir HFS, Proventil HFA,
Ventolin HFA, Maxair, or Alupent)
inhaled steroids (Azmacort, Flovent,
Pulmicort, Qvar)
combination of long-acting bronchodilator
and inhaled steroid ( ADVAIR HFA, Symbicort)
cromolyn (Intal)
nedocromil (Tilade)
ipratropium bromide (Atrovent).
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30. A
number of metered dose inhalers,including
AERX, AERODOSE,RESPIMAT has been
developed.
A.AERE
B.RESPIMAT
C.AERODOSE
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31. 





Dry Powder Inhaler…:
The drug is inhaled as cloud of fine particles
The drug is either preloaded in an inhalation device
or filled into hard gelatin capsules or foil glister
discs, which are loaded into a device prior to use
DPIs have several advantages over MDIs
propellant free and do not contain excipients, other
than carrier
they are breath actuated, avoiding the problems of
inhalation/actuation coordination encountered with
MDIs. Less potential for formulation problems
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32. 




Disadvantages of DPIs:
Liberation of the powder from the device and the
deaggregation of the particles are limited by the
patients ability to inhale, which in the case of
respiratory disease may be impaired
An increase in turbulent airflow created by an
increase in inhaled air velocity increases the de
aggregation of emerging particles, but also increases
the potential for inertial impaction in the upper
airways and throat, so a compromise has to be found
DPIs are exposed to ambient atmospheric
conditions, which may reduce formulation stability
DPIs are generally less efficient at drug delivery than
MDIs
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33. 





Formulating DPI :
To produce particles of suitable size, drug powders
are usually micronized
The high energy powders produced have poor flow
properties
The flowability of powder affected by physical
properties
To improve the flow property, poorly flowing drug
particles are generally mixed with large carrier
particles (usually 30-50um) of an excipient, usually
lactose
Once liberated from the device, the turbulent
airflow generated with in the inhalation device
should be sufficient for the de aggregation of the
drug or carrier aggregates
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34. 
Unit Dose Devices with drug in
hard gelatin capsule

The first DPI device developed
was the spinhaler for the
delivery of sodium
chromoglycate. Each dose,
contained in a hard gelatin
capsules, is loaded individually
into the device. The capsule,
placed in a loose fitting rotor, is
pierced by two metal needles an
either side of capsule. Inhaled
air flow through the device cause
a turbo vibratory air pattern as
the rotor rotates rapidly,
resulting in the powder being
dispersed through the capsule
walls and out through the
perforation into the air. A
minimum air flow rate of 3540ltrs per minute through the
device is required to produce
adequate vibrations through the
rotor.
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35. 




ROTAHALER:
Another unit dose DPI is the rota haler , which is a simple
two piece device
The gelatin capsule is inserted into an orifice at the rear of
the device and when the two sections are rotated a fin on
the inner barrel pulls the two halves of the capsule apart
During inhalation, the freed half of the capsule spins,
dispersing its contents, which are inhaled through the
mouth piece
Others include the aerohaler and cyclohaler
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36. 




Turbuhaler , has overcome the need for both a carrier
and loading of individual doses
The device contains a large number of doses of
undiluted, loosely aggregated micronized drug, which
is stored in reservoir from which it flows onto
rotating disc in the dosing unit
The fine holes in the disc are filled and excess drug
is removed by scrapers
As the rotating disc is turned by moving a turning grip
back and forth, one metered dose is presented to the
inhalation channel
A dose indicator is incorporated
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37. Nebulizers These are applied to aerosolize drug
solutions or suspension
 Two types of nebulizers are there
i.
Jet nebulizer
ii.
ultrasonic nebulizer

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38. 



JET NEBULIZER:
unctions by the Bernoulli principle
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 drug solution being drawn up from the
fluid reservoir and shattered into droplets in the gas
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39. 

Ultra sonic nebulizer: It uses a piezoelectric crystal
vibrating at the high frequency usually 1-3 MHz To
generate a fountain of liquid in the Nebulizer
chamber The higher the frequency, the smaller the
droplet produced
disadvantages: Time consuming Inefficient Large
amount of drug wastage,
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40. Formulation of Nebulizer fluids:
 These are formulated in water, occasionally with the
addition of co solvents and with the addition of
surfactants for suspension formulations
 Stabilizers such as anti oxidants and preservatives
may also be included
 The physical property of drug formulations may have
an effect on nebulization rates and particle size
 The viscosity, ionic strength, osmolarity, pH and
surface tension may prevent the nebulization of some
formulations
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41. 








Application of pulmonary drug delivery in Asthma
and COPD.
Recent role pulmonary delivery in Patients on
ventilators
Pulmonary delivery in cystic fibrosis
In migraine
Angina pectoris
Recent use of pulmonary drug delivery in
Transplantation
In emphysema
In Pulmonary arterial hypertension
In acute lung injury
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43. REFERENCES:
•Wiley VCH verlag GmbH. Gilbert S. Banker and
Christopher T. Rhodes, Modern Pharmaceutics, Second
edition, Volume 40,
•Leon Lachman, Herbert A. Lieber Man, Juseph L. Kanig,
M.E. Aulton, Pharmaceutics, The science of Dossage form
design. Second edition, 2002.
•Remington, The Science and Practice of Pharmacy, 21st
edition,
•Volume – I, published by Wolters Kluwer health (India)
Pvt. Ltd. New Delhi. S.P. Vyas and Roop K. Khar,
• Yie W. Chien, Kenneth S.E. Su, Shyi – Feu Chang. Nasal
Systemic Drug Delivery, Marcel Dekker, INC Volume
•The controlled delivery of drugs to the lung, International
journal of pharmaceutics 124(1995) 149-164.
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