1. DRUG DELIVERY TO LUNGS PRESENTED BY V.RAVALI(M.PHARMACY)
PHARMACEUTICS
2. Contents: Introduction Physiology of respiratory system
Disorders of lungs Strategies in pulmonary delivery Challenges in
pulmonary delivery Approaches in pulmonary delivery Control
delivery of drugs to lungs Interactions of excipients Methods of
aerosol analysis Applications Marketed products Recent and future
development Summary Conclusion References
3. Introduction: Pulmonary route possesses many advantages over
other routes of administration for the treatment of specific
disease states, particularly lung associated large protein
molecules which degrade in the gastrointestinal conditions and are
eliminated by the rst pass metabolism in the liver can be delivered
via the pulmonary route if deposited, in the respiratory zone of
the lungs. Devices used to deliver drug by pulmonary route area
based on one of three platforms pressurized metered dose inhaler,
nebulizer and dry powder.
4. Anatomy and physiology of the respiratory system:
Respiratory system of man consists Upper respiratory tract:
Consists of nose, nasal passages, para nasal sinuses, mouth,
eustachian tube, the pharynx to the esophagus, the larynx 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,
5. Pulmonary blood supply: The total surface area of the
alveolar capillary is 60-80sqm and capillary blood volume is
100-200 ml. This large surface area permits rapid absorption and
removal of any substance that penetrate the alveoli capillary
membrane. Thus they produce good sink conditions for drug
absorption.
6. Lung permeability: Lungs are highly permeable to water,
lipophilic materials and most gases. And Hydrophilic substances
with large molecular size and ionic species have limited
permeability. The alveolar type-1 cells with their tight junctions
limit the penetration of molecules with a diameter less than 1.2
nm. The normal alveolar epithelium is almost impermeable to protein
and small solutes. In contrast, micro vascular endothelium has
better permeation for substances over a large range of molecular
weight.
8. Advantages of pulmonary drug delivery: Non invasive method .
Effective drug targeting to the lungs for relatively common tract
diseases such as asthma, emphysema and chronic bronchitis. Provides
very rapid onset of action avoid gastrointestinal tract problems
such as poor solubility, low bioavailability, gut irritability,
unwanted metabolites, food effects and dosing variability.
Pulmonary drug delivery having very negligible side effects
9. Strategies of pulmonary delivery: Lung deposition and
particle size: Deposition of drug/aerosol in the airways depends on
four factors. The physico chemical properties of drug The
formulation The delivery/liberative device The patient (breathing
pattern and clinical status) The breathing parameters, such as
breathing frequency and tidal volumes also play a key role in
deposition of particles in lungs.
10. Lung deposition: Lung deposition Occurs mainly by 3
mechanisms. They are Inertial impaction Gravitational sedimentation
Brownian motion Inertial impaction: Where a bifurcation occurs in
the respiratory tract, the air stream changes direction and
particles within the air stream having, sufficiently high momentum,
will impact on the airway walls rather than follow the changing air
stream. Particles > 5m and particularly > 10m are deposited
by this mechanism.
11. Gravitational sedimentation: As the remaining small
particles move on to the central lung, the air velocity gradually
decreases too much lower values and the force of gravity becomes
important. Particles 1-5 um are deposited. Thus, gravitational
sedimentation of an Inhaled particle is dependent on its size and
density in addition to its residence time in the airways. 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). Particles smaller than 0.5 um
are deposited. The
12. Drug absorption via the lung: Major physiological factors
that affect pulmonary absorption are Mucociliary transport in the
airways that constantly drains fluid and solid particle (bacteria)
in a counter current flow to the oral cavity. The epithelial cells
in the alveoli are covered by a thin layer of so called epithelial
lining fluid. This fluid is in turn is covered by a monolayer of
lung surfactant. The epithelial cell layer forms the major barrier
to absorption of drug molecule. After passing the alveolar
epithelium, the molecule enters the interstitium being part of the
extra cellular space in side the tissue. Finally, for passage into
the blood the molecule have to pass the endothelial membrane of the
capillaries, separating the interstitial space from
13. Macrophages can also form a functional barrier for some
particular drug substances during pulmonary absorption. For an
efficient pulmonary absorption process, the alveolar membrane seems
to be an optimal absorption site for a number reasons. In contrast
to the airways, there is hardly any Muco ciliary clearance from the
alveoli. The alveolar membrane forms the largest surface area in
the lung. The area of the alveoli is 43-102 m2, which is large in
comparison to the surface area of the airways which have cumulative
area of about 2.5 m2. The alveolar epithelium is thinner and
leakier than
14. Challenges in pulmonary drug delivery: Low efficiency of
inhalation system: Efficiency of presently available inhalation
systems has generally too low which is important challenge in
pulmonary drug delivery. Optimum aerosol particle size is very
important for deep lung delivery. Optimum particle size for deep
lung deposition is 15 mm. Aerosol system should have to produce
optimum size particles because they are too small, they will be
exhaled. If the particles are too large, they affects on the
oropharynx and larynx. Less drug mass per puff: To get adequate
effect with the pulmonary drug delivery practical delivery of many
drug which require milligram doses but with most existing systems,
the total amount of drug per puff delivered
15. Poor formulation stability for drug: Most traditional small
molecule asthma drugs are crystalline and, in the case of
corticosteroids, relatively moisture resistant in the dry state.
They are also rather stable in liquids as compared to most
macromolecules, which are unstable in the liquid state, amorphous,
And highly moisture sensitive in the dry state. Improper dosing
reproducibility. Following are reason for Poor dosing
reproducibility like worsening of diseases, problem in device,
unstability of formulation. To get maximum dose reproducibility
patient education play important role.
17. Meter dose inhalers: In MDIs, drug is either dissolved or
suspended in a liquid propellant mixture together with other
excipients, including surfactants, lubricants for the valve
mechanism and co solvents By this MDIS a predetermined dose is
released as a spray on actuation metering valve.
18. 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
without adding bulk to the device. However a substantial
inspiratory flow rate is required for its operation.
19. Dry powder inhalers (DPIs): Dry powder systems are
occasionally prepared from the pure drug substance. More frequently
blend with lactose are prepared. The lactose blends consist of
respirable drug particles and large (50-150) exicipient particles.
The excipient is included as diluents to aid in dispensing the drug
and as a fluidizing agent to assist dispersion. Current challenges
facing the development of these systems for macromolecules include
moisture control, efficient powder manufacturing, reproducible
powder filling, unit dose packaging and development of efficient
reliable aerosol
20. A) Flex haler B) Diskus C) Disc haler D) Hand haler E)
Aerolizer Advantages: Disadvantages:
21. Precautions of DPI: Keep your dry powder inhaler in a dry
place at room temperature. Never place the DPI in water. Never
shake or breathe into the DPI. Never use a spacer device with your
DPI. Unlike other inhaled medications, you may not taste, smell, or
feel the dry powder. This experience may be different from what you
are used to. As long as you are following the directions, you will
get your full dose of medication. If you are using a corticosteroid
medication, rinse your mouth and gargle after using the DPI. Do
not
22. Nebulizers: Nebulizers are among the oldest devices used
for delivery of therapeutic agents. These formulations are conforms
to sterile product preparations. The mechanism of delivery is
either air blast or air jet and ultrasonic systems. Droplet
delivery from an air blast nebulizer is governed by the surface
tension, density and viscosity of the fluid. Current challenges
facing the development of liquid systems for macromolecules are
formulation stability, unit dose packing, high payload delivery and
development of efficient reliable devices.
23. Nebulizer Jet nebulizer: Ultra sonic nebulizer:
24. How to use nebulizer: Assemble the nebulizer according to
its instructions. These are the basic steps: Connect the hose to an
air compressor. Fill the medicine cup with your prescription.
Attach the hose and mouthpiece to the medicine cup. Place the
mouthpiece in your mouth. Breathe through your mouth until all the
medicine is used. (Often this takes about 10 - 15 minutes). Some
people use a nose clip to help them breathe only through the mouth.
Others prefer to use a mask. Wash the medicine cup and mouthpiece
with water, and air-dry until your next treatment.
25. Controlled delivery of drugs to lungs: Sustained release
from a therapeutic aerosol can prolong the residence of an
administered drug in the airways or alveolar region, minimize the
risk of adverse effects by decreasing its systemic absorption rate,
and increase patient compliance by reducing dosing frequency. A
sustained-release formulation must avoid the clearance mechanisms
of the lung, the mucociliary escalator of the conducting airways
and macrophages in the alveolar region. Liposomes: Liposomes, as a
pulmonary drug delivery vehicle, have been studied for years and
used as a means of delivering phospholipids to the alveolar surface
for treatment of neonatal respiratory distress syndrome. More
recently, they have been investigated as a vehicle for
sustained-release therapy in the treatment of lung disease, gene
therapy and as a method of
26. Large porous particles: A new type of aerosol formulation
is the large porous hollow particles, called Pulmospheres. They
have low particle densities, excellent dispersibility and can be
used in both MDI and DPI delivery systems. These particles can be
prepared using polymeric or no polymeric excipients, by solvent
evaporation and spray-drying techniques. Pulmospheres are made of
phosphatidylcholine, the primary component of human lung
surfactant. It has also been shown that Pulmospheres can increase
systemic bioavailability of certain drugs
27. Deep-lung delivery of therapeutic proteins: For many years,
medical science has been looking for an alternative to injections
for the delivery of macromolecule drugs. Due principally to their
size, these molecules, mostly proteins and peptides, cannot
naturally and efficiently pass through the skin or nasal membranes
without the use of penetration enhancers, such as detergents or
electrical impulses. If administered orally, they are digested or
degraded before they reach the blood stream. Therefore, oral,
transdermal and nasal routes of delivery are inefficient for these
molecules. In contrast, research has shown that many of those same
molecules are absorbed naturally and quickly into the bloodstream
if they are delivered to the deep
28. Transcytosis: The body absorbs peptides and proteins into
the blood stream by a natural process known as Transcytosis, which
occurs deep in the lung. Transcytosis allows drug molecules to move
across an impermeable cell membrane without creating holes in the
cells and destroying the barrier. The process is performed by
trillions of tiny membrane bubbles, or transcytotic vesicles. Small
molecules and peptides are also thought to be absorbed through the
lung surface by an analogous process called para cellular
transport.
29. Both transcytosis and paracellular transport are
sophisticated cell processes mediated by complex cell machinery.
The result of these two processes is a noninvasive means of
delivering proteins and peptides to the bloodstream with relatively
high bioavailability and without the use of penetration enhancers.
Because the molecules are delivered rapidly into the bloodstream,
there is a much more rapid onset of action than with any other
non-i.V. delivery method.
30. INTERACTIONS OF EXCIPIENTS:
31. Methods of aerosol size analysis: The regional distribution
of aerosols in the airways can be measured directly using gamma
scintigraphy, by radiolabelling droplets or particles, usually with
the short half-life gamma emitter technetium 99m (99mTc). However,
more commonly in vitro measurements of aerosol size are used to
predict clinical performance. The principal methods that have been
employed for size characterization of aerosols are : Microscopy,
Laser diffraction Cascade impaction Time of flight Phase doppler
technique
32. Applications pulmonary drug delivery: Pulmonary delivery
could also be used for delivery of vaccines. Inhaled vaccines may
be used to prevent influenza, pneumonia, tuberculosis, measles,
cytomegalovirus, asthma, and mucosal-entry diseases such as
sexually transmitted diseases including HIV. Pulmonary delivery
could also replace some oral drugs due to the much faster onset of
action with improved absorption and avoidance of first pass losses
with delivery through the GI tract. pulmonary delivery of
macromolecule drugs like protiens and peptides.
34. Recent developments: A. AERx AeroDose B. Respimat C.
35. Conclusion : As more efficient pulmonary delivery devices
and sophisticated formulations become 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 lung's 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 sideeffects and increase
clinical effectiveness and patient compliance.
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