Pulmonary route used to treat different respiratory diseases from last decade. The inhalation therapies involved the use of leaves from plants, vapours from aromatic plants, balsams, and myhrr. Pulmonary drug delivery is primarily used to treat conditions of the airways, delivering locally acting drugs directly to their site of action. Delivery of drugs directly to their site of action reduces the dose needed to produce a pharmacological effect.

1. 1
Pulmonary drug delivery system
Mr. Sagar Kishor Savale
[Department of Pharmaceutics]
avengersagar16@gmail.com
2015-2016
Department of Pharmacy (Pharmaceutics) | Sagar Savale
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2. Introduction
• Pulmonary route used to treat different respiratory diseases from
last decade.
• The inhalation therapies involved the use of leaves from plants,
vapours from aromatic plants, balsams, and myhrr.
• Pulmonary drug delivery is primarily used to treat conditions of
the airways, delivering locally acting drugs directly to their site
of action.
• Delivery of drugs directly to their site of action reduces the dose
needed to produce a pharmacological effect.
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• 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 (Chronic Obstructive Pulmonary
Disease) .
• This type of drug application in the therapy of these diseases is a clear
form of targeted drug delivery.
• Currently, over 25 drug substances are marketed as inhalation aerosol
products for local pulmonary effects and about the same number of
drugs are in different stages of clinical development.
Introduction
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• The drug used for asthma and COPD e.g..- β2-agonists such as
salbutamol (albuterol), Terbutalin formoterol, corticosteroids such as
budesonide, Flixotide or beclomethasone and mast-cell stabilizers such
as sodium cromoglycate or nedocromi,.
• The latest and probably one of the most promising applications of
pulmonary drug administration is
1) Its use to achieve systemic absorption of the administered
drug substances.
2) Particularly for those drug substances that exhibit a poor
bioavailability when administered by the oral route, as
for example peptides or proteins, the respiratory tract
might be a convenient port of entry.
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5. Anatomy and physiology of lungs
• The human respiratory system is a complicated organ system of very
close structure-function relationships
• The system consist of regions
 1-the conducting airways
 2-the respiratory region
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THE RESPIRATORY TRACT
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• The human respiratory system is a complicated organ system of very
close structure–function relationships.
The system consisted of two regions:
The conducting airway
The respiratory region.
• 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
• The human respiratory tract is a branching system of air channels with
approximately 23 bifurcations from the mouth to the alveoli.The major
task of the lungs is gas exchange, by adding oxygen to, and removing
carbon dioxide from the blood passing the pulmonary capillary bed.
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8. Anatomy and physiology of lungs
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9. Lung region
9
1. Nasopharynx region:
(NP)
2. Tracheobronchial
region: (TB)
3. Alveolar region: (AV)
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10. Types of cells present in lungs
Bronchi
10
1) Ciliated cells
2) Goblet cells
3) Serous cells
4) Brush cells
5) Clara cells
1) Ciliated cells
2) Clara cells
Bronchioles
Alveoli
1) Type-1 pneumocytes
2) Type-2 pneumocytes
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11. Factors affecting pulmonary drug delivery
• Inertial impaction
• Sedimentation
• Brownian diffusion
Mechanism of particle deposition in the
airways
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12. Physiological factors affecting particle deposition in
the airways
• Lung morphology
• Inspiratory flow rate
• Co-ordination of aerosol generation with inspiration
• Tidal volume
• Breath holding
• Disease states
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13. Pharmaceutical factors affecting aerosol deposition
• Aerosol velocity
• Size
• Shape
• Density
• Physical stability
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14. Advantages of pulmonary drug delivery
• 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
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15. Disadvantages of pulmonary drug delivery
• Complex delivery devices are required to target drugs to the airways
and these devices may be inefficient.
• Aerosol devices can be difficult to use
• Various factors affect the reproducibility of drug delivery to the lungs,
including physiological (respiratory maneuver) and pharmaceutical
(device, formulation) 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. Efficient drug delivery of slowly absorbed drugs must
overcome the ability of the lung to remove drug particles by
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CHALLENGES IN PULMONARY DRUG DELIVERY
 Low Efficiency of inhalation system
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.(0.5-1mm)
 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 to the
lower respiratory tract is too low less than 1000 mcg.
 Poor formulation stability for drug
Most traditional drugs are crystalline, in the case of corticosteroids,
and highly moisture sensitive drugs are unstable.
 Improper dosing reproducibility
Reason for Poor dosing reproducibility like worsening
of diseases’, problem in device, un stabality of formulation.
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FORMULATION APPROACHES
• Pulmonary delivered drugs are rapidly absorbed except large
macromolecules drugs, which may yield low bioavailability due to
enzymatic degradation and/or low mucosal permeability.
• Pulmonary bioavailability of drugs could be improved by including
various permeation enhancers such as surfactants, fatty acids, and
saccharides, chelating agents and enzyme inhibitors such as protease
inhibitors.
• The most important issue is the protein stability in the formulation: the
dry powder formulation may need buffers to maintain the pH, and
surfactants such as Tween to reduce any chance of protein aggregation.
The stabilizers such as sucrose are also added in the formulation to
prevent denaturation during prolonged storage.
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• Pulmonary bioavailability largely depends on the physical properties of
the delivered protein and it is not the same for all peptide and protein
drugs.
• Insulin liposomes are one of the recent approaches in the controlled
release aerosol preparation. Intratracheal delivery of insulin liposomes
(dipalmitoylphosphatidyl choline:cholesterol ,7:2) have significantly
enhanced the desired hypoglycemic effect.
• The coating of disodium fluorescein by hydrophobic lauric acid is also
an effective way to prolong the pulmonary residence time by increasing
the dissolution half time. In another method, pulmonary absorption
properties were modified for protein/peptide drug (rhGCSF)in
conjugation with polyethylene glycol (PEGylation) to enhance the
absorption ofthe protein drug by using intratracheal instillation delivery
in rat.
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AEROSOLS
• Aerosol preparations are stable dispersions or suspensions of solid
material and liquid droplets in a gaseous medium. 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.
• There are three commonly used clinical aerosols:
1. Jet or ultrasonic nebulizers,
2. Metered–dose Inhaler (MDI)
3. dry-powder inhaler (DPI)
• The basic function of these three completely different devices is to
generate a drug-containing aerosol cloud that contains the highest
possible fraction of particles in the desired size range.
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AEROSOL
•Definition
A suspension of very fine liquid or solid particles in a
gas.
•Key to aerosol therapy is aerosol particle
•Respirable range:1-5 micron
•80%drugs deposited in oropharynx
•10% in walls of inhaler
•10% in the lungs
( SP Newman et.al.1985 )
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AIM OF AEROSOL THERAPY
•To deliver a therapeutic dose of the selected agents to
the desired site of action.
•Choice of route for drug delivery
-Directly to the site of action
-Therapeutic action with side
Effects: high therapeutic index,
greater efficacy & safety
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•In mechanically ventilated patients
-51%within nebulizer unit
-2.2%IN Rt LUNG &0.9% IN Lt LUNG
(SH Thomas M fiddler et.Al.1993)
•In clinical settings, medical aerosols are generated with
atomizer, nebulizer or inhalers –devices that physically
disperse matter into small particles & suspend them into
a gas.
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CHARACTERISTICS OF THERAPEUTIC AEROSOLS
• Effective use of aerosols requires an understanding of characteristics of
the aerosols.
• Aerosol output (wt /minute)
• Emitted dose
This tells little about the amount of drug reaching the targeted site of
action.
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•A substantial proportion of particles that leave a
nebulizer may never reach the lungs.
•Effectiveness of medical aerosols depends on amount
of aerosol particles deposition to the lower respiratory
tract & deposition of aerosol influenced by many other
factors.
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FACTORS INFLUENCING DEPOSITION
• Physical & chemical properties of aerosols
• Anatomy of the respiratory tract
• Physiological factors
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PHYSICAL & CHEMICAL PROPERTIES OF AEROSOLS
GRAVITY
• Aerosol size must be >1 microns because at this mass
gravity loses its influence on particles. ( Chantal
Darquenne , G Kim Prisk et.al.2000 )
•Gravity influence is in direct relation with particle mass
•Greater mass—tendency to undergo proximal airway
deposition
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INERTIAL IMPACTION
Water particles
Gas molecules
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PARTICLE SIZE
•Aerosol particle size depends upon :
-- nebulizer chosen
--Method used to generate aerosol
•It is not possible to visually determine whether a
nebulizer is producing an optimal size particles…
•Aerosols traverse tubular strs in which turbulent flow is
the rule…
•>Particle size---- gravity influence
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•1-5 micron MMAD important determinant of its
deposition efficacy in LRT
•1-3 micron greater deposition
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31. Recent technologies of pulmonary drug delivery
• Nebulizers
• Metered Dose Inhaler(MDI)
• Dry Powder Inhaler(DPI)
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32. 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 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 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
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•It is an electric nebulizer
•Working principle : piezoelectric effect
ultrahigh frequency current
piezoelectric transducer
ultrahigh frequency vibrations
disk vibration
couplant (water bath)
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FEATURES OF ULTRASONIC NEBULIZER
•More expensive
•Heats up during operation , Less noise
•Less Rx time
•Large average particle size ( Joseph L Rau
et.al.2002 )
•Large output rate
•0.5 to 3 microns – 90 % of particles within effective range
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INDICATIONS FOR NEBULIZER
•Useful in children ,
Handicapped person ,
Seriously ill patients
•Ventilated patients
•Elderly individuals
•High doses can be given
•Combination drugs can be given
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•Enhancement of secretion clearance
•Sputum induction
•Humidification of respired gases
•Prevent dehydration
•Prevent or relieve bronchospasm
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Jet nebulizers Ultrasonic nebulizers
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NEBULIZER
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39. Jet nebulizer
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Jet nebulizer
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41. Ultrasonic nebulizer
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Ultrasonic nebulizer
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HAZARDS OF NEBULIZER
•Bronchospasm
•Over hydration
•Delivery of contaminated aerosols
•Tubing condensation
•Swelling of retained secretions
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DRUGS FOR NEBULIZATION
•Distilled water or normal saline
•Mucolytics : mesna , acetylcysteine
•Beta 2 agonists : salbutamol , terbutalin , fometerol ,
salmeterol
•Antimuscarinic : ipratropium bromide
•Steroids : budesonide
•Antibiotics
•Antifungal
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TECHNIQUE FOR USING NEBULIZER
• 1. Place drug solution in nebulizer,
employing a fill volume 2-6 ml
•2. Place nebulizer in Inspiratory line
• 3. Ensure airflow of 6-8 L/min through the
nebulizer.
• 4. Ensure adequate tidal volume ( 500 ml in
adults). Attempt to use duty cycle > 0.3, if
possible.
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•5. Observe nebulizer for adequate aerosol generation
throughout use.
•6. Disconnect nebulizer when all medication is
nebulized or when no more aerosol is being produced.
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Metered Dose Inhalers (MDI)
• Used for treatment of respiratory diseases such as asthma and COPD.
• They can be given in the form of suspension or solution.
• Particle size of less than 5 microns.
• Used to minimize the number of administrations errors.
• It can be deliver measure amount of medicament
accurately.
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Advantages of MDI
• It delivers specified amount of dose.
• Small size and convenience.
• Usually inexpensive as compare to dry powder inhalers and nebulizers.
• Quick to use.
• Multi dose capability more than 100 doses available.
Disadvantages of MDI
• Difficult to deliver high doses.
• There is no information about the number of doses left in the MDI.
• Accurate co-ordination between actuation of a dose and inhalation is essential.
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52. Metered dose inhalers
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Metered Dose Inhalers (MDI)
Active Ingredient Brand Manufacturer Country
Salbutamol pressurized
inhalation (100µg)
Asthalin Cipla India
albuterol Ventolin GlaxoSmithKline India
levalbuterol HCl Xopenex 3M Pharmaceuticals U.S.A.
Fluticasone50 μg Flixotide GlaxoSmithKline New Zealand
Formoterol Fumarate12
mcg
Ultratech India
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Dry powder inhalers (DPI)
• DPIs are bolus drug delivery devices that contain solid drug in a dry
powder mix (DPI) that is fluidized when the patient inhales.
• DPIs are typically formulated as one-phase, solid particle blends.The
drug with particle sizes of less than 5µm is used
• Dry powder formulations either contain the active drug alone or have a
carrier powder (e.g. lactose) mixed with the drug to increase flow
properties of drug.
• DPIs are a widely accepted inhaled delivery dosage form, particularly
in Europe, where they are currently used by approximately 40% of
asthma patients.
Advantages
Propellant-free.
Less need for patient co-ordination.
Less formulation problems.
Dry powders are at a lower energy state, which reduces the rate of
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Disadvantages
Dependency on patient’s inspiratory flow rate and profile.
Device resistance and other design issues.
Greater potential problems in dose uniformity.
 More expensive than pressurized metered dose inhalers.
 Not available worldwide
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.
Mulitidose 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.
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58. Dry powder inhalers
58
For successful delivery of drug particles
into the lung requires that particle size should
be controlled to <5 μm
Spinhaler
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59. Dry powder inhalers
59
Rotahaler Turbuhaler
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MARKETED DRUGS DRY POWDER INHALER
Active Ingredient Brand Manufacturer Country
Terbutaline 0.25mg Bricanyl AstraZeneca UK
Beclometasone
dipropionate 250mcg
Becloforte Cipla Limited India
Fluticasone propionate Flixotide GlaxoSmith
Kline
United
Kingom
Salbutamol Salbutamol Dry
Powder Capsules
Cipla Limited India
Ipratropium Bromide
20 mcg
ATEM Chiesi Farmaceutici Italy
Xinafoate Seretide Evohaler GlaxoSmithKline UK
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62. Applications
•For Asthma:
B-adrenergic agents- eg.salbutamol,terbutaline
•Pulmonary Infections:(Pulmonary aspargillosis)
• Antibiotics eg. Erythromycin & amphotericine-B
•Cardiovascular agents:Nifedipine,Nitroglycerine
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COMPARISION BETWEEN MDI &DPI
• High velocity aerosols
• Requires coordination
• Time consuming to teach
• Requires slow & deep breathing only
• Aerosol velocity depends on
inspiratory flow rate
• No coordination needed
• Easy to teach
• Requires high insp flow >28 l/min
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PATENTED DRUGS
Cited Patent
Filing date Issue date
Original Assignee
Title
US2470296 Apr 30, 1948 May 17, 1949 INHALATOR
US2533065 Mar 8, 1947 Dec 5, 1950
Micropulverized
Therapeutic agents
US4009280 Jun 9, 1975 Feb 22, 1977 Fisons Limited Powder composition for
inhalation therapy
US5795594
Mar 28, 1996 Aug 18, 1998 Glaxo Group Limited
Salmeterol xinafoate
with controlled particle
size
US6136295 Dec 15, 1998 Oct 24, 2000 MIT Aerodynamically light
particles for pulmonary
drug deliver
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RECENT ADVANCES
The Aerogen Pulmonary Delivery Technology
AeroDose inhaler.
AeroNeb portable nebulizer
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The AERx device (with dosage forms).
The AERx dosage form.
AERx nozzle array.
The AERx Pulmonary Drug Delivery System
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• The AERx aerosol drug delivery system was developed to efficiently
deliver topical and systemically active compounds to the lung in a way
that is independent of such factors as user technique or ambient
conditions.
• A single-use,disposable dosage form ensures sterility and robust
aerosol generation. This dosage form is placed into an electronically
controlled mechanical device for delivery.
• After the formulation is dispensed into the blister, a multilayer laminate
is heat-sealed to the top of the blister. This laminate, in addition to
providing the same storage and stability functions as the blister layer,
also contains a single-use disposable nozzle array.
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The Spiros Inhaler Technology
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• The inhaler has an impeller that is actuated,when the patient inhales, to
disperse and deliver the powder aerosol for inhalation.The core
technology was initially developed to overcome the patient
coordination required for metered-dose inhalers and the inspiratory
effort required for first-generation dry powder inhalers in treating
asthma.
• All motorized Spiros powder inhaler platforms use the same core
technology to achieve powder dispersion that is relatively independent
of inspiratory flow rate over a broad range. The high-speed rotating
impeller provides mechanical energy to disperse the powder.
• The Spiros DPI blister disk powder storage system is designed for
potentially moisture-sensitive substances (e.g., some proteins, peptides,
and live vaccines). The blister disk powder storage system contains 16
unit doses.
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A) Blisterdisk powder storage system.
B) The interior of a well in a
blisterdisk. Aerosol generator “core” technology
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The DirectHaler™ Pulmonary device platform
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• DirectHaler™ Pulmonary is an innovative and new device for
dry powder Each pre-metered, pre-filled pulmonary dose has its own
DirectHaler™ Pulmonary device.
• The device is hygienically disposable and is made of only 0,6 grammes
of Polypropylene. DirectHaler™ Pulmonary offers effective, accurate
and repeatable dosing in an intuitively easy-to-use device format.
 Sensitive powders
 Deep lung delivery
 High drug payloads
 New types of combination dosing
• The powder dose is sealed inside the cap
with a laminate foil strip,which is easily
torn off for dose-loading into the
PowderWhirl chamber, before removing
the cap and delivering the dose.
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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.
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•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.
•Anthony J. Hickey, Physiology of airway. In: Anthony J. Hickey, editor. Pharmaceutical
inhalation aerosols technology, second edition.vol-54.New York: Marcel Dekker;1992.p.1-24.
•Paul J. Atkins, Nicholas P. Barker, Donald P. Mathisen, The design and development of
inhalation drug delivery system. In : Anthony J. Hickey, editor. Pharmaceutical inhalation
aerosols technology, second edition.vol-54.New York: Marcel Dekker;1992.p.155-181.
•Critical Reviews in Therapeutic Drug Carrier Systems 14(4): 395-453.
•International Pharmaceutcial Aerosol Consortium, 1997. Ensurin patient care- the role of the
HFC MDI.
•Metered dose pressurized aerosols and the ozone layer. European Resp. J.3:495-497.
•Jain N. K, “Advances in Controlled and Novel Drug Delivery” 1st ed.(2010), CBS Publishers and
Distributors Pvt.Ltd. New Delhi, pp.120-156.
•Karhale A.A.et al(2012) “Pulmonary Drug Delivery system” International journal of PharmTech
Research(4)1,pp.293-305.
•Sunitha et al(2011) “Drug Delivery and its Development for Pulmonary System” International
Journal of Pharmaceutical, Chemical and Biological Sciences(1)1,pp.66-82
References
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