Pulmonary drug delivery

1www.pharmasastra.blogspot.com

CONTENTS
 INTRODUCTION.
 ANATOMY OF PULMONARY SYSTEM
 ADVANTAGES. & DISADVANTAGES.
 MECHANISMS OF PARTICLE DIPOSITION IN AIRWAYS
 FACTORS AFFECTING PARTICLE DISPOSITION IN AIRWAYS.
 PULMONARY DELIVERY DEVICES
 APPLICATION OF PDDS
 EVALUATION OF PDDS
 CASE STUDY
 REFERENCES

INTRODUCTION
 Pulmonary route was used to treat different respiratory diseases
from the last decade. The inhalation therapies involved the use of
leaves from plants, vapors from aromatic plants like balsams, and
myhrr.
 In the 1920 s adrenaline was introduced as a nebulizer solution, in
1925 nebulizer porcine insulin was used in investigational studies in
diabetes, and in 1945 pulmonary delivery of the newly revealed
penicillin was investigated.
 steroids had been introduced in between 1950s for the treatment of
asthma as a nebulizers .
 In 1956 the pressured metered dose inhaler (pMDI) was placed.
 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 .

INTRODUCTION
 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.
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 The drug used for asthma and COPD eg.- 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.

Fig 1: Different regions of the
human respiratory tract

ANATOMY AND PHYSIOLOGY OF LUNGS
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.
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.
5) 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 epithelium is much thinner and there is less
mucus in this region.

The alveolar region:-
 This is devoid of mucus and has a much flatter epithelium, which becomes
the simple squamous type,0.1–0.5 μm 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.
• 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 trache-obronchial 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 1–2 μm in
length. The cilia are hair-like projections about 0.25 μm in diameter and 5
μm 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.

ADVANTAGES:
 Rapid absorption and fast onset of action due to relatively large absorption
surface.
 It is needle free pulmonary delivery.
 It requires small and fraction of oral dose.
 Low concentration in the systemic circulation are associated with reduced
systemic side effects.
 Avoidance of the harsh environmental conditions in the gastrointestinal tract
(chemical and enzymatic degradation of drugs).
 Avoidance of gastrointestinal upset
 Avoidance of hepatic first pass metabolism and thus potential for dose
reduction compared to oral delivery.

 Difficulty in using aerosol devices.

 Oropharyngeal deposition gives local side effect.
 Low reproducibility of devices which is unacceptable in cases of
drugs with low therapeutic index
 Absorption limited by the mucous layer.
 Mucociliary clearance reduces the retention of drugs in the lungs [this
is not good in poorly soluble or slow absorbed
 Oropharyngeal deposition gives local side effect.
 Patient may have difficulty using the pulmonary drug devices correctly
 Necessitates frequent dosing
Disadvantages

OROPHARYNX
T-B AIRWAYS
PULMONARY PARENCHYMA
B
L
O
O
D
G
I
TRACT
LYMPH NODES
SITES OF DEPOSITION IN THE
LUNGS

Regions of Drug absorption
in the Pulmonary Epithelium

Mechanisms of particle deposition in the airways
Major:
Minor:
Diffusion
Sedimentation
Impaction
Interception
Electrostatic
Naso-pharyngeal:
impaction, sedimentation, electrostatic
(particles > 1 μm)
Tracheo-bronchial:
impaction, sedimentation, diffusion (particles
< 1 μm)
Pulmonary:
sedimentation, diffusion (particles < 0.1 μm)

1.Inertial impaction
 This is the main deposition mechanism for particles >1 μm
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
 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.

Impaction
Particle cannot follow the trajectory due to its inertia and hit the wall
called impaction. Impaction increases with particle size and flow rate.
This type of deposition occur through out the lung. This is important,
especially in the head airway where most of the large particles are
screened out
Impaction occurs mostly in the upper generation airways due to high
velocity

2.Sedimentation:-
 The dispersed phase undergoes sedimentation under the force of
gravity or by an imposed centrifugal force. It becomes highly
important for particles that reach airways where the airstream
velocity is relatively low, e.g. the bronchioles and alveolar region.
 Deposition by sedimentation increases with an increase in particle
mobility.
3.Brownian diffusion:-
 The deposition of particle by diffusion is significantt when the particle are
sufficiently small.
 This is of minor significance for particles >1 μm.
 The chances of particle deposition by diffusion increases with the particle
size decreases and it is independent of particle density.
 Brownian diffusion is also more common in regions where airflow is very
low or absent, e.g. in the alveoli.
4.Interception: is of important for fibers but it may not for drug delivery.
Generally Particles bigger than 10 μm will have impact in the upper airways
and are rapidly removed by swallowing, coughing and mucociliary
processes.

Sedimentation
• When gravitational force act on the particle
• Particles will settle to the lower surface of the airway. This occur
more in the lower generation where the velocity is much lower and the
airway is smaller
• Lung airways have different orientation so deposition of particle will
be different depending on the direction of the particle flow and
direction of gravitational force
Force
Force

Diffusion
Cause by Brownian motion
Diffusion is the deposition mechanism for small particles. Diffusion
depends increases with decreasing particle size and flow rate.
More deposition occurs in the alveoli region because longer
residence time and smaller airway.

APPLICATIONS
1) In Asthma and COPD:
 Asthma is a chronic lung that disease is characterized by
inflammation and narrowing of airways & it causes recurring period
so wheezing, shortness of breath, chest tightness and coughing. For
treatment of asthma for ex-levo salbutamol inhalers which show
greater efficacy as compare to salbutamol.
 COPD means chronic obstructive pulmonary diseases. For the
treatment of COPD titropium inhalers are present in market.
2) pulmonary delivery in patients on ventilators:
 Now a days Baby mask is used as patient device &. is attached to
spacer for small tidal volumes and low inspiratory flow rates infant and
young Childers.
 We can easily give medication to child up to 2 years by using baby mask
.
3) In cystic fibrosis: Ex:N-Acetylcysteine, Tobramycin
4)In Diabetes: Insulin Inhalers
5)In Migraine: e.g. Ergotamine
6)In Angina Pectoris: Nitroglycerine
7) Role in vaccination : Nearly 100 vaccines are approved in the U. S.
Recently inhaled measles vaccine given by nebulizer. & also for
influenza.

APPLICATIONS
 Pulmonary delivery of lower molecular weight Heparin.
 Controlled delivery of drugs to lungs
 Pulmonary delivery of drugs for bone disorders
 Pulmonary delivery of opioids as pain therapeutics
 Gene Therapy via Aerosol
 In Cancer chemotherapy

Factors effecting particle deposition in airways
1.Physiological Factors.
2.Pharmaceutical Factors.

PHYSIOLOGICAL FACTORS
 Lung morphology.
 Each successful production of the tracheo bronchial 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.
 Inspiratory flow rate(IFR)-
 When the IFR 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.
 Co-ordination of aerosol generation with inspiration.
 Tidal Volume.
 Breath Holding.
 Oral vs. Nasal breathing.

PHARMACEUTICAL FACTORS
1) Aerosol velocity:
 DPIs, nebulizers depend on inspired air (IFR) i.e. Droplets carried by the
effect of inspired only.
 PMDI’s generate droplets with velocities >IFR
therefore greater tendency to impact on the or pharyngeal region.
2)Shape.
 Shape of particles has a substantial effect on the aerodynamic
behaviour of particles.
3)Density.
4)Size of particles.

Factors effecting particle deposition in airways
 Aerosol property:
 Air Flow property:
 Respiratory tract:
Size distribution (MMD, AMD. Etc)
Concentration
Particle hygroscopicity
Gas particle interaction
Chemical reaction
Particle surface charge
Lung capacity
Breathing frequency
Lung structure and morphology
Model uses: Weibel, Raabe, and Horsfield

Aerosol Properties
 Size and density of the aerosol will determine where the aerosol will
deposit. Each of the major mechanisms are depended on particle
size and mass.
 Retention rate of aerosol is depended on the type of aerosol (wet/dry)
and on the chemical composition of aerosol.
 Particle interaction are important because it can lead to changes in
size and concentration via condensation and nucleation.

Air flow property
Breathing frequency determines the rate which air enter the lung and
exit. Breathing frequency is either controlled during respiratory study or
the patient breaths at normal breathing rate.

Respiratory tract
 Deposition varies depending the respiratory tract uses.
 This can be different type of lung, species, or different model.
 Model can range from a very simple idealized lung to a very
complicated airway arrangement.

Weibel’s Lung model
 Developed in 1963 by Weibel’s et al.
as a symmetrical tree lung model for adult
with 35 branching angle
 Feature a symmetry in all tubes of the
same generation with identical geometric
parameter (diameters, lengths, branching
and gravity angle)
 Same number of tubes along each
pathway
 Simplest model of human lung and is
widely used
 Used Bronchogram to develop the
model
Weibel,1963 plastic cast

Raabe Lung Model
Made in 1976 by the Lovelace foundation
The lung’s airways are asymmetric making the
model more realistic but difficult to model
Lung is divided into 5 area:
Right Upper
Right Middle
Right Lower
Left Upper
Left Lower
Structure of the lung was taken from replica of
human lung casts.

Deposition Experiment

Human Experiment
Most human experiments are for clinical trial of experimental drug.
Volunteer
breaths in
a specific
amount
Use to find
Particle size
Use to find Specific
activity
Capture
Exhale
aerosol
The exhale
aerosol sample is
collected at
different time
point for retention
rate
Ultrafine Particle Deposition in Subjects with Asthma 35www.pharmasastra.blogspot.com

Disorders of lungs:
 Acute bronchitis:
 Chronic bronchitis:
 Bronchiectasis:
 Asthma:
 Pulmonary hemorrhage
 Pulmonary emphysema:
 Pulmonary edema:

Pulmonary Delivery Devices
 Drug delivery to lung can be achieved primarily through two
mechanism, viz, via an aerosol or direct instillation
 Aerosol is more common for PDDS
 Aerosol preparations are stable dispersions or suspensions of solid
material or 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 respirable size range.

NEBULIZERS
 Nebulizers are widely used as aerosolize drug solutions or
suspensions for drug delivery to the lungs and are particularly useful
for the treatment of hospitalized patients.
 Delivered the drug in the form of mist into the lungs.
 There are two basic types:
1) Air jet(pneumatic)
2) Ultrasonic nebulizer(electric)

Jet nebulizers

In this device ultrasound waves
are generated by ceramic
piezoelectric crystal , which
vibration on electric excitation
The surface waves produce
small droplets that are carried
away by air stream for
inhalations
Ultrasonic nebulizers

Advantages of Nebulizers
 Droplet size 1-10um
 Allow adjustment of air flow to suit the inhalation rate of patients.
 Large quantity of drug can be delivered through continuous
nebulization.
 Aerosolized most of drug solutions
 Suitable for infants and people who are too sick.

Disadvantages of Nebulizers
 Time consuming
 Bulky
 Non- portable
 Content may be easily contaminated
 Relatively expensive
 Poor delivery efficacy
 Drug wastage
 Wide performance variation between different models and
operating conditions

 Used for treatment of respiratory diseases such as asthma and COPD.
 Metered-dose inhalers (MDIs), introduced in the mid 1950.
 Particle size of less than 5 microns.
 Used to minimize the number of administrations errors.
 It can be deliver measure amount of medicament
accurately.
43
Metered Dose Inhalers (MDI)

 In MDIs, drug is either dissolved or suspended in a liquid
propellant mixture together with other excipients, including
surfactants, and presented in a pressurized canister fitted
with a metering valve.
 A Predetermined dose is release when up on actuation.

Advantages of MDI
 It delivers specified amount of dose.
 Compact , Portable , 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.
 Sealed environment(no degradation of drug)
 Reproducible dosing
Disadvantages of MDI
 Difficult to deliver high doses, Maximum dose of 5mg
 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.
 High oral deposition
 For limited range of drugs availables

Essential requirements
Container:
Tin-plated steel, plastic coated glass or aluminum canisters.
Propellants:
1.Chloroflurocarbons.
2.Hydroflouroalkanes.
Metering Valve:
It permits the reproducible delivery of small volumes. It is
generally present in inverted position.
Actuators and Inhalational Aids: Spacer prevents exhaling
into the reservoir and improve the fraction of drug deposition
in the drug
Formulation Components: Propellants, surfactant
Filling Metered Dose Inhalers:
1.Cold Filling.
2.Pressure Filling.

Marketed products:
For Asthma
OMNARIS® (ciclesonide) Nasal Spray
ZETONNA™ (ciclesonide) Nasal Aerosol
For COPD:
BROVANA® (arformoterol tartrate) Inhalation Solution
XOPENEX® (levalbuterol HCl) Inhalation Solution
ALVESCO® (ciclesonide) Inhalation Aerosol
For Allergies

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
MARKETED DRUGS Dry Powder InhalerMetered Dose Inhalers (MDI)

Active Ingredient Brand Manufacturer Country
Salbutamol pressurised
inhalation (100µg)
Asthalin Cipla India
albuterol Ventolin GlaxoSmithKline India
levalbuterol HCl Xopenex 3M Pharnaceuticals U.S.A.
Fluticasone50 μg Flixotide GlaxoSmithKline New Zealand
Formoterol Fumarate12
mcg
Ultratech India

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
Therapetic 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
PATENTED DRUGS

Cited Patent Filing date Issue date Original
Assignee
Title
US6254854 May 11, 2000 Jul 3, 2001 The Penn
Research
Foundation
Porous particles
for deep lung
delivery
US6921528 Oct 8, 2003 Jul 26, 2005 Advanced
Inhalation
Research, Inc
Highly efficient
delivery of a large
therapeutic mass
aerosol
US7842310 Nov 19, 2002 Nov 30, 2010
Becton, Dickinson
and Company
Pharmaceutical
compositions in
particulate form
US7954491 Jun 14, 2004 Jun 7, 2011 Civitas
Therapeutics, Inc
Low dose
pharmaceutical
powders for
inhalations

DRY POWDER INHALERS(DPIs)
 This device dispenses a powder in a stream of inspired air
or as cloud of fine particles.
 The drug is either preloaded in a inhalation device or into
hard gelatin capsules or foil blister discs.

 They are propellant free and do not contain any excipient
other than carrier like lactose.
 Powder dispersion in DPI devices is accomplished passively,
by the patient’s own inspiratory effort or actively by
component( e.g. electronic vibrator, impeller ) in the DPI
device.
 DPIs are a widely accepted inhaled delivery dosage form,
particularly in Europe, where they are currently used by
approximately 40% of asthma patients.

CLASSIFICATION
They are commercially available in two types:
1.Unit dose ( drug filled gelatin capsule)
• Spinhaler.
• Rotahaler.
2.Multi dose( reservoir)
• Turbuhaler.
• Diskhaler.
The performance of DPI is generally dependent on the drug , carrier and
the design of the dosing device.
Micronized or microcrystalline drug with small particle size (<5um) is
desirable
To improve their handling from a manufacturing perspective, drug is
mixed with large lactose particles( bulking agent for micronized drug
PulmoSpheres which readily deaggregate with little energy

Spinhaler:The capsule is placed in a loose-fitting rotar and is pierced
through 2 needles.Inhaled air flow through the device causes
rotation of rotar resulting in the powder being dispersed to the
capsule walls and out through the perforations into the air
Rota haler: The capsule is inserted into an orifice at rear of the
device and when the two sections are rotated a fin on the inhaler
barrel pulls the two halves of the capsule spins,dispersing its
contents,which are inhaled through the mouthpiece.

Diskhaler:Here aluminium foil blisters are placed in
disc.Needle will pierce the blisters as air flows the blisters
causes the powder to disperse as the patient will inhales
through the mouthpiece.
Turbohaler:Here drug is present in reservoir from which it
flows to disc.The disc is rotated by moving the turning grip
back and forth thus drug is released which is inhaled by
patient.

Disk Haler

Dry Powder inhalers

Advantages of DPIs
 Compact
 Portable
 Breath actuated
 Easy to use
 No hand mouth-mouth co-ordination required
 Propellant free
 Less formulation problems.
 Dry powders are at a lower energy state, which reduces the rate of
chemical degradation.

Disadvantages of DPIs
 Respirable dose dependent on inspiratory flow rate
 Humidity may cause powders to aggregate and capsules to soften.
 Dose lost if patient inadvertently exhales into the DPI.
 Most DPIs contain Lactose

EVALUATION OF PDDD
 Cascade impactors
 In- vitro
 In-vivo
 Continuous cell cultures
 Primary cell cultures
 Air-interface Cultures
 Passive Inhalation
 Whole Body Exposure System
 Head only or Nose only exposure systems
 Direct Intratracheal Administration
 Intranasal Administration

Cascade impactors
 Cascade impactors operate on the principle of inertial impaction.
 Each stage of the impactor comprises a series of nozzles or jets
through which the sample laden air is drawn, directing any airborne
towards the surface of the collection plate for that particular stage.
 Whether a particular particle impacts on that stage is dependent on
its aerodynamic diameter.
 Particles having sufficient inertia will impact on that particular stage
collection plate, whilst smaller particles will remain entrained in the
air stream and pass to the next stage where the process is repeated.
 The stages are normally assembled in a stack or row in order of
decreasing particle size.
 As the jets get smaller, the air velocity increases such that smaller
particles are collected.

Cascade impactors
 At the end of the test, the particle mass relating to each stage is
recovered using a suitable solvent and then analysed usually using HPLC
to determine the amount of drug actually present.
 The Andersen Cascade Impactor (ACI) is most commonly used
impactor within the pharma industry for the testing of inhaled products.
 The ACI is an 8-stage cascade impactor suitable for measuring the
aerodynamic particle size distribution (APSD) of both MDIs and DPIs.
 This is also used to measure parameters like Fine Particle Fraction(FPF)
and mass median aerodynamic diameter(MMAD).
Limitation
 Measurements in cascade impactors are done at room temperature and
at low relative humidity which is not representative of human airways
ambient conditions.

Cascade impactors

In-vitro
 In vitro model is used in this method
 It is important that epithelial cells form a tight monolayer in order to
represent the natural epithelial barrier.
 Monolayer tightness and integrity are classically assessed by
measuring Trans Epithelial Electrical Resistance( TEER) and
potential difference across monolayer
 Monolayer of lung epithelial cell allow characterization of drug
transport, assessment of potential drug and formulation toxicity.

In-Vivo
 Animal study is carried out to get information on drug deposition,
metabolism, absorption and kinetic profile as well as drug and
formulation tolerability
 Non- human primates are used in advanced research
 By contrast , small rodent( mice , rats and guinea pigs ) are
common models for initial studies on pulmonary drug delivery.
 Human branching is symmetric , in contrast monopodial branching
of non human primates mammals.
 Different mucocilliary clearance
 Large mammal have longer airways than small rodents.

Continuous cell cultures
 Continuous cell culture is more reproducible and easier to use than
primary cell culture but often don’t have differentiated morphology and
biochemical characteristics of original tissue.
 There are few cell line derived from alveolar epithelial cells
 A549 is type II alveolar epithelial cell line that originates from human
lung adenocarcinoma.
 It is used to study metabolic and toxicological studies.

Air- Interface culture
 Air interface culture are models that allow aerosol particle to deposit
directly onto semi dry apical cell surface.
 Drug deposition and dissolution occur in a small volume of cell lining
fluid, a situation that mimics more closely the deposition on the lung
surface in vivo.
 The AIC showed greater similarity to airways epithelial morphology,
with greater glycoprotein secretion, more pronounced microvilli.

Passive Inhalation
 During passive inhalation of aerosolized drug, animal are kept
awake and allowed to breathe normally.
 Device most frequently used are nebulizers
 Passive inhalation is principally used in the mouse and less
frequently in larger animals(rat, dog, guinea pig)
 Drug concentration in the aerosol is determined by sampling.

Whole Body Exposure System
 In whole body exposure system, animal are placed in a sealed plastic
box that is connected to nebulizer or generator dry powder aerosol.
 There is potential drug absorption across the skin after deposition on
animal fur, from the nasal mucosa and from GIT.

Head only or Nose only exposure system
 In Head only or Nose only exposure systems, the animal is
attached to the exposure chamber and only the head or nose
is in contact with aerosol.
 The system can be designed for delivering drugs to one or
several animal.
 Compared to whole body exposure system, this method offer
several advantages

Direct intratracheal administration
 Dry powders can be delivered intratracheally using a powder
insufflator or by generating a powder aerosol.
 It is done to measure drug deposition and systemic drug
absorption.
 Advantages of intratracheal administration of drugs include the
perfect control of the drug dose delivered , absence of drug losses
in instrumentation, bypassing of nasal passages .

Intranasal administration
 Intranasal administration is mostly known for local drug delivery to the
nasal mucosa but it can be used for intrapulmonary drug
administration in mice.
 Intranasal administration is performed on the anaesthetized mouse
kept in a vertical position.
 With the help of micropipette, the drug solution is deposited on nostril
and simply aspired in respiratory airways during breathing.

Characterization of novel spray-dried
polymeric particles for controlled
pulmonary drug delivery

A. INTRODUCTION
B. MATERIALS AND METHODS
 1. Materials
 2. Preparation of nanoparticles
 3. Size measurements of nanoparticles prepared by
solvent evaporation
 4. Scanning electron microscopy (SEM)
 5. Preparation of spray-dried particles
 6. Size measurements of spray-dried particles
 7. Confocal laser scanning microscopy (CLSM)
 8. Gas adsorption measurements
 9. Aerodynamic properties
 10. In vitro drug release studies
C. RESULT AND DISCUSSION 76www.pharmasastra.blogspot.com

 Materials
 Poly(D,L-lactide-co-glycolide)
(PLGA) polymers
 Poly(vinyl alcohol) (PVA),
 Sildenafil
 Coumarin 6 (98%)

 Preparation of nanoparticles
 solvent evaporation technique
 Size measurement by DLS

 Scanning electron microscopy

 Preparation of spray-dried
particles
 Use of - Nano Spray Dryer B-90

 Size measurements of spray-
dried particles
 By- 1.SEM images
2. laser diffraction

 Confocal laser scanning
microscopy (CLSM)
 Spray-dried coumarin 6-loaded
particles, argon laser with an
excitation wavelength of 488 nm
 green fluorescence

Gas adsorption
measurements
To characterize the
surface properties
Adsorption and
desorption
measurements using
nitrogen

 Aerodynamic properties

RESEARCH PAPER

ABSTRACT

Materials and Methods
 Micronized crystalline fluorescein powder (Acid form; mean diameter
2.6 mm)
 Four grades of hydroxypropylcellulose (HPC; SL, L, M and H)
 Other chemicals (e.g., ethanol, acetonitrile and tetrabutylammonium
hydroxide)
 All chemical were of analytical grade and used as received from Wako
Pure Chemical Industries (Osaka, Japan).

Preparation of microspheres
Initially two types of fluorescein microsphere
are prepared using HPC-H
Fluorescein was suspended or dissolved in
aqueous or ethanol HPC-H solution (0.7–
2.0% w/v), respectively. spray dried
Similarly, fluorescein microsphere containing
each of other 3 grade were prepared, but
only from ethanol solution.
Both aqueous and ethanol spray solutions
were sprayed from a0.4mm at rate of
15ml/min and pressure of 2.5kg/ csq
Microsphere were characterized by SEM,X-
Ray Diffraction, solubility was determined.

Powder aerosol generation and aerosol
administration into the guinea pigs

Characterization of fluorescein microspheres with HPC

Effect of fluorescein–HPC ratio on fluorescein
disposition in the lung

Discussion
 Respirable-sized powder microspheres were successfully prepared
by spray-drying, and incorporating either crystalline or amorphous
fluorescein and a variety of HPC (SL, L, M and H types) at different
ratios (1:1–1:10)
 Respirable-sized fluorescein /HPC-H microspheres (ratio 1:4)
prolonged the retention time in the lungs, absorption became
reduced and extended when crystallinity was maintained
 In contrast, the absorption was successfully enhanced for the HPC-
H microspheres by incorporating amorphous fluorescein (ratio 1:4),
achieving a bioavailability of 88.0%
 Interestingly, irrespective of the fluorescein–HPC ratio or HPC
grade, all amorphous fluorescein /HPC microspheres showed rapid
absorption.
 This was primarily due to the enhanced dissolution of amorphous
fluorescein (6.5-fold greater solubility compared to the crystalline)

Conclusion
 The pulmonary absorption of poorly soluble fluorescein was enhanced
by preparing respirable sized microspheres with a mucoadhesive
polymer, HPC.
 The spray-drying of ethanol solutions, dissolving both fluorescein and
HPC, altered fluorescein’s crystallinity to the amorphous form, which
enhanced dissolution when compared to the crystalline counterpart.
 More importantly, these microspheres were successful in retarding
mucociliary clearance, when highly viscous HPCs (L, M and H types;
1:4) were employed.
 Consequently, amorphous fluorescein /HPC-H microspheres (ratio 1:4)
showed rapid absorption and, hence, achieved 88.0% bioavailability, a
value 1.9-fold higher than that obtained for crystalline fluorescein
(‘control’, 45.6%).
 This was only achieved by virtue of both increased dissolution of
amorphous fluorescein and the retarded mucociliary clearance in the
lung.

REFERENCES
1. CONTROLLED DRUG DELIVERY CONCEPTS AND
ADVANCES BY-S.P.VYAS & R.P.KHAR
2. MODERNPHARMACEUTICS FOUTH EDITION BY-
BANKER & RHODES
3. ADVANCE IN CONTROLLED AND NOVEL DRUG
DELIVERY BY-N.K. JAIN
 Enhanced pulmonary absorption following aerosol
administration of mucoadhesive powder microspheres
Masahiro Sakagami*, Kiyoyuki Sakon, Wataru Kinoshita, Yuji
Makino DDS Research Laboratories, TEIJIN Ltd.,
Asahigaoka, Hino, Tokyo 191-8512, Japan
1. WWW.Google.com

Pulmonary drug delivery

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