2

Aerosals and Aerosal Drug
Delivery System
Anyarat Wanitchakorn
Fellow in training Pediatric
Allergy and Immunology
Ramathibodi hospital
Scope for today
Aerosolized medications
Definition and Types of Aerosols
Factors That Affect Aerosol Deposition
Categories of aerosol drug delivery
devices
Points to consider in selection device

Current treatment guidelines for the
management of asthma and COPD
recommend inhaled therapy the
asprimary route for administering
2-agonists
Anticholinergics
corticosteroids
Middletons 8th edition

Aerosolized medications
Drug formulation properties
particle size distribution
selected the delivery system
Selection of an inhalation device
appropriate particle size and lung delivery
Inhalation technique
inspiratory flow rate, inspiratory volume,
and breath-holding time
determines the dose of inhaled drug
that deposits in the lung
Revolution
in 1989
The Montreal Protocol called for the
elimination of chlorofluorocarbons (CFCs) in
pMDIs as a response to the depletion of the
earths ozone layer by CFCs
The introduction of hydrofluoroalkane (HFA) as

an alternative propellant for pMDIs has led to
the availability of low-velocity propellant-driven
aerosols

Revolution
major design changes in all 3 categories of
aerosol drug delivery devices
pMDIs
dry powder inhalers (DPIs)
nebulizers
The innovation of DPIs has eliminated the need
for the actuation-inhalation coordination that is
required for pMDI drug delivery

Definition and Types of Aerosols
An aerosol
a two-phase system defined as a
dispersion or suspension of solid
particles or liquid droplets in a gaseous
medium (e.g., air, oxygen, heliox)
Living environments
natural : pollen, bacteria, viruses, house dust
man-made aerosols, : asbestos fibers, coal
and mineral dusts, cigarette smoke

ADVANTAGES AND DISADVANTAGES IN
RESPIRATORY DISEASE
ADVANTAGES
noninvasive and painless
delivers drugs directly to the airway surfaces,
receptor sites
delivery of high drug concentrations to the airway
more rapid onset of action
inhaled 2-agonist bronchodilators aerosal vs oral
reduced systemic dose and side effect

ADVANTAGES AND DISADVANTAGES IN
RESPIRATORY DISEASE
DISADVANTAGES
Less-than-optimal technique drug delivery
potentially and efficacy
Techniques differ between device categories and

devices within a specific category
less convenient than oral drug administration

more time is required for drug administration

Definitions for Commonly Used Terms
The prediction of deposition : efficiency for a

therapeutic aerosol based on
Mass Median Aerodynamic Diameter (MMAD) :
Divides the aerosol size distribution in half diameter at which
50% of the particles of an aerosol by mass are larger and
50% are smaller than the median diameter
Fine Particle Fraction (FPF)

the fraction of particles that can achieve deposition in the
lower respiratory tract

(a) cumulative
(b) distribution curves
for Beclovent (MDI)
used with an
Aerochamber
Br J Clin Pharmacol2003, 56, 588599

Dolovich MB. Aerosols In Asthma,
Philadelphia: Lippincott-Raven
Publishers, 1997; 13491366.
Labeled dose (LD)* or nominal dose

dose that is metered and specified on the
inhaler package
Emitted dose (ED) or delivered dose
The mass of drug emitted per actuation that is
actually available for inhalation at the
mouth
Factors That Affect Aerosol Deposition
(1) Physical factors

(2) Ventilatory
(3) Anatomic factors
(4) Patient-related
factors
PHYSICAL FACTORS:
PARTICLE SIZE DISTRIBUTION
The size of an aerosol particle is the primary

determinant of the site of lung deposition,
distribution of the drug within the lung, and
resulting deposition efficiency
Therapeutic aerosols targeted to the lower

respiratory tract are composed of particles
typically between 0.5 m and 10 m in diameter

PHYSICAL FACTORS:
Deposition of particles onto surfaces in the lung mainly
three physical mechanisms:

impaction
a function of particle inertia and affects particles
greater than 5 m
Sedimentation
gravitational forces acting on particles primarily
between 0.5 and 5 m
Diffusion
brownian motion and affecting particles smaller than
1 m in low-flow regions of the lung
PHYSICAL FACTORS:

Brownian motion

)

PHYSICAL FACTORS:
Mechanisms of lung deposition

>10um
Oropharyngeal
10-5 um large
conducting airway
oropharynx
<5um
(>50%=3
um)
The effect of aerosol particle size on the site of
preferential deposition in the airways
: , emove
Nose: > 10 um dremove
r
Mouth > 15 1imd
10 m
Fiirst
5- 6
generations)
(
_ 1-5 ,u:m
(Last 5- 6
generations)1
T
The effect of altering particle size
Total lung deposition

56% 46%
posterior thorax images of technetium-99mlabeled

albuterol aerosol deposition in the lungs
Am J Respir Crit Care Med 2005;172:1497-1504.

ANATOMIC FACTORS:
AIRWAY CALIBER AND DISTORTION DUE TO DISEASE
Healthy vs asthma pt with FEV1 =31%
The image on a gamma camera scan of lungs

after inhaling 0.9% saline aerosol containing
technetium-99m sulfur colloid
JAMA 1993;269:2106-9.
VENTILATORY FACTORS:
INSPIRATORY FLOW RATE AND BREATH HOLD
Deposition at airway bifurcations

exaggerated in airway narrowing secondary to disease
Particles larger than 5 m

deposit to a greater extent in conducting airway surfaces
and less in the peripheral lung
Particles smaller than 5 m

tend to deposit by sedimentation and diffusion on
successively smaller airways
VENTILATORY FACTORS:
INSPIRATORY FLOW RATE AND BREATH HOLD
Particles between 0.1 and 1.0 m

remain suspended, these particles tend to be exhaled
rather than deposited
20% of these extrafine pMDI aerosols will be exhaled
Aerosol particles and the air stream velocity

inhaling an aerosol at a low flow rate
impaction in larger airways
inhalation with a prolonged breath hold to
allow greater time for sedimentation and
diffusion occur in the peripheral airways

Maximum deposition is obtained in the pulmonary
region for particles approximately 3 m in size

The effect of the drug aerosols particle size on
therapeutic efficacy
(a) Percent improvement in forced expiratory volume in 1 s (FEV1) following inhalation

of two different size aerosols of salbutamol, 3.3 um and 7.7 um
(b) FEV1 following inhalation of two different size aerosols of ipratropium bromide, 3.3
um and 7.7 um
Johnson MA et al. Chest1989; 96: 110 [9].

PATIENT-RELATED FACTORS:
ABILITY TO CORRECTLY USE THE DELIVERY SYSTEM AND COMPLIANCE
pt have never been taught

pt have modified the technique after instruction
the various techniques that are appropriate for each
device
the advantages and disadvantages of each device
Health care providers should ensure that their

patients can and will use these devices correctly

NEBULIZERS FOR LIQUID FORMULATIONS
Jet Nebulizers
Conventional pneumatic
nebulizers
Jet Nebulizers
nebulizers
The MMAD of jet nebulizers used for therapy should

be between 2 and 4 m
jet nebulizer delivers aerosol continuously while the
patient inhales and exhales.
30% to 40% of the nominal dose is trapped in the
nebulizer
60% of the ED is wasted to the atmosphere during
exhalation
< 10% of the nebulizer contents to the patient

Jet Nebulizers
Conventional pneumatic nebulizers
breath- nhanced devices
e
allows additional room air to be entrained during
inspiration
increa sing the amount of useful aerosol for inhalation
air als o may be entrained through a T-piece or face ask
m g the jet air flow rate to meet the inspiratory
supplementin ents of the patient
flow requireme total drug delivered to the patient per unit
increase in th ulizers with additional air entrainment
time from neb
Jet Nebulizers
nebulizers
Solvent
rate ofevaporates
evaporationduring
depends on the volume of fluid placed in
nebulization
the reservoir
reservoir fill volume of 3 to 5 mL
the dead volume, at the end of nebulization(no further
aerosol is produced)
0.5 to 1.5 ml of concentrated solution is left
drug that is unavailable to the patient

Jet Nebulizers
The driving pressure or the flow rate of compressed air

affects aerosol output and particle size from jet NB
higher the pressure or flow rate, the greater the output

over time in terms of total solution aerosolized, and the
smaller the particle size
time required to deliver the medication

varies with the airflow rate used to drive the nebulize
Typical treatment times range between 5 and 15 minutes

Jet Nebulizers
Face masks
acutely ill or uncooperative patients such as infants and
toddlers
face mask with vent holes should be used reduce
deposition on the face and in the eyes

Jet Nebulizers
Mouthpiece
direct the aerosol toward the nose and mouth
usually in a child
blow-by technique

Exercise
Which one is suitable for patient?
this
A B
Ultrasonic Nebulizers
a piezoelectric crystal
vibrated at a high frequency
create standing waves on the surface of the
liquid overlying the crystal

operate at frequencies above 1 MHz

producing aerosols with MMADs between 2 and 12 m
an output that is two to three times higher than with most nebulizers
jet
F.Pereira Mucho.J Pediatr.2010

Droplets are formed that remain within the nebulizer until
they are swept out by a fan or the patients inspiratory
breath
Produced heat along with the aerosol, however

the ultrasonic nebulizer solution is sonicated

temperature can rise 10 to 15 C over a 10-min
adversely affect heat-sensitive components of formulations,
such as proteins
not suitable for nebulizing suspensions

NEBULIZERS: POINTS TO CONSIDER IN
SELECTION OF DEVICE

PRESSURIZED METERED-DOSE INHALERS
Formulation Issues
CFC propellant pMDIsHFA propellant pMDIs

(mandated by the Montreal Protocol)
HFA
medically safe
nontoxic to animals and humans
devoid of pharmacologic activity,
can be co-solved with
corticosteroids
HFA, hydrofluoroalkane
CFC, chlorofluorocarbon

High-speed photographs of the plume geometry
of albuterol aerosols
Top, HFA albuterol (Airomir, 3M Pharmaceuticals)

Bottom, CFC albuterol (Ventolin, GlaxoSmithKline)

Dolovich M, Leach C. Drug delivery devices and propellants. In: Busse W, Holgate S,
editors. Asthma and rhinitis. 2nd ed. Oxford: Blackwell Science; 2000
PRESSURIZED METERED-DOSE INHALERS
Formulation Issues
For salbutamol, fluticasone, budesonide, and beclomethasone,

particle size of the HFA suspension = CFC formulation
lung deposition averages 7% to 30%
Some HFA pMDIsreformulation as a solution and the introduction

of ethanol as a cosolvent
Some have concentrations of alcohol up to 37% (w/w)
may cause irritation on inhalation
Beclomethasone dipropionate (BDP) was formulated as a solution

when it transitioned to an HFA pMDI
led to production of a finer aerosol with an increased
HFA BDP is called an extrafine aerosol

Similarities and Differences between
HFA, pMDI ICS Aerosols

Scintigraphic images of the lungs
patient with asthma after inhalation of two different formulations of

radiolabeled beclomethasone dipropionate (BDP) pressurized
aerosol

Dolovich MB, Labiris NR.Proc Am Thorac Soc 2004;1:329-37
Breath-Actuated pMDIs
For poor actuation-inhalation coordination with use of
standard pMDIs
The Autohaler automatically actuates at
inspiratory flow rates of approximately 30 L/min
the Easibreathe actuates at 20 L/min
improve lung deposition over that achievable with

pMDIs alone

PRESSURIZED METERED-DOSE INHALERS (pMDIs):
POINTS TO CONSIDER IN SELECTION OF DEVICE

pMDIs and Spacers and Valved Holding Chambers
developed for use with pMDIs in response to difficulties encountered
problems are related to timing or hand-breath coordination
coordination of actuating the pMDI and inhaling the spray at the same time
increasing the probability of optimal delivery of the drug to the lung

pMDIs and Spacers and Valved Holding Chambers
Volumes for the various devices range from 15 to 750 mL

aerosol characteristics and drug yield affect by
one-way valve to convert an open tube into a reservoir
shape and volume of the device, flow of air through the
device
face masks mouthpieces, and manufacturing materials all
inhalation valve
used to contain the aerosol and reduce oropharyngeal deposition
(as a baffle)
must be able to withstand the initial pressure from the pMDI on
firing
must have a sufficiently low resistance to open readily on
inhalation

pMDIs and Spacers and Valved Holding
Chambers
Coordination is still required with all three types of

spacer design
decrease in drug output from plastic spacers is largely

due to the presence of electrostatic charge on the plastic
To decrease electrostatic charge

metallic-coated device
device manufactured from a nonelectrostatic plastic
washing the plastic device periodically with deionizing detergent

SPACERS AND VALVED HOLDING CHAMBERS (VHCs):

DRUGS IN POWDER FORM:
DRY POWDER INHALERS
Aerosols of dry powder are created by directing

air through an aliquot of loose powder
the dispersion of the powder into respirable

particles is dependent on the creation of
turbulent flow in the inhaler
a function of both the patients (ability to inhale the

powder at a sufficiently high inspiratory flow rate) and
the design of the powder device

DRY POWDER INHALERS
individual doses of drug from punctured gelatin

capsules
a tape system containing multiple seale single

d,
doses in a blister
a multidose reservoir powder system

DRY POWDER INHALERS
most powder-dispensing systems require the use of

a carrier substance
vehicle substance enable the powder to more readily

pass out of the device
carriers that are used include lactose and glucose

Fewer allergenic than to the surfactants and propellants
used in pMDIs

Electron micrographs of
a 2% albuterol sulphatelactose powder blend
(a) lactose particle with drug on its surface

(b) The higher magnification shows individual drug
particles (elongated crystals) on the lactose
Br J Clin Pharmacol2003, 56, 600612

DRY POWDER INHALERS
particle size of dry powder particles is on the

order of 1 to 2 m
the size of the lactose or glucose particles can

range from approximately 20 to 65 m
most of the carrier deposits in the oropharynx

DRY POWDER INHALERS
commercially available
passive, or patient-driven
rely on the patients effort to dispense
inspiratory
the dose from the device
resistance of a DPI
classified with respect to the inhalation flow
to produce a pressure drop 4 kPa across device

DRY POWDER INHALERS
low-resistance device : inspiratory flow of > 90 L/min

medium-resistance : inspiratory flow of 60 to 90
L/min
medium- to high-resistance : 50 to 60 L/min
high-resistance device allows < 50 L/min
Potential deposition of aerosol in
upper and lower airways

DRY POWDER INHALERS
appropriate procedure is described in the

package insert/patient information leaflet
Patients who do not perform these procedures

correctly may receive no dose!!
irrespective of the inhalation maneuver they

subsequently adopt
DRY POWDER INHALERS (DPIs):

1.
if.r)11- K
3n1~
i
Becloforte GSK
Beclomet easyhaler 200 meg/do se x 200

doses
Becotide
GSK 50 mcg/dose x 200 doses
CLernil Chiesi 50 mcg/dose x 200 doses
I C lenil forte 25 0 mcg/do se x .200
25
doses
CLenil compositum n1cg - salbutarnol lOO
Chiesi 50
g/dose x 200 doses
mc
.. - Budesonide Budccort Cipla I 00 rncg/dosc x 200 doses
200 mcg/dosc x 2 0 doses
Giona casyhalcr Orion I 00 rncg/dosc x 2 0 doses
200 rncg..... /dosc x 2 0

doses
I 'u I 111 icon Astraz.cncca 50 rncg/dosc x 200 doses
200 111 g....1dose x I 00

doses
l'ulrnicort turbuhaler Asrrazcncca I 00 mcu...../dosc x 200
doses
200 mcu...../dosc x I 00
Syrnbicort Q/4.5 strazcnccu 80 rncg formotero I 4 .5
doses
mcg/dose x 60 doses
Nmll.
j ~-
--.~~~~~~~~..,_~~~~ ....... ~~
iymbicort 16014.5 struz.cncca 160 rncg formoterol
-L5
~~~~~~---t
mcg/dose x 60 doses
i'
LI':i )j ii
O Q.' " ~
,J~u 1 tl!O 1/fl i''1
~,.n,wi 1tn '}fi:)'t11.:Jfl 1 J I 11
us
Uii~~1 \.11 tJ.
.
fl J. '1 /'lHH:J ~
t i
Flutica one .
Flixotidc inhaler . .
tJl1~ 1f 4t 25 rncg/dosc x 120 doses
WI 125 mcg/dosc x 120
doses
Scrctidc accuhaler GSK 250

100 mcg/dosc x 120 doses
rncg salrnetcrol
GSK 50
50/100
mcg/dose x 60 doses
Scrciidc accuhaler GK 250 mcg salrnetcrol 50
501250
mcg/dose x 60 doses
Scretidc cvohaler GSK 50 mcg - salmetcrol 25
25150 rncg/dose x 120 doses
Scretidc cvohaler GSK 125 mcg .... salmetcrol

25
25/125
mcg/dosc x 120 doses
Scretidc cvohaler G K 250 mcg - . alrneicrol
25
25/250
mcg/dose x 120 doses
Inhaler strategy, optimal inhalation technique and most
common problems with correct inhaler use in children
Age Optimal Most common

groups technique problems
pMD Childre > 8 Exhalation followed by inhaler Coordination of actuation and inhalation.
I n years actuation early during a slow Stop of inhalation at actuation.
Inhalation through the nose and the
(30 Vmin.) deep inhalation followed
actuation into
by 1 o sec. breath-holding
mouth.
Slow inhalation is difficult
Breath- Childre > 7 Exhalation followed by a slow Slow inhalation is difficult
actuated n years (30 Vmin) deep inhalation Stop of inhalation when dose is
pMDI followed by 10 sec. breath- released
holding
Dry powder Childre > 5 Exhalation followed by a Dose lost if child exhales through the
inhalers n years deep, inhaler
forceful inhalation Insufficient inhalation flow rate
(minimal effective flow varies Dose loading problems*
from one type of inhaler to
Spacer with A) Children < 3 Slow deep inhalation (30 Static electricity reduces output* (output
valve- years another
Vmin.) reduced
or
system (Use face mask) followed by 1 o sec. breath- after cleaning)
B) Children > 3 Air leakage during inhalation due to loosely
years holding fitting
(No face mask) Slow tidal breathing starting
face mask
immediately after actuation.
Multiple actuations into spacer
Actuation of only one dose
Crying during administration
per
inhalation
I/
Primary Care Respiratory Journal (2010); 19(3): 209-216
Proportion of patient age and aerosal device
Primary Care Respiratory Journal (2010); 19(3): 209-216

Summary
Aerosal therapy good route for drug

administration
A number of factors effect deposition of
aerosal in the lung
Aerosal particle size play important in
role
targeting lung
Appropriate region
drug formulations and device
need for improve its efficacy
Thank you for your attention
THAN YO
K ALLU YOU
FOR R
LOVE
THA CiAV M
T E E

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Aerosals and Aerosal Drug

Points to consider in selection device

Middletons 8th edition

The introduction of hydrofluoroalkane (HFA) as

Middletons 8th edition

Middletons 8th edition

Middletons 8th edition

Middletons 8th edition

Techniques differ between device categories and

less convenient than oral drug administration

Middletons 8th edition

The prediction of deposition : efficiency for a

Fine Particle Fraction (FPF)

Middletons 8th edition

Br J Clin Pharmacol2003, 56, 588599

Labeled dose (LD)* or nominal dose

(1) Physical factors

The size of an aerosol particle is the primary

Therapeutic aerosols targeted to the lower

Middletons 8th edition

Deposition of particles onto surfaces in the lung mainly

three physical mechanisms:

Mechanisms of lung deposition

Total lung deposition

posterior thorax images of technetium-99mlabeled

Am J Respir Crit Care Med 2005;172:1497-1504.

Healthy vs asthma pt with FEV1 =31%

The image on a gamma camera scan of lungs

Deposition at airway bifurcations

Particles larger than 5 m

Particles smaller than 5 m

Particles between 0.1 and 1.0 m

region for particles approximately 3 m in size

(a) Percent improvement in forced expiratory volume in 1 s (FEV1) following inhalation

Johnson MA et al. Chest1989; 96: 110 [9].

pt have never been taught

Health care providers should ensure that their

Middletons 8th edition

The MMAD of jet nebulizers used for therapy should

Middletons 8th edition

Middletons 8th edition

The driving pressure or the flow rate of compressed air

higher the pressure or flow rate, the greater the output

time required to deliver the medication

Middletons 8th edition

Middletons 8th edition

Middletons 8th edition

Middletons 8th edition

operate at frequencies above 1 MHz

F.Pereira Mucho.J Pediatr.2010

Produced heat along with the aerosol, however

not suitable for nebulizing suspensions

Middletons 8th edition

Middletons 8th edition

CFC propellant pMDIsHFA propellant pMDIs

Middletons 8th edition

Top, HFA albuterol (Airomir, 3M Pharmaceuticals)

Middletons 8th edition

For salbutamol, fluticasone, budesonide, and beclomethasone,

Some HFA pMDIsreformulation as a solution and the introduction

Beclomethasone dipropionate (BDP) was formulated as a solution

Middletons 8th edition

Middletons 8th edition

patient with asthma after inhalation of two different formulations of