INHALATION

DRUG DELIVERY SYSTEM

Why pulmonary drug administration?
and where?
1. Local therapy (in the airways) :
Asthma, COPD, Cystic Fibrosis, HIV, influenza
Advantages:
High dose at the site of action
Increased efficacy
Rapid onset of action
Reduced side-effects
2. Systemic therapy (airways but often alveoli) :
The lung as a port of entry for the systemic
administration of drug
Peptides and proteins (insulin, interferon-)
Morfine, Ergotamine, A
9
-tetrahydrocannabinol
Advantages of the Inhalation Route of Administration With
Aerosolized Drugs in Treating Pulmonary Diseases:
1. Aerosol doses are generally smaller than systemic doses. For
example, the oral dose of albuterol is 2 - 4 mg, whereas the inhaled
dose is 0.2 mg (via MDI) to 2.5 mg (via SVN).
2. Onset of effect is faster with inhalation than with oral
administration. For example, the onset of effect with oral albuterol is
about 30 min, whereas inhaled albuterol takes effect within about 5.
3. The drug is delivered directly to the target organ (lung), with
minimized systemic exposure.
4. Systemic adverse effects are less severe and less frequent with
inhalation than with systemic drug delivery (injection or oral) (eg, less
muscle tremor and tachycardia with -2 agonists; less
hypothalamic pituitary adrenal suppression with corticosteroids).
5. Inhaled drug therapy is painless and relatively comfortable.
MDI metered dose inhalei
SVN small volume nebulizer
COPD chionic obstiuctive pulmonaiy Gisease
Structure of the lung
The airways:
23 bifurcations through which
the air flows
Covered with mucus
Mucus is moved to the pharynx by cilia
Air flow rate is decreasing
turbulent laminar
Alveoli:
No mucus, no movement
Alveolar lining fluid (dipalmitoyl
phosphatidylcholine)
Thin membrane

The lung model of Weibel
generation
diameter
(cm)
length
(cm)
number
total cross
sectional
area (cm
2
)
trachea 0 1.80 12.0 1 2.54
1 1.22 4.8 2 2.33
2 0.83 1.9 4 2.13
bronchi
3 0.56 0.8 8 2.00
4 0.45 1.3 16 2.48
c
o
n
d
u
c
t
i
n
g

z
o
n
e

bronchioles
terminal bronchioles
5
+
16
0.35
+
0.06
1.07
+
0.17
32
+
610
4
3.11
+
180.0
17
18
respiratory
bronchioles
19
0.05 0.10 510
5
10
3

20
21 alveolar ducts
22
t
r
a
n
s
i
t
i
o
n
a
l

a
n
d

r
e
s
p
i
r
a
t
o
r
y

z
o
n
e
s

alveolar sacs 23 0.04 0.05 810
6
10
4

Cross sectional area of the airways
available for air flow
1
10
100
1000
10000
100000
0 10 20 30
airway generation
c
r
o
s
s

s
e
c
t
i
o
n

p
e
r

g
e
n
e
r
a
t
i
o
n

(
c
m
2
)
Conducting zone
generation 1-11
Transitional zone
generation 12-16
Respiratory zone
generation 17-23
Structure of the alveoli
Large surface area: 43-102 m
2

high degree of vascularization
Thin membrane
Covered with a thin layer of
fluid (ALF: alveolar lining fluid,
dipalmitoyl-
phosphatidylcholine)
Limited amount of proteolitic
enzymes
No mucus, nocilia, nomovement
Clearance of insoluble
particles: macrophages (weeks-
years)
Clearance of low molecular
weight soluble substances:
transepithelial transport
Another Physiological Adventage of Alveoli
No 1
st
Pass Metabolism
Small efflux transporter activity
Rich in protease inhibitor
Small volume of fluid (10 20 ml)
Prolonged residence time


No non invasive route of delivery provide the
speed of action that an inhaled drug can provide


structure of the alveolar membrane
Thin type I alveolar cells (0.05-0.1 m) with
a relatively large surface (6000 m
2)
cover
93 % of alveolar surface
Tight junctions space 5 nm
accessible for proteins up to 40 kD
Capilary endothelial pores: 10-15 nm
Caveolae
Transport through the epithelial cells
Non coated vesicles
Up to 1.7 x 10
6
caveolae per type I cell
40- 100 nm (up to 400 kDa)
Absorption over the alveolar endothelium
What is rate limiting?
Dissolution
transport over the alveolar-capillary
membrane
Others ?
Possible routes:
Passive transport through
hydrophilic pores (tight junctions
Passive transport through lipophilic
pathways (cell membranes?)
facilitated passive transport
active transport (caveolae)
Route of Absorbstion
Macromoleculules, throught tight junction
and endocytic veicles
Endogenous molecules (albumin,
immunoglobulin, transferrin) have spesific
receptor-mediated transport
Disodium cromoglikat and cycloleucyn
transported by carier mediated transport
Inhaled Peptides and Protein
Biasanya diberikan secara suntikan
Tidak nyaman, kepatahan kurang terutama
jika harus obat jalan
Route non invasive memberikan
bioavailabilitas jelek
Dikembangkan inhalasi
Contoh: insulin, LHRH
Peptida mudah terhidrolisis, protein sulit
karena ujungnya menekuk (globuler)

Factors affecting protein pulmonary
absorption
Size and volume:
proteins < 20 kDa are absorbed with near IV like
kinetics
Proteins > 20 kDa slow release pattern:
lung acts as a depot
Risk of depot formation or sequestering:
stimulation of defence mechanisms
(housekeeper cells, metabolising enzymes)
Immune respons or inflamatory reactions
Morphological changes in tissue
(irreversible!)
changes in gas permeability
reduced resistance against (pathogenic)
micro-organisms

Why inhalation delivery of peptides and
proteins ?
Poor oral bioavailability:
G-I tract environment:
pH (secondary and tertiary structure)
enzymatic activity in the G-I lumen
membrane transport (tight junctions size
limitation)
first pass metabolism
Mucosal (e.g. nasal, sublingual, buccal or rectal)
transport only feasible for smaller peptides (up to
10-18 amino acids)
Parenteral administration is uncomfortable for the
patient
Molecular weight : effect on bioavailability

Peptide Mw (Da) Tmax (hr) r.B.A.(%)
LHRH analog 1,067 1.0 4.6 - 95
DDAVP 1,209 0.5 84
Insulin 5,700 0.25 15-25
PTH 9,418 0.5 >20
GCSF 18,600 1.5 45
Glycos. Interferon o 19,000 6.0 <5
Human growth horm. 22,000 0.75 9 - 36
DNase 32,000 <2
Albumin 68,000 20.0 4-5
IgG 150,000 16.0 1.5-1.8
Enam peptida pertama memberikan bioavailabilitas yang
bagus karena tahan terhadap peptidase
Terjadi modifikasi pada ujung C atau N, atau
Terikat dengan cincin seperti siklosporin

Natural peptida (somastatin, VIP, Glucagon)
Terdegradasi di paru

Peptide and protein absorbtion
Siklosporin, kelarutan dalam air rendah
dissolution rate limiting step?
T maks Insulin reguler (60 180
menit)>insulin inhalasi (5 60 menit)
GCSF = granulocyte colony-stimulating factor; hGH = human growth hormone.
Inhalation Technology
The behaviour of an aerosol
particle in the airways
Determined by the physical interaction
between the particle and the airflow
The inhalation airflow generated by patients
shows large variations
Particles: manipulation of behaviour
through change of physical properties
Mass (size)
Density
Shape
Velocity
Forces acting on aerosol
particles in a bent airway duct
F
C
is the centrifugal force

F
C
= m.U
T
2
/R

F
D
is the drag force

F
D
= 3.t.q.U
PA
.D/C
C


F
G
is the force of gravity

F
G
= m.g


M= t/6 . D
3
.
P

Deposition mechanisms
in the respiratory tract
Inertial impaction
Sedimentation
Diffusion
Particle size, penetration
and deposition in the lung
>5 m
inertial impaction
in oropharnyx
1- 5 m
sedimentation in
deeper airways
< 1 m
diffusion and
exhalation
0
20
40
60
80
100
(%)
Deposition
Penetration
in target area
Particle diameter (

m)
P
e
r
c
e
n
t
a
g
e

p
e
n
e
t
r
a
t
i
o
n

/

d
e
p
o
s
i
t
i
o
n

Preferred
particle size
0.1 0.5 1 2 4 6 8 10
How can we combine high penetration changes
with high deposition changes??
Different groups (principles)
of aerosolisation devices for pulmonary drug delivery
Group 1: dry powder inhalers (dpis)

Group 2: metered dose inhalers (mdis)

Group 3: classic jet and ultrasonic nebulisers

Group 4: soft mist inhalers


Criteria for selection
of aerosolisation devices for pulmonary drug delivery
The target area for the drug (local or systemic delivery)

Patient factors

The therapeutic dose (range) for the drug

Stability of the drug (in aqueous solution or suspension)

The quantity of drug being available
particle size distribution in relation to the inhalation manoeuvre
inhaler handling and lung physiological parameters
microgram or milligram range
dry powder formulations may guarantee a greater stability
e.g. testing of small unformulated samples: preformulation phase
The most fundamental differences
between the four groups of inhalation devices
are:
the mode and rate with which the entire dose is aerosolised
the inhalation manoeuvre with which the aerosol is inhaled
This may have consequences for the deposition efficiency and
patient compliance
Example dry powder inhalers:
aerosolisation of the entire dose is in (split) seconds
using the energy within the generated air flow for dispersion*
the fine particle fraction may vary with the inspiratory flow rate
administration is in one single inhalation
instructions are to inhale deeply and forcefully (high flow rate?)
* With a few exeptions, e.g. Exubera
The most fundamental differences
between the four groups of inhalation devices
Metered dose inhalers:
instantaneous firing of the entire dose
propellant delivers the energy for aerosolisation
high plume velocity (CFC >>HFA)
co-ordination between firing of a dose and inhalation is required
Classic (jet) nebulisers:
the aerosolisation process requires several minutes
preparation and cleaning (disinfection) increase total nebulisation time
aerosolisation is continuous; inhalation is intermittent
patient can exercise a normal breathing pattern
Soft mist inhalers:
aerosolisation of the entire dose varies from seconds to minutes
production of a dense aerosol with low velocity
claims include monodisperse droplets
NEBULIZER
Aerosolization of solution or suspension done by:
1. Jet Nebulizer (umum)
Aliran gas dihasilkan oleh kompresor atau gas
yang dimampatkan

2. Ultrasonic nebulizer
Tenaga listrik menggetarkan lempengan
sehingga permukaan cairan bergetar dan
jadilah kabut.
The volume at the surface of a liquid is dispersed in
the airflow
1. Through momentum transfer from air to fluid:
Jet nebulizer
2. High frequency sound waves: Ultrasonic
nebulizer

Disadventage:
Long administration times (30 minutes)
Only about 10% lung deposition (highly variable)
The working principle
of jet and ultrasonic nebulisers
Jet nebulisers (basically two
fluid atomisers): droplet
formation is by a
combination of ligament
stripping and turbulent
rupture, resulting in a wide
droplet size distribution
Ultrasonic nebulisers: droplet formation occurs on
the tops of standing waves created by high
frequency vibration imposed (directly or
indirectly)upon the liquid surface
JET NEBULIZER DIAGRAM
Jet nebulisers: two examples
Exhaled air
Air valve (inlet)
Pressurized air
Baffle

Maximum level for drug
solution
Medic-Aide Sidestream
(open vent)
Pari LC Plus
(breath assisted open vent)
Classical nebulizers
Modern nebulizers:
Adaptive aerosol delivery
Registration of the inhalation flow
profile of the three preceding
breath cycles
Aerosol (ultrasonic) released only
during inspiration
600
300
0
300
600
F
l
o
w

m
l
/
s

inspiration
expiration
time
aerosol release
mouthpiece
baffle
medication
cham
ber
selection
buttons
electronics
How to use Jet Nebulizer
Nebulizers are used to treat
asthma, Chronic
Obstructive Pulmonary
Disease (COPD), and other
conditions where inhaled
medicines are indicated.

Nebulizers deliver a stream
of medicated air to the
lungs over a period of time.
Assemble the nebulizer according to its
instructions. Connect the hose to an air
compressor.
Fill the medicine cup with your prescription, according to the
instructions.
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, about 10-15 minutes. Some people use a nose
clip to help them breathe only through the mouth.
Some people prefer to use a mask.
Wash the medicine cup and mouthpiece with water, and air-dry until
your next treatment.
Wash the medicine cup and mouthpiece with water, and air-dry
until your next treatment.
Presurized Metered Dose Inhaler
The aerosol generation
Liquefied propellant
How the spray from a pressurized metered-dose inhaler is
formed.
The pressurized metered dose inhaler (pMDI)
Drugs in propellant:
Dissolved
Suspension (stability)
CFCs (Freon) banned and replaced by HFAs:
Tetrafluoro ethane (HFA134a) or Hepta Fluoro
propana (HFA 227)
Good hand-lung co-ordination required
Spacers
Autohaler
High speed of the droplets
Lung-deposition: 10-20%
Throat deposition: 70-90%

Lung deposition and actuator retention with a hydrofluoroalkane (HFA)
solution formulation of fenoterol and ipratropium bromide delivered
through actuator nozzles with diameters of 0.2 mm, 0.25 mm, and 0.3 mm.
The data are compared with values from a chlorofluorocarbon (CFC)
formulation containing the same drugs. * indicates a statistically significant
difference compared with HFA 0.3 mm.
Adventage of pMDI
Practical benefit: Small size, portability,
convenience, relatively unexpensive
The Multi Dose capability
Deliver of drug in few second, unlike nebulizer

Limitation of pMDI
Misuse, failure to coordinate actuation and
inhalation
Some patien suffer from cold propellant
(esspecially freon), cause stop inhaling

result in supoptimal dosing

Solution of disadventage
- Breath-Actuated pMDIs:
sense the patients inhalation through the actuator and fire the
inhaler automatically in synchrony.
ex: Autohaler (3M Pharmaceutical USA), Easibreate (Norton
Healtcare UK), K-Haler (Aldsworth UK), MD Turbo (Respiric,
USA), Xcelovent (Meridika, UK)

- Breath-coordinated Devices
ex: Easidose (Bespak, UK), BCI (Aeropharm, USA)

- Novel Devices: placing baffles near the actuator nozzle
Spacehaler (Celtech Medeva, USA), Tempo (Map Pharm, USA),
Bronchoair (Ger)

- Spacer Design

SPACER DEVICE
The larger the spacer better the dose available
However, increasing the spacer volume to 1 L
would probably be counterproductive, because
the spacer would no longer be easily
portable, and because it would be more difficult
for the patient to inhale the complete contents.


LINK Video
How to use jet/classic nebulizer:
http://www.youtube.com/watch?v=A7DhGX
0p1KY
How to use metered dose inhalers:
http://www.youtube.com/watch?v=A7DhGX
0p1KY&feature=channel
Dry powder inhaler (DPI)
Breath-controlled, breath-actuated
40 to 60 % lung deposition possible
No propellant
Stable formulations possible
For processing agglomerated particles required
In the aerosol de-agglomerated particles
required
Formulation
difficult
Functional parts of a DPI
Mouthpiece
Powder disperser
(disintegration principle)
Powder
formulation
Dose measuring
system
Or preloaded
cartidges
The design of DPIs
DPI performance
dose entrainment
powder disintegration
lung deposition
DPI design
powder formulation
dose system
disintegration principle
Patient
instruction
clinical picture
age and gender
training
smoker/non smoker
Patients effort
DPI air flow resistance
Flow parameters
peak flow rate (PIFR)
flow increase rate (FIR)
inhalation time
Variables and interactions
in the use of dry powder inhalers
From design
Powder formulations for particles of 2 - 5 m
Soft spherical pellets
Micronized drug
cohesive forces
instable
good de-
agglomeration
adhesive mixtures
Micronized drug with
(larger) carrier crystals
adhesive and cohesive
forces
stable systems
Difficult de-
agglomeration
Fine particle fractions
from different DPIs
TH: Turbuhaler
AH: Diskus
FDH: Flixotide
Diskhaler
BDH: Beclometasone
Diskhaler
SH: Spinhaler
CH: Cyclohaler

The relative lungdose decreases when the
inhalation flow rate increases
In order to compensate for
the relatively decreased lung
penetration the absolute fine
particle dose must increase
to keep the lung dose at the
same level.
Oropharyngeal deposition
increases, when the inhalation
flow rate increases
(F
C
= m.U
T
2
/R)
Carrier related variables
Size and size distribution
Impurities
storage and conditioning
Inhaler and
inhalation
Bulk properties
Surface properties
Example 1: Interpretations and understanding
Budesonide versus salbutamol fine particle fractions
from mixtures with different Respitose carriers
% fpf (stage 4+3+filter)
0
10
20
30
40
50
60
70
SV007 SV003 ML001
1% 2% 2% 0.5%
C N D H C N D H C N D H
C: Cyclohaler
N: Novolizer
D: Diskus
H: HandiHaler
budesonide
salbutamol
D
a
t
a

s
h
o
w
n

b
y

c
o
u
r
t
e
s
y

o
f

D
M
V
-
F
o
n
t
e
r
r
a
,

T
h
e

N
e
t
h
e
r
l
a
n
d
s

Obvious conclusion:
budesonide particles attach to the carrier surface
with higher force than salbutamol particles
4 kPa or 100 l/min
The effect of the carrier surface
properties is determined by:
The particle size of the carrier

The payload of the drug on the carrier

The bulk properties and mixing of the
powder mixture
Additives
Additives (force control agents) mentioned in
literature:
Lactose fines
Magnesium stearate
L-leucine

Effects of additives:
Competition for active sites
Change the payload of a mixture
Reduce press-on forces during mixing
Agglomeration of additives and drug



Powder
formulation
Desintegration
principe
poor
moderate
good
Generation of the aerosol in a DPI: a balance between
binding forces and de-agglomereation forces
Binding forces:
v.d. Waals forces
surface irregularities
impurities
capillaire forces
electrostatic forces
De-agglomeration forces:
shear and friction forces
Drag and lift forces
Impaction forces
The powder formulation
Nucleus agglommerate
Adhesive mixture Spherical pellets
Drug concentration
up to 10%
Mechanically stable
Difficult to break up
Low risk of inhaler
pollution

Drug concentration
up to 50% (or more)
Instable
Easy to break up
Low risk of inhaler
pollution

Drug concentration up
to 100%
Highly instable
Easy to break up
High risk of inhaler
pollution
Batch variability
Effective dry powder inhalation
requires good control of a series of processes
that are dominated by various forces, e.g.:
inertial and frictional forces during mixing
interparticulate forces in the powder blend
drag forces during dose entrainment
dispersion forces during inhalation
deposition forces in the respiratory tract
AHB01
formulation
DPI design
and
patient factors