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PP available in:
email : dds_spo@yahoo.com

Password : spodds2005
Fakultas Farmasi
Universitas Andalas
Padang
MDIs and DPIs TECHNOLOGY

Febriyenti
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Metered Dose Inhalers (MDIs)
Many drugs have been formulated for use with pressurized
metered-dose inhalers (pMDIs).
The main market for these devices is in the treatment of:
- asthma,
- allergic diseases,
- and chronic obstructive pulmonary disease (COPD),
for which approximately 500 million pMDIs are produced
each year.
Their major selling points are that they are cheap and
portable.
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What Is a Pressurized Metered-Dose Inhaler
(pMDI)?
The pMDI delivers a metered dose of a CFC or HFA drug
suspension or solution. It consists of three major
components:
1. A reservoir, containing drug suspended or dissolved in
liquefied gas propellant
2. A metering valve, which when depressed delivers a
known volume
3. A spray actuator, which, combined with the stem of the
metering valve, comprises a twin orifice expansion
chamber and spray nozzle
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Formulation
A typical pMDI contains:
1. Drug substance
2. Up to three different propellants
3. One or more surfactants or lubricants
Most current CFC-containing pMDIs are formulated using
micronized or spray dried drug particles held in suspension.
Surfactants are used to disperse drug particles in
suspension and for valve lubrication. Surfactant molecules
interact with each other, with drug particles, and with the
propellant, to stabilize drug particles in a predominantly
nonpolar propellant environment.
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Formulation
Oleic acid, sorbitan mono-oleate(Span80), sorbitan tri-
oleate (Span85) and phosphatidyl lecithin choline are the
commonly used surfactants in CFC containing pMDIs in
concentrations typically around 0.1% w/w but sometimes
as high as 2%w/w. High concentrations of nonvolatile
surfactants increase emitted droplet size, as they do not
evaporate from the surface of drug particles and may slow
down evaporation of volatile propellants.
At low drug concentration, emitted droplets will contain a
single drug particle and approximate to the original
micronized size. However, at higher drug concentrations,
droplets containing multiple drug particles will be
produced, leading to an increase in droplet size and
reducing drug delivery to the lungs.
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Formulation
The final particle size of solution formulations, in contrast,
will depend on the initial droplet size, the concentration of
nonvolatile components in the droplet, and the ambient
conditions. It is possible to use the drug concentration to
alter the final particle size. In practice, it is often difficult to
dissolve drug in CFC propellants, and drug may be lost to
the elastomers in the MDI valve. As will be discussed later,
the problems of solution aerosols of steroids using HFA
propellants have recently been overcome. Dissolved mint
extracts and micronized saccharin have been added to
formulations in an attempt to improve patient acceptability.
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Metering Valves
The main function of the metering valve is to deliver a
reproducible amount of the liquid phase of the formulation
in which the medication is either dissolved or dispersed.
Each valve consists of several components made of inert
materials. The metering tank contains a single dose of drug,
usually in the range of 25100 L (Fig. 2). Some valves such
as the 3M Neotechnic are surrounded by a larger reservoir
known as the retaining cup, which contains the next few
doses of drug. When the valve is actuated by depressing the
valve stem, the communication between the metering tank
and the retaining cup is closed, and the metering tank
empties through the opening of the valve stem.
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Metering Valves
The metered dose is ejected from the metering chamber
under the pressure of the boiling liquid propellant. The
vapor/liquid drug mixture then flows through the valve
stem orifice into the valve stem. When in the valve stem, it
expands by further vapor formation before discharge
through the spray orifice. The atomization process at the
final spray orifice is a two-phase gas/liquid air blast.
However, after droplet formation has taken place, the
droplets of the emerging cloud quickly evaporate and lose
their forward velocity. It is the CFCs capacity to both
generate sufficient vapor to produce sufficient two-phase
atomization without the need for an external power source
and to evaporate quickly after droplet generation has taken
place that makes the pMDI such a successful inhalation l
delivery system.
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Metering Valves
After actuation, the spring returns the valve to the resting
position and the metering tank refills from the retaining
cup. The retaining cup may hold as many as four or more
doses depending on the pMDI. The retaining cup is refilled
from the main reservoir through the opening in its base.
The concentration of suspension mixture available at the
inlet between the main reservoir and the retaining cup is
therefore very important in metering subsequent doses. If
the concentration of drug is low at the inlet, a low drug
dose concentration will appear in the retaining cup and the
metering tank and the patient will inhale a low dose.
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Aerosol Containers
Both aluminum and glass aerosol containers are available.
Aluminum aerosol canisters are light, impervious to light,
robust, and cheap to make. Glass containers are now very
rare. Typically they are laminated or plastic-coated so they
can withstand pressures of up to 150 psig. Occasionally the
inert nature of glass containers makes them a more suitable
choice for some solution formulations.
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Mouthpiece Design
Mouthpieces are usually made of polypropylene or
polyethylene materials. The stem of the MDI fits into the
actuator part of the mouthpiece, against which the valve of
the MDI is pressed. Depression of the valve allows
discharge of the aerosol through the small jet orifice of the
mouthpiece. The aerosol cloud generated after depression
of the valve stem is dependent on the geometric size of the
active drug particles (in the case of suspension), the volume
of the metering chamber, the vapor pressure of the
propellant formulation, and the diameter of the jet orifice
in the mouthpiece. The diameter of this orifice controls the
rate of spray of the formulation and has a critical effect on
the aerosol particle size produced.
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Mouthpiece Design
To make sure that this orifice does not become blocked
during repeated use with medications with a high drug
load, such as sodium cromoglycate 5-mg pMDIs, regular
removal and washing of the mouthpiece is recommended.
Drying is essential prior to further use.
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pMDI Technique
Surprisingly the optimal method of pMDI use is still
debated. Newman et al. demonstrated maximal
bronchodilatation and lung deposition with the MDI in the
mouth (the closed-mouth technique), (Table 2) slow (about
30 L/min), deep inhalation, and a 10-s breath-hold. Faster
inhalation was less effective, with more aerosol impacting
on the oropharynx, while a shorter period of breath-holding
allows insufficient time for sedimentation of particles in the
airways. Extending the breath-holding pause to 20 s has not
been shown to enhance Bronchodilatation. Others have
found a greater bronchodilator response at an inhalation
rate of 64 L/min compared to a very high inhalation rate of
192 L/min.
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pMDI Technique
Table 2 Correct Metered-Dose Inhaler Technique:
1. Remove the cap and shake the canister thoroughly.
2. Hold the canister upright and breathe out fully.
3. Place the mouthpiece between the lips, or 34 cm in
front of the open mouth.
4. Fire the inhaler while inhaling slowly and deeply.
5. Hold the breath for 10 s, or for as long as possible.
6. Wait approximately 1 min before taking a second dose.
a In very severe airways obstruction more than one
actuation may be necessary.
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pMDI Technique
The time interval between successive doses of
bronchodilator has been debated. Although manufacturers
often recommend a 1- to 2-min interval between successive
actuations, a longer time interval of 1020 min has been
suggested. This has the theoretical advantage of allowing
the second dose to penetrate further into the airways.
Other factors influencing dose delivery from pMDIs are
discussed below.
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pMDI Technique
Factors Influencing Dose Delivery from pMDI :
1. Coordination requirements
2. pMDI design
3. Reformulation from CFC to HFA propellants
4. Distance from actuation orifice
5. Temperature
6. Separation of drug and solvent

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Shaking the pMDI and Low First-Spray Drug Contents
from pMDIs
Patients are always instructed to shake their pMDI prior to
inhalation because of the potential problem of separation of
drug particles from the suspension. In laboratory trials of
pMDIs, the inhalers are usually primed by actuating on
several occasions before testing to encourage reproducible
performance. However, patients do not routinely prime their
pMDI by firing shots to waste before actuating and inhaling.
The drug content in the first spray was found to be very
erratic and was usually substantially less than the 100 g
claimed on the label. However, occasional first sprays
contained very high levels of drug, up to 208 g, for a label
claim of 100 g. The mean drug contents of the second and
third sprays were much closer to the label claim and less
variable.
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Shaking the pMDI and Low First-Spray Drug Contents
from pMDIs
The behavior of the contents of a pMDI in glass-walled containers. The
pMDI contains a suspension of micronized budesonide identical to that
used in the production pMDIs. It was shaken immediately before time
zero. Separation of the contents begins as soon as the pMDI is left in an
undisturbed state. Complete separation of the contents has occurred within
60 min of shaking.
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Incorrect pMDI Technique
As far back as 1965, Saunders found that 14 out of 46
patients studied were not using their inhalers correctly, and
11 of these were not achieving maximum therapeutic
effect. It is now accepted that many adults and most
children use their pMDIs incorrectly, and most health care
workers are also uncertain about their correct use. It is
estimated that between 25 and 38% of patients who use a
pMDI have never received verbal instructions on how to use
their device from a health care professional and many
patients do not receive follow-up assessment and
retraining. The most common errors are the inability to
coordinate inhalation with MDI actuation, to inhale too
quickly, and to exhale without a breath-hold.
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CFC-Free MDIs
CFC 11 and CFC 12 were used as propellants. In response to
the Montreal protocol, two propellants were identified as
replacements for chlorofluorocarbons (CFCs).
HFA 134a could replace the CFC 12, but a replacement for
CFC 11 has not been identified. However, ethanol is used as
a cosolvent and this can take the place of CFC11.
The other propellant1,1,1,2,3,3,3- heptafluoropropane
(HFC-227)is under active investigation.
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Future Research
The pMDI will continue to be one of the most popular drug
delivery devices for inhaled antiasthma drugs. The
increasing number of modifications to the standard inhaler
should improve drug delivery.
Future research is required in three main areas:
1. to reduce the marked variability in deposition of drug in
the lower airway;
2. to reduce the upper air way deposition of inhaled drug;
3. to include compliance monitors in the delivery device.
SAMPLE SLI DES
DPIs Technology
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Dry-Powder Inhalers (DPIs)
The first commercially successful dry-powder inhaler (DPI)
was Spinhaler, introduced by Fisons 30 years ago for the
delivery of disodium cromoglycate (DSCG). A number of
DPIs using different dosing principles have since then
reached the market. A major practical advantage with DPIs
as compared with pMDIs is that there is no need to
coordinate actuation and inhalation, since the dose will
follow the inhaled air into the lungs. In addition, some
patients using a pMDI stop inhaling when they feel the
aerosol cloud in their mouths. Multidose DPIs are as simple
to operate as the pMDIs and their size and compact design
make them equally convenient.
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Dry-Powder Formulations
An inhaled formulationbe it a pMDI, nebulized, or dry-
powder formulation is made up of two components: the
device and the pharmaceutical formulation. The device
determines the aerodynamic and flow properties and the
pharmaceutical formulation sets the physical and chemical
properties of the resulting formulation. Differences in the
aerodynamic and mechanical properties of the inhaler thus
will affect the quality of the resulting aerosol. Each
combination of device and pharmaceutical formulation has
to be judged on its own merits. The same effort also
deaggregates the powder into particles small enough to
have a fair chance to reach the patients lungs.
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Dry-Powder Formulations
A more forceful inhalation through an inspiratory flow
driven inhaler will result in better deaggregation, more fine
particles, and a higher amount of drug reaching the lungs.
With regard to the pharmaceutical formulation the size of
the substance crystals, or particles, after manufacturing is
much too large to allow the particles to reach the airways at
inhalation. The particles in the generated aerosol cloud
should have an aerodynamic diameter of about 24 m or
smaller to have a good chance of reaching the lower
airways during inhalation. In addition, it has been shown
that the fine-particle dose, defined as the dose of drug in
particles <5 m, is linearly correlated to the degree of lung
deposition for a range of DPIs.
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Dry-Powder Formulations
Thus, the manufactured large particles must be made
smaller, and it is common to mill or micronize the
crystals/particles down to the more optimal particle size, in
most cases around 24 m. An alternative to milling for the
production of the fine powder is spray drying, which allows
more control of particle shape, surface properties, and size.
For example, it has been shown that a spray-dried powder
formulation of DSCG can produce more drug in fine
particles than when the drug is micronize. Milling, or spray
drying however, generates another problem. The resulting
small particles cannot be handled in the pharmaceutical
production or in an inhaler, as the particles will adhere to
most surfaces due to Van der Waals and electrostatic
forces.
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Dry-Powder Formulations
The particles must be made larger again!
This problem has been solved in two distinctly different
ways. The one way is to use large, about 30- to 300-m
(most often 50- to 150-m) carrier particles, such as lactose
or glucose, which are blended with the smaller drug
particles. The surface of the carrier particles has energy-rich
sites and the small drug particles adhere to these sites on
the carrier particles at blending. First, the most energy-rich
sites are covered with drug particles and eventually also the
less energy- rich sites. The properties of the resulting,
ordered mixture pharmaceutical formulation, means that
the powder now can be handled in the production process,
in the inhaler, and at inhalation (Fig. 2).
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Dry-Powder Formulations
The adhesion of the small particles to the carrier must not
be too strong as they should detach during inhalation.
The roughness of the carrier and the time and speed of
mixing may have a significant effect on the adhesion of the
small particles to the carrier particle. Lactose with a smooth
surface has been shown to deliver a significantly higher
fine-particle fraction than lactose particles with a rougher
surface. For practical reasons, the different dose strengths
of the same formulation use the same amount of carrier
and thus, for the higher doses, each carrier particle carries
more drug.
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Dry-Powder Formulations
For the higher doses, where also the less energy-rich sites
are covered with drug particles, the mean strength of the
drugcarrier binding becomes weaker [e.g., the 500-g
fluticasone Diskus will deliver about 120 g (24% of the
nominal dose) as fine particles, while the 50-g fluticasone
Diskus will deliver only about 7 g (14% of the nominal
dose) as fine particlesa 20- instead of the expected 10-
fold difference. Optimization of the drug/carrier ratio as
well as reduction in carrier particle size has been shown to
increase the fine-particle fraction of drug in the aerosol.
Additional formulation components such as L-leucine or
magnesium stearate will change the binding forces
between drug and carrier and can increase the fine-particle
fraction.
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Dry-Powder Formulations
The other way to solve the problem with the small particles
and the Van der Waals and electrostatic forces is to tumble
the 2- to 4-m particles to form larger spheres. The
resulting spheres have free-flowing properties, meaning
that they can be handled in the pharmaceutical production
and in the inhaler. This method has been used for the
Turbuhaler formulations. The method is the same whether
the pharmaceutical formulation contains only pure drug, as
is the case for Pulmicort (budesonide) Turbuhaler, or when
a mixture of pure drug(s) and micronized lactose is used, as
is the case for Oxis (formoterol and lactose) and Symbicort
(budesonide, formoterol, and lactose) Turbuhaler. This
pharmaceutical principle will not give rise to any
nonlinearity when different strengths of the same
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Dry-Powder Formulations
substance are formulated, as the resulting pharmaceutical
formulation is a homogeneous mixture of the micronized
components.
A third way to formulate a dry powder is to take advantage
of the difference between geometric and aerodynamic
diameter. The aerodynamic diameter of a particle is
equivalent to the diameter of a unit-density sphere that has
the same terminal settling velocity in still air, and is the best
parameter for defining the dimension of aerosol particles. It
has been suggested that administering particles with a large
geometric diameter to the lungs may increase
bioavailability by reducing phagocytosis. Porous particles,
also known as large fluffy particles, have been designed to
reach the lower airways.
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Dry-Powder Formulations
They have a large geometric but a normal aerodynamic
diameter. Their actual geometric dimensions can be greater
than 30 m, but as they have a low density, their
aerodynamic diameter can still be less than 5 m, small
enough to deposit in the lungs
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Dispersion of Powders in a DPI
There are a number of forces that influence the dispersion
of the dry-powder particles into an aerosolized cloud
suitable for inhalation. These include Van der Waals,
electrostatic, capillary, and friction forces. Attraction of like
materials that is, drug particle to drug particleare called
cohesive forces and attraction of materials that are unlike
each otherfor example, the carrier particle to the drug
particle or the drug particle to the delivery device surface
are called adhesive forces.Within a dry powder, Van der
Waals forces are dominant. However, under special
conditions, capillary forces can be very much higher than
both Van der Waals and electrostatic forces.
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Dispersion of Powders in a DPI
Fortunately, capillary forces are produced only at
humidities that tend to rise to greater than 65%. They are
formed by the condensation of water that may form high
tensile liquid bridges. The observed electrostatic charge is
generated from particles that are separated from the bulk
material or where there is contact to other surfaces.
Mechanical interlocking and friction may be significant
between irregular, large carrier particles and small drug
particles. For example, small drug particles may enter into
cavities within the carrier particle, from which it may be
difficult for them to escape.
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Spacer Devices
The aerosol cloud from a pressurized metered dose inhaler
(pMDI) leaves the canister at a very high speed after
actuation. As a result, coordination of actuation and
inhalation can be very difficult, resulting in a high aerosol
deposition in the oropharynx and variation in the lung dose.
Spacers and holding chambers have been developed in an
attempt to overcome this problem. In principle, spacers are
extensions of the pMDI canister, allowing deceleration and
maturation of aerosol, while holding chambers are valved
spacers allowing breathing from a standing cloud of aerosol.
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Spacer Devices
Franklin (1958) developed a spacer to aid delivery of
hydrocortisone to the lungs via pMDI. He used a 14-in.
plastic tube, noting that approximately 50% of the steroid
delivered was deposited on the wall of the tube, and that
the use of the plastic tube unquestionably decreased the
dose of steroid administered, but had the desirable effect
of increasing the proportion entering the airway as
compared with that retained in the mouth. Two decades
later, various designsincluding large-volume spacers,
small-volume spacers, and tube-extensionshad been
developed for general clinical use, and the spacer concept
was subsequently extended to young children and infants.
The clinical effects of bronchodilators (ipratropium
bromide, salbutamol), and inhaled steroids delivered by
pMDI and spacer for young children were documented.
D
R
U
G

D
E
L
I
V
E
R
Y

S
Y
S
T
E
M

T
O

T
H
E

L
U
N
G
S

Spacer Devices
The primary objective of a spacer is to minimize the need
for coordination between actuation of the pMDI and
inhalation. In addition, the spacer should ensure that the
aerosol particles trail the inspiratory flow of the patient,
reduce the proportion of the dose contained in large
particles, and increase the proportion contained in small
particles. The need for coordination between actuation and
inhalation is reduced by presenting the aerosol to the
patient as a standing cloud of particles, which decreases
oropharyngeal deposition. Oropharyngeal deposition with
the actuator alone ranges from 30 to 70%, compared with
510% with spacer devices
D
R
U
G

D
E
L
I
V
E
R
Y

S
Y
S
T
E
M

T
O

T
H
E

L
U
N
G
S

Spacer Devices
Spacers reduce the need for coordination between
actuation and inhalation.
Spacers may improve the therapeutic index of inhaled
therapy.
Spacers may reduce cost of treatment from improved
drug delivery.
pMDIs should always be used with spacers in children.
Nebulizers should not be used for maintenance treatment
but may be useful in children with acute severe asthma.
Spacers should be used with facemasks in young children
until they can be trusted to inhale from a mouthpiece,
usually from around age 4.
D
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G

D
E
L
I
V
E
R
Y

S
Y
S
T
E
M

T
O

T
H
E

L
U
N
G
S

Spacer Devices
DPIs or breath-operated pMDIs are recommended for
patients who can reliably be expected to cooperate in all
circumstances