METERED DOSE INHALER
Presented by:
Aarohi Shah
M.Pharam
Department of Pharmaceutics and Pharmaceutical Technology
L.M. College of Pharmacy
We shall discuss:
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Advantages of Nasal Route as systemic delivery
Limitations
Anatomy of respiratory tract
Metered Dose inhalers design
NONPRESSURIZED SYSTEM
PRESSURIZED SYSTEM
Manufacturing of Inhalers
Novel Excipients for Inhalation Drug Delivery
Evaluation of MDI as per FDA
Recent innovation in MDI Technology
Application of MDI in Systemic Medication
Market formulations
References
Introduction
The first nasal administration of drugs
was primarily employed for local drug
effects.
The potential nasal route for systemic
delivery was discovered after the
observation that nasally administered
sympathomimetic and antihistaminic
drug for local action has significant
systemic effects.
Nasally administered small dose display
a rapid absorption that is comparable to
intravenously administered drugs.
Advantages of Nasal Route as
systemic delivery are:
A non-invasive route
Convenience of administration and amenable to
chronic self administration
Avoids first pass metabolism or gastro intestinal
tract destruction
A large permeable surface area and rich
vasculature availability
Plasma concentration time profile is comparable
to intravenous administration
Macromolecules like proteins and peptides can
be successfully administered.
Limitations:
Rapid mucociliary clearance
Chances of immunogenic reaction
Inadequate availability of toxicity
data for penetration enhancement
Nasal pathology may adversely affect
product effectiveness
Anatomy of respiratory tract
This must be understood as a tool for
formulating a potential dosage form
as an alternative for parenteral route.
Upper and lower respiratory tract
with portals of entry being either
nose or mouth.
Airway epithelium Columnar
epithelium
The mucous blanket
Various proteins
Nasal pH
Cilla
Vascularity
Mucociliary blanket
Airway
Metered Dose inhalers
It is composed of four essential
components: the base formulation
(Drug, propellant, excipients, etc.),
the container, the metering valve and
the actuator (or mouth piece)
The drug is delivered through a valve
in a metered volume from a volatile
propellant, pressurized container.
Metered Dose inhalers
Pressure
resistant
container
Liquid solution or
suspension
Metering
chamber
Valve stem
Actuator
Mouthpiece
Air inlet
Spray jet
Mainly two types of systems
are available
(A) NONPRESSURIZED SYSTEM
(B) PRESSURIZED SYSTEM
NONPRESSURIZED SYSTEM
Micronised drug is dissolved or dispersed in
liquefied propellant (CFC). Before the propellant
exits from the atomized nozzle, it is partially (1520%) evaporated and droplets are broken up by
the violent evaporation generating droplets with
wide distribution (1-5µm).
But due to alarms raised for stratospheric ozone
depletion, a more environment friendly
substitutes like Hydrofluoroalkane (HFA) came in
light. They have the limitation of poor solvency
which can be overcome by addition of cosolvents like ethanol.
Some patients cannot fulfill the co-ordination
requirements which is essential for maximum
therapeutic benefits, breath actuated powder
inhalers are developed.
Powder Delivery System
It’s a versatile system require some
degree of dexterity.
It is ozone friendly system requires
no CFC to disperse the drug.
A. Unit Dose Device
SPINHALER
ROTAHALER
SPINHALER
ROTAHALER
B. Multiple Dose device
TURBOHALER
B. Multiple Dose device
DISCHALER
Formulation
Particle size (< 5µm)
Blended with large lactose
particles
PulmoSphere
Manufacturing Process
single dose devices
Multi dose dispense discs
Nebulized Drug delivery
Systems
For acute care of nonambulatory,
hospitalized patients particularly with
co-ordination difficulties.
Not conveniently portable
Solutions or suspensions
Ultrasonic devices
Ultrasound waves - a ceramic
piezoelectric crystal
Air jet nebulizer
Nebulizer formulation:
The pharmaceutical solution
technology - parenteral products
Formulated in water
Co-solvents
pH above 5
PRESSURIZED SYSTEM
Compact pressurized dispensers designed for
oral use, which deliver discrete doses of
aerosolized medicament by inhalation to the
lungs.
The discharged spray undergoes flash
evaporation of propellant liquid to produce a
finely dispersed aerosol.
The deposition, dependent on the mass of
inhaled drug particles which have a suitably small
aerodynamic size to be deposited in the required
regions of the lungs.
MDIs are apparently simple delivery dosage
devices, but in practice very complex.
PRESSURIZED SYSTEM
Consists of
five basic
components :
– Drug
concentrate
– Liquefied
propellant
– Container
– Metering valve
– Actuator
Drug Concentrate
Drug powders
Usually suspension, occasionally
solution.
Particle size - below 10 m in
diameter and mostly below 5 m.
The particle size distribution
Drug Concentrate
Drug Suspension
Aggregate irreversibly and deposit
on pack surface
The liquid and solid-phase densities
Low solubility in the propellant
Physical stability of the suspension
assessed
Surfactants
Presence of minute amount of water.
Drug Concentrate
Drug Solution
When the drug is too soluble in propellant.
A co solvent is required and it is usually
ethanol.
ethanol concentration (30-50% by wt.) some disadvantages:
Retard evaporation of the spray, which
increases oropharyngeal drug deposition
and reduce respirable aerosol fraction.
Chemical instability of drug
Extraction from valve rubber seal
Propellants:
Mainly two types
Liquefied Compressed gases
e.g. CFC (chlorofluorocarbons),
HCFC(Hydrochlorofluorocarbons),
HFA(hydrofluoroalkanes)
Non Liquefied Compressed gases
e.g. N2, CO2
Liquefied compressed gases are preferred over
the other one because:
Flash evaporation to give aerosol of fine particle size.
Spray particle size remains constant during pack
emptying as inhaler vapor pressure is maintained at
constant level. While compressed gas aerosol
performance coarsens due to decrease in gas pressure
with increase in head space volume.
Propellants:
Currently only three propellants are approved
worldwide for MDI products: CFCs 11, 12, and
114
Now a days, study of propellants of low or zero
ozone depletion potential (ODP) is increasing.
e.g., HCFCs 22,142b, and 152a
Hydrofluroalkanes (HFA) are chlorine-free
and are judged to have zero ODP. HFA-134a is an
important promising replacent for CFC-12
Containers
Aluminum containers
They are light, strong, break resistant,
compact and light proof and significantly inert.
It is prepared by 2 methods
(1) Rapid impact “slugging”
(2) Precision deep-drawing – Uniform
wall thickness, greater strength.
• The cans should be capable of
withstanding internal pressure of at least
1000kPa (150 psig) without evident
distortion.
• Glass bottles
• Plasticized PVC non bonded coating
Metering Valves
Function
Complex assembly
The valve for suspension products
The typical metering valve
At rest
During Actuation
Discharging
During
release
Chamber refilling
Actuators (Adapter)
Discharge orifice (spray nozzle) and a
socket to engage and form a seal with
metering valve stem.
A remarkable variety of actuator designs.
But, original “band –tube” arrangement
with a separate mouthpiece cap remains
predominant.
Spacer
The problem of poor patient co-ordination
may also be reduced by using breath
actuated inhalers, which are activated by
the vacuum induced in the inhaler by an
adequate inhalation flow rate.
Manufacturing of Inhalers
Mainly 3 methods
(1) Cold Filling
(2) Pressure Filling
(3) Under Cup Filling
Low atmospheric relative humidity
should be maintained in filing area in
all the methods.
The primary steps for all the
methods
Unscrambler
I
Hot Air
II
III
(1) Cold Filling
The cold filling method is restricted to nonaqueous products and to those products
which are not adversely affected by low
temperatures in the range of -40°F.
Potential disadvantage include high
propellant vapor loss, high cost of
refrigerator and humidity control
equipment, a possible induction of
nonreversible induction of physical
changes in formulation.
Cold Filling
Chilled Product
Concentrate
IV
Chilled Propellant
Valve
V
VI
(2) Pressure Filling
Low boiling propellant
under pressure
Product
concentrate
Valve
IV
V
VI
(3) Under Cap Filling
Propellant filling
Product
concentrate
IV
V
VI
The Terminal Procedure
The containers pass through
heated water bath heated at 130°F
to test for leak and strength of
container.
The containers are then air dried,
capped and labeled.
Novel Excipients for
Inhalation Drug Delivery
Goals :
To expand the range of compound
To increase the clinical benefits obtained from
MDI by providing new capabilities like
sustained release or greater respirability.
Three primary Application :
(1) Suspension aids – to increase the number
of compounds that can be prepared as high
quality suspensions.
(2) Solubilizers – to enable solution formation
at high doses.
(3) Sustained release agents – to enhance
lung residence time of the compound.
Evaluation of MDI as per FDA
Appearance of container and closure system
Microbial Limits
Water or Moisture Content
Dehydrated Alcohol Content
Net Content (Fill) Weight
Drug Content (Assay)
Impurities and Degradation Products
Dose Content Uniformity
Particle Size Distribution
Spray Pattern
Plume Geometry
Leak Rate
Pressure Testing
Valve Delivery (Shot Weight)
Leachables
Particle droplet size analysis
Influence on
High speed flash photography and
halography
Laser diffraction size analysis
Phase Droplet Anemometer.
Microscopic analysis with an image
analyzer
Cascade Impactor
Particle droplet size analysis
Single Particle Optical Sizers (SPOS)
Disadvantages :
Drug particles are not distinguished from
excipients.
Sampling may not be representative of the
whole sample.
Assumption: the particles are spherical
and of equal density.
Light Scattering Counters
Spray pattern
Allows the cross sectional uniformity of
the spray to be determined at specified
distances away from the pump orifice tip.
In past FDA recommended : with
impaction on TLC plates and manual
interpretation of spray pattern.
FDA`2003 draft : non impaction method
based on laser sheet and digital camera
using electronic images and automated
analysis.
Plume Geometry
Side view parallel to the axis of the plume of the
spray or aerosol cloud to be determined.
In the past, the FDA recommended that plume
geometry could be characterized in terms of
plume angle, plume width, and plume height
using high-speed flash photography.
FDA’s 2003 draft : laser sheet and high-speed
digital camera with electronic images.
ImageTherm Developed a SprayVIEW system to
simplify the spray and plume geometry.
Plume geometry and spray pattern measurement
using SprayVIEW for an aqueous nasal spray.
Reproducibility of Valves
5 cans are selected from 100 cans supplied.
Actuator is kept in place and container is weighed
accurately to ±0.5 mg.
The valve is actuated once, container is
reweighed and weight loss is recorded.
Single actuations are repeated and weight loss is
measured each time. The time interval between
each individual actuation is recorded.
The regions required to be evaluated are of initial
actuations and actuations when aerosol container
was approximately 10, 30, 50, 70, 95% empty.
All actuations are performed with cans in inverted
position.
Loss of prime
It is defined as valve delivery 15% below the
mean.
Onset of loss of prime is shown to be dependent
on valve design as well as storage position.
Aerosol is weighed to the nearest milligram
before actuation.
Aerosol can is placed in inverted position and
press the actuator button for 3 seconds to ensure
delivery of full dose.
Let the unit stand at room temperature for 1
minute to allow complete evaporation of
propellant and the can is reweighed.
Valve delivery for actuation number 5 is
considered as representative of the delivery from
a fully primed metered dose valve.
Recent innovation in MDI
Technology
Research on area of formulations,
valves, canisters, elastomers,
mouthpieces, etc.
Other Improvements includes,
Breathe-actuation technology
Ability to deliver therapeutic proteins
and peptides
Sustained drug delivery
Improved shelf life
AERx® SYSTEM :
Sophisticated technology in order to
provide precise dosing which includes,
Controlled dose expression
Control of aerosol particle size
Management of the inhalation and delivery
Inhalation and delivery coordination is
optimized through a microprocessorcontrolled flow sensing system that
actuates delivery only at the beginning of
the inspiration and within the correct
inspiratory flow rate.
AERx® SYSTEM :
ADAPTIVE AEROSOL
DELIVERY TECHNOLOGY
Adapts to the patient’s breathing and
ensures accurate drug delivery. Detects
pressure changes during breathing and
constantly adapt to the inspiratory and
expiratory flow pattern of the patient.
AAD systems deliver drug until all the
preprogrammed dose has been received
and gives audible feedback at the
completion of treatment, irrespective of
the time taken.
ADAPTIVE AEROSOL
DELIVERY TECHNOLOGY
SPIROS INHALER TECHNOLOGY :
(DURA PHARMA)
Small handheld, breath-actuated, battery
operated system.
The high speed rotating impeller provides
mechanical energy for dispensing.
The Spiros DPI blisterdisk powder storage
system designed for potentially moisture
sensitive substance,(protein.peptides)
Clinical trials through phase-3 has been
completed for Albuterol sulfate and
Beclomethasone diproprionate.
Next generation model of this system is Spiros S2
which is motorless, cost effective, easy to use
and for both unit dose and multidose system
RESPIMAT: A NEW SOFT
MIST INHALER :
Patented mechanism of generating a
soft fine mist from dosed volume of
drug solution
It uses simply mechanical energy
Delivers multiple doses without
propellants
ELECTRONIC DPI FOR
INSULIN :
1st completely electronic DPI
Pulmonary insulin delivery requires a particle
diameter of 3.3 μm or less. This is achieved by
spray drying process.
Here in first step, the drug is aggeregated in
aluminum blister and then in 2nd step, high
frequency piezo vibrator deaggregates the
powder in primary particles but still in blister and
then in 3rd step, deaggregated particles
circulates the top of blister which is then forced
through pierced hole to air stream.
ELECTRONIC DPI FOR
INSULIN :
APPLICATION OF MDI IN
SYSTEMIC MEDICATION
Analgesics
• Butorphenol
• Enkephalins
• Buprenorphine
Cardiovascular drugs
• Dobutamine
• Angiotensin II antagonist
Endocrine Hormones
• Human Growth Hormones
• Calcitonin
• Luteinizing Hormone-Releasing Hormone
• Insulin
APPLICATION OF MDI IN
SYSTEMIC MEDICATION
β2- Adrenoreceptor Agonist
• Salbutamol
• Buxaterol
• Soterenol
• Fenoterol
• Isoprenalin
Anticholinergic drugs
• Atropin
• Ipratropium bromide
Antihistaminics
• Astemizol
• Cetirizin
• Levocarbastin
Market formulations
Drug
Salbutamol
Brand name
Company
Asthalin inhaler(200MD,
400 MD)
Cipla
Vent Easecaps
(dry powder inhalant)
Kresp
Terbutaline
Bricanyl inhaler/ misthaler
Astra zeneca
Fluticasone propionate
Seretide Accuhaler
Glaxo
Isoprenaline
Autohaler
Cipla
Salmeterol
Salmeter inhaler
Dr.Reddy
Salbutamol+Becometha
sone dipropionate
Aerocort inhaler
Cipla
Beclomethasone
Dipropionate
Beclate inhaler
(200MD,400MD)
Cipla
Budesonide
Budecort inhaler
Cipla
References:
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Controlled Drug Delivery: Concept and Advances
by S.P. Vyas and Roop K. Khar Pg. 315 – 382.
Drugs and the Pharmaceutical Sciences: Nasal
Systemic Drug Delivery, Volume 39 by Chien, Su
and Chang.
Encyclopedia of Pharmaceutical Technology;
Volume 9; Metered dose Inhalers: Non pressurized
systems; pg. 287 – 298
Encyclopedia of Pharmaceutical Technology;
Volume 9; Metered dose Inhalers: Pressurized
systems; pg. 299-329
The theory and practice of Industrial Pharmacy:
Leon Lachman; Third edition: Pg. 589 – 618.
Remington: The science and Pharmaceutical
Pharmacy; 20th Edition; volume I; pg. 963-979.
References:
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Test for reproducibility for metered dose aerosol
valves for Pharmaceutical solutions; A. Cutie, J.
Burger, C. Clawns; Journal of Pharmaceutical
Science: Volume 70; No. 9; September 1981, pg.
1085-1087.
Test method for evaluation of loss of prime in
metered dose aerosol; Eugene F., William G.:
journal of Pharmaceutical Science: Volume 77;
No. 1; January 1988, pg. 90-93.
www.fda.gov/cdere/guidance/2180dft.htm
Encyclopedia of Pharmaceutical Technology;
Volume 8: Intranasal Drug Delivery; pg.175-201.
Encyclopedia of Pharmaceutical Technology;
Volume 7: Hydrocarbons, pharmaceutical uses;
pg 161-180.
References:
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www.disprod.co.za
www.astrazeneca.no
www.zaversky.at
www.training.seer.cancer.gov
www.pharmatech.com