Transcript Theme lecture:

PREPARATION FOR
INHALATION.
Drugs under pressure.
Drugs that are under pressure preparation for inhalation
Propellant Based-Metered Dose Inhalers
this drug that are in special containers (canister) under
the gas pressure and containing one or more active
ingredients, as the solutions,
emulsions or suspensions, which are released from
canister in the aerosol, liquid or soft form
due pressing on the valve .
Aerosol is a dispersion of solid or liquid particles of
medicine substances in the gas, the size of which
depends on the prescription.
Features of pMDI
•The drug product consists of: container, actuator,
formulation and protective packaging; dosing
performance is highly dependent on the design of the
device.
•The drug delivered to the patient consists of: API,
excipients, propellant and/or solvent.
•Aerosolization of the formulation from the pressurized
canister is highly transient, complex and rapid.
•The concept of classical bioequivalence and
bioavailability is not usually applicable for inhalation
aerosols.
The advantage of the preparation for
inhalation:
• Ease of use, aesthetics, hygiene.
• Availability of high efficiency at relatively low
cost drugs.
• Use the metered device providing exact dosing.
• Preparations for inhalation give rapid therapeutic
effect.
• Canister is tightly closed, ensuring sterility and the
drug protecting from the impact of the external
factors.
• When a large number of manipulations do not need a
large number of staff.
Disadvantages of the drug under
pressure:
 relatively high cost;
 possibility of explosion of the canister due
impact or high temperature;
 air pollution by drugs and propellants at
the manipulation.
Classification of the
drug under pressure
Pharmaceutical – are composed of the canister, valvespray systems and content of different consistency,
which are released from canister at the pressing on
the valve due propellant. The structure of this product
includes MS, auxiliary substances and propellants.
Medical – this means one or more MS in the form of
solid or liquid particles, obtained by means of special
stationary and intended primarily for inhalation
administration.
Classification of the pharmaceutical
drug under pressure by appointment:
1.
2.
3.
4.
5.
inhalation,
otolaryngology,
dermatological,
dental,
proctologic et al.
Pharmaceutical drug under pressure
• topical (skin) therapy for local anaesthesia
and cooling for
• sports injuries;
• sub-lingual sprays for angina pectoris;
• nasal sprays for allergic rhinitis and
sinusitis;
• vaginal foams for contraception;
• rectal foams for colitis.
Formulation
Active Pharmaceutical Ingredients
•Micronized
•Spray Dried
•Freeze Dried
•Others
Excipients / Surfactants (improve valve
lubrication, enhance API solubility and increase
homogeneity of the suspension)
Propellants - HFA 134a and 227
Solvents - ethanol (increase API solubility,
increase miscibility of the surfactant and lower
vapour pressure of propellant)
Principal Control Factors
•Momentum
(Particle/Droplet Size and Mass, Morphology, Shape and
Velocity)
•Particle Design
•Formulation
•Aerosol Generation
•Plume Manipulation (delivery system specific)
•Delivery Timing Relative to Aspiratory Cycle
Synchronize propulsion and inhalation dynamics
Closure Container System/Primary
Packaging
Container/canister (reservoir)
• Coated (chemically or plasma)
• Uncoated high grade aluminium
Valve (seal and volume control)
• Retention – Gaskets
• need to prime
• Non-retention
• no need to prime
Nozzle (modify the rate of flow, speed, direction, mass,
shape, pressure of stream)
Actuator/Mouthpiece
(affect spray pattern and droplet/particle size)
Canisters and valve-spray devices
1 - canister;
2 - sprayer - mouthpiece;
3 - metering valve;
4 - siphon tube;
5 - solution of MS;
6 - a vapour of the
propellant;
7 - propellant.
Capacity from 3 ml
to 3 litters.
a - two-phase system;
b - three-phase system;
a
b
Types
1. Two-phase system.
(Gas & liquid)
2. Three-phase system.
(Gas, liquid, solid/liquid).
Classification of canisters depend
on material
1.
2.
3.
4.
Metal
Glass
Plastic
Combined
Requirements to the glass
canisters:
• should withstand the internal pressure (at
least 2 MPa)
• should be resistant to impact
• should be chemically and thermally stable
• should not have internal stresses of glass
• should have a uniform thickness of the
• walls and bottom
• should have a minimum flat surfaces
Requirements to the
another canisters:
Plastics must be employed to coat the glass
to improve safety characteristics or to coat
metal containers to improve corrosion
resistance and enhances the stability of
formulation.
Suitable metals include stainless steel,
aluminium and tin-plated steel.
Classification of the metering
valve depend on principle of
operation:
1. Spring in force when you
click vertically down on
the actuator;
2. Oscillated springless when you
click by the side on the actuator;
3. Valves with screw valve.
Classification of the metering valve
depend on the way of fixing to the
canister:
1. fixed by decompressing on the
vertical walls;
2. by the process of rolling of the
valve body on the special walls;
3. by screw metering valve on
the neck canister.
Classification of the metering valve
depend on appointment:
1. standard valves for liquid
products,
2. for the foams;
3. for the viscous products;
4. for the powders and suspensions.
Types of the Nebulizers
•
•
•
•
•
•
•
Conventional Tee Nebulizers
Standard jet nebs w/ reservoir tubing
Venturi nebulizers
Passive and Active venturi nebulizer
Breath actuated nebulizers
Ultrasonic nebulizers
Vibrating mesh
Types of the actuators:
1. for inhalation,
2. for the treatment of
the asthma,
3. for suspension,
4. for film forming
composition;
5. nozzles dental, rectal,
vaginal.
Propellants
For pressurized metered dose inhalations
propellants perform the essential function
of expelling the material from the container
by supplying the necessary pressure within
the aerosol system.
They are liquefied or compounded gases
having vapor pressures exceeding
employed to obtain the necessary delivery
and spray characteristics of the aerosol.
The commonly used propellants in aerosol
systems are hydrocarbons, especially the
fluorochloro derivatives of methane and
ethane (Table ), the butanes and pentanes
and compressed gases are used.
Commonly used propellants in
aerosol systems
Propellants Molecular weight Vapor pressure
011(CCl3F)
012(CCl2F2)
114(C2Cl2F4)
134(CH2FCF3)
227(CHF2C2F5)
137.4
120.9
170.9
102.0
170.0
13.4
94.5
27.6
96.0
72.6
Classification of the propellants
depend on the vapor pressure:
1. The main, can create their
own pressure not less than
0.2 MPa,
2. Auxiliary - propellants creating
a pressure less than 0.1 MPa.
Classification of the propellants
depend on the states of aggregation:
1) Liquefied gases:
Freon , propane, butane, isobutane,
vinyl and metylhloryd et al.
2) Compressed (difficulty liquefied) gases:
nitrogen, nitrogen oxide, carbon dioxide;
3) easy volatile organic solvents:
metylenhloryd, ethylene chloride, etc.
Stages of the Drugs under pressure
production:
1.
2.
3.
4.
5.
6.
7.
8.
9.
Sanitary preparation of production
Preparation of concentrate - MS solution
Release him from insoluble impurities
Packing in containers
Sealing
Filling propellant
Check the strength and impermeability
Standardization
Design package for transportation
The advantages of the
emulsion systems – foams:
- provides economical dosing
- better contact with the mucous
membrane, provides long-acting of the MS ,
- under the influence of body temperature they
increase in the
volume, filling all vacancies and channels in the
rectum or vagina
- can move in proximal direction, and during 4
hours provide a high concentration of MS.
Factors that affect on the stability
of the foams:
•
•
•
•
•
•
concentration of the foam agent,
presence of the electrolyte
pH,
viscosity of the solution
concentration and type of the propellant,
presence of the additives.
The indicators used to evaluate the
foam:
•
•
•
•
•
•
•
•
•
appearance
issuing its type of container (smooth, jerky, loud)
stability and lifetime,
elastic properties of the foam
drying as a percentage of the time,
wetting properties,
density,
viscosity,
dispersion.
Classification of the foams
Classes
of the foams
Aqueous:
aqueous phase,
surface active
agents,
propellant.
Aqueous alcohol:
water
ethyl alcohol,
foam,
propellant.
Nonaqueous :
vegetable oil
or mineral oil,
surface
active agents
propellant
Suspension under pressure a heterogeneous dispersed systems are
characterized by the presence of th
insoluble in liquid concentrate solid phase.
Classification by composition:
1. They propellant may be included in
the soluble phase or dispersion medium.
2. The active substance is dispersed in nonvolatile solvent.
The main factors affecting on the
quality of suspensions:
1. physical and chemical properties of the
substances;
2. correlation between the components
of the filler;
3. features of the design and material of
the packaging;
4. temperature conditions of the
maintenances container.
Canisters Production:
Monoblock aluminium containers are made from
flat pieces forming presses for impact type.
Glass containers are made
of neutral borosilicate glass on the
automatic glass forming machines
by double firing in horizontal furnaces.
Plastic ones are
made by vacuum forming or molding by
pressure on the molding machines.
Methods of filling of the
containers by propellants:
1. Filling pressure (primary)
2. Low-temperature method or "cold filling“
3. Method of filling by the compressed gases
4. Method of filling by the
soluble compressed gases.
The steps of filling containers:
A. Washing, rinsing and drying of the containers
2. Blowing of the containers with sterile air
3. Filling the container with solution of concentrates
4. Remove air from the container by th e drop of liquid
propellant
5. Sealing of container by consolidation valve
6. Filling the propellant under pressure
7. Check for leaks and strength.
Storage:
• avoid impacts,
direct sunlight,
high temperature.
Aerosol Testing Devices
• Cascade Impactors-Provides aerodynamic particle sizing
and gives qty. of specific drug at a specific size
- Anderson Cascade, Marple Miller and Next Generation
Impactor
• Laser Diffraction Shines a laser beam through a particle
and measure the refraction of the laser light to determine
the size of the particle. Converts particle size to an
equivalent sphere.
- Malvern Mastersizer and Malvern Spraytech
• Breath Simulation- Harvard Pump
• Dose Assessment:
- Filter Collection for weight analysis
- Spectrophotometry / HPLC to assess drug presence
Aerosol Testing
Cascade Impactors
Advantages
Laser testing Advantages
Speed / Cost /Efficiency .
Measures particle size in real
time
Provides aerodynamic particle
size
Provides how much specific drug
Laser testing Disadvantages
at a specific size
Can only measure the particle
Cascade Impactors
size distribution of solution
Disadvantages
based drugs . With a
Continuous flow rate
suspension, does not
Long test times
differentiate between the
Requires testing to determine
carrier and the drug
amount of drug on each stage
Does not take into account the
During nebulizer testing
aerodynamics of a particle
(Specifically on Anderson
(How does the particle look to
impactor), drug may roll to the
a specific flow?)
next stage if plate is overfilled
Does not measure the quantity of
Evaporation during test
understates particle size
drug in specific particle size
Summary
• Primary packaging design of an aerosol delivery
system is an integral part of its function
• Optimizing the principal design control factors of
the drug product component will enhance the
delivery efficiency and improve the consistency
of the delivered dose
• Knowledge of optimizing these factors give us
the edge on delivering innovative therapeutic
agents