aerosol
DESCRIPTION
pharmaceuticsTRANSCRIPT
Tarun K. Mandal, Ph.D.
PULMONARY DRUG DELIVERY
Tarun K. Mandal, Ph.D.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
MISCELLANEOUS PREPARATIONS
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
AEROSOLS
Aerosols are defined as colloidal systems of very finely subdivided liquid or solid particles dispersed in and surrounded by a gas.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Classifications of Aerosol Products:
1. space sprays 2. surface coating 3. aerated sprays
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
1. Space sprays. Disperse the active ingredients as a finely divided spray with the particle no longer than 50 µm in diameter.
2. Surface coating. Disperse larger particle, generally
produce a wet or course spray.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
3. Aerated sprays. Disperse medicated foams,
vaginal foams, shaving cream.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Advantages of the Aerosol Dosage form:
Minimum Contamination Maximum Stability Reduces the irritation; cooling
effect Easy to control: physical form;
particle size; dose Clean process; require no wash-
up
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
The aerosols are used in pharmacy for local or systemic delivery of drugs.
The total sales of beta agonist and cromolyn sodium aerosols in the United States
1984 1988 Beta agonist $121,000,000
$238,000,000 Cromolyn sodium $12,000,000
$56,000,000.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Aerosols for local (topical) treatment:
1. Topical medication may be applied in a uniform thin layer to the skin, without touching the affected area
2. Aerosols are also used in the diagnosis, prevention or control of lung disease
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Aerosols for systemic treatment: Polypeptide drugs The advantages of therapeutic
aerosols1. The drugs begin to act very rapidly 2. Smaller dose can be used than with oral
or intravenous delivery3. Reduction in the incidence of systemic
side effect.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
OVERALL STRUCTURE AND FUNCTION OF THE RESPIRATORY TRACT
FUNCTION: The primary function of the respiratory tract is
gas exchange A secondary function is cleaning and
humidifying of the incoming air to prevent damage of this vital organ
Only delivery by breathing via mouth is considered for aerosol dosage forms.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
STRUCTURE: Upper airways oropharynx and larynx Lower airways
trachea which is followed by successive bifurcations into bronchi and bronchioli. terminal bronchioli then divide into respiratory bronchioli until the ultimate respiratory zone, the alveoli is reached.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
BLOOD AND LYMPH FLOW IN THE RESPIRATORY TRACT
Pulmonary vasculature forms a separate circuit from the systemic circulation.
The main pulmonary artery starts in the right ventricle, then it divides into two branches for the left and right lungs. Drugs absorbed into the pulmonary circulation will avoid the first-pass hepatic effect, although they could be metabolized in the respiratory tract.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
PHYSICAL MECHANISMS OF PARTICLE DEPOSITION IN RESPIRATORY TRACT
The three mechanisms of aerosol kinetics govern the majority of particle deposition within the respiratory tract.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
1. INERTIAL IMPACTION: Particles of diameters ranging from a
few microns to greater than 100µ. The inertia of an airborne particle will tend to cause it to travel in its initial path when the supporting airstream is suddenly deflected (turbinates, bifurcations).
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
2. SEDIMENTATION: Every particle allowed to fall in air
will accelerate to a terminal settling velocity (v) where the force of gravity is balanced by the resistance of the air through which the particle is falling:
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
2 r2 (d1 - d2) g v =--------------------- 9 n r =radius of the particle; d1 =density of the particle; d2 =density of air; n =viscosity of air; g = gravitational constant.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Factors that may increase particle deposition by sedimentation are:
a) increase in particle size b) decrease in airflow (breath- holding or
long slow breathing).
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
3. DIFFUSION: Particle deposition by diffusion or
brownian motion predominates for very small particles (5µ or less) and occurs predominantly in the periphery of the lung (respiratory bronchiole and alveolus).
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
FACTORS AFFECTING DEPOSITION
A wide range of other factors influences the deposition of aerosols within the respiratory tract.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
1. MODE OF INHALATION: The most important features of
inhalation are a) inhaled volumeb) flow ratec) breath holding pause maintained
at end inspiration
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
2. AEROSOL PROPERTIES: The vital physical property of the
aerosol itself is the aerodynamic diameter (the product of physical diameter and the square root of density).
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
aerodynamic diameter > 2 µm -deposition in the oropharynx -less reaches the most peripheral parts of the
lung The ideal size for a therapeutic aerosol
should not be more than 5 µm to penetrate into the tracheobronchial tree and smaller airways if peripheral deposition is required.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
AEROSOL FORMULATION
The Aerosol Principle1. Product Concentrate2. Propellant
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Product Concentrate
1. Active Ingredients2. Antioxidants3. Surface Active Agent4. Solvent
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Propellant Liquified Gas\MixtureExample: Fluorinated Hydrocarbon Nonliquified GasExample: Carbon Dioxide, Nitrogen, Nitrous
OxideAdvantages of Nitrogen as Propellent: 1. It is insoluble in the product concentrate2. It is an odorless and tasteless gas
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
The pressure of an Aerosol is critical to its performance. It can be controlled by:
1. The type and amount of propellant
2. Nature/Amount of the product concentrate
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Space Sprays- 85% PropellantSurface Sprays- 30-70% PropellantAerated Sprays- 6-10% Propellant
Blends of the various liquified gas propellants are generally used.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
AEROSOLS AND RAOULT'S LAW
The vapor pressure of pure propellant
11 (MW 137.4) at 210 C is p110 = 13.4 pounds/square inch (psi) and that of
propellant 12 (MW 120.9) is p120 = 84.9 psi.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
A 50:50 mixture of gram weight of the two propellants consists of 50 gm ÷ 137.4 g mole-1 =0.364 mole of propellant 11, and 50 gm ÷ 120.9 g mole-1 = 0.414 mole of propellant 12. What is the partial pressure of propellants 11 and 12 in the mixture and what is the total vapor pressure of this mixture?
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
p11= [n11/(n11+n12)] p110=[0.364/(0.364+0.414)](13.4)=6.27 psi
p12=[n12/(n11+n12)] p120 =[0.414/(0.364+0.414)](84.9)=45.2psi
The total vapor pressure of the mixture is
6.27 + 45.2 = 51.5 psi
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
TOXICITYThe Physiologic Effect Must Be Considered. Fluorinated Hydrocarbons have a relatively low
order of toxicity. Rapid and repeated use may exhibit Cardiotoxic Effect. Cardiac toxicity is likely to be a problem only for the occasional adult or child who deliberately abuses his/her metered dose inhaler, apparently to satisfy a craving for fluorinated hydrocarbon.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
AEROSOL SYSTEMS
Two-Phase Systems Liquid Phase1. Liquified Propellant2. Product Concentrate Vapor Phase
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Three-Phase Systems
1. Water immiscible liquid propellant
2. Highly aqueous product concentrate
3. Vapor phase.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Compressed Gas Systems Compressed, rather than liquefied, gases
may be used to prepare aerosols. The pressure of the compressed gas contained in the headspace of the aerosol container forces the product concentrate up the dip tube and out of the valve.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
FILLING OPERATIONS
Cool below their boiling points
Compress the gas at room temp.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Cold Filling:The product concentrate & the
propellant must be cooled to -300 to -400 deg F
DisadvantageAqueous systems cannot be filled,
water turns to ice at this low temp.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Pressure Filling: The product concentrate is
quantitatively placed in the aerosol container. This method is used for most Pharmaceutical formulations (aerosols)
Advantages: 1. Less danger of moisture
contamination 2. Less propellant is lost
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Testing the Filled Containers Test for leaks or weaknesses at 130
deg F Proper function of the valve Test for particle size distribution Test for accuracy and
reproducibility of dosage when using metered valve.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Packaging:Packaging is part of the
manufacturing process
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Labeling:Use warning labels whenever required. Avoid inhaling. Keep away from eyes or
other mucous membranes. Contents under pressure. Do not
puncture or incinerate container. Do not expose to heat or store at temp.
above 120 deg F (49 deg C). Do not inhale directly. Deliberate
inhalation of contents can cause death.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
TYPES OF INHALATION DEVICE
There are three types of device in common use.
METERED DOSE INHALER NEBULIZER DRY POWDERED INHALER
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
APPLICATION OF AEROSOL SYSTEMS: Formulation of products containing
therapeutically active ingredients. Pharmaceutical Aerosol: It may be defined as
an aerosol product containing therapeutically active ingredients dissolved, suspended, or emulsified in a propellant or a mixture of solvent and propellant and intended for oral or topical administration or administration into body cavities.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
SPRAYS: Sprays are aqueous or alcoholic or
glycerin solutions in the form of course droplets or as finely divided solids to be applied topically, most to the nasal-pharyngeal tract or to the skin.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Pharmaceutical Aerosols: Cromolyn Sodium Aerosol Trade Name: Intal Aerosol Mfg. : Fisons Use: Antiasthmatic ;Antiallergic Cromolyn sodium for inhalation usp: Trade name: Intal Use: Antiasthmatic
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Epinephrine inhalation solution usp: 1% Epinephrine aqueous solution use:
BronchodilatorWARNING: Protect from light. Do not use if brown in color or contains
precipitate.– Epinephrine inhalation aerosol usp:
This preparation is a solution of epinephrine in propellants and alcohol.
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Isoproterenol HCL inhalation aerosol usp:
Trade name: Isuprel Mistometer aqueous solution of isoproterenol HCL salt. It contains NaCl to achieve isotonicity.
Strength: 0.25, 0.5, 1% Use: Bronchodilator
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Isoproterenol sulfate inhalation usp:
Trade name: Norisordrine aerotrol contains 0.2% of the drug in metered aerosol.
Amyl nitrite inhalant usp: Use: Vasodilator
Tarun K. Mandal, Ph.D.
Pulmonary Drug Delivery
Propylhexadrine inhalant usp: Use: Adrenergic Metaproterenol sulfate inhalation
aerosol usp: Use: Bronchodilator Tuaminoheptane inhalant usp: Use: Vasoconstrictor
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
COLLODIONS: These are liquid preparations composed
of pyroxylin dissolved in alcohol and ether, with or without added medicinal substances.
Pyroxylin (soluble gun cotton) is obtained by the action of a mixture of nitric and sulfuric acids on cotton and consists of cellulose tetranitrate.
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Available commercially moistened with 30% alcohol.
Storage Highly flammable; must be stored away
from flame, well-closed containers, protect from light.
Use: "For external use only." Disadvantage: Inflexible in nature
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Flexible collodion: Prepared by adding 2% of camphor and 3% of castor oil to collodion.
Salicylic acid collodion: 10% solution of salicylic acid in flexible collodion.
Use: Keratolytic (Remove corns)Marketed Preparations:Compound W (Whitehall)
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Freezone (Whitehall)Direction of use:Apply one drop at a time onto the
corn--allow time to dry--apply next drop.
Caution: Salicylic acid can be irritating to normal, healthy skin.
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
LINIMENTS: Alcoholic or oleaginous solutions or
emulsions of various substances intended for external application to skin, generally with rubbing.
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Labels:1. External Use2. Shake Well
Storage:store in a tight container
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
GLYCEROGELATINS: Plastic masses intended for topical
application. Contains gelatin, glycerin, water,
medicinal agents. Medicinal agents: Zinc oxide, salicylic acid, resorcinol, and
other
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Application Procedure: Melted prior to application- cooled to
only slightly above body temp. Applied to the affected area. Allowed to remain in place for periods up to 6 weeks or longer.
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Usual Concentration of drugs 10%Typical FormulationMedicinal Substance 100gGelatin 150gGlycerin 400gPurified Water 350g 1000g
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Zinc Gelatin: Firm plastic mass containing 10% zinc
oxide in Glycerogelatin Base.Use: For the treatment of various ulcers.Make it soft on a water bath before
application.
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
PLASTERS: These are solid or semisolid
adhesive masses spread upon a suitable backing material.
Use: external application to a part of the body to provide prolong contact at that site.
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Backing Materials Used:Paper, Cotton, Silk, Plastic
Type: Medicated: For localized or systemic
effect Nonmedicated: For mechanical
support
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Commercially Available Plasters: Are used as back plasters, chest
plasters, breast plasters, kidney plasters, corn plasters.
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Salicylic Acid Plaster:Concentration 10 to 40%For maximum result soak the corn in
warm water for 15 to 30 minutes, prior to application of the plaster.
Do Not Use For More Than 14 Days
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
TAPES AND GAUZES:Adhesive Tape:Fabric and/or film evenly coated on
one side with a pressure sensitive adhesive mixture.
1. Sterile Tape2. Nonsterile Tape
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Absorbent Gauze: This is cotton or a mixture of cotton
and rayon in the form of a cloth. Gauze Bandage: This is one continuous piece of
absorbent gauze, tightly rolled in various widths and lengths and substantially free from loose threads.
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Adhesive Bandage: This is a compress of four layers of
absorbent or other suitable material, affixed to a film of fabric coated with a pressure sensitive adhesive substance.
-Sterile
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Petroleum Gauze: This is a absorbent gauze saturated
with white Petrolatum -Sterile Add white Petrolatum to dry sterile
absorbent gauze 60 g Petrolatum to 20 g gauze
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Rubbing Alcohol:
Contains about 70% of Ethyl Alcohol by volume.
Use: Externally for bedridden patients.1. Germicide for instruments 2. Skin cleanser prior to injection
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Isopropyl Rubbing Alcohol:
Contains about 70% by volume of Isopropyl Alcohol
Use: Disinfecting the skin ;Disinfecting needles and syringes.
Tarun K. Mandal, Ph.D.
Miscellaneous preparation
Hexachlorophene Liquid Cleanser:
1. Bacteriostatic Cleansing Agent2. Staphylococci