Aerosol

Tarun K. Mandal, Ph.D.

PULMONARY DRUG DELIVERY



Pulmonary Drug Delivery

MISCELLANEOUS PREPARATIONS



AEROSOLS

Aerosols are defined as colloidal systems of very finely subdivided liquid or solid particles dispersed in and surrounded by a gas.



Classifications of Aerosol Products:

1. space sprays 2. surface coating 3. aerated sprays



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.



3. Aerated sprays. Disperse medicated foams,

vaginal foams, shaving cream.



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



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.



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



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.



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.



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.



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.



PHYSICAL MECHANISMS OF PARTICLE DEPOSITION IN RESPIRATORY TRACT

The three mechanisms of aerosol kinetics govern the majority of particle deposition within the respiratory tract.



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).



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:



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.



Factors that may increase particle deposition by sedimentation are:

a) increase in particle size b) decrease in airflow (breath- holding or

long slow breathing).



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).



FACTORS AFFECTING DEPOSITION

A wide range of other factors influences the deposition of aerosols within the respiratory tract.



1. MODE OF INHALATION: The most important features of

inhalation are a) inhaled volumeb) flow ratec) breath holding pause maintained

at end inspiration



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).



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.



AEROSOL FORMULATION

The Aerosol Principle1. Product Concentrate2. Propellant



Product Concentrate

1. Active Ingredients2. Antioxidants3. Surface Active Agent4. Solvent



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



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



Space Sprays- 85% PropellantSurface Sprays- 30-70% PropellantAerated Sprays- 6-10% Propellant

Blends of the various liquified gas propellants are generally used.



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.



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?



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



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.



AEROSOL SYSTEMS

Two-Phase Systems Liquid Phase1. Liquified Propellant2. Product Concentrate Vapor Phase



Three-Phase Systems

1. Water immiscible liquid propellant

2. Highly aqueous product concentrate

3. Vapor phase.



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.



FILLING OPERATIONS

Cool below their boiling points

Compress the gas at room temp.



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.



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



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.



Packaging:Packaging is part of the

manufacturing process



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.



TYPES OF INHALATION DEVICE

There are three types of device in common use.

METERED DOSE INHALER NEBULIZER DRY POWDERED INHALER



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.



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.



Pharmaceutical Aerosols: Cromolyn Sodium Aerosol Trade Name: Intal Aerosol Mfg. : Fisons Use: Antiasthmatic ;Antiallergic Cromolyn sodium for inhalation usp: Trade name: Intal Use: Antiasthmatic



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.



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



Isoproterenol sulfate inhalation usp:

Trade name: Norisordrine aerotrol contains 0.2% of the drug in metered aerosol.

Amyl nitrite inhalant usp: Use: Vasodilator



Propylhexadrine inhalant usp: Use: Adrenergic Metaproterenol sulfate inhalation

aerosol usp: Use: Bronchodilator Tuaminoheptane inhalant usp: Use: Vasoconstrictor


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.



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



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)



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.



LINIMENTS: Alcoholic or oleaginous solutions or

emulsions of various substances intended for external application to skin, generally with rubbing.



Labels:1. External Use2. Shake Well

Storage:store in a tight container



GLYCEROGELATINS: Plastic masses intended for topical

application. Contains gelatin, glycerin, water,

medicinal agents. Medicinal agents: Zinc oxide, salicylic acid, resorcinol, and

other



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.



Usual Concentration of drugs 10%Typical FormulationMedicinal Substance 100gGelatin 150gGlycerin 400gPurified Water 350g 1000g



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.



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.



Backing Materials Used:Paper, Cotton, Silk, Plastic

Type: Medicated: For localized or systemic

effect Nonmedicated: For mechanical

support



Commercially Available Plasters: Are used as back plasters, chest

plasters, breast plasters, kidney plasters, corn plasters.



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



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



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.



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



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



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



Isopropyl Rubbing Alcohol:

Contains about 70% by volume of Isopropyl Alcohol

Use: Disinfecting the skin ;Disinfecting needles and syringes.



Hexachlorophene Liquid Cleanser:

1. Bacteriostatic Cleansing Agent2. Staphylococci

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Aerosol

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