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1、PULMONARY DRUG DELIVERY,Tarun K. Mandal, Ph.D.,Pulmonary Drug Delivery,MISCELLANEOUS PREPARATIONS,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.,Pulmonary Drug Delivery,Classificatio
2、ns of Aerosol Products: 1. space sprays 2. surface coating 3. aerated sprays,Pulmonary Drug Delivery,1. Space sprays. Disperse the active ingredients as a finely divided spray with the particle no longer than 50 m in diameter. 2. Surface coating. Disperse larger particle, generally produce a wet or
3、course spray.,Pulmonary Drug Delivery,3. Aerated sprays. Disperse medicated foams, vaginal foams, shaving cream.,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
4、; dose Clean process; require no wash-up,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 $
5、56,000,000.,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,Pulmonary Drug Delivery,Aerosols
6、for systemic treatment: Polypeptide drugs The advantages of therapeutic aerosols 1. The drugs begin to act very rapidly 2. Smaller dose can be used than with oral or intravenous delivery 3. Reduction in the incidence of systemic side effect.,Pulmonary Drug Delivery,OVERALL STRUCTURE AND FUNCTION OF
7、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.,Pulmonary Drug Deliver
8、y,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.,Pulmonary Drug Delivery,BLOOD AND
9、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 firs
10、t-pass hepatic effect, although they could be metabolized in the respiratory tract.,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.,Pulmonary Drug
11、 Delivery,1. INERTIAL IMPACTION: Particles of diameters ranging from a few microns to greater than 100. 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).,Pulmonary Drug Delivery,2. S
12、EDIMENTATION: 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:,Pulmonary Drug Delivery,2 r2 (d1 - d2) g v =- 9 n r =radius of the particle; d1 =density
13、of the particle; d2 =density of air; n =viscosity of air; g = gravitational constant.,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).,Pulmonary Drug Delivery,3. D
14、IFFUSION: Particle deposition by diffusion or brownian motion predominates for very small particles (5 or less) and occurs predominantly in the periphery of the lung (respiratory bronchiole and alveolus).,Pulmonary Drug Delivery,FACTORS AFFECTING DEPOSITION A wide range of other factors influences t
15、he deposition of aerosols within the respiratory tract.,Pulmonary Drug Delivery,1. MODE OF INHALATION: The most important features of inhalation are a) inhaled volume b) flow rate c) breath holding pause maintained at end inspiration,Pulmonary Drug Delivery,2. AEROSOL PROPERTIES: The vital physical
16、property of the aerosol itself is the aerodynamic diameter (the product of physical diameter and the square root of density).,Pulmonary Drug Delivery,aerodynamic diameter 2 m -deposition in the oropharynx -less reaches the most peripheral parts of the lung The ideal size for a therapeutic aerosol sh
17、ould not be more than 5 m to penetrate into the tracheobronchial tree and smaller airways if peripheral deposition is required.,Pulmonary Drug Delivery,AEROSOL FORMULATION The Aerosol Principle 1. Product Concentrate 2. Propellant,Pulmonary Drug Delivery,Product Concentrate 1. Active Ingredients 2.
18、Antioxidants 3. Surface Active Agent 4. Solvent,Pulmonary Drug Delivery,Propellant Liquified GasMixture Example: Fluorinated Hydrocarbon Nonliquified Gas Example: Carbon Dioxide, Nitrogen, Nitrous Oxide Advantages of Nitrogen as Propellent: 1. It is insoluble in the product concentrate 2. It is an o
19、dorless and tasteless gas,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,Pulmonary Drug Delivery,Space Sprays- 85% Propellant Surface Sprays- 30-70% Propellan
20、t Aerated Sprays- 6-10% Propellant Blends of the various liquified gas propellants are generally used.,Pulmonary Drug Delivery,AEROSOLS AND RAOULTS 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 =
21、84.9 psi.,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 va
22、por pressure of this mixture?,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,Pulmonary Drug Delivery,TOXICITY The Physiologic Effect Must B
23、e 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 cravi
24、ng for fluorinated hydrocarbon.,Pulmonary Drug Delivery,AEROSOL SYSTEMS Two-Phase Systems Liquid Phase 1. Liquified Propellant 2. Product Concentrate Vapor Phase,Pulmonary Drug Delivery,Three-Phase Systems 1. Water immiscible liquid propellant 2. Highly aqueous product concentrate 3. Vapor phase.,Pu
25、lmonary 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.,Pulmonary Drug Delivery,F
26、ILLING OPERATIONS Cool below their boiling points Compress the gas at room temp.,Pulmonary Drug Delivery,Cold Filling: The product concentrate & the propellant must be cooled to -300 to -400 deg F Disadvantage Aqueous systems cannot be filled, water turns to ice at this low temp.,Pulmonary Drug Deli
27、very,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,Pulmonary Drug Delivery,Testing the Filled Containers
28、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.,Pulmonary Drug Delivery,Packaging: Packaging is part of the manufacturing process,Pulmonary Drug Delivery,Labeling: Use
29、 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
30、death.,Pulmonary Drug Delivery,TYPES OF INHALATION DEVICE There are three types of device in common use. METERED DOSE INHALER NEBULIZER DRY POWDERED INHALER,Pulmonary Drug Delivery,APPLICATION OF AEROSOL SYSTEMS: Formulation of products containing therapeutically active ingredients. Pharmaceutical A
31、erosol: 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.,Pulmonary Drug Delivery,SPRAY
32、S: 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.,Pulmonary Drug Delivery,Pharmaceutical Aerosols: Cromolyn Sodium Aerosol Trade Name: Intal Aerosol Mfg. : Fi
33、sons Use: Antiasthmatic ;Antiallergic Cromolyn sodium for inhalation usp: Trade name: Intal Use: Antiasthmatic,Pulmonary Drug Delivery,Epinephrine inhalation solution usp: 1% Epinephrine aqueous solution use: Bronchodilator WARNING: Protect from light. Do not use if brown in color or contains precip
34、itate. Epinephrine inhalation aerosol usp: This preparation is a solution of epinephrine in propellants and alcohol.,Pulmonary Drug Delivery,Isoproterenol HCL inhalation aerosol usp: Trade name: Isuprel Mistometer aqueous solution of isoproterenol HCL salt. It contains NaCl to achieve isotonicity. S
35、trength: 0.25, 0.5, 1% Use: Bronchodilator,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,Pulmonary Drug Delivery,Propylhexadrine inhalant usp: Use: Adrenergic M
36、etaproterenol 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
37、 gun cotton) is obtained by the action of a mixture of nitric and sulfuric acids on cotton and consists of cellulose tetranitrate.,Miscellaneous preparation,Available commercially moistened with 30% alcohol. Storage Highly flammable; must be stored away from flame, well-closed containers, protect fr
38、om light. Use: “For external use only.“ Disadvantage: Inflexible in nature,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)
39、 Marketed Preparations: Compound W (Whitehall),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.,Miscellaneous preparation,LINIMENTS: Alcoholic
40、or oleaginous solutions or emulsions of various substances intended for external application to skin, generally with rubbing.,Miscellaneous preparation,Labels: 1. External Use 2. Shake Well Storage: store in a tight container,Miscellaneous preparation,GLYCEROGELATINS: Plastic masses intended for top
41、ical application. Contains gelatin, glycerin, water, medicinal agents. Medicinal agents: Zinc oxide, salicylic acid, resorcinol, and other,Miscellaneous preparation,Application Procedure: Melted prior to application- cooled to only slightly above body temp. Applied to the affected area. Allowed to r
42、emain in place for periods up to 6 weeks or longer.,Miscellaneous preparation,Usual Concentration of drugs 10% Typical Formulation Medicinal Substance 100g Gelatin 150g Glycerin 400g Purified Water 350g 1000g,Miscellaneous preparation,Zinc Gelatin: Firm plastic mass containing 10% zinc oxide in Glyc
43、erogelatin Base. Use: For the treatment of various ulcers. Make it soft on a water bath before application.,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 con
44、tact at that site.,Miscellaneous preparation,Backing Materials Used: Paper, Cotton, Silk, Plastic Type: Medicated: For localized or systemic effect Nonmedicated: For mechanical support,Miscellaneous preparation,Commercially Available Plasters: Are used as back plasters, chest plasters, breast plaste
45、rs, kidney plasters, corn plasters.,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,Miscellaneous preparation,TAPES AND GAUZES: Adhesiv
46、e Tape: Fabric and/or film evenly coated on one side with a pressure sensitive adhesive mixture. 1. Sterile Tape 2. Nonsterile Tape,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 absorb
47、ent gauze, tightly rolled in various widths and lengths and substantially free from loose threads.,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. -
48、Sterile,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,Miscellaneous preparation,Rubbing Alcohol: Contains about 70% of Ethyl Alcohol by volume. Use: Exter
49、nally for bedridden patients. 1. Germicide for instruments 2. Skin cleanser prior to injection,Miscellaneous preparation,Isopropyl Rubbing Alcohol: Contains about 70% by volume of Isopropyl Alcohol Use: Disinfecting the skin ;Disinfecting needles and syringes.,Miscellaneous preparation,Hexachlorophene Liquid Cleanser: 1. Bacteriostatic Cleansing Agent 2. Staphylococci,