Pulmonary Drug Delivery Systems Spring 2022 PDF

PHA 339 Alekha K. Dash, R.Ph., Ph.D. 1 Ø Understand different types, advantages and disadvantages of pulmonary drug delivery systems. Ø Understand various components and functioning of Aerosol delivery systems Ø Understand the preparation and stability aspects of aerosols Ø Understand the calculatio...

PHA 339 Alekha K. Dash, R.Ph., Ph.D. 1 Ø Understand different types, advantages and disadvantages of pulmonary drug delivery systems. Ø Understand various components and functioning of Aerosol delivery systems Ø Understand the preparation and stability aspects of aerosols Ø Understand the calculations for determining the vapor pressure of propellants. 2 Ø A Pulmonary Drug Delivery Systems consists of any procedure or device which allows a drug to be administered into the respiratory tract primarily through lungs. 3 Ø Therapeutic Gases: Inhaled anesthetic agents, Example: Desulfurane, Halothane etc. Ø Inhaled Aerosols: Solid or liquid particles dispersed in a gas. USP defines Aerosols as system under pressure. üPressurized metered dose inhalers (pMDI) üNebulizers üDry Powder Inhalers (DPI) § Proventil, Ventolin (Albuterol Sulfate)(Bronchospasm) 4 ØMetered dose inhalers (MDI): Products that are packaged under pressure and the active ingredient is released upon activation of an appropriate valve system. ØNebulizers: Continuously produce a dispersed cloud of liquid droplets in air stream. The aerosol cloud is than inspired and expired through normal breathing. ü Air Jet nebulizers: High velocity air stream ü Ultrasonic nebulizers: Piezoelectric crystal, vibrates under electric field ü Vibrating mesh nebulizers: Piezoelectric crystal to a laser-drilled metal mesh. ØDry Powder inhalers (DPI): Diverse group of portable devices that creates an aerosol of solid particles suspended in air. Detailed Information: Required textbook, Pharmaceutics by Dash et. al. 5 Ø Facilitates self-medication Ø May replace injectable products or dosage forms Ø A dose can be dispensed from the container without affecting its stability or sterility Ø Medication can be delivered directly to the affected area in a desired form Ø Irritation during mechanical application of topical preparations is reduced Ø Onset of drug response is faster than when drugs are given orally 6 Ø By virtue of its hermetic character, the aerosol container protects medicinal agents adversely affected by atmospheric oxygen and moisture. üBeing opaque, the usual aerosol container also protects drugs adversely affected by light. üIf the product is packaged under sterile conditions, sterility is maintained during the shelf-life of the product. Ø Bigger absorption area; abundant blood circulation Ø Drug can avoid to be destroyed or inactivated by the pH or enzymatic activity of the stomach or intestines, also can avoid the first pass effect. 7 Ø High cost. Ø Because of the volatility, the propellants has the refrigeration effect which can irritate the skin. Ø The fluorinated hydrocarbons may exhibit cardiotoxic effects following rapid and repeated use of the aerosol product. Ø Other disadvantages? 8 Ø Suspensions of fine solids or liquids in air or gas Ø Depends on the power of a liquefied or compressed gas to expel the contents from the container Ø Used in pharmaceuticals since the early 1950’s Ø Currently the most common type of pulmonary drug delivery systems Ø Future development of aerosols will be dependent on the development of new types of propellants 9 Ø Product concentrate Ø Propellant Ø Container Ø Valve Assembly: Valves and Actuator 10 Gasket seals valves and prevent flow of liquid Gasket opens, liquid forced through orifice, discharged through nozzle Ref: Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems 11 Ø An equilibrium exists between that portion of propellant which remains liquefied and that which vaporizes Ø The vapor phase exerts pressure in all directions: against the walls of the container, the valve assembly, and the surface of the liquid phase Ø This pressure upon actuation of the aerosol valve forces the liquid phase up the dip tube and out of the orifice of the valve into the atmosphere. 12 Ø As the propellant meets the air, it immediately evaporates due to the drop in pressure, leaving the product concentrate as airborne liquid droplets or dry particles, depending upon the formulation. Ø As the liquid phase is removed from the container, equilibrium between the propellant remaining liquefied and that in the vapor state is reestablished. 13 Ø Even during expulsion of the product from the aerosol package, the pressure within remains virtually constant, and the product may be continuously released at an even rate and with the same propulsion. Ø However, when the liquid reservoir is depleted, the pressure may not be maintained, and the gas may be expelled from the container with diminishing pressure until it is exhausted. 14 Ø The product concentrate is the active ingredient of the aerosol combined with the required adjuncts, such as antioxidants, surfaceactive agents, and solvents, to prepare a stable and efficacious product Formulation of Pharmaceutical Aerosols: Ø An aerosol formulation consists of two parts: the product concentrate and the propellant. Ø The different types of formulation systems can be: ü solution system or dispersion system, ü binary or ternary systems Ø There may be a single propellant or a combination of propellants 15 Ø One of the most important components of the aerosol package. Often termed heart of the aerosol Ø Responsible for developing the proper pressure necessary to expel the contents of the aerosol when the valve is opened Ø Helps to determine whether the product is a foam or a spray Ø Serves as a solvent for certain active ingredients (except compressed gas propellants) 16 Ø Liquefied gases: üA. Fluorinated hydrocarbons: used in most aerosols for oral and inhalation use § ex. Trichloromonofluoromethane Propellant 11 § dichlorodifluoromethane Propellant 12 § dichlorotetrafluoroethane Propellant 114 üB. Hydrocarbons: used in topical pharmaceutical aerosols § ex. Propane, butane, isobutane Ø Compressed gases: § ex: Nitrogen, carbon dioxide, nitrous oxide 17 Ø Chemically inert Ø Flammable Ø Non-toxic Ø Expensive Ø Deplete when compared with hydrocarbons (HC) ozone layer 18 Ø Chemically Ø No stable hydrolysis Ø Inflammable Ø Low order of toxicity Ø Less expensive Ø Environmentally acceptable 19 Ø Low expansion power and has no chilling effect. Ø Foams produced by them are less stable when compare with liquefied gas foams Ø Widely used in dispensing food and non-food products in original form i.e., semisolid. Ø Used as propellants in dental creams, hair preparations, ointments, antiseptics, germicide aerosols 20 Ø The vapor pressure of a mixture of propellants can be calculated using Dalton’s law of partial pressure and Raoult’s law Ø Dalton’s law -- the total pressure of a system is equal to the sum of the individual or partial pressures of the various components 21 Ø Raoult’s law -- the depression of the vapor pressure of a solvent by the addition of a solute is proportional to the mole fraction of the solute molecules in the solution pa = {na/ (na + nb)} pao = Xa pao where, pa = partial pressure of propellant A pao = vapor pressure of pure propellant A na = moles of propellant A nb = moles of propellant B Xa = mole fraction of component A Ø Equivalent equations are used to determine the partial pressure of propellant B, or C, or... 22 Dr Somnath Singh 23 pA = pA ° XA pB = pB ° XB pA and pB = partial pressures of A and B pA ° and pB ° = vapor pressures of pure components XA and XB = mole fraction of A and B 24 25 e.g. chloroform and acetone or water and ethanol 26 Precaution: use of Vaporizer 27 28 Ø Must be able to withstand pressures as high as 140 to 180 psi at 103 F. Containers used for aerosols fall into the following categories: § Metal -- tin-plated, aluminum, stainless steel § Glass -- uncoated or plastic coated glass § Synthetic resins or plastics 29 Ø The selection of the container for an aerosol product is based on üits adaptability to production methods ücompatibility with formulation components üability to sustain the pressure intended for the product üthe interest in design üaesthetic appeal on the part of the manufacturer ücost 30 Ø The function of the valve assembly is to permit the expulsion of the contents of the can in the desired form, at the desired rate, and, in the case of metered valves, in the proper amount or dose. Ø Among the materials used in the manufacture of the various valve parts are plastic, rubber, aluminum, and stainless steel. 31 the link between the dip tube hold the valve inand place supports the actuator and the stem and actuator delivers the formulation the the mechanism by whichin the proper to the chamber of actuatorform retracts when pressure the actuatorthereby returning the is released, the button that the user presses to activate the valve assembly the emission preventfor leakage of the of theformulation product when the valve is in the closed position. valve to the closed position bring the formulation from the container to the valve Ref: Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems 32 Ø Must be capable of being easily opened and closed Ø Must dispense the product in the correct physical form Ø Should deliver only a desired amount of product 33 Ø Valves can be broadly classified into two types: 1. Metered valves --these dispense a pre-determined quantity of material 2. Non-metered valves 34 Ø The actuator is attached to a valve and allows for easy opening and closing of the valve. Ø It also aids in producing the required type of product discharged. Ø Types of actuators include: spray, foam, solid stream, and special applications such as delivering to the nose, throat or eyes 35 Ø Cold Process: Ø both the product concentrate and the propellant must be cooled to temperatures of -30℉ to -40℉ Ø the chilled product concentrate is quantitatively metered into an equally cold aerosol container Ø the liquefied gas is added, the heavy vapors of the cold liquid propellant generally displace the air present in the container Ø When sufficient propellant has been added, the valve assembly is immediately inserted and crimped into place 36 Ø Pressure process Ø product concentrate is placed in container at room temperature Ø valve is crimped into place Ø trapped air is evacuated via vacuum Ø propellant is added through the valve using the vapor pressure of the propellant to force it through the valve 37 Ø Pressure filling is used for most pharmaceutical aerosols. Ø It has the advantage over the cold filling method in that there is less danger of moisture contamination of the product, and also less propellant is lost in the process. 38 Ø Propellant -- before 1978, fluorinated hydrocarbons were used as propellants. Ø The discovery of the ozone “hole” in the mid 70s led to the ban of the use of flourocarbon propellants in aerosols. Inhalation aerosols for oral and nasal use were exempted from the FDA ban. Ø Alternative such as hydrocarbons, compressed gases, and mechanical pumps continue to be developed 39 Containers -- Both glass and metal containers are generally used for pharmaceutical aerosols. Ø Glass is safely used when the total pressure of the system is less than 25 psi and there is less than 15% propellant in the system. Ø Special attention must be given to products having low pH or containing soaps. Ø If the product contains alcohol and is packaged in aluminum containers, care should be taken to avoid the possible chemical reaction. 40 Valves, actuators, and applicators – Ø Valves and Actuators are selected depending on the materials of construction, size of the orifice, and their specific applications. Ø Applicators are also selected depending upon the specific use of the aerosol product. 41 Ø Stability of aerosols must cover these 3 areas: 1. Concentrate and propellant -- the following physico-chemical parameters are used as an indicator of stability of the product: § § § § § § § vapor pressure pH density viscosity total weight assay of active ingredients color and odor 42 2. Container -- the container is examined for signs of corrosion during storage 3. Valve -- the valve should be examined to confirm that it is functioning, dispensing the product satisfactorily, and closing immediately after use 43 Ø Pharmaceutical aerosols can be evaluated by a series of physical, chemical, and biological tests A. Flammability and combustibility 1. Flash point -- the aerosol product is chilled to -25 F and transferred to a tag open cup apparatus. The temp. of the test product is slowly increased. The temp. at which the vapor ignites is taken as the flash point. 2. Flame projection -- this test measures the effect of an aerosol formulation on the extension of an open flame. Depending on its nature, the product is sprayed for about 4 seconds into a flame. The extension of the flame is measured with a ruler 44 B. Physico-chemical characteristics 1. Vapor pressure -- the pressure can be measured simply with a pressure gauge or other pressure reading devices 2. Density -- the density of an aerosol product can be determined by the use of a hydrometer or pycnometer 3. Moisture -- the Karl Fishcer or gas chromatograph method can be used to determine the moisture content of aerosol products 4. Identification of propellants -- GC and IR can be used for the identification of the propellants 45 C. Performance 1. Aerosol valve discharge rate -- the change in weight per time dispensed (discharge rate) expressed as grams per second can be determined by the change in weight after dispensing for a known time period 2. Spray patterns -- this method uses the impingement of the spray on a piece of paper that has been treated with a dye-talc mixture. The particles from the aerosol cause the dye to go into solution when they strike the paper and gives a record of the spray 46 3. Dosage with metered valves -- reproducibility of the dosage each time the valve is depressed is determined by analysis of the active ingredients. The amount of medication actually received by the patient is rather difficult to determine. An artificial respiratory system has been used for this purpose. 4. Foam stability -- can be evaluated visually, by measuring the required time to penetrate the foam, or by the use of a rotational viscometer 47 5. Particle size determination -- cascade impactor and light scatter decay methods are generally used for measuring particle size or aerosol formulation. In a cascade impactor, a stream of particles are projected through a series of nozzles and glass slides at a high velocity. The larger particles become impacted first on the lower velocity stages while the smaller particles pass on and are collected at higher velocity stages. 48 ØD. Biologic characteristics (testing) 1. a limited number of tests are used to evaluate the efficiency of an aerosol product. These tests should include: consideration of therapeutic activity; and toxicity (both topical and inhalation toxicities) 49 ØSimilar, with respect to formulations, stability and therapeutic efficacy. ØHowever, Aerosols differs from other dosage forms in their dependence upon üfunction of container, üvalve assembly and üpropellant. 50 Ø Aerosols can expel product as a fine mist, a coarse, wet or dry spray, a steady stream, fast breaking foam ØInhalation therapy for the treatment of Asthma: Fine liquid mist or as finely divided solid particles. Particles less than 6 micrometer will reach bronchioles and particles less than 2 micrometer will reach alveolar region ØDermatological spray: Coarse, powder or wet spray, a stream of liquid (local anesthetic) or an ointment like product ØNasal Aerosols: Fine particle or droplet for delivery through nose. 51 Example 1:What is the a vapor pressure of a 60:40 How to determine vapor pressure of a mixture of propane and isobutane. Information on two certain mixture? propellants is as follows: Property propane isobutane Molecular formula C3H8 C4H10 Molecular weight 44.1 58.1 Boiling point(℉ ) -43.7 10.9 Vapor pressure(psig@70℉ ) 110 30.4 Liquid density(g/ml @70℉ ) 0.50 0.56 Flash point(℉ ) -156 -117 52 1. Assumption: Ideal solution; No positive or negative deviation. 2. Determine the number of moles of each propellants: n propane = 60/44.1 = 1.36 n isobutane = 40/58.1=0.69 3. From Raoult’s Law; partial pressure exerted by the propane is P propane = [(n propane )/(n propane + n isobutane )]* P pure propane P propane = [(1.36)/(1.36+ 0.69)]* 110 = 72.98 psi 4. From Raoult’s Law; partial pressure exerted by the propane is P isobutane = [(n isobutane )/(n propane + n isobutane )]* P pure isobutane P isobutane = [(0.69)/(1.36+ 0.69)]* 30.4 = 10.23 psi 5. The total vapor pressure exerted by both gases P total = P isobutane + P propane = 72.98+ 10.23 = 83.21 psi at 70 o F 53 Question: The vapor pressure of a pure propellant 11 (MW 137.4) at 21°C is 13.4 pounds per square inch (psi) and that of propellant 12 (MW 120.9) is 84.9 psi. A 50:50 mixture by gram weight of the two propellants were used in preparing an aerosol. What is the total vapor pressure of this mixture? 54 ANSWER: PARTIAL PRESSURE 55 Aerosols Systems: Page 418 Ansel’s: Pharmaceutical Dosage forms and Drug Delivery Systems Ø Aerosols Filling operations: Page 422 Ansel’s: Pharmaceutical Dosage forms and Drug Delivery Systems Ø Ø Pharmaceutics: Basic Principles and Application to Pharmacy Practice by Dr Dash § Chapter 10- Aerosol dosage forms ØAnsel’s Pharmaceutical Dosage Forms and Drug Delivery Systems; § Chapter 14- Disperse Systems 57