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Aerosols 2020 newww (2).pptx

  1. Pharmaceutical Aerosols Pharmaceutical Aerosols 1
  2. Pharmaceutical Aerosols 2 Aerosols  Aerosols may be defined as dispersion phase system, in which very fine solid particles or liquid droplet get dispersed in the gas which act as continues phase.  Achievedby use of pressurized containers with liquefied or gaseous propellants  Also called pressurized dosage form  When pressure is applied to valve, contents expelled  Delivered form depends on formulation and valve type
  3. Pharmaceutical Aerosols 3 Pharmaceutical Aerosols  T o deliver active drugs for inhalation, nasal, buccal, and sublingual administration  Are also available for topical, rectal, and vaginal administration  Emit liquid/solid materials in gaseous medium when actuated Inhalation Aerosols  Contain active drug(s) in:  A liquefied propellant,  A mixture of solvents with a propellant or  A mixture of other additives and a propellant
  4. Pharmaceutical Aerosols 4 Pharmaceutical… Advantages:  Dose can be removed without contamination of the remaining  Hermetic character  protects drug from oxygen and moisture  Medication can be delivered to affected area in desired form  Usual containers protect drug from light  Sterility may also be maintained if packed in aseptic condition  Limit the potential for overuse of product compared to lotions
  5. Pharmaceutical… Advantages…  Irritation caused by mechanical application medication is reduced or eliminated  Application of medication in a uniform manner. of topical  Convenience of application  Easy requiring little or no wash-up by the user Disadvantages:  Expensive  Discomfort on injured skin  Limited safety (inflammable, pressurized) and clean process, Pharmaceutical Aerosols 5
  6. Pharmaceutical Aerosols 6 Drug delivery to the Respiratory Tract Mainly for treatment of local disorders, e.g.,asthma  Rapid onset of activity (e.g., bronchodilation in asthma)  Smaller doses can be administered  Reduced adverse effects Useful for delivery of drugs for which oral absorption is inappropriate Drug is poorly absorbed (e.g., sodium cromoglycate) Drug is rapidly metabolized (E.g., isoprenaline)  Bypassing liver first pass metabolism
  7. Drug delivery… sodium cromoglycate Lung may be used to deliver drugs for systemic effect due to:  Large surface area of alveoli  Abundance of capillaries (high perfusion) Example: Delivery of ergotamine for migraine Delivery of proteins and peptides (E.g., insulin) Pharmaceutical Aerosols 7
  8. Pharmaceutical Aerosols 8 Drug delivery… However, efficiency of inhalation therapy is not high because of the difficulty in targeting particles to the sites of maximal absorption Example: ~8% of the inhaled dose of sodium cromoglycate administered from a Spinhaler device reaches the alveoli
  9. The Respiratory Tract Pharmaceutical 9
  10. Deposition of particles and droplets  Respiratory dosage forms deliver drugs to the respiratory tract as either particles or droplets  Particles/droplets should be deposited to the required site of pharmacological action  For an optimum effect, the pharmaceutical scientist must fully understand and embrace the factors that affect deposition: 1.Physicochemical properties of the drug 2.The formulation 3.The delivery/liberating device and 4.The patient Pharmaceutical Aerosols 10
  11. Deposition… Most important physical property of an aerosol for inhalation is particle size To penetrate to the peripheral regions, aerosols require a size less than about 5 or 6 μm, with Less than 2 μm being preferable for alveolar deposition Larger particles or droplets are deposited in respiratory region Rapidly cleared by mucociliary action Drug becomes available for systemic absorption May potentially cause adverse effects the upper Pharmaceutical 11
  12. Effect of Particle size on Deposition Pharmaceutical Aerosols 12
  13. Pharmaceutical Aerosols 13 Mechanisms of Particle Deposition  Particle size affects the mechanisms  Four main mechanisms: 1. Inertial impaction:  When bifurcation occurs,  Particles > 5 μm & particularly >10 μm,  Common in the upper airways 2. Gravitational sedimentation:  Particles in the size range 0.5-3 μm,  In the small airways and alveoli,  For particles that have escaped impaction 3. Brownian diffusion: for particles < 0.5μm) 4. Electrostatic precipitation
  14. Mechanisms…. Pharmaceutical Aerosols 14
  15. Pharmaceutical Aerosols 15 Effect of breathing patterns on deposition  Large inhaled volume  greater peripheral distribution  Increasing inhalation flow rate enhances deposition in the larger airways by inertial impaction  Breath-holding after inhalation  deposition of particles by sedimentation and diffusion  Optimal deposition increases with duration of breath holding and depth of breathing!
  16. Pharmaceutical Aerosols 16 Aerosol Formulation  Aerosol formulation consists of two components: 1. Product concentrate 2. Propellant  Product concentrate = API + antioxidants + surface active agents + solvents/co-solvents  stable and efficacious product.  Concentrate can be a solution, suspension, emulsion, semisolid.
  17. Pharmaceutical Aerosols 17 Aerosol Formulation… Propellant  Liquefied gas or mixture of liquefied gases; or compressed gases  Provides the force that expels the product concentrate from the container in desired form  Dual role: as propellant and solvent/vehicle for the product concentrate (liquefied gases)
  18. Pharmaceutical Aerosols 18 Propellants 1.Chemicals with vapor pressure greater than atmospheric pressure (Liquefied propellants) or 2.Compressed gases They are: Responsible for developing pressure within the container and T o expel the product when the valve is opened and in the atomization or foam production of the product.
  19. Pharmaceutical Aerosols 19 Liquefied Propellants At room temperature and pressure these are gases  Readily liquefy by decreasing T0 or increasing P0 Head space filled with propellant vapour,  saturation vapour pressure at that temperature.  Traditionally used in aerosol products were the chlorofluorocarbons (CFCs)  Hydrofluoroalkanes (HFAs) are increasingly in use.
  20. Pharmaceutical Aerosols 20 Liquefied Propellants…  The CFCs currently employed in MDI formulations are CFC-11, CFC-12 and CFC-114  Formulations generally comprise blends of CFC-11 and CFC-12 or CFC-11, CFC-12, and CFC-114 CFCs:  Chemical inertness  Lack of toxicity  Non flammability & low explosiveness Propellant of choice for oral and inhalation
  21. Pharmaceutical Aerosols 21 Liquefied Propellants…  Reaction of CFCs with the ozone and their contribution to global warming is major environmental concern  Production of CFCs in developed countries was phased out in 1996  However, pharmaceutical aerosols are currently exempted
  22. Pharmaceutical Aerosols 22 Liquefied Propellants…  In household & cosmetic aerosols  CFCs replaced by hydrocarbons (HCs) such as propane and butane HCs are not appropriate alternatives to for inhalation  Alternatively, compressed gases such as N2, N2O and CO2 may be used Do not maintain constant pressure in canister duringuse  Non-ozone depleting alternatives to CFCs  HFAs (HFCs)  break down faster in the atmosphere
  23. Pharmaceutical Aerosols 23 Liquefied Propellants…  HFA-134a and HFA-227 are non-ozone depleting, non- flammable HFAs  widely investigated  However, these gases contribute to global warming  Have some physical properties which are similar to those of CFC-12 and, to a lesser extent, CFC-114  HFA-134a & HFA-227 are poor solvents for surfactants  Ethanol used to allow dissolution of surfactants in MDI  Ethanol has low volatility and hence may increase droplet size of emitted aerosol
  24. Pharmaceutical Aerosols 24 Liquefied Propellants… Hydrocarbons:  Used in topical aerosols  environmental acceptance and non reactivity (non ozone depleting)  Make three phase (two layers) aerosols because of their immiscibility with water  Propane, butane, and isobutane are the most commonly used  Used alone or blended
  25. Pharmaceutical Aerosols 25 Compressed Gases 1. Gases insoluble in the product concentrate (e.g., N2): Result in emission of product in essentially the same form as it was placed in the container 2. Slightly soluble gases (e.g., CO2 & N2O), expulsion with concentrate to achieve spraying or foaming Pressure diminishes as the product is used Higher gas pressures are required in these systems
  26. Pharmaceutical Aerosols 26 Aerosol Systems  Based on product concentrate: 1. Two phase systems 2. Three phase systems 3. Suspension or Dispersion systems
  27. Pharmaceutical Aerosols 27 Two Phase Systems  Consist of liquid phase containing liquefied propellant and product concentrate, and vapor phase  Are solution forms  However, propellants are poor solvents for most drugs  Cosolvents used: ethanol, propylene glycol, glycerin, acetone, ethyl acetate or isopropanol  Amount of propellant may vary from depends on types formulation
  28. Three-Phase Systems  Large volume of water replaces all or part of non aqueous solvent  Water-based systems  Layer of water-immiscible liquid propellant, a layer of highly aqueous product concentrate, and the vapor phase  Alcohol may be added to increase miscibility of water and propellant Pharmaceutical Aerosols 28
  29. Pharmaceutical Aerosols 29 Suspension/Dispersion Systems  Used to overcome difficulties of using cosolvents  Dispersion of APIs in propellant or mixture of propellants  Surfactants and suspending agents to reduce settling  Particle size control: caking, agglomeration, particle growth etc. must be considered (< 5 μm)  Dispersing agents (oleic acid)  reduce agglomeration, lubricate the valve
  30. Pharmaceutical Aerosols 30 Aerosol Container & Valve  Formulation components must not interact with container and valve  Valve and container must withstand pressure of formulation  Valve and container must resist corrosion  Must contribute to the form of the product to be emitted
  31. Aerosol Containers (Reading)  Different materials: 1. Glass (coated, uncoated) 2. Metal (tin-plated steel, aluminum, stainless steel) 3. Plastics  Selection of container depends on:  Adaptability to production methods  Compatibility with formulation  Ability to sustain the pressure of product  Design aesthetic appeal and cost Pharmaceutical Aerosols 31
  32. Valve Assembly  Permit expulsion of contents in a desired form, rate, and amount or dose (metered valves)  Materials must be inert to the formulations  Materials used: plastic, rubber, aluminum, and stainless steel Pharmaceutical Aerosols 39
  33. Parts of the Valve 1.Actuator:  The button patient presses for emission of product  Permits easy opening and closing of the valve  Product delivered through the orifice in the actuator  Actuator design together with type and amount of propellant used affects particle size of emitted product Pharmaceutical Aerosols 40
  34. Parts of the Valve… Pharmaceutical Aerosols 41
  35. Pharmaceutical Aerosols 42 Parts of the Valve… 2. Stem:  Supports actuator & transfers formulation into its chamber  Made from Nylon, brass or stainless steel  Orifice: 0.013-0.030 inch 3. Gasket:  Placed snugly with the stem  prevents leakage when valve is closed  Made from rubber
  36. Pharmaceutical Aerosols 43 Parts of the Valve… 4. Spring:  Holds the stem in place  Retracts actuator when pressure is released (valve closed)  Made from stainless steel 5. Housing:  Links dip tube with stem and actuator (nylon)  Has orifice at point of attachment to dip tube  determine delivery rate & the form in which product is emitted
  37. Parts of the Valve… 6. Mounting cup (Ferrule):  Holds the valve in place (attach valve to container)  Made from stainless steel, aluminum, brass  May be coated with inert material (e.g., an epoxy resin or vinyl) to prevent an undesired interaction 7. Dip tube:  Brings formulation from container to valve  Dimensions of dip tube and housing dictated by viscosity of product and desired delivery rate  Made of poly ethylene or poly propylene Pharmaceutical Aerosols 44
  38. The Valve Assembly Pharmaceutical Aerosols 45
  39. Aerosol Filling Operations A. Cold filling apparatus B. Pressure filling apparatus Pharmaceutical Aerosols 46
  40. Pharmaceutical Aerosols 47 Cold Filling  Both product concentrate & propellant cooled to −34.5 to −40°C  Chilled product concentrate quantitatively metered into an equally cold aerosol container  Liquefied gas is added  vapors of liquefied propellant displace air in the container  Valve assembly is inserted and crimped into place  Alternatively, both product concentrate and propellant chilled in a vessel  filled into a chilled container  valve placed and crimped  tested for leakage
  41. Cold Filling… Pharmaceutical 48
  42. Cold Filling…  Aqueous systems cannot be filled by this process??  Not suitable for formulations unstable in cold temperature  HC propellants cannot be filled by this method. Pharmaceutical Aerosols 49
  43. Pharmaceutical Aerosols 50 Pressure Filling  Product concentrate is quantitatively placed in aerosol container at room temperature  Valve assembly is inserted and crimped into place  Liquefied gas, under pressure, is metered into the valve stem from a pressure burette  Propellant may also be filled by ‘under-the-cup’ method  Advantages over cold filling:  Less danger of moisture contamination of product  Less propellant is lost in the process
  44. Pressure Filling… Pharmaceutical Aerosols 51
  45. Pharmaceutical Aerosols 52 …. Large scale aerosol filling equipments are composed of:  Concentrate filler  Valve placer  Purger and Vacuum Crimper  Pressure Filler  Leak test tank
  46. Pharmaceutical Aerosols 53 Delivering Inhalation Aerosols  Currently three main types of aerosol generating devices for use in inhaled drug therapy: 1.Metered-dose inhalers (MDIs) 2.Dry powder inhalers (DPIs); and 3.Nebulizers
  47. Pharmaceutical Aerosols 54 Metered Dose Inhalers (MDIs)  It is most commonly used inhalation drug delivery devices  Drug either dissolved or suspended in a liquid propellant mixture with other excipients, including surfactants  Employed when the formulation is a potent medication  Amount of material discharged is regulated by an auxiliary valve chamber
  48. MDIs… Pharmaceutical Aerosols 55
  49. MDIs… Effectiveness of delivering medication to reaches of the lungs depends on:  Particle size of inhaled drug  Breathing patterns and depth of respiration the lower Pharmaceutical Aerosols 57
  50. Pharmaceutical Aerosols 58 Advantages of MDIs  Portable and compact  Many doses (~ 200) are stored in the small canister  Dose delivery is reproducible  Protect drug from oxidative degradation and microbiological contamination
  51. Disadvantages of MDIs Inefficient drug delivery (high pharyngeal deposition)  The first droplets exit at a high velocity (> 30m/s) Much drug lost through impaction of droplets in the oropharyngeal areas Pharmaceutical Aerosols 59 Their incorrect use by patients Droplet size emitted may be deposition. large for deep lung
  52. Pharmaceutical Aerosols 60 Proper Administration and Use Ideally, MDIs should be actuated during a course of slow, deep inhalation,  breath-holding  exhale slowly Coordinate inhalation (after exhaling as completely as possible) and pressing down of the inhaler Use of an extender device (spacer) with the inhaler for patients who cannot properly use inhalers Effectively assist the delivery of medication despite improper patient inhalation technique Patient is permitted to separate activation of the aerosol from inhalation by up to 3 to 5 seconds
  53. Proper administration…  Spacer (extender) reduces aerosol velocity and  Droplet size is decreased because there is time for vaporization of the propellant (s) cause less deposition of medication in the oropharynx  But, they may be cumbersome Pharmaceutical Aerosols 61
  54. Dry Powder Inhalers (DPIs)  Drug inhaled as cloud of fine particles  Powder either preloaded in device or filled into hard gelatin capsules or foil blister discs  loaded into device prior to use Pharmaceutical Aerosols 62
  55. Pharmaceutical Aerosols 63 DPIs…  Drug powders are usually micronized (<5μm)  Mixed with larger 'carrier' particles (usually 30-60μm) inert excipient, usually lactose improves liberation of drug, uniformity of capsule or device filling  Air flow should be sufficient for deaggregation of drug/carrier aggregates  larger carrier particles impact in the throat and smaller drug particles are carried
  56. Pharmaceutical Aerosols 64 DPIs…  Success of DPI formulations depends on:  Adhesion of drug and carrier  Ability of drug to desorb from carrier during inhalation  Adhesion and desorption depends on the morphology of particle surfaces and surface energies  Performance of DPIs is thus strongly dependent on formulation factors, and on the construction of the delivery device and inhalation technique
  57. Pharmaceutical Aerosols 65 DPIs… Advantages over MDIs  Propellant free and except carrier (solid)  Breath actuated  do not contain any excipient avoid problems of inhalation- actuation coordination  Dose counters are available in new designs
  58. Pharmaceutical Aerosols 66 DPIs… Disadvantages  Liberation of powders & deaggregation of particles are limited by patient's ability to inhale  An increase in turbulent air flow increases the potential for inertial impaction in the upper airways and throat
  59. Types of DPIs 1. Unit-dose devices with drug in hard gelatin capsules 2. Multidose devices with drug in foil blisters 3. Multidose devices with drug preloaded in inhaler Figure: Spinhaler vid Pharmaceutical Aerosols 67
  60. Pharmaceutical Aerosols 71 Nebulizers  Deliver relatively large volumes of drug solutions and suspensions  Used for drugs that cannot be conveniently formulated into MDIs or DPIs  Drug may be inhaled during normal tidal breathing through a mouthpiece or face-mask  Useful for children, elderly and patients with arthritis  For acute conditions, hospitalized patients
  61. Nebulizers… 1.Jet nebulizers  Use compressed gas (air or O2) from cylinder, hospital air- line …to convert a liquid into a spray  Jet of high-velocity gas is passed either tangentially or coaxially through narrow nozzle  Negative pressure (where the air jet emerges) causes liquid to be drawn up a feed tube from a reservoir vid Pharmaceutical Aerosols 72
  62. Jet nebulizers…  Rate of gas flow driving atomization is major determinant of aerosol droplet size and rate of drug delivery  Patient coordination not required  Lack of portability  Pressurized gas source required  Lengthy treatment time ,,,, Pharmaceutical Aerosols 73
  63. Nebulizers... 2. Ultrasonic wave nebulizers  Energy necessary to atomize liquids comes piezoelectric crystal vibrating at high frequency At high ultrasonic intensities a fountain of liquid is formed in the nebulizer chamber from Pharmaceutical Aerosols 74
  64. Evaluation of Pharmaceutical Aerosols A. Flammability and combustibility 1.Flame Projection  Effect of an aerosol formulation on extension of an open flame  Product is sprayed for 4 seconds into a flame  Exact length measured with ruler Pharmaceutical Aerosols 76
  65. Evaluation of Pharmaceutical Aerosols…. 2. Flash point  Using standard Tag Open Cap Apparatus  Product chilled to temperature of -25ºF and transferred to the test apparatus  Temperature increased slowly  temperature at which the vapor ignites taken as flash point Pharmaceutical Aerosols 77
  66. Pharmaceutical Aerosols 78 Evaluation of Pharmaceutical Aerosols…. B. Physiochemical characteristics 1.Vapor pressure  Determined by pressure gauge  Variation in pressure from container to indicates the presence of air in headspace 2. Moisture content  By Karl Fischer method or gas chromatography 3. Identity test container
  67. Pharmaceutical Aerosols 79 Evaluation of Pharmaceutical Aerosols…. C. Performance 1.Aerosol valve discharge rate  Determined by taking an aerosol of known weight and discharging the contents for given time  By reweighing the container after time limit, change in weight per time (g/sec) dispensed is discharge rate
  68. Pharmaceutical Aerosols 80 Evaluation of Pharmaceutical Aerosols…. 2. Dose uniformity  Reproducibility of doses delivered each time the valve is depressed  Accurate weighing of filled container followed by dispensing of several doses  Container can be reweighed  Difference in weight divided by No. of doses, gives the average dosage  Assay of the contents delivered is another method
  69. Pharmaceutical Aerosols 81 Evaluation of Pharmaceutical Aerosols…. 3. Leakage  Used to estimate the weight loss 4. Net contents  To check whether sufficient product has been placed in container  T arred cans are filled and reweighed  difference calculated or  Weigh filled container, dispensing the contents, then weigh the container
  70. Evaluation of Pharmaceutical Aerosols…. 5. Particle size distribution  By using Cascade Impactor  Carrying particles in a stream of air through a series of smaller jet openings  The heavier and larger diameter particles are impacted on a slide under the larger opening  As the openings get smaller, the next larger particles are deposited on the next slides Pharmaceutical Aerosols 82
  71. Evaluation of Pharmaceutical Aerosols…. 6. Spray patterns  Based on the impingement of the spray on a piece of paper that has been treated with a dye (oil or water soluble)  Particles that strike the paper cause the dye to dissolve and absorbed onto the paper  This can be used for comparison of spray pattern Pharmaceutical Aerosols 83

Hinweis der Redaktion

  1. CFC-11, CFC-12 and CFC-114 Trichlorofluoromethane ,Dichlorodifluoromethane 1,2-Dichlorotetrafluoroethane respectively
  2. HFA 134a (1,1,1,2-tetrafluoroethane) HFA 227 (heptafluoropropane; Apaflurane)
  3. Actuator: it is the button that the user presses to activate the valve assembly for emission of the product. The actuator permits easy opening and closing of the valve Large orifices and less propellant are used for products to be emitted as foams and solid streams than for those intended to be sprays or mists
  4. Hydrocarbon propellant cannot be filled into aerosol containers using cold filling apparatus because large amount of propellant escapes out and vaporizes. This may lead to formation of an explosive mixture.
  5. The baffle helps ensure the formation of respirable particles, and prevents inhalation of oversized droplets of medication