Aerosal&aerosal drug delivery system


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Aerosal & aerosal drug delivery system

Presented by Anyarat Wanitchakorn, MD.

Jan15, 2014

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Aerosal&aerosal drug delivery system

  1. 1. Aerosals and Aerosal Drug Delivery System Anyarat Wanitchakorn Fellow in training Pediatric Allergy and Immunology Ramathibodi hospital
  2. 2. Scope for today • • • • Aerosolized medications Definition and Types of Aerosols Factors That Affect Aerosol Deposition Categories of aerosol drug delivery devices • Points to consider in selection device
  3. 3. • Current treatment guidelines for the management of asthma and COPD – recommend inhaled therapy as the primary route for administering • β2-agonists • Anticholinergics • corticosteroids Middleton’s 8th edition
  4. 4. Aerosolized medications Drug formulation properties • particle size distribution • selected the delivery system Selection of an inhalation device • appropriate particle size and lung delivery Inhalation technique • inspiratory flow rate, inspiratory volume, and breath-holding time • determines the dose of inhaled drug that deposits in the lung Middleton’s 8th edition
  5. 5. Revolution in 1989 • The Montreal Protocol called for the elimination of chlorofluorocarbons (CFCs) in pMDIs as a response to the depletion of the earth’s ozone layer by CFCs • The introduction of hydrofluoroalkane (HFA) as an alternative propellant for pMDIs has led to the availability of low-velocity propellant-driven aerosols Middleton’s 8th edition
  6. 6. Revolution • major design changes in all 3 categories of aerosol drug delivery devices • pMDIs • dry powder inhalers (DPIs) • nebulizers • The innovation of DPIs has eliminated the need for the actuation-inhalation coordination that is required for pMDI drug delivery Middleton’s 8th edition
  7. 7. Definition and Types of Aerosols An aerosol • a two-phase system defined as a dispersion or suspension of solid particles or liquid droplets in a gaseous medium (e.g., air, oxygen, heliox) • Living environments • natural : pollen, bacteria, viruses, house dust • man-made aerosols, : asbestos fibers, coal and mineral dusts, cigarette smoke Middleton’s 8th edition
  8. 8. ADVANTAGES AND DISADVANTAGES IN RESPIRATORY DISEASE ADVANTAGES – noninvasive and painless – delivers drugs directly to the airway surfaces, receptor sites – delivery of high drug concentrations to the airway – more rapid onset of action – inhaled β2-agonist bronchodilators aerosal vs oral – reduced systemic dose and side effect Middleton’s 8th edition
  9. 9. ADVANTAGES AND DISADVANTAGES IN RESPIRATORY DISEASE DISADVANTAGES – Less-than-optimal technique   drug delivery   potentially and efficacy – Techniques differ between device categories and devices within a specific category – less convenient than oral drug administration – more time is required for drug administration Middleton’s 8th edition
  10. 10. Definitions for Commonly Used Terms The prediction of deposition : efficiency for a therapeutic aerosol based on • Mass Median Aerodynamic Diameter (MMAD) : – Divides the aerosol size distribution in half diameter at which 50% of the particles of an aerosol by mass are larger and 50% are smaller than the median diameter • Fine Particle Fraction (FPF) – the fraction of particles that can achieve deposition in the lower respiratory tract Middleton’s 8th edition
  11. 11. Definitions for Commonly Used Terms (a) cumulative (b) distribution curves for Beclovent (MDI) used with an Aerochamber Br J Clin Pharmacol2003, 56, 588–599 Dolovich MB. Aerosols In Asthma, Philadelphia: Lippincott-Raven Publishers, 1997; 1349–1366.
  12. 12. Definitions for Commonly Used Terms • Labeled dose (LD)* or nominal dose – dose that is metered and specified on the inhaler package • Emitted dose (ED) or delivered dose – The mass of drug emitted per actuation that is actually available for inhalation at the mouth
  13. 13. Factors That Affect Aerosol Deposition (1) Physical factors (2) Ventilatory (3) Anatomic factors (4) Patient-related factors
  14. 14. PHYSICAL FACTORS: PARTICLE SIZE DISTRIBUTION • The size of an aerosol particle is the primary determinant of the site of lung deposition, distribution of the drug within the lung, and resulting deposition efficiency • Therapeutic aerosols targeted to the lower respiratory tract are composed of particles typically between 0.5 μm and 10 μm in diameter Middleton’s 8th edition
  15. 15. PHYSICAL FACTORS: PARTICLE SIZE DISTRIBUTION Deposition of particles onto surfaces in the lung mainly three physical mechanisms: • impaction • a function of particle inertia and affects particles greater than 5 μm • Sedimentation • gravitational forces acting on particles primarily between 0.5 and 5 μm • Diffusion • brownian motion and affecting particles smaller than 1 μm in low-flow regions of the lung
  16. 16. PHYSICAL FACTORS: PARTICLE SIZE DISTRIBUTION การเคลือนทีแบบบราวน์ ่ ่ Brownian motion ตั้งชื่อตามนักพฤกษศาสตร์ โรเบิร์ต บราวน์) หมายถึงการเคลื่อนที่ของ อนุภาคในของไหล (ของเหลวหรื อ ก๊าซ) ที่เชื่อว่าเป็ นไปโดยสุ่ ม หรื อ แบบจาลองคณิ ตศาสตร์ที่ใช้เพื่ออธิบาย การเคลื่อนที่แบบสุ่ มดังกล่าว มักเรี ยก กันว่า ทฤษฎีอนุภาค
  17. 17. PHYSICAL FACTORS: PARTICLE SIZE DISTRIBUTION Mechanisms of lung deposition >10um Oropharyngeal 10-5 um large conducting airway oropharynx <5um (>50%=3um) F.Pereira Muchão.J Pediatr.2010
  18. 18. The effect of aerosol particle size on the site of preferential deposition in the airways
  19. 19. The effect of altering particle size Total lung deposition 56% 46% posterior thorax images of technetium-99m–labeled albuterol aerosol deposition in the lungs Am J Respir Crit Care Med 2005;172:1497-1504.
  20. 20. ANATOMIC FACTORS: AIRWAY CALIBER AND DISTORTION DUE TO DISEASE Healthy vs asthma pt with FEV1 =31% The image on a gamma camera scan of lungs after inhaling 0.9% saline aerosol containing technetium-99m sulfur colloid JAMA 1993;269:2106-9.
  21. 21. VENTILATORY FACTORS: INSPIRATORY FLOW RATE AND BREATH HOLD • Deposition at airway bifurcations – exaggerated in airway narrowing secondary to disease • Particles larger than 5 μm • deposit to a greater extent in conducting airway surfaces and less in the peripheral lung • Particles smaller than 5 μm • tend to deposit by sedimentation and diffusion on successively smaller airways
  22. 22. VENTILATORY FACTORS: INSPIRATORY FLOW RATE AND BREATH HOLD • Particles between 0.1 and 1.0 μm • remain suspended, these particles tend to be exhaled rather than deposited • 20% of these extrafine pMDI aerosols will be exhaled • Aerosol particles and the air stream velocity • inhaling an aerosol at a low flow rate impaction in larger airways • inhalation with a prolonged breath hold  allow greater time for sedimentation and diffusion to occur in the peripheral airways • Maximum deposition is obtained in the pulmonary region for particles approximately 3 μm in size
  23. 23. The effect of the drug aerosol’s particle size on therapeutic efficacy (a) Percent improvement in forced expiratory volume in 1 s (FEV1) following inhalation of two different size aerosols of salbutamol, 3.3 um and 7.7 um (b) FEV1 following inhalation of two different size aerosols of ipratropium bromide, 3.3 um and 7.7 um Johnson MA et al. Chest1989; 96: 1–10 [9].
  24. 24. PATIENT-RELATED FACTORS: ABILITY TO CORRECTLY USE THE DELIVERY SYSTEM AND COMPLIANCE – pt have never been taught – pt have modified the technique after instruction – the various techniques that are appropriate for each device – the advantages and disadvantages of each device • Health care providers should ensure that their patients can and will use these devices correctly Middleton’s 8th edition
  25. 25. NEBULIZERS FOR LIQUID FORMULATIONS Jet Nebulizers Conventional pneumatic nebulizers
  26. 26. Jet Nebulizers Conventional pneumatic nebulizers • The MMAD of jet nebulizers used for therapy should be between 2 and 4 μm • jet nebulizer delivers aerosol continuously while the patient inhales and exhales. – 30% to 40% of the nominal dose is trapped in the nebulizer – 60% of the ED is wasted to the atmosphere during exhalation – < 10% of the nebulizer contents to the patient Middleton’s 8th edition
  27. 27. Jet Nebulizers Conventional pneumatic nebulizers “breath-enhanced” devices • allows additional room air to be entrained during inspiration • increasing the amount of useful aerosol for inhalation • air also may be entrained through a T-piece or face mask supplementing the jet air flow rate to meet the inspiratory flow requirements of the patient • increase in the total drug delivered to the patient per unit time from nebulizers with additional air entrainment
  28. 28. Jet Nebulizers Conventional pneumatic nebulizers Solvent evaporates during nebulization • rate of evaporation depends on the volume of fluid placed in the reservoir • reservoir fill volume of 3 to 5 mL • the dead volume, at the end of nebulization(no further aerosol is produced) • 0.5 to 1.5 ml of concentrated solution is left  drug that is unavailable to the patient Middleton’s 8th edition
  29. 29. Jet Nebulizers Conventional pneumatic nebulizers The driving pressure or the flow rate of compressed air • affects aerosol output and particle size from jet NB • higher the pressure or flow rate, the greater the output over time in terms of total solution aerosolized, and the smaller the particle size • time required to deliver the medication – varies with the airflow rate used to drive the nebulize – Typical treatment times range between 5 and 15 minutes Middleton’s 8th edition
  30. 30. Jet Nebulizers Conventional pneumatic nebulizers Face masks • acutely ill or uncooperative patients such as infants and toddlers • face mask with vent holes should be used  reduce deposition on the face and in the eyes Middleton’s 8th edition
  31. 31. Jet Nebulizers Conventional pneumatic nebulizers Mouthpiece • direct the aerosol toward the nose and mouth • usually in a child • “blow-by” technique Middleton’s 8th edition
  32. 32. Exercise • Which one is suitable for this patient? A B
  33. 33. Ultrasonic Nebulizers • a piezoelectric crystal – vibrated at a high frequency – create standing waves on the surface of the liquid overlying the crystal Middleton’s 8th edition
  34. 34. Ultrasonic Nebulizers operate at frequencies above 1 MHz producing aerosols with MMADs between 2 and 12 μm an output that is two to three times higher than with most jet nebulizers F.Pereira Muchão.J Pediatr.2010
  35. 35. Ultrasonic Nebulizers • Droplets are formed that remain within the nebulizer until they are swept out by a fan or the patient’s inspiratory breath • Produced heat along with the aerosol, however – the ultrasonic nebulizer solution is sonicated – temperature can rise 10° to 15° C over a 10-min – adversely affect heat-sensitive components of formulations, such as proteins • not suitable for nebulizing suspensions Middleton’s 8th edition
  37. 37. PRESSURIZED METERED-DOSE INHALERS Formulation Issues • CFC propellant pMDIsHFA propellant pMDIs (mandated by the Montreal Protocol) • HFA – – – – medically safe nontoxic to animals and humans devoid of pharmacologic activity, can be co-solved with corticosteroids HFA, hydrofluoroalkane CFC, chlorofluorocarbon Middleton’s 8th edition
  38. 38. High-speed photographs of the plume geometry of albuterol aerosols • Top, HFA albuterol (Airomir, 3M Pharmaceuticals) • Bottom, CFC albuterol (Ventolin, GlaxoSmithKline) Middleton’s 8th edition Dolovich M, Leach C. Drug delivery devices and propellants. In: Busse W, Holgate S, editors. Asthma and rhinitis. 2nd ed. Oxford: Blackwell Science; 2000
  39. 39. PRESSURIZED METERED-DOSE INHALERS Formulation Issues • For salbutamol, fluticasone, budesonide, and beclomethasone, – particle size of the HFA suspension = CFC formulation – lung deposition averages 7% to 30% • Some HFA pMDIsreformulation as a solution and the introduction of ethanol as a cosolvent • Some have concentrations of alcohol up to 37% (w/w) – may cause irritation on inhalation • Beclomethasone dipropionate (BDP) was formulated as a solution when it transitioned to an HFA pMDI – led to production of a finer aerosol with an increased – HFA BDP is called an extrafine aerosol Middleton’s 8th edition
  40. 40. Similarities and Differences between HFA, pMDI ICS Aerosols Middleton’s 8th edition
  41. 41. Scintigraphic images of the lungs • patient with asthma after inhalation of two different formulations of radiolabeled beclomethasone dipropionate (BDP) pressurized aerosol Middleton’s 8th edition Dolovich MB, Labiris NR.Proc Am Thorac Soc 2004;1:329-37
  42. 42. Breath-Actuated pMDIs • For poor actuation-inhalation coordination with use of standard pMDIs • The Autohaler automatically actuates at – inspiratory flow rates of approximately 30 L/min – the Easibreathe actuates at 20 L/min • improve lung deposition over that achievable with pMDIs alone Middleton’s 8th edition
  44. 44. pMDIs and Spacers and Valved Holding Chambers • developed for use with pMDIs in response to difficulties encountered • problems are related to timing or hand-breath coordination – coordination of actuating the pMDI and inhaling the spray at the same time • increasing the probability of optimal delivery of the drug to the lung Middleton’s 8th edition
  45. 45. pMDIs and Spacers and Valved Holding Chambers • Volumes for the various devices range from 15 to 750 mL • aerosol characteristics and drug yield affect by – one-way valve to convert an open tube into a reservoir – shape and volume of the device, flow of air through the device – face masks’ mouthpieces, and manufacturing materials all • inhalation valve – used to contain the aerosol and reduce oropharyngeal deposition (as a baffle) – must be able to withstand the initial pressure from the pMDI on firing – must have a sufficiently low resistance to open readily on inhalation Middleton’s 8th edition
  46. 46. pMDIs and Spacers and Valved Holding Chambers • Coordination is still required with all three types of spacer design • decrease in drug output from plastic spacers is largely due to the presence of electrostatic charge on the plastic • To decrease electrostatic charge – metallic-coated device – device manufactured from a nonelectrostatic plastic – washing the plastic device periodically with deionizing detergent Middleton’s 8th edition
  48. 48. DRUGS IN POWDER FORM: DRY POWDER INHALERS • Aerosols of dry powder are created by directing air through an aliquot of loose powder • the dispersion of the powder into respirable particles is dependent on the creation of turbulent flow in the inhaler • a function of both the patient’s (ability to inhale the powder at a sufficiently high inspiratory flow rate) and the design of the powder device Middleton’s 8th edition
  49. 49. DRUGS IN POWDER FORM: DRY POWDER INHALERS • individual doses of drug from punctured gelatin capsules • a tape system containing multiple sealed, single doses in a blister • a multidose reservoir powder system Middleton’s 8th edition
  50. 50. DRUGS IN POWDER FORM: DRY POWDER INHALERS • most powder-dispensing systems require the use of a carrier substance • vehicle substance enable the powder to more readily pass out of the device • carriers that are used include lactose and glucose – Fewer allergenic than to the surfactants and propellants used in pMDIs Middleton’s 8th edition
  51. 51. Electron micrographs of a 2% albuterol sulphate–lactose powder blend • (a) lactose particle with drug on its surface • (b) The higher magnification shows individual drug particles (elongated crystals) on the lactose Br J Clin Pharmacol2003, 56, 600–612
  52. 52. DRUGS IN POWDER FORM: DRY POWDER INHALERS • particle size of dry powder particles is on the order of 1 to 2 μm • the size of the lactose or glucose particles can range from approximately 20 to 65 μm • most of the carrier deposits in the oropharynx Middleton’s 8th edition
  53. 53. DRUGS IN POWDER FORM: DRY POWDER INHALERS • commercially available – passive, or patient-driven – rely on the patient’s inspiratory effort to dispense the dose from the device • resistance of a DPI – classified with respect to the inhalation flow – to produce a pressure drop 4 kPa across device Middleton’s 8th edition
  54. 54. DRUGS IN POWDER FORM: DRY POWDER INHALERS • • • • low-resistance device : inspiratory flow of > 90 L/min medium-resistance : inspiratory flow of 60 to 90 L/min medium- to high-resistance : 50 to 60 L/min high-resistance device allows < 50 L/min
  55. 55. Potential deposition of aerosol in upper and lower airways Middleton’s 8th edition
  56. 56. DRUGS IN POWDER FORM: DRY POWDER INHALERS • appropriate procedure is described in the package insert/patient information leaflet • Patients who do not perform these procedures correctly may receive no dose!! • irrespective of the inhalation maneuver they subsequently adopt
  58. 58. Inhaler strategy, optimal inhalation technique and most common problems with correct inhaler use in children Primary Care Respiratory Journal (2010); 19(3): 209-216
  59. 59. Proportion of patient age and aerosal device Primary Care Respiratory Journal (2010); 19(3): 209-216
  60. 60. Summary • Aerosal therapy  good route for drug administration • A number of factors effect deposition of aerosal in the lung • Aerosal particle size play important role in targeting lung region • Appropriate drug formulations and device need for improve its efficacy
  61. 61. Thank you for your attention