Inhalation 2015
- 1. An Overview of Pharmaceutical Inhalation Technology Aryo Nikopour March 2015 Chapman University, Pharmaceutical Sciences
- 2. Why Should We Inhale? One of the oldest forms of drug delivery A patient compliant route (think of smokers) An instantaneous route (think of smokers) A robust delivery route (think of smokers)
- 5. Why is it effective? Part 1
- 6. Why is it effective? Part 2 Relatively low metabolic activity of the lungs Moist surface with surfactants This organ is designed for absorption Many diseases affect the lung
- 7. Parameters for Success Reproducible - UniformReproducible - Uniform Pure - ChemicallyPure - Chemically Efficient – SmallEfficient – Small Specific – Not too Small, nor too BigSpecific – Not too Small, nor too Big Cost – Not too expensive relative to currentCost – Not too expensive relative to current therapiestherapies
- 8. Applicable Therapies Local Delivery Asthma COPD Lung Surfactant Deficiency Anti-infective Systemic Delivery Diabetes Low gut absorption API’s Rapid onset therapeutics
- 9. Dosage Forms pressurized Metered Dose Inhaler (pMDI) o Breath-actuated Dry Powder Inhaler (DPI) o Active Nebulizers o Jet o Ultrasonic o Mesh
- 10. Organization Involved in OINDP Regulatory bodies in the European Union, Japan and USA International Regulation and Harmonization The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human use (ICH) Drug Safety, Quality and Efficacy-The Pharmacopoeia USP, EP, BP,JP Device Safety, Quality and Efficacy – International Standards Organization (ISO), ISO27427:2009
- 11. Organization Involved in OINDP Expert Groups European Pharmaceutical Aerosol Group (EPAG) International Pharmaceutical Consortium On regulation and Science (IPAC-RS) Product Quality Research Institute (PQRI)
- 12. Guidelines Guidance for Industry: MDI and DPI Drug Products, CMC ICH (www.ICH.org) ICH Q1 Stability ICH Q2 (R2) Analytical Method Validation ICH Q8(R1) Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality Systems
- 13. pMDI Components
- 15. pMDI – Valve
- 17. Propellant? CFC ban! A major component of the pMDI is the propellant Clean Air Act of 1990 & Montreal Protocol of 1997 Phases out the use of CFC’s in consumer products… Including medicinal Alternative is HFA’s
- 18. CFC’s versus HFA’s Propellant Designation CFC-11 CFC-12 CFC-114 HFA-134a HFA-227ea B.P. (ºC) +23.7 -29.8 +3.6 -26.5 -17.3 Vapor Pressure (psig @ 20ºC) 1.8 67.6 11.9 68.4 56.0 Density (g/mL) 1.49 1.33 1.47 1.21 1.41 H20 Solubility (ppm) 110 120 130 610 2200 Dipole Moment (debye) 0.45 0.51 0.66 2.06 0.93 More info can be found @ http://www.solvay-fluor.com/product/properties/0,0,-_EN-1000700,00.html
- 19. DPI – Components A PI D ispersion E xcipients S tability E xcipients D ry P ow der D ispersive M echanism P ackaging D evice D ry Pow der Inhaler Com ponents
- 20. DPI – New & Old Traditional – Lactose Blends w/ API Modern – Engineered Particles of API
- 21. DPI – Devices
- 22. Nebulizers – Jet A Nebulizer is a device that can convert a liquid into aerosol droplets to produce a respirable cloud suitable for inhalation Jet Nebulizers use a compressed sir to atomize drug solution to produce a fine mist using the Bernoulli principal.
- 23. Nebulizers – Jet Jet nebulizers are sub-divided in three types: Standard Constant output throughout the respiratory cycle Breath Enhanced Constant output but provides higher output during inhalation Breath Actuated
- 24. Nebulizers – Ultrasonic Ultrasonic Nebulizers use electricity to vibrate a piezoelectric crystal at high frequency. The resultant vibration are transmitted to a reservoir containing the liquid drug, creating a series of waves from which liquid droplets separate to form an aerosol. MiniBreeze Ultrasonic Nebulizer
- 25. Nebulizers – Mesh There are two categories of mesh-type nebulizers: static mesh and vibrating mesh nebulizers: Static mesh nebulizers apply pressure on the inhalation solution in order to force it through a static sieving mesh. OMRON HEALTHCARE, INC
- 26. Nebulizers – Mesh (Conti.) Vibrating mesh nebulizers work by using deformations or vibrations of the mesh to push the inhalation solution through the aperture plate. A ring-shaped piezoelectric element having contact with the mesh plate sets same into vibrations. The inhalation solution is in direct contact with the sieving mesh. Mesh plate apertures are ca. 3.8 µm in diameter, which is the smallest size technically achievable (for reasons of blocking). The mesh generates a mono disperse aerosol cloud whose finest droplets are only slightly smaller than the aperture diameter. Larger droplets are then formed by coagulation while the smaller ones are formed by evaporation.
- 27. Characterization Of Inhalation Products There is no truth in particle sizing!
- 28. Stakeholders in Quality Analytical Testing During Drug Development Tox/PKRA
- 29. Aerodynamic Particle Size Given by the Equation: ρStokesAero DD = µ ρ 18 2 ∆ = gD Vt Stokes Law:Stokes Law: For optimal aerosol performance, it is desirable to have a small andFor optimal aerosol performance, it is desirable to have a small and light particlelight particle
- 30. Aerodynamic Diameter The behavior (settling velocity) of spherical particle can be described by Stokes law: 2r²g(ρp – ρf) Vs = _________________ 9 η where: Vs is the particles’ settling velocity g is the acceleration due to gravity ρp is the density of the particles ρf is the density of the fluid r is the Stokes radius of the particle η is the fluid viscosity.
- 31. Lung Physiology
- 32. Inhalation and Disposition The behavior of inhaled particles differs significantly from that of inhaled gaseous or volatile compounds. The deposition of volatile compounds in the lungs is mainly dependent on the water solubility of the compound – the more the compound is water soluble the less deep it will penetrate in the lung. The deposition of particulate matter is mainly dependent on its aerodynamic diameter.
- 33. Particle Size (Aerodynamic Size Distribution) Together with delivered dose uniformity, the Aerodynamic Particle Size Distribution (APSD) is widely recognized as a Critical Quality Attribute (CGA) in the in vitro characterization of inhaled and nasal products since it is the APSD of an aerosol cloud that defines where the particles in that cloud are deposited following inhalation. It is generally accepted that to be therapeutically effective, the particles should be in the range of 1 to 5 microns since particles > 5 microns will generally impact in the oropharynx and be swallowed whereas those < 1 micron may remain entrained in the airstream and be exhaled during the next breathing cycle.
- 34. Particle Size (Aerodynamic Size Distribution) The preferred instrument of choice for measuring the APSD of inhaled and nasal products is the cascade impactor because: • Cascade impactors measure aerodynamic particle size • Cascade impactors measure active pharmaceutical ingredient • Cascade impactors measure the entire dose
- 35. The Gold Standard – ACI Andersen Cascade Impactor
- 37. The New ACI – NGI Next Generation Impactor
- 38. Dosage Unit Sampling Apparatus (DUSA)
- 39. Delivered Dose The Delivered or Emitted Dose is the total amount of drug emitted from the inhaler device and hence available to the user. Its uniformity is a Critical Quality Attribute (CQA) in determining the safety, quality and efficacy of an orally inhaled and nasal drug product (OINDP). Based on an original design by Charles Thiel in 3M’s laboratories in Minneapolis, USA, the Dosage Unit Sampling Apparatus (DUSA) for MDIs has been designed specifically for the sampling and testing of Metered Dose Inhalers (MDIs). It is used to perform those tests specified in the Pharmacopoeias relating to “delivered” or “emitted” dose, namely “Delivered Dose Uniformity” and “Delivered Dose Uniformity over the Entire Contents”. Copley Scientific
- 40. Dose Content Uniformity Is the simplest, yet hardest assay 50 70 90 110 130 150 0 25 50 75 100Shot # APIContent(mg) 60 80 100 120 0 25 50 75 100Shot #APIContent(mg)
- 41. Dosage Unit Sampling Apparatus for Nebulizers
- 42. Dosage Unit Sampling Apparatus for Nebulizers Nebulizers convert liquids into a cloud of droplets suitable for respiration. Conventional nebulizers are widely used in both hospital and home. Their main advantage is that unlike other devices, they require little or no coordination on the part of the patient in order to use them. The breathing pattern employed in the testing of nebulizers is particularly important since in vivo this determines the amount of active available to the user. For this reason, the two tests specified in the Pharmacopoeias to characterize delivered dose, Active Substance Delivery Rate and Total Active Substance Delivered are based on tidal flow conditions generated by a breath simulator, as opposed to fixed flow rates. The Dosage Unit Sampling Apparatus (DUSA) for Nebulizers consists of a Breath Simulator to generate the specified breathing profile, a filter holder containing the filter to capture the drug and a suitable mouthpiece adapter to connect the filter holder to the nebulizer under test. Various patterns are available for neonatal, infant, child and adult applications. Copley Scientific
- 43. Non-Traditional Techniques A brief overview
- 45. Aerosizer – Time of Flight
- 46. Summary Pulmonary aerosols are an effective and accepted dosage form IAL can now support all required analyses Simple physics can explain most techniques Thanks for your time, questions and attention
- 47. It may be the Best Drug Delivery System, but It will Kill you