Enhancing Pharmaceutical Inhalers Efficiency with Lung Modeling

1. 2004 Mechanical & Industrial Engineering, University of Toronto A Device to Model a Human Lung to Determine the Delivery Efficiency of Inhaled Pharmaceutical Aerosols

2. 2004 Mechanical & Industrial Engineering, University of Toronto • Overview • Background • Existing Models • Developed Models • Flexible Lung Model • Rigid Lung Model • Testing Methodology • Model Assessment and Conclusion

3. 2004 Mechanical & Industrial Engineering, University of Toronto Medication Administration Medications are administrated by: • Oral ingestion • Intravenous Injections • Respiratory system (Pharmaceutical Inhalers)

4. 2004 Mechanical & Industrial Engineering, University of Toronto Pharmaceutical Inhalers Advantages Quick absorption into the blood stream  Less medicine for similar therapeutic result Projection 50% of medication through inhalers Problem Less than 20% of inhaled dosage reaches the lower respiratory system Need More efficient pharmaceutical inhalers  Means of testing pharmaceutical inhalers

5. Inhalers Pressurized Metered Dose Inhaler (pMDI) Breath Activated Inhaler Pressurized Aerosol Inhaler with Spacer Nebulizer Dry Powder Inhaler (DPI)

6. Test Inhaler • ADVAIR pMDI 120 dose (125 mcg) • Treats the two main components of asthma, airway constriction and inflammation • Each dose contains 25 mcg salmeterol xinafoate and 125 mcg fluticasone propionate • Inhalers doped with Rose Bengal Dye for visualization purposes

7. 2004 Mechanical & Industrial Engineering, University of Toronto • Spectrophotometer Allows for precise measurements of flow concentration in all regions of the lung model Consists of: • A source that generates electromagnetic radiation • A dispersion device that selects a particular wavelength from the broad band radiation of the source • A sample area • A detector to measure the intensity of radiation

8. 2004 Mechanical & Industrial Engineering, University of Toronto • Available Solutions • Computer / Mathematical Models • Physical Models • Twin Impinger • Cascade Impactor • Limitations • Our Goal: Devise a physical lung model, superior to the existing models, to test pharmaceutical inhalers

9. 2004 Mechanical & Industrial Engineering, University of Toronto Lung Properties Human Respiratory System Mouth/Nose  Trachea  Bronchioles  Alveoli Alveoli

10. Lung Geometry • Weibel Model A • Number of generations, z • Branch diameter • Branch length

11. 2004 Mechanical & Industrial Engineering, University of Toronto Lung Geometry • Weibels Model Z (Branching generation) N (z) (Number of branches) = 2 Z d (z) (Branch diameter) = do x 2 –z/3 • 23 generations of bronchiole branching • Average Trachea diameter is 1.8 cm

12. Particle Deposition • Methods and Areas of Particle Deposition • Impaction • Sedimentation • Diffusion

13. 2004 Mechanical & Industrial Engineering, University of Toronto Weibels Model

14. 2004 Mechanical & Industrial Engineering, University of Toronto Physical Lung Properties • Average volume of inhaled air is 500cc • Average pressure difference is 2mm Hg • Approximation of airflow within the human lung: • Quiet breathing = 0.4 litres/s • Mild Exercise = 1.25 – 1.5 litres/s

15. 2004 Mechanical & Industrial Engineering, University of Toronto • Existing Models Computer / Mathematical Models • Not very accurate, based only on mathematical equations • No physical data to support the models • Do not account for the randomness of particle flow and deposition inside a complex organ like the human lung Physical Models • Twin Impinger • Cascade Impactor

16. 2004 Mechanical & Industrial Engineering, University of Toronto • Twin Impinger • Tests the lung penetration capability of a pressurized metered dose inhaler (pMDI)

17. Twin Impinger Apparatus

18. Cascade Impactor • Measures the aerodynamic size distribution and mass concentration levels of solid particulates and liquid aerosols

19. Cascade Impactor Apparatus

20. Other Design Concepts • Medical Tubing Concept • Positive displacement pump • Standard medical tubing • Standard connectors • Advantage: Ease of separation • Concern: Flow obstruction at junctions

21. Existing Solutions • Computer/Mathematical Models • Limited to the accuracy of the governing equations • Requires experimental verification

22. 2004 Mechanical & Industrial Engineering, University of Toronto • Limitations Twin Impinger • Only 2 compartments • Simplified particle flow path • No flow visualization Cascade Impactor • No set path to follow • No flow visualization

23. MUSSL Lung Model Based on Direct Flow Visualization • A transparent lung model • Use particle deposition tracing • Ink Visualization • X-ray Scintigraphy using Radiolabeled particles • Planar Laser Imaging

24. Design Concepts • Expanding-Contracting Lung Design • Machined representation of lung covered with silicon membrane • Expanded by external breathing bag • Difficult to control expansion and contraction

25. Detailed Design Description • Drawing of lung • Machining of lung • Mouth-trachea induction port • Ventilator/breathing apparatus • Tracer dye labeled aerosol • Filtration and resistance devices • Testing and Apparatus Setup

26. Drawing of the Lung • AutoCAD Representation • 2-D • 8 to 9 generations • Approx. 750 branches

27. Drawing of Lung • SolidWorks 2003 Drawing

28. a) The sketch is projected to offset plane. b) The inter-planes are created. c) Circles are drawn on the midlines. d) Circles are extruded to planes. Drawing Procedure

29. Machining of Lung • MasterCAM file conversion

30. Machining of Lung • Machining of Bronchial Tree • Completed by Excentrotech Precision Ltd. • G-code generation: MasterCAM • High-speed 5-axis CNC mill

31. Machining of Lung • Machining of Exit Channels • Completed by MIE Machine Shop • G-code generation: MasterCAM • 3-axis CNC mill

32. Final Design • Machined representation of human lung in aluminum

33. Mouth-Trachea Induction Port • Simulates the filtering effects and geometric properties of the mouth and throat • Schematics provided by Nuclear Medicine Department at McMaster University

34. 2004 Mechanical & Industrial Engineering, University of Toronto Mouth and trachea induction port development and assembly • Counter bored for the insertion of the adapter • Adapter to provide un obstructed/continuous flow • Not a permanent fit allows switch to the clear mouth/trachea port

35. 2004 Mechanical & Industrial Engineering, University of Toronto • Creating the 3-D Model

36. 2004 Mechanical & Industrial Engineering, University of Toronto • Design Requirements • Model must transparent to allow for easy flow visualization to take place • Model must be able to mimic basic mechanical proprieties of an average human lung • Air Volume ( 500 cc ) • Pressure ( 750 mmHg )

37. 2004 Mechanical & Industrial Engineering, University of Toronto • Construction Overview • 3-D Model Creation Stages • Construction of the wax model • Coating of the model with the flexible elastomer shell • Separation of the model from the cured flexible shell

38. 2004 Mechanical & Industrial Engineering, University of Toronto Stage 1 Creating the Wax Model

39. 2004 Mechanical & Industrial Engineering, University of Toronto Second Attempt:Heating of the Mold Plate was heated above melting temperature of the wax Allowed for uniform cooling of wax

40. 2004 Mechanical & Industrial Engineering, University of Toronto Completed Wax Model

41. 2004 Mechanical & Industrial Engineering, University of Toronto Mouth/trachea induction port Lung model Outlet port Stand

42. Hollow, flexible cast of a human lung According to a procedure developed at North Carolina State University • Silicon or latex hollow cast could be used as a breathing model

43. Hollow Cast Model