1. Novel Design of a Dry Powder Inhaler (DPI) for the Treatment of Acute Asthmatic Episodes University of Pittsburgh Senior Design – BioE 1160/1161 Annemarie K. Alderson Anindita Saha Stephanie T. Shaulis Robert J. Toth April 18, 2005 Mentor: Timothy E. Corcoran, Ph.D

2. Presentation Outline Background Problem Statement Project Goals Design Considerations Prototype Development Testing Final Design

3. Background Asthma Immunologic condition Causes inflammation Increased resistance to airflow Due to smooth muscle constriction Non-specific chemical/physical triggers Induces hyper-reactivity American Lung Association estimates 20 million Americans suffer from some form of asthma

4. Problem Statement Current treatment technologies do not adequately meet the needs of asthmatics who suffer from minor bronchial constrictions during physical activity Rescue medications Delivered by metered dose inhalers (MDI) Use CFC propellants Inefficient drug deposition Complex shapes Inefficient portability Utilize rigid materials of construction Precise patient coordination required Dispensing and inhalation Boehringer Ingelheim, Inc.

5. Project Goals To design and develop a dry-powder, single- dose, disposable inhaler To create a prototype that is self contained, ruggedly constructed, lightweight, small, ergonomically designed, and portable To be used by asthmatic individuals who desire a temporary alternative to traditional devices during physical activity

6. Design Considerations Dry powder inhaler over metered dose inhaler Device load dosage of 25 ± 1 mg Albuterol sulfate as bronchiodilator Lactose as excipient Test drug: 70% lactose, 30% micronized atropine Optimum transport of medication to bronchioles 5 μm particle size Effective dispersion © McGraw-Hill Companies, Inc

7. Design Considerations Heyder J, et al. Deposition of particles in human respiratory tract in the size range of 0.005-15 µm. J Aerosol Sci; 17: 811–25. © McGraw-Hill Companies, Inc

8. Design Considerations Anthropometric constraints for mouthpiece and device body Average inspiration flow of 30-100 L/min for inhalation drug therapy 1 Material of construction-low density polyethylene 1 Corcoran, et al. Unpublished data.

9. Iterative Design Process Create solid model (SolidWorks) Perform CFD (COSMOS) Turbulent / time-independent simulation Physiologic boundary conditions Bulk flow convergence parameter Obtain aerosol dynamics within device consistent with 5  m particle deposition Modify/refine the model Re-perform CFD testing Continue cycle until acceptable solid model completed

10. Prototype Development Summary 10 solid models developed Initial CFD indicated rotational flow Inefficient at dispersing and depositing micron- sized particles Rotation due to boundary conditions Outlet volumetric flow vs. outlet pressure 60 L/min vs. 1 mmHg below ambient P Improved boundary conditions implemented Bulk flow patterns observed Model-8 rapid prototyped through Quickparts.com

11. Initial CFD Model

12. Model-8 Re in = 10307 Re body = 3436 Flow = 32.5 L/min

13. Prototype (Model-8)

14. Methods Used to Test Performance Inlet port Laser aperture Prototype Vacuum line Diffractive Laser Detector

15. Testing Results Flow rate from vacuum line ~ 44 L/min 34%

16. Testing Results Flow rate through device ~8 L/min 11%

17. Device Modifications Inadequate flow through device Increase diameter of pressure opening 2 mm  3 mm Add second opening Incorporate modifications into models 9 and 10

18. Model-10 Re in = 13743 Re body = 8671 Flow = 42.4 L/min

19. Model-10 Prototype

20. Testing Results Flow rate through device ~38 L/min 51%

21. Testing Results Flow rate through device ~38 L/min 63%

22. Conclusions Particle dispersion under 5µm observed Separation of drug and excipient Indicative of effective drug deposition Flow through device consistent with physiological inspiration levels Range covers healthy and asthmatic individuals Prototype performance consistent with design specifications

23. Acknowledgements Dr. Timothy Corcoran & Amy Marcinkowski Drs. Hal Wrigley & Linda Baker Mark Gartner Department of Bioengineering

24. Questions?

25. Materials Selection Plastics Comparison Plastic TypeDensity (g/cc) Impact Strength (J/cm) Rockwell Hardness [R] ABS1.086.40115 LD-polyethylene0.916.9460 PET1.301.40110 Polypropylene1.0711.5091 Polystyrene1.002.9475 PVC1.3713.9080 ABS/PVC Blend0.9812.50102 Note: Heat sealing properties of LDPE would contribute to the sealing/activation mechanism Quickparts prototype material 1.12 g/cc

26. Regulatory Information Inhalers are regulated by the FDA’s Center for Drug and Evaluation Research FDA regulations Drug product Components and composition Specs for formulation components Manufacturers and method(s) of manufacture and packaging Specifications for the drug product Container and closure systems Drug product stability Drug product characterization studies Labeling considerations

27. Human Factors Analysis Ergonomic considerations in design No sharp edges or corners Hand force required to grip negligible Anthropometric data of 5% female to 95% compared Basic motor skill use needed to operate Simple design for ease of operation Lightweight for ease of portability

28. Project Breakdown Anindita Anthropometric constraints Regulatory information DHF Annemarie Materials selection Aesthetics DHF Robert Solid model development CFD simulation Design report document Stephanie Flow inhalation Drug dosage size Testing DHF

29. Model-3

30. Model-6

31. Model-7

32. Model-9