Sievers Fehsenfeld2


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  • Sievers Fehsenfeld2

    1. 1. MEDICAL AEROSOLS TO IMPROVE GLOBAL HEALTH R.E. Sievers 1,2 , S. Winston, S.P. Cape 1,2 , D. Bennett 1 , J.L. Burger 2 , D.H. McAdams 2 , B.P. Quinn 1 , J.A. Searles 1 , D.M. Krank 1 , P. Pathak 1 , P. A. Bhagwat 1 , L.G. Rebits 1 , K.O. Kisich 3 , R. Dhere 4 , P. Kulkarni 4 , V. Vaidya 4 , R. Muley 4 , K. Powell 5 , C. Shermer 5 , L. Chan 5 , D. Griffin 6 , W-H. Lin 6 , P. Rota 7 , M. Papania 7 1 Aktiv-Dry LLC, 6060 Spine Road, Boulder, CO, USA 2 Center for Pharmaceutical Biotechnology, Department of Chemistry and Biochemistry, and CIRES, University of Colorado, Boulder, CO, USA 3 National Jewish Medical and Research Center, Denver, CO, USA 4 Serum Institute of India, Ltd., Pune, India 5 BD Technologies, Research Triangle Park, NC, USA 6 Johns Hopkins School of Public Health, Baltimore, MD, USA 7 Centers for Disease Control and Prevention, Atlanta, GA, USA
    2. 2. A lecture to honor Dr. Fred Fehsenfeld for all he has done for my group and for CIRES Sept.24, 2008
    3. 3. Fehsenfeld and Sievers Group Collaborations <ul><li>Over 3 decades, Fred Fehsenfeld and I have mentored together a number of students and post-docs: </li></ul><ul><li>Students: </li></ul><ul><ul><li>Susan Wells Buhr Jim Roberts </li></ul></ul><ul><ul><li>Tom Ryerson Michael Phillips </li></ul></ul><ul><ul><li>Martin Buhr Mark Bollinger </li></ul></ul><ul><ul><li>Steve Montzka Ric Hutte* </li></ul></ul><ul><ul><li>Eric Williams </li></ul></ul><ul><ul><li> </li></ul></ul><ul><ul><li>  </li></ul></ul><ul><li>In addition, we have had several collaborators at both NOAA and CU with whom we have co-authored papers: </li></ul><ul><li>  </li></ul><ul><li>Collaborators: </li></ul><ul><ul><li>Paul Goldan </li></ul></ul><ul><ul><li>Richard Norton Dan Albritton </li></ul></ul><ul><ul><li>Michael Trainer David Fahey </li></ul></ul><ul><ul><li>David Parrish Bill Kuster </li></ul></ul><ul><ul><li>Bob Barkley* Barbara Watkins Miles </li></ul></ul><ul><ul><li>Robert Meglen John Birks </li></ul></ul>
    4. 4. <ul><li>Every generation may believe that it faces unprecedented and “the Worst” challenges: </li></ul><ul><li>Consider the 20 th and 21 st Centuries </li></ul><ul><ul><ul><li>World War I, the “War to end All Wars.” </li></ul></ul></ul><ul><ul><ul><li>Global Influenza Pandemic 1918 </li></ul></ul></ul><ul><ul><ul><li>The Great Depression of 1929 </li></ul></ul></ul><ul><ul><ul><li>The Dust Bowl and collapse of farming </li></ul></ul></ul><ul><ul><ul><li>Racial and Religious Intolerance — The Ku Klux Klan and the Holocaust </li></ul></ul></ul><ul><ul><ul><li>World War II/ Fascism and Communism </li></ul></ul></ul><ul><ul><ul><li>Nuclear and Biological Weapons 1950-1990 </li></ul></ul></ul><ul><ul><ul><li>Cuban Missile Crisis and Viet-Nam War </li></ul></ul></ul><ul><ul><ul><li>Terrorism and 9/11 </li></ul></ul></ul><ul><ul><ul><li>Global Pollution and Climate Change </li></ul></ul></ul><ul><ul><ul><li>Global Disease, Poverty, and Hunger </li></ul></ul></ul><ul><ul><ul><li>  Energy, Housing, and Economic Turmoil </li></ul></ul></ul>
    5. 5. Henao, An Overview of Aerosol Immunization, Meeting of the WHO Steering Committee on New Delivery Systems, 2004
    6. 6. Henao-Restrepo and Papania, NIH Vaccines Conference, Rockville, Dec 2003
    7. 7. Dry Powder Measles Vaccine Team Aktiv-Dry LLC, Prime Contractor; Bob Sievers ,Principal Investigator; funded by a grant from the Foundation for the National Institutes of Health in the Grand Challenges in Global Health initiative. Subcontractors: Serum Institute of India BD Technologies University of Colorado National Jewish Medical and Research Center Johns Hopkins University University of Kansas RPC Formatec Consultants: John Carpenter, School of Pharmacy, CU Health Sciences Center Paul Rota and Mark Papania, US Centers for Disease Prevention and Control (CDC) University of Maryland Vaccine Research Center Winston Consulting Witham Consulting
    8. 8. Project Objectives <ul><li>Synthesize a stable respirable microparticulate dry powder measles vaccine by CAN-BD </li></ul><ul><li>Develop at least 2 simple, very inexpensive unidose active DPI devices that can deliver well dispersed fine particles </li></ul><ul><li>Install GMP Bubble Dryer at the Serum Institute of India in Pune, India (now operational) </li></ul><ul><li>Assess excipient and vaccine safety pre-clinically in rodents and Non-Human Primates, then clinically in Phase I trials in India </li></ul><ul><li>Deliverable: Successful completion of Phase I clinical trials for improved needle-free inhalable dry powder measles vaccine </li></ul>
    9. 9. GRAND CHALLENGE 3: NEEDLE-FREE DELIVERY <ul><li>Maintain viral activity of attenuated Edmonston-Zagreb measles vaccine through stabilization in glassy dry respirable microparticles upon drying, then in a state of suspended animation for many months. </li></ul><ul><li>The aggregate, upon dispersion from an active dry powder inhaler, must deposit in the moist respiratory tract where microparticles will rapidly dissolve in mucosa and replicate many-fold over a few days to stimulate immune responses. </li></ul><ul><li>As the immune responses develop, the viremia must subside and the antibodies persist. </li></ul>
    10. 10. GRAND CHALLENGE 3: NEEDLE-FREE DELIVERY <ul><li>Needed: </li></ul><ul><li>Well-formulated free flowing stable microparticles with less than 1% residual moisture, with high virus titers, dissolved within ~5 seconds. </li></ul><ul><li>Inexpensive uni-dose blister packs or containers to protect vaccine from contamination, decomposing, reaction with water, oxidants and UV for 2 years, and to reduce vaccine wastage. (Presently 40% is destroyed.) </li></ul><ul><li>Simple active dry powder inhalers that can disperse powder agglomerates to generate high emitted doses with high fine particle fractions. </li></ul>
    11. 11. <ul><ul><ul><li>Stabilize and make dry powders with larger fine particle fraction </li></ul></ul></ul><ul><ul><ul><li>Package and seal individually as unit doses to: </li></ul></ul></ul><ul><ul><ul><ul><ul><li>- Extend lifetime </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- Pre-measure the dose </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- Protect powder against moisture, oxidants, and UV light </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- Protect vaccine against contamination </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- Reduce bioburden and eliminate pathogens </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- Reduce vaccine wastage </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- Allow serial administration of vaccines </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>- Allow formulation in optimal matrix for each vaccine </li></ul></ul></ul></ul></ul>STRATEGIES EMPLOYED FNIH GRANT 1077
    12. 12. <ul><ul><ul><li>Prepare vaccine aerosol precursors in manufacturing plant rather than in the field </li></ul></ul></ul><ul><ul><ul><li>Provide dispersion and aerosolization on site with only muscle power, and without line current or batteries </li></ul></ul></ul><ul><ul><ul><li>Separate and re-use aerosolizer and disperser; then incinerate each reservoir and mask or mouthpiece </li></ul></ul></ul><ul><ul><ul><li>Avoid carrying water to the field (vaccine ~10 times lighter). </li></ul></ul></ul>STRATEGIES EMPLOYED FNIH GRANT 1077 (continued)
    13. 13. Immunization in Difficult Circumstances ©Dr. Gordon Perkin Nepal 1999 Polio Outreach- Upper Nile region of Southern Sudan ©UNICEF ©UNICEF PATH
    14. 14. <ul><ul><ul><li>Powders inherently more stable than liquids </li></ul></ul></ul><ul><ul><ul><li>No line current or batteries required </li></ul></ul></ul><ul><ul><ul><li>Lower risk of disease transmission </li></ul></ul></ul><ul><ul><ul><li>Less vaccine wastage </li></ul></ul></ul><ul><ul><ul><li>More difficult to contaminate; no water or reconstitution needed, so easier to carry </li></ul></ul></ul><ul><ul><ul><li>No skin puncture or contact with blood </li></ul></ul></ul><ul><ul><ul><li>No re-use of needles </li></ul></ul></ul>Summary of Some Dry Powder Advantages over Liquid Vaccines
    15. 15. Measles Aerosol Vaccines in Humans 3 million humans immunized effectively with wet mist aerosol measles vaccine in Mexico (Valdespino, De Castro, et al.) Revaccination protection from mucosal pulmonary aerosol superior to SC injection in S. Africa (Dilraj, et al.) Nasal administration of large droplets gave poor seroconversion results in Chile (Simon, Levine, et al.) WHO Wet Mist Aerosol Group has been administering wet mists of SII Edmonston-Zagreb measles vaccine with 3 devices in Phase I clinical trials in India.
    16. 16. <ul><ul><ul><li>System description </li></ul></ul></ul><ul><ul><ul><ul><li>Leads to high seroconversion </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Live virus titer per loaded dose at end of shelf life = 1000 CCID 50 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Filled mass of powder per dose = 10 mg </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cost of device and powder is less than or equal to $0.26 adjusted for inflation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>The delivery system will be needle-free </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Safe for human administration </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Meet WHO + UNICEF requirements </li></ul></ul></ul></ul>Product Specifications
    17. 17. The Principle of the New CAN-BD Process <ul><li>In CAN-BD, the vaccine formulation solution/suspension in water is mixed intimately in a low volume tee with CO 2 at 80-100 bar to form an emulsion. </li></ul><ul><li>The emulsion, stabilized with myo-inositol or other sugars and the other traditional excipients in the SIIL vaccine (excepting sorbitol), is rapidly expanded to atmospheric pressure through a flow restrictor to generate aerosols of microbubbles and microdroplets. </li></ul><ul><li>The aerosol plume is dried at temperatures below 50-70 °C as it mixes with a sheath of nitrogen in the drying chamber. </li></ul><ul><li>Dry fine powders are collected on filters and packaged to exclude moisture (aluminum foil blister packs or capsules with Al-film/ polymer laminates for packaging). </li></ul>Carbon Dioxide Assisted Nebulization with a Bubble Dryer®
    18. 18. CAN-BD Nebulizer Drug Solution or Vaccine Suspension Near-critical or Supercritical CO 2 (80 to 100 atm) Flow Restrictor Tube ID = 75  m 10 cm Emulsion of product stream in liquid CO 2 CO 2 flashes upon rapid 100X decompression to atmospheric pressure Restrictor Tip
    19. 19. Tuberculosis Antibiotics Ciprofloxacin HCl Moxifloxacin HCl Rifampin Capreomycin Amikacin Drying T (C) 60 60 30 60 60 Solvent Water Water Ethyl Acetate Water Water Mean aero dia (µm) 1.2 1.1 0.78 1.3 1.2 95% cutoff (µm) 2.2 1.9 1.3 2.6 2.2 % < 5 um 89 56 86 77 84 Retained Activity 93% ± 20% 81% ± 43% 109% ± 34% 95% ± 7% 104% ± 7% AKTIV-DRY
    20. 20. Assembly: Raul and Mihesh
    21. 21. CAN-BD Generated Particles of Measles Vaccine Formulation Myo-inositol based placebo (M50)
    22. 22. Physical Properties of Powders Dried by CAN-BD <ul><li>Other variants of myo -inositol formulations also have similar properties </li></ul><ul><ul><li>Fine Particle Fractions </li></ul></ul><ul><ul><ul><li>About 45-50% < 5.8 µm and about 20% < 3.3 µm </li></ul></ul></ul><ul><ul><li>Glass Transition Temperature (Tg) </li></ul></ul><ul><ul><ul><li>Onset Tg = 45 - 60 °C; and Midpoint Tg = 50 - 65 °C </li></ul></ul></ul>
    23. 23. Replication of Live Measles Virus Vaccine in Cotton Rat Lungs (K.O. Kisich)
    24. 24. <ul><li>Low hygroscopicity; water content of formulation less than 1% </li></ul><ul><li>Widely distributed naturally in human cells </li></ul><ul><li>Phase I Clinical trial showed oral administration of 18 g/day for three months had no serious adverse effects (S. Lam et al . Cancer Epidemiol Biomarkers Prev 2006; 15 (8)) </li></ul><ul><li>Costs less than $8000 per metric ton; not animal-derived; isolated from rice in Asia </li></ul>Chemical Structure of Myo-inositol Myo-inositol --newly shown to be stabilizing
    25. 25. CAN-BD Processing *Hydrophobic Vaccines Live attenuated measles virus Live attenuated influenza virus Hepatitis B surface antigen(HBsAg) Antibodies PRIMATZED® anti-CD4 Human IgG Anti-human lambda light chain Proteins Alpha-1-antitrypsin Trypsinogen Lactate dehydrogenase Lysozyme Insulin Alkaline phosphatase Nucleotides siRNA duplex Aptamers DNA single strand Formulation Constituents Sugars Buffers: Tricine, sodium potassium phosphate, sodium acetate Surfactants: Palmitic acid, stearic acid, Tween 20, Tween 80, Pluronic F68 Amino acids: Arginine, methionine, leucine, glycine, etc. Metal chelating agents: EDTA, DTPA Antibiotics Moxifloxacin Tobramycin Amoxycillin Doxycycline Cefazolin Ciprofloxacin Amikacin Capreomycin Rifampin Antivirals siRNA Relenza Other PEG PVP Hydrolyzed gelatin Sodium chloride DPPC (lung surfactant) Salbutamol (asthma drug) Albuterol sulfate Cromolyn sodium Phytosterols* (nutraceutical) Naproxen* Budesonide* Betamethasone* Amphotericin B* Cyclosporin* Myo-inositol and other sugars
    26. 26. Aktiv-Dry PuffHaler™ DPI System <ul><li>TWO SEPARABLE COMPONENTS -- </li></ul><ul><li>ONE REUSABLE AND ONE DISPOSABLE </li></ul><ul><li>Aerosolization assembly (~ 500 uses per day) </li></ul><ul><ul><li>Pliable polymeric bulb </li></ul></ul><ul><ul><li>Equipped with pressure release valve </li></ul></ul><ul><ul><li>Compartment to hold blister </li></ul></ul><ul><li>Patient Interface (use only once) </li></ul><ul><ul><li>Collapsible plastic bag reservoir </li></ul></ul><ul><ul><li>Permeable filter facemask or mouthpiece with vents </li></ul></ul>
    27. 27. PuffHaler ® Aerosol Delivery System <ul><li>Utilizes air expansion through a pressure release valve </li></ul>Top View Side View
    28. 31. Some Advances to Celebrate <ul><li>Dried and micronized stabilized live virus measles vaccine without greater loss of viral activity than in present commercial lyophilization. </li></ul><ul><li>Pressure release valves and syringes facilitate dispersion and create stable aerosol clouds comparable to newly FDA-approved active DPI. </li></ul><ul><li>Greatly reduced cost and complexity of DPI‘s. </li></ul><ul><li>Reduced water content of powders to < 1%. </li></ul><ul><li>Myo-inositol stabilized powders pass the WHO test for stability at 37 degrees Celsius for one week with less than one log loss in viral activity. </li></ul>
    29. 32. “ GRAND CHALLENGE ” Bob Sievers Campan Marble Lourdes, France Gift installed in Norlin Historic Quadrangle at University of Colorado In gratitude for the support by the Foundation for the National Institutes of Health
    30. 35. Fehsenfeld-Sievers Publications <ul><li>“ Development of a Semi-Continuous Method for the Measurement of Nitric Acid Vapor and Particulate Nitrate and Sulfate,” S.M Buhr, M.P. Buhr, F.C. Fehsenfeld, J.S. Holloway, U. Karst, R.B. Norton, D.D. Parish, and R.E. Sievers, Atmospheric Environment, 29:19, 2609-2624 (1995). </li></ul><ul><li>&quot;Assessment of Pollutant Emission Inventories by Principal Component Analysis of Ambient Air Measurements,&quot; M.P. Buhr, M. Trainer, D. D. Parrish, R.E. Sievers, and F.C. Fehsenfeld, Geophys. Res. Lett., 19, 10, 1009-1012 (1992). </li></ul><ul><li>&quot;Contribution of Organic Nitrates to the Total Reactive Nitrogen Budget at a Rural Eastern U.S. Site,&quot; M.P. Buhr, D. D. Parrish, R. B. Norton, F.C. Fehsenfeld and R.E. Sievers, J. Geophys. Res., 95, 9809-9816, (1990). </li></ul><ul><li>&quot;Monoterpene Hydrocarbons in the Nighttime Troposphere,&quot; J.M. Roberts, C.J. Hahn, F.C. Fehsenfeld, J.M. Warnock, D.L. Albritton, and R.E. Sievers, Environ. Sci. Technol., 19, 364 (1985). </li></ul><ul><li>&quot;Measurements of Anthropogenic Hydrocarbon Concentration Ratios in the Rural Troposphere: Discrimination between Background and Urban Sources,&quot; J.M. Roberts, R.S. Hutte, F.C. Fehsenfeld, D.C. Albritton and R.E. Sievers, Atmos. Env., 19, 1945 (1985). </li></ul><ul><li>&quot;Measurements of Hydrocarbon Concentration Ratios and NOx Concentrations in the Rural Troposphere: Estimation of Air Mass Photochemical Age and Discrimination between Background and Urban Sources,&quot; J.M. Roberts, F.C. Fehsenfeld, D.L. Albritton, and R.E. Sievers, &quot;Environmental Impact of Natural Emissions,&quot; V.P. Aneja, Ed., APCA Specialty Conf., Research Triangle Park, NC, 233-250 (1984). </li></ul><ul><li>&quot;Measurements of Aromatic Hydrocarbon Ratios and NOx Concentrations in the Rural Troposphere: Observation of Air Mass Photochemical Aging and NOx Removal,&quot; J.M. Roberts, F.C. Fehsenfeld, S.C. Liu, M.J. Bollinger, C. Hahn, D.L. Albritton and R.E. Sievers, Atmospheric Environment, 18, 2421-2432 (1984). </li></ul><ul><li>&quot;Measurement of Monoterpene Hydrocarbons at Niwot Ridge, Colorado,&quot; J.M. Roberts, F.C. Fehsenfeld, D.L. Albritton, and R.E. Sievers, J. Geophysical Research, 88, C15, 10667-10678 (1983). </li></ul><ul><li>&quot;Conversion of NO2, HNO3, and N-Propyl Nitrate to NO by a Gold-Catalyzed Reduction with CO,&quot; M.J. Bollinger, R.E. Sievers, D.W. Fahey, and F.D. Fehsenfeld, Anal. Chem., 55, 1980-1986 (1983). </li></ul><ul><li>&quot;Sampling and Analysis of Monoterpene Hydrocarbons in the Atmosphere with Tenax GC Porous Polymer,&quot; J.M. Roberts, F.C. Fehsenfeld, D.L. Albritton, and R.E. Sievers, Chapter 23 in &quot;Identification and Analysis of Organic Pollutants in Air,&quot; Ann Arbor Science Publishers, Ann Arbor, MI (1983). </li></ul><ul><li>&quot;Techniques for the Measurements of Atmospheric Hydrocarbons at a Remote Rural Site,&quot; J.M. Roberts, P.D. Goldan, D.L. Albritton, F.C. Fehsenfeld, and R.E. Sievers, &quot;Proceedings of Symposium on Pollutant Monitoring of Ambient Air and Stationary Sources, Raleigh, NC, May 4-7, 1982.&quot; </li></ul><ul><li>Chapter in Book Entitled &quot;Electron Capture-Theory and Practice in Chromatography,&quot; Elsevier Publishing Co., 1981 &quot;Selective Electron Capture Sensitization,&quot; M.P. Phillips, P.D. Goldan, F.C. Fehsenfeld, and R.E. Sievers. </li></ul><ul><li>&quot;Vinyl Chloride Detection at Sub-ppb Levels Using a Chemically Sensitized Electron Capture Detector,&quot; P.D. Goldan, F.C. Fehsenfeld, W.C. Kuster, M.P. Phillips and R.E. Sievers, Anal. Chem., 52, 1751 (1980). </li></ul><ul><li>&quot;Selective Electron-Capture Sensitization,&quot; R.E. Sievers, M.P. Phillips, R.M. Barkley, M.A. Wizner, M.J. Bollinger, R.S. Hutte, and F.C. Fehsenfeld, J. Chromatogr., 186, 3 (1979). </li></ul><ul><li>&quot;Selective Electron Capture Sensitization: Enhancement of Electron Capture Detector Sensitivity to Non-Electron Attaching Compounds by Nitrous Oxide Added to the Carrier Gas,&quot; M.P. Phillips, R.E. Sievers, P.D. Goldan, W.C. Kuster, and F.C. Fehsenfeld, Anal. Chem., 51, 1819 (1979). </li></ul>