Skip to main content
SpringerLink
Log in

Development of the Exubera® Insulin Pulmonary Delivery System

  • Chapter
  • First Online:
Mucosal Delivery of Biopharmaceuticals

Abstract

Development of Exubera® (insulin powder for inhalation) presented numerous challenges as a first-in-class product. These challenges included developing (a) the first room temperature stable insulin formulation, (b) a spray-drying process to produce a fine respirable powder with the physical attributes needed for efficient aerosolization, (c) a filling and packaging process capable of accurately and reproducibly dispensing fine powders, (d) a durable inhaler that enables reliable dosing to the patient under a variety of dosing scenarios and environmental conditions, and (e) a clinical program for Type 1 and Type 2 diabetics involving parallel measurements of pulmonary function. Insulin was formulated with sodium citrate, mannitol, and glycine in a homogenous aqueous solution prior to spray drying. Spray-drying equipment was designed and scaled up, to produce powder with tight control over particle size (mean ≈ 2 µm) and moisture content (< 2 %). The resulting amorphous powder was purposely designed to provide a high glass transition temperature (T g) that minimized insulin mobility (thus reactivity). Fine powder handling and packaging technology was developed to reproducibly fill blister packages containing 1.7 and 5.1 mg of powder (1 and 3 mg insulin per blister, respectively). The heat-sealed perimeter of the blisters prevented moisture ingress and provided room temperature storage for 18 and 24 months in the USA and EU, respectively. The Exubera® inhaler was designed for reproducible delivery and simple 5-step operation: (1) extension of the device chamber, (2) insertion of blister, (3) manual pump of handle to compress a defined volume of air (as the energy source for aerosolization), (4) button actuation to release the compressed air and thereby extract the insulin powder from the blister and disperse it as a fine aerosol into the chamber, and (5) rotation of the chamber mouthpiece to enable dose administration via inhalation of the standing aerosol cloud. Exubera® delivered insulin to the deep lung where it was absorbed into the blood stream with similar reproducibly and effectiveness as subcutaneous injections. Exubera® gained FDA and EMA approval in 2006, validating the technological and clinical efforts of Pfizer, Nektar, and Sanofi-Aventis. However, Exubera® was not a commercial success and was removed from the market in 2007. Lessons learned from the technology integration, the partnership between technology provider and sponsor, and the brief market experience are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Narayan KMW, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for developing diabetes mellitus in the United States. JAMA. 2003;290:1884–90.

    Article  CAS  PubMed  Google Scholar 

  2. Home PD, Boulton AJM, Jimenez J, Landgraf R, Osterbrink B, Christiansen JS. Issues relating to the early or earlier use of insulin in type 2 diabetes. Pract Diabetes Int. 2003;20:63–71.

    Article  Google Scholar 

  3. American Diabetes Association (ADA). Test of glycemia in diabetes. Diabetes Care. 2002;25:S97–S9.

    Article  Google Scholar 

  4. Rosenstock J, for the Exubera® Phase III Study Group. Mealtime rapid-acting inhale insulin (Exubera®) improves glycemic control in patients with type 2 diabetes failing combination oral agents: a 3-month, randomized, comparative trial. Diabetes. 2002;51:A132.

    Google Scholar 

  5. Zambanini A, Newson RB, Maisey M, Feher MD. Injection related anxiety in insulin-treated diabetes. Diabetes Res Clin Pract. 1999;46:239–46.

    Article  CAS  PubMed  Google Scholar 

  6. Home PD. Intensive insulin therapy in clinical practice. Diabetologia. 1997;40:S83–S7.

    Article  CAS  PubMed  Google Scholar 

  7. Cefalu WT. Rationale for and strategies to achieve glycemic control. In: Leahy JL, Cefalu WT, editors Insulin therapy. New York: Marcel Dekker; 2002. pp. 1–11.

    Google Scholar 

  8. Patton JS. Mechanisms of macromolecule absorption by the lungs. Adv Drug Del Rev. 1996;19:3–36.

    Article  CAS  Google Scholar 

  9. Smith SJ, Bernstein JA. In: Hickey AJ, editor. Inhalation aerosols: physical and biological basis for therapy. New York: Marcel Dekker; 1996. pp. 233–69.

    Google Scholar 

  10. Patton JS, Bukar J, Nagarajan S. Inhaled insulin. Adv Drug Del Rev. 1999;35:235–47.

    Article  CAS  Google Scholar 

  11. Patton JS, Bukar JG, Eldon MA. Clinical pharmacokinetics and pharmacodynamics of inhaled insulin. Clin Pharmacokinet. 2004;43:781–801.

    Article  CAS  PubMed  Google Scholar 

  12. Patton JS, Platz RM. Routes of delivery: case studies. pulmonary delivery of peptides and proteins for systemic action. Adv Drug Del Rev. 1992;8:176–96.

    Article  Google Scholar 

  13. White S, Bennett DB, Cheu S, Conley PW, Guzek DB, Gray S, Howard J, Malcolmson R, Parker JM, Roberts P, Schumacher JD, Sadrzadeh N, Seshadri S, Sluggett GW, Stevenson CL, Harper NJ. EXUBERA®: pharmaceutical development of a novel product for pulmonary delivery of insulin. Diabetes Technol Ther. 2005;7:896–906.

    Article  CAS  PubMed  Google Scholar 

  14. Harper NJ, Gray S, de Groot J, Parker JM, Sadrzadeh N, Schuler C, Schumacher JD, Seshadri S, Smith AE, Steeno GS, Stevenson CL, Taniere R, Wang M, Bennett DB. Design and performance of the exubera pulmonary insulin delivery system. Diabetes Technol Ther. 2007;9:16–27.

    Article  Google Scholar 

  15. Skyler JS, for the Exubera® Phase III Study Group. Efficacy and safety of inhaled insulin (Exubera®) compared to subcutaneous insulin therapy in an intensive insulin regimen in patients with type 1 diabetes: results of a 6-month, randomized, comparative trial. Diabetes. 2002;51:A134.

    Article  Google Scholar 

  16. Gelfand RA, Schwartz S, Horton M, Law CG, Pun EF. Pharmacological reproducibility of inhaled human insulin pre-meal dosing in patients with type 2 diabetes mellitus (NIDDM). Diabetes. 1998;47:0388.

    Google Scholar 

  17. Balanger A, for the Exubera® Phase III Study Group. Efficacy and safety of inhaled insulin (Exubera®) compared to subcutaneous insulin therapy in an intensive insulin regimen in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial. Diabetologia. 2002;45:A260.

    Google Scholar 

  18. Gelfand RA, Schwartz SL, Horton M, Law CG, Pun EF. Pharmacological reproducibility of inhaled human insulin dosed pre-meal in patients with type 2 diabetes mellitus. Diabetes. 2002;51:A202.

    Article  Google Scholar 

  19. Quattrin T, Belanger A, Bohannon NJV, Schwartz SL. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes. Diabetes Care. 2004;27:2622–27.

    Article  CAS  PubMed  Google Scholar 

  20. Hollander PA, Blonde L, Rowe R, Mehta AE, Milburn JL, Hershon KS, Chaisson JL, Levin SR. Efficacy and safety of inhaled insulin in patients with type 2 diabetes: a 6-month, randomized, comparative trial. Diabetes Care. 2004;27:2356–62.

    Article  CAS  PubMed  Google Scholar 

  21. Ashurst I, Malton A, Prime D, Sumby S. Latest advances in the development of dry powder inhalers. Pharm Sci Technol Today. 2000;3:246–56.

    Article  CAS  Google Scholar 

  22. Pikal MJ, Rigsbee DR. Dynamics of pharmaceutical amorphous solids: the study of enthalpy relaxation by isothermal microcalorimetry. Pharm Res. 1997;14:1379–87.

    Article  CAS  PubMed  Google Scholar 

  23. Hancock BC, Parks M. What is the true solubility advantage for amorphous pharmaceuticals? Pharm Res. 2000;17:397–404.

    Article  CAS  PubMed  Google Scholar 

  24. Hancock BC, Shamblin SL, Zografi G. Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures. Pharm Res. 1995;12:799–806.

    Article  CAS  PubMed  Google Scholar 

  25. Franks F, Hatley RHM, Mathias SF. Materials science and the production of shelf-stable biologicals. Pharm Technol Int. 1991;3:24–34.

    Google Scholar 

  26. Lechuga-Ballesteros D, Kuo MC, Liang Y, Malcolmson R, Miller DP, Sekulic S, Seshadri S, Stults CLM, Tan T, Joshi V, Zhen C, Williams L, Bennett DB. The physical stability of insulin powder for inhalation. AAPS J. 2004;6:R6137.

    Google Scholar 

  27. Kajiwara K, Franks F, Echlin P, Greer AL. Structural and dynamic properties of crystalline and amorphous phases in raffinose-water mixtures. Pharm Res. 1999;16:1441–8.

    Article  CAS  PubMed  Google Scholar 

  28. Lechuga-Ballesteros D, Miller DP, Zhang J. Residual water in amorphous solids: measurements and effects on stability. In: Levine H, ed. Progression amorphous food and pharmaceutical systems. London: The Royal Society of Chemistry; 2002.

    Google Scholar 

  29. Duddu SP, Zhang G, Dal Monte PR. The relationship between protein aggregation and molecular mobility below the glass transition temperature of lyophilized formulations containing a monoclonal antibody. Pharm Res. 1997;14:596–600.

    Article  CAS  PubMed  Google Scholar 

  30. Hancock BC, Zografi G. The relationship between glass transition temperature and the water content of amorphous pharmaceutical solids. Pharm Res. 1994;11:471–7.

    Article  CAS  PubMed  Google Scholar 

  31. Suen C, Bennett DB, Sadrzadeh N, Seshadri S, Stevenson CL, Tan MM, Wang ML, Kelly KE. Solution and solid state structural stability of insulin. AAPS J. 2004;6:M1261.

    Google Scholar 

  32. Pittman I, Tager HS. A spectroscopic investigation of the conformational dynamics of insulin in solution. Biochemistry. 1995;34:10578–90.

    Article  CAS  PubMed  Google Scholar 

  33. Dong A, Caughey WS. Infrared methods for study of hemoglobin reactions and structures. Methods Enzymol. 1994;232:139–75.

    Article  CAS  PubMed  Google Scholar 

  34. Sadrzadeh N, Wang ML, Yu M, Antonino L, Stevenson CL, Bennett DB, Kelly ME. The chemical stability of spray dried insulin powder for inhalation. AAPS J. 2004;6:M1261.

    Google Scholar 

  35. Sadrzadeh N, Miller DP, Lechuga-Ballesteros D, Harper N, Stevenson CL, Bennett DB. Solid-state stability of spray-dried insulin powder for inhalation: chemical kinetics and structural relaxation modeling of exubera above and below the glass transition temperature. J Pharm Sci. 2010;99:3698–710.

    CAS  PubMed  Google Scholar 

  36. Malcolmson R, De Moor CP, Miller DP, Liang Y, Zhen C, Kim Y, Merchant J, Bennett D, Mazumder MK, Saracovan I, Sekulic S. Physical properties of bulk insulin powder for inhalation. AAPS J. 2004;6:R6169.

    Google Scholar 

  37. Stahl K, Claesson M, Lilliehorn P, Linden H, Backstrom K. The effect of process variables on the degradation and physical properties of spray dried insulin intended for inhalation. Int J Pharm. 2002;233:227–37.

    Article  CAS  PubMed  Google Scholar 

  38. Vehring R, Tep V, Foss WR. Novel experimental method indicates proteins and peptides are protected from high gas temperatures during spray drying. AAPS PharmSci. 2003;5:M1247.

    Google Scholar 

  39. Schuler C, Mao Z, Cameron J. Nektar’s dry-powder durable pulmonary drug delivery system: principles of operation. Proceedings of the 31st International Symposium on Controlled Release of Bioactive Materials, Hawaii; 2004.

    Google Scholar 

  40. Bakshi A, Paboojian A, Rasmussen D, Tuttle D, Snyder H, Clark A, Smith A, Schuler C. Inhale’s dry-powder pulmonary drug delivery system: challenges to current modeling of gas-solid flows. 3rd ASME/JSME Fluids Engineering Conference, San Francisco, CA; 1999.

    Google Scholar 

  41. Gray S, Parker J, deGroot J, Ozawa L, Chwa T, Harper N. Performance robustness characteristics of insulin powder for inhalation using a pneumatic inhalation device. Drug Delivery to the Lungs 15, London, UK; 2004.

    Google Scholar 

  42. Byron PB. Prediction of drug residence times in regions of the human respiratory tract following aerosol inhalation. J Pharm Sci. 1986;75:433–8.

    Article  CAS  PubMed  Google Scholar 

  43. Exubera Product Label, www.accessdata.fda.gov/drugsatfda_docs/label/2008/021868S016S017lbl.pdf.

  44. Kaptiza C, Heise T, Pfutzner A, Steiner S, Heiniemann L, Kave K. Dose-response characteristics for a new pulmonary insulin formulation and inhaler. Diabetologia. 2000;40(Supp 1):A46.

    Google Scholar 

  45. FDA Advisory Committee Meeting, September 5, 2005 slides, http://www.fda.gove/ohrms/dockets/ac/o5/slides/2004-4169S1_00_slide-Index.htm.

  46. Exubera Briefing Document, http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4169B1_01_01-Pfizer-Exubera.pdf

  47. Skyler JS, Jovanovic L, Klioze S, Reis j, Dugan W. Two-year safety and efficacy of inhaled human insulin (Exubera) in adult patients with type 1 diabetes. Diabetes Care. 2007;30:579–85.

    Article  CAS  PubMed  Google Scholar 

  48. Quattrin T, Bélanger A, Bohannon NJ, Schwartz SL. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes results of a 6-month, randomized, comparative trial. Diabetes Care. 2004;27:2622–27.

    Article  CAS  PubMed  Google Scholar 

  49. http://clinicaltrials.gov/show/NCT00734591.

  50. Heinemann L. The failure of exubera: are we beating a dead horse? J Diabetes Sci Technol. 2008;2:518–29.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would like to thank the Exubera® team members within Pfizer, Nektar, and Sanofi-Aventis for their technical inspiration and teamwork.

Author information

Authors and Affiliations

  1. Pharmaceutical Consultants, 100 W. El Camino Real #48, 94040, Mountain View, CA, USA

    Cynthia L. Stevenson & David B. Bennett

Authors
  1. Cynthia L. Stevenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David B. Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cynthia L. Stevenson .

Editor information

Editors and Affiliations

  1. IINFACTS - Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Superior de Ciências da Saúde-Norte, CESPU, Gandra, Portugal

    José das Neves

  2. NEWTherapies Group, INEB – Instituto de Engenharia Biomédica, Porto, Portugal

    Bruno Sarmento

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Stevenson, C., Bennett, D. (2014). Development of the Exubera® Insulin Pulmonary Delivery System. In: das Neves, J., Sarmento, B. (eds) Mucosal Delivery of Biopharmaceuticals. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-9524-6_21

Download citation

Publish with us

Policies and ethics

Search

Navigation