Skip to main content
SpringerLink
Log in

Technosphere®: An Inhalation System for Pulmonary Delivery of Biopharmaceuticals

  • Chapter
  • First Online:
Mucosal Delivery of Biopharmaceuticals

Abstract

Technosphere® is an innovative technology developed by MannKind Corporation for drug delivery through the pulmonary route. Mainly composed of an inert excipient, fumaryl diketopiperazine, the microparticles rapidly dissolve in the lung lining fluid, permitting a rapid drug release and providing a fast onset of action. Additionally, the excipient is also rapidly cleared from the lung and excreted in urine, thus contributing for the safety profile of the system. Several drugs are currently being tested using this technology, with insulin and glucagon-like peptide 1 being in clinical trials. In this chapter, the characteristics and abilities of Technosphere® will be fully presented, the capacity to act as inhalable drug carrier examined and the safety profile analyzed. Additionally, interesting studies regarding the patients and physicians perceptions will be described. As a whole, it is intended to provide a comprehensive view of Technosphere® properties and achievements, identifying possible limitations still to overcome.

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. Siekmeier R, Scheuch G. Inhaled insulin—does it become reality? J Physiol Pharmacol. 2008;59(Supp 6):81–113.

    PubMed  Google Scholar 

  2. Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392(1–2):1–19.

    Article  CAS  PubMed  Google Scholar 

  3. Grenha A, Al-Qadi S, Seijo B, Remuñán-López C. The C potential of chitosan for pulmonary drug delivery. J Drug Deliv Sci Technol. 2010;20(1):33–43.

    CAS  Google Scholar 

  4. Almeida AJ, Souto E. Solid lipid nanoparticles as a drug delivery system for peptides and proteins. Adv Drug Deliv Rev. 2007;59(6):478–90.

    Article  CAS  PubMed  Google Scholar 

  5. Ungaro F, d’Angelo I, Miro A, La Rotonda MI, Quaglia F. Engineered PLGA nano- and micro-carriers for pulmonary delivery: challenges and promises. J Pharm Pharmacol. 2012;64(9):1217–35.

    Article  CAS  PubMed  Google Scholar 

  6. Potocka E, Cassidy J, Haworth P, Heuman D, van Marle S, Baughman JR. Pharmacokinetic characterization of the novel pulmonary delivery excipient fumaryl diketopiperazine. J Diabetes Sci Technol. 2010;4(5):1164–73.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Cassidy J, Amin N, Marino M, Gotfried M, Meyer T, Sommerer K, Baughman R. Insulin lung deposition and clearance following Technosphere® insulin inhalation powder administration. Pharm Res. 2011;28(9):2157–64.

    Article  CAS  PubMed  Google Scholar 

  8. Feldstein R, Glass J, Steiner S, Self assembling diketopiperazine drug delivery system. United States Patent 5352461 A, 1994.

    Google Scholar 

  9. Steiner S, Feldstein R, Lian H, Rhodes C, Shen G, Microparticles for lung delivery comprising diketopiperazine. United States Patent 6071497 A, 2000.

    Google Scholar 

  10. Cornacchia C, Cacciatore I, Baldassarre L, Mollica A, Feliciani F, Pinnen F. 2,5-Diketopiperazines as neuroprotective agents. Mini Rev Med Chem. 2012;12:2–12.

    Article  CAS  PubMed  Google Scholar 

  11. Martins MB, Carvalho I. Diketopiperazines: biological activity and synthesis. Tetrahedron. 2007;63(40):9923–32.

    Article  CAS  Google Scholar 

  12. Bergeron RJ, Phanstiel O, Yao GW, Milstein S, Weimar WR. Macromolecular self-assembly of diketopiperazine tetrapeptides. J Am Chem Soc. 1994;116(19):8479–84.

    Article  CAS  Google Scholar 

  13. Luo T-JM, Palmore GTR. Influence of structure on the kinetics of assembly of cyclic dipeptides into supramolecular tapes. J Phys Org Chem. 2000;13(12):870–9.

    Article  CAS  Google Scholar 

  14. Kaur N, Zhou B, Breitbeil F, Hardy K, Kraft KS, Trantcheva I, Phanstiel O IV. A delineation of diketopiperazine self-assembly processes: Understanding the molecular events involved in Nϵ-(fumaroyl)diketopiperazine of l-Lys (FDKP) interactions. Mol Pharm. 2008;5(2):294–315.

    Article  CAS  PubMed  Google Scholar 

  15. Neumiller J, Campbell R. Technosphere insulin: an inhaled prandial insulin product. Biodrugs. 2010;24(3);165–72.

    Article  CAS  PubMed  Google Scholar 

  16. Leone-Bay A, Baughman R, Smutney C, Kocinsky J. Innovation in drug delivery by inhalation. OnDrugDelivery Magazine. 2010;4–8. Available at www.ondrugdelivery.com.

  17. Neumiller J, Campbell R, Wood L. A review of inhaled Technosphere insulin. Ann Pharmacother. 2010;44:1231–9.

    Article  CAS  PubMed  Google Scholar 

  18. Leone-Bay A, Grant M, Greene S, Stowell G, Daniels S, Smithson A, Villanueva S, Cope S, Carrera K, Reyes S, Richardson P. Evaluation of novel particles as an inhalation system for GLP-1. Diabetes Obes Metab. 2009;11(11):1050–9.

    Article  CAS  PubMed  Google Scholar 

  19. Angelo R, Rousseau K, Grant M, Leone-Bay A, Richardson P. Technosphere® insulin: defining the role of technosphere particles at the cellular level. J Diabetes Sci Technol. 2009;3(3):545–54.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Leone-Bay A, Smutney C, Kocinsky J. Pulmonary drug delivery—simplified. OnDrugDelivery Magazine. 2011;18–21. Available at www.ondrugdelivery.com.

  21. Boss AH, Petrucci R, Lorber D. Coverage of prandial insulin requirements by means of an ultra-rapid acting inhaled insulin. J Diabetes Sci Technol. 2012;6(4):773–9.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Walters DV. Lung lining liquid—the hidden depths. Neonatology. 2002;81(Suppl. 1):2–5.

    CAS  Google Scholar 

  23. Kyle H, Ward J, Widdicombe J. Control of pH of airway surface liquid of the ferret trachea in vitro. J Appl Physiol. 1990;68:135–40.

    CAS  PubMed  Google Scholar 

  24. Steiner S, Pfützner A, Wilson B, Harzer O, Heinemann L, Rave K. Technosphere™/insulin—proof of concept study with a new insulin formulation for pulmonary delivery. Exp Clin Endocrinol Diabetes. 2002;110(1):17–21.

    Article  CAS  PubMed  Google Scholar 

  25. Rave K, Heise T, Heinemann L, Boss A. Inhaled Technosphere® insulin in comparison to subcutaneous regular human insulin: time action profile and variability in subjects with type 2 diabetes. J Diabetes Sci Technol. 2008;2(2):205–12.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Lian H, Steiner SS, Sofia RD, Woodhead JH, Wolf HH, White HS, Shen GS, Rhodes CA, McCabe RT. A self-complementary, self-assembling microsphere system: application for intravenous delivery of the antiepileptic and neuroprotectant compound felbamate. J Pharm Sci. 2000;89(7):867–75.

    Article  CAS  PubMed  Google Scholar 

  27. Pfützner A, Flacke F, Pohl R, Linkie D, Engelbach M, Woods R, Forst T, Beyer J, Steiner S. Pilot study with Technosphere/PTH(1–34)—a new approach for effective pulmonary delivery of parathyroid hormone (1–34). Horm Metab Res. 2003;35:319–23

    Article  Google Scholar 

  28. Steiner S, Gelber C, Feldstein R, Pohl R, Compositions for treatment or prevention of bioterrorism, United States Patent 20040018152 A1, 2006.

    Google Scholar 

  29. Hoyer H, Perera G, Bernkop-Schnürch A. Noninvasive delivery systems for peptides and proteins in osteoporosis therapy: a retroperspective. Drug Dev Ind Pharm. 2010;36(1):31–44.

    Article  CAS  PubMed  Google Scholar 

  30. Toulis K, Anastasilakis A, Polyzos S, Makras P. Targeting the osteoblast: approved and experimental anabolic agents for the treatment of osteoporosis. Hormones. 2011;10(3):174–95.

    Article  PubMed  Google Scholar 

  31. Lim V, Clarke BL. New therapeutic targets for osteoporosis: beyond denosumab. Maturitas. 2012;73(3):269–72.

    Article  CAS  PubMed  Google Scholar 

  32. Ahrén B, Holst JJ, Mari A. Characterization of GLP-1 effects on β-cell function after meal ingestion in humans. Diabetes Care. 2003;26(10):2860–4.

    Article  PubMed  Google Scholar 

  33. Yusta B, Baggio LL, Estall JL, Koehler JA, Holland DP, Li H, Pipeleers D, Ling Z, Drucker DJ. GLP-1 receptor activation improves β cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 2006;4:391–406.

    Article  CAS  PubMed  Google Scholar 

  34. D’Alessio DA, Vahl TP. Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes. Am J Physiol Endocrinol Metab. 2004;286(6):E882–90.

    Article  Google Scholar 

  35. Vilsbøll T, Agersø H, Krarup T, Holst JJ. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. J Clin Endocrinol Metab. 2003;88(1):220–4.

    Article  PubMed  Google Scholar 

  36. Marino M, Costello D, Baughman R, Boss A, Cassidy J, Damico C, van Marle S, van Vliet A, Richardson P. Pharmacokinetics and pharmacodynamics of inhaled GLP-1 (MKC253): proof-of-concept studies in healthy normal volunteers and in patients with type 2 diabetes. Clin Pharmacol Ther. 2010;88(2):243–50.

    Article  CAS  PubMed  Google Scholar 

  37. Hellström PM, Smithson A, Stowell G, Greene S, Kenny E, Damico C, Leone-Bay A, Baughman R, Grant M, Richardson P. Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat. Regul Pept. 2012;179(1–3):71–6.

    Article  PubMed  Google Scholar 

  38. Hellström PM, Hein J, Bytzer P, Björnssön E, Kristensen J, Schambye H. Clinical trial: the glucagon-like peptide-1 analogue ROSE-010 for management of acute pain in patients with irritable bowel syndrome: a randomized, placebo-controlled, double-blind study. Aliment Pharmacol Ther. 2009;29(2):198–206.

    Article  PubMed  Google Scholar 

  39. MannKind. 2013-06-20;http://www.mannkindcorp.com/.

  40. Rave K, Heise T, Pfützner A, Boss AH. Coverage of postprandial blood glucose excursions with inhaled Technosphere insulin in comparison to subcutaneously injected regular human insulin in subjects with type 2 diabetes. Diabetes Care. 2007;30(9):2307–8.

    Article  CAS  PubMed  Google Scholar 

  41. Rave K, Potocka E, Boss AH, Marino M, Costello D, Chen R. Pharmacokinetics and linear exposure of AFRESA™ compared with the subcutaneous injection of regular human insulin. Diabetes Obes Metab. 2009;11(7):715–20.

    Article  CAS  Google Scholar 

  42. Mandal T. Inhaled insulin for diabetes mellitus. Am J Health Syst Pharm. 2005;62:1359–64.

    Article  CAS  PubMed  Google Scholar 

  43. Potocka E, Amin N, Cassidy J, Schwartz S, Gray M, Richardson P, Baughman R. Insulin pharmacokinetics following dosing with Technosphere insulin in subjects with chronic obstructive pulmonary disease. Curr Med Res Opin. 2010;26(10):2347–53.

    Article  CAS  PubMed  Google Scholar 

  44. Potocka E, Baughman RA, Derendorf H. Population pharmacokinetic model of human insulin following different routes of administration. J Clin Pharmacol. 2011;51(7):1015–24.

    Article  CAS  PubMed  Google Scholar 

  45. Heise T, Brugger A, Cook C, Eckers U, Hutchcraft A, Nosek L, Rave K, Troeger J, Valaitis P, White S, Heinemann L. PROMAXX® inhaled insulin: safe and efficacious administration with a commercially available dry powder inhaler. Diabetes Obes Metab. 2009;11(5):455–9.

    Article  CAS  PubMed  Google Scholar 

  46. Perera AD, Kapitza C, Nosek L, Fishman RS, Shapiro DA, Heise T, Heinemann L. Absorption and metabolic effect of inhaled insulin: intrapatient variability after inhalation via the Aerodose insulin inhaler in patients with type 2 diabetes. Diabetes Care. 2002;25(12):2276–81.

    Article  CAS  PubMed  Google Scholar 

  47. Kim D, Mudaliar S, Chinnapongse S, Chu N, Boies SM, Davis T, Perera AD, Fishman RS, Shapiro DA, Henry R. Dose-response relationships of inhaled insulin delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes. Diabetes Care. 2003;26(10):2842–7.

    Article  CAS  PubMed  Google Scholar 

  48. Rave K, Bott S, Heinemann L, Sha S, Becker RHA, Willavize SA, Heise T. Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin. Diabetes Care. 2005;28(5):1077–82.

    Article  CAS  PubMed  Google Scholar 

  49. Heinemann L. New ways of insulin delivery. Int J Clin Pract. 2010;64(Suppl 166):29–40.

    Article  Google Scholar 

  50. Pfützner A, Mann A, Steiner SS. Technosphere™/insulin—a new approach for effective delivery of human insulin via the pulmonary route. Diabetes Technol Ther. 2002;4(5):589–94.

    Article  PubMed  Google Scholar 

  51. Rosenstock J, Lorber DL, Gnudi L, Howard CP, Bilheimer DW, Chang PC, Petrucci RE, Boss AH, Richardson PC. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. Lancet. 2010;375(9733):2244–53.

    Article  CAS  PubMed  Google Scholar 

  52. Zisser H, Jovanovic L, Markova K, Petrucci R, Boss A, Richardson P, Mann A. Technosphere insulin effectively controls postprandial glycemia in patients with type 2 diabetes mellitus. Diabetes Technol Ther. 2012;14(11):997–1001.

    Article  CAS  PubMed  Google Scholar 

  53. Rosenstock J, Bergenstal R, DeFronzo RA, Hirsch IB, Klonoff D, Boss AH, Kramer D, Petrucci R, Yu W, Levy B. Efficacy and safety of Technosphere inhaled insulin compared with Technosphere powder placebo in insulin-naive type 2 diabetes suboptimally controlled with oral agents. Diabetes Care. 2008;31(11):2177–82.

    Article  CAS  PubMed  Google Scholar 

  54. Pfützner A, Forst T. Pulmonary insulin delivery by means of the Technosphere™ drug carrier mechanism. Expert Opin Drug Deliv. 2005;2(6):1097–106.

    Article  PubMed  Google Scholar 

  55. Tack C, Christov V, de Galan B, Derwahl K-M, Klausmann G, Pelikánová T, Perušičová J, Boss A, Amin N, Kramer D, Petrucci R, Yu W. Randomized forced titration to different doses of Technosphere® insulin demonstrates reduction in postprandial glucose excursions and hemoglobin A1c in patients with type 2 diabetes. J Diabetes Sci Technol. 2008;2(1):47–57.

    Article  PubMed Central  PubMed  Google Scholar 

  56. Raskin P, Heller S, Honka M, Chang PC, Boss AH, Richardson PC, Amin N. Pulmonary function over 2 years in diabetic patients treated with prandial inhaled Technosphere insulin or usual antidiabetes treatment: a randomized trial. Diabetes Obes Metab. 2012;4(2):163–73.

    Article  Google Scholar 

  57. Smutney C, Friedman E, Polidoro J, Amin N. Inspiratory efforts achieved in use of the Technosphere® insulin inhalation system. J Diabetes Sci Technol. 2009;3(5):1175–82.

    Article  PubMed Central  PubMed  Google Scholar 

  58. Kling J. Dreamboat sinks prospects for fast approval of inhaled insulin. Nat Biotech. 2011;29(3):175–6.

    Article  CAS  Google Scholar 

  59. Heinemann L. The failure of Exubera: are we beating a dead horse? J Diabetes Sci Technol. 2008;2(3):518–29.

    Article  PubMed Central  PubMed  Google Scholar 

  60. Rubin R, Peyrot M. Factors associated with physician perceptions of and willingness to recommend inhaled insulin. Curr Med Res Opin. 2011;27(2):285–94.

    Article  CAS  PubMed  Google Scholar 

  61. Rubin R, Peyrot M. Psychometric properties of an instrument for assessing the experience of patients treated with inhaled insulin: the Inhaled Insulin Treatment Questionnaire (IITQ). Health Qual Life Outcomes. 2010;8(1):32.

    Article  PubMed Central  PubMed  Google Scholar 

  62. Peyrot M, Rubin R. Effect of Technosphere inhaled insulin on quality of life and treatment satisfaction. Diabetes Technol Ther. 2010;12(1):49–55.

    Article  PubMed  Google Scholar 

  63. Peyrot M, Rubin R. Patient-reported outcomes in adults with type 2 diabetes using mealtime inhaled Technosphere insulin and basal insulin versus premixed insulin. Diabetes Technol Ther. 2011;13(12):1201–6.

    Article  CAS  PubMed  Google Scholar 

  64. Peyrot M, Rubin R. Perceived medication benefits and their association with interest in using insulin type 2 diabetes: a model of patients’ cognitive framework. Patient Prefer Adherence. 2011;5:255–65.

    Article  PubMed Central  PubMed  Google Scholar 

  65. Setter SM, Levien TL, Iltz JL, Odegard PS, Neumiller JJ, Baker DE, Campbell RK. Inhaled dry powder insulin for the treatment of diabetes mellitus. Clin Ther. 2007;29(5):795–813.

    Article  CAS  PubMed  Google Scholar 

  66. Brunton S. Insulin delivery systems: reducing barriers to insulin therapy and advancing diabetes mellitus treatment. Am Med. 2008;121(Suppl 6):35–41.

    Article  Google Scholar 

  67. Bailey CJ, Barnett AH. Inhaled insulin: new formulation, new trial. Lancet. 2010;375(9733):2199–201.

    Article  PubMed  Google Scholar 

  68. Hegewald M, Crapo R, Jensen R. Pulmonary function changes related to acute and chronic administration of inhaled insulin. Diabetes Technol Ther. 2007;9(Suppl 1):S. 93–101.

    Google Scholar 

  69. Lasagna-Reeves CA, Clos AL, Midoro-Hiriuti T, Goldblum RM, Jackson GR, Kayed R. Inhaled insulin forms toxic pulmonary amyloid aggregates. Endocrinology. 2010;151(10):4717–24.

    Article  CAS  PubMed  Google Scholar 

  70. Richardson P, Boss A. Technosphere insulin technology. Diabetes Technol Ther. 2007;9(Suppl 1):65–72.

    Google Scholar 

  71. Sarala N, Bengalorkas G, Bhuvana K. Technosphere: new drug delivery system for inhaled insulin. Pract Diabetes. 2012;29:23–4.

    Article  Google Scholar 

  72. Depreter F, Pilcer G, Amighi K. Inhaled proteins: challenges and perspectives. Int J Pharm. 2013;447(1–2):251–80.

    Article  CAS  PubMed  Google Scholar 

  73. Videira M, Botelho MF, Santos AC, Gouveia LF, Pedroso de Lima JJ, Almeida AJ. Lymphatic uptake of pulmonary delivered radiolabelled solid lipid nanoparticles. J Drug Target. 2002;10:607–13.

    Article  CAS  PubMed  Google Scholar 

  74. Al-Qadi S, Grenha A, Carrión-Recio D, Seijo B, Remuñán-López C. Microencapsulated chitosan nanoparticles for pulmonary protein delivery: in vivo evaluation of insulin-loaded formulations. J Control Release. 2012;157:383–90.

    Article  CAS  PubMed  Google Scholar 

  75. Poyner EA, Alpar HO, Almeida AJ, Gamble MD, Brown MRW. A comparative study on the pulmonary delivery of tobramycin encapsulated into liposomes and PLA microspheres following intravenous and endotracheal delivery. J Control Release. 1995;(31):41–8.

    Article  Google Scholar 

  76. International Conference on Harmonisation, Guideline ICH S7A, Safety pharmacology studies for human pharmaceuticals, 2000.

    Google Scholar 

  77. European Medicines Agency, EMEA/CHMP/QWP/396951/2006, Guideline on excipients in the dossier for application for marketing authorisation of a medicinal product; 2006

    Google Scholar 

  78. Food and Drug Administration, Guidance for industry: nonclinical studies for the safety evaluation of pharmaceutical excipients; 2005.

    Google Scholar 

Download references

Acknowledgments

The authors acknowledge the Portuguese government (Fundação para a Ciência e Tecnologia) and FEDER: research project PTDC/SAU-FCF/100291/2008, PTDC/DTP-FTO/0094/2012 and strategic projects PEst-OE/SAU/UI4013/2011 and PEst-OE/EQB/LA0023/2013.

Author information

Authors and Affiliations

  1. iMed.UL, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

    António J. Almeida

  2. CBME—Centre for Molecular and Structural Biomedicine/IBB—Institute for Biotechnology and Bioengineering, Faculty of Sciences and Technology, University of Algarve, Campus de Gambelas, 8005–139, Faro, Portugal

    Ana Grenha

Authors
  1. António J. Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Grenha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ana Grenha .

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

Almeida, A., Grenha, A. (2014). Technosphere®: An Inhalation System for Pulmonary Delivery of Biopharmaceuticals. In: das Neves, J., Sarmento, B. (eds) Mucosal Delivery of Biopharmaceuticals. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-9524-6_22

Download citation

Publish with us

Policies and ethics

Search

Navigation