Skip to main content

Insulin Lung Deposition and Clearance Following Technosphere® Insulin Inhalation Powder Administration

ABSTRACT

Purpose

To determine distribution and deposition of Technosphere® Insulin (TI) inhalation powder and the rate of clearance of fumaryl diketopiperazine (FDKP; major component of Technosphere particles) and insulin from the lungs.

Methods

Deposition and distribution of 99mpertechnetate adsorbed onto TI immediately after administration using the MedTone® inhaler was quantified by gamma-scintigraphy. Clearance from the lungs was studied in a second experiment by serial bronchoalveolar lavage (BAL) after administration of TI inhalation powder and assay of the recovered fluid for FDKP and insulin.

Results

Following inhalation, ~60% of radioactivity (adsorbed on TI) emitted from the inhaler was delivered to the lungs; the remainder of the emitted dose was swallowed. Clearance from the lung epithelial lining fluid (ELF) of FDKP and insulin have a half-life of ~1 hour.

Conclusion

TI inhalation powder administered via the MedTone inhaler was uniformly distributed throughout the lungs; ~40% of the initial cartridge load reached the lungs. Insulin and FDKP are quickly cleared from the lungs, mainly by absorption into the systemic circulation. The terminal clearance half-life from the lung ELF, estimated from sequential BAL fluid measurements for both components, was ~1 hour. Since there is an overnight washout period, the potential for accumulation on chronic administration is minimal.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

Tc:

99mTechnetium

AUC0–t :

area under the insulin concentration-time curve from 0 to time t

BAL:

bronchoalveolar lavage

ELF:

epithelial lining fluid of the lungs

FDKP:

fumaryl diketopiperazine

FEV1 :

forced expiratory volume in 1 s

IVC:

inspiratory vital capacity

MEF25%FVC :

mid-expiratory flow at 25% of forced vital capacity

MEF50%FVC :

mid-expiratory flow at 50% of forced vital capacity

MEF75%FVC :

mid-expiratory flow at 75% of forced vital capacity

PFT:

pulmonary function testing

sRAW :

specific airway resistance

T:

total amount of radioactivity in the cartridge

TI:

Technosphere Insulin

tmax :

time to maximum observed drug concentration

Tndel :

total amount of 99mTc-TI inhalation powder that is not delivered to the body

REFERENCES

  1. 1.

    Leone-Bay A, Grant M. Technosphere technology: a platform for inhaled protein therapeutics. ONdrugDelivery. 2006:11–18. Available from: www.Ondrugdelivery.com.

  2. 2.

    Richardson PC, Boss AH. Technosphere® Insulin technology. Diab Technol Ther. 2007;9 Suppl 1:S65–72.

    CAS  Google Scholar 

  3. 3.

    United States Pharmacopeia–National Formulary (USP–NF). Aerosols, Nasal Sprays, Metered-Dose Inhalers, and Dry Powder Inhalers <601>. The United States Pharmacopeia USP 29; The National Formulary NF 24 through First Supplement. Rockville, MD: U.S.P.C. Inc.

  4. 4.

    Dunbar C, Scheuch G, Sommerer K, DeLong M, Verma A, Batycky R. In vitro and in vivo dose delivery characteristics of large porous particles for inhalation. Int J Pharm. 2002;245(1–2):179–89.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    American Thoracic Society. Standardization of spirometry, 1994 update. Am J Respir Crit Care Med. 1995;152:1107–36.

    Google Scholar 

  6. 6.

    Rennard S, Basset G, Lecossier D, O’Donnell K, Pinkston P, Martin P, et al. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol. 1986;60(2):532–8.

    PubMed  CAS  Google Scholar 

  7. 7.

    Gotfried M, Danzinger L, Rodvold K. Steady-state plasma and intrapulmonary concentrations of leofloxin and ciprofloxin in healthy human subjects. Chest. 2001;119(4):1114–22.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Pfützner A, Sommerer K, Meyer T, Haussermann S, Flacke F, Steiner S, et al. Lung distribution of radiolabeled Technosphere/Insulin. Diabetes. 2003;52 Suppl 1:A107 [abstract 459-P].

    Google Scholar 

  9. 9.

    Cassidy J, Marino M, Amin N, Gotfried M, Baughman R, Gray M, et al. Lung deposition and absorption of AFRESA (Technosphere Insulin) [abstract 433-P]. Diabetes. 2009;58 Suppl 1:A115.

    Google Scholar 

  10. 10.

    Gotfried M, Cassidy J, Marino M, Amin N, Baughman R, Gray M, et al. Lung deposition and absorption of insulin from Technosphere insulin [abstract 955]. Diabetologia. 2009;52 Suppl 1:S375.

    Google Scholar 

  11. 11.

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

    Google Scholar 

  12. 12.

    Okamoto H, Todo H, Iida K, Danjo K. Dry powders for pulmonary delivery of peptides and proteins. Inhaled Insulin: Lung Deposition and Clearance. 2002;20:71–82.

    CAS  Google Scholar 

  13. 13.

    Smutney CC, Friedman EM, Polidoro JM, Amin N. Inspiratory efforts achieved in use of the Technosphere® Insulin inhalation system. J Diab Sci Technol. 2009;3(5):1–8.

    Google Scholar 

  14. 14.

    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. Diab Obes Metab. 2009;11(7):715–20.

    Article  CAS  Google Scholar 

  15. 15.

    Muchmore D, Silverman B, de la Pena A, Tobin J. The AIR® inhaled insulin system: system components and pharmacokinetics/glucodynamic data. Diab Technol Ther. 2007;9 Suppl 1:S41–7.

    CAS  Google Scholar 

  16. 16.

    Rave K, Bott S, Heineman L, Sha S, Becker R, Willaviza S, et al. Time action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin. Diabetes Care. 2005;28(5):1077–82.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Brain J, Finch G, Riese R, Schwartz P, Teeter J. Trough insulin levels in bronchoalveolar lavage following inhalation of human insulin (Exubera®) in patients with diabetes mellitus [abstract A53]. Am J Resp Crit Care Med. 2008;177:A616.

    Google Scholar 

  18. 18.

    Lombry C, Edwards D, Preat V, Vanbever R. Alveolar macrophages are a primary barrier to pulmonary absorption of macromolecules. Am J Physiol Lung Cell Mol Physiol. 2004;286(5):L1002–8.

    PubMed  Article  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS

The authors extend their appreciation to Dr. Andreas Pfützner, University of Applied Sciences, Bingen, Germany, the principal investigator, and the staff at Inamed, Gauting, Germany, for the excellent conduct of the radiolabeled study; the research coordinators at Pulmonary Associates, Phoenix, AZ, USA, and the Endoscopy Department of John C. Lincoln North Mountain Hospital, Phoenix, AZ, USA, for conducting a quality bronchoscopy study; and the staffs at BARC, Lake Success, NY, USA (serum insulin), and QPS, Newark, DE, USA (serum and BAL FDKP and BAL insulin), for their excellent bioanalytical analysis of the samples; and Sungita Patel, who excelled as the clinical monitor for the BAL study.

Author information

Affiliations

Authors

Corresponding author

Correspondence to James P. Cassidy.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cassidy, J.P., Amin, N., Marino, M. et al. Insulin Lung Deposition and Clearance Following Technosphere® Insulin Inhalation Powder Administration. Pharm Res 28, 2157–2164 (2011). https://doi.org/10.1007/s11095-011-0443-4

Download citation

KEY WORDS

  • Afrezza®
  • fumaryl diketopiperazine
  • inhalation powder
  • insulin clearance
  • insulin lung disposition
  • Technosphere Insulin inhalation powder