Log in / Register
Home arrow Health arrow Advances in pulmonary drug delivery


  • • The development of Pulmozyme and Exubera has shown that both local and systemic use of inhaled proteins can be safe and efficacious.
  • • There are a number of opportunities for future success including inhaled antibodies, approaches to address protease-antiprotease imbalances contributing to lung disease, and PEGylated proteins and peptides to improve pharmacokinetics.
  • • Future therapies should concentrate on unmet medical needs and validated targets.
  • • High-efficiency delivery systems are needed with careful consideration of aerosol properties for reproducible delivery to the lung with high deposition efficiency in the alveolar region.
  • • Cost needs to be considered. Advances in protein manufacture and biosimilars to reduce cost will help.


  • 1. Depreter F, Picher C, Amighi K. Inhaled proteins: Challenges and perspectives. International Journal of Pharmaceutics 447: 251-280 (2013).
  • 2. Kane C, O’Neil K, Conk M, Picha K. Inhalation delivery of protein therapeutics. Inflammation & Allergy—Drug Targets 12(2): 81-87 (2013).
  • 3. Patton JS, Byron PR. Inhaling medicines: Delivering drugs to the body through the lungs. Nature Reviews—Drug Discovery 6: 67-74 (2007).
  • 4. Wolff RK. Safety of inhaled proteins for therapeutic use. Journal of Aerosol Medicine 11(4): 197-219 (1998). jam.1998.11.197.
  • 5. McElroy MC, Kirton C, Gliddon D, Wolff RK. Inhaled biopharmaceutical drug development: Non-clinical considerations and case studies. Inhalation Toxicology 5(4): 219-232 (2013).
  • 6. Siekmeier R, Scheuch S. Systemic treatment by inhalation of macromolecules— Principles, problems and examples. Journal of Physiology and Pharmacology 59(Suppl. 6): 53-79 (2008).
  • 7. Ponce R, Abad L, Amaravadi L, Gelzleichter T, Gore E, Green J et al. Immunogenicity of biologically-derived therapeutics: Assessment and interpretation of nonclinical safety studies. Regulatory Toxicology and Pharmacology 54: 164-182 (2009).
  • 8. ICH S6 (R1). Preclinical safety evaluation of biotechnology-derived pharmaceuticals (2011). S6_R1/Step4/S6_R1_Guideline.pdf. Accessed Jan, 2016.
  • 9. Cavagnaro J. The principles of the ICH S6 and the case-by-case approach. In Preclinical Safety Evaluation of Biopharmaceuticals: A Science-Based Approach to Facilitating Clinical Trials, Cavagnaro J, ed. John Wiley & Sons, Hoboken, NJ, pp. 45-65 (2008).
  • 10. Clarke J, Hurst C, Martin P, Vahle J, Ponce R, Mounho B, Heidel S, Andrews L, Reynolds T, Cavagnaro J. Duration of chronic toxicity studies for biotechnology- derived pharmaceuticals: Is 6 months still appropriate? Regulatory Toxicology and Pharmacology 50: 2-22 (2008).
  • 11. Green JD. Pharmaco-toxicological expert report: Pulmozyme™, rhDNase, Genentech, Inc. Human & Experimental Toxicology 13(Suppl.): S1-S42 (1994).
  • 12. Siekmeier R, Scheuch G. Inhaled insulin—Does it become reality? Journal of Physiology and Pharmacology 59(Suppl. 6): 81-113 (2008).
  • 13. Mastrandrea LD. Inhaled insulin: Overview of a novel route of insulin administration. Vascular Health and Risk Management 3(6): 47-58 (2010).
  • 14. Fineberg SE, Kawabata T, Finco-Kent D, Liu C, Krasner A. Antibody response to inhaled insulin in patients with type 1 or type 2 diabetes. Journal of Clinical Endocrinology & Metabolism 90: 3287-3294 (2005).
  • 15. McConnell WR, Finch GL, Elwell MR, Kawabata T, Moutvic R, Shaw M, Stammberger I. Toxicological investigations on inhaled insulin. Society of Toxicology Annual Meeting, San Diego (2006).
  • 16. Vick A, Wolff R, Koester A, Reams R, Deaver D, Heidel S. A 6-month inhalation study to characterize the toxicity, pharmacokinetics, and pharmacodynamics of human insulin inhalation powder (HIIP) in Beagle dogs. Journal of Aerosol Medicine 20: 112-126 (2007).
  • 17. Gopalakrishnan V, Uster P, Cow G, McDonald P. Four week repeat dose inhalation safety of insulin in dogs. Journal of Aerosol Medicine 14: 379-421 (2001).
  • 18. FDA. Pharmacological/toxicological evaluation—Exubera®, NDA 21-868 (2005). ClinPharm-Toxicology.pdf. Accessed Jan, 2016.
  • 19. Greene S, Nikula K, Poulin D, McInally K, Reynolds J. Assessment of long-term nonclinical safety of Technosphere® particles and AFREZZA® inhalation powder. Presented at the Society of Toxicology 52th Annual Meeting, San Antonio, TX (March 10-14, 2013); Toxicological Sciences 132(Suppl. 1): 263 (2013).
  • 20. AFREZZA. Medication guide and instructions for use (2014). http://www.mannkind- Accessed Jan, 2016.
  • 21. Muggenburg BA, Hoover MD, Griffith BP, Haley PJ, Snipes MB, Wolff RK, Yeh HC, Burckart GJ, Mauderly JL. Administration of cyclosporine by inhalation: A feasibility study in beagle dogs. Journal of Aerosol Medicine 3(1): 1-13 (1990).
  • 22. Wang T, Noonberg S, Steigerwalt R, Lynch M, Kovelesky RA, Rodriguez CA, Sprugel K, Turner N. Preclinical safety evaluation of inhaled cyclosporine in propylene glycol. Journal of Aerosol Medicine 20: 417-428 (2007).
  • 23. Niven R, Lynch M, Moutvic R, Gibbs S, Briscoe C, Raff H. Safety and toxicology of cyclosporine in propylene glycol after 9-month aerosol exposure to beagle dogs. Journal of Aerosol Medicine and Pulmonary Drug Delivery 24: 205-212 (2011).
  • 24. Groves S, Galazka M, Johnson B, Corcoran T, Verceles A, Britt E, Todd N, Griffith B, Smaldone GC, Iacono A. Inhaled cyclosporine and pulmonary function in lung transplant recipients. Journal of Aerosol Medicine and Pulmonary Drug Delivery 23: 31-39 (2010).
  • 25. Niven RW, Verret W, Raff H, Corcoran TE, Dilly SG. The challenges of developing an inhaled cyclosporine product for lung transplant patients. Respiratory Drug Delivery 1: 51-60 (2012).
  • 26. Hubbard RC, McElvaney NG, Sellers SE, Healy JT, Czerski DB, Crystal RG. Recombinant DNA-produced alpha 1-antitrypsin administered by aerosol augments lower respiratory tract antineutrophil elastase defenses in individuals with alpha 1-antitrypsin deficiency. Journal of Clinical Investigation 84(4): 1349-1354 (1989).
  • 27. Siekmeier R. Lung deposition of inhaled alpha-1-proteinase inhibitor (alpha 1-P1)— Problems and experience of alpha 1-P1 inhalation therapy in patients with hereditary alpha 1-P1 deficiency and cystic fibrosis. European Journal of Medical Research 15: 164-174 (2010).
  • 28. Kamada. Kamada meets primary endpoint of U.S. Phase 2 study of inhaled alpha-1 antitrypsin for the treatment of alpha-1 antitrypsin deficiency. Accessed Aug 30, 2016.
  • 29. Sabin AB. Immunization against measles by aerosol. Reviews of Infectious Diseases 5: 514-523 (1983).
  • 30. Valdespino-Gomez JL, de Lourdes Garcia-Garcia M, Fernandez-de-Castro J, Henao- Restrepo AM, Bennett J, Sepulveda-Amor J. Measles aerosol vaccination. Current Topics in Microbiology and Immunology 304: 165-193 (2006).
  • 31. Henao-Restrepo AM, Greco M, Laurie X, John O, Aguado T. Measles aerosol vaccine project. Proceedia in Vaccinology 2: 147-150 (2010).
  • 32. WHO. Measles aerosol vaccine project: Report to SAGE (2012). zation/. ../3_MeaslesAerosolVaccineProject-report. Accessed Jan, 2016.
  • 33. Burger JL, Cape SP, Braun CS, McAdams DH, Best JA, Bhagwat P, Pathak P, Rebits LG, Sievers RE. Stabilizing formulations for inhalable powders of live-attenuated measles virus vaccine. Journal of Aerosol Medicine and Pulmonary Drug Delivery 21(1): 25-34 (2008).
  • 34. Lin WH, Griffin DE, Rotab PA, Papania M, Cape SP, Bennett D et al. Successful respiratory immunization with dry powder live-attenuated measles virus vaccine in rhesus macaques. Proceedings of the National Academy of Sciences of the United States of America 108(7): 2987-2992 (2011).
  • 35. Agarkhedkar S, Kulkarni SP, Winston S, Sievers R, Dhere RM, Gunale B, Powell K, Rota PA, Papania M. Safety and immunogenicity of dry powder measles vaccine administered by inhalation: A randomized controlled Phase I clinical trial. Vaccine 32: 6791-6797 (2014).
  • 36. Garrison Jr LP, Bauch CT, Bresnahan BW, Hazlet TK, Kadiyala S, Veenstra DL. Using cost-effectiveness analysis to support research and development portfolio prioritization for product innovations in measles vaccination. Journal of Infectious Diseases 204: S124-S132 (2011).
  • 37. Sweeney TD, Marian M, Achilles M, Bussiere J, Ruppel J, Shoenhoff M, Mrsny RJ. Biopharmaceutics of immunoglobin transport across lung epithelium. In Respiratory Drug Delivery VII, P Byron et al., eds. Serentec Press, Raleigh, NC, pp. 59-66 (2000).
  • 38. Fahy JV, Cockcroft DW, Boulet LP, Wong HH, Deschesnes F, Davis EE, Ruppel J, Su JQ, Adelman DC. Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects. American Journal of Respiratory and Critical Care Medicine 160(3): 1023-1027 (1999).
  • 39. Catley MC, Coote J, Bari M, Tomlinson KL. Monoclonal antibodies for the treatment of asthma. Pharmacology & Therapeutics 132: 333-351 (2011).
  • 40. Moss RB, Milla C, Colombo J, Accurso F, Zeitlin PL, Clancy JP et al. Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: A randomized placebo-controlled phase 2b trial. Human Gene Therapy 18: 726-732 (2007).
  • 41. Zabner J, Ramsey BW, Meeker DP, Aitken ML, Balfour RP, Gibson RL et al. Repeat administration of an adenovirus vector encoding cystic fibrosis transmembrane conductance regulator to the nasal epithelium of patients with cystic fibrosis. Journal of Clinical Investigation 97: 1504-1511 (1996).
  • 42. Harvey BG, Leopold PL, Hackett NR, Grasso TM, Williams PM, Tucker AL et al. Airway epithelial CFTR mRNA expression in cystic fibrosis patients after repetitive administration of a recombinant adenovirus. Journal of Clinical Investigation 104: 1245-1255 (1999).
  • 43. Moss RB, Rodman D, Spencer LT, Aitken ML, Zeitlin PL, Waltz D et al. Repeated adeno-associated virus serotype 2 aerosol-mediated cystic fibrosis transmembrane regulator gene transfer to the lungs of patients with cystic fibrosis: A multicenter, doubleblind, placebo-controlled trial. Chest 125: 509-521 (2004).
  • 44. Griesenbach U, Alton EW. Expert opinion in biological therapy: Update on developments in lung gene transfer. Expert Opinion on Biological Therapy 13: 345-360 (2013).
  • 45. Alton EW, Boyd AC, Cheng SH, Davies JC, Davies LA, Dayan A et al. Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung. Gene Therapy 21(1): 89-95 (2014). Accessed May, 2014.
  • 46. DNA Science Blog: A Checklist for Gene Therapy from the UK Cystic Fibrosis Trial (2014). fibrosis-trial/. Accessed May, 2014.
  • 47. Densmore CL, Orson FM, Xu B, Kinsey BM, Waldrep JC, Hua P et al. Aerosol delivery of robust polyethyleneimine-DNA complexes for gene therapy and genetic immunization. Molecular Therapy 1: 180-188 (2000).
  • 48. Gautam A, Densmore CL, Xu B, Waldrep JC. Enhanced gene expression in mouse lung after PEI-DNA aerosol delivery. Molecular Therapy 2: 63-70 (2000).
  • 49. Gautam A, Densmore CL, Waldrep JC. Pulmonary cytokine responses associated with PEI-DNA aerosol gene therapy. Gene Therapy 8: 254-257 (2001).
  • 50. Gautam A, Densmore CL, Golunski E, Xu B, Waldrep JC. Transgene expression in mouse airway epithelium by aerosol gene therapy with PEI-DNA complexes. Molecular Therapy 3: 551-556 (2001).
  • 51. Densmore CL, Kleinerman ES, Gautam A, Jia S-F, Xu B, Worth LL et al. Growth suppression of established human osteosarcoma lung metastases in mice by aerosol gene therapy with PEI-p53 complexes. Cancer Gene Therapy 8: 619-627 (2001).
  • 52. Densmore CL. Polyethyleneimine-based gene therapy by inhalation. Expert Opinion on Biological Therapy 3: 1083-1092 (2003).
  • 53. FDA. Guidance for industry: Gene therapy clinical trials—Observing subjects for delayed adverse events. FDA, Rockville, MD (2006).
  • 54. Weers JG, Miller DP. Formulation design of dry powders for inhalation. Journal of Pharmaceutical Sciences 104(10): 3259-3288 (2015).
  • 55. Sakagami M. Systemic delivery of biotherapeutics through the lung: Opportunities and challenges for improved lung absorption. Therapeutic Delivery 4(12): 1511-1525
  • (2013) .
  • 56. Lechuga-Ballesteros D, Miller DP. Advances in respiratory and nasal drug delivery. Molecular Pharmaceutics 12(8): 2561 (2015).
  • 57. Muralidharan P, Mallory E, Malapit M, Hayes Jr D, Mansour HM. Inhalable PEGylated phospholipid nanocarriers and PEGylated therapeutics for respiratory delivery as aerosolized colloidal dispersions and dry powder inhalers. Pharmaceutics 6: 333-353
  • (2014) .
  • 58. DeGeorge J, Ahn CH, Andrews PA, Brower ME, Choi YS, Chun MY et al. Considerations for toxicology studies of respiratory drug products. Regulatory Toxicology and Pharmacology 25: 189-193 (1997).
  • 59. FDA. Draft guidance for industry and staff: Nonclinical evaluation of reformulated drug products and products intended for administration by an alternate route (2008). guidances/ucm079245.pdf+&cd=1&hl=en&ct=clnk&gl=us. Accessed Jan, 2016.
  • 60. Working PK, Newman MS, Johnson J, Cornacoff JB. Safety of poly(ethylene glycol) and poly(ethylene glycol) derivatives. In Poly(Ethylene Glycol): Chemistry and Biological Applications, Harris M, Zalipsky S, eds. Division of Polymer Chemistry Symposium, 213th National Meeting of the ACS, San Francisco, CA (April 13-17, 1997). American Chemical Society (ACS), Washington, DC, pp. 45-57 (1998) (ACS Symposium Series, No. 680).
  • 61. Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs 22(5): 315-329 (2008).
  • 62. Gursahani H, Riggs-Sauthier J, Pfeiffer J, Lechuga-Ballesteros D, Fishburn CS. Absorption of polyethylene glycol (PEG) polymers: The effect of PEG size on permeability. Journal of Pharmaceutical Sciences 98(8): 2847-2856 (2009).
Found a mistake? Please highlight the word and press Shift + Enter  
< Prev   CONTENTS   Next >
Business & Finance
Computer Science
Language & Literature
Political science