Advertisement

Respiratory Drug/Vaccine Delivery Using Nanoparticles

  • Joanne M. Ramsey
  • Alice McCloskey
  • Rachel Gaul
  • Elena Fernandez Fernandez
  • Louise Sweeney
  • Catherine M. Greene
  • Ronan Macloughlin
  • Sally-Ann CryanEmail author
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 41)

Abstract

Respiratory diseases account for a very significant portion of worldwide morbidity and mortality but to-date only a limited number of therapeutics are available for direct delivery via inhalation. Nanotechnology offers a range of potential benefits to facilitate the targeted delivery/co-delivery of existing therapeutic agents and to support the delivery of more advanced biotherapeutics e.g. proteins, gene medicines. The clinical and commercial translation of inhalable nanomedicines is not trivial and presents significant formulation, manufacturing, assessment and regulatory challenges. Herein, we explore the range of respiratory diseases being targeted using nanoparticle-based delivery systems for therapeutics and vaccines, the composition and manufacture of these nanoparticles, their integration into relevant inhaler devices, the methods being used to characterize these nanoparticles in vitro and in vivo and the regulatory requirements governing inhaled nanomedicines.

Keywords

Respiratory drug delivery Nanoparticles Nanomedicine Therapeutics Vaccines Inhalation Aerosol 

References

  1. 1.
    Dufort S, Bianchi A, Henry M, Lux F, Le Duc G, Josserand V, et al. Nebulized gadolinium-based nanoparticles: a theranostic approach for lung tumor imaging and radiosensitization. Small. 2015;11(2):215–21.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Elhissi A, Hidayat K, Phoenix DA, Mwesigwa E, Crean S, Ahmed W, et al. Air-jet and vibrating-mesh nebulization of niosomes generated using a particulate-based proniosome technology. Int J Pharm. 2013;444(1–2):193–9.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Porsio B, Cusimano MG, Schillaci D, Craparo EF, Giammona G, Cavallaro G. Nano into micro formulations of tobramycin for the treatment of Pseudomonas aeruginosa infections in cystic fibrosis. Biomacromolecules. 2017;18(12):3924–35.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Silva AS, Sousa AM, Cabral RP, Silva MC, Costa C, Miguel SP, et al. Aerosolizable gold nano-in-micro dry powder formulations for theragnosis and lung delivery. Int J Pharm. 2017;519(1–2):240–9.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Vencken S, Foged C, Ramsey JM, Sweeney L, Cryan SA, MacLoughlin RJ, et al. Nebulised lipid-polymer hybrid nanoparticles for the delivery of a therapeutic anti-inflammatory microRNA to bronchial epithelial cells. ERJ Open Res. 2019;5(2)Google Scholar
  6. 6.
    Park CW, Li X, Vogt FG, Hayes D Jr, Zwischenberger JB, Park ES, et al. Advanced spray-dried design, physicochemical characterization, and aerosol dispersion performance of vancomycin and clarithromycin multifunctional controlled release particles for targeted respiratory delivery as dry powder inhalation aerosols. Int J Pharm. 2013;455(1–2):374–92.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Li X, Vogt FG, Hayes D Jr, Mansour HM. Physicochemical characterization and aerosol dispersion performance of organic solution advanced spray-dried microparticulate/nanoparticulate antibiotic dry powders of tobramycin and azithromycin for pulmonary inhalation aerosol delivery. Eur J Pharm Sci. 2014;52:191–205.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sung JC, Padilla DJ, Garcia-Contreras L, Verberkmoes JL, Durbin D, Peloquin CA, et al. Formulation and pharmacokinetics of self-assembled rifampicin nanoparticle systems for pulmonary delivery. Pharm Res. 2009;26(8):1847–55.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Duan J, Vogt FG, Li X, Hayes D Jr, Mansour HM. Design, characterization, and aerosolization of organic solution advanced spray-dried moxifloxacin and ofloxacin dipalmitoylphosphatidylcholine (DPPC) microparticulate/nanoparticulate powders for pulmonary inhalation aerosol delivery. Int J Nanomedicine. 2013;8:3489–505.PubMedPubMedCentralGoogle Scholar
  10. 10.
    El-Gendy N, Pornputtapitak W, Berkland C. Nanoparticle agglomerates of fluticasone propionate in combination with albuterol sulfate as dry powder aerosols. Eur J Pharm Sci. 2011;44(4):522–33.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Bhavna, Ahmad FJ, Mittal G, Jain GK, Malhotra G, Khar RK, et al. Nano-salbutamol dry powder inhalation: a new approach for treating broncho-constrictive conditions. Eur J Pharm Biopharm 2009;71(2):282–291.Google Scholar
  12. 12.
    Berger WE, Noonan MJ. Treatment of persistent asthma with Symbicort (budesonide/formoterol inhalation aerosol): an inhaled corticosteroid and long-acting beta2-adrenergic agonist in one pressurized metered-dose inhaler. J Asthma. 2010;47(4):447–59.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Molimard M, Till D, Stenglein S, Singh D, Krummen M. Inhalation devices for long-acting beta2-agonists: efficiency and ease of use of dry powder formoterol inhalers for use by patients with asthma and COPD. Curr Med Res Opin. 2007;23(10):2405–13.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kuzmov A, Minko T. Nanotechnology approaches for inhalation treatment of lung diseases. J Control Release. 2015;219:500–18.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Garbuzenko OB, Ivanova V, Kholodovych V, Reimer DC, Reuhl KR, Yurkow E, et al. Combinatorial treatment of idiopathic pulmonary fibrosis using nanoparticles with prostaglandin E and siRNA(s). Nanomedicine. 2017;13(6):1983–92.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cova E, Colombo M, Inghilleri S, Morosini M, Miserere S, Penaranda-Avila J, et al. Antibody-engineered nanoparticles selectively inhibit mesenchymal cells isolated from patients with chronic lung allograft dysfunction. Nanomedicine (Lond). 2015;10(1):9–23.CrossRefGoogle Scholar
  17. 17.
    Cova E, Inghilleri S, Pandolfi L, Morosini M, Magni S, Colombo M, et al. Bioengineered gold nanoparticles targeted to mesenchymal cells from patients with bronchiolitis obliterans syndrome does not rise the inflammatory response and can be safely inhaled by rodents. Nanotoxicology. 2017;11(4):534–45.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Machelart A, Salzano G, Li X, Demars A, Debrie AS, Menendez-Miranda M, et al. Intrinsic antibacterial activity of nanoparticles made of beta-Cyclodextrins potentiates their effect as drug Nanocarriers against tuberculosis. ACS Nano. 2019;13(4):3992–4007.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Altenburg AF, van de Sandt CE, Li BW, MacLoughlin RJ, Fouchier RA, van Amerongen G, et al. Modified vaccinia virus Ankara preferentially targets antigen presenting cells in vitro, ex vivo and in vivo. Sci Rep. 2017;7(1):8580.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Holzer B, Morgan SB, Matsuoka Y, Edmans M, Salguero FJ, Everett H, et al. Comparison of Heterosubtypic protection in ferrets and pigs induced by a single-cycle influenza vaccine. J Immunol. 2018;200(12):4068–77.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Low N, Bavdekar A, Jeyaseelan L, Hirve S, Ramanathan K, Andrews NJ, et al. A randomized, controlled trial of an aerosolized vaccine against measles. N Engl J Med. 2015;372(16):1519–29.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Meyer M, Garron T, Lubaki NM, Mire CE, Fenton KA, Klages C, et al. Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses. J Clin Invest. 2015;125(8):3241–55.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zhao L, Seth A, Wibowo N, Zhao C-X, Mitter N, Yu C, et al. Nanoparticle vaccines. Vaccine. 2014;32(3):327–37.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Fromen CA, Robbins GR, Shen TW, Kai MP, Ting JP, DeSimone JM. Controlled analysis of nanoparticle charge on mucosal and systemic antibody responses following pulmonary immunization. Proc Natl Acad Sci. 2015;112(2):488–93.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Manolova V, Flace A, Bauer M, Schwarz K, Saudan P, Bachmann MF. Nanoparticles target distinct dendritic cell populations according to their size. Eur J Immunol. 2008;38(5):1404–13.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Li AV, Moon JJ, Abraham W, Suh H, Elkhader J, Seidman MA, et al. Generation of effector memory T cell–based mucosal and systemic immunity with pulmonary nanoparticle vaccination. Sci Transl Med. 2013, 5(204):204ra130–0.Google Scholar
  27. 27.
    Bobo D, Robinson KJ, Islam J, Thurecht KJ, Corrie SR. Nanoparticle-based medicines: a review of FDA-approved materials and clinical trials to date. Pharm Res. 2016;33(10):2373–87.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ragelle H, Danhier F, Préat V, Langer R, Anderson DG. Nanoparticle-based drug delivery systems: a commercial and regulatory outlook as the field matures. Expert Opin Drug Deliv. 2017;14(7):851–64.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sahdev P, Ochyl LJ, Moon JJ. Biomaterials for nanoparticle vaccine delivery systems. Pharm Res. 2014;31(10):2563–82.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Su L, Li R, Khan S, Clanton R, Zhang F, Lin Y-N, et al. Chemical Design of both a glutathione-sensitive Dimeric drug guest and a glucose-derived Nanocarrier host to achieve enhanced osteosarcoma lung metastatic anticancer selectivity. J Am Chem Soc. 2018;140(4):1438–46.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Verma NK, Crosbie-Staunton K, Satti A, Gallagher S, Ryan KB, Doody T, et al. Magnetic core-shell nanoparticles for drug delivery by nebulization. J Nanobiotechnol 2013;11(1):1.Google Scholar
  32. 32.
    Rodrigues TC, Oliveira MLS, Soares-Schanoski A, Chavez-Rico SL, Figueiredo DB, Gonçalves VM, et al. Mucosal immunization with PspA (Pneumococcal surface protein A)-adsorbed nanoparticles targeting the lungs for protection against pneumococcal infection. PLoS One. 2018;13(1):e0191692.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nelli RK, Kuchipudi SV, White GA, Perez BB, Dunham SP, Chang K-C. Comparative distribution of human and avian type sialic acid influenza receptors in the pig. BMC Vet Res. 2010;6(1):4.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Guo X, Zhang X, Ye L, Zhang Y, Ding R, Hao Y, et al. Inhalable microspheres embedding chitosan-coated PLGA nanoparticles for 2-methoxyestradiol. J Drug Target. 2014;22(5):421–7.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Menon JU, Ravikumar P, Pise A, Gyawali D, Hsia CC, Nguyen KT. Polymeric nanoparticles for pulmonary protein and DNA delivery. Acta Biomater. 2014;10(6):2643–52.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Banura N, Murase K. Magnetic particle imaging for aerosol-based magnetic targeting. Jpn J Appl Phys. 2017;56(8):088001.CrossRefGoogle Scholar
  37. 37.
    Dames P, Gleich B, Flemmer A, Hajek K, Seidl N, Wiekhorst F, et al. Targeted delivery of magnetic aerosol droplets to the lung. Nat Nanotechnol. 2007;2(8):495.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bandyopadhyay A, Moitra S. Bio-organic nanoparticles: breaking the barrier in nanoparticle-mediated pulmonary drug delivery. Int J Pulm & Res Sci. 2017;1(4):555568.Google Scholar
  39. 39.
    Zhang J, Wu L, Chan H-K, Watanabe W. Formation, characterization, and fate of inhaled drug nanoparticles. Adv Drug Deliv Rev. 2011;63(6):441–55.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    de Souza CC, Daum N, Lehr C-M. Carrier interactions with the biological barriers of the lung: advanced in vitro models and challenges for pulmonary drug delivery. Adv Drug Deliv Rev. 2014;75:129–40.CrossRefGoogle Scholar
  41. 41.
    Wang W, Zhu R, Xie Q, Li A, Xiao Y, Li K, et al. Enhanced bioavailability and efficiency of curcumin for the treatment of asthma by its formulation in solid lipid nanoparticles. Int J Nanomedicine. 2012;7:3667.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Liu C, Shi J, Dai Q, Yin X, Zhang X, Zheng A. In-vitro and in-vivo evaluation of ciprofloxacin liposomes for pulmonary administration. Drug Dev Ind Pharm. 2015;41(2):272–8.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kelly C, Lawlor C, Burke C, Barlow JW, Ramsey JM, Jefferies C, et al. High-throughput methods for screening liposome-macrophage cell interaction. J Liposome Res. 2015;25(3):211–21.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Patil TS, Deshpande AS. Nanostructured lipid carriers-based drug delivery for treating various lung diseases: a state-of-the-art review. Int J Pharm. 2018;547(1–2):209–25.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Grabowski N, Hillaireau H, Vergnaud J, Santiago LA, Kerdine-Romer S, Pallardy M, et al. Toxicity of surface-modified PLGA nanoparticles toward lung alveolar epithelial cells. Int J Pharm. 2013;454(2):686–94.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Rajitha P, Gopinath D, Biswas R, Sabitha M, Jayakumar R. Chitosan nanoparticles in drug therapy of infectious and inflammatory diseases. Expert Opin Drug Deliv. 2016;13(8):1177–94.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hibbitts A, Lieggi N, McCabe O, Thomas W, Barlow J, O’Brien F, et al. Screening of siRNA nanoparticles for delivery to airway epithelial cells using high-content analysis. Ther Deliv. 2011;2(8):987–99.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Kaminskas LM, McLeod VM, Ryan GM, Kelly BD, Haynes JM, Williamson M, et al. Pulmonary administration of a doxorubicin-conjugated dendrimer enhances drug exposure to lung metastases and improves cancer therapy. J Control Release. 2014;183:18–26.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Garbuzenko OB, Winkler J, Tomassone MS, Minko T. Biodegradable Janus nanoparticles for local pulmonary delivery of hydrophilic and hydrophobic molecules to the lungs. Langmuir. 2014;30(43):12941–9.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Vaidya B, Parvathaneni V, Kulkarni NS, Shukla SK, Damon JK, Sarode A, et al. Cyclodextrin modified erlotinib loaded PLGA nanoparticles for improved therapeutic efficacy against non-small cell lung cancer. Int J Biol Macromol. 2019;122:338–47.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Andrade F, Videira M, Ferreira D, Sarmento B. Micelle-based systems for pulmonary drug delivery and targeting. Drug Deliv Lett. 2011;1(2):171–85.Google Scholar
  52. 52.
    Guthi JS, Yang S-G, Huang G, Li S, Khemtong C, Kessinger CW, et al. MRI-visible micellar nanomedicine for targeted drug delivery to lung cancer cells. Mol Pharm. 2009;7(1):32–40.CrossRefGoogle Scholar
  53. 53.
    Grotz E, Tateosian NL, Salgueiro J, Bernabeu E, Gonzalez L, Manca ML, et al. Pulmonary delivery of rifampicin-loaded soluplus micelles against Mycobacterium tuberculosis. J Drug Deliv Sci Tec. 2019;101170Google Scholar
  54. 54.
    Amani A, York P, Chrystyn H, Clark BJ. Evaluation of a nanoemulsion-based formulation for respiratory delivery of budesonide by nebulizers. AAPS PharmSciTech. 2010;11(3):1147–51.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Arbain NH, Salim N, Masoumi HRF, Wong TW, Basri M, Rahman MBA. In vitro evaluation of the inhalable quercetin loaded nanoemulsion for pulmonary delivery. Drug Deliv Transl Res. 2019;9(2):497–507.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Chiang P-C, Alsup JW, Lai Y, Hu Y, Heyde BR, Tung D. Evaluation of aerosol delivery of nanosuspension for pre-clinical pulmonary drug delivery. Nanoscale Res Lett. 2009;4(3):254.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm. 2010;392(1–2):1–19.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Mukherjee A, Paul M, Mukherjee S. Recent Progress in the Theranostics application of Nanomedicine in lung Cancer. Cancers (Basel). 2019;11(5)Google Scholar
  59. 59.
    Silva RM, Anderson DS, Peake J, Edwards PC, Patchin ES, Guo T, et al. Aerosolized silver nanoparticles in the rat lung and pulmonary responses over time. Toxicol Pathol. 2016;44(5):673–86.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Müller RH, Mäder K, Gohla S. Solid lipid nanoparticles (SLN) for controlled drug delivery – a review of the state of the art. Eur J Pharm Biopharm. 2000;50(1):161–77.CrossRefGoogle Scholar
  61. 61.
    Haworth CS, Bilton D, Chalmers JD, Davis AM, Froehlich J, Gonda I, et al. Inhaled liposomal ciprofloxacin in patients with non-cystic fibrosis bronchiectasis and chronic lung infection with Pseudomonas aeruginosa (ORBIT-3 and ORBIT-4): two phase 3, randomised controlled trials. Lancet Respir Med. 2019;7(3):213–26.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Gibbons AM, McElvaney NG, Taggart CC, Cryan S-A. Delivery of rSLPI in a liposomal carrier for inhalation provides protection against cathepsin L degradation. J Microencapsul. 2009;26(6):513–22.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Gibbons A, Padilla-Carlin D, Kelly C, Hickey AJ, Taggart C, McElvaney NG, et al. The effect of liposome encapsulation on the pharmacokinetics of recombinant secretory leukocyte protease inhibitor (rSLPI) therapy after local delivery to a guinea pig asthma model. Pharm Res. 2011;28(9):2233–45.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Aragao-Santiago L, Hillaireau H, Grabowski N, Mura S, Nascimento TL, Dufort S, et al. Compared in vivo toxicity in mice of lung delivered biodegradable and non-biodegradable nanoparticles. Nanotoxicology. 2016;10(3):292–302.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Garg T, Rath G, Goyal AK. Inhalable chitosan nanoparticles as antitubercular drug carriers for an effective treatment of tuberculosis. Artif Cells Nanomed Biotechnol. 2016;44(3):997–1001.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Rubin BK. Physiology of airway mucus clearance. Respir Care. 2002;47(7):761–8.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Yang M, Yamamoto H, Kurashima H, Takeuchi H, Yokoyama T, Tsujimoto H, et al. Design and evaluation of inhalable chitosan-modified poly (dl-lactic-co-glycolic acid) nanocomposite particles. Eur J Pharm Sci. 2012;47(1):235–43.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Al-Nemrawi N, Alshraiedeh NA, Zayed A, Altaani B. Low molecular weight chitosan-coated PLGA nanoparticles for pulmonary delivery of tobramycin for cystic fibrosis. Pharmaceuticals. 2018;11(1):28.CrossRefGoogle Scholar
  69. 69.
    Paul P, Sengupta S, Mukherjee B, Shaw TK, Gaonkar RH, Debnath MC. Chitosan-coated nanoparticles enhanced lung pharmacokinetic profile of voriconazole upon pulmonary delivery in mice. Nanomedicine. 2018;13(5):501–20.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Schuster BS, Suk JS, Woodworth GF, Hanes J. Nanoparticle diffusion in respiratory mucus from humans without lung disease. Biomaterials. 2013;34(13):3439–46.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Suk JS, Kim AJ, Trehan K, Schneider CS, Cebotaru L, Woodward OM, et al. Lung gene therapy with highly compacted DNA nanoparticles that overcome the mucus barrier. J Control Release. 2014;178:8–17.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Beyerle A, Merkel O, Stoeger T, Kissel T. PEGylation affects cytotoxicity and cell-compatibility of poly (ethylene imine) for lung application: structure–function relationships. Toxicol Appl Pharmacol. 2010;242(2):146–54.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Chittasupho C, Xie S-X, Baoum A, Yakovleva T, Siahaan TJ, Berkland CJ. ICAM-1 targeting of doxorubicin-loaded PLGA nanoparticles to lung epithelial cells. Eur J Pharm Sci. 2009;37(2):141–50.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Li K, Liang N, Yang H, Liu H, Li S. Temozolomide encapsulated and folic acid decorated chitosan nanoparticles for lung tumor targeting: improving therapeutic efficacy both in vitro and in vivo. Oncotarget. 2017;8(67):111318.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Guo Y, Wang L, Lv P, Zhang P. Transferrin-conjugated doxorubicin-loaded lipid-coated nanoparticles for the targeting and therapy of lung cancer. Oncol Lett. 2015;9(3):1065–72.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Chono S, Tanino T, Seki T, Morimoto K. Efficient drug targeting to rat alveolar macrophages by pulmonary administration of ciprofloxacin incorporated into mannosylated liposomes for treatment of respiratory intracellular parasitic infections. J Control Release. 2008;127(1):50–8.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Costa A, Sarmento B, Seabra V. Mannose-functionalized solid lipid nanoparticles are effective in targeting alveolar macrophages. Eur J Pharm Sci. 2018;114:103–13.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Chan H-K, Kwok PCL. Production methods for nanodrug particles using the bottom-up approach. Adv Drug Deliv Rev. 2011;63(6):406–16.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Singh M, Manikandan S, Kumaraguru A. Nanoparticles: a new technology with wide applications. Res J Nanosci Nanotechno. 2011;1(1):1–11.CrossRefGoogle Scholar
  80. 80.
    Mu RH. Manufacturing of nanoparticles by milling and homogenization techniques. Nanoparticle technology for drug delivery: CRC Press. 2006:45–76.Google Scholar
  81. 81.
    Cho EJ, Holback H, Liu KC, Abouelmagd SA, Park J, Yeo Y. Nanoparticle characterization: state of the art, challenges, and emerging technologies. Mol Pharm. 2013;10(6):2093–110.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    CDER Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Products - Quality Considerations. Draft Guidance for Industry. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/metered-dose-inhaler-mdi-and-dry-powder-inhaler-dpi-drug-products-quality-considerations: FDA; 2018.
  83. 83.
    Dailey LA, Schmehl T, Gessler T, Wittmar M, Grimminger F, Seeger W, et al. Nebulization of biodegradable nanoparticles: impact of nebulizer technology and nanoparticle characteristics on aerosol features. J Control Release. 2003;86(1):131–44.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Pritchard JN. Industry guidance for the selection of a delivery system for the development of novel respiratory products. Expert Opin Drug Deliv. 2015;12(11):1755–65.CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Fernández Fernández E, Santos-Carballal B, de Santi C, Ramsey JM, MacLoughlin R, Cryan S-A, et al. Biopolymer-based nanoparticles for cystic fibrosis lung gene therapy studies. Materials. 2018;11(1):122.CrossRefGoogle Scholar
  86. 86.
    Graczyk H, Bryan LC, Lewinski N, Suarez G, Coullerez G, Bowen P, et al. Physicochemical characterization of nebulized superparamagnetic iron oxide nanoparticles (SPIONs). J Aerosol Med Pulm Drug Deliv. 2015;28(1):43–51.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Beck-Broichsitter M, Kleimann P, Schmehl T, Betz T, Bakowsky U, Kissel T, et al. Impact of lyoprotectants for the stabilization of biodegradable nanoparticles on the performance of air-jet, ultrasonic, and vibrating-mesh nebulizers. Eur J Pharm Biopharm. 2012;82(2):272–80.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Najlah M, Vali A, Taylor M, Arafat BT, Ahmed W, Phoenix DA, et al. A study of the effects of sodium halides on the performance of air-jet and vibrating-mesh nebulizers. Int J Pharm. 2013;456(2):520–7.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Sawicki GS, Goldman DP, Chan W, Casey A, Greenberg J, Romley JA. Patient preference for treatment administration in cystic fibrosis. Am J Pharm. 2015;7(4):174–81.Google Scholar
  90. 90.
  91. 91.
    Hibbitts A, O'mahony A, Forde E, Nolan L, Ogier J, Desgranges S, et al. Early-stage development of novel cyclodextrin-siRNA nanocomplexes allows for successful postnebulization transfection of bronchial epithelial cells. J Aerosol Med Pulm Drug Deliv. 2014;27(6):466–77.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Ari A, Areabi H, Fink JB. Evaluation of aerosol generator devices at 3 locations in humidified and non-humidified circuits during adult mechanical ventilation. Respir Care. 2010;55(7):837–44.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Bennett G, Joyce M, Sweeney L, MacLoughlin R. In vitro determination of the Main effects in the Design of High-Flow Nasal Therapy Systems with respect to aerosol performance. Pulmonary Therapy. 2018:1–14.Google Scholar
  94. 94.
    Ari A, Fink JB. Differential medical aerosol device and interface selection in patients during spontaneous, conventional mechanical and noninvasive ventilation. J Aerosol Med Pulm Drug Deliv. 2016;29(2):95–106.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Dubus JC, Vecellio L, De Monte M, Fink JB, Grimbert D, Montharu J, et al. Aerosol deposition in neonatal ventilation. Pediatr Res. 2005;58(1):10.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Dugernier J, Reychler G, Wittebole X, Roeseler J, Depoortere V, Sottiaux T, et al. Aerosol delivery with two ventilation modes during mechanical ventilation: a randomized study. Ann Intensive Care. 2016;6(1):73.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    MacLoughlin R, Telfer C, Clark A, Fink J. Aerosol: a novel vehicle for pharmacotherapy in neonates. Curr Pharm Des. 2017;23(38):5928–34.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Réminiac F, Vecellio L, Loughlin RM, Le Pennec D, Cabrera M, Vourc'h NH, et al. Nasal high flow nebulization in infants and toddlers: an in vitro and in vivo scintigraphic study. Pediatr Pulmonol. 2017;52(3):337–44.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Grainger CI, Greenwell LL, Lockley DJ, Martin GP, Forbes B. Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier. Pharm Res. 2006;23(7):1482–90.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Salomon JJ, Muchitsch VE, Gausterer JC, Schwagerus E, Huwer H, Daum N, et al. The cell line NCl-H441 is a useful in vitro model for transport studies of human distal lung epithelial barrier. Mol Pharm. 2014;11(3):995–1006.CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Johnson LG, Dickman KG, Moore KL, Mandel LJ, Boucher RC. Enhanced Na+ transport in an air-liquid interface culture system. Am J Phys. 1993;264(6 Pt 1):L560–5.Google Scholar
  102. 102.
    Tsuchiya S, Gota Y, Okumura H, Nakae S, Konno T, Tada K, et al. Induction of maturation in cultured human Monocytic leukemia cells by a Phorbol Diester. Cancer Res. 1982;42(4):1530–6.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Terpstra GK, De Weger RA, Wassink GA, Kreuknit J, Huidekoper HJ. Changes in alveolar macrophage enzyme content and activity in smokers and patients with chronic obstructive lung disease. Int J Clin Pharmacol Res. 1987;7(4):273–7.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Rothen-Rutishauser BM, Kiama SG, Gehr P. A three-dimensional cellular model of the human respiratory tract to study the interaction with particles. Am J Respir Cell Mol Biol. 2005;32(4):281–9.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Franzdóttir SR, Axelsson IT, Arason AJ, Baldursson Ó, Gudjonsson T, Magnusson MK. Airway branching morphogenesis in three dimensional culture. Respir Res. 2010;11(1):162.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Gill BJ, Gibbons DL, Roudsari LC, Saik JE, Rizvi ZH, Roybal JD, et al. A synthetic matrix with independently tunable biochemistry and mechanical properties to study epithelial morphogenesis and EMT in a lung adenocarcinoma model. Cancer Res. 2012;72(22):6013–23.CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    O'Leary C, Cavanagh B, Unger RE, Kirkpatrick CJ, O'Dea S, O'Brien FJ, et al. The development of a tissue-engineered tracheobronchial epithelial model using a bilayered collagen-hyaluronate scaffold. Biomaterials. 2016;85:111–27.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Huh D, Hamilton GA, Ingber DE. From three-dimensional cell culture to organs-on-chips. Trends Cell Biol. 2011;21(12):745–54.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Huh D, Kim HJ, Fraser JP, Shea DE, Khan M, Bahinski A, et al. Microfabrication of human organs-on-chips. Nat Protoc. 2013;8:2135.CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE. Reconstituting organ-level lung functions on a Chip. Science. 2010;328(5986):1662.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Huh D, Torisawa YS, Hamilton GA, Kim HJ, Ingber DE. Microengineered physiological biomimicry: organs-on-chips. Lab Chip. 2012;12(12):2156–64.CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Huh D. A human breathing lung-on-a-Chip. Ann Am Thorac Soc. 2015;12(Suppl 1):S42–S4.CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Nassiri Koopaei N, Abdollahi M. Opportunities and obstacles to the development of nanopharmaceuticals for human use. Daru. 2016;24(1):23.CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Li W, Yang Y, Wang C, Liu Z, Zhang X, An F, et al. Carrier-free, functionalized drug nanoparticles for targeted drug delivery. Chem Commun. 2012;48(65):8120–2.CrossRefGoogle Scholar
  115. 115.
    Bailey MM, Berkland CJ. Nanoparticle formulations in pulmonary drug delivery. Med Res Rev. 2009;29(1):196–212.CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Fattal E, Tsapis N. Nanomedicine technology: current achievements and new trends. Clinical and Translational Imaging. 2014;2(1):77–87.CrossRefGoogle Scholar
  117. 117.
    Haque S, Whittaker MR, McIntosh MP, Pouton CW, Kaminskas LM. Disposition and safety of inhaled biodegradable nanomedicines: opportunities and challenges. Nanomedicine. 2016;12(6):1703–24.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Marasini N, Haque S, Kaminskas LM. Polymer-drug conjugates as inhalable drug delivery systems: a review. Curr Opin Colloid Interface Sci. 2017;31:18–29.CrossRefGoogle Scholar
  119. 119.
    Hayashi Y. Designing in vitro assay systems for hazard characterization. Basic strategies and related technical issues. Exp Toxicol Pathol. 2005;57:227–32.CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Constant S, Huang S, Wiszniewski L, editors. An in vitro testing strategy for the development of novel inhaled therapeutics using human 3D airway epithelium model (Mucilair™). J Aerosol Med Pulm Drug Deliv; 2013.: Mary Ann Liebert, Inc..Google Scholar
  121. 121.
    Fytianos K, Drasler B, Blank F, von Garnier C, Seydoux E, Rodriguez-Lorenzo L, et al. Current in vitro approaches to assess nanoparticle interactions with lung cells. Nanomedicine (Lond). 2016;11(18):2457–69.CrossRefGoogle Scholar
  122. 122.
    Grenha A, Grainger CI, Dailey LA, Seijo B, Martin GP, Remuñán-López C, et al. Chitosan nanoparticles are compatible with respiratory epithelial cells in vitro. Eur J Pharm Sci. 2007;31(2):73–84.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Kroll A, Pillukat MH, Hahn D, Schnekenburger J. Current in vitro methods in nanoparticle risk assessment: limitations and challenges. Eur J Pharm Biopharm. 2009;72(2):370–7.CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Jakubowski W, Bartosz G. 2, 7-dichlorofluorescin oxidation and reactive oxygen species: what does it measure? Cell Biol Int. 2000;24(10):757–60.CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Guadagnini R, Halamoda Kenzaoui B, Walker L, Pojana G, Magdolenova Z, Bilanicova D, et al. Toxicity screenings of nanomaterials: challenges due to interference with assay processes and components of classic in vitro tests. Nanotoxicology. 2015;9(sup1):13–24.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Poh TY, Ali N, Mac Aogain M, Kathawala MH, Setyawati MI, Ng KW, et al. Inhaled nanomaterials and the respiratory microbiome: clinical, immunological and toxicological perspectives. Part Fibre Toxicol. 2018;15(1):46.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Piret JP, Bondarenko OM, Boyles MSP, Himly M, Ribeiro AR, Benetti F, et al. Pan-European inter-laboratory studies on a panel of in vitro cytotoxicity and pro-inflammation assays for nanoparticles. Arch Toxicol. 2017;91(6):2315–30.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Han X, Gelein R, Corson N, Wade-Mercer P, Jiang J, Biswas P, et al. Validation of an LDH assay for assessing nanoparticle toxicity. Toxicology. 2011;287(1–3):99–104.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Mottas I, Milosevic A, Petri-Fink A, Rothen-Rutishauser B, Bourquin C. A rapid screening method to evaluate the impact of nanoparticles on macrophages. Nanoscale. 2017;9(7):2492–504.CrossRefPubMedPubMedCentralGoogle Scholar
  130. 130.
    Chen R, Huo L, Shi X, Bai R, Zhang Z, Zhao Y, et al. Endoplasmic reticulum stress induced by zinc oxide nanoparticles is an earlier biomarker for nanotoxicological evaluation. ACS Nano. 2014;8(3):2562–74.CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Goldberg AM, Frazier JM, Brusick D, Dickens MS, Flint O, Gettings SD, et al. Framework for validation and implementation of in vitro toxicity tests. In Vitro Cellular & Developmental Biology-Animal. 1993;29(9):688–92.CrossRefGoogle Scholar
  132. 132.
    Accomasso L, Cristallini C, Giachino C. Risk assessment and risk minimization in Nanomedicine: a need for predictive, alternative, and 3Rs strategies. Front Pharmacol. 2018;9:228.CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Nakane H. Translocation of particles deposited in the respiratory system: a systematic review and statistical analysis. Environ Health Prev Med. 2012;17(4):263.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Ryan GM, Bischof RJ, Enkhbaatar P, McLeod VM, Chan LJ, Jones SA, et al. A comparison of the pharmacokinetics and pulmonary lymphatic exposure of a generation 4 PEGylated dendrimer following intravenous and aerosol administration to rats and sheep. Pharm Res. 2016;33(2):510–25.CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Zolnik BS, Sadrieh N. Regulatory perspective on the importance of ADME assessment of nanoscale material containing drugs. Adv Drug Deliv Rev. 2009;61(6):422–7.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Tseng C-L, Wu SY-H, Wang W-H, Peng C-L, Lin F-H, Lin C-C, et al. Targeting efficiency and biodistribution of biotinylated-EGF-conjugated gelatin nanoparticles administered via aerosol delivery in nude mice with lung cancer. Biomaterials. 2008;29(20):3014–22.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Singh RP, Ramarao P. Accumulated polymer degradation products as effector molecules in cytotoxicity of polymeric nanoparticles. Toxicol Sci. 2013;136(1):131–43.CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Diot P, Palmer LB, Smaldone A, DeCEelieGermana J, Grimson R, Maldone GC. RhDNase I aerosol deposition and related factors in cystic fibrosis. Am J Respir Crit Care Med. 1997;156(5):1662–8.CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Heyder J. Deposition of inhaled particles in the human respiratory tract and consequences for regional targeting in respiratory drug delivery. Proc Am Thorac Soc. 2004;1(4):315–20.CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Cryan S-A, Sivadas N, Garcia-Contreras L. In vivo animal models for drug delivery across the lung mucosal barrier. Adv Drug Deliv Rev. 2007;59(11):1133–51.CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Hofmann W, Asgharian B, Bergmann R, Anjilvel S, Miller FJ. The effect of heterogeneity of lung structure on particle deposition in the rat lung. Toxicol Sci. 2000;53(2):430–7.CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Miller F, Mercer R, Crapo J. Lower respiratory tract structure of laboratory animals and humans: dosimetry implications. Aerosol Sci Technol. 1993;18(3):257–71.CrossRefGoogle Scholar
  143. 143.
    Black KC, Ibricevic A, Gunsten SP, Flores JA, Gustafson TP, Raymond JE, et al. In vivo fate tracking of degradable nanoparticles for lung gene transfer using PET and Cerenkov imaging. Biomaterials. 2016;98:53–63.CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Schneider CS, Xu Q, Boylan NJ, Chisholm J, Tang BC, Schuster BS, et al. Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation. Sci Adv. 2017;3(4)Google Scholar
  145. 145.
    Carlon M, Toelen J, Van der Perren A, Vandenberghe LH, Reumers V, Sbragia L, et al. Efficient gene transfer into the mouse lung by fetal Intratracheal injection of rAAV2/6.2. Mol Ther. 2010;18(12):2130–8.CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Kawabata A, Baoum A, Ohta N, Jacquez S, Seo G-M, Berkland C, et al. Intratracheal Administration of a Nanoparticle-Based Therapy with the angiotensin II type 2 receptor gene attenuates lung Cancer growth. Cancer Res. 2012;72(8):2057–67.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Galindo-Filho VC, Ramos ME, Rattes CS, Barbosa AK, Brandão DC, Brandão SCS, et al. Radioaerosol pulmonary deposition using mesh and jet nebulizers during noninvasive ventilation in healthy subjects. Respir Care. 2015;60(9):1238–46.CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Weers J, Metzheiser B, Taylor G, Warren S, Meers P, Perkins WR. A gamma scintigraphy study to investigate lung deposition and clearance of inhaled amikacin-loaded liposomes in healthy male volunteers. J Aerosol Med Pulm Drug Deliv. 2009;22(2):131–8.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Bhavna, Ahmad FJ, Mittal G, Jain GK, Malhotra G, Khar RK, et al. Nano-salbutamol dry powder inhalation: a new approach for treating broncho-constrictive conditions. Eur J Pharm Biopharm. 2009;71(2):282–91.CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Vij N, Min T, Bodas M, Gorde A, Roy I. Neutrophil targeted nano-drug delivery system for chronic obstructive lung diseases. Nanomedicine. 2016;12(8):2415–27.CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Semmler-Behnke M, Takenaka S, Fertsch S, Wenk A, Seitz J, Mayer P, et al. Efficient elimination of inhaled nanoparticles from the alveolar region: evidence for interstitial uptake and subsequent Reentrainment onto airways epithelium. Environ Health Perspect. 2007;115(5):728–33.CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Nowak N, Kakade PP, Annapragada AV. Computational fluid dynamics simulation of airflow and aerosol deposition in human lungs. Ann Biomed Eng. 2003;31(4):374–90.CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Xi J, Yang T, Talaat K, Wen T, Zhang Y, Klozik S, et al. Visualization of local deposition of nebulized aerosols in a human upper respiratory tract model. J Vis. 2018;21(2):225–37.CrossRefGoogle Scholar
  154. 154.
    Rösslein M, Liptrott NJ, Owen A, Boisseau P, Wick P, Herrmann IK. Sound understanding of environmental, health and safety, clinical, and market aspects is imperative to clinical translation of nanomedicines. Nanotoxicology. 2017;11(2):147–9.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Stark WJ. Nanoparticles in biological systems. Angew Chem Int Ed. 2011;50(6):1242–58.CrossRefGoogle Scholar
  156. 156.
    Mostafalou S, Mohammadi H, Ramazani A, Abdollahi M. Different biokinetics of nanomedicines linking to their toxicity; an overview. BioMed Central. 2013;Google Scholar
  157. 157.
    Robinson RLM, Lynch I, Peijnenburg W, Rumble J, Klaessig F, Marquardt C, et al. How should the completeness and quality of curated nanomaterial data be evaluated? Nanoscale. 2016;8(19):9919–43.CrossRefGoogle Scholar
  158. 158.
    Bawa R, Barenholz Y, Owen A. The challenge of regulating Nanomedicine: key issues. Nanomedicines. 2016:290–314.Google Scholar
  159. 159.
    Berkner S, Schwirn K, Voelker D. Nanopharmaceuticals: tiny challenges for the environmental risk assessment of pharmaceuticals. Environ Toxicol Chem. 2016;35(4):780–7.CrossRefPubMedPubMedCentralGoogle Scholar
  160. 160.
    FDA. Guidance for industry considering whether an FDA-regulated product involves the application of nanotechnology. 2014. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/considering-whether-fda-regulated-product-involves-application-nanotechnology.
  161. 161.
    Standard for Respiratory Therapy Equipment EN 13544–1 2009. https://standards.cen.eu/.
  162. 162.
    CHMP Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products. 2006. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmaceutical-quality-inhalation-nasal-products_en.pdf.
  163. 163.
    Ph. Eur. Preparations for nebulisation: Characterisation. https://www.edqm.eu/en/european-pharmacopoeia-ph-eur-9th-edition.
  164. 164.
    USP. Products for nebulization: Characterization. https://www.usp.org/.
  165. 165.
    USP. Orally Inhaled and Nasal Products. https://www.usp.org/.

Copyright information

© American Association of Pharmaceutical Scientists 2020

Authors and Affiliations

  • Joanne M. Ramsey
    • 1
    • 2
    • 3
  • Alice McCloskey
    • 1
    • 2
    • 3
  • Rachel Gaul
    • 1
    • 2
    • 4
  • Elena Fernandez Fernandez
    • 4
  • Louise Sweeney
    • 5
  • Catherine M. Greene
    • 4
  • Ronan Macloughlin
    • 5
  • Sally-Ann Cryan
    • 1
    • 2
    • 3
    • 6
    • 7
    Email author
  1. 1.School of Pharmacy & Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI)Dublin 2Ireland
  2. 2.Tissue Engineering Research Group(RCSI)Dublin 2Ireland
  3. 3.Science Foundation Ireland Centre for Research in Medical Devices (CURAM), NUIG & RCSIGalwayIreland
  4. 4.Department of Clinical MicrobiologyRoyal College of Surgeons in Ireland, Education and Research Centre, Beaumont HospitalDublinIreland
  5. 5.Aerogen Ltd.GalwayIreland
  6. 6.Trinity Centre for Biomedical EngineeringTrinity College DublinDublin 2Ireland
  7. 7.Science Foundation Ireland Advanced Materials & Bioengineering Research Centre (AMBER) Centre, TCD &RCSIDublin 2Ireland

Personalised recommendations