Skip to main content
SpringerLink
Log in

Near Elimination of In Vitro Predicted Extrathoracic Aerosol Deposition in Children Using a Spray-Dried Antibiotic Formulation and Pediatric Air-Jet DPI

  • Original Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

This study evaluated the in vitro aerosol performance of a dry powder antibiotic product that combined a highly dispersible tobramycin powder with a previously optimized pediatric air-jet dry powder inhaler (DPI) across a subject age range of 2–10 years.

Methods

An excipient enhanced growth (EEG) formulation of the antibiotic tobramycin (Tobi) was prepared using a small particle spray drying technique that included mannitol as the hygroscopic excipient and trileucine as the dispersion enhancer. The Tobi-EEG formulation was aerosolized using a positive-pressure pediatric air-jet DPI that included a 3D rod array. Realistic in vitro experiments were conducted in representative airway models consistent with children in the age ranges of 2–3, 5–6 and 9–10 years using oral or nose-to-lung administration, non-humidified or humidified airway conditions, and constant or age-specific air volumes.

Results

Across all conditions tested, mouth-throat depositional loss was < 1% and nose-throat depositional loss was < 3% of loaded dose. Lung delivery efficiency was in the range of 77.3–85.1% of loaded dose with minor variations based on subject age (~ 8% absolute difference), oral or nasal administration (< 2%), and delivered air volume (< 2%). Humidified airway conditions had an insignificant impact on extrathoracic depositional loss and significantly increased aerosol size at the exit of a representative lung chamber.

Conclusions

In conclusion, the inhaled antibiotic product nearly eliminated extrathoracic depositional loss, demonstrated high efficiency nose-to-lung antibiotic aerosol delivery in pediatric airway models for the first time, and provided ~ 80% lung delivery efficiency with little variability across subject age and administered air volume.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

3D:

Three-dimensional

B#:

Bifurcation number

CDC:

Centers for Disease Control and Prevention

CFD:

Computational fluid dynamics

DF:

Deposition fraction

DPI:

Dry powder inhaler

ED:

Emitted dose

EEG:

Excipient enhanced growth

FPF:

Fine particle fraction

HP:

High performance

HPLC:

High performance liquid chromatography

LC–MS:

Liquid chromatography-mass spectrometry

MMAD:

Mass median aerodynamic diameter

MN:

Mannitol

MP:

Mouthpiece

MT:

Mouth-throat

NGI:

Next Generation Impactor

RH:

Relative humidity

SD:

Standard deviation

TB:

Tracheobronchial

Tobi:

Tobramycin

USP:

United States Pharmacopeia

References

  1. Weers JG, Son Y-J, Glusker M, Haynes A, Huang D, Kadrichu N, Le J, Li X, Malcolmson R, Miller DP, Tarara TE, Ung K, Clark A. Idealhalers versus realhalers: Is it possible to bypass deposition in the upper respiratory tract? J Aerosol Med Pulm Drug Deliv. 2019;32:55–69.

    Article  PubMed  Google Scholar 

  2. De Boer A, Hagedoorn P, Hoppentocht M, Buttini F, Grasmeijer F, Frijlink H. Dry powder inhalation: past, present and future. Expert Opin Drug Deliv. 2017;14:499–512.

    Article  PubMed  Google Scholar 

  3. Islam N, Cleary MJ. Developing an efficient and reliable dry powder inhaler for pulmonary drug delivery - A review for multidisciplinary researchers. Med Eng Phys. 2012;34:409–27.

    Article  PubMed  Google Scholar 

  4. Lexmond AJ, Hagedoorn P, Frijlink HW, Rottier BL, de Boer AH. Prerequisites for a dry powder inhaler for children with cystic fibrosis. PLoS ONE. 2017;12: e0183130.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lexmond AJ, Kruizinga TJ, Hagedoorn P, Rottier BL, Frijlink HW, De Boer AH. Effect of inhaler design variables on paediatric use of dry powder inhalers. PLoS ONE. 2014;9: e99304.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Everard ML. Inhaler devices in infants and children: Challenges and solutions. Journal of Aerosol Medicine-Deposition Clearance and Effects in the Lung. 2004;17:186–95.

    Article  CAS  Google Scholar 

  7. Lindert S, Below A, Breitkreutz J. Performance of dry powder inhalers with single dosed capsules in preschool children and adults using improved upper airway models. Pharmaceutics. 2014;6:36–51.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Devadason S, Everard M, MacEarlan C, Roller C, Summers Q, Swift P, Borgstrom L, Le Souëf P. Lung deposition from the Turbuhaler in children with cystic fibrosis. Eur Respir J. 1997;10:2023–8.

    Article  CAS  PubMed  Google Scholar 

  9. Below A, Bickmann D, Breitkreutz J. Assessing the performance of two dry powder inhalers in preschool children using an idealized pediatric upper airway model. Int J Pharm. 2013;444:169–74.

    Article  CAS  PubMed  Google Scholar 

  10. Borgstrom L, Bengtsson T, Derom E, Pauwels R. Variability in lung deposition of inhlaed drug, within and between asthmatic patients, with a pMDI and a dry powder inhaler, Turbuhaler. International Journal of Pharmaceutics. 2000;193:227–30.

  11. Borgstrom L, Olsson B, Thorsson L. Degree of throat deposition can explain the variability in lung deposition of inhaled drugs. J Aerosol Med. 2006;19:473–83.

    Article  PubMed  Google Scholar 

  12. Tiddens HA, Geller DE, Challoner P, Speirs RJ, Kesser KC, Overbeek SE, Humble D, Shrewsbury SB, Standaert TA. Effect of dry powder inhaler resistance on the inspiratory flow rates and volumes of cystic fibrosis patients of six years and older. Journal Of Aerosol Medicine-Deposition Clearance And Effects In The Lung. 2006;19:456–65.

    Article  CAS  Google Scholar 

  13. Everard ML. Aerosol delivery in infants and young children. Journal of Aerosol Medicine-Deposition Clearance and Effects in the Lung. 1996;9:71–7.

    Article  CAS  Google Scholar 

  14. Ruzycki CA, Golshahi L, Vehring R, Finlay WH. Comparison of in vitro deposition of pharmaceutical aerosols in an idealized child throat with in vivo deposition in the upper respiratory tract of children. Pharm Res. 2014;31:1525–35.

    Article  CAS  PubMed  Google Scholar 

  15. Golshahi L, Finlay WH. An idealized child throat that mimics average pediatric oropharyngeal deposition. Aerosol Sci Technol. 2012;46:i–iv.

    Article  CAS  Google Scholar 

  16. Haynes A, Geller D, Weers J, Ament B, Pavkov R, Malcolmson R, Debonnett L, Mastoridis P, Yadao A, Heuerding S. Inhalation of tobramycin using simulated cystic fibrosis patient profiles. Pediatr Pulmonol. 2016;51:1159–67.

    Article  PubMed  Google Scholar 

  17. Rubin BK. Pediatric aerosol therapy: New devices and new drugs. Respir Care. 2011;56:1411–21.

    Article  PubMed  Google Scholar 

  18. Farkas D, Hindle M, Bonasera S, Bass K, Longest W. Development of an inline dry powder inhaler for oral or trans-nasal aerosol administration to children. J Aerosol Med Pulm Drug Deliv. 2020;33:83–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Weers JG, Miller DP. Formulation design of dry powders for inhalation. J Pharm Sci. 2015;104:3259–88.

    Article  CAS  PubMed  Google Scholar 

  20. Son Y-J, Longest PW, Hindle M. Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: Effect of spray drying process conditions on aerosol performance. Int J Pharm. 2013;443:137–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Feng A, Boraey M, Gwin M, Finlay P, Kuehl P, Vehring R. Mechanistic models facilitate efficient development of leucine containing microparticles for pulmonary drug delivery. Int J Pharm. 2011;409:156–63.

    Article  CAS  PubMed  Google Scholar 

  22. Vehring R. Pharmaceutical particle engineering via spray drying. Pharm Res. 2008;25:999–1022.

    Article  CAS  PubMed  Google Scholar 

  23. Vehring R, Foss WR, Lechuga-Ballesteros D. Particle formation in spray drying. J Aerosol Sci. 2007;38:728–46.

    Article  CAS  Google Scholar 

  24. Hindle M, Longest PW. Condensational growth of combination drug-excipient submicrometer particles for targeted high efficiency pulmonary delivery: Evaluation of formulation and delivery device. J Pharm Pharmacol. 2012;64:1254–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Son Y-J, Longest PW, Tian G, Hindle M. Evaluation and modification of commercial dry powder inhalers for the aerosolization of submicrometer excipient enhanced growth (EEG) formulation. Eur J Pharm Sci. 2013;49:390–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Longest PW, Son Y-J, Holbrook LT, Hindle M. Aerodynamic factors responsible for the deaggregation of carrier-free drug powders to form micrometer and submicrometer aerosols. Pharm Res. 2013;30:1608–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Longest P, Farkas D, Hassan A, Hindle M. Computational fluid dynamics (CFD) simulations of spray drying: linking drying parameters with experimental aerosolization performance. Pharm Res. 2020;37:101–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hassan A, Farkas D, Longest W, Hindle M. Characterization of excipient enhanced growth (EEG) tobramycin dry powder aerosol formulations. Int J Pharm. 2020;591: 120027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bonasera S. Formulation, characterization and pharmacokinetic modeliing of excipient enhanced growth spray-dried inhalation powders. Dissertation, Virginia Commonwealth University, Richmond, VA. 2021;

  30. Farkas D, Bonasera S, Bass K, Hindle M, Longest PW. Advancement of a positive-pressure dry powder inhaler for children: use of a vertical aerosolization chamber and three-dimensional rod array interface. Pharm Res. 2020;37:177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Farkas D, Hindle M, Longest PW. Development of an inline dry powder inhaler that requires low air volume. J Aerosol Med Pulm Drug Deliv. 2018;31:255–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Farkas D, Hindle M, Longest PW. Application of an inline dry powder inhaler to deliver high dose pharmaceutical aerosols during low flow nasal cannula therapy. Int J Pharm. 2018;546:1–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Farkas D, Hindle M, Longest PW. Efficient nose-to-lung aerosol delivery with an inline DPI requiring low actuation air volume. Pharm Res. 2018;35:194.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Bass K, Farkas D, Hassan A, Bonasera S, Hindle M, Longest W. High-efficiency dry powder aerosol delivery to children: Review and application of new technologies. J Aerosol Sci. 2021;153: 105692.

    Article  CAS  PubMed  Google Scholar 

  35. Geller DE, Weers J, Heuerding S. Development of an inhaled dry-powder formulation of Tobramycin using PulmoSphereTM technology. J Aerosol Med Pulm Drug Deliv. 2011;24:175–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Weers J. Inhaled antimicrobial therapy - Barriers to effective treatment. Adv Drug Deliv Rev. 2015;85:24–43.

    Article  CAS  PubMed  Google Scholar 

  37. Robertson JM, Friedman EM, Rubin BK. Nasal and sinus disease in cystic fibrosis. Paediatr Respir Rev. 2008;9:213–9.

    Article  PubMed  Google Scholar 

  38. Bonestroo HJ, de Winter-de Groot KM, van der Ent CK, Arets HG. Upper and lower airway cultures in children with cystic fibrosis: do not neglect the upper airways. J Cyst Fibros. 2010;9:130–4.

    Article  PubMed  Google Scholar 

  39. Sawicki GS, Sellers DE, Robinson WM. High treatment burden in adults with cyctic fibrosis: challenges to disease self-management. J Cyst Fibros. 2009;8:91–6.

    Article  PubMed  Google Scholar 

  40. Geller DE, Konstan MW, Smith J, Noonberg SB, Conrad C. Novel tobramycin inhalation powder in cystic fibrosis subjects: Pharmacokinetics and safety. Pediatr Pulmonol. 2007;42:307–13.

    Article  PubMed  Google Scholar 

  41. Bass K, Longest PW. Development of DPI patient interfaces for improved aerosol delivery to children. AAPS PharmSciTech. 2020;21:157.

    Article  CAS  PubMed  Google Scholar 

  42. Phalen RF, Oldham MJ, Beaucage CB, Crocker TT, Mortensen JD. Postnatal enlargement of human tracheobronchial airways and implications for particle deposition. Anat Rec. 1985;212:368–80.

    Article  CAS  PubMed  Google Scholar 

  43. Kuczmarski RJ. CDC growth charts: United States, US Department of Health and Human Services, Centers for Disease Control and …, 2000.

  44. Wachtel H, Bickmann D, Breitkreutz J, Langguth P. Can pediatric throat models and air flow profiles improve our dose finding strategy. Respiratory Drug Delivery. 2010;2010:195–204.

    Google Scholar 

  45. Golshahi L, Noga ML, Finlay WH. Deposition of inhaled micrometer-sized particles in oropharyngeal airway replicas of children at constant flow rates. J Aerosol Sci. 2012;49:21–31.

    Article  CAS  Google Scholar 

  46. DeHaan WH, Finlay WH. In vitro monodisperse aerosol deposition in a mouth and throat with six different inhalation devices. J Aerosol Med. 2001;14:361–7.

    Article  CAS  PubMed  Google Scholar 

  47. DeHaan WH, Finlay WH. Predicting extrathoracic deposition from dry powder inhalers. J Aerosol Sci. 2004;35:309–31.

    Article  CAS  Google Scholar 

  48. Bickmann D, Wachtel H, Kroger R, Langguth P. Examining inhaler perforance using a child’s throat model. Respiratory Drug Delivery. 2008;2008:565–9.

    Google Scholar 

  49. Cheng YS. Aerosol deposition in the extrathoracic region. Aerosol Sci Technol. 2003;37:659–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Xi J, Longest PW. Transport and deposition of micro-aerosols in realistic and simplified models of the oral airway. Ann Biomed Eng. 2007;35:560–81.

    Article  PubMed  Google Scholar 

  51. Bass K, Farkas D, Longest W. Optimizing Aerosolization Using Computational Fluid Dynamics in a Pediatric Air-Jet Dry Powder Inhaler. AAPS PharmSciTech. 2019;20:329.

    Article  PubMed  Google Scholar 

  52. Rosenow T, Oudraad MCJ, Murray CP, Turkovic L, Kuo W, de Bruijne M, Ranganathan SC, Tiddens HAWM, and Stick SM. PRAGMA-CF. A quantitative structural lung disease computed tomography outcome in young children with cystic fibrosis. American Journal of Respiratory and Critical Care Medicine. 2015;191:1158–1165.

  53. ICRP. Human respiratory tract model for radiological protection, Elsevier Science Ltd., New York, 1994.

  54. Longest W, Hassan A, Farkas D, and Hindle M. Computational fluid dynamics (CFD) guided spray drying recommendations for improved aerosol performance of a small-particle antibiotic formulation. Pharm Res. 2022;https://doi.org/10.1007/s11095-022-03180-7

  55. Chua H, Collis G, Newbury A, Chan K, Bower G, Sly P, Le Souef P. The influence of age on aerosol deposition in children with cystic fibrosis. Eur Respir J. 1994;7:2185–91.

    Article  CAS  PubMed  Google Scholar 

  56. Everard M, Hardy J, Milner A. Comparison of nebulised aerosol deposition in the lungs of healthy adults following oral and nasal inhalation. Thorax. 1993;48:1045–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Geller DE. Aerosol antibiotics in cystic fibrosis. Respir Care. 2004;54:658–70.

    Article  Google Scholar 

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R01HD087339 and by the National Heart, Lung and Blood Institute of the National Institutes of Health under Award Number R01HL139673. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, 401 West Main Street, P.O. Box 843015, Richmond, Virginia, 23284-3015 , USA

    Dale Farkas, Morgan L. Thomas & Worth Longest

  2. Department of Pharmaceutics, Virginia Commonwealth University, Richmond, Virginia, USA

    Amr Hassan, Serena Bonasera, Michael Hindle & Worth Longest

Authors
  1. Dale Farkas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Morgan L. Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amr Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Serena Bonasera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Hindle
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Worth Longest
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Worth Longest.

Ethics declarations

Author Disclosure Statement

Virginia Commonwealth University is currently pursuing patent protection of devices and methods described in this study, which if licensed and commercialized, may provide a future financial interest to the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farkas, D., Thomas, M.L., Hassan, A. et al. Near Elimination of In Vitro Predicted Extrathoracic Aerosol Deposition in Children Using a Spray-Dried Antibiotic Formulation and Pediatric Air-Jet DPI. Pharm Res 40, 1193–1207 (2023). https://doi.org/10.1007/s11095-022-03316-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-022-03316-9

KEY WORDS

Search

Navigation