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Pharmaceutical Research

, 35:5 | Cite as

Numerical Comparison of Nasal Aerosol Administration Systems for Efficient Nose-to-Brain Drug Delivery

  • Jingliang Dong
  • Yidan Shang
  • Kiao Inthavong
  • Hak-Kim Chan
  • Jiyuan TuEmail author
Research Paper

Abstract

Purpose

Nose-to-brain drug administration along the olfactory and trigeminal nerve pathways offers an alternative route for the treatment of central nervous system (CNS) disorders. The characterization of particle deposition remains difficult to achieve in experiments. Alternative numerical approach is applied to identify suitable aerosol particle size with maximized inhaled doses.

Methods

This study numerically compared the drug delivery efficiency in a realistic human nasal cavity between two aerosol drug administration systems targeting the olfactory region: the aerosol mask system and the breath-powered bi-directional system. Steady inhalation and exhalation flow rates were applied to both delivery systems. The discrete phase particle tracking method was employed to capture the aerosol drug transport and deposition behaviours in the nasal cavity. Both overall and regional deposition characteristics were analysed in detail.

Results

The results demonstrated the breath-powered drug delivery approach can produce superior olfactory deposition with peaking olfactory deposition fractions for diffusive 1 nm particles and inertial 10 μm. While for particles in the range of 10 nm to 2 μm, no significant olfactory deposition can be found, indicating the therapeutic agents should avoid this size range when targeting the olfactory deposition.

Conclusions

The breath-powered bi-directional aerosol delivery approach shows better drug delivery performance globally and locally, and improved drug administration doses can be achieved in targeted olfactory region.

KEY WORDS

drug administration nose-to-brain numerical modelling olfactory particle deposition 

Abbreviations

BBB

Blood-brain barrier

CNS

Central nervous system

CT

Computed tomography

DPM

Discrete phase model

LC

Left chamber

RC

Right chamber

Notes

Acknowledgments and Disclosures

This study was funded by the National Natural Science Foundation of China (Grant No.: 91643102) and Australian Research Council (Project ID: DP160101953).

References

  1. 1.
    Drettner B, Falck B, Simon H. Measurements of the Air Conditioning Capacity of the Nose During Normal and Pathological Conditions and Pharmacological Influence. Acta Otolaryngol. 1977;84(1–6):266–77.CrossRefPubMedGoogle Scholar
  2. 2.
    Keck T, Leiacker R, Heinrich A, Kuhnemann S, Rettinger G. Humidity and temperature profile in the nasal cavity. Rhinology. 2000;38(4):167–71.PubMedGoogle Scholar
  3. 3.
    Mygind N, Vesterhauge S. Aerosol distribution in the nose. Rhinology. 1978;16(2):79–88.PubMedGoogle Scholar
  4. 4.
    Rissler J, Swietlicki E, Bengtsson A, Boman C, Pagels J, Sandström T, et al. Experimental determination of deposition of diesel exhaust particles in the human respiratory tract. J Aerosol Sci. 2012;48:18–33.Google Scholar
  5. 5.
    Bell IR, Koithan M. A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross-adaptation, and time-dependent sensitization in a complex adaptive system. BMC Complement Altern Med. 2012;12:191–1.Google Scholar
  6. 6.
    Wichers LB, Rowan IIIWH, Nolan JP, Ledbetter AD, McGee JK, Costa DL, et al. Particle Deposition in Spontaneously Hypertensive Rats Exposed via Whole-Body Inhalation: Measured and Estimated Dose. Toxicol Sci. 2006;93(2):400–10.Google Scholar
  7. 7.
    Djupesland PG. Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review. Drug Deliv Transl Res. 2013;3(1):42–62.CrossRefPubMedGoogle Scholar
  8. 8.
    Frey WH, Liu J, Chen X, Thorne RG, Fawcett JR, Ala TA, et al. Delivery of 125I-NGF to the Brain via the Olfactory Route. Drug Deliv. 1997;4(2):87–92.Google Scholar
  9. 9.
    Dhuria SV, Hanson LR, Frey WH II. Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J Pharm Sci. 2010;99(4):1654–73.CrossRefPubMedGoogle Scholar
  10. 10.
    Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev. 2012;64(7):614–28.CrossRefPubMedGoogle Scholar
  11. 11.
    Chapman CD, Frey WH 2nd, Craft S, Danielyan L, Hallschmid M, Schioth HB, et al. Intranasal treatment of central nervous system dysfunction in humans. Pharm Res. 2013;30(10):2475–84.Google Scholar
  12. 12.
    Miyake MM, Bleier BS. The blood-brain barrier and nasal drug delivery to the central nervous system. Am J Rhinol Allergy. 2015;29(2):124–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Thorne RG, Pronk GJ, Padmanabhan V, Frey WH 2nd. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience. 2004;127(2):481–96.CrossRefPubMedGoogle Scholar
  14. 14.
    Ross TM, Martinez PM, Renner JC, Thorne RG, Hanson LR, Frey WH 2nd. Intranasal administration of interferon beta bypasses the blood-brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J Neuroimmunol. 2004;151(1–2):66–77.CrossRefPubMedGoogle Scholar
  15. 15.
    Banks WA, During MJ, Niehoff ML. Brain uptake of the glucagon-like peptide-1 antagonist exendin(9-39) after intranasal administration. J Pharmacol Exp Ther. 2004;309(2):469–75.CrossRefPubMedGoogle Scholar
  16. 16.
    Hanson LR, Frey WH. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2008;9(Suppl 3):S5–5.Google Scholar
  17. 17.
    Bahadur S, Pathak K. Physicochemical and physiological considerations for efficient nose-to-brain targeting. Expert Opin Drug Deliv. 2012;9(1):19–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Xi J, Zhang Z, Si XA. Improving intranasal delivery of neurological nanomedicine to the olfactory region using magnetophoretic guidance of microsphere carriers. Int J Nanomedicine. 2015;10:1211–22.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Suman JD, Laube BL, Dalby R. Comparison of nasal deposition and clearance of aerosol generated by nebulizer and an aqueous spray pump. Pharm Res. 1999;16(10):1648–52.CrossRefPubMedGoogle Scholar
  20. 20.
    Kimbell JS, Segal RA, Asgharian B, Wong BA, Schroeter JD, Southall JP, et al. Characterization of deposition from nasal spray devices using a computational fluid dynamics model of the human nasal passages. Journal of Aerosol Medicine: the Official Journal of the International Society for Aerosols in Medicine. 2007;20(1):59–74.Google Scholar
  21. 21.
    Inthavong K, Ge Q, Se CMK, Yang W, Tu JY. Simulation of sprayed particle deposition in a human nasal cavity including a nasal spray device. J Aerosol Sci. 2011;42(2):100–13.CrossRefGoogle Scholar
  22. 22.
    Tong X, Dong J, Shang Y, Inthavong K, Tu J. Effects of nasal drug delivery device and its orientation on sprayed particle deposition in a realistic human nasal cavity. Comput Biol Med. 2016;77:40–8.CrossRefPubMedGoogle Scholar
  23. 23.
    Lin HL, Wan GH, Chen YH, Fink JB, Liu WQ, Liu KY. Influence of nebulizer type with different pediatric aerosol masks on drug deposition in a model of a spontaneously breathing small child. Respir Care. 2012;57(11):1894–900.CrossRefPubMedGoogle Scholar
  24. 24.
    Dubosky MN, Brahmbhatt H, Vines DL. The Influence of flow rates through nebulizers on aerosol particle size and dose deposition in aerosol masks. Am J Resp Crit Care. 2014;189:A5695.Google Scholar
  25. 25.
    Ari A, de Andrade AD, Sheard M, AlHamad B, Fink JB. Performance Comparisons of Jet and Mesh Nebulizers Using Different Interfaces in Simulated Spontaneously Breathing Adults and Children. J Aerosol Med Pulm Drug Deliv. 2015;28(4):281–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Djupesland PG, Messina JC, Mahmoud RA. Breath powered nasal delivery: a new route to rapid headache relief. Headache. 2013;53(Suppl 2):72–84.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cady R. A novel intranasal breath-powered delivery system for sumatriptan: a review of technology and clinical application of the investigational product AVP-825 in the treatment of migraine. Expert Opin Drug Deliv. 2015;12(9):1565–77.CrossRefPubMedGoogle Scholar
  28. 28.
    Djupesland PG, Skretting A. Nasal Deposition and Clearance in Man: Comparison of a Bidirectional Powder Device and a Traditional Liquid Spray Pump. Journal Aerosol Med Pulm Drug Deliv. 2012;25(5):280–9.CrossRefGoogle Scholar
  29. 29.
    Corcoran TE. Imaging in Aerosol Medicine. Respir Care. 2015;60(6):850–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Xi JX, Wang ZX, Nevorski D, White T, Zhou Y. Nasal and Olfactory Deposition with Normal and Bidirectional Intranasal Delivery Techniques: In Vitro Tests and Numerical Simulations. Journal Aerosol Med Pulm Drug Deliv. 2017;30(2):118–31.CrossRefGoogle Scholar
  31. 31.
    Tu J, Inthavong K, Ahmadi G. Computational fluid and particle dynamics in the human respiratory system. In: Biological and Medical Physics, Biomedical Engineering, 1st edn. Netherlands: Springer; 2013. p. 374.  https://doi.org/10.1007/978-94-007-4488-2.
  32. 32.
    Dong J, Inthavong K, Tu J. Multiphase Flows in Biomedical Applications. In: Yeoh GH, editor. Handbook of Multiphase Flow Science and Technology. Singapore: Springer Singapore; 2017. p. 1–24.Google Scholar
  33. 33.
    Gizurarson S. Anatomical and Histological Factors Affecting Intranasal Drug and Vaccine Delivery. Curr Drug Deliv. 2012;9(6):566–82.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Djupesland PG, Skretting A, Winderen M, Holand T. Breath actuated device improves delivery to target sites beyond the nasal valve. Laryngoscope. 2006;116(3):466–72.CrossRefPubMedGoogle Scholar
  35. 35.
    Tepper SJ, Cady RK, Silberstein S, Messina J, Mahmoud RA, Djupesland PG, et al. AVP-825 breath-powered intranasal delivery system containing 22 mg sumatriptan powder vs 100 mg oral sumatriptan in the acute treatment of migraines (The COMPASS study): a comparative randomized clinical trial across multiple attacks. Headache. 2015;55(5):621–35.Google Scholar
  36. 36.
    Inthavong K, Tian L, Tu J. Lagrangian particle modelling of spherical nanoparticle dispersion and deposition in confined flows. J Aerosol Sci. 2016;96:56–68.CrossRefGoogle Scholar
  37. 37.
    Inthavong K, Tu JY, Ahmadi G. Computational modelling of gas-particle flows with different particle morphology in the human nasal cavity. J Comput Multiphase Flows. 2009;1:57–82.CrossRefGoogle Scholar
  38. 38.
    Ounis H, Ahmadi G. J.B. M. Brownian diffusion of submicrometer particles in the viscous sublayer. J Colloid Interface Sci. 1991;143(1):266–77.CrossRefGoogle Scholar
  39. 39.
    Li A, Ahmadi G. Dispersion and deposition of spherical particles from point sources in a turbulent channel flow. Aerosol Sci Technol. 1992;16(4):209–26.CrossRefGoogle Scholar
  40. 40.
    Groneberg DA, Witt C, Wagner U, Chung KF, Fischer A. Fundamentals of pulmonary drug delivery. Respir Med. 2003;97(4):382–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Wang Y, Li JY, Leavey A, O'Neil C, Babcock HM, Biswas P. Comparative Study on the Size Distributions, Respiratory Deposition, and Transport of Particles Generated from Commonly Used Medical Nebulizers. Journal Aerosol Med Pulm Drug Deliv. 2017;30(2):132–40.CrossRefGoogle Scholar
  42. 42.
    Schroeter JD, Musante CJ, Hwang DM, Burton R, Guilmette R, Martonen TB. Hygroscopic growth and deposition of inhaled secondary cigarette smoke in human nasal pathways. Aerosol Sci Technol. 2001;34(1):137–43.CrossRefGoogle Scholar
  43. 43.
    Zhang Z, Kleinstreuer C, Kim CS. Isotonic and hypertonic saline droplet deposition in a human upper airway model. J Aerosol Med. 2006;19(2):184–98.CrossRefPubMedGoogle Scholar
  44. 44.
    Hahn I, Scherer PW, Mozell MM. Velocity Profiles Measured for Air-Flow through a Large-Scale Model of the Human Nasal Cavity. J Appl Physiol. 1993;75(5):2273–87.CrossRefPubMedGoogle Scholar
  45. 45.
    Kelly JT, Prasad AK, Wexler AS. Detailed flow patterns in the nasal cavity. J Appl Physiol. 2000;89(1):323–37.CrossRefPubMedGoogle Scholar
  46. 46.
    Churchill SE, Shackelford LL, Georgi JN, Black MT. Morphological variation and airflow dynamics in the human nose. Am J Hum Biol. 2004;16(6):625–38.CrossRefPubMedGoogle Scholar
  47. 47.
    Schroeter JD, Kimbell JS, Asgharian B. Analysis of particle deposition in the turbinate and olfactory regions using a human nasal computational fluid dynamics model. J Aerosol Med. 2006;19(3):301–13.CrossRefPubMedGoogle Scholar
  48. 48.
    Garcia GJM, Bailie N, Martins DA, Kimbell JS. Atrophic rhinitis: a CFD study of air conditioning in the nasal cavity. J Appl Physiol. 2007;103(3):1082–92.CrossRefPubMedGoogle Scholar
  49. 49.
    Doorly DJ, Taylor DJ, Gambaruto AM, Schroter RC, Tolley N. Nasal architecture: form and flow. Philos T R Soc A. 2008;366(1879):3225–46.CrossRefGoogle Scholar
  50. 50.
    Tian L, Shang Y, Chen R, Bai R, Chen C, Inthavong K, et al. A combined experimental and numerical study on upper airway dosimetry of inhaled nanoparticles from an electrical discharge machine shop. Part Fibre Toxicol. 2017;14:24.Google Scholar
  51. 51.
    Shang YD, Dong JL, Inthavong K, Tu JY. Comparative numerical modeling of inhaled micron-sized particle deposition in human and rat nasal cavities. Inhal Toxicol. 2015;27(13):694–705.CrossRefPubMedGoogle Scholar
  52. 52.
    Shi H, Kleinstreuer C, Zhang Z. Laminar airflow and nanoparticle or vapor deposition in a human nasal cavity model. J Biomech Eng. 2006;128(5):697–706.CrossRefPubMedGoogle Scholar
  53. 53.
    Si XA, Xi J, Kim J, Zhou Y, Zhong H. Modeling of release position and ventilation effects on olfactory aerosol drug delivery. Respir Physiol Neurobiol. 2013;186(1):22–32.CrossRefPubMedGoogle Scholar
  54. 54.
    Brown JS, Wilson WE, Grant LD. Dosimetric comparisons of particle deposition and retention in rats and humans. Inhal Toxicol. 2005;17(7–8):355–85.CrossRefPubMedGoogle Scholar
  55. 55.
    Persson E, Larsson P, Tjalve H. Cellular activation and neuronal transport of intranasally instilled benzo(a)pyrene in the olfactory system of rats. Toxicol Lett. 2002;133(2–3):211–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Garcia GJM, Schroeter JD, Kimbell JS. Olfactory deposition of inhaled nanoparticles in humans. Inhal Toxicol. 2015;27(8):394–403.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Zhang Z, Kleinstreuer C, Kim CS. Cyclic micron-size particle inhalation and deposition in a triple bifurcation lung airway model. J Aerosol Sci. 2002;33(2):257–81.CrossRefGoogle Scholar
  58. 58.
    Bahmanzadeh H, Abouali O, Ahmadi G. Unsteady particle tracking of micro-particle deposition in the human nasal cavity under cyclic inspiratory flow. J Aerosol Sci. 2016;101:86–103.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.School of EngineeringRMIT UniversityBundooraAustralia
  2. 2.Advanced Drug Delivery Group, Faculty of PharmacyThe University of SydneySydneyAustralia
  3. 3.Key Laboratory of Ministry of Education for Advanced Reactor Engineering and Safety, Institute of Nuclear and New Energy TechnologyTsinghua UniversityBeijingChina

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