Targeted Drug Delivery to Upper Airways Using a Pulsed Aerosol Bolus and Inhaled Volume Tracking Method
The pulmonary route presents an attractive delivery pathway for topical treatment of lung diseases. While significant progress has been achieved in understanding the physical underpinnings of aerosol deposition in the lungs, our ability to target or confine the deposition of inhalation aerosols to specific lung regions remains meagre. Here, we present a novel inhalation proof-of-concept in silico for regional targeting in the upper airways, quantitatively supported by computational fluid dynamics (CFD) simulations of inhaled micron-sized particles (i.e. 1-10 μm) using an intubated, anatomically-realistic, multi-generation airway tree model. Our targeting strategy relies on selecting the particle release time, whereby a short-pulsed bolus of aerosols is injected into the airways and the inhaled volume of clean air behind the bolus is tracked to reach a desired inhalation depth (i.e. airway generations). A breath hold maneuver then follows to facilitate deposition, via sedimentation, before exhalation resumes and remaining airborne particles are expelled. Our numerical findings showcase how particles in the range 5-10 μm combined with such inhalation methodology are best suited to deposit in the upper airways, with deposition fractions between 0.68 and unity. In contrast, smaller (< 2 μm) particles are less than optimal due to their slow sedimentation rates. We illustrate further how modulating the volume inhaled behind the pulsed bolus, prior to breath hold, may be leveraged to vary the targeted airway sites. We discuss the feasibility of the proposed inhalation framework and how it may help pave the way for specialized topical lung treatments.
KeywordsInhalation medicine Aerosol transport CFD Lungs
The authors would like to thank Dr. Rami Fishler for fruitful discussions. This work was supported by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement No. 677772), and the Kamin Program from the Israel Innovation Authority (grant agreement No. 60509). The authors acknowledge COST Action MP1404 SimInhale ‘Simulation and pharmaceutical technologies for advanced patient-tailored inhaled medicines’, supported by the European Cooperation in Science and Technology (COST).
Compliance with Ethical Standards
Conflict of interests
The authors declare that they have no conflict of interest.
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- 2.Burrowes, K.S., Doel, T., Brightling, C.: Computational modeling of the obstructive lung diseases asthma and COPD. J. Transl. Med. 12(2:S5), 1–8 (2014)Google Scholar
- 6.Tu, J., Inthavong, K., Ahmadi, G.: Computational fluid and particle dynamics in the human respiratory system, 1st edn. Springer, Dordrecht (2013)Google Scholar
- 7.Weibel, E.R.: Morphometry of the human lung, 1st edn. Springer, Berlin (1963)Google Scholar
- 12.ICRP Protection International Commission on Radiological: ICRP publication 66: human respiratory tract model for radiological protection. Ann. ICRP 124(1–3), 1–482 (1994)Google Scholar
- 14.Finlay, W.H.: Motion of a single aerosol particle in a fluid. In: The Mechanics of Inhaled Pharmaceutical Aerosols, 1st edn. Academic Press, London (2001)Google Scholar
- 17.Edwards, D.A.: Large Porous Particles for Pulmonary Drug Delivery, Science (80-. ). 276(5320), 1868–1872 (1997)Google Scholar
- 22.Pourmehran, O., Rahimi-Gorji, M., Gorji-Bandpy, M., Gorji, T.B.: Simulation of magnetic drug targeting through tracheobronchial airways in the presence of an external non-uniform magnetic field using Lagrangian magnetic particle tracking. J. Magn. Magn. Mater. 393, 380–393 (2015)CrossRefGoogle Scholar
- 29.Reddy, R.M., Guntupalli, K.K.: Review of ventilatory techniques to optimize mechanical ventilation in acute exacerbation of chronic obstructive pulmonary disease. Int. J. COPD 2(4), 441–452 (2007)Google Scholar
- 33.Kobashi, S., Kuramoto, K., Hat, Y.: Functional assessment of individual lung lobes with MDCT images, in Theory and Applications of CT Imaging and Analysis. InTech (2011)Google Scholar
- 39.Lizal, F., et al.: Experimental methods for flow and aerosol measurements in human airways and their replicas. Eur. J. Pharm. Sci. (2017)Google Scholar
- 40.Koullapis, P., et al.: Regional aerosol deposition in the human airways: The SimInhale benchmark case and a critical assessment of in silico methods. Eur. J. Pharm. Sci. (2017)Google Scholar
- 44.Lavorini, F.: The challenge of delivering therapeutic aerosols to asthma patients. ISRN Allergy 2013(1), 102418 (2013)Google Scholar