Numerical evaluation of spray position for improved nasal drug delivery

Topical intra-nasal sprays are amongst the most commonly prescribed therapeutic options for sinonasal diseases in humans. However, inconsistency and ambiguity in instructions show a lack of definitive knowledge on best spray use techniques. In this study, we have identified a new usage strategy for nasal sprays available over-the-counter, that registers an average 8-fold improvement in topical delivery of drugs at diseased sites, when compared to prevalent spray techniques. The protocol involves re-orienting the spray axis to harness inertial motion of particulates and has been developed using computational fluid dynamics simulations of respiratory airflow and droplet transport in medical imaging-based digital models. Simulated dose in representative models is validated through in vitro spray measurements in 3D-printed anatomic replicas using the gamma scintigraphy technique. This work breaks new ground in proposing an alternative user-friendly strategy that can significantly enhance topical delivery inside human nose. While these findings can eventually translate into personalized spray usage instructions and hence merit a change in nasal standard-of-care, this study also demonstrates how relatively simple engineering analysis tools can revolutionize everyday healthcare. Finally, with respiratory mucosa as the initial coronavirus infection site, our findings are relevant to intra-nasal vaccines that are in-development, to mitigate the COVID-19 pandemic.

[1]  M. Powell Adult sinusitis. , 1993, Journal of the American Academy of Nurse Practitioners.

[2]  J. Kimbell,et al.  Ideal Particle Sizes for Inhaled Steroids Targeting Vocal Granulomas: Preliminary Study Using Computational Fluid Dynamics , 2018, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[3]  W. Shockley,et al.  Comparison of Airflow Between Spreader Grafts and Butterfly Grafts Using Computational Flow Dynamics in a Cadaveric Model , 2017, JAMA facial plastic surgery.

[4]  Jinxiang Xi,et al.  Numerical predictions of submicrometer aerosol deposition in the nasal cavity using a novel drift flux approach , 2008 .

[5]  Guillaume Houzeaux,et al.  Nasal sprayed particle deposition in a human nasal cavity under different inhalation conditions , 2019, PloS one.

[6]  M. Stremler,et al.  Exploring the dynamics of ‘2P’ wakes with reflective symmetry using point vortices , 2017, Journal of Fluid Mechanics.

[7]  S. A. Morsi,et al.  An investigation of particle trajectories in two-phase flow systems , 1972, Journal of Fluid Mechanics.

[8]  Jiyuan Tu,et al.  External characteristics of unsteady spray atomization from a nasal spray device. , 2013, Journal of pharmaceutical sciences.

[9]  A. Zanation,et al.  Impact of endoscopic craniofacial resection on simulated nasal airflow and heat transport , 2019, International forum of allergy & rhinology.

[10]  A S Wexler,et al.  Detailed flow patterns in the nasal cavity. , 2000, Journal of applied physiology.

[11]  B. Laube,et al.  The Effect of Formulation Variables and Breathing Patterns on the Site of Nasal Deposition in an Anatomically Correct Model , 2005, Pharmaceutical Research.

[12]  Saikat Basu Dynamics of vortices in complex wakes: Modeling, analysis, and experiments , 2014 .

[13]  M. Stremler,et al.  On point vortex models of exotic bluff body wakes , 2014 .

[14]  Vipra Kundoor,et al.  Effect of Formulation- and Administration-Related Variables on Deposition Pattern of Nasal Spray Pumps Evaluated Using a Nasal Cast , 2011, Pharmaceutical Research.

[15]  D. Kennedy,et al.  Adult Chronic Rhinosinusitis: Definitions, Diagnosis, Epidemiology, and Pathophysiology , 2003, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[16]  A. Yawar,et al.  On angled bounce-off impact of a drop impinging on a flowing soap film , 2017, 1705.05948.

[17]  Jeffry D. Schroeter,et al.  Dosimetry of nasal uptake of water-soluble and reactive gases: A first study of interhuman variability , 2009, Inhalation toxicology.

[18]  Guilherme J M Garcia,et al.  Creation of an idealized nasopharynx geometry for accurate computational fluid dynamics simulations of nasal airflow in patient‐specific models lacking the nasopharynx anatomy , 2017, International journal for numerical methods in biomedical engineering.

[19]  Julia S Kimbell,et al.  Quantification of airflow into the maxillary sinuses before and after functional endoscopic sinus surgery , 2013, International forum of allergy & rhinology.

[20]  A. Coniglio,et al.  Comparative Analysis of the Main Nasal Cavity and the Paranasal Sinuses in Chronic Rhinosinusitis: An Anatomic Study of Maximal Medical Therapy , 2018, 1811.00649.

[21]  Kevin W Eliceiri,et al.  NIH Image to ImageJ: 25 years of image analysis , 2012, Nature Methods.

[22]  Haribalan Kumar,et al.  Image‐based computational fluid dynamics in the lung: virtual reality or new clinical practice? , 2017, Wiley interdisciplinary reviews. Systems biology and medicine.

[23]  Jun Chang,et al.  Superior immune responses induced by intranasal immunization with recombinant adenovirus-based vaccine expressing full-length Spike protein of Middle East respiratory syndrome coronavirus , 2019, PloS one.

[24]  D. Leopold,et al.  Techniques of Intranasal Steroid Use , 2004, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[25]  M. Sung,et al.  Mucosal Immunization with Surface-Displayed Severe Acute Respiratory Syndrome Coronavirus Spike Protein on Lactobacillus casei Induces Neutralizing Antibodies in Mice , 2006, Journal of Virology.

[26]  Jiyuan Tu,et al.  Simulation of sprayed particle deposition in a human nasal cavity including a nasal spray device , 2011 .

[27]  M. Stremler,et al.  A mathematical model of 2P and 2C vortex wakes , 2011 .

[28]  Jiyuan Tu,et al.  Measurements of droplet size distribution and analysis of nasal spray atomization from different actuation pressure. , 2015, Journal of aerosol medicine and pulmonary drug delivery.

[29]  Richard N Dalby,et al.  Automated actuation of nasal spray products: determination and comparison of adult and pediatric settings , 2011, Drug development and industrial pharmacy.

[30]  Kerstin Pingel,et al.  50 Years of Image Analysis , 2012 .

[31]  Changning Guo,et al.  Assessment of the Influence Factors on Nasal Spray Droplet Velocity Using Phase-Doppler Anemometry (PDA) , 2011, AAPS PharmSciTech.

[32]  Dimitry E. Protsenko,et al.  Upper airway reconstruction using long‐range optical coherence tomography: Effects of airway curvature on airflow resistance , 2018, Lasers in surgery and medicine.

[33]  Julia S. Kimbell,et al.  Clinical questions and the role CFD can play , 2016 .

[34]  P. Longest,et al.  Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Development of a CFD Model. , 2016, Journal of aerosol medicine and pulmonary drug delivery.

[35]  Bruce Bryant,et al.  Perceiving Nasal Patency through Mucosal Cooling Rather than Air Temperature or Nasal Resistance , 2011, PloS one.

[36]  Kai Zhao,et al.  What is normal nasal airflow? A computational study of 22 healthy adults , 2014, International forum of allergy & rhinology.

[37]  P. Hopke,et al.  Numerical simulations investigating the regional and overall deposition efficiency of the human nasal cavity. , 2008, Inhalation toxicology.

[38]  M. Stremler,et al.  On the motion of two point vortex pairs with glide-reflective symmetry in a periodic strip , 2015 .

[39]  Warren H. Finlay,et al.  The Mechanics of Inhaled Pharmaceutical Aerosols: An Introduction , 2001 .

[40]  Frank H Wilhelm,et al.  The LifeShirt , 2003, Behavior modification.

[41]  Dennis O Frank-Ito,et al.  On computational fluid dynamics models for sinonasal drug transport: Relevance of nozzle subtraction and nasal vestibular dilation , 2017, International journal for numerical methods in biomedical engineering.

[42]  P. Longest,et al.  Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Development of a CFD Model. , 2016, Journal of aerosol medicine and pulmonary drug delivery.

[43]  C. Ebert,et al.  Comparative study of simulated nebulized and spray particle deposition in chronic rhinosinusitis patients , 2018, International forum of allergy & rhinology.

[44]  G. Scadding,et al.  Topical corticosteroids in chronic rhinosinusitis: a randomized, double-blind, placebo-controlled trial using fluticasone propionate aqueous nasal spray. , 2001, Rhinology.

[45]  Angelica Duran,et al.  An introduction , 1967, Rome Is Burning.

[46]  Wesley H. Stepp,et al.  Nasal Airflow Changes With Bioabsorbable Implant, Butterfly, and Spreader Grafts , 2020, The Laryngoscope.

[47]  Jiyuan Tu,et al.  From CT Scans to CFD Modelling – Fluid and Heat Transfer in a Realistic Human Nasal Cavity , 2009 .

[48]  H P Lee,et al.  A review of the implications of computational fluid dynamic studies on nasal airflow and physiology. , 2010, Rhinology.

[49]  Mandip Singh,et al.  Evaluation of different parameters that affect droplet-size distribution from nasal sprays using the Malvern Spraytec. , 2004, Journal of pharmaceutical sciences.

[50]  Kamarul Arifin Ahmad,et al.  Review: A critical overview of limitations of cfd modeling in nasal airflow , 2012 .

[51]  R A Guilmette,et al.  Characterization of nasal spray pumps and deposition pattern in a replica of the human nasal airway. , 2001, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[52]  K P Van de Woestijne,et al.  Influence of awareness of the recording of breathing on respiratory pattern in healthy humans. , 1997, The European respiratory journal.

[53]  O. Price,et al.  Simulation of the phase change and deposition of inhaled semi-volatile liquid droplets in the nasal passages of rats and humans , 2016 .

[54]  D. J. Taylor,et al.  Nasal architecture: form and flow , 2008, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[55]  J. Kimbell,et al.  Characterizing Nasal Delivery in 3D Models Before and After Sinus Surgery , 2018 .

[56]  M. Benninger Editors and Reviewers: Supporting Peer-Review Publishing , 2003 .

[57]  Richard N. Shiffman,et al.  Clinical practice guideline: Adult sinusitis , 2007, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.