Absorption and Clearance of Pharmaceutical Aerosols in the Human Nose: Development of a CFD Model.

Abstract Purpose: The objective of this study was to develop a computational fluid dynamics (CFD) model to predict the deposition, dissolution, clearance, and absorption of pharmaceutical particles in the human nasal cavity. Methods: A three-dimensional nasal cavity geometry was converted to a surface-based model, providing an anatomically-accurate domain for the simulations. Particle deposition data from a commercial nasal spray product was mapped onto the surface model, and a mucus velocity field was calculated and validated with in vivo nasal clearance rates. A submodel for the dissolution of deposited particles was developed and validated based on comparisons to existing in vitro data for multiple pharmaceutical products. A parametric study was then performed to assess sensitivity of epithelial drug uptake to model conditions and assumptions. Results: The particle displacement distance (depth) in the mucus layer had a modest effect on overall drug absorption, while the mucociliary clearance rate was f...

[1]  Melvin E Andersen,et al.  Incorporation of tissue reaction kinetics in a computational fluid dynamics model for nasal extraction of inhaled hydrogen sulfide in rats. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[2]  Geng Tian,et al.  Application of a new dosimetry program TAOCS to assess transient vapour absorption in the upper airways , 2010, Inhalation toxicology.

[3]  M. Hindle,et al.  Evaluation of the Respimat Soft Mist Inhaler using a concurrent CFD and in vitro approach. , 2009, Journal of aerosol medicine and pulmonary drug delivery.

[4]  F. Merkus,et al.  The Nasal Mucociliary Clearance: Relevance to Nasal Drug Delivery , 1991, Pharmaceutical Research.

[5]  Clement Kleinstreuer,et al.  Modeling of inertial particle transport and deposition in human nasal cavities with wall roughness , 2007 .

[6]  A. Falcão,et al.  Intranasal drug delivery: how, why and what for? , 2009, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[7]  I. Andersen,et al.  Clearance of inhaled particles from the human nose. , 1973, Archives of internal medicine.

[8]  Lisbeth Illum,et al.  Absorption Enhancers for Nasal Drug Delivery , 2003, Clinical pharmacokinetics.

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

[10]  B. Laube,et al.  Devices for aerosol delivery to treat sinusitis. , 2007, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[11]  R. Walenga,et al.  Variability in Nose-to-Lung Aerosol Delivery. , 2014, Journal of aerosol science.

[12]  C. Kleinstreuer,et al.  Transport and Uptake of MTBE and Ethanol Vapors in a Human Upper Airway Model , 2006, Inhalation toxicology.

[13]  Guilherme J M Garcia,et al.  Interindividual variability in nasal filtration as a function of nasal cavity geometry. , 2009, Journal of aerosol medicine and pulmonary drug delivery.

[14]  A. Skretting,et al.  Nasal deposition and clearance in man: comparison of a bidirectional powder device and a traditional liquid spray pump. , 2012, Journal of aerosol medicine and pulmonary drug delivery.

[15]  J. Ultman,et al.  A CFD-PBPK hybrid model for simulating gas and vapor uptake in the rat nose. , 1998, Toxicology and applied pharmacology.

[16]  J. Wen,et al.  Comparison of micron- and nanoparticle deposition patterns in a realistic human nasal cavity , 2009, Respiratory Physiology & Neurobiology.

[17]  Jinxiang Xi,et al.  Simulation of airflow and aerosol deposition in the nasal cavity of a 5-year-old child , 2011 .

[18]  Lisbeth Illum,et al.  Nanoparticles for direct nose-to-brain delivery of drugs. , 2009, International journal of pharmaceutics.

[19]  N. Jones,et al.  The rheology of nasal mucus: a review. , 1998, Clinical otolaryngology and allied sciences.

[20]  J. Hardy,et al.  Intranasal drug delivery by spray and drops , 1985, The Journal of pharmacy and pharmacology.

[21]  C. Lehr,et al.  Drug transport across pulmonary epithelial cell monolayers: effects of particle size, apical liquid volume, and deposition technique. , 2010, Journal of aerosol medicine and pulmonary drug delivery.

[22]  P. Roache.  Perspective: A Method for Uniform Reporting of Grid Refinement Studies , 1994 .

[23]  L. Hanson,et al.  Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease , 2008, BMC Neuroscience.

[24]  Denis Wirtz,et al.  Micro- and macrorheology of mucus. , 2009, Advanced drug delivery reviews.

[25]  C Kleinstreuer,et al.  Laminar airflow and nanoparticle or vapor deposition in a human nasal cavity model. , 2006, Journal of biomechanical engineering.

[26]  Jeffry D Schroeter,et al.  Characterization of deposition from nasal spray devices using a computational fluid dynamics model of the human nasal passages. , 2007, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[27]  Kevin R Minard,et al.  Comparative Risks of Aldehyde Constituents in Cigarette Smoke Using Transient Computational Fluid Dynamics/Physiologically Based Pharmacokinetic Models of the Rat and Human Respiratory Tracts. , 2015, Toxicological sciences : an official journal of the Society of Toxicology.

[28]  M. Hindle,et al.  Improving the lung delivery of nasally administered aerosols during noninvasive ventilation-an application of enhanced condensational growth (ECG). , 2011, Journal of aerosol medicine and pulmonary drug delivery.

[29]  P. Royall,et al.  Differences in physical chemistry and dissolution rate of solid particle aerosols from solution pressurised inhalers. , 2014, International journal of pharmaceutics.

[30]  Hussain,et al.  Intranasal drug delivery. , 1998, Advanced drug delivery reviews.

[31]  Tilo Winkler,et al.  Lung physiology and aerosol deposition imaged with positron emission tomography. , 2013, Journal of aerosol medicine and pulmonary drug delivery.

[32]  L. Illum.  Nasal drug delivery: new developments and strategies. , 2002, Drug discovery today.

[33]  L. Illum,et al.  Intranasal delivery: physicochemical and therapeutic aspects. , 2007, International journal of pharmaceutics.

[34]  L. Illum.  Transport of drugs from the nasal cavity to the central nervous system. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[35]  S. Garg,et al.  Permeability issues in nasal drug delivery. , 2002, Drug discovery today.

[36]  Per Gisle Djupesland,et al.  Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review , 2012, Drug Delivery and Translational Research.

[37]  Geng Tian,et al.  Development of a CFD boundary condition to model transient vapor absorption in the respiratory airways. , 2010, Journal of biomechanical engineering.

[38]  J. Zahm,et al.  Rheological properties controlling mucociliary frequency and respiratory mucus transport. , 1987, Biorheology.

[39]  M. Andersen,et al.  Use of a pharmacokinetic-driven computational fluid dynamics model to predict nasal extraction of hydrogen sulfide in rats and humans. , 2006, Toxicological sciences : an official journal of the Society of Toxicology.

[40]  F. Fry,et al.  Regional deposition and clearance of particles in the human nose , 1973 .

[41]  Jeffry D Schroeter,et al.  Analysis of particle deposition in the turbinate and olfactory regions using a human nasal computational fluid dynamics model. , 2006, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[42]  B. Jafek.  Ultrastructure of human nasal mucosa , 1983, The Laryngoscope.

[43]  Selcan Türker,et al.  Nasal route and drug delivery systems , 2004, Pharmacy World and Science.

[44]  B. Laube,et al.  Validity of in vitro tests on aqueous spray pumps as surrogates for nasal deposition, absorption, and biologic response. , 2006, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[45]  M. Gumbleton,et al.  The particle has landed--characterizing the fate of inhaled pharmaceuticals. , 2010, Journal of aerosol medicine and pulmonary drug delivery.

[46]  Lena Pereswetoff-Morath,et al.  Microspheres as nasal drug delivery systems. , 1998, Advanced drug delivery reviews.

[47]  R. Walenga,et al.  The Use of Condensational Growth Methods for Efficient Drug Delivery to the Lungs during Noninvasive Ventilation High Flow Therapy , 2013, Pharmaceutical Research.

[48]  Julia S. Kimbell,et al.  Particle Deposition in Human Nasal Airway Replicas Manufactured by Different Methods. Part I: Inertial Regime Particles , 2004 .

[49]  T. Mano,et al.  Solubility and dissolution profile assessment in drug discovery. , 2007, Drug metabolism and pharmacokinetics.

[50]  Kumar A. Shah,et al.  In Vitro Aqueous Fluid-Capacity-Limited Dissolution Testing of Respirable Aerosol Drug Particles Generated from Inhaler Products , 2010, Pharmaceutical Research.

[51]  Raymond A. Guilmette,et al.  Morphometry of Human Nasal Airways In Vivo Using Magnetic Resonance Imaging , 1989 .

[52]  D. Klee,et al.  Influence of particle size and material properties on mucociliary clearance from the airways. , 2010, Journal of aerosol medicine and pulmonary drug delivery.

[53]  P. Fedkiw,et al.  Mass-transport models to predict toxicity of inhaled gases in the upper respiratory tract. , 1996, Journal of applied physiology.

[54]  B. Laube,et al.  Comparison of Nasal Deposition and Clearance of Aerosol Generated by a Nebulizer and an Aqueous Spray Pump , 1999, Pharmaceutical Research.

[55]  Yen Cu,et al.  Mathematical modeling of molecular diffusion through mucus. , 2009, Advanced drug delivery reviews.

[56]  L. Illum.  Nasal drug delivery--possibilities, problems and solutions. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[57]  Marianne Geiser,et al.  Particle Retention in Airways by Surfactant , 1990 .

[58]  Matthew R. Johnson,et al.  Experimental measurements and computational modeling of aerosol deposition in the Carleton-Civic standardized human nasal cavity , 2010 .

[59]  R. Tarran,et al.  Rationale for Hypertonic Saline Therapy for Cystic Fibrosis Lung Disease , 2007, Seminars in respiratory and critical care medicine.

[60]  Trond Holand,et al.  Breath Actuated Device Improves Delivery to Target Sites Beyond the Nasal Valve , 2006, The Laryngoscope.

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

[62]  P. Longest,et al.  Transient Absorption of Inhaled Vapors into a Multilayer Mucus–Tissue–Blood System , 2010, Annals of Biomedical Engineering.

[63]  Jeffry D Schroeter,et al.  Effects of Surface Smoothness on Inertial Particle Deposition in Human Nasal Models. , 2011, Journal of aerosol science.

[64]  R. Kinget,et al.  Nasal mucoadhesive drug delivery: background, applications, trends and future perspectives. , 2005, Advanced drug delivery reviews.