Targeted drug-aerosol delivery in the human respiratory system.

Inhalation of drug aerosols is a modern pathway to combat lung diseases. It is also becoming the preferred route for insulin delivery, pain management, cancer therapy, and nanotherapeutics. Popular delivery devices include nebulizers, metered-dose inhalers, and dry-powder inhalers. They are all nondirectional and hence have typically low particle deposition efficiencies in desired nasal or lung areas. Thus, for specific disease treatment with costly and/or aggressive medicine, it is necessary to provide targeted drug-aerosol delivery to predetermined sites in the human respiratory system. Experimental measurements and computer models of particle transport and deposition in nasal and lung airway models are presented. Furthermore, the underlying methodology and performance of pressurized metered dose inhalers as well as new smart inhaler systems are discussed. To maximize respiratory drug delivery to specific sites, an optimal combination of particle characteristics, inhalation waveform, particle release position, and drug-aerosol dosage has to be achieved.

[1]  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.

[2]  Y. Cheng,et al.  An experimental method for measuring aerosol deposition efficiency in the human oral airway. , 1997, American Industrial Hygiene Association journal.

[3]  W. Finlay,et al.  In vitro intersubject and intrasubject deposition measurements in realistic mouth-throat geometries , 2004 .

[4]  M Lippmann,et al.  Experimental measurements and empirical modelling of the regional deposition of inhaled particles in humans. , 1980, American Industrial Hygiene Association journal.

[5]  Clement Kleinstreuer,et al.  Nanoparticle transport and deposition in bifurcating tubes with different inlet conditions , 2004 .

[6]  J. Heyder,et al.  New regional deposition data of the human respiratory tract , 1983 .

[7]  Simon Cawthorne,et al.  Particle engineering techniques for inhaled biopharmaceuticals. , 2006, Advanced drug delivery reviews.

[8]  Clement Kleinstreuer,et al.  Computational analyses of a pressurized metered dose inhaler and a new drug-aerosol targeting methodology. , 2007, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[9]  J. Oppenheimer Device Selection and Outcomes of Aerosol Therapy: Evidence-Based Guidelines , 2006 .

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

[11]  B. Asgharian,et al.  A MONTE CARLO CALCULATION OF THE DEPOSITION EFFICIENCY OF INHALED PARTICLES IN LOWER AIRWAYS , 1994 .

[12]  P. J. Hunter,et al.  Generation of an Anatomically Based Three-Dimensional Model of the Conducting Airways , 2000, Annals of Biomedical Engineering.

[13]  J. Crane,et al.  Reduction of the Cardiovascular Effects of Inhaled Fenoterol by Use of a Valved Holding Chamber Device , 1989 .

[14]  C. Kleinstreuer,et al.  Fluid-structure interaction effects on sac-blood pressure and wall stress in a stented aneurysm. , 2005, Journal of biomechanical engineering.

[15]  Wei-Chung Su,et al.  Deposition of Fiber in the Human Nasal Airway , 2005 .

[16]  W. Finlay,et al.  In vitro effect of a holding chamber on the mouth-throat deposition of QVAR (hydrofluoroalkane-beclomethasone dipropionate). , 2002, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[17]  P. Reddy,et al.  Recent Advances in Novel Drug Delivery Systems , 2003 .

[18]  D. Edwards The macrotransport of aerosol particles in the lung: Aerosol deposition phenomena , 1995 .

[19]  Clement Kleinstreuer,et al.  Micro-particle transport and deposition in a human oral airway model , 2002 .

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

[21]  P. Jaques,et al.  Analysis of Total Respiratory Deposition of Inhaled Ultrafine Particles in Adult Subjects at Various Breathing Patterns , 2004 .

[22]  B J B M Wolters,et al.  A patient-specific computational model of fluid-structure interaction in abdominal aortic aneurysms. , 2005, Medical engineering & physics.

[23]  Günter Oberdörster,et al.  Ultrafine Particle Deposition in Humans During Rest and Exercise , 2003, Inhalation toxicology.

[24]  A. Black,et al.  Regional deposition of 2.5-7.5 μm diameter inhaled particles in healthy male non-smokers , 1978 .

[25]  W. Finlay,et al.  Improved numerical simulation of aerosol deposition in an idealized mouth-throat , 2004 .

[26]  David F. Fletcher,et al.  Influence of Air Flow on the Performance of a Dry Powder Inhaler Using Computational and Experimental Analyses , 2005, Pharmaceutical Research.

[27]  S. Simpson,et al.  In vivo measurements of nasal airway dimensions and ultrafine aerosol deposition in the human nasal and oral airways , 1996 .

[28]  Clement Kleinstreuer,et al.  Biofluid Dynamics: Principles and Selected Applications , 2006 .

[29]  H. Smyth,et al.  Alternative propellant aerosol delivery systems. , 2005, Critical reviews in therapeutic drug carrier systems.

[30]  Clement Kleinstreuer,et al.  Comparison of micro- and nano-size particle depositions in a human upper airway model , 2005 .

[31]  Goodarz Ahmadi,et al.  Airflow and Deposition of Nano-Particles in a Human Nasal Cavity , 2006 .

[32]  Clement Kleinstreuer,et al.  Low-Reynolds-Number Turbulent Flows in Locally Constricted Conduits: A Comparison Study , 2003 .

[33]  W Stahlhofen,et al.  Experimental determination of the regional deposition of aerosol particles in the human respiratory tract. , 1980, American Industrial Hygiene Association journal.

[34]  T. Bengtsson,et al.  Dose delivery late in the breath can increase dry powder aerosol penetration into the lungs. , 2005, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[35]  J. Hanes,et al.  New polymeric carriers for controlled drug delivery following inhalation or injection. , 2002, Biomaterials.

[36]  A. P. Watkins,et al.  An experimental investigation of the spray issued from a pMDI using laser diagnostic techniques. , 1997, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[37]  J. Heyder,et al.  Deposition of inhaled particles in the human respiratory tract and consequences for regional targeting in respiratory drug delivery. , 2004, Proceedings of the American Thoracic Society.

[38]  H Kitaoka,et al.  A three-dimensional model of the human airway tree. , 1999, Journal of applied physiology.

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

[40]  S. Schürch,et al.  Structural and Interfacial Aspects of Particle Retention , 2000 .

[41]  Albert H. L. Chow,et al.  Particle Engineering for Pulmonary Drug Delivery , 2007, Pharmaceutical Research.

[42]  P. C. Emmett,et al.  Measurements of the total and regional deposition of inhaled particles in the human respiratory tract , 1982 .

[43]  Charles A. Taylor,et al.  Intracranial and abdominal aortic aneurysms: similarities, differences, and need for a new class of computational models. , 2008, Annual review of biomedical engineering.

[44]  Bean T. Chen,et al.  Particle Deposition in a Cast of Human Oral Airways , 1999 .

[45]  Norman Chigier,et al.  A Numerical and Experimental Study of Spray Dynamics in a Simple Throat Model , 2002 .

[46]  H. Chan,et al.  Effect of moisture on the electrostatic charge properties of metered dose inhaler aerosols , 2006 .

[47]  David M. Broday,et al.  Growth and Deposition of Hygroscopic Particulate Matter in the Human Lungs , 2001 .

[48]  C. Leach,et al.  Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. , 1998, The European respiratory journal.

[49]  A. Gosman,et al.  Aspects of computer simulation of liquid-fuelled combustors , 1981 .

[50]  Anthony J. Hickey,et al.  Pharmaceutical Inhalation Aerosol Technology , 2003 .

[51]  Imre Balásházy,et al.  Inspiratory Deposition Efficiency of Ultrafine Particles in a Human Airway Bifurcation Model , 2003 .

[52]  G. Yu,et al.  Computer Simulation of the Flow Field and Particle Deposition by Diffusion in a 3-D Human Airway Bifurcation , 1996 .

[53]  N. Khorsand,et al.  In Vitro Performance of Two Common Valved Holding Chambers with a Chlorofluorocarbon‐Free Beclomethasone Metered‐Dose Inhaler , 2003, Pharmacotherapy.

[54]  L. Gradon,et al.  Temporary and spatial deposition of aerosol particles in the upper human airways during breathing cycle , 2002 .

[55]  Marc A Simon,et al.  Current and future considerations in the use of mechanical circulatory support devices. , 2008, Annual review of biomedical engineering.

[56]  D. Fisher,et al.  Deposition Characteristics of Aerosol Particles in Sequentially Bifurcating Airway Models , 1999 .

[57]  Y. Cheng,et al.  Measurements of airway dimensions and calculation of mass transfer characteristics of the human oral passage. , 1997, Journal of biomechanical engineering.

[58]  D. Steinman,et al.  Two-equation turbulence modeling of pulsatile flow in a stenosed tube. , 2004, Journal of biomechanical engineering.

[59]  Timothy J. Pedley,et al.  Pulmonary Fluid Dynamics , 1977 .

[60]  Clement Kleinstreuer,et al.  Laminar-to-turbulent fluid-particle flows in a human airway model , 2003 .

[61]  Clement Kleinstreuer,et al.  Cyclic micron-size particle inhalation and deposition in a triple bifurcation lung airway model , 2002 .

[62]  Yu Zhang,et al.  Measurement of the Effect of Cartilaginous Rings on Particle Deposition in a Proximal Lung Bifurcation Model , 2005 .

[63]  J. Tu,et al.  A Numerical Study of Spray Particle Deposition in a Human Nasal Cavity , 2006 .

[64]  A. Gosman,et al.  Aspects of Computer Simulation of Liquid-Fueled Combustors , 1983 .

[65]  J. Marijnissen,et al.  Optimization of Aerosol Drug Delivery , 2003, Springer Netherlands.

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

[67]  Thomas Heistracher,et al.  Computation of local enhancement factors for the quantification of particle deposition patterns in airway bifurcations , 1999 .

[68]  D. Wilcox Turbulence modeling for CFD , 1993 .

[69]  T B Martonen,et al.  Three-dimensional fluid particle trajectories in the human larynx and trachea. , 1996, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[70]  Françoise J. Prêteux,et al.  Virtual investigation of pulmonary airways in volumetric computed tomography , 2004, Comput. Animat. Virtual Worlds.

[71]  A. Hickey,et al.  Dry powder inhaler formulation. , 2005, Respiratory care.

[72]  P. Dario,et al.  A drug delivery system based on alginate microspheres: Mass-transport test and in vitro validation , 2007, Biomedical microdevices.

[73]  G. Yu,et al.  Fluid Flow and Particle Diffusion in the Human Upper Respiratory System , 1998 .

[74]  J. Staniforth,et al.  Active and intelligent inhaler device development. , 2004, International journal of pharmaceutics.

[75]  Huawei Shi Numerical Simulation of Airflow, Particle Deposition and Drug Delivery in a Representative Human Nasal Airway Model , 2007 .

[76]  Silverthorn Dee Unglaub Human Physiology: An Integrated Approach , 1998 .

[77]  M Lippmann,et al.  The effect of particle size on the regional deposition of inhaled aerosols in the human respiratory tract. , 1969, American Industrial Hygiene Association journal.

[78]  J. Wright,et al.  Systematic review of clinical effectiveness of pressurised metered dose inhalers versus other hand held inhaler devices for delivering corticosteroids in asthma , 2001, BMJ : British Medical Journal.

[79]  Goodarz Ahmadi,et al.  PARTICLE DEPOSITION IN A NEARLY DEVELOPED TURBULENT DUCT FLOW WITH ELECTROPHORESIS , 1999 .

[80]  Imre Balásházy,et al.  Particle deposition in airway bifurcations–II. Expiratory flow , 1993 .

[81]  Yuji Yamada,et al.  Diffusional deposition of ultrafine aerosols in a human nasal cast , 1988 .

[82]  J. L. Rau,et al.  Device selection and outcomes of aerosol therapy: Evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. , 2005, Chest.

[83]  Andrew Clark,et al.  Pulmonary Delivery Technology: Recent Advances and Potential for the New Millennium , 2003 .

[84]  K. Nikander,et al.  Adaptive Aerosol Delivery (AAD®) technology , 2004, Expert opinion on drug delivery.

[85]  G. Rudolf,et al.  Intercomparison of Experimental Regional Aerosol Deposition Data , 1989 .

[86]  Yung-sung Cheng,et al.  Gas Collection Efficiency and Entrance Flow Effect of an Annular Diffusion Denuder , 1996 .

[87]  Yung Sung Cheng,et al.  Aerosol Deposition in the Extrathoracic Region , 2003, Aerosol science and technology : the journal of the American Association for Aerosol Research.

[88]  Warren H. Finlay,et al.  On the suitability of k–ε turbulence modeling for aerosol deposition in the mouth and throat: a comparison with experiment , 2000 .

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

[90]  M. Sakagami,et al.  In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery. , 2006, Advanced drug delivery reviews.

[91]  P. Zanen Targetting Aerosols to Disease Areas , 2003 .

[92]  Ted B. Martonen,et al.  A numerical study of particle motion within the human larynx and trachea , 1999 .

[93]  Charles Taylor,et al.  EXPERIMENTAL AND COMPUTATIONAL METHODS IN CARDIOVASCULAR FLUID MECHANICS , 2004 .

[94]  T. Martonen,et al.  Factors affecting the deposition of inhaled porous drug particles. , 2002, Journal of pharmaceutical sciences.

[95]  Günter Oberdörster,et al.  Estimation of the Deposition of Aerosolized Drugs in the Human Respiratory Tract Due to Hygroscopic Growth , 1989 .

[96]  A. Tsuda,et al.  Gravitational deposition in a rhythmically expanding and contracting alveolus. , 2003, Journal of applied physiology.

[97]  David L. Swift,et al.  Deposition of Ultrafine Aerosols in the Head Airways During Natural Breathing and During Simulated Breath Holding Using Replicate Human Upper Airway Casts , 1995 .

[98]  Goodarz Ahmadi,et al.  Dispersion and deposition of Brownian particles from point sources in a simulated turbulent channel flow , 1991 .

[99]  A. Wexler,et al.  Interaction of epithelium with mesenchyme affects global features of lung architecture: a computer model of development. , 2007, Journal of applied physiology.

[100]  C. Kleinstreuer,et al.  Simulation and Analysis of High-Speed Droplet Spray Dynamics , 2007 .

[101]  R. B. Campbell,et al.  The drug loading, cytotoxicty and tumor vascular targeting characteristics of magnetite in magnetic drug targeting. , 2007, Biomaterials.

[102]  Goodarz Ahmadi,et al.  Dispersion and Deposition of Spherical Particles from Point Sources in a Turbulent Channel Flow , 1992 .

[103]  Steven H Frankel,et al.  Numerical modeling of pulsatile turbulent flow in stenotic vessels. , 2003, Journal of biomechanical engineering.

[104]  M. Newhouse,et al.  The Effect of Biphasic Inhalation Profiles on The Deposition And Clearance of Coarse (6.5 μ m) Bolus Aerosols , 2007 .

[105]  B. O'connor The ideal inhaler: design and characteristics to improve outcomes. , 2004, Respiratory medicine.

[106]  Imre Balásházy,et al.  Deposition of aerosols in asymmetric airway bifurcations , 1995 .

[107]  David L. Swift,et al.  Deposition of Inhaled Particles in the Oral Airway During Oronasal Breathing , 1989 .

[108]  C Kleinstreuer,et al.  Targeted drug aerosol deposition analysis for a four-generation lung airway model with hemispherical tumors. , 2003, Journal of biomechanical engineering.

[109]  Yung-sung Cheng,et al.  Particle Deposition in a Cast of Human Tracheobronchial Airways , 2005 .

[110]  Gerhard Scheuch,et al.  Targeting delivery of aerosols to different lung regions. , 2002, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[111]  Y. Cheng,et al.  Respiratory deposition patterns of salbutamol pMDI with CFC and HFA-134a formulations in a human airway replica. , 2001, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[112]  David A Edwards,et al.  Bioengineering of therapeutic aerosols. , 2002, Annual review of biomedical engineering.

[113]  Clement Kleinstreuer,et al.  Gas–solid two-phase flow in a triple bifurcation lung airway model , 2002 .

[114]  C. Dunbar ATOMIZAT10N MECHANISMS OF THE PRESSURIZED METERED DOSE INHALER , 1997 .

[115]  Thomas Heistracher,et al.  Local particle deposition patterns may play a key role in the development of lung cancer. , 2003, Journal of applied physiology.

[116]  Clement Kleinstreuer,et al.  Species heat and mass transfer in a human upper airway model , 2003 .

[117]  P Cinquin,et al.  Model driven therapy - the instance of computer assisted medical interventions. , 2003, Methods of information in medicine.

[118]  R. Sussman,et al.  Ultrafine particle deposition in a human tracheobronchial cast , 1990 .

[119]  Charles Hirsch,et al.  Anatomically based three-dimensional model of airways to simulate flow and particle transport using computational fluid dynamics. , 2005, Journal of applied physiology.

[120]  N. Chigier,et al.  Characterization of the laryngeal jet using phase Doppler interferometry. , 2000, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[121]  Hak-Kim Chan,et al.  Dry powder aerosol delivery systems: current and future research directions. , 2006, Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine.

[122]  P. Byron Prediction of drug residence times in regions of the human respiratory tract following aerosol inhalation. , 1986, Journal of pharmaceutical sciences.

[123]  Gerald C. Smaldone,et al.  Drug Delivery to the Lung , 2001 .

[124]  T. Voshaar,et al.  A review of the development of Respimat Soft Mist Inhaler. , 2004, International journal of pharmaceutics.

[125]  P. Worth Longest,et al.  Efficient computation of micro-particle dynamics including wall effects , 2004 .

[126]  S. Newman Spacer Devices for Metered Dose Inhalers , 2004, Clinical pharmacokinetics.

[127]  J. Panda,et al.  The present and future of nanotechnology in human health care. , 2007, Nanomedicine : nanotechnology, biology, and medicine.

[128]  M. Maniscalco,et al.  Sounding airflow enhances aerosol delivery into the paranasal sinuses , 2006, European journal of clinical investigation.

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

[130]  J. Heyder,et al.  The macrotransport properties of aerosol particles in the human oral-pharyngeal region , 1998 .

[131]  C. Kleinstreuer,et al.  Airflow structures and nano-particle deposition in a human upper airway model , 2004 .

[132]  L. Illum Nanoparticulate systems for nasal delivery of drugs: a real improvement over simple systems? , 2007, Journal of pharmaceutical sciences.