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Targeting the Pulmonary Delivery via Optimizing Physicochemical Characteristics of Instilled Liquid and Exploring Distribution of Produced Liquids by Bench-Top Models and Scintigraphy of Rabbits- Lungs

Authors: Mohammad Nasri, Hossein Mirshekarpour


We aimed to investigate how can target and optimize pulmonary delivery distribution by changing physicochemical characteristics of instilled liquid.Therefore, we created a new liquids group: a. eligible for desired distribution within lung because of assorted physicochemical characteristics b. capable of being augmented with a broad range of chemicals inertly c. no interference on respiratory function d. compatible with airway surface liquid We developed forty types of new liquid,were composed of Carboxymethylcellulose sodium,Glycerin and different types of Polysorbates.Viscosity was measured using a Programmable Rheometer and surface tension by KRUSS Tensiometer.We subsequently examined the liquids and delivery protocols by simple and branched glass capillary tube models of airways.Eventually,we explored pulmonary distribution of liquids being augmented with technetium-99m in mechanically ventilated rabbits.We used a single head large field of view gamma camera.Kinematic viscosity between 0.265Stokes and 0.289Stokes,density between 1g/cm3 and 1.5g/cm3 and surface tension between 25dyn/cm and 35dyn/cm were the most acceptable.

Keywords: physicochemical characteristics, pulmonary delivery, Liquid instillation into airway, Optimal distribution

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[1] K. J. Cassidy, J. L. Bull, M. R. Glucksberg, C. A. Dawson, S. T. Haworth, R. Hirschl, N. Gavriely and J. B. Grotberg, A rat lung model of instilled liquid transport in the pulmonary airways, Journal of Applied Physiology 90 (2001), no. 5, 1955-1967.
[2] D. Halpern, O. E. Jensen and J. B. Grotberg, A theoretical study of surfactant and liquid delivery into the lung, Journal of Applied Physiology 85 (1998), no. 1, 333-352.
[3] F. F. Espinosa and R. D. Kamm, Bolus dispersal through the lungs in surfactant replacement therapy, Journal of Applied Physiology 86 (1999), no. 1, 391-410.
[4] J. C. Anderson, R. C. Molthen, C. A. Dawson, S. T. Haworth, J. L. Bull, M. R. Glucksberg and J. B. Grotberg, Effect of ventilation rate on instilled surfactant distribution in the pulmonary airways of rats, Journal of Applied Physiology 97 (2004), no. 1, 45-56.
[5] C. L. Kerr, Y. Ito, S. E. E. Manwell, R. A. W. Veldhuizen, L. J. Yao, L. A. McCaig and J. F. Lewis, Effects of surfactant distribution and ventilation strategies on efficacy of exogenous surfactant, Journal of Applied Physiology 85 (1998), no. 2, 676-684.
[6] D. Halpern, H. Fujioka, S. Takayama and J. B. Grotberg, Liquid and surfactant delivery into pulmonary airways, Respiratory Physiology and Neurobiology (2008).
[7] Y. L. Zhang, O. K. Matar and R. V. Craster, A theoretical study of chemical delivery within the lung using exogenous surfactant, Medical Engineering & Physics 25 (2003), no. 2, 115-132.
[8] D. J. Smith, L. M. Gambone, T. Tarara, D. R. Meays, L. A. Dellamary, C. M. Woods and J. Weers, Liquid dose pulmonary instillation of gentamicin pulmospheres® formulations: Tissue distribution and pharmacokinetics in rabbits, Pharmaceutical Research 18 (2001), no. 11, 1556-1561.
[9] R. Banerjee, J. R. Bellare and R. R. Puniyani, Effect of phospholipid mixtures and surfactant formulations on rheology of polymeric gels, simulating mucus, at shear rates experienced in the tracheobronchial tree, Biochemical Engineering Journal 7 (2001), no. 3, 195-200.
[10] J. R. Badia, D. Soy, M. Adrover, M. Ferrer, M. Sarasa, A. Alarco?n, C. Codina and A. Torres, Disposition of instilled versus nebulized tobramycin and imipenem in ventilated intensive care unit (icu) patients, Journal of Antimicrobial Chemotherapy 54 (2004), no. 2, 508-514.
[11] J. J. Haitsma, U. Lachmann and B. Lachmann, Exogenous surfactant as a drug delivery agent, Advanced Drug Delivery Reviews 47 (2001), no. 2-3, 197-207.
[12] M. Ikegami, K. Wada, G. A. Emerson, C. M. Rebello, R. E. Hernandez and A. H. Jobe, Effects of ventilation style on surfactant metabolism and treatment response in preterm lambs, American Journal of Respiratory and Critical Care Medicine 157 (1998), no. 2, 638-644.
[13] M. Krause, T. Olsson, A. B. Law, R. A. Parker, D. P. Lindstrom, H. W. Sundell and R. B. Cotton, Effect of volume recruitment on response to surfactant treatment in rabbits with lung injury, American Journal of Respiratory and Critical Care Medicine 156 (1997), no. 3 I, 862-866.
[14] J. Michna, A. H. Jobe and M. Ikegami, Positive end-expiratory pressure preserves surfactant function in preterm lambs, American Journal of Respiratory and Critical Care Medicine 160 (1999), no. 2, 634-639.
[15] C. Sekins; K. Michael (San Diego, Shaffer; Thomas H. (Lansdowne, PA), Wolfson; Marla R. (Wyndmoor, PA) "Apparatus for pulmonary delivery of drugs with simultaneous liquid lavage and ventilation", vol. 5,562,608, BioPulmonics, Inc. (Redmond, WA) Temple University (Philadelphia, PA) USA, October 8, 1996 p. 112 of 134.
[16] O. K. Matar, R. V. Craster and M. R. E. Warner, Surfactant transport on highly viscous surface films, Journal of Fluid Mechanics 466 (2002), 85- 111.
[17] Y. Zheng, H. Fujioka, J. C. Grotberg and J. B. Grotberg, Effects of inertia and gravity on liquid plug splitting at a bifurcation, Journal of Biomechanical Engineering 128 (2006), no. 5, 707-716.
[18] F. F. Espinosa and R. D. Kamm, Meniscus formation during tracheal instillation of surfactant, Journal of Applied Physiology 85 (1998), no. 1, 266-272.
[19] K. Wada, A. H. Jobe and M. Ikegami, Tidal volume effects on surfactant treatment responses with the initiation of ventilation in preterm lambs, Journal of Applied Physiology 83 (1997), no. 4, 1054-1061.
[20] M. F. Krause, C. Jakel, J. Haberstroh, J. Schulte-Monting, J. U. Leititis and M. Orlowska-Volk, Alveolar recruitment promotes homogeneous surfactant distribution in a piglet model of lung injury, Pediatric Research 50 (2001), no. 1 I, 34-43.
[21] J. L. Bull, S. Tredici, E. Komori, D. O. Brant, J. B. Grotberg and R. B. Hirschl, Distribution dynamics of perfluorocarbon delivery to the lungs: An intact rabbit model, Journal of Applied Physiology 96 (2004), no. 5, 1633-1642.
[22] B. J. Smith and D. P. Gaver, The pulsatile propagation of a finger of air within a fluid-occluded cylindrical tube, Journal of Fluid Mechanics 601 (2008), 1-23.
[23] U. Kaisers and K. P. Kelly, Liquid ventilation, British Journal of Anaesthesia 91 (2003), no. 1, 143-151.
[24] K. J. T. S. Manaker, "Liquid ventilation," Up To Date 16.1, P. E. Parsons (Editor), Up To Date, Inc., January 2008.
[25] S. Tredici, F. Tredici, D. O. Brant, R. B. Hirschl and J. L. Bull, Effect of viscosity on instilled perfluorocarbon distribution in rabbit lungs, Journal of Biomechanical Engineering 128 (2006), no. 6, 857-861.
[26] W. W. Fox, C. A. Cox, C. M. Weis, M. R. Wolfson and T. H. Shaffer, Comparison of perfluorochemical fluids used for liquid ventilation: Effect of endotracheal tube flow resistance, Pediatric Pulmonology 23 (1997), no. 6, 449-456.
[27] K. J. Cassidy, N. Gavriely and J. B. Grotberg, Liquid plug flow in straight and bifurcating tubes, Journal of Biomechanical Engineering 123 (2001), no. 6, 580-589.
[28] M. Vasudevan and C. F. Lange, Surface tension effects on instability in viscoelastic respiratory fluids, Mathematical Biosciences 205 (2007), no. 2, 180-194.
[29] A. L. Hazel and M. Heil, Three-dimensional airway reopening: The steady propagation of a semi-infinite bubble into a buckled elastic tube, Journal of Fluid Mechanics (2003), no. 478, 47-70.
[30] G. M. Roomans, I. Kozlova, H. Nilsson, V. Vanthanouvong, B. Button and R. Tarran, Measurements of airway surface liquid height and mucus transport by fluorescence microscopy, and of ion composition by x-ray microanalysis, Journal of Cystic Fibrosis 3 (2004), no. Supplement 2, 135-139.
[31] S. Sch├╝rch, M. Geiser, M. M. Lee and P. Gehr, Particles at the airway interfaces of the lung, Colloids and Surfaces B: Biointerfaces 15 (1999), no. 3-4, 339-353.
[32] J. H. Widdicombe, Regulation of the depth and composition of airway surface liquid, Journal of Anatomy 201 (2002), no. 4, 313-318.
[33] H. Nilsson, I. Kozlova, V. Vanthanouvong and G. M. Roomans, Collection and x-ray microanalysis of airway surface liquid in the mouse using ion exchange beads, Micron 35 (2004), no. 8, 701-705.
[34] A. J. Hirsh, Altering airway surface liquid volume: Inhalation therapy with amiloride and hyperosmotic agents, Advanced Drug Delivery Reviews 54 (2002), no. 11, 1445-1462.
[35] M. Heil, A. L. Hazel and J. A. Smith, The mechanics of airway closure, Respiratory Physiology & Neurobiology, in Press, Corrected Proof.
[36] M. Vasudevan and C. F. Lange, Property dependence of onset of instability in viscoelastic respiratory fluids, International Journal of Engineering Science 43 (2005), no. 15-16, 1292-1298.
[37] J. B. Grotberg, "Respiratory fluid mechanics and transport processes," Annual Review of Biomedical Engineering, vol. 3, 2001, pp. 421-457.
[38] K. Nag, A. Hillier, K. Parsons and M. F. Garcia, Interactions of serum with lung surfactant extract in the bronchiolar and alveolar airway models, Respiratory Physiology & Neurobiology 157 (2007), no. 2-3, 411-424.
[39] S.-H. Yu, P. G. R. Harding and F. Possmayer, Artificial pulmonary surfactant: Potential role for hexagonal hii phase in the formation of a surface-active monolayer, Biochimica et Biophysica Acta (BBA) - Biomembranes 776 (1984), no. 1, 37-47.
[40] H. Bachofen and S. Sch├╝rch, Alveolar surface forces and lung architecture, Comparative Biochemistry and Physiology - Part A: Molecular & Integrative Physiology 129 (2001), no. 1, 183-193.
[41] S. Schurch, P. Gehr, V. Im Hof, M. Geiser and F. Green, Surfactant displaces particles toward the epithelium in airways and alveoli, Respiration Physiology 80 (1990), no. 1, 17-32.
[42] D. A. Sabatini, R. C. Knox, J. H. Harwell and B. Wu, Integrated design of surfactant enhanced dnapl remediation: Efficient supersolubilization and gradient systems, Journal of Contaminant Hydrology 45 (2000), no. 1-2, 99-121.
[43] S. C. Sweetman, Martindale: The complete drug reference, vol. 1, Pharmaceutical Press, 2007.
[44] M. Bertram G. Katzung, PhD, Basic and clinical pharmacology, Mc Graw Hill, 2007.
[45] J. P. Remington and A. R. Gennaro, Remington: The science and practice of pharmacy, Mack Pub. Co., 1995.
[46] N. T. Griscom and M. E. B. Wohl, Dimensions of the growing trachea related to age and gender, American Journal of Roentgenology 146 (1986), no. 2, 233-237.
[47] T. E. Keats, Atlas of roentgenographic measurement, 1990.
[48] T. E. Keats and C. Sistrom, Atlas of radiologic measurment, Mosby, 2001.
[49] A. Michael P. Czervinske; Sherry L. Barnhart, RRT, Perinatal and pediatric respiratory care, vol. 1, SAUNDERS, 2003.
[50] J. L. Bull and J. B. Grotberg, Surfactant spreading on thin viscous films: Film thickness evolution and periodic wall stretch, Experiments in Fluids 34 (2003), no. 1, 1-15.
[51] M. S. Loewen and D. L. Walner, Dimensions of rabbit subglottis and trachea, Laboratory Animals 35 (2001), no. 3, 253-256.
[52] P. Flecknell, Manual of rabbit medicine and surgery, Blackwell Sciences, 2000.
[53] H. D. Yung and R. A. Freedman, University physics, Addison Wesley Publishing Co. Inc., 1996.
[54] S. T. Ballard, J. C. Parker and C. R. Hamm, Restoration of mucociliary transport in the fluid-depleted trachea by surface-active instillates, American Journal of Respiratory Cell and Molecular Biology 34 (2006), no. 4, 500-504.
[55] K. Cassidy, D. Halpern, B. Ressler, P. Howell and J. B. Grotberg, Surfactant effects on the stability of a viscous fluid lining a capillary tube, FASEB Journal 11 (1997), no. 3.
[56] J. Hohlfeld, H. Fabel and H. Hamm, The role of pulmonary surfactant in obstructive airways disease, European Respiratory Journal 10 (1997), no. 2, 482-491.
[57] G. Enhorning, J. Hohlfeld, N. Krug, G. Lema and R. C. Welliver, Surfactant function affected by airway inflammation and cooling: Possible impact on exercise-induced asthma, European Respiratory Journal 15 (2000), no. 3, 532-538.
[58] S. Jayaraman, N. S. Joo, B. Reitz, J. J. Wine and A. S. Verkman, Submucosal gland secretions in airways from cystic fibrosis patients have normal
[na+] and ph but elevated viscosity, Proceedings of the National Academy of Sciences of the United States of America 98 (2001), no. 14, 8119-8123.
[59] A. Silberberg, Biorheological matching: Mucociliary interaction and epithelial clearance, Biorheology 20 (1983), no. 2, 215-222.
[60] P. Wollmer, K. Backstrom, H. Zhao, P. G. Nilsson and B. Jonson, Surface active agents as enhancers of alveolar absorption, Pharmaceutical Research 17 (2000), no. 1, 38-41.
[61] J. C. B. James Swarbrick, Encyclopedia of pharmaceutical technology, vol. 1, Marcel Dekker, Inc., 2002.