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The Nasal Mucociliary Clearance: Relevance to Nasal Drug Delivery

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Abstract

Mucociliary clearance is an important physiological defense mechanism of the respiratory tract to protect the body against noxious inhaled materials. This process is responsible for the rapid clearance of nasally administered drugs from the nasal cavity to the nasopharynx, thereby interfering with the absorption of drugs following intranasal application. This review describes the mucociliary system and the methods used for its characterization. Examples are given of the effects of drugs and additives on its functioning. Further, possible approaches are presented for increasing the residence time of drugs in the nasal cavity, thereby improving intranasal drug delivery.

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REFERENCES

  1. Y. W. Chien. Transnasal Systemic Medications, Elsevier, Amsterdam, 1985.

    Google Scholar 

  2. Y. W. Chien, K. S. E. Su, and S. F. Chang. Nasal Systemic Drug Delivery, Marcel Dekker, New York, 1989.

    Google Scholar 

  3. D. R. Adams. Transitional epithelial zone of the bovine nasal mucosa. Am. J. Anat. 176:159–170 (1986).

    Google Scholar 

  4. M. Boysen. The surface structure of the human nasal mucosa. I. Ciliated and metaplastic epithelium in normal individuals. A correlated study by scanning/transmission electron and light microscopy. Virchows Arch. (Cell Pathol.) 40:279–294 (1982).

    Google Scholar 

  5. B. Petruson, H. A. Hansson, and G. Karlsson. Structural and functional aspects of cells in the nasal mucociliary system. Arch. Otolaryngol. 20:518–541 (1984).

    Google Scholar 

  6. P. Satir. The generation of ciliary motion. J. Protozool. 31:8–12 (1984).

    Google Scholar 

  7. A. Wanner. Clinical aspects of mucociliary transport. Am. Rev. Resp. Dis. 116:73–125 (1977).

    Google Scholar 

  8. G. S. M. J. E. Duchateau, K. Graamans, J. Zuidema, and F. W. H. M. Merkus. Correlation between nasal ciliary beat frequency and mucus transport rate in volunteers. Laryngoscope 95:854–859 (1985).

    Google Scholar 

  9. A. M. Lucas and L. C. Douglas. Principles underlying ciliary activity in the respiratory tract. Arch. Otolaryngol. 20:518–541 (1934).

    Google Scholar 

  10. P. Satir and M. A. Sleigh. The physiology of cilia and mucociliary interactions. Annu. Rev. Physiol. 52:137–155 (1990).

    Google Scholar 

  11. I. Andersen and D. F. Proctor. Measurement of nasal mucociliary clearance. Eur. J. Resp. Dis. 64 (Suppl. 127):37–40 (1983).

    Google Scholar 

  12. J. G. Hardy, S. W. Lee, and C. G. Wilson. Intranasal drug delivery by spray and drops. J. Pharm. Pharmacol. 37:294–297 (1985).

    Google Scholar 

  13. A. S. Harris, I. M. Nilsson, Z. G. Wagner, and U. Alkner. Intranasal administration of peptides: Nasal deposition, biological response, and absorption of desmopressin. J. Pharm. Sci. 75:1085–1088 (1986).

    Google Scholar 

  14. L. Illum, H. Jörgensen, H. Bisgaard, O. Krogsgaard, and N. Rossing. Bioadhesive microspheres as a potential nasal drug delivery system. Int. J. Pharm. 39:189–199 (1987).

    Google Scholar 

  15. K. Takeuchi, Y. Sakakura, S. Murai, and Y. Majima. Nasal mucociliary clearance in Sjögrens syndrome. Acta Otolaryngol. 108:126–129 (1989).

    Google Scholar 

  16. E. Puchelle, F. Aug, Q. T. Pham, and A. Bertrand. Comparison of three methods for measuring nasal mucociliary clearance in man. tActa Otolaryngol. 91:297–303 (1981).

    Google Scholar 

  17. M. F. Quinlan, S. D. Salman, D. L. Swift, H. N. Wagner Jr., and D. F. Proctor. Measurement of mucociliary function in man. Am. Rev. Resp. Dis. 99:13–23 (1969).

    Google Scholar 

  18. Y. S. Sakakura, Y. Sasaki, R. B. Hornick, Y. Togo, A. R. Schwartz, H. B. Wagner Jr., and D. F. Proctor. Mucociliary function during experimentally induced rhinovirus infection in man. Ann. Otol. 82:203–211 (1973).

    Google Scholar 

  19. I. B. Andersen, P. C. Camner, P. L. Jensen, K. Philipson, and D. F. Proctor. Nasal clearance in monozygotic twins. Am. Rev. Resp. Dis. 110:301–305 (1974).

    Google Scholar 

  20. H. Simon, B. Drettner, and B. Jung. Messung des Schleimhauttransportes in menschlichen Nase mit 51Cr markierten Harzkügelchen. Acta Otolanryngol. 83:378–389 (1977).

    Google Scholar 

  21. M. A. Sackner. Mucociliary transport. Ann. Otol. 87:474–483 (1978).

    Google Scholar 

  22. J. H. L. van Ree and H. A. E. van Dishoeck. Some investigations on nasal ciliary activity. Pract. Otorhinolaryng. 24:383–390 (1962).

    Google Scholar 

  23. D. Passali, L. Bellussi, M. Bianchini Ciampoli, and E. De Seta. Experiences in the determination of nasal mucociliary transport time. Acta Otolaryngol. 97:319–323 (1984).

    Google Scholar 

  24. D. Passali and M. Bianchini Ciampoli. Normal values of mucociliary transport time in young subjects. Int. J. Pedia. Otorhinolaryngol. 9:151–156 (1985).

    Google Scholar 

  25. H. J. M. van de Donk, A. G. M. van den Heuvel, J. Zuidema, and F. W. H. M. Merkus. The effect of nasal drops and their additives on human nasal mucociliary clearance. Rhinology 20:127–137 (1982).

    Google Scholar 

  26. Y. Sakakura, K. Ukai, Y. Majima, S. Murai, T. Harada, and Y. Miyoshi. Nasal mucociliary clearance under various conditions. Acta Otolaryngol. 96:167–173 (1983).

    Google Scholar 

  27. J. Rutland and P. J. Cole. Nasal mucociliary clearance and ciliary beat frequency in cystic fibrosis compared with sinusitis and bronchiectasis. Thorax 36:654–658 (1981).

    Google Scholar 

  28. C. Marriott. The viscoelastic nature of mucus secretion. Chest 80 (Suppl.):804–808 (1981).

    Google Scholar 

  29. K. T. Morgan, D. L. Patterson, and E. H. Gross. Frog palate mucociliary apparatus: Structure, function, and response to formaldehyde gas. Fund. Appl. Toxicol. 4:58–68 (1984).

    Google Scholar 

  30. H. Winet, G. T. Yates, T. Y. Wa, and J. Head. On the mechanisms of mucociliary flows III. Flow-velocity profiles in frog palate mucus. J. Appl. Physiol. Resp. Environ. Exercise Physiol. 56:785–794 (1984).

    Google Scholar 

  31. M. J. Dulfano and K. B. Adler. Physical properties of sputum. VII. Rheological properties and mucociliary transport. Am. Rev. Resp. Dis. 112:341–347 (1975).

    Google Scholar 

  32. E. Puchelle and J. M. Zahm. Influence of rheological properties of human bronchial secretions on the ciliary beat frequency. Biorheology 21:265–272 (1984).

    Google Scholar 

  33. Y. Majima, Y. Sakakura, T. Matsubara, Y. Hamaguchi, K. Hirata, K. Takeuchi, and Y. Miyoshi. Rheological properties of middle ear effusions from children with otitis media with effusion. Ann. Otorhinolaryngol. 95 (Suppl):1–4 (1986).

    Google Scholar 

  34. Y. Majima, M. Inagaki, K. Hirata, K. Takeuchi, A. Morishita, and Y. Sakakura. The effect of an orally administered proteolytic enzyme on the elasticity and viscosity of nasal mucus. Arch. Otorhinolaryngol. 244:355–359 (1988).

    Google Scholar 

  35. H. J. M. van de Donk, J. Zuidema, and F. W. H. M. Merkus. The influence of the pH and osmotic pressure upon tracheal ciliary beat frequency as determined with a new photoelectric registration device. Rhinology 18:93–104 (1980).

    Google Scholar 

  36. U. Mercke, C. H. Håkansson, and N. G. Toremalm. A method for standardized studies of mucociliary activity. Acta Otolaryngol. 78:118–123 (1974).

    Google Scholar 

  37. J. C. Hybbinette and U. Mercke. A method for evaluating the effect of pharmacological substances on mucociliary activity in vitro. Acta Otolaryng. 93:151–159 (1982).

    Google Scholar 

  38. W. I. Lee and P. Verdugo. Ciliary activity by laser light scattering spectroscopy. J. Appl. Physiol. Ann. Biomed. Eng. 5:248–259 (1977).

    Google Scholar 

  39. L. B. Wong, I. F. Miller, and D. B. Yeates. Stimulation of ciliary beat frequency by autonomic agonists: In vivo. J. Appl. Physiol. 65:971–981 (1988).

    Google Scholar 

  40. T. Dalhamn. A method for determination in vivo of the rate of ciliary beat and mucus flow in the trachea. Ada Physiol. Scand. 33:1–5 (1955).

    Google Scholar 

  41. S. J. Hennessey, L. B. Wong, D. B. Yeates, and I. F. Miller. Automated measurement of ciliary beat frequency. J. Appl. Physiol. 60:2109–2113 (1986).

    Google Scholar 

  42. T. Dalhamn and R. Rylander. Frequency of ciliary beat measured with a photo-sensitive cell. Nature 196:592–593 (1962).

    Google Scholar 

  43. J. Yager, T. M. Chen, and M. J. Dulfano. Measurement of frequency of ciliary beats of human respiratory epithelium. Chest 73:627–633 (1978).

    Google Scholar 

  44. D. Eshel, Y. Grossman, and Z. Priel. Spectral characterization of ciliary beating: variations of frequency with time. Am. J. Physiol. 249 (Cell Physiol. 18):C160–C165 (1985).

    Google Scholar 

  45. P. C. Braga, G. D. Oglio, R. Bossi, and L. Allegra. Simple and precise method for counting ciliary beats directly from the TV monitor screen. J. Pharmacol. Methods 16:161–169 (1986).

    Google Scholar 

  46. H. Teichtal, P. L. Wright, and R. L. G. Kirsner. Measurement of in vitro ciliary beat frequency: A television-video modification of the transmitted light technique. Med. Biol. Eng. Comput. 24:193–196 (1986).

    Google Scholar 

  47. J. Hee and R. Guillerm. Discussion on smoke and mucociliary transport. Eur. J. Resp. Dis. 66 (Suppl. 139):86–88 (1985).

    Google Scholar 

  48. K. Ukai, Y. Sakakura, and S. Saida. Interaction between mucociliary transport and the ciliary beat of chicken nasal mucosa. Arch. Otolaryngol. 242:255–231 (1985).

    Google Scholar 

  49. H. Lioté, J. M. Zahm, D. Pierrot, and E. Puchelle. Role of mucus and cilia in nasal mucociliary clearance in healthy subjects. Am. J. Resp. Dis. 140:132–136 (1989).

    Google Scholar 

  50. C. K. Luk and M. J. Dulfano. Effect of pH, viscosity, and ionic strength changes on ciliary beat frequency of human bronchial explants. Clin. Sci. 64:449–451 (1983).

    Google Scholar 

  51. W. A. J. J. Hermens and F. W. H. M. Merkus. The influence of drugs on nasal ciliary movement. Pharm. Res. 4:445–449 (1987).

    Google Scholar 

  52. D. Pavia, P. P. Sutton, M. T. Lopez-Vidriero, J. E. Agnew, and S. W. Clarke. Drug effects on mucociliary function. Eur. J. Resp. Dis. 64 (Suppl. 128):304–317 (1983).

    Google Scholar 

  53. H. J. M. van de Donk, S. Jadoenath, J. Zuidema, and F. W. H. M. Merkus. The effects of drugs on ciliary motility I. Decongestants. Int. J. Pharm. 12:57–65 (1982).

    Google Scholar 

  54. H. J. M. van de Donk, A. L. M. van Egmond, J. Zuidema, and F. W. H. M. Merkus. The effects of drugs on ciliary motility II. Antimicrobial agents. Int. J. Pharm. 12:67–76 (1982).

    Google Scholar 

  55. H. J. M. van de Donk, A. L. M. van Egmond, A. G. M. van den Heuvel, J. Zuidema, and F. W. H. M. Merkus. The effects of drugs on ciliary motility. III. Local anaesthetics and antiallergic drugs. Int. J. Pharm. 12:77–85 (1982).

    Google Scholar 

  56. H. J. M. van de Donk, J. Zuidema, and F. W. H. M. Merkus. The effects of nasal drops on the ciliary beat frequency of chicken embryo tracheas. Rhinology 19:215–230 (1981).

    Google Scholar 

  57. H. J. M. van de Donk, I. P. Muller-Plantema, J. Zuidema, and F. W. H. M. Merkus. The effects of preservatives on the ciliary beat frequency of chicken embryo tracheas. Rhinology 18:119–133 (1981).

    Google Scholar 

  58. A. H. Batts, C. Marriott, G. P. Martin, and S. W. Bond. The effect of some preservatives used in nasal preparations on mucociliary clearance. J. Pharm. Pharmacol. 41:156–159 (1989).

    Google Scholar 

  59. A. H. Batts, C. Marriott, G. P. Martin, C. F. Wood, and S. W. Bond. The effect of some preservatives used in nasal preparations on the mucus and ciliary components of mucociliary clearance. J. Pharm. Pharmacol. 42:145–151 (1990).

    Google Scholar 

  60. J. Levrier, S. Molon-Noblot, D. Duval, and K. G. Lloyd. A new ex vivo method for the study of nasal drops on ciliary function. Fund. Clin. Pharmacol. 3:471–482 (1989).

    Google Scholar 

  61. S. Hirai, T. Yashiki, and H. Mima. Mechanisms for the enhancement of the nasal absorption of insulin by surfactants. Int. J. Pharm. 9:173–184 (1981).

    Google Scholar 

  62. A. E. Pontirolli, M. Alberetto, A. Secchi, G. Dossi, I. Bosi, and G. Pozza. Insulin given intranasally induces hypoglycemia in normal and diabetic subjects. Br. Med. J. 284:303–306 (1982).

    Google Scholar 

  63. A. C. Moses, J. S. Flier, G. S. Gordon, R. D. Silver, and M. C. Carey. Transnasal insulin delivery: Structure-function studies of absorption enhancing adjuvants. Clin. Res. 32:245A (1984).

    Google Scholar 

  64. G. S. M. J. E. Duchateau, J. Zuidema, and F. W. H. M. Merkus. Bile salts and intranasal drug delivery. Int. J. Pharm. 31:193–199 (1986).

    Google Scholar 

  65. J. P. Longenecker, A. C. Moses, J. S. Flier, R. D. Silver, M. C. Carey, and E. J. Dubovi. Effects of sodium taurodihydrofusidate on nasal absorption of insulin in sheep. J. Pharm. Sci. 76:351–355 (1987).

    Google Scholar 

  66. M. J. M. Deurloo, W. A. J. J. Hermens, S. G. Romeyn, J. C. Verhoef, and F. W. H. M. Merkus. Absorption enhancement of intranasally administered insulin by sodium taurodihydrofusidate in rabbits and rats. Pharm. Res. 6:853–856 (1990).

    Google Scholar 

  67. W. A. J. J. Hermens, P. M. Hooymans, J. C. Verhoef, and F. W. H. M. Merkus. Effects of absorption enhancers on human nasal tissue ciliary movement in vitro. Pharm. Res. 7:144–146 (1990).

    Google Scholar 

  68. G. P. Martin, C. Marriott, and I. W. Kellaway. Direct effect of bile salts and phopholipids on the physical properties of mucus. Gut 19:103–107 (1978).

    Google Scholar 

  69. L. Öhman, R. Hahnenberger, and E. D. B. Johansson. 17β-Estradiol levels in blood and cerebrospinal fluid after ocular and nasal administration in women and female rhesus monkeys (Macaca mulatta). Contraception 22:349–385 (1980).

    Google Scholar 

  70. R. N. Bawarshi-Nassar, A. A. Hussain, and P. A. Crooks. Nasal absorption and metabolism of progesterone and 17β-estradiol in the rat. Drug Metab. Dispos. 17:248–254 (1989).

    Google Scholar 

  71. W. A. J. J. Hermens, M. J. M. Deurloo, S. G. Romeyn, J. C. Verhoef, and F. W. H. M. Merkus. Nasal absorption enhancement of 17β-estradiol by dimethyl-β-cyclodextrin in rabbits and rats. Pharm. Res. 7:500–503 (1990).

    Google Scholar 

  72. N. G. M. Schipper, W. A. J. J. Hermens, S. G. Romeyn, J. Verhoef, and F. W. H. M. Merkus. Nasal absorption of 17β-estradiol and progesterone from a dimethyl-β-cyclodextrin inclusion formulation in rats. Int. J. Pharm. 64:61–66 (1990).

    Google Scholar 

  73. K. Uekama. Cyclodextrin inclusion compounds: Effects on stability and biopharmaceutical properties. In D. D. Breimer and P. Speiser (eds.), Topics in Pharmaceutical Sciences, Elsevier, Amsterdam, 1987, pp. 181–194.

    Google Scholar 

  74. K. Uekama, T. Fujinaga, F. Hirayama, M. Otagiri, and M. Yamasaki. Inclusion complexation of steroid hormones with cyclodextrins in water and in solid phase. Int. J. Pharm. 10:1–15 (1982).

    Google Scholar 

  75. W. A. J. J. Hermens, C. W. J. Belder, J. M. W. M. Merkus, P. M. Hooymans, J. Verhoef, and F. W. H. M. Merkus. Intranasal estradiol administration to oophorectomized women. Eur. J. Obstet. Gynecol. Reprod. Biol. 40:35–41 (1991).

    Google Scholar 

  76. F. W. H. M. Merkus, J. Verhoef, S. G. Romijn, and N. G. M. Schipper. Absorption enhancing effect of cyclodextrins on intranasally administered insulin in rats. Pharm. Res. 8:588–592 (1991).

    Google Scholar 

  77. K. Uekama and M. Otagiri. Cyclodextrins in drug carrier systems. CRC Crit. Rev. Ther. Drug Carrier Syst. 3:1–40 (1980).

    Google Scholar 

  78. S. Gizurarson. Animal models for intranasal drug delivery studies. Acta Pharm. Nor. 2:105–122 (1990).

    Google Scholar 

  79. F. Y. Aoki and J. C. W. Crawley. Distribution and removal of human serum albumin-technetium-99m instilled intranasally. Br. J. Clin. Pharmacol. 3:869–878 (1976).

    Google Scholar 

  80. N. Mygind. Nasal Allergy, 2nd ed., Alden Press, Oxford, 1979, pp. 257–270.

    Google Scholar 

  81. A. S. Harris, E. Svensson, Z. G. Wagner, S. Lethagen, and I. M. Nilsson. Effect of viscosity on particle size, deposition, and clearance of nasal delivery systems containing desmopressin. J. Pharm. Sci. 77:405–408 (1988).

    Google Scholar 

  82. A. S. Harris, M. Ohlin, E. Svensson, S. Lethagen, and I. M. Nilsson. Effect of viscosity on the pharmacokinetics and biological response to intranasal desmopressin. J. Pharm. Sci. 78:470–471 (1989).

    Google Scholar 

  83. A. K. Pennington, J. H. Ratcliffe, C. G. Wilson, and J. G. Hardy. The influence of solution viscosity on nasal spray deposition and clearance. Int. J. Pharm. 43:221–224 (1988).

    Google Scholar 

  84. L. Ilium, N. F. Farraj, H. Critchley, and S. S. Davis. Nasal administration of gentamicin using a novel microsphere delivery system. Int. J. Pharm. 46:261–265 (1988).

    Google Scholar 

  85. E. Björk and P. Edman. Characterization of degradable starch microspheres as a nasal delivery system for drugs. Int. J. Pharm. 62:187–192 (1990).

    Google Scholar 

  86. N. F. Farraj, B. R. Johansen, S. S. Davis, and L. Illum. Nasal administration of insulin using bioadhesive microspheres as a delivery system. J. Control. Rel. 13:253–261 (1990).

    Google Scholar 

  87. K. Morimoto, K. Morisaka, and A. Kamada. Enhancement of nasal absorption of insulin and calcitonin using polyacrylic acid gel. J. Pharm. Pharmacol. 37:134–136 (1985).

    Google Scholar 

  88. T. Nagai, J. Nishimoto, N. Nambu, Y. Suzuki, and K. Sekine. Powder dosage form of insulin for nasal administration. J. Control. Rel. 1:15–22 (1984).

    Google Scholar 

  89. I. Gonda and E. Gipps. Model of disposition of drugs administered into the human nasal cavity. Pharm. Res. 7:69–75 (1990).

    Google Scholar 

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  1. Center for Bio-Pharmaceutical Sciences, Subdivision of Pharmaceutical Technology and Biopharmaceutics, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands

    Nicolaas G. M. Schipper, J. Coos Verhoef & Frans W. H. M. Merkus

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  1. Nicolaas G. M. Schipper
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  2. J. Coos Verhoef
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  3. Frans W. H. M. Merkus
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Schipper, N.G.M., Verhoef, J.C. & Merkus, F.W.H.M. The Nasal Mucociliary Clearance: Relevance to Nasal Drug Delivery. Pharm Res 8, 807–814 (1991). https://doi.org/10.1023/A:1015830907632

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