Skip to main content
Log in

Nasal route and drug delivery systems

  • Published:
Pharmacy World and Science Aims and scope Submit manuscript

Abstract

Nasal drug administration has been used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. The nasal administration of drugs, including numerous compound, peptide and protein drugs, for systemic medication has been widely investigated in recent years. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in rapid systemic drug absorption. Several approaches are here discussed for increasing the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. The article highlights the importance and advantages of the drug delivery systems applied via the nasal route, which have bioadhesive properties. Bioadhesive, or more appropriately, mucoadhesive systems have been prepared for both oral and peroral administration in the past. The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. In this review we discuss the effects of microspheres and other bioadhesive drug delivery systems on nasal drug absorption. Drug delivery systems, such as microspheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and that swell easily when in contact with the nasal mucosa. These drug delivery systems have the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions. The mechanisms and effectiveness of these drug delivery systems are described in order to guide the development of specific and effective therapies for the future development of peptide preparations and other drugs that otherwise should be administered parenterally. As a consequence, bioavailability and residence time of the drugs that are administered via the nasal route can be increased by bioadhesive drug delivery systems. Although the majority of this work involving the use of microspheres, liposomes and gels is limited to the delivery of macromolecules (e.g., insulin and growth hormone), the general principles involved could be applied to other drug candidates. It must be emphasized that many drugs can be absorbed well if the contact time between formulation and the nasal mucosa is optimized.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kissel T, Werner U. Nasal delivery of peptides: an in vitro cell culture model for the investigation of transport and metabolism in human nasal epithelium. J Control Rel 1998; 53: 195–203.

    Google Scholar 

  2. Ridley D, Perkins AC, Washington N, Wilson CG, Wastie ML, Flynn PO et al. The effect of posture on nasal clearance of bioadhesive starch microspheres. S.T.P. Pharma Sci 1995; 5: 442–6.

    Google Scholar 

  3. Illum L. Drug delivery systems for nasal application. In: Hıncal AA, Kas HS, Sumnu M, editors. Third International Pharmaceutical Technology Symposium [Proceedings]. Ankara: Meteksan, 1985.

    Google Scholar 

  4. Sarkar MA. Drug metabolism in the nasal mucosa. Pharm Res 1992; 9: 1–9.

    Google Scholar 

  5. Brime B, Ballesteros MP, Frutos P. Preparation and in vitro characterization of gelatin microspheres containing Levodopa for nasal administration. J Microencap 2000; 6: 777–84.

    Google Scholar 

  6. Mygind N, Dahl R. Anatomy, physiology and function of the nasal cavities in health and disease. Adv Drug Del Rev 1998; 29: 3–12.

    Google Scholar 

  7. Özer AY. The importance of intranasal route for application of drugs and nasal drug delivery systems. Pharmacia-JTPA 1990; 30: 136–47.

    Google Scholar 

  8. Chien YW. Nasal drug delivery systems. In: Swarbrick J, editor. Novel drug delivery systems. New York: Marcel Dekker, 1992; 139–96.

    Google Scholar 

  9. Hussain AA. Intranasal drug delivery. Adv Drug Del Rev 1998; 29: 39–49.

    Google Scholar 

  10. Fisher AN, Brown K, Davis SS, Parr GD, Smith DA. The effect of molecular size on the nasal absorption of water-soluble compounds in the albino rat. J Pharm Pharmacol 1987; 39: 357–62.

    Google Scholar 

  11. Schipper NGM, Verhoef JC, Merkus HM. The nasal mucociliary clearance: relevance to nasal drug delivery. Pharm Res 1991; 8: 807–14.

    Google Scholar 

  12. Marttin E, Schipper NGM, Verhoef JC, Merkus WHM. Nasal mucociliary clearance as a factor in nasal drug delivery. Adv Drug Del Rev 1998; 29: 13–38.

    Google Scholar 

  13. Hasani A, Agnew JE, Pavia D, Vora H, Clarke SW. Effect of oral bronchodilators on lung mucociliary clearance during sleep in patients with asthma. Thorax 1993; 48: 287–9.

    Google Scholar 

  14. Wolff RK, Dolovich MB, Obminski G, Newhouse MT. Effects of exercise and eucapnic hyperventilation on bronchial clearance in man. J Appl Physiol 1977; 43: 46–50.

    Google Scholar 

  15. Verra F, Escudier E, Lebargy F, Bernaudin JF, Crèmoux HD, Bignon J. Ciliary abnormalities in bronchial epithelium of smokers, ex-smokers, and non-smokers. Am J Respir Crit Care Med 1995; 151: 630–4.

    Google Scholar 

  16. Haxel BR, Schäfer D, Klimek L. Prostaglandin E2 activates the ciliary beat frequency of cultured human nasal mucosa via the second messenger cyclic adenoside monophosphate. Eur Arc Otorhinolaryngol 2001; 258: 230–5.

    Google Scholar 

  17. Cho JH, Kwun YS, Jang HS, Kang JM, Won YS, Yoon HR. Long-term use of preservatives on rat nasal respiratory mucosa: effects of benzalkonium chloride and potassium sorbate. Laryngoscope 2000; 110: 312–7.

    Google Scholar 

  18. Behl CR, Pimplaskar HK, Sileno AP, Xia WJ, Gries WJ, Emeireles JC et al. Optimization of systemic nasal drug delivery with pharmaceutical excipients. Adv Drug Del Rev 1998; 29: 117–33.

    Google Scholar 

  19. Illum L, Jorgensen H, Bisgaard H, Krogsgaard O, Rossing N. Bioadhesive microspheres as a potential nasal drug delivery system. Int J Pharm 1987; 39: 189–99.

    Google Scholar 

  20. Rydèn L, Erdman P. Effects of polymers and microspheres on the nasal absorption of insulin in rats. Int J Pharm 1992; 83: 1–10.

    Google Scholar 

  21. Morath LP. Microspheres as nasal drug delivery systems. Adv Drug Del Rev 1998; 29: 185–94.

    Google Scholar 

  22. Björk E, Erdman P. Characterization of degradable starch microspheres as a nasal delivery system for drugs. Int J Pharm 1990; 62: 187–92.

    Google Scholar 

  23. Illum L, Farraj N, Davis SS. Nasal administration of gentamicin using a novel microsphere delivery system. Int J Pharm 1988; 46: 261–5.

    Google Scholar 

  24. Illum L, Farraj NF, Davis SS, Johansen BR, O'Hagan DT. Investigation of the nasal absorption of biosynthetic human growth hormone in sheep — use of a bioadhesive microsphere delivery system. Int J Pharm 1990; 63: 207–11.

    Google Scholar 

  25. Critichley H, Davis SS, Farraj NF, Illum L. Nasal absorption of desmopressin in rats and sheep. Effect of a bioadhesive microsphere delivery system. J Pharm Pharmacol 1993; 46: 651–6.

    Google Scholar 

  26. Björk E, Erdman P. Degradable starch microspheres as a nasal delivery system for insulin. Int J Pharm 1988; 47: 233–8.

    Google Scholar 

  27. Farraj NF, Johansen BR, Davis SS, Illum L. Nasal administration of insulin using bioadhesive microspheres as a delivery system. J Control Rel 1990; 13: 253–61.

    Google Scholar 

  28. Hinchcliffe M, Illum L. Intranasal insulin delivery and therapy. Adv Drug Del Rev 1999; 35: 199–234.

    Google Scholar 

  29. Illum L, Fisher AN, Jabbal-Gill I, Davis SS. Bioadhesive starch microspheres and absorption enhancing agents act synergistically to enhance the nasal absorption of polypeptides. Int J Pharm 2001; 222: 109–19.

    Google Scholar 

  30. Vyas SP, Bhatnagar S, Gogoi PJ, Jain NK. Preparation and characterization of HAS-propranolol microspheres for nasal administration. Int J Pharm 1991; 69: 5–12.

    Google Scholar 

  31. Alpar HO, Bowen JC, Brown MRW. Effectiveness of liposomes as adjuvants of orally and nasally administered tetanus toxoid. Int J Pharm 1992; 88: 335–44.

    Google Scholar 

  32. Maitani Y, Asano S, Takahashi S, Nakagaki M, Nagai T. Permeability of insulin entrapped in liposome through the nasal mucosa of rabbits. Chem Pharm Bull 1992; 40: 1569–72.

    Google Scholar 

  33. Muramatsu K, Maitani Y, Takayama K, Nagai T. The relationship between the rigidity of the liposomal membrane and the absorption of insulin after nasal administration of liposomes modified with an enhancer containing insulin in rabbits. Drug Dev Ind Pharm 1999; 25: 1099–105.

    Google Scholar 

  34. Law SL, Huang K J, Chou HY. Preparation of desmopressin-containing liposomes for intranasal delivery. J Control Rel 2001; 70: 375–82.

    Google Scholar 

  35. Iwanaga K, Matsumoto S, Morimoto K, Kakemi M, Yamashita S, Kimura T. Usefulness of liposomes as an intranasal dosage formulation for topical drug application. Biol Pharm Bull 2000; 23: 323–6.

    Google Scholar 

  36. Witschi C, Mrsny R. In vitro evaluation of microparticles and polymer gels for use as nasal platforms for protein delivery. Pharm Res 1999; 16: 382–90.

    Google Scholar 

  37. Lehr CM, Bouwstra JA, Schacht EH, Junginger HE. In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int J Pharm 1992; 78: 43–8.

    Google Scholar 

  38. Morimoto K, Tabata H, Morisaka K. Nasal absorption of nifedipine from gel preparations in rats. Chem Pharm Bull 1987; 35: 3041–4.

    Google Scholar 

  39. Morimoto K, Morisaka K, Kamada A. Enhancement of nasal absorption of insulin and calcitonin using polyacrylic acid gel. J Pharm Pharmacol 1985; 37: 134–6.

    Google Scholar 

  40. Zhou M, Donovan MD. Intranasal mucociliary of putative bioadhesive polymer gels. Int J Pharm 1996; 135: 115–25.

    Google Scholar 

  41. Merkus FWHM, Verhoef JC, Romeijn SG, Schipper NGM. Absorption enhancing effect of cyclodextrins on intarnasally administered insulin in rats. Pharm Res 1991; 8: 588–92.

    Google Scholar 

  42. Deponti R, Lardini E. Use of chemical enhancers for nasal drug delivery. Drug Dev Ind Pharm 1991; 17: 1419–36.

    Google Scholar 

  43. Hermens WAJJ, Hooymans PM, Verhoef JC, Merkus FWHM. Effects of absorption enhancers on human nasal tissue ciliary movement in vitro. Pharm Res 1990; 7: 144–6.

    Google Scholar 

  44. Hedın L, Olsson B, Dıczfalusy M, Flyg C, Petersson AS, Rosberg S et al. Intranasal administration of human growth hormone (hGH) in combination with a membrane permeation enhancer in patients with GH deficiency: a pharmacokinetic study. JCE & M 1993; 76: 962–7.

    Google Scholar 

  45. Kissel T, Drewe J, Bantle S, Rummelt A, Beglinger C. Tolerability and absorption enhancement of intranasally administered octreotide by sodium taurodihydrofusidate in healthy subjects. Pharm Res 1992; 9: 52–7.

    Google Scholar 

  46. Lee WA, Ennis RD, Longenecker JP, Bengtsson P. The bioavailability of intranasal salmon calcitonin in healthy volunteers with and without a permeation enhancer.Pharm Res 1994; 11: 747–50.

    Google Scholar 

  47. Laursen T, Ovesen P, Granjean S, Jensen S, Otto J, Jorgensen L et al. Nasal absorption of growth hormone in normal subjects: studies with four different formulations. Ann Pharmacoter 1994; 28: 845–8.

    Google Scholar 

  48. Drejer K, Vaag A, Bech K, Hansen P, Sorensen AR, Mygind N. Intranasal administration of insulin with phospholipid as absorption enhancer: pharmacokinetics in normal subjects. Diabet Med 1992; 9: 335–40.

    Google Scholar 

  49. Illum L, Farraj NF, Critchley H, Johansen BR, Davis SS. Enhanced nasal absorption of insulin in rats using lysophosphatidylcholine. Int J Pharm 1989; 57: 49–54.

    Google Scholar 

  50. Newman SP, Steed KP, Hardy JG, Wilding IR, Hooper G, Sparrow RA. The distribution of an intranasal formulation of insulin in healthy volunteers: effect of different administration techniques. J Pharm Pharmacol 1994; 46: 657–60.

    Google Scholar 

  51. Jorgensen S, Drejer K. Insulin analogues and nasal insulin delivery. In: Bailey CJ, Flatt PR, editors. New antidiabetic drugs. London: Smith-Gordon, 1990; 83–92.

    Google Scholar 

  52. Moses AC, Gordon GS, Carey MC, Flier JS. Insulin administration intranasally as an insulin-bile salt aerosol. Diabetes 1983; 32: 1040–7.

    Google Scholar 

  53. Yokosuka T, Omori Y, Hirata Y, Hirai S. Nasal and sublingual administration of insulin in man. J Jpn Diabetes Soc 1977; 20: 146–52.

    Google Scholar 

  54. Hirata Y, Yokosuka T, Kasahara T, Kikuchi M, Ooi K. Nasal administration of insulin in patients with diabetes. In: Baba S, Kaneko T, Yanaihara C, editors. Proceedings of the Symposium on Proinsulin, Insulin and C-Peptide, Tokushima, July 1978. Amsterdam: Excerpta Medica, 1979; 319–26.

    Google Scholar 

  55. Frauman AG, Jerums G, Louis WJ. Effects of intranasal insulin in non-obese type II diabetics. Diabetes Res Clin Pract 1987; 3: 197–202.

    Google Scholar 

  56. Salzman R, Manson JE, Griffing GT. Intranasal aerosolized insulin. Mixed-meal studies and long-term use in type I diabetes. New Engl J Med 1985; 312: 1078–84.

    Google Scholar 

  57. Paquot N, Scheen AJ, Franchimont P, Lefebvre P. The intranasal administration of insulin induces significant hypoglycaemia and classical counter-regulatory hormonal responses in normal man. Diabetes Metabol 1988; 14: 31–6.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Türker, S., Onur, E. & Ózer, Y. Nasal route and drug delivery systems. Pharm World Sci 26, 137–142 (2004). https://doi.org/10.1023/B:PHAR.0000026823.82950.ff

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:PHAR.0000026823.82950.ff

Navigation