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Absorption Enhancers for Nasal Drug Delivery

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Abstract

This paper describes the basic concepts for the transmucosal delivery of drugs, and in particular the use of the nasal route for delivery of challenging drugs such as polar low-molecular-weight drugs and peptides and proteins. Strategies for the exploitation of absorption enhancers for the improvement of nasal delivery are discussed, including consideration of mechanisms of action and the correlation between toxic effect and absorption enhancement. Selected enhancer systems, such as cyclodextrins, phospholipids, bioadhesive powder systems and chitosan, are discussed in detail. Examples of the use of these enhancers in preclinical and clinical studies are given. Methods for assessing irritancy and damage to the nasal membrane from the use of absorption enhancers are also described. Finally, the mucosal use of absorption enhancers (chitosan) for the improved nasal delivery of vaccines is reported with reference to recent phase I/II clinical studies.

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References

  1. Illum L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 2000; 11: 1–18

    Article  CAS  PubMed  Google Scholar 

  2. Illum L. Nasal drug delivery: possibilities, problems and solutions. J Control Release 2003; 87: 187–98

    Article  CAS  PubMed  Google Scholar 

  3. Moore KH, Hussey EK, Shaw S, et al. Safety, tolerability and pharmacokinetics of sumatriptan in healthy subjects following ascending single intranasal doses and multiple intranasal doses. Cephalalgia 1997; 17: 541–50

    Article  CAS  PubMed  Google Scholar 

  4. Krishnamoorthy R, Mitra AK. Prodrugs for nasal drug delivery. Adv Drug Deliv Rev 1998; 29: 135–46

    Article  CAS  PubMed  Google Scholar 

  5. Physician Desk Reference. Montvale (NJ): Medical Economics Company Inc, 2000

  6. O’Doherty DP, Bickerstaff DR, McCloskey EV, et al. A comparison of the acute effects of subcutaneous and intranasal calcitonin. Clin Sci 1990; 78: 215–9

    Article  PubMed  Google Scholar 

  7. Overgaard K, Agnusdel D, Hansen MA, et al. Dose response bioactivity and bioavailability of salmon calcitonin in premenopausal and postmenopausal women. Endocrinol Metab 1991; 72: 344–9

    Article  CAS  Google Scholar 

  8. Behl CR, Pimplaskar HK, Sileno AP, et al. Optimization of systemic nasal drug delivery with pharmaceutical excipients. Adv Drug Deliv Rev 1998; 29: 117–33

    Article  CAS  PubMed  Google Scholar 

  9. Swaan PW. Recent advances in intestinal macromolecular drug delivery via receptor-mediated transport pathways. Pharm Res 1998; 15: 826–34

    Article  CAS  PubMed  Google Scholar 

  10. Davis SS. Nasal vaccines. Adv Drug Deliv Rev 2001; 51: 24–42

    Article  Google Scholar 

  11. Hailey A. Strong medicine. London: Michael joseph, 1984: 428

    Google Scholar 

  12. Machida M, Sano K, Arakawa M, et al. Absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) from rat nasal mucosa. Pharm Res 1993; 10: 1372–7

    Article  CAS  PubMed  Google Scholar 

  13. Valensi P, Zirinis PH, Nicolas P, et al. Effect of insulin concentration on bioavailability during nasal spray administration. Pathol Biol (Paris) 1996; 44: 235–40

    CAS  Google Scholar 

  14. Baglioni C, Phipps RJ. Nasal absorption of interferon: enhancement by surfactant agents. J Interferon Res 1990; 10: 497–504

    Article  CAS  PubMed  Google Scholar 

  15. Gill IJ, Fisher AN, Hinchcliffe M, et al. Cyclodextrins as protection agents against enhancer damage in nasal delivery systems II. Effect on in vivo absorption of insulin and histopathology of nasal membrane. Eur J Pharm Sci 1994; 1: 237–48

    Article  CAS  Google Scholar 

  16. Wuthrich P, Martenet M, Buri P. Effect of formulation additives upon the intranasal bioavailability of a peptide drug: tetracosactide (ACTH1-24). Pharm Res 1994; 11: 278–82

    Article  CAS  PubMed  Google Scholar 

  17. Andersson M, Greiff L, Oman H, et al. Permeation of polysucrose 15000 across the human nasal mucosa in vivo. Allergy 1997; 52: 1229–32

    Article  CAS  PubMed  Google Scholar 

  18. Kowarski CR, Lin S, Kowarski AA. Effect of Brij 35 and Brij 96 on the nasal absorption of insulin in dogs [abstract]. J Pharm Sci 1987; 76: S78

    Google Scholar 

  19. Ozsoy Y, Tuncel T, Can A, et al. In vivo studies on nasal preparations of ciprofloxacin hydrochloride. Pharmazie 2000; 55: 607–9

    CAS  PubMed  Google Scholar 

  20. Kilian N, Muller DG. The effect of a viscosity and an absorption enhancer on the intra nasal absorption of metoprolol in rats. Int J Pharm 1998; 163: 211–7

    Article  CAS  Google Scholar 

  21. Maitani Y, Yamamoto T, Takayama K, et al. The effect of soybean-derived sterol and its glucoside as an enhancer of nasal absorption of insulin in rabbits in vitro and in vivo. Int J Pharm 1995; 117: 129–37

    Article  CAS  Google Scholar 

  22. Maitani Y, Nakamura K, Suenaga H, et al. The enhancing effect of soybean-derived sterylglucoside and β-sitosterol β-D-glucoside on nasal absorption in rabbits. Int J Pharm 2000; 200: 17–26

    Article  CAS  PubMed  Google Scholar 

  23. Yamamoto T, Maitani Y, Ando T, et al. High absorbency and subchronic morphologic effects on the nasal epithelium of a nasal insulin powder dosage form with soybean derived sterylglucoside mixture in rabbits. Biol Pharm Bull 1998; 21: 866–70

    Article  CAS  PubMed  Google Scholar 

  24. Aungst BJ. Site-dependence and structure-effect relationships for alkylglycosides as transmucosal absorption promoters for insulin. Int J Pharm 1994; 105: 219–25

    Article  CAS  Google Scholar 

  25. Pillion DJ, Atchison JA, Gargiulo C, et al. Insulin delivery in nosedrops: new formulations containing alkylglycosides. Endocrinology 1994; 135: 2386–91

    Article  CAS  PubMed  Google Scholar 

  26. Pillion DJ, Hosmer S, Meezan E. Dodecylmaltoside-mediated nasal and ocular absorption of lyspro-insulin: independence of surfactant action from multimer dissociation. Pharm Res 1998; 15: 1637–9

    Article  CAS  PubMed  Google Scholar 

  27. Pillion DJ, Recchia J, Wang P, et al. DS-1, a modified Quillaja saponin, enhances ocular and nasal absorption of insulin. J Pharm Sci 1995; 84: 1276–9

    Article  CAS  PubMed  Google Scholar 

  28. Recchia J, Lurantos MH, Amsden JA, et al. A semisynthetic Quillaja saponin as a drug delivery agent for aminoglycoside antibiotics. Pharm Res 1995; 12: 1917–23

    Article  CAS  PubMed  Google Scholar 

  29. Maitani Y, Igawa T, Machida Y, et al. Intranasal administration of β-interferon in rabbits. Drug Des Deliv 1986; 1: 65–70

    CAS  PubMed  Google Scholar 

  30. Aungst BJ, Rogers NJ, Shefter E. Comparison of nasal, rectal, buccal, sublingual and intramuscular insulin efficacy and the effects of a bile salt absorption promoter. J Pharmacol Exp Ther 1988; 244: 23–7

    CAS  PubMed  Google Scholar 

  31. Donovan MD, Flynn GL, Amidon GL. The molecular weight dependence of nasal absorption: the effect of absorption enhancers. Pharm Res 1990; 8: 808–15

    Article  Google Scholar 

  32. Bruce DG, Chisholm DJ, Storlien LH, et al. Meal-time intranasal insulin delivery in Type 2 diabetes. Diabetic Med 1991; 8: 366–70

    Article  CAS  PubMed  Google Scholar 

  33. Santus G, Rivolta R, Bottoni G, et al. Nasal formulations of ketorolac tromethamine: technological evaluation: bioavailability and tolerability in rabbits. Farmaco 1993; 12: 1709–23

    Google Scholar 

  34. Betbeder D, Sperandio S, Latapie JP, et al. Biovector nanoparticles improve antinociceptive efficacy of nasal morphine. Pharm Res 2000; 17: 743–8

    Article  CAS  PubMed  Google Scholar 

  35. Deurloo MJ, Hermens WA, Romeyn SG, et al. Absorption enhancement of intranasally administered insulin by sodium taurodihydrofusidate (STDHF) in rabbits and rats. Pharm Res 1989; 6: 853–6

    Article  CAS  PubMed  Google Scholar 

  36. Nolte MS, Taboga C, Salamon E, et al. Biological activity of nasally administered insulin in normal subjects. Horm Metab Res 1990; 22: 170–4

    Article  CAS  PubMed  Google Scholar 

  37. Baldwin PA, Klingbeil CK, Grimm CJ, et al. The effect of sodium tauro-24,25-dihydrofusidate on the nasal absorption of human growth hormone in three animal models. Pharm Res 1990; 7: 547–52

    Article  CAS  PubMed  Google Scholar 

  38. Lee WA, Narog BA, Patapoff TW, et al. Intranasal bioavailability of insulin powder formulations: effect of permeation enhancer-to-protein ratio. J Pharm Sci 1991; 80: 725–9

    Article  CAS  PubMed  Google Scholar 

  39. Yamamoto A, Morita T, Hashida M, et al. Effects of absorption promoters on the nasal absorption of drugs with various molecular weights. Int J Pharm 1993; 93: 91–9

    Article  CAS  Google Scholar 

  40. Hedin L, Olsson B, Diczfalusy M, et al. Intranasal administration of human growth hormone (hGH) in combination with a membrane permeation enhancer in patients with GH deficiency: a pharmacokinetic study. J Clin Endocrinol Metab 1993; 76: 962–7

    CAS  PubMed  Google Scholar 

  41. Lalej-Bennis D, Boillot J, Bardin C, et al. Six month administration of gelified intranasal insulin in 16 type 1 diabetic patients under multiple injections: efficacy vs subcutaneous injections and local tolerance. Diabetes Metab 2001; 27: 372–7

    CAS  PubMed  Google Scholar 

  42. Bechgaard E, Lindhardt K, Martinsen L. Intranasal absorption of melatonin in vivo bioavailability study. Int J Pharm 1999; 182: 1–5

    Article  CAS  PubMed  Google Scholar 

  43. Bagger MA, Nielsen HW, Bechgaard E. Nasal bioavailability of peptide T in rabbits: absorption enhancement by sodium glycocholate and glycofurol. Eur J Pharm Sci 2001; 14: 69–74

    Article  CAS  PubMed  Google Scholar 

  44. Donnelly A, Kellaway IW, Taylor G, et al. Absorption enhancers as tools to determine the route of nasal absorption of peptides. J Drug Target 1998; 5: 121–7

    Article  CAS  PubMed  Google Scholar 

  45. Drejer K, Vaag A, Bech K, et al. Intranasal administration of insulin with phospholipid as absorption enhancer: pharmacokinetics in normal subjects. Diabet Med 1992; 9: 335–40

    Article  CAS  PubMed  Google Scholar 

  46. Jacobs MA, Schreuder RH, Jap-A-Joe K, et al. The pharmacodynamics and activity of intranasally administered insulin in healthy male volunteers. Diabetes 1993; 42: 1649–55

    Article  CAS  PubMed  Google Scholar 

  47. Coates PA, Ismail IS, Luzio SD, et al. Intranasal insulin: the effects of three dose regimens on postprandial glycaemic profiles in type II diabetic subjects. Diabet Med 1995; 12: 235–9

    Article  CAS  PubMed  Google Scholar 

  48. Laursen T, Ovesen P, Grandjean B, et al. Nasal absorption of growth hormone in normal subjects: studies with four different formulations. Ann Pharmacother 1994; 28: 845–8

    Article  CAS  PubMed  Google Scholar 

  49. Moller J, Lauersen T, Mindeholm L, et al. Serum growth hormone (GH) profiles after nasally administered GH in normal subjects and GH deficient patients. Clin Endocrinol 1994; 40: 511–3

    Article  CAS  Google Scholar 

  50. Dua R, Duncan M, Hossein Z, et al. The influence of the enhancer dimyristoylphosphatidylglycerol and formulation factors on the nasal absorption of salmon calcitonin. Drug Deliv 1998; 5: 127–34

    Article  CAS  PubMed  Google Scholar 

  51. Critchley H, Davis SS, Farraj NF, et al. Nasal absorption of desmopressin in rats and sheep: effect of a bioadhesive microsphere delivery system. J Pharm Pharmacol 1994; 46: 651–6

    Article  CAS  PubMed  Google Scholar 

  52. Muramatsu K, Maitani Y, Takayama K, et al. 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

    Article  CAS  PubMed  Google Scholar 

  53. Merkus FW, Verhoef JC, Romeijn SG, et al. Absorption enhancing effect of cyclodextrins on intranasally administered insulin in rats. Pharm Res 1991; 8: 588–92

    Article  CAS  PubMed  Google Scholar 

  54. Schipper NGM, Romeijn SG, Verhoef JC, et al. Nasal insulin delivery with dimethyl-beta-cyclodextrin as an absorption enhancer in rabbits: powder more effective than liquid formulations. Pharm Res 1993; 10: 682–6

    Article  CAS  PubMed  Google Scholar 

  55. Watanabe Y, Matsumoto Y, Yamaguchi M, et al. Absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and blood leukocyte dynamics following intranasal administration in rabbits. Biol Pharm Bull 1993; 16: 93–5

    Article  CAS  PubMed  Google Scholar 

  56. Schipper NG, Verhoef JC, Romeijn SG, et al. Methylated β-cyclodextrins are able to improve the nasal absorption of salmon calcitonin. Calcif Tissue Int 1995; 56: 280–2

    Article  CAS  PubMed  Google Scholar 

  57. Matsubara K, Abe K, Me T, et al. Improvement of nasal bioavailability of luteinizing hormone-releasing hormone agonist, buserelin, by cyclodextrin derivative in rats. J Pharm Sci 1995; 84: 1295–300

    Article  CAS  PubMed  Google Scholar 

  58. Sakr FM. Nasal administration of glucagon combined with dimethyl-β-cyclodextrin: comparison of pharmacokinetics and pharmacodynamics of spray and powder formulations. Int J Pharm 1996; 132: 189–94

    Article  CAS  Google Scholar 

  59. Illum L, Farraj NF, Davis SS. Chitosan as a novel nasal delivery system for peptides drugs. Pharm Res 1994; 11: 1186–9

    Article  CAS  PubMed  Google Scholar 

  60. Roon KI, Soons PA, Uitendaal MP, et al. Pharmacokinetic profile of alniditan nasal spray during and outside migraine attacks. Br J Clin Pharmacol 1999; 47(3): 285–90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Illum L, Watts P, Fisher AN, et al. Novel chitosan based delivery systems for nasal administration of a LHRH-analogue. STP Pharm Sci 2000; 10: 89–94

    CAS  Google Scholar 

  62. Junginger HE, Thanou M, Luessen HL, Kotze AF, Verhoef JC. Safe mucosal penetration enhancers: a fiction?. Polymers as absorption enhancers for transmucosal drug delivery. In. Park K, Mrsny RJ, editors. Controlled drug delivery: designing technology for the future. ACS Symposium Series. Washington: ACS, 2000: 25–35

    Chapter  Google Scholar 

  63. Natsume H, Iwata S, Ohtake K, et al. Screening of cationic compounds as an absorption enhancer for nasal drug delivery. Int J Pharm 1999; 5: 1–12

    Article  Google Scholar 

  64. Tengamnuay P, Sahamethapat A, Sailasuta A, et al. Chitosans as nasal absorption enhancers of peptides: comparison between free amine chitosans and soluble salts. Int J Pharm 2000; 197: 53–67

    Article  CAS  PubMed  Google Scholar 

  65. Wang J, Sakai S, Deguchi Y, et al. Aminated gelatin as a nasal absorption enhancer for peptide drugs: evaluation of absorption enhancing effect and nasal mucosa perturbation in rats. J Pharm Pharmacol 2002; 54: 181–8

    Article  CAS  PubMed  Google Scholar 

  66. Lim ST, Forbes B, Martin GP, et al. In vivo and in vitro characterization of novel microparticulates based on hy-aluronan and chitosan hydroglutamate. AAPS PharmSciTech2 (4) Available from URL: http://www.PharmSciTech.com [Accessed 2003 Aug 22]

  67. Kararli TT, Needham TE, Schoenhard G, et al. Enhancement of nasal delivery of a rennin inhibitor in the rat using emulsion formulations. Pharm Res 1992; 9: 1024–8

    Article  CAS  PubMed  Google Scholar 

  68. Abe K, Irie T, Uekama K. Enhanced nasal delivery of luteinizing hormone releasing hormone agonist buserelin by oleic acid solubilized and stabilized in hydroxypropyl-β-cyclodextrin. Chem Pharm Bull (Tokyo) 1995; 43: 2232–7

    Article  CAS  Google Scholar 

  69. Kagatani S, Shinoda T, Fukui M, et al. Enhancement of nasal salmon calcitonin absorption by lauroylcarnitine chloride in rats. Pharm Res 1996; 13: 739–43

    Article  CAS  PubMed  Google Scholar 

  70. Kagatani S, Inaba N, Fukui M, et al. Nasal absorption kinetic behavior of azetirelin and its enhancement by acylcarnitines in rats. Pharm Res 1998; 15: 77–81

    Article  CAS  PubMed  Google Scholar 

  71. O’Hagan DT, Critchley H, Farraj NF, et al. Nasal absorption enhancers for biosynthetic human growth hormone in rats. Pharm Res 1990; 7: 772–6

    Article  PubMed  Google Scholar 

  72. El-Shafy MA, Kellaway IW, Taylor G, et al. Improved nasal bioavailability of FITC-dextran (MW 4300) from mucoadhesive microspheres in rabbits. J Drug Target 2000; 7: 355–61

    Article  CAS  PubMed  Google Scholar 

  73. Callens C, Remon JP. Evaluation of starch-maltodextrin-Carbopol 974 P mixtures for the nasal delivery of insulin in rabbits. J Control Release 2000; 66: 215–20

    Article  CAS  PubMed  Google Scholar 

  74. Yamamoto T, Maitani Y, Machida Y, et al. Ophthalmic and nasal delivery of insulin from oily suspensions in rabbits in vitro and in vivo. STP Pharm Sci 1994; 4: 133–8

    CAS  Google Scholar 

  75. Mitra R, Pezron I, Chu WA, et al. Lipid emulsions as vehicles for enhanced nasal delivery of insulin. Int J Pharm 2000; 15: 127–34

    Article  Google Scholar 

  76. Takenaga M, Serizawa Y, Azechi Y, et al. Microparticle resins as a potential nasal drug delivery system for insulin. J Control Release 1998; 52: 81–7

    Article  CAS  PubMed  Google Scholar 

  77. Watanabe Y, Utoguchi N, Ishii A, et al. Absorption enhancement of a protein drug by nitric oxide donor effect on nasal absorption of human granulocyte colony-stimulating factor. J Drug Target 2000; 8: 185–94

    Article  CAS  PubMed  Google Scholar 

  78. Abe K, Me T, Adachi H, et al. Combined use of 2-hydroxypropyl-β-cyclodextrin and a lipophilic absorption enhancer in nasal delivery of the LHRH agonist, buserelin acetate, in rats. Int J Pharm 1995; 123: 103–12

    Article  CAS  Google Scholar 

  79. 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

    Article  CAS  PubMed  Google Scholar 

  80. Morimoto K, Yamaguchi H, Iwakura Y, et al. Effects of viscous hyaluronate-sodium solutions on the nasal absorption of vasopressin and an analogue. Pharm Res 1991; 8: 471–4

    Article  CAS  PubMed  Google Scholar 

  81. Mishima M, Okada S, Wakita Y, et al. Promotion of nasal absorption of insulin by glycyrrhetinic acid derivatives. I. J Pharmacobiodyn 1989; 12: 31–6

    Article  CAS  PubMed  Google Scholar 

  82. Verhoef JC, Merkus FWHM. Nasal absorption enhancement: relevance to nasal drug delivery. In: De Boer AG, editor. Drug absorption enhancement, concept, possibilities, limitations and trends. Switzerland: Horwood, 1994: 119–53

    Google Scholar 

  83. Sayani AP, Chien YW. Systemic delivery of peptides and proteins across absorptive mucosae. Crit Rev Ther Drug Carrier Syst 1996; 13:85–184

    CAS  PubMed  Google Scholar 

  84. Lutz KL, Siahaan TJ. Molecular structure of the apical junction complex and its contribution to the paracellular barrier. J Pharm Sci 1997; 86: 977–84

    Article  CAS  PubMed  Google Scholar 

  85. Sezaki H. Mucosal penetration enhancement. J Drug Target 1995; 3: 175–7

    Article  CAS  PubMed  Google Scholar 

  86. Donovan MD, Huang Y. Large molecule and particulate uptake in the nasal cavity: the effect of size on nasal absorption. Adv Drug Deliv Rev 1998; 29: 147–55

    Article  CAS  PubMed  Google Scholar 

  87. Pereswetoff-Morath L. Microspheres as nasal drug delivery systems. Adv Drug Deliv Rev 1998; 29: 185–94

    Article  CAS  PubMed  Google Scholar 

  88. Illum L. Chitosan and its use as a pharmaceutical excipient. Pharm Res 1998; 15: 1326–31

    Article  CAS  PubMed  Google Scholar 

  89. Leone-Bay A, Paton DR, Variano B, et al. Acylated non-α-amino acids as novel agents for the oral delivery of heparin sodium, USP. J Control Release 1998; 50: 41–9

    Article  CAS  PubMed  Google Scholar 

  90. Morris MC, Deponier J, Mery J, et al. A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nature Biotech 2001; 19: 1173–6

    Article  CAS  Google Scholar 

  91. Verhoef JC, Schipper NGM, Romeijn SG, et al. The potential of cyclodextrins as absorption enhancers in nasal delivery of peptide drugs. J Control Release 1994; 29: 351–60

    Article  Google Scholar 

  92. Marttin E, Verhoef JC, Merkus FWHM. Efficacy, safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein drugs. J Drug Target 1998; 6: 17–36

    Article  CAS  PubMed  Google Scholar 

  93. Shao Z, Krishnamoorthy R, Mitra AK. Cyclodextrins as nasal absorption promoters of insulin: mechanistic evaluations. Pharm Res 1992; 9: 1157–63

    Article  CAS  PubMed  Google Scholar 

  94. Arima H, Wakamatsu K, Aritomi H, Irie T, Uekama K. Improvement in nasal delivery of insulin with simultaneous use of chemically-modified cyclodextrins in rats. In: Duchene D, editor. Minutes of the Fifth International Symposium on Cyclodextrins. Paris: Editions de Sante, 1992: 487–91

    Google Scholar 

  95. Merkus FW, Verhoef JC, Marttin E, et al. Cyclodextrins in nasal drug delivery. Adv Drug Deliv Rev 1999; 36: 41–57

    Article  CAS  PubMed  Google Scholar 

  96. Merkus FW, Verhoef JC, Romeijn SG, et al. Interspecies differences in the nasal absorption of insulin [letter]. Pharm Res 1991; 8: 1343

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  98. Hilsted J, Madsbad S, Hvidberg A, et al. Intranasal insulin therapy: the clinical realities. Diabetologia 1995; 38: 680–4

    Article  CAS  PubMed  Google Scholar 

  99. Röpke M, Hansen M, Carstens S, et al. Effects of a short-chain phospholipid on ion transport pathways in rabbit nasal airway epithelium. Am J Physiol 1996; 271: L646–55

    PubMed  Google Scholar 

  100. Chandler SG, Illum L, Thomas NW. Nasal absorption in rats: II. effect of enhancers on insulin absorption and nasal histology. Int J Pharm 1991; 76: 61–70

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  102. Cheng Y-H, Watts P, Hinchcliffe M, et al. Development of a novel nasal nicotine formulation comprising an optimal pulsatile and sustained plasma nicotine profile for smoking cessation. J Control Release 2002; 79: 243–54

    Article  CAS  PubMed  Google Scholar 

  103. Edman P, Bjork E. Routes of delivery: case studies (1) nasal delivery of peptide drugs. Adv Drug Deliv Rev 1992; 8: 165–77

    Article  CAS  Google Scholar 

  104. Nagai T, Nishimoto Y, Nambu N, et al. Powder dosage forms of insulin for nasal administration. J Control Release 1984; 1: 15–22

    Article  CAS  Google Scholar 

  105. Nagai T, Machida Y. Mucosal adhesive dosage forms. Pharm Int 1985; 6: 196–200

    Google Scholar 

  106. Oechslein CR, Fricker G, Kissel T. Nasal delivery of octreotide: absorption enhancement by particulate carrier systems. Int J Pharm 1996; 139: 25–32

    Article  CAS  Google Scholar 

  107. Provasi D, Minutello A, Catellani PL, et al. Nasal powders for calcitonin administration. Proc Int Symp Control Rel Bioact Mater 1992; 19: 421–2

    Google Scholar 

  108. Edman P, Bjork E, Ryden L. Microspheres as a nasal delivery system for peptide drugs. J Control Release 1992; 21: 165–72

    Article  CAS  Google Scholar 

  109. Illum L. Bioadhesive formulations for peptide delivery. In: Mathiowitz E, Lehr CM, Chickering D, editor. Bioadhesion in drug delivery: issues in fundamentals, novel approaches and development. New York: Marcel Dekker, 1998: 507–39

    Google Scholar 

  110. Illum L, Watts P, Fisher AN, et al. Intranasal delivery of morphine. J Pharmacol Exp Ther 2002; 301: 1–10

    Article  Google Scholar 

  111. Bacon A, Makin J, Sizer PJ, et al. Carbohydrate biopolymers enhance antibody responses to mucosally delivered vaccine antigens. Infect Immun 2000; 68: 5764–70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jabbal-Gill I, Fisher AN, Rappuoli R, et al. Stimulation in mice of mucosal and systemic antibody responses against Bordetella pertussis filamentous haemagglutinin and recombinant pertussis toxin after nasal administration with chitosan. Vaccine 1998; 16: 2039–46

    Article  CAS  PubMed  Google Scholar 

  113. Mills KGH, Cosgove H, McNeela EA, et al. Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin A. Infect Immun 2003; 71: 726–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Aspden TJ, Illum L, Skaugrud O. Chitosan as a nasal delivery system: evaluation of insulin absorption enhancement and effect on nasal membrane integrity using rat models. Eur J Pharm Sci 1996; 4: 23–31

    Article  CAS  Google Scholar 

  115. Arturrson P, Lindmark T, Davis SS, et al. Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharm Res 1994; 11: 1358–61

    Article  Google Scholar 

  116. Schipper NGM, Olsson S, Hoogstraate JA, et al. Chitosan as absorption enhancers for poorly absorbed drugs 2: mechanisms of absorption enhancement. Pharm Res 1997; 14: 923–9

    Article  CAS  PubMed  Google Scholar 

  117. Dodane V, Khan MA, Merwin JR. Effect of chitosan on epithelial permeability and structure. Int J Pharm 1999; 182: 21–32

    Article  CAS  PubMed  Google Scholar 

  118. Ranaldi G, Marigliano I, Vespignani I, et al. The effect of chitosan and other polycations on tight junction permeability in the human intestinal Caco-2 cell line. J Nutr Biochem 2002; 13: 157–67

    Article  CAS  PubMed  Google Scholar 

  119. Stenson WF, Easom RA, Riehl TE, et al. Regulation of paracellular permeability in Caco-2 cell monolayers by protein kinase C. Am J Physiol 1993; 265: G955–62

    CAS  PubMed  Google Scholar 

  120. Fasano A, Fiorentini C, Donelli G, et al. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J Clin Invest 1995; 96: 710–20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chan V, Mao H-Q, Leong KW. Chitosan-induced perturbation of dipalmitoyl-sn-glycero-3-phosphocholine membrane bilayer. Langmuir 2001; 17: 3749–56

    Article  CAS  Google Scholar 

  122. Aspden T, Illum L, Skaugrud O. The effect of chronic nasal application of chitosan solutions on cilia beat frequency in guinea pigs. Int J Pharm 1997; 153: 137–46

    Article  CAS  Google Scholar 

  123. Aspden TJ, Mason JDT, Nicholas S, et al. Chitosan as a nasal delivery system: the effect of chitosan solutions on in vitro and in vivo mucociliary transport rates in human turbinates and volunteers. J Pharm Sci 1997; 86: 509–13

    Article  CAS  PubMed  Google Scholar 

  124. Soane RJ, Frier M, Perkins A, et al. Evaluation of the clearance characteristics of bioadhesive systems in humans. Int J Pharm 1999; 178: 55–65

    Article  CAS  PubMed  Google Scholar 

  125. Soane RJ, Hinchcliffe M, Davis SS, et al. Clearance characteristics of chitosan based formulations in the sheep nasal cavity. Int J Pharm 2001; 217: 183–91

    Article  CAS  PubMed  Google Scholar 

  126. Ohtake K, Natsume H, Miyamoto M, et al. Enhancing mechanism of poly-L-arginine in nasal absorption of FITC-dextran. Proc Int Symp Control Rel Bioact Mater 1998; 25: 687–8

    Google Scholar 

  127. Dorado MA. Toxicological evaluation of intranasal peptide and protein drugs. In: Hsieh DS, editor. Drug permeation enhancement, theory and application. New York: Dekker, 1994: 345–81

    Google Scholar 

  128. Quadir M, Zia H, Needham TE. Toxicological implications of nasal formulations. Drug Deliv 1999; 6: 227–42

    Article  CAS  Google Scholar 

  129. Junginger HE, Verhoef JC. Macromolecules as safe penetration enhancers for hydrophilic drugs -a fiction?. Pharm Sci Technol Today 1998; 1: 370–6

    Article  CAS  Google Scholar 

  130. Nakamura K, Maitani Y, Takayama K. The enhancing effect of nasal absorption of FITC-dextran 4,400 by β-sitosterol β-D-glucoside in rabbits. J Control Release 2002; 79: 147–55

    Article  CAS  PubMed  Google Scholar 

  131. Reardon PM, Audus KL. Ammonium glycyrrhizinate (AMGZ) effects on membrane integrity. Int J Pharm 1993; 94: 161–70

    Article  CAS  Google Scholar 

  132. Schipper NGM, Vårum KM, Artursson P. Chitosan as absorption enhancers for poorly absorbed drugs 1: influence of molecular weight and degree of acetylation on drug transport across human intestinal epithelial Caco-2 cells. Pharm Res 1996; 13: 1668–92

    Article  Google Scholar 

  133. Sakai M, Imai T, Ohtake H, et al. Cytotoxicity of absorption enhancers in Caco-2 cell monolayers. J Pharm Pharmacol 1998; 50: 1101–8

    Article  CAS  PubMed  Google Scholar 

  134. Kotze AF, Thanou MM, Lussen HL, et al. Enhancement of paracellular drug transport with highly quaternised N-trimethyl chitosan chloride in neutral environments: in vitro evaluation in intestinal epithelial cells (Caco-2). J Pharm Sci 1999; 88: 253–7

    Article  CAS  PubMed  Google Scholar 

  135. Lindmark T, Schipper N, Lazorova L, et al. Absorption enhancement in intestinal epithelial Caco-2 monolayers by sodium caprate: assessment of molecular weight dependence and demonstration of transport routes. J Drug Target 1997; 5: 215–23

    Article  Google Scholar 

  136. Schmidt MC, Peter H, Lang SR, et al. In vitro models to study nasal mucosal permeability and metabolism. Adv Drug Deliv Rev 1998; 29: 51–79

    Article  PubMed  Google Scholar 

  137. 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 Release 1998; 53: 195–203

    Article  CAS  PubMed  Google Scholar 

  138. Marttin E, Verhoef JC, Spies F, et al. The effect of methylated beta-cyclodextrins on the tight j unction of the rat nasal respiratory epithelium: electron microscopic and confocal laser scanning microscopic visualization studies. J Control Release 1999; 57: 205–13

    Article  CAS  PubMed  Google Scholar 

  139. Hosoya K-I, Kubo H, Akutsu T, et al. Effect of sodium taurodihydrofusidate on nasal drug delivery: differences in its concentration and penetrant molecular weight. Arch Pharm Res 1994; 17: 57–9

    Article  CAS  PubMed  Google Scholar 

  140. Achterrath-Tuckermann U, Berthold K, Roux J, et al. Experimental studies on acute and chronic action of azelastine on nasal mucosa in guinea pigs, rats, and dogs. Arzneimittel Forschung 1997; 47: 1230–2

    CAS  PubMed  Google Scholar 

  141. Jian L, Li Wan Po A. Effects of insulin and nasal absorption enhancers on ciliary activity. Int J Pharm 1993; 95: 101–4

    Article  CAS  Google Scholar 

  142. Aspden TJ, Illum L, Skaugrud O. The absence of chitosan toxicity when applied to nasal mucosa. Proc Int Symp Control Rel Bioact Mater 1995; 22: 550–1

    Google Scholar 

  143. Gizurarson S, Marriott C, Martin GP, et al. The influence of insulin and some excipients used in nasal insulin preparations on mucociliary clearance. Int J Pharm 1990; 65: 243–7

    Article  CAS  Google Scholar 

  144. Chandler SG, Thomas NW, Illum L. Nasal absorption in the rat: III. effect of lysophospholipids on insulin absorption and nasal histology. Pharm Res 1994; 11: 1623–30

    Article  CAS  PubMed  Google Scholar 

  145. Bindseil E, Bechgaard E, Jorgensen L, et al. Morphological examination of rabbit nasal mucosa after exposure to acetylsalicylic acid, glycofurol 75 and ephedrine. Int J Pharm 1995; 119: 37–46

    Article  CAS  Google Scholar 

  146. Chandler SG, Thomas NW, Illum L. Nasal absorption in the rat: IV. membrane activity of absorption enhancers. Int J Pharm 1995; 117: 139–46

    Article  CAS  Google Scholar 

  147. Nakane S, Kakumoto M, Yukimatsu K, et al. Oramucosal delivery of LHRH: pharmacokinetic studies of controlled and enhanced transmucosal permeation. Pharm Dev Technol 1996; 1: 251–9

    Article  CAS  PubMed  Google Scholar 

  148. Abe K, Irie T, Ishiguro T, et al. Optimization effects of hydroxypropyl-β-cyclodextrin in combination with nasal absorption enhancer HPE-101. Proc Int Symp Control Rel Bioact Mater 1996; 23: 159–60

    Google Scholar 

  149. LeCluyse EL, Appel LE, Sutton SC. Relationship between drug absorption enhancing activity and membrane perturbing effects of acylcarnitines. Pharm Res 1991; 8: 84–7

    Article  CAS  PubMed  Google Scholar 

  150. Shao Z, Mitra AK. Nasal membrane and intracellular protein and enzyme release by bile salts and bile salt-fatty acid mixed micelles: correlation with facilitated drug transport. Pharm Res 1992; 9: 1184–9

    Article  CAS  PubMed  Google Scholar 

  151. Van de Donk HJM, Muller-Plantema IP, Zuidema J, et al. The effects of preservatives on the ciliary beat frequency of chicken embryo tracheas. Rhinology 1980; 18: 119–30

    PubMed  Google Scholar 

  152. Van de Donk HJM, Zuidema J, Merkus FWHM. Correlation between the sensitivity of the ciliary beat frequency of human adenoid tissue and chicken embryo tracheas for some drugs. Rhinology 1982; 20: 81–7

    PubMed  Google Scholar 

  153. Merkus P, Romeijn SG, Verhoef JC, et al. Classification of cilio-inhibiting effects of nasal drugs. Laryngoscope 2001; 111:595–602

    Article  CAS  PubMed  Google Scholar 

  154. Boek WM, Romeijn SG, Graamans K, et al. Validation of animal experiments on ciliary function in vitro: II. the influence of absorption enhancers, preservatives and physiologic saline. Acta Otolaryngol 1999; 119: 98–101

    Article  CAS  PubMed  Google Scholar 

  155. HaffejeeN, Du Plessis J, Muller DG, et al. Intranasal toxicity of selected absorption enhancers. Pharmazie 2001; 56: 882–8

    Google Scholar 

  156. Davis SS. Delivery of peptide and non-peptide drugs through the respiratory tract. Pharm Sci Technol Today 1999; 2: 450–6

    Article  CAS  PubMed  Google Scholar 

  157. Anton F, Herdegen T, Peppel P, et al. C-FOS-like immunoreactivity in rat brainstem neurons following noxious chemical stimulation of the nasal mucosa. Neuroscience 1991; 41: 629–41

    Article  CAS  PubMed  Google Scholar 

  158. Adriaens E, Remon JP. Gastropods as an evaluation tool for screening the irritating potency of absorption enhancers and drugs. Pharm Res 1999; 16: 1240–4

    Article  CAS  PubMed  Google Scholar 

  159. Illum L, Davis SS. Intranasal insulin: clinical pharmacokinetics. Clin Pharmacokinet 1992; 23: 30–41

    Article  CAS  PubMed  Google Scholar 

  160. Merkus, FWHM, Schipper NGM, Verhoef JC. The influence of absorption enhancers on intranasal insulin absorption in normal and diabetic subjects. J Control Release 1996; 41: 69–75

    Article  CAS  Google Scholar 

  161. Merkus FW, Schipper NGM, Verhoef JC, et al. Intranasal insulin absorption in volunteers and diabetes mellitus patients [abstract no. 401]. Therapie 1995; 50 Suppl. 1

    Google Scholar 

  162. Wilcock A, Pavis H, Edgecombe J, et al. Nasal morphine for the treatment of breakthrough pain in cancer patients. J Pain Symptom Manage 2002; 24: 598–602

    Article  PubMed  Google Scholar 

  163. Soane RJ. Bioadhesive polymers as intranasal drug delivery systems for peptide and protein drugs [Ph.D. thesis]. UK: University of Nottingham, 1999

    Google Scholar 

  164. McNeela E, O’Connor D, Jabbal-Gill I, et al. A mucosally delivered vaccine against diphtheria: Formulation of cross reacting material (CRM197) of diphtheria toxin with chitosan enhances local and systemic antibody and Th2 responses following nasal delivery. Vaccine 2000; 19: 1188–98

    Article  CAS  PubMed  Google Scholar 

  165. Illum L, Jabbal-Gill I, Hinchcliffe M, et al. Chitosan as a novel nasal delivery system for vaccines. Adv Drug Del Rev 2001; 51: 81–96

    Article  CAS  Google Scholar 

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  1. Institute of Pharmaceutical Sciences, University of Nottingham, Boots Science Building, University Park, Nottingham, NG7 2RD, UK

    Stanley S. Davis & Lisbeth Illum

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Davis, S.S., Illum, L. Absorption Enhancers for Nasal Drug Delivery. Clin Pharmacokinet 42, 1107–1128 (2003). https://doi.org/10.2165/00003088-200342130-00003

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