Intranasal insulin delivery and therapy

Advanced Drug Delivery Reviews

Volumn 35, Issue 2-3, 1999, Pages 199-234

  Hinchcliffe, Michael ^a   Illum, Lisbeth ^a  

^a Danbiosyst UK Ltd   (United Kingdom)

Author keywords

Absorption enhancers; Absorption promoters; Insulin; Intranasal absorption; Intranasal delivery; Pharmacokinetics

Indexed keywords

ANTIDIABETIC AGENT; INSULIN;

DIABETES MELLITUS; DRUG ABSORPTION; DRUG DELIVERY SYSTEM; FOOD INTAKE; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN RELEASE; INSULIN TREATMENT; INTRANASAL DRUG ADMINISTRATION; MEAN RESIDENCE TIME; NON INSULIN DEPENDENT DIABETES MELLITUS; NOSE MUCOSA; PERMEABILITY; PRIORITY JOURNAL; REVIEW; SUBCUTANEOUS DRUG ADMINISTRATION;

EID: 0032969698     PISSN: 0169409X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0169-409X(98)00073-8     Document Type: Review

References (248)

1. Bliss M. The history of insulin. Diabetes Care. 16(Suppl. 3):1993;4-7.
2. Eppstein D.A., Longenecker J.P. Alternative delivery systems for peptides and proteins as drugs. Crit. Rev. Ther. Drug Carrier Syst. 5:1988;99-139.
3. Lee V.H.L., Yamamoto A. Penetration and enzymic barriers to peptide and protein absorption. Adv. Drug Deliv. Rev. 4:1990;171-207.
4. Smith P.L., Wall D.A., Gochoco H., Wilson G. Routes of delivery: case studies. (5) Oral absorption of peptides and proteins. Adv. Drug Deliv. Rev. 8:1992;253-290.
5. S.S. Davis, Developing delivery systems for peptides and proteins, Scrip Mag. May (1992) 34-38.
6. M. Humphrey, The oral bioavailability of peptides and related drugs, in: S.S. Davis, L. Illum, E. Tomlinson (Eds.), Delivery Systems for Peptide Drugs, Plenum, New York, 1986, pp. 139-151.
7. V.H.L. Lee, S.D. Kashi, G.M. Grass, W. Rubas, Oral route of peptide and protein drug delivery, in: V.H.L. Lee (Ed.), Peptide and Protein Drug Delivery, Marcel Decker, New York, 1991, pp. 691-738.
8. Kennedy F.P. Recent developments in insulin delivery techniques. Drugs. 42:1991;213-227.
9. Home P.D., Gill G.V., Husband D., Kruszynska Y.T. Alternative routes and methods of insulin delivery. Neth. J. Med. 28(Suppl. I):1985;32-36.
10. J.C. Pickup, An introduction to the problems of insulin delivery, in: J.C. Pickup (Ed.), Biotechnology of Insulin Therapy, Blackwell Scientific, Oxford, 1991, pp. 1-23.
11. Pontiroli A.E., Calderara A., Pozza G. Intranasal drug delivery: potential advantages and limitations from a clinical pharmacokinetic perspective. Clin. Pharm. 17:1989;209-307.
12. Novo Nordisk A/S, Denmark, Diabetes research - improving quality of life, Press release, Novo Nordisk, Corporate PR and Press Relations, Washington, DC, June 26, 1991.
13. Brange J., Owens D.R., Kang S., Vølund A. Monomeric insulins and their experimental and clinical implications. Diabetes Care. 13:1990;923-954.
14. C.R. Kahn, Y. Shechter, Insulin, oral hypoglycaemic agents, and the pharmacology of the endocrine pancreas, in: L.S. Goodman, A. Gilman, A. Goodman (Eds.), The Pharmacological Basis of Therapeutics, 8th ed., Pergamon Press, New York, 1990, pp. 1463-1495.
15. Illum L., Davis S.S. Intranasal insulin: clinical pharmacokinetics. Clin. Pharm. 23:1992;30-41.
16. Koivisto V.A., Felig P. Alterations in insulin absorption and in blood glucose control associated with varying insulin injection sites in diabetic patients. Ann. Intern. Med. 92:1980;59-61.
17. ter Braak E.W.T.M., Bianchi R., Erkelens D.W. Faster, shorter and more profound action of Lys(B28)Pro(B29) human insulin analogue compared to regular insulin irrespective of injection site. Diabetes. 42:1993;207A.
18. Siddiqui O., Chien Y.W. Nonparenteral administration of peptide and protein drugs. Crit. Rev. Ther. Drug Carrier Syst. 3:1987;195-208.
19. Banga A.K., Chien Y.W. Systemic delivery of therapeutic peptides and proteins. Int. J. Pharm. 48:1988;15-50.
20. Y.W. Chien, Y. Chang, Historical developments of transnasal systemic medications, in: Y.W. Chien (Ed.), Transnasal Systemic Medications: Fundamentals, Developmental Concepts and Biomedical Assessments, Elsevier, Amsterdam, 1985, pp. 1-100.
21. S.S. Davis, Advanced delivery systems for peptides and proteins - pharmaceutical considerations, in: S.S. Davis, L. Illum, E. Tomlinson (Eds.), Delivery Systems for Peptide Drugs, Plenum, New York, 1986, pp. 1-21.
22. J.P. Longenecker, Nazlin® - transnasal systemic delivery of insulin, in: S.S. Davis, L. Illum, E. Tomlinson (Eds.), Delivery Systems for Peptide Drugs, Plenum, New York, 1986, pp. 211-220.
23. Woodyatt R.T. The clinical use of insulin. J. Metab. Res. 2:1922;793-801.
24. Chien Y.W., Chang S-F. Intranasal drug delivery for systemic medications. Crit. Rev. Ther. Drug Carrier Syst. 4:1987;67-194.
25. Y.W. Chien, K.S.E. Su, S-F. Chang, Intranasal delivery of peptide/protein drugs, intranasal delivery of nonpeptide molecules, intranasal delivery of diagnostic drugs, in: Y.W. Chien, K.S.E. Su, S-F. Chang (Eds.), Nasal Systemic Drug Delivery, Marcel Dekker, New York, 1989, pp. 89-298.
26. A.N. Fisher, Studies on the nasal absorption of drugs in animals, PhD thesis, University of Nottingham, UK, 1994.
27. Chang S.F., Chien Y.W. Intranasal drug administration for systemic medication. Pharm. Int. 5:1984;287-288.
28. L. Illum, Nasal delivery of peptides, factors affecting nasal absorption, in: D.J.A. Crommelin, K.K. Midha (Eds.), Topics in Pharmaceutical Sciences, Medpharm Scientific, Stuttgart, 1992, pp. 71-82.
29. Lilet H., Krzentowski G., Bodson A., Scheen A.J., Lefebvre P.J. Lack of beneficial effect of intermittent subcutaneous insulin delivery by pump in Type-1 diabetic patients. Diabete Metabol. 17:1991;363-372.
30. Yokosuka T., Omori Y., Hirata Y., Hirai S. Nasal and sublingual administration of insulin in man. J. Jpn. Diabetes Soc. 20:1977;146-152.
31. Moses A.C., Gordon G.S., Carey M.C., Flier J.S. Insulin administered intranasally as an insulin-bile salt aerosol - effectiveness and reproducibility in normal and diabetic subjects. Diabetes. 32:1983;1040-1047.
32. N. Mygind, Nasal Allergy, Blackwell Scientific, Oxford, 1978.
33. D.F. Proctor, I.B. Anderson (Eds.), The Nose: Upper Airway Physiology and the Atmospheric Environment, Elsevier Biomedical Press, Amsterdam, 1982.
34. N. Mygind, Nasal Allergy; Part 1: Ultrastructure, Blackwell Scientific, Oxford, 1978, pp. 3-56.
35. D.F. Proctor, The upper airway, in: D.F. Proctor, I.B. Anderson (Eds.), The Nose: Upper Airway Physiology and the Atmospheric Environment, Elsevier Biomedical Press, Amsterdam, 1982, pp. 23-43.
36. D.F. Proctor, J.C.F. Chang, Comparative anatomy and physiology of the nasal cavity, in: G. Reznik, S.F. Stinson (Eds.), Nasal Tumours in Animals and Man, Vol. 1, CRC Press, Boca Raton, FL, 1983, pp. 1-33.
37. D.F. Proctor, Nasal physiology in intranasal drug administration, in: Y.W. Chien (Ed.), Transnasal Systemic Medications: Fundamentals, Developmental Concepts and Biomedical Assessments, Elsevier, Amsterdam, 1985, pp. 101-106.
38. J.P. Schreider, Comparative anatomy and function of the nasal passages, in: C.S. Barrow (Ed.), Toxicology of the Nasal Passages, Hemisphere, Washington, 1986, pp. 1-25.
39. Y.W. Chien, K.S.E. Su, S-F. Chang, Anatomy and physiology of the nose, in: Y.W. Chien, K.S.E. Su, S-F. Chang (Eds.), Nasal Systemic Drug Delivery, Marcel Dekker, New York, 1989, pp. 1-26.
40. P.A. Hilger, Applied anatomy and physiology of the nose, in: G.L. Adams, L.R. Boies, P.A. Hilger (Eds.), Boies Fundamentals of Otolaryngology, W.B. Saunders Company, 1989, pp. 177-195.
41. K.S.E. Su, Nasal route for peptide and protein drug delivery, in: V.H.L. Lee (Ed), Peptide and Protein Drug Delivery, Marcel Decker, New York, 1991, pp. 595-631.
42. G.M. O'Donoghue, G.J. Bates, A.A. Narula, Clinical ENT, An Illustrated Textbook, The Nose and Sinues, Oxford University Press, Oxford, 1992, pp. 77-157.
43. N. Mygind, Upper airway: structure, function and therapy, in: F. Moren, M.B. Dolovich, M.T. Newhouse, S.P. Newman (Eds.), Aerosols in Medicine, Principles, Diagnosis and Therapy, Elsevier, Amsterdam, 1993, pp. 1-26.
44. L. Illum, A.N. Fisher, Intranasal delivery of peptides and proteins, in: A.L. Adjei, P.K. Gupta (Eds.), Inhalation Delivery of Therapeutic Peptides and Proteins, Lung Biology in Health and Disease, Vol. 107, Marcel Decker, New York, 1997, pp. 135-184.
45. Gizurarson S. Animal models for intranasal drug delivery studies: a review article. Acta Pharm. Nord. 2:1990;105-122.
46. Illum L. Nasal delivery. The use of animal models to predict performance in man. J. Drug Targeting. 3:1996;427-442.
47. Proctor D.F., Andersen I., Lundqvist G. Clearance of inhaled particles from the human nose. Arch. Intern. Med. 131:1973;132-139.
48. Mygind et al., Morphology of the upper airway epithelium, in: D.F. Proctor, I.B. Anderson (Eds.), The Nose: Upper Airway Physiology and the Atmospheric Environment, Elsevier Biomedical Press, Amsterdam, 1982, pp. 71-97.
49. S.P. Sorokin, The respiratory system, in: L. Weiss (Ed.), Histology, Elsevier, New York, 1983, pp. 788-797.
50. D.W. Fawcett, E. Raviola, Respiratory system, in: D.W. Fawcett, E. Raviola (Eds.), Bloom and Fawcetts; A Textbook of Histology, 12 ed., Chapman and Hall, New York, 1994, pp. 704-726.
51. A.B.J. Noach, M.A. Hurni, A.G. de Boer, D.D. Breimer, Drug transport and its enhancement via the paracellular pathway, in: A.G. de Boer (Ed.), Drug Absorption Enhancement, Harwood Academic, Basel, 1994, pp. 291-324.
52. Inagaki M., Sakakura Y., Itoh J., Ukai K., Miyoshi Y. Macromolecular permeability of the tight junction of the human nasal mucosa. Rhinology. 23:1985;213-221.
53. D.F. Proctor, The mucociliary system, in: D.F. Proctor, I.B. Anderson (Eds.), The Nose: Upper Airway Physiology and the Atmospheric Environment, Elsevier Biomedical Press, Amsterdam, 1982, pp. 245-278.
54. Duchateau G.S.M.J.E., Graamans K., Zuidema J., Merkus F.W.H.M. Correlation between ciliary beat frequency and mucus transport rate in volunteers. Laryngoscope. 95:1985;854-859.
55. Sleigh M.A., Blake J.R., Liron N. The propulsion of mucus by cilia. Am. Rev. Respir. Dis. 137:1988;726-741.
56. Petruson B., Hansson H.A., Karlsson G. Structural and functional aspects of cells in the nasal mucociliary system. Arch. Oto-Laryngol. 110:1984;576-581.
57. N. Cauna, Blood and nerve supply of the nasal lining, in: D.F. Proctor, I.B. Anderson (Eds.), The Nose: Upper Airway Physiology and the Atmospheric Environment, Elsevier Biomedical Press, Amsterdam, 1982, pp. 45-69.
58. Sarkar M.A. Drug metabolism in the nasal mucosa. Pharm. Res. 9:1992;1-9.
59. Irwin W.J., Holbrook P.A., Dey M.J. The stability of peptides in nasal enzymic systems. Int. J. Pharm. 113:1995;25-37.
60. Hadley W.M., Dahl A.R. Cytochrome P-450 dependent monooxygenase activity in nasal membranes of six species. Drug Metab. Dispos. 11:1983;275-276.
61. Kashi S.D., Lee V.H.L. Enkephalin hydrolysis in homogenates of various absorptive mucosae of the albino rabbit: similarities in rates and involvement of aminopeptidases. Life Sci. 38:1986;2019-2028.
62. Audus K.L., Tavakoli-Saberi M.R. Aminopeptidases of newborn bovine nasal turbinate epithelial cell cultures. Int. J. Pharm. 76:1991;247-255.
63. Hussain A.A., Iseki K., Kagoshima M., Dittert L.W. Hydrolysis of peptides in nasal cavity of humans. J. Pharm. Sci. 79:1990;947-948.
64. Mygind N., Winther B. Immunological barriers in the nose and paranasal sinuses. Acta. Oto-Larngol. 103:1987;363-368.
65. D.M. Weir, Immunology, 4th ed., Churchill Livingstone, Edinburgh, 1977, pp. 8-87.
66. Brandtzaeg P. Immunobarriers of the mucosa of the upper respiratory and digestive pathways. Acta Oto-Laryngol. 105:1988;172-180.
67. McGhee J.R., Kiyono H. New perspectives in vaccine development: mucosal immunity to infections. Infect. Agents Dis. 2:1993;55-73.
68. N. Mygind, Nasal Allergy; Part 3: Disease, Blackwell Scientific, Oxford, 1978, pp. 219-332.
69. Illum L., Jorgensen H., Bisgaard H. Bioadhesive microspheres as a potential nasal drug delivery system. Int. J. Pharm. 39:1987;189-199.
70. Schipper N.G.M., Verhoef J.C., Merkus F.W.H.M. The nasal mucociliary clearance: relevance to nasal drug delivery. Pharm. Res. 8:1991;807-814.
71. R.F. Phalen, Inhalation Studies: Foundations and Techniques, CRC Press, Boca Raton, FL, 1984.
72. O'Hagan D.T., Illum L. Absorption of peptides and proteins from the respiratory tract and the potential for development of locally administered vaccine. Crit. Rev. Ther. Drug Carrier Syst. 7:1990;35-97.
73. Aoki F.Y., Crawley J.C.W. Distribution and removal of human serum albumin-technetium-99m instilled intranasally. Br. J. Clin. Pharmacol. 3:1976;869-878.
74. Lee S.W., Hardy J.G., Wilson C.G., Smelt G.J.C. Nasal sprays and polyps. Nucl. Med. Commun. 5:1984;697-703.
75. Hardy J.G., Lee S.W., Wilson C.G. Intranasal drug delivery by spray and drops. J. Pharm. Pharmacol. 37:1985;294-297.
76. Harris A.S., Nilsson I.M., Wagner Z.G., Alkner U. Intranasal administration of peptides: nasal deposition, biological response, and absorption of desmopressin. J. Pharm. Sci. 75:1986;1085-1088.
77. Harris A.S., Hedner P., Vilhardt H. Nasal administration of desmopressin by spray and drops. J. Pharm. Pharmacol. 39:1987;932-934.
78. Harris A., Ohlin M., Lethagen S., Nilsson I.M. Effects of concentration and volume on nasal bioavailability and biological response to desmopressin. J. Pharm. Sci. 77:1988;337-339.
79. Harris A., Ohlin M., Svensson E., Lethagen S., Nilsson I.M. Effect of viscosity on particle size, deposition, and clearance of nasal systems containing desmopressin. J. Pharm. Sci. 77:1988;405-408.
80. Harris A.S., Ohlin M., Svensson E., Lethagen S., Nilsson I.M. Effect of viscosity on the pharmacokinetics and biological response to intranasal desmopressin. J. Pharm. Sci. 78:1989;470-471.
81. Newman S.P., Moren F., Clarke S.W. The nasal distribution of metered dose inhalers. J. Laryngol. Otol. 101:1987;127-132.
82. Pennington A.K., Ratcliffe J.H., Wilson C.G., Hardy J.G. The influence of solution viscosity on nasal spray deposition and clearance. Int. J. Pharm. 43:1988;221-224.
83. Newman S.P., Steed K.P., Hardy J.G., Wilding I.R., Hooper G., Sparrow R.A. The distribution of an intranasal insulin formulation in healthy volunteers: effect of different administration techniques. J. Pharm. Pharmacol. 46:1994;657-660.
84. Mygind N., Vesterhauge S. Aerosol distribution in the nose. Rhinology. 16:1978;79-88.
85. Liversidge G.G., Wilson C.G., Sternson L., Kinter L.B. Nasal delivery of a vasopressin antagonist in dogs. J. Appl. Physiol. 64:1988;377-383.
86. Wolff R.K., Allen D.L., Hughes B.L., Osier M., Dorato M.A. Nasal clearance in rhesus monkeys. J. Aerosol Med. 6:1993;111-119.
87. Sakakura Y., Ukai K., Majima Y., Murai S., Harada T., Miyoshi Y. Nasal mucociliary clearance under various conditions. Acta Oto-Laryngol. 96:1983;167-173.
88. Rashad M., Hady A., Shehata O., Hassan R. Nasal mucociliary function in different diseases of the nose. J. Laryngol. Otol. 97:1983;497-502.
89. Da-jun Y., Shi-fa X., De-zhu X., Gui-lian L., Jia-lan X., Jin-mei L., Tian C. Nasal mucociliary function in normal adults and different diseases. Chin. Med. J. 99:1986;969-972.
90. S.W. Bond, J.G. Hardy, C.G. Wilson, Deposition and clearance of nasal sprays, in: 2nd International Congress of Biopharmaceuticals and Pharmacokinetics, Salamanca, Spain, 1984, pp. 93-98.
91. Phillpotts R.J., Davies H.W., Willman J., Tyrrell D.A.J., Higgins P.G. Pharmacokinetics of intranasally applied medication during a cold. Antiviral Res. 4:1984;71-74.
92. Bascom R., Kesavanthan J., Fitzgerald T.K., Cheng K-H., Swift D.L. Sidestream tobacco smoke exposure acutely alters human nasal mucociliary clearance. Environ. Health Perspect. 103:1995;1026-1030.
93. Agostini A., Bertaccini G. Nasal absorption of caerulein. Lancet. 1:1969;580-581.
94. J. Sandow, W. Petri, Intranasal administration of peptides: biological activity and therapeutic efficacy, in: Y.W. Chien (Ed.), Transnasal Systemic Medications: Fundamentals, Developmental Concepts and Biomedical Assessments, Elsevier, Amsterdam, 1985, pp. 183-199.
95. Olanoff L.S., Titus C.R., Shea M.S., Gibson R.E., Brooks C.D. Effect of intranasal histamine on nasal mucosal blood flow and the antidiuretic activity of desmopressin. J. Clin. Invest. 80:1987;890-895.
96. Edwards P.A.W. Is mucus a selective barrier to macromolecules. Br. Med. Bull. 34:1978;55-56.
97. Raub T.J., Barsuhn C.L., Williams L.R. Use of a biophysical-kinetic model to understand the roles of protein binding and membrane partitioning on passive diffusion of highly lipophilic molecules across cellular barriers. J. Drug Targeting. 1:1993;269-286.
98. Hussain A.A., Hirai S., Bawarshi R. Nasal absorption of propranolol in rats. J. Pharm. Sci. 68:1979;1196.
99. Hussain A., Foster T., Hirai S., Kashihara T., Batenhorst R., Jones M. Nasal absorption of propranolol in humans. J. Pharm. Sci. 69:1980;1240.
100. Hussain A., Hirai S., Bawarshi R. Nasal absorption of propranolol from different dosage forms by rats and dogs. J. Pharm. Sci. 69:1980;1411-1413.
101. Hussain A., Kimura R., Huang C.H., Kashihara T. Nasal absorption of naloxone and buprenorphine in rats. Int. J. Pharm. 21:1984;233-237.
102. Bawarshi-Nassar R.N., Hussain A., Crooks P.A. Nasal absorption of 17α-ethinyloestradiol in the rat. J. Pharm. Pharmacol. 41:1989;214-215.
103. A.A. Hussain, R. Bawarshi-Nassar, C.H. Huang, Physicochemical considerations in intranasal drug administration, in: Y.W. Chien (Ed.), Transnasal Systemic Medications: Fundamentals, Developmental Concepts and Biomedical Assessments, Elsevier, Amsterdam, 1985, pp. 121-137.
104. Huang C.H., Kimura R., Bawarshi-Nassar R., Hussain A. Mechanism of nasal absorption of drugs I: Physicochemical parameters influencing the rate of in situ nasal absorption of drugs in rats. J. Pharm. Sci. 74:1985;608-611.
105. A.T. Florence, D. Attwood, Physicochemical Principles of Pharmacy, Macmillan, London, 1988.
106. McMartin C., Hutchinson L.E.F., Hyde R., Peters G.E. Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity. J. Pharm. Sci. 76:1987;535-540.
107. Fisher A.N., Brown K., Davis S.S., Parr G.D., Smith D.A. The effect of molecular size on the nasal absorption of water-soluble compounds in the albino rat. J. Pharm. Pharmacol. 39:1987;357-362.
108. Fisher A.N., Illum L., Davis S.S., Schacht E.H. Di-iodo-L-tyrosine-labelled dextrans as molecular size markers of nasal absorption in the rat. J. Pharm. Pharmacol. 44:1992;550-554.
109. Muranishi S., Sakai A., Yamada K., Murakami M., Takada K., Kiso Y. Lipophilic peptides: synthesis of lauroyl thyrotropin-releasing hormone and its biological activity. Pharm. Res. 8:1991;649-652.
110. Faraj J.A., Hussain A.A., Aramaki Y., Iseki K., Kagoshima M., Ditter L.W. Mechanism of nasal absorption of drugs. III: Nasal absorption of leucine enkephalin. J. Pharm. Sci. 79:1990;698-702.
111. Hirai S., Yashiki T., Mima H. Mechanisms for the enhancement of the nasal absorption of insulin by surfactants. Int. J. Pharm. 9:1981;173-184.
112. Hayakawa E., Yamamoto A., Shoji Y., Lee V.H.L. Effect of sodium glycocholate and polyoxyethylene-9-lauryl ether on the hydrolysis of varying concentrations of insulin in the nasal homogenates of the albino rabbit. Life Sci. 45:1989;167-174.
113. Gizurarson S., Bechgaard E. Study of nasal enzyme activity towards insulin in vitro. Chem. Pharm. Bull. 39:1991;2155-2157.
114. Hashimoto M., Takada K., Kiso Y., Muranishi S. Synthesis of palmitoyl derivatives of insulin and their biological activities. Pharm. Res. 6:1989;171-176.
115. Asada H., Douen T., Muakami M. Improvement of intestinal absorption of insulin by modification with fatty acids. Proc. Int. Symp. Control. Release Bioact. Mater. 19:1992;212-213.
116. Asada H., Douen T., Waki M. Absorption characteristics of chemically modified insulin derivatives with various fatty acids in the small and large intestine. J. Pharm. Sci. 84:1995;682-687.
117. Merkus F.W.H.M., Schipper N.G.M., Verhoef J.C. The influence of absorption enhancers on intranasal insulin absorption in normal and diabetic subjects. J. Control. Release. 41:1996;69-75.
118. Illum L. The nasal delivery of peptides and proteins. Tibtech. 9:1991;284-289.
119. J.C. Verhoef, F.W.H.M. Merkus, Nasal absorption enhancement: relevance to nasal drug delivery, in: A.G. de Boer (Ed.), Drug Absorption Enhancement, Harwood Academic, 1994, pp. 119-153.
120. Y.W. Chien, K.S.E. Su, S-F. Chang, Animal models used in nasal absorption studies, in: Y.W. Chien, K.S.E. Su, S-F. Chang (Eds.), Nasal Systemic Drug Delivery, Marcel Dekker, New York, 1989, pp. 27-37.
121. Horowitz S. Über die endonasale applikation von insulin. Z. Klin. Med. 116:1931;622-631.
122. Collens W.S., Goldzieher M.A. Absorption of insulin by nasal mucous membranes. Proc. Soc. Exp. Biol. Med. 29:1932;756-759.
123. Major R.H. The intranasal application of insulin. J. Lab. Clin. Med. 21:1935;278-280.
124. Major R.H. The intranasal application of insulin, experimental and clinical experiences. Am. J. Med. Sci. 192:1936;257-263.
125. Hankiss J., Hadhazy C.S. Resorption von insulin und asthmolysin von der nasenschleimhaut. Acta Med. Hung. 12:1958;107-114.
126. Carey M.C., Small D.M. Micelle formation by bile salts. Arch. Intern. Med. 130:1972;506-527.
127. Hirai S., Ikenaga T., Matsuzawa T. Nasal absorption of insulin in dogs. Diabetes. 27:1978;296-299.
128. Hirai S., Yashiki T., Mima H. Effect of surfactants on the nasal absorption of insulin in rats. Int. J. Pharm. 9:1981;165-172.
129. Aungst B.J., Rogers N.J., 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. 244:1988;23-27.
130. Tengamnuay P., Mitra A.K. Bile salt-fatty acid mixed micelles as nasal absorption promoters of peptides. II. In vivo nasal absorption of insulin in rats and effects of mixed micelles on the morphological integrity of the nasal mucosa. Pharm. Res. 7:1990;370-375.
131. Longenecker J.P., Moses A.C., Flier J.S., Silver R.D., Carey M.C., Dubovi E.J. Effects of sodium taurodihydrofusidate on nasal absorption of insulin in sheep. J. Pharm. Sci. 76:1987;351-355.
132. Deurloo M.J.M., Hermens A.J.J., Romeyn S.G., Verhoef J.C., Merkus F.W.H.M. Absorption enhancement of intranasally administered insulin by sodium taurodihydrofusidate (STDHF) in rabbits and rats. Pharm. Res. 6:1989;853-856.
133. Verhoef J., Deurloo M.J.M., Hermens W.A.J.J., Romeijn S.G., Merkus F.W.H.M. Absorption enhancement of intranasally administered insulin by STDHF in rabbits and rats. Proc. Int. Symp. Control. Release Bioact. Mater. 16:1989;85-86.
134. Yokosuka T. Studies on nasal administration of insulin in normal and diabetic subjects. J. Tokyo Women's Med. Coll. 48:1978;467-477.
135. Y. Hirata, T. Yokosuka, T. Kasahara, M. Kikuchi, K. Ooi, Nasal administration of insulin in patients with diabetes, in: S. Baba, T. Kaneko, C. Yanaihara (Eds.), Proceedings of the Symposium on Proinsulin, Insulin and C- Peptide, Tokushima, July 1978, Excerpta Medica, Amsterdam, 1979, pp. 319-326.
136. Pontiroli A.E., Alberetto M., Secchi A., Dossi G., Bosi I., Pozza G. Insulin given intranasally induces hypoglycaemia in normal and diabetic subjects. Br. Med. J. 284:1982;303-306.
137. Pontiroli A.E., Alberetto M., Pajetta E., Calderara A., Pozza G. Human insulin plus sodium glycocholate in a nasal spray formulation: improved bioavailability and effectiveness in normal subjects. Diabete Metabol. 13:1987;441-443.
138. Gordon G.S., Moses A.C., Silver R.D., Flier J.S., Carey M.C. Nasal absorption of insulin: enhancement by hydrophobic bile salts. Proc. Natl. Acad. Sci. USA. 82:1985;7419-7423.
139. J.S. Flier, A.C. Moses, G.S. Gordon, R.S. Silver, Intranasal administration of insulin, efficacy and mechanisms, in: Y.W. Chien (Ed.), Transnasal Systemic Medications: Fundamentals, Developmental Concepts and Biomedical Assessments, Elsevier, Amsterdam, 1985, pp. 217-226.
140. Frauman A.G., Jerums G., Louis W.J. Effects of intranasal insulin in non-obese type II diabetics. Diabetes Res. Clin. Pract. 3:1987;197-202.
141. Frauman A.G., Cooper M.E., Parsons B.J., Jerums G., Louis W.J. Long-term use of intranasal insulin in insulin-dependent diabetic patients. Diabetes Care. 10:1987;573-578.
142. Frauman A.G., Buchanan R., Jerums G., Louis W.J. Intranasal insulin (INI) treatment of type I diabetes: clinical and immunologic effects using two different absorption enhancing adjuvants. Diabetes Res. Clin. Pract. 5(Suppl. 1):1988;S162.
143. El-Etr M., Slama G., Desplanque N. Preprandial intranasal insulin as adjuvant therapy in type II diabetics. Lancet. 7:1987;1085-1086.
144. Lassmann-Vague V., Thiers D., Vialettes B., Vague Ph. Preprandial intranasal insulin. Lancet. 13:1988;367-368.
145. Salzman R., Manson J.E., Griffing G.T. Intranasal aerosolized insulin. Mixed-meal studies and long-term use in type I diabetes. New Engl. J. Med. 312:1985;1078-1084.
146. Moses A.C. Nasal absorption of insulin. Pharm. Weekbl. Sci. Ed. 10:1988;45-46.
147. Nolte M.S., Taboga C., Salamon E., Moses A., Longenecker J., Flier J., Karam J.H. Biological activity of nasally administered insulin in normal subjects. Horm. Metab. Res. 22:1990;170-174.
148. Sinay I.R., Schlimovich S., Damilano S. Intranasal insulin administration in insulin dependent diabetes: reproducibility of its absorption and effects. Horm. Metab. Res. 22:1990;307-308.
149. V. Lassmann-Vague, The intranasal route for insulin administration, in: J.C. Pickup (Ed.), Biotechnology of Insulin Therapy, Blackwell Scientific, Oxford, 1991, pp. 113-125.
150. Bruce D.G., Chisholm D.J., Storlien L.H., Borkman M., Kraegen E.W. Meal-time intranasal insulin delivery in type 2 diabetes. Diabetic Med. 8:1991;366-370.
151. Bruce D.G., Chisholm D.J., Storlien L.H., Kraegen E.W. Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes. Diabetes. 37:1988;736-744.
152. Murakami T., Sasaki Y., Yamajo R., Yata N. Effect of bile salts on the rectal absorption of sodium ampicillin in rats. Chem. Pharm. Bull. 32:1984;1948-1955.
153. Shiga M., Hayashi M., Horie T., Awazu S. Differences in the promotion mechanism of the colonic absorption of antipyrene, phenol red and cefmetazole. J. Pharm. Pharmacol. 39:1987;118-123.
154. W.A. Lee, Permeation enhancers for the nasal delivery of protein and peptide therapeutics, BioPharm, November/December (1990) 22-25.
155. Uchida N., Maitani Y., Machida Y., Nakagaki M., Nagai T. Influence of bile salts on the permeability of insulin through the nasal mucosa of rabbits in comparison with dextran derivatives. Int. J. Pharm. 74:1991;95-103.
156. Uchida N., Maitani Y., Machida Y., Nakagaki M., Nagai T. Influence of bile salts on the permeability through the nasal mucosa of rabbits of insulin in comparison with dextran derivatives. Drug Dev. Ind. Pharm. 17:1991;1625-1634.
157. Martin G.P., Marriott C., Kellaway I.W. Direct effect of bile salts and phospholipids on the physical properties of mucus. Gut. 19:1978;103-107.
158. Shao Z., Mitra A.K. 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. 9:1992;1184-1189.
159. Hersey S.J., Jackson R.T. Effect of bile salts on nasal permeability in vitro. J. Pharm. Sci. 76:1987;876-879.
160. Duchateau G.S.M.J.E., Zuidema J., Merkus F.W.H.M. Bile salts and intranasal drug absorption. Int. J. Pharm. 31:1986;193-199.
161. Hermens W.A.J.J., Hooymans P.M., Verhoef J.C., Merkus F.W.H.M. Effect of absorption enhancers on human nasal tissue ciliary movement in vitro. Pharm. Res. 7:1990;144-146.
162. Merkus F.W.H.M., Schipper N.G.M., Hermens W.A.J.J., Romeijn S.G., Verhoef J.C. Absorption enhancers in nasal drug delivery: efficacy and safety. J. Control. Release. 24:1993;201-208.
163. Helenius A., Simons K. Solubilization of membranes by detergents. Biochim. Biophys. Acta. 415:1975;29-79.
164. Aungst B.J., Rogers N.J. Site dependence of absorption-promoting actions of laureth-9, sodium salicylate, disodium EDTA, and aprotinin on rectal, nasal, and buccal insulin delivery. Pharm. Res. 5:1988;305-308.
165. Chandler S.G., Illum L., Thomas N.W. Nasal absorption in the rat. II. Effect of enhancers on insulin absorption and nasal histology. Int. J. Pharm. 76:1991;61-70.
166. I. Jabbal-Gill, A.N. Fisher, Hinchcliffe, J. Whetstone, N. Farraj, R. De Ponti, L. Illum, Cyclodextrins as protection agents against enhancer damage in nasal delivery systems II. Effect on in vivo absorption of insulin and histopathology of nasal membranes, Eur. J. Pharm. Sci. 1 (1994) 237-248.
167. Paquot N., Scheen A.J., Franchimont P., Lefebvre P. The intranasal administration of insulin induces significant hypoglycaemia and classical counter-regulatory hormonal responses in normal man. Diabete Metabol. 14:1988;31-36.
168. Gibaldi M., Feldman S. Mechanisms of surfactant effects on drug absorption. J. Pharm. Sci. 59:1970;579-588.
169. Florence A.T. Surfactant interactions with biomembranes and drug absorption. Pure Appl. Chem. 53:1981;2057-2068.
170. Daugherty A.L., Liggitt H.D., McCabe J.G., Moore J.A., Patton J.S. Absorption of recombinant methionyl-human growth hormone (Met-hGH) from rat nasal mucosa. Int. J. Pharm. 45:1988;197-206.
171. Ennis R.D., Borden L., Lee W.A. The effects of permeation enhancers on the surface morphology of the rat nasal mucosa: a scanning electron microscopy study. Pharm. Res. 7:1990;468-475.
172. Chandler S.G., Illum L., Thomas N.W. Nasal absorption in the rat. I. A method to demonstrate the histological effects of nasal formulations. Int. J. Pharm. 70:1991;19-27.
173. Donovan M.D., Flynn G.L., Amidon G.L. The molecular weight dependence of nasal absorption: the effect of absorption enhancers. Pharm. Res. 7:1990;808-815.
174. H. Critchley, Intranasal drug delivery, PhD Thesis, University of Nottingham, UK, 1989.
175. Adjei A., Sundberg D., Miller J., Chun A. Bioavailability of leuprolide acetate following nasal and inhalation delivery to rats and healthy humans. Pharm. Res. 9:1992;244-249.
176. Yamamoto A., Morita T., Hashida M., Sezaki H. Effect of absorption promoters on the nasal absorption of drugs with various molecular weights. Int. J. Pharm. 93:1993;91-99.
177. Cassidy M.M., Tidball C.S. Cellular mechanism of intestinal permeability alterations produced by chelation depletion. J. Cell Biol. 32:1967;685-698.
178. Lee V.H.L., Yamamoto A., Kompella U.B. Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Crit. Rev. Ther. Drug Carrier Syst. 8:1991;91-192.
179. Batts A.H., Marriott C., Martin G.P., Bond S.W., Greaves J.L., Wilson C.G. The use of a radiolabelled saccharin solution to monitor the effect of the preservatives thiomersal, benzalkonium chloride and EDTA on human nasal clearance. J. Pharm. Pharmacol. 43:1991;180-185.
180. Mishima M., Wakita Y., Nakano M. Studies on the promoting effects of medium chain fatty acid salts on the nasal absorption of insulin in rats. J. Pharmacobio-Dyn. 10:1987;624-631.
181. Y-F. Shiau, Lipid digestion and absorption, in: L.R. Johnson (Ed.), Physiology of the Gastrointestinal Tract, 2nd ed., Raven Press, New York, 1987, pp. 1527-1549.
182. Stafford R.E., Dennis E.A. Lysophospholipids as biosurfactants. Colloids Surfaces. 30:1988;47-64.
183. S. Jørgensen, K. Drejer, Insulin analogues and nasal insulin delivery, in: C.J. Bailey, P.R. Flatt (Eds.), New Antidiabetic Drugs, Smith-Gordon, London, 1990, pp. 83-92.
184. Hansen P., Drejer K., Engesgaard A., Guldhammer B., Hjortkjaer R.K., Mygind N., Soerensen A.R. Medium chain phospholipids enhance the transnasal absorption of insulin. Diabetes Res. Clin. Pract. 5(Suppl. 1):1988;A164.
185. Illum L., Farraj N.F., Critchley H., Johansen B.R., Davis S.S. Enhanced nasal absorption of insulin in rats using lysophosphatidylcholine. Int. J. Pharm. 57:1989;49-54.
186. Farraj N.F., Johansen B.R., Davis S.S., Illum L. Nasal administration of insulin using bioadhesive microspheres as a delivery system. J. Control. Release. 13:1990;253-261.
187. Chandler S.G., Thomas N.W., Illum L. Nasal absorption in the rat. III. Effect of lysophospholipids on insulin absorption and nasal histology. Pharm. Res. 11:1994;1623-1630.
188. Drejer K., Vaag A., Bech K., Hansen P., Soerensen A.R., Mygind N. Intranasal administration of insulin with phospholipid as absorption enhancer: pharmacokinetics in normal subjects. Diabetic Med. 9:1992;335-340.
189. Jacobs M.A.J.M., Schreuder R.H., Jap-A-Joe K., Nauta J.J., Andersen P.M., Heine R.J. The pharmacodynamics and activity of intranasally administered insulin in healthy male volunteers. Diabetes. 42:1993;1649-1655.
190. Hilsted J., Madsbad S., Hvidberg A., Rasmussen M.H. Intranasal insulin therapy: the clinical realities. Diabetologia. 38:1995;680-684.
191. Guldhammer B., Drejer K., Engesgaard A., Hansen P., Hjortkjaer R.K., Mygind N., Soerensen A.R. The absorption of intranasally administered insulin demonstrated by immunohistochemistry. Diabetes Res. Clin. Pract. 5(Suppl. 1):1988;A164.
192. Soerensen A.R., Drejer K., Engesgaard A. Rabbit model for studies of nasal administration of insulin and glucagon. Diabetes Res. Clin. Pract. 4(Suppl. 1):1988;A165.
193. Cho K.S., Proulx P. Studies on the mechanism of haemolysis by acylcarnitines, lysolecithins and acylcholines. Biochim. Biophys. Acta. 225:1971;214-223.
194. Weltzein H.U. Cytolytic and membrane-perturbing effects of lysophosphatidylcholine. Biochim. Biophys. Acta. 446:1979;411-421.
195. Weltzein H.U., Arnold B., Reuther R. Quantitative studies on lysolecithin-mediated haemolysis. Use of ether-deoxy lysolecithin analogues with varying aliphatic chain lengths. Biochim. Biophys. Acta. 559:1977;259-287.
196. Martin G.P., El-Hariri L.M., Marriott C. Bile salt- and lysophosphatidylcholine-induced membrane damage in human erythrocytes. J. Pharm. Pharmacol. 44:1992;646-650.
197. Jabbal-Gill I., Illum L., Farraj N.F., De Ponti R. Cyclodextrins as protection agents against enhancer damage in nasal delivery systems I. Assessment of effect by measurement of erythrocyte haemolysis. Eur. J. Pharm. Sci. 1:1994;229-236.
198. Chandler S.G., Thomas N.W., Illum L. Nasal absorption in the rat. IV. Membrane activity of absorption enhancers. Int. J. Pharm. 117:1995;139-146.
199. Umezawa H., Aoyagi T., Suda H., Hamada M., Takeuchi T. Bestatin, an inhibitor of aminopeptidase B, produced by actinomycetes. J. Antibiot. 29:1976;97-99.
200. M. Hanson, G. Gazdick, J. Cahill, M. Augustine, Intranasal delivery of the peptide, salmon calcitonin, in: S.S. Davis, L. Illum, E. Tomlinson (Eds.), Delivery Systems for Peptide Drugs, Plenum, New York, 1986, pp. 233-242.
201. Morimoto K., Miyazaki M., Yamaguchi H., Kakemi M. Effects of proteolytic enzyme inhibitors on nasal absorption of salmon calcitonin in rats. Int. J. Pharm. 113:1995;1-8.
202. O'Hagan D.T., Critchley H., Farraj N.F., Fisher A.N., Johansen B.R., Davis S.S., Illum L. Nasal absorption enhancers for biosynthetic human growth hormone in rats. Pharm. Res. 7:1990;772-776.
203. Barclay R.K., Phillipps M.A. Inhibition of the enzymatic degradation of Leu-enkephalin by puromycin. Biochem. Biophys. Res. Commun. 81:1978;1119-1123.
204. Raehs S.C., Sandow J., Merkle H.P. Absorption enhancement of bacitracin upon nasal absorption of GH-RH in rats. Proc. Int. Symp. Control. Release Bioact. Mater. 15:1988;72-73.
205. G. Hewlett, Apropos aprotinin: a review, Biotechnology, June (1990) 565-568.
206. Morimoto K., Miyazaki M., Yamaguchi H., Kakemi M. Effects of proteolytic enzyme inhibitors on the nasal absorption of vasopressin, an analogue and calcitonin. Proc. Int. Symp. Control. Release Bioact. Mater. 19:1992;218-219.
207. Mishima M., Okada S., Wakita Y., Nakano M. Promotion of nasal absorption of insulin by glycyrrhetinic acid derivatives. J. Pharmacobio-Dyn. 12:1989;31-36.
208. Schipper N.G.M., Romeijn S.G., Verhoef J.C., Merkus F.W.H.M. Nasal insulin delivery with dimethyl-β-cyclodextrin as an absorption enhancer in rabbits: powder more effective than liquid formulations. Pharm. Res. 10:1993;682-686.
209. Irie T., Wakamatsu K., Arima H., Aritomi H., Uekama K. Enhancing effects of cyclodextrins on nasal absorption of insulin in rats. Int. J. Pharm. 84:1992;129-139.
210. Irwin W.J., Dwivedi A.K., Holbrook P.A., Dey M.J. The effect of cyclodextrins on the stability of peptides in nasal enzymic systems. Pharm. Res. 11:1994;1698-1703.
211. Yoshida A., Arima H., Uekama K., Pitha J. Pharmaceutical evaluation of hydroxyalkyl ethers of β-cyclodextrins. Int. J. Pharm. 46:1988;217-222.
212. Merkus F.W.H.M., Verhoef J.C., Romeijn S.G., Schipper N.G.M. Absorption enhancing effect of cyclodextrins on intranasally administered insulin in rats. Pharm. Res. 8:1991;588-592.
213. Shao Z., Krishnamoorthy R., Mitra A.K. Cyclodextrins as nasal absorption promoters of insulin: mechanistic evaluations. Pharm. Res. 9:1992;1157-1163.
214. E. Marttins, Mechanistic studies in nasal drug delivery and absorption enhancement, PhD Thesis, University of Leiden, Nederland, 1997.
215. Marttins E., Verhoef J.C., Romeijn S.G., Merkus F.W.H.M. Effects of absorption enhancers on rat nasal epithelium in vivo: release of marker compounds in the nasal cavity. Pharm. Res. 12:1995;1151-1157.
216. Duchene D., Touchard F., Peppas N.A. Pharmaceutical and medical aspects of bioadhesive systems for drug administration. Drug Dev. Ind. Pharm. 14:1988;233-318.
217. Gu J., Robinson J.R., Leung S.S. Binding of acrylic polymers to mucin/epithelial surfaces: structure property relationships. Crit. Rev. Ther. Drug Carrier Syst. 5:1988;21-67.
218. Morimoto K., Morisaka K., Kamanda A. Enhancement of nasal absorption of insulin and calcitonin using polyacrylic acid gel. J. Pharm. Pharmacol. 37:1985;134-136.
219. Smart J.D., Kellaway I.W., Worthington H.E.C. An in-vitro investigation of mucos-adhesive materials for use in controlled drug delivery. J. Pharm. Pharmacol. 36:1984;295-299.
220. Junginger H.E. Bioadhesive polymer systems for peptide delivery. Acta Pharm. Technol. 36:1990;110-126.
221. Dondeti P., Zia H., Needham T.E. In vivo evaluation of spray formulations of human insulin for nasal delivery. Int. J. Pharm. 122:1995;91-105.
222. Dondeti P., Zia H., Needham T.E. Bioadhesive and formulation parameters affecting nasal absorption. Int. J. Pharm. 127:1996;115-133.
223. Nagai T., Nishimoto Y., Nambu N., Suzuki Y., Sekine K. Powder dosage form of insulin for nasal administration. J. Control. Release. 1:1984;15-22.
224. L. Illum, Microspheres as a potential controlled release nasal drug delivery system, in: S.S. Davis, L. Illum, E. Tomlinson (Eds.), Delivery Systems for Peptide Drugs, Plenum, New York, 1986, pp. 205-210.
225. Bjork E., Edman P. Degradable starch microspheres as a nasal delivery system for insulin. Int. J. Pharm. 47:1988;233-238.
226. Bjork E., Bjurstrom S., Edman P. Morphologic examination of rabbit nasal mucosa after nasal administration of degradable starch microspheres. Int. J. Pharm. 75:1991;73-80.
227. Bjork E., Holmberg K., Bake B., Edman P. Effect of degradable starch microspheres on the human mucociliary clearance. Proc. Int. Symp. Control. Release Bioact. Mater. 19:1992;417-418.
228. Artursson P. Epithelial transport of drugs in cell culture. I. A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells. J. Pharm. Sci. 79:1990;476-482.
229. Bjork E., Isaksson U., Edman P., Artursson P. Starch microspheres induce pulsatile delivery of drugs and peptides across the epithelial barrier by reversible separation of the tight junctions. J. Drug Targeting. 2:1995;501-507.
230. Pereswetoff-Morath L., Edman P. Dextran microspheres as a potential nasal drug delivery system for insulin - in vitro and in vivo properties. Int. J. Pharm. 124:1995;37-44.
231. Illum L., Farraj N.F., Fisher A.N., Gill I., Miglietta M., Benedetti L. Hyaluronic acid ester microspheres as a nasal delivery system for insulin. J. Control. Release. 29:1994;133-141.
232. Benedetti L. New biomaterials from hyaluronic acid. Med. Device Technol. 5:1994;32-37.
233. G.A.F. Roberts, Chitin Chemistry, Macmillan, London, 1992.
234. Illum L., Farraj N.F., Davis S.S. Chitosan as a novel nasal delivery system for peptide drugs. Pharm. Res. 11:1994;1186-1189.
235. T.J. Aspden, An evaluation of the potential use of chitosans in nasal peptide absorption systems, PhD Thesis, University of Nottingham, UK, 1996.
236. M. Hinchcliffe, The novel application of chitosan for the intranasal delivery of insulin, PhD Thesis, University of Nottingham, UK, 1996.
237. P.A. Sandford, Chitosan: commercial uses and potential applications, in: G. Skjåk-Bræk, T. Anthonsen, P Sandford (Eds.), Chitin and Chitosan, Sources, Chemistry, Biochemistry, Physical Properties and Applications, Elsevier Applied Science, London, 1989, pp. 51-69.
238. Quinton P.M., Philpott C.W. A role for anionic sites in epithelial architecture. J. Cell Biol. 56:1973;787-796.
239. Granger D.N., Kvielys P.R., Perry M.A., Taylor A.E. Charge selectivity of rat intestinal capillaries - influence of polycations. Gastroenterology. 91:1986;1443-1446.
240. Maitani Y., Machida Y., Nagai T. Influence of molecular weight and charge on nasal absorption of dextran and DEAE-dextran in rabbits. Int. J. Pharm. 49:1989;23-27.
241. Lehr C.M., Bouwstra J.A., Schacht E.H., Junginger H.E. In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers. Int. J. Pharm. 76:1992;43-49.
242. Artursson P., Lindmark T., Davis S.S., Illum L. Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharm. Res. 11:1994;1358-1361.
243. L.J. Filar, M.G. Wirick, Bulk and solution properties of chitosan, in: R.A.A. Muzzarelli, E.R. Pariser (Eds.), MIT Sea Grant Report MITSG 78-7, Proceedings of the First International Conference on Chitin/chitosan, Massachusetts, 1978, pp. 169-181.
244. Borchard G., Luessen H.L., de Boer A.G., Verhoef J.C., Lehr C.M., Junginger H.E. The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III: Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J. Control. Release. 39:1996;131-138.
245. V. Dodane, M.A. Khan, J.R. Merwin, Chitosan modulation of epithelial permeability and morphology, Presented at The Third European Congress of Pharmaceutical Sciences (organised by EUFEPS, UK Assoc. Pharm. Sci. and Pharm. Sci. Group of RPSG), Edinburgh, 15-17 September 1996.
246. Schipper N.G.M., Olsson S., Hoogstraate J.A., de Boer A.G., Varum K.M., Artursson P. Chitosans as absorption enhancers for poorly soluble drugs 2: Mechanism of absorption enhancement. Pharm. Res. 14:1997;923-929.
247. Aspden T.J., Adler J., Davis S.S., Skaugrud O., Illum L. Chitosan as a nasal delivery system: evaluation of the effect of chitosan on the mucociliary clearance rate in the frog palate model. Int. J. Pharm. 122:1995;69-78.
248. Aspden T.J., Illum L., Skaugrud O. The absence of chitosan toxicity when applied to nasal mucosa. Proc. Int. Symp. Control. Release Bioact. Mater. 22:1995;550-551.