Abstract
This study examined the application of previously characterized microparticles composed of hyaluronan (HA) and chitosan hydroglutamate (CH) as well as novel microparticles consisting of both polymers (HA/CH) to improve the nasal delivery of a model drug. The rabbit bioavailabilities of gentamicin incorporated in HA, CH, and HA/CH microparticles were increased 23-, 31-, and 42-fold, respectively, compared with the control intranasal solution of gentamicin, indicating that all test microparticles were retained for longer periods on the nasal mucosa of the rabbits as supported by previous in vitro dissolution as well as frog palate mucoadhesion studies, thereby improving drug absorption. The higher bioavailabilities of CH-based formulations (CH and HA/CH) suggest the penetration-enhancing effects of CH may also be partially responsible for the improvement. A model was developed, based on a glass impinger device, to deliver dry powder formulations reproducibly onto the surface of cultured cell monolayers. In vitro permeability and fluorescence microscopy studies on the tight junctions of the 16HBE14o- cell lines further confirmed the ability of CH-based formulations to enhance penetration. Furthermore, the in vitro absorption profile from cell culture studies was consistent with those determined from in vivo studies. The complementary effect from the mucoadhesive nature of HA coupled with the penetration-enhancing effects of CH makes the novel HA/CH formulation a promising nasal delivery system.
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References
Leung SS, Robinson JR. The contribution of anionic polymers structural features to mucoadhesion. J Contr Rel. 1998;5:223–231.
Smart JD. An in vitro assessment of some mucosa-adhesive dosage forms. Int J Pharm. 1991;73:69–74.
Khoshla R, Davis SS. The effect of polycarbophil on the gastric emptying of pellets. J Pharm Pharmacol. 1987;39:47–49.
Parfitt K, ed. Martindale: The extra pharmacopoeia. 31st ed. London: The Pharmaceutical Press; 1996:1754.
Griffiths MC, ed. USAN and the USP dictionary of drug names. United States Pharmacopeial Convention, Inc. 1988:277.
Bottenberg P, Cleymaet R, de Muynck C, et al. Development and testing of bioadhesive, fluoridecontaining slow-release tablets for oral use. J Pharm Pharmacol. 1991;43:457–464.
Pritchard K, Lansley AB, Martin GP, Helliwell M, Marriott C, Benedetti LM. Evaluation of the bioadhesive properties of hyaluronan derivatives: detachment weight and mucociliary transport rate studies. Int J Pharm. 1996;129:137–145.
Borchard G, Lueben HL, de Boer AG, Verhoef JC, Lehr CM, Junginger HE. 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 Rel. 1996;39:131–138.
Lim ST, Martin GP, Berry DJ, Brown MB. Preparation and evaluation of the in vitro release properties and mucoadhesion of novel microspheres of hyaluronic acid and chitosan. J Control Rel. 2000;66:281–292.
British Pharmacopoeia Commission. Apparatus A (glass impinger). Appendix XIIF. London:British Pharmacopoeia, The Stationary Office London. 1999;A209-A210.
Illum L, Farraj NF, Critchley H, Davis SS. Nasal administration of gentamicin using a novel microsphere delivery system. Int J Pharm. 1988;46:261–265.
Morimoto K, Yamaguchi H, Iwakura Y, et al. Effects of proteolytic enzyme inhibitors on the nasal absorption of vasopressin and analogue. Pharm Res. 1991;8:1175–1179.
Illum L, Farraj NF, Fisher AN, Giu I, Miglietta M, Benedetti LM. Hyaluronic acid ester microspheres as nasal delivery systems for insulin. J Control Rel. 1994;29:133–141.
Illum L. Bioadhesive formulations for nasal peptide delivery. In: Bioadhesive Drug Delivery Systems, Fundamentals, Novel Approaches and Development. Mathiowitz E (ed.). New York, Marcel Dekker. 1999;477–601.
Schipper NGM, Varum KM, Ocklind G, Stenberg P, Lennernas H, Artursson P. Chitosan as absorption enhancers of poorly absorbable drugs. 3. Influence of mucus as absorption enhancement. Eur J Pharm Sci. 1999;8:335–343.
Artursson P, Lindmark T, Davis SS, Illum L. Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharm Res. 1994;11:1358–1361.
Edman P, Bjork E, Ryden L. Microspheres as a nasal delivery system for peptide drugs. J Control Rel. 1992;21:165–172.
Berridge MV, Tan AS. Characterisation of the cellular reduction of 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)—subcellular localisation, substrate dependence, and involvement of mitochondrial electron transport in MTT reduction. Arch Biochem Biophys. 1993;303(2):474–482.
Westmoreland C, Walker T, Matthews J, Murdock J. Preliminary investigations into the use of a human bronchial cell line (16HBE14o-) to screen for respiratory toxins in vitro. Toxicol in Vitro. 1999;13(4–5):761–764.
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Published: October 17, 2001.
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Lim, S., Forbes, B., Martin, G. et al. In vivo and in vitro characterization of novel microparticulates based on hyaluronan and chitosan hydroglutamate. AAPS PharmSciTech 2, 20 (2001). https://doi.org/10.1208/pt020420
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DOI: https://doi.org/10.1208/pt020420