Peptides nasal absorption

In addition to peptide-based studies, degradation and absorption kinetics of a homologous series of acyclovir ester prodrugs have been studied using the in situ perfusion model [25, 26], The studies showed that due to high esterase activity of the rat nasal mucosa (96% disappearance of hexanoate prodrug of acyclovir in 960 min), the rat in situ model is an acceptable model to screen the nasal absorption of prodrugs. 

Agu RU, Vu Dang H, Jorissen M, Willems T, Kinget R, Verbeke N (2002) Nasal absorption enhancement strategies for therapeutic peptides an in vitro study using cultured human nasal epithelium. Int J Pharm 237 179-191. 

Tengamnuay P, Sahamethapat A, Sailasuta A, Mitra AK (2000) Chitosans as nasal absorption enhancers of peptides comparison between free amine chitosans and soluble salts. Int J Pharm 197 53-67. 

Wang J, Sakai S, Deguchi Y, Bi D, Tabata Y, Morimoto K (2002) Aminated gelatin as a nasal absorption enhancer for peptide drugs evaluation of absorption enhancing effect and nasal mucosa perturbation in rats. J Pharm Pharmacol 54 181— 188. 

The nose is equipped with a unique cellular architecture to perform several functions, including filtration of inspired particles, humidification of inspired air, olfaction, and some immunological functions [18,19], The nose is not specifically designed for nutrient or peptide drug absorption. However, the large absorptive capacity of the nasal epithelium has now been fully appreciated because of the extremely high bioavailability of nasally applied peptide drugs observed under certain experimental conditions (described below). 

The impact of the mucus layer of the nasal cavity on peptide drug absorption is poorly understood, but in the absence of absorption enhancers it could play a significant role in limiting drug absorption. Several agents that enhance nasal peptide drug absorption have demonstrable effects on the mucus layer (described below). 

Chitosan is a cationic polysaccharide produced from the deacetylation of chitin, a component of crab and shrimp shells [7,57,58], Chitin is composed of units of 2-deoxy-2-(acetylamino) glucose joined by glycosidic bonds that form a linear polymer. Ilium et al. [7,57,58] demonstrated the ability of chitosan to increase the bioavailability of insulin and other small peptides and polar macromolecules in different animal models. In both the sheep and rat models, the addition of chitosan at concentrations of 0.2%-0.5% to nasal formulations of insulin resulted in significant increases in plasma insulin and reductions in blood glucose. Reversibility studies indicated that the effect of chitosan on the nasal absorption of insulin... 

Individual members of the AG and SEFA family have been studied for their ability to promote the nasal and ocular absorption of peptide drugs in rats, mice, cats, dogs, and monkeys [1,6,10,53,54,84—90]. Dose-escalation studies were conducted in rats to determine the potencies of each of the AGs and SEFAs as enhancers for the ocular and nasal absorption of insulin and to determine the contribution of the alkyl chain and the sugar moiety. Insulin... 

Several peptide products used in the treatment of diabetes mellitus, in addition to insulin, are currently administered by subcutaneous injection and these drugs are candidates for development of nasal formulations. Glucagon-like peptide-1 (GLP-l)-related peptides stimulate the insulin response to glucose and diminish the release of glucagon after a meal. These effects diminish the excessive postprandial increase in glucose observed after a meal in persons with type 2 diabetes mellitus. GLP-1-related peptides must be administered by subcutaneous injection before meals in order to be effective. This requirement for injection before each meal is likely to impact the utilization of these products by persons with type 2 diabetes. Exendin-4 is a GLP-1-related peptide with a molecular mass of 4.2 kDa. The development of a GLP-1-related peptide nasal formulation containing an absorption enhancer would allow patients to scll-administer one of these drugs just before a meal without the need for a subcutaneous injection. 

Tengamnuay, P., and A.K. Mitra. 1990. Bile-salt fatty acid mixed micelles as nasal absorption promoters of peptides. I. Effects of ionic strength, adjuvant composition and lipid structure on the nasal absorption of [D-Arg2]kyotorphin. Pharm Res 7 127. 

Hussain, A., Hamadi, S., Kagashima, M., et al. Does increasing the lipophilicity of peptides enhance their nasal absorption J. Pharm. Sci. 80(12) 1180-1181, 1991. 

Ilium, L. (1992), Nasal delivery of peptides, factors affecting nasal absorption, in Topics in Pharmaceutical Sciences, Medpharm Scientific, Stuttgart, p. 71. 

Powder Dry blending Octreotide Dextran, microcrystalline cellulose, semicrystalline cellulose, hydoxyethyl starch, microcrystalline chitosan, pectin, alginic acid In rats Correlation between carrier calcium binding properties and their potential as nasal absorption enhancers for peptides 40... 

Oechslein, Fricker, and Kissel " studied various powder formulations of mucoadhesive polymers for their efficacy to increase the nasal absorption of octreotide in rats. Although chitosan showed the highest water uptake (chitosan > microcrystalline cellulose > semicrystalline cellulose > pectin = hydroxyethyl starch = alginic acid = Sephadex G25), the highest peptide drug bioavailability was found after coadministration of alginic acid and Sephadex G25 powders (4.1 and 5.56%, respectively). The authors concluded that the calcium-binding properties of the polymers used correlated better with the increased octreotide bioavailability. 

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