Nasal insulin absorption

S Hirai, T Yashiki, H Mima. (1981). Mechanisms for the enhancement of the nasal absorption of insulin by surfactants. Int J Pharm 9 173-184. 

JP Longenecker, AC Moses, JS Flier, RD Silver, MC Carey, EJ Dubovi. (1987). Effects of sodium taurodihydrofusidate on nasal absorption of insulin in sheep. J Pharm Sci 76 351-355. 

Seki T, Kanbayashi H, Nagao T, Chono S, Tomita M, Hayashi M, Tabata Y, Morimoto K (2005) Effect of aminated gelatin on the nasal absorption of insulin in rats. Biol Pharm Bull 28 510-514. 

Z. Shao, R. Krishnamoorthy, and A. K. Mitra. Cyclodextrins as nasal absorption promoters of insulin Mechanistic evaluations. Pharm Res 9 1157-1163 (1992). 

Relationship between HLB values of nonionic surfactant ethers and esters and the nasal absorption of insulin (lOU/kg) in rata measured as a percentage reduction (D) in glucose levels from 0-4h. Surfactant applied at a concentration of 1 . 9 ethers, 0 esters. Data... 

Nasal absorption. Sucrose ester of coconut fatty acid in aqueous ethanol solution (sucrose cocoate SL-40) administered intrana-sally to anesthetized male Sprague-Dawley rats at a dose of 0.5% sucrose cocoate with insulin, produced a rapid and significant increase in plasma insulin level with a concomitant decrease in blood glucose levels. Administration of a dose of 0.5% sucrose cocoate with calcitonin produced a rapid increase in plasma calcitonin levels and a concomitant decrease in plasma calcium levels . 

Fernandez-Urrusuno, R., Calvo, P., Remunan-Lopez, C., Vila-Jato, J. L., and Alonso, M. J. (1999). Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm. Res. 16,1576-1581. 

Another type of absorption enhancer, which has been shown to have a better safety profile, is cyclodextrin (CD) [39]. CDs have been shown to form inclusion complexes with lipophilic drugs, thereby improving their aqueous solubility and stability. A powdered insulin formulation containing dimethyl-(3-cyclodextrin improved the absolute bioavailability of insulin by 13% in rabbits compared to a control liquid formulation (1%) of insulin with dimethyl-(3-cyclodextrin [40]. Recently, hydroxypropyl (3-cyclodextrin has been shown to be more effective for enhancing the nasal absorption of acyclovir than a range of other absorption enhancers in vivo [41]. 

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... 

Soybean-derived sterol mixture (SS), soybean-derived steryl glucosides (SG), and their individual components have been extensively studied for their ability to promote the nasal absorption of drugs, particularly insulin [79,80], Maitani et al. [79] demonstrated that the nasal administration of SG plus insulin to rabbits resulted in significant reductions in blood glucose. The effect of SG was dose dependent to 1%, with a plateau being reached thereafter. Muramatsu et al. [81] have demonstrated that SG perturbs the phospholipids in artificial membranes (i.e., liposomes). Furthermore, circular dichroism studies with insulin in the presence or absence of SG have indicated that the enhancer had little effect on the dissociation of insulin hexamers to monomers. These results suggest that the action of SS and SG involves interaction with the nasal membrane rather than interaction with insulin molecules. 

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... 

Femandez-Urrasuno, R., et al. 1999. Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm Res 16 1576. 

Pillion, D.J., et al. 1995. DS-1, a modified Quillaja saponin, enhances ocular and nasal absorption of insulin. J Pharm Sci 84 1276. 

Maitani, Y., et al. 1995. 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 117 129. 

The enhancement of nasal absorption of insulin by hydrophobic bile salts has also been investigated. It was found that minor differences in the number, position, and orientation of the nuclear hydroxyl groups as well as alterations to side-chain conjugation can improve the adjuvant potency of bile salts. Moreover, the absorption of insulin positively correlated with an increase in the hydrophilicity of the steroid nucleus of the bile salts. In the presence of bile salts, nasal absorption of insulin reached peak levels within about lOmin, and some 10-20% of the dose was found to have been absorbed into the circulation. Marked increases in serum insulin levels were seen with sodium deoxycholate, the most lipophilic of the bile salts, whereas the least elevation—as well as least lowering of blood glucose levels—was seen with the most hydrophobic bile salt, sodium ursodeoxycholate [63],... 

Morimoto et al. [64] studied the nasal absorption of insulin using polyacrylic acid gel. When insulin was formulated with 0.1% w/v polyacrylic acid gel base (pH 6.5), the maximum hypoglycemic effect was seen 30 min following intranasal administration in 1% w/v gel base, however, it took lh to reach the maximum effect. There was no effect of the pH (4.5, 6.5, and 7.5) of 0.1% w/v polyacrylic acid gel on the extent of nasal absorption. 

Similar experiments were carried out using sucrose esters in nasal insulin formulations (Figure 7). It was observed that tetradecanoylsucrose and tridecanoylsucrose were more effective in stimulating insulin absorption as compared with decanoyl-sucrose and dodecanoylsucrose. But—compared with TDM at concentrations of 0.03%—the sucrose esters were less effective in promoting nasal absorption [66], Sucrose cocoate (SL-40) is produced by the chemical esterification of coconut oil with sucrose it has frequently been used in cosmetic and dental preparations as an excipient. When this excipient was formulated with insulin at 0.125,0.25, and 0.5% concentrations, the associated plasma levels of insulin increased rapidly whereas there was no enhancement of insulin plasma levels when insulin in saline was admin-... 

Chitosan is a linear cationic polysaccharide made up of copolymers of glucosamine and A-acetylglucosaminc. It is commercially obtained by alkaline deacetylation of chitin [53, 68] and has been used for the nasal delivery of a number of drugs. The usefulness of chitosan in the enhancement of nasal absorption was reported first by Ilium [69]. Later, Ilium and his group also published experimental results indicating that solution formulations with 0.5% chitosan promoted the absorption of nasally administered insulin in rat and sheep [70]. 

Hirai, S., Yashiki,T., and Matsuzawa,T., Nasal absorption of drugs. Effect of surfactants on the nasal absorption of insulin in rats, paper presented at the 98th annual meeting of the Pharmaceutical Society of Japan, Apr. 1978. 

Morimoto, K., Morisaka, K., and Kamada, A. (1985), Enhancement of nasal absorption of insulin and calcitonin using polyacrylic acid gel,/. Pharm. Pharmacol., 37,134-136. 

The nasal absorption of insulin after administration in chitosan powder was the most effective formulation for nasal delivery of insulin in sheep compared to chitosan nanoparticles and chitosan solution [11], Similarly, chitosan powder formulations have been shown to enable an efficient nasal absorption of goserelin in a sheep model where bioavailabilities of 20-40% were obtained depending on the nature of the formulation [9],... 

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