Insulin administration nasal

Ilium et al. [49] evaluated chitosan solutions as delivery platforms for nasal administration of insulin to rats and sheep. They reported a concentration-dependent absorption-enhancing effect with minimal histological changes of the nasal mucosa in all concentrations applied. 

Developments in the administration of insulin through the skin, the mouth, the nose, and the lung have been reviewed (183). Methods of absorption other than subcutaneous, such as nasal insulin, buccal insulin, rectal insulin, and insulin in enteric-coated capsules, are still experimental. A problem in nasal administration is still how to get a daily reproducible dose (184). The frequency of hypoglycemia is comparable to the frequency with subcutaneous insulin (185). Nasal irritation, sometimes with congestion, and dyspnea (186) can occur. Pulmonary insulin, delivered by aerosol inhalation, is another experimental method. No lung obstruction was reported, but the uptake varied considerably (187). 

Insulin is rapidly absorbed after nasal administration, but even with absorption enhancers its systemic availability is low and its metabolic effect very short (183). 

Tian, J., Atkinson, M., Clare-Salzler, M., Herschenfeld, A., Forsthuber, T., Lehmann, P. et al. (1996) Nasal administration of glutamic decarboxylase peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J. Exp. Med., 183, 1561-1567. 

Nagai, T., et al. 1984. Powder dosage form of insulin for nasal administration. J Control Release 1 15. 

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. 

Nasal administration of formulations containing insulin plus 0.125% TDM concurrently at time 0 caused a rapid and significant increase in plasma insulin levels and a corresponding decrease in blood glucose levels (described above). When an interval of 2 h elapsed between TDM addition and insulin administration, a significant attenuation was noted in the maximal increase in plasma insulin, as well as in the maximal reduction in blood glucose levels [10]. The experimental protocol described above was then used to assess the amount of insulin absorbed when the interval between TDM administration and insulin administration was... 

Ahsan, F., et al. 2001. Mutual inhibition of the insulin absorption-enhancing properties of dode-cylmaltoside and dimethyl-beta-cyclodextrin following nasal administration. Pharm Res 18 608. 

Fernandez-Urrusuno R, Romani D, Calvo P, Vila-Jato JL, Alonso MJ (1999) Development of a freeze-dried formulation of insulin-loaded chitosan nanoparticles intended for nasal administration. S.T.P. Pharma Sci 9 429-436... 

Insulin formulated with 0.06 or 0.125% hexadecylmaltoside produced a pronounced and rapid dose-dependent decrease in blood glucose levels after nasal administration. The effects of seven different alkylmaltosides were studied, and all the reagents (Figure 6) showed a similar maximal enhancement of insulin uptake when a concentration of 0.125% was employed. The figure demonstrates that TDM showed the greatest effect when concentrations of 0.03 and 0.06% were used. 

FIGURE 9 Effect of (a) concentrations, (b) osmolarity, and (c) medium of chitosan solution on mean serum glucose concentrations after nasal administration of lOIU/kg insulin to rats. Bars represent the standard deviation (SD) of five experiment. (Reproduced from ref. 73 with permission of Elsevier.)... 

FIGURE 10 Serum glucose level in four groups of diabetic rats (n = 6) A, untreated control group B, intravenous administration of 4 IU/kg insulin C, nasal administration of blank gel base D, nasal administration of 100gL/kg chitosan gel containing 4000IU/dL insulin. (Reproduced from ref. 75 with permission of Taylor Francis.)... 

Nagai, T., Nishimoto, Y., Nambu, N., Suzuki, Y., and Sekine, K. (1984), Powder dosage form of insulin for nasal administration, J. Controlled Release, 1,15-22. 

Crystalline cellulose, hydroxypropyl cellulose, and Carbopol 934 have been studied in combination with lyophilized insulin as bioadhesive powder dosage forms for nasal delivery. Each formulation tested resulted in an decrease in plasma glucose level after nasal administration in dog and rabbit models. The most effective formulation, crystalline cellulose blended with insulin, decreased the plasma glucose level to 49% of the control value. In ternary systems the lyophilized Carbopol 934 and insulin blend with crystalline cellulose powder has been the most effective, leading to a hypoglycemia on the order of one-third of the effect obtained after intravenous injection of the same dose of insulin. The plasma glucose levels obtained in the volunteers after administration of the insulin-Carbopol-crystalline cellulose powder formulation were quite variable [38],... 

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],... 

Farraj, N. F., Johansen, B. R., Davis, S. S., and Ilium, L. (1990), Nasal administration of insulin using bioadhesive microspheres as a delivery system, /. Controlled Release, 13, 253-261. 

Fig. 6 Concentration-time profile after nasal administration of 50 lU of insulin in a chitosan solution formulation to human volunteers (n = 8). Open square, nasal chitosan solution closed circle, subcutaneous. (Reprinted from Ref. " with permission from Wolters Kluwer Health, Adis International.)...

To increase the residence time in the nasal mucosa, a bioadhesive formulation may be one of the most reasonable approaches. In fact, microspheres containing bioadhesive polymers such as starch, albumin, and Sephadex with a particle size of 40-60 pm have been found to be cleared from the nasal cavity much more slowly than solutions. Starch microspheres improved the nasal absorption of insulin, with synergistic effects of some absorption enhancers in sheep. In another paper, dry powder containing starch and Carbopol 974P showed significantly higher bioavailability after nasal administration than the formulation without Carbopol. ° Chitosan, already mentioned above, also has a bioadhesive property and is found to be useful as a potent absorption enhancer for nasal peptide delivery. Other bioadhesive polymer systems,... 

With the exception of a few approved products for nasal administration of peptides and the very recent regulatory approvals of delivery systems for both pulmonary and buccal delivery of insulin, there is relatively little precedence with the worldwide regulatory approval process for non-invasive delivery systems incorporating protein or peptide pharmaceuticals. Consequently, there is limited specific information... 

FIGURE 40.11 Seram levels of immunoreactive insulin (IRI) and glucose after nasal administration of insulin... 

Fig. 38.10 Serum levels of immunoreactive insulin (IRI) and glucose after nasal administration of insulin (21 U/body) with HPE-101 (1% w/v) and/or HP-p-CyD (10% w/v) to ratsvt Insulin alone A, with HP-p-CyD A, with HPE-101 , with HPE-101 and HP-p-CyD. Each point represents the mean SE of four rats.

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