Nasal administration of insulin

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. 

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. 

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.

Hirata, Y., Kohama, T., and Ooi, K., 1983, Nasal administration of insulin in healthy subjects and diabetic patients, in Current and Future Therapies with Insulin (N. Sakamoto and K. G. M. M. Alberti, eds.), Excerpa Medica, Amsterdam, pp. 263-267. 

Vora, J. P., and Owens, D. R, 1991, Future trends in insulin therapy Clinical implications of novel insulin analogues and nasal administration of insulin, in Pharmacology of Diabetes. Present Practice and Future Perspectives (C. E. Mogensen and E. Standi, eds.), de Gruyter, Berlin, pp. 39-56. 

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). 

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. 

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... 

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. 

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.)... 

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],... 

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... 

Coating of PLGA nanoparticles with the mucoadhesive CS improves the stability of the particles in the presence of lysozyme and enhanced the nasal transport of the encapsulated tetanus toxoid. Nanoparticles made solely of CS are stable upon incubation with lysozyme. Moreover, these particles are very efficient in improving the nasal absorption of insulin as well as the local and systemic immune responses to tetanus toxoid, following intranasal administration. 

In 1992, Drejer et al. [31] investigated the pharmacokinetics of intranasal insulin containing a medium-chain phospholipid (didecanoyl-L-alpha-phosphatidylcho-line) as absorption enhancer in 11 normal volunteers. Intranasal insulin was absorbed in a dose-dependent manner with a mean plasma insulin peak 23 7 min after administration. Mean plasma glucose nadir was seen after 44 6min, 20min after intravenous injection. Moreover, intranasal administration of insulin resulted in a faster time-course of absorption than subcutaneous injection, and the bioavailability for the nasal formulation was 8.3% relative to an intravenous bolus injection when plasma insulin was corrected for endogenous insulin production estimated by C-peptide. 

PEGylated chitosan nanoparticles were shown to enhance insulin absorption to a greater extent compared with non-nanoparticulate forms of chitosan and insulin alone. Chitosan nanoparticles were also found to enhance nasal absorption of insulin in rabbit, regardless of chitosan molecular weight. Recently, Al-Qadi and co-workers reported that intratracheal administration of diy insulin powder microencapsulated in chitosan nanoparticles increased its distribution to the deep lungs, and facilitated release of a biologically active form of insulin to rat blood. Moreover, they observed a more pronounced and prolonged effect compared to non-formulated insulin. ... 

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