Oral insulin delivery

Chitosan capsules coated with HPMCP were also tested for insulin oral delivery (82). Using male Wistar rats, insulin-containing capsules were administered orally to the rats, each of which received, through polyethylene tubing, a total dose of 20 lU into their stomachs. The h5 oglycemic effect did not start until 6h after the administration. This was when the capsules had reached the colon. The bioavailability of the insulin from the CS formulation was 5.73% as compared to the intravenous injection. It was observed that certain absorption enhancers like sodium glycocholate increased the absorption of insulin in the large intestine (66). 

Figure 14. Effect of oral delivery of an insulin/polyacid matrix to diabetic rabbits on serum glucose, with and without adjuvants (sodium taurocholate, aprotinin).

Cui, F., Shi, K., Zhang, L., Tao, A., Kawashima, Y. (2006). Biodegradable nanoparticles loaded with insulin-phospholipid complex for oral delivery preparation, in vitro characterization and in vivo evaluation. Journal of Controlled Release, 114, 242-250. 

Morcol, T., et al. 2004. Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin. Int J Pharm 277 91. 

Al-Achi, A., and R. Greenwood. 1998. Erythrocytes as oral delivery systems for human insulin. Drug Dev Ind Pharm 24 67. 

Geary, R.S., and H.W. Schlameus. 1993. Vancomycin and insulin used as models for oral delivery of peptides. J Control Release 23 65. 

Polylactic acid has been studied extensively for controlled release applications ranging from the oral delivery of simple drugs such as indomethacin9 to the parental administration of complex proteins such as insulin.10 Polylactic acid of different molecular weights has been studied as matrix material for parenteral administration. Seki et al.11 used polylactic acid 6000 and Smith and Hunneyball8 used polylactic acid 100,000 for the controlled delivery of drugs by the parenteral route. Several polylactic acid systems have been studied for the controlled... 

Iwanaga, K., Ono, S., Narioka, K., et al. Oral delivery of insulin by using surface coating liposomes Improvement of stability of insulin in GI tract. Int. J. Pharm. 157 73-80, 1997. 

A. Bernkop-Schniirch. 2004. Development and in vivo evaluation of an oral insulin-PEG delivery system. Eur.J. Pharm. Sci. 22 315-323. 

The human intestine has evolved as a highly efficient organ to digest (i.e. hydrolyse) practically all the macromolecules in the human diet (albeit with the help of a few trillion bacteria ) with the exception of some plant fibres. To do this it possesses a formidable array of enzymes. This is particularly true for the digestion of proteins and peptides where peptidases are found in the stomach, are secreted by the pancreas in considerable quantities and are found on the surface of and inside intestinal epithelial cells. These enzymes work in a co-ordinated fashion to rapidly hydrolyse proteins. They present the major difficulty for designing oral delivery systems for therapeutic peptides, which may explain why 86 years after the first attempt to orally administer insulin (Bliss 1982), there is still not an oral insulin product available for diabetics. 

Hochman JH, Fix JA, LeCluyse EL (1994) In vitro and in vivo analysis of the mechanism of absorption enhancement by palmitoylcarnitine. J Pharmacol Exp Ther 269 813-822 Hoffman A, Qadri B (2008) Eligen insulin-a system for the oral delivery of insulin for diabetes. IDrugs 11 433 41... 

These polymer-coated liposomes showed high potency in oral delivery of peptide drugs such as insulin and calcitonin, mainly because of the mucoadhe-sion of the chitosan-coated liposomes to the intestinal tract (Takeuchi et al. 1996, 2001,2003,2005a). Similar trials have been reported by Guo et al. (2003), who investigated the effect of chitosan concentration and lipid type on the characteristics of chitosan-coated liposomes and their interactions with leupro-lide. They found that a thicker adsorptive layer could be realized by using low... 

The adverse environmental effects encountered in the GI tract compound to make the oral route highly unsuitable for the delivery of many macromolecules. For example, although insulin was commercially introduced in 1923, despite intensive research efforts directed towards attaining its oral delivery, all approaches have proven unsuccessful, and an oral form of insulin is as yet not commercially available. 

Cationic thiomers are obtained from chitosan by reaction of thioglycolic acid with the primary amino groups in chitosan mediated by EDCCl. Thiomers are useful to formulate oral delivery systems for insulin, calcitonin and heparin. However, carbodiimide treated heparin may lose some of its anticoagulant properties. The potential of chitosan for the oral administration of peptides is also under consideration. ... 

Although routine oral delivery of proteins has not been realized, some protein formulations have been developed for pulmonary delivery. Pulmonary delivery can result in either parenteral or local administration of the drug and, like oral delivery, is considered non-invasive. As with other routes of delivery, the size of the protein may limit its ability to be delivered systemi-cally via the pulmonary route of administration. Pulmozyme , a DNase-based formulation approved for the treatment of cystic fibrosis (CF), is delivered to the lungs by a nebulizer to clear blockage of the airways in the CF patient.Formulations for insulin to be administered by inhalation for systemic delivery of... 

Liposomes have received considerable attention as a possible delivery tool for peptide and protein drugs by protecting labile compounds from degradation or by enhancing the uptake of poorly absorbed compounds. Liposomes have been studied extensively as a potential oral delivery system for proteins, especially insulin, and the oral administration of liposome-entrapped insulin into diabetic rats has produced a significant fall in blood glucose levels. " There are three types of liposomes multilamellar liposomes (MLV), 0.05-10 pm small unilamellar liposomes (SUV),... 

Marschutz MK, Caliceti P, Bernkop-Schnurch A. Design and in vivo evaluation of an oral delivery system for insulin. Pharm Res 2000 17(12) 1468-1474. 

---