POLY(ALKYL CYANOACRYLATE) NANOSPHERES FOR ORAL-ADMINISTRATION OF INSULIN

Poly(alkyl cyanoacrylate) nanocapsules have been successfully used for oral administration of insulin in diabetic rats. This work reports a suitable formulation for insulin-loaded nanospheres composed of full p olymeric structures for med by polymerization of isobutyl cyanoacrylat e (IBCA) in an acidic medium, insulin (15 U/mL) being added to the pol ymerization medium 60 min after the onset of polymerization. These nan ospheres (MW 364) displayed a mean size of 145 nm and an association r ate of 1 U of insulin/mg of polymer. They protected insulin from the d egradation by proteolytic enzymes in vitro, especially when they were dispersed in an oily medium (Miglyol 812) containing surfactive agents (Poloxamer 188 and deoxycholic acid). When dispersed in the same medi um, insulin-loaded nanospheres (100 U/kg of body weight), administered perorally in streptozotocin-induced diabetic rats, provoked a 50% dec rease of fasted glycemia from the second hour up to 10-13 days. This e ffect was shorter (2 days) or absent when nanospheres were dispersed i n water with surfactive agents or not. Using C-14-labeled nanospheres loaded with [I-125]insulin, it was found that nanospheres increased th e uptake of [I-125]insulin or its metabolites in the gastrointestinal tract, blood, and liver while the excretion was delayed when compared to [I-125]insulin nonassociated to nanospheres; in addition, C-14- and I-125-radioactivities disappeared progressively as a function of time , parallel to the biological effect. Thus insulin-loaded nanospheres c an be considered as a convenient delivery system for oral insulin at t he prerequisite that they were dispersed in an oily phase containing s urfactants.