Poly(alkyl cyanoacrylate) Nanospheres for Oral Administration of Insulin

Abstract

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 polymeric structures formed by polymerization of isobutyl cyanoacrylate (IBCA) in an acidic medium, insulin (15 U/mL) being added to the polymerization medium 60 min after the onset of polymerization. These nanospheres (MW 364) displayed a mean size of 145 nm and an association rate of 1 U of insulin/mg of polymer. They protected insulin from the degradation 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 medium, insulin-loaded nanospheres (100 U/kg of body weight), administered perorally in streptozotocin-induced diabetic rats, provoked a 50% decrease of fasted glycemia from the second hour up to 10-13 days. This effect was shorter (2 days) or absent when nanospheres were dispersed in water with surfactive agents or not. Using 14C-labeled nanospheres loaded with [125I]insulin, it was found that nanospheres increased the uptake of [125I]insulin or its metabolites in the gastrointestinal tract, blood, and liver while the excretion was delayed when compared to [125I]insulin nonassociated to nanospheres; in addition, 14C- and 125I-radioactivities disappeared progressively as a function of time, parallel to the biological effect. Thus insulin-loaded nanospheres can be considered as a convenient delivery system for oral insulin at the prerequisite that they were dispersed in an oily phase containing surfactants.

Enhanced oral bioavailability of insulin-loaded solid lipid nanoparticles: pharmacokinetic bioavailability of insulin-loaded solid lipid nanoparticles in diabetic rats

“…Also, the bioadhesive properties of lipids can lead to a gradient diffusion of insulin from the high concentrations in the SLN matrix towards the intestinal cells. The association of both mechanisms has been related with the prolonged physiologic effect of insulin after oral administration (Damge et al, 1997). As shown in Table 2, insulin-loaded SLN showed better protection of insulin from harsh gastro intestinal environment than the insulin solution as evident from the data (C max 196.4 versus 16.4 only).…”

Atorvastatin calcium loaded chitosan nanoparticles: in vitro evaluation and in vivo pharmacokinetic studies in rabbits

“…Insulin entrapped in PACA nanospheres dispersed in an oily phase containing a surfactant produces prolonged hypoglycemia (Damge et al, 1997b). The fate of poly (isobutylcyanoacrylate) nanocapsules carrying insulin administered to rats was monitored by fluorescence and transmission electron microscopy (TEM) and evidenced intestinal absorption through the epithelial mucosa (PintoAlphandary et al, 2003).…”

Influence of polymers ratio on insulin-loaded nanoparticles based on poly-ε-caprolactone and Eudragit®RS for oral administration

“…The encapsulation of insulin into polymeric nanoparticles allowed insulin to be protected against degradation by proteolytic enzymes (i.e. trypsin, chymotrypsin), as previously shown by Damgé et al (1997) with poly(alkylcyanoacrylate) nanospheres. Indeed, non-encapsulated insulin does not affect glycemia after oral delivery.…”