Lipid nanoparticles as vehicles for oral delivery of insulin and insulin analogs: preliminary ex vivo and in vivo studies.

AIMS: Subcutaneous administration of insulin in patients suffering from diabetes is associated with the distress of daily injections. Among alternative administration routes, the oral route seems to be the most advantageous for long-term administration, also because the peptide undergoes a hepatic first-pass effect, contributing to the inhibition of the hepatic glucose output. Unfortunately, insulin oral administration has so far been hampered by degradation by gastrointestinal enzymes and poor intestinal absorption. Loading in lipid nanoparticles should allow to overcome these limitations. METHODS: Entrapment of peptides into such nanoparticles is not easy, because of their high molecular weight, hydrophilicity and thermo-sensitivity. In this study, this objective was achieved by employing fatty acid coacervation method: solid lipid nanoparticles and newly engineered nanostructured lipid carriers were formulated. Insulin and insulin analog-glargine insulin-were entrapped in the lipid matrix through hydrophobic ion pairing. RESULTS: Bioactivity of lipid entrapped peptides was demonstrated through a suitable in vivo experiment. Ex vivo and in vivo studies were carried out by employing fluorescently labelled peptides. Gut tied up experiments showed the superiority of glargine insulin-loaded nanostructured lipid carriers, which demonstrated significantly higher permeation (till 30% dose/mL) compared to free peptide. Approximately 6% absolute bioavailability in the bloodstream was estimated for the same formulation through in vivo pharmacokinetic studies in rats. Consequently, a discrete blood glucose responsivity was noted in healthy animals. CONCLUSIONS: Given the optimized ex vivo and in vivo intestinal uptake of glargine insulin from nanostructured lipid carriers, further studies will be carried out on healthy and diabetic rat models in order to establish a glargine insulin dose-glucose response relation.