PURPOSE: The bioavailability and local tolerability of insulin containing nanocomplexes from amine-modified poly(vinyl alcohol)-graft-poly(L-lactide) were studied in rats. Histology of the nasal epithelium was studied to document integrity of the mucosa. METHODS: Nanocomplexes (NC) were prepared by spontaneous self-assembly of insulin and the water-soluble amphiphilic polymer. Changes in blood glucose and insulin blood concentration were monitored in anesthetized rats using a glucose meter and enzyme-linked immunosorbent assay, respectively. Histological sections of the nasal cavity were examined after H&E staining by light microscopy. RESULTS: NC reduced blood glucose level in fasted healthy rats by 20% after 50-80 min and in streptozotocin induced diabetic rats by 30% within 75-95 min compared to basal levels. In both animal models significant concentrations of human insulin were detected, with relative bioavailabilities F(rel) of 2.8 up to 8.3%. The more hydrophobic, lactic acid grafted polyester were more effective at a threefold higher polymer concentration, increasing the relative bioavailability F(rel) of a 5 IU/kg dose from 2.8 to 5.7%. Histological examination of the nasal mucosa after 4 h showed no signs of toxicity at the site of nasal administration. CONCLUSIONS: These results demonstrate that the NC significantly enhanced insulin absorption, suggesting that amphiphilic biodegradable comb-polymers offer a promising approach for nasal peptide delivery.
PURPOSE: The bioavailability and local tolerability of insulin containing nanocomplexes from amine-modified poly(vinyl alcohol)-graft-poly(L-lactide) were studied in rats. Histology of the nasal epithelium was studied to document integrity of the mucosa. METHODS: Nanocomplexes (NC) were prepared by spontaneous self-assembly of insulin and the water-soluble amphiphilic polymer. Changes in blood glucose and insulin blood concentration were monitored in anesthetized rats using a glucose meter and enzyme-linked immunosorbent assay, respectively. Histological sections of the nasal cavity were examined after H&E staining by light microscopy. RESULTS: NC reduced blood glucose level in fasted healthy rats by 20% after 50-80 min and in streptozotocin induced diabeticrats by 30% within 75-95 min compared to basal levels. In both animal models significant concentrations of humaninsulin were detected, with relative bioavailabilities F(rel) of 2.8 up to 8.3%. The more hydrophobic, lactic acid grafted polyester were more effective at a threefold higher polymer concentration, increasing the relative bioavailability F(rel) of a 5 IU/kg dose from 2.8 to 5.7%. Histological examination of the nasal mucosa after 4 h showed no signs of toxicity at the site of nasal administration. CONCLUSIONS: These results demonstrate that the NC significantly enhanced insulin absorption, suggesting that amphiphilic biodegradable comb-polymers offer a promising approach for nasal peptide delivery.