Insulin containing nanocomplexes formed by self-assembly from biodegradable amine-modified poly(vinyl alcohol)-graft-poly(L-lactide): bioavailability and nasal tolerability in rats.
OBJECTIVE
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.
Simon
Michael
M
Department of Pharmaceutics and Biopharmacy, Philipps University, Ketzerbach 63, D-35032 Marburg, Germany.
Wittmar
Matthias
M
Kissel
Thomas
T
Linn
Thomas
T
D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D016503:Drug Delivery Systems; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D049329:Nanostructures / Q000737:chemistry*; D009297:Nasal Mucosa / Q000187:drug effects* / Q000473:pathology; D011091:Polyesters / Q000737:chemistry; D011142:Polyvinyl Alcohol / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin
D007328:Insulin; D011091:Polyesters; C033616:poly(lactide); D013311:Streptozocin; D011142:Polyvinyl Alcohol