Chitosan-coated solid lipid nanoparticles enhance the oral absorption of insulin.

The development of alternative routes to the conventional subcutaneous administration of insulin is expected to provide an important advance in the management of diabetes. The aim of this work was to produce and characterize chitosan-coated Witepsol 85E solid lipid nanoparticles (SLN) containing insulin, and to evaluate the potential of these colloidal carriers for oral administration. SLN were prepared by a modified solvent emulsification-evaporation method based on a water/oil/water double emulsion followed by chitosan adsorption to SLN surface. Optimized chitosan-coated SLN presented a mean particle size around 450 nm and were positively charged, indicating synergic properties for intestinal absorption. Higher extent of insulin permeation was observed for SLN and chitosan-coated SLN in a Caco-2 cell monolayer model. When comparing both SLN formulations, chitosan coating was shown to provide higher insulin permeation. Also, similar effects were also observed using a Caco-2/HT29 monolayer model, which more closely resemble the intestinal membrane, thus indicating that the mucoadhesive properties and permeation enhancement effect of chitosan may contribute significantly to the enhanced insulin permeation. After oral administration of insulin-loaded SLN to diabetic rats, a considerable hypoglycemic effect was observed for 24 h, which was more pronounced when chitosan-coated SLN were used, resulting in relative pharmacological bioavailabilities of 8% and 17% for uncoated and chitosan-coated SLN, respectively. Also, fluorescently labeled insulin was located on the intestinal walls and internalized into enterocytes after administration in chitosan-coated SLN, thus revealing the effectiveness of this nanocarrier in promoting the intestinal absorption of insulin. In conclusion, the use of chitosan-coated SLN may provide an interesting platform for the development of oral insulin formulations to be used in the management of diabetes.