A nano-delivery system based on preventing degradation and promoting absorption to improve the oral bioavailability of insulin

Abstract

Oral insulin delivery can improve patient compliance and simulate the portal-peripheral insulin concentration gradient produced by endogenous insulin, so oral insulin delivery has a broad prospect. However, some characteristics of the gastrointestinal tract, lead to low oral bioavailability. Therefore, a "ternary mutual-assist" nano-delivery system based on poly(lactide-co-glycolide) (PLGA) as the backbone combined with ionic liquids (IL) and vitamin B12-chitosan (VB12-CS) was constructed in this study, the protein protection performance of IL improves the room temperature stability of the loaded insulin during nanocarrier preparation, transportation and storage to a certain extent, and the protein protection function of IL combined with the slow degradation property of PLGA and the pH-responsive function of VB12-CS to prevent the degradation of insulin in the gastrointestinal tract. In addition, the mucosal adhesion function of VB12-CS, VB12 receptor- and clathrin-mediated transcellular transport involving VB12-CS and IL, and paracellular transport mediated by IL and CS can be combined to improve the intestinal epithelial transport efficiency of insulin, thus, the nanocarrier has stronger preventing degradation and promoting absorption effects. Pharmacodynamic studies showed that after oral administration of VB12-CS-PLGA@IL@INS NPs to diabetic mice, the blood glucose level decreased to about 13 mmol/L, below the critical point of 16.7 mmol/L, and the blood glucose reached a normal level, which was 0.4 times of the blood glucose value before administration, its relative pharmacological bioavailability was 31.8 %, higher than the general nanocarriers (10-20 %) and more beneficial to the clinical transformation of oral insulin.

Keywords: Insulin; Oral bioavailability; Preventing degradation; Promoting absorption; VB12-CS-PLGA@IL@INS NPs.