ABSTRACT
The evaluation of encapsulated insulin intestinal absorption enhancement was investigated by in vitro methods. Insulin-loaded microparticles (INS-MP) made of whey protein (WP) and alginate (ALG) were prepared by a cold gelation technique. Effect of INS encapsulation toward trypsin and chymotrypsin degradation was performed. Permeability studies using in vitro (Caco-2 cells) experiments were conducted. INS was partially protected by encapsulation toward enzymatic degradation. Moreover INS transport experiments showed that WP and, in lesser extent, ALG were able to enhance INS absorption both as MP and as polymeric solutions by opening the tight junctions. These experiments reinforced the interest of encapsulation in WP/ALG hydrogel combination.
Subject(s)
Alginates/administration & dosage , Drug Carriers/administration & dosage , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Milk Proteins/administration & dosage , Alginates/chemistry , Caco-2 Cells , Drug Carriers/chemistry , Glucuronic Acid/administration & dosage , Glucuronic Acid/chemistry , Hexuronic Acids/administration & dosage , Hexuronic Acids/chemistry , Humans , Hydrogels , Hypoglycemic Agents/chemistry , Insulin/chemistry , Intestinal Absorption/drug effects , Milk Proteins/chemistry , Whey ProteinsABSTRACT
PURPOSE: To evaluate the efficacy of mucoadhesive insulin-loaded whey protein (WP) /alginate (ALG) microparticles (MP) for oral insulin administration. METHODS: Insulin-loaded microparticles (ins-MP) made of whey protein and alginate were prepared by a cold gelation technique and an adsorption method, without adjunction of organic solvent in order to develop a biocompatible vehicle for oral administration of insulin. In vitro characterization, evaluations of ins-MP in excised intestinal tissues and hypoglycaemic effects after intestinal administration in healthy rats were performed RESULTS: The release properties and swelling behaviors, investigated in different pH buffers, demonstrated a release based on diffusion mechanism following matrix swelling. Mucoadhesion studies in rabbits and insulin transport experiments with excised intestinal rat tissues revealed that encapsulation in microparticles with mucoadhesive properties promotes insulin absorption across duodenal membranes and bioactivity protection. In vivo experiments reinforced the interest of encapsulation in whey protein/alginate combination. Confocal microscopic observations associated with blood glucose levels bring to light duodenal absorption of insulin biologically active following in vivo administration. CONCLUSIONS: Insulin-loaded WP/ALG MP with high quantities of drug entrapped, in vitro matrix swelling and protective effect as well as excellent mucohadesive properties was developped. Improvement of intestinal delivery of insulin and increased in bioavailability were recorded.
Subject(s)
Alginates/chemistry , Drug Carriers/chemistry , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Milk Proteins/chemistry , Tissue Adhesives/chemistry , Administration, Oral , Alginates/metabolism , Animals , Drug Carriers/metabolism , Duodenum/metabolism , Duodenum/ultrastructure , Glucuronic Acid/chemistry , Glucuronic Acid/metabolism , Hexuronic Acids/chemistry , Hexuronic Acids/metabolism , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Hydrogel, Polyethylene Glycol Dimethacrylate/metabolism , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Insulin/metabolism , Insulin/pharmacokinetics , Insulin/pharmacology , Male , Microspheres , Milk Proteins/metabolism , Rabbits , Rats , Rats, Wistar , Tissue Adhesives/metabolism , Whey ProteinsABSTRACT
Insulin was encapsulated into microparticles (MP) made of denaturized whey proteins (WP) and alginate (ALG) using an extrusion/cold gelation process with calcium ions. High encapsulation efficiency of 85% was obtained. Influence of insulin on polymeric viscosity and on microparticle behavior was evaluated. Insulin seemed to interact with WP chains by non covalent binding and steric hindrance. This influence was balanced by ALG addition. Nevertheless, insulin was released rapidly by diffusion at both acidic and intestinal dissolution media. Despite this fast in vitro release, WP/ALG MP showed an important enzymatic inhibition effect on trypsin and alpha-chymotrypsin. Thus, WP/ALG MP contributed to an effective insulin protection towards enzymatic degradation. The aforementioned results suggested that WP based microparticles are a promising carrier for improving oral delivery of insulin.
