Polymeric Nanoparticles For Oral Insulin Delivery: Preparation And Structure-performance Relationship

Oral insulin delivery is the convenient way to diabetic patients as it is the mostphysiological and comfortable means. However, it is a tough task for orally deliveringbioactive macromolecules, due to the highly organized array of barriers existed in thegastrointestinal (GI) tract, such as rapid enzymatic degradation and the poor intestinalabsorption. The polymeric nanoparticles protect insulin against degradation and facilitate theuptake of insulin through a paracellular or a transcellular pathway. Insulin loadedpH-sensitive nanoparticles, mucoadhesiven nanoparticles and PEGylated insulin loadedpH-sensitive nanoparticles were prepared and investigated as oral delivery systems for insulindelivery. With pH-sensitive nanoparticle as a model nanoparticle, the structure-performancerelationship of nanoparticle with different preparation condition was also evaluated.According to the principle of multiple emulsions solvent evaporation method, theinsulin-loaded poly (lactic-co-glycolic acid)/hydroxypropyl methylcellulose phthalate(PLGA/HP55) nanoparticles were prepared. The physicochemical characteristics, in vitrorelease of insulin and in vivo efficacy in diabetic rats of the nanoparticles were evaluated. Thenanoparticles showed the size of181nm, encapsulation efficiency of94%and goodpH-sensitive release property. When administered orally to diabetic rats, the nanoparticles candecrease rapidly the blood glucose level with a maximal effect between1and8h. Therelative bioavailability compared with subcutaneous injection (5IU/kg) in diabetic rats was11.3%.By filling of the mucoadhesive nanoparticles into the enteric capsule, we design andprepared a two-stage carrier delivery system. The stage-1carrier is the hard gelatin capsulescoated with pH sensitive enteric polymer, hydroxypropyl methylcellulose phthalate (HP55),which used to protect the nanoparticles through the stomach. The stage-2carrier is theinsulin-loaded cationic nanoparticles composed of the poly (lactic-co-glycolic acid)(PLGA)and Eurdragit RS (RS).The cationic nanoparticles aim to open the tight junction andenhance the absorption of released insulin. The nanoparticles were prepared with the multipleemulsions solvent evaporation method via ultrasonic emulsification. The optimizednanoparticles have a mean size of285nm, a positive zeta potential of42mV. The encapsulation efficiency was up to73.9%. In vitro results revealed that the initial burst releaseof insulin from nanoparticles was markedly reduced at pH1.2, which mimics the stomachenvironment. In vivo effects of the capsule containing insulin PLGA/RS nanoparticles werealso investigated in diabetic rat models. The oral delivered capsules induced a prolongedreduction in blood glucose levels. The pharmacological availability was found to beapproximately9.2%.PEGylation is an effective method to prolong the circulation half-life of insulin in vivo,recogition by the immune system and degradation by proteolytic enzymes. We designed andevaluated the feasibility combining insulin PEGylated insulin (PEG-ins) with pH-sensitivenanoparticles for oral insulin delivery. As we introduced the PLA (Mw=100000) as the carriermaterials, the pH-sensitive release of PEG-ins from the nanoparticles was improved. Morethan70%of insulin could be released from the PLA/HP55nanoparticles with the91%ofencapsulation efficiency. All the results of in vitro indicated that the integration of PLA/HP55nanoparticles with PEG-ins may be a promising approach for oral delivery of insulin withhighly potential bioavailability.At last, with pH-sensitive nanopartice as a model nanoparticle, thestructure-performance relationship of nanoparticle with different preparation condition wasalso evaluated. The PLGA/HP55nanoparticles were prepared via the emulsions solventdiffusion method with two different solvents, namely, DMSO and acetone/water. Themicrostructures of the nanoparticles were studied by the solubility parameters theory, DSC,FTIR, and the nitrogen adsorption technique. Phase-separated PLGA domains were observedfrom the nanoparticles prepared with both types of solvents. Mesopores were observed fromthe nanoparticles prepared with DMSO as the solvent and almost didn’t exist withacetone/water. The formation of mesopores accelerated the release of insulin, leading to noobvious pH-sensitivity of the nanoparticles prepared with DMSO. However, for thenanoparticles prepared with acetone/water, the release of insulin was pH-dependent.