Exenatide-loaded Polymeric Nano/Microspheres For Oral Administration

Protein and peptide oral delivery system has a very good patient compliance;however, low oral bioavailability is still a bottleneck to be resolved. The study is toprepare uniform-sized PLGA/SA nano/microspheres for Exenatide oral administration.The nano/microspheres were prepared by rapid membrane emulsification technique.We choose poly(lactic-co-glycolic acid)(PLGA) and stearylamine (SA) as complexpreparation materials. Compared with single PLGA prepared nano/microspheres, theburst release of nano/microspheres could be improved. The achieved positive chargecould facilitate the retention time of the nano/microspheres in the gastrointestinal tractwhich was beneficial to oral obsorption. The surface of nano/microspheres wasmodified by Poly(ethyleneglycol)(PEG) and CSKSSDYQC-peptide. Themodifications of PEG make nano/microspheres penetrate mucus and increase thecontact with intestinal epithelial cells; CSKSSDYQC-peptide was identified to havegood affinity with the goblet cell，which could prominently improve the transportefficiency of macromolecules across the intestinal mucosal barrier. Therefore, theconstructed peptide delivery system may exhibit promising potential for increasingoral bioavailability. The dissertation is divided into three parts：The first part focused on the preparation of PLGA/SA nano/microspheres bycombining double emulsion solvent evaporation method with premix membraneemulsification. By optimizing curing temperature， ultrasonic power， ratio ofPLGA/SA，molecular weight of PLGA and NH4HCO3concentration in internal waterphase, smooth nano/microspheres with positive surface charge， drug loadingefficiency above4%，entrapment rate above80%and cumulative drug release above80%could be obtained. Compared with PLGA nano/microspheres, PLGA/SAnano/microspheres with positive surface charge exhibited improved absorptionefficiency of Exenatide and a better hypoglycemic response following the multipleoral administrations.In the second part PLGA/SA nano/microspheres with different particle sizes (300nm,1μm, and4μm) were developed by combining ultrasonic with premix membrane emulsification and the relationship between particle size and oral bioavailability wasinvestigated. It was found that PLGA/SA nano/microspheres (1μm) demonstratedelevated intestinal absorption, systemic biodistribution and cumulative hypoglycemiceffect after oral gavage.The third part investigated the effects of PEG and CSKSSDYQC (CSK) peptidedouble-modification of PLGA/SA nano/microspheres on intestinal absorption,systemic biodistribution and cumulative hypoglycemic effect after oral gavage. It wasfound that the modifications of PEG not only extended the residence time ofnano/microspheres in vivo but also concomitantly enhanced its absorption in thegastrointestinal (GI) tract and exhibited more prolonged hypoglycemic activity. CSKpeptide could prominently improve the transport efficiency of nano/microspheresacross the intestinal mucosal barrier and exhibit more prolonged hypoglycemicactivity by its good affinity with the goblet cell.