Preparation Of Methacrylic Acid-based PH-sensitive Hydrogels For Oral Insulin Delivery

Generally,the most common treatment for diabetes is the subcutaneous injection of insulin which is painful and usually leads to poor patient compliance.Oral delivery is the most popular approach for drug delivery because of its convenience,good patient compliance and minor side effects.However,the oral bioavailability of insulin is hampered by its inherent instability in the gastrointestinal(GI)tract and its low permeability across biological membranes.A promising way to overcome this problem and increase the absorption of insulin is the use of insulin carriers,which could protect insulin against a disadvantageous gastric environment,control the drug release and enhance the penetrability of intestinal epithelium layer in intestine tract The intelligent hydrogels have the ability to response the stimuli-sensitive changes,such as pH,ionic strength,temperature and magnetic.The pH-sensitive hydrogels have been widely used for a controlled and site-specific drug delivery because they are able to respond to the pH values change by swelling-deswelling,and the pH values is an easy way to control in vitro and in vivo.However,most of methylacrylic acid-based pH-sensitive hydrogels are very brittle,which may limit their further use.Commonly,researchers have attempted to enhance mechanical strength of hydrogels by an increase of the chemical cross-linkers content,yet this way can reduce the swelling ratio of hydrogels.In this work,two types of pH-sensitive semi-IPN hydrogels were prepared utilizing the semi-interpenetrating network(semi-IPN)technique.The pH-sensitivity and oral insulin delivery of hydrogels were investigated in detail,and the key contents and conclusions in this paper can be described as follows:(1)A pH-sensitive CMC/PMAA semi-IPN hydrogel were prepared via radical polymerization of methylacrylic acid in the presence of CMC and crosslinking agent N,N'-methylenebis(acrylamide)(NNMBA)and initiator APS/TEMED.Successful preparation of resulted hydrogels was verified using Fourier transform infrared spectroscopy(FTIR),X-ray diffraction(XRD),thermogravimetric(TGA)measurements and scanning electron microscopy(SEM).Swelling behavior of hydrogels in buffer solution with different pH values showed their sensitivity to pH changes.The in vitro release behavior of insulin was pH dependent and the release of insulin was much lower at pH 1.2 compared to pH 6.8.Cytotoxicity assays indicated that the hydrogels showed good biocompatibility.Insulin was loaded into the hydrogel,a sustained reduction in blood glucose level was observed after oral administration of insulin-loaded hydrogel to diabetic rats.These results demonstrated that this CMC/PMAA hydrogel could be a promising carrier for oral protein drugs administration.(2)A series of pH-sensitive semi-IPN hydrogels PVA/P(HPMA-co-MAA)were prepared by radical copolymerization of HEMA and MAA in the presence of PVA with different content.The N,N'-methylenebis(acrylamide)(NNMBA),APS and TEMED was used as crosslinking agent and initiators,respectively.Successful fabrication of resulted hydrogels was verified using Fourier transform infrared spectroscopy(FTIR),X-ray diffraction(XRD),thermogravimetric(TGA)measurements and scanning electron microscopy(SEM).Swelling behavior of hydrogels in buffer solutions showed a simultaneous sensitivity to pH values and ionic strength.The in vitro insulin release experiment was carried out in buffer solution at pH 1.2 and 6.8.Results showed that the release of entrapped insulin was inhibited at pH 1.2 but obviously increased at pH 6.8.Cytotoxicity assays indicated that the hydrogels had good biocompatibility.Insulin was loaded into the hydrogel,after oral administration of insulin-loaded hydrogel to diabetic rats,a sustained reduction in blood glucose level was observed.These results indicated that this hydrogel may be a potential vehicle for oral insulin.