| In 2019,the number of people suffering from type 1 and type 2 diabetes in the world was about 463 million,and is anticipated to reach 700 million in 2045.Nowadays China has the largest number of diabetes patients in the world with 116 million.And the number will be up to 150 million by 2045.However,today's insulin administration is an injection method and relies on frequent daily injections,which is inconvenient and painful and contributes to the risk prone to hypoglycemia.The development of new insulin administration methods is a centurial problem that extremely needs to be solved.Compared with insulin injection,oral administration of insulin can mimic the way of endogenous insulin secretion under normal physiological conditions without the risk of hypoglycemia,and it is the most ideal administration of insulin with great convenience and good patient compliance.However,direct oral administration of insulin is easily degraded and inactivated by gastrointestinal enzymes,and insulin has large molecular weight,poor membrane permeability and low absorption efficiency.Microparticle administration has the ability to overcome the protease degradation barrier and gastrointestinal mucus barrier,and the safety of administration can be guaranteed adequately.If the administration efficiency is improved remarkably,it will be a highly promising oral administration strategy.In the study,a pH-responsive hydrophilic polymer microsphere was synthesized and prepared for use in oral insulin delivery system.Meanwhile the methods of experiments and dissipative particle dynamics(DPD)simulation were used to analyze the structure-properties of insulin-loaded polymer microspheres.The main research contents are as follows:(1)In order to overcome the barriers of enzyme degradation in gastric acid environment,initially a pH-responsive copolymer P(HEMA-co-MAA)with hydrophobic stability in gastric acid condition and swelling in intestinal fluid condition was successfully synthesized,which was applied to the oral administration system of insulin.The critical aggregation concentration(CAC)of the polymer is6.5?87 mg/L,and the polymer can self-assemble into microspheres at low concentrations.DPD simulation indicated that the pH-responsive blocks and hydrophobic blocks of the polymer microspheres form a uniformly distributed particle structure.The particle size of the microspheres loaded with insulin ranged from 700 nm to 1700 nm,the drug loading capacity ranged from 7.1% to 8.2%,and the encapsulation rate was 69.3% to 74.1%.Under the simulated gastric fluid(SGF)condition,the release amount of insulin-loaded microspheres for 10 hours was about50%.The drug was dispersed in the pH-sensitive phase of the polymer microspheres,and it was easy to diffuse directly into water for sudden release.Simultaneously the release amount of simulated intestinal fluid(SIF)reached 90%,demonstrating that the polymer microspheres composed of pH-responsive blocks and hydrophobic blocks could promote the complete release of insulin.At last,cytotoxicity test was carried out by CCK-8 method and the cell survival rate was above 90%,which indicated that the polymer microspheres had sound biocompatibility.(2)A pH-responsive amphiphilic block copolymer P(PLAMA-co-MAA)-b-PPEGMA was synthesized for the oral administration system of insulin to further ameliorate the performance of the drug loading and release of the insulin-loaded P(HEMA-co-MAA)polymer microspheres,and to elevate the ability of the polymer microspheres to overcome the gastrointestinal mucus barrier.The amphiphilic block copolymer and insulin can self-assemble to form polymer microspheres with core-shell structure under the condition of pH=5.DPD simulation showed that the P(PLAMA-co-MAA)blocks are uniformly distributed in the core layer.The water-based PPEGMA block is evenly distributed in the shell layer.The diameters of the hydrophilic microsphere loaded with insulin ranged from 250 nm to300 nm,and the loading capacity and encapsulation rate were 10.1%-13.6% and76.4%-83.5%,respectively,indicating that the microspheres had fair drug loading capacity.Under the SGF condition,the release amount of the insulin-carrying microspheres was less than 20% for 10 h.Insulin drugs were dispersed in the pH-sensitive core layer of the polymer microspheres.The interface between the pH-sensitive core layer and the hydrophilic shell layer could effectively prevent the direct diffusion of insulin into the water and greatly reduce the sudden release of the drug.As the release of SIF reached 85%,the hydrophilic shell had little effect on the pH-sensitive core layer,and the release of insulin was nearly thorough.In addition,the results of cytotoxicity evaluation illustrated that P(PLAMA-co-MAA)-b-PPEGMA polymer microspheres had sound biocompatibility and were suitable for oral insulin delivery system.(3)Compared with P(HEMA-co-MAA)polymer microspheres,the amphiphilic block copolymer P(PLAMA-co-MAA)-b-PPEGMA microspheres had smaller particle size,better drug loading performance and pH-sensitive release performance.The self-assemble process of P(PLAMA-co-MAA)-b-PPEGMA polymer microsphere was simulated by DPD method and the effect of preparation conditions on the structure of drug-loaded microspheres was studied so as to further study the microstructure-performance relationship of polymer microspheres.The results demonstrated that drug and amphiphilic polymer could form a multi-layer structure of drug layer,pH-sensitive hydrophobic layer and hydrophilic layer.The hydrophobic layer can lower the sudden release of drug in SGF and boost the complete release of drug in SIF.Meanwhile,the hydrophilic layer of PPEGMA can be helpful for polymer microspheres to overcome the barrier of gastrointestinal mucus layer.The results showed that pH-sensitive P(PLAMA-co-MAA)-b-PPEGMA polymer hydrophilic microspheres had fair drug loading capacity and excellent pH-sensitive release performance,which was beneficial to overcome protease degradation barrier and gastrointestinal mucus layer barrier,and thus was a potential oral insulin delivery system. |
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