双胍和季铵盐壳聚糖药物控释体系的制备与表征

发布时间：2018-01-11 17:43

本文关键词：双胍和季铵盐壳聚糖药物控释体系的制备与表征　出处：《华南农业大学》2016年硕士论文　论文类型：学位论文

【摘要】：壳聚糖(CS)是甲壳素脱乙酰基后得到的一种天然阳离子多糖,具有良好的生物相容性、抑菌性及抗氧化性。以CS为主的药物缓释体系,不仅能改善被包载药物的化学稳定性,延长药效,而且对环境和人体无毒且易降解,在现代农业与生物医药领域都有良好应用前景。本论文研究了三种CS及衍生物的药物缓释体系,主要研究结果如下:在第一部分中,以未改性CS作对照,分别以两种改性壳聚糖,双胍壳聚糖(BGCS)及季铵盐壳聚糖(HTCC)为壁材,吲哚-3-乙酸(IAA)为药物模型,通过乳化交联法制备并表征了两种载药微胶囊(MCs)缓释体系,并研究了它们的药物释放机理。首先对CS进行化学改性,制备了取代度不同的BGCS和HTCC,并选取取代度较低的改性壳聚糖作为载药壁材。然后通过单因素实验,分别考察了壁材浓度、交联剂的用量、交联时间以及油相/水相比例对载IAA的包封率(EE)的影响。并采用了IR、UV-vis、TGA以及SEM等手段对IAA-MCs进行了化学结构、热稳定性及表观形貌表征。结果表明:在载药能力和热稳定性方面,以两种改性CS壁材所制备的载药MCs均优于未改性CS,其中BGCS-MCs比HTCC-MCs具有更光滑紧致的表面形貌和更小的平均粒径(6.69μm)。在释药动力学研究中发现,三种MCs在水中的释放量均比在甲醇中大;和CS-MCs及BGCS-MCs相比,HTCC-MCs明显改善了突释现象。根据对三种CS-MCs的释药动力学模型的数学拟合发现,三种MCs的药物释放动力学方程均符合Korsmeyer-Peppas模型,且在水和甲醇介质中的释药过程均为Fickian扩散。在第二部分中,在改性CS-MCs壁材中加入聚阴离子型高分子材料木质素磺酸钠(SL),以1-萘乙酸甲酯(MNAA)为药物模型,采用复凝聚法制备了包载MNAA的MCs:BGCS/SL-MCs、HTCC/SL-MCs和CS/SL-MCs。通过单因素试验考察了CS及其衍生物的浓度、SL的浓度、芯壁比以及复凝聚时的pH对微胶囊EE的影响。同时用IR、UV-vis、TGA以及SEM对三种载药MCs的性质及表观形貌进行了表征。结果表明:在CS的氨基位引入强正电子基团,与聚阴离子性高分子材料SL产生更强的静电作用,故改性CS壁材制备的载药微胶囊具有稳定的化学结构、更高的包封率和热稳定性;在药物缓释机理研究中,BGCS/SL-MCs的缓释效果最佳,三组MCs的释放程度均随着环境温度升高而加大,且动力学缓释模型均属于Korsmeyer-Peppas模型。在第三部分中,在海藻酸钠水凝胶(SA-HG)载药体系中,引入改性CS以提高药物包封率和释药可控性。采用挤出-外源凝胶法,以CaCl2做交联剂,以5-氟尿嘧啶(5-FU)为药物模型,以CS为对照,将BGCS或HTCC与SA复合制备载5-FU的水凝胶球(HGBs)——CS/SA-HGBs、BGCS/SA-HGBs和HTCC/SA-HGBs。通过IR、UV-vis和TGA表征了凝胶球的物理化学性能,并测试其溶胀性与释药性。首先采用单因素确定制备成球的最优化条件:改性CS浓度0.5%,SA浓度3%,CaCl2浓度2%;与CS/SA-HGBs对照,BGCS/SA-HGBs和HTCC/SA-HGBs的EE分别提高了7.58%和11.0%。这是因为CS壁材改性后,引入的双胍或季铵基与SA上的羧基形成较强的氢键,因此提升了HGBs的热稳定性、机械性能和保水性。药物缓释实验结果表明,三种CS/SA-HGBs的溶胀率和药物释放速率均随pH变化发生规律性改变,因此具有良好的pH响应性;其缓释效果的强弱顺序为:HTCC/SA-HGBs,BGCS/SA-HGBs,HTCC/SA-HGBs。
[Abstract]:Chitosan (CS) is a natural cationic deacetylated chitin obtained polysaccharide has good biocompatibility, antibacterial and antioxidant activity. The drug delivery system based on CS, can not only improve the chemical stability of loaded drug and extend the efficacy, non-toxic to environment and human body and easy degradation, have good application prospect in modern agricultural and biological medicine. This thesis drug delivery system and three kinds of CS derivatives, the main results are as follows: in the first part, with the unmodified CS as control, respectively to two kinds of modified chitosan biguanide chitosan (BGCS) and quaternary ammonium salt of chitosan (HTCC) as wall material, indole -3- acetic acid (IAA) as drug model, through the emulsion crosslinking method of two kinds of drug loaded microcapsules preparation and characterization of (MCs) delivery system, and study their drug release mechanism. Firstly, CS was chemically modified, was prepared to replace Different degrees of BGCS and HTCC, and select the degree of substitution of modified chitosan with low drug loading as wall material. Then through the single factor experiment were investigated, wall material concentration, the amount of crosslinking agent, crosslinking time and oil / aqueous phase ratio of IAA encapsulation efficiency (EE) and the influence. Using IR, UV-vis, TGA, SEM and other means of the chemical structure of IAA-MCs, and the apparent morphology characterization of thermal stability. The results showed that: in the drug loading capacity and thermal stability, with two kinds of modified CS wall material prepared by loading MCs were better than that of unmodified CS, BGCS-MCs than HTCC-MCs with the surface morphology and the smaller is more smooth and compact with the average diameter (6.69 m). Found in the drug release kinetics study, three kinds of MCs release in the water than in methanol; compared with CS-MCs and BGCS-MCs, HTCC-MCs significantly improved the burst release phenomenon. According to the three release of CS-MCs pharmacokinetic model Mathematical fitting found that drug release kinetics of three kinds of MCs were consistent with the Korsmeyer-Peppas model, and in water and methanol in the medium of drug release process was the diffusion of Fickian. In the second part, adding a polyanionic material of sodium lignosulfonate in modified CS-MCs wall material (SL), 1- (naphthylacetate MNAA) as a model drug, using complex coacervation MNAA loaded MCs:BGCS/SL-MCs was prepared, HTCC/SL-MCs and CS/SL-MCs. were investigated through the single factor test the concentration of CS and its derivatives, the concentration of SL, and the influence of the ratio of core to wall complex coacervation pH on the micro capsule of EE. At the same time with the IR, UV-vis, TGA and SEM on three kinds of drug loaded MCs properties and surface morphology were investigated. The results showed that: in the introduction of strong amino CS positron group, produce stronger electrostatic interaction with poly anionic polymer material SL, the modified CS drug loaded microcapsules wall material preparation Has stable chemical structure, higher encapsulation efficiency and thermal stability; in the study of mechanism of drug release, sustained release effect of BGCS/SL-MCs is best, the release degree of three groups of MCs were increased as the ambient temperature increases, and the dynamics of releasing model belong to the Korsmeyer-Peppas model. In the third part, the sodium alginate hydrogel (SA-HG) carrier delivery system, the introduction of modified CS to improve the drug encapsulation efficiency and drug release control. By extrusion - exogenous gel method, using CaCl2 as crosslinking agent, 5- fluorouracil (5-FU) as drug model, compared with CS, BGCS or HTCC hydrogel microparticles and SA compound preparation containing 5-FU (HGBs CS/SA-HGBs, BGCS/SA-HGBs and HTCC/SA-HGBs.) by IR, UV-vis and TGA were used to characterize the physical and chemical properties of gel beads, and test the swelling and drug release. First determine the preparation conditions by single factor optimization ball: modified CS concentration 0.5%, SA The concentration of 3%, the concentration of CaCl2 2%; compared with CS/SA-HGBs, BGCS/SA-HGBs and HTCC/SA-HGBs EE were increased by 7.58% and 11.0%. this is because the CS wall material modified into double guanidine or Ji Anji and SA on the formation of a strong hydrogen bond of carboxyl, thus enhance the thermal stability of HGBs, mechanical properties and water retention agents. Release the experimental results show that the swelling rate and the drug release rate of CS/SA-HGBs was three pH with the change regularity of change, so it has good pH response; the sustained release effects of the strength of the order: HTCC/SA-HGBs, BGCS/SA-HGBs, HTCC/SA-HGBs.

【学位授予单位】：华南农业大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：O636.1;TQ460.4

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