京尼平交联壳聚糖的研究
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摘要
口服结肠定位给药系统是通过口服达到结肠定位释放的目的。目前广泛应用OCDDS的载体材料主要有偶氮类、多糖类等材料。偶氮类材料存在生物相容性差、细胞毒性大、不易降解等缺点。壳聚糖是一种生物相容性良好的天然多糖,在生物医药行业有着广泛的应用前景,尤其是壳聚糖及其衍生物所具有的pH敏感性,在口服结肠定位给药领域具有潜在的应用,但是它的机械性能较差、稳定性不好。本文制备了N-羧乙基壳聚糖/海藻酸钠共混膜,并摒弃了常规交联剂戊二醛选用了天然交联剂京尼平,从而有望进一步降低共混膜的细胞毒性、提高膜的力学能力并减缓膜的降解。此种结肠定位释放的药物载体膜具有制备工艺简单,给药受胃肠道环境影响较小等优点。在此基础上,利用静电喷雾技术研制出了一批具备成球性好、粒径均匀、环境友好等特点的海藻酸钠微球,通过后续工艺使N-羧乙基壳聚糖包覆在微球表面,再经过京尼平交联后制备出一种具有核壳结构的微囊,为新型微囊用于结肠定位释放开辟了道路。
具体内容和结论如下：
1、首先通过迈克尔加成反应制备一种水溶性的壳聚糖衍生物—N-羧乙基壳聚糖(CS-AA),然后选用京尼平作交联剂制备了N-羧乙基壳聚糖/海藻酸钠膜,并对其进行红外表征、核磁分析、溶胀动力学、模拟结肠环境的缓冲溶液中药物释放行为、酶降解实验和形貌分析等测试。结果表明这种共混膜具有良好的pH值响应性能,在pH=1.2缓冲溶液的溶胀率远远小于pH=7.4缓冲溶液时的溶胀率,pH=7.4缓冲溶液时5-氟尿嘧啶药物缓释量也大于pH=1.2环境,从而有可能使药物减少在胃部环境中流失及降低了胃部刺激,所以该共混膜能作为结肠定位控释的潜在载体。
2、通过改变静电喷雾技术的外部电压强度、注射器针头、推进速度等因素制备出200um左右的粒径均匀的海藻酸钠微球,并用激光粒度仪进行粒径分析。经过后续CS-AA包覆、京尼平交联,制备出一种具有发射荧光的微囊结构。主要对微囊进行了荧光显微镜分析、共聚焦激光扫描显微镜的核壳分析、形貌分析等方面的研究。确定了制备微囊的最优条件,有望以后用于生物医学甚至结肠定位载体的实验。
The objective of oral colon-specific drug delivery system (OCDDS) is the specific delivery of drugs to the human colon via the oral route. Chitosan, which is a natural polymer with good biocompatibility, has a broad foreground in biomedicine industry. Especially because of the pH sensitivity, chitosan and its derivatives have potential applications in OCDDS field. In this paper, N-carboxymethyl chitosan/sodium alginate blend membranes crosslinked by genipin were prepared. Genipin is a natural crosslinking agent, which has less cell cytotoxicity, better crosslinking ability and durability to enzymatic degradation than the common crosslinking agent glutaraldehyde. This kind of drug carrier membranes reduced the side-effect of drug to gastrointestinal environment, and were of simple preparation. Based on this, sodium alginate microspheres were fabricated using the electrostatic spray technology. The environment friendly, symmetry and sphericity of the microspheres are superiority. Then the microspheres were coated in a chitosan solution and cross-linked by genipin. As a result, the genipin cross-linked N-carboxymethyl chitosan/sodium alginate microcapsules were collected. The Details and conclusions are described as follows:
1, A series of blend membranes were prepared by a water-soluble chitosan (N-carboxymethyl chitosan, CS-AA) and sodium alginate (ALG) co-cross linked by genipin. Then the membranes loaded with drug (Fluorouracil,5-Fu) was produced with one method that is to add the drug into the blend of CS-AA/ALG before cross-linking with genipin, after that using UV specrum to test the drug release capability in different pH buffer solutions. The results indicated that the swelling ratio was slow in the strong acid medium due to formation of hydrogen bonds between CS-AA and alginate. At pH 7.4, the carboxylic acid groups on the CS-AA/ALG hydrogel became progressively ionized. In this case, the hydrogel swelled more significantly due to a large swelling force created by the electrostatic repulsion between the ionized acid groups. The release system released at pH 1.2 was relatively lower. The results suggested that the Chitosan-based hydrogel could be a suitable polymeric carrier for site-specific protein drug delivery in the colon.
2, A series of sodium alginate microspheres were fabricated by changing the external voltage values, promote speed and needles dimensions of electrostatic spray technology. Then uniform grading microspheres with diameter of about 200μm were chosen in particle size analysis using laser granulometer. Then the microspheres were coated in a chitosan solution and cross-linked by genipin.The genipin cross-linked CS-AA/ALG microcapsules were collected. The characterization was studied by the fluorescence microscopy analysis, the confocal laser scanning microscopy analysis and SEM etc, and the optimal conditions of the microcapsules were determined. It is possible that the genipin cross-linked CS-AA/ALG microcapsules will be used as colon-specific carrier.
具体内容和结论如下：
1、首先通过迈克尔加成反应制备一种水溶性的壳聚糖衍生物—N-羧乙基壳聚糖(CS-AA),然后选用京尼平作交联剂制备了N-羧乙基壳聚糖/海藻酸钠膜,并对其进行红外表征、核磁分析、溶胀动力学、模拟结肠环境的缓冲溶液中药物释放行为、酶降解实验和形貌分析等测试。结果表明这种共混膜具有良好的pH值响应性能,在pH=1.2缓冲溶液的溶胀率远远小于pH=7.4缓冲溶液时的溶胀率,pH=7.4缓冲溶液时5-氟尿嘧啶药物缓释量也大于pH=1.2环境,从而有可能使药物减少在胃部环境中流失及降低了胃部刺激,所以该共混膜能作为结肠定位控释的潜在载体。
2、通过改变静电喷雾技术的外部电压强度、注射器针头、推进速度等因素制备出200um左右的粒径均匀的海藻酸钠微球,并用激光粒度仪进行粒径分析。经过后续CS-AA包覆、京尼平交联,制备出一种具有发射荧光的微囊结构。主要对微囊进行了荧光显微镜分析、共聚焦激光扫描显微镜的核壳分析、形貌分析等方面的研究。确定了制备微囊的最优条件,有望以后用于生物医学甚至结肠定位载体的实验。
The objective of oral colon-specific drug delivery system (OCDDS) is the specific delivery of drugs to the human colon via the oral route. Chitosan, which is a natural polymer with good biocompatibility, has a broad foreground in biomedicine industry. Especially because of the pH sensitivity, chitosan and its derivatives have potential applications in OCDDS field. In this paper, N-carboxymethyl chitosan/sodium alginate blend membranes crosslinked by genipin were prepared. Genipin is a natural crosslinking agent, which has less cell cytotoxicity, better crosslinking ability and durability to enzymatic degradation than the common crosslinking agent glutaraldehyde. This kind of drug carrier membranes reduced the side-effect of drug to gastrointestinal environment, and were of simple preparation. Based on this, sodium alginate microspheres were fabricated using the electrostatic spray technology. The environment friendly, symmetry and sphericity of the microspheres are superiority. Then the microspheres were coated in a chitosan solution and cross-linked by genipin. As a result, the genipin cross-linked N-carboxymethyl chitosan/sodium alginate microcapsules were collected. The Details and conclusions are described as follows:
1, A series of blend membranes were prepared by a water-soluble chitosan (N-carboxymethyl chitosan, CS-AA) and sodium alginate (ALG) co-cross linked by genipin. Then the membranes loaded with drug (Fluorouracil,5-Fu) was produced with one method that is to add the drug into the blend of CS-AA/ALG before cross-linking with genipin, after that using UV specrum to test the drug release capability in different pH buffer solutions. The results indicated that the swelling ratio was slow in the strong acid medium due to formation of hydrogen bonds between CS-AA and alginate. At pH 7.4, the carboxylic acid groups on the CS-AA/ALG hydrogel became progressively ionized. In this case, the hydrogel swelled more significantly due to a large swelling force created by the electrostatic repulsion between the ionized acid groups. The release system released at pH 1.2 was relatively lower. The results suggested that the Chitosan-based hydrogel could be a suitable polymeric carrier for site-specific protein drug delivery in the colon.
2, A series of sodium alginate microspheres were fabricated by changing the external voltage values, promote speed and needles dimensions of electrostatic spray technology. Then uniform grading microspheres with diameter of about 200μm were chosen in particle size analysis using laser granulometer. Then the microspheres were coated in a chitosan solution and cross-linked by genipin.The genipin cross-linked CS-AA/ALG microcapsules were collected. The characterization was studied by the fluorescence microscopy analysis, the confocal laser scanning microscopy analysis and SEM etc, and the optimal conditions of the microcapsules were determined. It is possible that the genipin cross-linked CS-AA/ALG microcapsules will be used as colon-specific carrier.
引文
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