超分子插层及核—壳结构药物传输载体的研究
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摘要
阴离子层状材料－水滑石（LDHs）由于本身所具有的可插层组装性能，以及很好的生物相容性，将其构建成药物/水滑石超分子材料，应用于药物传输载体的研究越来越多。
本论文首次采用共沉淀法制备得到抗炎药物---芬布芬、二氟尼柳和布洛芬插层水滑石。对插层产物进行X射线粉末衍射（XRD）表征发现，插层后水滑石的层间距显著增加，表明确实得到了药物插层水滑石超分子材料。具体考察了pH 值、晶化时间、晶化温度、药物浓度和不同层板元素等对插层产物结构的影响，结果发现，药物分子在水滑石层间由低pH的单层排列转换为高pH的双层排列，从而导致插层产物的层间距显著增加。模拟肠液pH＝7.8的体液环境，对该超分子材料的释放性能进行研究。结果发现，确实实现了对药物的缓慢释放，并且相比较前人所做的工作，缓慢释放的效果有了显著的提高。比较不同层板元素的释放性能发现，Mg/Al要比Li/Al水滑石具有更好的应用效果。
针对药物插层水滑石普遍存在的问题，即无机水滑石材料在酸性条件下很容易溶解，在胃液的酸性环境中，水滑石层板迅速溶解，插层的药物完全释放，导致缓释效应不能实现。本论文将丙烯酸树酯中肠溶材料的耐酸性应用到药物缓释体系中，即先把药物插层到水滑石层间，然后在插层水滑石的颗粒外表面包覆一层丙烯酸树脂，构建一种核-壳结构复合材料。选定的丙烯酸树酯肠溶材料为目前被广泛应用的Eudragit? L 100 和 S 100，它们是由丙烯酸和丙烯酸甲酯按照不用的比例聚合而成的。两种材料都不溶于酸，Eudragit L、S分别于pH6.0和pH7.0开始溶解。因此采用丙烯酸树酯包覆后的核-壳结构复合材料具备了耐酸的性质，可以克服水滑石层板在胃液的强酸性环境中溶解，使药物在到达肠液后才开始释放，最终实现缓/控制释放的目的。
Layered double hydroxides (LDHs), or so-called anionic clays, consist of cationic brucite-like layers and exchangeable interlayer anions. Because of their biocompatibility, these layered inorganic solids can be used as host materials to create drug-LDH host-guest supramolecular structures. The interlayer anion exchangeable capability of LDHs meets the requirement of inorganic matrices for encapsulating functional drugs with negative charge in aqueous media.
The anti-inflammatory drug fenbufen，diflunisal and ibuprofen have been intercalated into layered double hydroxides for the first time by co-precipitation under a nitrogen atmosphere. The products have been characterized by powder X-ray diffraction (XRD), and show an expanded LDH structure, indicating that the drug have been successfully intercalated into LDH. In addition, the dependence of the nature of the fenbufen intercalation process on conditions such as pH value temperature, molar ratio, reaction time and chemical composition of the host have been systematically investigated. The interlayer distance in the intercalated materials increases with increasing pH value, resulting from a change in the arrangement of interlayer anions from monolayer to bilayer. Drug release characteristics of the pillared LDH materials were investigated by a dissolution test in a simulated intestinal fluid (buffer at pH 7.8). The results show that the drug release of supramolecular LDH materials was a slow process, especially in the case of Mg-Al intercalated materials, suggesting that these drug-inorganic hybrid materials can be used as an effective drug delivery system.
LDHs are basic compounds however, and will dissolve rapidly in gastric acid, with complete liberation of the intercalated drug in the stomach. This means the use of LDHs as drug delivery system will be limited because of complete liberation of the intercalated drug in the stomach.
In this paper, we have shown that intercalation of fenbufen in a layered double hydroxide followed by coating with enteric gives a composite material which shows
controlled release of the drug under in vitro conditions which model the passage of a material through the gastrointestinal tract. As the enteric coating we select Eudragit? L 100 and S 100, which have been widely used in this area. Those anionic copolymers of methacrylic acid and methyl methacrylate have a molecular weight of approximately 135,000 with a ratio of acid to ester of approximately 1:1 in Eudragit? L 100 and 1:2 in Eudragit? S 100. Both polymers are insoluble in aqueous acid solution but Eudragit? L 100 dissolves at pH 6 and above and Eudragit? L 100 at pH 7 and above. Work is underway in our laboratory to explore how the drug release characteristics may be modified by variation of the physicochemical properties of both the layered double hydroxide and the polymer coating.
本论文首次采用共沉淀法制备得到抗炎药物---芬布芬、二氟尼柳和布洛芬插层水滑石。对插层产物进行X射线粉末衍射（XRD）表征发现，插层后水滑石的层间距显著增加，表明确实得到了药物插层水滑石超分子材料。具体考察了pH 值、晶化时间、晶化温度、药物浓度和不同层板元素等对插层产物结构的影响，结果发现，药物分子在水滑石层间由低pH的单层排列转换为高pH的双层排列，从而导致插层产物的层间距显著增加。模拟肠液pH＝7.8的体液环境，对该超分子材料的释放性能进行研究。结果发现，确实实现了对药物的缓慢释放，并且相比较前人所做的工作，缓慢释放的效果有了显著的提高。比较不同层板元素的释放性能发现，Mg/Al要比Li/Al水滑石具有更好的应用效果。
针对药物插层水滑石普遍存在的问题，即无机水滑石材料在酸性条件下很容易溶解，在胃液的酸性环境中，水滑石层板迅速溶解，插层的药物完全释放，导致缓释效应不能实现。本论文将丙烯酸树酯中肠溶材料的耐酸性应用到药物缓释体系中，即先把药物插层到水滑石层间，然后在插层水滑石的颗粒外表面包覆一层丙烯酸树脂，构建一种核-壳结构复合材料。选定的丙烯酸树酯肠溶材料为目前被广泛应用的Eudragit? L 100 和 S 100，它们是由丙烯酸和丙烯酸甲酯按照不用的比例聚合而成的。两种材料都不溶于酸，Eudragit L、S分别于pH6.0和pH7.0开始溶解。因此采用丙烯酸树酯包覆后的核-壳结构复合材料具备了耐酸的性质，可以克服水滑石层板在胃液的强酸性环境中溶解，使药物在到达肠液后才开始释放，最终实现缓/控制释放的目的。
Layered double hydroxides (LDHs), or so-called anionic clays, consist of cationic brucite-like layers and exchangeable interlayer anions. Because of their biocompatibility, these layered inorganic solids can be used as host materials to create drug-LDH host-guest supramolecular structures. The interlayer anion exchangeable capability of LDHs meets the requirement of inorganic matrices for encapsulating functional drugs with negative charge in aqueous media.
The anti-inflammatory drug fenbufen，diflunisal and ibuprofen have been intercalated into layered double hydroxides for the first time by co-precipitation under a nitrogen atmosphere. The products have been characterized by powder X-ray diffraction (XRD), and show an expanded LDH structure, indicating that the drug have been successfully intercalated into LDH. In addition, the dependence of the nature of the fenbufen intercalation process on conditions such as pH value temperature, molar ratio, reaction time and chemical composition of the host have been systematically investigated. The interlayer distance in the intercalated materials increases with increasing pH value, resulting from a change in the arrangement of interlayer anions from monolayer to bilayer. Drug release characteristics of the pillared LDH materials were investigated by a dissolution test in a simulated intestinal fluid (buffer at pH 7.8). The results show that the drug release of supramolecular LDH materials was a slow process, especially in the case of Mg-Al intercalated materials, suggesting that these drug-inorganic hybrid materials can be used as an effective drug delivery system.
LDHs are basic compounds however, and will dissolve rapidly in gastric acid, with complete liberation of the intercalated drug in the stomach. This means the use of LDHs as drug delivery system will be limited because of complete liberation of the intercalated drug in the stomach.
In this paper, we have shown that intercalation of fenbufen in a layered double hydroxide followed by coating with enteric gives a composite material which shows
controlled release of the drug under in vitro conditions which model the passage of a material through the gastrointestinal tract. As the enteric coating we select Eudragit? L 100 and S 100, which have been widely used in this area. Those anionic copolymers of methacrylic acid and methyl methacrylate have a molecular weight of approximately 135,000 with a ratio of acid to ester of approximately 1:1 in Eudragit? L 100 and 1:2 in Eudragit? S 100. Both polymers are insoluble in aqueous acid solution but Eudragit? L 100 dissolves at pH 6 and above and Eudragit? L 100 at pH 7 and above. Work is underway in our laboratory to explore how the drug release characteristics may be modified by variation of the physicochemical properties of both the layered double hydroxide and the polymer coating.
引文
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