CN109180840A - 一类酸敏感型环糊精及其制备方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
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Abstract
本发明公开了一类酸敏感型β环糊精及其制备方法,酸敏感型环糊精结构式如下:
Description
技术领域
本发明属于医药用材料领域,具体涉及一类具有水溶性、又具有酸敏感的酸敏感型β环糊精及其制备方法。
背景技术
近年来,刺激响应型药物载体,在药物输送方面的研究越来越引起人们的关注。一般而言,刺激因素可分为内源性和外源性两类,而其中的内源性刺激因子指的是生物体内部环境因素包括生物介质中的pH值、某种离子强度、温度以及特定化学物质的浓度水平变化等,因其特异性等优点而被广泛运用在生物医学研究中。
在生物体内,正常组织一旦病变,局部的生物内环境必定发生相应的变化,例如病变的肿瘤细胞内环境偏弱酸性,而正常细胞的pH偏高些。
环糊精(cyclodextrin)又名环链淀粉,是6~8个D-葡萄糖分子通过α-1, 4-糖苷键连接,互为椅式构象的环状化合物。而环糊精由七分子D-葡萄糖所组成的,环糊精分子呈环形圆筒状,外表面亲水而内腔疏水。环糊精的疏水内腔可与一些空间匹配的分子形成包合物,从而对这种被包合的分子进行改性,如提高稳定性以及水溶性;由于环糊精的这种性质,它被越来越多的利用在生物医药领域。
被胺基修饰的环糊精为构成环糊精分子的 D(+)- 吡喃葡萄糖 C6 的任意一个或几个羟基被胺基取代的环糊精,然后对胺基环糊精上的支链进行改造,与柠康酸酐进行酰化反应,从而得到酸敏感型环糊精。
目前已有报道用环糊精或胺基环糊精,羟丙基环糊精等衍生物与难溶性药物进行包合,但是利用这类酸敏感型的刺激响应因子进行改造的环糊精暂未见报道。
发明内容
本发明目的是提供一类水溶性极佳、具有pH响应的、没有毒副作用的新型药物载体酸敏感型环糊精,其结构式如下:
其中m=5~7;n=0~2; R1选自H、CH3;R2选自H、CH3;R1和R2不同时为CH3。
本发明得到的酸敏感型环糊精是一种水溶性极好的药物载体,它利用环糊精疏水性内腔可与一些空间结构匹配的,难溶性的药物形成包合物,从而对这种被包合的药物进行改性,提高药物的稳定性以及水溶性。目前有许多具有抗肿瘤的活性化合物具有不错的疗效,但是由于本身水溶性或稳定性欠佳的原因,很难单独成药,例如抗癌药物青蒿琥酯、双氢青篙素、灯盏花乙素以及喜树碱等;本发明旨在得到一种水溶性极佳、稳定性极佳、没有毒副作用的药物载体。
本发明另一目的是提供上述酸敏感型环糊精的制备方法,该聚合物由几种胺基衍生化的环糊精与柠康酸酐或马来酸酐进行反应,通过进一步改变其侧链得到酸敏感型环糊精。
本发明方法如下:
(1)将胺基衍生化的环糊精溶于蒸馏水中,混匀;
(2)将柠康酸酐的乙腈溶液或马来酸酐的乙腈溶液加入到步骤(1)溶液中,搅拌混匀后加入三乙胺,在25℃~45℃下搅拌反应4~12小时,其中柠康酸酐或马来酸酐与胺基衍生化的环糊精的摩尔比为4:1~12:1,三乙胺与胺基衍生化的环糊精的摩尔比为30~60:1;
(3)反应完毕后,在反应物中添加2~3mol/L的HCl进行酸化至反应物pH为5.5~7,再将反应物慢慢滴入其体积3~10倍的有机溶剂中,搅拌,析出沉淀后,过滤,滤渣用同样的有机溶剂洗涤3~4次,所得固体干燥,即为酸敏感型环糊精。
所述胺基衍生化的环糊精为胺基环糊精、乙二胺环糊精或二乙烯三胺环糊精,当n=0时,为胺基环糊精;当n=1时,为乙二胺环糊精;当n=2时,为二乙烯三胺环糊精。
所述步骤(3)中的有机溶剂为甲醇,乙醇或丙酮。
本发明酸敏感型环糊精在弱酸性条件下会发生裂解,裂解产物为两种物质,其结构如下:
其中m=5~7;n=0~2;R1选自H、CH3;R2选自H、CH3;R1和R2不同时为CH3。
本发明的优点和效果如下:
本发明提供的酸敏感型环糊精是在胺基衍生化的环糊精上对其进行支链改造,可作为一种水溶性极佳,而且具有酸敏感的、没有或低毒副作用的药物载体;其中环糊精的空腔可以包合一些水溶性差的药物形成包合物,以增加药物的水溶性;另外,该载体能特异性地在肿瘤细胞(PH 5-6)内释放药物,以提高难溶性抗癌药物的生物利用度;另一方面,本发明所述的酸敏感型环糊精的制备方法操作简单,反应条件温和,纯度高,可用于工业化生产。
附图说明
图1是酸敏感型胺基β-环糊精(R1=H, R2=CH3)的核磁共振氢谱(1H NMR)图;
图2是酸敏感型乙二胺β-环糊精A(R1=H,R2=H)的核磁共振氢谱(1H NMR)图;
图3是酸敏感型乙二胺β-环糊精B(R1=H, R2=CH3)的核磁共振氢谱(1H NMR)图;
图4是酸敏感型二乙烯三胺β-环糊精(R1=H,R2=H)的核磁共振氢谱(1H NMR)图;
图5是酸敏感型胺基β-环糊精(R1= CH3, R2= H)与双氢青蒿素包合的核磁共振氢谱(1HNMR)图。
具体实施方式
下面通过实施例对本发明作进一步详细说明,但本发明保护范围不局限于所述内容。
实施例1:本实施例酸敏感型环糊精结构如下:
其中m=6;n=0;R1=CH3, R2=H。
将0.4mmol胺基β-环糊精用13mL蒸馏水搅拌溶解,混匀后加入柠康酸酐的乙腈溶液(柠康酸酐3.6mmol),搅拌10min,再加入13mmol三乙胺溶液进行反应,在25℃下搅拌10h,反应完成后,用2mol/L HCl调节pH至6.5,再将反应液慢慢滴入其体积10倍的甲醇中搅拌,沉淀析出,离心过滤,滤渣用甲醇洗涤3次,在55℃下烘干,得到的白色固体即为酸敏感型胺基β-环糊精,收率62%。从图1酸敏感型胺基β-环糊精的核磁共振氢谱图可以看出该化合物制备成功。
采用本实施例中制备的胺基β-环糊精与双氢青蒿素进行包合:将酸敏感型胺基β-环糊精与双氢青蒿素(摩尔比为1:3)在水溶液中混合搅拌3天,用0.45μm微孔滤膜过滤,再将滤液低压蒸馏旋干,得到包合物,结果见图5,从图中可以看出双氢青蒿素在以氘代水为溶剂的核磁谱图中相应的峰,说明包合物制备成功。
实施例2:本实施例酸敏感型环糊精结构如下:
其中m=6;n=1; R1=H, R2=H。
将0.4mmol乙二胺β-环糊精用13mL蒸馏水搅拌溶解,混匀后加入马来酸酐的乙腈溶液(马来酸酐4mmol),搅拌10min,再加入15mmol三乙胺溶液进行反应,在40℃下搅拌5h,反应完成后,用2mol/L HCl调节pH至6,再将反应液慢慢滴入其体积6倍的乙醇中搅拌,沉淀析出,离心过滤,滤渣用乙醇洗涤4次,在55℃下烘干,得到的白色固体即为酸敏感型乙二胺γ-环糊精,收率55%;从图2酸敏感型乙二胺β-环糊精的核磁共振氢谱图可以看出该化合物制备成功。
实施例3:本实施例酸敏感型环糊精结构如下:
其中m=6;n=1; R1=H, R2=CH3。
将0.4mmol乙二胺β-环糊精用13mL蒸馏水搅拌溶解,混匀后加入柠康酸酐的乙腈溶液(柠康酸酐4mmol),搅拌10min,再加入15mmol三乙胺溶液进行反应,在40℃下搅拌5h,反应完成后,用2mol/L HCl调节pH至6,再将反应液慢慢滴入其体积6倍的乙醇中搅拌,沉淀析出,离心过滤,滤渣用乙醇洗涤4次,在55℃下烘干,得到的白色固体即为酸敏感型乙二胺γ-环糊精,收率50%;从图3酸敏感型胺基β-环糊精的核磁共振氢谱图可以看出该化合物制备成功。
实施例4:本实施例酸敏感型环糊精结构如下:
其中m=6;n=2; R1=H, R2=H。
0.4mmol二乙烯三胺β-环糊精用13mL蒸馏水搅拌溶解,混匀后加入马来酸酐的乙腈溶液(马来酸酐4.8mmol),搅拌10min,再加入15mmol三乙胺溶液进行反应,在30℃下搅拌5h,反应完成后,用2mol/L HCl调节pH至6,再将反应液慢慢滴入其体积7倍的乙醇中搅拌,沉淀析出,离心过滤,滤渣用乙醇洗涤4次,在55℃下烘干,得到的白色固体即为酸敏感型二乙烯三胺β-环糊精,收率40%;从图4酸敏感型二乙烯三胺β-环糊精的核磁共振氢谱图可以看出该化合物制备成功。
实施例5:本实施例酸敏感型环糊精结构如下:
其中m=5;n=0; R1=H, R2=CH3。
将0.4mmol胺基α-环糊精用13mL蒸馏水搅拌溶解,混匀后加入柠康酸酐的乙腈溶液(柠康酸酐1.6mmol),搅拌10min,再加入12.8mmol三乙胺溶液进行反应,在25℃下搅拌12h,反应完成后,用2mol/LHCl调节pH至6.5,再将反应液慢慢滴入其体积3倍的丙酮中搅拌,沉淀析出,离心过滤,滤渣用丙酮洗涤3次,在55℃下烘干,得到的白色固体即为酸敏感型胺基α-环糊精,收率32%。
实施例6:本实施例酸敏感型环糊精结构如下:
其中m=6;n=0; R1=H, R2=H;
将0.4mmol胺基β-环糊精用13mL蒸馏水搅拌溶解,混匀后加入马来酸酐的乙腈溶液(马来酸酐2mmol),搅拌10min,再加入16mmol三乙胺溶液进行反应,在35℃下搅拌8h,反应完成后,用2.5mol/L HCl调节pH至6,再将反应液慢慢滴入其体积5倍的丙酮中搅拌,沉淀析出,离心过滤,滤渣用丙酮洗涤4次,在55℃下烘干,得到的白色固体即为酸敏感型胺基β-环糊精,收率29%。
实施例7:本实施例酸敏感型环糊精结构如下:
其中m=7;n=0;R1=CH3, R2=H;
将0.4mmol胺基γ-环糊精用13mL蒸馏水搅拌溶解,混匀后加入柠康酸酐的乙腈溶液(柠康酸酐2.4mmol),搅拌10min,再加入20mmol三乙胺溶液进行反应,在45℃下搅拌4h,反应完成后,用2.5mol/L HCl调节pH至6,再将反应液慢慢滴入其体积5倍的甲醇中搅拌,沉淀析出,离心过滤,滤渣用甲醇洗涤4次,在55℃下烘干,得到的白色固体即为酸敏感型胺基γ-环糊精,收率42%。
实施例8:本实施例酸敏感型环糊精结构如下:
其中m=5;n=0;R1=CH3, R2=H。
将0.4mmol胺基α-环糊精用13mL蒸馏水搅拌溶解,混匀后加入马来酸酐的乙腈溶液(马来酸酐2.8mmol),搅拌10min,再加入23mmol三乙胺溶液进行反应,在45℃下搅拌4h,反应完成后,用3mol/L HCl调节pH至6,再将反应液慢慢滴入其体积8倍的甲醇中搅拌,沉淀析出,离心过滤,滤渣用甲醇洗涤4次,在55℃下烘干,得到的白色固体即为酸敏感型α-胺基环糊精,收率55%。
Claims (4)
1.结构式如下式所示的酸敏感型环糊精:
其中m=5~7;n=0~2;R1选自H、CH3;R2选自H、CH3;R1和R2不同时为CH3。
2.权利要求1所述酸敏感型环糊精的制备方法,其特征在于,步骤如下:
(1)将胺基衍生化的环糊精溶于蒸馏水中,混匀;
(2)将柠康酸酐的乙腈溶液或马来酸酐的乙腈溶液加入到步骤(1)溶液中,搅拌混匀后加入三乙胺,在25℃~45℃下搅拌反应4~12小时,其中柠康酸酐或马来酸酐与胺基衍生化的环糊精的摩尔比为4:1~12:1,三乙胺与胺基衍生化的环糊精的摩尔比为30:1~60:1;
(3)反应完毕后,在反应物中添加2~3mol/L的HCl进行酸化至反应物pH为5.5~7,再将反应物慢慢滴入其体积3~10倍的有机溶剂中,搅拌,析出沉淀后,过滤,滤渣用同样的有机溶剂洗涤3~4次,所得固体干燥,即为酸敏感型环糊精。
3.根据权利要求2所述的酸敏感型环糊精的制备方法,其特征在于:胺基衍生化的环糊精为胺基环糊精、乙二胺环糊精或二乙烯三胺环糊精。
4.根据权利要求2所述的酸敏感型环糊精的制备方法,其特征在于:步骤(3)中的有机溶剂为甲醇,乙醇或丙酮。
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