CN108440632B - 3,7,12-三（三甲胺基）-胆烷酸脑磷脂酰胺制备方法 - Google Patents
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Abstract
本发明涉及一种由胆酸、三甲胺盐酸盐和脑磷脂为原料制备改性脑磷脂。本发明首先以胆酸为原料，用对甲苯磺酰氯将其3，7，12位羟基取代，制备出3，7，12‑三(对甲苯磺酰基)‑胆烷酸，然后用三甲胺的氨基取代对甲苯磺酰基，生成3，7，12‑三(三甲胺基)‑胆烷酸。再将3，7，12‑三(三甲胺基)‑胆烷酸的24位羧基酰氯化，然后与脑磷脂的氨基进行酰胺化反应，生成3，7，12‑三(三甲胺基)‑胆烷酸脑磷脂酰胺。制备工艺简单，提供了一种制备用于肝胆主动靶向脂质体的改性脑磷脂的新方法。
Description
技术领域
本发明属药物制剂及其辅料领域，特别是涉及一种由胆酸、三甲胺盐酸盐和脑磷脂(DSPE： 1，2-二硬酯酸-3-磷酯酰乙醇胺)为原料制备的用于脂质体的改性磷脂的制备方法。
背景技术
脂质体是将药物包封于类脂质双分子层内而形成的微型囊泡，国内外已上市的脂质体药物品种多为抗癌药物，抗癌药物脂质体是脂质体最重要的应用，近几年世界脂质体产品销售额增长率快速上升。
将药物包封成脂质体，可延长药物在血液中的滞留时间，使药物在体内缓慢释放，从而延长药物的作用时间。脂质体是类似生物膜结构的泡囊，具有很好的细胞亲和性与组织相容性，可长时间吸附于靶细胞周围，使药物能充分向靶细胞渗透，也可通过融合使药物进入靶细胞内。药物被脂质体包封后，主要被单核一巨噬细胞系统的巨噬细胞所吞噬而摄取，且在肝、脾和骨髓等单核-巨噬细胞较丰富的器官中浓集，而使药物在心、肾中累积量比游离药物低得多。如果将对心、肾有毒性的药物或对正常细胞有毒性的抗癌药物包封成脂质体，就可明显降低药物的毒性。另外一些不稳定的药物被脂质体包封后可受到脂质体双层膜的保护。如青霉素G或V的钾盐是对酸不稳定的抗生素，口服易被胃酸破坏，制成脂质体则可减少胃酸对其的破坏，提高口服的吸收效果。脂质体可以同时装载水溶性和脂溶性药物，药物以非共价键结合的方式被包裹，有利于药物释放。
制备脂质体的原料主要是天然或合成磷脂，在所有天然磷脂和合成磷脂中，由于脑磷脂头部基团小，容易形成非双层结构，比如形成六角相。因此通过增加极性基团体积对脑磷脂进行改性，可以得到能够形成磷脂双层结构的脂质体。
胆酸对肝胆具有良好的靶向性，且胆酸的3、7、12羟基及24位羧基被取代后，对其肝胆靶向性的影响不大。胆酸的3、7、12羟基被三甲胺取代后，通过24位羧基与脑磷脂的氨基进行酰胺化，制备出一种醇溶性较好的改性脑磷脂。
发明内容
本发明首先以胆酸为原料，用对甲苯磺酰氯将其3，7，12位羟基取代，制备出3，7，12 三(对甲苯磺酰基)-胆烷酸，然后用三甲胺的氨基取代对甲苯磺酰基，生成3，7，12-三(三甲胺)基-胆烷酸。然后将3，7，12-三(三甲胺基)-胆烷酸的24位羧基酰氯化，再与脑磷脂的氨基进行酰胺化反应，生成3，7，12-三(三甲胺基)-胆烷酸脑磷脂酰胺。
具体实施方式
实施例1
(1)3，7，12-三(三甲胺基)-胆烷酸的制备
于250ml反应瓶中，将0.01mol胆酸溶解于100ml氯仿和DMF的1∶1混合溶剂中，降温至0℃，分批加入0.03mol对甲苯磺酸氯，搅拌溶解，25℃下搅拌反应5小时，加入100ml 无水乙醇，有白色固体析出，过滤，无水乙醇洗涤三次，真空干燥；将0.03mol三甲胺盐酸盐溶解于100ml蒸馏水中，加热至80℃，搅拌下分批加入上述固体粉末，同时逐渐滴加10％的氢氧化钠溶液，使溶液保持在pH为8.0，需2小时，然后80℃保温反应3小时，冷却至室温，乙酸中和至pH值为7，蒸馏，浓缩，冷却，结晶，过滤，无水乙醇洗涤3次，真空干燥，得浅黄色固体粉末，备用；
(2)3，7，12-三(三甲胺基)-胆烷酰氯的制备
将上述(1)的产物溶解于100ml氯仿中，加入1.00gDMF，搅拌均匀，25℃下，将0.004mol 三光气溶于10ml氯仿中，然后搅拌下将三光气氯仿溶液缓慢滴入，需1小时。然后升温至 60℃，搅拌反应3小时，冷却至室温，得浅黄色液体，备用；
(3)3，7，12-三(三甲胺基)-胆烷酸脑磷脂酰胺的制备
在上述反应瓶中，将0.01mol脑磷脂分批加入，搅拌溶解，升温至60℃，搅拌反应5小时，减压蒸馏，蒸去氯仿，加入50ml无水乙醇，得褐色固体粉末，无水乙醇洗涤3次，真空干燥。
实施例2
分别用薄膜分散法和乙醚注入法制备脂质体，结果见表1。
(1)薄膜分散法：
将5g上述实施例1中制备的脂质溶解于100ml氯仿中，制备出脂质的氯仿溶液，旋转蒸发器减压蒸发，除去氯仿，器壁生成薄膜，然后加入100ml0.5％的磷酸盐缓冲溶液，振摇， 20KHz超声波分散1h，生成脂质体。电子显微镜测定脂质体粒径，并观察其形貌，测定其Zeta 电位。
(2)乙醚注入法：
取1g上述实施例1中制备的脂质溶于10ml乙醚液，细孔针头慢慢注入55～60℃的50ml0.5％的磷酸盐缓冲液中；放置2h，蒸发去乙醚，生成脂质体。电子显微镜测定脂质体粒径，并观察其形貌，测定其Zeta电位。
实施例3
分别将实施例2中薄膜分散法制备的多室脂质体和乙醚注入法制备的单室脂质体置于洁净的载玻片上，用熔点测定仪测定脂质体发生形变和坍塌时的温度。见表1。
表1实施例1制备的改性磷脂生成的脂质体的物理性能
Claims (1)
1.一种以胆酸、三甲胺、脑磷脂为原料制备改性脑磷脂的方法，包括下列步骤：
(1)3，7，12-三(三甲胺基)-胆烷酸的制备
于250ml反应瓶中，将0.01mol胆酸溶解于100ml氯仿和DMF的1∶1混合溶剂中，降温至0℃，分批加入0.03mol对甲苯磺酸氯，搅拌溶解，25℃下搅拌反应5小时，加入100ml无水乙醇，有白色固体析出，过滤，无水乙醇洗涤三次，真空干燥；将0.03mol三甲胺盐酸盐溶解于100ml蒸馏水中，加热至80℃，搅拌下分批加入上述固体粉末，同时逐渐滴加10％的氢氧化钠溶液，使溶液保持在pH为8.0，需2小时，然后80℃保温反应3小时，冷却至室温，乙酸中和至pH值为7，蒸馏，浓缩，冷却，结晶，过滤，无水乙醇洗涤3次，真空干燥，得浅黄色固体粉末，备用；
(2)3，7，12-三(三甲胺基)-胆烷酰氯的制备
将上述(1)的产物溶解于100ml氯仿中，加入1.00gDMF，搅拌均匀，25℃下，将0.004mol三光气溶于10ml氯仿中，然后搅拌下将三光气氯仿溶液缓慢滴入，需1小时， 然后升温至60℃，搅拌反应3小时，冷却至室温，得浅黄色液体，备用；
(3)3，7，12-三(三甲胺基)-胆烷酸脑磷脂酰胺的制备
在上述反应瓶中，将0.01mol脑磷脂分批加入，搅拌溶解，升温至60℃，搅拌反应5小时，减压蒸馏，蒸去氯仿，加入50ml无水乙醇，得褐色固体粉末，无水乙醇洗涤3次，真空干燥。
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