CN109481693B - 一种透明质酸-壬苯醇醚偶联物、制备方法及应用 - Google Patents
一种透明质酸-壬苯醇醚偶联物、制备方法及应用 Download PDFInfo
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Abstract
本发明公开了一种透明质酸‑壬苯醇醚偶联物、制备方法及应用。该透明质酸‑壬苯醇醚偶联物通过酯键连接透明质酸多糖及杀精药物壬苯醇醚，包括下列步骤：将透明质酸使用1‑(3‑二甲氨基丙基)‑3‑乙基碳二亚胺盐酸盐（EDCI）、4‑二甲氨基吡啶(DMAP)对透明质酸的羧基进行活化；将杀精药物壬苯醇醚使用4‑二甲氨基吡啶(DMAP)对杀精药物壬苯醇醚的羟基进行活化；将活化后的杀精药物与a步骤所得溶液混合进行控温反应，经后处理，即制备得到相应的透明质酸‑壬苯醇醚偶联物。本发明提供的透明质酸‑壬苯醇醚偶联物，具有温和、缓释、靶向的作用，不但可以实现更高效的杀精，且可以降低女性的不良反应，达到更佳的避孕效果。
Description
技术领域
本发明属于药物制剂领域，涉及一种具备良好生理活性和生物可降解性的透明质酸-壬苯醇醚偶联物，其作为高分子前体药物，本发明还涉及该偶联物的制备方法及其应用。
背景技术
外用杀精剂因具有不干扰内分泌功能，不给人体造成损伤，使用方便等的特点，一直受到育龄夫妇的欢迎。
壬苯醇醚的杀精活性是由药物分子直接损伤精子细胞膜的脂蛋白，导致膜的通透性增加，细胞内容物漏出引起精子制动最后死亡，用含有壬苯醇醚的膜剂处理过的人类精子失去原来的光泽感，表面变得高低不平，精子头部的脂膜，顶体部受到不同程度的破坏，并造成细胞内酶的泄露形成空泡样，线粒体鞘膜的部分消失，精子鞭毛的中段有断裂现象，甚至引起严重缺失，仅以纵行的轴丝相连。
而使用其后的妊娠率高于其他长效避孕措施，避孕效果较差，因其释放较快，没有选择性，导致局部浓度过大，会对女性生殖道上皮细胞造成一定的刺激，引起激惹，不适，存在约70％以上的女性在使用后出现局部瘙痒等症状。
药物-高分子偶联物广泛地应用于抗肿瘤、抗炎等领域，可以达到良好的增溶、靶向、缓控释的作用。作为生命有机体的重要组成部分的多糖，在控制细胞分裂、调节细胞生长以及维持生命有机体正常代谢等方面有有重要作用，同时，多糖具有优良的生物相容性并能够在生物体中酶解成易被活体吸收、无毒副作用的小分子物质，此外多糖的主链结构还有大量地氨基和羧基，易于化学修饰(如酰化、接枝与交联等)而改善其理化性质。故将多糖与药物分子进行偶联，具有其他高分子材料无法比拟的优势。却鲜见报道，将杀精药物与多糖偶联作为避孕的前体高分子药物应用。
发明内容
针对以上问题，本发明的目的是提供一种具有增强杀精效果、降低刺激性、延长作用时间且生物可降解的透明质酸-壬苯醇醚偶联物。该偶联物在水介质中可溶解，并可吸收大量水分，该偶联物制备工艺简单，具有良好的工业化生产潜力以及市场前景。
本发明的另一个目的是提供上述透明质酸-壬苯醇醚偶联物的制备方法及其在制药中的应用。
为达到上述目的，本发明提供一种新型的透明质酸-壬苯醇醚偶联物，该偶联物是在透明质酸(多糖分子)的羧基或衍生化形成的羧基上，通过酯化反应与杀精药物的羟基进行接合，使其具有高度的亲水性、靶向性、安全性、生物相容性。以透明质酸为骨架，透明质酸的羧基或透明质酸经衍生化形成的羧基与杀精药物壬苯醇醚的羟基反应而形成所述的透明质酸-壬苯醇醚偶联物。
所述的透明质酸-壬苯醇醚偶联物，其中选用的透明质酸，其分子量可选用3000DA至200000DA。
所述的透明质酸-壬苯醇醚偶联物的制备方法，包括下列步骤：
将适量透明质酸溶于第一溶剂中，使用1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、4-二甲氨基吡啶(DMAP)对多糖物质的羧基进行活化，将适量壬苯醇醚溶于第二溶剂中，使用4-二甲氨基吡啶(DMAP)对壬苯醇醚的羟基进行活化，将其与透明质酸溶液混合进行反应。
所述的制备方法，透明质酸所用第一溶剂优选自甲醇、乙腈、丙酮、水、或水：甲醇、水：乙腈、水：丙酮的混合溶剂。
所述的制备方法，壬苯醇醚所用第二溶剂优选自水、乙腈、甲醇、丙酮的一种或几种。
具体方案如下：
在含羧基或经衍生化形成含羧基的透明质酸分子链上引入壬苯醇醚，使其具有的亲水性、靶向性、生物相容性，实现杀精药物的靶向缓释，提高杀精效果，降低妊娠率，减少刺激性。因此这种透明质酸-壬苯醇醚偶联物可以作为一类优秀的杀精高分子前体药物，可用于制备成膜剂、栓剂进行外用给药。
透明质酸-壬苯醇醚偶联物的合成制备方法详细说明如下：
一、透明质酸-壬苯醇醚偶联物的制备
a.将透明质酸溶于第一溶剂中，使用1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、4-二甲氨基吡啶(DMAP)对多糖物质的羧基进行活化。
b.将适量壬苯醇醚溶于第二溶剂中，使用4-二甲氨基吡啶(DMAP)对壬苯醇醚的羟基进行活化。
c.将步骤a步骤b所得溶液混合，加入反应溶剂(水/甲醇混合物)，控温进行反应(使羧基与羟基反应形成酯键)，使用透析法除去未反应的小分子、催化剂(此为后处理步骤)等。
所述合成路线如下：
上述透明质酸-壬苯醇醚偶联物的制备方法中：步骤a所述溶剂优选为甲醇、乙腈、丙酮、水、或水/甲醇、水/乙腈、水/丙酮的混合溶剂，更优选为水/甲醇混合溶剂。
步骤b所述的溶剂优选为水、乙腈、甲醇、丙酮，更优选为甲醇。
步骤c所述a和b的混合溶液，其中透明质酸与壬苯醇醚的质量比优选为1～20:1，优选为1～8:1，更优选为4:1，步骤c所述控温反应，其温度为40℃～80℃。
相对于现有技术，本发明的有益效果：
一、本发明以透明质酸多糖与杀精药物壬苯醇醚缩合，得到一种高分子前体药物，其制备方法简单经济，容易实现工业化生产，条件温和、产率高；
二、本发明提供的透明质酸-壬苯醇醚偶联物，具有温和、缓释、靶向的作用，不但可以实现更高效的杀精，且可以降低女性的不良反应，达到更佳的避孕效果；
三、本发明提供的透明质酸-壬苯醇醚偶联物可以用作膜剂、栓剂等的活性成分，具有良好的生物安全性。
具体实施方式
下面通过实施例对本发明加以进一步的说明，但下述实施例并不限制本专利的权利范围。
实施例1：透明质酸-壬苯醇醚偶联物的合成
取1000mg透明质酸溶于1mmol的EDCI、1mmol的DMAP溶于100ml甲醇/ 水混合溶液(水：甲醇体积比为2:1)中，搅拌活化0.5h。取250mg壬苯醇醚、1mmol 的DMAP溶于30ml甲醇中，搅拌活化0.5h。氮气保护下，40℃反应12h，然后温度升至60℃，反应36h。反应结束后，收集溶液，置于透析袋中，透析72h提纯除杂，每8h更换透析液。除杂结束后，冷冻干燥得透明质酸-壬苯醇醚偶联物。
实施例2：透明质酸-壬苯醇醚偶联物的表征
表1和表2分别说明了不同溶剂对透明质酸-壬苯醇醚偶联物的粒径及产率影响以及不同多糖杀精药物质量比对接枝率的影响。
表1.不同溶剂对透明质酸-壬苯醇醚偶联物的粒径及产率影响
表2.不同多糖杀精药物质量比对接枝率的影响
实施例3：壬苯醇醚-透明质酸偶联物应用于膜剂制备
称取壬苯醇醚-透明质酸偶联物(约含壬苯醇醚1g)，甘油1g，置于烧杯中，加入20ml蒸馏水，微热、搅拌至溶解，放置冷却至室温。称取聚乙烯醇0486 7.5g，加入前述体系，放置过夜。待聚乙烯醇完全润湿膨胀后，置于水浴锅加热至完全溶解，保温静置超声脱气，将膜料倒入同温度玻璃板下沿，用推杆推动膜剂，移至烘箱，70℃鼓风干燥5～10min后脱膜，切成5cm*5cm的薄膜，备用。
同法制备壬苯醇醚膜、基质膜，供后续体内实验研究。
实施例4：体内杀精实验
将家兔按设计随机分为4组，分别为空白对照组，壬苯醇醚-透明质酸偶联物膜剂组，壬苯醇醚膜剂组，基质对照组，每组2只动物(雌雄各半)。将动情期雌兔置于仰卧位，使用特制塑料管插入家兔阴道内8～9cm处，将剪碎的药膜置于管中，用管芯将药膜推至阴道底部。给药10min后，基质组、壬苯醇醚-透明质酸偶联物膜剂组、壬苯醇醚膜剂组进行交配。空白对照组不给予任何药物，进行交配。分别于交配后的5min，10min、15min、30min、60min，用棉签从阴道深部沾取液体，涂布与载玻片，于显微镜下观察精子活动情况。共观察十个视野，结果如表3所示，可见壬苯醇醚-透明质酸偶联物明显提高杀精效果，且短时间作用即实现杀精，杀精持续时间长。
表3.壬苯醇醚-透明质酸偶联物膜家兔体内杀精效果
+：观察10个视野有≥1个活动精子
-：观察10个视野无1个活动精子
本发明以天然多糖透明质酸为骨架，在透明质酸的羧基上通过简单的酯化反应与杀精药物壬苯醇醚进行偶联。由于透明质酸对于水分具有极佳的亲和力，本发明的杀精剂-多糖偶联物具有吸收精液、缓慢释放杀精药物的特点，并可通过多糖物质与精子细胞膜表面的受体结合，主动靶向至精子细胞膜，释放药物，可以提高避孕效果。
以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.一种透明质酸-壬苯醇醚偶联物的制备方法，其特征包括下列步骤：
a. 将透明质酸溶于第一溶剂中，使用1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐（EDCI）、4-二甲氨基吡啶(DMAP)对透明质酸的羧基进行活化；
b. 将杀精药物壬苯醇醚溶于第二溶剂中，使用4-二甲氨基吡啶(DMAP)对杀精药物壬苯醇醚的羟基进行活化；
c. 将活化后的杀精药物与a步骤所得溶液混合进行控温反应，经后处理，即制备得到相应的透明质酸-壬苯醇醚偶联物；
所述的第一溶剂选自甲醇、乙腈、丙酮、水、或水：甲醇、水：乙腈、水：丙酮的混合溶剂；
所述的第二溶剂为水、乙腈、甲醇、丙酮的一种或几种。
2.根据权利要求1所述的制备方法，其特征在于，所述的透明质酸分子量为3000 DA~200000 DA。
3.根据权利要求1所述的制备方法，其特征在于，步骤c中，透明质酸与壬苯醇醚的质量比为1~8:1；步骤c所述控温反应，其温度为40 ℃~80 ℃。
4.根据权利要求1所述的制备方法，其特征在于，所述的透明质酸-壬苯醇醚偶联物是通过酯键连接而成的结构。
5.一种透明质酸-壬苯醇醚偶联物，其特征在于，由权利要求1~4任一项方法制备而成。
6.包含权利要求5所述的透明质酸-壬苯醇醚偶联物的高分子前体药物或用于外用给药的药理活性分子。
7.权利要求5所述的透明质酸-壬苯醇醚偶联物在制备高分子前体药物或用于外用给药的药理活性分子中的应用。
8.根据权利要求7所述的应用，其特征在于，将透明质酸-壬苯醇醚偶联物制成膜剂或凝胶剂，用于腔道给药。
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