CN116785316A - 一种聚氧乙烯脂肪醇醚氨甲环酸酯或其组合物在硬化治疗中的应用 - Google Patents
一种聚氧乙烯脂肪醇醚氨甲环酸酯或其组合物在硬化治疗中的应用 Download PDFInfo
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- CN116785316A CN116785316A CN202310747349.0A CN202310747349A CN116785316A CN 116785316 A CN116785316 A CN 116785316A CN 202310747349 A CN202310747349 A CN 202310747349A CN 116785316 A CN116785316 A CN 116785316A
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- Prior art keywords
- fatty alcohol
- tranexamic acid
- alcohol ether
- polyoxyethylene fatty
- acid ester
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Abstract
一种聚氧乙烯脂肪醇醚氨甲环酸酯或其组合物在硬化治疗中的应用，属于医药技术领域，通过酯键的形式将聚氧乙烯脂肪醇醚类化合物的羟基和氨甲环酸的羧基相连接，构建硬化剂用于血管瘤及脉管畸形、静脉曲张硬化治疗。聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂在血液中酯酶的作用下降解生成的氨甲环酸可以抑制纤溶酶活性，稳定形成的血栓不被重新降解。聚氧乙烯脂肪醇醚氨甲环酸酯类具有发泡性质和形成原位凝胶的性质，以制备成泡沫制剂或原位凝胶制剂，作为治疗药物聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂的递送系统。聚氧乙烯脂肪醇醚氨甲环酸酯硬化剂体内降解性好，降解产生的聚氧乙烯脂肪醇醚和氨甲环酸在治疗剂量下体内安全性好。
Description
技术领域
本发明属于医药技术领域，具体涉及一种聚氧乙烯脂肪醇醚氨甲环酸酯或其组合物在硬化治疗中的应用以及制备方法。
背景技术
静脉系统疾病主要包括下肢、生殖系统的静脉曲张和静脉畸形。静脉疾病多为慢性疾病，并以较严重的临床症状困扰着患者，严重影响患者身体健康和生活质量；下肢浅静脉曲张是血管外科最常见的疾病，在成人中发病率达5％～15％；生殖静脉曲张是男性不育、女性盆腔淤血综合征的病因之一；静脉畸形(venous malformation，VM)是一种较为常见的先天性脉管发育畸形，发病率为0.01％～0.02％，体积较大的病灶可造成明显的外观畸形和功能障碍，如视野遮蔽、气道梗阻、进食困难、面部器官变形及关节功能障碍等。在过去的20年里随着超声检查的广泛应用，静脉曲张的治疗也随着经皮静脉窦消融技术的引入发生了巨大的变化，包括静脉内激光治疗、射频消融术和液体或泡沫硬化疗法。
手术治疗是治疗静脉曲张的有效手段，但是由于手术治疗操作复杂，并且术后会留下疤痕等缺点，使得患者顺应性差。因此，使用硬化剂治疗静脉曲张成为临床医生和患者的首选。硬化剂是一类具有血管内皮细胞毒性的化合物，注射进入病变血管后导致血管内皮细胞损伤，使病变血管生成血栓，进而纤维化，最终被机体清除，达到改善症状的目的。临床上使用的硬化剂主要有乙醇、平阳霉素、鱼肝油酸钠、十四烷基硫酸钠、聚多卡醇等。其中，十四烷基硫酸钠和聚多卡醇属于表面活性剂类硬化剂，具有发泡性质，能制备成泡沫制剂，可防止药物注射进血管以后被血液稀释并提高药物在病变部位的滞留时间。目前临床使用最多的表面活性剂类硬化剂是聚多卡醇。
聚多卡醇是FDA批准使用治疗静脉曲张的硬化剂，是一种聚氧乙烯脂肪醇醚类化合物，具有12个碳原子的直链烷基和由9个环氧乙烷单元组成的聚环氧乙烷链。其烷烃链疏水，聚环氧乙烷链亲水，因此聚多卡醇具有表面活性性质，能破坏血管内皮细胞膜稳定性，从而诱发血栓形成，达到破坏病变血管的目的。(Polidocanol for endovenous microfoamsclerosant therapy[J].Expert Opin Investig Drugs,2009,18(12):1919-1927.)
但是，聚多卡醇作用效果过于温和，单次注射聚多卡醇能改善病变部位，但不能完全治愈，患者需要多次注射聚多卡醇，治疗周期可达数年之久，并往往难以根治静脉曲张。
为解决该问题，文献报道(A Novel Compound Sclerosant:Polidocanol-Bleomycin Foam[J].DERMATOLOGIC SURGERY,2020,49(12):1524-4725)使用聚多卡醇和作用效果强的硬化剂，如乙醇或平阳霉素制备成泡沫制剂，通过聚多卡醇泡沫制剂的性质，置换一部分血液，能防止血液对药物的稀释，从而提高乙醇或平阳霉素在病变部位的滞留时间。
但是上述方法存在的问题是同时联合使用乙醇或平阳霉素这种硬化效果强的药物，其副作用比如局部疼痛、肿胀，组织坏死等也会更强。
其次，导致硬化剂作用效果不佳的一部分原因也是由于新形成的血栓可能会被纤溶酶重新溶解，导致效果不佳。
因此，亟需开发一种更加安全便捷有效的表面活性剂类硬化剂及其递送系统。
氨甲环酸又名凝血酸，其结构和赖氨酸相似，能竞争性结合纤溶酶活性结构域中的赖氨酸结合位点，并且其与位点的结合能力强于赖氨酸和位点的结合力，因此，氨甲环酸能几乎完全抑制纤溶酶的活性，进而阻止了纤溶酶对血栓中纤维蛋白的溶解(The Role ofPlasminogen Activator Inhibitor Type-1in Fibrosis[J].Seminars in Thrombosis&Hemostasis,2017.)。氨甲环酸临床上广泛用于急性或慢性、局限性或全身性原发性纤维蛋白溶解亢进所致的各种出血，以及黄褐斑的治疗，大规模的临床试验充分证实了氨甲环酸凝血作用的疗效。值得注意的是，氨甲环酸本身并不能激发凝血反应，只能对已产生的血栓起到保护作用，这也保证了氨甲环酸的体内安全性。氨甲环酸的分子结构中有一个羧基和一个氨基，其氨基和羧基会以内盐的形式存在，当将氨甲环酸的羧基通过酯键形式和聚氧乙烯脂肪醇醚的羟基相连以后，新合成的聚氧乙烯脂肪醇醚氨甲环酸酯的末端会暴露氨甲环酸的氨基，使得新合成的化合物表现出阳离子表面活性剂的性质，因此其对血管内皮细胞的细胞毒性会显著增强。同时聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂的酯键在血液中降解并释放氨甲环酸，氨甲环酸可以抑制纤溶酶活性，防止血栓的溶解，对已经生成的血栓起到保护作用，最终促使血管纤维化从而导致血管闭锁，起到硬化治疗作用。
发明内容
本发明为克服现有表面活性剂类硬化剂药效不理想的缺陷，而提供了一种聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂及其自递送系统。即通过酯键的形式将聚氧乙烯脂肪醇醚类化合物的羟基和氨甲环酸的羧基相连接，构建硬化剂用于血管瘤及脉管畸形、静脉曲张硬化治疗中的应用。
本发明在血管硬化治疗实验中发现，将聚氧乙烯脂肪醇醚同氨甲环酸以酯键的形式相连接，构建成的阳离子表面活性剂具有显著的血管硬化效果。聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂具有良好血管硬化作用的机制为：破坏血管内皮细胞膜，使内皮细胞坏死，损伤血管壁，诱发血栓；同时聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂在血液中逐步代谢为氨甲环酸，氨甲环酸可以抑制纤溶酶原和纤溶酶的活性，防止血栓的溶解，对已经生成的血栓起到保护作用，最终使血管纤维化从而导致血管闭锁，起到硬化治疗作用。本发明实现了以“血管损伤-纤溶抑制”双重机制对需要硬化的脉管系统进行强力干预，增加了血栓的紧实性、稳固性与持续性，在最短时间内实现了血管硬化治疗作用。聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂是一种在血管瘤、脉管畸形以及静脉曲张的硬化治疗中具有极大治疗潜力的药物化合物。
聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂具有发泡性质，可以制备成泡沫剂给药；另外，聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂也具有接触水溶液后形成凝胶的性质，可以制备成原位凝胶制剂，不需要任何其他辅料辅助成型，就可以作为治疗药物聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂的自递送载体系统，极大地减少了非活性物质带来的潜在副作用和增加了血管硬化治疗靶部位的精准性和方便性，这一发现尚未有报道。
本发明的首要目的是提供一种聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐在硬化治疗中制备硬化剂的应用。
本发明的次要目的是提供一种聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐在制备治疗血管瘤、脉管畸形和下肢、生殖系统静脉曲张的药物中的应用。
本发明提供了一种聚氧乙烯脂肪醇醚氨甲环酸酯在药学上可接受的盐的合成方法，包括如下步骤：
步骤一：对氨甲环酸上的羧基进行酰氯化；
步骤二：通过酯化反应将酰氯化的氨甲环酸连接到脂肪醇聚氧乙烯醚的羟基上；
步骤三：加入药学上可接受的酸获得聚氧乙烯脂肪醇醚氨甲环酸酯在药学上可接受的盐。
其中，步骤一中氨甲环酸酰氯化反应使用的溶剂是二氯甲烷、氯仿、二氯乙烷，或者是两种任意混合溶剂。氨甲环酸混悬液在冰浴中冷却至0℃，滴入氯化亚砜后逐渐升温至室温，继续反应8-12h。
步骤一中对氨甲环酸羧基的酰氯化方法，具体是氯化亚砜酰氯化、草酰氯酰氯化，或者是琥珀酸酯活化的方法。
步骤二中滴加的脂肪醇聚氧乙烯醚疏水片段是C12～C18直链或支链烃基，亲水片段由1～30个环氧乙烷加聚组成，优选为3～22，是含一种烃基链的化合物，或者是含两种及以上不同烃基链的混合物。
步骤三中制备在药学上可接受的盐，采用的酸选自盐酸、硫酸、磷酸、乳酸、苯磺酸、草酸、琥珀酸、柠檬酸、酒石酸。
所述聚氧乙烯脂肪醇醚氨甲环酸酯其药学上可接受的盐结构如下：
R为C12～C18直链烃基或支链烃基；重复单元数目n为亲水片段，由1～30个环氧乙烷加聚组成，优选为3～22，进一步优选为7～15；HA为酸根，包括盐酸、硫酸、磷酸、乳酸、苯磺酸、草酸、琥珀酸、柠檬酸、酒石酸酸根。
本发明还提供用于静脉曲张治疗的含聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂的制剂及其制备方法。
用于静脉曲张治疗的聚氧乙烯脂肪醇醚氨甲环酸酯类原位凝胶制剂，其特征在于，将聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐置于甘油缩甲醛、甘油或甘油缩甲醛-甘油混合溶剂中，搅拌至溶解；上述溶液注入血管遇到血液后溶剂迅速扩散，聚氧乙烯脂肪醇醚氨甲环酸酯自发形成原位凝胶，而发挥治疗作用，聚氧乙烯脂肪醇醚氨甲环酸酯的质量分数为0.1％～10％。凝胶制剂中还可以加入药学上可接受的辅料，所述辅料包括乙醇、丙二醇(优选1,2-丙二醇)、分子量小于1000的聚乙二醇(PEG)、植烷三醇，用量质量分数为0.1％～45％。
用于静脉曲张治疗的聚氧乙烯脂肪醇醚氨甲环酸酯类泡沫制剂，其特征在于，临用前制成泡沫剂型给药，将聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐单一化合物或多个化合物的混合物，按照质量分数为0.1％～10％溶解在生理盐水中，以三通阀装置连接两个分别含有上述溶液和空气的注射器，以气液比为4：1，经三通阀反复推拉20余次进行气液混合，直至形成稳定的泡沫。其中还可以加入药学上可接受的辅料，所述辅料包括乙醇、丙二醇(优选1,2-丙二醇)、甘油、泊洛沙姆188、分子量小于1000的聚乙二醇(PEG)，用量质量分数为0.1％～45％。
用于静脉曲张治疗的聚氧乙烯脂肪醇醚氨甲环酸酯类泡沫制剂的冻干型注射剂，临用前用灭菌注射用水或在特定溶剂将聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐溶解制成泡沫剂型给药，其特征在于，聚氧乙烯脂肪醇醚氨甲环酸酯的质量分数为0.1％～10％。特定溶剂由注射用水和药学上可接受的辅料组成，所述辅料包括乙醇、丙二醇(优选1,2-丙二醇)、甘油、泊洛沙姆188、分子量小于1000的聚乙二醇(PEG)，用量质量分数为0.1％～45％。
上述不同剂型中，所述聚氧乙烯脂肪醇醚氨甲环酸酯是单一聚氧乙烯脂肪醇醚氨甲环酸酯化合物或多个不同的聚氧乙烯脂肪醇醚氨甲环酸酯化合物的混合物。所述不同的聚氧乙烯脂肪醇醚氨甲环酸酯是由不同的脂肪醇聚氧乙烯醚制备得到的。
综上所述，本发明的优点及积极效果为：本发明所述的聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂是在临床上常用的聚氧乙烯脂肪醇醚类硬化剂上通过酯键连接小分子药物氨甲环酸，使其由非离子表面活性剂变为可降解的阳离子型表面活性剂，增强其对血管内皮细胞的杀伤作用。聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂在血液中酯酶的作用下降解生成的氨甲环酸可以抑制纤溶酶活性，稳定形成的血栓不被重新降解。聚氧乙烯脂肪醇醚氨甲环酸酯类具有发泡性质和形成原位凝胶的性质，以制备成泡沫制剂或原位凝胶制剂，作为治疗药物聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂的递送系统。另外，聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂体内降解性好，降解产生的聚氧乙烯脂肪醇醚和氨甲环酸在治疗剂量下体内安全性好。
附图说明
图1是本发明聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂的合成示意图。
图2是聚氧乙烯脂肪醇醚氨甲环酸酯的核磁共振氢谱。
图3是聚氧乙烯脂肪醇醚氨甲环酸酯泡沫制剂显微镜下照片。
图4是聚氧乙烯脂肪醇醚氨甲环酸酯原位凝胶制剂照片。
图5是聚氧乙烯脂肪醇醚氨甲环酸酯对人脐静脉畸形细胞的细胞毒性结果。
图6是聚氧乙烯脂肪醇醚氨甲环酸酯作用于人脐静脉畸形细胞LDH释放率。
图7是聚氧乙烯脂肪醇醚氨甲环酸酯在血清中的降解速率结果。
图8是聚氧乙烯脂肪醇醚氨甲环酸酯降解产物对纤溶酶抑制性结果。
图9是小鼠尾静脉注射聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂的药效结果。
图10是小鼠经聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂治疗后主要器官的H&E染色结果。
具体实施方式
下面结合附图和具体实施方法对本发明的具体实施方式做进一步详细描述。以下实施例或者附图用于说明本发明，但不用来限制本发明的范围。
实验试剂及仪器：氨甲环酸(武汉拉那白医药化工有限公司)；聚氧乙烯脂肪醇醚AEO3(上海麦克林生化科技有限公司)；聚氧乙烯脂肪醇醚AEO5(上海麦克林生化科技有限公司)；聚氧乙烯脂肪醇醚AEO7(上海麦克林生化科技有限公司)；聚氧乙烯脂肪醇醚AEO9(上海麦克林生化科技有限公司)；聚氧乙烯脂肪醇醚AEO12(上海麦克林生化科技有限公司)；聚氧乙烯脂肪醇醚AEO15(上海麦克林生化科技有限公司)；聚多卡醇(上海麦克林生化科技有限公司)；亚硫酰氯(山东西亚化学工业有限公司)；生理盐水(山东禹王有限公司)；2mL注射器(山东禹王有限公司)；三通阀(山东禹王有限公司)；DMEM培养基(美国Corning公司)；胰蛋白酶(美国Sigma-Aldrich公司)；青霉素链霉素(美国Gibco公司)；CCK-8(上海碧云天生物技术有限公司)；4％多聚甲醛(武汉赛维尔生物科技有限公司)。
实施例1
聚氧乙烯脂肪醇醚氨甲环酸酯(AEOx-TA)的合成及表征
聚氧乙烯脂肪醇醚氨甲环酸酯，简称AEOx-TA，其中脂肪醇部分为C12直链烷烃，x表示环氧乙烷加成数目，本发明以x＝3,5,7,9,12和15为例，其合成过程如图1所示。聚氧乙烯脂肪醇醚氨甲环酸酯的合成方法如下：在500mL三颈烧瓶中加入TA (6mmol)，加入二氯甲烷(200mL)作为溶剂。反应体系在冰浴下冷却30min，至温度达到0℃，在冰浴下缓慢加入7.2mmol的氯化亚砜，在25℃下持续反应12h。然后，分别缓慢加入8.4mmol的AEO3、AEO5、AEO7、AEO9、AEO12和AEO15，在室温下继续反应24h，减压脱除二氯甲烷，收集产物。粗产物经二氧化硅柱层析纯化，二氯甲烷/甲醇(90:10-20:80,v/v)洗脱，加压过滤，真空干燥过夜，得到产物(AEO3-TA、AEO5-TA、AEO7-TA、AEO9-TA、AEO12-TA和AEO15-TA)。
聚氧乙烯脂肪醇醚氨甲环酸酯核磁共振谱图如图2所示：
AEO3-TA:1H NMR(600MHz,D2O)δ4.71(s,4H),3.70-3.31(m,7H),3.39(d,J＝6.6Hz,1H),
2.82(d,J＝7.0Hz,1H),1.23(s,22H),0.91-0.69(m,3H).
AEO5-TA:1H NMR(600MHz,D2O)δ4.71(s,5H),3.69-3.37(m,14H),3.39(d,J＝6.6Hz,
1H),2.81(d,J＝6.9Hz,1H),1.22-1.10(m,24H),0.92(dd,J＝121.9,9.6Hz,3H).
AEO7-TA:1H NMR(600MHz,D2O)4.71(d,J＝3.1Hz,8H),3.64-3.56(m,19H),3.39(s,1H),
2.81(d,J＝6.0Hz,1H),1.48-1.09(m,22H),1.09-0.78(m,3H).
AEO9-TA:1H NMR(600MHz,D2O)δ4.71(s,5H),3.69-3.52(m,30H),3.39(t,J＝5.8Hz,
1H),2.81(d,J＝6.9Hz,1H),1.02(d,J＝12.5Hz,22H),0.83(t,J＝6.4Hz,3H).
AEO12-TA:1H NMR(600MHz,D2O)δ4.71(s,10H),3.67-3.43(m,37H),3.39(t,J＝5.8Hz,
1H),2.81(d,J＝7.0Hz,1H),1.23(s,22H),0.83(s,3H).
AEO15-TA:1H NMR(600MHz,D2O)δ4.71(s,7H),3.67-3.45(m,52H),3.39(s,1H),3.39(t,J＝5.8Hz,1H),2.81(d,J＝6.9Hz,1H),1.22(s,22H),0.82(t,J＝6.7Hz,3H).
实施例2
聚氧乙烯脂肪醇醚氨甲环酸酯泡沫硬化剂制备及表征
泡沫剂的制备方法如下：取AEO3-TA、AEO5-TA、AEO7-TA、AEO9-TA、AEO12-TA和AEO15-TA各30mg，分别加1g生理盐水溶解，在其中一支注射器内抽取均匀配制的0.2mL3％液体，另一支注射器内为0.8mL空气，按气液比4：1置于三通阀装置内，反复推拉20次，至形成稳定泡沫，即得。
泡沫剂的表征方法如下：在显微镜下观察和拍摄了最佳工艺和处方下的泡沫制备过程，并记录了泡沫直径分布。结果如图3所示。AEO3-TA不能形成泡沫，而AEO5-TA泡沫由于其不稳定性而产生许多大气泡。AEO7-TA和AEO9-TA制备的泡沫排列紧密，但泡沫大小不均匀，而AEO12-TA和AEO15-TA制备的泡沫排列紧密，泡沫大小均匀。泡沫颗粒大小的均匀性对泡沫的稳定性有很大的影响。当泡沫的大小不均匀时，小气泡就会变成大气泡，这样泡沫破裂的速度就会更快。当泡沫尺寸小而均匀时，泡沫的比表面积较大，更适合血管硬化治疗。
实施例3
聚氧乙烯脂肪醇醚氨甲环酸酯凝胶剂制备及表征
凝胶制剂制备方法如下：将30mg AEO3-TA、AEO5-TA、AEO7-TA、AEO9-TA、AEO12-TA和AEO15-TA分别置于1g甘油缩甲醛中，搅拌至溶解，利用通针性实验，筛选出具有通针性、可注射用的处方制剂；接着，将具有通针性的AEOx-TA溶液注射进入生理盐水溶液中，观察样品是否凝固。结果如图4所示，AEO3-TA、AEO5-TA难以形成稳定凝胶，推测是由于其亲水链长度较短，不能形成交联的网状结构，而AEO7-TA、AEO9-TA、AEO12-TA和AEO15-TA均能形成较为稳定的凝胶，并且随着亲水链长度的增加，其胶凝性增强，推测是由于亲水链增长导致凝胶网络交联程度增强，从而形成更加稳定的凝胶结构。
效果实施例1
细胞毒性分析
将人脐静脉畸形细胞(HUVEC-TIE2-L914F)以1×105的细胞密度接种于96孔板中，孵育过夜使细胞贴壁。第二天更换培养液，加入不同浓度的药物，继续孵育1h，之后按照CCK-8说明书的方法测定细胞活力。如图5所示，随着药物浓度的增加，AEOx-TA对HUVEC-TIE2-L914F细胞的细胞毒性逐渐增强。同时本研究发现，随着AEOx-TA亲水性片段的增加，细胞存活率逐渐降低，说明AEOx-TA类表面活性剂的细胞毒性随着亲水性的增加而显著增强。此外，AEO9与POL具有相同的结构。与POL组比较，AEO9-TA组HUVEC-TIE2-L914F的存活率明显降低。上述结果表明，阳离子表面活性剂AEOx-TA的细胞毒性强于非离子表面活性剂POL。这是因为阳离子表面活性剂可以通过静电吸引吸附在带负电的细胞膜表面。
效果实施例2
细胞膜损伤机理考察
HUVEC-TIE2-L914F细胞(1×103细胞/孔)接种于96孔板，孵育过夜，再与100μM的AEOx-TA孵育12h，无细胞组为阴性组，无AEOx-TA组为阳性组。阳性组给予乳酸脱氢酶释放试剂(LDH)处理，取上清液。其余各组用孔板离心机400g离心5min，每孔取上清120μL加入另一个96孔板。然后在490nm处测定吸光度。如图6所示，随着AEOx-TA亲水性的增加，细胞中LDH的释放量逐渐增加，这与CCK-8细胞毒性的结果相似，说明AEOx-TA对细胞的部分损伤来自于对细胞膜的损伤。
效果实施例3
酯键降解速率
为了研究AEOx-TA酯键的降解性，将AEOx-TA与10％的血清在37℃水浴中孵育。随后加入4倍体积的冰甲醇停止反应，15000g离心得到上清。采用HPLC-MS法测定TA含量。由图7可以看出，AEO3-TA和AEO5-TA降解缓慢，完全降解时间约为30min，AEO7-TA和AEO9-TA完全降解时间约为25min，而AEO12-TA和AEO15-TA在血清中完全降解时间分别约为20min和10min。这些结果表明，随着AEOx-TA亲水性链的生长，酯键的降解速率逐渐增加。
效果实施例4
纤溶酶抑制性考察
为了研究AEOx-TA降解产物TA对纤溶酶(PLA)的抑制作用，将10％血清降解15min的AEOx-TA产物与PLA溶液混合，再孵育12h，采用合成发光底物法测定PLA的活性。如图8所示，AEO3-TA、AEO5-TA、AEO7-TA、AEO9-TA、AEO12-TA、AEO15-TA对PLA活性的抑制作用分别为85％、72％、68％、56％、38％和26％，其中AEO15-TA对PLA的抑制作用最强。结果表明，AEOx-TA的降解产物具有对PLA活性的抑制作用，并且PLA活性的抑制率与AEOx-TA降解释放TA的速率成正比。纤溶酶活性的抑制有利于血管纤维化过程。
效果实施例5
体内血管硬化效果评估
试验选择8周大昆明鼠，每组6只鼠(雌鼠3只，雄鼠3只)，体重约20g，尾静脉注射0.1mL上述血管硬化剂溶液，经过14天治疗后采用0.5W LED灯照射尾静脉显影拍照，结果如图9所示，生理盐水中可以看到一条清晰的黑色尾静脉血管，经过TA治疗以后，对血管没有影响，仍然能看到尾静脉。而经过AEO15-TA泡沫制剂和AEO15-TA凝胶制剂治疗以后的小鼠尾静脉消失不见。以上药效学实验证明了本发明对血管瘤、脉管畸形和静脉曲张硬化治疗的有效性。
效果实施例6
体内安全性评估
试验选择8周大昆明鼠，每组6只鼠(雌鼠3只，雄鼠3只)，体重约20g，尾静脉注射0.1mL AEO15-TA泡沫剂和AEO15-TA凝胶剂，经过14天治疗后的昆明鼠安乐处死后取心肝脾肺肾进行H&E染色分析。结果见图10，AEO15-TA泡沫剂和AEO15-TA凝胶剂在治疗之后均没有对昆明鼠的主要器官造成损伤。这一结果的可能原因是，虽然聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂的细胞毒性显著增强，但是聚氧乙烯脂肪醇醚氨甲环酸酯类硬化剂在血液中酯酶的作用下会快速降解，降解产生的聚氧乙烯脂肪醇醚和氨甲环酸在给药剂量下均安全无毒，因此不会对机体造成毒性。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (9)
1.一种聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐在硬化治疗中制备硬化剂的应用。
2.一种聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐在制备治疗血管瘤、脉管畸形和下肢、生殖系统静脉曲张的药物中的应用。
3.如权利要求1或2所述的应用，其特征在于，所述聚氧乙烯脂肪醇醚氨甲环酸酯在药学上可接受的盐的结构如下：
R为C12～C18直链烃基或支链烃基；重复单元数目n为：3～22；HA为酸根，包括盐酸、硫酸、磷酸、乳酸、苯磺酸、草酸、琥珀酸、柠檬酸、酒石酸酸根。
4.如权利要求3所述的应用，其特征在于，所述聚氧乙烯脂肪醇醚氨甲环酸酯在药学上可接受的盐的制备方法：
步骤一：对氨甲环酸上的羧基进行酰氯化；具体是氯化亚砜酰氯化，草酰氯酰氯化，或者是琥珀酸酯活化；酰氯化反应使用的溶剂是二氯甲烷、氯仿、二氯乙烷，或者是两种任意比例的混合溶剂；
步骤二：通过酯化反应将酰氯化的氨甲环酸连接到脂肪醇聚氧乙烯醚的羟基上；
步骤三：加入药学上可接受的酸获得聚氧乙烯脂肪醇醚氨甲环酸酯在药学上可接受的盐。
5.如权利要求1或2所述的应用，其特征在于，所述聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐被制备成能够形成原位凝胶的有机溶液型注射剂；所述有机溶液型注射剂由聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐和注射用有机溶剂甘油缩甲醛、甘油或甘油缩甲醛-甘油混合溶剂组成，聚氧乙烯脂肪醇醚氨甲环酸酯的质量分数为0.1％～10％。
6.如权利要求5所述的应用，其特征在于，所述有机溶液型注射剂中加入药学上可接受的辅料，所述辅料包括乙醇、丙二醇、分子量小于1000的聚乙二醇、植烷三醇，用量质量分数为0.1％～45％。
7.如权利要求1或2所述的应用，其特征在于，所述聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐被制备成水溶液型注射剂，临用前制成泡沫剂型给药，聚氧乙烯脂肪醇醚氨甲环酸酯的质量分数为0.1％～10％。
8.如权利要求7所述的应用，其特征在于，所述水溶液型注射剂中加入药学上可接受的辅料，所述辅料包括乙醇、丙二醇、甘油、泊洛沙姆188、分子量小于1000的聚乙二醇，用量质量分数为0.1％～45％。
9.如权利要求1或2所述的应用，其特征在于，所述聚氧乙烯脂肪醇醚氨甲环酸酯或其药学上可接受的盐被制备成冻干型注射剂，临用前用灭菌注射用水或在特定溶剂溶解制成泡沫剂型给药，聚氧乙烯脂肪醇醚氨甲环酸酯的质量分数为0.1％～10％；所述特定溶剂由注射用水和药学上可接受的辅料组成，所述辅料包括乙醇、丙二醇、甘油、泊洛沙姆188、分子量小于1000的聚乙二醇，用量质量分数为0.1％～45％。
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