CN103356485A - 水蛭素白蛋白纳米粒及其制备方法 - Google Patents
水蛭素白蛋白纳米粒及其制备方法 Download PDFInfo
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- CN103356485A CN103356485A CN2012101078875A CN201210107887A CN103356485A CN 103356485 A CN103356485 A CN 103356485A CN 2012101078875 A CN2012101078875 A CN 2012101078875A CN 201210107887 A CN201210107887 A CN 201210107887A CN 103356485 A CN103356485 A CN 103356485A
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- Medicinal Preparation (AREA)
Abstract
本发明属于药物制剂领域,涉及一种水蛭素白蛋白纳米粒的制备方法。该水蛭素白蛋白纳米粒主要由水蛭素、白蛋白、脱水剂、交联剂组成。制备方法为改造的去溶剂化-交联法。本发明制备的水蛭素白蛋白纳米粒在体内具备缓释功能,可延长药物的体内循环时间,粒径在160nm左右,能延长水蛭素在体内的半衰期,提高疗效,提高了水蛭素的生物利用度,而且具有生物相容性好,易降解,包封率及载药量高等优点。
Description
技术领域
本发明涉及一种水蛭素白蛋白纳米粒及其制备方法。
背景技术
水蛭素是水蛭中主要的有效抗凝血成分。水蛭为环节动物水蛭科水蛭(Hirudo aipponicaWhitman)和蚂蝗(Whitmaniapigrauhitman)或柳叶蚂蝗(Whitmania acranulaata Whitman)等的全体。水蛭素为一种氨基酸多肽由65个氨基酸残基组成,具抗凝活性。其N端含有3个二硫键,是核心区域,具疏水性,是凝血酶的活性位点。尾部C端含有较多的酸性氨基酸,为阻止凝血酶与纤维蛋白原的识别位点,产生抗凝作用。中部是水蛭素与凝血酶结合的催化位点。63位酪氨酸的硫酸化提高了水蛭素与凝血酶的结合能力,增强了其抗凝作用的特异性。通过系统查阅了有关水蛭素剂型研究、药理作用、临床应用等方面的文献报道,发现水蛭素的抗凝和抗血栓作用存在着剂量和时间的依赖性,目前临床应用最广泛的水蛭注射液半衰期短,水蛭素从血浆消除较快,其消除半衰期在多数动物种属不到1h。若能研制出水蛭素缓释制剂,延长水蛭素在体内的循环时间,从而达到更高的治疗效果,这无疑是水蛭素制剂的一大突破性进展。
临床研究表明水蛭素的主要药理作用有:(1)抗凝作用:水蛭中发现了多种物质,它们在凝血机制的不同环节起抑制作用,如凝血酶抑制剂水蛭素变异体家族、凝血因子Xa抑制剂antistasin、ghilanten;凝血因子VIII抑制剂;血小板糖蛋白抑制剂decorsin、ornatin;胶原诱导血小板聚集抑制剂Calin、Lapp等;(2)抗血栓作用:血管内血栓的形成,最根本的过程是由凝血酶引起的凝血作用。水蛭有直接溶解血栓的作用,它不仅可以与血浆中游离的凝血酶结合,还可中和与纤维蛋白结合的凝血酶,故水蛭素对各种血栓病有效,尤其对弥漫性血管内凝血作用显著;(3)抗肿瘤作用:水蛭的高抗凝作用作用有利于抗癌药理活性物质(如锰、镁、锌等元素)及免疫活性细胞侵入癌组织而杀伤癌细胞;(4)降血脂作用:动物实验表明,水蛭能显著降低高脂动物的血清胆固醇、甘油三酯、低密度脂蛋白,并提高高密度脂蛋白水平;(5)对脑血肿、皮下血肿作用:实验证明,凝血酶是神经毒性介质之一,低剂量能保护神经元和胶质细胞免受低血糖、缺血等损伤导致的细胞死亡,大剂量则可导致脑水肿,脑细胞不可逆损伤及脑细胞凋亡。目前该药临床主要用于抗凝抗血栓,其他临床应用较少。
水蛭素在体内半衰期短,导致该药口服生物利用度低,大大影响了水蛭素的治疗效果。水蛭素制剂工艺问题是制约水蛭素深入研究的主要障碍,如何通过制剂新技术延长水蛭素在体内的循环时间是对水蛭素进行深入研究的关键。水蛭素作为一种长期使用的药物,临床需要一种给药次数少、生物利用度高、稳定性好、制备简单的有利于患者使用的制剂。
纳米粒(nanoparticles)是利用天然高分子或合成的化学物质为载体制成的载药微粒,直径10~1000nm,当纳米粒的尺度达到纳米数量级时,由于量子尺寸效应、表面效应和宏观量子隧道效应,可展现出许多特有的性质。纳米粒具有靶向性,能直接向靶器官、靶细胞或细胞内靶结构输送药物,同时具有缓释、保护药物、提高疗效、降低毒副作用等优点
白蛋白纳米粒(albumin nanoparticle)是近年来正在发展的一种新型纳米粒给药系统,是一种由白蛋白制备而成的纳米颗粒。由于其稳定性较好,具有缓释作用,白蛋白纳米粒作为抗凝药物的载体具有广阔的应用前景和美好未来。把水蛭素制成白蛋白纳米粒(Albuminnanoparticle),可大大延长药物体内循环时间,从理论上和剂型上解决水蛭素的缓释性问题。本研究采用白蛋白材料,白蛋白材料具有安全无毒、无免疫原性、可生物降解、生物相容性好等优点,白蛋白纳米粒是以白蛋白为基质的纳米级微粒,而纳米粒载体系统又以其缓控释特性和保护药物作用,为其进一步应用展示了广阔的前景。白蛋白纳米粒与其它胶体载体系统如脂质体相比,白蛋白纳米粒具有更好的储存稳定性,并且释药性的可控性更好。
综上所述,将水蛭素制成水蛭素白蛋白纳米粒,预期可以达到延长药物作用时间、提高药物抗凝血效果等目的。虽然将药物制成纳米粒是常规的技术手段,但要研制出一种具有疗效好、释药可控、生物相容性好、稳定等优点的配方及制备方法并不是很容易的,需要付出创造性劳动,进行大量的试验和条件筛选。
发明内容
针对上述现有技术,本发明提供了一种水蛭素的新剂型,即:水蛭素白蛋白纳米粒,该制剂使水蛭素具有更高的化学稳定性,延长其半衰期;生物相容性好、稳定、释药可控,并提高了生物利用度。
本发明还提供了该水蛭素白蛋白纳米粒的制备方法,该方法可采用常规的工艺设备,制备周期短,操作简单。
本发明是通过以下技术方案实现的:
一种水蛭素白蛋白纳米粒,主要是由水蛭素、白蛋白载体、脱水剂、交联剂和注射用水组成的,以100ml纳米脂质载体制剂计,其组成如下:
优选的,以100ml纳米脂质载体制剂计,其组成如下:
所述白蛋白载体为牛血清蛋白(BSA)或人血清蛋白(HSA)任一种或任意组合。
所述脱水剂为无水乙醇。
所述交联剂为2.5%戊二醛。
所述附加剂为渗透压调节剂、金属离子络合剂、抗氧剂或防腐剂中的任一种或任意组合。所述附加剂可起到增加制剂稳定性、调节渗透压、抗氧化等作用。
所述渗透压调节剂包括丙二醇、丙三醇、甘露醇等。
所述金属离子络合剂包括EDTA、乙二铵四乙酸二钠盐等。
所述抗氧剂包括维生素C、维生素E等。
所述防腐剂包括苯扎溴铵、对羟基苯甲酸酯类、山梨酸等。
水蛭素白蛋白纳米粒的制备方法,包括以下步骤:
(1)分别取白蛋白、水蛭素置于锥形瓶中,加入10ml蒸馏水,超声溶解;
(2)于25℃的水浴中在800r/min转速下搅拌,以1.0ml/min向锥形瓶中滴加无水乙醇,发现出现乳白色乳光;
(3)滴加完乙醇后,加入2.5%的戊二醛;
(4)降低搅拌速度,于600r/min下固化12h,减压浓缩除乙醇,得到水蛭素白蛋白纳米粒。
还包括以下步骤:将制得的水蛭素白蛋白纳米粒进一步加入冻干保护剂,以制成冻干制剂。其中,对所制得的水蛭素白蛋白纳米粒进行冻干处理的工艺可为:将1~10wt%(重量比)的冻干保护剂溶于水蛭素白蛋白纳米混悬液中,然后分装于西林瓶中,置-80℃的超低温冰箱中预冻24h,取出,迅速移入冷冻干燥机中,冻干48h,加塞密封即可。
所述冻干保护剂为乳糖、葡萄糖、甘露醇、蔗糖、海藻糖、右旋糖苷或山梨醇中的任一种或任意组合。
本发明具有以下优点:
(1)木发明的水蛭素白蛋白纳米粒生物相容性好,能提高水蛭素在体内的半衰期,提高了水蛭素的抗凝效果,达到更好的治疗效果(参见图7)。
(2)本发明的水蛭素白蛋白纳米粒粒径在164nm左右,且在体内具备缓释功能,可延长药物的体内循环时间。采用透析法测定药物的体外释放度,结果显示纳米脂质载体表现出明显的缓释特点(参见图4)。
(3)本发明的工艺为改造的去溶剂化-交联法,具有制备工艺简单,成本低,工艺参数易于控制等特点。
附图说明
图1为水蛭素白蛋白纳米粒透射电镜图;
图2为水蛭素白蛋白纳米粒透射电镜图;
图3为水蛭素白蛋白纳米粒粒径分布图;其中,标题:粒径分布(Size distribution(s),横坐标:粒径(Diameter),纵坐标:百分率(%in class);
图4为水蛭素白蛋白纳米粒体外释放的释放百分率-时间曲线。
图5为水蛭素白蛋白纳米粒的DSC图谱。
图6为水蛭素白蛋白纳米粒X-射线衍射图谱
图7为水蛭素白蛋白纳米粒凝血酶时间与正常值百分比-时间曲线
具体实施方式
下面结合具体实施例对本发明做进一步的阐述,但本发明不局限于这些实施例。
实施例1制备水蛭素白蛋白纳米粒
步骤如下:(1)分别取白蛋白80mg、水蛭素20mg置于锥形瓶中,加入10ml蒸馏水,超声溶解;(2)于25℃的水浴中在800r/min转速下搅拌,以1.0ml/min向锥形瓶中滴加无水乙醇30ml,发现出现乳白色乳光;(3)滴加完乙醇后,加入2.5%的戊二醛20μul;(4)降低搅拌速度,于600r/min下固化12h,减压浓缩除乙醇,得到水蛭素白蛋白纳米粒。
实施例2制备水蛭素白蛋白纳米粒
步骤如下:(1)分别取白蛋白70mg、水蛭素30mg置于锥形瓶中,加入10ml蒸馏水,超声溶解;(2)于25℃的水浴中在800r/min转速下搅拌,以1.0ml/min向锥形瓶中滴加无水乙醇30ml,发现出现乳白色乳光;(3)滴加完乙醇后,加入2.5%的戊二醛30μl;(4)降低搅拌速度,于600r/min下固化12h,减压浓缩除乙醇,得到水蛭素白蛋白纳米粒。
用水稀释后,以H-7000型透射电子显微镜观测其形态,如图1所示。由图1可知,所得水蛭素白蛋白纳米粒大小均一、形态圆整。
实施例3制备水蛭素白蛋白纳米粒
步骤如下:(1)分别取白蛋白75mg、水蛭素25mg置于锥形瓶中,加入10ml蒸馏水,超声溶解;(2)于25℃的水浴中在800r/min转速下搅拌,以1.0ml/min向锥形瓶中滴加无水乙醇30ml,发现出现乳白色乳光;(3)滴加完乙醇后,加入2.5%的戊二醛40μul;(4)降低搅拌速度,于600r/min下固化12h,减压浓缩除乙醇,得到水蛭素白蛋白纳米粒,冻干。
其中,冻干工艺为:取10wt%的甘露醇与右旋糖酐(质量比为1∶1),溶于水蛭素白蛋白纳米粒中,然后分装于西林瓶中,置-80℃的超低温冰箱中预冻24h,取出,迅速移入冷冻干燥机中,-40℃、0.10mbar冻干48h,加塞密封即可。
实施例4制备水蛭素白蛋白纳米粒
步骤如下:(1)分别取白蛋白60mg、水蛭素40mg置于锥形瓶中,加入10ml蒸馏水,超声溶解;(2)于25℃的水浴中在800r/min转速下搅拌,以1.0ml/min向锥形瓶中滴加无水乙醇40ml,发现出现乳白色乳光;(3)滴加完乙醇后,加入2.5%的戊二醛30μl;(4)降低搅拌速度,于600r/min下固化12h,减压浓缩除乙醇,得到水蛭素白蛋白纳米粒。
其中,冻干工艺为:取5wt%的甘露醇,溶于水蛭素白蛋白纳米粒中,然后分装于西林瓶中,置-80℃的超低温冰箱中预冻24h,取出,迅速移入冷冻干燥机中,-40℃、0.10mbar冻干48h,加塞密封即可。
取适量冻干粉用水稀释后,以H-7000型透射电子显微镜观测其形态,如图2所示。由图2可知所得水蛭素白蛋白纳米粒大小均一、形态圆整、成型性好、粒径在160nm左右。
实施例5制备水蛭素白蛋白纳米粒
步骤如下:(1)分别取白蛋白80mg、水蛭素20mg置于锥形瓶中,加入10ml蒸馏水,超声溶解;(2)于25℃的水浴中在800r/min转速下搅拌,以1.0ml/min向锥形瓶中滴加无水乙醇35ml,发现出现乳白色乳光;(3)滴加完乙醇后,加入2.5%的戊二醛20μl;(4)降低搅拌速度,于600r/min下固化12h,减压浓缩除乙醇,得到水蛭素白蛋白纳米粒。
用水稀释后,以Zetasizer 3000HS型激光粒度分布仪测定粒径分布,测得平均粒径为164.1nm。如图3所示。
实施例6制备水蛭素白蛋白纳米粒
步骤如下:(1)分别取白蛋白70mg、水蛭素30mg置于锥形瓶中,加入10ml蒸馏水,超声溶解;(2)于25℃的水浴中在800r/min转速下搅拌,以1.0ml/min向锥形瓶中滴加无水乙醇30ml,发现出现乳白色乳光;(3)滴加完乙醇后,加入2.5%的戊二醛20μl;(4)降低搅拌速度,于600r/min下固化12h,减压浓缩除乙醇,得到水蛭素白蛋白纳米粒。
采用透析法测定药物的释放度:以PH为7.4的磷酸盐缓冲液(PBS)200ml为释放介质,搅拌速度为100r/min,温度为37±0.5℃。取样后采用凝血酶滴定法测定,计算累积释放百分率。如图4所示,水蛭素白蛋白纳米粒体外释放呈双相动力学,即最初为突释后为缓释。
实施例7水蛭素白蛋白纳米粒差示扫描量热法(DSC)分析
步骤如下:(1)分别取白蛋白、水蛭素、处方比例的物理混合物以及水蛭素白蛋白纳米粒冻干品10mg;(2)以氧化铝为参比,对4种样品进行DSC分析,扫描速率10℃/min,进行DSC扫描,扫描范围0~400℃,结果如图5所示(其中A为水蛭素;B为白蛋白;C为物理混合物;D为水蛭素白蛋白纳米粒),说明制成纳米粒后,水蛭素在纳米粒中以无定形的状态存在,即水蛭素白蛋白纳米粒冻干粉中形成了新的物相。
实施例8水蛭素白蛋白纳米粒X-射线衍射分析
步骤如下:(1)分别取白蛋白、水蛭素、处方比例的物理混合物以及水蛭素白蛋白纳米粒冻干品10mg,进行X-射线衍射分析(2)采用Cu靶X射线管,管压40kY,管流100mA,采用石墨弯晶单色器进行,Sc探测器,满标为104cps(count/per second)。扫描速度40℃/min,取样间隔0.02°,衍射角2.5°~50°,结果如图6所示(其中A为白蛋白;B为水蛭素;C为物理混合物;D为水蛭素白蛋白纳米粒),说明水蛭素已基本被包裹或吸附完全,不再以晶体结构存在,这一结论与DSC的分析结果一致。
实施例9药效学实验
步骤如下:(1)选用雄性Wistar大鼠,体重范围为240±10g,将大鼠分为三组,分别为:a水蛭素溶液组;b水蛭素白蛋白纳米粒;c水蛭素白蛋白纳米粒的物理混合物;(2)实验前将上面的三种处方配成含水蛭素为0.2mg/ml的溶液,分别尾静脉注射三种溶液,剂量定为0.5mg/kg,分别于给药后0.167、0.25、0.5、0.75、1、2、3、4、5、6、8和12h从眼底静脉丛取血,加入至经肝素钠润洗过的离心管中,4000r/min离心10min取上层血浆,-20℃冰箱保存待测;(3)凝血酶时间通过商品化的试剂盒测定。结果如图7所示。由图可知,白蛋白纳米粒显著提高了水蛭素的抗凝效果。
Claims (8)
3.根据权利要求1或2所述的水蛭素白蛋白纳米粒,其特征在于:所述白蛋白载体为牛血清蛋白(BSA)或人血清蛋白(HSA)任一种或任意组合。
4.根据权利要求1或2所述的水蛭素白蛋白纳米粒,其特征在于:所述脱水剂为无水乙醇。
5.根据权利要求1或2所述的水蛭素白蛋白纳米粒,其特征在于:所述交联剂为2.5%戊二醛。
6.一种制备权利要求1或2所述的水蛭素白蛋白纳米粒的方法,其特征在于:包括以下步骤:
(1)分别取白蛋白、水蛭素置于锥形瓶中,加入10ml蒸馏水,超声溶解;
(2)于25℃的水浴中在800r/min转速下搅拌,以1.0ml/min向锥形瓶中滴加无水乙醇,发现出现乳白色乳光;
(3)滴加完乙醇后,加入2.5%的戊二醛;
(4)降低搅拌速度,于600r/min下固化12h,减压浓缩除乙醇,得到水蛭素白蛋白纳米粒。
7.根据权利要求6所述的水蛭素白蛋白纳米粒的制备方法,其特征在于:还包括以下步骤:
将制得的水蛭素白蛋白纳米粒进一步加入冻干保护剂,以制成冻干制剂。
8.根据权利要求7所述的水蛭素白蛋白纳米粒,其特征在于:所述冻干保护剂为乳糖、葡萄糖、甘露醇、蔗糖、海藻糖、右旋糖苷、山梨醇中的任一种或任意组合。
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