CN111423484B - 一种β谷甾醇衍生物及其制备方法和应用 - Google Patents
一种β谷甾醇衍生物及其制备方法和应用 Download PDFInfo
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- CN111423484B CN111423484B CN202010136016.0A CN202010136016A CN111423484B CN 111423484 B CN111423484 B CN 111423484B CN 202010136016 A CN202010136016 A CN 202010136016A CN 111423484 B CN111423484 B CN 111423484B
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- sitosterol
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Abstract
本发明属于生物医药技术领域,公开了一种β谷甾醇衍生物及其制备方法和应用。该β谷甾醇衍生物可以与亲和素组装成的纳米颗粒。β谷甾醇衍生物及其纳米药物经动物试验证实能明显降低小鼠的睡眠潜伏时间,显著提高小鼠的睡眠时间、阈下催眠入睡率,有效改善了小鼠的睡眠质量,可用于进一步制备改善睡眠质量药物或保健品。
Description
技术领域
本发明属于生物医药技术领域,特别涉及一种β谷甾醇衍生物及其制备方法和应用。
背景技术
由于工作压力,社会竞争以及人口老龄化等因素的影响,在我国人群中,45.4%的人存在睡眠障碍问题,并与焦虑性心理障碍成正比。在美国约35%的人曾经有过睡眠障碍,17%的患者认为失眠严重影响其生活,85%的患者认为未得到有效治疗。睡眠障碍严重影响人们的生活质量和工作效率,研究显示,睡眠障碍会导致身体和智力发育迟缓,记忆力衰减,机体免疫力下降等。持续的睡眠障碍是抑郁患者的危险因子,也是精神***症和其他精神障碍的早期临床症状之一。目前,改善睡眠的药物多集中在褪黑素、帕罗西汀、舍曲林、米氮平、曲哇酮以及阿米替林等,这些物质虽然具有良好的改善睡眠的效果,在催眠剂量时可引起眩晕、困倦、乏力等不良反应,而且长期使用产生耐药性以及生理和心理上的依赖性。因此,研发高效、依赖性低以及无耐药性催眠药具有重大社会、经济意义。
β-谷甾醇(β-sitosterol,BS)是植物甾醇类成分之一,其广泛存在于自然界中的各种植物油、坚果等植物种子中,也存在于某些植物药中。其结构与胆固醇非常相似,具有***活性。其可抑制人白血病细胞的增殖(G2/M阻滞)、核内复制、以及α-微管蛋白和微管的聚合。β-谷甾醇以其特有的生物学特性和物理化学性质被较多地应用到医药行业中。β-谷甾醇为白色鳞片状、针状结晶或结晶性粉末,无臭、无味。在氯仿和二硫化碳中极易溶解,在乙醇或丙酮中微溶,在水中不溶。β-谷甾醇有降胆固醇、止咳、祛痰及抑制肿瘤和修复组织作用。用于II型高脂血症、动脉粥样硬化症和慢性气管炎,亦用于早期子***及皮肤溃疡等。由于其生物利用度极低、疏水性强(不溶于水,常温下微溶于丙酮和乙醇,可溶于苯、氯仿、乙酸乙酯、二硫化碳和石油醚、乙酸等)、细胞内累积量不足,且由于其在水中的溶解性太差,导致生物利用度低及体内传输、代谢等方面的缺点,限制其成为潜在治疗药物。因此,改善这类化合物的药代动力学特性十分必要。因此,通过有机合成方法合成其天然产物类似物,进行结构优化,构建产量更高,生物活性更好的新型β谷甾醇衍生物,并用于医药保健的开发研究具有重要意义。
生物素(Biotin,B)因其结构简单,分子量低,高肿瘤特异性及其生物素受体在肿瘤组织膜表面广泛高表达而被作为一种靶向配体广泛应用于各种抗癌药物的靶向递送运输等。生物素又称维生素H、辅酶R,是水溶性有益维生素,也属于维生素B族,分子量为244.31,基本结构为双环结构:I环为咪唑酮环,是与亲和素结合的部位;II为噻吩环,含一个戊酸侧链,其末端羧基可与生物大分子连接,形成生物素标记抗原、抗体、酶等。其化学结构中有咪唑酮环,可与亲和素(avidin,AV)和链霉亲和素(streptavidin,SA)特异性结合。生物素与亲和素之间结合的亲和力高(结合常数约为1×10-15mol/L,且可视为不可逆结合)、特异性强,各自均可以与各型大小分子结合,一分子链霉亲合蛋白可与四分子生物素结合,二者“链霉亲和素-生物素”结合反应时具有多级放大作用等优越性,其相关技术被广泛应用在各种标记免疫分析技术和肿瘤靶向治疗药物领域中,为基于B构建各种健康产品奠定了良好的分子基础。
最为关键的是,迄今为止,尚未见通过生物素修饰提高β谷甾醇溶解性及报道其具有改善睡眠的疗效,也未见将生物素修饰的β谷甾醇衍生物与亲和素特异结合构建成纳米颗粒及生物医药应用。
发明内容
为了克服现有技术中存在的缺点和不足,本发明的首要目的在于提供一种β谷甾醇衍生物。
本发明的再一目的在于提供一种上述β谷甾醇衍生物的制备方法。
本发明的又一目的在于提供上述β谷甾醇衍生物的应用。
本发明的又一目的在于提供一种由上述的β谷甾醇衍生物与亲和素组装成的纳米颗粒。
本发明的又一目的在于提供上述纳米颗粒的应用。
本发明的目的通过下述技术方案实现:
一种β谷甾醇衍生物,该衍生物具有如下式(I)所示的结构:
上述的一种β谷甾醇衍生物的制备方法,包括以下操作步骤:
将β谷甾醇溶于溶剂中,在脱水剂N,N'-二环己基碳二亚胺或1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,以及催化剂对二甲氨基吡啶作用下,0℃搅拌反应1~6h;然后按β谷甾醇摩尔比1:1-3倍量加入生物素,从冰浴中升高温度至室温,避光搅拌过夜;过滤液浓缩,冰***或异丙醇重结晶,层析或制备液相纯化,冻干即可获得结构如式(I)所示的β谷甾醇衍生物。
所述溶剂为CH2Cl2、DMSO或DMF;所述搅拌反应的时间为5h;所述室温为25℃。
所述β谷甾醇、脱水剂、催化剂的摩尔比为1:1:1~1:25:25。
上述的一种β谷甾醇衍生物及其药学上可接受的盐在制备改善睡眠药物或保健品中的应用。所述药物为片剂、胶囊、粉剂、颗粒剂、口服液、丸剂、散剂、缓释制剂、溶液剂、悬浮液、注射剂、微针、软膏、乳膏或栓剂。
一种由上述的β谷甾醇衍生物与亲和素组装成的纳米颗粒。
上述的纳米颗粒在制备改善睡眠药物或保健品中的应用。所述药物为片剂、胶囊、粉剂、颗粒剂、口服液、丸剂、散剂、缓释制剂、溶液剂、悬浮液、注射剂、微针、软膏、乳膏或栓剂。
具有式(Ⅰ)所示结构的β谷甾醇衍生物的合成示意图如图1所示。
本申请所述“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力,并且在生物学或其他方面没有不良作用的盐。本申请中的盐指用有机酸/无机酸形成的酸式盐,以及用有机碱/无机碱形成的碱式盐。
本发明的原理是:
本发明基于生物素和其与亲和素组装纳米药物及介导疾病细胞富集原理,以生物素修饰β谷甾醇解决其成药溶解性问题,同时生物素具有很好的水溶性、生物相容性和无免疫源性等优点,可以获得提高药效,增加选择性,降低毒副作用,更适合临床使用。
本发明人在设计和实验发明中发现通过生物素化学修饰的β谷甾醇化合物,显著增加了溶解性,尤其是其与亲和素纳米组装后,完全可以满足临床给药需求。
2%兔红细胞溶血试验表明本发明的生物素修饰的β谷甾醇衍生物或其纳米制剂在4h内未见红细胞溶血聚集,等价β谷甾醇剂量>60mg。家兔耳缘静脉刺激性实验表明本发明生物素修饰的β谷甾醇衍生物溶解在生理盐水中静脉滴注无血管刺激性。
溶解度实验表明,与原型相比(β谷甾醇不溶于水),生物素修饰后的β谷甾醇衍生物水溶性明显提高(约为5mg/ml),尤其是与亲和素组装成纳米制剂后,具有良好的水溶性(>20mg/ml),对药物剂型制备及血管给药等更加方便。
本发明相对于现有技术,具有如下的优点及有益效果:
本发明生物素修饰的β谷甾醇衍生物,以及将生物素修饰的β谷甾醇衍生物与亲和素特异结合构建成纳米药物***,极大地解决了β谷甾醇溶解性不好、疗效差、靶向性缺乏等技术问题,具有良好的临床应用前景。
附图说明
图1为B-BS合成示意图。
图2为B-BS系列与亲和素组装成纳米药物的示意图。
图3为β谷甾醇衍生物与亲和素组装成纳米颗粒的示意图。
具体实施方法
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1本发明β谷甾醇衍生物(B-BS)的制备
取β谷甾醇(0.15mmol)溶于60ml的DMSO中,在脱水剂DCC(3.0mmol)和催化剂DMAP(3.0mmol)作用下,0℃搅拌6h;然后按β谷甾醇摩尔比1:3倍加入生物素(B),从冰浴中升高温度至室温25℃,避光搅拌过夜。过滤液浓缩,冰***或异丙醇重结晶,层析或制备液相纯化,冻干即可获得β谷甾醇衍生物B-BS(收率约48%),质谱鉴定离子峰[M+H]+为:642.1。
1HNMR(400MHz,DMSO):生物素的特征峰:10.76-10.82(NH,2H,宽峰),4.47-4.65(2C-H,2H),2.80-3.10(CH2,2H),3.24(CH,1H),2.32(CH2,2H),1.23-1.68(3CH2,6H);β谷甾醇的特征峰:0.85-0.88(4CH3,12H),0.99-1.03(CH3,3H),1.08-1.38(7CH2,8CH,22H),2.09-2.31(2CH2,4H)。
IR:红外光谱中明显增加了1725cm-1的酯羰基峰,说明β谷甾醇和生物素通过酯键连接上。
上述质谱数据证明本实施例所得β谷甾醇衍生物具有如下所示结构:
实施例2β谷甾醇衍生物亲和素纳米颗粒的制备
取等量于β谷甾醇5g的经由实施例1制备的β谷甾醇衍生物(B-BS),先溶解于少量的DMSO或乙醇中,然后用注射用水稀释,加入氯化钠1.0g,再加入等摩尔亲和素(B-BS与亲和素组装可以按照多种摩尔比例1~4:1进行组装,如图2所示),室温搅拌均匀,即可得复合的β谷甾醇衍生物亲和素纳米颗粒,经过透射电镜表征,其纳米尺寸约为25nm(如图3所示)。
实施例3β谷甾醇衍生物注射液的制备
取等量于β谷甾醇30g的经由实施例1制备的β谷甾醇衍生物(B-BS),溶解于注射用水中,加入氯化钠5.0g搅拌均匀,稀盐酸调节pH=5.0,然后加入0.5%的注射用活性炭,60℃恒温30min,脱炭后,滤液加注射用水至1000ml,0.22μm的无菌滤膜过滤,2ml/支分装于玻璃曲颈安瓿中,熔封,100℃流通蒸汽湿热灭菌40min,然后贴标签保存。
实施例4β谷甾醇衍生物亲和素纳米注射液的制备
取等量于β谷甾醇30g的经由实施例1制备的β谷甾醇衍生物(B-BS),溶解于注射用水中,加入氯化钠5.0g和亲和素300.0g搅拌均匀,稀盐酸调节pH=5.0,然后加入0.5%的注射用活性炭,60℃恒温30min,脱炭后,滤液加注射用水至1000ml,0.22μm的无菌滤膜过滤,2ml/支分装于玻璃曲颈安瓿中,熔封,然后贴标签保存。
实施例5β谷甾醇衍生物亲和素纳米注射液的制备
取等量于β谷甾醇30g的经由实施例1制备的β谷甾醇衍生物(B-BS),溶解于注射用水中,加入氯化钠5.0g和亲和素150.0g搅拌均匀,稀盐酸调节pH=5.0,然后加入0.5%的注射用活性炭,60℃恒温30min,脱炭后,滤液加注射用水至1000ml,0.22μm的无菌滤膜过滤,2ml/支分装于玻璃曲颈安瓿中,熔封,然后贴标签保存。
实施例6β谷甾醇衍生物冻干粉的制备
取等量于β谷甾醇20g的经由实施例1制备的β谷甾醇衍生物(B-BS)粉末,加入注射用葡萄糖粉末25g搅拌均匀,按40mg/瓶无菌分装于玻璃曲颈安瓿中,冷冻干燥,钴60辐射灭菌,密封然后贴标签保存。
实施例7β谷甾醇衍生物纳米颗粒的血管刺激性试验
取用注射用水50ml稀释经过微量DMSO溶解好的实施例4制备的β谷甾醇衍生物亲和素纳米注射液40mg,实验家兔6只,随机3组(β谷甾醇衍生物亲和素纳米注射液药物组、β谷甾醇组及生理盐水组),其中生理盐水作对照,给家兔左耳缘静脉滴注生物素-β谷甾醇注射液,右耳缘静脉滴注同体积生理盐水,3h内滴注完成。滴注完成后取注射点下端1cm处的血管及心、肝、脾、肺、胰腺、肾和脑组织进行固定***溶液,石蜡包埋切片,HE染色,数字病理学分析评价。
经观察给药后每日家兔的饮食、毛发、***、呼吸、中枢神经***、四肢活动状态等均正常,无中毒表现。至约48h左右,处死的动物,观察直肠粘膜光滑平整,无异常;其余留存家兔逐日监测,无异常出现。到第七天处死动物,观察体重和参照《新药研究指南》对血管刺激进行分级。家兔血管刺激性试验的病理组织学检查结果为耳廓、表皮无异常,真皮血管内皮细胞无肿胀,毛细血管管壁无出血、坏死或炎性细胞浸润,软骨层、软骨细胞无增生或坏死,软骨细胞排列整齐;肝脏、心肌组织、脑组织、肺部、肾脏和胰腺组织均无异常。生理盐水对照组耳廓表皮无异常,真皮血管内皮细胞无肿胀,毛细血管壁无出血、坏死或炎性细胞浸润,软骨细胞排列整齐,无增生或坏死,软骨层、软骨细胞无增生或坏死。β谷甾醇衍生物亲和素纳米注射液药物组与β谷甾醇及生理盐水组在病理学组织上无明显差异,但溶解性显著变好。
实施例8实施例1制备的β谷甾醇衍生物改善睡眠的小鼠实验研究
实验动物:健康雄性昆明小鼠180只,4-5周,SPF级,体重18~22g,小鼠和饲料由SPF实验动物中心采购;置于22-25℃,相对湿度为50%~70%的饲养房中。
试验方法:
1)分组与给药:动物预饲1周后,随机分为3个实验组,第一组进行直接睡眠实验和延长戊巴比妥钠睡眠时间实验,第二组进行戊巴比妥钠阈下剂量催眠实验,第三组进行戊巴比妥钠睡眠潜伏期实验。每个实验组将50只小鼠按体重随机分成5个小组,每组10只动物。设对照组,β谷甾醇衍生物低、中、高剂量组(按体重50、100和200mg/kg设置剂量组),β谷甾醇(200mg/kg体重剂量组),熊果酸组(50mg/kg体重剂量组),灌胃给药,对照组灌服同样的溶媒,1次/d,连续30天。
2)直接睡眠实验:未次灌胃后,观察是否出现睡眠现象,睡眠以翻正反射消失为指标。当小鼠置于背卧位时,能立即翻正身位,如超过60秒不能翻正者,即认为翻正反射消失,进入睡眠。翻正反射恢复即为动物觉醒,翻正反射消失至恢复这段时间为动物睡眠时间,记录对照组与各剂量组入睡动物数及睡眠时间。
3)延长戊巴比妥钠睡眠时间实验:末次灌胃15分钟后,给各组动物腹腔注射50mg/kg体重的戊巴比妥钠,注射量为0.2mL/20g体重,以翻正反射消失为入睡判断标准,观察受试样品是否延长戊巴比妥钠睡眠时间。
4)戊巴比妥钠阈下剂量催眠实验:末次灌胃15分钟后,给各组动物腹腔注射25mg/kg体重的戊巴比妥钠,注射量为0.2mL/20g体重,以翻正反射消失达1分钟以上为入睡判断标准,记录30分钟内入睡动物数。
5)戊比妥钠睡眠潜伏期实验:末次灌胃15分钟后,给各组动物腹腔注射280mg/kg体重戊巴比妥钠,注射量为0.2mL/20g体重,以翻正反射消失为指标,观察受试样品对巴比妥钠睡眠潜伏期的影响。
实验结果:
1)对小鼠发育生长体重的影响:如下表1所示,与对照组相比,β谷甾醇几乎没有效果;熊果酸组和β谷甾醇衍生物中、高剂量组均有明显促生长作用,以β谷甾醇衍生物高剂量组效果最佳,小鼠体重增加>25%,且差异极显著统计学差异。
表1:对小鼠体重的影响
备注:与对照组相比,*,统计学差异显著(p<0.05);**,统计学差异极显著(p<0.01);AV±SD为平均值±误差值。
2)对小鼠直接睡眠作用的观察:如表2所示,在直接睡眠试验中,β谷甾醇组,熊果酸组以及β谷甾醇衍生物组各剂量组入睡动物数及睡眠时间均为0,表明这两种物质对小鼠无直接催眠作用,可用于后续三项指标的检测。
表2:对小鼠直接睡眠作用的观察
3)对延长戊巴比妥钠睡眠时间的影响:如表3所示,在延长戊巴比妥钠睡眠时间实验中,与对照组相比,β谷甾醇衍生物各剂量组和熊果酸组能延长戊巴比妥钠睡眠时间,以β谷甾醇衍生物中、高剂量组效果最佳,且具有统计学显著差异。
表3:对小鼠延长戊巴比妥钠睡眠时间的影响
备注:与对照组相比,*,统计学差异显著(p<0.05);**,统计学差异极显著(p<0.01);
4)对小鼠戊巴比妥钠阈下剂量催眠作用的影响:如表4所示,β谷甾醇衍生物各剂量组和熊果酸能显著提高小鼠睡眠率,与对照组相比,小鼠睡眠率分别提高了20%,50%、60%和20%,以高剂量组效果最佳。
表4:对小鼠戊巴比妥钠阈下剂量催眠作用的影响
备注:与对照组相比,*,统计学差异显著(p<0.05);**,统计学差异极显著(p<0.01);
5)对小鼠戊巴比妥钠诱导小鼠睡眠潜伏期的影响:如表5所示,对照组小鼠睡眠潜伏期为26.99min,β谷甾醇衍生物各剂量组以及熊果酸组对小鼠睡眠潜伏期均有缩短,其中以高剂量组潜伏期最短,且与对照组具有统计学差异显著。
表5:对小鼠戊巴比妥钠诱导小鼠睡眠潜伏期的影响
备注:与对照组相比,*,统计学差异显著(p<0.05);**,统计学差异极显著(p<0.01);
综合以上结果,β谷甾醇衍生物具有明显的改善小鼠睡眠的功效,且以剂量依赖性呈现效果更佳。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (5)
2.根据权利要求1所述的应用,其特征在于包括以下操作步骤:
将β谷甾醇溶于溶剂中,在脱水剂N,N'-二环己基碳二亚胺或1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,以及催化剂对二甲氨基吡啶作用下,0℃搅拌反应1~6h;然后按β谷甾醇摩尔比1:1-3倍量加入生物素,从冰浴中升高温度至室温,避光搅拌过夜;过滤液浓缩,冰***或异丙醇重结晶,层析或制备液相纯化,冻干即可获得结构如式(I)所示的β谷甾醇衍生物。
3.根据权利要求2所述的应用,其特征在于:所述溶剂为CH2Cl2、DMSO或DMF;所述搅拌反应的时间为5h;所述室温为25℃。
4.根据权利要求2所述的应用,其特征在于:所述β谷甾醇、脱水剂、催化剂的摩尔比为1:1:1~1:25:25。
5.根据权利要求1所述的应用,其特征在于:所述药物为片剂、胶囊、粉剂、颗粒剂、口服液、丸剂、散剂、缓释制剂、溶液剂、悬浮液、注射剂、微针、软膏、乳膏或栓剂。
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---|
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