CN103655540B - 杨梅素晶体化合物用于神经抑制剂的药物的应用 - Google Patents
杨梅素晶体化合物用于神经抑制剂的药物的应用 Download PDFInfo
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Abstract
本发明涉及杨梅素晶体化合物用于神经抑制剂的药物的应用,具体的说就是杨梅素晶体化合物在***领域的应用。
Description
技术领域
本发明涉及杨梅素用于神经抑制剂的药物的应用,具体的说就是杨梅素在麻醉剂领域的应用。
背景技术
杨梅素(Myricetin)如(I)所示,为一黄酮醇类天然化合物,黄色针状晶体,熔点为324.0~325.5℃,溶于甲醇、乙醇、丙酮或乙酸乙酯,微溶于水,难溶于氯仿、石油醚,置于空气中易氧化变绿。
(I)
目前对杨梅素已进行了较为广泛的药理研究,黄酮类天然产物是近年来天然药物和人类健康产品研究开发的热点,杨梅素具有清除自由基、抗氧化、抗血栓、抗肿瘤、消炎抗菌等多种功效,科学家开始研究杨梅素用于医药、食品、保健品和化妆品。国外保健品美国保健品药FYI已将杨梅素作为添加剂用作治疗预防关节炎和各种炎症,尤其对妊娠及哺乳期妇女和婴儿更加适合,由此杨梅素有望进一步开发为特殊人群的消炎用药,从而减轻西药抗生素对人体的毒副作用。随着杨梅素药理作用的进一步研究,市场对杨梅素的需求量将急剧增加,杨梅素的研究开发前景广阔。已公开的有关杨梅素的专利有:发明名称为“杨梅素在制备尿酸转运子URAT1抑制药物中的应用”的CN101181261A;公开了用作妇科炎症且发明名称为“杨梅素的制备方法、药物制剂及医药新用途”的CN10150175A;公开了用作预防和治疗老年痴呆症且发明名称为“蛇葡萄茎叶总黄酮及单一成分杨梅素的医药新用途”的CN101297900A。
但是,迄今为止有关杨梅素的其它更加高效和确切的作用靶点、机制等尚未被发现,经本发明人长期研究,发现杨梅素对神经活动具有一定的抑制作用。经过进一步研究,发明人发现杨霉素的特定晶形与杨霉素化合物相比对神经活动具有更好的抑制作用,特别是作为局部***物使用时。
***分为全身***、局部***和肌肉松弛药,局部***简称局麻药,作用于神经末梢及神经干,阻滞神经冲动的传导,使局部的感觉消失。临床上,理想的局麻药应该具备的特点:1)麻醉作用强,吸收快;2)无明显毒性,安全范围大,对神经组织及其他组织无刺激性和局部毒性;3)能透过粘膜并在组织中扩散,穿透神经组织的能力强;4)性质稳定等。
发明内容
基于上述认识,我们研究发现,杨梅素具有强烈的阻断神经信号转导系激活的作用。进一步的实验证明式(I)化合物晶体可以更直接与神经元发生专一性结合,并发生强大地抑制作用。
一方面,本发明提供了一种式(I)化合物的晶体;
另一方面,本发明提供了所述式(I)化合物的晶体的用途。
根据对杨梅素制剂的研究,发明了杨梅素可制成医疗上可接受的用作神经抑制剂的口服制剂、注射剂及其他给药途径的制剂。
具体实施方式
实施例1:杨梅素晶体化合物的制备
取100g商购杨霉素化合物,在通风橱中将称量好的化合物放入玛瑙研体中充分研磨使其混合均匀,然后将样品装入铂坩埚里。为使后期反应顺利进行,放入箱式炉中在80℃预烧、研磨。最后在80℃下恒温2h,经分阶段缓慢冷却到室温后,在坩埚底部得到块状晶体。
将上述所得块状晶体溶于无水丙酮中,在室温下搅拌数分钟至固体完全溶解,逐滴加入5%氢氧化钠水溶液,反应液由淡黄色清液变为酒红色清液,反应完全,旋转蒸发除去丙酮,向残液中加入热水至红色固体全部溶解,通入二氧化碳30min左右至反应液不再变色为止,有淡黄色固体产生,过滤,水洗,烘干,得到淡黄色晶体。对该晶体进行单晶X-射线衍射晶体学分析其晶体结构,其晶体学参数如上所述。
实施例2:杨梅素及其晶体对神经活动的抑制作用
表1中比较了式杨霉素化合物及其晶体的体外效能[抑制[35S]-叔丁基二环硫代磷酸葡(TBPS)的结合的能力],旋转棒TD50(半数试验动物不能在旋转的棒上停留1分钟时的剂量)和所有试验动物都能通过旋转棒试验前时间的长度(作用持续时间)。用于测量本发明化合物的体外和体内活性的这些方法完全公开在美国专利5,232,917中。TBPS测定得到了化合物的体外效能,而旋转棒测定评价了化合物的镇静剂/安眠剂活性。既然化合物的作用持续时间取决于剂量并将在更高的剂量下延长,于是在所有动物都没有通过旋转棒试验的最低剂量下测量作用持续时间。对于作用持续时间>240分钟的化合物,在240分钟时通过旋转棒试验的动物数记在圆括号中。可以看出,本发明化合物具有大于240分钟的生物学持续作用时间,此外,本发明化合物显示在240分钟时只有不到一半的动物通过旋转棒试验,这提示其作用持续时间明显更长。由此可以看出本发明化合物提供了独特而出乎意料的药动学性能,使得它们尤其可用作镇静剂/安眠剂和麻醉剂。
表1式I化合物及其晶体的生物活性比较
化合物 | TBPS IC50 (nM) | RR TD50 口服(mg/kg) | 作用持续时间(分钟) |
杨霉素化合物 | 67 | 41 | >240 (3/8通过) |
杨霉素化合物晶体 | 52 | 25 | >240 (1/8通过) |
实施例3:颗粒剂制备
配方:
杨梅素晶体化合物2000g
蔗糖5000g
糊精400g
乙醇适量
按普通制粒法制粒,分装成1000袋(每袋约7.4g),每袋含杨梅素2000mg。
实施例4:胶丸剂
配方:
杨梅素晶体化合物75g
聚乙二醇-400300g
按普通胶丸(软胶囊)剂制备方法制备,每粒内容物重约375mg,可得1000粒,每粒含杨梅素75mg。
实施例5:冻干粉针剂
配方:
杨梅素杨梅素晶体化合物25g
甘露醇100g
按普通冻干法制备成冻干制剂,可制得1000支25mg之规格的杨梅素冻干粉针。
实施例6:冻干粉针剂
配方:
杨梅素杨梅素晶体化合物100g
卵磷脂85g
甘露醇100g
按普通冻干法制备成冻干制剂,可制得1000支100mg之规格的杨梅素冻干粉针。
实施例7:口服液
配方:
杨梅素杨梅素晶体化合物360g
阿魏酸155g
蜂蜜1000g
蒸馏水加至10kg
按普通口服液制备方法制备,可得1000支(每支约重15g)的口服液。
实施例8:滴丸剂
配方:
杨梅素杨梅素晶体化合物10g
PEG-6000200g
按普通滴丸剂制备方法制备,每丸重约22.8mg,可得约10000粒,每丸含杨梅素约1mg。
实施例9:口腔速崩片
配方(1000片):
杨梅素杨梅素晶体化合物(粒径<35μm)20g
微晶纤维(100目)120g
乳糖(120目)54g
羧甲纤维素钠(80目)10g
聚乙二醇-10000(60目)8g
山梨醇(120目)40g
草莓香精0.1g
制备工艺:将杨梅素和上述各种原料进行超细化,按配方充分混匀后直接压片,即得每片含杨梅素(规格)20mg的口腔速崩片。
本发明提供的产品经药学研究,其结果如下:
结果表明本发明提供的样品,经过初步稳定性考察,产品质量基本稳定,可达一年以上。
虽然本发明以示例性实施例和实施方式进行描述,但所公开的***和方法并不局限于这些示例性实施例/实施方式。而且,可以理解的是本领域技术人员明显可以从以上描述中,且在没有背离目前公开的精神和范围的情况下,对所公开的***和方法进行修饰、改变和改善。因此,本发明明显地包括包含上述在其范围内的所有修饰、改变和改善。
Claims (4)
1.一种如(I)所示的晶体化合物的用途,其特征在于所述化合物用于制备抑制神经活动的药物
(I)
其中所述晶体化合物属于三斜晶系,P-1空间群,a=1.09091,b=1.16257,c=1.94343,α=81.38°,β=84.47°,γ=65.29°,V=2.2122。
2.据权利要求1所述的用途,其特征在于所述晶体化合物用于制备麻醉剂的药物。
3.根据权利要求1所述的用途,其特征在于所述晶体化合物用于制备抑制神经活动的药物时,有效剂量的范围在1mg-2000mg。
4.根据权利要求1所述的用途,其特征在于所述晶体化合物可制成医疗上可接受的注射剂、颗粒剂、丸剂、胶囊剂、喷雾剂、洗剂、栓剂、合剂、擦剂、贴剂、膜剂、纸型剂、混悬剂、酊剂、干糖浆剂、泡腾片、硬膏剂、软膏剂、糖浆剂、乳剂或散剂。
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