CN115245511B - 一种小檗碱和水飞蓟宾形成的盐、其制备方法和应用 - Google Patents
一种小檗碱和水飞蓟宾形成的盐、其制备方法和应用 Download PDFInfo
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- CN115245511B CN115245511B CN202110460032.XA CN202110460032A CN115245511B CN 115245511 B CN115245511 B CN 115245511B CN 202110460032 A CN202110460032 A CN 202110460032A CN 115245511 B CN115245511 B CN 115245511B
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Abstract
本发明属于医药技术领域，公开了一种小檗碱和水飞蓟宾形成的盐、其制备方法和应用。具体公开了一种小檗碱或二氢小檗碱与水飞蓟宾形成的盐，其中小檗碱与水飞蓟宾按摩尔比1:1的比例结合形成。该盐是不同于小檗碱、水飞蓟宾及其物理混合物的一种无定形态。该小檗碱与水飞蓟宾组成的盐可显著增加水飞蓟宾的溶出速率，并且两个药物有协同释放的特征,水飞蓟宾的口服生物利用度得到显著提高，具有增强的协同药理作用。具体地该小檗碱和水飞蓟宾形成的盐在动物实验中显示出优异的减轻体重、降低血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白‑胆固醇(LDL‑c)，降低血清谷丙转氨酶(ALT)、谷草转氨酶(AST)等作用。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种小檗碱与水飞蓟宾形成的盐及其制备方法；以及其制备预防或治疗肥胖、高脂血症、脂肪性肝病等代谢相关疾病药物中的用途。
背景技术
小檗碱(分子式：C20H18NO4，分子量：336.37)，是从中药黄连中分离的一种季铵生物碱，是黄连抗菌的主要有效成分。临床应用主要为防治痢疾的非处方药。小檗碱抗菌谱广，体外对多种革兰阳性及阴性菌均具抑菌作用，如对痢疾杆菌、结核杆菌、肺炎球菌、伤寒杆菌及白喉杆菌等都有抑制作用，其中对痢疾杆菌作用最强，几乎无抗药性和副作用。近年来，随着研究的不断深入，其应用范围有了新的发展。现代药理学研究证实小檗碱在调节血糖和脂质代谢、抗炎、降低血尿酸、抗类风湿性关节炎、以及抑制肿瘤细胞增殖、抗病毒等方面也具有显著作用。多项基础和临床证据证实小檗碱通过多种机制参与葡萄糖代谢。如视黄醇结合蛋白-4(RBP-4)和葡萄糖转运因子-4(GLUT-4)机制；增加肝细胞核因子-4a(HNF-4a的表达和葡萄糖激酶活性；逆转胰岛素受体(IRS)-1Ser307的磷酸化；上调IRS的表达等。小檗碱的降脂功能，分子机制涉及上调LDLR-mRNA水平，抑制3-羟基3-甲基戊二酰辅酶A还原酶(HMGR)基因表达，肝脏载脂蛋白(Apo)EmRNA表达增加，激活AMPK途径、固醇调节元件结合蛋白(SREBP)-C和CCAAT增强子结合蛋白(C/EBP)-α，氧化物酶体增殖物激活受体(PPAR)-γ、降低枯草溶菌素转化酶(PCSK)9基因的转录水平等。【1，2】另外，在治疗心血管系统疾病方面，小檗碱是一种多靶标的极具前景的候选物。小檗碱的心血管药理作用主要包括抗心律失常、抗心力衰竭、扩张血管和降低血压、调节脂代谢和抗动脉粥样硬化、抗血小板和抗血栓、抗脑缺血以及保护血管内皮、抗血管炎症和抑制肿瘤新生血管形成等作用。作用的靶细胞包括心肌细胞、血管内皮细胞、血管平滑肌细胞、血小板以及血液单核巨噬细胞等。具体的靶标主要是Ca2+通道、K+通道，M受体、腺苷受体，胆碱酯酶和ACE等。【3】小檗碱为黄色针状结晶，味极苦，口服吸收差，口服生物利用度小于5％。提高生物利用度，改善口感是增加其临床适用性的关键。
水飞蓟宾(分子式：C25H22O10，分子量：482.436)系从菊利植物水飞蓟(Silybummarianum)果实中提取分离而得的一种黄酮类化合物，具有明显的保护和稳定肝细胞膜的作用，可以改善肝功能，产生降酶效果，且不易发生酶反跳。水飞蓟宾作为保肝药物被广泛用于治疗肝炎、肝硬化、酒精肝及代谢中毒性肝损伤等疾病。其机制包括水飞蓟宾能稳定肝细胞膜及保持其完整性，并可促进肝细胞超微结构复原，促进正常肝细胞的分裂及生长，提高肝细胞合成RNA及蛋白质的能力，提高网状内皮系统制造巨噬细胞的能力，并加强巨噬细胞的活性，加速病毒的清除。同时，水飞蓟宾可促进脂肪转移及抗氧化作用，防止脂肪过度氧化及浸润，减轻肝脏脂肪变性；并可促进肝脏的代谢功能，增强其解毒作用，降低毒物对肝细胞的损伤。近年的研究表明，水飞蓟宾还具有降血脂、治疗糖尿病的作用，此外水飞蓟宾还具有抑制前列腺癌、结直肠癌、膀胱癌、肺癌、肝癌等癌症的作用；以及神经保护和免疫调节等作用。但是由于水飞蓟宾几乎不溶于水，口服吸收生物利用度低，极大地限制了临床的应用。
尽管小檗碱及水飞蓟宾具有许多相似的药理活性，并且研究表明两药连用具有协同效应，但因两药生物利用度低、且释放及吸收特性差异显著限制了其在临床上的使用，因此寻找一种提高小檗碱和水飞蓟宾的生物利用度并发挥两者的协同作用的方法在临床上具有非常重要的意义。成盐，可能改善药物的溶解度、溶出速率、稳定性及生物利用度等理化性质，已成为药物研发的一种新途径。
本发明将小檗碱与水飞蓟宾制成小檗碱-水飞蓟宾盐，该化合物可显著改善小檗碱及水飞蓟宾的溶出速率，实现两药同步释放，增加两药在预防或者治疗代谢相关疾病上的协同药理效应。
发明内容
本发明解决的技术问题是提供一种能稳定存在的小檗碱或二氢小檗碱与水飞蓟宾形成的盐，以及其制备方法和应用。该化合物能够改善小檗碱及水飞蓟宾的溶出速率，实现两药同步释放，从而增加两药在预防或者治疗代谢相关疾病上的协同药理效应。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供了一种小檗碱或二氢小檗碱和水飞蓟宾形成的盐，其特征在于，所述的盐是小檗碱或二氢小檗碱和水飞蓟宾结合形成的。
上述中，小檗碱的结构为:
R1为氯离子或者氢氧根，
二氢小檗碱的结构为:
R2为氯离子或者氢氧根，
水飞蓟宾的结构为:
进一步的，所述的盐的结构为：
所述的小檗碱与水飞蓟宾以1：1摩尔比形成盐，其核磁图谱特征为
1H NMR(400MHz,DMSO)δ12.22(s,1H),9.89(s,1H),8.93(s,1H),8.20(d,J＝8.8Hz,1H),8.00(d,J＝9.0Hz,1H),7.80(s,1H),7.09(s,1H),7.01(d,J＝2.3Hz,2H),6.99–6.90(m,2H),6.86(dd,J＝8.1,1.9Hz,1H),6.80(d,J＝8.1Hz,1H),6.18(s,2H),5.23(s,1H),5.19–5.11(m,2H),5.05–4.84(m,4H),4.76(d,J＝10.4Hz,1H),4.23(dd,J＝10.5,6.6Hz,1H),4.19–4.00(m,8H),3.78(s,4H),3.67–3.06(m,15H)。
进一步的，当使用CuKα辐射实验条件时，其粉末X射线衍射图谱无尖锐的衍射峰。
进一步的，用KBr压片测定得到的小檗碱-水飞蓟宾盐红外光谱在3200-3600cm-1处无小檗碱及水飞蓟宾的特征吸收峰，在1083cm-1处的C-O-C特征峰消失；在3198、3062、2941、2904、2844、1638、1601、1568、1506、1480、1457、1385、1362、1341、1272、1232、1188、1126、1099、1064、1034、994、972、935、911、855、818、740、647、637、626、529cm-1处存在红外光谱特征峰，其中红外光谱特征峰的允许偏差为±2cm-1。
进一步的，所述盐用差式扫描量热分析法测定，其在91.7cel和166.3cel处存在吸热峰，其中差式扫描量热分析特征峰的允许偏差为±2cel。
所述的盐是小檗碱或二氢小檗碱和水飞蓟宾结合形成。
所述的盐中，小檗碱或二氢小檗碱的剂量与水飞蓟宾的剂量之比为摩尔比1：1。
本发明技术方案的第二方面是提供了第一方面所述盐的制备方法，包括以下步骤，
(1)将盐酸小檗碱或二氢小檗碱加热溶解于10～300倍的水中；
(2)将水飞蓟宾分散于水和醇类溶剂中，加入0.5～1.5当量的碱，使其溶解，然后蒸出醇类有机溶剂，其中碱选自氢氧化钾、氢氧化钠，碳酸钾，碳酸钠；醇类溶剂选自甲醇、乙醇、异丙醇；水和甲醇的比例为1:1～10:1；
(3)在上述水飞蓟宾碱液的水溶液中，滴加盐酸小檗碱或者二氢小檗碱的水溶液，搅拌，有固体析出；
(4)滤出固体，干燥，得到小檗碱和水飞蓟宾组成的盐。
本发明技术方案的第三方面是提供了一种药物组合物，其特征在于，所述的药物组合物包含治疗有效量的第一方面所述的小檗碱或二氢小檗碱和水飞蓟宾形成的盐，以及药物上可接受的赋形剂。
本发明的的药物组合物包含上述小檗碱或二氢小檗碱和水飞蓟宾形成的盐和药学上可接受的赋形剂。本发明药物组合物的剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
上述剂型可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统，例如脂质体制剂。
本发明的药物组合物可根据本领域公知的方法制备。可通过将小檗碱水飞蓟宾盐与一种或多种药学上可接受的固体或液体赋形剂结合，制成适于人或动物使用的任何剂型。小檗碱水飞蓟宾盐或者含有其的本发明的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
例如，为了将小檗碱水飞蓟宾盐制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了制成胶囊剂，可以将有效成分小檗碱水飞蓟盐与稀释剂、助溶剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分小檗碱水飞蓟盐先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明双环醇类化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
本发明药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般而言，对于施用至人类受试者而言，小檗碱的剂量为按小檗碱计1-30mg/kg/日，优选2-25mg/kg/日，更优选5-20mg/kg/日；水飞蓟宾的剂量为按水飞蓟宾计1-25mg/kg/日，优选2-20mg/kg/日，更优选5-15mg/kg/日。
此外，上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。进而，本发明的盐可以与其它药物，例如，维生素E、奥贝胆酸、双环醇、多烯磷脂酰胆碱、甘草酸二胺、还原型谷胱甘肽、S-腺苷甲硫氨酸、熊去氧胆酸等，只要它们不损害小檗碱-水飞蓟宾盐作用即可。进而，当本发明的小檗碱水飞蓟宾盐与其它药物合用时，应根据实际情况调整它的剂量。
本发明技术方案的第四方面是提供第一方面所述的盐在制备预防或治疗代谢性疾病及相关疾病药物中的应用。
所述的代谢性疾病包括血糖代谢紊乱、血脂代谢紊乱、肥胖、脂肪性肝病以及动脉粥样硬化。所述血脂代谢紊乱包括高低密度脂蛋白-胆固醇、高总胆固醇、高低密度脂蛋白-胆固醇、高甘油三脂或低高密度脂蛋白-胆固醇；所述血糖代谢紊乱为高血糖、胰岛素抵抗；所述肥胖为体重增加、体脂率升高；所述脂肪性肝病为肝组织甘油三酯(TG)升高、肝指数增加、肝脂率增加、血清谷丙转氨酶(ALT)、谷草转氨酶(AST)增加、肝脏炎症因子升高。
所述的代谢相关疾病包括心脑血管疾病、神经退行性疾病。所述的心脑血管疾病包括动脉粥样硬化，高血压；神经退行性疾病包括阿尔茨海默病、帕金森。
有益技术效果
本发明的盐是不同于小檗碱、水飞蓟宾及其物理混合物的一种新化合物，与小檗碱与水飞蓟宾物理混合物的核磁图谱、粉末X射线衍射图谱、DSC谱图、红外光谱均不同。该盐可显著增加水飞蓟宾的溶出速率，并且两个药物有协同释放的特征,水飞蓟宾的口服生物利用度得到显著提高，具有增强的协同药理作用。
在高脂饮食诱导的金黄地鼠高血脂及脂肪性肝病模型中，本发明盐可降低模型动物血脂水平、改善肝功能。在高脂饮食诱导的Balbc小鼠肥胖模型种，本发明可显著降低模型动物体重。
附图说明
图1是小檗碱水飞蓟宾盐的核磁谱图。
图2是小檗碱与水飞蓟宾物理混合物的核磁谱图。
图3是小檗碱水飞蓟宾盐的红外光谱图。
图4是小檗碱与水飞蓟宾物理混合物的红外光谱图。
图5是小檗碱水飞蓟宾盐的DSC图。
图6是小檗碱与水飞蓟宾物理混合物的DSC图。
图7是小檗碱水飞蓟宾盐的粉末X衍射图。
图8是小檗碱与水飞蓟宾物理混合物的粉末X衍射图。
图9是小檗碱与水飞蓟宾物理混合物以及小檗碱水飞蓟宾盐中小檗碱以及水飞蓟宾在水中的累计溶出曲线图。
图10是小檗碱与水飞蓟宾物理混合物以及小檗碱-水飞蓟宾盐，灌胃给予C57小鼠，小鼠血浆中小檗碱的药时曲线。
图11是小檗碱与水飞蓟宾物理混合物以及小檗碱-水飞蓟宾盐，灌胃给予C57小鼠，小鼠血浆中水飞蓟宾的药时曲线。
图12是在高脂饮食诱导的金黄地鼠高血脂及脂肪性肝病模型中，不同给药组实验动物肝脏甘油三酯含量比较。
图13是在高脂饮食诱导的金黄地鼠高血脂及脂肪性肝病模型中，不同给药组实验动物血浆中胆固醇含量比较。
图14是在高脂饮食诱导的金黄地鼠高血脂及脂肪性肝病模型中，实验动物血浆中低密度脂蛋白-胆固醇含量比较。
图15是在高脂饮食诱导的金黄地鼠高血脂及脂肪性肝病模型中，实验动物血浆中甘油三酯含量比较。
图16是在高脂饮食诱导的金黄地鼠高血脂及脂肪性肝病模型中，实验动物血浆谷丙转氨酶含量比较。
图17是在高脂饮食诱导的金黄地鼠高血脂及脂肪性肝病模型中，实验动物血浆谷草转氨酶含量比较。
图18是在高脂饮食诱导的金黄地鼠高血脂及脂肪性肝病模型中，实验动物肝组织油红染色图片。
图19是在高脂饮食诱导的BalbC小鼠肥胖模型中，不同给药组实验动物体重变化比较。
具体实施方式
以下实施例可帮助本领域的技术人员更全面的理解本发明，但不以任何方式限制本发明，应理解，这些实施方式仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲述的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
所用小檗碱及水飞蓟宾购自南京泽朗生物有限公司，
实施例1小檗碱水飞蓟宾盐的制备
将3.7克小檗碱氯化物加入到500mL水中，在80℃加热溶解。另将4.8克水飞蓟宾加入到300mL乙醇和水中搅拌分散(乙醇/水＝1:1)，加入0.5g氢氧化钠搅拌，直至体系溶清，减压蒸出乙醇。向水飞蓟宾钠的水溶液中缓慢滴加上述小檗碱水溶液，同时在室温下搅拌，有固体析出。滴毕，过滤，固体50℃干燥12小时，得到小檗碱水飞蓟宾盐6.0克。图1
1H NMR(400MHz,DMSO)δ12.22(s,1H),9.89(s,1H),8.93(s,1H),8.20(d,J＝8.8Hz,1H),8.00(d,J＝9.0Hz,1H),7.80(s,1H),7.09(s,1H),7.01(d,J＝2.3Hz,2H),6.99–6.90(m,2H),6.86(dd,J＝8.1,1.9Hz,1H),6.80(d,J＝8.1Hz,1H),6.18(s,2H),5.23(s,1H),5.19–5.11(m,2H),5.05–4.84(m,4H),4.76(d,J＝10.4Hz,1H),4.23(dd,J＝10.5,6.6Hz,1H),4.19–4.00(m,8H),3.78(s,4H),3.67–3.06(m,15H).
对比例小檗碱水飞蓟宾混合物的制备
将3.7克小檗碱氯化物和4.8克水飞蓟宾加入到500mL甲醇中，加热溶解澄清。溶液减压蒸出溶剂，得到固体，研磨后50℃干燥12小时，得到小檗碱水飞蓟宾混合物8.0克。图2
1H NMR(400MHz,DMSO)δ11.89(d,J＝1.0Hz,1H),10.93(d,J＝2.0Hz,1H),9.90(s,1H),9.18(d,J＝0.9Hz,1H),8.96(s,1H),8.21(d,J＝9.2Hz,1H),8.01(d,J＝9.1Hz,1H),7.81(s,1H),7.09(d,J＝2.7Hz,2H),7.02(tt,J＝4.5,2.1Hz,2H),6.97(dd,J＝8.2,1.4Hz,1H),6.87(dd,J＝8.1,1.9Hz,1H),6.82(d,J＝8.0Hz,1H),6.18(s,2H),5.97–5.87(m,2H),5.82(d,J＝6.3Hz,1H),5.09(d,J＝11.3Hz,1H),4.95(ddd,J＝16.4,10.8,6.7Hz,4H),4.61(ddd,J＝11.2,6.1,4.9Hz,1H),4.17(dp,J＝5.9,1.8Hz,1H),4.09(d,J＝10.2Hz,6H),3.78(s,3H),3.59–3.50(m,1H),3.48–3.41(m,1H),3.21(t,J＝6.4Hz,2H),2.51(d,J＝7.5Hz,10H),1.06(t,J＝7.0Hz,2H).
实施例2.红外光谱测定
取各样品适量分别与KBr混合后压片。扫描范围是400-4000cm-1。图3、4为小檗碱与水飞蓟宾的物理混合物，小檗碱水飞蓟宾盐的红外光谱图。由图可见，小檗碱水飞蓟宾盐的红外光谱中，3454cm-1处的OH的自由震动峰消失。在1083cm-1处的C-O-C特征峰消失。
实施例3.DSC测定
取实施例1制备的小檗碱水飞蓟宾盐，精确称量样品2-5mg置于铝坩埚中，同时用同种类型的空坩埚作为参比。保护气氛为纯度为99％的氮气，流速为60ml/min。样品扫描的速率为10℃/min，扫描范匿为25-280℃。图5、6为小檗碱与水飞蓟宾的物理混合物，小檗碱水飞蓟宾盐的DSC图谱。由图显示，小檗碱水飞蓟盐，分别位于91.7℃和166.3℃处有吸热峰，小檗碱与水飞蓟宾的物理混合物在159.9℃处有吸热峰。
实施例4.X-ray粉末衍射测定
取各样品适量于铝制样品槽中制成分析样品，然后进行X射线粉术衍射。测定条件：CuKa靶作x射线源；电压：40kV，电流：35mA，扫描范围为3°<2θ<40°。图7、8为小檗碱与水飞蓟宾的物理混合物，小檗碱水飞蓟宾盐的X-ray粉末衍射图。由图可见，小檗碱与水飞蓟宾物理混合物有多个尖锐的衍射峰，小檗碱水飞蓟宾盐没有明显的衍射峰。
实施例5.累积溶出曲线测定
小檗碱测定色谱条件：色谱柱：Kromasil C18色谱柱(150mm×4.6mm,5μm)；流动相:乙腈-0.05mol/L磷酸二氢钠(用磷酸调节pH＝3)(28∶72)；流速:1.0ml/min；柱温:室温(25℃)；检测波长:345nm。
水飞蓟宾测定色谱条件色谱柱：Agilent ZORBAX Eclipse XDB C18柱(4.6×250mm，5μm)；流动相：甲醇-水-冰醋酸(48︰52︰1)；柱温：30℃；检测波长：287nm；流速：1mL·min-1；进样量：10μL。
取各样品按中国药典2015年版附录中有关桨法规定进行，转速100±1r/min,水浴温度37℃,溶出介质:水，投药量相当于小檗碱16mg，水飞蓟宾20mg，分别于0.25，0.5，1，2，3，5，6，8，10，12，24小时取样2ml，0.45um滤膜过滤，同时补充同温度2ml的溶出介质，取滤液1ml，流动相稀释后采用以上HPLC方法测定累计溶出量。图9为各样品中小檗碱及水飞蓟宾的累积溶出曲线。由图9可见，物理混合物中小檗碱15分钟溶出可达90％，水飞蓟宾24小时仅溶出5％。小檗碱水飞蓟宾盐延缓了小檗碱溶出速率，4小时溶出达到90％，同时水飞蓟宾溶出度显著升高，4小时累积溶出增至40％，两药的溶出行为具有一致性。小檗碱水飞蓟宾盐与两药的物理混合物的溶出行为明显不同，可能有利于两药协同发挥作用。
实施例6.血浆中小檗碱及水飞蓟宾的药时曲线
小檗碱测定色谱条件色谱柱：Shim-pack XR-ODSⅡcolumn(3mm×75mm，2.3μm)；内标(Internal standard，IS)：盐酸巴马汀；柱温：30℃；进样量：10μL；流动相：A为0.5％甲酸水溶液，B为乙腈，进行梯度洗脱(0-4min,85％A+15％B；5-6min,20％A+80％B)；流速：0.5mL/min。
质谱条件离子源：电喷雾离子化(ESI)；IS:5500V；温度：550℃；CUR：20V；CE：35V；DP：50V；CAD：mediam；检测方式：正离子模式；监测离子对：BBR m/z 398.2/308.2，IS m/z392.1/312.1。
将60只C57小鼠鼠随机分为2组，分别灌胃给予小檗碱与水飞蓟宾的物理混合物、小檗碱水飞蓟宾盐。分别于给药后0.25，0.5，1，3，6，12，24h处死两组各5只小鼠，取血500ul，置于含1％肝素钠的EP管中，3000rpm 4℃下离心10min，取血浆100μL于1.5mL EP管，按顺序加入10μL内标溶液，50μL 0.6M NaOH溶液及1.25mL无水乙醚，2500r/min涡旋震荡10min，随后12000rpm 4℃下离心10min，取上层乙醚500μL至新的EP管，于40℃下氮吹仪中吹干，100μL稀释液复溶，重复涡旋振荡及离心，取上清80μL至含有内插管的进样小瓶中，进行分析。图10为各样品中小檗碱的药-时曲线。由图10可见，小檗碱-水飞蓟宾共盐中小檗碱的生物利用度与两药的物理混合物一致。
实施例7.水飞蓟宾生物利用度测定
水飞蓟宾测定色谱条件【4】色谱柱：Kinetex XB-C18(2.1×50mm，2.6um)；流速:0.3mL/min；柱温：30℃；进样盘温度：6℃；进样体积10ul；流动相：纯水(含0.1％甲酸，A相)；乙腈(B相)；进行梯度洗脱：0-0.5min，20％B；0.5-1min，20-65％B；1-2.4min，65％B，2.4-2.5min 65％-90％B；2.5-3.4min，90％B；3.4-3.5min，90％-20％B；3.5-4.5min，20％B)。图11为各样品中水飞蓟宾的药-时曲线。由图11可见，小檗碱水飞蓟宾盐中水飞蓟宾的生物利用度显著高于小檗碱与水飞蓟宾的物理混合物。
实施例8.小檗碱水飞蓟宾盐的应用，其特征是用于制备治疗高脂血症及代谢相关脂肪性肝病药物中。本发明通过饲喂叙利亚金黄地鼠高脂饮食饲料，建立高脂血症及代谢性脂肪性肝病模型。
1.实验设计
将叙利亚金黄地鼠(8周龄)，随机分为4组，对照组(正常饮食)、模型组(高脂饮食)、小檗碱与水飞蓟宾物理混合物(高脂饮食+小檗碱与水飞蓟宾物理混合物)、小檗碱水飞蓟宾盐组(高脂饮食+小檗碱水飞蓟宾盐)，各组6只。以上各组动物分别灌胃给药，对照组及模型组地鼠给予10mL/kg/d蒸馏水。小檗碱和水飞蓟宾物理混合物组及小檗碱水飞蓟宾盐组两药剂量分别为48/kg/d，60mg/kg/d，每日给药1次，连续给药5周。给药结束后，腹腔注射1ml 20％水合氯醛麻醉处死动物，摘眼球采血，取肝脏。采用自动生化测定仪测定血生化指标。实验结果表明，小檗碱水飞蓟盐具有降低肝脏中的甘油三酯，降血脂的作用，且作用均优于小檗碱与水飞蓟宾物理混合物。因此，小檗碱-水飞蓟盐能够有效地防治高血脂及代谢性脂肪性肝病。
2.小檗碱水飞蓟宾盐对实验动物肝脏甘油三酯含量影响
肝脏甘油三酯含量测定结果示于图12和表1。
表1
高脂饮食模型动物肝脏中的甘油三酯较空白组显著升高。小檗碱水飞蓟宾盐有效降低高脂饮食引起的肝脏甘油三酯含量增加，而且降低程度比小檗碱水飞蓟宾物理混合物更显著。
3.小檗碱水飞蓟宾盐对实验动物血脂影响
血脂的检测主要针对血浆中胆固醇、低密度脂蛋白及甘油三酯的含量。
血浆胆固醇含量的结果示于图13和表2中。
表2
血浆低密度脂蛋白含量示于图14和表3中。
表3
血浆甘油三酯含量的结果示于图15和表4中。
表4
高脂饮食造模后，动物血浆中胆固醇、低密度脂蛋白及甘油三酯显著上升，小檗碱及水飞蓟宾物理混合物组具有降低血脂的作用，小檗碱水飞蓟宾盐能有效降低高脂饮食引起的血脂升高，而且降低程度比小檗碱-水飞蓟宾物理混合物更显著。
4.小檗碱水飞蓟宾盐对实验动物肝功能的改变
图16，表5为干预结束后各组叙利亚金黄地鼠谷丙转氨酶(ALT)水平的比较。
表7
由图可知，与空白对照组相比，模型组ALT水平显著升高。与模型组相比，小檗碱水飞蓟宾盐显著降低高脂饮食引起的ALT水平，而且降低程度比小檗碱-水飞蓟宾物理混合物更显著。
图17表6为干预结束后各组叙利亚金黄地鼠谷草转氨酶(AST)水平的比较。
表6
由图可知，与空白对照组相比，模型组动物的AST水平无显著差异。与模型组相比，小檗碱水飞蓟宾盐及小檗碱-水飞蓟宾物理混合物无显著差异。
图18为实验动物肝组织切片油红染色结果。
如图所示，与空白对照组相比，高脂饮食组的肝组织内脂质沉积明显增多；小檗碱水飞蓟宾盐组地鼠肝脏油红染色明显减轻，肝脏脂质沉积减少结果表明药物干预后能够抑制肝脏中甘油三酯等中性脂肪的沉积，改善肝脏脂肪变性，而且改善肝组织变性的程度要明显强于小檗碱水飞蓟宾物理混合物组。
实施例9.小檗碱水飞蓟宾盐的应用，其特征是用于制备治疗肥胖的药物中。本发明通过饲喂BalbC小鼠高脂饮食饲料，建立肥胖动物模型。
1.实验设计
将BalbC小鼠(8周龄)，随机分为4组，对照组(正常饮食)、模型组(高脂饮食)、小檗碱与水飞蓟宾物理混合物(高脂饮食+小檗碱与水飞蓟宾物理混合物)、小檗碱水飞蓟宾盐组(高脂饮食+小檗碱水飞蓟宾盐)，各组6只。以上各组动物分别灌胃给药，对照组及模型组地鼠给予10mL/kg/d蒸馏水。小檗碱和水飞蓟宾物理混合物组及小檗碱水飞蓟宾盐组两药剂量分别为48/kg/d，60mg/kg/d，每日给药1次，连续给药5周。每周记录动物体重，给药结束后，腹腔注射1ml 20％水合氯醛麻醉处死动物，取附睾脂肪。实验结果表明，小檗碱水飞蓟盐具有降低体重、降低附睾脂肪指数作用，且作用均优于小檗碱与水飞蓟宾物理混合物。因此，小檗碱水飞蓟盐能够有效地防治肥胖。
2.小檗碱水飞蓟宾盐对实验动物体重影响
实验期间每周记录小鼠体重，其体重变化如图19所示。由图可知，相比于正常饮食，高脂饮食显著增加BalbC小鼠体重。与模型组相比，小檗碱与水飞蓟宾物理混合物组的体重与模型组没有显著性差异。小檗碱水飞蓟宾盐显著降低高脂饮食引起的体重增加，降低体重的程度显著高于小檗碱与水飞蓟宾的物理混合物。
参考文献
1.小檗碱调节糖脂代谢机制研究进展.刘晓燕，刘剑，高宇，中国老年学杂志.2016，36(8)：4117-4119
2.小檗碱的临床研究进展.王晓红，医药前沿.2013，27：380-381
3.小檗碱心血管药理研究简要述评.王瑞国，方泰惠，第四届全国中医药免疫学术研讨会论文汇编.2007年09月30日
4.Caco2细胞单层模型中水飞蓟宾吸收机制研究.胡林，童焕，丁茹，王湛博，尤淋君，杨劲，中国药科大学学报.2018，49(2)：202-208
Claims (9)
1.一种小檗碱和水飞蓟宾形成的盐，其特征在于，所述盐的结构为:
2.根据权利要求1的盐，其特征在于，其中小檗碱的结构为:
R1为氯离子或者氢氧根，
水飞蓟宾的结构为:
3.权利要求1-2任一项的盐的制备方法，其特征在于，所述的制备方法包括以下步骤，
(1)将盐酸小檗碱加热溶解于10～300倍的水中；
(2)将水飞蓟宾分散于水和醇类溶剂中，加入0.5～1.5当量的碱，使其溶解，然后蒸出醇类有机溶剂，其中碱选自氢氧化钾、氢氧化钠，碳酸钾，碳酸钠；醇类溶剂选自甲醇、乙醇、异丙醇；水和甲醇的比例为1:1～10:1；
(3)在上述水飞蓟宾碱液的水溶液中，滴加盐酸小檗碱的水溶液，搅拌，有固体析出；
(4)滤出固体，干燥，得到小檗碱和水飞蓟宾组成的盐。
4.一种药物组合物，其特征在于，所述的药物组合物包含治疗有效量的权利要求1-2任一项所述的盐，以及药学上可接受的赋形剂。
5.权利要求1-2任一项的盐在制备预防或治疗代谢性疾病及相关疾病药物中的应用。
6.根据权利要求5的应用，其特征在于，所述的代谢性疾病包括血糖代谢紊乱、血脂代谢紊乱、肥胖、脂肪性肝病以及动脉粥样硬化。
7.根据权利要求6的应用，其特征在于，所述血脂代谢紊乱包括高低密度脂蛋白-胆固醇、高总胆固醇、高低密度脂蛋白-胆固醇、高甘油三脂或低高密度脂蛋白-胆固醇；所述血糖代谢紊乱为包括高血糖、胰岛素抵抗；所述肥胖包括体重增加、体脂率升高；所述脂肪性肝病包括肝组织甘油三酯(TG)升高、肝指数增加、血清谷丙转氨酶、谷草转氨酶增加。
8.根据权利要求5的应用，其特征在于，所述的代谢相关疾病包括心脑血管疾病。
9.根据权利要求8的应用，其特征在于，所述的心脑血管疾病包括动脉粥样硬化，高血压。
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| Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins;Francesco Di Pierro等;《Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy》;第8卷;89-96 * |
| The Quest to Enhance the Efficacy of Berberine for Type-2 Diabetes and Associated Diseases: Physicochemical Modification Approaches;Solomon Habtemariam;《Biomedicines .》;第8卷(第4期);1-19 * |
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