CN115768408A - 含有三七总皂苷、芦丁和银杏的有机溶胶-凝胶纳米组合物在增强脑和心血管保护中的作用及其制备方法 - Google Patents
含有三七总皂苷、芦丁和银杏的有机溶胶-凝胶纳米组合物在增强脑和心血管保护中的作用及其制备方法 Download PDFInfo
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Abstract
本发明涉及包含负载有植物化学活性成分的三种固体脂质纳米组分的有机溶胶‑凝胶纳米组合物：三七总皂苷从越南的三七中提取。芦丁从越南太平省中的槐树中提取，并且银杏从银杏树中提取。本发明的组合物已经显示具有低毒性和高生物利用度。特别地，该组合物对局部心肌缺血和心律失常是有效的，改善血液流变性、血小板循环和抗聚集以及血栓形成，将血脂降低到一定限度，并且对动脉粥样硬化具有良好的影响。该组合物具有预防自由基损伤的抗氧化效果，并且具有增强毛细管抗性、增强血管壁的效果，从而降低高血压风险，这相应地保护脑神经、预防中风，并且还用于在中风和其他出血性疾病后恢复以增强和重建受损血管的效果。
Description
技术领域
本发明涉及一种含有三七总皂苷、芦丁和银杏的有机溶胶-凝胶纳米组合物，其对增强脑和心血管保护有效，及其制备方法。
背景技术
三七总皂苷
三七是五加科人参的一种，其根用作药物，三七是历史悠久的传统药物，其中三七根能有效改善血管循环，改善血液停滞和停滞，轻微减少肿胀和疼痛，其中包括超过10种类型的提取皂苷。主要组分是含量高于人参的皂苷Rb1和Rg1。从三七根提取的总皂苷已经被用于制造药物数十年。三七总皂苷的主要活性组分的化学结构示于图1中。
芦丁
芦丁，也称为芸香苷、槲皮素-3-芸香苷和槐角苷，是一种在荞麦中发现的柑橘类黄酮糖苷(Kreft等人，1997)。在化学上，它是包含黄酮醇苷槲皮素以及二糖芸香糖的糖苷。已经证明其具有一些药理学活性，包括抗氧化、细胞学保护、血管保护、抗癌、神经保护和心脏保护。
银杏
银杏是银杏科(银杏树)的一种扇形叶木本植物的学名。还测试了来自银杏叶的提取物的化学成分。银杏中的银杏内酯的名称和结构如图2所示。白果内酯和银杏内酯都是银杏的主要组分，其具有银杏的所有生物学和/或药理学活性。然而，不清楚在这种治疗期间分子与药物相互作用的基本机制。山奈酚是槲皮素的代谢物，而异鼠李素是山奈酚的代谢物。银杏叶的市售银杏富含银杏叶的提取物的水-丙酮或水-乙醇，并且标准化为其类黄酮含量或其三倍。这些组分具有促进神经元的生长和银杏叶中黄烷醇抗氧化剂的特性，可诱导诸如精神改变和记忆改善的作用。
银杏的药理学功效：银杏在冠状动脉疾病、心律失常、糖尿病心肌病、痴呆和脑梗塞以及脂质调节的治疗中是有效的。
为了组合用于协同效应的上述成分，根据固体脂质纳米技术制备的本发明的组合物包含多个脂质药物偶联物纳米颗粒(LDCN)。显然，这是最现代的纳米药物制剂技术。该技术可以允许在纳米颗粒中装载多种药物成分。这样的脂质纳米颗粒具有共生物利用度，和根据共轭物增强效果的治疗功效，从而产生很好的治疗效果。
发明内容
本发明的目的是提供一种有机溶胶-凝胶纳米组合物，包含以下组分：
(a)固体脂质纳米银杏：15-30％；
(b)固体脂质纳米芦丁：5-25％；
(c)固体脂质纳米三七总皂苷：0.1-10％；
(d)大豆油：40-65％；
(e)卵磷脂：1-10％；
(f)吐温80：0.1-5％。
本发明的其它目的是提供一种用于制备上述组合物的方法，包括下述步骤：
i)制备载体溶液；
ii)制备三种活性成分/载体的共轭纳米脂质预悬浮液；
iii)制备三种活性成分的共轭预预溶胶-凝胶脂质纳米组合物；
iv)制备三种活性成分的共轭溶胶-凝胶脂质纳米组合物；和
v)获得成品组合物。
附图说明
图1显示了三七总皂苷的主要成分的化学结构。
图2示出了芦丁的化学结构。
图3显示了银杏的化学成分。
图4示出了制备有效增强脑和心血管保护的组合物的方法。
图5表示图表1：小鼠批次的随着时间变化的基线疼痛阈值。
图6表示图表2：小鼠批次治疗之后的随时间变化的疼痛阈值。
具体实施方式
根据本发明的有机溶胶-凝胶纳米组合物包含以下组分:
(a)固体脂质纳米银杏：15-30％；
(b)固体脂质纳米芦丁：5-25％；
(C)固体脂质纳米三七总皂苷：0.1-10％；
(d)大豆油：40-65％；
(e)卵磷脂：1-10％
(f)吐温80：0.1-5％
用乙醇溶剂从越南的三七(人参)提取三七总皂苷(PNS)。
购自越南纳米生物制造厂的三七总皂苷(PNS)固体脂质纳米颗粒具有以下参数：平均纳米颗粒尺寸为9.94nm，并且纳米颗粒中的PNS含量超过22％。
芦丁是在乙醇溶剂中从来自太平省的槐树中提取。
购自越南纳米生物制造厂的芦丁固体脂质纳米颗粒具有以下参数：平均纳米颗粒尺寸为11.25nm，并且纳米颗粒中的芦丁含量超过22％。
银杏购自陕西美禾生化有限公司(中国)。
购自越南纳米生物制造厂的固体脂质银杏(GBLB)纳米颗粒具有以下规格：平均纳米颗粒尺寸为9.943nm，并且纳米颗粒中的GBLB含量超过22％。
此外，还包括赋形剂材料，例如单硬脂酸甘油酯、硬脂酸、硬脂酸镁、吐温80、卵磷脂、木鳖油和大豆油。所有这些都是根据越南标准用作根据法规的药物配制材料的原料。
根据本发明使用的设备包括加热胶凝装置、温度控制器、真空成型装置和可控混合器。
用于制备根据本发明的组合物的方法包括以下步骤：
步骤1：制备载体溶液：将大豆油添加到反应烧瓶中。在70-100℃，优选80℃加热溶液。以250-350rpm均匀搅拌，优选300rpm。接着，向反应烧瓶中加入卵磷脂。搅拌并搅拌直至完全溶解。在约30-50分钟，优选45分钟之后，进一步将表面活性剂吐温80添加到反应烧瓶中。温和沸腾并在约80-100分钟内均匀搅拌，优选90分钟，直到载体溶液变得透明。
步骤2：制备三种活性成分/载体的共轭脂质纳米预悬浮液：缓慢地向反应烧瓶中添加固体脂质纳米三七总皂苷，同时在以400-600rpm，优选500rpm快速搅拌下将温度维持在80-90℃。搅拌并煮沸混合物直到固体脂质纳米三七总皂苷完全溶解。进一步向其中添加固体脂质纳米芦丁，同时维持相同温度和搅拌速度，直到固体脂质纳米芦丁完全溶解。然后，在保持相同温度和搅拌速度的同时向其中添加固体脂质纳米银杏，直到固体脂质纳米银杏完全溶解。
步骤3：制备三种活性成分的共轭预溶胶-凝胶脂质纳米组合物：在约3-24小时内混合含有三种固体脂质纳米组分的载体混合物。反应时间取决于每个产品批次的含量：在实验室约3小时，半工业生产约7小时，和工业生产18-24小时。
步骤4：制备三种活性成分的共轭溶胶-凝胶有机脂质纳米组合物：调整有机溶胶-凝胶组分的含量以实现标准技术参数，包括三七总皂苷、芦丁和银杏的含量。
步骤5：获得成品组合物：在凝胶分解温度下的凝胶形成包括在正常温度(室温)、储存温度(低于24℃)和在35-37℃(人体温度)下的凝胶分解。
实施例
实施例1：制备根据本发明的组合物的方法
使用以下组分制备组合物的一个软900mg胶囊：其中
(a)固体脂质纳米银杏：250mg；
(b)固体脂质纳米芦丁：25mg；
(C)固体脂质纳米三七总皂苷：125mg；
(d)大豆油：450mg；
(e)卵磷脂：40mg；
(f)吐温80：10mg。
将450mg的大豆油加入反应烧瓶中。在以300rpm均匀搅拌的同时，以80℃加热。然后，在沸腾搅拌下将40mg卵磷脂加入烧瓶中直至完全溶解。将10mg的吐温80进一步加入烧瓶中。降低至低于80℃并在90分钟内均匀搅拌。将125mg固体脂质纳米三七总皂苷缓慢加入反应烧瓶中。温度保持在90℃，搅拌速度升至500rpm。继续搅拌和沸腾直到完全溶解。用固体脂质纳米芦丁和固体脂质纳米银杏进行类似的程序。继续混合3小时。调节溶胶-凝胶组分以达到含量标准。
实施例2：组合物对慢性偏头痛的血管舒缩性疼痛消除作用的评价
在测试中，将白色小鼠随机分成5批，每批具有10只动物：对批次1(生物对照)进行0.2ml/10g水的口服给药；对批次2(型号)注射10mg/kg硝酸甘油(NTG)进行0.2mL/10g水的口服给药；对批次3(阳性对照)注射10mg/kg硝酸甘油进行40mg/kg普萘洛尔的口服给药；对批次4注射10mg/kg硝酸甘油以0.96丸剂/kg/天(相当于临床剂量)的剂量进行组合物的口服给药；对批次5注射10mg/kg硝酸甘油以2.88丸剂/kg/天(临床剂量的3倍)的剂量进行组合物的口服给药。
测试结果
基线疼痛阈值
表1.该组合物对痛敏计中疼痛诱发力的影响
曲线图1.小鼠批次随时间的基线疼痛阈值
表1和图的结果显示，模型批次中小鼠的基线疼痛阈值在研究的所有时间点降低，从第五天到第十一天最为显著(p＜0.05，p＜0.01，p＜0.001)。
经口施用40mg/kg普萘洛尔的小鼠批次的基线疼痛阈值在几乎所有时间点大于模型批次的基线疼痛阈值，在第九天和第十一天最显著(p＜0.05)。
以0.96丸剂/kg的剂量口服施用组合物的小鼠批次的基线疼痛阈值大于第五天的模型批次的基线疼痛阈值(p<0.05)，但在其他时间点没有不同(p>0.05)。
以2.88丸剂/kg的剂量口服施用组合物的小鼠批次的基线疼痛阈值大于第十一天的模型批次的基线疼痛阈值(p<0.05)，但在其他时间点没有不同(p>0.05)。
与40mg/kg普萘洛尔相比，组合物在两种剂量下的效果较差。
治疗后的疼痛阈值
表2.组合物对美元计中的诱导疼痛的力的影响
曲线图2.在一段时间内处理小鼠批次后的疼痛阈值
表2和曲线图2的结果显示：
在模型批次中的小鼠的NTG注射后的疼痛阈值在研究的所有时间点显著降低(p<0.05，p<0.01，和p<0.001)。
口服40mg/kg普萘洛尔批次中小鼠的口服给药后的疼痛阈值在所有时间点大于模型批次的疼痛阈值，这从第五天到第十一天最显著(p<0.05，p<0.01，p<0.001)。
口服0.96丸剂/kg组合物批次中小鼠的口服给药之后的疼痛阈值在几乎所有时间点大于模型批次的疼痛阈值，在第五天、第九天和第十一天最显著(p<0.05)。与40mg/kg普萘洛尔相比，效果较差。
口服2.88丸剂/kg组合物批次中小鼠的口服给药之后的疼痛阈值在几乎所有时间点都大于模型批次的疼痛阈值，从第五天到第十一天最为显著(p<0.05，p<0.01)。效果相当于40mg/kg普萘洛尔。
结论
剂量为0.96丸剂/kg和2.88丸剂/kg的组合物在慢性偏头痛模型中治疗后有效降低疼痛阈值。
剂量为2.88丸剂/kg的组合物比剂量为0.96丸剂/kg的组合物更有效，并且相当于40mg/kg普萘洛尔。
实施例3：对组合物对超前镇痛模型的镇静效果的研究
在测试中，将白色小鼠随机分成4批，每批具有10只动物：对批次1(生物对照)进行20mL/kg/天蒸馏水的口服给药；对批次2(阳性对照)进行2.4mg/kg/天地西泮的口服给药；对批次3进行0.96丸剂/kg/天(相当于临床剂量)剂量的组合物的口服给药；对批次4进行2.88丸剂/kg/天(临床剂量的3倍)剂量的组合物的口服给药。
结果
表3.组合物对小鼠引入闭合分支的次数和时间的影响
表3的结果显示，经口施用7天2.4mg/kg/天的地西泮和剂量为0.96丸剂/kg/天和2.88丸剂/kg/天的组合物之后，小鼠引入闭合端的次数和时间比药物预测试和生物对照批次更低，其中差异在统计学上显著(p<0.05)。组合物在两种剂量下的效果等同于2.4mg/kg/天的地西泮。
表4.组合物对小鼠引入开放分支的次数和时间的影响
来自表4的结果显示，在口服施用2.4mg/kg/天的地西泮和剂量为0.96丸剂/kg/天和2.88丸剂/kg/天的组合物7天后，与药物预测试相比和与生物对照批次相比，小鼠引入开放端的次数和时间增加，其中差异是统计学显著的(p<0.05)。组合物在两种剂量下的效果等同于2.4mg/kg/天的地西泮。
表5.组合物对小鼠开放分支处回避率的影响
表5的结果显示，在口服施用7天的2.4mg/kg/天的地西泮和剂量为0.96丸剂/kg/天和2.88丸剂/kg/天的组合物之后，与药物预测试和与生物对照批次相比，小鼠开放端的回避率降低，其中差异是统计学显著的(p<0.001)。组合物在两种剂量下的效果等同于2.4mg/kg/天的地西泮。
实施例4：组合物的抗惊厥效果评价
在测试中，将白色小鼠随机分成4批，每批具有10只动物：对批次1(生物对照)进行20mL/kg/天蒸馏水的口服给药；对批次2(阳性对照)进行2.4mg/kg/天地西泮的口服给药；对批次3进行0.96丸剂/kg/天(相当于临床剂量)剂量的组合物的口服给药；对批次4进行2.88丸剂/kg/天(临床剂量的3倍)剂量的组合物的口服给药。向小鼠注射尼可刹米后，记录小鼠的惊厥开始时间和死亡时间。
表6.所述组合物对在尼可刹米注射后的小鼠的惊厥开始时间和死亡时间的影响
表6的结果显示，2.4mg/kg/天的地西泮在延长尼可刹米注射后小鼠的惊厥开始时间和死亡时间方面发挥了作用，这与模型批次相比具有统计学意义(p<0.05)。
与模型批次相比，剂量为0.96丸剂/kg/天和2.88丸剂/kg/天的组合物倾向于延长尼可刹米注射后小鼠的惊厥发作时间和死亡时间，但差异在统计学上不显著，p>0.05。
Claims (2)
1.一种有机溶胶-凝胶纳米组合物，其含有有效增强脑和心血管保护的三七总皂苷、芦丁和银杏，其中所述组合物包含以下成分：
(a)固体脂质纳米银杏：15-30％；
(b)固体脂质纳米芦丁：5-25％；
(c)固体脂质纳米三七总皂苷：0.1-10％；
(d)大豆油：40-65％；
(e)卵磷脂：1-10％；
(f)吐温80：0.1-5％。
2.制备权利要求1的组合物的方法，所述方法包括以下步骤：
(i)制备载体溶液：将大豆油添加到反应烧瓶中，在70-100℃条件下加热，优选为80℃，并以250-350rpm，优选300rpm均匀搅拌；然后将卵磷脂加入反应烧瓶中，煮沸并搅拌直到完全溶解；在约30-50分钟，优选45分钟后，将表面活性剂吐温80 进一步加入烧瓶中，温和煮沸并均匀搅拌约80-100分钟，优选90分钟，直到载体溶液变得透明；
(ii)制备三种活性成分的共轭脂质纳米预悬浮液/载体：将固体脂质纳米三七总皂苷缓慢添加到反应烧瓶中，在400-600rpm，优选500rpm的快速搅拌下，保持在80-90℃，搅拌并煮沸，直到固体脂质纳米三七总皂苷完全溶解；进一步添加固体脂质纳米芦丁，保持在相同的温度和搅拌速度下，直到固体脂质纳米芦丁完全溶解，然后，向其中添加固体脂质纳米银杏，同时保持相同的温度和搅拌速度，直到固体脂质纳米银杏完全溶解；
(iii)制备三种活性成分的共轭预溶胶-凝胶脂质纳米组合物：含有三种固体脂质纳米组分的载体混合物在约3-24小时内混合，其中反应时间取决于每个产品批次的含量：在实验室中大约3小时，半工业生产大约7小时，和工业生产为18-24小时；
(iv)制备三种活性成分的共轭溶胶-凝胶脂质纳米组合物：调节有机溶胶-凝胶组分的含量以达到标准技术参数，包括三七总皂苷、芦丁和银杏的含量；以及
(v)获得成品组合物：在凝胶分解温度下的凝胶形成包括在常温(室温)和储存温度(低于24℃)下的凝胶化，以及在35-37℃(人体温度)下的凝胶分解。
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