CN113679664B - 白藜芦醇高分子水溶液及其制备方法 - Google Patents

白藜芦醇高分子水溶液及其制备方法 Download PDF

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CN113679664B
CN113679664B CN202010421302.1A CN202010421302A CN113679664B CN 113679664 B CN113679664 B CN 113679664B CN 202010421302 A CN202010421302 A CN 202010421302A CN 113679664 B CN113679664 B CN 113679664B
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孙锐杰
张雪
董磊
丁杰
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Shanghai Sandy Biopharmaceutical Co ltd
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Abstract

白藜芦醇高分子水溶液及其制备方法。本发明提供了一种白藜芦醇高分子水溶液，包括白藜芦醇和分散介质；所述白藜芦醇在高分子溶液中的重量百分比为0.20‑0.25％；所述分散介质包括如下成分及其重量百分比：聚乙二醇8‑12％、泊洛沙姆1.2‑1.3％、卡波姆940 0.25‑0.32％、碱性pH值调整剂，纯化水作为余量；其中聚乙二醇和泊洛沙姆的重量比为6:1‑10:1。本发明白藜芦醇高分子水溶液显著提高了白藜芦醇的稳定性。

Description

白藜芦醇高分子水溶液及其制备方法
技术领域
本发明属食品和生物医药领域，具体涉及含有白藜芦醇的液体分散体系。具体而言，本发明涉及一种具有优良的生物适应性的且稳定的白藜芦醇液体分散体系，本发明还涉及该白藜芦醇液体分散体系的制备方法。
背景技术
白藜芦醇(3,4’,5-三羟基茋(3,4’,5-trihydroxystilbene)，又称为芪三酚)是是一种多酚类化合物。它存在于红葡萄、花生、桑葚、虎杖、紫菀科植物(knotweed)、覆盆子(raspberry)、蓝莓等至少21个科、31个属的72种植物中，近年来，越来越多的科学研究表明白藜芦醇具有多种生物活性，包括具有降低血液粘稠度、抑制血小板凝结和血管舒张等药理作用，可用于动脉粥样硬化、冠心病、缺血性心脏病、高血脂等疾病防治作用。目前其广泛应用于食品、保健品、化妆品和医药等领域。目前已多个国家和地区都开发了白藜芦醇及其制品，例如美国已把白藜芦醇作为膳食补充剂，日本已将白藜芦醇作为食品添加剂，中国也已将含有白藜芦醇的植物提取物制成降脂美容的天然保健食品。
已知白藜芦醇具有多种生物活性和潜在的改善人体健康的价值，其用于人体时仍存在。白藜芦醇难溶于水，25度时在水中的溶解度仅0.03g/Kg，即0.003％；白藜芦醇易于其他化学物质反应，且对光不稳定，在Microherb稳定性试验中，高纯度的白藜芦醇乙醇溶液即使在避光条件下，也仅能稳定数天。白藜芦醇在紫外光照射下会产生荧光，当pH>10时，稳定性较差。这些均限制了白藜芦醇的广泛使用。
现有技术中很多研究将白藜芦醇制备成脂质体、纳米粒、包合物、分散片、凝胶剂、微囊、微球、微乳等新剂型，能够显著地提高药物稳定性和生物利用度。专利申请CN200680036429.X披露了含有至少一种多酚和聚乙二醇的组合物。所述多酚包括白藜芦醇。在该发明中，聚乙二醇用于掩盖这类多酚苦味的用途，但未提及白藜芦醇难溶性和稳定性差的技术问题，更未给出解决方案。专利申请号CN200880014227.4披露了含有(1)至少一种选自白藜芦醇和其盐的化合物，和(2)至少一种视黄素的组合物。在其实施例中披露了含有甘油和聚乙二醇的口服混悬液，但并未解决白藜芦醇的难溶性和分散体系稳定性的问题。专利申请CN2011101187277.6公开了亲水聚合物与白藜芦醇组成的结合物，其中亲水性聚合物包括聚乙二醇；该发明通过化学键接提高结合物的稳定性和水溶性，但同时也使结合物的体内活动更为复杂和不可预测。
有鉴于此，特提出本发明。
发明内容
本发明的目的在于开发一种稳定的生理活性可靠的白藜芦醇高分子水溶液，其提高了白藜芦醇在体外环境中的稳定性，同时也使其体内过程更加可靠和可预期。
本发明的进一步目的在于开发上述白藜芦醇高分子水溶液的制备方法，其工艺简单可靠。
本发明的进一步的目的在于开发一种可用于多种用途的白藜芦醇高分子水溶液，其可单独作为口服液，也可进一步加工作为个人护理制品、药物和膳食组合物的用途。例如，可作为食品添加剂进一步制备为功能性食品，可作为化妆品添加剂进一步制备为外用化妆品如面膜，也可进一步制备为药学上适用的口服液体制剂。
为了实现本发明的上述目的，特采用以下技术方案：
本发明白藜芦醇高分子水溶液，包括白藜芦醇和分散介质；所述白藜芦醇在高分子溶液中的重量百分比为0.20-0.25％；所述分散介质包括如下成分及其重量百分比：聚乙二醇8-12％、泊洛沙姆1.2-1.3％、卡波姆9400.25-0.32％、碱性pH值调整剂及水作为余量；聚乙二醇和泊洛沙姆的重量比为6:1-10:1；其中，聚乙二醇选自分子量200至800的聚乙二醇之一种或多种；泊洛沙姆选自分子量为4000-14000之间且HBL值在16-30范围内的泊洛沙姆之一种或多种；卡波姆选自分子量在7×105到4×106之间卡波姆940；上述白藜芦醇高分子水溶液所述任选地包括酸性pH值调整剂、抗菌防腐剂和矫味剂。
在一些具体的实施方式中，所述聚乙二醇选自聚乙二醇200、聚乙二醇400、聚乙二醇600和聚乙二醇800之一种或多种；所述泊洛沙姆为泊洛沙姆188。
在一些具体的实施方式中，所述聚乙二醇在所述高分子溶液中的重量百分比为9-11％，所述泊洛沙姆在所述高分子溶液中的重量百分比为1.2-1.3％；聚乙二醇和泊洛沙姆的重量比为7:1-9:1。
在一些具体的实施方式中，所述聚乙二醇和泊洛沙姆的重量比为7:1-8:1。
在一些具体的实施方式中，所述碱性pH值调整剂选自碳酸钠、氢氧化钠、三乙醇胺中之一种或几种，所述酸性pH值调整剂选自盐酸、柠檬酸、酒石酸。
在一些具体的实施方式中，所述聚乙二醇为聚乙二醇400。
上述白藜芦醇高分子水溶液的制备方法，包括以下步骤：
a)将卡波姆940加入纯水分散均匀备用，碱性pH调整剂纯水分散均匀备用；
b)白藜芦醇进行粉碎，溶解于聚乙二醇，再加入泊洛沙母充分混匀，加入纯水进行溶解混匀；
c)将步骤(a)制得的卡波姆940分散体系以碱性pH值调整剂溶液调整至pH值8-9，迅速加入到步骤(b)所制备的分散体系中，充分混合，制得白藜芦醇高分子水溶液。
在一些具体的实施方式中，在上述的白藜芦醇高分子水溶液的制备方法，在其步骤(a)中，在卡波姆940水溶液中，加入酸性pH值调整剂调整pH值至4-6。
在一些具体的实施方式中，在其步骤(c)制得的白藜芦醇高分子水溶液中，加入药学上可接受的防腐剂和调味剂。
本发明中“白藜芦醇”可以是天然来源或化学合成。本文使用术语“白藜芦醇”也包括其衍生物、代谢物或类似物。碳-碳双键可以是反式或顺式的，并包括顺式/反式混合物。被醚化或酯化的羟基可以衍生自具有1-26个碳原子的、未被取代的或被取代的、直链或支链的烷基，或衍生自具有1-26个碳原子的，未被取代的或被取代的、直链或支链的脂肪族的、芳脂族的或芳香族的羧酸。被醚化的羟基还可以是糖苷基团，被酯化的羟基还可以是葡糖苷酸或硫酸酯基团。本发明优选反式白藜芦醇。
本发明白藜芦醇高分子水溶液可用于多种用途。其可单独作为口服液，也可进一步加工作为个人护理制品、药物和膳食组合物的用途。例如，可作为食品添加剂进一步制备为功能性食品，可作为化妆品添加剂进一步制备为外用化妆品如面膜，也可进一步制备为药学上适用的口服液体制剂。其中“膳食组合物”包括任何类型的强化食品、临床营养物和膳食补充剂以及相应的添加剂，还包括功能食品以及营养药物或其它具有营养价值的药物制品，术语“功能食品”指能够提供更多健康益处的食物。
本发明特别适用于直接口服的产品形式。此时优选地添加甜味剂如蔗糖、阿斯巴甜以获得更好的口感，也可以添加矫味剂，如橙皮苷以获得更适宜经口服用。
本发明采用含有聚乙二醇、泊洛沙姆和水的液体分散体系，获得分散均匀、储存稳定的白藜芦醇高分子水溶液。发明人经过深入研究，发现本发明白藜芦醇高分子水溶液克服了常规增溶和助溶体系的热力学不稳定性，在有限的泊洛沙姆的用量下，长期存放和加速稳定性试验条件下，获得了卓越的稳定性。
本发明取得的突出的有益的技术，包括但不限于：
(1)本发明提供的白藜芦醇高分子水溶液，白藜芦醇以分子形式分散在分散介质中，使其体内过程更可靠，避免了增溶和助溶情形下体内过程的不可靠性；同时保持了较佳的光稳定性。
(2)本发明提供的白藜芦醇高分子水溶液可用于多种用途，包括口服方式和以适当形式外用，尤其是口服方式，克服了现有技术中白藜芦醇用于口服时的复杂处理过程。
(3)本发明提供的白藜芦醇高分子水溶液的制备方法，使用普通设备即可实现，为白藜芦醇广泛使用提供了产业化基础。
本发明的更多有益技术效果可经由上述表述的技术方案和相应的技术效果而推导得出。对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据上述表述获得更多有益技术效果。
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限制本发明的范围。
具体实施方式
实施例1：白藜芦醇高分子溶液的制备
按照表1所示的配方制备本发明白藜芦醇高分子溶液和对比例。对比例在目的是说明在本发明成分及比例之外未能完整实现本发明效果。处方一、处方二和处方三以及对比实施例均按照以下方法制备：
(1)将卡波姆940加入纯水分散均匀备用，碱性pH调整剂纯水分散均匀备用；
(2)白藜芦醇进行粉碎，溶解于聚乙二醇，再加入泊洛沙母充分混匀，加入纯水进行溶解混匀；
(3)将步骤(1)制得的卡波姆940分散体系以碱性pH值调整剂溶液调整至pH值8-9，迅速加入到步骤(2)所制备的分散体系中，充分混合，制得白藜芦醇高分子水溶液。
表1白藜芦醇高分子溶液实施例和对比例配方
Figure SMS_1
观察上述制备得到的白藜芦醇高分子溶液的外观，均澄清透明。
实施例2：高温、光照和室温放置稳定性试验
将实施例1所制得的样品分装在透明容器密封，参照药物稳定性试验方法，分别在40℃恒温避光、紫外光照射和室温避光条件下静置，并观察其性状变化，结果如表2所示，结果显示处方一、处方二和处方三在上述试验条件下具备更佳的稳定性。
表2白藜芦醇高分子溶液实施例和对比例稳定性试验结果
Figure SMS_2
Figure SMS_3
最后应说明的是，以上实施方式仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，但本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。

Claims (3)

1.一种白藜芦醇高分子水溶液，包括白藜芦醇和分散介质；所述白藜芦醇在高分子溶液中的重量百分比为0.20-0.25％；所述分散介质包括如下成分及其重量百分比：聚乙二醇400在所述高分子溶液中的重量百分比为9-11％，泊洛沙姆188在所述高分子溶液中的重量百分比为1.2-1.3％；聚乙二醇400和泊洛沙姆188的重量比为7:1-9:1，还包括分子量在7×105到4×106之间的卡波姆940、碱性pH值调整剂、纯化水作为余量；其中碱性pH值调整剂选自碳酸钠、氢氧化钠、三乙醇胺中之一种或几种；
上述白藜芦醇高分子水溶液还包括酸性pH值调整剂、抗菌防腐剂和矫味剂；
所述的白藜芦醇高分子水溶液通过以下方法制备，包括以下步骤：
a)将卡波姆940加入纯水分散均匀备用，碱性pH调整剂纯水分散均匀；再加入酸性pH值调整剂调整pH值至4-6；
b)白藜芦醇进行粉碎，溶解于聚乙二醇400，再加入泊洛沙姆188充分混匀，加入纯水进行溶解混匀；
c)将步骤(a)制得的卡波姆940分散体系以碱性pH值调整剂溶液调整至pH值8-9，迅速加入到步骤(b)所制备的分散体系中，加入药学上可接受的抗菌防腐剂和矫味剂，充分混合，制得白藜芦醇高分子水溶液。
2.如权利要求1所述的白藜芦醇高分子水溶液，其特征在于，所述聚乙二醇和泊洛沙姆的重量比为7:1-8:1。
3.如权利要求1至2任一所述的白藜芦醇高分子水溶液制备用于口服液、功能性食品和化妆品的用途。
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CN101744288A (zh) * 2010-01-27 2010-06-23 神舟天辰科技实业有限公司 一种含有辅酶q10的澄清口服制剂及其制备方法
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