CN108014104A - 一种增效型二氢杨梅素可溶型复合物及其制备方法 - Google Patents
一种增效型二氢杨梅素可溶型复合物及其制备方法 Download PDFInfo
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- CN108014104A CN108014104A CN201810059842.2A CN201810059842A CN108014104A CN 108014104 A CN108014104 A CN 108014104A CN 201810059842 A CN201810059842 A CN 201810059842A CN 108014104 A CN108014104 A CN 108014104A
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- Prior art keywords
- dihydromyricetin
- rebaudioside
- compound
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- main ingredient
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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Abstract
本发明公开了一种具有协同增强药效作用的二氢杨梅素复合物,包括二氢杨梅素为主药,其特征在于还包括瑞鲍迪苷A为药物辅料,所述二氢杨梅素主药和瑞鲍迪苷A药物辅料质量比在1:15‑1:30之间,其特征在于还包括瑞鲍迪苷A(CAS登记号58543‑16‑1,分子式C44H70O23,分子量967.03)纯度≥98%。本发明制备的二氢杨梅素复合物,在水溶液中,瑞鲍迪苷A自发形成胶束增溶二氢杨梅素,二氢杨梅素溶解度可达16.57mg/ml,且胶束粒径小,分布范围均一,药物稳定性良好,还显著提高加快二氢杨梅素口服后的吸收,提高口服生物利用度,同时瑞鲍迪苷A具有的抗糖尿病、抗炎等活性,使得二氢杨梅素复合物具有很好的协同药理活性,本发明的二氢杨梅素复合物制备工艺简单,适合大规模工业化生产,具有很好的经济性。
Description
技术领域
本发明涉及一种二氢杨梅素可溶型复合物,特别涉及一种具有协同增强药效作用的二氢杨梅素可溶型复合物及其制备方法。
背景技术
二氢杨梅素(Dihydromyricetin,CAS号27200-12-0)是广泛存在于天然植物中的一种多酚羟基双氢黄酮醇,又称蛇葡萄素、双氢杨梅树皮素,属黄酮类化合物,二氢杨梅素具有防治心血管疾病、抗肿瘤、抗氧化等多种药理活性,具有良好的药用价值,极具开发潜力。最新的研究表明,因二氢杨梅素具有显著的抗氧化、抗炎、清除自由基等广泛的药理学活性,在治疗糖尿病及其并发症方面,如糖尿病性角膜病变有着广阔的应用前景。但是二氢杨梅素存在如下不足,严重影响其开发和利用:(1)水溶解性差,二氢杨梅素在水相中20℃时,在水中溶解度约为0.084%;(2)分子结构不稳定,二氢杨梅素分子结构中含有多达6个酚羟基决定了二氢杨梅素具有比其他多酚类化合物更强的药理学活性,但是因为酚羟基极其不稳定,决定了二氢杨梅素的稳定性极其差,尤其是在水溶液中极其不稳定,容易氧化;(3)半衰期短、透生物膜性能差,口服等生物利用度极低。上述这些不足,严重限制了二氢杨梅素在临床和作为饮料、膳食剂等食品工业等领域的应用。因此,很有必要进一步探索一种经济又有效的新型二氢杨梅素制剂或产品。
二氢杨梅素在目前已知的多酚类化合物中,其抗氧化等药理学活性是最强的,这主要由其特殊的化学分子结构决定的。多酚类化合物,顾名思义,其分子结构中存在多个酚羟基,如姜黄素分子结构中有2个酚羟基,柚皮素分子结构中有3个酚羟基,白藜芦醇分子结构中有3个酚羟基,水飞蓟素分子结构中有4个酚羟基,芦丁分子结构中有4个酚羟基。而二氢杨梅素分子结构中则含有多达6个酚羟基,是目前已知的多酚类化合物中酚羟基最多的化合物之一。分子结构中含有多达6个酚羟基决定了二氢杨梅素具有比其他多酚类化合物更强的药理学活性,但是因为酚羟基极其不稳定,也决定了二氢杨梅素极其差的水溶液不稳定性。本发明人通过实验进行比较,发现目前已有的文献报道和技术均不能同时满足显著提高二氢杨梅素水溶解度及其在水溶液状态下稳定的要求。
采用纳米药物递送技术可以提高难溶性药物溶解度,提高药物水溶液稳定性,提高口服生物利用度。目前常用的纳米药物递送系统如胶束、纳米粒等主要采用聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇共聚物(PVCL-PVA-PEG)、聚羟基乙酸(PGA)、聚乳酸(PLA)、羟基乙酸与乳酸的共聚物(PLGA)、乙交酯-丙交酯-己内酯三元无规共聚物(PGLC)等高分子材料,其本身仅为一种载体而已,没有治疗作用,且这些人工合成的高分子材料载体,因存在降解性等问题,长期使用存在一定的安全隐患。如能使用天然提取物质,特别是天然提取的小分子物质作为一种新型载体,这种载体可起到构建纳米药物递送系统的作用,提高药物稳定性,增强口服药物吸收、提高疗效。目前已报道的天然小分子物质作为载体的有人参皂苷(发明专利申请号201310155639.2)、甜菊甙(现代食品科技,2014,30(1):115-119;JAgric Food Chem,2013,61(18):4433-4440)等。上述已有研究和报道的天然小分子物质作为载体可满足对白藜芦醇、姜黄素等多酚类化学物的包载,但是本发明人通过实验对比,发现目前已有的文献报道的人参皂苷、甜菊甙均不能同时满足二氢杨梅素水溶解度及其稳定性的要求。这是因为二氢杨梅素分子结构中含有多达6个酚羟基,极易被氧化,上述已有的文献报道的人参皂苷、甜菊甙等均无抗氧化活性或抗氧化活性很弱,对其包载的二氢杨梅素没有一个很好的抗氧化保护作用。因此,需要选择一种本身就有非常强抗氧化活性的天然小分子物质,起到抗氧化剂保护二氢杨梅素不被氧化失活,同时还能有效包封二氢杨梅素,从而提高二氢杨梅素在水溶液中的溶解度及其稳定性。
瑞鲍迪苷A(Rebaudioside A,CAS登记号58543-16-1,分子式C44H70O23,分子量967.03)是从菊科植物Stevia Rebaudia(该植物在我国称作甜叶菊)的叶子中提取出来的一种糖苷,作为一种新型天然甜味剂而广泛应用于食品、饮料、调味料的生产中。在南美洲使用甜叶菊作为药草和代糖已经有几百年历史。近年的研究表明,瑞鲍迪苷A具有强抗氧化活性(Saravanan R,Ramachandran V.Modulating efficacy of Rebaudioside A,aditerpenoid on antioxidant and circulatory lipids in experimental diabeticrats.Environ Toxicol Pharmacol.2013,36(2):472-83),同时,瑞鲍迪苷A具有强抗糖尿病、抗炎、免疫调节等作用( V, S, N,et al.Insight into anti-diabetic effect of low dose of stevioside.Biomed Pharmacother.2017,90:216-221)。本发明人研究发现,瑞鲍迪苷A可显著增溶二氢杨梅素,提高二氢杨梅素稳定性,并显著提高二氢杨梅素口服生物利用度。而从菊科植物Stevia Rebaudia(该植物在我国称作甜叶菊)的叶子中提取出来的另一种成分甜菊甙(又名甜菊糖苷,CAS登记号57817-89-7,分子式C38H60O18,分子量804.87),则未能达到同时提高二氢杨梅素水溶解度及其稳定性的作用。
发明内容
本发明的目的是提供一种创新性二氢杨梅素可水溶型复合物,改善二氢杨梅素分子稳定性,提高溶解度,提高与改善口服给药后的生物利用度,并提高二氢杨梅素的贮存稳定性,同时,构建二氢杨梅素复合物的载体是一种天然的安全的小分子物质,具有抗糖尿病、抗炎、免疫调节等作用,使得其构建的二氢杨梅素复合物具有协同增效的作用,例如,增强二氢杨梅素治疗糖尿病并发症如糖尿病性角膜病变和角膜神经病变的药效。同时,二氢杨梅素改善水溶解度,提高其在水溶液中的稳定性后,可拓展二氢杨梅素在食品工业领域的应用,例如,用于保健型饮料等。
本发明的另外一个目的是提供上述二氢杨梅素复合物的制备方法。
本发明技术构思:二氢杨梅素具有明确的促进上皮修复、抗炎、抗糖尿病和神经保护等药理学活性,但是二氢杨梅素分子结构极其不稳定、难溶于水、口服生物利用度低等问题严重限制了二氢杨梅素在临床药物治疗、食品工业等领域中的应用,且二氢杨梅素分子结构中含有6个酚羟基,是多酚类化合物中分子结构中酚羟基数最多的化合物之一,极易氧化失活,特别是在水溶液中极易氧化失活。而提高二氢杨梅素的稳定性,特别是提高其在水溶液中的稳定性,可显著拓展其临床应用(例如,可制备成口服液、滴眼液等水溶液制剂)及其在保健食品等领域的应用(例如,可制备成饮料等)。采用纳米药物递送系统将二氢杨梅素构建成纳米制剂,因纳米药物递送系统的本身所特有的优势,将使二氢杨梅素稳定性显著提高,提高口服生物利用度,增强疗效。而采用具有生物活性的小分子天然产物作为构建二氢杨梅素纳米制剂的载体,不仅起到有效构建杨梅素纳米制剂,还因载体具有药理学活性,则可进一步增强二氢杨梅素的药理学效应。本发明人研究发现,瑞鲍迪苷A在水溶液中可自发形成具有类似胶束的纳米结构,发挥增溶二氢杨梅素的作用,且因瑞鲍迪苷A本身就有强抗氧化活性,可起到保护包载的二氢杨梅素不被氧化失活。瑞鲍迪苷A胶束增溶的二氢杨梅素溶液,即二氢杨梅素胶束溶液,稳定性显著提高,进一步实验发现二氢杨梅素胶束溶液具有显著的提高口服生物利用度,提高二氢杨梅素治疗糖尿病性并发症如糖尿病性角膜病变的有效性作用。
本发明的技术方案:一种二氢杨梅素复合物,包括二氢杨梅素为主药,其特征在于还包括瑞鲍迪苷A作为药物辅料,所述二氢杨梅素主药和瑞鲍迪苷A药物辅料质量比在1:15-1:30之间。
所述的瑞鲍迪苷A(Rebaudioside A)为菊科植物Stevia Rebaudia(该植物在我国称作甜叶菊)的叶子中提取出来的一种糖苷(CAS登记号:58543-16-1,分子式:C44H70O23,分子量:967.03),瑞鲍迪苷A纯度≥98%。
本发明的二氢杨梅素复合物的制备方法如下:将二氢杨梅素和瑞鲍迪苷A溶解到无水乙醇中,通过40℃水浴旋转真空蒸发乙醇(可回收乙醇),在容器内部形成固体粉末即得本发明的二氢杨梅素复合物。制备工艺简单,绿色环保,适用于工业化大规模生产。
上述二氢杨梅素胶束复合物的制备方法,制得的二氢杨梅素复合物极易溶于水,溶解度可达16.57mg/ml,二氢杨梅素复合物溶于水后自发形成胶束,胶束粒径范围在6~15nm之间。
上述二氢杨梅素胶束复合物,适用于进一步制备成口服液等水溶液制剂,也适用于灌装胶囊,或者直接袋装成散剂。
上述二氢杨梅素胶束复合物的制备方法,制备过程及工艺简单,操作简单,无需喷雾干燥等大型仪器设备,适用于工业化生产,也非常适用于制药企业或食品企业等的洁净化工业生产。
本发明制备的二氢杨梅素复合物,因在水溶液中,复合物材料瑞鲍迪苷A可自组装形成胶束,快速增溶二氢杨梅素,使得二氢杨梅素在水溶液中有良好的溶解性,二氢杨梅素的溶解度可达16.57mg/ml,且胶束粒径极小,分布范围均一,药物稳定性良好。该二氢杨梅素复合物不但提高了二氢杨梅素在水溶液状态中的稳定性,还可显著增强口服生物利用度,本发明的实验结果表明,相同剂量的二氢杨梅素复合物在大鼠灌胃后的口服生物利用度是制备之前的二氢杨梅素普通粉末的10.9倍,同时瑞鲍迪苷A具有的抗糖尿病、抗炎等活性,使得二氢杨梅素复合物具有很好的协同治疗糖尿病性并发症如糖尿病性角膜病变和角膜神经病变的药效。因此,本发明的二氢杨梅素复合物具有很好的经济性。
附图说明
图1给药8周后对各组糖尿病小鼠角膜神经敏感度分析图。
具体实施方式
下面结合附图并通过具体实施例来进一步详细说明本发明。
实施例1:
将50mg二氢杨梅素、900mg瑞鲍迪苷A置于100mL圆底烧瓶中,加入50mL无水乙醇,充分溶解后,40℃水浴旋转真空蒸发无水乙醇并回收乙醇,得到二氢杨梅素和瑞鲍迪苷A的均匀分散的二氢杨梅素复合物。
实施例2:
将20mg二氢杨梅素、300mg瑞鲍迪苷A置于100mL圆底烧瓶中,加入30mL无水乙醇,充分溶解后,40℃水浴旋转真空蒸发无水乙醇并回收乙醇,得到二氢杨梅素和瑞鲍迪苷A的均匀分散的二氢杨梅素复合物。
实施例3:
将100mg二氢杨梅素、3000mg瑞鲍迪苷A置于100mL圆底烧瓶中,加入70mL无水乙醇,充分溶解后,40℃水浴旋转真空蒸发无水乙醇并回收乙醇,得到二氢杨梅素和瑞鲍迪苷A的均匀分散的二氢杨梅素复合物。
实验效果例1:本发明的二氢杨梅素复合物溶解性能及其水溶液稳定性测定。
实验药物:二氢杨梅素复合物(实施例1制备,设为实验组)。
对照药物:采用申请号201610378630.1已有发明专利技术制备的二氢杨梅素固体脂质纳米粒(对照1组),二氢杨梅素普通粉末(对照药物2)。
实验方法:取过量的实验药物、对照药物1和对照药物2,密封于棕色玻璃瓶中,加入5ml水,漩涡振荡一小时后,吸取液体,0.22μm微孔滤膜过滤后,将过滤所得的溶液分成两份,一份采用100倍甲醇溶解与稀释,高效液相色谱法测定浓度,另一份装于透明玻璃小瓶中,放置于常温(不避光),24小时候后将液体用0.22μm微孔滤膜过滤后,高效液相色谱法测定浓度,并计算药物含量和降解百分数。
实验结果表明,实验药物(即二氢杨梅素复合物)漩涡振荡一小时后溶解的量为16.57±0.92mg/ml,二氢杨梅素固体脂质纳米粒(对照1组)漩涡振荡一小时后溶解的量为1.9±0.4mg/ml,二氢杨梅素普通粉末(对照药物2)漩涡振荡一小时后溶解的量为0.80±0.2mg/ml。说明本发明技术制备的二氢杨梅素复合物显著提高与改善二氢杨梅素溶解性能。实验药物(即二氢杨梅素复合物)水溶液常温不避光放置24小时后,溶液中二氢杨梅素含量为初始溶液的87.4±3.1%,而二氢杨梅素固体脂质纳米粒(对照1组)和二氢杨梅素普通粉末(对照药物2)水溶液常温不避光放置24小时后,溶液中二氢杨梅素含量均只有初始溶液浓度的3.2±0.85%,说明本发明技术制备的二氢杨梅素复合物显著提高与改善二氢杨梅素水溶液的稳定性。
实验效果例2:本发明的二氢杨梅素复合物用于STZ诱导型糖尿病模型小鼠眼部并发症的有效性。
实验药物:二氢杨梅素复合物(实施例1制备,设为实验组)。
对照药物:采用申请号201610378630.1已有发明专利技术制备的二氢杨梅素固体脂质纳米粒(对照1组),二氢杨梅素普通粉末(对照药物2)。
实验动物与实验方法:因STZ诱导的糖尿病小鼠作为较公认的类似于人非增殖期糖尿病视网膜病变模型,本部分内容采用此模型进行研究。选用C57BL/6小鼠,雄性,6-8周龄,体重18~25克(购买自北京维通利华实验动物技术有限公司)。动物随机分为两组,一组采用新鲜配置的柠檬酸盐缓冲液(pH 4.5)配制STZ溶液后对小鼠进行腹腔注射,连续注射5天,在最后一次(第五次注射)后的第8天(一周后)对每小鼠测量血糖,连续测量3天,STZ注射组血糖值大于300mg/dL(16.7mmol/L)认为Ⅰ型糖尿病模型成功。模型成功后,将小鼠随机分成4组(即实验组、对照1组、对照2组、空白对照组),每组12只,灌胃剂量为150mg/kg体重(灌胃给药剂量结合文献报道确定),灌胃前,分别将实验组、对照1组和对照2组二氢杨梅素溶解或分散于水中,配制成二氢杨梅素浓度为15mg/ml,灌胃体积为0.1ml/10g体重(即150mg二氢杨梅素每公斤小鼠体重剂量灌胃),空白对照组灌胃给予相应体积的生理盐水,每天灌胃一次,连续灌胃8周,8周灌胃结束后对糖尿病小鼠的体重、空腹血糖、角膜敏感度进行测定。
实验结果表明,生理盐水对照组STZ腹腔注射建模的小鼠,逐渐表现出多饮、多食、多尿、体重下降等糖尿病典型症状,其血糖稳定维持在较高水平,体重较正常小鼠偏低,表明造模成功。而实验组(二氢杨梅素复合物)小鼠的体重和血糖指标则明显优于二氢杨梅素固体脂质纳米粒(对照1组)和二氢杨梅素普通粉末(对照药物2)组(表1)。检测小鼠的角膜敏感性,结果如图1所示,STZ建模糖尿病小鼠生理盐水对照组角膜敏感度显著下降(相比于正常小鼠,P<0.05),而采用本发明专利的二氢杨梅素复合物口服给药组,小鼠角膜敏感度则显著改善(相比于正常小鼠,P>0.05),而STZ建模糖尿病小鼠对照1组和对照2组,小鼠角膜敏感度改善不显著(相比于正常小鼠,P<0.05)。
表1正常和糖尿病模型小鼠在取样点时体重及血糖检测
实验效果例3:本发明的二氢杨梅素复合物大鼠口服生物利用度检测实验。
实验药物:二氢杨梅素复合物(实施例1制备,设为实验组)。
对照药物:采用申请号201610378630.1已有发明专利技术制备的二氢杨梅素固体脂质纳米粒(对照药物1),二氢杨梅素普通粉末(对照药物2)。
实验动物与实验方法:选用24只SD大鼠,雄性,体重290~310克(购买自北京维通利华实验动物技术有限公司)。动物随机分为三组,每组8只,实验前禁食过夜,灌胃前将实验药物、对照药物1和对照药物2分别以2mg/ml浓度溶解或分散于水中,以1ml/100g体重进行灌胃(即20mg二氢杨梅素每公斤大鼠体重剂量灌胃),在给药后的0.25、0.5、1、2、4、6、8、12和24小时,尾静脉取血0.25ml,肝素抗凝,离心分离血浆,高效液相色谱-质谱仪检测血样中二氢杨梅素浓度,DAS2.0软件处理与分析药物动力学参数。
实验结果如表1所示,实验组的Cmax显著高于对照药物1(P<0.05)和对照药物2组(P<0.05),实验组的AUC0-24h也显著优于对照药物1(P<0.05)和对照药物2组(P<0.05),达峰时间缩短,说明本发明的二氢杨梅素复合物具有更快的口服吸收,更好的口服吸收生物利用度。
表2口服药物动力学参数
药物动力学参数 | 实验组 | 对照药物1 | 对照药物2 |
Cmax(μg/mL) | 5.76±0.93 | 0.59±0.17 | 0.37±0.21 |
Tmax(h) | 1 | 2 | 6 |
AUC0-24h(μg/mL) | 33.47±2.83 | 5.73±2.11 | 3.06±0.54 |
Claims (4)
1.一种具有协同增强药效作用的二氢杨梅素复合物,包括二氢杨梅素为主药,其特征在于还包括瑞鲍迪苷A为药物辅料,所述二氢杨梅素主药和瑞鲍迪苷A药物辅料质量比在1:15-1:30之间。
2.如权利要求1所述的二氢杨梅素复合物,其特征在于所述瑞鲍迪苷A(CAS登记号58543-16-1,分子式C44H70O23,分子量967.03)纯度≥98%。
3.一种如权利要求1所述的二氢杨梅素复合物的制备方法,其特征在于包括以下步骤:将二氢杨梅素主药和瑞鲍迪苷A药物辅料溶解在无水乙醇中,通过旋转真空蒸发去除乙醇即得。
4.如权利要求3所述的二氢杨梅素复合物的制备方法,其特征在于制得的二氢杨梅素复合物溶于水后自组装形成胶束,胶束粒径范围在6-15nm之间。
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