CN108864128A - 四种苦木素工业制备方法及其制备药品、保健食品新用途 - Google Patents
四种苦木素工业制备方法及其制备药品、保健食品新用途 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
本发明涉及一种适合从东革阿里植物中提取四种苦木素成分的工业生产方法及制备产品用途。采用超声逆流水提取与硅胶‑低沸点溶剂层析技术将四种苦木素成分从东革阿里植物中分离、纯化。四种苦木素成分任一可以制备成口服制剂或注射液，用于改善男性迟发性性腺功能减退症和轻、中度抑郁症。该发明的生产方法连续性强、规模大、安全性高，适合工业放大；产品稳定度好、纯度高、不残留有毒溶剂，产品质量高；其药物应用潜力巨大，值得深入开发。
Description
技术领域
本发明四种苦木素的工业制备方法及其制备药品、保健食品新用途，具体涉及一种适合从东革阿里植物中提取四种苦木素成分的工业生产方法及制备用途。
背景技术
苦木素（quassin）是见于苦木科的一类含氧、结构复杂的降解萜类化合物。宽缨酮（eurycomanone）、宽缨醇（eurycomanol）、13α (21)-环氧宽缨酮（13α (21)-epoxyeurycomanone）以及13,21-双氢宽缨酮（13,21-dihydroeurycomanone）是东革阿里的重要有效成分，具有抗疟疾、杀菌、抗溃疡、解热的效能。
随着对东革阿里药物成分研究的不断深入，出现了多种制备东革阿里提取物的方法。资料显示，东革阿里提取主要采用溶剂回流法或煎煮法，如专利CN104757424A采用煎煮法提取；专利US20070224300A1采用沸水提取；“东革阿里对运动训练大鼠睾酮含量、物质代谢及抗运动疲劳能力的影响”文章采用沸水提取；“东革阿里化学成分的分离与鉴定”文章采用水回流提取。专利CN103408564A将东革阿里以有机溶剂提取；“东革阿里提取物抗疲劳作用的实验研究”文章使用醇提取工艺。除此之外，还有少数专利采用酶解法增加提取效率，如专利CN106366092A一种从东革阿里中分离高纯度宽缨酮的工业制备方法。上述方法存在诸多不足，比如高温提取浪费热能，有效成分破坏严重；溶剂提取成本高、污染环境；酶解法过程复杂，对生产设备、工艺要求高等。
苦木素的纯化分离方法选择是决定高质量产品的关键。发明CN103408564A采用石油醚脱脂、乙酸乙酯萃取、活性炭脱色、氯仿洗脱层析柱等步骤分离宽缨酮。该发明使用溶剂种类多样、处理步骤繁琐、溶剂毒性大、很难达到口服药物的安全要求。
东革阿里提取物的混合物药物研究开展已久，但是其主要药物成分作用机理及治疗应用却还未见报道。
在2009年的研究中，LOW教授等人制备东革阿里提取物，探讨其促睾酮活性机制，结果显示，东革阿里提取物能够增加睾丸的生精能力，增强不孕小鼠的繁育力，初步确证了东革阿里含有调节睾酮水平的成分。除此之外，近期的研究也指出，东革阿里中的苦木素是一种具有潜力的抗癌分子。东革阿里根提取物能通过p53通路诱导肝癌细胞HepG2凋亡。
发明内容
本发明的目的在于提供一种从东革阿里植物中工业化制备四种苦木素类有效成分的整体方法及其药物新用途。为达到此目的本发明提供如下技术方案：（1）超声逆流水提取：将东革阿里原料粉碎，用水溶液作溶媒在超声提取设备中逆流提取，提取液直接使用大孔树脂富集，乙醇洗脱，减压浓缩，得东革阿里提取物浸膏。（2）硅胶层析分离：将东革阿里浸膏载入硅胶柱中，采用沸程30-60的石油醚/乙醇梯度洗脱，分别截留四种苦木素。（3）截留后的苦木素高含量部分采用乙醇反复结晶，获得宽缨酮、宽缨醇、13α(21)-环氧宽缨酮以及13,21-双氢宽缨酮精品。四种苦木素精品成分经过HPLC检测含量大于95%。
上述步骤（1）超声逆流水提取特征在于东革阿里采用纯水溶液提取苦木素，对苦木素的提取针对性强；超声与循环逆流过程联合应用，利用物料与溶媒动态交互的逆流过程形成浓度梯度差，采用超声辅助加强提取效率，动态物料比为1:5~20，提取效率可达95%以上，提取用时比浸提减少50%以上。上述步骤（1）超声提取液过滤后直接采用弱极性大孔树脂吸附富集，HPLC检测饱和后用乙醇整体洗脱，洗脱液浓缩干燥，即可获得苦木素粗品。乙醇对苦木素有强的溶解性，可以使用最少溶剂快速浓缩大体积的提取液，适合工业化生产。上述步骤（2）硅胶层析分离用低沸点无毒性的混合溶剂体系——沸程30-60℃的石油醚/乙醇洗脱体系，分部收集苦木素组分。纯化过程使用的溶剂沸点低并且溶剂无毒、安全，有效成分收率高。上述步骤（3）苦木素纯品采用乙醇反复结晶，祛除纯化过程中的溶剂残留，进一步提高四种苦木素成分的含量，最终形成符合溶剂残留标准、含量大于95%的宽缨酮、宽缨醇、13α (21)-环氧宽缨酮以及13,21-双氢宽缨酮精品。本发明采用从东革阿里提取、分离、纯化苦木素的一整套方法，可以制备四种有药物价值的苦木素成分，生产过程环保，成本低廉，具有不可比拟的规模化生产优势。
四种苦木素成分中的一种或几种与药学上可接受的辅料混合，制备成注射剂、口服制剂及其缓释、控释制剂。制剂类型主要为胶囊剂、片剂、软胶囊、颗粒剂、分散剂、溶液剂、乳剂、悬浊剂等剂型。药物制剂主要辅料可以是淀粉、糖分、糊精、无机盐、微晶纤维素、可压性淀粉、甘露醇、羧甲基纤维素钠、乙醇、羟丙基纤维素、甲基纤维素和乙基纤维素、羟丙甲纤维素、羧甲基淀粉钠、交联聚乙烯比咯烷酮、交联羧甲基纤维素钠、硬脂酸镁、微粉硅胶、明胶、葡萄糖、土温 80、聚乙二醇、EDTA二钠、琼脂等。
前期研究已经表明，东革阿里提取物具有一定的药理作用，但是其主要成分及作用方式一直未能明确。我们经过研究发现，上述宽缨酮、宽缨醇、13α(21)-环氧宽缨酮以及13,21-双氢宽缨酮精品具有显著的药理活性，能够作用于小鼠的神经肌肉等系统，增强神经兴奋性和肌肉力量，提高小鼠的有氧活动耐性；提升下丘脑对多种激素的促进作用、促进垂体对激素的刺激作用，整体调节人体内分泌系统水平；加强大脑内啡肽和多巴胺的释放，减轻人体抑郁情绪。
本发明采用工业化制备苦木素的方法快速高效的获得宽缨酮、宽缨醇、13α (21)-环氧宽缨酮以及13,21-双氢宽缨酮高质量精品，并创造性的发现四种苦木素在提升神经系统兴奋性方面的显著作用，能够增强下丘脑的神经节敏感性，提高促激素分泌作用，预防和减缓男性迟发性性腺功能减退症；增强中枢神经兴奋度，减轻抑郁情绪，辅助治疗轻、中度抑郁症。
说明书附图
图1是宽缨酮结构式
图2是13,21-双氢宽缨酮结构式
图3是13α (21)-环氧宽缨酮结构式
图4是宽缨醇结构式
具体实施
实例1：将东革阿里生药5t粉碎，陆续推入逆流超声提取线腔体内，调节推料速度和水流速分别为400kg/h和3t/h；将超声提取液离心去除药粉沉淀，直接输送到大孔树脂腔体内吸附，待流出液检测饱和，换用乙醇洗脱，洗脱液浓缩，获得苦木素粗品；苦木素粗品用硅胶拌样，采用径高比为1/15的分离柱装柱；层析过程采用沸程30-60℃的石油醚/乙醇洗脱，洗脱梯度从19:1~7:3，HPLC检测流出液，分别截留四种苦木素目标组分，减压浓缩，获得四种苦木素组分纯品；纯品分别采用乙醇溶解，结晶釜注水结晶，最终获得宽缨酮精品4.0公斤；宽缨醇精品2.2公斤；13α (21)-环氧宽缨酮以及13,21-双氢宽缨酮精品各1公斤，HPLC检测外标值均大于95%。
实例2：将东革阿里生药5t粉碎，陆续推入逆流超声提取线腔体内，调节推料速度和溶媒流速，分别为400kg/h和8t/h；将超声提取液离心去除药粉沉淀，直接输送到大孔树脂腔体内吸附，待流出液检测饱和，换用乙醇洗脱，洗脱液浓缩，获得苦木素粗品；苦木素粗品用硅胶拌样，采用径高比为1/15的分离柱装柱；层析过程采用沸程30-60℃的石油醚/乙醇洗脱，洗脱梯度从9:1~4:1，HPLC检测流出液，分别截留四种苦木素目标组分，减压浓缩，获得四种苦木素组分纯品；纯品采用乙醇溶解，结晶釜注水结晶，最终获得宽缨酮精品4.3公斤；宽缨醇精品2.1公斤；13α(21)-环氧宽缨酮以及13,21-双氢宽缨酮精品各1.2公斤，HPLC检测外标值均大于95%。
实例3：宽缨酮胶囊的制备
1g宽缨酮纯品粉碎，过100目筛。称取淀粉17.187g，与宽缨酮粉末混合均匀，再加入微晶纤维素(101)7.8g，硬脂酸镁0.013g，总混均匀，用1号胶囊灌装，每粒装內容物0.26g。
实例4：13α (21)-环氧宽缨酮胶囊的制备：100g13α (21)-环氧宽缨酮精品过100目筛。称取淀粉395g，与13α (21)-环氧宽缨酮混合均匀，再加入环糊精、硬脂酸镁等辅料5g，总混均匀，用1号胶囊灌装，每粒装內容物0.25g。
实例5：小鼠腹腔注射宽缨酮、宽缨醇、13α(21)-环氧宽缨酮以及13,21-双氢宽缨酮精品后负重游泳实验：取雄性成年小鼠50只，随机分为对照一组、给药四组，每日腹腔注射给药一次（4mg/kg)，连续7天，末次给药后60min，将小鼠放入水槽时进行游泳试验，水深25cm，水温28-30℃。每鼠尾负重为体重7％，记录小鼠游泳持续时间，结果:对照组为60.5±15.9min，宽缨酮组105.2±21.9min；宽缨醇组95±15.6min；13α(21)-环氧宽缨酮组108±25.1min；13,21-双氢宽缨酮组100±20.2min，实验组与对照组比较均差异显著，（p＜0.01），表明四种苦木素化合物有明显增强体能、抗抑郁作用。
实例6：大鼠腹腔注射苦木素精品后血浆检测FSH和LH统计：将雄性大鼠10只分别注射0.5ml生理盐水后尾静脉取血，用ELISA试剂盒分别测定血浆FSH和LH；再给同批大鼠腹腔注射5mg/kg的宽缨酮后尾静脉取血，分别用ELISA试剂盒测定血浆FSH和LH，用药前后数据采用SPSS软件进行显著性分析，结果表明，注射宽缨酮后血浆FSH和LH水平均显著上升（P＜0.01）。
实例7：老年男性迟发性性腺功能减退症及抑郁症人群用药调查统计表：给老年人群（年龄＞60）和患有轻度、中度抑郁症人群口服含有苦木素的胶囊，调查苦木素对上述两种疾病的治疗作用，调查统计结果如下：
| 疾病名称 | 显效 | 有效 | 无效 |
| 抑郁症 | 10/50 | 30/50 | 10/50 |
| 男性迟发性性腺功能减退症 | 20/50 | 25/50 | 5/50 |
上述结果中，抑郁症显效表现为睡眠正常、心理测评正常、食欲正常；有效表现为睡眠有改善、心理测评水平提升、食欲增加、体重恢复；无效表现为睡眠没有改善、心理测评较差、食欲持续变差。男性迟发性性腺功能减退症（LOH）显效表现为血清睾酮正常、肌肉力量增强；有效表现为血清睾酮水平恢复、自觉体力增加；无效表现为睾酮水平持续降低，自觉无改善变化。
Claims (7)
1.四种苦木素的工业制备方法及其制备药品、保健食品新用途，其特征在于以下步骤：
（1）超声逆流水提取：将东革阿里原料粉碎，在超声提取设备中用水溶液作溶媒逆流提取，然后用树脂吸附浓缩，得东革阿里提取物浸膏；
（2）硅胶层析分离：将东革阿里浸膏载入硅胶柱中，用沸程30-60℃的石油醚/乙醇梯度洗脱，分段截留四种苦木素，经浓缩结晶得纯品。
2.根据权利要求1所述的四种苦木素的工业制备方法及其制备药品、保健食品新用途，其四种苦木素为宽缨酮、宽缨醇、13α (21)-环氧宽缨酮以及13,21-双氢宽缨酮。
3.根据权利要求1所述的四种苦木素的工业制备方法及其制备药品、保健食品新用途，其超声逆流水提取特征在于东革阿里采用结合超声水溶液与连续逆流提取苦木素，动态物料比为1:5~20。
4.四种苦木素的工业制备方法及其制备药品、保健食品新用途，其药物组合物特征在于含有宽缨酮、宽缨醇、13α (21)-环氧宽缨酮以及13,21-双氢宽缨酮一种或几种组合以及药学上可接受的辅料。
5.四种苦木素的工业制备方法及其制备药品、保健食品新用途，其所述含苦木素药物组合物优选剂型为口服制剂、注射剂；进一步优选口服制剂为胶囊剂、片剂、丸剂、软胶囊、散剂、颗粒剂、乳剂、混悬剂、溶液剂。
6.四种苦木素的工业制备方法及其制备药品、保健食品新用途，其特征在于宽缨酮、宽缨醇、13α (21)-环氧宽缨酮以及13,21-双氢宽缨酮一种或几种在剂量范围内制备用于改善和预防男性迟发性性腺功能减退症药物和保健食品的用途，优选剂量范围为0.05-3.00mg/kg。
7.四种苦木素的工业制备方法及其制备药品、保健食品新用途，其特征在于宽缨酮、宽缨醇、13α (21)-环氧宽缨酮以及13,21-双氢宽缨酮一种或几种在剂量范围内制备用于改善轻、中度抑郁症药物和保健食品的用途，优选剂量范围为0.02-3.00 mg/kg。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109432085A (zh) * | 2018-12-03 | 2019-03-08 | 清罗(北京)天然药物有限公司 | 宽缨酮在制备防治男性迟发性性腺功能减退症药物、食品和保健品中的应用 |
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