WO2018205191A1 - 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 PDF

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WO2018205191A1
WO2018205191A1 PCT/CN2017/083876 CN2017083876W WO2018205191A1 WO 2018205191 A1 WO2018205191 A1 WO 2018205191A1 CN 2017083876 W CN2017083876 W CN 2017083876W WO 2018205191 A1 WO2018205191 A1 WO 2018205191A1
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preparation
lignin
kinds
bitter
broad
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PCT/CN2017/083876
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French (fr)
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王惠芳
刘永周
夏传递
梁克
焦燕玲
董德顺
肖虎
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北京罗瑞生物科技有限公司
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Priority to PCT/CN2017/083876 priority Critical patent/WO2018205191A1/zh
Publication of WO2018205191A1 publication Critical patent/WO2018205191A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18Magnoliophyta (angiosperms)
    • A61K36/185Magnoliopsida (dicotyledons)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/06Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00General protective or antinoxious agents

Definitions

  • the industrial preparation method of four kinds of bitter lignin of the invention and the new use thereof for preparing medicines and health foods relates to an industrial production method suitable for extracting four kinds of bitter lignin components from Tongkat Ali plants and preparation uses thereof. Background technique
  • Quacsin is a class of oxygen-containing, structurally complex degraded terpenoids found in the family of Bitter Wood. Erythromonone, eurycomanol, 13 ⁇ (21)-epoxylenone (13 ⁇ (21)-epoxyeurycomanone), and 13,21-dihydroanthracene (13,21-di ydroeurycomanone) It is an important active ingredient of Tongkat Ali, with anti-malarial, bactericidal, anti-ulcer and antipyretic effects.
  • Tongkat Ali extraction mainly uses solvent reflux method or decoction method, such as patent CN10475 7424A, which is extracted by boiling method; patent US20070224300A1 uses boiling water extraction; "Tongkat Ali's testosterone content, substance metabolism and anti-sports in exercise training rats "The effect of fatigue ability” article using boiling water extraction; “Tiekat Ali chemical components separation and identification” article using water reflux extraction.
  • Patent CN103408564A extracts Tongkat Ali with an organic solvent; an experimental study on the anti-fatigue effect of Tongkat Ali extract uses an alcohol extraction process.
  • Tongkat Ali extract can increase the spermatogenic ability of testes and enhance the infertility of mice. Breeding, initially confirmed that Tongkat Ali contains ingredients that regulate testosterone levels. In addition, recent studies have also pointed out that bitter lignin in Tongkat Ali is a potential anticancer molecule. Tongkat Aligen extract can induce hepatoma cell HepG2 apoptosis through p53 pathway.
  • An object of the present invention is to provide an integrated method for industrially preparing four kinds of effective components of bitter lignin from Tongkat Ali plants and a new use thereof.
  • the present invention provides the following technical solutions: (1) Ultrasonic countercurrent water extraction: The Tongkat Ali raw material is pulverized, and the aqueous solution is used as a solvent to be countercurrently extracted in an ultrasonic extraction device, and the extract is directly enriched by macroporous resin. Ethanol elution, concentration under reduced pressure, and extract of Tongkat Ali extract. (2) Silica gel chromatography: The Tongkat Ali extract was loaded onto a silica gel column and eluted with a petroleum ether/ethanol gradient of boiling range 30-60 to separate the four lignin.
  • bitter lignin after the interception is repeatedly crystallized by ethanol to obtain a wide oxime, a broad sterol, a 13 ⁇ (21)-epoxylenone, and a 13,21-dihydroxanthone.
  • the content of the four bitter lignin extracts was determined by HPLC to be greater than 95%.
  • One or more of the four bitter lignin ingredients are mixed with a pharmaceutically acceptable adjuvant to prepare an injection, an oral preparation, and a sustained release, controlled release preparation thereof.
  • the preparation type is mainly a capsule, a tablet, a soft capsule, a granule, a dispersing agent, a solution, an emulsion, a suspension, and the like.
  • the main excipients of the pharmaceutical preparation may be starch, sugar, dextrin, inorganic salt, microcrystalline cellulose, compressible starch, mannitol, sodium carboxymethylcellulose, ethanol, hydroxypropylcellulose, methylcellulose and Cellulose, hypromellose, sodium carboxymethyl starch, crosslinked polyethylene pyrrolidone, croscarmellose sodium, magnesium stearate, micronized silica gel, gelatin, glucose, soil temperature 80, Polyethylene glycol, EDTA disodium, agar, and the like.
  • the above step (1) ultrasonic countercurrent water extraction is characterized in that Tongkat Ali extracts bitter lignin using a pure aqueous solution, and the extraction of bitter lignin is highly targeted; the combination of ultrasonic and cyclic countercurrent processes, using materials and solvents The countercurrent process of the state interaction forms the concentration gradient difference, and the ultrasonic extraction is used to enhance the extraction efficiency.
  • the dynamic material ratio is 1:5 ⁇ 20, the extraction efficiency is over 95%, and the extraction enthalpy is reduced by more than 50%.
  • the above steps (1) After the ultrasonic extract is filtered, it is directly adsorbed and enriched by a weakly polar macroporous resin, and after being saturated by HPLC, the whole is eluted with ethanol, and the eluent is concentrated and dried to obtain a crude lignin. Ethanol has strong solubility in bitter lignin, and it can be used to industrially produce a large volume of extract quickly by using a minimum solvent.
  • the above step (2) is separated by silica gel chromatography using a low-boiling non-toxic mixed solvent system, a boiling point of 30-60 ° C petroleum ether / ethanol elution system, and fractionally collecting the bitter lignin component.
  • the solvent used in the purification process has a low boiling point and the solvent is non-toxic, safe, and has a high yield of active ingredients.
  • the above step (3) pure lignin is repeatedly crystallized by ethanol to remove the solvent residue in the purification process, further increase the content of the four bitter lignin components, and finally form a broad ketone which meets the solvent residue standard and has a content of more than 95%.
  • the invention adopts a complete set of methods for extracting, separating and purifying bitter lignin from Tongkat Ali, and can prepare four kinds of bitter lignin components with drug value, the production process is environmentally friendly, the cost is low, and the unparalleled large-scale production advantage is obtained.
  • Tongkat Ali extract has certain pharmacological effects, but its main components and mode of action have not been clear.
  • System enhances nerve excitability and muscle strength, enhances aerobic activity tolerance in mice; enhances hypothalamic stimulation of various hormones, promotes stimulating effects of pituitary hormones, regulates endocrine system levels overall; strengthens endorphins in the brain And the release of dopamine reduces the body's depression.
  • the invention adopts the method for industrially preparing bitter lignin to quickly and efficiently obtain broad ketone, broad sterol, 13 ⁇
  • (21)-Epoxy-xanthone and 13,21-dihydroxanthone are of high quality, and creatively found that four kinds of lignin can enhance the excitability of the nervous system and enhance the ganglion of the hypothalamus. Sensitivity, improve hormone secretion, prevent and slow men's delayed hypogonadism; enhance central nervous system excitability, reduce depression, and adjuvant treatment of mild to moderate depression.
  • Example 1 5T pulverization of Tongkat Alisheng medicine was successively pushed into the countercurrent ultrasonic extraction line cavity, and the pushing speed and water flow rate were adjusted to 400 kg/h and 3 t/h, respectively; the ultrasonic extract was centrifuged to remove the powder precipitate. Directly transported to the macroporous resin chamber for adsorption, until the effluent is saturated, replaced with ethanol, and the eluent is concentrated to obtain crude lignin; the crude lignin is mixed with silica gel, and the aspect ratio is 1/15.
  • the separation column is packed; the chromatographic process is eluted with petroleum ether/ethanol at a boiling range of 30-60 ° C, and the elution gradient is from 19:1 to 7:3.
  • the effluent is detected by HPLC, and the four lignin targets are retained respectively.
  • the components are concentrated under reduced pressure to obtain four pure components of bitter lignin; the pure products are dissolved in ethanol, and the crystallizer is filled with water to crystallize, finally obtaining 4.0 kg of levonone; 2.2 kg of loose sterols; 13ot (21) - 1 kg of epoxy ketone and 13,21-dihydroxanthone each, the external standard value of HPLC detection is greater than 95%.
  • Example 2 5T pulverization of Tongkat Alisheng medicine, which was successively pushed into the countercurrent ultrasonic extraction line cavity, and adjusted the pushing speed and the solvent flow rate, respectively, 400 kg/h and 8 t/h; the ultrasonic extract was centrifuged to remove the powder precipitate.
  • the target component concentrated under reduced pressure, obtains four pure bitter lignin components; the pure product is dissolved in ethanol, and the crystallizer is water-injected and crystallized, finally obtaining 4.3 kg of ketone ketone fine product; 2.1 kilograms of broad sterol fine product; 13 ot (21) - Epoxy ketone and 13,21-dihydroxanthone are each 1.2 kg, and the external standard values of HPLC are more than 95%.
  • the lg loose ketone pure product is pulverized and passed through a 100 mesh sieve. 17.187g of starch was weighed and mixed with the broad ketone powder. Then, 7.8g of microcrystalline cellulose (101) and 0.013g of magnesium stearate were added. The mixture was evenly mixed and filled with No. 1 capsule. The content of each capsule was 0.26. g.
  • Example 5 Intraperitoneal weight-bearing swimming experiment in mice by intraperitoneal injection of levonone, sterol, 13ot(21)-epoxylenone, and 13,21-dihydroanthone
  • mice 50 male adult mice were randomly divided into control group, four groups, and administered once daily by intraperitoneal injection.
  • mice were placed in a water bath and subjected to a swimming test with a water depth of 25 cm and a water temperature of 28-30 °C.
  • the weight of each rat tail was 7%, and the mice were recorded for continuous swimming.
  • the group was 108 ⁇ 25.1 min in the oxydragon group and 100 ⁇ 20.2 min in the group of 13,21-dihydro-xanthone.
  • the experimental group and the control group were significantly different (p ⁇ 0.01), indicating that the four lignin compounds have Significantly enhance physical fitness and anti-depression.
  • Example 6 Plasma test after intraperitoneal injection of bitter lignin in rats FSH and LH statistics
  • Example 7 Statistical analysis of drug use in elderly men with delayed hypogonadism and depression
  • depression is marked by normal sleep, normal psychological assessment, and normal appetite; effective manifestations of improved sleep, increased psychological assessment, increased appetite, and weight recovery; ineffective manifestations of no improvement in sleep, psychological assessment Poor, appetite continues to worsen.
  • Male delayed hypogonadism (LOH) is marked by normal serum testosterone and increased muscle strength; effective manifestation is recovery of serum testosterone levels, increased physical strength; ineffective manifestations of testosterone levels continue to decrease, consciously no improvement.
  • the present invention relates to an industrial production method suitable for extracting four bitter lignin components from Tongkat Ali plants and a use for preparing the products.
  • the four lignin components were isolated and purified from the Tongkat Ali plant by ultrasonic countercurrent water extraction and silica gel-low boiling point solvent chromatography. Any of the four bitter lignin ingredients can be prepared as an oral preparation or injection for improving delayed onset hypogonadism and mild to moderate depression in men.
  • the production method of the invention has strong continuity, large scale and high safety, and is suitable for industrial amplification; the product has good stability, high purity, no residual toxic solvent, high product quality; and its drug application potential is huge, and it is worthy of deepening. Sequence table free content

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Abstract

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

四种苦木素工业制备方法及其制备药品、 保健食品新用途
技术领域
[0001] 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
[0002] 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-双氢宽缕酉同 ( 13,21-di ydroeurycomanone) 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。
[0003] 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 CN10475 7424A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 CN10636 6092A—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。
[0004] 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。
[0005] 东革阿里提取物的混合物药物研究幵展已久, 但是其主要药物成分作用机理及 治疗应用却还未见报道。 [0006] 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。
技术问题
[0007] 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。
问题的解决方案
技术解决方案
[0008] 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%。
[0009] 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 齐 ij、 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。
发明的有益效果
有益效果
[0010] 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, 提取用吋比浸提减少 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一沸程 30-60°C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。
[0011] 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。
[0012] 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。
对附图的简要说明
附图说明
[0013] 图 1是宽缨酮结构式
[0014] 图 2是 13,21-双氢宽缨酮结构式 [0015] 图 3是 13α (21)-环氧宽缨酮结构式
[0016] 图 4是宽缨醇结构式
实施该发明的最佳实施例
本发明的最佳实施方式
[0017] 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°C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; 13ot (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%。
[0018] 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°C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; 13ot(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%。
[0019] 实例 3: 宽缨酮胶囊的制备
[0020] lg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。
[0021] 实例 4: 13α (21)-环氧宽缨酮胶囊的制备
[0022] 100gl3a (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。
本发明的实施方式
[0023] 实例 5 : 小鼠腹腔注射宽缨酮、 宽缨醇、 13ot(21)-环氧宽缨酮以及 13,21-双氢宽 缨酮精品后负重游泳实验
[0024] 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, 将小鼠放入水槽吋进行游泳试验, 水 深 25cm, 水温 28-30°C。 每鼠尾负重为体重 7%, 记录小鼠游泳持续吋间, 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。
[0025] 实例 6: 大鼠腹腔注射苦木素精品后血浆检测 FSH和 LH统计表
[0026] 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 )
[] [表 1]
Figure imgf000006_0001
[0027] 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査统计表
[0028] 给老年人群 (年齢〉60) 和患有轻度、 中度抑郁症人群口服含有苦木素的胶囊 , 调査苦木素对上述两种疾病的治疗作用, 调査统计结果如下:
[] [表 2]
Figure imgf000007_0001
[0029] 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。
工业实用性
[0030] 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, 值得深入幵发。 序列表自由内容
[0031] 在此处键入序列表自由内容描述段落。

Claims

权利要求书
[权利要求 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°C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。
[权利要求 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。
[权利要求 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。
[权利要求 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。
[权利要求 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。
[权利要求 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、 13ot (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 0.05-3.00 mg/kg。
[权利要求 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、 13ot (21)-环氧宽缨酮以及 13,21-双氢宽缨酮一
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