WO2021012589A1 - Preparation method and application of standard lily bulb and rehmannia decoction having antidepressant effect - Google Patents

Preparation method and application of standard lily bulb and rehmannia decoction having antidepressant effect Download PDF

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WO2021012589A1
WO2021012589A1 PCT/CN2019/125797 CN2019125797W WO2021012589A1 WO 2021012589 A1 WO2021012589 A1 WO 2021012589A1 CN 2019125797 W CN2019125797 W CN 2019125797W WO 2021012589 A1 WO2021012589 A1 WO 2021012589A1
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decoction
preparation
standard
lily
rehmannia
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PCT/CN2019/125797
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French (fr)
Chinese (zh)
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马柯
王世军
王媛
赵海军
张洪秀
马山
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山东中医药大学
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A61K36/804—Rehmannia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8967—Lilium, e.g. tiger lily or Easter lily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/26—Conditioning of the fluid carrier; Flow patterns
    • G01N30/28—Control of physical parameters of the fluid carrier
    • G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient

Definitions

  • the invention belongs to the field of traditional Chinese medicine compound prescriptions, and specifically relates to a preparation method and application of a standard decoction of Baihe Dihuang Decoction with antidepressant effect.
  • Depression is a kind of mental illness whose main clinical symptoms are depression, slow thinking, and reduced or delayed speech movements.
  • the etiology is complex.
  • the Chinese medicine compound under the guidance of syndrome differentiation and treatment is characterized by its multiple components, multiple targets, and overall regulation. , Fits the nature of diseases caused by the complexity of the body, and shows unique advantages and good prospects in the prevention and treatment of depression.
  • there is no name for depression in traditional Chinese medicine there are many descriptions similar to the symptoms of the disease in historical documents, such as the lily disease recorded in the "Golden Chamber Synopsis”.
  • the diet, mentality, sleep, and behavioral abnormalities of Lily disease are very similar to the main clinical manifestations of depression.
  • Clinical application and basic research have found that Baihe Dihuang Decoction is effective in treating depression.
  • This application provides a method for preparing a standard decoction of Baihe Dihuang Decoction with antidepressant effect.
  • the antidepressant "standard decoction" of Baihe Dihuang Decoction is investigated. Depression and its pharmacological mechanism.
  • a method for preparing a standard decoction of Baihe Dihuang Decoction with antidepressant effect including the following steps:
  • step S3 adds the decoction of step S2 to step S1 and cooks it to obtain a standard decoction of Baihe Dihuang Decoction.
  • composition analysis of the standard decoction of Baihe Dihuang Decoction includes the following steps:
  • the mobile phase is acetonitrile-0.05% phosphoric acid water, gradient elution, the detection wavelength of ferulic acid component is 330nm, and the detection wavelength of dioscin component is 205nm;
  • the mobile phase is 1:99 acetonitrile-0.1% phosphoric acid aqueous solution, and the detection wavelength is 210nm;
  • the mobile phase of verbascum glycosides is methanol A-0.1% phosphoric acid aqueous solution, gradient elution; detection wavelength 334nm;
  • Baihe Dihuang Decoction increased the content of monoamine neurotransmitters 5-HT, NE and DA, decreased the content of inhibitory neurotransmitters and increased the content of excitatory neurotransmitters after intervention, and recovered with dual regulation GABA and glutamate balance and reduce the levels of pro-inflammatory cytokines Il-1 ⁇ , IL-6 and TNF- ⁇ .
  • High-throughput sequencing combined with preliminary bioinformatics analysis showed that compared with the model group, Baihe Dihuang Decoction (Zhongjing Yuggling) increased the prefrontal cortex and GABAergic neuron information encoding output genes GAD-67, VGAT, GAT after intervention -3mRNAs expression.
  • Baihe Dihuang Decoction (Zhongjing Yusweeping) intervention changes the neurotransmitters and cytokines in the serum of mice with depression-like behavior induced by LPS; enhances 5-HT(A), NE(B), DA(C) in model mice , GABA (D) neurotransmitter content, reduce glutamate (E), corticosterone (F), Il-1 ⁇ (G), IL-6 (H) and TNF- ⁇ (I) levels;
  • the preparation method of standard decoction includes the following steps:
  • the mobile phase is acetonitrile (A)-0.05% phosphoric acid water (B), and the elution gradient is 0-6min, 5%A; 6-15min, 5%-14%A; 15-25min, 14%A; 25-30min, 14% ⁇ 21%A; 30 ⁇ 35min, 21%A; 35 ⁇ 45min, 21% ⁇ 36%A; 45 ⁇ 51min, 36%A; 51 ⁇ 63min, 36% ⁇ 66.3%A; 63 ⁇ 70min, 66.3 %A; 70 ⁇ 83min, 66.3% ⁇ 100%A; 83 ⁇ 90min, 90%A, flow rate 1.0mL/min, column temperature 30°C, detection wavelength of ferulic acid component is 330nm, detection wavelength of dioscin component is 205nm, Inject 20 ⁇ L.
  • ferulic acid and diosgenin reference substance Take an appropriate amount of ferulic acid and diosgenin reference substance, accurately weigh it, add 80% methanol to make a reference substance solution with a concentration of 0.0200mg/mL, shake it well, and ultrasound for 5 minutes to completely dissolve it.
  • Microporous filter membrane (0.45 ⁇ m oil film) filter and get it.
  • test solution for determination of ferulic acid and diosgenin 400g fresh lily (fresh lily medicinal materials are broken into flakes, washed and wiped dry) 400g, accurately weighed, decocted in a casserole for 1.5h, concentrated into 200ml, and placed in an evaporating dish Evaporate to dryness in a water bath, grind the residue into a powder with a mortar, accurately weigh 2g, place it in a stoppered Erlenmeyer flask, accurately add 50ml of methanol, close the stopper, weigh it, ultrasonically treat it for 15 minutes, let it cool, Then weigh the weight, make up the weight loss with methanol, shake well, filter through the filter funnel first, filter through the microporous filter membrane (0.45 ⁇ m oil film), and take the additional filtrate to get it.
  • the mobile phase is acetonitrile-0.1% phosphoric acid (1:99) aqueous solution
  • the detection wavelength is 210nm
  • the flow rate is 1.0mL/min
  • the injection volume is 10 ⁇ L
  • the column temperature is 25°C
  • the verbascum glycoside mobile phase is methanol (A)-0.1% phosphoric acid aqueous solution (B)
  • the gradient elution program is 0 ⁇ 5min, 40% ⁇ 43%A; 5min ⁇ 10min, 43% ⁇ 56%A; 10min ⁇ 20min, 56% ⁇ 60%A; 20min ⁇ 25min, 60% ⁇ 40 %A.
  • the detection wavelength is 334nm
  • the flow rate is 1.0mL/min
  • the injection volume is 20 ⁇ L
  • the column temperature is 25°C.
  • test solution for determination of catalpol and verbascum glycosides 400g of fresh rehmannia glutinosa, accurately weighed, squeeze the juice with a juicer, and 200ml of juice, put the juice in an evaporating dish, put a water bath to steam dry, and first use a mortar for the residue Grind into powder, accurately weigh 2g, place it in a stoppered Erlenmeyer flask, accurately add 50ml of methanol, close the stopper, weigh it, ultrasonically treat it for 15 minutes, let it cool, then weigh it again, make up the weight loss with methanol, shake Evenly, filter through the filter funnel first, then filter through the microporous filter membrane (0.45 ⁇ m oil film) to obtain.
  • the external standard method was used to calculate the peak area to calculate the content of diosgenin and ferulic acid. The results are shown in Table 1. The external standard method was used to calculate the peak area to calculate the content of catalpol and verbascoside. The results are shown in Table 2.
  • the body surface area method According to the body surface area method, it was converted into the equivalent dose of 150g ⁇ kg -1 in rats, and 10ml ⁇ kg -1 per rat was given by intragastric administration daily.
  • the modified lipopolysaccharide method (Lipopolysaccharide, LPS) was used to construct internal heat depression Models were given continuous administration for 2 weeks at the same time, and fluoxetine was used as a positive control.
  • rats in the LPS model group, fluoxetine positive control group, and Baihe Dihuang Decoction treatment group were given intraperitoneal injections of LPS at a dose of 0.3 mg/kg, 0.5 ml each time, blank control group Only do the above actions and do not give corresponding drug injections.
  • Blank control group Control group, routinely raised under the above laboratory conditions, from the 4th day to the 17th day of the experiment, the same dose of Baihe Dihuang Decoction was given to the stomach by gavage.
  • the LPS model group is the LPS+Saline group. From the 4th day to the 17th day of the experiment, the same dose of Baihe Dihuang Decoction was given by intragastric administration.
  • Baihe Dihuang Decoction treatment group LPS+LBRD group
  • the Baihe Dihuang Decoction was administered by gavage at a dose of 95 g/kg, and the amount of gavage was calculated according to the body surface area method.
  • the modern Baihe Dihuang Decoction treatment group is: LPS+XDF group. From the 4th day to the 17th day of the experiment, the Baihe Dihuang Decoction was administered by gavage at a dose of 95g/kg, and the amount of gavage was calculated according to the body surface area method.
  • Fluoxetine positive control group LPS+Flu group, from the 4th day to the 17th day of the experiment, fluoxetine was given 10mg/kg intragastrically, and the intragastric dose was calculated according to the body surface area method.
  • the model and treatment schedule are shown in Figure 2.
  • Baihe Dihuang Decoction (Zhongjing Yusweeping) intervention significantly increased the intake of sugar and water, shortened the time of forced swimming and tail suspension, and increased the time of social behavior in the Y maze. It has a good antidepressant effect, and The efficacy is better than Baihe Dihuang Decoction Modern Recipe, the results are shown in Figure 3A, B, C, D, E.

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Abstract

The present invention relates to the field of traditional Chinese medicines, and specifically relates to a preparation method for a standard Lily Bulb and Rehmannia Decoction having an antidepressant effect. First, the records about the dosage of the classical formulation, Lily Bulb and Rehmannia Decoction, the origin of authentic medicinal materials, and the preparation method of the classical formulation in the historical documents are referred to; the "standard decoction" of the classical formulation, Lily Bulb and Rehmannia Decoction, is prepared; after intervention using Lily Bulb and Rehmannia Decoction, the content of monoamine neurotransmitters, 5-HT, NE and DA, is increased, the content of inhibitory neurotransmitters is decreased, and the content of excitatory neurotransmitters is increased; finally, active ingredients of the standard decoction are analyzed using a high-performance liquid chromatography, so as to provide a modern scientific basis for the depression treatment effect mechanism and formulation composition of the classical formulation, Lily Bulb and Rehmannia Decoction. The present invention has high theoretical significance and clinical value.

Description

[根据细则37.2由ISA制定的发明名称]　一种具有抗抑郁功效的百合地黄汤标准煎液的制备方法及其应用[Name of invention formulated by ISA according to Rule 37.2] 　The preparation method and application of a standard decoction of Baihe Dihuang Decoction with antidepressant effect 技术领域Technical field
本发明属于中药复方领域，具体涉及一种具有抗抑郁功效的百合地黄汤标准煎液的制备方法及应用。The invention belongs to the field of traditional Chinese medicine compound prescriptions, and specifically relates to a preparation method and application of a standard decoction of Baihe Dihuang Decoction with antidepressant effect.
背景技术Background technique
抑郁症是一种以情感消沉、思维迟钝、言语动作减少或迟缓为主要临床症状的精神类疾病，病因复杂，而辨证论治指导下的中药复方，以其多成分、多靶点、整体调节等特点，契合因机体复杂性而引发疾病的本质，在抑郁症防治方面显现出独特优势和良好前景。中医学虽无抑郁症之名，但历代文献中可见较多与本病症状相近的描述，如《金匮要略》中所记载的百合病。百合病所表现出的饮食、精神、睡眠、行为异常等与抑郁症主要临床表现非常相似。临床应用和基础研究发现百合地黄汤治疗抑郁症具有佳效。Depression is a kind of mental illness whose main clinical symptoms are depression, slow thinking, and reduced or delayed speech movements. The etiology is complex. The Chinese medicine compound under the guidance of syndrome differentiation and treatment is characterized by its multiple components, multiple targets, and overall regulation. , Fits the nature of diseases caused by the complexity of the body, and shows unique advantages and good prospects in the prevention and treatment of depression. Although there is no name for depression in traditional Chinese medicine, there are many descriptions similar to the symptoms of the disease in historical documents, such as the lily disease recorded in the "Golden Chamber Synopsis". The diet, mentality, sleep, and behavioral abnormalities of Lily disease are very similar to the main clinical manifestations of depression. Clinical application and basic research have found that Baihe Dihuang Decoction is effective in treating depression.
发明内容Summary of the invention
本申请提供了一种具有抗抑郁功效的百合地黄汤标准煎液的制备方法，通过确定相关的古代计量单位，选用改良的LPS诱导的内热型抑郁模型，考察百合地黄汤“标准煎液”抗抑郁作用及其药理机制。This application provides a method for preparing a standard decoction of Baihe Dihuang Decoction with antidepressant effect. By determining the relevant ancient measurement units and selecting an improved LPS-induced internal heat depression model, the antidepressant "standard decoction" of Baihe Dihuang Decoction is investigated. Depression and its pharmacological mechanism.
一种具有抗抑郁功效的百合地黄汤标准煎液的制备方法，包括以下步骤：A method for preparing a standard decoction of Baihe Dihuang Decoction with antidepressant effect, including the following steps:
(1)参考仲景原方百合地黄汤用法用量：百合七枚/擘、生地黄汁一升，上以水洗百合，渍一宿，当白沫出，去其水，更以泉水二升，煎取一升，去滓，内地黄汁，煎取一升五合，分温再服，中病，勿更服，大便当如漆；(1) Refer to the usage and dosage of Baihe Dihuang Decoction in Zhongjing's original prescription: seven lilies/bump, one liter of raw rehmannia juice, wash the lily on top, soak it overnight, when the foam comes out, remove the water, and use spring water for two liters. Decoction to take one liter, decontamination, mainland yellow juice, decoction to take one liter of five combinations, and then take it at separate temperatures, if you are sick, do not take more, the stool is like paint;
(2)标准：东汉一升认定为200ml；所用生地黄即现代所言鲜地黄，选取河南省焦作地区鲜地黄；湖北省神农架的百合鳞茎做为实测药材；(2) Standard: 200ml for one liter in the Eastern Han Dynasty; the raw rehmannia used is the fresh rehmannia in modern times, and the fresh rehmannia in Jiaozuo, Henan Province is selected; the lily bulb of Shennongjia in Hubei Province is used as the measured medicinal material;
(3)按照(2)的标准，采用(1)的量，得到标准煎液。(3) According to the standard of (2), use the amount of (1) to obtain the standard decoction.
上述的制备方法，具体步骤：The above preparation method, the specific steps:
S1河南省焦作地区鲜地黄，经过榨汁，得到鲜地黄榨汁；S1 Fresh Rehmannia glutinosa in Jiaozuo area, Henan Province, obtained fresh rehmannia glutinosa juice after juicing;
S2湖北省神农架的鲜百合鳞茎，水洗，渍一宿，以泉水煮取获得百合水煎液；S2 Fresh lily bulbs from Shennongjia, Hubei Province, washed with water, soaked overnight, and boiled with spring water to obtain lily decoction;
S3将步骤S2的煎液加入到步骤S1中，煮取，获得百合地黄汤的标准煎液。S3 adds the decoction of step S2 to step S1 and cooks it to obtain a standard decoction of Baihe Dihuang Decoction.
上述百合地黄汤标准煎液的具体成分分析，包括以下步骤：The specific composition analysis of the standard decoction of Baihe Dihuang Decoction includes the following steps:
(a)百合色谱条件及检测溶液的制备；(a) Lily chromatographic conditions and preparation of detection solutions;
流动相为乙腈－0.05％磷酸水，梯度洗脱，阿魏酸成分检测波长为330nm，薯蓣皂苷成分检测波长为205nm；The mobile phase is acetonitrile-0.05% phosphoric acid water, gradient elution, the detection wavelength of ferulic acid component is 330nm, and the detection wavelength of dioscin component is 205nm;
对照品溶液的制备；Preparation of reference solution;
供试品溶液的制备。Preparation of test solution.
(b)地黄色谱条件及检测溶液的制备(b) Ground yellow spectrum conditions and preparation of detection solution
流动相为1：99的乙腈-0.1％磷酸水溶液，检测波长为210nm；The mobile phase is 1:99 acetonitrile-0.1% phosphoric acid aqueous solution, and the detection wavelength is 210nm;
毛蕊花糖苷流动相为甲醇A-0.1％磷酸水溶液，梯度洗脱；检测波长334nm；The mobile phase of verbascum glycosides is methanol A-0.1% phosphoric acid aqueous solution, gradient elution; detection wavelength 334nm;
对照品溶液的制备；Preparation of reference solution;
供试品溶液的制备。Preparation of test solution.
上述成分测定方法判定的百合地黄标准煎液的质量。The quality of Lily Dihuang standard decoction determined by the above-mentioned component determination method.
上述具有抗抑郁功效的百合地黄汤标准煎液作为治疗抑郁症的药物的应用。The above-mentioned standard decoction of Baihe Dihuang Decoction with antidepressant effect is used as a medicine for treating depression.
与LPS模型组相比，百合地黄汤干预后增加了单胺类神经递质5-HT、NE和DA含量、降低抑制性神经递质含量并增加兴奋性神经递质含量，以双重调节恢复了GABA和谷氨酸平衡、降低促炎性细胞因子Il-1β、IL-6和TNF-α水平。高通量测序结合生物信息学初步分析显示，与模型组相比，百合地黄汤(仲景原方)干预后增加前额叶皮层中与GABA能神经元信息编码输出基因GAD-67、VGAT、GAT-3mRNAs的表达。Compared with the LPS model group, Baihe Dihuang Decoction increased the content of monoamine neurotransmitters 5-HT, NE and DA, decreased the content of inhibitory neurotransmitters and increased the content of excitatory neurotransmitters after intervention, and recovered with dual regulation GABA and glutamate balance and reduce the levels of pro-inflammatory cytokines Il-1β, IL-6 and TNF-α. High-throughput sequencing combined with preliminary bioinformatics analysis showed that compared with the model group, Baihe Dihuang Decoction (Zhongjing Yuanfang) increased the prefrontal cortex and GABAergic neuron information encoding output genes GAD-67, VGAT, GAT after intervention -3mRNAs expression.
我们利用高效液相色谱技术分析出鲜百合和鲜地黄汁中四四种抗抑郁药效活性成分，定性确定其含量之后，分别在同一中药混合液中测量四种物质的含量，我们发现薯蓣皂苷和阿魏酸含量在复方煎液中相比于鲜品中成分传递呈递减趋势，而毛蕊花糖苷和梓醇则呈递增趋势(表1-2)。We used high performance liquid chromatography to analyze the four or four antidepressant active ingredients in fresh lily and fresh rehmannia juice. After qualitatively determining their contents, we measured the contents of the four substances in the same traditional Chinese medicine mixture. We found that diosgenin The content of ferulic acid and ferulic acid in the compound decoction showed a decreasing trend compared with that in fresh products, while verbascum glycosides and catalpol showed an increasing trend (Table 1-2).
附图说明Description of the drawings
图1百合地黄汤(仲景原方)干预后明显改善LPS诱导的抑郁样行为。糖水摄取量(A)，缩短强迫游泳(B)和悬尾(C)不动时间及提升Y迷宫(D)中社交行为；Figure 1 Baihe Dihuang Decoction (Zhongjing Yuanfang) significantly improved LPS-induced depression-like behavior after intervention. Sugar water intake (A), shorten the immobility time of forced swimming (B) and tail suspension (C), and improve social behavior in Y maze (D);
图2造模及干预时间表；Figure 2 Model building and intervention schedule;
图3百合地黄汤(仲景原方)干预后改变LPS诱导抑郁样行为小鼠血清中神经递质及细胞因子；增强模型鼠中5-HT(A)、NE(B)、DA(C)、GABA(D)神经递质含量，降低谷氨酸(E)、皮质酮(F)、Il-1β(G)、IL-6(H)及TNF-α(I)水平；Figure 3 Baihe Dihuang Decoction (Zhongjing Yuanfang) intervention changes the neurotransmitters and cytokines in the serum of mice with depression-like behavior induced by LPS; enhances 5-HT(A), NE(B), DA(C) in model mice , GABA (D) neurotransmitter content, reduce glutamate (E), corticosterone (F), Il-1β (G), IL-6 (H) and TNF-α (I) levels;
其中图1及图3中：*代表与Control组比较，*P<0.01，**P<0.01，***P<0.001； #代表与LPS+Saline比较， #P<0.01， ##P<0.01， ###P<0.001。LPS+Saline：LPS+生理盐水组；LPS+Flu：LPS+氟西汀组；LPS+LBRD：LPS+百合地黄汤(仲景原方)组；LPS+XDF： LPS+现代百合地黄汤组。 In Figure 1 and Figure 3: * represents comparison with Control group, *P<0.01, **P<0.01, ***P<0.001;# represents comparison with LPS+Saline, # P<0.01, ## P< 0.01, ### P<0.001. LPS+Saline: LPS+normal saline group; LPS+Flu: LPS+fluoxetine group; LPS+LBRD: LPS+ Baihe Dihuang Decoction (Zhongjing Yuanfang) group; LPS+XDF: LPS+ Modern Baihe Dihuang Decoction group.
具体实施方式Detailed ways
实施例1Example 1
标准煎液的制备方法，包括以下步骤：The preparation method of standard decoction includes the following steps:
(1)选取河南焦作地区鲜地黄，经过多次榨汁，得出鲜地黄出汁率约为50％，即400g鲜地黄榨汁约200ml。选取湖北省神农架的百合鳞茎做为实测药材。测量后得出，百合鳞茎鲜时7枚(水洗，渍一宿)约400g，晒干后约重175g。(1) Selecting fresh rehmannia glutinosa in Jiaozuo area of Henan Province, after several times of juice extraction, the juice yield of fresh rehmannia glutinosa is about 50%, that is, 400g fresh rehmannia glutinosa juice is about 200ml. Lily bulbs from Shennongjia, Hubei Province were selected as the medicinal materials. After the measurement, 7 lily bulbs (washed in water, soaked for one night) are about 400g when they are fresh, and they weigh about 175g after being dried.
(2)七个湖北省神农架地区的鲜百合鳞茎，(水洗，渍一宿)约400g，以400ml泉水煮取获得200ml百合水煎液；(2) Seven fresh lily bulbs from the Shennongjia area of Hubei Province, (washed, soaked for one night) about 400g, boiled with 400ml spring water to obtain 200ml lily decoction;
(3)加200ml现榨河南省焦作的鲜地黄根(约400g鲜地黄榨取获得)混合进一步煮取，获得300ml百合地黄汤的标准煎液。(3) Add 200ml of freshly squeezed fresh Rehmannia glutinosa roots from Jiaozuo, Henan Province (about 400g of fresh Rehmannia glutinosa extract obtained) and mix for further cooking to obtain 300ml of standard decoction of Lily Rehmanniae Decoction.
实施例2Example 2
1.百合色谱条件及检测溶液的制备1. Lily chromatographic conditions and preparation of detection solution
流动相为乙腈(A)-0.05％磷酸水(B)，洗脱梯度0～6min，5％A；6～15min，5％～14％A；15～25min，14％A；25～30min，14％～21％A；30～35min，21％A；35～45min，21％～36％A；45～51min，36％A；51～63min，36％～66.3％A；63～70min，66.3％A；70～83min，66.3％～100％A；83～90min，90％A，流速1.0mL/min，柱温30℃，阿魏酸成分检测波长为330nm，薯蓣皂苷成分检测波长为205nm，进样20μL。The mobile phase is acetonitrile (A)-0.05% phosphoric acid water (B), and the elution gradient is 0-6min, 5%A; 6-15min, 5%-14%A; 15-25min, 14%A; 25-30min, 14%～21%A; 30～35min, 21%A; 35～45min, 21%～36%A; 45～51min, 36%A; 51～63min, 36%～66.3%A; 63～70min, 66.3 %A; 70～83min, 66.3%～100%A; 83～90min, 90%A, flow rate 1.0mL/min, column temperature 30℃, detection wavelength of ferulic acid component is 330nm, detection wavelength of dioscin component is 205nm, Inject 20μL.
对照品溶液的制备：Preparation of reference solution:
取阿魏酸、薯蓣皂苷对照品适量，精密称定，加80％甲醇均制成浓度为0.0200mg/mL的对照品溶液，摇匀，超声5分钟使之完全溶解，微孔滤膜(0.45μm油膜)滤过，即得。Take an appropriate amount of ferulic acid and diosgenin reference substance, accurately weigh it, add 80% methanol to make a reference substance solution with a concentration of 0.0200mg/mL, shake it well, and ultrasound for 5 minutes to completely dissolve it. Microporous filter membrane (0.45 μm oil film) filter and get it.
供试品溶液的制备：Preparation of test solution:
阿魏酸、薯蓣皂苷测定供试品溶液的制备：鲜百合(鲜百合药材掰成片状，洗净擦干表面水分)400g，精密称定，砂锅煎熬1.5h，浓缩成200ml，置蒸发皿中，放水浴锅蒸干，残渣先用研钵磨成粉末，精密称取2g，置于具塞三角瓶中，精密加入甲醇50ml，密塞，称定重量，超声处理15分钟，放冷，再称定重量，用甲醇补足所失重量，摇匀，先过滤漏斗滤过，继微孔滤膜(0.45μm油膜)滤过，取续滤液，即得。Preparation of test solution for determination of ferulic acid and diosgenin: 400g fresh lily (fresh lily medicinal materials are broken into flakes, washed and wiped dry) 400g, accurately weighed, decocted in a casserole for 1.5h, concentrated into 200ml, and placed in an evaporating dish Evaporate to dryness in a water bath, grind the residue into a powder with a mortar, accurately weigh 2g, place it in a stoppered Erlenmeyer flask, accurately add 50ml of methanol, close the stopper, weigh it, ultrasonically treat it for 15 minutes, let it cool, Then weigh the weight, make up the weight loss with methanol, shake well, filter through the filter funnel first, filter through the microporous filter membrane (0.45μm oil film), and take the additional filtrate to get it.
2.地黄色谱条件及检测溶液的制备2. Ground yellow spectrum conditions and preparation of detection solution
流动相为乙腈-0.1％磷酸(1：99)水溶液，检测波长为210nm，流速1.0mL/min，进样量10μL，柱温25℃；毛蕊花糖苷流动相为甲醇(A)－0.1％磷酸水溶液(B)，梯度洗脱程序为0～ 5min，40％～43％A；5min～10min，43％～56％A；10min～20min，56％～60％A；20min～25min，60％～40％A。检测波长334nm，流速1.0mL/min，进样量20μL，柱温25℃。The mobile phase is acetonitrile-0.1% phosphoric acid (1:99) aqueous solution, the detection wavelength is 210nm, the flow rate is 1.0mL/min, the injection volume is 10μL, the column temperature is 25℃; the verbascum glycoside mobile phase is methanol (A)-0.1% phosphoric acid aqueous solution (B), the gradient elution program is 0～5min, 40%～43%A; 5min～10min, 43%～56%A; 10min～20min, 56%～60%A; 20min～25min, 60%～40 %A. The detection wavelength is 334nm, the flow rate is 1.0mL/min, the injection volume is 20μL, and the column temperature is 25°C.
对照品溶液的制备：Preparation of reference solution:
取梓醇对照品适量，精密称定，加流动相制成浓度为0.5mg/ml的溶液，摇匀，超声5分钟使之完全溶解，微孔滤膜(0.45μm水膜)滤过，取续滤液，即得；取毛蕊花糖苷对照品适量，精密称定，加50％甲醇制成浓度为0.06μg/ml的溶液，溶解过滤即得。Take an appropriate amount of the catalpol reference substance, accurately weigh it, add the mobile phase to make a solution with a concentration of 0.5mg/ml, shake it well, and ultrasound for 5 minutes to completely dissolve it, filter it with a microporous membrane (0.45μm water membrane), and take Continue the filtrate to obtain; take an appropriate amount of verbascum glycoside reference substance, accurately weigh it, add 50% methanol to make a solution with a concentration of 0.06 μg/ml, and dissolve and filter it to obtain.
供试品溶液的制备：Preparation of test solution:
梓醇、毛蕊花糖苷测定供试品溶液的制备：鲜地黄400g，精密称定，置榨汁机榨汁，出汁200ml，将汁置于蒸发皿中，放水浴锅蒸干，残渣先用研钵磨成粉末，精密称取2g，置于具塞三角瓶中，精密加入甲醇50ml，密塞，称定重量，超声处理15分钟，放冷，再称定重量，用甲醇补足所失重量，摇匀，先过滤漏斗滤过，继微孔滤膜(0.45μm油膜)滤过，即得。Preparation of test solution for determination of catalpol and verbascum glycosides: 400g of fresh rehmannia glutinosa, accurately weighed, squeeze the juice with a juicer, and 200ml of juice, put the juice in an evaporating dish, put a water bath to steam dry, and first use a mortar for the residue Grind into powder, accurately weigh 2g, place it in a stoppered Erlenmeyer flask, accurately add 50ml of methanol, close the stopper, weigh it, ultrasonically treat it for 15 minutes, let it cool, then weigh it again, make up the weight loss with methanol, shake Evenly, filter through the filter funnel first, then filter through the microporous filter membrane (0.45μm oil film) to obtain.
取同一样品3份置于样品瓶中，按上述色谱条件进行测定。利用外标法以峰面积计算，计算出薯蓣皂苷和阿魏酸含量，结果见表1。利用外标法以峰面积计算，计算出梓醇和毛蕊花糖苷含量，结果见表2。Take 3 copies of the same sample and place them in a sample bottle, and perform the determination according to the above chromatographic conditions. The external standard method was used to calculate the peak area to calculate the content of diosgenin and ferulic acid. The results are shown in Table 1. The external standard method was used to calculate the peak area to calculate the content of catalpol and verbascoside. The results are shown in Table 2.
表1 供试品中薯蓣皂苷和阿魏酸的含量Table 1 The content of diosgenin and ferulic acid in the test product
化合物名称Compound name 保留时间keep time 面积area 高度height 浓度concentration 含量百分比Content percentage
阿魏酸标准品Ferulic acid standard 39.009±0.19039.009±0.190 2858359±452858359±45 196740±7196740±7 0.018±0.0045mg/ml0.018±0.0045mg/ml 无no
鲜百合供试品Fresh lily for test 39.098±0.21039.098±0.210 432371±64432371±64 26619±826619±8 0.002±0.0012mg/ml0.002±0.0012mg/ml 0.073±0.01％0.073±0.01%
百合地黄汤供试品Lily Dihuang Decoction for testing 39.145±0.20539.145±0.205 11872±1511872±15 941±4941±4 0.00007±0.000003mg/ml0.00007±0.000003mg/ml 0.00079±0.00004％0.00079±0.00004%
薯蓣皂苷标准品Dioscin Standard 87.778±0.18087.778±0.180 90001461±6590001461±65 1501861±81501861±8 0.02±0.03mg/ml0.02±0.03mg/ml 无no
鲜百合供试品Fresh lily for test 87.521±0.21687.521±0.216 35556366±8735556366±87 695458±11695458±11 0.007±0.00023mg/ml0.007±0.00023mg/ml 0.018±0.0006％0.018±0.0006%
百合地黄汤供试品Lily Dihuang Decoction for testing 87.634±0.22387.634±0.223 175717±98175717±98 10572±1010572±10 0.000039±0.000003mg/ml0.000039±0.000003mg/ml 0.00039±0.00003％0.00039±0.00003%
表2 供试品中梓醇和毛蕊花糖苷的含量Table 2 The content of catalpol and verbascoside in the test product
化合物名称Compound name 保留时间keep time 面积area 高度height 浓度concentration 含量百分比Content percentage
毛蕊花糖苷标准品Verbascum Glycoside Standard 10.392±0.09010.392±0.090 261981±25261981±25 16162±516162±5 0.049±0.002mg/ml0.049±0.002mg/ml 无no
鲜地黄汁供试品Fresh Rehmanniae Juice for Test 10.280±0.11210.280±0.112 6045±786045±78 357±9357±9 0.001±0.0004mg/ml0.001±0.0004mg/ml 0.006±0.0024％0.006±0.0024%
百合地黄汤供试品Lily Dihuang Decoction for testing 9.259±0.0859.259±0.085 371489±81371489±81 10042±1010042±10 0.07±0.009mg/ml0.07±0.009mg/ml 0.70±0.09％0.70±0.09%
梓醇标准品Catalpol Standard 3.702±0.0983.702±0.098 2923334±1192923334±119 592979±11592979±11 1±0.202mg/ml1±0.202mg/ml 无no
鲜地黄汁供试品Fresh Rehmanniae Juice for Test 3.736±0.1023.736±0.102 578621±144578621±144 60586±1460586±14 0.20±0.003mg/ml0.20±0.003mg/ml 1.0±0.15％1.0±0.15%
百合地黄汤供试品Lily Dihuang Decoction for testing 3.601±0.1133.601±0.113 477378±169477378±169 60810±1460810±14 0.16±0.008mg/ml0.16±0.008mg/ml 1.6±0.08％1.6±0.08%
对比例1Comparative example 1
现代百合地黄汤(XDF)的制备过程：干品百合45g，干品生地45g，泉水煎煮2次，每次30min，合并提取液300ml，备用。The preparation process of modern Baihe Dihuang Decoction (XDF): 45g of dried lily, 45g of dried lily, decocted in spring water for 2 times, 30min each time, combined with 300ml of extract, and set aside.
效果实施例1Effect Example 1
按体表面积法换算成大鼠的等效剂量150g·kg -1，按照每只大鼠10ml·kg -1每日行灌胃给药，采用改良脂多糖方法(Lipopolysaccharide，LPS)构建内热型抑郁模型，造模同时连续给药2周，氟西汀做阳性对照。 According to the body surface area method, it was converted into the equivalent dose of 150g·kg -1 in rats, and 10ml·kg -1 per rat was given by intragastric administration daily. The modified lipopolysaccharide method (Lipopolysaccharide, LPS) was used to construct internal heat depression Models were given continuous administration for 2 weeks at the same time, and fluoxetine was used as a positive control.
在第1天至第14天，给予LPS模型组、氟西汀阳性对照组、百合地黄汤组处理组的大鼠腹腔注射LPS，剂量为0.3mg/kg，每次注射0.5ml，空白对照组只做上述动作，不给予相应药物注射。From day 1 to day 14, rats in the LPS model group, fluoxetine positive control group, and Baihe Dihuang Decoction treatment group were given intraperitoneal injections of LPS at a dose of 0.3 mg/kg, 0.5 ml each time, blank control group Only do the above actions and do not give corresponding drug injections.
空白对照组：即Control组，常规饲养于如上实验室条件下，从实验第4天至17天，给予与百合地黄汤等剂量生理盐水灌胃。Blank control group: Control group, routinely raised under the above laboratory conditions, from the 4th day to the 17th day of the experiment, the same dose of Baihe Dihuang Decoction was given to the stomach by gavage.
LPS模型组即：LPS+Saline组，从实验第4天至第17天，给予与百合地黄汤等剂量生理盐水灌胃。The LPS model group is the LPS+Saline group. From the 4th day to the 17th day of the experiment, the same dose of Baihe Dihuang Decoction was given by intragastric administration.
百合地黄汤处理组即：LPS+LBRD组，从实验第4天至第17天，给予百合地黄汤95g/kg剂量灌胃，按照体表面积法计算灌胃量。In the Baihe Dihuang Decoction treatment group: LPS+LBRD group, from the 4th day to the 17th day of the experiment, the Baihe Dihuang Decoction was administered by gavage at a dose of 95 g/kg, and the amount of gavage was calculated according to the body surface area method.
现代百合地黄汤方处理组即：LPS+XDF组，从实验第4天至第17天，给予百合地黄汤95g/kg剂量灌胃，按照体表面积法计算灌胃量。The modern Baihe Dihuang Decoction treatment group is: LPS+XDF group. From the 4th day to the 17th day of the experiment, the Baihe Dihuang Decoction was administered by gavage at a dose of 95g/kg, and the amount of gavage was calculated according to the body surface area method.
氟西汀阳性对照组：即LPS+Flu组，从实验第4天至第17天，给予氟西汀10mg/kg剂量灌胃，按照体表面积法计算灌胃量。造模及治疗时间表如图2所示。Fluoxetine positive control group: LPS+Flu group, from the 4th day to the 17th day of the experiment, fluoxetine was given 10mg/kg intragastrically, and the intragastric dose was calculated according to the body surface area method. The model and treatment schedule are shown in Figure 2.
与空白对照组相比，LPS模型组SD大鼠在糖水偏好(SPT)值显著降低，摄入量减少(p<0.01)；其次，与空白对照组相比，LPS模型组SD大鼠肛温升高(p<0.01)，证明LPS有急性致热炎症反应，由此进一步实践说明LPS所诱导大鼠抑郁模型为内热型证候，结果见图3A,E。Compared with the blank control group, SD rats in the LPS model group had a significantly lower sugar preference (SPT) value and reduced intake (p<0.01); secondly, compared with the blank control group, SD rats in the LPS model group had anal temperature Elevated (p<0.01), which proves that LPS has an acute pyrogenic inflammatory response, and further practice shows that the rat depression model induced by LPS is an internal heat syndrome. The results are shown in Figure 3A, E.
与LPS模型组相比，百合地黄汤(仲景原方)干预后显著增加糖水摄取量、缩短强迫游泳和悬尾不动时间及提高Y迷宫中社交行为时间，具有良好的抗抑郁功效，且功效优于百合地黄汤现代方，结果详见图3A,B,C,D,E。Compared with the LPS model group, Baihe Dihuang Decoction (Zhongjing Yuanfang) intervention significantly increased the intake of sugar and water, shortened the time of forced swimming and tail suspension, and increased the time of social behavior in the Y maze. It has a good antidepressant effect, and The efficacy is better than Baihe Dihuang Decoction Modern Recipe, the results are shown in Figure 3A, B, C, D, E.

Claims (5)

  1. 一种具有抗抑郁功效的百合地黄汤标准煎液的制备方法，其特征在于，包括以下步骤：A method for preparing a standard decoction of Baihe Dihuang Decoction with antidepressant effect, which is characterized in that it comprises the following steps:
    (1)参考仲景原方百合地黄汤用法用量：百合七枚/擘、生地黄汁一升，上以水洗百合，渍一宿，当白沫出，去其水，更以泉水二升，煎取一升，去滓，内地黄汁，煎取一升五合，分温再服，中病，勿更服，大便当如漆；(1) Refer to the usage and dosage of Baihe Dihuang Decoction in Zhongjing's original prescription: seven lilies/bump, one liter of raw rehmannia juice, wash the lily on top, soak it overnight, when the foam comes out, remove the water, and use spring water for two liters. Decoction to take one liter, decontamination, mainland yellow juice, decoction to take one liter of five combinations, and then take it at separate temperatures, if you are sick, do not take more, the stool is like paint;
    (2)标准：东汉一升认定为200ml；所用生地黄即现代所言鲜地黄，选取河南省焦作地区鲜地黄；湖北省神农架的百合鳞茎做为实测药材；(2) Standard: 200ml for one liter in the Eastern Han Dynasty; the raw rehmannia used is the fresh rehmannia in modern times, and the fresh rehmannia in Jiaozuo, Henan Province is selected; the lily bulb of Shennongjia in Hubei Province is used as the measured medicinal material;
    (3)按照(2)的标准，采用(1)的量，得到标准煎液。(3) According to the standard of (2), use the amount of (1) to obtain the standard decoction.
  2. 根据权利要1所述的制备方法，其特征在于，具体步骤：The preparation method according to claim 1, wherein the specific steps are:
    (1)河南省焦作地区鲜地黄，经过榨汁，得到鲜地黄榨汁；(1) Fresh Rehmannia glutinosa in Jiaozuo area, Henan Province, obtained fresh rehmannia glutinosa juice after juicing;
    (2)湖北省神农架的鲜百合鳞茎，水洗，渍一宿，以泉水煮取获得百合水煎液；(2) Fresh lily bulbs from Shennongjia, Hubei Province, washed with water, soaked overnight, boiled with spring water to obtain lily decoction;
    (3)将步骤(2)的煎液加入到步骤(1)中，煮取，获得百合地黄汤的标准煎液。(3) The decoction of step (2) is added to step (1) and boiled to obtain the standard decoction of Baihe Dihuang Decoction.
  3. 权利要求1或2所述的百合地黄汤标准煎液的具体成分分析，其特征在于，包括以下步骤：The specific component analysis of the standard decoction of Baihe Dihuang Decoction according to claim 1 or 2, characterized in that it comprises the following steps:
    (a)百合色谱条件及检测溶液的制备；(a) Lily chromatographic conditions and preparation of detection solutions;
    流动相为乙腈A－0.05％磷酸水B，梯度洗脱，流速1.0mL/min，柱温30℃，阿魏酸成分检测波长为330nm，薯蓣皂苷成分检测波长为205nm；The mobile phase is acetonitrile A-0.05% phosphoric acid water B, gradient elution, flow rate 1.0mL/min, column temperature 30℃, detection wavelength of ferulic acid component is 330nm, and dioscin component detection wavelength is 205nm;
    对照品溶液的制备；Preparation of reference solution;
    供试品溶液的制备；Preparation of test solution;
    (b)地黄色谱条件及检测溶液的制备(b) Ground yellow spectrum conditions and preparation of detection solution
    流动相为1：99的乙腈-0.1％磷酸水溶液，检测波长为210nm，流速1.0mL/min，进样量10μL，柱温25℃；毛蕊花糖苷流动相为甲醇A-0.1％磷酸水溶液B，梯度洗脱；检测波长334nm，流速1.0mL/min，进样量20μL，柱温25℃；The mobile phase is 1:99 acetonitrile-0.1% phosphoric acid aqueous solution, the detection wavelength is 210 nm, the flow rate is 1.0 mL/min, the injection volume is 10 μL, and the column temperature is 25°C; the verbascum glycoside mobile phase is methanol A-0.1% phosphoric acid aqueous solution B, gradient Elution; detection wavelength 334nm, flow rate 1.0mL/min, injection volume 20μL, column temperature 25℃;
    对照品溶液的制备：Preparation of reference solution:
    供试品溶液的制备。Preparation of test solution.
  4. 采用权利要求3所述的成分测定方法判定权利要求1所述的百合地黄煎液的质量。The quality of the lily and rehmannia decoction described in claim 1 is determined by using the component determination method described in claim 3.
  5. 权利要求1所述的具有抗抑郁功效的百合地黄汤标准煎液作为治疗抑郁症的药物的应用。The use of the standard decoction of Baihe Dihuang Decoction with antidepressant effect according to claim 1 as a medicine for treating depression.
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