CN106860624B - Cimicifugae rhizoma extract, two cimicifugae flavone bases, and preparation method and application thereof - Google Patents
Cimicifugae rhizoma extract, two cimicifugae flavone bases, and preparation method and application thereof Download PDFInfo
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- CN106860624B CN106860624B CN201710056606.0A CN201710056606A CN106860624B CN 106860624 B CN106860624 B CN 106860624B CN 201710056606 A CN201710056606 A CN 201710056606A CN 106860624 B CN106860624 B CN 106860624B
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- cimicifuginone
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- 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)
- A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
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- 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
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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- 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
- A61K2236/30—Extraction of the material
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Abstract
The invention provides a cimicifuga extract and two cimicifuginone alkalines, which are prepared by using cimicifuga plants as raw materials, extracting the raw materials by using an organic solvent and then performing solvent extraction or chromatographic separation, thus obtaining the cimicifuga extract and two pure cimicifuginone alkalines, wherein the two cimicifuginone alkalines are cimicifuginone A and cimicifuginone B respectively, the extract and the two cimicifuginone alkalines can effectively inhibit the proliferation and growth of tumor cell lines such as human lung cancer cell line A549, human stomach cancer cell line MKN7, GSU, human melanoma cell line A375, human lung adenocarcinoma cell line NCI-H1975, human colon cancer cell line Colo-205, human leukemia cell line H L-60 and the like, and particularly the median lethal dose of the cimicifuginone alkali A and the cimicifuginone alkali B is in the concentration range of 1.36-21.09 mu M, which shows that the cimicifuginone alkali A (1) and the cimicifuginone alkali B (2) can:
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for preparing a cimicifuga extract and two new cimicifuga ketonekaline by using cimicifuga plants as raw materials and application of the two new cimicifuga ketonekaline in preparation of antitumor drugs.
Background
Cimicifuga genus (Cimicifuga) The plants are perennial herbs, are usually grown in mountain forest borders, forests or roadside grasses with an altitude of about 2000 m, and are mainly distributed in northern america, asia and northern temperate regions in europe. Wherein the cimicifugae rhizoma is a famous common Chinese medicine in China, and the black cimicifugae rhizoma (A. racemosa)C. racemosaBlack cohosh) is a health care medicine and dietary supplement that is highly recognized by the european and american society. Cimicifuga Rhizome is defined as Cimicifuga Cimicifuga in the section of the Chinese pharmacopoeia 2015 editionC. foetidaCimicifuga dahuricaC. dahuricaCimicifugae foetidaeC. heracleifoliaDried rhizome of (4). The earliest record of cimicifuga foetida comes from Shen nong Ben Cao Jing 25-220 years ago and is listed as the "top grade" medicinal material. The underground rhizome of cimicifuga foetida is used as a medicine, and has the main effects of removing all kinds of toxin, repelling pestilence, miasma, evil-toxin and raising yang and lifting sinking. The traditional Chinese medicine composition is mainly used for treating wind-heat characterization, wind-heat headache, toothache, aphtha, sore throat, measles without adequate eruption and yang-toxicity macula in clinic; prolapse of uterus, prolapse of anus, and prolapse of uterus.
Earlier researches show that the plants in the genus cimicifuga contain cycloartane-type triterpenes, 3-prenyl indole and the like, but at present, 3-prenyl indole dimer alkaloids (cimicifuginone alkali) with a highly unsaturated conjugated system are not found, and the antitumor cytotoxic activity of the alkaloids in the genus cimicifuga is not reported.
Disclosure of Invention
The invention aims to provide a cimicifuga extract with anti-tumor activity, which is realized by the following steps: cutting Cimicifuga rhizome into slices, drying, pulverizing, adding 8-12 times of organic solvent, and extracting at room temperature or under reflux for 2-3 times. Mixing extractive solutions, concentrating under reduced pressure to obtain extract, dissolving the extract in water, extracting with medium-low polarity organic solvent in equal volume, and recovering solvent to obtain extract. And (4) putting the extract on a macroporous resin column, collecting 70-95% of eluted parts, and drying to obtain the cimicifuga foetida extract.
The extract mainly contains dimeric indole alkaloid monomers, namely two cimicifuginone alkalis, namely cimicifuginone A (compound 1) and cimicifuginone B (compound 2), and is obtained by purifying a cimicifugine extract by using silica gel chromatography and Sephadex L H-20 columns to obtain two parts, and then crystallizing the two parts by using an organic solvent respectively to obtain pure cimicifuginone alkali A and pure cimicifuginone alkali B.
The organic solvent used for extraction and crystallization comprises methanol, ethanol, aqueous alcohol, ethyl acetate, dichloromethane, chloroform and other common medium and low polarity organic solvent systems. The medium and low polarity organic solvent used for extraction comprises petroleum ether, hexane, ethyl acetate, dichloromethane and chloroform. The macroporous resin column comprises common resin materials such as D101, AB-8 and the like.
The Cimicifuga plant comprises Cimicifuga racemosaC. foetidaCimicifuga dahuricaC. dahuricaCimicifugae foetidaeC. heracleifoliBlack cohosh of North AmericaC. racemosaCimicifugae foetidaeC. simplexYunnan cimicifugae foetidaeC. yunnanensisRhizoma cimicifugae with short fruitC. brachycarpaRhizoma cimicifugae from rhizoma arisaematisC. nanchuanensis、Small cimicifuga rhizomeC. acerinaIsocimicifuga plants.
The structural entities of the two cimicifuginone bases are:
compound (1): cimicifudione A, having the following structure:
compound (2): cimicifudione B, having the following structure:
the properties of the cimicifuginone bases A and B were tested by various spectroscopic techniques, including UV, IR, MS and NMR (1D and 2 DNMR) and X-ray single crystal diffraction, and after detailed analysis of the spectroscopic information, the structure was confirmed to be dimeric 3-prenyl indole alkaloid containing highly unsaturated conjugated system, which was found to be a novel compound by literature search.
Another objective of the invention is to provide the cimicifuga foetida extract, and cimicifuginone A (compound 1) and cimicifuginone B (compound A)The research selects seven tumor cell lines of human lung cancer cell line A549, human stomach cancer cell line MKN7, GSU, human melanoma cell line A375, human lung cancer cell line NCI-H1975, human colon cancer cell line Colo-205 and human leukemia cell line H L-60, and researches the antitumor activity of the seven tumor cell lines of human lung cancer cell line A549, human stomach cancer cell line MKN7, GSU, human melanoma cell line A375, human lung cancer cell line NCI-H1975, human colon cancer cell line Colo-205 and human leukemia cell line H L-60 on the antitumor activity of the extracts of cimicifuga foetida ketone alkali A and cimicifuga foetida ketone alkali B
Especially cimicifuginone B can make human leukemia cell H L-60 reach half lethal under the concentration of 1.36 +0.09 mu M.
The further research shows that the cimicifugine B can inhibit the proliferation of human leukemia H L-60 cells by promoting apoptosis, and the research result of the apoptosis promoting mechanism shows that the Bcl-2, Bax and Bcl-x L protein which can inhibit apoptosis is down-regulated, the cytochrome C which can promote apoptosis is released to be increased, the expression of activated caspase-3, caspase-8 and caspase-9 protein is increased, the Mitochondrial Membrane Potential (MMP) is reduced, and the DNA repair enzyme (PARP) is cracked to be increased.
The invention provides a cimicifuga extract with anti-tumor activity, and structures, preparation methods and applications of two novel diindole alkaloid compounds, namely cimicifuginone A (1) and cimicifuginone B (2). The invention takes cimicifuga plants as raw materials, after extraction with organic solventThe extraction and separation method has the advantages that the disadvantage that the cimicifuginone alkali is not obvious in color development and the traditional acid-base extraction method is difficult to enrich and obtain the extract with higher content is avoided, and the separation materials such as resin and gel are directly adopted to obtain the effective part extract with high content and the cimicifuginone alkali monomer pure product compound, so that the extract and the cimicifuginone alkali A and cimicifuginone alkali B can effectively inhibit the proliferation and the growth of tumor cell lines such as a human lung cancer cell line A549, a human gastric cancer cell line MKN7, GSU, a human melanoma cell line A375, a human lung adenocarcinoma cell line NCI-H1975, a human colon cancer cell line Colo-205 and a human leukemia cell line H L-60, wherein the median death amount of the cimicifuginone alkali A (1) and the median death amount of the cimicifuginone alkali B (2) are 1.36-21.09.2
The concentration range of (c). The invention develops the anti-tumor application of the dimeric indole alkaloid (cimicifuginone alkaloid) in the cimicifuga plants, expands the drug action of the cimicifuga plants, provides a basis for popularizing and utilizing traditional Chinese medicinal materials, and provides a new anti-tumor drug.
Drawings
FIG. 1 is a preparation of cimicifuginone A1H NMR Spectrum (500 MHz in)d 6-DMSO）。
FIG. 2 is a preparation of cimicifuginone A13C NMR Spectroscopy (125 MHz in)d 6-DMSO）。
FIG. 3 is an HMBC spectrum (500 MHz in) of cimicifuginone Ad 6-DMSO）。
FIG. 4 is an X-ray single crystal diffractogram of cimicifuginone A.
FIG. 5 is an IR spectrum of cimicifuginone A.
FIG. 6 is a mass spectrum of cimicifuginone base A.
FIG. 7 is a preparation of cimicifuginone B1H NMR Spectrum (500 MHz in)d 6-acetone）。
FIG. 8 is a preparation of cimicifuginone B13C NMR Spectroscopy (125 MHz in)d 6-acetone）。
FIG. 9 is an HMBC profile of cimicifuginone base B.
FIG. 10 is an IR spectrum of cimicifuginone B.
FIG. 11 is a mass spectrum of cimicifuginone base B.
Detailed Description
The invention is further explained by the accompanying drawings and examples.
Example 1
10 kg of dried rhizome of Yunnan largetrifolious bugbane rhizome, pulverizing, soaking and extracting twice with 95% ethanol solution of 80L for 5 days at room temperature, combining extracting solutions, steaming until no alcohol smell exists, obtaining 1000 g of total extract, dispersing the total extract with 2L water, sequentially and respectively extracting with petroleum ether and ethyl acetate in equal volumes, obtaining an ethyl acetate extraction part CRE (530 g), carrying out gradient elution on the ethyl acetate extraction part through a macroporous resin (D101) chromatographic column (30% -95%) ethanol, collecting 85% -95% elution part, and drying to obtain 20g of largetrifolious bugbane rhizome extract.
Example 2
The method comprises the steps of crushing 5 kg of dried rhizome of the cimicifuga foetida, leaching twice with 50L ethyl acetate solution at room temperature, 3 days each time, combining extracting solutions, steaming until no alcohol smell exists to obtain a total extract 200 g, dispersing the total extract with 2L water, sequentially and respectively extracting with petroleum ether and ethyl acetate in equal volumes to obtain an ethyl acetate extraction part CRE (100 g), carrying out gradient elution on the ethyl acetate extraction part through a macroporous resin (D101) chromatographic column (30% -95%) ethanol, collecting 80% -95% elution part to obtain a cimicifuga foetida extract, further carrying out Sephadex L H-20 column chromatographic separation, taking dichloromethane/methanol as a mobile phase, separating to obtain two parts, and respectively crystallizing in methanol to obtain a compound 1 (15 mg) and a compound 2 (17 mg).
Example 3
Crushing 5 kg of dried rhizome of black cohosh, adding 40L methanol, performing reflux extraction twice for 2 hours for the first time, filtering an extracting solution, adding 40L methanol, performing reflux extraction for 1 hour, combining the two extracting solutions, performing vacuum concentration to obtain an extract, suspending and dissolving the extract by using 3L water, performing equal-volume extraction by using dichloromethane sequentially to obtain 420 g of the extract, performing gradient elution by using ethanol of a macroporous resin (AB-8) chromatographic column (30% -95%), collecting 75% -95% of an eluted part, performing chromatographic separation by using a Sephadex L H-20 column, separating by using dichloromethane/methanol as a mobile phase to obtain two parts, and crystallizing in dichloromethane respectively to obtain a compound 1(45 mg) and a compound 2 (52 mg).
EXAMPLE 4 Pilot plant preparation of Compound 1
100 kg of dried rhizome of Cimicifuga dahurica, crushing, adding 1000L 95% ethanol, performing reflux extraction twice, performing reflux extraction for 3 hours for the first time and 2 hours for the second time, combining extracting solutions obtained in the two times, performing reduced pressure concentration to obtain 8 kg of extract, suspending and dissolving the extract with 20L water, performing equal-volume extraction with petroleum ether and ethyl acetate respectively to obtain an ethyl acetate extraction part CRE (4 kg), performing gradient elution on the ethyl acetate extraction part through a macroporous resin (D101) chromatographic column (30% -95%) ethanol, collecting 85% -95% elution part, performing Sephadex L H-20 column chromatographic separation, taking dichloromethane/methanol as a mobile phase, separating to obtain two parts, and performing crystallization to obtain a compound 1 (1.2 g) and a compound 2 (1.4 g) respectively.
Example 5
The physicochemical and UV, IR, MS spectral data of cimicifuginone a (compound 1) and cimicifuginone b (compound 2) are as follows:
cimicifuginone A: black crystals; developing with 10% sulfuric acid ethanol to obtain black brown color; UV (MeOH) lambdamax(log): 226(4.6), 275 (4.4), 395 (3.8) nm; IR (KBr)v max: 3396, 3307, 2965, 2924, 1636,1560, 1417 cm-1;1H NMR and13c NMR is shown in Table 2.1. HRESI-MS
: 395.1758 [M+H]+, Calcd forC26H23N2O2395.1760; ESI-MS（positive）
：395.39
, ESI-MS (negative)
：393.37
。
Cimicifuginone base B: a black amorphous powder; developing with 10% sulfuric acid ethanol to obtain black brown color; UV (MeOH) λ max (log) 225 (4.6), 273 (4.7), 417 (3.8) nm, IR (KBr) vmax 3352, 3275, 2970,2921, 1725, 1676, 1637, 1559, 1448 cm-1, 1H NMR, and 13C NMR are shown in Table 2.1. HRESI-MS
：463.2388 [M+H]+, Calcd for C31H31N2O2 463.2386; ESI-MS（positive）
：463.49
, ESI-MS(negative)
：461.33
。
Process for preparing cimicifuginone A and cimicifuginone B1H NMR,13The C NMR data and the assignments are shown in Table 1, and the assignments for each of the hydrogen and carbon signals were obtained by testing two-dimensional nuclear magnetic resonance spectra (HSQC, HMBC, NOESY). Where HSQC determines all methyl, methylene, methine signals and HMBC experiments determine the order of attachment of each hydrogen-carbon unit. The figures show the maps of cimicifuginone A (FIGS. 1-6) and cimicifuginone B (FIGS. 7-11).
TABLE 1 Cimicifuga ketotifen A (1) (1)d 6 -DMSO) and cimicifuginone base (2) ((ii)d 6 -acetone)
Is/are as follows1H (500 MHz) and13c (125 MHz) NMR data and Signal attribution
The structural formulas of the cimicifuginone A (1) and the cimicifuginone B (2) are as follows:
example 6 pharmacological Activity Studies of Cimicifuga extract, Cimicifuga ketolide A (1) and Cimicifuga ketolide B (2)
(1) Cell lines including human lung cancer cell line A549, human gastric cancer cell line MKN7, GSU, human melanoma cell line A375, human lung adenocarcinoma cell line NCI-H1975, human colon cancer cell line Colo-205 and human leukemia cell line H L-60, (2) inoculating cells in RPMI culture medium (containing 10% heat-inactivated fetal calf serum, 100U/ml penicillin G and 100. mu.g/ml streptomycin), and culturing at 37 deg.C and 5% CO2Culturing under saturated humidity, digesting cells in logarithmic phase, blowing into single cell suspension, inoculating into 96-well plate with density of 4 × 103Cells/well, 100. mu.l of medium per well, 5% CO at 37 ℃2Continuously culturing under saturated humidity, (3) after culturing cells for 24 hours, dissolving a compound into different concentrations by DMSO, adding 10 microliters of DMSO into each well, parallelly preparing three parts of DMSO into each concentration gradient, taking a control group only added with DMSO as a positive control group, continuously culturing for 72 hours, (4) fixing 10% trichloroacetic acid for 1 hour, washing by distilled water, (5) adding 100 microliters of SRB solution (4 mg/ml) into each well, dyeing for 20 minutes at room temperature, (6) removing supernatant, adding 100 microliters of 10 mM Tris solution into each well to dissolve SRB, (7) detecting OD values of each well by a microplate reader (detection wavelength: 490 nm), recording results, calculating the inhibition rate according to a formula, namely the inhibition rate (%) = (OD control-OD administration)/OD control × 100%, and calculating IC50。
The results of the experiments are shown in the following Table 2, and the results show that the cimicifuga foetida extract, the cimicifuginone A and the cimicifuginone B can effectively inhibit seven tumors, namely a human lung cancer cell line A549, a human gastric cancer cell line MKN7, GSU, a human melanoma cell line A375, a human lung adenocarcinoma cell line NCI-H1975, a human colon cancer cell line Colo-205 and a human leukemia cell line H L-60Proliferation of cell lines with a median lethal dose of 1.36-21.09
Especially, the concentration of the cimicifuginone B at 1.36 +0.09 mu M can enable human leukemia cells H L-60 to be half lethal, which indicates that the two compounds can be applied to the anti-tumor field.
Example 7 preparation of Cimicifuga extract tablets
Mixing cimicifugae rhizoma extract 100g with starch 850g, adding 10% starch slurry 20g to obtain soft material, adding magnesium stearate 0.2g and dry starch 18g, mixing, and pressing into 2000 tablets. Each tablet contains cimicifugae rhizoma extract 50 mg.
Example 8 preparation of Cimicifuga ketonic A formulations
(1) Making into tablet
Mixing cimicifuginone A10 g and starch 150g, adding 10% starch slurry 20g to obtain soft material, adding magnesium stearate 0.2g, and dry starch 18g, mixing, and pressing into 1000 tablets. Each tablet contains cimicifuginine A10 mg.
(2) Making into injection
Adding cimicifuginone A hydrochloride 10g, adding mannitol 25g, adding water for injection to 1000ml, heating to dissolve, and dissolving with 0.22
Filtering with microporous membrane, packaging 1ml of each bottle into 5ml penicillin bottles containing cimicifuone A10 mg, freeze drying in vacuum freeze dryer, taking out, capping, and packaging.
Example 9 preparation of Cimicifuga ketolide B formulations
(1) Making into tablet
Mixing 3.0g of cimicifuginone B with 10g of starch, adding 3g of 10% starch slurry to prepare a soft material, adding 0.3g of magnesium stearate and 2g of dry starch, mixing uniformly, and pressing into 100 tablets to obtain the tablet. Each tablet contains cimicifuginine B30 mg.
(2) Making into injection
Collecting cimicifuginine hydrobromide 1.0g, adding mannitol 10g, adding water for injection to 1000ml, heating to dissolve, and dissolving with 0.22
Filtering with microporous membrane, packaging 2ml each bottle into 5ml penicillin bottles containing 2.0 mg of cimicifuginone B, freeze drying in vacuum freeze dryer, taking out, capping, and packaging.
Claims (8)
1. Two cimicifugine bases in the cimicifuga foetida extract are respectively (1) cimicifugine base A, and the structural formula is as follows:
(2) cimicifudione B, having the following structural formula:
2. the preparation method of two cimicifugane alkaloids according to claim 1, comprises cutting cimicifuga plant rhizome into slices, drying, pulverizing, adding 8-12 times of organic solvent according to weight/volume ratio, extracting at room temperature or refluxing for 2-3 times, mixing extractive solutions, concentrating under reduced pressure to obtain extract, dissolving the extract in suspension with appropriate amount of water, extracting with middle and low polarity organic solvent at equal volume, recovering solvent to obtain extract, loading the extract onto macroporous resin column, collecting 70-95% ethanol eluate, drying to obtain cimicifugae rhizoma extract, purifying cimicifugae rhizoma extract with silica gel chromatography and Sephadex L H-20 column to obtain two parts, and crystallizing with organic solvent to obtain cimicifugane alkaloid A and cimicifugae rhizoma keto B.
3. The preparation method according to claim 2, wherein the organic solvent is selected from methanol, ethanol, aqueous alcohol, ethyl acetate, dichloromethane, and chloroform; the middle-low polarity organic solvent used for extraction is selected from petroleum ether, hexane, ethyl acetate, dichloromethane or trichloromethane; the macroporous resin column is made of resin materials of D101 and AB-8 types.
4. The process according to claim 2, wherein the organic solvent used for the crystallization is selected from methanol, ethanol, aqueous alcohol, ethyl acetate, dichloromethane, and chloroform.
5. The method of claim 2, wherein the cimicifuga plant is cimicifuga foetidaCimicifuga. foetidaCimicifuga dahuricaC. dahuricaCimicifugae foetidaeC. heracleifoliBlack cohosh of North AmericaC. racemosaCimicifugae foetidaeC. simplexYunnan cimicifugae foetidaeC. yunnanensisRhizoma cimicifugae with short fruitC. brachycarpaRhizoma cimicifugae from rhizoma arisaematisC. nanchuanensis、Small cimicifuga rhizomeC. acerina。
6. The use of two cimicifuginone bases according to claim 1 in the preparation of an anti-tumor medicament.
7. The use according to claim 6, wherein the tumor is caused by a human lung cancer cell line A549, a human gastric cancer cell line MKN7, GSU, a human melanoma cell line A375, a human lung adenocarcinoma cell line NCI-H1975, a human colon cancer cell line Colo-205, or a human leukemia cell line H L-60.
8. The use of claim 6, wherein the medicament is prepared by adding pharmaceutical excipients, and the preparation form is solid preparation or liquid preparation.
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| CN1475269A (en) * | 2003-07-31 | 2004-02-18 | 凯 曹 | Rhizoma cimicifugae extract and its preparation method |
| CN103172555A (en) * | 2012-12-07 | 2013-06-26 | 山东绿叶制药有限公司 | Indole alkaloid compound separated from rhizoma cimicifugae as well as preparation method and application thereof |
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| CN1475269A (en) * | 2003-07-31 | 2004-02-18 | 凯 曹 | Rhizoma cimicifugae extract and its preparation method |
| CN103172555A (en) * | 2012-12-07 | 2013-06-26 | 山东绿叶制药有限公司 | Indole alkaloid compound separated from rhizoma cimicifugae as well as preparation method and application thereof |
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