CN101549001A - Effective component of artemisia leaves and preparation method thereof - Google Patents
Effective component of artemisia leaves and preparation method thereof Download PDFInfo
- Publication number
- CN101549001A CN101549001A CNA200810052605XA CN200810052605A CN101549001A CN 101549001 A CN101549001 A CN 101549001A CN A200810052605X A CNA200810052605X A CN A200810052605XA CN 200810052605 A CN200810052605 A CN 200810052605A CN 101549001 A CN101549001 A CN 101549001A
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- Prior art keywords
- ethanol
- minute
- eluent
- mobile phase
- ethyl acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
The invention relates to an effective component of artemisia leaves as well as a preparation method and an application thereof. The preparation process of the effective component of the artemisia leaves comprises the following steps: (1) a mixture of ethyl acetate and ethanol is used as a solvent to extract the artemisia leaves; (2) dregs of a decoction are extracted with the ethanol so as to obtain an extracting solution; (3) the extracting solution is processed by chromatography through a chromatographic column to obtain an eluent; (4) the eluent is eluted by prepared liquid chromatogram gradient and is collected for 28.0-32.0 minutes, 36.0-40.0 minutes, 48.0-52.0 minutes, 52.0-56.0 minutes and 52.0-60.0 minutes to obtain the effective component by taking water and acetonitrile as flow phases.
Description
Technical field
The present invention relates to a kind of Chinese medicine extract for the treatment of tumor disease, relate in particular to the active component that from Folium Artemisiae Argyi, extracts, preparation and preparation method thereof and purposes.
Background technology
Tumor is a kind of commonly encountered diseases, frequently-occurring disease, and wherein malignant tumor is the most serious class disease of present harm humans health.At present in the industry to the treatment of malignant tumor mainly still based on operation, radiotherapy, chemotherapy, but many chemical anticarcinogenic drugs often involve normal cell when acting on target cell, cause serious side reaction.The genetoxic of plant amedica is not obvious, and Chinese herbal medicine is having special advantages and wide application prospect aspect the anticancer mutation, and Chinese medicine also plays the effect that can not be ignored in to the auxiliary treatment of tumor.Paclitaxel promptly is the good anticancer active native compound that has that typically obtains from plant, now has been developed as antitumor drug.The most serious tumor of China's hazardness is pulmonary carcinoma, nasopharyngeal carcinoma, the esophageal carcinoma, gastric cancer, colorectal cancer, hepatocarcinoma, breast carcinoma, cervical cancer, leukemia and lymphoma etc. at present.Particularly the incidence rate of hepatocarcinoma increases in recent years to some extent.Significant, the etiology of these tumors, pathogenesis and control thereof are the emphasis of China's tumor research.Cancer therapy drug and the anticancer ancillary drug of seeking high-efficiency low-toxicity are the important contents of current tumor research.
China's medicinal organism resource is very abundant, and its biological active substances is research and finds new drug guide chemicals, the natural treasure-house of developing new drug.At present, China extracts active substance from natural product, be used to be developed to treatment tumor disease, safety is good, toxicity is low new drug also seldom, extracts active substance from natural product, be developed to new drug, have significant application value and wide development prospect with antitumor curative effect.
Folium Artemisiae Argyi is a herbaceos perennial.Its chemical constituent that contains has, rhizome contains volatile oil, and main constituent is in the oil: and 8-Folium eucalypti globueli (Eucalyptus globulus Labill.) essence, α-absinthol (α-thujone), α-phellandrene (α-phellandrene), β-Flos Caryophylli alkene (β-caryophyllene), camphene, Camphora, carvone, trans reed alcohol (transcarveol), I-alpha-terpineol (I-α-terpineol).Its nature and flavor: bitter in the mouth, suffering, warm in nature.Return the liver,spleen,kidney warp.Its function cures mainly to: this product fragrance, bitter dry suffering looses, the blood of regulating the flow of vital energy, warming the meridian arteries and veins, by cold-damp, end cold type of pain, be gynecological's key medicine.With controlling coldness and pain in the epigastrium, coldness and unbalance in meridians, the infertile card that waits of cold womb is as Aifu Nuangong Wan.The parch to black hemostasis, the available deficiency and coldness menorrhagia of controlling, bleeding not during menses, vaginal bleeding during pregnancy is as Ass-hide Glue and Argyi Leaf Decoction.This product is smash floss, makes moxa roll, Ai Zhu, outer moxibustion energy dispersing cold for relieving pain, warm QI and blood.Fry in shallow oil the soup washout and can control eczema scabies, removing dampness to relieve itching.
Summary of the invention:
The object of the present invention is to provide the active component of Folium Artemisiae Argyi.
Another object of the present invention is to provide the preparation method of above-mentioned effective component of artemisia leaves.
The present invention also provides the preparation that contains above-mentioned effective component of artemisia leaves and the purposes of this component.
Effective component of artemisia leaves of the present invention, its preparation process may further comprise the steps:
Step 1: Folium Artemisiae Argyi is extracted as solvent with ethyl acetate and alcohol mixture,
Step 2: the medicinal residues ethanol extraction, obtain extracting solution,
Step 3: extracting solution gets eluent through column chromatography.
Step 4: the eluent that obtains with the preparative liquid chromatography gradient elution, mobile phase is water and acetonitrile, collects 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or 56.0-60.0 minute eluent and obtains active component 1 (or being called B07), active component 2 (or being called B09), active component 3 (or being called B12), active component 4 (or being called B13), active component 5 (or being called B14).
Wherein ethyl acetate described in the step 1 and alcoholic acid mixture, both ratios are ethyl acetate: ethanol=1-5: 1-5, are preferably ethyl acetate: ethanol=1-2: 1-2 most preferably is ethyl acetate: ethanol=1: 1.
In the described step, step 1 is specially: getting the Folium Artemisiae Argyi medical material, is solvent with ethyl acetate: ethanol=1-5: 1-5, and reflux, extract, is separated extracting solution with medicinal residues,
Step 2 is specially: medicinal residues obtain extracting solution with the ethanol extraction of 50-90%,
Step 3 is specially: above extracting solution is crossed the ODS-C18 post with sample on 5% dissolve with ethanol, at first, adopts 5% ethanol as mobile phase, changes 50% ethanol then as mobile phase, gets eluent,
Step 4 is specially: continue to separate the eluent that obtains with preparative liquid chromatography, mobile phase is water-A and acetonitrile-B, carries out gradient elution, and described gradient elution program is as follows:
Table 1: gradient elution table
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample 100% dissolve with ethanol separates through preparative liquid chromatography, collects 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or 56.0-60.0 minute solution solution obtains active component behind concentrate drying in the time period.
The preferred effective component of artemisia leaves preparation method of the present invention, comprise the following steps: the Folium Artemisiae Argyi pulverizing, add 6-10 and doubly measure ethyl acetate: ethanol=1: 1, reflux 1-2 hour, extract 1-3 time, medicinal residues add 6-10 and doubly measure 50-90% ethanol, reflux, filtrate merge extracting solution, after extracting solution concentrated, with sample on 5% dissolve with ethanol, mistake ODS-C18 post, at first, adopt 5% ethanol as mobile phase, change 50% ethanol then, get eluent as mobile phase, continue separation eluent with preparative liquid chromatography, separation condition is: chromatographic column is Agilent preparative column (Zorbax SB-C18; 21.2mm * 250mm), mobile phase is water A and acetonitrile B, the gradient elution program is as follows:
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample 100% dissolve with ethanol separates through preparative liquid chromatography, and time period 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or collected solution in 56.0-60.0 minute, solution obtains active component behind concentrate drying.
The most preferred effective component of artemisia leaves preparation method of the present invention comprises the following steps:
Folium Artemisiae Argyi is pulverized, add 8 times of amount ethyl acetate: ethanol=1: 1, reflux 1 hour, extract 2 times, medicinal residues add 8 times of amount 70% ethanol, and reflux 1 hour is extracted 2 times, filtrate merge extracting solution, after extracting solution concentrated, with sample on 5% dissolve with ethanol, mistake ODS-C18 post, at first, adopt 1250ml5% ethanol as mobile phase, change 1250ml50% ethanol then, get eluent as mobile phase, continue separation eluent with preparative liquid chromatography, separation condition: chromatographic column is Agilent preparative column (Zorbax SB-C18; 21.2mm * 250mm), mobile phase is water A and acetonitrile B, the gradient elution program is as follows
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample 100% dissolve with ethanol separates through preparative liquid chromatography, and time period 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or collected solution in 56.0-60.0 minute, solution obtains active component behind concentrate drying.
The active component composition such as the following table of collecting in 48.0-52.0 of the present invention minute, 52.0-56.0 minute, 56.0-60.0 minute
Table 2 component list
Folium Artemisiae Argyi B12 interpretation of mass spectra result
Folium Artemisiae Argyi B13 interpretation of mass spectra result
B14 interpretation of mass spectra result
Relevant structure is identified with reference to " uniting chemical dictionary CD-ROM " (The Combined Chemical Dictionary onCD-ROM) and affiliated pertinent literature.
The present invention also provides the pharmaceutical composition that is prepared into as active constituents of medicine with Chinese medicine active component of the present invention, and pharmaceutical composition of the present invention comprises active component, and said composition can also add the medicine acceptable carrier as required.
Compositions of the present invention is the pharmaceutical dosage forms of unit dose, and described unit dosage form is meant the unit of preparation, as every of tablet, and capsular every capsules, every bottle of oral liquid, every bag of granule etc.
Compositions of the present invention active component wherein, its shared percentage by weight in preparation can be 0.1-99.9%, all the other are the medicine acceptable carrier.
Compositions of the present invention obtains by above-mentioned active component and medicine acceptable carrier are mixed with.
Compositions of the present invention, its pharmaceutical dosage forms can be any pharmaceutically useful dosage form, and these dosage forms comprise: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, ointment, plaster, cream, spray, drop, patch.Preparation of the present invention, peroral dosage form preferably, as: capsule, tablet, oral liquid, granule, pill, powder, sublimed preparation, unguentum etc.
Compositions of the present invention, the preparation of its oral administration can contain excipient commonly used, such as binding agent, filler, diluent, tablet agent, lubricant, disintegrating agent, coloring agent, flavoring agent and wetting agent, can carry out coating to tablet in case of necessity.
The filler that is suitable for comprises cellulose, mannitol, lactose and other similar filler.Suitable disintegrating agent comprises starch, polyvinylpyrrolidone and starch derivatives, for example sodium starch glycollate.Suitable lubricant comprises, for example magnesium stearate.The acceptable wetting agent of appropriate drug comprises sodium lauryl sulphate.
Can fill by mixing, the method that tabletting etc. are commonly used prepares solid oral composition.Mix repeatedly active substance is distributed in those compositionss of a large amount of filleies of whole use.
The form of oral liquid for example can be aqueous or oily suspensions, solution, Emulsion, syrup or elixir, perhaps can be a kind of available water before use or other suitable composite dry products of carrier.This liquid preparation can contain conventional additive, such as suspending agent, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat, emulsifying agent, for example lecithin, anhydro sorbitol monooleate or arabic gum; Non-aqueous carrier (they can comprise edible oil), for example almond oil, fractionated coconut oil, such as oily ester, propylene glycol or the ethanol of the ester of glycerol; Antiseptic, for example para hydroxybenzene methyl ester or propyl p-hydroxybenzoate or sorbic acid, and if desired, can contain conventional flavouring agent or coloring agent.
For injection, the liquid unit dosage forms of preparation contains active substance of the present invention and sterile carrier.According to carrier and concentration, this chemical compound can be suspended or dissolving.The preparation of solution is normally by being dissolved in active substance in a kind of carrier filter-sterilized before it is packed into a kind of suitable bottle or ampoule, sealing then.For example a kind of local anesthetic of adjuvant, antiseptic and buffer agent also can be dissolved in this carrier.In order to improve its stability, can be after the bottle of packing into that this compositions is freezing, and under vacuum, water is removed.
Compositions of the present invention, when being prepared into medicament, optionally add suitable medicine acceptable carrier, described medicine acceptable carrier is selected from: mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, vitamin C, the EDTA disodium, EDTA calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and derivant thereof, alginate, gelatin, polyvinylpyrrolidone, glycerol, soil temperature 80, agar, calcium carbonate, calcium bicarbonate, surfactant, Polyethylene Glycol, cyclodextrin, beta-schardinger dextrin-, the phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc.
Compositions of the present invention is determined usage and dosage according to patient's situation in use, but obeys every day three times, each 1-20 agent, as: 1-20 bag or grain or sheet.
The present invention also provides the application at anti-tumor aspect of Chinese medicine active component of the present invention and pharmaceutical composition.Below be the data of pharmacological evaluation:
Screening active ingredients
Cell strain: HL-60 tumor cell
Cell culture and kind plate cell culture: use RPMI 1640 (Gibco) [adding the 2g/L sodium bicarbonate] 90%, hyclone (Ilex purpurea Hassk.[I.chinensis Sims) 10% Mixed culture HL 60 cells, density need be lower than 106/mL.Calculating needs cell total amount NT=ρ cellmL-1 * VT (ρ=2 * 104/mL), wherein VT=0.1mL * hole count+cell groove surplus.Suspension cell on the piping and druming culture bottle wall adds in the centrifuge tube.Get 10 μ L, add the blue dilution of 10 μ L Placenta Hominiss, viable count sum NL on the count plate, then the cell number N in the centrifuge tube is: NL/4 * 104 * 2 * V, wherein V is the liquor capacity in the centrifugal preceding centrifuge tube.It is centrifugal that (900rad/min 10min), inhales and removes supernatant, adds culture fluid V1 mL, and piping and druming makes the cell mixing, draws V2 mL and joins in the cell groove, makes V2=NT/N * V1.The culture fluid that adds VT-V2mL in the cell groove again with volley of rifle fire piping and druming, mixing, is got this liquid, and every hole adds 150 μ L.Choose 4 holes behind the kind plate and add 200 μ L culture fluid as blank, the residue hole adds 200 μ L PBS, to reduce the evaporation of culture fluid.
The dosage regimen effective component of artemisia leaves adds the DMSO dissolving of respective volume, and concentration is about 50mg/mL.The concussion dissolving, if there are a large amount of drops to glue wall, can be suitably centrifugal.Can store-20 ℃.The culture fluid that adds 220 μ L/ holes in 96 new orifice plates will be drawn 0.88 μ L medicinal liquid and add mixing, dilute 250 times, and the medicine that above-mentioned dilution is good has every hole, hole of cell to add 50 μ L to kind, and this moment, drug dilution was 1000 times, and promptly final concentration is 50ng/mL.Hatch 48h.Each concentration is established 4 parallel multiple holes, and every plate is established negative control group (add blank solution in the cell, blank solution is joined method---add the culture fluid of 200 μ L, will draw 0.88 μ LDMSO and add mixing), reaches positive controls (cisplatin final concentration 4 μ g/mL).SRB dyeing: after cell culture finishes, take out culture plate, every hole adds trichloroacetic acid (TCA) the 100 μ L fixed cells of 40% (mass/volume), and room temperature is placed 5min, places 1h in 4 ℃ of refrigerators.Deionized water wash 5 times of each hole of culture plate are to remove TCA.Behind air drying, every hole adds 0.4% SRB100 μ L (dissolving of 1% chromatographically pure acetic acid), place 20min under the room temperature, discard in each hole and wash 5 times with 1% acetic acid behind the liquid, remove unconjugated dyestuff, with 10mmol/L Tris150 μ L/ hole dissolving, 5min vibrates behind the air drying, use microplate reader (ELx 800) to measure, used wavelength is 490nm.
The calculating suppression ratio of suppression ratio is calculated as follows:
Drug effect the results are shown in Table 3.
Table 3
| Folium Artemisiae Argyi B07 component | Negative | Blank | Positive | |
| Average cell survival number | 0.10 | 0.35 | 0.07 | 0.12 |
| Suppression ratio (%) | 87.86 | 0 | 100 | 80.45 |
| RSD(％) | 5.44 | 2.89 | 7.99 | 4.21 |
| Folium Artemisiae Argyi B09 component | Negative | Blank | Positive | |
| Average cell survival number | 0.12 | 0.35 | 0.07 | 0.12 |
| Suppression ratio (%) | 82.86 | 0 | 100 | 80.45 |
| RSD(％) | 2.31 | 2.89 | 7.99 | 4.21 |
| Folium Artemisiae Argyi B12 component | Negative | Blank | Positive | |
| Average cell survival number | 0.10 | 0.35 | 0.07 | 0.12 |
| Suppression ratio (%) | 89.29 | 0 | 100 | 80.45 |
| RSD(％) | 2.83 | 2.89 | 7.99 | 4.21 |
| Folium Artemisiae Argyi B13 component | Negative | Blank | Positive | |
| Average cell survival number | 0.09 | 0.35 | 0.07 | 0.12 |
| Suppression ratio (%) | 94.11 | 0 | 100 | 80.45 |
| RSD(％) | 4.09 | 2.89 | 7.99 | 4.21 |
| Folium Artemisiae Argyi B14 component | Negative | Blank | Positive | |
| Average cell survival number | 0.09 | 0.35 | 0.07 | 0.12 |
| Suppression ratio (%) | 94.11 | 0 | 100 | 80.45 |
| RSD(％) | 4.09 | 2.89 | 7.99 | 4.21 |
Cell strain: Hep G2 tumor cell
Cell culture and kind plate cell culture: use DMEM high glycoform (Gibco) [adding the 3.7g/L sodium bicarbonate] 90%, hyclone (Ilex purpurea Hassk.[I.chinensis Sims) 10%, non essential amino acid (Gibco) 1% Mixed culture Hep G2 cell.Calculating needs cell total amount NT=ρ cellmL-1 * VT (ρ=2 * 103/mL), wherein VT=0.1mL * hole count+cell groove surplus.Suspension cell on the piping and druming culture bottle wall adds in the centrifuge tube.Get 10 μ L, add the blue dilution of 10 μ L Placenta Hominiss, viable count sum NL on the count plate, then the cell number N in the centrifuge tube is: NL/4 * 104 * 2 * V, wherein V is the liquor capacity in the centrifugal preceding centrifuge tube.It is centrifugal that (900rad/min 10min), inhales and removes supernatant, adds culture fluid V1 mL, and piping and druming makes the cell mixing, draws V2 mL and joins in the cell groove, makes V2=NT/N * V1.The culture fluid that adds VT-V2mL in the cell groove again with volley of rifle fire piping and druming, mixing, is got this liquid, and every hole adds 100 μ L, hatches 24h.Choose 4 holes adding culture fluid as blank after planting plate, the residue hole adds 100 μ L PBS, to reduce the evaporation of culture fluid.
The dosage regimen effective component of artemisia leaves is according to the weight of the medicine of institute's weighing, according to the weight of the medicine of institute's weighing, adds the DMSO dissolving of respective volume, and concentration is about 50mg/mL.The concussion dissolving, if there are a large amount of drops to glue wall, can be suitably centrifugal.Can store-20 ℃.96 orifice plates change liquid, and every hole adds fresh medium 150 μ L.The culture fluid that adds 220 μ L/ holes in 96 new orifice plates will be drawn 0.88 μ L medicinal liquid and add mixing, dilute 250 times, and the medicine that above-mentioned dilution is good has every hole, hole of cell to add 50 μ L to kind, and this moment, drug dilution was 1000 times, and promptly final concentration is 50 μ g/mL.Hatch 48h.Each concentration is established 4 (2) individual parallel multiple holes, and every plate is established negative control group (add blank solution in the cell, blank solution is joined method---add the culture fluid of 200 μ L, will draw 0.88 μ LDMSO adding mixing), positive controls (amycin final concentration 4 μ g/mL).The MTT colorimetric method for determining: take out culture plate, every hole, place to go supernatant, adding culture fluid-MTT mixed solution (culture fluid: 100 μ L MTT solution=10: 1), hatch 4h.Culture fluid is abandoned in suction, and every hole adds the DMSO of 150 μ L, vibration 10min, and 550nm microplate reader (Elx800) is measured.
The calculating suppression ratio of suppression ratio is calculated as follows:
Drug effect the results are shown in Table 4.
Table 4
| Folium Artemisiae Argyi B07 component | Negative | Blank | Positive | |
| Average cell survival number | 0.28 | 0.59 | 0.16 | 0.17 |
| Suppression ratio (%) | 73.02 | 0 | 100 | 96.86 |
| RSD(％) | 1.23 | 4.861 | 5.093 | 5.272 |
| Folium Artemisiae Argyi B09 component | Negative | Blank | Positive | |
| Average cell survival number | 0.38 | 0.59 | 0.16 | 0.17 |
| Suppression ratio (%) | 49.42 | 0 | 100 | 96.86 |
| RSD(％) | 5.81 | 4.861 | 5.093 | 5.272 |
| Folium Artemisiae Argyi B13 component | Negative | Blank | Positive | |
| Average cell survival number | 0.23 | 0.59 | 0.16 | 0.17 |
| Suppression ratio (%) | 84.30 | 0 | 100 | 96.86 |
| RSD(％) | 1.55 | 4.861 | 5.093 | 5.272 |
| Folium Artemisiae Argyi B14 component | Negative | Blank | Positive | |
| Average cell survival number | 0.28 | 0.59 | 0.16 | 0.17 |
| Suppression ratio (%) | 71.98 | 0 | 100 | 96.86 |
| RSD(％) | 1.26 | 4.86 | 5.09 | 5.27 |
Cell strain: K562 tumor cell
Cell culture and kind plate cell culture: use RPMI 1640 (Gibco) [adding the 2g/L sodium bicarbonate] 90%, calf serum (match is happy) 10%, non essential amino acid (Gibco) 1% Mixed culture K 562 cells.Calculating needs cell total amount NT=ρ cellmL-1 * VT (ρ=8 * 103/mL), wherein VT=0.1mL * hole count+cell groove surplus.Suspension cell on the piping and druming culture bottle wall adds in the centrifuge tube.Get 10 μ L, add the blue dilution of 10 μ L Placenta Hominiss, viable count sum NL on the count plate, then the cell number N in the centrifuge tube is: NL/4 * 104 * 2 * V, wherein V is the liquor capacity in the centrifugal preceding centrifuge tube.It is centrifugal that (900rad/min 10min), inhales and removes supernatant, adds culture fluid V1 mL, and piping and druming makes the cell mixing, draws V2 mL and joins in the cell groove, makes V2=NT/N * V1.The culture fluid that adds VT-V2mL in the cell groove again with volley of rifle fire piping and druming, mixing, is got this liquid, and every hole adds 100 μ L, hatches 24h.Choose 4 holes adding culture fluid as blank after planting plate, the residue hole adds 100 μ L PBS, to reduce the evaporation of culture fluid.
The dosage regimen effective component of artemisia leaves adds the DMSO dissolving of respective volume, and concentration is about 50mg/mL.The concussion dissolving, if there are a large amount of drops to glue wall, can be suitably centrifugal.Can store-20 ℃.96 orifice plates change liquid, and every hole adds fresh medium 150 μ L.The culture fluid that adds 220 μ L/ holes in 96 new orifice plates will be drawn 0.88 μ L medicinal liquid and add mixing, dilute 250 times, and the medicine that above-mentioned dilution is good has every hole, hole of cell to add 50 μ L to kind, and this moment, drug dilution was 1000 times, and promptly final concentration is 50 μ g/mL.Hatch 48h.Each concentration is established 4 (2) individual parallel multiple holes, and every plate is established negative control group (add blank solution in the cell, blank solution is joined method---add the culture fluid of 200 μ L, will draw 0.88 μ LDMSO adding mixing), positive controls (amycin final concentration 4 μ g/mL).SRB dyeing: after cell culture finishes, take out culture plate, every hole adds trichloroacetic acid (TCA) the 70 μ L fixed cells of 40% (mass/volume), places 1h in 4 ℃ of refrigerators.Deionized water wash 5 times of each hole of culture plate are to remove TCA.Behind air drying, every hole adds 0.4% SRB100 μ L (dissolving of 1% chromatographically pure acetic acid), place 20min under the room temperature, discard in each hole and wash 5 times with 1% acetic acid behind the liquid, remove unconjugated dyestuff, with 10mmol/L Tris150 μ L/ hole dissolving, 5min vibrates behind the air drying, use microplate reader (ELx800) to measure, used wavelength is 490nm.
The calculating suppression ratio of suppression ratio is calculated as follows:
Drug effect the results are shown in Table 5.
Table 5
| Folium Artemisiae Argyi B07 component | Negative | Blank | Positive | |
| Average cell survival number | 0.16 | 0.69 | 0.04 | 0.12 |
| Suppression ratio (%) | 81.62 | 0 | 100 | 87.19 |
| RSD(％) | 9.31 | 6.622 | 1.33 | 4.363 |
| Folium Artemisiae Argyi B12 component | Negative | Blank | Positive | |
| Average cell survival number | 0.12 | 0.69 | 0.04 | 0.12 |
| Suppression ratio (%) | 87.23 | 0 | 100 | 87.19 |
| RSD(％) | 3.45 | 6.622 | 1.33 | 4.363 |
| Folium Artemisiae Argyi B13 component | Negative | Blank | Positive | |
| Average cell survival number | 0.08 | 0.69 | 0.04 | 0.12 |
| Suppression ratio (%) | 93.15 | 0 | 100 | 87.19 |
| RSD(％) | 0.84 | 6.622 | 1.33 | 4.363 |
| Folium Artemisiae Argyi B14 component | Negative | Blank | Positive | |
| Average cell survival number | 0.09 | 0.69 | 0.04 | 0.12 |
| Suppression ratio (%) | 91.85 | 0 | 100 | 87.19 |
| RSD(％) | 1.52 | 6.62 | 1.33 | 4.36 |
Beneficial effect of the present invention is:
1. use the reverse phase silica gel post in the extraction and separation process of the present invention, can remove the impurity that easily formation is extremely adsorbed on the preparative hplc post such as chlorophyll effectively, improved content of effective, can obtain effective ingredient fast and accurately.
2. effective component of artemisia leaves chemical constituent provided by the invention is simply clear and definite, is easier to illustrate its mechanism of action on pharmacological research, is easier to the quality control of medicine aborning.
Method provided by the invention obtains containing B07, B09, B12, B13 first from the Folium Artemisiae Argyi medical material, the B14 active component, and first it is carried out medicine efficacy screening on various tumor cell strains, because composition is definite, content is clear and definite, preparation technology is convenient, and is active good, the suitable antitumor new Chinese medicine that is developed to.
Description of drawings
Fig. 1 is the HPLC analysis chart of effective component of artemisia leaves B07 of the present invention.
Fig. 2 is the HPLC analysis chart of effective component of artemisia leaves B09 of the present invention.
Fig. 3 is the HPLC analysis chart of effective component of artemisia leaves B12 of the present invention.
Fig. 4 is the HPLC analysis chart of effective component of artemisia leaves B13 of the present invention.
Fig. 5 is the HPLC analysis chart of effective component of artemisia leaves B14 of the present invention.
The specific embodiment
Further describe flesh and blood of the present invention below in conjunction with embodiments of the invention, this embodiment only is used to the present invention is described and the present invention is not limited.
The preparation of embodiment 1 effective component of artemisia leaves
Folium Artemisiae Argyi is pulverized, pulverize the back and cross 20 mesh sieves, add 8 times of amount ethyl acetate: ethanol=1: 1, reflux 1 hour is extracted 2 times, and medicinal residues add 8 times of amount 70% ethanol, reflux 1 hour, extract 2 times, filtrate merge extracting solution, after extracting solution concentrated, with sample on 5% dissolve with ethanol, cross the ODS-C18 post, at first, adopt 1250ml5% ethanol as mobile phase, change 1250ml 50% ethanol then as mobile phase, get eluent, continue separation eluent with preparative liquid chromatography, separation condition: chromatographic column is Agilent preparative column (Zorbax SB-C18; 21.2mm * 250mm), mobile phase is water A and acetonitrile B, the gradient elution program is as follows
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample 100% dissolve with ethanol separates through preparative liquid chromatography, and time period 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or collected solution in 56.0-60.0 minute, solution obtains active component behind concentrate drying.
The analysis of embodiment 2 effective component of artemisia leaves
Chromatographic conditionChromatographic column Agilent Zorbax SB-C18 post (4.6mm * 150mm, 5 μ m); Adopt gradient elution, mobile phase A is 0.2% glacial acetic acid aqueous solution mutually, and Mobile phase B is mutually for containing the acetonitrile solution of 0.2% glacial acetic acid; The gradient elution program is as follows: in the time of 0 minute, mobile phase A is that 90% 0.2% glacial acetic acid aqueous solution, Mobile phase B are the acetonitrile solution of 10% 0.2% glacial acetic acid; In the time of 10 minutes, mobile phase A is that 50% 0.2% glacial acetic acid aqueous solution, Mobile phase B are the acetonitrile solution of 50% 0.2% glacial acetic acid; In the time of 30 minutes, mobile phase A is that 5% 0.2% glacial acetic acid aqueous solution, Mobile phase B are the acetonitrile solution of 95% 0.2% glacial acetic acid; In the time of 35 minutes, mobile phase A is that 5% 0.2% glacial acetic acid aqueous solution, Mobile phase B are the acetonitrile of 95% 0.2% glacial acetic acid.Solution flow rate 0.5mLmin
-1It is long to detect the wavelength all-wave; 30 ℃ of column temperatures; ELSD condition: 105 ℃ of drift tube temperatures; Nitrogen flow rate 2.0L/min
The preparation of need testing solutionTake by weighing active component of the present invention, in volumetric flask, be diluted to scale, shake up, promptly with dissolve with methanol solution.
Assay methodThe accurate need testing solution of drawing injects chromatograph of liquid, measures.
Embodiment 3 effective component of artemisia leaves preparations
Get the effective component of artemisia leaves 1,2,3,4 of embodiment 1, or 5,0.5g and 10.5g Polyethylene Glycol-6000 mix homogeneously, heating and melting moves in the drop pill drip irrigation behind the change material, and medicine liquid droplet is to 6-8 ℃ of liquid paraffin, and oil removing makes 400 of drop pill.
Embodiment 4 effective component of artemisia leaves preparations
Get the effective component of artemisia leaves 1,2,3,4 of embodiment 1, or 5,0.5g, glucose 4.5g, sodium thiosulfate 0.9g and distilled water 1ml, behind the said components mix homogeneously, lyophilization, 500 of packing, promptly.
Get Lignum Dalbergiae Odoriferae oil 1.5g, join in the saturated hydroxypropyl of 13ml, stirring and dissolving filters, the filter leaf cold drying, Lignum Dalbergiae Odoriferae oil and the clathrate powder of hydroxypropyl.Except that above-mentioned Lignum Dalbergiae Odoriferae oil closes the clathrate powder of hydroxypropyl, get the effective component of artemisia leaves of embodiment 1 again, 0.5g, mannitol 5.5g, calcium disodium edetate 0.9g and distilled water 2ml, behind the said components mixing, lyophilization, 300 of packing, promptly.
Claims (10)
1, a kind of effective component of artemisia leaves, its preparation process may further comprise the steps:
Step 1: Folium Artemisiae Argyi is extracted as solvent with ethyl acetate and alcohol mixture,
Step 2: the medicinal residues ethanol extraction, obtain extracting solution,
Step 3: extracting solution gets eluent through column chromatography,
Step 4: with the eluent that the preparative liquid chromatography gradient elution obtains, mobile phase is water and acetonitrile, collects 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or 56.0-60.0 minute eluent and obtains active component.
2, the extract of claim 1 is characterized in that, ethyl acetate described in the step 1 and alcoholic acid mixture, and both ratios are ethyl acetate: ethanol=1-5: 1-5.
3, the extract of claim 1 is characterized in that, ethyl acetate described in the step 1 and alcoholic acid mixture, and both ratios are ethyl acetate: ethanol=1-2: 1-2.
4, the extract of claim 1 is characterized in that, ethyl acetate described in the step 1 and alcoholic acid mixture, and both ratios are ethyl acetate: ethanol=1: 1.
5, the extract of claim 1 is characterized in that, its preparation process may further comprise the steps:
The ethanol extraction of medicinal residues described in the step 2, described ethanol are the ethanol of 50-90%,
The column chromatography of process described in the step 3 is with sample on 5% dissolve with ethanol, crosses the ODS-C18 post, at first,
Adopt 5% ethanol as mobile phase, change 50% ethanol then, get eluent as mobile phase,
Step 4 is: continue to separate the eluent that obtains with preparative liquid chromatography, mobile phase is water-A and acetonitrile-B, carries out gradient elution.
6, the active component of claim 5 is characterized in that, described gradient elution program is as follows:
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample 100% dissolve with ethanol separates through preparative liquid chromatography, and time period 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or collected solution in 56.0-60.0 minute, solution obtains active component behind concentrate drying.
7, the pharmaceutical composition that contains any one active component of claim 1-6.
8, the preparation method of the active component of claim 1 is characterized in that, its preparation process may further comprise the steps:
Step 1: Folium Artemisiae Argyi is extracted as solvent with ethyl acetate and alcohol mixture,
Step 2: the medicinal residues ethanol extraction, obtain extracting solution,
Step 3: extracting solution gets eluent through column chromatography.
Step 4: with the eluent that the preparative liquid chromatography gradient elution obtains, mobile phase is water and acetonitrile, collects 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or 56.0-60.0 minute eluent and obtains active component.
9, the preparation method of the active component of claim 8 is characterized in that, in the described step, step 1 is: getting the Folium Artemisiae Argyi medical material, is solvent with ethyl acetate: ethanol=1-5: 1-5, and reflux, extract, is separated extracting solution with medicinal residues,
Step 2 is: described medicinal residues ethanol extraction, described ethanol are the ethanol of 50-90%,
The column chromatography of process described in the step 3 is with sample on 5% dissolve with ethanol, crosses the ODS-C18 post, at first,
Adopt 5% ethanol as mobile phase, change 50% ethanol then, get eluent as mobile phase,
Step 4 is: continue to separate the eluent that obtains with preparative liquid chromatography, mobile phase is water-A and acetonitrile-B, carries out gradient elution, and the gradient elution program is as follows:
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample 100% dissolve with ethanol separates through preparative liquid chromatography, and time period 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or collected solution in 56.0-60.0 minute, solution obtains active component behind concentrate drying.
10, the preparation method of the active component of claim 9 is characterized in that, step is as follows:
Folium Artemisiae Argyi is pulverized, add 8 times of amount ethyl acetate: ethanol=1: 1, reflux 1 hour, extract 2 times, medicinal residues add 8 times of amount 70% ethanol, and reflux 1 hour is extracted 2 times, filtrate merge extracting solution, after extracting solution concentrated, with sample on 5% dissolve with ethanol, mistake ODS-C18 post, at first, adopt 1250ml 5% ethanol as mobile phase, change 1250ml 50% ethanol then, get eluent as mobile phase, continue separation eluent with preparative liquid chromatography, separation condition: chromatographic column is Agilent preparative column (Zorbax SB-C18; 21.2mm * 250mm), mobile phase is water A and acetonitrile B, the gradient elution program is as follows
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample 100% dissolve with ethanol separates through preparative liquid chromatography, and time period 28.0-32.0 minute, 36.0-40.0 minute, 48.0-52.0 minute, 52.0-56.0 minute or collected solution in 56.0-60.0 minute, solution obtains active component behind concentrate drying.
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| CN102600225A (en) * | 2012-04-20 | 2012-07-25 | 河南省医药科学研究院 | Wormwood leaf extract and application thereof to preparation of anti-hepatitis B virus medicines |
| CN103272015A (en) * | 2013-03-29 | 2013-09-04 | 阚兆云 | Traditional chinese medicine extract |
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| CN100497395C (en) * | 2006-11-17 | 2009-06-10 | 华东理工大学 | Use of argyi leaf polysaccharide extract |
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| CN102600225A (en) * | 2012-04-20 | 2012-07-25 | 河南省医药科学研究院 | Wormwood leaf extract and application thereof to preparation of anti-hepatitis B virus medicines |
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| CN104478842A (en) * | 2014-12-24 | 2015-04-01 | 陕西嘉禾植物化工有限责任公司 | Method for extracting jaceosidin and eupatilin from folium artemisiaeargyi |
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