CN101433612B - Effective component of Chinese dittany bark as well as preparation method and use thereof - Google Patents
Effective component of Chinese dittany bark as well as preparation method and use thereof Download PDFInfo
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- CN101433612B CN101433612B CN2007101501375A CN200710150137A CN101433612B CN 101433612 B CN101433612 B CN 101433612B CN 2007101501375 A CN2007101501375 A CN 2007101501375A CN 200710150137 A CN200710150137 A CN 200710150137A CN 101433612 B CN101433612 B CN 101433612B
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Abstract
The invention relates to an effective component of dittany bark, which is characterized in that the effective component is prepared by the following steps: step one, using a mixture of ethyl acetate and ethanol as solvent to extract the dittany bark; step two, obtaining eluent through chromatography of the extract; and step three, using prepared liquid-phase chromatographic gradient to elute the eluent, and collecting the eluent for 52.0 to 56.0 minutes to obtain the effective component, wherein a mobile phase comprises water and methyl cyanide. The invention also provides a preparation method for the effective component and application thereof. The method obtains the effective component for the first time, and carries out drug effect screening on various tumor cell strains for the first time; and because the component is definite, the content is clear, the preparation process is simple and convenient, the effective component has good activity, the effective component is suitable to be developed into novel anti-tumor traditional Chinese medicine.
Description
Technical field
The present invention relates to a kind of Chinese medicine extract of treating tumor disease, relate in particular to the active component that from Cortex Dictamni, 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 one type of the most serious disease of present harm humans health.Be main still mainly to the treatment of malignant tumor in the industry at present, but many chemical anticarcinogenic drugs often involve normal cell when acting on target cell, cause serious side reaction with operation, radiotherapy, chemotherapy.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 from plant, obtains, and has been developed as antitumor drug at present.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, from natural product, extracts active substance; Be developed to new drug, have significant application value and wide development prospect with antitumor curative effect.
Cortex Dictamni, other titles: the Cortex Dictamni dittany gas plant Herba Cytisi sciparii green pepper ground sheep eight Gui cattle pericarpium Zanthoxyli stereotyped writing cattle main components of having a strong smell of having a strong smell in vain: root contains dictamine, dictamnolactone, sitosterol, obacunonic acid, trigonelline, choline.Still contain campesterol .beta.-fagarine, r one .gamma.-fagarine, dasycarpamin.Aerial parts contains psoralen and xanthotoxin.Root contains dictamine .beta.-fagarine .gamma.-fagarine, preceding .beta.-fagarine, different speckle boil forest-grass alkali, limonin, obacunone 、 fraxinellone and sitosterol, acidic materials and Saponin etc.
Function cures mainly: control the wind heat sore, scabies, itchy skin eruption, rheumatic arthralgia, jaundice.
1, heat-clearing and toxic substances removing, removing damp to relieve itching: with controlling the herpes simplex rash, many pus or yellow fluid are dripping, and skin is wet mashed, skin pruritus and rubella scabies.
2, heat-clearing and toxic substances removing dehumidifying: with controlling jaundice due to damp-heat and damp and hot arthromyodynia.
Summary of the invention:
The object of the present invention is to provide the active component of Cortex Dictamni.
Another object of the present invention is to provide the method for preparing of above-mentioned effective component of cortex dictamni.
The present invention also provides the preparation that contains above-mentioned effective component of cortex dictamni and the purposes of this component.
Effective component of cortex dictamni of the present invention, its preparation process may further comprise the steps:
Step 1: as solvent Cortex Dictamni is extracted with ethyl acetate and alcohol mixture;
Step 2: extracting solution gets eluent through column chromatography;
Step 3: with the eluent that the preparative liquid chromatography gradient elution obtains, mobile phase is water and acetonitrile, collects 52.0-56.0 minute eluent and obtains active component (or being called C13).
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 said step, step 1 is specially: getting the Cortex Dictamni medical material, is solvent with ethyl acetate: ethanol=1-5: 1-5, and reflux, extract, is separated extracting solution with medicinal residues, and the extracting solution that obtains after the separation is an extract 1,
Step 2 is specially: extract 1 is crossed the ODS-C18 post, at first, adopt 30%EtOH (5 BV; 1BV ≈ 250ml) as mobile phase, change 95%EtOH (5 BV) then as mobile phase, get eluent,
Step 3 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 flow velocity is 9-11ml/min, and column temperature is a room temperature, collects 52.0-56.0 minute eluent and obtains active component.
The program of gradient elution described in the step 3 is following:
| Time(min) | A(％) | B(％) |
| 0 4 19 54 64 | 80 80 50 5 5 | 20 20 50 95 95 |
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample is used 100% dissolve with ethanol, separates through preparative liquid chromatography, collects solution at time period 52.0-56.0 minute, and solution obtains active component behind concentrate drying.
The preferred effective component of cortex dictamni method for preparing of the present invention, comprise the following steps: with add after the Cortex Dictamni pulverizing medicinal materials ethyl acetate and ethanol (1: 0.8-1.2), reflux 0.8-1.2 hour; Extract 1-3 time; Merging filtrate gets extracting solution, and extracting solution is condensed into extractum, crosses the ODS-C18 post; At first, adopt 30%EtOH (5 BV; 1BV ≈ 250 ml) as mobile phase, get eluent (fr.4), change 95%EtOH (5 BV) then as mobile phase, get eluent II, with getting sample behind the eluent II concentrate drying; Continue to separate the sample that obtains with preparative liquid chromatography; The separation condition of preparative hplc: chromatographic column is a preparative column, and mobile phase is water and acetonitrile, and gradient elution, flow velocity are 9-11ml/min, and column temperature is a room temperature.
The most preferred effective component of cortex dictamni method for preparing of the present invention comprises the following steps: that reflux 1 hour is extracted 2 times with adding ethyl acetate and ethanol (1: 1) after the Cortex Dictamni pulverizing medicinal materials, and merging filtrate gets extracting solution; Extracting solution is condensed into extractum,, crosses the ODS-C18 post, at first, adopt 30%EtOH (5 BV with appearance on the dissolve with ethanol; 1BV ≈ 250ml) as mobile phase, get eluent (fr.4), change 95%EtOH (5 BV) then as mobile phase, get eluent II, with getting sample behind the eluent II concentrate drying; Continue to separate the sample that obtains with preparative liquid chromatography; The separation condition of preparative hplc: chromatographic column is preparative column ZorbaxSB-C18; 21.2mm * 250mm, mobile phase is water A and acetonitrile B, and the gradient elution program is following:
| Time(min) | A(％) | B(％) |
| 0 4 19 54 64 | 80 80 50 5 5 | 20 20 50 95 95 |
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample is used 100% dissolve with ethanol, separates through preparative liquid chromatography, collects solution at time period 52.0-56.0 minute, and solution obtains active component behind concentrate drying.
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 UD, and said 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 through 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 through 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, can this chemical compound be suspended or dissolving.The preparation of solution is normally through 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; Said medicine acceptable carrier is selected from: mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, vitamin C, 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-, phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc.
Compositions of the present invention is confirmed 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:
The present invention also provides the application at anti-tumor aspect of Chinese medicine active component of the present invention and pharmaceutical composition.
(1) cell strain: HL-60 tumor cell
Cell culture and kind plateAccording to the weight of the medicine of institute's weighing, add the DMSO dissolving of respective volume, 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 ℃.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 in the cell groove, adds VT-V2mL 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.
Dosage regimenThe culture fluid that in 96 new orifice plates, adds 220 μ L/ holes 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.Each hole of culture plate is with deionized water wash 5 times, to remove TCA.Behind air drying, every hole adds 0.4% SRB100 μ L (dissolving of 1% chromatographically pure acetic acid), room temperature held 20min; Discard in each hole and wash 5 times with 1% acetic acid behind the liquid; Remove unconjugated dyestuff, with the dissolving of 10mmol/L Tris150 μ L/ hole, 5min vibrates behind the air drying; Use ELIASA (ELx 800) to measure, used wavelength is 490nm.The calculating suppression ratio of suppression ratio calculates by following formula:
Drug effect resultSee table 1.According to HL-60 inhibition rate of tumor cell result, Cortex Dictamni C13 active component has the highly significant effect to suppressing the HL-60 tumor cell proliferation.
Table 1
| Experimental group | Negative | Blank | Positive | |
| Average cell survival number | 0.10 | 0.37 | 0.07 | 0.13 |
| Suppression ratio (%) | 91.00 | 0.00 | 100.00 | 79.17 |
| RSD(％) | 7.29 | 3.07 | 7.19 | 4.38 |
(2) cell strain: K562 tumor cell
Cell culture and kind plateSample preparation: according to the weight of the medicine of institute's weighing, add the DMSO dissolving of respective volume, 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 ℃.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.Kind of plate: 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 in the cell groove, adds VT-V2 mL 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.
Dosage regimen96 orifice plates change liquid, and every hole adds fresh medium 150 μ L.The culture fluid that in 96 new orifice plates, adds 220 μ L/ holes 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.Each hole of culture plate is with deionized water wash 5 times, to remove TCA.Behind air drying, every hole adds 0.4% SRB100 μ L (dissolving of 1% chromatographically pure acetic acid), room temperature held 20min; Discard in each hole and wash 5 times with 1% acetic acid behind the liquid; Remove unconjugated dyestuff, with the dissolving of 10mmol/L Tris150 μ L/ hole, 5min vibrates behind the air drying; Use ELIASA (ELx 800) to measure, used wavelength is 490nm.
D. the calculating suppression ratio of suppression ratio calculates by following formula:
Drug effect result sees table 2.According to K562 inhibition rate of tumor cell result, Cortex Dictamni C13 active component has the highly significant effect to suppressing the K562 tumor cell proliferation.
Table 2
| Experimental group | Negative | Blank | Positive | |
| Average cell survival number | 0.21 | 1.15 | 0.06 | 0.16 |
| Suppression ratio (%) | 86.01 | 0.00 | 100.00 | 91.10 |
| RSD(％) | 2.99 | 3.84 | 2.53 | 6.72 |
(3) cell strain: MCF-7 tumor cell
Cell culture and kind plateMake up a prescription: according to the weight of the medicine of institute's weighing, add the DMSO dissolving of respective volume, 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 ℃.Cell culture: use DMEM high glycoform (Gibco) [adding the 3.7g/L sodium bicarbonate] 90%, calf serum (match is happy) 10%, non essential amino acid (Gibco) 1% Mixed culture MCF-7 cell.Experimental technique: plant plate: 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 in the cell groove, adds VT-V2 mL 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.
Dosage regimenDosing: 96 orifice plates change liquid, and every hole adds fresh medium 150 μ L.The culture fluid that in 96 new orifice plates, adds 220 μ L/ holes 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 ELIASA (Elx800) is measured.
The calculating suppression ratio of suppression ratio calculates by following formula:
Drug effect resultSee table 6.According to MCF-7 inhibition rate of tumor cell result, Cortex Dictamni C13 active component has the highly significant effect to suppressing the MCF-7 tumor cell proliferation.
Table 6
| Experimental group | Negative | Blank | Positive | |
| Average cell survival number | 0.20 | 0.80 | 0.19 | 0.23 |
| Suppression ratio (%) | 97.87 | 0.00 | 100.00 | 93.65 |
| RSD(％) | 5.57 | 3.95 | 7.68 | 7.60 |
(4) pharmacological model: Hep G2 tumor cell
Cell culture and kind plateCell 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 in the cell groove, adds VT-V2mL 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.
Dosage regimenCortex Dictamni C13 active component 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 in 96 new orifice plates, adds 220 μ L/ holes 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 ELIASA (Elx800) is measured.
The calculating of suppression ratioSuppression ratio calculates by following formula:
Drug effect result sees table 4.According to Hep G2 inhibition rate of tumor cell result, Cortex Dictamni C13 active component has the highly significant effect to suppressing Hep G2 tumor cell proliferation.
Table 4
| Experimental group | Negative | Blank | Positive | |
| Average cell survival number | 0.31 | 0.57 | 0.16 | 0.19 |
| Suppression ratio (%) | 63.66 | 0.00 | 100.00 | 91.71 |
| RSD(％) | 2.75 | 7.59 | 8.49 | 6.34 |
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 chlorophyll etc. is prone on the preparative hplc post, form dead absorption effectively, improved content of effective, can obtain effective ingredient fast and accurately.
2. effective component of cortex dictamni chemical constituent provided by the invention is simply clear and definite, on pharmacological research, is easier to illustrate its mechanism of action, is easier to the quality control of medicine aborning.
Method provided by the invention obtains containing the C13 active component first from the Cortex Dictamni medical material, 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.
The specific embodiment
To combine embodiments of the invention further explain flesh and blood of the present invention below, 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 cortex dictamni
Get Cortex Dictamni medical material 250g, it is pulverized the back add ethyl acetate and ethanol (1: 1), reflux 1 hour is extracted 2 times, filtrate merge extracting solution.Extracting solution is condensed into extractum,, crosses the ODS-C18 post, at first, adopt 30%EtOH (5 BV with appearance on the dissolve with ethanol; 1BV ≈ 250ml) as mobile phase, get eluent (fr.4), change 95%EtOH (5 BV) then as mobile phase, get eluent II, with getting sample behind the eluent II concentrate drying; Continue to separate the sample that obtains with preparative liquid chromatography; The separation condition of preparative hplc: chromatographic column is preparative column Zorbax SB-C18; 21.2mm * 250mm, mobile phase is water A and acetonitrile B, and the gradient elution program is following:
| Time(min) | A(％) | B(％) |
| 0 4 19 54 64 | 80 80 50 5 5 | 20 20 50 95 95 |
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample is used 100% dissolve with ethanol, separates through preparative liquid chromatography, collects solution at time period 52.0-56.0 minute, and solution obtains active component behind concentrate drying.
The analysis of embodiment 2 effective component of cortex dictamni
HPLC-ELSD coupling to the effective component of cortex dictamni of embodiment 1 is analyzed
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 following: 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 get with dissolve with methanol solution.
Assay methodThe accurate need testing solution of drawing injects chromatograph of liquid, measures.
Embodiment 3 effective component of cortex dictamni preparations
Get effective component of cortex dictamni 0.5g and 10.5g Polyethylene Glycol-6000 mix homogeneously of embodiment 1, 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 cortex dictamni preparations
Get effective component of cortex dictamni 0.5g, glucose 4.5g, sodium thiosulfate 0.9g and the distilled water 1ml of embodiment 1, behind the said components mix homogeneously, lyophilization, 500 of packing promptly get.
Embodiment 5 effective component of cortex dictamni preparations
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 effective component of cortex dictamni 0.5g, mannitol 5.5g, calcium disodium edetate 0.9g and the distilled water 2ml of embodiment 1 again, behind the said components mixing, lyophilization, 300 of packing promptly get.
Claims (6)
1. the active component with Cortex Dictamni of antitumor action is characterized in that, is to be prepared by following steps:
Step 1, getting the Cortex Dictamni medical material, is solvent with ethyl acetate: ethanol=1-5: 1-5, and reflux, extract, is separated extracting solution with medicinal residues, and the extracting solution that obtains after the separation is an extract;
Step 2, extract is crossed the ODS-C18 post, at first, adopts 30% ethanol, change 95% ethanol then as mobile phase as mobile phase, eluent,
Step 3 is: continue to separate the eluent that obtains with preparative liquid chromatography, the separation condition of preparative hplc: chromatographic column is preparative column Zorbax SB-C18; 21.2mm * 250mm, mobile phase is water A and acetonitrile B, and the gradient elution program is following:
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample is used 100% dissolve with ethanol, separates through preparative liquid chromatography, collects solution at time period 52.0-56.0 minute, obtains active component after the solution concentration drying.
2. the active component 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.
3. the active component 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.
4. the pharmaceutical composition that contains any one active component of claim 1-3.
5. the method for preparing of the active component of claim 1 is characterized in that, its preparation process may further comprise the steps:
Step 1 is: getting the Cortex Dictamni medical material, is solvent with ethyl acetate: ethanol=1-5: 1-5, and reflux, extract, is separated extracting solution with medicinal residues, and the extracting solution that obtains after the separation is an extract;
Step 2 is: extract crossed the ODS-C18 post, at first, adopts 30% ethanol, change 95% ethanol then, get eluent as mobile phase as mobile phase,
Step 3 is: continue to separate the eluent that obtains with preparative liquid chromatography, chromatographic column is preparative column Zorbax SB-C18; 21.2mm * 250mm, mobile phase is water A and acetonitrile B, and the gradient elution program is following:
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample is used 100% dissolve with ethanol, separates through preparative liquid chromatography, collects solution at time period 52.0-56.0 minute, obtains active component after the solution concentration drying.
6. the method for preparing of the active component of claim 5 is characterized in that, may further comprise the steps:
Step 1, with adding ethyl acetate after the Cortex Dictamni pulverizing medicinal materials: ethanol=1: 1, reflux 1 hour is extracted 2 times, merging filtrate gets extracting solution;
Step 2, extracting solution is condensed into extractum, crosses the ODS-C18 post, at first, adopt 30% ethanol as mobile phase, eluent I, change 95% ethanol then as mobile phase, eluent II, with behind the eluent II concentrate drying sample;
Step 3, continue to separate the sample that obtains with preparative liquid chromatography; The separation condition of preparative hplc: chromatographic column is preparative column ZorbaxSB-C18; 21.2mm * 250mm, mobile phase is water A and acetonitrile B, and the gradient elution program is following:
Flow velocity is 10ml/min, and column temperature is a room temperature; Sample is used 100% dissolve with ethanol, separates through preparative liquid chromatography, collects solution at time period 52.0-56.0 minute, obtains active component after the solution concentration drying.
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