CN101721434B - Active ingredients of fomes officinalis, preparation method thereof and use thereof - Google Patents
Active ingredients of fomes officinalis, preparation method thereof and use thereof Download PDFInfo
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- CN101721434B CN101721434B CN2008101716297A CN200810171629A CN101721434B CN 101721434 B CN101721434 B CN 101721434B CN 2008101716297 A CN2008101716297 A CN 2008101716297A CN 200810171629 A CN200810171629 A CN 200810171629A CN 101721434 B CN101721434 B CN 101721434B
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- CN
- China
- Prior art keywords
- acid
- extract
- total triterpene
- fomitopsis officinalis
- fructificatio fomitopsis
- 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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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to active ingredients separated from polyporus officinalis Vill. : Fr. fomes officinalis (Vill.: Fr.) ames., which mainly comprise eburicoic acid, dehydroeburicoic acid, Versisponic acid D and the like and contain over 50 percent of total triterpenoid acid. The invention also provides a fomes officinalis total triterpenoid acid active ingredient prepared by a method of purification by a macroporous resin and provides a medicinal preparation of the active ingredient. Animal experiment results show that the active ingredients can effectively prevent and cure various tumors and have remarkable prevention and curing effects on liver cancer, stomach cancer or colon cancer.
Description
Technical field
The present invention relates to a kind of active component that separation obtains from Polyporaceae mushroom Fructificatio Fomitopsis Officinalis, and its preparation method, preparation and medical usage are provided.
Background technology
The camptothecine of in plant, finding in recent years, vinblastine, paclitaxel etc.; Has the good antitumor effect; Make the antitumor drug assembly of plant origin draw attention, but the plant amedica of having found also has some shortcomings, promptly medicine is killing and wounding cancerous cell simultaneously; Some normal organ-tissues of human body also there is certain infringement, untoward reaction such as feeling sick can appear in the patient, alopecia, bone marrow depression, thrombocytopenia and anemia.Remove in the Fructificatio Fomitopsis Officinalis medical material and contain outside the triterpene acids (being mainly tetracyclic triterpenes), also contain trace element such as aromatics, sesquiterpene (alkene) class, sterols, polysaccharide, tannin and mannitol and calcium, magnesium, phosphorus, cobalt like lanoline alkane type.
Summary of the invention
The technical problem that the present invention will solve is a kind of extracts of mainly being made up of the Fructificatio Fomitopsis Officinalis total triterpene acid of research and development, can treat tumor disease preferably, and toxicity is less.Total triterpene acid content is high in this extract, and Main Ingredients and Appearance is clearer in the total triterpene acid, the favorable reproducibility of product, and quality is controlled easily, thereby can reach the purpose of stable curative effect.
The present invention includes the method for preparing of Fructificatio Fomitopsis Officinalis total triterpene acid, and the Fructificatio Fomitopsis Officinalis total triterpene acid is the Chinese medicine preparation of active component with antitumor action.
For solving the problems of the technologies described above, the present invention's research is also formulated following technical scheme:
A kind of Fructificatio Fomitopsis Officinalis total triterpene acid extract is characterized in that by weight percentage, and wherein containing the Fructificatio Fomitopsis Officinalis total triterpene acid is 50%～99%.
Said Fructificatio Fomitopsis Officinalis total triterpene acid extract; It is characterized in that by weight percentage; Contain eburicoic acid 1.5-18%, dehydrogenation perforation keto acid 1.0-12%, 3-ketone group-dehydrogenation sulfurenic acid 1.2-8%, sulfurenic acid 0.5-10.6% in the extract; Form part with C, have one or two or two above compositions among fomelactone B, Versisponic acid D, dehydrogenation eburicoic acid, officinalic acid A, the officinalic acid G at least in C composition part.
Aforementioned Fructificatio Fomitopsis Officinalis total triterpene acid extract, the percentage by weight of Fructificatio Fomitopsis Officinalis total triterpene acid is 60-99% in the preferred extract; Perhaps; Contain eburicoic acid 2-18%, dehydrogenation perforation keto acid 2.5-12%, 3-ketone group-dehydrogenation sulfurenic acid 1.8-8%, sulfurenic acid 1.0-10.6% and C in the extract and form part, have or two or two above compositions among fomelactone B, Versisponic acid D, dehydrogenation eburicoic acid, officinalic acid A and the officinalic acid G at least in C composition part.
In the preferred Fructificatio Fomitopsis Officinalis total triterpene acid extract, the percentage by weight of Fructificatio Fomitopsis Officinalis total triterpene acid is 70-99%; Perhaps; Contain eburicoic acid 4.0-18%, dehydrogenation perforation keto acid 3.5-12%, 3-ketone group-dehydrogenation sulfurenic acid 2.1-8%, sulfurenic acid 2.4-10.6% and C in the extract and form part, have or two or two above compositions among fomelactone B, Versisponic acid D, dehydrogenation eburicoic acid, officinalic acid A and the officinalic acid G at least in C composition part.
More preferably in the Fructificatio Fomitopsis Officinalis total triterpene acid extract, the percentage by weight of Fructificatio Fomitopsis Officinalis total triterpene acid is 80-90%; Perhaps; Extract contains eburicoic acid 7-16%, dehydrogenation perforation keto acid 4.5-8%, 3-ketone group-dehydrogenation sulfurenic acid 2.6-5%), sulfurenic acid 2.7-7% and C form part, has or two or two above compositions among fomelactone B, Versisponic acid D, dehydrogenation eburicoic acid, officinalic acid A and the officinalic acid G at least during C forms part.
Those of ordinary skills can understand following situation: in the above-mentioned Fructificatio Fomitopsis Officinalis total triterpene acid extract, the percentage by weight of Fructificatio Fomitopsis Officinalis total triterpene acid is 99% just to equal pure Fructificatio Fomitopsis Officinalis total triterpene acid; Because the Fructificatio Fomitopsis Officinalis total triterpene acid is the effective site of extraction separation from the Chinese medicine Fructificatio Fomitopsis Officinalis; Wherein possibly contain some other compositions in a small amount of Fructificatio Fomitopsis Officinalis medical material; Other composition refers to non-triterpenes composition or because content is low or when invention is former thereby not have a triterpenic acid composition of evaluation because of means of testing etc.; Or some come from the impurity that produces in medical material itself or the extraction separation process, but these " other compositions that extract in the Fructificatio Fomitopsis Officinalis " or impurity do not influence the effect of medicine composite for curing tumor of the present invention; Here " on a small quantity " mean and be not more than 49% by weight that be preferably and be not more than 40%, better is to be not more than 20%, most preferably is to be not more than 15%.
The present invention includes a kind of Fructificatio Fomitopsis Officinalis total triterpene acid preparation method of extract, it comprises the steps:
A kind of Fructificatio Fomitopsis Officinalis total triterpene acid preparation method of extract comprises the steps:
(1) get Fructificatio Fomitopsis Officinalis, water and/or organic solvent extraction get extracting solution;
(2) step (1) extracting solution is directly gone up macroporous resin column absorption, perhaps, step (1) extracting solution is concentrated the back go up macroporous resin column absorption;
(3) macroporous resin column of absorption Fructificatio Fomitopsis Officinalis extract is carried out gradient elution;
(4) collect the eluent that is rich in the Fructificatio Fomitopsis Officinalis total triterpene acid, concentrate, get Fructificatio Fomitopsis Officinalis total triterpene acid extract;
Perhaps,, reclaim solvent with step (1) extracting solution, concentrate extractum, with 10%-50% ethanol dispersion extractum; Filter or centrifugal collecting precipitate, drying gets Fructificatio Fomitopsis Officinalis total triterpene acid extract.
In the method for preparing, when step (1) was extracted, organic solvent was meant that carbon number is C preferably
1-C
5Straight or branched lower alcohol, haloalkyl, petroleum ether, acetone, ethyl acetate; Extract with backflow, dipping, percolation, decocting or ultransonic method; Those of ordinary skills know, and according to different method for distilling, select the corresponding solvent that extracts.
Step (2) big pore resin is that in polystyrene type, polyacrylate or the polymethacrylates type any one or a few is the resin of framework material;
The solvent of the said gradient elution of step (3) is selected from water, C
1-C
5Straight or branched lower alcohol, petroleum ether, acetone, ethyl acetate or their mixture;
Perhaps, with straight or branched lower alcohol, dichloromethane or the chloroform supersound extraction Fructificatio Fomitopsis Officinalis of C1-C5, after extracting solution concentrated extractum, the 30%-45% ethanol of doubly measuring with the heavy 3-5 of extractum disperses extractum; Filter or centrifugal collecting precipitate, drying promptly gets Fructificatio Fomitopsis Officinalis total triterpene acid extract.
More preferably in the method for preparing, during extraction, used organic solvent is selected from the mixture of any one or they in methanol, ethanol, propanol, n-butyl alcohol, dichloromethane, the chloroform; Said macroporous resin is selected from D101, DM301, AB-8, ZTC-1, DM130, D1400, HPD100, SP825 or HP20 type resin; The gradient elution of macroporous resin column is that < 40% ethanol is removed impurity to first usefulness; Reuse 40-95% ethanol elution Fructificatio Fomitopsis Officinalis total triterpene acid; Perhaps use the mixed solution gradient elution macroporous resin column of petroleum ether and acetone; Collect the eluent of enrichment total triterpene acid, concentrate, obtain Fructificatio Fomitopsis Officinalis total triterpene acid extract; Perhaps use the mixed solution gradient elution macroporous resin column of petroleum ether and acetone, collect the eluent of enrichment total triterpene acid, concentrate, obtain Fructificatio Fomitopsis Officinalis total triterpene acid extract.
In the preferred manufacturing procedure, extracting solvent for use is 30-90% ethanol; The gradient elution of macroporous resin column is to remove impurity with 5%-35% ethanol earlier, and reuse 55%-90% ethanol elution Fructificatio Fomitopsis Officinalis total triterpene acid is collected the eluent that is rich in total triterpene acid; Concentrate, drying obtains Fructificatio Fomitopsis Officinalis total triterpene acid extract; Perhaps use the mixed solution gradient elution macroporous resin column of petroleum ether and acetone 15:0-1 (V/V); Collect the eluent of enrichment total triterpene acid, concentrate, obtain Fructificatio Fomitopsis Officinalis total triterpene acid extract.
In the preferred method for preparing, extracting solvent for use is 55-85% ethanol; Gradient elution is to remove impurity with 10-30% ethanol earlier; Reuse 60%-85% ethanol elution Fructificatio Fomitopsis Officinalis total triterpene acid; Collect the eluent of enrichment total triterpene acid, after concentrating, select for use in decompression, vacuum, the freezing or spray method any one to carry out drying; Obtain Fructificatio Fomitopsis Officinalis total triterpene acid extract, wherein containing the Fructificatio Fomitopsis Officinalis total triterpene acid by weight percentage is 50%～99%; Fructificatio Fomitopsis Officinalis total triterpene acid extract is mixed with pharmaceutically acceptable carrier, process oral formulations or injection.
Said Fructificatio Fomitopsis Officinalis total triterpene acid method for preparing, when used extraction, dispersion or gradient elution, used organic solvent is meant that carbon number is C
1-C
5Straight or branched lower alcohol (said lower alcohol particular methanol, ethanol, propanol and/or n-butyl alcohol), haloalkyl (the preferred monochloro methane of described haloalkyl, dichloromethane and/or chloroform); Water and lower alcohol are that V/V mixes (for example, in the water of certain milliliter number, adding the lower alcohol of certain milliliter number).During step (1) was extracted, preferred water and lower alcohol mixed proportion were 0-95% (for example, the 95%th, account for 95 milliliters by lower alcohol in 100 ml solns); Extract with backflow, dipping, percolation or decocting method.How gradient elution described in the abovementioned steps (3) is meant in eluent from few alcohol amount that contains that water, progressively strengthens to; Method is to remove impurity (for example using the removal of impurity of 10-38% lower alcohol) with the lower alcohol of 40% following concentration earlier preferably; Reuse 40-95% lower alcohol eluting total triterpenes; The eluent of Fructificatio Fomitopsis Officinalis total triterpene acid is rich in collection, concentrates, and obtains Fructificatio Fomitopsis Officinalis total triterpene acid extract.In the column chromatography process, can monitor elution process with thin layer chromatography by routine.
The present invention also comprises a kind of pharmaceutical composition of treating tumor, and aforementioned any Fructificatio Fomitopsis Officinalis total triterpene acid extract is mixed with pharmaceutically acceptable carrier, processes oral formulations or injection.Said pharmaceutically acceptable carrier comprises the conventional formulation adjuvant, also comprises the antioxidant, aminoacid, vitamin, carbohydrate or the plant extract that drug effect of the present invention are not had obviously influence.Said oral formulations is capsule, soft capsule, granule, oral liquid, tablet or drop pill, and said injection comprises lyophilized injectable powder or injection.
The present invention also comprises the application of aforementioned any Fructificatio Fomitopsis Officinalis total triterpene acid extract in preparation medicine for treating tumor thing.Said tumor comprises liver neoplasm, gastric cancer, colon cancer.
From Fructificatio Fomitopsis Officinalis, be divided into from obtaining 11 chemical compounds and be respectively eburicoic acid, dehydrogenation perforation keto acid, 3-ketone group-dehydrogenation sulfurenic acid, sulfurenic acid, Versisponic acid D, fomelactone B, dehydrogenation eburicoic acid, officinalic acid A, officinalic acid G, 24-methyl-lanost-8; 24-dien-23S, 26-lactone and 3-O-acetyl group eburicoic acid.Triterpene compound structure formula main in this extract is following:
Eburicoic acid dehydrogenation perforation keto acid
3-ketone group-dehydrogenation sulfurenic acid sulfurenic acid
Fomelactone B officinalic acid G
24-methyl-lanost-8，24-dien-23S，26-lactone Versisponic?acid?D
The present invention is the effective active composition with total triterpene acid in the Fructificatio Fomitopsis Officinalis; Be used to prepare the Chinese medicine preparation of treating tumor; This Chinese medicine preparation can be total triterpene acid and the mixing of pharmaceutically acceptable carrier in the Fructificatio Fomitopsis Officinalis, and pharmaceutically acceptable carrier comprises the adjuvant of oral formulations adjuvant or parenteral administration.Route of administration can be oral, injection, topical etc.
According to technical scheme of the present invention, this Chinese medicine preparation can be oral formulations or injection preparation, and wherein oral formulations comprises capsule, soft capsule, granule, oral liquid, tablet, drop pill etc.Injection type is injection or lyophilized injectable powder.Used adjuvant comprises: conventional adjuvants such as starch, sucrose, lactose, Icing Sugar, glucose, mannitol, xylitol, Polyethylene Glycol, isopropyl alcohol, soil temperature-80, glycerol, propylene glycol, microcrystalline Cellulose sodium, dextrin, cyclodextrin, sodium chloride, vitamin C, cysteine, citric acid, sodium thiosulfate, sodium sulfite, stearate and gelatin; Preparation later stage preparation technology and equipment all belong to the routine techniques of pharmaceutical field; The present invention does not limit this, so will not detail at this.
The present invention adopts total triterpene acid in the macroporous adsorbent resin technology enrichment Fructificatio Fomitopsis Officinalis; Not only total triterpene acid content height, and the fundamental component of total triterpene acid and relative amount thereof are clearer, are beneficial to quality control; Can make the product favorable reproducibility, thereby reach evident in efficacy and stable excellent results.
Owing to adopted the resin technology in the modernization of Chinese medicine technology, removed a large amount of impurity, the content of active component is higher, and cost is low, and technology is simple, is more suitable for industrialized great production, can be used for preparing various modern preparations.Infer that according to animal experimental data people's effective dose scope is 50mg-150mg/ days.Experiment shows Fructificatio Fomitopsis Officinalis total triterpene acid extract along with dosage increases, and tumour inhibiting rate also obviously increases.
The specific embodiment
Below specify the enforcement of technical scheme of the present invention through embodiment, but should not limit practical range of the present invention with this.
One, pharmacy test
Mushroom material source of the present invention belongs to (Fomes) Fructificatio Fomitopsis Officinalis (Fomes officinalis (Vill.etFr.) Ames) in Mycophyta Polyporaceae shelf fungus, calls to be the white hoof of hardship.(Yang Weixing, the common medicinal plants in Xinjiang is used collection of illustrative plates, Xinjiang science tech publishing house published in 2006).Material can come into operation in a variety of forms, as newly gather, unprocessed material.Dried material is used in this experiment.
Embodiment 1: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid extract
The Fructificatio Fomitopsis Officinalis medical material that 1kg pulverizes, the reflux, extract, of packing into jar is with the ethanol liquid reflux, extract, of 60% concentration 3 times; Each 2h, merge extractive liquid, adds suitable quantity of water and disperses behind the concentrating under reduced pressure; Directly be adsorbed on the DM301 macroporous resin, carry out gradient elution with 10-95% ethanol successively, follow the tracks of with thin layer chromatography and detect eluent; (the thin layer chromatography condition: developing solvent is a petroleum ether: acetone (2:1) or petroleum ether: the mixed solvent of ethyl acetate (4:1); With the silica gel plate after launching,, can contrast) with standard substance or reference substance with vanillin-concentrated sulphuric acid colour developing.Back 45-95% ethanol elution is collected in the progressively remove impurity of ethanol of preceding 10-40%, and concentrate drying gets, Fructificatio Fomitopsis Officinalis total triterpene acid extract 260g.
The content assaying method of total triterpene acid: sample thief, add the colour developing of an amount of vanillin-glacial acetic acid-perchloric acid after, under 535nm, measure absorbance, press one point external standard method, the content of calculating Fructificatio Fomitopsis Officinalis total triterpene acid.
Wherein each monomeric content assaying method mainly is reference literature (Wu Xia; The chemical constituent of Uigurs medicine Fructificatio Fomitopsis Officinalis, Semen Trachyspermi Ammi and bioactivity research; China Concord Medical Science University, thesis for the doctorate, 2005; Record " the total storehouse of china academia document Web publishing " in middle National IP Network), Fructificatio Fomitopsis Officinalis total triterpene acid of the present invention all adopts said method to measure with each monomeric content.
According to said method, with dried sample, chromatographic condition is: chromatographic column: Diamonsil C18 (250x4.6mm; 5 μ m), mobile phase: acetonitrile (B)-0.4% phosphate aqueous solution (A) carries out gradient elution, and 50%B-90% (0～70min); 90%B-95%B (70～75min), keep 5min then, flow velocity 0.8ml/min; Detect wavelength 210nm, writing time is greater than 90min.The content that records total triterpene acid in the extract is 85%; Eburicoic acid content 5.3%; The content of all the other triterpenic acid compounds is 79.7%; Wherein, also contain dehydrogenation perforation keto acid, 3-ketone group-dehydrogenation sulfurenic acid, sulfurenic acid, fomelactone B, Versisponic acid D, dehydrogenation eburicoic acid, officinalic acid A, officinalic acid G.
Embodiment 2: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid extract
The Fructificatio Fomitopsis Officinalis medical material that 1kg pulverizes, with the soak with ethanol 2h of 10L60% concentration, the percolation bucket of packing into extracts 3 times; Each 2h collects percolate, after concentrating; Mix a kind last D1400 macroporous resin column, after the absorption, with 10-20% ethanol (water/alcoholic acid V/V ratio; In full together, unless otherwise specified) after the remove impurity, 60%-70% ethanol elution (promptly resolving); Collect 60% ethanol elution (following the tracks of the detection eluent), concentrating under reduced pressure, vacuum drying with the TLC method; Promptly get Fructificatio Fomitopsis Officinalis total triterpene acid extract 280g, Fructificatio Fomitopsis Officinalis total triterpene acid content is 52.3%, and eburicoic acid content is 5.4%; The content of all the other triterpenic acid compounds is 46.9%, and wherein, dehydrogenation perforation keto acid is 2.8%, 3-ketone group-dehydrogenation sulfurenic acid is 2.1%, sulfurenic acid is 1.4%, fomelactone B is 1.8%, Versisponic acid D is 1.5%, the dehydrogenation eburicoic acid is 3.2%.
Embodiment 3: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid
The Fructificatio Fomitopsis Officinalis medical material that 1kg pulverizes, with the alcohol reflux of 15L70% concentration 3 times, each 2h; Collect extracting solution, after concentrating, mix after the last HP20 macroporous resin column of appearance adsorbs; With 25% ethanol remove impurity, 70% ethanol is resolved, and collects eluent; Concentrating under reduced pressure, vacuum drying promptly gets Fructificatio Fomitopsis Officinalis total triterpene acid extract 294g; The content of total triterpene acid is 60%, and eburicoic acid content is 7.5%, and the content of all the other triterpenic acid compounds is 52.5%; Wherein, dehydrogenation perforation keto acid is 3.4%, 3-ketone group-dehydrogenation sulfurenic acid is 2.8%, sulfurenic acid is 2.5%, Versisponicac id D is 0.78%, the dehydrogenation eburicoic acid is 5.5%, and officinalic acid A is 0.24%, officinalic acid G is 0.45%.
Embodiment 4: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid
The Fructificatio Fomitopsis Officinalis medical material that 1kg pulverizes, with the alcohol reflux of 18L75% concentration 3 times, each 3h; Collect extracting solution, after concentrating, mix after the last D101 macroporous resin column of appearance adsorbs; With 30% ethanol remove impurity, 85% ethanol is resolved, and collects eluent; Concentrating under reduced pressure, vacuum drying promptly gets Fructificatio Fomitopsis Officinalis total triterpene acid extract 360g; Using the content of determination of color Fructificatio Fomitopsis Officinalis total triterpene acid is 90%, and eburicoic acid content is 15.8%, and the content of all the other triterpenic acid compounds is 74.2%; Wherein, dehydrogenation perforation keto acid is 7.6%, 3-ketone group-dehydrogenation sulfurenic acid is 4.5%, sulfurenic acid is 6.4%, fomelactone B is 0.7%, Versisponicacid D is 1.5%, the dehydrogenation eburicoic acid is 1.4%, officinalic acid A is 0.67%, officinalic acid G is 0.34%.
Embodiment 5: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid
The Fructificatio Fomitopsis Officinalis medical material that 1kg pulverizes, with the alcohol reflux of 13L70% concentration 3 times, each 2h collects extracting solution; After concentrating, after aqueous dispersion, last AB-8 macroporous resin column; After the absorption, with 10% ethanol remove impurity, 80% ethanol is resolved; Collect eluent, concentrating under reduced pressure, vacuum drying; Promptly get Fructificatio Fomitopsis Officinalis total triterpene acid extract 286g, the content of Fructificatio Fomitopsis Officinalis total triterpene acid is 73%, and eburicoic acid content is 9%; The content of all the other triterpenic acid compounds is 64%, wherein, dehydrogenation perforation keto acid is 2.9%, 3-ketone group-dehydrogenation sulfurenic acid is 3.3%, sulfurenic acid is 4.1%, fomelactone B is 0.7%, Versisponicacid D is that 0.9% dehydrogenation eburicoic acid is 2.1%, officinalic acid A be 0.43% and officinalic acid G be 0.23%.
Embodiment 6: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid
The Fructificatio Fomitopsis Officinalis medical material that 1kg pulverizes, with the alcohol reflux of 13L65% concentration 3 times, each 2h collects extracting solution; After concentrating, after aqueous dispersion, last ZTC-1 macroporous resin column; After the absorption, with 15% ethanol remove impurity, 70% ethanol is resolved; Collect eluent, concentrating under reduced pressure, vacuum drying; Promptly get Fructificatio Fomitopsis Officinalis total triterpene acid extract 276g, the content of Fructificatio Fomitopsis Officinalis total triterpene acid is 60%, and eburicoic acid content is 8%; The content of all the other triterpenic acid compounds is 52%, wherein, dehydrogenation perforation keto acid is 1.1%, 3-ketone group-dehydrogenation sulfurenic acid is 3.2%, sulfurenic acid is 3.5%, fomelactone B is 0.7%, Versisponicacid D is 1.2%, the dehydrogenation eburicoic acid be 3.8% and officinalic acid A be 0.17%.
Embodiment 7: Fructificatio Fomitopsis Officinalis total triterpene acid isolation identification of the present invention
Get Fructificatio Fomitopsis Officinalis medical material 1kg, with the alcohol reflux of 90% concentration 3 times, each 2h; Extracting solution merges, and being evaporated to does not have the alcohol flavor, mixes after the last ZTC-1 macroporous resin column of appearance adsorbs; With 30% ethanol elution remove impurity, 90% ethanol elution desorbing, collect 90% ethanol elution, evaporated under reduced pressure; Promptly get Fructificatio Fomitopsis Officinalis total triterpene acid extract 400g, the content of total triterpene acid is 88% in the Fructificatio Fomitopsis Officinalis total triterpene acid extract, and eburicoic acid content is 6.8%.
Get above extract; Through the silica gel column chromatography rough segmentation, utilize petroleum ether: acetone (100:1-1:100, V/V) gradient elution obtains a plurality of streams parts; Adopt chloroform or methanol to carry out recrystallization to various flows part respectively again; Obtain eburicoic acid and dehydrogenation perforation keto acid respectively, again each stream part is utilized reversed phase column chromatography methanol-water system gradient elution, cooperate silica gel column chromatography to obtain other 9 chemical compounds.Through nuclear magnetic resonance technique and interpretation of mass spectra compound structure; Warp and document contrast (Fructificatio Fomitopsis Officinalis The Chemical Constituents (1); Chinese herbal medicine, 2005,6) confirm that all the other 9 chemical compounds are respectively 3-ketone group-dehydrogenation sulfurenic acid, sulfurenic acid, Versisponic acid D, fomelactone B, dehydrogenation eburicoic acid, officinalic acid A, officinalic acid G, 24-methyl-lanost-8; 24-dien-23S, 26-lactone and 3-O-acetyl group eburicoic acid.
Embodiment 8: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid extract
Get Fructificatio Fomitopsis Officinalis medical material 1kg, with 80% alcoholic solution reflux, extract, 4h of 20 times of amounts of medical material, totally three times; Behind the extracting solution concentrating under reduced pressure, after disperseing with 30% ethanol of 4 times of extractum amounts, high speed centrifugation; Precipitate behind 40 ℃ of following drying under reduced pressure, is promptly got Fructificatio Fomitopsis Officinalis total triterpene acid extract 520g.The content of Fructificatio Fomitopsis Officinalis total triterpene acid is 60% in this extract, and eburicoic acid content is 8%.
Embodiment 9: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid extract
Get Fructificatio Fomitopsis Officinalis medical material 1kg, with the methanol solution reflux, extract, 3h of 15 times of amounts, totally three times; Behind the extracting solution concentrating under reduced pressure, after disperseing with 40% ethanol of 4.5 times of extractum amounts, filter; Filtering residue at low temperature, after the drying, is promptly got Fructificatio Fomitopsis Officinalis total triterpene acid extract 600g.The content of Fructificatio Fomitopsis Officinalis total triterpene acid is 55% in this extract, and eburicoic acid content is 6%.
Embodiment 10: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid extract
Get Fructificatio Fomitopsis Officinalis medical material 5kg, with dichloromethane (or chloroform) the supersound extraction 2h of 10 times of amounts, totally three times, with the extracting solution concentrating under reduced pressure; After reclaiming solvent, after disperseing with 50% ethanol of 5 times of extractum amounts, after the filtration; With filtering residue low temperature, after the drying, promptly get Fructificatio Fomitopsis Officinalis total triterpene acid extract 610g.The content of Fructificatio Fomitopsis Officinalis total triterpene acid is 51% in this extract, and eburicoic acid content is 2.7%.
Embodiment 11: the preparation of Fructificatio Fomitopsis Officinalis total triterpene acid extract
Get Fructificatio Fomitopsis Officinalis medical material 2kg, with the dichloromethane supersound extraction 2.5h of 10 times of amounts, totally three times; With the extracting solution concentrating under reduced pressure, reclaim solvent after, after disperseing with 45% ethanol of 5 times of extractum amounts; After the filtration, with filtering residue low temperature, after the drying; Last ZTC-1 resin column, use petroleum ether: acetone carries out eluting by 15:1.Obtain sample 504g, the content of Fructificatio Fomitopsis Officinalis total triterpene acid is 87% in this extract, and eburicoic acid content is 29.3%.
Embodiment 12: Fructificatio Fomitopsis Officinalis total triterpene acid capsule
Get the Fructificatio Fomitopsis Officinalis total triterpene acid extract 100g of embodiment 2 methods preparation, 60 ℃ of dryings grind; Cross 80 mesh sieves, added the starch 98g and the magnesium stearate 2g of 80 mesh sieves, mix homogeneously; Process soft material in right amount with 80% ethanol, cross 30 mesh sieve system granules, oven dry; Make moisture less than 5%, cross 40 mesh sieve granulate, be sub-packed in No. 3 capsules.Every capsules contains Fructificatio Fomitopsis Officinalis total triterpene acid 0.1g, uses aluminium plastic composite packaging, promptly gets.Oral, 1 time 1, every day 2 times.
Embodiment 13: Fructificatio Fomitopsis Officinalis total triterpene acid tablet
Get the Fructificatio Fomitopsis Officinalis total triterpene acid extract 30g of embodiment 4 methods preparation, add starch 30g, microcrystalline Cellulose 10g granulates with 12 mesh sieves with 10% starch slurry in right amount, and dry below 50 ℃, dry granular adds magnesium stearate, granulate, and mixing, tabletting promptly gets.Oral, 1 time 1, every day 3 times.
Two, pharmacodynamics test
For the ease of understanding the therapeutic effect of Fructificatio Fomitopsis Officinalis total triterpene acid, the Fructificatio Fomitopsis Officinalis total triterpene acid that the present invention prepares with embodiment 4 has carried out following pharmacodynamic experiment (if no special instructions, the Fructificatio Fomitopsis Officinalis total triterpene acid promptly refers to Fructificatio Fomitopsis Officinalis total triterpene acid extract among the present invention).
Embodiment 1: the Fructificatio Fomitopsis Officinalis total triterpene acid is to mice H
22The influence of liver-cancer solid tumor
With normal saline with HCC H
22Be mixed with 2.5 * 10
7Individual cell/ml is inoculated in the mice oxter, and every Mus 0.2ml causes bearing mouse model.Tumor-bearing mice is divided into lotus tumor matched group at random, antitumor positive drug 5-fluorouracil group (30mg/kg), Fructificatio Fomitopsis Officinalis total triterpene acid little (50mg/kg), in (100mg/kg), big (200mg/kg) dose groups.The 5-fluorouracil group is pressed the 0.01ml/g intraperitoneal injection, the next day once; Each administration group is all by the 0.02ml/g gastric infusion, and lotus tumor matched group gives the equal-volume normal saline, once a day, and successive administration 10 days.After the last administration, strip tumor, claim that tumor is heavy, calculate tumor control rate.Experimental result is seen table 1:
Table 1 Fructificatio Fomitopsis Officinalis total triterpene acid is to mice H
22The influence that the liver-cancer solid tumor tumor weighs (x ± s)
Annotate: compare with model group,
*P<0.05,
*P<0.01 with
* *P<0.001.
Compare with lotus tumor matched group, each dose groups mouse tumor of Fructificatio Fomitopsis Officinalis total triterpene acid obviously dwindles, and has statistical significance.
Can find out from table 1: it is heavy obviously to reduce tumor after the 5-fluorouracil administration, and along with the increase that rat oral gavage is given Fructificatio Fomitopsis Officinalis total triterpene acid dosage, tumour inhibiting rate also obviously increases, and has certain dose-effect relationship.
Simultaneously, the present invention adopts the Fructificatio Fomitopsis Officinalis total triterpene acid for preparing in embodiment 2,3,4 and 6 to carry out that " the Fructificatio Fomitopsis Officinalis total triterpene acid is to mice H respectively
22The influence experiment of liver-cancer solid tumor ", the result shows that this total triterpene acid has the effect that suppresses tumor equally.
At the Fructificatio Fomitopsis Officinalis total triterpene acid to mice H
22In the hepatocarcinoma real experiment, in 10 days of administration, the rat of each dose groups does not see that body weight reduces, dystropic phenomenon, infers that this Fructificatio Fomitopsis Officinalis total triterpene acid extract toxicity is lower.
Embodiment 2: the external influence to HCC HepG2, colon cancer cell HCT-8, stomach cancer cell BGC-823 of Fructificatio Fomitopsis Officinalis total triterpene acid extract
DMEM cell culture fluid with containing 10%FBS is diluted to 5 variable concentrations with Fructificatio Fomitopsis Officinalis total triterpene acid extract, establishes from 200 μ g/ml, successively 2 doubling dilutions; I.e. 200,100,50,25 and 12.5 μ g/ml; Prepare three parts of said medicine altogether, adding inoculation respectively has in three 96 orifice plates of HepG2 HCC, HCT-8 colon cancer cell, BGC-823 stomach cancer cell every hole 200 μ l; Establish 5 multiple holes for every group, the cell matched group laterally arranges.Place 37 ℃, cultivate in the 5%CO2 incubator, every day the observation of cell state.Behind the drug effect 72 hours, take out 96 orifice plates, inhale and remove culture fluid in each hole, and add the MTT solution 200 μ l of 0.5mg/ml; The blank group that laterally arranges places 37 ℃, continues in the 5%CO2 incubator to cultivate after 4 hours and takes out; MTT solution in each hole of sucking-off adds DMSO solution 200 μ l respectively, and room temperature was placed 10 minutes; Fully concussion was measured the OD value at 570nm place after 60 seconds on 96 orifice plate enzymes mark detector, calculated growth inhibition ratio and the IC50 of each concentration group medicine to three kinds of cells.Experimental result is seen table 2:
Can know that by table 2 after the Fructificatio Fomitopsis Officinalis total triterpene acid extract of variable concentrations acted on HepG2, HCT-8, three kinds of cells of BGC-823, cell all received obvious suppression, and along with the increase of drug level, inhibitory action also strengthens.And Fructificatio Fomitopsis Officinalis total triterpene acid extract is respectively the IC50 of HepG2, HCT-8, three kinds of cells of BGC-823: (29.85 ± 3.93) μ g/ml, (19.17 ± 4.50) μ g/ml, (50.97 ± 8.24) μ g/ml.
The external influence of table 2 Fructificatio Fomitopsis Officinalis total triterpene acid extract to HCC HepG2, colon cancer cell HCT-8, stomach cancer cell BGC-823
Annotate: compare with matched group, administration group cell all receives obvious inhibition, has statistical significance,
*P<0.05,
* *P<0.001.
The result shows Fructificatio Fomitopsis Officinalis total triterpene acid extract of the present invention, and gastric cancer, colon cancer are also had therapeutical effect.Thus, our deducibility Fructificatio Fomitopsis Officinalis total triterpene acid of the present invention extract also can be used for people and other mammiferous oncotherapy, especially gastric cancer, colon cancer and hepatocarcinoma.
Claims (12)
1. Fructificatio Fomitopsis Officinalis total triterpene acid extract, by weight percentage, wherein containing the Fructificatio Fomitopsis Officinalis total triterpene acid is 50%～99%; Said Fructificatio Fomitopsis Officinalis total triterpene acid extract; It is characterized in that by weight percentage; Contain eburicoic acid 1.5-18%, dehydrogenation perforation keto acid 1.0-12%, 3-ketone group-dehydrogenation sulfurenic acid 1.2-8%, sulfurenic acid 0.5-10.6% in the extract; Form part with C, have one or two or two above compositions among fomelactone B, Versisponic acid D, dehydrogenation eburicoic acid, officinalic acid A, the officinalic acid G at least in C composition part;
Preparation method of extract comprises the steps: that (1) get Fructificatio Fomitopsis Officinalis, water and/or organic solvent extraction, extracting solution;
(2) step (1) extracting solution is directly gone up macroporous resin column absorption, perhaps, step (1) extracting solution is concentrated the back go up macroporous resin column absorption;
(3) macroporous resin column of absorption Fructificatio Fomitopsis Officinalis extract is carried out gradient elution;
(4) collect the eluent that is rich in the Fructificatio Fomitopsis Officinalis total triterpene acid, concentrate, get Fructificatio Fomitopsis Officinalis total triterpene acid extract; Used organic solvent is selected from the mixture of any one or they in methanol, ethanol, propanol, n-butyl alcohol, dichloromethane, the chloroform; Said macroporous resin is selected from D101, DM301, AB-8, ZTC-1, DM130, D1400, HPD100, SP825 or HP20 type resin; The gradient elution of macroporous resin column is that the ethanol of first usefulness＜40% is removed impurity; Reuse 40-95% ethanol elution Fructificatio Fomitopsis Officinalis total triterpene acid; Perhaps use the mixed solution gradient elution macroporous resin column of petroleum ether and acetone; Collect the eluent of enrichment total triterpene acid, concentrate, obtain Fructificatio Fomitopsis Officinalis total triterpene acid extract.
2. according to the said Fructificatio Fomitopsis Officinalis total triterpene acid of claim 1 extract, the percentage by weight of Fructificatio Fomitopsis Officinalis total triterpene acid is 60-99% in the extract; Perhaps; Contain eburicoic acid 2-18%, dehydrogenation perforation keto acid 2.5-12%, 3-ketone group-dehydrogenation sulfurenic acid 1.8-8%, sulfurenic acid 1.0-10.6% and C in the extract and form part, have or two or two above compositions among fomelactone B, Versisponic acid D, dehydrogenation eburicoic acid, officinalic acid A and the officinalic acid G at least in C composition part.
3. according to the said Fructificatio Fomitopsis Officinalis total triterpene acid of claim 2 extract, the percentage by weight of Fructificatio Fomitopsis Officinalis total triterpene acid is 70-99% in the extract; Perhaps; Contain eburicoic acid 4.0-18%, dehydrogenation perforation keto acid 3.5-12%, 3-ketone group-dehydrogenation sulfurenic acid 2.1-8%, sulfurenic acid 2.4-10.6% and C in the extract and form part, have or two or two above compositions among fomelactone B, Versisponic acid D, dehydrogenation eburicoic acid, officinalic acid A and the officinalic acid G at least in C composition part.
4. according to the said Fructificatio Fomitopsis Officinalis total triterpene acid of claim 3 extract, it is characterized in that: the percentage by weight of Fructificatio Fomitopsis Officinalis total triterpene acid is 80-90% in the extract; Perhaps; Extract contains eburicoic acid 7-16%, dehydrogenation perforation keto acid 4.5-8%, 3-ketone group-dehydrogenation sulfurenic acid 2.6-5%, sulfurenic acid 2.7-7% and C and forms part, has or two or two above compositions among fomelactone B, Versisponic acid D, dehydrogenation eburicoic acid, officinalic acid A and the officinalic acid G at least in C composition part.
5. Fructificatio Fomitopsis Officinalis total triterpene acid preparation method of extract is characterized in that comprising the steps: that (1) get Fructificatio Fomitopsis Officinalis, water and/or organic solvent extraction, extracting solution;
(2) step (1) extracting solution is directly gone up macroporous resin column absorption, perhaps, step (1) extracting solution is concentrated the back go up macroporous resin column absorption;
(3) macroporous resin column of absorption Fructificatio Fomitopsis Officinalis extract is carried out gradient elution;
(4) collect the eluent that is rich in the Fructificatio Fomitopsis Officinalis total triterpene acid, concentrate, get Fructificatio Fomitopsis Officinalis total triterpene acid extract; Used organic solvent is selected from the mixture of any one or they in methanol, ethanol, propanol, n-butyl alcohol, dichloromethane, the chloroform; Said macroporous resin is selected from D101, DM301, AB-8, ZTC-1, DM130, D1400, HPD100, SP825 or HP20 type resin; The gradient elution of macroporous resin column is that the ethanol of first usefulness＜40% is removed impurity; Reuse 40-95% ethanol elution Fructificatio Fomitopsis Officinalis total triterpene acid; Perhaps use the mixed solution gradient elution macroporous resin column of petroleum ether and acetone; Collect the eluent of enrichment total triterpene acid, concentrate, obtain Fructificatio Fomitopsis Officinalis total triterpene acid extract.
6. claim 5 method for preparing, wherein, extracting solvent for use is 30-90% ethanol; The gradient elution of macroporous resin column is to remove impurity with 5%-35% ethanol earlier, and reuse 55%-90% ethanol elution Fructificatio Fomitopsis Officinalis total triterpene acid is collected the eluent that is rich in total triterpene acid; Concentrate, drying obtains Fructificatio Fomitopsis Officinalis total triterpene acid extract; Perhaps use the mixed solution gradient elution macroporous resin column of petroleum ether and acetone 15: 0-1 (V/V); Collect the eluent of enrichment total triterpene acid, concentrate, obtain Fructificatio Fomitopsis Officinalis total triterpene acid extract.
7. a pharmaceutical composition of treating tumor is characterized in that each said Fructificatio Fomitopsis Officinalis total triterpene acid extract of claim 1 to 4 is mixed with pharmaceutically acceptable carrier, processes oral formulations or injection.
8. the pharmaceutical composition of claim 7, said pharmaceutically acceptable carrier refer to the conventional formulation adjuvant and/or the drug effect of each said Fructificatio Fomitopsis Officinalis total triterpene acid extract of claim 1 to 4 are not had antioxidant, aminoacid, vitamin, carbohydrate or the plant extract of obviously influence.
9. the pharmaceutical composition of claim 7, said oral formulations is capsule, granule, oral liquid, tablet or drop pill, said injection is lyophilized injectable powder or injection.
10. the pharmaceutical composition of claim 9, said capsule refers to soft capsule.
11. the application of each Fructificatio Fomitopsis Officinalis total triterpene acid extract of claim 1 to 4 in preparation medicine for treating tumor thing.
12. the described application of claim 11, said tumor refers to liver neoplasm, stomach or colon tumor.
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| CN104288655A (en) * | 2014-10-16 | 2015-01-21 | 济南新起点医药科技有限公司 | Preparation method of fomes officinalis cough and asthma treating tablets and application of fomes officinalis cough and asthma treating tablets in preparation of medicine for inhibiting cell proliferation of mouse teratoma cell F9 |
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| 吴霞.维吾尔药阿里红、阿育魏实的化学成分及生物活性研究.《中国协和医科大学博士研究生论文》.2006,45-48. * |
| 帕丽达等.阿里红多糖的提取及含量测定.《新疆医学院学报》.1998,第21卷(第2期),158-159. * |
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