CN1220518C - Chinese medicinal composition for anti-cancer and analgesia, its preparation method and its application in the preparation of product and medicine for treating cancer and analgesia - Google Patents
Chinese medicinal composition for anti-cancer and analgesia, its preparation method and its application in the preparation of product and medicine for treating cancer and analgesia Download PDFInfo
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Abstract
The present invention provides a Chinese medicine composition which is prepared from ganoderma, rabdosia, corydalis tuber, scutellaria root, fourstamen stephania root, radices pseudoginseng and licorice root as raw materials. A preparation method of the Chinese medicine composition comprises mixed extraction and target object extraction. Polysaccharide, lactone, alkaloid, flavone and saponin, or ganoderma glycopeptide, baicalin, rubescensin, adlumidin, tetrandrine, glycyrrhizin, isoliquiritigenin and arasapogenin are used as extracted effective components. The Chinese medicine composition can effectively resist cancers and alleviating pain, and has the characteristics of little side effect, high effective rate, easy use and controllable quality. The Chinese medicine composition can be used as a product for conditioning and treating cancerous persons or as an analgesic for advanced constitutional cancer pain and metastatic cancer pain.
Description
(1) technical field
The present invention relates to a kind of Chinese medicine composition of anticancer analgesic, the application in preparation treatment antineoplastic product and analgesic of the preparation method of said composition and said composition.
(2) background technology
Morphine is effective analgesic, can help the cancer patient analgesia of middle and advanced stage effectively, but its side effect, the particularly side effect of addiction aspect makes it be unfavorable for life-time service, and people are devoted to look for the alternative medicine of morphine always.Treatment of cancer is the project of medical circle common concern and emphasis tackling key problem.Western medicine has its limitation, and he merely is considered as a kind of material to human body, and constantly dissects into monomer, thereby treatment of diseases is lacked the idea that whole body is adjusted.And synthetic drug has than obvious toxic and side effects, easily produces medicine source property misery to the patient, and people are sought after improving autoimmune function, suppresses tumor cell, and toxic and side effects is little, natural drug evident in efficacy.Product of the present invention has embodied the Chinese medicine strengthening vital QI to eliminate pathogenic factors, the characteristics for the treatment of both the principal and secondary aspects of a disease.
(3) summary of the invention
An object of the present invention is to provide the Chinese medicine composition of the anticancer analgesic of a kind of good effect, few side effects;
Another object of the present invention provides the preparation method of described Chinese medicine composition;
A further object of the present invention provides the application of described Chinese medicine composition in preparation treatment antineoplastic product and analgesic.
These purposes of the present invention realize by following design: a kind of Chinese medicine composition of anticancer analgesic is characterized in that it is the medicament of being made by the following weight proportion raw material:
Ganoderma 3-4
Rabdosia rubescens 1.5-2.5
Rhizoma Corydalis 1-2
Radix Scutellariae 1-2
Radix Stephaniae Tetrandrae 1-2
Radix Notoginseng 0.5-1.5
Radix Glycyrrhizae 0.5-1.5
Best raw material weight proportioning is: Ganoderma: Rabdosia rubescens: Rhizoma Corydalis: Radix Scutellariae: Radix Stephaniae Tetrandrae: Radix Notoginseng: Radix Glycyrrhizae=3: 1.8: 1.8: 1.5: 1.2: 0.9: 0.9.
The best place of production of described Radix Scutellariae is Sichuan, and the optimal acquisition time is autumn; The best place of production of described Rabdosia rubescens is Henan, and the optimal acquisition time is May; Ganoderma obtains by cultivation/fermentation, the Ganoderma that can adopt the Shanghai institute of agricultural sciences to produce; The best place of production of Radix Glycyrrhizae is Gansu, and the optimal acquisition time is autumn; The best place of production of Radix Notoginseng is Yunnan, and the optimal acquisition time is autumn; The best place of production of Rhizoma Corydalis is Zhejiang, and the optimal acquisition time is summer; The best place of production of (powder) Radix Stephaniae Tetrandrae is Zhejiang, and the optimal acquisition time is autumn.
The present invention also relates to the preparation method of described Chinese medicine composition, comprise mixed extraction preparation method or goal object extraction preparation method, described mixed extraction preparation method comprises:
1) prepare raw material:
With Ganoderma, Rabdosia rubescens, Rhizoma Corydalis, Radix Scutellariae, Radix Stephaniae Tetrandrae, Radix Notoginseng, Radix Glycyrrhizae is that the ratio of 3-4: 1.5-2.5: 1-2: 1-2: 1-2: 0.5-1.5: 0.5-1.5 is mixed with the weight ratio, and described mixture is divided into 5 equal portions;
2) extract alkaloid:
I) a Chinese medicine mixture that step 1) is obtained obtains acidic ethanol extraction liquid with 0.1% hydrochloride ethanol liquid diafiltration or gradation leaching;
Ii) concentrating under reduced pressure obtains concentrate;
Iii) acid water (pH=4-5) washing in one embodiment, preferably makes this acidic aqueous liquid freeze overnight, filters, and obtains residue, and residue obtains acidic aqueous liquid with acid water (pH=4-5) washing;
Iv) in the acidic aqueous liquid that step I obtains in ii), add ammonia precipitation process, filter and obtain the total alkaloids precipitation; Perhaps
A) in the acidic aqueous liquid that step I obtains in ii), add diluted acid, use chloroform extraction, obtain chloroform layer and water layer to pH=2; Chloroform in the evaporation chloroform layer obtains weak alkaloid;
B) described water layer adds alkali to pH=6-7, uses chloroform extraction, obtains water layer and chloroform layer, and the chloroform in the evaporation chloroform layer obtains strong alkaloid;
C) above-mentioned b) water layer that obtains is adjusted to pH10 with alkali, uses butyl alcohol extraction then, and the butanols in the evaporation butanols layer obtains water miscible alkaloid;
D) merge above-mentioned a), b) and the alkaloid that c) obtains, obtain total alkaloids;
3) extract polysaccharide:
95-100 ℃ hot water extraction of a Chinese medicine mixture with step 1) obtains discards residue, and filtrate was placed after 12 hours, adds the ethanol of concentration more than 50%, the centrifugal polysaccharide precipitation that obtains in supernatant;
4) extract lactone:
With a Chinese medicine mixture aether backflow that step 1) obtains, remove pigment, reclaim ether, obtain total lactone;
5) extract Saponin:
The a Chinese medicine mixture that step 1) is obtained refluxes with petroleum ether, and the evaporation petroleum ether obtains the defat coarse powder, uses the 90-95% ethanol extraction, and concentrating under reduced pressure obtains concentrated solution;
A) concentrated solution is used chloroform, ethanol extraction successively, and reclaim under reduced pressure chloroform, ethanol obtain the general glycoside crude product; Perhaps
B) concentrated solution butyl alcohol extraction, the reclaim under reduced pressure butanols obtains the Saponin crude product;
6) extract flavone:
The a Chinese medicine mixture that obtains to step 1) adds the 70-80% alcohol dipping, the ethanol in the decompression recycling ethanol liquid, and the residue water dissolution filters, and obtains water liquid; With ethyl acetate extraction water liquid, the concentrating under reduced pressure acetic acid ethyl fluid obtains total flavones;
With step 2)-6) extract the alkaloid, polysaccharide, lactone, Saponin, the flavone mixing that obtain, obtain described Chinese medicine composition.
Described goal object is extracted preparation method and is comprised:
1) extract baicalin:
I) in above-mentioned Radix Scutellariae component, add 10-15 times of (volume) water gaging and decocted 1-2 hour, filter;
Ii) filtrate is transferred to pH 1-2, kept centrifugation 30-40 minute down at 80-90 ℃ with acid; Precipitate adds water and stirs, and adds alkali pH regulator is arrived neutrality, adds the doubly ethanol of (volume) amount of 3-5 again, filters;
Iii) in filtrate, add acid pH regulator is arrived 1-2, stir, kept 30-40 minute down, filter at 80-90 ℃;
Iv) the precipitate of gained is distinguished water, 50% washing with alcohol, and reuse 95% washing with alcohol or recrystallization obtain baicalin;
2) extract arasaponin:
I) with the solvable composition of concentration in the methanol extraction Radix Notoginseng root coarse powder below 50%, the concentrating under reduced pressure methanol extract liquid adds doubly (volume) water gaging of 3-5 in residue;
Ii) aqueous solution ether extraction, water layer reuse n-butanol extraction, evaporated under reduced pressure through silica gel column chromatography, is used CHCl
3-MeOH-H
2O obtains arasaponin than 65: 35: 10 eluting;
3) extract rubescensine A
With ether extraction Rabdosia rubescens leaf dried powder, discard residue, reclaim the ether in the ether solution, obtain green and brown color residue; Use the dissolve with methanol residue, decolouring obtains clear and bright methanol solution, and room temperature is placed and spent the night behind the concentrating under reduced pressure, filters methanol mother liquor evaporate to dryness, porphyrize; Use the ether eluting, crystallization;
4) extract corydalis:
A) cold-maceration: Yanhusuo is moistening with 14% ammonia, and add ether: chloroform: ethanol is 25: 8: 0.5 mixed solvent soaked overnight, filters; Evaporate to dryness filtrate obtains described corydalis; Perhaps
B) 95% ethanol extraction method i): Yanhusuo is moistening with strong aqua ammonia, adds described Yanhusuo and 95% ethanol, reflux, extract, in apparatus,Soxhlet's;
Ii) evaporate to dryness alcohol extract, residue add 1% hydrochloric acid and stir, and filter;
Iii) use 1% hydrochloric acid washing precipitate, filter;
Iv) merge ii) and the filtrate that iii) obtains, add ammonia and regulate pH to 9-10, chloroform extraction;
V) evaporate the chloroform in the chloroform layer, obtain described corydalis;
5) extract sinomenine:
The Radix Stephaniae Tetrandrae coarse powder is with 0.6% soak with sulphuric acid 4 times, and the sour water leachate is adjusted to pH=10 with lime cream, filters;
Be deposited in 60 ℃ of dryings down, be ground into fine particulate, obtain Radix Stephaniae Tetrandrae sand;
Soak 6 times each 5-6 hour with cold benzene;
Reclaim the benzene in the benzene liquid, dried residue;
The acetone that adds 20 times of volumes in residue makes its dissolving, is heated to 55 ℃, reclaims acetone to 1/4 of original volume, places, and cooling is filtered, and obtains crystallization;
Add 5-6 times of volume benzene and activated carbon in crystallization, room temperature was placed 30 minutes, filtered;
Reclaim the benzene in the benzene liquid, and, obtain sinomenine with the ethyl alcohol recrystallization of 20 times of volumes;
6) extract glycyrrhizin, isoliquiritigenin
The 90-95% ethanol extraction that Radix Glycyrrhizae is measured with 3-4 times (volume), ethanol liquid is through petroleum ether extraction, and water layer is admixed silica gel, uses MeOH-H
27: 3 eluting of O, concentrate eluant obtains residue;
In residue, add water to dissolving fully, in aqueous solution, add ethyl acetate extraction, ethyl acetate layer 5%Na
2CO
3The extraction of water liquid is adjusted to pH5-6 with diluted acid with sodium carbonate water liquid, the reuse ethyl acetate extraction, and dry acetic acid ethyl fluid separates through polyamide column, obtains glycyrrhizin and isoliquiritigenin with 10-90% ethanol water gradient elution;
7) make the ganoderan and above-mentioned steps 1 that comprises lucidum glycopeptide and Ganoderma β-D glucosan)-6) extract the active component obtain and mix and obtain described Chinese medicine composition.
The also available following method of described lucidum glycopeptide and Ganoderma β-D glucosan is extracted and is obtained:
I.a) pulverize behind the Ganoderma sporophore decontamination, add water 8-10 and doubly soaked 24 hours, be heated to 95-100 ℃ and stirred 8-10 hour down;
B) filter, preferably centrifugal or sheet frame separation and Extraction liquid and medicinal residues obtain filtrate and medicinal residues;
C) in medicinal residues, add water 3-4 and doubly carry out lixiviate, preferably stirred 8 hours down at 95-100 ℃; Repeating step b) and c),
II.a) Ganoderma fermentation liquid (containing fungus ball) is heated to 95-100 ℃, stirred 4 hours;
B) filter preferably centrifugal or sheet frame separation and Extraction liquid and fungus ball;
C) in the medicinal residues that contain fungus ball, add water 3-4 doubly (volume), extracted 2 hours, filter, separation and Extraction liquid and medicinal residues,
D) merge I.b), c) and II.c) in filtrate, be concentrated into the 1/8-1/10 of original volume, add edible ethanol (3-5 doubly), reach about 70% to ethanol, leave standstill alcohol and analysed 24 hours, use the centrifuge sediment separate out, recovered alcohol, dry sediment.Perhaps,
Ganoderma sporophore is carried out Soxhlet extract, with ethyl acetate extraction 4 hours, sucking filtration, the residue that obtains carried out Soxhlet again and extract, and with acetone extraction 4 hours, sucking filtration, the residue of gained was with 90% soak with ethanol 24 hours, and is centrifugal, sucking filtration; (PBS pH=7.0) extracts three times down at 80 ℃ residue, and 4 hours/time, sucking filtration discarded residue, and buffer is removed protein, and is centrifugal, and with the upper strata liquid dialysis of gained, preferably the clear water dialysis is 7 days, distill water dialysis 3 days with 0.2 mol phosphate buffer;
Add a large amount of acetone in non-dialysis liquid, precipitation occurs, abandoning supernatant precipitates and uses washing with acetone 6 times, obtains the powdery solid of required product.
The preparation method of Chinese medicine composition of the present invention further comprises step 8):
A) with described step 1)-7) active component that obtains is crushed to≤200 microns fine powders;
B) pulverize, dry nothing is leaked seed/nipa palm seed (PHOENIX DACTYLIFERA L) or Fructus punicae granati seed/short Semen Granati (PUNICA GRANAT-UN L), with the dehydrated alcohol extraction of 8 times of volumes, preferably extract merging filtrate, concentrating under reduced pressure three times, handle with ethinylation potassium, obtain powder
C) with a), b) material of gained is with 100-200: 1 weight ratio is mixed.
In one embodiment of the invention, with above-mentioned steps c) mixture that obtains incapsulates.
Product of the present invention can be mixed with multiple dosage form, preferably being mixed with capsule formulation carries out oral, described excipient and preparation technique are known in the pharmaceutics field, and those skilled in the art can obtain above-mentioned preparation according to corresponding document and technology of the prior art preparation.
(4) description of drawings
Fig. 1 shows that cancer patient takes behind starch (contrast), DHE (Opium class preparation) and the Chinese medicine composition of the present invention cancer pain to the influence degree of quality of life index of correlation.
Fig. 2 is the pain integration evaluation graph after the best cancer pain of different pharmaceuticals such as starch (contrast), DHE (Opium class preparation) and Chinese medicine composition of the present invention is alleviated.
Fig. 3 has shown after the different pharmaceutical effects such as starch (contrast), DHE (Opium class preparation) and Chinese medicine composition of the present invention that cancer pain in 24 hours alleviates the assessment of degree.
Fig. 4 is the assessment of average anticancer pain degree in 24 hours after starch, DHE (Opium class preparation) and the present composition effect.
Fig. 5 has shown the lethal effect of Chinese medicine composition of the present invention to cancerous cell.Fig. 5 a has shown the state of the preceding human liver cancer cell of administration; Fig. 5 b shows, gives human liver cancer cell degeneration in 12 hours behind the Chinese medicine composition of the present invention;
Fig. 5 c shows that 24 hours human liver cancer cells are destroyed after the administration.
Fig. 6 shows the influence of this compositions to cAMP content in the stomach organization.
(5) specific embodiment
Further set forth the present invention below by embodiment.
Take by weighing raw material (kilogram) by following proportioning
Rhizoma Corydalis 1.8 Radix Scutellariaes 1.5 Radixs Stephaniae Tetrandrae 1.2
Radix Notoginseng 0.9 Radix Glycyrrhizae 0.9
Mix above-mentioned raw materials, grind to form the Chinese medicine coarse powder, described coarse powder is divided into five equal portions for following 1)-5) individual extraction step use;
1) extract alkaloid:
I) with the above-mentioned a Chinese medicine coarse powder that obtains with 0.1% acidic alcohol (95%) liquid diafiltration or gradation leaching, obtain acidic ethanol extraction liquid;
Ii) concentrating under reduced pressure obtains concentrate;
Iii) acid water (pH=4-5) washing in one embodiment, preferably makes this acidic aqueous liquid freeze overnight, filters, and obtains residue, and residue obtains acidic aqueous liquid with acid water (pH=4-5) washing;
Iv) in the acidic aqueous liquid that step I obtains in ii), add ammonia precipitation process, filter and obtain the total alkaloids precipitation; Perhaps
A) in the acidic aqueous liquid that step I obtains in ii), add dilute hydrochloric acid, use chloroform extraction, obtain chloroform layer and water layer to pH=2; Chloroform in the evaporation chloroform layer obtains weak alkaloidal residue;
B) described water layer adds alkali to pH=6, uses chloroform extraction, obtains water layer and chloroform layer, and the chloroform in the evaporation chloroform layer obtains strong alkaloidal residue;
C) above-mentioned b) water layer that obtains is adjusted to pH10 with sodium hydroxide solution, uses butyl alcohol extraction then, and the butanols in the evaporation butanols layer obtains water miscible alkaloid;
Reclaim above-mentioned chloroform, butanols, recycle for extraction step.Make the cold drying of described alkaloid residue, crystallization.
2) extract polysaccharide:
Reach 2 hours with the above-mentioned Chinese medicine coarse powder that obtains of 95 ℃ hot water extraction, discard residue, filtrate was placed after 12 hours, added the ethanol of concentration 60% in supernatant, the centrifugal polysaccharide precipitation that obtains;
Described polysaccharide precipitation is refining with ether.
3) extract lactone:
With the above-mentioned Chinese medicine coarse powder aether backflow that obtains, by the polyamide column depigmentation, reclaim ether, obtain total lactone;
4) extract Saponin:
The above-mentioned Chinese medicine coarse powder that obtains is refluxed with petroleum ether, and the evaporation petroleum ether obtains the defat coarse powder, uses 95% ethanol extraction, and concentrating under reduced pressure obtains concentrated solution;
A) concentrated solution is used chloroform, ethanol extraction successively, and reclaim under reduced pressure chloroform, ethanol obtain the Saponin crude product; Perhaps
B) concentrated solution butyl alcohol extraction obtains the butanols layer, and the reclaim under reduced pressure butanols obtains the Saponin crude product.
5) extract flavone:
A) in the above-mentioned a Chinese medicine coarse powder that obtains, add 70% alcohol dipping, the ethanol in the decompression recycling ethanol liquid, the residue water dissolution filters, and obtains water liquid; With ethyl acetate extraction water liquid, the concentrating under reduced pressure acetic acid ethyl fluid obtains total flavones.
With step 1)-5) extract the alkaloid, polysaccharide, lactone, Saponin and the flavone mixing that obtain, obtain the Chinese medicine composition of anticancer analgesic of the present invention.
Embodiment 2
1) extract baicalin:
I) in 2 kilograms of Radix Scutellariaes, add 10 times of (volume) water gagings and decocted 1 hour, filter;
Ii) filtrate is transferred to pH2, kept centrifugation 30 minutes down at 80 ℃ with acid; Precipitate adds water and stirs, and adds alkali pH regulator is arrived neutrality, adds the ethanol of 5 times (volume) amount again, filters;
Iii) in filtrate, add hydrochloric acid,, stir, kept 30 minutes down, filter at 80 ℃ with pH regulator to 2;
Iv) the precipitate of gained usefulness is distinguished water, 50% washing with alcohol, and reuse 95% washing with alcohol or recrystallization obtain baicalin.
2) extract arasaponin:
I) with the solvable composition in 1.5 kilograms of Radix Notoginseng roots of methanol extraction coarse powder of 40%, the concentrating under reduced pressure methanol extract liquid adds 5 times of (volume) water gagings in residue;
Ii) aqueous solution ether extraction, water layer reuse n-butanol extraction, evaporated under reduced pressure through silica gel column chromatography, is used CHCl
3-MeOH-H
2O obtains arasaponin than 65: 35: 10 eluting.
3) extract rubescensine A
With 2.5 kilograms of Rabdosia rubescens leaf dried powders of ether extraction, discard residue, reclaim the ether in the ether solution, obtain green and brown color residue; The dissolve with methanol residue, decolouring obtains clear and bright methanol solution, and room temperature is placed and is spent the night behind the concentrating under reduced pressure, filters methanol mother liquor evaporate to dryness, porphyrize; The neutral Al of reuse
2O
3Absorption is used the ether eluting, crystallization.
4) extract corydalis:
2 kilograms of Yanhusuos are moistening with 14% ammonia, and add ether: chloroform: ethanol is 25: 8: 0.5 mixed solvent soaked overnight, filter; Evaporate to dryness filtrate obtains described corydalis.
5) extract sinomenine:
2 kilograms of Radix Stephaniae Tetrandrae coarse powder are with 0.6% soak with sulphuric acid 4 times, and the sour water leachate is adjusted to pH=10 with lime cream, filters;
Be deposited in 60 ℃ of dryings down, be ground into fine particulate, obtain Radix Stephaniae Tetrandrae sand;
Soak 6 times each 6 hours with cold benzene;
Reclaim the benzene in the benzene liquid, dried residue;
The acetone that adds 20 times of volumes in residue makes its dissolving, is heated to 55 ℃, reclaims acetone to 1/4 of original volume, places, and cooling is filtered, and obtains crystallization;
Add 5 times of volume benzene and activated carbon in crystallization, room temperature was placed 30 minutes, filtered;
Reclaim the benzene in the benzene liquid, and, obtain sinomenine with the ethyl alcohol recrystallization of 20 times of volumes.
6) extract glycyrrhizin, isoliquiritigenin
1.5 95% ethanol extraction that the kilogram Radix Glycyrrhizae is measured with 3 times (volume), ethanol liquid is through petroleum ether extraction, and water layer is used MeOH-H through the silicagel column eluting
2O is 7: 3 eluting, and concentrate eluant obtains residue;
In residue, add water to dissolving fully, in water liquid, add ethyl acetate extraction, ethyl acetate layer 5%Na
2CO
3The extraction of water liquid is adjusted to pH5 with dilute hydrochloric acid with sodium carbonate water liquid, the reuse ethyl acetate extraction, and dry acetic acid ethyl fluid separates through 60 order polyamide columns, and the ethanol water gradient elution of 10-90% obtains glycyrrhizin and isoliquiritigenin.
7) I.a) pulverize behind the Ganoderma sporophore decontamination, add water and soaked 24 hours for 8 times, be heated to 95 ℃ and stirred 8 hours down;
B) centrifugalize extracting solution and medicinal residues obtain filtrate and medicinal residues;
C) in medicinal residues, add water and carry out lixiviate for 3 times, stirred 8 hours down at 95 ℃; Repeating step b) and c),
II.a) Ganoderma fermentation liquid (containing fungus ball) is heated to 95 ℃, stirred 4 hours;
B centrifugalize extracting solution and fungus ball;
C) in the medicinal residues that contain fungus ball, add 3 times in water (volume), extracted 2 hours, filter, separation and Extraction liquid and medicinal residues,
D) merge I.b), c) and II.c) in filtrate, be concentrated into 1/8 of original volume, add edible ethanol (3-5 doubly), reach about 70% to ethanol, leave standstill alcohol and analysed 24 hours, use the centrifuge sediment separate out, recovered alcohol, dry sediment.
With above-mentioned steps 1)-7) extract the active component obtain and mix and obtain Chinese medicine composition of the present invention (1).
Chinese medicine composition (1) is crushed to≤200 microns fine powders (2);
Pulverize, dry nothing is leaked seed/nipa palm seed (PHOENIX DACTYLIFERA L), with the dehydrated alcohol extraction of 8 times of volumes, preferably extract three times, and merging filtrate, concentrating under reduced pressure is handled with ethinylation potassium, obtains powder (3),
With fine powder (2) and powder (3) with 100-200: 1 weight ratio is mixed, and incapsulates then, obtains the capsule of Chinese medicine composition of the present invention.
1) extract baicalin:
I) in 1 kilogram of Radix Scutellariae, add 10 times of (volume) water gagings and decocted 1 hour, filter;
Ii) filtrate is transferred to pH 2, kept 30 minutes centrifugation at 80 ℃ down with dilute hydrochloric acid; Precipitate adds water and stirs, and adds alkali pH regulator is arrived neutrality, adds the ethanol of 3 times (volume) amount again, filters;
Iii) in filtrate, add hydrochloric acid,, stir, kept 30 minutes down, filter at 80 ℃ with pH regulator to 2;
Iv) the precipitate of gained is distinguished water, 50% washing with alcohol, and reuse 95% washing with alcohol or recrystallization obtain baicalin.
2) extract arasaponin:
I) with the solvable composition in 0.5 kilogram of Radix Notoginseng root of methanol extraction coarse powder of 40%, the concentrating under reduced pressure methanol extract liquid adds 5 times of (volume) water gagings in residue;
Ii) aqueous solution ether extraction, water layer reuse n-butanol extraction, evaporated under reduced pressure through silica gel column chromatography, is used CHCl
3-MeOH-H
2O obtains arasaponin than 65: 35: 10 eluting.
3) extract rubescensine A
With 1.5 kilograms of Rabdosia rubescens leaf dried powders of ether extraction, discard residue, reclaim the ether in the ether solution, obtain green and brown color residue; The dissolve with methanol residue, decolouring obtains clear and bright methanol solution, and room temperature is placed and is spent the night behind the concentrating under reduced pressure, filters methanol mother liquor evaporate to dryness, porphyrize; The neutral Al of reuse
2O
3Absorption is used the ether eluting, crystallization.
4) extract corydalis:
1 kilogram of Yanhusuo is moistening with strong aqua ammonia, adds described Yanhusuo and 95% ethanol, reflux, extract, in apparatus,Soxhlet's;
Ii) evaporate to dryness alcohol extract, residue add 1% hydrochloric acid and stir, and filter;
Iii) use 1% hydrochloric acid washing precipitate, filter;
Iv) merge ii) and the filtrate that iii) obtains, add ammonia and regulate pH to 9, chloroform extraction;
V) evaporate the chloroform in the chloroform layer, obtain described corydalis;
5) extract sinomenine:
1 kilogram of Radix Stephaniae Tetrandrae coarse powder is with 0.6% soak with sulphuric acid 4 times, and the sour water leachate is adjusted to pH=10 with lime cream, filters;
Be deposited in 60 ℃ of dryings down, be ground into fine particulate, obtain Radix Stephaniae Tetrandrae sand;
Soak 6 times each 5 hours with cold benzene;
Reclaim the benzene in the benzene liquid, dried residue;
The acetone that adds 20 times of volumes in residue makes its dissolving, is heated to 55 ℃, reclaims acetone to 1/4 of original volume, places, and cooling is filtered, and obtains crystallization;
Add 5-6 times of volume benzene and activated carbon in crystallization, room temperature was placed 30 minutes, filtered;
Reclaim the benzene in the benzene liquid, and, obtain sinomenine with the ethyl alcohol recrystallization of 20 times of volumes.
6) extract glycyrrhizin, isoliquiritigenin
0.9 95% ethanol extraction that the kilogram Radix Glycyrrhizae is measured with 4 times (volume), ethanol liquid is through petroleum ether extraction, and water layer is admixed silica gel, uses MeOH-H
2O is 7: 3 eluting, and concentrate eluant obtains residue;
In residue, add water to dissolving fully, in water liquid, add ethyl acetate extraction, ethyl acetate layer 5%Na
2CO
3The extraction of water liquid is adjusted to pH5-6 with diluted acid with sodium carbonate water liquid, the reuse ethyl acetate extraction, and dry acetic acid ethyl fluid separates through polyamide column, and 10-90% ethanol water gradient elution obtains glycyrrhizin and isoliquiritigenin.
7) Ganoderma sporophore is carried out Soxhlet and extract, with ethyl acetate extraction 4 hours, sucking filtration, the residue that obtains carried out Soxhlet again and extract, and with acetone extraction 4 hours, sucking filtration, the residue of gained was with 90% soak with ethanol 24 hours, and is centrifugal, sucking filtration; (PBS pH=7.0) extracts three times down at 80 ℃ residue, and 4 hours/time, sucking filtration discarded residue, and buffer is removed protein, and is centrifugal, and the upper strata liquid clear water of gained was dialysed distill water dialysis 3 days 7 days with 0.2 mol phosphate buffer;
Add a large amount of acetone in non-dialysis liquid, precipitation occurs, abandoning supernatant precipitates and uses washing with acetone 6 times, obtains the powdery solid of required product.
With above-mentioned steps 1)-7) extract the active component mixing that obtains, this mixture is ground into fine powder, incapsulate for using.
Experimental example 1
The patient that will suffer from middle and terminal cancer is divided into 3 groups at random, with everyone 900mg starch, 900mgDHE (Opium class preparation) and 900mg Chinese medicine composition of the present invention to 3 groups of patient's administrations, after 24 hours patient's general activity, emotion, walk ability, appetite, sleep, delight of life, body temperature etc. are assessed, integration is high more, explanation is big more to the influence of quality of life, and the result as shown in Figure 1.
From Fig. 1 result as seen, starch can not change the influence of cancer pain to quality of life in contrast; Chinese medicine composition of the present invention can farthest improve patient's quality of life, for example influence of general activity, emotion, walk ability, appetite, sleep, delight of life, and body temperature is reduced to normal body temperature, its drug effect is better than DHE.
Experimental example 2
As described in the experimental example 1 to the cancer patient administration, and after the pain after the best cancer pain of medicine alleviated, administration in 24 hours cancer pain alleviate after degree and the different pharmaceutical effect in 24 hours average anticancer pain degree and assess, the result shows that Chinese medicine composition of the present invention has excellent analgesic effect shown in Fig. 2-4.
Experimental example 3
As described in the experimental example 1 to the cancer patient administration, assessment clinical adverse separately after 24 hours, the result is as shown in the table:
| Group | The example number | Have no side effect | Drowsiness | Dizzy | Feel sick | Vomiting | Nervous | Constipation | The sense of euphoria |
| The |
20 | 17 | 0 | 3 | 0 | 0 | 0 | 2 | 0 |
| |
20 | 6 | 9 | 14 | 5 | 2 | 1 | 1 | 2 |
| |
20 | 20 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
From The above results as seen, present composition side effect is lower than DHE, there is no the sense of euphoria of addiction and Opium class.
Experimental example 4
The Ultrastructural observation that Chinese medicine composition of the present invention influences hepatoma carcinoma cell:
The cultivation of I.SMMC 7721 hepatoma carcinoma cell:
1. went down to posterity once in the every 2-3 of cell: SMMC 7721 hepatoma cell strains days, select eugonic exponential phase cell for use, cell titer 250000/ml.
2. reagent and culture medium: DMEM culture fluid (containing 15% calf serum and 50 unit mycillins); Trypsinization liquid (containing 0.02%EDTA, 0.25% trypsin, PBS buffer).
3. divide bottle: the trophophase cell of from 30 milliliters of culture bottles, taking the logarithm, remove culture fluid in original bottle, add 1 milliliter of trypsinization liquid, digest to cell and feed status occurs, get pancreatin, add 5 milliliters of culture fluid, with suction pipe piping and druming, cell is come off at the bottom of bottle, cell is sucked on the coverslip of ready culture jar and surface spray carbon with suction pipe, inject the DMEM culture fluid, make cell titer be adjusted to 250000/ml.At 5% carbon dioxide, 37 ℃ of environment were cultivated 24 hours down.
II. grouping and medication: will divide the 36 ware cells of ware after 24 hours to be divided into matched group and test group immediately, every group of each 18 ware, wherein 9 wares are as the phenotype constructed observation, and 9 wares are observed as internal structure.The present composition after grouping is determined promptly the consumption with 200 micrograms/ware add the present composition.
III. observe and method:
Every group of every sample point was 3 samples as sample point in 4,12 and 24 hours after dosing.Cancer cell phenotype constructed observation: take out the coverslip that is loaded with the cultured cell strain earlier, immerse in 2.5% glutaraldehyde solution of pre-cooling, behind the critical point liver, make the sample surfaces metal spraying with FME COAT JEF-1100 type ion sputtering instrument, under JEO JXA-840 type scanner pad sub-microscope, do the cell phenotype structural analysis.
Cell interior constructed observation: draw cell culture fluid earlier, 2.5% glutaraldehyde solution that adds pre-cooling, wash three times with phosphate buffer after 2 hours, with the cell curet cultured cell is scraped, it is fixing that reuse 1% osmic acid is done the back, after the phosphate buffer flushing, use 75% ethanol dehydration, in the implantation agar, reuse Epon 812 embeddings, ultrathin section (500 ) is made in polymerization under 60 ℃ of states, behind acetic acid uranium and lead citrate double staining, under JEOL JEM-1200 type transmission electron microscope, perform an analysis.
The result shows that matched group is after 24 hours, and cell is paved with substantially, mainly is the planar growth state.
Test group was used behind the present composition 4 hours, and dialysis appears in the iuntercellular pseudopodium of planar growth, and dissociating appears in cell, the cell surface particle detachment, and cell demonstrates dehydration.After 12 hours, degeneration appears in this cell, and surface particles comes off, and pit appears in a part of cell.(seeing Fig. 5 b).After the administration 24 hours, the cell quantity of hepatoma carcinoma cell obviously reduced, cell loose from, surface particles disappears, the hepatoma carcinoma cell film is obviously damaged, the parts of fine after birth disappears, cell disruption.(seeing Fig. 5 c).
Result of the test shows that Chinese medicine composition of the present invention has the effect of killing hepatoma cell.
Experimental example 5
Chinese medicine composition of the present invention is to the influence of cAMP content in the stomach organization:
The generation of tumor and growth have directly related effect to levels of cyclic nucleotides, and it relates to the activity of cAMP, cGMP, cCMP level and its corresponding adenyl cyclase and phosphodiesterase.The Recent study results suggest, cGMP has leading position in normal structure regeneration, and cAMP occupies an leading position to the development of tumor tissues.This experimental example is illustrated its anticarcinogenic effect by observing Chinese medicine composition of the present invention to the influence of cAMP level in the cancerous tumor cell.
I. the foundation of people's gastric cancer nude mice model: select endoscope to draw materials, pathological section turns out to be patients with gastric cancer, gets its stomach organization during excision, and it is cut into 3mm
3Small-sized piece of tissue, it is subcutaneous to be inoculated in nude mice, 3 of every zone inoculations, the conventional raising.
II grouping and medication: establishing the strain of plantation stomach organization is the blank group; Select the gastric cancer nude mice model to set up 16 of back 72 hours experiment nude mices, be divided into negative control group and test group at random, 8 every group.Negative control group lumbar injection 0.9%NaCl 0.5ml/ only; The Chinese medicine composition of the present invention of test group lumbar injection equivalent (including 2.5 milligrams of Chinese medicine compositions of the present invention) once a day, was injected 5 days continuously.
III. draw materials and sample treatment: the nude mice of adopting dislocation of cervical vertebra to put to death negative control group and test group in 24 hours after the last medication is finished, win people's stomach organization of plantation, blot surperficial body fluid with filter paper, weigh quantitatively about about 50 milligrams (the blank group is directly weighed quantitatively).Add 1 milliliter of 50mM acetate buffer solution, after the homogenate with sample transfer to centrifuge tube.With 2 milliliters of flushings of dehydrated alcohol homogenizer, be incorporated in the centrifuge tube centrifugal (3000 rev/mins, 15 minutes), get supernatant, once more with 2 milliliters of washings of 75% ethanol homogenizer, cleaning mixture centrifugal (3000 rev/mins, 15 minutes) is got supernatant simultaneously, merge 2 centrifugal back supernatant and go into test tube, put 60 ℃ of drying in oven, preserve in 4 ℃ of environment of refrigerator, adopt 125I Marking ring nucleotide radiating immuning analysis technology to detect.
IV. result: Fig. 6 has shown that matched group and test group organize the cAMP level difference, and therefrom visible Chinese medicine composition of the present invention can improve the cAMP level (p＜0.01) of organizing very significantly.Compare and show: Chinese medicine composition of the present invention is higher 7.2 times than blank group, and is higher 4.2 times than negative control group.
Low and the phosphodiesterase activity of malignant tumor ubiquity adenylate cyclase activity rises, so cause the decline of cell second message,second messenger cAMP level, the further developing and worsen of activation tumor tissues.The cAMP level rises to some extent, and the development that has embodied the control cancerous issue plays a positive role.This shows that Chinese medicine composition of the present invention can be controlled the power of cancerous tissue cell effectively.
Claims (7)
1. the Chinese medicine composition of an anticancer analgesic is characterized in that, it is made by the following weight proportion raw material:
Ganoderma 3-4
Rabdosia rubescens 1.5-2.5
Rhizoma Corydalis 1-2
Radix Scutellariae 1-2
Radix Stephaniae Tetrandrae 1-2
Radix Notoginseng 0.5-1.5
Radix Glycyrrhizae 0.5-1.5
2. Chinese medicine composition according to claim 1, wherein the weight proportion of each raw material is: Ganoderma: Rabdosia rubescens: Rhizoma Corydalis: Radix Scutellariae: Radix Stephaniae Tetrandrae: Radix Notoginseng: Radix Glycyrrhizae=3: 1.8: 1.8: 1.5: 1.2: 0.9: 0.9.
3. the preparation method of Chinese medicine composition as claimed in claim 1 is characterized in that, it comprises mixed extraction preparation method or goal object extraction preparation method, wherein
Described mixed extraction preparation method comprises:
1) prepare raw material:
With Ganoderma, Rabdosia rubescens, Rhizoma Corydalis, Radix Scutellariae, Radix Stephaniae Tetrandrae, Radix Notoginseng, Radix Glycyrrhizae is that the ratio of 3-4: 1.5-2.5: 1-2: 1-2: 1-2: 0.5-1.5: 0.5-1.5 is mixed with the weight ratio, and described mixture is divided into 5 equal portions;
2) extract alkaloid:
I) a Chinese medicine mixture that step 1) is obtained obtains acidic ethanol extraction liquid with 0.1% hydrochloride ethanol liquid diafiltration or gradation leaching;
Ii) concentrating under reduced pressure obtains concentrate;
The iii) acid water of pH=4-5 washing is filtered, and obtains residue, and residue obtains acidic aqueous liquid with the acid water washing of pH=4-5;
Iv) in the acidic aqueous liquid that step I obtains in ii), add ammonia precipitation process, filter and obtain the total alkaloids precipitation; Perhaps
A) add diluted acid to pH=2 in the acidic aqueous liquid that step I obtains in ii), use chloroform extraction, obtain chloroform layer and water layer, the chloroform in the evaporation chloroform layer obtains weak alkaloid;
B) described water layer adds alkali to pH=6-7, uses chloroform extraction, obtains water layer and chloroform layer, and the chloroform in the evaporation chloroform layer obtains strong alkaloid;
C) above-mentioned b) water layer that obtains is adjusted to pH=10 with alkali, uses butyl alcohol extraction then, and the butanols in the evaporation butanols layer obtains water miscible alkaloid;
D) merge above-mentioned a), b) and the alkaloid that c) obtains, obtain total alkaloids;
3) extract polysaccharide:
95-100 ℃ hot water extraction of a Chinese medicine mixture with step 1) obtains discards residue, and filtrate was placed after 12 hours, adds the ethanol of concentration more than 50%, the centrifugal polysaccharide precipitation that obtains in supernatant;
4) extract lactone:
With a Chinese medicine mixture aether backflow that step 1) obtains, remove pigment, reclaim ether, obtain total lactone;
5) extract Saponin:
The a Chinese medicine mixture that step 1) is obtained refluxes with petroleum ether, and the evaporation petroleum ether obtains the defat coarse powder, uses the 90-95% ethanol extraction, and concentrating under reduced pressure obtains concentrated solution;
A) concentrated solution is used chloroform, ethanol extraction successively, and reclaim under reduced pressure chloroform, ethanol obtain the Saponin crude product; Perhaps
B) concentrated solution butyl alcohol extraction, the reclaim under reduced pressure butanols obtains the Saponin crude product;
6) extract flavone:
The a Chinese medicine mixture that obtains to step 1) adds the 70-80% alcohol dipping, the ethanol in the decompression recycling ethanol liquid, and the residue water dissolution filters, and obtains water liquid; With ethyl acetate extraction water liquid, the concentrating under reduced pressure acetic acid ethyl fluid obtains total flavones;
With step 2)-6) extract the alkaloid, polysaccharide, lactone, Saponin, the flavone mixing that obtain, obtain described Chinese medicine composition;
Described goal object is extracted preparation method and is comprised:
1) extract baicalin:
I) in the described Radix Scutellariae raw material of claim 1, add 10-15 times of volume decocting and boiled 1-2 hour, filter;
Ii) filtrate is transferred to pH1-2, kept centrifugation 30-40 minute down at 80-90 ℃ with acid; Precipitate adds water and stirs, and adds alkali pH regulator is arrived neutrality, adds the ethanol of 3-5 times of volume again, filters;
Iii) in filtrate, add acid pH regulator is arrived 1-2, stir, kept 30-40 minute down, filter at 80-90 ℃;
Iv) the precipitate of gained is distinguished water, 50% washing with alcohol, and reuse 95% washing with alcohol or recrystallization obtain baicalin;
2) extract arasaponin:
I) with the solvable composition of concentration in the root coarse powder of the described Radix Notoginseng raw material of methanol extraction claim 1 below 50%, the concentrating under reduced pressure methanol extract liquid adds 3-5 times of volume water gaging in residue;
Ii) aqueous solution ether extraction, water layer reuse n-butanol extraction, evaporated under reduced pressure through silica gel column chromatography, is used CHCl
3-MeOH-H
2O obtains arasaponin than 65: 35: 10 eluting;
3) extract rubescensine A
Leaf dried powder with the described Rabdosia rubescens raw material of ether extraction claim 1 discards residue, reclaims the ether in the ether solution, obtains green and brown color residue; Use the dissolve with methanol residue, decolouring obtains clear and bright methanol solution, and behind the concentrating under reduced pressure, room temperature is placed and spent the night, and filters methanol mother liquor evaporate to dryness, porphyrize; Use the ether eluting, crystallization;
4) extract corydalis:
A) cold-maceration: the described Rhizoma Corydalis material powder of claim 1 is moistening with 14% ammonia, and add ether: chloroform: ethanol is 25: 8: 0.5 mixed solvent soaked overnight, filters; Evaporate to dryness filtrate obtains described corydalis; Perhaps
B) 95% ethanol extraction method: i) Yanhusuo is moistening with strong aqua ammonia, adds described Yanhusuo and 95% ethanol, reflux, extract, in apparatus,Soxhlet's;
Ii) evaporate to dryness alcohol extract, residue add 1% hydrochloric acid and stir, and filter;
Iii) use 1% hydrochloric acid washing precipitate, filter;
Iv) merge ii) and the filtrate that iii) obtains, add ammonia and regulate pH to 9-10, chloroform extraction;
V) evaporate the chloroform in the chloroform layer, obtain described corydalis;
5) extract sinomenine:
The described Radix Stephaniae Tetrandrae raw material of claim 1 coarse powder is with 0.6% soak with sulphuric acid 4 times, and the sour water leachate is adjusted to pH=10 with lime cream, filters;
Be deposited in 60 ℃ of dryings down, be ground into fine particulate, obtain Radix Stephaniae Tetrandrae sand;
Soak 6 times each 5-6 hour with cold benzene;
Reclaim the benzene in the benzene liquid, dried residue;
The acetone that adds 20 times of volumes in residue makes its dissolving, is heated to 55 ℃, reclaims acetone to 1/4 of original volume, places, and cooling is filtered, and obtains crystallization;
Add 5-6 times of volume benzene and activated carbon in crystallization, room temperature was placed 30 minutes, filtered;
Reclaim the benzene in the benzene liquid, and, obtain sinomenine with the ethyl alcohol recrystallization of 20 times of volumes;
6) extract glycyrrhizin, isoliquiritigenin
The described licorice raw material of claim 1 is with the 90-95% ethanol extraction of 3-4 times of volume, and ethanol liquid is through petroleum ether extraction, and water layer is admixed silica gel, uses MeOH-H
27: 3 eluting of O, concentrate eluant obtains residue;
In residue, add water to dissolving fully, in aqueous solution, add ethyl acetate extraction, ethyl acetate layer 5%Na
2CO
3The extraction of water liquid is adjusted to pH=5-6 with diluted acid with sodium carbonate water liquid, the reuse ethyl acetate extraction, and dry acetic acid ethyl fluid separates through polyamide column, obtains glycyrrhizin and isoliquiritigenin with 10-90% ethanol water gradient elution;
7) extract ganoderan
I.a) pulverize behind the sporophore decontamination with the described Ganoderma raw material of claim 1, add water 8-10 and doubly soaked 24 hours, be heated to 95-100 ℃ and stirred 8-10 hour down;
B) filter, obtain filtrate and medicinal residues;
C) in medicinal residues, add water 3-4 and doubly carry out lixiviate;
II.a) fermentation liquid that contains fungus ball with the described Ganoderma raw material of claim 1 is heated to 95-100 ℃, stirs 4 hours;
B) filter;
C) in the medicinal residues that contain fungus ball, add water 3-4 times volume, extracted 2 hours, filter, separation and Extraction liquid and medicinal residues,
D) merge I.b), c) and II.c) in filtrate, be concentrated into the 1/8-1/10 of original volume, add edible ethanol 3-5 doubly, reach about 70% to ethanol, leave standstill alcohol and analysed 24 hours, use the centrifuge sediment separate out, recovered alcohol, dry sediment; Obtain comprising the ganoderan of lucidum glycopeptide and Ganoderma β-D glucosan; Perhaps,
The sporophore of the described Ganoderma raw material of claim 1 is carried out Soxhlet extract, with ethyl acetate extraction 4 hours, sucking filtration, the residue that obtains carried out Soxhlet again and extract, and with acetone extraction 4 hours, sucking filtration, the residue of gained was with 90% soak with ethanol 24 hours, and is centrifugal, sucking filtration; Residue extracts three times down at 80 ℃ with the phosphate buffer of 0.2 mol pH=7, and 4 hours/time, sucking filtration discarded residue, and buffer is removed protein, and is centrifugal, with the upper strata liquid dialysis of gained,
Add a large amount of acetone in non-dialysis liquid, precipitation occurs, abandoning supernatant precipitates and uses washing with acetone 6 times, obtains comprising the ganoderan of lucidum glycopeptide and Ganoderma β-D glucosan,
The ganoderan and above-mentioned steps 1 that comprise lucidum glycopeptide and Ganoderma β-D glucosan that step 7) is obtained)-6) extract the active component obtain and mix and obtain described Chinese medicine composition.
4. method according to claim 3, it also comprises step 8):
A) with described step 1)-7) active component that obtains is crushed to≤200 microns fine powders;
B) pulverize, dry nothing is leaked seed/nipa palm seed or Fructus punicae granati seed/short Semen Granati, with the dehydrated alcohol extraction of 8 times of volumes, concentrating under reduced pressure, handles with ethinylation potassium, obtains powder;
C) with a), b) material of gained is with 100-200: 1 weight ratio is mixed.
5. method according to claim 4, it also comprises step d): with c) in the mixture that obtains incapsulate.
6. the application of Chinese medicine composition as claimed in claim 1 in the preparation analgesic.
7. the application of Chinese medicine composition as claimed in claim 1 in the preparation antineoplastic product.
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| CN101152166B (en) * | 2007-09-06 | 2010-12-08 | 武汉大学 | Isoliquirtigenin gelling agent for treating hemorrhoids and method of preparing the same |
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| CN100446802C (en) * | 2005-12-27 | 2008-12-31 | 武汉哈福科技有限公司 | Crude drug for preventing tumor metastasis |
| CN101036638B (en) * | 2006-03-16 | 2011-02-09 | 南京医科大学 | Application of glycyrrhizin in the preparation of medicine for preventing and curing tumour |
| CN101116699B (en) * | 2006-08-01 | 2010-08-18 | 杨爱菊 | Medicine for treating tumor |
| CN102379990A (en) * | 2011-09-27 | 2012-03-21 | 北京绿源求证科技发展有限责任公司 | Traditional Chinese medicine for treating cancer ache |
| CN102319382A (en) * | 2011-10-10 | 2012-01-18 | 北京绿源求证科技发展有限责任公司 | Chinese medicine for treating carcinomatous pains |
| CN104434939B (en) * | 2014-11-14 | 2017-05-03 | 深圳大学 | Antitumor medicament composition of panax notoginseng saponins R7 and oridonin with capabilities of reducing toxicity and enhancing efficacy and application of antitumor medicament composition |
| CN105106307B (en) * | 2015-08-10 | 2020-10-20 | 上海中耀生物科技有限公司 | Traditional Chinese medicine composition for treating prostate cancer and preparation method and application thereof |
| CN107691485A (en) * | 2017-08-21 | 2018-02-16 | 长沙新气象自动化技术有限公司 | A kind of pond Chinese herbal medicinal bactericide and its manufacture craft |
| CN111084844A (en) * | 2020-01-09 | 2020-05-01 | 杨泰基 | Yanxiang stasis-removing composition and preparation method thereof |
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