CN102091314A - Composition of dried ginger and evodia rutaecarpa, preparation method thereof and application thereof in preparing attenuating synergistic medicament in radiotherapy and chemotherapy of cancer - Google Patents
Composition of dried ginger and evodia rutaecarpa, preparation method thereof and application thereof in preparing attenuating synergistic medicament in radiotherapy and chemotherapy of cancer Download PDFInfo
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Abstract
The invention relates to a natural pharmaceutical composition, a preparation method thereof and an application thereof in preparing an attenuating synergistic medicament in radiotherapy and chemotherapy of cancer. The natural pharmaceutical composition is composed of concentrated extract of decoctions of dried ginger and evodia rutaecarpa, gingerol, evodia rutaecarpa extract and evodiamine in proportion of (1-4):(3-7):(2-9):(2-3). The composition provided by the invention has good curative effects on vomit and the like caused by the side effects of radiotherapy and chemotherapy of cancer, and also plays an effect on inhibiting tumor.
Description
Technical field
The present invention relates to a kind of natural drug composition, relate more specifically to a kind ofly fry in shallow oil the natural drug composition that concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin are formed by Rhizoma Zingiberis Fructus Evodiae soup, the preparation method of this natural drug composition and this natural drug composition are being used for preparing the purposes that reduces the vomiting side effect that cancer is put, chemotherapy causes and the treatment cancer is played the medicine of potentiation.
Background technology
Cancer has become the big killer that the mankind face at present, and mortality rate is only second to cardiovascular disease, and is the trend that rises year by year.There is 180 extremely evil property tumor patients every year in China, wherein 2/3 patient accept to put, chemotherapy, though certain curative effect is arranged, put, in various degree side effect can appear in most of patient after the chemotherapy, wherein modal side effect be feel sick, gastrointestinal reaction such as vomiting.Frequent vomiting can cause Digestive system to be lost in a large number, and water, electrolyte, acid base imbalance make patient agonizing, have a strong impact on patient's life quality, not only can have influence on curative effect, even makes patient be difficult to stand and therapy discontinued.
At present, clinical Bendectin commonly used mainly contains histamine (H
2), acetylcholine (M) and dopamine (DA) receptor antagonist and cannabis medicine etc., but the weak curative effect of these medicines, and toxic and side effects is strong, is very limited in the application to putting, vomitting after the chemotherapy.Novel Bendectin is as NK
1Receptor antagonist and 5-HT
3Receptor antagonist class medicine, though to put, the vomiting antiemetic effect is good after the chemotherapy, costs an arm and a leg, the scope of application is narrow, and toxicity is big, clinically needs drug combinations more, and does not see the anticancer synergia effect, the development of the natural anti-cancer attenuation synergistic medicine that therefore waits in expectation.
Chinese medicine for cancer put, the research of chemotherapy attenuation synergistic, attract people's attention.Present still unmatchful anticancer disease is put, chemotherapy has the Chinese patent medicine that alleviates vomiting side effect and potentiation.Therefore, research and develop a kind of high-efficiency low-toxicity, cheap, can be used for of being easy to promote alleviate that cancer is put, emesis of chemotherapy side effect and the natural Chinese medicine that plays the efficacy enhancing and toxicity reducing effect become clinical problem demanding prompt solution.
Chinese medicine Rhizoma Zingiberis Recens (zingiber) is described as " vomiting panacea ".Gingerol is the active ingredient that extracts from Rhizoma Zingiberis Recens, the inventor observe gingerol can resist inorganic and organic poison copper sulfate and cisplatin due to vomit, and suppress the intestinal pheochromocyte and discharge to cause and tell factor 5-HT and P material, gingerol acts on the maximally related NK of emesis of chemotherapy
1And 5-HT
3Deng receptor, be many target spots, natural low toxicity Bendectin.Fructus Evodiae is the nearly dry mature fruit of rutaceae Fructus Evodiae, has the merit of cold relieving pain relieving, stopping nausea and vomiting by lowering the adverse flow of QI, supporing yang preventing or arresting vomiting.Rhizoma Zingiberis Fructus Evodiae soup is taken passages from " outer platform " volume six, cures mainly the cholera hardship and vomits and do not stop.This side is made up of the Rhizoma Zingiberis and the Fructus Evodiae, and prescription is simple, and cost is very low.In recent years, Rhizoma Zingiberis and Fructus Evodiae antitumaous effect are confirmed.Fructus Evodiae extract rutaecarpin (Evodiamine), molecular formula are C
19H
17N
3O.Rutaecarpin has and is good for the stomach, eases pain, ends and retch and end effect such as acid eructation, and numerous cell experiment confirms the anti-tumor activity of rutaecarpin, and its antitumor spectra is wide, is a kind of natural anti-cancer new drug that DEVELOPMENT PROSPECT is arranged.The inventor is through research and the experiment and the clinical practice of each a large amount of formula proportion, obtained optimal drug ratio compositions of the present invention at last, it is the compositions of the novelty of agreeing with mutually with polyceptor target spot ratio, and proved that it has fabulous curative effect to the side effect such as vomiting that cancer is put, chemotherapy causes and can play the auxiliary effect that suppresses tumor simultaneously, has finished the present invention thus.
Summary of the invention
First purpose of the present invention is to provide a kind of natural drug composition, and the said composition low toxicity is efficient, determined curative effect, is convenient to use and promotes, both can antitumor, and can resist again and side effect such as put, vomit after the chemotherapy.
Second purpose of the present invention is to provide the preparation method of above-mentioned natural drug composition.
The 3rd purpose of the present invention is to provide that above-mentioned natural drug composition reduces in preparation that cancer is put, chemotherapy side effect and the treatment cancer is played purposes in the medicine of efficacy enhancing and toxicity reducing effect.
A kind of natural drug composition provided by the invention, fry in shallow oil concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin by weight in 1-4 by Rhizoma Zingiberis Fructus Evodiae soup: the ratio of 3-7: 2-9: 2-3 is formed.
Above-mentioned natural drug composition, wherein to fry in shallow oil the usage ratio of concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin be 4: 7: 9 to Rhizoma Zingiberis Fructus Evodiae soup: 3.
Wherein, Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil concentrated extract, gingerol, Fructus Evodiae extract can be by well known to a person skilled in the art the conventional method acquisition of purifying, gingerol and rutaecarpin can commerce be buied, and the natural drug of the present invention that adopts these compositions of conventional method acquisition or adopt the commercial one-tenth of buying to be grouped into all can obtain identical curative effect.The method of below listing only is that the inventor thinks preferred method, and is not intended to the extracting method of each composition in this natural drug composition is made special restriction.
Preferably, the preparation method that Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil concentrated extract in the above-mentioned natural drug composition is:
According to proportion compatibility is to get Rhizoma Zingiberis, Fructus Evodiae at 1: 1, adds 10 times of amount distilled water, soaks 1h, heating decocts 1h on the electric furnace that adds asbestos gauge, silk filters, and preserves filtrate, and medicinal residues add 6 times of distilled water again, soak, decoct, filter with method, twice filtrate is mixed, and heating is concentrated into small size, ultrafiltration membrance filter, adopt 70 ℃ of drying under reduced pressure 36h of vacuum drying oven to get yellow powder, be Rhizoma Zingiberis Fructus Evodiae soup and fry in shallow oil concentrated extract
The preparation method of gingerol is in the above-mentioned natural drug composition:
Rhizoma Zingiberis is thinly sliced, and natural drying breaks into powder with the high speed Universalpulverizer, crosses 30 mesh sieves, and the fine powder that will sieve is again put into the big port grinding bottle of 5000mL, to soak 72h under the alcohol at normal temperature of 6 times of amounts 95%; At 40 ℃, supersound extraction 15min under the ultrasonic frequency of 40KHz, the centrifugal supernatant that obtains, residue discards; With supernatant decompress filter again, filtrate places the Rotary Evaporators vacuum concentration to get oil of ginger shape mixture, and carrying out this mixture repeatedly again, the concentrate drying purification obtains gingerol.
The Fructus Evodiae extract preparation method is in the above-mentioned natural drug composition:
Get the nearly dry mature fruit of Fructus Evodiae, drying is pulverized, and sieves, and adds 10 times of water gagings and refluxes each 2 hours 2 times.Merge filtrate twice, use ethyl acetate extraction, get organic facies and volatilize ethyl acetate, get Fructus Evodiae extract.
The rutaecarpin preparation method is in the above-mentioned natural drug composition:
The above-mentioned Fructus Evodiae extract utilization polyamide column chromatography that makes is with the mixed solvent eluting of 2 kinds of solvent compositions, in conjunction with thin layer chromatography, collect and contain the rutaecarpin eluent and volatilize solvent, recrystallizing methanol, faint yellow solid, surveying fusing point is 278 ℃, is rutaecarpin.
The present invention also provides the preferred manufacturing procedure of this natural drug composition, comprising:
(1) Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil the preparation of concentrated extract
According to proportion compatibility is to get Rhizoma Zingiberis, Fructus Evodiae at 1: 1, adds 10 times of amount distilled water, soaks 1h, heating decocts 1h on the electric furnace that adds asbestos gauge, silk filters, and preserves filtrate, and medicinal residues add 6 times of distilled water again, soak, decoct, filter with method, twice filtrate is mixed, and heating is concentrated into small size, ultrafiltration membrance filter, adopt 70 ℃ of drying under reduced pressure 36h of vacuum drying oven to get yellow powder, be Rhizoma Zingiberis Fructus Evodiae soup and fry in shallow oil concentrated extract.
(2) preparation of gingerol
Rhizoma Zingiberis is thinly sliced, and natural drying breaks into powder with the high speed Universalpulverizer, crosses 30 mesh sieves, and the fine powder that will sieve is again put into the big port grinding bottle of 5000mL, to soak 72h under the alcohol at normal temperature of 6 times of amounts 95%; At 40 ℃, supersound extraction 15min under the ultrasonic frequency of 40KHz; The centrifugal supernatant that obtains, residue discards; With supernatant decompress filter again, filtrate places the Rotary Evaporators vacuum concentration to get oil of ginger shape mixture, and carrying out this mixture repeatedly again, the concentrate drying purification obtains gingerol.
(3) Fructus Evodiae extract preparation
Get the nearly dry mature fruit of Fructus Evodiae, drying is pulverized, and sieves, and adds 10 times of water gagings and refluxes each 2 hours 2 times.Merge filtrate twice, use ethyl acetate extraction, get organic facies and volatilize ethyl acetate, get Fructus Evodiae extract.
(4) rutaecarpin preparation:
The above-mentioned Fructus Evodiae extract utilization polyamide column chromatography that makes is with the mixed solvent eluting of 2 kinds of solvent compositions, in conjunction with thin layer chromatography, collect and contain the rutaecarpin eluent and volatilize solvent, recrystallizing methanol, faint yellow solid, surveying fusing point is 278 ℃, is rutaecarpin.
(5) choose Rhizoma Zingiberis Fructus Evodiae soup in proportion and fry in shallow oil concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin, uniform mixing, promptly.
The preparation method of above-mentioned natural drug composition, also comprise: the product that step (5) makes is further made the capsule that contains natural drug composition 100mg or 200mg specification by the pharmacy means of routine, maybe will make the tablet that contains natural drug composition 100mg or 200mg specification by wet granulation technology.
The present invention comprises also that natural drug composition reduces in preparation that cancer is put, chemotherapy side effect and the treatment cancer is played purposes in the medicine of potentiation, and reduces the vomiting reaction that cancer is put, chemotherapy causes and the treatment cancer is played purposes in the medicine of potentiation in preparation.
The instructions of taking of natural drug composition of the present invention: the treatment cancer puts, available capsule of vomiting or tablet after the chemotherapy, and 600mg divides three times one after each meal for each person every day.
The beneficial effect of natural drug composition of the present invention aspect resisting emesis and inhibition tumor is as follows:
1, natural drug composition of the present invention has good resisting emesis effect, has now finished clinical preceding pharmaceutical research at mink vomiting model.The mink vomiting model that adopts us to initiate is observed this natural drug composition cisplatin is caused the antagonism over a period to come of mink vomiting model.Studies show that: this natural drug composition has tangible antagonism for the vomiting reaction of mink due to the cisplatin, and its effect is better than using separately Rhizoma Zingiberis Fructus Evodiae soup and fries in shallow oil concentrated extract, gingerol, Fructus Evodiae extract.Simultaneously, its reduction causes the rate aspect of vomitting, and its effect matches in excellence or beauty with the Western medicine ondansetron.
2, natural drug composition of the present invention has the effect that suppresses tumor, has now finished clinical preceding pharmaceutical research on mouse tumor model.Adopted mouse tumor model, observed the inhibitory action of natural drug composition mouse interior tumor.Studies show that: this natural drug composition has the obvious suppression effect for mouse interior tumor.
3, proved that in addition this natural drug composition can strengthen the inhibitory action of chemotherapeutics to tumor, now finished clinical preceding pharmaceutical research on the mouse tumor cell model.Adopted mouse tumor model, observed this natural drug composition and cyclophosphamide combined inhibitory action mouse interior tumor.Studies show that: this natural drug composition can obviously increase the inhibitory action of cyclophosphamide for tumor.
4, finished simultaneously in the research of the acute toxicology of mice, studies show that: this natural drug composition does not have influence to feed and behavioral activity etc., and internal organs and pathological observation be no abnormality seen also.Illustrate that this natural drug composition toxicity is very little.
5, the inventor fries in shallow oil concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin with Rhizoma Zingiberis Fructus Evodiae soup originally and makes up, and by the consumption proportion between definite these components of a large amount of experiments, make said composition bring into play good synergism, obtain unexpected effect.Pass through our experimentation repeatedly, make the inventor surprised be ratio between each component of natural drug composition of the present invention at 1-4: 3-7: 2-9: produced unexpected synergism during 2-3, potentiation is obvious, extraordinary effect is played in side effect, especially the usage ratio in each component is 4: 7: 9: 3 o'clock especially obvious, this is that the inventor pays a large amount of creative works by keeping punching and obtains on the paper basis of delivering before, and those of ordinary skills only can't simply obtain this ratio range and optimum amount ratio by disclosed content.
6, this natural drug composition Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil each component of concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin and all can be obtained by conventional means, some of them component for example gingerol also can be buied by commerce, and such compositions itself has the convenience of acquisition, lower-cost effect.This also is the product that has splendid curative effect and higher industrial practicality concurrently that the inventor obtains by a large amount of creative work sides.
The specific embodiment
Further set forth the preparation of natural drug composition of the present invention below by embodiment and test example, with and the beneficial effect in resisting emesis and antitumor, used.
Embodiment
(1) Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil the preparation of concentrated extract
According to proportion compatibility is to get Rhizoma Zingiberis, Fructus Evodiae at 1: 1, adds 10 times of amount distilled water, soaks 1h, heating decocts 1h on the electric furnace that adds asbestos gauge, silk filters, and preserves filtrate, and medicinal residues add 6 times of distilled water again, soak, decoct, filter with method, twice filtrate is mixed, and heating is concentrated into small size, ultrafiltration membrance filter, adopt 70 ℃ of drying under reduced pressure 36h of vacuum drying oven to get yellow powder, be Rhizoma Zingiberis Fructus Evodiae soup and fry in shallow oil concentrated extract.
(2) preparation of gingerol
Rhizoma Zingiberis is thinly sliced, and natural drying breaks into powder with the high speed Universalpulverizer, crosses 30 mesh sieves, and the fine powder that will sieve is again put into the big port grinding bottle of 5000mL, to soak 72h under the alcohol at normal temperature of 6 times of amounts 95%; At 40 ℃, supersound extraction 15min under the ultrasonic frequency of 40KHz; The centrifugal supernatant that obtains, residue discards; With supernatant decompress filter again, filtrate places the Rotary Evaporators vacuum concentration to get oil of ginger shape mixture, and carrying out this mixture repeatedly again, the concentrate drying purification obtains gingerol.
(3) Fructus Evodiae extract preparation
Get the nearly dry mature fruit of Fructus Evodiae, drying is pulverized, and sieves, and adds 10 times of water gagings and refluxes each 2 hours 2 times.Merge filtrate twice, use ethyl acetate extraction, get organic facies and volatilize ethyl acetate, get Fructus Evodiae extract.
(4) rutaecarpin preparation:
The above-mentioned Fructus Evodiae extract utilization polyamide column chromatography that makes is with the mixed solvent eluting of 2 kinds of solvent compositions, in conjunction with thin layer chromatography, collect and contain the rutaecarpin eluent and volatilize solvent, recrystallizing methanol, faint yellow solid, surveying fusing point is 278 ℃, is rutaecarpin.
Second step: the preparation of preparation
(1) preparation of natural drug composition capsule preparations of the present invention
The Rhizoma Zingiberis Fructus Evodiae soup that takes by weighing the above-mentioned steps preparation is respectively fried in shallow oil concentrated extract 16mg, gingerol 28mg, Fructus Evodiae extract 36mg and rutaecarpin 12mg, take by weighing starch 403mg, magnesium stearate 5mg simultaneously, uniform mixing, filled capsules is made the capsule of each pure heavy 500mg.
(2) preparation of natural drug composition tablet of the present invention
The Rhizoma Zingiberis Fructus Evodiae soup that takes by weighing the above-mentioned steps preparation is respectively fried in shallow oil concentrated extract 16mg, gingerol 28mg, Fructus Evodiae extract 36mg and rutaecarpin 12mg, take by weighing starch 303mg, lactose 100mg simultaneously, uniform mixing, with wet granulation, drying, mix with the 5mg magnesium stearate behind the granulate, tabletting is made the tablet of every pure heavy 500mg.
Drug effect and pharmacology's data:
Compositions is in following test example: the usage ratio that Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin is 4: 7: 9: 3.The inventor to above-mentioned each composition usage ratio at 1-4: 3-7: 2-9: the compositions that the multiple proportioning combination in the time of between the 2-3 obtains has been carried out and last identical experiment, find that all the natural drug composition in this amount ranges can obtain good synergism, to cancer put, chemotherapy side effect can play good effect and treatment for cancer is had potentiation.And, the inventor finds that it can also be the composition that obtains with conventional means that Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin, and be not only the composition that obtains with above-mentioned method, the compositions that above-mentioned four kinds of one-tenth of buying that made by conventional means or commercial are grouped into has the identical effect of compositions that makes with said method, its experimental data is no longer enumerated here, and those skilled in the art can approve this.Below be drug effect and the pharmacology's data that preferred embodiment obtains:
Test example 1: the pharmacodynamic study of natural drug composition treatment vomiting effect
1, test material
(1) Fructus Evodiae is bought and is accredited as by professor Qian Qiuhai of Shandong Traditional Chinese Medicine University the nearly dry mature fruit of rutaceae Fructus Evodiae by the big pharmacy of Qingdao all living creatures.Rhizoma Zingiberis is bought and is accredited as by professor Qian Qiuhai of Shandong Traditional Chinese Medicine University the dry rhizome of the cultivar Rhizoma Zingiberis Recens of zingiberaceous plant by the big pharmacy of Qingdao all living creatures.
(2) cisplatin (cisplatin), Shandong Qilu Pharmaceutical Factory produces, lot number: 903005CE, 20mg/ props up.
(3) Ondansetron Hydrochloride injection, the pharmacy of Olympic Competition health,, lot number: 090102,2ml:4mg.
(4) healthy adult mink, body weight 1.3-1.8kg, male, provide by special cultivation animal feeding center, Qingdao, every animal places the ferrum cage of 75cm * 50cm * 50cm separately, 24h natural light irradiation, ad lib drinking-water before the experiment.
2, test method:
Mink is divided into 7 groups at random, every group 6, the A group is the gingerol group, the B group is the Fructus Evodiae extract group, the C group is gingerol and Fructus Evodiae extract compatibility group (ratio is 7: 9), and the D group is fried in shallow oil concentrated extract for Rhizoma Zingiberis Fructus Evodiae soup, and (Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin by 4: 7: 9 to the E group: 3 mixed) for natural drug composition of the present invention, the F group is the cisplatin positive controls, and the G group is the ondansetron group.The A group is earlier with gingerol 10g.kg
-1(being equivalent to contain the crude drug amount) ig pretreatment, 30min gives cisplatin 7.5mg.kg
-1Ip; The B group gives Fructus Evodiae extract 10g.kg
-1(being equivalent to contain the crude drug amount) ig pretreatment, 30min gives cisplatin 7.5mg.kg
-1Ip; The C group gives gingerol and Fructus Evodiae extract compatibe drug 10g.kg
-1(being equivalent to contain the crude drug amount) ig pretreatment, 30min gives cisplatin 7.5mg.kg
-1Ip; The D group gives Rhizoma Zingiberis Fructus Evodiae soup and fries in shallow oil concentrated extract 10g.kg
-1(being equivalent to contain the crude drug amount) ig pretreatment, 30min gives cisplatin 7.5mg.kg
-1Ip; The E group gives natural drug composition 10g.kg of the present invention
-1(being equivalent to contain the crude drug amount) ig pretreatment, 30min gives cisplatin 7.5mg.kg
-1Ip; The F group gives normal saline, and 30min gives cisplatin 7.5mg.kg
-1Ip; The G group is earlier with ondansetron group 7.5g.kg
-1Pretreatment, 30min gives cisplatin 7.5mg.kg
-1Ip.For observing mink vomiting reaction in the 6h after administration, write down its vomiting incubation period, retch and vomiting number of times.
3, experimental result
Compare with matched group, each treatment group all can obviously alleviate retch and vomiting number of times and effective prolongation and vomit incubation period (P＜0.05, P＜0.01).Gingerol and Fructus Evodiae extract compatibility group prolong vomiting and are better than and the ondansetron group incubation period.Gingerol group, gingerol and Fructus Evodiae extract compatibility group, Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil the concentrated extract group, and natural drug composition of the present invention can effectively reduce the rate of vomitting that causes.It is identical with the ondansetron group that wherein gingerol and Fructus Evodiae extract compatibility group, Rhizoma Zingiberis Fructus Evodiae soup are fried in shallow oil the concentrated extract group; And causing the rate of vomitting, natural drug composition group of the present invention is lower than the ondansetron group.The results are shown in Table 1.
Table 1 extract compatibility to cisplatin (7.5mg/kg, ip) cause vomit the effect influence (
N=6)
Annotate: a is equivalent to contain the crude drug amount, compares with matched group
bP＜0.05,
cP＜0.01
Test example 2: the pharmacodynamic study of natural drug composition antitumor action of the present invention
1, experiment material
(1) Kunming mouse, body weight 20 ± 2g is by being provided by Qingdao City medicine inspecting institute Experimental Animal Center.Ad lib drinking-water before the experiment, the 24h natural light irradiation.
(2) cyclophosphamide, the permanent auspicious medical Pharmacy stock Co., Ltd in Jiangsu product.
2, test method:
(1) to mice S
180The inhibition test of sarcoma growth
Employing was gone down to posterity 5-7 days, and well-grown milky ascites is diluted to tumor cell suspension with an amount of physiological saline solution, and cell number is 10
7/ mL, 12 every group, the right axillary fossa subcutaneous vaccination of every Mus 0.2mL (contains oncocyte 2 * 10
6Individual).Inoculation random packet next day, experimental group natural drug composition of the present invention is divided into (400,200,100mg/mL) three dosage groups, every Mus is irritated stomach 0.5ml; Negative control group gives 0.5mL distilled water; The positive drug group gives cyclophosphamide 20gkg
-1D
-1, successive administration 10 days.The conventional raising, drinking-water, food is not limit.Drug withdrawal next day, mice all takes off cervical vertebra puts to death, and strips subcutaneous solid tumor tumor piece, weighs, and calculates tumor control rate (%) by following formula:
Tumor control rate=(the average tumor of the matched group average tumor of heavy (C)-experimental group heavy (T))/average tumor of matched group heavy (C)
(2) to rat liver cancer H
22The inhibition test of growth
Grouping, dosage, administering mode, experimental period and S
180The sarcoma strain is identical.
(3) to the inhibition test of mice ehrlich ascites tumor (solid tumor)
Grouping, dosage, administering mode, experimental period and S
180The sarcoma strain is identical.
3, result of the test
Three dosage groups of natural drug composition of the present invention are to S
180, H
22, EAC and negative control group relatively, inhibitory action is in various degree all arranged, especially the highest to the suppression ratio of tumor with high dose group.(as table 2,3,4)
Table 2 capsule is to S
180The tumor inhibition effect of mice (
N=12)
Compare with negative control group,
bP＜0.05,
cP＜0.01
Table 3 capsule is to H
22The tumor inhibition effect of mice (
N=12)
Compare with negative control group,
bP＜0.05
Table 4 capsule to the tumor inhibition effect of EAC mice (
N=12)
Compare with negative control group,
bP＜0.05,
cP＜0.01
Test example 3: natural drug composition of the present invention is for the pharmacodynamic study of chemotherapy medicine antitumor potentiation
1, experiment material
(1) Kunming mouse, body weight 20 ± 2g is by being provided by Qingdao City medicine inspecting institute Experimental Animal Center.Ad lib drinking-water before the experiment, the 24h natural light irradiation.
(2) cyclophosphamide, the permanent auspicious medical Pharmacy stock Co., Ltd in Jiangsu product.
2, test method:
(1) to mice S
180The inhibition test of sarcoma growth
Employing was gone down to posterity 5-7 days, and well-grown milky ascites is diluted to tumor cell suspension with an amount of physiological saline solution, and cell number is 10
7/ mL, 12 every group, the right axillary fossa subcutaneous vaccination of every Mus 0.2ml (contains oncocyte 2 * 10
6Individual).The inoculation next day random packet, experimental group natural drug composition of the present invention is divided into (10,5,2.5gkg
-1) three dosage groups, every Mus is irritated stomach 0.5ml, gives cyclophosphamide 10gkg simultaneously
-1D
-1Negative control group gives 0.5ml distilled water; The positive drug group gives cyclophosphamide 20gkg
-1D
-1, successive administration 10 days.The conventional raising, drinking-water, food is not limit.Drug withdrawal next day, mice all takes off cervical vertebra puts to death, and strips subcutaneous solid tumor tumor piece, weighs, and calculates tumor control rate (%) by following formula:
Tumor control rate=(the average tumor of the matched group average tumor of heavy (C)-experimental group heavy (T))/average tumor of matched group heavy (C)
(2) to rat liver cancer H
22The inhibition test of growth
Grouping, dosage, administering mode, experimental period and S
180The sarcoma strain is identical.
(3) to the inhibition test of mice ehrlich ascites tumor (solid tumor)
Grouping, dosage, administering mode, experimental period and S
180The sarcoma strain is identical.
3, result of the test
Under the situation that reduces the cyclophosphamide dosage, three dosage of natural drug composition of the present invention and cyclophosphamide combined medication group are to S
180, H
22, EAC and negative control group relatively, inhibitory action is in various degree all arranged, especially the highest to the suppression ratio of tumor with high dose group.And, to S
180, H
22, the EAC mice tumor inhibition effect in, the tumor inhibition effect of high dose natural drug composition group is remarkable, and is suitable with the positive drug effect.(as table 5,6,7)
Table 5 capsule is to S
180The tumor inhibition effect of mice (
N=12)
Compare with negative control group,
cP＜0.01
Compatibility drug group height: cyclophosphamide 10gkg
-1+ compositions 10gkg
-1In the compatibility drug group: cyclophosphamide 10gkg
-1+ compositions 5gkg
-1The compatibility drug group is low: cyclophosphamide 10gkg
-1+ compositions 2.5gkg
-1, down together
Table 6 capsule is to H
22The tumor inhibition effect of mice (
N=12)
Compare with negative control group,
bP＜0.05
Table 7 capsule to the tumor inhibition effect of EAC mice (
N=12)
Compare with negative control group,
cP＜0.05
Test example 4: the acute toxicity test of natural drug composition of the present invention
1, experimental animal:
Kunming mouse, body weight 20 ± 2g is provided by Qingdao City medicine inspecting institute Experimental Animal Center.
2, medicine:
Natural drug composition of the present invention, tragakanta
3, test method:
According to " the study of tcm new drug specification requirement " of National Drug Administration's promulgation in one on November 12, in 999 revision, natural drug of the present invention is carried out acute toxicity testing.Because of being subjected to drug level and volume restrictions, can't measure LD
50So, carry out the maximum dosage-feeding experiment.Get 30 of Kunming mouses, female half and half, ig gives capsule Chinese medicine 1g/mL, every 0.8mL, and it is long-pending that promptly the maximum of mice is irritated body of stomach, observes mice active state, diet, feces, breathing, body weight and death condition after the medication, observes 14d. continuously
4, result of the test:
Each organizes well-grown after the mouse stomach administration, weight increase, and behavior is normal, there is no death and significant reaction.Behind sacrifice of animal, the no abnormal phenomenon of each main organs of perusal.
The result shows that natural drug composition maximal dose oral application of the present invention does not have obvious damage to animal, does not find the toxic reaction to the body generation, is a kind of safe and reliable medicine.
Claims (7)
1. natural drug composition, it is characterized in that said composition fries in shallow oil concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin by weight in 1-4 by Rhizoma Zingiberis Fructus Evodiae soup: the ratio of 3-7: 2-9: 2-3 is formed,
Wherein Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil the preparation method of concentrated extract and is:
According to proportion compatibility is to get Rhizoma Zingiberis, Fructus Evodiae at 1: 1, adds 10 times of amount distilled water, soaks 1h, heating decocts 1h on the electric furnace that adds asbestos gauge, silk filters, and preserves filtrate, and medicinal residues add 6 times of distilled water again, soak, decoct, filter with method, twice filtrate is mixed, and heating is concentrated into small size, ultrafiltration membrance filter, adopt 70 ℃ of drying under reduced pressure 36h of vacuum drying oven to get yellow powder, be Rhizoma Zingiberis Fructus Evodiae soup and fry in shallow oil concentrated extract.
Wherein the preparation method of Fructus Evodiae extract is:
Get the nearly dry mature fruit of Fructus Evodiae, drying is pulverized, and sieves, and adds 10 times of water gagings and refluxes each 2 hours 2 times.Merge filtrate twice, use ethyl acetate extraction, get organic facies and volatilize ethyl acetate, get Fructus Evodiae extract.
Wherein the preparation method of rutaecarpin is:
The above-mentioned Fructus Evodiae extract utilization polyamide column chromatography that makes is with the mixed solvent eluting of 2 kinds of solvent compositions, in conjunction with thin layer chromatography, collect and contain the rutaecarpin eluent and volatilize solvent, recrystallizing methanol, faint yellow solid, surveying fusing point is 278 ℃, is rutaecarpin.
2. natural drug composition as claimed in claim 1, wherein to fry in shallow oil the usage ratio of concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin be 4: 7: 9 to Rhizoma Zingiberis Fructus Evodiae soup: 3.
3. natural drug composition as claimed in claim 1, wherein the preparation method of gingerol is:
Rhizoma Zingiberis is thinly sliced, and natural drying breaks into powder with the high speed Universalpulverizer, crosses 30 mesh sieves, and the fine powder that will sieve is again put into the big port grinding bottle of 5000mL, to soak 72h under the alcohol at normal temperature of 6 times of amounts 95%; At 40 ℃, supersound extraction 15min under the ultrasonic frequency of 40KHz, the centrifugal supernatant that obtains, residue discards; With supernatant decompress filter again, filtrate places the Rotary Evaporators vacuum concentration to get oil of ginger shape mixture, and carrying out this mixture repeatedly again, the concentrate drying purification obtains gingerol.
4. as the preparation method of the natural drug composition of claim 1 or 2, it is characterized in that this method comprises:
(1) Rhizoma Zingiberis Fructus Evodiae soup is fried in shallow oil the preparation of concentrated extract:
According to proportion compatibility is to get Rhizoma Zingiberis, Fructus Evodiae at 1: 1, adds 10 times of amount distilled water, soaks 1h, heating decocts 1h on the electric furnace that adds asbestos gauge, silk filters, and preserves filtrate, and medicinal residues add 6 times of distilled water again, soak, decoct, filter with method, twice filtrate is mixed, and heating is concentrated into small size, ultrafiltration membrance filter, adopt 70 ℃ of drying under reduced pressure 36h of vacuum drying oven to get yellow powder, be Rhizoma Zingiberis Fructus Evodiae soup and fry in shallow oil concentrated extract.
(2) preparation of gingerol:
Rhizoma Zingiberis is thinly sliced, and natural drying breaks into powder with the high speed Universalpulverizer, crosses 30 mesh sieves, and the fine powder that will sieve is again put into the big port grinding bottle of 5000mL, to soak 72h under the alcohol at normal temperature of 6 times of amounts 95%; At 40 ℃, supersound extraction 15min under the ultrasonic frequency of 40KHz, the centrifugal supernatant that obtains, residue discards; With supernatant decompress filter again, filtrate places the Rotary Evaporators vacuum concentration to get oil of ginger shape mixture, and carrying out this mixture repeatedly again, the concentrate drying purification obtains gingerol.
(3) Fructus Evodiae extract preparation:
Get the nearly dry mature fruit of Fructus Evodiae, drying is pulverized, and sieves, and adds 10 times of water gagings and refluxes each 2 hours 2 times.Merge filtrate twice, use ethyl acetate extraction, get organic facies and volatilize ethyl acetate, get Fructus Evodiae extract.
(4) rutaecarpin preparation:
The above-mentioned Fructus Evodiae extract utilization polyamide column chromatography that makes is with the mixed solvent eluting of 2 kinds of solvent compositions, in conjunction with thin layer chromatography, collect and contain the rutaecarpin eluent and volatilize solvent, recrystallizing methanol, faint yellow solid, surveying fusing point is 278 ℃, is rutaecarpin.
(5) choose Rhizoma Zingiberis Fructus Evodiae soup in proportion and fry in shallow oil concentrated extract, gingerol, Fructus Evodiae extract and rutaecarpin uniform mixing, promptly.
5. as the preparation method of claims 4 described natural drug compositions, also comprise: the product that step (5) makes is further made the capsule that contains natural drug composition 100mg or 200mg specification by the pharmacy means of routine, maybe will make the tablet that contains natural drug composition 100mg or 200mg specification by wet granulation technology.
As each described natural drug composition of claim 1-3 reduce in preparation that cancer is put, chemotherapy side effect and the treatment cancer is played purposes in the medicine of potentiation.
7. as the purposes of each described natural drug composition of claim 1-3 in preparing the medicine that reduces the vomiting reaction that cancer is put, chemotherapy causes and the treatment cancer is played potentiation.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102266547A (en) * | 2011-08-31 | 2011-12-07 | 南京财经大学 | Preparation method of ginger extract with detoxifying effect on exogenous carcinogens and product |
| CN103479987A (en) * | 2013-10-07 | 2014-01-01 | 大连杰信生物科技有限公司 | Preparation method and antioxidation and bacteriostatic actions of ethanol extract from ginger |
| CN106265704A (en) * | 2016-07-26 | 2017-01-04 | 河南大学 | The Traditional Chinese Herb combination of a kind of target tumor hypoxia microenvironment application in oncotherapy |
| CN106267109A (en) * | 2016-09-29 | 2017-01-04 | 宁波上山打老虎日化有限公司 | Rhizoma Zingiberis and Fructus Evodiae compositions and preparation method and the purposes in anticreep is grown thereof |
| CN106421709A (en) * | 2016-11-10 | 2017-02-22 | 马玉珍 | Medicine for treating nausea and vomiting in pregnancy |
| CN109970536A (en) * | 2019-04-22 | 2019-07-05 | 温州市人民医院 | A kind of extracting method of rhizoma zingiberis effective component |
| CN110049766A (en) * | 2016-12-06 | 2019-07-23 | Sg株式会社 | It is effective component for preventing or treating the composition of the disease as caused by caffeinism using evodia extract or rutaecarpin |
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| CN101401926A (en) * | 2008-11-11 | 2009-04-08 | 耿平 | Umbilicus-applied medicament for treating emesis of chemotherapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101401926A (en) * | 2008-11-11 | 2009-04-08 | 耿平 | Umbilicus-applied medicament for treating emesis of chemotherapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102266547A (en) * | 2011-08-31 | 2011-12-07 | 南京财经大学 | Preparation method of ginger extract with detoxifying effect on exogenous carcinogens and product |
| CN102266547B (en) * | 2011-08-31 | 2013-06-12 | 南京财经大学 | Preparation method of ginger extract with detoxifying effect on exogenous carcinogens and product |
| CN103479987A (en) * | 2013-10-07 | 2014-01-01 | 大连杰信生物科技有限公司 | Preparation method and antioxidation and bacteriostatic actions of ethanol extract from ginger |
| CN106265704A (en) * | 2016-07-26 | 2017-01-04 | 河南大学 | The Traditional Chinese Herb combination of a kind of target tumor hypoxia microenvironment application in oncotherapy |
| CN106267109A (en) * | 2016-09-29 | 2017-01-04 | 宁波上山打老虎日化有限公司 | Rhizoma Zingiberis and Fructus Evodiae compositions and preparation method and the purposes in anticreep is grown thereof |
| CN106421709A (en) * | 2016-11-10 | 2017-02-22 | 马玉珍 | Medicine for treating nausea and vomiting in pregnancy |
| CN110049766A (en) * | 2016-12-06 | 2019-07-23 | Sg株式会社 | It is effective component for preventing or treating the composition of the disease as caused by caffeinism using evodia extract or rutaecarpin |
| CN109970536A (en) * | 2019-04-22 | 2019-07-05 | 温州市人民医院 | A kind of extracting method of rhizoma zingiberis effective component |
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| CN102091314B (en) | 2012-05-23 |
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