CN102526667B - Loquat leaf/ginger composition for reducing vomiting due to cancer chemotherapy and enhancing effect of cancer chemotherapy, and preparation method thereof - Google Patents
Loquat leaf/ginger composition for reducing vomiting due to cancer chemotherapy and enhancing effect of cancer chemotherapy, and preparation method thereof Download PDFInfo
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- CN102526667B CN102526667B CN 201210014642 CN201210014642A CN102526667B CN 102526667 B CN102526667 B CN 102526667B CN 201210014642 CN201210014642 CN 201210014642 CN 201210014642 A CN201210014642 A CN 201210014642A CN 102526667 B CN102526667 B CN 102526667B
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Abstract
The invention relates to a natural drug composition, a preparation method thereof and use for preparation of drugs for reducing toxicity and enhancing the effect of cancer chemotherapy. The natural drug composition comprises a concentrated water extract of loquat leaf and ginger, gingerol, an ethanol extract of loquat leaf and ursolic acid, at a ratio of (3-8):(1-5):(3-9):(1-3). The composition can significantly relieve vomiting due to cancer chemotherapy as well as inhibit tumor growth.
Description
Technical field
The present invention relates to a kind of natural drug composition, relate more specifically to a kind of natural drug composition of being made up of Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid, the preparation method of this natural drug composition and this natural drug composition reduce vomiting side effect that cancer chemotherapy causes and the purposes that the treatment cancer is played the medicine of potentiation being used for preparing.
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, and wherein 2/3 patient accepts chemotherapy, though certain curative effect is arranged, side effect in various degree 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 that these medicines are vomitted after to chemotherapy, and toxic and side effects is strong, is very limited in the application.Novel Bendectin is as NK
1Receptor antagonist and 5-HT
3Receptor antagonist class medicine, though good to vomiting antiemetic effect after the chemotherapy, cost an arm and a leg, the scope of application is narrow, and toxicity is big, clinical many need drug combinations, and do not see the anticancer synergia effect, the development of the natural anti-cancer attenuation synergistic medicine that therefore waits in expectation.
Chinese medicine attracts people's attention for the research of cancer chemotherapy attenuation synergistic.Still unmatchful anticancer disease chemotherapy has the Chinese patent medicine that alleviates vomiting side effect and potentiation at present.Therefore, research and develop a kind of high-efficiency low-toxicity, cheap, the natural Chinese medicine that can be used for alleviating cancer chemotherapy vomiting side effect and playing the efficacy enhancing and toxicity reducing effect that is easy to promote becomes 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.Folium Eriobotryae is the dried leaves of the evergreen dungarunga plant of Rosaceae Folium Eriobotryae Eriobotrya japonica (Thunb) Lindl.Compendium of Material Medica is said: " stomach function regulating sending down the abnormal ascending QI, clearing away summer-heat poison." have the effect of nourishing the lung to arrest cough, stopping nausea and vomiting by lowering the adverse flow of QI, be usually used in controlling the cough due to lung-heat, disease such as vomit that gastric heat is contrary.In recent years, Folium Eriobotryae and Rhizoma Zingiberis Recens antitumaous effect are confirmed, especially the ursolic acid in Rhizoma Zingiberis Recens piquancy component and the Folium Eriobotryae.Studies show that the ursolic acid in the Folium Eriobotryae has resistant function to multiple carcinogenic, short cancer thing, and multiple malignant cell there are obvious cytotoxicity and induction of differentiation and anti-angiogenic formation effect, its anti-cancer and kill cancer action draws attention, is expected to become the effective new antitumor drug of low toxicity.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 its side effect such as vomiting that cancer chemotherapy is caused has fabulous curative effect 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, can resist side effect such as vomiting grade after the chemotherapy again.
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 the purposes of above-mentioned natural drug composition in preparing the medicine that reduces the cancer chemotherapy side effect and the treatment cancer is played the efficacy enhancing and toxicity reducing effect.
A kind of natural drug composition provided by the invention, by Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid by weight in 3-8: the ratio of 1-5: 3-9: 1-3 is formed.
Above-mentioned natural drug composition, wherein the usage ratio of Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid is 8: 5: 9: 3.
Wherein, Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid can be by well known to a person skilled in the art the conventional method acquisition of purifying, gingerol 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 of Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract is in the above-mentioned natural drug composition:
According to proportion compatibility is 1: 1 or 1-10: 1 other ratios are got Folium Eriobotryae, Rhizoma Zingiberis Recens, add 10 times of amount distilled water, soak 1h, heating decocted 20 minutes 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 lyophilization gets dry extract, pulverizes, sieve, promptly.
The preparation method of gingerol is in the above-mentioned natural drug composition:
Rhizoma Zingiberis Recens 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, soaks 72h down with 6 times of amount acetone room temperature; 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.
Folium Eriobotryae ethanol extraction preparation method is in the above-mentioned natural drug composition:
Exsiccant Folium Eriobotryae is pulverized, crossed the 20-40 mesh sieve, add 12 times of amount dehydrated alcohol, use apparatus,Soxhlet's reflux, extract, 3 times down for 90 ℃, each 10 hours, merge solvent and reclaim under reduced pressure and get extractum, drying is pulverized, and sieves, promptly.
The ursolic acid preparation method is in the above-mentioned natural drug composition:
With above-mentioned gained extractum respectively with petroleum ether, 1% sodium hydroxide solution with to be washed to eluate colourless, reuse dehydrated alcohol heating for dissolving, add active carbon reflux decolour 15min, filter. with hot ethanol cyclic washing residue, put coldly, leave standstill, the white plates crystallization, use recrystallization from hot methanol, promptly get ursolic acid.
The present invention also provides the preferred manufacturing procedure of this natural drug composition, comprising:
(1) preparation of Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract
According to proportion compatibility is 1: 1 or 1-10: 1 other ratios are got Folium Eriobotryae, Rhizoma Zingiberis Recens, add 10 times of amount distilled water, soak 1h, heating decocted 20 minutes 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 lyophilization gets dry extract, pulverizes, sieve, promptly.
(2) preparation of gingerol
Rhizoma Zingiberis Recens 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, soaks 72h down with 6 times of amount acetone room temperature; 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) Folium Eriobotryae ethanol extraction preparation
Exsiccant Folium Eriobotryae is pulverized, crossed the 20-40 mesh sieve, add 12 times of amount dehydrated alcohol, use apparatus,Soxhlet's reflux, extract, 3 times down for 90 ℃, each 10 hours, merge solvent and reclaim under reduced pressure and get extractum, drying is pulverized, and sieves, promptly.
(4) ursolic acid preparation
With above-mentioned gained extractum respectively with petroleum ether, 1% sodium hydroxide solution with to be washed to eluate colourless, reuse dehydrated alcohol heating for dissolving, add active carbon reflux decolour 15min, filter. with hot ethanol cyclic washing residue, put coldly, leave standstill, the white plates crystallization, use recrystallization from hot methanol, promptly get ursolic acid.
(5) choose Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid in proportion, 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 that also natural drug composition reduces the cancer chemotherapy side effect and the treatment cancer played purposes in the medicine of potentiation in preparation, and reduces purposes in vomiting reaction that cancer chemotherapy causes and the medicine that the treatment cancer is played potentiation in preparation.
The instructions of taking of natural drug composition of the present invention: available capsule of vomiting or tablet behind the treatment cancer chemotherapy, 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 Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction.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 makes up Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid originally, 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 3-8: 1-5: 3-9: produced unexpected synergism during 1-3, potentiation is obvious, extraordinary effect is played in side effect, especially the usage ratio in each component is 8: 5: 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 Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and each component of ursolic acid all can obtain by conventional means, some of them component for example gingerol also can be buied by commerce, such compositions itself has the convenience of acquisition, lower-cost effect, and 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
The first step: the preparation of various extracts
(1) preparation of Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract
According to proportion compatibility is 1: 1 or 1-10: 1 other ratios are got Folium Eriobotryae, Rhizoma Zingiberis Recens, add 10 times of amount distilled water, soak 1h, heating decocted 20 minutes 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 lyophilization gets dry extract, pulverizes, sieve, promptly.
(2) preparation of gingerol
Rhizoma Zingiberis Recens 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, soaks 72h down with 6 times of amount acetone room temperature; 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) Folium Eriobotryae ethanol extraction preparation
Exsiccant Folium Eriobotryae is pulverized, crossed the 20-40 mesh sieve, add 12 times of amount dehydrated alcohol, use apparatus,Soxhlet's reflux, extract, 3 times down for 90 ℃, each 10 hours, merge solvent and reclaim under reduced pressure and get extractum, drying is pulverized, and sieves, promptly.
(4) ursolic acid preparation
With above-mentioned gained extractum respectively with petroleum ether, 1% sodium hydroxide solution with to be washed to eluate colourless, reuse dehydrated alcohol heating for dissolving, add active carbon reflux decolour 15min, filter. with hot ethanol cyclic washing residue, put coldly, leave standstill, the white plates crystallization, use recrystallization from hot methanol, promptly get ursolic acid.
Second step: the preparation of preparation
(1) preparation of natural drug composition capsule preparations of the present invention
Take by weighing Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract 32mg, gingerol 20mg, Folium Eriobotryae ethanol extraction 36mg and the ursolic acid 12mg of above-mentioned steps preparation respectively, take by weighing starch 395mg, 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
Take by weighing Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract 32mg, gingerol 20mg, Folium Eriobotryae ethanol extraction 36mg and the ursolic acid 12mg of above-mentioned steps preparation respectively, take by weighing starch 295mg, 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 of Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid is 8: 5: 9: 3.The inventor to above-mentioned each composition usage ratio at 3-8: 1-5: 3-9: the compositions that the multiple proportioning combination in the time of between the 1-3 obtains has been carried out and last identical experiment, find that all the natural drug composition in this amount ranges can obtain good synergism, can play good effect and treatment for cancer is had potentiation the cancer chemotherapy side effect.And, the inventor finds that Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid can also be the compositions that obtains with conventional means, 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) Folium Eriobotryae is bought by the big pharmacy of Beijing Tongrentang, and Rhizoma Zingiberis Recens is purchased Yushan Hill degree of conquering east, and is accredited as the tuber of rosaceous plant Folium Eriobotryae dried leaves and zingiber by the director of studio of this institute.
(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 Folium Eriobotryae ethanol extraction group, the C group is gingerol and Folium Eriobotryae ethanol extraction compatibility group (ratio is 5: 9), and the D group is Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, and (Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid were by 8: 5: 9: 3 mixed) for natural drug composition of the present invention for the E group, 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 Folium Eriobotryae ethanol extraction 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 Folium Eriobotryae ethanol extraction 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 Folium Eriobotryae Rhizoma Zingiberis Recens decocting 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＜0.01).Each treatment group all can reduce the rate of vomitting that causes, and it is identical with the ondansetron group that Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract group causes the rate of vomitting; 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, compare with matched group,
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 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
Table 3 capsule is to H
22The tumor inhibition effect of mice (
N=12)
Compare with negative control group,
cP＜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 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 oncocyte with an amount of physiological saline solution and entreats liquid, 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.(as table 5,6,7)
Table 5 capsule is to S
180The tumor inhibition effect of mice (
N=12)
Compare with negative control group,
bP＜0.05,
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,
bP＜0.05,
cP＜0.01
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 (5)
1. natural drug composition that reduces the vomiting reaction that cancer chemotherapy causes and the treatment cancer is played potentiation, it is characterized in that said composition by Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid by weight in 3-8: the ratio of 1-5: 3-9: 1-3 is formed
Wherein the preparation method of Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract is:
According to proportion compatibility is 1-10: 1 gets Folium Eriobotryae, Rhizoma Zingiberis Recens, adds 10 times of amount distilled water, soaks 1h, heating decocted 20 minutes 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 lyophilization gets dry extract, pulverizes, sieve, promptly;
Wherein the preparation method of gingerol is:
Rhizoma Zingiberis Recens 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, soaks 72h down with 6 times of amount acetone room temperature; 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;
Wherein the preparation method of Folium Eriobotryae ethanol extraction is:
Exsiccant Folium Eriobotryae is pulverized, crossed the 20-40 mesh sieve, add 12 times of amount dehydrated alcohol, use apparatus,Soxhlet's reflux, extract, 3 times down for 90 ℃, each 10 hours, merge solvent and reclaim under reduced pressure and get extractum, drying is pulverized, and sieves, promptly;
Wherein preparation method of ursolic acid is:
With the above-mentioned Folium Eriobotryae ethanol extraction that makes respectively with petroleum ether, 1% sodium hydroxide solution with to be washed to eluate colourless, reuse dehydrated alcohol heating for dissolving, add active carbon reflux decolour 15min, filter,, put cold with hot ethanol cyclic washing residue, leave standstill, get the white plates crystallization, use recrystallization from hot methanol, promptly get ursolic acid.
2. natural drug composition as claimed in claim 1 is characterized in that wherein the usage ratio of Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid is 8: 5: 9: 3.
3. as the preparation method of the natural drug composition of claim 1 or 2, it is characterized in that this method comprises:
(1) preparation of Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract
According to proportion compatibility is 1-10: 1 gets Folium Eriobotryae, Rhizoma Zingiberis Recens, adds 10 times of amount distilled water, soaks 1h, heating decocted 20 minutes 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 lyophilization gets dry extract, pulverizes, sieve, promptly;
(2) preparation of gingerol
Rhizoma Zingiberis Recens 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, soaks 72h down with 6 times of amount acetone room temperature; 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) Folium Eriobotryae ethanol extraction preparation
Exsiccant Folium Eriobotryae is pulverized, crossed the 20-40 mesh sieve, add 12 times of amount dehydrated alcohol, use apparatus,Soxhlet's reflux, extract, 3 times down for 90 ℃, each 10 hours, merge solvent and reclaim under reduced pressure and get extractum, drying is pulverized, and sieves, promptly;
(4) ursolic acid preparation
The Folium Eriobotryae ethanol extraction that step (3) is made is respectively with petroleum ether, 1% sodium hydroxide solution with to be washed to eluate colourless, reuse dehydrated alcohol heating for dissolving, add active carbon reflux decolour 15min, filter,, put cold with hot ethanol cyclic washing residue, leave standstill, get the white plates crystallization, use recrystallization from hot methanol, promptly get ursolic acid;
(5) choose Folium Eriobotryae Rhizoma Zingiberis Recens decocting concentrated extract, gingerol, Folium Eriobotryae ethanol extraction and ursolic acid uniform mixing in proportion, promptly.
4. the preparation method of natural drug composition as claimed in claim 3, it is characterized in that also comprising: 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.
5. reduce purposes in vomiting reaction that cancer chemotherapy causes and the medicine that the treatment cancer is played potentiation as each described natural drug composition of claim 1-2 in preparation.
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| CN201110079464.2 | 2011-03-31 | ||
| CN 201210014642 CN102526667B (en) | 2011-03-31 | 2012-01-10 | Loquat leaf/ginger composition for reducing vomiting due to cancer chemotherapy and enhancing effect of cancer chemotherapy, and preparation method thereof |
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| CN104688748A (en) * | 2015-03-06 | 2015-06-10 | 福州大学 | Pharmaceutical composition containing ursolic acid and cyclophosphamide |
| CN106139047A (en) * | 2015-03-18 | 2016-11-23 | 陈文星 | A kind of alleviate chemicotherapy vomiting reaction and the collaborative Chinese medicine composition pressing down cancer |
| CN108484378A (en) * | 2018-03-26 | 2018-09-04 | 常德金德新材料科技股份有限公司 | The extracting method of gingerol in a kind of ginger |
| CN114796296A (en) * | 2022-05-17 | 2022-07-29 | 湖南中嘉生物医药有限公司 | Radix cynanchi bungei extract and application thereof |
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| JP2008307012A (en) * | 2007-06-18 | 2008-12-25 | Npo Japan Association Of Melinjo Indonesia | Melinjo healthy tea |
| CN101954022A (en) * | 2010-10-15 | 2011-01-26 | 林万硕 | Chinese medicinal composition for treating lung cancer |
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| JP2008307012A (en) * | 2007-06-18 | 2008-12-25 | Npo Japan Association Of Melinjo Indonesia | Melinjo healthy tea |
| CN101954022A (en) * | 2010-10-15 | 2011-01-26 | 林万硕 | Chinese medicinal composition for treating lung cancer |
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