CN103405721A - Pharmaceutical composition for inhibiting tumor metastasis and application thereof - Google Patents
Pharmaceutical composition for inhibiting tumor metastasis and application thereof Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition for inhibiting tumor metastasis and an application thereof. The pharmaceutical composition comprises the following Chinese medicinal raw materials in parts by weight: 1-4 parts of radix euphorbiae lantu, 40-52 parts of Oldenlandia diffusa, 40-52 parts of felwort, 20-30 parts of curcuma zedoary, 20-30 parts of burdock, 12-20 parts of herba epimedii, 12-20 parts of Poria cocos and 12-20 parts of loranthus parasiticus. The pharmaceutical composition disclosed by the invention has a remarkable effect for inhibiting tumor metastasis.
Description
Technical field
The invention belongs to the Chinese medicine technical field, be specifically related to a kind of pharmaceutical composition and application thereof of anti metastasis.
Background technology
According to World Health Organization (WHO) (WHO) statistics, the eighties in 20th century, the annual new cancered patient in the whole world approximately 7,000,000, died from approximately 5,000,000 people of cancer person every year.At the beginning of the fifties, China's cancer mortality accounts for the 9th or the 10th of whole causes of the death, and the seventies, China's cancer mortality leapt to the 3rd.Statistics in 1991, some big and medium-sized cities residents' of China cancer mortality have occupied the 1st of whole causes of the death.The annual new cancer stricken of China approximately 1,600,000 people, die from approximately 1,300,000 people of cancer person.Above-mentioned data shows: the cancer morbidity of the whole world and China is obviously increasing year by year.In addition, when China's cancer patient was medical, end-stage patients still occupied the majority, and had the operation of having lost and waited radical cure chance, the poor characteristics of therapeutic effect.Numerous medical personnels strengthen the research of oncotherapy, grasp and improve the therapeutic effect of existing various treatment meanss, to reducing cancer mortality, reduce relapse rate, and the quality of life of improving cancer patient is significant.By the level of present China cancer mortality, the whole nation just had 2 people to die from cancer in every 1 minute, will have every day people more than 2 800 to be seized life by cancer, will be equivalent to one and have the city of a population of one million to be destroyed in 1 year.Visible, cancer is commonly encountered diseases, frequently-occurring disease, to people's life and health person of having serious threat, is also huge on the impact of the development of the national economy.In the U.S., 83,000,000,000 dollars of annual treatment of cancer expenses, account for 14% of national medical expense.Almost everyone experiences the threat of cancer.Because whole world every year up to 6,300,000 people, and China every year has reached 1,300,000 people because of the number of cancer mortality because of the number of cancer mortality, and cancer patient every year with 3% speed increase, being equivalent to just has 1 family to be subject to the threat of cancer in every 200 families.
Chemotherapy is an important means for the treatment of at present cancer, and, in kill cancer cell, also there is toxicity in chemotherapeutics to organism normal cell.In recent years, along with continuing to bring out of PTS, the rational Application of Combination chemotherapy, the curative effect of chemotherapy is enhanced, but these medicines normal tissue organ simultaneously have infringement or toxic action, thereby reduce body's immunity, a series of toxicities such as bone marrow depression occur, affect the curative effect of chemotherapy, even force chemotherapy to stop.Clinical research shows, when chemotherapy according to the toxicity symptom of patient's body constitution, cancer staging and appearance, be aided with treatment by Chinese herbs, can effectively strengthen the effect of chemotherapy, can avoid to a certain extent or alleviate the toxicity of chemicotherapy again, extend patient's life cycle and improve patient's life quality.And Chinese medicine is as the advantageous resource of China, some medicine has obvious antitumor action, therefore from the traditional natural drug of China, screening high-efficiency low-toxicity, antitumor drug tool that targeting is strong is of great significance.
Summary of the invention
The present invention is according to Traditional Chinese medical theory, through a large amount of screenings to drug component, restructuring, trial, by a large amount of animal experiment studies, make again.Therefore, the object of the invention is to, by prescription again after the conventional medicament pharmacology is studied, provide a kind of pharmaceutical composition of anti metastasis.
The object of the present invention is achieved like this:
A kind of pharmaceutical composition of anti metastasis is prepared from by the traditional Chinese medicinal material raw materials that comprises following weight portion: Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae) 1-4 part, Herba Hedyotidis Diffusae 40-52 part, Radix Gentianae 40-52 part, Rhizoma Curcumae 20-30 part, Fructus Arctii 20-30 part, Herba Epimedii 12-20 part, Poria 12-20 part, Herba Taxilli 12-20 part.
Preferably, the pharmaceutical composition of above-mentioned anti metastasis is prepared from by the traditional Chinese medicinal material raw materials of following weight portion: Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae) 2-3 part, Herba Hedyotidis Diffusae 45-50 part, Radix Gentianae 45-50 part, Rhizoma Curcumae 23-27 part, Fructus Arctii 23-27 part, Herba Epimedii 15-18 part, Poria 15-18 part, Herba Taxilli 15-18 part.
The pharmaceutical composition of further preferably, above-mentioned anti metastasis is prepared from by the traditional Chinese medicinal material raw materials of following weight portion: 2 parts of the Radixs Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae), 48 parts of Herba Hedyotidis Diffusaes, 48 parts of Radix Gentianaes, 25 parts of Rhizoma Curcumae, 25 parts of Fructus Arctiis, 16 parts of Herba Epimedii, 16 parts, Poria, 16 parts of Herba Taxillis.
The pharmaceutical composition of further preferably, above-mentioned anti metastasis is oral formulations.Again further preferably, described oral formulations is tablet, capsule, granule, oral liquid.
By experimental study, find, the pharmaceutical composition anti metastasis formed by the Chinese crude drug of said ratio evident in efficacy.Therefore, second purpose of the present invention is to provide a kind of new medical use, i.e. the application of above-mentioned compositions in the medicine of preparation anti metastasis.The preferably application of above-mentioned compositions in the medicine for preparing the melanoma transfer.
The preparation method of the Chinese medicine oral liquid the present invention relates to comprises the steps:
(1) get Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae) 1-4 part, Herba Hedyotidis Diffusae 40-52 part, Radix Gentianae 40-52 part, Rhizoma Curcumae 20-30 part, Fructus Arctii 20-30 part, Herba Epimedii 12-20 part, Poria 12-20 part and Herba Taxilli 12-20 part of recipe quantity, clean roguing, dry, pulverize;
(2) more above-mentioned graininess medical material is added to water and cover powder 2cm, soak 1-1.2h, pull medical material out and put multi-functional extraction and decoct with water secondary in filling with, add up for the first time the water that medical material 8-10 doubly measures, decoct 2h, get decocting liquid, filter, add up for the second time the water that medical material 6-8 doubly measures, decoct 1h, get twice decocting liquid and merge, filter, while being concentrated into 90 ℃, relative density is the concentrated solution of 1.15g/mL;
(3) concentrated solution is set to 0 to-5 ℃ of deepfreeze 24h, cold preservation liquid is added to 0.3% filter aid kieselguhr, filter, the filtrate reconcentration contains 5-6g crude drug amount to every milliliter, set to 0-5 ℃ of deepfreeze 24h, cold preservation liquid filtered, add or do not add correctives after pack and obtain oral liquid.
According to the Chinese medicine Historical Data Data About, the pharmacologically active of the traditional Chinese medicinal material raw materials that the present invention adopts and source are as follows:
The Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae): the effect with removing fluid-retention by purgation, removing mass parasite killing.Edema abdominal distention; The expectorant carnivorism is long-pending; Trusted subordinate's pain; Lump in the abdomen; Tuberculosis; Scabies.Select Isolated From Thymelaeaceae Species Stellera chamaejasme L. Stellera chamaejasmeL.[Passerina chamaejasmeFisch.] root.
Herba Hedyotidis Diffusae: latin name Herba Hedyotis Diffusae has the effect of heat-clearing and toxic substances removing, dampness removing; Cure mainly: dyspnea and cough due to lung-heat; Laryngopharynx swelling and pain; The intestinal carbuncle; The furuncle and phyma skin infection; Venom; The puckery pain of pyretic stranguria; Edema; Dysentery; The intestinal inflammation; Jaundice due to damp-heat; Cancerous protuberance.Be selected from the dry herb of Maguireothamnus speciosus Herba Hedyotidis Diffusae Hedyotis diffusa Willd..
Radix Gentianae: heat clearing and damp drying; The eliminating pathogen in the liver arresting convulsion.Jaundice due to damp-heat; The urine leaching pain; Swelling of the vulva pudendal pruritus; Damp-heat vaginal discharge; The feeling of fullness in the head headache of liver and gall excess-fire; Conjunctival congestion and swelling pain; Deaf ear is swollen; The hypochondriac pain bitter taste; The calentura convulsion with spasms.Derive from root and the rhizome of gentianaceae plant Radix Gentianae (Gentiana scabra Bge.).
Rhizoma Curcumae: circulation of qi promoting removing blood stasis, removing food stagnancy pain relieving.For Dan abdominal mass mass in the abdomen, blood stasis amenorrhea, food stagnation distending pain; Early cervical carcinoma.Select the rhizome of zingiberaceous plant osmanthus Rhizoma Curcumae Curcuam kwangsiensis S.G.Leset C.F.Liang.
Fructus Arctii: have the effect of dispelling wind and heat pathogens, lung qi dispersing rash, sore-throat relieving eliminating stagnation, removing toxic substances and promoting subsidence of swelling, cure mainly cough due to pathogenic wind-heat, laryngopharynx swelling and pain, macule not thoroughly, rubella pruritus, sore swollen toxin.Be selected from the dry mature fruit of feverfew Fructus Arctii Arctium lappa L..
Herba Epimedii: kidney-replenishing, bone and muscle strengthening, wind-damp dispelling.For impotence and seminal emission, the muscles and bones flaccidity is soft, rheumatic arthralgia, numbness contracture; Climacteric hypertension.Select the dried leaves of Berberidaceae plant Herba Epimedii (Epimedium brevicornum Maxim.).
Poria: have diuretic, the effect of eliminating dampness by diuresis diuresis.Cure mainly dysuria; The edema distension; The phlegm retention cough with dyspnea; Vomiting; Insufficiency of the spleen lack of appetite; Have loose bowels; Palpitation and restlessness; Insomnia forgetfulness; The seminal emission nebulousurine.Select the dry sclerotia of On Polyporaceae Poria Poria cocos (Schw.) Wolf.
Herba Taxilli: invigorating the liver and kidney; Bone and muscle strengthening; Wind-damp dispelling; Antiabortive.Main soreness of waist and knee joint; A little less than the muscles and bones flaccidity; Limbs are hemiplegia; Rheumatic arthralgia; Head is wrong dizzy; Frequent fetal movement, metrostaxis.For rheumatic arthralgia, soreness of the waist and knees, muscles and bones is unable, and the metrorrhagia warp is many, blood leaking in gestation, frequent fetal movement; Hypertension.Select the dry stem and branch with leaf of Loranthaceae plant Herba Taxilli Taxillus chinensis (DC.) Danser.
The inventor shows by experimental study, and pharmaceutical composition anti metastasis determined curative effect of the present invention, can obviously suppress the growth of B16 cell in the C57BL/6 Mice Body after the gavage model mice.It has blood vessel dilating, increases the effect of wall of micrangium permeability and tissue fluid generation, does not increase the probability of tumor cell blood and/or lymph metastasis.On the contrary, pharmaceutical composition of the present invention obviously reduces its blood and lymph metastasis probability.Pharmaceutical composition anti metastasis effect of the present invention is remarkable, and without toxicity.
The specific embodiment
Be below specific embodiments of the invention, technical scheme of the present invention is done to further the description, but protection scope of the present invention is not limited to these embodiment.Every do not deviate from the change of the present invention design or be equal to substitute include within protection scope of the present invention.
Embodiment 1
Crude drug prescription: 2 kilograms of the Radixs Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae), 48 kilograms of Herba Hedyotidis Diffusaes, 48 kilograms of Radix Gentianaes, 25 kilograms of Rhizoma Curcumae, 25 kilograms of Fructus Arctiis, 16 kilograms of Herba Epimedii, 16 kilograms, Poria, 16 kilograms of Herba Taxillis.
Preparation method:
(1) get the Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae), Herba Hedyotidis Diffusae, Radix Gentianae, Rhizoma Curcumae, Fructus Arctii, Herba Epimedii, Poria and the Herba Taxilli of recipe quantity, clean roguing, dry, pulverize;
(2) more above-mentioned graininess medical material is added to water and cover powder 2cm, soak 1-1.2h, pull medical material out and put multi-functional extraction and decoct with water secondary in filling with, add up for the first time the water of 10 times of amounts of medical material, decoct 2h, get decocting liquid, filter, add up for the second time the water of 8 times of amounts of medical material, decoct 1h, get twice decocting liquid and merge, filter, while being concentrated into 90 ℃, relative density is the concentrated solution of 1.15g/mL;
(3) concentrated solution is set to 0 to-5 ℃ of deepfreeze 24h, cold preservation liquid is added to 0.3% filter aid kieselguhr, filter, the filtrate reconcentration contains 6g crude drug amount to every milliliter, sets to 0-5 ℃ of deepfreeze 24h, and cold preservation liquid is filtered, and packs and obtain oral liquid.
Embodiment 2
Crude drug prescription: 3 kilograms of the Radixs Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae), 40 kilograms of Herba Hedyotidis Diffusaes, 42 kilograms of Radix Gentianaes, 21 kilograms of Rhizoma Curcumae, 30 kilograms of Fructus Arctiis, 12 kilograms of Herba Epimedii, 20 kilograms, Poria, 20 kilograms of Herba Taxillis.
Preparation method:
(1) get the Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae), Herba Hedyotidis Diffusae, Radix Gentianae, Rhizoma Curcumae, Fructus Arctii, Herba Epimedii, Poria and the Herba Taxilli of recipe quantity, clean roguing, dry, pulverize;
(2) more above-mentioned graininess medical material is added to water and cover powder 2cm, soak 1-1.2h, pull medical material out and put multi-functional extraction and decoct with water secondary in filling with, add up for the first time the water of 8 times of amounts of medical material, decoct 2h, get decocting liquid, filter, add up for the second time the water of 8 times of amounts of medical material, decoct 1h, get twice decocting liquid and merge, filter, while being concentrated into 90 ℃, relative density is the concentrated solution of 1.15g/mL;
(3) concentrated solution is set to 0 to-5 ℃ of deepfreeze 24h, cold preservation liquid is added to 0.3% filter aid kieselguhr, filter, the filtrate reconcentration contains 5g crude drug amount to every milliliter, sets to 0-5 ℃ of deepfreeze 24h, and cold preservation liquid is filtered, and packs and obtain oral liquid.
Embodiment 3
Crude drug prescription: 1 kilogram of the Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae), 52 kilograms of Herba Hedyotidis Diffusaes, 45 kilograms of Radix Gentianaes, 30 kilograms of Rhizoma Curcumae, 22 kilograms of Fructus Arctiis, 20 kilograms of Herba Epimedii, 12 kilograms, Poria, 16 kilograms of Herba Taxillis.
Preparation method:
(1) get the Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae), Herba Hedyotidis Diffusae, Radix Gentianae, Rhizoma Curcumae, Fructus Arctii, Herba Epimedii, Poria and the Herba Taxilli of recipe quantity, clean roguing, dry, pulverize;
(2) more above-mentioned graininess medical material is added to water and cover powder 2cm, soak 1-1.2h, pull medical material out and put multi-functional extraction and decoct with water secondary in filling with, add up for the first time the water of 8 times of amounts of medical material, decoct 2h, get decocting liquid, filter, add up for the second time the water of 6 times of amounts of medical material, decoct 1h, get twice decocting liquid and merge, filter, while being concentrated into 90 ℃, relative density is the concentrated solution of 1.15g/mL;
(3) concentrated solution is set to 0 to-5 ℃ of deepfreeze 24h, cold preservation liquid is added to 0.3% filter aid kieselguhr, filter, the filtrate reconcentration contains 6g crude drug amount to every milliliter, sets to 0-5 ℃ of deepfreeze 24h, and cold preservation liquid is filtered, and packs and obtain oral liquid.
Embodiment 4, the Chinese medicine impact on spontaneous B16F10 melanoma metastasis mouse model
Cellar culture B16F10 melanoma cell, 4-5 days before experiment, press the 1:10 passage in Tissue Culture Flask, in order to avoid Growth of Cells excessively occurs not exclusively merging.Each culture bottle approximately contains 6-8 * 10
6Cell, the cell of the trophophase of taking the logarithm, discard culture fluid, cleans with PBS, adds 1mL 0.25% pancreatin+0.02% EDTA Digestive system, puts into cell culture incubator, after 1-3 min, raps culture bottle and make cell detachment.Add 10mL DMEM, blow and beat cell with pipet, obtain single cell suspension, proceed to the 50mL polypropylene centrifuge tube.Centrifuge cell (1200 rpm * 10min), then wash twice with PBS.With tongue, expect blue counting cells, adjusting cell concentration is 1 * 10
7/ mL, standby.
A clean level C57BL/6 mice is (female, 5-6 age in week, 16-20g), subcutaneous in mice left upper extremity armpit with every 200 μ l dose inoculations.The 6th day large young pathbreaker mice according to the upper primary tumor of left foot pad is divided into following two groups at random after inoculation:
Model control group (12): the purified water of gavage 150mL/kg Mouse Weight;
The Chinese medicine oral liquid of Chinese drug-treated group (12): gavage embodiment 1 preparation, dosage is the 100mL/kg Mouse Weight;
After the last administration the 2nd day, draw materials while namely inoculating the 20th day.Before two groups of each administrations of mice and the front major diameter (L) of vernier caliper measurement tumor and minor axis (W), the by formula L * W of all using that finally draw materials
2* 0.52 calculates gross tumor volume (V), and by (Vn-Vn-
1)/Vn-
1Calculate the tumor growth index, n is for measuring number of times.
Complete excision tumor while drawing materials, weigh after filter paper blots; Get liver, spleen, lung, cerebral tissue and draining lymph node at different levels, routine prepares paraffin section, and the impact of medicine on tumor cell blood and lymph metastasis observed in HE dyeing.Take liver, spleen, lung, brain occurs that metastasis is the hematogenous metastasis positive, in regional nodes, occurs that non-spreading property metastasis is the lymph metastasis positive.
After off-test, can find out by statistical results, gavage Chinese medicine can obviously suppress the growth of B16 cell in the C57BL/6 Mice Body.Chinese drug-treated group and matched group tumor heavily are respectively (5.01 ± 1.16) g and (7.27 ± 1.43) g, and the two difference has statistical significance (P<0.01).From the tumor growth index, its inhibitory action is more obvious at the experiment initial stage, and along with tumor is constantly grown, inhibition strength gradually weakens, and two groups of tumor volume difference are day by day obvious.
In addition, in 12 tumor-bearing mices of matched group, 10 find that there is lymphatic metastasis, the rate of transform 83.3%.Wherein 1 tumor body is larger, covers with whole axillary fossa, can't differentiate lymph node, but the offside axillary fossa has a positive lymph nodes, and all the other individualities have respectively 1～4 lymph node positive.Chinese drug-treated group has 4 examples that lymphatic metastasis, the rate of transform 33.3%, 1～3 of the number of metastatic lymph node occur.The tumor cell of invading lymph node is not gathered into cancer nests, and rapid differentiation and maturation, synthetic a large amount of melanin granule, and synthetic melanic juvenile cell seldom is shown in.And, in the tumor body, but often have large stretch of juvenile cell to exist.
Secondly, 12 mices of matched group are showed no liver, vertigo moves; Lung shifts 3 examples, the rate of transform 25.0%, and metastasis is minimum, is no more than a high power field.Spleen shifts 9 examples (comprising that above-mentioned 3 routine lungs shift), the rate of transform 75.0%, and the wherein visible spleen dorsal part of 4 routine naked eyes section blackening, and form has no obvious change.Under mirror, the distribution of metastasis is without evident regularity, and like in the majority along spleen trabeculae distribution person, and cell volume is larger, and the oncocyte volume be deep in excess syndrome’of the spleen matter is little, and Maturity is high.Under splenic capsule, shift not obvious, may be relevant with its compact structure.From the number of cases of transfer and looking down upon greatly of metastasis, the generation that spleen shifts is shifted and is occurred prior to lung.Chinese drug-treated group only finds that under 3 routine mirrors, visible spleen shifts, and the rate of transform 25.0% does not find that obvious lung shifts.Chinese drug-treated group is compared with matched group, and hematogenous metastasis and lymph metastasis rate all obviously reduce (P<0.05).
Claims (8)
1. the pharmaceutical composition of an anti metastasis, it is characterized in that: described compositions is prepared from by the traditional Chinese medicinal material raw materials that comprises following weight portion: Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae) 1-4 part, Herba Hedyotidis Diffusae 40-52 part, Radix Gentianae 40-52 part, Rhizoma Curcumae 20-30 part, Fructus Arctii 20-30 part, Herba Epimedii 12-20 part, Poria 12-20 part, Herba Taxilli 12-20 part.
2. the pharmaceutical composition of anti metastasis according to claim 1, it is characterized in that: described compositions is prepared from by the traditional Chinese medicinal material raw materials of following weight portion: Radix Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae) 2-3 part, Herba Hedyotidis Diffusae 45-50 part, Radix Gentianae 45-50 part, Rhizoma Curcumae 23-27 part, Fructus Arctii 23-27 part, Herba Epimedii 15-18 part, Poria 15-18 part, Herba Taxilli 15-18 part.
3. the pharmaceutical composition of anti metastasis according to claim 2, it is characterized in that: described compositions is prepared from by the traditional Chinese medicinal material raw materials of following weight portion: 2 parts of the Radixs Euphorbiae Fischerianae (Radix Euphorbiae Ebracteolatae), 48 parts of Herba Hedyotidis Diffusaes, 48 parts of Radix Gentianaes, 25 parts of Rhizoma Curcumae, 25 parts of Fructus Arctiis, 16 parts of Herba Epimedii, 16 parts, Poria, 16 parts of Herba Taxillis.
4. according to the pharmaceutical composition of claim 1 or 2 or 3 described anti metastasis, it is characterized in that: described compositions is oral formulations.
5. the pharmaceutical composition of anti metastasis according to claim 4, it is characterized in that: described oral formulations is tablet, capsule, granule, oral liquid.
6. according to the pharmaceutical composition of claim 1 or 2 or 3 described anti metastasis, it is characterized in that: described tumor is melanoma.
7. claim 1 or the 2 or 3 described compositionss application in the medicine of preparation anti metastasis.
8. claim 1 or the 2 or 3 described compositionss application in the medicine for preparing the melanoma transfer.
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