CN1961894B - A novel compound pharmaceutical composition, preparation method and use thereof - Google Patents
A novel compound pharmaceutical composition, preparation method and use thereof Download PDFInfo
- Publication number
- CN1961894B CN1961894B CN2005100450678A CN200510045067A CN1961894B CN 1961894 B CN1961894 B CN 1961894B CN 2005100450678 A CN2005100450678 A CN 2005100450678A CN 200510045067 A CN200510045067 A CN 200510045067A CN 1961894 B CN1961894 B CN 1961894B
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- Prior art keywords
- cordyceps mycelium
- injection
- kurarinone
- radix astragali
- extract
- Prior art date
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Landscapes
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Abstract
The invention relates to a method for preparing new compound drug, wherein it mainly comprises Cordyceps sinensis mycelium at 50-2000 deals or its extractive at 0.2-40 deals, and 10-500 deals of kuh-seng, while it also can contain 10-5000 deals of milk vetch root or the milk vetch root polysaccharide extractive at 0.1-100 deals, or the milk vetch root saponin at 0.1-100 deals. The invention can be made into oral or injection agent, with anti-cancer, antibiosis funtoins, etc.
Description
[technical field]
The invention belongs to medical technical field; Relate to a kind of pharmaceutical composition of processing by Cordyceps mycelium or its extract, kurarinone; The pharmaceutical composition of perhaps processing by Cordyceps mycelium or its extract, kurarinone and the Radix Astragali or its extract.
[background technology]
Cancer is one type of serious threat human life and healthy disease.Data show according to statistics; The annual newfound cancer patient of China is about about 1,000,000, seizes about 6,000,000 people's life every year in the whole world, and places dead edge to 1,000 ten thousand people; Along with going from bad to worse of environment for human survival, the incidence rate of cancer is ascendant trend year by year.World Health Organization's prediction 21 century cancer will become human " first killer ".Modern medicine mainly is that the operative treatment cooperation is put, chemotherapy to treatment for cancer at present, though operation can be removed primary lesion, can not fundamentally stop the regeneration and the breeding of cancerous cell; Though put, chemotherapy can kill cancerous cell, simultaneously a large amount of normal tissue cells suffered damage, and brings out gastrointestinal reaction, bone marrow depression and Liver and kidney, impairment of cardiac function, makes patient's health weak more, be difficult to further treatment.And the Chinese traditional treatment cancer has long history, has formed the theoretical system and treatment rule of own uniqueness.Work through vast medical worker has in recent years confirmed that the Chinese medicine cancer has outstanding effect, has particularly brought into play important effect to the rehabilitation behind the cancer operation and to the efficacy enhancing and toxicity reducing aspect of chemicotherapy.
Cordyceps is that section ergot fungus cordyceps sinensis bacterium Cordyceps sinensis (BerK.) Sacc. colonizes in Stroma and the larva cadaveric complex on the Vespertilio pretty young woman section insecticide.The property sweet, flat.Return lung, kidney channel.Has invigorating the lung and the kidney, hemostasis, clears phlegm.Be used for the chronic cough dyspnea due to deficiency, chronic cough is breathed out blood, impotence and seminal emission, soreness of waist and knee joint.Be a kind of famous and precious Chinese crude drug, report that in recent years it has immunity, the antitumor of adjusting, protects the liver, protects multiple pharmacological effect such as kidney, blood sugar lowering.The nutrient substance that contains 18 seed amino acids, mannitol, multivitamin and other multiple needed by human; Its main active is a polysaccharide, the polysaccharide that polysaccharide is made up of mannose, cordycepin, adenosine, galactose, arabinose, xylose essence, glucose, fucose.Because specific (special) requirements that growth is geographical and strict parasitics cause the Cordyceps resource extremely rare, being difficult for of in addition gathering makes that the wild cordyceps resource is original and just very lacks.Adding unordered in recent years coyoting digs excessively and makes worm grass resources face collapse.In recent years, both at home and abroad the expert extracts the Cordyceps fungus monomer through to the mycelial separation of wild Chinese caterpillar fungus, and is that the basis utilizes biological engineering method such as submerged fermentation with it, extracts the Cordyceps mycelium of artificial fermentation.Cordyceps mycelium is effective succedaneum of Cordyceps; According to scientist's analytical control, it has and the Cordyceps identical functions: go into lung, liver, kidney channel, have the effect of tonifying the lung, kidney tonifying, strong liver, QI invigorating, nourishing, health care; Have no side effect; The immunologic function that can improve human body can also resisting fatigue, decomposes the tired material in the muscle, endurance, improves the effect of motor capacity.
Kurarinone is the mixed base of oxymatrine and minute quantity N-oxysophocarpine; Be extraction separation and the white powder that obtains from the dry root of cassia leguminous plant Radix Sophorae Flavescentis (sophora flarescen Ait.); Recorded into the 16th 363 pages of national drug standards chemical drugs provincial standard rising national standards of National Drug Administration (Chinese Pharmacopoeia Commission's volume), wherein regulation contains oxymatrine (C
15H
24N
2O
2) must not be less than 98.0%.Kurarinone is tumor and hepatopathy adjuvant drug, kinds of tumor cells had suppress or lethal effect, and toxic and side effects is little, and can improve immunity, and be ideal cancer therapy drug.The structural formula of kurarinone is following:
Kurarinone
The Radix Astragali is the dry root of leguminous plant Radix Astagali Astragalus membranaceus (Fisch.) Bge.var.mongholicus (Bge.) Hsiao or Radix Astragali Astragalus membranaceus (Fisch.).Sweet, temperature is returned lung, spleen channel, has the effect of invigorating QI to consolidate the body surface resistance, diuresis detoxification, evacuation of pus, expelling pus and promoting granulation, and it is weak to be mainly used in the deficiency of vital energy; Anorexia and loose stool, sinking of QI of middle-JIAO, chronic diarrhea proctoptosis, the metrorrhagia of having blood in stool, exterior deficiency spontaneous perspiration; Deficiency of vital energy edema, carbuncle is difficult bursts, and burst for a long time and do not hold back, the blood deficiency dull yellowish colored skin, interior-heat is quenched one's thirst; Chronic nephritis albumen is sick, diabetes.Mainly contain compositions such as astragalus polysaccharides, Radix Astragali total saponins, flavonoid, alkaloid, glucuronic acid and trace element-selenium.Existing pharmacological testing shows that the Radix Astragali can promote immunologic function; Main effective ingredient is polysaccharide and saponin; Can significantly increase the total white blood cells in the blood, promote engulfing and sterilizing ability of neutrophilic granulocyte and macrophage, can obviously promote cellular immunization; Promote the lymphocyte transformation that PHA, ConA and phytolaccanine (PWM) etc. cause, improve the rat local graft versus host reaction that the malignant neoplastic disease human lymphocyte causes.Astragalus polysaccharides can significantly strengthen the mouse macrophage function; Promote IgM to form, improve the haematolysis ability of PFC, the mice swimming time that astragalus polysaccharides can also the significant prolongation hydrocortisone be exhausted; Increase its adrenal weight, to the significantly improvement effect of the equal tool of several anoxia model of mice; Can make normal and the cold-resistant life span prolongation of weak mice; Body weight, blood cell count and cellularity to mice after the radiation have obvious protective effect.
Utilizing interaction, the composition of prescription of Cordyceps mycelium, kurarinone, the Radix Astragali to be used for antineoplastic at present uses and does not also appear in the newspapers.
[summary of the invention]
In order to meet clinical needs, to the invention provides a kind of new antitumor medicine composition that is mainly used in, and its preparation method is provided.
Pharmaceutical composition of the present invention is mainly processed by Cordyceps mycelium and kurarinone, and its parts by weight are: 50～2000 parts of Cordyceps myceliums, 10～500 parts of kurarinones; Preferred umber is 200～1000 parts of Cordyceps myceliums, 20～150 parts of kurarinones; Best umber is 400 parts of Cordyceps myceliums, 60 parts of kurarinones.
The method for preparing of aforementioned pharmaceutical compositions is: Cordyceps mycelium body and function The suitable solvent and method are obtained its extract through extracting processing.The suitable solvent is meant the solvent that Chinese medicine extraction is commonly used, preferred water or alcohol, especially water or ethanol.Method for distilling can adopt the conventional method of Chinese medicine extraction, like infusion process, percolation, decocting method, reflux extraction or continuous extraction.
The concrete method for distilling of each crude drug is following:
The extraction processing technique of Cordyceps mycelium is following:
Get the Cordyceps mycelium culture, add the water reflux, extract, three times, each 2 hours, merge extractive liquid, filtered; Be concentrated into relative density 1.10～1.15, add ethanol and make and contain alcohol amount and reach 60%, cold preservation was left standstill 24 hours, filtered, and collected filter cake; Add suitable quantity of water and make dissolving, filter, add ethanol and make and contain the alcohol amount and reach 85%, cold preservation was left standstill 24 hours, filtered; Collect filter cake, 80% washing with alcohol, vacuum drying promptly gets.
Content through polysaccharide in the Cordyceps mycelium extract of this prepared is not less than 50%, and yield is 0.5～2%.
Except that adopting said method, also can obtain, but be not limited only to following method through following method:
Method one: get Cordyceps mycelium, 100 ℃ are extracted three times, add 10 times of amounts of water for the first time, add 8 times of amounts of water two, three times, and each 2 hours,
Merge extractive liquid, filters, and filtrating adds ethanol to be made and contain the alcohol amount and reach 65%, and cold preservation was left standstill 24 hours; Filter, filtrate recycling ethanol is not to there being the alcohol flavor, adds ethanol and makes and contain the alcohol amount and reach 85%, and cold preservation was left standstill 24 hours; Filter, behind filtrate recycling ethanol to the nothing alcohol flavor, be evaporated to the thick paste shape, spray drying promptly gets.
Content through polysaccharide in the Cordyceps mycelium extract of this prepared is not less than 35%, and yield is 4～9%.
Method two: get Cordyceps mycelium, 100 ℃ are extracted secondary, add 10 times of amounts of water for the first time, add 8 times of amounts of water, each 3 hours for the second time; Merge extractive liquid, filters, and the macroporous resin of filtrating is collected effluent, adds ethanol and makes and contain the alcohol amount and reach 65%; Cold preservation was left standstill 24 hours, filtered, and filtrate recycling ethanol is not to there being the alcohol flavor, added ethanol and made and contain the alcohol amount and reach 85%, and cold preservation was left standstill 24 hours; Filter, behind filtrate recycling ethanol to the nothing alcohol flavor, be evaporated to the thick paste shape, spray drying promptly gets.
Content through polysaccharide in the Cordyceps mycelium extract of this prepared is not less than 40%, and yield is 2～6%.
Aforementioned pharmaceutical compositions also can replace the Cordyceps mycelium medical material to feed intake by the Cordyceps mycelium extract; Calculate with respect to the yield of medical material according to extract, the parts by weight of composition material medicine are: 0.2～40 part of Cordyceps mycelium extract, 10～500 parts of kurarinones; Preferred umber is 1～20 part of Cordyceps mycelium extract, 20～150 parts of kurarinones; Best umber is 2～10 parts of Cordyceps mycelium extracts, 60 parts of kurarinones.Wherein the main effective ingredient of Cordyceps mycelium extract is a polysaccharide, preferably is not less than 30%.
For reaching better antitumous effect, also can add the Radix Astragali in the crude drug of pharmaceutical composition of the present invention and process, like its parts by weight that feed intake with medical material be: 50～2000 parts of Cordyceps myceliums, 10～500 parts of kurarinones, 10～5000 parts of the Radixs Astragali; Preferred umber is 200～1000 parts of Cordyceps myceliums, 20～150 parts of kurarinones, 50～2000 parts of the Radixs Astragali; Best umber is 400 parts of Cordyceps myceliums, 60 parts of kurarinones, 100 parts of the Radixs Astragali.
Cordyceps mycelium, the Radix Astragali can singly be carried or mix to obtain through refining and obtain its extract fully with The suitable solvent and method in the aforementioned pharmaceutical compositions, and total extract is processed clinically arbitrary or pharmaceutically acceptable dosage form with mixing acceptable accessories again." extract separately " and be meant that Cordyceps mycelium, each flavor medical material of the Radix Astragali extract separately through different processes respectively and obtain extract, each extract are mixed obtaining total extract again." mixed extraction " is meant, Cordyceps mycelium, the Radix Astragali two flavor medical materials extract together and obtain total extract.
In the above-mentioned composition, " extracting separately " method of Cordyceps mycelium can prepare with reference to preceding method.
In the above-mentioned composition, because astragalus polysaccharides and Radix Astragali total saponins all have anti-tumor activity, so " extracting separately " method of the Radix Astragali can adopt different method for distilling because of the difference of its active component, respectively as follows:
Be that the preparation technology of Radix Astragali extract (abbreviation Radix Astragali total saponins) of main effective ingredient is following with total saponins in the present composition:Get the Radix Astragali, decocte with water three times each 1.5 hours, adds 10 times of amounts of water for the first time; Two, be 8 times of amounts for three times, collecting decoction filters, and it is 1.20～1.25 (60 ℃) that filtrating is concentrated into relative density; Handle 2 times with ethanol precipitation, containing the alcohol amount in the solution for the first time is 75%, is 85% for the second time, and each all cold preservation is placed; Reclaim ethanol and be concentrated into every 1ml and be equivalent to crude drug 10g, be added on the macroporous adsorptive resins of having handled well, earlier with the water of 2 times of volumes towards post, 70% ethanol elution of 4 times of volumes of reuse; Collect eluent, concentrating under reduced pressure, vacuum drying promptly get.Radix Astragali total saponins extract yield through this prepared is 0.5～2%, and total saponin content is not less than 50%, and Astragaloside content is not less than 2.0%.
Except that adopting said method, also can obtain, but be not limited only to following method through following method:
Method one: get the Radix Astragali, decocte with water three times, each 2 hours, collecting decoction; Filter, it is 1.20～1.25 (60 ℃) that filtrating is concentrated into relative density, handles 2 times with ethanol precipitation; Containing amount of alcohol in the solution for the first time is 60%, is 85% for the second time, and each all cold preservation is placed; Reclaim ethanol and be concentrated into every 1ml and be equivalent to crude drug 10g, concentrating under reduced pressure, vacuum drying promptly get.Radix Astragali extract yield through this prepared is 3～5%, and total saponin content is not less than 30%, and Astragaloside content is not less than 1%.
Method two: get the Radix Astragali, decocte with water three times, each 1.5 hours; Collecting decoction filters, and it is 1.20～1.25 (60 ℃) that filtrating is concentrated into relative density; Use the ethanol precipitation processing to make for 1 time containing amount of alcohol is 60%, and cold preservation is placed, and reclaims ethanol and be concentrated into every 1ml to be equivalent to crude drug 10g; And concentrating under reduced pressure, vacuum drying, promptly get.Radix Astragali extract yield through this prepared is 2～4%, and total saponin content is for being not less than 40%, and Astragaloside content is not less than 1%.
Be that the preparation technology of Radix Astragali extract (abbreviation astragalus polysaccharides) of main effective ingredient is following with polysaccharide in the present composition:Get Milkvetch Root, add 7 times of amount 70% ethanol extraction secondaries, each 2 hours, extracting solution discarded, the slag extracting in water secondary of getting it filled; Extracting solution merges, and the ratio that is concentrated into extracting liquid volume and raw medicinal herbs is 1.05: 1, adds ethanol precipitation and makes and contain the alcohol amount and reach 70%, and filtration must precipitate; Deposition is used 70% washing with alcohol, and the macroporous resin of filtrating is filtered in the dissolving of reuse suitable quantity of water; Use water elution, collect water lotion, water lotion is concentrated into medicine liquid volume with the medical material ratio is 1: 2.5, add ethanol and make and contain alcohol and measure and reach 70%; Must precipitate, will precipitate with 95% ethanol and washing with acetone dehydration, drying under reduced pressure (60 ℃) promptly gets.Content through Radix Astragali Mongolici total polysaccharide in the Radix Astragali extract of this prepared is not less than 50%, and extract yield is 0.5～2%.
Except that adopting said method, also can obtain, but be not limited only to following method through following method:
Method one: get Milkvetch Root, add the water reflux, extract, three times, each 2 hours, merge extractive liquid; Filter, it is 1.15～1.23 that filtrate decompression is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 80%, leaves standstill 24 hours; Filter, deposition is dissolved in water, and filters, and adds ethanol again and makes and contain the alcohol amount and reach 85%; Left standstill 24 hours, and filtered, collecting precipitation, vacuum drying promptly gets.Radix Astragali extract yield through this prepared is 2～4%, and astragalus polysaccharides content is not less than 40%.
Method two: get Milkvetch Root, add 10 times of amount 80% ethanol extractions 4 hours, extracting solution discards, the slag extracting in water secondary of getting it filled; Each 2 hours, add 10 times of amounts of water at every turn, extracting solution merges, and filters; Filtrating adds ethanol to be made and contains alcohol amount and reach 85%, filters, and filtrate decompression is concentrated into the thick paste shape, and spray drying promptly gets.Radix Astragali extract yield through this prepared is 3～4%, and astragalus polysaccharides content is not less than 35%.
In the crude drug of aforementioned pharmaceutical compositions; Available Cordyceps mycelium extract, Radix Astragali extract replace the Cordyceps mycelium and the Radix Astragali to feed intake respectively making; Calculate with respect to the yield of medical material according to extract, following two kinds of different proportionings can be arranged, its parts by weight are respectively:
Proportioning 1: 0.2～40 part of Cordyceps mycelium extract, 10～500 parts of kurarinones, 0.1～100 part of astragalus polysaccharides; Preferred umber is 1～20 part of Cordyceps mycelium extract, 20～150 parts of kurarinones, 0.2～40 part of astragalus polysaccharides; Best umber is 2～10 parts of Cordyceps mycelium extracts, 60 parts of kurarinones, 0.5～2 part of astragalus polysaccharides.
Proportioning 2: 0.2～40 part of Cordyceps mycelium extract, 10～500 parts of kurarinones, 0.1～100 part of Radix Astragali total saponins; Preferred umber is 1～20 part of Cordyceps mycelium extract, 20～150 parts of kurarinones, 0.2～40 part of Radix Astragali total saponins; Best umber is 2～10 parts of Cordyceps mycelium extracts, 60 parts of kurarinones, 0.5～2 part of Radix Astragali total saponins.
In the said ratio, contain polysaccharide in the Cordyceps mycelium extract and preferably be not less than 30%; Astragalus polysaccharides content preferably is not less than 50%, and Radix Astragali total saponins content preferably is not less than 50%, and Astragaloside content wherein is not less than 2.0%.Cordyceps mycelium extract, Radix Astragali total saponins and astragalus polysaccharides all can make according to preceding method.
Aforementioned pharmaceutical compositions; Can process clinically arbitrary or pharmaceutically acceptable dosage form, like injection, oral normal release dosage form, sustained-release and controlled release dosage form, granule, pill, oral fluid agent, eye drop, nasal drop, ear drop, inhalant, suppository, ointment etc.Pharmaceutical composition preferred dosage form of the present invention is injection and oral formulations.
Pharmaceutical composition of the present invention can adopt the conventional method production in the existing pharmaceutical field, can add various pharmaceutically acceptable carriers when needing.Described carrier comprises the conventional diluent of pharmaceutical field, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant etc.
The present invention in order to increase its dissolubility, can add solubilizing agents such as tween 80 when processing injection.Can add the isoosmotic adjusting agent that is used to regulate osmotic pressure in the transfusion, for example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, lactic acid are received, glucose, xylitol, sorbitol and dextran etc., preferred sodium chloride or glucose.Can add excipient in the powder pin, for example, mannitol, glucose etc.
Aforementioned pharmaceutical compositions has effects such as antitumor, anti-hepatic injury, detoxifcation, antibiotic and enhancing human body immunity power.
The invention has the advantages that:
1. a kind of new Chinese medicine medicine for preventing compound recipe is provided, has satisfied urgent clinical needs.
2. pharmaceutical composition of the present invention has been carried out pharmaceutical research, the result shows that the present composition has obvious synergistic effect to radiotherapy; Chemotherapy is had attenuation and synergic effect, and the potentiation rate can reach 56%; Can obviously prolong ehrlich ascites carcinoma U
14The existence natural law of mice; And its effect is compared effect very significantly (p＜0.01) with single with Cordyceps mycelium, kurarinone and the Radix Astragali; Show that Cordyceps mycelium, kurarinone and Cordyceps mycelium, kurarinone and two kinds of compositionss of the Radix Astragali all have the effect of Synergistic, have improved patient's life quality.
3. pass through the different proportionings of the present composition to mice S
180The inhibiting pharmacodynamic study of tumor growth has filtered out the optimum ratio of the present composition.
4. the content to the main effective ingredient of present composition extract limits respectively, is convenient to control the quality of product.
5. the present composition has been carried out acute toxicity test, the result shows that present composition toxicity is little, and safety range is big.
6. the stability test result who pharmaceutical composition of the present invention is carried out shows that each item index is all more stable, has guaranteed safety of clinical administration.
7. Cordyceps mycelium, kurarinone and Radix Astragali clinical application determined curative effect, dosage reduces behind the drug combination, has broad application prospects.
Following Test Example further sets forth the beneficial effect of medicine according to the invention, and these Test Example comprise the pharmacodynamics test of pharmaceutical composition of the present invention.Cordyceps mycelium basis in the following Test Example
Embodiment 1Make the Cordyceps mycelium extract, Radix Astragali basis
Embodiment 2Make Radix Astragali total saponins and astragalus polysaccharides.Cordyceps mycelium extract, kurarinone compositions are called for short
The CK groupCordyceps mycelium extract, kurarinone, astragalus polysaccharides compositions are called for short
CKH 1Group, Cordyceps mycelium extract, kurarinone, Radix Astragali total saponins compositions are called for short
CKH 2Group.
Test Example 1 pharmacodynamics test-Cordyceps mycelium, kurarinone and Radix Astragali drug combination are to mice S
180
The tumor growth inhibitory action
Test sample matched group: sodium chloride injection (Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.)
Radix Astragali total saponins group: Radix Astragali total saponins injection, self-control, 2ml: be equivalent to Milkvetch Root 1g.
Astragalus polysaccharides group: astragalin injection, self-control, 2ml: be equivalent to Milkvetch Root 1g.
Cordyceps mycelium group: Cordyceps mycelium injection 2ml: be equivalent to Cordyceps mycelium medical material 4g.
Kurarinone group: self-control, 2ml: 0.2g
The compositions group:
CKH
1Group: self-control (prescription and method for preparing are referring to the preparation of embodiment 4 aqueous injection prescription 2);
CKH
2Group: self-control (prescription and method for preparing are referring to the preparation of embodiment 4 aqueous injection prescription 3);
230 of animal subject healthy mices, body weight 16～20g, male and female half and half, 10 every group.
Tumor strain mice S
180
Table 1 compositions is to mice S
180The tumor growth inhibitory action (x ± s, n=10)
Annotate: compare with the normal saline matched group
*P＜0.05,
*P＜0.01; Compare with the Radix Astragali total saponins group
aP＜0.01; Compare with the astragalus polysaccharides group
bP＜0.01; Compare with the Cordyceps mycelium group,
cP＜0.01; Compare with the kurarinone group,
dP＜0.01.
Test method is got and is inoculated the mice S that goes down to posterity
180, in homogenizer, add normal saline, process mice S
180The tumor homogenate, again with normal saline 1: 3 dilution, getting 0.2ml then, to inject oxter, a mice left side subcutaneous, weighed in 24 hours, mice gastric infusion every day once, administration volume identical (0.5ml/ is only), totally 7 days.Next day is put to death mice in drug withdrawal, and the subcutaneous tumors piece is peeled off in the also carefulness of weighing, and takes by weighing tumor in the EM50 electronic balance and weighs, and calculate tumour inhibiting rate.
Result of the test and conclusion can be found out that by table 1 result each test sample group and normal saline matched group compare mice S
180The tumor body all has remarkable inhibitory action (p＜0.05, p＜0.01); CKH
1(Cordyceps mycelium extract+kurarinone+astragalus polysaccharides) group, CKH
2(Cordyceps mycelium extract+kurarinone+Radix Astragali total saponins) group is compared with Radix Astragali total saponins group, astragalus polysaccharides group, Cordyceps mycelium group and kurarinone group, and difference is (p＜0.01) extremely significantly, points out three medicines to share the effect of Synergistic.The result shows; When the raw material weight proportioning of compositions is that ((0.2g～1.5g)+(0.5g～20g) Shi Junneng plays tumor killing effect preferably to the Radix Astragali to 2g～10g)+kurarinone to Cordyceps mycelium, and effect is best during wherein with Cordyceps mycelium 4g+ kurarinone 0.6g+ Radix Astragali 1g.
Test Example 2 Cordyceps myceliums and kurarinone drug combination are to the influence of ehrlich ascites carcinoma U14 mice increase in life span
The animal subject healthy mice, 60, body weight 20～25g, the male and female dual-purpose is divided into 6 groups at random, 10 every group.
Tumor strain mouse ascites cancer U
14
Test sample matched group: sodium chloride injection (Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.)
Cordyceps mycelium group: Cordyceps mycelium extract injection 2ml: be equivalent to Cordyceps mycelium medical material 4g.
Kurarinone group: self-control, 2ml: 0.2g.
Compositions group: CK group: specification: 2ml, be derived from embodiment 4 aqueous injection prescription 1, be divided into basic, normal, high three dose groups.
Test method mouse peritoneal inoculation ehrlich ascites carcinoma U
14Tumor strain bacteria suspension (suspension concentration 2 * 10
7/ ml, inoculum concentration 0.5ml/ are only).Inoculate next day, the mice random packet is weighed in, and presses table 2 intraperitoneal injection, every day 1 time, continuous 10 days.After this observe the death time of mice, the result representes [increase in life span=(test group The average survival time natural law-matched group The average survival time natural law)/matched group The average survival time natural law * 100%] with average survival natural law and increase in life span.
Table 2 Cordyceps mycelium and kurarinone drug combination are to ehrlich ascites carcinoma U
14The mice increase in life span
Influence (meansigma methods ± standard deviation, n=10)
Annotate: compare with the normal saline matched group:
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the Cordyceps mycelium group:
aP＜0.05,
bP＜0.01; Compare with the kurarinone group:
cP＜0.05,
dP＜0.01.
Result of the test and conclusion result of the test are seen table 2.Compare with the normal saline solution matched group, but the middle and high dose groups utmost point of CK injection significant prolongation U
14The existence natural law of mice (p＜0.01, p＜0.001), CK injection low dose group, Cordyceps mycelium injection group, Matrine Injection group can obviously prolong U
14The existence natural law of mice (p＜0.05).CK injection low dose group is compared ehrlich ascites carcinoma U with Cordyceps mycelium injection group, Matrine Injection group
14The mice increase in life span significantly increases (p＜0.05); The middle and high dose groups of CK injection is compared ehrlich ascites carcinoma U with Cordyceps mycelium injection group, Matrine Injection group
14The mice increase in life span extremely significantly increases (p＜0.01).Prompting, Cordyceps mycelium and kurarinone drug combination have synergistic function, at inhibition tumor, prolongation tumor patient remarkable effect are arranged aspect the time-to-live.
Test Example 3 Cordyceps myceliums, kurarinone drug combination are to the potentiation of radiotherapy
The animal subject healthy mice, 50, body weight 20～25g, the male and female dual-purpose is divided into 5 groups at random, 10 every group.
Tumor strain mice S
180Sarcoma.
Test sample matched group: sodium chloride injection (Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.)
Compositions group: CK group: specification: 2ml, be derived from embodiment 4 aqueous injection prescription 1, be divided into basic, normal, high three dose groups.
Every mice left fore of test method oxter subcutaneous vaccination S
180Tumor strain cell suspension (suspension concentration 2 * 10
7/ ml, inoculum concentration 0.2ml/ are only), weigh in during 24h.Inoculate next day, random packet, except that the blank group, all the other each groups are the 3rd day, the 6th day usefulness after inoculation all
60Co total irradiation, exposure dose are 0.05Gy/min.Inoculate next day, mice is pressed table 3 intraperitoneal injection, every day 1 time, continuous 10 days.Weigh in every day, observes the mice with tumor body weight change.24h after the last administration; Weigh in, put to death animal, peel off the subcutaneous tumors piece; Take by weighing the tumor body weight, calculate tumor control rate and potentiation rate [potentiation rate=(the average tumor of average tumor weight-radiotherapy of combination radiotherapy group and CK injection therapeutic alliance group is heavy)/average tumor of combination radiotherapy group heavy * 100%].
Table 3 Cordyceps mycelium, kurarinone drug combination to the potentiation of radiotherapy (meansigma methods ± standard deviation, n=10)
Compare with the blank group:
*P＜0.05,
*P＜0.01,
* *P＜0.001;
With
60The Co irradiation group is compared:
#P＜0.05,
##P＜0.01.
Result of the test and conclusion result of the test are seen table 3.Compare with the blank group,
60The Co irradiation is to mice S
180Sarcoma has significant inhibitory effect (p＜0.05);
60Co irradiation and the therapeutic alliance of basic, normal, high dosage CK injection are to mice S
180Sarcoma has utmost point significant inhibitory effect (p＜0.01, p＜0.001).With
60The Co irradiation group is compared,
60Co irradiation and the therapeutic alliance of low dosage CK injection are to mice S
180The inhibitory action of sarcoma significantly strengthens (p＜0.05),
60Co irradiation and the therapeutic alliance of middle and high dosage CK injection are to mice S
180The inhibitory action of sarcoma extremely significantly strengthens (p＜0.01).Result of the test shows that the CK injection can significantly strengthen
60The radiotherapy effect of Co irradiation, prompting, Cordyceps mycelium, kurarinone drug combination have the effect that strengthens radiotherapy effect.
Test Example 4 Cordyceps myceliums, kurarinone and Radix Astragali drug combination are to the potentiation and the Attenuation of chemotherapy (Cy)
The animal subject healthy mice, 80, body weight 20～25g, the male and female dual-purpose is divided into 8 groups at random, 10 every group.
Tumor strain mice S
180Sarcoma.
Test sample matched group: sodium chloride injection (Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd.);
Cyclophosphamide for injection (positive control): commercial, 100mg, Hualian Pharmaceutical Co., Ltd., Shanghai;
Compositions group: CKH
1Group: specification: 2ml, be derived from embodiment 4 aqueous injection prescription 2, be divided into basic, normal, high three dose groups; CKH
2Group: specification: 2ml, be derived from embodiment 4 aqueous injection prescription 3, be divided into basic, normal, high three dose groups.
Every mice left fore of test method oxter subcutaneous vaccination S
180Tumor strain cell suspension (suspension concentration 2 * 10
7/ ml, inoculum concentration 0.2ml/ are only).The inoculation next day, the mice random packet is weighed in, and presses table 4 intraperitoneal injection, the next day 1 time, continuous 10 days.Weigh in every day, observes the mice with tumor body weight change.24h after the last administration weighs in, and puts to death animal, peels off the subcutaneous tumors piece, takes by weighing the tumor body weight, calculates tumor control rate and potentiation rate [potentiation rate=(average tumor weight-chemotherapy of chemotherapy group and CKH
1Or CKH
2The average tumor of injection drug combination group is heavy)/the average tumor of chemotherapy group heavy * 100%].
Table 4 Cordyceps mycelium, kurarinone and Radix Astragali drug combination are to the potentiation and the Attenuation of chemotherapy
(meansigma methods ± standard deviation, n=10)
Annotate: compare with the blank group:
*P＜0.05,
*P＜0.01,
* *P＜0.001; Compare with the Cyclophosphamide for injection group:
#P＜0.05,
##P＜0.01.
Result of the test and conclusion result of the test are seen table 4.
(1) to the potentiation of chemotherapy: compare with the blank group, the independent medication of low dosage Cyclophosphamide for injection is to mice S
180Sarcoma has significant inhibitory effect (p＜0.05); Cyclophosphamide for injection and basic, normal, high dosage CKH
1, CKH
2The injection drug combination is to mice S
180Sarcoma has utmost point significant inhibitory effect (p＜0.01, p＜0.001).Compare Cyclophosphamide for injection and low dosage CKH with the cyclophosphamide group
1, CKH
2The injection drug combination is to mice S
180The inhibitory action of sarcoma significantly strengthens (p＜0.05), Cyclophosphamide for injection and middle and high dosage CKH
1, CKH
2The injection drug combination is to mice S
180The inhibitory action of sarcoma extremely significantly strengthens (p＜0.01).Result of the test shows, CKH
1, CKH
2Injection is the curative effect of enhanced electronic phosphamide significantly, prompting, and Cordyceps mycelium, kurarinone and Radix Astragali three drug combination have the effect that strengthens chemotherapeutic efficacy.
(2) to the Attenuation of chemotherapy: compare with the blank group, during the independent medication of Cyclophosphamide for injection, the peripheral leukocytes number of mice, thymus index, spleen index all extremely significantly reduce (p＜0.01).Compare Cyclophosphamide for injection and CKH with the Cyclophosphamide for injection group
1, CKH
2During the injection drug combination, CKH
1, CKH
2The injection low dosage can significantly suppress the reduction (p＜0.05) of mice peripheral leukocytes number, thymus index, spleen index, CKH
1, CKH
2The middle and high dosage of injection can extremely significantly suppress the reduction (p＜0.01) of mice peripheral leukocytes number, thymus index, spleen index.Result of the test shows, CKH
1, CKH
2Injection can significantly reduce the toxicity of cyclophosphamide, prompting, and Cordyceps mycelium, kurarinone and Radix Astragali three drug combination have the effect that reduces chemotherapeutic toxicity.
Test Example 5 injected in mice administration acute toxicity tests
(1) test method
Test sample: the CK injection, specification 2ml derives from embodiment 4 prescriptions 1; CKH
1Injection, specification 2ml derives from embodiment 4 prescriptions 2; CKH
2Injection, specification 2ml derives from embodiment 4 prescriptions 3.
Animal subject: mice, each 60 of every group of male and female, male body weight 25～28g, female body weight 21～24g.
Route of administration: intravenous injection, lumbar injection.
Observe special project: death toll, general state, body weight, cut open inspection, half lethal dose.
(2) result of the test
Require to carry out prerun according to acute toxicity test, lumbar injection and intravenous injection two route of administration all can't be measured the median lethal dose(LD 50) of medicine, also do not see tangible toxic reaction, so carry out a day maximum dosage-feeding test.Dosage: tail vein injection 0.1ml/10g, lumbar injection 0.1ml/10g, 1 time on the one.
Death toll: do not occur dead.
General state: no abnormality seen changes.
Body weight: in administration preceding 1 day, administration day, measured in 2,4,6,8,10,12,14 days after the administration; No abnormality seen changes.
Cut open inspection: the heart, liver, lung, kidney etc. organize no abnormality seen to change.
(3) conclusion
Death, CK, CKH appear in this experiment
1And CKH
2Injection is 0.1ml/10g to the maximum tolerated dose of male and female mouse vein and intraperitoneal injection, is equivalent to 100 times of maximum consumption 6ml of the 60kg body weight day for human beings.Show these article low toxicity, safe.
Test Example 6 composite injection stability tests
Test sample: the CK injection, specification 2ml derives from embodiment 5 prescriptions 1; CKH
1Injection, specification 2ml derives from embodiment 4 prescriptions 2; CKH
2Injection, specification 2ml derives from embodiment 4 prescriptions 3.
Investigation project: character, pH value, clarity, related substance, sign content; And at accelerated test 6 months and the aseptic and pyrogen test of long term test end of term increase.
1, influence factor's test
The strong illumination test: get test sample, putting illumination is interior the placement 10 days of lighting box of 4500Lx.
Hot test: get test sample, placed 40 ℃, 60 ℃ condition held respectively 10 days.
Low-temperature test: get test sample, in 4 ℃ of refrigerators, placed 10 days.
Above-mentioned test was respectively at the 5th, 10 day sampling and measuring.Relatively test each item index after the character, and with result and comparison in 0 day.
The result: illumination 4500Lx condition held 10 days, except that related substance slightly raise, all other indexs had no significant change.60 ℃ of condition held of high temperature 10 days, each item index does not have significant change.40 ℃ of high temperature, 4 ℃ of condition held of low temperature 10 days, each item index does not have significant change.
2, accelerated test
Method: the condition held 6 months of putting 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%.Respectively at taking a sample 1st month, 2 months, 3 months, 6 the end of month, relatively after the outward appearance, test each item index is with result and comparison in 0 month at duration of test; And at 6 aseptic and pyrogen tests of increase at the end of month.
Result: the condition held of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% 6 months; Removing related substance slightly increases, and outside sign content slightly descended, all other indexs had no significant change; At 6 the end of month of accelerated test, pyrogen, sterility test are all up to specification.
3, long term test
Method: the condition held 18 months of putting 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10%.Respectively at 3rd month, 6 months, 9 months, 12 months, 18 months, relatively after the outward appearance, test each item index was with result and comparison in 0 month; And at 18 aseptic and pyrogen tests of increase at the end of month.
The result: the condition held of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% 18 months, each item index has no significant change, and at 18 the end of month of long term test, pyrogen, sterility test are all up to specification.
Conclusion: reach a conclusion by above-mentioned investigation result, in each item test, CK injection, CKH
1Injection and CKH
2Injection is all more stable.
In sum, Cordyceps mycelium provided by the invention and kurarinone or the Radix Astragali, Cordyceps mycelium and kurarinone compositions have synergistic function, obviously are superior to the individually dosed drug effect of the Radix Astragali, Cordyceps mycelium or kurarinone.To CK injection, CKH
1Injection and CKH
2The stability test result that injection carries out shows that each item index of the injection that compositions provided by the invention is processed is all more stable, can be used for amplifying producing.
[specific embodiment]
Below come further to set forth preparation of drug combination method of the present invention through embodiment, but should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The adjuvant of each dosage form can be replaced with acceptable accessories in following examples, perhaps reduces, increases.
Cordyceps mycelium extract in following examples 3～11 and astragalus polysaccharides, Radix Astragali total saponins derive from second batch in Cordyceps mycelium extract and astragalus polysaccharides among the embodiment 1,2, three batches of extracts of Radix Astragali total saponins.
The preparation of embodiment 1 Cordyceps mycelium extract
Get Cordyceps mycelium culture 40kg, add the water reflux, extract, three times, each 2 hours, merge extractive liquid, filtered; Be concentrated into relative density 1.10～1.15, add ethanol and make and contain alcohol amount and reach 60%, cold preservation was left standstill 24 hours, filtered, and collected filter cake; Add suitable quantity of water and make dissolving, filter, add ethanol and make and contain the alcohol amount and reach 85%, cold preservation was left standstill 24 hours, filtered; Collect filter cake, 80% washing with alcohol, vacuum drying promptly gets.
Prepare three batches of extracts more respectively by above-mentioned technology, extract yield and content see the following form 5.
The assay of Cordyceps mycelium extract
The preparation precision of reference substance solution takes by weighing 105 ℃ of D-anhydrous glucose 5.0mg that are dried to constant weight and places 25ml volumetric flask adding distil water standardize solution, shakes up, and promptly gets reference substance solution.
These article 10mg is got in the preparation of need testing solution, places 50ml volumetric flask standardize solution, shakes up, and promptly gets.
The accurate absorption of the preparation of standard curve reference substance solution 0.25,0.75,1.25,2.0,2.5ml respectively place 10ml tool plug test tube; Each adds anthrone reagent (take by weighing 2g anthrone add the 100ml ethyl acetate in water-bath, be added to molten) 0.5ml and 3.0ml concentrated sulphuric acid mixing on vortex mixer immediately, and placement is cooled to room temperature.Make blank with distilled water with method, survey trap at the 630nm place.With reference substance solution concentration is abscissa, makes vertical coordinate with trap, calculates regression equation.
The accurate absorption of algoscopy need testing solution 2ml puts and uses the distilled water standardize solution in the 10ml measuring bottle, shakes up, and accurate again absorption 1ml promptly gets by measuring under the above-mentioned standard curve condition.
The discriminating of Cordyceps mycelium extract
(1) get the about 50mg of these article, add water 5ml dissolving after, add 5 of alkaline cupric tartrate test solutions; Heating promptly produces red precipitate, and cooling filters; Getting filtrating and adding 1 of hydrochloric acid and make acid, heating in water bath 10 minutes is put cold; Regulate pH value to neutral, add alkaline cupric tartrate test solution 0.5ml, heating in water bath promptly produces red copper oxidule precipitation.
(2) get the about 50mg of these article, add water 2ml dissolving after, add 5%d-naphthols alcoholic solution 0.5ml and shake up, slowly add sulphuric acid 3ml, two liquid level intersection displaing amaranth rings.
Three batches of Cordyceps mycelium extract yields of table 5 and assay result
The preparation of embodiment 2 Radix Astragali extracts
The preparation of Radix Astragali total saponins
Get Radix Astragali 40kg, decocte with water three times, each 1.5 hours, collecting decoction; Filter, it is 1.20～1.25 (60 ℃) that filtrating is concentrated into relative density, handles 2 times with ethanol precipitation, and containing the alcohol amount in the solution for the first time is 75%; Be 85% for the second time, each all cold preservation is placed, and reclaims ethanol and be concentrated into every 1ml to be equivalent to crude drug 10g, is diluted to every 1ml with water for injection and is equivalent to crude drug 1g; Cold preservation was placed 12 hours, filtered, and filtrate decompression concentrates, vacuum drying, promptly gets.
Make three batches of Radix Astragali total saponinss respectively, extract yield and content results see the following form 6.
The Radix Astragali total saponins discrimination test
Discrimination test one is got these article 0.01g, adds methanol 20ml, and reflux 1 hour filters; Filtrating be added on the neutral alumina post (100～120 orders, 5g is on the internal diameter 10～15mm), with 40% methanol 100ml eluting; Collect eluent, evaporate to dryness, residue add water 30ml makes dissolving; Extract 2 times with water saturated n-butyl alcohol jolting, each 20ml merges n-butyl alcohol liquid; With water washing 2 times, each 20ml; Discard water liquid, n-butyl alcohol liquid evaporate to dryness, residue add methanol 0.5ml makes dissolving, as need testing solution.Other gets the astragaloside reference substance, adds methanol and processes the solution that every 1ml contains 1mg, as reference substance solution.Drawing each 2 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, is developing solvent with lower floor's solution of chloroform-methanol-water (13: 7: 2), launches, take out, and airing, spray is with 10% ethanol solution of sulfuric acid, and it is clear to be heated to the speckle colour developing at 105 ℃.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, daylight shows down identical sepia speckle; Ultra-violet lamp (365nm) shows identical orange-yellow fluorescence speckle down.
Discrimination test two is got these article 0.01g, adds ethanol 30ml, and reflux 20 minutes filters; Filtrating adds 0.3% sodium hydroxide solution 15ml makes dissolving, filters, and filtrating is regulated pH value to 5～6 with dilute hydrochloric acid; Extract with ethyl acetate 15ml jolting, obtain acetic acid ethyl fluid, filter with the filter paper that is covered with anhydrous sodium sulfate; The filtrating evaporate to dryness, residue adds ethyl acetate 1ml makes dissolving, as need testing solution.Other gets Radix Astragali control medicinal material 2g, shines medical material solution in pairs with legal system.Draw each 10 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate,, launch as developing solvent with chloroform-methanol (10: 1), take out, airing is put in the ammonia steam and is inspected under the smoked rearmounted ultra-violet lamp (365nm).In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence principal spot of same color.
The Radix Astragali total saponins assay
The assay of total saponins
The preparation precision of reference substance solution takes by weighing the about 10mg of astragaloside reference substance that is dried to constant weight in 105 ℃, puts in the 100ml measuring bottle, adds dissolve with methanol and is diluted to scale, shakes up, and promptly gets (every 1ml contains astragaloside dry product 0.1mg).
These article 0.1g is got in the preparation of need testing solution, and accurate the title decides, and adds water 25ml and makes dissolving, moves in the separatory funnel, extracts 4 times with water saturated n-butyl alcohol jolting; Each 20ml merges n-butyl alcohol liquid, and with the saturated water washing twice of n-butyl alcohol, each 10ml discards water liquid; Evaporate to dryness in n-butyl alcohol to the water-bath, residue adds dissolve with methanol, moves in the 25ml measuring bottle, and adds methanol and be diluted to scale; Shake up, filter, get subsequent filtrate, promptly get.
The algoscopy precision is measured reference substance solution, each 1ml of need testing solution, puts the 25ml nessler colorimetric tube, puts evaporate to dryness in the water-bath, puts cold; Add freshly prepared 5% vanillin-glacial acetic acid solution 0.4ml, perchloric acid 1.6ml shakes up, and places 5 minutes; Put in the boiling water bath and developed the color 15 minutes, take out, put immediately and be cooled to room temperature in the ice bath, add the 8ml glacial acetic acid; Shake up, measure absorbance, calculate, promptly get in the 538nm wavelength.
The assay of astragaloside
Chromatographic condition and system suitability test are filler with the octadecyl silane; With acetonitrile-water (32: 68) is mobile phase; Evaporative light scattering detector.Number of theoretical plate calculates with the astragaloside peak and is not less than 4000.
It is an amount of that the preparation precision of reference substance solution takes by weighing the astragaloside reference substance, adds methanol and process the solution that every 1ml contains 0.5mg, promptly gets.
The preparation precision of need testing solution takes by weighing these article 0.04g, and accurate the title decides, and puts in the apparatus,Soxhlet's, adds methanol 40ml, and merceration spends the night, and it is an amount of to add methanol again; Reflux 4 hours, extracting solution reclaim solvent and are concentrated into driedly, and residue adds water 10ml, and slight fever makes dissolving, extracts 4 times with water saturated n-butyl alcohol jolting, at every turn 40ml; Merge n-butyl alcohol liquid, with ammonia solution thorough washing 2 times, 40ml discards ammoniacal liquor, n-butyl alcohol liquid evaporate to dryness at every turn; Residue adds water 5ml makes dissolving, put cold, through D101 type macroporous adsorptive resins (internal diameter 1.5cm, long 12cm), with water 50ml eluting; Discard water liquid, reuse 40% ethanol 30ml eluting discards eluent, continues with 70% ethanol 80ml eluting, collects eluent; Evaporate to dryness with dissolve with methanol and be transferred in the 5ml measuring bottle, adds methanol and is diluted to scale, shakes up, and promptly gets.
Accurate respectively reference substance solution 10 μ l, 20 μ l and the need testing solution 20 μ l of drawing of algoscopy inject chromatograph of liquid, measure, and calculate with 2 logarithmic equations of external standard, promptly get.
Table 6 three batches of Radix Astragali total saponins content, Astragaloside content and yield
The preparation of astragalus polysaccharides
Get Milkvetch Root 30kg, add 7 times of amount 70% ethanol extraction secondaries, each 2 hours, extracting solution discarded, the slag extracting in water secondary of getting it filled; Extracting solution merges, and the ratio that is concentrated into extracting liquid volume and raw medicinal herbs is 1.05: 1, adds ethanol precipitation and makes and contain the alcohol amount and reach 70%, and filtration must precipitate; Deposition is used 70% washing with alcohol, and the macroporous resin of filtrating is filtered in the dissolving of reuse suitable quantity of water; Use water elution, collect water lotion, water lotion is concentrated into medicine liquid volume with the medical material ratio is 1: 2.5, add ethanol and make and contain alcohol and measure and reach 70%; Must precipitate, will precipitate with 95% ethanol and washing with acetone dehydration, drying under reduced pressure (60 ℃) promptly gets.
Make three batches of astragalus polysaccharidess respectively, extract yield and content results see the following form 7.
The astragalus polysaccharides assay
The preparation of standard solution takes by weighing the glucose 100mg that is dried to constant weight through 105 ℃, and accurate the title decides, and puts in the 100ml measuring bottle, is dissolved in water, and is diluted to scale, shakes up.Precision is measured 10ml, puts in the 100ml measuring bottle, adds water to scale, shakes up, and is subsequent use.
Standard curve is drawn precision and is measured totally 6 parts of standard solution 0.1ml～0.6ml, puts respectively in the 25ml measuring bottle, adds water to 2.0ml, and adds phenol solution and (get phenol 300g; Aluminium flake 0.3g, sodium bicarbonate 0.15g mixes distillation, collects 182 ℃ of fractions; Be mixed with 5% aqueous solution) 1.0ml, shake up, drip concentrated sulphuric acid 5.0ml rapidly, shake up; Place 5min, put and heat 15min in the water-bath, take out, be cooled to room temperature rapidly; Other as blank, measures absorption value in the 490nm wavelength with the same operation repetitive of 2.0ml water, calculates regression equation.
Assay method is got Radix Astragali extract 0.5g and is put in the 25ml measuring bottle, and the method under the sighting target directrix curve drafting item is measured absorption value, according to the content of regression equation calculation polysaccharide from " adding water to 2.0ml " in accordance with the law.
The discriminating of astragalus polysaccharides
(1) get the about 0.2g of these article, add water 5ml dissolving after, add 5 of alkaline cupric tartrate test solutions; Heating promptly produces red precipitate, and cooling filters; Getting filtrating and adding 1 of hydrochloric acid and make acid, heating in water bath 10 minutes is put cold; Regulate pH value to neutral, add alkaline cupric tartrate test solution 0.5ml, heating in water bath promptly produces red copper oxidule precipitation.
(2) get the about 0.2g of these article, add water 2ml dissolving after, add 5% alpha-Naphthol alcoholic solution 0.5ml and shake up, slowly add sulphuric acid 3ml, two liquid level intersection displaing amaranth rings.
Three batches of astragalus polysaccharides content of table 7 and yield
The preparation of embodiment 3 present composition injectable powder
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium medical material 4kg)
Kurarinone 600g
Polyoxyethylene sorbitan monoleate 50g
Mannitol 200g
Sterile water for injection adds to 2000ml
Prepare 1000 altogether
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium medical material 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Milkvetch Root 1kg)
Polyoxyethylene sorbitan monoleate 50g
Mannitol 200g
Sterile water for injection adds to 2000ml
Prepare 1000 altogether
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium medical material 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Milkvetch Root 1kg)
Polyoxyethylene sorbitan monoleate 50g
Mannitol 200g
Sterile water for injection adds to 2000ml
Prepare 1000 altogether
Preparation technology:
1) vessel and the antibiotic glass bottle at first dosing used, plug etc. carry out aseptic process.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) get the water for injection of dosing amount 40%, add the polyoxyethylene sorbitan monoleate dissolving earlier fully, add the Chinese medicine extract of recipe quantity again, the heated and stirred dissolving fully.Kurarinone adds dosing amount 30% water for injection stirring and dissolving.Merge above-mentioned solution, add the dissolving of mannitol heated and stirred more fully, add sterile water for injection to full dose.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.22um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 4 hours then.
9) lyophilizing finishes, and lid is rolled in tamponade.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 4 present composition aqueous injection
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 4000ml
Prepare 2000 altogether
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Radix Astragali 1kg)
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 4000ml
Prepare 2000 altogether
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Radix Astragali 1kg)
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 4000ml
Prepare 2000 altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) get the water for injection of dosing amount 40%, add the polyoxyethylene sorbitan monoleate dissolving earlier fully, add the Chinese medicine extract of recipe quantity again, the heated and stirred dissolving fully.Kurarinone adds dosing amount 30% water for injection stirring and dissolving.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) with the solution sealing by fusing in glass ampule.
9) 100 ℃ of flowing steam sterilizations are 30 minutes.
10) while hot sample being put into 0.01% methylene blue solution hunts leak.
11) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5 present compositions transfusion
The sodium chloride transfusion:
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Polyoxyethylene sorbitan monoleate 50g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Radix Astragali 1kg)
Polyoxyethylene sorbitan monoleate 50g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Radix Astragali 1kg)
Polyoxyethylene sorbitan monoleate 50g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) handles the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) get the water for injection of dosing amount 40%, add the polyoxyethylene sorbitan monoleate dissolving earlier fully, add the Chinese medicine extract of recipe quantity again, the heated and stirred dissolving fully.Kurarinone, sodium chloride add dosing amount 30% water for injection stirring and dissolving.Merge above-mentioned solution, benefit adds to the full amount of water for injection.
3) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
4) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
5) through the microporous filter membrane fine straining of 0.45um.
6) clarity of inspection solution, the semi-finished product chemical examination.
7) fill is in the infusion bottle of 100ml.
8) 115 ℃ of pressure sterilizings are 30 minutes.
9) lamp inspection, finished product is examined entirely, the packing warehouse-in.
Glucose infusion liquid:
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Polyoxyethylene sorbitan monoleate 50g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Radix Astragali 1kg)
Polyoxyethylene sorbitan monoleate 50g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Radix Astragali 1kg)
Polyoxyethylene sorbitan monoleate 50g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Preparation technology:
1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
2) get the water for injection of dosing amount 40%, add the polyoxyethylene sorbitan monoleate dissolving earlier fully, add the Chinese medicine extract of recipe quantity again, the heated and stirred dissolving fully.Kurarinone, glucose add dosing amount 30% water for injection stirring and dissolving.Merge above-mentioned solution, benefit adds to the full amount of water for injection.
3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
6) through the microporous filter membrane fine straining of 0.45um.
7) clarity of inspection solution, the semi-finished product chemical examination.
8) fill is in the infusion bottle of 100ml.
9) 115 ℃ of pressure sterilizings are 30 minutes.
10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 present composition tablets
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Starch 120.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.5g
Carboxymethylstach sodium 7.0g
Prepare 2000 altogether
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Radix Astragali 1kg)
Starch 120.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.5g
Carboxymethylstach sodium 7.0g
Prepare 2000 altogether
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Radix Astragali 1kg)
Starch 120.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.5g
Carboxymethylstach sodium 7.0g
Prepare 2000 altogether
Preparation technology:
1) it is subsequent use Chinese medicine extract, kurarinone to be pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) hypromellose 2% the aqueous solution processed soluble in water is subsequent use.
4) with Chinese medicine extract, kurarinone, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and processes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) confirm sheet weight sheet by result of laboratory test.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 present composition capsules
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Starch 80.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Prepare 2000 altogether
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Radix Astragali 1kg)
Starch 80.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Prepare 2000 altogether
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Radix Astragali 1kg)
Starch 80.0g
Microcrystalline Cellulose 40.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 3.0g
Prepare 2000 altogether
Preparation technology:
1) it is subsequent use Chinese medicine extract, kurarinone to be pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) hypromellose 2% the aqueous solution processed soluble in water is subsequent use.
4) with Chinese medicine extract, kurarinone, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and processes suitable soft material.
5) cross 20 mesh sieve system granules.
6) granule is dried under 60 ℃ condition.
7) dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously.
8) sampling, the semi-finished product chemical examination.
9) loading amount of confirming according to chemical examination incapsulates.
10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 present composition granules
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Icing Sugar 1000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Radix Astragali 1kg)
Icing Sugar 1000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Radix Astragali 1kg)
Icing Sugar 1000.0g
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000 bags altogether
Preparation technology:
1) it is subsequent use sucrose to be pulverized 100 mesh sieves.It is subsequent use that Chinese medicine extract, kurarinone were pulverized 100 mesh sieves.
2) take by weighing raw material and adjuvant according to recipe quantity.
3) the method mix homogeneously that Chinese medicine extract, kurarinone and Icing Sugar is progressively increased with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and processes suitable soft material.
4) cross 20 mesh sieve system granules.
5) granule is dried under 60 ℃ condition.
6) dried granule is crossed 18 mesh sieve granulate.
7) sampling, the content of principal agent is confirmed loading amount in the semi-finished product chemical examination granule.
8) packing, finished product is examined entirely, the packing warehouse-in.
The preparation of 9 of the present invention groups of gold of embodiment composition soft capsule agent
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Soybean oil 500.0g
Soybean phospholipid 50g
Cera Flava 50g
Prepare 2000 altogether
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Radix Astragali 1kg)
Soybean oil 500.0g
Soybean phospholipid 50g
Cera Flava 50g
Prepare 2000 altogether
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Radix Astragali 1kg)
Soybean oil 500.0g
Soybean phospholipid 50g
Cera Flava 50g
Prepare 2000 altogether
Preparation technology:
Chinese medicine extract, kurarinone pulverize separately are crossed 100 mesh sieves, and with the soybean oil of recipe quantity and soybean phospholipid, Cera Flava heating and melting, mixing is put coldly, adds Chinese medicine extract, kurarinone grinds well, and is pressed into soft capsule and gets final product.
The preparation of embodiment 10 present composition drop pills
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Polyethylene glycol 6000 600g
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Radix Astragali 1kg)
Polyethylene glycol 6000 600g
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Radix Astragali 1kg)
Polyethylene glycol 6000 600g
Preparation technology:
With polyethylene glycol 6000 heating and melting in water-bath, treat to add Chinese medicine extract, kurarinone after whole fusions, stirring and dissolving, 60 mesh sieves filter, and keep 60 ℃ to splash in the liquid paraffin that is chilled to below 10 ℃ and process ball.
The preparation of embodiment 11 present composition oral liquids
Prescription:
Prescription 1
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Polyoxyethylene sorbitan monoleate 50g
Sodium benzoate 15g
Stevioside 10g
Water adds to 10000ml
Prepare 1000 altogether
Prescription 2
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Astragalus polysaccharides 15.6g (being equivalent to Radix Astragali 1kg)
Polyoxyethylene sorbitan monoleate 50g
Sodium benzoate 15g
Stevioside 10g
Water adds to 10000ml
Prepare 1000 altogether
Prescription 3
Cordyceps mycelium extract 34.8g (being equivalent to Cordyceps mycelium 4kg)
Kurarinone 600g
Radix Astragali total saponins 9.8g (being equivalent to Radix Astragali 1kg)
Polyoxyethylene sorbitan monoleate 50g
Sodium benzoate 15g
Stevioside 10g
Water adds to 10000ml
Prepare 1000 altogether
Preparation technology:
1) earlier that polyoxyethylene sorbitan monoleate is complete with the water dissolution of dosing amount 40%, again Chinese medicine extract is added the heated and stirred dissolving fully.Kurarinone adds dosing amount 30% water heating back dissolving fully.
2) sodium benzoate and stevioside is complete with the water dissolution of dosing amount 10%.
3) merge above-mentioned solution, mend and add water to full dose.
4) filtering with microporous membrane of mistake 0.8um.
5) semi-finished product chemical examination.
6) fill.Finished product is examined entirely, the packing warehouse-in.
Claims (4)
1. antitumor medicine composition; It is characterized in that said composition is mainly processed by following bulk drugs: the weight ratio of Cordyceps mycelium extract and kurarinone is: 10: 1,10: 3,4: 3,20: 1,20: 3,8: 3,50: 1 or 50: 3; Polysaccharide is not less than 30% in the wherein said Cordyceps mycelium extract.
2. antitumor medicine composition; It is characterized in that said composition is processed by following bulk drugs: the weight ratio of Cordyceps mycelium extract, kurarinone and astragalus polysaccharides is 20: 2: 5,10: 3: 5,4: 3: 40,40: 2: 5,20: 3: 5,8: 3: 40,100: 2: 5,50: 3: 5 or 20: 3: 40; Perhaps be: the weight ratio of Cordyceps mycelium extract, kurarinone and Radix Astragali total saponins is 20: 2: 5,10: 3: 5,4: 3: 40,40: 2: 5,20: 3: 5,8: 3: 40,100: 2: 5,50: 3: 5 or 20: 3: 40; Polysaccharide is not less than 30% in the wherein said Cordyceps mycelium extract; Described astragalus polysaccharides content is not less than 50%; The content of described Radix Astragali total saponins is not less than 50%, Astragaloside content is not less than 2.0% in the Radix Astragali total saponins.
3. like claim 1,2 described arbitrary pharmaceutical compositions, it is characterized in that said composition processes clinically any or pharmaceutically acceptable dosage form.
4. pharmaceutical composition as claimed in claim 3 is characterized in that said composition processes injection or oral formulations.
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| CN2005100450678A CN1961894B (en) | 2005-11-10 | 2005-11-10 | A novel compound pharmaceutical composition, preparation method and use thereof |
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| CN2005100450678A CN1961894B (en) | 2005-11-10 | 2005-11-10 | A novel compound pharmaceutical composition, preparation method and use thereof |
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| CN1961894A CN1961894A (en) | 2007-05-16 |
| CN1961894B true CN1961894B (en) | 2012-03-21 |
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| CN2005100450678A Expired - Fee Related CN1961894B (en) | 2005-11-10 | 2005-11-10 | A novel compound pharmaceutical composition, preparation method and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102168108B (en) * | 2010-12-17 | 2013-04-24 | 广东省微生物研究所 | Cordyceps cardinalis, method for preparing oosporin by using same and application of Cordyceps cardinalis |
| CN106166182A (en) * | 2016-06-29 | 2016-11-30 | 浙江圣博康药业有限公司 | A kind of Cordyceps complex capsule |
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