CN101002791A - Traditional Chinese medicine composition for treating cerebrovascular disease, and its preparing method - Google Patents
Traditional Chinese medicine composition for treating cerebrovascular disease, and its preparing method Download PDFInfo
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- CN101002791A CN101002791A CN 200710019421 CN200710019421A CN101002791A CN 101002791 A CN101002791 A CN 101002791A CN 200710019421 CN200710019421 CN 200710019421 CN 200710019421 A CN200710019421 A CN 200710019421A CN 101002791 A CN101002791 A CN 101002791A
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Abstract
A Chinese medicine for treating cerebrovascular disease contains iridoid glycoside (1-14 Wt portions) extracted from capejasmine fruit, and erigerontis flavone (1-2) extracted from fleabane herb. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to a kind of Chinese medicine composition for the treatment of cerebrovascular disease and preparation method thereof, in particular for the Chinese medicine and preparation method thereof of treatment cerebrovascular disease.
Background of invention
Cerebrovascular is a kind of worldwide commonly encountered diseases, and its feature is sickness rate height, case fatality rate height, disability rate height.At present, this type of disease generally all is to adopt chemicals to treat, but poor effect and toxic and side effects are bigger, and there is the problem of effectiveness, safety aspect in most drug, still lacks remarkable, the curative effect medicine permanent, safe in utilization of real effect.
Fructus Gardeniae is the dry mature fruit of Maguireothamnus speciosus Fructus Gardeniae [Gardenia jasminoides Ellis].This product is cold in nature, bitter in the mouth, GUIXIN, lung, tri-jiao channel.Effect is the pathogenic fire purging relieving restlessness, clearing away heat and promoting diuresis, removing pathogenic heat from blood and toxic substance from the body.It is vexed to be used for calentura, the jaundice dark coloured urine, and blood strangury and dry pain, heat in blood is told nosebleed, conjunctival congestion and swelling pain, pathogenic fire,toxin and furuncles, external treatment bruise pain.Disturb the heart in order to the treatment pathogenic heat more than clinical, flaming up of liver-fire, vexed gloomy, restlessness is not peaceful; Or fire-toxin is flourishing, hyperpyrexia agitation, the card of unconsciousness and delirium and the absurd row of various warm blood.Contain several iridoid glucosides, organic acid, pigment, volatile ingredient, polysaccharide component in the Fructus Gardeniae.Wherein Fructus Gardeniae total iridoid glycosides comprises jasminoidin (geniposide), Gardenoside (gardenoside), genipin gentiobiose glycosides (genipingentiobioside), shanzhiside (shanzhiside), Fructus Gardeniae ketoside (gardoside), Herba Paederiae time glycosides methyl ester (scandosidemethyl ester), takes off acetyl asperuloside acid methyl ester (methyl deacylasperulosi date), Fructus Gardeniae thuja acid (geniposidic acid) etc.
The Chinese medicine Herba Erigerontis has another name called Herba Erigerontis, is the dry herb of feverfew Erigeron breviscapus (Vant.) Hand.-Mazz. [Erigeron breviscapus (Vant.) Hand.-Mazz.].Mainly be distributed in provinces and regions, China southwest, head is stated from " the southern regions of the Yunnan Province book on Chinese herbal medicine ", records in one one of Pharmacopoeia of the People's Republic of China version in 1977.Herba Erigerontis hardship cold in nature, little, Gan Wenxin have the effect of expelling cold and relieving exterior syndrome, expelling wind and removing dampness, blood circulation promoting and blood stasis dispelling, dredge the meridian passage, anti-inflammatory analgetic.Mainly comprise lamp-dish flower acetic (also being called scutellarin), oil lamp cycle of sixty years element (also claiming breviscapine), apigenin and high baicalin in the Herba Erigerontis in the flavones ingredient of extraction separation.
Modern pharmacy studies have shown that: the pathogenesis complexity of cerebrovascular disease, the pharmacological action link of single medicine has limitation undoubtedly, fundamentally treat cerebrovascular disease and must intervene on a plurality of links.
Summary of the invention
The present invention to research and develop on a plurality of links intervene, the treatment for the treatment of both the principal and secondary aspects of a disease and pharmaceutical composition of prevention of brain angiopathy and preparation method thereof.
For addressing the above problem, the invention provides following technical scheme.
A kind of is the pharmaceutical composition of main active with jasminoidin, lamp-dish flower acetic or its salt, jasminoidin in the said composition: lamp-dish flower acetic or its salt are 14-1 by weight: 1-2 part.
Lamp-dish flower acetic or its salt are meant the lamp-dish flower acetic officinal salt, officinal salt commonly used has: lamp-dish flower acetic alkaline amino acid salt, lamp-dish flower acetic sodium salt, lamp-dish flower acetic potassium salt or calcium salt, lamp-dish flower acetic alkaline amino acid salt comprise lamp-dish flower acetic lysinate or lamp-dish flower acetic arginine salt.
Preferred is the pharmaceutical composition of main active, wherein jasminoidin with jasminoidin, lamp-dish flower acetic or its salt: lamp-dish flower acetic or its salt are 7-1 by weight: 1 part.
A kind of pharmaceutical composition for the treatment of cerebrovascular disease, the weight proportion that it is characterized in that described active component are Fructus Gardeniae extract iridoid glycoside 14-1 parts, flavone extract 1-2 part of Herba Erigerontis; Jasminoidin content is not less than 50% in the Fructus Gardeniae extract iridoid glycoside; Lamp-dish flower acetic content is not less than 50% in the flavone extract of Herba Erigerontis.The weight proportion of preferred active component is Fructus Gardeniae extract iridoid glycoside 7-1 part, 1 part of the flavone extract of Herba Erigerontis; Jasminoidin content is 70%～95% in the Fructus Gardeniae extract iridoid glycoside; Lamp-dish flower acetic content is 70%～95% in the Herba Erigerontis flavone extract.Its Fructus Gardeniae extract (iridoid glycoside) is the mixture of jasminoidin, Gardenoside and genipin gentiobiose glycosides or shanzhiside, and the flavone extract of Herba Erigerontis is the mixture of lamp-dish flower acetic, oil lamp cycle of sixty years element and apigenin or high baicalin.
A kind of pharmaceutical composition for the treatment of cerebrovascular disease, it is made by following bulk drugs: Fructus Gardeniae 14-1 part, Herba Erigerontis 7-14 part.The preferred feedstock survival dose is: Fructus Gardeniae 7-1 part, 7 parts of Herba Erigerontiss.Described preparation of drug combination method, the flavone extract preparation method of its Fructus Gardeniae extract and Herba Erigerontis is as follows:
By weight the difference weighting raw materials; Get Fructus Gardeniae, extract, concentrate ethanol extract, last activated-charcoal column with the 50%-100% alcoholic solution, elder generation's water eluting, reuse 30%-80% alcoholic solution eluting, the eluent of collection 30%-80% alcoholic solution is after concentrating, filter to such an extent that precipitate, dry sediment gets Fructus Gardeniae extract; Get Herba Erigerontis, use water extraction, add ethanol after aqueous extract concentrates after contain the alcohol amount and reach 35%-70%, leave standstill filtration, filtrate concentrate concentrated solution, regulate concentrated solution to acid with strong acid, get precipitation after leaving standstill filtration, will precipitate and use the 45-75% dissolve with ethanol, through the stand at low temperature after-filtration, get precipitation, dry sediment gets Herba Erigerontis extract; The Fructus Gardeniae extract and the Herba Erigerontis flavone extract that obtain are mixed with pharmaceutically acceptable carrier.Described pharmaceutically acceptable carrier comprises the carrier or the adjuvant of oral formulations and injection.
Preparation method is preferably: get Fructus Gardeniae, with 60%～90% ethanol extraction, concentrating ethanol extract to relative density is 1.1～1.20 (60 ℃), in concentrated solution, add entry, leave standstill after-filtration, activated-charcoal column on the filtrate, first water eluting, reuse 40%-70% ethanol elution, collect the 40%-70% ethanol elution, after eluent is concentrated, filter to such an extent that precipitate, dry sediment gets Fructus Gardeniae extract; Jasminoidin content is not less than 50% in the Fructus Gardeniae extract; Except that jasminoidin, also contain other iridoid glycoside composition in the Fructus Gardeniae extract,, and come from other the pharmaceutically acceptable composition of Fructus Gardeniae or the impurity of common content as Gardenoside, genipin gentiobiose glycosides or shanzhiside.Get Herba Erigerontis, use water extraction, add ethanol after aqueous extract concentrates after contain the alcohol amount and reach 40-60%, leave standstill filtration, filtrate concentrate concentrated solution, regulate concentrated solution to pH value 1-4 with hydrochloric acid, sulphuric acid or phosphoric acid, get precipitation after leaving standstill filtration, will precipitate and use the 50-65% dissolve with ethanol, through the stand at low temperature after-filtration, get precipitation, dry sediment gets Herba Erigerontis extract; Lamp-dish flower acetic content is not less than 50% in the flavone extract of Herba Erigerontis; In the Herba Erigerontis extract, except that lamp-dish flower acetic, also contain other chromocor compound,, and come from other the pharmaceutically acceptable composition of Herba Erigerontis or the impurity of common content as oil lamp cycle of sixty years element, apigenin or high baicalin.After getting Fructus Gardeniae extract and water for injection mixing, dissolving is filtered, and gets Fructus Gardeniae extract solution; After getting Herba Erigerontis extract, metal ion chelation agent and water for injection mixing, add alkaline PH regulator, filter, get Herba Erigerontis extract solution to pH value 8-10; With getting mixed liquor after Fructus Gardeniae extract solution and the mixing of Herba Erigerontis extract solution, regulate mixed liquor to pH value 8-10 with alkaline PH regulator, add water for injection, filter, get filtrate, embedding is sterilized.Metal ion chelation agent wherein can be disodium edetate and/or calcium disodium edetate.The PH regulator can be selected from a kind of in the liquor ammoniae fortis, sodium hydroxide, ethylenediamine of 1-10% or their mixture.
The preparation method of preferred pharmaceutical composition is: get Fructus Gardeniae, use 70%-80% ethanol extraction 2-3 time, each 1-2 hour, concentrated extracting solution to relative density is 1.1～1.20 (60 ℃), and concentrated solution adds water, leaves standstill after-filtration, activated-charcoal column on the filtrate, first water eluting, reuse 50%-60% ethanol elution, collect the 50%-60% ethanol elution, the 50%-60% ethanol elution is concentrated, after the stand at low temperature, filter and obtain precipitate, dry sediment gets Fructus Gardeniae extract; Jasminoidin content is 70%～95% and (generally just can thinks pure product more than 95%, often contain pharmaceutically acceptable other composition and/or impurity in the extract in the Fructus Gardeniae extract iridoid glycoside.Except that jasminoidin, also contain other iridoid glycoside composition in the Fructus Gardeniae extract,, and come from other the pharmaceutically acceptable composition of Fructus Gardeniae or the impurity of common content) as Gardenoside, genipin gentiobiose glycosides or shanzhiside.Get Herba Erigerontis, use water extraction 2-3 time, each 1-2 hour, after concentrating, aqueous extract adds ethanol after contain the alcohol amount and reach 45-50%, leave standstill filtration, filtrate concentrate concentrated solution, regulate concentrated solution to pH value 2-3 with hydrochloric acid, get precipitation after leaving standstill filtration, to precipitate and use the 55-60% dissolve with ethanol,, get precipitation through the stand at low temperature after-filtration, dry sediment gets Herba Erigerontis extract; Lamp-dish flower acetic content is 70%～95% and (generally just can thinks pure product more than 95%, often contain pharmaceutically acceptable other composition and/or impurity in the extract in the Herba Erigerontis flavone extract.In the Herba Erigerontis extract, except that lamp-dish flower acetic, also contain other chromocor compound,, and come from other the pharmaceutically acceptable composition of Herba Erigerontis or the impurity of common content) as oil lamp cycle of sixty years element, apigenin or high baicalin.After getting Fructus Gardeniae extract 74 gram and water for injection mixing, dissolving, filtration must Fructus Gardeniae extract solution; After getting disodium edetate or calcium disodium edetate 3.2 grams, Herba Erigerontis extract 13 grams and water for injection and mixing, add the 1-10% sodium hydroxide, filter to pH value 8.5-9, Herba Erigerontis extract solution; To get mixed liquor after Fructus Gardeniae extract solution and the mixing of Herba Erigerontis extract solution, regulate mixed liquor to pH value 8.5-9 with the 1-10% sodium hydroxide, after adding water for injection to 2000 milliliter, filter, get filtrate, embedding, after the sterilization, detecting pH value is 7.2～8.2, detects particulate matter, contain the above microgranule of 10 μ m among every 1ml and be no more than 20, contain the above microgranule of 25 μ m and be no more than 2.
Jasminoidin and lamp-dish flower acetic or its salt are the application of compositions in preparation treatment or prevention cerebrovascular disease medicament that main active is formed.Jasminoidin in the said composition: lamp-dish flower acetic or its salt are 14-1 by weight: 1-2 part.
The application of the compositions that the flavone extract of Fructus Gardeniae extract iridoid glycoside and Herba Erigerontis is formed in preparation treatment or prevention cerebrovascular disease medicament.Fructus Gardeniae extract iridoid glycoside 14-1 part by weight in the said composition, flavone extract 1-2 part of Herba Erigerontis; Jasminoidin content is not less than 50% in the Fructus Gardeniae extract iridoid glycoside; Lamp-dish flower acetic content is not less than 50% in the flavone extract of Herba Erigerontis.
The application of the compositions that Fructus Gardeniae and Herba Erigerontis are formed in preparation treatment or prevention cerebrovascular disease medicament.Its by weight, Fructus Gardeniae 14-1 part, Herba Erigerontis 7-14 part.
Application in aforementioned preparation treatment or the prevention cerebrovascular disease medicament, it is characterized in that preparing by reducing behind the ischemia content of MCP-1 in the rat cerebral tissue, prolong whole blood coagulation time in mice, promote fibrinous course of dissolution, reducing in the global brain ischemia cerebral tissue of mice broken end back MDA and generate, increase the SOD vigor and/or reduce LDH and discharge, produce the medicine of anticoagulation, anti-cerebral ischemia and cerebral anoxia effect.
The cerebrovascular disease of treatment of the present invention or prevention mainly is meant anticoagulation, anti-cerebral ischemia and cerebral anoxia.Pharmaceutical composition of the present invention is by reducing behind the ischemia content of MCP-1 in the rat cerebral tissue, prolong whole blood coagulation time in mice, promote fibrinous course of dissolution, reducing in the global brain ischemia cerebral tissue of mice broken end back MDA and generate, increase the SOD vigor and/or reduce LDH and discharge, demonstrate its many target spots concertedness, thereby the effect with remarkable anticoagulation, anti-cerebral ischemia and cerebral anoxia reaches the effect to the cerebrovascular disease treating both the principal and secondary aspects of a disease.
The present invention has studied the pharmaceutical composition with Herba Erigerontis and Fructus Gardeniae composition that is used for the treatment of cerebrovascular disease; The pharmaceutical composition of forming with the effective site of extraction separation in Herba Erigerontis and the Fructus Gardeniae, and effective site extracting method separately in Herba Erigerontis and the Fructus Gardeniae.The present invention also studies the pharmaceutical composition that effective ingredient jasminoidin and lamp-dish flower acetic are formed in Herba Erigerontis and the Fructus Gardeniae.Pharmaceutical composition of the present invention can contain adjuvant pharmaceutically commonly used or carrier, is prepared into conventional oral formulations or injection.
The present invention has further studied with described Fructus Gardeniae and Herba Erigerontis extract and has been active component, is used for the treatment of the prescription and the preparation process of the Chinese medicine of cerebrovascular disease.Wherein Herba Erigerontis extract is mainly lamp-dish flower acetic, and content is for being not less than 50%, and is preferred 70%～95%, and Fructus Gardeniae extract is mainly jasminoidin, and content is not less than 50%, is preferably 70%～95%.When the content of lamp-dish flower acetic in the plant extract or jasminoidin surpasses 95%, generally just think to contain the pure product of normal impurities.Lamp-dish flower acetic and jasminoidin also can be bought the commercial goods.Can as required lamp-dish flower acetic and the jasminoidin of buying be carried out preparing medicines behind the conventional purification again.
The pathogenesis complexity of cerebrovascular disease, the pharmacological action link of single medicine has limitation undoubtedly, fundamentally treat cerebrovascular disease and must intervene on a plurality of links.The present invention utilizes the compound preparation of Herba Erigerontis and Fructus Gardeniae, the pharmaceutical composition that comprises the effective site composition of extraction separation in Herba Erigerontis and the Fructus Gardeniae, and the pharmaceutical composition that effective ingredient is formed in Herba Erigerontis and the Fructus Gardeniae, many target spots of performance concertedness has solved the limitation of single medicine effect well on the mechanism of action.Pharmaceutical composition of the present invention is intervened treating both the principal and secondary aspects of a disease on a plurality of links of cerebrovascular disease outbreak process.The pharmacodynamic study result shows that two kinds of drug combinations can bring into play synergistic function on the pharmacology index.The bioavailability height of pharmaceutical composition of the present invention, rapid-action is particularly suited for the treatment of cerebrovascular disease.This Chinese medicine compound injection prescription element is few on the other hand, processing technology advanced person, and the quality of production is easy to control, is fit to large-scale production, and convenient transportation and storage help large-scale promotion application clinically.
Pharmaceutical composition of the present invention has the effect that treats and/or prevents cerebrovascular disease, and its principal indication has blood circulation promoting and blood stasis dispelling, and it is active to promote blood circulation, and is used for apoplectic hemiplegia, syndrome of static blood blocking collaterals; The arteriosclerosis cerebral thrombotic infarction, cerebral embolism, central retinal vein occlusion see syndrome of static blood blocking collaterals person, and other and cerebrovascular disease have the disease of directly or indirectly getting in touch.Suggestion with 0.9% isotonic sodium chloride or 5% etc. ooze 10% glucose injection dilution posterior vein and instil, when using the 2ml specification, each 3, every day 1 time, or according to the concrete state of an illness, in accordance with doctor's advice.The cubical content that this product is every bottle can be at 2～20ml.The specification of Shi Yonging is recommended as 2ml, 5ml, 10ml and 20ml clinically.
With after the Fructus Gardeniae pulverizing medicinal materials, more than 1 time, each extraction time is more than 0.5 hour with 50%～100% alcohol reflux of 5-25 times of weight (by medical material weight) among the present invention; Preferably with 60%～90% alcohol reflux of 7-15 times of weight (by medical material weight); More preferably with the 70%-80% alcohol reflux of 8-10 times of weight (by medical material weight); Filter extracting solution, after the merging, get Fructus Gardeniae medical material crude extract.Fructus Gardeniae medical material crude extract is concentrated into the extractum of relative density 1.1～1.20 (60 ℃); The water (by medical material weight) that adds 5-20 times of weight preferably adds the water of 7-15 times of weight, more preferably adds the water of 8-10 times of weight; After leaving standstill, filter; Filtrate concentrates, be splined on active carbon adsorption column, earlier with 1-10 times of (preferred 2-5 doubly) weight water (by medical material weight) eluting, doubly (preferred 6-10 doubly for reuse 5-15, more preferably 7-8 is doubly) 30%-80% ethanol (the preferred 40%-70% ethanol of weight (by medical material weight), more preferably 50%-60% ethanol) eluting is collected ethanol elution; With the concentrated back of ethanol elution deepfreeze (preferred temperature is controlled at 0～5 ℃), filter, get the precipitation drying, promptly get Fructus Gardeniae extract.
Further specifying of Fructus Gardeniae extraction process excellent results: the Fructus Gardeniae medical material is slightly carried in the process, as extracting with alcohol percolation method, handles a large amount of ethanol and can bring hidden danger to safety in production.Slightly carry if adopt water to do solvent, a large amount of also strippings thereupon of water-solubility impurity (pectin, phlegmatic temperament, polysaccharide etc.) make troubles for follow-up separation, purification work.Therefore the present invention selects for use a certain proportion of alcohol heating reflux slightly to extract.In the Fructus Gardeniae extract subtractive process, the present invention's macroporous resin of no use, because macroporous resin does not still have medicinal specification at present, and how residual impurity such as unconverted monomer, perforating agent, initiator and analyte thereof, dispersant and antiseptic are arranged, thereby will certainly damage human body.The present invention does not adopt traditional methods such as column chromatography and recrystallization yet, because these class methods generally need be used poisonous organic solvent (chloroform, methanol).Active carbon is as the advantage of refining material by contrast: (1) charcoal treatment do not have catabolite residual, do not use a class or two class organic solvents, the Product Safety height, domestic have the medicinal specification production of injection stage; (2) low price is fit to industrialized great production; (3) operating process is simple relatively.Therefore this patent selects for use activated carbon column chromatography that crude extract is carried out purification.
Get the Herba Erigerontis medical material among the present invention,, add the doubly water reflux, extract, of (preferred 6-10 doubly, more preferably 7-8 is doubly) weight more than 1 time of 5-15 by medical material weight, preferred 2-3 time, each more than 0.5 hour, preferably 1-2 hour, merge the Herba Erigerontis crude extract.After concentrating the Herba Erigerontis crude extract, add ethanol, the limit edged stirs, and reaches 35%-70% to containing the alcohol amount, preferably reaches 40%-60%; After more preferably reaching 45%-50%, leave standstill, filter, leave and take filtrate.The filtrate of leaving and taking is concentrated, regulate pH value to 1-4 (preferred PH2-3) with strong acid, leave standstill (carry out acid precipitation, promptly precipitate at acid condition), described strong acid can be selected hydrochloric acid, sulphuric acid, phosphoric acid or other pharmaceutically available acid for use).After the filtration, get precipitation, with 45-75% ethanol (preferred 50-65% ethanol, more preferably 55-60% ethanol) dissolving, the ethanol consumption so that precipitation be dissolved as substantially suitable, low temperature (preferred temperature is at 0-5 ℃) cold preservation; Filter cold preservation liquid, get and precipitate with after the 80%-100% washing with alcohol, drying promptly gets Herba Erigerontis extract.
The detection of pyromeconic acid in the Herba Erigerontis extract: (1) detects principle: pyromeconic acid is met ferric chloride and is shown red; (2) operating process: select for use with a collection of Herba Erigerontis medical material, get the method for 1g embodiment 7-12 respectively and extract the extract that obtains, add chloroform 60ml, warm macerating is 2 hours in 55～60 ℃ of hot baths, filter, filtrate is for point sample usefulness, simultaneously with the contrast of pyromeconic acid reference substance (this laboratory is from putting forward purity 99.5%) chloroformic solution point sample.Developing solvent: chloroform-dehydrated alcohol (1: 1), the silica gel G plate development, exhibition is apart from 20cm.Developer: 10% liquor ferri trichloridi.Spray behind the developer under the daylight whether pyromeconic acid relevant position color changes in the observation sample thin layer chromatography.The thin-layer sample chromatograph of this patent Herba Erigerontis medicinal substances extract is not all found to redden in pyromeconic acid relevant position color as a result.Promptly the pyromeconic acid harmful substance do not arranged so that the extract of the extracting method of this patent preparation is residual.
Further specifying of Herba Erigerontis extraction process excellent results: the organic solvent of the unique use of the present invention's (1) overall process is an ethanol, do not use organic reagents such as ethyl acetate, n-butyl alcohol, do not use purified material such as macroporous resin, polyamide, silica gel, avoided causing the residual of chemical impurity and chemical reagent, and reduced cost; (2) owing to adopt water to carry, contain low polarity liposoluble impurity such as oils and fats, pigment, quintessence oil in the extracting solution hardly; (3) adding ethanol carries out precipitate with ethanol and makes that pectin, phlegmatic temperament, polysaccharide isopolarity are removed greater than the impurity of lamp-dish flower acetic; (4) add acid in the purge process and regulate pH value, make that the phenolic acid acid ingredient---lamp-dish flower acetic precipitates, the purity of extract greatly improves; (5) Herba Erigerontis extract is not residual harmful substance a---pyromeconic acid.
The pharmaceutical composition that pharmaceutical composition that the effective site of extraction separation is formed in the pharmaceutical composition that Herba Erigerontis of the present invention and Fructus Gardeniae are formed, usefulness Herba Erigerontis and the Fructus Gardeniae and jasminoidin and lamp-dish flower acetic are formed, all can mix, make conventional oral formulations or injection with common carrier pharmaceutically.Oral carrier pharmaceutically commonly used has: hyprolose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose; Lactose, microcrystalline Cellulose, dextrin, starch, calcium phosphate; Pregelatinized Starch, polyvidone, sodium carboxymethyl cellulose, hypromellose; Pulvis Talci, magnesium stearate, micropowder silica gel, hydrogenated vegetable oil; Sodium lauryl sulphate, Tween 80; Hypromellose, ethyl cellulose etc.Injection of the present invention also can be selected following adjuvant for use: solubilizing agent is as Tween 80, pluronic F-68, polyoxyethylene hydrogenated Oleum Ricini etc.; Suspending agent is as sodium carboxymethyl cellulose, polyvidone, hydroxypropyl methylcellulose etc.; Antiseptic is as Metagin, second, third and butyl ester; The pH regulator agent is as citric acid and citrate; Phosphate etc.; Solvent is as water for injection, injection ethanol etc.
The principal agent in the injection prescription of the present invention and the proportioning feature of adjuvant are as follows according to weight ratio: Fructus Gardeniae extract 14-1 part, Herba Erigerontis extract 1-2 part and metal ion chelation agent 0.2-1 part, alkaline PH regulator is an amount of.Metal ion chelation agent wherein can be disodium edetate and/or calcium disodium edetate.The PH regulator can be selected from a kind of in liquor ammoniae fortis, sodium hydroxide, the ethylenediamine or their mixture.Depletion belongs to ion chelating agent and adds an amount of water for injection and make dissolving, described an amount of finger can make its dissolved amount, add Herba Erigerontis extract, and add injection water an amount of (water for injection that generally adds 10 times of weight of Herba Erigerontis extract), dropping contains the aqueous solution of 1-10% alkalescence PH regulator, regulate pH value to 8-10 (preferred 8.5-9), filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract, add water for injection, stir and make dissolving, filter, get Fructus Gardeniae extract solution.Merge above-mentioned Herba Erigerontis extract solution and Fructus Gardeniae extract solution, drip the aqueous solution that contains the alkaline PH regulator of 1-10% (preferred 1-5%) and regulate pH value, add injection water to every milliliter of injection and meet corresponding labelled amount to 8-10 (preferred PH8.5-9), the operating routine consumption adds needle-use activated carbon routinely, is incubated and stirs under 60～70 ℃ 20 minutes, puts and is chilled to room temperature, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing, promptly.
Lamp-dish flower acetic or to contain the dissolubility that lamp-dish flower acetic is not less than 50% Herba Erigerontis extract be a difficult problem, the present invention is by the alkaline PH regulator of once above adding in preparation medicine process, for example secondary is regulated pH value PH8-10 in the preparation process, has solved this difficult problem.Especially regulate the intermediate pH value, be included in the injection heat sterilization and before the pH value of injection be controlled between the PH8-10, not only the finished product pH value meets the pharmacopeia requirement, and has improved the clarity of finished product and the qualification rate that visible foreign matters is checked item greatly.
The end product quality standard of medicine of the present invention:
Character is the clear liquid of sundown to yellowish-brown.PH value is 7.2～8.2 (appendix VIIG of Chinese Pharmacopoeia version in 2005).
Particulate matter is got this product 25ml and is checked (appendix IXR of Chinese Pharmacopoeia version in 2005) in accordance with the law, contains the above microgranule of 10 μ m among every 1ml and must not cross 20, contains the above microgranule of 25 μ m and must not cross 2.
Protein is got this product 1ml, adds freshly prepared 30% sulfosalicylic acid test solution 1ml, mixes and places 5 minutes, muddiness must not occur.
Tannin is got this product 1ml, adds the freshly prepared normal saline 5ml that contains 1% Ovum Gallus domesticus album, mixes and places 10 minutes, muddiness or precipitation must not occur.
Resin is got this product 5ml, and 1 of dripping hydrochloric acid was newly placed 30 minutes, should not have the resin-like thing and separated out.
The accurate this product 10ml that draws of total solid puts in the evaporating dish that is dried to constant weight, evaporate to dryness, and drying is 3 hours under 105 ℃, and in the dislocation exsiccator, cooling is weighed.
Testing results such as clarity and color and luster, oxalates, potassium ion, heavy metal, arsenic salt, residue on ignition, content uniformity, aseptic, undue toxicity, depressor substance, anaphylaxis, haemolysis and cohesion, pyrogen show and meet relevant national standard.
Pharmaceutical composition of the present invention checks that the detection method of item is with reference to standard under appendix continuous item of Chinese Pharmacopoeia version in 2005.
Finger printing is according to high performance liquid chromatography (appendix VID of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica; With mobile phase 0.1% phosphoric acid (A)-acetonitrile (B), according to the form below carries out gradient elution; Flow velocity is per minute 0.8ml; The detection wavelength is 238nm.Number of theoretical plate should be not less than 1500 by the jasminoidin peak; The separating degree of jasminoidin and lamp-dish flower acetic should be greater than 1.5.
Table 1: gradient elution table
| Time (minute) | A(％) | B(％) |
| 0 5 15 22 39 43 51 60 | 93 88 85 74 66 60 0 0 | 7 12 15 26 34 40 100 100 |
The preparation of reference substance solution is accurate respectively to take by weighing at 2 hours jasminoidin of 60 ℃ of drying under reduced pressure and lamp-dish flower acetic reference substance in right amount, adds methanol and makes the mixed solution that contains certain density jasminoidin and lamp-dish flower acetic.
The preparation precision of need testing solution is measured this product 1ml, puts in the 10ml measuring bottle, adds methanol to scale, shakes up, and therefrom precision is measured 1ml again, puts in the 10ml measuring bottle, adds methanol to scale, shakes up, promptly.
The accurate need testing solution 10 μ l that draw of algoscopy inject high performance liquid chromatograph, write down 60 minutes chromatograms, promptly.The collection of illustrative plates of test sample (medicine of the present invention) is consistent with the reference substance collection of illustrative plates, and after rejecting solvent peak and proofreading and correct with multiple spot, similarity is not less than 0.90.
Assay is according to high performance liquid chromatography (appendix VID of Chinese Pharmacopoeia version in 2005).
Chromatographic condition and system suitability test: referring to the fingerprint image spectral term.
The preparation of reference substance solution: referring to the preparation method under the fingerprint image spectral term.
The preparation of need testing solution: referring to the preparation method under the fingerprint image spectral term.
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly.
The specific embodiment
The used Fructus Gardeniae medical material of the present invention converges core hall prepared slices of Chinese crude drugs company limiteies (Fructus Gardeniae GAP base) available from Jiangxi, meets 2005 editions Chinese Pharmacopoeia corresponding requirements.The Herba Erigerontis medical material meets 2005 editions Chinese Pharmacopoeia corresponding requirements available from Luxi County, Yunnan Province Honghe Qianshan Biological Engineering Co., Ltd. (Herba Erigerontis GAP base).Used adjuvant is provided by Anhui Shanhe Medical Accessary Material Co., Ltd., meets the respective country standard.
The used lamp-dish flower acetic of the present invention is available from Yunnan Honghe Qianshan Biological Engineering Co., Ltd., and jasminoidin all meets the respective country standard available from the dicotyledonous bio tech ltd in Sichuan.
Embodiment 1:
Get Fructus Gardeniae medicinal material coarse powder 10kg, with 50% ethanol 50kg reflux, extract, 3 times, each 2 hours, filter, merge extractive liquid,, concentrated extracting solution to relative density is 1.10 (60 ℃), add 50kg water, leave standstill, filter, filtrate concentrates, and is splined on active carbon adsorption column, uses earlier the 10kg water elution, reuse 30% ethanol 50kg eluting is collected 30% ethanol elution, concentrates the back in 0-5 ℃ of deepfreeze, filter to such an extent that precipitate, dry sediment obtains Fructus Gardeniae extract 284.2g.Extract carries out jasminoidin in the Fructus Gardeniae extract of assay with the method for assay in the quality standard content is: 58.22%.
Embodiment 2:
Get Fructus Gardeniae medicinal material coarse powder 10kg, with 60% ethanol 70kg reflux, extract, 3 times, each 2 hours, filter, merge extractive liquid,, concentrated extracting solution to relative density is 1.10 (60 ℃), add 70kg water, leave standstill, filter, filtrate concentrates, and is splined on active carbon adsorption column, uses earlier the 20kg water elution, reuse 40% ethanol 60kg eluting is collected 40% ethanol elution, concentrates the 0-5 ℃ of deepfreeze in back, filter to such an extent that precipitate, dry sediment obtains Fructus Gardeniae extract 264.8g.Extract carries out jasminoidin in the Fructus Gardeniae extract of assay with the method for assay in the quality standard content is: 65.81%.
Embodiment 3:
Get Fructus Gardeniae medicinal material coarse powder 10kg, with 70% ethanol 80kg reflux, extract, 3 times, each 2 hours, filter, merge extractive liquid,, concentrated extracting solution to relative density is 1.10 (60 ℃), add 80kg water, leave standstill, filter, filtrate concentrates, and is splined on active carbon adsorption column, uses earlier the 20kg water elution, reuse 50% ethanol 70kg eluting is collected 50% ethanol elution, concentrates the back in 0-5 ℃ of deepfreeze, filter to such an extent that precipitate, dry sediment obtains Fructus Gardeniae extract 240.1g.Extract carries out assay with the method for assay in the quality standard, and the content of jasminoidin is in the Fructus Gardeniae extract: 75.95%.
Embodiment 4:
Get Fructus Gardeniae medicinal material coarse powder 10kg, with 80% ethanol 100kg reflux, extract, 2 times, each 1 hour, filter, merge extractive liquid,, concentrated extracting solution to relative density is 1.10 (60 ℃), add 100kg water, leave standstill, filter, filtrate concentrates, and is splined on active carbon adsorption column, uses earlier the 20kg water elution, reuse 60% ethanol 80kg eluting is collected 60% ethanol elution, concentrates the back in 0-5 ℃ of deepfreeze, filter to such an extent that precipitate, dry sediment obtains Fructus Gardeniae extract 200.8g.Extract carries out jasminoidin in the Fructus Gardeniae extract of assay with the method for assay in the quality standard content is 92.80%.
Embodiment 5:
Get Fructus Gardeniae medicinal material coarse powder 10kg, with 90% ethanol 150kg reflux, extract, 2 times, each 1 hour, filter, merge extractive liquid,, concentrated extracting solution to relative density is 1.20 (60 ℃), add 150kg water, leave standstill, filter, filtrate concentrates, and is splined on active carbon adsorption column, uses earlier the 50kg water elution, reuse 70% ethanol 100kg eluting is collected 70% ethanol elution, is concentrated into 0-5 ℃ of deepfreeze behind the small size, filter to such an extent that precipitate, dry sediment obtains Fructus Gardeniae extract 170.6g.Extract carries out jasminoidin in the Fructus Gardeniae extract of assay with the method for assay in the quality standard content is: 95.53%.
Embodiment 6:
Get Fructus Gardeniae medicinal material coarse powder 10kg, with 100% ethanol 250kg reflux, extract, 2 times, each 1 hour, filter, merge extractive liquid,, concentrated extracting solution to relative density is 1.20 (60 ℃), add 200kg water, leave standstill, filter, filtrate concentrates, and is splined on active carbon adsorption column, uses earlier the 100kg water elution, reuse 80% ethanol 150kg eluting is collected 80% ethanol elution, concentrates the back in 0-5 ℃ of deepfreeze, filter to such an extent that precipitate, dry sediment obtains Fructus Gardeniae extract 124.3g.Extract carries out jasminoidin in the Fructus Gardeniae extract of assay with the method for assay in the quality standard content is: 95.81%.
Embodiment 7
Get Herba Erigerontis medical material 100kg, add 500kg water reflux, extract, 3 times, each 2 hours, extracting solution adds ethanol after concentrating, and the limit edged stirs, and reaches 35% to containing the alcohol amount, leave standstill, filter, regulate pH value to 4 with phosphoric acid behind the supernatant concentrating under reduced pressure, leave standstill, filter, precipitation filters to such an extent that precipitate with 0-5 ℃ of deepfreeze behind 45% dissolve with ethanol, and precipitate gets Herba Erigerontis extract 424.5g with 80% washing with alcohol after drying.Extract carries out lamp-dish flower acetic in the Herba Erigerontis extract of assay with the method for assay in the quality standard content is: 50.58%.
Embodiment 8
Get Herba Erigerontis medical material 100kg, add 600kg water reflux, extract, 3 times, each 2 hours, extracting solution adds ethanol after concentrating, and the limit edged stirs, and reaches 40% to containing the alcohol amount, leave standstill, filter, regulate pH value to 3 with phosphoric acid behind the supernatant concentrating under reduced pressure, leave standstill, filter, precipitation filters to such an extent that precipitate with 0-5 ℃ of deepfreeze behind 50% dissolve with ethanol, and precipitate gets Herba Erigerontis extract 370.2g with 90% washing with alcohol after drying.Extract carries out lamp-dish flower acetic in the Herba Erigerontis extract of assay with the method for assay in the quality standard content is: 66.98%.
Embodiment 9
Get Herba Erigerontis medical material 100kg, add 700kg water reflux, extract, 3 times, each 2 hours, extracting solution adds ethanol after concentrating, and the limit edged stirs, and reaches 45% to containing the alcohol amount, leave standstill, filter, regulate pH value to 3 with hydrochloric acid behind the supernatant concentrating under reduced pressure, leave standstill, filter, precipitation filters to such an extent that precipitate with 0-5 ℃ of deepfreeze behind 55% dissolve with ethanol, and precipitate gets Herba Erigerontis extract 308.6g with 90% washing with alcohol after drying.Extract carries out lamp-dish flower acetic in the Herba Erigerontis extract of assay with the method for assay in the quality standard content is: 71.54%.
Embodiment 10
Get Herba Erigerontis medical material 100kg, add 800kg water reflux, extract, 3 times, each 1.5 hours, extracting solution adds ethanol after concentrating, and the limit edged stirs, and reaches 50% to containing the alcohol amount, leave standstill, filter, regulate pH value to 3 with hydrochloric acid behind the supernatant concentrating under reduced pressure, leave standstill, filter, precipitation with behind 60% dissolve with ethanol in 0-5 ℃ of deepfreeze, filter to such an extent that precipitate, precipitate gets Herba Erigerontis extract 285.6g with 100% washing with alcohol after drying.Extract carries out lamp-dish flower acetic in the Herba Erigerontis extract of assay with the method for assay in the quality standard content is: 92.51%.
Embodiment 11
Get Herba Erigerontis medical material 100kg, add 1000kg water reflux, extract, 2 times, each 1 hour, extracting solution adds ethanol after concentrating, and the limit edged stirs, and reaches 60% to containing the alcohol amount, leave standstill, filter, regulate pH value to 2 with sulphuric acid behind the supernatant concentrating under reduced pressure, leave standstill, filter, precipitation filters to such an extent that precipitate with 0-5 ℃ of deepfreeze behind 65% dissolve with ethanol, and precipitate gets Herba Erigerontis extract 244.7g with 100% washing with alcohol after drying.Extract carries out lamp-dish flower acetic in the Herba Erigerontis extract of assay with the method for assay in the quality standard content is: 94.12%.
Embodiment 12
Get Herba Erigerontis medical material 100kg, add 1500kg water reflux, extract, 2 times, each 1 hour, extracting solution adds ethanol after concentrating, and the limit edged stirs, and reaches 70% to containing the alcohol amount, leave standstill, filter, regulate pH value to 1 with sulphuric acid behind the supernatant concentrating under reduced pressure, leave standstill, filter, precipitation with behind 75% dissolve with ethanol in 0-5 ℃ of deepfreeze, filter to such an extent that precipitate, precipitate gets Herba Erigerontis extract 204.8g with 100% washing with alcohol after drying.Extract carries out lamp-dish flower acetic in the Herba Erigerontis extract of assay with the method for assay in the quality standard content is: 94.53%.
Embodiment 13
Get disodium edetate 10 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 12.9 grams that 4.52 kilograms of Herba Erigerontis medical materials adopt embodiment 10 methods to prepare, and add injection water 129 gram, drip 10% liquor ammoniae fortis, regulate pH value to 8, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 182.2 grams that 9.07 kilograms of Fructus Gardeniae medical materials employing embodiment 4 methods prepare, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 10% liquor ammoniae fortis and regulate pH value to 8, add the injection water, add 20 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 14
Get disodium edetate 10 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 13.1 grams that 3.04 kilograms of Herba Erigerontis medical materials adopt embodiment 7 methods to prepare, and add injection water 131.2 gram, drip 10% liquor ammoniae fortis, regulate pH value to 8, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 182.1 grams that 6.41 kilograms of Fructus Gardeniae medical materials employing embodiment 1 methods prepare, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 10% liquor ammoniae fortis and regulate pH value to 8, add the injection water, add 20 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 15
Get calcium disodium edetate 5 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 13.3 grams that 4.66 kilograms of Herba Erigerontis medical materials adopt embodiment 10 methods to prepare, and add the water for injection of 10 times of weight, drip 10% ethylenediamine solution, regulate pH value to 8.5, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 92.3 grams that 4.60 kilograms of Fructus Gardeniae medical materials prepare by embodiment 4 methods, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 10% ethylenediamine solution and regulate pH value to 8.5, add the injection water, add 10 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 16
Get calcium disodium edetate 5 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 13.1 grams that 3.59 kilograms of Herba Erigerontis medical materials adopt embodiment 8 methods to prepare, and add the water for injection of 10 times of weight, drip 10% ethylenediamine solution, regulate pH value to 8.5, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 92.5 grams that 3.49 kilograms of Fructus Gardeniae medical materials employing embodiment 2 methods prepare, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.Merge above-mentioned two kinds of solution, drip 10% ethylenediamine solution and regulate pH value to 8.5, add the injection water, add 10 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 17
Get calcium disodium edetate 3.2 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 12.8 grams that 4.48 kilograms of Herba Erigerontis medical materials adopt embodiment 10 methods to prepare, and add the water for injection of 10 times of weight, drip 1%NaOH solution, regulate pH value to 8.5, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 74.1 grams that 3.69 kilograms of Fructus Gardeniae medical materials employing embodiment 4 methods prepare, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.Merge above-mentioned two kinds of solution, drip 1%NaOH solution and regulate pH value to 8.5, add the injection water, add 2 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 18
Get calcium disodium edetate 3.2 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 13.2 grams that 4.15 kilograms of Herba Erigerontis medical materials adopt embodiment 9 methods to prepare, and add the water for injection of 10 times of weight, drip 1%NaOH solution, regulate pH value to 8.5, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 74.3 grams that 3.09 kilograms of Fructus Gardeniae medical materials employing embodiment 3 methods prepare, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 1%NaOH solution and regulate pH value to 8.5, add the injection water, add 2 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 19
Get calcium disodium edetate 2 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 12.9 grams that 4.52 kilograms of Herba Erigerontis medical materials adopt embodiment 10 methods to prepare, and add the water for injection of 10 times of weight, drip 2%NaOH solution, regulate pH value to 9, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 52.2 grams that 2.60 kilograms of Fructus Gardeniae medical materials employing embodiment 4 methods prepare, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 2%NaOH solution and regulate pH value to 9, add the injection water, add 2 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 20
Get disodium edetate 2 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 13.1 grams that 4.59 kilograms of Herba Erigerontis medical materials adopt embodiment 10 methods to prepare, and add the water for injection of 10 times of weight, Dropwise 5 %NaOH solution, regulate pH value to 9, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 13.7 grams that 0.69 kilogram of Fructus Gardeniae medical material employing embodiment 4 method prepares, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, Dropwise 5 %NaOH solution is regulated pH value to 9, adds the injection water to 2000ml, adds 2 gram needle-use activated carbons, stir, and coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 21
Get disodium edetate 2 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 13.2 grams that 5.35 kilograms of Herba Erigerontis medical materials adopt embodiment 11 methods to prepare, and add the water for injection of 10 times of weight, Dropwise 5 %NaOH solution, regulate pH value to 9, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 13.8 grams that 0.82 kilogram of Fructus Gardeniae medical material employing embodiment 5 method prepares, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, Dropwise 5 %NaOH solution is regulated pH value to 9, adds the injection water to 2000ml, adds 2 gram needle-use activated carbons, stir, and coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 22
Get calcium disodium edetate 2 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 26.8 grams that 9.38 kilograms of Herba Erigerontis medical materials adopt embodiment 10 methods to prepare, and add the water for injection of 10 times of weight, drip 10%NaOH solution, regulate pH value to 10, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 13.4 grams that 0.67 kilogram of Fructus Gardeniae medical material employing embodiment 4 method prepares, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 10%NaOH solution and regulate pH value to 10, add the injection water, add 2 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 23
Get calcium disodium edetate 2 grams, add an amount of water for injection and make dissolving, add Herba Erigerontis extract 27.1 grams that 13.10 kilograms of Herba Erigerontis medical materials adopt embodiment 12 methods to prepare, and add the water for injection of 10 times of weight, drip 10%NaOH solution, regulate pH value to 10, filter, get Herba Erigerontis extract solution.Get Fructus Gardeniae extract 13.5 grams that 1.08 kilograms of Fructus Gardeniae medical materials employing embodiment 6 methods prepare, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 10%NaOH solution and regulate pH value to 10, add the injection water, add 2 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 24
Get disodium edetate 10 and restrain, add an amount of water for injection and make dissolving, add lamp-dish flower acetic 13.0 grams, and add the water for injection of 10 times of weight, drip 10% liquor ammoniae fortis, regulate pH value to 8, filter, get Herba Erigerontis extract solution.Get jasminoidin 182.3 grams, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 10% liquor ammoniae fortis and regulate pH value to 8, add the injection water, add 20 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 25
Get calcium disodium edetate 5 and restrain, add an amount of water for injection and make dissolving, add lamp-dish flower acetic 13.3 grams, and add the water for injection of 10 times of weight, drip 10% ethylenediamine solution, regulate pH value to 8.5, filter, get Herba Erigerontis extract solution.Get jasminoidin 92.6 grams, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 10% ethylenediamine solution and regulate pH value to 8.5, add the injection water, add 10 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 26
Get calcium disodium edetate 3.2 grams, add an amount of water for injection and make dissolving, adding lamp-dish flower acetic 12.9 restrains, and adds the water for injection of 10 times of weight, drips 1%NaOH solution, regulates pH value to 8.5, filters, and gets Herba Erigerontis extract solution.Get jasminoidin 74.0 grams, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 1%NaOH solution and regulate pH value to 8.5, add the injection water, add 2 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 27
Get disodium edetate 2 and restrain, add an amount of water for injection and make dissolving, add lamp-dish flower acetic 13.4 grams, and add the water for injection of 10 times of weight, Dropwise 5 %NaOH solution is regulated pH value to 9, filters, and gets Herba Erigerontis extract solution.Get jasminoidin 13.9 grams, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, Dropwise 5 %NaOH solution is regulated pH value to 9, adds the injection water to 2000ml, adds 2 gram needle-use activated carbons, stir, and coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 28
Get calcium disodium edetate 2 grams, add an amount of water for injection and make dissolving, adding lamp-dish flower acetic 27.1 restrains, and adds the water for injection of 10 times of weight, drips 10%NaOH solution, regulates pH value to 10, filters, and gets Herba Erigerontis extract solution.Get jasminoidin 13.2 grams, it is an amount of to add the injection water, stirs and makes dissolving, filters, and gets Fructus Gardeniae extract solution.
Merge above-mentioned two kinds of solution, drip 10%NaOH solution and regulate pH value to 10, add the injection water, add 2 gram needle-use activated carbons, stir to 2000ml, coarse filtration, fine straining, embedding, sterilization, leak detection, lamp inspection, lettering, packing gets product.The end product quality standard that meets the pharmacopeia regulation after testing.
Embodiment 29
With 4.48 kilograms of Herba Erigerontis medical materials adopt Herba Erigerontis extract 12.8 grams that embodiment 10 methods prepare, 3.69 kilograms of Fructus Gardeniae medical materials adopt Fructus Gardeniae extract 74.1 grams, microcrystalline Cellulose (filler) and carboxymethyl starch sodium (disintegrating agent) that embodiment 4 methods prepare 60 mesh sieves be mixed, add an amount of polyoxyethylene sorbitan monoleate (wetting agent), add 3% hydroxypropyl methylcellulose (the E5 type is a binding agent) aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate.40-50 ℃ of baking oven forced air drying.Dried granule is crossed 20 mesh sieve granulate, adds the Pulvis Talci of recipe quantity, mix homogeneously.Press No. 1 capsule of recipe quantity fill, promptly.
Embodiment 30
With 4.15 kilograms of Herba Erigerontis medical materials adopt Herba Erigerontis extract 13.2 grams that embodiment 9 methods prepare, 3.09 kilograms of Fructus Gardeniae medical materials adopt Fructus Gardeniae extract 74.3 grams, lactose (filler) and hyprolose (disintegrating agent) that embodiment 3 methods prepare 60 mesh sieves be mixed, add an amount of polyoxyethylene sorbitan monoleate (wetting agent), add 3% hydroxypropyl methylcellulose E5 (binding agent) aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate.40-50 ℃ of baking oven forced air drying.Dried granule is crossed 20 mesh sieve granulate, adds the Pulvis Talci of recipe quantity, and mix homogeneously, tabletting are promptly.
Pharmacodynamic experiment
This patent is by assay experiment and (2) the mice normal pressure hypoxia endurance test of MCP-1 in (1) rat cerebral tissue, proof is with respect to the injection made from the Fructus Gardeniae extract and the Herba Erigerontis extract of dosage, and this patent injection can have synergistic function aspect the time-to-live under the content of MCP-1 and the prolongation anoxia in mice condition in the rat cerebral tissue after reducing ischemia.
This patent is tested influence test and (5) mice global brain ischemia of fibrinolytic activity influence test, (4) of clotting time of mice by (3), proof is with respect to the blank group, the this patent injection can the significant prolongation whole blood coagulation time in mice, and fibrinous course of dissolution is had significant facilitation.This patent injection can also significantly reduce the generation of MDA in the global brain ischemia cerebral tissue of mice broken end back in addition, increases SOD vigor and the release that reduces LDH, has the effect of significant anti-cerebral ischemia.
The influence of MCP-1 in 1 pair of cerebral tissue of experimental example
(monocyte chemoattractant protein-1, MCP-1): chemotactic cytokine specially refers to the cytokine of one group of micromolecule quality to monocyte chemoattractant protein, participates in leucocyte migration, activation and chemotactic, plays the role of a nucleus in inflammatory reaction.MCP-1 is one of line-up of delegates of CC type chemotactic factor family.Cerebral ischemia can cause that rodent cerebral tissue MCP-1 albumen and mRNA expression increase.But neonatal period Hypoxia and ischemia induced strong MCP-1 expresses.Pang etc. utilize transforming growth factor
1(TGF β
1) suppress the MCP-1 expression, its level is descended, handle the hindbrain necrosis area through ischemia and significantly reduce.In MCP-1 knock out mice persistence middle cerebral artery occlusion model, damage side necrosis area descends 29% than wild-type mice.
Be subjected to reagent thing Herba Erigerontis extract (by embodiment 10 preparations) and Fructus Gardeniae extract (by embodiment 4 preparations).This laboratory extracts and assay; Adopt the said extracted thing according to following proportioning, the injection for preparing is as follows: (1) Fructus Gardeniae extract high-load injection (Fructus Gardeniae extract 91mg/ml); (2) Fructus Gardeniae extract low content injection (Fructus Gardeniae extract 6.5mg/ml); (3) Herba Erigerontis extract low content injection (Herba Erigerontis extract 6.5mg/ml); (4) Herba Erigerontis extract high-load injection (Herba Erigerontis extract 13mg/ml); (5) share prescription 1 (Fructus Gardeniae extract 91mg/ml+ Herba Erigerontis extract 6.5mg/ml); (6) share prescription 2 (Fructus Gardeniae extract 6.5mg/ml+ Herba Erigerontis extract 13mg/ml); Formulation method preparation according to embodiment 17.The 1st～6 kind of injection of above injection difference called after.
Dosage is provided with and 150 of grouping male SD rats, body weight 250～300g, available from west, Shanghai pul-Bi Kai laboratory animal company limited (SHANGHAI SIPPER-BK LAB ANIMAL CO., LTD.).With 10 every group, be divided into 15 groups at random, be respectively (1) normal group; (2) cerebral ischemia 12h model group; (3) the 1st kinds of injection treatment 12h groups; (4) the 2nd kinds of injection treatment 12h groups; (5) the 3rd kinds of injection treatment 12h groups; (6) the 4th kinds of injection treatment 12h groups; (7) the 5th kinds of injection treatment 12h groups; (8) the 6th kinds of injection treatment 12h groups; (9) cerebral ischemia 24h model group; (10) the 1st kinds of injection treatment 24h groups; (11) the 2nd kinds of injection treatment 24h groups; (12) the 3rd kinds of injection treatment 24h groups; (13) the 4th kinds of injection treatment 24h groups; (14) the 5th kinds of injection treatment 24h groups; (15) the 6th kinds of injection treatment 24h groups.The 1st～15 group of above each group difference called after.
Administration cerebral ischemia 12h treatment group respectively at modeling before each administration of 1h 1 time behind the 2h, modeling; Cerebral ischemia 24h treatment group respectively at modeling before after 2h and the modeling 1, each administration of 12h 1 time, dosage is 3ml/kg.Model group gives the normal saline of equal volume ratio.
4-0 sub-thread nylon wire 50mm is got in modeling, diameter 0.2mm, and 0.5mm is heated into smooth, spherical with head end, makes marks in line end 18.5mm place, and 75% ethanol cleans in the rearmounted heparinized saline standby.Rat with 3.5% chloral hydrate (350mg/kg) intraperitoneal injection of anesthesia, is lain on the back and is fixed on the operating-table.Get the cervical region median incision; passivity is separated thyroid; to turn on it and be protected; the separation right carotid (common carotid artery, CCA); external carotid artery (extrnealcarotid artery, ECA) and internal carotid artery (internal carotid artery; ICA); ligation ECA and CCA proximal part are equipped with line in the CCA distal end, put a bulldog clamp in the ICA proximal part; cut the V notched cut of an about 0.2mm in the nearly crotch of CCA; insert the bolt line, insertion depth 18.5mm ± 0.5mm makes the bolt line enter ICA; cross the MCA opening part; arrive anterior cerebral artery (anterior cerebral artery, ACA) initial part, the whole blood source of blocking-up MCA; tighten line fully; thyroid resets, and closes and the skin suture otch, and the bolt line stays about 1cm outward.Room temperature remains on 25 ℃ in the art, the insulation of postoperative rat, and dead and non-compliant animal is rejected.
Testing positive rat selects by system standard scoring in 5 fens.0 minute: the impassivity defective symptom; 1 minute: not tensible offside fore paw; 2 minutes: turn-take to inclined to one side side during walking; 3 minutes: fall to the hemiplegia inclination: 4 minutes: can not spontaneously walk loss of consciousness; Wherein 0,1,4 fen person is disallowable.
MCP-1 Determination on content sacrificed by decapitation animal in the cerebral tissue is taken out ischemia part cerebral tissue on ice pan, the back of weighing adds the normal saline of 10 times of volumes, make homogenate, the centrifugal 15min of 10000r/min under 4 ℃ of conditions draws supernatant, and the ELISA method is measured the MCP-1 concentration in the supernatant.Testing process is operated in strict accordance with the test kit description.MCP-1 ELISA test kit is available from Sweden Canag Diagnostics company.
Date processing and result be with SPSS software processes gained data, each organize data all with
± s represents, relatively adopts the t check to investigate significance between group, with P＜0.05 as significant indexes.Concertedness behind the drug combination adopts the equal Q-value analytic process of Nintaus.Q＝E
A+B/(E
A+E
B-E
A*E
B)。E in the formula
A+SBe that two medicines share the suppression ratio that suppresses the MCP-1 rising: E
AAnd E
BSuppression ratio for each prescription time spent; Q＜0.85 expression, two medicines have share antagonism; Q＞1.15 expressions, two medicines share synergistic function: 0.85＜Q＜1.15 expressions, two medicines share the effect of having only the drug effect addition.
Table 2: MCP-1 assay data in the cerebral tissue (
N=10)
| Group | 12h after the cerebral ischemia | Group | 24h after the cerebral ischemia |
| MCP-1 content (pg/ml) | MCP-1 content (pg/ml) | ||
| The 1st group | 98.914±5.433 | ||
| The 2nd group | 251.860±13.438 ** | The 9th group | 236.392±13.482 ** |
| The 3rd group | 136.264±8.041 ## | The 10th group | 158.852±7.768 ## |
| The 4th group | 170.861±9.654 ## | The 11st group | 196.620±11.745 ## |
| The 5th group | 240.131±15.499 | The 12nd group | 195.208±14.610 ## |
| The 6th group | 237.789±10.630 # | The 13rd group | 175.214±7.517 ## |
| The 7th group △ | 129.620±4.873 ## | The 14th group △△ | 115.052±3.580 ## |
| The 8th group △ | 161.040±5.852 ## | The 15th group △△ | 131.454±5.477 ## |
Remarks 1: compare with normal group,
*: p＜0.01; Compare with ischemia group,
#: p＜0.05;
##: p＜0.01
Remarks 2: use relatively with single,
△: summation action;
△ △: synergism
12h after the cerebral ischemia, ischemic tissue of brain MCP-1 content significantly raises than the 1st group, and MCP-1 content does not have remarkable difference than the 2nd group in the 5th group.3rd, 4,6,7,8 groups than the 2nd group of content that can significantly reduce MCP-1 in the cerebral tissue.Wherein share the 7th group is 1.032 with single Q-value with the 3rd, 5 group of comparison; Share the 8th group is 1.037 with single Q-value with the 4th, 6 group of comparison.Experiment shows that the drug effect of share back 12h is single addition with drug effect.
24h after the cerebral ischemia, ischemic tissue of brain MCP-1 content significantly raises than the 1st group, and the 10th group～the 15th group with respect to the 9th group of content that all can significantly reduce MCP-1 in the cerebral tissue.Wherein share the 14th group is 1.271 with single Q-value with the 10th, 12 group of comparison; Share the 15th group is 1.260 with single Q-value with the 11st, 13 group of comparison; All greater than 1.15.Experiment shows to share behind the 24h has synergistic function with respect to single with drug effect.
Experimental example 2 mice normal pressure hypoxia endurance tests
Be subjected to the reagent thing with experimental example 1.
The medical sodica calx of reagent, the 500g/ bottle, the land, Shanghai is chemical reagent factory all, lot number: 20050705.
Dosage is provided with and 70 of grouping ICR mices, male and female half and half, body weight 18-22g, available from west, Shanghai pul-Bi Kai laboratory animal company limited (SHANGHAI SIPPER-BKLAB ANIMAL CO., LTD.).With 10 every group, be divided into 7 groups at random, be respectively (1) blank group; (2) the 1st kinds of injection treatment groups; (3) the 2nd kinds of injection treatment groups; (4) the 3rd kinds of injection treatment groups; (5) the 4th kinds of injection treatment groups; (6) the 5th kinds of injection treatment groups; (7) the 6th kinds of injection treatment groups.The 1st～7 group of above each group difference called after.Dosage is 3ml/kg.
The hypoxia test method is got 10 125ml wide-mouth vials, adds the medical sodica calx of 50g in every bottle, and bottleneck is smeared vaseline and guaranteed sealing.After the above-mentioned animal grouping, drug dilution becomes variable concentrations, and each group is the intravenous injection relative medicine respectively, and the blank group gives isopyknic normal saline.Behind the intravenously administrable certain hour, 10 animals are put into 10 vials rapidly respectively, sealing bottleneck, manual time-keeping, the death time of each animal of observed and recorded.
Trial test is in order to determine the time-effect relationship of this product, select high dose Fructus Gardeniae extract injection before the formal test earlier for use, 30min, 60min, 120min, 240min carry out hypoxia test as stated above after administration, the record death time and with matched group relatively, the result shows behind the administration 30min the most obvious to the effect of mice prolonged survival period.
Date processing and result be with SPSS software processes gained data, each organize data all with
± s represents, relatively adopts the t check to investigate significance between group, with P＜0.05 as significant indexes.Concertedness behind the drug combination adopts the equal Q-value analytic process of Nintaus.Q＝E
A+B/(E
A+E
B-E
A*E
B)。E in the formula
A+BBe that two medicines share the suppression ratio that suppresses the MCP-1 rising; E
AAnd E
BSuppression ratio for each prescription time spent; Q＜0.85 expression, two medicines have share antagonism; Q＞1.15 expressions, two medicines have share synergistic function; 0.85＜Q＜1.15 expressions, two medicines share the effect of having only the drug effect addition.
The various prescription injection of table 3. to the influence of mice normobaric hypoxia time-to-live (n=10,
± s)
| Group | The anoxia time-to-live (min) | Group | The anoxia time-to-live (min) |
| The 1st group | 17.6±1.0 | ||
| The 2nd group | 19.3±1.5 ** | The 5th group | 19.0±1.0 ** |
| The 3rd group | 18.0±0.5 | The 6th group △△ | 20.8±1.1 ** |
| The 4th group | 18.5±0.8 * | The 7th group △△ | 19.7±0.8 ** |
Remarks 1: compare with normal group,
*: p＜0.05,
*: p＜0.01
Remarks 2: use relatively with single,
△ △: synergism
The normal mouse normobaric hypoxia time-to-live is 17.6 ± 1.0min, except that the 3rd group the mice time-to-live is not had the obviously improvement, but all the other each groups are the significant prolongation time-to-live (p＜0.01 or P＜0.05) all, and wherein the 6th group is 1.218 with single Q-value with the 2nd, 4 group of comparison; Share the 7th group is 1.188 with single Q-value with the 3rd, 5 group of comparison, all greater than 1.15.The drug effect that is compared to single usefulness after promptly share has synergistic function.
The influence of 3 pairs of clotting time of mice of experimental example
Be subjected to reagent thing Herba Erigerontis extract (by embodiment 10 preparations) and Fructus Gardeniae extract (by embodiment 4 preparations).This laboratory extracts and assay; Adopt the said extracted thing according to following proportioning, as follows according to the injection that the formulation method of embodiment 17 prepares: (1) share prescription 1 (Fructus Gardeniae extract 91mg/ml+ Herba Erigerontis extract 6.5mg/ml); (2) share prescription 2 (Fructus Gardeniae extract 6.5mg/ml+ Herba Erigerontis extract 13mg/ml).
Dosage is provided with and 30 of grouping ICR mices, male and female half and half, body weight 18-22g, available from west, Shanghai pul-Bi Kai laboratory animal company limited (SHANGHAI SIPPER-BK LAB ANIMAL CO., LTD.).With 10 every group, be divided into 3 groups at random, be respectively (1) blank group; (2) share prescription 1 injection treatment group; (3) share prescription 2 injection treatment groups.Dosage is 3ml/kg.
30 mices of coagulation time test method, be subjected to the reagent thing 5 days by the continuous injection of such scheme grouping, behind last 1 administration 30min, pluck eyeball and get blood, adopt slide method to measure whole blood coagulation time in mice (constantly provoke blood with fine needle, record the time of the blood streak occurs as clotting time).
Date processing and result relatively adopt the t check to investigate significance with SPSS software processes gained data between group, with P＜0.05 as significant indexes.The result: with respect to the blank group, but two share all significant prolongation whole blood coagulation time in mice (P＜0.01～P＜0.05) of prescription group injection, illustrate that this patent injection has significant facilitation to the anticoagulation process in the cerebrovascular disease therapy.
The influence of 4 pairs of fibrinolytic activity of experimental example
Be subjected to the reagent thing with experimental example 3
Reagent agar powder: go up the production of seamount Pu chemical industry company limited; Thrombin of beef and bovine fibrinogen (all purchase in Chinese pharmaceutical biological product and check institute)
Dosage is provided with and 30 of grouping ICR mices, male and female half and half, body weight 18-22g, available from west, Shanghai pul-Bi Kai laboratory animal company limited (SHANGHAI SIPPER-BK LAB ANIMAL CO., LTD.).With 10 every group, be divided into 3 groups at random, be respectively (1) blank group; (2) share prescription 1 injection treatment group; (3) share prescription 2 injection treatment groups.Dosage is 3ml/kg.
The preparation 1.5g agar powder of fibrin plate adds the 100ml distilled water, boil, make agar solution, be cooled to 50～60 ℃, get the fibrinogen solution of 80ml adding 0.5%, add thrombin solution (20u/ml), the mixing that turns round and round is immediately got 10ml solution and is poured into and make flat board in the Tissue Culture Dish, the place's of setting level cooling, put into 85 ℃ of baking oven 30min again, the cooling back is standby.
30 mices of test method were subjected to the reagent thing 5 days by the continuous injection of such scheme grouping, behind last 1 administration 30min, plucked eyeball and got blood, added 3.8% sodium citrate anticoagulant, with the centrifugal 10min of 3000r/min, got upper plasma.20 μ l blood plasma are put respectively on the heating fibrin plate, and 37 ℃ of constant incubators are placed 18h, observe to have or not the dissolving circle, and measure its area, weigh the size of fibrinolytic with dissolving circle area size.
Date processing and result relatively adopt the t check to investigate significance with SPSS software processes gained data between group, with P＜0.05 as significant indexes.The result: with respect to the blank group, two are share prescription group injection and all can make the dissolving circle area of heated plate enlarge markedly (P＜0.01～P＜0.05), illustrate that this patent injection has significant facilitation to fibrinous course of dissolution.
The test of experimental example 5 mice global brain ischemia
Be subjected to the reagent thing with experimental example 3
Reagent malonaldehyde (MDA) test kit, lot number: 060402, superoxide dismutase (SOD) test kit, lot number: 060402, lactic acid dehydrogenase (LDH) test kit, lot number: 060405, Coomassie brilliant blue is decided the protein reagent box, lot number: 060409, all build up bio-engineering research institute available from Nanjing.
Dosage is provided with and 30 of grouping ICR mices, male and female half and half, body weight 18-22g, available from west, Shanghai pul-Bi Kai laboratory animal company limited (SHANGHAI SIPPER-BK LAB ANIMAL CO., LTD.).With 10 every group, be divided into 3 groups at random, be respectively (1) blank group; (2) share prescription 1 injection treatment group; (3) share prescription 2 injection treatment groups.Dosage is 3ml/kg.
30 mices of global brain ischemia test method were subjected to the reagent thing 5 days by the continuous injection of such scheme grouping, behind last 1 administration 30min, breaked end behind the ear under the waking state, and 5min gets brain, with the brain homogenate of ice-cold normal saline preparation 10%.Press the test kit description and measure MDA, SOD and LDH level in the cerebral tissue.
Date processing and result relatively adopt the t check to investigate significance with SPSS software processes gained data between group, with P＜0.05 as significant indexes.The result: after the mice broken end global brain ischemia, two are share the generation that prescription group injection all can significantly reduce MDA in the cerebral tissue, increase the release (P＜0.01～P＜0.05) of SOD vigor and minimizing LDH.The pharmacological action basis that this patent injection anti-cerebral ischemia is described is relevant with LDH with adjusting SOD, MDA.
Claims (14)
1, a kind of is the pharmaceutical composition of main active with jasminoidin, lamp-dish flower acetic or its salt, it is characterized in that jasminoidin in the said composition: lamp-dish flower acetic or its salt are 14-1 by weight: 1-2 part.
2, the pharmaceutical composition of claim 1 is characterized in that jasminoidin in the said composition: lamp-dish flower acetic or its salt are 7-1 by weight: 1 part; The lamp-dish flower acetic officinal salt is selected from lamp-dish flower acetic alkaline amino acid salt, lamp-dish flower acetic sodium salt, lamp-dish flower acetic potassium salt or calcium salt.
3, a kind of pharmaceutical composition for the treatment of cerebrovascular disease, the weight proportion that it is characterized in that described active component are Fructus Gardeniae extract iridoid glycoside 14-1 parts, flavone extract 1-2 part of Herba Erigerontis; Jasminoidin content is not less than 50% in the Fructus Gardeniae extract iridoid glycoside; Lamp-dish flower acetic content is not less than 50% in the flavone extract of Herba Erigerontis.
4, the pharmaceutical composition of claim 3, the weight proportion that it is characterized in that described active component are Fructus Gardeniae extract iridoid glycoside 7-1 parts, 1 part of the flavone extract of Herba Erigerontis; Jasminoidin content is 70%～95% in the Fructus Gardeniae extract iridoid glycoside; Lamp-dish flower acetic content is 70%～95% in the Herba Erigerontis flavone extract.
5, the pharmaceutical composition of claim 3, it is characterized in that Fructus Gardeniae extract is the mixture of jasminoidin, Gardenoside and genipin gentiobiose glycosides or shanzhiside, the flavone extract of Herba Erigerontis is the mixture of lamp-dish flower acetic, oil lamp cycle of sixty years element and apigenin or high baicalin.
6, a kind of pharmaceutical composition for the treatment of cerebrovascular disease is characterized in that it is mainly made by following bulk drugs: Fructus Gardeniae 14-1 part, Herba Erigerontis 7-14 part.
7, the pharmaceutical composition of claim 6, wherein the crude drug consumption is: Fructus Gardeniae 7-1 part, 7 parts of Herba Erigerontiss.
8, claim 6 or 7 preparation of drug combination methods, wherein the flavone extract preparation method of Fructus Gardeniae extract and Herba Erigerontis is as follows:
Get Fructus Gardeniae, extract concentrated extracting solution, last activated-charcoal column with the 50%-100% alcoholic solution, elder generation's water eluting, reuse 30%-80% alcoholic solution eluting, the eluent of collection 30%-80% alcoholic solution is after concentrating, filter to such an extent that precipitate, dry sediment gets Fructus Gardeniae extract;
Get Herba Erigerontis, use water extraction, add ethanol after aqueous extract concentrates after contain the alcohol amount and reach 35%-70%, leave standstill filtration, filtrate concentrate concentrated solution, regulate concentrated solution to acid with strong acid, get precipitation after leaving standstill filtration, will precipitate and use the 45-75% dissolve with ethanol, through the stand at low temperature after-filtration, get precipitation, dry sediment gets Herba Erigerontis extract;
The Fructus Gardeniae extract and the Herba Erigerontis flavone extract that obtain are mixed with pharmaceutically acceptable carrier.
9, the preparation of drug combination method of claim 8 is characterized in that
Get Fructus Gardeniae, with 60%～90% ethanol extraction, concentrated extracting solution to relative density is 1.1～1.20 (60 ℃), concentrated solution adds water, leave standstill after-filtration, activated-charcoal column on the filtrate, first water eluting, reuse 40%-70% ethanol elution, collect the 40%-70% ethanol elution, after concentrating, filter to such an extent that precipitate, dry sediment gets Fructus Gardeniae extract; Jasminoidin content is not less than 50% in the Fructus Gardeniae extract;
Get Herba Erigerontis, use water extraction, add ethanol after aqueous extract concentrates after contain the alcohol amount and reach 40-60%, leave standstill filtration, filtrate concentrate concentrated solution, regulate concentrated solution to pH value 1-4 with hydrochloric acid, sulphuric acid or phosphoric acid, get precipitation after leaving standstill filtration, will precipitate and use the 50-65% dissolve with ethanol, through the stand at low temperature after-filtration, get precipitation, dry sediment gets Herba Erigerontis extract; Lamp-dish flower acetic content is not less than 50% in the flavone extract of Herba Erigerontis;
After getting Fructus Gardeniae extract and water for injection mixing, dissolving is filtered, and gets Fructus Gardeniae extract solution;
After getting Herba Erigerontis extract, metal ion chelation agent and water for injection mixing, add alkaline PH regulator, filter, get Herba Erigerontis extract solution to pH value 8-10;
With getting mixed liquor after Fructus Gardeniae extract solution and the mixing of Herba Erigerontis extract solution, regulate mixed liquor to pH value 8-10 with alkaline PH regulator, add water for injection, filter, get filtrate, embedding is sterilized.
10, the preparation of drug combination method of claim 9 is characterized in that:
Get Fructus Gardeniae, use 70%-80% ethanol extraction 2-3 time, each 1-2 hour, concentrated extracting solution to relative density is 1.1～1.20 (60 ℃), and concentrated solution adds water, leaves standstill after-filtration, activated-charcoal column on the filtrate, first water eluting, reuse 50%-60% ethanol elution, collect the 50%-60% ethanol elution, the 50%-60% ethanol elution is concentrated, after the stand at low temperature, filter and obtain precipitate, dry sediment gets Fructus Gardeniae extract; Jasminoidin content is 70%～95% in the Fructus Gardeniae extract iridoid glycoside;
Get Herba Erigerontis, use water extraction 2-3 time, each 1-2 hour, after concentrating, aqueous extract adds ethanol after contain the alcohol amount and reach 45-50%, leave standstill filtration, filtrate concentrate concentrated solution, regulate concentrated solution to pH value 2-3 with hydrochloric acid, get precipitation after leaving standstill filtration, to precipitate and use the 55-60% dissolve with ethanol,, get precipitation through the stand at low temperature after-filtration, dry sediment gets Herba Erigerontis extract; Lamp-dish flower acetic content is 70%～95% in the Herba Erigerontis flavone extract;
After getting Fructus Gardeniae extract 74 gram and water for injection mixing, dissolving, filtration must Fructus Gardeniae extract solution;
After getting disodium edetate or calcium disodium edetate 3.2 grams, Herba Erigerontis extract 13 grams and water for injection and mixing, add the 1-10% sodium hydroxide, filter to pH value 8.5-9, Herba Erigerontis extract solution;
To get mixed liquor after Fructus Gardeniae extract solution and the mixing of Herba Erigerontis extract solution, regulate mixed liquor to pH value 8.5-9 with the 1-10% sodium hydroxide, after adding water for injection to 2000 milliliter, filter, get filtrate, embedding, after the sterilization, detecting pH value is 7.2～8.2, detects particulate matter, contain the above microgranule of 10 μ m among every 1ml and be no more than 20, contain the above microgranule of 25 μ m and be no more than 2.
11, jasminoidin and lamp-dish flower acetic or its salt are the application of compositions in preparation treatment or prevention cerebrovascular disease medicament that main active is formed.
12, the application of the compositions of the flavone extract of Fructus Gardeniae extract iridoid glycoside and Herba Erigerontis composition in preparation treatment or prevention cerebrovascular disease medicament.
13, the application of the compositions of Fructus Gardeniae and Herba Erigerontis composition in preparation treatment or prevention cerebrovascular disease medicament.
14, the application in one of claim 11-13 item preparation treatment or the prevention cerebrovascular disease medicament, it is characterized in that preparation by reducing behind the ischemia MCP-1 content in the rat cerebral tissue, prolong whole blood coagulation time in mice, promote fibrinous course of dissolution, reducing in the global brain ischemia cerebral tissue of mice broken end back MDA and generate, increase the SOD vigor and/or reduce LDH and discharge, produces the medicine of anticoagulation, anti-cerebral ischemia and cerebral anoxia effect.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101485671B (en) * | 2008-01-16 | 2012-10-03 | 山东绿叶天然药物研究开发有限公司 | Novel medicinal use of 8-O-acetyl shanzhiside methylester |
| CN107782835A (en) * | 2017-12-08 | 2018-03-09 | 云南农业大学 | A kind of method of efficient liquid phase detection fleabane flower composition |
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| WO2022143252A1 (en) * | 2020-12-29 | 2022-07-07 | 云南生物谷药业股份有限公司 | Preparation method for pharmaceutical composition |
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| CN100421681C (en) * | 2004-06-11 | 2008-10-01 | 深圳市生物谷科技有限公司 | Chinese medicinal preparation for treating cardiovascular and cerebrovascular diseases and its preparing process |
| CN100368006C (en) * | 2005-04-01 | 2008-02-13 | 包德圻 | Medicine for treating cardiovascular disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101485671B (en) * | 2008-01-16 | 2012-10-03 | 山东绿叶天然药物研究开发有限公司 | Novel medicinal use of 8-O-acetyl shanzhiside methylester |
| CN107782835A (en) * | 2017-12-08 | 2018-03-09 | 云南农业大学 | A kind of method of efficient liquid phase detection fleabane flower composition |
| CN109222606A (en) * | 2018-10-18 | 2019-01-18 | 延安大学 | Grape skinner |
| WO2022143252A1 (en) * | 2020-12-29 | 2022-07-07 | 云南生物谷药业股份有限公司 | Preparation method for pharmaceutical composition |
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