CN1931216A

CN1931216A - Medicine composition of safflower and rhodiola root

Info

Publication number: CN1931216A
Application number: CN 200610153337
Authority: CN
Inventors: 蔡军
Original assignee: Individual
Current assignee: Haian Su Fu Technology Transfer Center Co Ltd
Priority date: 2005-09-14
Filing date: 2006-09-13
Publication date: 2007-03-21
Anticipated expiration: 2026-09-13
Also published as: CN1931216B

Abstract

The present invention belongs to the field of medicine technology, and is especially one kind of medicine composition for treating cardiac and cerebral vascular diseases and its preparation process. The medicine composition is prepared with safflower 500-10000 weight portions and rhodiola root 250-3000 weight portions; or prepared with safflower yellow pigment 50 weight portions and rhodiola root extract. The medicine composition may be prepared into different pharmaceutically acceptable forms, preferably injection and orally taken preparation. The medicine composition is used in treating coronary heart disease, angina pecoris, myocardial infaction, ischemic cerebral vascular diseases, etc.

Description

A kind of pharmaceutical composition of making by Flos Carthami and Radix Rhodiolae

[technical field]

The invention belongs to medical technical field, be specifically related to a kind of pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular disease and preparation method thereof.

[background technology]

Along with China steps into aging society gradually, living standards of the people improve, and rhythm of life is accelerated, and dietary habit is to hyperpyrexia, high fat development, and cardiovascular and cerebrovascular disease becomes threat human health and life-prolonging leading killer.According to the statistics of interrelated data in recent years, China accounts for about the half of the dead cause of disease because of cardiovascular and cerebrovascular disease death person every year.Its sickness rate height, hazardness is big, and mortality rate after the morbidity and disability rate are quite high, bring worry and burden for patient and family.Therefore, disclose the mechanism that cardiovascular and cerebrovascular disease takes place, develops, carry out effective prevention, treatment and rehabilitation, reduce and disable and mortality rate, be the direction that the personage of the world of medicine is devoted to develop always.

Flos Carthami is the dried floral of feverfew Flos Carthami (Cacthamus tinctonus.L), and the main effective ingredient of modern study proof Flos Carthami is the Carthamus yellow that is present in its water soluble ingredient.Carthamus yellow is the water soluble mixt that contains multiple chalcone, pharmacological evaluation proves that it has coronary artery dilator, improves blood supply of cardiac muscle, brings high blood pressure down, blood vessel dilating, improves organ blood supply, anticoagulation, suppress thrombosis, multiple pharmacological effect such as anoxia enduring, antiinflammatory.S-A Hydroxysafflor yellow A content is higher in the Carthamus yellow, has the pharmacodynamics effect representativeness.The patent relevant with Carthamus yellow has CN1085674, CN1368503, preparation method, preparation and the purposes etc. that relate to Carthamus yellow, in addition, Carthamus yellow and injection Carthamus yellow all have listing, authentication code: the accurate word Z20050145 of traditional Chinese medicines, Z20050146, preparation specification: every bottled 50mg (hydroxyl carthamin yellow A-containing 35mg), manufacturer: Zhejiang Yongning Pharmaceutical Factory.

Radix Rhodiolae is the dry root and rhizome of Crassulaceae plant Radix Rhodiolae Rhodiola crenulata (Hook.f.et Thoms.) H.Ohba, be perennial herb or semishrub plant, mainly be distributed in the former Soviet Union area and high and cold areas such as China northeast, North China, northwest and southwest.China's Radix Rhodiolae aboundresources, kind is numerous, there are 73 kinds approximately, study more Crassulaceae Rhodida plant at present, specifically be selected from rose-red Herba hylotelephii erythrosticti Rhodiola rosea, Radix Rhodiolae Rhodiola crendata, rib leaf Radix Rhodiolae Rhodiola henryi, Radix Rhodiolae Rhodiola sachlinensis, long whip Radix Rhodiolae Rhodiola fasskisa, Folium Trapae Radix Rhodiolae Rhodiola henryi, Rhodiola kirilowii (Regel) Maxim. Rhodiola kirilowii, Xima rhodiola Rhodiola himalensis, Radix Rhodiolae Rhodiola saera splits red Herba hylotelephii erythrosticti Rhodiola quadtifida, Rhodiola yunnanensis Rhodiola yunnanensis, big purplish red Herba hylotelephii erythrosticti Rhodiola atropupurea, alternate Radix Rhodiolae Rhodiola alterna, Pamir Radix Rhodiolae Rhodiola pantiro.Radix Rhodiolae is listed in the medicine top gradely, nontoxic in the Shennong's Herbal, obeys clothes of a specified duration more and does not hurt sb.'s feelings, and the effect of " QI invigorating of making light of one's life by commiting suicide " is arranged.In recent years, for the resources of medicinal plant of comprehensive utilization rhodiola, carried out extensive studies.Modern study shows that Radix Rhodiolae has effects such as significant defying age, radioprotective injury; In recent years result of study shows that Radix Rhodiolae also has unique effect aspect the preventing and treating of cardiovascular and cerebrovascular disease: Radix Rhodiolae can reduce myocardial oxygen consumption and oxygen consumption index, the antagonism arrhythmia, dosage increases can also reduce coronary resistance, and have certain bringing high blood pressure down and the effect of the heart rate that slows down, can also anticoagulant and the outer thrombosis of antibody; Myocardial damage person that myocardial ischemia is caused and cerebrovascular block the cerebral anoxia person who causes and possess the good curing protective effect.

Modern pharmacology and pharmacodynamic study show that all Flos Carthami or Carthamus yellow, Radix Rhodiolae are all having effect preferably aspect the treatment cardiovascular and cerebrovascular disease.But, utilizing interaction, the composition of prescription of Flos Carthami or Carthamus yellow and Radix Rhodiolae, the medicine of preparation treatment cardiovascular and cerebrovascular disease yet there are no report.

[summary of the invention]

The purpose of this invention is to provide a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, it is characterized in that this pharmaceutical composition mainly made by Flos Carthami and Radix Rhodiolae, both parts by weight are: 500～10000 parts on Flos Carthami, 250～3000 parts of Radix Rhodiolaes; Be preferably: 1000～5000 parts on Flos Carthami, 500～1500 parts of Radix Rhodiolaes; Optimum is: 2500 parts on Flos Carthami, 1000 parts of Radix Rhodiolaes.

Flos Carthami in the pharmaceutical composition of the present invention and Radix Rhodiolae can be with The suitable solvent respectively or mix through extracting processing and obtain its extract, and extract is made various any preparations with the pharmaceutic adjuvant hybrid process again.Described solvent is meant solvent pharmaceutically commonly used, preferred water or alcohol, and extracting method can extract with pharmaceutically conventional method, as infusion process, percolation, decocting method, reflux extraction, continuous extraction etc.The content of Carthamus yellow preferably is not less than 50% in the Flos Carthami extract wherein; The content of rhodioside preferably is not less than 3% in the Radix Rhodiolae extract wherein, and the content of total phenols and/or polysaccharide preferably is not less than 50%.

Pharmaceutical composition provided by the invention can also be made by Carthamus yellow and Radix Rhodiolae extract, the yield for preparing extract according to crude drug as can be known, its parts by weight are: 50 parts of Carthamus yellows, 1～500 part of Radix Rhodiolae extract; Be preferably: 50 parts of Carthamus yellows, 3～200 parts of Radix Rhodiolae extracts; More preferably: 50 parts of Carthamus yellows, 15～60 parts of Radix Rhodiolae extracts.

More than form,, can make the preparation of 100～1000 consumptions,, can be made into 500～1000,1～10 of each consumption as injection as if being unit with the gram.As tablet, can be made into 500～1000, take 1～10 at every turn.

More than form to be by weight as proportioning, when producing, can or reduce according to the corresponding proportion increase, as large-scale production can be raw material with the kilogram, or be unit with the ton, small-scale production can be unit with the gram also, weight can increase or reduce, but the weight proportion between each composition is constant.

The invention provides the extraction process of Flos Carthami, specific as follows:

Technology one: getting Flos Carthami, is that 3 sour water warm macerating extracts 2 to 4 times in 70 ℃ of temperature pH, is the sour water of 50 times of amounts, each 1.5 hours at every turn.Merge extractive liquid,, filter, collect filtrate, put coldly, adjust pH is to neutral, be evaporated to relative density 1.05～1.10, adding ethanol to determining alcohol is 70%, and cold preservation (below 10 ℃) was placed 24 hours, filters, filtrate is added on the macroporous adsorbent resin HPD100 column chromatography of having handled well (medical material and resin ratio are 1: 10 (W/V)), uses deionized water with 1～2.5ml/cm earlier ²Two bed volumes of the flow velocity eluting of/min use 60% ethanol with 1～2.5ml/cm then ²Five bed volumes of the flow velocity eluting of/min are collected 60% pure eluting part, and being evaporated to density is about 1.10, at 70 ℃ of dry or decompression rotary evaporation postlyophilizations of left and right sides reduced vacuum, promptly get Carthamus yellow then.

The yield of the Flos Carthami extract that extracts by this technology is 1～3%, and wherein the content of Carthamus yellow is not less than 70%.

Technology two: Flos Carthami is added water-cooled soaked 24 hours or decocted 1～1.5 hour, filter, it is 1.10～1.25 that filtrate is concentrated into relative density, adding ethanol is 80% to containing the alcohol amount, stir, 4 ℃ left standstill 24 hours, filtered filtrate recycling ethanol and to be concentrated into relative density be 1.15～1.20, the water that adds 5～10 times, 4 ℃ left standstill 12～24 hours, and the centrifugal precipitation of removing, centrifugal liquid are evaporated to extracting solution to contain crude drug be 1g/ml, with concentrated solution through macroporous adsorbent resin column chromatography, earlier be eluted to the Molish reaction with deionized water and ninhydrin reaction is negative, continuation is with the deionized water eluting of 4～6 column volumes and collect eluent, is concentrated into extracting solution and contains crude drug 1g/ml, last polyamide column, elder generation is eluted to colourless with deionized water, 4～8 column volumes of reuse 70～90% ethanol elutions are collected eluent, decompression recycling ethanol, lyophilization or spray drying obtain the orange colour amorphous powder, i.e. Carthamus yellow.

The yield of the Flos Carthami extract that extracts by this technology is 1.5～3%, and wherein the content of Carthamus yellow is not less than 70%.

Technology three: get Flos Carthami, add twice of 30 ℃ of warm macerating of water, add 5 times of amounts of water at every turn, warm macerating 24 hours, stir frequently therebetween, merge the water extract twice, filter, it is 1.10～1.25 that filtrate is evaporated to relative density for 50～90 ℃, get the Flos Carthami water extracting liquid, with this water extracting liquid, last bed volume is the polyamide column of 15 times of concentrated solution volumes, be negative with distilled water eluting Molish reaction and ninhydrin reaction, colourless with 95% ethanol elution again to eluent, collect eluent, reclaim ethanol, 50～90 ℃ of concentrating under reduced pressure dryings promptly get Carthamus yellow.

The yield of the Flos Carthami extract that extracts by this technology is 1～3%, and wherein the content of Carthamus yellow is not less than 50%.

Technology four: get Flos Carthami, add 15 times of amounts of water, soaking at room temperature 2 times (band stirs), each 1 hour, filter, filtrate is evaporated to relative density 1.14～1.16 for 60 ℃, add ethanol and make and contain alcohol amount, leave standstill cold preservation and spend the night, filter to 80%, filtrate recycling ethanol is to there not being the alcohol flavor, be added on (100～200 orders, polyamide consumption are about 10 times of applied sample amount) on the polyamide column of having handled well ethanol elution with 35%, collect second yellow band, concentrate drying promptly.

The yield of the Flos Carthami extract that extracts by this technology is 2～3%, and wherein the content of Carthamus yellow is not less than 55%.

The present invention also provides the extraction process of Radix Rhodiolae, and is specific as follows:

Technology one: get the Radix Rhodiolae medical material, be ground into coarse powder, with 70% ethanol extraction three times each 1 hour, add 10 times of amounts of alcohol for the first time, second and third time is respectively 8,8 times of amounts.Filter, merge extractive liquid,, recovery ethanol extremely every 5ml contains the 1g raw medicinal herbs, behind 2 times of amount defat with petroleum ether, discards petroleum ether liquid, and the water saturated n-butanol extraction of reuse is evaporated to the thick paste shape, and spray drying promptly gets Radix Rhodiolae extract.

The yield of the Radix Rhodiolae extract that makes by this technology is 10～20%, and rhodioside content is not less than 3% in the extract, and the content of total phenols is not less than 50%.

In case of necessity, also can further make with extra care, after the above-mentioned Radix Rhodiolae extract that obtains is dissolved with suitable quantity of water, be added on the macroporous resin column of handling well in advance, water liquid, 10% ethanol, 15% ethanol, 20% ethanol, 30% ethanol elution successively, elution speed is 10ml/min.Decompression recycling ethanol to relative density is 1.03～1.06 (60 ℃), and spray drying gets Radix Rhodiolae extract.

The yield of the Radix Rhodiolae extract that makes by this technology is 1～5%, and the content that rhodioside content is not less than 10% total phenols in the extract is not less than 60%.

Technology two: it is an amount of to get the Radix Rhodiolae medical material, adds 70% ethanol extraction 3 times, adds 10 times of amounts for the first time, refluxes 1 hour, adds 8 times of amounts for the second time, refluxes 1 hour, adds 8 times of amounts for the third time, refluxes 1 hour.Extracting solution filters, filtrate recycling ethanol, and to be evaporated to relative density be 1.05, adds 2 times of water gagings, stirs evenly, and cold preservation filtered more than 24 hours, and it is 1.05 that filtrate decompression is concentrated into relative density.Concentrated solution discards petroleum ether with partly measuring Petroleum ether extraction three times, reuse equivalent n-butanol extraction 4 times, and merge extractive liquid,, reclaim under reduced pressure, vacuum drying or spray drying promptly get extract.

The yield of the Radix Rhodiolae extract that extracts by this technology is 6.8～7.5%, and wherein the content of rhodioside is not less than 3%, and the content of total phenols is not less than 50%.

Technology three: it is an amount of to get the Radix Rhodiolae medical material, adds 70% ethanol extraction 3 times, adds 10 times of amounts for the first time, refluxes 1 hour, adds 8 times of amounts for the second time, refluxes 1 hour, adds 8 times of amounts for the third time, refluxes 1 hour.Extracting solution filters, filtrate recycling ethanol, and to be evaporated to relative density be 1.05, adds 2 times of water gagings, stirs evenly, and cold preservation filtered more than 24 hours, and it is 1.05 that filtrate decompression is concentrated into relative density.Get concentrated solution, last macroporous resin column or polyamide column with the water elution of 30 times of amounts of concentrated solution weight, discard eluent earlier, and 30 times of amounts of reuse, 80% ethanol elution is collected eluent, reclaim under reduced pressure, and vacuum drying or spray drying promptly get extract.

The yield of the Radix Rhodiolae extract that extracts by this technology is 6.5～7.0%, and wherein the content of rhodioside is not less than 3%, and the content of total phenols is not less than 50%.

Technology four: it is an amount of to get the Radix Rhodiolae medical material, adds 60% ethanol extraction 3 times, adds 10 times of amounts for the first time, refluxes 1 hour, adds 8 times of amounts for the second time, refluxes 1 hour, adds 8 times of amounts for the third time, refluxes 1 hour.Extracting solution filters, filtrate recycling ethanol, and to be evaporated to relative density be 1.05, add 2 times of water gagings, stir evenly, cold preservation is more than 24 hours, filter, it is 1.05 that filtrate decompression is concentrated into relative density, and adding ethanol, to make ethanol content be 80%, stir evenly, cold preservation filtered decompression filtrate recycling ethanol more than 24 hours, vacuum drying or spray drying promptly get extract.Or with decompression filtrate recycling ethanol, and to be evaporated to relative density be 1.05, with equivalent n-butanol extraction 4 times, merge extractive liquid,, reclaim under reduced pressure, vacuum drying or spray drying, extract.

The yield of the Radix Rhodiolae extract that extracts by this technology is 7.0～7.8%, and wherein the content of rhodioside is not less than 3%, and the content of total phenols is not less than 30%.

Technology five: it is an amount of to get the Radix Rhodiolae medical material, and extracting in water 3 times adds 10 times of amounts for the first time, refluxes 2 hours, adds 10 times of amounts for the second time, refluxes 2 hours.Extracting solution filters, and it is 1.05 that filtrate decompression is concentrated into relative density.Be divided into two parts, it is 1.05 that a filtrate decompression is concentrated into relative density, concentrated solution equivalent n-butanol extraction 3 times, and merge extractive liquid,, reclaim under reduced pressure, vacuum drying or spray drying promptly get extract 1; Another part adds ethanol to be made and contains alcohol amount and reach 85%, stirs evenly, and cold preservation filtered more than 24 hours, and the precipitate cold drying promptly gets extract 2.Extract 1 and extract 2 merging are promptly got total extract.

The yield of the Radix Rhodiolae extract that extracts by this technology is 7.0～8.0%, and wherein the content of rhodioside is not less than 3%, and the content of total phenols and polysaccharide is not less than 50%.

Technology six: it is an amount of to get the Radix Rhodiolae medical material, adds 70% ethanol extraction 3 times, adds 10 times of amounts for the first time, refluxes 1 hour, adds 8 times of amounts for the second time, refluxes 1 hour, adds 8 times of amounts for the third time, refluxes 1 hour.Extracting solution filters, and filtrate recycling ethanol, and to be evaporated to relative density be 1.05, concentrated solution be with equivalent n-butanol extraction 3 times, merge extractive liquid,, and reclaim under reduced pressure, vacuum drying or spray drying promptly get extract 1; Medicinal residues add 10 times of water gagings and extract 3 times, and each 2 hours, merging filtrate filtered, and it is 1.05 that filtrate decompression is concentrated into relative density, add ethanol and reach 85% to containing the alcohol amount, leave standstill more than 24 hours, filter, and the precipitate washing, vacuum drying or spray drying promptly get extract 2.United extraction thing 1 and extract 2 promptly get total extract.

The yield of the Radix Rhodiolae extract that extracts by this technology is 7.5～8.0%, and wherein the content of rhodioside is not less than 3.5%, and the content of total phenols and polysaccharide is not less than 50%.

Technology seven: it is an amount of to get the Radix Rhodiolae medical material, adds 70% ethanol extraction 3 times, adds 10 times of amounts for the first time, refluxes 1 hour, adds 8 times of amounts for the second time, refluxes 1 hour, adds 8 times of amounts for the third time, refluxes 1 hour.Filter, it is 1.05 that filtrate decompression is concentrated into relative density, last polyamide column, and first water eluting, reuse 80% ethanol elution is collected ethanol elution, and being evaporated to relative density is 1.05, and vacuum drying or spray drying get extract 1; It is 1.05 that water elution liquid is evaporated to relative density, adds ethanol and reaches 90% to containing the alcohol amount, leaves standstill more than 24 hours, filter, and the precipitate washing, vacuum drying or spray drying get extract 2.United extraction thing 1 and extract 2 promptly get total extract.

The yield of the Radix Rhodiolae extract that extracts by this technology is 7.0～7.5%, and wherein the content of rhodioside is not less than 3%, and the content of total phenols and polysaccharide is not less than 50%.

Technology eight: it is an amount of to get the Radix Rhodiolae medical material, adds 70% ethanol extraction 3 times, adds 10 times of amounts for the first time, refluxes 1 hour, adds 8 times of amounts for the second time, refluxes 1 hour, adds 8 times of amounts for the third time, refluxes 1 hour.Merge extractive liquid, filters filtrate recycling ethanol, and to be evaporated to relative density be 1.05, and concentrated solution adds 2 times of water gagings, stirs evenly, cold preservation is more than 24 hours, filter, it is 1.05 that filtrate decompression is concentrated into relative density, concentrated solution equivalent n-butanol extraction 3 times, merge extractive liquid,, reclaim under reduced pressure, vacuum drying or spray drying promptly get extract 1; Water liquid adds ethanol to be made and contains alcohol amount and reach 85%, stirs evenly, and leaves standstill more than 24 hours, filter, and the precipitate washing, vacuum drying or spray drying promptly get extract 2.United extraction thing 1 and extract 2 promptly get total extract.

The yield of the Radix Rhodiolae extract that extracts by this technology is 7.0～8.0%, and wherein the content of rhodioside is not less than 3.5%, and the content of total phenols and polysaccharide is not less than 50%.

Technology nine: it is an amount of to get the Radix Rhodiolae medical material, adds 70% ethanol extraction 3 times, adds 10 times of amounts for the first time, refluxes 1 hour, adds 8 times of amounts for the second time, refluxes 1 hour, adds 8 times of amounts for the third time, refluxes 1 hour.Extracting solution filters, filtrate recycling ethanol, and to be evaporated to relative density be 1.05, adds 2 times of water gagings, stirs evenly, and cold preservation filtered more than 24 hours, and it is 1.05 that filtrate decompression is concentrated into relative density.With equivalent n-butanol extraction 4 times, merge extractive liquid,, reclaim under reduced pressure, vacuum drying or spray drying promptly get extract.

The yield of the Radix Rhodiolae extract that extracts by this technology is 7.0～7.5%, and wherein the content of rhodioside is not less than 4%, and the content of total phenols is not less than 50%.

Technology ten: it is an amount of to get the Radix Rhodiolae medical material, and extracting in water 3 times adds 10 times of amounts for the first time, refluxes 2 hours, adds 10 times of amounts for the second time, refluxes 2 hours.Extracting solution filters, and it is 1.05 that filtrate decompression is concentrated into relative density.Add ethanol and make and contain alcohol amount and reach 85%, stir evenly, cold preservation filtered more than 24 hours, the precipitate cold drying, promptly.

The yield of the Radix Rhodiolae extract that extracts by this technology is 5.0～6.0%, and wherein the content of rhodioside is not less than 3.5%, and the content of polysaccharide is not less than 50%.

Pharmaceutical composition of the present invention can coronary artery dilator, and the alleviating vascular spasm increases coronary flow, improves coronary circulation, reduces coronary resistance; Reduce myocardial oxygen consumption and oxygen consumption index, the antagonism arrhythmia; Can anticoagulant, blood viscosity lowering improves hemorheology and microcirculation; Improve the heart blood supply function, reduce cerebral vascular resistance, increase cerebrovascular flow, improve brain microcirculation.Be mainly used in coronary heart disease, angina pectoris, myocardial infarction, ischemic cerebrovascular, and apoplexy and apoplexy sequela etc.

Pharmaceutical composition of the present invention can be made clinically any or pharmaceutically acceptable dosage form, optimizing injection or oral formulations with acceptable accessories; Can parenteral or mode such as oral administration be applied to the patient who needs this treatment.

When being used for parenteral, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or concentrated solution that injection can be divided into injection, injectable sterile powder and concentrated solution for injection.Injection means that the confession that medicine is made is injected into sterile solution type injection, emulsion-type injection or the suspension type injection of using in the body, can be used for intramuscular injection, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection of using for intravenous drip also claims venous transfusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available venous transfusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray drying method or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic concentrated solution of using for intravenous drip with preceding dilution.

Be used for when oral, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has buccal tablet, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coatel tablets etc.Capsule means medicine or is added with the adjuvant filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (soft gelatin capsule), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable adjuvant uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises drop pill, sugar pill, piller etc.Granule means that medicine and suitable adjuvant make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as granule), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral supernatant liquid preparation in suitable solvent.Oral suspensions means the slightly solubility solid drugs, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspension or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.

When making injection, can adopt the conventional method production in the existing pharmaceutical field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solutions; Non-aqueous solvent commonly used is a vegetable oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, Polyethylene Glycol etc.During the preparation injection, can add suitable additives according to the character of medicine, as osmotic pressure regulator, pH value regulator, solubilizing agent, filler, antioxidant, antibacterial, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol etc., preferred sodium chloride or glucose; PH value regulator commonly used comprises acetic acid-sodium acetate, lactic acid, citric acid-sodium citrate, sodium bicarbonate-sodium carbonate etc.; Solubilizing agent commonly used comprises polyoxyethylene sorbitan monoleate, propylene glycol, lecithin, polyoxyethylene castor oil etc.; Filler commonly used comprises lactose, mannitol, sorbitol, dextran etc.; Antioxidant commonly used has sodium sulfite, sodium sulfite, sodium pyrosulfite etc.; Antibacterial commonly used is phenol, cresol, chlorobutanol etc.Injection container commonly used has glass ampule, vial, plastic ampoule, plastic bottle etc.

When making oral formulations, can add suitable filler, binding agent, disintegrating agent, lubricant etc.Filler commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol etc.; Typical binders comprises sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.

The advantage of pharmaceutical composition of the present invention is:

(1) provides a kind of new being used to prepare the pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, met clinical needs;

(2) consumption to pharmaceutical composition Chinese medicine component of the present invention has carried out a large amount of screening experiment research, draws the weight proportion scope with significant curative effect;

(3) the present invention shows by the pharmacological effect experimentation, with Flos Carthami and Radix Rhodiolae, or be the medicine that raw material is made with Carthamus yellow and Radix Rhodiolae extract, can resist myocardial infarction, antiplatelet aggregation, antithrombotic, the Medulla Leporis seu Oryctolagi ischemical reperfusion injury there is protective effect, improve the hemodynamics of anesthetized dog, the mouse brain circulatory disturbance due to the acute ischemic anoxia is had protection, experimental studies results of the present invention proves, Flos Carthami and Radix Rhodiolae drug combination are synergism, drug effect obviously strengthens, and institute reaches effect, is that those of ordinary skills institute is beyond thought;

(4) in the pharmaceutical composition of the present invention, the Carthamus yellow structure is clear and definite, determined curative effect, active constituent content is definite in the Radix Rhodiolae extract, directly feed intake with Carthamus yellow and Radix Rhodiolae extract, preparation technology is easy, has avoided because the shortcoming that the quality of the pharmaceutical preparations that the crude drug mass discrepancy causes differs greatly, and the quality of the pharmaceutical preparations improves a lot, impurity content significantly reduces, and safety is higher.

Below routine by experiment beneficial effect of further setting forth pharmaceutical composition of the present invention, these experimental examples comprise pharmacological research, pharmacodynamic experiment, the stability experiment of pharmaceutical composition of the present invention.Pharmaceutical composition of the present invention has following beneficial effect, but this should be interpreted as that pharmaceutical composition of the present invention only has following beneficial effect.

Experimental example 1 pharmaceutical composition of the present invention is to the influence of rat experiment myocardial inyaretion scope

Animal subject: the Wistar rat, body weight 208～230g, is divided into 13 groups at random by 130.

Test sample: Carthamus yellow, self-control contains Carthamus yellow 75.2%;

Radix Rhodiolae extract, self-control, wherein the content of rhodioside is 12.3%, the content of total phenols is 61.3%;

Safflower uranidin injection liquid, self-control;

The Radix Rhodiolae extract injection, self-control;

Composite injection group (the different proportionings of Carthamus yellow+Radix Rhodiolae extract), self-control.

Experimental technique: rat is divided into 13 groups at random: the normal saline matched group; Safflower uranidin injection liquid group; Radix Rhodiolae extract injection group; Composite injection group: Carthamus yellow+Radix Rhodiolae extract (50mg+3mg, 50mg+10mg, 50mg+15mg, 50mg+20mg, 50mg+30mg, 50mg+45mg, 50mg+60mg, 50mg+75mg, 50mg+100mg, 50mg+200mg); Each medicine all is diluted to desired concn with normal saline, the tail vein injection administration.

The rat experiment myocardial infarction model: it is fixing that animal pentobarbital intraperitoneal injection of anesthesia (45mg/kg) is faced upward the position.Tracheal intubation is made the longitudinal incision of 2cm in breastbone left side, nearly breastbone side is cut off the 3rd, the 4th costicartilage, open the thoracic cavity after, connect artificial respirator (ventilation 2ml/100g, 50 times/min).Cut off pericardium, expose heart, left anterior descending coronary artery root threading is in order to ligation, and record standard II lead electrocardiogram was stablized 10 minutes, and the ligation left anterior descending coronary artery is closed the thoracic cavity.With syringe sucking-off animal throat secretions, make animal recover autonomous respiration.Behind the ligation coronary artery 15min, intravenously administrable.Behind the ligation coronary artery 4 hours, win heart, 5 of the following crosscuts of ligature, carry out chlorination nitro blue tetrazolium (N-BT) dyeing, calculating myocardium infarcted region area accounts for the percentage ratio of ventricle and heart area, and carries out statistical procedures (t check).The results are shown in Table 1.

Table 1 pharmaceutical composition of the present invention is to the influence of rat experiment myocardial inyaretion scope (x ± s)

Group	Dosage (mg/kg)	Infarcted region/ventricle (%)	Infarcted region/heart (%)
Group	Dosage (mg/kg)	Infarcted region/ventricle (%)	Infarcted region/heart (%)	Physiological saline control group safflower uranidin injection liquid group gadol extract parenteral solution group composite injection (50mg+3mg) composite injection (50mg+10mg) composite injection (50mg+15mg) composite injection (50mg+20mg) composite injection (50mg+30mg) composite injection (50mg+45mg) composite injection (50mg+60mg) composite injection (50mg+75mg) composite injection (50mg+100mg) composite injection (50mg+200mg)	20 20 20 20 20 20 20 20 20 20 20 20 20	34.76±7.11 23.21±6.98 ^27.32±6.23 ^19.87±6.12 ^#△△17.42±5.45 ^#△△14.26±3.96 ^##△△13.26±4.56 ^##△△11.85±4.88 ^##△△12.98±5.13 ^##△△13.88±4.96 ^##△△15.67±6.23 ^#△△16.52±5.04 ^#△△18.59±5.35 ^*#△△	28.89±5.10 19.56±5.73 ^22.33±5.18 ^16.56±5.12 ^#△13.31±4.77 ^#△△10.61±3.87 ^##△△10.01±3.66 ^##△△8.98±3.43 ^##△△9.72±3.89 ^##△△11.68±4.65 ^##△△12.98±5.11 ^#△△14.65±4.98 ^#△16.02±5.02 ^#△

Annotate: compare with the normal saline group, ^*P＜0.05, ^*P＜0.01; Compare with safflower uranidin injection liquid group, ^#P＜0.05, ^##P＜0.01; Compare with the gadol injection group, ^△P＜0.05, ^{△ △}P＜0.01.

Experimental result: as can be known by last table data

1) compares with the normal saline group, safflower uranidin injection liquid group and Radix Rhodiolae extract injection group all can significantly reduce rat heart muscle infarct size (p＜0.05), and the different proportioning groups of composite injection all can extremely significantly reduce rat heart muscle infarct size (p＜0.01).

2) compare with safflower uranidin injection liquid group, the different proportioning groups of composite injection all can significantly reduce rat heart muscle infarct size (p＜0.05, p＜0.01).

3) compare with Radix Rhodiolae extract injection group, the different proportioning groups of composite injection all can significantly reduce rat heart muscle infarct size (p＜0.05, p＜0.01).

Conclusion: each administration group all has tangible function of resisting myocardial ischemia (p＜0.05, p＜0.01), wherein the curative effect of the composite injection of Carthamus yellow and Radix Rhodiolae extract compatibility is better than single with Carthamus yellow or Radix Rhodiolae extract, Carthamus yellow+Radix Rhodiolae extract effect in (50mg+3mg)～(50mg+200mg) scope is all remarkable, points out two medicine compatibilities that synergistic function is arranged.

The antiplatelet aggregative activity of experimental example 2 pharmaceutical compositions of the present invention

Animal subject: the Wistar rat, body weight 201～225g, is divided into 8 groups at random by 80.

Test sample: Carthamus yellow, self-control contains Carthamus yellow 75.2%;

Safflower uranidin injection liquid, self-control;

The Radix Rhodiolae extract injection, self-control;

Composite injection (different proportioning), 5 groups, self-control.

Experimental technique: rat is divided into 8 groups at random, every group 10, be respectively normal saline matched group, safflower uranidin injection liquid group, Radix Rhodiolae extract injection group, the different proportioning groups (50mg+15mg, 50mg+20mg, 50mg+30mg, 50mg+45mg, 50mg+60mg) of composite injection.Each treated animal intraperitoneal injection, once a day, successive administration 7 days, after the last administration 1 hour, from abdominal aortic blood, anticoagulant adopted 3.28% sodium citrate after the Animal Anesthesia, with blood with 1: 9 mixed.With anticoagulated whole blood 1500rmin under 20 ℃ of conditions ^-1Centrifugal 5min obtains platelet rich plasma (PPR).After leaving and taking quantitative PPR, will remain PPR once more with 3000rmin ^-1Centrifugal 10min obtains the rich or poor platelet blood plasma of own control (PPP).Regulate PPR concentration with PPP, make each PPR concentration identical.In 37 ℃ constant temperature hole after the preheating, (final concentration is 3 μ mol.L to add ADP with PPR ^-1) cause and write down maximum agglutination rate by platelet aggregation.The results are shown in Table 2.

Table 2 antiplatelet aggregative activity (X ± SD)

Group	Dosage (mg/kg)	Mus number (only)	Maximum agglutination rate
Group	Dosage (mg/kg)	Mus number (only)	Maximum agglutination rate	Physiological saline control group safflower uranidin injection liquid group gadol extract parenteral solution group composition parenteral solution group (50mg+15mg) composition parenteral solution group (50mg+20mg) composition parenteral solution group (50mg+30mg) composition parenteral solution group (50mg+45mg) composition parenteral solution group (50mg+60mg)	- 20 20 20 20 20 20 20	10 10 10 10 10 10 10 10	91.44±18.52 72.07±18.11 ^76.35±17.69 ^61.20±16.13 ^#△58.94±15.46 ^#△54.21±15.89 ^#△56.38±17.64 ^#△58.87±16.43 ^**#△

Annotate: compare with the normal saline matched group, ^*P＜0.05, ^*P＜0.01; Compare with safflower uranidin injection liquid group, ^#P＜0.05; Compare with the gadol injection group, ^△P＜0.05.

Experimental result: as can be known by last table experimental data

1) compares with the normal saline matched group, safflower uranidin injection liquid group, Radix Rhodiolae extract injection group platelet maximum agglutination rate all significantly reduce (p＜0.05), and the platelet maximum agglutination rate of the different proportioning groups of composite injection all extremely significantly reduces (p＜0.01).

2) compare with safflower uranidin injection liquid group, the platelet maximum agglutination rate of the different proportioning groups of composite injection all significantly reduces (p＜0.05).

3) compare with Radix Rhodiolae extract injection group, the platelet maximum agglutination rate of the different proportioning groups of composite injection all significantly reduces (p＜0.05).

Conclusion: compare with the normal saline matched group, safflower uranidin injection liquid group, Radix Rhodiolae extract injection group and composite injection group all can significantly reduce the platelet maximum agglutination rate of rat, show that safflower uranidin injection liquid, Radix Rhodiolae extract injection and composite injection all have anti thrombotic action, wherein the composite injection curative effect is better than singly using the Radix Rhodiolae extract injection with safflower uranidin injection liquid and list, points out two medicine compatibilities that synergistic function is arranged; Wherein (Carthamus yellow+Radix Rhodiolae extract=50mg+30mg) organize, curative effect is the most remarkable with composite injection.

Experimental example 3 pharmaceutical compositions of the present invention are to thrombotic influence in the rat carotid artery

Animal subject: the Wistar rat, the male and female dual-purpose, body weight 207～227g, is divided into 8 groups at random by 80.

Test sample: Carthamus yellow, self-control contains Carthamus yellow 75.2%;

Safflower uranidin injection liquid, self-control;

The Radix Rhodiolae extract injection, self-control;

Composite injection (the different proportionings of Carthamus yellow+Radix Rhodiolae extract), 5 groups, self-control.

Experimental technique: rat is divided into 8 groups at random, every group 10, be respectively normal saline matched group, safflower uranidin injection liquid group, Radix Rhodiolae extract injection group, the different proportioning groups (the different proportionings of Carthamus yellow+Radix Rhodiolae extract: 50mg+15mg, 50mg+20mg, 50mg+30mg, 50mg+45mg, 50mg+60mg) of composite injection.The tail vein injection administration.The blank group gives the isometric(al) normal saline, and administration begins test after 20 minutes.Animal is with 2.5% pentobarbital sodium (25mg/kg) intraperitoneal injection of anesthesia, the rat dorsal position is fixed, separate right carotid, adopt electrical injuries carotid artery intima method, form instrument with the experimental thrombus in vivo of BT87-3 and measure different group animal carotid artery thrombus formation time.Electrode is seated on the carotid artery it carried out electricity irritation (2mA 7min), with induction electrode continuous measurement arterial distal surface temperature, observes the tremulous pulse temperature bust time.The record electricity irritation began to the time of aorta temperature bust, and this time is decided to be carotid artery thrombus formation time (surpassing 3000 seconds persons in 3000 seconds).Experimental result sees Table 3.

Experimental result: as can be known by last table experimental data

1) compares with the normal saline matched group, safflower uranidin injection liquid group, Radix Rhodiolae extract injection group rat carotid artery thrombus formation time all significantly reduce (p＜0.05), and the different proportioning group of composite injection rat carotid artery thrombus formation time all extremely significantly reduces (p＜0.01).

2) compare with safflower uranidin injection liquid group, the different proportioning group of composite injection rat carotid artery thrombus formation time all significantly reduces (p＜0.05).

3) compare with Radix Rhodiolae extract injection group, the different proportioning group of composite injection rat carotid artery thrombus formation time all significantly reduces (p＜0.05).

The pharmaceutical composition of the present invention of the different proportionings of table 3 is to thrombotic influence in the rat carotid artery

Group	Dosage (mg/kg)	Number of animals	Thrombus formation time (second)
Group	Dosage (mg/kg)	Number of animals	Thrombus formation time (second)	Physiological saline control group safflower uranidin injection liquid group gadol extract parenteral solution group composition parenteral solution group (50mg+15mg) composition parenteral solution group (50mg+20mg) composition parenteral solution group (50mg+30mg) composition parenteral solution group (50mg+45mg) composition parenteral solution group (50mg+60mg)	- 20 20 20 20 20 20 20	10 10 10 10 10 10 10 10	948.57±412.66 1521.46±423.11 ^1321.24±358.96 ^1746.38±314.55 ^#△1842.33±399.11 ^#△1967.82±510.03 ^#△1874.01±425.26 ^#△1794.65±497.56 ^**#△

Conclusion: Radix Rhodiolae extract injection, safflower uranidin injection liquid and composite injection group all can make thrombotic time lengthening in the rat carotid artery, and the curative effect of composite injection group is better than single with safflower uranidin injection liquid group and single with Radix Rhodiolae extract injection group, points out both that synergism is arranged.Wherein with composite injection (Carthamus yellow+Radix Rhodiolae extract 50mg+30mg) group, curative effect is the most remarkable.

Experimental example 4 pharmaceutical compositions of the present invention are to the protective effect of Medulla Leporis seu Oryctolagi ischemical reperfusion injury

Animal subject: rabbit, 78, body weight 2.2～2.7kg is divided into 13 groups at random, 6 every group.

Test sample: Carthamus yellow, self-control contains Carthamus yellow 75.2%;

Safflower uranidin injection liquid, self-control;

The Radix Rhodiolae extract injection, self-control;

Composite injection, this experiment adopt embodiment 6 prescriptions 1 medicine composition injection of the present invention that makes.

Experimental technique: rabbit is divided at random: ischemia-reperfusion group (I/R group), composite injection treatment group, Carthamus yellow treatment group, Radix Rhodiolae extract injection for treating group and Sham-operated control group (SOC group).(1) ischemia-reperfusion group (I/R group): 18, urethane lipoprotein solution lg/kg body weight auricular vein anesthesia with 25%, the cervical region median incision separates trachea and inserts tracheal casing pipe, expose bilateral carotid, close 20min with bulldog clamp both sides folder, cause cerebral ischemia, pine folder pours into 1h, 6h and 12h respectively again, each 6 of three time points.Behind pine folder 10min, auricular vein is injected normal saline 5ml/kg body weight respectively.(2) composite injection treatment group: 18, operation method is organized with I/R, each 6 of three time points, and behind pine folder 10min, auricular vein is injected composite injection 10mg/kg respectively.(3) safflower uranidin injection liquid treatment group: 18, operation method is organized with I/R, each 6 of three time points, and behind pine folder 10min, auricular vein is injected safflower uranidin injection liquid 20mg/kg respectively.(4) Radix Rhodiolae extract injection for treating group: 18, operation method is organized with I/R, each 6 of three time points, and behind pine folder 10min, auricular vein is injected Radix Rhodiolae extract injection 20mg/kg respectively.(5) Sham-operated control group (SOC group): 6, animal only row anesthesia and tremulous pulse exclusion and not pressing from both sides closes, and puts to death behind the 1h.Above-mentioned each group promptly breaks end after testing and finishing, and strips out brain in ice bath, separates on the ice pan and cuts bilateral hippocampus tissue, is placed in 4 ℃ of refrigerators with the tinfoil parcel to store, and is standby.Use the pH acidometer and detect hippocampal tissue PLA ₂Activity; Be used in weight in wet base method, TTC staining mensuration cortex brain water content, infarct size; Light microscopic is observed the cerebral tissue pathological change down.

Experimental result: (1) is to hippocampal tissue PLA ₂After active influence: I/R group is poured into 1h, 6h and 12h again, hippocampal tissue PLA ₂Activity obviously increases (p＜0.01) than SOC, and prolongs PLA with infusion time ₂The activity trend that tapers off, but comparing difference not significantly (p＞0.05) between each time point; Composite injection treatment group (1h, 6h, 12h) PLA ₂Active obviously reduction relatively has significant difference (p＜0.01) with SOC group and each corresponding time point of I/R, and with irritating time lengthening, PLA again ₂Activity is recovered to normal level gradually; Radix Rhodiolae extract injection for treating group and Flos Carthami flavochrome injection for treating group (1h, 6h, 12h) PLA ₂The active reduction relatively has notable difference (p＜0.05) with SOC group and each corresponding time point of I/R, and the effect of Radix Rhodiolae extract injection is lower than safflower uranidin injection liquid.

(2) to the influence of cortical tissue's water content (%) and infarct size (%): I/R organizes each time point brain water content and all increases; The composite injection treatment is organized each time point brain water content and I/R group and is compared obviously and alleviate (p＜0.01), and brain infarction area is compared obviously with the I/R group and dwindled (p＜0.01); Each time point brain water content of Radix Rhodiolae extract injection for treating group and Flos Carthami flavochrome injection for treating group is compared all with the I/R group and is alleviated (p＜0.01), and brain infarction area is compared all with the I/R group and dwindled (p＜0.05, p＜0.01).

(3) brain tissue pathology change: SOC organizes no infarction kitchen range, and the neuronal structure form is normal, continuously the matter edema; The I/R group has the infarction kitchen range, the neuron swelling of infarction kitchen range week, and cell outline is unclear, and interstitial edema is obvious; Composite injection treatment group, Radix Rhodiolae extract injection for treating group, safflower uranidin injection liquid treatment group infarction kitchen range area all dwindle, and the neuron swelling of infarction kitchen range week is not obvious, and interstitial edema obviously alleviates; The effect of composite injection treatment group is more obvious.

Conclusion: above-mentioned experimental result shows that composite injection, Radix Rhodiolae extract injection, safflower uranidin injection liquid all can be by reducing PLA ₂Activity is improved cerebral circulation, alleviates brain and lacks.Blood reperfusion injury, and performance cerebral protection.Composite injection all is higher than the effect of the independent medication of Radix Rhodiolae extract injection and Flos Carthami flavochrome injection in every index, point out two medical instruments that synergistic function is arranged.

Experimental example 5 present compositions are to the hemodynamic influence of anesthetized open-chest dog

Animal subject: hybrid dog, 20, body weight 11.2～13.5kg.

Test sample: Carthamus yellow, self-control contains Carthamus yellow 75.2%;

Safflower uranidin injection liquid, self-control;

The Radix Rhodiolae extract injection, self-control;

Experimental technique: dog is divided into 4 groups at random, 5 every group, is respectively normal saline matched group, safflower uranidin injection liquid group, Radix Rhodiolae extract injection group, composite injection group.Dog is taked under the right arm reclining malleation artificial respiration after anaesthetizing with pentobarbital sodium (30mg/kg) intravenous injection, opens breast between 4～5 sides of body of a left side, opens pericardium in distance vagus nerve 2cm place, and parietal layer is made outstanding bed it is sutured in thoracic wall, and heart is fully exposed.Separate aorta, aortic root be inserted in the electromagnetic flowmeter probe (10～12mm), measure cardiac output (CO); At the left anterior descending coronary artery root, separate visceral pericardium, isolate about 1cm coronary artery, be inserted in the electromagnetic flowmeter probe (2～3mm), measurement coronary flow (CBF); This two probe is connected on the LMTC-621 type electromagnetic flowmeter, separates a bilateral common carotid artery, intubate connects pressure transducer, record arteriotony (AP) and mean arterial pressure (MAP); With internal diameter is that the cardiac catheter of 1.5mm is inserted left ventricle from the apex of the heart, amplify left indoor pressure (LVP) by YZ-1 type pressure transducer through carrier wave, the LVP electric signal amplifies 10 times through direct current amplifier, write down left chamber EDP (LVEDP), with the LVP electric signal again through BMI type differentiator derivative recording left indoor pressure rate of change (dp/dt _Max), it is subcutaneous to insert the animal subject extremity with pin type electrode, and record mark II lead electrocardiogram (EGG-II) is to measure heart rate (HR).These parameters changes equal synchronous recording and leads instrument in RM-6300 physiology more.

Separate femoral artery and take out arterial blood, through External Carotid Artery for Intubation to the coronary sinus vein venous blood samples, according to CY-2 oxygen analyser operation instructions, add the anhydrous sodium sulfite crystallization with freshly prepared anaerobic solution (0.01M) borax soln and be mixed with 2% sodium sulfite solution zeroing, use with the distilled water of air balance temperature constant and make sensitivity adjusting.Treat to measure oxygen content with oxygen analyser behind the instrument stabilizer.Calculating myocardium oxygen consumption after the off-test.

After operation finishes, observe above-mentioned every index, after stable with the index of record value before as administration, behind the intravenously administrable in 1,3,5,10,20,30min, gather above-mentioned every index, and with every index rate of change (%) of each time point after the administration, the t-test that does significance pairing data between group with every index rate of change (%) of each corresponding time point of matched group handles.

Experimental result and conclusion: composite injection, safflower uranidin injection liquid, Radix Rhodiolae extract injection are to being tried dog heart rate (HR), mean arterial pressure (MBP), left indoor pressure (LVP) and ventricular muscles contractility (dp/dt _Max), myocardial oxygen consumption all has the reduction effect.Especially composite injection, the reduction amplitude is all obviously greater than safflower uranidin injection liquid group and Radix Rhodiolae extract injection group, myocardial oxygen consumption is in beginning reduction after the administration about 2 minutes, maximum is 25.9%, reach action time more than 30 minutes, the curative effect (p＜0.01) of highly significant is relatively arranged with matched group.

Test example 6 pharmaceutical compositions of the present invention are to the influence of ligation bilateral common carotid arteries mice survival rate

Animal subject: the Wistar rat, body weight 208～230g, half and half, 120 of male and female are divided into 12 groups at random.

Test sample: Carthamus yellow, self-control, the content of Carthamus yellow is 72.86%;

Radix Rhodiolae extract, self-control, wherein the content of rhodioside is 3.75%, the content of polysaccharide is 55.22%;

The different proportionings of compositions (Flos Carthami+Radix Rhodiolae), 5 groups, self-control.

Experimental technique: rat is divided into 12 groups at random, 10 every group, is respectively normal saline matched group, Radix Rhodiolae extract group, Carthamus yellow group, the different proportioning groups of compositions.Each administration group medicine all becomes suitable concentration with distilled water diluting before administration.

Each organizes equal one week of gastric infusion of rat, and once a day, the matched group gastric infusion is with the volume normal saline, and 20min separates bilateral common carotid arteries with urethane 1.3g/kg intraperitoneal injection of anesthesia after the last administration, and live time recorded in the ligation postscript.Experimental result sees Table 4.

Table 4 medicine is to the influence of ligation mice bilateral common carotid arteries (X ± S)

Group	Proportioning	Dosage (mg/kg)	Number of animals (only)	Time-to-live (min)
Group	Proportioning	Dosage (mg/kg)	Number of animals (only)	Time-to-live (min)	The different proportioning group of physiological saline control group carthamin yellow group gadol extract group composition (safflower: rhodiola root)	- - - 1000∶1500 1500∶1300 2000∶1100 2500∶1000 3000∶900 3500∶800 4000∶700 4500∶600 5000∶500	- 20 20 20 20 20 20 20 20 20 20 20	10 10 10 10 10 10 10 10 10 10 10 10	3.76±1.33 4.44±3.02 ^7.36±2.68 ^10.68±5.35 ^##△11.53±5.36 ^##△12.18±5.67 ^##△12.67±5.82 ^##△11.57±4.26 ^##△ 10.65±5.11 ^##△9.78±4.38 ^#△9.28±3.65 ^#△8.58±4.12 ^**#△

Annotate:: compare with the normal saline group, ^*P＜0.05, ^*P＜0.01; Compare with the Carthamus yellow group, ^#P＜0.05, ^##P＜0.01; Compare with the Radix Rhodiolae extract group, ^△P＜0.05, ^{△ △}P＜0.01.

Experimental result: as can be known by last table experimental result

1) compare with the normal saline matched group, Carthamus yellow group and Radix Rhodiolae extract group be the energy significant prolongation survival of rats time (p＜0.05) all, and each proportioning compositions group all can the utmost point significant prolongation survival of rats time (p＜0.01).

2) compare with the Carthamus yellow group, each proportioning composite injection group all can the significant prolongation survival of rats time (p＜0.05, p＜0.01).

3) compare with the Radix Rhodiolae extract group, each proportioning compositions group all can the significant prolongation survival of rats time (p＜0.05).

Conclusion: as can be known by above-mentioned experimental result, but each administration group gastric infusion is the time-to-live (p＜0.05, p＜0.01) of significant prolongation bilateral ligation mice all, compare with Radix Rhodiolae extract with Carthamus yellow with single, the time-to-live of each compositions group rat is longer.Prompting, Carthamus yellow and Radix Rhodiolae use in conjunction, Synergistic has protective effect to the mouse brain circulatory disturbance due to the acute ischemic anoxia.And Flos Carthami: Radix Rhodiolae=2500: 1000 o'clock, effect is best.

Experimental example 7: medicine composition injection stability test of the present invention

Test sample: composite injection, this experiment adopt embodiment 6 prescriptions 1 composite injection that makes.

Investigation project: character, pH value, clarity, related substance, sign content; And at accelerated tests 6 months and the aseptic and pyrogen test of long-term experiment end of term increase.

1, influence factor's experiment

The strong illumination experiment: get test sample, putting illumination is interior the placement 10 days of lighting box of 4500Lx.

High temperature experiment: get test sample, place respectively under 40 ℃, the 60 ℃ conditions and placed 10 days.

Low temperature test: get test sample, in 4 ℃ of refrigerators, placed 10 days.

Above-mentioned experiment was respectively at the 5th, 10 day sampling and measuring.Relatively test every index after the character, and with result and comparison in 0 day.

The result: placed 10 days under the illumination 4500Lx condition, except that related substance slightly raise, all other indexs had no significant change.Placed 10 days under 60 ℃ of conditions of high temperature, outward appearance becomes faint yellow clear liquid, indicates content and descends, and related substance slightly raises.Placed 10 days under 40 ℃ of high temperature, 4 ℃ of conditions of low temperature, every index does not have significant change.

2, accelerated tests

Method: put under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% and placed 6 months.Respectively at taking a sample 1st month, 2 months, 3 months, 6 the end of month, relatively after the outward appearance, test every index at experimental session, with result and comparison in 0 month; And at 6 aseptic and pyrogen tests of increase at the end of month.

Result: placed 6 months under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%, removing related substance slightly increases, and outside sign content slightly descended, all other indexs had no significant change, at 6 the end of month of accelerated tests, pyrogen, sterility test are all up to specification.

3, long-term experiment

Method: put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and placed 18 months.Respectively at 3rd month, 6 months, 9 months, 12 months, 18 months, relatively after the outward appearance, test every index, with result and comparison in 0 month; And at 18 aseptic and pyrogen tests of increase at the end of month.

The result: placed under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% 18 months, every index has no significant change, and at 18 the end of month of long-term experiment, pyrogen, sterility test are all up to specification.

Conclusion: reached a conclusion by above-mentioned investigation result, in every experiment, medicine composition injection of the present invention is more stable.

[specific embodiment]

The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.All technology that realizes based on foregoing of the present invention all belong to content of the present invention.

The preparation one of embodiment 1 Carthamus yellow

Getting Flos Carthami, is that 3 sour water warm macerating extracts 2 to 4 times in 70 ℃ of temperature pH, is the sour water of 50 times of amounts, each 1.5 hours at every turn.Merge extractive liquid,, filter, collect filtrate, put coldly, adjust pH is to neutral, be evaporated to relative density 1.05～1.10, adding ethanol to determining alcohol is 70%, and cold preservation (below 10 ℃) was placed 24 hours, filters, filtrate is added on the macroporous adsorbent resin HPD100 column chromatography of having handled well (medical material and resin ratio are 1: 10 (W/V)), uses deionized water with 1～2.5ml/cm earlier ²Two bed volumes of the flow velocity eluting of/min use 60% ethanol with 1～2.5ml/cm then ²Five bed volumes of the flow velocity eluting of/min are collected 60% pure eluting part, and being evaporated to density is about 1.10, at 70 ℃ of dry or decompression rotary evaporation postlyophilizations of left and right sides reduced vacuum, promptly get Carthamus yellow then.

The discriminating of Carthamus yellow

With the Carthamus yellow is reference substance, differentiates Carthamus yellow.

Respectively accurately claim to decide in the measuring bottle of S-A Hydroxysafflor yellow A and Flos Carthami flavochrome 1.0mg to 1ml, with water dissolution and be settled to scale.Draw above-mentioned two kinds of solution respectively, put in the thin layer gel GF 254 plate, with acetone: methanol: water (10: 2.5: 1.5) is developing solvent, and observe and can see corresponding fluorescence speckle at the 254nm place under uviol lamp.

Assay

The preparation of Carthamus yellow standard curve: the accurate title, decided S-A Hydroxysafflor yellow A 10mg, places the 100ml measuring bottle, and being dissolved in water is settled to scale, shakes up.Precision is measured above-mentioned solution 1ml, 2ml, 3ml, 4ml, 5ml respectively, places the 25ml measuring bottle respectively, and thin up is settled to scale, shakes up.Adopting ultraviolet spectrophotometry, measure absorbance at 403nm wavelength place, is vertical coordinate with the absorbance, and concentration is abscissa, the drawing standard curve.

The preparation of need testing solution: it is an amount of to get Flos Carthami extract, adds an amount of ultrasonic solution that makes dissolving be mixed with 20 μ g/ml of water, filters, and gets filtrate and adopts ultraviolet spectrophotometry, measures absorbance at 403nm wavelength place.Read the content of Carthamus yellow the need testing solution from standard curve, calculate, promptly.

Extract three batches of Flos Carthami extracts by above technology, its yield and content see Table 6, show, the yield of the Flos Carthami extract that extracts by this technology is 1.5～3%, and wherein the content of Carthamus yellow is not less than 70%.

The content of the yield and Flos Carthami flavochrome of table 5 Flos Carthami extract

Batch	Yield (%)	Carthamus tinctorius yellow color content (%)
Batch	Yield (%)	Carthamus tinctorius yellow color content (%)	1 2 3	2.11 2.01 1.72	75.8 75.2 80.5

The preparation two of embodiment 2 Carthamus yellows

Get Flos Carthami 250kg and decoct with water 1.5 hours, filter, it is 1.14 that filtrate is concentrated into relative density, to add ethanol in the concentrated solution to containing alcohol amount 80%, and constantly stir, precipitate 24 hours at 4 ℃, filter, filtrate recycling ethanol also is concentrated into the water that relative density is 8 times of 1.18 addings, precipitates 24 hours at 4 ℃, the centrifugal precipitation of removing, centrifugal liquid is evaporated to extracting solution and contains crude drug 1g/ml, and through macroporous adsorbent resin column chromatography, elder generation is eluted to the Molish reaction with deionized water and ninhydrin reaction is negative with concentrated solution, continue with the deionized water eluting of 6 column volumes and collect eluent, be concentrated into extracting solution and contain crude drug 1g/ml, last polyamide column is eluted to earlier colourless with deionized water, 8 column volumes of reuse 70～90% ethanol elutions, collect eluent, decompression recycling ethanol, lyophilization or spray drying, obtain the orange colour amorphous powder, i.e. Carthamus yellow.

Assay

The content of the yield and Flos Carthami flavochrome of table 6 Flos Carthami extract

Batch	Yield (%)	Carthamus tinctorius yellow color content (%)
Batch	Yield (%)	Carthamus tinctorius yellow color content (%)	1 2 3	1.85 1.98 2.15	72.52 72.86 73.22

The preparation of embodiment 3 Radix Rhodiolae total phenols

Get Radix Rhodiolae medical material 200kg, be ground into coarse powder,, add 10 times of amounts of alcohol for the first time, be respectively 8,8 times of amounts the two or three time with 70% ethanol extraction three times each 1 hour.Filter, merge extractive liquid,, recovery ethanol extremely every 5ml contains the 1g raw medicinal herbs, behind 2 times of amount defat with petroleum ether, discards petroleum ether liquid, and the water saturated n-butanol extraction of reuse is evaporated to the thick paste shape, and spray drying promptly gets the Radix Rhodiolae crude extract.

Radix Rhodiolae crude extract 10.05kg with after the suitable quantity of water dissolving, is added on the macroporous resin column of handling well in advance, water liquid, 10% ethanol, 15% ethanol, 20% ethanol, 30% ethanol elution successively, elution speed is 10ml/min.Decompression recycling ethanol to relative density is 1.03～1.06 (60 ℃), and spray drying gets the Radix Rhodiolae essence extract.

The assay of rhodioside

Chromatographic condition and system suitability test are filler with the octadecylsilane chemically bonded silica; With methanol-water (15: 85) is mobile phase, and the detection wavelength is 275nm.Number of theoretical plate calculates by the rhodioside peak should be not less than 1500.

The preparation precision of reference substance solution takes by weighing the rhodioside reference substance, adds methanol and makes the solution that every 1ml contains 0.5mg, promptly.

The preparation precision of need testing solution takes by weighing this product 0.1g, grinds well, and puts in the tool plug conical flask, accurate methanol 10ml, the close plug of adding, shake up, claim decide weight, supersound process 30 minutes is put coldly, and weight decided in title again, supply with methanol and to subtract weight loss, shake up, filter, get subsequent filtrate, promptly.

Accurate respectively reference substance solution and each 10ul of need testing solution of drawing of algoscopy injects chromatograph of liquid, measures, promptly.

The assay of total phenols:

It is an amount of that the preparation precision of reference substance solution takes by weighing the gallic acid reference substance, puts in the brown measuring bottle, adds water and make the solution that every 1ml contains gallic acid 0.05mg, promptly.

The preparation precision of standard curve is measured reference substance solution 0.5ml, 1.0ml, 2.0ml, 3.0ml, 4.0ml, 5.0ml, put respectively in the brown measuring bottle of 25ml, molybdenum wolframic acid test solution 1ml respectively phosphorates, add water 11.5ml more respectively, 11ml, 10ml, 9ml, 8ml, 7ml, be diluted to scale with 29% sodium carbonate liquor, shake up, placed 30 minutes, with the reagent corresponding is blank, according to ultraviolet one visible spectrophotometry (appendix VA of Chinese Pharmacopoeia version in 2005), measure absorbance at 760nm wavelength place, be vertical coordinate with the absorbance, concentration is abscissa, the drawing standard curve.

The preparation precision of need testing solution takes by weighing this product 25mg, puts in the 25ml measuring bottle, adds 60% ethanol to scale, shakes up, and sample is dissolved fully, and the accurate 2ml that draws puts in the 25ml measuring bottle, adds water to scale, shakes up, promptly.

The algoscopy precision is measured need testing solution 2ml, put in the brown measuring bottle of 25ml, method under the preparation of sighting target directrix curve, from " adding P-Mo-Wo acid test solution 1ml ", add water 10ml, measure absorbance in accordance with the law, from standard curve, read the amount (mg) of gallic acid in the need testing solution, calculate, promptly.

The yield of the Radix Rhodiolae extract that table 7 makes by above-mentioned technology and the content of rhodioside and total phenols

Batch	Yield (%)	The content of rhodioside (%)	The content of total phenols (%)
Batch	Yield (%)	The content of rhodioside (%)	The content of total phenols (%)	Second batch of Radix Rhodiolae extract of second batch of Radix Rhodiolae crude extract of first Radix Rhodiolae extract of first Radix Rhodiolae crude extract	10.05 2.98 11.02 3.01	5.2 18.4 4.7 12.3	56.5 65.3 55.6 61.3

First Radix Rhodiolae extract of above-mentioned gained is labeled as Radix Rhodiolae extract A.

The preparation of embodiment 4 Radix Rhodiolaes (total phenols+polysaccharide)

It is an amount of to get the Radix Rhodiolae medical material, adds 70% ethanol extraction 3 times, adds 10 times of amounts for the first time, refluxes 1 hour, adds 8 times of amounts for the second time, refluxes 1 hour, adds 8 times of amounts for the third time, refluxes 1 hour.Merge extractive liquid, filters filtrate recycling ethanol, and to be evaporated to relative density be 1.05, and concentrated solution adds 2 times of water gagings, stirs evenly, cold preservation is more than 24 hours, filter, it is 1.05 that filtrate decompression is concentrated into relative density, concentrated solution equivalent n-butanol extraction 3 times, merge extractive liquid,, reclaim under reduced pressure, vacuum drying or spray drying promptly get extract 1; Water liquid adds ethanol to be made and contains alcohol amount and reach 85%, stirs evenly, and leaves standstill more than 24 hours, filter, and the precipitate washing, vacuum drying or spray drying promptly get extract 2.United extraction thing 1 and extract 2 promptly get total extract.

The assay of rhodioside

Above-mentioned each 20ml of each sample liquid of the accurate absorption of the preparation of need testing solution, behind the evaporate to dryness, residue adds dissolve with methanol in the water-bath, moves to the 10ml measuring bottle, is diluted to scale with methanol, shakes up, and filters, and gets subsequent filtrate promptly.

The assay of total phenols:

Content Determination of Polysaccharide

The preparation precision of reference substance solution takes by weighing in 105 ℃ of glucose reference substances that are dried to constant weight an amount of approximately, adds methanol and makes the solution that every 1ml contains 0.15mg, promptly.

The preparation precision of standard curve is measured reference substance solution 1ml, 2ml, 3ml, 4ml, 5ml puts in the 10ml measuring bottle, and thin up shakes up to scale, as each reference substance solution.Precision is measured each reference substance solution 2ml respectively, put in the 25ml nessler colorimetric tube, add 2% phenol solution 1ml, shake up, add sulphuric acid 5.0ml rapidly, shake up, placed 5 minutes, put in the boiling water bath and heated 10 minutes, take out and be cooled to room temperature rapidly, measure according to ultraviolet visible spectrophotometry (appendix VA of Chinese Pharmacopoeia version in 2005), the place measures absorbance respectively at 488 ± 2nm wavelength, absorbance with mensuration is vertical coordinate (y), and the concentration of reference substance (μ g/ml) is abscissa (x), the drawing standard curve.

The preparation precision of need testing solution takes by weighing this product 25mg, puts in the 25ml measuring bottle, adds water to scale, shakes up, and the accurate 5ml that draws puts in the 25ml measuring bottle, adds water to scale, shakes up, promptly.

The algoscopy precision is measured need testing solution 2ml, put in the 25ml nessler colorimetric tube, measure absorbance from " adding 2% phenol solution 1ml " under the sighting target directrix curve preparation in accordance with the law, the amount of reading saccharide the need testing solution (with glucose meter) from standard curve, calculate, promptly.

Extract three batches of Radix Rhodiolae extracts by above technology, its yield and content see Table 8.

The content of rhodioside, total phenols and polysaccharide in the yield of table 8 Radix Rhodiolae extract and the extract

Batch	Yield (%)	Rhodioside content (%)	The content of total phenols and polysaccharide (%)
Batch	Yield (%)	Rhodioside content (%)	The content of total phenols and polysaccharide (%)	1 2 3	7.18 7.31 7.43	4.32 4.53 4.68	52.63 53.72 55.26

Second batch of Radix Rhodiolae extract of above-mentioned gained is labeled as Radix Rhodiolae extract B.

The preparation of embodiment 5 Radix Rhodiolae polysaccharides

It is an amount of to get the Radix Rhodiolae medical material, and extracting in water 3 times adds 10 times of amounts for the first time, refluxes 2 hours, adds 10 times of amounts for the second time, refluxes 2 hours.Extracting solution filters, and it is 1.05 that filtrate decompression is concentrated into relative density.Add ethanol and make and contain alcohol amount and reach 85%, stir evenly, cold preservation filtered more than 24 hours, the precipitate cold drying, promptly.

Content assaying method is seen embodiment 4.

Extract three batches of Radix Rhodiolae extracts by above technology, its yield and content see Table 9, show, the yield of the Radix Rhodiolae extract that extracts by this technology is 5.0～6.0%, and wherein the content of rhodioside is not less than 3.5%, and the content of polysaccharide is not less than 50%.

The content of rhodioside, polysaccharide in the yield of table 9 Radix Rhodiolae extract and the extract

Batch	Yield (%)	Rhodioside content (%)	The content of polysaccharide (%)
Batch	Yield (%)	Rhodioside content (%)	The content of polysaccharide (%)	1 2 3	5.36 5.51 5.73	3.62 3.75 3.81	53.32 55.22 55.62

Second batch of Radix Rhodiolae extract of above-mentioned gained is labeled as Radix Rhodiolae extract C.

The preparation of embodiment 6 pharmaceutical composition aqueous injection of the present invention

Prescription 1:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae total phenols 29.8g (being equivalent to crude drug 1000g)

Water for injection adds to 5000ml

Prepare 1000 altogether

Prescription 2:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae (total phenols+polysaccharide) 73.1g (being equivalent to crude drug 1000g)

Water for injection adds to 5000ml

Prepare 1000 altogether

Prescription 3:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae polysaccharide 5.51g (being equivalent to crude drug 1000g)

Water for injection adds to 5000ml

Prepare 1000 altogether

Method for making:

Carry and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse; Get the water for injection of dosing amount 80%, add Carthamus yellow and Radix Rhodiolae extract, the heated and stirred dissolving fully; Benefit adds to the full amount of water for injection; The needle-use activated carbon that adds dosing amount 0.1%, heated and stirred 15 minutes; Through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution; Microporous filter membrane fine straining through 0.45um; Check the clarity of solution, the semi-finished product chemical examination; With the solution sealing by fusing in glass ampule; 100 ℃ of flowing steam sterilizations 30 minutes; While hot sample being put into 0.01% methylene blue solution hunts leak; Lamp inspection, finished product is examined entirely, the packing warehouse-in.

The preparation of embodiment 7 pharmaceutical composition injectable powder of the present invention

Prescription 1:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae total phenols 29.8g (being equivalent to crude drug 1000g)

Mannitol 300g

Sterile water for injection adds to 5000ml

Prepare 1000 altogether

Prescription 2:

Carthamus yellow 49.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae total phenols 29.8g (being equivalent to crude drug 1000g)

Mannitol 300g

Sterile water for injection adds to 5000ml

Prepare 1000 altogether

Prescription 3:

Carthamus yellow 49.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae (total phenols+many 73.1g (being equivalent to crude drug 1000g)

Sugar)

Mannitol 300g

Sterile water for injection adds to 5000ml

Prepare 1000 altogether

Prescription 4:

Carthamus yellow 49.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae polysaccharide 5.51g (being equivalent to crude drug 1000g)

Mannitol 300g

Sterile water for injection adds to 5000ml

Prepare 1000 altogether

Method for making:

Vessel and antibiotic glass bottle that elder generation uses dosing, plugs etc. carry out aseptic process; Take by weighing supplementary material according to recipe quantity; Get the sterile water for injection of dosing amount 80%, Carthamus yellow and Radix Rhodiolae extract are added the heated and stirred dissolving fully.Add the dissolving of mannitol heated and stirred more fully, add sterile water for injection to full dose; The needle-use activated carbon that adds dosing amount 0.1%, heated and stirred 15 minutes; Through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution; Microporous filter membrane fine straining through 0.22um; Check the clarity of solution, the semi-finished product chemical examination; Be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then; Lyophilizing finishes, and lid is rolled in tamponade; Finished product is examined entirely, the packing warehouse-in.

The preparation of embodiment 8 pharmaceutical composition sodium chloride injections of the present invention

Prescription 1:

Carthamus yellow 20.1g (being equivalent to crude drug 1000g)

Radix Rhodiolae total phenols 45.2g (being equivalent to crude drug 1500g)

Sodium chloride 900g

Water for injection adds to 100000ml

Prepare 1000 bottles altogether

Prescription 2:

Carthamus yellow 20.1g (being equivalent to crude drug 1000g)

Radix Rhodiolae (total phenols+polysaccharide) 109.7g (being equivalent to crude drug 1500g)

Sodium chloride 900g

Water for injection adds to 100000ml

Prepare 1000 bottles altogether

Prescription 3:

Carthamus yellow 20.1g (being equivalent to crude drug 1000g)

Radix Rhodiolae polysaccharide 82.7g (being equivalent to crude drug 1500g)

Sodium chloride 900g

Water for injection adds to 100000ml

Prepare 1000 bottles altogether

Method for making:

Carry and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse; The water for injection of getting dosing amount 20% adds the heated and stirred dissolving fully with Carthamus yellow and Radix Rhodiolae extract.Sodium chloride is complete with the water for injection dissolving of dosing amount 40%; Merge two solution, benefit adds to the full amount of water for injection; The needle-use activated carbon that adds dosing amount 0.1%, heated and stirred 15 minutes; Through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution; Microporous filter membrane fine straining through 0.45um; Check the clarity of solution, the semi-finished product chemical examination; Fill is in the infusion bottle of 100ml; 115 ℃ of pressure sterilizings 30 minutes; Lamp inspection, finished product is examined entirely, the packing warehouse-in.

The preparation of embodiment 9 pharmaceutical composition glucose injections of the present invention

Prescription 1:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae total phenols 29.8g (being equivalent to crude drug 1000g)

Glucose 5000g

Water for injection adds to 100000ml

Prepare 1000 bottles altogether

Prescription 2:

Carthamus yellow 29.7g (being equivalent to crude drug 1500g)

Radix Rhodiolae total phenols 45.2g (being equivalent to crude drug 1500g)

Glucose 5000g

Water for injection adds to 100000ml

Prepare 1000 bottles altogether

Prescription 3:

Carthamus yellow 29.7g (being equivalent to crude drug 1500g)

Glucose 5000g

Water for injection adds to 100000ml

Prepare 1000 bottles altogether

Prescription 4:

Carthamus yellow 29.7g (being equivalent to crude drug 1500g)

Radix Rhodiolae polysaccharide 82.7g (being equivalent to crude drug 1500g)

Glucose 5000g

Water for injection adds to 100000ml

Prepare 1000 bottles altogether

Method for making:

Carry and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse, the water for injection of getting dosing amount 20% adds the heated and stirred dissolving fully with Carthamus yellow and Radix Rhodiolae extract.Glucose is complete with the water for injection dissolving of dosing amount 40%; Merge two solution, benefit adds to the full amount of water for injection; The needle-use activated carbon that adds dosing amount 0.1%, heated and stirred 15 minutes; Through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution; Microporous filter membrane fine straining through 0.45um; Check the clarity of solution, the semi-finished product chemical examination; Fill is in the infusion bottle of 100ml; 115 ℃ of pressure sterilizings 30 minutes; Lamp inspection, finished product is examined entirely, the packing warehouse-in.

The preparation of embodiment 10 pharmaceutical composition tablets of the present invention

Prescription 1:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae total phenols 29.8g (being equivalent to crude drug 1000g)

Starch 150g

Microcrystalline Cellulose 40g

The 2%HPMC aqueous solution is an amount of

Magnesium stearate 2g

Carboxymethylstach sodium 4g

Prepare 1000 altogether

Prescription 2:

Carthamus yellow 59.4g (being equivalent to crude drug 3000g)

Radix Rhodiolae total phenols 24.1g (being equivalent to crude drug 800g)

Starch 150g

Microcrystalline Cellulose 40g

The 2%HPMC aqueous solution is an amount of

Magnesium stearate 2g

Carboxymethylstach sodium 4g

Prepare 1000 altogether

Prescription 3:

Carthamus yellow 59.4g (being equivalent to crude drug 3000g)

Radix Rhodiolae (total phenols+polysaccharide) 58.5g (being equivalent to crude drug 800g)

Starch 150g

Microcrystalline Cellulose 40g

The 2%HPMC aqueous solution is an amount of

Magnesium stearate 2g

Carboxymethylstach sodium 4g

Prepare 1000 altogether

Prescription 4:

Carthamus yellow 59.4g (being equivalent to crude drug 3000g)

Radix Rhodiolae polysaccharide 44.1g (being equivalent to crude drug 800g)

Starch 150g

Microcrystalline Cellulose 40g

The 2%HPMC aqueous solution is an amount of

Magnesium stearate 2g

Carboxymethylstach sodium 4g

Prepare 1000 altogether

Method for making:

It is standby that Carthamus yellow and Radix Rhodiolae extract were pulverized 100 mesh sieves; Take by weighing various adjuvants according to recipe quantity; Hypromellose 2% the aqueous solution made soluble in water is standby; With Carthamus yellow, Radix Rhodiolae extract, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material; Cross 20 mesh sieve system granules; Granule is dried under 60 ℃ condition; Dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously; Sampling, the semi-finished product chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.

The preparation of embodiment 11 medicament composition capsule agent of the present invention

Prescription 1:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae total phenols 29.8g (being equivalent to crude drug 1000g)

Starch 30g

Microcrystalline Cellulose 2g

The 2%HPMC aqueous solution is an amount of

Magnesium stearate 1g

Prepare 1000 altogether

Prescription 2:

Carthamus yellow 99.0g (being equivalent to crude drug 5000g)

Radix Rhodiolae total phenols 15.1g (being equivalent to crude drug 500g)

Starch 30g

Microcrystalline Cellulose 2g

The 2%HPMC aqueous solution is an amount of

Magnesium stearate 1g

Prepare 1000 altogether

Prescription 3:

Carthamus yellow 99.0g (being equivalent to crude drug 5000g)

Radix Rhodiolae (total phenols+polysaccharide) 36.6g (being equivalent to crude drug 500g)

Starch 30g

Microcrystalline Cellulose 2g

The 2%HPMC aqueous solution is an amount of

Magnesium stearate 1g

Prepare 1000 altogether

Prescription 4:

Carthamus yellow 99.0g (being equivalent to crude drug 5000g)

Radix Rhodiolae polysaccharide 27.6g (being equivalent to crude drug 500g)

Starch 30g

Microcrystalline Cellulose 2g

The 2%HPMC aqueous solution is an amount of

Magnesium stearate 1g

Prepare 1000 altogether

Method for making:

It is standby that Carthamus yellow and Radix Rhodiolae extract were pulverized 100 mesh sieves; Take by weighing adjuvant according to recipe quantity; Hypromellose 2% the aqueous solution made soluble in water is standby; With Radix Rhodiolae extract, Carthamus yellow, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material; Cross 20 mesh sieve system granules; Granule is dried under 60 ℃ condition; Dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously; Sampling, the semi-finished product chemical examination; The loading amount of determining according to chemical examination incapsulates; Finished product is examined entirely, the packing warehouse-in.

The preparation of embodiment 12 medicament composition granule agent of the present invention

Prescription 1:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae total phenols 29.8g (being equivalent to crude drug 1000g)

Icing Sugar 900g

The 2%HPMC50% alcoholic solution is an amount of

Prepare 1000 bags altogether

Prescription 2:

Carthamus yellow 100.5g (being equivalent to crude drug 5000g)

Icing Sugar 900g

The 2%HPMC50% alcoholic solution is an amount of

Prepare 1000 bags altogether

Prescription 3:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae polysaccharide 55.1g (being equivalent to crude drug 1000g)

Icing Sugar 900g

The 2%HPMC50% alcoholic solution is an amount of

Prepare 1000 bags altogether

Method for making:

It is standby that sucrose was pulverized 100 mesh sieves; It is standby that Carthamus yellow and Radix Rhodiolae extract were pulverized 100 mesh sieves; Take by weighing adjuvant according to recipe quantity; With the method mix homogeneously that Carthamus yellow, Radix Rhodiolae extract and Icing Sugar progressively increase with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and makes suitable soft material; Cross 20 mesh sieve system granules; Granule is dried under 60 ℃ condition; Dried granule is crossed 18 mesh sieve granulate; Sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule; Packing, finished product is examined entirely, the packing warehouse-in.

The preparation of embodiment 13 drug composition oral liquid of the present invention

Prescription 1:

Carthamus yellow 50.5g (being equivalent to crude drug 2500g)

Radix Rhodiolae total phenols 29.8g (being equivalent to crude drug 1000g)

Sodium benzoate 15g

Stevioside 10g

Water adds to 10000ml

Prepare 1000 altogether

Prescription 2:

Carthamus yellow 40.2g (being equivalent to crude drug 2000g)

Radix Rhodiolae polysaccharide 55.1g (being equivalent to crude drug 1000g)

Sodium benzoate 15g

Stevioside 10g

Water adds to 10000ml

Prepare 1000 altogether

Prescription 3:

Carthamus yellow 49.5g (being equivalent to crude drug 2500g)

Sodium benzoate 15g

Stevioside 10g

Water adds to 10000ml

Prepare 1000 altogether

Method for making:

Carthamus yellow and Radix Rhodiolae extract is complete with the water dissolution of dosing amount 60%; Sodium benzoate and stevioside is complete with the water dissolution of dosing amount 20%; Merge above-mentioned two solution, mend and add water to full dose; Cross the filtering with microporous membrane of 0.8um; The semi-finished product chemical examination; Fill.Finished product is examined entirely, the packing warehouse-in.

Claims

1. a pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease is characterized in that, composition and the parts by weight of making the crude drug of the contained active ingredient of this pharmaceutical composition are: 500～10000 parts on Flos Carthami, 250～3000 parts of Radix Rhodiolaes.

2. pharmaceutical composition according to claim 1 is characterized in that, the composition of its crude drug and parts by weight are: 1000～5000 parts on Flos Carthami, 500～1500 parts of Radix Rhodiolaes.

3. pharmaceutical composition according to claim 2 is characterized in that, the composition of its crude drug and parts by weight are: 2500 parts on Flos Carthami, 1000 parts of Radix Rhodiolaes.

4. according to the described arbitrary pharmaceutical composition of claim 1～3, it is characterized in that, described Flos Carthami and Radix Rhodiolae are respectively or mix through extracting processing and obtain its extract, extract is made preparation with the pharmaceutic adjuvant hybrid process again, and the content of Carthamus yellow is not less than 50% in the Flos Carthami extract wherein; The content of rhodioside is not less than 3% in the Radix Rhodiolae extract wherein, and the content of total phenols and/or polysaccharide is not less than 50%.

5. pharmaceutical composition according to claim 1 is characterized in that, makes the composition of crude drug of the contained active ingredient of this pharmaceutical composition and parts by weight and can also be 50 parts of Carthamus yellows, 1～500 part of Radix Rhodiolae extract.

6. pharmaceutical composition according to claim 5 is characterized in that, the composition of its crude drug and parts by weight are: 50 parts of Carthamus yellows, 3～200 parts of Radix Rhodiolae extracts.

7. pharmaceutical composition according to claim 6 is characterized in that, the composition of its crude drug and parts by weight are: 50 parts of Carthamus yellows, 15～60 parts of Radix Rhodiolae extracts.

8. according to the described arbitrary pharmaceutical composition of claim 5～7, it is characterized in that the content of Carthamus yellow wherein is not less than 50%; The content of rhodioside is not less than 3% in the Radix Rhodiolae extract wherein, and the content of total phenols and/or polysaccharide is not less than 50%.

9. according to claim 1～3,5～7 described pharmaceutical compositions, it is characterized in that this pharmaceutical composition can be made clinically any or pharmaceutically acceptable dosage form.

10. pharmaceutical composition according to claim 9 is characterized in that this pharmaceutical composition can be made injection or oral formulations.