CN101176772B - Pharmaceutical composition made of cattail pollen and safflower - Google Patents
Pharmaceutical composition made of cattail pollen and safflower Download PDFInfo
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Abstract
The invention discloses a drug compound used for cardiovascular and cerebral diseases, the preparation method and the formulation containing the drug compound, belonging to the medical technical field. The raw material drugs for preparing the effective components in the drug compound are as follow: carrail pollen or the extract and safflower or the extract; the weight proportion is as follow: 1000 to 10000 of carrail pollen and 100 to 4000 of safflower; or 20 to 400 of the extract of carrail pollen and 2 to 120 of the extract of safflower. The drug compound can be made into acceptable clinical or pharmaceutical formulation; and formulation for oral use or injection is preferred. The invention has the advantages that: the pharmacological experiment proves that the drug compound has the synergistic interaction function, thereby, the effect is improved greatly compared to singly using carrail pollen or the extract and safflower or the extract.
Description
[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]
Medically, cardiovascular and cerebrovascular disease is meant that sclerosis takes place for heart and arteries and the heart ischemia that causes or hemorrhage disease comprise coronary heart disease, angina pectoris, hypertension, hyperlipidemia, arrhythmia, myocardial infarction, cerebral infarction, ischemic encephalopathy, cerebral thrombosis etc.The main pathogenic factor of these diseases is that arteriosclerosis causes luminal stenosis, pipeline obstruction, thereby causes cerebral ischemia, causes just that head is heavy, dizziness, headache, symptom such as uncomfortable in chest, and severe patient can cause the generation of apoplexy and myocardial infarction.
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.The characteristics that have repetition, SM again because of cardiovascular and cerebrovascular disease patient's treatment, and the toxic and side effects of chemicals is big, easily develops immunity to drugs, therefore researching and developing new Chinese medicine evident in efficacy, low toxicity is the direction that the personage of the world of medicine is devoted to develop.
Pollen Typhae is the dry pollen of the turbid Herba Typhae Typha of Typhaceae vegetation water angustifolia L, typha orientalis Typha orientalis Pres1 or congener.Sweet in the mouth, property is flat.Return liver, pericardium channel.Hemostasis is arranged, blood stasis dispelling, treating stranguria effect.Be used for spitting blood epistaxis, spitting of blood, metrorrhagia, traumatic hemorrhage, amenorrhea dysmenorrhea, gastral cavity ventral spine pain, tumbling and swelling, blood strangury and dry pain.
Pollen Typhae mainly contains steroid class, flavonoid, alkyl compound, acid ingredient, aminoacid, inorganic constituents etc., the pharmacological action of relevant Pollen Typhae report is a lot of in recent years, especially aspect cardiovascular, has microcirculation improvement, reduce serum cholesterol, atherosclerosis, can be used for cardiovascular disease such as coronary heart disease, angina pectoris, myocardial infarction, hyperlipidemia, hypertension, wherein flavone compound is its main effective ingredient.Pollen Typhae also has analgesic activity, the effect of coagulant blood, improves immunization, antiinflammatory action and intestinal tube effect etc. in addition.
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, and pharmacological evaluation proves that it has the energy metabolism of myocardial of improvement, alleviates the myocardial ischemia damage; Coronary artery dilator, improve blood supply of cardiac muscle; The effect of vascular smooth muscle under the expansion pathological state and inhibition vascular smooth muscle cell proliferation brings high blood pressure down; The neuronal cell hypoxic-ischemic there is stronger protective effect; Inhibition of endothelial cell proliferation stops endotheliocyte transition hypertrophy, stablizes tunica intima; Anticoagulation suppresses thrombosis; Free radical resisting, inhibition lipid peroxidation; Anoxia enduring, antiinflammatory reach multiple pharmacological effect such as immune effects.S-A Hydroxysafflor yellow A content is higher in the Carthamus yellow, has the pharmacodynamics effect representativeness.In recent years, the Flos Carthami preparation scope that is used for the treatment of cardiovascular and cerebrovascular disease clinically constantly enlarges.
Modern pharmacology and pharmacodynamic study show that all Pollen Typhae, Flos Carthami are all having effect preferably aspect the treatment cardiovascular and cerebrovascular disease.But, utilizing interaction, the composition of prescription of Pollen Typhae or Pollen Tyjphae extract and Flos Carthami or Flos Carthami extract, 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 the Pollen Typhae and Flos Carthami, both parts by weight are: 1000～10000 parts of Pollen Typhaes, 100～4000 parts on Flos Carthami; Be preferably: 2000～5000 parts of Pollen Typhaes, 200～2000 parts on Flos Carthami; Optimum is: 3000 parts of Pollen Typhaes, 500～1000 parts on Flos Carthami.
Pollen Typhae and Flos Carthami in the pharmaceutical composition of the present invention can be with The suitable solvent respectively or mix through extracting processing and obtain its extract, and extract is made any preparation 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 effective ingredient of gained total extract is mainly flavone compound and Flos Carthami flavochrome.
The present invention has carried out preferably the extraction process of Pollen Typhae, and step is as follows:
Get cattail pollen, add 70% ethanol extraction three times, extracted 3 hours at every turn.First and second time adds 14 times of amounts of alcohol, adds 10 times of amounts of alcohol for the third time.Merge extractive liquid, filters, and filtrate recycling ethanol to relative density is the concentrated solution of 1.04～1.06 (50 ℃), the water gaging dilution such as add, mixing, 4 ℃ of cold preservation 24 hours, centrifugal, get supernatant, extract 2 times with the jolting of equivalent petroleum ether, discard petroleum ether liquid, water liquid concentrate as for, residue adds low amounts of water makes dissolving, last AB-8 macroporous resin column, water, 35% ethanol, 70% ethanol elution are collected 70% ethanol elution respectively, reclaim ethanol, drying under reduced pressure, promptly.
Pollen Tyjphae extract yield by above-mentioned prepared is 2～4%, and flavonoid content is not less than 50%.
Pollen Typhae can also be extracted preparation by following method, but be not limited only to following method except that being adopted the said method extraction:
Technology one: get cattail pollen, decoct with water three times, first, second time is each to decoct 3 hours, added 12 times of amounts of water, decocted for the third time 2 hours, added 10 times of amounts of water.Merge extractive liquid, filters, and filtrate is concentrated into the clear paste that relative density is 1.10～1.15 (60 ℃), adds ethanol and reaches 80% to containing the alcohol amount, stir evenly, cold preservation, placement is spent the night, and filters, filtrate recycling ethanol is evaporated to the thick paste shape to there not being the alcohol flavor, vacuum drying, promptly.
Pollen Tyjphae extract yield by above-mentioned prepared is 10～20%, and flavonoid content is not less than 20%.
Technology two: get cattail pollen, decoct with water three times, first, second time is each to decoct 3 hours, added 12 times of amounts of water, decocted 10 times of amounts of amount of water for the third time 2 hours.Merge extractive liquid, filters, and filtrate is concentrated into the clear paste that relative density is 1.10～1.15 (60 ℃), add ethanol and reach 80%, stir evenly cold preservation to containing the alcohol amount, placement is spent the night, and filters, and filtrate recycling ethanol to relative density is the concentrated solution of 1.04～1.06 (60 ℃), after the water gaging dilution such as adding, extract 2 times, discard petroleum ether liquid with the jolting of equivalent petroleum ether, water liquid extracts 3 times with the jolting of equivalent water-saturated n-butanol, merges n-butanol extracting liquid, is concentrated into the thick paste shape, spray drying, promptly.
Pollen Tyjphae extract yield by above-mentioned prepared is 3～9%, and flavonoid content is not less than 30%.
Technology three: get cattail pollen, add 70% ethanol extraction three times, extracted 3 hours at every turn.First and second time adds 14 times of amounts of alcohol, adds 10 times of amounts of alcohol for the third time.Merge extractive liquid, filters, and filtrate recycling ethanol to relative density is the clear paste of 1.04～1.06 (50 ℃), the water gaging dilution such as add, mixing, 4 ℃ of cold preservation 24 hours, centrifugal, get supernatant, extract 2 times with the jolting of equivalent petroleum ether, discard petroleum ether liquid, water liquid extracts 3 times with the jolting of equivalent water-saturated n-butanol, merges n-butanol extracting liquid, is concentrated into the thick paste shape, spray drying, promptly.
Pollen Tyjphae extract yield by above-mentioned prepared is 5～10%, and flavonoid content is not less than 30%.
Technology four: get cattail pollen, decoct with water three times, first, second time is each to decoct 3 hours, added 12 times of amounts of water, decocted for the third time 2 hours.10 times of amounts of amount of water.Merge extractive liquid, filters, and filtrate is concentrated into the clear paste that relative density is 1.10～1.15 (60 ℃), add ethanol to content and reach 80%, stir evenly, placement is spent the night, filter, filtrate recycling ethanol to relative density is the concentrated solution of 1.04～1.06 (60 ℃), the water gaging dilution such as add after, extract 2 times with the jolting of equivalent petroleum ether, discard petroleum ether liquid, water liquid extracts 3 times with the jolting of equivalent water-saturated n-butanol, merges n-butanol extracting liquid, is concentrated into dried, residue adds low amounts of water makes dissolving, last macroporous resin column with the water elution of 1 times of column volume, discards water lotion earlier, 35% ethanol elution of 2 times of volumes of reuse, discard 35% ethanol elution, use 70% ethanol elution of 3 times of column volumes then, collect 70% ethanol elution, decompression recycling ethanol, be concentrated into the thick paste shape, spray drying, promptly.
Pollen Tyjphae extract yield by above-mentioned prepared is 1～5%, and flavonoid content is not less than 40%.
The present invention has carried out preferably the extraction process of Flos Carthami, and step is as follows:
Flos Carthami is added water-cooled to be 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, promptly.
The Flos Carthami extract yield of extracting by this technology is 1.5～3%, and wherein the content of Carthamus yellow is not less than 70%.
Flos Carthami can also extract preparation by following method, but be not limited only to following method except that adopting the said method extraction:
Technology one: getting Flos Carthami, is that 3 sour water warm macerating extracts two to four 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: 109 (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 speed eluting of/min are collected 60% pure eluting part, and being evaporated to density is about 1.10, then at 70 ℃ of dry or decompression rotary evaporation postlyophilizations of left and right sides reduced vacuum, promptly.
The Flos Carthami extract yield of extracting by this technology is 1～3%, and wherein the content of Carthamus yellow is not less than 70%.
Technology two: 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.
The Flos Carthami extract yield of extracting by this technology is 1～3%, and wherein the content of Carthamus yellow is not less than 50%.
Technology three: get Flos Carthami, add 15 times of amounts of water, soaking at room temperature secondary (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 added on (100～200 orders, polyamide consumption are about 10 times of applied sample amount) on the polyamide column of having handled well to there not being the alcohol flavor, ethanol elution with 35%, collect second yellow band, concentrate drying, promptly.
The Flos Carthami extract yield of extracting by this technology is 2～3%, and wherein the content of Carthamus yellow is not less than 55%.
Pharmaceutical composition provided by the invention can also be made by Pollen Tyjphae extract and Flos Carthami extract, the yield for preparing extract according to crude drug as can be known, its parts by weight are: 20～400 parts of Pollen Tyjphae extracts, 2～120 parts of Flos Carthami extracts; Be preferably: 30～250 parts of Pollen Tyjphae extracts, 4～60 parts of Flos Carthami extracts; More preferably: 60～120 parts of Pollen Tyjphae extracts, 8～30 parts of Flos Carthami extracts.
In the aforementioned pharmaceutical compositions, the main effective ingredient of Pollen Tyjphae extract wherein is a flavone compound, and content is not less than 20%, preferably is not less than 50%; The main component of Flos Carthami extract is a Carthamus yellow, and wherein the content of Carthamus yellow is not less than 50%, preferably is not less than 70%.
Each drug component gets consumption and gropes in a large number to sum up to draw through the inventor in the pharmaceutical composition of the present invention, and the consumption of each component all has better curative effect in above-mentioned weight range.Above-mentioned composition as if being unit with the gram, can be made the preparation of 100～1000 consumptions.As tablet, can make 100～10000,1～10 of each consumption, every day 1～5 time.As injection, can make 100～10000ml, each consumption 1～10ml, every day 1～5 time.More than form when producing and according to the corresponding proportion increase or to reduce, as large-scale production can be raw material with the kilogram, or is unit with the ton, and small-scale production can be unit with the gram also, weight can increase or reduce, but the constant rate of weight proportion between each composition.Above ratio obtains through science screening, and for especial patient, the ratio of can corresponding adjustment forming increases or reduce being no more than 100%.
Pharmaceutical composition of the present invention has microcirculation improvement; reduce serum cholesterol; atherosclerosis; improve energy metabolism of myocardial; alleviate the myocardial ischemia damage; coronary artery dilator; improve blood supply of cardiac muscle; the effect of vascular smooth muscle under the expansion pathological state and inhibition vascular smooth muscle cell proliferation; bring high blood pressure down; the neuronal cell hypoxic-ischemic there is stronger protective effect; inhibition of endothelial cell proliferation; stop endotheliocyte transition hypertrophy; stablize tunica intima, anticoagulation; suppress thrombosis, free radical resisting; suppress lipid peroxidation; anoxia enduring; antiinflammatory reaches multiple pharmacological effect such as immune effects, is mainly used in coronary heart disease; angina pectoris; myocardial infarction; cardiovascular and cerebrovascular diseases such as ischemic hypoxia cerebrovascular disease.
Pharmaceutical composition of the present invention can be mixed and made into clinically any or pharmaceutically acceptable dosage form with one or more pharmaceutically acceptable carriers, preferred oral preparation or injection are applied to the patient who needs this treatment in the mode of oral or parenteral.
When being used for oral administration, 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 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.
When pharmaceutical composition of the present invention is made 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.
When making injection, optional use solvent or non-aqueous solvent can add suitable additives according to the character of medicine.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.Additives commonly used comprise 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.
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 pharmacodynamic experiment research, by the influence of research pharmaceutical composition of the present invention to myocardial ischemia due to the ligation rat coronary artery, filters out the weight proportion scope with significant curative effect;
(3) the present invention shows by pharmacological experiment study, with Pollen Typhae and Flos Carthami, or be the medicine that raw material is made with Pollen Tyjphae extract and Flos Carthami extract, myocardial infarction area due to the remarkable reduction rat experiment myocardial inyaretion, significantly reduce systolic pressure and the diastolic pressure of the rat due to testing, significantly reduce the serum cholesterol and the triglyceride of diet hyperlipidemia rats, the thrombotic time in the prolong rats carotid artery, prolong the time-to-live of ligation bilateral common carotid arteries rat, alleviate cerebral ischemia, experimental studies results of the present invention proves, Pollen Typhae and Flos Carthami 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, effective ingredient is definite in the Pollen Tyjphae extract, effective ingredient Carthamus yellow structure in the Flos Carthami extract is clear and definite, determined curative effect, content is definite, directly feeds intake with Pollen Tyjphae extract and Flos Carthami extract, and preparation technology is easy, avoided because the shortcoming that the quality of the pharmaceutical preparations that the crude drug mass discrepancy causes differs greatly, the quality of the pharmaceutical preparations improves a lot, and impurity content significantly reduces, and safety is higher.
Below example is further set forth the pharmaceutical composition of the present invention beneficial effect of (being called for short the Pu Hong compositions) by experiment, and 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.Pollen Tyjphae extract in the experimental example comes from embodiment 1, and Flos Carthami extract comes from embodiment 2.
Experimental example 1 Pu Hong compositions is to the influence of myocardial ischemia due to the ligation rat coronary artery
Animal subject: Wistar rat, body weight 200～220g, male and female dual-purpose.
Test sample and dosage:
The myocardial ischemia matched group (dosage: 3ml/kg): normal saline, commercial;
Pollen Typhae group: Pollen Typhae capsule (being equivalent to Pollen Typhae 9g/ grain), self-control;
Flos Carthami group: safflower capsules (being equivalent to Flos Carthami 2.5g/ grain), self-control;
Pu Hong compositions group: Pu Hong composition capsule (the different proportionings of Pollen Typhae+Flos Carthami), self-control.
Experimental technique: get 230 of Wistar rats, be divided into 23 groups at random, every group 10, be respectively the myocardial ischemia matched group, the Pollen Typhae group, the Flos Carthami group, Pu Hong compositions group: 20 groups, Pollen Typhae+Flos Carthami: 1000mg+4000mg, 2000mg+100mg, 2000mg+500mg, 2000mg+1000mg, 2000mg+2000mg, 2000mg+4000mg, 3000mg+100mg, 3000mg+200mg, 3000mg+500mg, 3000mg+800mg, 3000mg+1000mg, 3000mg+2000mg, 3000mg+4000mg, 5000mg+100mg, 5000mg+200mg, 5000mg+500mg, 5000mg+1000mg, 5000mg+2000mg, 5000mg+4000mg, 10000mg+100mg.Each administration group is with normal saline and is mixed with gastric infusion behind the suspension, dosage dosage: 40mg/kg.
Rat is used urethane 1g/kg intraperitoneal injection of anesthesia, back of the body position is fixing, the record electrocardio connects artificial respirator and practices artificial respiration, and opens the thoracic cavity, cut off pericardium, each treated animal is pressed medicine gastric infusion separately, falls branch before the coronary artery of ligation left side behind the 3min, omnidistance record electrocardio 30min, 1h gets blood after the ligation, detects creatine phosphokinase (CK) and lactic acid dehydrogenase (LDH).Take out rat heart, with 4 of the even crosscuts of ventricular muscles, 0.5% chlorination nitro tetrazole is blue to dye along ligature, and with the ischemic areas on every myocardium two sides of planimeter survey, the calculating myocardium ischemic areas accounts for the percentage ratio of ventricle area.
Experimental result and conclusion: experimental result sees Table 1.
(1) after the ligation, the cardiac electrical QRS ripple of myocardial ischemia control rats all increases unusually suddenly, widens, and cardiac muscle is ischemia on a large scale, and biochemistry detection shows as CK and LDH all increases unusually, prompting modeling success.
(2) compare with the myocardial ischemia matched group, the Pu Hong compositions group of each proportioning extremely significantly reduces extremely significantly to reduce myocardial ischemia scope (p＜0.01) because of the electrocardio due to the ligation coronary artery and the abnormal change (p＜0.01) of biochemical indicator; Pollen Typhae group and Flos Carthami group all can significantly reduce significantly to reduce myocardial ischemia scope (p＜0.05) because of the electrocardio due to the ligation coronary artery and the abnormal change (p＜0.05) of biochemical indicator.
(3) effect of the Pu Hong compositions group of each proportioning all is better than Pollen Typhae group or the individually dosed effect of Flos Carthami group, prompting Pollen Typhae and Flos Carthami have synergistic function, aspect the treatment ischemic cardiovascular significant curative effect will arranged, 2000～5000 parts of Pollen Typhaes, the effect of each proportioning is more excellent (with the Pollen Typhae group or the Flos Carthami group is individually dosed compares in 200～2000 parts of scopes of Flos Carthami, p＜0.05, p＜0.05); When 3000 parts of Pollen Typhaes, 500～1000 parts on Flos Carthami, the effect optimum.
Table 1 Pu Hong compositions to the influence of myocardial ischemia due to the ligation rat coronary artery (X ± S, n=10)
Annotate:
*P＜0.05,
*Compare with the myocardial ischemia matched group in p＜0.01;
﹠amp;Compare with the Pollen Typhae group in p＜0.05;
$Compare with the Flos Carthami group in p＜0.05.
Experimental example 2 Pu Hong compositionss are to the influence of rat experiment myocardial inyaretion scope
Animal subject: Wistar rat, body weight 208～230g, male and female dual-purpose.
Test sample:
The normal saline matched group: normal saline, commercial;
The Pollen Tyjphae extract group: the Pollen Tyjphae extract injection (3ml: 300mg), self-control;
The Flos Carthami extract group: the Flos Carthami extract injection (3ml: 50mg), self-control;
Pu Hong compositions group: Pu Hong composite injection (the different proportionings of Pollen Tyjphae extract+Flos Carthami extract), self-control.
Experimental technique:
Get 140 of Wistar rats, be divided into 14 groups at random, 10 every group, be respectively: the normal saline matched group; The Pollen Tyjphae extract group; The Flos Carthami extract group; Pu Hong compositions group: 11 groups, Pollen Tyjphae extract+Flos Carthami extract (100mg+2mg, 100mg+4mg, 100mg+8mg, 100mg+15mg, 100mg+30mg, 100mg+45mg, 100mg+60mg, 100mg+75mg, 100mg+90mg, 100mg+100mg, 100mg+120mg); 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).
Table 2 Pu Hong compositions to the influence of rat experiment myocardial inyaretion scope (X ± S, n=10)
Annotate:
*P＜0.05,
*Compare with the normal saline group in p＜0.01;
#Compare with the Pollen Tyjphae extract group in p＜0.05;
$Compare with Flos Carthami extract in p＜0.05.
Experimental result and conclusion: experimental result sees Table 2.
(1) compare with the normal saline group, Pollen Tyjphae extract group and Flos Carthami extract all can significantly reduce rat heart muscle infarct size (p＜0.05), and Pu Hong compositions Different Weight umber group all can extremely significantly reduce rat heart muscle infarct size (p＜0.01).
(2) compare with Pollen Tyjphae extract or Flos Carthami extract group with single, composite injection Different Weight umber group reduces the better effects if of rat heart muscle infarct size; Especially during Pollen Tyjphae extract 100mg+ Flos Carthami extract 4～60mg, show the effect (p＜0.05) that better reduces the rat heart muscle infarct size, wherein during Pollen Tyjphae extract 100mg+ Flos Carthami extract 8～30mg, effect is more excellent.
Show, each administration group all has tangible function of resisting myocardial ischemia, wherein the curative effect of the composite injection of Pollen Tyjphae extract and Flos Carthami extract compatibility is better than single with Pollen Tyjphae extract or Flos Carthami extract, wherein Pollen Tyjphae extract+Flos Carthami extract is at 100mg: (effect is all remarkable in the scope of 2mg～120mg), point out two medicine compatibilities that synergistic function is arranged, in addition, Pollen Tyjphae extract+Flos Carthami extract is at 100mg: (more remarkable effect in the scope of 8mg～30mg), Pollen Tyjphae extract+Flos Carthami extract is 100mg: during 15mg, the effect optimum points out it may be optimal proportion.
Experimental example 3 Pu Hong compositionss are to the influence of rat blood pressure
Animal subject: healthy male rat, 60, body weight 200～230g.
Test sample:
Injection Pu Hong compositions 1: self-control, 3ml: 110mg contains Pollen Tyjphae extract 100mg, Flos Carthami extract 10mg;
Injection Pu Hong compositions 2: self-control, 3ml: 115mg contains Pollen Tyjphae extract 100mg, Flos Carthami extract 15mg;
Injection Pu Hong compositions 3: self-control, 3ml: 130mg contains Pollen Tyjphae extract 100mg, Flos Carthami extract 30mg;
Injection Pollen Tyjphae extract: self-control, 3ml: 300mg;
Injection Flos Carthami extract: self-control, 3ml: 50mg;
Sodium chloride injection: 250ml: 2.25g, Shangdong Changfu Jiejing Pharmaceutical Industry Co., Ltd..
Above-mentioned test sample is made into the test liquid of 1.0mg/ml respectively with sodium chloride injection.
Experimental technique:
Get 60 of healthy male rats, be divided into 6 groups at random, 10 every group, be respectively: normal saline matched group, injection Pollen Tyjphae extract group, injection Flos Carthami extract group, 1 group of injection Pu Hong compositions, 2 groups of injection Pu Hong compositionss, 3 groups of injection Pu Hong compositionss; Each medicine all is diluted to desired concn with normal saline, intravenous administration.
Each organizes rat all with 2% pentobarbital sodium 45mg/kg intraperitoneal injection of anesthesia.Separate trachea, insert tracheal casing pipe; Separate right common carotid artery, intubate is after pressure transducer connects GY-40 four road physiology monitor record systolic pressures (SAP) and diastolic pressure (DAP) writes down limbs II lead electrocardiogram simultaneously.Each administration group medicine injects femoral vein by the WZ-50G micro-injection pump with 15ml/kg per hour, and matched group gives sodium chloride injection, observe administration before, the periphery blood pressure of administration 1h and drug withdrawal 1h.
Table 3 Pu Hong compositions to the influence of rat blood pressure (X ± S, n=10)
Annotate:
*P＜0.05,
*Compare with the normal saline matched group in p＜0.01; Compare with injection Pollen Tyjphae extract group,
#Compare with injection Flos Carthami extract group in p＜0.05,
$P＜0.05.
Experimental result and conclusion: experimental result sees Table 3.
(1) compare with the normal saline matched group, the systolic pressure during injection Pu Hong compositions 1,2,3 administration group administration 1h all significantly reduces (p＜0.05), and diastolic pressure all extremely significantly reduces (p＜0.01); Systolic pressure after the administration during 1h and diastolic pressure all extremely significantly the utmost point reduce (p＜0.01);
(2) compare with the normal saline matched group, the systolic pressure during injection Pollen Tyjphae extract and Flos Carthami extract injection administration group administration 1h reduces, but does not have significant difference, and diastolic pressure significantly reduces (p＜0.05); Systolic pressure after the administration during 1h and diastolic pressure all significantly reduce (p＜0.05, p＜0.01).
(3) compare with injection Pollen Tyjphae extract group or Flos Carthami extract injection group, the effect of each compositions group all is better than effect (p＜0.05 of individually dosed group of injection Pollen Tyjphae extract or Flos Carthami extract injection, p＜0.05), prompting Pollen Tyjphae extract and Flos Carthami extract have synergistic function, aspect resisting hypertension significant curative effect will be arranged.
Experimental example 4 Pu Hong compositionss are to the influence of rat experiment hyperlipidemia
Animal subject: male rat, 70, body weight 220～240g.
Test sample:
The blank group: normal saline, commercial;
Pollen Tyjphae extract group: Pollen Tyjphae extract tablet (being equivalent to Pollen Typhae 9g/ sheet), self-control;
Flos Carthami extract group: Flos Carthami extract tablet (being equivalent to Flos Carthami 2.5g/ sheet), self-control;
1 group of Pu Hong compositions: the Pu Hong composition tablet (Pollen Typhae+Flos Carthami=3g+0.5g), self-control;
2 groups of Pu Hong compositionss: the Pu Hong composition tablet (Pollen Typhae+Flos Carthami=3g+0.8g), self-control;
3 groups of Pu Hong compositionss: the Pu Hong composition tablet (Pollen Typhae+Flos Carthami=3g+1g), self-control;
Experimental technique:
Get 60 of male rats, be divided into 6 groups at random, 10 every group, be respectively: blank group, Pollen Tyjphae extract group, Flos Carthami extract group, 1 group of Pu Hong compositions, 2 groups of Pu Hong compositionss, 3 groups of Pu Hong compositionss; After each medicine all is mixed with suspension with normal saline, gastric infusion.
Each organizes rat, behind cholesterol and the triglyceride levels, builds hyperlipidemia model before the survey medicine.Except that the blank group gives the normal diet, all the other each groups all give high lipid food (prescription is normal diet 86.8%, cholesterol 3%, Adeps Sus domestica 10%, the phonetic shallow lake 0.2% of rosickyite oxygen), feed was surveyed serum cholesterol and triglyceride levels after 10 days continuously, determined that hyperlipidemia model builds up.Continue to raise high lipid food after model builds up, according to separately dosage gastric infusion, every day, gastric infusion was 1 time respectively for the administration group, and successive administration was got blood again and surveyed cholesterol and triglyceride levels after 20 days.
Table 4 Pu Hong compositions to the influence of diet hyperlipemia rat serum cholesterol (X ± S, n=10)
Annotate:
*P＜0.05,
*Compare with the hyperlipidemia model group in p＜0.01;
﹠amp;Compare with the Pollen Tyjphae extract group in p＜0.05;
$Compare with the Flos Carthami extract group in p＜0.05;
#P＜0.01 with the experiment before compare.
Table 5 Pu Hong compositions to the influence of diet hyperlipemia rat serum triglycerides (X ± S, n=10)
Annotate:
*P＜0.05,
*Compare with the hyperlipidemia model group in p＜0.01;
﹠amp;Compare with the Pollen Tyjphae extract group in p＜0.05;
$Compare with the Flos Carthami extract group in p＜0.05;
#Compare with the blank group in p＜0.01.
Experimental result and conclusion: experimental result sees Table 4 and table 5.
(1) compare with the blank group, hyperlipidemia model group rat blood serum cholesterol and triglyceride all extremely significantly raise (p＜0.01), and the modeling success is described.
(2) compare with the hyperlipidemia model group, Pollen Tyjphae extract group and Flos Carthami extract group all can significantly reduce the serum cholesterol and the triglyceride levels (p＜0.05) of diet hyperlipemia rat, and Pu Hong compositions group can extremely significantly reduce the serum cholesterol and the triglyceride levels (p＜0.01) of diet hyperlipemia rat.
(3) compare with Pollen Tyjphae extract group or Flos Carthami extract group, serum cholesterol of each weight proportion group rat of Pu Hong compositions and triglyceride reduce amplitude and all are better than list with Pollen Tyjphae extract group or Flos Carthami extract group, and significant difference (p＜0.05) is arranged.
Show that the hypolipemic function of pharmaceutical composition of the present invention is better, and be better than single effect, point out two medicines that synergistic function is arranged, good curative effect will be arranged for the treatment hyperlipidemia with Pollen Typhae or Flos Carthami.
Experimental example 5 Pu Hong compositionss are to thrombotic influence in the rat carotid artery
Animal subject: Wistar rat, male and female dual-purpose, body weight 207～227g.
Test sample:
The normal saline matched group: normal saline, commercial;
Pollen Tyjphae extract group: Pollen Tyjphae extract granule (being equivalent to Pollen Typhae 300mg/ bag), self-control;
Flos Carthami extract group: Flos Carthami extract granule (being equivalent to Flos Carthami 50mg/ bag), self-control;
Pu Hong compositions group: the Pu Hong composition granule (Pollen Tyjphae extract+Flos Carthami extract=100mg+15mg), self-control.
Experimental technique:
Get 60 of Wistar rats, be divided into 6 groups at random, 10 every group, be respectively normal saline matched group, Pollen Tyjphae extract group, Flos Carthami extract group, Pu Hong compositions (the high, medium and low dosage group of Pollen Tyjphae extract+Flos Carthami extract=100mg+15mg).Each administration group medicine all is diluted to suitable concentration, gastric infusion with normal saline before 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 6.
Table 6 Pu Hong compositions is to thrombotic influence in the rat carotid artery
Annotate:
*P＜0.05,
*Compare with the normal saline matched group in p＜0.01;
#Compare with the Pollen Tyjphae extract group in p＜0.05;
﹠amp;Compare with the Flos Carthami extract group in p＜0.05.
Experimental result and conclusion: experimental result sees Table 6.
(1) compares with the normal saline matched group, Pollen Tyjphae extract group, the equal significant prolongation of Flos Carthami extract group rat carotid artery thrombus formation time (p＜0.05), the high, medium and low dosage group of Pu Hong compositions rat carotid artery thrombus formation time is utmost point significant prolongation (p＜0.01) all.
(2) compare the equal significant prolongation of the high, medium and low dosage rat carotid artery of Pu Hong compositions thrombus formation time (p＜0.05) with Pollen Tyjphae extract group or Flos Carthami extract group with single.
Show, Pollen Tyjphae extract group, Flos Carthami extract group, the high, medium and low dosage group of Pu Hong compositions all can make thrombotic time lengthening in the rat carotid artery, and the curative effect of the high, medium and low dosage group of Pu Hong compositions is better than single with Pollen Tyjphae extract group and Flos Carthami extract group, points out both that synergistic function is arranged.In addition, under the situation of same proportioning, effect is more excellent during high dose.
Test example 6 Pu Hong compositionss are to the influence of ligation bilateral common carotid arteries survival of rats rate
Animal subject: Wistar rat, body weight 208～230g, male and female half and half.
Test sample:
The normal saline matched group: normal saline, commercial;
Pollen Tyjphae extract group: Pollen Tyjphae extract capsule (being equivalent to Pollen Typhae 9g/ grain), self-control;
Flos Carthami extract group: Flos Carthami extract capsule (being equivalent to Flos Carthami 2.5g/ grain), self-control;
Pu Hong compositions group: the Pu Hong composition capsule (Pollen Typhae+Flos Carthami=3g+0.8g), self-control.
Experimental technique:
Get 60 of Wistar rats, be divided into 6 groups at random, 10 every group, be respectively normal saline matched group, Pollen Tyjphae extract group, Flos Carthami extract group, Pu Hong compositions (the high, medium and low dosage group of Pollen Typhae+Flos Carthami=3g+0.8g).Each administration group medicine all is diluted to suitable concentration with normal saline 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 7.
Table 7 Pu Hong compositions is to the influence of ligation rat bilateral common carotid arteries (X ± S)
Annotate: compare with the normal saline matched group,
*P＜0.05,
*P＜0.01; Compare with the Pollen Tyjphae extract group,
#P＜0.05,
##P＜0.01; Compare with the Flos Carthami extract group,
﹠amp;P＜0.05,
﹠amp; ﹠amp;P＜0.01.
Experimental result and conclusion: experimental result sees Table 7.
(1) compare with the normal saline matched group, Pollen Tyjphae extract group and Flos Carthami extract group is the energy significant prolongation survival of rats time (p＜0.05) all, and the high, medium and low dosage group of Pu Hong compositions all can the utmost point significant prolongation survival of rats time (p＜0.01).
(2) compare with Pollen Tyjphae extract group or Flos Carthami extract group with single, the high, medium and low dosage group of Pu Hong compositions all can the significant prolongation survival of rats time (p＜0.05, p＜0.05).
Show by above-mentioned experimental result, but the administration of the high, medium and low dosage group of Pu Hong compositions is the time-to-live of significant prolongation bilateral ligation rat all, compare the time-to-live significant prolongation of compositions group rat (p＜0.05) with Pollen Tyjphae extract group and Flos Carthami extract group with single.Prompting, Pollen Typhae and Flos Carthami use in conjunction, Synergistic, the time-to-live of rat behind the prolongation ligation rat bilateral common carotid arteries.And during high dose, effect is best.
Experimental example 7 Pu Hong compositionss are to the influence of cerebral ischemia
Animal subject: SD rat, body weight 220～250g, male and female half and half.
Test sample:
The normal saline matched group: normal saline, commercial;
Pollen Tyjphae extract group: Pollen Tyjphae extract capsule (being equivalent to Pollen Typhae 9g/ grain), self-control;
Flos Carthami extract group: Flos Carthami extract capsule (being equivalent to Flos Carthami 2.5g/ grain), self-control;
Pu Hong compositions group: the Pu Hong composition capsule (Pollen Typhae+Flos Carthami=3g+0.8g), self-control.
Experimental technique:
Get 70 of SD rats, be divided into 7 groups at random, 10 every group, be respectively sham operated rats, normal saline matched group, Pollen Tyjphae extract group, Flos Carthami extract group, Pu Hong compositions (the high, medium and low dosage group of Pollen Typhae+Flos Carthami=3g+0.8g).Each administration group medicine all is diluted to suitable concentration with normal saline and gavages before administration, 1 time/day, continuous 15 days, the normal saline matched group gavaged the normal saline of equivalent.Sham operated rats is removed not ligation common carotid artery, and all the other handle same matched group.After the last administration 1 hour, the center operation of the capable cervical region of rat etherization separated bilateral common carotid arteries, treat that animal is clear-headed after, the ligation bilateral common carotid arteries recovers cerebral blood supply again after 30 minutes, after 24 hours, it is standby that broken end is got brain.
Cerebral tissue LDH, SOD activity and MDA Determination on content: the rat broken end is got brain, place to go cerebellum and brain stem, make 10% homogenate, press TBA colorimetric method for determining MDA content, measure the SOD activity with pyrogallol autoxidation method,, measure protein content in the cerebral tissue with the Hartree method with photoelectricity colorimetric method for determining LDH activity.
Statistical procedures: all measurement datas represent with X ± S that all the significance of group difference is checked with t.
Table 8 Pu Hong compositions to the influence of rat cerebral tissue's ischemical reperfusion injury (X ± S, n=10)
Annotate: compare with sham operated rats,
﹠amp;P＜0.01; Compare with the normal saline matched group,
*P＜0.05,
*P＜0.01; Compare with the Pollen Tyjphae extract group,
#P＜0.05; Compare with the Flos Carthami extract group,
△P＜0.05.
Experimental result and conclusion: experimental result sees Table 8.
This experiment is on rat whole brain ischemical reperfusion injury model, observe the LDH release that Pollen Tyjphae extract and Flos Carthami extract all can significantly suppress the ischemia-reperfusion cerebral tissue, significantly reduce the generation of perfusion back cerebral tissue lipid peroxidation product MDA again, make active significantly raise (p＜0.05) of cerebral tissue SOD; Pu Hong compositions senior middle school low dose group is compared with Pollen Tyjphae extract or Flos Carthami extract group with single, and significant difference (p＜0.05) is arranged, and shows, Pollen Typhae and Flos Carthami use in conjunction, Synergistic, thus the cerebral tissue reperfusion injury alleviated, and effect is more excellent during high dose.
[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 embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.Adjuvant in following examples in the preparation of each dosage form can be replaced with acceptable accessories, perhaps reduces, increases.The used Pollen Tyjphae extract of experimental example comes from embodiment 1, and Flos Carthami extract comes from embodiment 2.
The preparation of embodiment 1 Pollen Tyjphae extract
The preparation of Pollen Tyjphae extract
Get cattail pollen, add 70% ethanol extraction 3 times, extracted 3 hours at every turn.First and second time adds 14 times of amounts of alcohol, adds 10 times of amounts of alcohol for the third time.Merge extractive liquid,, filter, filtrate recycling ethanol to relative density is the concentrated solution of 1.04～1.06 (50 ℃), adds to wait water gaging to dilute, mixing, 4 ℃ of cold preservation 24 hours, centrifugal, get supernatant, extract 2 times with the jolting of equivalent petroleum ether, discard petroleum ether liquid, water liquid extracts 3 times with the jolting of equivalent water-saturated n-butanol, merges n-butanol extracting liquid, be concentrated into dried, residue adds low amounts of water makes dissolving, last AB-8 macroporous resin column, water, 35% ethanol, 70% ethanol elution respectively, collect 70% ethanol elution, reclaim ethanol, drying under reduced pressure, promptly.
Prepare three batches of Pollen Tyjphae extracts respectively, yield sees Table 9.
The assay of Pollen Tyjphae extract
Flavonoid content is measured
High performance liquid chromatography
Chromatographic condition and system suitability: with the octadecylsilane chemically bonded silica is filler; With methanol-0.4% phosphoric acid liquid (50: 50) is mobile phase; The detection wavelength is 360nm; Calculate post with isorhamnetin, kaempferol, Quercetin and imitate, theoretical cam curve is 3000～4000.
The preparation of reference substance solution: accurate respectively Quercetin, nimbecetin, the isorhamnetin reference substance that takes by weighing through the phosphorus pentoxide dried overnight is an amount of, respectively adds methanol and makes the solution that every 1ml contains 0.04mg, 0.02mg, 0.1mg, in contrast product solution.Stepwise dilution is made into a series of reference substance solution respectively again, promptly.
The preparation of need testing solution: get Cattail Pollen 1.0g, the accurate title, decide, and puts in the 250ml conical flask, add methanol 100ml supersound extraction 40min, put cold filtration, get filtrate, extracting solution evaporate to dryness, residue add methanol 225% hydrochloric acid (4: 1) mixed liquor 25ml, backflow 45min, put cold, be transferred in the 50ml measuring bottle, add methanol, shake up to scale, get centrifugal in right amount, promptly.
Algoscopy: accurate respectively above-mentioned reference substance solution of absorption and need testing solution be 20 μ l respectively, inject the chromatograph of liquid injector of 5 μ l quantity tubes, measure, promptly.
Three batches of Pollen Tyjphae extracts to above-mentioned preparation carry out assay respectively, and measurement result sees Table 9.
The assay result and the yield of table 9 Pollen Tyjphae extract
The preparation of embodiment 2 Flos Carthami extracts
The preparation of Flos Carthami extract
Flos Carthami is added water-cooled to be 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, promptly.
Prepare three batches of Flos Carthami extracts respectively, yield sees Table 10.
The discriminating of Flos Carthami extract
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.
The assay of Flos Carthami extract
Carthamus tinctorius yellow color content is measured
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.
By three batches of Flos Carthami extracts that above technology is extracted, its yield and content see Table 10.
The content of the yield and Flos Carthami flavochrome of table 10 Flos Carthami extract
The preparation of embodiment 3 Pu Hong composition tablets
Prescription one:
Pollen Tyjphae extract 105.6g (being equivalent to cattail pollen 3000g)
Flos Carthami extract 9.4g (being equivalent to flos carthami 500g)
Pregelatinized Starch 75g
Microcrystalline Cellulose 20g
Low-substituted hydroxypropyl cellulose 20g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 4g
Carboxymethylstach sodium 8g
Prepare 1000 altogether
Prescription two:
Pollen Tyjphae extract 105.6g (being equivalent to cattail pollen 3000g)
Flos Carthami extract 15.04g (being equivalent to flos carthami 800g)
Pregelatinized Starch 80g
Microcrystalline Cellulose 25g
Low-substituted hydroxypropyl cellulose 25g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5g
Carboxymethylstach sodium 10g
Prepare 1000 altogether
Prescription three:
Pollen Tyjphae extract 105.6g (being equivalent to cattail pollen 3000g)
Flos Carthami extract 18.8g (being equivalent to flos carthami 1000g)
Pregelatinized Starch 80g
Microcrystalline Cellulose 25g
Low-substituted hydroxypropyl cellulose 25g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5g
Carboxymethylstach sodium 10g
Prepare 1000 altogether
Preparation technology:
(1) it is standby Pollen Tyjphae extract and Flos Carthami extract to be pulverized 100 mesh sieves.
(2) take by weighing raw material and adjuvant according to recipe quantity.
(3) hypromellose 2% the aqueous solution made soluble in water is standby.
(4) with Pollen Tyjphae extract, Flos Carthami extract, pregelatinized Starch, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
(5) cross 20 mesh sieve system granules.
(6) granule is dried under 60 ℃ condition.
(7) dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously.
(8) sampling, the semi-finished product chemical examination.
(9) the sheet weight sheet of determining according to chemical examination.
(10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 4 Pu Hong composition capsules
Prescription one:
Pollen Tyjphae extract 100g
Flos Carthami extract 1g
Pregelatinized Starch 80g
Microcrystalline Cellulose 30g
Low-substituted hydroxypropyl cellulose 20g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5g
Prepare 1000 altogether
Prescription two:
Pollen Tyjphae extract 100g
Flos Carthami extract 10g
Pregelatinized Starch 80g
Microcrystalline Cellulose 30g
Low-substituted hydroxypropyl cellulose 20g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5g
Prepare 1000 altogether
Prescription three:
Pollen Tyjphae extract 100g
Flos Carthami extract 15g
Pregelatinized Starch 85g
Microcrystalline Cellulose 30g
Low-substituted hydroxypropyl cellulose 20g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5g
Prepare 1000 altogether
Prescription four:
Pollen Tyjphae extract 100g
Flos Carthami extract 30g
Pregelatinized Starch 90g
Microcrystalline Cellulose 35g
Low-substituted hydroxypropyl cellulose 25g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 6g
Prepare 1000 altogether
Prescription five:
Pollen Tyjphae extract 100g
Flos Carthami extract 120g
Pregelatinized Starch 120g
Microcrystalline Cellulose 50g
Low-substituted hydroxypropyl cellulose 30g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 8g
Prepare 1000 altogether
Preparation technology:
(1) it is standby Pollen Tyjphae extract and Flos Carthami extract to be pulverized 100 mesh sieves.
(2) take by weighing raw material and adjuvant according to recipe quantity.
(3) hypromellose 2% the aqueous solution made soluble in water is standby.
(4) with Pollen Tyjphae extract, Flos Carthami extract, pregelatinized Starch, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
(5) cross 20 mesh sieve system granules.
(6) granule is dried under 60 ℃ condition.
(7) dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously.
(8) sampling, the semi-finished product chemical examination.
(9) loading amount of determining according to chemical examination incapsulates.
(10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5 Pu Hong composition granules
Prescription one:
Pollen Tyjphae extract 70.4g (being equivalent to cattail pollen 2000g)
Flos Carthami extract 9.4g (being equivalent to flos carthami 500g)
Icing Sugar 600g
Dextrin 300g
Steviosin 10g
Fructus Citri Limoniae essence is an amount of
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000g altogether
Prescription two:
Pollen Tyjphae extract 70.4g (being equivalent to cattail pollen 2000g)
Flos Carthami extract 18.8g (being equivalent to flos carthami 1000g)
Icing Sugar 600g
Dextrin 300g
Steviosin 10g
Fructus Citri Limoniae essence is an amount of
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000g altogether
Prescription three:
Pollen Tyjphae extract 176g (being equivalent to cattail pollen 5000g)
Flos Carthami extract 9.4g (being equivalent to flos carthami 500g)
Icing Sugar 500g
Dextrin 300g
Steviosin 15g
Fructus Citri Limoniae essence is an amount of
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000g altogether
Prescription four:
Pollen Tyjphae extract 176g (being equivalent to cattail pollen 5000g)
Flos Carthami extract 18.8g (being equivalent to flos carthami 1000g)
Icing Sugar 500g
Dextrin 280g
Steviosin 15g
Fructus Citri Limoniae essence is an amount of
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000g altogether
Preparation technology:
(1) it is standby sucrose to be pulverized 80 mesh sieves; It is standby that Pollen Tyjphae extract and Flos Carthami extract was pulverized 100 mesh sieves.
(2) take by weighing raw material and adjuvant according to recipe quantity.
(3) the method mix homogeneously that Pollen Tyjphae extract, Flos Carthami extract and Icing Sugar, steviosin are progressively increased with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and makes suitable soft material,
(4) cross 20 mesh sieve system granules.
(5) granule is dried under 60 ℃ condition.
(6) dried granule is crossed 18 mesh sieve granulate, sprays into an amount of Fructus Citri Limoniae essence.
(7) sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule.
(8) packing, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 Pu Hong composition oral liquid
Prescription one:
Pollen Tyjphae extract 70.4g (being equivalent to cattail pollen 2000g)
Flos Carthami extract 1.88g (being equivalent to flos carthami 100g)
Propylene glycol 80ml
Sodium benzoate 15g
Stevioside 10g
Purified water adds to 1000ml
Prepare 1000ml altogether
Prescription two:
Pollen Tyjphae extract 70.4g (being equivalent to cattail pollen 2000g)
Flos Carthami extract 37.6g (being equivalent to flos carthami 2000g)
Propylene glycol 80ml
Sodium benzoate 15g
Stevioside 10g
Purified water adds to 1000ml
Prepare 1000ml altogether
Prescription three:
Pollen Tyjphae extract 176g (being equivalent to cattail pollen 5000g)
Flos Carthami extract 1.88g (being equivalent to flos carthami 100g)
Propylene glycol 100ml
Sodium benzoate 20g
Stevioside 15g
Purified water adds to 1000ml
Prepare 1000ml altogether
Prescription four:
Pollen Tyjphae extract 176g (being equivalent to cattail pollen 5000g)
Flos Carthami extract 37.6g (being equivalent to flos carthami 2000g)
Propylene glycol 100ml
Sodium benzoate 20g
Stevioside 15g
Purified water adds to 1000ml
Prepare 1000ml altogether
Preparation technology:
(1) fully with heated and stirred dissolving in the purified water of Pollen Tyjphae extract and Flos Carthami extract adding dosing amount 50%; It is complete to add the propylene glycol stirring and dissolving again.
(2) sodium benzoate and stevioside is complete with the water dissolution of dosing amount 20%.
(3) merge above-mentioned solution, add purified water to full dose.
(4) filtering with microporous membrane of mistake 0.8 μ m.
(5) semi-finished product chemical examination.
(6) fill.Finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 pharmaceutical composition aqueous injection of the present invention
Prescription one:
Pollen Tyjphae extract 100g
Flos Carthami extract 5g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 1000ml
Prepare 1000ml altogether
Prescription two:
Pollen Tyjphae extract 100g
Flos Carthami extract 10g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 1000ml
Prepare 1000ml altogether
Prescription three:
Pollen Tyjphae extract 100g
Flos Carthami extract 15g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 1000ml
Prepare 1000ml altogether
Prescription four:
Pollen Tyjphae extract 100g
Flos Carthami extract 30g
Polyoxyethylene sorbitan monoleate 50g
Water for injection 1000ml
Prepare 1000ml altogether
Prescription five:
Pollen Tyjphae extract 100g
Flos Carthami extract 60g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 1000ml
Prepare 1000ml altogether
Prescription six:
Pollen Tyjphae extract 100g
Flos Carthami extract 90g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 1000ml
Prepare 1000ml altogether
Prescription seven:
Pollen Tyjphae extract 100g
Flos Carthami extract 100g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 1000ml
Prepare 1000ml altogether
Prescription eight:
Pollen Tyjphae extract 100g
Flos Carthami extract 120g
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 1000ml
Prepare 1000ml altogether
Preparation technology:
(1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
(2) polyoxyethylene sorbitan monoleate is made 20% aqueous solution, added Pollen Tyjphae extract and Flos Carthami extract, the heated and stirred dissolving fully.
(3) benefit adds to the full amount of water for injection.
(4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
(5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
(6) through the microporous filter membrane fine straining of 0.45 μ m.
(7) clarity of inspection solution, the semi-finished product chemical examination.
(8) with the solution sealing by fusing in glass ampule.
(9) 100 ℃ of flowing steam sterilizations 30 minutes.
(10) while hot sample being put into 0.01% methylene blue solution hunts leak.
(11) lamp inspection, finished product is examined entirely, the packing warehouse-in.
Claims (9)
1. a pharmaceutical composition that is used for cardiovascular and cerebrovascular disease is characterized in that, make its contained composition and effectiveness crude drug consist of the Pollen Typhae and Flos Carthami, its parts by weight are: 1000～10000 parts of Pollen Typhaes, 100～4000 parts on Flos Carthami; Or form by Pollen Tyjphae extract and Flos Carthami extract, its parts by weight are: 20～400 parts of Pollen Tyjphae extracts, 2～120 parts of Flos Carthami extracts.
2. pharmaceutical composition according to claim 1 is characterized in that, the parts by weight of Pollen Typhae and Flos Carthami are: 2000～5000 parts of Pollen Typhaes, 200～2000 parts on Flos Carthami.
3. pharmaceutical composition according to claim 2 is characterized in that, the parts by weight of Pollen Typhae and Flos Carthami are: 3000 parts of Pollen Typhaes, Flos Carthami 500-1000 part.
4. according to the described preparation of drug combination method of the arbitrary claim of claim 1～3, it is characterized in that, described Pollen Typhae and Flos Carthami can be with The suitable solvent respectively or mix through extracting processing and obtain its extract, total extract is made preparation with the pharmaceutic adjuvant hybrid process again, and the main effective ingredient of gained total extract is a flavone compound and Flos Carthami flavochrome.
5. pharmaceutical composition according to claim 1 is characterized in that, the parts by weight of Pollen Tyjphae extract and Flos Carthami extract are: 30～250 parts of Pollen Tyjphae extracts, 4～60 parts of Flos Carthami extracts.
6. pharmaceutical composition according to claim 5 is characterized in that, its parts by weight are: 60～120 parts of Pollen Tyjphae extracts, 8～30 parts of Flos Carthami extracts.
7. according to claim 1,5, the described pharmaceutical composition of 6 arbitrary claim, it is characterized in that the main effective ingredient of described Pollen Tyjphae extract is a flavone compound, content is not less than 20%; The main component of Flos Carthami extract is a Carthamus yellow, and wherein the content of Carthamus yellow is not less than 50%.
8. according to claim 1～3, the described pharmaceutical composition of 5～6 arbitrary claim, it is characterized in that this pharmaceutical composition can combine with acceptable accessories makes clinically any or pharmaceutically acceptable dosage form.
9. pharmaceutical composition according to claim 8 is characterized in that, clinically described or pharmaceutically acceptable dosage form is oral formulations or injection.
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| CN200610070056XA CN101176772B (en) | 2006-11-09 | 2006-11-09 | Pharmaceutical composition made of cattail pollen and safflower |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1660284A (en) * | 2004-12-14 | 2005-08-31 | 李捍雄 | Compound preparation of notoginseng and safflower for treating cardiovascular and cerebrovascular diseases |
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