CN100509009C - Chinese medicinal preparation for treating heart cerebrovascular disease and ischemic apoplexia and making method thereof - Google Patents
Chinese medicinal preparation for treating heart cerebrovascular disease and ischemic apoplexia and making method thereof Download PDFInfo
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Abstract
A Chinese medicine for treating cardiovascular and cerebrovascular diseases and ischemic apoplex is prepared from red peony root, capejasmine fruit and astragalus root. The prescription and preparing process of its injection and its other clinical forms are also disclosed.
Description
Technical field
The invention belongs to medical technical field, specifically relating to a kind of is the Chinese medicine preparation of feedstock production with Radix Paeoniae Rubra, Fructus Gardeniae and the Radix Astragali three flavor Chinese crude drugs, be particularly related to the preparation technology of the effective site of two flavor Chinese medicines, the invention still further relates to prescription, moulding process and the clinical application dosage form of injection.
Background technology
Cerebral infarction is a kind of of cardiovascular and cerebrovascular disease.Though it is a lot of to treat the medicine of cardiovascular and cerebrovascular disease at present in the world, but because drug resistance, the dependency of Western medicine, and cost an arm and a leg, and the exploitation of form of Chinese drug and drug effect relatively lags behind, and still needs to continually develop new high-efficiency low-toxicity, reasonable price, medicine easy to use and meets clinical needs.
The treatment cardiovascular and cerebrovascular disease of present clinical use, the Chinese medicine preparation of cerebral infarction are based on oral formulations, though oral formulations has certain curative effect, but because the first pass effect of this dosage form, make its onset slow, bioavailability is low, and stroke patient is taken inconvenience, therefore can not satisfy the needs of clinical application far away.
Radix Paeoniae Rubra is the dry root of ranunculaceae plant Radix Paeoniae (Paeonia lactiflora Pall.), Paeonia obovata Maxim. (Paeonia obovatamaxim.) or CHUANSHAO medicine (Paeonia veitchii Lynch); The property hardship is slightly cold, and returns Liver Channel; Effect with heat-clearing and toxic substances removing, eliminating stasis to stop pain.Main effective ingredient in the Radix Paeoniae Rubra is water miscible monoterpene glycosides compound, and is wherein the highest with paeoniflorin content, and other also have lactone glucoside of Radix Paeoniae, oxypaeoniflorin, benzoylpaeoniflorin, lacdtlorin etc.
According to the literature, the preparation method of traditional Radix Paeoniae Alba total glycosides has water alcohol method and pure water law (referring to cloudy strong chief editor.Chinese medicine modern study and clinical practice, Beijing: the People's Health Publisher, 2000: 354), the Radix Paeoniae Alba total glycosides content that this method obtains was relatively low; In recent years, more document is reported and is adopted macroporous adsorbent resin exquisite glycoside composition (referring to Chinese herbal medicine, 29 (10): 664-667), the Radix Paeoniae Alba total glycosides content that this method obtains is higher; But because the adsorption and the elute effect of macroporous adsorbent resin is subjected to multiple factor affecting, so in the application to this method, preferred various operating conditions can further improve the content of Radix Paeoniae Alba total glycosides.
Fructus Gardeniae is the dry mature fruit of Maguireothamnus speciosus Fructus Gardeniae (Gardenia jasminoides Ellis); The property hardship, cold, GUIXIN, lung, tri-jiao channel; Effect with pathogenic fire purging relieving restlessness, clearing away heat and promoting diuresis, removing pathogenic heat from blood and toxic substance from the body.The effective constituent that mainly contains of treatment cerebrovascular disease is the iridoid glycoside compounds in the Fructus Gardeniae, mainly contains jasminoidin, geniposide, all square rafter glycosides, shanzhiside etc.
Bibliographical information, and employing macroporous adsorbent resin exquisiteness (referring to: Chinese herbal medicine, 33 (9): 794-796), the content of the water alcohol method that the content of Fructus Gardeniae total glycosides is more traditional obviously improves.On this basis, preferred various operating conditions can further improve the content of Fructus Gardeniae total glycosides.
The Radix Astragali is the dry root of leguminous plant Radix Astagali (Astragalus membranaceus (Fisch) Bge.Var.mongholicus (Beg) Hsiao.) or Radix Astragali (Astragalus membranaceus (Fisch.) Beg.); Property is sweet, warm, returns lung, spleen channel; Effect with invigorating QI to consolidate the body surface resistance, diuresis poison holding, evacuation of pus, expelling pus and promoting granulation.The effective constituent that mainly contains of treatment cerebrovascular disease is a Radix Astragali total glycosides in the Radix Astragali.
Bibliographical information, and employing macroporous adsorbent resin exquisiteness (referring to: Chinese patent medicine, 25 (11): 866-868), the content of the water alcohol method that the content of Radix Astragali total glycosides is more traditional obviously improves.On this basis, preferred various operating conditions can further improve the content of Radix Astragali total glycosides.
The present invention is formulated through the intermediate that extracts exquisite technology and make by Radix Paeoniae Rubra, Fructus Gardeniae and the Radix Astragali three flavor Chinese crude drugs, preparation effective ingredient of the present invention is clear and definite, quality controllable, easy to use, use Drug therapy cardiovascular and cerebrovascular disease of the present invention, cerebral infarction onset rapidly, determined curative effect, bioavailability height, have no drug resistance and dependency.From the Chinese patent medicine of listing treatment cardiovascular and cerebrovascular vessel, do not see that having with above-mentioned three kinds of Chinese herbal medicine is the injecting medicine-feeding form that prescription is made.
Summary of the invention
The invention provides a kind of Chinese medicine preparation for the treatment of cardiovascular and cerebrovascular disease, said preparation is a raw material by Chinese medicine Radix Paeoniae Rubra, Fructus Gardeniae and the Radix Astragali, is processed into active constituents of medicine through extraction, becomes with this activity further to be equipped with the medicine acceptable carrier and to make.
Another object of the present invention provides two kinds of Chinese crude drugs---the effective site preparation technology of Radix Paeoniae Rubra, Fructus Gardeniae and the Radix Astragali.
Chinese medicine preparation of the present invention is made by following Chinese medicine raw materials by weight proportion,
1～3 part of Radix Paeoniae Rubra, 0.8～3 part of Fructus Gardeniae, 1～3 part of the Radix Astragali.Preferably Radix Paeoniae 1-1.5 part, Fructus Gardeniae 0.8-1,1 part of the Radix Astragali, more preferably: 1 part of 1.1 parts of Radix Paeoniae, Fructus Gardeniae 0.9, the Radix Astragali.
In more than forming, part be weight portion, weight is calculated with crude drug, and every part if be unit with the kilogram, more than form and can be made into 3000 doses of pharmaceutical preparatioies, described 3000 doses of fingers, the final drug preparation of making, as make 3000 of capsule preparations, 3000 in tablet, granule 3000 grams, oral liquid 3000ml, injection 3000ml etc.
More than form to be by weight as proportioning, when producing, can increase or reduce according to corresponding proportion, as large-scale production can be unit with the kilogram, or be unit with the ton, small-scale production can be unit with the milligram also, weight can increase or reduce, but the constant rate of the raw medicinal herbs weight proportion between each composition.
The ratio of above weight proportion obtains through science screening, for especial patient, and as serious symptom or light disease, fat or modest patient, the proportioning of the amount of can corresponding adjustment forming increases or reduces being no more than 100%, and drug effect is constant.
Single medicinal material in more than forming also can be replaced by the suitable Chinese medicine with identical property of medicine, and its drug effect of the Chinese medicine preparation after the replacement is constant.
Chinese medicine preparation of the present invention is to process through extraction or other modes by the raw material of Chinese medicine that above-mentioned prescription is formed, and makes pharmaceutically active substance, subsequently, with this material is raw material, adds the medicine acceptable carrier when needing, and makes according to the routine techniques of galenic pharmacy.Described active substance can obtain by extracting raw material of Chinese medicine respectively, also can obtain by the co-extracted raw material of Chinese medicine, also can obtain by other modes, as: by pulverize, squeeze, calcine, grind, sieve, percolation, extraction, water are carried, alcohol extraction, ester are carried, methods such as ketone is carried, chromatography obtain, these active substances can be the material of extractum form, can be that dry extract also can be a fluid extract, make different concentration according to the different needs decision of preparation.
Pharmaceutically active substance in the Chinese medicine preparation of the present invention, its shared percentage by weight in preparation can be 0.1-99.9%, all the other are the medicine acceptable carrier.Pharmaceutical preparation of the present invention exists with unit dosage form, and described unit dosage form is meant the unit of preparation, as every of tablet, and capsular every capsules, every bottle of oral liquid, every bag of granule, every of injection etc.
Chinese medicine preparation of the present invention can be any pharmaceutically useful dosage form, and these dosage forms comprise: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, ointment, plaster, cream, spray, drop, patch.Preparation of the present invention, preferably injection, most preferably lyophilized injectable powder.
Chinese medicine preparation of the present invention, the preparation of its oral administration can contain excipient commonly used, such as binding agent, filler, diluent, tablet agent, lubricant, disintegrating agent, coloring agent, flavoring agent and wetting agent, can carry out coating to tablet in case of necessity.
The filler that is suitable for comprises cellulose, mannitol, lactose and other similar filler.Suitable disintegrating agent comprises starch, polyvinylpyrrolidone and starch derivatives, for example sodium starch glycollate.Suitable lubricant comprises, for example magnesium stearate.The acceptable wetting agent of appropriate drug comprises sodium lauryl sulphate.
Can fill by mixing, the method that tabletting etc. are commonly used prepares solid oral composition.Mix repeatedly active substance is distributed in those compositionss of a large amount of filleies of whole use.
The form of oral liquid for example can be aqueous or oily suspensions, solution, Emulsion, syrup or elixir, perhaps can be a kind of available water before use or other suitable composite dry products of carrier.This liquid preparation can contain conventional additive, such as suspending agent, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat, emulsifying agent, for example lecithin, anhydro sorbitol monooleate or arabic gum; Non-aqueous carrier (they can comprise edible oil), for example almond oil, fractionated coconut oil, such as oily ester, propylene glycol or the ethanol of the ester of glycerol; Antiseptic, for example para hydroxybenzene methyl ester or propyl p-hydroxybenzoate or sorbic acid, and if desired, can contain conventional flavouring agent or coloring agent.
For injection, the liquid unit dosage forms of preparation contains active substance of the present invention and sterile carrier.According to carrier and concentration, this chemical compound can be suspended or dissolving.The preparation of solution is normally by being dissolved in active substance in a kind of carrier filter-sterilized before it is packed into a kind of suitable bottle or ampoule, sealing then.For example a kind of local anesthetic of adjuvant, antiseptic and buffer agent also can be dissolved in this carrier.In order to improve its stability, can be after the bottle of packing into that this compositions is freezing, and under vacuum, water is removed.
Chinese medicine preparation of the present invention, when being prepared into medicament, optionally add suitable medicine acceptable carrier, described medicine acceptable carrier is selected from: mannitol, sorbitol, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, vitamin C, the EDTA disodium, EDTA calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and derivant thereof, alginate, gelatin, polyvinylpyrrolidone, glycerol, soil temperature 80, agar, calcium carbonate, calcium bicarbonate, surfactant, Polyethylene Glycol, cyclodextrin, β-cyclodextrin, the phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc.
Preparation of the present invention is determined usage and dosage according to patient's situation in use, but obeys every day three times, each 1-20 agent, as: 1-20 bag or grain or sheet.
Chinese medicine preparation of the present invention preferably adopts following method preparation.
(1) get Radix Paeoniae Rubra, water heating extraction 2～3 times, each 1～3 hour, extracting solution merged, filter, it is 1.10～1.20 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 60～80%, add 10～20% alkali again and make the solution pH value reach 6～8, cold preservation 12～48 hours filters; Filtrate recycling ethanol is to there not being the alcohol flavor, thin up to relative density is 1.10～1.20, stir evenly, filter macroporous adsorption resin chromatography post on the filtrate, wash with water earlier to eluent and do not have reducing sugar reaction, the ethanol elution of reuse 20～80% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Paeoniae Rubra total glycosides;
(2) get Fructus Gardeniae, water heating extraction 2～3 times, each 1～3 hour, extracting solution merged, and filtered, and it is 1.10～1.20 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 60～80%, and cold preservation 12～48 hours is filtered; Filtrate recycling ethanol is not to there being the alcohol flavor, and thin up to relative density is 1.10～1.20, adds dilute hydrochloric acid and makes the solution pH value reach 2～3, and cold preservation 12～48 hours filters; Filtrate adds 10～20% alkali makes the solution pH value reach 7, stirs evenly, and filters macroporous adsorption resin chromatography post on the filtrate, washing with water earlier to eluent does not have reducing sugar reaction, and the ethanol elution of reuse 20～80% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Fructus Gardeniae total glycosides;
(3) get the Radix Astragali, water heating extraction 2～3 times, each 1～3 hour, extracting solution merges, and filters, and it is 1.30～1.50 that filtrate is concentrated into relative density, centrifugal, get macroporous adsorption resin chromatography post on the supernatant, washing with water earlier to eluent does not have reducing sugar reaction, the ethanol elution of reuse 20～80%, collect ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Astragali total glycosides;
(4) get the product of above-mentioned (1)～(3), mix, make pharmaceutical preparation according to the galenic pharmacy routine techniques.Preferably make injection, compound method is as follows: get above-mentioned (1)～(3) compositions, add an amount of water for injection gradation dissolving, add pharmaceutic adjuvant, stirring is fully dissolved it, and solution adds the injection active carbon, boils 10～15 minutes, filter while hot, filtrate is crossed micro-filtration membrane, gets micro-filtrate; Micro-filtrate is crossed the ultrafilter membrane of 6000～30000 molecular weight, gets ultrafiltrate, and filtrate is made injection by the preparation common process, comprises liquid infusion agent, injection powder pin.
Preparation of the present invention wherein contains 1.5～4 parts of Radix Paeoniae Rubra total glycosidess, 3～7 parts of Fructus Gardeniae total glycosides, 1～3 part of Radix Astragali total glycosides.
Effective ingredient peoniflorin in the Chinese medicine of the present invention, jasminoidin, astragaloside adopt the high-efficient liquid phase technique detection level, and Radix Astragali total glycosides adopts spectrophotography to detect.
Pharmaceutic adjuvant of the present invention is one or more in soil temperature 80, mannitol, lactose, glucose, PVP, the sodium chloride; Described Radix Paeoniae Rubra total glycosides compositions is to be the main index that detects with the peoniflorin, and paeoniflorin content is higher than 30%; The Fructus Gardeniae total glycosides compositions is to be the main index that detects with the jasminoidin, and jasminoidin content is higher than 40%; The Radix Astragali total glycosides compositions is to be the main index that detects with the Radix Astragali total glycosides, and total glycosides content is higher than 30%.
Described Radix Paeoniae Rubra total glycosides, wherein Radix Paeoniae Rubra total glycosides content is 50～95%, paeoniflorin content is 30～60%.
Described Fructus Gardeniae total glycosides, wherein Fructus Gardeniae total glycosides content is 50～95%, jasminoidin content is 40～80%.
Described Radix Astragali total glycosides, wherein Radix Astragali total glycosides content is 30～80%, Astragaloside content is 1～5%.
The prescription screening test
1. in vitro tests (rabbit extracorporeal platelet aggregation rate mensuration):
1.1 test method:
White big ear rabbit procaine local anesthesia, the blood-letting of carotid artery intubate, 3.8% sodium citrate 1:9 anticoagulant, with the centrifugal 10min of 800r/min, get platelet rich plasma (PRP), remainder is centrifugal with 3000r/min, get platelet poor plasma (PPP), aggregation inducing agent PAF (final concentration 0.37 μ g/ml), the medicine 10ul that adds variable concentrations among every pipe 250 μ l PRP, add normal saline 10ul among the PRP of contrast, incubation 5 minutes uses LG-PABER platelet aggregation thrombin analyser (Beijing Steellex Scientific Instrument Company's production) to detect platelet aggregation rate then.
1.2 test medicine
Medicine 1 Radix Paeoniae Rubra total glycosides compositions (paeoniflorin content is 30～60%) below is shown with the peoniflorin scale
Medicine 2 Fructus Gardeniae total glycosides compositionss (jasminoidin content is 40～80%) below are shown with the jasminoidin scale
Medicine 3 Radix Astragali total glycosides compositionss (Radix Astragali total glycosides content is 30～80%) below are shown with the Radix Astragali total glycosides scale
1.3 the uniform Design experiment and the result of peoniflorin, jasminoidin, the research of Radix Astragali total glycosides compatibility:
1.3.1 determine the level of uniform Design according to the amount effect relation curve of peoniflorin, jasminoidin, Radix Astragali total saponins:
5 levels (concentration) of uniform Design are as follows respectively:
Peoniflorin in the medicine 1: IC
10=1.53mg/ml, IC
20=2.59mg/ml, IC
30=4.18mg/ml, IC
40=5.51mg/ml, IC
50=6.83mg/ml
Jasminoidin in the medicine 2: IC
10=0.84mg/ml, IC
20=3.46mg/ml, IC
30=6.08mg/ml, IC
40=8.69mg/ml, IC
50=11.31mg/ml
Radix Astragali total saponins in the medicine 3: IC
10=0.26mg/ml, IC
20=0.72mg/ml, IC
30=1.19mg/ml, IC
40=1.65mg/ml, IC
50=2.11mg/ml
1.3.2 Radix Astragali total saponins, peoniflorin and the research of jasminoidin compatibility:
Adopt U
5(5
3) table, the results are shown in Table 1.
Table 1 Radix Astragali total saponins, peoniflorin and jasminoidin compatibility Uniform Design result (X ± SD)
Above result is through the Master software analysis, and the proportion compatibility of determining peoniflorin, jasminoidin and Radix Astragali total glycosides is 3:6:1.
2. in vivo test (timing of mouse lung thromboembolism):
2.1 test method:
98 of mices are divided into 7 groups at random, and 14 every group, male and female half and half, i.e. matched group, five dosage groups of administration group, positive control drug aspirin 40mg/kg dosage group.More than each the group press 0.1ml/10g tail vein injection administration 1 time respectively, the aspirin gastric infusion, for three days on end.1h behind the last filling stomach, 5min behind the intravenous administration, (ADP15 μ g/ only to cause suppository from mouse tail vein injection 0.1ml mixing, epinephrine 10 μ g/ only), dyspnea with rapid and short breath appears breathing in animal immediately, and is stiff, and record recovers the required time of autonomic activities from injecting derivant to mice, as the pulmonary infarction time, data are organized a t check.
2.2 Radix Astragali total saponins, peoniflorin and jasminoidin compatibility in vivo test research:
2.2.1 dosage:
According to pertinent literature, select the dosage of Radix Astragali total saponins, peoniflorin and jasminoidin to carry out Uniform Design, the proportion compatibility of checking in vitro tests, and the dosage of tentatively definite vivo medicine-feeding, concrete dosage level is as follows:
Peoniflorin dosage (mg/kg) in the medicine 1: 4.8,2.4,1.2,0.6,0.3
Jasminoidin dosage (mg/kg) in the medicine 2: 9.6,4.8,2.4,1.2,0.6
Radix Astragali total glycosides dosage (mg/kg) in the medicine 3: 1.6,0.8,0.4,0.2,0.1
2.2.2 Uniform Design result:
Adopt U
5(5
3) table, the results are shown in Table 2.
Table 2 Radix Astragali total saponins, peoniflorin and jasminoidin compatibility uniform Design in vivo test result (X ± SD)
Above result is through the Master software analysis, when the proportion compatibility of conclusive evidence Radix Astragali total saponins, peoniflorin and jasminoidin is 1:3:6, the time of pulmonary infarction is for the shortest, and the dosage of Radix Astragali total saponins is that the dosage of 0.1mg/kg, peoniflorin is the dosage of 0.3mg/kg, jasminoidin when being 0.6mg/kg, still has excellent curative.
3. conclusion:
According to in the upper body and external result of the test, determine that compatibility is as follows:
The effective ingredient ratio is: peoniflorin 3, jasminoidin 6, Radix Astragali total glycosides 1;
The intermediate ratio is: Radix Paeoniae Rubra total glycosides 1.5～4, Fructus Gardeniae total glycosides 3～7, Radix Astragali total glycosides 1～3;
The medical material ratio is: Radix Paeoniae Rubra 1～3, Fructus Gardeniae 1～3, the Radix Astragali 1～3.
Pharmacodynamic test of active extract
1. materials and methods
Medicine: the Radix Astragali+Radix Paeoniae Rubra+Fructus Gardeniae
(Bayer A.G produces nimodipine preparation stock solution, the packing of BeiJing, China Bayer HealthCare Co, lot number: CANAL
2), 10mg/50ml, intraperitoneal injection, 0.002g/kg, once a day.
2. pulmonary infarction timing
100 of mices are divided into 5 groups at random, and 20 every group, male and female half and half, promptly matched group is subjected to three dosage groups of reagent (Radix Astragali+Radix Paeoniae Rubra+Fructus Gardeniae) 1～20mg/kg, positive control drug aspirin 40mg/kg.More than each the group press 0.1ml/10g tail vein injection administration 1 time respectively, the aspirin gastric infusion, for three days on end.1h behind the last filling stomach, 5min behind the intravenous administration, (ADP15 μ g only to cause suppository from mouse tail vein injection 0.1ml mixing, epinephrine 10 μ g only), dyspnea with rapid and short breath appears breathing in animal immediately, and is stiff, and record recovers the required time of autonomic activities from injecting derivant to mice, as the pulmonary infarction time, data are organized a t check.
3. rabbit extracorporeal platelet aggregation rate is measured
White big ear rabbit procaine local anesthesia, the blood-letting of carotid artery intubate, 3.8% sodium citrate 1:9 anticoagulant, with the centrifugal 10min of 800r/min, get platelet rich plasma (PRP), remainder is centrifugal with 3000r/min, get platelet poor plasma (PPP), aggregation inducing agent ADP (final concentration 15 μ mol/L) and PAF ((final concentration 0.37 μ g/ml), what add variable concentrations among every pipe 250 μ l PRP is subjected to reagent 10ul, add buffer 10ul incubation among the PRP of contrast 5 minutes, and used LG-PABER platelet aggregation thrombin analyser (Beijing Steellex Scientific Instrument Company's production) to detect platelet aggregation rate then.
4. Mus focal cerebral ischemia model
Rat is divided into 6 groups at random, promptly normal group, model group, nimodipine group, be subjected to three dosage groups of reagent.Each treated animal intraperitoneal injection every day 1 time, for three days on end.After the last administration, get rat, (400mg/kg ip), with the mid point of lateral position along right external auditory canal and right eye outer canthus line, cuts the about 2cm of skin perpendicular to line, cuts off fascia, and the passivity separating muscle exposes zygomatic arch with 10% chloral hydrate anesthesia.Bite zygomatic arch broken with mosquito forceps, zygomatic arch and mandibular bone are strutted, be fixed on the Mus plate with little drag hook pulling, expose the major part of squamosal bone, about 2～the 4mm in the front lower place of uniting before cheekbone and squamosal bone holes with electric bench drill at the place then, open the microcephalia window of the about 2mm of a diameter, see through cerebral dura mater this moment, be middle cerebral artery (MCA) with regard to a visible straight and few ramose little blood vessel.It is almost vertically passed by tractus olfactorius and upwards goes; puncture cerebral dura mater with the fine needle acupuncture needle; expose medium-sized artery; after the affirmation electric knife put the bipolar coagulation position; select the maximum electricity to coagulate switch, 1mm is to one section middle cerebral artery between the inferior cerebral vein in the electric tractus olfactorius with fixed attention, and electricity coagulated 4～6 seconds; when coagulating, electricity avoids ischemia and injury cerebral tissue, available wet cotton balls protection.Dab on the cranium window with fritter muscular tissue behind the blocking-up middle cerebral artery, then the layer-by-layer suture wound.Postoperative steams again raises.Above process is all carried out under room temperature constant (24～25 ℃) situation, is beneficial to estimate the cerebral ischemia situation.Observe postoperative 4h, 24h influence to its behavior scoring.Behind the modeling 24h, the carotid artery blood-letting, the test index of correlation, and put to death rat immediately, and take out cerebral tissue, observe the variation of cerebral infarct size and infraction rate.
5. to the influence of focal cerebral ischemia in rats model platelet aggregation rate
The focal cerebral ischemia in rats model copy is the same, the tail intravenously administrable, 24h lumbar injection 10% chloral hydrate anesthesia after the modeling, the blood-letting of carotid artery intubate, 3.8% sodium citrate 1:9 anticoagulant, with the centrifugal 10min of 1000r/min, get platelet rich plasma (PRP), remainder is centrifugal with 3000r/min, get platelet poor plasma (PPP), the aggregation inducing agent uses LG-PABER platelet aggregation thrombin analyser (Beijing Steellex Scientific Instrument Company's production) to detect platelet aggregation rate with ADP (final concentration 15 μ mol/L) then.
All data all adopt the t method of inspection, carry out significance relatively.
The result
1. to the influence of pulmonary infarction time: each dosage group of the Radix Astragali, Radix Paeoniae Rubra and Fructus Gardeniae compatibility all can obviously shorten the mouse lung thromboembolism time, promotes the recovery of mice autonomic activities, with the model group comparing difference significance is arranged all.
2. to the influence of rabbit extracorporeal platelet aggregation rate: each dosage group of the external Radix Astragali, Radix Paeoniae Rubra and Fructus Gardeniae compatibility all has inhibitory action to PAF and the inductive rabbit platelet aggregation rate of ADP, and comparing difference all has highly significant between the matched group.
3. to MCAO infarct size and ethological influence: be white in color (normal cerebral tissue is rose) by the brain tissue slice visible modeling Mus infraction cerebral tissue that dyes, boundary is clearly demarcated, and the scoring of MCAO group behavioristics obviously raises.Three dosage group infarct sizes of the Radix Astragali, Radix Paeoniae Rubra and Fructus Gardeniae compatibility, infraction rate all obviously reduce, and behavioristics's scoring (24h) also obviously descends, and with the MCAO model group significant difference is arranged relatively.
4. to the influence of MCAO rat platelet aggregation rate: three dosage intravenously administrables of the results suggest Radix Astragali, Radix Paeoniae Rubra and Fructus Gardeniae compatibility have inhibitory action to the inductive rat model platelet aggregation rate of ADP, with the model group comparing difference significance are arranged.
The present invention uses the macroporous resin isolation technics, adopts sample on the aqueous solution, the abundant eluting of washing back reuse 50～90% ethanol, and eluent adopts decompression recycling ethanol, and vacuum drying each compositions is further made injection according to conventional moulding process as intermediate.The extraction ratio height of the method compositions, K cryogenic treatment has been avoided the destruction of effective ingredient; Whole process operation is simple, uses general in the world non-secondary pollution solvent, has reduced subsequent treatment work, has reduced production cost, is fit to very much suitability for industrialized production.Studies show that in a large number D101, AB-8, D-3520, HPD-400, HPD-100 type macroporous resin are better to the adsorbing separation effect of above-mentioned three kinds of compositionss.
The present invention has following characteristics:
1, medicine of the present invention is made up of Radix Paeoniae Rubra, Fructus Gardeniae and the Radix Astragali three flavor medicines, the main effective ingredient of treatment cardiovascular and cerebrovascular disease is water miscible monoterpene glycosides compound in the Radix Paeoniae Rubra, the effective constituent that mainly contains of treatment cardiovascular and cerebrovascular disease is water miscible iridoid glycoside compounds in the Fructus Gardeniae, and the effective constituent that mainly contains of treatment cardiovascular and cerebrovascular disease is water miscible Radix Astragali total glycosides in the Radix Astragali.Therefore the preparation method of medicine of the present invention is selected the feasibility route that is suitable for suitability for industrialized production for use according to the physicochemical property of the contained main effective ingredient of each medicine, and it is clear and definite, quality controllable that institute separates the effective ingredient of the compositions that obtains and final preparation.
2, prescription screening of the present invention is through external and intravital lot of experiments, and used dosage and compatibility are reasonable, determined curative effect; The present invention simultaneously scientifically uses the medical material consumption, has avoided the waste of herb resource.
3, dosage form of the present invention is an injection, comprises liquid infusion agent, injection powder pin, can be directly used in intramuscular injection, intravenous drip, thereby onset is rapid, bioavailability is high, is specially adapted to the treatment of cardiovascular and cerebrovascular disease, cerebral infarction.
4, medicine of the present invention and each compositions studies show that through safety and stability experiment indexs such as clarity, hemolytic, color and luster, pH value, thermal source, zest all meet " the pertinent regulations of 2005 editions injections of Chinese pharmacopoeia.
5, lyophilized injectable powder of the present invention except that having the injection characteristics, still has convenient, the portable characteristics of storing.
6, the Pharmacodynamic test of active extract of medicine of the present invention shows, aspect treatment cardiovascular and cerebrovascular disease, cerebral infarction, has definite curative effect.
Pharmaceutical preparation of the present invention, the effect characteristics mainly are cardiovascular and cerebrovascular disease, the cerebral infarction at deficiency in origin and excess in superficiality, these deficiency syndrome performance of the existing deficiency of vital energy, also have obstruction of collaterals by blood stasis and the mark excess syndrome that has certain thermal image concurrently, the time should look after the one side of deficiency in origin such as the deficiency of vital energy in treatment, strengthen the effect of treatment blood stasis again, therefore, control is because cold and coolly excessively just hinder, and accomplishes to uncharm and just do not hinder.From the clinical state of an illness, being more suitable for being used at ordinary times, body constitution is not acute stage and the reconvalescent that the good acute cerebral ischemic stroke patient and the state of an illness lay particular stress on.
Technology of the present invention can improve active component content, removes a large amount of impurity, has lowered the clinical application amount greatly; Repeatability, good stability are easy to control the quality simultaneously; And the yield height of raw material, cost is low, is fit to suitability for industrialized production; Use the solvent of non-secondary pollution, integrate with international standard.
The specific embodiment
Further specify the present invention below by embodiment, but not as limitation of the present invention.
Embodiment 1
The preparation of lyophilized injectable powder
(1) get Radix Paeoniae Rubra 1.1Kg, add 18 times of amounts of water, divide three times heating extraction, each 2 hours, extracting solution merged, and filtered, and it is 1.17 that filtrate is concentrated into relative density, added ethanol and made and contain the alcohol amount and reach 75%, added 10% alkali again and made solution pH value 8, and cold preservation 24 hours filters; Filtrate recycling ethanol is to there not being the alcohol flavor, thin up to relative density is 1.10～1.20, stirs evenly, and filters, macroporous adsorption resin chromatography post on the filtrate, washing with water earlier to eluent does not have reducing sugar reaction, and the ethanol elution of reuse 70% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Paeoniae Rubra total glycosides 30.7g, and wherein paeoniflorin content is 12.3g.
(2) get Fructus Gardeniae 0.9Kg, add 24 times of amounts of water, divide three times heating extraction, each 2 hours, extracting solution merged, and filtered, and it is 1.12 that filtrate is concentrated into relative density, added ethanol and made and contain the alcohol amount and reach 80%, and cold preservation 48 hours is filtered; Filtrate recycling ethanol is not to there being the alcohol flavor, and thin up to relative density is 1.10～1.20, adds dilute hydrochloric acid and makes the solution pH value reach 3, and cold preservation 48 hours filters; Filtrate adds 10% alkali makes the solution pH value reach 7, stir evenly, filter, macroporous adsorption resin chromatography post on the filtrate, washing with water earlier to eluent does not have reducing sugar reaction, the ethanol elution of reuse 80%, collect ethanol elution, decompression recycling ethanol, vacuum drying, get Fructus Gardeniae total glycosides 56.1g, wherein jasminoidin content is 26.9g.
(3) get Radix Astragali 1Kg, add 22 times of amounts of water, divide three times heating extraction, each 2 hours, extracting solution merged, and filtered, filtrate is concentrated into relative density and is 1.42, and is centrifugal, gets macroporous adsorption resin chromatography post on the supernatant, washing with water earlier to eluent does not have reducing sugar reaction, and the ethanol elution of reuse 70% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Astragali total glycosides 14.3g, and wherein Astragaloside content is 0.4g.
(4) get above-mentioned (1)～(3) product each 1/3rd, add an amount of water for injection gradation dissolving, add pharmaceutic adjuvant, stir it fully dissolved, solution adds the injection active carbon, boils 10～15 minutes, filters while hot, filtrate is crossed micro-filtration membrane, micro-filtrate; Micro-filtrate is crossed the ultrafilter membrane of 10000 molecular weight, gets ultrafiltrate 1000ml, and filtrate is made the lyophilized injectable powder bottle by the preparation common process.
Embodiment 2
The preparation of liquid infusion agent
(1) get Radix Paeoniae Rubra 1.1Kg, add 18 times of amounts of water, divide three times heating extraction, each 2 hours, extracting solution merged, and filtered, and it is 1.17 that filtrate is concentrated into relative density, added ethanol and made and contain the alcohol amount and reach 75%, added 10% alkali again and made solution pH value 8, and cold preservation 24 hours filters; Filtrate recycling ethanol is to there not being the alcohol flavor, thin up to relative density is 1.10～1.20, stirs evenly, and filters, macroporous adsorption resin chromatography post on the filtrate, washing with water earlier to eluent does not have reducing sugar reaction, and the ethanol elution of reuse 70% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Paeoniae Rubra total glycosides 30.7g, and wherein paeoniflorin content is 12.3g.
(2) get Fructus Gardeniae 0.9Kg, add 24 times of amounts of water, divide three times heating extraction, each 2 hours, extracting solution merged, and filtered, and it is 1.12 that filtrate is concentrated into relative density, added ethanol and made and contain the alcohol amount and reach 80%, and cold preservation 48 hours is filtered; Filtrate recycling ethanol is not to there being the alcohol flavor, and thin up to relative density is 1.10～1.20, adds dilute hydrochloric acid and makes the solution pH value reach 3, and cold preservation 48 hours filters; Filtrate adds 10% alkali makes the solution pH value reach 7, stir evenly, filter, macroporous adsorption resin chromatography post on the filtrate, washing with water earlier to eluent does not have reducing sugar reaction, the ethanol elution of reuse 80%, collect ethanol elution, decompression recycling ethanol, vacuum drying, get Fructus Gardeniae total glycosides 56.1g, wherein jasminoidin content is 26.9g.
(3) get Radix Astragali 1Kg, add 22 times of amounts of water, divide three times heating extraction, each 2 hours, extracting solution merged, and filtered, filtrate is concentrated into relative density and is 1.42, and is centrifugal, gets macroporous adsorption resin chromatography post on the supernatant, washing with water earlier to eluent does not have reducing sugar reaction, and the ethanol elution of reuse 70% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Astragali total glycosides 14.3g, and wherein Astragaloside content is 0.4g.
(4) get above-mentioned (1)～(3) product each 1/3rd, add an amount of water for injection gradation dissolving, add pharmaceutic adjuvant, stir it fully dissolved, solution adds the injection active carbon, boils 10～15 minutes, filters while hot, filtrate is crossed micro-filtration membrane, micro-filtrate; Micro-filtrate is crossed the ultrafilter membrane of 10000 molecular weight, gets ultrafiltrate 1000ml, and filtrate is made the injection injection by the preparation common process.
Embodiment 3
The preparation of tablet,
In the 1st step, the 2nd step and the 3rd step are as the step (1) of embodiment 1 and 2, step (2), step (3) step (4) be get above-mentioned (1)～(2) compositions each 1/3rd, add pharmaceutic adjuvant, be prepared into 1000 in tablet according to the tablet routine techniques, but coating in case of necessity.
Embodiment 4
The preparation of capsule,
In the 1st step, the 2nd step and the 3rd step as the step (1) of embodiment 1 and 2, step (2), step (3) step (4) are to get above-mentioned (1)～(2) compositions respectively 1/3rd, and the adding pharmaceutic adjuvant is prepared into 1000 of capsules according to the capsule routine techniques.
Embodiment 5
The preparation of granule,
In the 1st step, the 2nd step and the 3rd step as the step (1) of embodiment 1 and 2, step (2), step (3) step (4) are to get above-mentioned (1)～(2) compositions respectively 1/3rd, and the adding pharmaceutic adjuvant is prepared into granule 1000g according to the granule routine techniques.
Claims (10)
1, a kind of Chinese medicine preparation for the treatment of cardiovascular and cerebrovascular disease is characterized in that, is made by following Chinese medicinal raw materials: Radix Paeoniae Rubra 1-3 part, 0.8～3 part of Fructus Gardeniae, Radix Astragali 1-3 part.
2, the Chinese medicine preparation of claim 1 is characterized in that, is made by following Chinese medicinal raw materials: 1 part of Radix Paeoniae Rubra 1-1.5 part, Fructus Gardeniae 0.8-1, the Radix Astragali.
3, the Chinese medicine preparation of claim 1 is characterized in that, is made by following Chinese medicinal raw materials: 1 part of 1.1 parts of Radix Paeoniae Rubra, Fructus Gardeniae 0.9, the Radix Astragali.
4, the Chinese medicine preparation of claim 1, it is characterized in that, be selected from following dosage form: tablet, capsule, oral liquid, suck agent, granule, pill, powder, unguentum, sublimed preparation, suspensoid, injection, suppository, cream, spray, drop or patch.
5, the Chinese medicine preparation of claim 4 is characterized in that, described injection is the injectable powder of injection.
6, the Chinese medicine preparation of claim 4 is characterized in that, described dosage form is a drop pill.
7, the preparation method of the Chinese medicine preparation of claim 1, it is characterized in that, through following steps, the raw material of Chinese medicine process that prescription is formed is extracted or other processing modes, make pharmaceutically active substance, with this material is raw material, adds the medicine acceptable carrier when needing, and makes pharmaceutical preparation according to the routine techniques of galenic pharmacy.
8, the preparation method of claim 7 is characterized in that, described extraction or other processing modes are selected from pulverizing, squeeze, calcine, grind, sieve, percolation, extraction, water are carried, alcohol extraction, ester are carried, ketone is carried or chromatography.
9, the preparation method of claim 8 is characterized in that, the process following steps:
(1) get Radix Paeoniae Rubra, water heating extraction 2～3 times, each 1～3 hour, extracting solution merged, filter, it is 1.10-1.20 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 60-80%, add 10～20% alkali again and make the solution pH value reach 6～8, cold preservation 12-48 hour, filter; Filtrate recycling ethanol is to there not being the alcohol flavor, thin up to relative density is 1.10-1.20, stir evenly, filter macroporous adsorption resin chromatography post on the filtrate, wash with water earlier to eluent and do not have reducing sugar reaction, the ethanol elution of reuse 20～80% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Paeoniae Rubra total glycosides;
(2) get Fructus Gardeniae, water heating extraction 2-3 time, each 1～3 hour, extracting solution merges, filter, it is 1.10-1.20 that filtrate is concentrated into relative density, adds ethanol and makes and contain the alcohol amount and reach 60-80%, cold preservation 12～48 hours, filter: filtrate recycling ethanol is not to there being the alcohol flavor, and thin up to relative density is 1.10-1.20, adds dilute hydrochloric acid and makes the solution pH value reach 2～3, cold preservation 12～48 hours filters; Filtrate adds 10～20% alkali makes the solution pH value reach 7, stirs evenly, and filters macroporous adsorption resin chromatography post on the filtrate, washing with water earlier to eluent does not have reducing sugar reaction, and the ethanol elution of reuse 20～80% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Fructus Gardeniae total glycosides;
(3) get the Radix Astragali, water heating extraction 2-3 time, each 1-3 hour, extracting solution merges, and filters, and it is 1.30～1.50 that filtrate is concentrated into relative density, centrifugal, get macroporous adsorption resin chromatography post on the supernatant, washing with water earlier to eluent does not have reducing sugar reaction, the ethanol elution of reuse 20～80%, collect ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Astragali total glycosides;
(4) get the product of above-mentioned (1)～(3), mix, make pharmaceutical preparation according to the galenic pharmacy routine techniques.
10, the preparation method of claim 9 is characterized in that, the process following steps:
(1) get Radix Paeoniae Rubra 1.1Kg, add 18 times of amounts of water, divide three times heating extraction, each 2 hours, extracting solution merged, and filtered, and it is 1.17 that filtrate is concentrated into relative density, added ethanol and made and contain the alcohol amount and reach 75%, added 10% alkali again and made solution pH value 8, and cold preservation 24 hours filters; Filtrate recycling ethanol is to there not being the alcohol flavor, thin up to relative density is 1.10～1.20, stirs evenly, and filters, macroporous adsorption resin chromatography post on the filtrate, washing with water earlier to eluent does not have reducing sugar reaction, and the ethanol elution of reuse 70% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Paeoniae Rubra total glycosides 30.7g, and wherein paeoniflorin content is 12.3g;
(2) get Fructus Gardeniae 0.9Kg, add 24 times of amounts of water, divide three times heating extraction, each 2 hours, extracting solution merged, and filtered, and it is 1.12 that filtrate is concentrated into relative density, added ethanol and made and contain the alcohol amount and reach 80%, and cold preservation 48 hours is filtered; Filtrate recycling ethanol is not to there being the alcohol flavor, and thin up to relative density is 1.10-1.20, adds dilute hydrochloric acid and makes the solution pH value reach 3, and cold preservation 48 hours filters; Filtrate adds 10% alkali makes the solution pH value reach 7, stir evenly, filter, macroporous adsorption resin chromatography post on the filtrate, washing with water earlier to eluent does not have reducing sugar reaction, the ethanol elution of reuse 80%, collect ethanol elution, decompression recycling ethanol, vacuum drying, get Fructus Gardeniae total glycosides 56.1g, wherein jasminoidin content is 26.9g;
(3) get Radix Astragali 1Kg, add 22 times of amounts of water, divide three times heating extraction, each 2 hours, extracting solution merged, and filtered, filtrate is concentrated into relative density and is 1.42, and is centrifugal, gets macroporous adsorption resin chromatography post on the supernatant, washing with water earlier to eluent does not have reducing sugar reaction, and the ethanol elution of reuse 70% is collected ethanol elution, decompression recycling ethanol, vacuum drying gets Radix Astragali total glycosides 14.3g, and wherein Astragaloside content is 0.4g;
(4) get above-mentioned (1)～(3) product each 1/3rd, add an amount of water for injection gradation dissolving, add pharmaceutic adjuvant, stir it fully dissolved, solution adds the injection active carbon, boils 10-15 minute, filters while hot, filtrate is crossed micro-filtration membrane, micro-filtrate; Micro-filtrate is crossed the ultrafilter membrane of 10000 molecular weight, gets ultrafiltrate 1000ml, and filtrate is made lyophilized injectable powder by the preparation common process.
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| CN104857010A (en) * | 2015-04-22 | 2015-08-26 | 张永胜 | Geniposide, baicalin and paeoniflorin pharmaceutical composition |
| CN108567920B (en) * | 2018-06-09 | 2020-10-27 | 东莞市中医院 | Traditional Chinese medicine composition for treating acute ischemic stroke |
| CN112843133A (en) * | 2021-03-05 | 2021-05-28 | 刘树民 | Traditional Chinese medicine composition for treating cerebral infarction and preparation method thereof |
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