CN105596788A - Cerebrovascular disease prevention and treatment pharmaceutical preparation and preparation method thereof - Google Patents
Cerebrovascular disease prevention and treatment pharmaceutical preparation and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a cerebrovascular disease prevention and treatment pharmaceutical preparation and a preparation method thereof, wherein gastrodia elata, processed eucommia ulmoides, processed radix aconiti kusnezoffii, processed radix aconiti lateralis preparata, radix angelicae pubescentis, ligusticum sinense oliv, radix scrophulariae, angelica sinensis, rehmannia glutinosa, cyathula officinalis kuan, viscum coloratum, and notopterygium incisum are subjected to extraction refining, and a proper amount of an auxiliary material is added to prepare the cerebrovascular disease prevention and treatment pharmaceutical preparation. According to the present invention, the cerebrovascular disease prevention and treatment pharmaceutical preparation has effects of liver pacifying, endogenous wind stopping, blood circulation activation, cold expelling, tendon relaxing and pain stopping, and mainly used for treatments of ischemic cerebrovascular diseases caused by hyperactive liver yang causing wind and meridian stagnation caused by cold-damp, wherein the symptoms comprise tendon and vessel pain, numbness of limbs, difficult walking, lumbar and leg aching pain, headache, dizziness, sluggish complexion, slurred speech and the like; and compared with the preparation in the prior art, the preparation of the present invention is the active site extraction preparation, and has characteristics of high purity, low taking dose, high bioavailability, stable quality, excellent treatment effect, low toxicity, and good safety.
Description
Technical field:
The present invention relates to pharmaceutical preparation of anti-treatment cranial vascular disease and preparation method thereof, belong to the technical field of medicine.
Background technology:
Cranial vascular disease refers to that the various causes of disease cause cerebrovascular infringement and the cerebral tissue change that causes. Acute onset is also rapidThe cranial vascular disease that occurs brain disorder is called ACVD, also claims cerebrovas-cularaccident, headstroke or cerebral apoplexy, hasFall ill high, disability rate height and the high feature of recurrence rate, be middle-aged and old common frdquently encountered diseases. Cranial vascular disease, angiocardiopathy andMalignant tumour occupies the front three of mankind's natural death reason. The incidence of disease of cranial vascular disease is because of different areas, nationality, lifeBeing accustomed to waiting and difference, is 110～2,00/,100,000 at China's cranial vascular disease incidence of disease, illness rate 394～7,19/,100,000, the death rate116～1,42/,100,000, aspect sex, the ratio of men and women's incidence of disease is 1.3～1.7: 1; Aspect the age, because the age is brainArteriosclerotic one can not intervention hazards, and therefore, with the growth at age, the danger that cranial vascular disease occurs moreGreatly, the age is larger, and the incidence of disease is higher. Particularly attract people's attention, a middle-aged person of present about 40 years old suffers from the general of cranial vascular diseaseRate is also significantly rising, and middle-aged population body active prevention cranial vascular disease has become an instant problem. In recent years,Due to the raising for the treatment of level, the death rate of cranial vascular disease decreases, but disability rate is still high, approximately 80% survivalPerson still has dysfunction in various degree, has brought white elephant to patient family and society. Therefore reduce disability rate, improveRehabilitation speed and prevention are to treat at present this sick task of top priority.
The technology of the present invention is to carry out technological improvement on the powerful gastrodia capsule of original product basis, and prescription is by rhizoma Gastrodiae, DuSecondary (salt system), wild aconite root, RADIX ACONITI LATERALIS PREPARATA, levisticum, Jehol Ligusticum Rhizome, radix scrophulariae, Radix Angelicae Sinensis, glutinous rehmannia, radix cyathulae, mistletoe, notopterygium root composition, former formulationMethod for making is that crude extracts rear rhizoma Gastrodiae pulverizing and other medicinal materials are mixed with and are formed, and its function cures mainly as " loose wind is invigorated blood circulation, and relaxing muscles and tendons onlyBitterly. Be used for wind-induced muscle arteries and veins and take along pain, extremity numbness, inconvenient walking, waist and leg ache, headache and dizziness etc. ". Clinical application for many yearsShow, former formulation clinical efficacy is good, but has the following disadvantages: (1) former formulation cures mainly completely with TCM-related Terms statement, not in conjunction with westDoctor's explanation treatment is what disease, brought certain limitation to the popularization of this medicine, and clinical practice applies to treat in ischemic brainMuscle arteries and veins pain, extremity numbness that wind, cerebral thrombus, cerebral arteriovenous malformation, cerebral blood supply insufficiency, hypertension etc. cause, inconvenient walking, waist legAche, the diseases such as headache and dizziness; (2) former formulation preparation technology is coarse, and technology content is not high, is mainly reflected in: 1. only in former preparationIn work, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four traditional Chinese medicine material, all contain a large amount of volatile materials, adopt ordinary preparation technology not protect completelyVolatile materials and cause it to lose in a large number, cannot ensure drug quality and curative effect; 2. former preparation is only slightly to carry and processing, itsIn contain a large amount of impurity, bring following problem to preparation: the one, make its amount of formulation large containing a large amount of impurity, make troubles to medication,The 2nd, some impurity water imbibition is strong, easily makes its preparation moisture absorption rotten, cannot ensure drug quality and curative effect; 3. will in former preparationRhizoma Gastrodiae is made preparation after directly pulverizing, and brings following problem to preparation: the one, and make its amount of formulation large containing a large amount of impurity, to medication bandIt is inconvenient to come, and the 2nd, the direct starch of medicinal material, active principle can not absorb completely, makes its bioavilability low; The 3rd, medicinal material is straightConnect starch, taking rear active ingredient needs stripping to absorb process, makes its drug effect slow. Make a general survey of whole preparation workSkill, quality and curative effect that can not fine embodiment preparation. Now enter process modification by technological innovation, compared with prior art, have withLower superiority: taking dose reduces, and bioavilability significantly improves, and drug effect is fast, and toxic and side effect is low, and medication is safer, facesBed better efficacy, drug quality is more stable.
In order to reach above-mentioned technology, applicant has carried out a large amount of explorations and research.
Summary of the invention:
The object of the invention is to: be to provide a kind of pharmaceutical preparation of preventing and treating cranial vascular disease and preparation method thereof, thisThe medicine of invention has no side effect, and result for the treatment of is good, and rapid-action, and bioavilability is high, and the quality of the pharmaceutical preparations is stable, existing to solveThe problem that technology exists.
The present invention is achieved in that according to listed as parts by weight, it by rhizoma Gastrodiae 2%～18%, the bark of eucommia processed 9.5%～11.5%, wild aconite root 0.5%～1.5%, RADIX ACONITI LATERALIS PREPARATA 0.5%～1.5%, levisticum 5%～7%, Jehol Ligusticum Rhizome 6.5%～7.5%, profoundGinseng 6.5%～7.5%, Radix Angelicae Sinensis 11%～13%, glutinous rehmannia 18.5%～20.5%, radix cyathulae 6.5%～7.5%, mistletoe6.5%～7.5%, notopterygium root 11%～13% is prepared from through extracting processing. Say accurately, calculate according to weight, it is by rhizoma Gastrodiae9.6%, the bark of eucommia 10.3% processed, wild aconite root 1.2%, RADIX ACONITI LATERALIS PREPARATA 1.2%, levisticum 6.0%, Jehol Ligusticum Rhizome 7.1%, radix scrophulariae 7.1%, Radix Angelicae Sinensis12.0%, glutinous rehmannia 19.3%, radix cyathulae 7.1%, mistletoe 7.1%, notopterygium root 12.0% are prepared from through extracting processing.
The pharmaceutical preparation that the present invention prevents and treats cranial vascular disease is preparation like this:
(1) take rhizoma Gastrodiae raw medicinal material, add 30%～90% alcohol extract, filter, obtain ethanol extract for subsequent use, remaining dayAnaesthetic slag is for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillations and extract 4～10 hours, separate,Obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoeMerge, add 6～12 times of water gagings and extract 1～4 time, each 1～4 hour, merge extract, filter, filtrate is concentrated into containing crude drug denseDegree is the liquid of 1: 1～3: 1, lets cool to room temperature, adds ethanol to make solution contain alcohol amount and reaches 40%～80%, leaves standstill 8～48 hours,Get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaiming ethanol and being concentrated into relative density is 1.05～1.40 (60DEG C) medicinal extract, merge volatile oil, then add auxiliary material routinely preparation process make different pharmaceutical preparations.
Specifically: take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 2 times, each 2 hours, merge,Filter, obtain ethanol extract for subsequent use, the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal materials useSteam distillation extracts 6 hours, separates, and obtains volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, system are attachedSon, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, mergeExtract, filters, and the liquid that it is 1.0: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to make solution contain alcohol amountReach 60%, leave standstill 24 hours, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaim ethanol and be concentrated into relativelyDensity is the medicinal extract of 1.05～1.40 (60 DEG C), merge volatile oil, then add auxiliary material routinely preparation process make different medicinesThing preparation.
(2) take rhizoma Gastrodiae raw medicinal material, add 30%～90% alcohol extract, filter, obtain ethanol extract for subsequent use, remaining dayAnaesthetic slag is for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatile oil standbyWith; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merging, add 6～12 times of water gagings extract 1～4 time, and each 1～4 hour, merge extract, filter, it is 1: 1～3 that filtrate is concentrated into containing crude drug concentration:1 liquid, lets cool to room temperature, is added on resin column, with 30%～90% ethanol elution, collects eluent, with rhizoma Gastrodiae alcohol extractMerge, reclaim ethanol and be also concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), merge volatile oil, then add auxiliary material byConventional formulation technique is made different pharmaceutical preparations.
Specifically: take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 2 times, each 2 hours, merge,Filter, obtain ethanol extract for subsequent use, the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal materials useSupercritical CO2Extract, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia, radix aconiti agrestis, monkshood, radix scrophulariae, glutinous rehmannia,Radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filter,The liquid that it is 1.0: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, is added on large pore resin absorption column, uses 60% ethanolWash-out, collects eluent, merges with rhizoma Gastrodiae alcohol extract, and reclaiming ethanol and being concentrated into relative density is 1.05～1.40 (60 DEG C)Medicinal extract, merge volatile oil, then add auxiliary material routinely preparation process make different pharmaceutical preparations.
(3) take rhizoma Gastrodiae raw medicinal material, add 30%～90% alcohol extract, filter, filtrate recycling ethanol is also concentrated into phaseBe the medicinal extract of 1.05～1.40 (60 DEG C) to density, obtain rhizoma Gastrodiae alcohol-extracted extract for subsequent use, the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum,Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and a day anaestheticSlag, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merge, and add 6～12 times of water gagings and extract 1～4 time,Each 1～4 hour, merge extract, filter, filtrate, by film separating and filtering, is collected filtered fluid, and filter is concentrated into relative density and isThe medicinal extract of 1.05～1.40 (60 DEG C), merges with rhizoma Gastrodiae alcohol-extracted extract, volatile oil, then add auxiliary material routinely preparation process makeDifferent pharmaceutical preparations.
Specifically: take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 2 times, each 2 hours, closeAnd, filtering, filtrate recycling ethanol is also concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), obtains rhizoma Gastrodiae alcohol-extracted extract standbyWith, the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate,Obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoeMerge, add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filter, filtrate is passed through ceramic membraneSeparating and filtering, collects filtered fluid, and filter is concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), with rhizoma Gastrodiae alcohol-extracted extract,Volatile oil merge, then add auxiliary material routinely preparation process make different pharmaceutical preparations.
In the preparation method of above-mentioned control cerebrovascular disease medicament preparation, described pharmaceutical preparation is oral formulations, comprisesGranule, oral liquid, pill, tablet, hard shell capsules, soft capsule and dripping pill etc.
Specifically, in the above-mentioned pharmaceutical preparation and preparation method of preventing and treating cranial vascular disease, described pharmaceutical preparation is hardCapsule; Described preparation method is: taking polyethylene glycol-6000 and PEG-4000 mix heating and melting, add volatilizationOil, medicinal extract, stir, and is transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, and dripping becomes ball, de-oiling, low temperature drying, filling inIn Capsules, to obtain final product.
Pharmaceutical preparation side of the present invention separates: apoplexy is disorderly inverse due to qi and blood, produces wind, fire, phlegm, the stasis of blood, cause the resistance of brain vessle-Bi symptom-complex orBlood overflows outside brain arteries and veins. Clinical, speech no tiltedly taking unexpected confused servant, hemiplegia, dispute stuttering puckery or in silence, hemianesthesia is as primary symptom.This disease is roughly equivalent to ischemic and the hemorrhagic cerebrovascular disease of doctor trained in Western medicine. Apoplexy is many, and because amassing, damage just declines, overstrain internal injury, diet notJoint, emotional stress etc., cause stagnation of blood stasis, accumulation phlegm-heat in the interior, or liver yang causing wind, bleeding resulting from adverse flow of QI, and cause that the resistance of brain vessle-Bi symptom-complex or blood overflowOutside brain arteries and veins, send out. Its inducement is common: weather cataclysm, and bother excessively, feelings will swashs mutually, falls to flutter and exerts wound etc. Apoplexy position at brain, withThe heart, kidney,liver,spleen are closely related. Its interpretation of the cause, onset and process of an illness has void, fire, wind, phlegm, gas, blood six end, and interacts under certain condition, mutuallyFor cause and effect. Characteristic of disease mostly is asthenia in origin and asthenia in superficiality, upper excess and lower deficiency, and this is few for the deficiency of liver-yin and kidney-yin, qi and blood decline, be designated as febrile disease complicated by wind, phlegm wet stop up contain,Stagnation of blood stasis, qi and blood are against random. Its basic pathogenesis is then that qi and blood is disorderly inverse, above disturbs in brain. The treatment of apoplexy, acute stage, is worked as with eliminating evilBe main, conventional calming the liver to stop the wind, clearing heat and eliminating phlegm, the pain of reducing phlegm internal organs, the method such as promoting blood circulation and removing obstruction in channels, inducing resuscitation is had one's ideas straightened out. Close card control with eliminating evil have one's ideas straightened out awakeGod, the exhaustion of vital energy at the critical stage of an illness is controlled with strengthening body resistance, is rescued cloudy Hui Yang. Convalescence and sequela phase, controlling should strengthening vital QI to eliminate pathogenic factors, conventionally educates that the moon relieves dizziness, high fever, infantile convulsions, epilepsy, etc., beneficial gasThe method such as invigorate blood circulation. In side, with rhizoma Gastrodiae, the bark of eucommia, radix cyathulae, the flat liver west wind of mistletoe, remove obstruction in channels to relieve pain; Radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis enriching yin are supportedBlood, with the moon sun; Monkshood, radix aconiti agrestis is warming channel and expelling cold, removes obstruction in channels to relieve pain; Notopterygium root, levisticum, Jehol Ligusticum Rhizome are dispeled the wind, dehumidifying, loose cold, remove obstruction in channels to relieve pain.All medicines share, and play suppressing hyperactive liver for calming endogenous wind altogether, and Huoxue San " is cold, the merit of relaxing muscles and tendons pain relieving.
Function of the present invention cures mainly: suppressing hyperactive liver for calming endogenous wind, Huoxue San " is cold, relaxing muscles and tendons pain relieving. Due to liver yang causing wind, Cold-dampnessIschemia apoplexy, cerebral thrombus, cerebral arteriovenous malformation, cerebral embolism, cerebral infarction, cerebral blood supply insufficiency, hypertension, encephalatrophy, vascularThe cranial vascular disease such as dull-witted is shown in that muscle arteries and veins takes along pain, extremity numbness, inconvenient walking, waist and leg ache, headache and dizziness, look dull, languageUnfavorable etc.
In order to verify that medicine of the present invention has good result for the treatment of, applicant has carried out series of experimental research, concreteAs follows:
One, craft screening and preliminary comparative efficacy test
(1) process route and sample preparation
1, former preparation process (former medicine) and sample preparation: get prescription 12 taste medicinal materials, Rhizoma Gastrodiae powder is broken into fine powder, levisticum, ligusticumicBasis, Radix Angelicae Sinensis, notopterygium root are extracted volatile oil, seven tastes such as the dregs of a decoction and the bark of eucommia, and boiling secondary, 3 hours for the first time, 2 hours for the second time,Collecting decoction, filters, and filtrate is condensed into cream, with above-mentioned powder, mixes, and dry, pulverize, sieve, and granulation, dry, spray intoVolatile oil, mixes, and packs and obtain former formulation samples. Inventory is 2.5 times of recipe quantities, and the amount of making is 1800g. Sample is compiledNumber: 20091018.
2, new technology 1 and sample preparation: get prescription 12 taste medicinal materials, Rhizoma Gastrodiae powder is broken into meal, adds 5 times of amount 50% ethanol and returnsStream extracts 2 times, and each 2 hours, merge, filter filtrate recycling ethanol to be concentrated into relative density be 1.25～1.40 (60 DEG C)Medicinal extract, obtain rhizoma Gastrodiae alcohol-extracted extract for subsequent use, levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root extract volatile oil, seven tastes such as the dregs of a decoction and the bark of eucommia, add waterDecoct secondary, 3 hours for the first time, 2 hours for the second time, collecting decoction, filtered, and it is 1.25～1.40 that filtrate is concentrated into relative densityThe medicinal extract of (60 DEG C), with above-mentioned rhizoma Gastrodiae alcohol-extracted extract, mixes, and dry, pulverize, sieve, and granulation, dry, spray into volatile oil,Mix, pack and get final product. Inventory is 2.5 times of recipe quantities, and the amount of making is 1530g. Sample number into spectrum: QL0910-1.
3, new technology 2 and sample preparation: get prescription 12 taste medicinal materials, Rhizoma Gastrodiae powder is broken into meal, adds 5 times of amount 50% ethanol and returnsStream extracts 2 times, and each 2 hours, merge, filter, obtain ethanol extract for subsequent use, the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Levisticum, Jehol Ligusticum Rhizome, whenReturn, notopterygium root extract volatile oil, seven tastes such as the dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia bark of eucommia, boiling secondary, 3 hours for the first time, secondInferior 2 hours, collecting decoction, filtered, and the liquid that it is 1.0: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, was added to macropore and inhaledOn attached resin column, use 60% ethanol elution, collect eluent, merge with rhizoma Gastrodiae alcohol extract, reclaim ethanol and be concentrated into relatively closeDegree is the medicinal extract of 1.25～1.40 (60 DEG C), dry, pulverize, sieve, and granulation, dry, spray into volatile oil, mix sealingPack and get final product. Inventory is 2.5 times of recipe quantities, and the amount of making is 330g. Sample number into spectrum: QL0910-2.
4, new technology 3 and sample preparation: get prescription 12 taste medicinal materials, Rhizoma Gastrodiae powder is broken into meal, adds 5 times of amount 50% ethanol and returnsStream extracts 2 times, and each 2 hours, merge, filter, the dregs of a decoction are for subsequent use, filtrate recycling ethanol be concentrated into relative density and be 1.25～The medicinal extract of 1.40 (60 DEG C), obtains rhizoma Gastrodiae alcohol-extracted extract for subsequent use, and levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root are extracted volatile oil, the dregs of a decoction and rhizoma GastrodiaeSeven tastes such as the dregs of a decoction, the bark of eucommia, boiling secondary, 3 hours for the first time, 2 hours for the second time, collecting decoction, merged extract, filterCross, filtrate is filtered by ceramic membrane separation, collects filtered fluid, and it is soaking of 1.25～1.40 (60 DEG C) that filter is concentrated into relative densityCream, with above-mentioned rhizoma Gastrodiae alcohol-extracted extract, mixes, and dry, pulverize, sieve, and granulation, dry, spray into volatile oil, mix sealingPack and get final product. Inventory is 2.5 times of recipe quantities, and the amount of making is 1450g. Sample number into spectrum: QL0910-3.
5, new technology 4 and sample preparation: get prescription 12 taste medicinal materials, Rhizoma Gastrodiae powder is broken into meal, adds 5 times of amount 50% ethanol and returnsStream extracts 2 times, and each 2 hours, merge, filter, obtain ethanol extract for subsequent use, levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root are extracted volatile oil,Seven tastes such as the dregs of a decoction and the bark of eucommia, boiling secondary, 3 hours for the first time, 2 hours for the second time, merge extract, filter, filtrate is denseBe reduced to and contain the liquid that crude drug concentration is 1.0: 1, let cool to room temperature, add ethanol to make solution contain alcohol amount and reach 60%, leave standstill 24 hours,Get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaiming ethanol and being concentrated into relative density is 1.25～1.40 (60DEG C) medicinal extract, dry, pulverize, sieve, granulation, dry, spray into volatile oil, mix, pack and get final product. InventoryBe 2.5 times of recipe quantities, the amount of making is 360g. Sample number into spectrum: QL0910-4.
6, new technology 5 and sample preparation: get prescription 12 taste medicinal materials, Rhizoma Gastrodiae powder is broken into meal, adds 5 times of amount 50% ethanol and returnsStream extracts 2 times, each 2 hours, merge, filter, obtain ethanol extract for subsequent use, the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use, levisticum, Jehol Ligusticum Rhizome, whenReturn, notopterygium root extracts volatile oil, seven tastes such as the dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia, boiling secondary, 3 hours for the first time, for the second time 2Hour, merge extract, filter, the liquid that it is 1.0: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to makeSolution reaches 60% containing alcohol amount, leaves standstill 24 hours, gets supernatant liquid filtering and obtains ethanol, merges with rhizoma Gastrodiae alcohol extract, reclaims ethanol alsoBeing concentrated into relative density is the medicinal extract of 1.25～1.40 (60 DEG C), dry, pulverize, sieve, and granulation, dry, spray into volatilizationOil, mixes, and packs and get final product. Inventory is 2.5 times of recipe quantities, and the amount of making is 450g. Sample number into spectrum: QL0910-5.
(2) pharmacodynamics contrast experiment experiment purpose: the former medicine of known powerful gastrodia elata-cortex capsule has and presses down platelet aggregationMake use, this experiment, with the positive contrast medicine of the former medicine of gastrodia elata-cortex capsule, is observed 5 kinds of powerful gastrodia elata-cortex capsule test medicines and (is surveyedReagent 1,2,3,4,5) impact of the blood platelet MA on normal rats in vitro ADP and thrombin induction.
1, experiment material
1.1 animal used as test Sprague-Dawley (SD) rats, male, body weight 280-320g, clean level, by University Of SuzhouMedical college's Experimental Animal Center provide (production licence XCYK (Soviet Union): No2002-0008, occupancy permit SYXK (Soviet Union):No2002-0037). Feeding conditions is as follows: six cages, and 22 DEG C of room temperatures, humidity 50-60%, well-ventilated, manually round the clock(12h/12h), freely ingest and take the photograph water. Before experiment, animal is adapted in feeding environment to 1 week.
1.2 laboratory apparatus TYXN-96 multifunctional intellectual blood pool instrument, the research of Shanghai GM mechanical & electrical technology; 80-2 is desk-topLow speed centrifuge, operating theater instruments factory of Shanghai Medical apparatus Co., Ltd.
The powerful former medicine of gastrodia elata-cortex capsule of 1.3 medicines and reagent (20091018) and 5 kinds of powerful gastrodia elata-cortex capsule testsMedicine [test medicine 1 (QL0910-1), test medicine 2 (QL0910-2), test medicine 3 (QL0910-3), test medicine 4 (QL0910-4), surveyReagent 5 (QL0910-5)], sample provides by seminar, is made into suspension with distilled water; Biphosphate is received (DihydrogenThe product batch number F20090624 of Phosphate traditional Chinese medicines group); (DisodiumPhosphate traditional Chinese medicines group produces sodium hydrogen phosphateProduct batch number 20090915); Chinese holly edge acid sodium (reagent one factory in SodiumCitrate Shanghai produces product batch number 96-02-03);ADP (Solarbio produces, product batch number A8290); Fibrin ferment (Thrombin) (Sigma) is produced, product batch number 9002-04-4)。
2, experimental technique
70 of the healthy male SD rats of 2.1 experimental designs, body weight 280-320g, is divided into 7 groups at random, and 10 every group, respectivelyFor Normal group, the former medicine group of powerful gastrodia elata-cortex capsule (former medicine group, 350mg/kg are equivalent to a day dosing 4.2g) and powerful skyFiber crops eucommia bark capsules test medicines 1 (300mg/kg is equivalent to a day dosing 3.6kg), 2 (67mg/kg is equivalent to day dosing 0.8), 3(283mg/kg is equivalent to a day dosing 3.4g), 4 (70mg/kg is equivalent to a day dosing 0.84g),, 5 (89mg/kg is equivalent to day clothesAmount 1.07g) group. The powerful former medicine of gastrodia elata-cortex capsule of administration group rat oral gavage or respectively test medicine, Normal group is pressed 0.2ml/100g gavage distilled water, every day 1 time, continuous 4 weeks. The administration of rat last is abdominal aortic blood mensuration ADP and fibrin ferment after 2 hoursThe blood platelet MA (Fig. 1) of induction
The mensuration rat last administration of 2.2 platelet aggregations is anaesthetized abdominal aortic blood and is measured hematoblastic after 2 hoursLarge PAR. Follow these steps to operation:
(1) anti-coagulants adopts 3.28% Chinese holly edge acid, and blood drawing amount should be 9: 1 with the ratio of anti-coagulants, mixes immediately 2～3Inferior.
(2) obtain sample be PRP (being rich in hematoblastic blood plasma) under 20～25 DEG C of conditions centrifugal speed with 500r/min,Time 5Min left and right, uses horizontal type centrifuger. (3) treat slowly natural stall of centrifuge, then take out, in order to avoid in cell inflow PRP,As find in PRP still the centrifugal a moment under these conditions containing RBC. ADP and fibrin ferment for aggregation inducing agent, measure blood plateletLarge PAR
2.3 statistical analysis data are with means standard deviationRepresent. Corresponding journey in application SPSS (10.0 editions)Order, carries out statistical disposition to data. Statistical analysis adopts one-way analysis of variance (one-wayANOVA), and p < 0.05 is statisticsLearn difference and have conspicuousness.
3, the powerful former medicine of gastrodia elata-cortex capsule of result normal rat gavage or test medicine 1,2,3,4, after 54 weeks, get blood and carry outExtracorporeal platelet aggregation experiment. Result shows: with the platelet aggregation rate of the external ADP of rats in normal control group and thrombin inductionRelatively, give former medicine and 5 kinds of test medicines and all can significantly reduce the platelet aggregation rate of ADP and thrombin induction. The results detailed in Table1, table 2.
4, the powerful former medicine of gastrodia elata-cortex capsule of conclusion and test medicine 1,2,3,4,5 all have the work that suppresses platelet aggregationWith.
The inhibitory action (mean ± SD, N=10) of the platelet aggregation of table 1 to normal rats in vitro ADP induction
| Group | Dosage | The platelet aggregation rate (%) of ADP induction |
| Normal group | -- | 55.70±5.65 |
| Former medicine group | 350mg/kg | 42.51±8.22** |
| 1 group of test medicine | 300mg/kg | 44.49±7.98* |
| 2 groups of test medicines | 67mg/kg | 49.64±13.74 |
| 3 groups of test medicines | 283mg/kg | 43.43±12.69** |
| 4 groups of test medicines | 70mg/kg | 45.29±8.79* |
| 5 groups of test medicines | 89mg/kg | 41.94±13.10** |
Note: administration group VS normal group, * P < 0.05, * * P < 0.01.
The inhibitory action (mean ± SD, N=10) of the platelet aggregation of table 2 to normal rats in vitro thrombin induction
| Group | Dosage | The platelet aggregation rate (%) of Thrombin induction |
| Normal group | -- | 85.00±8.46 |
| Former medicine group | 350mg/kg | 44.64±21.62** |
| 1 group of test medicine | 300mg/kg | 45.55±24.55** |
| 2 groups of test medicines | 67mg/kg | 47.36±27.44** |
| 3 groups of test medicines | 283mg/kg | 46.61±20.93** |
| 4 groups of test medicines | 70mg/kg | 43.95±21.72** |
| 5 groups of test medicines | 89mg/kg | 44.87±19.43** |
Note: administration group VS normal group, * * P < 0.01.
5, overall merit: although 5 kinds of test medicines (new technology) are suppressing the effect of platelet aggregation without conspicuousness with former medicineDifference does not have trend of obvious reduced but test medicine 1 group (new technology 1) and test medicine 3 groups (new technologies 3) on dosage, saysBright little to changing technique (reduction medication dose) directive significance, test medicine 2 groups (new technologies 2) is although obvious on dosageReduce, but pharmacological action is not as other groups (other new technologies), may adopt macroporous resin purification to process active principle is damagedConsume too large, so this method is not suitable for this product technology of preparing, test medicine 4 groups (new technologies 4) and test 5 groups of (new technology 5) results of medicineComparatively desirable, but 5 groups of inhibitory action at the platelet aggregation to normal rats in vitro ADP induction of test medicine are than test medicine 4Obviously, its reason is that after rhizoma Gastrodiae alcohol extracting, the dregs of a decoction do not utilize to group, possible loss water soluble ingredient, consider, selects the 5th kind newlyProcess route is as the process modification research direction of powerful gastrodia elata-cortex capsule, i.e. rhizoma Gastrodiae alcohol extracting, and the dregs of a decoction and other medicinal materials mergeWater extract-alcohol precipitation.
(3) pharmacodynamics confirmatory experiment object: the former medicine of known powerful gastrodia elata-cortex capsule is clinically for after headstrokeLose the diseases such as the ache tendon and vessel that causes of disease, extremity numbness, inconvenient walking, waist and leg ache, headache and dizziness, there is good curative effect, andCan improve Patients with Stroke Hemorheology and suppress platelet aggregation. The former medicine of powerful gastrodia elata-cortex capsule is to platelet aggregationHave inhibitory action, this experiment, with the positive contrast medicine of the former medicine of powerful gastrodia elata-cortex capsule, is observed powerful gastrodia elata-cortex capsule testMedicine 5 (hereinafter to be referred as test medicine) to intraluminal middle cerebral artery occlusion in rats block 2 hours/reperfusion injury neuroprotection and to brainThe impact of the rheology of apoplexy rat blood and platelet aggregation.
1, experiment material
1.1 animal used as test Sprague-Dawley (SD) rats, male, body weight 280-320g, clean level, by University Of SuzhouMedical college's Experimental Animal Center provide (production licence XCYK (Soviet Union): No2002-0008, occupancy permit SYXK (Soviet Union):No2002-0037. Feeding conditions is as follows: six cages, 22 DEG C of room temperatures, humidity 50-60%, well-ventilated, manually (12h/ round the clock12h), the water of freely ingesting. Before experiment, animal is adapted in feeding environment to 1 week.
1.2 laboratory apparatus TYXN-96 multifunctional intellectual blood pool instrument, Shanghai General Machinery & Electric technology Inst.; 80-2 platformFormula low speed centrifuge, operating theater instruments factory of Shanghai Medical apparatus Co., Ltd.
The powerful former medicine of gastrodia elata-cortex capsule of 1.3 medicines and reagent and powerful gastrodia elata-cortex capsule test medicine 5 (are carried by seminarFor) distilled water is made into suspension; (DihydrogenPhosphate traditional Chinese medicines group produces sodium dihydrogen phosphate, lot numberF20090624); Sodium hydrogen phosphate (DisodiumPhosphate traditional Chinese medicines group produces, product batch number 20090915); The acid of Chinese holly edgeSodium (reagent one factory in SodiumCitrate Shanghai produces, product batch number 96-02-03); (solarbio produces ADP, product batch numberA8290); Fibrin ferment (Thrombin) (Sigma produces product batch number 9002-04-4).
2, experimental technique
60 of the healthy male SD rats of 2.1 experimental designs, body weight 280-320g, intends being divided into 6 groups, 10 every group, is respectivelySham-operation group, ischemia/reperfusion control group, (former medicine group, 350mg/kg are equivalent to day clothes to the former medicine group of powerful gastrodia elata-cortex capsuleAmount 4.2g) and test medicine 178mg/kg group (being equivalent to a day dosing 2.14g), 89mg/kg group (being equivalent to a day dosing 1.07g) and44.5mg/kg (being equivalent to a day dosing 0.535g). Within after cerebral ischemic reperfusion in rats 2 hours, carry out behaviouristics scoring according to 6 point-scores,According to behaviouristics scoring (table 1), rat is assigned to ischemia/reperfusion control group and each administration group at random. Then the powerful rhizoma Gastrodiae of gavageThe former medicine of eucommia bark capsules and test medicine, sham-operation group and model group rat are pressed 0.2ml/100g gavage distilled water, every day 1 time, continuous 4Week. Rat is in preoperative and postoperative 1d, 3d, 7d, 14d, 21d and adopt CornerTest and two kinds of sides of CylinderTest for 28 daysMethod is measured nervous symptoms, and measures weekly body weight once, and rat last (postoperative 28 days) administration is abdominal aortic blood survey after 2 hoursDetermine high, medium and low viscosity, plasma viscosity, fibrinogen, packed cell volume, erythrocyte sedimentation rate, the erythrocyte aggregation index, red thin cut of whole bloodThe maximum gathering of blood platelet of the hemorheology indexs such as born of the same parents' rigidity index and erythrocyte electrophoresis index and ADP and thrombin inductionRate; And after broken end gets rat whole brain and take a picture, brain is cut into 5 with specific rat brain mould, every is thick is 3mm, after photographMeasure the volume of the remaining brain tissue of damage side. Then brain sheet is fixed with 4% formaldehyde, after row FFPE, done HE dyeing, light microscopicThe degree of impairment (Fig. 1) of lower observation damage side brain tissue nerve cell.
The each group of table 1 rat ischemia 2 hours/pour into again nervous symptoms scoring after 2 hours (N＝10)
2.2 set up intraluminal middle cerebral artery occlusion in rats blocks and pours into cerebral ischemic model with 4% chloraldurate (350mg/kg, ip) fiber crops againAfter liquor-saturated, rat back of the body position is fixing, neck median incision, separates right carotid and wears 2 sutures for subsequent use, then separates in neck, outside neckArtery, and ligation external carotid artery. At the arteria carotis communis proximal part suture ligature having separated, distal end is blocked blood with artery clampStream, between this, cuts an osculum, and the nylon wire (4-0) that one end is heated into round bead shape (diameter < 0.3mm) inserts osculum, goesFall artery clamp, nylon wire is slowly pushed into arteriae cerebri initiating terminal (18-19mm), supply to make by the blood of blocking-up arteria cerebri mediaBecome arteria cerebri media ischemic, ischemic pours into after two hours again. Skin suture. Sham-operation tissue separates artery but plug wire not. WholeIndividual anestheticing period, adopt automatic temperature control heating pad by the temperature control of rat anus at 37 ± 0.5 DEG C.
2.3 rat behaviors are learned and are measured rat cerebral ischemias 2 hours/pour into again and within latter 2 hours, carry out behaviouristics according to 6 point-scores and commentDivide [6]: 0 point: there is no neurologically handicapped. 1 point: block branch hole eyelid and dwindle or the not tensible of homonymy forward pawl. 2 points: animal persistenceTurn great circle to homonymy. 3 points: animal is persistent turns ringlet or repeated to same sideway swivel to homonymy. 4 points: animal almost liesMotionless at offside. 5 points: Animal Anesthesia is dead after recovering. Rat is in preoperative and postoperative 1d, 3d, 7d, 14d, 21d and adopting for 28 daysTwo kinds of methods of CornerTest and CylinderTest are measured nervous symptoms, CornerTest (angle method of testing): ratBe placed in the middle of the cardboard that is angle, after rat deeply enters, can be forward or to enterprising enter, then turn to other end opening. countingRat deflection number of times. every mouse is tested 20 times. Then calculate the ratio of turn right number of times and total degree. Rat has only hadEntirely turn to the back side just to calculate effectively. CylinderTest: rat is placed in cylinder barrel, observes rat and do vertical along cylinder barrel wallAbout when straight motion, the access times of limb, measure in 10 minutes 20 times altogether. Final scoring is with (before non-damage forelimb motion-damageThe motion of limb forelimb)/(+2 motions of non-damage forelimb motion) meter.
The mensuration rat broken end of the remaining brain tissue volume of 2.4 Damage of Rats side is got brain, removes olfactory bulb, cerebellum and low level brainDry, be divided into 5 with crown 4 cuttves of cutting of specific rat brain mould, the first cutter is the utmost point and optic chiasma line midpoint before brain, the second cutterAt optic chiasma position, the 3rd cutter is at infundibular stalk place, four blade infundibular stalk and leaf tail and between. Every thick is 3mm, after taking a picture, surveysThe volume of the remaining brain tissue of side is hindered in setting loss, represents to damage side brain tissue volume/non-damage side brain tissue volume.
2.5 hemorheological mensuration rat last (postoperative 28 days) administrations after 2 hours abdominal aorta get whole blood, adoptHigh, medium and low viscosity, plasma viscosity, the fibrinogen, red cut of MVIS-2000 fully automatic blood rheological analysis system measurement whole bloodThe hemorheology indexs such as cell pack, erythrocyte sedimentation rate, erythrocyte aggregation index, Rigidity of red cells exponential sum erythrocyte electrophoresis index.
The mensuration rat of 2.6 platelet aggregations time (postoperative 28 days) administration after 2 hours abdominal aortic blood to measure blood littleThe MA of plate. Follow these steps to operation: (1) anti-coagulants adopts 3.28% Chinese holly edge acid, the ratio of blood drawing amount and anti-coagulantsShould be 9: 1, mix immediately 2～3 times. (2) obtain sample be PRP (being rich in hematoblastic blood plasma) under 20～25 degree conditions fromHeart speed is with 500r/mIn, and time 5Min left and right, uses horizontal type centrifuger. (3) treat slowly natural stall of centrifuge, then take out,In order to avoid in cell inflow PRP, as still contained RBC centrifugal a moment under these conditions in discovery PRP. Aggregation inducing agent with ADP withFibrin ferment, measures blood platelet MA.
2.7 statistical analysis data are with means standard deviationRepresent. Corresponding journey in application SPSS (10.0 editions)Order, carries out statistical disposition to data. Statistical analysis adopts one-way analysis of variance (one-wayANOVA), and P < 0.05 is statisticsLearn difference and have conspicuousness.
3, result
The improvement that the former medicine of 3.1 powerful gastrodia elata-cortex capsule and test medicine are learned symptom to Cerebral Ischemia/Reperfusion rat behavior is doneWith. CornerTest result shows: the ischemia-reperfusion control rats percentage sham-operation group that (strong side) turns to the rightObviously increase. Compared with ischemia-reperfusion control rats, with gavage time lengthening, former medicine 350mg/kg and test medicine 178mg/The number of times that kg and 89mg/kg rat are turned to the right significantly reduces, and postoperative gavage 3-7d starts onset, postoperative gavage 28d ratThe number of times of turning to the right reduces the most obvious. Test medicine 44.5mg/kg rat onset time is postoperative gavage 14d, and gavage 28d subtractsFew the most remarkable. The results detailed in Table 1. Cylindertest result shows: ischemia-reperfusion control rats is due to left limb meritDysfunction, the number of times ratio of the strong side forelimb (right side forelimb) of use is done evil through another person, and group is obvious to be increased; With ischemia-reperfusion control rats phaseRatio, with gavage time lengthening, the rat 178mg/kg and the 89mg/kg right side forelimb access times that give former medicine and test obviously subtractFew, the forelimb of getting involved (left side forelimb) access times obviously increase. Postoperative gavage 14d starts onset, and postoperative gavage 28d effectObviously. The results detailed in Table 2. Results suggest: the former medicine of powerful gastrodia elata-cortex capsule and test medicine are to cerebral ischemia/reperfusion injury ratBehaviouristics defect has improvement effect.
The former medicine of 3.2 powerful gastrodia elata-cortex capsule and test medicine lack the brain that affects of cerebral ischemia/reperfusion injury rat body weightThe body weight recruitment of postoperative first week each group rat of blood/reperfusion injury is all very little, increases in time, gives former medicine and test medicineThe rat body weight increase of 178mg/kg and 89mg/kg is obviously fast compared with ischemia/reperfusion control group. But test medicine 44.5mg/kg ratBody weight increases with ischemia/reperfusion control group without significant difference. The results detailed in Table 2. Results suggest: powerful gastrodia elata-cortex capsule is formerMedicine and test medicine can promote the recovery of cerebral ischemia/reperfusion injury rat body weight.
The former medicine of 3.3 powerful gastrodia elata-cortex capsule and the impact of test medicine on Cerebral Ischemia/Reperfusion Damage of Rats side brain volume.Ischemia Injury is damaged in early days owing to there being obvious encephaledema according to the literature, and damage side brain tissue volume obviously increases.And there is remarkable atrophy, smaller volume at cerebral ischemic injury later stage (after cerebral ischemia 4 weeks) damage side brain tissue. Therefore, brain lacksThe courageous and upright damage later stage measure the remaining brain tissue volume of damage side can between react the degree of injury of brain tissue. With bibliographical information oneCause, originally studies have shown that brain tissue atrophy is surveyed in damage in 4 weeks after cerebral ischemia/reperfusion injury of rats, volume obviously diminishes, and gives formerThe Damage of Rats side brain tissue volume of medicine and test medicine 178mg/kg and 89mg/kg significantly increases compared with ischemia/reperfusion control group. GivePrediction reagent 44.5mg/kg rat also makes to damage side brain tissue volume to be increased to some extent, but does not reach the level of signifiance statistically.The results detailed in Table 4. Results suggest: the former medicine of powerful gastrodia elata-cortex capsule and the brain tissue of test medicine to cerebral ischemia/reperfusion injuryThere is protective effect.
The impact that the former medicine of 3.4 powerful gastrodia elata-cortex capsule and test medicine change Cerebral Ischemia/Reperfusion cerebral morphology.HE coloration result shows: cerebral ischemia/reperfusion injury of rats is after 4 weeks, and the cell number of damage zone brain tissue is obviously less, and givesThe cell number of the Damage of Rats district brain tissue of former medicine and test medicine 178mg/kg and 89mg/kg is remarkable compared with ischemia/reperfusion control groupIncrease. The former medicine of powerful gastrodia elata-cortex capsule and test medicine can improve Cerebral Ischemia/Reperfusion rat cerebral tissue morphology.
The former medicine lattice test of 3.5 powerful gastrodia elata-cortex capsule medicine is done the improvement of Cerebral Ischemia/Reperfusion hemorheology of ratChange with generation, the development of cerebral infarction and have close relationship by Hemorheology. Patient or rat after headstroke according to the literatureIts Hemorheology occurs abnormal, shows as blood viscosity rising, erythrocyte aggregation increase, and fibrinogen content increasesDeng. Consistent with bibliographical information, after cerebral ischemia/reperfusion injury of rats, the 4 weeks high, medium and low viscosity of cutting of rat whole blood is all compared with sham-operation groupObviously raise, fibrinogen content and packed cell volume also significantly increase, though erythrocyte aggregation index and rigidity index are to some extentIncrease, but do not reach the level of signifiance statistically. The former medicine of powerful gastrodia elata-cortex capsule and test medicine 178m/kg and 89mg/kgGavage all can significantly reduce the high, medium and low viscosity of cutting of whole blood in 4 weeks, and obviously reduce fibrinogen content and reduce packed cell volume,Test medicine 178mg/kg and 89mg/kg can also significantly reduce the rigidity index of erythrocyte aggregation index. Test medicine 44.5mg/kgAlso be improved the trend that hemorheology of rat is sent out, but in whole blood, cut the remarkable reduction of viscosity, other indexs all do not reach statisticsThe level of signifiance on. The results detailed in Table 5. Results suggest: the former medicine of powerful gastrodia elata-cortex capsule and test medicine are to cerebral ischemia/fill with againNote hemorheology of rat has improvement effect.
The former medicine of 3.6 powerful gastrodia elata-cortex capsule and test medicine to normal rat and Cerebral Ischemia/Reperfusion rats in vitro ADP andThe inhibitory action of the platelet aggregation of fibrin ferment (Thrombin) induction. The powerful former medicine of gastrodia elata-cortex capsule of normal rat gavage orTest medicine, after 4 weeks, is got blood and is carried out extracorporeal platelet aggregation experiment. Give former medicine and test medicine rat ADP and thrombin inductionPlatelet aggregation rate all obviously reduces, and test medicine group is dose dependent. The results detailed in Table 6, table 7. Further experiment is seenExamine the former medicine of powerful gastrodia elata-cortex capsule and test medicine Cerebral Ischemia/Reperfusion rats in vitro ADP and fibrin ferment (Thrombin) are luredThe impact of the platelet aggregation of leading. The powerful former medicine of gastrodia elata-cortex capsule of Cerebral Ischemia/Reperfusion rat oral gavage or test medicine are got blood for 4 weeksCarry out extracorporeal platelet aggregation experiment. Result shows: Cerebral Ischemia/Reperfusion rat is by the platelet aggregation of ADP and thrombin inductionCollection rate is all significantly higher than sham-operation group, and the platelet aggregation rate that gives former medicine and test medicine rat ADP and thrombin induction compares brainIschemia/reperfusion rat all obviously reduces, and test medicine group is dose dependent. The results detailed in Table 8, table 9. Results suggest: strongThe former medicine of power gastrodia elata-cortex capsule and test medical instrument have the effect that suppresses platelet aggregation.
Table 2 is learned the improvement effect (mean ± SD, N=10) of symptom to Cerebral Ischemia/Reperfusion rat behavior
Note: ischemia/reperfusion control group VS sham-operation group,##P < 0.01; Administration group VS ischemia/reperfusion control group, * * P <0.01。
The impact (mean ± SD, N=10) of table 3 on Cerebral Ischemia/Reperfusion rat body weight
Note: ischemia/reperfusion control group VS sham-operation group,##P < 0.01; Administration group VS ischemia/reperfusion control group, * P <0.05，**P＜0.01。
Table 4 is surveyed the impact (mean ± SD, N=10) of brain volume on Cerebral Ischemia/Reperfusion Damage of Rats
Note: ischemia/reperfusion control group VS sham-operation group,##P < 0.01; Administration group VS ischemia/reperfusion control group, * * P <0.01。
The improvement effect (mean ± SD, N=10) of table 5 to Cerebral Ischemia/Reperfusion hemorheology of rat
Note: ischemia/reperfusion control group VS sham-operation group,##P < 0.01; Administration group VS ischemia/reperfusion control group, * P <0.05，**P＜0.01。
The inhibitory action (mean ± SD, N=10) of the platelet aggregation of table 6 to normal rat ADP induction
Note: administration group VS normal group, * * P < 0.01.
The inhibitory action (mean ± SD, N=10) of table 7 to normal rat thrombin induction platelet aggregation
Note: administration group VS normal group, * * P < 0.01.
The inhibitory action (mean ± SD, N=10) of the platelet aggregation of table 8 to ischemia/reperfusion rat ADP induction
Note: ischemia/reperfusion control group VS sham-operation group,##P < 0.01; Administration group VS ischemia/reperfusion control group * * P <0.01。
Table 9 is to Cerebral Ischemia/Reperfusion rat fibrin ferment (Thrombin)
The inhibitory action (mean ± SD, N=10) of the platelet aggregation of induction
Note: ischemia/reperfusion control group VS sham-operation group,##P < 0.01; Administration group VS ischemia/reperfusion control group * * P <0.01。
4, conclusion: in test medicine (new technology preparation), dosage blocks 2 hours/reperfusion injury to intraluminal middle cerebral artery occlusion in ratsNeuroprotection and the impact on the rheology of headstroke rat blood and platelet aggregation thereof and former medicine there was no significant difference, have increasingStrong trend, but test medicine (new technology preparation) high dose group is obviously better than former medicine, for process modification innovation provides feasible reliableTheoretical foundation.
Two, preparation process thereof and quality comparative study
(1) Study on Preparation
1, prescription: rhizoma Gastrodiae 139.2g, the bark of eucommia (salt system) 147.8g, wild aconite root 17.4g, monkshood (system) 17.4g, levisticum86.8g, Jehol Ligusticum Rhizome 102.6g, radix scrophulariae 102.6g, Radix Angelicae Sinensis 174g, glutinous rehmannia 278.2g, radix cyathulae 102.6g, mistletoe 102.6g, Qiang174g lives.
2, method for making: get prescription medicinal material, rhizoma Gastrodiae adds 5 times of amount 50% alcohol refluxs and extracts 3 times, each 2 hours, merge, filter,Ethanol extract is for subsequent use, the dregs of a decoction are for subsequent use, levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four tastes add 6 times of water gagings and extract 6 little through steam distillationTime, separate, obtain volatile oil for subsequent use, the aqueous solution filters for subsequent use, the dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia, radix aconiti agrestis, monkshood, radix scrophulariae, glutinous rehmannia,Radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, filter, merge above-mentioned water-solubleLiquid, the liquid that it is 1: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to make solution contain alcohol amount and reaches 60%, leaves standstill12 hours, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaim ethanol and be concentrated into relative density be 1.25～The medicinal extract of 1.35 (60 DEG C) is for subsequent use; Taking polyethylene glycol-6000 and PEG-4000 mix heating and melting, add volatile oil, soakCream, stirs, and is transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, and dripping becomes ball, de-oiling, and low temperature drying, filling, make1000, to obtain final product.
3, technological process:
4, extraction, purifying process research
4.1 Extraction Process of Volatile Oils are preferred
The investigation of the amount of 4.1.1 adding water doubly, in prescription ratio, takes levisticum 43.4g, Jehol Ligusticum Rhizome 51.3, Radix Angelicae Sinensis 87g, notopterygium root 87gDeng four traditional Chinese medicine material, get altogether three parts, every part of 268.7g, adds respectively 4 times of amounts, 5 times of amounts, 6 times of water gaging distillating extracting oils, respectively carriesGet 5 hours, receive distillate, with petroleum ether condenser pipe and volatile oil extractor inwall, merge benzinum liquid and oil-water fluid,With petroleum ether extraction three times, each 15ml, merges benzinum liquid, filters, with 10ml petroleum ether with anhydrous sodium sulfate dehydrationFunnel, low temperature is waved loose benzinum to constant weight, weighs the weight of volatile oil, to obtain final product. The results are shown in Table 1.
The investigation of table 1 amount of adding water doubly
| Doubly amount adds water | The amount (g) of volatile oil |
| 4 times of amounts | 1.5742 |
| 5 times of amounts | 1.6047 |
| 6 times of amounts | 1.6125 |
As seen from the experiment, the 4 times of amounts of measuring gained volatile oil that add water are lower; The 5 times of amounts that add water and 6 times of amount gained volatile oilAmount substantially suitable, and what all add water 4 times of amounts is many. Determine that therefore last the doubly amount that adds water is 5 times of amounts.
4.1.2 pretreatment mode, in prescription ratio, takes levisticum 43.4g, Jehol Ligusticum Rhizome 51.3, Radix Angelicae Sinensis 87g, notopterygium root 87g etc. fourTaste medicinal material, gets three parts altogether, every part of 268.7g, and totally three parts, every part all adds 5 times of water gagings, and first part of direct distillating extracting oil 5 is littleTime, second part of first cold soaking 1 hour, redistillation is extracted volatile oil 5 hours, and the 3rd part is first heated to 80 DEG C of temperature and soaks 1 hour, redistillationExtract volatile oil 5 hours, receive respectively distillate, with petroleum ether condenser pipe and volatile oil extractor inwall, merge oilEther liquid and oil-water fluid, with petroleum ether extraction three times, each 15ml, merges benzinum liquid, filter with anhydrous sodium sulfate dehydration, with10ml petroleum ether funnel, and low temperature waves loose benzinum to constant weight, weighs the weight of volatile oil, to obtain final product; Gained volatile oil is anotherDevice is collected for subsequent use. The results are shown in Table 2.
The investigation of table 2 pretreatment mode
| Pretreatment mode | The amount (g) of volatile oil |
| Directly distillation is extracted | 1.5984 |
| First cold soaking 1 hour, redistillation is extracted | 1.6077 |
| First 80 DEG C of temperature are soaked 1 hour, and redistillation is extracted | 1.6294 |
As seen from the experiment, be first heated to 80 DEG C of temperature and soak 1 hour, the extraction efficiency that volatile oil is extracted in redistillationHeight, determines that therefore last being first heated to 80 DEG C of temperature soaks 1 hour, and redistillation is extracted volatile oil 5 hours.
4.1.3 the investigation of distillation time, in prescription ratio, takes levisticum 43.4g, Jehol Ligusticum Rhizome 51.3, Radix Angelicae Sinensis 87g, notopterygium root 87gDeng four traditional Chinese medicine material, get altogether three parts, every part of 268.7g, totally three parts, add respectively 5 times of water gagings, be first heated to 80 DEG C of temperature and soak 1 hour, thenDistillation is extracted 4 hours, 5 hours, 6 hours respectively, receives distillate, in petroleum ether condenser pipe and volatile oil extractorWall, merges benzinum liquid and oil-water fluid, and with petroleum ether extraction three times, each 15ml, merges benzinum liquid, with anhydrous sodium sulfateDehydration filters, and with 10ml petroleum ether funnel, and low temperature waves loose benzinum to constant weight, weighs the weight of volatile oil, to obtain final product; InstituteObtaining the another device of volatile oil collects for subsequent use. The results are shown in Table 3.
The investigation of table 3 distillation time
| Distillation time | The amount (g) of volatile oil |
| 4 hours | 1.5943 |
| 5 hours | 1.6239 |
| 6 hours | 1.6287 |
As seen from the experiment, because distillation is insufficient, the amount of 4 hours gained volatile oil of distillation is lower; Distill 5 hours withThe efficiency of 6 hours is substantially suitable, for saving time and the energy, determines and selects distillation 5 hours. Comprehensive above test, this preparationExtraction Process of Volatile Oil is: get four tastes such as levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root and add 5 times of water gagings, being heated to 80 DEG C of temperature soaked after 1 hour,Distillation is extracted 5 hours. In large production, because being difficult for extracting, volatile oil makes, and in production, volatile oil yield is extremely low. For making this workSkill more adapts to the large needs of producing, and in this product, the four taste distillations such as levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root are extracted 6 hours, receive distillate,Add 20% sodium chloride, put in freezer and leave standstill refrigeration 24 hours, make profit layering, point get volatilization oil reservoir, to obtain final product.
4.2 rhizoma Gastrodiae alcohol extraction processes are preferred
4.2.1 determining alcohol is investigated the content assaying method with reference to rhizoma Gastrodiae in Chinese pharmacopoeia version in 2010, uses respectively 30% secondAlcohol, 50% ethanol, 70% alcohol reflux extract 3 hours, measure the content of Gastrodin in Rhizoma Gastrodiae, the results are shown in Table 4.
The investigation of table 4 rhizoma Gastrodiae technique
| Determining alcohol (%) | Gastrodin content (mg/g) |
| 30 | 2.495 |
| 50 | 2.605 |
| 70 | 2.505 |
As seen from the experiment, the content of Gastrodin in Gastrodia eleta Bl. has certain difference with extracting solvent strength difference; WithWhen 50% alcohol extract, content is the highest, identical with Diluted Alcohol with official method, therefore select the alcohol extracting taking 50% ethanol as rhizoma GastrodiaeConcentration.
4.2.2 other alcohol extracting factors are investigated
(1) factor that factor level establishment impact is extracted mainly contains the following aspects: alcohol adding amount, extraction time, extractionNumber of times etc. Therefore we have carried out the orthogonal investigation of 3 factor 3 levels to these three principal elements, with preferred optimal processing parameter.The factor level table of orthogonal test is in table 5.
Table 5 rhizoma Gastrodiae alcohol extracting orthogonal test factor level table
(2) index is selected with evaluation result using the extracted amount of Gastrodin in extract as orthogonal test evaluation index; DryCream yield directly affects the regulation that day takes dosage and single oral dose, therefore also using it as one of orthogonal test evaluation index. This examinationTest that to intend adopting comprehensive scoring method to carry out process conditions preferred, due to dry cream yield with day take dosage and single oral dose is relevant, specifyIts balance is divided into 40 points, and active ingredient in the Gastrodin side of being can directly reflect extraction effect, therefore specify the balance of these two indexsDivide and be 60 points.
(3) 50g rhizoma Gastrodiae meal is got in sample preparation, carries out alcohol extracting by the each orthogonal test condition of table 6, and extract concentrates and determinesHold to 100ml, for subsequent use.
(4) Gastrodin extracted amount mensuration is got reserve liquid 2ml and is settled to 25ml, measures gastrodin content, calculating GastrodinExtracted amount.
(5) dry cream yield is measured the accurate liquid 20ml of each orthogonal test after concentrated that get, and puts respectively and has been dried to constant weightIn evaporating dish, water bath method, residue in 105 DEG C dry 3 hours, take out, put in drier and place 30 minutes, weigh, calculate dryCream yield. The results are shown in Table 6.
Table 6 rhizoma Gastrodiae alcohol extracting orthogonal experiments table
Note: dry cream yield scoring=(dry cream yield/maximum dry cream yield) × 40
Gastrodin extracted amount scoring=(Gastrodin extracted amount/maximum Gastrodin extracted amount) × 60
Comprehensive grading=dry cream yield scoring+Gastrodin extracted amount scoring
Table 7 rhizoma Gastrodiae alcohol extracting analysis of variance table
| Soruces of variation | Quadratic sum | The free degree | All sides | F value | Factor impact |
| Alcohol adding amount A | 255.06 | 2 | 127.53 | 4.26 | Not remarkable |
| Extraction time B | 46.45 | 2 | 23.22 | 0.77 | Not remarkable |
| Extraction time C | 1226.33 | 2 | 613.16 | 20.46 | Significantly |
| Error | 23.63 | 2 | 0.06 |
Note: F0.05(2，2)＝19.00；F0.01(2，2)＝99.00
From table 6,7 analysis results, each factor effect primary and secondary is C > A > B; C is because have significant difference, in A factorA3＞A2＞A1So, select A3; B in B factor2＞B3＞B1So, select B2; C in C factor3＞C2＞C1So, select C3。Therefore optimised process is A3B2C3. Consider that production reality and factor affect difference, intend rhizoma Gastrodiae alcohol extraction process for adding 5 times of amounts 50%Ethanol, extracts 3 times, extracts 2 hours at every turn.
4.3 extraction process by water are preferred
4.3.1 factor level is established the factor that affects water extraction and is mainly contained the following aspects: amount of water, extraction time, carryGet number of times etc. Therefore we have carried out the orthogonal investigation of 3 factor 3 levels to these three principal elements, with preferred optimised process ginsengNumber. The factor level table of orthogonal test is in table 8.
Table 8 water extraction orthogonal test factor level table
4.3.2 index selects extracted amount using Gastrodin in extract as orthogonal test evaluation index; Prescription Chinese medicineAlso contain the fat-soluble active ingredients such as phenols, terpene, alkaloid, in order fully to reflect extraction effect, we measure in extractThe content of 60% ethanol soluble extraction, and also make orthogonal test evaluation index with it; In addition, dry cream yield is also to evaluate extraction effectConventional index, therefore also using it as one of orthogonal test evaluation index. This test intended adopts comprehensive scoring method to carry out technique barPart is preferred, due to dry cream yield and effect amount not proportional, specify that its balance is divided into 20 points, Gastrodin and 60% ethanol leachActive ingredient in the thing side of being, can directly reflect extraction effect, is 40 points therefore specify that the balance of these two indexs divides.
4.3.3 1/5 recipe quantity medicinal material is got in sample preparation, and part medicinal material, after 1,2 techniques are extracted, is collected the dregs of a decoction, by table 8Each orthogonal test condition is carried out water extraction, and liquid, with after 300 order filter-cloth filterings, concentrates and be settled to 500ml. For subsequent use.
4.3.4 Gastrodin extracted amount mensuration is got reserve liquid 10ml and is settled to 25ml, measures gastrodin content, calculates rhizoma GastrodiaeThe extracted amount of element.
4.3.5 dry cream yield is measured the accurate liquid 20ml getting after each orthogonal test concentrates, and puts respectively and has been dried to constant weightEvaporating dish in, water bath method, residue in 105 DEG C dry 3 hours, take out, put in drier and place 30 minutes, weigh, calculateDry cream yield.
4.3.6 reserve liquid 50ml is got in ethanol (60%) determination of extractives, adds respectively ethanol and makes to reach 60% containing alcohol amount, leaves standstillRefrigerate 24 hours, filter, filtrate water bath method, residue in 105 DEG C dry 3 hours, take out, be placed in drier and place 30 pointsClock, weighs, and calculates extract yield. The results are shown in Table 9
Table 9 water extraction orthogonal experiments table
Note: dry cream yield scoring=(dry cream yield/maximum dry cream yield) × 20
60% ethanol soluble extraction scoring=(extract yield/maximum extract yield) × 40
Gastrodin extracted amount scoring=(Gastrodin extracted amount/maximum Gastrodin extracted amount) × 40
Comprehensive grading=dry cream yield scoring+60% ethanol soluble extraction scoring+Gastrodin extracted amount scoring
Table 10 water extraction analysis of variance table
| Soruces of variation | Quadratic sum | The free degree | All sides | F value | Factor impact |
| A | 2.26 | 2 | 1.13 | 0.01 | Not remarkable |
| B | 3098.34 | 2 | 1549.17 | 19.41 | Significantly |
| C | 19.87 | 2 | 9.93 | 0.12 | Not remarkable |
| Error | 159.62 | 2 | 79.81 |
Note: F0.05(2，2)＝19.00；F0.01(2，2)＝99.00
From table 9,10 analysis results, each factor effect primary and secondary is B > C > A; B is because have significant difference, A factorMiddle A2＞A3＞A1So, select A2; B in B factor2＞B3＞B1So, select B2; C in C factor2＞C3＞C1So, selectC2, therefore optimised process is A2B2C2. Consider production cost, so to add 10 times of water gagings, extract 2 times, extract for the first time 3 littleTime, extract 2 hours for the second time.
4.4 alcohol precipitation processes are preferred
4.4.1 factor level is established the factor that affects alcohol precipitation and is mainly contained the following aspects: liquor strength, alcohol precipitation are pure and strongDegree, time of repose etc. Therefore we have carried out the orthogonal investigation of 3 factor 3 levels to these three principal elements, with preferred best workSkill parameter. The factor level table of orthogonal test is in table 11.
Table 11 alcohol precipitation orthogonal test factor level table
4.4.2 evaluation index and preparation method are using the extracted amount of Gastrodin in extract as orthogonal test evaluation index;Prescription Chinese medicine also contains the fat-soluble active ingredients such as phenols, terpene, alkaloid, and this technique has been purified with 60% alcohol precipitation, dry creamYield is directly to reflect alcohol precipitation purification effect, also directly takes the regulation of dosage and single oral dose impact day, therefore also with its work simultaneouslyFor one of orthogonal test evaluation index. It is preferred that this test intended employing comprehensive scoring method carries out process conditions, because dry cream yield is straightConnect impact day and take dosage and single oral dose, can reflect alcohol precipitation purification effect, specify that its balance is divided into 40 points, Gastrodin is Fang ZhongyouEffect composition, can directly reflect extraction effect, is 60 points therefore specify that the balance of these two indexs divides.
4.4.3 recipe quantity medicinal material is got in sample preparation, and part medicinal material, after 1,2,3 techniques are extracted, is collected the dregs of a decoction, each by table 11Orthogonal test condition is carried out water extraction, and liquid, with after 300 order filter-cloth filterings, concentrates and be settled to 500ml. For subsequent use.
4.4.4 Gastrodin extracted amount mensuration is got reserve liquid 2ml and is settled to 25ml, measures gastrodin content, calculates GastrodinExtracted amount.
4.4.5 dry cream yield is measured the accurate liquid 20ml getting after each orthogonal test concentrates, and puts respectively and has been dried to constant weightEvaporating dish in, water bath method, residue in 105 DEG C dry 3 hours, take out, put in drier and place 30 minutes, weigh, calculateDry cream yield. The results are shown in Table 12
Table 12 alcohol precipitation orthogonal experiments table
Note: dry cream yield scoring=(dry cream yield/maximum dry cream yield) × 40
Gastrodin extracted amount scoring=(Gastrodin extracted amount/maximum Gastrodin extracted amount) × 60
Comprehensive grading=dry cream yield scoring+Gastrodin extracted amount scoring
Table 13 alcohol precipitation analysis of variance table
| Soruces of variation | Quadratic sum | The free degree | All sides | F value | Factor impact |
| Liquor strength A | 1334.63 | 2 | 667.31 | 39.64 | Significantly |
| Alcohol precipitation determining alcohol B | 73.90 | 2 | 36.95 | 2.20 | Not remarkable |
| Time of repose C | 42.36 | 2 | 21.18 | 1.26 | Not remarkable |
| Error | 33.67 | 2 | 16.83 |
Note: F0.05(2，2)＝19.00；F0.01(2，2)＝99.00
From table 12,13 analysis results, each factor effect primary and secondary is A > B > C; A is because have significant difference, A factorMiddle A1＞A2＞A3So, select A1; B in B factor3＞B2＞B1So, select B3; C in C factor1＞C2＞C3So, selectC1, therefore optimised process is A1B3C1. Considering production technology reality, is that liquor strength is 1ml liquid so select alcohol precipitation processBe equivalent to 1.0g crude drug in whole, add ethanol to reaching 60% containing alcohol amount, leave standstill 12 hours.
5, preparations shaping technical study
5.1 medicinal extract preparations are prepared by extraction, purifying process. The another device of volatile oil is collected, and medicinal extract part is evaporated toRelative density is 1.25～1.35 (60 DEG C), for subsequent use.
The selection of 5.2 matrix and cooling agent
5.2.1 the selection of cooling agent is by prerun, and during taking atoleine as cooling agent, the sedimentation of ball material is very fast, and moulding is poor; WithWhen dimethicone is cooling agent, the sedimentation of ball material is slower, energy moulding; During taking vegetable oil as cooling agent, the sedimentation of ball material is slow, mouldingPoor; So selecting dimethicone is that cooling agent is better.
5.2.2 the selection of matrix contains the feature of volatile oil and the easy moisture absorption of medicinal extract in conjunction with our clinical practice and prescription, pressesIt is preferred that following table is carried out matrix, with dimethicone be cooling agent, dripping temperature is 60 DEG C, water dropper bore is 1/2mm (inside/outside footpathMm). Taking dispersion situation, mobility and moulding situation as evaluation index, each index is 3 points, 2 points and 1 point by good extremely poor scoring, withAccumulative total scoring is comprehensive grading.
Table 14 Screening matrix result
| Composition | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| Medicine | 50 | 50 | 50 | 50 | 50 | 50 | 60 | 60 | 60 | 60 | 40 | 40 |
| PEG-4000 | 50 | 25 | 0 | 0 | 0 | 25 | 20 | 0 | 0 | 20 | 40 | 20 |
| PEG-6000 | 0 | 25 | 50 | 0 | 25 | 0 | 20 | 40 | 20 | 0 | 20 | 40 |
| PEG-8000 | 0 | 0 | 0 | 50 | 25 | 25 | 0 | 0 | 20 | 20 | 0 | 0 |
| Dispersion situation | 1 | 3 | 2 | 2 | 2 | 2 | 2 | 2 | 2 | 1 | 2 | 2 |
| Mobility | 1 | 2 | 2 | 1 | 1 | 1 | 2 | 1 | 1 | 2 | 1 | 2 |
| Moulding situation | 1 | 1 | 1 | 1 | 2 | 2 | 2 | 2 | 2 | 1 | 2 | 2 |
| Comprehensive grading | 3 | 6 | 5 | 4 | 5 | 5 | 6 | 5 | 5 | 4 | 5 | 6 |
The judge that each proportioning test is carried out, the better proportioning composition of screening has respectively medicine: PEG-4000: PEG-6000(2: 1: 1,3: 1: 1 and 2: 1: 2), consider medicine carrying amount and preparation dose relation, select with PEG-4000: PEG-6000 (1:1) be matrix; Medicine: matrix (3: 2) is molding formula proportioning.
The screening of 5.2 moulding process is taking PEG-4000: PEG-6000 (1: 1) as matrix, and dimeticone is cooling agent drippingBecome ball, taking the weight differential coefficient of variation of dripping pill as index, the internal-and external diameter size of screening water dropper, drip speed, drip apart from and cooling agentTemperature design 4 factor 3 horizontal quadrature screening tests, in table 15. With roundness (minor axis/minor axis), relative mark that ball is heavyAccurate deviation (RSD), yield rate are index, and the optimum determining value of each index is decided to be to 100 points, determine according to the importance of each factorIts balance is divided into 30,30,40, obtains formula: the heavy RSD/ ball of the piller of comprehensive grading=roundness/maximum roundness × 30+ weightRSD × 30+ yield rate/maximum yield rate × 40, result of the test in table 16, variance analysis in table 17.
Table 15 moulding process screening factor level table
Table 16 moulding process screening scheme and result
Table 17 moulding process screening variance analysis
| Soruces of variation | Quadratic sum | The free degree | All sides | F value | Factor impact |
| Coolant temperature (DEG C) A | 628.64 | 2 | 314.32 | 25.97 | Significantly |
| Drip footpath (inside/outside mm/mm) B | 453.46 | 2 | 226.73 | 18.74 | Not remarkable |
| Drip apart from (cm) C | 765.95 | 2 | 382.97 | 31.65 | Significantly |
| Drip speed (d/min) D error | 24.20 | 2 | 12.10 |
Note: F0.05(2，2)＝19.00；F0.01(2，2)＝99.00
From table analysis result, each factor effect primary and secondary is C > A > B > D; A, C be because have significant difference, A factorMiddle A2＞A3＞A1So, select A2; B in B factor1＞B2＞B3So, select B1; C in C factor3＞C2＞C1So, selectC3; D in D factor2＞D3＞D1So, select D2, therefore best moulding process is A2B1C3D2, coolant temperature is 10～15DEG C, water dropper internal-and external diameter is 1/3mm, drips apart from being 10cm, dripping speed is 40/min.
4.3 pilot scale researches are got 20 times of recipe quantity medicinal materials, by work out to such an extent that process route carries out middle trial production, to production workSkill index is carried out comprehensive assessment, and medicinal material and finished product are carried out to performance rating, and each main active ingredient is followed the tracks of to detection, resultIn table 18.
Table 18 pilot plant test result
Middle trial production result shows, the every technical parameter of this product is stable, and feasible process be described, is applicable to producing in batches.
(2) 10 times of recipe quantity medicinal materials are got in quality comparative study, make finished product by former preparation process thereof; Separately getting 10 times locatesSide's amount medicinal material, makes finished product by improving technique, and simulation listing packaging, adopts constant temperature accelerated test (T=37 DEG C, RH=75%) rightTwo kinds of products are done comprehensive comparative study, the results are shown in following table 18, table 19.
Table 18 technique comparative illustration
Table 19 different process manufactured goods quality stability comparing result
Three, preparation pharmacodynamics experimental study
A brute force day eucommia bark capsules (concentrated type) is the new drug of Sanli Pharmaceutical Co., Ltd., Guizhou's development, main containing skyThe compositions such as fiber crops, the bark of eucommia. The court is entrusted by the said firm, and the anti-cerebral ischemia pharmacological action of powerful gastrodia elata-cortex capsule is testedObserve, now experiment observed result be reported as follows:
(1) test material
1. medicine and reagent are subject to reagent: powerful gastrodia elata-cortex capsule is by client Guizhou three power pharmacy Limited Liability public affairsDepartment provides, lot number: 2009001, and state: evenly micropill shape; Quantity: 8kg; Positive control drug is the powerful gastrodia tuber eucommia glue of former preparationCapsule, is produced by Sanli Pharmaceutical Co., Ltd., Guizhou, lot number: 100306; State: homogeneous powder powder; Quantity: 5kg. Be subject to reagentAll face the used time with positive drug and be made into suspension with distilled water. Red tetrazolium (TTC) is that Shanghai Ling Jin Fine Chemical Co., Ltd producesProduct, lot number: 20050508.
2. animal SD male rat, body weight 250 ± 30g; Kunming mouse, male and female half and half, body weight 20 ± 2g, by Soviet UnionState university medical board Experimental Animal Center provides, the quality certification number: 2007003.
3. instrument LBY-NJ2 type platelet aggregation instrument (Beijing Pu Sheng instrument company), 7170 automatic clinical chemistry analyzers(HIT), BS110S precise electronic balance (Beijing Sai Duolisi joint-stock company), SHA-C temperature controlled water bath oscillator(all over the country industrial corporation in Shenzhen), LXB-B low speed large capacity centrifuge (Town in Shanghai booth instrument and equipment factory), FASCO type is certainly completeMoving quick blood viscosity analyzer (the how biological Gong Wu of University Of Chongqing's dimension research institute).
(2) method and result
1. the resistance to anoxic experiment of mouse
1.1 on the resistance to anoxic of mouse normal pressure affect 50 of mouse, be divided at random 5 groups, i.e. powerful day of blank group, reagentFiber crops eucommia bark capsules low dose group (0.375g/kg), middle dosage group (0.75g/kg), high dose group (1.5g/kg), original product group(0.48g/kg) 10 every group. Gastric infusion, once a day, successive administration 7 days, 1h after time administration, is not placed in mouse respectivelyIn 250ml wide-mouth bottle, in bottle, place 10g soda lime, seal bottleneck with vaseline. Measure mouse stops from being closed to breathe in bottleTime only, result and the comparison of blank group, with t test and judge, it has there was no significant difference. Result shows, with control group ratio, low, the middle dosage group of powerful gastrodia elata-cortex capsule extended to some extent to the mouse survival time, but without obvious significant difference (P >0.05), high dose group can obviously extend the mouse normal pressure time-to-live (p < 0.05), the results are shown in Table 1.
The impact of the powerful gastrodia elata-cortex capsule of table 1 on mouse normobaric hypoxia
With control group comparison,*P＜0.05
1.2 affect grouping and medication with 1.1 to the breathing time of dehiscing due to mouse broken end. After not inferior administration 1h,Break end rapidly in mouse ear bottom, record after each group of mouse breaks end and dehisce the snorting time, with t test and judge, it has or not conspicuousnessDifference. Result shows, with control group comparison, powerful gastrodia elata-cortex capsule high dose group can obviously extend the mouse breathing time of dehiscing(p < 0.05), low, middle dosage group extends to some extent to the mouse breathing time of dehiscing, but without obvious significant difference (P > 0.05),The results are shown in Table 2.
The powerful gastrodia elata-cortex capsule of table 2 is on the dehisce impact of breathing time of mouse broken end
With control group comparison, * P < 0.05
2. the impact of powerful gastrodia elata-cortex capsule on intraluminal middle cerebral artery occlusion in rats focal cerebral ischemia
2.1 modellings adopt line bolt legal system for middle cerebral artery infarction model, SD male rat, 10% chloraldurate(350mg/kg), after intraperitoneal anesthesia, along neck midsection skin, separate that right neck is total, the outer and internal carotid of neck. In neck, neck is always movingArteries and veins place closes with artery clamp folder, ligation external carotid artery proximal part and distal end, and cut off centre. By moving in external carotid artery free-end and neckArteries and veins is in alignment, and nylon wire is inserted by external carotid artery, and insertion is rear with No. 0 silk thread ligation, in case hemorrhage, open internal carotidPlace's artery clamp, inserts internal carotid by nylon wire, continues to be inserted into encephalic, in the time having slight resistance, stops, and insertion depth approximately2cm. After sham-operation treated animal anesthesia, only peel off that neck is total, in neck and external carotid artery and not ligation).
2.2 animal groupings and administration rat are divided into 6 groups at random, are respectively sham-operation group, model group (arteria cerebri media stalkPlug group) powerful gastrodia tuber eucommia low dose group, middle dosage group, high dose group, positive drug contrast medicine (original product) group. Sham-operation group:After rat anesthesia, only separate that neck is total, in neck and external carotid artery and not ligation. Each reagent group molding front every day of gastric infusion 1 time, connectsContinuous administration 5 days, molding after time administration 1h, 6h administration 1 time again after middle cerebral artery infarction. Sham-operation group and model group are correspondingThe capacity physiological saline such as time gavage.
2.3 nervous symptoms are marked each treated animal after middle cerebral artery infarction 24h, by Bederson[3]Method to oftenMouse is marked. According to its symptom grading, totally 10 points. Concrete methods of marking is as follows.
Result demonstration, the nervous symptoms scoring of sham-operation group is 0, model group is 6.2 ± 2.3, occurs significantly neural barrierHinder symptom, the middle and high dosage group of powerful gastrodia elata-cortex capsule rat nervous symptoms all obviously improves, and is respectively 3.4 ± 2.1,2.9 ± 2.2 (p < 0.05), low dose group effect is not remarkable, the results are shown in Table 3.
After 2.4 cerebral infarct sizes are measured infraction 24h, rat broken end is got brain, puts 20min in DEG C refrigerator of brain-20, removes olfactory bulb,Cerebellum and low brain stem, on average cut five cuttves along coronal-plane. Then rapidly brain sheet is placed in to 5ml, the red tetrazolium that concentration is 2%(contain 0.1mol/LK2HPO4) in solution, 37 DEG C of incubation 30min of lucifuge, stir once every 7-8min therebetween, dyed after,Normal cerebral tissue takes on a red color, and infarct is organized as white, carefully takes out white infarct district and weighs, and accounts for blocking tissue's weightIt is infarction size for the heavy percentage calculation of full brain. With t test and judge, it has there was no significant difference. Result demonstration, sham-operation group is largeBrain is all even rose, does not occur ischemic necrosis; Model group is shown in obvious cerebral infarction kitchen range. With model control group comparison, strongThe middle and high dosage group of power gastrodia elata-cortex capsule cerebral infarction degree obviously reduces (P < 0.05), in table 3.
The impact of table 3 on the scoring of focal cerebral ischemia in rats Range of Cerebral Infarction and nervous symptoms (n=10,)
With model group comparison, * P < 0.05
After 2.5 histopathology histological observation rat cerebral ischemia 24h, it is conventional fixing that broken end is got brain, gets cerebral infarction district groupKnit FFPE, HE dyeing. Under light microscopic, sham-operation group respective regions has no damage, and eucaryotic cell structure is complete. Model group cortical cellStructural damage, space between cells increases, and sees neuron oedema; Hippocampal CA 1 cell arrangement is loose, endochylema engrain, karyon pyknosis. By forcePower gastrodia elata-cortex capsule high dose group and model group comparison, cortical cell damage obviously alleviates, rarely seen indivedual edema, hippocampusCA1 district cellular morphology is substantially complete, without obvious karyopyknosis. In, low dose group cortex and Hippocampal CA 1 neural cell injuryPathology is not improved.
2.6 powerful gastrodia elata-cortex capsules are large on the active impact of focal cerebral ischemia in rats serum lactic dehydrogenase (SLDH) (LDH)After mouse middle cerebral artery infarction 24h, with 10% chloraldurate (350mg/kg) intraperitoneal anesthesia, abdominal aortic blood 2ml, 3000Turn/min, centrifugal 10min, gets determination of serum LDH activity. It has there was no significant difference t test and judge. Result shows, and does evil through another personThe comparison of art group, model group rat blood serum LDH is active obviously to raise (P < 0.05), the middle and high dosage group of powerful gastrodia elata-cortex capsule withThe comparison of model group group, active obviously reduce (the P < 0.05) of Serum LDH, low dose group LDH activity declines to some extent, but without statisticsDifference (P > 0.05), the results are shown in Table 4.
The impact of table 4 on Level In Rats With Focal Cerebral Ischemia Serum LDH activity
With the comparison of sham-operation group,#P < 0.05; With model group comparison,*p＜0.05
2.7 powerful gastrodia elata-cortex capsules are on the hemorheological intraluminal middle cerebral artery occlusion in rats that affects of focal cerebral ischemia in ratsAfter infraction 24h, 10% chloraldurate (350mg/kg) intraperitoneal anesthesia, abdominal aortic blood 5ml injects anti-freezing in vitro, slow up and downAfter slow rotation blood fully mixes it, measure hemorheological indexes. Result shows, with the comparison of sham-operation group, modelControl group plasma viscosity, WBV (high, medium and low cutting), whole blood reduced viscosity, packed cell volume all obviously raise (P <0.05). With model group comparison, powerful gastrodia elata-cortex capsule high dose group is to plasma viscosity, WBV (high, medium and low cutting), completeBlood reduced viscosity, packed cell volume all significantly reduce (P < 0.05). It is (high, medium and low that middle dosage group can obviously reduce WBVCut) (all P < 0.05), other indexs are had no significant effect; Low dose group effect is not obvious, the results are shown in Table 5.
Table 5 on the hemorheological impact of Level In Rats With Focal Cerebral Ischemia (n=6,)
With the comparison of sham-operation group, * p < 0.05; With model group comparison,#p＜0.05。
Powerful gastrodia elata-cortex capsule on rats after cerebral ischemic reperfusion cerebral index, brain water content affect grouping and administration with2, not 1h after time administration, rat 10% chloraldurate (350mg/kg) intraperitoneal anesthesia, ligation bilateral common carotid arteries 30min, then fill withAfter note 24h, on ice pan, rat is breaked end and gets brain rapidly, remove the following position of brain stem and weigh, calculate cerebral index. Be placed in 105 DEG CIn baking box, bake to constant weight, calculate its brain water content.
Cerebral index=full brain weight in wet base/body weight × 100% brain water content=(brain weight in wet base-brain stem weight)/brain weight in wet base × 100%
Result demonstration, with the comparison of sham-operation group, model group brain water content significantly increases (P < 0.05), and cerebral index has increaseTrend, but not statistically significant. The powerful middle and high dosage group of gastrodia elata-cortex capsule and model group comparison, cerebral index and brain water contentAll obviously reduce (P < 0.05), the results are shown in Table 6.
The impact of table 6 on cerebral ischemia-reperfusion injury in rats cerebral index, brain water content
With the comparison of sham-operation group,#P < 0.05; With model group comparison, * p < 0.05
4. the impact of powerful gastrodia elata-cortex capsule on thrombosis and platelet aggregation
The 4.1 powerful gastrodia elata-cortex capsule mouse experimental thrombosis formation effect SD of Chinese People's Anti-Japanese Military and Political College rat male and female dual-purposes, are divided into 5 at randomGroup: physiological saline control group, the basic, normal, high dosage group of powerful gastrodia tuber eucommia (is respectively 0.09g/kg, 0.18g/kg, 0.36g/And positive drug Nimodipine group kg). Every day gastric infusion 1 time, continuous 5 days, 60min after last administration, yellow Jackets 30mg/Kg Intravenous Anesthesia layback position is fixing, and neck median incision separates right carotid and left side vena jugularis externa for subsequent use. Get internal diameter1.5mm, the siliconized polyethylene Guan Yigen of long 12cm, inserts No. 4 surgical thread of a length 6cm, in pipe, fills with heparin-saline(50U/ml), then left vena jugularis externa and RCCA are inserted respectively in the two ends of pipe, form arteria carotis-jugular vein path,Open blood flow 15min, in take-off pipe, silk thread is weighed, and deducts the former weight of silk thread, is wet weight of thrombus. With t test and judge, it has or notSignificant difference. Result demonstration, the middle and high dosage group of powerful gastrodia elata-cortex capsule has obvious inhibitory action to thrombosis,Its inhibiting rate is respectively 19.4% and 20.1%, the results are shown in Table 7.
The powerful gastrodia elata-cortex capsule of table 7 on thrombotic impact (n＝8)
With the comparison of physiological saline control group, * p < 0.05
4.2 powerful gastrodia elata-cortex capsules affect 24 of rabbit to platelet aggregation, are divided at random 4 groups, every group 6Only, multiple capsule 0.18g/kg group, 0.36g/kg group, physiological saline control group and original product 0.48g/kg group of powerful gastrodia tuber eucommia.Medication is with 4.1,60min after last administration, and yellow Jackets 30mg/kg Intravenous Anesthesia, faces upward position fixing, and cut neck centerMouthful, separate right carotid, insert polyethylene pipe and get blood 20ml, be placed in sodium citrate anti-freezing centrifuge tube (9: 1), centrifugal800rpm, 5min, sucts a layer suspension and is platelet rich plasma (PRP); Centrifugal 3000rpm again, 10min, sucts suspension and makesPlatelet poor plasma (PPP). Get 4 cuvettes, one adds PPP200ul, and another three add respectively PRP200ul, put gathering37 DEG C of preheating 3min in instrument first survey the platelet count of PPP, then survey PRP platelet count in mensuration hole, then with PPP dilution PRPPlatelet count is to measuring aequum. The PRP and the PPP measuring cup that mix up platelet count are put in platelet aggregation instrument mensuration hole, inBe equipped with and in PRP cup, add one of stirring rod, then add adenosine diphosphate (Adenosinediphosphate:ADP) 7.5 μ mol/L or fibrin ferment (Thrombin:Thr) 3.5u/ml, records curve of platelet aggregation after 5min. According to administration group and physiological salineThe gathering curve of group, observing 1,3,5min aggregation intensity and maximum aggregation intensity (MA), and calculates and assembles inhibition percentage.With t test and judge, it has there was no significant difference.
Result demonstration, with the comparison of physiological saline group, the each dosage of powerful gastrodia elata-cortex capsule can obviously suppress the blood of ADP inductionPlatelet is assembled, in table 8. The platelet aggregation that Thr is induced only high dose group produces obvious inhibitory action impact, the results are shown in Table 9.
The impact of the platelet aggregation of table 8 on ADP induction (n=6,)
With the comparison of physiology salt group water, * p < 0.05, * * p < 0.01
The impact of the platelet aggregation of table 9 on fibrin ferment Thr induction (n=6,)
With the comparison of physiological saline group, * p < 0.05, * p < 0.01
(3) conclusion experiment adopts the resistance to anoxia model of mouse, intraluminal middle cerebral artery occlusion in rats focal cerebral ischemia and ischemia-reperfusionTwo models, have observed the effect of powerful gastrodia elata-cortex capsule anti-cerebral ischemia, and have observed and the closely-related anti-blood of cerebral ischemiaBolt formation and the impact on platelet aggregation, conclusion is as follows:
1. when powerful gastrodia elata-cortex capsule 0.72g/kg can obviously extend mouse normal pressure time-to-live and broken end and dehisces to breatheBetween.
2. powerful gastrodia elata-cortex capsule 0.18g/kg, 0.36g/kg can obviously reduce cerebral infarction to focal cerebral ischemia in ratsScope, improves nervous symptoms, reduces serum lactic dehydrogenase (SLDH) activity; Cerebral ischemia-reperfusion injury in rats is obviously reduced to cerebral indexAnd brain water content, the preventive and therapeutic effect of powerful gastrodia elata-cortex capsule 0.36g/kg is similar to original product 0.48g/kg. HistopathologyThe demonstration of histological observation result, powerful gastrodia elata-cortex capsule 0.36g/kg can obviously alleviate cortex and the hippocampus due to cerebral infarctionCA1 district neure damage degree.
3. powerful gastrodia elata-cortex capsule obviously suppresses the platelet aggregation of ADP and THR induction, 0.18g/kg and 0.36/kgObviously suppress the formation of experimental thrombosis, inhibiting rate is respectively 19.4% and 20.1%. Powerful gastrodia elata-cortex capsule obviously reducesExperimental cerebral ischemia rat plasma viscosity, WBV (high, medium and low cutting), whole blood reduced viscosity and packed cell volume.
Four, acute toxicity test research
Summary is observed the acute toxicity of powerful gastrodia elata-cortex capsule to mouse. Mouse single gastric infusion, cannot without deathObtain median lethal dose, adopt maximum dosage-feeding 40g/kg.d-1(three times on the one gavages) Continuous Observation 14 days, has no mouse deadDie, general status is good, without anomaly, shows that powerful gastrodia elata-cortex capsule is very low to chmice acute toxicity.
1 experiment material
1.1 animal Kunming mouses, male and female half and half, body weight 18-22g. Carried by University Of Suzhou's medical board Experimental Animal CenterConfession, the quality certification number: SCXK (Soviet Union) 2009-12.
The powerful gastrodia elata-cortex capsule of 1.2 medicines (lot number: 2009001, specification: the powerful gastrodia tuber eucommia glue that does not add auxiliary materialSac extract) provided by Sanli Pharmaceutical Co., Ltd., Guizhou. Before experiment, powerful gastrodia elata-cortex capsule is worn into carefully with mortarPowder, is mixed with suspension with distilled water for subsequent use.
2 experimental techniques
2.1 measure median lethal dose (LD50) get 40 of mouse, male and female half and half, body weight 18-22g, is divided into 4 group (10 at randomOnly/group): be respectively blank group (same volume distilled water), powerful gastrodia elata-cortex capsule 10.5g/kg.d-1、11.3g/kg.d-1、12.1g/kg.d-1、13g/kg.d-1(maximum suspendible concentration), fasting (can't help water) is after 12 hours, single gastric infusion(0.4ml/10g), observe mouse ordinary circumstance (changes of weight, diet, fur, behavior, secretion, excreta etc.) and inPoison, death condition, Continuous Observation 14 days.
2.2 40 of maximum dosage-feeding experiment mices, male and female half and half, body weight 18-22g, is divided into blank group, brute force at randomGastrodia elata-cortex capsule group. Powerful gastrodia elata-cortex capsule is pressed 40g/kg.d-1Divide three gastric infusions (0.4ml/10g), blankGroup, to same volume distilled water, is observed general activity situation and the death toll of mouse, Continuous Observation 14 days.
3 results
During the each administration group of 3.1 powerful gastrodia elata-cortex capsule mouse experiment, have no dead, general status good (body weight, drinkFood, fur, behavior, secretion, excreta etc.), cannot obtain median lethal dose (LD50)。
3.2 adopt maximum dosage-feeding 40g/kg.d-1(be approximately equivalent to clinical every day of dosage 110 times) gavage, experiment periodsBetween Mice Body weight average increase, with blank group without significant difference (in table 1), diet and movable normal, fur is smooth, mouth, nose,Eye waits no abnormality seen secretion, and after administration, only the 1st day stool is brown soft stool, urine no abnormality seen.
The comparison of the powerful gastrodia elata-cortex capsule maximum dosage-feeding of table 1 experiment mice body weight
Detailed description of the invention
Embodiment 1: rhizoma Gastrodiae 139.2g, the bark of eucommia (salt system) 147.8g, wild aconite root 17.4g, monkshood (system) 17.4g, levisticum86.8g, Jehol Ligusticum Rhizome 102.6g, radix scrophulariae 102.6g, Radix Angelicae Sinensis 174g, glutinous rehmannia 278.2g, radix cyathulae 102.6g, mistletoe 102.6g, Qiang174g lives.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillationsExtract 6 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filterCross, the liquid that it is 1: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to make solution contain alcohol amount and reaches 60%, leaves standstill24 hours, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaim ethanol and be concentrated into relative density be 1.05～The medicinal extract of 1.40 (60 DEG C) is for subsequent use; Taking polyethylene glycol-6000 and PEG-4000 mix heating and melting, add volatile oil, soakCream, stirs, and is transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, and dripping becomes ball, de-oiling, and low temperature drying, filling in hollowIn capsule, make 1000, obtain capsule of the present invention, specification: every dress 0.3g. Usage and dosage: oral, one time 2, one day2 times.
Embodiment 2: rhizoma Gastrodiae 1392g, the bark of eucommia (salt system) 1478g, wild aconite root 174g, monkshood (system) 174g, levisticum 868g, ligusticumicThis 1026g, radix scrophulariae 1026g, Radix Angelicae Sinensis 1740g, glutinous rehmannia 2782g, radix cyathulae 1026g, mistletoe 1026g, notopterygium root 1740g.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material water steamedHeat up in a steamer and extract 6 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filterCross, the liquid that it is 1: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to make solution contain alcohol amount and reaches 60%, leaves standstill24 hours, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaim ethanol and be concentrated into relative density be 1.05～The medicinal extract of 1.40 (60 DEG C) is for subsequent use; Taking polyethylene glycol-6000 and PEG-4000 mix heating and melting, add volatile oil, soakCream, stirs, and is transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, and dripping becomes ball, de-oiling, and low temperature drying, filling in hollowIn capsule, make 10000, obtain capsule of the present invention, specification: every dress 0.3g. Usage and dosage: oral, one time 2, oneDay 2 times.
Embodiment 3: rhizoma Gastrodiae 139.2g, the bark of eucommia (salt system) 147.8g, wild aconite root 17.4g, monkshood (system) 17.4g, levisticum86.8g, Jehol Ligusticum Rhizome 102.6g, radix scrophulariae 102.6g, Radix Angelicae Sinensis 174g, glutinous rehmannia 278.2g, radix cyathulae 102.6g, mistletoe 102.6g, Qiang174g lives.
Take rhizoma Gastrodiae raw medicinal material, add 3 times of amount 90% alcohol refluxs and extract 1 time, extract 4 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillationsExtract 10 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 12 times of water gagings and extract 1 time, extract 4 hours, filter, and it is 1 that filtrate is concentrated into containing crude drug concentration: 1 liquid, let cool to room temperature, add ethanol to make solution contain alcohol amount and reach 40%, leave standstill 12 hours, get supernatant liquid filtering and obtain ethanolLiquid, merges with rhizoma Gastrodiae alcohol extract, and reclaiming ethanol and being concentrated into relative density is that the medicinal extract of 1.05～1.40 (60 DEG C) is for subsequent use; Get poly-Ethylene glycol-6000 and PEG-4000 mix heating and melting, add volatile oil, medicinal extract, stir, and are transferred to pill dripping machineIn in 60 DEG C of insulations 10 minutes, dripping becomes ball, de-oiling, low temperature drying, filling in Capsules, make 1000, obtain thisInvention capsule, specification: every dress 0.3g. Usage and dosage: oral, one time 2, an order 2 times.
Embodiment 4: embodiment 1: rhizoma Gastrodiae 139.2g, the bark of eucommia (salt system) 147.8g, wild aconite root 17.4g, monkshood (system)17.4g, levisticum 86.8g, Jehol Ligusticum Rhizome 102.6g, radix scrophulariae 102.6g, Radix Angelicae Sinensis 174g, glutinous rehmannia 278.2g, radix cyathulae 102.6g, mistletoe102.6g, notopterygium root 174g.
Take rhizoma Gastrodiae raw medicinal material, add 8 times of amount 30% alcohol refluxs and extract 4 times, each 1 hour, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillationsExtract 4 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 6 times of water gagings and extract 4 times, each 1 hour, filter, it is 2 that filtrate is concentrated into containing crude drug concentration:1 liquid, lets cool to room temperature, adds ethanol to make solution contain alcohol amount and reaches 80%, leaves standstill 48 hours, gets supernatant liquid filtering and obtains ethanolLiquid, merges with rhizoma Gastrodiae alcohol extract, and reclaiming ethanol and being concentrated into relative density is that the medicinal extract of 1.05～1.40 (60 DEG C) is for subsequent use; Get poly-Ethylene glycol-6000 and PEG-4000 mix heating and melting, add volatile oil, medicinal extract, stir, and are transferred to pill dripping machineIn in 60 DEG C of insulations 10 minutes, dripping becomes ball, de-oiling, low temperature drying, filling in Capsules, make 1000, obtain thisInvention capsule, specification: every dress 0.3g. Usage and dosage: oral, one time 2,2 times on the one.
Embodiment 5: rhizoma Gastrodiae 139.2g, the bark of eucommia (salt system) 147.8g, wild aconite root 17.4g, monkshood (system) 17.4g, levisticum86.8g, Jehol Ligusticum Rhizome 102.6g, radix scrophulariae 102.6g, Radix Angelicae Sinensis 174g, glutinous rehmannia 278.2g, radix cyathulae 102.6g, mistletoe 102.6g, Qiang174g lives.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillationsExtract 6 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filterCross, the liquid that it is 1: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to make solution contain alcohol amount and reaches 60%, leaves standstill24 hours, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaim ethanol and be concentrated into relative density be 1.05～The medicinal extract of 1.40 (60 DEG C), dry, pulverize into fine powder, adds right amount of auxiliary materials, grinds well, and is pressed into 10000, obtains flexible glue of the present inventionCapsule, specification: every dress 0.3g. Usage and dosage: oral, one time 2,2 times on the one.
Embodiment 6: rhizoma Gastrodiae 13.92g, the bark of eucommia (salt system) 14.78g, wild aconite root 1.74g, monkshood (system) 1.74g, levisticum8.68g, Jehol Ligusticum Rhizome 10.26g, radix scrophulariae 10.26g, Radix Angelicae Sinensis 17.4g, glutinous rehmannia 27.82g, radix cyathulae 10.26g, mistletoe 10.26g, Qiang17.4g lives.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 30% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillationsExtract 6 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge, filter filtrateBe concentrated into containing the crude drug concentration liquid that is 1: 1, let cool to room temperature, add ethanol to make solution contain alcohol amount and reach 60%, leave standstill 24 littleTime, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaiming ethanol and being concentrated into relative density is 1.05～1.40The medicinal extract of (60 DEG C) is for subsequent use; Taking polyethylene glycol-6000 and PEG-4000 mix heating and melting, add volatile oil, medicinal extract,Stir, be transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, dripping becomes ball, de-oiling, and low temperature drying, makes 1000 balls,Obtain pill of the present invention, specification: the heavy 30mg of every ball. Usage and dosage: oral, 20 balls, 2 times on the one.
Embodiment 7: rhizoma Gastrodiae 139.2g, the bark of eucommia (salt system) 147.8g, wild aconite root 17.4g, monkshood (system) 17.4g, levisticum86.8g, Jehol Ligusticum Rhizome 102.6g, radix scrophulariae 102.6g, Radix Angelicae Sinensis 174g, glutinous rehmannia 278.2g, radix cyathulae 102.6g, mistletoe 102.6g, Qiang174g lives.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 30% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillationsExtract 6 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge, filter filtrateBe concentrated into and contain the liquid that crude drug concentration is 1: 1, let cool to room temperature, add ethanol to make solution contain alcohol amount and reach 60%, leave standstill 24 hours,Get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaiming ethanol and being concentrated into relative density is 1.05～1.40 (60DEG C) medicinal extract, add right amount of auxiliary materials, mix, granulate, dry, add moderate lubrication agent, mix, compressing tablet, film coating, makes10000, obtain tablet of the present invention, specification: every heavy 0.3g. Usage and dosage: oral, one time 2,2 times on the one.
Embodiment 8: rhizoma Gastrodiae 28.9g, the bark of eucommia (salt system) 166.2g, wild aconite root 21.7g, monkshood (system) 21.7g, levisticum101.2g, Jehol Ligusticum Rhizome 108.4g, radix scrophulariae 108.4g, Radix Angelicae Sinensis 187.9g, glutinous rehmannia 296.3g, radix cyathulae 108.4g, mistletoe 102.4g,Notopterygium root 187.9g.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillationsExtract 6 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filterCross, the liquid that it is 1: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to make solution contain alcohol amount and reaches 60%, leaves standstill24 hours, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaiming ethanol and being concentrated into relative density is 1.05The medicinal extract of～1.40 (60 DEG C) is for subsequent use; Taking polyethylene glycol-6000 and PEG-4000 mix heating and melting, add volatile oil,Medicinal extract, stirs, and is transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, and dripping becomes ball, de-oiling, and low temperature drying, filling in skyIn heart-soothing capsule, make 1000, obtain capsule of the present invention, specification: every dress 0.3g. Usage and dosage: oral, one time 2, oneDay 2 times.
Embodiment 9: rhizoma Gastrodiae 260g, the bark of eucommia (salt system) 137.3g, wild aconite root 7.2g, monkshood (system) 7.2g, levisticum 72.3g,Jehol Ligusticum Rhizome 93.9g, radix scrophulariae 93.9g, Radix Angelicae Sinensis 160g, glutinous rehmannia 267.4g, radix cyathulae 93.9g, mistletoe 93.9g, notopterygium root 160g.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillationsExtract 6 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filterCross, the liquid that it is 1.0: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to make solution contain alcohol amount and reaches 60%, quietPut 24 hours, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaiming ethanol and being concentrated into relative density is 1.05The medicinal extract of～1.40 (60 DEG C) is for subsequent use; Taking polyethylene glycol-6000 and PEG-4000 mix heating and melting, add volatile oil,Medicinal extract, stirs, and is transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, and dripping becomes ball, de-oiling, and low temperature drying, filling in skyIn heart-soothing capsule, make 1000, obtain capsule of the present invention, specification: every dress 0.3g. Usage and dosage: oral, one time 2, oneDay 2 times.
Embodiment 10: rhizoma Gastrodiae 6.96kg, the bark of eucommia (salt system) 7.39kg, wild aconite root 0.87kg, monkshood (system) 0.87kg, levisticum4.33kg, Jehol Ligusticum Rhizome 5.13kg, radix scrophulariae 5.13kg, Radix Angelicae Sinensis 8.7kg, glutinous rehmannia 13.91kg, radix cyathulae 5.13kg, mistletoe 5.13kg,Notopterygium root 8.7kg.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillationsExtract 6 hours, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filterCross, the liquid that it is 1.0: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to make solution contain alcohol amount and reaches 60%, quietPut 24 hours, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaiming ethanol and being concentrated into relative density is 1.05The medicinal extract of～1.40 (60 DEG C) is for subsequent use; Taking polyethylene glycol-6000 and PEG-4000 mix heating and melting, add volatilizationOil, medicinal extract, stir, and is transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, and dripping becomes ball, de-oiling, low temperature drying, filling inIn Capsules, make 50000, obtain capsule of the present invention, specification: every dress 0.3g. Usage and dosage: oral, one time 2Grain, 2 times on the one.
Embodiment 11: rhizoma Gastrodiae 139.2g, the bark of eucommia (salt system) 147.8g, wild aconite root 17.4g, monkshood (system) 17.4g, levisticum86.8g, Jehol Ligusticum Rhizome 102.6g, radix scrophulariae 102.6g, Radix Angelicae Sinensis 174g, glutinous rehmannia 278.2g, radix cyathulae 102.6g, mistletoe 102.6g, Qiang174g lives.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, river oxKnee, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filter filtrateBe concentrated into and contain the liquid that crude drug concentration is 1.0: 1, let cool to room temperature, be added on large pore resin absorption column, use 60% ethanol elution,Collect eluent, merge with rhizoma Gastrodiae alcohol extract, reclaim ethanol and be concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C)For subsequent use; Taking polyethylene glycol-6000 and PEG-4000 mix heating and melting, add volatile oil, medicinal extract, stir, and shiftTo in pill dripping machine in 60 DEG C of insulations 10 minutes, dripping becomes ball, de-oiling, low temperature drying, filling in Capsules, make 50000Grain, obtains capsule of the present invention, specification: every dress 0.3g. Usage and dosage: oral, one time 2,2 times on the one.
Embodiment 12: rhizoma Gastrodiae 1392g, the bark of eucommia (salt system) 1478g, wild aconite root 174g, monkshood (system) 174g, levisticum 868g,Jehol Ligusticum Rhizome 1026g, radix scrophulariae 1026g, Radix Angelicae Sinensis 1740g, glutinous rehmannia 2782g, radix cyathulae 1026g, mistletoe 1026g, notopterygium root 1740g.
Take rhizoma Gastrodiae raw medicinal material, add 3 times of amount 30% alcohol refluxs and extract 2 times, each 1 hour, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, river oxKnee, mistletoe merge, and add 12 times of water gagings and extract 1 time, extract 4 hours, filter the medicine that it is 2: 1 that filtrate is concentrated into containing crude drug concentrationLiquid, lets cool to room temperature, is added on polyamide resin column, uses 80% ethanol elution, collects eluent, merge with rhizoma Gastrodiae alcohol extract,Reclaiming ethanol and being concentrated into relative density is that the medicinal extract of 1.05～1.40 (60 DEG C) is for subsequent use; Taking polyethylene glycol-6000 and poly-second twoAlcohol-4000 mix heating and melting, add volatile oil, medicinal extract, stir, be transferred in pill dripping machine in 60 DEG C of insulations 10 minutes,Dripping becomes ball, de-oiling, and low temperature drying, filling in Capsules, make 10000, obtain capsule of the present invention, specification: everyGrain dress 0.3g. Usage and dosage: oral, one time 2,2 times on the one.
Embodiment 13: rhizoma Gastrodiae 1392g, the bark of eucommia (salt system) 1478g, wild aconite root 174g, monkshood (system) 174g, levisticum 868g,Jehol Ligusticum Rhizome 1026g, radix scrophulariae 1026g, Radix Angelicae Sinensis 1740g, glutinous rehmannia 2782g, radix cyathulae 1026g, mistletoe 1026g, notopterygium root 1740g.
Take rhizoma Gastrodiae raw medicinal material, add 8 times of amount 90% alcohol refluxs and extract 1 time, each 4 hours, filter, obtain alcohol extractLiquid is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, pointFrom, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, Mongolian oak are postedIntercrescence also, adds 8 times of water gagings and extracts 4 times, each 1 hour, filter, the liquid that it is 1: 1 that filtrate is concentrated into containing crude drug concentration, let cool toRoom temperature, is added on polyamide resin column, uses 40% ethanol elution, collects eluent, merges with rhizoma Gastrodiae alcohol extract, reclaims ethanol alsoThe medicinal extract that is concentrated into relative density and is 1.05～1.40 (60 DEG C) is for subsequent use; Taking polyethylene glycol-6000 and PEG-4000 mixHeating and melting, adds volatile oil, medicinal extract, stirs, and is transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, and dripping becomes ball, de-Oil, low temperature drying, filling in Capsules, make 10000, obtain capsule of the present invention, specification: every dress 0.3g. WithMethod consumption: oral, one time 2,2 times on the one.
Embodiment 14: rhizoma Gastrodiae 139.2g, the bark of eucommia (salt system) 147.8g, wild aconite root 17.4g, monkshood (system) 17.4g, levisticum86.8g, Jehol Ligusticum Rhizome 102.6g, radix scrophulariae 102.6g, Radix Angelicae Sinensis 174g, glutinous rehmannia 278.2g, radix cyathulae 102.6g, mistletoe 102.6g, Qiang174g lives.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter filtrateReclaim ethanol and be concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), obtaining rhizoma Gastrodiae alcohol-extracted extract for subsequent use, remaining rhizoma GastrodiaeThe dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatile oil standbyWith; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merge, and add 10 timesWater gaging extracts 2 times, and 3 hours for the first time, 2 hours for the second time, merge extract, filter, filtrate is filtered by ceramic membrane separation, receivesCollection filtered fluid, it is that the medicinal extract of 1.05～1.40 (60 DEG C) is for subsequent use that filter is concentrated into relative density; Taking polyethylene glycol-6000 and poly-second twoAlcohol-4000 mix heating and melting, add volatile oil, medicinal extract, stir, be transferred in pill dripping machine in 60 DEG C of insulations 10 minutes,Dripping becomes ball, de-oiling, and low temperature drying, filling in Capsules, make 1000, obtain capsule of the present invention, specification: everyDress 0.3g. Usage and dosage: oral, one time 2,2 times on the one.
Embodiment 15: rhizoma Gastrodiae 1392g, the bark of eucommia (salt system) 1478g, wild aconite root 174g, monkshood (system) 174g, levisticum 868g,Jehol Ligusticum Rhizome 1026g, radix scrophulariae 1026g, Radix Angelicae Sinensis 1740g, glutinous rehmannia 2782g, radix cyathulae 1026g, mistletoe 1026g, notopterygium root 1740g.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter filtrateReclaim ethanol and be concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), obtaining rhizoma Gastrodiae alcohol-extracted extract for subsequent use, remaining rhizoma GastrodiaeThe dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatile oil standbyWith; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merge, and add 10 timesWater gaging extracts 2 times, and 3 hours for the first time, 2 hours for the second time, merge extract, filter, filtrate is filtered by ceramic membrane separation, receivesCollection filtered fluid, it is that the medicinal extract of 1.05～1.40 (60 DEG C) is for subsequent use that filter is concentrated into relative density; Taking polyethylene glycol-6000 and poly-second twoAlcohol-4000 mix heating and melting, add volatile oil, medicinal extract, stir, be transferred in pill dripping machine in 60 DEG C of insulations 10 minutes,Dripping becomes ball, de-oiling, and low temperature drying, filling in Capsules, make 10000, obtain capsule of the present invention, specification: everyGrain dress 0.3g. Usage and dosage: oral, one time 2,2 times on the one.
Embodiment 11: rhizoma Gastrodiae 139.2g, the bark of eucommia (salt system) 147.8g, wild aconite root 17.4g, monkshood (system) 17.4g, levisticum86.8g, Jehol Ligusticum Rhizome 102.6g, radix scrophulariae 102.6g, Radix Angelicae Sinensis 174g, glutinous rehmannia 278.2g, radix cyathulae 102.6g, mistletoe 102.6g, Qiang174g lives.
Take rhizoma Gastrodiae raw medicinal material, add 5 times of amount 50% alcohol refluxs and extract 3 times, each 2 hours, merge, filter, obtain secondAlcohol extract is for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, river oxKnee, mistletoe merge, and add 10 times of water gagings and extract 2 times, 3 hours for the first time, 2 hours for the second time, merge extract, filter filtrateBe concentrated into and contain the liquid that crude drug concentration is 1: 1, let cool to room temperature, be added on large pore resin absorption column, use 60% ethanol elution, receiveCollection eluent, merges with rhizoma Gastrodiae alcohol extract, reclaims ethanol and is concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), dryDry, be ground into fine powder, add right amount of auxiliary materials, grind well, be pressed into 10000, obtain soft capsule of the present invention, specification: every dress0.25g. Usage and dosage: oral, one time 2,2 times on the one.
Brief description of the drawings:
The Technology Roadmap of Fig. 1 on normal rats in vitro platelet aggregation impact
The Technology Roadmap of Fig. 2 om observation damage side brain tissue nerve cell
Fig. 3 preparation technology flow chart.
Claims (11)
1. a pharmaceutical preparation of preventing and treating cranial vascular disease, is characterized in that: according to listed as parts by weight, it by rhizoma Gastrodiae 2%～18%, the bark of eucommia 9.5%～11.5% processed, wild aconite root 0.5%～1.5%, RADIX ACONITI LATERALIS PREPARATA 0.5%～1.5%, levisticum 5%～7%,Jehol Ligusticum Rhizome 6.5%～7.5%, radix scrophulariae 6.5%～7.5%, Radix Angelicae Sinensis 11%～13%, glutinous rehmannia 18.5%～20.5%, radix cyathulae6.5%～7.5%, mistletoe 6.5%～7.5%, notopterygium root 11%～13% are prepared from through extracting processing.
2. according to the pharmaceutical preparation of preventing and treating cranial vascular disease claimed in claim 1, it is characterized in that: according to listed as parts by weight,It is by rhizoma Gastrodiae 9.6%, the bark of eucommia processed 10.3%, wild aconite root 1.2%, RADIX ACONITI LATERALIS PREPARATA 1.2%, levisticum 6.0%, Jehol Ligusticum Rhizome 7.1%, radix scrophulariae7.1%, Radix Angelicae Sinensis 12.0%, glutinous rehmannia 19.3%, radix cyathulae 7.1%, mistletoe 7.1%, notopterygium root 12.0% are through extracting processing preparationForm.
3. the preparation method who prevents and treats cerebrovascular disease medicament preparation as described in claim 1 and 2, is characterized in that: take rhizoma GastrodiaeRaw medicinal material, 30%～90% alcohol reflux that adds 3～8 times of amounts extracts 1～4 time, each 1～4 hour, merges extract, filterCross, obtain ethanol extract for subsequent use, the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material watersSteam distillation extracts 4～10 hours, separates, and obtains volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, system are attachedSon, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merge, and add 6～12 times of water gagings and extract 1～4 time, each 1～4 hour, merge and extractLiquid, filters, and it is the liquid of 1: 1～2: 1 that filtrate is concentrated into containing crude drug concentration, lets cool to room temperature, adds ethanol to make solution contain alcohol amountReach 40%～80%, leave standstill 8～48 hours, get supernatant liquid filtering and obtain ethanol, merge with rhizoma Gastrodiae alcohol extract, reclaim ethanol denseBeing reduced to relative density is the medicinal extract of 1.05～1.40 (60 DEG C), merge volatile oil, then add auxiliary material routinely preparation process makeDifferent pharmaceutical preparations.
4. the preparation method who prevents and treats as claimed in claim 3 cerebrovascular disease medicament preparation, is characterized in that: take rhizoma Gastrodiae raw materialMedicinal material, adds 5 times of amount 50% alcohol refluxs and extracts 3 times, and each 2 hours, merge, filter, obtain ethanol extract for subsequent use, remaining rhizoma GastrodiaeThe dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material steam distillations and extract 6 hours, separate, obtain volatilizationOil is for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merge, and add10 times of water gagings extract 2 times, and 3 hours for the first time, 2 hours for the second time, merge extract, filter, filtrate is concentrated into containing crude drug concentrationBe the liquid of 1: 1, let cool to room temperature, add ethanol to make solution contain alcohol amount and reach 60%, leave standstill 24 hours, get supernatant liquid filtering and obtain secondAlcohol liquid, merges with rhizoma Gastrodiae alcohol extract, reclaims ethanol and is concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), and merging is wavedHair oil, then add auxiliary material routinely preparation process make different pharmaceutical preparations.
5. the preparation method who prevents and treats cerebrovascular disease medicament preparation as described in claim 1 and 2, is characterized in that: take rhizoma GastrodiaeRaw medicinal material, 30%～90% alcohol reflux that adds 3～8 times of amounts extracts 1～4 time, each 1～4 hour, merges extract, filterCross, obtain ethanol extract for subsequent use, the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal materials with superCritical CO2Extract, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae,Huang, radix cyathulae, mistletoe merge, and add 6～12 times of water gagings and extract 1～4 time, each 1～4 hour, merge extract, filter filterIt is the liquid of 1: 1～2: 1 that liquid is concentrated into containing crude drug concentration, lets cool to room temperature, is added on resin column, washes with 30%～90% ethanolDe-, collect eluent, merge with rhizoma Gastrodiae alcohol extract, reclaiming ethanol and being concentrated into relative density is soaking of 1.05～1.40 (60 DEG C)Cream, merge volatile oil, then add auxiliary material routinely preparation process make different pharmaceutical preparations.
6. the preparation method who prevents and treats as claimed in claim 5 cerebrovascular disease medicament preparation, is characterized in that: take rhizoma Gastrodiae raw materialMedicinal material, adds 5 times of amount 50% alcohol refluxs and extracts 3 times, and each 2 hours, merge, filter, obtain ethanol extract for subsequent use, remaining rhizoma GastrodiaeThe dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatile oil standbyWith; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merge, and add 10 timesWater gaging extracts 2 times, and 3 hours for the first time, 2 hours for the second time, merge extract, filter, it is 1: 1 that filtrate is concentrated into containing crude drug concentrationLiquid, let cool to room temperature, be added on large pore resin absorption column, use 60% ethanol elution, collect eluent, with rhizoma Gastrodiae alcohol extractMerge, reclaim ethanol and be also concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), merge volatile oil, then add auxiliary material byConventional formulation technique is made different pharmaceutical preparations.
7. the preparation method who prevents and treats cerebrovascular disease medicament preparation as described in claim 1 and 2, is characterized in that: take rhizoma GastrodiaeRaw medicinal material, 30%～90% alcohol reflux that adds 3～8 times of amounts extracts 1～4 time, each 1～4 hour, merges extract, filterCross, filtrate recycling ethanol is also concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), obtains rhizoma Gastrodiae alcohol-extracted extract for subsequent use, more thanThe lower rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take levisticum, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatilizationOil is for subsequent use; The remaining dregs of a decoction and the rhizoma Gastrodiae dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merge, and add6～12 times of water gagings extract 1～4 time, and each 1～4 hour, merge extract, filter, filtrate, by film separating and filtering, was collectedFiltrate, filter is concentrated into the medicinal extract that relative density is 1.05～1.40 (60 DEG C), merges, then adds with rhizoma Gastrodiae alcohol-extracted extract, volatile oilEnter auxiliary material routinely preparation process make different pharmaceutical preparations.
8. the preparation method who prevents and treats cerebrovascular disease medicament preparation as described in claim 1 and 2, is characterized in that: take rhizoma GastrodiaeRaw medicinal material, adds 5 times of amount 50% alcohol refluxs and extracts 3 times, and each 2 hours, merge, filter, filtrate recycling ethanol is also concentrated intoRelative density is the medicinal extract of 1.05～1.40 (60 DEG C), obtains rhizoma Gastrodiae alcohol-extracted extract for subsequent use, and the remaining rhizoma Gastrodiae dregs of a decoction are for subsequent use; Take solelyWork, Jehol Ligusticum Rhizome, Radix Angelicae Sinensis, notopterygium root four taste raw medicinal material supercritical COs2Extract, separate, obtain volatile oil for subsequent use; The remaining dregs of a decoction and rhizoma GastrodiaeThe dregs of a decoction, the bark of eucommia processed, wild aconite root, RADIX ACONITI LATERALIS PREPARATA, radix scrophulariae, glutinous rehmannia, radix cyathulae, mistletoe merge, and add 10 times of water gagings and extract 2 times, firstInferior 3 hours, 2 hours for the second time, merge extract, filter, filtrate is filtered by ceramic membrane separation, collects filtered fluid, and filter is concentratedBe the medicinal extract of 1.05～1.40 (60 DEG C) to relative density, merge, then add auxiliary material routinely with rhizoma Gastrodiae alcohol-extracted extract, volatile oilPreparation process is made different pharmaceutical preparations.
9. according to the pharmaceutical preparation of preventing and treating cranial vascular disease described in claim 4,6,8, it is characterized in that: described pharmaceutical preparationFor oral formulations, comprise granule, oral liquid, pill, tablet, hard shell capsules, soft capsule and dripping pill etc.
10. according to the pharmaceutical preparation and the preparation method that prevent and treat cranial vascular disease described in claim 9, it is characterized in that: describedPharmaceutical preparation is hard capsule; Described preparation method is: taking polyethylene glycol-6000 and PEG-4000 mix and add hot meltMelt, add volatile oil, medicinal extract, stir, be transferred in pill dripping machine in 60 DEG C of insulations 10 minutes, dripping becomes ball, de-oiling, low temperatureDry, filling in Capsules, to obtain final product.
11. according to the pharmaceutical preparation of preventing and treating cranial vascular disease described in claim 7, it is characterized in that: described pharmaceutical preparation masterBe used for headstroke, cerebral thrombus, cerebral arteriovenous malformation, cerebral embolism, cerebral infarction, cerebral blood supply insufficiency, hypertension, encephalatrophy, vascularThe muscle arteries and veins that the cranial vascular disease such as dull-witted causes is taken along pain, extremity numbness, inconvenient walking, waist and leg ache, headache and dizziness, look dull,Dysphonia etc.
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| CN107929563A (en) * | 2017-12-20 | 2018-04-20 | 贵州三力制药股份有限公司 | Strength gastrodia elata-cortex capsule and its component detection method |
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| CN1616053A (en) * | 2004-09-28 | 2005-05-18 | 徐新盛 | Soft capsule containing medicine and its preparing method |
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| CN1537571A (en) * | 2003-04-15 | 2004-10-20 | 毛友昌 | Strong Rhizoma Gastrodiae and eucommia bark granule, and its prepn. method |
| CN1528436A (en) * | 2003-10-09 | 2004-09-15 | 贵州三力制药有限责任公司 | Chinese medicine preparation using rhizoma gastrodiae and eucommia as main material and preparing method thereof |
| CN1616053A (en) * | 2004-09-28 | 2005-05-18 | 徐新盛 | Soft capsule containing medicine and its preparing method |
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| CN107929563A (en) * | 2017-12-20 | 2018-04-20 | 贵州三力制药股份有限公司 | Strength gastrodia elata-cortex capsule and its component detection method |
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