CN101919926B - Traditional Chinese medicine for treating migraine and preparation method thereof - Google Patents
Traditional Chinese medicine for treating migraine and preparation method thereof Download PDFInfo
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- CN101919926B CN101919926B CN2010102528254A CN201010252825A CN101919926B CN 101919926 B CN101919926 B CN 101919926B CN 2010102528254 A CN2010102528254 A CN 2010102528254A CN 201010252825 A CN201010252825 A CN 201010252825A CN 101919926 B CN101919926 B CN 101919926B
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Abstract
The invention relates to a traditional Chinese medicine for treating migraine and a preparation method thereof. The formulation of the traditional Chinese medicine for treating the migraine comprises the following raw materials in parts by weight: 187-563 parts of Szechuan lovage rhizome, 187-563 parts of radix angelicae, 93-280 parts of fructus evodiae and 4.1-12.4 parts of menthol crystal. The preparation method for the traditional Chinese medicine for treating the migraine comprises the following steps: 1) weighing the raw materials according to the proportioning; 2) crushing, percolating and concentrating the Szechuan lovage rhizome and the radix angelicae to granulate, and then drying and finishing granule; 3) extracting the fructus evodiae, drying under reduced pressure to obtain a dry extract; 4) packing the menthol crystal and drying; and 5) mixing and crushing the fructus evodiae dry extract and the beta cyclodextrin clathrate compound of the menthol crystal, sieving to granulate, drying, finishing granule, and mixing evenly with the Szechuan lovage rhizome and radix angelicae granule and then encapsulating.
Description
Technical field
The present invention relates to a kind of Chinese medicine, relate in particular to migrainous Chinese medicine of a kind of treatment and preparation method thereof.
Background technology
Migraine is a kind of headache of periodical attack, and Chang Fanfu shows effect, and has a strong impact on patient's live and work.Nearly 2.4 hundred million migraineurs in the whole world; Investigate by 1988 international association (IHS) diagnostic criterias of having a headache, U.S. prevalence women is 17.6%, and the male is 6%; China's nineteen eighty-threes six big city investigation migraine annual morbidity 20.2/10 ten thousand, prevalence 523.9/10 ten thousand.WHO thinks, the severe migraine occupies preceding 20 of internal disease of the modal people's of making disablement.
Doctor trained in Western medicine is still not fully aware of to the definite pathophysiological mechanism of migraine morbidity at present; Though some Western medicine such as 5-hydroxytryptamine receptor agonist, Ergota amine medicine, NSAID and opium analgesics are being obtained bigger progress aspect the alleviation acute migraine attack; But only be symptomatic treatment; Can not effect a radical cure, and these symptomatic treatments are not all effective to all migraineurs.Therefore, carry out in a deep going way migrainous research, the development more efficient drug, significant.
Migraine belongs to categories such as motherland's medical science " headache ", " wind syndrome of head ", and there is abundant argumentation in Ancient Times in China doctor family to its symptom, etiology and pathogenesis etc." General Treatise on the Cause and Symptoms of Diseases women's head-ornaments wind time " of Sui Dynasty Chao Yuanfang (550-630 A.D.) at first proposes the disease of " wind syndrome of head ", and " disease is controlled because of arteries and veins " points out: " anemogenous headache or half of hemialgia all blow because of air-cooled institute, meet air-cooled then send out ".Chinese medicine is thought " on the height of mountain peak, only wind can arrive ", it is thus clear that ailment said due to cold or exposure is the key factor that causes primary disease.Wind is " first of the six climate exopathogens ", " length of all kinds of diseases and ailments ", is prone to hold under the arm the cold-evil for suffering from, the easy damaged yang-energy of cold being a kind of YIN pathogen, and clear sun is obstructed, and cold blood stasis, passages through which vital energy circulates are not smooth, then inadequate anxious and pain.Primary disease shows effect repeatedly, and touching difficulty more just can be consumed yang-energy.There is the scholar to think that deficiency of spleen-YANG and kidneyYANG is the basis that primary disease takes place.It is thus clear that " wind ", " trembling with fear ", " stasis of blood " are occupied critical role in the morbidity of primary disease.
Since several thousand, the Chinese medicine migraine has accumulated rich experience, obtains good and clinical curative effect, and has special advantages.At present the migrainous Chinese patent medicine of treatment many from suppressing the hyperactive liver, the legislation of invigorating blood circulation, dispel the wind, rare temperature is led to the prescription of invigorating blood circulation.Therefore, exploitation has that temperature logical is invigorated blood circulation, the Chinese patent medicine of wind-expelling pain-stopping effect is used to treat migraine and is necessary.
Summary of the invention
The present invention is directed to the deficiency of prior art, migrainous Chinese medicine of a kind of treatment and preparation method thereof is provided, whole prescription is with Wen Tongwei master; Can the clear sharp head; Strengthen the effect of treatment headache, can help this side's of system the diffusing property of temperature again, in the migrainous while of treatment; Look after migraineur's gastrointestinal symptoms, had significant analgesia role.
The technical scheme that the present invention solves the problems of the technologies described above is following: the migrainous Chinese medicine of a kind of treatment, the prescription of said Chinese medicine is made up of each raw material of following parts by weight: Rhizoma Chuanxiong 187～563, the Radix Angelicae Dahuricae 187～563, Fructus Evodiae 93～280 and Mentholum 4.1～12.4.
On the basis of technique scheme, the present invention can also do following improvement.
Further, each raw materials in part by weight is in the prescription of said Chinese medicine: Rhizoma Chuanxiong 375, the Radix Angelicae Dahuricae 375, Fructus Evodiae 187 and Mentholum 8.3.
Further, the migrainous Chinese medicine of said treatment is processed capsule.
Further, the migrainous preparation method of Chinese medicine of described treatment may further comprise the steps:
1) takes by weighing following each raw materials of parts by weight: Rhizoma Chuanxiong 187～563, the Radix Angelicae Dahuricae 187～563, Fructus Evodiae 93～280 and Mentholum 4.1～12.4;
2) Rhizoma Chuanxiong and the Radix Angelicae Dahuricae are ground into coarse powder,, make solvent with 4～12 times of amount 80% ethanol, behind dipping 12～36h according to percolation; Carry out percolation, collect the liquid of filtering, diacolation liquid recycling ethanol is concentrated into the thick paste shape; Add 1 times of amount dextrin, mixing uses 95% ethanol to be wetting agent; Process granule, in dry, granulate below 60 ℃, subsequent use;
3) with Fructus Evodiae with 70% alcohol reflux secondary, extracted 1～3 hour for the first time, extracted collecting decoction 0.8～2.5 hour for the second time; Filter, reclaim ethanol, be concentrated into the thick paste shape, in-0.09Mpa～-vacuum of 0.07Mpa; Less than 75 ℃ of following drying under reduced pressure, get dry extract, subsequent use;
4) Mentholum is dissolved in ethanol, with 5～15 times of amount betacyclodextrin enclose, enclose 0.8～2.5h under 40 ℃ of stirrings places, and sedimentation filters, the collecting precipitation thing, and washing, drying, subsequent use;
5) Fructus Evodiae dry extract and Mentholum betacyclodextrin clathrate are mixed pulverizing, cross 60 mesh sieves, add 95% ethanol, process granule, dry below 60 ℃, granulate with Rhizoma Chuanxiong, Radix Angelicae Dahuricae granule mixing, is processed granule, incapsulates, and promptly gets.
Further, said step 2) after measuring 80% ethanol and make solvent and preferably flood 24 hours with 8 times in, carries out percolation.
Further, preferred for the first time the extraction 2 hours in the said step 3), preferred for the second time the extraction 1.5 hours.
Further, preferably with 10 times of amount betacyclodextrin enclose, preferred enclose is 1.5 hours under 40 ℃ of stirrings in the said step 4).
Further, said capsule is No. 1 capsule.
The method for using of Chinese medicine of the present invention: one time 4,3 times on the one, a course of treatment 12 Mondays.
In the Chinese medicine of the present invention's prescription: Rhizoma Chuanxiong blood-activating and qi-promoting, wind-expelling pain-stopping; The Radix Angelicae Dahuricae and blood circulation promoting medicine compatibility use, and can strengthen its invigorating blood circulation effect, and can declares clear key, make the logical blood of key alive and bitterly only; Fructus Evodiae can dispersing cold for relieving pain, stopping nausea and vomiting by lowering the adverse flow of QI, supporing yang antidiarrheal, with controlling headache due to JUE YIN disorder; Mentholum has effects such as dispelling wind, heat clearing away, detoxifcation, and Mentholum property is scurried, and with warm nature medicine mutually 5, both can increase the analgesic effect, can prevent again its too temperature loose and impairment of YIN.
The migrainous herbal function of treatment of the present invention: warming the meridian and activating blood circulation, wind-expelling pain-stopping.Being used of Rhizoma Chuanxiong, the Radix Angelicae Dahuricae, Fructus Evodiae and Herba Menthae makes whole prescription with Wen Tongwei master, can the clear sharp head; Strengthen the effect of treatment headache, can help this side's of system the diffusing property of temperature again, in the migrainous while of treatment; Looked after migrainous gastrointestinal symptoms; Have significant analgesia role, have calm preferably, syngignoscism simultaneously, migrainous simultaneous phenomenon is also had better therapeutic effect.
The specific embodiment
Below principle of the present invention and characteristic are described, institute gives an actual example and only is used to explain the present invention, is not to be used to limit scope of the present invention.
Embodiment 1
Each raw materials in part by weight is in the prescription of the migrainous Chinese medicine of the said treatment of the embodiment of the invention: Rhizoma Chuanxiong 375, the Radix Angelicae Dahuricae 375, Fructus Evodiae 187 and Mentholum 8.3.
The weight that accurately takes by weighing each raw material is following: Rhizoma Chuanxiong 375 grams, the Radix Angelicae Dahuricae 375 grams, Fructus Evodiae 187 grams and Mentholum 8.3 grams; The Rhizoma Chuanxiong and the Radix Angelicae Dahuricae are ground into coarse powder,, make solvent, flood after 24 hours with 8 times of amount 80% ethanol according to percolation (Chinese Pharmacopoeia appendix IO); Carry out percolation, collect the liquid of filtering, diacolation liquid recycling ethanol is concentrated into the thick paste shape; Add 1 times of amount dextrin, mixing uses 95% ethanol to be wetting agent, processes granule; Dry below 60 ℃, granulate, subsequent use; Fructus Evodiae is with 70% alcohol reflux secondary, and 2 hours for the first time, 1.5 hours for the second time, collecting decoction filtered, and reclaims ethanol, is concentrated into the thick paste shape, and in vacuum-0.08Mpa, drying under reduced pressure below 75 ℃ gets dry extract, and is subsequent use; Mentholum is dissolved in ethanol, and with 10 times of amount betacyclodextrin enclose, enclose is 1.5 hours under 40 ℃ of stirrings, places, and sedimentation filters, the collecting precipitation thing, and washing, drying, subsequent use.Fructus Evodiae dry extract and Mentholum betacyclodextrin clathrate are mixed pulverizing, cross 60 mesh sieves, add 95% ethanol, process granule, dry below 60 ℃, granulate, with Rhizoma Chuanxiong, Radix Angelicae Dahuricae granule mixing, the capsule of packing into No. 1 is processed 1000, promptly gets.
Embodiment 2
Each raw materials in part by weight is in the prescription of the migrainous Chinese medicine of the said treatment of the embodiment of the invention: Rhizoma Chuanxiong 187, the Radix Angelicae Dahuricae 187, Fructus Evodiae 93 and Mentholum 4.1.
The weight that accurately takes by weighing each raw material is following: Rhizoma Chuanxiong 187 grams, the Radix Angelicae Dahuricae 187 grams, Fructus Evodiae 93 grams and Mentholum 4.1 grams; The Rhizoma Chuanxiong and the Radix Angelicae Dahuricae are ground into coarse powder,, make solvent, flood after 12 hours with 4 times of amount 80% ethanol according to percolation (Chinese Pharmacopoeia appendix IO); Carry out percolation, collect the liquid of filtering, diacolation liquid recycling ethanol is concentrated into the thick paste shape; Add 1 times of amount dextrin, mixing uses 95% ethanol to be wetting agent, processes granule; Dry below 60 ℃, granulate, subsequent use.Fructus Evodiae is with 70% alcohol reflux secondary, and 1 hour for the first time, 0.8 hour for the second time, collecting decoction filtered, and reclaims ethanol, is concentrated into the thick paste shape, and in vacuum-0.07Mpa, drying under reduced pressure below 75 ℃ gets dry extract, and is subsequent use; Mentholum is dissolved in ethanol, and with 5 times of amount betacyclodextrin enclose, enclose is 0.8 hour under 40 ℃ of stirrings, places, and sedimentation filters, the collecting precipitation thing, and washing, drying, subsequent use.Fructus Evodiae dry extract and Mentholum betacyclodextrin clathrate are mixed pulverizing, cross 60 mesh sieves, add 95% ethanol, process granule, dry below 60 ℃, granulate with Rhizoma Chuanxiong, Radix Angelicae Dahuricae granule mixing, incapsulates, and processes 500, promptly gets.
Embodiment 3
Each raw materials in part by weight is in the prescription of the migrainous Chinese medicine of the said treatment of the embodiment of the invention: Rhizoma Chuanxiong 563, the Radix Angelicae Dahuricae 563, Fructus Evodiae 280 and Mentholum 12.4.
The weight that accurately takes by weighing each raw material is following: Rhizoma Chuanxiong 563 grams, the Radix Angelicae Dahuricae 563 grams, Fructus Evodiae 280 grams and Mentholum 12.4 grams; The Rhizoma Chuanxiong and the Radix Angelicae Dahuricae are ground into coarse powder,, make solvent, flood after 36 hours with 12 times of amount 80% ethanol according to percolation (Chinese Pharmacopoeia appendix IO); Carry out percolation, collect the liquid of filtering, diacolation liquid recycling ethanol is concentrated into the thick paste shape; Add 1 times of amount dextrin, mixing uses 95% ethanol to be wetting agent, processes granule; Dry below 60 ℃, granulate, subsequent use.Fructus Evodiae is with 70% alcohol reflux secondary, and 3 hours for the first time, 2.5 hours for the second time, collecting decoction filtered, and reclaims ethanol, is concentrated into the thick paste shape, and in vacuum-0.09Mpa, drying under reduced pressure below 75 ℃ gets dry extract, and is subsequent use; Mentholum is dissolved in ethanol, and with 15 times of amount betacyclodextrin enclose, enclose is 2.5 hours under 40 ℃ of stirrings, places, and sedimentation filters, the collecting precipitation thing, and washing, drying, subsequent use.Fructus Evodiae dry extract and Mentholum betacyclodextrin clathrate are mixed pulverizing, cross 60 mesh sieves, add 95% ethanol, process granule, dry below 60 ℃, granulate, with Rhizoma Chuanxiong, Radix Angelicae Dahuricae granule mixing, the capsule of packing into No. 1 is processed 1500, promptly gets.
Concrete test example
The mensuration of test example 1 parameters
1) get the capsular content 4g of the described treatment migraine Chinese medicine that the above embodiment of the present invention 1 makes, porphyrize added diethyl ether 20 minutes, and reflux 1 hour is put coldly, filter, and the filtrating evaporate to dryness, residue adds ethyl acetate 1mL makes dissolving, as need testing solution.Other gets the Rhizoma Chuanxiong control medicinal material, shines medical material solution in pairs with legal system.According to thin layer chromatography (an appendix VI of 2005 editions pharmacopeia B) test, draw each 5 μ L of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate; With normal hexane-ethyl acetate (9: 1) is developing solvent, launches, and takes out; Dry, put under the ultra-violet lamp (365nm) and inspect.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
2) get the capsular content 4g of the described treatment migraine Chinese medicine that the above embodiment of the present invention 1 makes, porphyrize, the 80mL that adds diethyl ether, reflux 40 minutes is put coldly, filters, the filtrating evaporate to dryness, residue adds ethyl acetate 1mL makes dissolving, as need testing solution.Other gets imperatorin, isoimperatorin reference substance, adds ethyl acetate and processes the solution that every 1mL contains 1mg respectively, as reference substance solution.Test according to thin layer chromatography (an appendix VI of 2005 editions pharmacopeia B); Draw each 5 μ L of above-mentioned three kinds of solution, put respectively on same silica gel g thin-layer plate, so that petroleum ether (60 ℃～90 ℃)-E-C (3: 2: 1) is developing solvent; Launch below 25 ℃; Take out, dry, put under the ultra-violet lamp (365nm) and inspect.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the fluorescence speckle of same color.
3) get the capsular content 2g of the above embodiment of the present invention 1 described treatment migraine Chinese medicine, porphyrize adds ethanol 10mL, and supersound process 20 minutes filters, and filtrating is as need testing solution.Other gets Fructus Evodiae control medicinal material 0.5g, shines medical material solution in pairs with legal system; Test according to thin layer chromatography (an appendix VI of 2005 editions pharmacopeia B); Draw each 5 μ L of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with cyclohexane extraction-ethyl acetate-methanol-triethylamine (19: 5: 1: 1) be developing solvent; Launch; Take out, dry, put under the ultra-violet lamp (365nm) and inspect.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
4) get the capsular content 2g of the above embodiment of the present invention 1 described treatment migraine Chinese medicine, porphyrize adds petroleum ether 10mL, close plug, and jolting 10 minutes was placed 20 minutes, filtered, and filtrating is as need testing solution.Other gets the Mentholum reference substance, adds petroleum ether and processes the solution that every 1mL contains 2mg, as reference substance solution.According to thin layer chromatography (an appendix VI of 2000 editions pharmacopeia B) test, draw each 10 μ L of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate; With normal hexane-ethyl acetate (8: 2) is developing solvent; Launch, take out, dry; Spray is with the anisaldehyde test solution, and it is clear to be heated to the speckle colour developing at 105 ℃.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the fluorescence speckle of same color, concrete outcome is as shown in table 1.
The parameters regulation of table 1 embodiment of the invention 1 described treatment migraine Chinese medicine
The migrainous Chinese medicine of the embodiment of the invention 1 described treatment meets the relevant each item regulation (appendix IL of Chinese Pharmacopoeia version in 2005) of capsule item.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and measure, obtain similar result.
Test example 2 assays
Measure the content of the embodiment of the invention 1 described treatment migraine Chinese medicine according to HPLC (an appendix VI of 2005 editions pharmacopeia D).
Chromatographic condition and system suitability test are filler with the octadecylsilane chemically bonded silica; Acetonitrile-water (47: 53) is a mobile phase; The detection wavelength is 290nm.Theoretical cam curve is calculated by rutaecarpin should be not less than 7000.
Rutaecarpin is got in the preparation of reference substance solution, the rutaecarpine reference substance is an amount of, and accurate the title decides, and adds methanol and processes the solution that every 1mL contains 0.05mg approximately, promptly gets.
These article are got in the preparation of need testing solution, and porphyrize is got 2.0g, and accurate the title decides, and puts in the tool plug conical flask, the accurate methanol 25mL that adds, and close plug is claimed to decide weight, shakes up, and filters, and gets subsequent filtrate, promptly gets.
Accurate respectively reference substance solution and each the 10 μ L of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, and promptly get.
Every in the migrainous Chinese medicine of the embodiment of the invention 1 described treatment contains Fructus Evodiae with rutaecarpin (C
19H
17N
30) and rutaecarpine (C
16H
13N
30) meter, must not be less than 0.33mg.
The result shows: every contains rutaecarpin and rutaecarpine is 0.41mg, meets the requirements.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and measure, obtain similar result.
Test example 3 limit test of microbe
According to " Chinese pharmacopoeia 2000 version appendix " microbial limit test " carries out limit test of microbe to this oral formulations, to judge preparation and degree former, that adjuvant receives microbial contamination thereof, comprises the inspection of microbiological contamination amount and control bacterium.
Randomly draw the migrainous Chinese medicine of treatment of the present invention, the antibacterial culturing temperature is 30 ℃～35 ℃, and mycete, yeast cultivation temperature are 23 ℃～28 ℃, and control bacterium cultivation temperature is 36 ± 1 ℃.
1) inspected number of test sample
The inspected number of every batch of test sample is 10g, and test sample is all taken from the packing unit more than 2.
2) preparation of test liquid
Taking by weighing test sample 10g, put among the 0.9% aseptic sodium chloride solution 100mL, grind with mortar, is test liquid behind the mixing.
3) bacterium liquid is used in contrast
Control strain is escherichia coli [CMCC (B) 44 102], Salmonella (CMCC (B) 50 094), Pseudomonas aeruginosa (CMCC (B) 10 104) and staphylococcus aureus (CMCC (B) 26 003).
Get nutrient agar inclined-plane fresh cultured thing 1 oese of corresponding bacterial strain, be seeded in the nutrient broth medium, cultivate after 18～20 hours, be diluted to 1: 10
6The addition of contrast bacterium is 50～100.
4) inspection method
(1) antibacterial, mycete and yeast counting
Adopt plate colony count.
Get even test liquid, further be diluted to 1: 10
2Dilution factor.Get each 1mL of test liquid of 10 times of dilutions of two-stage respectively, put in the plate of the about 90mm of diameter, the about 15mL of about 45 ℃ culture medium of reinjecting, mixing after waiting to solidify, is inverted and is cultivated, and every dilution factor is made 2 plates.
Nutrient agar is used in count of bacteria, and mold count is with brave red agar culture medium.
The bacterium number is measured the negative control test
Get each 1mL of diluent that is for experiment, put in 4 aseptic plates, medium preparation flat board, cultivation, the inspection used by antibacterial, mold count respectively must not be grown bacterium.
The antibacterial culturing time is 48 hours, at 24 and 48 hours some meter clump counts, is as the criterion with 48 hours clump counts respectively.Mycete, Yeast Cultivation time are 72 hours, at 48 and 72 hours some meter clump counts, generally are as the criterion with 72 hours clump counts respectively.
Nutrient agar panel point meter bacteria colony count, brave red agar plate point meter mold colony number, the dull and stereotyped point of yeast extract powder peptone agar glucose meter yeast clump count.Bacterium colony is disregarded interior as spreading growth in flakes.
Behind the some meter, calculate the average clump count of each dilution level, by bacterium number report rule report bacterium number.
(2) escherichia coli (Escherichia coli) inspection
Get test liquid 10mL (quite test sample 1g), direct inoculation after increasing the bacterium separation and Culture, carries out Gram, biochemical test and the inspection of serum agglutination test item.
Get 3 parts of cholate lactose mediums, every part of each 100mL, 2 parts of test liquids that add ormal weight respectively, wherein 1 part adds contrast bacterium liquid and makes positive control, and the diluent of the 3rd part of adding and test liquid equivalent is made negative control.Cultivated 18～24 hours.Negative control is answered asepsis growth.All the other 2 parts of culture streak inoculations are dull and stereotyped in EMB agar flat board or maconkey agar, cultivate 18～24 hours.When the flat board of positive control is positive bacterium colony, the dull and stereotyped aseptic length of being born of test sample, or bacterium colony is arranged but be different from colibacillary characteristic, be judged to and do not detect escherichia coli.
5) result judges
Bacteria colony count should should should detect less than 100/g, escherichia coli less than 1000/g, mycete and yeast clump count, and concrete outcome is as shown in table 2.
The limit test of microbe result of the migrainous Chinese medicine of table 2 embodiment of the invention 1 described treatment
| Assay | |
| Bacterial population | ＜1000/g |
| Fungi count and yeast count | ＜100/g |
| Coliform count | Do not detect |
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and measure, obtain similar result.
Therefore, the microbial limit composite demand of the described treatment migraine of embodiment of the invention 1-3 Chinese medicine.
Test example 4 stability checkings
Require the migrainous Chinese medicine of the embodiment of the invention 1 described treatment is proceeded the reserved sample observing of December, 18 months and 24 months according to two appendix XIX of Chinese Pharmacopoeia version in 2005 C medicine stability test guideline, investigated the stability of the migrainous Chinese medicine of treatment of the present invention.
1) sample, instrument and reagent
(1) control sample
Control sample:
Rutaecarpin lot number: 802-9401 Nat'l Pharmaceutical & Biological Products Control Institute
Mentholum lot number: 0909-200006 Nat'l Pharmaceutical & Biological Products Control Institute
Control medicinal material:
Rhizoma Chuanxiong lot number: 0918-200004 Nat'l Pharmaceutical & Biological Products Control Institute
Fructus Evodiae lot number: 0728-200005 Nat'l Pharmaceutical & Biological Products Control Institute
(2) sample
Sample: the migrainous Chinese medicine of the embodiment of the invention 1 described treatment.
(3) instrument
Agilent high performance liquid chromatogram analyzer; ZB-1C type medicine disintegration tester; Constant Temp. Oven; Bacteriological incubator; Mold incubator etc.
(4) reagent
Formic acid, ethanol, ethyl acetate, toluene, dichloromethane, glacial acetic acid, methanol, n-butyl alcohol etc. are analytical pure; Silica gel G: chromatography is used.
2) investigation project
Character, discriminating, inspection (moisture, disintegration, weight differential, microbial limit).
The result shows: the sample of the December of the embodiment of the invention 1 described treatment migraine Chinese medicine, 18 months and 24 months, and performance temperature meets the requirements, and microbiological indicator also meets the requirements.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and measure, obtain similar result.
Conclusion: the migrainous Chinese medicine of the described treatment of the embodiment of the invention preserve 18 months outward appearances at normal temperatures and inherent quality very stable; Indivedual capsules have moisture absorption phenomenon in the time of 24 months, tentatively confirm as: room temperature, sealing; Dry place preserves, and effect duration is tentative to be 18 months (1.5 years).
Concrete application test example
The migrainous Chinese medicine of Test Example 1 treatment is to the influence of nitroglycerin type Migraine Rats
A. experiment material
1) animal
No-special pathogen level (Specific pathogen Free:SPF) rat (Sprague Dawley, SD), the male and female dual-purpose, body weight 200～228g, Beijing dimension tonneau China animal experiment technique company provides, and credit number is SCXK (capital) 2007-0001.Sub-cage rearing is in Basic Theories of Chinese Medicine institute laboratory animal room of Chinese department of Chinese medicine institute (cleaning level), 23～25 ℃ of temperature, and humidity 40%～60%, aseptic bar-shaped forage feed is freely drunk water.
2) medicine and reagent
Receive reagent: the migrainous Chinese medicine of the embodiment of the invention 1 described treatment.Adult (in 70Kg) clinical consumption 11.35g crude drug/sky; According to " experimental animal is pressed body surface area than equivalent conversion ratio with the people "; The test with the treatment migrainous Chinese medicine rat dose,equivalent=11.35 * 0.018 * 1000/200=1.022g/Kg, get 0.341g/Kg, 1.022g/Kg, 3.065g/Kg respectively as rat test little, in, heavy dose.Be made into the solution of 34.1mg/mL, 102.2mg/mL, 306.5mg/mL respectively with deionized water.
Positive control drug: Sumatriptan Succinate sheet, trade name are easypro especially, specification: 25mg/ grain, 2/box, the accurate word H20030086 of traditional Chinese medicines, batch number: 10-070101, Simcere Pharmaceutical Co., Ltd..The Sumatriptan Succinate sheet, by adult's 25mg/ grain, during outbreak each 2, being equivalent to rat dosage every day is 4.5mg/Kg, is made into the concentration of 0.45mg/ml with deionized water.Compound cavel capsule, Inner Mongol gouy Tai Danlong Pharmaceutical Co., Ltd, lot number: 20061006.Compound cavel capsule is by adult's 0.25g/ grain, every day 3 times, each 5, is made into the concentration of 33.75mg/ml with deionized water.
Reagent: nitroglycerin injection, the accurate word of traditional Chinese medicines: H11020289, specification: 1mL:5mg, 10/box, batch number: 20071127, Beijing Yimin Pharmaceutical Co., Ltd..Sodium chloride injection, the accurate word H11021192 of traditional Chinese medicines, specification: 500mL:4.5g, batch number: 0711212W, Beijing Double-Crane Pharmaceutical Co., Ltd.Chloral hydrate is analytical pure, lot number: 050308, and Beijing chemical reagents corporation provides, and is made into 3.5% concentration with deionized water, and anaesthesia dosage is 1mL/100g.
Test kit: iodine [
125I] 6-ketone-PGF
1 αThe radioimmunoassay, RIA medicine box, lot number: 20080430, Beijing pul great achievement bio tech ltd provides; Iodine [
125I] thromboxane B
2The radioimmunoassay, RIA medicine box, lot number: 20080430, Beijing pul great achievement bio tech ltd provides; Iodine [
125I] calcitonin-gene-related peptide radioimmunoassay, RIA medicine box, lot number: 20080430, Beijing pul great achievement bio tech ltd provides; Iodine [
125I] Endothelin radioimmunoassay, RIA medicine box, lot number: 20080430, Beijing pul great achievement bio tech ltd provides; Nitric oxide (NO) testing cassete, lot number: 20080405, the Coomassie brilliant blue protein determination kit, lot number: 20080408, building up bio-engineering research by Nanjing provides; Norepinephrine (Noradrenaline, NE), lot number: 20080516, BioSource Europe S.A. provides; 5-hydroxy tryptamine (Serotonin, 5-HT), lot number: 20080516, BioSource Europe S.A. provides.
3) instrument
Electronic balance, model: JA1003N, Shanghai Precision Scientific Apparatus Co., Ltd produces.Super high power magnetic stirring apparatus S-6, power 40W, Beijing Jin Bei moral industry and trade company limited is produced.The LGR10-4.2 centrifuge, Beijing Medical Centrifugal Machine Factory produces.DY89-I type electric driven glass refiner, numbering: 9309, Ningbo Xin Zhike device institute is produced.Sn-69513 type immunity enumerator, a Shanghai nuclear institute day ring photoelectric instrument company limited is produced.The SK-1 vortex mixer, Changzhou Guohua Electric Appliance Co., Ltd. produces.722N type visible spectrophotometer, Shanghai Precision Scientific Apparatus Co., Ltd produces.Cut high speed dispersion device in the XHF-1, Shanghai gold reach biochemical instrument factory and produce.Finland's pipettor, Lei Bo Analytical Instrument Co., Ltd in Shanghai produces.The HH-4 thermostat water bath, Changzhou Guohua Electric Appliance Co., Ltd. produces.80-2 type low speed centrifuge, Shanghai Surgical Operation Equipment Factory produces.100 ℃ of water-baths, Beijing Medical Equipment Plant produces.Sai Duolisi BS110S electronic scale, German Sai Duolisi company produces.
B. method and result
1) method
1.1 grouping, administration
The SD rat is divided into 7 groups at random, 12 every group, is respectively blank group, model group, Sumatriptan Succinate sheet group, compound cavel capsule group, the large, medium and small dose groups of the migrainous Chinese medicine of treatment.Blank group, model group are irritated stomach normal saline 1mL/100g equal every day; Sumatriptan Succinate sheet group, compound cavel capsule group, treatment migrainous Chinese medicine large, medium and small dose groups are respectively given the drug solution of respective concentration, irritate stomach 1mL/100g every day.
1.2 modeling
Successive administration 5 days, other each group was pressed nitroglycerin method reports such as () Tassorelli abdominal part hypodermic nitroglycerin (10mg/Kg) half an hour after administration, duplicated Nerve in Migraine Model, for three days on end except that the blank group in the 6th day.
1.3 behavioristics's observation index
Last modeling (the 8th day) back is observed and is respectively organized rat behavior variation 4 hours, is observation index with rat number of times difficult to tackle.
1.4 draw materials and sample disposal
1.4.1 get the blood modeling after 4 hours; Rat with chloral hydrate anesthesia, is taken off caval vein blood 2mL, inject the ice-cold centrifuge tube that contains 7.5% disodiumedetate, 30 μ L and aprotinin 40 μ L; Shake up gently; 4 ℃, 3000r/ minute centrifugal 10 minutes, are isolated 0.8mL (supply that CGRP and ET detect with) and 0.2mL anticoagulate plasma (supplying the 5-HT detection to use) respectively; Take off caval vein blood 2M1, inject the ice-cold centrifuge tube that contains indometacin-about 0.2mL of EDTA.Na2 liquid and (supply TXB
2And 6-Keto-PGF
1α detect with), shake up gently, 4 ℃, 3000r/ minute, centrifugal 10 minutes, isolate anticoagulate plasma 0.5mL, all anticoagulate plasmas by numbering put into-86 ℃ of cryogenic refrigerators store, subsequent use.
1.4.2 after getting cerebral tissue and getting blood, with the animal sacrificed by decapitation, get brain at once; Remove meninges and blood vessel, isolate the about 600mg of cerebral tissue that contains brain stem, thalamus, hypothalamus zone, weigh on the stannum pool paper; 0.9% normal saline 1mL and the 1N glacial acetic acid 0.5mL that add pre-cooling carry out homogenate in homogenizer, reuse 1N sodium hydroxide 0.5mL neutralization, and cerebral tissue concentration is 20%; 4 ℃, 3500r/ minute, centrifugal 30 minutes.Get each 0.5mL of supernatant respectively, supply NO and 5-HT, NE to detect usefulness, all supernatant are put into-86 ℃ of cryogenic refrigerators storages, subsequent use by numbering.
1.5 index detects
Adopt radio immunoassay to measure plasma calcitonin gene related peptide (CGRP), Endothelin (ET), thromboxane B2 (TKB
2), 6-ketone-PGF1 (6-Keto-PGF
1 α), 5-hydroxy tryptamine (5-HT), cerebral tissue 5-HT and norepinephrine (NE).Adopt colorimetric method for determining cerebral tissue NO, put by PLA General Hospital Science and Technology Development Center and exempt from responsible detection.
1.6 statistical procedures
Adopt SPSS 12.0 statistical softwares (software of SPSS Inc.'s exploitation, English full name is Statistical Product and Service Solutions, means " statistics product and service solution ") to analyze.The conversion of taking the logarithm of heterogeneity of variance data, mean relatively adopts one factor analysis of variance.Experimental result model group and blank group compare, and compare in twos between each administration group and model group, adopt q method of inspection (student-Newman-Keuls:SNK), two-sided test, significant difference P＜0.05.
2) result
2.1 influence to the number of times difficult to tackle of rat in the last modeling 4 hours
Nitroglycerin is modeling for three days on end, after the last modeling each group number of times difficult to tackle is observed 4 hours continuously, and the result sees table 3.Model group and blank group relatively have statistical significant difference (P＜0.05), and each administration group and model group relatively all have statistical significant difference (P＜0.05).
The migrainous Chinese medicine of table 3 embodiment of the invention 1 described treatment to the influence of the number of times difficult to tackle of rat in the last modeling 4 hours (
inferior/4h)
| Group | n | Number of times difficult to tackle |
| The blank group | 12 | 15.33±11.70 |
| Model group | 12 | 88.08±19.30 △ |
| Sumatriptan Succinate sheet group | 12 | 18.67±15.16 ★ |
| The compound cavel capsule group | 12 | 17.75±15.84 ★ |
| The heavy dose group of treatment migraine Chinese medicine | 12 | 21.08±14.63 ★ |
| The middle dose groups of treatment migraine Chinese medicine | 12 | 33.17±27.50 ★ |
| The small dose group of treatment migraine Chinese medicine | 12 | 32.67±21.73 ★ |
Annotate: △ representes to compare with the blank group: P＜0.05, ★ representes to compare with model group: P＜0.05.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and make an experiment, obtain similar result.
2.2 influence to nitroglycerin type Migraine Rats monoamine neurotransmitters
The migrainous Chinese medicine of table 4 embodiment of the invention 1 described treatment is to the influence (
pg/mL) of nitroglycerin type Migraine Rats monoamine neurotransmitters
Annotate: △ representes to compare with the blank group: P＜0.05, ★ representes to compare with model group: P＜0.05.
Can find out that from table 4 model group blood 5-HT, cerebral tissue 5-HT content compares with the blank group and statistical significant difference is all arranged (P＜0.05), each administration group blood 5-HT, cerebral tissue 5-HT content are compared with model group all has statistical significant difference (P＜0.05).Each organizes cerebral tissue NE content does not relatively have statistical significant difference (P＞0.05) in twos.Explain that the migrainous Chinese medicine of treatment has the effect that improves cerebral tissue and blood 5-HT.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and measure, obtain similar result.
2.3 influence to nitroglycerin type Migraine Rats cerebral tissue NO content
Collect 84 big rat brain tissue homogenate's samples altogether, utilization Coomassie brilliant blue method is measured protein content, and the sample requirement is bigger, and the less tissue homogenate sample of content can not detect, so each group all has the sample disappearance, the result is as shown in table 6.
The migrainous Chinese medicine of table 5 embodiment of the invention 1 described treatment is to the influence (
μ mol/gprot) of nitroglycerin type Migraine Rats cerebral tissue NO
| Group | n | Brain NO |
| The blank group | 11 | 1.23±1.08 |
| Model group | 11 | 3.56±4.21 |
| Sumatriptan Succinate sheet group | 10 | 2.34±3.85 |
| The compound cavel capsule group | 10 | 1.84±2.88 |
| The heavy dose group of treatment migraine Chinese medicine | 11 | 1.41±2.18 |
| The middle dose groups of treatment migraine Chinese medicine | 10 | 1.32±0.70 |
| The small dose group of treatment migraine Chinese medicine | 9 | 1.52±1.21 |
Can find out that from table 5 each dose groups of the migrainous Chinese medicine of the embodiment of the invention 1 described treatment has the trend that reduces nitroglycerin type Migraine Rats cerebral tissue NO content, does not relatively have statistical significant difference (P＞0.05) in twos but respectively organize cerebral tissue NO content.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and make an experiment, obtain similar result.
2.4 to nitroglycerin type Migraine Rats blood CGRP, TXB
2, 6-Keto-PGF
1 αThe influence of content
The migrainous Chinese medicine of table 6 embodiment of the invention 1 described treatment is to nitroglycerin type Migraine Rats blood CGRP, TXB
2, 6-Keto-PGF
1 αThe influence of content (
Pg/mL)
Can find out that from table 6 each organizes rat plasma CGRP, TXB
2, 6-Keto-PGF
1 αContent does not more all have statistical significant difference (P＞0.05) in twos.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and make an experiment, obtain similar result.
2.5 influence to nitroglycerin type Migraine Rats blood Endothelin (ET) content
Collect 84 rat anticoagulate plasmas altogether, utilization measured by radioimmunoassay blood ET content, less anticoagulate plasma can not detect, model group, each scarce 1 sample of Sumatriptan Succinate sheet group, concrete outcome is as shown in table 7.
The migrainous Chinese medicine of table 7 embodiment of the invention 1 described treatment is to the influence (
pg/mL) of nitroglycerin type Migraine Rats blood ET content
| Group | n | ET |
| The blank group | 12 | 87.55±18.52 |
| Model group | 11 | 72.91±19.05 |
| Sumatriptan Succinate sheet group | 11 | 96.22±23.96 |
| The compound cavel capsule group | 12 | 98.06±23.00 |
| The heavy dose group of treatment migraine Chinese medicine | 12 | 74.01±20.73 |
| The middle dose groups of treatment migraine Chinese medicine | 12 | 84.29±26.24 |
| The small dose group of treatment migraine Chinese medicine | 12 | 95.47±25.27 |
Can find out that from table 7 each dose groups of the migrainous Chinese medicine of the embodiment of the invention 1 described treatment has the trend that improves blood ET content, does not relatively have statistical significant difference (P＞0.05) in twos but respectively organize rat serum ET content.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and make an experiment, obtain similar result.
The migrainous Chinese medicine of Test Example 2 embodiment of the invention, 1 described treatment is to the influence of " syndrome of blood stasis " rat model hemorheology and platelet aggregation
A. experiment material
1) animal
84 of SPF level SD rats, body weight 260～280g, male and female half and half are available from Test Animal Centre, Academy of Military Medical Sciences, P.L.A's (licence numbering: SCXK (army) 2002-001).Sub-cage rearing is in Basic Theories of Chinese Medicine institute laboratory animal room of Chinese department of Chinese medicine institute (cleaning level), 23～25 ℃ of temperature, and humidity 40%～60%, aseptic bar-shaped forage feed is freely drunk water.
2) medicine and reagent
Receive reagent: the migrainous Chinese medicine of treatment of the present invention is provided lot number by the Drug Manufacturing Room of Beijing University of Chinese Medicine: 20080303.Adult (in 70Kg) clinical consumption 11.35g crude drug/sky; According to " experimental animal is pressed body surface area than equivalent conversion ratio with the people "; The test with the treatment migrainous Chinese medicine rat dose,equivalent=11.35 * 0.018 * 1000/200=1.022g/kg, get 0.341g/Kg, 1.022g/Kg, 3.065g/Kg respectively as rat test little, in, heavy dose.Be made into the solution of 34.1mg/mL, 102.2mg/mL, 306.5mg/mL respectively with deionized water.
Positive control drug: Aspirin Enteric-coated Tablets, trade name Baysprin, specification: 100mg/ sheet; 30/box, import medicine registration certificate number: H20050059, batch number: BTA6E91; BayerHealthCare AG produces; By adult 100mg/d amount, being equivalent to rat dosage every day is 9mg/kg, is made into the concentration of 0.9mg/mL with deionized water; Compound cavel capsule, Inner Mongol gouy Tai Danlong Pharmaceutical Co., Ltd, lot number: 20061006.Compound cavel capsule is by adult's 0.25g/ grain, every day 3 times, each 5, is made into the concentration of 33.75mg/mL with deionized water.
Reagent: the adrenalin hydrochloride injection, specification: 1mL/ props up, and 10/box, batch number: 071102, Guangzhou Baiyunshan Mingxing Pharmaceutical Co., Ltd. provides.Urethanes (urethane), batch number: 040427, Beijing chemical reagents corporation provides.Adenosine diphosphate (ADP) (ADP), batch number: 9908128, the beautiful pearl east wind in Shanghai Bioisystech Co., Ltd provides.Sodium chloride injection, the accurate word H11021192 of traditional Chinese medicines, specification: 500mL:4.5g, batch number: 0711212W, the Beijing Double-Crane Pharmaceutical Co., Ltd provides.
Test kit: Fibrinogen (FIB) assay test kit, batch number: 1320091, sun biotech company in Shanghai provides.
3) instrument
The PA-3210 platelet aggregation instrument, the first science production of Japanese DIC capital of a country; LBY-N6A cleans rotating cylinder viscometer automatically, and Beijing Puli gives birth to company and produces; The LBY-NW1 capillary viscosimeter, Beijing Puli gives birth to company and produces; PRECIL C2000-4 blood pool appearance, Beijing Puli gives birth to company and produces; KH-120M trace capillary tube centrifuge, Japanese KUBOTA HEMATOCRIT produces; The LXJ-II centrifugal precipitation mechanism, medical analytical instrument factory in Shanghai produces; The JA1003N electronic balance, Shanghai Precision Scientific Apparatus Co., Ltd produces.
B. method and result
1) method
1.1 grouping, administration
The SD rat is divided into 7 groups at random, and male and female half and half, are divided into normal control group, epinephrine model group, aspirin group, compound cavel capsule group, the large, medium and small dose groups of the migrainous Chinese medicine of treatment by 12 every group.Normal control group, epinephrine model group are irritated stomach normal saline 1mL/100g equal every day; The aspirin group, compound cavel capsule group, treatment migrainous Chinese medicine large, medium and small dose groups are respectively given the drug solution of respective concentration, irritate stomach 1mL/100g every day.
1.2 modeling
Successive administration modeling after 5 days; The 5th except that the normal control group; All the other each treated animals were pressed body weight subcutaneous injection adrenalin hydrochloride 0.1mL/100g in 1 hour according to the method in " herbal pharmacology research methodology " behind the filling stomach, after 2 hours rat were placed 4 ℃ of water-baths 5 minutes; The commensurability adrenalin hydrochloride of subcutaneous again injection at a distance from 2 hours duplicates " syndrome of blood stasis " rat model model.Morning next day, gastric infusion was after 1 hour, and the anesthesia of 200g/L urethane is abdominal aortic blood down, in 2 hours, detects index.
1.3 index detects
1.3.1 respectively being organized rat, the influence of hemorheology of rat anaesthetizes with the 200g/L urethane respectively morning next day after modeling, by abdominal aortic blood, and liquor sodii citratis anticoagulant (volume ratio 1: 9).Get the 700ul whole blood and slowly add in the Instrument measuring cup, 37 ℃ of preparatory temperature 1 minute measure 10,50 and the WBV of 200s-1.Part blood plasma adopts capillary tube method to measure packed cell volume as plasma viscosity mensuration, adopts the Clauss freezing method to press explanation mensuration Fibrinogen (FIB) content in the test kit.
1.3.2 to the influence of rat platelet aggregation rate by abdominal aortic blood, liquor sodii citratis anticoagulant (volume ratio 1: 9), 1000r/ minute centrifugal 10 minutes, preparation platelet rich plasma (PRP) was got a certain amount of subsequent use.Again that remainder is centrifugal 15 minutes with 3000r/ minute; Preparation platelet poor plasma (PPP); PRP is mixed with PPP by a certain percentage; (this moment, platelet count was 3 * 912/L), used ADP to be derivant, adopted the maximum agglutination rate of platelet aggregation in the turbidimetry for Determination certain hour with the platelet appearance transmittance to be transferred to about 4000.
1.4 statistical procedures
Adopt the SPSS12.0 statistical software; Measurement data carries out comparing in twos between one factor analysis of variance and group with mean ± standard deviation
expression.Two-sided test, significant difference P＜0.05.
2) experimental result
2.1 to before the rat administration and the influence of body weight before the modeling
Each reaches the preceding weight ratio of modeling before organizing the rat administration, and difference not statistically significant (P＞0.05) explains that the body weight of respectively organizing rat is suitable, has comparability between group.(seeing table 8)
Compare
between the rat body weight group before table 8 administration and before the modeling
| Group | n | Body weight before the administration | Body weight before the modeling |
| The normal control group | 12 | 284.42±2.75 | 289.25±2.45 |
| Model control group | 12 | 286.42±2.15 | 290.08±2.02 |
| The aspirin group | 12 | 284.58±2.39 | 289.50±1.78 |
| The compound cavel capsule group | 12 | 284.83±1.95 | 289.08±1.38 |
| The heavy dose group of treatment migraine Chinese medicine | 12 | 284.50±2.50 | 288.58±1.68 |
| The middle dose groups of treatment migraine Chinese medicine | 12 | 284.92±2.71 | 289.17±2.08 |
| The small dose group of treatment migraine Chinese medicine | 12 | 284.83±2.41 | 289.83±1.69 |
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and make an experiment, obtain similar result.
2.2 influence to stasis syndrome card hemorheology of rat
Result of study shows that model group rat whole blood and plasma viscosity, packed cell volume, Fibrinogen and platelet aggregation rate all obviously raise, and compares with the normal control group to have statistical significant difference (P＜0.05).Blood stasis state sticking, dense, that coagulate, gather appears in the hemorheology that shows rat model, and prompting stasis syndrome card rat model is set up successfully.
The migrainous Chinese medicine of table 9 embodiment of the invention 1 described treatment is to the influence
of syndrome of blood stasis rat WBV and plasma viscosity
Annotate: ▲ expression is compared with model group: P＜0.05, and # representes to compare with the aspirin group: P＜0.05,
■ representes to compare with compound cavel capsule: P＜0.05.
Can know that by result in the table 9 the migrainous Chinese medicine heavy dose of the embodiment of the invention 1 described treatment can obviously reduce high, medium and low viscosity and the plasma viscosity cut of rat whole blood, relatively have statistical significant difference (P＜0.05) with model group.Treat in the migrainous Chinese medicine dosage can obviously reduce the whole blood height, in cut viscosity and plasma viscosity, relatively have statistical significant difference (P＜0.05) with model group.Treat migrainous Chinese medicine low dose and can reduce the whole blood height and cut viscosity, relatively have statistical significant difference (P＜0.05), can reduce and cut viscosity and plasma viscosity in the whole blood, relatively do not have statistical significant difference (P＞0.05) with model group with model group.
The aspirin group can obviously reduce high, medium and low viscosity and the plasma viscosity cut of rat whole blood, relatively has statistical significant difference (P＜0.05) with model group; The whole blood of aspirin group is high, medium and low cuts viscosity and plasma viscosity is lower than treatment large, medium and small dose groups of migrainous Chinese medicine and compound cavel group, has statistical significant difference (P＜0.05).
The compound cavel group can reduce that the rat whole blood is low cuts viscosity and plasma viscosity, relatively has statistical significant difference (P＜0.05) with model group, can reduce the whole blood height, in cut viscosity, relatively do not have statistical significant difference (P＞0.05) with model group; The high, medium and low viscosity of cutting of the whole blood of compound cavel group does not relatively have statistical significant difference (P＞0.05) with the large, medium and small dose groups of the migrainous Chinese medicine of treatment; Its plasma viscosity and the heavy dose of group of the migrainous Chinese medicine of treatment relatively have statistical significant difference (P＜0.05), with in the migrainous Chinese medicine of treatment, small dose group relatively do not have statistical significant difference (P＞0.05).
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and make an experiment, obtain similar result.
The migrainous Chinese medicine of table 10 embodiment of the invention 1 described treatment is to syndrome of blood stasis rat packed cell volume, fibrinogenic influence
| Group | n | Packed cell volume (%) | Fibrinogen (g/l) |
| The normal control group | 12 | 42.11±1.22 ▲ | 2.50±0.24 ▲ |
| Model control group | 12 | 46.85±1.40 | 5.38±0.33 |
| The aspirin group | 12 | 43.34±0.88 ▲ | 4.83±0.49 ▲ |
| The compound cavel capsule group | 12 | 44.81±1.53 ▲# | 4.83±0.42 ▲ |
| The heavy dose group of treatment migraine Chinese medicine | 12 | 43.95±1.44 ▲ | 4.93±0.31 ▲ |
| The middle dose groups of treatment migraine Chinese medicine | 12 | 44.74±0.95 ▲# | 4.87±0.39 ▲ |
| The small dose group of treatment migraine Chinese medicine | 12 | 45.25±1.01 ▲# | 5.08±0.46 |
Annotate: ▲ represent each group and model group relatively: P＜0.05, # representes to compare with the aspirin group: P＜0.05.
Can know that by result in the table 10 the big or middle dosage of the embodiment of the invention migrainous Chinese medicine of 1 described treatment can obviously reduce packed cell volume and the Fibrinogen of rat, relatively have statistical significant difference (P＜0.05) with model group.Treat migrainous Chinese medicine low dose and can obviously reduce packed cell volume, relatively have statistical significant difference (P＜0.05) with model group; Can reduce Fibrinogen, relatively not have statistical significant difference (P＞0.05) with model group.
The aspirin group can obviously reduce packed cell volume and the Fibrinogen of rat, relatively has statistical significant difference (P＜0.05) with model group.The packed cell volume of aspirin group is lower than in the migrainous Chinese medicine of treatment, small dose group and compound cavel group, has statistical significant difference (P＜0.05).The Fibrinogen of aspirin group is lower than treatment big or middle dose groups of migrainous Chinese medicine and compound cavel group, does not have statistical significant difference (P＞0.05).The compound cavel group can obviously reduce rat packed cell volume and Fibrinogen, relatively has statistical significant difference (P＜0.05) with model group.The large, medium and small dose groups of the migrainous Chinese medicine of the packed cell volume of compound cavel group, Fibrinogen and treatment does not relatively have statistical significant difference (P＞0.05).
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and make an experiment, obtain similar result.
2.3 influence to stasis syndrome card rat platelet aggregation rate
The migrainous Chinese medicine of table 11 embodiment of the invention 1 described treatment is to the influence
of syndrome of blood stasis rat platelet maximum agglutination rate
| Group | n | Platelet maximum agglutination rate (%) |
| The normal control group | 12 | 54.21±3.20▲ |
| Model control group | 12 | 71.53±3.13 |
| The aspirin group | 12 | 48.60±2.39▲ |
| The compound cavel capsule group | 12 | 59.49±4.07▲# |
| The heavy dose group of treatment migraine Chinese medicine | 12 | 62.61±4.75▲# |
| The middle dose groups of treatment migraine Chinese medicine | 12 | 56.56±4.64▲# |
| The small dose group of treatment migraine Chinese medicine | 12 | 61.01±4.52▲# |
Annotate: ▲ represent each group and model group relatively: P＜0.05, # representes to compare with the aspirin group: P＜0.05.
Can know by result in the table 11; The embodiment of the invention large, medium and small dosage of the migrainous Chinese medicine of 1 described treatment and aspirin group, compound cavel group all can obviously reduce the rat platelet maximum agglutination rate, relatively have statistical significant difference (P＜0.05) with model group.The platelet maximum agglutination rate of aspirin group is lower than treatment large, medium and small dose groups of migrainous Chinese medicine and compound cavel group, has statistical significant difference (P＜0.05).The platelet maximum agglutination rate of compound cavel group does not relatively have statistical significant difference (P＞0.05) with the large, medium and small dose groups of the migrainous Chinese medicine of treatment.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and make an experiment, obtain similar result.
Toxicity, pharmacology, evaluating drug effect conclusion
1, pharmacology, evaluating drug effect
(1) the migrainous Chinese medicine analgesic activity research of treatment
Get the migrainous Chinese medicine of the above embodiment of the present invention 1 described treatment; Measure the rat brain blood flow through Doppler; The migrainous Chinese medicine of research the above embodiment of the present invention 1 described treatment is to the influence of rat serum flow; The result shows that dose groups and small dose group in the migrainous Chinese medicine of the above embodiment of the present invention 1 described treatment all can obviously increase the cerebral blood flow of rat, have statistical significance with normal saline group comparing difference.
1. the analgesic activity of migrainous Chinese medicine is treated in hot plate method research;
2. the analgesic activity of migrainous Chinese medicine is treated in the research of acetic acid twisting method.
The result shows: the hot plate threshold of pain of middle dose groups, heavy dose of group and small dose group obviously prolongs than the normal saline group; Comparing difference has statistical significance (P＜0.05) between group, explains that the migrainous Chinese medicine of the above embodiment of the present invention 1 described treatment has good analgesic activity to the pain due to the physical stimulation; The chemical stimulation that glacial acetic acid is caused; What the migrainous Chinese medicine of the above embodiment of the present invention 1 described treatment can obviously reduce mice turns round the body number of times, compares with the normal saline group, and difference has statistical significance (P＜0.05); And prompting increases with dosage, and effect strengthens.
(2) the migrainous Chinese medicine of treatment is to the collaborative syngignoscism of sub-threshold dose pentobarbital sodium
The result: the syngignoscism with stable group is the strongest, and the hypnosis incidence rate reaches 87.5%, and effect is superior to normal saline group, compound cavel capsule group, small dose group and heavy dose of group, and difference has statistical significance (P＜0.05); The syngignoscism of middle dose groups is taken second place, and reaches 62.5%, with stable group, compound cavel capsule group ratio, difference not statistically significant, but is superior to the normal saline group, and difference has statistical significance (P＜0.01); The migrainous Chinese medicine small dose group of treatment of the present invention is suitable with the syngignoscism of heavy dose of group, and the hypnosis incidence rate is 50%, is superior to the normal saline group, and difference has statistical significance (P＜0.05); The hypnosis incidence rate of compound cavel capsule is 31.25%, compares the difference not statistically significant with normal saline.
(3) the migrainous Chinese medicine of treatment is to the influence of rat brain blood flow
Measure the rat brain blood flow through Doppler, study the influence of the migrainous Chinese medicine of treatment of the present invention the rat serum flow.
The result shows the middle dose groups of the migrainous Chinese medicine of the embodiment of the invention 1 described treatment and the cerebral blood flow that small dose group all can obviously increase rat, has statistical significance with normal saline group comparing difference.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and carry out above-mentioned test, obtain similar result.
2, toxicological test situation
(1) acute toxicity test
Requirement according to " provisions for new drugs approval "; The medication gastric infusion consistent with the clinical administration approach adopted in experiment; Give the above embodiment of the present invention 1 described treatment migrainous Chinese medicine; Since can not survey the calculating half lethal dose of treating migrainous Chinese medicine (median lethal dose, LD50), so carry out animal maximum dosage-feeding determination test; Recording it is 151.2g crude drug/kg to its mouse oral maximum dosage-feeding, is equivalent to 799 times of clinical anthropomorphic consumption 0.227g crude drug/kg (becoming body weight for humans to press the 60kg conversion).
The result shows: after oral administration was treated migrainous Chinese medicine, 20 mices toxic reaction and death did not all occur in 7 days, and ordinary circumstance is good, and hair color is normal, activity freely, feed, drinking-water and two just normal.Dissect each organ of perusal animal and do not find that all obvious color and form change; Show that acute toxicity is low, oral safety.
(2) long term toxicity test
The result shows: 1. in 13 weeks of administration, treat migrainous Chinese medicine little, in, heavy dose of group compares with matched group, hematology's each item index there are no significant difference.In 26 weeks of administration, middle dose groups platelet count (PLT), thrombocytocrit (PCT) are apparently higher than matched group, and heavy dose of group PLT, PCT and matched group are relatively, there was no significant difference.Analysis-by-synthesis prompting, this in PLT, the PCT of the dose groups no practical significance that fluctuates.In 26 weeks of administration, heavy dose of group MCVU (MCV) is starkly lower than matched group, and middle dose groups and heavy dose of group RDW (RDW) are apparently higher than matched group; Middle dose groups is starkly lower than matched group with heavy dose of group MPV, PDW.After 4 weeks of drug withdrawal, heavy dose of group RDW is apparently higher than matched group.More than these all belong to the fluctuation in the normal range value, no practical significance.Other indexs of hematology and the matched group of the same period compare, meaning that there are no significant.
2. in 13 week and 26 weeks of administration; Heavy dose of group blood urea nitrogen (BUN) is all apparently higher than matched group; This results suggest: this medicine heavy dose can produce influence to a certain degree to the glomerule function, therefore, when clinical trial, should pay close attention to the variation of patient's glomerule function.After 4 weeks of drug withdrawal, this index and matched group there was no significant difference.In 26 weeks of administration, middle dose groups glutamic oxaloacetic transaminase, GOT (AST) is apparently higher than matched group.At administration 13 week heavy dose of group uric acid (UAC), and in 26 weeks of administration dose groups UAC, all apparently higher than matched group.In 13 weeks of administration, heavy dose of group glucose (GLU) is apparently higher than matched group, and in 26 weeks of administration, heavy dose of group and middle dose groups GLU are starkly lower than matched group.In 13 weeks of administration, heavy dose of group total protein (TP) and albumin (ALB) are all apparently higher than matched group.In 26 weeks of administration, middle dose groups and heavy dose of group T-BIL are starkly lower than matched group.After 4 weeks of drug withdrawal, middle dose groups TP is apparently higher than matched group.The variation of These parameters all within normal fluctuation range, no practical significance.Blood biochemical learns other indexs and the matched group of the same period compares, difference that there are no significant.
3. give rat continuous irrigation clothes treatment migrainous 13 weeks of Chinese medicine, 26 weeks and 4 weeks of drug withdrawal, outward appearance sign, behavioral activity, body weight, feed and the defecation etc. of rat are all normal.None routine rats death.The organ coefficient of rat major organs does not all have obvious change.22 kinds of internal organs such as the heart, liver, spleen, lung, kidney, adrenal gland, pancreas, thymus, thyroid, brain, spinal cord, lymph node, prostate, testis, epididymis, ovary, uterus, stomach, duodenum, ileum, colon, bladder are carried out pathologic finding, do not see drug-induced pathomorphology damage.
Conclusion: heavy dose of 19.44 crude drugs of the migrainous Chinese medicine of the embodiment of the invention 1 described treatment/kg (quite clinical consumption 102 times) can produce influence to a certain degree to the glomerule function; After 4 weeks of drug withdrawal; Compare there was no significant difference between the BUN group; And middle dosage 9.72g crude drug/kg (quite clinical consumption 51 times), low dose of 4.86g crude drug/kg (be equivalent to clinical consumption 25.5 times) do not see obvious influence, when clinical trial, should pay close attention to the variation of patient's glomerule function.
(3) pathology
Conclusion: each each organs and tissues of administration group and control rats of (1) each phase and nervous system morphology finding are similar; (2) immune system morphology finding no abnormality seen; (3) do not see that the nervous tissue, parenchymal viscera and the parenchyma that are caused by drug intoxication are rotten and sexually revise, and by inflammatory reaction that drug intoxication caused.
Get the migrainous Chinese medicine of described treatment that the above embodiment of the present invention 2-3 makes and carry out above-mentioned test, obtain similar result.
Therefore, the migrainous Chinese medicine of treatment of the present invention, treatment headache effectively, safety and do not have toxic and side effects in the migrainous while of treatment, can be looked after migraineur's gastrointestinal symptoms, and migraineur's simultaneous phenomenon is also had better therapeutic effect.
The above is merely preferred embodiment of the present invention, and is in order to restriction the present invention, not all within spirit of the present invention and principle, any modification of being done, is equal to replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (5)
1. the migrainous Chinese medicine of treatment is characterized in that the prescription of said Chinese medicine is made up of each raw material of following parts by weight: Rhizoma Chuanxiong 187～563, the Radix Angelicae Dahuricae 187～563, Fructus Evodiae 93～280 and Mentholum 4.1～12.4.
2. the migrainous Chinese medicine of treatment according to claim 1 is characterized in that each raw materials in part by weight is in the prescription of said Chinese medicine: Rhizoma Chuanxiong 375, the Radix Angelicae Dahuricae 375, Fructus Evodiae 187 and Mentholum 8.3.
3. the migrainous Chinese medicine of treatment according to claim 1 and 2 is characterized in that the migrainous Chinese medicine of said treatment is processed capsule.
4. the migrainous preparation method of Chinese medicine of treatment is characterized in that, may further comprise the steps:
1) takes by weighing following each raw materials of parts by weight: Rhizoma Chuanxiong 187～563, the Radix Angelicae Dahuricae 187～563, Fructus Evodiae 93～280, Mentholum 4.1～12.4;
2) Rhizoma Chuanxiong and the Radix Angelicae Dahuricae are ground into coarse powder,, make solvent with 80% ethanol according to percolation, behind the dipping, percolation; The collection liquid of filtering, diacolation liquid recycling ethanol is concentrated into the thick paste shape, adds the dextrin mixing; Reuse 95% ethanol is wetting agent, processes granule, and final drying, granulate are subsequent use;
3) with Fructus Evodiae with 70% alcohol reflux secondary, collecting decoction filters, and reclaims ethanol, is concentrated into the thick paste shape, drying under reduced pressure again, dry extract, subsequent use;
4) Mentholum is dissolved in an amount of ethanol, places with the betacyclodextrin enclose, sedimentation filters, the collecting precipitation thing, and washing, drying, subsequent use;
5) Fructus Evodiae dry extract and Mentholum betacyclodextrin clathrate are mixed pulverizing, cross 60 mesh sieves, add 95% ethanol, process granule, dry, granulate with Rhizoma Chuanxiong, Radix Angelicae Dahuricae granule mixing, incapsulate, and promptly get.
5. the migrainous preparation method of Chinese medicine of treatment according to claim 4 is characterized in that, said capsule is No. 1 capsule.
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| CN104435589A (en) * | 2014-10-29 | 2015-03-25 | 济南方宇文化传媒有限公司 | Traditional Chinese medicine preparation for treating migraine and preparation method thereof |
| CN105770109A (en) * | 2016-05-13 | 2016-07-20 | 河南省洛阳正骨医院河南省骨科医院 | Salt packet for relieving human muscular pain and preparation method thereof |
| CN114246830A (en) * | 2021-12-24 | 2022-03-29 | 上海凯宝药业股份有限公司 | Solid preparation for treating migraine and preparation method thereof |
| CN114515319A (en) * | 2021-12-28 | 2022-05-20 | 上海凯宝药业股份有限公司 | Traditional Chinese medicine composition for treating migraine and application thereof |
| CN114515309A (en) * | 2021-12-28 | 2022-05-20 | 上海凯宝药业股份有限公司 | External preparation for dispelling wind and relieving pain and preparation method thereof |
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