CN103768494A - Pharmaceutical composition for treating migraine as well as preparation method and application thereof - Google Patents
Pharmaceutical composition for treating migraine as well as preparation method and application thereof Download PDFInfo
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- CN103768494A CN103768494A CN201210397369.1A CN201210397369A CN103768494A CN 103768494 A CN103768494 A CN 103768494A CN 201210397369 A CN201210397369 A CN 201210397369A CN 103768494 A CN103768494 A CN 103768494A
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- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a pharmaceutical composition for treating migraine as well as preparation method and application thereof. The pharmaceutical composition mainly comprises the following raw materials by weight: 1-15 parts of Ligusticum wallichii, 1-11 parts of dahurian angelica roots, 2-18 parts of chrysanthemum, 1-15 parts of curcuma tubers, 1-15 parts of uncaria, 0.2-1.8 parts of asarum, 1-18 parts of ligusticum and 0.8-8 parts of scorpion, and the pharmaceutical composition is used for treating migraine; the method comprises the following steps: weighing the medicinal materials; extracting the medicinal materials with water or alcoholic solution; condensing the extract, drying, crushing, and obtaining the pharmaceutical composition. The pharmaceutical composition provided by the invention can be used for treating migraine, and has the advantages of reasonable composition, clear drug effect, conveniences of modern preparation and quality control, little toxic and side effects, safety and effectiveness; the raw material source is easily available, and the process is easy to be industrialized; the pharmaceutical composition can be prepared into various common oral dosage forms, and thereby providing convenience and effectiveness for clinic with controllable quality, and providing more benefits for patients with social benefits.
Description
Technical field
The present invention relates to the field of Chinese medicines.The present invention is specifically related to a kind of pharmaceutical composition and its preparation method and application, relates in particular to one and treats migrainous pharmaceutical composition and its preparation method and application.
Background technology
Migraine is the headache that a kind of nerve-dysfunction of blood vessel of periodical attack causes, take the migraine of repeatedly showing effect or bilatenal headache as feature, often has family history.
Migraine belongs to the most general neurological disorder, is modal symptom in general family medicine, and migrainous prevalence and sickness rate are all very high, and take the course of disease, length, sharp ache, intermittence are shown effect repeatedly, touching difficulty is more as feature.Bring great misery and heavy medicine burden to patient and family thereof, cause psychology, society and economic problems in various degree simultaneously.
Investigation demonstration, it is 13% that domestic 10 city Neurology Departments are added up migrainous annual prevalence; Prevalence in child and teenager is 7.7%; 3% general population suffers from chronic headache (monthly having a headache >=15 days), and the migrainous sex ratio of women's migraine and male is about 2-3:1.Hebetic women more easily suffers from headaches, and compares with teenager with male children, and the risk that women suffers from headaches will exceed 1.5 times, suffers from migrainous risk and exceeds 1.7 times." China's headache Epidemiological study " result that Chinese Medical Association's pain credit meeting is announced shows, in inland of China 18-65 year crowd, migraine attack rate is 23.8%, nearly 1/4 Chinese (exceed 1,300,000,000 calculating by the All population capacities of the 5th national census statistics, nearly exceed 300,000,000 people) suffer headache puzzlement.Every City patient spends 1098.08 yuan for the treatment of headaches every year on average.
Over nearly 5 years, migrainous sickness rate is in rising trend.The increase of headache number mainly contains two large reasons.The one, pressure strengthens, and occurs that the people of the emotional problem such as anxiety, depression is more and more, and the patient who is wrapped with by tension headache also increases thereupon; Stay up late, bend over one's desk working for a long time, sleep and be irregular etc. and also can cause headache; The 2nd, compared with in the past, along with the gradually enhancing of people to health care consciousness, patient is more ready that hospital finds the cause of disease.The market of migraine treatment medicine is will potentiality unlimited.
At present, World Health Organization is decided to be one of chronic disease disabling most by serious migraine, because it has the feature of outbreak repeatedly, can increase complication risk, can make cerebral infarction risk increase by 2.16 times, makes alba abnormal risk increase by 3.9 times.Investigation also shows, 85% the people work of therefore cannot concentrating one's energy.
Chemical medicine is mainly used in migrainous acute treatment and prophylactic treatment, and commercially available main species has beta-adrenergic blocking agent: most widely used general, as Propranolol; Antidepressant: as amitriptyline, nortriptyline; Calcium-channel antagonists: as verapamil, nimodipine; 5-HT antagonist: as methysergide; Anticonvulsant: valproic acid; Vitamins: riboflavin (vitamin B2).
Along with the lasting dilatation in migraine remedy market, Chinese patent medicine has occupied more and more important position therein, has the huge market demand.For migraine, the traditional Chinese medical science is emphasized " while sending out, take stopgap measures, effect a permanent cure at ordinary times ", and for etiology and pathogenesis and the pathological characteristic of migraine complexity, Chinese patent medicine carries out multipath, many target spots and multi-level Comprehensive Treatment, has obvious advantage, makes up the deficiency of chemical medicine.
But the migrainous Chinese medicine of current treatment can not be treated migraine effectively, therefore, exploitation one can effectively be treated migrainous Chinese medicine and be necessitated.
Summary of the invention
Therefore, the object of the invention is, for the deficiency that there is no at present effectively to treat migrainous Chinese medicine, provides one to treat migrainous pharmaceutical composition and its preparation method and application, thereby can effectively treat migraine, and the toxic and side effects of this pharmaceutical composition is little, safe and effective; And its raw material sources are easy to get, and technical process is easy to industrialization.
Unless specialized, " compound extract " herein all refers to " not containing the migrainous pharmaceutical composition for the treatment of of carrier and/or adjuvant ".
For above-mentioned purpose, technical scheme provided by the invention is as follows:
On the one hand, the invention provides one and treat migrainous pharmaceutical composition, described pharmaceutical composition is mainly made up of each raw material of following parts by weight: 0.8 ~ 8 part of 1 ~ 11 part of 1 ~ 15 part of Rhizoma Chuanxiong, 1 ~ 11 part of the Radix Angelicae Dahuricae, 2 ~ 18 parts of Flos Chrysanthemis, 1 ~ 15 part of Radix Curcumae, 1 ~ 15 part of Ramulus Uncariae Cum Uncis, 0.2 ~ 1.8 part of Herba Asari, Rhizoma Ligustici and Scorpio.
Preferably, described Rhizoma Chuanxiong is that 4 ~ 12 parts, the Radix Angelicae Dahuricae are that 3 ~ 9 parts, Flos Chrysanthemi are that 6 ~ 14 parts, Radix Curcumae are that 4 ~ 12 parts, Ramulus Uncariae Cum Uncis are that 4 ~ 12 parts, Herba Asari are that 0.6 ~ 1.4 part, Rhizoma Ligustici are that 3 ~ 9 parts and Scorpio are 2 ~ 6 parts.
Preferably, described Rhizoma Chuanxiong is that 8 parts, the Radix Angelicae Dahuricae are that 6 parts, Flos Chrysanthemi are that 10 parts, Radix Curcumae are that 8 parts, Ramulus Uncariae Cum Uncis are that 8 parts, Herba Asari are that 1 part, Rhizoma Ligustici are that 6 parts and Scorpio are 4 parts.
Preferably, described pharmaceutical composition also comprises pharmaceutically acceptable carrier and/or adjuvant.
More preferably, the dosage form of described pharmaceutical composition is capsule, tablet, granule or drop pill.
On the other hand, the invention provides the preparation method of the migrainous pharmaceutical composition for the treatment of described in the invention described above, described method is undertaken by the method comprising the following steps: take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae, Ramulus Uncariae Cum Uncis, Herba Asari, Rhizoma Ligustici and Scorpio, take water or alcoholic solution as solvent, by be selected from decoction, reflux, extract,, vapor distillation extraction, supersound extraction, merceration, microwave extraction and high pressure extract one or more method extract, after again extracting solution being concentrated, dry, pulverize, to obtain final product.
Preferably, concentrate by rotary evaporation, decocting and concentrating or thin film concentration under normal pressure or reduced pressure.
Preferably,, lyophilization dry by vacuum drying, spraying or drying under reduced pressure are dried.
Preferably, said method comprising the steps of:
1) take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae, Ramulus Uncariae Cum Uncis, Herba Asari, Rhizoma Ligustici and Scorpio, water or alcoholic solution pass through extraction by steam distillation, collect volatile oil, filtrate for later use, also preferably, uses water or the alcoholic solution of 10-12 times of volume of the quality of medicinal material taking to extract, more preferably, extract 5-6 hour, most preferably, described alcoholic solution is alcoholic solution;
2) again by medicinal residues water or alcoholic solution reflux, extract,, filter, merge with the filtrate in step 1), preferably, use water or the alcoholic solution of 10-12 times of volume of the medical material weight taking to extract, also preferably, extract 5-6 hour, most preferably, described alcoholic solution is alcoholic solution;
3) filtrate merging is concentrated, dry, obtain extract I;
4) by after the volatile oil inclusion obtaining in step 1), add extract I, to obtain final product.
Preferably, the concentration of described alcoholic solution is 60-80 volume %.
Preferably, said method comprising the steps of:
1) take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae and Rhizoma Ligustici, after pulverizing and sieving, extract by supercritical extraction, collect volatile oil, medicinal residues are for subsequent use, more preferably, cross 40 mesh sieves;
2) take Ramulus Uncariae Cum Uncis, Herba Asari and scorpion powder and be broken into coarse powder, mix with the medicinal residues in step 1), add alcoholic solution and soak, percolation extracts, until percolate color is light, more preferably, adds percent by volume and be the soak with ethanol 24 hours of 60-80%;
3) again by step 2) percolate that obtains is concentrated, dry, sprays into volatile oil, mixes, to obtain final product.
Preferably, said method comprising the steps of:
1) take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae and Rhizoma Ligustici, water or alcoholic solution reflux, extract,, collect volatile oil, and filtrate for later use more preferably, uses water or the alcoholic solution of 10-12 times of volume of the quality of medicinal material taking to extract, and also preferably, extracts 5-6 hour;
2) filtrate is concentrated, dry, obtain extract II;
3) take Ramulus Uncariae Cum Uncis, Herba Asari and Scorpio, water or alcoholic solution reflux, extract,, filter, and filtrate is condensed into thick paste, obtains extract III, and more preferably, the alcohol reflux that is 60-80% by volume ratio, also preferably, extracts each 1.0 hours 2 times;
4) extract II is added in extract III, mix, after dry, pulverize, spray into the volatile oil that step 1) makes, mix, to obtain final product.
Preferably, in step 1), before water or alcoholic solution extract, also comprise the step of the water soaking of the 10-12 times of volume that adds the medical material weight taking, preferably, soak 2 hours.
Preferably, described method is undertaken by the method comprising the following steps: described method is undertaken by the method comprising the following steps: take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae, Ramulus Uncariae Cum Uncis, Herba Asari, Rhizoma Ligustici and Scorpio, carried out reflux, extract,, decocted and extract or percolation extraction by water or alcoholic solution.
More preferably, in the time that percolation extracts, take after medical material, after being pulverized, add after alcohol solution dipping, percolation extracts, and collects percolation for the 5 times of volumes of liquid of just filtering, and is concentrated into thick paste I; Continue again percolation, until percolate color is light, collects percolate, then be concentrated into thick paste II; Then thick paste I and thick paste II are mixed, to obtain final product; Also preferably, add the alcohol solution dipping 24 hours that percent by volume is 60-85%.
Preferably, when by reflux, extract,, take after medical material, after water or alcoholic solution reflux, extract,, merging filtrate, dry, to obtain final product; More preferably, with get quality of medicinal material 10-12 times of volume or alcoholic solution 2-3 time, 1-2 hour, also preferably, extracts each 1.5 hours three times at every turn.
Preferably, in the time decocting extraction, take after medical material, soak after rear decoction extraction, merging filtrate, dry, to obtain final product; More preferably, by water boiling and extraction 2-3 time of 10-12 times of volume of getting quality of medicinal material, 1-2 hour, also preferably, extracts each 1.5 hours three times at every turn.
Also preferably, described alcoholic solution alcoholic solution, more preferably, the concentration of described alcoholic solution is 60-80 volume %.
Preferably, also comprise and add appropriate pharmaceutically acceptable carrier and/or adjuvant, make the step of capsule, tablet, granule or drop pill.
Preferably, described capsule is soft capsule.
Again on the one hand, the invention provides the migrainous compositions for the treatment of described in a kind of the invention described above in the application for the preparation of in the migrainous medicine for the treatment of.
Pharmaceutical composition of the present invention, can be used for treating migraine, its reasonable recipe, and drug effect is clear and definite, and is beneficial to and is prepared into modernization preparation and is convenient to quality control; Toxic and side effects is little, safe and effective; And its raw material sources are easy to get, technical process is easy to industrialization, can make as required various common peroral dosage forms, for clinical provide convenient, more effectively, the more controlled modern Chinese medicine of quality, for patient brings more interests, thereby produce huge social benefit.
The specific embodiment
Below in conjunction with the specific embodiment, the present invention is described in further detail, and the embodiment providing is in order to illustrate the present invention, rather than in order to limit the scope of the invention.
Unless specialized, Rhizoma Chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae, Ramulus Uncariae Cum Uncis, Herba Asari, Rhizoma Ligustici and Scorpio used in following examples are all purchased from Chang'an, Anguo City Chinese crude drug company limited.
Unless specialized, ferulic acid, ligustilide and luteoloside used in following examples are all purchased from Nat'l Pharmaceutical & Biological Products Control Institute.
Unless specialized, in following examples, reagent used is analytical pure level reagent, and can be commercially available from regular channel.
Embodiment 1
Prescription: Rhizoma Chuanxiong 4.6Kg, Radix Angelicae Dahuricae 4.6Kg, Flos Chrysanthemi 9.3Kg, Radix Curcumae 4.6Kg, Ramulus Uncariae Cum Uncis 4.6Kg, Herba Asari 0.9Kg, Rhizoma Ligustici 4.6Kg and Scorpio 3.7Kg.
Get above-mentioned medical material, add 12 times of volume (volume/weight, L/Kg) water soaking 2 hours, extraction by steam distillation 6 hours, collects volatile oil, filtrate for later use, medicinal residues add 10 times of volume (volume/weight, L/Kg) water reflux, extract, 1h, filters, and all filtrate merges, while being evaporated to 50 ℃, relative density is 1.15 ~ 1.20, add ethanol to concentration of alcohol 80 volume %, place the precipitation of spending the night, filter, decompression filtrate recycling ethanol is extremely without alcohol taste, be concentrated into 50 ℃ of relative densities approximately 1.10, drying under reduced pressure, obtains extract I;
The inclusion of volatile oil: take appropriate beta-schardinger dextrin-, add (the volume/weight of 5 times of volumes, L/Kg) water is made beta-schardinger dextrin-saturated solution, keep 50 ℃ of constant temperature, mixing speed 700r/min, in volatile oil: beta-schardinger dextrin-=1: 8(volume/mass) ratio slowly drip volatile oil, with magnetic stirring apparatus inclusion 2h, take out and put refrigerator and cooled and hide 24h.Sucking filtration, uses a small amount of water washing.Collect filtering residue, 40 ℃ dry, obtains volatile oil beta-CD inclusion complex.
Above-mentioned volatile oil inclusion complex is added in extract I, and equivalent increases progressively and mixes, and makes the compound extract for the preparation of pharmaceutical composition of the present invention, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
Adopt 90% ethanol wet granulation, concrete preparation method is as follows: by the above-mentioned compound extract making, starch+lactose+microcrystalline Cellulose by taking in right amount, after mix homogeneously, cross 80 mesh sieves, adding 90 volume % alcoholic solution granulates in right amount, 20 mesh sieve granulate are crossed in 40 ℃ of forced air dryings after 3 hours, obtain the granule of pharmaceutical composition of the present invention.
Embodiment 2
Prescription: Rhizoma Chuanxiong 2.4Kg, Radix Angelicae Dahuricae 1.8Kg, Flos Chrysanthemi 2.9Kg, Radix Curcumae 2.4Kg, Ramulus Uncariae Cum Uncis 2.4Kg, Herba Asari 0.3Kg, Rhizoma Ligustici 1.8Kg and Scorpio 1.3Kg.
Get Rhizoma Chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae, Rhizoma Ligustici, pulverized 40 orders, carry out CO
2supercritical extraction, is placed in extraction kettle, sets extracting pressure 25MPa, and 50 ℃ of extraction temperature, extract 4 hours, collects volatile oil, and medicinal residues are for subsequent use;
All the other flavour of a drug are ground into coarse powder, mix with above-mentioned medicinal residues, add 80 volume % soak with ethanol after 24 hours, slowly percolation, light to percolate color till, under condition of normal pressure, rotate evaporation and concentration to 50 ℃ relative density approximately 1.10, spraying is dry, sprays into volatile oil, mixes, make the compound extract for the preparation of pharmaceutical composition of the present invention, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
After adopting wet granulation prepared by tablet forming technique, concrete preparation method is as follows: compound extract, lactose+starch+microcrystalline Cellulose are taken according to quantity, after mix homogeneously, cross 80 mesh sieves, the alcoholic solution (1%) that adds polyvinylpyrrolidone is granulated in right amount, 50 ℃ of dry 20 mesh sieve granulate of crossing after 2 hours, then add magnesium stearate lubricant+micropowder silica gel, tabletting, obtains the tablet of pharmaceutical composition of the present invention.
Embodiment 3
Compound extract prepared by embodiment 2, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
Compound extract, starch+microcrystalline Cellulose+mannitol, citric acid are taken according to quantity, after mix homogeneously, cross 80 mesh sieves, the alcoholic solution (2%) that adds polyvinylpyrrolidone is granulated in right amount, 50 ℃ of dry 20 mesh sieve granulate of crossing after 2 hours, then add lubricant micropowder silica gel, encapsulated, obtain the capsule of pharmaceutical composition of the present invention.
Embodiment 4
Prescription: Rhizoma Chuanxiong 5.8Kg, Radix Angelicae Dahuricae 4.4Kg, Flos Chrysanthemi 8.7Kg, Radix Curcumae 5.8Kg, Ramulus Uncariae Cum Uncis 5.8Kg, Herba Asari 0.9Kg, Rhizoma Ligustici 4.4Kg and Scorpio 2.9Kg.
Get Rhizoma Chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae, Rhizoma Ligustici, add the water soaking 2 hours of 10 times of volumes (volume/weight, L/Kg), extraction by steam distillation 5 hours, collect volatile oil, when water liquid thin film concentration to 40 ℃, relative density is 1.10 ~ 1.15, adds ethanol to concentration of alcohol 70 volume %, the placement precipitation of spending the night, filter, decompression filtrate recycling ethanol, to without alcohol taste, is concentrated into thick paste, drying under reduced pressure or spraying are dry, obtain extract II;
60 volume % alcohol reflux of 8 times of volumes for all the other flavour of a drug (volume/weight, L/Kg) 2 times, each 1.0 hours, concentrating under reduced pressure becomes thick paste, obtain extract III, add extract II, mix, drying under reduced pressure, pulverize, spray into volatile oil, mix, make the compound extract for the preparation of pharmaceutical composition of the present invention, for the following embodiment of preparation of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
Adopt the preparation of dry granulation technique, concrete preparation method is as described below: compound extract, pregelatinized Starch, lactose, microcrystalline Cellulose, magnesium stearate are taken according to quantity, cross 100 mesh sieves after mix homogeneously, dry-pressing is granulated, cross 20 mesh sieve granulate, pack, obtains compound granular agent of the present invention.
Embodiment 5
Compound extract prepared by embodiment 4, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The compound preparation formula of pharmaceutical composition of the present invention is made up of following component:
Macrogol 4000,6000 is heated to 80 ℃ in water-bath, after whole meltings, adds compound extract, be stirred to dissolving, be uniformly dispersed; Dripping after 75 ℃ of sealed thermal insulating 30min, splashes in the liquid paraffin of 5 ~ 15 ℃; By to the greatest extent also erasing liquor paraffin body of the drop pill drop forming, drying, obtains compound dripping pill of the present invention.
Embodiment 6
Prescription: Rhizoma Chuanxiong 11.6Kg, Radix Angelicae Dahuricae 8.7Kg, Flos Chrysanthemi 13.5Kg, Radix Curcumae 11.6Kg, Ramulus Uncariae Cum Uncis 11.6Kg, Herba Asari 1.4Kg, Rhizoma Ligustici 8.7Kg and Scorpio 5.8Kg.
By 10 times of volume (volume/weight for above-mentioned medical material, L/Kg) 80 volume % alcohol reflux three times, each 1.5h, filter, merge three times extracting solution, reclaim solvent, decocting and concentrating to 50 ℃ relative density approximately 1.10, spraying is dry, makes the compound extract for the preparation of pharmaceutical composition of the present invention, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
After adopting wet granulation prepared by encapsulated technique, concrete preparation method is as follows: compound extract, lactose+starch, citric acid are taken according to quantity, after mix homogeneously, cross 80 mesh sieves, the alcoholic solution (2%) that adds polyvinylpyrrolidone is granulated in right amount, 50 ℃ of dry 20 mesh sieve granulate of crossing after 2 hours, then add lubricant, encapsulated, obtain compound capsule of the present invention.
Embodiment 7
Compound extract prepared by embodiment 6, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
Compound extract, lactose+starch+microcrystalline Cellulose are taken according to quantity, cross 80 mesh sieves after mix homogeneously, the alcoholic solution (5%) that adds ethyl cellulose is granulated in right amount, 60 ℃ of dry 20 mesh sieve granulate of crossing after 1.5 hours, then add lubricant, tabletting, obtains compound tablet of the present invention.
Embodiment 8
Embodiment 6 is shown in compound extract of the present invention preparation, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
Above-mentioned compound extract was pulverized to 80 mesh sieves, add glycerol+vegetable oil+methyl parahydroxybenzoate to mix, made capsule casing material with gelatin, be pressed into soft capsule.
Embodiment 9
Prescription: Rhizoma Chuanxiong 8Kg, Radix Angelicae Dahuricae 6Kg, Flos Chrysanthemi 10Kg, Radix Curcumae 8Kg, Ramulus Uncariae Cum Uncis 8Kg, Herba Asari 1Kg, Rhizoma Ligustici 6Kg and Scorpio 4Kg.
Above-mentioned pulverizing medicinal materials is become to coarse powder, add 85 volume % soak with ethanol after 24 hours, slowly percolation, the percolate of 5 times of volumes of the first liquid of filtering of collection, is evaporated to separately thick paste I, continue percolation, till light to percolate color, under reduced pressure, rotate evaporation and concentration to thick paste and thick paste II, thick paste I and thick paste II are mixed, make the compound extract for the preparation of pharmaceutical composition of the present invention, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
Macrogol 4000,6000 is heated to 85 ℃ in water-bath, after whole meltings, adds compound extract, be stirred to dissolving, be uniformly dispersed; Dripping after 70 ℃ of sealed thermal insulating 40min, splashes in the dimethicone of 0 ~ 10 ℃; Dimethicone is use up and wiped to the drop pill drop of formation, and drying, makes drop pill.
Embodiment 10
Prescription: Rhizoma Chuanxiong 4Kg, Radix Angelicae Dahuricae 8Kg, Flos Chrysanthemi 14Kg, Radix Curcumae 4Kg, Ramulus Uncariae Cum Uncis 8Kg, Herba Asari 0.6Kg, Rhizoma Ligustici 3Kg and Scorpio 2Kg.
Above-mentioned medical material is added to 12 times of volume (volume/weight, L/Kg) water soaking 1 hour, decocting boils three times, each 1.5 hours, filter, filtrate decompression is concentrated into thick paste, vacuum drying, make the compound extract for the preparation of pharmaceutical composition of the present invention, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
Adopt 85% ethanol wet granulation, concrete preparation method is as follows: by the above-mentioned compound extract making, dextrin+cane sugar powder+citric acid+carboxymethyl cellulose by taking in right amount, after mix homogeneously, cross 80 mesh sieves, adding 85% alcoholic solution granulates in right amount, 20 mesh sieve granulate are crossed in 40 ℃ of forced air dryings after 3 hours, obtain the granule of pharmaceutical composition of the present invention.
Embodiment 11
Prescription: Rhizoma Chuanxiong 8Kg, Radix Angelicae Dahuricae 6Kg, Flos Chrysanthemi 10Kg, Radix Curcumae 8Kg, Ramulus Uncariae Cum Uncis 12Kg, Herba Asari 1Kg, Rhizoma Ligustici 6Kg and Scorpio 4Kg.
Above-mentioned pulverizing medicinal materials is crossed to 40 mesh sieves, add 8 times of volume (volume/weight, L/Kg) 80 volume % ethanol are in 50 ℃ of supersound extraction 2 times, each 2 hours, sucking filtration, filtrate merges, decompression and solvent recovery, is concentrated into 50 ℃ of relative densities approximately 1.05, and spraying is dry, make the compound extract for the preparation of pharmaceutical composition of the present invention, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
After adopting wet granulation prepared by tablet forming technique, concrete preparation method is as follows: compound extract, modified starch+Icing Sugar+sodium carboxymethyl cellulose+citric acid are taken according to quantity, after mix homogeneously, cross 100 mesh sieves, adding 85 volume % alcoholic solution granulates in right amount, 50 ℃ of dry 20 mesh sieve granulate of crossing after 2 hours, then add magnesium stearate lubricant+Pulvis Talci, tabletting, obtains the tablet of pharmaceutical composition of the present invention.
Embodiment 12
Prescription: Rhizoma Chuanxiong 12Kg, Radix Angelicae Dahuricae 3Kg, Flos Chrysanthemi 6Kg, Radix Curcumae 12Kg, Ramulus Uncariae Cum Uncis 4Kg, Herba Asari 1.4Kg, Rhizoma Ligustici 9Kg and Scorpio 6Kg.
Above-mentioned pulverizing medicinal materials is crossed to 40 mesh sieves, carry out the supercritical extraction of carbon dioxide, extracting pressure 25MPa, 50 ℃ of extraction temperature, extraction time 4 hours, entrainer 80 volume % ethanol, collect extract.Extract decompression and solvent recovery to without alcohol taste, is diluted with water to relative density approximately 1.05, and lyophilization, makes the compound extract for the preparation of pharmaceutical composition of the present invention, for the following embodiment of the preparation of pharmaceutical composition of the present invention.
The pharmaceutical formulation of pharmaceutical composition of the present invention is made up of following component:
PEG20000,6000 is heated to 85 ℃ in water-bath, after whole meltings, adds compound extract, be stirred to dissolving, be uniformly dispersed; Dripping after 80 ℃ of sealed thermal insulating 50min, splashes in the liquid paraffin of 10 ~ 25 ℃; By to the greatest extent also erasing liquor paraffin body of the drop pill drop forming, drying, obtains compound dripping pill of the present invention.
The compound recipe compound extract that test example 1 the present invention makes mainly contains the mensuration of effective component content
The contrast of the compound extract that the compound extract of embodiment 9 and traditional method make
The compound extract that traditional handicraft method makes: take medical material by prescription, add water to and do not have 5 centimetres of medical materials, soak 30 minutes, decoct 2 times, each 30 minutes, filter, filtrate merges, and is concentrated into thick paste, to obtain final product.
The assay of ferulic acid, ligustilide and luteoloside in compound extract described in embodiment 9 and traditional handicraft
1. chromatographic condition and system suitability
Chromatographic column: Dikma Diamonsil-C
18post (250 × 4.6mm, 5 μ m), mobile phase is acetonitrile (A)-0.1% phosphate aqueous solution (B), gradient elution program: 0～15min A-B (18:82), 15～30minA-B (18:82 → 20:80), 30～35min A-B (20:80 → 30:70), flow velocity: 1.0ml/min, detect wavelength: 320nm, column temperature: 35 ℃.
2. mix the preparation of reference substance solution
Take respectively ferulic acid, ligustilide and luteoloside reference substance appropriate, accurately weighed, make the mixing reference substance solution of every 1ml containing ferulic acid 3.22 μ g, ligustilide 1.32 μ g and luteoloside 2.34 μ g.
3. the preparation of need testing solution
Get compound extract prepared in embodiment 9 and traditional handicraft, precision takes in right amount (approximately amounting to Flos Chrysanthemi crude drug 0.2g), puts in tool plug triangular flask, precision adds 25ml methanol, close plug, weighed quality, supersound extraction 30min, put to room temperature, the quality of supplying less loss with methanol, shakes up, and leaves standstill, get supernatant 0.45 μ m microporous filter membrane and filter, get subsequent filtrate and get final product.
4. the mensuration of sample
Be prepared by the preparation method of above-mentioned need testing solution, analyze by above-mentioned chromatographic condition sample introduction, the content of ferulic acid, ligustilide and luteoloside (get three parallel sample and measure, be i.e. n=3) in working sample, the results are shown in shown in following table 1 in accordance with the law.
The comparison of table 1 Different Extraction Method main active
Experimental result shows, technique of the present invention, compared with traditional handicraft, has significant advantage aspect the rate of transform of main active ferulic acid, ligustilide, luteoloside etc.
The analgesic effect of test example 2 pharmaceutical compositions of the present invention
Adopt rat nitroglycerin type migraine test model, observe the analgesic effect of pharmaceutical composition of the present invention.
The granule that reagent: embodiment 4 invents, the drop pill that embodiment 9 invents; Ergotamine and caffeine tablet, every containing gynergen 1mg, by the production of Xinyi, Shanghai medicine (group) company limited, lot number: 100821; Nitroglycerin injection, every milliliter contains nitroglycerin 5mg, is produced lot number: 20100514 by Mingxing Pharmaceutical Factory, Guangzhou; Put and exempt from institute calcitonin-gene-related peptide radioimmunoassay kits Gou Bai PLA General Hospital Science and Technology Development Center.
Animal: SD rat, Beijing experimental animal technology company limited of dimension tonneau China, animal quality certification SCXK (capital) 2006-0009,2007-0001.
Get body weight 180-220g SD rat, successive administration 7 days, after administration in the 7th day except matched group lumbar injection nitroglycerin 10mg/kg, for three days on end, after last modeling, 1-4h observes Animal Behavior Science index, result as described in Table 2.
The red appearing and subsiding time comparison of table 2 rat ears (X ± S, n=10)
Result shows, after last modeling, 1-4h rat occurs that ears are rubescent, forelimb is frequently scratched one's head, climbs the phenomenons such as cage increased frequency, give after pharmaceutical composition of the present invention, can significantly improve the behavior symptom of rat: do not occur all the time the red symptom of ear, in the unit interval, number of times difficult to tackle obviously reduces (P<0.01).
After modeling 6 hours, put to death rat, collect blood, place after 1h, centrifugal, get serum, adopt the variation of its jugular vein Plasma Calcitonin Gene-related Peptide (CGRP) content of measured by radioimmunoassay, result is as described in Table 3.
The relevant phthalein content (X ± S, n=9) of calcitonin gene in table 3 rat carotid artery blood plasma
Result demonstration, with model group comparison, in medicine jugular vein blood plasma, CGRP content significantly reduces, and has significant difference (P<0.01).Show that pharmaceutical composition of the present invention has and improves significantly and control action the Migraine Rats behavior symptom of nitroglycerin induction, alleviates migraine.Its mechanism of action may be the level by regulating CGRP in Migraine Rats blood plasma, thereby improves cerebrovascular shrink function obstacle.
Describe now embodiment of the present invention in detail, believed employing disclosed content above, clearly can do for a person skilled in the art a lot of improvement and variation, can apply to greatest extent the present invention, and can not deviate from essence spirit of the present invention.Within all these changes and improvements are all thought scope of the present invention, therefore, before preferred embodiment only illustrate, but not limit the scope of the invention by any way.
Claims (11)
1. the migrainous pharmaceutical composition for the treatment of, described pharmaceutical composition is mainly made up of each raw material of following parts by weight: 0.8 ~ 8 part of 1 ~ 11 part of 1 ~ 15 part of Rhizoma Chuanxiong, 1 ~ 11 part of the Radix Angelicae Dahuricae, 2 ~ 18 parts of Flos Chrysanthemis, 1 ~ 15 part of Radix Curcumae, 1 ~ 15 part of Ramulus Uncariae Cum Uncis, 0.2 ~ 1.8 part of Herba Asari, Rhizoma Ligustici and Scorpio.
2. the migrainous pharmaceutical composition for the treatment of according to claim 1, it is characterized in that, described Rhizoma Chuanxiong is that 4 ~ 12 parts, the Radix Angelicae Dahuricae are that 3 ~ 9 parts, Flos Chrysanthemi are that 6 ~ 14 parts, Radix Curcumae are that 4 ~ 12 parts, Ramulus Uncariae Cum Uncis are that 4 ~ 12 parts, Herba Asari are that 0.6 ~ 1.4 part, Rhizoma Ligustici are that 3 ~ 9 parts and Scorpio are 2 ~ 6 parts.
3. the migrainous compositions for the treatment of according to claim 1 and 2, it is characterized in that, described Rhizoma Chuanxiong is that 8 parts, the Radix Angelicae Dahuricae are that 6 parts, Flos Chrysanthemi are that 10 parts, Radix Curcumae are that 8 parts, Ramulus Uncariae Cum Uncis are that 8 parts, Herba Asari are that 1 part, Rhizoma Ligustici are that 6 parts and Scorpio are 4 parts, preferably, described pharmaceutical composition also comprises pharmaceutically acceptable carrier and/or adjuvant, more preferably, the dosage form of described pharmaceutical composition is capsule, tablet, granule or drop pill.
4. according to the preparation method of the migrainous compositions for the treatment of described in any one in claims 1 to 3, described method is undertaken by the method comprising the following steps: take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae, Ramulus Uncariae Cum Uncis, Herba Asari, Rhizoma Ligustici and Scorpio, take water or alcoholic solution as solvent, by being selected from decoction, reflux, extract, vapor distillation extracts, supersound extraction, merceration, the method of one or more in microwave extraction and high pressure extract is extracted, after again extracting solution being concentrated, dry, pulverize, obtain, preferably, by rotary evaporation under normal pressure or reduced pressure, decocting and concentrating or thin film concentration concentrate, or preferably, pass through vacuum drying, spraying is dry, lyophilization or drying under reduced pressure are dried.
5. the preparation method of the migrainous compositions for the treatment of according to claim 4, is characterized in that, it is characterized in that, said method comprising the steps of:
1) take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae, Ramulus Uncariae Cum Uncis, Herba Asari, Rhizoma Ligustici and Scorpio, water or alcoholic solution pass through extraction by steam distillation, collect volatile oil, filtrate for later use, preferably, extract with water or the alcoholic solution of 10-12 times of volume of the quality of medicinal material taking,, also preferably, extract 5-6 hour, most preferably, described alcoholic solution is alcoholic solution;
2) again by medicinal residues water or alcoholic solution reflux, extract,, filter, merge with the filtrate in step 1), preferably, the water of 10-12 times of volume of medication slag amount or alcoholic solution extract, and also preferably, extract 1 hour, and most preferably, described alcoholic solution is alcoholic solution;
3) filtrate merging is concentrated, dry, obtain extract I;
4) by after the volatile oil inclusion obtaining in step 1), add extract I, to obtain final product;
Preferably, the concentration of described alcoholic solution is 60-80 volume %.
6. the preparation method of the migrainous compositions for the treatment of according to claim 4, is characterized in that, said method comprising the steps of:
1) take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae and Rhizoma Ligustici, after pulverizing and sieving, extract by supercritical extraction, collect volatile oil, medicinal residues are for subsequent use, preferably, cross 40 mesh sieves;
2) take Ramulus Uncariae Cum Uncis, Herba Asari and scorpion powder and be broken into coarse powder, mix with the medicinal residues in step 1), add alcoholic solution and soak, percolation extracts, until percolate color is light, preferably, adds percent by volume and be the alcohol solution dipping 24 hours of 60-85%;
3) again by step 2) percolate that obtains is concentrated, dry, sprays into volatile oil, mixes, to obtain final product.
7. the preparation method of the migrainous compositions for the treatment of according to claim 4, comprises the following steps:
1) take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae and Rhizoma Ligustici, water or alcoholic solution, by reflux, extract,, are collected volatile oil, filtrate for later use, preferably, uses water or the alcoholic solution of 10-12 times of volume of the medical material weight taking to extract, also preferably, extract 5-6 hour;
2) filtrate is concentrated, dry, obtain extract II;
3) take Ramulus Uncariae Cum Uncis, Herba Asari and Scorpio, water or alcoholic solution, by reflux, extract,, filter, and filtrate is condensed into thick paste, obtain extract III, and preferably, the alcohol reflux that is 60-80% by volume ratio, more preferably, extracts each 1.0 hours 2 times;
4) extract II is added in extract III, mix, after dry, pulverize, spray into the volatile oil that step 1) makes, mix, to obtain final product.
8. the preparation method of the migrainous compositions for the treatment of according to claim 7, is characterized in that, in step 1), before water or alcoholic solution extract, also comprise the step of the water soaking of the 10-12 times of volume that adds the medical material weight taking, preferably, soak 2 hours.
9. the preparation method of the migrainous compositions for the treatment of according to claim 4, it is characterized in that, described method is undertaken by the method comprising the following steps: take Ligusticum chuanxiong, the Radix Angelicae Dahuricae, Flos Chrysanthemi, Radix Curcumae, Ramulus Uncariae Cum Uncis, Herba Asari, Rhizoma Ligustici and Scorpio, extract or percolation extraction by reflux, extract,, decoction;
Preferably, in the time that percolation extracts, take after medical material, after being pulverized, add after alcohol solution dipping, percolation extracts, and collects percolation for the 5 times of volumes of liquid of just filtering, and is concentrated into thick paste I; Continue again percolation, until percolate color is light, collects percolate, then be concentrated into thick paste II; Then thick paste I and thick paste II are mixed, to obtain final product; More preferably, add the alcohol solution dipping 24 hours that percent by volume is 60-85%;
Or preferably, when by reflux, extract,, take after medical material, after reflux, extract,, merging filtrate, dry, to obtain final product, more preferably, with get quality of medicinal material 10-12 times of volume or alcoholic solution 2-3 time, each 1-2 hour, also preferably, extracts each 1.5 hours three times;
Or preferably, in the time decocting extraction, take after medical material, soak after rear decoction extraction merging filtrate, dry, to obtain final product, more preferably, by water boiling and extraction 2-3 time of 10-12 times of volume of getting quality of medicinal material, each 1-2 hour, also preferably, extracts each 1.5 hours three times;
Also preferably, described alcoholic solution alcoholic solution, more preferably, the concentration of described alcoholic solution is 60-80%.
10. according to the preparation method of the migrainous compositions for the treatment of described in any one in claim 4 to 9, it is characterized in that, also comprise and add appropriate pharmaceutically acceptable carrier and/or adjuvant, make the step of capsule, tablet, granule or drop pill, preferably, described capsule is soft capsule.
11. according to the migrainous compositions of the treatment described in any one in claims 1 to 3 in the application in migrainous medicine for the preparation for the treatment of.
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Effective date of registration: 20231016 Address after: 4th Floor, Building B1, No. 306 Huiren Road, Binhai Science and Technology Park, Binhai New Area, Tianjin, 300451 Patentee after: Heguang Traditional Chinese Medicine Technology (Tianjin) Co.,Ltd. Address before: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee before: Tianjin Institute of Pharmaceutical Research Co.,Ltd. |