CN1569142A - Gastrodia tuber contained refractory headache treating formulation and its preparation technique and quality control method - Google Patents

Abstract

The invention provides a Gastrodia tuber contained refractory headache treating formulation and its preparation technique and quality control method, wherein the preparation is prepared from gastrodia tuber, achyranthes and cyathula root, scrophularia root, dried rehmannia root, Chinese angelica root, eucommia bark.

Description

Gastrodia tuber contained refractory headache treating formulation and preparation technology thereof and method of quality control

Technical field: the present invention relates to a kind of gastrodia tuber contained refractory headache treating formulation and other preparation technology and method of quality control, belong to the technical field of medicine.

Technical background: gastrodia tuber contained refractory headache treating formulation has nourishing and suppressing Yang, dispel the wind, the effect of strengthening the bones and muscles, be mainly used in intractable headache, numb in every limb for a long time, chronic waist and leg ache, wherein Tianmatoufengling Capsule is on the books in the 5th of China's the Sanitation Ministry medicine standard Traditional Chinese medicine historical preparation; In former technique, Rhizoma Gastrodiae powder is broken into 100 purpose fine powders, and its dissolution rate is not high, and bioavailability is lower; In addition owing to contain a large amount of lymphatic temperaments and lipopolysaccharides etc. and draw moist material in this Chinese medicine preparation, thus the solid pharmaceutical preparation of this product easy moisture absorption in storage process, thus affect the quality of medicine; Owing to do not have strict method of quality control in the former technique, the product quality reliability that obtains is not high in addition, and result for the treatment of is not obvious.

Summary of the invention: the object of the present invention is to provide a kind of gastrodia tuber contained refractory headache treating formulation; Another purpose is to provide the preparation technology of this gastrodia tuber contained refractory headache treating formulation; The 3rd purpose of the present invention provides the method for quality control of gastrodia tuber contained refractory headache treating formulation.

The present invention is directed to prior art, Rhizoma Gastrodiae powder is broken into fine powder more than 100 orders, to increase rate of release and the burst size of medicine, bioavailability is improved; Cross large pore resin absorption column after medicinal material decocts, can effectively remove the impurity such as a large amount of carbohydrate in the decocting liquid, inorganic salts, lymphatic temperament, strengthened the stability of product, solved the problems such as the easy moisture absorption of solid pharmaceutical preparation and ejection preparation erious adverse reaction. The present invention's traditional Chinese medicine pellet technology, number of patent application of utilizing the applicant to apply for a patent is in addition: 200410021682.0, first medicine is made the formulation of making again various needs behind the micropill with diverse ways; Both improve the bioavilability of medicine, can also cover bad smell and the taste of medicine; Increase the stability of medicine, be convenient to quality control and storage; Make compressibility and good fluidity, non-friable; Easily make slow, controlled release or targeting preparation etc., and improved the quality of product, guaranteed product can long term storage, transportation, packing. The present invention consists of like this: calculate according to composition by weight: it mainly is prepared from by rhizoma Gastrodiae 25-100, root of bidentate achyranthes 25-100, radix scrophulariae 25-100, glutinous rehmannia 75-300, Radix Angelicae Sinensis 107.5-430, bark of eucommia 21.5-86, Ligusticum wallichii 25-100, mistletoe 107.5-430, mother chrysanthemum 25-100, yncaria stem with hooks 25-100. Specifically: it mainly is prepared from by rhizoma Gastrodiae 50g, root of bidentate achyranthes 50g, radix scrophulariae 50g, glutinous rehmannia 150g, Radix Angelicae Sinensis 215g, bark of eucommia 43g, Ligusticum wallichii 50g, mistletoe 215g, mother chrysanthemum 50g, yncaria stem with hooks 50g. Preparation of the present invention comprises: capsule, soft capsule, injection, freeze-dried powder, tablet, granule, dripping pill, micro-capsule, micropill, pill, condensed pill, oral liquid, syrup, mixture, sustained release preparation, quick releasing formulation, controlled release preparation, targeting preparation, powder, spray, vina, tincture, lozenge, extract, liquid extract for the preparation that all medical science allow. The preparation technology of gastrodia tuber contained refractory headache treating formulation: according to given formula rate, Rhizoma Gastrodiae powder is broken into fine powder more than 100 orders, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks boiling, collecting decoction filters, and filtrate is crossed large pore resin absorption column, collect eluent and reduced pressure concentration and become medicinal extract, add the Rhizoma Gastrodiae powder mixing, granulate, make again the product of different preparations at last with diverse ways.

Technique when the present invention makes capsule is: Rhizoma Gastrodiae powder is broken into fine powder more than 100 orders, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks are pulverized respectively, boiling 2～5 times, each 1～8 hour, collecting decoction, filter, filtrate is crossed large pore resin absorption column, use ethanol elution, collect eluent and reduced pressure concentration and become medicinal extract, add the Rhizoma Gastrodiae powder mixing, dry with vacuum drying, spray-drying or freeze-drying, be ground into the above fine powder of 60 orders, the microcrystalline cellulose with 0.1～5 times of amount of medicinal powder amount mixes again, make particle diameter less than the micropill of 2mm take the ethanolic solution of 2～10%PVP as binder, filling, namely get capsule. Micropill among the present invention also available 1～10% film coating liquid carries out dressing to it, and then loads into capsule; The bioavilability of medicine can be both improved like this, bad smell and the taste of medicine can also be covered; Increase the stability of medicine, be convenient to quality control and storage; Make compressibility and good fluidity, non-friable.

The experimental result that we carried out the selection of micropill auxiliary material when the present invention made capsule is:

1, the presentation quality of different prescription micropills:

Drug powder	Excipient	Wetting agent	Adhesive	Appearance character
					2 parts of drug powders	1 part of starch	90% ethanol	3％PVP	Spherical, smooth, rounding
2 parts of drug powders	1 part of microcrystalline cellulose	90% ethanol	3％PVP	Spherical, smooth, rounding
					2 parts of drug powders	1 part of stearic acid	90% ethanol	3％PVP	Block
2 parts of drug powders	1 part of ethyl cellulose	90% ethanol	3％PVP	Spherical, rough, rounding not
					2 parts of drug powders	1 part of equal proportion mixing starch, microcrystalline cellulose	90% ethanol	3％PVP	Sphere, rough
2 parts of drug powders	1 part of equal proportion mixing starch, ethyl cellulose	90% ethanol	3％PVP	Spherical, smooth, rounding
					2 parts of drug powders	1 part of equal proportion mixed microcrystalline cellulose, stearic acid	90% ethanol	3％PVP	Block

2, according to above test, select the good prescription of appearance character to carry out the distribution test of micropill size granularity:

Prescription	Cross 40 orders	The 40-30 order	The 30-18 order	18 orders but
					Medicinal powder: starch=2: 1	3％	18％	70％	9％
Medicinal powder: microcrystalline cellulose=2: 1	9％	41％	38％	12％
					Medicine: starch: ethyl cellulose=1: 0.5: 0.5	4％	28％	60％	8％

3, the measurement result of all the other projects:

Prescription	Leach time min	Moisture absorption percentage %
				24 hours	48 hours
		Medicinal powder: starch=2: 1	15			12.2	14.8
Medicinal powder: microcrystalline cellulose=2: 1	18			8.9	12.0
		Medicine: starch: ethyl cellulose=1: 0.5: 0.5	22			8.8	11.2
Medicinal powder	—			12.9	15.0

Show according to above result of the test: medicine is even, moderate with 2 to the 1 micropill sizes that are mixed with microcrystalline cellulose, and hygroscopicity is little, good stability. Operability and the quality of its preparation micropill all meet the requirements. So the present invention selects microcrystalline cellulose as the excipient of preparation micropill.

The technique that the present invention makes tablet is: get rhizoma Gastrodiae and pulverize, use alcohol extract, merge extract, Recycled ethanol also is condensed into medicinal extract, namely get Rhizoma Gastrodiae extract, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks are pulverized respectively the above fine powder of 60 orders, mix with the sodium carboxymethyl starch of Rhizoma Gastrodiae extract, medicinal powder amount 0.5-10%, and use alcohol granulation, sodium carboxymethyl starch with medicinal powder amount 0.5-2% mixes again, compressing tablet carries out dressing with the 2-8% film coating agent to plain sheet, namely gets tablet.

It is bad that the present invention makes the disintegrative of tablet, so add disintegrant, we select the experimental result of disintegrant to be:

Disintegrant	Consumption	Disintegration time	Appearance character
				Starch	2％	19min	Easily moisture absorption, medicine stability is slightly poor
Sodium carboxymethyl starch	2％	8min	Hardness is good, outward appearance compressibility and flowability all meet the requirements
				Silica	2％	23min	Compressibility and flowability are all bad
The low substituted hydroxy-propyl fiber	2％	12min	Hardness and outward appearance are slightly poor

So the present invention is with the disintegrant of sodium carboxymethyl starch as the preparation tablet.

The technique that the present invention makes soft capsule is: get each medicinal material and pulverize respectively, wherein Radix Angelicae Sinensis, Ligusticum wallichii supercritical fluid extraction get Radix Angelicae Sinensis, Rhizoma Chuanxiong extract; The rhizoma Gastrodiae alcohol extract namely gets Rhizoma Gastrodiae extract. All the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum, yncaria stem with hooks extract with semi-bionic extraction, mix with Radix Angelicae Sinensis, Rhizoma Chuanxiong extract, Rhizoma Gastrodiae extract again, join to make in the soft capsule auxiliary material of 0.5-5% and be uniformly dispersed, pill, namely get soft capsule, used soft capsule auxiliary material is soya-bean oil: Tween-80: ethyl cellulose=5～15: 1～10: 3～8 mixture.

The experimental result that the selection of our auxiliary material was carried out when the present invention made soft capsule is:

Auxiliary material	Medicine: auxiliary material	Appearance character
			Soya-bean oil	1∶2	The content shape is inhomogeneous, easily layering, and loading amount is also inaccurate
Soya-bean oil: Tween-80: beeswax=2: 1: 1.5	1∶2	Good fluidity, but be easy to seepage
			Soya-bean oil: Tween-80: aluminum monostearate=2: 1: 1.5	1∶2	Good stability, but poor fluidity are difficult for pill
Soya-bean oil: Tween-80: ethyl cellulose=2: 1: 1.5	1∶2	Good fluidity, easy pill, and easy to leak not

According to above experimental result, the present invention is with soya-bean oil, Tween-80, the ethyl cellulose auxiliary material as soft capsule processed.

The technique that the present invention makes dripping pill is: get each medicinal material and pulverize respectively, wherein rhizoma Gastrodiae, yncaria stem with hooks alcohol extract get rhizoma Gastrodiae, uncaria extract; Other gets Radix Angelicae Sinensis, Ligusticum wallichii extraction by steam distillation, gets Radix Angelicae Sinensis, Rhizoma Chuanxiong extract; All the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum water boiling and extraction, alcohol precipitation, concentrated, merge with the said extracted thing again, other gets and mixes with the said extracted thing after 1-8 doubly measures the PEG-4000 melting, splashes in the dimethicone and cools off, and namely gets pill.

When the present invention made dripping pill, we had carried out selection, experiment to matrix and condensing agent:

Matrix	Medicine: matrix	Condensing agent	Melting, shaping situation and Deposition Situation	Leach the time
					Glycerine	1∶1	Atoleine	Be difficult for mixing, the toughness material is separated out, and sinking speed is fast, and ball shape is flat, and roundness is bad.	18min
Glycerine	1∶2	Soya-bean oil	Easy mixing, sinking speed is moderate, and ball shape rounding is non-caked.	25min
					Glycerine	1∶3	Dimethicone	Easy mixing, sinking speed is slightly fast, and ball shape is rounding not, not moulding.	19min
Gelatin	1∶1	Atoleine	Easily mix, sinking speed is slightly fast, and ball shape is rounding not, hangover	30min
					Gelatin	1∶2	Soya-bean oil	Be difficult for mixing, be difficult for solidified forming, difference of hardness, dripping difficulty	29min
Gelatin	1∶3	Dimethicone	Easily mix, sinking speed is moderate, and ball shape is good, and bonding keeps up with	35min
					PEG-4000	1∶1	Atoleine	Be difficult for mixing, the toughness material is separated out, and sinking speed is fast, and ball shape is flat, and roundness is bad.	7min
PEG-4000	1∶2	Soya-bean oil	Easy mixing, sinking speed is slightly fast, and ball shape is rounding not, not moulding.	9min
					PEG-4000	1∶3	Dimethicone	Easily mix, sinking speed is moderate, and formability is good, and smooth surface is fine and close, and rounding is non-caked	10min

Odium stearate	1∶1	Atoleine	Can mix, sinking speed is moderate, and ball shape rounding is non-caked	14min
					Odium stearate	1∶2	Soya-bean oil	Easy mixing, sinking speed is slightly fast, and formability is good, and is non-caked.	15min
Odium stearate	1∶3	Dimethicone	The energy mixing, sinking speed is slightly fast, and ball shape is rounding not, not moulding.	18min

More than in the experiment, make matrix with PEG-4000, mix according to 1: 3 ratio with medicine, dimethicone is done the melting of the pill of condensing agent, and shaping situation and Deposition Situation are best, and it is short to leach the time, has reached quick-acting purposes.

The technique that the present invention makes freeze-dried powder is: get each medicinal material and pulverize respectively, wherein Radix Angelicae Sinensis, Ligusticum wallichii supercritical fluid extraction get Radix Angelicae Sinensis, Rhizoma Chuanxiong extract; The rhizoma Gastrodiae alcohol extract, namely get Rhizoma Gastrodiae extract, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum, yncaria stem with hooks extract with semi-bionic extraction, filter, filtrate is crossed large pore resin absorption column, use ethanol elution, collect eluent and reduced pressure concentration and become medicinal extract, again with Radix Angelicae Sinensis, Rhizoma Chuanxiong extract, lactose and the sweet mellow wine of Rhizoma Gastrodiae extract, total liquid 1-30% mix, add to the full amount of water for injection, the adjusting liquid PH value is 2-7, filters can, freeze drying namely gets freeze drying powder injection.

Because the outward appearance after the herb liquid freeze drying of the present invention is bad, still in liquid, add which kind of excipient and carried out series of experiments:

Excipient	Consumption	Appearance character
			Glucose	10％	Color is even, but big gun and Study of Volume Expansion have been arranged,
Trehalose	10％	Irregular colour is even, and volume obviously dwindles
			Lactose	10％	The color is too dark, and volume has slightly to have and dwindles
Glycine	10％	Irregular colour is even, volumetric expansion, a big gun
			Sucrose	10％	Color is even, and volume slightly has and dwindles
Sweet mellow wine	10％	Irregular colour is even, and volume has the phenomenon of dwindling
			Inositol	10％	Irregular colour is even, and volume obviously dwindles
Lactose and sweet mellow wine	Equal proportion is mixed; 10%	Color is even, constancy of volume, and profile is better

According to above experimental result, select lactose and sweet mellow wine to mix the excipient for preparing freeze-dried powder as the present invention.

The technique that the present invention makes injection is: get each medicinal material and pulverize respectively, wherein rhizoma Gastrodiae, Radix Angelicae Sinensis, Ligusticum wallichii, yncaria stem with hooks supercritical fluid extraction, get extract 1, the residue root of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum water boiling and extraction, more than after stone sulphur method is processed, once reaching once with the ethanol alcohol precipitation, contain for the first time the alcohol amount and be 50-75%, the alcohol amount that contains that secondary and secondary are later is 75%-99.9%, and Recycled ethanol namely gets extract 2 after the liquid ultrafiltration, the glucose of doubly measuring with extract 1, total liquid 0.01-0.5 mixes, add to the full amount of water for injection, the adjusting liquid PH value is 2-7, filters, embedding, sterilization namely get ejection preparation.

Because this traditional Chinese medicine injection is hypotonic solution, can produce human body when human body is arrived in intravenous injection stimulates, but also can affect the absorption of medicine, so test for adding the sort of osmotic pressure regulator when we make intravenous fluid:

Osmotic pressure regulator	Consumption	Effect
			Glucose	5％	Pharmacological evaluation has no adverse reaction; Also produce without precipitation in the storage process
Common salt	5％	Pharmacological evaluation has no adverse reaction; But there is a small amount of precipitation to produce in the storage process
			Sweet mellow wine	5％	The nothing precipitation produces but affects human body to the absorption of medicine
Sorbierite	5％	Produce without precipitation, but diuresis is arranged, affect human body to the absorption of medicine
			Xylitol	5％	The nothing precipitation produces but in the pharmacological evaluation mouse kidney is had infringement

According to above experimental result, among the present invention with glucose as osmotic pressure regulator.

Say accurately: the prescription of granulation agent of the present invention is: rhizoma Gastrodiae 25g, root of bidentate achyranthes 25g, radix scrophulariae 25g, glutinous rehmannia 75g, Radix Angelicae Sinensis 107.5g, bark of eucommia 21.5g, Ligusticum wallichii 25g, mistletoe 107.5g, mother chrysanthemum 25g, yncaria stem with hooks 25g, sucrose 200g. Preparation technology is: get rhizoma Gastrodiae, sucrose and be ground into respectively 120 purpose fine powders, 65% alcohol extract of all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks usefulness 3500ml 2 times, each 2h, filtrate recycling ethanol and reduced pressure concentration become medicinal extract, mix with Rhizoma Gastrodiae powder, cane sugar powder, granulate, packing namely gets granule.

The prescription that the present invention makes syrup is: rhizoma Gastrodiae 100g, root of bidentate achyranthes 100g, radix scrophulariae 100g, glutinous rehmannia 300g, Radix Angelicae Sinensis 430g, bark of eucommia 86g, Ligusticum wallichii 100g, mistletoe 430g, mother chrysanthemum 100g, yncaria stem with hooks 100g, sucrose 500g. Preparation technology is: get each medicinal material and be ground into respectively meal, wherein rhizoma Gastrodiae, yncaria stem with hooks 2000ml80% alcohol extract 3 times, each 2h merges extract, and Recycled ethanol and reduced pressure concentration become medicinal extract, drying under reduced pressure, get rhizoma Gastrodiae, uncaria extract, other gets Radix Angelicae Sinensis, Ligusticum wallichii extraction by steam distillation, filters, filtrate is condensed into medicinal extract, drying under reduced pressure gets Radix Angelicae Sinensis, Rhizoma Chuanxiong extract, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum boiling 3 times, decocting time is respectively 3h, 2h, 1h, filter, filtrate is condensed into medicinal extract, drying under reduced pressure, and get final product, other gets sucrose and joins and make fully dissolving in the water that boils, and will the said extracted thing adds in the sucrose liquid mix, and filters, can namely gets syrup.

In the 16 of the Sanitation Ministry medicine standard Traditional Chinese medicine historical preparation, only stipulated the discriminating of oleanolic acid and Radix Angelicae Sinensis control medicinal material in the quality standard of Tianmatoufengling Capsule in addition, its method of quality control is not strict, and the product quality reliability that obtains is not high. So the present invention has increased the micro-discriminating of Tianmatoufengling Capsule powder, the discriminating of Gastrodin and Ligusticum wallichii control medicinal material has also increased the assay of Gastrodin. Wherein increase the micro-discriminating of gastrodia tuber contained refractory headache treating formulation powder, can more clearly understand the microcosmos of this pharmaceutical preparation; Increase the discriminating of Gastrodin and Ligusticum wallichii control medicinal material, can more effective quality to whole product monitor; Having increased the assay of Gastrodin, is because Gastrodin is the drug effect composition of gastrodia tuber contained refractory headache treating formulation treatment headache, increase its assay after, can control better the quality of product, thereby more effectively guarantee the curative effect of preparation of the present invention.

In order to prove the curative effect of Gastrodin, we have also carried out the migrainous observation experiment of Therapeutic Efficacy of Gastrodin blood vessel:

1, data and method:

1.1 physical data: vascular migraine patient 40 examples, male 12 examples, women 28 examples, age 15-55 year, average 36.7 years old. By at random, the double blinding principle is divided into treatment group and control group, each 20 example. There are extremity numbness 8 examples in course of disease year in May during morbidity, dizzy 21 examples, tinnitus 6 examples. Show as cycle pollex sample and have an intense pain, take volume, white section as main, the companion feels sick, vomiting 30 examples. All meet diagnostic criteria and get rid of other brain diseases.

1.2 method: curative effect judging standard: (produce effects) evident in efficacy namely had a headache and alleviated fully. Effectively namely headache is alleviated substantially or to some extent, but not fully control. Efficient (%) of the ratio of produce effects case in this case group. Adopt domestic WX-753B micro-circle microscope, WX-811 microcirculation meter, double window television scanning and quantitative assay recorder, L-80 palette level type computer, survey bulbar conjunctiva capilary form, the blood flow attitude bulbar Conjunctiva Microcirculation indexs such as blood vessel ambient conditions respectively at treatment fore-and-aft observing experimenter eyes white. Medication: Injectio of gastrodine and alone physiological saline 250ml drip-feed that treatment group and control group add with 250ml with physiological saline respectively, every day 1 time, totally 8 days.

1.3 statistical procedures: relatively check with X2 between enumeration data.

2 results:

2.1 comparativity between group. Be between headache situation, bulbar Conjunctiva Microcirculation index before the treatment without significance difference opposite sex P＞0.05 between two groups, data has comparativity.

2.2 curative effect is relatively between two groups: as shown in table 1, treatment group obvious effective rate, efficient control group P＞0.01 that all is better than.

Curative effect compares n% between table 1 liang group

Group	Example number n	Produce effects	Produce effects+effectively
				Treatment group	20	15(75)*	19(95)*
Control group	20	6(30)

*P＜0.01

2.3 two groups of bulbar Conjunctiva Microcirculation results are more as shown in table 2 before and after the treatment, the microcirculation qualitative index that treatment group is observed all be better than control group P＜0.01.

Two groups of bulbar Conjunctiva Microcirculation qualitative index results compare n% before and after table 2 treatment

Observation index	Example number n	Treatment group	Control group
				The capilary thickness is uneven	20	1(5)	18(90)
Capillary network (opening) is few	20	0	8(40)
				The pipe sample is unusual	20	2(10)	9(45)
A/V＞1∶3	20	2(10)	17(85)

Ischemic region	20	0	8(40)
				Blood flow is mudflow slowly	20	2	18(90)
Erythrocyte aggregation	20	0	14(70)
				Ooze out around the pipe sample	20	0	9(45)

3 discuss: this experiment usefulness Therapeutic Efficacy of Gastrodin 20 routine vascular migraines are respond well, efficiently reach 95%. Its obvious effective rate, efficient control group P＜0.01 that all is significantly higher than. The bulbar Conjunctiva Microcirculation function is significantly improved P＜0.01. The prompting Injectio of gastrodine may by improving brain blood circulation situation, greatly be alleviated headache.

The method of quality control of the method for quality control of gastrodia tuber contained refractory headache treating formulation of the present invention, particularly capsule preparations, it comprises: proterties, discriminating, inspection, assay, wherein:

[proterties] this product is capsule, and content is brown color powder or particle; Gas delicate fragrance, mildly bitter flavor.

This product content is got in [discriminating] (1), and porphyrize is put microscopically and observed: prothenchyma (of wood) ellipse or class polygonal, and diameter 1～1000 μ m, wall thickness 1～100 μ m, lignify, pit is obvious. Screw thread, reticulate pattern and annular duct diameter 1～200 μ m. Needle-like calcium oxalate crystal bunchy or be dispersed in, long 1～500 μ m.

(2) get this product content, porphyrize adds alcohol heating reflux and extracts, and leaves standstill, and gets supernatant, adds hot reflux behind the adding hydrochloric acid, and is concentrated, and concentrate extracts with benzinum after adding suitable quantity of water, and extract evaporate to dryness, residue add ethanol makes dissolving, as need testing solution. Other evens up pier tartaric acid reference substance, adds the ethanol dissolving, in contrast product solution. According to Chinese Pharmacopoeia thin-layered chromatography test, draw above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, take chloroform: methyl alcohol=1～99: 99～1 as solvent, launches, and takes out, and dries, and sprays with phosphomolybdic acid ethanol solution, dries by the fire 5～50 minutes. In the test sample chromatogram, with the corresponding position of reference substance chromatogram on, the spot of aobvious same color.

(3) get this product content, porphyrize adds chloroform: methyl alcohol=1～99: 99～1 mixed solutions, and jolting, ultrasonic processing after soaking filters, and filtrate volatilizes, and residue adds chloroform, stirs evenly, and gets supernatant as need testing solution. Other gets the Radix Angelicae Sinensis control medicinal material, is made in the same way of control medicinal material solution. According to Chinese Pharmacopoeia thin-layered chromatography test, draw need testing solution, control medicinal material solution, put respectively on same silica gel g thin-layer plate, take n-hexane: ethyl acetate=1～99: 99～1 as solvent, launches, and taking-up is dried, and puts under the ultraviolet lamp and inspects. In the test sample chromatogram, with the corresponding position of control medicinal material chromatogram on, the fluorescence spot of aobvious two same colors.

(4) get this product content, porphyrize adds methyl alcohol: ethyl acetate=1～99: dissolve in 99～1 mixed solutions, place, frequently jolting filters, filtrate evaporate to dryness, residue add the dissolving of water low-grade fever, filter, filtrate is extracted with ethyl acetate, discards the ethyl acetate extract, and water layer extracts with n-butanol, merge n-butanol extracting liquid, evaporate to dryness, residue add methyl alcohol makes dissolving, as need testing solution. Other gets the rhizoma Gastrodiae control medicinal material, is made in the same way of control medicinal material solution. Get again the Gastrodin reference substance, add the methyl alcohol dissolving, in contrast product solution. Test according to the Chinese Pharmacopoeia thin-layered chromatography, draw above-mentioned need testing solution and control medicinal material solution, reference substance solution, put respectively on same silica gel g thin-layer plate, take ethyl acetate: acetone: methyl alcohol: water=1～150: 0.1～10: 0.1～10: 0.01～10 as solvent, launch, take out, dry, spray is with vanillic aldehyde sulfuric acid test solution, and it is clear to be heated to the spot colour developing. In the test sample chromatogram, with control medicinal material chromatogram and the corresponding position of reference substance chromatogram on, the spot of aobvious same color.

(5) get this product content, porphyrize adds the ultrasonic processing of ethyl acetate, filters, and filtrate evaporate to dryness, residue add methyl alcohol makes dissolving, as need testing solution. Other gets the Ligusticum wallichii control medicinal material, is made in the same way of control medicinal material solution. According to the test of Chinese Pharmacopoeia thin-layered chromatography, draw above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, take benzinum: ether: glacial acetic acid=1～100: 0.1～50: 0.01～10 as solvent, launches, and takes out, dry, put under the ultraviolet lamp and inspect. In the test sample chromatogram, with the corresponding position of control medicinal material chromatogram on, the fluorescence spot of aobvious same color.

[inspection] should meet every regulation relevant under the Chinese Pharmacopoeia capsule item.

[assay] is according to the Chinese Pharmacopoeia high effective liquid chromatography for measuring.

Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Acetonitrile: water: phosphoric acid=0.1～100: 5～1000: 0.01～10 is mobile phase; The detection wavelength is 10～1000nm. Number of theoretical plate calculates by the Gastrodin peak should be not less than 100～10000.

The preparation of reference substance solution: it is an amount of to get the Gastrodin reference substance, and drying is accurately weighed, adds the methyl alcohol dissolving, and get final product.

The preparation of need testing solution: get this product content under the content uniformity item, porphyrize, mixing, accurately weighed, put in the apparatus,Soxhlet's, add methyl alcohol, place, add again an amount of methyl alcohol and put and add hot reflux in the water-bath, in extract dislocation evaporating dish, the a small amount of methanol wash of container, washing lotion is incorporated in the evaporating dish, evaporate to dryness, residue adds methyl alcohol makes dissolving, stirs drying with a small amount of silica gel in water-bath, and the silica gel of anticipating and loading of packing into is done the column top, 3g, 15 * 200mm, 110 ℃ of dryings 30 minutes, an amount of methyl alcohol of evaporating dish: ethyl acetate=1～99: 99～1 washings, washing lotion adds the dried post of silica gel, add again methyl alcohol: ethyl acetate=1～99: 99～1 wash-outs, collect eluent, evaporate to dryness, residue adds the methyl alcohol dissolving, be transferred in the 5ml measuring bottle, and be diluted to scale, shake up, filter, and get final product.

Determination method is accurate reference substance solution and the need testing solution drawn respectively, and the injection liquid chromatography is measured, and be get final product.

Every of this product contains rhizoma Gastrodiae with Gastrodin C₁₃H ₁₈O ₇Meter should be more than or equal to 0.04mg.

Compared with prior art: high, the good stability of the gastrodia tuber contained refractory headache treating formulation bioavailability that uses this method to make, solved the easy moisture absorption of solid pharmaceutical preparation problem, be convenient to quality control and storage, and easily make slow, controlled release or targeting preparation, thereby improved the quality of product, all technical meets Pharmacopoeia of the People's Republic of China requirement, the preparation that obtains has nourishing and suppressing Yang, dispel the wind, the effect of strengthening the bones and muscles, be mainly used in treating intractable headache, numb in every limb for a long time, the diseases such as chronic waist and leg ache have reached goal of the invention.

The specific embodiment:

Embodiments of the invention 1:

Rhizoma Gastrodiae 50g root of bidentate achyranthes 50g radix scrophulariae 50g glutinous rehmannia 150g Radix Angelicae Sinensis 215g bark of eucommia 43g

Ligusticum wallichii 50g mistletoe 215g mother chrysanthemum 50g yncaria stem with hooks 50g microcrystalline cellulose 180g

Rhizoma Gastrodiae powder is broken into 120 purpose fine powders, and all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks are ground into respectively meal, boiling 3 times, and decocting time is respectively 3h, 2h, 1h. Collecting decoction, filter, filtrate is crossed large pore resin absorption column, uses 50% ethanol elution, collect eluent and reduced pressure concentration and become medicinal extract, add the Rhizoma Gastrodiae powder mixing, spray-drying is ground into 100 purpose fine powders again, mix with microcrystalline cellulose, ethanolic solution take 5%PVP is made particle diameter as 18～20 purpose micropills as binder, with 6% film coating liquid micropill is carried out dressing again, filling, namely gets capsule.

Embodiments of the invention 2:

Rhizoma Gastrodiae 25g root of bidentate achyranthes 25g radix scrophulariae 25g glutinous rehmannia 75g Radix Angelicae Sinensis 107.5g bark of eucommia 21.5g

Ligusticum wallichii 25g mistletoe 107.5g mother chrysanthemum 25g yncaria stem with hooks 25g sodium carboxymethyl starch 9g

Rhizoma Gastrodiae powder is used 250ml70% alcohol extract 3 times after being broken into meal, and each 2h merges extract, and Recycled ethanol also is condensed into medicinal extract. All the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks are pulverized respectively 80 purpose fine powders, mix with the sodium carboxymethyl starch of Rhizoma Gastrodiae extract, 4.5g, and use alcohol granulation, sodium carboxymethyl starch with 4.5g mixes again, compressing tablet, with 3% film coating agent plain sheet is carried out dressing, namely get tablet.

Embodiments of the invention 3:

Rhizoma Gastrodiae 100g root of bidentate achyranthes 100g radix scrophulariae 100g glutinous rehmannia 300g Radix Angelicae Sinensis 430g bark of eucommia 86g

Ligusticum wallichii 100g mistletoe 430g mother chrysanthemum 100g yncaria stem with hooks 100g soya-bean oil 170ml

Tween-80 85ml ethyl cellulose 100g

Get each medicinal material and be ground into respectively meal, wherein Radix Angelicae Sinensis, Ligusticum wallichii supercritical fluid extraction, pressure is 34.5MPa during extraction, and temperature is 60 ℃, and ethanol is made modifier, gets Radix Angelicae Sinensis, Rhizoma Chuanxiong extract; Rhizoma Gastrodiae 1000ml70% alcohol extract 3 times, each 2h merges extract, and Recycled ethanol and reduced pressure concentration become medicinal extract, and drying under reduced pressure namely gets Rhizoma Gastrodiae extract. All the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum, yncaria stem with hooks are that 2.0,6.5,9.0 water extraction is got three times with pH respectively, extraction time is respectively 2h, 0.5h, 0.5h, filter, merging filtrate, reduced pressure concentration becomes medicinal extract, drying under reduced pressure mixes with Radix Angelicae Sinensis, Rhizoma Chuanxiong extract, Rhizoma Gastrodiae extract again. Other gets soya-bean oil, Tween-80, ethyl cellulose and mixes, and above-mentioned medicinal powder is joined to make in the mixed liquor be uniformly dispersed, and pill namely gets soft capsule.

Embodiments of the invention 4:

Rhizoma Gastrodiae 50g root of bidentate achyranthes 50g radix scrophulariae 50g glutinous rehmannia 150g Radix Angelicae Sinensis 215g bark of eucommia 43g

Ligusticum wallichii 50g mistletoe 215g mother chrysanthemum 50g yncaria stem with hooks 50g PEG-4000 300ml

Get each medicinal material and be ground into respectively meal, wherein rhizoma Gastrodiae, yncaria stem with hooks 1000ml75% alcohol extract 3 times, each 2h merges extract, and Recycled ethanol and reduced pressure concentration become medicinal extract, and drying under reduced pressure gets rhizoma Gastrodiae, uncaria extract. Other gets Radix Angelicae Sinensis, Ligusticum wallichii extraction by steam distillation, filters, and filtrate is condensed into medicinal extract, and drying under reduced pressure gets Radix Angelicae Sinensis, Rhizoma Chuanxiong extract. All the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum boiling 5 times, decocting time is respectively 6h, 4h, 3h, 2h, 1h, filters, and filtrate is concentrated, use the ethanol alcohol precipitation, containing the alcohol amount is 75%, and Recycled ethanol also is condensed into medicinal extract, drying under reduced pressure, mix with the said extracted thing, mix with the said extracted thing after taking polyethylene glycol-4000 melting in addition, splash in the dimethicone and cool off, namely get pill.

Embodiments of the invention 5:

Rhizoma Gastrodiae 100g root of bidentate achyranthes 100g radix scrophulariae 100g glutinous rehmannia 300g Radix Angelicae Sinensis 430g bark of eucommia 86g

Ligusticum wallichii 100g mistletoe 430g mother chrysanthemum 100g yncaria stem with hooks 100g lactose 550g sweet mellow wine 45g

Get each medicinal material and be ground into respectively meal, wherein Radix Angelicae Sinensis, Ligusticum wallichii supercritical fluid extraction, pressure is 34.5MPa during extraction, and temperature is 60 ℃, and ethanol is made modifier, gets Radix Angelicae Sinensis, Rhizoma Chuanxiong extract; Rhizoma Gastrodiae 1000ml70% alcohol extract 3 times, each 2h merges extract, and Recycled ethanol and reduced pressure concentration become medicinal extract, and drying under reduced pressure namely gets Rhizoma Gastrodiae extract. All the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum, yncaria stem with hooks are that 2.0,6.5,9.0 water extraction is got three times with pH respectively, extraction time is respectively 2h, 0.5h, 0.5h, filter, merging filtrate, filtrate is crossed large pore resin absorption column, use ethanol elution, collect eluent and reduced pressure concentration and become medicinal extract, with Radix Angelicae Sinensis, Rhizoma Chuanxiong extract, Rhizoma Gastrodiae extract, lactose and sweet mellow wine mix again, inject water to 1000ml, regulating liquid PH value is 6.5, filters can, freeze drying namely gets freeze drying powder injection.

Embodiments of the invention 6:

Rhizoma Gastrodiae 50g root of bidentate achyranthes 50g radix scrophulariae 50g glutinous rehmannia 150g Radix Angelicae Sinensis 215g bark of eucommia 43g

Ligusticum wallichii 50g mistletoe 215g mother chrysanthemum 50g yncaria stem with hooks 50g glucose 50g

Get each medicinal material and be ground into respectively meal, wherein rhizoma Gastrodiae, Radix Angelicae Sinensis, Ligusticum wallichii, yncaria stem with hooks supercritical fluid extraction, pressure is 34.5MPa during extraction, and temperature is 60 ℃, and ethanol is made modifier, gets extract 1. The residue root of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum boiling 3 times, amount of water is 6,4,4 times of amounts, decocting time is 3h, 2h, 1h, filter, merging filtrate, filtrate with ethanol alcohol precipitation twice, contain the alcohol amount and are respectively 65%, 85% after stone sulphur method is processed. Recycled ethanol namely gets extract 2 after the liquid ultrafiltration. Mix with extract 1, glucose, inject water to 1000ml, regulating liquid PH value is 7, filters, and embedding, sterilization namely get ejection preparation.

Embodiments of the invention 7:

Rhizoma Gastrodiae 25g root of bidentate achyranthes 25g radix scrophulariae 25g glutinous rehmannia 75g Radix Angelicae Sinensis 107.5g bark of eucommia 21.5g

Ligusticum wallichii 25g mistletoe 107.5g mother chrysanthemum 25g yncaria stem with hooks 25g sucrose 200g

Get rhizoma Gastrodiae, sucrose and be ground into respectively 120 purpose fine powders, 65% alcohol extract of all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks usefulness 3500ml 2 times, each 2h, filtrate recycling ethanol and reduced pressure concentration become medicinal extract, mix with Rhizoma Gastrodiae powder, cane sugar powder, granulate, packing namely gets granule.

Embodiments of the invention 8:

Rhizoma Gastrodiae 100g root of bidentate achyranthes 100g radix scrophulariae 100g glutinous rehmannia 300g Radix Angelicae Sinensis 430g bark of eucommia 86g

Ligusticum wallichii 100g mistletoe 430g mother chrysanthemum 100g yncaria stem with hooks 100g sucrose 500g

Get each medicinal material and be ground into respectively meal, wherein rhizoma Gastrodiae, yncaria stem with hooks 2000ml80% alcohol extract 3 times, each 2h merges extract, and Recycled ethanol and reduced pressure concentration become medicinal extract, and drying under reduced pressure gets rhizoma Gastrodiae, uncaria extract. Other gets Radix Angelicae Sinensis, Ligusticum wallichii extraction by steam distillation, filters, and filtrate is condensed into medicinal extract, and drying under reduced pressure gets Radix Angelicae Sinensis, Rhizoma Chuanxiong extract. All the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum boiling 3 times, decocting time is respectively 3h, 2h, 1h, filters, and filtrate is condensed into medicinal extract, drying under reduced pressure, and get final product. Other gets sucrose and joins and make fully dissolving in the water that boils, and will the said extracted thing adds in the sucrose liquid mix, and filters, and can namely gets syrup.

Embodiments of the invention 9: the method for quality control of Tianmatoufengling Capsule agent

[proterties] this product is capsule, and content is brown color powder or particle; Gas delicate fragrance, mildly bitter flavor.

This product content is got in [discriminating] (1), and porphyrize is put microscopically and observed: prothenchyma (of wood) ellipse or class polygonal, and diameter 70～180 μ m, wall thickness 3～8 μ m, lignify, pit is obvious. Screw thread, reticulate pattern and annular duct diameter 8～30 μ m. Needle-like calcium oxalate crystal bunchy or be dispersed in, long 25～75 μ m.

(2) get the content of 10 of this product, porphyrize adds ethanol 20ml, added hot reflux 40 minutes, leave standstill, get supernatant 10ml, add hydrochloric acid 1ml, add hot reflux and be concentrated into about 5ml after 1 hour, add water 10ml, 60～90 ℃ of 20ml extract with benzinum, the extract evaporate to dryness, residue adds ethanol 1ml makes dissolving, as need testing solution. Other evens up pier tartaric acid reference substance, adds ethanol and makes the solution that every 1ml contains 1mg, in contrast product solution. Test according to thin-layered chromatography (an appendix VI of Chinese Pharmacopoeia version in 2000 B), draw each 2 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, take chloroform: methyl alcohol=40: 1 is as solvent, launch, take out, dry, spray is with 5% phosphorus aluminic acid ethanolic solution, about 10 minutes of 110 ℃ of bakings. In the test sample chromatogram, with the corresponding position of reference substance chromatogram on, the spot of aobvious same color.

(3) get the content of 25 of this product, porphyrize adds chloroform: methyl alcohol=2: 1 mixed solution 30ml, and jolting was soaked after 1 hour ultrasonic processing 30 minutes, filtration, filtrate volatilizes, and residue adds chloroform 1ml, stirs evenly, and gets supernatant as need testing solution. Other gets Radix Angelicae Sinensis control medicinal material 1g, is made in the same way of control medicinal material solution. Test according to thin-layered chromatography (an appendix VI of Chinese Pharmacopoeia version in 2000 B), draw need testing solution 10 μ l, control medicinal material solution 1 μ l, put respectively on same silica gel g thin-layer plate, take n-hexane: ethyl acetate=9: 1 launches as solvent, takes out, dry, put under the ultraviolet lamp 365nm and inspect. In the test sample chromatogram, with the corresponding position of control medicinal material chromatogram on, the fluorescence spot of aobvious two same colors.

(4) get this product content 3g, porphyrize adds methyl alcohol: ethyl acetate=30ml placed 24 hours in 2: 9, frequently jolting filters the filtrate evaporate to dryness, residue adds the dissolving of water 30ml low-grade fever, filters, and filtrate is extracted 2 times with ethyl acetate, each 20ml discards the ethyl acetate extract, and water layer extracts 3 times with n-butanol, each 15ml merges n-butanol extracting liquid, evaporate to dryness, residue adds methyl alcohol 1ml makes dissolving, as need testing solution. Other gets rhizoma Gastrodiae control medicinal material 1.0g, is made in the same way of control medicinal material solution. Get again the Gastrodin reference substance, add methyl alcohol and make the solution that every 1ml contains 1mg, in contrast product solution. Test according to thin-layered chromatography (an appendix VI of Chinese Pharmacopoeia version in 2000 B), draw each 10 μ l of above-mentioned need testing solution and control medicinal material solution, reference substance solution 2 μ l, put respectively on same silica gel g thin-layer plate, take ethyl acetate: acetone: methyl alcohol: water=13: 1: 1: 0.5 as solvent, launches, take out, dry, spray is with vanillic aldehyde sulfuric acid test solution, and 105 ℃ to be heated to spot colour developing clear. In the test sample chromatogram, with control medicinal material chromatogram and the corresponding position of reference substance chromatogram on, the spot of aobvious same color.

(5) get this product content 1g, porphyrize adds the ultrasonic processing of ethyl acetate 20ml 20 minutes, filters, and filtrate evaporate to dryness, residue add methyl alcohol 1ml makes dissolving, as need testing solution. Other gets Ligusticum wallichii control medicinal material 0.1g, is made in the same way of control medicinal material solution. Test according to thin-layered chromatography (an appendix VI of Chinese Pharmacopoeia version in 2000 B), draw each 10 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, take benzinum: ether: glacial acetic acid=10: 3: 0.1 is as solvent, launch, take out, dry, put under the ultraviolet lamp 365nm and inspect. In the test sample chromatogram, with the corresponding position of control medicinal material chromatogram on, the fluorescence spot of aobvious same color.

[inspection] should meet every regulation relevant under the capsule item (an appendix I of Chinese Pharmacopoeia version in 2000 L).

[assay] measured according to high performance liquid chromatography (an appendix VI of Chinese Pharmacopoeia version in 2000 D).

Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Acetonitrile: water: phosphoric acid=1.5: 98.4: 0.1 is mobile phase; The detection wavelength is 222nm. Number of theoretical plate calculates by the Gastrodin peak should be not less than 1500.

The preparation of reference substance solution: it is an amount of to get the Gastrodin reference substance, and 80 ℃ of dryings 1 hour are accurately weighed, add methyl alcohol and make the reference substance solution that every 1ml contains 50 μ g, and get final product.

The preparation of need testing solution: get this product content under the content uniformity item, porphyrize, mixing, precision takes by weighing 0.6g, puts in the apparatus,Soxhlet's, adds methyl alcohol 30ml, placed 12 hours, and added again methyl alcohol and put in right amount and added hot reflux in the water-bath 6 hours, in extract dislocation evaporating dish, the a small amount of methanol wash of container, washing lotion is incorporated in the evaporating dish, evaporate to dryness, residue adds 80% methyl alcohol 2ml makes dissolving, stirs drying with a small amount of silica gel in water-bath, and the silica gel of anticipating and loading of packing into is done the column top, 3g, 15 * 200mm, 110 ℃ of dryings 30 minutes, an amount of methyl alcohol of evaporating dish: ethyl acetate=washing in 1: 9, washing lotion adds the dried post of silica gel, add again methyl alcohol: ethyl acetate=1: 9 120ml wash-out, collect eluent, evaporate to dryness, residue adds the methyl alcohol dissolving, be transferred in the 5ml measuring bottle, and be diluted to scale, shake up, 0.45 μ m filters, and get final product.

Determination method: precision is drawn reference substance solution and each 5 μ l of need testing solution respectively, and the injection liquid chromatography is measured, and be get final product.

Every of this product contains rhizoma Gastrodiae with Gastrodin C₁₃H ₁₈O ₇Meter should be more than or equal to 0.04mg.

Pharmacological effect:

The pharmacological evaluation of one, the present invention's calmness, analgesic activity:

1, material:

1.1 medicine: medicine A: prepare according to common process.

Medicine B: according to method preparation of the present invention.

1.2 animal: Kunming kind small white mouse, body weight 18～22g, male and female have concurrently.

2, method and result:

2.1 the impact on spontaneous activity in mice: get 30 of small white mouses, male and female half and half are divided into treatment A group, treatment B group and blank group at random, and 10 every group, water 16h is can't help in fasting before the experiment. Blank gives isometric(al) physiological saline. More than equal gastric infusions. Behind the administration 1h, measure the movable number of times of respectively organizing in every mouse 10min. Experimental result sees Table 1.

Table 1 is on the impact of spontaneous activity in mice

Group	Dosage g/kg	The mouse number	Spontaneous activity	Inhibiting rate %	P
						Treatment A	20	10	205.5±65.2	31.5	＜0.05
Treatment B	20	10	146.8±73.5	50.9	＜0.01
						The blank group	-	10	298.4±58.2	-	-

2.2 the analgesic activity to mouse: get 30 of small white mouses, male and female half and half are divided into treatment A group, treatment B group and blank group, 10 every group at random. The blank group gives isometric(al) physiological saline. More than equal gastric infusions. Behind the administration 1h, the equal lumbar injection 0.6% acetic acid 0.2ml/ of each mouse only. Observe interior each mouse of 10min and the writhing response number of times occurs. Experimental result sees Table 2.

The analgesic activity of table 2 pair mouse

Group	Dosage g/kg	The mouse number	The writhing response number of times appears	P
					Treatment A	20	10	14.1±2.9	＜0.01
Treatment B	20	10	10.3±3.0	＜0.01
					The blank group	-	10	20.2±3.5	-

3, discuss, this experiment shows: medicine B is to the effect of spontaneous activity in mice and better than medicine A to the analgesic activity of mouse, and namely medicine B is than the good effect of medicine A treatment headache.

Two, the present invention treats the clinical observation of tension-type headache

1, object and method

1.1 object and grouping: all excuse pains meet following standard person treat-and-release person and are research object: top, temporo, volume and occipitalia present without the pulsation dull pain! At least show effect more than 10 times; The degree of headache belongs to slight or moderate, is lock ring or weight sense (non-pulsation); Each pain continues more than the 30min to 7d; The headache not because physical exertion increases the weight of, do not accompany nauseating, the vomiting, without photophobia or phonophobia; Get rid of the headache that other diseases causes. Selected object divides treatment group and control group at random. Two groups of case-datas see Table 1.

Table 1 liang group case-data

Group	Age/year	Man's example	Woman's example	Ictal catatonic type example	Chronic catatonic type example
						Treatment group	29.28±10.06	14	40	16	38
Control group	29.08±10.75	10	40	14	36

1.2 methods for the treatment of: the diagnostic criteria according to world headache association and the headache classification committee is further divided into ictal tension-type headache and chronic tension-type headache two classes. Treatment group is used medicine containing gastrodia tuber for curing wind syndrome of head, 2 tablets/times, 3 times/d; Cobastab₁20mg/ time, 3 times/d, oryzanol 20mg/ time, 3 times/d. Control group uses amitriptyline 25-50mg/qh, B₁20mg/ time, 3 times/d, oryzanol 20mg/ time, 3 times/d.

1.3 efficacy assessment standard: headache disappears for curing; The headache duration shortens more than 1/2, is produce effects; It is effective that the headache duration shortens 1/2; Headache is without changing, for invalid.

1.4 side reaction order of severity evaluation: be divided into without, slight, moderate and severe. Symptom can be stood as slightly; Need symptomatic treatment, for slightly; Needing drug withdrawal is severe.

2, result: the statistics curative effect is observed in treatment after 4 weeks. Effective 45 examples for the treatment of group, invalid 6 examples, efficient 88.8%; Effective 45 examples of control group, invalid 5 examples, efficient 90%, two group of contrast t=0.795, P=0.431, no significant difference; See Table 2.

The Comparison of therapeutic of table 2 liang group

Curative effect		The recovery from illness example	The produce effects example	Effectively routine	Invalid example	Efficient	Two groups of contrasts
								Treatment group	The outbreak catatonic type	1	4	6	5	88.8％	t-0.795
Chronic catatonic type	8	20	9	1
					Control group	The outbreak catatonic type	4		4	6	0	90％	P-0.431
Chronic catatonic type	2	16	13	5

The clinical manifestation of two groups of side reactions mainly be drowsiness, dry is bitter, constipation, weak, dreaminess etc.; Through two groups of P values of Chi-square Test are drowsiness having more than 0.05, dry is bitter, weak, constipation and blurred vision, see Table 3. Two groups of the orders of severity of side reaction have obvious difference, t=-3.466, and P=0.001 sees Table 4.

The Chi-square Test of table 3 liang group side reaction

Side reaction	Treatment group		Control group		The P value
						Example	Rate %	Example	Rate %
	Drowsiness	0	0	16						32	0.000
Dry is bitter					4	7	18	36	0.000
	Become secret	2	3	10						20	0.019
Weak					0	0	26	52	0.000
	Dreaminess	4	7	2						4	0.420
Blurred vision					0	0	4	8	0.044
	Filtration aroused in interest	0	0	1						2	0.322
The retention of urine					0	0	1	2	0.182

The contrast of the table 4 side reaction order of severity

Group	Without example	Slight example	The moderate example	The severe example	Two groups of contrasts
						Treatment group	48	6	0	0	t--3.466
Control group	30	19	1	0	P-0.001

3, discuss: the present invention treats tension-type headache, with amitriptyline in treatment in contrast. The Different therapeutical effect that the result is two groups is not obvious, but two groups difference is obvious in the observation of side effect, and the prompting treatment group is better than control group.

Claims (13)

1, a kind of gastrodia tuber contained refractory headache treating formulation is characterized in that: calculate according to composition by weight: it mainly is prepared from by rhizoma Gastrodiae 25-100, root of bidentate achyranthes 25-100, radix scrophulariae 25-100, glutinous rehmannia 75-300, Radix Angelicae Sinensis 107.5-430, bark of eucommia 21.5-86, Ligusticum wallichii 25-100, mistletoe 107.5-430, mother chrysanthemum 25-100, yncaria stem with hooks 25-100.

2, according to gastrodia tuber contained refractory headache treating formulation claimed in claim 1, it is characterized in that: specifically: it mainly is prepared from by rhizoma Gastrodiae 50g, root of bidentate achyranthes 50g, radix scrophulariae 50g, glutinous rehmannia 150g, Radix Angelicae Sinensis 215g, bark of eucommia 43g, Ligusticum wallichii 50g, mistletoe 215g, mother chrysanthemum 50g, yncaria stem with hooks 50g.

3, according to claim 1 or 2 described gastrodia tuber contained refractory headache treating formulations, it is characterized in that: preparation of the present invention comprises: capsule, soft capsule, injection, freeze-dried powder, tablet, granule, dripping pill, micro-capsule, micropill, pill, condensed pill, oral liquid, syrup, mixture, sustained release preparation, quick releasing formulation, controlled release preparation, targeting preparation, powder, spray, vina, tincture, lozenge, extract, liquid extract for the preparation that all medical science allow.

4, such as the preparation technology of claim 1,2 or 3 described gastrodia tuber contained refractory headache treating formulations, it is characterized in that: according to given formula rate, Rhizoma Gastrodiae powder is broken into fine powder more than 100 orders, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks boiling, collecting decoction, filter, filtrate is crossed large pore resin absorption column, collect eluent and reduced pressure concentration and become medicinal extract, add the Rhizoma Gastrodiae powder mixing, granulate, make again the product of different preparations at last with diverse ways.

5, according to the preparation technology of gastrodia tuber contained refractory headache treating formulation claimed in claim 4, it is characterized in that: the technique when the present invention makes capsule is: Rhizoma Gastrodiae powder is broken into fine powder more than 100 orders, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks are pulverized respectively, boiling 2～5 times, each 1～8 hour, collecting decoction, filter, filtrate is crossed large pore resin absorption column, use ethanol elution, collect eluent and reduced pressure concentration and become medicinal extract, add the Rhizoma Gastrodiae powder mixing, dry with vacuum drying, spray-drying or freeze-drying, be ground into the above fine powder of 60 orders, the microcrystalline cellulose with 0.1～5 times of amount of medicinal powder amount mixes again, make particle diameter less than the micropill of 2mm take the ethanolic solution of 2～10%PVP as binder, filling, namely get capsule, the micropill among the present invention also available 1～10% film coating liquid carries out dressing to it, and then loads capsule.

6, according to the preparation technology of gastrodia tuber contained refractory headache treating formulation claimed in claim 4, it is characterized in that: the technique when the present invention makes tablet is: get rhizoma Gastrodiae and pulverize, use alcohol extract, merge extract, Recycled ethanol also is condensed into medicinal extract, namely get Rhizoma Gastrodiae extract, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks are pulverized respectively the above fine powder of 60 orders, mix with the sodium carboxymethyl starch of Rhizoma Gastrodiae extract, medicinal powder amount 0.5-10%, and use alcohol granulation, the sodium carboxymethyl starch with medicinal powder amount 0.5-2% mixes compressing tablet again, with the 2-8% film coating agent plain sheet is carried out dressing, namely get tablet.

7, according to the preparation technology of gastrodia tuber contained refractory headache treating formulation claimed in claim 4, it is characterized in that: the technique that the present invention makes soft capsule is: get each medicinal material and pulverize respectively, wherein Radix Angelicae Sinensis, Ligusticum wallichii supercritical fluid extraction get Radix Angelicae Sinensis, Rhizoma Chuanxiong extract; The rhizoma Gastrodiae alcohol extract namely gets Rhizoma Gastrodiae extract. All the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum, yncaria stem with hooks extract with semi-bionic extraction, mix with Radix Angelicae Sinensis, Rhizoma Chuanxiong extract, Rhizoma Gastrodiae extract again, join to make in the soft capsule auxiliary material of 0.5-5% and be uniformly dispersed, pill, namely get soft capsule, used auxiliary material is soya-bean oil: Tween-80: ethyl cellulose=5～15: 1～10: 3～8 mixture.

8, according to the preparation technology of gastrodia tuber contained refractory headache treating formulation claimed in claim 4, it is characterized in that: the technique that the present invention makes pill is: get each medicinal material and pulverize respectively, wherein rhizoma Gastrodiae, yncaria stem with hooks alcohol extract get rhizoma Gastrodiae, uncaria extract; Other gets Radix Angelicae Sinensis, Ligusticum wallichii extraction by steam distillation, gets Radix Angelicae Sinensis, Rhizoma Chuanxiong extract; All the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum water boiling and extraction, alcohol precipitation, concentrated, merge with the said extracted thing again, other gets and mixes with the said extracted thing after 1-8 doubly measures the PEG-4000 melting, splashes in the dimethicone and cools off, and namely gets pill.

9, according to the preparation technology of gastrodia tuber contained refractory headache treating formulation claimed in claim 4, it is characterized in that: the technique that the present invention makes freeze drying powder injection is: get each medicinal material and pulverize respectively, wherein Radix Angelicae Sinensis, Ligusticum wallichii supercritical fluid extraction get Radix Angelicae Sinensis, Rhizoma Chuanxiong extract; The rhizoma Gastrodiae alcohol extract, namely get Rhizoma Gastrodiae extract, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum, yncaria stem with hooks extract with semi-bionic extraction, filter, filtrate is crossed large pore resin absorption column, use ethanol elution, collect eluent and reduced pressure concentration and become medicinal extract, again with Radix Angelicae Sinensis, Rhizoma Chuanxiong extract, lactose and the sweet mellow wine of Rhizoma Gastrodiae extract, total liquid 1-30% mix, add to the full amount of water for injection, the adjusting liquid PH value is 2-7, filters can, freeze drying namely gets freeze drying powder injection.

10, according to the preparation technology of gastrodia tuber contained refractory headache treating formulation claimed in claim 4, it is characterized in that: the technique that the present invention makes ejection preparation is: get each medicinal material and pulverize respectively, wherein rhizoma Gastrodiae, Radix Angelicae Sinensis, Ligusticum wallichii, yncaria stem with hooks supercritical fluid extraction, get extract 1, the residue root of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum water boiling and extraction, more than after stone sulphur method is processed, once reaching once with the ethanol alcohol precipitation, contain for the first time the alcohol amount and be 50-75%, the alcohol amount that contains that secondary and secondary are later is 75%-99.9%, Recycled ethanol, namely get extract 2 after the liquid ultrafiltration, the glucose of doubly measuring with extract 1, total liquid 0.01-0.5 mixes, and adds to the full amount of water for injection, the adjusting liquid PH value is 2-7, filter, embedding, sterilization namely get ejection preparation.

11, according to the preparation technology of gastrodia tuber contained refractory headache treating formulation claimed in claim 4, it is characterized in that: the prescription of granulation agent of the present invention is: rhizoma Gastrodiae 25g, root of bidentate achyranthes 25g, radix scrophulariae 25g, glutinous rehmannia 75g, Radix Angelicae Sinensis 107.5g, bark of eucommia 21.5g, Ligusticum wallichii 25g, mistletoe 107.5g, mother chrysanthemum 25g, yncaria stem with hooks 25g, sucrose 200g. Preparation technology is: get rhizoma Gastrodiae, sucrose and be ground into respectively 120 purpose fine powders, 65% alcohol extract of all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, Radix Angelicae Sinensis, the bark of eucommia, Ligusticum wallichii, mistletoe, mother chrysanthemum, yncaria stem with hooks usefulness 3500ml 2 times, each 2h, filtrate recycling ethanol and reduced pressure concentration become medicinal extract, mix with Rhizoma Gastrodiae powder, cane sugar powder, granulate, packing namely gets granule.

12, according to the preparation technology of gastrodia tuber contained refractory headache treating formulation claimed in claim 4, it is characterized in that: the prescription that the present invention makes syrup is: rhizoma Gastrodiae 100g, root of bidentate achyranthes 100g, radix scrophulariae 100g, glutinous rehmannia 300g, Radix Angelicae Sinensis 430g, bark of eucommia 86g, Ligusticum wallichii 100g, mistletoe 430g, mother chrysanthemum 100g, yncaria stem with hooks 100g, sucrose 500g. Preparation technology is: get each medicinal material and be ground into respectively meal, wherein rhizoma Gastrodiae, yncaria stem with hooks 2000ml80% alcohol extract 3 times, each 2h merges extract, and Recycled ethanol and reduced pressure concentration become medicinal extract, drying under reduced pressure, get rhizoma Gastrodiae, uncaria extract, other gets Radix Angelicae Sinensis, Ligusticum wallichii extraction by steam distillation, filters, filtrate is condensed into medicinal extract, drying under reduced pressure gets Radix Angelicae Sinensis, Rhizoma Chuanxiong extract, all the other roots of bidentate achyranthes, radix scrophulariae, glutinous rehmannia, the bark of eucommia, mistletoe, mother chrysanthemum boiling 3 times, decocting time is respectively 3h, 2h, 1h, filter, filtrate is condensed into medicinal extract, drying under reduced pressure, and get final product, other gets sucrose and joins and make fully dissolving in the water that boils, and will the said extracted thing adds in the sucrose liquid mix, and filters, can namely gets syrup.

13, such as the method for quality control of claim 1,2 or 3 described gastrodia tuber contained refractory headache treating formulations, the method of quality control of capsule preparations particularly, it comprises: proterties, discriminating, inspection, assay is characterized in that: proterties: this product is capsule, and content is brown color powder or particle; Gas delicate fragrance, mildly bitter flavor;

Differentiate: (1) gets this product content, porphyrize, putting microscopically observes: prothenchyma (of wood) ellipse or class polygonal, diameter 1～1000 μ m, wall thickness 1～100 μ m, lignify, pit is obvious, screw thread, reticulate pattern and annular duct diameter 1～200 μ m, needle-like calcium oxalate crystal bunchy or be dispersed in, long 1～500 μ m;

(2) get this product content, porphyrize adds alcohol heating reflux and extracts, leave standstill, get supernatant, add hot reflux behind the adding hydrochloric acid, concentrated, concentrate extracts with benzinum after adding suitable quantity of water, and extract evaporate to dryness, residue add ethanol makes dissolving, as need testing solution, other evens up pier tartaric acid reference substance, adds the ethanol dissolving, in contrast product solution, test according to the Chinese Pharmacopoeia thin-layered chromatography, draw above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, take chloroform: methyl alcohol=1～99: 99～1 as solvent, launch, take out, dry, spray is with phosphomolybdic acid ethanol solution, dried by the fire 5～50 minutes, in the test sample chromatogram, with the corresponding position of reference substance chromatogram on, the spot of aobvious same color;

(3) get this product content, porphyrize adds chloroform: methyl alcohol=1～99: 99～1 mixed solutions, and jolting, ultrasonic processing after soaking filters, and filtrate volatilizes, and residue adds chloroform, stirs evenly, and gets supernatant as need testing solution. Other gets the Radix Angelicae Sinensis control medicinal material, is made in the same way of control medicinal material solution, according to the test of Chinese Pharmacopoeia thin-layered chromatography, draw need testing solution, control medicinal material solution, put respectively on same silica gel g thin-layer plate, take n-hexane: ethyl acetate=1～99: 99～1 as solvent, launches, take out, dry, put under the ultraviolet lamp and inspect, in the test sample chromatogram, with the corresponding position of control medicinal material chromatogram on, the fluorescence spot of aobvious two same colors;

(4) get this product content, porphyrize, add methyl alcohol: ethyl acetate=1～99: dissolve in 99～1 mixed solutions, place, frequently jolting, filter, the filtrate evaporate to dryness, residue adds the dissolving of water low-grade fever, filter, filtrate is extracted with ethyl acetate, discards the ethyl acetate extract, water layer extracts with n-butanol, merge n-butanol extracting liquid, evaporate to dryness, residue add methyl alcohol makes dissolving, as need testing solution, other gets the rhizoma Gastrodiae control medicinal material, is made in the same way of control medicinal material solution, gets the Gastrodin reference substance again, add the methyl alcohol dissolving, product solution according to the test of Chinese Pharmacopoeia thin-layered chromatography, is drawn above-mentioned need testing solution and control medicinal material solution in contrast, reference substance solution, put respectively on same silica gel g thin-layer plate, take ethyl acetate: acetone: methyl alcohol: water=1～150: 0.1～10: 0.1～10: 0.01～10 as solvent, launches, and takes out, dry, spray is with vanillic aldehyde sulfuric acid test solution, and it is clear to be heated to the spot colour developing, in the test sample chromatogram, with control medicinal material chromatogram and the corresponding position of reference substance chromatogram on, the spot of aobvious same color;

(5) get this product content, porphyrize adds the ultrasonic processing of ethyl acetate, filters, and filtrate evaporate to dryness, residue add methyl alcohol makes dissolving, as need testing solution. Other gets the Ligusticum wallichii control medicinal material, is made in the same way of control medicinal material solution, according to the test of Chinese Pharmacopoeia thin-layered chromatography, draw above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, take benzinum: ether: glacial acetic acid=1～100: 0.1～50: 0.01～10 as solvent, launches, take out, dry, put under the ultraviolet lamp and inspect, in the test sample chromatogram, with the corresponding position of control medicinal material chromatogram on, the fluorescence spot of aobvious same color;

Check: should meet every regulation relevant under the Chinese Pharmacopoeia capsule item;

Assay: according to the Chinese Pharmacopoeia high effective liquid chromatography for measuring;

Chromatographic condition and system suitability: be filler with octadecylsilane chemically bonded silica; Acetonitrile: water: phosphoric acid=0.1～100: 5～1000: 0.01～10 is mobile phase; The detection wavelength is 10～1000nm, and number of theoretical plate calculates by the Gastrodin peak should be not less than 100～10000;

The preparation of reference substance solution: it is an amount of to get the Gastrodin reference substance, and drying is accurately weighed, adds the methyl alcohol dissolving, and get final product;

The preparation of need testing solution: get this product content under the content uniformity item, porphyrize, mixing, accurately weighed, put in the apparatus,Soxhlet's, add methyl alcohol, place, add again an amount of methyl alcohol and put and add hot reflux in the water-bath, in extract dislocation evaporating dish, the a small amount of methanol wash of container, washing lotion is incorporated in the evaporating dish, evaporate to dryness, residue adds methyl alcohol makes dissolving, stirs drying with a small amount of silica gel in water-bath, and the silica gel of anticipating and loading of packing into is done the column top, 3g, 15 * 200mm, 110 ℃ of dryings 30 minutes, an amount of methyl alcohol of evaporating dish: ethyl acetate=1～99: 99～1 washings, washing lotion adds the dried post of silica gel, add again methyl alcohol: ethyl acetate=1～99: 99～1 wash-outs, collect eluent, evaporate to dryness, residue adds the methyl alcohol dissolving, be transferred in the 5ml measuring bottle, and be diluted to scale, shake up, filter, and get final product;

Determination method is accurate reference substance solution and the need testing solution drawn respectively, and the injection liquid chromatography is measured, and be get final product.