CN1827147A - Dispersible tablet with gastrodia tuber for treating headache, its preparation and quality control method - Google Patents
Dispersible tablet with gastrodia tuber for treating headache, its preparation and quality control method Download PDFInfo
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Abstract
The invention relates to Tianshu dispersion tablet for treating cephalalgia, the process for preparation and method of quality control, wherein the tablet is prepared from Ligusticum wallichii, rhizoma Gastrodiae, cross bonded polyvinylpyrrolidone, low substituted methylcellulose propylene glycol ether, miropowdered silica gel, crystalline cellulose, magnesium stearate, and aspartame.
Description
Technical field: the present invention relates to a kind of dispersible tablet with gastrodia tuber and preparation method and method of quality control for the treatment of headache, belong to technical field of Chinese medicine.
Background technology: if effective drug main Rhizoma Chuanxiong of Chinese traditional treatment migraine and gastrodia tuber preparation, wherein day easypro preparation is made up of Rhizoma Gastrodiae and Rhizoma Chuanxiong two flavor Chinese medicines, effect with the suppressing the hyperactive liver of invigorating blood circulation, be mainly used in angioneurotic headache due to the blood stasis, be widely used in all kinds of headaches of control, studies show that, use day easypro preparation can the alleviating pain degree, shorten the headache duration of seizure, especially can comparatively ideal control of seizures number of times, alleviate the patient to a great extent throughout the year by the misery of headache puzzlement, and do not have tangible untoward reaction.Use the more day relieving capsule that is in the market, but local drug concentration was crossed high weak point after capsule existed the patient to take medicine, and a kind of quick-effective preparation that dispersible tablet is a development in recent years to get up, the good reputation that " Peroral solid dosage form liquid " is arranged, the advantage that integrates tablet and oral liquid, and overcome both deficiency, can solve the problem that existing capsule exists.In addition,, guarantee the clinical efficacy of medicine, need to formulate rationally and the stabilized quality control criterion in order to investigate and control the quality of product comprehensively.
Summary of the invention:
The objective of the invention is to: a kind of dispersible tablet with gastrodia tuber and preparation method and method of quality control for the treatment of headache is provided, the present invention on the basis of existing technology, it is dispersible tablet that the sky relieving capsule is changed agent, overcome the deficiency of existing capsule, more help drug absorption, significantly improved its bioavailability, convenient patient's medication; And studied and defined scientific and reasonable method of quality control, to control effectively and to improve the quality of products.
The present invention constitutes like this: it is prepared from Rhizoma Chuanxiong 784g, Rhizoma Gastrodiae 196g and crospolyvinylpyrrolidone 100g, low-substituted hydroxypropyl cellulose 77g, micropowder silica gel 18g, microcrystalline Cellulose 200g, magnesium stearate 3g, aspartame 2g.
The preparation method of dispersible tablet with gastrodia tuber is: gets Rhizoma Chuanxiong and Rhizoma Gastrodiae and pulverizes, mixes, and with 90% alcohol reflux twice, each 2 hours, merge extractive liquid,, filtration, filtrate recycling ethanol and to be condensed into 55～60 ℃ of relative densities be 1.27 clear paste; Medicinal residues decoct with water twice, and each 1 hour, collecting decoction filtered, and it is 1.27 clear paste that filtrate is condensed into 55～60 ℃ of relative densities, merges with above-mentioned clear paste, and vacuum drying is pulverized, and crosses 80 mesh sieves; With low-substituted hydroxypropyl cellulose, micropowder silica gel, crospolyvinylpyrrolidone, microcrystalline Cellulose and aspartame mix homogeneously, with 95% ethanol system soft material, 20 eye mesh screens are granulated, in 60 ℃ ± 5 ℃ dryings, dried granule adds magnesium stearate with 20 eye mesh screen granulate in the granule behind the granulate, mix homogeneously, tabletting, packing, promptly.
The method of quality control of dispersible tablet with gastrodia tuber is: described method of quality control mainly comprise in character, discriminating, inspection and the assay project partly or entirely; Wherein differentiate the thin layer chromatography discriminating that comprises Rhizoma Gastrodiae in the preparation and Rhizoma Chuanxiong; Assay is that the contained content of ferulic acid of Rhizoma Chuanxiong in the preparation is measured.
The discrimination method of Rhizoma Gastrodiae is to be contrast with the gastrodine reference substance, and with chloroform: the upper solution of methanol=3: 1 is the thin layer chromatography of developing solvent; The discrimination method of Rhizoma Chuanxiong is to be contrast with the Rhizoma Chuanxiong control medicinal material, and with normal hexane: ethyl acetate=9: 1 is the thin layer chromatography of developing solvent.
Concrete discrimination method comprises the part or all of of following project:
(1) get 3 in this preparation, porphyrize adds water 15ml and makes dissolving, filters, and filtrate is extracted with ether 25ml jolting, discards ether solution, and water layer extracts with n-butyl alcohol 20ml jolting, divides and gets n-butyl alcohol liquid, and evaporate to dryness, residue add methanol 1ml makes dissolving, as need testing solution; Other gets the gastrodine reference substance, adds methanol and makes the solution that every 1ml contains 0.5mg, in contrast product solution; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel g thin-layer plate of adhesive with the sodium carboxymethyl cellulose, with chloroform: the upper solution of methanol=3: 1 is developing solvent, launch, take out, dry, spray is with 15% phosphomolybdic acid ethanol solution, 105 ℃ of heating 10 minutes; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color;
(2) get 2 in this preparation, porphyrize, the 20ml that adds diethyl ether, reflux 1 hour filters, and filtrate volatilizes, and residue adds ethyl acetate 2ml makes dissolving, as need testing solution; Other gets Rhizoma Chuanxiong control medicinal material 1g, shines medical material solution in pairs with legal system; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 2 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with normal hexane: ethyl acetate=9: 1 is developing solvent, launches, take out, dry, put under the ultra-violet lamp and inspect, in the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
The content of ferulic acid assay method is to be contrast with the ferulic acid reference substance in the Rhizoma Chuanxiong, and with methanol: 1% acetum=40: 60 is the high performance liquid chromatography of mobile phase.
Concrete content assaying method is:
According to an appendix VID of Chinese Pharmacopoeia version in 2005 high effective liquid chromatography for measuring:
Chromatographic condition and system suitability test are filler with the octadecylsilane chemically bonded silica; With methanol: 1% acetum=40: 60 is a mobile phase; The detection wavelength is 323nm; Number of theoretical plate calculates by the ferulic acid peak should be not less than 3000;
It is an amount of that the ferulic acid reference substance is got in the preparation of reference substance solution, and accurate the title decides, and adds 50% ethanol and makes the solution that every 1ml contains 10 μ g, promptly;
This preparation under the weight differential item is got in the preparation of need testing solution, and porphyrize is got about 1g, the accurate title, decide, and puts in the tool plug conical flask, the accurate 50% ethanol 50ml that adds, close plug claims to decide weight, and supersound process is 30 minutes under power 300W, frequency 50kHz condition, put coldly, claim again to decide weight, supply the weight that subtracts mistake with 50% ethanol, shake up, filter, get subsequent filtrate, promptly;
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly;
Every in this preparation contains Rhizoma Chuanxiong with ferulic acid C
10H
10O
4Meter must not be less than 0.25mg.
Method of quality control of the present invention comprises:
Character: medicine is that pale brown color is to brown color chips; Special fragrance is arranged, and mildly bitter flavor is puckery;
Differentiate: (1) gets 3 in this preparation, and porphyrize adds water 15ml and makes dissolving, filters, filtrate is extracted with ether 25ml jolting, discards ether solution, and water layer extracts with n-butyl alcohol 20ml jolting, divides and gets n-butyl alcohol liquid, evaporate to dryness, residue add methanol 1ml makes dissolving, as need testing solution; Other gets the gastrodine reference substance, adds methanol and makes the solution that every 1ml contains 0.5mg, in contrast product solution; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel g thin-layer plate of adhesive with the sodium carboxymethyl cellulose, with chloroform: the upper solution of methanol=3: 1 is developing solvent, launch, take out, dry, spray is with 15% phosphomolybdic acid ethanol solution, 105 ℃ of heating 10 minutes; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color;
(2) get 2 in this preparation, porphyrize, the 20ml that adds diethyl ether, reflux 1 hour filters, and filtrate volatilizes, and residue adds ethyl acetate 2ml makes dissolving, as need testing solution; Other gets Rhizoma Chuanxiong control medicinal material 1g, shines medical material solution in pairs with legal system; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 2 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with normal hexane: ethyl acetate=9: 1 is developing solvent, launches, take out, dry, put under the ultra-violet lamp and inspect, in the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color;
Check: dispersing uniformity is got 2 in this preparation, puts in 20 ℃ ± 1 ℃ the 100ml water jolting 3 minutes, all disintegrate and sieve by No. two;
Dissolution is got this preparation, according to two appendix XC of Chinese Pharmacopoeia version in 2005 dissolution method three therapeutic methods of traditional Chinese medicine, is solvent with water 200mL, rotating speed is that per minute 75 changes, and operation in accordance with the law is in the time of 20 minutes, it is an amount of to get solution, filters with 0.45 μ m filter membrane, as need testing solution; Measure according to the method under the assay item, calculate every stripping quantity; Limit is 70% of a content, should be up to specification;
Other should meet relevant every regulation under an appendix ID of Chinese Pharmacopoeia version in 2005 the tablet item;
Assay: shine an appendix VID of Chinese Pharmacopoeia version in 2005 high effective liquid chromatography for measuring:
Chromatographic condition and system suitability test are filler with the octadecylsilane chemically bonded silica; With methanol: 1% acetum=40: 60 is a mobile phase; The detection wavelength is 323nm; Number of theoretical plate calculates by the ferulic acid peak should be not less than 3000;
It is an amount of that the ferulic acid reference substance is got in the preparation of reference substance solution, and accurate the title decides, and adds 50% ethanol and makes the solution that every 1ml contains 10 μ g, promptly;
This preparation under the weight differential item is got in the preparation of need testing solution, and porphyrize is got about 1g, the accurate title, decide, and puts in the tool plug conical flask, the accurate 50% ethanol 50ml that adds, close plug claims to decide weight, and supersound process is 30 minutes under power 300W, frequency 50kHz condition, put coldly, claim again to decide weight, supply the weight that subtracts mistake with 50% ethanol, shake up, filter, get subsequent filtrate, promptly;
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly;
Every in this preparation contains Rhizoma Chuanxiong with ferulic acid C
10H
10O
4Meter must not be less than 0.25mg.
The traditional Chinese medical science thinks that excessive rising of liver-YANG, congestion internal resistance are the main pathogeny of vascular headache.Rule of treatment suppressing the hyperactive liver and subsiding YANG relieves dizziness, high fever, infantile convulsions, epilepsy, etc., sensible activeization silt.This preparation is made by Rhizoma Chuanxiong, Rhizoma Gastrodiae two herbal medicines, wherein Rhizoma Chuanxiong has strong function of promoting blood circulation to disperse blood clots, the energy expansion of cerebral vascular, improve brain blood circulation, reduce platelet aggregation and adhesion function, thereby reduce the release of vaso-active substance (Kallidin I, 5-hydroxy tryptamine etc.), the alleviating vascular spasm alleviates or removes headache and show effect.Rhizoma Gastrodiae has the suppressing the hyperactive liver to relieve the wind syndrome effect, and pharmacological evaluation shows that Rhizoma Gastrodiae has obvious analgesia, calmness and hypotensive effect, can improve body anti-anoxia ability and microcirculation improvement.Both share has blood-activating and qi-promoting, suppressing the hyperactive liver and network, and the effect of wind-expelling pain-stopping is mainly used in angioneurotic headache due to the blood stasis, and with the passing of time disease sees headache, localized pain, or it is dizzy to hold concurrently, uneasy sleeping at night, dark tongue quality or ecchymosis.
Compared with prior art, dispersible tablet of the present invention has following advantage: disintegration time is short, good dispersing state; The medicine stripping is rapid, absorbs soon the bioavailability height; Production equipment is identical with conventional tablet, is suitable for industrialized great production; Taking convenience and method are various, can directly swallow or disperse back and fruit juice, milk etc. and clothes in water, especially are fit to the patient of old, children and dysphagia; Produce, carry, convenient transportation, steady quality.In addition, method of quality control precision height of the present invention, favorable reproducibility, measurement result is accurate, can effectively guarantee the clinical efficacy of said preparation.
The applicant has carried out a series of experimentation, with the preparation technology and the method for quality control science, reasonable, feasible of assurance preparation of the present invention, thereby makes said preparation have good curative effect.
One, Study on Preparation
1. extract determining of amount of water and alcohol adding amount
Test method: getting a recipe quantity medical material, add the water extraction and 90% ethanol extraction of 12 times, 10 times, 8 times, 6 times amounts respectively, is evaluation index with the paste-forming rate, selects the best to add water and alcohol adding amount, and result of the test is as follows:
| Alcohol adding amount (doubly) | Paste-forming rate (%) | Amount of water (doubly) | Paste-forming rate (%) |
| 12 | 55.6 | 12 | 41.5 |
| 10 | 54.3 | 10 | 39.7 |
| 8 | 47.5 | 8 | 32.2 |
| 6 | 41.8 | 6 | 29.5 |
Result of the test shows, it is the most suitable that employing adds 10 times of amounts 90% ethanol and water extraction, its paste-forming rate does not have marked difference apparently higher than adding 8 times of amounts, paste-forming rate when 6 times of amounts are extracted with the extraction paste-forming rate that adds 12 times of amounts, therefore determines to extract amount of water and alcohol adding amount is respectively 10 times of amounts.
2. the screening of preparation process prescription
Table 1 preparation prescription craft screening
| Form | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | |
| It easypro extract powder (g) | A recipe quantity | A recipe quantity | A recipe quantity | A recipe quantity | |
| Microcrystalline Cellulose (g) | 250 | -- | 150 | 200 | |
| Crospolyvinylpyrrolidone (g) | -- | 225 | 75 | 100 | |
| Low-substituted hydroxypropyl cellulose (g) | 100 | 80 | 20 | 27 | |
| Micropowder silica gel (g) | 50 | 30 | 25 | 18 | |
| Magnesium stearate (g) | 3 | 3 | 3 | 3 | |
| Aspartame (g) | 5 | 2 | 2 | 2 | |
| Wetting agent | 70% ethanol | 95% ethanol | 95% ethanol | 95% ethanol | |
| Evaluation index and result | The granule compressibility | Generally | Well | Generally | Well |
| The granulation complexity | More sticking | Easily | Easily | Easier | |
| The tablet appearance character | The inhomogeneous aberration of color and luster is obvious | Bright and clean color and luster is even | Bright and clean color and luster is even | Bright and clean color and luster is even | |
| Disintegration | ＞3min | ＞3min | ＞2min | ＜2min | |
| Mouthfeel | Generally | Better | Better | Better | |
Method for making: except that magnesium stearate, all the other uniform mixing of respectively distinguishing the flavor of add respectively and as above show described wetting agent system soft material with above each side, granulate 60 ℃ ± 5 ℃ oven dry, 20 mesh sieve granulate with 20 mesh sieves, sneak into magnesium stearate, tabletting, the result shows: it is 4 ideal to write out a prescription, therefore determine that prescription 4 finally writes out a prescription for dispersible tablet with gastrodia tuber, adopt prescription 4 to carry out middle trial production, the finished product recovery rate is higher as a result, and this feasible process is described, be fit to the industrialized great production requirement, the test data of three batches of pilot products sees Table 2.
Dispersible tablet with gastrodia tuber determines that finally prescription is as follows:
It easypro extract powder (a prescription medical material is carried)
Crospolyvinylpyrrolidone 100g
Low-substituted hydroxypropyl cellulose 77g
Micropowder silica gel 18g
Microcrystalline Cellulose 200g
Magnesium stearate 3g
Aspartame 2g
Make 1000 altogether, every heavy 0.70g.
Preparation technology: the dry extract of getting recipe quantity, low-substituted hydroxypropyl cellulose, micropowder silica gel, crospolyvinylpyrrolidone, microcrystalline Cellulose and aspartame mix homogeneously with recipe quantity, with 95% ethanol system soft material, 20 eye mesh screens are granulated, in 60 ℃ ± 5 ℃ dryings, dried granule is with 20 eye mesh screen granulate, add the magnesium stearate of recipe quantity in the granule behind the granulate, mix homogeneously is pressed into 1000, packing, promptly.
The result of the test of three batches of pilot products of table 2
| Lot number | 050301 | 050302 | 050303 |
| Medical material inventory (kg) | 9.8 | 9.8 | 9.8 |
| Dry extract amount (kg) | 3.03 | 2.98 | 3.07 |
| Low-substituted hydroxypropyl cellulose (kg) | 0.77 | 0.77 | 0.77 |
| Crospolyvinylpyrrolidone (kg) | 1.00 | 1.00 | 1.00 |
| Microcrystalline Cellulose (kg) | 2.00 | 2.00 | 2.00 |
| Aspartame (kg) | 0.02 | 0.02 | 0.02 |
| Micropowder silica gel (kg) | 0.18 | 0.18 | 0.18 |
| Magnesium stearate (kg) | 0.03 | 0.03 | 0.03 |
| Theoretical yield (sheet) | 10000 | 10000 | 10000 |
| Actual production (sheet) | 9096 | 9120 | 8904 |
| Yield rate (%) | 90.96 | 91.20 | 89.04 |
Conclusion: three batches of pilot product result of the tests of this preparation show that its technology is reasonable, stable, and the finished product recovery rate is higher, and the gained finished product is through quality inspection, and the result shows all up to specification.
Two, toxicologic study
The LD of Rhizoma Gastrodiae extractum (every suitable crude drug 7.14g) 1 ip of male mice
50Be 0.36ml/10g, quite crude drug 0.514g/10g; Rhizoma Chuanxiong water solublity crude preparation by using awards the LD of ip in mice and im
50Be respectively 65.86 and 66.42g/kg.The LD of ligustrazine mice iv
50Be 239mg/kg, continuous 4wk, the weight of animals, hemogram, liver, renal function and histopathologic examination show no obvious abnormalities.
Bone marrow cells in mice is dyed city's body to the various dose group of dispersible tablet with gastrodia tuber and polychromatophilia micronucleus in erythrocytes rate does not have the significance increase, illustrates that this medicine does not have the hereditary material existence of damage bone marrow cells in mice in the used dosage range of this experiment.
Three, pharmacodynamic study
Only contain Rhizoma Gastrodiae and Rhizoma Chuanxiong two flavor medical materials in the preparation of the present invention, be mainly used in the treatment angioneurotic headache, two flavors share, and mainly play promoting blood circulation and stopping pain.
The main pharmacodynamics research of Rhizoma Gastrodiae: the vanillyl alcohol of ip200mg/kg and Vanillin liquid can reduce spontaneous activity in mice, and present calm peak value when 15-30min, point out it to have sedation; Rhizoma Gastrodiae water preparation and Armillaria mellea fermented solution all have the obvious suppression effect to the mice autonomic activities; Rhizoma Gastrodiae water preparation, Armillaria mellea fermented solution can reduce mice and enter the length of one's sleep; Vanillyl alcohol liquid, Rhizoma Gastrodiae water preparation, Armillaria mellea fermented solution, Rhizoma Gastrodiae injection and go gastrodin part all can prolong mouse sleep time; Ip in mice vanillyl alcohol liquid, Vanillin liquid, Rhizoma Gastrodiae water preparation, Armillaria mellea fermented solution are observed it to the convulsions phenomenon that pentetrazole causes, all can improve CD50 CD
50Gastrodia elata polysaccharide has the effect of enhancing body nonspecific immunity and cellular immunization; Gastrodia elata polysaccharide has direct repression to vesicular stomatitis virus (VSV) in tissue culture.
The main pharmacodynamics research of Rhizoma Chuanxiong: Rhizoma Chuanxiong has tangible sedation.Movable inhibited to animal brain when Rhizoma Chuanxiong volatile oil is a small amount of, and medulla oblongata respiratory center, vasomotor center and spinal reflex maincenter are had excitation.The Rhizoma Chuanxiong decoct all can suppress its spontaneous activity for respectively large and small Mus ig, and the mouse sleep time that pentobarbital sodium is caused prolongs, and the excitation that can resist caffeine (20mg/kg), but the rat that can not resist due to the pentetrazole is fainted from fear.Rhizoma Chuanxiong water extract and alkaloid thereof can be expanded crown and blood vessel, and coronary blood flow increasing improves the myocardial ischemia situation, and behind the anesthetized dog iv ligustrazine, arteria coronaria and cerebral blood flow increase, and arteria coronaria, cerebrovascular and Peripheral resistance reduce; Ligustrazine also can obviously increase the cardiac output of rat, reduces Peripheral resistance, and reduces pulmonary vascular resistance; Rhizoma Chuanxiong, Rhizoma Chuanxiong total alkaloids and ligustrazine can make the anesthetized dog vascular resistance descend, and brain, femoral artery and lower extremity blood flow amount are increased; Ligustrazine prolonged in the external ADP inductive platelet aggregation time, and accumulative platelet is had depolymerisation.
Four, method of quality control research
(1) sample and contrast medicine source
Sample: the applicant's self-control, lot number is: 050201,050202,050203.
The ferulic acid reference substance derives from Nat'l Pharmaceutical ﹠ Biological Products Control Institute, lot number: 0773-9910.
The gastrodine reference substance derives from Nat'l Pharmaceutical ﹠ Biological Products Control Institute, lot number: 0807-9903.
The Rhizoma Chuanxiong control medicinal material derives from Nat'l Pharmaceutical ﹠ Biological Products Control Institute, lot number: 0918-200004.
(2) character
This preparation is that dry extract adds appropriate amount of auxiliary materials, forms through pelletizing press sheet, and through many batch sample trial-productions, its appearance character is pale brown color to brown color chips as a result, therefore, is defined as under the dispersible tablet with gastrodia tuber quality standard character item: medicine is that pale brown color is to brown color chips; Special fragrance is arranged, and mildly bitter flavor is puckery.
(3) differentiate
With reference to the national drug standards WS of State Food and Drug Administration
3-134 (Z-022)-2001 (Z) day relieving capsule is differentiated item content down, with the method for thin layer this preparation principal agent Rhizoma Gastrodiae, Rhizoma Chuanxiong is differentiated.
1, the thin layer of Rhizoma Gastrodiae is differentiated
(1) get 3 in this preparation, porphyrize adds water 15ml and makes dissolving, filters, and filtrate is extracted with ether 25ml jolting, discards ether solution, and water layer extracts with n-butyl alcohol 20ml jolting, divides and gets n-butyl alcohol liquid, and evaporate to dryness, residue add methanol 1ml makes dissolving, as need testing solution.Other gets the gastrodine reference substance, adds methanol and makes the solution that every ml contains 0.5mg, in contrast product solution.Test according to thin layer chromatography (appendix VIB of Chinese Pharmacopoeia version in 2005), draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel g thin-layer plate of adhesive with the sodium carboxymethyl cellulose, upper solution with chloroform-methanol (3: 1) is developing solvent, launch, take out, dry, spray is with 15% phosphomolybdic acid ethanol solution, 105 ℃ of heating 10 minutes.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color.
(2) selection of point sample amount
Through experimental selection need testing solution and reference substance solution each point sample 5 μ l, 10 μ l, speckle is better, comparatively clear when found that need testing solution and reference substance solution point sample 5 μ l.So this standard reference material solution and need testing solution select for use 5 μ l as the point sample amount.
(3) specificity experiment
Get the negative sample 0.501g that lacks Rhizoma Gastrodiae, make negative need testing solution, launch the back and do not have corresponding speckle, illustrate that negative sample is noiseless to this experiment at the reference substance place by last method operation.
2, the thin layer of Rhizoma Chuanxiong is differentiated
(1) get 2 in this preparation, porphyrize, the 20ml that adds diethyl ether, reflux 1 hour filters, and filtrate volatilizes, and residue adds ethyl acetate 2ml makes dissolving, as need testing solution.Other gets Rhizoma Chuanxiong control medicinal material 1g, with the legal system medical material solution of taking a picture in pairs.Test according to thin layer chromatography (appendix VIB of Chinese Pharmacopoeia version in 2005), draw each 2 μ l of above-mentioned two kinds of solution, putting respectively on same silica gel g thin-layer plate, is developing solvent with normal hexane-ethyl acetate (9: 1), launches, take out, dry, put under the ultra-violet lamp and inspect, in the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
(2) selection of point sample amount
Through experimental selection need testing solution and reference substance solution each point sample 2 μ l, 5 μ l, 10 μ l, speckle is better, comparatively clear when found that need testing solution and reference substance solution point sample 2 μ l.So this standard reference material solution and need testing solution select for use 2 μ l as the point sample amount.
(3) specificity experiment
Get the negative sample 0.5088g that lacks Rhizoma Chuanxiong, make negative need testing solution, launch the back and do not have corresponding speckle, illustrate that negative sample is noiseless to this experiment at the reference substance place by last method operation.
(4) check
1, dissolution test: this product is a dispersible tablet, so work out the dissolution test item.
(1) instrument and reagent:
The RCZ-813 medicament dissolution instrument; RZQ-8A digestion instrument Autosampler.
Sample source: great virtue pharmaceutcal corporation, Ltd in Zhejiang provides (lot number: 050201,050202,050203).
(2) selection of dissolution medium
Get this preparation (lot number 050201), according to dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005 three therapeutic methods of traditional Chinese medicine), be dissolution medium with water, 0.1mol/L hydrochloric acid solution, 0.5% sodium dodecyl sulfate solution 200mL respectively, rotating speed is that per minute 100 changes, and operation in accordance with the law is respectively in the time of 2,5,10,15,20,30,45,60 minutes, get solution 3ml, filter, get subsequent filtrate, replenish corresponding dissolution medium 3ml simultaneously as need testing solution.Measure according to the method under the assay item, calculate every stripping quantity.The results are shown in Table 3.
Table 3 dissolution medium is selected
By table 3 as seen, the stripping percentage rate basically identical of water and 0.5% sodium dodecyl sulfate solution, and the stripping percentage rate of 0.1mol/L hydrochloric acid solution is lower slightly, so dissolution medium is selected water for use.
(3) selection of dissolving-out method
Because it is lower that this preparation contains ferulic acid, so select the three therapeutic methods of traditional Chinese medicine for use.
(4) selection of rotating speed
Get this preparation (lot number 050201), according to dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005 three therapeutic methods of traditional Chinese medicine), with water 200mL is dissolution medium, rotating speed is respectively per minute 100 commentaries on classics, 75 commentaries on classics, 50 are changeed, operation in accordance with the law, in the time of 2,5,10,15,20,30,45,60 minutes, get solution 3ml respectively, get subsequent filtrate as need testing solution; While supplementing water 3ml.Measure according to the method under the assay item, calculate every stripping quantity.The results are shown in Table 4.
The selection of table 4 rotating speed
| Time (branch) rotating speed (rev/min) | 2 | 5 | 10 | 15 | 20 | 30 | 45 | 60 |
| 100 | 88.69 | 101.58 | 109.46 | 111.04 | 111.66 | 112.28 | 112.72 | 112.68 |
| 75 | 65.64 | 96.13 | 104.92 | 107.32 | 107.67 | 107.60 | 108.22 | 109.14 |
| 50 | 26.27 | 44.33 | 57.71 | 64.56 | 67.50 | 70.87 | 71.05 | 73.75 |
By table 4 as seen, rotating speed is that per minute 75 changes and the 100 stripping quantity basically identicals that change, and the stripping quantity that per minute 50 changes is lower, is that per minute 75 changes so select rotating speed.
(5) checking of dissolution determination method
1) linearity
Precision is measured reference substance solution (15.74 μ g/ml) 0.5,1,3,5,10 μ l, reference substance solution (0.06295mg/ml) 5,10,15,20 μ l, inject chromatograph of liquid, measure peak area Y (seeing Table 5), (μ g) is abscissa with sample size, and peak area is a vertical coordinate, makes standard curve, and the calculating regression equation gets: y=5042.4x-22.804, R
2=0.9999, the result shows that sample size has good linear relationship in 0.008～1.259 μ g scope.
Table 5 ferulic acid linear relationship is investigated
| Sample size (μ g) | 0.008 | 0.016 | 0.047 | 0.079 | 0.157 | 0.315 | 0.630 | 0.944 | 1.259 |
| Peak area | 34.8 | 71.7 | 220.0 | 365.5 | 731.6 | 1569.3 | 3153.2 | 4739.3 | 6327.68 |
2) instrument precision: get same test sample (lot number: 050201) solution, press the chromatographic condition under the assay item, repeat sample introduction 6 times, measure peak area, RSD is 0.66% (n=6) as a result, sees Table 6.
The test of table 6 ferulic acid dissolution precision
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 | RSD％ |
| Peak area | 199.17 | 199.47 | 199.9 | 195.71 | 200.49 | 200.29 | 0.89 |
3) ruggedness (stability): get same test sample (lot number: 050201) solution, at interval certain hour is measured once, RSD=0.66% (n=6) the results are shown in Table 7 as a result.The result shows that need testing solution is basicly stable in 38 hours.
Table 7 ferulic acid dissolution stability test
| Time (hour) | 0 | 12 | 21 | 26 | 35 | 38 | RSD％ |
| Peak area | 199.17 | 199.47 | 199.9 | 195.71 | 200.49 | 200.29 | 0.89 |
4) repeatability: get 10 in this preparation (lot number 050201), the accurate title, decided porphyrize, precision takes by weighing 6 parts of 0.4g, puts in the 100ml measuring bottle, and it is an amount of to add water, ultrasonic 30 minutes, put coldly, add water to scale, shake up, filter, get subsequent filtrate, measure, calculate content of ferulic acid in every 1g preparation according to the method under the assay item.Average out to 0.468 as a result, and RSD=0.64% (n=6) sees Table 8.
Table 8 ferulic acid dissolution replica test result
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 | Meansigma methods | RSD％ |
| Content mg/g | 0.472 | 0.469 | 0.464 | 0.468 | 0.466 | 0.471 | 0.468 | 0.64 |
5) specificity is got the adjuvant of recipe quantity, and the simulation dissolution determination method is mixed with the solution of respective concentration, measures according to the method under the assay item, and the result does not have chromatographic peak on reference substance chromatograph relevant position.
6) accuracy: get 6 parts in known content sample (lot number 050201), precision takes by weighing 0.2g, puts in the 100ml measuring bottle, the accurate ferulic acid reference substance that adds is an amount of, and it is an amount of to add water, ultrasonic 30 minutes, put coldly, add water to scale, shake up, filter, get subsequent filtrate, measure, calculate content according to the method under the assay item, the result shows: this preparation ferulaic acid content average recovery rate is 100.3%, RSD=1.8%.(seeing Table 9).
Table 9 ferulic acid dissolution content recovery test
| Numbering | Sample weighting amount (g) | Content in the sample (mg) | Addition (mg) | The amount of recording (mg) | Response rate % | Average recovery rate % | RSD％ |
| 1 | 0.2005 | 0.0938 | 0.1161 | 0.2128 | 102.45 | 100.3 | 1.8 |
| 2 | 0.2046 | 0.0958 | 0.1161 | 0.2147 | 102.41 | ||
| 3 | 0.2034 | 0.0952 | 0.1161 | 0.2112 | 99.93 | ||
| 4 | 0.2014 | 0.0943 | 0.1161 | 0.2104 | 100.04 | ||
| 5 | 0.2041 | 0.0955 | 0.1161 | 0.2101 | 98.67 | ||
| 6 | 0.2053 | 0.0961 | 0.1161 | 0.2103 | 98.41 |
(6) dissolution determination method
1) drafting of stripping curve
Get three batches in this preparation (lot number: 050201,050202,050203), according to dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005 three therapeutic methods of traditional Chinese medicine), with water 200ml is solvent, rotating speed is that per minute 75 changes, operation in accordance with the law, in the time of 2,5,10,15,20,30,45,60 minutes, get solution 3ml respectively, get subsequent filtrate as need testing solution; While supplementing water 3ml.Measure according to the method under the assay item, calculate every stripping quantity, and draw stripping curve figure in each time.The results are shown in Table 10.
Table 10 dispersible tablet with gastrodia tuber accumulation stripping percentage rate
| The time lot number | 2 minutes | 5 minutes | 10 minutes | 15 minutes | 20 minutes | 30 minutes | 45 minutes | 60 minutes |
| 050201 | 65.64 | 96.13 | 104.92 | 107.32 | 107.67 | 107.60 | 108.22 | 109.14 |
| 050202 | 47.55 | 78.77 | 91.30 | 93.94 | 93.36 | 95.19 | 94.48 | 95.35 |
| 050203 | 49.12 | 85.29 | 93.66 | 96.04 | 96.14 | 96.73 | 98.17 | 97.06 |
2) stripping uniformity test
Get this preparation a collection of (lot number 050201), according to 1) method measure, and draw the homogeneity collection of illustrative plates, see Table 11.
Table 11 dispersible tablet with gastrodia tuber uniformity test is table as a result
| The time numbering | 2 minutes | 5 minutes | 10 minutes | 15 minutes | 20 minutes | 30 minutes | 45 minutes | 60 minutes |
| 1 | 59.73 | 95.44 | 105.12 | 106.88 | 108.51 | 108.12 | 108.90 | 108.84 |
| 2 | 72.10 | 97.77 | 104.78 | 109.22 | 106.92 | 106.73 | 106.97 | 111.00 |
| 3 | 66.50 | 88.61 | 105.51 | 105.27 | 107.06 | 106.56 | 107.02 | 107.42 |
| 4 | 64.26 | 96.51 | 103.16 | 105.62 | 107.20 | 106.68 | 106.87 | 108.12 |
| 5 | 75.26 | 100.74 | 106.50 | 108.63 | 108.43 | 109.74 | 110.93 | 110.25 |
| 6 | 56.00 | 97.72 | 104.47 | 108.31 | 107.90 | 107.76 | 108.64 | 109.20 |
| On average | 59.73 | 95.44 | 105.12 | 106.88 | 108.51 | 108.12 | 108.90 | 108.84 |
| RSD(％) | 11.1 | 4.3 | 1.1 | 1.5 | 0.7 | 1.1 | 1.5 | 1.2 |
(7) three batch sample dissolution determinations
(lot number: 050201,050202,050203), measure according to dissolution determination method in the quality standard of the present invention, three batch sample strippings the results are shown in Table 12 to get three batches in this preparation.
Table 12 dispersible tablet with gastrodia tuber three batch sample stripping results
| Lot number | 050201 | 050202 | 050203 |
| Stripping quantity (%) | 105、105、109、 111、108、110 | 105、89、102、107、 109、103 | 104、102、102、 104、103、106 |
The result shows: 20 minutes stripping quantities of this preparation are all more than 85%, and the general requirement to the dissolution limit in the pharmacopeia is 70%, so the dissolution limit of this preparation is decided to be 70%.
(8) dissolution test method
According to above-mentioned result of the test, formulate following dispersible tablet with gastrodia tuber dissolution test method: get this preparation, according to dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2005 three therapeutic methods of traditional Chinese medicine), with water 200mL is solvent, and rotating speed is that per minute 75 changes, operation in accordance with the law, in the time of 20 minutes, get solution, filter with 0.45 μ m filter membrane, as need testing solution.Measure according to the method under the assay item, calculate every stripping quantity.Limit is 70% of a content, should be up to specification.
2, dispersing uniformity is got 2 in this preparation, puts jolting in the 100ml water, in 20 ℃ ± 1 ℃ water, 3 minutes all disintegrate and by No. 2 the sieve.
Table 13 jitter time is investigated the result
| Lot number | 050201 | 050202 | 050203 |
| Time (min) | 1 | 1 | 1 |
3, arsenic salt checks that by an appendix IX of Chinese Pharmacopoeia version in 2000 F arsenic salt inspection technique first method result is up to specification.
Table 14 arsenic salt measurement result
| Lot number | 050201 | 050202 | 050203 |
| Arsenic salt | ＜5ppm | ＜5ppm | ＜5ppm |
4, heavy metal checks that by an appendix IX of Chinese Pharmacopoeia version in 2000 E heavy metal inspection technique second method result is up to specification.
Table 15 determining heavy metals result
| Lot number | 050201 | 050202 | 050203 |
| Heavy metal | ＜10ppm | ＜10ppm | ＜10ppm |
5, tablet weight variation
This preparation sheet is great in 0.3g, presses a regulation of Chinese Pharmacopoeia version in 2000 tablet weight variation and should get 20 inspections of three batch samples in ± 5%, the results are shown in following table 16.
Table 16 tablet weight variation check result
This preparation three batch sample measurement results show that tablet weight variation is all within prescribed limit.
6, microbial limit
Check that according to microbial limit test (appendix XIII of Chinese Pharmacopoeia version in 2000) check result of three batch samples sees the following form.
Table 17 limit test of microbe result
| Lot number | 050201 | 050202 | 050203 |
| Bacterial population (individual/g) | Up to specification | Up to specification | Up to specification |
| Fungi count (individual/g) | Up to specification | Up to specification | Up to specification |
| Escherichia coli (individual/g) | Do not detect | Do not detect | Do not detect |
| Demodicid mite alive (individual/g) | Do not detect | Do not detect | Do not detect |
(5) assay
Through being processed into, wherein the effective constituent that mainly contains of Rhizoma Chuanxiong is a ferulic acid to this preparation by Rhizoma Chuanxiong, Rhizoma Gastrodiae, and is existing by adopting content of ferulic acid in the high effective liquid chromatography for measuring sample, can effectively control the quality of the pharmaceutical preparations.
1, instrument and reagent
HP 1100 series liquid chromatograph instrument.
The ferulic acid reference substance provides (lot number is 0773-9910) by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.Methanol is chromatographically pure, and water is redistilled water, and all the other are analytical pure.Sample provides (lot number: 050201,050202,050203) by Zhejiang great virtue pharmaceutcal corporation, Ltd.
2, measure the selection of wavelength: it is an amount of to get the ferulic acid reference substance, uses the DAD detector, scans in 200～400nm scope, and ferulic acid has absorption maximum at 323nm wavelength place as a result, is chosen as 323nm so detect wavelength.
3, chromatographic condition: with the octadecylsilane chemically bonded silica is filler; With methanol-1% acetum (40: 60) is mobile phase; The detection wavelength is 323nm; Flow velocity 1.0ml/min.It is noiseless that the ferulic acid peak is better separated and lack flavor with the impurity peak energy with this understanding.
4, specificity: make blank liquid to lacking Rhizoma Chuanxiong blank sample equally by the need testing solution preparation method, sample introduction is measured.The result shows that it is noiseless to the ferulic acid peak to lack the Rhizoma Chuanxiong blank, proves that the ferulic acid composition of measuring by this method has specificity.
5, the selection of extraction conditions:
(1) choice of Solvent, compares so selected for use 30% ethanol, 50% ethanol, 70% ethanol, ethanol, methanol as extracting solvent respectively because ferulic acid is soluble in ethanol water, the results are shown in Table 18.
Table 18 extracts choice of Solvent
| Extract solvent | 30% ethanol | 50% ethanol | 70% ethanol | Ethanol | Methanol |
| Content (mg/g) | 0.402 | 0.441 | 0.445 | 0.348 | 0.403 |
The result shows, serves as to extract solvent with 30% ethanol, ethanol, methanol, and the result is on the low side, and with 50% ethanol, 70% ethanol content basically identical as a result, is the extraction solvent so select 50% ethanol for use.
(2) being chosen under the situation of determining solvent of extracting method compared heating and refluxing extraction and ultrasonic extracting method, the results are shown in Table 19.
The selection of table 19 extracting method
| Extracting method | Ultrasonic 20 minutes | Ultrasonic 30 minutes | Ultrasonic 60 minutes | Refluxed 1 hour |
| Content (mg/g) | 0.401 | 0.456 | 0.455 | 0.465 |
The result as seen, content is on the low side slightly in the time of ultrasonic 20 minutes, and other method content basically identical, so selected supersound extraction for use 30 minutes.
(3) comparison of extracting quantity of solvent has been compared different extraction quantity of solvent under the sampling amount same case, the results are shown in Table 20.The result as seen, the content basically identical is elected 50ml as so extract quantity of solvent.
Table 20 extracts the selection of quantity of solvent
| Extract quantity of solvent (ml) | 25 | 50 | 100 |
| Content (mg/g) | 0.449 | 0.456 | 0.449 |
6, linear relationship: precision is measured reference substance solution (15.74 μ g/ml) 0.5,1,3,5,10 μ l, reference substance solution (0.06295mg/ml) 5,10,15,20 μ l, inject chromatograph of liquid, measure peak area Y (seeing Table 21), (μ g) is abscissa with sample size, and peak area is a vertical coordinate, the drawing standard curve, and the calculating regression equation gets: y=5042.4x-22.804, R
2=0.9999, the result shows that sample size has good linear relationship in 0.008～1.259 μ g scope.
Table 21 ferulic acid linear relationship is investigated
| Sample size (μ g) | 0.008 | 0.016 | 0.047 | 0.079 | 0.157 | 0.315 | 0.630 | 0.944 | 1.259 |
| Peak area | 34.8 | 71.7 | 220.0 | 365.5 | 731.6 | 1569.3 | 3153.2 | 4739.3 | 6327.68 |
7, instrument precision: get same test sample (lot number: 050201) solution, by above chromatographic condition, repeat sample introduction 6 times, measure peak area, RSD is 0.66% (n=6) as a result, sees Table 22.
The test of table 22 ferulic acid precision
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 | RSD％ |
| Peak area | 519.31 | 516.74 | 523.16 | 518.83 | 514.4 | 514.08 | 0.66 |
8, ruggedness (stability): get same test sample (lot number: 050201) solution, at interval certain hour is measured once, RSD=0.66% (n=6) the results are shown in Table 23 as a result.The result shows that need testing solution is basicly stable in 38 hours.
Table 23 ferulic acid stability test
| Time (hour) | 0 | 12 | 21 | 26 | 35 | 38 | RSD％ |
| Peak area | 519.31 | 516.74 | 523.16 | 518.83 | 514.4 | 514.08 | 0.66 |
9, repeatability: precision takes by weighing same lot number sample (lot number: 050201) 6 parts, extract by the method in the quality standard of the present invention, measure peak area and calculate ferulaic acid content (mg/g), the result: the average content of this preparation ferulic acid is 0.460mg/g, RSD=0.68% (n=6) sees Table 24.
Table 24 ferulic acid replica test
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 | On average | RSD％ |
| Content (mg/g) | 0.456 | 0.461 | 0.455 | 0.462 | 0.462 | 0.461 | 0.460 | 0.68 |
10, accuracy: precision takes by weighing known content sample (lot number: 050201) 9 parts, the accurate ferulic acid reference substance that adds is an amount of, extract by the method in the quality standard of the present invention, record peak area and calculate content, the result shows: this preparation ferulaic acid content average recovery rate is 99.0%, RSD=1.3%.(seeing Table 25).
Table 25 ferulaic acid content recovery test
| Numbering | Sample weighting amount (g) | Content in the sample (mg) | Addition (mg) | The amount of recording (mg) | Response rate % | Average recovery rate % | RSD％ |
| 1 | 0.4013 | 0.1846 | 0.1888 | 0.3733 | 99.91 | 99.0 | 1.3 |
| 2 | 0.4015 | 0.1847 | 0.1888 | 0.3694 | 97.78 | ||
| 3 | 0.4036 | 0.1857 | 0.1888 | 0.3734 | 99.39 | ||
| 4 | 0.5032 | 0.2315 | 0.2518 | 0.4759 | 97.07 | ||
| 5 | 0.5074 | 0.2334 | 0.2518 | 0.4830 | 99.13 | ||
| 6 | 0.5024 | 0.2311 | 0.2518 | 0.4834 | 100.20 | ||
| 7 | 0.6073 | 0.2794 | 0.3148 | 0.5884 | 98.19 | ||
| 8 | 0.6010 | 0.2765 | 0.3148 | 0.5944 | 101.02 | ||
| 9 | 0.6039 | 0.2778 | 0.3148 | 0.5859 | 97.90 |
11, sample determination and limits: measure three batch samples by the method in the quality standard of the present invention, the results are shown in Table 26.According to this three lot data, contain Rhizoma Chuanxiong with ferulic acid (C so limit ordered temporarily to every
10H
10O
4) meter, must not be less than 0.25mg.
Table 26 ferulaic acid content measurement result
| Lot number | Content 1 (mg/ sheet) | Content 2 (mg/ sheet) | Average content (mg/ sheet) | Relative deviation % |
| 050201 | 0.322 | 0.325 | 0.32 | 0.51 |
| 050202 | 0.348 | 0.350 | 0.35 | 0.47 |
| 050203 | 0.343 | 0.343 | 0.34 | 0.10 |
The specific embodiment:
Embodiments of the invention 1: Rhizoma Chuanxiong 784g, Rhizoma Gastrodiae 196g and crospolyvinylpyrrolidone 100g, low-substituted hydroxypropyl cellulose 77g, micropowder silica gel 18g, microcrystalline Cellulose 200g, magnesium stearate 3g, aspartame 2g
Get Rhizoma Chuanxiong and Rhizoma Gastrodiae and pulverize, mix, with 90% alcohol reflux twice, each 2 hours, merge extractive liquid,, filtration, filtrate recycling ethanol and to be condensed into 55～60 ℃ of relative densities be 1.27 clear paste; Medicinal residues decoct with water twice, and each 1 hour, collecting decoction filtered, and it is 1.27 clear paste that filtrate is condensed into 55～60 ℃ of relative densities, merges with above-mentioned clear paste, and vacuum drying is pulverized, and crosses 80 mesh sieves; With low-substituted hydroxypropyl cellulose, micropowder silica gel, crospolyvinylpyrrolidone, microcrystalline Cellulose and aspartame mix homogeneously, with 95% ethanol system soft material, 20 eye mesh screens are granulated, in 60 ℃ ± 5 ℃ dryings, dried granule adds magnesium stearate with 20 eye mesh screen granulate in the granule behind the granulate, mix homogeneously, be pressed into 1000, packing, promptly.This product oral meal, one time 4,3 times on the one.
Embodiments of the invention 2: described method of quality control comprises following content:
Character: medicine is that pale brown color is to brown color chips; Special fragrance is arranged, and mildly bitter flavor is puckery;
Differentiate: (1) gets 3 in this preparation, and porphyrize adds water 15ml and makes dissolving, filters, filtrate is extracted with ether 25ml jolting, discards ether solution, and water layer extracts with n-butyl alcohol 20ml jolting, divides and gets n-butyl alcohol liquid, evaporate to dryness, residue add methanol 1ml makes dissolving, as need testing solution; Other gets the gastrodine reference substance, adds methanol and makes the solution that every 1ml contains 0.5mg, in contrast product solution; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel g thin-layer plate of adhesive with the sodium carboxymethyl cellulose, with chloroform: the upper solution of methanol=3: 1 is developing solvent, launch, take out, dry, spray is with 15% phosphomolybdic acid ethanol solution, 105 ℃ of heating 10 minutes; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color;
(2) get 2 in this preparation, porphyrize, the 20ml that adds diethyl ether, reflux 1 hour filters, and filtrate volatilizes, and residue adds ethyl acetate 2ml makes dissolving, as need testing solution; Other gets Rhizoma Chuanxiong control medicinal material 1g, shines medical material solution in pairs with legal system; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 2 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with normal hexane: ethyl acetate=9: 1 is developing solvent, launches, take out, dry, put under the ultra-violet lamp and inspect, in the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color;
Check: dispersing uniformity is got 2 in this preparation, puts in 20 ℃ ± 1 ℃ the 100ml water jolting 3 minutes, all disintegrate and sieve by No. two;
Dissolution is got this preparation, according to two appendix XC of Chinese Pharmacopoeia version in 2005 dissolution method three therapeutic methods of traditional Chinese medicine, is solvent with water 200mL, rotating speed is that per minute 75 changes, and operation in accordance with the law is in the time of 20 minutes, it is an amount of to get solution, filters with 0.45 μ m filter membrane, as need testing solution; Measure according to the method under the assay item, calculate every stripping quantity; Limit is 70% of a content, should be up to specification;
Other should meet relevant every regulation under an appendix ID of Chinese Pharmacopoeia version in 2005 the tablet item;
Assay: shine an appendix VID of Chinese Pharmacopoeia version in 2005 high effective liquid chromatography for measuring:
Chromatographic condition and system suitability test are filler with the octadecylsilane chemically bonded silica; With methanol: 1% acetum=40: 60 is a mobile phase; The detection wavelength is 323nm; Number of theoretical plate calculates by the ferulic acid peak should be not less than 3000;
It is an amount of that the ferulic acid reference substance is got in the preparation of reference substance solution, and accurate the title decides, and adds 50% ethanol and makes the solution that every 1ml contains 10 μ g, promptly;
This preparation under the weight differential item is got in the preparation of need testing solution, and porphyrize is got about 1g, the accurate title, decide, and puts in the tool plug conical flask, the accurate 50% ethanol 50ml that adds, close plug claims to decide weight, and supersound process is 30 minutes under power 300W, frequency 50kHz condition, put coldly, claim again to decide weight, supply the weight that subtracts mistake with 50% ethanol, shake up, filter, get subsequent filtrate, promptly;
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly;
Every in this preparation contains Rhizoma Chuanxiong with ferulic acid C
10H
10O
4Meter must not be less than 0.25mg.
Embodiments of the invention 3: method of quality control can comprise following content:
Character: medicine is that pale brown color is to brown color chips; Special fragrance is arranged, and mildly bitter flavor is puckery;
Differentiate: get 3 in this preparation, porphyrize adds water 15ml and makes dissolving, filters, and filtrate is extracted with ether 25ml jolting, discards ether solution, and water layer extracts with n-butyl alcohol 20ml jolting, divides and gets n-butyl alcohol liquid, and evaporate to dryness, residue add methanol 1ml makes dissolving, as need testing solution; Other gets the gastrodine reference substance, adds methanol and makes the solution that every 1ml contains 0.5mg, in contrast product solution; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel g thin-layer plate of adhesive with the sodium carboxymethyl cellulose, with chloroform: the upper solution of methanol=3: 1 is developing solvent, launch, take out, dry, spray is with 15% phosphomolybdic acid ethanol solution, 105 ℃ of heating 10 minutes; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color;
Assay: shine an appendix VID of Chinese Pharmacopoeia version in 2005 high effective liquid chromatography for measuring:
Chromatographic condition and system suitability test are filler with the octadecylsilane chemically bonded silica; With methanol: 1% acetum=40: 60 is a mobile phase; The detection wavelength is 323nm; Number of theoretical plate calculates by the ferulic acid peak should be not less than 3000;
It is an amount of that the ferulic acid reference substance is got in the preparation of reference substance solution, and accurate the title decides, and adds 50% ethanol and makes the solution that every 1ml contains 10 μ g, promptly;
This preparation under the weight differential item is got in the preparation of need testing solution, and porphyrize is got about 1g, the accurate title, decide, and puts in the tool plug conical flask, the accurate 50% ethanol 50ml that adds, close plug claims to decide weight, and supersound process is 30 minutes under power 300W, frequency 50kHz condition, put coldly, claim again to decide weight, supply the weight that subtracts mistake with 50% ethanol, shake up, filter, get subsequent filtrate, promptly;
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly;
Every in this preparation contains Rhizoma Chuanxiong with ferulic acid C
10H
10O
4Meter must not be less than 0.25mg.
Embodiments of the invention 4: method of quality control can comprise following content:
Character: medicine is that pale brown color is to brown color chips; Special fragrance is arranged, and mildly bitter flavor is puckery;
Differentiate: get 2 in this preparation, porphyrize, the 20ml that adds diethyl ether, reflux 1 hour filters, and filtrate volatilizes, and residue adds ethyl acetate 2ml makes dissolving, as need testing solution; Other gets Rhizoma Chuanxiong control medicinal material 1g, shines medical material solution in pairs with legal system; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 2 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with normal hexane: ethyl acetate=9: 1 is developing solvent, launches, take out, dry, put under the ultra-violet lamp and inspect, in the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color;
Check: dissolution is got this preparation, according to two appendix XC of Chinese Pharmacopoeia version in 2005 dissolution method three therapeutic methods of traditional Chinese medicine, is solvent with water 200mL, rotating speed is that per minute 75 changes, and operation in accordance with the law is in the time of 20 minutes, it is an amount of to get solution, filters with 0.45 μ m filter membrane, as need testing solution; Measure according to the method under the assay item, calculate every stripping quantity; Limit is 70% of a content, should be up to specification;
Other should meet relevant every regulation under an appendix ID of Chinese Pharmacopoeia version in 2005 the tablet item.
Embodiments of the invention 5: method of quality control can comprise following content:
Character: medicine is that pale brown color is to brown color chips; Special fragrance is arranged, and mildly bitter flavor is puckery;
Check: dispersing uniformity is got 2 in this preparation, puts in 20 ℃ ± 1 ℃ the 100ml water jolting 3 minutes, all disintegrate and sieve by No. two;
Dissolution is got this preparation, according to two appendix XC of Chinese Pharmacopoeia version in 2005 dissolution method three therapeutic methods of traditional Chinese medicine, is solvent with water 200mL, rotating speed is that per minute 75 changes, and operation in accordance with the law is in the time of 20 minutes, it is an amount of to get solution, filters with 0.45 μ m filter membrane, as need testing solution; Measure according to the method under the assay item, calculate every stripping quantity; Limit is 70% of a content, should be up to specification;
Other should meet relevant every regulation under an appendix ID of Chinese Pharmacopoeia version in 2005 the tablet item;
Assay: shine an appendix VID of Chinese Pharmacopoeia version in 2005 high effective liquid chromatography for measuring:
Chromatographic condition and system suitability test are filler with the octadecylsilane chemically bonded silica; With methanol: 1% acetum=40: 60 is a mobile phase; The detection wavelength is 323nm; Number of theoretical plate calculates by the ferulic acid peak should be not less than 3000;
It is an amount of that the ferulic acid reference substance is got in the preparation of reference substance solution, and accurate the title decides, and adds 50% ethanol and makes the solution that every 1ml contains 10 μ g, promptly;
This preparation under the weight differential item is got in the preparation of need testing solution, and porphyrize is got about 1g, the accurate title, decide, and puts in the tool plug conical flask, the accurate 50% ethanol 50ml that adds, close plug claims to decide weight, and supersound process is 30 minutes under power 300W, frequency 50kHz condition, put coldly, claim again to decide weight, supply the weight that subtracts mistake with 50% ethanol, shake up, filter, get subsequent filtrate, promptly;
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly;
Every in this preparation contains Rhizoma Chuanxiong with ferulic acid C
10H
10O
4Meter must not be less than 0.25mg.
Claims (8)
1. dispersible tablet with gastrodia tuber for the treatment of headache, it is characterized in that: it is prepared from Rhizoma Chuanxiong 784g, Rhizoma Gastrodiae 196g and crospolyvinylpyrrolidone 100g, low-substituted hydroxypropyl cellulose 77g, micropowder silica gel 18g, microcrystalline Cellulose 200g, magnesium stearate 3g, aspartame 2g.
2. treat the preparation method of the dispersible tablet with gastrodia tuber of headache according to claim 1, it is characterized in that: get Rhizoma Chuanxiong and Rhizoma Gastrodiae and pulverize, mix, with twice of 90% alcohol reflux, each 2 hours, merge extractive liquid,, filter filtrate recycling ethanol and to be condensed into 55～60 ℃ of relative densities be 1.27 clear paste; Medicinal residues decoct with water twice, and each 1 hour, collecting decoction filtered, and it is 1.27 clear paste that filtrate is condensed into 55～60 ℃ of relative densities, merges with above-mentioned clear paste, and vacuum drying is pulverized, and crosses 80 mesh sieves; With low-substituted hydroxypropyl cellulose, micropowder silica gel, crospolyvinylpyrrolidone, microcrystalline Cellulose and aspartame mix homogeneously, with 95% ethanol system soft material, 20 eye mesh screens are granulated, in 60 ℃ ± 5 ℃ dryings, dried granule adds magnesium stearate with 20 eye mesh screen granulate in the granule behind the granulate, mix homogeneously, tabletting, packing, promptly.
3. the method for quality control of the dispersible tablet with gastrodia tuber of treatment headache as claimed in claim 1 or 2 is characterized in that: described method of quality control mainly comprise in character, discriminating, inspection and the assay project partly or entirely; Wherein differentiate the thin layer chromatography discriminating that comprises Rhizoma Gastrodiae in the preparation and Rhizoma Chuanxiong; Assay is that the contained content of ferulic acid of Rhizoma Chuanxiong in the preparation is measured.
4. according to the method for quality control of the dispersible tablet with gastrodia tuber of the described treatment of claim 3 headache, it is characterized in that: the discrimination method of Rhizoma Gastrodiae is to be contrast with the gastrodine reference substance, and with chloroform: the upper solution of methanol=3: 1 is the thin layer chromatography of developing solvent; The discrimination method of Rhizoma Chuanxiong is to be contrast with the Rhizoma Chuanxiong control medicinal material, and with normal hexane: ethyl acetate=9: 1 is the thin layer chromatography of developing solvent.
5. according to the method for quality control of the dispersible tablet with gastrodia tuber of claim 3 or 4 described treatments headache, it is characterized in that: concrete discrimination method comprise following project partly or entirely:
(1) get 3 in this preparation, porphyrize adds water 15ml and makes dissolving, filters, and filtrate is extracted with ether 25ml jolting, discards ether solution, and water layer extracts with n-butyl alcohol 20ml jolting, divides and gets n-butyl alcohol liquid, and evaporate to dryness, residue add methanol 1ml makes dissolving, as need testing solution; Other gets the gastrodine reference substance, adds methanol and makes the solution that every 1ml contains 0.5mg, in contrast product solution; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel g thin-layer plate of adhesive with the sodium carboxymethyl cellulose, with chloroform: the upper solution of methanol=3: 1 is developing solvent, launch, take out, dry, spray is with 15% phosphomolybdic acid ethanol solution, 105 ℃ of heating 10 minutes; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color;
(2) get 2 in this preparation, porphyrize, the 20ml that adds diethyl ether, reflux 1 hour filters, and filtrate volatilizes, and residue adds ethyl acetate 2ml makes dissolving, as need testing solution; Other gets Rhizoma Chuanxiong control medicinal material 1g, shines medical material solution in pairs with legal system; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 2 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with normal hexane: ethyl acetate=9: 1 is developing solvent, launches, take out, dry, put under the ultra-violet lamp and inspect, in the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color.
6. according to the method for quality control of the dispersible tablet with gastrodia tuber of the described treatment of claim 3 headache, it is characterized in that: the content of ferulic acid assay method is to be contrast with the ferulic acid reference substance in the Rhizoma Chuanxiong, and with methanol: 1% acetum=40: 60 is the high performance liquid chromatography of mobile phase.
7. according to the method for quality control of the dispersible tablet with gastrodia tuber of claim 3 or 6 described treatments headache, it is characterized in that: concrete content assaying method is:
According to an appendix VID of Chinese Pharmacopoeia version in 2005 high effective liquid chromatography for measuring:
Chromatographic condition and system suitability test are filler with the octadecylsilane chemically bonded silica; With methanol: 1% acetum=40: 60 is a mobile phase; The detection wavelength is 323nm; Number of theoretical plate calculates by the ferulic acid peak should be not less than 3000;
It is an amount of that the ferulic acid reference substance is got in the preparation of reference substance solution, and accurate the title decides, and adds 50% ethanol and makes the solution that every 1ml contains 10 μ g, promptly;
This preparation under the weight differential item is got in the preparation of need testing solution, and porphyrize is got about 1g, the accurate title, decide, and puts in the tool plug conical flask, the accurate 50% ethanol 50ml that adds, close plug claims to decide weight, and supersound process is 30 minutes under power 300W, frequency 50kHz condition, put coldly, claim again to decide weight, supply the weight that subtracts mistake with 50% ethanol, shake up, filter, get subsequent filtrate, promptly;
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly;
Every in this preparation contains Rhizoma Chuanxiong in ferulic acid C10H1004, must not be less than 0.25mg.
8. according to the method for quality control of the dispersible tablet with gastrodia tuber of the described treatment of claim 3 headache, it is characterized in that: described method of quality control comprises:
Character: medicine is that pale brown color is to brown color chips; Special fragrance is arranged, and mildly bitter flavor is puckery;
Differentiate: (1) gets 3 in this preparation, and porphyrize adds water 15ml and makes dissolving, filters, filtrate is extracted with ether 25ml jolting, discards ether solution, and water layer extracts with n-butyl alcohol 20ml jolting, divides and gets n-butyl alcohol liquid, evaporate to dryness, residue add methanol 1ml makes dissolving, as need testing solution; Other gets the gastrodine reference substance, adds methanol and makes the solution that every 1ml contains 0.5mg, in contrast product solution; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 5 μ l of above-mentioned two kinds of solution, put respectively in same be on the silica gel g thin-layer plate of adhesive with the sodium carboxymethyl cellulose, with chloroform: the upper solution of methanol=3: 1 is developing solvent, launch, take out, dry, spray is with 15% phosphomolybdic acid ethanol solution, 105 ℃ of heating 10 minutes; In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color;
(2) get 2 in this preparation, porphyrize, the 20ml that adds diethyl ether, reflux 1 hour filters, and filtrate volatilizes, and residue adds ethyl acetate 2ml makes dissolving, as need testing solution; Other gets Rhizoma Chuanxiong control medicinal material 1g, shines medical material solution in pairs with legal system; Test according to an appendix VIB of Chinese Pharmacopoeia version in 2005 thin layer chromatography, draw each 2 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with normal hexane: ethyl acetate=9: 1 is developing solvent, launches, take out, dry, put under the ultra-violet lamp and inspect, in the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show the fluorescence speckle of same color;
Check: dispersing uniformity is got 2 in this preparation, puts in 20 ℃ ± 1 ℃ the 100ml water jolting 3 minutes, all disintegrate and sieve by No. two;
Dissolution is got this preparation, according to two appendix XC of Chinese Pharmacopoeia version in 2005 dissolution method three therapeutic methods of traditional Chinese medicine, is solvent with water 200mL, rotating speed is that per minute 75 changes, and operation in accordance with the law is in the time of 20 minutes, it is an amount of to get solution, filters with 0.45 μ m filter membrane, as need testing solution; Measure according to the method under the assay item, calculate every stripping quantity; Limit is 70% of a content, should be up to specification;
Other should meet relevant every regulation under an appendix ID of Chinese Pharmacopoeia version in 2005 the tablet item;
Assay: shine an appendix VID of Chinese Pharmacopoeia version in 2005 high effective liquid chromatography for measuring:
Chromatographic condition and system suitability test are filler with the octadecylsilane chemically bonded silica; With methanol: 1% acetum=40: 60 is a mobile phase; The detection wavelength is 323nm; Number of theoretical plate calculates by the ferulic acid peak should be not less than 3000;
It is an amount of that the ferulic acid reference substance is got in the preparation of reference substance solution, and accurate the title decides, and adds 50% ethanol and makes the solution that every 1ml contains 10 μ g, promptly;
This preparation under the weight differential item is got in the preparation of need testing solution, and porphyrize is got about 1g, the accurate title, decide, and puts in the tool plug conical flask, the accurate 50% ethanol 50ml that adds, close plug claims to decide weight, and supersound process is 30 minutes under power 300W, frequency 50kHz condition, put coldly, claim again to decide weight, supply the weight that subtracts mistake with 50% ethanol, shake up, filter, get subsequent filtrate, promptly;
Accurate respectively reference substance solution and each the 10 μ l of need testing solution of drawing of algoscopy inject chromatograph of liquid, measure, promptly;
Every in this preparation contains Rhizoma Chuanxiong in ferulic acid C10H1004, must not be less than 0.25mg.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102846967A (en) * | 2011-06-29 | 2013-01-02 | 湖南中医药大学 | A pure-component Chinese medicinal preparation for treating headache and its preparation process |
| CN102028883B (en) * | 2009-09-28 | 2013-06-05 | 江苏康缘药业股份有限公司 | Standard fingerprint spectrum of Chinese medicinal composition, and measurement method and application thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885985A (en) * | 2012-11-02 | 2013-01-23 | 北京联合大学生物化学工程学院 | Preparation method and application of rhizoma gastrodiae and rhizoma chuanxiong compound extract |
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2006
- 2006-04-17 CN CNB2006102003599A patent/CN100518798C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102028883B (en) * | 2009-09-28 | 2013-06-05 | 江苏康缘药业股份有限公司 | Standard fingerprint spectrum of Chinese medicinal composition, and measurement method and application thereof |
| CN102846967A (en) * | 2011-06-29 | 2013-01-02 | 湖南中医药大学 | A pure-component Chinese medicinal preparation for treating headache and its preparation process |
| CN102846967B (en) * | 2011-06-29 | 2015-08-26 | 湖南中医药大学 | A kind of pure component Chinese medicine preparation and preparation technology treating headache |
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