CN1935202B - Monkshood extract and its preparing method - Google Patents
Monkshood extract and its preparing method Download PDFInfo
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- CN1935202B CN1935202B CN2005100217067A CN200510021706A CN1935202B CN 1935202 B CN1935202 B CN 1935202B CN 2005100217067 A CN2005100217067 A CN 2005100217067A CN 200510021706 A CN200510021706 A CN 200510021706A CN 1935202 B CN1935202 B CN 1935202B
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Abstract
The present invention provides a radix aconiti kusnezoffii extract. It is an extract obtained by using radix aconiti kusnezofficc or its prepared product as raw material, adding water or organic solvent through a certain extraction and preparation process. In every gram of said extract total alkaloid content is 0.75-3.00mg by aconitene C34H47NO11 according to the bromcresol green method and diester alkaloid content is 0.01mg-0.60mg by aconitene C34H47NO11 according to the iron isoxime carboxylate method. Said invention also provides the medicine composition containing said extract. The invention definitely distinguish the crude from the prepared product, thereby solving the problem of the safety when radix aconiti kusnezoffii is used in clinic, enlarging drug source and saving prepared cost; and the inventive medicine all has a better drug effect under the different extraction conditions, provides a new selection for clinic and is convenient for patients to use.
Description
Technical field
The present invention relates to a kind of Radix Aconiti extract, belong to the field of Chinese medicines.
Background technology
Radix Aconiti is the dry parent root of ranunculaceae plant Aconitum carmichjaelii Debx. Aconitum carmichaeli Debx..Go up sentence and excavate late June to August, removes daughter root, fibrous root and silt, dries.In the Chinese Pharmacopoeia 2005 editions, stipulate very toxicly, be generally and concoct the back and use.Because of its good expelling wind and removing dampness, antalgic effect.Be used for the treatment of anemofrigid-damp arthralgia among the people and preparation, arthralgia, trusted subordinate's cold type of pain, cold cancer disease such as have a pain causes the frequent generation of intoxication accident.
At its processed goods Radix Aconiti Preparata of clinical main application, in the processing concocting process, the very strong di esters alkaloid (aconitine etc.) of contained toxicity in the product of giving birth to, facile hydrolysis generates the less monoesters Alkaloid of toxicity, continue hydrolysis, then generate toxicity littler not with the alkaloid of ester bond, and play the effect of attenuation.Document shows: mainly by the process that heats and water floats, be that the di esters alkaloids content descends, reach the purpose of attenuation, but unavoidably reduce total alkaloid contents in concocting process that process time is long again.
Clinically, medicated wine is still the most widely used dosage form of present Radix Aconiti, and the document statistics shows, the toxicity ratio that medicated wine causes can reach 55.53%, and main cause wine itself has the effect of blood circulation, is easy to absorb and diffusion, be generally used for anemofrigid-damp arthralgia and have expelling wind and activating blood circulation, the function of pain relieving dissipating blood stasis.The aconite alkaloids owner will comprise fat-soluble biological alkali such as aconitine, mesaconitine, hypaconitine, and it is easily molten in wine.In the medicated wine of general autogamy, the medicament sources complexity, large usage quantity, the square medicine of compatibility is improper; The concentration of wine is higher, can reach 35%-45%; The infusion time is longer, and concentration is higher; Time of Administration is long, or emergency case takes, and easily cause poisoning, and aconitine is unsettled in alcohol as for whether relevant with toxicity, relevant report is not arranged.When the patient used, the pharmacopeia regulation will be decocted first, and fries in shallow oil use for a long time, and as for will how long being decocted first, amount of water, decoction number of times, firepower are difficult to controlled in practice, are not easy to the control of big production operation and quality.
Summary of the invention
Technical program of the present invention lies in providing a kind of Radix Aconiti extract, another technical scheme of the present invention provides pharmaceutical composition that contains this Radix Aconiti extract and preparation method thereof.
The invention provides a kind of Radix Aconiti extract, it is to be raw material by Radix Aconiti Radix Aconiti Kusnezoffii or its processed product, adds the extract of water or organic solvent extraction preparation, wherein, contain total alkaloids in the every gram extract of extract, press the bromocresol green method with aconitine C
34H
47NO
11Meter contains the dibasic acid esters alkaloid at 0.75～3.00mg, according to isoxime hydroxyl iron processes aconitine C
34H
47NO
11To fall into a trap at 0.01mg～0.60mg.
Wherein, described Radix Aconiti or its processed product are: Radix Aconiti, Radix Aconiti Preparata, wherein, contain in the every gram extract of Radix Aconiti total alkaloids by the bromocresol green method with aconitine C
34H
47NO
11Meter contains the dibasic acid esters alkaloid according to isoxime hydroxyl iron processes aconitine C at 1.10～3.00mg
34H
47NO
11To fall into a trap at 0.15mg～0.60mg; Contain total alkaloids in the every gram extract of Radix Aconiti Preparata by bromocresol green method aconitine C
34H
47NO
11Meter contains aconitine C at 0.75～2.20mg
34H
47NO
11According to high-efficient liquid phase technique at 0.01mg～0.05mg.
With the aconitine is index components, measure aconitine and total content of giving birth to alkali in the extract of the present invention, because the alkaloids composition is the active component of extract of the present invention, it also is toxic component, therefore, quality control to the alkaloids composition is extremely important, has directly influenced effective, the safety of medicine.Only the medicine in the scope of above-mentioned quality control could satisfy safety, effective, just can be convenient to clinical use.
Described Radix Aconiti extract is by the preparation of following method: gets the Radix Aconiti pharmaceutical decocting piece, adds 9～11 times of water gagings for the first time, soaked 20-40 minute, decocted 5.5～6.5 hours, add 7～9 times of water gagings the 2nd time, decocted 4.55～5.5 hours, and filtration, concentrated, drying, promptly;
Or, get the Radix Aconiti Preparata pharmaceutical decocting piece, for the first time add 9～11 times of water gagings, soaked 30 minutes, decocted 3.5～4.5 hours, add 9～11 times of water gagings the 2nd time, decocted 3.5～4.5 hours, filtration, concentrated, drying, promptly.
Further, it is by following method preparation:
Get the Radix Aconiti pharmaceutical decocting piece, for the first time add 10 times of water gagings, soaked 30 minutes, decocted 6 hours, add 8 times of water gagings the 2nd time, decocted 5 hours, filtration, filtrate is concentrated, is drying to obtain;
Get the Radix Aconiti Preparata pharmaceutical decocting piece, for the first time add 10 times of water gagings, soaked 30 minutes, decocted 4 hours, add 10 times of water gagings the 2nd time, decocted 4 hours, filtration, filtrate is concentrated, is drying to obtain.
The invention provides a kind of pharmaceutical composition, it is to be active component by described Radix Aconiti extract, adds the medicament that acceptable accessories or complementary composition are prepared from.
Wherein, described medicament is granule, capsule, tablet, pill, mixture.
The present invention also provides this preparation of drug combination method, and it comprises the steps:
A, get the Radix Aconiti pharmaceutical decocting piece, add 9～11 times of water gagings for the first time, soaked 20-40 minute, decocted 5.5～6.5 hours, add 7～9 times of water gagings the 2nd time, decocted 4.55～5.5 hours, filtration, concentrated, drying, promptly;
Or, get the Radix Aconiti Preparata pharmaceutical decocting piece, for the first time add 9～11 times of water gagings, soaked 30 minutes, decocted 3.5～4.5 hours, add 9～11 times of water gagings the 2nd time, decocted 3.5～4.5 hours, filtration, concentrated, drying, promptly;
B, the dry thing of a step is added the medicament that acceptable accessories or complementary composition are prepared from.
Wherein, step a is specific as follows:
Get the Radix Aconiti pharmaceutical decocting piece, for the first time add 10 times of water gagings, soaked 30 minutes, decocted 6 hours, add 8 times of water gagings the 2nd time, decocted 5 hours, filtration, filtrate is concentrated, is drying to obtain;
Get the Radix Aconiti Preparata pharmaceutical decocting piece, for the first time add 10 times of water gagings, soaked 30 minutes, decocted 4 hours, add 10 times of water gagings the 2nd time, decocted 4 hours, filtration, filtrate is concentrated, is drying to obtain.
Wherein, described concentrating is that filtrate decompression is concentrated into relative density 1.02～1.05,60 ℃; Described drying means is a marumerization, and inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃.
Medicine of the present invention has solved the problem that the patient uses inconvenience and safety, comparing clear and definite differentiation to giving birth to product and processed product qualitatively, solved the safety issue that Radix Aconiti uses clinically, enlarged the medicine source, saved process of preparing Chinese medicine cost treatment cost, and under the different extraction conditions, all have drug effect preferably, provide new selection for clinical.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The specific embodiment
The preparation of embodiment 1 Radix Aconiti Preparata water extract
Get Radix Aconiti Preparata medical material 12.50kg, with water logging bubble 30min, add to 10 times of water gagings and decoct, decocting time is got respectively and is boiled back 4h, add 10 times of water gagings the 2nd time, decocted 4 hours, and filtered merging filtrate, be evaporated to 1.02 ~ 1.05 (60 ℃), be drying to obtain the 2.20Kg extract, inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃.
The preparation of embodiment 2 Radix Aconiti Preparata water extract
Get Radix Aconiti Preparata medical material 11.50kg, with water logging bubble 30min, add to 9 times of water gagings and decoct, decocting time is got respectively and is boiled back 4.5h, add 9 times of water gagings the 2nd time, decocted 3.5 hours, and filtered merging filtrate, be evaporated to 1.02 ~ 1.05 (60 ℃), be drying to obtain the 2.08Kg extract, inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃.
The preparation of embodiment 3 medicinal granules of the present invention
Get Radix Aconiti Preparata medical material 12.05kg,, add to 11 times of water gagings and decoct with water logging bubble 30min, decocting time is got respectively and is boiled back 4.5h, adds 11 times of water gagings, decocts 4.5 hours for the 2nd time, filter, merging filtrate is evaporated to 1.02 ~ 1.05 (60 ℃), is drying to obtain the 2.15Kg extract, inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃, and get extract and add starch granulation, granulate, make granule.
The preparation of embodiment 4 Radix Aconiti water extract tablets
Get Radix Aconiti medical material 11.350kg,, add to 10 times of water gagings and decoct with water logging bubble 30min, decocting time boils back 6h, adds 10 times of water gagings, decocts 4 hours for the 2nd time, filter, merging filtrate is evaporated to 1.02 ~ 1.05 (60 ℃), be drying to obtain the 2.06Kg extract, inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃, get extract and add starch granulation, granulate, tabletting is made tablet.
The preparation of embodiment 5 Radix Aconiti water extract capsules
Get Radix Aconiti medical material 12.7.kg,, add to 9 times of water gagings and decoct with water logging bubble 30min, decocting time is got respectively and is boiled back 5.5h, adds 7 times of water gagings, decocts 4.55 hours for the 2nd time, filter, merging filtrate is evaporated to 1.02 ~ 1.05 (60 ℃), be drying to obtain the 2.26Kg extract, inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃, get extract and add starch granulation, granulate, encapsulated, make capsule.
The preparation of embodiment 6 Radix Aconiti water extract capsules
Get Radix Aconiti medical material 12.7.kg,, add to 11 times of water gagings and decoct with water logging bubble 30min, decocting time is got respectively and is boiled back 6.5h, adds 9 times of water gagings, decocts 5.5 hours for the 2nd time, filter, merging filtrate is evaporated to 1.02 ~ 1.05 (60 ℃), be drying to obtain the 2.26Kg extract, inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃, get extract and add starch granulation, granulate, encapsulated, make capsule.
Embodiment 6 method of quality control
[character] this product be pale brown color to brown particle, feeble QI, mildly bitter flavor is puckery.
[discriminating] gets this product 2g, and porphyrize is put in the tool plug conical flask, add ammonia solution 5ml, add ether 30ml, supersound extraction 10 minutes, jolting 20 minutes, filter, filtrate is put in the separatory funnel, adds the 0.25mol/L sulfuric acid solution, and jolting is extracted, divide and get acid solution, the photograph spectrophotography (" appendix VA of Chinese pharmacopoeia version in 2000) measure.At 231nm and 275nm wavelength place absorption maximum is arranged.
[inspection] should meet every regulation relevant under the granule item (" appendix IC of Chinese pharmacopoeia version in 2000).
[limit examine]
One, Radix Aconiti is measured according to spectrophotography (" appendix VA of Chinese pharmacopoeia version in 2000).
1, the drafting precision of standard curve takes by weighing aconitine reference substance 20mg and adds an amount of anhydrous alcohol solution, moves in the 10ml measuring bottle, adds dehydrated alcohol to scale, shakes up, promptly.Precision is measured aconitine titer 0,0.50,1.00,1.25,1.50,2.00,2.50ml, puts in the 25ml volumetric flask, adds ethanol to 2.5ml, the alkaline oxammonium hydrochloride. test solution 1.5ml of accurate adding, water-bath is 10 minutes in 60 ~ 65 ℃, takes out, and puts cold, add 13ml ferric perchlorate test solution, shake up, placed 5 minutes, the accurate perchloric acid test solution 8ml that adds, shake up, be settled to scale with ferric perchlorate's test solution.Make reference with blank, under 520nm, measure its absorbance, handle with the mapping of trap value and through rectilinear regression with biological alkali number, must linear equation.
2, the preparation of need testing solution respectively precision take by weighing Radix Aconiti granule 3g, add ammonia solution 5ml, with the continuous jolting of ether 50ml 1 hour, reuse ether 50ml divided 3 washings, filter, merging filtrate and washing liquid, low temperature evaporate to dryness, the 5ml that adds diethyl ether dissolving, volatilize, add ethanol 2.5ml dissolving, put in the 25ml volumetric flask, calculate and try to achieve the dibasic acid esters alkaloid from " the alkaline oxammonium hydrochloride. of accurate adding " to " under 520nm, measuring its absorbance "
Every bag of 2g of this product contains Radix Aconiti with aconitine (C
34H
47NO
11) meter, must not be higher than 1.2mg.
Two, Radix Aconiti Preparata is measured according to high-efficient liquid phase technique (" an appendix VI of Chinese pharmacopoeia version in 2000 D).
2, mark liquid curve and range of linearity precision take by weighing aconitine reference substance 5.0mg, after the dichloromethane dissolving, move in the 100ml volumetric flask, add methylene chloride to scale, shake up, and promptly get (aconitine is 0.01mg/ml).Get contrast liquid 2,4,6,8,10 μ l sample introductions respectively, in chromatographic condition VP-ODS 150L * 4.6mm chromatographic column mobile phase: methanol: water: chloroform: triethylamine (70: 30: 2: 0.1), detect wavelength: 230nm flow velocity 1.00ml/min column temperature: measure under 30 ℃ in accordance with the law, with biological alkali number and peak area value mapping, get equation of linear regression.Accurate this product 2g adds ammonia solution 3ml, and with the continuous jolting of ether 30ml 1 hour, reuse ether 50ml divided 3 washings, filter, merging filtrate and washing liquid, low temperature evaporate to dryness, the 5ml that adds diethyl ether dissolving, volatilize, residue adds methylene chloride and makes dissolving, is transferred in the 1ml volumetric flask, adds methylene chloride to scale, microporous filter membrane with 0.22 μ m filters, and it is standby to get subsequent filtrate.Under selected chromatographic condition, need testing solution sample introduction 10 μ l measure in accordance with the law, and the record peak area value calculates content respectively by external standard method.
Every bag of 2g of this product contains Radix Aconiti Preparata with aconitine (C
34H
47NO
11) meter, must not be higher than 0.10mg.
[assay] measured according to spectrophotography (appendix VA of Chinese Pharmacopoeia version in 2000).
1, the mark drafting precision that pushes away curve takes by weighing aconitine reference substance 10mg and adds an amount of chloroform dissolving, moves in the 100ml measuring bottle, adds chloroform to scale, shakes up, promptly.Precision is measured aconitine titer 0,0.50,1.00,1.25,1.50,2.00,2.50ml, places separatory funnel respectively, and the accurate atmosphere that adds is imitative to 20.0ml.With first part be blank, respectively add 10mlpH6.1 ± 0.1 bromocresol green dyestuff then, shake well left standstill 1 hour, chloroform solution is filtered in the 25ml volumetric flask and with chloroform and is diluted to scale.In 410nm wavelength place, measure trap blank, test liquid respectively.Handle with the mapping of biological alkali number and trap value and through rectilinear regression, linear equation.
2, the preparation of need testing solution respectively precision take by weighing single minimum package content, it is standby to press differential method, replace chloroform with E-C (3: 1) mixed liquor, put in the evaporating dish, water-bath low temperature evaporate to dryness adds diethyl ether-chloroform (3: 1) mixed liquor 5ml evaporate to dryness, add chloroform and make dissolving, standardize solution is in 1ml, and each mensuration is got the solution of 0.1ml respectively, is transferred in the separatory funnel, add chloroform to 20ml, promptly.Measure to " 410nm wavelength place " from " adding 10mlpH6.1 ± 0.1 bromocresol green dyestuff " in accordance with the law, calculate and try to achieve total alkaloid content
Every bag of 2g of this product contains Radix Aconiti with aconitine (C
34H
47NO
11) meter, must not be less than 2.2mg.
Every bag of 2g of this product contains Radix Aconiti Preparata with aconitine (C
34H
47NO
11) meter, must not be less than 1.5mg.
Below method by the test of pesticide effectiveness beneficial effect of the present invention is further described.
The screening test of test example 1 Radix Aconiti extract extraction process different parameters of the present invention
(1) screening test
1, experiment material
1.1 medicine
Radix Aconiti (Radix Aconiti, Radix Aconiti Preparata): be subjected to the reagent thing,, identify that through this school crude drug teaching and research room is accredited as the dry parent root of Aconitum carmichjaelii Debx. Aconitum carmichaeli Debx., gathers then available from river, Sichuan oil.The product of giving birth to and processed product soak 30min with 3 times of water gagings respectively, add to 10 times of water gagings and decoct, and decocting time is got respectively and boiled back 15min, 30min, 60min, 120min, 3h, 4h, 7 time points of 6h, and decocting the concentrating under reduced pressure that finishes is that every ml contains crude drug in whole 1g.According to uniform designs table, Radix Aconiti (Radix Aconiti, Radix Aconiti Preparata) decoction 15min, 30min, 60min, 120min, 3h, 4h, 7 time points of 6h are got clinical dosage (3g/60kg.d respectively
-1) 24 times, 3 times, 48 times, 12 times, 1 times, 36 times and 6 times.Facing the time spent, to be mixed with 12%, 1.5%, 24%, 6%, 0.5%, 18%, 3% medicinal liquid respectively with distilled water standby.
Dexamethasone acetate: positive drug, Zhejiang Province XianJu Pharmacy stock Co., Ltd produces.Authentication code: the accurate word H33020822 of traditional Chinese medicines.Product batch number: 040209.Specification: 0.75mg/ sheet.It is standby to be mixed with 0.03% medicinal liquid with distilled water during experiment.
Tramadol: positive drug, Shijiazhuang Pharmaceutical Group Co Ltd produces.Authentication code: the accurate word H10960106 of traditional Chinese medicines.Product batch number: 031003.Specification: 50mg/ sheet.It is standby to be mixed with 1% medicinal liquid with distilled water during experiment.
1.2 animal
Kunming mouse is provided laboratory animal production licence number: 04-11 by Chengdu University of Traditional Chinese Medicine Animal Experimental Study center.The SD rat is provided laboratory animal production licence number: 04-11 by Chengdu University of Traditional Chinese Medicine Animal Experimental Study center.The quarantine back is standby.
2, experimental technique
2.1 antiinflammatory test
2.1.1 dimethylbenzene auricle edema test
2.1.1.1 Radix Aconiti auricle edema test
Xu Shuyun, Bian Rulian, old repairing. pharmacological experimental methodology (the 2nd edition). Beijing: People's Health Publisher, 1991,719
2.1.1.1 Radix Aconiti Preparata auricle edema test
Xu Shuyun, Bian Rulian, old repairing. pharmacological experimental methodology (the 2nd edition). Beijing: People's Health Publisher, 1991,719
2.1.2 Ovum Gallus domesticus album pedal swelling test
Xu Shuyun, Bian Rulian, old repairing. pharmacological experimental methodology (the 3rd edition). Beijing: People's Health Publisher, 2002,911
2.1.3 Oleum Tiglii granuloma test
Xu Shuyun, Bian Rulian, old repairing. pharmacological experimental methodology (the 3rd edition). Beijing: People's Health Publisher, 2002,918
2.2 analgesic test
2.2.1 writhing test
2.2.1.1 Radix Aconiti writhing test
Xu Shuyun, Bian Rulian, old repairing. pharmacological experimental methodology (the 3rd edition). Beijing: People's Health Publisher, 2002,882
2.2.1.2 Radix Aconiti Preparata writhing test
Xu Shuyun, Bian Rulian, old repairing. pharmacological experimental methodology (the 3rd edition). Beijing: People's Health Publisher, 2002,882
2.2.2 hot plate test
2.2.2.1 Radix Aconiti hot plate test
Xu Shuyun, Bian Rulian, old repairing. pharmacological experimental methodology (the 3rd edition). Beijing: People's Health Publisher, 2002,885
2.2.2.2 Radix Aconiti Preparata hot plate test
Xu Shuyun, Bian Rulian, old repairing. pharmacological experimental methodology (the 3rd edition). Beijing: People's Health Publisher, 2002,885
3, experimental result
3.1 antiinflammatory test
3.1.1 dimethylbenzene auricle edema test
The remarkable swelling of 1.5h auricle after the modeling of model group mice, thickness increases.Radix Aconiti is except that the 3h group, and all the other each groups all can obviously suppress dimethylbenzene induced mice auricle edema; Each administration group swelling auricle of Radix Aconiti Preparata all dwindles, and wherein 15min group, 1h group, 2h group, 3h group swelling auricle dwindle significantly.Compare with model group, significance or utmost point significant difference are arranged.Through regression analysis, the optimal conditions that Radix Aconiti, Radix Aconiti Preparata performance suppress the mice auricle swelling drug effect is 6h, 48 times.The result sees table 1,2 and regression analysis for details.
Table 1 Radix Aconiti xylol causes scorching mice auricle swelling
Annotate: compare * P＜0.05, * *＜P0.01, * * * P＜0.001 with model group.
Regression analysis:
Optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=8.5
Table 2 Radix Aconiti Preparata xylol causes scorching mice auricle swelling
Annotate: compare * P＜0.05, * *＜P0.01 with model group.
Regression analysis:
Optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=5.96
3.1.2 Ovum Gallus domesticus album pedal swelling test
Very fast swelling behind the right sufficient sole of the foot injection Ovum Gallus domesticus album of model group rat, the 1h swelling of injection back reaches the peak, and still swelling is obvious behind the 6h.Each time dosage group of Radix Aconiti also all has the effect of obvious inhibition rat paw edema.Through regression analysis, the optimal conditions of Radix Aconiti performance drug effect: 0.5h, 1h, 2h, 3h, 4h, 6h are respectively 1.642h, 38.69 times, 1.434h, 40.76 times, 1.676h, 30.52 times, 0.25h, 34.46 times, 6h, 48 times and 0.6065h, 35.12 times.The result sees table 3 and regression analysis for details.
Table 3 pair Ovum Gallus domesticus album causes scorching rat paw edema
Annotate: compare * P＜0.05, * *＜P0.01, * * * P＜0.001 with model group.
Regression analysis:
0.5h: optimal conditions: X
1=1.642h, X
2=38.69 times of expection result of the test: Y=3.61
1h: optimal conditions: X
1=1.434h, X
2=40.76 times of expection result of the test: Y=3.69
2h: optimal conditions: X
1=1.676h, X
2=30.52 times of expection result of the test: Y=3.84
3h: optimal conditions: X
1=0.25h, X
2=34.46 times of expection result of the test: Y=3.42
4h: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=5.18
6h: optimal conditions: X
1=0.6065h, X
2=35.12 times of expection result of the test: Y=7.15
3.1.3 Oleum Tiglii granuloma test
1 all body weight do not increase after the modeling of model group rat, and counter have the trend of alleviating, and it is more to ooze out liquid measure, and granulation hyperplasia is remarkable.In 1 week of Radix Aconiti drug treatment, each organizes rat body weight all significantly increases, and granulation hyperplasia significantly alleviates, and 2h group, 3h group, 4h group transudate significantly reduce, and compare with model group, and significance or utmost point significant difference are arranged.Through regression analysis, the optimal time dosage of Radix Aconiti performance drug effect is body weight: 6h, 48 times, transudate: 3.677h, 17.64 times, granuloma: 6h, 19.42 times.The result sees table 4 and regression analysis for details.
Table 4 pair Oleum Tiglii
Annotate: compare * P＜0.05, * *＜P0.01, * * *＜P0.001 with model group.
Regression analysis:
Body weight: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=4.18
Transudate: optimal conditions: X
1=3.677h, X
2=17.64 times of expection result of the test: Y=4.89
Granulation is heavy: optimal conditions: X
1=6h, X
2=19.42 times of expection result of the test: Y=7.40
3.2 analgesic test
3.2.1 writhing test
Pain is obvious behind model group injected in mice 0.6% acetic acid, and it is frequent to turn round the body number of times.Radix Aconiti 6h group is turned round body significant prolongation incubation period, compares with model group, and utmost point significant difference is arranged; All the other each groups are turned round the trend that body has obvious prolongation incubation period, but compare not statistically significant with model group.Remove Radix Aconiti 30min group, outside the Radix Aconiti Preparata 15min group, all the other each time dosage groups are turned round the body number of times and are significantly reduced, and compare with model group, and significance or utmost point significant difference are arranged.Regression analysis shows that the Best Times dosage of Radix Aconiti, Radix Aconiti Preparata performance drug effect is 6 hours 48 times.The result sees table 5,6 for details.
Table 5 Dichlorodiphenyl Acetate causes the shadow of pain mice
Annotate: compare * *＜P0.01, * * * P＜0.001 with model group.
Regression analysis:
Turn round body incubation period: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=6.97
Turn round the body number of times: optimal conditions: X
1=5.552h, X
2=48 times of expection result of the test: Y=6.95
Table 6 pair glacial acetic acid causes pain
Annotate: compare * P＜0.05, * *＜P0.01, * * * P＜0.001 with model group.
Regression analysis:
Incubation period: optimal conditions: X
1=6h, X
2=32.58 times of expection result of the test: Y=2.83
Turn round the body number of times: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=9.78
3.2.2 hot plate test
Respectively organize basic pain threshold there was no significant difference before the administration.30min and 60min after the administration, Radix Aconiti 15min group, 1h group and 4h group pain threshold obviously prolong; 90min and 120min behind the medicine, Radix Aconiti 30min group pain threshold obviously prolongs.Radix Aconiti Preparata 15min group, 30min group, 2h group, 3h group and 6h group pain threshold all have prolongation at different time.Compare with model group, significance or utmost point significant difference are arranged.Through regression analysis, the Best Times dosage of Radix Aconiti performance drug effect be 6 hours 48 times.Behind the Radix Aconiti Preparata medicine 1.5h, 2h the performance drug effect Best Times dosage be 6 hours 48 times.Result's part table 7,8 and regression analysis of knowing clearly.
Table 7 Radix Aconiti causes the influence of pain mice pain threshold (second) to hot plate
Annotate: compare * P＜0.05, * *＜P0.01 with model group.
Regression analysis:
0.5h: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=9.46
1h: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=8.48
1.5h: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=2.92
2h: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=4.54
Table 8 Radix Aconiti Preparata causes pain mice pain threshold (second) to hot plate
Annotate: compare * P＜0.05, * *＜P0.01 with model group.
Regression analysis:
0.5h: optimal conditions: X
1=6h, X
2=19.42 times of expection result of the test: Y=4.36
1h: optimal conditions: X
1=4.517h, X
2=7.298 times of expection result of the test: Y=5.15
1.5h: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=7.34
2h: optimal conditions: X
1=6h, X
2=48 times of expection result of the test: Y=6.31
The above-mentioned test of pesticide effectiveness proves, with water logging bubble 30min, adds to that 10 times of water gagings decoct 15min, 1h, 2h, 4h, 6h antiinflammatory, analgesic activity is more excellent, and the medicine of the present invention for preparing under 15min, 2h, 4h, the 6h condition is an optimal drug.
The safety testing of test example 2 Radix Aconiti extract extraction process different parameters of the present invention
1. Radix Aconiti animal acute toxicity test data
1.1. experiment material
1.1.1. medicine
Each time point decocting liquid of Radix Aconiti is subjected to the reagent thing, and 15min, 30min, 1h, 2h, 3h, 4h and 6h contain the crude drug amount and be 3.33g/ml, and the test lot number is provided by pharmaceutical college of Chengdu University of Traditional Chinese Medicine: 050624, irritate the stomach mice with each decocting liquid.
1.1.2. animal
The SPF mice, male and female half and half, body weight 18-22g is provided by Chengdu University of Traditional Chinese Medicine Animal Experimental Study center, the quality certification number: the real moving pipe matter 04-11 in river, the quarantine back is standby.
1.2. experimental technique
Prerun: get some of SPF mices, male and female half and half, water 12hr is can't help in fasting, and complete dead, complete the living that records 15min by test measured, and is LD
5030min, 1h, 2h, 3h, 4h and 6h irritate stomach, 24h successive administration 3 times with the dosage of the maximum volume 0.4ml/10g.B.W of mice tolerance.Observe 3d continuously, the record animal has non-toxic reaction and experiment front and back body weight change, is maximum tolerated dose (MTD) not produce dead dosage.
Get 50 of SPF mices, male and female half and half, water 12hr is can't help in fasting, is divided into 15 groups at random by body weight, 10 every group.Complete dead complete living at 15min set 3 dosage groups between the amount again, irritates the medicinal liquid of stomach respective concentration respectively; Observed 7 days continuously, record animal dead number of elements is asked its LD
50
Get 140 of SPF mices, male and female half and half, water 12hr is can't help in fasting, is divided into 6 groups at random by body weight, 20 every group.Be blank group (N=20), 30min group (N=20), 1h group (N=20), 2h group (N=20), 3h group (N=20), 4h group (N=20) and 6h group (N=20).Irritate the medicinal liquid of stomach respective concentration, 24h successive administration 3 times respectively with the dosage of the maximum volume 0.4ml/10g.B.W of mice tolerance; Observed 7 days continuously, the record animal has non-toxic reaction and experiment front and back body weight change, is maximum tolerated dose (MTD) not produce dead dosage.
Above result all handles with the SPSS12.0 statistical software.
1.3. experimental result
1.3.1 Radix Aconiti 15min time point medicinal liquid result
Behind the SPF mouse stomach Radix Aconiti 15min time point medicinal liquid, all occur being slow in action, dull spirit, etc. toxic reaction in various degree, death mostly occurs after administration dead in 24 hours.The animal dead situation sees table 9 for details.
Y＝-12.546+0.10854X r＝0.324
LD
50＝115.58g/kg。
Table 9 15min Radix Aconiti gastric infusion is to the influence of animal dead
| Group | Animal (only) | Dosage (g/kg) | Death toll (only) |
| 1 2 3 4 5 | 10 10 10 10 10 | 99.9 106.89 114.38 122.38 133.20 | 0 3 4 7 10 |
1.3.2 Radix Aconiti 30min, 1h, 2h, 3h, 4h and 6h time point medicinal liquid result
Behind SPF mouse stomach Radix Aconiti 30min, 1h, 2h, 3h, 4h and the 6h time point medicinal liquid, grow healthy, fleshiness, dense and glossy by hair, be close to its body, bright and flexible, the N/R secretions of eyes, crissum cleaning, it is normal to ingest, the extremity stalwartness, spontaneous activity is normal, and body weight increases gradually.Not interior animal dead and toxicity in the 7d.Naked eyes became celestial and do not see obvious pathological change when experiment finished.
2.4. experiment conclusion
Each time point decocting liquid result of SPF mouse stomach Radix Aconiti: SPF mouse stomach Radix Aconiti decocting liquid: Radix Aconiti: 15minLD
50Be 115.58g crude drug in whole/kg (be equivalent to approximately people's consumption 2312 times).30min, 1h, 2h, 3h, 4h and 6h MTD are 399.6g crude drug in whole/kg (be equivalent to approximately people's consumption 7992 times).
Radix Aconiti decocts 15min and still has certain toxicity, and decocting time reaches does not have overt toxicity substantially more than the 30min.
2. Radix Aconiti Preparata animal acute toxicity test data
2.1. experiment material
2.1.1. medicine
Each time point decocting liquid of Radix Aconiti Preparata is subjected to the reagent thing, and containing the crude drug amount respectively is that 15min, 30min, 1h, 2h, 3h, 4h and 6h are 3.33g/ml, and the test lot number is provided by pharmaceutical college of Chengdu University of Traditional Chinese Medicine: 0500627, irritate the stomach mice with each decocting liquid.
2.1.2. animal
The SPF mice, male and female half and half, body weight 18-22g is provided by Chengdu University of Traditional Chinese Medicine Animal Experimental Study center, the quality certification number: the real moving pipe matter 04-11 in river, the quarantine back is standby.
2.2. experimental technique
Prerun: get the SPF mice, male and female half and half, water 12hr is can't help in fasting, and each time point decocting liquid of 15min, 30min, 1h, 2h, 3h, 4h and 6h is irritated stomach, 24h successive administration 3 times with the dosage of the maximum volume 0.4ml/10g.B.W of mice tolerance.Observe 3d continuously, animal does not all have dead and tangible toxic reaction, and not producing dead dosage with this is maximum tolerated dose (MTD).
Get 160 of SPF mices, male and female half and half, water 12hr is can't help in fasting, is divided into 8 groups at random by body weight, 20 every group.Be blank group (N=20), 15min group (N=20), 30min group (N=20), 1h group (N=20), 2h group (N=20), 3h group (N=20), 4h group (N=20) and 6h group (N=20).Irritate the medicinal liquid of stomach respective concentration, 24h successive administration 3 times respectively with the dosage of the maximum volume 0.4ml/10g.B.W of mice tolerance; Observed 7 days continuously, the record animal has non-toxic reaction and experiment front and back body weight change, is maximum tolerated dose (MTD) not produce dead dosage.
Above result all handles with the SPSS12.0 statistical software.
2.3. experimental result
Behind each time point decocting liquid of SPF mouse stomach Radix Aconiti Preparata 5min, 30min, 1h, 2h, 3h, 4h and 6h, grow healthy, fleshiness, dense and glossy by hair, be close to its body, bright and flexible, the N/R secretions of eyes, crissum cleaning, it is normal to ingest, the extremity stalwartness, spontaneous activity is normal, and body weight increases gradually.Not interior animal dead and toxicity in the 7d.Naked eyes became celestial and do not see obvious pathological change when experiment finished.
2.4. experiment conclusion
SPF mouse stomach Radix Aconiti Preparata 15min, 30min, 1h, 2h, 3h, 4h and 6h MTD are 399.6g crude drug in whole/kg (be equivalent to people's consumption 7992 times); Dead or unusual toxic reaction does not all appear in all animals.
Radix Aconiti Preparata decocting liquid does not have overt toxicity.
Above-mentioned drug effect, safety test prove, adopts the product of method preparation of the present invention, in the critical field of quality control, reached safety, effectively, provides a kind of new selection for clinical.
Claims (6)
1. Radix Aconiti extract is characterized in that: it is to be raw material by Radix Aconiti Radix Aconiti Kusnezoffii or its processed product, adds the extract of water or organic solvent extraction preparation, and wherein, described Radix Aconiti or its processed product are: Radix Aconiti, Radix Aconiti Preparata;
Described Radix Aconiti preparation method of extract is: gets the Radix Aconiti pharmaceutical decocting piece, for the first time adds 9～11 times of water gagings, soaked 20-40 minute, decocted 5.5～6.5 hours, add 7～9 times of water gagings the 2nd time, decocted 4.55～5.5 hours, and filtration, concentrated, drying, promptly;
The preparation method of described Radix Aconiti Preparata extract is: gets the Radix Aconiti Preparata pharmaceutical decocting piece, for the first time adds 9～11 times of water gagings, soaked 30 minutes, decocted 3.5～4.5 hours, add 9～11 times of water gagings the 2nd time, decocted 3.5～4.5 hours, and filtration, concentrated, drying, promptly;
Wherein, described concentrating is that filtrate decompression is concentrated into 1.02～1.05,60 ℃; Described drying means is a marumerization, and inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃.
2. Radix Aconiti extract according to claim 1 is characterized in that: it is by following method preparation:
Described Radix Aconiti preparation method of extract is: gets the Radix Aconiti pharmaceutical decocting piece, for the first time adds 10 times of water gagings, soaked 30 minutes, decocted 6 hours, add 8 times of water gagings the 2nd time, decocted 5 hours, and filtration, filtrate is concentrated, is drying to obtain;
The preparation method of described Radix Aconiti Preparata extract is: gets the Radix Aconiti Preparata pharmaceutical decocting piece, for the first time adds 10 times of water gagings, soaked 30 minutes, decocted 4 hours, add 10 times of water gagings the 2nd time, decocted 4 hours, and filtration, filtrate is concentrated, is drying to obtain;
Wherein, described concentrating is that filtrate decompression is concentrated into 1.02～1.05,60 ℃; Described drying means is a marumerization, and inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃.
3. pharmaceutical composition, it is to be active component by claim 1 or 2 described Radix Aconiti extracts, adds the medicament that acceptable accessories or complementary composition are prepared from.
4. pharmaceutical composition according to claim 3 is characterized in that: described medicament is granule, capsule, tablet, pill or mixture.
5. method for preparing claim 3 or 4 described pharmaceutical compositions, it comprises the steps:
A, get the Radix Aconiti pharmaceutical decocting piece, add 9～11 times of water gagings for the first time, soaked 20-40 minute, decocted 5.5～6.5 hours, add 7～9 times of water gagings the 2nd time, decocted 4.55～5.5 hours, filtration, concentrated, drying, promptly;
Or, get the Radix Aconiti Preparata pharmaceutical decocting piece, for the first time add 9～11 times of water gagings, soaked 30 minutes, decocted 3.5～4.5 hours, add 9～11 times of water gagings the 2nd time, decocted 3.5～4.5 hours, filtration, concentrated, drying, promptly;
B, the dry thing of a step is added the medicament that acceptable accessories or complementary composition are prepared from;
Wherein, described concentrating is that filtrate decompression is concentrated into 1.02～1.05,60 ℃; Described drying means is a marumerization, and inlet temperature is: 90～100 ℃, leaving air temp is: 60～65 ℃.
6. preparation of drug combination method according to claim 5, it is characterized in that: step a is specific as follows:
Get the Radix Aconiti pharmaceutical decocting piece, for the first time add 10 times of water gagings, soaked 30 minutes, decocted 6 hours, add 8 times of water gagings the 2nd time, decocted 5 hours, filtration, filtrate is concentrated, is drying to obtain;
Get the Radix Aconiti Preparata pharmaceutical decocting piece, for the first time add 10 times of water gagings, soaked 30 minutes, decocted 4 hours, add 10 times of water gagings the 2nd time, decocted 4 hours, filtration, filtrate is concentrated, is drying to obtain.
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| 孙秀梅、尉小慧、张兆旺等.用均匀设计优选川乌的"半仿生提取法"工艺条件.中药材22 12.1999,22(12),649-650. * |
| 张兆旺、孙秀梅、尉小慧等.川乌2种方法提取液的成分比较.中成药21 1.1999,21(1),5-6. |
| 张兆旺、孙秀梅、尉小慧等.川乌2种方法提取液的成分比较.中成药21 1.1999,21(1),5-6. * |
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| 曹晖.乌头炮制品煎煮前后生物碱含量变化的初步研究.江西中医学院学报6 2.1994,6(2),35-37. * |
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