CN101439074A - Rhizoma atractylodis total terpene alcohol extract as well as preparation method and application thereof - Google Patents
Rhizoma atractylodis total terpene alcohol extract as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a rhizoma atractylodis total arborinol extract and a preparation method thereof. The rhizoma atractylodis total arborinol extract is an extract which is rich in rhizoma atractylodis sesquiterpene alcohol and obtained from dry rhizome of feverfew rhizoma atractylodis such as Atractylis lancea and/or Atractylodes chinensis (Atractylodes lancea DC.var.chinensis Kitam.) by means of extraction and refining. The rhizoma atractylodis total arborinol extract comprises the following components: (1) 65 percent to 95 percent of atractylol, wherein, the atractylol is the mixture of hinesol and Beta-eucalyptol and the proportion of the hinesol and the Beta-eucalyptol is 1:0.5 to 1:2; (2) 2.5 pecent to 20 percent of atisine chloride atractydin; and (3) compounds of other sesquiterpene alcohols, sesquiterpenes and polyacetylenes; wherein, the total content of the sesquiterpenes is no more than 2 percent. The rhizoma atractylodis total arborinol extract can effectively reserve and highlight pharmacological and pharmacodynamical functions of the extract and meanwhile greatly reduces acute toxicity, stimulation and relative side effects.
Description
Technical field
The present invention relates to a kind of extract, relate in particular to a kind of atractylol (hinesol+sagittol) that contains and be the Rhizoma Atractylodis total terpineol extract and the Preparation method and use of key component.
Technical background
Rhizoma Atractylodis (Rhizoma Atractylodis) are the dry rhizome of feverfew Atractylodes lancea (Thunb.) DC. Atractylodes lancea (Thunb.) DC. or Atractylis chinensis Atractylodes chinensis (DC.) Koidz..
The Chinese medicine record, Rhizoma Atractylodis acrid in the mouth, hardship, warm in nature, return spleen, stomach, Liver Channel, the effect that have drying damp and strengthening spleen, expelling wind and cold, makes eye bright is mainly used in distension and fullness in the abdomen, has loose bowels, disease (Yin Junfang etc. such as edema, beriberi flaccidity syndrome and arthralgia syndrome, rheumatic arthralgia, anemofrigid cold, nyctalopia nyctalopia.The Advance on Pharmacological Activities of [WTBX medicinal plants, pharmacy practice magazine, 2008:26 (4): 252-254).Chinese medicine is learned and is thought, it is dry that Rhizoma Atractylodis are given birth to moral character, and human body is had side effect, therefore need concoct to go to its " dry " (Luo Xuelun, the experimentation that Rhizoma Atractylodis are concocted, Chinese new medicine, 2003 medical material; 2 (5): 39-40).
Modern study is the result show, Rhzoma Atractylodis Lanceae volatile oil is its main active, its contained various active composition has remarkable pharmacologically active, it is active that for example hinesol has the proton pump inhibition, sagittol has the active function that suppresses the gastrointestinal tract histamine receptor, and atisine chloride atractydin has (Xu Laying etc., Rhizoma Atractylodis chemical constituent and the pharmacology activity research progress such as active function that suppresses the lipoxygenase activity and regulate the gastrointestinal movement function, Hubei College Of Traditional Chinese Medicine's journal, 2004; 6 (2): 51-53).
The process of preparing Chinese medicine goes dry modern study to think about Rhizoma Atractylodis, and Rhizoma Atractylodis are by concocting, and part that can be removed volatile oil slows down dry property, reduces toxic and side effects.Source investigation is thought again, and the various concocting methods of Rhizoma Atractylodis all can make Rhzoma Atractylodis Lanceae volatile oil content reduce, but its component no significant difference, illustrate that Rhizoma Atractylodis are concocted to go its dry property only relevant with the reduction of total volatile oil content; But also have data to think, the process of preparing Chinese medicine research of Rhizoma Atractylodis is not enough deeply with comprehensive.Whether its volatile oil component is the main component of Rhizoma Atractylodis " dry property ", is still waiting further investigation and inquires into (Xu Laying etc., Rhizoma Atractylodis chemical constituent and pharmacology activity research progress, Hubei College Of Traditional Chinese Medicine's journal, 2004; 6 (2): 51-53; Xu Dechun etc., Rhizoma Atractylodis concoct primary research at all times, the time precious traditional Chinese medical science traditional Chinese medicines, 2001; L2 (3): 257-258).
Obviously, still deposit contradiction about the modern study of Rhizoma Atractylodis active component and the dry property of process of preparing Chinese medicine removal: on the one hand, research confirms that the Rhzoma Atractylodis Lanceae volatile oil composition is its main active, and on the other hand, the process of preparing Chinese medicine is removed can cause in the dry process volatile oil content and sharply reduced.
Summary of the invention
Technical problem to be solved of the present invention provides a kind of Rhizoma Atractylodis total terpineol extract and preparation method thereof, this extract can effectively keep and the pharmacology pharmacodynamic effect of outstanding extract, reduces the acute toxicity and the side effect relevant with zest of extract simultaneously significantly.
The present inventor is careful relatively to be had research data now and finds that by experimental study Rhizoma Atractylodis are concocted when causing the reduction of volatile oil total amount, and the variation that the contained sesquiterpenoid active component of its volatile oil is formed is less relatively; But, should be bigger to the sesquiterpene composition influence of the contained low boiling range of Rhzoma Atractylodis Lanceae volatile oil based on the concocting process of parch.Available data should be careful inadequately relevant with its detection to low polarity and high volatile volatile sesquiterpene constituents about the result of study of " the various concocting methods of Rhizoma Atractylodis all can make Rhzoma Atractylodis Lanceae volatile oil content reduce, but its component no significant difference ".Usually, the skin penetration of sesquiterpene constituents is stronger, therefore has certain zest; The sesquiterpene constituents has significant central activity influence more, and all there is dependency in these with traditional medicine described " property is dry ".
The inventor is surprised to find by experimental study, to conventional solvent extraction, vapor distillation and supercritical CO
2The Rhzoma Atractylodis Lanceae volatile oil that extracts gained carries out rectification process, obtain the Rhizoma Atractylodis extract of low sesquiterpene alkene constituents thus, can effectively keep and the pharmacology pharmacodynamic effect of outstanding extract, also reduce the acute toxicity and the side effect relevant of extract simultaneously significantly with zest.Because of extract obtained key component is sesquiterpenoid constituents atractylol (hinesol+sagittol) and alkynes active component atisine chloride atractydin etc., for the ease of statement, the present invention is called " Rhizoma Atractylodis total terpineol " with this extract.
The present invention at first provides a kind of Rhizoma Atractylodis total terpineol extract, the extract that be rich in Rhizoma Atractylodis sesquiterpenoid of described Rhizoma Atractylodis total terpineol extract for from the dry rhizome of feverfew Rhizoma Atractylodis Atracty lislancea and/or Atractylodes chinensis (Atractylodes lancea DC.var.chinensis Kitam.), obtaining by extraction, purification step, the constituent of described Rhizoma Atractylodis total terpineol extract is:
(1) content range of atractylol is 65%～95% weight, and wherein, described atractylol is the mixture of hinesol and sagittol, and both weight ratios are 1:0.5～2;
(2) content of atisine chloride atractydin can be about 2.5%～20%; And
(3) other sesquiterpene alcohols, carbene class and the sesquiterpene compounds of surplus, wherein, the total content of sesquiterpene is no more than 2%.
Described " other sesquiterpenoid compounds " is meant the sesquiterpenoid compounds except that atractylol that exists in the extract; " other carbene compounds " is meant the alkynes constituents except that atisine chloride atractydin that exists in the extract.Described " sesquiterpene compounds " can include but not limited to following all or several compositions: α-and/or nopinene (α-/β-pinene), sabinene (sabinene), myrcene (myrcene), α-and/or β-phellandrene (α-/β-phellandrene), α-3-carene (α-3-carene), to P-cymene (p-cymene), limonene (limonene), β-ocimene (β-ocimenum), terpinolene (terpinolene), Borneolum Syntheticum (borneol), elemene (elemene), Flos Caryophylli alkene (caryophyllene), Humuleno (humulene), curcumene (curcumene), ar-curcumene (Ar-Curcumene), selinene (selinene), Rhizoma Zingiberis Recens are finished alkene (zingibirene), Cadinene (cadinene) etc.
In preferred embodiments, the content of atractylol is about 70%～90% weight in the constituent of described Rhizoma Atractylodis total terpineol extract, and the content of atisine chloride atractydin is about 5%～15% weight.
In the preferred embodiment, atractylol content is about 75%～85% weight in the constituent of described Rhizoma Atractylodis total terpineol extract, and atisine chloride atractydin content is about 7.5%～12.5% weight.
Extract of the present invention has significant prevention and therapeutical effect to tentative gastrointestinal ulceration, and thus, the present invention's Rhizoma Atractylodis total terpineol extract can be used to prepare the Pharmaceutical composition of corresponding uses.
Rhizoma Atractylodis total terpineol extract of the present invention is that the Rhzoma Atractylodis Lanceae volatile oil that routine is extracted is carried out rectification process and obtains.
In this description, " hinesol (English name " hinesol) ", molecular formula C
15H
26O, its structure is:
" sagittol (β-eudesmol) ", molecular formula C
15H
26O.Its structure is:
Atractylol content adopts gas chromatogram (GC) method mensuration under " Chinese Pharmacopoeia version in 2000 " appendix VIE item in the Rhizoma Atractylodis extract of the present invention:
Chromatographic condition and system suitability test: Agilent 6890N chromatograph (U.S. Agilent company), chromatographic column is the HP-5 quartz capillary column, flame ionization ditector (FID).Adopt temperature programming: initial 100 ℃, be warming up to 250 ℃ with 6 ℃, kept 2 minutes; Detector temperature is 280 ℃; Injector temperature is 230 ℃; Press before the post and be 6.0psi.Number of theoretical plate calculates by the hinesol peak and is not less than 5000, and the separating degree of each component peaks and internal standard substance mass peak should meet the requirements.
Get sagittol, hinesol respectively, add ethyl acetate respectively and make dissolving in right amount, and be diluted to scale, respectively as sagittol, hinesol reference substance solution (containing sagittol, hinesol 1mg among every 1ml respectively).Get sagittol, the detection of hinesol reference substance solution air inlet chromatography respectively, calculate peak area with area normalization method.
Other gets test sample 25mg, and accurate the title decides, and puts in the 25ml measuring bottle, adds acetic acid ethyl dissolution, and is diluted to scale, shakes up.As need testing solution.Get need testing solution, cross 0.45 μ m microporous filter membrane, discard filtrate just.Getting subsequent filtrate air inlet chromatography detects.Calculate peak area with area normalization method.
Calculate the content of sagittol, hinesol in the test sample respectively with external standard method.The content that the content of sagittol, hinesol in the test sample is added and obtains total terpene alcohol in the extract.
The Rhizoma Atractylodis of the embodiment of the invention are waved terpenes component content employing gas chromatography-mass spectrography (GC-MS) method detection in the extract, and its GC conditions is with the atractylol content detection.Atisine chloride atractydin content in Rhzoma Atractylodis Lanceae volatile oil and the total terpene alcohol extract adopts the high performance liquid chromatography (HPLC) of standard control to measure.
Except that specified otherwise, content described in the present invention is percentage composition by weight; Ratio between described each composition is meant content ratio between by weight each composition.
Secondly, the invention provides a kind of Rhizoma Atractylodis total terpineol method for preparing extractive, described method may further comprise the steps at least:
1) extracts: the extract acquisition oil-like extracts, the i.e. Rhzoma Atractylodis Lanceae volatile oil that promptly adopt suitable extracting method from the Rhizoma Atractylodis rhizome, to extract to be rich in volatile ingredient;
2) refining: i.e. fractional distillation refining step 1) gained oil-like extracts, collecting with the sesquiterpenoid is the fraction of key component, discarding with the sesquiterpene is low boiling range fraction and the nonvolatile fatty acid and the organic acid composition of key component.
Above-mentioned steps 1) the Rhzoma Atractylodis Lanceae volatile oil extracting method mainly includes but not limited to vapor distillation, organic solvent extraction and/or supercritical CO described in
2Extraction.Under the general environment temperature (10 ℃～30 ℃), the extract obtained grease that is generally of these extracting method, because of being rich in volatile ingredient, the present invention continues to use this area custom naming method, is referred to as Rhzoma Atractylodis Lanceae volatile oil.According to the comparative study result, the present invention preferably adopts steam distillation and supercritical CO
2Extraction extracts volatile oil; Consider that based on yield and preparation cost the special preferred water steam distillation of the present invention legal system is equipped with Rhzoma Atractylodis Lanceae volatile oil.
Obviously, it will be understood by those skilled in the art that the difference of the system pressure that adopts according to distillation process, corresponding variation will take place thereupon with the corresponding boiling range of above-mentioned each fraction.Usually, in step 2 of the present invention) in the rectified purified process, when system pressure remains at 2～15mmHg, described sesquiterpene is that the fraction of key component typically refers to boiling range at 110 ℃ of fractions below-130 ℃, the inventive method is collected with the sesquiterpenoid be key component fraction then normally boiling range from 120 ℃-130 ℃ to 160 ℃-180 ℃ fraction.Obviously, rectified purified step of the present invention also comprises atmospheric distillation, and the boiling range that is collected fraction raises to some extent.
Under the general environment temperature (10 ℃～30 ℃), step 2 of the present invention) the rectification products therefrom can be a grease, also can be semisolid or solid content.Usually, the main chemical constituent of rectification products therefrom as mentioned " Rhizoma Atractylodis total terpineol extract " described.
Studies show that the acute toxicity of the refining gained Rhizoma Atractylodis total terpineol extract of the present invention significantly reduces than Rhzoma Atractylodis Lanceae volatile oil, the toxic and side effects relevant with zest also significantly reduces.The present invention's Rhizoma Atractylodis total terpineol extract has significant anti-gastrointestinal tract ulcer function, and its effect is better than corresponding volatile oil.These results show that sesquiterpene chemical constituent contained in the Rhzoma Atractylodis Lanceae volatile oil not only has toxic action, the antiulcer activity that its zest effect can antagonism sesquiterpene alcohols; In addition because Rhizoma Atractylodis total terpineol extract anti-gastrointestinal tract ulcer function also is better than the pure product hinesol of approximate content and by the atractylol of pure product hinesol and sagittol preparation, point out contained atisine chloride atractydin constituents in total terpene alcohol extract can strengthen the antiulcer activity of sesquiterpene alcohols.In addition, from containing the CO of more relatively organic acid composition
2The side effect of supercritical extraction gained volatile oil can judge that its contained irritating organic acid composition also can have side effects.
The present invention's Rhizoma Atractylodis total terpineol extract has significant anti-gastrointestinal tract ulcer function, and toxicity is low, and side effect is little, and therefore can be used as active ingredient in pharmaceutical is used to prevent and treat gastrointestinal ulceration.Described gastrointestinal ulceration can comprise gastric ulcer, duodenal ulcer etc.
The pharmaceutical composition that contains the Rhizoma Atractylodis total terpineol extract can be according to the conventional method preparation of knowing in this area.Usually, in the unit dosage forms of described pharmaceutical composition, the content of Rhizoma Atractylodis total terpineol extract can be about 30mg～600mg, wherein, is preferably about 50～200mg.Its described pharmaceutical composition can be an oral solid formulation, for example tablet, capsule, granule etc.; Also can be liquid-state preparation, as suspension, emulsion etc.; Can also be the parenteral preparation, for example be prepared into suitable Percutaneously administrable preparation etc.
Pharmaceutical research shows that gained Rhizoma Atractylodis total terpineol extract of the present invention has than the stronger pharmacotoxicological effect of Rhizoma Atractylodis processed product extract, and toxic and side effects significantly reduces.Different with the concocting method that adopts various " going dry " up to now, the present invention is in the toxic and side effects that reduces extract, and the present invention's Rhizoma Atractylodis total terpineol extract can fully keep the contained pharmacological component of crude drug.According to available data, it is generally acknowledged that " dry " property composition in so-called in the ethnopharmacology " going dry " is a volatile oil component; Yet result of study can be judged according to the present invention, and in the Rhzoma Atractylodis Lanceae volatile oil, the main chemical constituent relevant with toxicity and zest side effect should be the low boiling range component based on sesquiterpene, but not whole volatile oil component; On the contrary, be main volatile oil component as the sesquiterpenoid of main active, its toxic and side effects is lower.In addition, according to the present invention, contained nonvolatile organic acid also is one of its zest composition in the Rhizoma Atractylodis extract.Based on above-mentioned discovery, the present invention can adopt and give birth to the described Rhizoma Atractylodis total terpineol extract of product medicinal material extract, the active ingredient loss due to can avoiding thus concocting.
Below be the present invention's specific embodiment, these embodiment only are used for further setting forth content of the present invention, and the scope of the invention are not constituted any restriction.
Description of drawings
Fig. 1 is that the embodiment of the invention 1 is given birth to the product medical material through vapor distillation extraction, the refining gained Rhizoma Atractylodis total terpineol extract GC chromatogram of rectification under vacuum; Wherein, atractylol and sagittol get retention time and are respectively 10.050min and 11.211min;
Fig. 2 is that the Rhizoma Atractylodis total terpineol of embodiment 1 extracts the HPLC chromatogram; Wherein, atractylol and sagittol get retention time and are all 6.810min, and the retention time of atisine chloride atractydin is 6.141min.
The specific embodiment
Embodiment 1Rhzoma Atractylodis Lanceae volatile oil, total terpene alcohol extract preparation
(1) medical material and the process of preparing Chinese medicine
Rhizoma Atractylodis are given birth to the product medical material: Rhizoma Atractylodis Atractylis lancea dry rhizome.Available from Luotian, Hubei.Pulverize, sieve.
Rhizoma Atractylodis are concocted medical material: by nineteen ninety-five version " operate under an appendix ID of the Chinese pharmacopoeia parched with bran method item, cool, pulverizing is sieved.
(2) extract
Vapor distillation: get the Rhizoma Atractylodis product of giving birth to respectively and split in the different distilling apparatus with process of preparing Chinese medicine medicinal powder 4kg, with reference to the Chinese Pharmacopoeia method, vapor distillation extracts 8h, makes oil-water separation, collects volatile oil.
Normal hexane extraction: the Rhizoma Atractylodis medical material, pulverize, get powder 2kg, add normal hexane 15L reflux, extract, 1hr, extract 3 times, merge extractive liquid,, decompression and solvent recovery gets oil-like extracts.
CO
2Supercritical extraction (CO
2-SFE): the Rhizoma Atractylodis medical material, pulverize in (greater than 10 orders), the material granule 10kg that gets it filled inserts CO
2In the supercritical extraction equipment, carry out continuous extraction 3hr.Extraction conditions: extracting pressure is 15MPa, and extraction temperature is 40 ℃, and separating pressure is 5-6MPa, and separation temperature is 45 ℃.
Detect Different Extraction Method gained oil-like extracts (Rhzoma Atractylodis Lanceae volatile oil), the result is as follows:
Table 1. Different Extraction Method is extract obtained
Steam distillation gained volatile oil testing result shows that behind (1) Rhizoma Atractylodis medicinal material processing, its volatile oil content significantly reduces; (2) although the atractylol in the gained volatile oil, atisine chloride atractydin percentage composition change not quite before and after the Rhizoma Atractylodis medicinal material processing, the sesquiterpene component content has reduction (about 60%) more significantly.
Compare with vapor distillation gained volatile oil: (1) normal hexane extraction yield is lower, and each key component content is approximate; (2) CO
2-SFE extract yield is higher, but atractylol, that atisine chloride atractydin gets content is all lower.Gas chromatographic detection confirms CO after adopting esterification
2Fatty acid and non-volatile organic acid content are higher in-the SFE extract.
(3) rectified purified
Equipment basic parameter: rectifying column king-post diameter 80mm, the efficient rustless steel θ ring of filler: 2.0mm * 2.0mm, effectively packing section height: 1.5m; Tower still volume: 5L adopts the heating of outer circulation heat-conducting oil system, heating general power 20kW, adjustable power; Overhead condenser is a coil pipe type, heat exchange area 0.5m
2Vacuum pump, speed of exhaust 10L/s, end vacuum 20Pa.
Rhizoma Atractylodis vapor distillation, n-hexane extract and CO
2Each 320g of-SFE extract is respectively charged into the tower still, the recirculated water cooling, and evacuation makes system pressure maintain about 8mmHg, and the heating of outer circulation heat-conducting oil system makes tower still gradient increased temperature.According to the preliminary experiment result, collect fraction below 120 ℃ and 120 ℃～180 ℃ fraction respectively.
Detect the extract obtained refined products of Different Extraction Method, the result is as follows:
Table 2. is extracted the rectification product thing of extract preparation by difference
The refined products testing result shows, (1) Different Extraction Method gained volatile oil is after rectified purified, and the sesquiterpene component content all significantly reduces in the gained refined products; (2) Different Extraction Method gained volatile oil is after rectified purified, and the composition of atractylol, atisine chloride atractydin reaches unanimity in the gained refined products; (3) behind the Rhizoma Atractylodis medicinal material processing, significantly reduce by the productive rate of the inventive method gained end-product, and atisine chloride atractydin content is relatively low in the end-product; (4) Different Extraction Method gained volatile oil is after rectified purified, and the productive rate of its end-product has than big-difference, and wherein, the solvent extraction method productive rate is minimum; (5) rectified purifiedly can effectively remove irritating sesquiterpene constituents and nonvolatile organic acid composition.
The product of giving birth to medical material is analyzed collection of illustrative plates respectively as depicted in figs. 1 and 2 through the GC and the HPLC of vapor distillation and rectification under vacuum gained end-product.Among Fig. 1, atractylol and sagittol get retention time and are respectively 10.050min and 11.211min; Among Fig. 2, atractylol and sagittol get retention time and are all 6.810min, and the retention time of atisine chloride atractydin is 6.141min.Rhizoma Atractylodis extract GC-MS analysis result sees Table 3.
Table 3. Rhizoma Atractylodis extract GC-MS analyzes
Annotate: sample 1, give birth to product medical material vapor distillation extract; Sample 2 is concocted medical material vapor distillation extract;
In addition, the Rhizoma Atractylodis medical material of different batches is handled through said method, the content of atractylol (hinesol+sagittol) is mostly between about 65%～95% in the total terpene alcohol extract of gained, and the content of hinesol and sagittol ratio can be at about 1:0.5 between about 1:2; The content of atisine chloride atractydin is mostly between about 2.5%～20%; The total content of sesquiterpene all can be controlled in below 2%.
(1) given the test agent embodiment 1 described each extract, comprising
Sample 1: Rhizoma Atractylodis are given birth to product medical material vapor distillation extract;
Sample 2: Rhizoma Atractylodis are concocted medical material vapor distillation extract;
Sample 3: Rhizoma Atractylodis are given birth to the product medical material through vapor distillation, rectified purified gained Rhizoma Atractylodis total terpineol extract.
(2) animal subject mice
(3) test method literature method (chief editor such as Li Yikui, herbal pharmacology experimental methodology, Shanghai science tech publishing house, Shanghai, 1991; P528～531)
(4) result of the test
Sample 1:LD
50=2.394 ± 0.652g/kg;
Sample 2:LD
50=5.743 ± 1.861g/kg;
Sample 3:LD
10=12.76 ± 2.846g/kg;
Experimental result shows that after Rhizoma Atractylodis were concocted, the acute toxicity of gained vapor distillation extract decreased; Rhizoma Atractylodis extract fails to detect LD after rectified purified
50, press literature method and calculate LD
10, the result shows that the acute toxicity of refined products reduces significantly.
Embodiment 3The total terpene alcohol of Rhzoma Atractylodis Lanceae volatile oil is to the effect of gastric ulcer animal model
1. the effect of acute gastric ulcer
(1) given the test agent embodiment 1 described each extract, comprising
Sample 1: Rhizoma Atractylodis are given birth to product medical material vapor distillation extract;
Sample 2: Rhizoma Atractylodis are concocted medical material vapor distillation extract;
Sample 3: Rhizoma Atractylodis are given birth to the product medical material through vapor distillation, rectified purified gained Rhizoma Atractylodis total terpineol end-product.
Sample 4: hinesol.
Sample 5: atractylol (hinesol: sagittol=5:3).
Sample 6: contrast medicine ranitidine.
(2) test method:
Adopt rat pyloric ligation ulcers gastric ulcer animal model.Totally 70 of SD rats, body weight 175.5 ± 12.7.Before the experiment, divided the cage fasting 48 hours with rat, the fasting phase can freely drink water.
During experiment, the rat etherization also is fixed on the Mus plate, from ensiform process of sternum lower edge ventrimeson open abdomen, and the about 2～3cm of otch.Push away on pointing gently at costal margin position, left side, make stomach be exposed to otch.The ligation of stomach pylorus underpass is sewed up incision of abdominal wall, iodine disinfection then.Postoperative, rat random packet, 10 every group.Each group is irritated stomach respectively and is subjected to the reagent thing, and model group gives the equivalent solvent.Behind the pylorus ligation, stop to supply water, put to death rat after 18 hours, open the abdominal cavity,, stomach is taken out, be dipped in 1% formalin, fix 10 minutes at nearly diaphragm place ligation esophagus for food.Cut coat of the stomach along greater gastric curvature, clean gastric content, coat of the stomach is launched, be fixed on the stencil plate with pin.With the naked eye or magnifier observe the gastric mucosa face, write down every group of ulcerogenic Mus number, ulcer number, ulcer level, ulcer area or ulcer index and pathological changes situation.
Ulcer level:, be divided into 4 grades by the pathological changes situation:
One-level (erosion) d (ulcer diameter)＜1mm;
Secondary (aphtha) 1mm＜d＜3mm;
Three grades of (big ulcer) d〉3mm;
Level Four (perforation is arranged).
Ulcer area: measure maximum vertical footpath and transverse diameter by the ulcer center, with formula S=π * (d
1/ 2) * (d
2/ 2) calculate.S is the ulcer area in the formula, and π is a pi, d
1Be the vertical footpath of the maximum of measuring, d by the ulcer center
2Be the maximum transverse diameter of measuring by the ulcer center.
Ulcer index: according to the form below ulcer index standard, find ulcer index according to the ulcer area.
Table 4. ulcer index standard (mm
2)
(3) result of the test:
Experimental result shows, compares with model group, and each given the test agent all can produce certain antiulcer drug effect.
Relatively as seen the experimental result of each given the test agent compares with sample 1 drug effect, and sample 2 curative effects make moderate progress, and sample 3 drug effect the bests show that the terpenes composition minimizing of extract moderate stimulation helps improving drug effect.
Relatively the experimental result of each given the test agent 4,5 as seen, hinesol and sagittol should all be the antiulcer activity compositions; Because sample 5 antiulcer drug effects are better than sample 1 and sample 2, show the drug action that the contained terpenes composition of the latter can the antagonism main active; Sample 3 drug effect the bests, show refining remove zest terpenes composition after, comprise that the antiulcer action of atisine chloride atractydin related component can further manifest.
The effect of table 5. Chinese People's Anti-Japanese Military and Political College Mus acute gastric ulcer (n=10, X ± SD)
2. chronic gastric ulcer effect
(1) given the test agent embodiment 1 described each extract, comprising
Sample 1: Rhizoma Atractylodis are given birth to product medical material vapor distillation extract;
Sample 2: Rhizoma Atractylodis are concocted medical material vapor distillation extract;
Sample 3: Rhizoma Atractylodis are given birth to product medical material vapor distillation extract through rectified purified gained end-product.
Sample 4: hinesol.
Sample 5: atractylol (hinesol: sagittol=5:3).
Sample 6: contrast medicine ranitidine.
(2) the test method rats acetic acid burns type gastric ulcer animal model.
During experiment, the etherization rat also is fixed on the Mus plate, and the sterile working is from ensiform process of sternum lower edge ventrimeson open abdomen, the about 2～3cm of otch.Duodenum is ticked gently below the liver of right side with curved hemostat, move to glandular stomach portion outside the abdomen gently then, at facies ventralis, body of stomach and the pyloric antrum intersection of stomach, with flat 0.4～0.5mm under the serous coat, the acetic acid 0.05ml formation pimple of injection 10% of thrusting of microsyringe.Stomach is sent back to gently, sew up abdominal muscle, skin suture then.With iodine tincture, alcohol disinfecting, the conventional raising.After the operation, rat random packet, 12 every group.From performing the operation next day, each given the test agent group is irritated the corresponding given the test agent of stomach respectively, and model group gives the equivalent normal saline, continuous irrigation stomach 9 days.Put to death in the 11st day, and opened abdomen, ligation pylorus and cardia are got stomach and are dipped in 1% formalin, fix 10 minutes.Cut off along greater gastric curvature, stomach is turned up, outwell content, wash out food debris gently.Ulcer is rounded or oval, and central concave is swelled all around slightly, and blood capillary gathers.The ulcer that has healed has protuberance on every side slightly, and the surface is ruddy, and as seen radial microgroove is arranged.
With the equal value representation ulcer index of the major diameter of ulcer and minor axis, carry out statistical procedures, calculate the ulcer healing percentage rate, estimate the facilitation of given the test agent to ulcer healing.
Ulcer healing percentage rate (%)=
(model group ulcer diameter average-experimental group ulcer diameter average)/model group ulcer diameter average * 100%
(3) result of the test: by experimental result shown in the table 6 as seen: (i) compare with model group, each given the test agent all can produce certain antiulcer drug effect; (ii) compare with sample 1 drug effect, sample 2 curative effects make moderate progress, and sample 3 drug effects are further improved, and show that the terpenes composition minimizing of extract moderate stimulation helps improving drug effect; (iii) the experimental result of each given the test agent 4,5 shows that hinesol and sagittol should all be the antiulcer activity compositions; (iv) sample 5 antiulcer drug effects are better than sample 1, show the antiulcer activity that the contained zest polar component of the latter can the antagonism total extract; (after v) sample 3 drug effects showed refining removal zest composition, the antiulcer action of related components such as atisine chloride atractydin can further manifest.
The effect of table 6 Chinese People's Anti-Japanese Military and Political College Mus chronic gastric ulcer (n=12, X ± SD)
Embodiment 4The observation of Different Preparation Rhzoma Atractylodis Lanceae volatile oil diarrhea inducing side effect
(1) given the test agent:
Sample 1: Rhizoma Atractylodis are given birth to product medical material vapor distillation extract;
Sample 2: Rhizoma Atractylodis are given birth to product medical material CO2 supercritical extract;
Sample 3: Rhizoma Atractylodis are concocted medical material vapor distillation extract;
Sample 4: Rhizoma Atractylodis are given birth to the product medical material through vapor distillation, rectified purified gained Rhizoma Atractylodis total terpineol end-product;
Sample 5: atractylol (hinesol: sagittol=5:3).
(2) test method:
30 of healthy male mices are divided into 3 groups at random by body weight, and 10 every group (seeing Table 6), the normal control group is normally fed with normal saline, and all the other are respectively organized every Mus and irritate the corresponding given the test agent of stomach every day, successive administration 7 days, every group of mice body weight of weighing in the 7th day.Calculate body weight change in seven days.Beginning fasting in the 8th day.Every Mus is irritated the normal saline suspension 0.5ml that stomach contains 0.2g/ml charcoal end, taking off cervical vertebra behind the 30min puts to death, open abdomen and separate mesentery, the clip upper end is to pylorus, and the lower end places on the pallet to the intestinal tube of ileocecus, gently small intestinal is pulled into straight line, measure intestinal tube length as " small intestinal total length ", the distance in forward position, end is calculated the charcoal end and is advanced percentage rate as " the charcoal end is propulsive distance in small intestinal " from pylorus to charcoal.
The charcoal end advances percentage rate=charcoal end at the propulsive distance of enteral/small intestinal total length * 100%
Experimental result is shown in Table 7:
The side effect of table 7 Different Preparation diarrhea inducing relatively
(2) result of the test:
Obvious loose stool all appears in 2 groups of mices of sample 1 and sample, have loose bowels and indigestion and loss of appetite, become thin, limbs fatigue, body temperature symptom on the low side; 3 groups of symptoms of sample alleviate to some extent; Sample 4 and sample are not seen above-mentioned symptom for 5 groups.
Advance the result as seen from the charcoal end, sample 1 and 2 pairs of intestinal movement function effects are bigger, and sample 3 influences are less, and sample 4 and 5 then influence is very little.
Claims (8)
1, a kind of Rhizoma Atractylodis total terpineol extract, the extract that be rich in Rhizoma Atractylodis sesquiterpenoid of described Rhizoma Atractylodis total terpineol extract for from the dry rhizome of feverfew Rhizoma Atractylodis Atractylis lancea and/or Atractylodes chinensis (Atractylodeslancea DC.var.chinensis Kitam.), obtaining by extraction, purification step, the constituent of described Rhizoma Atractylodis total terpineol extract is:
(1) content range of atractylol is 65%～95% weight, and wherein, described atractylol is the mixture of hinesol and sagittol, and both ratios are 1: 0.5～2;
(2) content of atisine chloride atractydin is 2.5%～20% weight; And
(3) other sesquiterpene alcohols, sesquiterpene and the carbene compounds of surplus; Wherein, the total content of sesquiterpene is no more than 2% weight.
2, the described Rhizoma Atractylodis total terpineol extract of claim 1, in the constituent of wherein said Rhizoma Atractylodis total terpineol extract, the content of atractylol is 70%～90% weight, the content of atisine chloride atractydin is 5%～15% weight.
3, the described Rhizoma Atractylodis total terpineol extract of claim 2, in the constituent of wherein said Rhizoma Atractylodis total terpineol extract, atractylol content is 75%～85% weight, atisine chloride atractydin content is 7.5%～12.5% weight.
4, the described Rhizoma Atractylodis total terpineol preparation method of extract of claim 1 may further comprise the steps:
(1) extracts: adopt steam distillation, solvent extraction method and/or CO
2Supercritical extraction extracts from the Rhizoma Atractylodis dry rhizome and obtains oil-like extracts;
(2) refining: fractional distillation refining step (1) gained oil-like extracts, in this step:
Discarding with the sesquiterpene is the low boiling range fraction of key component;
Collection is the fraction of key component with the sesquiterpenoid; And
Discard nonvolatile fatty acid and organic acid composition.
5, the described Rhizoma Atractylodis total terpineol preparation method of extract of claim 4, wherein said step (2) is rectification under vacuum, in described step, the sesquiterpene that is discarded is that the fraction of key component is meant 2～15
Boiling range is at 110 ℃ of fractions below-130 ℃ under the mmHg pressure, the fraction of key component that collected with the sesquiterpenoid is be meant under 2～15mmHg pressure boiling range from 120 ℃-130 ℃ to 160 ℃-180 ℃ fraction.
6, contain the pharmaceutical composition that right requires 1 described Rhizoma Atractylodis total terpineol extract, in the described pharmaceutical composition, containing the Rhizoma Atractylodis total terpineol extract in its unit formulation is 20mg～600mg.
7, the purposes of the described pharmaceutical composition of claim 6 in the medicine of preparation treatment peptic ulcer disease.
8, in the described purposes of claim 7, its peptic ulcer disease comprises gastric ulcer and duodenal ulcer.
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