CN101940566B - Application and preparation of bitter orange extract meranzin hydrate for preparing enterocinetic kinetic medicaments - Google Patents
Application and preparation of bitter orange extract meranzin hydrate for preparing enterocinetic kinetic medicaments Download PDFInfo
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- CN101940566B CN101940566B CN2010102021057A CN201010202105A CN101940566B CN 101940566 B CN101940566 B CN 101940566B CN 2010102021057 A CN2010102021057 A CN 2010102021057A CN 201010202105 A CN201010202105 A CN 201010202105A CN 101940566 B CN101940566 B CN 101940566B
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Abstract
The invention discloses application and a preparation of bitter orange extract meranzin hydrate for preparing enterocinetic kinetic medicaments. A method for preparing the meranzin hydrate comprises the following steps of: pulverizing bitter orange, and performing reflux by using ethyl acetate to extract filter liquor; concentrating the filter liquor under reduced pressure, adding acetone for dissolving, putting the mixture on a silicagel column, eluting by using petroleum ether and the acetone, merging eluent, and concentrating under the reduced pressure; and adding alcohol for dissolving and centrifuging, and freeze-drying supernatant to obtain the meranzin hydrate. In the application, the meranzin hydrate is separated and extracted from the bitter orange, and experiments prove that the enterocinetic kinetic effect of the bitter orange extract meranzin hydrate far exceeds that of hesperidin and naringin, so the prejudice that people consider the hesperidin and the naringin as the active ingredients of the traditional Chinese medicine bitter orange with the enterocinetic kinetic pharmacological effect all the time is corrected.
Description
Technical field
The present invention relates to the Chinese medicine Fructus Aurantii extract, the hydration meranzin that is specifically related to from Fructus Aurantii, extract and the purposes of hydration meranzin.
Background technology
Existing research shows, the hydration meranzin, and chemistry is by name: 7-methoxyl group-8-(2 ', 3 '-dihydroxy-3 '-methyl butyl)-coumarin, English name: merazin hydrate, molecular weight are 278, and chemical formula is:
Mainly be present in the plants such as the heavy peristome Radix Angelicae Sinensis of heracleum hemsleyanum michaux, Rutaceae Fructus Cnidii, Folium Et Cacumen Murrayae, lobule Folium Et Cacumen Murrayae, not appearing in the newspapers is present in the Fructus Aurantii (Fructus Aurantii Immaturus).
The Chinese medicine Fructus Aurantii, latin name Fructus Aurantii, an another name shell, river Fructus Aurantii, merchant's shell, Fructus Aurantii (parched) are the dry immature fruit of rutaceae Citrus aurantium Linn. (Citrus aurantium L.) and variety thereof.Known Fructus Aurantii has the effect that promotes intestinal motive force, be widely used in treating digestive tract disease (referring to " pharmacology of Chinese materia medica ". Hou Jiayu edits .2002.8, front page .p118).The pharmacology effective ingredient of 2005 editions records of Chinese Pharmacopoeia Fructus Aurantii is Hesperidin and naringin; But have research (referring to official's good fortune orchid etc. Pericarpium Citri Reticulatae and Hesperidin are to the intestine in vitro motional effects. the time precious traditional Chinese medical science traditional Chinese medicines; 2002; 13 (2)) find that the intestinal motive force experiment of these two kinds of compositions of Hesperidin and naringin does not have obvious curative effects.
Summary of the invention
The objective of the invention is to from the Chinese medicine Fructus Aurantii, extract and obtain a kind of new effective ingredient---hydration meranzin; And the effect components of finding short intestinal motive force in the Fructus Aurantii body is main relevant with the hydration meranzin; But not Hesperidin and naringin, the hydration meranzin is only the effective ingredient of the short intestinal motive force pharmacological action of Fructus Aurantii.
Further purpose of the present invention is with the Fructus Aurantii to be the pharmaceutically acceptable various pharmaceutical preparatioies that feedstock production goes out to comprise Fructus Aurantii extract hydration meranzin.
The inventor discovers: the effect components of short intestinal motive force is main relevant with the hydration meranzin in the Fructus Aurantii body, but not that prior art is thought is relevant with Hesperidin and naringin.
The method of separation and Extraction hydration meranzin is from Fructus Aurantii: pulverize Fructus Aurantii, extract filtrating with ethyl acetate backflow, add acetone solution after filtrate decompression is concentrated, go up on silicagel column; First with the petroleum ether eluting, reuse petroleum ether: acetone=20: 1, petroleum ether: acetone=10: 1, and the acetone eluting is respectively once; Merge eluent, concentrating under reduced pressure adds the alcohol dissolving; Centrifugal, get supernatant, lyophilization.
The present invention has corrected people and has thought that always Hesperidin and naringin are the prejudice of the short intestinal motive force pharmacological action effective ingredient of Chinese medicine Fructus Aurantii; Original main relevant through the effect components of discovering the short intestinal motive force of Fructus Aurantii carefully with the hydration meranzin, rather than Hesperidin and naringin.Inventor's separation and Extraction from Fructus Aurantii goes out the hydration meranzin, and through experiment confirm Fructus Aurantii extract hydration meranzin can significantly suppress spontaneous activity, antagonism Ach, the BaCl of rat small intestine in vitro smooth muscle
2Or the intestinal that 5-HT etc. causes shrinks spasm, and it acts on considerably beyond Hesperidin and naringin.On the basis of this research, the inventor obtains a kind of medicine that comprises Fructus Aurantii extract hydration meranzin, and this medicine will be a kind of well short intestinal motive force medicine.
Description of drawings
Fig. 1: the HPLC chromatogram of blank serum;
Fig. 2: the HPLC chromatogram of pastille serum;
Fig. 3: the HPLC chromatogram of JIAWEI XIAOYAO SAN decoction;
Fig. 4: hydration meranzin spectrogram in the pastille serum;
Fig. 5: hydration meranzin spectrogram in the Fructus Aurantii.
The specific embodiment
Embodiment 1: the hydration meranzin is as the discovery of Fructus Aurantii active component
Blank serum: healthy subjects serum, n=6;
Pastille serum: serum behind the oral JIAWEI XIAOYAO SAN 30min of healthy subjects, n=6.
JIAWEI XIAOYAO SAN: ZHIZHI (1g), Cortex Moutan (1g), Radix Bupleuri (1.7g); Poria (1.7g), the Rhizoma Atractylodis Macrocephalae (1g), Radix Angelicae Sinensis (1.7g); Cortex Magnoliae Officinalis (2g), Fructus Aurantii (2g), the Radix Paeoniae Alba (1.7g), Rhizoma Zingiberis Recens (4g); Get angry boiling back slow fire boiling 40 minutes * 2 times after liquid medicine does not have, soaks half an hour in Radix Puerariae (2.7g), Fructus Jujubae (1g), Herba Menthae (1g), Radix Glycyrrhizae (1g) 14 flavors.
Sample treatment: get blank serum 1ml, 100 water-baths 10 minutes are smashed with refiner, and centrifugal 20 minutes kinds of 8500 commentaries on classics/min are got supernatant and blown with nitrogen current, are settled to 150 μ l, and are to be measured; Pastille serum processing method is identical.
With HPLC blank serum, pastille serum and Jiawei Xiaoyao power preparation are analyzed, chromatogram is seen Fig. 1～Fig. 3 respectively.The inventor finds: retention time of existence is 26.020 peak in Jiawei Xiaoyao power preparation; And in the pastille serum of JIAWEI XIAOYAO SAN, be 25.803 peak with there being a retention time; And this unknown peak does not have in blank serum, and explanation causes by taking medicine.Through chromatogram and retention time analysis explanation, these two peaks possibly be same substance (unknown component X), and derive from JIAWEI XIAOYAO SAN.Unknown component X spectrogram is seen accompanying drawing 4 in the pastille serum.
Subsequently, JIAWEI XIAOYAO SAN 14 flavor crude drugs are divided into four groups at random, take by weighing by the amount in the whole square preparation: first group: ZHIZHI (1g), Cortex Moutan (1g), Radix Bupleuri (1.7g); Second group: Poria (1.7g), the Rhizoma Atractylodis Macrocephalae (1g), Radix Angelicae Sinensis (1.7g); The 3rd group: Cortex Magnoliae Officinalis (2g), Fructus Aurantii (2g), the Radix Paeoniae Alba (1.7g), Rhizoma Zingiberis Recens (4g); The 4th group: Radix Puerariae (2.7g), Fructus Jujubae (1g), Herba Menthae (1g), Radix Glycyrrhizae (1g).Above four groups of crude drugs are carried out efficient liquid phase chromatographic analysis.Sample introduction 6 times is learnt that by retention time and spectrogram unknown component X derives from the crude drug Fructus Aurantii.The spectrogram of unknown component X is seen accompanying drawing 5 in the Fructus Aurantii.
Embodiment 2: from crude drug Fructus Aurantii separation and Extraction hydration meranzin
With the unknown component X of silica gel column chromatography separation and purification from Fructus Aurantii, detailed process is following: take by weighing the Fructus Aurantii 2g of pulverizing, the 20ml ethyl acetate backflow is extracted 1.5h; Extract three times, add the 2ml acetone solution behind the concentrating under reduced pressure, go up on silicagel column; First with petroleum ether 100ml eluting, reuse petroleum ether: acetone 20: 1,10: 1, each 100ml of acetone eluting; Merging eluent is eluent 1, and concentrating under reduced pressure adds the centrifugal 15min of 2ml dissolve with methanol 15000r/min rotating speed.Get the supernatant sample introduction.Detect its purity through analytical type HPLC, calculate purity＞98% by the peak area normalization method.Through 5 preparations of preparation HPLC, work under the volume overload condition, sampling volume 10ml gets not principal component 19.63mg, yield 0.0098%.
Identify that to carrying out composition after the prepared product lyophilization in conjunction with the full charcoal spectrum of collection of illustrative plates DMSO-C13-2006-8-2HX-0815, hydrogen spectrum, mass spectrum, infrared and bibliographical information physical data are judged the test sample article Rf of institute (EtoAc) 0.3, molecular weight is 278, and molecular formula is C
15H
18O
5,, confirm that sample is the hydration meranzin in conjunction with documents and materials.
Embodiment 3: hydration meranzin pharmacodynamic experiment
180～220g SD rat (male and female have both) is divided into 6 groups at random; Every group 15, be respectively A (distilled water) group, B (hydration meranzin) group, C (Hesperidin) group, D (naringin) group, E (hydration meranzin+atropine) group, F (Hesperidin+atropine) group, G (naringin+atropine) group.
Each group is irritated the liquid 0.3mL/d that takes medicine, continuous irrigation clothes 3d, 1 time/d.The A group is irritated clothes 199% distilled water; B and E group are irritated clothes hydration meranzin (20mg/ml), C and F group filling clothes Hesperidin (20mg/ml), D and G group and are irritated clothes naringin (20mg/ml).Irritate each 0.3mL of clothes said medicine behind the 4d fasting 12h, simultaneously E group, F group and G group lumbar injection 0.0003g/kg morphine hydrochloride.Irritate clothes BD 2000 aqueous solution 0.4mL behind the 20min, rat is put to death in dislocation behind the 15min, cuts open the belly; To rectum end, stomach is got at the place with pylorus from cardia in separation, gastric content fully is dissolved in 1.5mL carbon tetrachloride, 0.5mL dehydrated alcohol and 2mL distilled water is housed in vitro; The centrifugal 15min of 3500r/min; Getting supernatant, survey absorbance in nine 620nm places with spectrophotometer, is 100% with the absorbance average of distilled water group; All the other respectively organize absorbance by comparison gained percent be relative gastric pigment residual rate, as the index of gastric emptying.Measure respectively from pylorus to pigment simultaneously and reach the distance to ileocecus foremost, the ratio of the two is average intestinal propulsion ratio.Take out duodenum; Preparation isolated rat duodenum flesh BIAO and BEN places in the Magnus' bath that fills the 20ml tyrode's solution blowing air; 38 ± 0.5 ℃ of constant temperature; Tension load 1g, the adding of stable back causes convulsion agent acetylcholine (1ug/ml-0.1ml), barium chloride (20%-0.1ml), 5-HT (10mg/ml-0.1ml), treats that it steadily adds above-mentioned each medicinal liquid in the back.Measure its administration front and back amplitude, calculate its antagonistic rate.
Paired observation hydration Pericarpium Citri Reticulatae lactone, Pericarpium Citri Reticulatae glycosides and naringin are to the effect of rat small intestine contraction intensity, and hydration Pericarpium Citri Reticulatae lactone can significantly suppress spontaneous activity, antagonism Ach, the BaCl of rat small intestine in vitro smooth muscle
2Or the intestinal that causes of 5-HT shrinks spasm, and then both effects are not obvious.
Pericarpium Citri junoris lactone, Hesperidin and naringin antagonism Ach, BaCl
2, 5-HT effect relatively
Annotate: * and Hesperidin and naringin be P＜0.001 relatively
Pericarpium Citri junoris lactone, Hesperidin and naringin compare the effect of average intestinal propulsion ratio and relative gastric pigment residual rate
Annotate: N=15, compare p＜0.001 with the distilled water group
Embodiment 4: hydration meranzin preparation of pharmaceutical compositions
Get the hydration meranzin extract among the embodiment 2, prepare various pharmaceutically acceptable various forms of Pharmaceutical compositions by conventional method known in the art.
Hydration meranzin sheet: add starch in the hydration meranzin extract freeze-drying powder, cross 80 mesh sieves, fully add binding agent behind the mixing, process granule; In 600 ℃ of dryings, granulate adds lubricating substance; Tabletting, sheet heavily are 0.05 or 0.01g, and every contains hydration meranzin 20mg.
Hydration meranzin capsule: add starch in the hydration meranzin extract freeze-drying powder, cross 80 mesh sieves, fully add binding agent behind the mixing, process granule, in 600 ℃ of dryings, granulate encapsulatedly promptly get, every heavy 0.4g.
Claims (1)
1. the hydration meranzin is used to prepare the purposes of short intestinal motive force medicine.
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| CN2010102021057A CN101940566B (en) | 2008-08-01 | 2008-08-01 | Application and preparation of bitter orange extract meranzin hydrate for preparing enterocinetic kinetic medicaments |
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| CN2010102021057A CN101940566B (en) | 2008-08-01 | 2008-08-01 | Application and preparation of bitter orange extract meranzin hydrate for preparing enterocinetic kinetic medicaments |
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| CN2008100319740A Division CN101328162B (en) | 2008-08-01 | 2008-08-01 | Use of citrus aurtantium extract hydration meranzin for preparing gastrointestinal dynamic promoting drugs and preparation |
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| CN109705077B (en) * | 2017-10-26 | 2022-09-02 | 江苏康缘药业股份有限公司 | Coumarin compound and preparation method and application thereof |
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Non-Patent Citations (5)
| Title |
|---|
| Saied, Sumayya等.Two new coumarins from Murraya paniculata.《Journal of Asian Natural Products Research》.2008,第10卷(第6期),第515-519页，化合物5，摘要. * |
| Sergio Rosselli1,等.Antibacterial and Anticoagulant Activities of Coumarins Isolated from the Flowers of Magydaris tomentosa.《Planta Medica》.2007,第73卷(第2期),第116-120页,化合物7,摘要. * |
| 周吕.基础与临床.《胃肠动力学-基础与临床》.科学出版社,1999,第293-301、773-787页. * |
| 官福兰,等.枳壳及辛弗林对小鼠胃排空和小肠推进功能的影响.《现代中西医结合杂志》.2002,第11卷(第11期),第1001-1003页. * |
| 陈艳，等.蛇床子的化学成分及药理作用的研究进展.《沈阳药科大学学报》.2006,第23卷(第4期),第256-260页，化合物5. * |
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