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CN102068535A - Citrus aurantium or Fructus aurantii total flavonoids extract extracted by ethanol reflux and use thereof - Google Patents

Citrus aurantium or Fructus aurantii total flavonoids extract extracted by ethanol reflux and use thereof Download PDF

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Publication number
CN102068535A
CN102068535A CN 201010608298 CN201010608298A CN102068535A CN 102068535 A CN102068535 A CN 102068535A CN 201010608298 CN201010608298 CN 201010608298 CN 201010608298 A CN201010608298 A CN 201010608298A CN 102068535 A CN102068535 A CN 102068535A
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fructus aurantii
ethanol
fructus
extract
under reduced
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CN102068535B (en
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吕武清
唐春山
谢宁
杨小玲
孙继寅
宋友昕
李志勇
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JIANGXI QINGFENG PHARMACEUTICAL RES CO Ltd
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JIANGXI QINGFENG PHARMACEUTICAL RESEARCH CO LTD
Jiangxi Qingfeng Pharmaceutical Co ltd
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Priority to PCT/CN2011/078014 priority patent/WO2012088885A1/en
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Abstract

The invention relates to a immature bitter orange or bitter orange total flavone extract, which is prepared by cutting immature bitter orange or bitter orange into pieces or crushing, adding 30-90% ethanol with the volume of 5-16 times of the total bitter orange or bitter orange for reflux extraction for 1-3 times, and performing reflux extraction for 1-3 hours each time, and filtering; mixing the filtrates, recovering ethanol from the filtrate, passing the aqueous solution through a treated nonpolar macroporous resin, eluting with water and ethanol with the concentration of less than 20% in sequence to remove impurities, eluting with 25-90% ethanol and 0.5-2% sodium hydroxide, collecting ethanol eluate, concentrating under reduced pressure to obtain a fluid extract with the relative density of about 1.20-1.40 (50-70 ℃), drying under reduced pressure at the temperature of 60-80 ℃, and pulverizing to obtain an immature bitter orange or bitter orange total flavone extract which can be used for treating gastrointestinal dyskinesia type functional dyspepsia; the medicine application of epigastric pain, abdominal distension, anorexia, eructation, nausea, vomiting and vomiting caused by chemotherapy drugs or other reasons.

Description

The Fructus Aurantii Immaturus of alcohol reflux or Fructus Aurantii extractive of general flavone and uses thereof
Technical field
The present invention relates to a kind of Fructus Aurantii Immaturus of alcohol reflux or Fructus Aurantii extractive of general flavone and uses thereof.
Background technology
Functional dyspepsia (FD) is a kind of common, frequently-occurring disease.Be called gastric dynamic dysfunction again, or gastric motility disorder.Be a kind of common clinical syndrome, the foreign statistic data shows that 1/3 crowd suffered from FD, accounts for 20%～30% of gop number.Domestic account for digestion be out-patient about 50%, betide 20%～40% normal population.In addition, can cause vomiting after the tumor patient chemotherapy more than 80%, preventing or arresting vomiting is mainly based on medicines such as paspertin metoclopramide, ondansetrons, but the chemical medicine preventing or arresting vomiting is with asthenia, dizziness, headache, even nape muscle spasm symptom might occur.
Western medical treatment is mainly based on motilium, cisapride, mosapride etc. at present; But with its a large amount of uses, finding has obvious heart toxic and side effects, and many patients the Q-T interval occurs and prolong and arrhythmia after using cisapride, serious adverse reaction such as torsades de pointes type chamber speed particularly, even cause death.For this reason, FDA Food and Drug Administration is decided by that on July 23rd, 2000 rose and stops to use this medicine that China Drug Administration has also made qualification to the use of cisapride, but still can use under the doctor instructs.
Chinese traditional treatment is with the dispelling the stagnated QI removing food stagnancy, and the painful abdominal mass class Chinese medicine that looses reduces phlegm; Stop in treatment is stagnant, feeling of fullness distending pain etc., Fructus Aurantii Immaturus is one of representative medicine.Fructus Aurantii Immaturus, Fructus Aurantii are dry young fruit or the immature fruit of rutaceae Citrus aurantium Linn. Citrus aurantium L. and variety or Fructus Citri sinensis Citrus sinensis Osbeckr.Fructus Aurantii Immaturus, Fructus Aurantii are from Shennong's Herbal, " Mingyi Bielu " record: " removing breast side of body accumulation of phlegm in the hypochondrium; by cutting off the water; broken solid; that relieving distension is full ", initiate zhishi daozhi pills to make by hand from Jin Dynasty Lee physician Dong Yuan " differentiation on endogenous ", clinical formulation is used and modern Chinese medicine large-scale production and be used for digestive tract disease up till now, and there is nearly 2,000 years history front and back; Fructus Aurantii Immaturus, Fructus Aurantii main component are flavone etc., and its decocting liquid and Hesperidin etc. can significantly strengthen normal mouse and atropine produces the ahead running that mice suppresses the small intestinal of model, has the effect of short digestive tract power.But Fructus Aurantii Immaturus, Fructus Aurantii only are used for clinical formulation and Chinese patent medicine preparation on a small quantity, and ample resources is not used widely, and its natural dispelling the stagnated QI removing food stagnancy effect may promote that the effect class same sex of medicine for stomach dynamic is not fully excavated with the modern times.
Summary of the invention
The purpose of this invention is to provide a kind of Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone of alcohol reflux, be used for gastrointestinal motility obstruction type functional dyspepsia; Upper abdominal pain, abdominal distention, anorexia, belch, feel sick, vomiting that vomiting and chemotherapeutics or other reasons cause.
Fructus Aurantii Immaturus provided by the invention or Fructus Aurantii extractive of general flavone, by Fructus Aurantii Immaturus or Fructus Aurantii are obtained with alcohol reflux, wherein the alcohol reflux method is: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces or pulverizing, 30%～90% alcohol reflux 1～3 time that adds 5～16 times of volumes, each reflux, extract, 1～3 hour filters; Merging filtrate, filtrate recycling ethanol, the non-polar macroporous resin of aqueous solution by having handled well, water, the ethanol elution below 20% are removed impurity successively, and reuse 25%～90% ethanol, 0.5%～2% sodium hydroxide eluting are collected ethanol elution, be evaporated to the fluid extract of relative density about 1.20～1.40 (50 ℃～70 ℃), the exsiccant temperature of drying under reduced pressure is 60～80 ℃, pulverizes, promptly.
Preferably, concrete alcohol reflux method is as follows: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces or pulverizing, add 40%～85% alcohol reflux 2～3 times of 6～14 times of volumes, each reflux, extract, 1～2.5 hour filters; Merging filtrate, filtrate recycling ethanol, the non-polar macroporous resin of aqueous solution by having handled well, water, the ethanol elution below 20% are removed impurity successively, reuse 30%～85% ethanol, 0.5%～1.8% sodium hydroxide eluting, collect ethanol elution, be evaporated to the fluid extract of relative density about 1.25～1.40 (55 ℃～70 ℃), drying under reduced pressure, exsiccant temperature is 65～80 ℃, pulverize, promptly.
Preferably, concrete alcohol reflux method is as follows: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces or pulverizing, add 45%～80% alcohol reflux 2～3 times of 7～12 times of volumes, each reflux, extract, 1.5～2.5 hours filters; Merging filtrate, filtrate recycling ethanol, the non-polar macroporous resin of aqueous solution by having handled well, water, the ethanol elution below 20% are removed impurity successively, reuse 35%～75% ethanol, 0.5～1.6% sodium hydroxide eluting, collect ethanol elution, be evaporated to the fluid extract of relative density about 1.25～1.35 (55 ℃～65 ℃), drying under reduced pressure, exsiccant temperature is 70～80 ℃, pulverize, promptly.
Preferably, concrete alcohol reflux method is as follows: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces or pulverizing, add 55%～75% alcohol reflux 2～3 times of 7～11 times of volumes, each reflux, extract, 1.5～2 hours filters; Merging filtrate, filtrate recycling ethanol, the non-polar macroporous resin of aqueous solution by having handled well, water, the ethanol elution below 20% are removed impurity successively, reuse 40%～65% ethanol, 0.5～1.3% sodium hydroxide eluting, collect ethanol elution, be evaporated to the fluid extract of relative density about 1.30～1.35 (60 ℃～65 ℃), drying under reduced pressure, exsiccant temperature is 70～75 ℃, pulverize, promptly.
Preferably, concrete alcohol reflux method is as follows: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces or pulverizing, add 65% alcohol reflux 3 times of 9 times of volumes, each reflux, extract, 1.5 hours filters; Merging filtrate, filtrate recycling ethanol, the non-polar macroporous resin of aqueous solution by having handled well, water, the ethanol elution below 20% are removed impurity successively, reuse 40%～55% ethanol, 0.8～1.2% sodium hydroxide eluting, collect ethanol elution, be evaporated to the fluid extract of relative density about 1.30 (60 ℃), drying under reduced pressure, exsiccant temperature is 75 ℃, pulverize, promptly.
Preferably, concrete alcohol reflux method is as follows: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces or pulverizing, add 60%～70% alcohol reflux 2 times of 7～9 times of volumes, each reflux, extract, 1.5 hours filters; Merging filtrate, filtrate recycling ethanol, the non-polar macroporous resin of aqueous solution by having handled well, water, the ethanol elution below 20% are removed impurity successively, reuse 40%～55% ethanol, 0.7%～1.3% sodium hydroxide eluting, collect ethanol elution, be evaporated to the fluid extract of relative density about 1.30 (60 ℃), drying under reduced pressure, exsiccant temperature is 75 ℃, pulverize, promptly.
Preferably, concrete alcohol reflux method is as follows: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces or pulverizing, add 70% alcohol reflux 2 times of 8 times of volumes, each reflux, extract, 2 hours filters; Merging filtrate, filtrate recycling ethanol, the non-polar macroporous resin of aqueous solution by having handled well, water, the ethanol elution below 20% are removed impurity successively, reuse 40%～50% ethanol, 0.9%～1.1% sodium hydroxide eluting, collect ethanol elution, be evaporated to the fluid extract of relative density about 1.30 (60 ℃), drying under reduced pressure, exsiccant temperature is 75 ℃, pulverize, promptly.
Preferably, concrete alcohol reflux method is as follows: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces, add 65% alcohol reflux 2 times of 7 times of volumes, each reflux, extract, 2 hours filters; Merging filtrate, filtrate recycling ethanol, the D101 macroporous resin column of aqueous solution by having handled well, water, 15% ethanol, 45% ethanol, 1% sodium hydroxide eluting are collected 45% ethanol elution successively, are evaporated to the fluid extract of relative density about 1.30 (60 ℃), drying under reduced pressure, exsiccant temperature is 75 ℃, pulverizes, promptly.
Preferably, wherein 15% ethanol part elution volume is every 1ml resin 3ml eluting, selects every 1ml resin 4ml eluting during 45% ethanol elution.
Preferably, wherein Fructus Aurantii Immaturus or Fructus Aurantii are pulverized by 8 mesh sieves.
Preferably, general flavone content more than 50% wherein.
Preferably, general flavone content more than 80% wherein.
Preferably, wherein also comprise flavonoid chemical constituent and acceptable liposoluble ingredient medically thereof, the flavonoid chemical constituent contains one or more in naringin, neohesperidin, Hesperidin, new naringin, Radix seu Folium Tosicodendri Delavayi glucoside and the aglycon thereof.
Preferably, wherein naringin content, neohesperidin content reach more than 25% respectively.
Preferably, wherein the macroporous resin applied sample amount by resin volume (ml): crude drug quality (g) is 5: 1.
Preferably, the last sample flow velocity of wherein every 1ml resin is between 1.25～1.55ml/h.
Preferably, the elution flow rate of wherein every 1ml resin is between 1.25～1.45ml/h, and described non-polar macroporous resin blade diameter length ratio is 1: 10, and the static adsorption time of medicinal liquid is 1 hour behind the last sample.
Preferably, wherein said non-polar macroporous resin repeats after 8 times to wash with water to neutrality with the 5% sodium hydroxide solution immersion of 10 times of amounts 2 hours; 3% hydrochloric acid solution of 10 times of amounts of reuse soaked 2 hours, washed with water to neutrality to use with the back of regenerating.
On the one hand, the invention provides the purposes that Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone are used to prepare treatment gastrointestinal motility obstruction type functional dyspepsia disease medicament.
On the one hand, the invention provides the purposes that Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone are used to prepare the vomiting disease medicament that treatment chemotherapeutics or other reasons cause.
On the one hand, the invention provides the purposes that Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone are used to prepare treatment Upper abdominal pain disease medicament.
On the one hand, the invention provides the purposes that Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone are used to prepare treatment abdominal distention, anorexia, belch disease medicament.
On the one hand, the invention provides the purposes that Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone are used to prepare the nauseating disease medicament of treatment.
On the other hand, the present invention also provides a kind of Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone preparation, and said preparation is a main active with described Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone.
Experimental data proves that Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone that alcohol reflux of the present invention obtains can be used for treating gastrointestinal motility obstruction type functional dyspepsia; Upper abdominal pain, abdominal distention, anorexia, belch, feel sick, vomiting that vomiting and chemotherapeutics or other reasons cause.
More importantly be that Fructus Aurantii Immaturus that alcohol reflux of the present invention obtains or Fructus Aurantii extractive of general flavone are except that having the effect of significant promotion gastric motility, and be also extremely effective to the vomiting of drug-induceds such as cisplatin, has the unexistent effect of motilium.The heart toxic and side effects that does not have simultaneously cisapride, mosapride again, the cardiac safety risk that can thoroughly avoid cisapride, mosapride to cause.
And medical science and study of pharmacy personnel can't learn that in advance Fructus Aurantii Immaturus or Fructus Aurantii extractive of general flavone that alcohol reflux of the present invention obtains have above-mentioned good effect in advance under the prerequisite of not doing experiment.
In sum, the Fructus Aurantii Immaturus of alcohol reflux acquisition provided by the invention or Fructus Aurantii extractive of general flavone and uses thereof bring significant technique effect.
The specific embodiment
Embodiment 1
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces, add 35% alcohol reflux 3 times of 10 times of volumes, each reflux, extract, 1.5 hours filters; Merging filtrate, filtrate recycling ethanol, the AB-8 macroporous resin of aqueous solution by having handled well, water, 18% ethanol elution are removed impurity successively, and reuse 37% ethanol, 0.5% sodium hydroxide eluting are collected 37% ethanol elution, be evaporated to the fluid extract of relative density about 1.22 (50 ℃), drying under reduced pressure (63 ℃) is pulverized, promptly.
Embodiment 2
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces, add 56% alcohol reflux 3 times of 6 times of volumes, each reflux, extract, 1 hour filters; Merging filtrate, filtrate recycling ethanol, the D101 macroporous resin of aqueous solution by having handled well, water, 16% ethanol elution are removed impurity successively, and reuse 35% ethanol, 0.7% sodium hydroxide eluting are collected 35% ethanol elution, be evaporated to the fluid extract of relative density about 1.20 (55 ℃), drying under reduced pressure (60 ℃) is pulverized, promptly.
Embodiment 3
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces, add 40% alcohol reflux 2 times of 11 times of volumes, each reflux, extract, 1 hour filters; Merging filtrate, filtrate recycling ethanol, the D101 macroporous resin of aqueous solution by having handled well, water, 14% ethanol elution are removed impurity successively, and reuse 40% ethanol, 0.8% sodium hydroxide eluting are collected 40% ethanol elution, be evaporated to the fluid extract of relative density about 1.23 (55 ℃), drying under reduced pressure (65 ℃) is pulverized, promptly.
Embodiment 4
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces, add 45% alcohol reflux 3 times of 5 times of volumes, each reflux, extract, 1 hour filters; Merging filtrate, filtrate recycling ethanol, the D101 macroporous resin of aqueous solution by having handled well, water, 15% ethanol elution are removed impurity successively, and reuse 35% ethanol, 0.6% sodium hydroxide eluting are collected 35% ethanol elution, be evaporated to the fluid extract of relative density about 1.20 (60 ℃), drying under reduced pressure (70 ℃) is pulverized, promptly.
Embodiment 5
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces, add 55% alcohol reflux 2 times of 12 times of volumes, each reflux, extract, 2 hours filters; Merging filtrate, filtrate recycling ethanol, the AB-8 macroporous resin of aqueous solution by having handled well, water, 10% ethanol elution are removed impurity successively, and reuse 45% ethanol, 0.8% sodium hydroxide eluting are collected 45% ethanol elution, be evaporated to the fluid extract of relative density about 1.22 (58 ℃), drying under reduced pressure (65 ℃) is pulverized, promptly.
Embodiment 6
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces, add 50% alcohol reflux 2 times of 7 times of volumes, each reflux, extract, 2 hours filters; Merging filtrate, filtrate recycling ethanol, the D101 macroporous resin of aqueous solution by having handled well, water, 15% ethanol elution are removed impurity successively, and reuse 45% ethanol, 1.1% sodium hydroxide eluting are collected 45% ethanol elution, be evaporated to the fluid extract of relative density about 1.25 (55 ℃), drying under reduced pressure (65 ℃) is pulverized, promptly.
Embodiment 7
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, pulverize, add 60% alcohol reflux 2 times of 8 times of volumes, each reflux, extract, 2.5 hours filters; Merging filtrate, filtrate recycling ethanol, the AB-8 macroporous resin of aqueous solution by having handled well, water, 9% ethanol elution are removed impurity successively, and reuse 42% ethanol, 0.8% sodium hydroxide eluting are collected 42% ethanol elution, be evaporated to the fluid extract of relative density about 1.30 (50 ℃), drying under reduced pressure (65 ℃) is pulverized, promptly.
Embodiment 8
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, pulverize, add 60% alcohol reflux 2 times of 8 times of volumes, each reflux, extract, 2.5 hours filters; Merging filtrate, filtrate recycling ethanol, the AB-8 macroporous resin of aqueous solution by having handled well, water, 14% ethanol elution are removed impurity successively, and reuse 50% ethanol, 0.9% sodium hydroxide eluting are collected 50% ethanol elution, be evaporated to the fluid extract of relative density about 1.30 (55 ℃), drying under reduced pressure (65 ℃) is pulverized, promptly.
Embodiment 9
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, pulverize, add 70% alcohol reflux 2 times of 9 times of volumes, each reflux, extract, 2 hours filters; Merging filtrate, filtrate recycling ethanol, the AB-8 macroporous resin of aqueous solution by having handled well, water, 8% ethanol elution are removed impurity successively, and reuse 45% ethanol, 0.9% sodium hydroxide eluting are collected 45% ethanol elution, be evaporated to the fluid extract of relative density about 1.25 (55 ℃), drying under reduced pressure (70 ℃) is pulverized, promptly.
Embodiment 10
Preparation method: get Fructus Aurantii Immaturus or Fructus Aurantii, pulverize, add 65% alcohol reflux 2 times of 9 times of volumes, each reflux, extract, 2 hours filters; Merging filtrate, filtrate recycling ethanol, the AB-8 macroporous resin of aqueous solution by having handled well, water, 15% ethanol elution are removed impurity successively, and reuse 45% ethanol, 0.9% sodium hydroxide eluting are collected 45% ethanol elution, be evaporated to the fluid extract of relative density about 1.30 (60 ℃), drying under reduced pressure (70 ℃) is pulverized, promptly.
Embodiment 11
Get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces, add 65% alcohol reflux 3 times of 7 times of volumes, each reflux, extract, 1.5 hours filters; Merging filtrate, filtrate recycling ethanol, the D101 macroporous resin column of aqueous solution by having handled well, water, 15% ethanol, 40% ethanol, 1% sodium hydroxide eluting successively, collect 40% ethanol elution, be evaporated to the fluid extract of relative density about 1.30 (60 ℃), drying under reduced pressure (75 ℃), pulverize, promptly.
Embodiment 12
Get Fructus Aurantii Immaturus or Fructus Aurantii, be cut into decoction pieces, add 65% alcohol reflux 2 times of 7 times of volumes, each reflux, extract, 2 hours filters; Merging filtrate, filtrate recycling ethanol, the D101 macroporous resin column of aqueous solution by having handled well, water, 15% ethanol, 45% ethanol, 1% sodium hydroxide eluting successively, collect 45% ethanol elution, be evaporated to the fluid extract of relative density about 1.30 (60 ℃), drying under reduced pressure (75 ℃), pulverize, promptly.
Experimental data 1: extraction process optimization research
Flavonoid glycoside compound generally is soluble in hot water, methanol, ethanol, pyridine and the dilute alkaline soln, and indissoluble or be insoluble in the organic solvents such as benzene, ether, chloroform, petroleum ether.Main active in the Fructus Aurantii Immaturus is to be the flavanone constituents of representative with naringin and neohesperidin, and the polarity of these flavanones is all bigger than general flavones ingredient, in water soluble and the low-concentration ethanol, is soluble in the Diluted Alcohol solution of hot water or heat.
According to the physicochemical property of contained main chemical compositions in the medical material,,, adopt alcohol extraction, the method for purification by macroporous resin on the extracting solution simultaneously in conjunction with the trial test result with reference to relevant document.
Investigate the rate of transform that index is respectively the rate of extract, general flavone content and total flavones
1. the extraction process condition is preferred
1.1 extraction choice of Solvent
The Fructus Aurantii Immaturus pulverizing medicinal materials is crossed 8 mesh sieves, get 12 parts, be divided into 4 groups, every group average three parts, water, 65% ethanol, 95% ethanol and saturated limewater extract separately.The results are shown in Table 1.
Table 1 extracts choice of Solvent
Conclusion: as shown in Table 1, three kinds of extraction solvents are best with 65% ethanol extraction effect, serve as to extract solvent with 65% ethanol therefore.
1.2 the selection of medical material granularity
The Fructus Aurantii Immaturus that crushes is sieved, respectively drink sheet, be broken into the Semen Glycines size particles, three parts in 8 orders, 20 orders, 40 orders, totally 15 parts, add alcohol reflux respectively.The results are shown in Table 2.
The selection of table 2 medical material granularity
Figure BSA00000400091700082
Conclusion: as can be known by relevant data in the table 2, add alcohol reflux, the granularity of medical material has bigger difference, be not that the medical material granule is thin more good more, wherein the highest with the rate of transform that is broken into Semen Glycines size particles and 8 order medical material the rate of extract and total flavonoid glycoside, actual in conjunction with producing, select the Semen Glycines size particles as the final particle size after cracking of medical material.
1.3 the preferred extraction process of orthogonal experiment
According to above experimental result, existing with extraction time in the leaching process (A), extraction time (B), add 65% amount of alcohol (C), extract before four of soak times (D) as the investigation factor, each factor is established three levels, presses L9 (3 4) orthogonal table carries out orthogonal experiment design (table 3, table 4), investigating index is the rate of extract and the total flavonoid glycoside rate of transform.
Table 3 factor level table
Figure BSA00000400091700091
Get 27 parts of Fructus Aurantii Immaturus medical material granules, every group average three parts, totally nine groups, press table 4 L9 (34) orthogonal test table design experiment.The results are shown in Table 4.
Table 4 L9 (3 4) orthogonal test table
Figure BSA00000400091700092
(1) intuitive analysis:
The rate of extract optimised process: B 3C 3A 3D 1(B, C are principal element)
Total flavonoid glycoside rate of transform optimised process: B 3C 3A 1D 1(B, C are principal element)
(2) variance analysis
The results are shown in Table 5.
Table 5 is the variance analysis of index with the total flavonoid glycoside rate of transform
Figure BSA00000400091700101
*F 1-0.05(2，2)＝19.0 **F 1-0.01(2，2)＝99.0
(3) conclusion: intuitive analysis as can be known, extraction time (B) and solvent for use volume (C) are bigger to extraction effect influence, extraction time (A) and soak time (D) are less to the extraction effect influence.With the rate of transform is that index is carried out variance analysis, and table 5 analysis result has further been verified the intuitive analysis conclusion, and promptly set factor B, C have considerable influence to extraction effect.Because factor A is less to decocting influential effect, determine tentatively that thus extraction conditions is that 18 times of amount 65% ethanol (with the medical material weight ratio) are carried (8 times, 5 times, 5 times) 3 times, each extraction time 1h, medical material does not soak.
2. demonstration test
Get 3 parts of Fructus Aurantii Immaturus medical materials (Semen Glycines size particles), carry out demonstration test by the optimum extraction process condition that orthogonal test is chosen, that is: (8 times/1h, 5 times/1h, 5 times/1h) extract respectively 3 times, medical material does not soak 18 times of amount 65% ethanol.The results are shown in Table 6.
Table 6 demonstration test measurement result
Figure BSA00000400091700102
Conclusion: as shown in Table 6, press selection process 65% ethanol extraction 3 times, total flavonoid glycoside is existing to be suggested more than 95%, and three sample total flavonoid glycoside rates of transform more consistent (RSD is 1.88%), and the result shows that the last optimum extraction process of determining is reasonable, stable.
Experimental data 2: the purification research of citrus aurantium total flavone extract
2.1 separation purifying technique is investigated
The Fructus Aurantii Immaturus medical material proposes a large amount of water-solubility impurities after with 65% ethanol extraction, must be further purified processing to 65% ethanol extract, to improve the content of flavonoids effective constituent, water-solubility impurity mostly is inorganic salt, saccharide, pectin and protein-based, and the active component in the Fructus Aurantii Immaturus is a flavone compound, according to flavonoid thing characteristic and present China isolation and purification method commonly used, therefore select to come this flavones ingredient of enriching and purifying with macroporous resin.
Investigate by applied sample amount, determine that finally the macroporous resin adsorption 200g crude drug of 1000ml is as final applied sample amount (being 0.2g crude drug/ml resin).
Afterwards, by the investigation of elution volume, determine that 15% ethanol part elution volume is defined as 3000ml (being every 1ml resin 3ml 15% ethanol elution), selects during 45% ethanol elution with 4000ml (1ml resin 4ml 45% ethanol elution).
Again further, by the investigation of last sample flow velocity, determine to go up the sample flow velocity and should be chosen in better (the last sample flow velocity that is every 1ml resin is between 1.25～1.55ml/h) between 1250ml/h～1550ml/h.
2.2 the orthogonal optimum seeking macroporous resin is optimized technology
According to above experimental result, existing with elution flow rate, macroporous resin blade diameter length ratio and last sample after each factor is established three levels as the investigation factor three of static adsorption times of medicinal liquid, press L 9 (3 4) orthogonal table carries out orthogonal experiment design (table 7, table 8), the investigation index is the content and the total flavonoid glycoside rate of transform of the rate of extract, total flavonoid glycoside.
Table 7 factor level table
Figure BSA00000400091700111
Get and be equivalent to 9 parts of crude drug 200g aqueous solutions, by table 8L9 (3 4) on the macroporous resin (every resin dress 1000ml macroporous resin) of anticipating, use the water of 4000ml, ethanol, 4000ml 45% ethanol and 3000ml 95% ethanol elution of 3000ml 15% respectively.The results are shown in Table 8.
Table 8 L9 (3 4) orthogonal test table
Figure BSA00000400091700112
Figure BSA00000400091700121
(1) intuitive analysis
Analyze the rate of extract optimised process: A according to the R value 1B 1C 3(A is a principal element)
Analyze total flavonoid glycoside rate of transform optimised process: A according to the R value 1B 1C 3(A is a principal element)
(2) variance analysis
The results are shown in Table 9, table 10.
Table 9 is the variance analysis of index with the rate of extract
Figure BSA00000400091700122
Table 10 is the variance analysis of index with the total flavonoid glycoside rate of transform
Figure BSA00000400091700123
*F 1-0.05(2，2)＝19.0 **F 1-0.01(2，2)＝99.0
(3) conclusion: intuitive analysis as can be known, the elution flow rate of resin (A) is a principal element, the static adsorption time (B) of medicinal liquid influence is less behind blade diameter length ratio of macroporous resin (C) and the last sample.The rate of transform with the rate of extract and total flavonoid glycoside is that index is carried out variance analysis, and analysis result has further been verified the intuitive analysis conclusion in the table 9,10, and promptly set factor A has considerable influence to elute effect.Because general flavone content is the leading indicator of this project, column chromatographic column footpath determines tentatively that than suitability for industrialized production reality optimum condition is A 1B 1C 2That is: elution flow rate is 1250～1450ml/h (elution flow rate that is every 1ml resin is between 1.25～1.45ml/h), and blade diameter length ratio is 1: 10, and the static adsorption time of medicinal liquid is 1 hour behind the last sample.
2.3 demonstration test and the test of resin access times
Get Fructus Aurantii Immaturus medical material (Semen Glycines size particles) and add alcohol reflux, reclaim ethanol, aqueous solution is 13 parts, and every part is equivalent to the 200g crude drug, standby.
A. get 1 part and be splined on 1000ml macroporous resin (the resin column blade diameter length ratio is 1: 10), last sample flow velocity is 1400ml/h, static adsorption 1 hour.Ethanol, 4000ml 45% ethanol and 3000ml 95% ethanol elution of water, 3000ml 15% of using 4000ml successively is with the flow velocity eluting of 1400ml/h.Collect 45% ethanol elution and carry out assay.The results are shown in Table 11.
B. with a with after resin do not have the alcohol flavor to be washed to, other gets this resin on the sample of a refrigerator cold-storage, the step reprocessing of pressing a.Resin carries out absorption next time (the same a.b of following steps) successively.
Table 11 demonstration test measurement result
Figure BSA00000400091700131
Conclusion: as can be seen from Table 11 by the demonstration test that optimised process carried out, the sample total flavonoid glycoside content and the total flavonoid glycoside rate of transform that repeat 8 gained all increase.And every index homogeneous of sample, stable, this technology the best, stable is described.Need later on resin is carried out Regeneration Treatment for 8 times in use simultaneously.
2.4 service test after the resin regeneration
5% sodium hydroxide solution of resin with 10 times of amounts soaked 2 hours, wash with water to neutrality; 3% hydrochloric acid solution of 10 times of amounts of reuse soaked 2 hours, washed with water to neutrality.The resin that regeneration is good by the following method absorb-elute 3 times successively of demonstration test and the test of resin access times, calculates the rate of extract, the Liquid Detection total flavonoid glycoside content and the rate of transform.The results are shown in Table 12.
Service test after table 12 resin regeneration
Figure BSA00000400091700141
Operating position was good after the result showed resin regeneration.
According to above-mentioned separation, purification research, merge extractive liquid, after the medicinal material extract filters, the D101 macroporous resin column of filtrate by having handled well, and water, 15% ethanol, 45% ethanol, 1% sodium hydroxide eluting are collected 45% ethanol elution successively.
Experimental data 3: the research of citrus aurantium total flavone extract drying means and baking temperature
Get Fructus Aurantii Immaturus medical material 1kg, totally 10 parts, according to above-mentioned definite extraction, purifying process, behind extraction, purification, collect 45% ethanol elution, decompression recycling ethanol also is concentrated into the extractum of relative density about 1.30 (60 ℃), adopts oven drying method, boulton process to compare research respectively to above-mentioned extractum.Oven drying method and boulton process carry out the comparison of 5 kinds of different temperatures (50 ℃, 65 ℃, 75 ℃, 85 ℃, 95 ℃) respectively.Investigate the content of total flavonoid glycoside.The results are shown in Table 13 and table 14.
The measurement result of table 13 oven drying method different temperatures
Figure BSA00000400091700142
The measurement result of table 14 boulton process different temperatures
Figure BSA00000400091700151
From table 13,14 as can be known, oven drying method is long than the dry required time of vacuum on same temperature levels, and effect is not as vacuum drying.The sample color and luster of oven drying method oven dry is relatively poor, be difficult for pulverizing, and along with the rising of temperature, oven drying method easily causes carbonization because of hot-spot, thereby causes the color sample blackout that effective ingredient is lost.Easy-to-drawly during vacuum drying driedly become cellular, help pulverizing, and color and luster is better, vacuum drying temperature is controlled at about 75 ℃ and is advisable simultaneously, saves time and can not cause losing of effective ingredient.
Below all select for use embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extracts as experimental group
Experimental data 4: effect is told in Fructus Aurantii Immaturus total flavones glucoside extract town
4.1 the Fructus Aurantii Immaturus total flavones glucoside extract causes the influence of pigeon vomiting to copper sulfate
60 of pigeons, body weight 280～350g, male and female half and half.Be divided into 6 groups at random: matched group, embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extracts (20,40,80,160mgkg -1) 4 dosage group and positive drug group (fourth beautiful jade 40mgkg -1), 10 every group, ♀ ♂ half and half.Each is organized the pigeon fasting and can't help water 16 hours, next day single administration, matched group gives distilled water and irritates stomach, other groups are irritated stomach relative medicines, 10mlkg -1Respectively organize pigeon after 1 hour and give 3.5% copper-bath 10mgkg -1Irritate the stomach modeling.Record is respectively organized pigeon vomiting latent time and is vomitted number of times in 2 hours, and result of the test shows, the Fructus Aurantii Immaturus total flavones glucoside extract (20,40,80,160mgkg -1) single administration all can not prolong the vomiting latent time of pigeon due to the copper sulfate, but the Fructus Aurantii Immaturus total flavones glucoside extract (40,80mgkg -1) single administration can reduce the vomiting number of times of pigeon due to the copper sulfate, sees Table 15.
Table 15 Fructus Aurantii Immaturus total flavones glucoside extract causes the influence of pigeon vomiting to copper sulfate
Figure BSA00000400091700152
Figure BSA00000400091700161
Annotate: compare with matched group, *P＜0.05, *P＜0.01
4.2 the Fructus Aurantii Immaturus total flavones glucoside extract causes the influence of pigeon vomiting to cisplatin
80 of pigeons, body weight 280～350g, male and female half and half.Be divided into 8 groups at random: matched group, embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extracts (20,40,80,160mgkg -1) 4 dosage group and positive drug 3 groups of (fourth beautiful jade 80,160mgkg -1With Ondansetron Hydrochloride injection 5ugkg -1) 10 every group, ♀ ♂ half and half.Each is organized the pigeon fasting and can't help water 16 hours, next day single administration, matched group gives distilled water and irritates stomach, other groups give relative medicine, pneumoretroperitoneum injection in 1 hour gives 13mgkg -1Cisplatin for inj.Record is respectively organized pigeon vomiting latent time and is vomitted number of times in 4 hours, and result of the test shows, Fructus Aurantii Immaturus total flavones glucoside extract 80mgkg -1Single administration can prolong the vomiting time of pigeon due to the cisplatin, but 20,40 and 160mgkg -1The time all can not prolong the vomiting time of pigeon due to the cisplatin; The Fructus Aurantii Immaturus total flavones glucoside extract (80,160mgkg -1) single administration can reduce the vomiting number of times of pigeon due to the cisplatin, sees Table 16
Table 16 Fructus Aurantii Immaturus total flavones glucoside extract causes the influence of pigeon vomiting to cisplatin
Figure BSA00000400091700162
Figure BSA00000400091700163
Annotate: compare with matched group, *P＜0.05, *P＜0.01
4.3 the Fructus Aurantii Immaturus total flavones glucoside extract causes the influence of hybrid dog vomiting to apomorphine
56 of hybrid dogs, body weight 8.0～10.0kg, male and female half and half.Be divided into 7 groups at random: matched group, embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extracts (15,30,60,120mgkg -1) 4 dosage group and 2 groups of (motilium 30mgkg of positive drug -1With metoclopramide injection 1mgkg -1), 8 every group, ♀ ♂ half and half.Each is organized the fasting of hybrid dog and can't help water 16 hours, next day single administration, matched group gives distilled water and irritates stomach, other groups give relative medicine and irritate stomach, 5mlkg -1Give 500ugkg after 1 hour -1The apomorphine subcutaneous injection.Record is respectively organized hybrid dog vomiting latent time and is vomitted number of times in 1 hour.Result of the test shows, the Fructus Aurantii Immaturus total flavones glucoside extract (15,30,60,120mgkg -1) single administration all can not reduce apomorphine and cause hybrid dog vomiting number of times; The Fructus Aurantii Immaturus total flavones glucoside extract (15,30,120mgkg -1) also can not prolong the vomiting latent time that apomorphine causes the hybrid dog, but Fructus Aurantii Immaturus total flavones glucoside extract 60mgkg -1The time can prolong the vomiting latent time of hybrid dog, see Table 17.
Table 17 Fructus Aurantii Immaturus total flavones glucoside extract causes the influence of hybrid dog vomiting to apomorphine
Figure BSA00000400091700171
Figure BSA00000400091700172
Annotate: compare with matched group, *P＜0.05
Experimental data 5: the Fructus Aurantii Immaturus total flavones glucoside extract is to the intestinal progradation
5.1 the Fructus Aurantii Immaturus total flavones glucoside extract causes the influence of the low mice of intestinal function to dopamine
70 of mices, body weight 19～22g is divided into 7 groups at random: matched group, model group, embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extracts (25,50,100,200mgkg -1) 4 dosage group and positive drug group (motilium 50mgkg -1), 10 every group, ♀ ♂ half and half.Each is organized the mice fasting and can't help water 16 hours, next day single administration, matched group is irritated the stomach distilled water, other groups give relative medicine and irritate stomach.Except that matched group, all the other mices give 1.7mgkg to each mouse stomach after 30 minutes -1The modeling of dopamine hydrochloride inj subcutaneous injection, 70 mices gavage 2% sodium carboxymethyl cellulose carbon powder suspension 0.2ml10g respectively after 20 minutes -1, mice takes off neck execution after 20 minutes, takes out gastrointestinal immediately, and distance and the small intestinal total length of carbon powder front end to pylorus measured in tiling, calculates with ratio between two and advances percentage rate.Result of the test shows, subcutaneous injection 1.7mgkg -1The dopamine intestinal that can obviously suppress mice advance, the Fructus Aurantii Immaturus total flavones glucoside extract (25,50,100mgkg -1) can improve the mice intestinal propelling activity that suppresses by dopamine, see Table 18.
Table 18 Fructus Aurantii Immaturus total flavones glucoside extract causes the propulsive influence of mice intestinal to dopamine
Figure BSA00000400091700181
Annotate: compare with matched group, △Compare with model group P＜0.05, *P＜0.05, *P＜0.01
5.2 the Fructus Aurantii Immaturus total flavones glucoside extract causes the influence of the low mice of intestinal function to atropine
70 of mices, body weight 19～22g is divided into 7 groups at random: matched group, model group, embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extracts (25,50,100,200mgkg -1) 4 dosage group and positive drug group (motilium 50mgkg -1), 10 every group, ♀ ♂ half and half.Each is organized the mice fasting and can't help water 16 hours, next day single administration, matched group is irritated the stomach distilled water, other groups give relative medicine and irritate stomach.Except that matched group, all the other mices give 2.5mgkg to each mouse stomach after 30 minutes -1The modeling of atropine subcutaneous injection, 70 mices gavage 2% sodium carboxymethyl cellulose carbon powder suspension 0.2ml10g respectively after 20 minutes -1, mice takes off neck execution after 20 minutes, takes out gastrointestinal immediately, and distance and the small intestinal total length of carbon powder front end to pylorus measured in tiling, calculates with ratio between two and advances percentage rate.Result of the test shows, subcutaneous injection 2.5mgkg -1The atropine intestinal that can obviously suppress mice advance Fructus Aurantii Immaturus total flavones glucoside extract 50mgkg -1Can improve the mice intestinal propelling activity that suppresses by atropine, see Table 19.
Table 19 Fructus Aurantii Immaturus total flavones glucoside extract causes the propulsive influence of mice intestinal to atropine
Figure BSA00000400091700191
Figure BSA00000400091700192
Annotate: compare with matched group, △P＜0.05; Compare with model group, *P＜0.05
5.3 the Fructus Aurantii Immaturus total flavones glucoside extract causes the influence of the low mice of intestinal function to epinephrine
70 of mices, body weight 19～22g is divided into 7 groups at random: matched group, model group, embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extracts (25,50,100,200mgkg-1) 4 dosage groups and positive drug groups (motilium 50mgkg-1), 10 every group, ♀ ♂ half and half.Each is organized the mice fasting and can't help water 16 hours, next day single administration, matched group is irritated the stomach distilled water, other groups give relative medicine and irritate stomach.Except that matched group, all the other mices give 0.5mgkg to each mouse stomach after 30 minutes -1The modeling of adrenalin hydrochloride injection subcutaneous injection, 70 mices gavage 2% sodium carboxymethyl cellulose carbon powder suspension 0.2ml10g-1 respectively after 20 minutes, mice takes off neck execution after 20 minutes, take out gastrointestinal immediately, tiling, measure distance and the small intestinal total length of carbon powder front end, calculate with ratio between two and advance percentage rate to pylorus.Result of the test shows, subcutaneous injection 0.5mgkg -1The epinephrine intestinal that can obviously suppress mice advance, the Fructus Aurantii Immaturus total flavones glucoside extract (25,50,100,200mgkg -1) all can not improve mice intestinal propelling activity by epinephrine inhibited, see Table 20.
Table 20 Fructus Aurantii Immaturus total flavones glucoside extract causes the propulsive influence of mice intestinal to epinephrine
Figure BSA00000400091700193
Figure BSA00000400091700194
Annotate: compare with matched group, △ △P＜0.01
Experimental data 6: the Fructus Aurantii Immaturus total flavones glucoside extract is to gastric secretion, gastric acid and pepsic influence
6.1 influence to gastric secretion, gastric acid
48 of rats, body weight 230～270g is divided into 6 groups at random: matched group, embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extracts (20,40,80,160mgkg -1) 4 dosage group and positive drug group (motilium 40mgkg -1), 8 every group, ♀ ♂ half and half.The rat fasting be can't help water 36 hours before the test, gastric infusion of rat, and matched group gives distilled water, and other groups give relative medicine.The administration while, each rat is opened the abdominal cavity under the ether light anaesthesia, the ligation pylorus, and 5 hours rat gastric juice behind the collection pylorus ligation, with the centrifugal 5min of 3000r/min, gastric contents such as place to go food debris are with the accurate weighing gastric juice of graduated cylinder amount.Measure gastric juice 1ml, place conical flask to add the equivalent distilled water, mix homogeneously adds each 2 of free acid indicator 0.5% pair of dimethyl azoaniline alcoholic solution and total acid indicator 0.5% phenolphthalein alcoholic solution, if contain hydrochloric acid, promptly be cherry red in the mixing gastric juice.With the NaOH of burette dropping 0.01mol/L,, limit edged shaking flasks disappears to red, begins to occur till the orange colour.Be the terminal point of free hydrochloric acid.Write down the amount that spends till NaOH no longer deepens to redness, be the terminal point of total acidity.Write down twice titration and spend NaOH solution total amount.Calculate concentration and total secretory volume of free hydrochloric acid and total acid.Result of the test shows, the Fructus Aurantii Immaturus total flavones glucoside extract (20,40,80mgkg -1) gastric secretion of pylorus ligation rat there is not obvious influence, but Fructus Aurantii Immaturus total flavones glucoside extract 160mgkg -1Can reduce the gastric secretion of rat; The Fructus Aurantii Immaturus total flavones glucoside extract (80,160mgkg -1) concentration of can raise pylorus ligation rat free hydrochloric acid and total acid, but each dosage of Fructus Aurantii Immaturus total flavones glucoside extract (20,40,80,160mgkg -1) secretory volume of free hydrochloric acid and total acid there is not influence, see Table 21.
Table 21 Fructus Aurantii Immaturus total flavones glucoside extract is to the influence of rat gastric secretion, free hydrochloric acid and total acid concentration
Figure BSA00000400091700201
Figure BSA00000400091700202
Annotate: compare * P＜0.05, * * P＜0.01 with matched group
6.2 to pepsic influence
The capillary glass-tube that internal diameter 1～2mm thickness is well-balanced is cleaned and to be dried, and gets an amount of Ovum Gallus domesticus album and fully beats even back and use filtered through gauze, and above-mentioned glass capillary is utilized siphonage, fills Ovum Gallus domesticus album (manage planted agent do not have bubble sneak into).Be positioned over then in 85 ℃ of heat steams and make protein coagulating.After cooling, take out paraffin with the sealing of protein pipe two ends, standby in the storage refrigerator.Get the conical flask that gastric juice 1ml puts into 50ml during experiment, add 0.05N hydrochloric acid solution 15ml, shake up, put two of long approximately 2.5cm protein pipe into.Filled in bottleneck, be put in 37 ℃ of calorstats temperature and incubate 24h.Measure the length (mm) of protein pipe two ends transparent part with chi and ask its meansigma methods, calculate pepsic unit=meansigma methods with following formula with the value of four ends 2* 16.Result of the test shows, each dosage of Fructus Aurantii Immaturus total flavones glucoside extract (20,40,80,160mgkg -1) pepsin activity of pylorus ligation rat there is not obvious influence, see Table 22.
Table 22 Fructus Aurantii Immaturus total flavones glucoside extract is to the influence of rat free hydrochloric acid, total acid secretory volume and pepsin activity
Figure BSA00000400091700211
Figure BSA00000400091700212
Experimental data 7: the Fructus Aurantii Immaturus total flavones glucoside extract is to the influence of smooth muscle
7.1 influence to the gastrointestinal smooth muscle that exsomatizes
Select the healthy adult rat for use, the head of fiercelying attack causes dusk, takes out full stomach and duodenum stage casing 1-2cm rapidly, and the place cuts off along greater gastric curvature, with containing 95%O 2And 5%CO 2The Krebs liquid (composition: NaCl 117mmol/L, KCl 4.8mmol/L, CaCl of the fully saturated pH 7.35～7.45 of mist 22.5mmol/L, MgCl 21.2mmol/L, NaH 2PO 41.2mmol/L, NaHCO 325mmol/L, Glucose 11mmol/L) repeatedly the flushing exenterate, get at the bottom of the gastric antrum stomach function regulating longitudinal and transverse flesh bar and duodenum stage casing respectively and be about 1cm, wide about 0.5cm, the ventilation hook is fixed in the bottom, the upper end links to each other with transducer (JH-2 type muscular tension pick off), and it is inserted in the bath pipe that fills oxygen-saturated Krebs liquid (pH 7.35～7.45) 20ml, the adjustment preload is 1g, change liquid once every 20min, in body lotion, inject oxygen by the ventilation hook, use BL-420E biological function experimental system and write down its tension force and frequency.Outer tube through constant current infusion pump [continue, constant temperature (37 ± 0.5 ℃), constant speed (3～4ml/min)] perfusion to keep temperature in the bath.After treating that specimen is stable, add medicine ultimate density to be measured and be respectively 0.25mg/L, 0.4mg/L, 0.55mg/L, 0.7mg/L, 0.85mg/L and 1.00mg/L, record is also observed medication front and back frequency and tension change.The isolated test result shows, embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extract (0.25mg.ml -1～1.0mg.ml -1) can reduce longitudinal and transverse shape flesh and duodenum smooth muscle tension force at the bottom of the gastric antrum stomach function regulating, suppress gastrointestinal motility, see Table 23～27.
Table 23 Fructus Aurantii Immaturus total flavones glucoside extract is to the influence of exsomatize gastric antrum transversal tension force and frequency
Figure BSA00000400091700221
Figure BSA00000400091700222
Annotate: with comparison before the administration, *P＜0.05, *P＜0.01
Table 24 Fructus Aurantii Immaturus total flavones glucoside extract is to the influence of exsomatize gastric antrum longitudinal muscle tension force and frequency
Figure BSA00000400091700223
Annotate: with comparison before the administration, *P＜0.05, *P＜0.01
Table 25 Fructus Aurantii Immaturus total flavones glucoside extract to the stomach that exsomatizes at the bottom of the influence of transversal tension force and frequency
Figure BSA00000400091700225
Figure BSA00000400091700226
Annotate: with comparison before the administration, *P＜0.05, *P＜0.01
Table 26 Fructus Aurantii Immaturus total flavones glucoside extract to the stomach that exsomatizes at the bottom of the influence of longitudinal muscle tension force and frequency
Figure BSA00000400091700232
Annotate: with comparison before the administration, *P＜0.05, *P＜0.01
Table 27 Fructus Aurantii Immaturus total flavones glucoside extract is to the influence of exsomatize duodenum stage casing tension force and frequency
Figure BSA00000400091700233
Figure BSA00000400091700234
Annotate: with comparison before the administration, *P＜0.05, *P＜0.01
7.2 to influence at body duodenum smooth muscle
56 of rats, body weight 180～230g is divided into 7 groups at random: matched group, model group, embodiment 12 Fructus Aurantii Immaturus total flavones glucoside extracts (20,40,80,160mgkg -1) 4 dosage group and positive drug group (fourth beautiful jade 40mgkg -1), 8 every group, ♀ ♂ half and half.The rat oral gavage administration, matched group and model group give distilled water, and other groups give relative medicine.Each is organized the rat fasting and can't help water 16 hours, next day single administration, except that matched group, all the other rats give 1.5mgkg to each rat oral gavage after 30 minutes -1The modeling of dopamine hydrochloride inj subcutaneous injection, chloral hydrate anesthesia, open the abdominal cavity along the abdomen median line, select the duodenum about 2-3cm in stage casing, be fixed on the intestinal segment two ends on the aperture of intestinal tube stationary pipes both sides with stitching thread, stitching thread of reuse is sewn on an end on the intermediary intestinal wall of intestinal segment, and the other end is passed by intestinal tube stationary pipes central authorities and is connected on the JH-2 type muscular tension pick off, and writes down the tension force and the frequency of each rat preduodenal by BL-420E biological function experimental system.Result of the test shows, subcutaneous injection 1.5mgkg -1Dopamine can obviously be suppressed at the tension force and the frequency of body rat preduodenal, the Fructus Aurantii Immaturus total flavones glucoside extract (20,40,80,160mgkg -1) can improve tension force and frequency by the rat preduodenal of dopamine inhibition, see Table 28.
Table 28 Fructus Aurantii Immaturus total flavones glucoside extract is to the influence in body duodenum stage casing tension force and frequency
Figure BSA00000400091700241
Figure BSA00000400091700242
Annotate: compare with matched group, △P＜0.05; Compare with model group, *P＜0.05, *P＜0.01

Claims (24)

1.一种枳实或枳壳总黄酮提取物，通过将枳实或枳壳用乙醇回流提取得到，其中乙醇回流提取方法是：取枳实或枳壳，切成饮片或粉碎，加5～16倍体积的30％～90％乙醇回流提取1～3次，每次回流提取1～3小时，滤过；合并滤液，滤液回收乙醇，水溶液通过已处理好的非极性大孔树脂，依次用水、20％以下的乙醇洗脱除去杂质，再用25％～90％乙醇、0.5％～2％氢氧化钠洗脱，收集乙醇洗脱液，减压浓缩至相对密度约1.20～1.40(50℃～70℃)的流浸膏，减压干燥，干燥的温度为60～80℃，粉碎，即得。1. An extract of total flavonoids from Fructus Fructus Fructus or Fructus Fructus Aurantii, obtained by refluxing Fructus Fructus Fructus or Fructus Aurantii with ethanol, wherein the ethanol reflux extraction method is: get Fructus Fructus Fructus Fructus Fructus Fructus or Fructus Fructus Citrifolia, cut into decoction pieces or pulverize, add 5～ 16 times the volume of 30% ~ 90% ethanol reflux extraction 1 ~ 3 times, each reflux extraction 1 ~ 3 hours, filtered; combined filtrate, filtrate recovery ethanol, aqueous solution through the treated non-polar macroporous resin, followed by Elute with water and ethanol below 20% to remove impurities, then elute with 25% to 90% ethanol and 0.5% to 2% sodium hydroxide, collect the ethanol eluate, concentrate under reduced pressure to a relative density of about 1.20 to 1.40 (50 ℃～70 ℃), dry under reduced pressure, the drying temperature is 60～80 ℃, pulverize, to get final product. 2.如权利要求1所述的枳实或枳壳总黄酮提取物，具体的乙醇回流提取方法如下：取枳实或枳壳，切成饮片或粉碎，加6～14倍体积的40％～85％乙醇回流提取2～3次，每次回流提取1～2.5小时，滤过；合并滤液，滤液回收乙醇，水溶液通过已处理好的非极性大孔树脂，依次用水、20％以下的乙醇洗脱除去杂质，再用30％～85％乙醇、0.5％～1.8％氢氧化钠洗脱，收集乙醇洗脱液，减压浓缩至相对密度约1.25～1.40(55℃～70℃)的流浸膏，减压干燥，干燥的温度为65～80℃，粉碎，即得。2. Fructus Aurantii or Fructus Aurantii total flavonoids extract as claimed in claim 1, concrete ethanol reflux extraction method is as follows: get Fructus Aurantii or Fructus Aurantii, cut into decoction pieces or pulverize, add 40%～14 times of volume Reflux extraction with 85% ethanol for 2 to 3 times, each time for 1 to 2.5 hours, and filter; combine the filtrate, recover ethanol from the filtrate, and pass the aqueous solution through the treated non-polar macroporous resin, followed by water, ethanol below 20% Elute to remove impurities, then elute with 30% to 85% ethanol and 0.5% to 1.8% sodium hydroxide, collect the ethanol eluate, and concentrate under reduced pressure to a flow with a relative density of about 1.25 to 1.40 (55°C to 70°C). The extract is dried under reduced pressure at a drying temperature of 65-80°C, crushed, and obtained. 3.如权利要求1或2所述的枳实或枳壳总黄酮提取物，具体的乙醇回流提取方法如下：取枳实或枳壳，切成饮片或粉碎，加7～12倍体积的45％～80％乙醇回流提取2～3次，每次回流提取1.5～2.5小时，滤过；合并滤液，滤液回收乙醇，水溶液通过已处理好的非极性大孔树脂，依次用水、20％以下的乙醇洗脱除去杂质，再用35％～75％乙醇、0.5～1.6％氢氧化钠洗脱，收集乙醇洗脱液，减压浓缩至相对密度约1.25～1.35(55℃～65℃)的流浸膏，减压干燥，干燥的温度为70～80℃，粉碎，即得。3. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as claimed in claim 1 or 2, concrete ethanol reflux extraction method is as follows: get Fructus Fructus Aurantii or Fructus Aurantii, cut into decoction pieces or pulverize, add 7～12 times of volumes of 45 %-80% ethanol reflux extraction 2-3 times, each reflux extraction 1.5-2.5 hours, filtered; combined filtrate, filtrate recovered ethanol, aqueous solution passed through the treated non-polar macroporous resin, followed by water, 20% or less ethanol to remove impurities, then elute with 35% to 75% ethanol and 0.5 to 1.6% sodium hydroxide, collect the ethanol eluate, concentrate under reduced pressure to a relative density of about 1.25 to 1.35 (55°C to 65°C) Fluid extract, dried under reduced pressure at 70-80°C, crushed to obtain. 4.如权利要求1-3任一项所述的枳实或枳壳总黄酮提取物，具体的乙醇回流提取方法如下：取枳实或枳壳，切成饮片或粉碎，加7～11倍体积的55％～75％乙醇回流提取2～3次，每次回流提取1.5～2小时，滤过；合并滤液，滤液回收乙醇，水溶液通过已处理好的非极性大孔树脂，依次用水、20％以下的乙醇洗脱除去杂质，再用40％～65％乙醇、0.5～1.3％氢氧化钠洗脱，收集乙醇洗脱液，减压浓缩至相对密度约1.30～1.35(60℃～65℃)的流浸膏，减压干燥，干燥的温度为70～75℃，粉碎，即得。4. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as described in any one of claim 1-3, concrete ethanol reflux extraction method is as follows: get Fructus Aurantii or Fructus Aurantii, cut into decoction pieces or pulverize, add 7～11 times 55% to 75% of the volume of ethanol was refluxed for 2 to 3 times, each refluxed for 1.5 to 2 hours, filtered; the filtrate was combined, the ethanol was recovered from the filtrate, and the aqueous solution was passed through the treated non-polar macroporous resin, followed by water, Elute with less than 20% ethanol to remove impurities, then elute with 40% to 65% ethanol and 0.5 to 1.3% sodium hydroxide, collect the ethanol eluate, concentrate under reduced pressure to a relative density of about 1.30 to 1.35 (60°C to 65 ℃) liquid extract, dried under reduced pressure, the drying temperature is 70-75 ℃, pulverized, to get final product. 5.如权利要求1-4任一项所述的枳实或枳壳总黄酮提取物，具体的乙醇回流提取方法如下：取枳实或枳壳，切成饮片或粉碎，加9倍体积的65％乙醇回流提取3次，每次回流提取1.5小时，滤过；合并滤液，滤液回收乙醇，水溶液通过已处理好的非极性大孔树脂，依次用水、20％以下的乙醇洗脱除去杂质，再用40％～55％乙醇、0.8～1.2％氢氧化钠洗脱，收集乙醇洗脱液，减压浓缩至相对密度约1.30(60℃)的流浸膏，减压干燥，干燥的温度为75℃，粉碎，即得。5. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as described in any one of claim 1-4, concrete ethanol reflux extraction method is as follows: get Fructus Aurantii or Fructus Aurantii, be cut into decoction pieces or pulverize, add 9 times of volume Reflux extraction with 65% ethanol for 3 times, reflux extraction for 1.5 hours each time, and filter; combine the filtrates, recover ethanol from the filtrates, pass the aqueous solution through the treated non-polar macroporous resin, and then elute with water and ethanol below 20% to remove impurities , and then eluted with 40% to 55% ethanol and 0.8 to 1.2% sodium hydroxide, collected the ethanol eluate, concentrated under reduced pressure to a liquid extract with a relative density of about 1.30 (60°C), dried under reduced pressure, and dried at a temperature of 75 ° C, crushed, that is. 6.如权利要求1-4任一项所述的枳实或枳壳总黄酮提取物，具体的乙醇回流提取方法如下：取枳实或枳壳，切成饮片或粉碎，加7～9倍体积的60％～70％乙醇回流提取2次，每次回流提取1.5小时，滤过；合并滤液，滤液回收乙醇，水溶液通过已处理好的非极性大孔树脂，依次用水、20％以下的乙醇洗脱除去杂质，再用40％～55％乙醇、0.7％～1.3％氢氧化钠洗脱，收集乙醇洗脱液，减压浓缩至相对密度约1.30(60℃)的流浸膏，减压干燥，干燥的温度为75℃，粉碎，即得。6. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as described in any one of claim 1-4, concrete ethanol reflux extraction method is as follows: get Fructus Aurantii or Fructus Aurantii, cut into decoction pieces or pulverize, add 7～9 times 60% to 70% of the volume of ethanol was refluxed and extracted twice, each time refluxed for 1.5 hours, and filtered; the filtrate was combined, the ethanol was recovered from the filtrate, and the aqueous solution was passed through the treated non-polar macroporous resin, followed by water, 20% or less Remove impurities by ethanol elution, then elute with 40% to 55% ethanol and 0.7% to 1.3% sodium hydroxide, collect the ethanol eluate, concentrate under reduced pressure to a fluid extract with a relative density of about 1.30 (60°C), reduce Press and dry, the drying temperature is 75°C, and pulverize to obtain. 7.如权利要求1-4任一项所述的枳实或枳壳总黄酮提取物，具体的乙醇回流提取方法如下：取枳实或枳壳，切成饮片或粉碎，加8倍体积的70％乙醇回流提取2次，每次回流提取2小时，滤过；合并滤液，滤液回收乙醇，水溶液通过已处理好的非极性大孔树脂，依次用水、20％以下的乙醇洗脱除去杂质，再用40％～50％乙醇、0.9％～1.1％氢氧化钠洗脱，收集乙醇洗脱液，减压浓缩至相对密度约1.30(60℃)的流浸膏，减压干燥，干燥的温度为75℃，粉碎，即得。7. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as described in any one of claim 1-4, concrete ethanol reflux extraction method is as follows: get Fructus Aurantii or Fructus Aurantii, be cut into decoction pieces or pulverize, add 8 times of volume 70% ethanol reflux extraction twice, reflux extraction for 2 hours each time, filtered; combined filtrate, filtrate recovered ethanol, aqueous solution passed through the treated non-polar macroporous resin, followed by water, ethanol below 20% to remove impurities , and then eluted with 40% to 50% ethanol and 0.9% to 1.1% sodium hydroxide, collected the ethanol eluate, concentrated under reduced pressure to a liquid extract with a relative density of about 1.30 (60°C), dried under reduced pressure, and dried The temperature is 75 ℃, crushed, that is. 8.如权利要求1-4任一项所述的枳实或枳壳总黄酮提取物，具体的乙醇回流提取方法如下：取枳实或枳壳，切成饮片，加7倍体积的65％乙醇回流提取2次，每次回流提取2小时，滤过；合并滤液，滤液回收乙醇，水溶液通过已处理好的D101大孔树脂柱，依次用水、15％乙醇、45％乙醇、1％氢氧化钠洗脱，收集45％乙醇洗脱液，减压浓缩至相对密度约1.30(60℃)的流浸膏，减压干燥，干燥的温度为75℃，粉碎，即得。8. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as described in any one of claim 1-4, concrete ethanol reflux extraction method is as follows: get Fructus Fructus Aurantii or Fructus Aurantii, cut into decoction pieces, add 65% of 7 times of volume Ethanol reflux extraction twice, each reflux extraction for 2 hours, filtered; combined filtrate, filtrate recovered ethanol, the aqueous solution passed through the treated D101 macroporous resin column, followed by water, 15% ethanol, 45% ethanol, 1% hydrogenation For sodium elution, collect the 45% ethanol eluate, concentrate under reduced pressure to a liquid extract with a relative density of about 1.30 (60°C), dry under reduced pressure at 75°C, and pulverize to obtain. 9.如权利要求8所述的枳实或枳壳总黄酮提取物，其中15％乙醇部分洗脱体积为每1ml树脂用3ml洗脱，45％乙醇洗脱时选择每1ml树脂用4ml洗脱。9. Fructus Fructus Aurantii or Fructus Aurantii total flavonoids extract as claimed in claim 8, wherein 15% ethanol part elution volume is that every 1ml resin is eluted with 3ml, when 45% ethanol elution selects every 1ml resin with 4ml elution . 10.如权利要求1-9任一项所述的枳实或枳壳总黄酮提取物，其中枳实或枳壳破碎成黄豆大小颗粒。10. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as described in any one of claim 1-9, wherein Fructus Fructus Aurantii or Fructus Aurantii is broken into soybean size particle. 11.如权利要求1～10任一项所述的枳实或枳壳总黄酮提取物，其中总黄酮含量50％以上。11. The total flavonoid extract of Fructus Aurantii or Fructus Aurantii as described in any one of claims 1 to 10, wherein the total flavonoid content is more than 50%. 12.如权利要求11所述的枳实或枳壳总黄酮提取物，其中总黄酮含量80％以上。12. the Fructus Aurantii or Fructus Aurantii total flavone extract as claimed in claim 11, wherein the total flavonoid content is more than 80%. 13.如权利要求1～12任一项所述的枳实或枳壳总黄酮提取物，其中还包含黄酮类化学成分及其医学上可以接受的酚酸类成分，黄酮类化学成分含柚皮苷、新橙皮苷、橙皮苷、新柚皮苷、野漆树苷及其苷元中的一种或多种。13. the total flavonoids extract of Fructus Aurantii or Fructus Aurantii as described in any one of claims 1～12, wherein also comprise flavonoid chemical composition and its medically acceptable phenolic acid composition, flavonoid chemical composition contains pomelo peel One or more of glycosides, neohesperidin, hesperidin, neonaringin, rhodolin and their aglycones. 14.如权利要求13所述的枳实或枳壳总黄酮提取物，其中柚皮苷含量、新橙皮苷含量分别达25％以上。14. The total flavonoids extract of Fructus Aurantii or Fructus Aurantii as claimed in claim 13, wherein the contents of naringin and neohesperidin reach more than 25% respectively. 15.如权利要求1～14任一项所述的枳实或枳壳总黄酮提取物，其中大孔树脂上样量按树脂体积(ml)∶生药质量(g)为5∶1。15. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as described in any one of claims 1～14, wherein macroporous resin sample amount is 5: 1 by resin volume (ml): crude drug quality (g). 16.如权利要求1～15任一项所述的枳实或枳壳总黄酮提取物，其中每1ml树脂的上样流速在1.25～1.55ml/h之间。16. The total flavonoids extract of Aurantii Fructus or Fructus Aurantii as described in any one of claims 1 to 15, wherein the sample loading flow rate per 1 ml of resin is between 1.25 to 1.55 ml/h. 17.如权利要求1-16任一项所述的枳实或枳壳总黄酮提取物，其中每1ml树脂的洗脱流速为1.25～1.45ml/h之间，所述非极性大孔树脂径高比为1∶10，上样后药液的静态吸附时间为1小时。17. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as described in any one of claim 1-16, wherein the elution flow rate of every 1ml resin is between 1.25～1.45ml/h, and described nonpolar macroporous resin The diameter-to-height ratio is 1:10, and the static adsorption time of the drug solution after loading the sample is 1 hour. 18.如权利要求1-17任一项所述的枳实或枳壳总黄酮提取物，其中所述非极性大孔树脂重复8次后用10倍量的5％氢氧化钠溶液浸泡2小时，用水洗至中性；再用10倍量的3％盐酸溶液浸泡2小时，用水洗至中性以再生后使用。18. the Fructus Aurantii or Fructus Aurantii total flavonoids extract as described in any one of claim 1-17, soak 2 with the 5% sodium hydroxide solution of 10 times of amount after repeating 8 times Hours, washed with water until neutral; then soaked in 10 times the amount of 3% hydrochloric acid solution for 2 hours, washed with water until neutral for regeneration and use. 19.权利要求1～18任一项所述的枳实或枳壳总黄酮提取物用于制备治疗胃肠运动障碍型功能性消化不良疾病药物的用途。19. The use of the total flavonoid extract of Fructus Aurantii or Fructus Aurantii according to any one of claims 1 to 18 for preparing a drug for treating gastrointestinal motility disorder type functional dyspepsia. 20.权利要求1～18任一项所述的枳实或枳壳总黄酮提取物用于制备治疗化疗药物或其他原因引起的呕吐疾病药物的用途。20. The use of the total flavonoid extract of Fructus Aurantii or Fructus Aurantii according to any one of claims 1 to 18 for the preparation of drugs for treating chemotherapy drugs or other causes of vomiting. 21.权利要求1～18任一项所述的枳实或枳壳总黄酮提取物用于制备治疗上腹疼痛疾病药物的用途。21. The use of the total flavonoid extract of Fructus Aurantii or Fructus Aurantii according to any one of claims 1 to 18 for the preparation of medicines for treating epigastric pain diseases. 22.权利要求1～18任一项所述的枳实或枳壳总黄酮提取物用于制备治疗腹胀、厌食、嗳气疾病药物的用途。22. The use of the total flavonoid extract of Fructus Aurantii or Fructus Aurantii according to any one of claims 1 to 18 for preparing medicines for treating abdominal distension, anorexia and belching. 23.权利要求1～18任一项所述的枳实或枳壳总黄酮提取物用于制备治疗恶心疾病药物的用途。23. The use of the total flavonoid extract of Fructus Aurantii or Fructus Fructus Fructus of any one of claims 1 to 18 for preparing a medicine for treating nausea. 24.一种枳实或枳壳总黄酮提取物制剂，该制剂以权利要求1～18任一项所述的枳实或枳壳总黄酮提取物为主要活性成分。24. A preparation of total flavonoids extract of Fructus Aurantii or Fructus Aurantii, which uses the Fructus Aurantii or total flavonoids extract of Fructus Aurantii according to any one of claims 1 to 18 as the main active ingredient.
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CN109316487A (en) * 2018-11-20 2019-02-12 河南中医药大学 A kind of extraction method and application of components for treating respiratory inflammation in Fructus Aurantii
CN109316487B (en) * 2018-11-20 2021-03-19 河南中医药大学 A kind of extraction method and application of components for treating respiratory inflammation in Fructus Aurantii
CN109912666A (en) * 2019-03-14 2019-06-21 重庆市铜梁区子奇药材有限公司 A method of extracting high-purity aurantiin and neohesperidin simultaneously from Fructus Aurantii
CN109912666B (en) * 2019-03-14 2023-04-11 重庆市铜梁区子奇药材有限公司 Method for simultaneously extracting high-purity naringin and neohesperidin from fructus aurantii
CN113616744A (en) * 2021-09-01 2021-11-09 山西大学 Preparation method and application of millet whole grain flavone active component

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