CN103211858B - Si-Jun-Zi dropping pill preparation - Google Patents
Si-Jun-Zi dropping pill preparation Download PDFInfo
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- CN103211858B CN103211858B CN201310148576.8A CN201310148576A CN103211858B CN 103211858 B CN103211858 B CN 103211858B CN 201310148576 A CN201310148576 A CN 201310148576A CN 103211858 B CN103211858 B CN 103211858B
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Abstract
The invention discloses a Si-Jun-Zi dropping pill preparation comprising volatile oil, Si-Jun-Zi total polysaccharides and matrixes, wherein the volatile oil is obtained through carrying out carbon dioxide supercritical extraction on roasted white atractylodes rhizome; the Si-Jun-Zi total polysaccharides are extracted from the following four raw medicines in parts by mass: 2 parts of codonopsis pilosula, 2 parts of roasted white atractylodes rhizome residue, 2 parts of poria cocos and 1 part of prepared licorice root, and the roasted white atractylodes rhizome residue is the residual substance after the volatile oil is obtained through carrying out carbon dioxide supercritical extraction on the roasted white atractylodes rhizome; the matrixes are xylitol and hydroxypropyl methyl cellulose; and the mass ratio of the Si-Jun-Zi total polysaccharides to the volatile oil to xylitol to hydroxypropyl methyl cellulose is 1:(0.01-0.03):(4-5):(0.01-0.03). According to the invention, xylitol and hydroxypropyl methyl cellulose are cooperatively used and the prepared dropping pill is good in hardness, so that the fragile problem of the dropping pill is solved and the characteristics of capability of dropping and condensing of the dropping pill are not influenced. Proved by experiments, the Si-Jun-Zi dropping pill disclosed by the invention has stronger effects on the aspects of nourishing qi, invigorating spleen and promoting enterogastric movement.
Description
Technical field
The invention belongs to field of pharmaceutical technology, relate to a kind of four gentleman's dropping pill formulations, its main active substances is total polysaccharides.
Background technology
Decoction of four noble drugs sees the earliest " Song's formulary of peaceful benevolent dispensary ", is the square foundation of air making-up and spleen enlivening, adopts Radix Ginseng in former side, but conventional Radix Codonopsis replaces Radix Ginseng in modern Chinese medicine medication.In Chinese Pharmacopoeia (2010 editions), it is made up of Radix Codonopsis, Poria, Rhizoma Atractylodis Macrocephalae (parched), Radix Glycyrrhizae Preparata four Chinese medicine, and mass ratio is 2:2:2:1, has effect of replenishing QI to invigorate the spleen, cures mainly battalion's deficiency of defensive qi, and representing prescription is decoction of four noble drugs.
Polysaccharide compound, as a kind of novel drugs, has the advantages such as toxic and side effects is little, safety is high, good effect, therefore in clinical practice, demonstrates more and more wide prospect.Now confirm, polysaccharide has the biologic activity widely such as antitumor and immunological enhancement, antiinflammatory, antiviral, anticoagulation, blood sugar lowering.Four gentleman's total polysaccharidess are the same with other Pharmaceutical Polysaccharides has extensive pharmacological action, wherein the most remarkable to the immunization of body.
Immunoregulation effect: immunoreation relates generally to macrophage and lymphocyte.Liu Liang etc. with the mice of the cyclophosphamide of 100mg/kg dosage induction gut associated lymphatic tissue injury for model, oral give decoction of four noble drugs total polysaccharides after, Peyer ' s footing amount returns to normal level substantially, and Peyer ' s ties inner cell quantity, CD3
+and IgA
+cell quantity also all has and to a certain degree rises, and this experiment shows that the administration of decoction of four noble drugs total polysaccharide oral administration has the effect to a certain degree improving gut mucosal immune function.Liu Yuhong detects the impact on HepG2 cell lines and mouse spleen lymphocyte hypertrophy of decoction of four noble drugs total polysaccharides by adopting tetrazolium bromide (MTT) method, result shows, decoction of four noble drugs total polysaccharides has no significant effect HepG2 cell in vitro, but can significantly promote splenocyte hypertrophy, prove the immunity of four gentleman's polysaccharide energy enhancing body from another point of view.
Antitumor action: tumor cell has unlimited value-added ability, once canceration occurs tissue, its cell will infinitely rise in value rapidly.The polysaccharide with antitumor action is mainly divided into two classes, and a class has direct cytotoxic activity to tumor cell, in vitro can direct killing off tumor cells; The another kind of immunization antitumor indirectly by enhancing body.Liu Yuhong adopts tetrazolium bromide (MTT) method to detect the impact on HepG2 cell lines and mouse spleen lymphocyte hypertrophy of decoction of four noble drugs total polysaccharides.Result shows that decoction of four noble drugs total polysaccharides does not have the effect of direct Tumor suppression and acellular toxic action, but polysaccharide component wherein passes through the growth of its immunological enhancement active energy Tumor suppression.This is consistent with the idea of Chinese medicine compound wholistic therapy, meets the feature for the treatment of by Chinese herbs tumor.Li Zhuangang proves that decoction of four noble drugs can inducing mouse bladder cancer apoptosis of tumor cells by experiment, mouse tumor is characteric apoptotic form under being organized in Electronic Speculum, experiment simultaneously shows that heavy dose of decoction of four noble drugs can obviously promote to express, and tumor cell shows as the representative configuration of apoptosis under Electronic Speculum.This proves that decoction of four noble drugs plays antitumor action by directly and indirectly approach.
Anti-gastrointestinal disease effect: decoction of four noble drugs is the basic prescription of invigorating the spleen and benefiting QI, syndrome of deficiency of spleen qi is multisystem centered by digestive system, multiple organ dysfunction syndrome group, namely based on digestion, motion, malabsorption.The research such as Peng Cheng finds decoction of four noble drugs to gastric juice amount, gastric acid pH value without impact, but obviously can increase the content of chief cell endoenzyme unit granule, improve the length of coagulated protein in pepsin digestion capillary glass-tube, by promoting the synthesis of pepsinogen, improve pepsic activity, thus improve digestion power.Wang Wenbo etc. report decoction of four noble drugs and are used for the treatment of functional dyspepsia disease, result shows, decoction of four noble drugs treatment functional dyspepsia determined curative effect, the poor appetite occurred clinical syndrome of spleen-deficiency patients with functional dyspepsia, abdominal distention, loose stool, weak etc. have good therapeutical effect, overall clinical efficacy rate reaches 92.3%.
The existing dosage form of four gentleman, what pharmacopeia was recorded only has four gentleman's pills, market has four gentleman's granules, Sijunzi mixture, medicinal tea, pill (watered pill).By the improving dosage form to four gentleman's compound recipes, improve therapeutic effect further, for patient provides taking convenience, the novel form of therapeutic effect excellence, has certain society and economy meaning.Compare with injection, drop pill remains the feature that onset is very fast, bioavailability is high to a certain extent, Chinese medicine injection can be avoided again directly to enter acute toxicity that blood may cause and anaphylaxis.
Relative to other dosage forms, dropping pill formulation absorbs fast, the drop pill prepared with water-soluble base, and dissolve scattered time limit is mostly at 5 ~ 15min, be no more than 30min, so rapid-action, drop pill removes can be oral, also can sublingual administration, absorb directly into blood by oral mucosa, onset is faster.Dropping pill formulation is the same with tablet, also can be made into slow releasing preparation, particularly for the chemical medicine that some half-life is shorter, making after sustained-release dropping pill can obvious prolong half-life, this kind of drop pill medicine slow releasing from carrier, maintaining medicine desired concn, can be long-acting, oral administration, except reaching except slow releasing function, also can reduce the deactivation at digestive tract and liver.Drop pill compares with other peroral dosage forms, and volume is little, and quality is light, uses convenient.Take not by ante cibum or affect after meal, component uses more convenient, overcomes the drawback of some medicine once oral half or 1/4.Clinical practice shows, topical application drop pill medicine has the features such as concentration is high, not easily loss, drug effect is long, times for spraying is few.Drop pill preparation time is short, and range of temperature is little, and medicine stability increases, and is also applicable to costly medicine, oxidizable, facile hydrolysis, easily draws preparation that is wet and volatility medicine.These features of drops, four gentleman's preparations that to be very suitable for polysaccharide, volatile oil be main active.
Summary of the invention
The object of this invention is to provide a kind of four gentleman's dropping pill formulations being main component with total polysaccharides, volatile oil.Four gentleman's drop pill of the present invention are for replenishing QI to invigorate the spleen and promote that there is stronger effect gastrointestinal motility aspect.
Four gentleman's dropping pill formulations provided by the present invention, are specifically made up of volatile oil, four gentleman's total polysaccharidess and substrate;
Described volatile oil is that Rhizoma Atractylodis Macrocephalae (parched) obtains through carbon dioxide supercritical fluid extraction;
Described four gentleman's total polysaccharidess are extracted and are obtained from four kinds of crude drug of following mass fraction: Radix Codonopsis 2 parts, Rhizoma Atractylodis Macrocephalae (parched) residue 2 parts, 2 parts, Poria, Radix Glycyrrhizae Preparata 1 part, and described Rhizoma Atractylodis Macrocephalae (parched) residue is for by Rhizoma Atractylodis Macrocephalae (parched) remaining material after volatile oil described in described carbon dioxide supercritical fluid extraction;
Described substrate is xylitol and hydroxypropyl emthylcellulose (HPMC);
The quality proportioning of described four gentleman's total polysaccharidess, described volatile oil, described xylitol and described hydroxypropyl emthylcellulose is 1:0.01 ~ 0.03:4 ~ 5:0.01 ~ 0.03.
Adopt the xylitol of natural botanical source to be substrate, be due to its good biocompatibility, biodegradable, have no side effect.By xylitol and hydroxypropyl emthylcellulose with the use of, drop pill can be made to have good hardness, both solved the problem that drop pill is frangible, do not affect again the condensing characteristic of its dripping process, meanwhile, hydroxypropyl emthylcellulose has slow releasing function, is beneficial to the absorption of effective ingredient.
In one embodiment of the invention, the quality proportioning of described four gentleman's total polysaccharidess, described volatile oil, described xylitol and described hydroxypropyl emthylcellulose (HPMC) is specially 1:0.01:4:0.016.
In the present invention, the condition of described carbon dioxide supercritical fluid extraction is specially pressure 40 ~ 45MPa, temperature 35 ~ 45 DEG C, time 1.5 ~ 2h.In one embodiment of the invention, the condition of described carbon dioxide supercritical fluid extraction is specially pressure 45MPa, temperature 40 DEG C, time 2h.
Another object of the present invention is to provide the preparation method of four gentleman's dropping pill formulations.
The preparation method of four gentleman's dropping pill formulations provided by the present invention specifically can comprise the steps:
(1) adopt the volatile oil in carbon dioxide supercritical fluid extraction Rhizoma Atractylodis Macrocephalae (parched), collect Rhizoma Atractylodis Macrocephalae (parched) residue simultaneously;
(2) after described for step (1) Rhizoma Atractylodis Macrocephalae (parched) residue being mixed according to following portions by weight with Radix Codonopsis, Poria and Radix Glycyrrhizae Preparata, extract four gentleman's total polysaccharidess: after the mixing of described Radix Codonopsis 2 parts, described Rhizoma Atractylodis Macrocephalae (parched) residue 2 parts, 2 parts, described Poria, described Radix Glycyrrhizae Preparata 1 part, extract four gentleman's total polysaccharidess;
(3) described four gentleman's total polysaccharidess, described volatile oil, xylitol and hydroxypropyl emthylcellulose are prepared four gentleman's dropping pill formulations according to the ratio that quality proportioning is 1:0.01 ~ 0.03:4 ~ 5:0.01 ~ 0.03.
In said method step (1), the condition of described carbon dioxide supercritical fluid extraction can be 40 ~ 45MPa, temperature 35 ~ 45 DEG C, time 1.5 ~ 2h; In one embodiment of the invention, the condition of described carbon dioxide supercritical fluid extraction is specially pressure 45MPa, temperature 40 DEG C, time 2h; In step (3), the quality proportioning of described four gentleman's total polysaccharidess, described volatile oil, described xylitol and described hydroxypropyl emthylcellulose specifically can be 1:0.01:4:0.016.
In described four gentleman's dropping pill formulations and preparation method thereof, the extracting method of described four gentleman's total polysaccharidess can comprise the step of carrying out enzymolysis removal albumen with the Aqueous extracts of protease to four kinds of crude drug (quality proportioning is the same).
The Aqueous extracts of described four kinds of crude drug prepares according to the method comprised the steps: (a1) adds the petroleum ether of 5 times of weight in described four kinds of crude drug, and reflux, extract, 1h, volatilizes described petroleum ether;
(a2) by the 85%(volume fraction of step (a1) gained medicinal residues by described four kinds of crude drug 5 times of weight) ethanol extraction 1h, volatilize described ethanol;
(a3) by the distilled water reflux, extract, of step (a2) gained medicinal residues by described four kinds of crude drug 10 times of weight, thus the Aqueous extracts of described four kinds of crude drug is obtained.
In one embodiment of the invention, described protease is specially papain.
Can be 50-60 DEG C by the temperature of described papain enzymolysis, pH value can be 5-6, and enzymolysis time can be 3h; The proportioning of described papain and described crude drug can be 240-360U:100g.In one embodiment of the invention, be specially 50 DEG C by the temperature of described papain enzymolysis, pH value is specially 6; The proportioning of described papain and described crude drug is specially 240U:100g.
In practical operation, with after described papain enzymolysis also need in the water-bath of 100 DEG C deactivation 10min, to remove the impact of papain.
Further, in the present invention, the preparation method of described four gentleman's total polysaccharidess specifically comprises the steps:
(1) in four kinds of crude drug of following parts by weight, add the petroleum ether of described four kinds of crude drug 5 times of weight, reflux, extract, 1h, volatilize described petroleum ether: Radix Codonopsis 2 parts, Rhizoma Atractylodis Macrocephalae (parched) 2 parts, 2 parts, Poria, Radix Glycyrrhizae Preparata 1 part, described Rhizoma Atractylodis Macrocephalae (parched) is the Rhizoma Atractylodis Macrocephalae (parched) adopting carbon dioxide supercritical fluid extraction to cross volatile oil component;
(2) by the 85%(volume fraction of step (1) gained medicinal residues by described four kinds of crude drug 5 times of weight) ethanol extraction 1h, volatilize described ethanol;
(3) by the distilled water reflux, extract, 2 time of step (2) gained medicinal residues by described four kinds of crude drug 10 times of weight, each 3h, 8 layers of filtered through gauze, merging filtrate, concentrated filtrate is equal with total grams of four kinds of crude drug described in step (1) to the milliliter number of its volume, obtains the Aqueous extracts of concentrated solution 1(and described four kinds of crude drug);
(4) with papain, enzymolysis is carried out to step (3) gained concentrated solution 1, and by hydrogen peroxide for decoloration, obtain concentrated solution 2;
(5) in step (4) gained concentrated solution 2, add the dehydrated alcohol of described concentrated solution 2 two volumes amount, put into refrigerator, leave standstill 24h, sucking filtration, filtering residue washs with dehydrated alcohol, acetone, petroleum ether successively, and cryostat is dry, obtains described four gentleman's total polysaccharidess.
In the above-mentioned methods, in step (1), the condition of described carbon dioxide supercritical fluid extraction can be 40 ~ 45MPa, temperature 35 ~ 45 DEG C, time 1.5 ~ 2h; In one embodiment of the invention, the condition of described carbon dioxide supercritical fluid extraction is specially pressure 45MPa, temperature 40 DEG C, time 2h.
In the above-mentioned methods, in step (4), can be 50-60 DEG C (as 50 DEG C) the temperature that described concentrated solution 1 carries out enzymolysis with described papain, pH value can be 5-6(as pH6.0), enzymolysis time can be 3h; The proportioning of described papain and described crude drug can be 240-360U:100g(as 240U:100g).
In one embodiment of the invention, the preparation method of described four gentleman's drop pill specifically comprises the steps:
(1) preparation of mixed-matrix: the ratio being 1: 0.003 ~ 0.006 in mass ratio by xylitol and hydroxypropyl emthylcellulose is mixed homogeneously;
(2) described volatile oil, described four gentleman's total polysaccharidess are joined in mixed-matrix prepared by step (1), obtain mixture, make in described mixture, the mass ratio of described four gentleman's total polysaccharidess, described volatile oil and described mixed-matrix is 1: 0.01 ~ 0.03: 4.012 ~ 5.03;
(3) by step (2) gained mixture at about 80 ± 5 DEG C heating and meltings, be the water dropper of 2mm with internal diameter, the distance controlling water dropper distance coolant liquid level is 15 ± 5cm, is in the described coolant of 3 ± 2 DEG C, forms drop pill with the speed instillation temperature that a speed is 15 ± 2/min;
(4) the described coolant on drop pill surface in step (3) is sucked, and dry described four gentleman's drop pill.
In the four gentleman's dropping pill formulations prepared by said method, the quality proportioning of four gentleman's total polysaccharidess, volatile oil, xylitol and hydroxypropyl emthylcellulose is about 1:0.01 ~ 0.03:4 ~ 5:0.01 ~ 0.03.
In the above-mentioned methods, in step (1), the mass ratio of described xylitol and described hydroxypropyl emthylcellulose specifically can be 1: 0.004; In step (2), the mass ratio of described four gentleman's total polysaccharidess, described volatile oil and described mixed-matrix specifically can be 1: 0.01: 4.016; In step (3), the temperature of described mixture heating and melting specifically can be 85 DEG C; The described distance controlling water dropper distance coolant liquid level specifically can be 15cm, and described speed specifically can be 15/min, and the temperature of described coolant specifically can be 5 DEG C; Described coolant specifically can be simethicone; Described in step (4), coolant specifically can be simethicone.In the four gentleman's dropping pill formulations prepared by the method, the quality proportioning of described four gentleman's total polysaccharidess, described volatile oil, described xylitol and described hydroxypropyl emthylcellulose is specially 1:0.01:4:0.016.
The present invention by xylitol and hydroxypropyl emthylcellulose with the use of, drop pill can be made to have good hardness, both solved the problem that drop pill is frangible, not affect again the characteristic of its dripping and condensation.Four gentleman's dropping pill formulations provided by the present invention, have drug-eluting compared with boiling extraction with traditional water decoction fast, good absorbing, bioavailability is high, taking convenience, and the advantages such as medicine dispersion is fast, good absorbing, stability enhancing, have good DEVELOPMENT PROSPECT.Experiment proves, four gentleman's drop pill provided by the present invention, for replenishing QI to invigorate the spleen aspect, have stronger effect compared with traditional decoction.
Detailed description of the invention
The experimental technique used in following embodiment if no special instructions, is conventional method.
Material used in following embodiment, reagent etc., if no special instructions, all can obtain from commercial channels.
Quantitative data involved in following embodiment, all arranges and repeats experiment for three times, and its result is three meansigma methodss repeated.
Radix Codonopsis (Anguo City Qi Ao prepared slices of Chinese crude drugs company limited, lot number: 100417101); Poria (Anguo City Qi Ao prepared slices of Chinese crude drugs company limited, lot number: 100301111); Rhizoma Atractylodis Macrocephalae (parched) (Anguo City Qi Ao prepared slices of Chinese crude drugs company limited, lot number: 100428101); Radix Glycyrrhizae Preparata (Anguo City Qi Ao prepared slices of Chinese crude drugs company limited, lot number: 105668192); Radix Et Rhizoma Rhei (Haozhou city of Gansu Province Jing Wan Chinese herbal medicine beverage factory, lot number: 110901); Simethicone (Tianjin Heng Xing chemical reagent company limited, lot number: 20091221); Petroleum ether (30 ~ 60) (Tianjin Heng Xing chemical reagent company limited, lot number: 20090221); Dehydrated alcohol (Tianjin Jin Feng Chemical Co., Ltd., lot number: 20110306); Xylitol (Shandong Futian Medicine Industry Co., Ltd., lot number: 11031908); Hydroxypropyl emthylcellulose (Shandong auspicious safe chemical industry (group) company limited); Papain (Guangxi Academy Biological Research Institute, U.S. cutter board, vigor 240U/g, lot number 20110422); Radix Et Rhizoma Rhei (Haozhou city of Gansu Province Jing Wan Chinese herbal medicine beverage factory, lot number: 110901); Serum starch enzyme reagent kit (build up Bioengineering Research Institute and produce, lot number: 20110620) by Nanjing; 1% methyl orange (analytical pure, Tianjin recovery fine chemistry industry institute), 5% sodium bicarbonate (analytical pure, Tianjin Shen Tai chemical reagent company limited, lot number: 110801), sodium chloride (analytical pure, Tianjin Kermel Chemical Reagent Co., Ltd., lot number: 20100427).Motilin (MTL), vasoactive intestinal peptide (VIP), PGE2 (PGE2) and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SP), be ELISA kit, produced by R & D company of the U.S., import subpackage, lot number 201110, upper SeaBird match company provides.
SPE-SED supercritical CO
2extraction element (Applied Separation company of the U.S.); Agilent6890N-5973inent gas chromatograph-mass spectrometer (GC-MS); 721 visible spectrophotometers (Shanghai essence Science and Technology Ltd.); ZZ-6 mice autonomic activities tester (Chengdu TME Technology Co., Ltd.); Tired transfer rod instrument (Chengdu TME Technology Co., Ltd.) of ZB200; FSH-II type high speed electric homogenizer (Danyang, Jintan City door quartz glass factory); LD5-10 type centrifuge (Beijing Medical Centrifugal Machine Factory); Spectra Max190 microplate reader (branch and subsidiaries of the U.S.); MH-5000 adjustable electric hot jacket (high honour instrument manufacturing company limited of Jintan City of Jiangsu Province); 78X-2 tablet four-function disintegration tester (Shanghai Huanghai Sea medicine inspection instrument plant); JA4003 precision electronic balance (upper current chart level instruments and meters company limited); The multiplex vacuum pump of SHB-III A circulating water type (Shanghai Yu Kang Science & Teaching Instrument equipment company limited); HY-081 slide gauge (Hangzhou beneficial guarded blade utility knife tool company limited of China); HH-6 digital display thermostat water bath (Guo Hua Electrical Appliances Co., Ltd); DHG-9075A baking oven (the permanent Science and Technology Ltd. in Shanghai); The dropper etc. of different size.
The preparation of embodiment 1, four gentleman's dropping pill formulation and Function Identification thereof
One, the preparation of four gentleman's dropping pill formulations
1, the extraction of volatile oil
Above-mentioned raw materials medicine Rhizoma Atractylodis Macrocephalae (parched) is carried out carbon dioxide supercritical fluid extraction as follows, obtains volatile oil:
(1) 20g is pulverized uniform crude drug Rhizoma Atractylodis Macrocephalae (parched) and load 30mL extraction still, utilize SPE-SED supercritical CO
2extraction element carries out carbon dioxide supercritical fluid extraction volatile oil;
(2) the extracting pressure 45MPa of carbon dioxide supercritical fluid extraction volatile oil is controlled, extraction temperature 40 DEG C, extraction time 2h.
(3) extracting gained volatile oil is green transparent liquid, and contained active component is analyzed through GC-MS and is mainly: juniper camphor.
2, the extraction of four gentleman's total polysaccharidess and purification
Four kinds of crude drug: Radix Codonopsis 10.00g, Rhizoma Atractylodis Macrocephalae (parched) 10.00g, Poria 10.00g, Radix Glycyrrhizae Preparata 5.00g.
The Rhizoma Atractylodis Macrocephalae (parched) residue carrying out volatile oil extraction through step 1 is mixed with the consumption of its excess-three kind crude drug (Radix Codonopsis, Poria and Radix Glycyrrhizae Preparata) according to " Radix Codonopsis 10.00g, Rhizoma Atractylodis Macrocephalae (parched) residue 10.00g, Poria 10.00g, Radix Glycyrrhizae Preparata 5.00g ", after mixing, following method carries out extraction and the purification of total polysaccharides, obtains four gentleman's total polysaccharidess:
(1) petroleum ether backflow: 35g tetra-gentleman medicinal powder will be amounted to, add the petroleum ether being equivalent to crude drug 5 times of weight (175g), backflow 1h, volatilizes solvent;
(2) alcohol reflux: add in medicinal residues be equivalent to crude drug 5 times of weight (175g) 85% ethanol, backflow 1h, volatilize solvent;
(3) water extraction: add the distilled water (350g, i.e. 350mL) being equivalent to crude drug 10 times of weight in medicinal residues and extract, extract 2 times altogether, each 3h, filtered through gauze, merging filtrate, is concentrated into 35mL by filtrate, is equivalent to 1g medical material/mL;
(4) enzymolysis: adopt papain to carry out deproteinization process, controlling bath temperature is 50 DEG C, pH value is 6, enzymolysis time is 3h, enzyme dry powder consumption is 1%(and the 0.35g papain of four kinds of crude drug gross masses, is dissolved in 50mL distilled water), calculating enzyme alive is 240U:100g with the proportioning of four kinds of crude drug, after enzymolysis, in the water-bath of 100 DEG C, deactivation 10min, to remove remaining papain, adds the H of 0.1% of crude drug gross mass
2o
2decolouring;
(5) precipitate with ethanol: the dehydrated alcohol adding 2 times of volumes (170mL), places refrigerator, and leave standstill 24h, sucking filtration, filtering residue washs successively with dehydrated alcohol, acetone, petroleum ether respectively, and cryostat is dry, obtains four gentleman's total polysaccharidess.
3, the preparation of four gentleman's dropping pill formulations
(1) preparation of mixed-matrix: the ratio being 1: 0.004 in mass ratio by xylitol and hydroxypropyl emthylcellulose is mixed homogeneously;
(2) four gentleman's total polysaccharidess that volatile oil step 1 obtained, step 2 obtain join in mixed-matrix prepared by step (1), obtain mixture.Wherein the mass ratio of four gentleman's total polysaccharidess, volatile oil and mixed-matrix is 1: 0.01: 4.016;
(3) step (2) gained mixture is stirred, at 85 DEG C of heating and meltings, stir, be the water dropper of 2mm with internal diameter, control the distance 15cm of water dropper apart from liquid coolant (simethicone) liquid level, it is in the coolant simethicone of 5 DEG C that the speed being 15/min with a speed instills temperature, forms drop pill;
(4) the coolant simethicone on drop pill surface in step (3) is sucked, dry four gentleman's drop pill.
In the four gentleman's dropping pill formulations prepared by said method, the quality proportioning of four gentleman's total polysaccharidess, volatile oil, xylitol and hydroxypropyl emthylcellulose is 1:0.01:4:0.016.
Two, the Function Identification of four gentleman's dropping pill formulations
1, the experimentation of four gentleman's dropping pill formulation replenishing QI to invigorate the spleen effects
Laboratory animal: kunming mice, male and female half and half, body weight 18-20g, is purchased from Mountain Western Medicine S University's Experimental Animal Center, quality certification SCXK-201101.
Medicine: four gentleman's dropping pill formulations prepared by step one, decoction of four noble drugs Aqueous extracts, and Radix Et Rhizoma Rhei extract.Wherein, decoction of four noble drugs Aqueous extracts is prepared as follows and obtains: by four kinds of crude drug Radix Codonopsis, Rhizoma Atractylodis Macrocephalae (parched), Poria, Radix Glycyrrhizae Preparata in mass ratio 2:2:2:1 ratio mixing, add the water of 8 times of quality, soak 1h, decoct 2h, double gauze filters, filtering residue is repeated the above step adding water, decoct, filter, repeats 2 times, merge the filtrate decocted for 3 times, filtrate is concentrated into 1.75g/mL, and cold preservation is for subsequent use.Radix Et Rhizoma Rhei extract is prepared as follows and obtains: Radix Et Rhizoma Rhei is soaked 1h by the water getting 3 times of quality, water boiling and extraction 15min, and double gauze filters, filtering residue adds the soak by water 15min of 2 times of quality, and merging filtrate, is concentrated into 1.5g/mL, sealing, cold preservation (for making mice with spleen deficiency model) for subsequent use.
The experiments such as swimming, transfer rod, autonomic activities are selected in this research, observe medicine to the antifatigue effect of mice with spleen deficiency; Select serum amylase to observe the improvement result of medicine to mice with spleen deficiency digestive function; By observing medicine to immune influence to the result that affects of Spleen coefficient and thymus coefficient.Specific as follows:
(1) grouping and modeling
96 kunming mice stochastic averagina are divided into 6 groups (16/group), often organize male and female half and half, i.e. dosage group (containing four gentleman total polysaccharides 1g/kg), four gentleman's drop pill low dose group (containing four gentleman total polysaccharides 0.5g/kg) in blank group, model control group, decoction of four noble drugs group (35g crude drug/kg), four gentleman's drop pill high dose group (containing four gentleman total polysaccharides 2g/kg), four gentleman's drop pill.Except blank group gavages except tap water, all the other are respectively organized gavage Radix Et Rhizoma Rhei water extract 37.5g/kg and carry out modeling, once a day, and continuous modeling 2 weeks.Gavage Radix Et Rhizoma Rhei water extract after two weeks, compared with blank group, modeling mice occurs alarmming the phenomenon such as hair, movable minimizing, dietary amount minimizing, illustrates that modeling mice has had insufficiency of the spleen symptom.After two weeks, except blank group gavages except tap water, all the other respectively organize swimming every day once (makes mice continue maintain insufficiency of the spleen symptom and have deficiency of vital energy symptom concurrently, merge the phenomenon such as animal appearance activity minimizing, drowsiness after swimming model), and gavage corresponding medicine, namely model control group gavages the mixture (xylitol: HPMC mass ratio is 1: 0.004) (3.5g/kg) of xylitol and hydroxypropyl emthylcellulose (HPMC), decoction of four noble drugs group gavages decoction of four noble drugs Aqueous extracts, and the high, medium and low dosage group of four gentleman's drop pill gavages four gentleman's drop pill solution of respective concentration.Each group gavages two weeks continuously, once a day.
(2) mice with spleen deficiency physical tiredness model is affected
A. turn-club test
When medicine gavages the 14th day, turn-club test detection is carried out to each group of mice, specific as follows:
By the adjustment of rotational speed of tired for ZB-200 transfer rod instrument to 40r/min, synchronously 5 mices are placed on transfer rod, test first three day adaptability transfer rod 3 times, each 10min, after administration 1h, it is on 40r/min transfer rod that each group of mice is placed on rotating speed, the time that record mice stops on transfer rod, if fallen in 2min, it is put immediately rod continues experiment (with reference to " and Zhang Lin, Wei Jianyi, Han Degang etc. glutinous rehmannia soup against fatigue is to the experimentation of mouse anti-reflecting fatigue effect. Taishan Hospital's journal; 2009,30(3): 161-164 ").
B. swimming test
When medicine gavages the 15th day, swimming test detection is carried out to each group of mice, specific as follows:
Mice is placed in water temperature 25 ± 1 DEG C, swimming trunk that the depth of water is about 30cm, after administration 1h, swimming trunk will put into, record starts to enter the water surface to mice head from swimming can not lift the time, as mice swimming time (with reference to " and Zhang Lin, Wei Jianyi, Han Degang etc. glutinous rehmannia soup against fatigue is to the experimentation of mouse anti-reflecting fatigue effect. Taishan Hospital's journal; 2009,30(3): 161-164 ").
Result shows: compared with blank group, model control group mice swimming time obviously shortens (P<0.01); All the other are respectively organized without significant difference.Compared with model control group, decoction of four noble drugs group, the high, medium and low each dosage group swimming time of four gentleman's drop pill all have prolongation, wherein decoction of four noble drugs Aqueous extracts group, high, the middle dosage group of four gentleman's drop pill have significant difference (P<0.01), and four gentleman's drop pill high dose group action effects are significantly better than decoction of four noble drugs group (P<0.05).Compare with blank group, the model group mice transfer rod time obviously shortens (P<0.05), compare with model control group, all there are prolongation decoction of four noble drugs group, four gentleman's drop pill high, medium and low each dosage group transfer rod times, wherein high, the middle dosage group of four gentleman's drop pill has significant difference (P<0.01, P<0.05), and effect is better than decoction of four noble drugs group.The results are shown in Table 1.
Table 1 four gentleman drop pill is on mice with spleen deficiency swimming and the impact of transfer rod time
Note: compare △ P<0.05, △ △ P<0.01 with blank group; * P<0.05, * * P<0.01 is compared with model control group; ▲ P<0.05 is compared with decoction of four noble drugs group.
(3) on the impact of mice with spleen deficiency autonomic activities
When medicine gavages the 15th day, autonomic activities detection is carried out to each group of mice, specific as follows:
1h after administration, is placed in ZB-200 type toy autonomic activities instrument by mice, adapt to 5min, record 5min in mice activity number of times (with reference to " and the side of magnifying, Jin Ruomin, Meng Xianli etc. pharmacology and herbal pharmacology are tested. Shanghai science tech publishing house; 2006, the second edition, 34-35 ").
Result shows: compare with blank group, model control group mice autonomic activities number of times significantly reduces (P<0.01); Compare with model control group, decoction of four noble drugs group, four gentleman's drop pill high, medium and low dosage group autonomic activities times obviously extend (P<0.05, or P<0.01), four gentleman's drop pill high dose group exercising results are better than decoction of four noble drugs group (P<0.05).The results are shown in Table 2.
Table 2 four gentleman drop pill is on the impact of mice with spleen deficiency autonomic activities
Note: compare △ P<0.05, △ △ P<0.01 with blank group; * P<0.05, * * P<0.01 is compared with model control group; ▲ P<0.05 is compared with decoction of four noble drugs group.
(4) on the impact of mice with spleen deficiency immune organ and serum amylase
1h after last administration, on the one hand, orbital venous plexus gets blood, and 3000r/min is centrifugal, gets serum, measures content of Diastase in blood serum with serum starch enzyme reagent kit.On the other hand, put to death mice, get thymus and spleen, weigh, calculate organ coefficient (organ coefficient=organ weights (g)/Mouse Weight (g)) (with reference to " and Gan Jingyi, Gong Zhongfu, Cheng Guilin etc. decoction of four noble drugs is on the impact of Rats with Spleen-deficiency serum digestive enzyme and gut hormone. Chinese Veterinary Journal; 2011,42(2): 43-44 ").
Immune organ quality measurements shows: compared with blank group, model control group Spleen coefficient and thymus coefficient obviously reduce (P<0.01); Compared with model group, decoction of four noble drugs group, four gentleman's drop pill high, medium and low dosage group Spleen coefficient and thymus coefficient all have certain increase, and decoction of four noble drugs group, four gentleman's drop pill high, middle dosage group action effect significantly (P<0.05, P<0.01), illustrate that four gentleman's drop pill can increase the immune organ quality of mice with spleen deficiency.The results are shown in Table 3.
Table 3 four gentleman drop pill is on the impact of mice with spleen deficiency Spleen coefficient and thymus coefficient
Note: compare △ P<0.05, △ △ P<0.01 with blank group; * P<0.05, * * P<0.01 is compared with model control group.
Serum amylase testing result shows: compare with blank group, and model control group mice serum amylase (AMS) significantly reduces (P<0.01); Compare with model control group, decoction of four noble drugs group, four gentleman's drop pill be high, in, dosage group serum amylase obviously increases (P<0.05, or P<0.01); Compare with decoction of four noble drugs group, the effect of four gentleman's drop pill high, middle dosage group better (P>0.05).The results are shown in Table 4.
Table 4 four gentleman drop pill is on the impact of amylase content in mice with spleen deficiency serum
Note: compare △ P<0.05, △ △ P<0.01 with blank group; * P<0.05, * * P<0.01 is compared with model control group; ▲ P<0.05 is compared with decoction of four noble drugs group.
2, four gentleman's dropping pill formulations experimentation that gastrointestinal motility in mice is affected
Laboratory animal: kunming mice, male and female half and half, body weight 18-20g, is purchased from Mountain Western Medicine S University's Experimental Animal Center, quality certification SCXK-201101.
Medicine: four gentleman's dropping pill formulations prepared by step one, decoction of four noble drugs Aqueous extracts, and Radix Et Rhizoma Rhei extract.Wherein, decoction of four noble drugs Aqueous extracts is prepared as follows and obtains: by four kinds of crude drug Radix Codonopsis, Rhizoma Atractylodis Macrocephalae (parched), Poria, Radix Glycyrrhizae Preparata in mass ratio 2:2:2:1 ratio mixing, add the water of 8 times of quality, soak 1h, decoct 2h, double gauze filters, filtering residue is repeated the above step adding water, decoct, filter, repeats 2 times, merge the filtrate decocted for 3 times, filtrate is concentrated into 1.75g/mL, and cold preservation is for subsequent use.Radix Et Rhizoma Rhei extract is prepared as follows and obtains: Radix Et Rhizoma Rhei is soaked 1h by the water getting 3 times of quality, water boiling and extraction 15min, and double gauze filters, filtering residue adds the soak by water 15min of 2 times of quality, and merging filtrate, is concentrated into 1.5g/mL, sealing, cold preservation (for making mice with spleen deficiency model) for subsequent use.
This research selects alvine pushing rate, gastric emptying amount to observe medicine and to digest and assimilate mice with spleen deficiency and the impact of gastrointestinal activity, selects motilin, vasoactive intestinal peptide, PGE2 and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 several index observing medicine on the impact of mice with spleen deficiency gut hormone.Specific as follows:
(1) grouping and modeling
72 kunming mice stochastic averagina are divided into 6 groups (12/group), often organize male and female half and half, i.e. dosage group (containing four gentleman total polysaccharides 1g/kg), four gentleman's drop pill low dose group (containing four gentleman total polysaccharides 0.5g/kg) in blank group, model control group, decoction of four noble drugs group (35g crude drug/kg), four gentleman's drop pill high dose group (containing four gentleman total polysaccharides 2g/kg), four gentleman's drop pill.Every day two divided doses, adopt the method for limit administration limit modeling, gavage except tap water except blank group in the morning, all the other each group gavages corresponding medicine, namely model control group gavages the mixture (xylitol: HPMC mass ratio is 1: 0.004) (3.5g/kg) of xylitol and hydroxypropyl emthylcellulose (HPMC), decoction of four noble drugs group gavages decoction of four noble drugs Aqueous extracts, four gentleman's drop pill are high, in, low dose group gavages four gentleman's drop pill solution of respective concentration, gavage except tap water except blank group in the afternoon, all the other are respectively organized gavage Radix Et Rhizoma Rhei water extract 37.5g/kg and carry out modeling, after administration every afternoon, each group of mice except blank group is placed in water temperature 25 ± 1 DEG C, the depth of water is about in the swimming trunk of 30cm, pick up after swimming 10min and dry up, within continuous two weeks, (make mice swimming every day once, to continue to maintain insufficiency of the spleen symptom and having deficiency of vital energy symptom concurrently, namely appearance activity reduces, the phenomenons such as drowsiness).
(2) on the impact of mice with spleen deficiency alvine pushing rate and gastric emptying amount
When medicine gavages the 15th day, each group of mice is carried out to the detection of alvine pushing rate and gastric emptying amount, specific as follows:
30min after administration, gavages 1% methyl orange, and dosage is after 0.1mL/10g, 20min, and eyeball of mouse gets blood till death, weighs Mouse Weight, dissects, intercepts stomach, then intercept small intestinal by after the ligation of Mouse Stomach two ends.With in tape measure to pylorus, down to the Length of intestine of ileocecus, and the orange red dye partial-length of methyl.Calculate methyl orange propelling rate, propelling rate=advance distance (cm)/small intestinal total length (cm) × 100%.Stomach being placed in 5mL concentration is 1%(1g/100ml) sodium bicarbonate solution, break with shears, soak after half an hour, the centrifugal 10min of 2000r/min, gets supernatant, surveys its absorbance (A), calculates gastric emptying amount, gastric emptying amount=(1-A)/A
contrast× 100%(A
contrast1% methyl orange for 0.25mL is dissolved in the absorbance of 5mL sodium bicarbonate solution).
Alvine pushing rate testing result shows: compared with blank group, model control group alvine pushing rate increases to some extent.Compare with model control group, all the other each dosage groups all decrease, but without significant difference.
Gastric emptying amount testing result shows: compared with the contrast of blank group, model control group, decoction of four noble drugs group gastric emptying amount have remarkable reduction (P<0.01), and all the other respectively organize no significant difference.Compare with model control group, four gentleman's drop pill high and low dose group gastric emptying amounts have obvious increase (P<0.05), and middle dosage group enlarges markedly (P<0.01), and decoction of four noble drugs group is increase tendency, without significant change.Compare with decoction of four noble drugs group, all there were significant differences (P<0.01) for the high, medium and low dosage group of four gentleman's drop pill.The results are shown in Table 5.
Table 5 four gentleman drop pill is on the impact of mice with spleen deficiency alvine pushing rate and stomach residual quantity
Note: compare △ P<0.05, △ △ P<0.01 with blank group; * P<0.05, * * P<0.01 is compared with model group; ▲ P<0.05, ▲ ▲ P<0.01 is compared with decoction of four noble drugs group.
(3) on the impact of the active intestinal peptide of mice with spleen deficiency serum motilin and small intestine homogenate liquid, PGE2 and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2
When medicine gavages the 15th day, each group of mice is carried out to the detection of serum motilin (MTL) and small intestine homogenate liquid activity intestinal peptide (VIP), PGE2 (PGE2) and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SP), specific as follows:
Mice is got blood from canthus, and the centrifugal 10min of 3500r/min, gets serum, with ELESA kit measurement mice serum motilin.Intercept intestinal tube, weigh, make 10% tissue homogenate, the centrifugal 10min of 2500r/min, gets supernatant, measures VIP, PGE2, SP content in mouse small intestine homogenate by ELESA method.ELESA operation is carried out with reference to corresponding test kit description.Below, after respectively organizing data compilation, process with statistical method, comparative analysis.
Serum motilin testing result shows: compare with blank group, and motilin (MTL) level of model control group mice is that significance raises trend (P<0.01).Compare with model control group, four gentleman's drop pill high, middle dosage group Mouse Stomach therbligs (MTL) level is in obviously reducing trend (P<0.05), decoction of four noble drugs group is in obviously raising trend (P<0.05), four gentleman's drop pill low dose group are reduction trend, but no significant difference.Compare with decoction of four noble drugs group, the high, medium and low dosage group of four gentleman's drop pill all has notable difference (P<0.01, or P<0.05).The results are shown in Table 6.
Table 6 four gentleman drop pill is on the impact of mice with spleen deficiency motilin
Note: compare △ P<0.05, △ △ P<0.01 with blank group; Compare * P<0.05, * * P<0.01 with model control group, compare ▲ P<0.05, ▲ ▲ P<0.01 with decoction of four noble drugs group.
The testing result display of the active intestinal peptide of small intestine homogenate liquid, PGE2 and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2: compare with blank group, the active intestinal peptide content of model control group small intestine homogenate liquid is rising trend, and there is significant difference (P<0.05), compare with model control group, decoction of four noble drugs group and four gentleman's drop pill low dose group small intestine homogenate liquid active intestinal peptide level obviously reduce and have significant difference (P<0.05, P<0.01), high, the middle dosage group of four gentleman's drop pill is reduction trend, no significant difference.Compared with blank group, model control group PGE2 (PGE2) level has significance to raise (P<0.01), compare with model control group, decoction of four noble drugs group, four gentleman's drop pill high doses and low dose group all have notable difference (P<0.05), in four gentleman's drop pill, dosage group is reduction trend, no significant difference.Compare with blank group, model control group, four gentleman's drop pill high dose group Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SP) levels all have significant difference (P<0.01), and decoction of four noble drugs group, high, the middle dosage group of four gentleman's drop pill all have notable difference (P<0.05).Compare with model control group, decoction of four noble drugs group, the equal no significant difference of four gentleman's drop pill each dosage group.The results are shown in Table 7.
Table 7 four gentleman drop pill is on the impact of mice with spleen deficiency vasoactive intestinal peptide, PGE2 and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2
Note: compare △ P<0.05, △ △ P<0.01 with blank group; * P<0.05, * * P<0.01 is compared with model control group.
Claims (17)
1. four gentleman's dropping pill formulations, are made up of volatile oil, four gentleman's total polysaccharidess and substrate;
Rhizoma Atractylodis Macrocephalae (parched) obtains through carbon dioxide supercritical fluid extraction by described volatile oil;
Described four gentleman's total polysaccharidess are extracted and are obtained from four kinds of crude drug of following mass fraction: Radix Codonopsis 2 parts, Rhizoma Atractylodis Macrocephalae (parched) residue 2 parts, 2 parts, Poria, Radix Glycyrrhizae Preparata 1 part, and described Rhizoma Atractylodis Macrocephalae (parched) residue is for by Rhizoma Atractylodis Macrocephalae (parched) remaining material after volatile oil described in described carbon dioxide supercritical fluid extraction;
Described substrate is xylitol and hydroxypropyl emthylcellulose;
The quality proportioning of described four gentleman's total polysaccharidess, described volatile oil, described xylitol and described hydroxypropyl emthylcellulose is 1:0.01 ~ 0.03:4 ~ 5:0.01 ~ 0.03.
2. four gentleman's dropping pill formulations according to claim 1, is characterized in that: the quality proportioning of described four gentleman's total polysaccharidess, described volatile oil, described xylitol and described hydroxypropyl emthylcellulose is 1:0.01:4:0.016.
3. four gentleman's dropping pill formulations according to claim 1, is characterized in that: the condition of described carbon dioxide supercritical fluid extraction is pressure 40 ~ 45MPa, temperature 35 ~ 45 DEG C, time 1.5 ~ 2h.
4. four gentleman's dropping pill formulations according to claim 1, is characterized in that: the extracting method of described four gentleman's total polysaccharidess comprises the step of carrying out enzymolysis removal albumen with the Aqueous extracts of protease to described four kinds of crude drug.
5. four gentleman's dropping pill formulations according to claim 4, is characterized in that: described protease is papain.
6. four gentleman's dropping pill formulations according to claim 5, is characterized in that: be 50-60 DEG C by the temperature of described papain enzymolysis, and pH value is 5-6, and enzymolysis time is 3 h.
7. four gentleman's dropping pill formulations according to claim 6, is characterized in that: be 50 DEG C by the temperature of described papain enzymolysis, and pH value is 6.
8. four gentleman's dropping pill formulations according to claim 5, is characterized in that: the proportioning of described papain and described four kinds of crude drug is 240-360U:100g.
9. four gentleman's dropping pill formulations according to claim 8, is characterized in that: the proportioning of described papain and described four kinds of crude drug is 240U:100g.
10. the preparation method of four gentleman's dropping pill formulations, comprises the steps:
(1) adopt the volatile oil in carbon dioxide supercritical fluid extraction Rhizoma Atractylodis Macrocephalae (parched), collect Rhizoma Atractylodis Macrocephalae (parched) residue simultaneously;
(2) by after four of following portions by weight kinds of crude drug mixing, four gentleman's total polysaccharidess are extracted: Radix Codonopsis 2 parts, the described Rhizoma Atractylodis Macrocephalae (parched) residue of step (1) 2 parts, 2 parts, Poria, Radix Glycyrrhizae Preparata 1 part;
(3) described four gentleman's total polysaccharidess, described volatile oil, xylitol and hydroxypropyl emthylcellulose are prepared four gentleman's dropping pill formulations according to the ratio that quality proportioning is 1:0.01 ~ 0.03:4 ~ 5:0.01 ~ 0.03.
11. methods according to claim 10, is characterized in that: in step (1), and the condition of described carbon dioxide supercritical fluid extraction is pressure 40 ~ 45MPa, temperature 35 ~ 45 DEG C, time 1.5 ~ 2h;
In step (3), the quality proportioning of described four gentleman's total polysaccharidess, described volatile oil, described xylitol and described hydroxypropyl emthylcellulose is 1:0.01:4:0.016.
12. methods according to claim 10, is characterized in that: the extracting method of described four gentleman's total polysaccharidess comprises the step of carrying out enzymolysis removal albumen with the Aqueous extracts of protease to the described four kinds of crude drug in claim 10.
13. methods according to claim 12, is characterized in that: described protease is papain.
14. methods according to claim 13, is characterized in that: be 50-60 DEG C by the temperature of described papain enzymolysis, and pH value is 5-6, and enzymolysis time is 3 h
15. method according to claim 14, is characterized in that: be 50 DEG C by the temperature of described papain enzymolysis, pH value is 6.
16. methods according to claim 13, is characterized in that: described in described papain and claim 10, the proportioning of four kinds of crude drug is 240-360U:100g.
17. methods according to claim 16, is characterized in that: described in described papain and claim 10, the proportioning of four kinds of crude drug is 240U:100g.
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