CN103211858A - Si-Jun-Zi dropping pill preparation - Google Patents
Si-Jun-Zi dropping pill preparation Download PDFInfo
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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 a total polysaccharides.
Background technology
Decoction of four noble drugs sees " Song's formulary of peaceful benevolent dispensary " the earliest, is the basis side of air making-up and spleen enlivening, adopts Radix Ginseng among the former side, but Radix Codonopsis commonly used replaces Radix Ginseng in the modern Chinese medicine medication.It is made up of Radix Codonopsis, Poria, Rhizoma Atractylodis Macrocephalae (parched), Radix Glycyrrhizae Preparata four Chinese medicine in the Chinese Pharmacopoeia (2010 editions), and mass ratio is 2:2:2:1, and the effect of replenishing QI to invigorate the spleen is arranged, and cures mainly battalion's deficiency of defensive qi, and representing prescription is decoction of four noble drugs.
Polysaccharide compound has advantages such as toxic and side effects is little, safe, good effect as a kind of novel drugs, therefore demonstrates more and more wide prospect in clinical practice.Confirm that now polysaccharide has 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 medicinal polysaccharide to have extensive pharmacological action, wherein the most remarkable to the immunization of body.
Immunoregulation effect: immunoreation relates generally to macrophage and lymphocyte.It is model that Liu Liang etc. induce the mice of intestinal mucosa associated lymphoid tissue damage with the cyclophosphamide of 100mg/kg dosage, and after the orally give decoction of four noble drugs total polysaccharides, Peyer ' s footing amount returns to normal level substantially, Peyer ' s knot inner cell quantity, CD3
+And IgA
+Cell quantity also all has to a certain degree rising, and this experiment shows that the administration of decoction of four noble drugs compound recipe total polysaccharides oral administration has the effect that to a certain degree improves gut mucosal immune function.Liu Yuhong detects the decoction of four noble drugs total polysaccharides to human hepatoma cell strain HepG2 and the outgrowth influence of mouse spleen lymphocyte by adopting tetrazolium bromide (MTT) method, the result shows, the decoction of four noble drugs total polysaccharides does not have obvious influence external to the HepG2 cell, but can significantly promote the 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, in case canceration takes place tissue, its cell will infinitely rise in value rapidly.Polysaccharide with antitumor action mainly is divided into two classes, and a class has direct cytotoxic activity to tumor cell, can directly kill tumor cell external; Another kind of immunization by enhancing body is antitumor indirectly.Liu Yuhong adopts tetrazolium bromide (MTT) method to detect the decoction of four noble drugs total polysaccharides to human hepatoma cell strain HepG2 and the outgrowth influence of mouse spleen lymphocyte.The result shows that the decoction of four noble drugs total polysaccharides does not have directly to suppress the effect and the acellular toxic action of tumor, but polysaccharide component wherein can suppress growth of tumor by its immunological enhancement activity.This idea with the Chinese medicine compound wholistic therapy is consistent, meets the treatment by Chinese herbs features of tumor.But Li Zhuangang proves decoction of four noble drugs inducing mouse bladder cancer apoptosis of tumor cells by experiment, mouse tumor is organized in and is characteristic apoptosis form under the 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 proof decoction of four noble drugs can be by direct and indirect approach performance antitumor action.
The anti-gastrointestinal disease effect: decoction of four noble drugs is the basic prescription of invigorating the spleen and benefiting QI, and syndrome of deficiency of spleen qi is to be multisystem, the multiple organ dysfunction syndrome group at center with the digestive system, promptly based on digestion, motion, malabsorption.Peng Cheng etc. discover that decoction of four noble drugs does not have influence to gastric juice amount, gastric acid pH value, but can obviously increase the particulate content of chief cell endoenzyme unit, improve the length of coagulated protein in the pepsin digestion capillary glass-tube, by promoting the synthetic of pepsinogen, improve pepsic activity, thereby improve digestion power.Wang Wenbo etc. have reported that decoction of four noble drugs is used for the treatment of the functional dyspepsia disease, the result shows, decoction of four noble drugs treatment functional dyspepsia determined curative effect, the poor appetite that clinical syndrome of spleen-deficiency patients with functional dyspepsia is occurred, abdominal distention, loose stool, weak etc. has therapeutical effect preferably, and clinical total effective rate reaches 92.3%.
Four gentleman's existing dosage form, pharmacopeia record have only four gentleman's pills, four gentleman's granules are arranged, four gentleman's mixture, medicinal tea, pill (watered pill) on the market.Improve by the dosage form to four gentleman's compound recipes, further improve therapeutic effect, for the patient provides taking convenience, the novel form of therapeutic effect excellence has certain social and economic implications.Compare with injection, drop pill has kept the characteristics that onset is very fast, bioavailability is high to a certain extent, acute toxicity and the anaphylaxis that can avoid Chinese medicine injection may cause directly into blood again.
With respect to other dosage forms, dropping pill formulation absorbs fast, and with the drop pill of water-soluble base preparation, dissolve scattered time limit is mostly at 5～15min, be no more than 30min, so rapid-action, drop pill removes can be oral, also but sublingual administration absorbs directly into blood by oral mucosa, and onset is faster.Dropping pill formulation is the same with tablet, also can be made into slow releasing preparation, particularly for short chemical medicine of some half-life, make behind the sustained-release dropping pill obviously prolong half-life, this kind drop pill medicine slowly discharges from carrier, keeps the medicine desired concn, can be long-acting, oral administration also can reduce the deactivation at digestive tract and liver except reaching the slow releasing function.Drop pill and other peroral dosage forms compare, and volume is little, and light weight is used convenient.Take and be not subjected to ante cibum or influence after meal, component uses more convenient, has overcome once oral half sheet of some medicine or 1/4 drawback.Clinical practice shows that topical application drop pill medicine has characteristics such as concentration height, difficult loss, drug effect length, medication number of times lack.The drop pill preparation time is short, and range of temperature is little, and medicine stability increases, and also is applicable to costly medicine, easily oxidation, facile hydrolysis, easily draws the preparation of wet and volatility medicine.These characteristics of drops, being very suitable for polysaccharide, volatile oil is four gentleman's preparations of main active.
Summary of the invention
The purpose of this invention is to provide a kind of is four gentleman's dropping pill formulations of 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 the gastrointestinal motility aspect that stronger effect is arranged.
Four gentleman's dropping pill formulations provided by the present invention specifically are 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 from four kinds of crude drug of following mass fraction and obtained: 2 parts of Radix Codonopsis, 2 parts of Rhizoma Atractylodis Macrocephalae (parched) residues, 2 parts in Poria, 1 part of Radix Glycyrrhizae Preparata, described Rhizoma Atractylodis Macrocephalae (parched) residue are with Rhizoma Atractylodis Macrocephalae (parched) remaining material behind the described volatile oil of 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.
Adopting the xylitol in natural plants source is substrate, is because its good biocompatibility, biodegradable has no side effect.Xylitol and hydroxypropyl emthylcellulose are used, can make drop pill have good hardness, both solved the frangible problem of drop pill, do not influence the condensing characteristic of its system process again, simultaneously, 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, 35～45 ℃ of temperature, time 1.5～2h.In one embodiment of the invention, the condition of described carbon dioxide supercritical fluid extraction is specially pressure 45MPa, 40 ℃ of temperature, time 2h.
Another object of the present invention provides 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) volatile oil in the employing carbon dioxide supercritical fluid extraction Rhizoma Atractylodis Macrocephalae (parched) is collected the Rhizoma Atractylodis Macrocephalae (parched) residue simultaneously;
(2) with the described Rhizoma Atractylodis Macrocephalae (parched) residue of step (1) with after Radix Codonopsis, Poria and Radix Glycyrrhizae Preparata mix according to following portions by weight, extract four gentleman's total polysaccharidess: after 2 parts of described Radix Codonopsis, 2 parts of described Rhizoma Atractylodis Macrocephalae (parched) residues, 2 parts in described Poria, 1 part of mixing of described Radix Glycyrrhizae Preparata, extract four gentleman's total polysaccharidess;
(3) be that the ratio of 1:0.01～0.03:4～5:0.01～0.03 prepares four gentleman's dropping pill formulations with described four gentleman's total polysaccharidess, described volatile oil, xylitol and hydroxypropyl emthylcellulose according to the quality proportioning.
In said method step (1), the condition of described carbon dioxide supercritical fluid extraction can be 40～45MPa, 35～45 ℃ of temperature, time 1.5～2h; In one embodiment of the invention, the condition of described carbon dioxide supercritical fluid extraction is specially pressure 45MPa, 40 ℃ of temperature, time 2h; In the 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 that with protease the water extract of four kinds of crude drug (the quality proportioning is the same) being carried out enzymolysis removes proteic step.
The water extract of described four kinds of crude drug prepares according to the method that comprises the steps: (a1) add the petroleum ether of 5 times of weight in described four kinds of crude drug, reflux, extract, 1h volatilizes described petroleum ether;
(a2) by the 85%(volume fraction of step (a1) gained medicinal residues with 5 times of weight of described four kinds of crude drug) ethanol extraction 1h, volatilize described ethanol;
(a3), thereby obtain the water extract of described four kinds of crude drug by the distilled water reflux, extract, of step (a2) gained medicinal residues with 10 times of weight of described four kinds of crude drug.
In one embodiment of the invention, described protease is specially papain.
Temperature with described papain enzymolysis can be 50-60 ℃, and 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 ℃ with 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 also needing deactivation 10min in 100 ℃ water-bath behind the described papain enzymolysis, to remove the influence of papain.
Further, in the present invention, the preparation method of described four gentleman's total polysaccharidess specifically comprises the steps:
(1) petroleum ether of 5 times of weight of the described four kinds of crude drug of adding in four kinds of crude drug of following parts by weight, reflux, extract, 1h, volatilize described petroleum ether: 2 parts of Radix Codonopsis, 2 parts of Rhizoma Atractylodis Macrocephalae (parched)s, 2 parts in Poria, 1 part of Radix Glycyrrhizae Preparata, described Rhizoma Atractylodis Macrocephalae (parched) is crossed the Rhizoma Atractylodis Macrocephalae (parched) of volatile oil component for adopting carbon dioxide supercritical fluid extraction;
(2) by the 85%(volume fraction of step (1) gained medicinal residues with 5 times of weight of described four kinds of crude drug) ethanol extraction 1h, volatilize described ethanol;
(3) by step (2) gained medicinal residues with the distilled water reflux, extract, of 10 times of weight of described four kinds of crude drug 2 times, each 3h, 8 layers of filtered through gauze, merging filtrate, concentrated filtrate to the milliliter number of its volume equates that with total gram number of four kinds of crude drug described in the step (1) obtaining concentrated solution 1(is the water extract of described four kinds of crude drug);
(4) with papain step (3) gained concentrated solution 1 is carried out enzymolysis, and, obtain concentrated solution 2 with the hydrogen peroxide decolouring;
(5) dehydrated alcohol of the described concentrated solution 2 two volumes amounts of adding in step (4) gained concentrated solution 2 is put into refrigerator, leaves standstill 24h, sucking filtration, filtering residue washs with dehydrated alcohol, acetone, petroleum ether successively, and the constant temperature lyophilization gets described four gentleman's total polysaccharidess.
In said method, in the step (1), the condition of described carbon dioxide supercritical fluid extraction can be 40～45MPa, 35～45 ℃ of temperature, time 1.5～2h; In one embodiment of the invention, the condition of described carbon dioxide supercritical fluid extraction is specially pressure 45MPa, 40 ℃ of temperature, time 2h.
In said method, in the step (4), the temperature of described concentrated solution 1 being carried out enzymolysis with described papain can be 50-60 ℃ (as 50 ℃), and pH value can be 5-6(such as pH6.0), enzymolysis time can be 3h; The proportioning of described papain and described crude drug can be 240-360U:100g(such 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: is that 1: 0.003～0.006 mixed is even with xylitol and hydroxypropyl emthylcellulose by mass ratio;
(2) described volatile oil, described four gentleman's total polysaccharidess are joined in the mixed-matrix of step (1) preparation, obtain mixture, make in the 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) with step (2) gained mixture at 80 ± 5 ℃ of left and right sides heating and meltings, with internal diameter is the water dropper of 2mm, the control water dropper is 15 ± 5cm apart from the distance of coolant liquid level, with drip speed be the speed of 15 ± 2/min to splash into temperature be in 3 ± 2 ℃ the described coolant, form drop pill;
(4) inhale the described coolant go to drop pill surface in the step (3), and dry described four gentleman's drop pill.
In the four gentleman's dropping pill formulations that obtain by method for preparing, 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 said method, in the step (1), the mass ratio of described xylitol and described hydroxypropyl emthylcellulose specifically can be 1: 0.004; In the 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 the step (3), the fused temperature of described mixture heated specifically can be 85 ℃; The control water dropper specifically can be 15cm apart from the described distance of coolant liquid level, and described speed specifically can be 15/min, and the temperature of described coolant specifically can be 5 ℃; Described coolant specifically can be simethicone; Coolant specifically can be simethicone described in the step (4).In the four gentleman's dropping pill formulations that prepare by this 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 is used xylitol and hydroxypropyl emthylcellulose, can make drop pill have good hardness, has both solved the frangible problem of drop pill, does not influence the characteristic of its system and condensation again.Four gentleman's dropping pill formulations provided by the present invention, decocting the extract phase ratio with traditional water, to have a medicine stripping fast, good absorbing, advantages such as that bioavailability height, taking convenience, medicine disperse is fast, good absorbing, stability enhancing have DEVELOPMENT PROSPECT preferably.Experiment showed, four gentleman's drop pill provided by the present invention for the replenishing QI to invigorate the spleen aspect, compare with traditional decoction and have stronger effect.
The specific embodiment
Employed experimental technique is conventional method if no special instructions among the following embodiment.
Used material, reagent etc. if no special instructions, all can obtain from commercial channels among the following embodiment.
Related quantitative data among the following embodiment all is provided with repeated experiments three times, and its result is three multiple meansigma methodss.
(Australia's prepared slices of Chinese crude drugs company limited, lot number: 100417101) are prayed in the Anguo City to Radix Codonopsis; (Australia's prepared slices of Chinese crude drugs company limited, lot number: 100301111) are prayed in the Anguo City to Poria; (Australia's prepared slices of Chinese crude drugs company limited, lot number: 100428101) are prayed in the Anguo City to Rhizoma Atractylodis Macrocephalae (parched); (Australia's prepared slices of Chinese crude drugs company limited, lot number: 105668192) are prayed in the Anguo City to Radix Glycyrrhizae Preparata; Radix Et Rhizoma Rhei (Anhui, capital, city, Haozhou, Gansu Province Chinese medicine beverage factory, lot number: 110901); (reagent company limited, lot number: 20091221) are learned in permanent Xinghua, Tianjin to simethicone; (reagent company limited, lot number: 20090221) are learned in permanent Xinghua, Tianjin to petroleum ether (30～60); (the Feng Huagong company limited is advanced in Tianjin to dehydrated alcohol, lot number: 20110306); Xylitol (Shandong Futian Medicine Industry Co., Ltd., lot number: 11031908); Hydroxypropyl emthylcellulose (the auspicious safe chemical industry in Shandong (group) company limited); Papain (Guangxi Academy Biological Research Institute, U.S. cutter board, vigor 240U/g, lot number 20110422); Radix Et Rhizoma Rhei (Anhui, capital, city, Haozhou, Gansu Province Chinese medicine beverage factory, lot number: 110901); Serum starch enzyme reagent kit (build up bio-engineering research and produce, lot number: 20110620) by Nanjing; 1% methyl orange (analytical pure, Tianjin recovery fine chemistry industry institute), 5% sodium bicarbonate (analytical pure, the safe chemical reagent company limited in Shen, Tianjin, 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 P material (SP) are the ELISA test kit, produce by U.S. R﹠D company, and the import packing, lot number 201110, last SeaBird match company provides.
The SPE-SED supercritical CO
2Extraction element (U.S. Applied Separation company); The 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.); The 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 (U.S. branch and subsidiaries); The adjustable electric jacket of MH-5000 (Jintan City, Jiangsu Province high honour instrument Manufacturing Co., Ltd); 78X-2 tablet four-function disintegration tester (Shanghai Huanghai Sea medicine inspection instrument plant); JA4003 precise electronic balance (going up the flat instrument and meter company limited of current chart); SHB-III A circulation ability of swimming is used vacuum pump (Shanghai Yu Kang science and education instrument and equipment company limited) more; HY-081 slide gauge (the beneficial guarded blade utility knife of Hangzhou China has limit company); HH-6 digital display thermostat water bath (state China Electrical Appliances Co., Ltd); DHG-9075A baking oven (the permanent Science and Technology Ltd. in Shanghai); The dropper of different size etc.
The preparation and the Function Identification thereof of embodiment 1, four gentleman's dropping pill formulations
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 the uniform crude drug Rhizoma Atractylodis Macrocephalae (parched) 30mL that packs into and extract still, utilize the SPE-SED supercritical CO
2Extraction element carries out carbon dioxide supercritical fluid extraction volatile oil;
(2) the extracting pressure 45MPa of control carbon dioxide supercritical fluid extraction volatile oil, 40 ℃ of extraction temperature, extraction time 2h.
(3) extraction 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.
To mix with the consumption of its excess-three kind crude drug (Radix Codonopsis, Poria and Radix Glycyrrhizae Preparata) through the Rhizoma Atractylodis Macrocephalae (parched) residue that step 1 was carried out volatile oil extraction according to " Radix Codonopsis 10.00g, Rhizoma Atractylodis Macrocephalae (parched) residue 10.00g, Poria 10.00g, Radix Glycyrrhizae Preparata 5.00g ", mix extraction and purification that the following method in back is carried out total polysaccharides, obtain four gentleman's total polysaccharidess:
(1) petroleum ether refluxes: will amount to 35g four gentleman's medicinal powders, and add the petroleum ether that is equivalent to 5 times of weight of crude drug (175g), backflow 1h volatilizes solvent;
(2) alcohol reflux: add 85% the ethanol be equivalent to 5 times of weight of crude drug (175g) in the medicinal residues, backflow 1h volatilizes solvent;
(3) water is carried: add the distilled water (350g, i.e. 350mL) that is equivalent to 10 times of weight of crude drug in the medicinal residues and extract, extract altogether 2 times, and each 3h, filtered through gauze, merging filtrate is concentrated into 35mL with filtrate, is equivalent to 1g medical material/mL;
(4) enzymolysis: adopt papain to carry out deproteinization and handle, the control bath temperature is 50 ℃, pH value is 6, enzymolysis time is 3h, enzyme dry powder consumption is that the 1%(of four kinds of crude drug gross masses is the 0.35g papain, is dissolved in the 50mL distilled water), calculating the enzyme proportioning with four kinds of crude drug alive is 240U:100g, behind the enzymolysis in 100 ℃ water-bath deactivation 10min add 0.1% H of crude drug gross mass to remove remaining papain
2O
2Decolouring;
(5) precipitate with ethanol: add the dehydrated alcohol of 2 times of volumes (170mL), place refrigerator, leave standstill 24h, sucking filtration, filtering residue wash successively with dehydrated alcohol, acetone, petroleum ether respectively, and the constant temperature lyophilization gets four gentleman's total polysaccharidess.
3, the preparation of four gentleman's dropping pill formulations
(1) preparation of mixed-matrix: is that 1: 0.004 mixed is even with xylitol and hydroxypropyl emthylcellulose by mass ratio;
(2) four gentleman's total polysaccharidess of the volatile oil that step 1 is obtained, step 2 acquisition join in the mixed-matrix of step (1) preparation, 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 ℃ of heating and meltings, stir, with internal diameter is the water dropper of 2mm, control water dropper apart from liquid coolant (simethicone) liquid level apart from 15cm, with drip speed be the speed of 15/min to splash into temperature be in 5 ℃ the coolant simethicone, form drop pill;
(4) inhale the coolant simethicone that goes to drop pill surface in the step (3), the dry four gentleman's drop pill that get.
In the four gentleman's dropping pill formulations that obtain by method for preparing, 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, four gentleman's dropping pill formulation replenishing QI to invigorate the spleen experimental study of effect
Laboratory animal: kunming mice, male and female half and half, body weight 18-20g purchases the Experimental Animal Center in Mountain Western Medicine S University, quality certification SCXK-201101.
Medicine: four gentleman's dropping pill formulations of step 1 preparation, decoction of four noble drugs water extract, and Radix Et Rhizoma Rhei extract.Wherein, decoction of four noble drugs water extract is prepared as follows and obtains: the mixed that four kinds of crude drug Radix Codonopsis, Rhizoma Atractylodis Macrocephalae (parched), Poria, Radix Glycyrrhizae Preparata are pressed mass ratio 2:2:2:1, the water that adds 8 times of quality soaks 1h, decocts 2h, double gauze filters, with adding water, decoction, filtering step more than the filtering residue repetition, repeat 2 times, merge the filtrate of 3 decoctions, filtrate is concentrated into 1.75g/mL, and cold preservation is standby.Radix Et Rhizoma Rhei extract is prepared as follows and obtains: the water of getting 3 times of quality soaks 1h with Radix Et Rhizoma Rhei, water boiling and extraction 15min, and double gauze filters, the decocting that filtering residue adds 2 times of quality boils 15min, and merging filtrate is concentrated into 1.5g/mL, sealing, cold preservation standby (being used to make the mice with spleen deficiency model).
Experiments such as swimming, transfer rod, autonomic activities are selected in this research for use, observe the antifatigue effect of medicine to mice with spleen deficiency; Select for use serum amylase to observe the improvement effect of medicine to the mice with spleen deficiency digestive function; Observe medicine to immune influence by the result that influences to spleen coefficient and thymus coefficient.Specific as follows:
(1) grouping and modeling
96 kunming mices are divided into 6 groups (16/group) at random, every group of male and female half and half, i.e. blank group, model control group, decoction of four noble drugs group (dosage group (containing four gentleman's total polysaccharides 1g/kg), four gentleman's drop pill low dose group (containing four gentleman's total polysaccharides 0.5g/kg) in 35g crude drug/kg), four gentleman's drop pill high dose group (containing four gentleman's total polysaccharides 2g/kg), the four gentleman's drop pill.Except that the blank group gavages the tap water, all the other each groups are irritated stomach Radix Et Rhizoma Rhei water extract 37.5g/kg and are carried out modeling, once a day, and continuous 2 weeks of modeling.Gavage Radix Et Rhizoma Rhei water extract after two weeks, compare with the blank group, phenomenons such as hair, movable minimizing, dietary amount minimizing appear alarmming in the modeling mice, illustrate that the modeling mice has had insufficiency of the spleen symptom.After two weeks, except that the blank group gavages the tap water, all the other are respectively organized every day swimming and once (make mice continue to keep insufficiency of the spleen symptom and have deficiency of vital energy symptom concurrently, phenomenons such as animal appearance activity minimizing behind the merging swimming model, drowsiness), and gavage corresponding medicine, be model control group gavage xylitol and hydroxypropyl emthylcellulose (HPMC) mixture (xylitol: the HPMC mass ratio is 1: 0.004) (3.5g/kg), the decoction of four noble drugs group gavages decoction of four noble drugs water extract, 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 gavaged for two weeks continuously, once a day.
(2) to the influence of mice with spleen deficiency muscle power fatigue model
A. transfer rod experiment
When medicine gavages the 14th day, each group mice is carried out the transfer rod experiment detect, specific as follows:
The rotating speed of the tired transfer rod instrument of ZB-200 is adjusted to 40r/min, synchronously 5 mices are placed on the transfer rod, test first three day adaptability transfer rod 3 times, each 10min, behind the administration 1h, it is on the 40r/min transfer rod that each group mice is placed on rotating speed, the time that the record mice stops on transfer rod, if fall in the 2min, with its put immediately rod go up to continue experiment (with reference to " and Zhang Lin, Wei Jianyi, Han Degang etc. glutinous rehmannia soup against fatigue is to the mouse anti-reflecting fatigue experimental study of effect. Taishan Hospital's journal; 2009,30(3): 161-164 ").
B. swimming test
When medicine gavages the 15th day, each group mice is carried out swimming test detect, specific as follows:
Mice is placed the swimming case of 25 ± 1 ℃ of water temperatures, the about 30cm of the depth of water, behind the administration 1h, to put into the swimming case, record begins to enter the water surface to the mice head from swimming and can not lift the time, as the mice swimming time (with reference to " and Zhang Lin, Wei Jianyi, Han Degang etc. glutinous rehmannia soup against fatigue is to the mouse anti-reflecting fatigue experimental study of effect. Taishan Hospital's journal; 2009,30(3): 161-164 ").
The result shows: compare with the blank group, model control group mice swimming time obviously shortens (P＜0.01); The no significant difference of all the other each groups.Compare with model control group, decoction of four noble drugs group, high, medium and low each the dosage group swimming time of four gentleman's drop pill all have prolongation, wherein decoction of four noble drugs water extract group, four gentleman's drop pill height, middle dosage group 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 the 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, high, medium and low each dosage group transfer rod time of four gentleman's drop pill, wherein four gentleman's drop pill height, middle dosage group have significant difference (P＜0.01, P＜0.05), and effect is better than the decoction of four noble drugs group.The results are shown in Table 1.
Table 1 four gentleman's drop pill are to mice with spleen deficiency swimming and the influence of transfer rod time
Annotate: compare △ P＜0.05, △ △ P＜0.01 with the blank group; Compare * P＜0.05, * * P＜0.01 with model control group; With decoction of four noble drugs group comparison ▲ P＜0.05.
(3) to the influence of mice with spleen deficiency autonomic activities
When medicine gavages the 15th day, each group mice is carried out autonomic activities detect, specific as follows:
1h after the administration places mice in the ZB-200 type toy autonomic activities instrument, adapts to 5min, the active number of times of mice in the record 5min (with reference to " side of magnifying, Jin Ruomin, Meng Xianli etc. pharmacology and herbal pharmacology experiment. Shanghai science tech publishing house; 2006, second edition, 34-35 ").
The result shows: compare with the 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, high, medium and low dosage group autonomic activities time of four gentleman's drop pill obviously prolong (P＜0.05, or P＜0.01), and 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's drop pill are to the influence of mice with spleen deficiency autonomic activities
Annotate: compare △ P＜0.05, △ △ P＜0.01 with the blank group; Compare * P＜0.05, * * P＜0.01 with model control group; With decoction of four noble drugs group comparison ▲ P＜0.05.
(4) to the influence of mice with spleen deficiency immune organ and serum amylase
1h after the last administration, on the one hand, the eye socket venous plexus is got blood, and 3000r/min is centrifugal, gets serum, measures serum amylase content with serum starch enzyme reagent kit.On the other hand, put to death mice, get thymus and spleen, weigh, calculating organ coefficient (organ coefficient=organ weights (g)/mice body weight (g)) (with reference to " Gan Jingyi, Gong Zhongfu, Cheng Guilin etc. decoction of four noble drugs is to the influence of Rats with Spleen-deficiency serum digestive enzyme and gut hormone. Chinese veterinary's magazine; 2011,42(2): 43-44 ").
Immune organ quality testing result shows: compare with the blank group, model control group spleen coefficient and thymus coefficient obviously reduce (P＜0.01); Compare 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 height, middle dosage group action effect be (P＜0.05 significantly, P＜0.01), illustrates 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's drop pill are to the influence of mice with spleen deficiency spleen coefficient and thymus coefficient
Annotate: compare △ P＜0.05, △ △ P＜0.01 with the blank group; Compare * P＜0.05, * * P＜0.01 with model control group.
The serum amylase testing result shows: compare with the blank group, model control group mice serum amylase (AMS) significantly reduces (P＜0.01); With model control group relatively, decoction of four noble drugs group, four gentleman's drop pill height, in, dosage group serum amylase obviously increases (P＜0.05, or P＜0.01); With the decoction of four noble drugs group relatively, four gentleman's drop pill height, the effect of middle dosage group be (P〉0.05) better.The results are shown in Table 4.
Table 4 four gentleman's drop pill are to the influence of amylase content in the mice with spleen deficiency serum
Annotate: compare △ P＜0.05, △ △ P＜0.01 with the blank group; Compare * P＜0.05, * * P＜0.01 with model control group; With decoction of four noble drugs group comparison ▲ P＜0.05.
2, four gentleman's dropping pill formulations are to the experimentation of mice gastrointestinal motility influence
Laboratory animal: kunming mice, male and female half and half, body weight 18-20g purchases the Experimental Animal Center in Mountain Western Medicine S University, quality certification SCXK-201101.
Medicine: four gentleman's dropping pill formulations of step 1 preparation, decoction of four noble drugs water extract, and Radix Et Rhizoma Rhei extract.Wherein, decoction of four noble drugs water extract is prepared as follows and obtains: the mixed that four kinds of crude drug Radix Codonopsis, Rhizoma Atractylodis Macrocephalae (parched), Poria, Radix Glycyrrhizae Preparata are pressed mass ratio 2:2:2:1, the water that adds 8 times of quality soaks 1h, decocts 2h, double gauze filters, with adding water, decoction, filtering step more than the filtering residue repetition, repeat 2 times, merge the filtrate of 3 decoctions, filtrate is concentrated into 1.75g/mL, and cold preservation is standby.Radix Et Rhizoma Rhei extract is prepared as follows and obtains: the water of getting 3 times of quality soaks 1h with Radix Et Rhizoma Rhei, water boiling and extraction 15min, and double gauze filters, the decocting that filtering residue adds 2 times of quality boils 15min, and merging filtrate is concentrated into 1.5g/mL, sealing, cold preservation standby (being used to make the mice with spleen deficiency model).
This research is selected for use intestinal propelling rate, gastric emptying amount to observe medicine mice with spleen deficiency is digested and assimilated and the active influence of gastrointestinal, selects the influence to the mice with spleen deficiency gut hormone of motilin, vasoactive intestinal peptide, PGE2 and several index observing medicines of P material for use.Specific as follows:
(1) grouping and modeling
72 kunming mices are divided into 6 groups (12/group) at random, every group of male and female half and half, i.e. blank group, model control group, decoction of four noble drugs group (dosage group (containing four gentleman's total polysaccharides 1g/kg), four gentleman's drop pill low dose group (containing four gentleman's total polysaccharides 0.5g/kg) in 35g crude drug/kg), four gentleman's drop pill high dose group (containing four gentleman's total polysaccharides 2g/kg), the four gentleman's drop pill.Gradation administration every days two, adopt the method for limit administration limit modeling, gavage tap water except that the blank group morning, all the other each groups gavage corresponding medicine, be model control group gavage xylitol and hydroxypropyl emthylcellulose (HPMC) mixture (xylitol: the HPMC mass ratio is 1: 0.004) (3.5g/kg), the decoction of four noble drugs group gavages decoction of four noble drugs water extract, four gentleman's drop pill height, in, low dose group gavages four gentleman's drop pill solution of respective concentration, gavage tap water except that the blank group afternoon, all the other each groups are irritated stomach Radix Et Rhizoma Rhei water extract 37.5g/kg and are carried out modeling, after administration every afternoon finishes, the mice of respectively organizing except that the blank group is placed 25 ± 1 ℃ of water temperatures, in the swimming case of the about 30cm of the depth of water, pick up behind the swimming 10min and dry up, continuous two weeks (make mice swimming every day once, be to keep insufficiency of the spleen symptom and have deficiency of vital energy symptom concurrently in order to continue, i.e. appearance activity reduces, phenomenons such as drowsiness).
(2) to the influence of mice with spleen deficiency intestinal propelling rate and gastric emptying amount
When medicine gavages the 15th day, each group mice is carried out the detection of intestinal propelling rate and gastric emptying amount, specific as follows:
30min after the administration gavages 1% methyl orange, and dosage is 0.1mL/10g, and behind the 20min, eyeball of mouse is got blood till death, and weighing mice body weight is dissected, and with intercepting stomach after the two ends ligation of mice stomach, intercepts small intestinal again.With in the tape measure to pylorus, down to the intestinal tube length of ileocecus, and the orange red partial-length that dyes of methyl.Calculate methyl orange propelling rate, propelling rate=advance distance (cm)/small intestinal total length (cm) * 100%.It is 1%(1g/100ml that stomach is placed 5mL concentration) sodium bicarbonate solution, break with shears, soak half an hour after, the centrifugal 10min of 2000r/min gets supernatant, surveys its absorbance (A), calculates the gastric emptying amount, gastric emptying amount=(1-A)/A
Contrast* 100%(A
ContrastBe dissolved in the absorbance of 5mL sodium bicarbonate solution for 1% methyl orange of 0.25mL).
Intestinal propelling rate testing result shows: compare with the blank group, model control group intestinal propelling rate increases to some extent.Compare with model control group, all the other each dosage groups all decrease, but do not have significant difference.
Gastric emptying amount testing result shows: compare with the contrast of blank group, model control group, decoction of four noble drugs group gastric emptying amount have significantly and reduce (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 the decoction of four noble drugs group is increase tendency, no significant change.Compare with the 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's drop pill are to the influence of mice with spleen deficiency intestinal propelling rate and stomach residual quantity
Annotate: compare △ P＜0.05, △ △ P＜0.01 with the blank group; Compare * P＜0.05, * * P＜0.01 with model group; With decoction of four noble drugs group comparison ▲ P＜0.05, ▲ ▲ P＜0.01.
(3) to the influence of the active intestinal peptide of mice with spleen deficiency serum motilin and small intestinal homogenate, PGE2 and P material
When medicine gavages the 15th day, each group mice is carried out the detection of serum motilin (MTL) and the active intestinal peptide (VIP) of small intestinal homogenate, PGE2 (PGE2) and P material (SP), specific as follows:
Mice is got blood from the canthus, and the centrifugal 10min of 3500r/min gets serum, with ELESA kit measurement mice serum motilin.The intercepting intestinal tube is weighed, and makes 10% tissue homogenate, and the centrifugal 10min of 2500r/min gets supernatant, measures VIP, PGE2, SP content in the mouse small intestine homogenate with the ELESA method.The ELESA operation is carried out with reference to reagent corresponding box description.After below respectively organizing data compilation, handle comparative analysis with statistical method.
Serum motilin testing result shows: compare with the blank group, the motilin of model control group mice (MTL) level is significance rising trend (P＜0.01).Compare with model control group, four gentleman's drop pill height, middle dosage group mice motilin (MTL) level are obvious reduction trend (P＜0.05), the decoction of four noble drugs group is obvious rising trend (P＜0.05), and four gentleman's drop pill low dose group are reduction trend, but no significant difference.Compare with the 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's drop pill are to the influence of mice with spleen deficiency motilin
Annotate: compare △ P＜0.05, △ △ P＜0.01 with the blank group; With model control group relatively * P＜0.05, * * P＜0.01, with decoction of four noble drugs group comparison ▲ P＜0.05, ▲ ▲ P＜0.01.
The testing result of the active intestinal peptide of small intestinal homogenate, PGE2 and P material shows: compare with the blank group, the active intestinal peptide content of model control group small intestinal homogenate is rising trend, and has significant difference (P＜0.05), compare with model control group, the active intestinal peptide of decoction of four noble drugs group and four gentleman's drop pill low dose group small intestinal homogenates level obviously reduces and has a significant difference (P＜0.05, P＜0.01), four gentleman's drop pill height, middle dosage group are reduction trend, no significant difference.Compare with the blank group, model control group PGE2 (PGE2) level has significance rising (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), the dosage group is reduction trend, no significant difference in four gentleman's drop pill.Compare with the blank group, model control group, four gentleman's drop pill high dose group P material (SP) levels all have significant difference (P＜0.01), and decoction of four noble drugs group, four gentleman's drop pill height, middle dosage group all have notable difference (P＜0.05).Compare decoction of four noble drugs group, the equal no significant difference of each dosage group of four gentleman's drop pill with model control group.The results are shown in Table 7.
Table 7 four gentleman's drop pill are to the influence of mice with spleen deficiency vasoactive intestinal peptide, PGE2 and P material
Annotate: compare △ P＜0.05, △ △ P＜0.01 with the blank group; Compare * P＜0.05, * * P＜0.01 with model control group.
Claims (9)
1. four gentleman's dropping pill formulations are made up of volatile oil, four gentleman's total polysaccharidess and substrate;
Described volatile oil obtains Rhizoma Atractylodis Macrocephalae (parched) through carbon dioxide supercritical fluid extraction;
Described four gentleman's total polysaccharidess are extracted from four kinds of crude drug of following mass fraction and obtained: 2 parts of Radix Codonopsis, 2 parts of Rhizoma Atractylodis Macrocephalae (parched) residues, 2 parts in Poria, 1 part of Radix Glycyrrhizae Preparata, described Rhizoma Atractylodis Macrocephalae (parched) residue are with Rhizoma Atractylodis Macrocephalae (parched) remaining material behind the described volatile oil of 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, 35～45 ℃ of temperature, time 1.5～2h.
4. the preparation method of four gentleman's dropping pill formulations comprises the steps:
(1) volatile oil in the employing carbon dioxide supercritical fluid extraction Rhizoma Atractylodis Macrocephalae (parched) is collected the Rhizoma Atractylodis Macrocephalae (parched) residue simultaneously;
(2) with the described Rhizoma Atractylodis Macrocephalae (parched) residue of step (1) with after Radix Codonopsis, Poria and Radix Glycyrrhizae Preparata mix according to following portions by weight, extract four gentleman's total polysaccharidess: after 2 parts of described Radix Codonopsis, 2 parts of described Rhizoma Atractylodis Macrocephalae (parched) residues, 2 parts in described Poria, 1 part of mixing of described Radix Glycyrrhizae Preparata, extract four gentleman's total polysaccharidess;
(3) be that the ratio of 1:0.01～0.03:4～5:0.01～0.03 prepares four gentleman's dropping pill formulations with described four gentleman's total polysaccharidess, described volatile oil, xylitol and hydroxypropyl emthylcellulose according to the quality proportioning.
5. method according to claim 4 is characterized in that: in the step (1), the condition of described carbon dioxide supercritical fluid extraction is pressure 40～45MPa, 35～45 ℃ of temperature, time 1.5～2h;
In the 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.
6. according to arbitrary described four gentleman's dropping pill formulations among the claim 1-3, or claim 4 or 5 described methods, it is characterized in that: the extracting method of described four gentleman's total polysaccharidess comprises that with protease the water extract of described four kinds of crude drug being carried out enzymolysis removes proteic step.
7. four gentleman's dropping pill formulation or methods according to claim 6 is characterized in that: described protease is papain.
8. four gentleman's dropping pill formulation or methods according to claim 7 is characterized in that: the temperature with described papain enzymolysis is 50-60 ℃, and pH value can be 5-6, and enzymolysis time can be 3h; Or
The proportioning of crude drug described in described papain and the claim 1 is 240-360U:100g.
9. four gentleman's dropping pill formulation or methods according to claim 8 is characterized in that: the temperature with described papain enzymolysis is 50 ℃, and pH value is 6; Or
The proportioning of crude drug described in described papain and the claim 1 is 240U:100g.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104958636A (en) * | 2015-07-29 | 2015-10-07 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal composition for treating functional dyspepsia and preparation method of medicinal composition |
| CN113713077A (en) * | 2021-10-12 | 2021-11-30 | 袁泳晴 | Sijunzi ointment and preparation method thereof |
| CN114366790A (en) * | 2022-01-27 | 2022-04-19 | 冯利 | Traditional Chinese medicine composition for preventing and treating tumor and treating after-appetite loss and gastrointestinal reaction |
| CN115530306A (en) * | 2022-10-13 | 2022-12-30 | 广东好味鲜菜品与营养研究所 | Radix pseudostellariae-containing bubble beverage capable of strengthening spleen and enhancing immunity and production process thereof |
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| CN1872260A (en) * | 2005-06-01 | 2006-12-06 | 天津天士力制药股份有限公司 | Method for preparing drop pills of ageratum vital qi |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104958636A (en) * | 2015-07-29 | 2015-10-07 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicinal composition for treating functional dyspepsia and preparation method of medicinal composition |
| CN113713077A (en) * | 2021-10-12 | 2021-11-30 | 袁泳晴 | Sijunzi ointment and preparation method thereof |
| CN114366790A (en) * | 2022-01-27 | 2022-04-19 | 冯利 | Traditional Chinese medicine composition for preventing and treating tumor and treating after-appetite loss and gastrointestinal reaction |
| CN114366790B (en) * | 2022-01-27 | 2023-03-14 | 冯利 | Traditional Chinese medicine composition for preventing and treating anorexia and gastrointestinal reaction after tumor treatment |
| CN115530306A (en) * | 2022-10-13 | 2022-12-30 | 广东好味鲜菜品与营养研究所 | Radix pseudostellariae-containing bubble beverage capable of strengthening spleen and enhancing immunity and production process thereof |
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