CN103083408A - Composition of traditional Chinese medicine extracts, and preparation method and application thereof - Google Patents
Composition of traditional Chinese medicine extracts, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a composition of traditional Chinese medicine extracts, and a preparation method and an application thereof. The composition is composed of extracts obtained from crude drugs of rhizoma corydalis and radix angelicae dahuricae. The composition can be used for treating and/or preventing a plurality of aches and depression which are caused by qi stagnation and blood stasis, and has the advantages of safety, efficiency, controllability, etc.
Description
Technical field
The present invention relates to a kind of Chinese medicine extraction compositions.Specifically, described compositions is to get as raw material prepares take Rhizoma Corydalis (Rhizoma corydalis) and the Radix Angelicae Dahuricae (Angelica dahurica) extract separately.The invention still further relates to the preparation method and its usage of described Chinese medicine extraction compositions.
Background technology
Pain is a kind of offending sensation and the emotional experience relevant to tissue injury or potential tissue injury, is also the disease that the mankind experience the earliest and are familiar with.Pain not only makes patient's disablement, cause income descend or lose the job, and the person's that makes the chronic pain independence of personality is on the hazard, and the patient can feel that life loses interest and meaning, and severe patient causes the breakdown of a family, commits suiside and even jeopardize society." exempting pain is the whole mankind's right " proposed in the 9th world's pain conference holding in Vienna in 1999 " pain is not only a kind of symptom, is also a kind of disease " first.
The diagnosis and treatment of the origin of Chinese medicine and theory characteristic and pain card are put into practice closely related.According to motherland's theory of medicine: health is inside and outside to be produced a kind of insufferable suffering and cries bitterly.Meng Qingyun thinks that pain demonstrate,proves theoretical developments and experienced with the cold and heat cause of disease, QI and blood pathogenesis and acted on " interior warp " epoch that passages through which vital energy circulates, the five internal organs class are divided into sign; Divide card from diseases caused by exogenous pathogenic factor, internal injury, establish the Zhong Jing epoch that pain is demonstrate,proved the determination for the treatment of based on pathogenesis obtained through differentiation of symptoms and signs system; In-depth and foundation pain are demonstrate,proved theory of pathogenesis take Li Dongyuan, Zhu Danxi as representative, from the gold dollar epoch that gas, blood, expectorant, Yu Lifa opinion are controlled; Break through " pain is without reinforcement " forbidden zone, advocate Ming Dynasty Warm-recuperation school epoch (Meng Qingyun, Research Institute of Basic Theories, China Academy of Traditional Chinese Medicine, journal of shanghai Chinese medicine [J] .1999,33 (3): 4-6) that all methods of pain are controlled in temperature compensation.The traditional Chinese medical science thinks that the pathogenesis of pain has: stagnation of QI and blood may bring about pain; Rong Ze is not bitterly; Canonical pain etc. not.Chinese medicine thinks, personal passages through which vital energy circulates is popular, and the QI and blood ring turns, inside and outside the up and down, when having.If the pathogenic factor addition, gas is capable not smooth, and blood fortune is uncomfortable, and QI and blood is obstructed, pain occurs.For the treatment of pain, from ancient times to the present always take determination for the treatment of based on pathogenesis obtained through differentiation of symptoms and signs as main flow, take the etiology and pathogenesis of pain as point of penetration, make laws with " leading to ".Arthralgia is followed general rule not bitterly, Rong Ze not bitterly, canonical is bitterly rule not.The profound scholar ancestor of the Qing Dynasty discusses " the logical three therapeutic methods of traditional Chinese medicine is had nothing in common with each other, and regulating QI and blood transfer blood gentle, lead to also ... making that empty person helps is logical, and cold person's using warming therapy makes logical ... ".For arthralgia, blood-activating and qi-promoting, dredging the meridian are the base therapy principle, take blood circulation promoting medicine, QI regulating medicine as basic Chinese medicine commonly used, improve symptom to reach, and dispel induced pain pathogenic factor and elimination or alleviate the purpose of its pain pathogenesis.
YUANHU ZHITONG PIAN is the compound recipe of Rhizoma Corydalis and the Radix Angelicae Dahuricae, have regulate the flow of vital energy, invigorate blood circulation, the effect of pain relieving, be usually used in treating qi depression to blood stasis stomachache, hypochondriac pain, headache and dysmenorrhea (China national committee of pharmacopeia, Chinese Pharmacopoeia [M]. Beijing: Chemical Industry Press, 2005:362).Studies have shown that now, YUANHU ZHITONG PIAN has good analgesic effect (Yang Qian, Wang Siwang. tetrahydropalmatine and total coumarin angelica dahurica, total volatile oil compatibility comparative study of pharmacodynamics, modern biomedical progress [J] .2009,9 (15): 2814-2816.).The chemical composition of Rhizoma Corydalis pain relieving is mainly Corydaline (d-corydaline), tetrahydropalmatine (dl-THP), Rhizoma Corydalis element in the last of the ten Heavenly stems (corydalis J), corydalis (corydalis L), wherein the analgesic activity with dl-THP is the strongest, corydalis takes second place, Corydaline, Rhizoma Corydalis element in the last of the ten Heavenly stems be (Zheng Hanchen again, Cai Shaoqing. medicobotany and the pharmacognosy [M]. the 4th edition. Beijing: the People's Health Publisher, 2006:284).The chemical composition of Radix Angelicae Dahuricae pain relieving is mainly the volatile oil material (Zhang Fuqiang such as the coumarin substances such as imperatorin (imperatorin), isoimperatorin (isoimperatorin), oxypeucedanin (oxypeucedanin) and methyl cyclodecane, Agidol, tetradecene, the people such as Nie Hong. Nanjing University of Traditional Chinese Medicine's journal (natural science edition) [J] .2002,18 (3): 190-192).
Depression refers to take significantly and depressed, the mobility that continue go down, thinking and the slow class mood disorders as main clinical characteristics of cognitive function.Development along with society, the quickening of people's life and work rhythm, people are bearing life stress and are increasing the increasing stress cause, cause the problems such as depressed, dejected, depression and Mental Subnormality, the sickness rate of having a depression is improved constantly, affected modern's life.The clinical practice of anti-depression drug is subjected to the restriction of the shortcomings such as its drug resistance and side effect, and Chinese Traditional Medicine has rich experience and a large amount of document records aspect Cure of depression.Though Chinese medicine is without the name of " depression ", from its characteristics of incidence and clinical realization, with mental diseases such as " strongly fragrant disease ", " Bulbus Lilii syndrome ", " hysteria " of Chinese medicine, " epilepsy ", " palpitations with fear ", certain contact is arranged.Modern pharmacology experiment showed, the active closely related of depression and the interior monoamine oxidase, MAO (MAO) of body.Separate the active component that obtains from Chinese medicine, can affect the activity of MAO.For example, separate the protopine that obtains and get rid of in the head experiment the mice that TST tests and 5-HTP induces from Radix dactylicapni (Radix Dactylicapnotis), demonstrate good antidepressant activity; In addition, separate the coumarins such as 6-(3-methylbut-2-enyl)coumestrol. that obtain from Fructus Psoraleae, can significantly reduce the dead time of mice in the FST experiment, on its autonomic activities without impact, can increase the contents level (Zhu Lin of the interior 5-hydroxy tryptamine of brain and DOPA, the progress of antidepressant plant amedica, medical Leader [J] .2010,29 (10): 1287-1291).
Summary of the invention
The present invention relates to a kind of Chinese medicine extraction compositions, it is comprised of the extract that obtains from Rhizoma Corydalis and Radix Angelicae Dahuricae crude drug respectively, and the preparation method of described extract is as follows:
The preparation method of Rhizoma Corydalis extract: get the corydalis tuber medicinal material powder, the ethanol/water of the 40%-80% that doubly measures with 2-4 soaks, reflux 2-4 hour, collect extracting solution, add again ethanol/water reflux 1-3 hour of the 40%-80% that 1-3 doubly measures, collect extracting solution, merge secondary raffinate, filter, filtrate is concentrated into without the alcohol flavor; Select the ion exchange resin chromatography purification, reclaim solvent, vacuum drying gets extractum, pulverizes, and sieves, and gets Rhizoma Corydalis extract.
The preparation method of Radix Angelicae Dahuricae extract: get the angelica root powder, the ethanol/water of the 50%-90% that doubly measures with 4-6 soaks, reflux 2-4 hour, collect extracting solution, add again ethanol/water reflux 1-3 hour of the 50%-90% that 4-6 doubly measures, collect extracting solution, merge secondary raffinate, filter, filtrate is concentrated into without the alcohol flavor; Select the macroporous resin chromatography purification, reclaim solvent, vacuum drying gets the yellowish-brown powder, and absolute ethanol washing reclaims ethanol, and vacuum drying gets extractum, pulverizes, and sieves, and gets Radix Angelicae Dahuricae extract.
In described Chinese medicine extraction compositions, Rhizoma Corydalis extract and Radix Angelicae Dahuricae extract are according to the parts by weight proportioning, and its ratio of weight and number is 1-100: 1-50, and the preferred weight portion rate is 10-100: 5-50, and more preferably ratio of weight and number is 20-100: 10-50.
Described Chinese medicine extraction compositions also can comprise arbitrary pharmaceutically acceptable carrier, and it comprises diluent, excipient, filler, wetting agent, disintegrating agent, correctives and binding agent etc.
In addition, the invention still further relates to a kind of method for preparing described Chinese medicine extraction compositions.At first according to the method described above obtain corresponding extract respectively from Rhizoma Corydalis and Radix Angelicae Dahuricae crude drug; Secondly two kinds of Chinese medicine extract are mixed according to concrete ratio of weight and number, after adding at last appropriate carrier, mixing is to prepare arbitrary pharmaceutically acceptable dosage form, as injection, infusion solution, mixture, tablet, hard capsule, soft capsule, pill, drop pill, granule, patch and cataplasma etc., be preferably hard capsule.
The invention still further relates to described Chinese medicine extraction compositions and treat and/or prevent by the purposes in the medicine of the pain of caused by energy stagnation and blood stasis in preparation, described pain can comprise stomachache, hypochondriac pain, headache and dysmenorrhea.In addition, the invention still further relates to described Chinese medicine extraction compositions and treat and/or prevent purposes in the medicine of depression in preparation.Using method and the using dosage of described Chinese medicine extraction compositions depend on many factors, as persistent period of patient's age, body weight, sex, health status, diet and symptom and order of severity etc.Those skilled in the art can easily determine its using method and using dosage according to above-mentioned factor.
Chinese medicine extraction compositions in the present invention is that the inventor is from the theory of traditional Chinese medical science blood circulation promoting and blood stasis dispelling regulating QI to relieve pain, following traditional proved recipe---on the basis of Yuanhu Zhitong Prescription and the utilization clear and definite Rhizoma Corydalis of modern science and technology and the Radix Angelicae Dahuricae two flavor crude drugs active component separately, two extracts of distinguishing the flavor of crude drugs are made up and make.Prove through pharmacodynamics test (mouse writhing experiment and hot-plate): the writhing that extractive composition of the present invention can effectively reduce mice test period in lick the pawl number of times, and then show described extractive composition treat with prevent irritation aspect compare with traditional prescribed preparation and have identical or more excellent effect.
The present inventor carries out antidepressant activity network target to 17 kinds of main activated monomers (seeing Table 1) relevant to analgesia in Rhizoma Corydalis and the Radix Angelicae Dahuricae two flavor crude drugs and predicts, as shown in Figure 1.
Table 1 is used for 17 kinds of activated monomers of antidepressant activity prediction
As can be seen from the figure, described 17 kinds of monomer component overwhelming majority act on ABO and HSP90AA1 target point protein, and are both relevant with thrombocytopenia.Simultaneously, described 17 kinds of molecule great majority act on CYP2C9, GSK3B, HSPA8, MAOB, NR3C1, PDE4B, PDE4D, PDE5A and SULT1A1 target point protein, these target point proteins are all closely relevant with the melancholia, and MAOB is also relevant with the muscular rigidity disease simultaneously.Prove through antidepressant test (mice forced swimming test etc.): Chinese medicine ingredients compositions of the present invention can effectively shorten the dead time of mice forced swimming and can effectively resist by the mouse temperature decline due to reserpine, blepharoptosis and akinetic sign, so show described compositions treat with prevention of depression aspect compare with positive control drug (fluoxetine) and have identical or more excellent effect.
Described Chinese medicine ingredients compositions is carried out long term toxicity test, its result proof oral administration safety; And because compositions of the present invention is to be formed through the extract combination that special extraction separation process obtains by two flavor crude drugs, has higher controllability compared to traditional prescribed preparation, for manufacture standardization and the curative effect controllability of described compositions have been established material base.
Description of drawings
Fig. 1 has shown that the antidepressant activity of 17 kinds of activated monomers in Rhizoma Corydalis and the Radix Angelicae Dahuricae predicts the outcome.
Fig. 2 has shown that Chinese medicine extraction compositions of the present invention is on the impact of rat diastolic blood vessel activity.Result shows, each is organized extractive composition and all has significant vasodilator effect (P＜0.05).
The specific embodiment
Further set forth Chinese medicine extraction compositions of the present invention below in conjunction with specific embodiment.The following example only is explanation the present invention, and should not be understood as limitation of the present invention.
Except specified otherwise, the conventional method that the experimental technique in following embodiment is well known to the skilled person; Described reagent and experiment material all can obtain from commercial channels.
In following embodiment, Rhizoma Corydalis used and the Radix Angelicae Dahuricae all meet the pertinent regulations under each medical material item of text of Pharmacopoeia of People's Republic of China version in 2005.Through identifying, each medical material title conforms to material object, and quality all meets standards of pharmacopoeia.
1. the preparation of Chinese medicine extraction compositions of the present invention
1.1 material
Rhizoma Corydalis originates from Hebei province available from Hebei province's Anguo Chinese crude drug company limited, and sample preservation is in Institute Of Chinese Materia Medica Of China Academy of Chinese Medical Sciences, and lot number is yp0031; The Radix Angelicae Dahuricae originates from Hangzhou available from Hebei province's Anguo Chinese crude drug company limited, and sample preservation is in Institute Of Chinese Materia Medica Of China Academy of Chinese Medical Sciences, and lot number is yp0032; NaOH (analytical pure, continent, Tianjin chemical reagent factory); Dehydrated alcohol (analytical pure, the Huifeng, Jinan reaches the chemical development company limited); Ammonia (analytical pure, Jinan century sensible chemical industry company limited); Hydrochloric acid (analytical pure, the source chemistry company limited that granary is rich); Pure water (Hangzhou Wahaha Group Co.,Ltd); 732 type cation exchange resiies (Shanghai remittance pearl resin company limited); D101-1 type macroporous resin (Anhui Samsung resin Science and Technology Ltd.); Capsule shells (the satisfied capsule company limited in Zhejiang Province).
1.2 extract Preparation Example
Extract Preparation Example 1:
Rhizoma Corydalis extract 1:
Get Rhizoma Corydalis 500g, with 70% soak with ethanol of 2 times of amounts 30 hours, reflux 3 hours was collected extracting solution, then added 70% alcohol heating reflux 2 hours of 2 times of amounts, collected extracting solution, merged secondary raffinate, filtered, and filtrate is condensed into without the alcohol flavor.Select 732 type cation exchange resin wet method dress posts, blade diameter length ratio is about 1: 10, loading, and applied sample amount is that corydalis tuber medicinal material and resin volume ratio are 1: 1 (g/mL), uses the purified water of 5BV with the elution speed remove impurity of 0.5BV/h.Then with 70% ethanol elution that contains ammonia of 4BV, elution speed is 1BV/h, reclaims solvent, and drying under reduced pressure gets extractum, pulverizes, and sieves, and gets Rhizoma Corydalis extract 1.
Radix Angelicae Dahuricae extract 1:
Get angelica root powder 500g, add 60% soak with ethanol 30 hours of 6 times of amounts, reflux 3 hours is collected extracting solution, then adds 60% alcohol heating reflux 2 hours of 6 times of amounts, collects extracting solution, merges secondary raffinate, filters, and filtrate is condensed into without the alcohol flavor.Select D101-1 type macroporous resin wet method dress post, loading, standing adsorption 30min, with the flow velocity remove impurity with 1.0mL/min of 10% ethanol of 2BV, the reject liquid of mixing, then contain the 30% alcoholic solution eluting of 0.5%NaOH with 3BV, collect eluent, to 3-4, reclaim ethanol with the dilute hydrochloric acid adjust pH, vacuum drying gets the yellowish-brown powder, then uses absolute ethanol washing, reclaims ethanol, vacuum drying, get extractum, pulverize and sieve, get Radix Angelicae Dahuricae extract 1.
Extract Preparation Example 2:
Rhizoma Corydalis extract 2:
Get Rhizoma Corydalis 500g, with 50% soak with ethanol of 4 times of amounts 20 hours, reflux 3 hours was collected extracting solution, then added 50% alcohol heating reflux 2 hours of 4 times of amounts, collected extracting solution, merged secondary raffinate, filtered, and filtrate is condensed into without the alcohol flavor.Select 732 type cation exchange resin wet method dress posts, blade diameter length ratio is about 1: 10, loading, and applied sample amount is that corydalis tuber medicinal material and resin volume ratio are 1: 1 (g/mL), uses the purified water of 5BV with the elution speed remove impurity of 0.5BV/h.Then with 70% ethanol elution that contains ammonia of 4BV, elution speed is 1BV/h, reclaims solvent, and drying under reduced pressure gets extractum, pulverizes, and sieves, and gets Rhizoma Corydalis extract 2.
Radix Angelicae Dahuricae extract 2:
Get angelica root powder 500g, add 50% soak with ethanol 20 hours of 7 times of amounts, reflux 3 hours is collected extracting solution, then adds 50% alcohol heating reflux 2 hours of 7 times of amounts, collects extracting solution, merges secondary raffinate, filters, and filtrate is condensed into without the alcohol flavor.Select D101-1 type macroporous resin wet method dress post, loading, standing adsorption 30min, with the flow velocity remove impurity with 1.0mL/min of 10% ethanol of 2BV, the reject liquid of mixing, then contain the 30% alcoholic solution eluting of 0.5%NaOH with 3BV, collect eluent, to 3-4, reclaim ethanol with the dilute hydrochloric acid adjust pH, vacuum drying gets the yellowish-brown powder, then uses absolute ethanol washing, reclaims ethanol, vacuum drying, get extractum, pulverize and sieve, get Radix Angelicae Dahuricae extract 2.
Extract Preparation Example 3:
Rhizoma Corydalis extract 3:
Get Rhizoma Corydalis 500g, with 60% soak with ethanol of 3 times of amounts 24 hours, reflux 3 hours was collected extracting solution, then added 60% alcohol heating reflux 2 hours of 3 times of amounts, collected extracting solution, merged secondary raffinate, filtered, and filtrate is condensed into without the alcohol flavor.Select 732 type cation exchange resin wet method dress posts, blade diameter length ratio is about 1: 10, loading, and applied sample amount is that corydalis tuber medicinal material and resin volume ratio are 1: 1 (g/mL), uses the purified water of 5BV with the elution speed remove impurity of 0.5BV/h.Then with 70% ethanol elution that contains ammonia of 4BV, elution speed is 1BV/h, reclaims solvent, and drying under reduced pressure gets extractum, pulverizes, and sieves, and gets Rhizoma Corydalis extract 3.
Radix Angelicae Dahuricae extract 3:
Get angelica root powder 500g, add 5 times of amount 70% soak with ethanol 24 hours, reflux 3 hours is collected extracting solution, then adds 70% alcohol heating reflux 2 hours of 5 times of amounts, collects extracting solution, merges secondary raffinate, filters, and filtrate is condensed into without the alcohol flavor.Select D101-1 type macroporous resin wet method dress post, loading, standing adsorption 30min, with the flow velocity remove impurity with 1.0mL/min of 10% ethanol of 2BV, the reject liquid of mixing, then contain the 30% alcoholic solution eluting of 0.5%NaOH with 3BV, collect eluent, to 3-4, reclaim ethanol with the dilute hydrochloric acid adjust pH, vacuum drying gets the yellowish-brown powder, then uses absolute ethanol washing, reclaims ethanol, vacuum drying, get extractum, pulverize and sieve, get Radix Angelicae Dahuricae extract 3.
1.3 Chinese medicine extraction compositions Preparation Example
Compositions A Preparation Example:
Getting above-mentioned Rhizoma Corydalis extract 1 and Radix Angelicae Dahuricae extract 1, is two kinds of extracts to be mixed evenly in 20: 50 according to ratio of weight and number, can add pharmaceutically acceptable carrier, is packed in capsule shells, makes the hard capsule of described Chinese medicine extraction compositions A.
Compositions B Preparation Example:
Getting above-mentioned Rhizoma Corydalis extract 2 and Radix Angelicae Dahuricae extract 2, is two kinds of extracts to be mixed evenly in 60: 30 according to ratio of weight and number, can add pharmaceutically acceptable carrier, is packed in capsule shells, makes the hard capsule of described Chinese medicine extraction compositions B.
Compositions C Preparation Example:
Getting above-mentioned Rhizoma Corydalis extract 3 and Radix Angelicae Dahuricae extract 3, is two kinds of extracts to be mixed evenly in 100: 10 according to ratio of weight and number, can add pharmaceutically acceptable carrier, is packed in capsule shells, makes the hard capsule of described Chinese medicine extraction compositions C.
2. pass through the effective substance of everted intestinal sac Study of Traditional Chinese Medicine extractive composition
existing document based on the active substance basis of Rhizoma Corydalis and the Radix Angelicae Dahuricae and quality standard aspect, the present inventor has determined that 17 chemical monomer compositions for the effective substance of studying compositions of the present invention (are respectively imperatorin, isoimperatorin, osthole, protopine, berberine hydrochloride, tetrahydropalmatine, scopoletin, xanthotoxin, oxypeucedanin, bergapton, N-1, Pimpinellin, α-allocryptopine, byak-angelicin, Byakangelicol, coptisine and corydaline), and above-mentioned chemical monomer is applied in the experiment of everted intestinal sac absorption composition Study.
2.1 material
2.1.1 instrument
ALC-M type tissue-organ water-bath system (Shanghai Alcott bio tech ltd), BP110S type electronic analytical balance (Sartorius company); Agilent 1200 series of high efficiency liquid chromatographic system (G1312A binary pump, the G1314AVWD detector), MTN-2800W type Nitrogen evaporator (AUTO SCIENCE company), GTR16-2 type high speed centrifuge (the sharp centrifuge company limited in Beijing epoch north), KH3200E type ultrasonic cleaner (Kunshan and wound ultrasonic instrument company limited).
2.1.2 medicine and reagent
Acetonitrile (chromatographically pure, Fisher company), methanol (chromatographically pure, Fisher company), distilled water (China Academy Of Traditional Chinese Medicine Traditional Chinese Medicine Research Institute's self-control), pure water (Hangzhou Wahaha Group Co.,Ltd).Other reference substance used is as shown in table 2:
Table 2 everted intestinal sac absorbs composition Study reference substance list used
2.1.3 animal
The SD rat, male, body weight 250 ± 10g is provided by Department Of Medicine, Peking University Laboratory Animal Science section, the quality certification number: SCXK (capital) 2006-0008.
2.1.4 Tai Shi (Tyrode) buffer
With 8.0g NaCl, 0.28g KCl, 1.0g NaHCO
3, 0.05g NaH
2PO
4And 0.1gMgCl
2Be dissolved in the 500mL distilled water airtight cold preservation; With 0.2g CaCl
2Be dissolved in airtight cold preservation in the 500mL distilled water; To both evenly mix under constantly stirring before use, and add the 1.0g glucose and get final product.
2.2 experimental technique
2.2.1 the assay method of 17 index components of YUANHU ZHITONG PIAN
Adopt the method for reporting in document to measure 17 index components, concrete operation method sees Yingchun Zhang for details, Haiyu Xu, the people such as Xiaomeng Chen, Journal of Pharmaceutical and Biomedical Analysis.56 (2011): 497-504.Wherein, chromatograph and mass spectrum condition are as follows:
Chromatographic condition: Agilent XDB C
18Chromatographic column (4.6mm * 50mm, 1.8 μ m); Mobile phase: A:0.3% formic acid water (ammonia is transferred PH=2.7), B: acetonitrile; The gradient elution program is as follows: 0-4min, 20-40%B; 4-6min, 40-80%B; 6-8.5min, 80%B; Flow velocity: 0.6ml/min; Agilent 1200 RRLC chromatographs (Agilent).
Mass spectrum condition: Agilent RRLC-QQQ (Agilent); Positive ion mode detects; Electron spray capillary voltage: 4000V; Atomisation pressure: 38psi; Nitrogen: flow is 10L/min, and temperature is 345 ℃; Sweep limits: m/z 100-500.The mass spectrum optimal conditions of each compound is as shown in table 3:
The mass spectrum optimal conditions of 17 compounds of table 3
2.2.2 the preparation of Yuanhu Zhitong Prescription test liquid
Rhizoma Corydalis, angelica root are pulverized respectively, crossed 40 mesh sieves, get respectively Yanhusuo 200g and Dahurian Angelica Root 100g, add 4 times of amount 70% ethanol, soak 1h, reflux twice, extracted 2 hours at every turn, filter, merging filtrate reclaims solvent, and drying under reduced pressure obtains extractum.Extractum is dissolved with tyrode's solution, make respectively the suspension of basic, normal, high concentration, every milliliter contained amount is respectively 40mg, 80mg, 160mg, uses for the intestinal valgus test.
The operation 2.2.3 intestinal turns up
After the rat of fasting 12h before experiment was weighed, disconnected cervical vertebra was put to death, and cuts off respectively skin and muscle along ventrimeson and hunter's line.The intestinal segment interval of investigating is 10cm, and beginning to measure 10cm downwards from the following 10cm of pylorus is the first jejunal segment; Measuring 10cm after the 10cm of interval is the second jejunal segment again; Beginning upwards to measure 10cm from the above 5cm of ileocecal valve is ileal segment.The intestinal tube of cutting is put into 0 ℃ of tyrode's solution rinse, extremely without till intestinal contents.The soft end of self-control silica gel sleeve pipe is inserted intestinal tube, use the silk thread ligation, carefully intestinal is overturn.Rinse inner surface with 0 ℃ of tyrode's solution, the other end is become cryptomere with the silk thread ligation.Intestinal tube is put into the maxwell bath pipe that fills 37 ℃ of constant temperature tyrode's solutions of 25ml, begun to provide mist (95%O
2And 5%CO
2).Inject the 2ml tyrode's solution in intestinal tube, then intestinal tube is put into the pastille tyrode's solution of variable concentrations (representing large, medium and small three dosages).After administration 120min, take out respectively three sections all intestinal juice of enteral, merge intestinal juice.Sample is put into clean EP pipe, and is stand-by in-20 ℃ of upright preservations.Experiment is vertically cut intestinal tube open after finishing, and naturally spreads out and measure length and width on filter paper, records absorption area A.
2.2.4 the preparation of need testing solution
Get 300 μ L from intestinal tube respectively in different time points, dry up with nitrogen after accurate measuring 250 μ L, add 25 μ L 70% dissolve with methanol, with 0.22 μ m membrane filtration, after injecting 10 μ L, use the RRLC-QQQ-MS systematic analysis, substitution standard curve calculating concentration.
2.2.5 statistical method
Medicine accumulative total absorbtivity is pressed Q=C
nV calculates.Q is each time point Heavy metal amount of medicine.
2.3 result and discussion
Above-mentioned test is carried out on the document basis, adopt the analytical method of RRLC-QQQ-MS, can carry out qualitative and quantitative analysis to 17 index components in 9min, analysis time is shorter, the method has lower detectability and quantitative limit simultaneously, and sensitivity is higher.Blank intestinal absorption liquid does not disturb chromatographic behavior and the mass spectrum behavior of 17 index components, can use the method that has established and carry out the analysis of intestinal absorption liquid.Yuanhu Zhitong Prescription for different dosing dosage is as shown in table 4 by the accumulative total absorbtivity of three sections intestinal absorption:
As can be seen from Table 4, the composition that in extracting solution, content is higher is followed successively by: corydaline＞coptisine＞imperatorin＞protopine＞isoimperatorin＞α-allocryptopine＞N-1; And the composition that content is higher in intestinal absorption liquid is followed successively by: protopine＞corydaline＞α-allocryptopine＞tetrahydropalmatine＞coptisine＞byak-angelicin＞imperatorin.This shows, larger variation has occured in 17 component contents in Yuanhu Zhitong Prescription and ratio before and after administration, to the analysis of chemical composition in intestinal absorption liquid, help the effective substance of clear and definite Yuanhu Zhitong Prescription.In addition, in Yuanhu Zhitong Prescription, the absorbance of 17 index components is as shown in table 5:
The absorbance of 17 index components in table 5 Yuanhu Zhitong Prescription
As can be seen from Table 5, the absorbance of Byakangelicol, byak-angelicin, three compositions of tetrahydropalmatine is higher, is finally to transport to high concentration from low concentration, belongs to Active transport; The compositions such as scopoletin, protopine, α-allocryptopine, imperatorin, osthole are substantially equal in the intestinal absorption accumulative total absorbtivity of high dose and middle dosage, intestinal absorption liquid concentration is basic identical, illustrate that there is saturated phenomenon in these compositions, its absorption is relevant with intestinal transporter; The absorbance of the composition such as N-1, corydaline in high, medium and low dosage do not have significant difference, and these compositions may pass through passive diffusion absorption.
3. pharmacodynamics test
According to the result of intestinal valgus test, the composition that content is higher in intestinal absorption liquid has protopine, corydaline, α-allocryptopine, tetrahydropalmatine, coptisine, byak-angelicin, imperatorin, illustrates that these composition drug effect activity values get further research.The present inventor is according to the regulation requirement of state food drug surveilance office " medicine registration management way ", the design experiment scheme has been carried out following pharmacodynamics test research (to vasodilator effect, writhing test, hot plate test, antidepressant test and the long term toxicity test of rat chest aorta ring).
3.1 the vasodilator effect to the rat chest aorta ring
3.1.1 material
3.1.1.1 medicine
Make respectively the hard capsule of Chinese medicine extraction compositions A, B, C according to method described in above-described embodiment, the 0.3g/ grain.Positive control drug: YUANHU ZHITONG PIAN (pharmaceutical factory in another name for Sichuan Province, Sichuan, lot number: 100502).
3.1.1.2 animal
SPF level SD rat is provided by Beijing Vital River Experimental Animals Technology Co., Ltd., the animal quality certification number: SCXK (capital) 2006-009.
3.1.2 experimental technique
3.1.2.1 experimental animal grouping
Select the SD rat, body weight is 220-250g, and is female, is divided at random negative control group (blank), positive controls (YUANHU ZHITONG PIAN group), extractive composition A group, extractive composition B group and extractive composition C group.
3.1.2.2 the preparation for reagent liquid
Get the hard capsule of three kinds of extractive composition A, B, C, remove the hard capsule skin, pulverize, cross sieve No. 6, add tyrode's solution to be prepared into respectively to organize (respectively organizing concentration and be 0.1765g crude drug/ml) for reagent liquid of extractive composition; YUANHU ZHITONG PIAN is removed coating, pulverizes, and crosses sieve No. 6, and (concentration is 0.1765g crude drug/ml) to add tyrode's solution to be prepared into positive controls; The negative matched group of blank tyrode's solution.According to the operation of turning up of above-mentioned intestinal, prepare respectively intestinal absorption liquid, each three intestinal segments, each intestinal tube approximately prepare the 2ml left and right, merge respectively intestinal juice, obtain respectively respectively to organize intestinal absorption liquid for reagent liquid.Supply in reagent liquid cooling frozen being placed on-20 ℃ refrigerator the intestinal absorption liquid of preparation standby.
3.1.2.3 rat chest aorta ring preparation
Get male SD rat, the thoracic cavity is cut off in cervical region dislocation, takes out rapidly the thoracic aorta bar, is positioned in the K-H liquid of 4 ℃, and is placed on ice and separates.Carefully peel off the fat and the connective tissue that are attached to thoracic aorta, crosscut becomes the long vascular ring of 2-3mm.Vascular ring is hung in the bath that presets 5mlK-H liquid, temperature constant is 37.0 ± 0.2 ℃, continues to pass into 95%O
2And 5%CO
2Mist.One end of specimen is fixed, and the other end connects ALC-M in vitro tissue organ experimental system, the variation of recording tension force in experimentation through tonotransducer.Stable process first begins with 0g tension force, after keeping 30min, regulates its basic tension force to 1g, balance 1h, during change a K-H liquid every 20min.After aortic annulus is stable, stimulate with KCl (60mmol/L), use K-H liquid eluting after shrinking amplitude stabilization, to excite maximum collapse and to make the vasoconstriction state more stable.
3.1.2.4 the mensuration of rat chest aorta narrowing of the ring and diastolic function
Clean vascular ring for several times with K-H liquid, make it keep basic tension force.Then using KCl (60mmol/L) to bring out maximum shrinkage amplitude is 100%, add respectively each group according to 3.1.2.2 item preparation for reagent liquid, bring out with the antiotasis diastole amplitude after administration and KCl the amount effect curve that ratio between maximum shrinkage amplitude is made vasorelaxation action; The maximum shrinkage amplitude that drug-induced shrinkage amplitude all causes take KCl (60mmol/L) for the second time represents with percentage ratio as the relative standard value.
3.1.2.5 statistical analysis
Diastolic rate is that after administration, antiotasis compares with the blood vessel maximum collapse tension force that KCl causes the amplitude that descends.Experimental result under different quality concentration all with
Form represents, Origin 8.0 softwares are used for the above-mentioned amount effect curve of match and calculate ceiling effect (Emax) and half-maximal effect concentration (ED50).
3.1.3 result and discussion
Chinese medicine extraction compositions of the present invention to the diastole effect of rat chest aorta as shown in Figure 1.As can be seen from Figure 1, extractive composition A, B, each group of C all show diastolic blood vessel activity, compare with negative control, and extractive composition A, B, C all have significance (P＜0.05) to the diastole activity of blood vessel; Compare with the YUANHU ZHITONG PIAN positive controls, the diastolic blood vessel activity of isodose extractive composition A, B, C does not have significant difference, illustrates that extractive composition A, B, C and YUANHU ZHITONG PIAN have equivalence.
3.2 writhing test
3.2.1 material
3.2.1.1 medicine
Make respectively the hard capsule of Chinese medicine extraction compositions A, B, C according to the described method in above-described embodiment, the 0.3g/ grain.Positive control drug: YUANHU ZHITONG PIAN (pharmaceutical factory in another name for Sichuan Province, Sichuan, lot number: 100502).
3.2.1.2 animal
SPF level Kunming mouse is provided by Beijing Vital River Experimental Animals Technology Co., Ltd., the animal quality certification number: SCXK (capital) 2006-0009.
3.2.2 experimental technique
Select 50 of Kunming mouses, male and female half and half, body weight 18-22g is divided into 5 groups at random: normal saline group, extractive composition A group, extractive composition B group, extractive composition C group and positive controls (YUANHU ZHITONG PIAN group).In experiment first three day, gavage respectively extractive composition A (5g crude drug amount/kg), extractive composition B (5g crude drug amount/kg) and extractive composition C (5g crude drug amount/kg) with the 2nd, 3,4 group; With the 1st group and the 5th group gavage respectively normal saline and YUANHU ZHITONG PIAN (5g crude drug amount/kg), once a day, totally 5 days.40min after the last administration, inject 0.7% acetum (0.1mL/10g body weight) in each group mouse peritoneum, (writhing response shows as abdominal part contraction, body distortion respectively to organize the mouse writhing number of times in 10min and 20min after record injection acetum respectively, hind leg stretches and arm is raised), and calculate the pain inhibition percentage.
3.2.3 result and discussion
The impact that extractive composition A, B, C test mouse writhing is as shown in table 6.As can be seen from Table 5, reaction all has obvious inhibitory action (P＜0.05-0.001) to each group of extractive composition A, B, C to mouse writhing; Compare with YUANHU ZHITONG PIAN, effect does not have significant difference to mouse writhing with extractive composition A, B, the C of dosage, has equivalence.
The impact of table 6 extractive composition on the mouse writhing test
**P＜0.01 *P＜0.05
3.3 hot plate induced pain test
3.3.1 material
3.3.1.1 medicine
Make respectively the hard capsule of Chinese medicine extraction compositions A, B, C according to the described method in above-described embodiment, the 0.3g/ grain.Positive control drug: YUANHU ZHITONG PIAN (pharmaceutical factory in another name for Sichuan Province, Sichuan, lot number: 100502).
3.3.1.2 animal
SPF level Kunming mouse is provided by Beijing Vital River Experimental Animals Technology Co., Ltd., the animal quality certification number: SCXK (capital) 2006-0009.
3.3.2 experimental technique
Select Kunming mouse, body weight 18-22g, male and female half and half are first predicted every secondary average of valve bitterly.Method: mice is placed in 55 ℃ of constant temperature beakers, being that reaction is as observation index after occurring slandering.With pain threshold 40 of the mices of 10-30 second, be divided at random 5 groups, gavage respectively extractive composition A (5g crude drug amount/kg), extractive composition B (5g crude drug amount/kg) and extractive composition C (5g crude drug amount/kg) with the 2nd, 3,4 group; Gavage respectively normal saline and YUANHU ZHITONG PIAN (5g crude drug amount/kg), every day 1 time, totally 5 days with the 1st group and the 5th group.After last administration 15 ', 30 ', 1.0h, 1.5h, 2.0h, 3.5h and 7.0h measure and record the pain response time (pressing calculating in 60 seconds greater than 60 seconds persons).
3.3.3 result and discussion
The impact that extractive composition A, B, C test mice hot plate induced pain is as shown in table 7.As can be seen from Table 7, A, B, three groups of extractive compositions of C can significantly improve the pain valve (P＜0.05-0.001) of mice; Compare with YUANHU ZHITONG PIAN, isodose extractive composition A, B, C do not have significant difference, have equivalence.
3.4 antidepressant test
3.4.1 material
3.4.1.1 instrument
DT21TB electronic clinical thermometer (Shanghai Medical Instrument and Meter Factory); Agilent 1100LC type chromatograph (U.S. Anjelen Sci. ﹠ Tech. Inc); DECADE II SDC type electrochemical detector (Dutch ANTEC company); Biofuge Stratos low-temperature and high-speed centrifuge (Germany); VCX130 type Ultrasonic Cell Disruptor (U.S. SONICS).
3.4.1.2 medicine and reagent
Make respectively the hard capsule of Chinese medicine extraction compositions A, B, C according to the described method in above-described embodiment, the 0.3g/ grain.Fluoxetine hydrochloride dispersible tablet (factory: PATHEON FRANCE, minute packing factory: gift comes Suzhou pharmaceutical Co. Ltd, lot number J20050122); Reserpine injection (Guangdong Bangmin Pharmaceutical Co., Ltd., lot number 090918); Norepinephrine (NE), 5-hydroxy tryptamine (5-HT), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA), 4-hydroxy-3-methoxy-.alpha.-toluic acid. (HVA) are the Sigma product.Hplc grade methanol (Fisher), sodium dihydrogen phosphate, perfluorooctane sulfonate, ethylenediaminetetraacetic acid, potassium chloride are that Import Analysis is pure, other reagent are domestic analytical pure.
3.4.1.3 animal
SPF level Kunming mouse is provided by Beijing Vital River Experimental Animals Technology Co., Ltd., the animal quality certification number: SCXK (capital) 2006-0009.
3.4.2 experimental technique
3.4.2.1 mice forced swimming test
Normal mouse is divided into the hard capsule (being divided into three groups) of blank group, fluoxetine group (dosage is 0.033g/kg), Chinese medicine extraction compositions A, B, C, 10 every group according to randomized blocks.Each group of extractive composition is all by the dosed administration of 5g crude drug amount/kg body weight, and once a day, successive administration 7 days is for the blank group is used deionized water.1h tests after the last administration.Single mice is placed in the water vat of 23 ± 2 ℃ of high 20cm, diameter 18cm, depth of water 10cm, water temperature, be 6 minutes observing time, initial 2 minutes be mice to the adaptive time of environment, record the dead time (s) of accumulative total in rear 4 minutes.
3.4.2.2 mice reserpine antagonistic effect
Normal mouse is divided into the hard capsule (being divided into three groups) of blank group, model group, positive drug fluoxetine group (dosage is 0.033g/kg), Chinese medicine extraction compositions A, B, C, 10 every group according to randomized blocks.Each group is all by the dosed administration of 5g crude drug amount/kg body weight, once a day, successive administration 7 days, blank group and model group are used deionized water.The reserpine of lumbar injection 1mg/kg immediately after the last administration, blank group injected in mice equivalent normal saline.Carry out blepharoptosis and akinetic observation after 120 minutes, calculate antagonism percentage rate (blepharoptosis antagonism percentage rate=[1-open eyes can not animal number of elements/animal number] * 100%; Motion can not resist percentage rate=[1-motion can not animal number of elements/animal number] * 100%); Carry out the observation of temperature decline after 180 minutes, measurement mice anus temperature breaks end rapidly after 24 hours and takes out brain, weighs.Add and organize lysate, every 10mg tissue adds 50 μ L lysates (contain 0.01% Cys, the perchloric acid of 0.2mol/L, the EDETATE SODIUM of 0.5mmol/L, in be designated as the DHBA of 0.002 μ g/L); After ultrasonication 10s, in 4 ℃ of centrifugal 30min of 15000rpm, get supernatant again with the centrifugal 30min of same rotational speed in ice bath, then get supernatant with 0.22 μ m membrane filtration, get 20 μ L and adopt high performance liquid chromatography to carry out the mensuration of neurotransmitter in mouse brain.
Chromatographic condition: Column C18 chromatographic column (4.6 * 150mm, 5 μ m); Mobile phase is methanol: buffer=10: 90, and buffer is for containing 100mmol/L sodium dihydrogen phosphate, 0.75mmol/L perfluorooctane sulfonate, the aqueous solution of 0.027mmol/L ethylenediaminetetraacetic acid and 8mmol/L potassium chloride; Flow velocity is 1.0mL/min.
3.4.2.3 statistical analysis
All data all with
SPSS 13.0 statistical softwares are adopted in expression, and the content results of mice forced swimming test and monoamine neurotransmitter adopts one factor analysis of variance (one-way ANOVA), and reserpine antagonistic effect result adopts X
2Check.
3.4.3 result and discussion
3.4.3.1 the impact on the mice forced swimming
As can be seen from Table 8, compare with the blank group, fluoxetine group and Chinese medicine extraction compositions A, each group of B, C all can significantly shorten the dead time of mice forced swimming.
Table 8 on the impact of mice forced swimming dead time (
N=10)
Compare with the blank group, * P＜0.05, * * P＜0.01
3.4.3.2 reserpine is caused mouse temperature, blepharoptosis and akinetic impact
As can be seen from Table 9, show temperature decline, blepharoptosis, motion after model group lumbar injection reserpine and can not wait sign, comparing with Normal group all has significant difference; Each group of the hard capsule of Chinese medicine extraction compositions A, B, C all can significantly be resisted by the mouse temperature due to reserpine and descend, and relatively has significant difference with model group.
Table 9 on reserpine cause mouse temperature, blepharoptosis and akinetic impact (
N=10)
Annotate: compare * P＜0.05, * * P＜0.01 with the blank group;
Compare with model group,
△P＜0.05,
△ △P＜0.01
3.4.3.3 reserpine is caused the impact of monoamine neurotransmitter in mouse brain and metabolite content thereof
As shown in table 10, compare with the blank group, model group mouse brain NE, 5-HT, 5-HIAA, DA, HVA content obviously reduce; Compare with model group, extractive composition A, B, C all can significantly improve NE, 5-HT content in mouse brain; Compositions B group significantly increases 5-HIAA content; Compositions C group increases 5-HIAA content; Compositions A group and compositions B group all can improve DA content in mouse brain; Compositions B group can improve HVA content in mouse brain.
Table 10 on reserpine cause monoamine neurotransmitter in mouse brain impact (
N=10)
Annotate: compare * P＜0.05, * * P＜0.01 with the blank group;
Compare with model group,
△P＜0.05,
△ △P＜0.01
3.5 long term toxicity test
The present inventor has also carried out long term toxicity test research to Chinese medicine extraction compositions of the present invention, result shows: to 9 the week age rat gavaged in continuous 180 days (test establish altogether four groups: it is high, medium and low that (dosage is respectively 5.4g/kg, 2.7g/kg, 1.35g/kg, be equivalent to respectively 120,60,30 times of clinical Coming-of-Age Day consumption) three dosage group and blank groups, in administration 90 days, 180 days and drug withdrawal after 30 days, put to death respectively rat, check each treated animal physiochemical indice and blood biochemical index.The internal organs such as all animal hearts, liver, spleen, lung, kidney, brain, thymus, adrenal gland are carried out perusal, and the calculating organ index of weighing, simultaneously blank and the high dose group animal heart, liver, spleen, lung, kidney, brain (brain, cerebellum, brain stem), hypophysis, sciatic nerve, spinal cord (cervical part of esophagus, breast section, waist section), thyroid, thymus, pancreas, adrenal gland, salivary gland, esophagus, Stomach duodenum, ileum, colon, bladder, lymph node, trachea, aorta are carried out the pathomorphism inspection.Compare with the blank group, the These parameters of each administration treated animal in different dosing cycle is not all found obviously abnormal, and hematology and biochemical indexes are all in range of normal value.Therefore, of the present inventionly respectively organize extractive composition to adopt oral administration be safe.
Claims (7)
1. a Chinese medicine extraction compositions, is characterized in that described compositions is comprised of the extract that obtains respectively from Rhizoma Corydalis and Radix Angelicae Dahuricae crude drug, wherein:
Described Rhizoma Corydalis extract is obtained through following methods:
Get the corydalis tuber medicinal material powder, the ethanol/water that is the 40%-80% that doubly measures of 2-4 with mass concentration soaks, reflux 2-4 hour, collect extracting solution, adding mass concentration is ethanol/water reflux 1-3 hour of the 40%-80% that doubly measures of 1-3 again, collects extracting solution, merges secondary raffinate, filter, filtrate is concentrated into without the alcohol flavor; Select the ion exchange resin chromatography purification, reclaim solvent, vacuum drying gets extractum, pulverizes, and sieves, and gets Rhizoma Corydalis extract;
Described Radix Angelicae Dahuricae extract is obtained through following methods:
Get the angelica root powder, the ethanol/water that is the 50%-90% that doubly measures of 4-6 with mass concentration soaks, reflux 2-4 hour, collect extracting solution, adding mass concentration is ethanol/water reflux 1-3 hour of the 50%-90% that doubly measures of 4-6 again, collects extracting solution, merges secondary raffinate, filter, filtrate is concentrated into without the alcohol flavor; Select the macroporous resin chromatography purification, regulate pH value with dilute hydrochloric acid, reclaim solvent, vacuum drying gets the yellowish-brown powder, and absolute ethanol washing reclaims ethanol, and vacuum drying gets extractum, pulverizes, and sieves, and gets Radix Angelicae Dahuricae extract;
And in described compositions, the ratio of weight and number of Rhizoma Corydalis extract and Radix Angelicae Dahuricae extract is 1-100: 1-50.
2. Chinese medicine extraction compositions according to claim 1 is characterized in that in described compositions, the ratio of weight and number of Rhizoma Corydalis extract and Radix Angelicae Dahuricae extract is 10-100: 5-50.
3. the described Chinese medicine extraction compositions of according to claim 1 to 2 any one is characterized in that in described compositions, the ratio of weight and number of Rhizoma Corydalis extract and Radix Angelicae Dahuricae extract is 20-100: 10-50.
4. the described Chinese medicine extraction compositions of according to claim 1 to 3 any one, it is characterized in that described compositions also can comprise arbitrary pharmaceutically acceptable carrier, it comprises diluent, excipient, filler, wetting agent, disintegrating agent, correctives and binding agent etc.
5. a method for preparing Chinese medicine extraction compositions according to claim 1, is characterized in that at first obtaining corresponding extract respectively from Rhizoma Corydalis and Radix Angelicae Dahuricae crude drug according to the method in claim 1; Secondly two kinds of Chinese medicine extract are mixed according to concrete ratio of weight and number, after adding at last appropriate carrier, mixing is to prepare arbitrary pharmaceutically acceptable dosage form, as injection, infusion solution, mixture, tablet, hard capsule, soft capsule, pill, drop pill, granule, patch and cataplasma etc., be preferably hard capsule.
6. Chinese medicine extraction compositions according to claim 1 treats and/or prevents by the purposes in the medicine of the pain of caused by energy stagnation and blood stasis in preparation, and wherein said pain comprises stomachache, hypochondriac pain, headache and dysmenorrhea etc.
7. Chinese medicine extraction compositions according to claim 1 treats and/or prevents purposes in the medicine of depression in preparation.
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| CN103893170A (en) * | 2014-04-11 | 2014-07-02 | 白玲强 | Medicinal composition for treating complications after hysterectomy and application thereof |
| CN117031043A (en) * | 2023-09-28 | 2023-11-10 | 中国中医科学院中药研究所 | Identification method of artificial tiger bone meal detection markers |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103893170A (en) * | 2014-04-11 | 2014-07-02 | 白玲强 | Medicinal composition for treating complications after hysterectomy and application thereof |
| CN103893170B (en) * | 2014-04-11 | 2016-01-20 | 青岛市海慈医疗集团 | A kind ofly prevent and treat pharmaceutical composition and the application thereof that postoperative complication is cut in palace |
| CN117031043A (en) * | 2023-09-28 | 2023-11-10 | 中国中医科学院中药研究所 | Identification method of artificial tiger bone meal detection markers |
| CN117031043B (en) * | 2023-09-28 | 2024-01-02 | 中国中医科学院中药研究所 | Identification method of artificial tiger bone meal detection markers |
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