CN101422587A - Medicine preparation for treating gynecologic disease - Google Patents
Medicine preparation for treating gynecologic disease Download PDFInfo
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- CN101422587A CN101422587A CNA2008102336967A CN200810233696A CN101422587A CN 101422587 A CN101422587 A CN 101422587A CN A2008102336967 A CNA2008102336967 A CN A2008102336967A CN 200810233696 A CN200810233696 A CN 200810233696A CN 101422587 A CN101422587 A CN 101422587A
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Abstract
The invention relates to a compound pharmaceutical preparation using natural plants as medicinal components and treating gynecologic diseases. The invention relates to an oral preparation prepared by using materials with the following weight portions: 450 portions of radix salviae miltiorrhizae, 250 portions of rhizoma zedoariae, 250 portions of bupleurum marginatum, 150 portions of pseudo-ginseng, 250 portions of red paeonia, 250 portions of angelica, 175 portions of trigone, 150 portions of rhizoma cyperi, 175 portions of fumitory and 100 portions of liquorice. The application adopts specific medicinal materials and specific amount, has reliable compositional components and the preparation has the functions of promoting blood circulation by removing blood stasis and diminishing inflammation, relieving the depressed liver, regulating menstruation and relieving pain and softening hard masses and relieving stasis. Pharmacodynamic tests prove that the compound pharmaceutical preparation can cause the atrophy and necrosis of ectopic endometrium of experimental rat endometrium to eliminate pelvic inflammatory diseases, and simultaneously the compound pharmaceutical preparation has the functions of anti-inflammatory, stopping pain, anti-platelet aggregation, and inhibiting the in vitro or spasm and contraction of uterus in vivo caused by pituitrin. The compound pharmaceutical preparation is used for treating menoxenia caused by woman blockage of blood stasis, dysmenorrhea, discomfort in menstrual period, abdominal mass accumulation and pelvic endometriosis.
Description
Technical field
The present invention relates to a kind of is the compound medicinal formulation that is used for gynaecopathia of medicinal component with the natural plants.
Background technology
World Health Organization (WHO) shows Chinese women's investigation: the women of China 41% suffers from gynaecopathia in various degree, and sickness rate is ascendant trend year by year, gynecopathy therapeutic pharmaceutical market scale enlarges rapidly, the medicine of market expectation good effect, gynaecopathia that toxic and side effects is low.
Chinese patent application 97120991.X discloses a kind of " gynecopathy Chinese medicine preparation ", its composition is: Radix Salviae Miltiorrhizae, Rhizoma Curcumae, Radix Bupleuri, Radix Paeoniae Rubra, Radix Angelicae Sinensis, rhizoma sparganic, Rhizoma Cyperi, Rhizoma Corydalis, Oletum Trogopterori, Radix Achyranthis Bidentatae, Radix Curcumae, Radix Glycyrrhizae, Radix Notoginseng, described preparation are oral formulations.
Summary of the invention
The object of the present invention is to provide the pharmaceutical preparation of a kind of good effect, treatment gynaecopathia that toxic and side effects is low.
The pharmaceutical preparation of treatment gynaecopathia of the present invention is the oral formulations of being made by the following materials based on weight medicine: Radix Salviae Miltiorrhizae 450, Rhizoma Curcumae 250, HERBA BUPLEURI 250, Radix Notoginseng 150, Radix Paeoniae Rubra 250, Radix Angelicae Sinensis 250, rhizoma sparganic 175, Rhizoma Cyperi 150, Rhizoma Corydalis 175, Radix Glycyrrhizae 100.
Having adopted Radix Salviae Miltiorrhizae in the application's prescription is monarch drug, described Radix Salviae Miltiorrhizae is the dry root of labiate Salvia miltiorrhiza Bge Salviayunnanensis D.H.Wight, main product Yunnan, different with used usually Radix Salviae Miltiorrhizae, Radix Salviae Miltiorrhizae is the dry root and rhizome of Salvia miltiorrhizaBge..The HERBA BUPLEURI that the application adopted is the dry herb of samphire HERBA BUPLEURI Bupleurum marginatumWall.ex DC., bupleurum microcephalum Diels Bupleurum microcephalum Diels, Maerkang Radix Bupleuri Bupleurum malconense Shanet Y.Li or little Radix Bupleuri Bupleurum tenue Buch.-Ham.ex D.Don, also inequality with used usually Radix Bupleuri, Radix Bupleuri is the dry root of Bupleurum chinense DC. or Radix Bupeuri Scorzonerfolii. Bupleurum scorzonerifolium Willd..The application adopts specific medical material and specific consumption, and prescription element is reasonable, has blood circulation promoting and blood stasis dispelling, depressed liver-energy dispersing and QI regulating, menstruction regulating and pain relieving, the effect of softening the hard mass eliminate indigestion.Studies have shown that through pharmacodynamics test, this medicine can make the in utero Ectopic Endometrium atrophy of film disease of rat experiment temper, downright bad also eliminate pelvic inflammation, what have simultaneously that antiinflammatory, pain relieving, antiplatelet aggregation, inhibition pituitrin cause exsomatizes or shrinks at the body hysterospasm.Be used for menoxenia due to women's stagnation of blood stasis, dysmenorrhea, menstrual period, uncomfortable, WEIJIA was gathered, endometriosis of pelvis sees above-mentioned symptom person.Have very good effect and application prospect for the treatment gynaecopathia.
Conventional oral dose, a 10～15g, 2 times on the one.
Pharmacodynamic experiment of the present invention:
Experiment purpose:
Experimentation the present invention is to the isolated rat uterus, assemble and the influence of rat endometrium dystopy model at body rat uterus, rabbit platelet.Plan provides the pharmacodynamics foundation to regulating menstruation, hemostasis of the present invention, blood circulation promoting and blood stasis dispelling, treatment endometriosis etc.
Test material:
1, animal: the SD rat, female, body weight 150-250g. Mus 2-25 in age month.Provide by Yunnan Province animal housing of natural drug pharmacology key lab.Healthy rabbits, 1.5～2.0kg, male and female are usefulness all, is provided by animal section of unming Medical College.
2, medicine and reagent: the present invention's (embodiment 1 described pharmaceutical preparation) is provided by Yunnan, Yunnan rainbow natural drug limited company, supplies behind the distilled water diluting to use.Patent 97120991.X contrast medicine provides method for making by inventor Cai Lishan, and rainbow natural drug limited company in Yunnan, Yunnan provides (the following patent matched group that all is called) by prepared.The positive control medicine: DALAZUO, Yangzhou, Jiangsu pharmaceutical factory produces.Platelet aggregation derivant adenosine diphosphate (ADP) (ADP) is Switzerland's import packing.Universal DAKOLSAB+KIT, and the PEROXIDASE test kit (available from DAKO Coorporation, Carpinteria, CA).
Anti-Mus NK cell antibody MCA1427, anti-mouse macrophage MCA341R, anti-Mus cd8 cell MCA48G, anti-Mus dendritic cell MCA1029G is all available from Serotec Ltd.
3, instrument: Shimadzu (balance recorder of U～135C), high power microscope, LBY-NJ2 blood pool instrument (Beijing Puli gives birth to the biochemical instrument center and produces).
Method and result:
1, isolated uterine experiment of the present invention
The preparation krebs solution contains: NaCl 7.5, KCl 0.35, CaCl
20.06, MgCl
20.05, NaH
2PO
40.1, NaHCO
31.0, glucose 0.5g/L.
Two days in advance to rat skin lower injection diethylstilbestrol 0.1mg/kg.d.Rat is put to death in the cervical vertebra dislocation, cuts open the belly and takes out the uterus, places krebs solution, and with a side cornua uteri two ends ligation, an end is fixed on the ventilation hook, and the other end links to each other with tonotransducer, places the Maxwell pipe of 20mL krebs solution.About 1g that loads, 31 ± 0.5 ℃ of operating temperatures, logical oxygen 1-2 bubble/second, balance 45min, every 15min changes liquid once.Tonotransducer links to each other with balance recorder, recording curve.
After writing down one section normal uterus shrinkage curve, splash into a certain amount of suspension of the present invention, recording curve splashes into neurohypophyseal hormone (1.39 * 10
-5U/mL), recording curve once more.After changing the liquid recovery for three times, write down one section normalized curve, splash into dosage neurohypophyseal hormone, recording curve.Statistical method adopts pairing t-test.
Result's (table 1) shows, the present invention external (1.5,3.0mg crude drug/mL) significantly strengthens isolated rat uterus maximum shrinkage amplitude (P＜0.05); (3.0mg crude drug/mL) significantly reduces basic tension force (P＜0.01), and is significantly resisting neurohypophyseal hormone effect (P＜0.05) aspect the basic tension force maximum shrinkage amplitude.And of the present invention group of each effect all is better than the patent matched group.
Table 1 the present invention to the influence in isolated rat uterus (Mean ± SD, n=6)
* match t-test before P＜0.05, * * P＜0.01 and administration.
2, the present invention tests in the body uterus
Female rats is used diethylstilbestrol 1mg/kg.d subcutaneous injection successive administration two days, carry out manually emotionally.3% pentobarbital sodium 0.1mL/kg ip anesthetized animal, lower abdomen are done a kerf separation and are appeared the uterus, fix a side cornua uteri ovary end and a vagina end with the bottle of preserving moisture, and the centre connects tonotransducer with suture, load Ig.Epigastrium is done a kerf, separates duodenum, in order to administration.
Behind the balance 30min, the record normalized curve.Through femoral vein iv1.0u/kg neurohypophyseal hormone, recording curve.After waiting to recover normally, give a certain amount of the present invention, recording curve behind the 60min through duodenum.The neurohypophyseal hormone of iv Isodose once more, recording curve.Statistical method adopts pairing t-test.
The result shows (table 2), the present invention (13.3,26.6g crude drug/kg) is to being dual regulation at body rat uterus contraction frequency, significantly resisting neurohypophyseal hormone effect (P＜0.05) aspect contraction frequency and the shrinkage amplitude simultaneously.The patent matched group has similar effect, but waits dosage group drug effect to be lower than this patent group.
Table 2 the present invention to the influence in the big uterus of body (Mean ± SD, n=6)
The patent matched group
| 13.3 | Contraction frequency/min | 5.4±1.3 | 6.4±1.7 | 4.3±0.3 | 4.8±0.3 | 4.6±0.9 |
| Maximum shrinkage amplitude cm | 9.5±3.0 | 13.4±6.8 | 11.1±2.9 | 10.1±5.1 | 12.2±3.8 | |
| Diastole tension force g | 0.8±0.2 | 1.0±0.4 | 0.8±0.3 | 0.9±0.5 | 1.3±0.4 |
* pairing t-test before and after the P＜0.05 administration;
☆Give neurohypophyseal hormone front and back difference before P＜0.05 administration, after administration
Difference is matched t-test before and after swashing to lobus posterior hypophyseos.
3, the external rabbit platelet of the present invention gathers experiment
Adopt the blood pool instrument to carry out by the BornShi turbidimetry, get each 300 μ L of platelet rich plasma (PPP) and platelet poor plasma (PRP) respectively in opacity tube, place preheating gate; In the PPP pipe, add solvent or medicinal liquid 10 μ L, 37 ℃ of constant temperature incubation 10min.With the zeroing of PPP pipe, reuse PRP manages amplitude modulation during mensuration; Stable back adds derivant ADP3.0 μ M in PRP under bar magnet stirs, record 5min maximum agglutination rate calculates suppression ratio.
The result shows that 10g/L the present invention reaches 60% to the external platelet aggregation suppression ratio of the inductive rabbit of ADP, and the external platelet aggregation suppression ratio of the rabbit of patent matched group is 40%.2 all embody stronger effect, but of the present invention group is better than matched group.
4, rat endometrium dystopy of the present invention model experiment
Animal model is set up and administration: with 34 60 days rheological properties adult females not 28 of copulation SD rats cause the gynecopathy model with experimental technique, get normal endometrial tissue when 6 experiments finish in addition and be contrast.At first 21 rats are used the method modeling of having established under narcotism.Downcut the left side cornua uteri respectively behind ligation uterus and fallopian tube end and the cervix uteri end, place physiological saline solution, downcut 5 of about 2cm * 2cm piece of tissue, be sewn to respectively on the ileocecus mesentery with 50 not damaged silk threads, keep the abdominal cavity moistening with physiological saline solution in the art, the whole surgery process keeps aseptic condition.Open after 15 days abdomen see rat endometrium plant successfully back same day with method with other 7 rat modelings.
Whole experimental session rat feeding detects rat body weight weekly in animal section of natural drug pharmacology key lab of unming Medical College, feed common rat feed, lets alone drinking-water, the natural lighting environment.
The 2nd batch of 7 rats are decided to be the 1st group, be postoperative early treatment group, 21 are divided into 3 groups at random in addition, the 2nd group is the treatment group, the 3rd group is the treatment matched group, and the 4th group is modeling blank group, and the 1st, 2 group gives behind the 2g/kg.d distilled water diluting of the present invention gradation respectively and irritate stomach, the 3rd group is given behind the DALAZUO 60mg/kg.d distilled water diluting gradation and irritates stomach, and the 4th group is given normal saline 2ml/d gradation and irritate stomach.The 2nd day filling stomach after 45 days put to death the excessive anesthesia of all laboratory animals after the 2nd batch of modeling, gets ectopic focus and rats in normal control group left side capable pathologic finding of cornua uteri and SABC and detects.Focus and film recording are all measured in each operation.
Pathologic finding and SABC detect; Ectopic focus is organized all and was decided 24 hours with 10% neutral formalin is liquid-solid, be embedded in the paraffin after the conventional dehydration of ethanol, every specimen cuts 2-3 thick sections of 5um and is attached on the slide that poly-D-lysine is handled air-dry, put and hatch in the dimethylbenzene liquid 5 minutes twice, remove in the rearmounted dehydrated alcohol of too much debris 3 minutes twice, removed in rearmounted 95% ethanol of too much debris 3 minutes twice, remove in the rearmounted distilled water of too much debris 30 second aquation.With Universal DAKO LSAB+KIT, the PEROXIDASE test kit carries out SABC and detects after the aquation, presses the operation of test kit operation instruction.
Hatched 5 minutes with 3% hydrogenperoxide steam generator after carefully drying too much water after the specimen aquation, PBS liquid flushing is carefully dried for twice after the too much debris and anti-hatching 15 minutes, after carefully drying too much debris twice, the flushing of PBS liquid hatched 15 minutes with strepto-desmin catalase, PBS liquid flushing is carefully dried for twice after the too much debris with DAB liquid and is hatched DAB liquid flushing after 5 minutes, the reuse distilled water flushing, haematoxylin liquid is redyed and is mentioned 10 times after the back is invaded in ammonia, distilled water washed in the rearmounted distilled water 2 minutes gently, dehydration then, sealing is to be checked.
The pale brown color of immunohistochemical staining result is positive, and blue color is negative.
Each tissue specimen is all done the HE stained in addition and is detected the endometrial cell degree of degeneration.
The scoring of focus inner membrance epithelial cell preservation degree; By following standard scoring; Intact preservation was commented 3 fens; Medium degree preservation companion leukocyte is invaded profit and was commented 2 fens; Preserve relatively poorly, only meet epithelial cell and commented 1 fen; No epithelial cell retains comments 0 fen; Every rat is got 2-3 specimen, makes even after every group totally 20 specimen are marked and divides equally.
Represent with rectangular histogram, as Fig. 1.
Immunohistochemical staining is analyzed; Each specimen get 3-4 high power lens visuals field (
*400 times) to observe, the ratio of immunocyte sum is according to following standard scoring; The NK cell.Account for 0%-1% negative (-), account for 2%-4% positive (+), surpassing 5% is strong positive (++); Macrophage accounts for 0%-39% negative (-), accounts for 40%-60% positive (+); Surpassing 60% is strong positive (++); Cd8 cell accounts for 0%-6% negative (-), accounts for 7%-10% positive (+), and surpassing 10% is strong positive; Dendritic cell account for 0%-3% negative (-), account for 4%--7% positive (+), and surpassing 7% is strong positive (++).
Each organizes number of elements such as the following table (table 3) of rat feminine gender and positive (comprising the positive and strong positive).
Statistical analysis uses the SPSS9.0 version capable X of statistical software
2Check, P＜=0.05 think that significance is arranged is poor.
Table 3 immunohistochemical staining is respectively organized the numerical table of rat feminine gender and positive (comprising the positive and strong positive)
The result shows: ectopic focus endometrial epithelial cell degree of degeneration early treatment organizes more obvious than treatment group, treatment group and treatment contrast no significant difference, 3 dosage groups of the present invention all than blank group and etc. dosage patent matched group obvious, blank group intimal epithelium cell also has obvious degeneration, but P〉0.05, there is not significant difference on the statistics.
Intralesional NK cellular infiltration positive rate positive rate early treatment group, treatment group and treatment matched group are respectively 85.7%, 71.4%, 57.1%, normal group is 66.7%, and the blank group is 14.3%, preceding four groups are compared p between any two〉0.05, there was no significant difference on the statistics, but preceding four groups with blank group p＜0.05 relatively between any two, significant difference is arranged on the statistics; The intralesional macrophage is invaded profit positive rate early treatment group, treatment group and treatment matched group are respectively 28.6%, 42.9%, 28.6%, be higher than 0% of normal group, 85.7% low than blank group, preceding four groups are compared p between any two〉0.05, there was no significant difference on the statistics, but preceding four groups with blank group p＜0.05 relatively between any two, significant difference is arranged on the statistics; The intralesional cd8 cell is invaded profit positive rate early treatment group, and treatment group and treatment matched group are 57.1%, than 28.6% height of 16.7% and blank group of normal group, but p〉0.05, there was no significant difference on the statistics; The intralesional dendritic cell are invaded profit positive rate positive rate early treatment group, and treatment group and treatment matched group are respectively 57.1%, 57.1%, 42.9%, than 28.6% height of 0% and blank group of normal group, but p〉0.05, there was no significant difference on the statistics.
Experiment conclusion:
1, the present invention external (1.5,3.0mg crude drug/mL) significantly strengthens isolated rat uterus maximum shrinkage amplitude (P＜0.05); (3.0mg crude drug/mL) significantly reduces basic tension force (P＜0.01), and is significantly resisting neurohypophyseal hormone effect (P＜0.05) aspect basic tension force and the maximum shrinkage amplitude.2, the present invention (13.3,26.6g crude drug/kg) is to being dual regulation at body rat uterus contraction frequency, significantly resisting neurohypophyseal hormone effect (P＜0.05) aspect shrinkage factor and the shrinkage amplitude simultaneously.3, the present invention (10g/L) assembles external rabbit platelet inhibitory action, and suppression ratio reaches 60%.4, the present invention (5.32g crude drug/kg.d) similar with DALAZUO to rat endometrium dystopy disease model curative effect, it is better that the early treatment organizes curative effect, its curative effect realizes that by two-ways regulation cell and humoral immune function more single immunostimulant of the mechanism of action or immunosuppressant are better.5, the patent matched group all shows better action in each experiment, and its effect is compared with of the present invention group, and of the present invention group all is better than the patent matched group.
In sum, pharmacodynamics test of the present invention shows that the uterine contraction behavior has dual regulation and anticoagulant, illustrates that this product has menstruction regulating and pain relieving and blood circulation invigorating efficacies; This product has the effect of dwindling similar in appearance to DALAZUO on the model of endometriosis, may show antiinflammatory repercussive curative effect by regulating cell and humoral immunization.The present invention is the modern preparation of natural plant, and no overt toxicity and side effect have one's own knack.
Description of drawings
Fig. 1 is a rat endometrium dystopy model experiment scoring rectangular histogram.
Among the figure: treatment group and early treatment's group are the present invention.
The specific embodiment
Embodiment 1: get Radix Salviae Miltiorrhizae 450, Rhizoma Curcumae 250, HERBA BUPLEURI 250, Radix Notoginseng 150, Radix Paeoniae Rubra 250, Radix Angelicae Sinensis 250, rhizoma sparganic 175, Rhizoma Cyperi 150, Rhizoma Corydalis 175, Radix Glycyrrhizae 100 (being parts by weight).
More than ten the flavor medical materials, percolation under Radix Salviae Miltiorrhizae, Rhizoma Curcumae, Radix Notoginseng, Radix Angelicae Sinensis, Rhizoma Corydalis photograph fluid extract and the extractum item (" an appendix I of Chinese pharmacopoeia O), make solvent with 70% ethanol, flood and carry out percolation after 24 hours, the collection liquid of filtering, decompression recycling ethanol also is concentrated into the thick paste that relative density is about 1.30 (50 ℃); The five tastes such as medicinal residues and all the other HERBA BUPLEURI decoct with water secondary, decoct 2 hours at every turn, and collecting decoction filters, and filtrate is concentrated into the thick paste that relative density is 1.30 (50 ℃); Merge above-mentioned two kinds of thick pastes, add Mel (refining) 100, sugar refinery 165, potassium sorbate 3 (being parts by weight), mixing promptly gets the soft extracts preparation.
Embodiment 2: get Radix Salviae Miltiorrhizae 450, Rhizoma Curcumae 250, HERBA BUPLEURI 250, Radix Notoginseng 150, Radix Paeoniae Rubra 250, Radix Angelicae Sinensis 250, rhizoma sparganic 175, Rhizoma Cyperi 150, Rhizoma Corydalis 175, Radix Glycyrrhizae 100 (being parts by weight).
More than ten the flavor medical materials, adding 8 times of amount 60% ethanol is that solvent refluxing extracted 1.5 hours, leaches medicinal liquid, and medicinal residues continued to add 6 times of amount 60% alcohol reflux 1.5 hours, merge medicinal liquid, decompression recycling ethanol also is concentrated into the thick paste that relative density is about 1.15 (50 ℃); Spray drying, medicated powder adds mannitol and micropowder silica gel, makes piller, promptly gets oral administration pills.
Embodiment 3: get Radix Salviae Miltiorrhizae 450, Rhizoma Curcumae 250, HERBA BUPLEURI 250, Radix Notoginseng 150, Radix Paeoniae Rubra 250, Radix Angelicae Sinensis 250, rhizoma sparganic 175, Rhizoma Cyperi 150, Rhizoma Corydalis 175, Radix Glycyrrhizae 100 (being parts by weight).
More than ten flavor medical materials, after 12 times in water amount decocted 2 hours, water liquid adopted macroporous adsorbent resin D-101 absorption, the ethanol elution with 70%, the collection eluent, decompression recycling ethanol also is concentrated into the thick paste that relative density is about 1.30 (50 ℃), microwave drying; Dry medicated powder adds an amount of dextrin granulates, and drying adds magnesium stearate, and filled capsules or direct compression promptly get capsule preparations or tablet.
Claims (1)
1, a kind of pharmaceutical preparation for the treatment of gynaecopathia is characterized in that it being the oral formulations of being made by the following materials based on weight medicine: Radix Salviae Miltiorrhizae 450, Rhizoma Curcumae 250, HERBA BUPLEURI 250, Radix Notoginseng 150, Radix Paeoniae Rubra 250, Radix Angelicae Sinensis 250, rhizoma sparganic 175, Rhizoma Cyperi 150, Rhizoma Corydalis 175, Radix Glycyrrhizae 100.
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| CNA2008102336967A CN101422587A (en) | 2008-12-09 | 2008-12-09 | Medicine preparation for treating gynecologic disease |
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| CNA2008102336967A CN101422587A (en) | 2008-12-09 | 2008-12-09 | Medicine preparation for treating gynecologic disease |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103341006A (en) * | 2013-08-02 | 2013-10-09 | 韩乃枝 | Medicine for treating dysmenorrheal and preparation method thereof |
| CN103386077A (en) * | 2012-05-08 | 2013-11-13 | 四川滇虹医药开发有限公司 | Compound traditional Chinese medicine used for treating dysmenorrhoea and endometriosis, and preparation method thereof |
-
2008
- 2008-12-09 CN CNA2008102336967A patent/CN101422587A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103386077A (en) * | 2012-05-08 | 2013-11-13 | 四川滇虹医药开发有限公司 | Compound traditional Chinese medicine used for treating dysmenorrhoea and endometriosis, and preparation method thereof |
| CN103386077B (en) * | 2012-05-08 | 2015-09-23 | 四川滇虹医药开发有限公司 | A kind ofly be used for the treatment of herbal mixture of dysmenorrhea and endometriosis and preparation method thereof |
| CN103341006A (en) * | 2013-08-02 | 2013-10-09 | 韩乃枝 | Medicine for treating dysmenorrheal and preparation method thereof |
| CN103341006B (en) * | 2013-08-02 | 2014-12-24 | 韩旭萍 | Medicine for treating dysmenorrheal and preparation method thereof |
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Open date: 20090506 |