CN1267130C - Chinese five-kind compound medicine for treating premenstrual symptomgroup and its preparation method - Google Patents
Chinese five-kind compound medicine for treating premenstrual symptomgroup and its preparation method Download PDFInfo
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Abstract
The present invention relates to a novel five-kind compound medicine prepared from pure traditional Chinese medicines for treating premenstrual syndrome and a preparation method thereof. The compound medicine of the present invention is prepared from the following raw materials and/or pharmaceutic adjuvants of white peony root, tree peony bark and nutgrass galingale rhizome. The preparation method comprises the following steps that the white peony root is extracted by soaking with ethanol, adsorbed with a resin column, and eluted to obtain an extract of the white peony root. The tree peony bark is distillated with steam, a receiving liquid is refrigerated, filtered and crystallized to obtain an extract of the tree peony bark. The nutgrass galingale rhizome is heated for extracting volatile oil, and beta-cyclodextrin is added to obtain an inclusion compound of the volatile oil of the nutgrass galingale rhizome and the beta-cyclodextrin. The novel five-kind compound medicine prepared from pure traditional Chinese medicines for treating premenstrual syndrome of the present invention has the advantages of obvious curative effect, few medicinal ingredients, high purity and little side effect. The prepration method of the medicine of the present invention has the advantages of high extraction rate, high purity and simple operation, and is suitable for industrial production.
Description
(1) technical field under
The present invention relates to a kind of Chinese medicine composition for the treatment of premenstrual tension syndrome and preparation method thereof.
(2) background technology
At present, the Western medicine of treatment premenstrual tension syndrome is less, and effect is undesirable, and certain side effect is arranged.Premenstruum is combined the Chinese medicine of levying in treatment, and general prescription is bigger, complex manufacturing.As publication number be 1220163, patent name is the Chinese patent of " medicine of treatment premenstrual tension ", it is made of by a certain percentage Radix Bupleuri, Fructus Aurantii, Cortex Albiziae, Radix Curcumae, Rhizoma Cyperi, Pericarpium Citri Reticulatae Viride, Fructus Liquidambaris, Semen Citri Reticulatae, Radix Angelicae Sinensis, the Radix Paeoniae Alba, Rhizoma Chuanxiong, Poria, Pericarpium Arecae, Radix Glycyrrhizae 14 flavor Chinese medicines, belong to Chinese medicine six class novel formulation, because it is many that its prescription is formed, preparation is complicated, the curative effect instability is unfavorable for suitability for industrialized production.
(3) summary of the invention
The present invention provides a kind of and has treated the Chinese medicine composition that premenstrual tension syndrome is evident in efficacy, flavour of a drug are few, purity is high, quality controllable in order to overcome the deficiency of above technology, and the preparation method of above-mentioned Chinese medicine composition.
The present invention realizes by following measure:
Chinese medicine composition of the present invention is made by following raw material and pharmaceutically acceptable auxiliaries, the Radix Paeoniae Alba, Cortex Moutan, Rhizoma Cyperi.
Chinese medicine composition of the present invention, the preferable part by weight of described raw material is:
1200～1800 parts of the Radix Paeoniae Albas
1200～1800 parts of Cortex Moutans
1200～1800 parts of Rhizoma Cyperis.
Chinese medicine composition of the present invention, the optimum weight ratio of described raw material is:
1500 parts of the Radix Paeoniae Albas
1500 parts of Cortex Moutans
1500 parts of Rhizoma Cyperis.
Chinese medicine composition of the present invention, dosage form is preferably capsule.Described capsule is to be made by the extract of above-mentioned raw materials, and the composition of described extract is:
A: content of paeoniflorin is greater than 30.0% in the Radix Paeoniae Alba extract, and the content of Radix Paeoniae Alba total glucosides is greater than 52.0% in the Radix Paeoniae Alba extract;
B: the content of paeonol is greater than 90% in the Cortex Moutan extract;
C: volatile oil contents is greater than 6.0% in the Rhizoma Cyperi extract.
Above-mentioned capsule formulation, pharmaceutic adjuvant are calcium bicarbonate, and the consumption of calcium bicarbonate and Radix Paeoniae Alba extract, Cortex Moutan extract and Rhizoma Cyperi volatile oil Benexate Hydrochloride total amount weight ratio are 1: 1-3.
The preparation method of above-mentioned capsule formulation may further comprise the steps:
A: the preparation method of Radix Paeoniae Alba extract: get Radix Paeoniae Alba decoction pieces, add 8 times of amount 70% soak with ethanol and spend the night heating and refluxing extraction secondary, each 3 hours, merge extractive liquid, filters filtrate recycling ethanol, be concentrated into relative density and be 1.12 concentrated solution, thin up is by the macroporous resin column of having handled well, after adding water washing, use 40% ethanol elution, collect eluent, reclaim ethanol, be concentrated into dried, vacuum drying, pulverize, sieve, promptly get Radix Paeoniae Alba extract;
B: the preparation method of Cortex Moutan extract: get the Cortex Moutan granule, add the water of 12 times of amounts of medical material, add the sodium chloride of 1% medical material amount, steam distillation 4 hours; The reception liquid cooling is hidden, and filters, and gets crystallization; Mother solution adds 1% sodium chloride again, heats redistillation, collects the distillate of mother solution 1/3 volume, and refrigerator and cooled is hidden, and filters, and merges twice crystallization, and cold drying is pulverized, and sieves, and gets Cortex Moutan extract;
C: get the Rhizoma Cyperi medicinal material coarse powder, add the water of 6 times of amounts, soaked overnight, heating extraction volatile oil 8 hours gets oil water mixture, reuse 30-60 ℃ petroleum ether extraction, the petroleum ether extraction layer reclaims petroleum ether, gets volatile oil; Take by weighing the beta-schardinger dextrin-of 12 times of amounts of volatile oil, add 50% ethanol of 2 times of amounts of beta-schardinger dextrin-, grind to form pasty state, slowly drip volatile oil, after adding, continue to grind, filter, cold drying is pulverized, and sieves, and promptly gets the Rhizoma Cyperi volatile oil Benexate Hydrochloride;
D: get above Radix Paeoniae Alba extract, Cortex Moutan extract and Rhizoma Cyperi volatile oil Benexate Hydrochloride, add a certain amount of calcium bicarbonate mix homogeneously, sieve, be sub-packed in the capsule, promptly.
Below for the results of pharmacodynamic test of medicine of the present invention
One. medicine analgesia of the present invention, calmness and the influence that isolated uterine is shunk thereof
1. experiment material
Medicine of the present invention (1g is equivalent to crude drug 29.47g) provides lot number by plant chamber, Jiangsu Province Medicine Primary Institute: 20010604-5; Ease pill (concentrated pill), Henan Province Wanxi Pharmacy Stock Co., Ltd product, lot number: 20010707.Be made into the suspension of respective concentration with preceding with 0.5%CMC-Na, used dosage is except that experiment in vitro in the experiment, and all the other are by the crude drug amount.Drug dose of the present invention is by amount of powder in the experiment in vitro.
JINGQIANPING KELI, company of Jiangsu Yangzijiang Pharmaceutical Group product, lot number: 010221.Be made into the suspension of respective concentration with preceding with 0.5%CMC-Na, used dosage is by grain amount in the experiment.
Oxytocin inj (oxytocin injection), Taizhou Biochemical Pharmaceutical Factory's product, lot number: 990620-2.Diethylstilbestrol injection, Shanghai the 9th pharmaceutical factory's product, lot number: 980605.Neostigmine methylsulfate (injection), Shanghai Xinyi Pharmaceutical Factory product, lot number: 980202-17.Atropine, the import packing.
Other reagent are commercially available analytical pure.
2. method and result
2.1 experimental technique
2.1.1 isolated uterine experiment (external perfusion method)
The SD rat is 48hr sc diethylstilbestrol 0.1mg/kg before experiment, manually causes rutting period, improves the sensitivity of uterus to medicine.After making the rat deep anaesthesia with pentobarbital sodium 50mg/kg ip during experiment, open the abdominal cavity rapidly, peel off fatty tissue around the uterus gently, threading ligation vagina end and body of uterus top, make it stripped, place the glass dish that fills Rockwell liquid immediately, carefully remove residual connective tissue and fat.Uterus vagina end ligature is fixed in the bath bottom that fills Rockwell liquid, and top, uterus line links to each other with the transducer of 16 road physiology pharmacology monitors.The operating temperature of water bath with thermostatic control and constantly feeds O in working solution about 35 ℃
2(60--80 bubble/minute).After writing down one section normalized curve, add different pharmaceutical, 30 minutes shrinkage curves after the record administration are observed the uterotonic frequency in administration front and back, amplitude and uterine motility (frequency * amplitude).
After (10mu/ml), contraction frequency obviously increases behind the uterine smooth muscle adding oxytocin of normal contraction, and uterine motility obviously strengthens, and peaks in about 10 minutes, is stabilized in this level subsequently, disappears gradually after 40 minutes.Be chosen in the oxytocin effect and add medicine to be measured after 15 minutes, 30 minutes shrinkage curves after the record administration are observed the uterotonic frequency in administration front and back, amplitude and uterine motility (frequency * amplitude).
2.1.2 the calm experiment of mice (photocell method)
Ray Of Light is shone on the photocell of offside, animal activity once interdicts light once, causes that electric current changes once, and then counter records once.Movable number of times in the record mice 5min is as observation index.
2.1.3 mice analgesic experiment (writhing method)
0.6% acetum is injected in the mouse peritoneal, cause the deep, large tracts of land and more persistent pain stimulation causes white mice to produce " turning round body " reaction (abdominal part indent, trunk and back leg extension, hips up).Observation gives the number of times that " turning round body " reaction takes place for each mice in the acetum 15 minutes, as test index
2.1.4 mouse small intestine advances experiment
The experiment proxima luce (prox. luc) is given the mice fasting, makes 1% suspension with carminum and 10% arabic gum, gives mouse stomach by 0.1ml/10g dosage, takes off cervical vertebra behind the 20min and puts to death, and cuts open the belly immediately, and digestive tube is intactly extracted from cardia to rectum end.Do not add the traction Horizon and spread out, survey the distance of the red forward position of its total length and record, calculate the percentage ratio of itself and gastrointestinal tract total length to cardia.
2.2 statistics and check
All data are all used mean+SD, and (X ± SD) expression, experimental result is all checked with T-test.
2.3 experimental result
2.3.1 medicine of the present invention is to the influence of normal isolated rat uterine smooth muscle
Manufacture isolated rat uterus specimen by the isolated uterine experimental technique, treat after its activity steadily medicine to be measured drug powder suspension of the present invention and positive control drug JINGQIANPING KELI suspension to be added the perfusion groove respectively, make the final concentration of medicine of the present invention be respectively 0.02,0.05,0.10mg/ml; JINGQIANPING KELI is 0.40mg/ml.30min uterine activity situation after the record administration is observed and the relatively variation of administration front and back uterine activity.The results are shown in Table 1,2,3.
By table 1 as seen, three kinds of concentration of medicine of the present invention (0.02,0.05,0.1mg/ml) and JINGQIANPING KELI (0.4mg/ml) all can obviously reduce the contraction frequency of rat normal uterus smooth muscle.
By table 2 as seen, medicine 0.05 of the present invention and 0.10mg/ml and JINGQIANPING KELI 0.4mg/ml can obviously reduce the shrinkage amplitude of normal uterus smooth muscle.
By table 3 as seen, each concentration of medicine of the present invention all has in various degree inhibitory action to the contractility of normal uterine smooth muscle.
2.3.2 medicine of the present invention is to the enhanced influence of isolated rat uterine contraction due to the oxytocin
Manufacture isolated rat uterus specimen by the isolated uterine experimental technique; treat one section normalized curve of its movable steadily back record; then add oxytocin injection (10mu/ml); cause the uterine smooth muscle activeness to strengthen, add medicine to be measured drug suspension of the present invention and JINGQIANPING KELI suspension behind the 15min respectively.Uterine activity situation in the 30min after the record administration is observed and the relatively variation of administration front and back uterine activity.The results are shown in Table 4,5,6.
4-6 can find out from table, and the normal uterus smooth muscle is after giving oxytocin injection 10mu/ml, and contraction frequency and amplitude and contractility all significantly increase.
By table 4 as seen, medicine 0.05 of the present invention, 0.2mg/ml and JINGQIANPING KELI 0.8mg/ml can more obviously reduce the contraction frequency that uterine smooth muscle increases considerably.
By table 5 as seen, medicine 0.2mg/ml of the present invention and JINGQIANPING KELI 0.8mg/ml can obviously reduce the shrinkage amplitude that uterine smooth muscle rises due to the oxytocin.
By table 6 as seen, each dosage of medicine of the present invention all can be at the too high contractility of uterine smooth muscle that suppresses in varying degrees due to the oxytocin.
2.3.3 medicine of the present invention is to the influence of normal spontaneous activity in mice
Kunming mouse is divided into the blank group at random, the basic, normal, high dosage group of medicine of the present invention, ease pill group and JINGQIANPING KELI group are irritated stomach respectively and are given blank solvent, medicine 2.5g/kg of the present invention, 5g/kg, 10g/kg, ease pill 12g/kg and JINGQIANPING KELI 30g/kg.Every day 1 time, for three days on end.1hr places program control autonomic activities case to treat earlier to write down movable number of times in its 5min after it adapts to 3min mice after the last administration, the results are shown in Table 7.
By table 7 as seen, ease pill and JINGQIANPING KELI and medicine 10g/kg of the present invention all have the obvious suppression effect to normal spontaneous activity in mice.
2.3.4 the influence of medicine Dichlorodiphenyl Acetate induced mice writhing response of the present invention
The same 2.2.3 of Kunming mouse random packet and administration, the every Mus ip 0.6% acetic acid 0.2ml/ of 1hr only writes down the writhing response number of times that each Mus is caused by acetic acid in the 15min after the last administration.
By table 8 as seen, medicine 5g/kg of the present invention and 10g/kg can obviously reduce the number of times of acetic acid induced mice writhing response, and effect is similar with JINGQIANPING KELI to ease pill.
2.3.5 medicine of the present invention is to the enhanced influence of neostigmine induced mice enterokinesia
Kunming mouse is divided into the blank group at random, neostigmine matched group, medicine of the present invention basic, normal, high dosage group, ease pill group, JINGQIANPING KELI group and atropine matched group.Blank group and neostigmine group are all irritated stomach and are given blank solvent, and all the other groups give medicine 2.5g/kg of the present invention, 5g/kg, 10g/kg, ease pill 12g/kg and JINGQIANPING KELI 30g/kg successively.Every day 1 time, for three days on end.Atropine is disposable gastric infusion 10mg/kg before experiment.Ip sulphuric acid neostigmine 0.1mg/kg behind the last administration 30min, ig 1% carminum suspension 0.1ml/10g behind the 20min takes off cervical vertebra and puts to death mice behind the 20min, cut open the belly to get full intestinal and measure calculating, the results are shown in Table 9.
By table 9 as seen, three dosage of Bai Xiangdan strengthen the enterokinesia of neostigmine induced mice all significant inhibitory effect.
Table 1. medicine of the present invention is (inferior/10min) (X ± SD) to the influence of normal isolated rat uterine smooth muscle contraction frequency
| Group | Concentration (mg/ml) | n | Before the administration | After the administration | ||
| 10′ | 20′ | 30′ | ||||
| JINGQIANPING KELI | 0.40 | 6 | 5.5±1.8 | 3.2±2.3 | 3.0±1.9 * | 4.2±1.5 |
| Medicine of the present invention | 0.02 | 6 | 6.2±1.7 | 4.5±1.9 | 4.2±.1.9 | 3.8±1.8 * |
| 0.05 | 6 | 6.5±0.8 | 4.8±1.9 | 4.3±1.6 * | 4.3±1.2 ** | |
| 0.10 | 6 | 7.2±1.0 | 5.3±1.6 * | 4.3±1.9 ** | 5.5±1.4 * | |
*P＜0.05,
*P＜0.01 and is compared before the self administration.
Table 2. medicine of the present invention is to the influence (g) of normal isolated rat uterine smooth muscle shrinkage amplitude (X ± SD)
| Group | Concentration (mg/ml) | n | Before the administration | After the administration | ||
| 10′ | 20′ | 30′ | ||||
| JINGQIANPING KELI | 0.40 | 6 | 4.573±1.178 | 3.566±1.222 | 2.080±1.378 ** | 2.814±0.871 ** |
| Medicine of the present invention | 0.02 | 6 | 3.094±0.928 | 2.435±1.82 | 2.226±1.319 | 2.230±1.034 |
| 0.05 | 6 | 5.006±0.669 | 4.191±0.955 | 3.496±1.499 * | 3.551±1.248 * | |
| 0.10 | 6 | 5.466±1.295 | 4.002±1.665 | 3.876±1.801 | 2.959±2.034 * | |
*P＜0.05,
*P＜0.01 and is compared before the self administration.
Table 3. medicine of the present invention is to the influence (frequency * amplitude) of normal isolated rat uterine smooth muscle energy (X ± SD)
| Group | Concentration (mg/ml) | n | Before the administration | After the administration | ||
| 10′ | 20′ | 30′ | ||||
| JINGQIANPING KELI | 0.40 | 6 | 24.83±10.29 | 9.93±6.40 * | 7.30±5.23 ** | 11.18±3.69 * |
| Medicine of the present invention | 0.02 | 6 | 18.22±3.73 | 10.94±5.58 * | 8.99±5.69 ** | 7.76±2.90 *** |
| 0.05 | 6 | 32.76±7.26 | 20.02±9.49 * | 14.01±6.88 *** | 14.29±2.92 *** | |
| 0.10 | 6 | 39.61±12.92 | 20.31±9.75 * | 14.09±2.37 *** | 15.13±9.51 ** | |
*P＜0.05,
*P＜0.01,
* *P＜0.001 and is compared before the self administration.
Table 4. medicine of the present invention is (inferior/10min) (X ± SD) to the influence of oxytocin model isolated uterine smooth muscle contraction frequency
| Group | Concentration (mg/ml) | n | Before the administration | Give oxytocin (10mu/ml) | After the administration | ||
| 10′ | 20′ | 30′ | |||||
| JINGQIANPING KELI | 0.80 | 10 | 0.5±1.1 *** | 7.3±1.9 | 5.3±2.1 * | 4.7±2.3 * | 3.6±2.0 *** |
| Medicine of the present invention | 0.05 | 8 | 1.5±2.8 *** | 10.3±2.4 | 8.0±2.3 | 1.4±2.7 * | 7.0±2.6 * |
| 0.10 | 8 | 0.5±1.1 *** | 10.3±2.1 | 8.9±2.1 | 8.3±2.7 | 8.0±2.4 | |
| 0.20 | 8 | 1.0±2.8 *** | 7.5±1.9 | 5.3±2.4 | 3.9±3.2 ** | 2.3±2.8 ** | |
*P＜0.05,
*P＜0.01,
* *P＜0.001, with give oxytocin after compare.
Table 5. medicine of the present invention is to the influence (g) of oxytocin model isolated uterine smooth muscle contraction amplitude (X ± SD)
| Group | Concentration (mg/m 1) | n | Before the administration | Give oxytocin (10mu/ml) | After the administration | ||
| 10′ | 20′ | 30′ | |||||
| JINGQIANPING KELI | 0.80 | 10 | 0.151±0.330 *** | 4.634±3.215 | 2.922±2.296 | 2.371±2.268 | 2.020±2.471 * |
| Medicine of the present invention | 0.05 | 8 | 0.244±0.461 *** | 4.160±2.546 | 3.575±2.214 | 3.183±2.144 | 2.729±2.035 |
| 0.10 | 8 | 0.255±0.537 ** | 4.627±2.484 | 3.131±1.812 | 3.156±2.013 | 2.590±1.771 | |
| 0.20 | 8 | 0.041±0.109 *** | 5.001±2.788 | 3.476±1.368 | 2.305±2.166 * | 1.268±1.610 ** | |
*P＜0.05,
*P＜0.01,
* *P＜0.001, with give oxytocin after compare.
Table 6. medicine of the present invention is to the influence (frequency * amplitude) of oxytocin model isolated uterine smooth muscle contraction (X ± SD)
| Group | Concentration (mg/ ml) | n | Before the administration | Give oxytocin (10mu/ml) | After the administration | ||
| 10′ | 20′ | 30′ | |||||
| JINGQIANPING KELI | 0.80 | 10 | 0.36±0.76 * | 33.69±27.24 | 14.47±13.77 | 12.15±13.71 * | 10.26±14.25 * |
| Medicine of the present invention | 0.05 | 8 | 1.42±2.64 *** | 41.29±24.91 | 26.76±15.19 | 21.84±15.75 | 17.05±11.73 * |
| 0.10 | 8 | 0.24±0.49 *** | 48.49±27.68 | 28.70±18.43 * | 27.02±18.11 | 21.97±15.78 * | |
| 0.20 | 8 | 0.29±0.811 ** | 37.55±28.18 | 18.86±13.59 | 11.95±15.14 * | 4.26±6.26 ** | |
*P＜0.05,
*P＜0.01,
* *P＜0.001, with give oxytocin after compare.
Table 7. medicine of the present invention is (inferior/5min) (X ± SD) to the influence of normal spontaneous activity in mice
| Group | Dosage (g/kg) | n | The spontaneous activity number |
| Blank | - | 10 | 255.8±35.8 |
| Ease pill | 12 | 10 | 174.0±57.5 ** |
| JINGQIANPING KELI | 30 | 10 | 194.6±48.1 ** |
| Medicine of the present invention | 2.5 | 10 | 250.8±85.0 |
| 5 | 10 | 247.8±77.0 | |
| 10 | 10 | 199.1±41.0 ** |
*Compare with the blank group p＜0.01.
The influence of table 8. medicine Dichlorodiphenyl Acetate of the present invention induced mice writhing response (inferior/15min) (X ± SD)
| Group | Dosage (g/kg) | n | Turn round the body number of times |
| Negative control | - | 10 | 31.0±8.2 |
| Ease pill | 12 | 10 | 19.0±11.0 * |
| JINGQIANPING KELI | 30 | 10 | 16.9±9.0 ** |
| Medicine of the present invention | 2.5 | 10 | 31.9±15.7 |
| 5 | 10 | 17.2±8.1 ** | |
| 10 | 10 | 13.6±1.7 ** |
P＜0.05,
*Compare with negative control group in p＜0.01.
Table 9. medicine of the present invention is to (the X ± SD) of the enhanced influence of small intestinal peristalsis due to the neostigmine
| Group | Dosage (g/kg) | n | Propelling rate (%) |
| Blank | - | 12 | 69.34±9.71 ** |
| Neostigmine | 1×10 -4 | 10 | 83.94±11.85 |
| Atropine | 0.01 | 12 | 60.88±9.35 *** |
| Ease pill | 12 | 10 | 46.05±5.47 ** |
| JINGQIANPING KELI | 30 | 10 | 42.46±9.80 *** |
| Medicine of the present invention | 2.5 | 10 | 44.72±4.83 *** |
| 5 | 10 | 44.84±5.38 *** | |
| 10 | 10 | 56.76±8.72 *** |
*P＜0.01,
* *Compare with the neostigmine group in p＜0.001.
3. conclusion:
Through preceding lower abdominal distention pain is the cardinal symptom of premenstrual tension syndrome, and then symptom is more outstanding as concurrent dysmenorrhea, and its mechanism is not normal relevant with the abdominal viscera smooth muscle contraction.Medicine of the present invention can significantly suppress contraction frequency, amplitude and the contractility in the uterus after normal isolated uterine of rat and the oxytocin effect, illustrate that it not only can reduce the too high uterine smooth muscle tonicity that oxytocin causes, and normal uterine smooth muscle energy is also had than the obvious suppression effect.In addition, medicine of the present invention also has the obvious suppression effect to the enhancing of the caused small intestinal peristalsis of neostigmine; The effect that also has clear improvement of Dichlorodiphenyl Acetate induced mice writhing response.But small intestine movement of mice propelling rate there is not obvious influence.The pharmacodynamics basis that this shows medicine relieving spasm to stop pain effect of the present invention may be its mitigation to the too high tonicity of abdominal viscera smooth muscle.
Except that pain, the abnormal change of emotion is the another cardinal symptom of premenstrual tension syndrome, mainly show as excited, irritated irritability etc.This experiment finds that by the observation to the calm experiment of mice medicine 10g/kg of the present invention can significantly reduce the spontaneous activity of normal mouse.This shows that medicine of the present invention not only has analgesic effect, also have certain sedation.This may also be one of pharmacodynamics basis of its treatment premenstrual tension syndrome.
Two. medicine of the present invention is to the influence of the overt behavior variation of premenstrual tension syndrome reversed syndrome of mepatic qi model of rhesus monkey and endocrine hormone and neurotransmitter index
1. this experiment adopts premenstrual tension syndrome reversed syndrome of mepatic qi macaque model to observe the therapeutical effect of the endocrine regulation that medicine of the present invention causes this model, observes its influence to each parahormone in serum and the urine simultaneously.
Laboratory animal: female young macaque (24), the Rhesus Macacus kind, body weight 4.0-5.0kg is provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center.
24 macaques are divided into 6 groups at random, per 4 one group.First group as the normal control group; Second group is the blank group of modeling, gets the middle daystart modeling (be about the onset of ovulation this moment, the property skin is swollen the most obvious) of macaque menstrual cycle.Female monkey is caught up with into the compression cage, and extruding can be exceeded slightly with macaque in activity, and every day, continuously extruded 7h pushed modeling 7 days (macaque is still in the compression cage when not pushing), monitor that with monitor its expression behavior changes simultaneously, and video recording was taken pictures.The compression cage after 7 days is emitted macaque in modeling.The 3rd group gives JINGQIANPING KELI simultaneously in modeling, and dosage 0.4g granule/kg washes back 1.5ml/kg open with warm water, and per os gavages.Other three groups modeling give respectively simultaneously medicine of the present invention big (2.25g/kg), in (1.35g/kg), low dose of (0.45g/kg).Before administration time is every morning extruding feeding, once a day, continuous 7 days.Each phase after modeling, monitor that with monitor its expression behavior changes equally, and video recording is taken pictures.
Each monkey in that the same period, genus was not got blood respectively, is collected urine sample.Got after the hematuria menstruation in period ovulation back 5-7 days, 3-5 days premenstruum, menstrual phase 1-2 days 7-10 days.The hind leg vein is got blood 4ml, puts into centrifuge with the centrifugal 20min of 3000rpm, gets serum.With prolactin antagonist (PRL), estradiol (E in serum measured by radioimmunoassay and the urine
2), progesterone (P) content; Survey the content of 5-hydroxy tryptamine (5-HT), dopamine (DA), epinephrine (E), norepinephrine (NE) in serum and the urine sample with high performance capillary electrophoresis.
2. experimental result
2.1 the behavior of macaque expression changes after the modeling administration
During extruding modeling administration (luteal phase), the model control group macaque sees difference slightly before macaque property skin and expression behavior variation and the administration, its expression behavior of a period of time (premenstruum) after putting back to former cage to the menstrual onset but has notable difference, be in particular in: after the administration its activity than administration before and the modeling matched group obviously reduce, aggressivity obviously descends, cry reduces, performance is comparatively quiet, with the preceding performance of modeling is not similar, condition improved is big with the modeling administration, middle dosage group is good, modeling administration small dose group and positive administration group are taken second place, and the results are shown in Table 10.
Do not belong to the behavior of macaque expression after table 10 administration same period
2.2 neurotransmitter and hormone-content testing result in serum and the urine
Estradiol (E in reversed syndrome of mepatic qi model of rhesus monkey serum and the urine
2), progesterone (P) content significantly reduces, lactotropin (PRL) level obviously raises; 5-hydroxy tryptamine (5-HT) content raises in serum and the urine, dopamine in the serum (DA) and epinephrine (E) level there are no significant difference; Norepinephrine in the blood (NE) level is all than the normal group height.The reduction of model macaque estradiol, progesterone level and to the rising of lactotropin level due to medicine of the present invention stimulates modeling has good correction and regulating action.Can make its recovery or near normal level.Model macaque 5-HT level raise due to modeling stimulated, the NE level raises, and had good correction and regulating action.Can make its recovery or near normal level.
Medicine of the present invention raises to the rising of model macaque 5-HT level, NE level, has good correction and regulating action.Can make its recovery or near normal level.Illustrate that medicine of the present invention changes pointed therapeutical effect to the caused monoamines neural inverse of premenstrual tension syndrome reversed syndrome of mepatic qi matter content.
Show that more than medicine of the present invention presents good therapeutical effect to premenstrual tension syndrome reversed syndrome of mepatic qi model of rhesus monkey " symptom performance ", can significantly improve, eliminate the modeling macaque through clinical symptoms and signs such as preceding irritated irritabilities.Medicine of the present invention has good correction and regulating action to the reduction of premenstrual tension syndrome reversed syndrome of mepatic qi model macaque estradiol, progesterone level with to the rising of lactotropin level, can make its recovery or near normal level.Illustrate that medicine of the present invention changes pointed role of correcting to caused gonadal hormone of premenstrual tension syndrome reversed syndrome of mepatic qi and regulate hormone level thereof.
Three. toxicologic study:
1. acute toxicity test: mice is the LD of oral medicine of the present invention once
50For greater than 10g/kg; The LD of mouse peritoneal injection medicine of the present invention
50Be 57.8 (54.2-61.7) mg/kg.
2. general pharmacology test: the oral medicine of the present invention of Kunming mouse, mice behavior, movable no abnormal, the spontaneous activity number in the animal 5min does not have significant difference.Healthy hybrid dog is irritated stomach and gives medicine of the present invention under the anesthesia situation, each time point sampling determination result shows that the large and small dosage of medicine of the present invention does not all make significant difference to the every index of anesthetized dog electrocardiogram, heart rate and respiratory system.
3. long term toxicity test: medicine of the present invention is carried out the rat long term toxicity test.Experimental result shows that the safe dose of the continuous 26 all oral medicines of the present invention of rat is more than the 291mg/kg.Medicine of the present invention is carried out the dog long term toxicity test.This experimental result shows that the safe dose of the continuous 26 all oral medicines of the present invention of dog is more than the 146mg/kg.
In sum, the present invention treats the Chinese medicine five class compound drugs of premenstrual tension syndrome, have evident in efficacy, effect is reliable and stable, take the advantage for taking convenience.It is strong that the preparation method of medicine of the present invention has an extraction ratio height, purity height, quality controllability, is fit to the advantage of suitability for industrialized production.
(4) specific embodiment
Embodiment 1:
A: the preparation method of Radix Paeoniae Alba extract: get Radix Paeoniae Alba decoction pieces 1200g, adding 9600 milliliter of 70% soak with ethanol spends the night, the heating and refluxing extraction secondary, each 3 hours, merge extractive liquid, filters filtrate recycling ethanol, be concentrated into relative density and be 1.12 concentrated solution, thin up becomes the medicinal liquid 1200mL that is equivalent to crude drug 1g to every 1mL, by the D101 macroporous resin column of having handled well (sample is 1: 1.2 (v/v) with the ratio of resin), behind the last sample, left standstill 1 hour, add water elution to MOlish reaction negative (volume is about 12000 milliliters), add 12000 milliliter of 40% ethanol elution, collect eluent, reclaim ethanol, be concentrated into driedly, 40 ℃ of vacuum dryings are pulverized, cross 60 mesh sieves, promptly get the about 48g of Radix Paeoniae Alba extract;
B: the preparation method of Cortex Moutan extract: get Cortex Moutan coarse powder 1200g, add 14400 ml water soaked overnight, add 12g sodium chloride, feed water vapour, distilled 8 hours; The reception liquid cooling is hidden, and filters, and gets crystallization; Mother solution adds 12g sodium chloride again, the heating redistillation, and the distillate of collection mother solution 1/3 volume, refrigerator and cooled is hidden, and filters, and merges twice crystallization, pulverizes, and crosses 60 mesh sieves, gets the about 9.72g of Cortex Moutan extract;
C: the preparation method of attached volatile oil and Benexate Hydrochloride thereof: (Φ 0.25 ± 0.1cm) 1200g adds 7200 milliliters water, soaked overnight to get Rhizoma Cyperi medical material granule, heating extraction volatile oil 8 hours is collected about 6 milliliters of volatile oil, adds 72g beta-schardinger dextrin-(g), add 144 milliliter of 50% ethanol again, grind to form pasty state, slowly drip volatile oil, after adding, continue to grind 60 minutes, filter, 40 ℃ of dryings, pulverize, cross 60 mesh sieves, promptly get the about 67.2g of Rhizoma Cyperi volatile oil Benexate Hydrochloride;
D: get above Radix Paeoniae Alba extract, Cortex Moutan extract and Rhizoma Cyperi volatile oil Benexate Hydrochloride, add the about 125g of calcium bicarbonate and make total amount reach 250g, mix homogeneously is crossed 60 mesh sieves, is sub-packed in 1000 capsules, promptly.
Embodiment 2:
A: the preparation method of Radix Paeoniae Alba extract: get Radix Paeoniae Alba decoction pieces 1800g, adding 14400 milliliter of 70% soak with ethanol spends the night, the heating and refluxing extraction secondary, each 3 hours, merge extractive liquid, filters filtrate recycling ethanol, be concentrated into relative density and be 1.12 concentrated solution, thin up becomes 1800 milliliters of medicinal liquids that are equivalent to crude drug 1g to every 1mL, by the D101 macroporous resin column of having handled well (sample is 1: 1.2 (v/v) with the ratio of resin), behind the last sample, left standstill 1 hour, add water elution to Molish reaction negative (volume is about 18000 milliliters), add 18000 milliliter of 40% ethanol elution, collect eluent, reclaim ethanol, be concentrated into driedly, 40 ℃ of vacuum dryings are pulverized, cross 60 mesh sieves, promptly get Radix Paeoniae Alba extract and be about 72g;
B: the preparation method of Cortex Moutan extract: get Cortex Moutan coarse powder 1800g, the water logging bubble that adds 21600 milliliters spends the night, and adds 18g sodium chloride, feeds water vapour, distills 8 hours; The reception liquid cooling is hidden, and filters, and gets crystallization; Mother solution adds 18g sodium chloride again, the heating redistillation, and the distillate of collection mother solution 1/3 volume, refrigerator and cooled is hidden, and filters, and merges twice crystallization, pulverizes, and crosses 60 mesh sieves, gets the about 14.6g of Cortex Moutan extract;
C: the preparation method of attached volatile oil and Benexate Hydrochloride thereof: (Φ 0.25 ± 0.1cm) 1800g adds 10800 milliliters water, soaked overnight to get Rhizoma Cyperi medical material granule, heating extraction volatile oil 8 hours is collected 9 milliliters of volatile oil, adds 108g beta-schardinger dextrin-(g), add 216 milliliter of 50% ethanol again, grind to form pasty state, slowly drip volatile oil, after adding, continue to grind 60 minutes, filter, 40 ℃ of dryings, pulverize, cross 60 mesh sieves, promptly get the about 101g of Rhizoma Cyperi volatile oil Benexate Hydrochloride;
D: get above Radix Paeoniae Alba extract, Cortex Moutan extract and Rhizoma Cyperi volatile oil Benexate Hydrochloride, add the about 62g of calcium bicarbonate and make total amount reach 250g, mix homogeneously is crossed 60 mesh sieves, is sub-packed in 1000 capsules, promptly.
Embodiment 3:
A: the preparation method of Radix Paeoniae Alba extract: get Radix Paeoniae Alba decoction pieces 1500g, adding 12000 milliliter of 70% soak with ethanol spends the night, the heating and refluxing extraction secondary, each 3 hours, merge extractive liquid, filters filtrate recycling ethanol, be concentrated into relative density and be 1.12 concentrated solution, thin up becomes 1500 milliliters of medicinal liquids that are equivalent to crude drug 1g to every 1mL, by the D101 macroporous resin column of having handled well (sample is 1: 1.2 (v/v) with the ratio of resin), behind the last sample, left standstill 1 hour, add water elution to Mol ish reaction negative (volume is about 15000 milliliters), add 15000 milliliter of 40% ethanol elution, collect eluent, reclaim ethanol, be concentrated into driedly, 40 ℃ of vacuum dryings are pulverized, cross 60 mesh sieves, promptly get the about 60g of Radix Paeoniae Alba extract;
B: the preparation method of Cortex Moutan extract: get Cortex Moutan coarse powder 1500g, add 18000 ml water soaked overnight, add 15g sodium chloride, feed water vapour, distilled 8 hours; The reception liquid cooling is hidden, and filters, and gets crystallization; Mother solution adds 15g sodium chloride again, the heating redistillation, and the distillate of collection mother solution 1/3 volume, refrigerator and cooled is hidden, and filters, and merges twice crystallization, pulverizes, and crosses 60 mesh sieves, gets the about 12g of Cortex Moutan extract;
C: the preparation method of attached volatile oil and Benexate Hydrochloride thereof: (Φ 0.25 ± 0.1cm) 1500g adds 9000 milliliters water, soaked overnight to get Rhizoma Cyperi medical material granule, heating extraction volatile oil 8 hours is collected volatile oil 7.5mL, adds the 90g beta-schardinger dextrin-, add 180mL50% ethanol again, grind to form pasty state, slowly drip volatile oil, after adding, continue to grind 60 minutes, filter, 40 ℃ of dryings, pulverize, cross 60 mesh sieves, promptly get the about 84g of Rhizoma Cyperi volatile oil Benexate Hydrochloride;
D: get above Radix Paeoniae Alba extract, Cortex Moutan extract and Rhizoma Cyperi volatile oil Benexate Hydrochloride, add the about 94g of calcium bicarbonate, making gross weight is 250g, and mix homogeneously is crossed 60 mesh sieves, is sub-packed in 1000 capsules, promptly.
The capsule that the invention described above embodiment 1-3 obtains is measured research to active constituent content in each effective ingredient component and the preparation, and content of paeoniflorin is greater than 30.0% in the Radix Paeoniae Alba extract; The content of Radix Paeoniae Alba total glucosides is greater than 52.0% in the Radix Paeoniae Alba extract; The content of paeonol is greater than 90% in the Cortex Moutan extract; Volatile oil contents is greater than 6.0% in the Rhizoma Cyperi extract (inclusion complex).Every in this preparation contains peoniflorin must not be lower than 17.5mg; The content of every Radix Paeoniae Alba total glucosides of this product must not be lower than 30.0mg; Every of this product contains paeonol must not be lower than 10.0mg; The content of Rhizoma Cyperi volatile oil must not be lower than 1.7% in this product, reaches the requirement of Chinese medicine five kind new medicines.
Embodiment 4:
A: the preparation method of Radix Paeoniae Alba extract: get Radix Paeoniae Alba decoction pieces 2500g, adding 20000 milliliter of 70% soak with ethanol spends the night, the heating and refluxing extraction secondary, each 3 hours, merge extractive liquid, filters filtrate recycling ethanol, be concentrated into relative density and be 1.12 concentrated solution, thin up becomes the medicinal liquid 2500mL that is equivalent to crude drug 1g to every 1mL, by the D101 macroporous resin column of having handled well (sample is 1: 1.2 (v/v) with the ratio of resin), behind the last sample, left standstill 1 hour, add water elution to Molish reaction negative after, adds 25000 milliliter of 40% ethanol elution, the collection eluent, reclaim ethanol, be concentrated into driedly, 40 ℃ of vacuum dryings are pulverized, cross 60 mesh sieves, promptly get the about 100g of Radix Paeoniae Alba extract;
B: the preparation method of Cortex Moutan extract: get Cortex Moutan coarse powder 1200g, add medical material 14400 ml water soaked overnight, add 12g sodium chloride, feed water vapour, distilled 8 hours; The reception liquid cooling is hidden, and filters, and gets crystallization; Mother solution adds 12g sodium chloride again, the heating redistillation, and the distillate of collection mother solution 1/3 volume, refrigerator and cooled is hidden, and filters, and merges twice crystallization, pulverizes, and crosses 60 mesh sieves, gets the about 9.72g of Cortex Moutan extract;
C: the preparation method of attached volatile oil and Benexate Hydrochloride thereof: (Φ 0.25 ± 0.1cm) 800g adds the water of 4800 times of amounts, soaked overnight to get Rhizoma Cyperi medical material granule, heating extraction volatile oil 8 hours is collected about 4 milliliters of volatile oil, adds 48g beta-schardinger dextrin-(g), add 100 milliliter of 50% ethanol again, grind to form pasty state, slowly drip volatile oil, after adding, continue to grind 60 minutes, filter, 40 ℃ of dryings, pulverize, cross 60 mesh sieves, promptly get the about 45g of Rhizoma Cyperi volatile oil Benexate Hydrochloride;
D: get above Radix Paeoniae Alba extract, Cortex Moutan extract and Rhizoma Cyperi volatile oil Benexate Hydrochloride, add a certain amount of amylum pregelatinisatum and make total amount reach 200g, mix homogeneously, tabletting makes 1000 finished products.
Embodiment 5:
A: the preparation method of Radix Paeoniae Alba extract: get Radix Paeoniae Alba decoction pieces 1800g, add 14400 milliliter of 70% soak with ethanol and spend the night, heating and refluxing extraction secondary, each 3 hours, merge extractive liquid,, filter, filtrate recycling ethanol is concentrated into dried, 40 ℃ of vacuum dryings, pulverize, cross 60 mesh sieves, promptly get Radix Paeoniae Alba extract and be about 250g;
B: the preparation method of Cortex Moutan extract: get Cortex Moutan coarse powder 2400g, add medical material 28800 ml water soaked overnight, heating and refluxing extraction secondary, each 5 hours, merge extractive liquid, filters, and is concentrated into dried, 40 ℃ of vacuum dryings are pulverized, and get Cortex Moutan extract and are about 300g;
C: the preparation method of attached volatile oil and Benexate Hydrochloride thereof: (Φ 0.25 ± 0.1cm) 1200g adds the water of 7200 times of amounts, soaked overnight to get Rhizoma Cyperi medical material granule, heating extraction volatile oil 8 hours is collected about 6 milliliters of volatile oil, adds 72g beta-schardinger dextrin-(g), add 144 milliliter of 50% ethanol again, grind to form pasty state, slowly drip volatile oil, after adding, continue to grind 60 minutes, filter, 40 ℃ of dryings, pulverize, cross 60 mesh sieves, promptly get the about 67.2g of Rhizoma Cyperi volatile oil Benexate Hydrochloride;
D: get above Radix Paeoniae Alba extract, Cortex Moutan extract and Rhizoma Cyperi volatile oil Benexate Hydrochloride, add a certain amount of dextrin mix homogeneously, make the 1000g granule, it is packed to press 5g/.
Claims (7)
1. Chinese medicine composition for the treatment of premenstrual tension syndrome is characterized in that: makes by following raw material and pharmaceutically acceptable auxiliaries,
The Radix Paeoniae Alba, Cortex Moutan, Rhizoma Cyperi.
2. the Chinese medicine composition of treatment premenstrual tension syndrome according to claim 1 is characterized in that: the part by weight of described raw material is:
1200～1800 parts of the Radix Paeoniae Albas
1200～1800 parts of Cortex Moutans
1200～1800 parts of Rhizoma Cyperis.
3. the Chinese medicine composition of treatment premenstrual tension syndrome according to claim 2 is characterized in that: the part by weight of described raw material is:
1500 parts of the Radix Paeoniae Albas
1500 parts of Cortex Moutans
1500 parts of Rhizoma Cyperis.
4. according to the Chinese medicine composition of claim 1,2 or 3 each described treatment premenstrual tension syndromes, it is characterized in that: the dosage form of described compound medicine is a capsule.
5. the Chinese medicine composition of treatment premenstrual tension syndrome according to claim 4 is characterized in that: capsule is to be made by the extract of described raw material, and the composition of described extract is:
A: content of paeoniflorin is greater than 30.0% in the Radix Paeoniae Alba extract, and the content of Radix Paeoniae Alba total glucosides is greater than 52.0% in the Radix Paeoniae Alba extract;
B: the content of paeonol is greater than 90% in the Cortex Moutan extract;
C: volatile oil contents is greater than 6.0% in the Rhizoma Cyperi extract.
6. the Chinese medicine composition of treatment premenstrual tension syndrome according to claim 5, it is characterized in that: described pharmaceutic adjuvant is a calcium bicarbonate, and the consumption of calcium bicarbonate and Radix Paeoniae Alba extract, Cortex Moutan extract and Rhizoma Cyperi volatile oil Benexate Hydrochloride total amount weight ratio are 1: 1-3.
7. the preparation method of the Chinese medicine composition of the described treatment premenstrual tension syndrome of claim 4 is characterized in that: may further comprise the steps:
A: the preparation method of Radix Paeoniae Alba extract: get Radix Paeoniae Alba decoction pieces, add 8 times of amount 70% soak with ethanol and spend the night heating and refluxing extraction secondary, each 3 hours, merge extractive liquid, filters filtrate recycling ethanol, be concentrated into relative density and be 1.12 concentrated solution, thin up is by the macroporous resin column of having handled well, after adding water washing, use 40% ethanol elution, collect eluent, reclaim ethanol, be concentrated into dried, vacuum drying, pulverize, sieve, promptly get Radix Paeoniae Alba extract;
B: the preparation method of Cortex Moutan extract: get the Cortex Moutan granule, add the water of 12 times of amounts of medical material, add the sodium chloride of 1% medical material amount, steam distillation 4 hours; The reception liquid cooling is hidden, and filters, and gets crystallization; Mother solution adds 1% sodium chloride again, heats redistillation, collects the distillate of mother solution 1/3 volume, and refrigerator and cooled is hidden, and filters, and merges twice crystallization, and cold drying is pulverized, and sieves, and gets Cortex Moutan extract;
C: get the Rhizoma Cyperi medicinal material coarse powder, add the water of 6 times of amounts, soaked overnight, heating extraction volatile oil 8 hours gets oil water mixture, reuse 30-60 ℃ petroleum ether extraction, the petroleum ether extraction layer reclaims petroleum ether, gets volatile oil; Take by weighing the beta-schardinger dextrin-of 12 times of amounts of volatile oil, add 50% ethanol of 2 times of amounts of beta-schardinger dextrin-, grind to form pasty state, slowly drip volatile oil, after adding, continue to grind, filter, cold drying is pulverized, and sieves, and promptly gets the Rhizoma Cyperi volatile oil Benexate Hydrochloride;
D: get above Radix Paeoniae Alba extract, Cortex Moutan extract and Rhizoma Cyperi volatile oil Benexate Hydrochloride, add a certain amount of calcium bicarbonate mix homogeneously, sieve, be sub-packed in the capsule, promptly.
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