CN1768820A - Dysmenorrhea treating pharmaceutical formulation and preparation method thereof - Google Patents

Abstract

The invention provides a medicinal preparation for treating dysmenorrhea and its preparing method, wherein the preparation is a capsule prepared from Chinese angelica root, cyperus tuber, root of herbaceous peony, root of red rooted saliva, corydalis tuber, toosendan fruit, Ligusticum wallichii, licorice root, safflower and right amount of adjuvant.

Description

Pharmaceutical preparation of treatment dysmenorrhea and preparation method thereof

Technical field: the present invention relates to a kind of pharmaceutical preparation for the treatment of dysmenorrhea and preparation method thereof, belong to technical field of medicaments.

Background technology: menopathy is meant the cycle, menstrual period of menstruation, through amount, unusual through matter, or follow menstrual cycle the disease of significant discomfort symptom to occur, be gynecological's frequently-occurring disease, have a strong impact on women's Health and Living quality, even hinder and to pass through normally and breed; The women is on the occasion of menstrual period, or before and after row, periodicity lower abdomen pain occurs or draw the waist sacrum bitterly, very then severe pain is called dysmenorrhea to faintness person, also claims abdominal pain during menstruation, wherein primary dysmenorrhea is one of common gynecological diseases of adolescence women, sickness rate reaches 30%～50%, and about 10% patient is difficult to normally work and live in menstrual period owing to pain.

At present on the treatment dysmenorrhea mainly with chemical medicine pain relieving alleviating pain, but can not effect a permanent cure, and toxic and side effects is very big.And Chinese medicine is owing to focus on conditioning, can play the effect for the treatment of both the principal and secondary aspects of a disease and has no side effect, and comes into one's own day by day on the treatment dysmenorrhea.Prior art discloses the peaceful granule of a kind of Chinese medicine dysmenorrhea (application number 03112601.4), dysmenorrhea is had certain curative effect and has no side effect, but it exists dose big and absorb slowly, can not alleviate shortcomings such as disease, bioavailability are low rapidly.

Summary of the invention:

The objective of the invention is to: a kind of pharmaceutical preparation for the treatment of dysmenorrhea and preparation method thereof is provided, medicament of the present invention not only to dysmenorrhea evident in efficacy, have no side effect, and dose is little, absorption is rapid, bioavailability is high, can alleviate disease rapidly, to overcome the deficiencies in the prior art.

The present invention is achieved in that according to listed as parts by weight it adds appropriate amount of auxiliary materials for 200～450 parts by 600～900 parts of Radix Angelicae Sinensis (parched with wine), 600～900 parts of Rhizoma Cyperi (processed with vinegar), 600～900 parts of Radix Paeoniae Alba (parched)s, 600～900 parts of Radix Salviae Miltiorrhizaes, 600～850 parts of Rhizoma Corydalis (processed with vinegar), 600～850 parts of Fructus Toosendan (parched), 300～500 parts of Rhizoma Chuanxiong (parched), 200～400 parts of Radix Glycyrrhizae Preparatas, Flos Carthami and is prepared into capsule.

Specifically, calculate according to weight, it adds adjuvant 1000g by Radix Angelicae Sinensis (parched with wine) 793g, Rhizoma Cyperi (processed with vinegar) 793g, Radix Paeoniae Alba (parched) 793g, Radix Salviae Miltiorrhizae 793g, Rhizoma Corydalis (processed with vinegar) 714g, Fructus Toosendan (parched) 714g, Rhizoma Chuanxiong (parched) 476g, Radix Glycyrrhizae Preparata 317g, Flos Carthami 398g and is prepared into capsule.

Described adjuvant is the mixture of dextrin and starch.

The proportioning of dextrin and starch is a dextrin in the adjuvant: starch is 3: 1.

The pharmaceutical preparation that the present invention treats dysmenorrhea is preparation like this: take by weighing the medical material Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched), the Radix Glycyrrhizae Preparata and Flos Carthami, with Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched) and Radix Glycyrrhizae Preparata add 4～16 times of decoctings and boil 1～3 time, each 0.5～3 hour, filter, medicinal residues add Flos Carthami, continue to decoct 1～2 time, each 0.2～1 hour, collecting decoction, filter, the filtrate standing over night is surveyed relative density and is 1.10～1.12 clear paste when getting supernatant concentration to 85 ℃, put cold, the ethanol of adding 40%～70%, stir evenly, leave standstill and made precipitation in 12～48 hours, get supernatant, reclaim ethanol, the survey relative density is 1.20～1.35 thick paste when being evaporated to 85 ℃, at 60 ℃ of following drying under reduced pressure, pulverizes, cross 60～100 mesh sieves, add adjuvant, mixing, alcohol granulation with an amount of 80%～98%, dry, granulate, encapsulated, promptly.

The best preparation method that the present invention treats the pharmaceutical preparation of dysmenorrhea is: take by weighing medical material Radix Angelicae Sinensis (parched with wine) 793g, Rhizoma Cyperi (processed with vinegar) 793g, Radix Paeoniae Alba (parched) 793g, Radix Salviae Miltiorrhizae 793g, Rhizoma Corydalis (processed with vinegar) 714g, Fructus Toosendan (parched) 714g, Rhizoma Chuanxiong (parched) 476g, Radix Glycyrrhizae Preparata 317g and Flos Carthami 398g, with Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched) and Radix Glycyrrhizae Preparata add 8 times of decoctings and boiled 2 hours, filter, medicinal residues add Flos Carthami, continue to decoct 0.5 hour, collecting decoction, filter, the filtrate standing over night is surveyed relative density and is 1.10～1.12 clear paste when getting supernatant concentration to 85 ℃, put cold, the ethanol of adding 50% stirs evenly, and leaves standstill and makes precipitation in 24 hours, get supernatant, reclaim ethanol, the survey relative density is 1.20～1.35 thick paste when being evaporated to 85 ℃, at 60 ℃ of following drying under reduced pressure, pulverize, cross 80 mesh sieves, add adjuvant 1000g, mixing, alcohol granulation with an amount of 95%, drying, granulate, encapsulated, make 1000, promptly.

Medicine of the present invention has the effect of menstruction regulating and pain relieving, mainly be applicable to because of the dysmenorrhea of caused by energy stagnation and blood stasis and the treatment of all cards of menoxenia, see that mainly disease is that feelings will is not smooth, the breast side of body and breast expand, belch does not relax, through the twinge of row lower abdomen, pain in fixed position, complexion is brown turbid, or squamous and dry skin, the course of disease is longer, and tongue is dim or ecchymosis, hesitant pulse or heavy string arranged.The dysmenorrhea of assertive evidence be since stagnation of QI-blood due to, qi depression to blood stasis, then venation is obstructed, stagnation of QI and blood may bring about pain.So promoting flow of QI and blood is worked as in treatment, blood-activating analgetic, the stasis of blood is removed ruton, and its pain is from ending.Go the relatively greasy of Radix Rehmanniae to mend with SIWU TANG in the side, wherein Chinese angelica blood supplementing is invigorated blood circulation, menstruction regulating and pain relieving, and the pain relieving of Radix Paeoniae Alba suppressing the hyperactive liver, nourishing blood for regulating menstruation, the pain relieving of Rhizoma Chuanxiong blood-activating and qi-promoting adds Flos Carthami, Radix Salviae Miltiorrhizae is good at invigorating blood circulation, and then the power of menstruction regulating and pain relieving benefit is strong; More use Rhizoma Cyperi, Fructus Toosendan dispersing the stagnated live-QI to relieve the stagnation of QI, promoting the circulation of QI to relieve pain; The Rhizoma Corydalis promoting the circulation of QI analgesic therapy of invigorating blood circulation; Radix Glycyrrhizae Preparata escorts middle Jiao, coordinating the actions of various ingredients in a prescription.All medicines are harmonious, and play the merit of menstruction regulating and pain relieving altogether.Wherein, Rhizoma Chuanxiong: suffering, temperature.Return liver, gallbladder, pericardium channel.Blood-activating and qi-promoting, wind-expelling pain-stopping.Be used for menoxenia, amenorrhea dysmenorrhea ， mass in the abdomen stomachache, the twinge of the breast side of body, tumbling and swelling, headache, rheumatic arthralgia.Fructus Toosendan: hardship, cold; Slightly poisonous.Return liver, small intestinal, urinary bladder channel.The soothing liver-QI promoting the circulation of QI to relieve pain, anthelmintic.Be used for the breast side of body, abdominal distention, colic, abdominal pain due to worm stagnation.Radix Salviae Miltiorrhizae: if be slightly cold.GUIXIN, Liver Channel.Stasis-dispelling and pain-killing, the dysmenorrhea of invigorating blood circulation, relieving restlessness clears away heart-fire.Be used for menoxenia, amenorrhea dysmenorrhea ， lumps in the chest and abdomen, breast ventral spine pain, pyretic arthralgia pain, skin infection swells and ache, dysphoria and insomnia; Hepatosplenomegaly, angina pectoris.Radix Glycyrrhizae: sweet, flat.GUIXIN, lung, spleen, stomach warp.Invigorating the spleen and replenishing QI, heat-clearing and toxic substances removing, expelling phlegm for arresting cough, relieving spasm to stop pain, coordinating the actions of various ingredients in a prescription.Be used for weakness of the spleen and stomach, fatigue and weakness, shortness of breath and palpitation, cough with copious phlegm, gastral cavity abdomen, the anxious pain of extremity contraction, carbuncle sore tumefacting virus, cushion toxicity, strong.The Radix Paeoniae Alba: if, acid, be slightly cold, return liver, spleen channel.The suppressing the hyperactive liver pain relieving, nourishing blood for regulating menstruation, astringing YIN to stop sweating.It is dizzy to be used to have a headache, hypochondriac pain, stomachache, limb pain twin, blood deficiency and yellow complexion, menoxenia, spontaneous perspiration, night sweat.Radix Angelicae Sinensis: sweet, hot, warm.Return liver, the heart, spleen channel.Enrich blood and invigorate blood circulation, menstruction regulating and pain relieving, loosening bowel to relieve constipation.Be used for blood deficiency and yellow complexion, dizzy cardiopalmus, menoxenia, amenorrhea dysmenorrhea, asthenia cold abdominalgia, dryness of the intestine constipation, rheumatic arthralgia, injury from falling down, ulcer sores.The Radix Angelicae Sinensis (processed with wine) promoting blood circulation to restore menstrual flow.Be used for the amenorrhea dysmenorrhea, rheumatic arthralgia, injury from falling down.Rhizoma Corydalis: hot, bitter, temperature.Return liver, spleen channel.Invigorate blood circulation promoting the circulation of QI, pain relieving.Be used for the breast side of body, epigastric pain, amenorrhea dysmenorrhea, postpartum stagnation, tumbling and swelling.Flos Carthami: suffering, temperature.GUIXIN, Liver Channel.Promoting blood circulation to restore menstrual flow, eliminating stasis to stop pain.Be used for amenorrhea, dysmenorrhea, the not all right ， mass in the abdomen of lochia mass in the abdomen, injury from falling down, skin infection swells and ache.Rhizoma Cyperi: hot, little hardship, little sweet, flat.Return liver, spleen, tri-jiao channel.Promoting QI circulation for relieving depression, menstruction regulating and pain relieving.Be used for stagnation of QI due to depression of the liver, breast, the side of body, abdominal distention, dyspepsia, breast gastral cavity painful abdominal mass is vexed, colic of cold type stomachache, distending pain of the breast, menoxenia, amenorrhea dysmenorrhea.

Compared with prior art, medicine of the present invention is a pure Chinese medicinal preparation, have no side effect and evident in efficacy, can treating both the principal and secondary aspects of a disease to dysmenorrhea: and medicine of the present invention be capsule, have dose little, absorb fast, can alleviate disease, advantage that bioavailability is high rapidly.

The pharmacological research of medicine of the present invention:

One, the analgesic mechanism of this product dysmenorrhea Yiganning capsule and the ovarian hormone pathogenesis experimental study in primary dysmenorrhea:

1, materials and methods:

1.1 material: animal is selected 40 of health, female, unpregnancy Wister rats, body constitution amount 180～220g for use.Experiment medicine this product dysmenorrhea Yiganning capsule, every contains crude drug 5.791g, and the sodium carboxymethyl cellulose (CMC) with 1% during experiment is made into the outstanding liquid that mixes, and uses for rat oral gavage.

1.2 method: animal grouping: animal is divided into normal control group (abbreviation normal group) at random by the body constitution amount, dysmenorrhea model group, model+Chinese drug-treated group (abbreviation Chinese drug-treated group), model+aspirin group (being called for short the Western medicine group), totally 4 groups, 10 every group.

Modeling method: model group, Chinese drug-treated group, Western medicine group all continuous 10d give rat skin lower injection E2,1st, 10 days subcutaneous administration 0.5mg/ (d), Yu Ri is 0.2mg/ (d), again behind the 40h of interval, the abdominal cavity injects oxytocin 2L/ with the dilution of 2% tween 80, after observing the interior writhing response incidence rate of 30min, 60min, eye socket is got blood.

Dosage and medication: dosage: normal group, model group gavage equal-volume 1% sodium carboxymethyl cellulose (CMC) every day, and Chinese drug-treated group is irritated stomach (ig) dysmenorrhea Yiganning capsule 2.25g/kg, and drug level is 0.5g/mL, press 0.02mL/g, gastric infusion, 1 time/d, continuous 10d.Western medicine group ig aspirin phenacetin caffeine 25mg/kg, drug level is 1.25mg/mL, presses the 0.02mL/g gastric infusion, 1 time/d, continuous 3d.Medication: Chinese drug-treated group is irritated 1 time/d of stomach from the beginning administration of modeling day, continuously 10d; The Western medicine group is irritated 1 time/d of stomach, continuously 3d from the 8d beginning administration of modeling; The equal-volume distilled water is given in normal group, model group filling every day.

Observation item and detection method: general state is observed body constitution, hair color, the mental status and the active situation of each group rat.The writhing response incidence rate observe to inject observe 30 behind the oxytocin, 60min writhing response incidence rate.Hypothalamus, hypophysis, ovary, uterus, peripheral blood β-EP assay take out hypothalamus, hypophysis, ovary, uterus for 4 groups respectively, after placing 100 ℃ of normal saline to boil 5min, cooling rapidly is behind scales/electronic balance weighing, place miniature homogenizer, after adding an amount of 0.1NHCl placement 100min, add 0.1NaOH 1mL, it is centrifugal to shake up the back, 3000r/min, take out supernatant behind the 20min, place-20 ℃ of preservations, the stand-by method of exempting from of putting is measured β-EP content.Put and exempt from medicine box and provide by the sharp biotechnology center of Beijing sea section.Eye socket was got blood 1mL before each was organized and puts to death, and the centrifuging and taking supernatant is put-30 ℃ of preservations, put the method for exempting from batch mensuration.Serum E ₂, each treated animal of P Determination on content put to death before eye socket get whole blood 1mL, the centrifuging and taking supernatant is put-30 ℃ of preservations, waits to put the method for exempting from and detects.Tectology is observed light microscopy specimen 10% formaldehyde fixed, paraffin embedding, HE dyeing.Statistical method adopts respectively according to data character: F, q, t check.

2, result:

2.1 general state-normal control group generally in order, the ear color is ruddy, and spirit is normal, and is movable sensitive, shows no obvious abnormalities.Model control group rat hair color is glossy, and spirit is excited, and irritability is irritated shape.Chinese drug-treated group generally in order, the ear color is ruddy, spirit is normal, and is movable sensitive, shows no obvious abnormalities same substantially normal group.The general situation of Western medicine group is fair, and spirit is normal, and is movable sensitive, shows no obvious abnormalities.The observation of writhing response incidence rate sees Table 1 to the influence of writhing response due to the oxytocin.

2.2 this product dysmenorrhea Yiganning capsule is to the influence of B-EP content: 4 treated animal hypothalamuses, hypophysis, ovary, uterus β-EP assay the results are shown in Table 2; 4 treated animal blood plasma β-EP assays the results are shown in Table 3; 4 treated animal serum E2, P content relatively see Table 4.

The influence of writhing response due to the table 1 pair oxytocin (X ± S)

Group	Size of animal	Dosage μ/only	Turn round the body number of animals	Turn round the body number of times (inferior/30min)	Turn round the body number of animals	Turn round the body number of times (inferior/60min)
							Normal group	10	2	5	2.5±2.55**	1 △△	0.1±0.32*
Model group	10	2	10	11.6±8.03	9	4±5.12
							The Western medicine group	10	2	9	5±6.67*	4 △	0.7±0.27*
Chinese drug-treated group	10	2	8	3.1±2.42**	2 △△	0.4±0.84*

Annotate: compare * P＜0.05 with model group, material P＜0.01.Compare with model group ^△P＜0.05, ^{△ △}P＜0.01.

Table 2 four treated animal hypothalamuses, hypophysis, ovary, uterus B-EP content relatively (X ± S, pg/mL)

Group	n	Hypothalamus	Hypophysis	Ovary	The uterus
						Normal group	9	103.88±62.36	093.59±288.32**	56.52±32.51**	79.49±31.25 △
Model group	9	40.28±13.33	526.26±158.33	29.27±7.10	35.24±16.68
						The Western medicine group	9	55.66±17.50 △△	605.63±105.64 △△	35.13±8.18Δ	38.13±17.87 △
Chinese drug-treated group	9	110.65±36.42** ##	1216.97±283.08** ##	62.94±23.83** #	83.08±42.16* #

Annotate; Compare P＜0.05 with model group, compare with normal group P＜0.01 ^△P＜0.05, ^{△ △}Compare with the Western medicine group P＜0.01 ^#P＜0.05, ^##P＜0.01.

As can be seen from Table 2, the β in the hypothalamus of Chinese drug-treated group, hypophysis, ovary, uterus-EP content is significantly higher than model group, Western medicine group (P＜0.01), and Chinese drug-treated group uterus β-EP and normal group be there was no significant difference (P＞0.05) relatively.The β in Western medicine group and normal group uterus-EP content relatively has significant difference (P＜0.05), and each β-EP value is a little more than model group, Western medicine group, but there was no significant difference (P＞0.05).β-EP content is the highest with hypophysis.

Table 34 treated animal blood plasma β-EP content comparison (X ± S, pg/mL)

Group	N	Blood plasma β-EP
			Normal group	9	46.47±16.71
Model group	9	87.23±20.28
			The Western medicine group	9	08.95±18.74 △
Chinese drug-treated group	9	68.13±64.59 #

Annotate: compare P＜0.01 with model group, compare with normal group ^△Compare with the Western medicine group P＜0.05 ^#P＜0.01.

As can be seen from Table 3, Chinese drug-treated group serum-EP content is significantly higher than model group, Western medicine group (P＜0.01), and the Western medicine group is higher than model group, but there was no significant difference (P＞0.05), normal group is significantly higher than model group (P＜0.01).

The comparison of table 44 treated animal serum E2, P content (X ± S)

Group	n	E2(pmol/L)	P(pmol/L)
				Normal group	9	8.4±2.23	8.12±0.71*
Model group	9	3.87±3.44	6.07±0.73
				The Western medicine group	9	1.71±1.77 △	6.60±0.66 △
Chinese drug-treated group	9	8.95±1.87*#	8.99±1.08*#

Annotate: compare * P＜0.01 with model group, compare with normal group ^△#P＜0.05 is compared with the Western medicine group in P＜0.05.

Table 4 shows, model group serum E ₂Be significantly higher than normal group, model group (P＜0.01), blood-serum P then significantly is lower than normal group, model group (P＜0.01).Chinese drug-treated group serum E ₂Content significantly is lower than Western medicine group, model group (P＜0.01), and P content then is significantly higher than model group, Western medicine group (P＜0.01), with normal group there was no significant difference (P＞0.05).

Two, the experimentation of this product dysmenorrhea Yiganning capsule treatment dysmenorrhea:

1, experiment material: medicine-this product dysmenorrhea Yiganning capsule, 5.791g crude drug/grain.Animal cleaning level Kunming mouse, body weight 18～22g, male and female dual-purpose; The SD rat, body weight 160～180g, female.Instrument-DGS-type animal blood pressure organ measuring instrument

2, method and result:

2.1 this product dysmenorrhea Yiganning capsule is to the influence of primary dysmenorrhea: get 40 of 18～22g mices, female, be divided into 4 groups, every group 10, except that the normal control group, every the equal subcutaneous injection diethylstilbestrol of animal 0.2mg/20g, for three days on end, in the 1st day beginning gastric infusion, continuous 4 days, 1hr after the last administration, every animal is lumbar injection oxytocin 2u/20g again, observe and write down the incubation period of turning round body number of times and writhing response generation of mice in the 20min, it the results are shown in Table 5.

Table 5 dysmenorrhea Yiganning capsule causes the influence (X ± S) of pain mice to oxytocin

Group	n	Dosage (g/kg)	Incubation period (min)	Turn round body number of times (inferior)	Suppression ratio (%)
						Matched group	10	--	5.75±1.5	11.2±2.9	--
Low dose group	10	8.85	10.4±3.7*	5.4±2.3*	51.8
						Middle dosage group	10	17.70	12.8±4.3*	4.2±2.4*	62.5
High dose group	10	35.40	13.0±4.2*	4.4±2.5*	60.7

Annotate: * and matched group compare, P＜0.01

2.2 this product dysmenorrhea Yiganning capsule is to the uterotonic influence of normal isolated rat: get healthy do not have hinder, promptly isolate after the ablactation and body weight is 40 of the female Mus of 180～200g with male Mus, be divided into 4 groups, 10 every group, its group technology is the same.Only test preceding 38～42h subcutaneous injection diethylstilbestrol oil solution 0.4mg/, during experiment rat is shot dead, cut off the abdominal cavity rapidly, peel off fatty tissue around the uterus, triangle connecting place in the uterus is cut off, and gets one jiao and does experiment, and another angle is put to store up in the liquid and stored standby in 4～8e.The lower end, one silver coin palace of experimental animal is pricked with toe-in, be fixed in the curved end of breather, be located at the bath bottom, the upper end is pricked with toe-in, is fixed in the record lever.Have the uterus to store up liquid in the bath in advance, bath temperature is 30 ± 0.5 ℃, 60～80/min of bubble.After leaving standstill 30min, write down one section normalized curve, add each 0.4ml of the peaceful syrup of dysmenorrhea of precious electuary of dysmenorrhea and various dose again, act on 10min respectively, it the results are shown in Table 6.

Table 6 dysmenorrhea Yiganning capsule is to the influence of normal isolated rat uterine smooth muscle contractile function (X ± S)

Group	n	Dosage (mg/ml)	Frequency (inferior/10min)	Amplitude (mm)	Vigor
						Matched group	10	--	5.1±1.37	5.2±2.04	27.92±13.5
Low dose group	10	0.5	3.6±1.43**	3.5±1.25**	13.2±7.5△
						Middle dosage group	10	1.0	2.6±1.71△	1.8±0.76△	4.6±3.7△
High dose group	10	2.0	2.5±2.12△	1.7±1.36△	6.0±5.5△

Annotate: compare * P＞0.05, * * P＜0.05, △ P＜0.01 with matched group

2.3 this product dysmenorrhea Yiganning capsule is to the influence of isolated rat uterine smooth muscle contractile function due to the oxytocin: get healthy do not have hinder, promptly isolate after the ablactation and 30 of the female Mus of body weight 180～200g with male Mus, divide equally is 5 groups, every group 6, its experimental technique is seen 2.2, and adds oxytocin (10mu/ml) 0.4ml at the uterine smooth muscle of normal contraction.Write down the reaction behind the oxytocin effect uterus 10min then, and when adding oxytocin, add the peaceful syrup of dysmenorrhea of precious electuary of isopyknic dysmenorrhea and variable concentrations more respectively, relatively behind the administration 10min with the difference of simple oxytocin effect, it the results are shown in Table 7.

The influence of isolated rat uterine smooth muscle contractile function due to the table 7 dysmenorrhea Yiganning capsule oxytocin (X ± S)

Group	n	Dosage (mg/ml)	Frequency (inferior/10min)	Amplitude (mm)	Vigor
						Matched group	6	--	1.9±1.1 △△△	3.5±3.9 △△△	8.1±10.7 △△△

The oxytocin group	6	10mu/ml	4.8±0.9***	19.5±10.5***	88.3±43.8***
						Low dose group	6	0.5	2.9±0.7** △△	11.9±8.5** △	36.1±27.6** △△△
Middle dosage group	6	1.0	3.0±0.8** △△△	12.5±10.3** △	38.8±32.0** △△△
						High dose group	6	2.0	2.6±0.8* △△△	9.9±9.4* △	30.2±35.0* △△△

Annotate: compare * P＞0.05, * * P＜0.05, * * * P＜0.01 with matched group;

Compare with the oxytocin group, ^△P＞0.05, ^{△ △}P＜0.05, ^{△ △ △}P＜0.01

The clinical observation on the therapeutic effect of this product:

(1) clinical observation of this product dysmenorrhea Yiganning capsule treatment dysmenorrhes:

1. physical data:

1.1 case source: 148 routine experimenters are and are in hospital and the outpatient.

1.2 the age composition of case: the maximum age is 36 years old in the case, and minimal ages is 14 years old, and 21 years old mean age, concrete age distribution sees table 8 for details.

Table 8 this product " peaceful " clinical observation age distribution situation of dysmenorrhea

Age	＜15	15-	20-	25-	30-	35-	Add up to
								Routine number distributes	1	70	50	18	6	3	148
Percent of total (%)	0.7	47.3	33.8	12.2	4.1	1.9	100

2. clinical data:

2.1 diagnosis and light and heavy degree grade scale

2.1.1 diagnostic criteria: (primary dysmenorrhea) serves as main stating with menstrual phase and front and back lower abdomen periodicity pain thereof, gets rid of inflammation simultaneously, uterus tumor, the secondary dysmenorrhea due to structural diseases such as endometriosis become.

2.1.2 light and heavy degree grade scale: this standard is formulated about the new Chinese medicine pertinent regulations of treatment dysmenorrhea according to health ministry.Based on following 15 symptom score score values, press score value what and fixed light, in, severe.15 symptoms and score value thereof are as follows: menstrual period and front and back lower abdomen pain thereof, and score value is 5 minutes; Pain unbearably, score value is 1 minute; Feel restless, score value is 1 minute; Shock, score value is 2 minutes; Complexion is white all of a sudden, and score value is 0.5 minute; Dripping cold sweat, score value are 1 minute; Extreme cold of the limbs, score value are 1 minute; Need lie up, score value is 1 minute; Influence work and study, score value is 1 minute; Do not alleviate with general pain relieving measure, score value is 1 minute; Postpone with general pain relieving measure pain, score value is 0.5 minute; Companion's waist is ached, and score value is 0.5 minute; With nausea and vomiting, score value is 0.5 minute; Companion's rectal tenesmus, score value is 0.5 minute; Pain is in 1 day, and score value is 0.5 minute, and every increase added 0.5 fen in 1 day.

Concrete grade scale: (1) severe: menstrual period or its front and back lower abdomen pain are felt restless unbearably, have a strong impact on work, study and daily life.Patient must lie up, and aches with waist, and complexion is white all of a sudden, dripping cold sweat, and extreme cold of the limbs, vomiting diarrhea or rectal tenesmus adopt the pain relieving measure, do not have obviously and alleviate.Dysmenorrhea symptom score value was 14 fens above persons.(2) moderate: menstrual period or its front and back lower abdomen pain accompany waist to ache unbearably, and nausea and vomiting, extremity are not warm, postpone with pain relieving measure pain.Dysmenorrhea symptom score value is at the 8-13.5 branch.(3) slight: menstrual period or its front and back lower abdomen pain are obvious, and companion's waist is ached, but can adhere to work, and no General Symptoms need be used analgesic sometimes.Dysmenorrhea symptom score value is below 8 minutes.

2.2 case constitutes situation: this group case all is a primary dysmenorrhea, and wherein unmarried 138 examples account for 93.3%, and married 10 examples account for 6.7%.Severe pain accounts for 29.3% of sum through 44 examples, and moderate pain accounts for 61.5% of sum through 91 examples, and mild pain accounts for 9.2% of sum through 13 examples.

2.3 the course of disease: what the course of disease was the longest in the case is 23 years, and the shortest is 1 year, average 3.5 years.

2.4 treatment:

2.4.1 medicine: this product dysmenorrhea Yiganning capsule.

2.4.2 Therapeutic Method: this product is oral, one time 5,3 times on the one.

2.4.4 the treatment time and the course of treatment: medication when dysmenorrhea just begins to show effect, be 15 days the course of treatment.An all patients all medication treat a course of treatment.

2.5 curative effect determinate standard: this standard is formulated about the pertinent regulations of the new Chinese medicine of treatment dysmenorrhea by health ministry: recovery from illness: integration returned to 0 fen after the medication, stomachache and other transference cure, and three menstrual cycle of drug withdrawal are the recidivist not.Produce effects: treatment back integration is reduced to preceding below 1/2 of integration of treatment, and stomachache obviously alleviates, and all the other symptoms take a turn for the better.Effectively: treatment back integration is reduced to the 1/2-3/4 of the preceding integration of treatment, and stomachache alleviates, and all the other symptoms take a turn for the better.Invalid: stomachache and other symptom do not have change, treatment back integration reduce that foot therapy foreset not divides 3/4.

3. result:

3.1 total effects: 27 examples of fully recovering, cure rate are 18.2%; Produce effects 78 examples, obvious effective rate are 52.7%; Effective 33 examples, effective percentage are 22.4%; Invalid 10 examples, inefficiency are 6.7%; Total effective rate is 93.3%.

3.2 dysmenorrhea curative effect in various degree sees Table 9.

Table 9 is light, in, severe classification curative effect table

	Recovery from illness	Produce effects	Effectively	Invalid	Total effective rate
						Severe	21(47.7％)	15(34.1％)	7(15.9％)	1(2.3％)	97.7％
Moderate	5(5.5％)	54(59.3％)	23(25.3％)	9(9.9％)	90.1％
						Slightly	1(7.7％)	9(69.2％)	3(23.1％)	0(0％)	100％

Find out that from last table this product dysmenorrhea Yiganning capsule is 97.7% to the total effective rate of severe dysmenorrhea, moderate be 90.1%, slight is 100%.Therapeutic effect to severe is better than moderate, and this clinically highly significant.

4. model case: open X, the woman, 26 years old, unmarried, first visit on February 23 in 1996.The patient lower abdomen pain occurred 12 years before telling menstrual period, and each pain continues 2d, and the near conscious lower abdomen pain of menstruation is recently felt restless unbearably, and is agonizing, can't operate as normal learn, and took tablet for alleviating pain and did not alleviate.It is white all of a sudden to examine disease meeting color quarter, extreme cold of the limbs, and waist is ached, nausea and vomiting, rectal tenesmus, body of the tongue is light red, thin white fur of tongue, stringy and tense pulse.Menstruation situation: menophania 13 years old; Menstrual period 3d; Cycle 30d; The menstruation color is dark red, and amount is many, and matter is thick, and a small amount of clot is arranged.Gynecologial examination: no abnormal.Diagnosis: primary dysmenorrhea, symptom score value 14 minutes, weight classification: severe.The dysmenorrhea Yiganning capsule is taken in treatment, pain complete obiteration after 2 days, and all the other simultaneous phenomenons disappear, and the symptom score value is 0 minute, follows up a case by regular visits to three menstrual cycle dysmenorrheas and does not recur.

(2) clinical efficacy of this product dysmenorrhea Yiganning capsule treatment primary dysmenorrhea:

1. clinical data: this is organized in 45 examples, minimum 12 years old of age, and maximum 24 years old, wherein≤and 15 years old 12 example, 16～18 years old 22 example,＞18 years old 11 example; Married 7 examples of not educating, unmarried 38 examples; The course of disease is the shortest 6 months, and is the longest 10 years, average 5 years; Mild pain is through (refer to that menstrual period or its front and back lower abdomen pain are obvious, companion's waist is ached, but can adhere to work, and no General Symptoms need be obeyed analgesic sometimes) 15 examples; Moderate pain is through (lower abdomen pain is accompanied the waist ache unbearably before and after referring to menstrual period or menstrual period, and nausea and vomiting, extremity are not warm, postpones with pain relieving measure pain) 21 examples; Severe pain is through (referring to menstrual period or its front and back lower abdomen pain unbearably, feel restless, have a strong impact on work and study and daily life, must lie up, with waist ache, pale complexion, dripping cold sweat, extreme cold of the limbs, vomiting and diarrhoea, or rectal tenesmus adopt the pain relieving measure not have obvious alleviation) 9 examples.

2. Therapeutic Method: oral this product dysmenorrhea Yiganning capsule, 3 times on the one, one time 5, in beginning to take medicine, to through clean drug withdrawal through preceding 1 week.

3. therapeutic outcome: clinical cure in the recent period: take medicine back stomachache and other transference cure, 3 menstrual cycle of drug withdrawal do not recur 16 examples; Produce effects: stomachache obviously alleviates, and all the other transference cures or alleviate refuse to obey that analgesic can adhere to work 13 examples; Effectively: stomachache alleviates, and all the other symptoms take a turn for the better, and the clothes analgesic can be adhered to work 12 examples; Invalid: stomachache and other symptom do not have 4 examples of change.Total effective rate 91.1%.

4, conclusion: the pathogeny of primary dysmenorrhea mainly is the influence that is subjected to paathogenic factor at intermenstrual period, causes dashing appointing stasis of blood resistance or cold accumulating in meridian, makes QI-blood circulation not smooth, and consequently " stagnation of QI and blood may bring about pain " is obstructed in the circulation of uterus menses; Or dash to appoint, uterus lose in moistening foster, not flourish and pain.The traditional Chinese medical science thinks that the key of treatment dysmenorrhea is pain relieving, and the method for pain relieving, no more than " promoting flow of QI and blood ", so-called " general rule is not bitterly ".So select medicine for use, the suitable temperature of one because of blood gets Wen Zehang, must be trembled with fear and then coagulate, and desires it and leads to also, necessary using warming therapy; It is two for pain relieving, and all drug for invigorating blood circulation and eliminating stasis all have the effect of promoting flow of QI and blood, so can select some can promoting flow of QI and blood, the medicine of analgesic effect be arranged again.Go the relatively greasy of Radix Rehmanniae to mend with SIWU TANG among the we, wherein Chinese angelica blood supplementing is invigorated blood circulation, menstruction regulating and pain relieving, and the pain relieving of Radix Paeoniae Alba suppressing the hyperactive liver, nourishing blood for regulating menstruation, the pain relieving of Rhizoma Chuanxiong blood-activating and qi-promoting adds Flos Carthami, Radix Salviae Miltiorrhizae is good at invigorating blood circulation, and then the power of menstruction regulating and pain relieving benefit is strong; More use Rhizoma Cyperi, Fructus Toosendan dispersing the stagnated live-QI to relieve the stagnation of QI, promoting the circulation of QI to relieve pain; The Rhizoma Corydalis promoting the circulation of QI analgesic therapy of invigorating blood circulation; Radix Glycyrrhizae Preparata escorts middle Jiao, coordinating the actions of various ingredients in a prescription.All medicines are harmonious, and play the merit of menstruction regulating and pain relieving altogether.

The research of this product preparation method:

1. decocting process research: the factor that influence decocts mainly contains the following aspects: medical material soak time, amount of water, decocting time, decoction number of times etc.Make explicit provisions to decocting number of times and decocting time in the primary standard, promptly decoct with water secondary, 2 hours for the first time, 0.5 hour for the second time (under behind the Flos Carthami).So this test does not remake investigation to decocting number of times and decocting time, in addition the medical material soak time and the amount of water of not clearly defining in the standard is investigated:

2.1 soak time is investigated:

(1) sample preparation: get 1/10 prescription water gaging and carry medical material, amount to 579g (wherein Radix Angelicae Sinensis 79.3g, Rhizoma Cyperi 79.3g, Radix Paeoniae Alba 79.3g, Radix Salviae Miltiorrhizae 79.3g, Rhizoma Corydalis 71.4g, Fructus Toosendan 71.4g, Rhizoma Chuanxiong 47.6g, Radix Glycyrrhizae Preparata 31.7g, Flos Carthami 39.8g), carrying out medical material by table 10 requirement soaks, extracts, after medicinal liquid filters with 300 order filter clothes, standing over night, get supernatant concentration and be settled to 100ml, standby.

Table 10 medical material soaks, extracting parameter

Tested number	Amount of water (doubly)	Soak time (h)	Extracting parameter
				1 2 3	8 8 8	0 1 2	Extract 2 times, extracted 2 times in 2,0.5 hours, extracted 2,0.5 hours 2 times in 2,0.5 hours

(2) index is selected: peoniflorin is the effective ingredient of the Radix Paeoniae Alba in the prescription, with its extracted amount as one of preferred evaluation index of test; In addition, dried cream yield directly has influence on the molding of preparation, the regulation of determination date clothes dosage and single oral dose also, so also with it as testing one of preferred evaluation index.

(3) dried cream yield is measured: precision is got the medicinal liquid 25ml after each test concentrates, and puts in the evaporating dish that has been dried to constant weight water bath method respectively, residue takes out in 105 ℃ of dryings 3 hours, puts in the exsiccator and places 30 minutes, weigh, calculate dried cream yield, result of the test sees Table 11.

Table 11 medical material soak time is investigated table as a result

Tested number	Soak time (h)	Dried cream yield (%)	Peoniflorin extracted amount (g)
				1 2 3	0 1 2	13.8 15.2 15.8	0.498 0.512 0.515

As seen from the experiment, the medical material soak time is little to peoniflorin extracted amount and the influence of dried cream yield, and therefore, in the extraction process, medical material just can not soak and directly decoct.

2.2 amount of water is investigated:

(1) sample preparation: get 1/10 prescription water gaging and carry medical material, amount to 579g (wherein Radix Angelicae Sinensis 79.3g, Rhizoma Cyperi 79.3g, Radix Paeoniae Alba 79.3g, Radix Salviae Miltiorrhizae 79.3g, Rhizoma Corydalis 71.4g, Fructus Toosendan 71.4g, Rhizoma Chuanxiong 47.6g, Radix Glycyrrhizae Preparata 31.7g, Flos Carthami 39.8g), carrying out medical material by table 10 requirement soaks, extracts, after medicinal liquid filters with 300 order filter clothes, standing over night, get supernatant concentration and be settled to 100ml, standby.

Table 12 medical material adds water, extracting parameter

Tested number	Amount of water (doubly)	Extracting parameter
			1 2 3	6 8 10	Extract 2 times, extracted 2 times in 2,0.5 hours, extracted 2,0.5 hours 2 times in 2,0.5 hours

(2) index is selected and assay method: investigate with soak time, the results are shown in Table 13.

Table 13 amount of water is investigated table as a result

Sequence number	Amount of water (doubly)	Dry extract yield (%)	Peoniflorin extracted amount (g)
				1 2 3	6 8 10	11.28 15.12 16.04	0.476 0.514 0.526

Result of the test shows that it is suitable with the peoniflorin extracted amount with 10 times of water gaging dry extract yields to add 8 times of water gagings, all is better than 6 times of water gagings, and in order to save production cost, we select to add 8 times of water gagings is technological parameter.

2.3 impurity removal process is investigated: because the water extracted immersing paste amount is big, contain too many invalid components, for preparations shaping, reduce dose simultaneously, this product is taked certain method remove impurity, at first use natural sedimentation, but effect is undesirable, so this product adopts alcohol deposition method.

2.3.1 precipitate with ethanol test: get five parts in sample after the above-mentioned decocting and concentrating, every part of 100ml adds ethanol precipitation by table 5 requirement, and make and contain alcohol amount and reach the regulation requirement, leave standstill, filter, the filtrate water bath method, dried cream yield of the same mensuration and peoniflorin extracted amount, result of the test sees Table 14.

The different alcohol precipitation concentrations of table 14 are to the influence of technology

Sequence number	Sampling amount (ml)	Contain alcohol amount (%)	Dried cream yield (%)	Peoniflorin extracted amount (mg)
					1	100	0	14.42	0.512
2	100	50	6.16	0.504
					3	100	60	5.40	0.420
4	100	70	4.81	0.408

Result of the test shows: with the increase of alcohol precipitation concentration, dried cream yield obviously reduces, and also in various degree reduction thereupon of effective ingredient.By contrast, behind 50% ethanol precipitation, dried cream yield reduces more, and paeoniflorin content decline is not obvious, so select this alcohol precipitation concentration.

2.3.2 the medicinal liquid of different densities is to the influence of precipitate with ethanol: get this product recipe quantity medical material 5791g, except that Flos Carthami, eight flavors such as all the other Radix Angelicae Sinensis add 8 times of water gagings and decocted 2 hours, filter, medicinal residues add Flos Carthami, continue to decoct 0.5 hour, collecting decoction filters the filtrate standing over night, get supernatant and be divided into 5 parts, be concentrated into regulation density respectively, add ethanol and make and contain the alcohol amount and reach 50%, leave standstill, filter, decompression filtrate recycling ethanol also is concentrated into the clear paste that relative density is 1.10～1.20 (80 ℃); Qinghuo reagent, dried cream yield of the same mensuration and peoniflorin extracted amount, result of the test sees Table 15.

The medicinal liquid of table 15 different densities is to the influence of precipitate with ethanol

Sequence number	Medicinal liquid density	Contain alcohol amount (%)	Dried cream yield (%)	Peoniflorin extracted amount (g)
					1	1.10	50	5.88	1.24
2	1.12	50	5.92	1.12
					3	1.15	50	6.54	0.89
4	1.20	50	6.62	0.76

Result of the test shows: with the increase of medicinal liquid density, dried cream yield obviously reduces, and also in various degree reduction thereupon of effective ingredient.By contrast, density is that 1.10 and 1.12 medicinal liquid carries out after precipitate with ethanol handles, and dried cream yield reduces less, and paeoniflorin content descends not obvious, so the density of selection concentrated solution is 1.10～1.12.

2.3.3 the investigation of different time of repose: get this product recipe quantity medical material 5791g, except that Flos Carthami, eight flavors such as all the other Radix Angelicae Sinensis add 8 times of water gagings and decocted 2 hours, filter, medicinal residues add Flos Carthami, continue to decoct 0.5 hour, collecting decoction filters the filtrate standing over night, get supernatant and be divided into 5 parts, be concentrated into regulation density respectively, add ethanol and make and contain the alcohol amount and reach 50%, the according to the form below test, filter, decompression filtrate recycling ethanol also is concentrated into the clear paste that relative density is 1.10～1.20 (80 ℃); Qinghuo reagent, dried cream yield of the same mensuration and peoniflorin extracted amount, result of the test sees Table 16.

The different time of repose of table 16 are to the influence of precipitate with ethanol

Sequence number	Time of repose behind the precipitate with ethanol (h)	Dried cream yield (%)	Peoniflorin extracted amount (g)
				1	0	7.96	1.28
2	4	7.42	1.25
				3	12	6.92	1.22
4	24	6.12	1.20
				5	48	5.98	1.19

Result of the test shows: with the increase of time of repose, dried cream yield obviously reduces, and also in various degree reduction thereupon of effective ingredient.By contrast, time of repose is 24 hours and 48 hours, and dried cream yield reduces more, and paeoniflorin content descends not obvious, but for saving time, is 24 hours so select time of repose.

2.4 concentration technology is investigated: get 1/2 recipe quantity medical material, amount to 2896g, after the preferred technological parameter extraction that gets of preceding test, filtrate is divided into 2 parts, adopt respectively normal pressure and concentrating under reduced pressure (0.06～-0.08Mpa, 80 ℃) to relative density be the extractum of 1.35～1.38 (60 ℃), it is an amount of to get extractum respectively, press preceding method and measure paeoniflorin content, result such as table 17:

Table 17 concentration technology is investigated

Tested number	Normal pressure concentrates paeoniflorin content (g)	Concentrating under reduced pressure paeoniflorin content (g)
			1 2 3	2.56 2.63 2.62	2.51 2.57 2.59

Result of the test shows, normal pressure concentrate and concentrating under reduced pressure the other side in the effective ingredient peoniflorin do not have obvious influence.Consider concentrating under reduced pressure have concentration time short, heat-sensitive materials in the prescription is destroyed little advantage, so we with the concentrated mode in this technology be decided to be concentrating under reduced pressure (parameter is :-0.06～-0.08Mpa, 80 ℃).

2.5 drying process is determined: in order to keep wherein effective ingredient as far as possible, we select 60 ℃ to be baking temperature, and constant pressure and dry and two kinds of drying modes of drying under reduced pressure compared, content of paeoniflorin, extract powder color and luster and drying time in the gained extract powder being that index carries out preferably the results are shown in Table 18 to drying mode.

Table 18 drying process is investigated the result

Drying mode	Condition	Paeoniflorin content (mg/g)	Color and luster	Drying time (h)
					Atmospheric depressurized	60℃ 60℃，-0.07～-0.08Mpa	4.89 4.97	Brown	77 26

Last watch test result shows, constant pressure and dry is compared with drying under reduced pressure, extract powder color, extractum content of paeoniflorin do not have significant change, but the constant pressure and dry time is longer, and the drying under reduced pressure time is shorter, if adopt drying under reduced pressure, help shortening the production cycle, enhance productivity, thus we with drying mode be defined as drying under reduced pressure (60 ℃ ,-0.07～-0.08Mpa).

3. preparations shaping technical study:

3.1 extract powder physical property research: in the physical property of extract powder, to the bigger factor of capsule moulding process influence be: the hygroscopicity of extract powder and flowability.The hygroscopicity size of extract powder represents with the moisture absorption percentage rate that usually mobile quality is generally with representing angle of repose.

3.1.1 extract powder preparation: get dried extractum, pulverize, cross 80 mesh sieves, standby.

3.1.2 extract powder moisture absorption percentage rate is measured: it is an amount of to get extract powder, put P2O5 exsiccator inner drying 48 hours, the glass exsiccator that simultaneously bottom is filled the NaCl supersaturated solution is put into 25 ℃ of calorstats maintenances 24 hours, the interior humidity relatively of exsiccator this moment is 75%, in the weighing botle of dry constant weight, add an amount of extract powder, the about 2mm of thickness, precision is weighed in the rearmounted above-mentioned glass exsiccator, open the weighing bottle cap, in 25 ℃ of calorstats, preserve, regularly (6,12,24,48,60h) weighing is calculated as follows the moisture absorption percentage rate, the results are shown in Table 19.

Table 19 extract powder moisture absorption percentage rate is measured

Time (hour)	6	12	24	48	60
						Moisture absorption percentage rate (%)	7.42	11.25	13.62	17.17	19.36

3.1.3 extract powder angle of repose is measured: adopt the fixed funnel method to measure its angle of repose: with 3 funnels series connection and be fixed in suitable height (3cm) on the graph paper of horizontal positioned, carefully extract powder is poured in the uppermost funnel along hopper walls, till the extract powder apex partis petrosae termination that forms on the graph paper contacts bottom bell mouth, measure the conical base diameter, be calculated as follows out a angle of repose:

Table 20 extract powder measurement result angle of repose

Tested number	1	2	3	Meansigma methods
					Angle of repose	47.46°	47.69°	47.51°	47.55°

The moisture absorption percentage rate of extract powder and angle of repose measurement result show that this extract powder hygroscopicity is strong, mobile poor, can not directly carry out capsular filling, recharge capsule after should considering to add the appropriate amount of auxiliary materials granulation.

3.2 adjuvant screening:

3.2.1 the supplementary product kind screening: take by weighing dry extract and adjuvant by table 21 requirement, mixing is made soft material in right amount with 95% ethanol, and cross 40 mesh sieves and make wet granular, in 60 ℃ of oven dry, reuse 40 mesh sieve granulate.It is an amount of to get granule, presses preceding method and measures moisture absorption percentage rate and angle of repose, the results are shown in Table 22,23.

The compatibility prescription of table 21 different auxiliary material

The experiment number	Composition	Prescription (g)
								1	2	3	4	5	6
		1 2 3 4 5 6	Extract powder amylodextrin microcrystalline cellulose 1+2 1+3 2+3	35 10	35 10	35 10	35 10							35 10	35 10

Annotate: 1+2 is that starch adds dextrin; 1+3 is that starch adds microcrystalline cellulose; 2+3 is that dextrin adds microcrystalline cellulose.The full recipe quantity extractum of this product is 350g, makes 1000 capsules, and the design loading amount is the 0.45g/ grain, so need add adjuvant 100g.

Table 22 different auxiliary material granule moisture absorption percentage rate is measured

Adjuvant	Time (hour)
						6	12	24	48	60
	Amylodextrin microcrystalline cellulose 1+2 1+3 2+3	3.17 2.88 3.89 2.62 3.09 2.99	5.22 4.97 6.32 4.13 5.24 4.89	6.85 6.28 8.16 5.86 6.41 5.97	8.05 7.82 9.88 6.98 7.96 7.36						9.16 8.61 10.14 7.74 8.75 8.25

Table 23 different auxiliary material granule measurement result angle of repose

Tested number	Starch	Dextrin	Microcrystalline cellulose	1+2	1+3	2+3
							Angle of repose	35.24°	34.87°	37.45°	33.45°	35.26°	36.45°

Result of the test shows, adds hydroscopicity and mobile the improvement obviously behind the adjuvant in the dry extract, and 6 kinds of adjuvants are compared, and the effect of improving that dextrin adds starch is better than other several adjuvants, and therefore, can select dextrin to add starch is this pharmaceutical adjunct.

3.2.2 selected supplementary product consumption is determined: in " supplementary product kind screening " test, the mixture that adds 10g dextrin and starch in every 35g dry extract has been obtained the satisfied anti-moisture absorption and the effect that improves liquidity.In order to determine optimum consumption parameter, carry out the consumption test by table 24, and press preceding method and measure moisture absorption percentage rate and angle of repose, the results are shown in Table 25,26.

The compatibility prescription of table 24 different auxiliary material consumption

The experiment number	Composition	Prescription (g)
					1	2	3
		1 2 3	Extract powder dextrin+amylodextrin+amylodextrin+starch	35 5				35 10	35 15

Table 25 different auxiliary material consumption granule moisture absorption percentage rate is measured

The prescription number	Time (hour)
						6	12	24	48	60
	1 2 3	3.98 3.69 3.48	5.96 5.44 5.12	7.52 6.86 6.50	8.85 8.37 7.81						9.96 9.11 8.74

Table 26 different auxiliary material consumption granule measurement result angle of repose

The prescription number	1	2	3
				Angle of repose	36.23°	34.89°	34.06°

Result of the test shows, prescription 2,3 granules of making are compared with the granule that the starch mixed accessories is made with dextrin during " supplementary product kind screening " tested, and moisture absorption percentage rate and flowability are more or less the same, and all are better than writing out a prescription 1.Because prescription 2 adjuvant use amounts are less, for saving production cost, we select to write out a prescription and 2 are the supplementary product consumption parameter, add dextrin and starch mixture 100g in promptly every 350g extractum.

3.2.3 the mixed accessories proportioning is selected: in " supplementary product kind screening " test, the mixture that adds 10g dextrin and starch in every 35g dry extract has been obtained the satisfied anti-moisture absorption and the effect that improves liquidity.In order to determine optimum proportioning parameter, carry out the consumption test by table 27 dextrin and starch proportioning, and press preceding method and measure moisture absorption percentage rate and angle of repose, the results are shown in Table 28,29.

The different compatibility prescriptions that mix the ratio of adjuvant consumption of table 27

The experiment number	Composition	Prescription (g)
						1	2	3	4
		1 2 3 4	Extract powder dextrin: starch (1: 2) dextrin: starch (1: 1) dextrin: starch (2: 1) dextrin: starch (3: 1)	35 10	35 10					35 10	35 10

Table 28 different auxiliary material proportioning granule moisture absorption percentage rate is measured

The prescription number	Time (hour)
						6	12	24	48	60
	1 2 3 4	3.41 3.29 3.08 2.86	5.64 5.40 5.12 4.93	7.32 6.98 6.50 5.94	8.47 8.16 7.81 7.12						9.26 9.07 8.74 8.15

Table 29 different auxiliary material proportioning granule measurement result angle of repose

The prescription number	1	2	3	4
					Angle of repose	35.73°	34.65°	33.86°	33.25°

Result of the test shows that granule moisture absorption percentage rate and flowability that proportioning 4 is made are more or less the same, and all is better than writing out a prescription 1,2,3, so this product ratio of adjuvant is a dextrin: starch (3: 1).

3.3 the granulation concentration of alcohol is investigated: in the pelletization, we once selected for use 80% ethanol, 95% ethanol and dehydrated alcohol as wetting agent, were that index is carried out preferably them with the complexity of granulating with making particulate fine powder amount.The soft material viscosity made of 80% ethanol is excessive as a result, be difficult to granulate, and the soft material viscosity that dehydrated alcohol is made is too small, it is too much to cross 60 mesh sieve content of powder in the granule of making, by contrast, it is less to cross 60 mesh sieve content of powder in the granule that 95% alcohol granulation is easier to and makes, and therefore selected 95% ethanol is the granulation wetting agent.See Table 30.

Table 30 different concentration ethanol granulation result

Concentration of alcohol	80％	95％	Anhydrous
				Soft material viscosity granulation situation is crossed 60 order proportion of powder	Disaster 18.1%	Moderate easy 22.4%	Xiao Yi 36.9%

3.4 granulation mass density measurement: take by weighing the about 5g of granule, put in the 10ml graduated cylinder, hands is held graduated cylinder by falling within on the plank under the 5cm height, vibrate 5 times repeatedly after, read the volume number, calculate bulk density, the results are shown in Table 31.

Table 31 extract powder bulk density measurement result table

Tested number	1	2	3	Meansigma methods
					Bulk density (g/ml)	0.60	0.62	0.61	0.61

By measurement result as can be known, the average bulk density of this product granule is 0.61g/ml, and as if the capsule with its canned one-tenth 0.45g/ grain, the particulate volume of then every capsules is 0.81ml, can select Capsules (volume: 0.96ml) No. 0.

3.5 the granule critical relative humidity is measured: it is an amount of to get granule, put P2O5 exsiccator inner drying 48 hours, in the weighing botle of dry constant weight, add an amount of extract powder, the about 2mm of thickness, precision is weighed in the glass exsiccator that is placed on the supersaturated solution that fills 7 kinds of variable concentrations sulfuric acid solutions and different salt in the table 17 respectively, opens the weighing bottle cap, keeps weighing after 96 hours in 25 ℃ of calorstats, calculate the moisture absorption percentage rate, the results are shown in Table 32.

Content moisture absorption percentage rate (%) under the different relative humiditys of table 32

	Sulfuric acid concentration			The supersaturated solution of various salt
								54％	48％	44％	NaBr	NaCl	KCl	KNO 3
	Relative humidity (%) moisture absorption percentage rate (%)	29.55 0.48	40.52 1.34	48.52 3.02	57.70 5.16	75.28 11.24	84.26 20.84								92.48 27.54

This product granule critical relative humidity is about 60%.So when production this product, the relative humidity of granule storage environment and filling workshop condition should be controlled in 60%, to reduce the influence of moisture content to granule stability, guarantees product quality.

4. pilot scale: get 10 times of recipe quantity medical materials, by work out to such an extent that process route carries out middle trial production, the production technology index is carried out comprehensive assessment, medical material and finished product are carried out performance rating, each main effective ingredient is followed the tracks of detection, the results are shown in Table 33.

Table 33 pilot plant test result

Lot number

2004101

200402

200403

The decocting herbs total amount (kg) that feeds intake	58 paeoniflorin contents are 2%	58 paeoniflorin contents are 2%	58 paeoniflorin contents are 2%
				The decoction situation	Add 8 times of decoctings and boil (2h, 0.5h) 2 times	Add 8 times of decoctings and boil (2h, 0.5h) 2 times	Add 8 times of decoctings and boil (2h, 0.5h) 2 times
The concentration technology parameter	-0.07MaP, 80 ℃ of relative densities: 1.36	-0.07MaP, 80 ℃ of relative densities: 1.36	-0.07MaP, 80 ℃ of relative densities: 1.36
				The drying process parameter	-0.07MaP、60℃	-0.07MaP、60℃	-0.07MaP、60℃
Dried cream amount (kg)	3.72	3.75	3.76
				Pulverize screen cloth (order)	80	80	80
Extract powder amount (kg)	3.55	3.56	3.58
				Add adjuvant amount (kg)	1	1	1
Theoretical yield (grain)	10000	10000	10000
				Actual production (grain)	9400	9400	9450
Yield rate (%)	94.0	94.0	94.5
				Differentiate	Up to specification	Up to specification	Up to specification
Check	Up to specification	Up to specification	Up to specification
				Paeoniflorin content (mg/ grain)	6.8	6.9	6.2

Middle trial production result shows that the every technical parameter of this product is stable, and feasible process is described, is fit to produce in batches.

The formula proportion of this product: Radix Angelicae Sinensis 10～20%, Rhizoma Cyperi 10～20%, the Radix Paeoniae Alba 10～20%, Radix Salviae Miltiorrhizae 10～20%, Rhizoma Corydalis 10～20%, Fructus Toosendan 10～20%, Rhizoma Chuanxiong 5～10%, Radix Glycyrrhizae Preparata 2～10%, Flos Carthami 2～10%

Actual proportioning: Radix Angelicae Sinensis (wine stir-fry) 13.7%, Rhizoma Cyperi (vinegar system) 13.7%, the Radix Paeoniae Alba (stir-fry) 13.7%, Radix Salviae Miltiorrhizae 13.7%, Rhizoma Corydalis (vinegar system) 12.3%, Fructus Toosendan (stir-fry) 12.3%, Rhizoma Chuanxiong (stir-fry) 8.2%, Radix Glycyrrhizae Preparata 5.5%, Flos Carthami 6.9%.

The specific embodiment:

Embodiments of the invention 1: take by weighing medical material Radix Angelicae Sinensis (parched with wine) 793g, Rhizoma Cyperi (processed with vinegar) 793g, Radix Paeoniae Alba (parched) 793g, Radix Salviae Miltiorrhizae 793g, Rhizoma Corydalis (processed with vinegar) 714g, Fructus Toosendan (parched) 714g, Rhizoma Chuanxiong (parched) 476g, Radix Glycyrrhizae Preparata 317g and Flos Carthami 398g is with Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched) and Radix Glycyrrhizae Preparata add 8 times of water, decoct 2 hours, filter, medicinal residues add Flos Carthami, continue to decoct collecting decoction 0.5 hour, filter, the filtrate standing over night is surveyed relative density and is 1.10～1.12 clear paste when getting supernatant concentration to 85 ℃, put cold, the ethanol of adding 50%, stir evenly, leave standstill and made precipitation in 24 hours, get supernatant, reclaim ethanol, the survey relative density is 1.20～1.35 thick paste when being evaporated to 85 ℃, at 60 ℃ of following drying under reduced pressure, pulverizes, cross 80 mesh sieves, the mixture 1000g that adds dextrin and starch, mixing, alcohol granulation with an amount of 95%, dry, granulate, encapsulated, make 1000, that is every dress 0.45g.This product is oral, one time 5,3 times on the one.

Embodiments of the invention 2: take by weighing medical material Radix Angelicae Sinensis (parched with wine) 600g, Rhizoma Cyperi (processed with vinegar) 600g, Radix Paeoniae Alba (parched) 600g, Radix Salviae Miltiorrhizae 600g, Rhizoma Corydalis (processed with vinegar) 600g, Fructus Toosendan (parched) 600g, Rhizoma Chuanxiong (parched) 300g, Radix Glycyrrhizae Preparata 200g and Flos Carthami 200g, with Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched) and Radix Glycyrrhizae Preparata add 4 times of water, decoct 0.5 hour, filter, medicinal residues add Flos Carthami, continue to decoct 0.2 hour, collecting decoction filters, the filtrate standing over night, survey relative density when getting supernatant concentration to 85 ℃ and be 1.10～1.12 clear paste, put coldly, add 40% ethanol, stir evenly, leave standstill and made precipitation in 12 hours, get supernatant, reclaim ethanol, the survey relative density is 1.20～1.35 thick paste when being evaporated to 85 ℃, at 60 ℃ of following drying under reduced pressure, pulverize, cross 60 mesh sieves, the mixture 600g that adds dextrin and starch, mixing, the alcohol granulation with an amount of 80%, drying, granulate, encapsulated, make 1000, promptly.

Embodiments of the invention 3: take by weighing medical material Radix Angelicae Sinensis (parched with wine) 900g, Rhizoma Cyperi (processed with vinegar) 900g, Radix Paeoniae Alba (parched) 900g, Radix Salviae Miltiorrhizae 900g, Rhizoma Corydalis (processed with vinegar) 850g, Fructus Toosendan (parched) 850g, Rhizoma Chuanxiong (parched) 500g, Radix Glycyrrhizae Preparata 400g and Flos Carthami 450g, with Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched) and Radix Glycyrrhizae Preparata add 16 times of decoctings and boil 3 times, 3 hours for the first time, 2 hours for the second time, 1 hour for the third time, filter, medicinal residues add Flos Carthami, continue to decoct 2 times, 1 hour for the first time, 0.5 hour for the second time, collecting decoction filtered, the filtrate standing over night, survey relative density when getting supernatant concentration to 85 ℃ and be 1.10～1.12 clear paste, put coldly, add 70% ethanol, stir evenly, leave standstill and made precipitation in 48 hours, get supernatant, reclaim ethanol, the survey relative density is 1.20～1.35 thick paste when being evaporated to 85 ℃, at 60 ℃ of following drying under reduced pressure, pulverize, cross 100 mesh sieves, the mixture 1500g that adds dextrin and starch, mixing, the alcohol granulation with an amount of 98%, drying, granulate, encapsulated, make 1000, promptly.

Embodiments of the invention 4: take by weighing medical material Radix Angelicae Sinensis (parched with wine) 700g, Rhizoma Cyperi (processed with vinegar) 700g, Radix Paeoniae Alba (parched) 700g, Radix Salviae Miltiorrhizae 700g, Rhizoma Corydalis (processed with vinegar) 700g, Fructus Toosendan (parched) 650g, Rhizoma Chuanxiong (parched) 400g, Radix Glycyrrhizae Preparata 300g and Flos Carthami 300g is with Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched) and Radix Glycyrrhizae Preparata add 6 times of water, decoct 2 times, each 1 hour, filter, medicinal residues add Flos Carthami, continue to decoct 1 hour, collecting decoction, filter, the filtrate standing over night is surveyed relative density and is 1.10～1.12 clear paste when getting supernatant concentration to 85 ℃, put cold, the ethanol of adding 60% stirs evenly, and leaves standstill and makes precipitation in 20 hours, get supernatant, reclaim ethanol, the survey relative density is 1.20～1.35 thick paste when being evaporated to 85 ℃, at 60 ℃ of following drying under reduced pressure, pulverize, cross 70 mesh sieves, add the mixture 500g of dextrin and starch, mixing, alcohol granulation with an amount of 80%, drying, granulate, encapsulated, make 1000, promptly.

Embodiments of the invention 5: take by weighing medical material Radix Angelicae Sinensis (parched with wine) 800g, Rhizoma Cyperi (processed with vinegar) 800g, Radix Paeoniae Alba (parched) 800g, Radix Salviae Miltiorrhizae 800g, Rhizoma Corydalis (processed with vinegar) 750g, Fructus Toosendan (parched) 790g, Rhizoma Chuanxiong (parched) 450g, Radix Glycyrrhizae Preparata 350g and Flos Carthami 400g, with Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched) and Radix Glycyrrhizae Preparata add 10 times of decoctings and boiled 3 hours, filter, medicinal residues add Flos Carthami, continue to decoct 0.5 hour, collecting decoction, filter, the filtrate standing over night is surveyed relative density and is 1.10～1.12 clear paste when getting supernatant concentration to 85 ℃, put cold, the ethanol of adding 65% stirs evenly, and leaves standstill and makes precipitation in 36 hours, get supernatant, reclaim ethanol, the survey relative density is 1.20～1.35 thick paste when being evaporated to 85 ℃, at 60 ℃ of following drying under reduced pressure, pulverize, cross 90 mesh sieves, add the mixture 900g of dextrin and starch, mixing, alcohol granulation with an amount of 96%, drying, granulate, encapsulated, make 1000, promptly.

Claims (6)

1. pharmaceutical preparation for the treatment of dysmenorrhea, it is characterized in that: according to listed as parts by weight, it adds appropriate amount of auxiliary materials for 200～450 parts by 600～900 parts of Radix Angelicae Sinensis (parched with wine), 600～900 parts of Rhizoma Cyperi (processed with vinegar), 600～900 parts of Radix Paeoniae Alba (parched)s, 600～900 parts of Radix Salviae Miltiorrhizaes, 600～850 parts of Rhizoma Corydalis (processed with vinegar), 600～850 parts of Fructus Toosendan (parched), 300～500 parts of Rhizoma Chuanxiong (parched), 200～400 parts of Radix Glycyrrhizae Preparatas, Flos Carthami and is prepared into capsule.

2. according to the pharmaceutical preparation of the described treatment dysmenorrhea of claim 1, it is characterized in that: calculate according to weight, it adds adjuvant 1000g by Radix Angelicae Sinensis (parched with wine) 793g, Rhizoma Cyperi (processed with vinegar) 793g, Radix Paeoniae Alba (parched) 793g, Radix Salviae Miltiorrhizae 793g, Rhizoma Corydalis (processed with vinegar) 714g, Fructus Toosendan (parched) 714g, Rhizoma Chuanxiong (parched) 476g, Radix Glycyrrhizae Preparata 317g, Flos Carthami 398g and is prepared into capsule.

3. according to the pharmaceutical preparation of claim 1 or 2 described treatment dysmenorrheas, it is characterized in that: described adjuvant is the mixture of dextrin and starch.

4. according to the pharmaceutical preparation of claim 2 or 3 described treatment dysmenorrheas, it is characterized in that: the proportioning of dextrin and starch is a dextrin in the adjuvant: starch is 3: 1.

5. as the preparation method of the pharmaceutical preparation of treatment dysmenorrhea as described in the claim 1～4 any, it is characterized in that: take by weighing the medical material Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched), the Radix Glycyrrhizae Preparata and Flos Carthami, with Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched) and Radix Glycyrrhizae Preparata add 4～16 times of decoctings and boil 1～3 time, each 0.5～3 hour, filter, medicinal residues add Flos Carthami, continue to decoct 1～2 time, each 0.2～1 hour, collecting decoction, filter, the filtrate standing over night, survey relative density when getting supernatant concentration to 85 ℃ and be 1.10～1.12 clear paste, put coldly, add 40%～70% ethanol, stir evenly, leave standstill and made precipitation in 12～48 hours, get supernatant, reclaim ethanol, the survey relative density is 1.20～1.35 thick paste when being evaporated to 85 ℃, at 60 ℃ of following drying under reduced pressure, pulverize, cross 60～100 mesh sieves, add adjuvant, mixing, alcohol granulation with an amount of 80%～98%, drying, granulate, encapsulated, promptly.

6. according to the preparation method of the pharmaceutical preparation of the described treatment dysmenorrhea of claim 5, it is characterized in that: take by weighing medical material Radix Angelicae Sinensis (parched with wine) 793g, Rhizoma Cyperi (processed with vinegar) 793g, Radix Paeoniae Alba (parched) 793g, Radix Salviae Miltiorrhizae 793g, Rhizoma Corydalis (processed with vinegar) 714g, Fructus Toosendan (parched) 714g, Rhizoma Chuanxiong (parched) 476g, Radix Glycyrrhizae Preparata 317g and Flos Carthami 398g is with Radix Angelicae Sinensis (parched with wine), Rhizoma Cyperi (processed with vinegar), Radix Paeoniae Alba (parched), Radix Salviae Miltiorrhizae, Rhizoma Corydalis (processed with vinegar), Fructus Toosendan (parched), Rhizoma Chuanxiong (parched) and Radix Glycyrrhizae Preparata add 8 times of decoctings and boiled 2 hours, filter, medicinal residues add Flos Carthami, continue to decoct 0.5 hour, collecting decoction filters, the filtrate standing over night, survey relative density when getting supernatant concentration to 85 ℃ and be 1.10～1.12 clear paste, put coldly, add 50% ethanol, stir evenly, leave standstill and made precipitation in 24 hours, get supernatant, reclaim ethanol, the survey relative density is 1.20～1.35 thick paste when being evaporated to 85 ℃, at 60 ℃ of following drying under reduced pressure, pulverize, cross 80 mesh sieves, add adjuvant 1000g, mixing, the alcohol granulation with an amount of 95%, drying, granulate, encapsulated, make 1000, promptly.