CN1943662A - The Chinese traditional medicinal composition granules for treating galactophore disease and its preparation method and its products - Google Patents

Abstract

This invention provides a preparing method of the Chinese traditional medicinal composition granules for treating galactophore disease. The method consists of the following steps: (1)Take tangerine leafs, radices salviae, Chinese honeylocust, cowherb seed, Chinaberry fruit and earthworm. (2)Fry the tangerine leafs, radices salviae, Chinese honeylocust, cowherb seed,, Chinaberry fruit in water separately, combine the fried liquids, filter them and have the filtered liquid concentrated. (3)Add earthworm to concentrated liquid obtained in step (2), mix it even. (4)Use 60-90% ethanol to abstract the concentrated liquid obtained in step (3), filter the abstracted liquid, reclaim ethanol and concentrate it till it forms into thick cream. (5)Add one or manifold of the following ingredients: cane sugar, lactose, xylitol and tangerine sugar, add an amount of starch, starch gum, then mix them even, boil to make them into the form of granules. The method is easy operated with low production costs and high efficiency. This invention also provides a kind of the Chinese traditional medical granules made by the above preparing method.

Description

Preparation method of the Chinese medicine granules of treatment mastopathy and products thereof

Technical field

The present invention relates to preparation method of a kind of Chinese medicine granules for the treatment of mastopathy and products thereof, belong to technical field of Chinese medicines.

Background technology

Theory of Chinese medical science think distending pain of the breast, cyclomastopathy be the Liver Channel QI-blood circulation smooth due to." danxi's experiential therapy " said: " QI and blood dash and, ten thousand diseases are not given birth to, one have looking angry strongly fragrant, then all diease occurrences, the disease of ancients' body is born in strongly fragrant more." liver, the happiness bar reaches, dislike depressed, main catharsis and store blood.Depressed emotion usually, wood lose bar and reach, the liver failing to maintain the normal flow of QI, and cause depression of liver-QI; Qi as the commander of blood, the capable then blood of gas is capable, and the stagnation of QI is blood stasis then, and QI and blood week loss degree pents up in breast stomach network, and newborn network meridian and vessels obstruction is obstructed, stagnation of QI and blood may bring about pain and cause mastalgia; Liver-QI transversely invading the stomach, dysfunction of the spleen in transportation is given birth in expectorant is turbid, and it is nuclear that qi depression to blood stasis is held the expectorant knot under the arm poly-, follows through staying poly-Ruzhong, so the Ruzhong caking.Control when suitable depressed liver-energy dispersing and QI regulating, blood circulation promoting and blood stasis dispelling, dispersing swelling and dissipating binds is with pain relieving.Development along with society, the quickening of life, work rhythm, increase from each side pressure, the number of women of suffering from disease of hyperplasia of mammary glands glands sharply increases, make the medicine of various these type of diseases of treatment occur in succession, but on the market medicine of common treatment cyclomastopathy class disease all in various degree have defectives such as curative effect is remarkable inadequately.

The medicine of treatment mastopathy is divided into Western medicine and Chinese medicine two big classes at present, and the Western medicine majority has stronger side effect; The Chinese medicine preparation of selling on the market has sheet, capsule, granule, but because the extraction production technology difference that each dosage form adopted causes this pharmaceutical composition can not reach the curative effect that makes patient satisfaction, can not make this pharmaceutical composition give play to its due therapeutic effect.

" in one one of the Chinese pharmacopoeia nineteen ninety-five version " RUKUAIXIAO PIAN " of record, its preparation method is as follows: Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water secondary, each 1 hour, collecting decoction filters, and filtrate is concentrated into 550ml, add Pheretima, mix, with 70% alcohol reflux secondary, 2 hours for the first time, 1 hour for the second time, filter, merging filtrate reclaims ethanol, be concentrated into the thick paste shape, drying under reduced pressure becomes dry extract, pulverizes, and adds right amount of auxiliary materials, mixing, make granule, sugar coating, promptly.Though coated tablet have dosage accurately, steady quality, take advantages such as easy to carry, dissolution is poor, onset is slow, bioavailability is low, production routine is many, the more high shortcoming of cost but exist, and the taking dose of said preparation big (a 4-6 sheet) makes the displeased acceptance of many patients.

Application number is to disclose a kind of Chinese medicine granules for the treatment of mastopathy in 200510000429 the patent application, its preparation method is as follows: Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae and Fructus Toosendan are decocted with water secondary, each 1 hour, collecting decoction, filter, it is 1.25-1.30 (85 ℃) that filtrate is concentrated into relative density, puts cold standby; Pheretima, Semen Vaccariae filter with 60-90% alcohol reflux secondary 2 hours first time 1 hour second time, and merging filtrate adds in the above-mentioned concentrated solution, adjusts amount of alcohol and reaches 60-80%, reclaims ethanol and is condensed into thick paste, and the adding adjuvant is made granule.What this method adopted is that normal pressure decocts, and that normal pressure decocts the active ingredient that is difficult to the seed medical material of Semen Vaccariae and so on is fully fried; In addition, its method of granulating that adopts is the extrusion granulator method, and the baking temperature of extrusion granulator method in dry run can't be effectively controlled, active ingredient is lost very big in the granulation dry run in the medicine, and the mixing during extrusion granulator legal system grain, granulation, dry each operation must finish step by step, and production efficiency is low.

Summary of the invention

The object of the present invention is to provide a kind of easy and simple to handle, production efficiency height, and prepared Chinese medicine granules curative effect height, the method for preparing Chinese medicine granules that the drug absorption degree is good, this Chinese medicine granules is used for the treatment of disease of hyperplasia of mammary glands glands.

The preparation method of the Chinese medicine granules of treatment mastopathy of the present invention may further comprise the steps:

1) takes by weighing Folium Citri tangerinae 10-103 weight portion, Radix Salviae Miltiorrhizae 10-103 weight portion, Spina Gleditsiae 6.8-69 weight portion, Semen Vaccariae 6.8-69 weight portion, Fructus Toosendan 6.8-69 weight portion and Pheretima 6.8-69 weight portion;

2) Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water, collecting decoction filters, and filtrate is concentrated into 550 unit volumes;

3) Pheretima is added step 2) in the concentrated solution of gained, mix homogeneously;

4) with the concentrated solution of step 3) gained with 60～90% alcohol reflux, filter, merging filtrate reclaims ethanol and is concentrated into the thick paste shape;

5) in the thick paste of step 4) gained, add an amount of starch, dextrin, mixing then, boiling granulating.

Wherein, Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water twice, each 1 hour step 2).Described decoction can decoct or the pressurization decoction for normal pressure, and preferred pressurization decocts, and feeds steam pressure 0.1～0.4Mpa.The decocting method of boiling adopts the pressurization decocting method can improve kind of the decocting rate of subclass medical material active ingredient to a great extent, as Semen Vaccariae, Fructus Toosendan.

Wherein, the concentrated solution of step 3) gained is preferably used 70% alcohol reflux twice, 2 hours for the first time, 1 hour for the second time.

Wherein, preferably dry air temperature is controlled at 70～80 ℃ during boiling granulating in the step 5), can reduces the loss of active ingredient like this.

The present invention also provides a kind of Chinese medicine granules of the treatment mastopathy that is prepared by the inventive method.

Folium Citri tangerinae and Radix Salviae Miltiorrhizae are monarch drug in the pharmaceutical composition of the present invention, and the cloudy Liver Channel edema caused by disorder of QI of sufficient Jue is put down, gone into to Folium Citri tangerinae hardship, suffering, property, have the effect of soothing the liver, circulation of qi promoting, the poison that reduces phlegm, subsides a swelling.Key medicine for treatment nodules of the breast, acute mastitis." book on Chinese herbal medicine converge with speech " " Folium Citri tangerinae, soothing the liver, the contrary gas that looses, decide hypochondriac pain medicine also ... disease is hypochondriac pain, is acute mastitis ... "." Bencao Jingshu " " Folium Citri tangerinae, married woman's acute mastitis, interior postpartum mastitis, breast carcinoma, acute mastitis, that uses all imitates ... ".Radix Salviae Miltiorrhizae, the property hardship, tepor is gone into the heart, Liver Channel, has blood circulation promoting and blood stasis dispelling, evacuation of pus, the analgesic effect is share with Folium Citri tangerinae, and the merit of long memorial liver and qi blood circulation promoting and blood stasis dispelling is the monarch drug of this prescription altogether altogether.The Spina Gleditsiae detumescence, evacuation of pus, " detailed outline " claims Spina Gleditsiae " to control carbuncle, acute mastitis ", Semen Vaccariae, promoting the circulation of blood is stimulated the menstrual flow, and skin ulcer is held back in detumescence, and two medicines share the merit of common principal drug assistance disperse blood stasis and dredge collateral eliminating stagnation, are ministerial drug altogether.Fructus Toosendan nature and flavor bitter cold, the principal drug assistance clearing away liver-fire, the pain that relieves the pain is adjuvant drug in the side.Pheretima property is salty, tremble with fear, go into Liver Channel, both had the suppressing the hyperactive liver collateral dredging, and the merit of hard masses softening and resolving is drawn all medicines again and gone into Liver Channel, is messenger drug in the side.Above Six-element medicine share, and is total to the long memorial liver and qi, blood circulation promoting and blood stasis dispelling, and the effect of dissolving breast mass can effectively be treated owing to depression of liver-QI cystic hyperplasia of breast such as caused by energy stagnation and blood stasis cyclomastopathy, distending pain of the breast.

The granule that preparation method of the present invention obtains, prove that by pharmacodynamic study its curative effect has significance to improve than coated tablet, the dissolution of comparing with tablet is better, improve moisture resistance, and absorption is fast, produce effects is rapid, and bioavailability is greatly improved, and owing to change granule into by tablet, simplified production process, production cost obtains saving, and can also overcome the excessive shortcoming of tablet product dose, makes the patient more acceptant.

In addition, the boiling granulating method is to utilize air-flow powder suspension, is fluidization, sprays into adhesive liquid again, makes the powder granulating that condenses.Adopt the boiling granulating method in the preparation method of the present invention, its dry and step of granulating is finished, effective ingredient is difficult for loss, makes active constituent content higher, and the granule melting that makes is good, epigranular, the granule that is difficult for hardening in storage for a long time.

The inventor compares the different method of granulating that tablet and granule are adopted when technical study, and method is as follows:

To spray-drying process method, boiling granulating method, the prepared granule of extrusion granulator method and the primary standard tablet that adopts in the technology, press commercially available back, adopt the water isolation type electro-heating standing-temperature cultivator,, and can monitor true temperature and humidity at 40 ± 2 ℃ of temperature, relative humidity 75 ± 5%.Take a sample respectively once 1st month, 2 months, 3 months, 6 the end of month at duration of test, press the study on the stability project and detect.Different pharmaceutical quality stability is investigated and be the results are shown in Table 1.

Table 1 different pharmaceutical quality stability result

Method of granulating	Product batch number	Outward appearance				Moisture				Grain graininess uniformity (≤8%)				Content of hesperidin (mg/g)
																		1	2	3	6	1	2	3	6	1	2	3	6	1	2	3	6
		The spray-drying process method	06 0106 01	+	+	+	Have and harden	3％	3％	5％	6％	+	+	+	13％	0.42	0.42																	0.41	0.40
06 0109 02	+																	+	+	Have and harden	2％	3％	4％	7％	+	+	+	16％	0.41	0.41	0.40	0.40
			06 0112 03	+	+	+	Have and harden	3％	4％	5％	6％	+	+	+	15％	0.42	0.41																0.41	0.40

The boiling granulating method	06 0115 04	+	+	+	+	3％	3％	3％	3.5 ％	+	+	+	+	0.48	0.48	0.47	0.46
																		06 0118 05	+	+	+	+	3％	3％	3％	3.5 ％	+	+	+	+	0.51	0.50	0.50	0.48
	06 0121 06	+	+	+	+	2％	2％	3％	3％	+	+	+	+	0.50	0.50	0.50	0.49
																		The extrusion granulator method	06 0124 07	+	+	Have and harden	Caking	3％	4％	6％	8％	+	+	17 ％	23％	0.43	0.43	0.42	0.40
06 0127 08	+	+	Have and harden	Caking	3％	4.5 ％	6％	7％	+	+	16 ％	25％	0.45	0.44	0.43	0.41
																	06 0130 09		+	+	Have and harden	Caking	3.5 ％	4％	6％	9％	+	+	18 ％	27％	0.42	0.42	0.41	0.40

"+" expression meets particulate requirement

Above result shows: the stability of method of granulating is followed successively by boiling granulating method＞spray-drying process method＞extrusion granulator method.What the tablet granulation method adopted is conventional extrusion granulator method, and its content has significance to reduce than the made granule of boiling granulating method, though and its automaticity of spray-drying process and boiling granulating method are high equally, the too high loss of effective components of temperature is very big.So, select for use the boiling granulating method to carry out particulate preparation in line with the factor of constant product quality, determined curative effect and energy savings two aspects.

The inventor is that the method for granulating in 200510000429 the patent application compares with the method for granulating among the present invention and application number when technical study.

Respectively produce 3 batches of granules according to above-mentioned two kinds of method of granulating, investigate, the results are shown in Table 2 according to the requirement of granule:

3 kinds of method for making gained of table 2 granule quality situation is investigated

Method of granulating	Product batch number	Outward appearance	Moisture (≤5%)	Grain graininess uniformity (≤8%)	Melting	Content of hesperidin (mg/g)
							Granule method of granulating of the present invention-boiling granulating method	0601 0501	Pale brown color is to tan granule	3.0％	5％	Well	0.51
0601 0802	Pale brown color is to tan granule	2.5％	6％	Well	0.49
						0601 1103		Pale brown color is to tan granule	3.0％	6％	Well	0.50
Granule method of granulating-extrusion granulator method in 2,005 1,000 0429 No. 1 patent applications	0601 1404	Pale brown color is to tan granule	4.0％	10％	Well								0.43
						0601 1705	Irregular colour is even	3.5％	8％	Well	0.42
	0601 2006	Pale brown color is to tan granule	3.5％	9％	Well							0.43

As can be seen from the above table, the granule that the conventional extrusion granulator method that is adopted in No. 200510000429 patent applications makes, its uniform particles can not reach requirement, and because the baking temperature height, the lack of homogeneity of particle drying, not only make content of effective reduce, also make the granule appearance character not reach requirement easily.The uniform particles that the boiling granulating method makes, complete adds that the gas flow temperature of feeding when this method is granulated can be regulated, and so not only can reduce the loss of active ingredient, can also guarantee particulate appearance character.

Baking temperature in extrusion granulator method and its dry run of spray-drying process method can't be effectively controlled, active ingredient is lost very big in the granulation dry run in the medicine, and the mixing during extrusion granulator legal system grain, granulation, dry each operation must finish step by step, and production efficiency is low; The spray-drying process method is suitable for Chinese medicine extraction concentrated solution convection drying granulates, and generally is used for the granulation of the full extractum sheet of tablet, and the granule that adds a large amount of adjuvants for needs is granulated improper.

Operation has not only been simplified in the application of boiling granulating method in this medication preparation, improved production efficiency, and the granule of the method for granulating in No. 200510000429 patent applications of granule mass ratio of preparation is better, the raising of significance is arranged than tablet on curative effect, medicine of the present invention can obviously alleviate scorching liquid induced mice ear swelling degree and the swelling rate of causing, suppress the granulation tissue hyperplasia that foreign body causes, suppress venous thrombosis, showing that medicine of the present invention has significantly invigorates blood circulation and antiinflammatory action, and effect obviously is better than the RUKUAIXIAO KELI in RUKUAIXIAO PIAN and No. 200510000429 patent applications.Thereby make this pharmaceutical composition aspect the treatment disease of hyperplasia of mammary glands glands huge breakthrough and raising arranged.

The specific embodiment

Further describe the preparation method of the Chinese medicine granules of treatment mastopathy of the present invention below, but therefore the present invention is not subjected to any restriction.

The preparation of [embodiment 1] granule

Take by weighing each raw material by following weight: Folium Citri tangerinae 412.5g, Radix Salviae Miltiorrhizae 412.5g, Spina Gleditsiae 275g, Semen Vaccariae 275g, Fructus Toosendan 275g, Pheretima 275g.

Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water, feed steam pressure 0.1～0.4Mpa, decoct twice, each 1 hour, collecting decoction filters, and filtrate is concentrated into 138ml, adds Pheretima, mix, with 70% alcohol reflux secondary, 2 hours for the first time, 1 hour for the second time, filter, merging filtrate reclaims ethanol and is concentrated into thick paste, and is an amount of with sucrose and starch, dextrin, mixing, boiling granulating, dry air temperature are controlled at 70～80 ℃, drying, granulate, packing, promptly.

The preparation of [embodiment 2] granule

Take by weighing each raw material by following weight: Folium Citri tangerinae 412.5g, Radix Salviae Miltiorrhizae 412.5g, Spina Gleditsiae 275g, Semen Vaccariae 275g, Fructus Toosendan 275g, Pheretima 275g.

Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water, feed steam pressure 0.1～0.4Mpa, decoct twice, each 1 hour, collecting decoction filtered, filtrate is concentrated into 138ml, adds Pheretima, mixes, with 70% alcohol reflux secondary, 2 hours for the first time, 1 hour for the second time, filter, merging filtrate, reclaim ethanol and be concentrated into thick paste, an amount of with sucrose 500g and starch, dextrin, mixing, boiling granulating, dry air temperature is controlled at 70～80 ℃, drying, granulate, packing, promptly.

The preparation of [embodiment 3] granule

Take by weighing each raw material by following weight: Folium Citri tangerinae 104g, Radix Salviae Miltiorrhizae 104g, Spina Gleditsiae 70g, Semen Vaccariae 70g, Fructus Toosendan 70g, Pheretima 70g.

Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water, feed steam pressure 0.1～0.4Mpa, decoct twice, each 1 hour, collecting decoction filtered, filtrate is concentrated into 550ml, adds Pheretima, mixes, with 70% alcohol reflux secondary, 2 hours for the first time, 1 hour for the second time, filter, merging filtrate, reclaim ethanol and be concentrated into thick paste, an amount of with sucrose 125g and starch, dextrin, mixing, boiling granulating, dry air temperature is controlled at 70～80 ℃, drying, granulate, packing, promptly.

The preparation of [embodiment 4] granule

Take by weighing each raw material by following weight: Folium Citri tangerinae 1030g, Radix Salviae Miltiorrhizae 1030g, Spina Gleditsiae 687g, Semen Vaccariae 687g, Fructus Toosendan 687g, Pheretima 687g.

Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water, feed steam pressure 0.1～0.4Mpa, decoct twice, each 1 hour, collecting decoction filtered, filtrate is concentrated into 1375ml, adds Pheretima, mixes, with 70% alcohol reflux secondary, 2 hours for the first time, 1 hour for the second time, filter, merging filtrate, reclaim ethanol and be concentrated into thick paste, an amount of with sucrose 1250g and starch, dextrin, mixing, boiling granulating, dry air temperature is controlled at 70～80 ℃, drying, granulate, packing, promptly.

The preparation of [embodiment 5] granule

Take by weighing each raw material by following weight: Folium Citri tangerinae 412.5g, Radix Salviae Miltiorrhizae 412.5g, Spina Gleditsiae 275g, Semen Vaccariae 275g, Fructus Toosendan 275g, Pheretima 275g.

Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water, feed steam pressure 0.1～0.4Mpa, decoct twice, each 1 hour, collecting decoction filters, and filtrate is concentrated into 550ml, adds Pheretima, mix, with 70% alcohol reflux secondary, 2 hours for the first time, 1 hour for the second time, filter, merging filtrate reclaims ethanol and is concentrated into thick paste, and it is an amount of to add lactose, starch, dextrin, mixing, boiling granulating, dry air temperature are controlled at 70～80 ℃, drying, granulate, packing, promptly.

The pharmacodynamics test of [test example 1] pharmaceutical composition of the present invention

Test material

Medicine of the present invention: the granule that the embodiment of the invention 1 is prepared.

Positive control medicine I: RUKUAIXIAO PIAN, the tablet that makes by the inventive method.

Positive control medicine II: RUKUAIXIAO KELI, application number are the granule that the method in 20051000429.1 the patent application makes.

Blank: normal saline.

Laboratory animal: 60 of Kunming mouses, male and female half and half, average weight 20 ± 2g, 70 of rats, male and female dual-purpose, average weight 240 ± 20g, each treated animal number: 20 every group of mices, 10～16 every group of rats.(providing) by Chinese Medical Sciences University's Experimental Animal Center

Medication

Every test is all adopted and clinical consistent route of administration, i.e. gastric infusion, every day secondary.

Test one, pharmaceutical composition of the present invention cause the therapeutic effect test of mice ear to Oleum Tiglii

Test method:

Get 80 Kunming mouses, male and female half and half, weight average 20 ± 2g is divided into the normal saline contrast at random, medicine group of the present invention (consumption is 5g/kg) and positive control drug I RUKUAIXIAO PIAN and positive drug contrast medicine II RUKUAIXIAO KELI.Each group successive administration 5 days before causing scorching test, after the last administration 30 minutes, cause scorching liquid (Oleum Tiglii 5ml, ethanol 2ml with the Oleum Tiglii mixing, ether 2ml, water 1ml) the roundlet cotton balls of Jin Paoing is smeared mice left side ear, and after 4 hours, dislocation is put to death, cut ears, (internal diameter 7mm, external diameter 7.5mm) lays onesize auricle from the ears same area with card punch, uses marine products JN-A type precision torsion balance and weighs.Judge the index of inflammatory reaction weight with ear swelling degree (left ear weight-auris dextra is heavy) and swelling rate (swelling degree/auris dextra is heavy) conduct, compare between the work group.

The result: the control group mice ear swelling was serious than the medication group after as seen naked eyes caused inflammation, and transudate is many during punching, and the auricle color is red.Mice ear degree and the swelling rate measured see Table 3.

Table 3 pharmaceutical composition of the present invention is to causing the influence of scorching liquid induced mice ear swelling

Group	Number of animals (only)	Dosage (g/kg)	Ear swelling degree (the mg of X ± SD)	Ear swelling rate (the % of X ± SD)
					Normal saline	20	(0.2ml/10g)	7.97± 3.51	0.985±0.443
Positive control drug I	20	5	5.21± 3.10*	0.646±0.387*
					Positive control drug II	20	5	4.75± 2.65*	0.502±0.283*
Medicine group of the present invention	20	5	3.81± 2.78**	0.453±0.244**

Annotate: * and normal saline group are relatively; * P＜0.05; * P＜0.01

The result shows, relative physiologic saline group, and medicine of the present invention and positive control medicine I, II compare Oleum Tiglii to be mixed and causes scorching liquid induced mice ear swelling inhibitory action is all arranged.But cause in the influence of scorching liquid induced mice ear swelling in that Oleum Tiglii is mixed, medicine of the present invention has been compared utmost point significant difference with positive control medicine I, II, and its inhibitory action is apparently higher than positive control medicine I, II.

[test example 2] pharmaceutical composition of the present invention is to the therapeutic effect test of rat granulation tissue hyperplasia due to the plastic hoop

Get 64 of Wistar rats, male and female half and half, weight average 240 ± 20g is divided into three groups at random by sex, and each is organized respectively to sub-normal saline to test first three day, be subjected to reagent and positive control drug, etherization on the 4th respectively buries a plastic hoop ( 7mm in the outer  9mm, high  3mm) up and down at rat back, postoperative first three day intramuscular injection ampicillin prevents incision infection, and each group continues to award relative medicine simultaneously.Sacrificed by decapitation after 12 days is got band girdle and is weighed from granulation tissue.Estimate the inhibitory action of medicine with the granulation tissue average weight to granulation tissue hyperplasia.(seeing Table 4)

Table 4 pharmaceutical composition of the present invention is to the effect of rat granulation tissue hyperplasia due to the plastic hoop

Group	Granulation tissue (individual)	Dosage (g/kg)	Granulation tissue weight (the g of X ± SD)
				Normal saline	16	(2ml/100g)	0.583±0.256
Positive drug I	16	2.5	0.432±0.227*
				Positive drug II	16	2.5	0.394±0.235*
Medicine of the present invention	16	2.5	0.293±0.129**

Annotate: * and normal saline be * * P＜0.01 relatively

The result shows that the average weight of the granulation tissue of medicine group of the present invention and positive control drug I, II is starkly lower than the saline control group, and medicine group of the present invention and positive control drug I, II result relatively have significant difference.Illustrate that medicine of the present invention has the effect that suppresses granulation tissue hyperplasia, it acts on apparently higher than positive control medicine medicine I, II.

[test example 3] pharmaceutical composition of the present invention is to the thrombotic influence test of rat vein

Get 40 of Wistar rats, male and female half and half are divided into three groups at random, irritate stomach respectively and give normal saline, medicine of the present invention and positive control medicine, after three days, the pentobarbital sodium intraperitoneal anesthesia, in median abdominal incision, expose the abdominal cavity, separate postcava,, the accurate recording ligation time, cut open the belly after 2 hours and cut off vein in the ligature upper end with No. zero silk thread ligation postcava in left renal vein branch below with little shears, portable silk thread is cut isolating vein downwards as much as possible, be put on the template and set, accurately measure the long blood vessel of the following 1.2cm of knot institute line, extrude the thrombosis bar on template with pincet with chi, after inhaling the water of dehematizing with filter paper, thrombosis is moved on the sulphuric acid scraps of paper of weighing in advance with the iris tweezers.Take by weighing wet weight of thrombus with Shanghai JN-A type precision torsion balance.Each is organized wet weight of thrombus and sees Table 5.

Table 5 pharmaceutical composition of the present invention is to the thrombotic influence of rat vein

Group	Number of animals (only)	Dosage (g/kg)	Wet weight of thrombus (the mg of X ± SD)
				Normal saline	10	(2mg/100g)	25.49±6.52
Positive control drug I	10	2.1	19.45±5.23*
				Positive control drug II	10	2.1	17.36±5.14*
Medicine of the present invention	10	2.1	11.02±4.35**

Annotate: * and normal saline compare, * P＜0.05, * *＜0.001

The result shows that medicine of the present invention and positive control medicine group wet weight of thrombus are starkly lower than the saline control group, but under medicine of the present invention and positive control drug I, the II same dose, effect has significant difference, illustrates that drug effect of the present invention obviously is better than the positive control drug group.

Experimental result:

Medicine of the present invention can obviously alleviate scorching liquid induced mice ear swelling degree and the swelling rate of causing, suppress the granulation tissue hyperplasia that foreign body causes, suppress venous thrombosis, showing that medicine of the present invention has significantly invigorates blood circulation and antiinflammatory action, and effect obviously is better than positive control medicine RUKUAIXIAO PIAN and RUKUAIXIAO KELI.

The acute toxicity test of [test example 4] pharmaceutical composition of the present invention

One, test material

Medicine of the present invention: the granule that the embodiment of the invention 1 is prepared.

Laboratory animal: 20 of Kunming mouses, male and female half and half, average weight 20 ± 2g (Chinese Medical Sciences University's Experimental Animal Center provides)

Two, test method

Test is 2.3g/ml (crude drug) with the medicinal liquid Cmax, and after 12 hours, irritate stomach and give medicine of the present invention by animal by fasting for mice, and maximum administration volume is the 0.8ml/20g body weight.Observe the variation of animal after the administration and write down animal living or death number in the week.

Result of the test: this group experimental observation compares peace and quiet after animal is irritated stomach, the movable minimizing, and recovery is not normally seen gastrointestinal reaction after half an hour approximately.Record maximum tolerated dose, the results are shown in Table 6.

The The acute toxicity tests of table 6 pharmaceutical composition of the present invention

Number of animals (only)	Cmax (g/ml)	Maximum volume (ml)	Administration number of times (ml/20g)	Maximum tolerated dose (g/ml)	Be equivalent to human body medication multiple
						20	2.3	0.8	3	276	335

Can not measure LD after the administration of conclusion (of pressure testing) mouse stomach ₅₀Value.Mouse stomach medicine of the present invention maximum tolerated dose on the one is 276g/kg, is equivalent to 335 times of clinical one day dosage of people's (70kg meter), shows that pharmaceutical composition clinical application of the present invention is safe.

The clinical observation on the therapeutic effect test of [test example 5] pharmaceutical composition of the present invention

One, physical data

Accept case 717 examples altogether for medical treatment, be divided into treatment group (medicine group of the present invention) 380 examples at random, and matched group (positive controls I, II) 337 examples.

(1) treatment case 380 examples, the women, the age, the course of disease was the longest 15 years from 20 years old～56 years old 33.6 years old mean age, and is the shortest 1 month; Matched group 170 examples, the women, at 20 years old～52 years old age, 34.1 years old mean age, the course of disease is the longest 13 years, and is the shortest 20 days.Two groups of age distribution contrasts see Table 7.

Age distribution of table 7 case and chronological table

Group	The example number	0～	30～	40～	50～	Mean age
							Matched group I	170	25	65	54	26	33.6
Control Group II	167	23	55	60	29	35.4
							The treatment group	380	45	190	112	43	34.2

Annotate: treatment group and matched group be p＞0.05 relatively

This table shows the case age distribution and the age there was no significant difference of treatment group, matched group, both tool comparabilities.

(2) severity extent:

Slightly: mastalgia based on dull pain, scurry pain, one-sided or bilateral lump in breast is single lump or is graininess and scope is little, or is streak and softer, is confined to 1 quadrant.

Moderate: distending pain of the breast is obvious, lump is bigger, involves two breasts, and scope is at two quadrants.

Severe: breast twinge or be and weigh down pain, touch a tender spot obviously, lump is big, involves two breasts, and scope is at two quadrants.

Slightly, moderate, severe situation such as table 8.

Table 8 patient severity extent comparison sheet

Group	The example number	Slightly	Moderate	Severe
					The treatment group	380 examples	86 examples	182 examples	112 examples
Matched group I	170 examples	51 examples	72 examples	47 examples
					Control Group II	167 examples	48 examples	69 examples	50 examples

Two groups of relatively treatment group state of an illness are slightly heavy, but do not have significant difference (P＞0.05)

Two, Therapeutic Method:

All case is the outpatient, and totally 717 examples are divided into treatment group (Drug therapy of the present invention) 380 examples at random, matched group (positive drug treatment matched group I, II) 337 examples, 3 courses of treatment of observing time.

1, treatment group: take the prepared granule of embodiment 1, each one bag (10g), every day 3 times, 30 days is a course of treatment.

2, positive controls I: take RUKUAIXIAO PIAN (being prepared by 95 editions disclosed methods of pharmacopeia), each 5, every day 3 times, 30 days is a course of treatment.

Positive controls II: RUKUAIXIAO KELI, application number are the granule that 20051000429.1 methods make, each one bag (10g), and every day 3 times, 30 days is a course of treatment.

Three, efficacy assessment standard

" disease of tcm diagnosis criterion of therapeutical effect " with reference to State Administration of Traditional Chinese Medicine's promulgation

(1) recovery from illness: mastalgia and lump disappear, and take the photograph sheet or near infrared ray breast examination instrument inspection confirmation in conjunction with X line molybdenum palladium breast.

(2) produce effects: mastalgia alleviates, and lump dwindles more than 1/2, takes the photograph sheet or near infrared ray somascope inspection confirmation in conjunction with X line molybdenum palladium breast.

(3) effective: mastalgia alleviates, and lump dwindles not as good as 1/2, and the basic and clinical symptoms of auxiliary examination meets.

(4) invalid: mastalgia does not subtract, and lump do not see and dwindle, and is identical before symptom and the treatment.

Four, therapeutic outcome

Therapeutic outcome sees Table 9.

Table 9 clinical efficacy result of the test

Grouping	The example number	Recovery from illness (%)	Produce effects (%)	Effectively (%)	Invalid (%)	Effective percentage (%)
							Medication therapy groups of the present invention	380	171 (45.00)	114 (30.00)	86 (22.63)	9 (2.37)	97.63

Positive controls I	170	63 (37.06)	48 (28.24)	36 (21.12)	23 (13.53)	86.47
							Positive controls II	167	63 (37.72)	49 (29.34)	36 (21.56)	19 (11.38)	88.62

The cure rate of relatively treatment group of three groups of comprehensive therapeutic effects and total effective rate all are significantly higher than positive controls (P＜0.05), and there were significant differences for the two, show that treatment group curative effect is better than matched group.

Two groups of characteristic of diseases of treatment group and matched group and curative effect relatively see Table 10.

Table 10 liang group characteristic of disease and curative effect are relatively

Group	Degree	Add up to	Recovery from illness	Produce effects	Effectively	Invalid	Obvious effective rate
								The treatment group	Slight moderate severe	86 182 112	40 81 48	25 66 29	21 31 26	0 4 9	75.6％ 80.8％ 68.8％
Matched group I	Slight moderate severe	51 72 47	19 28 17	20 24 10	16 14 11	4 6 9	60.8％ 72.2％ 57.4％
								Control Group II	Slight moderate severe	48 69 50	16 27 16	17 23 11	10 12 15	5 7 8	68.75％ 72.5％ 54.0％

By the visible state of an illness of table 10 and therapeutic effect relationship no significant difference in the treatment group, to gently, in, the cyclomastopathy of severe all has significant curative effect, treatment group curative effect all is significantly higher than matched group I, II (p＜0.05)

Five, model case

1, Zhang, the women, 43 years old, the teacher is married.

Two nearly 3 weeks of swelling of the breast piece pain of cause are in JIUYUE in 1999 first visit on the 17th.

Patient's bimastism pain before nearly 3 weeks, character is distending pain, scurries bitterly that pain degree can tolerate, but spontaneous remission, oneself touching two breasts has lump.And feel irritated irritability, bitter taste, fullness and distention in the chest and hypochondrium, and the few color of long-term menstrual blood volume is dark, and the confusion of the menstrual cycle is successively indefinite.

Have a medical check-up: ordinary circumstance still can, two breasts are human-like, skin does not have redness, nipple-areola does not have deformity.Can touch two lumps of 3cm * 3cm in quadrant of right breast, in the matter, clear border, mobility is good does not have adhesion with skin, can touch the lump of 4cm * 4cm in the left newborn quadrant, clear border in the matter, the good and skin of mobility does not have adhesion, dimly red tongue, stringy and hesitant pulse.

Tcm diagnosis: nodules of the breast (qi stagnation and blood stasis type)

Western medicine diagnose: two newborn hypertrophy diseases

The near infrared ray scanography: two breasts are dispersed in light grey patch shadow.The RT that has a blood test, urine RT, electrocardiogram are all normal and look into liver, renal function.

Take the prepared granule of the embodiment of the invention 1, one time 1 bag (10g), 3 times on the one, further consultation after taking medicine ten, mastalgia alleviates, and lump dwindles, and irritated irritability and breast side of body feeling of distension and oppression disappear, menstruation is not risen, dimly red tongue, stringy and hesitant pulse is obeyed medicine 3 boxes of the present invention again, further consultation after ten days, it is the same that the tongue arteries and veins improves surplus card.Obeyed ten, its menstrual onset increases through amount again, and color shoals.Shared medicine 30 days obtains clinical recovery.

Near infrared ray is checked: two breasts are negative

Check blood RT, urine RT, electrocardiogram, liver, renal function are normal.

Follow up a case by regular visits to February after the drug withdrawal, curative effect keeps.

2, grandson patient so-and-so, the women, 34 years old, accounting, married.

Because of " two newborn pain, lump 3 years surplus " in first visit on May 14 in 1999.

The patient has pain when beginning two breast before 3 years, has lump whenever to increase the weight of in menstrual pain, and it is big that lump becomes, through after pain slightly subtract but do not disappear, pain increases the weight of over nearly several months, once multiple Drug therapy, and curative effect is not obvious, existing disease: two newborn pain, character is twinge, is difficult for alleviating, and idol has susceptible to lose temper due to restlessness, insomnia and dreamful sleep, the few color of long-term menstrual blood volume is dark.

Have a medical check-up: ordinary circumstance is good, and two breasts are human-like, the skin of breast redness, nipple-areola does not have deformity, no abnormal secretions, can touch the sheet block thing maximum 4cm * 4cm that swells in many places under two breasts are upward outer and outer, tenderness (), dimly red tongue, tongue limit have ecchymosis point, white, the rolling pulse of tongue.The near infrared ray scanography, two newborn light transmissions are relatively poor.Tcm diagnosis: nodules of the breast (qi stagnation and blood stasis type); Western medicine diagnose: two cyclomastopathy cards.The RT that has a blood test, urine RT, electrocardiogram, liver, renal function are all normal.

Therapeutic Method: take the prepared granule of the embodiment of the invention 1, each 1 bag (10g), and every day 3 times, further consultation after ten days, right lump in breast and in-scope reduce.Advise and continue to take medicine, further consultation after ten days, left newborn pain disappears, and right newborn pain obviously alleviates, and the lump scope reduces, and body of the tongue transfers to light red, does not see obvious ecchymosis; Obey again ten days except that still have irritated all diseases all disappear.Efficacy determination is a clinical recovery.

The near infrared ray scanography: two breasts are negative

Check blood RT, urine RT, electrocardiogram, hepatic and renal function are all normal.Follow up a case by regular visits to February after the drug withdrawal, two newborn pain lumps do not recur.

Comprehensive The above results shows: pharmaceutical composition total effects of the present invention is better than the positive control medicine, can effectively treat cystic hyperplasia of breast such as cyclomastopathy, mammary swelling be painful, and clinical drug safety.

Claims (7)

1. preparation method for the treatment of the Chinese medicine granules of mastopathy may further comprise the steps:

1) takes by weighing Folium Citri tangerinae 10-103 weight portion, Radix Salviae Miltiorrhizae 10-103 weight portion, Spina Gleditsiae 6.8-69 weight portion, Semen Vaccariae 6.8-69 weight portion, Fructus Toosendan 6.8-69 weight portion and Pheretima 6.8-69 weight portion;

2) Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water, collecting decoction filters, and filtrate is concentrated into 550 unit volumes;

3) Pheretima is added step 2) in the concentrated solution of gained, mix homogeneously;

4) with the concentrated solution of step 3) gained with 60～90% alcohol reflux, filter, merging filtrate reclaims ethanol and is concentrated into the thick paste shape;

5) in the thick paste of step 4) gained, add an amount of starch, dextrin, mixing then, boiling granulating.

2, method according to claim 1 is characterized in that, during boiling granulating, dry air temperature is controlled at 70～80 ℃ in the step 5).

3, method according to claim 2 is characterized in that step 2) in Folium Citri tangerinae, Radix Salviae Miltiorrhizae, Spina Gleditsiae, Semen Vaccariae and Fructus Toosendan are decocted with water twice, each 1 hour.

4, method according to claim 3 is characterized in that step 2) described in decoction decoct for pressurization, feed steam pressure 0.1～0.4Mpa.

5, method according to claim 4 is characterized in that, with the concentrated solution of step 3) gained with 70% alcohol reflux twice, 2 hours for the first time, 1 hour for the second time.

6, method according to claim 5 is characterized in that, in the step 5), also adds in sucrose, lactose, xylitol and the steviosin of 300～650 weight portions one or more in the thick paste of step 4) gained.

7, a kind of Chinese medicine granules of the treatment mastopathy for preparing by each described method among the claim 1-6.