CN1872210A - Compound preparation of Chinese traditional medicine for treating acute and chronic hepatitis, and preparation method - Google Patents

Abstract

A Chinese medicine for treating acute and chronic hepatitides is prepared proportionally from flavescent sophora root, capejasmine fruit, phellodendron bark, red sage root and silymarinum. Its preparing process is also disclosed.

Description

Compound Chinese medicinal preparation of treatment acute, chronic hepatitis and preparation method thereof

Technical field:

The present invention relates to a kind of compound Chinese medicinal preparation for the treatment of acute, chronic hepatitis and preparation method thereof, belong to the technical field of herbal pharmaceutical.

Background technology:

Clinical common first type, B-mode, third type, hepatitis E are the general infectious disease, mainly be divided into acute hepatitis (icteric and non-icteric type are arranged), chronic hepatitis (chronic persistent type, chronic active sexual type) (also shown as jaundice or do not had jaundice), belong to sick categories such as the traditional Chinese medical science " jaundice ", " hypochondriac pain ", " strongly fragrant disease ", " gathering ".The traditional Chinese medical science thinks, primary disease is many to be caused because of experiencing damp and hot, epidemic disease or the improper institute of diet, and damp-heat accumulation occupies critical role in the whole process of hepatitis.It mainly shows as the appearance jaundice, yellow urine such as strong tea, and nauseating, anorexia, gastral cavilty and the vexed pain of right rib etc. belong to the miscellaneous diseases class in the traditional Chinese medical science.Acute, chronic hepatitis and have or not jaundice no matter, all visible inappetence, gastral cavity be vexed feels sick, hypochondriac pain abdominal distention, limbs is because of heavy weak or anemogenous jaundice, syndrome of accumulated dampness-heats such as also visible red tongue greasy fur, stringy pulse, stringy and rolling pulse.

The clinical types of drugs that is used for the treatment of hepatitis is various, antiviral therapy no matter Western medicine, Chinese medicine all in the exploratory stage.More medicine is intended to protect hepatocyte, function of gallbladder promoting, improves symptom, shortens the course of disease and anti-hepatic fibrosis.Chinese medicine has curative effect and more vast market preferably in this regard.In recent years the Herba Sedi granule of Sheng Chaning, YIGANNING CHONGJI, the bitter yellow intravenous fluid that the hepatitis B series of instant powder that Changchun, Benxi produce, Changshu pharmaceutical factory produce, and all in liver disease, obtain certain curative effect according to the bifendate of tcm clinical development, potenlin etc.Chinese medicine is the treasure-house of a greatness, has a lot of outstanding prescriptions to wait us and studies, develops, is applied to clinical.In order to bring into play the advantage of national medicine on liver disease, we proved recipe clinical life-time service, effective adopt reasonable process be developed into determined curative effect, cost low, have no side effect, patient is easy to the anti-hepatitis preparation taking and accept.

Summary of the invention:

The objective of the invention is to: a kind of compound Chinese medicinal preparation for the treatment of acute, chronic hepatitis and preparation method thereof is provided, and the present invention adopts rational preparation technology, gained preparation bioavailability height, absorb soon, determined curative effect, cost is low, have no side effect, taking convenience, patient is easy to accept.

The present invention constitutes like this: calculate according to composition by weight, it is to add appropriate amount of auxiliary materials again for 1～10 part with 50～500 parts of Radix Sophorae Flavescentiss, 50～500 parts of Fructus Gardeniaes, 50～500 parts of Cortex Phellodendris, 100～1000 parts of Radix Salviae Miltiorrhizaes, silymarin to make tablet, dispersible tablet, capsule, soft capsule, microcapsule, granule, injection, injectable powder, lyophilized injectable powder, pellet, drop pill, syrup, powder, extractum, soft extract, oral liquid and other are the acceptable dosage form pharmaceutically.

Specifically, calculate according to composition by weight, it is to add appropriate amount of auxiliary materials again for 5 parts with 200 parts of Radix Sophorae Flavescentiss, 200 parts of Fructus Gardeniaes, 200 parts of Cortex Phellodendris, 600 parts of Radix Salviae Miltiorrhizaes, silymarin to make granule, tablet, dispersible tablet, capsule, soft capsule, powder, pellet, drop pill or oral liquid.

The preparation method of compound Chinese medicinal preparation of treatment acute, chronic hepatitis is: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, adds silymarin and appropriate amount of auxiliary materials, makes different preparations according to a conventional method.

Dispersible tablet in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, adds silymarin, the microcrystalline Cellulose of 50～200 weight portions, the mannitol of 1～10 weight portion; In addition get 3～7% carboxymethyl starch sodium, 2～5% low-substituted hydroxypropyl cellulose by weight, mixing, get its 3/5 with above-mentioned material mixing, make binding agent with the aqueous solution of concentration 2～5% polyvinylpyrrolidones, wet of 40 mesh sieve systems, granulate; The mixed powder that adds 0.5～1% magnesium stearate, 1～3% micropowder silica gel by weight and remain 2/5 carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose in the granule that makes, mixing, tabletting, promptly.

Granule in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, add silymarin, mixing adds the sucrose of 500～700 weight portions, the dextrin granulation of 100～200 weight portions again, drying, promptly.

Pellet in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, the starch that adds silymarin and 100～500 weight portions, with concentration is 70～85% alcoholic solution system soft material, and the soft material that makes is with micropill mechanism ball, and wet feed pushed the 0.8mm sieve aperture, the wet grain of strip cuts off round as a ball, 50～60 ℃ of drying and mouldings are crossed 16～20 mesh sieves and are selected ball, promptly.

Soft capsule in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, adds silymarin, other adds the ethyl cellulose of 5～20 weight portions, the tween 80 of 1～10 weight portion, mixing; Press medication amount: substrate amount=1: 1.5～1: 2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100: 45: 100: 2, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 60～90 minutes, stirred 3～5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity is less than 40%, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, dry 2～5 hours of the typing of rolling, and 25 ± 5 ℃ of baking temperatures, dry relative humidity is lower than 40%, and drying time is at 24～48 hours, promptly.

Drop pill in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae decocts with water three times, 1.5 hours for the first time, second, three times each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, adds silymarin, other adds the Macrogol 4000 of 2 times of weight of aforementioned material, the polyoxyethylene monostearate S-40 of 1 times of weight, mix homogeneously, fusion in the water-bath stirs evenly, drip and in dimethicone, become ball, drip apart from 4～6cm, drip footpath 2.5mm/2mm mixes 80 ± 5 ℃ of ointment temperature, liquid coolant height 70 ± 5cm, promptly.

Tablet in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, adds the starch of silymarin and 10～100 weight portions, other adds 3～5% carboxymethyl starch sodium by weight, mixing is with 20～50% alcohol granulations, drying, granulate, add 1～3% carboxymethyl starch sodium, 0.5～1% magnesium stearate by weight, mixing, tabletting, coating, promptly.

Oral liquid in the described preparation prepares like this: gets Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decocts with water three times, and 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, adds the sodium benzoate of silymarin, 1～10 weight portion tween 80,1～5 weight portion, other adds 2～5% aspartame by weight, mixing filters, sterilization, add distilled water to 1000ml, promptly.

Capsule in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, and it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, add silymarin, the starch of 50～200 weight portions, the calcium sulfate mix homogeneously of 5～30 weight portions, use alcohol granulation, filling, promptly.

Among the we, Radix Sophorae Flavescentis bitter cold, heat clearing and damp drying, detoxifcation parasite killing; Fructus Gardeniae bitter cold, clearing away heat-damp and promoting diuresis, cool the blood dissipate blood stasis; At the pathogenesis of primary disease damp-heat accumulation, with clearing away heat-damp and promoting diuresis, so Radix Sophorae Flavescentis, Fructus Gardeniae are monarch drug altogether.Cortex Phellodendri bitter cold, clearing away heat-fire, dampness detoxifcation, the merit of principal drug assistance clearing heat and expelling damp is ministerial drug; The Radix Salviae Miltiorrhizae hardship is slightly cold, blood circulation promoting and blood stasis dispelling, and inducing menstruation to relieve menalgia, existing merit of ending hypochondriac pain has the tonneau passages through which vital energy circulates again to help eliminating evil usefulness, is adjuvant drug; Five kinds of Chinese medicine is played sharp dampness-heat in the liver and gallbladder altogether, invigorating the spleen and regulating the stomach, and the effect of blood circulation promoting and blood stasis dispelling has better curative effect to the excess syndrome hepatitis of damp-heat accumulation.

Compared with prior art, micropill disintegrative provided by the present invention is good, the bioavailability height, and zest is little, is particularly suitable for the old people and swallow tablet or the inconvenient patient of capsule take; It is more that dispersible tablet is taken mode, can swallow, buccal and sucking take, it is convenient to use more than other oral solid formulation, simultaneously, this medicine is met water can rapid disintegrate form homodisperse aqueous solution in 3 minutes, solved the not high problem of effective ingredient bioavailability; Soft capsule in soft gel coat, has solved drug blockage medicine and has met damp and hot problem of unstable, can also cover adverse drug taste, abnormal smells from the patient, plays the effect that increases stability, improves bioavailability; The granule good mouthfeel absorbs soon the bioavailability height simultaneously; Tablet dose is accurate, and the content content difference is little, and molding is better, and disintegration time is short.

Pharmacopeia regulation dispersible tablet must disintegrate fully in the 3min in 19 ℃～21 ℃ water, and suspension ability, bioavailability, dispersed homogeneous degree etc. are also had higher requirements.The applicant finds that in the process of development dispersible tablet extract of the present invention has hygroscopicity greatly, makes the kind and the consumption of various adjuvants in the moulding process prescription are selected to require very strictness, and deviation is arranged slightly, will cause product defective.

The diameter of micropill is less than 2.5mm, and class is in particle properties, the bioavailability height.The applicant is when this product of development, and maximum difficulty is exactly that the extractum hygroscopicity is strong and mobile poor, and poor plasticity is difficult to molding and molten diffusing slower.

Soft capsule disintegrate in gastrointestinal tract is fast, and after softgel shell broke, medicine disperseed rapidly, so the drug release stripping is fast, produce effects is rapid, the bioavailability height; Semi-transparent soft capsule can protect medicine not to be subjected to the effect of oxygen, light in dampness and the air with packaging material preferably, thereby improves the stability of labile element; So the stability of soft capsule itself and moulding process directly influence the stability of product, be very crucial technology.

The applicant finds in the process of development drop pill, substrate polyethylene glycols commonly used is that esterification forms, be the surface-active water-soluble base of a kind of tool (fusing point is 46～51 ℃), dissolubility to insoluble drug is not good, we add S-40 change polyethylene glycols itself and do not have close ester structure and surface-active character, help the absorption of medicine, if but the consumption of S-40 is too high, and can cause product to draw moist enhancing.

The applicant has also carried out a series of test, with the supplementary product kind of the preparation technology of preferred pharmaceutical preparation of the present invention, use and usage ratio etc., makes it reach optimum efficiency.

Experimental example 1: Study on Forming

(1) dispersible tablet moulding process

Meet water rapidly disintegrate form the water dispersion tablet of uniform sticky suspension, it is poor to have solved disintegrative, stripping is shortcoming slowly, the dispersible tablet that the applicant makes is complete disintegrate in the 3min in 19 ℃ of-21 ℃ of water, suspension ability is good, bioavailability is high, be uniformly dispersed.

1. adjuvant screening

The prescription number	Disintegrating agent		Binding agent	Evaluation index
						Carboxymethyl starch sodium+low-substituted hydroxypropyl cellulose		The aqueous solution of polyvinylpyrrolidone (%)	Disintegration time (min)	Dispersing uniformity
	Add	In add
			1	1/5	4/5	1～2	3.5				Good
2	2/5	3/5						2～5	1.4	Fine
			3	3/5	2/5	2～5	2.8				Fine
4	4/5	1/5						5～8	3.8	Good
			5	5/5	0	1～2	4.6				Generally

6

0

5/5

5～8

6.4

Generally

As can be seen from the above table, 2 made its disintegration times of slice, thin piece of filling a prescription are the shortest, and dispersing uniformity is fine, meets the requirement of dispersible tablet.

(2) pellet moulding process

The micropill diameter is less than 2.5mm, and class is in particle properties, the bioavailability height, and the applicant is when development product of the present invention, and maximum difficulty is exactly that the extractum hygroscopicity is strong and mobile poor, and poor plasticity is difficult to molding and molten diffusing slower.When development product micropill of the present invention, the micropill manufacturing technology and the adjuvant that adopt the applicant's screening to obtain make product be easy to disintegrate, and the bioavailability height is well-behaved.

Get mixed powder, make wetting agent in right amount with alcoholic solution, wet granulation process is made soft material, makes it to reach to hold agglomeratingly, and that pinches can loose, standby.Research emphasis is the influence of concentration of alcohol to pill, and experimental result sees the following form.

Concentration of alcohol is investigated

Tested number	Concentration of alcohol (%)	System soft material situation
			1	50～70	Soft material easily bonds
2	70～85	Soft material is moderate
			3	85～95	Soft material viscosity is not enough

The result as seen, it is comparatively desirable to adopt 70～85% alcoholic solution to be that binding agent is granulated.

(3) soft capsule moulding process

Soft capsule disintegrate in gastrointestinal tract is fast, and after softgel shell broke, medicine disperseed rapidly, so the drug release stripping is fast, produce effects is rapid, the bioavailability height; Semi-transparent soft capsule can protect medicine not to be subjected to the effect of oxygen, light in dampness and the air with packaging material preferably, thereby improves the stability of labile element, so capsular stability and moulding process are very crucial technology.

1. disperse medium (or claiming substrate) is selected

At fill material and substrate energy mix homogeneously, and under the prerequisite of unobstructed defeated material of energy and pelleting, reduce substrates quantity as far as possible.By test of many times, determine medication amount (g): be advisable in substrate amount (g)=1: 1.5～2, experimental result sees the following form.

The substrates quantity investigation table

Medication amount: substrate amount (g: g)	1∶0.5～1∶1	1∶1.5～1∶2	1∶2～1∶2.5
				Quality of liquid medicine	Viscosity is big, mobile poor	Viscosity, flowability are all good	Differences in viscosity is mobile strong

2. capsule shells prescription screening

According to the form below proportion scale batching, put into the 500ml bottle,suction, 65 ± 5 ℃ of water-baths are dissolved, automatic stirringization glue, the while evacuation, about vacuum 0.095Mpa, insulation was placed 1～2 hour after 3～5 hours, filtered glue, get a part of glue and measure viscosity and other performance, part glue evenly is paved into skim (smear below earlier one deck liquid paraffin) on iron plate, be positioned over to observe the rubber performance next day and judge again, with the investigation result of each index by good to poorly using " +++" successively, " ++ ", "+",, "-" expression the results are shown in Table.

Rubber batching The selection result

Prescription	Viscosity (mpas)	Flexibility	Elasticity	Toughness	Characteristics	Overall merit
							Gelatin: glycerol: water (100g: 35g: 100g)	3.82	-	-	+	Crisp, hard	Difference
Gelatin: glycerol: water (100g: 45g: 100g)	3.32	+	++	+++	Tough, good film-forming property	Fine
							Gelatin: glycerol: water (100g: 55g: 100g)	3.65	+	++	+++	Good springiness	Generally
Gelatin: glycerol: water (100g: 45g: 80g)	3.37	++	++	+	Good springiness, viscosity is big	Good
							Gelatin: glycerol: water (100g: 45g: 120g)	3.12	+++	+	-	Too soft	Difference
Gelatin: glycerol: sorbitol: water (100g: 35g: 5: 100g)	3.43	-	+	++	Tough	Better

Through above screening, overall merit is considered the characteristics of fill material, and selecting prescription 2 is gelatin 100: glycerol 45: water 100.

3. opacifier is selected

The transparent adhesive tape softgel shell easily causes instability, so need to add a certain amount of opacifier.Select titanium dioxide (titanium dioxide) to make opacifier through investigation and can reach effective shaded effect, and steady quality, not with rubber cement and fill material generation chemical change.Its consumption is through investigating with gelatin: glycerol: water: titanium dioxide=100: 45: 100: 2 are advisable, and little to the rubber quality influence, the results are shown in following table.

Opacifier consumption option table

Usage ratio	The rubber transparency	Rubber cement viscosity (MpaS)	Overall merit
				Gelatin: glycerine: water: titanium dioxide (100g: 45g: 100g: 0.5g) gelatin: glycerine: water: titanium dioxide (100g: 45g: 100g: 1g) gelatin: glycerine: water: titanium dioxide (100g: 45g: 100g: 2g) gelatin: glycerine: water: titanium dioxide (100g: 45g: 100g: 3g)	Translucent translucent opaque	3.12 3.19 3..36 3.52	The good inadequately viscosity of the not enough consumption of consumption is bigger

Experiment showed, and add the opacifier more stable quality in the capsule formula.

(4) drop pill moulding process

1. the screening of substrate

The drop pill drug loading is less, if substrate, drip distance, fusion fluid temperature, drip the character that speed is not suitable for medicine, product not only is difficult to molding, and dose is big, and the patient uses and be inconvenient.

The fusion situation comparison sheet of substrate and principal agent

The prescription number	Prescription 1	Prescription 2	Prescription 3	Prescription 4	Prescription 5	Prescription 6
							Medicine (g)	10	10	10	10	10	10
Macrogol 4000 (g)	30	20	20	25	-	-
							Polyethylene glycol 6000 (g)	-	10	-	20	30	-
S-40	-	-	10	10	10	20
							The fusion situation of principal agent and substrate	Principal agent can merge with substrate, but system does not have flowability	Principal agent can merge with substrate, and system is mobile general	Principal agent can merge with substrate, and the system flowability is fine	Principal agent can merge with substrate, and the system flowability is fine	Principal agent can merge with substrate, but system does not have flowability	Principal agent and substrate merge relatively poor
The drop pill outward appearance	-	Roundness is poor, and hangover is arranged slightly	Smooth, roundness is good	Smooth, roundness is good	-	-
							Drop pill hardness	-	Hardness is little	Hardness is better	Hardness is better	-	-
The ball method of double differences is different	-	15.7％	5.1％	11.4％	-	-
							Dissolve scattered time limit (min)	-	6～8	3～4	9～11	-	-

Last table result shows, the write out a prescription good fluidity of 3 fusion medicinal liquids, drug loading is bigger, the drop pill good moldability, smooth, mellow and full, the ball method of double differences is different little, molten loosing comparatively fast, and this is because the esterification of polyethylene glycols substrate forms, it is a kind of surface-active water-soluble base (fusing point is 46～51 ℃) that has, S-40 has changed polyethylene glycols itself and has not had close ester structure and surface-active character, improves the dissolubility of insoluble drug, helps the absorption of medicine.

2. drip distance, drip selection fast, temperature

The internal diameter of water dropper is that 2mm, external diameter are 2.5mm.Evaluation index: the heavy qualification rate of ball is by mass discrepancy requirement of Pharmacopoeia of the People's Republic of China version in 2005: meet ± 15% within.

Group	Temperature/℃	Drip distance/cm	Liquid coolant height/cm	Heavy qualification rate/the % of ball
					1	65～75	1～3	55～65	78.3
2	65～75	4～6	65～75	87.4
					3	65～75	7～9	75～85	82.0
4	75～85	1～3	65～75	91.3
					5	75～85	4～6	75～85	92.2
6	75～85	7～9	55～65	90.0
					7	85～95	1～3	75～85	91.2
8	85～95	4～6	55～65	89.1
					9	85～95	7～9	65～75	88.2

The result shows, the optimum condition of drop pill of the present invention: drip to become ball in dimethicone, drip apart from 4～6cm, drip footpath 2.5mm/2mm mixes 75～85 ℃ of ointment temperature, liquid coolant height 65～75cm.

The applicant has also carried out a series of experiments, has effective effect to prove medicine provided by the invention.

Experimental example 2: pharmacodynamic study

One, material:

Medicine and reagent: the former powder of the present invention, every 1g powder is equivalent to crude drug 5.56g; Carbon tetrachloride (CCL ₄) be commercially available analytical pure, dilute with Oleum Arachidis hypogaeae semen during use; And D-galactosamine (D-GaIN) hydrochlorate, available from fine chemistry branch of branch cooperation center of Beijing section; Bifendate is tested the pharmaceutical factory available from institute of Materia Medica,Chinese Academy of Medical Sciences: dehydrocholic acid, cyclophosphamide (cy), levamisole are commercially available; RPMl ₁₆₄₀Complete culture solution: RPMl ₁₆₄Gibco company produces and adds 10% newborn calf serum, and L-glutaminate 2Mm, penicillin 100u/ml, streptomycin 100u/ml form; Concanavalin A, Con A (DonA), Sigma company product. ³H-TDR ( ³H-thymus pyrimidine glycosides), Institute for Atomic Research, Beijing produces; Sulfur second outer coffin hydrochlorate culture medium, Haidian District, Beijing City microorganism culturing products factory is produced; Dimethyl diaminophenazine chloride reagent and paddy third transaminase (SGPT) are measured medicine box, millet straw transaminase (SGPT) is measured medicine box, serum albumin mensuration medicine box, total serum protein mensuration medicine box, all available from the Beijing Chemical Plant.

Animal: Kunming mouse, NIH kind mice, C ₃₇The BL/6 mice, male, 18～22g; Wistar kind male rat.All available from animal housing of China Academy of TCM.

Two, method and result

1, medicine of the present invention is to the influence of the acute and chronic hepatic injury of animal

1. medicine of the present invention is to CCL ₄The influence of induced mice acute liver damage

50 of Kunming mouses are divided into 5 groups at random; Be respectively matched group, model group, bifendate 0.3g/kg group, 3g/kg of the present invention and 1g/kg group.Each administration group according to dosage every day gastric infusion once, matched group and model group wait the normal saline of capacity simultaneously, continuous 6 days, after the administration in the morning on the 5th 1 hour, model group and each administration group mouse subcutaneous injection 0.5%CCL ₄0.1ml/kg (10ml/kg) capacity normal saline such as matched group subcutaneous injection, afternoon on the same day, reinforcement was administered once, behind the fasting 12h, 1h after administration in the morning on the 6th, broken end is got blood, centrifugal (10,000g * 5min), measure SGPT and SGOT unit of activity in the serum with reitman-frankel method.

Table 1 the present invention is to CCL ₄Due to the influence (X ± SD) of acute liver damage mice serum transaminase

Group	Dosage (g/kg)	Number of animals (only)	Serum transaminase unit of activity (u/100ml serum)
					SGPT	SGOT
			Matched group	-			10	85.30±5.44**	128.9±47.23***
Model group	0.5％CCL 410ml/kg	10			178.86±76.66	243.16±45.68
			The present invention 1	3+CCL 4			10	97.9±17.46**	185.32±49.15*
The present invention 2	1+CCL 4	10			103.3±27.19*	144.75±22.97***
			Bifendate	0.3+CCL 4			10	107.09±20.84**	173.2±73.55*

*, * * and * * * and model compare P＜0.05, P＜0.01 and P＜0.001.

Table 1 is the result show, mouse subcutaneous injection CCL ₄Back 24h, serum SGPT and SGOT vigor are apparently higher than matched group.Bifendate group and 3g/kg of the present invention and 1g/kg group mice serum SGTP and SGOT vigor all significantly are lower than model group, (P＜0.05, P＜0.01 and P＜0.001).There is not marked difference (P＞0.05) between the present invention and the bifendate group.

2. medicine of the present invention is to the influence of D-galactosamine induced mice acute liver damage

Experiment grouping is all 1. identical with above-mentioned experiment with medication, respectively organizes mouse subcutaneous injection D the morning on the 5th in administration AlN0.8g/kg (capacity 0.1ml/10g), capacity normal saline such as matched group subcutaneous injection, afternoon on the same day, reinforcement was administered once, behind the fasting 12h after administration in the morning on the 6th 1h broken end get blood, centrifugal (10,000g * 5min), measure SG-PT, SGOT vigor in the serum with reitman-frankel method.

Table 2 the present invention is to the influence of acute liver damage mice serum transaminase due to the D-gallon (X ± SD)

Group	Dosage (g/kg)	Number of animals (only)	Serum transaminase unit of activity (u/100ml serum)
					SGPT	SGOT
			Matched group	-			13	92.89±17.68**	142.83±23.98**
Model group	D-GalN0.8g/kg	12			267.08±153.77	239.45±82.97
			The present invention 1	3+D-GalN			13	160.31±42.99*	167.32±59.06*
The present invention 2	1+GalN	13			166.43±44.29*	171.17±41.05*
			Bifendate	0.3+CCL 4			12	141.25±43.16*	177.87±33.02*

* compare P＜0.05 and P＜0.01 with * * and model.

Table 2 is the result show, behind the mouse subcutaneous injection D-GalN24h, serum transaminase vigor obviously raise (P＜0.01), 3g/kg of the present invention, 1g/kg and bifendate 0.3g/kg group mice serum transfer amine enzyme activity significantly are lower than model group (P＜0.05), all do not have marked difference (P＜0.05) between two dosage groups of the present invention and the bifendate group.

3. medicine of the present invention is to CCL ₄Due to the influence of rat chronic hepatic injury

Get 106 of male rats, body weight 130～140g is divided into 5 groups at random, matched group (20), model group (22), bifendate group 150mg/kg (20).

Each administration group according to dosage every day gastric infusion once, continuous three months.In administration the 5th day subcutaneous injection CCL weekly ₄0.2ml/100g, CCL ₄Concentration is followed successively by 5%, 10%, 20% and 30%, and per three weeks increase progressively a concentration.Last injection CCL ₄Behind the 48h (fasting 12h), each organizes 8 rats of sacrificed by decapitation, gets liver and weighs, and calculates liver index (hepatic tissue weight/body weight * 100%).The residue rat adopts the eye socket rear vein beard to get blood.All blood sample are centrifugal, and (10,000g * 5min) measures serum SGPT and SGOT vigor with reitman-frankel method; Measure The Total albumen content with biuret method; Measure serum albumin levels with the bromocresol green method; Measure the content of THP in the serum with alkali hydrolysis method.Then remain rat and continue in accordance with regulations once (each group CCL that all stops using of dosage gastric infusion every day ₄), totally 14 days, fasting was after 12 hours, and broken end is got blood and is got liver.Measure the content of SGPT, SGOT, total protein, albumin and THP in the serum by above-mentioned same procedure.

Table 3 the present invention is to CCL ₄Due to the influence of chronic hepatic injury rats death rate

Group	Dosage (g/kg)	Number of animals (only)	Death toll	Mortality rate
					(only)	(only)
			Matched group	-			20	1	5*
Model group	CCL 4	22			6	27.3
			The present invention 1	1+CCL 4			22	3	13.6
The present invention 2	0.3+CCL 4	22			1	4.5*
			Bifendate	0.15+CCL 4			20	3	15

* compare P＜0.05 (X with model group ²Check).

Table 3 is the result show, rat is injected CCL continuously ₄During three months; the part animal dead; the model group disability rate is 27.3%; with normal group significant difference (P＜0.05) is arranged relatively; the mortality rate of 1g/kg of the present invention, 0.3g/kg and bifendate 0.15g/kg group is respectively 13.6%, 4.5% and 20%; the result shows that each administration group can make the animal dead rate descend, and wherein the 0.3g/kg group has remarkable protective effect (P＜0.05).

Table 4 the present invention is to CCL ₄Due to the influence of chronic hepatic injury rat blood serum transaminase

Group	Dosage (g/kg)	Serum transaminase unit of activity (μ/100ml serum) CCL that stops using 4Continue treatment time (X ± SD)
						2d		14d
		SGPT	SGOT	SGTP	SGOT
						Matched group		269.6±36.7***	484.1± 76.5(17)***	234.4±24.3***	377.9± 40.0(9)***
Model group	CCL 4	484.7±216.5	635.9±161.4(17)	309.1±44.6	345.9±96.7(8)
						The present invention 1	CCL 4	484.7±216.5	635.9± 161.4(17)***	309.1±44.6**△ △	345.9±967(8)

The present invention 2	0.3+CCL 4	384.2±128.0***	615.0± 142.0(19)***	244.1±23.3***	295.2± 26.5(11)**
						Bifendate	0.15+CCL 4	538.8±241.9*	673.3± 196.0(14***)	236.5±23.5***	339.5± 36.8(8)***

*, * * * and model group be P＜0.02, P＜0.001 relatively; △ △ and bifendate group be P＜0.01 relatively.

Table 4 is the result show, rat continuous subcutaneous injection CCL ₄After three months, serum SGPT and SGOT vigor significantly strengthen, and compare P＜0.001 with matched group.Each dosage group rat blood serum transaminase vigor of the present invention significantly reduces, and compares P＜0.001 and P＜0.01 with model group.There was no significant difference between each dosage group of the present invention.Bifendate group rat blood serum transfer amine enzyme activity also significantly is lower than model group (P＜0.05 and P＜0.001), there was no significant difference between of the present invention group and the bifendate group.Stop to inject CCL ₄Continue medication after 14 days, model group rat blood serum transaminase vigor recovers to some extent, but still be significantly higher than normal control group (P＜0.001), each dosage group of the present invention and bifendate group rat blood serum transaminase vigor all significantly are lower than model group (P＜0.01 and P＜0.001), and there was no significant difference between the matched group, also there was no significant difference between the present invention and the bifendate group.

Table 5 the present invention is to CCL ₄Due to chronic liver decrease the influence of total serum protein, albumin content

Group	Dosage (g/kg)	CCL stops using 4Continue treatment 2d		CCL stops using 4Continue treatment 14d
						Serum albumin	Total serum protein	Serum albumin	Total serum protein
		(g/dl)	(g/dl)	(g/dl)	(g/dl)
						Matched group		(19)4.32±0.29**	861±0.57***	(9)4.33±0.30	8.49±0.82
Model group	CCL 4	(16)3.92±0.17	7.68±0.49	(8)4.27±0.22	8.07±0.44
						The present invention 1	1+CCL 4	(19)4.31± 0.33***	8.24±0.78	(8)4.33±0.30	8.07±0.48
The present invention 2	0.3+CCL 4	(21)4.42± 0.29***△	8.03±0.72	(11)4.63± 0.25**	9.16±1.03* △
						Bifendate	0.15+CCL 4	(16)4.21±0.31**	8.20±0.45**	(8)4.57±0.19**	8.37±0.53

*, * * and * * * and model group compare P＜0.05, P＜0.01 and P＜0.001; △ and bifendate group be P＜0.05 relatively.

Table 5 is the result show: rat continuous subcutaneous injection CCL ₄Three months, serum albumin and The Total albumen content all significantly descend, each dosage group of the present invention and bifendate group rat blood serum albumin all are significantly higher than model group (P＜0.01 and P＜0.001), and 0.3g/kg group of the present invention is significantly higher than bifendate group (P＜0.05).Administration group The Total albumen content also increases to some extent, and wherein bifendate and model group relatively have significant difference (P＜0.01), 1g/kg group of the present invention and model group relatively, the P value is near 0.05, (t=1.85) inactive CCL ₄After two weeks, albumin and total protein content go up to some extent in the model group rat blood serum, albuminous content still is higher than model group in each administration group rat blood serum, and 0.3g/kg group wherein of the present invention and bifendate group and model group relatively still have significance poor (P＜0.01).And 0.3g/kg group of the present invention is significantly higher than bifendate group (P＜0.05).

2, medicine of the present invention is to the influence of normal anesthetized rat bile flow

The used Wistar male rat that is of laboratory animal, anaesthetize (1g/kg) with urethane behind the fasting 12h, face upward the fixedly about 2cm of tailing edge abdomen median line otch of position, find duodenum downwards from stomachus pyloricus, and in the descendant duodenum mesentery, find white bile duct, under bile duct, wear a fine rule, on bile duct, cut one " V " shape otch with eye scissors, the biliary drainage pipe that is about the about 1.5mm of 5cm diameter is inserted to the liver aspect, as seen there is pistac bile to flow out immediately, the fine rule of wearing cutter is in advance tied bile duct, and collect bile with a little conical flask, collect 30min bile before the experiment, then by duodenal administration.Capacity normal saline such as matched group injection, collect after the administration 0～30 ', 30～60 ', 60～90 ', 90～120 ' and 120～180 ' time in bile flow, calculate bile flow and increase percentage rate:

Bile flow * 100% before (the preceding bile flow of bile flow-administration after the administration)/administration

Table 6 the present invention is to the influence of normal anesthetized rat bile flow

Group	Number of animals (only)	Dosage (g/kg)	The bile amount increases percentage rate % after the administration
								0～30′	30～60′	60～90′	90～120′	120～18′
			Matched group	11	-	-18.6± 22.9	-24.0± 25.4						-27.3± 23.2	-33.2± 16.2	-36.5± 45.9
The present invention 1	18	3						13.4±22.*** △△△	17.5± 30.0***△	15.0± 25.7***	13.3± 27.2***	-7.8± 24.5△△*
			The present invention 2	10	1	-10.9±22.3 △△△	-0.1±18.6 △						2.0± 24.7*	9.4± 24.7*	-28.2± 19.9△△
Dehydrocholic acid	10							80.4± 64.0***	60.9± 81.3**	46.3± 63.6**	47.9± 90.8	40.9± 64.5**

*, * * and * * * medicine and matched group compare P＜0.05, P＜0.01 and P＜0.001; △, △ △ and △ △ △ medicine dehydrocholic acid be P＜0.05, P＜0.01 and P＜0.001 relatively.

Table 6 is the result show, behind the normal rat injecting normal saline in 3 hours choleresis reduce gradually, 3g/kg of the present invention group after administration 30 ', 60 ', 90 ', the 120 ' bile flow to each interval in 180 ' time is all apparently higher than matched group (P＜0.001 and P＜0.01).1g/kg group rat bile flow also has increase to a certain degree, respectively after administration 90 ' and 120 ' time period in bile flow be significantly higher than matched group.Dehydrocholic acid after administration in 3 hours bile flow all apparently higher than matched group (P＜0.001 P＜0.01 and P＜0.05).

3, medicine of the present invention is to effect of immunologic function

1. medicine of the present invention is to the influence of mouse T cell propagation

48 of NIH mices are divided into 6 groups at random, are respectively normal control group, CY model group, CY+LMS positive controls, the heavy dose of group of CY+ the present invention (2g/kg), CY+ small dose group of the present invention (0.5g/kg), except that the normal control group.After each organized mouse peritoneal injection CY100mg/kg, the CY+LMS positive controls gavaged LMS25mg/kg every day, and CY+ the present invention respectively organizes gastric infusion according to dosage.Continuous 7 days, the normal control group was obeyed the equivalent normal saline every day.Respectively organize mice on the 7th and pluck the disconnected vertebra of eyeball blood-letting and put to death, asepticly routinely get spleen and prepare splenocyte, use RPMI ₁₆₄₀Complete culture solution is made into 5 * 10 ⁶/ ml splenocyte suspension adds 96 well culture plates, and every hole 100ml adds every 1ml in every hole again and contains ConA10ugRPM ₁₆₄₀Complete culture solution 100 μ 1 are put 37 ℃ of 5%CO ₂Incubator is cultivated 72h, 6～8h before finishing cell culture, and every hole adds 3H-TdR0.5uci, and liquid scintillation instrument (Beckman company) is surveyed CPM.

Table 7 the present invention is to the influence of cell proliferation under the mice spleen

Group	Mus number (n)	Dosage (mg/kg)	H-TDR mixes * the C value
				X±SD
			The normal control group		8	-	8907±833
The cyclophosphamide model group	8	Cy100		1991±181△△△
			Cyclophosphamide+levamisole group		8	A Cy100+ left side 25	8046±1329***
The heavy dose of group of cyclophosphamide+the present invention	8	Cy100+ hardship 2000		6773±766***
			Dosage group among cyclophosphamide+the present invention		8	Cy100+ hardship 1000	5836±773***
Cyclophosphamide+small dose group of the present invention	8	Cy100+ hardship 500		5313±365***

△ △ △ and normal control group be P＜0.001 relatively, and * * * and model group be P＜0.001 relatively.

From table 7 result as seen, Cy model group mice spleen t cell proliferation and normal control group relatively have obviously and weaken (P＜0.001).Illustrate that CY has obviously suppressed the propagation of mice splenic t-cell.Cy+ levamisole group mice spleen T cell proliferation and Cy model group be than the remarkable rising of cpm value, near normal control group level (P＞0.05), shows that levamisole has restitution to immunosuppressed mice splenic t-cell propagation due to the Cy.The large, medium and small dosage group of Cy+ the present invention mice spleen T cell proliferation has tangible rising (P＜0.001) with the Cy model group than all, illustrates that the present invention has restitution to immunosuppressed mice splenic t-cell propagation due to the Cy.

2. medicine of the present invention is to the influence of Turnover of Mouse Peritoneal Macrophages (M Φ) phagocytic function

40 of NIH kind mices, be divided into 5 groups at random, be respectively normal control group, LMS positive controls, the heavy dose of group of the present invention (2g/kg), middle dosage group (1g/kg), small dose group (0.5g/kg), the LMS positive controls gavages LMS every day, the present invention respectively organizes dosage gastric infusion every day, continuous 7 days, the normal control group gave the equivalent normal saline.Each is organized in administration the 4th day, only injects 10% sulphur glycollate culture medium 0.8ml/ to each Mus intraperitoneal, to induce abdominal cavity M Φ, respectively organizes the disconnected vertebra of mice difference blood-letting and puts to death in the 8th day.After preparing mouse peritoneal M Φ routinely, be made into 5 * 106/ml M Φ suspension with the RPM1640 complete culture solution.The list of references method is carried out M Φ phagocytic function and is detected, and surveys the OD value with Bio-Rad company microplate reader under the 492nm wavelength.

Table 8 the present invention is to the influence of mouse peritoneal M Φ phagocytic function

Group	Mus number (n)	Dosage	OD/( X±SD)
				The normal control group	8	-	0.364±0.029
The levamisole group	8	2.5mg/kg	0.523±0.029
				The heavy dose of group of the present invention	8	2g/kg	0.532±0.036
Dosage group among the present invention	8	1g/kg	0.473±0.027
				Small dose group of the present invention	8	0.5g/kg	0.332±0.084

* * and normal group be P＜0.001 relatively.

Table 8 is the result show, levamisole, 2g/kg of the present invention, 1g/kg group all have facilitation to mouse peritoneal M Φ phagocytic function, compare with the normal control group, and highly significant difference (P＜0.001) is arranged, and 0.5g/kg group no significant difference (P＞0.05).

Three, discuss

The present invention is a pure Chinese medicinal preparation, full side has effects such as clearing heat and expelling damp, promoting the function of the gallbladder to alleviate jaundice, blood circulation promoting and blood stasis dispelling, the existing report of the main herbal medicine efficacy of this side, Herba Artemisiae Scopariae, Fructus Gardeniae, Radix Salviae Miltiorrhizae all have obvious hepatoprotective effect, every index of hepatic injury is made moderate progress, hepatoprotective effect mechanism may with suppress glycuronidase, decompose thereby reduce glucal, the function of detoxification that increases liver is relevant.Find Radix Salviae Miltiorrhizae in the clinical practice to acute and chronic active stage, chronic persistent hepatitis, even the liver-fire case of some refractory is all had curative effect preferably, and non-evident effect.Fructus Gardeniae, Cortex Phellodendri, the various preparations of Radix Sophorae Flavescentis can promote bile secretion to anesthetized dog, Cavia porcellus, rat, and certain choleretic effect is arranged.Radix Sophorae Flavescentis composition matrine can make peripheral leukocytes increase in addition, and the leukocytes phagocytic ability strengthens, but the immunoreation of enhancing body.Most of medicines among this side all have tangible antiinflammatory action as Radix Sophorae Flavescentis, Cortex Phellodendri, Radix Salviae Miltiorrhizae, Fructus Gardeniae etc., help to eliminate the early stage cellular swelling of hepatitis, alleviate hepatocellular degeneration and necrosis, alleviate hepatic fibrosis.Above-mentioned this medicine treatment chronic persistent hepatitis that act as provides the pharmacology foundation.

The main pharmacodynamics result of study shows that the present invention has the effect of prevention and the acute and chronic chronic persistent hepatitis of treatment animal, can obviously reduce CCL ₄The mice serum transaminase that causes with D-CalN increases, and effect of reducing enzyme levels is similar to the 0.3g/kg bifendate, illustrates that this herbal mixture has the better protect effect to acute liver damage.

Experimental result proves that also the present invention also has choleretic effect, and the normal rat choleresis is increased, and a little less than low dose of (1g/kg) group effect, heavy dose of (3g/kg) effect is more remarkable, but all is weaker than dehydrocholic acid.Immune function experiment is the result prove, immunity is subjected to press down mice spleen T cell proliferation in the present invention and the IL-2 generation all has certain restitution, and normal functions of murine peritoneal macrophages is also had facilitation.These results show that the present invention is to the cell that participates in the body cell immunologic function with can activate T, B cell, the lymphokine IL-2 of NK cell and the class important cells-M Φ that participates in the body non-specific immunity all have potentiation in various degree, this side is described except that hepatoprotective effect is arranged, also has immunological enhancement.

In sum, experiment confirm the present invention has good hepatoprotective effect and raise immunity, is a kind of medicine of up-and-coming treatment acute, chronic hepatitis for clinical use.

Experimental example 3: toxicological study

1, preparation oral maximum tolerance determination of the present invention

Purpose: observe toxic reaction and death condition that once heavy dose of oral test medicine produces animal.

Be subjected to reagent: the former powder of the present invention (call the present invention in the following text, every gram is equivalent to crude drug 5.56g).

Method: 20 of Kunming mouses, body weight 18.8 ± 0.9g, male and female half and half, test is preceding with dissolved in distilled water medicine (every 1ml solution contains 0.167g of the present invention, symphysis medicine 0.93g).0.5ml/10g body weight gastric infusion is pressed in mice fasting 12 hours, and administration is 3 times in 1 day, continues after the administration to raise 7 days, observes the mice active situation, weighs in 7th.

The result: dead mouse does not take place in 7 days, well-grown, the 7th daily weight is 27.6 ± 1.34g, and average weight increases by 8.8 ± 1.3g, and the activity of administration mice on the same day reduces (perusal) to some extent, recovers normal behind the 12h, and other does not see any untoward reaction.

Conclusion: the oral maximum tolerated dose of mice of the present invention is greater than 138.8g/kg, and this dosage is equivalent to be equivalent to more than 464 times of rat effective dose more than 140 multiples of mice effective dose, is equivalent to more than 52 times of clinical people's consumption (adult presses 60kg and calculates).

Discuss: experiment is adopted and is observed this compound recipe acute toxicity with clinical identical route of administration method, and the result shows that oral administration is not found the overt toxicity reaction, because of medicine dissolution and administration capacity limit, escalated dose again.This compound oral maximum tolerated dose has reached mice and more than 140 times and 464 times of rat hepatoprotective effect effective dose, this shows that this Chinese medicine preparation is safe.

The specific embodiment:

Embodiment 1: get Radix Sophorae Flavescentis 200g, Fructus Gardeniae 200g, Cortex Phellodendri 200g, Radix Salviae Miltiorrhizae 600g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds 5g silymarin, 100g microcrystalline Cellulose, 5g mannitol; In addition get 5% carboxymethyl starch sodium, 4% low-substituted hydroxypropyl cellulose by weight, mixing, get its 3/5 with above-mentioned material mixing, make binding agent with the aqueous solution of concentration 3% polyvinylpyrrolidone, wet of 40 mesh sieve systems, granulate; The mixed powder that adds 0.8% magnesium stearate, 2% micropowder silica gel by weight and remain 2/5 carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose in the granule that makes, mixing, tabletting promptly gets dispersible tablet.This product oral, one time 1,3 times on the one.

Embodiment 2: get Radix Sophorae Flavescentis 100g, Fructus Gardeniae 50g, Cortex Phellodendri 500g, Radix Salviae Miltiorrhizae 100g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds 10g silymarin, 50g microcrystalline Cellulose, 1g mannitol; In addition get 3% carboxymethyl starch sodium, 2% low-substituted hydroxypropyl cellulose by weight, mixing, get its 3/5 with above-mentioned material mixing, make binding agent with the aqueous solution of concentration 2% polyvinylpyrrolidone, wet of 40 mesh sieve systems, granulate; The mixed powder that adds 0.5% magnesium stearate, 1% micropowder silica gel by weight and remain 2/5 carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose in the granule that makes, mixing, tabletting promptly gets dispersible tablet.

Embodiment 3: get Radix Sophorae Flavescentis 200g, Fructus Gardeniae 50g, Cortex Phellodendri 400g, Radix Salviae Miltiorrhizae 100g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds 1g silymarin, 200g microcrystalline Cellulose, 10g mannitol; In addition get 7% carboxymethyl starch sodium, 5% low-substituted hydroxypropyl cellulose by weight, mixing, get its 3/5 with above-mentioned material mixing, make binding agent with the aqueous solution of concentration 5% polyvinylpyrrolidone, wet of 40 mesh sieve systems, granulate; The mixed powder that adds 1% magnesium stearate, 3% micropowder silica gel by weight and remain 2/5 carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose in the granule that makes, mixing, tabletting promptly gets dispersible tablet.

Embodiment 4: get Radix Sophorae Flavescentis 250g, Fructus Gardeniae 100g, Cortex Phellodendri 500g, Radix Salviae Miltiorrhizae 200g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), add the 1g silymarin, mixing adds sucrose 600g, dextrin 150g again and granulates, drying promptly gets granule.This product boiled water is taken after mixing it with water, one time 1 bag, 3 times on the one.

Embodiment 5: get Radix Sophorae Flavescentis 300g, Fructus Gardeniae 200g, Cortex Phellodendri 500g, Radix Salviae Miltiorrhizae 300g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), add the 5g silymarin, mixing adds sucrose 700g, dextrin 200g again and granulates, drying promptly gets granule.

Embodiment 6: get Radix Sophorae Flavescentis 300g, Fructus Gardeniae 500g, Cortex Phellodendri 300g, Radix Salviae Miltiorrhizae 500g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), add the 10g silymarin, mixing adds sucrose 500g, dextrin 100g again and granulates, drying promptly gets granule.

Embodiment 7: get Radix Sophorae Flavescentis 400g, Fructus Gardeniae 400g, Cortex Phellodendri 100g, Radix Salviae Miltiorrhizae 300g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), add 10g silymarin and 300g starch, with concentration is 65% alcoholic solution system soft material, the soft material that makes micropill mechanism ball, and wet feed pushed the 0.8mm sieve aperture, the wet grain of strip cuts off round as a ball, 50～60 ℃ of drying and mouldings are crossed 18 mesh sieves and are selected ball, promptly get pellet.This product oral, one time 1 ball, 3 times on the one.

Embodiment 8: get Radix Sophorae Flavescentis 400g, Fructus Gardeniae 500g, Cortex Phellodendri 200g, Radix Salviae Miltiorrhizae 700g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), add 5g silymarin and 500g starch, with concentration is 85% alcoholic solution system soft material, the soft material that makes micropill mechanism ball, and wet feed pushed the 0.8mm sieve aperture, the wet grain of strip cuts off round as a ball, 50～60 ℃ of drying and mouldings are crossed 20 mesh sieves and are selected ball, promptly get pellet.

Embodiment 9: get Radix Sophorae Flavescentis 400g, Fructus Gardeniae 300g, Cortex Phellodendri 300g, Radix Salviae Miltiorrhizae 800g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), add 1g silymarin and 100g starch, with concentration is 50% alcoholic solution system soft material, the soft material that makes micropill mechanism ball, and wet feed pushed the 0.8mm sieve aperture, the wet grain of strip cuts off round as a ball, 50～60 ℃ of drying and mouldings are crossed 16 mesh sieves and are selected ball, promptly get pellet.

Embodiment 10: get Radix Sophorae Flavescentis 500g, Fructus Gardeniae 500g, Cortex Phellodendri 300g, Radix Salviae Miltiorrhizae 800g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds the 1g silymarin, other adds 10g ethyl cellulose, 5g soil temperature-80, mixing; Press medication amount: substrate amount=1: 1.8 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100: 45: 100: 2, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 75 minutes, stirred 3～5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity is less than 40%, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, dry 2～5 hours of the typing of rolling, and 25 ± 5 ℃ of baking temperatures, dry relative humidity should be lower than 40%, and promptly got soft capsule at 24～48 hours drying time.This product oral, one time 1,3 times on the one.

Embodiment 11: get Radix Sophorae Flavescentis 500g, Fructus Gardeniae 400g, Cortex Phellodendri 100g, Radix Salviae Miltiorrhizae 1000g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds the 5g silymarin, other adds 5g ethyl cellulose, 1g soil temperature-80, mixing; Press medication amount: substrate amount=1: 1.5 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100: 45: 100: 2, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 60 minutes, stirred 3～5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity is less than 40%, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, dry 2～5 hours of the typing of rolling, and 25 ± 5 ℃ of baking temperatures, dry relative humidity should be lower than 40%, and promptly got soft capsule at 24～48 hours drying time.

Embodiment 12: get Radix Sophorae Flavescentis 500g, Fructus Gardeniae 50g, Cortex Phellodendri 50g, Radix Salviae Miltiorrhizae 1000g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds the 10g silymarin, other adds 20g ethyl cellulose, 10g soil temperature-80, mixing; Press medication amount: substrate amount=1: 2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100: 45: 100: 2, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 90 minutes, stirred 3～5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity is less than 40%, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, dry 2～5 hours of the typing of rolling, and 25 ± 5 ℃ of baking temperatures, dry relative humidity should be lower than 40%, and promptly got soft capsule at 24～48 hours drying time.

Embodiment 13: get Radix Sophorae Flavescentis 100g, Fructus Gardeniae 50g, Cortex Phellodendri 50g, Radix Salviae Miltiorrhizae 700g decocts with water three times, 1.5 hours for the first time, second, three times each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds the 5g silymarin, other adds the Macrogol 4000 of 2 times of weight of aforementioned material, the polyoxyethylene monostearate S-40 of 1 times of weight, mix homogeneously fuses in the water-bath, stirs evenly, drip and in dimethicone, become ball, drip apart from 4～6cm, drip footpath 2.5mm/2mm mixes 80 ± 5 ℃ of ointment temperature, liquid coolant height 70 ± 5cm promptly gets drop pill.This product oral, one time 1 ball, 3 times on the one.

Embodiment 14: get Radix Sophorae Flavescentis 50g, Fructus Gardeniae 50g, Cortex Phellodendri 500g, Radix Salviae Miltiorrhizae 900g decocts with water three times, 1.5 hours for the first time, second, three times each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds the 1g silymarin, other adds the Macrogol 4000 of 2 times of weight of aforementioned material, the polyoxyethylene monostearate S-40 of 1 times of weight, mix homogeneously fuses in the water-bath, stirs evenly, drip and in dimethicone, become ball, drip apart from 4～6cm, drip footpath 2.5mm/2mm mixes 80 ± 5 ℃ of ointment temperature, liquid coolant height 70 ± 5cm promptly gets drop pill.

Embodiment 15: get Radix Sophorae Flavescentis 200g, Fructus Gardeniae 200g, Cortex Phellodendri 400g, Radix Salviae Miltiorrhizae 500g decocts with water three times, 1.5 hours for the first time, second, three times each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds the 10g silymarin, other adds the Macrogol 4000 of 2 times of weight of aforementioned material, the polyoxyethylene monostearate S-40 of 1 times of weight, mix homogeneously fuses in the water-bath, stirs evenly, drip and in dimethicone, become ball, drip apart from 4～6cm, drip footpath 2.5mm/2mm mixes 80 ± 5 ℃ of ointment temperature, liquid coolant height 70 ± 5cm promptly gets drop pill.

Embodiment 16: get Radix Sophorae Flavescentis 500g, Fructus Gardeniae 500g, Cortex Phellodendri 500g, Radix Salviae Miltiorrhizae 500g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds 5g silymarin and 50g starch, other adds 4% carboxymethyl starch sodium by weight, mixing is used 35% alcohol granulation, drying, granulate, add 2% carboxymethyl starch sodium, 0.8% magnesium stearate by weight, mixing, tabletting, coating promptly gets tablet.This product oral, one time 1,3 times on the one.

Embodiment 17: get Radix Sophorae Flavescentis 50g, Fructus Gardeniae 100g, Cortex Phellodendri 500g, Radix Salviae Miltiorrhizae 900g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds 10g silymarin and 10g starch, other adds 3% carboxymethyl starch sodium by weight, mixing is used 20% alcohol granulation, drying, granulate, add 1% carboxymethyl starch sodium, 0.5% magnesium stearate by weight, mixing, tabletting, coating promptly gets tablet.

Embodiment 18: get Radix Sophorae Flavescentis 50g, Fructus Gardeniae 200g, Cortex Phellodendri 400g, Radix Salviae Miltiorrhizae 600g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds 8g silymarin and 100g starch, other adds 5% carboxymethyl starch sodium by weight, mixing is used 50% alcohol granulation, drying, granulate, add 3% carboxymethyl starch sodium, 1% magnesium stearate by weight, mixing, tabletting, coating promptly gets tablet.

Embodiment 19: get Radix Sophorae Flavescentis 100g, Fructus Gardeniae 200g, Cortex Phellodendri 300g, Radix Salviae Miltiorrhizae 400g decoct with water three times, and 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds 3g silymarin, 5g soil temperature-80,3g sodium benzoate, other adds 3% aspartame by weight, mixing filters, sterilization, add distilled water to 1000ml, promptly get oral liquid.This product oral, a 10ml, 3 times on the one.

Embodiment 20: get Radix Sophorae Flavescentis 100g, Fructus Gardeniae 300g, Cortex Phellodendri 50g, Radix Salviae Miltiorrhizae 600g decoct with water three times, and 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds 5g silymarin, 1g soil temperature-80,1g sodium benzoate, other adds 2% aspartame by weight, mixing filters, sterilization, add distilled water to 1000ml, promptly get oral liquid.

Embodiment 21: get Radix Sophorae Flavescentis 200g, Fructus Gardeniae 400g, Cortex Phellodendri 50g, Radix Salviae Miltiorrhizae 100g decoct with water three times, and 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), adds 3g silymarin, 10g soil temperature-80,5g sodium benzoate, other adds 5% aspartame by weight, mixing filters, sterilization, add distilled water to 1000ml, promptly get oral liquid.

Embodiment 22: get Radix Sophorae Flavescentis 300g, Fructus Gardeniae 100g, Cortex Phellodendri 100g, Radix Salviae Miltiorrhizae 400g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, and filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), add 10g silymarin, 100g starch, 15g calcium sulfate mix homogeneously, use alcohol granulation, filling promptly gets capsule.This product oral, one time 1,3 times on the one.

Embodiment 23: get Radix Sophorae Flavescentis 200g, Fructus Gardeniae 200g, Cortex Phellodendri 200g, Radix Salviae Miltiorrhizae 1000g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, and filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), add 8g silymarin, 50g starch, 5g calcium sulfate mix homogeneously, use alcohol granulation, filling promptly gets capsule.

Embodiment 24: get Radix Sophorae Flavescentis 500g, Fructus Gardeniae 300g, Cortex Phellodendri 400g, Radix Salviae Miltiorrhizae 600g decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, and filtrate is concentrated into the clear paste that relative density is 1.12～1.15 (25 ℃), add 1g silymarin, 200g starch, 30g calcium sulfate mix homogeneously, use alcohol granulation, filling promptly gets capsule.

Claims (11)

1. compound Chinese medicinal preparation for the treatment of acute, chronic hepatitis, it is characterized in that: calculate according to composition by weight, it is to add appropriate amount of auxiliary materials again for 1～10 part with 50～500 parts of Radix Sophorae Flavescentiss, 50～500 parts of Fructus Gardeniaes, 50～500 parts of Cortex Phellodendris, 100～1000 parts of Radix Salviae Miltiorrhizaes, silymarin to make tablet, dispersible tablet, capsule, soft capsule, microcapsule, granule, injection, injectable powder, lyophilized injectable powder, pellet, drop pill, syrup, powder, extractum, soft extract, oral liquid and other are the acceptable dosage form pharmaceutically.

2. according to the compound Chinese medicinal preparation of the described treatment acute, chronic hepatitis of claim 1, it is characterized in that: calculate according to composition by weight, it is to add appropriate amount of auxiliary materials again for 5 parts with 200 parts of Radix Sophorae Flavescentiss, 200 parts of Fructus Gardeniaes, 200 parts of Cortex Phellodendris, 600 parts of Radix Salviae Miltiorrhizaes, silymarin to make granule, tablet, dispersible tablet, capsule, soft capsule, powder, pellet, drop pill or oral liquid.

3. treat the preparation method of the compound Chinese medicinal preparation of acute, chronic hepatitis as claimed in claim 1 or 2, it is characterized in that: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, and it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, add silymarin and appropriate amount of auxiliary materials, make different preparations according to a conventional method.

4. according to the preparation method of the compound Chinese medicinal preparation of the described treatment acute, chronic hepatitis of claim 3, it is characterized in that: the dispersible tablet in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, adds silymarin, the microcrystalline Cellulose of 50～200 weight portions, the mannitol of 1～10 weight portion; In addition get 3～7% carboxymethyl starch sodium, 2～5% low-substituted hydroxypropyl cellulose by weight, mixing, get its 3/5 with above-mentioned material mixing, make binding agent with the aqueous solution of concentration 2～5% polyvinylpyrrolidones, wet of 40 mesh sieve systems, granulate; The mixed powder that adds 0.5～1% magnesium stearate, 1～3% micropowder silica gel by weight and remain 2/5 carboxymethyl starch sodium and low-substituted hydroxypropyl cellulose in the granule that makes, mixing, tabletting, promptly.

5. according to the preparation method of the compound Chinese medicinal preparation of the described treatment acute, chronic hepatitis of claim 3, it is characterized in that: the granule in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, add silymarin, mixing, add the sucrose of 500～700 weight portions, the dextrin granulation of 100～200 weight portions again, drying, promptly.

6. according to the preparation method of the compound Chinese medicinal preparation of the described treatment acute, chronic hepatitis of claim 3, it is characterized in that: the pellet in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae decocts with water three times, 1.5 hours for the first time, second, three times each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, adds the starch of silymarin and 100～500 weight portions, is 70～85% alcoholic solution system soft material with concentration, the soft material that makes micropill mechanism ball, wet feed pushed the 0.8mm sieve aperture, and the wet grain of strip cuts off round as a ball, 50～60 ℃ of drying and mouldings, cross 16～20 mesh sieves and select ball, promptly.

7. according to the preparation method of the compound Chinese medicinal preparation of the described treatment acute, chronic hepatitis of claim 3, it is characterized in that: the soft capsule in the described preparation prepares like this; Getting Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae decocts with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, adds silymarin, other adds the ethyl cellulose of 5～20 weight portions, the tween 80 of 1～10 weight portion, mixing; Press medication amount: substrate amount=1: 1.5～1: 2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100: 45: 100: 2, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 65 ± 5 ℃ gradually after 60～90 minutes, stirred 3～5 hours and simultaneously evacuation remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, mould rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity is less than 40%, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, dry 2～5 hours of the typing of rolling, and 25 ± 5 ℃ of baking temperatures, dry relative humidity is lower than 40%, and drying time is at 24～48 hours, promptly.

8. according to the preparation method of the compound Chinese medicinal preparation of the described treatment acute, chronic hepatitis of claim 3, it is characterized in that: the drop pill in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae decocts with water three times, 1.5 hours for the first time, second, three times each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, add silymarin, other adds the Macrogol 4000 of 2 times of weight of aforementioned material, the polyoxyethylene monostearate S-40 of 1 times of weight, mix homogeneously, fusion in the water-bath, stir evenly, drip and in dimethicone, to become ball, drip apart from 4～6cm, drip footpath 2.5mm/2mm, mix 80 ± 5 ℃ of ointment temperature, liquid coolant height 70 ± 5cm, promptly.

9. according to the preparation method of the compound Chinese medicinal preparation of the described treatment acute, chronic hepatitis of claim 3, it is characterized in that: the tablet in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae decocts with water three times, 1.5 hours for the first time, second, three times each 1 hour, collecting decoction filtered, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, the starch that adds silymarin and 10～100 weight portions, other adds 3～5% carboxymethyl starch sodium, mixing by weight, with 20～50% alcohol granulations, drying, granulate adds 1～3% carboxymethyl starch sodium by weight, 0.5～1% magnesium stearate, mixing, tabletting, coating, promptly.

10. according to the preparation method of the compound Chinese medicinal preparation of the described treatment acute, chronic hepatitis of claim 3, it is characterized in that: the oral liquid in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae decocts with water three times, 1.5 hours for the first time, second, three times each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, add silymarin, 1～10 weight portion tween 80, the sodium benzoate of 1～5 weight portion, other adds 2～5% aspartame, mixing by weight, filter, sterilization adds distilled water to 1000ml, promptly.

11. preparation method according to the compound Chinese medicinal preparation of the described treatment acute, chronic hepatitis of claim 3, it is characterized in that: the capsule in the described preparation prepares like this: get Radix Sophorae Flavescentis, Fructus Gardeniae, Cortex Phellodendri, Radix Salviae Miltiorrhizae and decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, it is 1.12～1.15 clear paste that filtrate is concentrated into 25 ℃ of relative densities, add silymarin, the starch of 50～200 weight portions, the calcium sulfate mix homogeneously of 5～30 weight portions, use alcohol granulation, filling, promptly.