CN100387280C - Phlegm transforming Chinese medicinal formulation for children and its preparation method - Google Patents

Abstract

The present invention relates to a phlegm transforming traditional Chinese medicine preparation for a baby and a preparation method thereof. In the present invention, Concretio Silicea Bambusae, prepared arisaema tuber, platycodon, acori graminei, Radix Trichosanthis, fried stiff silkorm, mint, dried tangerine peel, sichuan fritillary bulb, tall gastrodis tuber, prepared pinellia and sucrose powder are prepared into medicinal powder. The preparation not only can be used for relieving cough, reducing phlegm, and eliminating the symptoms of infantile cough and excessive phlegm, but also can be used for clearing away heat, freeing the lung and recovering the Xuanjiang of the lung. Compared with the prior art, the present invention has the advantages of high disintegration speed, fast absorption, obvious effect, high bioavailability, easy dose control, etc., and is particularly suitable for the taking of a baby.

Description

Be used for children's's expectorant Chinese medicine preparation and preparation method thereof

Technical field:

The present invention relates to a kind of children's's of being used for expectorant Chinese medicine preparation and preparation method thereof, belong to technical field of medicaments.

Background technology:

Expectorant be disease, very extensive, promptly refer to the visible phlegm that excretes, refer to show as the special symptom of expectorant again.The generation of expectorant and lung, spleen, kidney three dirty relations are comparatively close.Lung governing coordinative activities of viscera, exopathogen are attacked lung, impaired depurative descending of lung QI, and lung Tianjin can be condensed and is expectorant.Children's is tender and lovely because of internal organs, and shape gas does not fill, and lung being a delicate viscus, defending outer function can not self-regulated because of, cold in addition temperature, is easily attacked by exopathogen.All evil chief criminal's lungs are defended, and lung is subjected to its heresy, clear respectful dereliction of duty, and impaired depurative descending of lung QI, disorder of QI movement can not circulation of qi promoting and compress body fluid, and poly-liquid becomes expectorant, and sputum retardance air flue is so see cough.Children's's phlegm-resolving pill of record is a kind of children's's of being used for expectorant good medicine in the 15 in Ministry of Public Health Chinese traditional patent formulation preparation, but its disintegration rate slow, absorb slow, bioavailability is lower, and dosage is bigger, not too is suitable for child administration.

Summary of the invention:

The objective of the invention is to: a kind of children's's of being used for expectorant Chinese medicine preparation and preparation method thereof is provided, medicine disintegration rate of the present invention is fast, absorption is fast, instant effect, bioavailability height and dosage are controlled easily, are suitable for child administration, to overcome the deficiencies in the prior art.

The present invention is achieved in that according to weight and calculates that it is prepared into powder by Concretio Silicea Bambusae 110g, Rhizoma Arisaematis (processed) 44g, Radix Platycodonis 67g, Rhizoma Acori Graminei 22g, Radix Trichosanthis 67g, Bombyx Batryticatus (parched) 89g, Herba Menthae 33g, Pericarpium Citri Reticulatae 67g, Bulbus Fritillariae Cirrhosae 89g, Rhizoma Gastrodiae 33g and Rhizoma Pinelliae Preparata 67g and cane sugar powder 312g.

It is preparation like this that the present invention is used for children's's expectorant Chinese medicine preparation: take by weighing Concretio Silicea Bambusae, Rhizoma Arisaematis (processed), Radix Platycodonis, Rhizoma Acori Graminei, Radix Trichosanthis, Bombyx Batryticatus (parched), Herba Menthae, Pericarpium Citri Reticulatae, Bulbus Fritillariae Cirrhosae, Rhizoma Gastrodiae and Rhizoma Pinelliae Preparata, dry by the fire 1～3 hour down to water content＜4.0～6.0% at 50～60 ℃ and 70～80 ℃ respectively, pulverize, cross 100～140 mesh sieves, mixed 20～40 minutes, standby; Take by weighing sucrose, be ground into 100～140 order powder, the medical material of above-mentioned pulverizing and cane sugar powder were mixed 20～40 minutes, add 95% alcohol granulation then, dry under 70～80 ℃ of conditions, granulate, pack, promptly.

The best preparation method that the present invention is used for children's's expectorant Chinese medicine preparation is: take by weighing Concretio Silicea Bambusae 110g, Rhizoma Arisaematis (processed) 44g, Radix Platycodonis 67g, Rhizoma Acori Graminei 22g, Radix Trichosanthis 67g, Bombyx Batryticatus (parched) 89g, Herba Menthae 33g, Pericarpium Citri Reticulatae 67g, Bulbus Fritillariae Cirrhosae 89g, Rhizoma Gastrodiae 33g and Rhizoma Pinelliae Preparata 67g, above-mentioned medical material is dried by the fire 2 hours down to water content＜5.0% at 55 ℃ and 75 ℃ respectively, pulverize, cross 120 mesh sieves, standby; Take by weighing cane sugar powder 312g, be ground into 120 order powder, the medical material of above-mentioned pulverizing and cane sugar powder were mixed 30 minutes, add 95% alcohol granulation then, dry under 70～80 ℃ of conditions, granulate, pack is made 500 bags, promptly.

Medicine of the present invention cures mainly card and stops up for flu ailment said due to cold or exposure, cough breath, fever of the body expectorant.Characteristic of the wind being light and upward, Jiao that goes against one's superiors more, lung is defended and is stood in the breach, the damp and hot heresy that is affected by the cold, impairment of dispersing and descending function of the lung, and it is out of breath to cause cough, fever of the body expectorant is stopped up.Be monarch drug with Concretio Silicea Bambusae, Bulbus Fritillariae Cirrhosae, Bombyx Batryticatus among the we, be used for removing heat-phlegm, relieving convulsion relieving dizziness, high fever, infantile convulsions, epilepsy, etc.; With Rhizoma Arisaematis, Rhizoma Gastrodiae, the Rhizoma Pinelliae, Pericarpium Citri Reticulatae and be ministerial drug, be used for drying dampness to eliminate phlegm; With Herba Menthae, Radix Platycodonis and be adjuvant drug, be used for dispelling wind and heat pathogens, lung qi dispersing cough-relieving; Radix Trichosanthis promote the production of body fluid moisturize, the Rhizoma Acori Graminei inducing resuscitation, Radix Platycodonis more has the up merit of medicine carrying, for assistant makes it product.All medicines share, but both relieving cough and resolving phlegm, the disease of eliminating littleization cough with copious phlegm, but reducing heat and dispersing lung-QI again, function falls in a surname who recovers lung, thus treating both the principal and secondary aspects of a disease reaches therapeutic effect.The present invention be the medium and small youngster's phlegm-resolving pill of prior art change the agent product, compared with prior art, the present invention have disintegration rate fast, absorb fast, instant effect, the advantage of child administration is controlled, is particularly suitable for to bioavailability height and dosage easily.

Be drug effect and the quality of verifying this product, the applicant has carried out relevant research, and its result of study is as follows:

Stability test:

One, accelerated stability test: three batch samples of this product were placed 3 months under the accelerated stability test condition, and every index and 0 month detection data are relatively investigated its sample stability.The result shows that at duration of test, the character of sample, discriminating, assay, microbial limit are all up to specification.The result of the test of 3 batch samples sees Table 1, table 2 and table 3.

The table 1 children's accelerated stability test result () that looses of reducing phlegm

The table 2 children's accelerated stability test result (two) that looses of reducing phlegm

The investigation project	0 month	January	February	March	Conclusion
						Character	This product is a brown yellow granule shape powder; Gas perfume (or spice), it is little sweet to distinguish the flavor of.	This product is a brown yellow granule shape powder; Gas perfume (or spice), it is little sweet to distinguish the flavor of	This product is a brown yellow granule shape powder; Gas perfume (or spice), it is little sweet to distinguish the flavor of	This product is a brown yellow granule shape powder; Gas perfume (or spice), it is little sweet to distinguish the flavor of	Up to specification
Differentiate (1)	Up to specification	Up to specification	Up to specification	Up to specification	Up to specification
						Differentiate (2)	Up to specification	Up to specification	Up to specification	Up to specification	Up to specification
Differentiate (3)	Up to specification	Up to specification	Up to specification	Up to specification	Up to specification
						Assay: every 1g contains Pericarpium Citri Reticulatae with Hesperidin (C 28H 34O 15) meter, must not be less than 2.5mg	3.7	3.7	3.7	3.6	Up to specification
Content uniformity	Up to specification	Up to specification	Up to specification	Up to specification	Up to specification
						Moisture	2.3%	2.5%	2.7%	2.6%	Up to specification
Total number of bacteria	200/g	250/g	250/g	350/g	Up to specification
						Total number of molds	＜10/g	＜10/g	＜10/g	＜10/g	Up to specification
Escherichia coli	Do not detect	Do not detect	Do not detect	Do not detect	Up to specification
						Demodicid mite lives	Do not detect	Do not detect	Do not detect	Do not detect	Up to specification

The table 3 children's accelerated stability test result (three) that looses of reducing phlegm

Two, long-term stable experiment:

With the detection that the many batches of samples that keep sample are are newly revised and enlarged quality standard, it the results are shown in Table 4.

Table 4 test result of samples that keeps sample

Sample	Sample 1	Sample 2	Sample 3	Sample 4	Sample 5	Sample 6
							Microscopical identification	Up to specification	Up to specification	Up to specification	Up to specification	Up to specification	Up to specification
The Herba Menthae thin layer is differentiated	Up to specification	Up to specification	Up to specification	Up to specification	Up to specification	Up to specification
							Content of hesperidin (mg/g)	3.5	2.9	3.6	3.8	4.1	3.2

As shown in Table 4: the sample that keeps sample detects by the quality standard project of newly revising and enlarging, and is all up to specification, illustrates that the quality standard of newly revising and enlarging is feasible.

The pharmacodynamics test of this product:

Purpose: observe this product antitussive, eliminate the phlegm, the effect of enhancing immunity.

Method: adopt mice ammonia to draw the method for coughing, the phenol red excretion method of mice is to mouse immune organ and leukocytic effect.

Conclusion: can suppress the mouse cough that ammonia causes, have antitussive action; Can strengthen mice to phenol red excretion, have phlegm-dispelling functions; Can make the immune organ weightening finish, leukocyte is obviously raise, showing has certain immunological enhancement.

1, test material:

1.1 medicine and reagent: this product children's is made in 0.5%CMC-Na and contains 0.3g/ml, 0.15g/ml, 0.08g/ml (content is with the crude drug amount) at reduce phlegm time spent of loosing; Ammonium chloride: lot number 20000301, chemical reagent work of Juhua Group Co. produces, and the time spent is made into 3.33% solution with distilled water; Phenol red: east, Wenzhou City, Zhejiang Province rises chemical reagent factory and produces lot number 990112; Ammonia: chemical reagent work of bottle kiln medication chemistry factory produces lot number 970309; Carbetapentane citrate: Dandong Parmaceutical Factory produces, lot number 991085, and the time spent is made into the solution of 2.0mg/ml with distilled water.

1.2 animal: the ICR mice, body weight 18-22g is provided by Zhejiang Province's Experimental Animal Center, the quality certification number: No. the (1996) 001, the real moving accurate word in Zhejiang.

1.3 instrument: 721 type spectrophotometers: Shanghai the 3rd analytical tool factory produces.

2, test method and result:

2.1 this product children's reduces phlegm to loose mice ammonia is drawn the influence of coughing: get 50 of mices, male and female half and half, body weight 18-22g is divided into 5 groups at random, carbetapentane citrate 50mg/kg group; Children's's three dosage groups (12,6,3g/kg) of loosing of reducing phlegm; Matched group, 0 05%CMC-Na 25ml/kg (down together).Each organizes equal gastric infusion, and the filling body of stomach is long-pending to be 0.25ml/10g, continuous 7 days.After the last administration 1 hour, be placed in the bell glass of the about 1.3L of inverted volume, in put a cotton balls, draw ammonia 0.3ml with the 1ml syringe, inject cotton balls, put into cover rapidly, and pick up counting, observe and write down the cough latent period and the number of times of coughing in 3 minutes of mice, the results are shown in Table 5.

Table 5 children's is reduced phlegm and is loose to ammonia induced mice cough latent period and the influence (x ± S n=10) of cough number of times in 3 minutes

Group	Dosage	Cough latent period (S)	The number of times (inferior) of coughing in 3 minutes
				Contrast	-	73±16.2	28.5±9.7
Carbetapentane citrate	50mg/kg	125.4±35.0**	18.4±7.4**
				Children's is reduced phlegm diffusing	1.9g/kg	78.6±17.5	27.4±9.2
Children's is reduced phlegm diffusing	3.8g/kg	84.5±33.2*	18.9±8.1*
				Children's is reduced phlegm diffusing	7.5g/kg	104.2±33.8**	17.4±6.9**

Annotate: compare * P＜0.05 with matched group, * * P＜0.01 (down together)

But children's's 7.5g/kg, 3.8g/kg group significant prolongation ammonia induced mice cough latent period of loosing of reducing phlegm as a result, and significantly reduce the mice number of times of coughing in 3 minutes.

The diffusing influence 2.2 children's is reduced phlegm to the phenol red excretion amount of mice:

The foundation of phenol red standard curve: take by weighing phenol red 100mg, be dissolved among the 100ml0.1mol/LNa0 H, make into 1mg/ml concentration, diluting successively with distilled water is 20,10,5,3,1,0.5 and 0.1 μ g/ml, in wavelength 546nm place colorimetric, its regression equation is Y=1.027 * 10 in 721 type spectrophotometers ^-3+ 0.0748X (Y=0.9994).

Animal grouping and medication are tested with antitussive, and ammonium chloride dosage is for irritating stomach 1.0g/kg.Each treated animal after last 1 administration 30 minutes, lumbar injection 5% phenol red normal saline solution 500mg/kg, after 30 minutes mice is put to death, separate trachea, cut the one section trachea (trachea equal in length between group) to the trachea bifurcation from thyroid cartilage, put into the beaker that fills the 2ml normal saline, with vortex mixer vibration 10 minutes, solution is sucked in vitro, add 0.1ml, 1mol/LNa0H solution, make towards Xian's liquid to be alkalescence, in wavelength 546nm colorimetric, according to phenol red standard curve, convert out phenol red amount, the results are shown in Table 6.

Table 6 children's the influence (x ± s n=10) of loosing of reducing phlegm to the phenol red excretion amount of mice trachea section

Group	Dosage	The phenol red excretion amount of trachea (μ g/ml)
			Contrast	-	0.91±0.33
Carbetapentane citrate	1.0g/kg	2.33±1.18**
			Children's is reduced phlegm diffusing	1.9g/kg	1.06±0.31
Children's is reduced phlegm diffusing	3.8g/kg	1.40±0.59*
			Children's is reduced phlegm diffusing	7.5g/kg	2.31±0.33**

By table 6 as seen, reduce phlegm 7.5g/kg, the 3.8g/kg group of loosing of this product children's can significantly increase the phenol red excretion amount of trachea.

2.3 the effect to immune organ: 50 of mices, body weight 15.18g divides matched group, children's the high, medium and low dosage group of loosing of reducing phlegm.Matched group, children's are reduced phlegm and are loose high, medium and low dosage group, dosage with 2.1, administration time 10d, and each is organized after the last administration the 2nd day and puts to death mice, collects blood, gets spleen, thymus, surveys leukocyte, the results are shown in Table 7.

Table 7 children's reduce phlegm loose to immune organ and leukocytic influence (x ± s, n=10)

Group	Dosage (g/kg)	WBC(× 10 9S/L)	Index and spleen index (mg/10g)	Thymus index (mg/10g)
					Contrast	-	5.86±0.88	51.7±3.3	19.0±3.8
Children's is reduced phlegm diffusing	7.5	7.61±1.13*	61.3±4.8*	29.3±4.2**
					Children's is reduced phlegm diffusing	3.8	7.12±1.23*	56.2±2.7*	28.2±6.4**
Children's is reduced phlegm diffusing	1.9	7.06±.11*	60.5±5.1*	23.8±3.2*

See by table 7, with matched group relatively: reduce phlegm diffusing high dose group, middle dosage group, low dosage, leukocyte count of children's significantly increases (p＜0.05); Children's reduce phlegm diffusing high dose group, there were significant differences (p＜0.05) for middle dosage group index and spleen index; Reduce phlegm diffusing high dose group, middle dosage group thymus index of children's has highly significant difference (p＜0.01), and children's is reduced phlegm and loose that there were significant differences (p＜0.05) for the low dose group thymus index.

3, conclusion: above pharmacodynamics test shows, the significant prolongation ammonia induced mice cough latent period of loosing but this product children's is reduced phlegm, and significantly reduce the mice number of times of coughing in 3 minutes, have certain antitussive effect; Can significantly increase the phenol red excretion amount of trachea, have certain phlegm-dispelling functions; Can significantly increase the weight of immune organ, leukocyte count is significantly increased, show the immunity that can strengthen mice.

This product children's's rat long term toxicity test that looses that reduces phlegm:

Make a summary: with the SD rat this product children's is reduced phlegm to loose and carry out long term toxicity test, divide 14g/kg, 7g/kg, 3.5g/kg and matched group, gastric infusion is 3 months continuously, continue after 1/3 drug withdrawal to observe for 3 weeks, observe through general situation, hematological indices, blood biochemical value index, gross anatomy and histopathology are observed.As a result, reduce phlegm loose high, medium and low dosage group and matched group of children's relatively do not have tangible toxicity, and both there was no significant differences illustrate that it is safe taking 3 months under above-mentioned dosage continuously.

1. test objective: observe giving children's continuously and reduce phlegm and loose because savings and to the toxic reaction and the order of severity that rat produces, provide the target organ of toxic reaction and the reversibility of infringement thereof is determined nontoxic amounts of reactants.

2. material:

2.1 be subjected to the reagent thing: this product children's reduce phlegm diffusing (every 1g is equivalent to crude drug 0.7g) standby with the liquid that 0.5%CMC-Na is made into 1.4g/ml, 0.7g/ml, 0.35g/ml.

2.2 instrument: Hitachi's 7060 type automatic clinical chemistry analyzers; Smart Scape 2000 type biology microscope analysis software, 18 cell counters of Celly H-318 three classification.

2.3 animal: 7 age in week 80 of SD rats,, body weight ♀ 88 ± 5g, ♂ 91 ± 4g, ♀ ♂ half and half, Zhejiang Province's Experimental Animal Center provides, the quality certification number: No. the (1996) 001, the real moving word in Zhejiang.

2.4 raising condition: the Laboratory Animal Facility condition quality certification number: the accurate word s96-040 of Zhejiang Laboratory Animal Facility condition number.

3. method and result:

3.1 grouping and dosage: 80 of SD rats, observation earlier adapted to for 1 week before the experiment, was divided into 4 groups at random by sex, body weight.Acute toxicity test in mice shows that this test sample toxicity is lower, can not survey LD ₅₀Maximum tolerated dose (MTD) 24.8g/kg (in the crude drug amount, down together), no dead mouse.Consider solution preparation situation and the clinical dosage of using of people, people's clinical dosage is 4.2g/ days, and we choose following dosage and test:

Heavy dose of group, 14g/kg by weighing machine (people is in 15kg, down together), is equivalent to 50 times of people's clinical dosage.In dosage group: 7g/kg, be equivalent to 25 times of people's clinical dosage.Small dose group, 3.5g/kg is equivalent to 12.5 times of people's clinical dosage.Matched group gavages isopyknic distilled water.

3.2 administration from date :-2000 on the 14th June in 2000, on JIUYUE 14,3 totally months.

3.3 method: behind the rat packet numbering, every morning is pressed the 1ml/100g gastric infusion 1 time, and gastric infusion is 3 months continuously.Observe (1) food-intake, behavior performance, feces character and other symptom, sign.Jede Woche is surveyed 1 body weight, and adjusts dose according to body weight change.(2) routine blood test: leukocyte (WBC), leukocyte differential count, erythrocyte (RBC), hemoglobin (HGB), packed cell volume (HCT), platelet (PLT), bleeding time, clotting time (3) blood biochemical: alanine aminotransferase (ALT-D), Aspartic Acid aminotransferase (AST-D), alkali phosphatase (ALP), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine (Cr), cholesterol (CH0), bilirubin (Tbil) (4) gross anatomy and histopathologic examination: last administration 24 hours, get 14 of rats (♀ ♂ half and half) anesthesia for every group, after getting carotid artery blood survey hematological indices and biochemical indexes, cut open the breast abdomen, each internal organs is carried out macroscopy, note exception, timely record, core then, liver, spleen, the lung kidney, brain, ovary, the uterus, testis, epididymis, thymus, the adrenal gland, precision is weighed, and calculating organ index [(organ weights (g) * 100/ body weight)], to the heart, liver, spleen, lung, kidney, brain, testis, epididymis, ovary, cutting into slices in the uterus, makes light microscopy checking.Measure routine blood test value, blood biochemical value 3 weeks again after the remaining rat drug withdrawal.

3.4 result:

3.4.1 general situation matched group and each dosage group are in whole each administration therebetween, outward appearance is normal, activity freely, the hair color light, stool is shaped, color and luster is normal, body weight growth there was no significant difference between each group, body weight change sees Table 8, table 9.

By table 8, table 9 as seen, respectively organized the prolongation of male and female rat along with test period in 3 months, body weight gain speed is approaching, there was no significant difference.

Table 8 children's reduce phlegm loose long term toxicity test rat (♀) body weight change (X ± S, n=10)

Cycle	Matched group (g)	Heavy dose of group (g)	Middle dosage group (g)	Small dose group (g)
					0	120±4	118±5	117±3	125±5
1	168±9	167±14	160±5	167±7
					2	195±10	201±18	184±7	208±6
3	212±14	212±20	199±6	204±11
					4	229±20	238±24	227±25	225±10
5	249±21	252±11	234±12	246±10
					6	264±20	261±10	246±11	264±10
7	273±20	268±14	251±7	271±15
					8	278±23	278±19	262±5	279±18
9	282±24	284±17	270±10	284±20
					10	291±26	292±18	277±9	283±21
11	297±25	302±28	282±9	289±20
					12	304±29	313±37	290±12	294±21
13	312±29	313±28	301±12	302±24

Table 9 children's reduce phlegm loose long term toxicity test rat (♂) body weight change (X ± S, n=10)

3.4.2 hematological examination: rat docking point is measured the blood time, capillary tube method is surveyed clotting time; Rat carotid artery is got blood, measures the routine blood test value, and administration the results are shown in Table 10 after 3 months, and drug withdrawal the results are shown in Table 11 after 3 weeks.

The conventional value of table 10 rat serum is checked (x ± s n=10)

Project	Matched group	Heavy dose of group	Middle dosage group	Small dose group
					WBC(10 9/L)	8.55±2.09	19.44±1.99	8.97±1.90	8.21±1.05
Lymph(％)	78.57±3.64	76.51±17.66	81.87±4.65	77.24±5.98
					Mid(％)	10.40±1.89	8.87±2.84	8.27±2.46	11.41±3.96
Gran(％)	11.03±2.68	9.90±3.71	10.71±3.62	9.86±3.14
					RBC(10 12/L)	4.96±0.69	6.07±1.23	5.89±1.35	5.26±1.02
HGB(g/l)	138.8±13.8	139.7±9.5	136.3±9.4	141.4±7.3
					HCT(％)	46.6±5.86	50.1±6.89	44.17±5.91	46.74±4.84
PLT(10 9/L)	907.6±185.3	878.0±179.2	808.9±196.1	901.7±152.1
					Bleeding time (min)	15.65±4.93	11.51±3.64	12.51±5.11	13.25±4.52
Clotting time (min)	4.55±3.45	3.68±2.25	4.12±1.65	4.35±3.25

Annotate: compare p＜0.05**p＜0.01 (down together) with matched group

The conventional value of 3 all rat serum is checked (x ± s n=6) after table 11 drug withdrawal

By table 10 as seen, the RBC number with the relatively more heavy dose of group of matched group has highly significant to increase.There is remarkable increase (P＜0.05) (P＜0.01), middle dosage group; Relatively heavy dose of group bleeding time obviously shortens (P＜0.05) with matched group; The every indexs in drug withdrawal 3 week back there are no significant difference.

Check 3.4.3 blood biochemical is learned: rat carotid artery is got blood, and is centrifugal, gets serum and does the inspection of blood biochemical value with Hitachi's 7060 type automatic clinical chemistry analyzers, the results are shown in Table 12, and drug withdrawal the results are shown in Table 13 after 3 weeks.

By table 12, table 13 as seen, compare with matched group: the alanine transaminase (ALT-D) of heavy dose of group, middle dosage group has significant difference (p＜0.05); Aspartic Acid aminotransferase (AST-D) has highly significant difference (P＜0.01); Alkali phosphatase (ALP) has highly significant difference p＜0.01); With matched group relatively heavy dose of group cholesterol (CH0) there were significant differences p＜0.05); The Aspartic Acid aminotransferase (AST-D) of the relatively more heavy dose of group of rat blood biochemical values and matched group, middle dosage group has highly significant difference (p＜0.01) after 3 weeks of drug withdrawal; There were significant differences (p＜0.05) with matched group relatively heavy dose of group alkali phosphatase (ALP); Other equal zero difference.

Table 12 rat blood biochemical analysis (x ± s n=10)

Project	Matched group	Heavy dose of group	Middle dosage group	Small dose group
					ALT-D(u/L)	40.2±8.9	31.8±7.0*	30.7±6.1*	36.0±8.5
AST-D(u/L)	259.2±48.6	196.0±30.4**	199.6±27.5**	266.3±44.4
					ALP(u/L)	47.4±13.3	75.6±20.6**	76.6±20.0**	58.0±19.9
BUN(mmol/L)	6.19±0.79	6.70±0.84	6.26±0.77	6.32±0.74
					Cr(umol/L)	60.0±2.8	61.0±3.8	61.2±4.8	57.9±3.4
CHO(umol/L)	1.46±0.21	1.20±0.21	1.32±0.21	1.33±0.29
					TP(g/L)	64.4±1.8	62.6±4.5	64.8±4.2	62.9±3.2
ALB(g/L)	29.4±2.0	27.9±2.3	29.4±3.0	28.1±1.7
					G(g/L)	35.1±2.5	34.8±2.6	35.6±2.3	35.0±2.6
Tbil(umol/L)	3.92±1.82	4.22±2.56	4.06±2.31	3.86±2.35

Rat blood biochemical analysis after 3 weeks of table 13 drug withdrawal (x ± s, n=6)

Project	Matched group	Heavy dose of group	Middle dosage group	Small dose group
					ALT-D(u/L)	41.2±7.5	38.7±5.6*	37.5±5.1*	40.3±3.9
AST-D(u/L)	289.2±46.6	218.0±38.4**	224.2±31.5**	266.5±47.8
					ALP(u/L)	49.5±12.4	68.9±17.3*	65.7±18.2	55.5±20.1
BUN(mmol/L)	6.28±0.66	6.56±0.78	6.68±0.69	6.55±0.59
					Cr(umol/L)	61.0±2.9	62.3±3.6	59.4±4.2	58.1±3.6
CHO(umol/L)	1.48±0.20	1.29±0.26	1.38±0.23	1.36±0.25
					TP(g/L)	63.5±2.6	61.8±4.3	62.4±3.6	64.2±3.7
ALB(g/L)	27.7±3.0	28.6±2.8	30.1±3.2	29.4±2.3
					G(g/L)	35.6±2.4	33.9±2.2	36.1±2.6	34.3±2.2
Tbil(umol/L)	3.65±2.12	3.72±1.86	3.86±2.44	3.56±2.15

Rats Organs and Tissues assessment of indices rat sacrificed by exsanguination is dissected immediately, wins main organs, takes by weighing the internal organs weight in wet base, obtains organ index, sees Table 14.

By table 14 as seen, female rats and matched group compare: male rat and matched group compare: the cardiac index of heavy dose of group has remarkable increase (p＜0.05), the liver index of heavy dose of group, middle dosage group has remarkable increase (p＜0.05), the index and spleen index of heavy dose of group, low dose group has remarkable increase (p＜0.01, p＜0.05, p＜0.01), adrenal gland's index of middle dosage group significantly increases (p＜0.05).

Table 14 rat (♀) organ index (g/100g) (X ± S n=7)

Project	Matched group	Heavy dose of group	Middle dosage group	Small dose group
					The heart	0.321±0.021	0.295±0.021*	0.309±0.027	0.336±0.022
Liver	2.786±0.164	3.058±0.214*	3.129±0.151*	2.760±0.119
					Spleen	0.162±0.036	0.207±0.028*	0.189±0.013	0.208±0.006*
Lung	0.481±0.028	0.508±0.082	0.470±0.031	0.440±0.043
					Kidney	0.651±0.030	0.758±0.046**	0.738±0.048*	0.760±0.042**
Brain	0.446±0.018	0.458±0.020	0.436±0.031	0.440±0.021
					Ovary	0.052±0.015	0.047±0.005	0.041±0.009	0.047±0.006
The uterus	0.182±0.031	0.222±0.048	0.174±0.041	0.186±0.020
					Thymus	0.105±0.046	0.088±0.033	0.101±0.041	0.080±0.028
The adrenal gland	0.021±0.004	0.023±0.002	0.029±0.003*	0.023±0.008

By table 15 as seen, male rat and matched group compare: the cardiac index of middle dosage group has remarkable increase (p＜0.05), the liver index of middle dosage group has remarkable increase (p＜0.01), the kidney index of heavy dose of group, middle dosage group, low dose group has remarkable increase (p＜0.05, p＜0.05, p＜0.05), heavy dose of group brain lot number has remarkable increase (p＜0.05).

Table 15 rat (♂) organ index (g/100g) (x ± S ll=7)

Project	Matched group	Heavy dose of group	Middle dosage group	Small dose group
					The heart	0.287±0.013	0.262±0.117	0.310±0.017*	0.291±0.025
Liver	2.692±0.240	2.936±0.209	3.144±0.257**	2.730±0.116
					Spleen	0.167±0.017	0.161±0.033	0.168±0.018	0.169±0.017
Lung	0.349±0.036	0.360±0.053	0.360±0.049	0.367±0.012
					Kidney	0.670±0.027	0.711±0.053*	0.737±0.066*	0.730±0.031*
Brain	0.432±0.025	0.462±0.019*	0.455±0.029	0.451±0.024
					Ovary	0.713±0.035	0.654±0.076	0.677±0.049	0.665±0.053
The uterus	0.243±0.015	0.226±0.031	0.242±0.022	0.251±0.022
					Thymus	0.105±0.046	0.088±0.033	0.101±0.041	0.080±0.028
The adrenal gland	0.018±0.003	0.020±0.003	0.020±0.001	0.017±0.001

3.4.5 the rat sacrificed by exsanguination is dissected immediately, wins main organs, makes pathologic finding under the mirror, the results are shown in Table 16.

Table 16 Rats Organs and Tissues pathomorphism is observed (n=10)

4. discuss and brief summary: this experimental result shows that after 3 months, movable from start to finish normal behind three dosage oral administrations of rat, the end any symptom occurs with dead.Body weight gain and matched group be there was no significant difference relatively.

The inspection of routine blood test value is found: have highly significant to increase (p＜0.01) with the RBC number of the bigger group of matched group amount group, middle dosage group has remarkable increase (p＜0.05); Compare heavy dose of group bleeding time with matched group and obviously shorten (p＜0.05); The every indexs in drug withdrawal 3 week back there are no significant difference.

The inspection of blood biochemical value is found: alanine transaminase (ALT-D) dominance difference (p＜0.01) the Aspartic Acid aminotransferase (AST-D) of heavy dose of group, middle dosage group has highly significant difference (p＜0.01); Alkali phosphatase (ALP) has highly significant difference (p＜0.01); There were significant differences (p＜0.05) with matched group relatively heavy dose of group cholesterol (CHO); The Aspartic Acid aminotransferase (AST-D) of the relatively more heavy dose of group of rat blood biochemical values and matched group, middle dosage group has highly significant difference (p＜0.01) after 3 weeks of drug withdrawal; There were significant differences (p＜0.05) with matched group relatively heavy dose of group alkali phosphatase (ALP).

The organ index value shows: female rats and matched group compare: the cardiac index of heavy dose of group has remarkable increase (p＜0.05), the liver index of heavy dose of group, middle dosage group has the index and spleen index of the heavy dose of group of remarkable increase (p＜0.05), low dose group to have the kidney index of the heavy dose of group of remarkable increase (p＜0.05), middle dosage group, low dose group that remarkable increase (p＜0.01 is arranged, p＜0.05, p＜0.01), adrenal gland's index of middle dosage group significantly increases (p＜0.05).Male rat and matched group compare: the cardiac index of middle dosage group has remarkable increase (p＜0.05), the liver stolen goods index of middle dosage group has remarkable increase (p＜0.01), the kidney index of heavy dose of group, middle dosage group, low dose group has remarkable increase (P＜0.05, p＜0.05, p＜0.05), heavy dose of group brain lot number has remarkable increase (p＜0.05).

Pathologic finding is found: each organizes each internal organs of rat does not all have organic variation.

In sum, rat is to children's's successive administration 3 months of loosing that reduces phlegm, and each dosage group and matched group relatively do not have overt toxicity, are safe under above-mentioned dosage.

This product children's is reduced phlegm to loose and is treated the bronchitic clinical observation on the therapeutic effect of child:

Test site: First People's Hospital, Hangzhou, Zhejiang province city

One, physical data: select all Chinese medical discriminations that meets to belong to the expectorant heat syndrome that the diseases caused by exogenous pathogenic factor ailment said due to cold or exposure causes, Western medicine diagnose is acute bronchitis, asthmatic bronchitis child patient 148 examples, test group 113 examples wherein, wherein male 48 examples, woman's 65 examples, matched group 35 examples, male 15 examples, woman's 20 examples, through chi-square analysis, X ²=0.06, there was no significant difference (P＞0.05).The treatment group is the oldest to be 13 years old, and minimum is 3 years old, and the mean age is 7.27 ± 2.68; Matched group is the oldest to be 14 years old, and minimum is 3 years old, and the mean age is 7.23 ± 2.82, through t check, t=0.07, there was no significant difference (P＞0.05).Credit is analysed by statistics, and treatment group and matched group there are no significant at aspects such as age, sexes difference has comparability.

Two, test method:

1, diagnostic criteria: Western medicine diagnose standard: with reference to higher medical universities and colleges teaching material " pediatrics, clinically with cough, cough up phlegm, out of breath be the children acute bronchitis of cardinal symptom, the patient of asthmatic bronchitis.

Chinese medical discrimination standard: be the diseases caused by exogenous pathogenic factor heat-phlegm syndrome: cough is coughed up phlegm, and the expectorant character is pus, sticking pus or sticking turbid expectorant, often is difficult for expectoration, or the heating of holding concurrently, watery nasal discharge, pharyngalgia, red tongue, yellow fur, slippery and rapid pulse.Wherein, having vitals pathological changes such as other severe cardiac, liver, kidney to reach is foreclosed by the chronic cough due to the other factorses such as tuberculosis, fungus, the patient that pants.

2, symptom and sign are represented with the sxemiquantitative integration method, and primary symptom is asymptomatic to be 0 minute, slightly be that 2 minutes, moderate are that 4 minutes, severe are 6 minutes; Inferior disease is asymptomatic to be 0 minute, slightly be that 1 minute, moderate are that 2 minutes, severe are 3 minutes.Its weight grade scale sees Table 17.

Table 17 symptom and sign weight hierarchical table

Primary symptom	Do not have (0 minute)	Gently (2 minutes)	In (4 minutes)	Heavy (6 minutes)
					Cough	Do not have	Be interrupted cough daytime, do not influence orthobiosis	Symptom is between weight	Cough round the clock frequent or apasm of coughing influence rest and sleep
Cough up phlegm	Do not have	The amount of coughing up phlegm is few round the clock, or expectorant sound is arranged in the larynx	Symptom is between weight	The amount of coughing up phlegm is many round the clock, or expectorant is low voice speaking in the larynx
					Out of breath	Do not have	Idol has outbreak, and degree is light, does not influence sleep or movable	Symptom is between weight	Symptom is obvious, is persistence, can not put down for sleeping in, influence sleep or movable
Inferior disease	Do not have (0 minute)	Gently (1 minute)	In (2 minutes)	Heavy (3 minutes)
					Do moist rale	Do not have	Idol is heard	Be dispersed in	Be abound with
Wheezing sound	Do not have	Idol is heard, or occurs in cough, the back of deeply breathing	Be dispersed in	Be abound with
					Heating	Do not have	37.3-37.7℃	37.8-38.2℃	＞38.2℃
Pharyngalgia	Do not have	Feel pharyngalgia slightly	Pharyngalgia is obvious, does not swallow but do not influence	Pharyngalgia more very, influence is swallowed
					Watery nasal discharge	Do not have	The tears amount is few	The tears amount is more, and influence is breathed slightly	The tears amount is many, must handkerchief paper commonly used

Annotate: during above semiography, all with a minute value representation.

3, Therapeutic Method: treatment group: 113 examples, take this product children's reduce phlegm diffusing, each one bag (2g), 3 times on the 1st oral, 5 days is a course of treatment.Matched group: 35 examples, take XIAOER ZHIKE TANGJIANG, each 5.10ml, every day 3.4 times is oral, and 5 days is a course of treatment.Stop using during taking other cough-relieving, the class medicine reduces phlegm, relievings asthma.

4, health giving quality index: 1. symptom: the degree and the persistent period of the weight of coughing, cough up phlegm, pant; 2. sign: body temperature, cardiopulmonary sign, rale, wheezing sound etc.;

5, curative effect determinate standard: (1) bronchitis efficacy determination: clinic control: clinical symptoms and sign disappear substantially, and integration descends 〉=90%; Produce effects: clinical symptoms and sign significantly alleviate, and integration descends 〉=60%; Effectively: clinical symptoms and sign slightly alleviate, and integration descends 〉=30%; Invalid: clinical symptoms and sign do not take a turn for the better, and integration descends not as good as 30%.(2) cough, expectorant, individual event symptom efficacy determination out of breath: clinic control: cough, cough up phlegm, symptom out of breath disappears substantially; Produce effects: cough, cough up phlegm, symptom out of breath is clearly better, and is light by heavy one; Effectively: cough, cough up phlegm, symptom out of breath take a favorable turn, by heavily in or by in to light; Invalid: as to cough, cough up phlegm, symptom out of breath do not take a turn for the better, or increase the weight of.

Three, result:

1, treatment group efficacy result: 113 routine patients are clinic control 14 examples (12.39%) after treating, produce effects 29 examples (25.66%), and effective 64 examples (56.63%), invalid 6 examples (5.31%), it is 38.05% that control shows rate, total effective rate is 94.69%.The total mark difference is 10.36+3.28 before and after the treatment, and through the t check, t=32.9 has utmost point significant difference (P＜0.01).

Wherein, individual event symptom curative effect is: cough symptom, clinic control 48 examples, produce effects 23 examples, effective 32 examples, invalid 10 examples: the symptom of coughing up phlegm, clinic control 55 examples, produce effects 3 examples, effective 35 examples, invalid 14 examples; Symptom out of breath, clinic control 75 examples, produce effects 2 examples, effective 19 examples, invalid 17 examples.

2, matched group efficacy result: 35 routine patients are clinic control 5 examples (14.29%) after treating, produce effects 11 examples (31.43%), and effective 15 examples (42.86%), invalid 4 examples (11.42%), it is 45.71% that control shows rate, total effective rate is 88.57%.Front and back treatment total mark difference is 9.06 ± 3.19, and through the t check, t=16.8 has utmost point significant difference (P＜0.01).

3, two groups of curative effects relatively: total mark is 15.4 ± 2.7 before the treatment of treatment group, and treatment back integration is 5.24 ± 2.99; Total mark is 14.83 ± 3.31 before the treatment of control group, and treatment back integration is 5.77 ± 4.36; The result shows: through t check, t ₁=1.03, t ₂=0.82, integration relatively there are no significant difference (P＞0.05) before and after treatment group and the treatment of control group; Two groups general curative effect is suitable substantially.

Treatment group clinic control 4 examples, produce effects 29 examples, effective 64 examples, invalid 6 examples; Matched group clinic control 5 examples, produce effects 11 examples, effective 15 examples, invalid 4 examples.Both check through Ridit, U=0.28, and there was no significant difference (P＞0.05) is analysed in credit by statistics

4, during the treatment, treatment group and matched group are not all found untoward reaction.

Four, discuss: the traditional Chinese medical science is thought, the infantile cough abundant expectoration is the flu ailment said due to cold or exposure, and impairment of dispersing and descending function of the lung causes the heap soil or fertilizer over and around the roots of fever of the body expectorant, and it is out of breath to cough.Children's is reduced phlegm to loose and is made up of kinds of traditional Chinese medicines such as Concretio Silicea Bambusae, Bulbus Fritillariae Cirrhosae, Radix Platycodonis, the Rhizoma Pinelliae, Herba Menthaes, adopts dispelling wind and heat pathogens such as Herba Menthae, Fructus Citri tangerinae be awake, and expelling phlegm for arresting cough such as Bulbus Fritillariae Cirrhosae, the Rhizoma Pinelliae, Concretio Silicea Bambusae reach therapeutic effect.Clinical test results shows: the total mark difference is 10.36 ± 3.28 before and after the treatment of treatment group, and through the t check, t=32.9 has utmost point significant difference (P＜0.01).Clinic control 14 examples (12.39%), produce effects 29 examples (25.66%), effective 64 examples (56.63%), invalid 6 examples (5.31%), it is 38.05% that control shows rate, total effective rate is 94.69%.Compare with the matched group curative effect, through the Ridit check, U=0.28, there was no significant difference (P＞0.05) is analysed in credit by statistics.Two groups of therapeutic equivalences are described.Individual event symptom curative effect shows: cough symptom, clinic control 71 examples; The symptom of coughing up phlegm, clinic control 58 examples; Symptom out of breath, clinic control 77 examples.Illustrating that this product children's is reduced phlegm is dispersed in cough, excessive phlegm, aspect out of breath and has excellent curative.During treating, two groups of patients all do not find untoward reaction.

Five, conclusion: this product children's reduce phlegm be dispersed in the treatment Chinese medical discrimination belong to the expectorant heat syndrome that the diseases caused by exogenous pathogenic factor ailment said due to cold or exposure causes, Western medicine diagnose is that the child patient of acute bronchitis, asthmatic bronchitis has curative effect preferably, and is clinical safe in utilization, effective.

This product children's's determining of day labor technology index that reduce phlegm:

Reducing phlegm diffusing because of this product children's is powder, and the equal un-extracted of all medical materials, pulverizing medicinal materials directly feed intake after becoming fine powder, so the investigation project has only been selected the index of baking temperature as control moisture content.Granule after making is put into baking oven, after spending the night, survey its moisture content.It the results are shown in Table 18.

Table 18 baking temperature is to the influence of moisture content

Sequence number	Temperature (℃)	Moisture content (%)
			I	50-60	7.0
II	60-70	3.5
			III	70-80	2.5
IV	80-90	2.5

By table 18 as seen, after III, IV scheme were carried out drying, finished product moisture content was suitable substantially, considers factors such as production cost, so select the III scheme, promptly baking temperature is 70-80 ℃.

The specific embodiment:

Embodiments of the invention 1: take by weighing Concretio Silicea Bambusae 110g, Rhizoma Arisaematis (processed) 44g, Radix Platycodonis 67g, Rhizoma Acori Graminei 22g, Radix Trichosanthis 67g, Bombyx Batryticatus (parched) 89g, Herba Menthae 33g, Pericarpium Citri Reticulatae 67g, Bulbus Fritillariae Cirrhosae 89g, Rhizoma Gastrodiae 33g and Rhizoma Pinelliae Preparata 67g, above-mentioned medical material is dried by the fire 2 hours down to water content＜5.0% at 55 ℃ and 75 ℃ respectively, pulverize, cross 120 mesh sieves, standby; Take by weighing cane sugar powder 312g, be ground into 120 order powder, the medical material of above-mentioned pulverizing and cane sugar powder were mixed 30 minutes, add 95% alcohol granulation then, dry under 70～80 ℃ of conditions, granulate, pack is made 500 bags, every bag of 2g, promptly.This product is orange-yellow graininess powder, gas perfume (or spice), and it is little sweet to distinguish the flavor of.Boiled water clothes or swallow, below 1 years old, a 1g, 2 times on the one.1-3 year, a 1g, 3 times on the one; More than 3 years old, a 2g, 3 times on the one.

Embodiments of the invention 2: take by weighing Concretio Silicea Bambusae 110g, Rhizoma Arisaematis (processed) 44g, Radix Platycodonis 67g, Rhizoma Acori Graminei 22g, Radix Trichosanthis 67g, Bombyx Batryticatus (parched) 89g, Herba Menthae 33g, Pericarpium Citri Reticulatae 67g, Bulbus Fritillariae Cirrhosae 89g, Rhizoma Gastrodiae 33g and Rhizoma Pinelliae Preparata 67g, dry by the fire 1 hour down to water content＜6.0% at 50 ℃ and 70 ℃ respectively, pulverize, cross 100 mesh sieves, mixed 20 minutes, standby; Take by weighing sucrose 312g, be ground into 100 order powder, the medical material of above-mentioned pulverizing and cane sugar powder were mixed 20 minutes, add 95% alcohol granulation then, dry under 70～80 ℃ of conditions, granulate, pack, promptly.

Embodiments of the invention 3: take by weighing Concretio Silicea Bambusae 110g, Rhizoma Arisaematis (processed) 44g, Radix Platycodonis 67g, Rhizoma Acori Graminei 22g, Radix Trichosanthis 67g, Bombyx Batryticatus (parched) 89g, Herba Menthae 33g, Pericarpium Citri Reticulatae 67g, Bulbus Fritillariae Cirrhosae 89g, Rhizoma Gastrodiae 33g and Rhizoma Pinelliae Preparata 67g, dry by the fire 3 hours down to water content＜4.0% at 60 ℃ and 80 ℃ respectively, pulverize, cross 140 mesh sieves, mixed 40 minutes, standby; Take by weighing sucrose 312g, be ground into 140 order powder, the medical material of above-mentioned pulverizing and cane sugar powder were mixed 40 minutes, add 95% alcohol granulation then, dry under 70～80 ℃ of conditions, granulate, pack, promptly.

Embodiments of the invention 4: take by weighing Concretio Silicea Bambusae 110g, Rhizoma Arisaematis (processed) 44g, Radix Platycodonis 67g, Rhizoma Acori Graminei 22g, Radix Trichosanthis 67g, Bombyx Batryticatus (parched) 89g, Herba Menthae 33g, Pericarpium Citri Reticulatae 67g, Bulbus Fritillariae Cirrhosae 89g, Rhizoma Gastrodiae 33g and Rhizoma Pinelliae Preparata 67g, dry by the fire 2.5 hours down to water content＜5.0% at 52 ℃ and 75 ℃ respectively, pulverize, cross 130 mesh sieves, mixed 35 minutes, standby; Take by weighing sucrose, be ground into 130 order powder, the medical material of above-mentioned pulverizing and cane sugar powder were mixed 35 minutes, add 95% alcohol granulation then, dry under 70～80 ℃ of conditions, granulate, pack, promptly.

Claims (2)

1. one kind is used for children's's expectorant Chinese medicine preparation, and it is prepared into powder by Concretio Silicea Bambusae 110g, Rhizoma Arisaematis (processed) 44g, Radix Platycodonis 67g, Rhizoma Acori Graminei 22g, Radix Trichosanthis 67g, Bombyx Batryticatus (parched) 89g, Herba Menthae 33g, Pericarpium Citri Reticulatae 67g, Bulbus Fritillariae Cirrhosae 89g, Rhizoma Gastrodiae 33g and Rhizoma Pinelliae Preparata 67g and cane sugar powder 312g; It is characterized in that: take by weighing Concretio Silicea Bambusae, Rhizoma Arisaematis (processed), Radix Platycodonis, Rhizoma Acori Graminei, Radix Trichosanthis, Bombyx Batryticatus (parched), Herba Menthae, Pericarpium Citri Reticulatae, Bulbus Fritillariae Cirrhosae, Rhizoma Gastrodiae and Rhizoma Pinelliae Preparata, dry by the fire 1～3 hour down to water content＜4.0～6.0% at 50～60 ℃ and 70～80 ℃ respectively, pulverize, cross 100～140 mesh sieves, mixed 20～40 minutes, standby; Take by weighing sucrose, be ground into 100～140 order powder, the medical material of above-mentioned pulverizing and cane sugar powder were mixed 20～40 minutes, add 95% alcohol granulation then, dry under 70～80 ℃ of conditions, granulate, pack, promptly.

2. according to the described children's's expectorant Chinese medicine preparation that is used for of claim 1, it is characterized in that: take by weighing Concretio Silicea Bambusae 110g, Rhizoma Arisaematis (processed) 44g, Radix Platycodonis 67g, Rhizoma Acori Graminei 22g, Radix Trichosanthis 67g, Bombyx Batryticatus (parched) 89g, Herba Menthae 33g, Pericarpium Citri Reticulatae 67g, Bulbus Fritillariae Cirrhosae 89g, Rhizoma Gastrodiae 33g and Rhizoma Pinelliae Preparata 67g, above-mentioned medical material is dried by the fire 2 hours down to water content＜5.0% at 55 ℃ and 75 ℃ respectively, pulverize, cross 120 mesh sieves, standby; Take by weighing cane sugar powder 312g, be ground into 120 order powder, the medical material of above-mentioned pulverizing and cane sugar powder were mixed 30 minutes, add 95% alcohol granulation then, dry under 70～80 ℃ of conditions, granulate, pack is made 500 bags, promptly.