CN1145787A - Medicine for gastric diseases and its prepn - Google Patents

Abstract

The medicine is prepared with rhubarb and other five kinds of Chinese medicinal material including citron fruit, areca, curcuma zedoaria, etc. During prepn, rhubarb is ground and sieved to obtain rhubarb powder, other medicinal materials are decocted with water into paste, rhubarb powder and paste are mixed, and the mixture is produced into the medicine prepn through extrusion, drying at 60 deg.C and sieving with 20-40 mesh sieve. The medicine is mainly used in curing chronic gastritis, chronic cholecystitis, gastroneurosis, etc. with obvious curative effect.

Description

A kind of stomach medicine and preparation method thereof

The invention belongs to Chinese patent medicine, particularly treat the Chinese patent medicine and preparation method thereof of gastropathy.

Epigastric fullness is that the conscious gastral cavity abdomen of patient painful abdominal mass is vexed, distension, pain discomfort, and, heating installation indigestion and loss of appetite with lack of appetite, constipation or half congealed and not well etc. is the gastrointestinal tract illness of main clinical manifestation, belongs to multiple, common disease.This disease is common in multiple diseases such as the chronic gastritis, chronic cholecystitis, stomach neurosis of modern medicine, and the course of disease is long, easily outbreak repeatedly, the state of an illness, card marquis complexity, relatively refractory.

Before the present invention makes, put down in writing " Rhei Pill of leading a cow " of indivedual diseases in the treatment epigastric fullness in " special effect doctor state " of the Ming Dynasty, cure mainly interior-heat stomachache, steam upper punch and vomitting.Its prescription is: four liang of HEIQIANNIU, rice is fried half a lifetime, gets the head end, one or two 2 money.Todaiwo,rhizoma wine is fried, one or two 5 money.Semen Arecae, Fructus Aurantii Immaturus, Cortex Magnoliae Officinalis, rhizoma sparganic, each six money of Rhizoma Curcumae.

In Qing Dynasty's " collection of prescriptions with notes " (drawing Zhang Zihe side) " Muxiang Binlang Wan " arranged, it is stagnant to cure mainly the breast abdomen, feeling of fullness knot pain, constipation and anuresis, or the dysentery of having loose bowels, tenesmus, intermittent fever due to retention of food food stagnation.Rhizoma Curcumae vinegar boils, and rhizoma sparganic vinegar boils, and Rhizoma Coptidis Fructus Evodiae soup is fried, and Cortex Phellodendri wine is fried, and Fructus Aurantii, Pericarpium Citri Reticulatae go white, and Pericarpium Citri Reticulatae Viride vinegar is fried, Semen Arecae, each five money of the Radix Aucklandiae, Radix Et Rhizoma Rhei steeping in wine one or two, two liang of Rhizoma Cyperi, HEIQIANNIU, the Natrii Sulfas watered pill, amount people deficiency and excess clothes.

In the modern Chinese medicine, adopt the part or all of of above-mentioned ancient proved recipe, to be decocted in water for oral dose more; Or make powder, its dose is big, mouthfeel is poor, easily adhere to the oral cavity, inconvenience is swallowed.In the existing medical skill, the report of the Chinese patent medicine for the treatment of at epigastric fullness is not arranged specially.There is not this type of Chinese patent medicine to come out yet.

The objective of the invention is provides a kind of pure Chinese medicinal granule patients oral for the special treatment at epigastric fullness, its dose little (at every turn take contain only three grams of crude drug, day dosing is six grams only), and taking convenience has no side effect, and is evident in efficacy.

The objective of the invention is to realize by following proposal:

Stomach medicine of the present invention is the Chinese patent medicine of granular preparation, and its prescription consists of: Radix Et Rhizoma Rhei powder 3.0g, Fructus Aurantii Immaturus 0.93g, Semen Arecae 0.69g, rhizoma sparganic 0.46g, Rhizoma Curcumae 0.46g, Semen Lepidii (Semen Descurainiae) 0.46g.The granule of (this amount is clothes dosage on the one, divides secondary to take) this medicine is mixed and made into the clear paste that water boiling concentration forms by the Radix Et Rhizoma Rhei powder that takes by weighing by above-mentioned weight ratio and all the other five kinds of Chinese medicine.

Its concrete operations are:

1. get the raw materials ready: select for use do not have to go rotten, free from insect pests, unmetamorphosed dry Radix Et Rhizoma Rhei, Fructus Aurantii Immaturus, Semen Arecae, rhizoma sparganic, Rhizoma Curcumae, Semen Lepidii (Semen Descurainiae), Radix Et Rhizoma Rhei mechanical lapping is become powder, sieved with No. six, it is standby to stay the fine powder that sieves (be no less than sieve preceding 95%);

The batching: by following weight ratio take by weighing above-mentioned Six-element Chinese medicine get the raw materials ready stand-by, Radix Et Rhizoma Rhei powder: Fructus Aurantii Immaturus: Semen Arecae: rhizoma sparganic: Rhizoma Curcumae: Semen Lepidii (Semen Descurainiae)=3.00: 0.93: 0.69: 0.46: 0.46: 0.46;

3. boil medicine: with above-mentioned except that Radix Et Rhizoma Rhei powder and Chinese medicine of the five flavours, that is: Fructus Aurantii Immaturus, Semen Arecae, rhizoma sparganic, Rhizoma Curcumae, Semen Lepidii (Semen Descurainiae), be blended together, add the water that is equivalent to 14 times of amounts of this Chinese medicine of the five flavours gross weight, conventional decocting Chinese medicine 30 minutes, filter cloth filters, and keeps filtrate, filtering residue is again by this method decocting, and so decocting is three times; Abandon filtering residue, it is stand-by to merge three filtrates (medicine soup);

4. system cream: centrifugal 15 minutes of speed with above-mentioned filtrate is changeed (rpm) with per minute 3000 on centrifuge discards precipitation.Then supernatant is carried out conventional concentrating under reduced pressure, when the milliliter number that is concentrated liquid is equivalent to 0.7 times of used Radix Et Rhizoma Rhei powder gram number, stop concentrating under reduced pressure, make their relation meet following equation: concentrated solution milliliter number: Radix Et Rhizoma Rhei gram number=0.7: 1.This concentrated solution is clear paste.Measure in 60 ℃ of temperature, the relative density of this clear paste should be 1.02-1.04.

5. granulating: above-mentioned Radix Et Rhizoma Rhei powder and clear paste are in Radix Et Rhizoma Rhei powder (g): the ratio of clear paste (ml)=0.7: 1 is its uniform mixing, conventional extruding granulating, and 60 ℃ of dryings are crossed the 20-40 mesh sieve with dried medicine grain, and the medicine particle packing check after sieving is finished product.

Description of drawings:

Fig. 1: stomach medicine preparation technology flow chart of the present invention.

In the present invention:

Rheum officinale: bitter, cold. Purgating fu-organs to eliminate heat effect under stronger the rushing down is arranged, be treatment constipation with heat retention or half congealed and not well key medicine. " medicine justice " calls its " specialize in the heart (stomach) distention and fullness in the abdomen, the accumulation of heat of chest stomach is gathered phlegm in fact, the constipation hemostasis ", very is. The fire that again can hardship falls inflammation is alonely compeled the UGB of the absurd row of blood for the treated powder heat symptoms caused by an exopathgen, and good therapeutic effect is arranged.

The rheum officinale master contains anthraquinone derivative, a part is free state, such as Rhein, Chrysophanol, archen, aloe-emodin, Physcion, major part is bonding state, such as Rhein-8-glycoside, Physcion glycoside, aloe-emodin monoglucoside, chrysophanol monoglucoside and Sennoside A, B, C, E, F etc. Contain again rhatannin, aliphatic acid, calcium oxalate, glucose, fructose and much starch.

Active ingredient under rheum officinale rushes down is the anthracene glucoside, mainly is Sennosides, uses the position mainly at large intestine, can increase enterocinesia, suppresses moisture absorption in the intestines, promotes defecation; Rheum officinale has anti-infectious function, and multiple Gram-positive and negative bacteria are all had inhibitory action, and wherein the most responsive is staphylococcus and streptococcus, is corynebacterium diphtheriae, Typhoid and paratyphoid bacillus, Diplococcus pneumopniae, shigella dysenteriae etc. secondly; Infected by influenza also has inhibitory action; Because due to the tannin, so the constipation phenomenon is arranged again after rushing down; Stomach invigorating and choleretic effect are arranged; In addition, stop blooding in addition, protect the liver, the effect such as step-down, serum cholesterol-lowering.

The dried immature fruit of citron orange: bitter, hot, be slightly cold. Can relieving stagnant Qi except ruffian, reduce phlegm that it is long-pending to disappear, be used for the treatment of dyspepsia, phlegm stagnates. The stomach and intestine thermojunction stagnation of the circulation of vital energy, and see the cards such as feeling of oppression and fullness in the chest and epigastrium distending pain, good therapeutic effect is all arranged. Modern dilatation of the stomach, the gastroptosis etc. of being used for also have certain curative effect. " not Lu " calls it can " except chest side of body phlegm addiction, by ceasing fire, broken solid, dissipate-swelling be full, epigastric oppression ruffian pain, contrary gas, side of body wind pain, the peace stomach Qi is ended loose stool " etc., and is rather definite.

The dried immature fruit of citron orange (bitter orange) pericarp contains volatile oil (90% is d-limonen, a small amount of citral, dextrorotation linalool etc.), glycosides displayed (being mainly hesperidine, neohesperidin, naringin, rhoifolin and winter glucoside etc.), N-methyltyramine, oxedrine etc.

The dried immature fruit of citron orange can be alleviated the little enterospasm due to acetylcholine or the barium chloride. The dog that gastric fistula, intestinal fistula are arranged is gavaged dried immature fruit of citron orange decocting liquid, and can make stomach and intestine shrink the rhythm and pace of moving things increases; Decoction to pregnant, unpregnancy rabbit exsomatize, uterus in place all is excitation. The intravenous injection of decoction tincture has cardiotonic to the animal isolated heart. Dried immature fruit of citron orange parenteral solution vein is annotated body can increase coronary artery, brain, renal blood flow, reduces brain, renal vascular resistance. The dried immature fruit of citron orange can make gallbladder contraction, and Oddi's sphincter tension force increases, and stronger antiallergic activity is arranged, and suppresses in addition thrombotic effect.

Betel nut: bitter, hot, temperature. Can promoting the circulation of qi, long-pending, the Li Shui of disappearing, expelling parasite. We's usefulness is mainly got its promoting the circulation of qi, the long-pending merit that disappears, to control the diseases such as stagnation of QI due to dyspepsia, abdominal distention constipation. Certainly, because the full distending pain person of gastral cavity abdomen ruffian is seen in malnutrition due to parasitic infestation, also very effective.

Betel nut contains arecaline, arecaidine, guvacolines, and reaches condensed tannin, fat oil, areca red, starch, resin etc.

Arecoline is killed effect to armed tapeworm, teniarhynchosis, pinworm, ascarid, ancylostome, whipworm, fasciloopsis etc., and bilharzial infection is had certain preventive effect; The choline effect of pressing down is arranged, and excited cholinoceptor promotes saliva, and sweat gland secretion increases enterokinesia, and decreased heart rate brings high blood pressure down, and eye drip can make contracted pupil.

Rhizoma Curcumae: bitter, hot, warm.The circulation of qi promoting of energy removing blood stasis, the removing food stagnancy pain relieving.Normal and rhizoma sparganic mutual reinforcement between is a usefulness, the lump in the abdomen of treatment qi depression to blood stasis, trusted subordinate's stasis of blood pain, and food stagnation abdominal distention.Modern times are used for multiple cancer kinds such as cervical cancer, and effect is in various degree all arranged." Bencao Tujing " said: " the present doctor family controls and gathers the medicine of all gas for wanting most.Good with cyperus iria L. rhizoma scirpi with using.”

Rhizoma Curcumae contains volatile oil, is mainly in the oil that curzerenone, Rhizoma Curcumae are rare, curcumin etc.In recent years from oil, isolate anticancer active ingredient curcumenol, curdione again.Antitumaous effect is arranged, except that direct effect, also can make the host hold different in nature immunologic function and strengthen and obtain tangible immunoprotection effect; Curcumin can suppress platelet to be built up, have anti-thrombosis function, can excited gastrointestinal smooth muscle to digestive tract; Curcumenol and hemiterpene chemical compound thereof have significant antiearly pregnancy effect; Volatile oil can suppress staphylococcus aureus, beta hemolytic streptococcus, escherichia coli, Bacillus typhi, vibrio cholera etc.

Rhizoma sparganic: bitter, hot, flat.The circulation of qi promoting of energy removing blood stasis, the removing food stagnancy pain relieving.Be usefulness directly mutually often with Rhizoma Curcumae, cards such as the lump in the abdomen of treatment qi depression to blood stasis and food stagnation abdominal distention.Wang Haogu is said: " rhizoma sparganic, Rhizoma Curcumae are controlled the long-pending hard person of piece skin ulcer, be hard masses should be resolved gradually also." rhizoma sparganic contains the volatilization wet goods, by reducing platelet count, suppresses platelet function, suppresses inside and outside coagulation function, promotes fibrinolytic etc., and thrombus in vivo is formed with inhibitory action.Decoct can be strengthened shrinking to the isolated rabbit intestinal, and tonicity raises.

Semen Lepidii (Semen Descurainiae): bitter, hot, Great Cold.Function eliminating the pathogens from the lung inducing diuresis to remove edema.Diseases caused by retention of fluid and expectorant water in the special eliminating the pathogens from the lung, and smelting breast abdomen phlegm retention belongs to the damp and hot resistance person of accumulateing.In addition, modern single with grinding not clothes, the sick heart failure of treatment pulmonary heart disease is seen generalized edema with distention of the chest and abdomen dyspnea with rapid respiration person, and certain curative effect is arranged.Shennong's Herbal is called it: " main abdominal mass is gathered stagnation of QI, and the diet cold and heat are broken hard by evil, the tonneau water channel " truly has its effect.

Semen Lepidii (Semen Descurainiae) has the branch of southern Semen Lepidii (mature seed of Lepidium sativum L.) and northern Semen Lepidii (mature seed of descurainia sophia (l.) webb ex prantl).Lepidii,semen contains material, sinigrin, fatty oil, protein, saccharide of cardiotonic etc.; Semen Descurainiae contains volatile oil (containing isothiocyanic acid benzyl fat, the rare propyl ester of isothiocyanic acid etc. in the oil), fatty oil, cardiotonic glycoside (one name alleoside A) etc.Two kinds of Semen Lepidii (Semen Descurainiae) alcohol extracts all have cardiotonic, can make myocardial contraction strengthen decreased heart rate.Can increase output to weak heart, reduce venous pressure.Diuresis is still arranged.

The present invention is made up of above-mentioned Radix Et Rhizoma Rhei, Fructus Aurantii Immaturus, Semen Arecae, rhizoma sparganic, Rhizoma Curcumae, Semen Lepidii (Semen Descurainiae) Six-element medicine.Radix Et Rhizoma Rhei bitter cold in the side, consumption reach full side half, the function stomach function regulating that expels the heat-evil, and the removing blood stasis purging FU-organs, stasis removing makes stagnant pathogenic heat, qi and blood stagnation and the gastral cavity abdomen feeling of fullness distending pain that therefore causes, belching and acid regurgitation, all diseases of constipation are alleviated or are eliminated, and are to be monarch drug.The Fructus Aurantii Immaturus toil is slightly cold, and the function circulation of qi promoting removes painful abdominal mass, and promoting digestion and removing stagnation closes monarch drug and forms and hold gas half, to strengthen the power of relieving distension and oppression; The arduous temperature of Semen Arecae, association's monarch drug and QI and blood is taken into account, the expectorant food is also controlled, and becomes the cathartic purging FU-organs altogether, eliminates stagnant merit; Be ministerial drug altogether.Rhizoma sparganic, Rhizoma Curcumae, mutual reinforcement between are usefulness, function circulation of qi promoting removing food stagnancy, and blood stasis-eliminating and stagnation-dissipating, it is kind that to control blood stasis depressed, and diseases such as the feeling of fullness distending pain due to diet gathers have the meaning of " hard masses should be resolved gradually "; Semen Lepidii (Semen Descurainiae) can eliminating the pathogens from the lung closing of gas and row phlegm retention, waterway helps monarch, ministerial drug to divide the removing food stagnancy pathogenic heat that stagnate, with except that distension; Be adjuvant drug altogether.All medicines share, the stomach function regulating that becomes to expel the heat-evil altogether, and the circulation of qi promoting purging FU-organs, blood stasis dispelling is loose long-pending, the merit during the painful abdominal mass that disappears is smooth.Through long-term clinical observation, use because of the long-pending heat of gastrointestinal, the epigastric fullness due to the qi and blood stagnation really belongs to effective side.

In the present invention, Radix Et Rhizoma Rhei is a monarch drug, and gives birth to usefulness, and it rushes down and is main effect down.Contain more composition in the Radix Et Rhizoma Rhei, wherein can be water-soluble aloe-emodin arranged, other is water-soluble hardly as emodin, chrysophanic acid.Senna Fructus A, B are also water insoluble, but exist then in water dissolubility bigger as the anthraquinone glycoside form.For guaranteeing the catharsis effect of former powder, the present invention still design with the Radix Et Rhizoma Rhei levigation mix with the extract of other medicines again granulate comparatively suitable.

The present invention, Semen Arecae includes multiple alkaloid, and arecoline can be miscible with water, and arecaidine is soluble in water.Hesperidin in the Fructus Aurantii Immaturus, it is soluble in water that naringin can be slightly soluble in the water Neosynephrine, the curcumin water soluble in the Rhizoma Curcumae, contained sinigrin water soluble in the Semen Lepidii (Semen Descurainiae).Rhizoma sparganic is fried in shallow oil the also available water boiling and extraction of soup custom by tradition, extracts so above medicine all designs with water boil, on the basis that keeps the each taking dose of original crude drug powder, dwindles and takes volume, reduces the unit dose package volume, is convenient to take and carry.

Preserve the effect of monarch drug Radix Et Rhizoma Rhei again in order to reduce dose, the way that design is granulated with the spissated thick paste of the fried liquid of Radix Et Rhizoma Rhei powder and other five kinds of medicines can be without other excipient, and makes the sugar type granules that contains the crude drug powder, the manufactured goods dosing is little, is beneficial to directly to use mixing in water for oral taking.The temperature of granulation after drying should suit, because of wherein containing rhubarb powder, generally should be about 60 ℃, and baking temperature is too high, is unfavorable for the preservation of combined anthraquinone.

Less because of crude drug powder dose, once amount only is 3g, and wherein Radix Et Rhizoma Rhei powder is 1.5g.Go out composition in order to preserve decocting as far as possible, so design the present invention does not adopt the decocting in water alcohol deposition method, only with fried liquid filtering simmer down to thick paste, its relative density is that 1.02-1.04 gets final product.

Because of containing sugared electuary, sugar content is more, and is not really suitable to some disease, and patient is also glad sometimes to take, and so the present invention makes sugar-free granule, dosing is reduced, and 1.6g only also can directly pour in the mouth and use mixing in water for oral taking at every turn, welcome by patient, and curative effect does not subtract.

Embodiment one: the preparation of stomach medicine of the present invention

1. get the raw materials ready: select for use from storehouse do not have to go rotten, free from insect pests, unmetamorphosed dry Radix Et Rhizoma Rhei, Fructus Aurantii Immaturus, Semen Arecae, rhizoma sparganic, Rhizoma Curcumae, each is some for Semen Lepidii (Semen Descurainiae).Radix Et Rhizoma Rhei mechanical lapping is become powder, sieved with No. six, the fine powder that sieves is no less than 95% before sieving, and it is standby to stay the fine powder that sieves.

2. prepare burden: take by weighing above-mentioned getting the raw materials ready, Radix Et Rhizoma Rhei powder 3.0Kg, Fructus Aurantii Immaturus 0.93Kg, Semen Arecae 0.69Kg, rhizoma sparganic, Rhizoma Curcumae, each 0.46Kg of Semen Lepidii (Semen Descurainiae), stand-by.

3. boil medicine: five kinds of Chinese medicine such as the above-mentioned Fructus Aurantii Immaturus that takes by weighing, Semen Arecae, rhizoma sparganic, Rhizoma Curcumae, Semen Lepidii (Semen Descurainiae) are blended in the medicine cylinder, are 3.0kg altogether, add 42kg water, conventional decocting 30 minutes, filter cloth filters, and keeps filtrate, filtering residue is again by this method decocting, and so decocting is three times; Abandon filtering residue, it is stand-by to merge three filtrates (medicine soup);

4. system cream: centrifugal 15 minutes of speed with above-mentioned filtrate is changeed (rpm) with per minute 3000 on centrifuge discards precipitation.Then supernatant is carried out routine be evaporated to its volume when being 2.1L till.This concentrated solution is clear paste, and its relative density should be 1.02-1.04.

5. granulating: the Radix Et Rhizoma Rhei powder 3.0kg that the 2nd step was taken by weighing and 2100 milliliters of mix homogeneously of clear paste of the 4th step gained, the conventional granulating that pushes.The medicine grain in 60 ℃ of dryings, is crossed 30 mesh sieves with dried medicine grain, and the medicine grain after sieving is finished product.Obtain granule 4800 grams approximately.

With reference to the many batch samples of embodiment one trial-production, wherein five batches of preproduction experimental datas are listed in table 1 to the inventor:

It is real that the grain amount recovery rate is answered the real subpackage amount of subpackage amount that table 1 lot number extracts the deserved grain amount of inventory dry extract weight dry extract yield Radix Et Rhizoma Rhei powder amount

(kg) (kg) (%) (kg) (kg) (kg) (%) (bag) (bag) 40,511 3.90 0.37 9.49 3.9 4.27 3.9 91.3 2,437 242,040,515 1.95 0.18 9.23 1.95 2.13 1.9 89.2 1,187 117,540,810 3.90 0.38 9.74 3.9 4.28 4.0 93.4 2,500 249,040,905 3.12 0.30 9.62 3.12 3.42 3.1 90.6 1,937 192,150,402 2.73 0.26 9.52 2.73 2.99 2.8 93.6 1,750 1736 embodiment two: the different grinding particle sizes of rheum officinale are granulated relatively

According to the general requirement of preparation granule, select the Radix Et Rhizoma Rhei powder of three kinds of fineness to granulate.Comparative result is as follows, with better by No. six sifters.The results are shown in table 2:

Table 2 Radix Et Rhizoma Rhei powder fineness is made No. five sieves of granule situation more fiber fines, and appearance poor is sieved seldom fiber fines No. six, and outward appearance is sieved seldom fiber fines better No. seven, and outward appearance is good, but screen analysis difficulty embodiment three: the medicinal material extract experiment

In the prescription ratio, get rhizoma sparganic, Rhizoma Curcumae, Fructus Aurantii Immaturus, Semen Arecae, medical materials such as Semen Lepidii (Semen Descurainiae) are 50g altogether, investigates amount of water, soak time, decocting time and decocts the influence of number of times to extraction effect with orthogonal experiment.With dried cream recovery rate and two of ethanol extraction conductances is index, and definite ethanol extraction yield is an optimum process condition when yield of high dry extract is higher.Its assay method is as follows:

1. dry extract recovery rate: it is one of index of weighing extraction effect that water logging goes out dry extract.The height of its recovery rate directly influences curative effect of medication.So being chosen as and decocting the extraction index is reasonable, effective control device.Assay method is accurately measured the decocting liquid cumulative volume earlier, therefrom measures the 50ml decocting liquid again, and in the vaporizer of the dry constant weight of impouring, water-bath is concentrated into dried, moves into 105 ℃ of oven dryings 3 hours, takes out, and puts in the exsiccator and cools off 30 minutes, weighs, and calculates.

Formula:

2. ethanol extraction (ethanol leachable) yield:, can not reflect fully that effective site extracts situation, so the while is a screening index with the ethanol extraction yield again because the extractum yield has certain sum of errors impurity to disturb.Assay method is measured earlier accurately the decocting liquid cumulative volume, therefrom gets the 50ml decocting liquid more in addition, adds dehydrated alcohol, makes that to contain determining alcohol be 80%, places.Filter, wash precipitation three times with dehydrated alcohol.Fling to ethanol, measure dry extract weight, calculate by 1. methods.

Formula:

3. orthogonal test: select orthogonal test Lg (3 ⁴) table, EXPERIMENTAL DESIGN, arrange and the results are shown in Table 3, table 4, table 5 and table 6:

Table 3 experimental establishment and result

The gauge outfit design	????A	????B	????C	????D	Experimental result
							Row number	????1	????2	????3	????4	Y％	Z％
????1 ????2 ????3 ????4 ????5 ????6 ????7 ????8 ????9	????1 ????1 ????1 ????2 ????2 ????2 ????3 ????3 ????3	????1 ????2 ????3 ????1 ????2 ????3 ????1 ????2 ????3	????1 ????2 ????3 ????2 ????3 ????1 ????3 ????1 ????2	????1 ????2 ????3 ????3 ????1 ????2 ????2 ????3 ????1	?9.16 ?7.12 ?1?0.23 ?7.99 ?6.47 ?4.84 ?2.20 ?5.82 ?5.38	4.83 3.75 4.29 4.10 3.04 2.76 0.94 2.86 2.54
							????K1 ????K2 ????K3 ?Y??K1 ????K2 ????K3 ????R ????SS	????26.51 ????19.30 ????13.40 ????8.83 ????6.43 ????4.47 ????4.36 ????28.741	????19.35 ????19.41 ????20.45 ????6.45 ????6.47 ????6.82 ????0.37 ????0.255	????19.82 ????20.49 ????18.90 ????6.61 ????6.83 ????6.30 ????0.53 ????0.425	????21.01 ????14.17 ????24.04 ????7.00 ????4.72 ????8.01 ????3.29 ????17.175	?9 ?∑Y＝59.21 ?i＝1 ?9 ?(∑Y) 2＝3505.28 i＝1
????K1 ????K2 ????K3 Z???K1 ????K2 ????K3 ????R ????SS	????12.87 ????9.90 ????6.34 ????4.29 ????3.30 ????2.11 ????2.18 ????7.126	????9.87 ????9.65 ????9.59 ????3.29 ????3.22 ????3.20 ????0.09 ????0.015	????10.45 ????10.39 ????8.27 ????3.48 ????3.46 ????2.76 ????0.72 ????1.028	????10.41 ????7.45 ????11.2?5 ????3.47 ????2.48 ????3.75 ????1.27 ????3.410		9 ∑Z＝29.11 i＝1 9 (∑Z) 2＝847.39 i＝1

Table 4 factor level table

Factor level

Amount of water (A) soak time (B) decocting time (C) decocts 36 times of 2 10 times of 1 14 times of number of times (D) 0.5 hour 0.5 hour 1 time 1 hour 0.75 hour 2 times 1.5 hours 1 hour 3 times

Table 5 variance analysis (water extraction dry extract) soruces of variation sum of deviation square degree of freedom variance F value significance A SS _A=28.741 2 14.3705 112.7 * * B SS _B=0.255 2 0.1275C SS _C=0.425 2 0.2125 1.7D SS _D=17.175 2 8.5875 67.4 * F _0.05 ^(2.2)=19.0 F _0.01 ^(2.2)=99.0*--significance * *--utmost point significance

Table 6 variance analysis (ethanol extraction) soruces of variation sum of deviation square degree of freedom variance F value significance A SS _A=7.126 2 3.563 475.1 * * B SS _B=0.015 2 0.0075C SS _C=1.028 2 0.514 68.5 * D SS _D=3.410 2 1.705 227.3 * *

4. interpretation of result

4.1 water extraction dry extract yield index

SS _BMinimum is with SS _BBe error variance SS _e, getting amount of water through variance analysis has the influence of utmost point significance to dry extract, and extraction time has the significance influence, and decocting time does not have the significance influence; Can be got by range analysis, the influence of dry extract is in proper order: A＞D＞C＞B; Getting optimum process condition by intuitive analysis is A ₁B ₃C ₂D ₃

4.2 ethanol extraction yield index

SS _BMinimum is with SS _BBe error variance SS _e, getting amount of water through variance analysis, extraction time has the influence of utmost point significance, and there is the significance influence extraction time; The order that can be influenced the ethanol extraction yield by range analysis is: A＞D＞C＞B, optimum process condition are A ₁B ₁C ₁D ₃

Repeated trials: press A ₁B ₁C ₁D ₃Condition is tested, and getting the ethanol extraction yield is 4.98%, and the dry extract yield is 9.49%, and the ethanol extraction yield is than the highest A in the quadrature experiment ₁B ₁C ₁D ₁Good, and the dry extract yield is not the highest, illustrates that technology is reasonable.

5. experiment conclusion

Through experimentation, obtain rhizoma sparganic, Rhizoma Curcumae, Fructus Aurantii Immaturus, Semen Arecae, Semen Lepidii (Semen Descurainiae) optimum extraction process, the material of promptly getting it filled adds 14 times of water gagings, soaks half an hour, extracts 3 times, each half an hour.Embodiment four: the experiment of granule type selecting

1. extractum and medicated powder usage ratio are determined experiment

The dense thick situation of extractum and the difficulty or ease of granulation and molding character have bigger relation, and the ratio of extractum and medicated powder also has a direct impact granulating, and for this reason, has carried out following experiment.The results are shown in Table 7:

Table 7 medicinal liquid concentrates volume, and (ml: g) making the soft material situation, to make soft material at 0.4: 1 more dried to the ratio that medicine concentrates dosage and Radix Et Rhizoma Rhei powder that influences of making soft material, be difficult for uniform mixing, can granulate behind the increasing water gaging and make the suitable granulation of soft material at 0.7: 1, it is rarer usually that easy uniform mixing is made soft material at 0.9: 1, is difficult for granulating

By above experiment as can be known: extractum is better with 0.7: 1 with the ratio of medicated powder.This moment, its relative density was between 1.02～1.04 after measured, saw Table 8:

Table 8 concentrated solution density (60 ℃ of heat are surveyed)

Inventory (kg) concentrated solution volume (ml) density

2???????????1400???????????1.02

2???????????1400???????????1.02

2???????????1400???????????1.03

2???????????1400???????????1.02

2 1,400 1.04 embodiment five: screen sizes is determined experiment

Adopt the comparison of granulating of 18 orders, 12 orders, three kinds of screen clothes of 22 orders, the results are shown in table 9:

Table 9 granulation screen sizes is made the granule situation

12 order epigranulars, particulate is less, but rectangular person is more, and outward appearance is relatively poor

18 order epigranulars, particulate is on the high side, and the strip person is more, and outward appearance is better

22 order epigranulars, particulate is more, and the strip person is few, and outward appearance is good, easily swallows

By above experiment and consider the finished product outward appearance and the importance of difficulty or ease of swallowing, decision is granulated with 22 mesh sieves.Embodiment six: quality investigation: by " Chinese pharmacopoeia 1990 editions and " provisions for new drugs approval "

About the revision of Chinese medicine part and the content of supplementary provisions are carried out.The results are shown in Table 10:

Table 10 three batch sample quality investigation table water content granularity assay lot number character identification health examinations

(%) (order) % (g/g) 40511 yellowish-brown granules, mildly bitter flavor 1. is at Radix Et Rhizoma Rhei control medicinal material phase 5.61 20-40 3.068 assorted bacterium＜10/g

Emodin reference substance chromatograph

Show identical mycete＜10/g on the relevant position

The speckle 40515 yellowish-brown granules of color, mildly bitter flavor 2. are Semen Arecae control medicinal material color 5.68 20-40 2.897 escherichia coli not

Show on the spectrum relevant position and detect mutually

With Chinese red speckle 40810 yellowish-brown granules, mildly bitter flavor 3. is at Neosynephrine reference substance color 4.82 20-40 2.957

Showing the demodicid mite that lives mutually on the spectrum relevant position does not detect

Aubergine speckle embodiment seven together: pharmacodynamic analysis

1. to the influence of gastrointestinal movement

1.1 influence to the mice gastric emptying

50 of mices, body weight 19-20g, male and female half and half, fasting is 15 hours before the experiment, freely drinks water.Be divided into 5 groups at random, 10 every group, press the administration of the subcutaneous injection of dosage shown in the table 1, injection capacity is 0.2ml/10g.After the administration 50 minutes, every Mus is irritated stomach 0.1% methyl orange solution 0.2ml, and dislocation is put to death animal and cut open the belly and win stomach and place in the small beaker after 20 minutes, adds the 10ml distilled water, cuts off stomach with little shears along greater gastric curvature, and gastric content is fully washed in water, uses NaHCO ₃Solution is regulated pH value to 6.0-6.5, centrifugal 10 minutes of 2000rpm, get supernatant with 751 type spectrophotometer colorimetrics (λ: 420nm), the optical density of measurement solution.And add optical density that the 10ml distilled water measures as radix methyl orange optical density with 0.1% methyl orange 0.2ml.And by following formula calculating methyl orange stomach residual rate.

The results are shown in Table 11, stomach medicine of the present invention does not have the obvious effect that influences the gastric emptying motion. table 11 (group number of animals (only) dosage of X ± SD) (methyl orange Stomach residue rate (%) distilled water group 10--43.6 ± 8.9 stomach medicine group 10 0.25 40.1 ± 4.6 stomach medicine group 10 0.50 40.3 ± 3.0 stomach medicine group 10 1.00 46.1 ± 7.6 neostigmine groups 10 1 * 10 of the present invention of the present invention of the present invention of g crude drug/Kg)^-430.9 ± 11.3 ^**: compare P＜0.05 with the distilled water group

1.2 influence to normal mouse intestinal progradation:

50 of mices, 17-19g, male and female half and half, fasting is 15 hours before the experiment, freely drinks water.Animal is divided into 5 groups at random, presses the gastric infusion of dosage shown in the table 2, and the administration capacity is 0.1ml/10g, only gavages prepared Chinese ink liquid 0.2ml/ after 15 minutes again.Put to death after 20 minutes, measure the move distance of prepared Chinese ink, and calculate prepared Chinese ink propelling rate % at small intestinal. The results are shown in Table 12, stomach medicine of the present invention does not have obvious influence to normal mouse intestinal ahead running. table 12 (group number of animals (only) dosage of X ± SD) (prepared Chinese ink propelling rate (%) distilled water group 10--62.2 ± 6.8 stomach medicine group 10 0.25 62.3 ± 3.5 stomach medicine group 10 0.50 61.3 ± 3.0 stomach medicine group 10 1.00 63.3 ± 9.5 neostigmine groups 10 2.0 * 10 of the present invention of the present invention of the present invention of g crude drug/kg)^-389.6 ± 10.2 ^{* *}

* *: with the distilled water group relatively P＜0.0011.3 to the hyperfunction influence of neostigmine induced mice intestinal motility: table 13 (group number of animals (only) dosage of X ± SD) (prepared Chinese ink propelling rate (%) distilled water+group 10--62.2 ± 6.8 prepared Chinese ink liquid neostigmines 2.0 * 10 of g crude drug/kg) ^-3+ group 10 66.5 ± 15.0 ^{△ △ △}Stomach medicine prepared Chinese ink liquid 0.25 neostigmine 2.0 * 10 of the present invention ^-3

+ group 10 61.8 ± 3.3 ^{△ △ △}Stomach medicine prepared Chinese ink liquid 0.50 neostigmine 2.0 * 10 of the present invention ^-3

+ group 10 89.6 ± 10.2 ^{* *}Prepared Chinese ink liquid * * *: compare P＜0.001 △ △ △: compare P＜0.001 with the neostigmine group with the distilled water group

40 of mices, 17-19g, male and female half and half, fasting is 15 hours before the experiment, freely drinks water.Be divided into 4 groups at random, press the gastric infusion of dosage shown in the table 13.Matched group gavages distilled water, and all the other each groups all gavage neostigmine methylsulfate 2 * 10 earlier ^-3G/kg, each group is irritated gastric capacity and is 0.2ml/10g, after 15 minutes, gavages the prepared Chinese ink or the prepared Chinese ink liquid 0.1ml/10g that contain stomach medicine of the present invention more respectively, after 20 minutes, puts to death animal and gets small intestinal, measures the prepared Chinese ink advance distance, calculates prepared Chinese ink propelling rate %.

The results are shown in Table 13, stomach medicine of the present invention has the hyperfunction effect of the neostigmine induced mice intestinal motility of inhibition.

1.4 influence to the inhibition of atropine induced mice intestinal motility: 40 of mices, 17-19g, male and female half and half, fasting is 15 hours before the experiment, freely drinks water.Animal is divided into 4 groups at random, presses the gastric infusion of dosage shown in the table 4.Matched group gavages distilled water, and all the other each groups all gavage atropine 2 * 10 earlier ^-3G/kg, each is organized the administration capacity and is 0.2ml/10g, after 15 minutes, gavages the prepared Chinese ink liquid or the prepared Chinese ink liquid 0.1ml/10g that contain stomach medicine of the present invention more respectively, after 20 minutes, puts to death animal and gets small intestinal, measures the prepared Chinese ink advance distance, calculates prepared Chinese ink propelling rate %.

The results are shown in Table 14, stomach medicine of the present invention can not resist the inhibitory action of atropine to the mouse small intestine motion, and heavy dose of group also has synergism to its inhibit feature.

Table 14 (group number of animals (only) dosage of X ± SD) (prepared Chinese ink propelling rate (%) distilled water+group 10--62.2 ± 6.8 prepared Chinese ink liquid atropine 2.0 * 10 of g crude drug/kg) ^-3+ group 10 39.5 ± 7.1 ^{* *}Stomach medicine prepared Chinese ink liquid 0.25 atropine 2.0 * 10 of the present invention ^-3+ group 10 29.2 ± 8.2 ^{* * △ △}Stomach medicine prepared Chinese ink liquid 0.50 atropine 2.0 * 10 of the present invention ^-3

Organize 10 44.0 ± 9.2 ^{* *}Prepared Chinese ink liquid * * *: compare P＜0.001 △ △: compare P＜0.01 with the atropine group with the distilled water group

1.5 direct influence to the rat colon movement:

40 of rats, 210-240g, male and female half and half, the experiment proxima luce (prox. luc) is got rats by intraperitoneal injection 1% pentobarbital sodium 4ml/kg anesthesia, cut off the hair at abdomen middle part, do the long otch of 3-4cm at the abdomen middle part along ventrimeson, by the sterile working, open the abdominal cavity, the plastic tube that is 1mm to internal diameter inserts colon 1cm by ileocecus, and ligation is fixed, and conduit is drawn from the back by muscle skin, in order to administration, after abdominal incision is sewed up rat put back in the cage single cage and feed.Water is can't help in the fasting of postoperative rat.Get the postoperative rat next day and be divided into 4 groups at random, by the prepared Chinese ink liquid from plastic catheter to colon perfusion or the prepared Chinese ink liquid 0.4ml/100g that contain medicine shown in the table 5 by.After 10 minutes, rat is put to death, open the abdominal cavity immediately, large intestine is cut by anus to caecum end, be placed on the glass plate, measure its large intestine total length and prepared Chinese ink advance distance, calculate prepared Chinese ink propelling rate with little shears.

The results are shown in Table 15, the stomach medicine group of the present invention of each dosage all has the effect of the rat of promotion large intestine ahead running.

(X ± SD) group number of animals dosage colon length prepared Chinese ink advance distance advances percentage rate to table 15

(only) (g crude drug/kg) (cm) is (%) distilled water group 10--14.85 ± 1.65 5.15 ± 1.58 34.8 ± 11.2 stomach medicine groups 10 0.25 14.50 ± 1.77 11.15 ± 4.08 of the present invention (cm) ^{* *}76.2 ± 21.2 ^{* *}Stomach medicine group 10 0.50 14.20 ± 2.20 10.85 ± 2.63 of the present invention ^{* *}76.7 ± 17.3 ^{* *}Magnesium sulfate group 10 8 * 10 ^-114.00 ± 1.22 12.20 ± 2.38 ^{* *}86.9 ± 14.1 ^{* *}* *: compare P＜0.001 with the distilled water group

1.6 influence to mice defecation T/A:

50 of mices, 19-20g, male and female half and half, fasting is 24 hours before the experiment, freely drinks water.Animal is divided into 5 groups at random, presses and irritates stomach shown in the table 6 to pastille prepared Chinese ink liquid or prepared Chinese ink liquid, 0.25ml/10g.Experimentation is freely drunk water.Each Mus is placed in and observes in the box that is covered with filter paper, and the time of the first row of record mice melena, feces character and number etc. were observed eight hours continuously.

The results are shown in Table 16, heavy dose of stomach medicine group of the present invention has the mice of shortening row's melena time, and amount waits effect with increasing just.(the group number of animals dosage of X ± SD) begins bowel movement character in the venting feces eight hours to table 16

(only) (the g crude drug/kg) time (min) is just counted (grain) distilled water group 10--373 ± 50 2.7 ± 1.5 normal stomach medicine groups 10 0.25 287 ± 64 of the present invention ^*3.1 ± 1.0 normal stomach medicine groups 10 0.50 362 ± 30 5.7 ± 1.3 of the present invention ^{* *}Normal stomach medicine group 10 1.00 271 ± 59 of the present invention ^*6.7 ± 1.1 ^{* *}Soft rare hard magnesium sulfate group 10 5.0 183 ± 43 ^{* *}14.3 ± 1.8 ^{* *}Shapeless loose stool

*: compare P＜0.01, * * *: compare P＜0.001 with the distilled water group with the distilled water group

2. to the influence of gastric acid, pepsinia:

28 of rats, 220-240g, male and female half and half.Fasting 24 hours is freely drunk water.Be divided into 4 groups at random, with the slight anesthetized animal of ether, cut off the hair of abdominal part, open in xiphoid-process lower edge ventrimeson and to be about the 2-3cm otch, carefully propose stomach, in pylorus and the suture ligation of duodenum junction, carefully avoid blood vessel, inject medicine or distilled water immediately in duodenum, dosage is shown in Table 7, and capacity is 1ml/100g.Sew up the incision, after send back in the cage, water is prohibited in the postoperative fasting, put to death animal in 5 hours, take out stomach, collect gastric juice in graduated centrifuge tube, with 3000rpm centrifugal 15 minutes, draw supernatant, measure the gastric juice amount respectively, total acidity, total acid output, pepsin activity, pepsin output, the acid base neutralization titration method is adopted in gastric acidity determination, and determination of peptic activity adopts the Mett method.

Table 17 stomach medicine of the present invention is to the influence of rat gastric juice, gastric acid secretion (the total acid output of group number of animals dosage gastric juice amount total acidity of X ± SD)

(n) (g crude drug/kg) (ml/ only) is (μ Eq/h) distilled water group 7--8.89 ± 2.14 129.4 ± 13.6 227.4 ± 49.3 stomach medicine groups 8 0.2 5 4.63 ± 1.66 of the present invention (mEq/l) ^{* *}124.8 ± 11.9 115.1 ± 42.0 ^{* *}Stomach medicine group 6 0.50 3.42 ± 0.8 of the present invention ^{* *}127.7 ± 8.7 87.6 ± 22.8 ^{* *}Cimetidine group 72 * 10 ^-13.00 ± 1.15 ^{* *}71.4 ± 13.5 ^{* *}40.8 ± 10.1 ^{* *}

* *: compare P＜0.001 with the distilled water group

The results are shown in Table 17, table 18, stomach medicine group of the present invention has the minimizing gastric secretion, reduces total acid output, the effect of pepsin output; Stomach medicine of the present invention has the effect that increases pepsin activity.

Table 18 stomach medicine of the present invention is to the influence of rat stomach proteinase activity and output thereof (the group number of animals dosage pepsin activity pepsin of X ± SD) output

(n) (((distilled water group 7--207.9 ± 38.9 358.3 ± 55.8 stomach medicine groups 8 0.25 330.1 ± 45.20 of the present invention of active unit/h) of active unit/ml) of g crude drug/kg) ^{* *}303.7 ± 108.3 stomach medicine groups 6 0.58 357.7 ± 53.0 of the present invention ^{* *}241.3 ± 53.3 ^*Cimetidine group 72 * 10 ^-1201.6 ± 23.3 118.3 ± 37.3 ^{* *}

*: compare P＜0.01 * * *: compare P＜0.001 with the distilled water group with the distilled water group

3. to the excretory influence of rat bile:

32 of male rats, 110-130g.Fasting is 16 hours before the experiment, freely drinks water.Animal is divided into 4 groups at random during experiment, adopt the appropriate 30mg/kg of the receiving intraperitoneal anesthesia of 0.6% penta crust after, back of the body position is fixing.Cut about 2cm along the abdomen median line, open the abdominal cavity.Peeling operation common bile duct, plug sword-shaped needle carry out biliary drainage and collect bile.After waiting to stablize 20 minutes, record bile secretion basic value (ml/30min) is pressed dosage shown in the table 9 then by duodenal administration, and the administration capacity is (1ml/100g).Collected bile once every 30 minutes after the administration, after the record administration 30 minutes, 60 minutes, 90 minutes bile flow carried out cross-reference t with each group bile flow with basic value and checks.

The results are shown in Table 19, heavy dose of stomach medicine of the present invention has the effect that increases the rat bile flow.

Table 19 (X ± SD)

Number of animals dosage bile flow (ml/30min) group

(n) (before the administration of g crude drug/kg) after the administration (min)

30 60 90 distilled water groups 8--0.22 ± 0.05 0.20 ± 0.04 0.20 ± 0.02 0.22 ± 0.05 stomach medicine group 8 2.0 0.20 ± 0.03 0.25 ± 0.03 of the present invention ^*0.23 ± 0.03 0.21 ± 0.02 stomach medicine group of the present invention 8 0.5 0.20 ± 0.03 0.21 ± 0.03 0.19 ± 0.04 0.20 ± 0.02 cholagogic tablet group 8 1.5 tablets/kg 0.19 ± 0.05 0.26 ± 0.07 ^*0.29 ± 0.06 ^*0.22 ± 0.04

*P＜0.05????**P＜0.01

3. in above-mentioned effect experiment, the dosage of stomach medicine group of the present invention is respectively clinical once intend 5,10,20 times of consumption (0.25g crude drug/kg, 0.5g crude drug/kg, 1.0g crude drugs/kg)

Experiment shows that the present invention does not have obviously effect to the gastric emptying motion and the intestinal propulsion motion of normal mouse.Can impel the rat intestinal peristalsis to accelerate significantly, shorten the mice defecation time, increase the feces amount, reach the diffusing long-pending function of purging FU-organs.

The present invention has an inhibitory action for the mouse small intestine due to neostigmine motion is hyperfunction, and low dose of do not have obvious effect to the inhibition of atropine induced mice intestinal motility, and heavy dose has the inhibitory action of collaborative atropine to the mouse small intestine motion.Show mouse small intestine motion under the drug effect is the inhibition influence.

Gastric analysis shows, the present invention has the gastric acid secretion of minimizing amount, reduces the effect of total acid output and pepsin output, so can reduce it to gastric mucosal damage under the pathological state.In experiment, we find that also mucous secretion obviously increases in the stomach medicine group rat stomach of the present invention, illustrates that the speed relaxation grain that is good for the stomach has certain protection or alleviates gastric mucosal damage, promotes the effect that gastric mucosal lesion heals.

The experiment of bile secretion shows that heavy dose of stomach medicine of the present invention can increase the bile flow of rat.

This shows that the present invention does not have obviously effect to the gastric emptying motion and the intestinal propulsion motion of normal mouse.But can impel the rat intestinal peristalsis to accelerate significantly, shorten the mice defecation time, increase the feces output.

The present invention has an inhibitory action for the mouse small intestine due to neostigmine motion is hyperfunction, and low dose of do not have obvious effect to the inhibition of atropine induced mice intestinal motility, and heavy dose has the inhibitory action of collaborative atropine to the mouse small intestine motion.

The present invention has and reduces the gastric acid secretion amount, reduce the effect of total acid output and pepsin output, and tool promotes the effect of bile secretion.Embodiment eight: acute toxicity test

Give the stomach medicine suspension of the present invention (50ml/kg) of mouse gavaging 20%, recording its maximum tolerated dose is 18.8g crude drug in whole/kg, is equivalent to clinical plan 376 times with the dosage one time oral dose.Mouse stomach gives the acute toxic reaction of stomach medicine of the present invention.

1. medicine: stomach medicine of the present invention: being made up of Six-element Chinese medicines such as Radix Et Rhizoma Rhei, is sepia sugar-free granule, and every gram contains crude drug in whole 1.88g, by the preparation of Chengdu Chinese medicine institute, lot number: 40511.Get stomach medicine of the present invention during test and add an amount of distilled water grinding mixing, make per 100 milliliters of suspensions that contain the Cmax of stomach medicine 20g of the present invention.

2. animal: one-level Kunming mouse: provided by Huaxi Medical Univ's Experimental Animal Center, produce full lattice card number: No. 82, the real moving Guan Zhidi in river, feedstuff: the Mus pellet, Huaxi Medical Univ's Experimental Animal Center provides.

3. experimental technique: get 20 of body weight 19-20g mices, male and female half and half once gavaged 20% stomach medicine suspension 0.5ml/10g of the present invention at 10 o'clock in the morning and (are equivalent to 18.8g crude drug in whole/kg).One week of breeding observing after the administration, find in the observation period that only administration animal on the same day drains soft stool, do not see all the other abnormal responses, the outward appearance dietary behavior of animal is movable normal in the observation period, does not have dead the generation.It gavages drug dose and is equivalent to clinical plan with 376 times of the dosage one time oral dose (1 amount of gavaging 18.8g crude drug in whole of the mice/each dose 3.0g of the clinical 60kg people of kg ÷ crude drug in whole/60kg).

4. experimental result: the present invention has certain pharmacological action to the mice digestive system, but the acute toxicity of this medicine is minimum, and the single administration amount reaches 376 times of clinical people's consumption, does not also have dead the generation, so this medicine maximum tolerated dose is 18.8g crude drug in whole/kg.Embodiment nine: long term toxicity test

The present invention gives rat oral gavage 6.0g crude drug in whole/kg body weight d; 3.0g crude drug in whole/kg body weight d; Administration in continuous 30 days, the behavior performance of the large and small dosage treated animal of result, body weight change, routine blood test, the perusal of blood biochemical and important organ, an inspection index result such as histopathology and matched group be no significant difference relatively all.The present invention shows that by the rat long term toxicity test its toxicity is low, and using dosage safety is intended in clinical trial.

1. medicine: stomach medicine of the present invention: sepia sugar-free granule, every gram contains crude drug in whole 1.88g, by the preparation of Chengdu Chinese medicine institute, lot number: 40511.Get stomach medicine of the present invention during test and add an amount of distilled water and grind mixing, make per 100 milliliters and contain stomach medicine 20g of the present invention (0.375g crude drug in whole/ml) and per 100 milliliters contain the stomach medicine 10g of the present invention (suspension of two kinds of concentration of 0.188g crude drug in whole/ml).

2. animal: one-level SD rat, male and female half and half, body weight 115-140g is provided by Huaxi Medical Univ's Experimental Animal Center, produces the quality certification: No. 85, the real moving Guan Zhidi in river.

3. experimental technique: 80 of rats, male and female half and half in one week of breeding observing, are divided into three groups (because of acute toxicity test in mice is only obtained the maximum tolerated dose value, so only establish two dosage groups of height) at random by body weight.Press appearance gastric infusions such as the listed dosage of table 20, matched group gives distilled water (16ml/kg).Be administered once every day, continuous 30 days (according to body weight change, adjusting dosage weekly once).After the drug withdrawal 24 hours, each group was put to death 20 animals, and remaining animal continues two week of breeding observing back and puts to death.In the entire test, each is organized rat and all freely drinks water, feed, and room temperature 20-26 ℃, relative humidity 70-80%, natural lighting, scavenger fan ventilates.

Experimental observation index and detection time see Table 21.After the test last administration 24 hours, get 20 (male and female half and half) animals for every group, below getting the blood work, the eye socket venous plexus detects: measure erythrocyte (RBC) counting with the Japanese East Asia CC-180 of company type electronics hemocytometer, and leukocyte (WBC) counting, hemoglobin (Hb) is measured; Platelet Counting under the biological microscope (Pt) and differential blood count; Measure serum ALT (ALT) with reitman-frankel method; Measure serum alkaline phosphatase (ALP) with King's method; Measure total serum protein (TP) with biuret method; Measure serum albumin (ALB) with the bromocresol green method, measure serum urea nitrogen (BUN), measure serum creatinine (Crea), the results are shown in Table 22-26 with the alkaline picric acid method with oxalic acid-oxime method.

Behind the rat extracting blood, take off cervical vertebra and put to death, dissect.The perusal main organs has or not pathological changes, cores then, liver, spleen, lung, kidney, adrenal gland weigh on electronic balance, calculates organ coefficient; The results are shown in Table 7.Get organ paraffin embedding such as above internal organs and thymus, stomach, duodenum, section, HE dyeing again, do the pathology histological examination.

Heavy dose of group and matched group respectively stay 10 animal drug withdrawals to observe for two weeks, administration expiration is surveyed organizes respectively that 20 rat bloods are learned, blood biochemicals are learned and significant difference does not more all appear in every desired value such as pathology and matched group, so when end is observed in drug withdrawal, only make the body weight observation on Growth and measure.

4. experimental result: at this experimental session, the rare soft shaping of in the administration process, defecating of heavy dose of treated animal, chaeta is little alarms, and body is slightly become thin, but body weight gain and matched group comparison there was no significant difference.Successive administration 30 days, large and small dosage group of administration and matched group compare, and hematology, blood biochemical are learned relevant index and be there is no significant difference, dissect the perusal main organs, no abnormality seen.Histopathologic examination, organs such as the heart of administration treated animal, liver, spleen, lung, kidney, adrenal gland, thymus, stomach, duodenum do not have tangible pathomorphology damage and relatively do not have obvious change with matched group.

The grouping of table 20 rat is clinical 60kg people with dosage group number of animals dosed administration approach

(only) (multiple distilled water group 30--PO--stomach medicine of the present invention group 20 3.0 PO 60 stomach medicine group 30 6.0 PO 120 of the present invention of consumption per day of g crude drug/kgd)

Annotate: the acute toxicity test of stomach medicine of the present invention shows that the very low survey of said preparation toxicity does not go out LD50 and do not see the overt toxicity reaction yet, so only establish height in the rat long term toxication, low two dosage groups.

Table 21 observation index and detection time detection time observation index experiment beginning every day weekly after the administration drug withdrawal in 30 days behavior in 14 days performance √ √ body weight √ √ √ hematology √ blood biochemical learn the √ gross necropsy √ Histopathology √ table 22 stomach medicine of the present invention successive administration impact to rat body weight in 30 days (g, behind the group dosed administration of X ± SD) (my god)

(g. crude drug in whole/kg.d) preceding 7 15 22 30 drug withdrawals 14 of administration (my god) matched group--127.9 ± 6.8 160.3 ± 15.8 161.4 ± 15.0 174.4 ± 15.1 201.9 ± 26.8 243.7 ± 44.2 stomach medicine group 3.0 128.0 ± 7.2 159.6 ± 13.8 158.2 ± 15.0 171.3 ± 17.5 206.8 ± 21.7 stomach medicine groups 6.0 128.0 ± 7.5 152.9 ± 12.8 157.1 ± 11.8 168.9 ± 12.2 191.0 ± 15.6 216.3 ± 25.1 of the present invention of the present invention are annotated: matched group, before the administration of heavy dose of group, number of animals respectively is 30 after the administration, and small dose group is 20.

Two all number of animals respectively are 10 after matched group, the drug withdrawal of heavy dose of group.

T check, with matched group relatively: be P＞0.05 table 23 stomach medicine of the present invention successive administration 30 days learns index to rat blood influence (the group dosage number of animals RBC WBC Hb Pl of X ± SD)

(g crude drug in whole/kg.d) (only) is (109/l) (g/L) (109/L) control group--20 7.38 ± 0.57 15.43 ± 3.17 144.90 ± 7.00 839.2D ± 101.10 stomach medicine of the present invention groups, 3.0 20 7.68 ± 0.72 13.82 ± 4.63 144.90 ± 8.30 844.20 ± 127.80 stomach medicine group 6.0 20 7.20 ± 0.52 15.86 ± 4.19 141.60 ± 9.20 822.30 ± 87.20 t checks of the present invention (1012/L), with control group relatively: be P＞0.05 table 24 stomach medicine of the present invention successive administration impact on the rat leukocyte differential counting in 30 days (group dosage number of animals N (%) L (%) E (%) M (%) of X ± SD)

((n) control group--20 20.5 ± 3.2 77.9 ± 4.6 0.8 ± 1.0 0.9 ± 0.9 stomach medicine group 3.0 20 19.9 ± 4.5 78.1 ± 4.7 0.9 ± 0.7 1.1 ± 1.0 stomach medicine group 6.0 20 21.3 ± 4.1 76.8 ± 4.2 0.9 ± 0.8 1.0 ± 1.1N of the present invention of the present invention: neutrophil leucocyte L: lymphocyte E: acidophil M of g crude drug in whole/kg.d): monocyte t check, with control group relatively: be P＞0.05 table 25 stomach medicine of the present invention successive administration impact on rats'liver, renal function in 30 days (group dosage number of animals TP ALB BIN Crea ALP ALT of X ± SD)

(the g crude drug in whole/kg.d), (only), (g/L), (g/L), (Mmol/L), (μ mol/L), (μ), (μ) control group--20 66.3 ± 2.6 42.8 ± 3.1 5.6 ± 0.8 101.5 ± 57.2 12.3 ± 2.7 19.9 ± 2.6 stomach medicine group 3.0 20 66.2 ± 1.9 43.5 ± 3.2 5.3 ± 1.4 117.4 ± 52.4 14.1 ± 5.4 20.8 ± 4.9 stomach medicine group 6.0 20 67.7 ± 2.6 41.6 ± 3.0 5.3 ± 0.7 96.2 ± 43.0 13.7 ± 6.3 21.1 ± 3.5 t checks of the present invention of the present invention; With control group relatively: be P＞0.05 table 26 stomach medicine of the present invention successive administration impact to the rat Main Organ Coefficients in 30 days (g/100g body weight, the group dosage number of animals conscience spleen lung kidney adrenal gland of X ± SD)

(g crude drug in whole/kg.d) (only) control group--20 0.32 ± 0.03 2.76 ± 0.33 0.28 ± 0.06 0.58 ± 0.16 0.67 ± 0.07 0.0208 ± 0.0061 stomach medicine group 3.0 20 0.31 ± 0.02 2.72 ± 0.30 0.27 ± 0.07 0.58 ± 0.07 0.66 ± 0.04 0.0200 ± 0.0060 stomach medicine group 6.0 20 0.31 ± 0.03 2.78 ± 0.42 0.26 ± 0.04 0.59 ± 0.17 0.68 ± 0.06 0.0203 ± 0.0029t checks of the present invention of the present invention compares with control group: be P＞0.05

5. experiment conclusion: the present invention gives rat oral gavage 6.8g crude drug in whole/kg body weight .d; 3.0g crude drug in whole/kg body weight .d is equivalent to 120 times and 60 times of clinical 60kg people's consumption per day, continuous 30 days, heavy dose of treated animal body weight gain was slower, but with matched group there was no significant difference relatively.The behavior of large and small dosage treated animal performance, blood routine inspection and blood biochemistry checking and matched group comparison there are no significant difference.Main organs such as the heart of animal, liver, spleen, lung, kidney, adrenal gland, thymus, stomach, duodenum also do not have tangible pathomorphology damage, relatively do not have obvious histopathology with matched group and change.Observe the body weight observation on Growth measurement result of heavy dose of animal of 14 days after the drug withdrawal, compare P＞0.05 with control animals.

Said preparation shows that by a large amount of long term toxicity tests its toxicity is low, and using dosage safety is intended in clinical trial.Embodiment ten: stability relatively

By the requirement of " provisions for new drugs approval " " about Chinese medicine revision and supplementary provisions partly " to the stability of drug products test, the present invention's 40810,40816,40,818 three batch samples are placed room temperature carried out 0 month, the investigation in January, February, March, the results are shown in Table 27, table 28 and table 29 with regard to contents such as character (moisture absorption is softening), discriminating, moisture content, granularity inspection, assay, health examinations.By table 27-29 as can be known, product character of the present invention does not have big variation, the no moisture absorption and ruckbildung; Show the same color speckle on the thin layer discriminating of Radix Et Rhizoma Rhei, Semen Arecae, three medicines of Fructus Aurantii Immaturus and control medicinal material or the reference substance chromatograph relevant position, water content is between 4.48-4.91, granularity is all up to specification, contain general anthraquinone in emodin between 2.90%-3.08% (mg/g).Above situation illustrates that all product of the present invention has good stable.1. sample one:

The preliminary definitiveness test report of preparation sample title: stomach medicine of the present invention

Standing time (experiment date) is project as a result		0 month	January	February	March
						Character		Dark brown granular, bitter in the mouth, the no moisture absorption and softening	Dark brown granular, bitter in the mouth, the no moisture absorption and softening	Dark brown granular bitter in the mouth, the no moisture absorption and softening	Dark brown granular, bitter in the mouth, the no moisture absorption and softening
Differentiate	The thin layer identification experiment of Radix Et Rhizoma Rhei	On Radix Et Rhizoma Rhei control medicinal material and emodin reference substance chromatograph relevant position, show the same color speckle
						The thin layer identification experiment of Semen Arecae	On Semen Arecae control medicinal material chromatograph relevant position, show identical Chinese red speckle
	The contained Neosynephrine thin layer of Fructus Aurantii Immaturus is differentiated	On Neosynephrine reference substance chromatograph relevant position, show identical aubergine speckle
						Check	Moisture content (%)	????4.60	????4.48	????4.51	????4.58
Granularity	Up to specification	Up to specification	Up to specification	Up to specification
					Assay		Contain the general anthraquinone class in emodin % (g/g)	????2.955	????2.969	????2.966	????2.960
Health examination	Antibacterial mycete pathogenic bacterium demodicid mite alive	＜10/g＜10/g does not detect	＜10/g＜10/g does not detect	＜10/g＜10/g does not detect		＜10/g＜10/g does not detect

2. sample two:

Preparation preliminarily stabilised test report sample title: stomach medicine of the present invention

Standing time (experiment date) is project as a result		0 month	January	February	March
						Character		Dark brown granular, bitter in the mouth, the no moisture absorption and softening	Dark brown granular, bitter in the mouth, the no moisture absorption and softening	Dark brown granular, bitter in the mouth, the no moisture absorption and softening	Dark brown granular, bitter in the mouth, the no moisture absorption and softening
Differentiate	The thin layer identification experiment of Radix Et Rhizoma Rhei	On Radix Et Rhizoma Rhei control medicinal material and emodin reference substance chromatograph relevant position, show the same color speckle
						The thin layer identification experiment of Semen Arecae	On Semen Arecae control medicinal material chromatograph relevant position, show identical Chinese red speckle
	The contained Neosynephrine thin layer of Fructus Aurantii Immaturus is differentiated	On Neosynephrine reference substance chromatograph relevant position, show identical aubergine speckle
						Check	Moisture content (%)	????4.80	????4.79	????4.83	????4.89
Granularity	Up to specification	Up to specification	Up to specification	Up to specification
					Assay		Contain the general anthraquinone class in emodin % (g/g)	????3.012	????3.082	????2.998	????3.065
Health examination	Antibacterial mycete pathogenic bacterium demodicid mite alive	＜10/g＜10/g does not detect	＜10/g＜10/g does not detect	＜10/g＜10/g does not detect		＜10/g＜10/g does not detect

3. sample three:

Preparation preliminarily stabilised test report sample title: stomach medicine lot number of the present invention: 40818

Standing time (experiment date) is project as a result		0 month	January	February	March
						Character		Dark brown granular, bitter in the mouth, the no moisture absorption and softening	Dark brown granular, bitter in the mouth, the no moisture absorption and softening	Dark brown granular, bitter in the mouth, the no moisture absorption and softening	Dark brown granular, bitter in the mouth, the no moisture absorption and softening
Differentiate	The thin layer identification experiment of Radix Et Rhizoma Rhei	On Radix Et Rhizoma Rhei control medicinal material and emodin reference substance chromatograph relevant position, show the same color speckle
						The thin layer identification experiment of Semen Arecae	On Semen Arecae control medicinal material chromatograph relevant position, show identical Chinese red speckle
	The contained Neosynephrine thin layer of Fructus Aurantii Immaturus is differentiated	On Neosynephrine reference substance chromatograph relevant position, show identical aubergine speckle
						Check	Moisture content (%)	????4.81	????4.88	????4.85	????4.91
Granularity	Symbol platform regulation	Up to specification	Up to specification	Up to specification
					Assay		Contain the general anthraquinone class in emodin % (g/g)	???? ????2.933	????2.975	????2.902	????2.900
Health examination	Antibacterial mycete pathogenic bacterium demodicid mite alive	＜10/g＜10/g does not detect	＜10/g＜10/g does not detect	＜10/g＜10/g does not detect		＜10/g＜10/g does not detect

Embodiment 11: clinical practice

The inventor carries out clinical prerun in June, 1994 to this medicine, totally 35 examples.The result: stomach medicine of the present invention is 68.57% to the obvious effective rate of epigastric fullness, and total effective rate is 94.29%.Do not find that in clinical prerun process this medicine has obvious adverse reaction, now is summarized as follows clinical pre-test result.

1. physical data: 35 routine cases, male's 21 examples wherein, women's 14 examples; Minimum 31 years old of age, maximum 65 years old, 45 years old mean age; Chronic gastritis 23 examples wherein, chronic cholecystitis 12 examples; 8 examples that epigastric fullness is slight, moderate 20 examples, severe 7 examples.

2. case is selected: selecting Western medicine diagnose is that chronic gastritis or chronic cholecystitis and the adult patients with the dialectical genus syndrome of liver-stomach heat of epigastric fullness cardinal symptom or eating accumulation are as the object of observation.

3. diagnostic criteria

3.1 tcm diagnosis

3.1.1 conscious stomach is glutted, distension or distending pain discomfort

3.1.2 show effect repeatedly more than 2 months

3.2 Chinese medical discrimination

3.2.1 syndrome of liver-stomach heat

Primary symptom: full vexed, distension of the gastral cavity side of body or scorching hot pain

Inferior disease: xerostomia, bitter taste; Lack of appetite is indigestion and loss of appetite; The belch singultus; Irritated irritability; Acid regurgitation

Noisy; Constipation with dry stool

Sign: red tongue, yellow and thin fur, stringy pulse or stringy and rapid pulse

3.2.2 eating accumulation

Primary symptom: chest distress, painful abdominal mass plug do not relax or distending pain or abdominal distention tenderness

Inferior disease: constipation, lack of appetite are indigestion and loss of appetite, belching and acid regurgitation, feel sick, vomiting, fidgety

Signs: yellow fur, slippery and rapid pulse

(above two cards, all possess each one of primary symptom, inferior disease or more than, tongue, the pulse condition person of meeting are promptly diagnosable simultaneously)

3.3 Western medicine diagnose

3.3.1 chronic gastritis: slightly

3.3.2 chronic cholecystitis: slightly

4. therapeutic outcome

4.1 total effects: 35 routine patients, after treatment, obtain and cure 14 examples, produce effects 10 examples, effective 9 examples, invalid 2 examples, total effective rate 94.29%.

4.2 symptom curative effect: symptoms such as stomach is glutted, distension or distending pain, appetite minimizing, constipation, belch all have extremely significantly before the treatment improves (seeing 30 tables)

Table 30 symptom curative effect

Stomach is glutted, distension appetite reduces the dim gas of constipation

Or distending pain (routine number) (routine number) (routine number) (routine number) symptom grade (branch)

00 24 6 26 15 29 6 241 8673528 62 20 4 18 5 10 3 13 53 7141518 0R1,0.6980 0.6482 0.6673 0.6543R2,0.3020 0.3519 0.4227 0.3457U, 9.12 4.29 3.54 4.47P after controlling before controlling after controlling before controlling after controlling before controlling after controlling before controlling＜0.001＜0.001＜0.001＜0.001

4.3 untoward reaction: in clinical prerun process, slight stomachache sense is arranged after 2 examples are taken medicine, separate the spontaneous remission of suffering from abdominal pain after an action of the bowels, do not influence and continue to take medicine.

5. model case

5.1 example one, outstanding * *, the woman, 59 years old, the retired cadre, upper abdomen distending pain repeatedly, hiccough is year surplus, and recurrence increases the weight of to accompany bitter taste indigestion and loss of appetite, constipation 3 days, the T.P.R that haves a medical check-up, BP.Normally, stringy pulse, yellow fur, painful sickly complexion, the skin sclera does not have xanthochromia, the cardiopulmonary no abnormality seen, abdomen is plentiful, and is soft, the upper abdomen tenderness, no rebound tenderness, liver, spleen, gallbladder all do not lay one's hand on and, no enclosed mass is kowtowed drum, moves turbid (one), and is surplus no special." ultrasound diagnosis " gallbladder size is normal, and wall thickness is crude, does not see the calculus shadow, suggestion: chronic cholecystitis.The white total points of blood, white blood total points, sum 8.5 * 10 ⁹/ L, neutrality 80%, lymph 20%, diagnosis: epigastric fullness, the syndrome of liver-stomach heat type is obeyed stomach medicine 1.6g of the present invention, day 2 times, defecate next day 2 times, abdominal distention and pain, hiccough is clearly better, and serve on three, and symptom disappears substantially, stomach does not have tenderness, and appetite increases, and stool is normal, the white total points of check blood, sum 6.5 * 10 ⁹/ L, neutrality 70%, lymph 30%.Efficacy evaluation is a clinical cure.

5.2 example two, Wu * *, the man, 35 years old, the cadre, upper abdomen dull pain, distension, food back aggravation can temporarily alleviate behind the hiccough belch, defecate not well 2 years surplus.Be diagnosed as " chronic superficial gastritis " through gastroscopy.Careless before two days because of diet, the upper abdomen distension, the pain increased, and the companion feels sick, anorexia, belch is frequent, and yellow urine is few, defecates and does not separate in two days, promptly seeks medical advice.The T.P.R that haves a medical check-up, BP is normal, and stringy and rolling pulse, yellow fur are greasy slightly, the acute pain sickly complexion, the skin slight perspiration, no xanthochromia, the cardiopulmonary no abnormality seen, abdomen is smooth, and is soft, the liver spleen do not lay one's hand on and, the dark tenderness of upper abdomen, no rebound tenderness, borborygmus increase slightly, and are surplus no special, diagnosis: epigastric fullness, the eating accumulation type is promptly taken stomach medicine 1.6g of the present invention, twice of day clothes, defecated the same day once, amount is many, and abdominal distention and pain obviously alleviates, and serve on three, abdominal distention, belch disappears, and it is normal that appetite is recovered, and the stomach tenderness disappears.Efficacy evaluation is a clinical cure.

In sum, the present invention has following characteristics:

1. cure mainly ruffian full disease, i.e. chronic gastritis on the modern medicine, chronic cholecystitis, gastric neurosis etc. on the traditional Chinese medicine; Expel the heat-evil and the logical internal organs of stomach, stagnation resolvation, along the stomach promoting the circulation of qi, take disappear as mend, evident in efficacy;

2. the high amount of medicine is little, defeats with a force inferior in number, effective (not yet finding the Chinese patent drug that uses the crude drug amount to lack than the present invention at present);

3. do not contain any chemical addition agent, excipient etc. in the powder, be pure Chinese medicinal preparation, human body is not had bad side effect;

4. taking convenience is easily swallowed, good absorbing, drug effect be fast;

5. preparation technology is simple, can form rapidly large-scale production, meets the need of market.

Claims (2)

1. stomach medicine, the prescription that it is characterized in that it consists of: Radix Et Rhizoma Rhei powder 3.0g, Fructus Aurantii Immaturus 0.93g, Semen Arecae 0.69g, rhizoma sparganic 0.46g, Rhizoma Curcumae 0.46g, Semen Lepidii (Semen Descurainiae) 0.46g (twice on the one dose), its granule is mixed by Radix Et Rhizoma Rhei powder that takes by weighing by above-mentioned weight ratio and the clear paste that formed by all the other five kinds of Chinese medicine water boiling concentration.

2. the preparation method of stomach medicine of the present invention belongs to the preparation method of Chinese patent medicine, it is characterized in that this preparation method comprises:

1). get the raw materials ready: select for use do not have to go rotten, free from insect pests, unmetamorphosed dry Radix Et Rhizoma Rhei, Fructus Aurantii Immaturus, Semen Arecae, rhizoma sparganic, Rhizoma Curcumae, Semen Lepidii (Semen Descurainiae), Radix Et Rhizoma Rhei mechanical lapping is become powder, sieved with No. six, it is standby to get the fine powder that sieves;

2). the batching: by following weight ratio take by weighing above-mentioned Six-element Chinese medicine get the raw materials ready stand-by, Radix Et Rhizoma Rhei powder: Fructus Aurantii Immaturus: Semen Arecae: rhizoma sparganic: Rhizoma Curcumae: Semen Lepidii (Semen Descurainiae)=3.00: 0.93: 0.69: 0.46: 0.46: 0.46;

3). boil medicine: with in the above-mentioned Six-element medicine except that Radix Et Rhizoma Rhei powder and Fructus Aurantii Immaturus, Semen Arecae, rhizoma sparganic, Rhizoma Curcumae, Semen Lepidii (Semen Descurainiae) mix, add the water that is equivalent to six times of amounts of this Chinese medicine of the five flavours gross weight, conventional decocting Chinese medicine 45 minutes, filter cloth filters, keep filtrate, filtering residue by this method decocting, is fried in shallow oil three times more altogether, abandon filtering residue, it is stand-by to merge three filtrates;

4). system cream: with centrifugal 15 minutes of above-mentioned filtrate 3000rpm, abandon precipitation, the supernatant routine is evaporated to when the milliliter number that is concentrated liquid is equivalent to 0.7 times of used Radix Et Rhizoma Rhei powder and stops to concentrate, and is clear paste;

5). granulating: above-mentioned Radix Et Rhizoma Rhei powder and clear paste are in Radix Et Rhizoma Rhei powder (g): the ratio of clear paste (ml)=0.7: 1 is its uniform mixing, conventional extruding granulating, 60 ℃ of dryings are crossed the 20-40 mesh sieve, and the medicine particle packing check after sieving is finished product.