CN101049486A - Enteric soluble preparation of Chinese traditional medicine for treating chronic ulcerative colitis - Google Patents
Enteric soluble preparation of Chinese traditional medicine for treating chronic ulcerative colitis Download PDFInfo
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Abstract
An enteric Chinese medicine for treating chronic ulcerative colitis is prepared from 6 Chinese-medicinal materials including black plum, coptis root, dried ginger, poppy capsule, etc.
Description
Technical field:
The present invention relates to field of traditional Chinese.Be specifically related to a kind of enteric Chinese medicine preparation for the treatment of chronic ulcerative colitis.
Background technology:
Chronic ulcerative colitis (Nonspecific UC) is a kind of cause of disease and pathogenesis all not bright rectum and colon chronic inflammatory disease, main clinical manifestation is generally regular diarrhoea, mucopurulent bloody stool, stomachache and tenesmus, this disease course of disease is tediously long, delay repeatedly; extent of disease is extensive, and diseased region mainly is positioned at the mucous layer of colon, based on ulcer; involve rectum and sigmoid colon more, spreads all over whole colon sometimes.It has acute fulminant form's case fatality rate height, chronic lasting type canceration rate height, easy characteristics such as outbreak repeatedly, and does not have specific medicament at present, so classified as one of modern difficult treatment by World Health Organization (WHO).American-European countries's sickness rate is higher according to statistics, and prevalence accounts for 40,/10 ten thousand～1,00/,100,000; Sickness rate accounts for 3,/10 ten thousand～11.5/10 ten thousand.Have not yet to see accurate statistical report data in China, but should the trend of increasing be arranged the disease sickness rate in recent years.Clinical see that with 20～40 years old age person men and women's sickness rate difference is not obvious more, wherein have 5%～10% patient canceration can occur, situation allows of no optimist.Chronic ulcerative colitis is called " cancer that is not cancer " by medical circle, belong to world-famous puzzle.
Treat the Western medicine oral formulations of UC at present: sulfasalazine (SASP) is to treat the UC drug of first choice at present.Orally absorbed in a large number, produce untoward reaction such as headache, nephrotoxicity, and cause not having the capacity medicine and arrive at colon by the harmonization of the stomach small intestinal.For overcoming above-mentioned untoward reaction, competitively occurred the alternative SASP of many 5-ASA sustained-release preparations and prodrug in recent years abroad and entered clinical use.Though these novel formulation conlon targeting release effects are remarkable, untoward reaction is few, and preparation costs an arm and a leg, and need take for a long time and keep treatment, and the patient is difficult to bear economically.Conventional medicaments such as meticortelone, cortisone, hydrocortisone and coupling immunomodulator oral medication UC can cross 90% to short-term relief of symptoms effective percentage, but prolonged application produces side effect such as moon face, acne, insomnia, the reduction of body anti-infection ability, and can not prevent recurrence; Immunomodulator is owing to have cytotoxic effect, and prolonged application can cause serious consequences such as Liver and kidney toxicity, leukopenia, needs careful medication.As a whole, in the process of treatment UC, the difficult people's will to the greatest extent of the application of Western medicine.
In addition, the oral preparation of Chinese traditional medicinal of treatment UC: GUCHANG ZHIXIE WAN, the peaceful sheet of the intestines and stomach, thousand happiness sheets and invigorating the spleen and replenishing QI ball etc., be common oral preparation, oral through the stomach absorption, can not avoid the head of liver, stomach to cross absorption effect, curative effect is not good enough.
Local administration preparation about treatment UC: local colon administration preparation commonly used at present has liquid enema, foam etc.But enema mostly is hospital preparation greatly, faces with preparation, mostly is Chinese herbs decoction or Chinese patent medicine diluent, in reasonable compatibility, extracting method, the clarity of medicinal liquid, the viscosity of medicine curative effect shortage pharmaceutics is studied, and more lacks the strict quality standard.Foam is to be popular in the novel form of American-European a kind of UC of treatment in recent years.
Treatment UC also can adopt operative treatment, but can bring out multiple complications, as intestinal perforation, anal fistula, anal fissure, toxic megacolon, colon massive hemorrhage, colon carcinogenesis, septic shock, toxic colon and the false polyp of colon etc.
Above-mentioned situation shows that the Western medicine toxic and side effects of existing treatment chronic ulcerative colitis is big, the conventional absorption treatment of Chinese medicine is long the course of treatment, DeGrain, operative treatment complication rate height.So press for little, the effect of a kind of toxic and side effects of research significantly, the pharmaceutical preparation of stable curative effect, drug safety is very necessary.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, designs a kind of good effect, the medicine of the treatment chronic ulcerative colitis that side effect is little.
The invention provides a kind of new product of Chinese medicine (GUCHANG ZHIXIE WAN, intestine-stabling and anti-diarrheal enteric coated tablet) for the treatment of chronic ulcerative colitis.According to the difference of stomach (pH0.9～1.5), small intestinal (pH6.0～6.8) and colon (pH6.5～7.5) pH select for use can by colonic enzyme or bacterial degradation, the pH sensitivity, at the soluble coating material of colon medicine is carried out coating, to reach colon locating administrated purpose, can improve drug effect like this, medicine is concentrated play a role, reduce untoward reaction in the local patholoic change position.Like this after the medicine oral administration, in stomach and small intestinal, do not discharge, have only the caecum of arrival or colon position just to locate release, can avoid the head of liver, stomach to cross absorption effect, improve bioavailability, so not only reduce the toxic and side effects of conventional oral administration, and can also conduct drugs to affected area, reduce dosage, improve curative effect, thereby improve patient's compliance.
The enteric Chinese medicine preparation of treatment chronic ulcerative colitis of the present invention (GUCHANG ZHIXIE WAN, intestine-stabling and anti-diarrheal enteric coated tablet) is made up of crude drug and the coating material of following weight %, and the crude drug total amount is 100%: Fructus Mume 12%～32%, Rhizoma Coptidis 10%～28%, Rhizoma Zingiberis 10%～28%, the Radix Aucklandiae 8%～22%, Pericarpium Papaveris 8%～22%, Rhizoma Corydalis 8%～22%.The coating material total amount is 100%: acrylic resin II number 16%～37%, hydroxypropylmethyl cellulose phthalate (HPMCP) 37%～72%, magnesium stearate 5%～11%, lactose 3%～7%, pigment starch 4%～9%.
The enteric Chinese medicine preparation of treatment chronic ulcerative colitis of the present invention (GUCHANG ZHIXIE WAN, intestine-stabling and anti-diarrheal enteric coated tablet) is made up of crude drug and the coating material of following weight %,
(1) raw material:
Fructus Mume 12%～18% Rhizoma Coptidis 10%～24% Rhizoma Zingiberis 10%～20%
The Radix Aucklandiae 8%～18% Pericarpium Papaveris 8%～18% Rhizoma Corydalis 8%～18%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～68%
Magnesium stearate 5～10%
Lactose 3%～7%
Pigment starch 4%～9%.
The enteric Chinese medicine preparation of treatment chronic ulcerative colitis of the present invention (GUCHANG ZHIXIE WAN, intestine-stabling and anti-diarrheal enteric coated tablet) is made up of crude drug and the coating material of following weight %,
(1) raw material:
Fructus Mume 12%～27% Rhizoma Coptidis 10%～20% Rhizoma Zingiberis 10%～16%
The Radix Aucklandiae 8%～14% Pericarpium Papaveris 8%～22% Rhizoma Corydalis 8%～16%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～58%
Magnesium stearate 5%～11%
Lactose 3%～6%
Pigment starch 4%～9%.
The enteric Chinese medicine preparation of treatment chronic ulcerative colitis of the present invention (GUCHANG ZHIXIE WAN, intestine-stabling and anti-diarrheal enteric coated tablet) is made up of crude drug and the coating material of following weight %,
(1) raw material:
Fructus Mume 12%～24% Rhizoma Coptidis 10%～16% Rhizoma Zingiberis 10%～24%
The Radix Aucklandiae 8%～22% Pericarpium Papaveris 8%～14% Rhizoma Corydalis 8%～14%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～64%
Magnesium stearate 5%～11%
Lactose 3%～7%
Pigment starch 4%～8%.
The invention provides a kind of preparation method for the treatment of the enteric agents of chronic ulcerative colitis, this method comprises the following steps:
(1) preparation method of label: Fructus Mume, Rhizoma Coptidis, Rhizoma Zingiberis, the Radix Aucklandiae, Pericarpium Papaveris and Rhizoma Corydalis Six-element, through system only, section, after the drying, getting ginger powder, to be broken into fine powder standby.Other gets Rhizoma Coptidis, Pericarpium Papaveris, Rhizoma Corydalis, the Radix Aucklandiae, adds 75% alcohol reflux secondary, adds 6 times of amount ethanol for the first time, adds 4 times of amount ethanol for the second time, and each 2 hours, filter, standby behind the filtrate recycling ethanol.Medicinal residues and Fructus Mume decoct with water secondary, add 10 times of water gagings for the first time, decoct 2 hours, for the second time add 8 times of water gagings, decocted 1.5 hours, filter, filtrate and said extracted liquid merge, and decompression (0.08Mpa, 70 ℃) is concentrated into the thick paste that relative density is 1.38 (60 ℃ of surveys), add above-mentioned fine powder, mixing, drying, be ground into fine powder, granulate, be pressed into 1000, promptly;
(2) coating material preparation method: get acrylic resin II number and the hydroxypropylmethyl cellulose phthalate mix homogeneously, standby.Lactose and pigment starch is dissolved in 1 times of amount distilled water adds in the above-mentioned fine powder, water is made soft material, 26 ℃ dry down, relative humidity 30%, the granulation of sieving mixes magnesium stearate with granule, as the enteric film coating material;
(3) coating operation: the enteric film coating material is dissolved in the dehydrated alcohol, makes the coating solution that concentration is 8% (W/V), in fluid bed, carry out coating and make finished product.Atomisation pressure is 0.3Mpa in the coating operation, feed liquor speed 3mLmin
-1, inlet temperature is 35 ℃, and outlet temperature is 30 ℃, and the dry air flow is 300m
3H
-1
Technical scheme of the present invention is based on following research:
Formulating of the present invention:
1, the consumption of the selection of enteric coatings material and principal agent and coating material is investigated
The intestine-stabling and anti-diarrheal enteric coatel tablets are Chinese medicine half extractum sheets, and moisture absorption is arranged, and therefore the selection to coating material has certain requirement.Enteric coating material should and gastric acid, disintegrate and discharge medicine rapidly in duodenum, " Lac " is the key component of enteric coating, use the earliest, but repeatedly be indicated as labile polymer, its pH value has determined it to dissolve when higher pH (being approximately 7.2), so no longer select for use.This test is carried out preferably conventional lubricants, correctives and coloring agent in the coating material, and finally definite lubricant selects for use magnesium stearate, correctives to select for use lactose, coloring agent to select pigment starch for use.Adopting orthogonal experiment again, is measurement index with slice, thin piece hardness, chooses the enteric film coating material.Through analysis-by-synthesis, determine to form ratio between slice, thin piece enteric film coating material prescription and coating material and the medicated core weight.
Experimental design
(1) three factors, three horizontal L9 (3 are selected in factor, level design for use
4) show to carry out preferably.(seeing Table 1)
Table 1 factor level table
| Level | Factor | ||
| A (coating material I) | B (coating material II) | C (supplementary product consumption/label weight) | |
| 1 2 3 | Acrylic resin I acrylic resin II acrylic resin III number | Cellulose acetate phthalate ester (CAP) hydroxypropylmethyl cellulose phthalate (HPMCP) polyvinyl acetate phthalate ester (PVAP) | 5％～6％ 6％～7％ 7％～8％ |
(2) experimental establishment and tables of data (seeing Table 2)
Table 2 experimental establishment and orthogonal test table
| Gauge outfit design row number | 1 A | 2 B | 3 C | 4 D | Hardness (kg) |
| 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 1 3 | 5.5 8.6 5.9 7.3 7.6 7.2 7.8 5.8 5.6 |
Annotate: above data are the meansigma methods of measuring 5 times
More than preferred result, in conjunction with needs of production, so it is acrylic resin П number that final definite intestine-stabling and anti-diarrheal enteric coatel tablets are selected coating material I for use, coating material II is a hydroxypropylmethyl cellulose phthalate, and coating is 6%～7% with material and label weight ratio.
2, enteric coatings material usage ratio is investigated
Adopting orthogonal experiment, is measurement index with slice, thin piece disintegration and friability, chooses enteric film coating material percentage by weight.Through analysis-by-synthesis, determine percentage by weight between the enteric film coating material prescription.
Experimental design
(1) three factors, three horizontal L9 (3 are selected in factor, level design for use
4) table carries out preferred (seeing Table 3)
Table 3 factor level table
| Level | Factor | ||
| A (acrylic resin II) | B (hydroxypropylmethyl cellulose phthalate) | C (adjuvant commonly used) | |
| 1 2 3 | 0～15％ 16～37％ 38～100％ | 73～100％ 37～72％ 0～36％ | 0～12％ 12～27％ 0～27％ |
(2) experimental establishment and tables of data (seeing Table 4)
Table 4 experimental establishment and orthogonal test table
| Gauge outfit design row number | 1 A | 2 B | 3 C | 4 D | Disintegration time (min) (behind the 2h in PB pH6.8) | Friability (%) |
| 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 1 3 | 43 38 42 39 38 37 46 42 40 | 4.32 3.69 4.30 2.98 2.86 3.07 4.28 4.02 4.21 |
Annotate: above data are the meansigma methods of measuring 5 times
Disintegration time is good with the little person of numerical value.Therefore, it is 16%～37% that analysis result promptly adds acrylic resin II percentage by weight, and the hydroxypropylmethyl cellulose phthalate percentage by weight is 37%～72%, and all the other ordinary coating material weight percentage ratios are 12%～27%.
Friability is good with the little person of numerical value.Therefore, it is 16%～37% that analysis result finally selects to add acrylic resin II percentage by weight, and the hydroxypropylmethyl cellulose phthalate percentage by weight is 37%～72%, and all the other ordinary coating material weight percentage ratios are 12%～27%.
The preferred result of above index is identical, in conjunction with needs of production, be analyzed as follows: three factors all have the significance influence to disintegration time, and only have factor A that friability is had the significance influence, so final determine that the enteric coatings material is to add 16%～37% by weight percentage acrylic resin II number, hydroxypropylmethyl cellulose phthalate adds 37%～72% by weight percentage, and all the other ordinary coating materials add 12%～27% by weight percentage.
3, magnesium stearate, lactose and pigment starch usage ratio are investigated
Adopting orthogonal experiment, is measurement index to prepare enteric thin film coating material angle of repose, chooses in the enteric film coating material.Through analysis-by-synthesis, determine in the enteric film coating material prescription percentage by weight between magnesium stearate, lactose and the pigment starch.
Experimental design
(1) three factors, three horizontal L9 (3 are selected in factor, level design for use
4) table carries out preferred (seeing Table 5)
Table 5 factor level table
| Level | Factor | ||
| A (magnesium stearate) | B (lactose) | C (pigment starch) | |
| 1 2 3 | 0～4％ 5～11％ 12～27％ | 8～27％ 3～7％ 0～2％ | 0～3％ 4～9％ 0～13％ |
(2) experimental establishment and tables of data (seeing Table 6)
Table 6 experimental establishment and orthogonal test table
| Gauge outfit design row number | 1 A | 2 B | 3 C | 4 D | Angle of repose (℃) |
| 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 1 3 | 45.38 38.96 44.98 29.87 35.32 30.09 43.88 31.26 35.19 |
Annotate: above data are the meansigma methods of measuring 5 times
Angle of repose be the expression mobility of particle index, angle of repose little then good fluidity.Analysis result shows: A
2B
2C
2Combination help particulate flowability.So final selection result is: stearyl ester magnesium percentage by weight is 5%～11%, and the lactose percentage by weight is 3%～7%, and pigment starch percentage by weight is 4%～9%.
Comprehensive analysis results shows, the enteric film coating material of intestine-stabling and anti-diarrheal enteric coatel tablets is made of by weight percentage following kind: acrylic resin II number 16%～37%, hydroxypropylmethyl cellulose phthalate 37%～72%, magnesium stearate 5%～11%, lactose 3%～7%, pigment starch 4%～9%.And coating material consumption and label percentage by weight are 6%～7%.
One, pharmacodynamics test
Be subjected to the reagent thing: the intestine-stabling and anti-diarrheal enteric coatel tablets, brown medicated powder, the 1g tablet is equivalent to the 3.33g crude drug.Press the fresh preparation of desired concn with distilled water before the experiment.Positive drug is a GUCHANG ZHIXIE WAN, and the 1g pill is equivalent to the 1g crude drug.
Animal subject: ICR strain white mice, SD strain rat, Cavia porcellus, male and female half and half or single male, body weight: mice 18～22g, rat 220～300g, Cavia porcellus 340～420g.Animal feeding condition: laboratory air-conditioning temperature control, 25～28 ℃ of room temperatures, relative humidity 45%～75%.
Test method and result: route of administration explanation: in view of this medicine is an enteric coated tablet, can orally absorb, then be difficult to full wafer animal and irritate stomach, then lose the enteric meaning as irritating stomach with medicated powder in the intestinal disintegrate the people.So animal employing coloclysis dose regimen is promptly used a thin plastic pipe, front end is used to burn and is timed, and inserts the about 2cm of colon (mice), 3cm (rat), and an animal low level is used light finger light press anus 1min, so that medicinal liquid gos deep into a colon high position as far as possible behind the injection medicinal liquid.GUCHANG ZHIXIE WAN is still used Gastric lavage.
1, to 2, the 4-dinitrochlorobenzene causes the influence of Cavia porcellus acute ulcer colitis model
60 of healthy male guinea pigs, body weight 340～420g all cuts off hair (1 * 2) cm2 approximately at its back and abdominal part respectively, is divided into 6 groups immediately, and 10 every group, that is: normal saline matched group: NS 2ml/100g; Model control group: NS 2ml/100g; Model+positive drug control group (GUCHANG ZHIXIE WAN 6.0g crude drug/kg); The large, medium and small dosage group of model+intestine-stabling and anti-diarrheal enteric coatel tablets (6.0,3.0,1.5g crude drug/kg).The model preparation: except that the normal saline matched group, other each group is all smeared the dinitrochlorobenzene mixed liquor I in its depilation place, and (2,4 dinitrochlorobenzene and acetone are pressed 0.4g: the 1ml 1ml mixing), hair dryer dries up.After 15 days, (2,4 dinitrochlorobenzene and acetone are pressed 0.2g: the 1ml 1ml mixing), hair dryer dries up to smear dinitrochlorobenzene mixed liquor I I for the second time at the Cavia porcellus abdominal part.After 18 days, inserting the about 6cm of intestinal tube, and (2,4 dinitrochlorobenzene and acetone are pressed 0.2g: the 0.5ml 1ml mixing), the 21st day execution animal to inject dinitrochlorobenzene mixed liquor I II through the Cavia porcellus anus.Administration: normal saline matched group, model control group modeling simultaneously respectively coloclysis the capacity normal saline such as give, GUCHANG ZHIXIE WAN group, the large, medium and small dosage group of intestine-stabling and anti-diarrheal enteric coatel tablets are irritated the medicinal liquid that stomach, coloclysis such as give at the capacity various dose respectively simultaneously in modeling, once a day.Observation index: general situation and the feces of Cavia porcellus; Behind the sacrifice of animal, cut open the colon of getting the above 9～12cm place of anus immediately and do pathologic finding.As a result, the model control group animal is after the 15th day Cavia porcellus abdominal part smeared dinitrochlorobenzene mixed liquor I I, and significantly red and swollen and scleroma all appearred in the animal abdominal part in the 18th day, and the obvious horripilation of animal, and hunchbacked recessed abdomen illustrates that Cavia porcellus is by dinitrochlorobenzene sensitization.Behind the anus injection dinitrochlorobenzene increased frequency, part animal dead tangible loose stool appearred, in 2 hours.The general situation of each administration group Cavia porcellus makes moderate progress than model control group, the molding of part animal stool, and number of times reduces.
Pathological examination shows, the seriality pathological changes of human ulcerative colitis appears being similar in model group animal colon, show as intestinal wall, mucosa and Submucosa height congestion and edema, and ulcer that occurs differing in size and necrosis, the visible a large amount of cell infiltration of ulcer bottom Submucosa and surrounding tissue.The heavy dose of group of intestine-stabling and anti-diarrheal enteric coatel tablets with matched group relatively; ulcer has dwindling to a certain degree; Submucosa edema degree alleviates; around reaching, the ulcer bottom organizes the matter hypertrophy; the visible newborn mucous membrane tissue in part ulcer bottom; illustrate that this medicine can alleviate the inflammation degree of colon, improve the colonic mucosa pathology damage, colonic mucosa is had the certain protection effect.
2, to the influence of rat chronic ulcerative colitis model
Preparation of model: get the colonic mucosa of rat of the same race, normal saline is cleaned, and adds an amount of normal saline and makes tissue homogenate,-20 ℃ freezing 24 hours, the molten back of freezing is got its supernatant and is purified with 4000 rev/mins of centrifugal 30min, measure protein content, refrigerator storage is standby.During use with complete Freund ' s adjuvant by emulsifying in 1: 1, it is standby to be mixed with the antigen emulsion.Get 70 of male SD rats, body weight 220～300g, get 10 at random and be the normal control group, 60 rats are animal pattern in addition, i.e. injections of antigens emulsion 4mg in every sufficient sole of the foot first, and in the 10th, 17,24,31 day respectively at the sufficient sole of the foot, back, groin, intraperitoneal injection antigen 4mg (the last injection does not add adjuvant).Last injection back the 2nd day is with pentobarbital sodium ip anesthesia, and the formalin solution 2ml coloclysis with 1.5% was kept somewhere 1 hour, used the normal saline eluting, and reuse antigen liquid 1ml (contain 4mg, do not add adjuvant) coloclysis is kept somewhere 2 hours afterwash.Put to death animal on the 20th day after the above-mentioned processing, cut open rapidly and get above colon 6～8cm, fix with 10% formalin solution apart from anus 2cm, pathological section, HE dyeing, light microscopic is observed down.Administration situation: in modeling in the time of the 31st day, rat model is divided into 5 groups (each group has individual animal death) at random, it is model group, model+positive drug (GUCHANG ZHIXIE WAN) group, the large, medium and small dosage group of model+intestine-stabling and anti-diarrheal enteric coatel tablets, and beginning administration: saline control group and model control group coloclysis wait outside the capacity saline, positive controls is irritated stomach and is given above-mentioned medicinal liquid 2.0ml/100g body weight, intestine-stabling and anti-diarrheal enteric coatel tablets then coloclysis award variable concentrations medicinal liquid 2.0ml/100g body weight (respectively organizing dosage with experiment 1), once a day, successive administration is 20 days.Observation index: the general situation of observing animal when (1) modeling and administration: expression, activity, hair, appetite, stool and body weight (weighing once weekly) change.Put to death animal when (2) experiment finishes, cut open and get colon and do pathological examination with 10% formalin fixed.The result: cardinal symptom occurs and extinction time: diarrhoea appears in rat model in about 20 days, behind formalin and the antigen liquid perfusion, bloody purulent stool appears in rat model, with appetite minimizings, the Of-thin that disappears, movablely reduce, erect mao, crispatura, performance such as hair is not bright and clean.After the treatment, each treated animal above-mentioned symptom of administration obviously improves, and the heavy dose of treated animal of GUCHANG ZHIXIE WAN and intestine-stabling and anti-diarrheal enteric coatel tablets suffer from diarrhoea about 8～10 days and alleviated or stop, and other symptoms are obviously improvement also; In the antidiarrheal enteric coatel tablets, small dose group treatment still has 4/10 and 6/9 rat that diarrhoea is arranged when finishing.The all no abnormal performance of normal rats.Test rat appetite and body weight change: rat appetite and body weight change such as table 7 and table 8 during modeling and the administration, model group rat appetite obviously reduces, and body weight obviously reduces, with the relatively more equal P of normal control group＜0.01; All obviously recover by appetite and body weight after treatment for the big or middle dosage group of GUCHANG ZHIXIE WAN and intestine-stabling and anti-diarrheal enteric coatel tablets, compare P＜0.01 or P＜0.05 with model group, and small dose group appetite and body weight all have certain increase than model group, but do not have tangible statistical significance (P＞0.05).
Table 7. intestine-stabling and anti-diarrheal enteric coatel tablets are to the influence of chronic ulcerative colitis rat model body weight (x ± s)
| Group | Number of animals (n) | Dosage (the g crude drug/kg) | The variation of rat body weight (g) during modeling and the administration | ||
| Before the modeling | Before the administration | After the administration 20 days | |||
| Normal group model group model+GUCHANG ZHIXIE WAN group antidiarrheal enteric coatel tablets model+heavy dose of group model+middle dosage group model+small dose group | 10 9 11 11 10 9 | - - 6.0 6.0 3.0 1.5 | 245.5±14.2 238.2±25.7 241.7±16.0 230.1±18.6 248.4±26.1 233.9±15.4 | 295.2±25.6 267.8±23.4 ** 254.5±26.8 ** 262.8±28.4 ** 268.5±26.7 * 266.3±27.0 ** | 337.8±22.1##++ 235.2±24.3## 302.4±21.5##++ 297.0±39.8##++ 280.1±27.6++ 254.7±14.8 |
Compare with the normal control group
*P＜0.05,
*P＜0.01; With comparison #P＜0.05 before the administration, ##P＜0.01;
With model group comparison+P＜0.05, ++ P＜0.01
Table 8. intestine-stabling and anti-diarrheal enteric coatel tablets are to the influence of chronic ulcerative colitis rat model appetite (x ± s)
| Group | Number of animals (n) | Dosage (the g crude drug/kg) | The variation of rat appetite during modeling and the administration (g/100g body weight) | ||
| Before the modeling | Before the administration | After the administration 20 days | |||
| Normal group model group model+pellet for curing diarrhea group antidiarrheal enteric coatel tablets model+heavy dose of group model+middle dosage group model+small dose group | 10 9 11 11 10 9 | - - 6.0 6.0 3.0 1.5 | 8.3±1.9 7.9±1.6 7.7±1.5 8.6±2.2 7.3±1.4 7.6±1.1 | 8.5±2.1 6.3±1.0 ** 6.0±0.7 ** 5.9±0.9 ** 5.8±1.1 ** 6.5±0.8 ** | 8.1±1.8++ 4.8±1.4# 7.4±2.0#++ 7.3±1.8#++ 6.7±2.5+ 6.1±1.3 |
Compare with the normal control group
*P＜0.01; With comparison #P＜0.05 before the administration, ##P＜0.01;
With model group comparison+P＜0.05, ++ P＜0.01
Pathology are the result show, the necrosis of model control group mucosa large tracts of land, structural deterioration, and ulcer that occurs differing in size and petechia.Ulcer can be involved Submucosa, the visible a large amount of cell infiltration of ulcer bottom Submucosa and surrounding tissue; The heavy dose of treated animal of positive drug GUCHANG ZHIXIE WAN group and intestine-stabling and anti-diarrheal enteric coatel tablets with model group relatively, colonic mucosa is complete substantially, ulcer has dwindling to a certain degree, the edema degree alleviates under the mucosa, the regional area mucosa is thinner, and body of gland is not of uniform size, is newborn shape body of gland, ulcer bottom and surrounding tissue hypertrophy are obvious, the visible newborn mucous membrane tissue in part ulcer bottom; In, the visible big amount lymphocyte of small dose group, cell infiltration, erosion and ulcer, but light than model group.Illustrate that this medicine can alleviate the inflammation degree of colon, improve the colonic mucosa pathology damage, colonic mucosa is had the certain protection effect.
3, antidiarrheal experiment
3,1. the intestine-stabling and anti-diarrheal enteric coatel tablets cause the effect of diarrhea of mouse to Oleum Ricini
Get 60 of mices, body weight 18～22g, male and female half and half are divided into 6 groups immediately, 10 every group, be normal control group (NS0.2ml/10g), Oleum Ricini diarrhoea model group, the large, medium and small dosage group (8.0,4.0 of model+intestine-stabling and anti-diarrheal enteric coatel tablets, 2.0g crude drug/kg), model+GUCHANG ZHIXIE WAN positive controls (the 8.0g crude drug/kg).Except that the normal control group, all the other each dosage treated animals are all irritated stomach and are given Oleum Ricini 0.3ml/10g, continuous three days.After the success of diarrhoea model, except that normal group and model group, all the other respectively organize administration 0.2ml/10g, the GUCHANG ZHIXIE WAN gastric infusion, the administration of intestine-stabling and anti-diarrheal enteric coatel tablets coloclysis continuous 7 days, places metabolic cage with mice after the last administration, metabolic cage underlying one clean filter paper is observed mice defecation frequency, shape, color in 4 hours.Observing the weight of animals during modeling and the administration changes.The results are shown in Table 9.
Table 9. intestine-stabling and anti-diarrheal enteric coatel tablets cause the influence (x ± s) of diarrhea of mouse to Oleum Ricini
| Group | Number of animals (n) | Body weight change (g) | Feces (4h) | ||||
| Before the modeling | After the modeling | After the treatment | Number of times | Shape | Color | ||
| Normal group model group model+pellet for curing diarrhea group intestine-stabling and anti-diarrheal enteric coatel tablets model+heavy dose of group model+middle dosage group model+small dose group | 10 10 10 10 10 10 | 19.8±1.2 19.2±1.4 20.1±1.1 20.3±0.8 20.5±1.0 19.4±1.3 | 20.4±1.5 18.3±1.8 ** 18.5±1.5 ** 17.9±1.7 ** 18.4±1.9 ** 17.8±2.1 ** | 21.1±1.7 17.3±2.2 ** 19.1±2.5 18.6±1.8 18.7±2.4 18.1±2.0 | 12.3±2.8## 17.5±3.1 ** 8.6±3.8## 8.4±2.6## 10.2±3.4## 12.3±2.6## | The rare water sample soft grit of solids shape soft grit shape is granular or paste is granular or paste | Dark brown pale brown darkish complexion is brown dark brown dark brown |
Compare with the normal control group
*P＜0.01; Compare ##P＜0.01 with model control group
Result's demonstration, model group mice body weight obviously reduces (P＜0.01), and after the Drug therapy, GUCHANG ZHIXIE WAN positive group and each dosage treated animal body weight of intestine-stabling and anti-diarrheal enteric coatel tablets increase obviously than model group, but add up not remarkable (P＞0.05).Model group feces is rare water sample, pale brown color, often; Positive group and each dosage group treatment back defecation frequency obviously reduce, and are the granular or paste of brownish black.Illustrate that the intestine-stabling and anti-diarrheal enteric coatel tablets cause diarrhea of mouse to Oleum Ricini certain therapeutical effect is arranged.
3,2 intestine-stabling and anti-diarrheal enteric coatel tablets cause the effect of diarrhea of mouse to Radix Et Rhizoma Rhei
Get 60 of mices, body weight 18～22g, male and female half and half are divided into 6 groups immediately, 10 every group, be normal control group (NS0.2ml/10g), Radix Et Rhizoma Rhei diarrhoea model group, the large, medium and small dosage group (8.0,4.0 of model+intestine-stabling and anti-diarrheal enteric coatel tablets, 2.0g crude drug/kg), model+GUCHANG ZHIXIE WAN positive controls (the 8.0g crude drug/kg).Except that the normal control group, all the other each dosage group mices are all irritated stomach and give Radix Et Rhizoma Rhei (100% immersion) 0.3ml/10g, continuous three days.After the success of diarrhoea model, except that normal control group and model group, all the other each groups are irritated stomach or coloclysis administration 0.2ml/10g, continuous 7 days, after the last administration mice is placed metabolic cage, metabolic cage underlying one clean filter paper is observed mice defecation frequency, shape, color in 4 hours.Observing the weight of animals during modeling and the administration changes.The results are shown in Table 10.
The result shows, model group mice body weight obviously reduces, and after the Drug therapy, positive group of GUCHANG ZHIXIE WAN and the heavy dose of treated animal body weight of intestine-stabling and anti-diarrheal enteric coatel tablets increase obviously (P＜0.05) than model group, in, small dose group also rises appreciably than model group, but statistics not significantly (P＞0.05).Model group feces is rare water sample, not molding, and pale brown color, often; Positive group and each dosage group defecation frequency obviously reduce (P＜0.05 or P＜0.01), are the granular or paste of brownish black.Illustrate that the intestine-stabling and anti-diarrheal enteric coatel tablets have the antagonism Radix Et Rhizoma Rhei to cause the effect of diarrhea of mouse.
Table 10. intestine-stabling and anti-diarrheal enteric coatel tablets cause the influence (x ± s) of diarrhea of mouse to Radix Et Rhizoma Rhei
| Group | Number of animals (n) | Body weight change (g) | Feces (4h) | ||||
| Before the modeling | After the modeling | After the treatment | Number of times | Shape | Color | ||
| Normal group model group model+positive group antidiarrheal enteric coatel tablets model+heavy dose of group model+middle dosage group model+small dose group | 10 10 10 10 10 10 | 20.8±1.2 20.7±1.0 20.4±1.4 20.9±1.1 19.4±1.3 20.1±1.3 | 21.4±2.3 18.1±3.0 ** 17.7±2.1 ** 18.4±1.7 ** 17.8±2.1 ** 17.6±2.9 ** | 22.6±2.5 17.5±2.8 ** 20.6±3.6# 20.9±2.6## 19.5±3.2 * 18.2±3.5 ** | 10.3±2.8 15.8±3.4 7.4±3.0## 7.1±3.5## 9.4±3.2## 11.6±3.5## | The rare water sample of solids is granular granular or paste is granular or paste | Dark brown pale brown darkish complexion is brown dark brown dark brown |
Compare with the normal control group
*P＜0.05
*P＜0.01; Compare #P＜0.05##P＜0.01 with model control group
4, conclusion (of pressure testing)
Experimental result shows, the inflammation degree that the intestine-stabling and anti-diarrheal enteric coatel tablets can alleviate 2, the 4-dinitrochlorobenzene causes Cavia porcellus acute ulcer colitis, can resist the general symptom of chronic ulcerative colitis rat model, can eliminate hyperemia, edema, the glutinous company of intestinal mucosa, suppress the formation and development of ulcer, improve the colonic mucosa pathology damage, colonic mucosa inflammation and ulcer are had certain therapeutical effect.The diarrhoea that can obviously suppress Radix Et Rhizoma Rhei and Oleum Ricini induced mice.
Two, toxicology test
1, acute toxicity test
Be subjected to the reagent thing: the intestine-stabling and anti-diarrheal enteric coatel tablets, brown medicated powder, 1g medicated powder is equivalent to the 3.33g crude drug.It is standby to be mixed with the suspension of 50% (availability Cmax) with distilled water during test.
Animal subject: ICR strain white mice, male and female half and half, body weight 18～22g.The animal feeding condition: laboratory air-conditioning temperature control, 20～25 ℃ of room temperatures, relative humidity 50%～70%, ventilation fan ventilates, available light 12h/ day, raise in cages by sex, 5 in every cage, per three days cleaning cage houses are once.
Test method: in view of this medicine is an enteric coated tablet, can orally absorb, then be difficult to full wafer animal and irritate stomach, then lose the enteric meaning as irritating stomach with medicated powder in the intestinal disintegrate the people.So animal is adopted the coloclysis dose regimen, promptly uses a thin plastic pipe, front end is used to burn and is timed, and inserts the about 2cm of colon, and an animal low level is used light finger light press anus 1min after injecting medicinal liquid, so that medicinal liquid gos deep into a colon high position as far as possible.
Get 15 of mices, male and female are regardless of, and average mark is 3 groups at random, and coloclysis gives 50%, 25%, 12.5% intestine-stabling and anti-diarrheal enteric coatel tablets suspension 0.3ml/10g respectively, carries out LD
50Prediction.Animal expression, activity, hair in three days as a result, ingest, feces, body weight etc. there is no abnormal change, and fail to measure the Dm and the Dn of this medicine, so carry out the maximum dosage-feeding test.
Get 20 of ICR strain white mice, male and female half and half, water 12h is can't help in fasting, gives 0.3ml/10g with the Cmax coloclysis of this medicine 50%, connect in one day to three times, 4h adds up dosage 90ml/kg, i.e. 45g/kg at interval, amount to 149.9g crude drug/kg, freely absorb drinking water after the administration, observe 7d.The result: the movable minimizing after the each administration of mice is normal behind the 2h.Continue to observe 7 days, none is only dead for 20 mices, and hair, behavior, activity, food just, body weight (before the test: 20.1 ± 1.2g, the test back: 21.7 ± 1.4g) there is no unusual.The dislocation of the 8th day cervical vertebra is put to death, each Mus heart of gross necropsy, liver, spleen, lung, kidney, stomach, intestinal, rectum, thymus, adrenal gland, ovary or testis and thoracic cavity and abdominal cavity main organs and body cavity, do not see color is arranged, paramophia changes.
Result of the test: the movable minimizing after the each administration of mice is normal behind the 2h.Continue to observe 7 days, none is only dead for 20 mices, and hair, behavior, activity, food just, body weight (before the test: 20.1 ± 1.2g, the test back: 21.7 ± 1.4g) there is no unusual.The dislocation of the 8th day cervical vertebra is put to death, each Mus heart of gross necropsy, liver, spleen, lung, kidney, stomach, intestinal, rectum, thymus, adrenal gland, ovary or testis and thoracic cavity and abdominal cavity main organs and body cavity, do not see color is arranged, paramophia changes.
Conclusion (of pressure testing): the intestine-stabling and anti-diarrheal enteric coatel tablets are 45g/kg/ day to the maximum dosage-feeding of ICR strain mice coloclysis administration, amount to 149.9g crude drug/kg, are equivalent to 600 times of clinical people's consumption with weighing machine, show that this medicine does not have the overt toxicity effect.
2, long term toxicity test
Be subjected to the reagent thing: the intestine-stabling and anti-diarrheal enteric coatel tablets, brown medicated powder, 1g medicated powder is equivalent to the 3.33g crude drug.The 40C refrigerator is preserved, and presses the fresh preparation of desired concn with distilled water.
Animal subject: SD strain rat; Male and female half and half, body weight 80～100g.Get 160 of healthy white rats, be divided into 4 groups at random, 40 every group, male and female half and half, that is: 1. normal control group: irritate stomach with capacity 20ml/kg such as distilled water; 2. the intestine-stabling and anti-diarrheal enteric coatel tablets are heavy dose of organizes: irritate stomach with 40% intestine-stabling and anti-diarrheal enteric coatel tablets suspension 20ml/kg, promptly 8.0g/kg amounts to crude drug 26.6g/kg, is equivalent to 106 times of clinical people's consumption; 3. dosage group in the intestine-stabling and anti-diarrheal enteric coatel tablets: the suspension 20ml/kg with 20% concentration irritates stomach, and promptly 4.0g/kg amounts to crude drug 13.3g/kg, is equivalent to clinical people approximately and intends 53 times of consumption every day; 4. intestine-stabling and anti-diarrheal enteric coatel tablets small dose group: the suspension 20ml/kg with 10% irritates stomach, and promptly 2.0g/kg amounts to crude drug 6.7g/kg, is equivalent to clinical adult approximately and intends 26.5 times of consumption every day.
The animal feeding condition: the air-conditioning temperature control, 20～26 ℃ of room temperatures, relative humidity 45%～75%, lamp ventilates with ventilation fan.Animal is divided the cage group support by sex, and 5 in every cage cleans the Mus house every day once.The food solid feed, drink tap water, drinking water freedom.The animal adaptability begins administration after raising a week.
Instrument: Hitachi's 7071 blood counting instruments, japanese product; AEC type automatic clinical chemistry analyzer, U.S.'s prestige show and reach company's product.
Test method: route of administration: clinical human oral medication, so the rat oral gavage administration is consistent with the clinical administration approach.
Grouping and dosage design: with 160 of SD rats, be divided into 4 groups at random, 40 every group, male and female half and half.Grouping situation and dosage design are as previously mentioned.
The administration cycle: according to 2 months situation of clinical course of treatment, the long poison cycle of rat is 6 months.In administration after 3 months every group put to death 1/2 (20) animal at random, in administration after 6 months every group put to death residue 2/3 animal (12) at random and carry out relevant the inspection, 8 convalescent periods tests of doing two weeks of drug withdrawal in addition.Administration 6 days weekly during the administration, once a day, in the morning 8～9 o'clock administration.
The animal processing method: 3,6 months and drug withdrawal convalescent period after administration, in the last administration after 24 hours, under 12 hours situations on an empty stomach, the anesthesia of rats by intraperitoneal injection pentobarbital sodium is got blood through femoral artery, and the sacrificed by decapitation animal performs an autopsy on sb and cuts open and get main organs.
General situation of observation and inspection project and body weight change: observe outward appearance, hair, behavior, activity, the secretions respectively organize rat day by day, ingest, situations such as breathing, feces, claim rat body weight weekly 1 time, and change the administration capacity of adjusting with body weight.Measure simultaneously rats eating amount once (every group hero or female rats feed on the one total amount divided by its TBW) weekly, represent with the g/100g body weight.
Hematological examination: after administration 3,6 months and drug withdrawal convalescent period, tested rat is weighed, lumbar injection 3% pentobarbital sodium (30mg/kg) anesthesia, femoral artery blood sampling 0.5ml, anticoagulant heparin, measure the every index of routine blood test with blood counting instrument: red blood cell count(RBC) (RBC), content of hemoglobin (HGB), platelet count (PLT), numeration of leukocyte (WBC), and lymphocyte (LYM), mononuclear cell (MID), the shared percentage ratio of neutrophilic granulocyte (GRN).
Blood biochemical learn to be checked: after administration 3,6 months and drug withdrawal convalescent period, rat anesthesia, femoral artery is got blood 3～4ml, centrifugalize serum is measured blood parameters with full automatic biochemical apparatus: alanine aminotransferase (ALT), aspartate amino transferase (AST), alkali phosphatase (ALP), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine (CRE), total bilirubin (TB), blood glucose (GLU), T-CHOL 10 indexs such as (CHOL).
Coagulation time test: capillary tube method.
Electrocardiogram: in administration 6 months and drug withdrawal convalescent period, under pentobarbital sodium intraperitoneal injection of anesthesia state, main check criteria II lead electrocardiogram, and measure indexs such as PR interval, QRS interval, QT interval, the T wave-wave width of cloth and heart rate.
System's anatomic observation: sacrificed by decapitation animal after administration 3,6 months and drug withdrawal convalescent period, carry out obduction immediately, main organs and body cavitys such as each treated animal heart of naked eyes gross examination of skeletal muscle, liver, spleen, lung, kidney, adrenal gland, thymus, uterus, ovary, testis, epididymis, prostate, stomach, intestinal, bladder, thoracic cavity, abdominal cavity.
Main organs coefficient: after system dissects, take out 13 internal organs such as the heart, liver, spleen, lung, kidney, adrenal gland, thymus, prostate, testis, epididymis, uterus, ovary and brain, weigh and calculate organ coefficient (organ weights/body weight).
Histopathological examination: get 24 tissues such as the rat heart, liver, spleen, lung, kidney, brain, stomach, duodenum, ileum, colon, pancreas, hypophysis, spinal cord (thoracic vertebra section), breastbone (bone and bone marrow), mesenteric lymph node, bladder, testis, epididymis, uterus, ovary, thymus, adrenal gland, thyroid and prostate, 10% formaldehyde fixed, specimens paraffin embedding slices, HE dyeing, optical microscope check down whether each internal organs has pathology to change.
Statistical method: all (x ± s) expression, the t that relatively adopts in twos of mean checks experimental data between group with mean+SD.
Result of the test
Influence to general situation of rat and body weight change: after the administration rat generally in order, hair luster, behavior, movable normal, eat just normal,, nose do not have pathological changes such as secretions and dyspnea, skin does not have tinea pedis and ulcer.Each is organized rat body weight and increases each administration group rat body weight situation of change and matched group comparison there was no significant difference (P＞0.05) gradually; Each treated animal food ration is not seen notable difference.Above presentation of results intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion 3 months and 6 months do not have obvious influence to general situation of rat and body weight change.Body weight change the results are shown in Table 11 and table 12; The food-intake variation sees Table 13.
Influence to rat blood: after administration 3 months, 6 months and convalescent period, each organizes rat under nembutal ip anesthesia, from femoral artery blood sampling carrying out blood routine inspection.The result shows that in the time of 3 months, the mononuclear cell percentage ratio of dosage treated animal obviously reduces (P＜0.05) in the intestine-stabling and anti-diarrheal enteric coatel tablets in administration, but numerical value does not have tangible dose-dependence still in the normal physiological scope yet.Intestine-stabling and anti-diarrheal enteric coatel tablets administration group rat blood is learned other indexs and the matched group checked and is compared, and (P＞0.05) has no significant change.When administration 6 months and convalescent period, intestine-stabling and anti-diarrheal enteric coatel tablets administration group rat blood is learned and is checked index and matched group relatively, and (P＞0.05) has no significant change.Above result shows that the intestine-stabling and anti-diarrheal enteric coatel tablets to the influence of rat blood Non Apparent Abnormality, the results are shown in Table 14.
To the biochemical influence of rat blood: after administration 3 months, 6 months and convalescent period, each treated animal is got blood from femoral artery under nembutal ip anesthesia, carries out every blood biochemical with automatic biochemical analyzer and learns and check.The result shows that after 6 months, heavy dose of group rat blood serum blood urea nitrogen descends statistical significance (P＜0.01) is arranged at intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion; In dosage group rat blood serum creatinine descend and the cholesterol rising has statistical significance (P＜0.05 or P＜0.01), but numerical value does not have tangible dose-dependence still in the normal physiological scope yet.And during convalescent period, intestine-stabling and anti-diarrheal enteric coatel tablets administration group rat blood biochemical analysis index and matched group relatively, (P＞0.05) has no significant change.Above result shows that intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion to rat liver function, kidney merit and the influence of other biochemical indicator Non Apparent Abnormalities, the results are shown in Table 15.
To Electrocardiographic influence: after administration 6 months and convalescent period, under pentobarbital sodium intraperitoneal injection of anesthesia state, bioassay standard II lead electrocardiogram.The result shows that each administration group rat heart rate is normal, and the rhythm of the heart is neat, and PR interval, QRS interval, QT interval, T involve other each ripple no abnormality seens, with the more no abnormal change of control rats electrocardiogram.Show that intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion to the no abnormal influence of rat electrocardiogram, the results are shown in Table 16.
System's anatomic observation: after administration 3 months, 6 months and convalescent period, every treated animal 20 of sacrificed by decapitation, 12 respectively only reaches 8 rats, immediately by only performing an autopsy on sb, observe the color, form, pathological changes of main organs such as the heart, liver, spleen, lung, kidney, stomach, duodenum, jejunum, colon, bladder, adrenal gland, thymus, testis, epididymis, ovary, uterus, brain, hypophysis, abdominal cavity, thoracic cavity and body cavity etc.The result shows that the main organs of each treated animal and body cavity do not have color and paramophia, and naked eyes are not found pathological change.
Organ coefficient is measured: after administration 3 months, 6 months and convalescent period, win the heart, liver, spleen, lung, kidney, adrenal gland, thymus, prostate, testis, epididymis, uterus, ovary and the brain of every animal after the postmortem immediately, inhale the liquid of dehematizing with filter paper, claim weight in wet base with the balance of different ranges respectively by the internal organs size, calculate organ coefficient (g/100g body weight or mg/100g body weight).The result shows, each organ coefficient of administration group rat is all in the normal physiological scope, and with blank group not statistically signigicant (P＞0.05) relatively.Show that intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion to the no abnormal influence of Rats Organs and Tissues coefficient, the results are shown in Table 17.
Histopathological examination: after administration 3 months, 6 months and convalescent period, each treated animal is won totally 24 tissues such as the heart, liver, spleen, lung, kidney, brain, stomach, duodenum, ileum, colon, pancreas, hypophysis, spinal cord, breastbone (bone and bone marrow), mesenteric lymph node, bladder, testis, epididymis, uterus, ovary, thymus, adrenal gland, thyroid and prostate respectively.10% formaldehyde fixed, specimens paraffin embedding slices, pathological examination is carried out in HE dyeing under the optical microscope.The result shows, each organs and tissues clear in structure of intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion group rat is found pathological changes such as the cell infiltration relevant with administration, hyperemia, edema, degeneration, necrosis, compares with matched group, all no significant difference.Show that intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion does not cause that toxic pathology changes.
Conclusion (of pressure testing): the intestine-stabling and anti-diarrheal enteric coatel tablets give the continuous gastric infusion of rat after 6 months, do not cause tangible toxic reaction, and providing the nontoxic amounts of reactants of rat with weighing machine is 8.0g/kg, amounts to crude drug 26.6g/kg, is equivalent to 106 times of clinical people's consumption.
The influence that table 11 intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion changes male rat body weight (g) (x ± s)
| Administration time (week) | Matched group | Intestine-stabling and anti-diarrheal enteric coatel tablets 8.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 4.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 2.0g/kg |
| Administration front 123456789 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 | 92.1±6.5 116.4±11.1 146.3±14.1 175.4±18.0 204.6±19.5 228.2±20.9 260.6±24.4 282.0±23.9 299.4±24.6 314.3±26.8 331.2±36.7 346.5±36.2 362.4±31.4 376.8±28.7 391.8±28.8 403.1±32.2 420.6±31.0 431.7±34.9 440.3±31.8 442.2±31.0 454.4±35.7 454.1±33.6 458.8±34.4 470.7±35.1 477.0±36.2 478.6±33.9 479.3±34.8 479.6±37.6 485.0±41.9 491.0±45.6 | 92.7±5.9 109.9±9.4 143.1±17.4 172.3±17.1 208.3±26.4 236.6±28.7 266.1±27.5 284.9±33.1 295.4±35.6 305.8±36.9 323.6±28.0 337.1±29.2 358.6±37.2 373.6±32.3 377.1±36.5 404.4±46.4 419.7±47.6 424.4±50.3 429.3±40.8 432.5±48.9 441.0±52.7 444.1±51.8 449.1±48.5 462.8±52.3 464.5±53.9 464.4±50.6 467.8±48.0 474.3±53.8 480.8±51.1 483.8±54.8 | 90.5±6.3 110.9±11.0 139.9±13.4 166.6±15.2 195.8±18.1 220.5±20.0 256.6±23.6 274.2±28.5 290.2±27.3 300.3±38.2 319.4±30.5 336.0±32.2 353.7±33.9 368.4±38.5 382.0±39.2 401.2±44.9 414.9±45.6 421.8±51.4 428.3±50.6 432.7±49.0 437.6±49.4 441.0±47.2 452.9±46.2 456.8±52.8 462.2±50.8 463.4±48.7 468.6±44.2 473.9±46.9 475.0±44.8 476.5±40.8 | 91.1±7.0 112.4±9.8 140.5±12.3 169.3±14.8 199.2±24.3 226.4±19.7 254.4±22.2 276.5±24.1 294.1±19.7 309.8±21.9 329.4±28.7 342.7±29.8 366.8±40.1 380.1±33.2 399.1±37.9 407.2±45.3 423.3±51.9 433.6±50.3 442.6±53.6 443.7±54.1 452.2±54.4 454.5±47.9 473.8±49.0 477.8±55.6 479.6±52.3 481.1±50.8 485.5±55.4 491.4±54.4 492.5±52.8 495.3±62.0 |
Annotate: n is a number of animals; Reach 1～13 week, n=20 before the administration; 14～27 weeks, n=10; 28～29 weeks, n=4
The influence that table 12 intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion changes female rats body weight (g) (x ± s)
| Administration time (week) | Matched group | Intestine-stabling and anti-diarrheal enteric coatel tablets 8.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 4.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 2.0g/kg |
| Administration front 123456789 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 | 90.4±5.5 105.8±7.0 117.3±10.2 131.1±15.4 146.1±14.8 158.5±16.0 174.5±17.1 189.4±18.1 204.2±19.2 218.0±21.7 225.6±19.4 234.5±20.6 243.7±21.1 249.9±20.1 256.6±29.5 257.8±26.7 265.7±23.7 271.0±25.2 276.3±24.9 279.2±27.9 281.4±25.3 282.9±25.7 283.8±25.9 284.2±25.6 288.2±23.1 292.3±24.3 294.1±25.3 297.9±20.4 301.5±23.8 302.8±25.1 | 89.5±5.4 108.6±6.2 113.0±14.8 141.6±17.9 151.9±15.8 164.7±24.8 179.6±26.6 194.8±22.8 202.5±28.2 221.2±18.5 228.6±16.9 239.6±24.7 246.3±26.8 256.8±29.4 265.8±22.7 268.4±20.5 272.2±18.5 274.7±17.7 275.6±17.1 275.1±20.0 279.8±20.4 285.2±19.1 286.5±19.0 288.5±15.4 289.9±17.5 293.1±19.6 295.0±20.1 305.2±21.0 306.8±22.0 307.3±24.3 | 87.5±6.1 104.6±6.9 118.6±11.0 128.4±12.0 148.7±18.4 160.9±15.8 183.7±21.0 192.0±19.2 200.6±24.7 224.8±26.9 230.7±20.2 240.1±19.8 257.8±24.8 264.3±18.8 262.2±18.3 270.5±18.4 271.0±16.6 275.5±18.1 277.5±21.6 279.3±18.7 280.6±17.3 284.8±20.1 287.0±23.2 292.4±24.6 292.4±24.6 293.7±22.3 292.4±22.0 307.8±21.3 309.3±20.0 308.0±20.5 | 89.2±6.0 103.9±9.8 112.6±16.2 126.3±14.7 137.1±20.1 148.3±20.6 166.7±18.0 187.2±25.4 198.7±17.4 210.7±19.2 220.7±25.9 224.7±24.2 239.8±20.8 250.1±24.5 254.4±19.9 262.5±16.9 263.5±17.6 265.1±16.5 268.1±15.9 270.3±17.6 273.0±16.8 275.3±15.4 276.6±17.6 279.6±15.3 279.6±15.3 282.2±16.6 286.8±14.1 291.8±14.0 294.0±18.7 296.8±17.0 |
Annotate; N is a number of animals; Reach 1～13 week, n=20 before the administration; 14～27 weeks, n=10; 28～29 weeks, n=4
The influence that table 13 intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion changes rat every hectogram body weight every day food-intake (g)
| Administration time (week) | Matched group | Intestine-stabling and anti-diarrheal enteric coatel tablets 8.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 4.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 2.0g/kg | ||||
| Male | Female | Male | Female | Male | Female | Male | Female | |
| Administration front 123456789 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 | 17.4 13.9 13.6 11.4 11.2 8.7 7.3 6.8 6.6 6.0 5.6 5.9 5.7 6.3 6.4 5.7 5.3 5.4 5.1 4.8 4.5 4.7 4.6 4.4 4.6 5.0 5.1 4.9 4.6 4.9 | 18.7 14.3 14.1 11.9 12.5 10.1 9.1 9.8 9.1 8.1 7.8 7.6 7.9 7.2 7.5 6.7 6.4 6.1 5.9 6.4 6.3 6.1 5.8 6.0 6.1 5.8 5.7 6.0 6.1 5.9 | 16.8 14.1 13.9 11.2 10.7 8.9 7.6 6.6 7.2 5.8 6.0 6.2 6.7 6.1 6.7 5.4 5.9 5.6 5.4 4.6 5.0 5.1 4.9 5.1 4.9 5.3 5.4 5.2 5.0 5.1 | 15.5 15.1 13.9 11.6 13.1 10.3 8.6 8.9 8.9 7.7 7.5 8.0 7.6 7.7 8.4 6.6 6.5 6.2 6.1 5.8 6.2 5.8 5.9 5.8 6.5 6.6 6.1 5.6 6.3 6.1 | 16.3 12.8 12.7 12.4 10.1 8.8 7.8 6.3 6.5 5.6 5.5 5.3 5.3 6.0 5.8 6.1 5.4 5.3 5.3 5.1 4.9 4.5 4.8 4.9 5.3 4.8 5.0 5.4 5.3 5.4 | 17.3 13.9 13.8 12.7 12.9 11.6 9.5 9.7 9.1 7.5 7.3 7.2 7.3 7.6 7.9 6.9 6.8 7.0 6.2 6.9 6.7 6.5 6.3 6.6 6.9 6.8 6.7 6.2 5.9 6.0 | 17.1 13.6 14.5 11.0 11.8 9.0 6.8 7.2 7.1 6.1 5.9 5.6 5.2 5.7 5.9 5.8 5.0 4.9 5.0 4.8 5.0 4.9 4.8 4.6 5.1 4.7 5.3 4.6 4.7 4.8 | 18.1 15.6 13.3 12.2 12.0 9.9 9.3 9.0 9.8 8.8 8.1 7.7 7.8 8.1 8.4 7.0 6.7 6.5 6.9 6.7 6.6 6.4 5.6 5.7 6.9 6.1 6.0 5.9 6.4 6.2 |
Table 14 intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion is learned the influence (x ± s) of index to rat blood
| Administration time | Project | Matched group | Intestine-stabling and anti-diarrheal enteric coatel tablets 8.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 4.g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 2.0g/kg |
| Three months n=20 | RBC(10 12/L) HGB(g/L) PLT(10 9/L) WBC(10 9/ L) LYM (%) MID (%) GRN (%) clotting time (s) | 9.0±0.5 174.1±5.1 776.5±141.5 10.8±3.1 69.0±2.5 8.2±1.8 22.9±2.0 23.9±8.0 | 8.9±0.6 174.3±7.1 782.9±149.1 11.7±3.5 68.7±3.0 7.1±1.7 24.4±2.9 27.5±8.6 | 8.9±0.5 .176.2±7.2 782.3±125.7 11.9±3.3 70.2±4.3 6.7±2.1 * 23.1±4.1 24.0±9.1 | 9.0±0.6 178.3±7.1 755.0±163.0 11.6±3.4 69.6±3.7 7.0±2.0 23.5±3.9 25.6±7.5 |
| Six months n=12 | RBC(10 12/L) HGB(g/L) PLT(10 9/L) WBC(10 9/ L) LYM (%) MID (%) GRN (%) clotting time (s) | 8.7±0.7 178.6±9.1 720.3±175.7 10.3±3.7 69.7±2.5 8.1±2.6 22.3±3.9 27.5±12.9 | 8.6±0.5 177.1±7.6 651.0±173.5 12.4±3.7 69.8±3.5 7.4±2.0 22.8±3.1 29.3±9.1 | 8.8±0.5 179.2±5.9 692.1±152.5 11.1±3.0 69.7±3.2 7.6±2.7 22.8±2.6 25.5±10.7 | 8.8±0.6 177.7±8.9 701.2±140.6 11.3±3.3 68.9±3.4 7.8±2.2 23.3±3.9 33.5±13.4 |
| Convalescence n=8 | RBC(10 12/L) HGB(g/L) PLT(10 9/L) WBC(10 9/ L) LYM (%) MID (%) GRN (%) clotting time (s) | 8.9±0.4 175.1±8.4 789.8±137.9 12.9±4.7 69.8±3.6 6.9±2.1 23.3±3.2 31.3±9.6 | 8.9±0.7 176.1±11.4 712.8±174.6 12.5±5.3 70.0±5.7 6.5±1.7 23.5±5.5 34.4±12.5 | 9.1±0.4 179.4±6.5 746.0±176.9 11.6±3.7 69.1±4.4 6.9±2.5 24.0±4.0 29.4±10.7 | 9.0±0.8 178.6±10.1 793.9±105.0 11.7±4.5 68.4±4.6 5.9±2.0 25.7±4.6 32.1±8.9 |
Annotate: n is a number of animals.
Compare with matched group,
*P＜0.05
Table 15 intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion is to the influence of rat blood biochemical indicator (x ± s)
| Administration time | Project | Matched group | Intestine-stabling and anti-diarrheal enteric 8.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 4.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 2.0g/kg |
| Three months n=20 | ALT(U/L) AST(U/L) ALP(U/L) BUN(mmol/L) CRE(μmol/L) TP(g/L) ALB(g/L) GLU(mmol/L) TB(μmol/L) CHOL(mmol/L) | 41.50±12.24 69.24±16.53 91.33±15.67 7.00±1.02 67.26±13.83 68.31±3.44 30.43±3.10 6.86±0.63 4.45±2.07 1.18±0.32 | 43.36±8.67 67.88±13.72 90.48±19.62 7.11±1.03 69.08±10.53 67.97±3.79 30.69±2.79 6.93±0.78 4.35±1.10 1.36±0.26 | 37.52±7.71 76.10±17.76 93.90±25.57 6.80±0.89 60.38±15.72 67.77±4.56 30.34±4.41 6.55±0.64 4.71±1.36 1.32±0.29 | 37.41±8.18 72.25±14.72 93.51±22.40 6.32±1.15 71.27±11.09 66.38±3.90 30.61±3.15 6.67±0.86 4.23±1.47 1.30±0.31 |
| Six months n=12 | ALT(U/L) AST(U/L) ALP(U/L) BUN(mmol/L) CRE(μmol/L) TP(g/L) ALB(g/L) GLU(mmol/L) TB(μmol/L) CHOL(mmol/L) | 46.93±5.46 69.44±9.55 91.08±16.65 5.89±0.35 48.78±4.52 67.26±3.35 30.48±3.51 6.27±0.59 3.40±0.51 1.22±0.16 | 46.69±11.82 65.88±12.39 82.38±20.04 5.15±0.61 ** 46.45±3.95 70.62±4.86 32.20±5.17 5.91±0.79 3.14±0.42 1.33±0.24 | 42.10±8.99 65.26±14.89 78.02±24.55 5.83±1.47 43.71±4.92 67.31±3.90 31.62±4.07 5.96±0.65 3.18±0.39 1.45±0.18 ** | 44.60±5.58 76.27±10.27 86.28±14.97 5.65±1.25 48.05±5.04 68.48±4.60 30.75±4.16 6.62±0.75 3.15±0.24 1.36±0.27 |
| Convalescence n=8 | ALT(U/L) AST(U/L) ALP(U/L) BUN(mmol/L) CRE(μmol/L) TP(g/L) ALB(g/L) GLU(mmol/L) TB(μmol/L) CHOL(mmol/L) | 43.55±6.18 66.59±11.88 83.34±6.63 6.48±0.29 51.65±1.96 68.39±2.49 28.85±2.65 6.80±0.86 2.83±0.18 1.44±0.22 | 45.33±3.61 64.99±7.42 78.69±6.09 6.39±0.85 51.26±3.11 66.38±2.85 27.91±2.06 7.01±0.51 3.06±0.43 1.33±0.17 | 41.06±2.85 66.69±13.80 75.99±12.98 5.84±0.84 50.05±2.54 68.16±1.28 28.25±2.19 6.76±0.52 2.90±0.41 1.27±0.22 | 38.49±3.95 76.10±12.84 82.21±21.90 6.22±0.84 50.94±3.48 66.15±3.90 30.18±3.35 6.61±0.27 2.93±0.32 1.27±0.20 |
Annotate: n is a number of animals
Compare with matched group,
*P＜0.05;
*P＜0.01
14d is to the influence of rat ECG (x ± s) after table 16 intestine-stabling and anti-diarrheal enteric coatel tablets gastric infusion 6 months and the drug withdrawal
| Administration time | Project | Matched group | Intestine-stabling and anti-diarrheal enteric coatel tablets 8.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 4.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 2.0g/kg |
| Six months n=12 | HR is (inferior/min) PR interval (s) QRS interval (s) QT interval (s) T wave amplitude (mV) | 369.5±52.8 0.046±0.006 0.018±0.003 0.053±0.009 0.134±0.023 | 378.7±43.6 0.047±0.003 0.016±0.005 0.051±0.008 0.123±0.027 | 342.4±36.5 0.045±0.004 0.019±0.006 0.048±0.006 0.117±0.030 | 349.9±40.7 0.046±0.005 0.020±0.006 0.053±0.006 0.125±0.026 |
| Convalescent period n=8 | HR, (inferior/min) PR interval, (s) QRS interval, (s) QT interval, (s) T wave amplitude, (mV) | 338.7±45.3 0.042±0.008 0.017±0.004 0.053±0.012 0.120±0.035 | 363.3±33.7 0.047±0.003 0.018±0.006 0.058±0.014 0.111±0.032 | 370.9±38.8 0.042±0.002 0.017±0.002 0.054±0.004 0.114±0.040 | 349.5±28.7 0.046±0.005 0.019±0.006 0.056±0.006 0.115±0.027 |
Annotate: n is a number of animals.
The administration of table 17 intestine-stabling and anti-diarrheal enteric coatel tablets after 3 months to the influence of Rats Organs and Tissues coefficient (x ± s)
| Administration time | Project | n | Matched group | Intestine-stabling and anti-diarrheal enteric coatel tablets 8.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 4.0g/kg | Intestine-stabling and anti-diarrheal enteric coatel tablets 2.0g/kg |
| Three months | Brain (g/100g) heart (g/100g) liver (g/100g) spleen (g/100g) lung (g/100g) kidney (g/100g) adrenal gland (mg/100g) thymus gland (g/100g) prostate (g/100g) testis (g/100g) epididymis (g/100g) uterus (g/100g) ovary (mg/100g) | 20 20 20 20 20 20 20 20 10 10 10 10 10 | 0.61±0.14 0.30±0.03 2.84±0.24 0.34±0.07 0.57±0.11 0.60±0.06 17.5±5.9 0.11±0.04 0.18±0.04 0.84±0.11 0.42±0.04 0.24±0.05 51.6±8.8 | 0.59±0.14 0.31±0.04 2.96±0.36 0.35±0.08 0.53±0.10 0.61±0.05 17.9±6.8 0.10±0.03 0.17±0.04 0.82±0.09 0.39±0.05 0.26±0.06 55.4±8.7 | 0.62±0.13 0.32±0.04 2.92±0.33 0.35±0.06 0.55±0.10 0.62±0.05 18.8±5.8 0.10±0.04 0.18±0.04 0.87±0.08 0.38±0.07 0.24±0.05 55.0±7.2 | 0.60±0.12 0.31±0.03 2.91±0.20 0.36±0.08 0.56±0.08 0.60±0.05 17.9±6.3 0.10±0.03 0.20±0.04 0.90±0.10 0.40±0.06 0.25±0.07 51.2±6.8 |
| Six months | Brain (g/100g) heart (g/100g) liver (g/100g) spleen (g/100g) lung (g/100g) kidney (g/100g) adrenal gland (mg/100g) thymus gland (g/100g) prostate (g/100g) testis (g/100g) epididymis (g/100g) uterus (g/100g) ovary (mg/100g) | 12 12 12 12 12 12 12 12 6 6 6 6 6 | 0.52±0.12 0.31±0.03 2.69±0.30 0.30±0.06 0.59±0.06 0.62±0.08 18.7±6.6 0.10±0.07 0.23±0.06 0.74±0.10 0.29±0.02 0.28±0.12 52.9±6.1 | 0.53±0.14 0.32±0.03 2.79±0.26 0.29±0.07 0.64±0.10 0.63±0.06 17.4±6.5 0.10±0.06 0.21±0.05 0.69±0.05 0.31±0.02 0.27±0.09 54.8±7.6 | 0.52±0.13 0.31±0.03 2.84±0.31 0.28±0.04 0.61±0.15 0.64±0.09 18.3±7.6 0.11±0.06 0.21±0.06 0.74±0.11 0.29±0.06 0.24±0.07 49.1±6.6 | 0.53±0.12 0.31±0.04 2.78±0.38 0.27±0.08 0.56±0.09 0.62±0.07 16.4±6.8 0.09±0.06 0.22±0.06 0.74±0.13 0.31±0.03 0.25±0.07 51.6±8.4 |
| Convalescent period | Brain (g/100g) heart (g/100g) liver (g/100g) spleen (g/100g) lung (g/100g) kidney (g/100g) adrenal gland (mg/100g) thymus gland (g/100g) prostate (g/100g) testis (g/100g) epididymis (g/100g) uterus (g/100g) ovary (mg/100g) | 8 8 8 8 8 8 8 8 4 4 4 4 4 | 0.52±0.11 0.31±0.03 2.76±0.24 0.29±0.04 0.53±0.11 0.62±0.04 18.5±5.9 0.07±0.02 0.20±0.03 0.72±0.11 0.29±0.04 0.32±0.08 50.3±6.1 | 0.58±0.14 0.33±0.05 2.91±0.26 0.29±0.07 0.55±0.14 0.63±0.05 18.8±8.1 0.08±0.02 0.19±0.05 0.74±0.08 0.32±0.03 0.38±0.09 50.4±8.6 | 0.55±0.15 0.33±0.06 2.64±0.31 0.27±0.05 0.54±0.14 0.64±0.09 20.9±6.9 0.06±0.02 0.22±0.06 0.70±0.10 0.31±0.06 0.31±0.10 52.9±7.0 | 0.54±0.12 0.32±0.08 2.66±0.34 0.28±0.07 0.60±0.09 0.65±0.09 18.6±4.9 0.07±0.02 0.20±0.06 0.69±0.12 0.29±0.06 0.25±0.05 47.3±8.7 |
Annotate: n is a number of animals.
Three, study on the stability
1, the constant temperature and humidity accelerated test is pressed commercially available back with the intestine-stabling and anti-diarrheal enteric coatel tablets, puts the environment of (40 ± 2) ℃, relative humidity (75 ± 5) % and places 6 months down, and respectively at 0,1, the inspection of Chinese Pharmacopoeia prescriptive procedure press in sampling in 3,6 months.
2, keep sample for a long time test with the intestine-stabling and anti-diarrheal enteric coatel tablets by commercially available back, put the environment of (25 ± 2) ℃, relative humidity (60 ± 10) % and placed 6 months down, respectively at 0,1, the inspection of Chinese Pharmacopoeia prescriptive procedure press in sampling in 3,6 months.
The result shows: intestine-stabling and anti-diarrheal enteric coatel tablets color no change, all meet weight differential and disintegration the pharmacopeia regulation, and release, assay meet the requirements, and intestine-stabling and anti-diarrheal enteric coatel tablets good stability is described, meet the Chinese Pharmacopoeia regulation.
Four, clinical observation
1, clinical research plan and research approach brief introduction
Trial drug: intestine-stabling and anti-diarrheal enteric coatel tablets
Test objective: safety and effectiveness to intestine-stabling and anti-diarrheal enteric coatel tablets treatment chronic ulcerative colitis (incoordination between the liver and spleen of having loose bowels) are made an appraisal.
EXPERIMENTAL DESIGN: at random, double blinding dual analog, positive drug parallel control, multicenter II clinical trial phase
The experimenter selects: 18～65 years old age, male or female, signature Informed Consent Form
Sample content: totally 240 examples, treatment group, matched group half and half
Trial drug: investigational agent, intestine-stabling and anti-diarrheal enteric coatel tablets; Contrast medicine: GUCHANG ZHIXIE WAN.
Therapeutic scheme: test group medication: intestine-stabling and anti-diarrheal enteric coatel tablets, 5 slices/time, warm water delivery service, 3 times/day;
The GUCHANG ZHIXIE WAN placebo, 5g/ time, warm water delivery service, 3 times/day.
Matched group medication: GUCHANG ZHIXIE WAN, 5g/ time, warm water delivery service, 3 times/day;
Intestine-stabling and anti-diarrheal enteric coatel tablets placebo, 5 slices/time, warm water delivery service, 3 times/day.
The course of treatment: 8 weeks
Observation index
Curative effect index: the therapeutic effect of syndrome of leading indicator 1, the incoordination between the liver and spleen of having loose bowels card
2, the curative effect of disease of treatment chronic ulcerative colitis
Less important index 1, fibercolonscopy or barium enema
2, stool routine examination
Safety indexes: blood, urine, stool routine examination, the heart, liver, renal function
Statistical analysis: main curative effect and safety indexes (FAS, PPS, SS)
Curative effect and safety evaluatio: according to evaluation criterion, in conjunction with clinical meaning, analysis-by-synthesis.
Expection test progress: confess from the medicine, finish in 1 year.
2, clinical trial present situation brief introduction:
1, official written reply: the intestine-stabling and anti-diarrheal enteric coatel tablets have obtained State Food and Drug Administration's approval and have carried out clinical trial.
2, clinical trial unit:
Clinical trial responsible department: Huaxi Hospital Attached to Sichuan Univ
Clinical trial participant: the hospital of traditional Chinese hospital, Shaanxi Province
No.1 Hospital of Guiyang Traditional Chinese Medicine College
Attached Hospital, Changchun Chinese Medicinal College
First Affiliated Hospital of Heilongjiang University of Chinese Medicine
3, progress: enter case and go into the group stage.
The present invention prepares the intestine-stabling and anti-diarrheal enteric coatel tablets and selects for use the enteric film coating material to be pharmaceutic adjuvant, and shows that through animal pharmacology, toxicological test this invention is taken for a long time, and is nontoxic.Also show that with existing treatment colitis product pharmacodynamics contrast test this invention not only has significant therapeutical effect, and it can directly arrive focal zone and play direct therapeutical effect.At China chronic ulcerative colitis patient cumulative year after year, to the increase day by day of pharmaceutical requirements amount, this invention must be created considerable economic, removes the misery of extensive patients, benefits the society, and good social benefit is arranged.
The specific embodiment
Below in conjunction with instantiation the present invention is described in further detail.
Embodiment 1:
Take by weighing raw material and coating material (g) by following proportioning
Raw material: Fructus Mume 120 (12.0%) Rhizoma Coptidis 280 (28.0%) Rhizoma Zingiberiss 280 (28.0%)
The Radix Aucklandiae 80 (8.0%) Pericarpium Papaveriss 100 (10.0%) Rhizoma Corydalis 140 (14.0%)
Coating material: acrylic resin II numbers 3.2 (16%)
Hydroxypropylmethyl cellulose phthalate 14.4 (72%)
Magnesium stearate 1.0 (5%)
Lactose 0.6 (3%)
Pigment starch 0.8 (4%)
The preparation method of label: Fructus Mume, Rhizoma Coptidis, Rhizoma Zingiberis, the Radix Aucklandiae, Pericarpium Papaveris and Rhizoma Corydalis Six-element, through system only, section, after the drying, getting ginger powder, to be broken into fine powder standby.Other gets Rhizoma Coptidis, Pericarpium Papaveris, Rhizoma Corydalis, the Radix Aucklandiae, adds 75% alcohol reflux secondary, adds 6 times of amount ethanol for the first time, adds 4 times of amount ethanol for the second time, and each 2 hours, filter, standby behind the filtrate recycling ethanol.Medicinal residues and Fructus Mume decoct with water secondary, add 10 times of water gagings for the first time, decoct 2 hours, for the second time add 8 times of water gagings, decocted 1.5 hours, filter, filtrate and said extracted liquid merge, and decompression (0.08Mpa, 70 ℃) is concentrated into the thick paste that relative density is 1.38 (60 ℃ of surveys), add above-mentioned fine powder, mixing, drying, be ground into fine powder, granulate, be pressed into 1000, promptly;
The coating material preparation method: get acrylic resin II number and the hydroxypropylmethyl cellulose phthalate mix homogeneously, standby.Lactose and pigment starch is dissolved in 1 times of amount distilled water adds in the above-mentioned fine powder, water is made soft material, 26 ℃ dry down, relative humidity 30%, the granulation of sieving mixes magnesium stearate with granule, as the enteric film coating material;
Coating operation: coating material is dissolved in the dehydrated alcohol, makes the coating solution that concentration is 8% (W/V), in fluid bed, carry out coating, atomisation pressure is 0.3Mpa, feed liquor speed 3mLmin-1, and inlet temperature is 35 ℃, outlet temperature is 30 ℃, and the dry air flow is 300m
3H
-1
Embodiment 2:
Take by weighing raw material and coating material (g) by following proportioning
Raw material: Fructus Mume 228 (22.8%) Rhizoma Coptidis 182 (18.2%) Rhizoma Zingiberiss 182 (18.2%)
The Radix Aucklandiae 136 (13.6%) Pericarpium Papaveriss 136 (13.6%) Rhizoma Corydalis 136 (13.6%)
Coating material: acrylic resin II numbers 5.0 (25%)
Hydroxypropylmethyl cellulose phthalate 11.0 (55%)
Magnesium stearate 1.6 (8%)
Lactose 1.0 (5%)
Pigment starch 1.4 (7%)
The method for making of label, the method for making of coating material and coating operation such as embodiment 1.
Embodiment 3:
Take by weighing raw material and coating material (g) by following proportioning
Raw material: Fructus Mume 187 (18.7%) Rhizoma Coptidis 158 (15.8%) Rhizoma Zingiberiss 238 (23.8%)
The Radix Aucklandiae 196 (19.6%) Pericarpium Papaveriss 83 (8.3%) Rhizoma Corydalis 138 (13.8%)
Coating material: acrylic resin II numbers 5.8 (29%)
Hydroxypropylmethyl cellulose phthalate 10.0 (50%)
Magnesium stearate 1.8 (9%)
Lactose 1.0 (5%)
Pigment starch 1.4 (7%)
The method for making of label, the method for making of coating material and coating operation such as embodiment 1.
Embodiment 4:
Take by weighing raw material and coating material (g) by following proportioning
Raw material: Fructus Mume 320 (32.0%) Rhizoma Coptidis 100 (10.0%) Rhizoma Zingiberiss 100 (10.0%)
The Radix Aucklandiae 220 (22.0%) Pericarpium Papaveriss 180 (18.0%) Rhizoma Corydalis 80 (8.0%)
Coating material: acrylic resin II numbers 4.6 (23%)
Hydroxypropylmethyl cellulose phthalate 12.2 (61%)
Magnesium stearate 1.4 (7%)
Lactose 0.8 (4%)
Pigment starch 1.0 (5%)
The method for making of label, the method for making of coating material and coating operation such as embodiment 1.
Embodiment 5:
Take by weighing raw material and coating material (g) by following proportioning
Raw material: Fructus Mume 258 (25.8%) Rhizoma Coptidis 118 (11.8%) Rhizoma Zingiberiss 116 (11.6%)
The Radix Aucklandiae 103 (10.3%) Pericarpium Papaveriss 192 (19.2%) Rhizoma Corydalis 213 (21.3%)
Coating material: acrylic resin II numbers 7.4 (37%)
Hydroxypropylmethyl cellulose phthalate 7.2 (36%)
Magnesium stearate 2.2 (11%)
Lactose 1.4 (7%)
Pigment starch 1.8 (9%)
The method for making of label, the method for making of coating material and coating operation such as embodiment 1.
Claims (9)
1, a kind of enteric Chinese medicine preparation for the treatment of chronic ulcerative colitis is characterized in that this Chinese medicine preparation is that raw material and coating material by following weight % makes:
(1) raw material:
Fructus Mume 12%～32% Rhizoma Coptidis 10%～28% Rhizoma Zingiberis 10%～28%
The Radix Aucklandiae 8%～22% Pericarpium Papaveris 8%～22% Rhizoma Corydalis 8%～22%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～72%
Magnesium stearate 5%～11%
Lactose 3%～7%
Pigment starch 4%～9%.
2, a kind of enteric Chinese medicine preparation for the treatment of chronic ulcerative colitis is characterized in that this Chinese medicine preparation is that raw material and coating material by following weight % makes:
(1) raw material:
Fructus Mume 12%～18% Rhizoma Coptidis 10%～24% Rhizoma Zingiberis 10%～20%
The Radix Aucklandiae 8%～18% Pericarpium Papaveris 8%～18% Rhizoma Corydalis 8%～18%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～68%
Magnesium stearate 5%～10%
Lactose 3%～7%
Pigment starch 4%～9%.
3, a kind of enteric Chinese medicine preparation for the treatment of chronic ulcerative colitis is characterized in that this Chinese medicine preparation is that raw material and coating material by following weight % makes:
(1) raw material:
Fructus Mume 12%～27% Rhizoma Coptidis 10%～20% Rhizoma Zingiberis 10%～16%
The Radix Aucklandiae 8%～14% Pericarpium Papaveris 8%～22% Rhizoma Corydalis 8%～16%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～58%
Magnesium stearate 5～11%
Lactose 3%～6%
Pigment starch 4%～9%.
4, a kind of enteric Chinese medicine preparation for the treatment of chronic ulcerative colitis is characterized in that this Chinese medicine preparation is that raw material and coating material by following weight % makes:
(1) raw material:
Fructus Mume 12%～24% Rhizoma Coptidis 10%～16% Rhizoma Zingiberis 10%～24%
The Radix Aucklandiae 8%～22% Pericarpium Papaveris 8%～14% Rhizoma Corydalis 8%～14%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～64%
Magnesium stearate 5%～11%
Lactose 3%～7%
Pigment starch 4%～8%.
5, the preparation method of the enteric Chinese medicine preparation of the described treatment chronic ulcerative colitis of a kind of claim 1 is characterized in that this method comprises the following steps:
(1) raw material:
Fructus Mume 12%～32% Rhizoma Coptidis 10%～28% Rhizoma Zingiberis 10%～28%
The Radix Aucklandiae 8%～22% Pericarpium Papaveris 8%～22% Rhizoma Corydalis 8%～22%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～72%
Magnesium stearate 5%～11%
Lactose 3%～7%
Pigment starch 4%～9%
(3) method for making:
1. the preparation method of label: Fructus Mume, Rhizoma Coptidis, Rhizoma Zingiberis, the Radix Aucklandiae, Pericarpium Papaveris and Rhizoma Corydalis Six-element, through clean system, section is after the drying, getting ginger powder, to be broken into fine powder standby, other gets Rhizoma Coptidis, Pericarpium Papaveris, Rhizoma Corydalis, the Radix Aucklandiae, adds 75% alcohol reflux secondary, adds 6 times of amount ethanol for the first time, add for the second time 4 times of amount ethanol, each 2 hours, filter, standby behind the filtrate recycling ethanol; Medicinal residues and Fructus Mume decoct with water secondary, add 10 times of water gagings for the first time, decoct 2 hours, for the second time add 8 times of water gagings, decocted 1.5 hours, filter, filtrate and said extracted liquid merge ,-0.08Mpa, and 70 ℃ are evaporated to the thick paste that relative density is 60 ℃ of surveys 1.38, add above-mentioned fine powder, mixing, drying, be ground into fine powder, granulate, be pressed into 1000, promptly;
2. coating material preparation method: get acrylic resin II number and the hydroxypropylmethyl cellulose phthalate mix homogeneously, standby, lactose and pigment starch is dissolved in adds in the above-mentioned fine powder in 1 times of amount distilled water, water is made soft material, dry under 26 ℃, relative humidity 30%, the granulation of sieving, magnesium stearate is mixed with granule, as the enteric film coating material;
3. coating operation: the enteric film coating material is dissolved in the dehydrated alcohol, makes the coating solution that concentration is 8%W/V, in fluid bed, carry out coating and make finished product.
6, the preparation method of the enteric Chinese medicine preparation of the described treatment chronic ulcerative colitis of a kind of claim 2 is characterized in that this method comprises the following steps:
(1) raw material:
Fructus Mume 12%～18% Rhizoma Coptidis 10%～24% Rhizoma Zingiberis 10%～20%
The Radix Aucklandiae 8%～18% Pericarpium Papaveris 8%～18% Rhizoma Corydalis 8%～18%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～68%
Magnesium stearate 5%～10%
Lactose 3%～7%
Pigment starch 4%～9%.
(3) method for making
1. the preparation method of label: Fructus Mume, Rhizoma Coptidis, Rhizoma Zingiberis, the Radix Aucklandiae, Pericarpium Papaveris and Rhizoma Corydalis Six-element, through clean system, section is after the drying, getting ginger powder, to be broken into fine powder standby, other gets Rhizoma Coptidis, Pericarpium Papaveris, Rhizoma Corydalis, the Radix Aucklandiae, adds 75% alcohol reflux secondary, adds 6 times of amount ethanol for the first time, add for the second time 4 times of amount ethanol, each 2 hours, filter, standby behind the filtrate recycling ethanol; Medicinal residues and Fructus Mume decoct with water secondary, add 10 times of water gagings for the first time, decoct 2 hours, for the second time add 8 times of water gagings, decocted 1.5 hours, filter, filtrate and said extracted liquid merge ,-0.08Mpa, and 70 ℃ are evaporated to the thick paste that relative density is 60 ℃ of surveys 1.38, add above-mentioned fine powder, mixing, drying, be ground into fine powder, granulate, be pressed into 1000, promptly;
2. coating material preparation method: get acrylic resin II number and the hydroxypropylmethyl cellulose phthalate mix homogeneously, standby, lactose and pigment starch is dissolved in adds in the above-mentioned fine powder in 1 times of amount distilled water, water is made soft material, dry under 26 ℃, relative humidity 30%, the granulation of sieving, magnesium stearate is mixed with granule, as the enteric film coating material;
3. coating operation: the enteric film coating material is dissolved in the dehydrated alcohol, makes the coating solution that concentration is 8%W/V, in fluid bed, carry out coating and make finished product.
7, the preparation method of the enteric Chinese medicine preparation of the described treatment chronic ulcerative colitis of a kind of claim 3 is characterized in that this method comprises the following steps:
(1) raw material:
Fructus Mume 12%～27% Rhizoma Coptidis 10%～20% Rhizoma Zingiberis 10%～16%
The Radix Aucklandiae 8%～14% Pericarpium Papaveris 8%～22% Rhizoma Corydalis 8%～16%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～58%
Magnesium stearate 5%～11%
Lactose 3%～6%
Pigment starch 4%～9%
(3) method for making:
1. the preparation method of label: Fructus Mume, Rhizoma Coptidis, Rhizoma Zingiberis, the Radix Aucklandiae, Pericarpium Papaveris and Rhizoma Corydalis Six-element, through clean system, section is after the drying, getting ginger powder, to be broken into fine powder standby, other gets Rhizoma Coptidis, Pericarpium Papaveris, Rhizoma Corydalis, the Radix Aucklandiae, adds 75% alcohol reflux secondary, adds 6 times of amount ethanol for the first time, add for the second time 4 times of amount ethanol, each 2 hours, filter, standby behind the filtrate recycling ethanol; Medicinal residues and Fructus Mume decoct with water secondary, add 10 times of water gagings for the first time, decoct 2 hours, for the second time add 8 times of water gagings, decocted 1.5 hours, filter, filtrate and said extracted liquid merge ,-0.08Mpa, and 70 ℃ are evaporated to the thick paste that relative density is 60 ℃ of surveys 1.38, add above-mentioned fine powder, mixing, drying, be ground into fine powder, granulate, be pressed into 1000, promptly;
2. coating material preparation method: get acrylic resin II number and the hydroxypropylmethyl cellulose phthalate mix homogeneously, standby, lactose and pigment starch is dissolved in adds in the above-mentioned fine powder in 1 times of amount distilled water, water is made soft material, dry under 26 ℃, relative humidity 30%, the granulation of sieving, magnesium stearate is mixed with granule, as the enteric film coating material;
3. coating operation: the enteric film coating material is dissolved in the dehydrated alcohol, makes the coating solution that concentration is 8%W/V, in fluid bed, carry out coating and make finished product.
8, the preparation method of the enteric Chinese medicine preparation of the described treatment chronic ulcerative colitis of a kind of claim 4 is characterized in that this method comprises the following steps:
(1) raw material:
Fructus Mume 12%～24% Rhizoma Coptidis 10%～16% Rhizoma Zingiberis 10%～24%
The Radix Aucklandiae 8%～22% Pericarpium Papaveris 8%～14% Rhizoma Corydalis 8%～14%
(2) coating material:
Acrylic resin II number 16%～37%
Hydroxypropylmethyl cellulose phthalate 37%～64%
Magnesium stearate 5%～11%
Lactose 3%～7%
Pigment starch 4%～8%
(3) method for making:
1. the preparation method of label: Fructus Mume, Rhizoma Coptidis, Rhizoma Zingiberis, the Radix Aucklandiae, Pericarpium Papaveris and Rhizoma Corydalis Six-element, through clean system, section is after the drying, getting ginger powder, to be broken into fine powder standby, other gets Rhizoma Coptidis, Pericarpium Papaveris, Rhizoma Corydalis, the Radix Aucklandiae, adds 75% alcohol reflux secondary, adds 6 times of amount ethanol for the first time, add for the second time 4 times of amount ethanol, each 2 hours, filter, standby behind the filtrate recycling ethanol; Medicinal residues and Fructus Mume decoct with water secondary, add 10 times of water gagings for the first time, decoct 2 hours, for the second time add 8 times of water gagings, decocted 1.5 hours, filter, filtrate and said extracted liquid merge ,-0.08Mpa, and 70 ℃ are evaporated to the thick paste that relative density is 60 ℃ of surveys 1.38, add above-mentioned fine powder, mixing, drying, be ground into fine powder, granulate, be pressed into 1000, promptly;
2. coating material preparation method: get acrylic resin II number and the hydroxypropylmethyl cellulose phthalate mix homogeneously, standby, lactose and pigment starch is dissolved in adds in the above-mentioned fine powder in 1 times of amount distilled water, water is made soft material, dry under 26 ℃, relative humidity 30%, the granulation of sieving, magnesium stearate is mixed with granule, as the enteric film coating material;
3. coating operation: the enteric film coating material is dissolved in the dehydrated alcohol, makes the coating solution that concentration is 8%W/V, in fluid bed, carry out coating and make finished product.
9, according to claim 5,6,7 or 8 each described a kind of preparation methoies for the treatment of the enteric Chinese medicine preparation of chronic ulcerative colitis, it is characterized in that the condition of wherein said step (3) coating operation is atomisation pressure 0.3Mpa, feed liquor speed 3mlmin
-1, 35 ℃ of inlet temperatures, 30 ℃ of outlet temperatures, dry air flow 300m
3H
-1
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610025453 CN101049486A (en) | 2006-04-05 | 2006-04-05 | Enteric soluble preparation of Chinese traditional medicine for treating chronic ulcerative colitis |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610025453 CN101049486A (en) | 2006-04-05 | 2006-04-05 | Enteric soluble preparation of Chinese traditional medicine for treating chronic ulcerative colitis |
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| Publication Number | Publication Date |
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| CN101049486A true CN101049486A (en) | 2007-10-10 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008592A (en) * | 2010-12-10 | 2011-04-13 | 上海复旦复华药业有限公司 | Method for preparing Gentongping tablets |
| CN103520661A (en) * | 2012-07-06 | 2014-01-22 | 王保安 | Traditional Chinese medicinal enteric-coated tablets for treating proctitis, colitis and irritable bowel syndrome, as well as preparation method and application thereof |
-
2006
- 2006-04-05 CN CN 200610025453 patent/CN101049486A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008592A (en) * | 2010-12-10 | 2011-04-13 | 上海复旦复华药业有限公司 | Method for preparing Gentongping tablets |
| CN103520661A (en) * | 2012-07-06 | 2014-01-22 | 王保安 | Traditional Chinese medicinal enteric-coated tablets for treating proctitis, colitis and irritable bowel syndrome, as well as preparation method and application thereof |
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