CN101152307B

CN101152307B - Traditional Chinese medicine soft capsule for treating abdominal pain and lax, and method for preparing the same

Info

Publication number: CN101152307B
Application number: CN2006101406179A
Authority: CN
Inventors: 曾雄辉
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-09-30
Filing date: 2006-09-30
Publication date: 2012-02-22
Anticipated expiration: 2026-09-30
Also published as: CN101152307A

Abstract

The invention discloses a soft capsule of traditional Chinese medicine for remedying the bellyache and the diarrhea and the preparation method of the soft capsule. Clove, corktree bark, liquorice, tangerine peel and cassia bark are decocted; filtrate is condensed as thick ointment; run oil and menthol are added into the thick ointment to be mixed uniformly for obtaining a traditional Chinese medicine combination; the soft capsule is prepared by adding the officinal auxiliary materials with the pharmic acceptable quantity into the traditional Chinese medicine combination. The soft capsule of traditional Chinese medicine which is prepared by the invention has the advantages of simple technology, good curative effect and being convenient for taking and can be used for remedying the symptoms of inappetence, the nausea and vomitus, the abdominal flatulence and diarrhea, the dyspepsia etc.

Description

A kind of treatment stomachache, diarrheal Chinese medicinal soft capsule and preparation method thereof of being used for

Technical field

The present invention relates to a kind of treatment stomachache, diarrheal Chinese medicinal soft capsule of being used for; Be specifically related to a kind ofly be used to treat unhygienic diet, cold warm discomfort or being not acclimatized and cause cold-damp to be stagnated; The Chinese medicinal soft capsule of the abdominal pain diarrhea that gastrointestinal discord causes the present invention also relates to the method for preparing of this Chinese medicinal soft capsule.

Background technology

The diarrhoea that unhygienic diet or being not acclimatized cause, stomachache are because people's body reacts a kind of imbalance of conditions such as new weather, physical features, water quality, food.Infantile diarrhea is one group to be increased by many cause of diseases, the multifactor times of defecation that causes and the character of defecating is changed into the UDC of characteristics.Can be divided into infectious and non-infectious two kinds.Onset can be delayed can be anxious, and light disease only has gastrointestinal symptom, inappetence, and idol has vomiting, times of defecation to increase and character changes; Heavy person's times of defecation will reach surplus one day ten time, even tens times, stool can be water sample, pasty state, mucus shape, and significantly dehydration and electrolyte disturbance and whole body poisoning symptom such as hyperpyrexia, agitation, lethargy etc. can appear simultaneously in the bloody purulent stool separated that has.The most onset of infantile diarrhea is very anxious, and frequent diarrhoea can make intravital moisture and nutrient lose rapidly, causes acute dehydration.Generally be to take that symptom does not take a turn for the better behind the ORT, lethargy, fever, frequent vomiting, water sample stool occur, even have pus and blood just, should remove hospital admission immediately, but continuous supplementary oral liquor body on the way.

The normal clinical commonly used drug of adult that unhygienic diet or being not acclimatized cause and infantile diarrhea is HUOXIANG ZHENGQI WAN/water and infection and digestant such as berberine; But HUOXIANG ZHENGQI WAN/water and berberine have strong impulse property abnormal smells from the patient, are difficult for the particularly child patient acceptance for the patient.

Summary of the invention

The purpose of this invention is to provide and a kind ofly can be used to treat unhygienic diet, cold warm discomfort or being not acclimatized by effective treatment that the patient is easy to accept and cause cold-damp to be stagnated, the Chinese medicinal soft capsule of the abdominal pain diarrhea that the gastrointestinal discord causes.

Another object of the present invention provides a kind of method for preparing above-mentioned Chinese medicinal soft capsule.

For realizing the foregoing invention purpose, the inventor designs a kind of treatment stomachache, diarrheal Chinese medicinal soft capsule of being used for through a large amount of experiments and performing creative labour on the basis of existing technology, comprises softgel shell and capsule liquid, and described capsule liquid comprises following components by part by weight:

Chinese medicine composition 6-15 dispersant 12-16 suspending agent 0.4～0.7;

Described Chinese medicine composition is formed by the following components in part by weight processing and preparing:

Heat up in a steamer oily 10-50 Flos Caryophylli 5-40 Cortex Phellodendri 5-40 Radix Glycyrrhizae 20-70

Pericarpium Citri Reticulatae 10-35 Cortex cinnamomi japonici (Ramulus Cinnamomi) 5-50 Mentholum 1-15.

Preferably, described Chinese medicine composition is formed through processing and preparing by following parts by weight of Chinese traditional medicine raw material:

Heat up in a steamer oily 15-40 Flos Caryophylli 10-25 Cortex Phellodendri 10-30 Radix Glycyrrhizae 25-50

Pericarpium Citri Reticulatae 12-25 Cortex cinnamomi japonici (Ramulus Cinnamomi) 10-30 Mentholum 2-8.

Most preferably, described Chinese medicine composition is formed through processing and preparing by following parts by weight of Chinese traditional medicine raw material:

Heat up in a steamer oily 20-30 Flos Caryophylli 10-25 Cortex Phellodendri 12-25 Radix Glycyrrhizae 30-45

Pericarpium Citri Reticulatae 15-25 Cortex cinnamomi japonici (Ramulus Cinnamomi) 15-25 Mentholum 3-6.

The described oil that heats up in a steamer is creosote, pine tar or bamboo tar.

Described dispersant is polyethylene glycols or vegetable oil; Described suspending agent is one or more the mixture in Cera Flava, lecithin, aluminum monostearate, ethyl cellulose, the propylene glycol.

Described vegetable oil is a kind of of Oleum Arachidis hypogaeae semen, soybean oil, Oleum sesami, Oleum Brassicae campestris or other consumption vegetable oil or several kinds mixture wherein.

The antiseptic and/or the surfactant that contain convention amount in the described capsule liquid.

Described antiseptic is parabens or glycerol monostearate; Described surface activity reaches and is tween or span.

Described softgel shell comprises following components by part by weight:

Gelatin 80～120 glycerol 30～60 water 80～120 oxybenzene second fat 8～16

The oxide 0.5～5 of ferrum.

A kind of method for preparing above-mentioned Chinese medicinal soft capsule comprises the steps:

With Flos Caryophylli, Cortex Phellodendri, Radix Glycyrrhizae, Pericarpium Citri Reticulatae, Cortex cinnamomi japonici (Ramulus Cinnamomi) decocte with water 2-3 time, each 1-3 hour, collecting decoction filtered, and surveying relative density when filtrating is condensed into 60 ℃ is the thick paste of 1.10-1.30; Wherein amount of water be Flos Caryophylli, Cortex Phellodendri, Radix Glycyrrhizae, Pericarpium Citri Reticulatae, Cortex cinnamomi japonici (Ramulus Cinnamomi) gross weight 6-10 doubly; To heat up in a steamer oil and Mentholum and join in the thick paste, and stir, and get Chinese medicine composition, and add dispersant and suspending agent, colloid mill is ground to mix homogeneously, gets capsule liquid, adopts compacting or dropping preparation method to be packed into softgel shell, is prepared into soft capsule.

The method of the above-mentioned Chinese medicinal soft capsule of another kind of preparation comprises the steps:

1. getting Cortex Phellodendri is 60～90% alcohol heating reflux 2～3 times in percent by volume, each 1～3 hour, filter, and merging filtrate, filtrate recycling ethanol filters to there not being the alcohol flavor, and A must filtrate; Or,

Cortex Phellodendri is processed into coarse powder, and doubly measuring saturated limewater with 8-12 is solvent, supersound extraction 2-3 time, 15-30min/ time; Extracting solution is mixed with the solution of counting 30-35mg/ml with crude drug, filters, add the NaCl placement and spend the night; Filter, oven dry is dissolved in water in deposition, filters; It is 1～2 that filtrating adds hydrochloric acid accent pH, treats that post precipitation filters, and A must filtrate;

2. with Flos Caryophylli, Radix Glycyrrhizae, Pericarpium Citri Reticulatae and Cortex cinnamomi japonici (Ramulus Cinnamomi) decocte with water 2～3 times, each 1～3 hour, collecting decoction filtered, and surveyed relative density when filtrating is concentrated into 60 ℃ and be 1.10～1.30 extractum B; Wherein amount of water is Flos Caryophylli, Radix Glycyrrhizae, Pericarpium Citri Reticulatae and Cortex cinnamomi japonici (Ramulus Cinnamomi) gross weight 6～10 times;

3. the A that will filtrate mixes with extractum B, and relative density is 1.10～1.30 extractum when being concentrated into 60 ℃, drying; Process fine powder, add and heat up in a steamer oil and Mentholum, stir; Get Chinese medicine composition, add dispersant and suspending agent, colloid mill is ground to mix homogeneously; Get capsule liquid, adopt compacting or dropping preparation method to be packed into softgel shell, be prepared into soft capsule.

The described oil that heats up in a steamer is with Fagaceae plant Fagus sinensis Oliv. Fagus sinensis Oliv.; Natural beech section natural plant Zelkova schneideriana Hand.-Mazz.; Maple, Xylosmae japonici, Quercus acutissima Carr., Pinaceae pinaceae Pinus pinus plant pinaster or Juniperus rigida Sieb.et Zucc., bamboo places distillating still to distill, and gets dry distillation liquid and under 180-360 ℃ of condition, distills; The fraction that collection is heavier than water, handle as follows:

1. add the aqueous slkali that percentage by weight is 5-20%, stir crystallisation by cooling;

2. filter, discard filtrating, the washing of filtering residue clear water discards washings; Adding weight percent concentration is the 20-35% sulfuric acid solution, stirs, and discards sulfate wastewater; Clear water washing back is rectification under vacuum under the 0.08-0.09MPa condition in vacuum, collects 130-155 ℃ rectification branch, promptly gets;

Described fraction: aqueous slkali: the weight part ratio of sulfuric acid solution is 1-3: 2-4: 2-3.5.

Add calcium acetate or magnesium acetate solution that percentage by weight is 10-30% after 1. described step stirs again; Described fraction: the weight part ratio of calcium acetate or magnesium acetate is 1-3: 4-7.

Described step aqueous slkali 1. is sodium hydroxide or potassium hydroxide solution.

The described oil that heats up in a steamer is with Fagaceae plant Fagus sinensis Oliv. Fagus sinensis Oliv.; Natural beech section natural plant Zelkova schneideriana Hand.-Mazz., maple, Xylosmae japonici, Quercus acutissima Carr., Pinaceae pinaceae Pinus pinus plant pinaster or Juniperus rigida Sieb.et Zucc., bamboo places distillating still to distill; Getting dry distillation liquid distills under 180-360 ℃ of condition; The collection fraction heavier than water places rectifying still, is 130-155 ℃ in temperature, withdrawing moisture and light fraction under the vacuum 0.08-0.09MPa condition; With the freezing 12-48 hour crystallization under subzero 20 to 0 ℃ of conditions of the fraction in the rectifying still, the crystal centrifugalize obtains heating up in a steamer oily crystal.

Described softgel shell is to place water to make its imbibition in gelatin, in addition glycerol and remaining water is heated to 70-80 ℃, mix homogeneously; Add expansible gelatin, stir fusion; Be incubated 0.5-1.5 hour, vacuum suction is removed bubble, filters; Add oxybenzene second fat, iron oxide red, mixing, 75 ℃ of heat preservation for standby use.

The vacuum of described vacuum suction is-0.08Mpa.

Also add antiseptic and/or surfactant in the described capsule liquid.

The Chinese medicine composition of Chinese medicinal soft capsule of the present invention is that the inventor preferably comes out from crude drug through a large amount of tests, and having stagnation is rushed down, and is used for adult and infantile diarrhea that eating and drinking without temperance or being not acclimatized cause, belongs to damp and hot, dyspepsia card person.Card is seen: inappetence, nausea and vomiting, abdominal distention diarrhoea, dyspepsia.Heating up in a steamer the oils main component is guaiacol (Guaiacol), kreosol (Crosol) and other phenols; Act on similarly with phenol, but its toxicity and zest are all less, are colourless or pale yellow oily liquid; Scurrying property cigarette is smelly; Flavor burns strong, has pharmacological actions such as anticorrosion, antibacterial, local anaesthesia, the clinical treatment that is used for antidiarrheal, whole intestinal and toothache.The Chinese medicine composition of preparation of the present invention has intensive penetrance smoke; For covering the bad smell of medicine; Make the patient be easy to accept; The inventor has carried out a large amount of research to the dosage form of preparation and the selection of used adjuvant, and the moulding process to preparation has carried out performing creative labour simultaneously, finally confirms to select for use soft capsule prepn.

Flos Caryophylli (Eugenia caryophyllata Thunb) is the dry flower of plant clove of myrtaceae; Containing volatile oil is Oleum Caryophylli, be mainly in the Oleum Caryophylli eugenol (Eugenol), acetyleugenol (Acetyleu-genol) and a small amount of α-with β-Flos Caryophylli hydrocarbon (Caryo-phyllene); Secondly be Humuleno (Humulene), chavicol (Chavicol), ylangene (α-Ylangene).Still contain 4 kinds of chromocor derivatives in the alabastrum, be all glycosides million, wherein two kinds is plain (Rhamnetin) and kaempferol (Kaempferol) of Fructus rhamni (Rhamnus davurica Pall.); Other has oleanolic acid (Olean-olicacid), eugenin, eugenitin (Eugenitin), isoeugenitin (Isoeugenitin) etc.Have warming middle-JIAO to send down the adverse QI, reinforcing the kidney and supporting YANG can be used for Deficiency and coldness of spleen and stomach, singultus vomiting, and lack of appetite is told and let out, genuinely convinced cold type of pain, diseases such as impotence due to deficiency of the kidney.

Cortex Phellodendri (Cortex phellodendri) is the dry bark of Rutaceae Cortex Phellodendri (Phelloden-dron amurense Rupr.), and bitter in the mouth is cold in nature, returns kidney, urinary bladder channel.The main component of Cortex Phellodendri is the bitter rope (Li-monin) of berberine (Berberine) and Fructus Citri Limoniae; And contain a small amount of fibrauretin (Palmatine) and obacunone (Obakunone), staphylococcus aureus, bloody dysentery bacterium, gonococcus etc. there are strong effect antibacterial action, suppress the cellular antibody generation.Have effects such as antiinflammatory, blood pressure lowering.Clinical warm dysentery, yellow cellulitis, leukorrhagia, pyretic stranguria, beriberi, flaccidity base, the hectic fever due to YIN-deficiency consumptive fever of being used for; Night sweat, seminal emission, sore swollen toxin, the treatment of diseases such as eczema pruritus.Cortex Phellodendri plays antibiotic, spasmolytic effect in preparation of the present invention.

Pericarpium Citri Reticulatae has the be good for the stomach effect of sharp intestinal of fragrance; The inventor studies the plant amedica composition in the preparation of the present invention and the interaction of guaiacol; It is unexpected that the discovery Pericarpium Citri Reticulatae have significant effects to the pharmacokinetic parameter of guaiacol; And the mean dissolution time of guaiacol measured, experimental details is following:

Materials and methods: the 1. preparation of pill: with the powder mixes of Flos Caryophylli dry extract 4g, Cortex Phellodendri 6g, Radix Glycyrrhizae 3g, Pericarpium Citri Reticulatae 6g; Add glycerol, water and creosote; In the porcelain alms bowl, knead 5min; Process creosote ball (P4R) that is about 4.8mg and the pill (P4R-CUP2) that does not contain Pericarpium Citri Reticulatae, contain the pill (P4R-1/2CUP2) of half amount Pericarpium Citri Reticulatae.2. the mensuration of guaiacol stripping from pill: in (37 ± 0.5) ℃, 6 pills are put into dissolution medium, stir with 100r/min.Respectively at 5,10,20,40, behind the 60min, behind the sampling 1mL, supply volume with fresh medium again.Sample liquid is crossed microporous filter membrane, gets 500 μ L subsequent filtrates, adds mark liquid and 500 μ L ethyl acetate in the 20 μ L.Mixed liquor is stirred 3min, with the centrifugal 3min of 5000r/min, get ethyl acetate layer injection GC-MS system and analyze behind the mixing, observe the stripping of guaiacol from pill.3. pharmacokinetic: the Wistar ST in 10 ages in week is a rat feeding after 2 months, and the rat of choosing body weight 400～450g carries out pharmacokinetic.Fasting 18h is with pentobarbital sodium (30mg/kg) intraperitoneal injection of anesthesia, the jugular vein intubate in the left side then.P4R is bonded at the stomach probe tip, inserts administration in the stomach, distilled water 0.3mL reinjects.After the administration 0.5,10,20,30,60,90,120,180,240,300min, blood sampling 0.5mL is centrifugal from intubate, blood plasma-20 ℃ preservation.Oral castor oil causes the diarrheal rat model and also makes an experiment as stated above.4. the guaiacol concentration in the blood plasma: add buffer in the 150 μ L blood plasma, 37 ℃ of incubation 2h add 1N hydrochloric acid (60 μ L), fluorophenol (20 μ L) and ethyl acetate (1mL) again, stir 3min, with the centrifugal 3min of 5000r/min.The ethyl acetate soluble fraction is analyzed with GC-MS, and the standard curve that gets guaiacol concentration in the blood plasma is Y=0.0005X+0.0086 (r=0.999).

The result: 1. 5,10, during 20min, the dissolution rate of guaiacol from P4R-CUP2 is significantly higher than the dissolution rate of guaiacol from P4R, P4R-1/2CUP2.The MRT of P4R group guaiacol obviously prolongs than P4R-CUP2.Because AUC in two groups the blood _0～5hThere is not significant difference, so think that the effect of Pericarpium Citri Reticulatae prolongation MRT is the influence that receives MDT.The diarrhoea of 2. bringing out for Oleum Ricini, Pericarpium Citri Reticulatae also have the effect that prolongs MRT.After diarrhoea group rat was taken medicine, guaiacol concentration was similar with normal rat in the blood plasma, but the T of guaiacol _Max, AUC _0～5h, mean residence time (MRT) is lower than normal group, but C _MaxBe higher than normal group.3. normal rat is taken behind the P4R 5min that contains (286 ± 8) μ g guaiacol and can be detected guaiacol in the blood plasma, and behind 45～115min, guaiacol concentration peaking is lower than detectable limit in the blood plasma behind the 5h.Because prolonging MRT and MDT is the index that medicine has continuous action, therefore think that the lasting anti-diarrhea effect of pill is relevant with Pericarpium Citri Reticulatae.

Radix Glycyrrhizae in the preparation of the present invention has analgesia, detoxifcation, protection gastric mucosa, the effect of coordinating the actions of various ingredients in a prescription.

The inventor filters out through lot of test has increased the Cortex cinnamomi japonici (Ramulus Cinnamomi) composition on the basis of original prescription; And confirmed its consumption, because the Cortex cinnamomi japonici powder Cortex cinnamomi japonici (Ramulus Cinnamomi) has the effect of warming the interior cold expelling, have synergism with other composition; Make curative effect improve greatly, disease makes lasting medicine.

The technological difficulties of soft capsule mainly are the preparation of capsule liquid, and for guaranteeing the uniform and stable of capsule liquid, general capsule liquid is made up of medicine, dispersant and suspending agent.How to select suitable dispersant and suspending agent, need do creationary research.

One, the selection of dispersant: the selection of medicine dispersant is one of key of development soft capsule, and it should be able to guarantee the accuracy and the stability of formulation of content, thereby guarantees the safety and effectiveness of medicine.At present common dispersants has consumption vegetable oil and Polyethylene Glycol-400 (PEG-400), and the inventor screens above the two consumption through testing.

Get three parts of Chinese medicine compositions, add soybean oil, Oleum Arachidis hypogaeae semen and the Polyethylene Glycol-400 of capacity respectively, fully mix, put in 2000 rev/mins the centrifuge centrifugal 20 minutes after colloid mill ground 30 minutes, the deposition situation of observing two mixed liquors, the result sees table 1.

The different dispersant sedimentation of table 1 situation result of the test

Can know that by result of the test two kinds of consumption vegetable oil and Polyethylene Glycol-400 all can be used as the dispersant of this prescription.But discover that Polyethylene Glycol-400 pair softgel shell has induration, need to add propylene glycol and regulate; In addition, dry run must appropriately be grasped drying time than very fast when being dispersant with Polyethylene Glycol-400, and overlong time can make softgel shell break, and the time is too short, since liquid aqueous in the soft capsule, soft capsule seepage in storage period then caused; Then there is not above-mentioned shortcoming with vegetable oil as dispersant.So vegetable oil is an optimal choice, have good stable property for guaranteeing soft capsule prepn, this prescription preparation selects for use the consumption vegetable oil as dispersant.Through experiment confirm, used vegetable oil can also be Oleum sesami, Oleum Brassicae campestris and other edible vegetable oil, all can obtain essentially identical effect.

Two, the selection of dispersive agent ratio: the consumption of dispersant directly has influence on the yield rate and the loading amount of soft capsule.Dispersive agent ratio is low excessively, good stability, but mobile poor, be difficult for pelleting, yield rate is low; Dispersive agent ratio is excessive, and the thixotroping value is low, good fluidity, but loading amount is big and be easy to seepage.Therefore screen the dispersant of different proportion, thereby confirm optimal proportion.Get the medicated powder of three parts of equivalent, add not commensurability vegetable oil respectively, fully mix after colloid mill ground 30 minutes, observe its state, the result sees table 2.

The selection result of the test of table 2 dispersive agent ratio

Can know that by result in the table when the ratio of dispersant and medicated powder was 1.5: 1, the flowability of medicinal liquid can satisfy the requirement of soft capsule pressing.In that further the test back is definite, be 1.2: 1～1.6: 1 o'clock in ratio, better effects is all arranged, best with 1.4: 1 o'clock.

Three, the selection of suspending agent: in the process of preparation sample, find; When simple medication powder and vegetable oil suspendible, effect is not desirable especially, is very necessary so need to select suitable suspending agent; Adding its Chinese medicine of soft capsule of processing behind the suspending agent is to be scattered in the oil with molecularity; Oil phase gets into blood through lymph in vivo, does not receive the influence of first pass effect, thereby produces high bioavailability.The kind of suspending agent is a lot of like Cera Flava, lecithin, aluminum monostearate, ethyl cellulose, and suspending agent can be the mixture of above-mentioned one or more.Because the Cera Flava cost is minimum and be easy to get, so the inventor preferentially selects Cera Flava to make an experiment as suspending agent, as suspending agent, carries out the screening of suspending agent consumption with different Cera Flava ratios, the result sees table 3.

The selection result of the test of table 3 suspending agent ratio

Can find out that by last table the consumption of suspending agent is 5% o'clock of medicated powder, be fit to that medicinal liquid is even, and is easy to suppress soft capsule for this prescription.After further testing, find that the Cera Flava consumption is the effect that all can play stably in 4%～7% scope of medicated powder amount, optimised quantity is 6% again.Back inventor still studies other several kinds of suspending agents respectively, finds that the suspending agent consumption is at 4%～7% o'clock that medicated powder is, can play the effect of stablizing suspending.It is best suspending agent that final inventor still selects Cera Flava.

In order to guarantee the steady quality of final products, also can in capsule liquid, also to add a certain amount of antiseptic, like parabens, glyceryl monostearate etc.; According to circumstances different; Addition is also different, and is general in about 0.3% of amount of liquid medicine, as long as reach fungistatic effect.Can also add an amount of surfactant, like the Tweens span, addition is fitted situation and is decided, and generally is no more than 1%, with can make capsule liquid mix homogeneously, stabilize to good.

In research capsule liquid, the inventor has also accomplished the research to softgel shell, and situation is following:

The composition of softgel shell comprises the selection of sizing material, plasticizer, water, four types of materials of additives.In principle, the water content of Chinese medicinal soft capsule shell is suitable low, can reduce medicine like this and absorb water from softgel shell.Because the special state of Chinese medicine content is difficult for adopting transparent softgel shell, should adopt coloring agent to make the softgel shell color and luster be deeper than the color and luster of content.The material that soft capsule shell is commonly used is glycerol (plasticizer), gelatin, water, and capsular elasticity and hardness depend on the weight ratio between gelatin in the softgel shell, plasticizer and the water.Usually the suitable weight ratio of soft capsule material is: plasticizer: gelatin=0.4～0.6: 1.0, and water: dry gelatin=1: 1.The inventor through repetition test optimization, has confirmed that the listed ratio of table 4 prepares soft capsule shell according to this characteristics of prescriptions.

Table 4 softgel shell prescription

Place water to make its imbibition in gelatin, in addition glycerol and remaining water are heated to 70-80 ℃, mix homogeneously adds expansible gelatin; Stir, fusion is incubated 0.5-1.5 hour, and vacuum suction is removed bubble; Filter, add oxybenzene second fat, iron oxide red, mixing, 75 ℃ of heat preservation for standby use;

In the technical process of research soft capsule, can use some method of quality control inevitably, so the inventor these method of quality control are improved, as the means of control soft capsule product quality.

The soft capsule of the present invention preparation can be covered the smelly and bright strong taste of scurrying property cigarette of drug substance contents, the problem that change is made us or made groups of people be difficult to take etc., and make that it is clean and tidy, attractive in appearance, swallow easily; Dosage is accurate relatively, and degree of accuracy is higher, can reach the metering of milligram/grain; Bioavailability of medicament is high, and comparatively speaking, capsule and tablet, pill are different; Need not add binding agent and pressure during preparation, belong to dissolving or trickle powder again basically and be scattered in the content, in case disintegrate just together discharges; Imitate rapidly so be, it is good obviously also to absorb soon than pill, tablet; The reason that bioavailability of medicament is high; Reach the needed haemoconcentration of identical drug effect, the unit administration amount of soft capsule reaches the curative effect of tablet with identical purpose etc. with regard to reducing relatively, and test shows; Soft capsule of the present invention and tablet be once oral 100mtg respectively; The 6 examples capsule person that admits defeated is on average peaked at the 1.5h blood level, is 6g/ml; 6 example clothes tablet persons are on average just peaked at the 2.5h blood level, and are had only 3.5 μ g/ml in addition.Improve medicine stability.Like photosensitive medicine, meet damp and hot unsettled medicine, the medicine of easy oxidation etc., because its relative closure encystation, so can be prepared into the soft capsule that adds opacifier, protection medicine receives the effect of oxygen, light in wet and the air, thereby improves its stability; Contain a large amount of creosotes in the Chinese medicine composition of the present invention, be difficult for processing ball, tablet, and the soft capsule prepn of processing has digestive tract good absorbing effect, curative effect height, good stability, dosage advantage accurately, carry light and handy, easy to use.

Pharmacodynamics test research shows that medicine of the present invention can significantly reduce the loose stool number of mice, has anti-diarrhea effect; Can promote the gastric emptying motion of mice; The intestinal propulsion of the hyperfunction model mice of intestinal motion due to inhibition normal mouse and the neostigmine, thereby the absorption of promotion nutrient substance; Promote the secretion of gastric juice and suppress pepsic activity, improve digestive function.Thereby for treatment inappetence, nausea and vomiting, abdominal distention, diarrhoea, dyspepsia etc. provide the pharmacodynamics foundation.

Pharmacodynamics test research

Having of the medicine of the present invention antidiarrheal function that stagnates is used to treat adult that unhygienic diet or being not acclimatized cause and children's's inappetence, nausea and vomiting, abdominal distention, diarrhoea, dyspepsia etc.

This research is adopted Oleum Ricini induced mice diarrhoea and Folium Sennae induced mice diarrheal anti-diarrhea effect, small intestine movement of mice is advanced and to the hyperfunction model mice intestinal propulsion of intestinal motional effects due to the neostigmine, to mice gastric emptying motional effects and to the test method that influences of rat gastric acid, pepsinia, to verify the drug effect of medicine of the present invention.

1 experiment material

Animal: white mice, the Kunming kind, one-level is qualified, male and female half and half, body weight 18-21g; The SD rat, male and female half and half, body weight 180～200g, more than provide by The Fourth Military Medical University's Experimental Animal Center.

Medicine and reagent: the used preparation of test group is the soft capsule prepn (creosote 20kg, Flos Caryophylli 25kg, Cortex Phellodendri 35kg, Radix Glycyrrhizae 70kg, Pericarpium Citri Reticulatae 10kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 50kg, Mentholum 1kg) according to the embodiment of the invention two preparations; It is the lab scale medicine; Lot number 060319 is provided by Jiangxi Yaodu Renhe Pharmaceutical Co., Ltd.Control drug: ZHENGLUOWAN, lot number 20060115, Japanese Taiko Pharmaceutical Co., Ltd.; Oleum Ricini, commercial, lot number 20060202, Nanchang white clouds medication chemistry factory; Folium Sennae, commercial, face the time spent to be mixed with 15% suspension; The methyl-sulfuric acid neostigmine, lot number: 2006201, letter friendship Pharmaceutical is produced; Metoclopramide, lot number: 20060301, Beijing doube bridge drugmaker; Motilium, lot number: 200601140, Xian-Janssen Pharmaceutical Ltd. produces; Phenol reagent: (Folin-Ciocalteu) institute's compound method is seen " herbal pharmacology experimental methodology ", Li Yikui, Science and Technology of Shanghai publishing house, P242; BHb, Shanghai uncle bio tech ltd difficult to understand, lot number: G200601; L-Tyrosine, Shanghai uncle bio tech ltd difficult to understand, lot number: 20018402; 0.1% thimerosal, 5% trichloroacetic acid, 0.5mol/l sodium carbonate, 0.3mol/l hydrochloric acid, 0.04mol/l hydrochloric acid.

Instrument: the multi-functional analyzer of BECKMAN series type; PHS-3C type acidometer, Shanghai thunder magnetic instrument plant; Sartrius electronic balance (precision 1/1000).

Strain: escherichia coli (44101), Bacillus typhi (50096), shigella flexneri (51571), staphylococcus aureus (26001), beta hemolytic streptococcus (32172), medicine inspecting institute provides by Beijing.

Culture medium: peptone (Japanese import), beef extract (the long Yang Shenghuazhipinchang in Shanghai produces).

2 experimental techniques and result

2.1 external bacteriostatic experiment

Get some of small test tubes of sterilization, dilute the lab scale medicine with corresponding culture medium, its terminal hair tripe was respectively 1: 4,1: 8,1: 16,1: 32,1: 64,1: 128,1: 256,1: 512 ... Every pipe dress 1ml.Every pipe adds .01ml10 ^-3The fresh bacterium liquid of dilution is doubly put to cultivate in 37 ℃ of incubators to observe after 18 hours and is had or not bacterial growth.If the medicine color is dark or opaque, can't judge when having or not bacterial growth, can move on to suspicious pipe again on the plate culture medium, cultivate after 18 hours to observe and have or not bacterial growth.The highest drug dilution degree that antibacterial does not grow is the minimum inhibitory concentration of this medicine, and the result sees table 1.

Visible by table 5, medicine of the present invention all has inhibitory action in various degree to escherichia coli, dysentery bacterium, staphylococcus aureus, beta hemolytic streptococcus etc.

The external bacteriostasis of table 5

2.2 the analgesic activity of woolfe-Macdonald method research

Choose the threshold of pain 5-20 100 of white mice between second with hot plate method; Be divided into 5 groups at random by body weight; The positive drug matched group is irritated stomach and is given the obtain solution 0.4mL/20g of ZHENGLUOWAN institute; Be 1g/kg, the high, medium and low dose groups of soft capsule is irritated the dosing 0.4mL/20g of lab scale medicine institute that stomach is given variable concentrations, i.e. 1.8g/kg, 0.9g/kg, 0.45g/kg respectively; Blank group group is irritated the normal saline 0.4mL/20g of stomach equal volume.Write down after the administration 30,60 respectively, threshold of pain response time of white mice in the 90min.Experimental result is seen table 6.

The influence

of table 6 pair white mice hot plate pain threshold

Table 6 is the result show: the middle and high dose groups of soft capsule has very significant analgesia role in 60min, have statistical significance, compares (P＜0.01) with matched group.

2.3 to Oleum Ricini induced mice diarrheal anti-diarrhea effect

Choose 50 of white mice; Be divided into 5 groups at random by body weight; The positive drug matched group is irritated stomach and is given the obtain solution 0.4mL/20g of ZHENGLUOWAN institute; Be 1g/kg, the high, medium and low dose groups of soft capsule is irritated the dosing 0.4mL/20g of lab scale medicine institute that stomach is given variable concentrations, i.e. 1.8g/kg, 0.9g/kg, 0.45g/kg respectively; Blank group group is irritated the normal saline 0.4mL/20g of stomach equal volume.Successive administration 3 days is irritated stomach and is given Semen Ricini fluid 0.4mL/20g behind the last administration 1h; Then with the mice sub-cage rearing, 1 in every cage, cage heelpiece adularescent filter paper is surveyed the incubation period of its appearance, and every h changes paper 1 time, observes 6h continuously, the loose stool number on the recorder chart.Experimental result is seen table 7.

Table 7 pair Oleum Ricini induced mice diarrheal anti-diarrhea effect

Annotate: compare * * P＜0.01 with the blank group, * P＜0.05 (down together).

Table 7 is the result show, the low and high dose group of soft capsule can make the loose stool of mice obviously reduce, parallel with positive control (P＜0.01).

2.4 to Folium Sennae induced mice diarrheal anti-diarrhea effect

Choose 50 of white mice; Be divided into 5 groups at random by body weight; The positive drug matched group is irritated stomach and is given the obtain solution 0.4mL/20g of ZHENGLUOWAN institute; Be 1g/kg, the high, medium and low dose groups of soft capsule is irritated the dosing 0.4mL/20g of lab scale medicine institute that stomach is given variable concentrations, i.e. 1.8g/kg, 0.9g/kg, 0.45g/kg respectively; Blank group group is irritated the normal saline 0.4mL/20g of stomach equal volume.Successive administration 3 days is irritated stomach and is given Folium Sennae suspension 0.4mL/20g behind the last administration 1h; With the mice sub-cage rearing, 1 in every cage, cage heelpiece adularescent filter paper are surveyed it, are surveyed the incubation period of its appearance, per hour change paper 1 time, observe 6h continuously, the loose stool number on the recorder chart then.Experimental result is seen table 8.

Table 8 pair Folium Sennae induced mice diarrheal anti-diarrhea effect

After the visible blank control group of table 8 result was given Folium Sennae, the loose stool of mice increased, and has showed symptom of diarrhea, and the low dose group of soft capsule can make the loose stool of mice reduce, and middle and high dose groups can make the loose stool of mice obviously reduce (P＜0.01).

2.5 influence to normal mouse intestinal ahead running

Choose 50 of white mice; Be divided into 5 groups at random by body weight; The positive drug matched group is irritated stomach and is given the obtain solution 0.4mL/20g of ZHENGLUOWAN institute; Be 1g/kg, the high, medium and low dose groups of soft capsule is irritated the dosing 0.4mL/20g of lab scale medicine institute that stomach is given variable concentrations, i.e. 1.8g/kg, 0.9g/kg, 0.45g/kg respectively; Blank group group is irritated the normal saline 0.4mL/20g of stomach equal volume.Successive administration 3 days is irritated stomach and is given active carbon 0.4mL/ only behind the last administration 1h; Putting to death animal after 20 minutes, is starting point with the pylorus, measures the distance that active carbon is urged into and the total length of small intestinal.Calculate the propelling rate of active carbon then:

Result such as table 9.

The influence of table 9 pair normal mouse intestinal ahead running

Table 9 result shows that dose groups in the soft capsule can suppress the propelling moving (P≤0.05) of the small intestinal of normal mouse, and the visible trend that suppresses intestinal motility of other each group, but not statistically significant.

2.6 neostigmine is caused the hyperfunction model intestinal propulsion of mice intestinal motional effects

Choose 50 of white mice; Be divided into 5 groups at random by body weight; The positive drug matched group is irritated stomach and is given the obtain solution 0.4mL/20g of ZHENGLUOWAN institute; Be 1g/kg, the high, medium and low dose groups of soft capsule is irritated the dosing 0.4mL/20g of lab scale medicine institute that stomach is given variable concentrations, i.e. 1.8g/kg, 0.9g/kg, 0.45g/kg respectively; Blank group group is irritated the normal saline 0.4mL/20g of stomach equal volume.Successive administration 5d, last administration 40min lumbar injection neostigmine 0.1mg/kg causes the hyperfunction model of small intestinal; Irritating stomach behind the 15min gives active carbon 0.4mL/ only; Putting to death animal behind the 20min, is starting point with the pylorus, measures the distance that active carbon is urged into and the total length of small intestinal.Calculate the propelling rate of active carbon then:

Result such as table 10.

Table 10 pair neostigmine causes the inhibitory action of the hyperfunction model intestinal propulsion motion of mice intestinal

Table 10 result shows the ahead running (P＜0.01) of the small intestinal of low and the hyperfunction model that high dose group can obviously suppress.Middle dose groups has the trend that suppresses motion, but not statistically significant.

2.7 to normal mouse gastric emptying motional effects

Choose 50 of white mice; Be divided into 5 groups at random by body weight; The positive drug matched group is irritated stomach and is given the obtain solution 0.4mL/20g of ZHENGLUOWAN institute; Be 1g/kg, the high, medium and low dose groups of soft capsule is irritated the dosing 0.4mL/20g of lab scale medicine institute that stomach is given variable concentrations, i.e. 1.8g/kg, 0.9g/kg, 0.45g/kg respectively; Blank group group is irritated the normal saline 0.4mL/20g of stomach equal volume.Successive administration 5d, last administration 1h irritate stomach and give gelatinized corn starch 0.8mL/ only, put to death animal behind the 20min, and ligation cardia and pylorus are got stomach then.The full weight of stomach with clean after the net weight difference be residual quantity, and then calculate residual rate.Experimental result is seen table 11.

The facilitation of table 11 pair normal mouse gastric emptying motion

Table 11 sees that the middle dosage of soft capsule can promote the gastric emptying motion of mice, compares (P＜0.05) with matched group.

2.8 to the pepsic influence of rat gastric acid

Choose 50 of white mice; Be divided into 5 groups at random by body weight; The positive drug matched group is irritated stomach and is given the obtain solution 0.4mL/20g of ZHENGLUOWAN institute; Be 1g/kg, the high, medium and low dose groups of soft capsule is irritated the dosing 0.4mL/20g of lab scale medicine institute that stomach is given variable concentrations, i.e. 1.8g/kg, 0.9g/kg, 0.45g/kg respectively; Blank group group is irritated the normal saline 0.4mL/20g of stomach equal volume.

Successive administration 10d, fasting 48 hours is freely drunk water.The etherization animal is used in the back, cuts off the hair of abdominal part, routine disinfection skin, and hunter's line is opened the otch of about 2.5cm in the xiphoid-process lower edge, and the careful stomach of mentioning is used the suture ligation at pylorus and duodenum joint portion, avoids blood vessel.The syringe duodenal administration is used in the back, sends back to after the stitching in the cage, and water is prohibited in the postoperative fasting, and 5 hours femoral vein are got blood and put to death animal, take out stomach, collect gastric juice in graduated centrifuge tube, with the centrifugal 15min of 3000r/min, draws supernatant and surveys gastric acid, pepsin respectively.The gastric acid amount is calculated by the NaoH of the 0.01mmol/L that consumes; Pepsin is pressed " herbal pharmacology experimental methodology ", Li Yikui, Science and Technology of Shanghai publishing house, and P242 stipulates pepsic assay method.Experimental result is seen table 12.

The influence of table 12 pair rat gastric acid pepsin activity

Table 12 is the result show: the middle and high dose groups of soft capsule can improve pepsic activity, has statistical significance, compares (P＜0.01) with matched group.

3 discuss

Experimentation through pharmacodynamics shows that medicine of the present invention can significantly reduce the loose stool number of mice, has anti-diarrhea effect; Can promote the gastric emptying motion of mice; The intestinal propulsion of the hyperfunction model mice of intestinal motion due to inhibition normal mouse and the neostigmine, thereby the absorption of promotion nutrient substance; Promote the secretion of gastric juice and suppress pepsic activity, improve digestive function.Thereby for treatment inappetence, nausea and vomiting, abdominal distention, diarrhoea, dyspepsia etc. provide the pharmacodynamics foundation.

The specific embodiment:

Embodiment one

Capsule liquid: Chinese medicine composition 10kg, soybean oil 12kg, Cera Flava 0.4kg

Softgel shell: gelatin 110kg, glycerol 50kg, water 100kg, oxybenzene second fat 15kg, iron oxide red 2.0kg;

Forming of described Chinese medicine composition by creosote 50kg, Flos Caryophylli 15kg, Cortex Phellodendri 10kg, Radix Glycyrrhizae 35kg, Pericarpium Citri Reticulatae 30kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 40kg, Mentholum 2kg processing and preparing;

Method for preparing:

The preparation of creosote:

Place distillating still to distill Fagaceae plant Fagus sinensis Oliv., get dry distillation liquid and under 180 ℃ of conditions, distill, collect the fraction heavier, handle as follows than water:

1. add percentage by weight and be 15% sodium hydroxide solution, stir crystallisation by cooling;

2. filter, discard filtrating, the washing of filtering residue clear water discards washings; Adding weight percent concentration is 35% sulfuric acid solution, stirs, and discards sulfate wastewater; Clear water washing back is rectification under vacuum under the 0.08-0.09MPa condition in vacuum, collects 130-155 ℃ rectification branch, promptly gets wooden pomegranate oil;

Described fraction: sodium hydroxide solution: the weight part ratio of sulfuric acid solution is 1: 2: 3;

The preparation of preparation:

With Flos Caryophylli, Cortex Phellodendri, Radix Glycyrrhizae, Pericarpium Citri Reticulatae, Cortex cinnamomi japonici (Ramulus Cinnamomi) decocte with water 2 times, 2 hours for the first time, 1 hour for the second time, collecting decoction filtered, and surveyed relative density when filtrating is condensed into 60 ℃ and be 1.15 thick paste; Wherein amount of water is respectively Flos Caryophylli, Cortex Phellodendri, Radix Glycyrrhizae, Pericarpium Citri Reticulatae, Cortex cinnamomi japonici (Ramulus Cinnamomi) gross weight 10,8 times; 50kg creosote and Mentholum are joined in the thick paste, stir, get Chinese medicine composition.

Get Chinese medicine composition 10kg and add dispersant soybean oil and suspending agent Cera Flava, colloid mill is ground to mix homogeneously, adopts dropping preparation method to be packed into softgel shell, is prepared into soft capsule.

Wherein softgel shell is to place water to make its imbibition in gelatin, in addition glycerol and remaining water is heated to 80 ℃, and mix homogeneously adds expansible gelatin; Stir, fusion is incubated 1.0 hours, and vacuum suction is removed bubble; Filter, add oxybenzene second fat, iron oxide red, mixing, 75 ℃ of heat preservation for standby use.

Embodiment two

Capsule liquid: Chinese medicine composition 12kg, Oleum Arachidis hypogaeae semen 16kg, lecithin 0.7kg, tween 80 0.1kg

Softgel shell: gelatin 100kg, glycerol 30kg, water 120kg, oxybenzene second fat 8kg, iron oxide black 3.0kg;

Described Chinese medicine composition is to be prepared from creosote 20kg, Flos Caryophylli 25kg, Cortex Phellodendri 35kg, Radix Glycyrrhizae 70kg, Pericarpium Citri Reticulatae 10kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 50kg, Mentholum 1kg;

Method for preparing:

The preparation of creosote:

Place distillating still to distill natural Zelkova schneideriana Hand.-Mazz., get dry distillation liquid and under 200 ℃ of conditions, distill, collect the fraction heavier, handle as follows than water:

1. add percentage by weight and be 5% sodium hydroxide solution, stir, add percentage by weight and be 15% calcium acetate solution, crystallisation by cooling;

2. filter, discard filtrating, the washing of filtering residue clear water discards washings; Adding weight percent concentration is 25% sulfuric acid solution, stirs, and discards sulfate wastewater; Clear water washing back is rectification under vacuum under the 0.08-0.09MPa condition in vacuum, collects 130-155 ℃ rectification branch, promptly gets wooden pomegranate oil;

Described fraction: sodium hydroxide solution: calcium acetate solution: the weight part ratio of sulfuric acid solution is 2: 3: 5: 2.5;

The preparation of preparation:

With Flos Caryophylli, Cortex Phellodendri, Radix Glycyrrhizae, Pericarpium Citri Reticulatae, Cortex cinnamomi japonici (Ramulus Cinnamomi) decocte with water 3 times, 2 hours for the first time, 3 hours for the second time, 1 hour for the third time, collecting decoction filtered, and surveyed relative density when filtrating is condensed into 60 ℃ and be 1.20 thick paste; Wherein amount of water is respectively Flos Caryophylli, Cortex Phellodendri, Radix Glycyrrhizae, Pericarpium Citri Reticulatae, Cortex cinnamomi japonici (Ramulus Cinnamomi) gross weight 8,10,6 times; 20kg creosote and Mentholum are joined in the thick paste, stir, get Chinese medicine composition;

Get Chinese medicine composition 12kg and add dispersant Oleum Arachidis hypogaeae semen, suspending agent lecithin and surfactant tween 80, colloid mill is ground to mix homogeneously, adopts pressing to be packed into softgel shell, is prepared into soft capsule.

Wherein softgel shell is to place water to make its imbibition in gelatin, in addition glycerol and remaining water is heated to 70 ℃, and mix homogeneously adds expansible gelatin; Stir, fusion is incubated 0.5 hour, and vacuum suction is removed bubble; Filter, add oxybenzene second fat, iron oxide black, mixing, 75 ℃ of heat preservation for standby use;

Embodiment three

Capsule liquid: Chinese medicine composition 14kg, Polyethylene Glycol-200 13kg, aluminum monostearate 0.2kg, propylene glycol 0.4kg, ethyl hydroxybenzoate 0.1kg, tween 20 0.1kg;

Softgel shell: gelatin 105kg, glycerol 45kg, water 85kg, oxybenzene second fat 12kg, iron oxide red 2.5kg;

Described Chinese medicine composition is to be prepared from creosote 35kg, Flos Caryophylli 5kg, Cortex Phellodendri 40kg, Radix Glycyrrhizae 40kg, Pericarpium Citri Reticulatae 35kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 20kg, Mentholum 8kg;

Method for preparing:

The preparation of creosote:

Place distillating still to distill maple, get dry distillation liquid and under 360 ℃ of conditions, distill, collect the fraction heavier, handle as follows than water:

1. add percentage by weight and be 20% sodium hydroxide solution, stir, add percentage by weight and be 30% magnesium acetate solution, crystallisation by cooling;

2. filter, discard filtrating, the washing of filtering residue clear water discards washings; Adding weight percent concentration is 20% sulfuric acid solution, stirs, and discards sulfate wastewater; Clear water washing back is rectification under vacuum under the 0.08-0.09MPa condition in vacuum, collects 130-155 ℃ rectification branch, promptly gets wooden pomegranate oil;

Described fraction: sodium hydroxide solution: magnesium acetate solution: the weight part ratio of sulfuric acid solution is 3: 4: 7: 3.5;

The preparation of preparation:

With Flos Caryophylli, Cortex Phellodendri, Radix Glycyrrhizae, peptone skin, Cortex cinnamomi japonici (Ramulus Cinnamomi) decocte with water 2 times, 2 hours for the first time, 1.5 hours for the second time, collecting decoction filtered, and surveyed relative density when filtrating is condensed into 60 ℃ and be 1.30 thick paste; Wherein amount of water be respectively Flos Caryophylli, Cortex Phellodendri, Radix Glycyrrhizae, Pericarpium Citri Reticulatae, Cortex cinnamomi japonici (Ramulus Cinnamomi) gross weight 6,8, doubly; 35kg creosote and Mentholum are joined in the thick paste, stir, get Chinese medicine composition;

Get Chinese medicine composition 14kg and add dispersant Polyethylene Glycol-200, suspending agent aluminum monostearate and ethyl cellulose, antiseptic ethyl hydroxybenzoate, surfactant tween 20; Colloid mill is ground to mix homogeneously; Adopt dropping preparation method to be packed into softgel shell, be prepared into soft capsule.

Wherein softgel shell is to place water to make its imbibition in gelatin, in addition glycerol and remaining water is heated to 75 ℃, and mix homogeneously adds expansible gelatin; Stir, fusion is incubated 1.5 hours, and vacuum suction is removed bubble; Filter, add oxybenzene second fat, iron oxide red, mixing, 75 ℃ of heat preservation for standby use;

Embodiment four

Capsule liquid: Chinese medicine composition 6kg, Oleum Brassicae campestris 15kg, aluminum monostearate 0.5kg, glycerol monostearate 0.1kg, Tween-60 0.1kg;

Softgel shell: gelatin 120kg, glycerol 40kg, water 80kg, oxybenzene second fat 10kg, iron oxide black 5.0kg;

Described Chinese medicine composition is to be prepared from creosote 40kg, Flos Caryophylli 20kg, Cortex Phellodendri 5kg, Radix Glycyrrhizae 50kg, Pericarpium Citri Reticulatae 20kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 40kg, Mentholum 10kg;

Method for preparing:

The preparation of creosote:

Place distillating still to distill Xylosmae japonici, get dry distillation liquid and under 300 ℃ of conditions, distill, collect the fraction heavier, handle as follows than water:

1. add percentage by weight and be 10% potassium hydroxide solution, stir, add percentage by weight and be 10% magnesium acetate solution, crystallisation by cooling;

2. filter, discard filtrating, the washing of filtering residue clear water discards washings; Adding weight percent concentration is 30% sulfuric acid solution, stirs, and discards sulfate wastewater; Clear water washing back is rectification under vacuum under the 0.08-0.09MPa condition in vacuum, collects 130-155 ℃ rectification branch, promptly gets wooden pomegranate oil;

Described fraction: potassium hydroxide solution: magnesium acetate solution: the weight part ratio of sulfuric acid solution is 2.5: 3: 4: 2;

The preparation of preparation:

Wherein the method for preparing of Chinese medicine composition is with embodiment three, and the survey relative density is 1.10 thick paste when wherein filtrating being condensed into 60 ℃;

Get Chinese medicine composition 6kg and add dispersant Oleum Brassicae campestris, suspending agent aluminum monostearate, antiseptic glycerol monostearate, surfactant Tween-60, colloid mill is ground to mix homogeneously, adopts pressing to be packed into softgel shell, is prepared into soft capsule.

Wherein the preparation of softgel shell is with embodiment two;

Embodiment five

Capsule liquid: Chinese medicine composition 8kg, Polyethylene Glycol-400 13kg, Cera Flava 0.3kg, lecithin 0.2kg, ethyl hydroxybenzoate 0.1kg, tween 20 0.1kg;

Softgel shell: gelatin 90kg, glycerol 35kg, water 90kg, oxybenzene second fat 13kg, iron oxide red 1.0kg;

Described Chinese medicine composition is to be prepared from pine tar 30kg, Flos Caryophylli 10kg, Cortex Phellodendri 20kg, Radix Glycyrrhizae 45kg, Pericarpium Citri Reticulatae 25kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 30kg, Mentholum 5kg;

Method for preparing:

The preparation of pine tar:

Place distillating still to distill pinaster, get dry distillation liquid and under 280 ℃ of conditions, distill, collect the fraction heavier, handle as follows than water:

1. add percentage by weight and be 12% potassium hydroxide solution, stir, add percentage by weight and be 20% magnesium acetate solution, crystallisation by cooling;

2. filter, discard filtrating, the washing of filtering residue clear water discards washings; Adding weight percent concentration is 28% sulfuric acid solution, stirs, and discards sulfate wastewater; Clear water washing back is rectification under vacuum under the 0.08-0.09MPa condition in vacuum, collects 130-155 ℃ rectification branch, promptly gets unguentum picis pini;

Described fraction: potassium hydroxide solution: magnesium acetate solution: the weight part ratio of sulfuric acid solution is 1.5: 2.5: 6: 3;

The preparation of preparation:

1. getting Cortex Phellodendri is 90% alcohol heating reflux 2 times in percent by volume, 2 hours for the first time, and 1.5 hours for the second time, filter, merging filtrate, filtrate recycling ethanol filters to there not being the alcohol flavor, and A must filtrate;

2. with Flos Caryophylli, Radix Glycyrrhizae, Pericarpium Citri Reticulatae and Cortex cinnamomi japonici (Ramulus Cinnamomi) decocte with water 3 times, 2 hours for the first time, 3 hours for the second time, 1 hour for the third time, collecting decoction filtered, and surveyed relative density when filtrating is concentrated into 60 ℃ and be 1.10 extractum B; Wherein amount of water is respectively Flos Caryophylli, Radix Glycyrrhizae, Pericarpium Citri Reticulatae and Cortex cinnamomi japonici (Ramulus Cinnamomi) gross weight 10,8,6 times;

3. the A that will filtrate mixes with extractum B, and relative density is 1.30 extractum when being concentrated into 60 ℃, and drying is processed fine powder, adds 30kg pine tar and Mentholum, stirs, and gets Chinese medicine composition;

Get Chinese medicine composition 8kg and add dispersant Polyethylene Glycol-400, suspending agent Cera Flava and lecithin, antiseptic ethyl hydroxybenzoate, surfactant tween 20, colloid mill is ground to mix homogeneously, adopts dropping preparation method to be packed into softgel shell, is prepared into soft capsule.

Wherein the preparation of softgel shell is with embodiment three;

Embodiment six

Capsule liquid: Chinese medicine composition 15kg, Oleum sesami 14kg, ethyl cellulose 0.6kg, glycerol monostearate 0.1kg, Arlacel-60 0.1kg;

Softgel shell: gelatin 80kg, glycerol 60kg, water 110kg, oxybenzene second fat 16kg, iron oxide red 0.5kg;

Described Chinese medicine composition is to be prepared from bamboo tar 10kg, Flos Caryophylli 18kg, Cortex Phellodendri 30kg, Radix Glycyrrhizae 30kg, Pericarpium Citri Reticulatae 12kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 5kg, Mentholum 15kg;

Method for preparing:

The preparation of bamboo tar:

Place distillating still to distill in bamboo, get dry distillation liquid and under 180 ℃ of conditions, distill, collect the fraction heavier and place rectifying still than water; In temperature is 130-155 ℃; Withdrawing moisture and light fraction under the vacuum 0.08-0.09MPa condition, with the crystallization in freezing 12 hours under subzero 20 conditions of the fraction in the rectifying still, the crystal centrifugalize obtains the bamboo tar crystal; Place normal temperature condition, subsequent use;

The preparation of preparation:

1. getting Cortex Phellodendri is 75% alcohol heating reflux 3 times in percent by volume, 3 hours for the first time, and 2 hours for the second time, 1 hour for the third time, filter, merging filtrate, filtrate recycling ethanol filters to there not being the alcohol flavor, and A must filtrate;

2. with Flos Caryophylli, Radix Glycyrrhizae, Pericarpium Citri Reticulatae and Cortex cinnamomi japonici (Ramulus Cinnamomi) decocte with water 2 times, 2 hours for the first time, 1.5 hours for the second time, collecting decoction filtered, and surveyed relative density when filtrating is concentrated into 60 ℃ and be 1.20 extractum B; Wherein amount of water is Flos Caryophylli, Radix Glycyrrhizae, Pericarpium Citri Reticulatae and Cortex cinnamomi japonici (Ramulus Cinnamomi) gross weight 8,6 times;

3. the A that will filtrate mixes with extractum B, and relative density is 1.10 extractum when being concentrated into 60 ℃, and drying is processed fine powder, adds 10kg bamboo tar and Mentholum, stirs, and gets Chinese medicine composition;

Get Chinese medicine composition 15kg and add dispersant Oleum sesami, suspending agent ethyl cellulose, antiseptic glycerol monostearate, surfactant Arlacel-60, colloid mill is ground to mix homogeneously, adopts pressing to be packed into softgel shell, is prepared into soft capsule.

Wherein the preparation of softgel shell is with embodiment one.

Embodiment seven

Capsule liquid: Chinese medicine composition 9kg, Oleum Brassicae campestris 14.5kg, aluminum monostearate 0.5kg, ethyl cellulose 0.1kg, glycerol monostearate 0.1kg, Tween-40 0.15kg;

Softgel shell: gelatin 85kg, glycerol 43kg, water 92kg, oxybenzene second fat 13.5kg, iron oxide black 2.5kg;

Described Chinese medicine composition is prepared from creosote 45kg, Flos Caryophylli 12kg, Cortex Phellodendri 25kg, Radix Glycyrrhizae 60kg, Pericarpium Citri Reticulatae 18kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 35kg, Mentholum 14kg;

Method for preparing:

The preparation of creosote:

Place distillating still to distill Quercus acutissima Carr., get dry distillation liquid and under 360 ℃ of conditions, distill, collect the fraction heavier and place rectifying still than water; In temperature is 130-155 ℃; Withdrawing moisture and light fraction under the vacuum 0.08-0.09MPa condition, with the crystallization in freezing 48 hours under 0 ℃ of condition of the fraction in the rectifying still, the crystal centrifugalize obtains the creosote crystal; Place normal temperature condition, subsequent use;

The preparation of preparation:

1. getting Cortex Phellodendri is 60% alcohol heating reflux 2 times in percent by volume, 1.5 hours for the first time, and 3 hours for the second time, filter, merging filtrate, filtrate recycling ethanol filters to there not being the alcohol flavor, and A must filtrate;

2. with Flos Caryophylli, Radix Glycyrrhizae, Pericarpium Citri Reticulatae and Cortex cinnamomi japonici (Ramulus Cinnamomi) decocte with water 2 times, 3 hours for the first time, 1 hour for the second time, collecting decoction filtered, and surveyed relative density when filtrating is concentrated into 60 ℃ and be 1.30 extractum B; Wherein amount of water is Flos Caryophylli, Radix Glycyrrhizae, Pericarpium Citri Reticulatae and Cortex cinnamomi japonici (Ramulus Cinnamomi) gross weight 9,8,6 times;

3. the A that will filtrate mixes with extractum B, and relative density is 1.20 extractum when being concentrated into 60 ℃, and drying is processed fine powder, adds 45kg creosote and Mentholum, stirs, and gets Chinese medicine composition;

Get Chinese medicine composition 9kg and add dispersant Oleum Brassicae campestris, suspending agent aluminum monostearate and ethyl cellulose, antiseptic glycerol monostearate, surfactant Arlacel-40, colloid mill is ground to mix homogeneously, adopts dropping preparation method to be packed into softgel shell, is prepared into soft capsule.

Wherein the preparation of softgel shell is with embodiment one.

Embodiment eight

Capsule liquid: Chinese medicine composition 12.5kg, Polyethylene Glycol-600 13kg, propylene glycol 0.55kg, ethyl hydroxybenzoate 0.1kg, Tween-40 0.12kg

Softgel shell: gelatin 85kg, glycerol 57kg, water 95kg, oxybenzene second fat 10kg, iron oxide black 3.2kg;

Described Chinese medicine composition is to be prepared from creosote 15kg, Flos Caryophylli 21kg, Cortex Phellodendri 12kg, Radix Glycyrrhizae 25kg, Pericarpium Citri Reticulatae 23kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 45kg, Mentholum 6kg;

Method for preparing:

The preparation of creosote:

Place distillating still to distill natural Zelkova schneideriana Hand.-Mazz., get dry distillation liquid and under 220 ℃ of conditions, distill, collect the fraction heavier and place rectifying still than water; In temperature is 130-155 ℃; Withdrawing moisture and light fraction under the vacuum 0.08-0.09MPa condition, with the crystallization in freezing 20 hours under subzero 10 ℃ of conditions of the fraction in the rectifying still, the crystal centrifugalize obtains the creosote crystal; Place normal temperature condition, subsequent use;

The preparation of preparation:

The method for preparing of Chinese medicine composition is with embodiment five;

Wherein 1. step is processed into coarse powder with Cortex Phellodendri, is solvent with 10 times of amount saturated limewaters, supersound extraction 2 times, 20min for the first time; 10min is mixed with the solution of counting 33mg/ml with crude drug with extracting solution for the second time, filters, and adds the NaCl placement and spends the night; Filter, oven dry is dissolved in water in deposition, filters; It is 1～2 that filtrating adds hydrochloric acid accent pH, treats that post precipitation filters, and A must filtrate;

Get Chinese medicine composition 12.5kg and add dispersant Polyethylene Glycol-600, suspending agent propylene glycol, antiseptic list ethyl hydroxybenzoate, surfactant Tween-40, colloid mill is ground to mix homogeneously, adopts dropping preparation method to be packed into softgel shell, is prepared into soft capsule.

Wherein the preparation of softgel shell is with embodiment one.

Embodiment nine

Capsule liquid: Chinese medicine composition 7.5kg, soybean oil 15.5kg, Cera Flava 0.45kg, single ethyl hydroxybenzoate 0.1kg, tell apparent-40 0.12kg

Softgel shell: gelatin 115kg, glycerol 35kg, water 105kg, oxybenzene second fat 10kg, iron oxide red 3.2kg;

Described Chinese medicine composition is to be prepared from creosote 25kg, Flos Caryophylli 24kg, Cortex Phellodendri 15kg, Radix Glycyrrhizae 55kg, Pericarpium Citri Reticulatae 32kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 30kg, Mentholum 3kg;

Method for preparing:

The method for preparing of wood pomegranate oil is with embodiment three;

The method for preparing of Chinese medicine composition is with embodiment six;

Step is solvent 1. for Cortex Phellodendri is processed into coarse powder with 8 times of amount saturated limewaters, supersound extraction 3 times, 30 minutes for the first time; 20 minutes for the second time, 15 minutes for the third time, extracting solution is mixed with the solution of counting 30mg/ml with crude drug, filter; Add the NaCl placement and spend the night, filter, oven dry is dissolved in water in deposition, filters; It is 1～2 that filtrating adds hydrochloric acid accent pH, treats that post precipitation filters, and A must filtrate;

Get Chinese medicine composition 7.5kg and add dispersant soybean oil, suspending agent Cera Flava, antiseptic list ethyl hydroxybenzoate, surfactant Tween-40, colloid mill is ground to mix homogeneously, adopts dropping preparation method to be packed into softgel shell, is prepared into soft capsule.

Wherein the preparation of softgel shell is with embodiment one.

Embodiment ten

Capsule liquid: Chinese medicine composition 10.5kg, Oleum sesami 12.5kg, ethyl cellulose 0.65kg, single ethyl hydroxybenzoate 0.1kg, Tween-40 0.12kg

Softgel shell: gelatin 119kg, glycerol 33kg, water 118kg, oxybenzene second fat 11kg, iron oxide black 1.5kg;

Described Chinese medicine composition is to be prepared from creosote 48kg, Flos Caryophylli 8kg, Cortex Phellodendri 18kg, Radix Glycyrrhizae 35kg, Pericarpium Citri Reticulatae 18kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 15kg, Mentholum 12kg;

Method for preparing:

The method for preparing of wood pomegranate oil is with embodiment four;

The method for preparing of Chinese medicine composition is with embodiment eight;

Wherein step is solvent 1. for Cortex Phellodendri is processed into coarse powder with 12 times of amount saturated limewaters, supersound extraction 3 times, 30 minutes for the first time; 20 minutes for the second time, 15 minutes for the third time, extracting solution is mixed with the solution of counting 35mg/ml with crude drug, filter; Add the NaCl placement and spend the night, filter, oven dry is dissolved in water in deposition, filters; It is 1～2 that filtrating adds hydrochloric acid accent pH, treats that post precipitation filters, and A must filtrate;

Get Chinese medicine composition 10.5kg and add dispersant Oleum sesami, suspending agent ethyl cellulose, antiseptic list ethyl hydroxybenzoate, surfactant Tween-40, colloid mill is ground to mix homogeneously, adopts dropping preparation method to be packed into softgel shell, is prepared into soft capsule.

Wherein the preparation of softgel shell is with embodiment one.

Embodiment 11

Capsule liquid: Chinese medicine composition 14.5kg, Oleum Arachidis hypogaeae semen 14.3kg, lecithin 0.48kg, single ethyl hydroxybenzoate 0.1kg, Tween-40 0.12kg

Softgel shell: gelatin 112kg, glycerol 52kg, water 101kg, oxybenzene second fat 13.5kg, iron oxide red 1.5kg;

Described Chinese medicine composition is to be prepared from pine tar 32kg, Flos Caryophylli 7kg, Cortex Phellodendri 37kg, Radix Glycyrrhizae 65kg, Pericarpium Citri Reticulatae 27kg, Cortex cinnamomi japonici (Ramulus Cinnamomi) 13kg, Mentholum 7kg;

Method for preparing:

Wherein the method for preparing of pine tar is with embodiment five;

The method for preparing of Chinese medicine composition is with embodiment seven;

Wherein step is a solvent with 10,9 times of amount saturated limewaters respectively 1. for Cortex Phellodendri is processed into coarse powder, supersound extraction 2 times, 25 minutes for the first time; 20 minutes for the second time, extracting solution is mixed with the solution of counting 32mg/ml with crude drug, filter, add the NaCl placement and spend the night; Filter, oven dry is dissolved in water in deposition, filters; It is 1～2 that filtrating adds hydrochloric acid accent pH, treats that post precipitation filters, and A must filtrate;

Get Chinese medicine composition 14.5kg and add dispersant Oleum Arachidis hypogaeae semen, suspending agent lecithin, antiseptic list ethyl hydroxybenzoate, surfactant Tween-40, colloid mill is ground to mix homogeneously, adopts dropping preparation method to be packed into softgel shell, is prepared into soft capsule.

Wherein the preparation of softgel shell is with embodiment one.

Claims

1. one kind is used for treatment stomachache, diarrheal Chinese medicinal soft capsule, is made up of softgel shell and capsule liquid, it is characterized in that described capsule liquid is made up of following components by part by weight:

Chinese medicine composition 6-15 dispersant 12-16 suspending agent 0.4～0.7;

Described Chinese medicine composition is formed through processing and preparing by following parts by weight of Chinese traditional medicine raw material:

Pericarpium Citri Reticulatae 10-35 Cortex cinnamomi japonici (Ramulus Cinnamomi) 5-50 Mentholum 1-15;

The wherein said oil that heats up in a steamer is to place distillating still to distill in maple, Xylosmae japonici, Quercus acutissima Carr., Juniperus rigida Sieb.et Zucc. or bamboo, gets dry distillation liquid and under 180-360 ℃ of condition, distills, and collects the fraction heavier than water, handles as follows:

2. filter, discard filtrating, the washing of filtering residue clear water; Discard washings, adding weight percent concentration is the 20-35% sulfuric acid solution, stirs; Discard sulfate wastewater, clear water washing back is rectification under vacuum under the 0.08-0.09MPa condition in vacuum, and the rectification branch of collecting 130-155 ℃ promptly gets; Described fraction: aqueous slkali: the weight part ratio of sulfuric acid solution is 1-3: 2-4: 2-3.5.

2. according to the described Chinese medicinal soft capsule of claim 1, it is characterized in that described Chinese medicine composition is formed through processing and preparing by following parts by weight of Chinese traditional medicine raw material:

3. according to the described Chinese medicinal soft capsule of claim 2, it is characterized in that described Chinese medicine composition is formed through processing and preparing by following parts by weight of Chinese traditional medicine raw material:

4. according to claim 1,2 or 3 described Chinese medicinal soft capsule, it is characterized in that described dispersant is polyethylene glycols or vegetable oil; Described suspending agent is one or more the mixture in Cera Flava, lecithin, aluminum monostearate, ethyl cellulose, the propylene glycol.

5. Chinese medicinal soft capsule as claimed in claim 4 is characterized in that described vegetable oil is a kind of of Oleum Arachidis hypogaeae semen, soybean oil, Oleum sesami, Oleum Brassicae campestris or other consumption vegetable oil or several kinds mixture wherein.

6. like claim 1,2 or 3 described Chinese medicinal soft capsule, it is characterized in that also containing in the described capsule liquid antiseptic and/or the surfactant of convention amount.

7. Chinese medicinal soft capsule as claimed in claim 6 is characterized in that described antiseptic is parabens or glycerol monostearate; Described surfactant is tween or span.

8. according to claim 1,2 or 3 described Chinese medicinal soft capsule, it is characterized in that described softgel shell comprises following components by part by weight:

The oxide 0.5～5 of gelatin 80～120 glycerol 30～60 water 80～120 ethyl hydroxybenzoates 8～16 ferrum.

9. a method for preparing claim 1,2 or 3 described Chinese medicinal soft capsule comprises the steps:

10. a method for preparing claim 1,2 or 3 described Chinese medicinal soft capsule comprises the steps:

11., it is characterized in that adding again after 1. described step stirs calcium acetate or the magnesium acetate solution that percentage by weight is 10-30% according to the described Chinese medicinal soft capsule of claim 1; Described fraction: the weight part ratio of calcium acetate or magnesium acetate is 1-3: 4-7.

12., it is characterized in that described step aqueous slkali 1. is sodium hydroxide or potassium hydroxide solution according to the described Chinese medicinal soft capsule of claim 1.

13. according to claim 1,2 or 3 described Chinese medicinal soft capsule; It is characterized in that the described oil that heats up in a steamer is to place distillating still to distill in maple, Xylosmae japonici, Quercus acutissima Carr., Juniperus rigida Sieb.et Zucc. or bamboo; Getting dry distillation liquid distills under 180-360 ℃ of condition; The collection fraction heavier than water places rectifying still, is 130-155 ℃ in temperature, withdrawing moisture and light fraction under the vacuum 0.08-0.09MPa condition; With the freezing 12-48 hour crystallization under subzero 20 to 0 ℃ of conditions of the fraction in the rectifying still, the crystal centrifugalize obtains heating up in a steamer oily crystal.

14. according to claim 1,2 or 3 described Chinese medicinal soft capsule, it is characterized in that described softgel shell is to place water to make its imbibition in gelatin, in addition glycerol and remaining water be heated to 70-80 ℃, mix homogeneously; Add expansible gelatin, stir fusion; Be incubated 0.5-1.5 hour, vacuum suction is removed bubble, filters; Add ethyl hydroxybenzoate, iron oxide red, mixing, 75 ℃ of heat preservation for standby use.

15., it is characterized in that the vacuum of described vacuum suction is-0.08Mpa according to the described Chinese medicinal soft capsule of claim 15.