The purpose of this invention is to provide and a kind ofly can make patient's hepatic fibrosis and reversing liver cirrhosis, promptly can be used for the Chinese medicine compound of clinical treatment hepatic fibrosis, liver cirrhosis and prepare the method for this combination drug.
According to the TCM theory, the treatment prescription should be based upon on the dialectical basis of the traditional Chinese medical science.The differential diagnosis in tcm diagnosis pattern of syndrome of most of chronic hepatitiss and liver cirrhosis patient is syndrome of stagnation of liver qi and spleen deficiency and obstruction of collaterals by blood stasis disease, and the corresponding rule of treatment should be benefiting QI and nourishing blood, blood circulation promoting and blood stasis dispelling, the liver soothing and the spleen invigorating.The present invention follows this rule of treatment, provides a kind of Chinese medicine compound based on the long-term treatment experience, shows that through a large amount of clinical test results people's hepatitis fibrosis and early stage liver cirrhosis can alleviate and reverse, thereby has realized purpose of the present invention.
The Chinese medicine compound of reverse hepatic fibrosis provided by the present invention, liver cirrhosis, it is characterized in that raw materials used by following weight part ratio, and the preparation method of Chinese formulated products is made medicament routinely, perhaps by the water of following raw materials according and/or alcohol extract is made active component and pharmaceutically acceptable additives are formed:
Radix Astragali 15-50, Radix Salviae Miltiorrhizae 15-100, Radix Angelicae Sinensis 10-50, Caulis Spatholobi 20-100, Flos Carthami 10-50, Rhizoma Chuanxiong 10-50, Rhizoma Cyperi 10-50, Radix Paeoniae Rubra 10-50, Radix Bupleuri 10-50, Pericarpium Citri Reticulatae 10-50.
Parts by weight of raw materials ratio preferable in above-mentioned Chinese medicine compound is:
Radix Astragali 20-45, Radix Salviae Miltiorrhizae 40-80, Radix Angelicae Sinensis 20-45, Caulis Spatholobi 40-80, Flos Carthami 20-45, Rhizoma Chuanxiong 20-45, Rhizoma Cyperi 20-45, Radix Paeoniae Rubra 20-40, Radix Bupleuri 20-40, Pericarpium Citri Reticulatae 20-35.
Can add 1 flavor or 2 flavor accessory drugss in above-mentioned Chinese medicine compound again, Fructus Polygoni Orientalis and Fructus Corni are formed the combination drug that is made of 12 flavor Chinese medicines.The adding weight portion of water Radix Polygoni Ciliinerve and Fructus Corni is respectively 1-30 part.
Above-mentioned two kinds of Chinese medicine compound of the present invention Chinese formulated products or water and/or alcohol are routinely extracted the preparation method that obtains active component and be can be made into various dosage form, for example, dissolved granule, decoction, capsule, tablet or injection injection etc. can be made into, and various excipient of the prior art can be used.But preferably adopt following preparation method for improving drug effect Chinese medicine compound medicament of the present invention.
(a) take by weighing the following traditional Chinese medicines material and make raw material:
Radix Astragali 15-50 weight portion, Radix Salviae Miltiorrhizae 15-100 weight portion, Radix Angelicae Sinensis 10-50 weight portion, Flos Carthami 20-45 weight portion, Rhizoma Chuanxiong 10-15 weight portion, Rhizoma Cyperi 10-50 weight portion, Rhizoma Cyperi 10-50 weight portion, Radix Paeoniae Rubra 20-40 weight portion, Radix Bupleuri 20-40 weight portion, Pericarpium Citri Reticulatae 20-35 weight portion, Caulis Spatholobi 40-80 weight portion;
(b) use alcohol or water to Flos Carthami, Radix Angelicae Sinensis, Rhizoma Cyperi, Radix Salviae Miltiorrhizae and Caulis Spatholobi reflux, extract,, obtain yellow volatile oil extracting solution as active component I;
(c) residue in the step (b) and Radix Paeoniae Rubra, the Radix Astragali, Radix Bupleuri, Rhizoma Chuanxiong, Pericarpium Citri Reticulatae water are extracted 1-3 hour twice at 100 ℃, merge resulting water extract as active ingredient II;
(d) directly active ingredient I and II mixing and adding additives, make various dosage forms; Or
(e) in active component II, add additives and again it is mixed with active component I, make various dosage forms.
Wherein in the described raw material of step (c), can also add Fructus Polygoni Orientalis 1-30 weight portion, make active component II.
In addition, can also comprise the following steps: (f) Fructus Corni drying in the above-mentioned preparation, be ground into fine powder the 1-30 weight portion; In step (d), the medicated powder in active component I and II and the step (f) is mixed and the adding additives, make various dosage forms or in active component II, add additives and the medicated powder in the step (f) is mixed, add additives and the medicated powder in the step (f) is mixed again with among the active component II, mix with active component I again, make various dosage forms.
In the preparation method of compound medicine agent in the present invention, can adopt alcohols commonly used such as ethanol, isopropyl alcohol, propanol or butanols during with alcohol extraction, but wherein preferably use ethanol, and being to use concentration in the ethanol extraction step is the ethanol of 50-95%, soak Flos Carthami, Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis, Rhizoma Cyperi and Caulis Spatholobi, the volatile oil component in the Chinese medicine is dissolved in the ethanol.Soak and at room temperature use the above-mentioned Chinese medicine 1-10 of soak with ethanol days that are equivalent to Chinese medicine volume 10-20 times.Ethanol obtains containing the ethanol volatile oil solution of extractive of volatile oil 30-50 weight % in the separation soak.
Ethanol extraction also can be undertaken by the backflow alcoholic solution, in reflux, add above-mentioned Chinese crude drug and alcoholic solution (preferably with adding reflux behind the soak with ethanol Chinese crude drug together), reflux 1-4 hour, can obtain the higher extractive of volatile oil of concentration (concentration 50-70 weight %).
Reach the case of in clinical, utilizing compound of Chinese medicine liver cirrhosis disease of the present invention below by embodiment and give further knot explanation in detail the present invention.
The preparation of embodiment 1 Chinese medicine compound electuary of the present invention
Take by weighing Chinese medicine by prescription: Radix Astragali 127g, Radix Salviae Miltiorrhizae, each 261g of Caulis Spatholobi, Radix Paeoniae Rubra 103g, Radix Angelicae Sinensis, Rhizoma Chuanxiong, Flos Carthami, Rhizoma Cyperi, Pericarpium Citri Reticulatae, each 87g of Radix Bupleuri, Fructus Polygoni Orientalis, each 65g of Fructus Corni.
Edible ethanol 12kg with 70% soaked Flos Carthami, Radix Angelicae Sinensis, Rhizoma Cyperi, Radix Salviae Miltiorrhizae and Caulis Spatholobi after one day, and ethanol and Chinese medicine are put into reflux together, and reflux 2.5 hours obtains yellow ethanol volatile oil extracting solution 85g (volatile oil content is 60%).Elimination ethanol after the backflow extracting, Chinese crude drug is added the 17kg decocting in Radix Paeoniae Rubra, the Radix Astragali, Radix Bupleuri, Rhizoma Chuanxiong, Pericarpium Citri Reticulatae and Fructus Polygoni Orientalis add the still of boiling medicine boiled 3 hours, leaching decocting liquid adds 15kg water again and carried out decocting the second time 2 hours, the elimination Chinese crude drug gets decocting liquid for the second time, and the Chinese crude drug filtering residue uses extruder with 10kg/cm
2Pressure pushes and obtains squeezed fluid and the merging of secondary decocting liquid.Add dextrin 100g mix homogeneously, directly decocting liquid is made the graininess micropowder with spray granulation.
Fructus Corni is dried under 90 ℃, is ground into micropowder, and with above-mentioned graininess micropowder mix homogeneously after, the ethanol extractive of volatile oil is sprayed in the micropowder equably, make 1000g dark-brown 12 the flavor Chinese medicine compound electuaries (to call electuary A in the following text).
The preparation of embodiment 2 Chinese medicine compound decoctions of the present invention
Press embodiment 1 described method, but do not add Fructus Polygoni Orientalis and Fructus Corni in the prescription, simultaneously in preparation, do not add dextrin, obtain the merging of squeezed fluid and secondary decocting liquid after, be concentrated to about 1000g and add ethanol volatile oil extracting solution, promptly make dark-brown 10 flavor Chinese medicine compound decoctions (to call decoction in the following text a).
The preparation of embodiment 3 Chinese medicine compound electuary B-D
Press embodiment 1 described method, but Radix Salviae Miltiorrhizae is got 70g in the prescription, the Radix Astragali is got 180g, and Flos Carthami is got 150g, and Pericarpium Citri Reticulatae, Radix Bupleuri are respectively got 35g, and Radix Angelicae Sinensis, Rhizoma Chuanxiong are respectively got 130g other is prepared 1000g Chinese medicine compound electuary (to call electuary B in the following text) with embodiment with 1.
Press embodiment 1 described method, but the prescription in Caulis Spatholobi get 80g, Radix Salviae Miltiorrhizae is got 201g, Flos Carthami is got 200g, Rhizoma Cyperi get 45g other with embodiment 1 identical preparation 1000g Chinese medicine compound electuary (to call electuary C in the following text).
Press embodiment 1 described method, but the Radix Astragali, Rhizoma Chuanxiong are respectively got 45g in the prescription, Radix Salviae Miltiorrhizae is got 201g, and Caulis Spatholobi is got 201g, and Flos Carthami is got 100g, Rhizoma Cyperi, Pericarpium Citri Reticulatae, Radix Bupleuri respectively get 120g other with embodiment 1 identical preparation 1000g Chinese medicine compound electuary (to call electuary D in the following text).
The preparation of embodiment 4 Chinese medicine compound decoction b, c, pill d
Press embodiment 2 described prescription proportionings, but the decocting method system of Chinese medicine decoction decoction routinely decocts altogether three times, add water 10kg for the first time and decocted 4 hours, second and third time adds water 5kg respectively, decocts 2 hours, and collecting decoction is concentrated to 1000g (to call decoction b in the following text).
Press embodiment 2 described prescription proportionings, but soak raw material with dehydrated alcohol (concentration of alcohol is 95%).The ethanol consumption soaks that separate raw materials obtains ethanol extract after 48 hours so that the thorough impregnation raw material is advisable.Ethanol obtains about 200ml extracting solution and adds entry again and make decoction C to 1000ml in the separated extracting solution.
Press embodiment 1 described prescription proportioning, but 1000 of the preparation method pill agent of medicine pill routinely, every contains the about 1.2-1.4g of crude drug, to call pill d in the following text.
The discriminating of embodiment 5 Chinese medicine compound medicaments
Treating excess syndrome is executed the prepared Chinese medicine compound electuary of the present invention of 1-4 and each 5g of decoction carries out discrimination test as follows respectively.The agent 5g that gets it filled adds ethanol 20ml, reflux 30 minutes, put coldly, filter, filtrate is put and is concentrated into about 1ml in the water-bath, it is an amount of to add neutral alumina, mixes drying in water-bath thoroughly, be contained on the neutral alumina pillar that fills in advance (100-200 order, 2g, internal diameter 10-15mm), with ethyl acetate one methanol (1: 1) 50ml eluting, collect eluent, evaporate to dryness, residue adds methanol 1ml makes dissolving, as need testing solution.Other gets the paeoniflorin reference substance, adds methanol and makes the solution that every 1ml contains 1mg, in contrast product solution.Test according to thin layer chromatography (appendix VIB of Chinese Pharmacopoeia nineteen ninety-five version), draw each 10 μ l of above-mentioned two kinds of solution, put respectively on same silica gel C lamellae, with chloroform-methanol-ethyl acetate (8: 4: 1) is developing solvent, launch, take out, dry, spray is with 5% vanillin sulfuric acid solution, and it is clear that hot blast blows to the speckle colour developing.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color.
Through health examination, should meet the pertinent regulations of (86) " medicine sanitary standard " promulgated by the ministries or commissions of the Central Government.
Chinese medicine compound medicament of the present invention has the function of the liver soothing and the spleen invigorating, removing heat from blood resolving depression, blood circulation promoting and blood stasis dispelling, benefiting QI and nourishing blood, can be used for treating diseases such as chronic hepatitis, hepatic fibrosis and early stage liver cirrhosis.The medicine that adopts all is a formulary drug in the Chinese medicine compound, and all medicines are all nontoxic.Have no adverse reaction and side effect through a large amount of clinical practice therapeutic processes for many years, all obtain good result curing hepatic fibrosis and early stage liver cirrhosis.Further specify the present invention below by the clinical practice example.
Application examples 1
Utilize the Chinese medicine compound electuary of embodiment 1 preparation, to treatment group usage and consumption for taking a 18g, 3 times on the one, logotype 6 months after mixing it with hot water.Group is taken commodity medicine YIGANNING CHONGJI in contrast, and usage and consumption are with the treatment group.Patient's basic condition is listed in table 1.
The table 1 grouping routine number average course of disease average course of disease early stage ALT HBsAg of chronic hepatitis B (+) HBeAg (+)
85 32.62 5.6 31 27 11 16 61 85 59 matched groups 22 33.54 5.3 15 412 15 22 14 were organized in heavy liver cirrhosis rising treatment during (year) (year) was light
To above-mentioned treatment chronic hepatitis B 107 examples (85 examples are organized in treatment, matched group 22 examples), systematic observation the each patient treat before and after the histological variation of liver biopsy pathology before and after clinical card shape, sign, liver function, serum hepatic fibrosis index and the treatment.
Wherein: 1. the improvement situation of patient's clinical symptoms: the treatment group is 78%, and matched group is 37%.The variation of patients serum ALT normalization rate: the treatment group is 82%, and contrast component 11%.Therefore, utilize Chinese medicine compound electuary treatment of the present invention, significantly the clinical card shape of relieve chronic hepatopath reduces serum glutamic pyruvic transminase.
2. change about hepatic fibrosis serum index and illustrate by Fig. 1-Fig. 4.
By Fig. 1-shown in Figure 4, Serum hyaluronic acid, serum I collagen type v, four fibrosis indexs such as serum II type i collagen and serum laminin, the patient of treatment group all significantly descends, and shows that hepatic fibrosis activeness and fibrosis obviously alleviate.
3. for the histological variation characteristics of liver biopsy pathology before and after the treatment:
(1). inflammation (bridging necrosis, chip necrosis) alleviates or disappears;
(2). fiber laydown and interval alleviate or disappear;
(3). liver cell regeneration;
(4) .S3 and S4 all can obviously reverse.
Prove that through clinical trial take Chinese medicine electuary treatment of the present invention 6 months, each phase fibrosis patient all obvious reverse can occur, wherein the S1 reversion rate 16%, S2 reversion rate 78%, and S3 (liver cirrhosis early stage) 82%, S4 (being early stage liver cirrhosis) reversion rate is 75%.
Application examples 2
Utilize the Chinese medicine compound decoction of embodiment 2 preparations that the treatment group is carried out clinical trial, matched group uses YIGANNING CHONGJI, and usage and consumption are with application examples 1.
62 routine chronic viral hepatitis Bs are comprised early stage liver cirrhosis, and through half a year Chinese medicine compound decoction and contrast medicine treatment, liver is worn Histological change before and after the contrast therapy, prove Chinese medicine compound of the present invention to scorching card in the hepatitis B liver go down and Fibrotic reverse has obvious curative effects.Be embodied in:
Treatment group (40 example)
In the portal area around inflammation and the portal area chip necrosis (PN) obviously alleviate or disappear (the T cell obviously reduces) (Fig. 8); Bridging necrosis disappear (Fig. 6) in the lobule more; The liver cell regeneration reparation is good.
2. but fibrosis complete obiteration (Fig. 7) around the portal area; The portal area that enlarges dwindles (Fig. 5); In the lobule on a large scale fiber laydown can disappear or only stay fine fibre every (Fig. 6); The leaflet structure disorder can recover (Fig. 7,9) fully.
3. early stage liver cirrhosis: the fibrosis scope is obviously dwindled, and liver cell regeneration is good, or forms than greater tubercle (Figure 11) or be connected to sheet, nodular structure disappear (Figure 10); In the hepatic tissue rarely seen fine fibre every.
4. established liver cirrhosis is obviously stenosis at interval, and elastic fibers in the fibrous septum and I, III Collagen Type VI obviously reduce (Figure 12).
5. SABC shows, treats postactivated Kupffer cell and activates sternzellen and obviously reduce.The capillary vascularization of hole week significantly recovers under the Electronic Speculum, and liver cell mitochondria is abundant, the rough endoplasmic reticulum prosperity, and microvillus increases.
Matched group (22 example)
At different levels, phase pathological changes comprises early stage liver cirrhosis, and it is how constant or have and increase the weight of to treat after 6 months fibrosis, though have to have to a certain degree inflammation to disappear than the treatment group be weak (not shown).
Statistical result to above-mentioned 62 example treatments is:
1.12 the concurrent S1 of routine chronic viral hepatitis B, S2, S3 phase fibrosis patient takes the Chinese medicine compound decoction and treats half a year, twice hepatic tissue biopsy pathology inspection shows before and after the treatment, 10.0 ± 8.64 2.58 ± 2.07 (P<0.01) that drop to treatment after of hepatic fibrosis index before by treatment, 18.25 ± 7.40 8.50 ± 2.70 (P<0.01) that drop to treatment after of inflammation index before by treatment, and liver is worn the pathology no change before and after YIGANNING matched group (8 example) treatment, proof Chinese medicine can make human hepatic fibrosis, comprises that the liver liver cirrhosis takes a turn for the worse.
2. with Chinese medicine compound decoction treatment chronic hepatitis B liver fiber and early stage liver cirrhosis 28 examples (comprising S1, S2, S3 phase), other establishes YIGANNING matched group 14 examples, the half a year course of treatment.After treating half a year, treatment group symptom takes a turn for the better 62.96%, matched group 34.48%; ALT is treatment group often 90.91% again, matched group 20%.Fibrosis serum index hyaluronic acid, IV Collagen Type VI, PIIIP and laminin (Ln) obviously descend in middle recurrence due to taking drug decoction treatment back, and matched group decline is not obvious.Treatment front and back liver is worn pathologic finding and shows, liver inflammation scoring 9.13 ± 4.62 before by treatment drops to 5.45 ± 2.73 (P<0.05) after the treatment, fiber scoring 8.89 ± 6.69 before by treatment drops to 5.80 ± 1.62 (P<0.05) after the treatment, and matched group does not have significant change (P<0.05).This group patient histopathology studies show that the necrosis of liver inflammation obviously absorbs because of the treatment of Chinese medicine compound decoction, and the fibrous septum disappears or obviously attenuates.
Application examples 3
Carry out the clinical trial of compound of Chinese medicine effect by the method for application examples 1.Set up 3 groups of treatments and organize every group 12 example.Divide and to take embodiment 3 made electuary B, electuary C and electuary D in addition, after treatment in 6 months, the improvement situation of patient's clinical symptoms is listed in table 2.Also list the result who takes electuary A and YIGANNING CHONGJI for comparison sheet 2.
Table 2
| Treatment is organized 1 treatment and is organized 2 treatments and organize 3 treatments and organize 4 matched groups |
Take the medicament clinical symptoms and improve (%) | Electuary A electuary B electuary C electuary D YIGANNING 78 56 62 61 22 |
Application examples 4
Carrying out the clinical degree of compound of Chinese medicine effect by the method for application examples 2 tests.Set up 2 groups of treatments and organize every group 15 example.Take embodiment 4 made decoction b, pill c (taking the each ball of pill, three times on the one) respectively, list in table 3 through the improvement situation of the clinical symptoms of 6 months treatment chronic hepatitis Bhepatic fibrosis.In order also to list the result of service decoction a and YIGANNING CHONGJI in the comparison sheet 3.
Table 3
| Treatment is organized 1 treatment and is organized 2 treatments and organize 3 matched groups |
Take the medicament clinical symptoms and improve (%) | Decoction a decoction b decoction c pill d YIGANNING 62.96 50.14 46.29 67.10 34.48 |
Can see that by the foregoing description and application examples result Chinese medicine compound of the present invention has significant curative effect to treatment hepatic fibrosis and early stage liver cirrhosis.Particularly adopt prepared its therapeutic effect of medicament of medicament preparation method of the present invention more obvious.
Simple declaration to accompanying drawing.
Fig. 1 is the situation of change of Serum hyaluronic acid in the liver fiber serum index.
Fig. 2 is the situation of change of serum I collagen type v in the liver fiber serum index.
Fig. 3 is the situation of change of blood-serum P IIIP in the liver fiber serum index.
Fig. 4 is the situation of change of serum laminin in the liver fiber serum index.
Fig. 5 is the pathological tissue photo, and wherein A is the preceding situation of treatment, and B is for being treatment back situation.As seen from the figure, control preceding portal area collagen and increase, have at interval to form, instead around the portal area, back see a few cell and control.
Fig. 6 is the pathological tissue photo, and wherein A is the preceding situation of treatment, and B is treatment back situation.As seen from the figure, most bridging necrosiss before controlling, and it is light to control in back portal area and the lobule inflammation, rarely seen minority fiber every.
Fig. 7 is the pathological tissue photo, and wherein A is the preceding situation of treatment, and B is treatment back situation.As seen from the figure, control most bridging fibrosises in preceding portal area and the lobule, and only visible slight amount aristiform is fibrous around controlling the portal area, back.
Fig. 8 is the pathological tissue photo, and wherein A is the preceding situation of treatment, and B is treatment back situation.As seen from the figure, chip necrosis before controlling, hepatic necrosis in the lobule, and it is neat to control lobule border, back, liver cell regeneration, the time see double-core.
Fig. 9 is the pathological tissue photo, and wherein A is the preceding situation of treatment, and B is treatment back situation.As seen from the figure, control a large amount of type i collagen depositions in the preceding fibrous septum, and see a small amount of type i collagen fiber around controlling the portal area, back.
Figure 10 is the pathological tissue photo, and wherein A is the preceding situation of treatment, and B is treatment back situation.As seen from the figure, control anterior tubercle and be fiber and separate, to walk (individual) sinus hepaticus net fibre every interior blood vessel normal substantially and control the back fiber.
Figure 11 is the pathological tissue photo, and wherein A is the preceding situation of treatment, and B is treatment back situation.As seen from the figure, see interior at interval a large amount of I, III Collagen Type VI before controlling, and control header area under control and the interval thereof that the back collagen deposition sees expansion.
Figure 12 is the pathological tissue photo, and wherein A is the preceding situation of treatment, and B is treatment back situation.As seen from the figure, it is wide to control space before, contains more elastic fibers and collagen, and it is narrow at interval to control the back, contains a small amount of elastic fibers and collagen.