CN101015574B - Preparing method of traditional Chinese medicine pills for treating hepatitis - Google Patents
Preparing method of traditional Chinese medicine pills for treating hepatitis Download PDFInfo
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Abstract
The invention discloses a preparation method of a Chinese medicinal pill. The preparation method comprises decocting Penthorum chinense in water for 2-3 times for 1-3h each time, mixing decoctions, filtering, concentrating, cooling, adding ethanol to 55-70% for precipitating, stirring, standing, filtering to obtain filtrate and filter residue, cleaning the filter residue with ethanol, mixing the cleaning solutions and filtrate, recovering ethanol, concentrating to obtain an extract with relative density of 1.30-1.35, mixing with starch, drying, pulverizing, adding 65-85% ethanol, granulating, and packaging. The invention has the advantages of low dose, good dissolubility, and convenient administration. The inventive pill can be used to treat hepatitis, such as chronic active hepatitis, hepatitis B, and acute viral hepatitis.
Description
Technical field
The present invention relates to a kind of enzyme of falling that has, protect the liver, the preparation method of the medicine pill of jaundice eliminating, especially a kind of preparation method that is used for the treatment of the medicine pill of chronic active hepatitis, hepatitis B, acute viral hepatitis.
Background technology
This product prescription is from " Drug Standard of Ministry of Public Health of the Peoples Republic of China Chinese traditional patent formulation preparation " the 13rd GANSU KELI, and standard No. be [WS3-B-2526-97], and its preparation method is for " get Herba Lysimachiae Clethroids 1000g; chopping, decoct with water each 2 hours three times; collecting decoction, filter, filtrate is condensed into the clear paste of relative density 1.15～1.18 (60～65 ℃); cooling; add ethanol and make and contain the alcohol amount and reach 60%, stir, leave standstill; filtration, precipitation merges washing liquid and filtrate with 60% washing with alcohol three times, recovery ethanol and to be condensed into relative density be 1.30～1.32 thick paste, add an amount of sucrose and starch, mixing, system granule, drying, make 540g, promptly ".Former side is used for for many years clinical with the granule form, determined curative effect.But the once oral 9g of former dosage form (GANSU KELI), dose is big; Contain sugar in the granule, the use crowd is limited, and diabetics should not use.Therefore we to consider to reform dosage form be ball (concentrating micropill) agent.Simultaneously also provide more more options for clinical application.Because it is less to concentrate the micropill particle diameter, easily swallow, and adjuvant does not contain sugar; Adopt Modern New Technology, new technology preparation to concentrate micropill, can reduce supplementary product consumption significantly and reduce dose, be easier to accept, and suitable crowd is extensive into the patient.Concentrated micropill also has fast instant loosing, and carries, transports, takes advantages such as all convenient.
Summary of the invention
The purpose of this invention is to provide a kind of easy for patients to accept, dose is little, fast instantly loose, taking convenience, be suitable for the method for the wide medicine pill that is used for the treatment of chronic active hepatitis, hepatitis B, acute viral hepatitis of crowd.
For realizing goal of the invention, the inventor has filtered out the method for the medicine pill that is used for the treatment of chronic active hepatitis, hepatitis B, acute viral hepatitis on the basis of test of many times, and described method comprises following steps:
1. Herba Lysimachiae Clethroids is decocted with water 2-3 time, each 1-3 hour, collecting decoction filtered, filtrate is condensed under 60-65 ℃ of condition and surveys relative density is the clear paste of 1.10-1.20, and cooling adds ethanol and makes and contain the alcohol amount and reach 55-70%, stirs, leave standstill, filter, get filtering residue and filtrate A;
2. filtering residue merges washing liquid and filtrate A with the washing with alcohol of 50-90% 2-3 time, and reclaim ethanol and also be condensed into to be the thick paste of 1.30-1.35, to add appropriate amount of starch, mix 40 ℃ of condition downside relative densities, drying, pulverizing gets medicated powder; It is an amount of to add 65-85% ethanol, pill, and packing, packing, promptly.
1. described step is that Herba Lysimachiae Clethroids is decocted with water 3 times, and each 2 hours, collecting decoction filtered, and filtrate is condensed into and surveys relative density under 60-65 ℃ of condition is the clear paste of 1.15-1.18.
Described step amount of water 1. is respectively: for the first time 12 times of medical material amounts, 10 times of medical material amounts, 8 times of medical material amounts for the third time for the second time.
1. described step adds ethanol makes and contains alcohol amount and reach 60%.
Described step 2. filtering residue merges washing liquid and filtrate A with 60% washing with alcohol 3 times, recovery ethanol and to be condensed into 40 ℃ of condition downside relative densities be the thick paste of 1.30-1.32.
Details are as follows to the preparation technology of described pill for the inventor:
One, process rationality research and explanation
1, technical study explanation
The primary standard method for making is for " get Herba Lysimachiae Clethroids 1000g, chopping decocts with water each 2 hours three times; collecting decoction, filters, and filtrate is condensed into the clear paste of relative density 1.15～1.18 (60～65 ℃), cooling; add ethanol and make and contain the alcohol amount and reach 60%, stir, leave standstill, filter; precipitation merges washing liquid and filtrate with 60% washing with alcohol three times, and reclaiming ethanol and being condensed into relative density is 1.30～1.32 thick paste; add an amount of sucrose and starch, mixing is made granule; drying, makes 540g, promptly.”
Since clear and definite extraction time of primary standard method for making and time, the amount of water when clearly not extracting, and the amount of water when therefore needing extraction is studied; The clear and definite alcohol precipitation process condition of primary standard, washing of precipitate solvent and concentration, therefore not clear and definite cleaning solvent consumption needs the cleaning solvent consumption is studied; Change pill into by granule, also tackle preparations shaping technology and study.
2, Study on extraction
(1) water absorption rate is measured:
It is an amount of to take by weighing the Herba Lysimachiae Clethroids medical material, adds 15 times of water gagings and soaks, and to the saturating heart of medical material, leaches unabsorbed water liquid, and trying to achieve water absorption rate is 289.7%.
(2) extract the amount of water screening
Take by weighing medical material 100g respectively, decoct with water three times, each 2 hours, decocting liquid filtered, and merges three times filtrate, is condensed into extractum, weighs.Survey quercetin content, dried cream yield in the extractum.Result of the test sees Table 1.
Higher because of the water absorption rate of this product medical material, and this product medical material is herb, and volume is big, is 12 times of medical material amounts so intend extracting the highest amount of water.
1
#: for the first time 12 times of amounts, 10 times of amounts, 8 times of amounts for the third time for the second time.
2
#: for the first time 10 times of amounts, 8 times of amounts, 6 times of amounts for the third time for the second time.
3
#: for the first time 8 times of amounts, 6 times of amounts, 4 times of amounts for the third time for the second time.
Table 1 extracts amount of water screening test table as a result
From experimental result as can be known, 1
#Best, so the amount of water that determine to decoct extracts is: 12 times of medical material amounts, 10 times of medical material amounts, 8 times of medical material amounts for the third time for the second time for the first time.
(3) alcohol precipitation process research
The material of getting it filled is an amount of, decocts with water each 2 hours three times, for the first time 12 times of medical material amounts, 10 times of medical material amounts, 8 times of medical material amounts for the third time for the second time, decocting liquid filters, and merges three times filtrate, is concentrated into the clear paste of relative density 1.15～1.18 (60～65 ℃), be cooled to room temperature, add ethanol and make and contain alcohol amount and reach 60%, accelerate slowly to stir, leave standstill, filter, must precipitate.Precipitation is divided equally three parts, and according to the form below adds 60% washing with alcohol, and the residue after the washing is dried to constant weight, gets dry residue.With quercetin content in the dry residue is index, and experimental result sees Table 2.
Table 2 washing of precipitate ethanol consumption screening table
From experimental result as can be known, the precipitate with ethanol postprecipitation adds 6 times, 9 times amount 60% washing with alcohol, and quercetin content is low in the residue after the washing.And Mongolian oak content does not have significant difference in the residue after 6 times, 9 times amounts are washed, and takes all factors into consideration from saving the cost aspect, determines this product precipitate with ethanol postprecipitation, measures 60% washing with alcohol 3 times, each 2 times of amounts with 6 times.
The extraction process checking
Get Herba Lysimachiae Clethroids 2kg, decoct with water three times, each 2 hours, 12 times of medical material amounts for the first time, 10 times of medical material amounts for the second time, 8 times of medical material amounts for the third time, decocting liquid filters, and merges three times filtrate, be concentrated into the clear paste of relative density 1.15～1.18 (60～65 ℃), be cooled to room temperature, add ethanol and make and contain alcohol amount and reach 60%, accelerate slowly to stir, leave standstill, filter, clear paste (1.16,65 ℃ of relative densities), be cooled to room temperature, add ethanol and make and contain alcohol amount and reach 60%, accelerate slowly to stir, leave standstill, filter, filtrate is deposited in addition.Precipitation is measured 60% washing with alcohol 3 times with 6 times, and each 2 times of amounts merge washing liquid and filtrate, reclaims ethanol and also is condensed into extractum, weighs.Survey quercetin content, dried cream yield in the extractum.(repeated trials 3 times) result of the test sees Table 12.3.
Table 12.3 extraction process demonstration test is table as a result
Experimental result shows that this extraction process is reasonable, feasible, has repeatability, operability.
3, separation, purification, concentrated, drying process research
(1) separation, purifying process research.
After extracting solution merged, 200 mesh sieves filtered, and got filtrate, concentrated.Behind the precipitate with ethanol, the filter paper sucking filtration gets pure filtrate.After the Cake Wash, sucking filtration gets pure filtrate, merges pure filtrate, reclaims ethanol, concentrates.
(2) concentration technology research
1. extracting solution concentrates
For improving thickening efficiency as far as possible, reducing production costs, shorten concentration time, avoid the destruction of long-time heating to effective ingredient, adopt triple effect concentrating under reduced pressure method to concentrate.Actual conditions is: temperature: one imitates 80 ℃; Two imitate 70 ℃; 60 ℃ of triple effects.Vacuum: one imitates 0.04Mpa; Two imitate 0.06Mpa; Triple effect 0.08Mpa.
2. pure filtrate concentrates
Precipitate with ethanol rear filtrate and washing of precipitate rear filtrate merge, first decompression recycling ethanol, and reconcentration gets clear paste (relative density is about 1.15～1.17,70 ℃ of surveys).Actual conditions is: temperature: 70 ℃～80 ℃; Vacuum: 0.06Mpa～0.08Mpa;
3. clear paste concentrates
Because of the concentrating under reduced pressure device is the totally enclosed type concentrator, it is too big that extractum is concentrated into relative density, gets cream not to the utmost, and the extractum loss is big.So medicinal liquid is concentrated into clear paste (about 1.15～1.17, the 70 ℃ of surveys of relative density) with the concentrating under reduced pressure device behind the precipitate with ethanol, select steam to concentrate again.For making things convenient for next drying process, determine that clear paste is concentrated into the thick paste of relative density 1.30～1.32 (60 ℃ of surveys) with steam.
(3) extract dry technical study
This product extractum is water extract-alcohol precipitation extractum, has stronger viscosity.Once adopted spray drying process that material is carried out drying, the sticking wall of material, bonding are seriously lost greatly as a result, so adopt bake drying commonly used.Adopt bake drying, temperature is bigger to the quality influence of material, so the temperature of need during to drying screened.
1. extract dry temperature screening
Get same thick extractum (1.30,60 ℃ of relative densities), bake drying under 70 ℃, 80 ℃, 90 ℃ conditions is taken a sample in different time sections respectively, and the moisture in the test sample product is index with thick skin cellulose content in the constant weight sample and the broken situation of dried cream powder.Result of the test sees Table 4.
Table 4 extract dry temperature screening table
According to table 4 result of the test, determine that this product extract dry temperature is 80 ℃.
2. adjuvant and amount screening during extract dry
From extract dry temperature screening test as can be known, the dried cream hygroscopicity of this product is strong, and the pure difficulty of powder is so consider to add in the extractum adjuvant drying.Intend adding starch commonly used.
Get 0.1 times of thick extractum of recipe quantity (1.30,60 ℃ of relative densities) respectively, according to the form below adds starch and mixes, and 80 ℃ of dryings, with the hygroscopicity power of dried cream after the drying, pulverizes difficulty or ease for investigating index, and result of the test sees Table 5.
Adjuvant and amount screening table during table 5 extract dry
Annotate: dried cream hygroscopicity: "-" expression hygroscopicity is strong.
Pulverize difficulty or ease: "+" expression is pulverized easily.
Table 5 experimental result shows: 2, a little less than No. 3 dried cream hygroscopicity of sample, easily pulverize.Take all factors into consideration from reducing dose and cost aspect, select No. 2.Promptly one times of thick extractum of recipe quantity adds about 325g starch.
3. determine extract dry technology
Get the thick paste of relative density 1.30～1.32 (60 ℃ of surveys), add appropriate amount of starch, mix 80 ℃ of bake dryings.
5, preparations shaping Journal of Sex Research
(1) recipe quantity design
1. dose is determined
According to the each dose of primary standard (GANSU KELI standard), be equivalent to primary dose 16.7g, determine that this product (liver Soviet Union ball) dose is consistent with primary standard (GANSU KELI standard), promptly each dose is equivalent to primary dose 16.7g.
By experiment as can be known, this product paste-forming rate is about 8.1%, promptly takes the dry extract amount at every turn and is about 1.35g, and adjuvant is about 0.65g, amounts to 2.00g, promptly takes about 2.0g at every turn.
2. preparation prescription design
A, extraction part medical material are 8350g, and dried cream amount is about 676g.
B, the about 325g of adjuvant amount.
Amount to 1001g, make 500 bottles, every bottle of heavily about 2.0g.
(2) preparations shaping research:
1. medicated powder granularity
Because of this product pill less, so higher to the medicated powder fineness requirement.According to experience in the past, determine that this product medicated powder is fine powder.
2. wetting agent and consumption screening
Because of this product is the medicated powder pill, so need to add wetting agent.According to this product dried cream powder character, intending ethanol is the wetting agent of this product.
A ethanol consumption
Get one times of recipe quantity medicated powder 1000g, add 30% ethanol, to the medicated powder complete wetting, the system soft material.Calculate ethanol percentage consumption about 28%.
B, concentration of alcohol are determined
Get one times of recipe quantity medicated powder, the adding different concentration ethanol is moistening fully, system soft material, pill.Serves as to investigate index with the soft material quality with becoming the ball situation, the results are shown in Table 12.6.
Table 12.6 wetting agent screening table
From result of the test as can be known: 4
#The soft material quality is better, easily pill.So determine that this product wetting agent concentration of alcohol is 80%.
3. pill piece
The powder of getting it filled adds 28% 80% ethanol pill piece, the uniform ball piece of color and luster.Mass production adopts kneading machine, and limited production and medicine can carry out in basin.
4. pill bar, gradation and round:
Big production adopted the machine pill, and limited production is with rubbing ball wrench worker preparation with the hands.
The pill bar is most important to moulding the pill quality.The fineness and the ball method of double differences that directly have influence on pill are different.Cause that shaping is not bright and clean, the inconsistent main cause of thickness is the temperature of soft material.Therefore need the soft material temperature is screened.
Get the ball piece that makes, the temperature of according to the form below is carried out the pill bar, and gradation serves as to investigate index with pill bar situation and gradation situation, the results are shown in Table 7.
Table 7 pill bar, gradation temperature investigation table
As known from Table 7, this product pill bar, gradation temperature are 5 ℃ ± 2.
5. wet ball drying:
The wet exsiccant factor of ball of influence mainly is a temperature.Therefore need wet ball baking temperature is screened.
Get the wet ball of going up that makes respectively, the temperature of according to the form below is carried out drying, and it is moisture below 9% to be dried to a ball.Quality with a ball serves as to investigate index, the results are shown in Table 8.
The wet ball baking temperature screening of table 8 table
As known from Table 8,3
#Baking temperature is better, so this product selects 3
#40 ℃ of dryings of promptly wet ball elder generation 1.5 hours are warming up to 60 ℃ of dryings more gradually.
6. select ball
The pill of screening 2.5mm～1.0mm.
7. determine pill making craft
Get dried cream, be ground into fine powder, add about 28% 80% ethanol, the system soft material, on made the pellet processing machine pill of ball bar, gradation temperature, wet ball is 40 ℃ of dryings 1.5 hours earlier, be warming up to 60 ℃ of dryings (will stir in the dry run) more gradually, be dried to moisture below 9.0%, must do ball, the pill of screening 2.5mm～1.0mm.
6, packing
(1) critical relative humidity is measured
Get 5 parts of concentrated micropills respectively, every part of about 1g puts into the environment of relative humidity 33%, 42.8%, 59.7%, 75.3%, 81% respectively, places 72 hours in 25 ℃ of incubators, takes out weighing, calculates moisture absorption weightening finish percentage rate, the results are shown in Table 9.With moisture absorption weightening finish percentage rate is ordinate, and relative humidity is that abscissa is made curve, the results are shown in Figure 1.
Table 9 critical relative humidity investigation table
Result of the test shows: this kind critical relative humidity is 67%.So this product is 25 ℃ of temperature, relative humidity carries out packing below 65%, can not influence the quality of product.
(2) packing condition
In 300,000 grades of clean areas (18 ℃～25 ℃ of room temperatures, relative humidity is below 65%), carry out packing.
7, packaging material determines
For being convenient for carrying, transporting, taking, determine this product medicinal high-density polyethylene bottle packing of oral administration solid.
12.5 pilot scale research
By the process conditions of determining, manufacture experimently ten batches in test agent (lot number: 031201,031202,031203; 040801,040802,040803,040804; 050101,050102,050103) three batches of pilot experiments of 12.5.1 (031201,031202,031203) the results are shown in Table 10, table 11
Test agent creation data table in the table 10
Table 11 pilot scale sample quality inspection knot
(12.5.2 040801,040802,040803,040804) four batches of pilot experiments the results are shown in Table 12,
Table 13
Test agent creation data table in the table 12
Table 13 pilot scale sample quality inspection knot
12.5.3 (050101,050102,050103) three batches of pilot experiments the results are shown in Table 14, table 15
Test agent creation data table in the table 14
Table 15 pilot scale sample quality inspection knot
Experimental result shows, every regulation that pilot scale samples met pill is relevant, and this preparation process is stablized feasible.
Description of drawings
The critical relative humidity figure of Fig. 1 pill of the present invention
Pharmacodynamic study
Medicine of the present invention pulls the root vegetables single by genuine traditional Chinese medicine and forms, and has the enzyme of falling, and protects the liver removing jaundice, the effect of invigorating the spleen. Be used for CAH, hepatitis B, also can be used for acute viral hepatitis. This pharmaceutically dosage form also has granule on market at present, records in " Drug Standard of Ministry of Public Health of the Peoples Republic of China Traditional Chinese medicine historical preparation " the 13rd. Former granule clinical practice for many years, determined curative effect, but oral 9g once, dose is big, reduces patient's compliance. The present invention adopts concentrated pellet preparations, and small size is easily swallowed, and auxiliary material do not contain sugar, therefore can reduce dose, and concentrated micropill also has fast and leach, and carries, transports, stores the advantages such as convenient.
This research is by causing the impact of acute liver model to D-Gal and carbon tetrachloride, the impact that the mouse hemolytic antibody is generated is to the observation of the impact of mouse macrophage system phagocytic function, with the drug effect of checking medicine of the present invention.
1 experiment material
Animal: small white mouse, the Kunming kind, one-level is qualified, male and female half and half, body weight 18-22g is provided by The Fourth Military Medical University's Experimental Animal Center.
Medicine and reagent: the used preparation of test group is that namely the lab scale medicine is provided by Jiangxi Yaodu Renhe Pharmaceutical Co., Ltd, lot number 060519 according to the concentrated pellet preparations of the embodiment of the invention 1 preparation. Control drug: GANSU KELI, Sichuan doctor pharmaceutcal corporation, Ltd produces, lot number 051223. D-Gal is produced by SIGMA CHEMICAL CO., and all tested medicines all are made into desired concn with distilled water and use for experiment.
Reagent: serum glutamic pyruvic transminase (ALT) kit, lot number 060710; Glutamic-oxalacetic transaminease (AsT) kit, lot number 060710; Co., Ltd provides by Bai Ding bioengineering (Beijing). Malondialdehyde Kit (MDA), superoxide dismutase (SOD) kit, building up bio-engineering research by Nanjing is provided.
Instrument: AUTOTECH-128 type automatic clinical chemistry analyzer.
2 experimental techniques and result
2.1 D-Gal is caused the impact of acute liver model
Get 60 of body weight 18～22g mouse, male and female half and half are divided into blank group, model control group, lab scale medicine high dose, middle dosage, low dosage and GANSU KELI group at random. Each group is pressed the dosage gastric infusion of table 1, successive administration 3 days, 50min after the last administration, except the blank group, all the other respectively organize lumbar injection 650mg/kgD-amine-galactose, get blood from the mouse orbit veniplex behind the 24h, survey Serum ALT, AST, SOD and MDA content; Get the part mouse liver through 10% formaldehyde fixedly more than the 48h, FFPE, section, HE dyeing, Microscopic observation each treated animal liver organization structure and lesion characteristic. The result of variations that each organizes mice serum ALT, AST sees Table 16; Mice serum SOD vigor and MDA content influence see Table 17.
Table 16 pair D-Gal causes acute hepatic injury mice Serum ALT and AST impact
Annotate: compare with model control group,*P＜0.05，
**P＜0.01; With blank group ratio,ΔΔP＜0.01。
Experimental result shows that the lab scale medicine has obvious prevention D-Gal to cause that acute liver model Serum ALT, AST activity increase effect, has compared significant difference (P＜0.01) with model control group.
Table 17 pair D-Gal causes acute hepatic injury mice serum activity of SOD and MDA content influence
Annotate: compare with model control group,*P＜0.05，
**P＜0.01; With blank group ratio,ΔΔP＜0.01。
Experimental result shows, compares with the blank group, and the MDA content rising in the model group mice serum is (P＜0.01) significantly; MDA content in the high, medium and low dosage group of lab scale medicine and the GANSU KELI group mice serum is starkly lower than model group, P＜0.05 and P＜0.01.
With blank group ratio, active obviously reduce (P＜0.05) of SOD in the model group mice serum; SOD activity in the high, medium and low dosage group of lab scale medicine and the GANSU KELI group mice serum is apparently higher than model group, P＜0.05.
2.2 D-Gal is caused the pathological observation of acute liver.
Dissect and check: the blank group does not have obvious pathology; Model control group Mouse Liver weight increases, and is yellowish-brown to aubergine, and tangent plane turns up, and sepage is more; Each treatment group all has in various degree similar form to model group, and lesion degree obviously alleviates. Micro-pathologic finding: blank group mouse: the lobuli hepatis structural integrity, no pathology changes. The model control group mouse: liver cell is hydropic degeneration, endochylema puffing and the visible point-like of muddy swelling liver cell and focal necrosis widely, and Visible Core is cracked, and acidophilic body and fat become the portal area inflammatory cell infiltration. GANSU KELI group mouse: the liver cell cloudy swelling, the endochylema puffing is obvious, visible spotty necrosis, visible focal necrosis still, the visible a small amount of inflammatory cell infiltration in portal area. Lab scale medicine high dose group mouse: accidental slight spotty necrosis slight cloudy swelling appears, in indivedual liver cells. Dosage group mouse in the lab scale medicine: the slight hepatic cell cloudy swelling has the littler spotty necrosis of minority scope, the visible a small amount of inflammatory cell infiltration in portal area. Lab scale medicine low dose group mouse: liver cell hydropic degeneration, endochylema puffing and cloudy swelling, visible spotty necrosis, accidental slight focal necrosis, the visible inflammatory cell infiltration in portal area.
2.3 carbon tetrachloride is caused the impact of acute liver model
Get 60 of body weight 18～22g mouse, male and female half and half are divided into blank group, model control group, lab scale medicine high dose, middle dosage, low dosage and GANSU KELI group at random. Each group is pressed the dosage gastric infusion of table 3, successive administration 3 days, and 1h is except the blank group after the last administration, and all the other are respectively organized equal gavage and give 0.12%
CCl
4Soybean oil solution 10ml/kg behind the 24h, gets its serum and surveys ALT and AST activity, and experimental result sees Table 18.
Table 18 pair carbon tetrachloride causes the impact (x ± s) of acute liver model
Annotate: with the model control group ratio,*P＜0.05，
**P＜0.01; With blank group ratio,ΔΔP＜0.01。
Experimental result shows that lab scale medicine group has obvious prevention carbon tetrachloride to cause that acute hepatic injury mice model Serum ALT, AST activity increase effect, has compared significant difference (P＜0.05) with model control group.
2.4 the impact to the generation of mouse hemolytic antibody
Get 50 of body weight 18～22g mouse, male and female half and half are got chicken red blood cell and are made into 5% normal saline suspension, and every mouse lumbar injection 0.2ml immunity with mouse random packet after the immunity, sees Table 4. Each group is pressed table 4 dosage gastric infusion, every day 1 time, and successive administration 7 days, the blank group gives with volume distilled water. 1h after the last administration, mouse eyeground vein clump is got blood, centrifuging and taking serum, with 100 times of normal saline dilutions, other gets the dilution in 1: 10 of 3 GPS physiological saline, and is for subsequent use as complement. Getting above-mentioned dilution 1ml mixes with 5% chicken red blood cell 0.5ml, in 0 ℃ of ice bath, add complement 0.5ml, be incubated 30min in 37 ℃ of incubators, take out 0 ℃ of cessation reaction, centrifugal, get supernatant in " 721 " spectrophotometer colorimetric, transfer " 0 " with increase serum blank tube not, 540nm measures optical density, generate index with OD value as serum hemolysin, the results are shown in Table 19.
The impact that table 19 pair mouse hemolytic antibody generates
Annotate: with blank group ratio,*P＜0.05，
**P＜0.01。
Table 19 is the result show, the lab scale medicine can obviously promote the mice serum hemolytic antibody to generate, each administration group mice serum hemolysin OD value has significant difference (P＜0.05 or P＜0.01) with the blank group than all, illustrates that lab scale medicine and control drug GANSU KELI all have the function that improves humoral immunity of organism.
2.5 the impact to mouse macrophage system (RES) phagocytic function
Get 50 of body weight 18～22g healthy mices, male and female half and half by the body weight random packet, see Table 5. Each group is pressed table 5 dosage gastric infusion, every day 1 time, successive administration 7 days. 30min after the last administration, by mouse carbon particle clearance method, the india ink 0.1ml/10g body weight of 8: 1 normal saline dilutions of tail vein injection, respectively after injection 2min, 6min with heparin solution moistening suction pipe in advance, the eyeground vein clump is got blood 20 μ l, is dissolved in 2ml 0.1%
Na
2CO
3Mixing in the solution, " 721 " spectrophotometer 640nm wavelength place colorimetric is dissolved in 1%Na with the normal small white mouse blood of 20 μ l2CO
3Transfer " 0 " point among the solution 2ml behind the mixing, photometry density (OD) value is calculated as follows phagocytic index K. With the t method of inspection significance of difference between each administration group and blank group relatively, the results are shown in Table 20.
The impact of table 20 pair mouse macrophage system (RES) phagocytic function
Annotate: with blank group ratio,*P＜0.05，
**P＜0.01。
By table 20 result as seen, lab scale medicine group can obviously improve the phagocytic index of small white mouse reticuloendothelial system (RES), with blank group ratio significant difference (P＜0.05) is arranged. Control drug GANSU KELI group also can improve the phagocytic index of small white mouse reticuloendothelial system (RES), but not statistically significant.
3 discuss
Glutamic-pyruvic transaminase (ALT), glutamic-oxalacetic transaminease (AST) content in liver cell are higher, the important index enzyme that raises in the serum when being hepar damnification. Detecting serum alt, AST activity level and can judge the order of severity of hepatic injury, is the sensitive indicator of hepatocellular damage. Pharmacodynamic experiment is the result show, medicine of the present invention has obvious prevention D-Gal hydrochloride, carbon tetrachloride to cause the effect that mice serum ALT, AST activity increase, and illustrates that this medicine has the effect of certain protecting liver, lowering enzymes.
The experimental results shows, free radical participates in many basic life processes, such as biological oxidation, cell proliferation, body aging etc., radical reaction is the molecular pathology basis that causes numerous disease and body injury, and it causes damage mechanism mainly is the biomembrane lipid peroxidating that free radical causes. The main mechanism that D-Gal causes hepatocellular injury is because the lipid peroxidation chain reaction of free radical and startup thereof. In the peroxidatic reaction of lipid process, unrighted acid oxidation Decomposition release reaction aldehyde such as MDA, 4-hydroxyl nonene (4-HNE) etc., the amount of measuring MDA often can reflect body inner lipid peroxidating degree, indirectly reflects body tissue, cellular damage degree. SOD is the scavenger of super oxygen radical cation, can suppress the peroxidatic reaction of lipid that free radical starts, and when liver cell was subjected to the free radical attack, SOD can reduce because of its exhaustion. SOD plays vital effect to the oxidative and anti-oxidative balance of body, and this enzyme can be removed the ultra-oxygen anion free radical Cell protection and avoid damage. The height of SOD vigor has reflected the ability of body removing free radical indirectly, and MDA content and SOD vigor have reacted the degree of medicine to the peroxidation damage in the liver. Experimental result also shows can raise SOD activity in the hepatic injury mouse blood of medicine of the present invention, and reduces the MDA content in the blood. Illustrate that we can Anti-lipid peroxidation, improve the ability of body Anti-lipid peroxidation. Pathological examination shows that liver must be answered capsule can make mouse liver cell degeneration necrosis degree alleviate, particularly heavy dose of group only indivedual liver cells cloudy swelling appears, basic approach normal. Pathology prompting medicine of the present invention can improve liver tissue injury.
Experimental study by pharmacodynamics shows that medicine of the present invention has ALT, AST effect in the liver injury model of the reduction mouse blood; Improve SOD vigor and reduction MDA content in the liver injury model mouse blood, have the effect of the mouse of raising immunity of organisms. Illustrate that medicine of the present invention has good protecting liver, lowering enzymes pharmacological action, thereby be treatment CAH, hepatitis B, acute viral hepatitis provides the pharmacodynamics foundation.
The specific embodiment
1. with Herba Lysimachiae Clethroids 8350g, decoct with water 3 times, each 2 hours, collecting decoction filtered, and filtrate is condensed into and surveys relative density under 60-65 ℃ of condition is 1.15 clear paste, and cooling adds ethanol and makes and contain the alcohol amount and reach 60%, stirs, and leaves standstill, filter, filtering residue and filtrate A;
2. filtering residue merges washing liquid and filtrate A with 60% washing with alcohol 3 times, reclaims ethanol and is condensed into that to survey relative density under 40 ℃ of conditions be 1.32 thick paste, adds appropriate amount of starch, mixes, and drying is pulverized, and gets medicated powder; It is an amount of to add 80% ethanol, pill, and packing, packing, promptly.
1. with Herba Lysimachiae Clethroids 8400g, decoct with water 2 times, 3 hours for the first time, 1 hour for the second time, collecting decoction, filter, filtrate is condensed into and surveys relative density under 60-65 ℃ of condition is 1.20 clear paste, and cooling adds ethanol and makes and contain the alcohol amount and reach 70%, stir, leave standstill, filter, get filtering residue and filtrate A;
2. filtering residue merges washing liquid and filtrate A with 50% washing with alcohol 2 times, reclaims ethanol and is condensed into that to survey relative density under 40 ℃ of conditions be 1.35 thick paste, adds appropriate amount of starch, mixes, and drying is pulverized, and gets medicated powder; It is an amount of to add 65% ethanol, pill, and packing, packing, promptly.
1. with Herba Lysimachiae Clethroids 8300g, decoct with water 3 times 2 hours for the first time, 3 hours for the second time, 1 hour for the third time, collecting decoction, filter, filtrate is condensed under 60-65 ℃ of condition and surveys relative density is 1.10 clear paste, and cooling adds ethanol and makes and contain the alcohol amount and reach 55%, stir, leave standstill, filter, get filtering residue and filtrate A;
2. filtering residue merges washing liquid and filtrate A with 90% washing with alcohol 3 times, reclaims ethanol and is condensed into that to survey relative density under 40 ℃ of conditions be 1.30 thick paste, adds appropriate amount of starch, mixes, and drying is pulverized, and gets medicated powder; It is an amount of to add 85% ethanol, pill, and packing, packing, promptly.
Embodiment 4
1. with Herba Lysimachiae Clethroids 8320g, decoct with water 3 times 3 hours for the first time, 2 hours for the second time, 1 hour for the third time, collecting decoction, filter, filtrate is condensed under 60-65 ℃ of condition and surveys relative density is 1.18 clear paste, and cooling adds ethanol and makes and contain the alcohol amount and reach 65%, stir, leave standstill, filter, get filtering residue and filtrate A;
2. filtering residue merges washing liquid and filtrate A with 80% washing with alcohol 3 times, reclaims ethanol and is condensed into that to survey relative density under 40 ℃ of conditions be 1.30 thick paste, adds appropriate amount of starch, mixes, and drying is pulverized, and gets medicated powder; It is an amount of to add 70% ethanol, pill, and packing, packing, promptly.
Claims (1)
1. preparation method that is used for the treatment of the medicine pill of hepatitis is characterized in that described method comprises following steps:
A, extraction:
Get Herba Lysimachiae Clethroids and decoct with water three times, each 2 hours, 12 times of medical material amounts for the first time, 10 times of medical material amounts for the second time, 8 times of medical material amounts for the third time, decocting liquid filters, merge three times filtrate, 60～65 ℃ of clear paste that are concentrated into relative density 1.15～1.18 are cooled to room temperature, add ethanol and make and contain alcohol amount and reach 60%, slowly accelerate to stir, leave standstill, filter, filtrate is deposited in addition; Precipitation is measured 60% washing with alcohol 3 times with 6 times, and each 2 times of amounts merge washing liquid and filtrate;
B, separation and purification, concentrated:
After extracting solution merged, 200 mesh sieves filtered, and got extracting solution filtrate; Behind the precipitate with ethanol, the filter paper sucking filtration gets pure filtrate; After the Cake Wash, sucking filtration gets pure filtrate, merges pure filtrate, reclaims ethanol, concentrates; Be concentrated into the clear paste of relative density about 1.15～1.17 when medicinal liquid is with 70 ℃ of concentrating under reduced pressure devices behind the precipitate with ethanol, select steam to concentrate again; The thick paste of relative density 1.30～1.32 when clear paste is concentrated into 60 ℃ with steam;
C, extract dry:
Get 60 ℃ record the thick paste of relative density 1.30～1.32, add appropriate amount of starch, mix 80 ℃ of bake dryings;
D, pill:
Get dried cream, be ground into fine powder, add about 28% 80% ethanol, the system soft material, on made the pellet processing machine pill of ball bar, gradation temperature, 40 ℃ of dryings of wet ball elder generation 1.5 hours, be warming up to 60 ℃ of dryings more gradually, will stir in the dry run, be dried to moisture below 9.0%, must do ball, the pill of screening 2.5mm～1.0mm;
E, packing:
With the medicinal high-density polyethylene bottle packing of oral administration solid promptly.
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| CN101721488B (en) * | 2009-12-08 | 2011-11-09 | 湖南省中药提取工程研究中心有限公司 | Pharmaceutical composition for treating liver diseases and prepration method thereof |
| CN102342963B (en) * | 2011-10-19 | 2013-07-10 | 西安大唐制药集团有限公司 | Preparation process for Gansu soft capsule |
| CN104274501A (en) * | 2013-07-09 | 2015-01-14 | 四川天寿药业有限公司 | Pharmaceutical composition and preparation method thereof |
| CN108245539A (en) * | 2018-04-13 | 2018-07-06 | 宇妥藏药股份有限公司 | A kind of preparation method of liver Soviet Union capsule |
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Non-Patent Citations (1)
| Title |
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| 中华人民共和国药典委员会.中华人民共和国卫生部药品标准中药成方制剂第十三册.1997,87. * |
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