CN101177424A - High-purity silybin meglumine, preparation method as well as application in preparing medicine treating hepatitis and liver hurt thereof - Google Patents
High-purity silybin meglumine, preparation method as well as application in preparing medicine treating hepatitis and liver hurt thereof Download PDFInfo
- Publication number
- CN101177424A CN101177424A CNA2006100974485A CN200610097448A CN101177424A CN 101177424 A CN101177424 A CN 101177424A CN A2006100974485 A CNA2006100974485 A CN A2006100974485A CN 200610097448 A CN200610097448 A CN 200610097448A CN 101177424 A CN101177424 A CN 101177424A
- Authority
- CN
- China
- Prior art keywords
- silybin meglumine
- meglumine
- silybin
- peaks
- powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to silibinin meglumine with high purity, the preparation method and the application in preparing the drugs for treating acute attack of acute hepatitis and chronic hepatitis and toxic liver injury, belonging to medical technical field. The content of the silibinin meglumine with high purity is more than 98% tested using HPLC, thereby the drawbacks of bad safety for clinical application and bad quality controllability due to low purity of silibinin meglumine are overcome. The invention has the advantages of high purity, good stability and safety and improved human bioavailability compared to former oral preparation since the silibinin meglumine with high purity can be used for injection preparation.
Description
Technical field:
The present invention relates to a kind of medical technical field, be specifically related to a kind of highly purified silybin meglumine, its preparation method and the application in the medicine of acute attack stage for preparing treatment acute hepatitis, chronic hepatitis and toxic hepatitis thereof.
Background technology:
The sixties in last century, the West Germany pharmacy men that with HWagner are representative find to contain novel flavones ingredient in feverfew Silymarin [Silybum marianum] seed, include silibinin, Silydianin, Silychristin and silybonol, the general name silymarin.Wherein main component is a silibinin, and proves through pharmacological evaluation, has the protection liver plasma membrane; improve the liver function effect, can resist the liver injury due to the multiple hepatotoxic agent, and toxicity is extremely low; thereby cause the attention of many countries, cause the research work of Silymarin to spread all over five continents.By 1978, ten years are only arranged, more than 20 countries such as West Germany successively deliver the Silymarin research paper and reach 105,60 pieces, and wherein pharmacology and clinically account for over halfly makes Silymarin become the worldwide medicinal plant that protects the liver.Abroad, in order to the grand diseases such as the acute and chronic hepatitis of treatment, liver cirrhosis that have been widely used in for the silymarin several formulations of representative of liver.
China introduced Silymarin in 1972 by West Germany, and popularizing planting is achieved success in various places, and Silymarin seed active principle-total flavones that China introduces a fine variety is made Yiganling tablet, and clinical application is provided.Jiangsu Province had set up the extraction separation of silibinin scientific research cooperative groups to silibinin in 1980, the preparation of water-soluble silibinin and preparation, content assaying method, percentage absorptivity and quality standard etc. have been carried out systematic research, the water-soluble silybin meglumine of being developed is on probation through 11 clinical units, prove evident in efficacy, treatment chronic persistent hepatitis 256 examples, total effective rate 74.6%, wherein obvious effective rate is 52.0%.
According to the statistical information of Ministry of Health's issue, the M ﹠ M of viral hepatitis accounts for the first place in the transmissible disease of statutory report.China's hepatitis average attack rate is about 1,00/,100,000, about 1,200,000 examples of promptly annual New Development hepatitis.According to another the seroepidemiological survey of 92～95 years national viral hepatitis, the general crowd's of China hepatitis B (hepatitis B) viral surface antigen (HbsAg) carrying rate is 9.7%, estimates that about 1.2 hundred million people carry hepatitis B virus (HBV).The morbidity of chronic hepatopathy and mortality ratio are respectively 16 ‰ and 24.9/10 ten thousand, calculate that in view of the above the whole nation has 2,000 ten thousand routine chronic hepatitis patients approximately, and annual about 300,000 people die from chronic hepatopathy.Liver cancer mortality is 14.8/10 ten thousand, and is annual because of about 180,000 examples of PLC mortality.
Be used for clinical silybin meglumine [national drug standards WS-10001-(HD-0925)-2002] now and contain silymarin meglumine and must not be less than 96.0%, contain silybin meglumine and must not be less than 75.0%, purity is not high, can only be used for oral preparations.And silybin meglumine is a weak acid and weak base salt, poor stability, and the silibinin of insoluble is separated out easily in oral back under gastric acid environment, influence absorption of human body, causes human bioavailability low.
Chinese patent (application number: 200410023872,200510080657) disclose the technology of making injection preparation with silybin meglumine; Chinese patent (the patent No.: 200410041363) disclose " a kind of new preparation process of Herba Silybi mariani extract meglumine salt "; But the content of the silybin meglumine that above-mentioned document is mentioned HPLC method all of no use is measured and is recorded content more than 98.0%.
The evaluation principle of medicine is " safe, effective, controlled ".Use the silybin meglumine that uses clinically now and have the relevant silybin meglumine of report to study in document or the patent documentation, there is no useful HPLC method and measure the content that flies Ji guest meglumine more than 98.0%, this brings uncontrollable factor with regard to the clinical application of giving silybin meglumine, stay unsafe hidden danger, the clinical application of silybin meglumine is restricted.
At above problem, the invention provides a kind of highly purified silybin meglumine, use high effective liquid chromatography for measuring, the content of silybin meglumine is more than 98.0%.
Summary of the invention:
In order to solve above the deficiencies in the prior art, the invention provides a kind of highly purified silybin meglumine, measure with the HPLC method, be reference substance with the silibinin, the content of silybin meglumine is more than 98.0%.The present invention also provides a kind of and has prepared the method for high purity silybin meglumine and disclose a kind of high purity silybin meglumine for the treatment of significant quantity and pharmaceutical composition of pharmaceutically acceptable carrier of containing.
Compared with prior art, highly purified silybin meglumine provided by the invention is measured with HPLC, content is more than 98%, overcome that former silybin meglumine purity is low, content is in the deficiency more than 75%, eliminated the clinical application potential safety hazard brought because silybin meglumine purity is low and the phenomenon of quality controllability difference.Because the purity height, good stability, security is good, and silybin meglumine can be made injection preparation, has improved human bioavailability than in the past oral preparations, has given full play to the treatment disease effect of silybin meglumine.
The hemolytic evidence of disclosed high purity silybin meglumine of this patent and commercially available silybin meglumine raw material, highly purified silybin meglumine does not have hemolytic action, and more safe than commercially available silybin meglumine, toxicity reduces.
Concrete scheme is as follows:
The invention discloses a kind of highly purified silybin meglumine, use high effective liquid chromatography for measuring, the content of silybin meglumine is more than 98.0%, and its preparation method comprises the steps:
Commercially available silybin meglumine adds Virahol, the reflux sample dissolution, and filtered while hot, filtrate is placed in refrigerator, filters, and filtrate decompression concentrates solvent evaporated, and drying gets the khaki color powder;
Get (1) gained powder, adding distilled water stirs, and makes dissolving, filters, and filtrate adds saturated aqueous common salt, places in refrigerator, filters, and drying gets pale yellow powder;
Get (2) gained powder, add Virahol, the reflux sample dissolution, filtered while hot, filtrate is placed in refrigerator, filters, and filtrate decompression concentrates solvent evaporated, and drying gets pale yellow powder.
Highly purified silybin meglumine disclosed by the invention is used the high performance liquid chromatography external standard method, is reference substance with the silibinin, and the content of silybin meglumine is more than 98.0%.
Highly purified silybin meglumine disclosed by the invention is characterized in that, uses the high performance liquid chromatography external standard method, is reference substance with the silibinin, and the content of silybin meglumine is more than 98.0%; Its feature also is, in the high performance liquid chromatography area normalization collection of illustrative plates, have 5 chromatographic peaks, wherein No. 2 peaks, No. 3 peaks are two main peaks of silibinin, and their peak area sum accounts for more than 95.5% of total peak area, and No. 5 peaks are the Isosilybin peak, its peak area accounts for below 0.5% of total peak area, 1 peak number and No. 4 peaks are the unknown material mass peak, and the peak area at No. 1 peak accounts for below 0.5% of total peak area, and the peak area at No. 4 peaks accounts for below 3.5% of total peak area; The relative retention time at 5 peaks is followed successively by: No. 1 peak: 0.520～0.575, No. 2 peaks: 1.000, No. 3 peaks: 1.110～1.135, No. 4 peaks: 1.251～1.320, No. 5 peaks: 1.495～1.590.
The efficient liquid-phase chromatography method of the highly purified silybin meglumine of said determination is as follows:
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is weighting agent; With methanol-water-0.5mol/L potassium primary phosphate (10: 10: 1) is moving phase (with 0.2mol/L phosphorus acid for adjusting pH value to 4.0), and detecting wavelength is 288nm.Number of theoretical plate calculates by the silibinin peak should be not less than 3000.
Assay method: silybin meglumine 15mg, the accurate title, decide, and puts in the 50ml measuring bottle, it is an amount of to add methyl alcohol, and supersound process 20 minutes is put cold, add methyl alcohol to scale, shake up, precision is measured 5ml, puts in the 25ml measuring bottle, add moving phase and be diluted to scale, shake up, precision is measured 20ul and is injected liquid chromatograph, the record color atlas; The silibinin reference substance 10mg that other learns from else's experience 105 ℃ and is dried to constant weight measures with method, and with calculated by peak area, the result multiply by 1.405, promptly by external standard method.
Other conditions of above high performance liquid chromatography are:
Chromatographic column: Discovery ODS-C18 post, 25cmX4.6mm, 5um;
Column temperature: 30 ℃;
Flow velocity: 1.0ml/ minute.
The preparation method of highly purified silybin meglumine disclosed by the invention comprises the steps:
(1) commercially available silybin meglumine adds Virahol, the reflux sample dissolution, and filtered while hot, filtrate is placed in 4 ℃ of refrigerators, filters, and filtrate decompression concentrates solvent evaporated, and 40 ℃ of vacuum-dryings get the khaki color powder;
(2) get (1) gained powder, adding distilled water stirs, and makes dissolving, filters, and filtrate adds saturated aqueous common salt, places in 4 ℃ of refrigerators, filters, and drying gets pale yellow powder;
(3) get (2) gained powder, add Virahol, the reflux sample dissolution, filtered while hot, filtrate is placed in 4 ℃ of refrigerators, filters, and filtrate decompression concentrates solvent evaporated, and 40 ℃ of vacuum-dryings get pale yellow powder.
The preparation method of above-mentioned highly purified silybin meglumine, wherein:
The amount that adds Virahol in the step (1) is 30～50 times of silybin meglumine, and the temperature of concentrating under reduced pressure is 40～70 ℃;
The amount that adds distilled water in the step (2) is 5～15 times of silybin meglumine, and whipping temp is 0～10 ℃, and the amount that adds saturated aqueous common salt is 10～20 times of silybin meglumine;
The amount that adds Virahol in the step (3) is 60～100 times of silybin meglumine, and the temperature of concentrating under reduced pressure is 40～70 ℃.
Among the preparation method of above-mentioned highly purified silybin meglumine, commercially available silybin meglumine is for meeting the chemical of national drug standards WS-10001-(HD-0925)-2002.
Preparation method's process of above-mentioned highly purified silybin meglumine is simple, easy to operate, and agents useful for same and equipment are common agents and equipment, is fit to big production, does not have environmental protection hidden danger.
The invention also discloses a kind of pharmaceutical composition of highly purified silybin meglumine, wherein contain highly purified silybin meglumine and pharmaceutically acceptable carrier.Be specifically related to oral preparations, as conventional tablet, capsule, dispersible tablet, granule, enteric coated tablet, slow releasing tablet, orally disintegrating tablet; Injection preparation is as freeze-dried powder, aseptic subpackaged injectable sterile powder, infusion preparation, little pin.
The pharmaceutical composition that contains highly purified silybin meglumine disclosed by the invention, the silybin meglumine and the pharmaceutically acceptable carrier that wherein contain 10～200mg, be preferably the silybin meglumine and the pharmaceutically acceptable carrier that contain 25mg or 50mg or 100mg,, lemon flavour sweet, talcum powder etc. as starch, lactose, Microcrystalline Cellulose, sodium starch glycolate, pregelatinized Starch, N.F,USP MANNITOL, Magnesium Stearate, cross-linked polyvinylpyrrolidone, aspa.
The invention also discloses the application of a kind of highly purified silybin meglumine in the medicine of acute attack stage for preparing treatment acute hepatitis, chronic hepatitis and toxic hepatitis.
The pharmacodynamic study of the freeze-dried powder that highly purified silibinin Portugal first ammonia is made and hemolytic test research are as follows:
Silybin meglumine (freeze-drying) powder pin Pharmacodynamic test of active extract
1. silybin meglumine (freeze-drying) powder is at CCl
4The influence of induced mice acute liver damage
1.1 method
Get 60 of healthy male Kunming kind small white mouses, body weight 18-22g.Be divided at random: 1. normal control group; 2. model group; 3. Glycyrrhizic acid,diammonium salt control group (30mg/kg); 4. silybin meglumine (freeze-drying) powder pin low dose group (25mg/kg); 5. dosage group (50mg/kg) in silybin meglumine (freeze-drying) the powder pin; 6. silybin meglumine (freeze-drying) powder pin high dose group (100mg/kg).Every group 10.Glycyrrhizic acid,diammonium salt control group and be subjected to the basic, normal, high dosage group of reagent to be the tail intravenously administrable; Normal control group and model group give isopyknic physiological saline.Each organized successive administration 3 days, once a day.1h after administration in the morning on the 4th, model group and each administration group mouse be subcutaneous injection 0.5%CCl respectively
4Peanut oil solution 10ml/kg, normal group subcutaneous injection equal-volume physiological saline.Afternoon on the same day, reinforcement was administered once, and that night, water was can't help in fasting.1h after the last administration in the morning on the 5th weighs, and the eye socket venous plexus is got blood, and separation of serum adopts kit measurement serum GOT, GPT.
1.2 result
Model group mice serum GOT, GPT content significantly raise.Each dosage group mice serum GOT of silybin meglumine (freeze-drying) powder pin, GPT content significantly reduce, the property of comparing with model group that there were significant differences.The results are shown in Table 1.
Table 1 silybin meglumine (freeze-drying) powder is at CCl
4Due to influence (n=10, the X ± SD) of acute liver damage mice serum transaminase
Annotate: with the normal group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001; With the model group ratio
△P＜0.05,
△ △P＜0.01,
△ △ △P＜0.001.
2. silybin meglumine (freeze-drying) powder is at the influence of rat acute liver injury due to the D-Gal amine
2.1 method
Get 60 of healthy male SD rats, body weight 180-220g is divided at random: 1. normal control group; 2. model group; 3. Glycyrrhizic acid,diammonium salt control group (15mg/kg); 4. silybin meglumine (freeze-drying) powder pin low dose group (15mg/kg); 5. dosage group (30mg/kg) in silybin meglumine (freeze-drying) the powder pin; 6. silybin meglumine (freeze-drying) powder pin high dose group (60mg/kg).Every group 10.Glycyrrhizic acid,diammonium salt control group and be subjected to the basic, normal, high dosage group of reagent to be the tail intravenously administrable; Normal control group, model group give isopyknic physiological saline respectively.Each organized administration successively 3 days, once a day.1h after administration in the morning on the 4th, model group and each administration group rat give D-GlaN 600mg/kg in the abdominal cavity respectively, normal group abdominal injection equal-volume physiological saline.Afternoon on the same day, reinforcement was administered once.Be administered once in 5th, and behind abdominal injection D-GlaN 24h: after weighing respectively, get blood by the eye socket venous plexus, separation of serum adopts kit measurement serum GOT, GPT.2.2 result
Model group rat blood serum GOT, GPT content significantly raise; Part of hepatocytes hydropic degeneration in the liver leaflet, the liver cell spotty necrosis that is dispersed in has cell infiltration in necrotic area and the portal area.Each dosage group rat blood serum GOT of silybin meglumine (freeze-drying) powder pin, GPT content significantly reduce, the property of comparing with model group that there were significant differences; Hepatocellular injury significantly alleviates than model group, is dose-effect relationship.The results are shown in Table 2.
Table 2 silybin meglumine (freeze-drying) powder is at due to the D-GlaN
The influence of Rats with Acute Liver Injury serum transaminase (n=10, X ± SD)
Annotate: with the normal group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001; With the model group ratio
△P＜0.05,
△ △P＜0.01,
△ △ △P＜0.001.
3. silybin meglumine (freeze-drying) powder is at CCl
4Due to the influence of rat chronic liver injury
3.1 method
Press literature method, get 60 of healthy male SD rats, body weight 150 ± 20g is divided at random: 1. normal control group; 2. model group; 3. Glycyrrhizic acid,diammonium salt control group (15mg/kg); 4. silybin meglumine (freeze-drying) powder pin low dose group (15mg/kg); 5. dosage group (30mg/kg) in silybin meglumine (freeze-drying) the powder pin; 6. silybin meglumine (freeze-drying) powder pin high dose group (60mg/kg).Every group 10.Each administration group be intraperitoneal injection (ip, 0.5ml/100g), normal group and model group abdominal injection equal-volume physiological saline.Model group and each administration group rat be subcutaneous injection CCl weekly
40.2ml/100g body weight 1 time, normal group subcutaneous injection equal-volume physiological saline.CCl
4Concentration is followed successively by 5%, 10%, 20%, 30%, and per 3 weeks increase progressively a concentration, continuous 3 months.From giving CCl
4First three day beginning administration, continuous 3 months.Weigh weekly once, change dosage.In last subcutaneous injection CCl
4After 48 hours: after 1. weighing respectively, urethane anesthesia is dissected, and separates common bile duct, and the biliary tract intubate is collected bile (the results are shown in the cholagogic test); 2. separate carotid artery, intubate is got blood, and separation of serum adopts kit measurement serum GOT, GPT, total serum protein, serum albumin, serum THP content.
3.2 result
The model group rat body weight significantly reduces, and the liver index significantly increases; Serum GOT, GPT content significantly raise, and total serum protein, albumin, THP content significantly reduce; The obvious steatosis of liver cell around the liver leaflet central vein, part of hepatocytes disintegration necrosis, there is cell infiltration the necrotic area.Silybin meglumine (freeze-drying) powder pin low dosage and middle dosage group rat body weight and normal group compare, property that there were significant differences, and high dose group rat body weight and normal group relatively do not have the significance difference opposite sex; Each dosage group rats'liver index of silybin meglumine (freeze-drying) powder pin significantly reduces, the property of comparing with model group that there were significant differences; Each dosage group rat blood serum GOT, GPT content significantly reduce, the property of comparing with model group that there were significant differences; Total serum protein, albumin, THP content significantly increase, the property of comparing with model group that there were significant differences; Hepatocellular injury significantly alleviates than model group, is dose-effect relationship.The results are shown in Table 3, table 4.
Table 3 silybin meglumine (freeze-drying) powder is at CCl
4Due to
Chronic hepatic injury rat body weight and the influence of liver exponential (n=10, X ± SD)
Annotate: with the normal group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001; With the model group ratio
△P＜0.05,
△ △P＜0.01,
△ △ △P＜0.001.
Table 4 silybin meglumine (freeze-drying) powder is at CCl
4Due to influence (n=10, the X ± SD) of chronic hepatic injury rat blood serum transaminase, albumen, THP index
Annotate: with the normal group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001; With the model group ratio
△P＜0.05,
△ △P＜0.01,
△ △ △P＜0.001.
4. silybin meglumine (freeze-drying) powder is at CCl
4Due to rat chronic liver injury model rat bile excretory influence
4.1 method
Animal grouping, modeling and medication are with 3.3.Modeling and administration were got 8 rats for every group after 3 months, weighed respectively, and urethane anesthesia separates common bile duct, and the biliary tract intubate is collected bile.
4.2 result
Compare with model group, each the dosage group administration of silybin meglumine (freeze-drying) powder pin all can significantly increase the rat model choleresis after 3 months.The results are shown in Table 5.
Table 5 silybin meglumine (freeze-drying) powder is at CCl
4Due to chronic hepatic injury rat bile excretory influence (n=8, X ± SD)
Annotate: with the normal group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001; With the model group ratio
△P＜0.05,
△ △P＜0.01,
△ △ △P＜0.001.
5. silybin meglumine (freeze-drying) powder is at the influence of normal rat choleresis
5.1 method
Get 40 of male SD rats, body weight 200 ± 20g is divided at random: 1. normal control group; 2. Glycyrrhizic acid,diammonium salt control group (15mg/kg); 3. silybin meglumine (freeze-drying) powder pin low dose group (15mg/kg); 4. dosage group (30mg/kg) in silybin meglumine (freeze-drying) the powder pin; 5. silybin meglumine (freeze-drying) powder pin high dose group (60mg/kg).Every group 8.Each group adopts femoral vein administration (1ml/100g), and the normal control group gives equal-volume physiological saline.Water is can't help in the 12h fasting before the test, 20% urethane solution intraperitoneal injection of anesthesia (7.5ml/kg) back is fixing, open the abdominal cavity along ventrimeson, find stomachus pyloricus, the upset duodenum, find white toughness bile duct, and the separation threading, the ligation pars papillaris is with scalp acupuncture biliary tract intubate, be pushed into liver on the conduit, fix with line.Stablize 20min, collect normal biliary secretion volume in the 30min earlier, each organizes as above method administration respectively, and 30min, 60min respectively measure choleresis once after administration, compares with choleresis before the medicine.
5.2 result
Compare with normal group, each dosage group of silybin meglumine (freeze-drying) powder pin all can significantly increase biliary secretory volume, is certain dose-effect relationship.The results are shown in Table 6.
Table 6 silybin meglumine (freeze-drying) powder is at the influence of normal rat choleresis (n=8, X ± SD)
Annotate: with the normal group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001.
6. silybin meglumine (freeze-drying) powder is at mouse immune organ weight's influence
6.1 method
Get 60 of the healthy young mouse of Kunming kind, body weight 11-15g, male and female half and half are divided at random: 1. normal control group; 2. endoxan group; 3. Glycyrrhizic acid,diammonium salt control group (30mg/kg); 4. silybin meglumine (freeze-drying) powder pin low dose group (25mg/kg); 5. dosage group (50mg/kg) in silybin meglumine (freeze-drying) the powder pin; 6. silybin meglumine (freeze-drying) powder pin high dose group (100mg/kg).Every group 10.Each administration group is intravenously administrable, and normal control group and endoxan group give isopyknic physiological saline every day.Each organizes administration every day 1 time, in the 4th day of administration, removes the normal control group, every treated animal equal subcutaneous injection endoxan every day, and dosage is 0.015g/kg, continuous 4 days.Each organized successive administration 7 days.Animal is put to death in 24 hours backs of weighing after the last administration, dissects taking-up spleen, thymus gland and liver and weighs respectively, calculates organ index.And organize a statistical test.
6.2 result
With the normal group ratio, endoxan can significantly reduce thymus index and the index and spleen index of mouse.Compare with the endoxan group, silybin meglumine (freeze-drying) powder pin has certain increase immunocompromised mouse immune organ weight's trend, but results of statistical analysis shows there was no significant difference.The results are shown in Table 7.
Table 7 silybin meglumine (freeze-drying) powder is at mouse immune organ weight's influence (n=10, X ± SD, mg/g body weight)
Annotate: with the normal group ratio
*P＜0.05; With endoxan group ratio
△P＜0.05.
7. silybin meglumine (freeze-drying) powder is at the influence (carbon clearance test) of macrophage phagocytosis of mice
7.1 method
Get 60 of healthy male mice in kunming, body weight 18-22g is divided at random: 1. normal control group; 2. endoxan group; 3. Glycyrrhizic acid,diammonium salt control group (30mg/kg); 4. silybin meglumine (freeze-drying) powder pin low dose group (25mg/kg); 5. dosage group (50mg/kg) in silybin meglumine (freeze-drying) the powder pin; 6. silybin meglumine (freeze-drying) powder pin high dose group (100mg/kg).Every group 10.The equal intravenously administrable of each administration group, normal control group and endoxan group give isopyknic physiological saline every day.Each organizes administration every day 1 time, in the 4th day of administration, and endoxan group subcutaneous injection every day endoxan, dosage is 0.015g/kg, continuous 4 days.Each organized successive administration 7 days.15min injects 20% india ink 1ml/100g by the tail vein after the last administration.Get blood 25 μ l respectively at injection back 2min and 10min eye socket venous plexus, put into and fill 0.1%Na
2CO
3In the test tube of solution 2ml, shake up the back in 675nm
[10](absorbancy, OD is with 0.1%Na for the optical density(OD) of each pipe of wavelength place survey
2CO
3The liquid zeroing) be calculated as follows and clean up index (K): and compare between organizing.
K＝(LgOD
1-LgOD
2)/(t
2-t
1)
7.2 result
Compare with normal group, endoxan can significantly reduce thymus index and the index and spleen index of mouse, significantly reduces mouse monokaryon macrophage phagocytic ability.Compare with the endoxan group, silybin meglumine (freeze-drying) powder pin can significantly improve mouse monokaryon macrophage phagocytic ability.The results are shown in Table 8.
Table 8 silybin meglumine (freeze-drying) powder is at the influence of macrophage phagocytosis of mice and immune organ (n=10, X ± SD)
Annotate: with the normal group ratio,
*P＜0.05,
*P＜0.01,
* *P＜0.001; With endoxan group ratio,
△P＜0.05,
△ △P＜0.01,
△ △ △P＜0.001.
8. silybin meglumine (freeze-drying) powder is at the influence of mice serum hemolytic antibody generation
8.1 method
Get 60 of healthy Kunming kind small white mouses, male and female half and half, body weight 18-22g is divided at random: 1. normal control group; 2. endoxan group (0.015g/kg); 3. Glycyrrhizic acid,diammonium salt control group (30mg/kg); 4. silybin meglumine (freeze-drying) powder pin low dose group (25mg/kg); 5. dosage group (50mg/kg) in silybin meglumine (freeze-drying) the powder pin; 6. silybin meglumine (freeze-drying) powder pin high dose group (100mg/kg).Every group 10.The equal intravenously administrable of each administration group, normal control group and endoxan group give isopyknic physiological saline.Each organizes administration every day 1 time, successive administration 7 days.In the 3rd day of administration, endoxan group subcutaneous injection every day endoxan, dosage is 0.015g/kg, continuous 5 days.And in the 3rd day of administration, simultaneously again by every 0.2ml, ip 20% sheep red blood cell (SRBC) suspension.24h extracts eyeball of mouse and gets blood after the last administration, and room temperature is placed 1h, centrifugal (2000r/min) 20min, get upper serum, 10 mixing are on the same group done 800 times of dilutions with physiological saline, take out 1ml then respectively and put into test tube successively, every pipe adds the guinea pig serum of 0.5ml 5% sheep red blood cell (SRBC) suspension and 1ml dilution in 1: 10, move in 37 ℃ of waters bath with thermostatic control after reaction tubes shaken up and be incubated 1h, the centre gently jolting once, reaction is finished, move in the ice bath termination reaction immediately.Reaction tubes is got supernatant liquor 1ml after with the centrifugal 20min of 2000r/min adds 3ml cyanmethemoglobin reagent, shake up, place 10min, on ultraviolet-visible pectrophotometer with the 540nm colorimetric.Other establishes and does not add complement (guinea pig serum) and with the blank pipe of physiologic saline for substitute, other operation is all identical.Get 0.25ml 5% sheep red blood cell (SRBC) suspension, be diluted to 4ml, shake up, 540nm colorimetric behind the placement 10min (with the distilled water zeroing) with cyanmethemoglobin reagent.With following formula calculation sample half hemolysis value (HC
50):
Sample HC
50=(absorbancy during sample absorbancy/sheep red blood cell (SRBC) HD50) * extension rate
8.2 result
Compare with normal group, endoxan can significantly suppress antibody and form.Silybin meglumine (freeze-drying) powder forms at the mice serum hemolytic antibody does not have obviously influence.The results are shown in Table 9.
The influence that table 9 silybin meglumine (freeze-drying) powder generates at the mice serum hemolytic antibody (n=10, X ± SD)
Annotate: with the normal group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001.
9. silybin meglumine (freeze-drying) powder is at the influence of mouse delayed type hypersensitivity
9.1 method
Get 60 of healthy Kunming kind small white mouses, male and female half and half, body weight 18-22g is divided at random: 1. normal control group; 2. endoxan group; 3. Glycyrrhizic acid,diammonium salt control group (30mg/kg); 4. silybin meglumine (freeze-drying) powder pin low dose group (25mg/kg); 5. dosage group (50mg/kg) in silybin meglumine (freeze-drying) the powder pin; 6. silybin meglumine (freeze-drying) powder pin high dose group (100mg/kg).Every group 10.The equal intravenously administrable of each administration group, normal control group and endoxan group give isopyknic physiological saline.Each organizes administration every day 1 time, successive administration 7 days.In the 3rd day of administration, endoxan group subcutaneous injection every day endoxan, dosage is 0.015g/kg, continuous 5 days.And in the 3rd day of administration, every mouse cut off belly wool with operating scissors, and the about 3cm * 3cm of scope evenly smears sensitization with 1%DNFB 50 μ l.After the last administration, 1%DNFB solution is drawn 10 μ l with pipettor evenly be applied in ear two sides, a mouse left side and attack, mouse is put to death in the cervical vertebra dislocation behind the 24h, cuts left and right sides auricular concha, taking off the auricle of diameter 7mm with punch tool and weigh, is the swelling degree with the difference of left and right sides auricle weight.Take by weighing the weight of thymus gland, spleen and liver simultaneously, calculate its organ coefficient.
9.2 result
Compare with normal group, endoxan can significantly reduce thymus index and the index and spleen index of mouse, significantly reduces auricular concha swelling degree.Compare with the endoxan group, each dosage group of silybin meglumine (freeze-drying) powder pin all can significantly improve mouse auricular concha swelling degree.Illustrate that silybin meglumine (freeze-drying) powder has enhancement at the specific cellular immunity of mouse.The results are shown in Table 10.
Table 10 silybin meglumine (freeze-drying) powder is at the influence of mouse delayed type hypersensitivity (n=10, X ± SD)
Annotate: with the normal group ratio
*P＜0.05,
*P＜0.01,
* *P＜0.001; With endoxan group ratio
△P＜0.05,
△ △P＜0.01,
△ △ △P＜0.001.Auricular concha swelling degree=M left side ear-M auris dextra.
The silybin meglumine hemolytic test
1. method
The concentration of preparation silybin meglumine is 50mg/ml, get 7 in test tube, the 1-5 pipe adds 0.1ml respectively, 0.2ml, 0.3ml, 0.4ml, the silybin meglumine of 0.5ml, and be diluted to 2.5ml with physiological saline, in No. 6, No. 7 test tubes, add physiological saline and distilled water 2.5ml (complete hemolysis contrast) respectively.Last every pipe all adds 2% rabbit erythrocyte suspension 2.5ml, shakes up gently, puts in 37 ℃ of water-baths, writes down 15min respectively, 30min, 45min, 1.0h, 2.0h, 3.0h, the haemolysis of each pipe of 4.0h and aggegation situation.
2. result
The high purity silybin meglumine is dissolved in when final concentration is 5mg/ml in the test tube does not have haemolysis and agglutination to rabbit erythrocyte; Commercially available silybin meglumine raw material has haemolysis and agglutination to rabbit erythrocyte when final concentration is 1-5mg/ml in test tube.The results are shown in Table 10, table 11.
Table 10 self-control silybin meglumine hemolytic test table
Annotate: "-" be haemolysis not; " ± " part haemolysis; "+" complete hemolysis
The commercially available silybin meglumine hemolytic test of table 11 table
Annotate: "-" be haemolysis not; " ± " part haemolysis; "+" complete hemolysis
Description of drawings:
Fig. 1, embodiment 1 silybin meglumine high-efficient liquid phase chromatogram
Fig. 2, embodiment 2 silybin meglumine high-efficient liquid phase chromatograms
Fig. 3, embodiment 3 silybin meglumine high-efficient liquid phase chromatograms
Embodiment:
Embodiment 1:
Get the commercially available silybin meglumine of 30g, add the 1500ml Virahol, the reflux sample dissolution kept 0.5 hour, filtered while hot, filtrate were placed 8 hours in 4 ℃ of refrigerators, filtered, filtrate is 70 ℃ of concentrating under reduced pressure solvent evaporated, 40 ℃ of vacuum-drying 24 hours, the khaki color powder; Add 360ml distilled water, 10 ℃ were stirred 10 minutes, made dissolving, filtered, and filtrate adds the 480ml saturated aqueous common salt, places in 4 ℃ of refrigerators and spends the night, and filtered, and 40 ℃ of vacuum-drying 24 hours gets pale yellow powder; Add the 2000ml Virahol again, the reflux sample dissolution, filtered while hot, filtrate was placed 8 hours in 4 ℃ of refrigerators, filtered, filtrate is 70 ℃ of concentrating under reduced pressure solvent evaporated, 40 ℃ of vacuum-drying 24 hours, pale yellow powder 16.8g.
Final gained pale yellow powder is carried out assay, and the result is as follows:
Chromatographic column: Discovery ODS-C18 post, 25cmX4.6mm, 5um; Column temperature: 30 ℃; Flow velocity: 1.0ml/ minute.
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is weighting agent; With methanol-water-0.5mol/L potassium primary phosphate (10: 10: 1) is moving phase (with 0.2mol/L phosphorus acid for adjusting pH value to 4.0), and detecting wavelength is 288nm.Number of theoretical plate calculates by the silibinin peak should be not less than 3000.
Assay method: silybin meglumine 15mg, the accurate title, decide, and puts in the 50ml measuring bottle, it is an amount of to add methyl alcohol, and supersound process 20 minutes is put cold, add methyl alcohol to scale, shake up, precision is measured 5ml, puts in the 25ml measuring bottle, add moving phase and be diluted to scale, shake up, precision is measured 20ul and is injected liquid chromatograph, the record color atlas; The silibinin reference substance 10mg that other learns from else's experience 105 ℃ and is dried to constant weight, measure with method, with calculated by peak area, the result multiply by 1.405 by external standard method, promptly getting content is 98.5%, in the liquid chromatogram, the ratio that the peak area at 1～No. 5 peak accounts for total peak area is respectively 0.17%, 50.19%, 46.70%, 2.75%, 0.18%, color atlas is seen Fig. 1.
Embodiment 2:
Get the commercially available silybin meglumine of 30g, add the 900ml Virahol, the reflux sample dissolution kept 45 minutes, filtered while hot, filtrate were placed 8 hours in 4 ℃ of refrigerators, filtered, filtrate is 40 ℃ of concentrating under reduced pressure solvent evaporated, 40 ℃ of vacuum-drying 24 hours, the khaki color powder; Add 120ml distilled water, 0 ℃ was stirred 10 minutes, made dissolving, filtered, and filtrate adds the 240ml saturated aqueous common salt, places in 4 ℃ of refrigerators and spends the night, and filtered, and 40 ℃ of vacuum-drying 24 hours gets pale yellow powder; Add the 1200ml Virahol again, the reflux sample dissolution, filtered while hot, filtrate was placed 8 hours in 4 ℃ of refrigerators, filtered, filtrate is 40 ℃ of concentrating under reduced pressure solvent evaporated, 40 ℃ of vacuum-drying 24 hours, pale yellow powder 17.5g.
Embodiment 3:
Get the commercially available silybin meglumine of 30g, add the 1200ml Virahol, the reflux sample dissolution kept 15 minutes, filtered while hot, filtrate were placed 8 hours in 4 ℃ of refrigerators, filtered, filtrate is 60 ℃ of concentrating under reduced pressure solvent evaporated, 40 ℃ of vacuum-drying 24 hours, the khaki color powder; Add 240ml distilled water, 3 ℃ were stirred 10 minutes, made dissolving, filtered, and filtrate adds the 360ml saturated aqueous common salt, places in 4 ℃ of refrigerators and spends the night, and filtered, and 40 ℃ of vacuum-drying 24 hours gets pale yellow powder; Add the 1600ml Virahol again, the reflux sample dissolution, filtered while hot, filtrate was placed 8 hours in 4 ℃ of refrigerators, filtered, filtrate is 50 ℃ of concentrating under reduced pressure solvent evaporated, 40 ℃ of vacuum-drying 24 hours, pale yellow powder 18.5g.
Embodiment 4: the preparation of silybin meglumine tablets agent
Prescription:
Silybin meglumine 50g
Lactose 100g
Microcrystalline Cellulose 50g
Sodium starch glycolate 12g
Magnesium Stearate 3g
Starch slurry is an amount of
Be prepared into 1000
The preparation method:
Earlier above-mentioned material separated pulverizing is crossed 100 mesh sieves, take by weighing recipe quantity silybin meglumine, lactose, Microcrystalline Cellulose, sodium starch glycolate, thorough mixing is even, add the appropriate amount of starch slurry and make softwood, cross 16 mesh sieve system wet granulars, 80 ℃ of dryings are after 2 hours, the whole grain of 16 orders, after the adding Magnesium Stearate mixes, the compacting silybin meglumine tablets.
Embodiment 5: the preparation of silybin meglumine capsule
Prescription: silybin meglumine 50g
Pre-paying starch 50g
Microcrystalline Cellulose 60g
Sodium starch glycolate 12g
Magnesium Stearate 2g
Starch slurry is an amount of
Be prepared into 1000
The preparation method:
Earlier above-mentioned material separated pulverizing is crossed 100 mesh sieves, take by weighing recipe quantity silybin meglumine, pre-paying starch, Microcrystalline Cellulose, sodium starch glycolate, thorough mixing is even, add the appropriate amount of starch slurry and make softwood, cross 16 mesh sieve system wet granulars, 80 ℃ of dryings are after 2 hours, the whole grain of 16 orders, add Magnesium Stearate and mix, the can capsule gets final product.
Embodiment 6: the preparation of silybin meglumine dispersible tablet
Prescription: silybin meglumine 100g
N.F,USP MANNITOL 55g
Microcrystalline Cellulose 40g
Crosslinked carboxymethyl fecula sodium 25g
The sweet 5g of aspa
Lemon flavour 2g
Talcum powder 3g
Starch slurry is an amount of
Be prepared into 1000
The preparation method:
Earlier above-mentioned material separated pulverizing is crossed 100 mesh sieves, silybin meglumine, N.F,USP MANNITOL, Microcrystalline Cellulose, crosslinked carboxymethyl fecula sodium thorough mixing is even, add appropriate amount of starch slurry system softwood, cross 16 order system wet granulars, 80 ℃ of dryings are after 2 hours, cross the whole grain of 16 mesh sieves, add that aspa is sweet, citric acid and talcum powder, thorough mixing is even, and compressing tablet gets final product
Embodiment 7: the preparation of silybin meglumine orally disintegrating tablet
Prescription: silybin meglumine 50g
N.F,USP MANNITOL 40g
Microcrystalline Cellulose 20g
Lactose 22g
Cross-linked polyvinylpyrrolidone 30g
Sodium bicarbonate 12g
Citric acid 15g
Talcum powder 4g
The sweet 3g of aspa
Lemon flavour 1.5g
Be prepared into 1000
The preparation method:
Above-mentioned material is crossed 100 mesh sieves respectively, earlier that silybin meglumine, N.F,USP MANNITOL, cross-linked polyvinylpyrrolidone, sodium bicarbonate, aspa is sweet, lemon flavour mixes, in addition Microcrystalline Cellulose, lactose, citric acid are mixed, said mixture and talcum powder thorough mixing is even, and directly pressed powder gets final product.
Embodiment 8: the preparation of silybin meglumine enteric coated tablet
Prescription: silybin meglumine 100g
Lactose 100g
Microcrystalline Cellulose 24g
Croscarmellose sodium 20g
Polyvinylpyrrolidone 50% alcoholic solution 3g (in polyvinylpyrrolidone)
Magnesium Stearate 3g
Be prepared into 1000
Enteric coating liquid: cellulose acetate-phthalate 18g
Vanay 1.8g
Acetone 50% aqueous solution 180ml
1000 of dressing amounts
The preparation method:
Earlier above-mentioned material was pulverized 100 mesh sieves, silybin meglumine, lactose, Microcrystalline Cellulose, croscarmellose sodium thorough mixing is even, add an amount of polyvinylpyrrolidone 50% alcoholic solution system softwood, cross 16 mesh sieve system wet granulars, 80 ℃ of dryings are after 2 hours, and the whole grain of 16 mesh sieves adds Magnesium Stearate and mixes, compressing tablet, dressing gets final product.
Embodiment 9: the preparation of silybin meglumine injection liquid
Prescription: silybin meglumine 25g
Water for injection adds to 2000ml
Be prepared into 1000 bottles
The preparation method:
Silybin meglumine is dissolved constant volume with water for injection, add the 1.0g gac and stir 20min, filtering decarbonization, nitrogen can 2ml is filled in sterile filtration, seals, 100 ℃ of sterilization 30min, leak detection, the lamp inspection gets final product.Embodiment 10: the preparation of silybin meglumine infusion solutions
Prescription: silybin meglumine 2g
Sodium-chlor 90g
Water for injection adds to 10000ml
The preparation method:
Silybin meglumine and sodium-chlor are dissolved constant volume with water for injection, add the 5g gac and stir 20min, filtering decarbonization, sterile filtration is filled the nitrogen embedding in the 250ml infusion bottle, 100 ℃ of sterilization 30min, leak detection, the lamp inspection gets final product
Embodiment 11: the preparation of injection silybin meglumine
Prescription: silybin meglumine 25g
N.F,USP MANNITOL 80g
Meglumine 1g
Water for injection adds to 2000ml
Be prepared into 1000 bottles
The preparation method:
Take by weighing silybin meglumine, N.F,USP MANNITOL, meglumine adds the dissolving of injection water and is settled to 2000ml; add the 1.0g medicinal carbon, whip attachment 20min depyrogenation, filtering decarbonization; sterile filtration, can 2ml filtrate is put in the freeze drying box to the 7ml cillin bottle; pre-freeze 2-4 hour, adopt a sublimation drying, high dry temperature is lower than 45 ℃; cycle is 24-36 hour, and the freeze-drying tamponade that finishes is shut down; outlet rolls lid, and leak detection promptly.
Claims (7)
1. highly purified silybin meglumine, it is characterized in that: use high effective liquid chromatography for measuring, the content of silybin meglumine is more than 98.0%, and its feature is that also its preparation method comprises the steps:
(1) commercially available silybin meglumine adds Virahol, the reflux sample dissolution, and filtered while hot, filtrate is placed in refrigerator, filters, and filtrate decompression concentrates solvent evaporated, and drying gets the khaki color powder;
(2) get (1) gained powder, adding distilled water stirs, and makes dissolving, filters, and filtrate adds saturated aqueous common salt, places in refrigerator, filters, and drying gets pale yellow powder;
(3) get (2) gained powder, add Virahol, the reflux sample dissolution, filtered while hot, filtrate is placed in refrigerator, filters, and filtrate decompression concentrates solvent evaporated, and drying gets pale yellow powder.
2. highly purified silybin meglumine as claimed in claim 1, it is characterized in that: using the high performance liquid chromatography external standard method, is reference substance with the silibinin, and the content of silybin meglumine is more than 98.0%; Its feature also is, in the high performance liquid chromatography area normalization collection of illustrative plates, have 5 chromatographic peaks, wherein No. 2 peaks, No. 3 peaks are two main peaks of silibinin, and their peak area sum accounts for more than 95.5% of total peak area, and No. 5 peaks are the Isosilybin peak, its peak area accounts for below 0.5% of total peak area, No. 1 peak and No. 4 peaks are the unknown material mass peak, and the peak area at No. 1 peak accounts for below 0.5% of total peak area, and the peak area at No. 4 peaks accounts for below 3.5% of total peak area; The relative retention time at 5 peaks is followed successively by: No. 1 peak: 0.520～0.575, No. 2 peaks: 1.000, No. 3 peaks: 1.110～1.135, No. 4 peaks: 1.251～1.320, No. 5 peaks: 1.495～1.590;
It is as follows that its feature also is to measure the efficient liquid-phase chromatography method of highly purified silybin meglumine:
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is weighting agent; With methanol-water-0.5mol/L potassium primary phosphate (10: 10: 1) is moving phase (with 0.2mol/L phosphorus acid for adjusting pH value to 4.0), and detecting wavelength is 288nm.Number of theoretical plate calculates by the silibinin peak should be not less than 3000;
Chromatographic column: Discovery ODS-C18 post, 25cmX4.6mm, 5um; Column temperature: 30 ℃; Flow velocity: 1.0ml/ minute;
Assay method: silybin meglumine 15mg, the accurate title, decide, and puts in the 50ml measuring bottle, it is an amount of to add methyl alcohol, and supersound process 20 minutes is put cold, add methyl alcohol to scale, shake up, precision is measured 5ml, puts in the 25ml measuring bottle, add moving phase and be diluted to scale, shake up, precision is measured 20ul and is injected liquid chromatograph, the record color atlas; The silibinin reference substance 10mg that other learns from else's experience 105 ℃ and is dried to constant weight measures with method, and with calculated by peak area, the result multiply by 1.405, promptly by external standard method.
3. the preparation method of a highly purified silybin meglumine as claimed in claim 1 is characterized in that this preparation method comprises the steps:
(1) commercially available silybin meglumine adds Virahol, the reflux sample dissolution, and filtered while hot, filtrate is placed in 4 ℃ of refrigerators, filters, and filtrate decompression concentrates solvent evaporated, and 40 ℃ of vacuum-dryings get the khaki color powder;
(2) get (1) gained powder, adding distilled water stirs, and makes dissolving, filters, and filtrate adds saturated aqueous common salt, places in 4 ℃ of refrigerators, filters, and drying gets pale yellow powder;
(3) get (2) gained powder, add Virahol, the reflux sample dissolution, filtered while hot, filtrate is placed in 4 ℃ of refrigerators, filters, and filtrate decompression concentrates solvent evaporated, and 40 ℃ of vacuum-dryings get pale yellow powder.
4. method according to claim 3, wherein:
The amount that adds Virahol in the step (1) is 30～50 times of silybin meglumine, and the temperature of concentrating under reduced pressure is 40～70 ℃;
The amount that adds distilled water in the step (2) is 5～15 times of silybin meglumine, and whipping temp is 0～10 ℃, and the amount that adds saturated aqueous common salt is 10～20 times of silybin meglumine;
The amount that adds Virahol in the step (3) is 60～100 times of silybin meglumine, and the temperature of concentrating under reduced pressure is 40～70 ℃.
5. the pharmaceutical composition of a highly purified silybin meglumine wherein contains the silybin meglumine and the pharmaceutically acceptable carrier of the claim 1 for the treatment of significant quantity.
6. the pharmaceutical composition of a highly purified silybin meglumine as claimed in claim 5 wherein contains silybin meglumine and the pharmaceutically acceptable carrier of 10～200mg.
7. the application of highly purified silybin meglumine as claimed in claim 1 in the medicine of acute attack stage for preparing treatment acute hepatitis, chronic hepatitis and toxic hepatitis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100974485A CN101177424A (en) | 2006-11-09 | 2006-11-09 | High-purity silybin meglumine, preparation method as well as application in preparing medicine treating hepatitis and liver hurt thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100974485A CN101177424A (en) | 2006-11-09 | 2006-11-09 | High-purity silybin meglumine, preparation method as well as application in preparing medicine treating hepatitis and liver hurt thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101177424A true CN101177424A (en) | 2008-05-14 |
Family
ID=39403868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006100974485A Pending CN101177424A (en) | 2006-11-09 | 2006-11-09 | High-purity silybin meglumine, preparation method as well as application in preparing medicine treating hepatitis and liver hurt thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101177424A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108456199A (en) * | 2017-02-20 | 2018-08-28 | 南京宸翔医药研究有限责任公司 | A kind of production technology, pharmaceutical composition and its clinical application of high-purity silymarin meglumine |
| CN109557038A (en) * | 2018-11-20 | 2019-04-02 | 江苏中兴药业有限公司 | A kind of detection method of silibinin meglumine content |
| CN114569538A (en) * | 2021-03-31 | 2022-06-03 | 南京宸翔医药研究有限责任公司 | Novel high-purity silybin meglumine pharmaceutical preparation as well as preparation method and application thereof |
-
2006
- 2006-11-09 CN CNA2006100974485A patent/CN101177424A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108456199A (en) * | 2017-02-20 | 2018-08-28 | 南京宸翔医药研究有限责任公司 | A kind of production technology, pharmaceutical composition and its clinical application of high-purity silymarin meglumine |
| CN109557038A (en) * | 2018-11-20 | 2019-04-02 | 江苏中兴药业有限公司 | A kind of detection method of silibinin meglumine content |
| CN109557038B (en) * | 2018-11-20 | 2021-06-01 | 江苏中兴药业有限公司 | Method for detecting content of silybin meglumine |
| CN114569538A (en) * | 2021-03-31 | 2022-06-03 | 南京宸翔医药研究有限责任公司 | Novel high-purity silybin meglumine pharmaceutical preparation as well as preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102772500A (en) | Relingqing Polygonum capitatum Buch-Ham ex D.Don raw material extract with anti-inflammatory action | |
| CN1706397B (en) | Composition of paeoniflorin and peony lactone glycoside with function of increasing leukocyte | |
| CN1985864A (en) | Medicine composition of glycyrrhizic acid or its salt, ginseng and glossy ganoderma | |
| CN100574768C (en) | A kind of anticancer pharmaceutical composition and its production and use | |
| CN101177424A (en) | High-purity silybin meglumine, preparation method as well as application in preparing medicine treating hepatitis and liver hurt thereof | |
| CN103191289A (en) | Synchronous preparation method of four effective parts in medicine pair of common anemarrhena rhizome and amur corktree bark and application thereof | |
| CN100563630C (en) | The preparation method that is used for the treatment of the menoxenia Chinese medicine preparation | |
| CN1947747B (en) | Traditional Chinese medicine composition containing luteolin and capsule of sweeping forsythia and its preparation method and use | |
| CN114177244B (en) | Traditional Chinese medicine composition for treating thyroid cancer and preparation method thereof | |
| CN1931233B (en) | Medicine composition of red sage and epimedium for treating cardiac and cerebral vascular diseases | |
| CN100382799C (en) | Power for intravenous injection with liver-protecting action, and its preparation and quality control method | |
| CN100482266C (en) | Medical composite prepared by sarcandra and oldenlandia | |
| CN107485615A (en) | Purposes of the Ligustrum robust glycosides C and combinations thereof in treatment hyperlipidemia and slimming medicine is prepared | |
| CN100563647C (en) | The Pharmaceutical composition of Herba Erigerontis and sodium tanshinon IIA silate injection | |
| CN104383547B (en) | Herba Saussureae Involueratae extract phosphatide complexes, oral disnitegration tablet and preparation method thereof | |
| CN101049355B (en) | Composition of medication prepared from safflower and leaves of hawthorn | |
| CN100434091C (en) | Fenugreek seed extract and its preparing process and application | |
| CN101524397B (en) | Licorice flavonoids antitussive and application thereof | |
| CN1977888B (en) | Medicinal composition of baicalin, ganoderma lucidum and salvia miltrorrhiza | |
| CN101880217B (en) | Medicinal composition for treating immunological diseases, preparation and application thereof | |
| CN101450117A (en) | Rheumatism treatment technique | |
| CN101176769B (en) | Pharmaceutical composition of cattail pollen and red orpin | |
| CN100448450C (en) | Pharyngolaryngitis-treating pharmaceutical compositions and its preparing method | |
| CN1981833B (en) | Medicinal composition of elutriate, virgate wormwood herb and and cape-jasmine | |
| CN101190254B (en) | Medicinal composition containing kudzu root or its extract and mongolian snakegourd or its extract |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: Cong Xiaodong Document name: Written notice of preliminary examination of application for patent for invention |
|
| C06 | Publication | ||
| PB01 | Publication | ||
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: Cong Xiaodong Document name: Notification of Publication of the Application for Invention |
|
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: Cong Xiaodong Document name: Notification before expiration of term |
|
| DD01 | Delivery of document by public notice |
Addressee: Cong Xiaodong Document name: Notification that Application Deemed to be Withdrawn |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080514 |