CN1981833B - Medicinal composition of elutriate, virgate wormwood herb and and cape-jasmine - Google Patents

Medicinal composition of elutriate, virgate wormwood herb and and cape-jasmine Download PDF

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CN1981833B
CN1981833B CN2006101634739A CN200610163473A CN1981833B CN 1981833 B CN1981833 B CN 1981833B CN 2006101634739 A CN2006101634739 A CN 2006101634739A CN 200610163473 A CN200610163473 A CN 200610163473A CN 1981833 B CN1981833 B CN 1981833B
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extract
herba artemisiae
parts
fructus gardeniae
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CN1981833A (en
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黄振华
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Haian Su Fu Technology Transfer Center Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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Abstract

A medicinal composition for preparing the medicines to treat hepatism and protect liver is prepared proportionally from silibinin or its derivative or silybin, oriental wormwood or its extract, and capejasmine or its extract. Its preparing process is also disclosed.

Description

The pharmaceutical composition of silibinin, Herba Artemisiae Scopariae and Fructus Gardeniae
1, technical field
The present invention relates to the pharmaceutical composition made by silibinin or derivatives thereof or silymarin, Herba Artemisiae Scopariae or its extract and Fructus Gardeniae or its extract and preparation method thereof and the application in the medicine of preparation treatment hepatic disease, belong to medical technical field.
2, background technology
China is hepatopathy big country, and viral hepatitis, hepatic fibrosis, fatty liver, alcoholic liver, liver lesion induced by drugs injure hepatopathys such as hepatocarcinoma has in recent years become one of principal disease of current threat human health.In China, Patients with Viral Hepatitis and hepatitis B virus carriers promptly account for more than 10% of national population respectively, and the appearance of particularly a large amount of liver cirrhosis, Patients with Fatty Liver has caused that vast medical worker more and more payes attention to; Hepatitis is one of common but severe infectious disease, wherein based on viral hepatitis.According to incompletely statistics, have 8～10% to be hepatitis B virus carriers at present in the population of China, and still have every year a considerable amount of new patients to increase.Viral hepatitis can be divided on type: acute hepatitis, chronic hepatitis, hepatitis gravis and gallbladder hepatitis.
Liver is a digestive gland maximum in the human body.Also be the central station of body intracellular metabolic, nourishing the liver, hepatoprotective are that everyone should take seriously.Though the medicine of treatment hepatopathy has many kinds at present, because the pathogenesis of hepatopathy is not illustrated fully, mostly is and improves liver function, promotes liver cell regeneration, strengthens the medicine of the functions such as detoxification ability of liver.Press for a kind for the treatment of both the principal and secondary aspects of a disease at present, the medicine of reinforcement and elimination in combination.
Silymarin is that the fruit of feverfew Herba Silybi mariani Silybum marianum (L) Gaertn is through extracting the bulky powder of refining gained, recorded into the 7th 30 pages of national drug standards chemical drugs provincial standard rising national standards of National Drug Administration (Chinese Pharmacopoeia Commission's volume), wherein regulation is pressed dry product calculating, the moisture silibin that flies calculates with silibinin, must not be less than 68%, contain silibinin and Isosilybin and must not be less than 30%.Silibinin is that extraction separation processing gets in feverfew Herba Silybi mariani Silybummarianum (L) the Gaertn fruit.Silybin meglumine is the addition product of silibinin and meglumine, the soluble derivative that belongs to silibinin, recorded into the 10th 52 pages of national drug standards chemical drugs provincial standard rising national standards of National Drug Administration (Chinese Pharmacopoeia Commission's volume), wherein regulation is pressed dry product calculating, contain silymarin meglumine and must not be less than 96.0%, contain silybin meglumine (C 25H 22O 10C 7H 17NO 5) must not be less than 75.0%.The effect that silybin meglumine has protection and stablizes liver plasma membrane; can fall enzyme, jaundice eliminating and promote liver cell regeneration; good liver-protective effect is arranged; and can promote liver cell regeneration, medicine liver poisoning, various acute, chronic hepatitis, first cirrhosis, fatty liver all there are good effect.
Herba Artemisiae Scopariae is the dry aerial parts of feverfew BINHAO Artemisia scoparia Waldst.et Kit. or Herba Artemisiae Scopariae Artemisia capillaries Thumb., and the beginning is stated from Shennong's Herbal, cold nature, bitter in the mouth, suffering.Clearing away heat-damp and promoting diuresis is arranged, promoting the function of the gallbladder to alleviate jaundice effect.Be mainly used in the jaundice oliguria, the eczema pruritus, diseases such as infectious jaundice type hepatitis are the Chinese medicine that protects the liver commonly used clinically.Herba Artemisiae Scopariae can be protected liver plasma membrane, prevent hepatic necrosis, promotes liver cell regeneration and improves liver microcirculation, and main chemical compositions is flavonoid, Coumarins, chromogen ketone, coumaric acid and volatilization wet goods.
Fructus Gardeniae is the dry mature fruit of Maguireothamnus speciosus Fructus Gardeniae Gardenia jasminoides Ellis, and the beginning is stated from Shennong's Herbal, bitter in the mouth cold in nature, and GUIXIN, lung, tri-jiao channel have the pathogenic fire purging relieving restlessness, clearing away heat and promoting diuresis, the effect of removing pathogenic heat from blood and toxic substance from the body.It is vexed to be used for calentura, the jaundice dark coloured urine, and blood strangury and dry pain, heat in blood is told nosebleed, conjunctival congestion and swelling pain, pathogenic fire,toxin and furuncles, external treatment bruise pain.Fructus Gardeniae function of gallbladder promoting, jaundice eliminating effect are stronger, and it is best that the product of giving birth to are treated the icterohepatitis effect.Mainly contain effective ingredient such as jasminoidin, Gardenoside, Fructus Gardeniae glycosides, gardoside and Fructus Gardeniae thuja acid in the Fructus Gardeniae.
Utilize the interaction of silibinin or derivatives thereof or silymarin, Herba Artemisiae Scopariae or its extract and Fructus Gardeniae or its extract at present, composition of prescription is used for the treatment of the medicine of hepatic disease aspect, does not appear in the newspapers as yet.
3, summary of the invention
In order to meet clinical needs, better treat hepatic disease, improve the people ' s health level, the invention provides a kind of pharmaceutical composition and its production and use, mainly be prepared from by silibinin or derivatives thereof or silymarin, Herba Artemisiae Scopariae or its extract and Fructus Gardeniae or its extract, at aspects such as treatment hepatitis, control liver cirrhosis, produced beyond thought effect.
Pharmaceutical composition of the present invention, mainly be prepared from by silibinin or derivatives thereof or silymarin, Herba Artemisiae Scopariae or its extract and Fructus Gardeniae or its extract, its parts by weight are: 25～400 parts of silibinin or derivatives thereof or silymarin, 750～16000 parts of Herba Artemisiae Scopariaes, 400～6500 parts of Fructus Gardeniaes; Be preferably: 50～200 parts of silibinin or derivatives thereof or silymarin, 1500～8000 parts of Herba Artemisiae Scopariaes, 800～3200 parts of Fructus Gardeniaes; Optimum is: 100 parts of silibinin or derivatives thereof or silymarin, 3000～4000 parts of Herba Artemisiae Scopariaes, 1600 parts of Fructus Gardeniaes.
Pharmaceutical composition of the present invention, the derivant of silibinin comprise silybin meglumine, silymarin meglumine, Isosilybin meglumine.
Herba Artemisiae Scopariae in the aforementioned pharmaceutical compositions and Fructus Gardeniae can singly be carried or mix to obtain through refining and obtain extract fully with The suitable solvent and method, total extract is made arbitrary preparation with silibinin or derivatives thereof or silymarin and mixing acceptable accessories again, contained main effective ingredient is total flavones and total glycosides in the gained total extract, and the total content of the effective ingredient of total extract is not less than 25%.
Herba Artemisiae Scopariae mentioned above can obtain Herba Artemisiae Scopariae extract through extracting processing with The suitable solvent, wherein solvent preferred water or ethanol, and the extracting method of Herba Artemisiae Scopariae can be infusion process, percolation, decocting method, reflux extraction or continuous extraction.As preparing Herba Artemisiae Scopariae extract by water extract-alcohol precipitation.
The invention provides the preferred for preparation technology of a kind of Herba Artemisiae Scopariae, specific as follows:
Get Herba Artemisiae Scopariae, decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, and filtrate is concentrated into every 1ml and contains crude drug 2g, adds ethanol and makes and contain the alcohol amount and reach 70%, cold preservation 24 hours filters, and filtrate recycling ethanol contains crude drug 5g to every 1ml, adds ethanol again and makes and contain the alcohol amount and reach 85%, cold preservation 24 hours filters, and filtrate recycling ethanol extremely every 1ml contains crude drug 10g, add the about 5 times of amounts of water, cold preservation 48 hours filters, filtrate is condensed into the thick paste shape, vacuum drying, promptly.The Herba Artemisiae Scopariae extract yield that makes by this technology is 2～3%, and total flavones in the extract (in anhydrous rutin) content should be no less than 20%.
Herba Artemisiae Scopariae extract also can be by following prepared, but is not limited only to following method:
Technology one: get Herba Artemisiae Scopariae, decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, filtrate is concentrated into every 1ml and contains crude drug 2g, adds ethanol and makes and contain alcohol amount and reach 85%, cold preservation 24 hours, filter, filtrate recycling ethanol extremely every ml contains crude drug 10g, adds the about 5 times of amounts of water, cold preservation 48 hours filters, and filtrate is condensed into the thick paste shape, vacuum drying, promptly.The Herba Artemisiae Scopariae extract yield that makes by this technology is 5～6%, and total flavones in the extract (in anhydrous rutin) content should be no less than 10%.
Technology two: get Herba Artemisiae Scopariae, decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, filtrate is concentrated into every 1ml and contains crude drug 2g, adds ethanol and makes and contain alcohol amount and reach 75%, cold preservation 24 hours, filter, filtrate recycling ethanol extremely every ml contains crude drug 10g, adds the about 5 times of amounts of water, cold preservation 48 hours filters, and filtrate is condensed into the thick paste shape, vacuum drying, promptly.The Herba Artemisiae Scopariae extract yield that makes by this technology is 7～8%, and total flavones in the extract (in anhydrous rutin) content should be no less than 6%.
Fructus Gardeniae mentioned above can obtain Fructus Gardeniae extract through extracting processing with The suitable solvent, wherein solvent preferred water or ethanol, and the extracting method of Fructus Gardeniae can be infusion process, percolation, decocting method, reflux extraction or continuous extraction.As preparing Fructus Gardeniae extract by water extract-alcohol precipitation.
The invention provides the preferred for preparation technology of a kind of Fructus Gardeniae, specific as follows:
Get Fructus Gardeniae, be ground into coarse powder, decoct with water three times, first and second time each 1 hour, 0.5 hour for the third time, collecting decoction filtered, and filtrate is concentrated into every 1ml and contains crude drug 1g, add ethanol and make and contain alcohol amount and reach 70%, cold preservation 24 hours filters, and filtrate recycling ethanol contains crude drug 3g to every 1ml, add ethanol and make and contain alcohol amount and reach 85%, cold preservation 24 hours filters, and filtrate recycling ethanol contains crude drug 5g to every 1ml, add the about 5 times of amounts of water, cold preservation 48 hours filters, filtrate is condensed into thick paste, vacuum drying, promptly.The Fructus Gardeniae extract yield that makes by this technology is 2～4%, and the content of total glycosides (in jasminoidin) is no less than 50% in the extract.
Fructus Gardeniae extract also can be by following prepared, but is not limited only to following method:
Technology one: get Fructus Gardeniae, be ground into coarse powder, decoct with water three times, first and second time each 1 hour, 0.5 hour for the third time, collecting decoction filtered, and filtrate is concentrated into every 1ml and contains crude drug 1g, add ethanol and make and contain alcohol amount and reach 70%, cold preservation 24 hours filters, and filtrate recycling ethanol contains crude drug 2g to every 1ml, add ethanol and make and contain alcohol amount and reach 75%, cold preservation 12 hours filters, and filtrate recycling ethanol contains crude drug 5g to every 1ml, add the about 5 times of amounts of water, cold preservation 48 hours filters, filtrate is condensed into thick paste, vacuum drying, promptly.Fructus Gardeniae extract yield by this prepared is 3～4%, and the content of total glycosides (in jasminoidin) is no less than 40% in the extract.
Technology two: get Fructus Gardeniae, be ground into coarse powder, decoct with water secondary, 1.5 hours for the first time, 1 hour for the second time, collecting decoction filtered, and filtrate is concentrated into every 1ml and contains crude drug 1g, add ethanol and make and contain alcohol amount and reach 60%, cold preservation 12 hours filters, and filtrate recycling ethanol contains crude drug 2g to every 1ml, add ethanol and make and contain alcohol amount and reach 75%, cold preservation 12 hours filters, and filtrate recycling ethanol contains crude drug 3g to every 1ml, add the about 5 times of amounts of water, cold preservation 48 hours filters, filtrate is condensed into thick paste, vacuum drying, promptly.The Fructus Gardeniae extract yield that makes by this technology is 4～5%, and the content of total glycosides (in jasminoidin) is no less than 35% in the extract.
Herba Artemisiae Scopariae in the aforementioned pharmaceutical compositions and Fructus Gardeniae can also processing obtains mattress Cape jasmine extract through mixed extraction with The suitable solvent, wherein solvent preferred water or ethanol, extracting method can be infusion process, percolation, decocting method, reflux extraction or continuous extraction.As preparing mattress Cape jasmine extract by water extract-alcohol precipitation.
The invention provides the preferred for preparation technology of a kind of Herba Artemisiae Scopariae, Fructus Gardeniae mixed extraction, specific as follows:
Get Herba Artemisiae Scopariae and be cut into segment, Fructus Gardeniae is ground into coarse powder, decocts with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction, filter, filtrate is concentrated into every 1ml and contains crude drug 2g, adds ethanol and makes and contain alcohol amount and reach 70%, cold preservation 24 hours, filter, filtrate recycling ethanol contains crude drug 5g to every 1ml, adds ethanol again and makes and contain the alcohol amount and reach 85%, cold preservation 24 hours, filter, filtrate recycling ethanol extremely every 1ml contains crude drug 10g, adds the about 5 times of amounts of water, cold preservation 48 hours, filter, filtrate is condensed into the thick paste shape, vacuum drying, promptly.The mattress Cape jasmine extract yield that makes by this technology is 3～5%, contains total flavones (in rutin) in the extract, should be no less than 10%; Contain total glycosides (in jasminoidin), should be no less than 20%.
Mattress Cape jasmine extract also can be by following prepared, but is not limited only to following method:
Technology one: get Herba Artemisiae Scopariae and be cut into segment, Fructus Gardeniae is ground into coarse powder, decocts with water secondary, 1.5 hours for the first time, 1 hour for the second time, collecting decoction, filter, filtrate is concentrated into every 1ml and contains crude drug 2g, adds ethanol and makes and contain alcohol amount and reach 70%, cold preservation 12 hours, filter, filtrate recycling ethanol contains crude drug 3g to every 1ml, adds ethanol again and makes and contain the alcohol amount and reach 75%, cold preservation 24 hours, filter, filtrate recycling ethanol extremely every 1ml contains crude drug 5g, adds the about 5 times of amounts of water, cold preservation 48 hours, filter, filtrate is condensed into the thick paste shape, vacuum drying, promptly.The mattress Cape jasmine extract yield that makes by this technology is 6～8%, contains total flavones (in rutin) in the extract, should be no less than 6%; Contain total glycosides (in jasminoidin), should be no less than 10%.
Technology two: get Herba Artemisiae Scopariae and be cut into segment, Fructus Gardeniae is ground into coarse powder, decocts with water three times, 1 hour for the first time, second and third time each 0.5 hour, collecting decoction, filter, filtrate is concentrated into every 1ml and contains crude drug 2g, adds ethanol and makes and contain alcohol amount and reach 70%, cold preservation 24 hours, filter, filtrate recycling ethanol contains crude drug 3g to every 1ml, adds ethanol again and makes and contain the alcohol amount and reach 75%, cold preservation 12 hours, filter, filtrate recycling ethanol extremely every 1ml contains crude drug 5g, adds the about 5 times of amounts of water, cold preservation 24 hours, filter, filtrate is condensed into the thick paste shape, vacuum drying, promptly.The mattress Cape jasmine extract yield that makes by this technology is 5～6%, contains total flavones (in rutin) in the extract, should be no less than 8%; Contain total glycosides (in jasminoidin), should be no less than 15%.
Herba Artemisiae Scopariae in the aforementioned pharmaceutical compositions and Fructus Gardeniae can also replace feeding intake making with Herba Artemisiae Scopariae extract and Fructus Gardeniae extract respectively.(yield of Herba Artemisiae Scopariae extract is 2～3% with respect to the yield of medical material according to extract, the yield of Fructus Gardeniae extract is 2～4%) calculate, present composition parts by weight are: 25～400 parts of silibinin or derivatives thereof or silymarin, 15～480 parts of Herba Artemisiae Scopariae extract, 8～260 parts of Fructus Gardeniae extracts; Be preferably: 50～200 parts of silibinin or derivatives thereof or silymarin, 30～240 parts of Herba Artemisiae Scopariae extract, 16～128 parts of Fructus Gardeniae extracts; Optimum is: 100 parts of silibinin or derivatives thereof or silymarin, 60～120 parts of Herba Artemisiae Scopariae extract, 32～64 parts of Fructus Gardeniae extracts.Herba Artemisiae Scopariae extract contains total flavones (in anhydrous rutin) and is not less than 6%, preferably is not less than 20%; Fructus Gardeniae extract contains total glycosides (in jasminoidin) and is not less than 35%, preferably is not less than 50%.
The derivant of the silibinin in the pharmaceutical composition of the present invention comprises silybin meglumine, silymarin meglumine, Isosilybin meglumine.
More than form to be by weight as proportioning, when producing, can or reduce according to the corresponding proportion increase, as large-scale production can be unit with the kilogram, or be unit with the ton, small-scale production can be unit with the gram also, weight can increase or reduce, but the constant rate of weight proportion between each composition.
More than form,, can make the preparation of 100～10000 consumptions,, can be made into 100～10000,1～10 of each consumption as injection as if being unit with the gram.As tablet, can be made into 100～10000, take 1～10 at every turn.
The ratio of above weight proportion obtains through science screening, and for especial patient, the ratio of can corresponding adjustment forming increases or reduce being no more than 100%.
The consumption of drug component of the present invention is groped to sum up to draw through the inventor in a large number, and each amounts of components all has better curative effect in above-mentioned weight portion scope.
The present invention shows through pharmacodynamics, pharmacology's animal experiment study result, and the medicine by silibinin or derivatives thereof or silymarin, Herba Artemisiae Scopariae or its extract and Fructus Gardeniae or its extract are made has anti-carbon tetrachloride (CCl 4) due to fibrosis effect, significantly reduce hepatic fibrosis index: the concentration of hyaluronic acid (HA) and laminin (LN); To carbon tetrachloride (CCl 4) hepatic injury of poisoning induced rat acute has protective effect, makes the ALT of liver and AST that tangible restitution be arranged; To carbon tetrachloride (CCl 4) ALT, LTG and the MDA of liver of poisoning induced mice have tangible restitution; To carbon tetrachloride (CCl 4) liver, the spleen index of poisoning mice have good reduction effect; The DHBV virus of duck infection there is the effect of obvious inhibition; Isothiocyanic acid is caused the high bilirubin of mice serum tangible reduction effect, and serum total bilirubin and conjugated bilirubin content are reduced.Experimental studies results of the present invention shows that silibinin or derivatives thereof or silymarin, Herba Artemisiae Scopariae or its extract and Fructus Gardeniae or its extract drug combination are synergism, and drug effect obviously strengthens.
The invention provides a kind of medicine that is used to prepare treatment hepatic disease aspect.The effect that silibinin in the pharmaceutical composition of the present invention has protection and stablizes liver plasma membrane, can fall enzyme, jaundice eliminating and promote liver cell regeneration, play good liver-protective effect, and can promote liver cell regeneration, medicine liver poisoning, various acute, chronic hepatitis, first cirrhosis, fatty liver all there are good effect; Herba Artemisiae Scopariae can be protected liver plasma membrane, prevent hepatic necrosis, promotes liver cell regeneration and improves liver microcirculation; Fructus Gardeniae function of gallbladder promoting, jaundice eliminating effect are stronger, and it is best that the product of giving birth to are treated the icterohepatitis effect.Three medicine composition of prescription are brought into play effects such as promoting the function of the gallbladder to alleviate jaundice, the liver protecting jointly, are particularly useful for treating icterohepatitis, and there is unexpected effect control liver cirrhosis aspect.
Pharmaceutical composition of the present invention can be mixed and made into clinically any or pharmaceutically acceptable dosage form with one or more pharmaceutically acceptable carriers, preferred oral preparation or injection are applied to the patient who needs this treatment in the mode of oral or parenteral.
When being used for oral administration, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and the auxiliary materials and mixing compacting that suits form, based on oral ordinary tablet, other has buccal tablet, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coatel tablets etc.Capsule means medicine or is added with the adjuvant filling in Capsules or be sealed in solid preparation in the soft capsule material, according to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (soft gelatin capsule), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable adjuvant uniform mixing, and the spherical or near-spherical solid preparation so that proper method is made comprises drop pill, sugar pill, piller etc.Granule means that medicine and suitable adjuvant make the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as granule), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution makes for oral supernatant liquid preparation in suitable solvent.Oral suspensions means the slightly solubility solid drugs, is dispersed in the liquid medium, makes for oral suspension body preparation, also comprises dry suspension or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.
When being used for parenteral, can be made into injection.Injection means the intravital solution of confession injection, emulsion or the suspension that medicine is made and supplies to face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or concentrated solution that injection can be divided into injection, injectable sterile powder and concentrated solution for injection.Injection means that the confession that medicine is made is injected into sterile solution type injection, emulsion-type injection or the suspension type injection of using in the body, can be used for intramuscular injection, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and wherein large volume (generally the being not less than 100ml) injection of using for intravenous drip also claims venous transfusion.Injectable sterile powder means that confession that medicine is made is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension, available suitable solvent for injection preparation back injection, also available venous transfusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray drying method or freeze-drying etc.Concentrated solution for injection means that confession that medicine is made faces the aseptic concentrated solution of using for intravenous drip with preceding dilution.
When pharmaceutical composition of the present invention is made oral formulations, can add suitable filler, binding agent, disintegrating agent, lubricant etc.Filler commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, microcrystalline Cellulose, lactose, pregelatinized Starch, mannitol etc.; Typical binders comprises sodium carboxymethyl cellulose, PVP-K30, hydroxypropyl cellulose, starch slurry, methylcellulose, ethyl cellulose, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dried starch, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises magnesium stearate, Pulvis Talci, sodium lauryl sulphate, micropowder silica gel etc.
When making injection, optional use solvent or non-aqueous solvent can add suitable additives according to the character of medicine.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solutions; Non-aqueous solvent commonly used is a vegetable oil, is mainly the injection soybean oil, and other also have the aqueous solution of ethanol, propylene glycol, Polyethylene Glycol etc.Additives commonly used comprise osmotic pressure regulator, pH value regulator, solubilizing agent, filler, antioxidant, antibacterial, emulsifying agent, suspending agent etc.Osmotic pressure regulator commonly used comprises sodium chloride, glucose, potassium chloride, magnesium chloride, calcium chloride, sorbitol etc., preferred sodium chloride or glucose; PH value regulator commonly used comprises acetic acid-sodium acetate, lactic acid, citric acid-sodium citrate, sodium bicarbonate-sodium carbonate etc.; Solubilizing agent commonly used comprises polyoxyethylene sorbitan monoleate, propylene glycol, lecithin, polyoxyethylene castor oil etc.; Filler commonly used comprises lactose, mannitol, sorbitol, dextran etc.; Antioxidant commonly used has sodium sulfite, sodium sulfite, sodium pyrosulfite etc.; Antibacterial commonly used is phenol, cresol, chlorobutanol etc.Injection container commonly used has glass ampule, vial, plastic ampoule, plastic bottle etc.
The present composition has the following advantages:
(1) provides a kind of pharmaceutical composition and preparation method thereof of effective treatment hepatic disease, satisfied urgent clinical needs;
(2) first the interaction and the composition of prescription of the present composition carried out pharmacodynamic study, found that the present composition has remarkable anti-carbon tetrachloride (CCl 4) inductive rat liver fibrosis effect, filter out weight proportion scope with significant curative effect;
(3) the present invention shows by pharmacological experiment study, and the present composition is to CCl 4Inductive chmice acute hepatic injury, acetaminophen cause the chmice acute hepatic injury and have remarkable protective effect; Isothiocyanic acid is caused the high bilirubin of mice serum tangible reduction effect, and serum total bilirubin and conjugated bilirubin content are reduced; There is obvious inhibition duck to infect the effect of DHBV virus; In above-mentioned each experimental group, present composition experimental group is compared with silybin meglumine group, Herba Artemisiae Scopariae or its extract, Fructus Gardeniae or its extract with single, enhancing evident in efficacy, it is remarkable to show that silybin meglumine, Herba Artemisiae Scopariae or its extract and Fructus Gardeniae or its extract three medicines share the hepatic disease effect, and consequently those skilled in the art institute is beyond thought;
(4) stability experiment that carries out shows that the every index of medicine composition injection of the present invention is all more stable, has guaranteed safety of clinical administration;
(5) silybin meglumine has the effect of protecting and stablizing liver plasma membrane, can fall enzyme, jaundice eliminating and promote liver cell regeneration, play good liver-protective effect, and can promote liver cell regeneration, medicine liver poisoning, various acute, chronic hepatitis, first cirrhosis, fatty liver all there are good effect; Herba Artemisiae Scopariae can be protected liver plasma membrane, prevent hepatic necrosis, promotes liver cell regeneration and improves liver microcirculation; Fructus Gardeniae function of gallbladder promoting, jaundice eliminating effect are stronger, and it is best that the product of giving birth to are treated the icterohepatitis effect.Three medicine drug combination determined curative effects, and reduced relative dosage, be with a wide range of applications.
Below routine by experiment beneficial effect of further setting forth medicine of the present invention.In the following experimental example: the compositions of silybin meglumine, Herba Artemisiae Scopariae or its extract and Fructus Gardeniae or its extract is hereinafter to be referred as water mattress Cape jasmine compositions.Used Herba Artemisiae Scopariae extract is taken from embodiment 1 in the experimental example, and Fructus Gardeniae extract is taken from embodiment 2.
Experimental example 1 water mattress Cape jasmine compositions drug combination drug efficacy study-Chinese People's Anti-Japanese Military and Political College's Hepar Mus fibrosis effect
Laboratory animal: the Wistar rat, body weight 180～230g, male.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
Model group: CCl 4Injection, self-control;
Silybin meglumine group: silybin meglumine tablets agent, Weifang Zhongshi Pharmaceutical Co., Ltd.;
Herba Artemisiae Scopariae group: Herba Artemisiae Scopariae extract tablet, self-control;
Fructus Gardeniae group: Fructus Gardeniae extract tablet, self-control;
Water mattress Cape jasmine compositions group: water mattress Cape jasmine composition tablet, self-control.
Experimental technique:
Get 10 of Wistar rats, subcutaneous injection Oleum Arachidis hypogaeae semen 3ml/kg, every day 1 time, totally 10 weeks are as the blank group.The Liver Fibrosis Model group is used 40% carbon tetrachloride (CCl 4) peanut oil solution presses the 3ml/kg subcutaneous injection, 2 times weekly, in totally 8 weeks, induces Liver Fibrosis Model.
Get 220 of Liver Fibrosis Model rats, be divided into 22 groups at random, be respectively model group, the silybin meglumine group, the Herba Artemisiae Scopariae group, the Fructus Gardeniae group, (18 groups of water mattress Cape jasmine compositions groups, silybin meglumine+Herba Artemisiae Scopariae+Fructus Gardeniae, weight proportion is: 25+16000+6500,25+750+1600,25+16000+400,50+1500+800,50+1500+3200,50+8000+1600,50+4000+1600,100+4000+1600,200+4000+1600,50+3000+1600,100+3000+1600,200+3000+1600,200+1500+1600,200+8000+800,200+8000+3200,400+750+400,400+16000+1600,400+750+6500), 10 every group.Except that matched group, all the other each groups continue with 40% carbon tetrachloride (CCl 4) peanut oil solution 3ml/kg subcutaneous injection, every day 1 time.Silybin meglumine group, Herba Artemisiae Scopariae group, Fructus Gardeniae group, water mattress Cape jasmine compositions group be the gastric infusion relative medicine simultaneously, 2 weeks of successive administration.Slaughter rat after 10 weeks, blood 2ml gets in the sterile working, separation of serum, and-20 ℃ of preservations detect hepatic fibrosis index with radioimmunology: hyaluronic acid (HA) and laminin (LN).
Experimental result and conclusion: experimental result sees Table 1.
(1) compare with the blank group, model group rat blood serum HA, LN content have utmost point significant difference (p＜0.01), and the modeling success is described.
(2) compare with model group, each proportioning group treatment heptic fibrosis rat blood serum HA of water mattress Cape jasmine compositions and LN water mean pole significantly are lower than model group (p＜0.01), silybin meglumine group, Herba Artemisiae Scopariae group and Fructus Gardeniae group treatment heptic fibrosis rat blood serum HA and LN level all significantly are lower than model group (p＜0.05), point out each administration group all can significantly improve the hepatic fibrosis serological index, have the effect of anti-hepatic fibrosis.
(3) compare with silybin meglumine, Herba Artemisiae Scopariae or Fructus Gardeniae with single, each proportioning group of water mattress Cape jasmine compositions can significantly reduce the concentration (p＜0.05) of hepatic fibrosis index hyaluronic acid (HA) and laminin (LN), can improve hepatic fibrosis, have the effect of anti-hepatic fibrosis.
Conclusion: The above results shows, silybin meglumine, Herba Artemisiae Scopariae and Fructus Gardeniae three flavor medicine compatibilities, synergistic function is arranged, and action effect is relevant with proportioning, in each parts by weight, when weight proportion is a silybin meglumine: Herba Artemisiae Scopariae: Fructus Gardeniae=(50～200): (1500～8000): effect is better when (800～3200), and the wherein wt proportioning is a silybin meglumine: Herba Artemisiae Scopariae: Fructus Gardeniae=100: (3000～4000): 1600 o'clock, best results, pointing out it is best proportioning.
Table 1 water mattress Cape jasmine composition tablet is to CCl 4Due to hepatic fibrosis rats serological index influence (X ± SD, n=10)
Figure DEST_PATH_G200610163473901D00011
Annotate: compare with the blank group, ZeroP＜0.01; Compare with model group, *P＜0.05, *P＜0.01; Compare with the silybin meglumine group, ﹠amp;P＜0.05; Compare with the Herba Artemisiae Scopariae group, #P＜0.05; Compare with the Fructus Gardeniae group, △P＜0.05.
Experimental example 2 water mattress Cape jasmine compositionss are to carbon tetrachloride (CCl 4 ) cause the protective effect of rat acute hepatic injury
Animal subject: the Wistar rat, body weight 200～220g, is divided into 14 groups at random by 140.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
Model group: CCl 4Injection, self-control;
Silybin meglumine group: silybin meglumine injection, self-control (crude drug is commercial);
Herba Artemisiae Scopariae extract group: Herba Artemisiae Scopariae extract injection, self-control;
Fructus Gardeniae extract group: Fructus Gardeniae extract injection, self-control;
Water mattress Cape jasmine composite injection group, self-control.
Test kit: glutamate pyruvate transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST) test kit, commercial, Shanghai Biological Products Inst., Ministry of Public Health.
Experimental technique:
Get 140 of Wistar rats, be divided into 14 groups at random, be respectively the different proportioning groups of blank group, model group, silybin meglumine group, Herba Artemisiae Scopariae extract group, Fructus Gardeniae extract group, water mattress Cape jasmine composite injection, 10 every group.Blank group lumbar injection 0.9% normal saline 10ml/kg, all the other respectively organize rat successive administration three days (lumbar injection), and fasting 5.5h gives 25%CCl respectively behind the last administration 2h 4Peanut oil solution, dosage sees Table 2.Give rats eating behind the carbon tetrachloride.In giving carbon tetrachloride fasting 12 hours after 24 hours, jugular vein is got each rat serum, and the centrifugal 10min separation of serum of 3000r/min is pressed ALT, and AST measures description, carries out glutamate pyruvate transaminase (ALT) and glutamic oxaloacetic transaminase, GOT (AST) determination of activity.
Table 2 water mattress Cape jasmine composite injection is to carbon tetrachloride (CCl 4) cause the rat acute hepatic injury protective effect (X ± SD, n=10)
Figure G061G3473920061226D000101
Annotate: compare with the blank group, *P＜0.01; Compare with model group, #P＜0.05, ##P＜0.01; Compare with the silybin meglumine group, ﹠amp;P＜0.05; Compare with the Herba Artemisiae Scopariae extract group, ★P＜0.05; Compare with the Fructus Gardeniae extract group, △P＜0.05.
Experimental result: experimental result sees Table 2.
(1) model group has been compared utmost point significant difference (p＜0.01) with the blank group, and the modeling success is described.
(2) compare with model group, each administration group is all to carbon tetrachloride (CCl 4) hepatic injury of poisoning induced rat acute has remarkable protective effect, the ALT of liver and AST have tangible restitution, all have significant statistical significance (p＜0.05).Water mattress Cape jasmine composite injection various dose proportioning group is compared with silybin meglumine or Herba Artemisiae Scopariae extract or Fructus Gardeniae extract with single, and significant difference (p＜0.05) shows that silybin meglumine, Herba Artemisiae Scopariae and Fructus Gardeniae use in conjunction are synergistic function.
(3) compare with the blank group, the ALT and the AST of mattress Cape jasmine composite injection various dose proportioning group liver do not have significant difference, can make the ALT and the AST level of liver recover normal, show that the effect of recovering liver function is remarkable, its curative effect is relevant with the dosage ratio of compositions, silybin meglumine in the water mattress Cape jasmine composite injection: Herba Artemisiae Scopariae extract: Fructus Gardeniae extract=100: 60: effect is best during 32g.
Experimental example 3 water mattress Cape jasmine compositionss are to carbon tetrachloride (CCl 4 ) influence of poisoning mice ALT, LTG, MDA
Animal subject: healthy Kunming mouse, body weight 18～22g.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
CCl 4Matched group: CCl 4Injection, self-control;
Silybin meglumine group: silybin meglumine capsule, self-control (crude drug is commercial);
Herba Artemisiae Scopariae extract group: Herba Artemisiae Scopariae extract capsule, self-control;
Fructus Gardeniae extract group: Fructus Gardeniae extract capsule, self-control;
1 group of water mattress Cape jasmine compositions: water mattress Cape jasmine composition capsule (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+60mg+32mg), self-control;
2 groups of water mattress Cape jasmine compositionss: water mattress Cape jasmine composition capsule (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+120mg+64mg), self-control;
3 groups of water mattress Cape jasmine compositionss: water mattress Cape jasmine composition capsule (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+240mg+128mg), self-control.
Experimental technique:
Get 80 of mices, be divided into 8 groups at random, be respectively blank group, CCl 4Matched group, silybin meglumine group, Herba Artemisiae Scopariae extract group, Fructus Gardeniae extract group, 1 group of water mattress Cape jasmine compositions, 2 groups of water mattress Cape jasmine compositionss, 3 groups of water mattress Cape jasmine compositionss, 10 every group.Each administration group is with normal saline and is configured to gastric infusion behind the suspension.Blank group lumbar injection 0.9% normal saline 10ml/kg, the equal lumbar injection CCl of all the other each treated animals 410ml/kg, overnight fasting.Administration group gastric infusion, every day 1 time, continuous 10d, matched group is given the normal saline of respective volume, and after last administration, the sacrificed by decapitation animal is got the blood regulating liver-QI and measures serum glutamic pyruvic transminase (ALT), glyceric acid three ester (LTG), malonaldehyde (MDA) respectively.
Experimental result and conclusion: experimental result sees Table 3.
(1) CCl 4Matched group has been compared utmost point significant difference (p＜0.01) with the blank group, the modeling success is described.
(2) each administration group is all to carbon tetrachloride (CCl 4) in ALT, LTG and the MDA of liver of mould induced mice tangible restitution (p＜0.05, p＜0.01) is arranged.Wherein the effect of water mattress Cape jasmine compositions group all obviously is better than single with silybin meglumine or Herba Artemisiae Scopariae extract or Fructus Gardeniae extract (p＜0.05).Show that silybin meglumine, Herba Artemisiae Scopariae extract and Fructus Gardeniae extract compatibility have tangible restitution to ALT, LTG and the MDA of the liver of carbon tetrachloride poisoning induced mice, make ALT, LTG and the MDA level of liver recover normal, comparing with the blank group does not have notable difference.Show that silybin meglumine, Herba Artemisiae Scopariae extract and Fructus Gardeniae extract compatibility are evident in efficacy.
Table 3 water mattress Cape jasmine composition capsule is to carbon tetrachloride (CCl 4) poisoning mice ALT, LTG, MDA influence (X ± SD, n=10)
Figure G061G3473920061226D000121
Annotate: compare with the blank group, *P＜0.01; With CCl 4Matched group is compared, #P＜0.05, ##P＜0.01; Compare with the silybin meglumine group, ﹠amp;P＜0.05; Compare with the Herba Artemisiae Scopariae extract group, △P＜0.05; Compare with the Fructus Gardeniae extract group, ZeroP＜0.05.
Experimental example 4 water mattress Cape jasmine compositionss are to carbon tetrachloride (CCl 4 ) liver, the influence of spleen index of acute liver damage mice due to the poisoning
Animal subject: healthy Kunming mouse, body weight 18～22g, is divided into 8 groups at random by 80.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
CCl 4Model group: CCl 4Injection, self-control;
Silybin meglumine group: silybin meglumine injection, self-control (crude drug is commercial);
Herba Artemisiae Scopariae extract group: Herba Artemisiae Scopariae extract injection, self-control;
Fructus Gardeniae extract group: Fructus Gardeniae extract injection, self-control;
Water mattress Cape jasmine composite injection group (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+60mg+32mg): be divided into basic, normal, high three dosage groups, self-control.
Experimental technique:
Get 80 of mices, be divided into 8 groups at random, be respectively blank group, CCl 4Model group, silybin meglumine group, Herba Artemisiae Scopariae extract group, Fructus Gardeniae extract group, basic, normal, high three the dosage groups of water mattress Cape jasmine composite injection, 10 every group.Blank group lumbar injection 0.9% normal saline 10ml/kg, the equal lumbar injection CCl of all the other each treated animals 410ml/kg, overnight fasting.Administration group intraperitoneal injection, every day 1 time, dosage sees Table 4, continuous 10d, matched group is given the normal saline of respective volume, and after last administration, the sacrificed by decapitation animal is got liver and spleen, inhales the liquid of dehematizing, and cuts off fat, mesentery, accurately weighs.
Experimental result: experimental result sees Table 4.
Each administration group can both significantly reduce carbon tetrachloride (CCl 4) liver, the spleen index (p＜0.05, p＜0.01) of poisoning mice.Wherein the effect of water mattress Cape jasmine composite injection group all obviously is better than single with silybin meglumine or Herba Artemisiae Scopariae extract or Fructus Gardeniae extract (p＜0.05).Show that silybin meglumine, Herba Artemisiae Scopariae and Fructus Gardeniae compatibility have remarkable reduction carbon tetrachloride (CCl 4) liver of poisoning mice, the effect of spleen index, comparing with the blank group does not have significant difference.And relevant with the dosage of compositions, effect is best during high dose.
Table 4 water mattress Cape jasmine compositions is to carbon tetrachloride (CCl 4) influence of liver, the spleen index of acute liver damage mice due to the poisoning (X ± SD, n=10)
Figure DEST_PATH_G061G3473920071108D000031
Annotate: compare with the blank group, *P＜0.01; With CCl 4Model group is compared, #P＜0.05, ##P＜0.01; Compare with the silybin meglumine group, ﹠amp;P＜0.05; Compare with the Herba Artemisiae Scopariae extract group, ★P＜0.05; Compare with the Fructus Gardeniae extract group, △P＜0.05.
Experimental example 5 water mattress Cape jasmine compositionss are to carbon tetrachloride (CCl 4 ) influence of poisoning rat SDH activity, hepatic glycogen content and liver coefficient
Animal subject: the Wistar rat, body weight 180～230g, male and female are regardless of.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
Model group: CCl 4Injection, self-control;
Silybin meglumine group: silybin meglumine capsule, self-control (crude drug is commercial);
Herba Artemisiae Scopariae extract group: Herba Artemisiae Scopariae extract capsule, self-control;
Fructus Gardeniae extract group: Fructus Gardeniae extract capsule, self-control;
Water mattress Cape jasmine compositions group: water mattress Cape jasmine composition capsule (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=10mg+120mg+64mg), be divided into basic, normal, high three dosage groups, self-control.
Experimental technique:
Get 80 of Wistar rats, weigh, from the rat tail vein blood sampling, timely separation of serum, the foundation level of survey serum SDH.Be divided into 8 groups then at random, the conventional raising, matched group: every rat is according to 2ml/kg sterile saline subcutaneous injection; Model group and each medicine group give every rat according to 2ml/kgCCl 4Subcutaneous injection is to duplicate the chemical liver injury model.Get next day respectively organize rat serum after, irritate stomach normal saline 4ml/kg, the corresponding medicine of drug administration group gastric infusion, successive administration 10 days for matched group and model group.Experiment finishes (the 12nd day) time weighs, get blood after disconnected neck put to death animal, in time separate liver, the normal saline flushing blood stasis is weighed behind the filter paper suck dry moisture, and gets liver and survey hepatic glycogen content.
Experimental result and conclusion: experimental result sees Table 5 and table 6.
Table 5 water mattress Cape jasmine composition capsule is to CCl 4The active influence of rat blood serum SDH (X ± SD, n=10)
Figure G061G3473920061226D000141
Annotate: with compare before the experiment, *P＜0.01; Compare with model group, #P＜0.05, ##P＜0.01.
(1) the serum SDH activity of each treated animal before the experiment, there are no significant for group difference, through CCl 4After the processing, test the active and matched group comparing difference very remarkable (p＜0.01) of each treated animal serum SDH, show the modeling success.
(2) compare with model group, silybin meglumine group, Herba Artemisiae Scopariae extract group and Fructus Gardeniae extract group significantly reduce serum SDH activity (p＜0.05); Each dosage group of water mattress Cape jasmine compositions extremely significantly reduces serum SDH activity (p＜0.01), and the serum SDH activity of basic, normal, high dosage group is near the matched group level.
Table 6 water mattress Cape jasmine composition capsule is to CCl 4The influence of rats'liver glycogen content and liver coefficient (X ± SD, n=10)
Annotate: compare with matched group, *P＜0.01; Compare with model group, #P＜0.05, ##P＜0.01.
(1) model group is compared with matched group, and after the demonstration animal via was crossed the CCl4 processing, hepatic glycogen content extremely significantly reduced (p＜0.01), and the liver coefficient extremely significantly increases (p＜0.01), prompting modeling success.
(2) compare with model group, silybin meglumine group, Herba Artemisiae Scopariae extract group and Fructus Gardeniae extract group significantly increase hepatic glycogen content (p＜0.05), significantly reduce liver coefficient (p＜0.05); Each dosage group of water mattress Cape jasmine compositions extremely significantly increases hepatic glycogen content (p＜0.01), extremely significantly reduces liver coefficient (p＜0.01).
Above-mentioned experimental result shows, water mattress Cape jasmine compositions can obviously reduce hepatocellular degeneration and downright bad degree (the SDH activity change can sensitively be reacted the degree of hepatocellular degeneration, necrosis), reduce the hepatic tissue pathology degree of injury, liver cell regeneration is obvious, and prompting water mattress Cape jasmine compositions is to CCl 4Cause the rat acute hepatic injury good protective action is arranged.
Experimental example 6 water mattress Cape jasmine compositionss are to the inhibitory action of DHBV-DNA
Animal subject: commercially available 1 age in days Beijing duck.
Test sample and dosage:
Blank group: 0.9% normal saline solution, self-control;
Positive controls: acyclovir (ACV) injection (dosage: 50mg/kg), self-control;
The silybin meglumine group: the silybin meglumine injection (dosage: 20mg/kg), self-control (crude drug is commercial);
The Herba Artemisiae Scopariae extract group: the Herba Artemisiae Scopariae extract injection (dosage: 20mg/kg), self-control;
The Fructus Gardeniae extract group: the Fructus Gardeniae extract injection (dosage: 20mg/kg), self-control;
Water mattress Cape jasmine compositions low dose group: water mattress Cape jasmine composite injection (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+60mg+32mg, dosage: 10mg/kg), self-control;
Dosage group in the water mattress Cape jasmine compositions: water mattress Cape jasmine composite injection (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+60mg+32mg, dosage: 15mg/kg), self-control;
Water mattress Cape jasmine compositions high dose group: water mattress Cape jasmine composite injection (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+60mg+32mg, dosage: 20mg/kg), self-control.
Virus: DHBV positive serum.
Experimental technique:
(1) animal model: Beijing duck is got blood through sufficient intravenous injection 0.2ml DHBV positive serum behind the 7d, and separation of serum is preserved check for-20 ℃.
(2) Drug therapy: filter out 48 of the positive ducks that infect successfully, be divided into 8 groups at random, 6 every group.Be respectively blank group, positive controls, silybin meglumine group, Herba Artemisiae Scopariae extract group, Fructus Gardeniae extract group, basic, normal, high three the dosage groups of water mattress Cape jasmine composite injection, dosage sees Table 7.Intravenous administration, 2 weeks of administration.Respectively at before the medicine, after medication the 7th day, medication the 14th day and the drug withdrawal the 3rd day, from duck lower limb vein haemospasia, separation of serum ,-20 ℃ of preservations are to be tested.
(3) detection method: adopt DHBV-DNA Dot Blot method, with hybridization spot absorbance (A) as specimen DHBV-DNA level value.
(4) statistical procedures: relatively, adopt paired t-test before medication group different time dna content and the medication; Same time D NA content of medication group and virus control group relatively adopt the t check.
Experimental result: experimental result sees Table 7.
(1) compare with the blank group, each administration group all obviously suppresses DHBV virus (p＜0.05, p＜0.01).
(2) effect of water mattress Cape jasmine composite injection group all obviously is better than single with silybin meglumine or Herba Artemisiae Scopariae extract or Fructus Gardeniae extract (p＜0.05), and with on the same group the treatment before compare, do not have knock-on and the preceding comparing difference of administration remarkable (p＜0.01) after the drug withdrawal, and positive controls relatively there is not significant difference after drug withdrawal with before the administration.And relevant with the dosage of compositions, effect of high dosage is best.
Table 7 water mattress Cape jasmine composite injection to the inhibitory action of DHBV-DNA (X ± SD, n=6)
Figure G061G3473920061226D000161
Annotate: with compare before the treatment on the same group, *P＜0.05, *P＜0.01; Compare with the blank group, ﹠amp;P＜0.05, ﹠amp; ﹠amp;P＜0.01; Compare with the silybin meglumine group, #P＜0.05; Compare with the Herba Artemisiae Scopariae extract group, ★P＜0.05; Compare with the Fructus Gardeniae extract group, △P＜0.05.
Experimental example 7 water mattress Cape jasmine compositionss are to the how influence of fat mice serum content of bilirubin of isothiocyanic acid-1-
Animal subject: healthy Kunming mouse, body weight 24～28g, the male and female dual-purpose, is divided into 8 groups at random by 80.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
Model group: isothiocyanic acid-1-is the fat injection how, self-control;
Silybin meglumine group: silybin meglumine injection, self-control (crude drug is commercial);
Herba Artemisiae Scopariae extract group: Herba Artemisiae Scopariae extract injection, self-control;
Fructus Gardeniae extract group: Fructus Gardeniae extract injection, self-control;
Water mattress Cape jasmine composite injection group (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+60mg+32mg): be divided into basic, normal, high three dosage groups, self-control.
Test kit: the determination of bilirubin medicine box, commercial, Shanghai Rongsheng Bioisystech Co., Ltd.
Experimental technique:
Get 80 of mices, be divided into 8 groups at random, be respectively blank group, model group, silybin meglumine group, Herba Artemisiae Scopariae extract group, Fructus Gardeniae extract group, basic, normal, high three the dosage groups of water mattress Cape jasmine composite injection, 10 every group.Except that the blank group, the equal intraperitoneal injection of all the other each treated animals, successive administration 3 days, fasting 4h, last administration 1h, lumbar injection give 0.3% isothiocyanic acid-1-how fat peanut oil solution 60mg/kg.Give isothiocyanic acid-1-how behind the fat 4h, mice is feeding once more, rechallenge behind the 24h gives isothiocyanic acid-1-how fat the 3rd day, fasting 5h, each Mus of 3h is plucked the right eye ball and gets blood 3000r/min after the administration, centrifugal 10 minutes, separation of serum was by the requirement of test kit description, carry out total bilirubin and conjugated bilirubin and measure, the mensuration wavelength is 600nm.The result organizes a significant difference relatively by the t check.
Table 8 water mattress Cape jasmine composite injection to the influence of isothiocyanic acid mice serum total bilirubin, conjugated bilirubin content (X ± SD, n=10)
Figure G061G3473920061226D000171
Annotate: compare with the blank group, *P＜0.01; Compare with model group, #P＜0.05, ##P＜0.01; Compare with the silybin meglumine group, ﹠amp;P＜0.05; Compare with the Herba Artemisiae Scopariae extract group, ★P＜0.05; Compare with the Fructus Gardeniae extract group, △P＜0.05.
Experimental result: experimental result sees Table 8.
(1) model group has been compared utmost point significant difference (p＜0.01) with the blank group, and the modeling success is described.
(2) each administration group all causes the high bilirubin of mice serum to isothiocyanic acid tangible reduction effect (p＜0.05, p＜0.01).Wherein the effect of water mattress Cape jasmine compositions group all obviously is better than single with silybin meglumine or Herba Artemisiae Scopariae extract or Fructus Gardeniae extract (p＜0.05).Show that silybin meglumine, Herba Artemisiae Scopariae and Fructus Gardeniae compatibility cause the high bilirubin of mice serum to isothiocyanic acid tangible reduction effect is arranged, serum total bilirubin and conjugated bilirubin content are reduced.
The above results shows that silybin meglumine, Herba Artemisiae Scopariae and Fructus Gardeniae have synergistic function, and comparing with the blank group does not have notable difference.And relevant with the dosage of compositions, effect of high dosage is best.
The influence of experimental example 8 water mattress Cape jasmine compositions Abensanil (AP) poisoning mice ALT, AST activity and GSH content
Animal subject: healthy Kunming mouse, body weight 18～22g.
Test sample:
Blank group: 0.9% normal saline solution, self-control;
AP matched group: AP injection, self-control;
Silybin meglumine group: silybin meglumine granule, self-control (crude drug is commercial);
Herba Artemisiae Scopariae extract group: Herba Artemisiae Scopariae extract granule, self-control;
Fructus Gardeniae extract group: Fructus Gardeniae extract granule, self-control;
Water mattress Cape jasmine compositions group: water mattress Cape jasmine composition granule (silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=10mg+120mg+64mg), be divided into basic, normal, high three dosage groups, self-control.
Experimental technique:
Get 80 of mices, be divided into 8 groups at random, be respectively blank group, AP matched group, silybin meglumine group, Herba Artemisiae Scopariae extract group, Fructus Gardeniae extract group, basic, normal, high three the dosage groups of water mattress Cape jasmine compositions, 10 every group.Except that the blank group, the equal lumbar injection AP100ml/kg of all the other each treated animals, overnight fasting.Administration group gastric infusion, every day 1 time, continuous 10d, matched group is given the normal saline of respective volume, after last administration, lumbar injection AP100mg/kg is behind the fasting 3h, the sacrificed by decapitation animal is got the blood regulating liver-QI and measures serum glutamic pyruvic transminase (ALT), glutathione S-transferase (GST) and reduced glutathion (GSH) respectively.
The influence of table 9 water mattress Cape jasmine composition granule Abensanil (AP) poisoning mice ALT, GST activity and GSH content (X ± SD, n=10)
Figure DEST_PATH_G061G3473920071108D000051
Annotate: compare with the blank group, *P＜0.01; Compare with the AP matched group, #P＜0.05, ##P＜0.01; Compare with the silybin meglumine group, ﹠amp;P＜0.05; Compare with the Herba Artemisiae Scopariae extract group, △P＜0.05; Compare with the Fructus Gardeniae extract group, ZeroP＜0.05.
Experimental result and conclusion: experimental result sees Table 9.
(1) compare with the blank group, the AP matched group extremely significantly reduces GSH content and the utmost point significantly improves ALT, GST activity (p＜0.01), and the modeling success is described.
(2) compare with the blank group, each administration group can both improve the GSH content and reduction ALT, GST activity (p＜0.05, p＜0.01) of the liver of acetaminophen (AP) poisoning induced mice.
(3) wherein the effect of water mattress Cape jasmine composition granule group all obviously is better than single with silybin meglumine or Herba Artemisiae Scopariae extract or Fructus Gardeniae extract (p＜0.05).The liver that shows silybin meglumine, Herba Artemisiae Scopariae and Fructus Gardeniae compatibility Abensanil poisoning mice has tangible restitution, makes ALT, the GST level of liver recover normal, and comparing with the blank group does not have notable difference.Along with the increase of dosage, increase GSH content and reduce the active effect increasing of ALT, GST, effect is best during high dose.
Experimental example 9 injected in mice administration acute toxicity testings
(1) experimental technique
Test sample: water mattress Cape jasmine composite injection (self-control, 10ml: silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+60mg+32mg).
Animal subject: mice, each 5 of every group of male and female, male body weight 25～28g, female body weight 21～24g.
Route of administration: intravenous injection, lumbar injection.
Observation item: death toll, general state, body weight, cut open inspection, median lethal dose(LD 50).
(2) experimental result
Require to carry out prerun according to acute toxicity testing, lumbar injection and intravenous injection two route of administration all can't be measured the median lethal dose(LD 50) of medicine, also do not see tangible toxic reaction, so carry out maximum dosage-feeding experiment in a day.Dosage: tail vein injection 0.2ml/10g, lumbar injection 0.2ml/10g, 2 times on the one.
Death toll: do not occur dead.
General state: no abnormality seen changes.
Body weight: in administration preceding 1 day, administration day, measured in 1,3,7,14 day after the administration; No abnormality seen changes.
Cut open inspection: the heart, liver, lung, kidney etc. organize no abnormality seen to change.
(3) conclusion
Occur death in this experiment, infer that water mattress Cape jasmine composite injection is 0.4ml/10g to the maximum tolerated dose of male and female mouse vein and intraperitoneal injection, is equivalent to 100 times of maximum consumption 20ml of the 50kg body weight day for human beings.Show this product low toxicity, safe.
Experimental example 10 water mattress Cape jasmine composite injection stability experiments
Test sample: water mattress Cape jasmine composite injection (self-control, 10ml: silybin meglumine+Herba Artemisiae Scopariae extract+Fructus Gardeniae extract=100mg+60mg+32mg).
Investigation project: character, pH value, clarity, related substance, sign content; And at accelerated tests 6 months and the aseptic and pyrogen test of long-term experiment end of term increase.
1, influence factor's experiment
The strong illumination experiment: get test sample, putting illumination is interior the placement 10 days of lighting box of 4500Lx.
High temperature experiment: get test sample, place respectively under 40 ℃, the 60 ℃ conditions and placed 10 days.
Low temperature test: get test sample, in 4 ℃ of refrigerators, placed 10 days.
Above-mentioned experiment was respectively at the 5th, 10 day sampling and measuring.Relatively test every index after the character, and with result and comparison in 0 day.
The result: placed 10 days under the illumination 4500Lx condition, except that related substance slightly raise, all other indexs had no significant change.Placed 10 days under 60 ℃ of conditions of high temperature, outward appearance becomes faint yellow clear liquid, indicates content and descends, and related substance slightly raises.Placed 10 days under 40 ℃ of high temperature, 4 ℃ of conditions of low temperature, every index does not have significant change.
2, accelerated tests
Method: put under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% and placed 6 months.Respectively at taking a sample 1st month, 2 months, 3 months, 6 the end of month, relatively after the outward appearance, test every index at experimental session, with result and comparison in 0 month; And at 6 aseptic and pyrogen tests of increase at the end of month.
Result: placed 6 months under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5%, removing related substance slightly increases, and outside sign content slightly descended, all other indexs had no significant change, at 6 the end of month of accelerated tests, pyrogen, sterility test are all up to specification.
3, long-term experiment
Method: put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and placed 18 months.Respectively at 3rd month, 6 months, 9 months, 12 months, 18 months, relatively after the outward appearance, test every index, with result and comparison in 0 month; And at 18 aseptic and pyrogen tests of increase at the end of month.
The result: placed under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% 18 months, every index has no significant change, and at 18 the end of month of long-term experiment, pyrogen, sterility test are all up to specification.
Conclusion: reached a conclusion by above-mentioned investigation result, in every experiment, water mattress Cape jasmine composite injection is more stable.
Investigation project: character, pH value, clarity.
Long-time stability experimental technique and result: each compositions of this product is put under the condition of 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% and placed 6 months, 12 months, every index has no significant change, and experimental result shows that the long-term placement of this product composite injection is basicly stable.
4, the specific embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The adjuvant of each dosage form can be replaced with acceptable accessories in following examples, perhaps reduces, increases.Used Herba Artemisiae Scopariae extract is taken from embodiment 1 among the embodiment 4～10, and Fructus Gardeniae extract is taken from embodiment 2, and silybin meglumine is commercial, Jiangsu Zhongxing Pharmaceutical Co., Ltd..
The preparation of embodiment 1 Herba Artemisiae Scopariae extract
The preparation method of Herba Artemisiae Scopariae extract
Get Herba Artemisiae Scopariae, decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, and filtrate is concentrated into every 1ml and contains crude drug 2g, adds ethanol and makes and contain the alcohol amount and reach 70%, cold preservation 24 hours filters, and filtrate recycling ethanol contains crude drug 5g to every 1ml, adds ethanol again and makes and contain the alcohol amount and reach 85%, cold preservation 24 hours filters, and filtrate recycling ethanol extremely every 1ml contains crude drug 10g, add the about 5 times of amounts of water, cold preservation 48 hours filters, filtrate is condensed into the thick paste shape, vacuum drying, promptly.
The Herba Artemisiae Scopariae extract identification experiment
Get this product powder 1g, porphyrize adds water 40ml, and dilute hydrochloric acid 1ml is heated to about 80 ℃, put coldly, filter, in the filtrate dislocation separatory funnel, add ethyl acetate extraction 2 times, each 20ml, combined ethyl acetate liquid, evaporate to dryness, residue add ethanol 2ml makes dissolving, as need testing solution.Other gets Herba Artemisiae Scopariae control medicinal material 3g, adds water 50ml, boils 5～10 minutes, puts coldly, filters, and filtrate adds ethyl acetate 10ml, shines medical material solution in pairs with legal system.Test according to thin layer chromatography (2005 editions one appendix VI B of Chinese Pharmacopoeia), draw above-mentioned need testing solution, each 5 μ l of control medicinal material solution, putting in same sodium carboxymethyl cellulose respectively is on the silica gel g thin-layer plate of adhesive, with petroleum ether (60～90 ℃)-ethyl acetate-acetone (5: 3: 2) is developing solvent, launch, take out, dry, spray is put under the ultra-violet lamp (365nm) and is inspected with 5% potassium hydroxide-ethanol solution.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show same color fluorescence speckle.
The Herba Artemisiae Scopariae extract assay
The preparation of reference substance solution: precision takes by weighing at the control substance of Rutin 10mg of 120 ℃ of drying under reduced pressure to constant weight, puts in the 50ml measuring bottle, adds an amount of 70% ethanol, put that slight fever makes dissolving in the water-bath, put coldly, add 70% ethanol to scale, shake up, promptly get (containing anhydrous rutin 0.2mg among every 1ml).
The preparation of standard curve: precision is measured reference substance solution 0.0,1.0,2.0,3.0,4.0,5.0 and 6.0ml, put respectively in the 25ml measuring bottle, respectively add 70% ethanol to 6ml, add 5% sodium nitrite solution 1ml, shake up, placed 6 minutes, add 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, hydro-oxidation sodium test solution 10ml adds ethanol again to scale, shake up, placed 15 minutes, and, measured trap at the wavelength place of 507nm according to spectrophotography (an appendix V of Chinese Pharmacopoeia version in 2000 B), with the trap is that vertical coordinate, concentration are abscissa, the drawing standard curve.
Algoscopy: it is an amount of that precision is measured this product, is added on the polyamide column (50 orders, the 2g that have handled well, internal diameter 12～15mm, wet method dress post) on, use the 50ml water elution, discard eluent, use 70% ethanol elution, collect the about 25ml of eluent, put in the 25ml measuring bottle, add 70% ethanol dilution, shake up to scale, precision is measured 5ml respectively, puts first, in two 25ml measuring bottles of second, add 5% sodium nitrite solution 1ml in the first bottle, shake up, placed 6 minutes, add 10% aluminum nitrate solution 1ml, shake up, placed 6 minutes, in first, each hydro-oxidation sodium test solution 10ml in two bottles of the second adds ethanol dilution again to scale, shake up, placing 15 minutes, according to spectrophotography (an appendix V of Chinese Pharmacopoeia version in 2000 B), is blank with the second bottle, wavelength place at 507nm measures trap, read the amount of rutin the need testing solution from standard curve, calculate, promptly.
This product is pressed dry product and is calculated, and contains total flavones in anhydrous rutin, should be no less than 20%.
According to above-mentioned technology, make Herba Artemisiae Scopariae extract three batch samples, its content and yield see Table 10.
Table 10 Herba Artemisiae Scopariae extract general flavone content and yield
The preparation of embodiment 2 Fructus Gardeniae extracts
The preparation method of Fructus Gardeniae extract
Get Fructus Gardeniae, be ground into coarse powder, decoct with water three times, first and second time each 1 hour, 0.5 hour for the third time, collecting decoction filtered, and filtrate is concentrated into every 1ml and contains crude drug 1g, add ethanol and make and contain alcohol amount and reach 70%, cold preservation 24 hours filters, and filtrate recycling ethanol contains crude drug 3g to every 1ml, add ethanol and make and contain alcohol amount and reach 85%, cold preservation 24 hours filters, and filtrate recycling ethanol contains crude drug 5g to every 1ml, add the about 5 times of amounts of water, cold preservation 48 hours filters, filtrate is condensed into thick paste, vacuum drying, promptly.
The Fructus Gardeniae extract identification experiment
Get this product powder 0.5g, add 75% ethanol 10ml and make dissolving, filter, filtrate is as need testing solution.Other gets the jasminoidin reference substance, adds ethanol and makes the solution that every 1ml contains 4mg, in contrast product solution.Test according to thin layer chromatography (an appendix VI of Chinese Pharmacopoeia version in 2005 B), draw each 5 μ l of above-mentioned two kinds of solution, put respectively on same silica gel g thin-layer plate, with ethyl acetate-acetone-formic acid-water (5: 5: 1: 1) be developing solvent, launch, take out, dry, spray is with sulphuric acid ethanol (5 → 10) solution, and it is clear to be heated to the speckle colour developing at 110 ℃.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color.
The Fructus Gardeniae extract assay is measured according to high performance liquid chromatography (an appendix VI of Chinese Pharmacopoeia version in 2005 D).
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; Acetonitrile-water (15: 85) is a mobile phase; The detection wavelength is 238nm.Number of theoretical plate calculates by the jasminoidin peak should be not less than 1500.
The preparation of reference substance solution: it is an amount of that precision takes by weighing the jasminoidin reference substance, adds methanol and make the solution that every 1ml contains 30 μ g, promptly.
The preparation of need testing solution: get this product powder 0.1g[and get this product powder mensuration moisture (an appendix IX of Chinese Pharmacopoeia version in 2005 H first method) simultaneously in addition, the accurate title, decide, and puts in the tool plug conical flask, the accurate methanol 25ml that adds, close plug claims to decide weight, supersound process 10 minutes is put coldly, claims to decide weight again, supply the weight that subtracts mistake with methanol, shake up, filter, precision is measured subsequent filtrate 10ml, puts in the 25ml measuring bottle, adds methanol to scale, shake up, filter, promptly.
Algoscopy: accurate respectively reference substance solution and each 10 μ l of need testing solution of drawing, inject chromatograph of liquid, measure, promptly.According to above-mentioned technology, make Fructus Gardeniae extract three batch samples, its content and yield see Table 11.
Table 11 Fructus Gardeniae extract total glycosides content and yield
Figure G061G3473920061226D000231
Embodiment 3 Herba Artemisiae Scopariae Fructus Gardeniaes mix the preparation of carrying thing
The Herba Artemisiae Scopariae Fructus Gardeniae mixes the preparation method of carrying thing
Get Herba Artemisiae Scopariae and be cut into segment, Fructus Gardeniae is ground into coarse powder, feeds intake by weight 2: 1, decoct with water three times, 1.5 hours for the first time, second and third time each 1 hour, collecting decoction filters, and filtrate is concentrated into every 1ml and contains crude drug 2g, adding ethanol makes and contains alcohol amount and reach 70%, cold preservation 24 hours filters, and filtrate recycling ethanol extremely every 1ml contains crude drug 5g, adding ethanol again makes and contains alcohol amount and reach 85%, cold preservation 24 hours filters, and filtrate recycling ethanol extremely every 1ml contains crude drug 10g, add the about 5 times of amounts of water, cold preservation 48 hours filters, and filtrate is condensed into the thick paste shape, vacuum drying, promptly.
According to above-mentioned technology, make mattress Cape jasmine extract three batch samples, its content and yield see Table 12.
Table 12 mattress Cape jasmine extract total glycosides content, general flavone content and yield
Figure G061G3473920061226D000232
The preparation of embodiment 4 water mattress Cape jasmine composition powder injections
Prescription one:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 30g (being equivalent to crude drug 1500g)
Fructus Gardeniae extract 16g (being equivalent to crude drug 800g)
Polyoxyethylene sorbitan monoleate 15g
Mannitol 350g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Prescription two:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 60g (being equivalent to crude drug 3000g)
Fructus Gardeniae extract 32g (being equivalent to crude drug 1600g)
Polyoxyethylene sorbitan monoleate 20g
Mannitol 400g
Sterile water for injection adds to 3000ml
Prepare 1000 altogether
Annotate: the total content of the effective ingredient of total extract is not less than 25%
Concrete steps:
(1) vessel of at first dosing being used and antibiotic glass bottle, plug etc. carry out aseptic process.
(2) take by weighing raw material and adjuvant according to recipe quantity.
(3) Herba Artemisiae Scopariae extract is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Gardeniae extract and silybin meglumine are added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, add sterile water for injection to full dose.
(4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
(5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
(6) through the microporous filter membrane fine straining of 0.22 μ m.
(7) clarity of inspection solution, the semi-finished product chemical examination.
(8) be sub-packed in the antibiotic glass bottle half tamponade.Sample is put into the freeze dryer lyophilization.Pre-freeze-45 ℃ 5 hours, low-temperature vacuum drying-45 ℃～0 ℃ 20 hours was warming up to 25 ℃ of vacuum dryings 3 hours then.
(9) lyophilizing finishes, and lid is rolled in tamponade.
(10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 5 water mattress Cape jasmine compositions aqueous injection
Prescription one:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 60g (being equivalent to crude drug 3000g)
Fructus Gardeniae extract 32g (being equivalent to crude drug 1600g)
Polyoxyethylene sorbitan monoleate 50g
Water for injection adds to 10000ml
Prepare 1000 altogether
Prescription two:
Silybin meglumine 50g
Herba Artemisiae Scopariae extract 60g (being equivalent to crude drug 3000g)
Fructus Gardeniae extract 32g (being equivalent to crude drug 1600g)
Polyoxyethylene sorbitan monoleate 40g
Water for injection adds to 10000ml
Prepare 1000 altogether
Prescription three:
Silybin meglumine 200g
Herba Artemisiae Scopariae extract 60g (being equivalent to crude drug 3000g)
Fructus Gardeniae extract 32g (being equivalent to crude drug 1600g)
Polyoxyethylene sorbitan monoleate 60g
Water for injection adds to 10000ml
Prepare 1000 altogether
Annotate: the total content of the effective ingredient of total extract is not less than 25%
Concrete steps:
(1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
(2) Herba Artemisiae Scopariae extract is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Gardeniae extract and silybin meglumine are added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.
(3) and above-mentioned solution, benefit adds to the full amount of water for injection.
(4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
(5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
(6) through the microporous filter membrane fine straining of 0.45 μ m.
(7) clarity of inspection solution, the semi-finished product chemical examination.
(8) with the solution sealing by fusing in glass ampule.
(9) 100 ℃ of flowing steam sterilizations 30 minutes.
(10) while hot sample being put into 0.01% methylene blue solution hunts leak.
(11) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 6 water mattress Cape jasmine compositions sodium chloride transfusion
Prescription one:
Silybin meglumine 50g
Herba Artemisiae Scopariae extract 60g (being equivalent to crude drug 3000g)
Fructus Gardeniae extract 16g (being equivalent to crude drug 800g)
Polyoxyethylene sorbitan monoleate 15g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription two:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 60g (being equivalent to crude drug 3000g)
Fructus Gardeniae extract 16g (being equivalent to crude drug 800g)
Polyoxyethylene sorbitan monoleate 20g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription three:
Silybin meglumine 200g
Herba Artemisiae Scopariae extract 60g (being equivalent to crude drug 3000g)
Fructus Gardeniae extract 16g (being equivalent to crude drug 8000g)
Polyoxyethylene sorbitan monoleate 30g
Sodium chloride 900g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Annotate: the total content of the effective ingredient of total extract is not less than 25%
Concrete steps:
(1) handles the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
(2) Herba Artemisiae Scopariae extract is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Gardeniae extract and silybin meglumine are added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.With sodium chloride with an amount of water for injection dissolving fully, merge above-mentioned solution, benefit adds to the full amount of water for injection.
(3) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
(4) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
(5) through the microporous filter membrane fine straining of 0.45 μ m.
(6) clarity of inspection solution, the semi-finished product chemical examination.
(7) fill is in the infusion bottle of 100ml.
(8) 115 ℃ of pressure sterilizings 30 minutes.
(9) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 7 water mattress Cape jasmine compositions glucose infusion liquids
Prescription one:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 30g (being equivalent to crude drug 1500g)
Fructus Gardeniae extract 32g (being equivalent to crude drug 1600g)
Polyoxyethylene sorbitan monoleate 20g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription two:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 60g (being equivalent to crude drug 3000g)
Fructus Gardeniae extract 32g (being equivalent to crude drug 1600g)
Polyoxyethylene sorbitan monoleate 25g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Prescription three:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 120g (being equivalent to crude drug 4000g)
Fructus Gardeniae extract 32g (being equivalent to crude drug 1600g)
Polyoxyethylene sorbitan monoleate 30g
Glucose 5000g
Water for injection adds to 100000ml
Prepare 1000 bottles altogether
Annotate: the total content of the effective ingredient of total extract is not less than 25%
Concrete steps:
(1) carries and handle the previous day such as pipeline that dosing uses and container etc., face with the fresh water for injection flushing of preceding reuse.
(2) Herba Artemisiae Scopariae extract is added in the water for injection of dosing amount 30% the heated and stirred dissolving fully.Fructus Gardeniae extract and silybin meglumine are added a small amount of water for injection, add the polyoxyethylene sorbitan monoleate heated and stirred dissolving of recipe quantity.Merge above-mentioned solution, benefit adds to the full amount of water for injection.Glucose is complete with the water for injection dissolving of dosing amount 40%, heated and boiled 15 minutes.
(3) merge above-mentioned solution, benefit adds to the full amount of water for injection.
(4) needle-use activated carbon of adding dosing amount 0.1%, heated and stirred 15 minutes.
(5) through sand filtration rod filtering decarbonization.Measure the also pH value of regulator solution.
(6) through the microporous filter membrane fine straining of 0.45 μ m.
(7) clarity of inspection solution, the semi-finished product chemical examination.
(8) fill is in the infusion bottle of 100ml.
(9) 115 ℃ of pressure sterilizings 30 minutes.
(10) lamp inspection, finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 8 water mattress Cape jasmine composition tablets
Prescription:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 120g
Fructus Gardeniae extract 64g
Starch 45.0g
Microcrystalline Cellulose 45.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 8.0g
Carboxymethylstach sodium 15.0g
Prepare 1000 altogether
Annotate: the total content of the effective ingredient of total extract is not less than 25%
Concrete steps:
(1) it is standby Herba Artemisiae Scopariae extract, silybin meglumine and Fructus Gardeniae extract pulverize separately to be crossed 100 mesh sieves.
(2) take by weighing raw material and adjuvant according to recipe quantity.
(3) hypromellose 2% the aqueous solution made soluble in water is standby.
(4) with silybin meglumine, Fructus Gardeniae extract, Herba Artemisiae Scopariae extract, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
(5) 20 mesh sieve system granules.
(6) granule is dried under 60 ℃ condition.
(7) dry good granule adds magnesium stearate and carboxymethylstach sodium, crosses 18 mesh sieve granulate, mix homogeneously.
(8) sampling, the semi-finished product chemical examination.
(9) the sheet weight sheet of determining according to chemical examination.
(10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 9 water mattress Cape jasmine composition capsules
Prescription one:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 60g
Fructus Gardeniae extract 32g
Starch 20.0g
Microcrystalline Cellulose 60.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 5.0g
Prepare 1000 altogether
Prescription two:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 120g
Fructus Gardeniae extract 64g
Starch 25.0g
Microcrystalline Cellulose 70.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 8.0g
Prepare 1000 altogether
Prescription three:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 240g
Fructus Gardeniae extract 128g
Starch 35.0g
Microcrystalline Cellulose 80.0g
The 2%HPMC aqueous solution is an amount of
Magnesium stearate 10.0g
Prepare 1000 altogether
Annotate: the total content of the effective ingredient of total extract is not less than 25%
Concrete steps:
(1) it is standby Herba Artemisiae Scopariae extract, silybin meglumine and Fructus Gardeniae extract pulverize separately to be crossed 100 mesh sieves.
(2) take by weighing raw material and adjuvant according to recipe quantity.
(3) hypromellose 2% the aqueous solution made soluble in water is standby.
(4) with silybin meglumine, Fructus Gardeniae extract, Herba Artemisiae Scopariae extract, starch, microcrystalline Cellulose mix homogeneously, adding 2%HPMC aqueous solution is an amount of, stirs, and makes suitable soft material.
(5) cross 20 mesh sieve system granules.
(6) granule is dried under 60 ℃ condition.
(7) dry good granule adds magnesium stearate, crosses 18 mesh sieve granulate, mix homogeneously.
(8) sampling, the semi-finished product chemical examination.
(9) loading amount of determining according to chemical examination incapsulates.
(10) finished product is examined entirely, the packing warehouse-in.
The preparation of embodiment 10 water mattress Cape jasmine composition granules
Prescription one:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 60g
Fructus Gardeniae extract 32g
Icing Sugar 500.0g
Dextrin 280
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000g altogether
Prescription two:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 120g
Fructus Gardeniae extract 64g
Icing Sugar 400.0g
Dextrin 200
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000g altogether
Prescription three:
Silybin meglumine 100g
Herba Artemisiae Scopariae extract 240g
Fructus Gardeniae extract 128g
Icing Sugar 300.0g
Dextrin 150
The 2%HPMC50% alcoholic solution is an amount of
Prepare 1000g altogether
Annotate: the total content of the effective ingredient of total extract is not less than 25%
Concrete steps:
(1) it is standby sucrose to be pulverized 100 mesh sieves.It is standby that Herba Artemisiae Scopariae extract, silybin meglumine and Fructus Gardeniae extract pulverize separately are crossed 100 mesh sieves.
(2) take by weighing raw material and adjuvant according to recipe quantity.
(3) the method mix homogeneously that Herba Artemisiae Scopariae extract, silybin meglumine, Fructus Gardeniae extract and Icing Sugar, dextrin are progressively increased with equivalent, adding 2%HPMC50% alcoholic solution is an amount of, stirs, and makes suitable soft material.
(4) 20 mesh sieve system granules.
(5) granule is dried under 60 ℃ condition.
(6) dried granule is crossed 18 mesh sieve granulate.
(7) sampling, the content of principal agent is determined loading amount in the semi-finished product chemical examination granule.
(8) packing, finished product is examined entirely, the packing warehouse-in.

Claims (9)

1. pharmaceutical composition for the treatment of hepatic disease, it is characterized in that, the crude drug of making its contained composition and effectiveness is silybin meglumine, Herba Artemisiae Scopariae and Fructus Gardeniae, and its parts by weight are: 25～400 parts of silybin meglumines, 750～16000 parts of Herba Artemisiae Scopariaes, 400～6500 parts of Fructus Gardeniaes.
2. pharmaceutical composition as claimed in claim 1 is characterized in that, the parts by weight of crude drug are: 50～200 parts of silybin meglumines, 1500～8000 parts of Herba Artemisiae Scopariaes, 800～3200 parts of Fructus Gardeniaes.
3. pharmaceutical composition as claimed in claim 2 is characterized in that, the parts by weight of crude drug are: 100 parts of silybin meglumines, 3000～4000 parts of Herba Artemisiae Scopariaes, 1600 parts of Fructus Gardeniaes.
4. as the described preparation of drug combination method of the arbitrary claim of claim 1～3, it is characterized in that, described Herba Artemisiae Scopariae, Fructus Gardeniae are with The suitable solvent respectively or mix through extracting processing and obtain its extract, total extract is made preparation with silybin meglumine and pharmaceutic adjuvant hybrid process again, and contained main effective ingredient is total flavones and total glycosides in the gained total extract.
5. pharmaceutical composition for the treatment of hepatic disease, it is characterized in that, this pharmaceutical composition is made by silybin meglumine, Herba Artemisiae Scopariae extract and Fructus Gardeniae extract, and its parts by weight are: 25～400 parts of silybin meglumines, 15～480 parts of Herba Artemisiae Scopariae extract, 8～260 parts of Fructus Gardeniae extracts.
6. pharmaceutical composition as claimed in claim 5 is characterized in that, its parts by weight are: 50～200 parts of silybin meglumines, 30～240 parts of Herba Artemisiae Scopariae extract, 16～128 parts of Fructus Gardeniae extracts.
7. pharmaceutical composition as claimed in claim 6 is characterized in that, its parts by weight are: 100 parts of silybin meglumines, 60～120 parts of Herba Artemisiae Scopariae extract, 32～64 parts of Fructus Gardeniae extracts.
8. as the described pharmaceutical composition of the arbitrary claim of claim 5～7, it is characterized in that Herba Artemisiae Scopariae extract wherein contains total flavones and is not less than 6%, Fructus Gardeniae extract contains total glycosides and is not less than 35%.
9. as claim 1～3, the described pharmaceutical composition of 5～7 arbitrary claim, it is characterized in that this pharmaceutical composition and mixing acceptable accessories are made clinically any or pharmaceutically acceptable dosage form.
CN2006101634739A 2005-12-05 2006-12-04 Medicinal composition of elutriate, virgate wormwood herb and and cape-jasmine Expired - Fee Related CN1981833B (en)

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Publication number Priority date Publication date Assignee Title
CN1466984A (en) * 2002-12-06 2004-01-14 贵州神奇制药有限公司 Medicine for treating hepatitis
CN1537582A (en) * 2003-04-15 2004-10-20 毛友昌 Shenqi Gankang granule contg. ginseng and ast4ragalus mongholicus for treating liver disease, and its prepn. method

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1466984A (en) * 2002-12-06 2004-01-14 贵州神奇制药有限公司 Medicine for treating hepatitis
CN1537582A (en) * 2003-04-15 2004-10-20 毛友昌 Shenqi Gankang granule contg. ginseng and ast4ragalus mongholicus for treating liver disease, and its prepn. method

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