CN101244059B - Compound silibinin injection, preparation method and application thereof - Google Patents
Compound silibinin injection, preparation method and application thereof Download PDFInfo
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- CN101244059B CN101244059B CN2008100843007A CN200810084300A CN101244059B CN 101244059 B CN101244059 B CN 101244059B CN 2008100843007 A CN2008100843007 A CN 2008100843007A CN 200810084300 A CN200810084300 A CN 200810084300A CN 101244059 B CN101244059 B CN 101244059B
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Abstract
The invention relates to a compound silybin injection for curing liver diseases, a preparation method and the application. The preparation method is characterized in that: the injection comprises silybin, matrine compound and menstruum with polyethylene glycol; the silybin and the matrine compound are dissolved in the menstruum with polyethylene glycol into a solution and then the solution is made into an injection. The compound silybin injection has the advantages that, found by chance: besides the silybin and the matrine compound have the function of curing liver diseases concurrently, the matrine compound has the property of improving or increasing the solubility of the silybin, in particular the admixture of the silybin and the matrine compound has fine solubility in the menstruum with polyethylene glycol, and the solution can be made into the injections according with the requirement of clinical preparation.
Description
Technical field
The present invention relates to a kind of treat hepatic disease contain compound injection of silibinin and preparation method thereof.Belong to field of medicine preparations.
Background technology
Hepatic disease is a kind of frequently-occurring disease and commonly encountered diseases in China.Matrine, oxymatrine are alkaloid compound, and hepatitis virus and liver are had definite therapeutical effect, have been used for the treatment of acute, chronic hepatitis clinically.Silibinin (Silibinin) is a kind of flavone compound of extraction separation from Compositae Herba Silybi mariani fruit, is insoluble in water, and is easily molten in alkali liquor.It has hepatoprotective effect, clinically has been used for the treatment of acute or chronic hepatitis.Because the silibinin poorly water-soluble is prepared into it water soluble salt usually to be prepared into ejection preparation, has certain side effect.
Summary of the invention
Be to solve the defective that Silybinin injection exists in the prior art, the object of the present invention is to provide a kind of bioavailability high, have no side effect and preparation compound silibinin injection and its production and application easily.
The invention provides a kind of compound silibinin injection, it comprises silibinin, matrine compound and contains the Polyethylene Glycol solvent, it is characterized in that silibinin and matrine compound be dissolved in containing making injection again after the Polyethylene Glycol solvent becomes solution.
Above-mentioned described compound silibinin injection, wherein said matrine compound can be matrine, oxymatrine, sophor-anol, dehydrogenation matrine etc., the present invention preferably uses matrine and/or oxymatrine, more preferably matrine.
Above-mentioned described compound silibinin injection, wherein said Polyethylene Glycol is selected from one or more in Macrogol 200, Liquid Macrogol, PEG400 and the Macrogol 600.
Described compound injection is not particularly limited the proportioning of these two kinds of active ingredients.The present invention is unexpected to find that matrine can improve or improve silibinin dissolubility, the particularly dissolubility in containing the Polyethylene Glycol solvent, and the consumption of increase matrine compound can increase the dissolubility of silibinin.As preferably, the proportioning between described matrine compound and the silibinin is by weight calculating more than or equal to 1/5.Further, the proportioning between preferred described silibinin and the matrine compound is 1～5: 1～25 by weight calculating, and most preferably is 1: 2.
Solvent of the present invention comprises Polyethylene Glycol at least, and described Polyethylene Glycol is selected from one or more in Macrogol 200, Liquid Macrogol, PEG400 and the Macrogol 600.Described solvent can also comprise other organic solvents simultaneously again, for example comprises in water, propylene glycol, glycerol or the ethanol one or more.
If desired, can also comprise adjuvants such as osmotic pressure regulator, pH regulator agent in the injection of the present invention.Wherein, contain one or more the adjuvant that is selected from sodium chloride, mannitol, glycine, sorbitol, lactose, xylitol, dextran, inositol, glucosan, the glucose in the preferred described injection.
The present invention also provides a kind of method for preparing described compound silibinin injection, it is characterized in that comprising silibinin and matrine compound be dissolved in containing the step that the Polyethylene Glycol solvent becomes solution.
As one of specific embodiment, preparation method of the present invention comprises the steps:
(1), is dissolved into solution with containing the Polyethylene Glycol solvent with silibinin and matrine or oxymatrine mix homogeneously;
(2) water for injection and/or other adjuvant will be added in step (1) the gained solution;
(3) step (2) gained solution is made intermediate through membrane filtration;
(4) step (3) gained intermediate is added an amount of water for injection standardize solution, packing, sterilization, packing gets product.
Wherein, the preparation method of above-mentioned described compound silibinin injection, described adjuvant can be selected from one or more in sodium chloride, mannitol, glycine, sorbitol, lactose, xylitol, dextran, inositol, glucosan, the glucose.
Silibinin is because poorly soluble, not only oral silibinin bioavailability is lower, and need it is prepared into water soluble salt during preparation silibinin ejection preparation in the prior art, silybin-N-methylglucamine etc. for example, perhaps by transferring pH value to increase dissolubility, not only side effect is bigger, and complex process.The present invention is surprised to find that, silibinin and matrine compound, during as oxymatrine or matrine use in conjunction except having the effect of Synergistic treatment hepatic disease, matrine compound also has improvement or improves silibinin dissolubility performance, especially silibinin and matrine compound mixture have good dissolubility in containing the Polyethylene Glycol solvent, can make the injection that meets the clinical preparation requirement.Thereby the present invention has solved the problem that silibinin is difficult to make injection well, can reach the requirement of injection fully, and has no side effect.
1. dissolubility test:
Silibinin, silibinin and oxymatrine, silibinin and the matrine dissolubility in different solvent media (Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, propylene glycol, glycerol, ethanol or water) are investigated in this test.Result of the test sees Table 1.
Table 1 silibinin dissolubility test is dissolubility (mg/ml) as a result
Above presentation of results, the mixture favorable solubility of Macrogol 200,300,400 or 600 pairs of silibinin, silibinin and matrines or oxymatrine.The compositions of silibinin and matrine or oxymatrine can obviously improve the dissolubility of silibinin in Polyethylene Glycol.
2. dosing test:
One, silibinin dosing test: every of following solution is prepared 3 parts, add 100,200 respectively, the 500ml normal saline observes and place observation in 12 hours.
(1): the Macrogol 200 solution 1ml of 60mg/ml silibinin.
(2): (1)+4ml dehydrated alcohol mixing.
(3): (1)+4ml propylene glycol (glycerol) mixing.
(4): (1)+4ml PEG400+5ml dehydrated alcohol mixing.
(5): (1)+4ml Liquid Macrogol+3ml propylene glycol mixing.
(6): (1)+4ml Macrogol 600+5ml glycerol mixing.
Result of the test shows all have milky white precipitate to separate out immediately during the dosing dissolving, shakes up the back milky white precipitate and does not disappear, and crosses 12 hours observation milky white precipitates and does not still disappear.Illustrate: though silibinin dissolubility in Macrogol 200,300,400,600 is better, dosing still can not be satisfied the requirement of injection, can't make injection with bibliographical information and conform to.
Two, silibinin and the dosing of oxymatrine compositions test: every of following solution is prepared 3 parts, add 100,200 respectively, the 500ml normal saline observes and place observation in 12 hours.
Silibinin and oxymatrine part by weight are respectively: 1: 2
(1): (content of silibinin still is the Macrogol 200 solution 1ml of total amount 90mg/ml and oxymatrine compositions: 60mg/ml).
(2): (1)+4ml dehydrated alcohol mixing.
(3): (1)+4ml propylene glycol (glycerol) mixing.
(4): (1)+4ml PEG400+5ml dehydrated alcohol mixing.
(5): (1)+4ml Liquid Macrogol+3ml propylene glycol mixing.
(6): (1)+4ml Macrogol 600+5ml glycerol mixing.
Result of the test:
Be dissolved in 100ml respectively: all clarify during above solution dosing, shake up back solution and also clarify, place after 12 hours above solution and still clarify.
Be dissolved in 200ml respectively: all clarify during above solution dosing, shake up back solution and also clarify, place after 12 hours above solution and still clarify.
Be dissolved in 500ml respectively: all clarify during above solution dosing, shake up back solution and also clarify, place after 12 hours above solution and still clarify.
Three, silibinin and matrine part by weight are respectively: 1: 1
(1): (content of silibinin still is the Macrogol 200 solution 1ml of total amount 120mg/ml and matrine composition: 60mg/ml).
(2): (1)+4ml dehydrated alcohol mixing.
(3): (1)+4ml propylene glycol (glycerol) mixing.
(4): (1)+4ml PEG400+5ml dehydrated alcohol mixing.
(5): (1)+4ml Liquid Macrogol+3ml propylene glycol mixing.
(6): (1)+4ml Macrogol 600+5ml glycerol mixing.
Result of the test:
Be dissolved in 100ml respectively: all clarify during above solution dosing, shake up back solution and also clarify, placing after 12 hours above solution has a little precipitation separates out except that (1), and all the other solution are still clarified.
Be dissolved in 200ml respectively: all clarify during above solution dosing, shake up back solution and also clarify, place after 12 hours above solution and still clarify.
Be dissolved in 500ml respectively: all clarify during above solution dosing, shake up back solution and also clarify, place after 12 hours above solution and still clarify.
Indulge the above, use Polyethylene Glycol, solute effect was the most obvious when for example Macrogol 200,300,400 or 600 was made solvent, all can not meet the clarifying requirement of dosing as not adding Polyethylene Glycol during dosing, but the silibinin dosing is all undesirable separately.It is obvious to add matrine compound (as matrine or oxymatrine) increase silibinin dissolubility effect.
3. compound silibinin injection pharmacokinetics is estimated:
Animal: 12 of Kunming kind rats, male
Medicine: silibinin reference substance (Nat'l Pharmaceutical ﹠ Biological Products Control Institute); Silibinin capsule (the Jiangsu first sign Chinese closes pharmaceutical Co. Ltd, and specification is 35mg); Silibinin matrine injection (pressing embodiment 1 preparation).
Method:
(300 ± 20g) are divided into 2 groups at random, 6 every group, give the silibinin capsule respectively on an empty stomach with 12 rats; The tail vein is given the silibinin injection, and its dosage is 200mg/kg, fasting 12h before the administration, after the administration respectively at 5,15,30min, 1,2,4,6,8,12h gets whole blood 1.0mL, handle, the sample introduction analysis, result of the test is as shown in table 2.
Table 2 pharmacokinetics test result
| Pharmacokinetic parameters | The silibinin matrine injection | The silibinin capsule |
| AUC(h/μg/ml) | 28.46 | 9.58 |
| Tmax(min) | 5 | 30 |
| Cmax(μg/ml) | 19.36 | 4.15 |
| T1/2(Ke，h) | 3.369 | 3.457 |
Conclusion (of pressure testing) explanation: the silibinin matrine injection just reaches the blood drug level peak value when administration 5min, half-life and oral administration are basic identical, and the bioavailability of curve calculation under same dose is nearly 3 times of conventional capsule agent during by medicine.
4. the silibinin injection is to the preventive and therapeutic effect of rat non-alcoholic stellato-hepatitis
Animal: 40 of male SD rats, body weight 150～180g.
Medicine: cholesterol and sodium cholate, the oxytetracycline injection, TG, TC measure test kit, AST, ALT, MDA, SOD detection kit etc., silibinin capsule (the Jiangsu first sign Chinese closes pharmaceutical Co. Ltd, and specification is 35mg), silibinin matrine injection (pressing embodiment 1 preparation).
Method: with 40 of male SD rats after adaptability fed for 1 week.Be divided into 4 groups at random according to body weight: normal control group (A group), pathology matched group (B group), silibinin oral group of (C group), silibinin matrine injection group (D group), 10 every group.B, C and D group give high fat diet (being that normal diet adds Adeps Sus domestica 15%, cholesterol 2%, sodium cholate 0.5%, yolk powder 5%), and by 10mg/100g dosage lumbar injection oxytetracycline (every 1ml injection contains medicine 20mg).Administration was 1 time in per five days, and the C group gives the gastric infusion silibinin, 100mg/kg, and every day 1 time, the D group gives tail intravenously administrable silibinin matrine injection, 30mg/kg, every day 1 time.Other two groups gavage normal saline, 100mg/kg, every day 1 time.The A group gives normal diet and feeds, in the same time of B, C and D group injection oxytetracycline, in the normal saline lumbar injection of equal volume ratio.4 groups of beverages are tap water, freely drink.
Taking of specimen: 8 weekends of Drug therapy, the fasting 12h of all rats elder generation, the back of weighing with 20g/L nembutal solution 1mg/kg intraperitoneal injection anesthesia after, open behind the abdomen at first perusal liver situation, from the heart blood sampling, blood sampling centrifuging and taking serum in half an hour is to be checked.Get the same position 1cm * 1cm of leftlobe of liver * 1cm tissue and place formalin fixedly to treat pathological section, it is to be checked to get all the other hepatic tissues-70 ℃ preservation at last.Result of the test is shown in table 3,4 and 5.
Table 3 Serum ALT, TG, TC, MDA and SOD change
| Group | ALT(U/L) | TG(nmol/L) | TC(nmol/L) | MDA(nmol/L) | SOD(U/L) |
| A | 48.6±5.6 | 0.86±0.24 | 1.14±0.14 | 6.84±1.22 | 167.5±36.3 |
| B | 412.7±19.3 ** | 1.55±0.23 ** | 3.83±0.26 ** | 9.34±1.83 ** | 81.1±16.2 ** |
| C | 273.1±11.4 ** | 1.02±0.29 *△ | 1.76±0.18△△ | 7.15±1.35△ | 121.4±19.1 *△ |
| D | 274.2±10.6 ** | 1.03±0.35 *△ | 1.68±0.22△△ | 7.16±1.21△ | 126.3±15.9 *△ |
Compare with the A group
*P＜0.05,
*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with the B group.
The variation of TG, TeMDA, SOD content in table 4 liver tissues of rats
| Group | TG(mmol/L) | TC(mmol/L) | MDA(nmol/g prot) | SOD(U/g prot) |
| A | 1.23±0.22 | 1.58±0.26 | 2.79±0.92 | 78.12±11.25 |
| B | 5.53±1.24 ** | 3.22±1.17 ** | 4.11±1.42 ** | 41.26±7.66 ** |
| C | 3.47±1.28 **△ | 2.11±0.78△ | 3.51±1.08 *△ | 70.01±9.14△△ |
| D | 3.54±1.12 **△ | 1.95±0.65△ | 3.54±0.86 *△ | 73.51±10.25△△ |
Compare with the A group
*P＜0.05,
*P＜0.01; Compare △ P＜0.05, △ △ P＜0.01 with the B group.
The variation of table 5 rat liver PPARamRNA level
| Group | PPARa/GAPDH |
| A | 1.53±0.19 |
| B | 0.89±0.12 ** |
| C | 1.18±0.18 *△ |
| D | 1.21±0.16 *△ |
Compare with the A group
*P＜0.05,
*P＜0.01; Compare △ P＜0.05 with the B group
Conclusion: as can be seen from above data, the silibinin matrine injection is when administration 1/3rd oral dosage, can reduce disease Mus serum AST activity equally, lipid and MDA content in low serum and the hepatocyte, SOD activity improving, improve the expression of hepatocyte PPARot mRNA, improve the pathological change of non-alcoholic fatty liver disease.
Compound silibinin injection of the present invention, by with silibinin and matrine compound with after the solvent dissolving back that contains Polyethylene Glycol and normal saline the mixings dosing, place observation in 12 hours, solution is clarified, and illustrates that this injection and normal saline compatibility stablize.The present invention has solved the problem of silibinin poorly water-soluble cleverly, can reach the requirement of injection fully, and the Silybinin injection that is provided has the high advantage of bioavailability.
The specific embodiment
Below the present invention laid down a definition or illustrate by embodiment.
Embodiment 1
1. medicine is formed:
Matrine 30g
Silibinin 60g
Macrogol 200 5000ml
Water for injection is an amount of
Be configured to 10000ml
2. preparation method: get the recipe quantity Macrogol 200, will be in 60 ℃ by prescription uniform silibinin of mixed and the dissolving of matrine mixture, adding injection water 4000ml dissolving, is the membrane ultrafiltration of 3000-100000Dolton with the molecular weight that dams, and removes pyrogen, use 0.22 μ m membrane filtration degerming at last, add the injection water and be settled to 10000ml, 1000 of packing, sterilization, packing promptly gets injection silibinin finished product.
Embodiment 2
1. medicine is formed:
Matrine 60g
Silibinin 60g
PEG400 1000ml
Propylene glycol 500ml
Water for injection is an amount of
Be configured to 5000ml
2. preparation method: get the recipe quantity PEG400, in 60 ℃ will be by the dissolving of the prescription uniform silibinin of mixed and matrine mixture, it is even to add mixed with propylene glycol, adds injection water 3000ml dissolving, with the molecular weight that dams is the membrane ultrafiltration of 3000-100000Dolton, remove pyrogen, use 0.22 μ m membrane filtration degerming at last, add the injection water and be settled to 5000ml, 1000 of packing, sterilization, packing promptly gets injection silibinin finished product.
Embodiment 3
1. medicine is formed:
Matrine 120g
Silibinin 60g
Macrogol 600 500ml
Glycerol 1000ml
Dehydrated alcohol 50ml
Water for injection is an amount of
Be configured to 5000ml
2. preparation method: get the recipe quantity Macrogol 600, to add glycerol, dehydrated alcohol mix homogeneously by the dissolving of the prescription uniform silibinin of mixed and matrine mixture in 60 ℃, add injection water 3000ml dissolving, with the molecular weight that dams is the membrane ultrafiltration of 3000-100000Dolton, remove pyrogen, use 0.22 μ m membrane filtration degerming at last, add the injection water and be settled to 5000ml, 1000 of packing, sterilization, packing promptly gets injection silibinin finished product.
Embodiment 4
1. medicine is formed:
Oxymatrine 120g
Silibinin 60g
Liquid Macrogol 5000ml
Glycerol 2000ml
Dehydrated alcohol 500ml
Water for injection is an amount of
Be configured to 10000ml
2. preparation method: get the recipe quantity PEG400, to add glycerol, dehydrated alcohol mix homogeneously by the dissolving of the prescription uniform silibinin of mixed and oxymatrine mixture in 60 ℃, add injection water 2000ml dissolving, with the molecular weight that dams is the membrane ultrafiltration of 3000-100000Dolton, remove pyrogen, use 0.22 μ m membrane filtration degerming at last, add the injection water and be settled to 10000ml, 1000 of packing, sterilization, packing promptly gets injection silibinin finished product.
Embodiment 5
1. medicine is formed:
Oxymatrine 120g
Silibinin 60g
PEG400 10000ml
NaCl 2250g
Water for injection is an amount of
Be configured to 250000ml
2. preparation method: get the recipe quantity Macrogol 200, to add injection water 50000ml dissolved dilution by the dissolving of the prescription uniform silibinin of mixed and oxymatrine mixture in 60 ℃, and add sodium chloride again and make dissolving, with the molecular weight that dams is the membrane ultrafiltration of 3000-100000Dolton, remove pyrogen,, add the injection water and be settled to 250000ml with 0.22 μ m membrane filtration degerming, 1000 of packing, sterilization, packing promptly gets injection silibinin finished product.
Embodiment 6
1. medicine is formed:
Matrine 120g
Silibinin 60g
Liquid Macrogol 1000ml
Mannitol 240g
Water for injection is an amount of
Be configured to 5000ml
2. preparation method: get the recipe quantity PEG400, will be in 60 ℃ by prescription uniform silibinin of mixed and the dissolving of matrine mixture, it is even to add mixed with propylene glycol, add injection water 3000ml dissolving, add mannitol again, glycine makes dissolving, with the molecular weight that dams is the membrane ultrafiltration of 3000-100000Dolton, remove pyrogen, use 0.22 μ m membrane filtration degerming at last, add the injection water and be settled to 5000ml, 1000 of packing, pre-freeze is with dry, roll lid, get injection silibinin finished product.
Embodiment 7
1. medicine is formed:
Matrine 60g
Silibinin 60g
Macrogol 600 1000ml
Propylene glycol 500ml
Mannitol 240g
Glycine 50g
Water for injection is an amount of
Be configured to 5000ml
2. preparation method: get the recipe quantity Macrogol 600, will be in 60 ℃ by prescription uniform silibinin of mixed and the dissolving of matrine mixture, it is even to add mixed with propylene glycol, add injection water 3000ml dissolving, add mannitol again, glycine makes dissolving, with the molecular weight that dams is the membrane ultrafiltration of 3000-100000Dolton, remove pyrogen, use 0.22 μ m membrane filtration degerming at last, add the injection water and be settled to 5000ml, 1000 of packing, pre-freeze is with dry, roll lid, get injection silibinin finished product.
Embodiment 8
1. medicine is formed:
Matrine 12g
Silibinin 60g
PEG400 1500ml
Glycerol 500ml
Dehydrated alcohol 50ml
Water for injection is an amount of
Be configured to 5000ml
2. preparation method: get the recipe quantity PEG400, to add glycerol, dehydrated alcohol mix homogeneously by the dissolving of the prescription uniform silibinin of mixed and matrine mixture in 60 ℃, add injection water 7500ml dissolving, with the molecular weight that dams is the membrane ultrafiltration of 3000-100000Dolton, remove pyrogen, use 0.22 μ m membrane filtration degerming at last, add the injection water and be settled to 10000ml, 1000 of packing, sterilization, packing promptly gets injection silibinin finished product.
Embodiment 9
1. medicine is formed:
Matrine 300g
Silibinin 60g
Macrogol 200 500ml
Glycerol 500ml
Dehydrated alcohol 50ml
Water for injection is an amount of
Be configured to 5000ml
2. preparation method: get the recipe quantity Macrogol 200, to add glycerol, dehydrated alcohol mix homogeneously by the dissolving of the prescription uniform silibinin of mixed and matrine mixture in 60 ℃, add injection water 3000ml dissolving, with the molecular weight that dams is the membrane ultrafiltration of 3000-100000Dolton, remove pyrogen, use 0.22 μ m membrane filtration degerming at last, add the injection water and be settled to 5000ml, 1000 of packing, sterilization, packing promptly gets injection silibinin finished product.
Embodiment 9
1. medicine is formed:
Oxymatrine 600g
Silibinin 60g
Macrogol 600 500ml
Dehydrated alcohol 50ml
Water for injection is an amount of
Be configured to 5000ml
2. preparation method: get the recipe quantity Macrogol 200, to add the dehydrated alcohol mix homogeneously by the dissolving of the prescription uniform silibinin of mixed and matrine mixture in 60 ℃, add injection water 3000ml dissolving, with the molecular weight that dams is the membrane ultrafiltration of 3000-100000Dolton, remove pyrogen, use 0.22 μ m membrane filtration degerming at last, add the injection water and be settled to 5000ml, 1000 of packing, sterilization, packing promptly gets injection silibinin finished product.
The present invention is described according to preferred embodiment.Should be understood that the description of front and embodiment are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (8)
1. compound silibinin injection, the solvent that it comprises silibinin, matrine compound and contains Polyethylene Glycol, it is characterized in that silibinin and matrine compound be dissolved in and make injection again after the solvent that contains Polyethylene Glycol becomes solution, wherein said matrine compound is matrine or oxymatrine, described Polyethylene Glycol is selected from a kind of in Macrogol 200, Liquid Macrogol, PEG400 and the Macrogol 600, and the weight ratio between described matrine compound and the silibinin is 1～2: 1～2.
2. compound silibinin injection according to claim 1, wherein said matrine compound are matrine.
3. compound silibinin injection according to claim 1, the weight ratio between wherein said matrine compound and the silibinin are 1: 2.
4. according to each described compound silibinin injection of claim 1-3, also contain in water, ethanol, propylene glycol or the glycerol one or more in the wherein said solvent.
5. according to each described compound silibinin injection of claim 1-3, wherein also contain one or more the adjuvant that is selected from sodium chloride, mannitol, glycine, sorbitol, lactose, xylitol, dextran, inositol, glucosan, the glucose.
6. a method for preparing according to each described compound silibinin injection of claim 1-5 is characterized in that comprising silibinin and matrine compound are dissolved in the step that the solvent that contains Polyethylene Glycol becomes solution.
7. the preparation method of compound silibinin injection according to claim 6 comprises the steps:
(1), is dissolved into solution with containing the Polyethylene Glycol solvent with silibinin and matrine or oxymatrine mix homogeneously;
(2) water for injection and/or other adjuvant will be added in step (1) the gained solution;
(3) step (2) gained solution is made intermediate through membrane filtration;
(4) step (3) gained intermediate is added an amount of water for injection standardize solution, packing, sterilization, packing gets product.
8. the preparation method of compound silibinin injection according to claim 7, wherein said adjuvant is selected from one or more in sodium chloride, mannitol, glycine, sorbitol, lactose, xylitol, dextran, inositol, glucosan, the glucose.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1397277A (en) * | 2002-08-16 | 2003-02-19 | 广州瑞济生物技术有限公司 | Process for preapring silymanium injection |
| CN1400003A (en) * | 2002-08-16 | 2003-03-05 | 广州瑞济生物技术有限公司 | Medicine composition for curing hepatitis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1397277A (en) * | 2002-08-16 | 2003-02-19 | 广州瑞济生物技术有限公司 | Process for preapring silymanium injection |
| CN1400003A (en) * | 2002-08-16 | 2003-03-05 | 广州瑞济生物技术有限公司 | Medicine composition for curing hepatitis |
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