CN101019859A - Water soluble silymarin and its prepn - Google Patents
Water soluble silymarin and its prepn Download PDFInfo
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- CN101019859A CN101019859A CNA2007100106129A CN200710010612A CN101019859A CN 101019859 A CN101019859 A CN 101019859A CN A2007100106129 A CNA2007100106129 A CN A2007100106129A CN 200710010612 A CN200710010612 A CN 200710010612A CN 101019859 A CN101019859 A CN 101019859A
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Abstract
The water soluble silymarin preparation consists of silymarin, meglumine, PVP and poloxamer. It is prepared through dissolving silymarin and cosolvent in ethanol, filtering, reflux reaction and concentrating to obtain extractum; drying to obtain dry paste; redissolving, vacuum concentrating to crystallize, suction filtering to obtain crystal; ethanol washing, suction filtering, re-crystallizing and drying to obtain crystal; crushing, mixing and packing to obtain the water soluble silymarin preparation. The present invention features high water solubility, high stability and high bioavailability.
Description
Technical field
The present invention relates to a kind of medicinal derivative and preparation method thereof, particularly relate to a kind of water soluble silymarin and preparation method thereof, belong to technical field of medicine synthesis.
Background technology
Silymarin is extraction separation and the lignin flavone compounds that obtains from Compositae Silybum plant Herba Silybi mariani fruit; have significant protection and stablize the liver plasma membrane effect; and can promote liver cell regeneration; the liver that various poisonous substances are caused damages protection and the therapeutical effect that has in various degree, and the Yiganling tablet of selling on the market is exactly the single preparations of ephedrine of silymarin.Because silymarin itself is the flavone compound that is insoluble in water, make the problem of aspects such as existing the dissolution that influences medicine and bioavailability behind the preparation, have a strong impact on the performance of efficacy of drugs.Also sell a kind of silybin meglumine tablets on the market, be isolated monomeric compound silibinin and the synthetic product of meglumine from silymarin, water soluble, help improving its oral administration biaavailability, but the less stable in water of silybin-N-methylglucamine is placed 30 minutes just muddinesses, people have carried out further research and development again for this reason, for example publication number is that the Chinese invention patent application 03138788.8 of CN1565440 has provided " a kind of silymarin meglumine clathrate and preparation method thereof ", it is characterized in that it is made up of following component: (consumption is a weight portion) silymarin meglumine 1-4, cyclodextrin (or cholic acid, starch, carbamide, glucosan) 2-5, water 25-200; Publication number is that the Chinese invention patent application 200410041363.6 of CN1594315 has also provided " a kind of new preparation process of Herba Silybi mariani extract meglumine salt ", it is characterized in that: be dissolved in Herba Silybi mariani extract and meglumine in the organic solvent respectively, again two solution are merged, stir, promptly generate the Herba Silybi mariani extract meglumine salt, filtration, drying, promptly; Described organic solvent is methanol, ethanol, isopropyl alcohol or ethyl acetate.That publication number is that the Chinese invention patent application 200510078724.9 of CN1875962 provides then is " prescription of silibinin-n-methylglucamine drop pills and preparation technology thereof ", the effective ingredient and the effective site that it is characterized in that it are made up of following components in weight percentage: 1～50 part of silybin-N-methylglucamine, 3～150 parts of Polyethylene Glycol.Though the silybin-N-methylglucamine that provides in the technique scheme can improve silymarin meglumine clathrate bioavailability, but its water solublity and stability still have necessity of further raising, also do not find the relevant report of water soluble silymarin as medicine on the market.
Summary of the invention
Purpose of the present invention just is to overcome the prior art above shortcomings, provide a kind of water solublity and stable better water-solubility silymarin and preparation method thereof, the prescription of this water soluble silymarin is to have increased cosolvents such as polyvinylpyrrolidone and poloxamer on the meglumine basis again, thereby make water solublity of the present invention and stability better, and have fast, the high aqueous solution of bioavailability long characteristics standing time of dissolving.
The technical solution that the present invention provides is: the component of this water soluble silymarin includes silymarin, meglumine, is characterized in also including polyvinylpyrrolidone (PVP) and poloxamer 188, and the parts by weight that each component adds are:
3～7 parts of silymarin, 1.5～3 parts of meglumines,
Polyvinylpyrrolidone (PVP) 0.5-1.5 part, 188 0.2～0.8 part of poloxamer.
The preparation method of this water soluble silymarin that the present invention provides is:
(1). dissolving
Silymarin is dropped in the synthesis tank, dissolve after-filtration fully with ethanol, each cosolvent dissolves after-filtration fully with ethanol, adds while hot to mix to few 30 minutes in the silymarin solution, and solution temperature is 70～80 ℃ in jar;
(2). reaction
Stirred the back back flow reaction at least 30 minutes, the temperature of backflow is 70～80 ℃;
(3). reclaim solvent
Reaction obtains fluid extract with the solvent vacuum concentration in the synthesis tank after finishing, and temperature is 55～65 ℃, and vacuum is-0.04---0.06Mpa;
(4). fluid extract is put into drying chamber preheating at least 30 minutes under 70-75 ℃ of temperature, and the beginning evacuation reaches in vacuum-0.09Mpa, begins drying temperature 60-65 ℃ the time in jar and obtains dry extract at least after 3 hours;
(5). heavy molten
The dry extract that obtains is put in the synthesis tank again, added ethanol once more and make it to dissolve fully after-filtration, solution temperature is 70～80 ℃ in jar;
(6). reclaim solvent
To crystallization occurring, temperature is 55～65 ℃ with the solvent vacuum concentration in the synthesis tank, and vacuum is-0.06Mpa;
(7). crystallization
When having crystallization to occur in the solvent in to be synthesized jar, stop to concentrate, put into crystallizing tank crystallization 24 hours at least;
(8). sucking filtration
After the crystallization 24 hours, sucking filtration jar sucking filtration is put in crystallization, obtained crystalline solid after liquid pumps, add the ethanol of 1～2 times of amount of crystalline solid again, washing, sucking filtration;
(9). the crystalline solid drying
To obtain crystalline solid once more and put into drying chamber, preheating is 25～35 minutes under 70-75 ℃ of temperature, the beginning evacuation, vacuum reaches-0.09Mpa, jar in began drying at least 3 hours temperature 60-65 ℃ the time, obtain the water soluble silymarin crystalline solid;
(10). pulverize, mix, pack
Water soluble silymarin crystalline solid to be pulverized sent in the pulverizer pulverize, the material after the pulverizing enters in the mixer and mixes, and promptly gets the water soluble silymarin finished product.
Each component and equipment of the present invention in the water soluble silymarin prescription that the present invention provides all can be purchased from the market.
The present invention is when selecting cosolvent for use, main is water solublity, the toxicological effect of considering them, and most importantly can they make silymarin arrive target cell smoothly at the intravital solubilization-aid effect of people, finish the hydrotropy effect, wherein the effect of each cosolvent in the prescription is:
1. meglumine
Be white crystalline powder; Odorless almost, it is little sweet to distinguish the flavor of, and is with salty and bitter; Meglumine shows alkalescence, slightly is dissolved in ethanol, methanol, and it can become stable salt with after silymarin combines, and their combination forms with the hydrogen bond stable bond.
After meglumine-silymarin combination, dielectric viscosity is very big when drying, forms solidfied material.
Meglumine is transparent in visible light and ultraviolet ray range, therefore can directly detect with visible light or ultraviolet light in assay and stripping experiment.
Meglumine is nontoxic, enter human body after, get rid of by kidney external, to the human body nonirritant.
2. poloxamer
Be a kind of macromolecule non-ionic surface active agent, its advantage is: as multiduty pharmaceutic adjuvant, its toxicity is low, and zest is little, is widely used in medical science, pharmaceutical field.Poloxamer is a kind of by novel nontoxic adjuvant that polyoxyethylene-the polyoxypropylene copolymerization forms, it is to skin mucosa nonirritant and anaphylaxis, can strengthen the dissolubility of insoluble drug, in addition, poloxamer also has temperature-sensitive sol-gel transition characteristic, is liquid when lower temperature, is soft gel near human body temperature the time, at muscle or the subcutaneous drug-reservoir that forms, drug slow is discharged absorb.Simultaneously, poloxamer has very strong emulsification to oils and fats, some oil solution emulsifyings can be formed O/W type Emulsion, has certain targeting.Particularly, can form O/W type Emulsion, strengthen the water-soluble effect of silymarin greatly, avoid the water insoluble and phenomenon that is difficult to absorb of silymarin with after silymarin combines.
3. polyvinylpyrrolidone (be called for short PVP)
It is a kind of synthesising macromolecule copolymer; its vinyl is chain and connects. and this product is white odorless, tasteless powder; easily moisture absorption; in water, ethanol, chloroform, isopropyl alcohol, dissolve; be insoluble to acetone and ether, have good dissolubility, biocompatibility, physiology inertia, film property, film body protective capability and with the compound ability of multiple organic and inorganic chemical compound, more stable to acid, salt and heat; pharmaceutical grade PVP pharmaceutically is being widely used, one of three big medicinal new adjuvants of advocating for the world.Most widely used is the binding agent of tablet, granule.PVP also can be used as capsular fluidizer, the detoxicant of medicament for the eyes and lubricant, the cosolvent of injection, the dispersant of liquid preparation, the stabilizing agent of enzyme and temperature-sensitive medicine.
Compared with prior art, beneficial effect of the present invention is:
1. water solublity improves, and 1 gram dissolves in the 10ml water.
2. stability improves, and the aqueous solution room temperature places that 48 hours solution is haze-free does not separate out.
3. hygroscopicity reduces, and humidity 65% is placed and gained in weight less than 0.1% in 24 hours.
Description of drawings
Accompanying drawing is a process chart of the present invention.
The specific embodiment
Now in conjunction with the accompanying drawings and embodiments the present invention is done further narration:
Embodiment 1
Earlier 3 kilograms of silymarin are dropped in the synthesis tank, dissolve after-filtration fully with ethanol, with 1.5 kilograms of meglumines, 0.7 kilogram of polyvinylpyrrolidone (PVP), 188 0.3 kilograms of poloxamers dissolve after-filtration fully with ethanol, add while hot to mix in the silymarin solution and stirred 30 minutes, solution temperature is 78 ℃ in jar, stirred the back back flow reaction 30 minutes, the temperature that refluxes is 78 ℃, after reaction finishes, solvent vacuum concentration in the synthesis tank is obtained 7.3 kilograms of fluid extracts, temperature is 60 ℃, vacuum is-0.05Mpa, again fluid extract is put into drying chamber preheating 30 minutes under 70-75 ℃ of temperature, the beginning evacuation, reach in vacuum-0.09Mpa, begin temperature 60-65 ℃ the time in jar to obtain 5.5 kilograms of water soluble silymarin dry extracts after dry 3 hours, again put into the water soluble silymarin dry extract that obtains in the synthesis tank, add ethanol once more and make it to dissolve fully after-filtration, amount of alcohol added is 10 times of dry extract amount, solution temperature is 78 ℃ in jar, with the solvent vacuum concentration in the synthesis tank to crystallization occurring, temperature is 60 ℃, vacuum is-0.06Mpa, when having crystallization to occur in the solvent in to be synthesized jar, stop to concentrate, put into the crystallizing tank crystallization 24 hours, after the crystallization 24 hours, crystal solution is put into sucking filtration jar sucking filtration, after pumping, crystal solution obtains filter cake, the ethanol that adds 1.5 times of amounts of filter cake again, washing, obtain filter cake again behind the sucking filtration once more, to obtain filter cake once more and put into drying chamber, preheating is 30 minutes under 70-75 ℃ of temperature, the beginning evacuation, vacuum reaches-0.09Mpa, began temperature 60-65 ℃ the time in jar dry 3 hours, and obtained 5.4 kilograms on water soluble silymarin crystalline solid, the water soluble silymarin crystalline solid sent in the pulverizer pulverize, material after the pulverizing enters in the mixer and mixes, and at last mixed material is packed, and sells as the water soluble silymarin finished product.
It is more than 98% that the water soluble silymarin that the present invention provides is produced yield, and product content is 40.5%, no matter is content, or dissolubility, all reach international level, its bioavailability is the several times of silymarin, thereby has reached the effect of effectively utilizing silymarin.
Embodiment 2
Earlier 5 kilograms of silymarin are dropped in the synthesis tank, dissolve after-filtration fully with ethanol, with 2 kilograms of meglumines, 1 kilogram of polyvinylpyrrolidone (PVP), 188 0.5 kilograms of poloxamers dissolve after-filtration fully with ethanol, add while hot to mix in the silymarin solution and stirred 30 minutes, solution temperature is 78 ℃ in jar, stirred the back back flow reaction 30 minutes, the temperature that refluxes is 78 ℃, after reaction finishes, solvent vacuum concentration in the synthesis tank is obtained 11.6 kilograms of fluid extracts, temperature is 60 ℃, vacuum is-0.05Mpa, again fluid extract is put into drying chamber preheating 30 minutes under 70-75 ℃ of temperature, the beginning evacuation, reach in vacuum-0.09Mpa, begin temperature 60-65 ℃ the time in jar to obtain 8.6 kilograms of water soluble silymarin dry extracts after dry 3 hours, again put into the water soluble silymarin dry extract that obtains in the synthesis tank, add ethanol once more and make it to dissolve fully after-filtration, amount of alcohol added is 10 times of dry extract amount, solution temperature is 78 ℃ in jar, with the solvent vacuum concentration in the synthesis tank to crystallization occurring, temperature is 60 ℃, vacuum is-0.06Mpa, when having crystallization to occur in the solvent in to be synthesized jar, stop to concentrate, put into the crystallizing tank crystallization 24 hours, after the crystallization 24 hours, crystal solution is put into sucking filtration jar sucking filtration, after pumping, crystal solution obtains filter cake, the ethanol that adds 1.5 times of amounts of filter cake again, washing, obtain filter cake again behind the sucking filtration once more, to obtain filter cake once more and put into drying chamber, preheating is 30 minutes under 70-75 ℃ of temperature, the beginning evacuation, vacuum reaches-0.09Mpa, began temperature 60-65 ℃ the time in jar dry 3 hours, obtain 8.4 kilograms on water soluble silymarin crystalline solid, the water soluble silymarin crystalline solid sent in the pulverizer pulverize, material after the pulverizing enters in the mixer by vacuum feeder and mixes, at last mixed material is packed, sold as the water soluble silymarin finished product.
It is more than 98% that the water soluble silymarin that the present invention provides is produced yield, and product content is 44.5%, no matter is content, or dissolubility, all reach international level, its bioavailability is the several times of silymarin, thereby has reached the effect of effectively utilizing silymarin.
Embodiment 3
Earlier 7 kilograms of silymarin are dropped in the synthesis tank, dissolve after-filtration fully with ethanol, with 3 kilograms of meglumines, 1.5 kilograms of polyvinylpyrrolidones (PVP), 188 0.8 kilograms of poloxamers dissolve after-filtration fully with ethanol, add while hot to mix in the silymarin solution and stirred 30 minutes, solution temperature is 78 ℃ in jar, stirred the back back flow reaction 30 minutes, the temperature that refluxes is 78 ℃, after reaction finishes, solvent vacuum concentration in the synthesis tank is obtained 16.5 kilograms of fluid extracts, temperature is 60 ℃, vacuum is-0.05Mpa, again fluid extract is put into drying chamber preheating 30 minutes under 70-75 ℃ of temperature, the beginning evacuation, reach in vacuum-0.09Mpa, begin temperature 60-65 ℃ the time in jar to obtain 12.5 kilograms of water soluble silymarin dry extracts after dry 3 hours, again put into the water soluble silymarin dry extract that obtains in the synthesis tank, add ethanol once more and make it to dissolve fully after-filtration, amount of alcohol added is 10 times of dry extract amount, solution temperature is 78 ℃ in jar, with the solvent vacuum concentration in the synthesis tank to crystallization occurring, temperature is 60 ℃, vacuum is-0.06Mpa, when having crystallization to occur in the solvent in to be synthesized jar, stop to concentrate, put into the crystallizing tank crystallization 24 hours, after the crystallization 24 hours, crystal solution is put into sucking filtration jar sucking filtration, after pumping, crystal solution obtains filter cake, the ethanol that adds 1.5 times of amounts of filter cake again, washing, obtain filter cake again behind the sucking filtration once more, to obtain filter cake once more and put into drying chamber, preheating is 30 minutes under 70-75 ℃ of temperature, the beginning evacuation, vacuum reaches-0.09Mpa, began temperature 60-65 ℃ the time in jar dry 3 hours, obtain 12.1 kilograms on the plain crystalline solid of water soluble silymarin, water solublity Herba Silybi mariani dry extract sent in the pulverizer pulverize, material after the pulverizing enters in the mixer by vacuum feeder and mixes, at last mixed material is packed, sold as the water soluble silymarin finished product.
It is more than 98% that the water soluble silymarin that the present invention provides is produced yield, and product content is 45.0%, no matter is content, or dissolubility, all reach international level, its bioavailability is the several times of silymarin, thereby has reached the effect of effectively utilizing silymarin.
Claims (2)
1. water soluble silymarin, its component includes silymarin, meglumine, it is characterized in that also including polyvinylpyrrolidone (PVP) and poloxamer 188, and the parts by weight that each component adds are:
3～7 parts of silymarin, 1.5～3 parts of meglumines,
Polyvinylpyrrolidone (PVP) 0.5-1.5 part,
188 0.2～0.8 part of poloxamer.
2. the method for preparing the described water soluble silymarin of claim 1 is characterized in that being made up of following steps:
(1). dissolving
Silymarin is dropped in the synthesis tank, dissolve after-filtration fully with ethanol, each cosolvent dissolves after-filtration fully with ethanol, adds while hot to mix to few 30 minutes in the silymarin solution, and solution temperature is 70～80 ℃ in jar;
(2). reaction
Stirred the back back flow reaction at least 30 minutes, the temperature of backflow is 70～80 ℃;
(3). reclaim solvent
Reaction obtains fluid extract with the solvent vacuum concentration in the synthesis tank after finishing, and temperature is 55～65 ℃, and vacuum is-0.04---0.06Mpa;
(4). fluid extract is put into drying chamber preheating at least 30 minutes under 70-75 ℃ of temperature, and the beginning evacuation reaches in vacuum-0.09Mpa, begins drying temperature 60-65 ℃ the time in jar and obtains dry extract at least after 3 hours;
(5). heavy molten
The dry extract that obtains is put in the synthesis tank again, added ethanol once more and make it to dissolve fully after-filtration, solution temperature is 70～80 ℃ in jar;
(6). reclaim solvent
To crystallization occurring, temperature is 55～65 ℃ with the solvent vacuum concentration in the synthesis tank, and vacuum is-0.06Mpa;
(7). crystallization
When having crystallization to occur in the solvent in to be synthesized jar, stop to concentrate, put into crystallizing tank crystallization 24 hours at least;
(8). sucking filtration
After the crystallization 24 hours, sucking filtration jar sucking filtration is put in crystallization, obtained crystalline solid after liquid pumps, add the ethanol of 1～2 times of amount of crystalline solid again, washing, sucking filtration;
(9). the crystalline solid drying
To obtain crystalline solid once more and put into drying chamber, preheating is 25～35 minutes under 70-75 ℃ of temperature, the beginning evacuation, vacuum reaches-0.09Mpa, jar in began drying at least 3 hours temperature 60-65 ℃ the time, obtain the water soluble silymarin crystalline solid;
(10). pulverize, mix, pack
Water soluble silymarin crystalline solid to be pulverized sent in the pulverizer pulverize, the material after the pulverizing enters in the mixer and mixes, and promptly gets the water soluble silymarin finished product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100106129A CN100542529C (en) | 2007-03-16 | 2007-03-16 | The water soluble silymarin composition and method of making the same |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100106129A CN100542529C (en) | 2007-03-16 | 2007-03-16 | The water soluble silymarin composition and method of making the same |
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| Publication Number | Publication Date |
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| CN101019859A true CN101019859A (en) | 2007-08-22 |
| CN100542529C CN100542529C (en) | 2009-09-23 |
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| CNB2007100106129A Expired - Fee Related CN100542529C (en) | 2007-03-16 | 2007-03-16 | The water soluble silymarin composition and method of making the same |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552358A (en) * | 2011-12-31 | 2012-07-11 | 沈阳药科大学 | Silymarin composition and preparation method thereof |
| CN104906031A (en) * | 2014-03-11 | 2015-09-16 | 范永明 | Water-soluble silymarin oral liquid |
| CN106667998A (en) * | 2017-02-13 | 2017-05-17 | 内蒙古昶辉生物科技股份有限公司 | Method for preparing water-soluble silymarin |
| CN110022685A (en) * | 2017-02-14 | 2019-07-16 | 泰国组织工程和干细胞卓越中心 | For improving the water-soluble method of sesamin |
| CN110772447A (en) * | 2019-12-16 | 2020-02-11 | 江苏中兴药业有限公司 | Method for preparing silymarin skin care product |
-
2007
- 2007-03-16 CN CNB2007100106129A patent/CN100542529C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552358A (en) * | 2011-12-31 | 2012-07-11 | 沈阳药科大学 | Silymarin composition and preparation method thereof |
| CN102552358B (en) * | 2011-12-31 | 2015-06-24 | 沈阳药科大学 | Silymarin composition and preparation method thereof |
| CN104906031A (en) * | 2014-03-11 | 2015-09-16 | 范永明 | Water-soluble silymarin oral liquid |
| CN106667998A (en) * | 2017-02-13 | 2017-05-17 | 内蒙古昶辉生物科技股份有限公司 | Method for preparing water-soluble silymarin |
| CN110022685A (en) * | 2017-02-14 | 2019-07-16 | 泰国组织工程和干细胞卓越中心 | For improving the water-soluble method of sesamin |
| CN110772447A (en) * | 2019-12-16 | 2020-02-11 | 江苏中兴药业有限公司 | Method for preparing silymarin skin care product |
| CN110772447B (en) * | 2019-12-16 | 2022-05-03 | 江苏中兴药业有限公司 | Method for preparing silymarin skin care product |
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| Publication number | Publication date |
|---|---|
| CN100542529C (en) | 2009-09-23 |
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Assignee: Panjin Tianyuan Pharmaceutical Co., Ltd. Assignor: Li Bao Contract record no.: 2012210000046 Denomination of invention: Water soluble silymarin composition and its preparation method Granted publication date: 20090923 License type: Exclusive License Open date: 20070822 Record date: 20120315 |
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Granted publication date: 20090923 Termination date: 20160316 |