CN106667998A - Method for preparing water-soluble silymarin - Google Patents
Method for preparing water-soluble silymarin Download PDFInfo
- Publication number
- CN106667998A CN106667998A CN201710074937.7A CN201710074937A CN106667998A CN 106667998 A CN106667998 A CN 106667998A CN 201710074937 A CN201710074937 A CN 201710074937A CN 106667998 A CN106667998 A CN 106667998A
- Authority
- CN
- China
- Prior art keywords
- silymarin
- parts
- meglumine
- glucose
- temperature
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- SEBFKMXJBCUCAI-UHFFFAOYSA-N NSC 227190 Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC=C(C=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-UHFFFAOYSA-N 0.000 title claims abstract description 59
- SEBFKMXJBCUCAI-HKTJVKLFSA-N silibinin Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-HKTJVKLFSA-N 0.000 title claims abstract description 57
- 235000017700 silymarin Nutrition 0.000 title claims abstract description 53
- 229960004245 silymarin Drugs 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 26
- 229960003194 meglumine Drugs 0.000 claims description 26
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 24
- 239000008103 glucose Substances 0.000 claims description 24
- 239000000047 product Substances 0.000 claims description 23
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 17
- 229930003268 Vitamin C Natural products 0.000 claims description 17
- 235000019154 vitamin C Nutrition 0.000 claims description 17
- 239000011718 vitamin C Substances 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 102000011759 adducin Human genes 0.000 claims description 2
- 108010076723 adducin Proteins 0.000 claims description 2
- 239000006184 cosolvent Substances 0.000 abstract description 9
- 230000002349 favourable effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 235000001727 glucose Nutrition 0.000 description 22
- 239000002904 solvent Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 6
- FDQAOULAVFHKBX-UHFFFAOYSA-N Isosilybin A Natural products C1=C(O)C(OC)=CC(C2C(OC3=CC(=CC=C3O2)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000014899 silybin Nutrition 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229930003944 flavone Natural products 0.000 description 3
- 235000011949 flavones Nutrition 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 3
- 235000010234 sodium benzoate Nutrition 0.000 description 3
- 239000004299 sodium benzoate Substances 0.000 description 3
- FDQAOULAVFHKBX-KMRPREKFSA-N (+)-Isosilybin A Natural products C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC(=CC=C3O2)[C@@H]2[C@@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-KMRPREKFSA-N 0.000 description 2
- FDQAOULAVFHKBX-HKTJVKLFSA-N (2r,3r)-3,5,7-trihydroxy-2-[(2r,3r)-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2,3-dihydrochromen-4-one Chemical compound C1=C(O)C(OC)=CC([C@@H]2[C@H](OC3=CC(=CC=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-HKTJVKLFSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 2
- KDMGQPNVTKUNHV-UHFFFAOYSA-N Isosilybin Natural products C1=C(O)C(OC)=CC=C1C1C(CO)OC2=CC=C(C3C(C(=O)C4=C(O)C=C(O)C=C4O3)O)C=C2O1 KDMGQPNVTKUNHV-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 2
- VLGROHBNWZUINI-UHFFFAOYSA-N Silybin Natural products COc1cc(ccc1O)C2OC3C=C(C=CC3OC2CO)C4Oc5cc(O)cc(O)c5C(=O)C4O VLGROHBNWZUINI-UHFFFAOYSA-N 0.000 description 2
- 241000320380 Silybum Species 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- -1 flavone lignan Chemical class 0.000 description 2
- 150000002213 flavones Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229920001993 poloxamer 188 Polymers 0.000 description 2
- 229940044519 poloxamer 188 Drugs 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 229950000628 silibinin Drugs 0.000 description 2
- 229940043175 silybin Drugs 0.000 description 2
- SEBFKMXJBCUCAI-WAABAYLZSA-N (2r,3r)-3,5,7-trihydroxy-2-[(2s,3s)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2,3-dihydrochromen-4-one Chemical compound C1=C(O)C(OC)=CC([C@H]2[C@@H](OC3=CC=C(C=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 SEBFKMXJBCUCAI-WAABAYLZSA-N 0.000 description 1
- YEDFEBOUHSBQBT-UHFFFAOYSA-N 2,3-dihydroflavon-3-ol Chemical compound O1C2=CC=CC=C2C(=O)C(O)C1C1=CC=CC=C1 YEDFEBOUHSBQBT-UHFFFAOYSA-N 0.000 description 1
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 241000189115 Catananche Species 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- CYGIJEJDYJOUAN-UHFFFAOYSA-N Isosilychristin Natural products C1=C(O)C(OC)=CC(C2C3C=C(C4C(C3=O)(O)OCC42)C2C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 CYGIJEJDYJOUAN-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 235000010841 Silybum marianum Nutrition 0.000 description 1
- RIAZZJBPJQWPIS-UHFFFAOYSA-N Silychristin Natural products COc1cc(ccc1O)C2OC3C(C=C(C=C3O)C4Oc5cc(O)cc(O)c5C(=O)C4O)C2CO RIAZZJBPJQWPIS-UHFFFAOYSA-N 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 229930003939 flavanonol Natural products 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 150000002304 glucoses Chemical class 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- FDQAOULAVFHKBX-DBMPWETRSA-N isosilybin Chemical compound C1=C(O)C(OC)=CC(C2C(OC3=CC(=CC=C3O2)[C@@H]2[C@H](C(=O)C3=C(O)C=C(O)C=C3O2)O)CO)=C1 FDQAOULAVFHKBX-DBMPWETRSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229930013686 lignan Natural products 0.000 description 1
- 235000009408 lignans Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002995 phenylpropanoid derivatives Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- BMLIIPOXVWESJG-LMBCONBSSA-N silychristin Chemical compound C1=C(O)C(OC)=CC([C@H]2[C@@H](C3=C(C(=CC(=C3)[C@@H]3[C@H](C(=O)C4=C(O)C=C(O)C=C4O3)O)O)O2)CO)=C1 BMLIIPOXVWESJG-LMBCONBSSA-N 0.000 description 1
- BMLIIPOXVWESJG-UHFFFAOYSA-N silychristin A Natural products C1=C(O)C(OC)=CC(C2C(C3=C(C(=CC(=C3)C3C(C(=O)C4=C(O)C=C(O)C=C4O3)O)O)O2)CO)=C1 BMLIIPOXVWESJG-UHFFFAOYSA-N 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to water-soluble silymarin and a preparation method thereof. A more proper co-solvent type is selected, and a secondary synthesis method is adopted, so that the dissolubility and stability of a water-soluble silymarin product are greatly improved; the method is simple, easy and favorable for industrial production.
Description
Technical field
The present invention relates to the preparation method of water soluble silymarin.
Background technology
Silymarin (silmyarin) is from catananche's Herba Silybi mariani [silybum marinaum (L) Gaenrt]
The flavone lignan component that flavanonol obtained by extracting in fruit and seed is condensed with phenyl propanoid derivative,
Acetone, ethyl acetate, methanol and ethanol are dissolved in, chloroform is slightly soluble in, water is practically insoluble in.Substantial amounts of research shows silymarin-group
Compound has extensive pharmacologically active, is expanded to defying age, is prevented and treated atherosclerosiss etc. by prevention, treatment acute, chronic hepatitis
Aspect；Such as ksoottva have studied Herba Silybi mariani extract and mice Hangzhoupro hypercholesterolemia and LDL oxidation acted on, and recognize
For the ability that silymarin can improve anti-LDL；Feng Quan etc. causes Transient Forebrain Ischemia model to inquire into using four blood vessel blocking methods
The mechanism of Sematron on Cerebral Ischemia Damage protective effect, it is believed that silymarin can improve antioxidant ability of organism, lacks to brain
Blood is damaged significant protective effect.Be used in the world at present preparation silymarin (trade name Legalon, silybin and
Milk Thistle etc.) in total flavones lignanoid content be 80% or so, mainly contain silibinin (silybin,
Silibinin), Isosilybin (isosilybin, isosilibinin), Silychristin (siliehristin), Herba Silybi mariani
Peaceful (silidinain) four kinds of isomerss.
The water-fast characteristic of silymarin so as to be extremely restricted in application, make exist after preparation effectively into
Divide the defects such as dissolubility is low, bioavailability is low, medicine stability is poor, have a strong impact on the performance of efficacy of drugs.Therefore, existing skill
Art has been proposed for preparing the thinking of water soluble silymarin.Someone is synthesized silymarin and meglumine, is obtained water-soluble
Property silymarin product, 40% total flavones are generally comprised in product, solve silymarin it is water insoluble and affect biological utilisation
Problem, can preferably be dissolved in water, be readily absorbed by utilize, but, only introduce meglumine cosolvent be also the failure to obtain
Obtain gratifying water solublity and stability.On this basis, somebody proposes for silymarin meglumine to carry out cyclodextrin bag
Close, further to improve its water solublity；It has been proposed that to increase polyvinylpyrrolidone and pool Luo Samu on the basis of meglumine
Deng cosolvent, so as to obtain water solublity and the more preferable silymarin product of stability；Someone coordinates on the basis of meglumine to be made
Improve its water solublity and bioavailability with Polyethylene Glycol.Though the water soluble silymarin product in above-mentioned various schemes
So its water solublity is significantly improved for more former silymarin, but, the stability of its aqueous solution, clarity and water-soluble speed
Degree is still unsatisfactory, and portioned product occurs as soon as muddiness after being dissolved in water 30 minutes, and some products will be more than more than 15 minutes
Settled solution can be obtained.Therefore, the drawbacks described above for existing for water soluble silymarin in prior art and deficiency, it is of the invention
Purpose is to provide a kind of water soluble silymarin that dissolving is fast, bioavailability is high, stable and preparation method thereof.
The content of the invention
The invention provides a kind of preparation method of water soluble silymarin, comprises the following steps：
（1）Get the raw materials ready：Silymarin 5-8 parts, meglumine 2-3 parts, glucose 0.5-1 parts, vitamin C 1-2 parts；
（2）With 5-8 times of 95% ethanol dissolving silymarin measured of silymarin in synthesis tank so as to become settled solution；Add
Temperature is increased to 40-60 DEG C by the meglumine and glucose of half amount, stirring and evenly mixing under room temperature, continues to stir, and keeps 30-60
Minute；
（3）Filter, by filtrate Jing it is concentrated in vacuo for dry extract after, insert again in synthesis tank, add 95% ethanol dissolving, then add
Enter remaining meglumine, glucose, temperature is increased to 40-60 DEG C by stirring and evenly mixing under room temperature, continue to stir, kept for 30-60 point
Clock；After a small amount of water dissolution vitamin C, in adding synthesis tank, temperature is increased to into 80-90 DEG C, maintains 30-60 minutes；
（4）Filter, filtrate Jing membrane separations, lyophilization obtains water soluble silymarin product.
Wherein membrance separation can choose the filter membrane that membrane aperture is 0.15-0.25 microns and be filtered.
Present invention also offers by obtained in said method water soluble silymarin, water solublity is excellent, and dissolving is fast and stable.
It is known in the art that the third material of insoluble drug and addition to be formed in a solvent the network between shla molecule
Compound, associated complex or double salt etc., are conventional hydrotropy methods to increase medicine dissolubility in a solvent.Conventional cosolvent is main
It is divided into two big class：One class is some organic acid and its sodium salt, such as：Sodium benzoate, sodium salicylate, para-amino benzoic acid etc.；It is another
Class is amides compound, such as：Carbamide, nicotinic acid amide, acetamide etc..It is existing a large amount of for refractory components silymarin
Research confirms that meglumine can cross hydrogen bonded into stable compound with silymarin, and the compound water soluble is good, together
When, meglumine is entered after human body, not only can not affect the physiologically active of silymarin directly by kidney degraded heel row except external,
It is simultaneously also nonirritant to human body, it is the good cosolvent of silymarin.But, meglumine silymarin there is also dissolving it is slow,
The unstable shortcoming of dissolving rear solution, therefore, in order to obtain more preferable water miscible silymarin product, research worker continues
Other cosolvents are added on the basis of meglumine silymarin, to obtaining more preferable effect.The present inventor is also thus, substantial amounts of
In trial, inventors be surprised to learn that and add a small amount of glucose, the more excellent silymarin product of performance can be obtained, and pass through
The method of secondary synthesis, cooperation is ascorbic to be used, and the water soluble silymarin product for obtaining can be completely dissolved in 2 minutes,
And place under room temperature remain within one week keep clarification.Its concrete mechanism is unclear, inventor's conjecture, meglumine be by glucose and
Monomethyl amine N- methyl-D-glucarnines made by Jing catalytic hydrogenation reactions in ethanol solution, it can be formed easily with silymarin
The complex of water is dissolved in, and glucose possesses the group similar with meglumine, it can play the effect similar to meglumine.But
It is that inventor is, it was also found that glucose itself can not be separately as the cosolvent of silymarin, and its consumption is only capable of certain
In the range of play the effect of auxiliary.
Present inventor has carried out lot of experiments, and because needing the factor of consideration too many, and screening process is repeatedly, under
Text provide only the experimental result of part, it was demonstrated that different cosolvents are on the water miscible effect of silymarin and impact.
Experiment material：Silymarin, ethanol, meglumine, glucose, PVP, PEG200, sodium benzoate, Poloxamer 188
Experimental technique：
The inventive method 1：The method of embodiment 1, obtains product 1.
Method 2：6 parts of silymarin, 2 parts of meglumines, 0.5 part of glucose, 1 part of vitamin C are stirred in synthesis tank, temperature
Degree is increased to 60 DEG C, maintains 1 minute, filters, and membrane separation, lyophilization obtains product 2.
Method 3：With " 2 parts of meglumines, 0.5 part of glucose, 1 part of vitamin C " in 3.5 parts of meglumine replacement methods 2, its
Remaining same method 2, obtains product 3.
Method 4：With " the 2 parts of Portugal's first in " 3 parts of meglumines, 1.4 parts of PVP, 0.6 part of Poloxamer 188 " replacement method 2
Amine, 0.5 part of glucose, 1 part of vitamin C ", remaining obtains product 4 with method 2.
Method 5：With in " 2 parts of meglumines, 1.5 parts of PEG200 " replacement method 2 " 2 parts of meglumines, 0.5 part of glucose, 1
Part vitamin C ", remaining obtains product 5 with method 2.
Method 6：With " 2 portions of meglumines, 0.5 portion of Fructus Vitis viniferae in " 2 parts of meglumines, 1.5 parts of sodium benzoate " replacement method 2
Sugar, 1 part of vitamin C ", remaining obtains product 6 with method 2.
Method 7：With in " 2 parts of meglumines, 1.5 parts of glucoses " replacement method 1 " 2 parts of meglumines, 0.5 part of glucose, 1
Part vitamin C ", vitamin C step is removed, and obtains product 7.
Method 8：With in " 2 parts of meglumines, 1 part of vitamin C " replacement method 1 " 2 parts of meglumines, 0.5 part of glucose, 1 part
Vitamin C ", glucose step is removed, and obtains product 8.
Detection method：The detection method of medicine solubility property is carried out according to 2010 editions pharmacopeia, weighs the said goods 1-8 each
1g, in being placed in the distilled water of 25 DEG C ± 2 DEG C of certain capacity, every 1min strength shaking 30s, the dissolving feelings observed in 30min
Condition.
Dissolubility criterion is：
Easily dissolve：Mean that solute 1g (ml) can dissolve in solvent is less than 1ml；
It is readily soluble：Mean that solute 1g (ml) can dissolve in solvent 1~less than 10ml；
Dissolving：Mean that solute 1g (ml) can dissolve in solvent 10~less than 30ml；
It is slightly molten：Mean that solute 1g (ml) can dissolve in solvent 30~less than 100ml；
Slightly soluble：Mean that solute lg (ml) can dissolve in solvent 100~less than 1000ml；
Soluble,very slightly：Mean that solute 1g (ml) can dissolve in solvent 1000~less than 10 000ml；
It is almost insoluble or insoluble：Mean that solute 1g (ml) can not be completely dissolved in the 000ml of solvent 10.
Stability criterion is：
It is extremely stable：72 hours without substantially muddy；
It is more stable：24 hours without substantially muddy；
Typically：Occur within 1 hour muddy；
It is poor：Occur after 30 minutes muddy；
Extreme difference：Occur after 5 minutes muddy.
As a result it is as shown in the table.
As can be seen here, the cosolvent species that the present invention is more suitable for by selection, and the method for employing secondary synthesis, greatly
The solubility property and stability that improve water soluble silymarin product, and the inventive method is simple, beneficial to industry
Change big production.
Specific embodiment
The present invention is illustrated in more detail with reference to detailed description below.
Embodiment 1
Get the raw materials ready silymarin 60kg, meglumine 20kg, glucose 0.5kg, vitamin C 1kg；Silymarin 6 is used in synthesis tank
Again the 95% ethanol dissolving silymarin of amount, becomes settled solution；The meglumine and glucose of half amount are added, is stirred under room temperature
Mix, temperature is increased to into 60 DEG C, continue to stir, kept for 50 minutes；Filter, by filtrate Jing it is concentrated in vacuo for dry extract after, then
It is secondary to insert in synthesis tank, the dissolving of 95% ethanol is added, remaining meglumine and glucose are added, stirring and evenly mixing under room temperature, by temperature
Degree is increased to 50 DEG C, continues to stir, and is kept for 60 minutes；After a small amount of water dissolution vitamin C, in adding synthesis tank, by temperature liter
Up to 90 DEG C, maintain 50 minutes；Filter, the filter membrane separating treatment of 0.20 micron of filtrate Jing, lyophilization obtains water solublity Herba Silybi mariani
Plain product 80kg.
Embodiment 2
Get the raw materials ready silymarin 50kg, meglumine 20kg, glucose 1kg, vitamin C 1.5kg；Silymarin 5 is used in synthesis tank
Again the 95% ethanol dissolving silymarin of amount, becomes settled solution；The meglumine and glucose of half amount are added, is stirred under room temperature
Mix, temperature is increased to into 60 DEG C, continue to stir, kept for 60 minutes；Filter, by filtrate Jing it is concentrated in vacuo for dry extract after, then
It is secondary to insert in synthesis tank, the dissolving of 95% ethanol is added, remaining meglumine and glucose are added, stirring and evenly mixing under room temperature, by temperature
Degree is increased to 50 DEG C, continues to stir, and is kept for 60 minutes；After a small amount of water dissolution vitamin C, in adding synthesis tank, by temperature liter
Up to 90 DEG C, maintain 50 minutes；Filter, the filter membrane separating treatment of 0.25 micron of filtrate Jing, lyophilization obtains water solublity Herba Silybi mariani
Plain product 70kg.
Claims (3)
1. a kind of preparation method of water soluble silymarin, comprises the following steps：
（1）Get the raw materials ready：Silymarin 5-8 parts, meglumine 2-3 parts, glucose 0.5-1 parts, vitamin C 1-2 parts；
（2）With 5-8 times of 95% ethanol dissolving silymarin measured of silymarin in synthesis tank so as to become settled solution；Add
Temperature is increased to 40-60 DEG C by the meglumine and glucose of half amount, stirring and evenly mixing under room temperature, continues to stir, and keeps 30-60
Minute；
（3）Filter, by filtrate Jing it is concentrated in vacuo for dry extract after, insert again in synthesis tank, add 95% ethanol dissolving, then add
Enter remaining meglumine, glucose, temperature is increased to 40-60 DEG C by stirring and evenly mixing under room temperature, continue to stir, kept for 30-60 point
Clock；After a small amount of water dissolution vitamin C, in adding synthesis tank, temperature is increased to into 80-90 DEG C, maintains 30-60 minutes；
（4）Filter, filtrate Jing membrane separations, lyophilization obtains water soluble silymarin product.
2. preparation method as claimed in claim 1, wherein membrance separation can choose the filter membrane that membrane aperture is 0.15-0.25 microns and enter
Row is filtered.
3. water soluble silymarin product obtained in the method as described in claim 1 and 2.
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| CN101810660A (en) * | 2009-12-31 | 2010-08-25 | 江苏健佳药业有限公司 | Water-soluble silymarin and preparation method thereof |
| CN102552358A (en) * | 2011-12-31 | 2012-07-11 | 沈阳药科大学 | Silymarin composition and preparation method thereof |
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| CN1565440A (en) * | 2003-07-10 | 2005-01-19 | 烟台同和医药科技有限公司 | Silymarin Methylglucamine clathrate compound and its preparation method |
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