CN103462975A - Inclusion compound of mangiferin and alkaline cyclodextrin - Google Patents
Inclusion compound of mangiferin and alkaline cyclodextrin Download PDFInfo
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- CN103462975A CN103462975A CN2013104361517A CN201310436151A CN103462975A CN 103462975 A CN103462975 A CN 103462975A CN 2013104361517 A CN2013104361517 A CN 2013104361517A CN 201310436151 A CN201310436151 A CN 201310436151A CN 103462975 A CN103462975 A CN 103462975A
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- China
- Prior art keywords
- cyclodextrin
- chimonin
- alkaline
- mangiferin
- clathrate
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Links
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 82
- 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 title claims abstract description 71
- AEDDIBAIWPIIBD-ZJKJAXBQSA-N mangiferin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=C(OC=2C(=CC(O)=C(O)C=2)C2=O)C2=C1O AEDDIBAIWPIIBD-ZJKJAXBQSA-N 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 title abstract description 7
- YWQSXCGKJDUYTL-UHFFFAOYSA-N Mangiferin Natural products CC(CCC=C(C)C)C1CC(C)C2C3CCC4C(C)(C)CCCC45CC35CCC12C YWQSXCGKJDUYTL-UHFFFAOYSA-N 0.000 title abstract 5
- 229940043357 mangiferin Drugs 0.000 title abstract 5
- 239000009633 chimonin Substances 0.000 claims description 64
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 7
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 7
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 25
- 238000002360 preparation method Methods 0.000 abstract description 24
- 238000006243 chemical reaction Methods 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 14
- 239000000243 solution Substances 0.000 abstract description 11
- 239000007864 aqueous solution Substances 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000007788 liquid Substances 0.000 abstract description 5
- -1 amino-substituted cyclodextrin Chemical class 0.000 abstract description 3
- 230000003993 interaction Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000002585 base Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 125000003368 amide group Chemical group 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 230000006103 sulfonylation Effects 0.000 description 6
- 238000005694 sulfonylation reaction Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 3
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 3
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 description 1
- 241000208223 Anacardiaceae Species 0.000 description 1
- 241000605445 Anemarrhena asphodeloides Species 0.000 description 1
- 241000596154 Belamcanda Species 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 241000252983 Caecum Species 0.000 description 1
- 108010025880 Cyclomaltodextrin glucanotransferase Proteins 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 241001093152 Mangifera Species 0.000 description 1
- 240000007228 Mangifera indica Species 0.000 description 1
- 235000014826 Mangifera indica Nutrition 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- TZRXHJWUDPFEEY-UHFFFAOYSA-N Pentaerythritol Tetranitrate Chemical compound [O-][N+](=O)OCC(CO[N+]([O-])=O)(CO[N+]([O-])=O)CO[N+]([O-])=O TZRXHJWUDPFEEY-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- JVFGXECLSQXABC-UHFFFAOYSA-N ac1l3obq Chemical compound O1C(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(O)C2O)C(COCC(O)C)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC2C(O)C(O)C1OC2COCC(C)O JVFGXECLSQXABC-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003602 anti-herpes Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229950005162 benexate Drugs 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004534 cecum Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000753 hepatic injury Toxicity 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Abstract
The invention discloses an inclusion compound of mangiferin and alkaline cyclodextrin. The alkaline cyclodextrin in the inclusion compound is amino-substituted cyclodextrin, and the amino-substituted cyclodextrin forms ionic interaction with hydroxide radicals on the mangiferin under the condition that an alkaline environment is formed in an aqueous solution in addition to clathration of a cavity of the amino-substituted cyclodextrin and mangiferin molecules, so that the mangiferin forms a solution in water in a very wide concentration range so that the formation of a medicament of mangiferin liquid preparation is faciliated. The inclusion compound provided by the invention has high stability, good safety and solubility and high bioavailability, and a preparation method is simple and easy to operation, low in cost and mild in reaction condition, so that the inclusion compound is suitable for industrial production.
Description
Technical field
Invention relates to the pharmaceutical technology field, relates to specifically a kind of ionic drug chimonin and alkaline cyclodextrin clathrate and preparation method thereof.
Technical background
Chimonin is present in fruit, leaf, the bark of Anacardiaceae plant Fructus Mangifera Indicae (Mangifera indica L.), rhizome, the aerial parts of the liliaceous plant Rhizoma Anemarrhenae (Anemarrhena asphodeloides Bge.); In the plants such as the flower of irides Rhizoma Belamcandae [Belamcanda chinensis(L.) DC.], leaf, its molecular formula is C
19h
18o
11, relative molecular mass is 422.33, No. CAS: 4773-96-0, and its structural formula is:
The chimonin pharmacological function: this product has the central nervous system of inhibition, antiinflammatory, antibacterial, anti-herpes simplex virus, function of gallbladder promoting and immunization, and to the simulated high altitude acute hypoxia, hepatic injury has protective effect.Pharmacological evaluation shows, this product is used for the treatment of chronic bronchitis good therapeutic effect, is the main effective ingredient of ZANGYINCHEN treatment hepatitis, is antiviral active component in Asphodeloides Bge Rhizome.But chimonin dissolubility in water is very poor, and bioavailability is low, thus certain limitation its extensive use.Obtain through the cyclodextrin glycosyltransferase catalytic degradation and cyclodextrin is starch, passed through by D (+)-pyrans Glucopyranose.
αthe half-natural compound of-Isosorbide-5-Nitrae-glycosidic bond bonding ring formation, can form clathrate with multi-medicament, improves water solublity, stability and the bioavailability of medicine.
The Chinese patent that publication number is CN1977855A relates to chimonin cyclodextrin clathrate and preparation thereof.Wherein, cyclodextrin and derivant thereof comprise alpha-cyclodextrin, beta-schardinger dextrin-, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin.The Chinese patent that publication number is CN101019877A adopts HP-β-CD and chimonin to form the pharmaceutical composition containing clathrate.These clathrates to a certain extent, have improved chimonin dissolution rate and bioavailability, and being convenient to preparation becomes various dosage forms.But, these clathrates are limited to the solubilising degree of medicine chimonin, having limited this medicine preparation becomes liquid preparation (for example oral liquid and injection), and existing clathrate dissolubility in water in the time of 25 ℃ is that 10 ~ 35.99mg/mL(calculates with the amount of chimonin).
Summary of the invention
The object of the invention is to provide a kind of good water solubility, the chimonin that stability is high and the clathrate of alkaline cyclodextrin, the acquisition of clathrate has overcome the shortcomings such as chimonin is poorly soluble, bioavailability is low, increasing of preparation type for chimonin provides more support simultaneously, and clathrate is comprised of according to mol ratio 4:1-1:10 chimonin and alkaline cyclodextrin.
For realizing purpose of the present invention, the present invention adopts following technical scheme:
The cyclodextrin of studying morely (Cyclodextrin, be called for short CD) and what have important practical usage is the molecule that contains 6,7,8 glucose units, be called α-, β-and gamma-cyclodextrin.According to the result of X-line crystal diffraction, infrared spectrum and spectral analysis of the nuclear magnetic resonance, each D (+)-Glucopyranose. that determine to form cyclodextrin molecular is chair conformation, each glucose unit all with α-Isosorbide-5-Nitrae-glycosidic bond in conjunction with ring formation.Because the glycosidic bond that connects glucose unit can not rotate freely, cyclodextrin is that the large end of both ends open, an end is little, the cylinder three-dimensional ring structure of hollow, in its empty structure, intracavity section is because the shielding action that is subject to c h bond has formed hydrophobic region, all hydroxyls are in the molecule outside, and big opening end is by C
2and C
3secondary hydroxyl form, the osculum end is by C
6primary hydroxyl form, there is very strong hydrophilic, its structure is:
Q=6 wherein, within 7,8 o'clock, be respectively α-, β-, gamma-cyclodextrin.
The D (+) that the alkalescence cyclodextrin is the formation cyclodextrin molecular-Glucopyranose. C
2, C
3and/or C
6hydroxyl replace to be generated alkaline cyclodextrin by amido, the compound that contains acidic-group is had to solubilizing effect preferably.
The existing document of the synthetic reference of alkalescence cyclodextrin carries out; cyclodextrin first reacts with sulfonylation agent and generates sulfonylation cyclodextrin [R.C. Petter; J.S. Salek; C.T. Sikorski; G. Kumaravel; and F.-T. Lin:J. Am. Chem. Soc. 112,3860 – 3868 (1990)], cyclodextrin can be at D (+)-2 of Glucopyranose .s, 3 and/or 6 upper sulfonylations that occur.Sulfonylation agent commonly used is benzene sulfonyl chloride and p-methyl benzene sulfonic chloride.Then at amine under the nucleophilic attack for reagent; sulfonyl on the sulfonylation cyclodextrin breaks away from; by amido, reacted; generate alkaline cyclodextrin [B.L. May; S.D. Kean; C.J. Easton, and S.F. Lincoln:J. Chem. Soc., Perkin Trans. 13157 – 3160 (1997)].Wherein, described amine can be the organic group of all kinds of amino-containeds for reagent, comprises ammonia, methylamine, ethamine, propylamine, butylamine, ethylenediamine, ethanolamine, acetamide and diethylenetriamine etc.As, paratoluensulfonyl chloride reacts with beta-schardinger dextrin-and generates single 6-tolysulfonyl-beta-schardinger dextrin-(6-OTs-β-CD), 6-OTs-β-CD generates list-[6-amido-6-deoxidation]-beta-schardinger dextrin-by the reduction of intermedium nitrine cyclodextrin, to 6-OTs-β-CD, add in ethylenediamine or diethylenetriamine solution, reaction obtains other alkaline cyclodextrin, and reaction equation is as follows:
Wherein, as preferably, described alkaline cyclodextrin is for having formula
shown in structure:
Wherein m be 0 to 7, n be 1 to 8 and m+n=6,7 or 8 in one;
R
1, R
2and R
3for-OH or-RNH
2and R
1, R
2and R
3in have one at least for-RNH
2;
R is (CH
2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
x, x is more than or equal to 0 integer.
Formula
in middle m+n=6,7 or 8 one, mean cyclodextrin of the present invention can for α-, β-or gamma-cyclodextrin, wherein, n is at least in the described alkaline cyclodextrin molecular of 1 expression has at least a D (+)-Glucopyranose. parent hydroxy to be modified by amido, and now m is 5,6 or 7; And each D (+)-Glucopyranose. that m is the described alkaline cyclodextrin formation cyclodextrin molecular of 0 expression is all modified by amido.
Formula
middle R
1, R
2and R
3in have one at least for-RNH
2meaning that described alkaline cyclodextrin modified D (+)-Glucopyranose. molecule by amido and be at least the monoamine base and modify, can, at 2,3 or 6, can be also that the diamine base is modified or R
1, R
2and R
3all modified.
Also defined the amido-RNH of modification cyclodextrin in formula II
2in R, R is (CH
2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
xthe amido that means modification cyclodextrin can be the organic amino group such as ammonia, methylamine, ethamine, ethylenediamine, ethanolamine, acetamide and diethylenetriamine, and wherein, x is more than or equal to 0 integer, is preferably 0 to 10, more preferably 0,1,2,3 or 4.
Preferably, described alkaline cyclodextrin has structure shown in formula II,
II
Wherein n be 1 and m+n=6,7 or 8 in one;
R
1, R
2or R
3for-RNH
2;
R is (CH
2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
x, x is 0,1,2,3 or 4.
More preferably, described alkaline cyclodextrin is a kind of in list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[6-amido-6-deoxidation]-beta-schardinger dextrin-, list-[2-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[3-(methylamino)-6-deoxidation]-alpha-cyclodextrin, list-[6-(ethanol amido)-6-deoxidation]-gamma-cyclodextrin.
The preparation method of chimonin of the present invention and alkaline cyclodextrin clathrate, concrete steps are:
(1) ratio of adding 10～40ml water in 0.09～1.5g alkalescence cyclodextrin, alkaline cyclodextrin is made to aqueous solution, then under 20～60 ℃, add chimonin, stir and carry out inclusion reaction 0.5-24h, obtain inclusion complex in solution, wherein the mol ratio of chimonin and alkaline cyclodextrin is 4:1～1:10;
(2) after the reaction, solution is through filtering, and filtrate is concentrated, dry, obtains chimonin and alkaline cyclodextrin clathrate.
The stirring means that inclusion reaction in preparation method of the present invention adopts is a kind of for grinding in paddling process, mechanical mixing method, ultrasonic agitation method.
Adopt conventional paddling process, the mechanical mixing method of grinding, by mechanical strength, make the reactant contact, carry out inclusion reaction.The inclusion reaction time often needed is longer, in the scope of 5-24h.And adopting the ultrasonic agitation method to carry out inclusion reaction, the response time is in the scope of 0.5-4h, but the problem that exists cost to improve.Therefore, three kinds of modes that stirring means is all inclusion reaction.
The inventive method is with respect to advantage and the technique effect of prior art:
1, the present invention is directed to chimonin water solublity present situation on the low side, synthetic alkaline cyclodextrin is the cyclodextrin that amido replaces, the amido of cyclodextrin replaces, except the clathration of cyclodextrin cavity and chimonin molecule, owing to forming alkaline environment in aqueous solution, form ionic interaction with the hydroxyl on chimonin, thereby make chimonin form solution in very wide concentration range in water, just the formation of chimonin liquid preparation, and the clathrate formed has higher stability;
2, chimonin provided by the invention and the alkaline cyclodextrin clathrate dissolubility in water (amount with chimonin is calculated) between 35 ~ 200mg/mL in the time of 25 ℃, can form solution in water in very wide concentration range, be convenient to the formation of chimonin Liquid drug preparation;
3, clathrate preparation method of the present invention is simple, easy to operate, and cost is low, reaction condition is gentle, is suitable for suitability for industrialized production;
4, the clathrate that the present invention makes has good in the property of medicine to straight caecum target spot, and safe, good stability, dissolubility is good, easy to use, avoids chimonin to be released and to destroy at digestive tract, the bioavailability that improves medicine increases the dissolubility of medicine, improves the stripping of medicine.
The specific embodiment
Below by embodiment, the present invention is described in further detail; but protection domain of the present invention is not limited to described content; the preparation method of embodiment neutral and alkali cyclodextrin is with reference to R.C. Petter; J.S. Salek; C.T. Sikorski; G. Kumaravel; and F.-T. Lin:J. Am. Chem. Soc. 112; 3860 – 3868 (1990) and B.L. May; S.D. Kean; C.J. Easton, and S.F. Lincoln:J. Chem. Soc., the disclosed method of Perkin Trans. 13157 – 3160 (1997) is implemented.
embodiment 1:chimonin and alkaline cyclodextrin clathrate, comprise chimonin and alkaline cyclodextrin, and wherein the mol ratio of chimonin and alkaline cyclodextrin is 4:1, and concrete preparation method is as follows:
1, the preparation of sulfonylation cyclodextrin
Get the beta-schardinger dextrin-53g after recrystallization, be dissolved in the 325mL distilled water, after fully stirring, solution becomes white emulsion, add sodium hydroxide solution (4.5g, 15mL), stir 1.5h, weighing paratoluensulfonyl chloride 7g, be dissolved in the 20mL acetonitrile solution, this solution slowly be added drop-wise in beta-schardinger dextrin-alkali liquor to stirring at room 2h, sucking filtration is removed a small amount of insoluble matter, regulate filtrate pH value to 7.5 with 2M hydrochloric acid, now have a large amount of precipitations to produce, sucking filtration is removed filtrate.To be precipitated and dissolved in 120mL water under heating in, filter while hot insoluble matter, filtrate is at 0 ℃ of recrystallization 12h, and the precipitation reusable heat water recrystallization obtained after filtration repeatedly, 60 ℃ of vacuum drying 12 h obtain the about 4.5g of pure single 6-tolysulfonyl-beta-schardinger dextrin-, productive rate 8%.
2, the preparation of amido modification cyclodextrin
Getting single 6-tolysulfonyl-beta-schardinger dextrin-(3g) adds in the 20mL ethylenediamine solution, at 80 ℃ of reaction 8h, after cooling, reactant liquor is splashed in acetone, collecting precipitation can obtain list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-(2.3g), productive rate 84%.
The preparation of the chimonin that 3, mol ratio is 4:1 and list-[6-(ethylenediamine base)-6-deoxidation]-Benexate Hydrochloride
Taking list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-0.09g is dissolved in the 20ml distilled water and makes aqueous solution, then add chimonin 0.14g under 25 ℃, mechanical agitation reaction 12h, sucking filtration falls insoluble matter, filtrate is concentrated, 45 ℃ of oven dry of normal pressure, obtain clathrate, and clathrate dissolubility in water at 25 ℃ the time is that 41mg/mL(calculates with the amount of chimonin).
embodiment 2:chimonin and alkaline cyclodextrin clathrate, comprise chimonin and alkaline cyclodextrin, wherein the mol ratio of chimonin and list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-is 4:1, and the preparation method of alkaline cyclodextrin is with embodiment 1, and concrete preparation method is as follows:
Taking list-[6-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-0.11g is dissolved in the 20ml distilled water and makes aqueous solution, then add chimonin 0.14g under 40 ℃, stirring reaction 8h, filter out insoluble matter, filtrate is concentrated, lyophilization, obtain clathrate, and clathrate dissolubility in water in the time of 25 ℃ is that 52mg/mL(calculates with the amount of chimonin).
embodiment 3:chimonin and alkaline cyclodextrin clathrate, comprise chimonin and alkaline cyclodextrin, and wherein the mol ratio of chimonin and list-[6-amido-6-deoxidation]-beta-schardinger dextrin-is 2:1, and concrete preparation method is as follows:
Taking list-[6-amido-6-deoxidation]-beta-schardinger dextrin-0.094g is dissolved in the 20ml distilled water and makes aqueous solution, then add chimonin 0.07g under 30 ℃, ultrasonic (frequency is 30000 hertz) stirs 1h, filter out insoluble matter, filtrate is concentrated, the reduced vacuum drying, obtain clathrate, and clathrate dissolubility in water at 25 ℃ the time is that 36mg/mL(calculates with the amount of chimonin).
embodiment 4:this ionic drug chimonin and alkaline cyclodextrin clathrate, comprise chimonin and alkaline cyclodextrin, and wherein the mol ratio of chimonin and list-[3-(methylamino)-6-deoxidation]-alpha-cyclodextrin is 1:3, and concrete preparation method is as follows:
Taking list-[3-(methylamino)-6-deoxidation]-alpha-cyclodextrin 0.49g is dissolved in the 30ml distilled water and makes aqueous solution, then add chimonin 0.07g under 60 ℃, stirring reaction 12h, sucking filtration falls insoluble matter, filtrate is concentrated, 40 ℃ of oven dry of normal pressure, obtain clathrate, and clathrate dissolubility in water at 25 ℃ the time is that 85mg/mL(calculates with the amount of chimonin).
embodiment 5:this ionic drug chimonin and alkaline cyclodextrin clathrate, comprise chimonin and alkaline cyclodextrin, and wherein the mol ratio of chimonin and list-[6-(ethanol amido)-6-deoxidation]-gamma-cyclodextrin is 1:5, and concrete preparation method is as follows:
Taking list-[6-(ethanol amido)-6-deoxidation]-gamma-cyclodextrin 1.11g is dissolved in the 40ml distilled water and makes aqueous solution, then add chimonin 0.07g under 30 ℃, grind and stir 24h, sucking filtration falls insoluble matter, filtrate is concentrated, lyophilization, obtain clathrate, and clathrate dissolubility in water at 25 ℃ the time is that 120mg/mL(calculates with the amount of chimonin).
embodiment 6:this ionic drug chimonin and alkaline cyclodextrin clathrate, comprise chimonin and alkaline cyclodextrin, and wherein the mol ratio of chimonin and list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-is 1:10, and concrete preparation method is as follows:
Taking list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-0.9g is dissolved in the 10ml distilled water and makes aqueous solution, then add chimonin 0.07g under 50 ℃, ultrasonic (frequency is 30000 hertz) stirring reaction 3h, sucking filtration falls insoluble matter, filtrate is concentrated, spray drying, obtain clathrate, and clathrate dissolubility in water at 25 ℃ the time is that 195mg/mL(calculates with the amount of chimonin)
The explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof.It should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention, can also carry out some improvement and modification to the present invention, these improvement and modification also fall in the protection domain of the claims in the present invention.
Claims (4)
1. a chimonin and alkaline cyclodextrin clathrate, it is characterized in that: it comprises chimonin and alkaline cyclodextrin, wherein the mol ratio of chimonin and alkaline cyclodextrin is 4:1-1:10.
2. chimonin and alkaline cyclodextrin clathrate according to claim 1 is characterized in that alkaline cyclodextrin has structure shown in formula I:
I
Wherein m be 0 to 7, n be 1 to 8 and m+n=6,7 or 8 in one;
R
1, R
2and R
3for-OH or-RNH
2and R
1, R
2and R
3in have one at least for-RNH
2;
R is (CH2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
x, x is more than or equal to 0 integer.
3. chimonin and alkaline cyclodextrin clathrate according to claim 2 is characterized in that alkaline cyclodextrin has structure shown in formula II:
II
Wherein n be 1 and m+n=6,7 or 8 in one;
R
1, R
2or R
3for-RNH
2; R is (CH
2)
x, NH (CH
2)
x, NH (CH
2)
xnH (CH
2)
x, CO (CH
2)
xor O (CH
2)
x, x is 0,1,2,3 or 4.
4. chimonin and alkaline cyclodextrin clathrate according to claim 3 is characterized in that: a kind of in list-[6-amido-6-deoxidation]-beta-schardinger dextrin-, list-[6-(ethylenediamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[2-(diethylenetriamine base)-6-deoxidation]-beta-schardinger dextrin-, list-[3-(methylamino)-6-deoxidation]-alpha-cyclodextrin, list-[6-(ethanol amido)-6-deoxidation]-gamma-cyclodextrin of alkaline cyclodextrin.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104857003A (en) * | 2015-04-10 | 2015-08-26 | 昆明理工大学 | Ursolic acid and amine cyclodextrin clathrate compound |
| GB2576301A (en) * | 2018-07-06 | 2020-02-19 | Clement Idowu Olusola | Mangiferin-containing skin-care compositions and methods |
| US10624830B2 (en) | 2017-11-30 | 2020-04-21 | L'oreal | Aqueous compositions with mangiferin for cosmetic applications |
| CN111194908A (en) * | 2020-01-16 | 2020-05-26 | 河南科技学院 | Preparation method of Pickering high internal phase emulsion gel based on mangiferin/gamma-cyclodextrin compound |
| US10898420B2 (en) | 2016-10-31 | 2021-01-26 | L'oreal | Compositions containing phenolic compounds having synergistic antioxidant benefits |
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2013
- 2013-09-24 CN CN2013104361517A patent/CN103462975A/en active Pending
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| LIZHEN HUANG,ET AL: "Investigation on a host–guest inclusion system by b-cyclodextrin derivative and its analytical application", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| XUEMIN YANG, ET AL: "Host–guest inclusion system of mangiferin with β-cyclodextrin and its derivatives", 《MATERIALS SCIENCE AND ENGINEERING C》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104857003A (en) * | 2015-04-10 | 2015-08-26 | 昆明理工大学 | Ursolic acid and amine cyclodextrin clathrate compound |
| US10898420B2 (en) | 2016-10-31 | 2021-01-26 | L'oreal | Compositions containing phenolic compounds having synergistic antioxidant benefits |
| US10624830B2 (en) | 2017-11-30 | 2020-04-21 | L'oreal | Aqueous compositions with mangiferin for cosmetic applications |
| GB2576301A (en) * | 2018-07-06 | 2020-02-19 | Clement Idowu Olusola | Mangiferin-containing skin-care compositions and methods |
| CN111194908A (en) * | 2020-01-16 | 2020-05-26 | 河南科技学院 | Preparation method of Pickering high internal phase emulsion gel based on mangiferin/gamma-cyclodextrin compound |
| CN111194908B (en) * | 2020-01-16 | 2022-06-17 | 河南科技学院 | Preparation method of Pickering high internal phase emulsion gel based on mangiferin/gamma-cyclodextrin compound |
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