CN105770908A - Ginsenoside cyclodextrin inclusion compound and preparation method thereof - Google Patents
Ginsenoside cyclodextrin inclusion compound and preparation method thereof Download PDFInfo
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- CN105770908A CN105770908A CN201610246109.2A CN201610246109A CN105770908A CN 105770908 A CN105770908 A CN 105770908A CN 201610246109 A CN201610246109 A CN 201610246109A CN 105770908 A CN105770908 A CN 105770908A
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- China
- Prior art keywords
- ginsenoside
- cyclodextrin
- beta
- preparation
- clathrate
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Links
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 51
- 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 51
- 229930182494 ginsenoside Natural products 0.000 title claims abstract description 50
- 229940089161 ginsenoside Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 title abstract description 15
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims abstract description 33
- 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 claims abstract description 31
- TXEWRVNOAJOINC-UHFFFAOYSA-N ginsenoside Rb2 Natural products CC(=CCCC(OC1OC(COC2OCC(O)C(O)C2O)C(O)C(O)C1O)C3CCC4(C)C3C(O)CC5C6(C)CCC(OC7OC(CO)C(O)C(O)C7OC8OC(CO)C(O)C(O)C8O)C(C)(C)C6CCC45C)C TXEWRVNOAJOINC-UHFFFAOYSA-N 0.000 claims abstract description 18
- FBFMBWCLBGQEBU-RXMALORBSA-N (2s,3r,4s,5s,6r)-2-[(2r,3r,4s,5s,6r)-2-[[(3s,5r,6s,8r,9r,10r,12r,13r,14r,17s)-3,12-dihydroxy-4,4,8,10,14-pentamethyl-17-[(2s)-6-methyl-2-[(2s,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyhept-5-en-2-yl]-2,3,5,6,7,9,11,12,13,15,16,17-dodecah Chemical compound O([C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(C[C@@H]([C@H]4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3C[C@H]2O)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C)(C)CC1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O FBFMBWCLBGQEBU-RXMALORBSA-N 0.000 claims abstract description 15
- FBFMBWCLBGQEBU-GYMUUCMZSA-N 20-gluco-ginsenoside-Rf Natural products O([C@](CC/C=C(\C)/C)(C)[C@@H]1[C@H]2[C@H](O)C[C@H]3[C@](C)([C@]2(C)CC1)C[C@H](O[C@@H]1[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O2)[C@@H](O)[C@H](O)[C@@H](CO)O1)[C@H]1C(C)(C)[C@@H](O)CC[C@]31C)[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 FBFMBWCLBGQEBU-GYMUUCMZSA-N 0.000 claims abstract description 15
- HYPFYJBWSTXDAS-UHFFFAOYSA-N Ginsenoside Rd Natural products CC(=CCCC(C)(OC1OC(CO)C(O)C(O)C1O)C2CCC3(C)C4CCC5C(C)(C)C(CCC5(C)C4CC(O)C23C)OC6OC(CO)C(O)C(O)C6OC7OC(CO)C(O)C(O)C7O)C HYPFYJBWSTXDAS-UHFFFAOYSA-N 0.000 claims abstract description 15
- PWAOOJDMFUQOKB-WCZZMFLVSA-N ginsenoside Re Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](O[C@@H]2[C@H]3C(C)(C)[C@@H](O)CC[C@]3(C)[C@@H]3[C@@]([C@@]4(CC[C@@H]([C@H]4[C@H](O)C3)[C@](C)(CCC=C(C)C)O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C)(C)C2)O[C@H](CO)[C@@H](O)[C@@H]1O PWAOOJDMFUQOKB-WCZZMFLVSA-N 0.000 claims abstract description 15
- AOGZLQUEBLOQCI-UHFFFAOYSA-N ginsenoside-Re Natural products CC1OC(OCC2OC(OC3CC4(C)C(CC(O)C5C(CCC45C)C(C)(CCC=C(C)C)OC6OC(CO)C(O)C(O)C6O)C7(C)CCC(O)C(C)(C)C37)C(O)C(O)C2O)C(O)C(O)C1O AOGZLQUEBLOQCI-UHFFFAOYSA-N 0.000 claims abstract description 15
- UOJAEODBOCLNBU-UHFFFAOYSA-N vinaginsenoside R4 Natural products C1CC(C2(CC(O)C3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O UOJAEODBOCLNBU-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 13
- CNHRRMQBWQJRPN-UHFFFAOYSA-N chikusetsusaponin LM5 Natural products C1CC(C2(CC(O)C3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OC(CO)C(O)C1O CNHRRMQBWQJRPN-UHFFFAOYSA-N 0.000 claims abstract description 9
- JDCPEKQWFDWQLI-LUQKBWBOSA-N ginsenoside Rc Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)O[C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(CC[C@H]4C(C)(C)[C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)CC[C@]4(C)[C@H]3C[C@H]2O)C)(C)CC1)O[C@@H]1O[C@@H](CO)[C@H](O)[C@H]1O JDCPEKQWFDWQLI-LUQKBWBOSA-N 0.000 claims abstract description 9
- SPFXZQZPHXUJSR-UHFFFAOYSA-N ginsenoside-Rc Natural products CC(=CCCC(C)(OC1OC(CO)C(O)C(O)C1OC2OC(CO)C(O)C2O)C3CCC4(C)C3C(O)CC5C6(C)CCC(OC7OC(CO)C(O)C(O)C7OC8OC(CO)C(O)C(O)C8O)C(C)(C)C6CCC45C)C SPFXZQZPHXUJSR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012047 saturated solution Substances 0.000 claims abstract description 3
- 238000003756 stirring Methods 0.000 claims description 14
- 241000208340 Araliaceae Species 0.000 claims description 7
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 claims description 7
- 235000003140 Panax quinquefolius Nutrition 0.000 claims description 7
- 235000008434 ginseng Nutrition 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 229920001353 Dextrin Polymers 0.000 claims description 4
- 239000004375 Dextrin Substances 0.000 claims description 4
- 235000019425 dextrin Nutrition 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 229930182470 glycoside Natural products 0.000 claims description 3
- 150000002338 glycosides Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 150000007949 saponins Chemical class 0.000 claims description 3
- 239000000344 soap Substances 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 2
- 239000001397 quillaja saponaria molina bark Substances 0.000 claims description 2
- 229930182490 saponin Natural products 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- REFMTLIXGKZVDF-ZEBDFXRSSA-N (2R)-2-[(1R,2R,6S,7S)-3,5-dioxo-4-azatricyclo[5.2.1.02,6]decan-4-yl]propanoic acid Chemical group C([C@H]1C2)C[C@H]2[C@@H]2[C@H]1C(=O)N([C@H](C)C(O)=O)C2=O REFMTLIXGKZVDF-ZEBDFXRSSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 31
- BGHNZAWRRWLKPO-UHFFFAOYSA-N Ginsenoside F1 Natural products CC(=C)CCCC(C)(OC1OC(CO)C(O)C(O)C1O)C2CCC3(C)C2C(O)CC4C5(C)CCC(O)C(C)(C)C5C(O)CC34C BGHNZAWRRWLKPO-UHFFFAOYSA-N 0.000 abstract description 14
- XNGXWSFSJIQMNC-FIYORUNESA-N ginsenoside F1 Chemical group O([C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(C[C@H](O)[C@H]4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3C[C@H]2O)C)(C)CC1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O XNGXWSFSJIQMNC-FIYORUNESA-N 0.000 abstract description 14
- NODILNFGTFIURN-GZPRDHCNSA-N ginsenoside Rb2 Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H](O)[C@@H]1O)O)O[C@@](C)(CCC=C(C)C)[C@@H]1[C@@H]2[C@@]([C@@]3(CC[C@H]4C(C)(C)[C@@H](O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O5)O)CC[C@]4(C)[C@H]3C[C@H]2O)C)(C)CC1)O[C@@H]1OC[C@H](O)[C@H](O)[C@H]1O NODILNFGTFIURN-GZPRDHCNSA-N 0.000 abstract description 9
- PFSIGTQOILYIIU-UHFFFAOYSA-N ginsenoside Rb3 Natural products CC(=CCCC(C)(O)C1CCC2(C)C3CCC4C(C)(C)C(CCC4(C)C3CC(OC5OC(COC6OCC(O)C(O)C6O)C(O)C(O)C5O)C12C)OC7OC(CO)C(O)C(O)C7OC8OC(CO)C(O)C(O)C8O)C PFSIGTQOILYIIU-UHFFFAOYSA-N 0.000 abstract description 9
- ZTQSADJAYQOCDD-UHFFFAOYSA-N ginsenoside-Rd2 Natural products C1CC(C2(CCC3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OCC(O)C(O)C1O ZTQSADJAYQOCDD-UHFFFAOYSA-N 0.000 abstract description 9
- 238000000634 powder X-ray diffraction Methods 0.000 description 29
- 239000003814 drug Substances 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000012982 microporous membrane Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 230000009471 action Effects 0.000 description 3
- 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 3
- -1 cyclic oligosaccharide Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 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 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000006069 physical mixture Substances 0.000 description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 241000193755 Bacillus cereus Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 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 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 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 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000032895 transmembrane transport Effects 0.000 description 1
- 229930182493 triterpene saponin Natural products 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a ginsenoside cyclodextrin inclusion compound and a preparation method thereof.The compound comprises ginsenoside and cyclodextrin, wherein the molar ratio of ginsenoside to cyclodextrin is (1:2)-(1:20), the ginsenoside is ginsenoside F1 or ginsenoside Re or ginsenoside Rd or ginsenoside Rb2 or ginsenoside Rc, and the cyclodextrin is hydroxypropyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin; the compound is prepared through a saturated solution method or an ultrasonic method; after ginsenoside and cyclodextrin form the compound, the solubility of the compound in water is greatly improved. The preparation method is simple and convenient to implement, mild in condition, easy to implement and capable of being used for developing novel prepartions of ginsenoside.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to cyclodextrin clathrate and the preparation side thereof of five kinds of ginsenosides
Method.
Background technology
Ginsenoside is triterpene saponin compounds, is primarily present in rare Chinese medicine Radix Ginseng and Radix Panacis Quinquefolii, is
Their active component, has the pharmacological actions such as preferable antitumor, anti-alzheimer disease, cardiovascular disease resistant.But Radix Ginseng soap
The universal poorly water-soluble of glycosides, and unstable, cause its vivo biodistribution availability low, it is impossible to play its drug action well, even
Some toxic and side effects can be produced.Accordingly, it would be desirable to take the technological means of necessity it to be improved, to improve the property such as its water solublity
Matter so that it is be more suitable for medicinal.
Cyclodextrin (cyclodextrin is called for short CD) is that amylose is at the cyclodextrin glucose base produced by bacillus cereus
The cyclic oligosaccharide generated under transferring enzyme effect, common for α-, β-and gamma-cyclodextrin three kinds.Wherein, beta-schardinger dextrin-is due to the most
Cheap and easy to get and the character of low toxicity and become study hotspot.Research shows, constitutes each D(+ of beta-schardinger dextrin-molecule)-pyrans Portugal
Grape sugar is all chair conformation, and each glucose unit all connects cyclization with α-Isosorbide-5-Nitrae-glycosidic bond.Owing to connecting glucose unit
Glycosidic bond can not rotate freely so that beta-schardinger dextrin-formed two openings small one and large one, the cylinder solid knot of central hollow
Structure.In its cavity structure, intracavity portion defines hydrophobic interval due to the shielding action by c h bond, and all of hydroxyl
Being distributed in outside molecule, big opening end is made up of C2, C3 position secondary hydroxyl, and osculum end is made up of C6 position primary hydroxyl, has stronger parent
Aqueous.
After drug molecule forms clathrate with cyclodextrin and derivant thereof, medicine water-soluble can be increased, improve it stable
Property, also can cover its bad smell, reduce its in gastrointestinal zest and untoward reaction the release time extending medicine and
Improve the bioavailability of medicine, and there is segmented intestine targeted property.Meanwhile, application cyclodextrin inclusion technique can be prevented effectively from or reduce
The use of organic solvent, surfactant and lipid.The advantage of cyclodextrin clathrate maximum is that it can change from molecular level
The character of medicine and to the pharmacokinetics process of medicine almost without interference.There are about 30 kinds at present in the world containing cyclodextrin
Pharmaceutical preparation lists, and the effect of cyclodextrin is mainly in these formulations: replace in injection or topical application preparation prescription
Organic solvent；Improve the oral administration biaavailability of class ii and some iv class medicine；Reduce GI irritation and increase medicine
Transdermal diffusivity etc..Studying through animal and human experimentation and show, cyclodextrin can improve nearly all types of drug
Transmembrane transport character.
Beta-schardinger dextrin-is as one the most widely used in cyclodextrin family, but owing to its water solublity is the best so that its
Application receives bigger restriction.To this end, the beta-cyclodextrin derivative of various chemical modifications arises at the historic moment.Wherein, hydroxy propyl-Beta-ring
Dextrin (HP-β-CD) and sulfobutyl ether-beta-cyclodextrin (SBE-β-CD) are to transform the most successful two in beta-cyclodextrin derivative
Kind, its water solublity is significantly improved relative to beta-schardinger dextrin-, and has more preferable biological safety, has the most become FDA and has criticized
The accurate two kinds of cyclodextrin derivative used.
In sum, HP-β-CD or two kinds of cyclodextrin derivative of sulfobutyl ether-beta-cyclodextrin and Radix Ginseng are utilized
Saponin forms clathrate, can be substantially improved the water solublity of guest molecule, to adapt it to the requirement of liquid preparation, make ginsenoside
Medical value preferably played.
Summary of the invention
It is an object of the invention to provide the cyclodextrin clathrate of the ginsenoside of a kind of highly-water-soluble, this clathrate contains
Ginsenoside and cyclodextrin, wherein ginsenoside includes GF1 (Ginsenoside F1), ginsenoside Re
(Ginsenoside Re), ginsenoside Rd (Ginsenoside Rd), ginsenoside Rb2 (Ginsenoside Rb2) or people
Ginseng saponin Rc(Ginsenoside Rc)；Cyclodextrin is HP-β-CD or sulfobutyl ether-beta-cyclodextrin, and Radix Ginseng soap
Glycosides is 1:2 ~ 1:20 with the mol ratio of cyclodextrin.
The chemical structural formula of described ginsenoside is as follows:
。
Ginsenoside of the present invention can use saturated solution inclusion method to be prepared with the clathrate of cyclodextrin, i.e. exists
In the aqueous solution dissolved with HP-β-CD or sulfobutyl ether-beta-cyclodextrin, excess is added while stirring at 25～60 DEG C
Ginsenoside, wherein ginsenoside is 1:1 ~ 1:10 with the mol ratio of cyclodextrin, continues lucifuge stirring 24 ~ 72 h after having added,
Filtering off insoluble matter, solution decompression is evaporated the cyclodextrin clathrate i.e. obtaining ginsenoside.
Ginsenoside of the present invention can also use ultrasonic method, i.e. 25～60 DEG C of temperature with the clathrate of cyclodextrin
In the range of degree, in the just cyclodextrin aqueous solution in ultrasonic, add ginsenoside, after then proceeding to lucifuge ultrasonic 1～10 h,
Filtering off insoluble matter, evaporated under reduced pressure solvent i.e. obtains the pulverulent solids clathrate of ginsenoside and cyclodextrin.
Ginsenoside obtained by the present invention all uses X-ray powder diffraction to carry out table with the clathrate of cyclodextrin
Levy (see accompanying drawing 3 to accompanying drawing 10).From each collection of illustrative plates it can be seen that after clathrate is formed, its powder diffraction form all becomes
Change, become consistent with its host molecule i.e. HP-β-CD or sulfobutyl ether-beta-cyclodextrin.And distinguish therewith,
The physical mixture (mol ratio 1:1) that ginsenoside is formed with HP-β-CD or sulfobutyl ether-beta-cyclodextrin only shows
Go out the simple adduction of its two kinds of components (ginsenoside and cyclodextrin) diffraction form.This also demonstrates the formation of described clathrate.
The clathrate of the ginsenoside obtained by the present invention and cyclodextrin, its water solublity in terms of the quality of ginsenoside, its
The HP-β-CD of middle GF1 or the water solublity of sulfobutyl ether-beta-cyclodextrin inclusion compound increase respectively to inclusion
Water miscible 30.1 and 27.6 times of GF1 before, the HP-β-CD of Ginsenoside Rc or sulfobutyl ether-β-ring
The water solublity of cyclodextrin inclusion compound increase respectively to inclusion before water miscible 1.2 and 2.3 times of Ginsenoside Rc, ginsenoside Re's
The water solublity of HP-β-CD or sulfobutyl ether-beta-cyclodextrin inclusion compound increases respectively to ginsenoside Re before inclusion
Water miscible 347 and 382.5 times, the HP-β-CD of ginsenoside Rd or the water of sulfobutyl ether-beta-cyclodextrin inclusion compound
Dissolubility increase respectively to inclusion before water miscible 251.5 and 332 times of ginsenoside Rd, the hydroxy propyl-Beta-ring of ginsenoside Rb2
The water solublity of dextrin or sulfobutyl ether-beta-cyclodextrin inclusion compound increase respectively to inclusion before ginsenoside Rb2 water miscible 8.8
With 14.6 times.
The preparation method of clathrate of the present invention is simple and easy to do, mild condition, is suitable for industrialized production.
Accompanying drawing explanation
Fig. 1 is X-ray powder diffraction (XRD) collection of illustrative plates before and after ginsenoside Rb2 and HP-β-CD inclusion；
Fig. 2 is X-ray powder diffraction (XRD) collection of illustrative plates before and after ginsenoside Rb2 and sulfobutyl ether-beta-cyclodextrin inclusion；
Fig. 3 is X-ray powder diffraction (XRD) collection of illustrative plates before and after GF1 and HP-β-CD inclusion；
Fig. 4 is X-ray powder diffraction (XRD) collection of illustrative plates before and after GF1 and sulfobutyl ether-beta-cyclodextrin inclusion；
Fig. 5 is X-ray powder diffraction (XRD) collection of illustrative plates before and after ginsenoside Rd and HP-β-CD inclusion；
Fig. 6 is X-ray powder diffraction (XRD) collection of illustrative plates before and after ginsenoside Rd and sulfobutyl ether-beta-cyclodextrin inclusion；
Fig. 7 is X-ray powder diffraction (XRD) collection of illustrative plates before and after ginsenoside Re and HP-β-CD inclusion；
Fig. 8 is X-ray powder diffraction (XRD) collection of illustrative plates before and after ginsenoside Re and sulfobutyl ether-beta-cyclodextrin inclusion；
Fig. 9 is X-ray powder diffraction (XRD) collection of illustrative plates before and after Ginsenoside Rc and HP-β-CD inclusion；
Figure 10 is X-ray powder diffraction (XRD) collection of illustrative plates before and after Ginsenoside Rc and sulfobutyl ether-beta-cyclodextrin inclusion；
In figure: A is ginsenoside；B is HP-β-CD or sulfobutyl ether-beta-cyclodextrin；C is ginsenoside and hydroxypropyl
The physical mixture (mol ratio 1:1) of group-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin；D be ginsenoside with hydroxy propyl-Beta-
Cyclodextrin or the clathrate of sulfobutyl ether-beta-cyclodextrin.
Detailed description of the invention
Further the method for the invention is described below by embodiment, but scope is not by institute
The restriction of row embodiment.
Embodiment 1: GF1 and the preparation of hydroxypropyl-beta-cyclodextrin inclusion
In the reaction bulb of 25 mL, add HP-β-CD (161.8 mg, 0.1 mmol) and add 20 mL distilled water
Stirring, to dissolving, is subsequently adding GF1 (63.87 mg, 0.1 mmol), and at 25 DEG C, lucifuge stirs 72 h, crosses and filters
Removing insoluble matter, then the filtering with microporous membrane by 0.45 μm, filtrate is evaporated and i.e. obtains white powder, is dried 24 h at vacuum drying oven,
Obtain the clathrate of the solid clathrates of GF1 and HP-β-CD, obtained ginsenoside and cyclodextrin
All using X-ray powder diffraction to carry out characterizing (Fig. 3), the water solublity contrast before and after inclusion is shown in Table 1.
Embodiment 2: GF1 and the preparation of sulfobutyl ether-beta-cyclodextrin inclusion compound
In the reaction bulb of 25 mL, add sulfobutyl ether-beta-cyclodextrin (700 mg, 0.5 mmol) and add 20 mL distilled water
Stirring, to dissolving, is subsequently adding GF1 (63.87 mg, 0.1 mmol), ultrasonic 10 h of lucifuge at 25 DEG C, crosses and filter
Removing insoluble matter, then the filtering with microporous membrane by 0.45 μm, filtrate is evaporated and i.e. obtains white powder, is dried 24 h at vacuum drying oven,
Obtain the inclusion of the solid clathrates of GF1 and sulfobutyl ether-beta-cyclodextrin, obtained ginsenoside and cyclodextrin
Thing all uses X-ray powder diffraction to carry out characterizing (Fig. 4), and the water solublity contrast before and after inclusion is shown in Table 1.
Embodiment 3: ginsenoside Re and the preparation of hydroxypropyl-beta-cyclodextrin inclusion
In the reaction bulb of 25 mL, add HP-β-CD (1132.6 mg, 0.7 mmol) and add 20 mL distilled water
Stirring, to dissolving, is subsequently adding ginsenoside Re (94.72 mg, 0.1 mmol), and at 60 DEG C, ultrasonic 1 h of lucifuge, is filtered to remove
Insoluble matter, then the filtering with microporous membrane by 0.45 μm, filtrate is evaporated and i.e. obtains white powder, is dried 24 h at vacuum drying oven, i.e.
Obtaining the solid clathrates of ginsenoside Re and HP-β-CD, obtained ginsenoside is complete with the clathrate of cyclodextrin
Portion uses X-ray powder diffraction to carry out characterizing (Fig. 7), and the water solublity contrast before and after inclusion is shown in Table 1.
Embodiment 4: ginsenoside Re and the preparation of sulfobutyl ether-beta-cyclodextrin inclusion compound
In the reaction bulb of 25 mL, add sulfobutyl ether-beta-cyclodextrin (1400 mg, 1 mmol) and add 20 mL distilled water and stir
Mixing to dissolving, be subsequently adding ginsenoside Re (94.72 mg, 0.1 mmol), at 60 DEG C, lucifuge continues stirring 24 h, filters
Removing undissolved medicine, then the filtering with microporous membrane by 0.45 μm, filtrate is evaporated and i.e. obtains white powder, at vacuum drying oven
Being dried 24 h, obtain the solid clathrates of ginsenoside Re and sulfobutyl ether-beta-cyclodextrin, obtained ginsenoside sticks with paste with ring
The clathrate of essence all uses X-ray powder diffraction to carry out characterizing (Fig. 8), and the water solublity contrast before and after inclusion is shown in Table 1.
Embodiment 5: ginsenoside Rd and the preparation of hydroxypropyl-beta-cyclodextrin inclusion
In the reaction bulb of 25 mL, add HP-β-CD (485.4 mg, 0.3 mmol) and add 20 mL distilled water
Stirring, to dissolving, is subsequently adding ginsenoside Rd (94.72 mg, 0.1 mmol), and at 50 DEG C, lucifuge stirs 48 h, crosses and filters
Removing undissolved medicine, then the filtering with microporous membrane by 0.45 μm, filtrate is evaporated and i.e. obtains white powder, does at vacuum drying oven
Dry 24 h, obtain the solid clathrates of ginsenoside Rd and HP-β-CD, obtained ginsenoside and cyclodextrin
Clathrate all uses X-ray powder diffraction to carry out characterizing (Fig. 5), and the water solublity contrast before and after inclusion is shown in Table 1.
Embodiment 6: ginsenoside Rd and the preparation of sulfobutyl ether-beta-cyclodextrin inclusion compound
In the reaction bulb of 25 mL, add sulfobutyl ether-beta-cyclodextrin (980 mg, 0.7 mmol) and add 20 mL distilled water
Stirring, to dissolving, is subsequently adding ginsenoside Rd (94.72 mg, 0.1 mmol), and at 50 DEG C, ultrasonic 7 h of lucifuge, are filtered to remove
Undissolved medicine, then the filtering with microporous membrane by 0.45 μm, filtrate is evaporated and i.e. obtains white powder, is dried at vacuum drying oven
24 h, obtain the solid clathrates of ginsenoside Rd and sulfobutyl ether-beta-cyclodextrin, obtained ginsenoside and cyclodextrin
Clathrate all uses X-ray powder diffraction to carry out characterizing (Fig. 6), and the water solublity contrast before and after inclusion is shown in Table 1.
Embodiment 7: ginsenoside Rb2 and HP-β-CD or the preparation of sulfobutyl ether-beta-cyclodextrin, method is same
Implementing 1, difference is that ginsenoside is 1:10 with the mol ratio of cyclodextrin, and reaction temperature is 35 DEG C；Obtained ginsenoside
X-ray powder diffraction is all used to carry out characterizing (Fig. 1,2) with the clathrate of cyclodextrin, the water solublity contrast before and after inclusion
It is shown in Table 1.
Embodiment 8: Ginsenoside Rc and HP-β-CD or the preparation of sulfobutyl ether-beta-cyclodextrin, method is with real
Executing 1, difference is that ginsenoside is 1:5 with the mol ratio of cyclodextrin, and reaction temperature is 45 DEG C；Obtained ginsenoside and ring
The clathrate of dextrin all uses X-ray powder diffraction to carry out characterizing (Fig. 9,10), and the water solublity contrast before and after inclusion is shown in Table
1。
Table 1: GF1, Rc, Re, Rd and Rb2 are formed with HP-β-CD or sulfobutyl ether-beta-cyclodextrin respectively
Water solublity contrast (in terms of the quality of ginsenoside, unit: mg/mL) before and after clathrate
。
Claims (3)
1. the cyclodextrin clathrate of a ginsenoside, it is characterised in that: it includes ginsenoside and cyclodextrin, wherein Radix Ginseng soap
Glycosides is 1:2 ~ 1:20 with the mol ratio of cyclodextrin, and ginsenoside is GF1, ginsenoside Re, ginsenoside Rd, Radix Ginseng
Saponin Rb2 or Ginsenoside Rc, cyclodextrin is HP-β-CD or sulfobutyl ether-beta-cyclodextrin.
2. the preparation method of the cyclodextrin clathrate of the ginsenoside described in claim 1, it is characterised in that: use saturated solution
Inclusion method prepares the cyclodextrin clathrate of ginsenoside, i.e. while stirring to dissolved with hydroxy propyl-Beta-ring at 25～60 DEG C
Adding ginsenoside in the aqueous solution of dextrin or sulfobutyl ether-beta-cyclodextrin, wherein ginsenoside with the mol ratio of cyclodextrin is
Should be 1:1 ~ 1:10, continue lucifuge stirring 24 ~ 72 h, filter off insoluble matter after having added, solution decompression is evaporated and i.e. obtains ginsenoside
Cyclodextrin clathrate.
The preparation method of the cyclodextrin clathrate of ginsenoside the most according to claim 1, it is characterised in that: preparation process
Middle employing supersound process substitutes stir process.
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