CN107735080B - 一种人参皂苷c-k口服固体制剂及其制备方法 - Google Patents
一种人参皂苷c-k口服固体制剂及其制备方法 Download PDFInfo
- Publication number
- CN107735080B CN107735080B CN201580081215.3A CN201580081215A CN107735080B CN 107735080 B CN107735080 B CN 107735080B CN 201580081215 A CN201580081215 A CN 201580081215A CN 107735080 B CN107735080 B CN 107735080B
- Authority
- CN
- China
- Prior art keywords
- ginsenoside
- solid preparation
- oral solid
- preparation
- preparation according
- 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.)
- Active
Links
- FVIZARNDLVOMSU-IRFFNABBSA-N ginsenoside C-K Chemical compound 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)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 FVIZARNDLVOMSU-IRFFNABBSA-N 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims abstract description 55
- 239000007787 solid Substances 0.000 title claims abstract description 30
- 238000002156 mixing Methods 0.000 claims abstract description 16
- 239000012876 carrier material Substances 0.000 claims abstract description 13
- 239000008187 granular material Substances 0.000 claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 10
- 238000002844 melting Methods 0.000 claims abstract description 9
- 230000008018 melting Effects 0.000 claims abstract description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 13
- 229920001531 copovidone Polymers 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 9
- 229930003427 Vitamin E Natural products 0.000 claims description 9
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 9
- 239000012943 hotmelt Substances 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 9
- 235000019165 vitamin E Nutrition 0.000 claims description 9
- 229940046009 vitamin E Drugs 0.000 claims description 9
- 239000011709 vitamin E Substances 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 8
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 7
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 7
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 229940032147 starch Drugs 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000000155 melt Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 claims 2
- 238000001727 in vivo Methods 0.000 abstract description 7
- 229930182494 ginsenoside Natural products 0.000 description 12
- 229940089161 ginsenoside Drugs 0.000 description 11
- 241000700159 Rattus Species 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 8
- 238000004090 dissolution Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 7
- 239000012738 dissolution medium Substances 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
- 239000012530 fluid Substances 0.000 description 4
- 238000003304 gavage Methods 0.000 description 4
- 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 description 4
- 238000009474 hot melt extrusion Methods 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 230000036186 satiety Effects 0.000 description 4
- 235000019627 satiety Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- MXRGSJAOLKBZLU-UHFFFAOYSA-N 3-ethenylazepan-2-one Chemical compound C=CC1CCCCNC1=O MXRGSJAOLKBZLU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 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 description 2
- 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 description 2
- 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 description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 2
- 239000006069 physical mixture Substances 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 1
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- UFNDONGOJKNAES-UHFFFAOYSA-N Ginsenoside Rb1 Natural products CC(=CCCC(C)(OC1OC(COC2OC(CO)C(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)C6CC(O)C45C)C UFNDONGOJKNAES-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 240000004371 Panax ginseng Species 0.000 description 1
- 235000002789 Panax ginseng Nutrition 0.000 description 1
- 241000180649 Panax notoginseng Species 0.000 description 1
- 235000003143 Panax notoginseng Nutrition 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 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 description 1
- OORMXZNMRWBSTK-LGFJJATJSA-N dammarane Chemical compound C1CCC(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@H]([C@H](C)CCCC(C)C)[C@H]4CC[C@@H]3[C@]21C OORMXZNMRWBSTK-LGFJJATJSA-N 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- GZYPWOGIYAIIPV-JBDTYSNRSA-N ginsenoside Rb1 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](O)[C@H]1O GZYPWOGIYAIIPV-JBDTYSNRSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- 239000011521 glass Substances 0.000 description 1
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000010226 intestinal metabolism Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- NWMIYTWHUDFRPL-UHFFFAOYSA-N sapogenin Natural products COC(=O)C1(CO)C(O)CCC2(C)C1CCC3(C)C2CC=C4C5C(C)(O)C(C)CCC5(CCC34C)C(=O)O NWMIYTWHUDFRPL-UHFFFAOYSA-N 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- -1 saponin compounds Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
Images
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
-
- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
一种人参皂苷C‑K口服固体制剂及其制备方法。所述的人参皂苷C‑K口服固体制剂是将人参皂苷C‑K与载体材料熔融后，挤出制粒，然后将所述颗粒与其他辅料混合制备而成。该口服固体制剂提高了人参皂苷C‑K的溶解性、体内生物利用度和依从性。
Description
技术领域
本发明属于医药技术领域，具体涉及一种人参皂苷C-K口服固体制剂及其制备方法。
背景技术
人参皂苷C-K(20-O-β-D-glucopyranosyl-20-(S)-protopanaxadiol)属四环三萜达玛烷型人参皂苷，按其皂苷元母核结构分型，其属于二醇型人参皂苷，是其它天然二醇型人参皂苷如人参皂苷Rb1、Rb2、Rc等在人肠道内的主要降解产物。该化合物早在1972年，利用土壤微生物降解二醇型人参皂苷鉴定真性人参皂苷苷元结构时就已被发现，后来在三七和人参果中也分离到了该化合物，但含量仅为0.03％左右。
虽然该化合物早已被发现并鉴定了结构，但一直未获得足够的重视。直到上世纪九十年代初，随着天然皂苷类化合物肠道代谢研究的深入和厌氧培养技术的成熟，人参皂苷C-K才又回到科学家的视野中。之后，在口服人参皂苷Rb2后的Wistar大鼠大肠内容物中分离到了人参皂苷C-K。此后，大量试验证明，在大鼠肠道中出现的人参皂苷C-K并不是胃酸水解的产物，而是通过肠道微生物降解得到的。进而有学者提出了Rb1、Rb2和Rc降解到C-K的具体代谢途径，对人参皂苷在体内的活性成分研究起到了里程碑式的作用。
通过近二十年的研究发现人参皂苷C-K是一个多靶点，高活性物质，其不但在抗肿瘤、抗炎、保肝和抗过敏方面体现了良好的活性，而且在神经系统及免疫系统方面也具有很好的调节作用。但因为该化合物水溶性非常差，在肠道中的吸收很少，生物利用度低，阻碍了其在临床上的应用。到目前为止，还未见人参皂苷C-K新药上市的报道。
为解决人参皂苷C-K水溶性的问题，已有专利文献，如CN200410002110中披露了一种抗肿瘤的人参皂苷C-K注射剂及其制备方法，但该注射剂不仅需要加入各种增溶剂、稳定剂、等渗调节剂等以达到剂型本身的要求，而且人参皂苷C-K的溶液不稳定，会影响注射剂的质量和使用时间，更重要的是注射液剂型不合适临床上慢性疾病的长期使用，患者的依从性不高。
发明内容
本发明的目的在于通过对人参皂苷C-K的物理化学性质进行研究，并通过大量试验筛选研究，提供一种溶出度好、生物利用度高、质量稳定的人参皂苷C-K口服固体制剂及其制备方法。
该制剂含有由人参皂苷C-K和载体材料制成的熔融挤出颗粒，以及其他辅料。
该制剂通过将人参皂苷C-K和载体材料熔融后，挤出制粒，然后将所述颗粒与其他辅料混合制备而成。
本发明的人参皂苷C-K口服固体制剂，所述的载体材料选自聚乙二醇、共聚维酮、聚乙二醇/乙烯基己内酰胺/醋酸乙烯酯共聚物、羟丙基甲基纤维素乙酸琥珀酸酯、维生素E聚乙二醇琥珀酸酯中的一种或几种。
优选地，所述的人参皂苷C-K口服固体制剂，其中人参皂苷C-K和载体材料的重量比为1:0.5～15，优选重量比为1:1～5。
优选地，所述的人参皂苷C-K口服固体制剂，其中载体材料由聚乙二醇、共聚维酮、聚乙二醇/乙烯基己内酰胺/醋酸乙烯酯共聚物、羟丙基甲基纤维素乙酸琥珀酸酯、维生素E聚乙二醇琥珀酸酯中的两种组成，特别是由共聚维酮和维生素E聚乙二醇琥珀酸酯组成。
进一步优选地，所述的人参皂苷C-K口服固体制剂，人参皂苷C-K和两种载体材料的重量比为1:0.5～10:0.1～1，优选重量比为1:1～5:0.2～0.6，特别是重量比为1:3:0.4。
此外，所述的人参皂苷C-K口服固体制剂，其中涉及的其他辅料还包括如下的一种或多种：填充剂、崩解剂、增溶剂和润滑剂。
优选地，所述的人参皂苷C-K口服固体制剂，所述的填充剂选自微晶纤维素、乳糖、淀粉、预胶化淀粉、甘露醇和蔗糖中的一种或几种。
优选地，所述的人参皂苷C-K口服固体制剂，所述的崩解剂选自羧甲基淀粉钠、交联聚维酮、低取代羟丙基纤维素和交联羧甲基纤维素钠中的一种或几种。
优选地，所述的人参皂苷C-K口服固体制剂，所述的润滑剂选自硬脂酸镁、胶体二氧化硅和滑石粉中的一种或几种。
本发明的另一目的是提供所述人参皂苷C-K口服固体制剂的制备方法，该方法包括以下步骤：将人参皂苷C-K和载体材料加热熔融；将熔液利用热熔挤出机挤出制粒；将颗粒与其他辅料混合均匀，制备成口服固体制剂。
本发明的人参皂苷C-K口服固体制剂在模拟体内胃液(pH1.2)和肠液(pH6.8)中溶出度与普通物理混合物相比，在两种介质中溶出效果均得到了明显提高。可见，本发明能大大改善人参皂苷C-K的溶出性能。
体内药物代谢动力学研究显示，在空腹和饱腹两种情况下，本发明制剂相比物理混合物均能明显提高了人参皂苷C-K在体内的生物利用度，有非常大的临床应用价值。
与现有技术相比，本发明所涉及的人参皂苷C-K口服固体制剂具有如下优点：
(1)本发明中人参皂苷C-K以玻璃态分散在基质中，形成无定型的原料，获得高度分散的产品，增加了原料药的溶解性能，并将其制成适合临床使用的剂型，提高了人参皂苷C-K在体内的生物利用度，从而降低了临床使用的规格剂量，提高了临床依从性。
(2)本发明通过合理使用载体材料和配比，克服了热熔挤出过程中较高温度对人参皂苷C-K质量的影响，制得的热熔挤出物透明度好，易于成形。
(3)本发明所需辅料种类少，且均为常用辅料，制得的制剂质量可控，稳定性好。
(4)制备过程比较简单，操作方便，适合工艺化大生产。
附图说明
图1为实施例1中人参皂苷C-K原料药的粉末X-射线衍射图谱；
图2为实施例1中制备的人参皂苷C-K热熔挤出颗粒的粉末X-射线衍射图谱。
具体实施方式
以下结合实施例对本发明进行详细说明，必须指出，以下实施例只用于说明本发明，而不是对本发明的限制。
实施例1
| 人参皂苷C-K | 1份 |
| 共聚维酮 | 3份 |
| 维生素E聚乙二醇琥珀酸酯(TPGs) | 0.4份 |
| 微晶纤维素 | 5份 |
| 交联聚维酮 | 3份 |
| 胶体二氧化硅 | 0.12份 |
| 硬脂酸镁 | 0.08份 |
制备方法：
(1)将100g人参皂苷C-K、300g共聚维酮和40g TPGs混匀后投入到已经预热至120℃～170℃的热熔挤出机中或者将100g人参皂苷C-K，300g共聚维酮和40g TPGs同时投入到已经预热至120℃～170℃的热熔挤出机中；
(2)上述物料被挤出后，冷却粉碎过20～80目筛，即得到人参皂苷C-K热熔挤出颗粒；
(3)在人参皂苷C-K热熔挤出颗粒中加入500g微晶纤维素、300g交联聚维酮和12g胶体二氧化硅混合均匀，再加入8g硬脂酸镁混合均匀，按每片含50mg人参皂苷C-K的规格压片，即得。
实施例2
| 人参皂苷C-K | 1份 |
| 聚乙二醇/乙烯基己内酰胺/醋酸 | 3份 |
| 微晶纤维素 | 4份 |
| 乳糖 | 2份 |
| 交联羧甲基纤维素钠 | 1.5份 |
| 胶体二氧化硅 | 0.12份 |
| 硬脂酸镁 | 0.08份 |
制备方法：
(1)将100g人参皂苷C-K和300g Soluplus混匀后投入到已经预热至120℃～170℃的热熔挤出机中或者将100g人参皂苷C-K和300g Soluplus同时投入到已经预热至120℃～170℃的热熔挤出机中；
(2)上述物料被挤出后，冷却粉碎过20～80目筛，即得到人参皂苷C-K热熔挤出颗粒；
(3)在人参皂苷C-K热熔挤出颗粒中加入400g微晶纤维素、200g乳糖、150g交联羧甲基纤维素钠和12g胶体二氧化硅混合均匀，再加入8g硬脂酸镁混合均匀，按每片或每粒含50mg人参皂苷C-K的规格压片或灌胶囊，即得。
实施例3
| 人参皂苷C-K | 1份 |
| 共聚维酮 | 6份 |
| 维生素E聚乙二醇琥珀酸酯(TPGs) | 0.8份 |
| 微晶纤维素 | 5份 |
| 交联羧甲基纤维素钠 | 3份 |
| 胶体二氧化硅 | 0.12份 |
| 硬脂酸镁 | 0.08份 |
制备方法：
(1)将100g人参皂苷C-K、600g共聚维酮和80g TPGs混匀后投入到已经预热至120℃～170℃的热熔挤出机中或者将100g人参皂苷C-K、600g共聚维酮和80g TPGs同时投入到已经预热至120℃～170℃的热熔挤出机中；
(2)上述物料被挤出后，冷却粉碎过20～80目筛，即得到人参皂苷C-K热熔挤出颗粒；
(3)在人参皂苷C-K热熔挤出颗粒中加入500g微晶纤维素、300g交联羧甲基纤维素钠、12g胶体二氧化硅混合均匀，再加入8g硬脂酸镁混合均匀，按每片或每粒含50mg人参皂苷C-K的规格压片或灌成胶囊，即得。
对比实施例1
制备方法：
(1)将100g人参皂苷C-K与318g乳糖、140g微晶纤维素、30g聚维酮、12g交联羧甲基纤维素钠混合均匀；
(2)加入6g硬脂酸镁混合均匀，按每片含50mg人参皂苷C-K的规格压片，即得。
实施例4溶出对比研究
人体在空腹时胃液pH约为1.2，肠液pH值约为6.8，本试验对实施例1和对比实施例1进行体外溶出对比测试研究，测试条件如下所示：
溶出方法：USPⅡ法(浆法)
溶出介质：pH1.2溶出介质900ml，在15、30、45、60min取样。
pH6.8溶出介质900ml，在15、30、45、60min取样。
转速：100rpm
温度：37.5℃
测试剂量：50mg(人参皂苷)/杯
结果见下表：
在pH1.2溶出介质的溶出测试结果
C-K增溶片在pH6.8溶出介质的溶出测试结果
对比实施例1在模拟体内胃液(pH1.2)、肠液(pH6.8)中溶出度均小于10％，而实施例1在两种介质中溶出效果均得到了明显增加。可见，本发明能大大改善人参皂苷C-K的溶出性能。
实施例5生物利用度对比研究
将SD大鼠12只，雄性，随机分成3组，每组4只，分别灌胃给予实施例1和对比实施例1的样品，给药后于0.25，0.5，1.0，1.5，2.0，3.0，4.0，6.0，8.0和12h，经大鼠眼球后静脉丛取静脉血0.2ml，置肝素化试管中，11000rpm离心5min，分离血浆，采用LC-MS/MS法测定血浆中人参皂苷C-K的浓度。采用Phoenix 1.3软件计算大鼠灌胃给药后的主要药动学参数(Tmax，Cmax，AUC，MRT，t1/2)。具体安排见下表
试验分组表
注：其中禁食组在给药前禁食12h，自由饮水，给药后2h统一提供食物。不禁食组动物在整个试验过程不限食和进水。
大鼠空腹灌胃给予10mg/kg受试制剂1和参比制剂后，血浆中人参皂苷的浓度和药动学参数见下表。
大鼠空腹灌胃给予10mg/kg各制剂后人参皂苷的血浆浓度(ng/mL)
大鼠空腹灌胃给予10mg/kg各制剂后人参皂苷的药动学参数
大鼠饱腹灌胃给予10mg/kg受试制剂1和参比制剂后，血浆中人参皂苷C-K的浓度和药动学参数见下表。
大鼠饱腹灌胃给予10mg/kg各制剂后人参皂苷的血浆浓度(ng/mL)
大鼠饱腹灌胃给予10mg/kg各制剂后人参皂苷的药动学参数
体内药物代谢动力学研究显示，空腹和饱腹给予不同人参皂苷C-K样品后均呈现出较为一致的药动学性能结果：空腹状态，实施例1的AUC比对比实施1增加45％以上；饱腹状态，实施例1的AUC比对比实施例1增加60％以上。可见，实施例1明显提高了人参皂苷C-K在体内的生物利用度。
实施例6稳定性
将实施例1制备得到的片剂，双铝包装后放置于40℃±2℃、RH75％±5％条件下，进行稳定性研究，测得的稳定性数据如下：
结果显示，在储存条件为40℃±2℃、RH75％±5％放置6个月后，所设定的检测指标均无明显变化，表明样品较为稳定。
Claims (9)
1.一种人参皂苷C-K口服固体制剂，其特征在于含有由人参皂苷C-K和载体材料制成的熔融挤出颗粒，以及其他辅料，其中所述的载体材料由共聚维酮和维生素E聚乙二醇琥珀酸酯组成，其中人参皂苷C-K和共聚维酮、维生素E聚乙二醇琥珀酸酯的重量比为1:0.5～10:0.1～1。
2.根据权利要求1所述的人参皂苷C-K口服固体制剂，其特征在于它通过将人参皂苷C-K和载体材料熔融后，挤出制粒，然后将所述颗粒与其他辅料混合制备而成。
3.根据权利要求1所述的人参皂苷C-K口服固体制剂，其特征在于：人参皂苷C-K和共聚维酮、维生素E聚乙二醇琥珀酸酯的重量比为1:1～5:0.2～0.6。
4.根据权利要求3所述的人参皂苷C-K口服固体制剂，其特征在于：人参皂苷C-K和共聚维酮、维生素E聚乙二醇琥珀酸酯的重量比为1:3:0.4。
5.根据权利要求1～4任一项所述的人参皂苷C-K口服固体制剂，其特征在于：所述的其他辅料包括如下的一种或多种：填充剂、崩解剂、增溶剂和润滑剂。
6.根据权利要求5的人参皂苷C-K口服固体制剂，其特征在于：所述的填充剂选自微晶纤维素、乳糖、淀粉、预胶化淀粉、甘露醇和蔗糖中的一种或几种。
7.根据权利要求5的人参皂苷C-K口服固体制剂，其特征在于：所述的崩解剂选自羧甲基淀粉钠、交联聚维酮、低取代羟丙基纤维素和交联羧甲基纤维素钠中的一种或几种。
8.根据权利要求5的人参皂苷C-K口服固体制剂，其特征在于：所述的润滑剂选自硬脂酸镁、胶体二氧化硅和滑石粉中的一种或几种。
9.一种根据权利要求1～5任一项所述的人参皂苷C-K口服固体制剂的制备方法，其特征在于，包括以下步骤：将人参皂苷C-K和载体材料加热熔融；将熔液利用热熔挤出机挤出制粒；将颗粒与其他辅料混合均匀，制备成口服固体制剂。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2015/000488 WO2017004733A1 (zh) | 2015-07-03 | 2015-07-03 | 一种人参皂苷c-k口服固体制剂及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107735080A CN107735080A (zh) | 2018-02-23 |
| CN107735080B true CN107735080B (zh) | 2020-10-23 |
Family
ID=57684834
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580081215.3A Active CN107735080B (zh) | 2015-07-03 | 2015-07-03 | 一种人参皂苷c-k口服固体制剂及其制备方法 |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US20180185399A1 (zh) |
| CN (1) | CN107735080B (zh) |
| WO (1) | WO2017004733A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112999167B (zh) * | 2021-03-01 | 2023-05-02 | 安徽九华华源药业有限公司 | 人参子速释微丸及其制备方法 |
| KR20240074961A (ko) * | 2022-11-15 | 2024-05-29 | 한국한의약진흥원 | 저분자 성분의 함량 증진을 위한 경옥고의 가공방법, 이렇게 얻어진 미세 콜로이드 분산체 및 이를 포함하는 조성물 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1623554A (zh) * | 2003-12-06 | 2005-06-08 | 山东绿叶天然药物研究开发有限公司 | 一种以c－k为有效成分的抗癌辅助药物及其应用 |
| CN1879647A (zh) * | 2006-04-29 | 2006-12-20 | 杭州创新中药标准化研究所有限公司 | 原人参二醇固体分散体及其制备方法 |
| CN102740841A (zh) * | 2009-12-08 | 2012-10-17 | 株式会社一和 | 含有20-O-β-D-吡喃葡糖基-20(S)-原人参二醇的固体分散体 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4344934A (en) * | 1978-11-20 | 1982-08-17 | American Home Products Corporation | Therapeutic compositions with enhanced bioavailability |
| KR0164266B1 (ko) * | 1996-02-22 | 1999-01-15 | 오오니시 쿠니히로 | 인삼사포닌 장내세균 대사물 및 이를 유효성분으로하는 제암제제 |
| CA2407027C (en) * | 2000-04-20 | 2011-02-15 | Rtp Pharma Inc. | Improved water-insoluble drug particle process |
| JP2004534811A (ja) * | 2001-06-22 | 2004-11-18 | ファイザー・プロダクツ・インク | ポリマーと薬剤の集合体を含む医薬組成物 |
| US20030129250A1 (en) * | 2001-11-20 | 2003-07-10 | Advanced Inhalation Research Inc. | Particulate compositions for improving solubility of poorly soluble agents |
| AR038681A1 (es) * | 2002-02-14 | 2005-01-26 | Solvay Pharm Bv | Formulacion oral de solucion solida de una sustancia activa pobremente soluble en agua |
| GB2447898B (en) * | 2007-03-24 | 2011-08-17 | Reckitt Benckiser Healthcare | A tablet having improved stability with at least two actives |
| NZ605440A (en) * | 2010-06-10 | 2014-05-30 | Abbvie Bahamas Ltd | Solid compositions comprising an hcv inhibitor |
| IE20100799A1 (en) * | 2010-12-22 | 2012-08-01 | Eurand Pharmaceuticals Ltd | Pharmaceutical composites of poorly water soluble drugs and polymers |
| CA2935307C (en) * | 2013-12-31 | 2023-05-09 | Ascendia Pharmaceuticals, Llc | Pharmaceutical compositions for poorly water-soluble compounds |
-
2015
- 2015-07-03 US US15/741,245 patent/US20180185399A1/en not_active Abandoned
- 2015-07-03 CN CN201580081215.3A patent/CN107735080B/zh active Active
- 2015-07-03 WO PCT/CN2015/000488 patent/WO2017004733A1/zh active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1623554A (zh) * | 2003-12-06 | 2005-06-08 | 山东绿叶天然药物研究开发有限公司 | 一种以c－k为有效成分的抗癌辅助药物及其应用 |
| CN1879647A (zh) * | 2006-04-29 | 2006-12-20 | 杭州创新中药标准化研究所有限公司 | 原人参二醇固体分散体及其制备方法 |
| CN102740841A (zh) * | 2009-12-08 | 2012-10-17 | 株式会社一和 | 含有20-O-β-D-吡喃葡糖基-20(S)-原人参二醇的固体分散体 |
Non-Patent Citations (6)
| Title |
|---|
| 乔艳丽等.溶剂蒸发法和热熔挤出法制备苯扎贝特固体分散体.《中国医药工业杂志》.2011,(第09期), * |
| 于永新等.聚乙二醇1000维生素E琥珀酸酯应用进展.《沈阳药科大学学报》.2006,(第06期), * |
| 孙考祥等.人参皂苷Rg_3固体分散体的制备与体外特性研究.《中草药》.2008,(第01期), * |
| 李慧等.热熔挤出法制备联苯双酯固体分散体的工艺.《沈阳药科大学学报》.2008,(第07期), * |
| 赵优曼等.热熔挤出法制备尼美舒利固体分散体.《中国药学杂志》.2013,(第03期), * |
| 陈玉红等.热熔挤出技术制备艾拉莫德固体分散体及体外溶出度的影响因素研究.《中国药学杂志》.2013,(第17期), * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2017004733A1 (zh) | 2017-01-12 |
| US20180185399A1 (en) | 2018-07-05 |
| CN107735080A (zh) | 2018-02-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104721142B (zh) | 一种利伐沙班固体分散体及其制备方法 | |
| JP6522853B2 (ja) | Ｓｏｍｃｌ−９１１２固体分散体、その製造方法およびそれを含むｓｏｍｃｌ−９１１２固体製剤 | |
| WO2013139111A1 (zh) | 黄蜀葵花总黄酮提取物及其制备方法 | |
| CN110114063B (zh) | 鲁拉西酮固体分散体及其制备方法 | |
| CN115427022B (zh) | 药物组合物、制备方法及其使用方法 | |
| CN103690545A (zh) | 口服泼尼松择时释放制剂及其制备方法 | |
| CN107735080B (zh) | 一种人参皂苷c-k口服固体制剂及其制备方法 | |
| CN107303278B (zh) | 一种hc-1119固体分散体及其制备方法 | |
| CN108785256B (zh) | 一种固体分散体及其制备方法 | |
| WO2024093944A1 (zh) | 一种姜黄素衍生物的固体分散体及其制备和应用 | |
| CN102379885A (zh) | 一种三七三醇皂苷肠溶微丸及其胶囊剂和制备方法 | |
| CN103610658A (zh) | 一种免疫调节剂缓释剂及其制备方法 | |
| CN103393611A (zh) | 一种盐酸伊伐布雷定片剂及其制备方法 | |
| CN103222964B (zh) | 一种奥利司他口服制剂及其制备方法 | |
| WO2016029494A1 (zh) | 微晶纤维素在制备美索舒利制剂中的用途及其制备方法 | |
| WO2022028264A1 (zh) | 富马酸奥比特嗪肠溶微丸及其制备方法和用途 | |
| CN115227652A (zh) | 一种米哚妥林片及其制备方法 | |
| CN114392249A (zh) | 一种多糖铁复合物的肠溶微丸及粉末直压片剂 | |
| WO2017032111A1 (zh) | 二羟基丙酮在制备抗肿瘤的药物中的用途 | |
| WO2016150355A1 (zh) | 提高绿原酸生物利用度的绿原酸酰化物及应用 | |
| CN112500358A (zh) | 赛乐西帕晶型及其制备方法 | |
| CN110354082A (zh) | 3,5,7-三羟基黄酮类衍生物的固体分散体 | |
| CN112972396A (zh) | 一种非布司他控释组合物及其制备方法 | |
| CN105412021B (zh) | 热熔挤出法制备银杏内酯b无定形固体分散体 | |
| EP4427747A1 (en) | Solid dispersion, preparation method therefor, and solid formulation containing same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: The invention relates to a ginsenoside c-k oral solid preparation and a preparation method thereof Effective date of registration: 20201226 Granted publication date: 20201023 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020330001302 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20210425 Granted publication date: 20201023 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020330001302 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Ginsenoside c-k oral solid preparation and preparation method thereof Effective date of registration: 20210729 Granted publication date: 20201023 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330000982 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20230130 Granted publication date: 20201023 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330000982 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: An oral solid preparation of ginsenoside C-K and its preparation method Effective date of registration: 20230228 Granted publication date: 20201023 Pledgee: Industrial Commercial Bank of China Ltd. Taizhou Jiaojiang branch Pledgor: ZHEJIANG HISUN PHARMACEUTICAL Co.,Ltd. Registration number: Y2023330000447 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |