CN1634885B - 米格列奈晶型及其制备方法 - Google Patents
米格列奈晶型及其制备方法 Download PDFInfo
- Publication number
- CN1634885B CN1634885B CN 200410088900 CN200410088900A CN1634885B CN 1634885 B CN1634885 B CN 1634885B CN 200410088900 CN200410088900 CN 200410088900 CN 200410088900 A CN200410088900 A CN 200410088900A CN 1634885 B CN1634885 B CN 1634885B
- Authority
- CN
- China
- Prior art keywords
- mitiglinide
- preparation
- crystal formation
- solvent
- pharmaceutical composition
- 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.)
- Expired - Fee Related
Links
- 229960003365 mitiglinide Drugs 0.000 title claims abstract description 57
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 title claims abstract description 56
- 238000000034 method Methods 0.000 title description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- 239000013078 crystal Substances 0.000 claims description 30
- 230000015572 biosynthetic process Effects 0.000 claims description 20
- -1 perhydroisoindole-2-yl Chemical group 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000013543 active substance Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003405 delayed action preparation Substances 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 4
- 239000006188 syrup Substances 0.000 claims description 4
- 235000020357 syrup Nutrition 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
- 239000006187 pill Substances 0.000 claims description 3
- 230000005855 radiation Effects 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000006072 paste Substances 0.000 claims description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
- 239000002131 composite material Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- LPUHHUHHKIXBCP-UHFFFAOYSA-L calcium butanoate dihydrate Chemical compound O.O.[Ca++].CCCC([O-])=O.CCCC([O-])=O LPUHHUHHKIXBCP-UHFFFAOYSA-L 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 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 description 3
- 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 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- LXAHHHIGZXPRKQ-UHFFFAOYSA-N 5-fluoro-2-methylpyridine Chemical compound CC1=CC=C(F)C=N1 LXAHHHIGZXPRKQ-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 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 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 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 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- 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 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 150000003376 silicon Chemical class 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- NGSFWBMYFKHRBD-UHFFFAOYSA-N sodium;2-hydroxypropanoic acid Chemical compound [Na+].CC(O)C(O)=O NGSFWBMYFKHRBD-UHFFFAOYSA-N 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- ZAVXXBAIPSQJGS-UHFFFAOYSA-B tetracalcium;tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O.[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O.[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O ZAVXXBAIPSQJGS-UHFFFAOYSA-B 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种治疗糖尿病药物米格列奈的新晶型、含有它的组合物及其制备方法，米格列奈是治疗II型糖尿病的药物，化学名是(—)—2(S)—苄基—4—氧—4—(顺式全氢化异吲哚—2—基)丁酸钙盐二水合物，本发明的新晶型具有稳定性高的特点。
Description
技术领域：
本发明涉及一种治疗糖尿病药物的结晶形态，特别是米格列奈的新晶型、含有它的组合物及其制备方法。
背景技术：
米格列奈(mitiglinide)的化学名是(—)—2(S)—苄基—4—氧—4—(顺式全氢化异吲哚—2—基)丁酸钙盐二水合物。米格列奈是治疗II型糖尿病的新型药物，与传统磺酰脲类药物相比，给药后起效迅速而作用时间短，可抑制II型糖尿病特征性的餐后高血糖，安全性高，耐受性好；与同属美格列脲类药物的瑞格列奈、那格列奈相比，疗效更强。相关信息披露有：美国专利US6133454、US5202335；欧洲专利EP 0967204；Chem.Pharm.Bull.1997，45(9)：1518～1520和1998，46(2)：337～340；Drugs of the Future2000，25(10)：1034～1042。现有文献中无有关米格列奈晶型的公开报道。
发明内容
本发明提供一种结晶形态的米格列奈化合物，该结晶形态的米格列奈与非结晶形态和其他形态的米格列奈相比，具有稳定性好，适合大规模生产，有利于制剂过程中的操作，产品质量可控等优点。
本发明的具有良好稳定性的米格列奈晶型是将米格列奈溶于合适的溶剂中，然后加入一定比例的水，放置析晶，过滤，真空干燥后形成的一种新形态的米格列奈结晶。该晶型的米格列奈使用Cu—Ka辐射，以2θ角度和晶面间距(d值)表示的X—射线粉末衍射在约5.0(17.6)、5.9(15.0)、14.6(6.1)、15.1(5.9)和17.2(5.1)有特征峰，如图1所示。
本发明的米格列奈晶型是在制备米格列奈产品过程中形成的，米格列奈晶型在产物中的比例为50％以上可达到本发明的目的，优选的是70％以上，更优选的是85％以上。
本发明还提供一种制备本发明米格列奈晶型的方法。该方法包括以下步骤：
(1)将米格列奈溶解于1～100倍的溶剂中；
(2)加入溶剂量1～10％的水，放置析晶；
(3)过滤，5～50％水与溶剂的混合液洗涤；
(4)35～55℃真空干燥
在步骤(1)所用的溶剂选自下述溶剂中的一种或多种：甲醇、乙醇、丙醇、异丙醇、N，N—二甲基甲酰胺。
使用本方法制得的米格列奈晶型的纯度可达到85％以上。
本发明还提供用本发明的米格列奈晶型制成的药物组合物。
本发明米格列奈晶型组合物含有生理有效量的本发明的米格列奈晶型和适宜的药用赋形剂，所述组合物是米格列奈晶型与药用赋形剂配制成的医学上可接受的药物制剂。
本发明的药物制剂可以是任何可药用的剂型，这些剂型包括：片剂、胶囊剂、口服液、糖浆剂、颗粒剂、丸剂、散剂、膏剂、丹剂、注射剂、栓剂、霜剂、喷雾剂、滴丸剂、贴剂、缓释制剂、控释制剂。
本发明的药物制剂，其口服给药的制剂可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。
适用的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂。适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠。适宜的润滑剂，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
可通过混合，填充，压片等常用的方法制备固体口服组合物。进行反复混合可使活性物质分布在整个使用大量填充剂的那些组合物中。
口服液体制剂的形式例如可以是水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂，或者可以是一种在使用前可用水或其它适宜的载体复配的干燥产品。这种液体制剂可含有常规的添加剂，诸如悬浮剂，例如山梨醇、糖浆、甲基纤维素、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶或氢化食用脂肪，乳化剂，例如卵磷脂、脱水山梨醇一油酸酯或阿拉伯胶；非水性载体(它们可以包括食用油)，例如杏仁油、分馏椰子油、诸如甘油的酯的油性酯、丙二醇或乙醇；防腐 剂，例如对羟基苯甲酯或对羟基苯甲酸丙酯或山梨酸，并且如果需要，可含有常规的香味剂或着色剂。
对于注射剂，制备的液体单位剂型含有本发明的活性物质和无菌载体。根据载体和浓度，可以将此化合物悬浮或者溶解。溶液的制备通常是通过将活性物质溶解在一种载体中，在将其装入一种适宜的小瓶或安瓿前过滤消毒，然后密封。辅料例如一种局部麻醉剂、防腐剂和缓冲剂也可以溶解在这种载体中。为了提高其稳定性，可在装入小瓶以后将这种组合物冰冻，并在真空下将水除去。
以上制剂中所用赋形剂选自：甘露醇、山梨醇、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素C、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、土温80、琼脂、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β—环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的制剂可以通过药剂学常规技术制备。
以下通过稳定性实验数据说明本发明的优良效果。
实验一米格列奈新晶型稳定性考察
取同一个批号的米格列奈新晶型样品，取适量装于三个平皿中，分别置于下述条件(45001x±5001x光照、45℃高温、相对湿度92.5％高湿度)下考察其晶型稳定性，晶型含量测定结果如表一所示。
表一米格列奈新晶型稳定性考察结果
本发明制备的米格列奈新晶型及米格列奈新晶型组合物具有良好的晶型稳定性，便于生产、运输和储存。经试验表明，新晶型的米格列奈可在常温条件下保持2年以上晶型基本不改变，药物含量不降低，完全符合药物的要求。
附图说明：
图1是米格列奈新晶型的X—射线粉末衍射图谱。
图2是米格列奈新晶型的红外吸收光谱。
具体实施方式：
下面的实施例将对本发明做进一步的解释，但是本发明并不仅仅局限于这些实施例，这些实施例不以任何方式限制本发明的范围。本领域的技术人员在权利要求的范围内所作出的某些改变和调整也应认为属于本发明的范围。
实施例1
在250ml烧瓶中加入5克米格列奈，室温下加入50ml乙醇使之溶解，加入2.5ml水，摇匀后放置过夜析晶，过滤，10％水—乙醇洗涤，40℃真空干燥8小时，即得纯度90％的米格列奈新晶型。
实施例2
在250ml烧瓶中加入5克米格列奈，室温下加入25ml甲醇使之溶解，加入2.5ml水，摇匀后放置过夜析晶，过滤，20％水—甲醇洗涤，40℃真空干燥8小时，即得纯度88％的米格列奈新晶型。
实施例3
在250ml烧瓶中加入5克米格列奈，室温下加入200ml异丙醇使之溶解，加入5ml水，摇匀后放置过夜析晶，过滤，5％水—异丙醇洗涤，45℃真空干燥8小时，即得纯度85％的米格列奈新晶型。
实施例4制备米格列奈新晶型的片剂
按下述方法制备每片含5mg米格列奈新晶型的片剂：
配方：米格列奈5g，微晶纤维素27.5g，乳糖28.7g，玉米淀粉10g，羟丙基纤维素3g，硬脂酸镁0.8g，制成1000片。
方法：将上述主、辅料分别过100目筛，按处方量分别称取之；按等量递增法将主药与辅料混合均匀；半成品检验，测定颗粒含量，确定平均片重；用φ7mm 小凹冲模压片，即可。
实施例5米格列奈新晶型物理特性的测定
通过X—射线衍射方法将新晶型的米格列奈粉末置于粉末衍射仪上，以4度/分的扫描速率在2.6～40度2θ角之间进行扫描，使用Cu—Ka40Kv～100mAX射线辐射，以2θ角度和晶面间距(d值)表示的新晶型的米格列奈的X—射线粉末衍射应在约5.0(17.6)、5.9(15.0)、14.6(6.1)、15.1(5.9)和17.2(5.1)有特征峰，如图1所示。
用FT—IR分光光度仪检查米格列奈新晶型的红外光谱显示，新晶型的米格列奈在约3424、2854～2926、1618、1495～1562、1449、1335(cm-1)处有特征谱带，如图2所示。
Claims (10)
1.一种米格列奈晶型，其特征在于，使用Cu-Ka辐射以2θ角度和晶面间距(d值)表示，其具有如图1所示的X射线粉末衍射图谱，其中所述的米格列奈是指(-)-2(S)-苄基-4-氧-4-(顺式全氢化异吲哚-2-基)丁酸钙盐二水合物。
2.一种制备米格列奈药物制剂的药物活性物质，由米格列奈组成，其中含有权利要求1所述的米格列奈晶型在50％以上，其中所述的米格列奈是指(-)-2(S)-苄基-4-氧-4-(顺式全氢化异吲哚-2-基)丁酸钙盐二水合物。
3.权利要求2的药物活性物质，其中含有权利要求1所述的米格列奈晶型在85％以上。
4.含有权利要求1的米格列奈晶型的药物组合物，其特征在于，它含有生理有效量的权利要求1所述的米格列奈晶型和适宜的药物赋形剂。
5.权利要求4所述的药物组合物，其特征在于其为适合药用的任何剂型。
6.权利要求5所述的药物组合物，其特征在于所述剂型选自：片剂、胶囊剂、口服液、糖浆剂、颗粒剂、散剂、膏剂、丹剂、注射剂、栓剂、霜剂、喷雾剂、滴丸剂、贴剂、缓释制剂、控释制剂。
7.权利要求6所述的药物组合物，其特征在于所述剂型是片剂或胶囊剂。
8.权利要求1所述的米格列奈晶型的制备方法，包括下述步骤：
(1)将米格列奈溶解于1～100倍的溶剂中；
(2)加入溶剂量1～10％的水，放置析晶；
(3)过滤，5～50％水与溶剂的混合液洗涤；
(4)35～55℃真空干燥，其中所述的米格列奈是指(-)-2(S)-苄基-4-氧-4-(顺式全氢化异吲哚-2-基)丁酸钙盐二水合物。
9.根据权利要求8所述的制备方法，其特征在于，步骤(1)所述的溶剂选自下述溶剂中的一种或多种：甲醇、乙醇、丙醇、异丙醇、N，N-二甲基甲酰胺。
10.根据权利要求8所述的制备方法，其特征在于，步骤(3)所述的溶剂选自下述溶剂中的一种或多种：甲醇、乙醇、丙醇、异丙醇、N，N-二甲基甲酰胺。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410088900 CN1634885B (zh) | 2004-11-09 | 2004-11-09 | 米格列奈晶型及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410088900 CN1634885B (zh) | 2004-11-09 | 2004-11-09 | 米格列奈晶型及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1634885A CN1634885A (zh) | 2005-07-06 |
| CN1634885B true CN1634885B (zh) | 2011-05-04 |
Family
ID=34847529
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410088900 Expired - Fee Related CN1634885B (zh) | 2004-11-09 | 2004-11-09 | 米格列奈晶型及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1634885B (zh) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0507534A1 (en) * | 1991-03-30 | 1992-10-07 | Kissei Pharmaceutical Co., Ltd. | Succinic acid compounds |
| CN1261879A (zh) * | 1997-07-03 | 2000-08-02 | 阿迪尔公司 | 制备取代的全氢化异吲哚的方法 |
-
2004
- 2004-11-09 CN CN 200410088900 patent/CN1634885B/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0507534A1 (en) * | 1991-03-30 | 1992-10-07 | Kissei Pharmaceutical Co., Ltd. | Succinic acid compounds |
| CN1261879A (zh) * | 1997-07-03 | 2000-08-02 | 阿迪尔公司 | 制备取代的全氢化异吲哚的方法 |
Non-Patent Citations (8)
| Title |
|---|
| JP特开2001-261644A 2001.09.26 |
| JP特开2001-261645A 2001.09.26 |
| JP特开平4-356459A 1992.12.10 |
| JP特开平6-340623A，公开日 1994.12.13 |
| L.A.Sorbera et al.Mitiglinide calcium hydrate.Drugs of the future25 10.2000,25(10),1034-1042. |
| L.A.Sorbera et al.Mitiglinide calcium hydrate.Drugs of the future25 10.2000,25(10),1034-1042. * |
| Toshiaki Yamaguchi et al.Preparation of optically active succinic acid derivatives.Ⅲ.Regioselective condensation reactions of optically active2-substituted succinic acids with diimidazolide.Yakugaku Zasshi118 6.1998,118(6),248-255. |
| Toshiaki Yamaguchi et al.Preparation of optically active succinic acid derivatives.Ⅲ.Regioselective condensation reactions of optically active2-substituted succinic acids with diimidazolide.Yakugaku Zasshi118 6.1998,118(6),248-255. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1634885A (zh) | 2005-07-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6936274B2 (en) | Storage stable thyroxine active drug formulations and methods for their production | |
| DE69519664T2 (de) | Verfahren zur herstellung fester pharmazeutischer dosierungsform | |
| DE69418252T2 (de) | Stabilisierte, feste pharmazeutische Zubereitung, die Dextromethorphan Phenylpropanolamine und Coffein enthält | |
| NO172168B (no) | Fremgangsmaate for fremstilling av faste nifedipinpreparater med hoey biotilgjengelighet og med forlenget virkning | |
| JPH10194969A (ja) | 錠剤組成物 | |
| JPH09508913A (ja) | 微粉化ネビボロールを含有する組成物 | |
| US20180147183A1 (en) | Use of r-oxiracetam in pharmaceutical field | |
| CN102949377B (zh) | 乙酰唑胺缓释胶囊及其制备方法 | |
| US20030099699A1 (en) | Storage stable thyroxine active drug formulations and methods for their production | |
| CN111991362A (zh) | 一种替格瑞洛缓释片及其制备方法 | |
| CN101597272B (zh) | 艾拉莫德的钾盐化合物,其制备方法和药物应用 | |
| JP2532224B2 (ja) | ニコランジル錠剤の製法 | |
| CN105753719B (zh) | 一种盐酸曲恩汀化合物 | |
| CN101993417B (zh) | 磷酸二甲啡烷的稳定晶型 | |
| CN116098864B (zh) | 一种利那洛肽干混悬剂及其制备方法 | |
| CN1634885B (zh) | 米格列奈晶型及其制备方法 | |
| CN109157527B (zh) | 一种厄贝沙坦胶囊及其制备方法 | |
| AU2012241189A1 (en) | Fast Dissolving Solid Dosage Form | |
| WO2017093890A1 (en) | Clobazam tablet formulation and process for its preparation | |
| WO2005020979A1 (en) | A process for the preparation of pharmaceutical compositions of nateglinide | |
| CN114788817A (zh) | 苯海拉明药物组合物 | |
| CN104130246A (zh) | 一种1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的新晶型及其制备方法 | |
| US6784315B2 (en) | Stilbene derivative crystal and method for producing the same | |
| JPH11116465A (ja) | 迅速溶解性製剤およびその製造法 | |
| KR20080030835A (ko) | 약학 조성물 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: BEIJING LELIJIAN BIOTECHNOLOGY CO., LTD. Free format text: FORMER OWNER: BEIJING FU KANG REN BIO-PHARM TECH CO., LTD. Effective date: 20110307 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 100070 ROOM 307, NO.9, KEXING ROAD, FENGTAI, BEIJING TO: 100070 A1602, NO.4, FUFENG ROAD, FENGTAI DISTRICT, BEIJING |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20110307 Address after: 100070 Beijing city Fengtai District Fung Fu Road No. 4 A1602 Applicant after: Beijing Lelijian Biotechnology Co., Ltd. Address before: 100070 Beijing Fengtai Branch Road No. 9 room 307 Applicant before: Beijing Fu Kang Ren Bio-pharm Tech Co., Ltd. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160414 Address after: Hangzhou City, Zhejiang province Yuhang District 310013 West Street warehouse before No. 1500 Building 1 room 237 Patentee after: Hangzhou Zhepu Taikang Biological Medicine Technology Co Ltd Address before: 100070 Beijing city Fengtai District Fung Fu Road No. 4 A1602 Patentee before: Beijing Lelijian Biotechnology Co., Ltd. |
|
| DD01 | Delivery of document by public notice |
Addressee: Hangzhou Zhepu Taikang Biological Medicine Technology Co Ltd Document name: Notification of Passing Examination on Formalities |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190628 Address after: 528244 Hecun Industrial Zone, Lishui Town, Nanhai District, Foshan City, Guangdong Province Patentee after: Foshan Yibaosheng Pharmaceutical Co., Ltd. Address before: 310013 237, room 1, 1500 West Wen Yi Road, Cang Qian street, Yuhang District, Hangzhou, Zhejiang. Patentee before: Hangzhou Zhepu Taikang Biological Medicine Technology Co Ltd |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110504 Termination date: 20201109 |