CN110664812A - 一种包含咪唑并异吲哚类衍生物的药物组合物 - Google Patents
一种包含咪唑并异吲哚类衍生物的药物组合物 Download PDFInfo
- Publication number
- CN110664812A CN110664812A CN201910585752.1A CN201910585752A CN110664812A CN 110664812 A CN110664812 A CN 110664812A CN 201910585752 A CN201910585752 A CN 201910585752A CN 110664812 A CN110664812 A CN 110664812A
- Authority
- CN
- China
- Prior art keywords
- acid
- pharmaceutical composition
- total weight
- formula
- amount
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 39
- NVZLBPXTJTXPDC-UHFFFAOYSA-N pyrrolo[3,4-e]benzimidazole Chemical class C1=CC2=NC=NC2=C2C=NC=C21 NVZLBPXTJTXPDC-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 230000002378 acidificating effect Effects 0.000 claims abstract description 19
- 239000000126 substance Substances 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims description 40
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 36
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 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 12
- 235000015165 citric acid Nutrition 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 229920002472 Starch Polymers 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 10
- 239000008107 starch Substances 0.000 claims description 10
- 235000019698 starch Nutrition 0.000 claims description 10
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 239000011975 tartaric acid Substances 0.000 claims description 9
- 235000002906 tartaric acid Nutrition 0.000 claims description 9
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- 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 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000008101 lactose Substances 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 229920002785 Croscarmellose sodium Polymers 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
- 239000000314 lubricant Substances 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
- 229960000913 crospovidone Drugs 0.000 claims description 6
- 239000000945 filler Substances 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 6
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 229920000881 Modified starch Polymers 0.000 claims description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 229940049654 glyceryl behenate Drugs 0.000 claims description 5
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 235000015424 sodium Nutrition 0.000 claims description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 5
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 5
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- SJZRECIVHVDYJC-UHFFFAOYSA-N 4-hydroxybutyric acid Chemical compound OCCCC(O)=O SJZRECIVHVDYJC-UHFFFAOYSA-N 0.000 claims description 4
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 239000001361 adipic acid Substances 0.000 claims description 4
- 235000011037 adipic acid Nutrition 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- 229960005070 ascorbic acid Drugs 0.000 claims description 4
- 229960005261 aspartic acid Drugs 0.000 claims description 4
- 235000003704 aspartic acid Nutrition 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 229960004365 benzoic acid Drugs 0.000 claims description 4
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 235000011087 fumaric acid Nutrition 0.000 claims description 4
- 239000000174 gluconic acid Substances 0.000 claims description 4
- 235000012208 gluconic acid Nutrition 0.000 claims description 4
- 235000013922 glutamic acid Nutrition 0.000 claims description 4
- 229960002989 glutamic acid Drugs 0.000 claims description 4
- 239000004220 glutamic acid Substances 0.000 claims description 4
- 229960003943 hypromellose Drugs 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 229960002510 mandelic acid Drugs 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 4
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- 229940107700 pyruvic acid Drugs 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- 229960004889 salicylic acid Drugs 0.000 claims description 4
- 239000000454 talc Substances 0.000 claims description 4
- 229910052623 talc Inorganic materials 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims 2
- 230000001070 adhesive effect Effects 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000008119 colloidal silica Substances 0.000 claims 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 claims 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229910002027 silica gel Inorganic materials 0.000 claims 1
- 229920000858 Cyclodextrin Polymers 0.000 description 19
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 14
- 101710120843 Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 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 11
- 238000004090 dissolution Methods 0.000 description 8
- 239000001116 FEMA 4028 Substances 0.000 description 7
- 229960004853 betadex Drugs 0.000 description 7
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 6
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- -1 oxygen free radical Chemical class 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 210000001744 T-lymphocyte Anatomy 0.000 description 3
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- YZOUYRAONFXZSI-SBHWVFSVSA-N (1S,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-37,39,40,41,42,43,44,45,46,47,48,49-dodecamethoxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38-diol Chemical compound O([C@@H]([C@H]([C@@H]1OC)OC)O[C@H]2[C@@H](O)[C@@H]([C@@H](O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3O)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O[C@@H]3[C@@H](CO)O[C@@H]([C@H]([C@@H]3OC)OC)O3)O[C@@H]2CO)OC)[C@H](CO)[C@H]1O[C@@H]1[C@@H](OC)[C@H](OC)[C@H]3[C@@H](CO)O1 YZOUYRAONFXZSI-SBHWVFSVSA-N 0.000 description 2
- PCWPQSDFNIFUPO-VDQKLNDWSA-N (1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37S,38R,39S,40R,41S,42R,43S,44R,45S,46R,47S,48R,49S)-37,39,41,43,45,47,49-heptakis(2-hydroxyethoxy)-5,10,15,20,25,30,35-heptakis(hydroxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontane-36,38,40,42,44,46,48-heptol Chemical compound OCCO[C@H]1[C@H](O)[C@@H]2O[C@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O[C@H]5O[C@H](CO)[C@@H](O[C@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O[C@H]8O[C@H](CO)[C@@H](O[C@H]1O[C@@H]2CO)[C@@H](O)[C@@H]8OCCO)[C@@H](O)[C@@H]7OCCO)[C@@H](O)[C@@H]6OCCO)[C@@H](O)[C@@H]5OCCO)[C@@H](O)[C@@H]4OCCO)[C@@H](O)[C@@H]3OCCO PCWPQSDFNIFUPO-VDQKLNDWSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 2
- 208000002177 Cataract Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 229960001375 lactose Drugs 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QJDCERFMSYFHLS-SANMLTNESA-N 2-[4-[4-[4-[(5S)-6-fluoro-5H-imidazo[5,1-a]isoindol-5-yl]piperidin-1-yl]phenyl]pyrazol-1-yl]ethanol Chemical compound FC1=C2[C@@H](N3C(C2=CC=C1)=CN=C3)C1CCN(CC1)C1=CC=C(C=C1)C=1C=NN(C=1)CCO QJDCERFMSYFHLS-SANMLTNESA-N 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 208000013452 Fallopian tube neoplasm Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102000008015 Hemeproteins Human genes 0.000 description 1
- 108010089792 Hemeproteins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000016604 Lyme disease Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- BYHJHXPTQMMKCA-QMMMGPOBSA-N N-formyl-L-kynurenine Chemical compound [O-]C(=O)[C@@H]([NH3+])CC(=O)C1=CC=CC=C1NC=O BYHJHXPTQMMKCA-QMMMGPOBSA-N 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 206010061372 Streptococcal infection Diseases 0.000 description 1
- 230000006044 T cell activation Effects 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
- 230000006052 T cell proliferation Effects 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 230000004913 activation Effects 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
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000036506 anxiety Effects 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
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000001125 extrusion 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
- 206010017758 gastric cancer Diseases 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- DIRLEDPEXJLCIL-JCWBWLHSSA-N succinyl-β-cyclodextrin Chemical compound OC(=O)CCC(=O)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](COC(=O)CCC(O)=O)[C@H]([C@H]([C@@H]3O)O)O[C@H]3O[C@H](COC(=O)CCC(O)=O)[C@H]([C@H]([C@@H]3O)O)O[C@H]3O[C@H](COC(=O)CCC(O)=O)[C@H]([C@H]([C@@H]3O)O)O[C@H]3O[C@H](COC(=O)CCC(O)=O)[C@H]([C@H]([C@@H]3O)O)O3)[C@@H](O)[C@@H]2O)COC(=O)CCC(=O)C)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O)[C@@H]3O[C@@H]1COC(=O)CCC(O)=O DIRLEDPEXJLCIL-JCWBWLHSSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000004383 yellowing Methods 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Psychiatry (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Ophthalmology & Optometry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Hospice & Palliative Care (AREA)
- Molecular Biology (AREA)
- Inorganic Chemistry (AREA)
- AIDS & HIV (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种包含咪唑并异吲哚类衍生物的药物组合物。具体而言，本发明涉及的药物组合物包含式(I)所示化合物或其药学上可接受的盐，以及酸性物质。所述的药物组合物具有改善的生物利用度。
Description
技术领域
本发明涉及一种包含咪唑并异吲哚类衍生物的药物组合物及其制 备方法。
背景技术
吲哚胺-吡咯-2,3-双加氧酶(Indoleamine-pyrrole-2,3-dioxygenase， IDO)是一种含铁血红素单体蛋白，由403个氨基酸残基组成，包括两 个折叠的α-螺旋结构域，大结构域包含催化口袋，底物可在催化口袋 内与IDO发生疏水等作用。IDO是催化色氨酸转化为甲酰犬尿氨酸的 酶，广泛分布在人和其他哺乳动物(兔、鼠)除肝脏以外的组织中，是肝 脏以外唯一可催化色氨酸分解代谢的限速酶，而色氨酸是细胞维持活 化和增殖所必需的氨基酸，也是构成蛋白质不可缺少的重要成分。IDO 与干扰素(interferon，IFN)、白细胞介素(interleukin，IL)、肿瘤坏死因 子等多种细胞因子关系密切，它们在一定条件下可激活IDO。而T-细 胞的细胞周期中存在一个对色氨酸水平非常敏感的调节点，一方面， IDO使局部色氨酸耗竭，致使T-细胞停滞于G1期中期，从而抑制了T 细胞的增殖；另一方面，IDO催化色氨酸代谢产生的主要产物犬尿素 由氧自由基介导引起细胞内氧化剂和抗氧化剂改变而诱导T-细胞凋亡， 这是存在于机体的固有的免疫抑制机制。目前大量研究表明IDO在白 血病细胞中较高表达，使局部T细胞增殖受抑，抑制T-细胞介导的免 疫反应，使T-细胞活化信号转导受阻，从而介导肿瘤细胞逃逸免疫系 统的攻击。已经发现大多数人类肿瘤组成性地表达IDO。因此，IDO 是一个具潜力的癌症免疫治疗的靶标。
IDO抑制剂作为药物在医药行业具有良好的应用前景。 WO2016169421公开了一种结构新型的高效低毒的选择性IDO抑制剂 化合物，具有优异的效果和作用，特别是优异的药代吸收活性，其化 学名为(S)-2-(4-(4-(4-(6-氟-5H-咪唑并[5,1-a]异吲哚-5-基)哌啶-1-基)苯 基)-1H-吡唑-1-基)乙醇，其化学结构如式(I)所示，
我们在研究中发现，将式(I)所示化合物制备成药物组合物时， 存在生物利用度不足的问题。即使加大组合物剂量，生物利用度仍提 高不明显，这就给式(I)所示化合物的临床应用带来了困难。
发明内容
为解决上述技术问题，本发明的目的在于提供一种包含式(I)所 示化合物的药物组合物，其具有改善的生物利用度。
本发明一方面提供了一种药物组合物，包含式(I)所示化合物或 其药学上可接受的盐，以及酸性物质。
在某些实施方式中，所述酸性物质制成0.1mol/L水溶液时的pH 不大于3。
所述酸性物质可以是有机酸或无机酸，例如可以是盐酸、苯磺酸、 对甲苯磺酸、硫酸、甲磺酸、乙酸、丙酸、丙二酸、草酸、葡萄糖酸、 琥珀酸、马来酸、富马酸、乳酸、酒石酸、苹果酸、柠檬酸、丙酮酸、 羟基丁酸、己二酸、水杨酸、双羟萘酸、邻苯二甲酸、天冬氨酸、谷 氨酸、扁桃酸、苯甲酸和抗坏血酸中的一种或多种，优选柠檬酸和/或 酒石酸。所述酸性物质的含量范围可以是基于组合物总重量计1％ -70％，优选5％-60％，更优选10％-55％。
本发明另一方面提供了一种药物组合物，包含式(I)所示化合物 或其药学上可接受的盐，以及环糊精。
所述环糊精可以是α-环糊精、β-环糊精、γ-环糊精或它们的衍生物。 已知的环糊精衍生物包括但不限于磺烷基醚环糊精衍生物、烷基醚环 糊精衍生物(例如，甲基、乙基和丙基醚环糊精)、羟烷基环糊精衍生 物、硫烷基醚环糊精衍生物、羧化环糊精衍生物(例如琥珀酰基-β-环 糊精等)、硫酸化环糊精衍生物等。例如，所述的环糊精可以是磺丁基-β-环糊精、羟丙基-β-环糊精、羟乙基-β-环糊精、葡萄糖基-β-环糊精、 甲基-β-环糊精。所述环糊精的含量范围可以是基于组合物总重量计1％ -70％，优选5％-60％，更优选10％-55％。
本发明的药物组合物中，所述式(I)所示化合物的含量范围可以 是基于组合物总重量计1％-30％，优选5％-25％。
在某些实施方式中，本发明所述药物组合物还包含填充剂，填充 剂可以是微晶纤维素、甘露醇、预胶化淀粉、乳糖等中的一种或多种。 基于组合物的总重量，所述填充剂含量为约10％-70％。
在某些实施方式中，本发明所述药物组合物还包含崩解剂，崩解 剂可以是交联羧甲基纤维素钠、淀粉、羧甲基淀粉钠及交联聚维酮中 的一种或多种。基于组合物的总重量，所述崩解剂含量可为1％-30％。
在某些实施方式中，本发明所述药物组合物还包含粘合剂，所述 粘合剂可以是羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙 烯吡咯烷酮、甲基纤维素等中的一种或多种。基于组合物的总重量， 所述粘合剂含量可为0.5％-15％。
在某些实施方式中，本发明所述药物组合物还包含润滑剂，所述 润滑剂可以是硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、 氢化植物油、微粉硅胶、滑石粉、胶态二氧化硅中的一种或多种。基 于组合物的总重量，润滑剂的含量可为0.5％-5％。
在某些实施方式中，本发明所述药物组合物为口服制剂，优选片 剂或胶囊剂。
本发明另一方面提供了一种药物组合物，包含：
1)式(I)所示化合物或其药学上可接受的盐，优选其含量为基于 组合物总重量计1％-30％，优选5％-25％；
2)酸性物质，选自盐酸、苯磺酸、对甲苯磺酸、硫酸、甲磺酸、乙 酸、丙酸、丙二酸、草酸、葡萄糖酸、琥珀酸、马来酸、富马酸、乳 酸、酒石酸、苹果酸、柠檬酸、丙酮酸、羟基丁酸、己二酸、水杨酸、 双羟萘酸、邻苯二甲酸、天冬氨酸、谷氨酸、扁桃酸、苯甲酸和抗坏 血酸中的一种或多种，优选柠檬酸和/或酒石酸，优选其含量为基于组 合物总重量计1％-70％，优选5％-60％，更优选10％-55％。
3)填充剂，选自微晶纤维素、甘露醇、预胶化淀粉、乳糖等中的一 种或多种，优选所述填充剂含量为基于组合物总重量计10％-70％；
4)崩解剂，选自交联羧甲基纤维素钠、淀粉、羧甲基淀粉钠及交联 聚维酮中的一种或多种，优选所述崩解剂含量为基于组合物的总重量 计1％-30％；
5)粘合剂，选自羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、 聚乙烯吡咯烷酮、甲基纤维素等中的一种或多种，优选所述粘合剂含 量为基于组合物的总重量计0.5％-15％；
6)润滑剂，选自硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸 钠、氢化植物油、微粉硅胶、滑石粉、胶态二氧化硅中的一种或多种， 优选所述润滑剂含量为基于组合物的总重量计0.5％-5％。
本发明另一方面提供了一种药物组合物，包含：
1)式(I)所示化合物或其药学上可接受的盐，优选其含量为基于 组合物总重量计1％-30％，优选5％-25％；
2)环糊精，选自磺丁基-β-环糊精、羟丙基-β-环糊精、羟乙基-β-环 糊精、葡萄糖基-β-环糊精或甲基-β-环糊精，优选其含量为基于组合物 总重量计1％-70％，优选5％-60％，更优选10％-55％。
3)填充剂，选自微晶纤维素、甘露醇、预胶化淀粉、乳糖等中的一 种或多种，优选所述填充剂含量为基于组合物总重量计10％-70％；
4)崩解剂，选自交联羧甲基纤维素钠、淀粉、羧甲基淀粉钠及交联 聚维酮中的一种或多种，优选所述崩解剂含量为基于组合物的总重量 计1％-30％；
5)粘合剂，选自羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、 聚乙烯吡咯烷酮、甲基纤维素等中的一种或多种，优选所述粘合剂含 量为基于组合物的总重量计0.5％-15％；
6)润滑剂，选自硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸 钠、氢化植物油、微粉硅胶、滑石粉、胶态二氧化硅中的一种或多种， 优选所述润滑剂含量为基于组合物的总重量计0.5％-5％。
本发明所述的药物组合物中式(I)所示化合物或其药学上可接受 的盐的含量可以是1-1000mg，优选10-500mg，更优选20-200mg。
本发明另一方面提供了一种制备本发明所述的药物组合物的方法， 包括将式(I)所示化合物或其药学上可接受的盐与一种或多种药学上 可接受的辅料混合的步骤。
例如，所述方法可以包含将式(I)所示化合物或其药学上可接受 的盐与酸性物质及一种或多种药学上可接受的辅料混合的步骤。
例如，所述方法可以包含将式(I)所示化合物或其药学上可接受 的盐与环糊精及一种或多种药学上可接受的辅料混合的步骤。
本发明所述的药物组合物可以通过本领域公知的方法进行制备。 例如，在颗粒剂的情况下，可根据需要将式(I)所示化合物或其药学 上可接受的盐以及赋形剂、粘合剂、崩解剂、润湿剂等混合进行搅拌 制粒、挤出制粒、转动制粒、喷雾一步制粒等来制造，直接干法制粒 亦可。此外，也可采用微丸上药方式制备。此外，也可根据需要进行 整粒、粉碎。进而，也可进一步向上述颗粒剂中加入赋形剂、崩解剂、 粘合剂、抗氧剂、着色剂等进行压片制成片剂或者直接灌胶囊。
本发明所述的药物组合物可用于预防和/或治疗预防具有IDO介导 的色氨酸代谢途径的病理学特征的疾病。这些疾病包括诸如AIDS等病 毒的感染，诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例 如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、 焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠 癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性 疾病，其中所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃 癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、前列腺癌、骨癌、肾 癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、黑色 素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈 部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明所述的式(I)所示化合物或其药学上可接受的盐可以是任意 形式，具体形式包括但不限于：无定形、任意晶型、水合物、溶剂合 物等。
本发明通过在组合物中添加酸性物质或环糊精，出人意料地将组 合物的生物利用度大大提高，有利于药物发挥药效。
附图说明
图1为实施例1-3所得制剂的体外溶出曲线图；
图2为实施例1-3所得制剂的模拟给药溶出曲线图；
图3为实施例4所得制剂的模拟给药溶出曲线图；
图4为实施例1、2、4所得制剂在人体内的平均血药浓度-时间曲 线对比图。
具体实施方式
实施例1：未添加酸性物质的处方
式(I)所示化合物药物组合物处方(质量百分比)：
将式(I)所示化合物、乳糖、微晶纤维素和交联羧甲基纤维素钠 进行混合，加入聚乙烯吡咯烷酮的水溶液，进行湿法制粒，整粒机进 行湿整粒，流化床干燥，整粒机进行干整粒后加入硬脂酸镁混合，压 片，用薄膜包衣预混剂包衣，制备规格为100mg的式(I)所示化合物 的片剂。
实施例2：添加柠檬酸处方
式(I)所示化合物药物组合物处方(质量百分比)：
将式(I)所示化合物、乳糖、微晶纤维素和交联聚乙烯吡咯烷酮 进行混合，加入聚乙烯吡咯烷酮的乙醇水溶液，进行湿法制粒，整粒 机进行湿整粒，流化床干燥，整粒机进行干整粒；柠檬酸粉碎后，采 用乙醇水溶液进行一步制粒后进行干整粒；将湿法制粒后的式(I)所 示化合物的颗粒、柠檬酸制粒后颗粒、交联聚乙烯吡咯烷酮(外加) 及硬脂酸镁混合，压片，用薄膜包衣预混剂包衣，制备规格为100mg 的式(I)所示化合物的片剂。
实施例3：添加酒石酸处方
式(I)所示化合物药物组合物处方(质量百分比)：
根据实施例2的方法，制备含100mg的式(I)所示化合物的片剂。
实施例4：添加磺丁基-β-环糊精处方
式(I)所示化合物药物组合物处方(45片)：
将式(I)所示化合物、乳糖、微晶纤维素、交联羧甲基纤维素钠、 磺丁基-β-环糊精和聚乙烯吡咯烷酮混合均匀，加入硬脂酸镁，混匀， 压片。
实施例5：体外溶出试验
根据中国药典2015年版四部通则0931第二法，对实施例1-3制得 的片剂样品进行体外溶出度测定。使用0.08％的十二烷基硫酸钠的 pH4.5醋酸盐缓冲液1000ml作为溶出介质，并在37±0.5℃下以75rpm 的桨速进行溶出试验，试验结果如图1所示。
结果表明，实施例1-3的片剂样品能在45min内溶出完全，溶出 良好。
实施例6：模拟给药试验
根据中国药典2015年版四部通则0931第二法，对实施例1-4制得 的片剂样品进行模拟给药试验。分别投入6片实施例1-4制得的片剂， 使用50ml pH3.0盐酸+100ml纯化水作为溶出介质，并在37±0.5℃下 以75rpm的桨速进行溶出试验，试验结果如图2、3所示。
结果表明，尽管体外溶出实验合格，但在模拟人体服用药物给药 的溶出方法下未加酸性物质的实施例1的样品基本不溶出；而加入了 酸性物质的实施例2、3样品能在45min内溶出85％以上，溶出良好。 加入了环糊精的实施例4样品能在45min内溶出85％以上，溶出良好。 制剂在模拟体内环境下的优异溶出有利于药物被人体吸收，增加生物 利用度。
实施例7
使用实施例1、实施例2和实施例4的片剂样品，在健康人体中测 定药物的药代动力学参数。选择男性健康受试者单次口服6片片剂样 品(非交叉)，受试者在试验前日晚进统一清淡饮食，晚饭后禁食至次 日晨，于试验当日清晨空腹用200ml温水口服试验药。受试者两周期 服药后，按试验设计时间点采取静脉血，采用LC-MS/MS测得全血中 TCS的经时血药浓度，平均血药浓度-时间曲线见图4，平均AUC和 Cmax数据见下表。
从结果可以看出，实施例1片剂虽然体外溶出良好，但是体内的 生物利用度较差。而加入了柠檬酸的实施例2片剂生物利用度很高， AUC是没有添加酸性物质的片剂的3倍。酸性物质的加入极大地提高 了药物在体内的暴露量，增强了药效。实施例4片剂较实施例1片生 物利用度有大幅改善，同时个体差异显著改善。
Claims (11)
1.药物组合物，包含式(I)所示化合物或其药学上可接受的盐，以及酸性物质，
2.根据权利要求1所述的药物组合物，其特征在于，所述酸性物质制成0.1mol/L水溶液时的pH不大于3。
3.根据权利要求1所述的药物组合物，其特征在于，所述酸性物质为有机酸或无机酸，优选盐酸、苯磺酸、对甲苯磺酸、硫酸、甲磺酸、乙酸、丙酸、丙二酸、草酸、葡萄糖酸、琥珀酸、马来酸、富马酸、乳酸、酒石酸、苹果酸、柠檬酸、丙酮酸、羟基丁酸、己二酸、水杨酸、双羟萘酸、邻苯二甲酸、天冬氨酸、谷氨酸、扁桃酸、苯甲酸和抗坏血酸中的一种或多种，更优选柠檬酸和/或酒石酸，优选酸性物质的含量范围为基于组合物总重量计的1％-70％，更优选5％-60％，最优选10％-55％。
4.根据权利要求1所述的药物组合物，其特征在于，所述式(I)所示化合物的含量范围为基于组合物总重量计的1％-30％，优选5％-25％。
5.根据权利要求1所述的药物组合物，其特征在于，所述的药物组合物还包含填充剂，优选微晶纤维素、甘露醇、预胶化淀粉、乳糖中的一种或多种，优选所述填充剂含量为基于组合物的总重量的10％-70％。
6.根据权利要求1所述的药物组合物，其特征在于，所述的药物组合物还包含崩解剂，优选交联羧甲基纤维素钠、淀粉、羧甲基淀粉钠及交联聚维酮中的一种或多种，优选所述崩解剂含量为基于组合物的总重量的1％-30％。
7.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物还包含粘合剂，优选羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素中的一种或多种，优选所述粘合剂含量为基于组合物的总重量的0.5％-15％。
8.根据权利要求1所述的药物组合物，其特征在于，所述药物组合物还包含润滑剂，优选硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、微粉硅胶、滑石粉、胶态二氧化硅中的一种或多种，优选所述润滑剂含量为基于组合物的总重量的0.5％-5％。
9.药物组合物，包含(含量基于组合物的总重量计)：
1)式(I)所示化合物或其药学上可接受的盐，含量1％-30％，优选5％-25％；
2)酸性物质，选自盐酸、苯磺酸、对甲苯磺酸、硫酸、甲磺酸、乙酸、丙酸、丙二酸、草酸、葡萄糖酸、琥珀酸、马来酸、富马酸、乳酸、酒石酸、苹果酸、柠檬酸、丙酮酸、羟基丁酸、己二酸、水杨酸、双羟萘酸、邻苯二甲酸、天冬氨酸、谷氨酸、扁桃酸、苯甲酸和抗坏血酸中的一种或多种，优选柠檬酸和/或酒石酸，含量1％-70％，优选5％-60％，更优选10％-55％。
3)填充剂，选自微晶纤维素、甘露醇、预胶化淀粉、乳糖中的一种或多种，含量10％-70％；
4)崩解剂，选自交联羧甲基纤维素钠、淀粉、羧甲基淀粉钠及交联聚维酮中的一种或多种，含量1％-30％；
5)粘合剂，选自羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素中的一种或多种，含量0.5％-15％；
6)润滑剂，选自硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、微粉硅胶、滑石粉、胶态二氧化硅中的一种或多种，含量0.5％-5％。
10.根据权利要求1-9任意一项所述的药物组合物，其特征在于，所述药物组合物为口服制剂，优选片剂或胶囊剂。
11.一种制备如权利要求1-10所述的药物组合物的方法，包括将式(I)所示化合物或其药学上可接受的盐、酸性物质以及一种或多种药学上可接受的辅料混合的步骤。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2018107084769 | 2018-07-02 | ||
| CN201810708476 | 2018-07-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110664812A true CN110664812A (zh) | 2020-01-10 |
| CN110664812B CN110664812B (zh) | 2023-04-07 |
Family
ID=69068811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910585752.1A Active CN110664812B (zh) | 2018-07-02 | 2019-07-01 | 一种包含咪唑并异吲哚类衍生物的药物组合物 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110664812B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016169421A1 (zh) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用 |
| WO2018072742A1 (zh) * | 2016-10-21 | 2018-04-26 | 江苏恒瑞医药股份有限公司 | 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法 |
| WO2018072743A1 (zh) * | 2016-10-21 | 2018-04-26 | 苏州盛迪亚生物医药有限公司 | Pd-1抗体与ido抑制剂联合在制备抗肿瘤的药物中的用途 |
-
2019
- 2019-07-01 CN CN201910585752.1A patent/CN110664812B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016169421A1 (zh) * | 2015-04-21 | 2016-10-27 | 江苏恒瑞医药股份有限公司 | 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用 |
| WO2018072742A1 (zh) * | 2016-10-21 | 2018-04-26 | 江苏恒瑞医药股份有限公司 | 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法 |
| WO2018072743A1 (zh) * | 2016-10-21 | 2018-04-26 | 苏州盛迪亚生物医药有限公司 | Pd-1抗体与ido抑制剂联合在制备抗肿瘤的药物中的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110664812B (zh) | 2023-04-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US12171768B2 (en) | IRAK4 degraders and uses thereof | |
| RU2744432C2 (ru) | Фармацевтическая композиция, включающая ингибитор янус-киназы или его фармацевтически приемлемую соль | |
| CN103889425B (zh) | 含有7-[4-(4-苯并[b]噻吩-4-基-哌嗪-1-基)丁氧基]-1H-喹啉-2-酮或其盐的片剂 | |
| ES2988678T3 (es) | Un comprimido que comprende un derivado de metoxiurea y partículas de manitol | |
| JP2013505897A (ja) | Ｓ−アデノシルメチオニン製剤の改善された薬物動態 | |
| ES2437072T5 (es) | Preparación sólida | |
| TW200304379A (en) | Pharmaceutical composition | |
| TW201442712A (zh) | 有機化合物之調配物 | |
| JP6680297B2 (ja) | 経口投与用医薬組成物 | |
| JP2021121645A (ja) | １５β−ヒドロキシ−酢酸オサテロンの結晶多形 | |
| KR20250121109A (ko) | Irak4 분해제 및 이의 용도 | |
| WO2006040779A2 (en) | Controlled release gastric floating matrix formulation containing imatinib | |
| CN106551946B (zh) | 一种含三氟胸苷和盐酸替比嘧啶的药物组合物及制备方法 | |
| US20200009098A1 (en) | Eflornithine and sulindac, fixed dose combination formulation | |
| CN110664812B (zh) | 一种包含咪唑并异吲哚类衍生物的药物组合物 | |
| WO2014112530A1 (ja) | ５－ヒドロキシ－１ｈ－イミダゾール－４－カルボキサミドを含有する錠剤 | |
| CN102512389B (zh) | 非索非那定盐酸盐口腔崩解药物组合物 | |
| WO2019230937A1 (ja) | 溶出性に優れた経口固形製剤 | |
| JP7355846B2 (ja) | 固形製剤 | |
| CN116847842A (zh) | Irak4降解剂和其用途 | |
| WO2010010367A1 (en) | Solid pharmaceutical composition comprising exemestane | |
| KR102330953B1 (ko) | 소듐-1-[6-(모르폴린-4-일)피리미딘-4-일]-4-(1h-1,2,3-트리아졸-1-일)-1h-피라졸-5-올레이트를 함유하는 제약 투여 형태 | |
| TW200423972A (en) | Tablet having improved solubility | |
| JP6673798B2 (ja) | カペシタビンを有効成分とするフィルムコート医薬製剤 | |
| JP6707471B2 (ja) | ピロールカルボキサミドの固形組成物 |
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 |