CN112843053A - NS5A inhibitor composition - Google Patents
NS5A inhibitor composition Download PDFInfo
- Publication number
- CN112843053A CN112843053A CN202011364022.8A CN202011364022A CN112843053A CN 112843053 A CN112843053 A CN 112843053A CN 202011364022 A CN202011364022 A CN 202011364022A CN 112843053 A CN112843053 A CN 112843053A
- Authority
- CN
- China
- Prior art keywords
- formula
- composition
- optionally
- acid salt
- capsule
- 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
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- 239000000203 mixture Substances 0.000 title claims abstract description 188
- 101800001014 Non-structural protein 5A Proteins 0.000 title description 2
- 239000003112 inhibitor Substances 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 79
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 239000002245 particle Substances 0.000 claims abstract description 54
- 239000004480 active ingredient Substances 0.000 claims abstract description 44
- 239000002775 capsule Substances 0.000 claims description 91
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 80
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 65
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 65
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 65
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 65
- 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 57
- 229930195725 Mannitol Natural products 0.000 claims description 57
- 239000000594 mannitol Substances 0.000 claims description 57
- 235000010355 mannitol Nutrition 0.000 claims description 57
- -1 inorganic acid salt Chemical class 0.000 claims description 47
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 41
- 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 41
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 41
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 41
- 235000019359 magnesium stearate Nutrition 0.000 claims description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 39
- 239000007884 disintegrant Substances 0.000 claims description 39
- 239000003085 diluting agent Substances 0.000 claims description 38
- 239000000314 lubricant Substances 0.000 claims description 31
- 229920000881 Modified starch Polymers 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 27
- 229920002472 Starch Polymers 0.000 claims description 26
- 239000008107 starch Substances 0.000 claims description 26
- 229940032147 starch Drugs 0.000 claims description 26
- 235000019698 starch Nutrition 0.000 claims description 26
- 238000009472 formulation Methods 0.000 claims description 23
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 22
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 22
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 22
- 229960001021 lactose monohydrate Drugs 0.000 claims description 22
- 239000000600 sorbitol Substances 0.000 claims description 22
- 235000010356 sorbitol Nutrition 0.000 claims description 22
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 21
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 21
- 229930006000 Sucrose Natural products 0.000 claims description 19
- 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 19
- 239000005720 sucrose Substances 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 17
- 229960004793 sucrose Drugs 0.000 claims description 15
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 11
- 229960000913 crospovidone Drugs 0.000 claims description 11
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 11
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 11
- 239000003826 tablet Substances 0.000 claims description 11
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 10
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 10
- 229940077388 benzenesulfonate Drugs 0.000 claims description 9
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 9
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 9
- 229960002920 sorbitol Drugs 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 8
- 229940043264 dodecyl sulfate Drugs 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 8
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 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
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 7
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 7
- 239000008109 sodium starch glycolate Substances 0.000 claims description 7
- 239000000454 talc Substances 0.000 claims description 7
- 235000012222 talc Nutrition 0.000 claims description 7
- 229910052623 talc Inorganic materials 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 6
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 5
- 235000010443 alginic acid Nutrition 0.000 claims description 5
- 229920000615 alginic acid Polymers 0.000 claims description 5
- 238000005429 filling process Methods 0.000 claims description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 claims description 4
- 229940080296 2-naphthalenesulfonate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 claims description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 claims description 4
- 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 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 4
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 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
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical group [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 claims description 4
- 229940072056 alginate Drugs 0.000 claims description 4
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 claims description 4
- 229940072107 ascorbate Drugs 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- 229940009098 aspartate Drugs 0.000 claims description 4
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 4
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 claims description 4
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 4
- 150000007942 carboxylates Chemical group 0.000 claims description 4
- MRKZAZMYXYSBDG-UHFFFAOYSA-N cyclopentyl propanoate Chemical compound CCC(=O)OC1CCCC1 MRKZAZMYXYSBDG-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 4
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 claims description 4
- 229940050411 fumarate Drugs 0.000 claims description 4
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 claims description 4
- 229940050410 gluconate Drugs 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 4
- DOUHZFSGSXMPIE-UHFFFAOYSA-N hydroxidooxidosulfur(.) Chemical compound [O]SO DOUHZFSGSXMPIE-UHFFFAOYSA-N 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- 229940099584 lactobionate Drugs 0.000 claims description 4
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 claims description 4
- 229940070765 laurate Drugs 0.000 claims description 4
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 4
- 125000005341 metaphosphate group Chemical group 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 claims description 4
- 235000001968 nicotinic acid Nutrition 0.000 claims description 4
- 239000011664 nicotinic acid Substances 0.000 claims description 4
- 229940049964 oleate Drugs 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 125000004334 oxygen containing inorganic group Chemical group 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 229940075930 picrate Drugs 0.000 claims description 4
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 claims description 4
- 229950010765 pivalate Drugs 0.000 claims description 4
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 claims description 4
- 229960001860 salicylate Drugs 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 4
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 claims description 4
- 229940086735 succinate Drugs 0.000 claims description 4
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 4
- 229940095064 tartrate Drugs 0.000 claims description 4
- 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 4
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 claims description 4
- 229940070710 valerate Drugs 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007900 aqueous suspension Substances 0.000 claims description 3
- 239000000839 emulsion Substances 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- 239000006210 lotion Substances 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000006072 paste Substances 0.000 claims description 3
- 239000008188 pellet Substances 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- 239000001177 diphosphate Substances 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 2
- 235000011180 diphosphates Nutrition 0.000 claims description 2
- 229950005627 embonate Drugs 0.000 claims description 2
- 229940001447 lactate Drugs 0.000 claims description 2
- 229910000039 hydrogen halide Inorganic materials 0.000 claims 1
- 239000012433 hydrogen halide Substances 0.000 claims 1
- 208000005176 Hepatitis C Diseases 0.000 abstract description 9
- 208000010710 hepatitis C virus infection Diseases 0.000 abstract description 8
- 238000004090 dissolution Methods 0.000 description 45
- 238000000034 method Methods 0.000 description 38
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 34
- 239000000741 silica gel Substances 0.000 description 24
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
Abstract
The invention provides a composition. The composition comprises a compound shown as a formula (I) or a formula (II) or pharmaceutically acceptable salt thereof as an active ingredient, or a compound shown as a formula (III) or (IV) as an active ingredient. The particle size of the active ingredient satisfies the following conditions: d is more than or equal to 20 mu m50Less than or equal to 50 mu m. The composition can be used for treating viral hepatitis C, and has high safety and quick action.
Description
Technical Field
The invention relates to the field of pharmacy, in particular to a composition for treating hepatitis C and a capsule thereof.
Background
Viral Hepatitis type C is a global infectious disease caused by Hepatitis C Virus (HCV), mainly spreading with blood, blood products and body fluids, 55-85% of patients progress to chronic Hepatitis after acute infection with HCV, about 5-15% progress to cirrhosis after 20 years of infection, the annual incidence rate of decompensation of cirrhosis is 3-4%, 2-4% of cirrhosis patients progress to liver cancer (HCC) every year, HCV has serious harm to the health and life of patients, and CHC patients have hidden symptoms, the diagnosis rate and antiviral treatment rate of HCV infection are low, and there are many hidden infection sources in the population, which has become a serious social and public health problem.
Data updated by the World Health Organization (WHO)2016, month 4, show a global chronic HCV infection rate of about 1.1% and an infected person of about 1 million. With the increasing public health and health consciousness and the increasing popularization of basic knowledge of hepatitis c, the detection rate of patients and the proportion of people willing to receive treatment are increasing, and therefore, the people needing treatment and the clinical requirements are expected to be larger and larger.
HCV includes at least 6 genotypes and multiple subtypes, with genotype 1 being reported most common worldwide in 2014, followed by genotypes 3, 2 and 4. In china, genotypes 1b and 2a are more common, with genotype 1b predominant (56.8%), followed by genotypes 2 (24.1%) and 3 (9.1%), with no genotype 4 and 5 found, and relatively few genotype 6 (6.3%).
Therefore, the development of more and more effective drugs for treating viral hepatitis C as soon as possible is a goal of continuous efforts of drug developers.
The prior art CN105693700B provides compounds (I), (II) and their pharmaceutically acceptable salts, which have better biological properties, but the prior art research is still in earlier preclinical research, and in order to facilitate the development of clinical research, further research on the properties of the drugs is needed to find the drug salt form and the drug dosage form suitable for human administration.
Disclosure of Invention
The inventors of the present application have developed a pharmaceutical preparation containing a compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient by experiments on the basis of the development of a novel drug (a compound represented by formula (I) or formula (II)). In the development process, the inventor finds that the compound shown in the formula (I) or the formula (II) or the pharmaceutically acceptable salt thereof and the auxiliary material provided by the invention are easy to mix uniformly, and the particle size of the active ingredient meets the following conditions: d is more than or equal to 20 mu m50Less than or equal to 50 mu m, the prepared composition has better dissolution rate, wide disintegrant adaptability, wide filler adaptability and wide compound proportion adaptability, and is particularly suitable for capsule preparations. Meanwhile, the preparation process of the capsule preparation is simple, and the production steps are few, so that the production cost of the new medicine can be greatly reduced, and the development progress of the new medicine is accelerated.
Based on this, in a first aspect of the invention, a composition is presented. According to an embodiment of the present invention, the composition comprises a compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient,
the particle size of the active ingredient satisfies the following conditions: d is more than or equal to 20 mu m50Less than or equal to 50 mu m. Hair-like deviceIt has been found that when the particle size of the active ingredient is 20 μm or less D50In the range of ≦ 50 μm, the composition according to the inventive examples dissolved out rapidly. The composition provided by the embodiment of the invention can effectively treat the viral hepatitis C, and has high safety and quick response.
According to an embodiment of the invention, the particle size of the active ingredient satisfies the following condition: d is more than or equal to 20 mu m50≤35μm;
According to an embodiment of the invention, the particle size of the active ingredient satisfies the following condition: d is not less than 35 mu m50≤50μm;
According to an embodiment of the invention, the particle size of the active ingredient satisfies the following condition: d is not more than 25 mu m50≤45μm;
According to an embodiment of the invention, the particle size of the active ingredient satisfies the following condition: d50About 20 μm, about 22 μm, about 24 μm, about 26 μm, about 28 μm, about 30 μm, about 32 μm, about 34 μm, about 36 μm, about 38 μm, about 40 μm, about 42 μm, about 44 μm, about 46 μm, about 48 μm or about 50 μm.
According to an embodiment of the present invention, the above composition may further comprise at least one of the following additional technical features:
according to an embodiment of the invention, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.
According to an embodiment of the present invention, the inorganic acid salt or the organic acid salt is a mono-salt or a di-salt.
According to a specific embodiment of the present invention, the inorganic acid salt is selected from a hydrohalide salt, a halogen series oxygen-containing inorganic acid salt, a carbon series oxygen-containing inorganic acid salt, a nitrogen series oxygen-containing inorganic acid salt, a boron series oxygen-containing inorganic acid salt, a silicon series oxygen-containing inorganic acid salt, a phosphorus series oxygen-containing inorganic acid salt, or a sulfur series inorganic acid salt; the organic acid salt is selected from carboxylate, sulfonate, sulfinate or thiocarboxylate.
According to a further embodiment of the invention, the inorganic acid salt is selected from the group consisting of hydrochloride, sulfate, bisulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate or metaphosphate; the organic acid salt is selected from formate, acetate, benzoate, malonate, succinate, methanesulfonate, ethanesulfonate, citrate, benzenesulfonate, p-toluenesulfonate, malate, tartrate, succinate, fumarate, glycolate, isethionate, maleate, lactate, lactobionate, embonate, salicylate, galactarate, glucoheptonate, mandelate, gluconate, 1, 2-ethyldisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethylsulfonate, glycerophosphate, heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, succinate, methanesulfonate, ethanesulfonate, mesylate, isovalerate, and isovalerate, Laurate, lauryl sulfate, nicotinate, oleate, palmitate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, or valerate.
According to an embodiment of the invention, the inorganic acid salt is a phosphate.
According to an embodiment of the invention, the inorganic acid salt is a diphosphate.
According to an embodiment of the invention, the pharmaceutically acceptable salt is a phosphate salt, the phosphate salt of the compound of formula (I) has the structure of formula (III), the phosphate salt of the compound of formula (II) has the structure of formula (IV),
in the process of developing the pharmaceutical preparation, the inventor finds that when the pharmaceutically acceptable salt is selected from phosphate, the composition has high solubility, stable dissolution rate and is more suitable for patent medicine, and the discovery can further accelerate the development of new medicines.
According to an embodiment of the invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof is 20% to 45%, or 20% to 42%, or 21% to 39%, or 22% to 38%, or 23% to 37%, or 24% to 36%, 25% to 35%, or 26% to 34%, or 27% to 33%, or 28% to 32%, or 29% to 31%, or 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40%, or about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35% based on the total weight of the composition. The inventor finds that the mass fraction of the compound shown in the formula (III) in the composition has better fluidity in the range, the production feasibility is improved, and the stability, the effectiveness and the safety of the effect of the composition for treating the viral hepatitis C can be effectively ensured.
According to an embodiment of the invention, the composition further comprises a pharmaceutically acceptable adjuvant comprising at least one selected from the group consisting of diluents, disintegrants, glidants and lubricants.
According to an embodiment of the invention, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose.
According to an embodiment of the invention, the disintegrant comprises one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch. The inventor finds that the dissolution rate of the composition is better by using one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium and sodium carboxymethyl starch as a disintegrating agent.
According to an embodiment of the invention, the glidant is aerosil, or talc.
According to an embodiment of the invention, the lubricant is magnesium stearate.
According to the embodiment of the invention, the mass fraction of the microcrystalline cellulose is 15-40% based on the total weight of the composition. The inventor finds that the content of the microcrystalline cellulose is 15-40%, and the dissolution rate of the composition is stable.
According to the embodiment of the invention, the mass fraction of one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 30-50% based on the total weight of the composition. The inventor finds that the composition is fast and stable in dissolution when the mass fraction of one or more of mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 30-50%.
According to the embodiment of the invention, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose in a mass ratio of 1: 1-1: 3.
According to an embodiment of the present invention, the mass fraction of the disintegrant is 1% to 12% based on the total weight of the composition. The inventors found that, in the present composition, the dissolution rate of the composition is decreased by increasing the content of the disintegrant, and that the composition is rapidly and stably dissolved when the content of the disintegrant is in the range of 1% to 12%.
According to the embodiment of the invention, the mass fraction of the glidant is 0.5-2% based on the total weight of the composition.
According to the embodiment of the invention, the mass fraction of the lubricant is 0.5-5% based on the total weight of the composition; in some embodiments, the lubricant is present in an amount of 0.5% to 2% by weight, based on the total weight of the composition. The inventors have found that, in the present composition, an increase in the content of the lubricant decreases the dissolution rate of the composition, and that the content of the lubricant is within the range described in the present invention, and that the dissolution of the composition is fast and stable.
According to an embodiment of the invention, the composition is in the form of an oral formulation.
According to an embodiment of the invention, the composition is in the form of a solid oral formulation.
According to an embodiment of the invention, the composition is in the form of a capsule, tablet, pellet, powder, sustained release formulation, aqueous suspension, ointment, paste, emulsion, lotion, gel, solution, spray, inhalant or patch.
In a second aspect of the invention, the invention proposes a capsule filled with contents comprising a composition as described previously. The capsule provided by the embodiment of the invention can be used for effectively treating the viral hepatitis C, and has good stability and rapid dissolution.
In a third aspect of the invention, the invention proposes a capsule filled with a content. According to an embodiment of the invention, the content comprises: the mass fraction of the compound shown in the formula (III) or the formula (IV) is 20 to 45 percent based on the total weight of the content, and the particle size of the compound shown in the formula (III) or the compound shown in the formula (IV) meets the following condition: d is more than or equal to 20 mu m50Less than or equal to 50 mu m. The capsule provided by the embodiment of the invention can be used for effectively treating the viral hepatitis C, and has the advantages of good stability, rapid dissolution and high safety.
According to an embodiment of the present invention, the capsule may further comprise at least one of the following additional technical features:
according to an embodiment of the present invention, the compound represented by formula (III) or formula (IV) is used in an amount of 20 to 45 parts by weight, the diluent is used in an amount of 50 to 75 parts by weight, the disintegrant is used in an amount of 1 to 12 parts by weight, the glidant is used in an amount of 0.5 to 2 parts by weight, and the lubricant is used in an amount of 0.5 to 5 parts by weight.
According to a particular embodiment of the invention, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, lactose.
According to a further embodiment of the invention, the disintegrant comprises one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate.
According to yet another embodiment of the invention, the disintegrant is croscarmellose sodium.
According to a further embodiment of the invention, the glidant is aerosil or talc.
According to yet another embodiment of the invention, the lubricant is magnesium stearate.
According to the embodiment of the invention, the microcrystalline cellulose is used in an amount of 15-40 parts by weight. The inventor finds that the dissolution rate of the capsule content is more stable when the microcrystalline cellulose is used in an amount of 15-40 parts by weight.
According to an embodiment of the present invention, the one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch, and sucrose is used in an amount of 30 to 50 parts by weight. The inventor finds that the composition is dissolved out quickly and more stably when one or more of mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose are used in an amount of 30-50 parts by weight.
According to the embodiment of the invention, the mass ratio of the microcrystalline cellulose to one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose in the diluent is 1: 1-1: 3.
According to the embodiment of the invention, the mass ratio of the microcrystalline cellulose to the mannitol is 1: 1-1: 3.
According to an embodiment of the invention, the capsule is a single-dose formulation, i.e. the capsule is adapted to be administered to a patient once a day to exert an advantageous pharmacological effect, or a multi-dose formulation, i.e. the capsule is adapted to be administered to a patient several times a day or more to exert an advantageous pharmacological effect.
In a fourth aspect of the invention, the invention proposes a method for preparing a capsule as described previously. According to an embodiment of the invention, the method comprises:
(1) premixing a proper amount of a compound shown as a formula (I), a formula (II), a formula (III) or a formula (IV) with a diluent, a disintegrant and a glidant to obtain a first mixture;
(2) subjecting the second mixture to a second mixing treatment with a lubricant so as to obtain a second mixture; and
(3) subjecting the second mixture to a capsule filling process so as to obtain said capsules.
According to the method for preparing the capsule, the powder is adopted to directly fill the capsule, the preparation process is simple, the production procedures are few, energy and time are saved, the equipment and operation costs are reduced, the process adaptability is strong, the continuous and stable production of the dosage form can be realized, and the prepared capsule has good stability and is quickly dissolved out.
According to an embodiment of the present invention, the method may further include at least one of the following additional technical features:
according to the embodiment of the invention, the compound shown in the formula (I), the formula (II), the formula (III) or the formula (IV), the diluent, the disintegrant, the glidant and the lubricant are sieved by a 60-mesh sieve in advance. Further, the size of the raw material powder for preparing the capsule is uniform, and the continuous and stable production of the capsule preparation is realized.
According to an embodiment of the present invention, the above method further comprises controlling the particle size of the compound represented by formula (I), or formula (II), or formula (III), or (IV) to 20 μm ≦ D50≤50μm。
According to the embodiment of the invention, the time of the first mixing treatment is 15min to 30min, and the time of the second mixing treatment is 3min to 7 min.
According to the specific embodiment of the present invention, the time of the first mixing process is 20min, and the time of the second mixing process is 5 min.
A method of making a capsule according to a specific embodiment of the present invention comprises:
(1) d with a proper particle size of 20 mu m or less50Pre-mixing a compound of formula (I), or formula (II), or formula (III), or (IV) with a diluent, disintegrant, glidant to obtain a first mixture, optionallyThe time of the combination treatment is 15min to 30 min;
(2) subjecting the first mixture and a lubricant to a second mixing treatment to obtain a second mixture, wherein the second mixing treatment time is 3-7 min optionally;
(3) and subjecting the second mixture to a capsule filling process so as to obtain said capsules.
Detailed Description
Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described herein, as such embodiments may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications and patents referred to herein are incorporated by reference in their entirety.
Where a range of values is provided, it is understood that any intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the stated limits, ranges excluding either or both of those included limits are also included in the invention. Certain ranges are provided herein as values previously recited with the term "about". The term "about" is used herein to provide literal support for the precise numerical value preceding it, as well as numerical values that are near or approximate to the preceding term. In determining whether a value is near or approximately a specifically stated value, the near or approximately unrecited value may be a value that, in the context in which it is provided, provides substantial equivalence to the specifically stated value. The term "about" or "approximately" refers to an error that is acceptable for a particular value, as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.
Reference may be made to a number of documents on this subject for these and other pharmaceutically acceptable adjuvants or processes mentioned herein, see in particular Handbook of Pharmaceutical Excipients, 3 rd edition, edited by Arthur h.kibbe, American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London; and Lexikon der Hilfsstuffe fur Pharmazie, Kosmetik and angrenzene Gebiete, edited by H.P. Fiedler, 4 th edition, Cantor, Aulentorf and earlier versions.
The compositions or formulations provided herein can be administered to a patient alone, or can be co-administered or co-administered with other active agents. The terms "co-administration" and "combination" include the simultaneous or sequential administration of two or more therapeutic agents without a specific time period. In one embodiment, the agents are both present in the cell or in the body of the individual, or both exert a biological or therapeutic effect. In one embodiment, each therapeutic agent is in the same composition or unit dosage form. In other embodiments, each therapeutic agent is in a different composition or unit dosage form. In certain embodiments, the first agent is administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of the second therapeutic agent.
By "active ingredient" or "active agent" is meant a substance used in therapy (e.g., human therapy, veterinary therapy), including prophylactic and therapeutic therapies. The active ingredient includes any substance used as a medicament for treating, preventing, delaying, alleviating or ameliorating a disease, condition or disorder.
The term "pharmaceutically acceptable salt" means, which may be an inorganic acid salt or an organic acid salt; in some embodiments, the inorganic or organic acid salt may be a mono-or di-salt. In some embodiments, the inorganic acid salt is selected from a hydrohalic acid salt, a halogen series oxygen-containing inorganic acid salt, a carbon series oxygen-containing inorganic acid salt, a nitrogen series oxygen-containing inorganic acid salt, a boron series oxygen-containing inorganic acid salt, a silicon series oxygen-containing inorganic acid salt, a phosphorus series oxygen-containing inorganic acid salt, or a sulfur series inorganic acid salt; the organic acid salt is selected from carboxylate, sulfonate, sulfinate or thiocarboxylate. In other embodiments, the inorganic acid salt is selected from the group consisting of a hydrochloride, sulfate, bisulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, or metaphosphate salt. In some embodiments, the organic acid salt is selected from formate, acetate, benzoate, malonate, succinate, methanesulfonate, ethanesulfonate, citrate, benzenesulfonate, p-toluenesulfonate, malate, tartrate, succinate, fumarate, glycolate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, gluconate, 1, 2-ethyldisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethylsulfonate, glycerophosphate, heptanoate, salts of organic acids, citrates, benzenesulfonate, salts of benzoic acid, salts of sulfonic acid, salts of p-toluenesul, Hexanoate, 2-hydroxy-ethanesulfonate, laurate, lauryl sulfate, nicotinate, oleate, palmitate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, or valerate.
The term "oral formulation" refers to a formulation form which is orally administered and in which a drug absorbs into blood in the gastrointestinal tract, and includes tablets, granules, capsules, oral solutions, and the like.
The term "solid oral formulation" refers to tablets, dispersible tablets, fast dissolving tablets, orally dispersible tablets, lyophilized units, porous tablets, conventional tablets, coated tablets, uncoated tablets, enteric-coated tablets (gasto-resistant tablets), effervescent tablets, soluble tablets, chewable tablets, oral lyophilisates, powders, oral powders, pills, capsules and/or granules. In some embodiments, the solid oral formulation is a capsule.
The term "diluent" refers to microcrystalline cellulose, lactose monohydrate, lactose, compressible sugars, sugar, dextrose, mannitol, dextrin, maltodextrin, sorbitol, xylitol, sodium chloride, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, magnesium oxide, kaolin, powdered cellulose, pregelatinized starch, barium sulfate, magnesium trisilicate, aluminum hydroxide, and combinations thereof. In some embodiments, the diluent of the present invention comprises at least microcrystalline cellulose. In other embodiments, the diluent of the present invention comprises microcrystalline cellulose and one or more selected from the group consisting of mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose.
The term "disintegrant" disintegrants include, but are not limited to, corn starch, CMC-Ca, CMC-Na, microcrystalline cellulose, crosslinked polyvinylpyrrolidone (PVP) (e.g., as known and commercially available under the trade name XL from ISP corporation), alginic acid, sodium alginate and guar gum.
The term "glidant" includes, but is not limited to: silicon dioxide, micropowder silica gel, magnesium trisilicate, powdered cellulose, starch and talcum powder. In some embodiments of the invention, the retention aid is aerosil or talc.
The term "lubricant" includes, but is not limited to: mg, Al or Ca stearate, PEG 4000-8000, talc, sodium benzoate, glyceryl mono-fatty acids (e.g.having a molecular weight of from 200 to 800 daltons, such as glyceryl monostearate (e.g.Danisco, UK)), glyceryl dibehenate (e.g.Comritolo 888TM, gattefosse France), glyceryl palmitostearate (e.g.Precirol, gattefosse France), polyethylene glycol (PEG, BASF), hydrogenated cottonseed oil (Lubirabtm, Edward Mendell, Ltd.), castor oil (Cutina HR, Henkel). In some embodiments of the invention, the lubricant is magnesium stearate.
The invention provides a composition which comprises a compound shown as a formula (I) or a formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient,
the particle size of the active ingredient satisfies the following conditions: d is more than or equal to 20 mu m50≤50μm。
In some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d is more than or equal to 20 mu m50≤35μm;
In some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d is not less than 35 mu m50≤50μm;
In some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d is not more than 25 mu m50≤45μm;
In some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 20 μm, about 22 μm, about 24 μm, about 26 μm, about 28 μm, about 30 μm, about 32 μm, about 34 μm, about 36 μm, about 38 μm, about 40 μm, about 42 μm, about 44 μm, about 46 μm, about 48 μm or about 50 μm.
In some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 20 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 22 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 24 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 26 μm;in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 28 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 30 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 32 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 34 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 36 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 38 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 40 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 42 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 44 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 46 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50About 48 μm; in some embodiments of the invention, the particle size of the active ingredient satisfies the following condition: d50Is about 50 μm.
The composition of the invention can effectively treat the viral hepatitis C and has high safety.
In some embodiments of the invention, the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt.
In some embodiments of the invention, the inorganic or organic acid salt is a mono-or di-salt.
In some embodiments of the present invention, the inorganic acid salt is selected from a hydrohalic acid salt, a halogen series oxygen-containing inorganic acid salt, a carbon series oxygen-containing inorganic acid salt, a nitrogen series oxygen-containing inorganic acid salt, a boron series oxygen-containing inorganic acid salt, a silicon series oxygen-containing inorganic acid salt, a phosphorus series oxygen-containing inorganic acid salt, or a sulfur series inorganic acid salt.
In some embodiments of the invention, the inorganic acid salt is selected from the group consisting of a hydrochloride, sulfate, bisulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, or metaphosphate.
In some embodiments of the invention, the organic acid salt is selected from a carboxylate, a sulfonate, a sulfinate, or a thiocarboxylate.
In some embodiments of the invention, the organic acid salt is selected from formate, acetate, benzoate, malonate, succinate, methanesulfonate, ethanesulfonate, citrate, benzenesulfonate, p-toluenesulfonate, malate, tartrate, succinate, fumarate, glycolate, isethionate, maleate, lactate, lactobionate, pamoate, salicylate, galactarate, glucoheptonate, mandelate, gluconate, 1, 2-ethyldisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethylsulfonate, glycerophosphate, and mixtures thereof, Heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, laurate, lauryl sulfate, nicotinate, oleate, palmitate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, or valerate.
In some embodiments of the invention, the pharmaceutically acceptable salt is a phosphate salt.
In some embodiments of the invention, the pharmaceutically acceptable salt is a diphosphate salt.
In some embodiments of the invention, the phosphate salt of the compound of formula (I) has the structure of formula (III),
in some embodiments of the invention, the phosphate salt of the compound of formula (II) has a structure of formula (IV),
the invention provides a composition which comprises a compound shown as a formula (III) as an active ingredient,
the invention provides a composition which comprises a compound shown as a formula (IV) as an active ingredient,
in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 20% to 45%, or 20% to 42%, or 21% to 39%, or 22% to 38%, or 23% to 37%, or 24% to 36%, 25% to 35%, or 26% to 34%, or 27% to 33%, or 28% to 32%, or 29% to 31%, or 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40%, or about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35%, based on the total weight of the composition.
In some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 20% to 45% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 20% to 42% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 21% to 39% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 22% to 38% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 23% to 37% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 24% to 36% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or pharmaceutically acceptable salt thereof in the composition of the present invention is 25% to 35% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound represented by formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 26% to 34% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 27% to 33% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 28% to 32% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 29% to 31% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 20% to 25% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or pharmaceutically acceptable salt thereof in the composition of the present invention is 25% to 30% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is 30% to 35% based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof in the composition of the present invention is at or 35% to 40% based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 25%, based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the present invention is about 26%, based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 27%, based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 28%, based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 29%, based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 30%, based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 31%; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 32%, based on the total weight of the composition; in some embodiments of the invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the invention is about 33%, based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, in the composition of the present invention is about 34%, based on the total weight of the composition; in some embodiments of the present invention, the mass fraction of the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof in the composition of the present invention is about 35%, based on the total weight of the composition.
In some embodiments of the invention, the composition further comprises a pharmaceutically acceptable adjuvant comprising one or more of diluents, disintegrants, glidants, and lubricants.
In some embodiments of the invention, the composition further comprises at least a diluent.
In some embodiments of the invention, the composition further comprises a pharmaceutically acceptable adjuvant consisting of a diluent, a disintegrant, a glidant, and a lubricant.
In some embodiments of the invention, the diluent comprises at least microcrystalline cellulose.
In some embodiments of the invention, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose. In some embodiments of the invention, the diluent comprises microcrystalline cellulose and mannitol. In some embodiments of the invention, the diluent comprises microcrystalline cellulose and lactose. In some embodiments of the invention, the diluent comprises microcrystalline cellulose and pregelatinized starch.
In some embodiments of the invention, the disintegrant comprises one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate. In some embodiments of the invention, the disintegrant is crospovidone; in some embodiments of the invention, the disintegrant is croscarmellose sodium, and in some embodiments of the invention, the disintegrant is sodium starch glycolate.
In some embodiments of the invention, the glidant is aerosil or talc. In some embodiments of the invention, the glidant is aerosil.
In some embodiments of the invention, the lubricant is magnesium stearate.
In some embodiments of the present invention, the microcrystalline cellulose is present in an amount of 15 to 40% by weight, based on the total weight of the composition.
In some embodiments of the present invention, the mass fraction of the one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose is 30 to 50% based on the total weight of the composition. In some embodiments of the present invention, the mannitol is present in an amount of 30 to 50% by weight, based on the total weight of the composition. In some embodiments of the present invention, the lactose is present in an amount of 30 to 50% by weight, based on the total weight of the composition. In some embodiments of the present invention, the pregelatinized starch is present in an amount of 30 to 50% by weight, based on the total weight of the composition.
In some embodiments of the present invention, the mass ratio of the microcrystalline cellulose to one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch, and sucrose in the diluent is 1:1 to 1: 3. In some embodiments of the invention, the mass ratio of microcrystalline cellulose to mannitol in the diluent is 1:1 to 1: 3. In some embodiments of the invention, the mass ratio of microcrystalline cellulose to lactose in the diluent is 1:1 to 1: 3. In some embodiments of the invention, the mass ratio of microcrystalline cellulose to pregelatinized starch in the diluent is from 1:1 to 1: 3.
In some embodiments of the invention, the mass fraction of the disintegrant is 1% to 12% based on the total weight of the composition. The inventors found that, in the present composition, the dissolution rate of the composition is decreased by increasing the content of the disintegrant, and that the composition is rapidly and stably dissolved when the content of the disintegrant is in the range of 1% to 12%.
In some embodiments of the invention, the glidant is present in an amount of 0.5 to 2 weight percent, based on the total weight of the composition.
In some embodiments of the invention, the lubricant is present in an amount of 0.5% to 5% by weight, based on the total weight of the composition; in some embodiments, the lubricant is present in an amount of 0.5% to 2% by weight, based on the total weight of the composition.
In some embodiments of the invention, the composition is in the form of an oral formulation.
In some embodiments of the invention, the composition is in the form of a solid oral formulation.
In some embodiments of the invention, the composition is in the form of a capsule, tablet, pellet, powder, sustained release formulation, aqueous suspension, ointment, paste, emulsion, lotion, gel, solution, spray, inhalant or patch.
The invention provides a capsule filled with contents, wherein the contents are the composition.
The invention also proposes a capsule filled with contents comprising: the mass fraction of the compound shown in the formula (III) is 20-45% based on the total weight of the content, and the particle size of the compound shown in the formula (III) meets the following conditions: d is more than or equal to 20 mu m50≤50μm。
The invention also proposes a capsule filled with contents comprising: the mass fraction of the compound shown in the formula (IV) is 20-45% based on the total weight of the content, and the particle size of the compound shown in the formula (IV) meets the following conditions: d is more than or equal to 20 mu m50≤50μm。
In some embodiments of the invention, the capsule provided by the invention can be used for effectively treating the viral hepatitis C, and has good stability, rapid dissolution and high safety.
In some embodiments of the present invention, the capsule provided by the present invention comprises 20 to 45 parts by weight of the compound represented by formula (III), 50 to 75 parts by weight of the diluent, 1 to 12 parts by weight of the disintegrant, 0.5 to 2 parts by weight of the glidant, and 0.5 to 5 parts by weight of the lubricant.
In some embodiments of the present invention, the capsule provided by the present invention comprises 20 to 45 parts by weight of the compound represented by formula (IV), 50 to 75 parts by weight of the diluent, 1 to 12 parts by weight of the disintegrant, 0.5 to 2 parts by weight of the glidant, and 0.5 to 5 parts by weight of the lubricant.
In some embodiments of the invention, the invention provides capsules wherein the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, and starch.
In some embodiments of the invention, the invention provides capsules wherein the disintegrant comprises one or more of crospovidone, low substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate.
In some embodiments of the invention, the invention provides capsules wherein the disintegrant is croscarmellose sodium.
In some embodiments of the invention, the capsule provided herein wherein the disintegrant is crospovidone.
In some embodiments of the invention, the invention provides a capsule wherein the disintegrant is sodium starch glycolate.
In some embodiments of the invention, the capsule provided herein wherein the glidant is aerosil or talc.
In some embodiments of the invention, the invention provides capsules wherein the lubricant is magnesium stearate.
In some embodiments of the present invention, the microcrystalline cellulose is 15 to 40 parts by weight in the capsule provided by the present invention.
In some embodiments of the present invention, the capsule provided by the present invention may further comprise one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch, and sucrose in an amount of 30 to 50 parts by weight.
In some embodiments of the present invention, the capsule provided by the present invention, wherein the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, and sucrose in a mass ratio of 1:1 to 1: 3.
In some embodiments of the invention, the capsule provided by the invention has a mass ratio of the microcrystalline cellulose to the mannitol of 1: 1-1: 3.
In some embodiments of the present invention, the capsule is a single-dose formulation or a multi-dose formulation, wherein the single-dose formulation is a capsule suitable for administration to a patient one dose per day to exert a beneficial effect, and the multi-dose formulation is a capsule suitable for administration to a patient one or more doses per day to exert a beneficial effect.
The present invention provides a method of preparing the aforementioned capsule. According to an embodiment of the invention, the method comprises:
(1) premixing a proper amount of a compound shown as a formula (I), a formula (II), a formula (III) or a formula (IV) with a diluent, a disintegrant and a glidant to obtain a first mixture;
(2) subjecting the second mixture to a second mixing treatment with a lubricant so as to obtain a second mixture; and
(3) subjecting the second mixture to a capsule filling process so as to obtain said capsules.
According to the embodiment of the invention, the compound shown in the formula (I), the formula (II), the formula (III) or the formula (IV), the diluent, the disintegrant, the glidant and the lubricant are sieved by a 60-mesh sieve in advance.
According to an embodiment of the present invention, the above method further comprises controlling the particle size of the compound represented by formula (I), or formula (II), or formula (III), or (IV) to 20 μm ≦ D50≤50μm。
According to the embodiment of the invention, the time of the first mixing treatment is 15min to 30min, and the time of the second mixing treatment is 3min to 7 min.
According to the specific embodiment of the present invention, the time of the first mixing process is 20min, and the time of the second mixing process is 5 min.
According to a specific embodiment of the present invention, the method of preparing a capsule comprises:
(1) d with a proper particle size of 20 mu m or less50Premixing the compound shown in the formula (I), or the formula (II), or the formula (III) or the formula (IV) with a diluent, a disintegrant and a glidant to obtain a first mixture, wherein the time of the first mixing treatment is 15-30 min;
(2) subjecting the first mixture and a lubricant to a second mixing treatment to obtain a second mixture, wherein the second mixing treatment time is 3-7 min optionally;
(3) and subjecting the second mixture to a capsule filling process so as to obtain said capsules.
Detailed Description
The following detailed description of embodiments of the invention is intended to be illustrative, and not to be construed as limiting the invention.
Example 1
Compound III capsules were prepared according to the formula shown below and dissolution was measured.
The preparation method comprises the following steps:
(1) drug particle size D of Compound III50Sieving microcrystalline cellulose, mannitol, croscarmellose sodium, aerosil and magnesium stearate with a 60-mesh sieve;
(2) weighing the following components in proportion by prescription:
compound III: 29.27;
microcrystalline cellulose: 22.24;
mannitol: 44.49, respectively;
croscarmellose sodium: 2.00;
silica gel micropowder: 1.00;
magnesium stearate: 1.00;
in total: 100.
(3) mixing the microcrystalline cellulose, mannitol, croscarmellose sodium and compound III in the prescribed amount for 20min to be uniform to obtain a mixture;
(3) adding sieved magnesium stearate with a formula proportion into the mixture, mixing for 5min to be uniform, filling into capsules with 100mg specification, and measuring the dissolution rate of the capsules according to a dissolution rate measuring method (0931 second method in the general rules of Chinese pharmacopoeia 2015 edition) by using 0.1M HCl as a dissolution medium at 100rpm by a basket method, wherein the acceptable dissolution rate standard is 15min or more and 85%.
As a result: the dissolution rate of the capsule within the particle size range within 15 minutes is (97 +/-1.85)%, which is more than 85%.
Example 2
Compound III capsules were prepared according to the formula shown below and dissolution was measured.
The preparation method comprises the following steps:
(1) drug particle size D of Compound III50Sieving microcrystalline cellulose, mannitol, croscarmellose sodium, aerosil and magnesium stearate 35.9 μm with 60 mesh sieve;
(2) weighing the following components in proportion by prescription:
compound III: 29.27;
microcrystalline cellulose: 22.24;
mannitol: 44.49, respectively;
croscarmellose sodium: 2.00;
silica gel micropowder: 1.00;
magnesium stearate: 1.00;
in total: 100.
(3) mixing the microcrystalline cellulose, mannitol, croscarmellose sodium and compound III in the prescribed amount for 20min to be uniform to obtain a mixture;
(3) adding sieved magnesium stearate with a formula proportion into the mixture, mixing for 5min to be uniform, filling into capsules with 100mg specification, and measuring the dissolution rate of the capsules according to a dissolution rate measuring method (0931 second method in the general rules of Chinese pharmacopoeia 2015 edition) by using 0.1M HCl as a dissolution medium at 100rpm by a basket method, wherein the acceptable dissolution rate standard is 15min or more and 85%.
As a result: the dissolution rate of the capsule within the particle size range within 15 minutes is (100 +/-0.82)%, which is more than 85%.
Example 3
Compound III capsules were prepared according to the formula shown below and dissolution was measured.
The preparation method comprises the following steps:
(1) drug particle size D of Compound III50Sieving microcrystalline cellulose, mannitol, croscarmellose sodium, aerosil and magnesium stearate with a 60-mesh sieve;
(2) weighing the following components in proportion by prescription:
compound III: 29.27;
microcrystalline cellulose: 22.24;
mannitol: 44.49, respectively;
croscarmellose sodium: 2.00;
silica gel micropowder: 1.00;
magnesium stearate: 1.00;
in total: 100.
(3) mixing the microcrystalline cellulose, mannitol, croscarmellose sodium and compound III in the prescribed amount for 20min to be uniform to obtain a mixture;
(3) adding sieved magnesium stearate with a formula proportion into the mixture, mixing for 5min to be uniform, filling into capsules with 100mg specification, and measuring the dissolution rate of the capsules according to a dissolution rate measuring method (0931 second method in the general rules of Chinese pharmacopoeia 2015 edition) by using 0.1M HCl as a dissolution medium at 100rpm by a basket method, wherein the acceptable dissolution rate standard is 15min or more and 85%.
As a result: the dissolution rate of the capsule within the particle size range within 15 minutes is (102 +/-0.63)%, which is more than 85%.
Comparative example 1
Compound III capsules were prepared according to the formula shown below and dissolution was measured.
The preparation method comprises the following steps:
(1) drug particle size D of Compound III5013.5 μm microcrystalline cellulose, mannitol, croscarmellose sodium, aerosil, stearic acidSieving magnesium with 60 mesh sieve;
(2) weighing the following components in proportion by prescription:
compound III: 29.27;
microcrystalline cellulose: 22.24;
mannitol: 44.49, respectively;
croscarmellose sodium: 2.00;
silica gel micropowder: 1.00;
magnesium stearate: 1.00;
in total: 100.
(3) mixing the microcrystalline cellulose, mannitol, croscarmellose sodium and compound III in the prescribed amount for 20min to be uniform to obtain a mixture;
(4) adding sieved magnesium stearate with a formula proportion into the mixture, mixing for 5min to be uniform, filling into capsules with 100mg specification, and measuring the dissolution rate of the capsules according to a dissolution rate measuring method (0931 second method in the general rules of Chinese pharmacopoeia 2015 edition) by using 0.1M HCl as a dissolution medium at 100rpm by a basket method, wherein the acceptable dissolution rate standard is 15min or more and 85%.
As a result: the dissolution rate of the capsule within the particle size range within 15 minutes is (83 +/-3.13)%, which is less than 85%.
Comparative example 2
Compound III capsules were prepared according to the formula shown below and dissolution was measured.
The preparation method comprises the following steps:
(1) drug particle size D of Compound III50Sieving microcrystalline cellulose, mannitol, croscarmellose sodium, aerosil and magnesium stearate with a 60-mesh sieve;
(2) weighing the following components in proportion by prescription:
compound III: 29.27;
microcrystalline cellulose: 22.24;
mannitol: 44.49, respectively;
croscarmellose sodium: 2.00;
silica gel micropowder: 1.00;
magnesium stearate: 1.00;
in total: 100.
(3) mixing the microcrystalline cellulose, mannitol, croscarmellose sodium and compound III in the prescribed amount for 20min to be uniform to obtain a mixture A;
(4) adding sieved magnesium stearate with the formula proportion into the mixture A, mixing for 5min to be uniform, filling into capsules with the specification of 100mg, and measuring the dissolution rate of the capsules according to a dissolution rate measuring method (a second method of 0931 in the general rules of Chinese pharmacopoeia 2015 edition) by using 0.1M HCl as a dissolution medium at 100rpm by a basket method, wherein the acceptable dissolution rate standard is 15min or more and 85%.
As a result: the dissolution rate of the capsule within the particle size range within 15 minutes is (80 +/-3.67)%, which is less than 85%.
Example 4
Compound III capsules were prepared according to the following formulation and dissolution was measured.
The preparation method comprises the following steps:
(1) particle size D of Compound III5034.8 μm, sieving microcrystalline cellulose, mannitol, lactose, pregelatinized starch, croscarmellose sodium, crospovidone, carboxymethyl starch sodium, silica gel micropowder and magnesium stearate with 60 mesh sieve;
(2) weighing the sieved components according to the following formula proportion, and mixing for about 20min to be uniform to obtain a mixture;
(3) adding sieved magnesium stearate, mixing for 5min, and making capsule.
Prescription A: compound III: 29.27, microcrystalline cellulose: 22.24, mannitol: 44.49, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00; in total: 100.
and a prescription B: compound III: 29.27, microcrystalline cellulose: 22.24, mannitol: 44.49, crospovidone: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription C: compound III: 29.27, microcrystalline cellulose: 22.24, mannitol: 44.49, carboxymethyl starch sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription D: compound III: 29.27, microcrystalline cellulose: 21.24, mannitol: 42.49, croscarmellose sodium: 5.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription E: compound III: 29.27, microcrystalline cellulose: 19.58, mannitol: 39.15, croscarmellose sodium: 10.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription F: compound III: 29.27, microcrystalline cellulose: 22.24, lactose: 44.49, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription G: compound III: 29.27, microcrystalline cellulose: 22.24, pregelatinized starch: 44.49, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription H: compound III: 29.27, microcrystalline cellulose: 33.37, mannitol: 33.36, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription I: compound III: 29.27, microcrystalline cellulose: 16.68, mannitol: 50.05, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription J: compound III: 40.97, microcrystalline cellulose: 18.34, mannitol: 36.69, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription K: compound III: 35.12, microcrystalline cellulose: 20.29, mannitol: 40.59, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription L: compound III: 30.73, microcrystalline cellulose: 21.76, mannitol: 43.51, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription M: compound III: 27.32, microcrystalline cellulose: 22.89, mannitol: 45.79, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription N: compound III: 24.58, microcrystalline cellulose: 23.81, mannitol: 47.61, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 1.00, Total: 100.
prescription O: compound III: 29.27, microcrystalline cellulose: 22.41, mannitol: 44.82, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 0.50, total: 100.
prescription P: compound III: 29.27, microcrystalline cellulose: 22.08, mannitol: 44.15, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 0.50, total: 100.
prescription Q: compound III: 29.27, microcrystalline cellulose: 20.91, mannitol: 41.82, croscarmellose sodium: 2.00, silica gel micropowder: 1.00, magnesium stearate: 0.50, total: 100.
the dissolution rate of the capsule with the prescription of 4-1 and 4-2 is determined by a dissolution rate determination method (second method of 0931 of the general rules of Chinese pharmacopoeia 2015 edition) by taking 0.1M HCl as a dissolution medium by a basket method at 100rpm according to the method, and the acceptable standard of the dissolution rate is more than or equal to 85 percent within 15 min.
As a result: the dissolution test result shows that the dissolution rate is more than 85% in 15 min.
Example 5
In order to further verify the stability of the capsule disclosed by the invention, a capsule sample is prepared by adopting a formula A in example 4, the capsule sample is placed for 6 months under the conditions of 40 ℃ and 75% of relative humidity according to the guiding principle of a raw material drug and preparation stability test in 9001 of China pharmacopoeia 2015 edition four, and samples are taken for detecting properties, dissolution rates, related substances and contents in 1,2, 3 and 6 months, wherein the dissolution conditions are 0.1M HCl as a dissolution medium, and the basket method is carried out at 100 rpm. The test results are shown in table 1, and the results prove that the compound III capsule prepared by the invention has good stability.
TABLE 1
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (13)
1. A composition comprising a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient,
the particle size of the active ingredient satisfies the following conditions: d is more than or equal to 20 mu m50≤50μm;
Optionally, the particle size of the active ingredient satisfies the following condition: d is more than or equal to 20 mu m50≤35μm;
Optionally, the particle size of the active ingredient satisfies the following condition: d is not less than 35 mu m50≤50μm;
Optionally, the particle size of the active ingredient satisfies the following condition: d is not more than 25 mu m50≤45μm;
Optionally, the particle size of the active ingredient is belowThe following conditions: d50About 20 μm, about 22 μm, about 24 μm, about 26 μm, about 28 μm, about 30 μm, about 32 μm, about 34 μm, about 36 μm, about 38 μm, about 40 μm, about 42 μm, about 44 μm, about 46 μm, about 48 μm or about 50 μm.
2. The composition of claim 1, wherein the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt;
optionally, the inorganic or organic acid salt is a mono-or di-salt;
optionally, the inorganic acid salt is selected from hydrogen halide acid salt, halogen series oxygen-containing inorganic acid salt, carbon series oxygen-containing inorganic acid salt, nitrogen series oxygen-containing inorganic acid salt, boron series oxygen-containing inorganic acid salt, silicon series oxygen-containing inorganic acid salt, phosphorus series oxygen-containing inorganic acid salt or sulfur series inorganic acid salt;
the organic acid salt is selected from carboxylate, sulfonate, sulfinate or thiocarboxylate;
optionally, the inorganic acid salt is selected from the group consisting of a hydrochloride, sulfate, bisulfate, nitrate, borate, hydrobromide, hydroiodide, carbonate, bicarbonate, sulfite, perchlorate, persulfate, hemisulfate, bisulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, or metaphosphate;
the organic acid salt is selected from formate, acetate, benzoate, malonate, succinate, methanesulfonate, ethanesulfonate, citrate, benzenesulfonate, p-toluenesulfonate, malate, tartrate, succinate, fumarate, glycolate, isethionate, maleate, lactate, lactobionate, embonate, salicylate, galactarate, glucoheptonate, mandelate, gluconate, 1, 2-ethyldisulfonate, 2-naphthalenesulfonate, oxalate, trifluoroacetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethylsulfonate, glycerophosphate, heptanoate, hexanoate, 2-hydroxy-ethanesulfonate, succinate, methanesulfonate, ethanesulfonate, mesylate, isovalerate, and isovalerate, Laurate, lauryl sulfate, nicotinate, oleate, palmitate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, or valerate;
optionally, the inorganic acid salt is a phosphate salt;
optionally, the inorganic acid salt diphosphate.
4. the composition according to any one of claims 1 to 3, wherein the mass fraction of the compound of formula (I) or formula (II) or the pharmaceutically acceptable salt thereof is 20% to 45%, or 20% to 42%, or 21% to 39%, or 22% to 38%, or 23% to 37%, or 24% to 36%, 25% to 35%, or 26% to 34%, or 27% to 33%, or 28% to 32%, or 29% to 31%, or 20% to 25%, 25% to 30%, 30% to 35%, or 35% to 40%, or about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, or about 35%, based on the total weight of the composition.
5. The composition of any one of claims 1-4, further comprising a pharmaceutically acceptable adjuvant comprising at least one selected from the group consisting of diluents, disintegrants, glidants, and lubricants;
optionally, the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose;
optionally, the disintegrant comprises one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate;
optionally, the glidant is aerosil or talc;
optionally, the lubricant is magnesium stearate.
6. The composition according to claim 5, wherein the mass fraction of the microcrystalline cellulose is 15-40% based on the total weight of the composition;
optionally, the mass fraction of one or more of mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 30-50% based on the total weight of the composition;
optionally, the mass ratio of the microcrystalline cellulose to one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 1: 1-1: 3;
optionally, the mass fraction of the disintegrant is 1-12% based on the total weight of the composition;
optionally, the mass fraction of the glidant is 0.5-2% based on the total weight of the composition;
optionally, the lubricant is present in an amount of 0.5 to 5% by weight, based on the total weight of the composition.
7. The composition according to any one of claims 1 to 6, wherein the composition is in the form of an oral formulation;
optionally, the composition is in the form of a solid oral formulation;
optionally, the composition is in the form of a capsule, tablet, pellet, powder, sustained release formulation, aqueous suspension, ointment, paste, emulsion, lotion, gel, solution, spray, inhalant or patch.
8. A capsule filled with contents, characterized in that the contents comprise a composition according to any one of claims 1 to 6.
9. A capsule filled with contents, characterized in that the contents comprise: the compound shown in the formula (III) or the formula (IV) and a diluent, a disintegrant, a glidant and a lubricant, wherein the mass part of the compound shown in the formula (III) or the formula (IV) is 20-45%, and the particle size of the compound shown in the formula (III) or the formula (IV) meets the following condition: d is more than or equal to 20 mu m50≤50μm。
10. The capsule according to claim 9, wherein the compound of formula (III) or formula (IV) is used in an amount of 20 to 45 parts by weight, the diluent is used in an amount of 50 to 75 parts by weight, the disintegrant is used in an amount of 1 to 12 parts by weight, the glidant is used in an amount of 0.5 to 2 parts by weight, and the lubricant is used in an amount of 0.5 to 2 parts by weight.
11. The capsule according to claim 9 or 10, wherein the diluent comprises microcrystalline cellulose and one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, dibasic calcium phosphate, starch, sucrose;
optionally, the disintegrant comprises one or more of crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium starch glycolate;
optionally, the glidant is aerosil;
optionally, the lubricant is magnesium stearate;
optionally, the microcrystalline cellulose is used in an amount of 15-40 parts by weight;
optionally, the dosage of one or more of mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 30-50 parts by weight;
optionally, the mass ratio of the microcrystalline cellulose in the diluent to one or more selected from mannitol, lactose monohydrate, pregelatinized starch, sorbitol, calcium hydrogen phosphate, starch and sucrose is 1: 1-1: 3.
12. The capsule according to claim 8 or 9, wherein the capsule is a single dose formulation or a multi dose formulation.
13. A method of making a capsule comprising:
(1) d with the particle diameter of 20 mu m or less50Premixing the compound shown in the formula (I), or the formula (II), or the formula (III) or the formula (IV) with a diluent, a disintegrant and a glidant to obtain a first mixture, wherein the time of the first mixing treatment is 15-30 min;
(2) subjecting the first mixture and a lubricant to a second mixing treatment to obtain a second mixture, wherein the second mixing treatment time is 3-7 min optionally;
(3) and subjecting the second mixture to a capsule filling process so as to obtain said capsules.
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