WO2007126039A1 - Préparation antibiotique macrolide enrobée - Google Patents
Préparation antibiotique macrolide enrobée Download PDFInfo
- Publication number
- WO2007126039A1 WO2007126039A1 PCT/JP2007/059144 JP2007059144W WO2007126039A1 WO 2007126039 A1 WO2007126039 A1 WO 2007126039A1 JP 2007059144 W JP2007059144 W JP 2007059144W WO 2007126039 A1 WO2007126039 A1 WO 2007126039A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- macrolide antibiotic
- substituted
- atom
- coated preparation
- Prior art date
Links
- 239000003120 macrolide antibiotic agent Substances 0.000 title claims abstract description 166
- 238000002360 preparation method Methods 0.000 title claims abstract description 119
- 239000011248 coating agent Substances 0.000 claims abstract description 77
- 150000003839 salts Chemical class 0.000 claims abstract description 56
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 53
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 51
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 51
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
- 125000006239 protecting group Chemical group 0.000 claims abstract description 20
- 230000003115 biocidal effect Effects 0.000 claims abstract description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 81
- 239000000126 substance Substances 0.000 claims description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 45
- 125000003107 substituted aryl group Chemical group 0.000 claims description 43
- 150000001875 compounds Chemical class 0.000 claims description 40
- 238000000576 coating method Methods 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 125000005842 heteroatom Chemical group 0.000 claims description 31
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 30
- 229910052717 sulfur Inorganic materials 0.000 claims description 29
- 229920001577 copolymer Polymers 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 28
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 238000006116 polymerization reaction Methods 0.000 claims description 26
- 125000004434 sulfur atom Chemical group 0.000 claims description 25
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 239000000178 monomer Substances 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
- -1 pyrazole-1-yl Chemical group 0.000 claims description 20
- 239000008187 granular material Substances 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 17
- 238000009472 formulation Methods 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 238000003860 storage Methods 0.000 claims description 17
- 229920002554 vinyl polymer Polymers 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 12
- 150000001735 carboxylic acids Chemical class 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- 238000007334 copolymerization reaction Methods 0.000 claims description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 7
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 claims description 6
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 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
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 5
- 244000309464 bull Species 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 239000008199 coating composition Substances 0.000 claims description 5
- 239000010936 titanium Substances 0.000 claims description 5
- 229910052719 titanium Inorganic materials 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical group [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 3
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 3
- 125000005549 heteroarylene group Chemical group 0.000 claims description 3
- 125000006588 heterocycloalkylene group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 claims description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 3
- 229920001451 polypropylene glycol Polymers 0.000 claims description 3
- 125000005649 substituted arylene group Chemical group 0.000 claims description 3
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical compound OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 claims description 2
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 claims description 2
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 claims description 2
- 101100240517 Caenorhabditis elegans nhr-11 gene Proteins 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-L catecholate(2-) Chemical compound [O-]C1=CC=CC=C1[O-] YCIMNLLNPGFGHC-UHFFFAOYSA-L 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 229920002521 macromolecule Polymers 0.000 claims 1
- 150000002825 nitriles Chemical class 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 67
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- 239000003814 drug Substances 0.000 description 16
- 238000004519 manufacturing process Methods 0.000 description 13
- 208000015181 infectious disease Diseases 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 239000004480 active ingredient Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 238000004811 liquid chromatography Methods 0.000 description 9
- 238000004806 packaging method and process Methods 0.000 description 9
- 241000894006 Bacteria Species 0.000 description 8
- 241000194017 Streptococcus Species 0.000 description 8
- 239000007884 disintegrant Substances 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000011593 sulfur Chemical group 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241000233866 Fungi Species 0.000 description 5
- 241000204031 Mycoplasma Species 0.000 description 5
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 5
- 241000251468 Actinopterygii Species 0.000 description 4
- 241000271566 Aves Species 0.000 description 4
- 208000035473 Communicable disease Diseases 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 241000193996 Streptococcus pyogenes Species 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 239000007902 hard capsule Substances 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 150000004677 hydrates Chemical class 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 3
- 241000606768 Haemophilus influenzae Species 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- WOBHKFSMXKNTIM-UHFFFAOYSA-N Hydroxyethyl methacrylate Chemical compound CC(=C)C(=O)OCCO WOBHKFSMXKNTIM-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229960003276 erythromycin Drugs 0.000 description 3
- 229940047650 haemophilus influenzae Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 238000005507 spraying Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 description 2
- 229920002818 (Hydroxyethyl)methacrylate Polymers 0.000 description 2
- 108700028369 Alleles Proteins 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 241000606153 Chlamydia trachomatis Species 0.000 description 2
- 241000193403 Clostridium Species 0.000 description 2
- 206010010741 Conjunctivitis Diseases 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 241000194033 Enterococcus Species 0.000 description 2
- IMROMDMJAWUWLK-UHFFFAOYSA-N Ethenol Chemical compound OC=C IMROMDMJAWUWLK-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 241000605909 Fusobacterium Species 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 241000590002 Helicobacter pylori Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- RZPAKFUAFGMUPI-UHFFFAOYSA-N Oleandomycin Natural products O1C(C)C(O)C(OC)CC1OC1C(C)C(=O)OC(C)C(C)C(O)C(C)C(=O)C2(OC2)CC(C)C(OC2C(C(CC(C)O2)N(C)C)O)C1C RZPAKFUAFGMUPI-UHFFFAOYSA-N 0.000 description 2
- 239000004104 Oleandomycin Substances 0.000 description 2
- 241000606860 Pasteurella Species 0.000 description 2
- 241000606856 Pasteurella multocida Species 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010037075 Protozoal infections Diseases 0.000 description 2
- 206010062255 Soft tissue infection Diseases 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 241000191980 Staphylococcus intermedius Species 0.000 description 2
- 241000193985 Streptococcus agalactiae Species 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000011203 antimicrobial therapy Methods 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 description 2
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 2
- 229940038705 chlamydia trachomatis Drugs 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229960004100 dirithromycin Drugs 0.000 description 2
- WLOHNSSYAXHWNR-NXPDYKKBSA-N dirithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H]2O[C@H](COCCOC)N[C@H]([C@@H]2C)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 WLOHNSSYAXHWNR-NXPDYKKBSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960001398 flurithromycin Drugs 0.000 description 2
- XOEUHCONYHZURQ-HNUBZJOYSA-N flurithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@@](C)(F)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 XOEUHCONYHZURQ-HNUBZJOYSA-N 0.000 description 2
- 229940037467 helicobacter pylori Drugs 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 125000005397 methacrylic acid ester group Chemical group 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229930187734 mycinamicin Natural products 0.000 description 2
- 230000001272 neurogenic effect Effects 0.000 description 2
- 229960002351 oleandomycin Drugs 0.000 description 2
- RZPAKFUAFGMUPI-KGIGTXTPSA-N oleandomycin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@]2(OC2)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C RZPAKFUAFGMUPI-KGIGTXTPSA-N 0.000 description 2
- 235000019367 oleandomycin Nutrition 0.000 description 2
- 229940051027 pasteurella multocida Drugs 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000003505 polymerization initiator Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 238000010526 radical polymerization reaction Methods 0.000 description 2
- 229910052705 radium Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 208000023504 respiratory system disease Diseases 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229960005224 roxithromycin Drugs 0.000 description 2
- 229910052701 rubidium Inorganic materials 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 206010040872 skin infection Diseases 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 229940030998 streptococcus agalactiae Drugs 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 208000019206 urinary tract infection Diseases 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000052 vinegar Substances 0.000 description 2
- 235000021419 vinegar Nutrition 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- ZUGIGWIPEYNYJV-FZWPAWTOSA-N (3r,4s,5r,6s,7s,9r,11r,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-12,13-dihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@H](C)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ZUGIGWIPEYNYJV-FZWPAWTOSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- XLPJNCYCZORXHG-UHFFFAOYSA-N 1-morpholin-4-ylprop-2-en-1-one Chemical compound C=CC(=O)N1CCOCC1 XLPJNCYCZORXHG-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- WDQMWEYDKDCEHT-UHFFFAOYSA-N 2-ethylhexyl 2-methylprop-2-enoate Chemical compound CCCCC(CC)COC(=O)C(C)=C WDQMWEYDKDCEHT-UHFFFAOYSA-N 0.000 description 1
- OWHSTLLOZWTNTQ-UHFFFAOYSA-N 2-ethylhexyl 2-sulfanylacetate Chemical compound CCCCC(CC)COC(=O)CS OWHSTLLOZWTNTQ-UHFFFAOYSA-N 0.000 description 1
- RUMACXVDVNRZJZ-UHFFFAOYSA-N 2-methylpropyl 2-methylprop-2-enoate Chemical compound CC(C)COC(=O)C(C)=C RUMACXVDVNRZJZ-UHFFFAOYSA-N 0.000 description 1
- CFVWNXQPGQOHRJ-UHFFFAOYSA-N 2-methylpropyl prop-2-enoate Chemical compound CC(C)COC(=O)C=C CFVWNXQPGQOHRJ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WHNPOQXWAMXPTA-UHFFFAOYSA-N 3-methylbut-2-enamide Chemical compound CC(C)=CC(N)=O WHNPOQXWAMXPTA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- AWQSAIIDOMEEOD-UHFFFAOYSA-N 5,5-Dimethyl-4-(3-oxobutyl)dihydro-2(3H)-furanone Chemical compound CC(=O)CCC1CC(=O)OC1(C)C AWQSAIIDOMEEOD-UHFFFAOYSA-N 0.000 description 1
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 241000606750 Actinobacillus Species 0.000 description 1
- 241000588986 Alcaligenes Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000606125 Bacteroides Species 0.000 description 1
- 241001148536 Bacteroides sp. Species 0.000 description 1
- 241000606660 Bartonella Species 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- 241000180135 Borrelia recurrentis Species 0.000 description 1
- 241000589969 Borreliella burgdorferi Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241001148534 Brachyspira Species 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000589875 Campylobacter jejuni Species 0.000 description 1
- 241001647372 Chlamydia pneumoniae Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000595586 Coryne Species 0.000 description 1
- 241000186216 Corynebacterium Species 0.000 description 1
- 241001518260 Corynebacterium minutissimum Species 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 241000223935 Cryptosporidium Species 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000605721 Dichelobacter nodosus Species 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000186394 Eubacterium Species 0.000 description 1
- 206010016952 Food poisoning Diseases 0.000 description 1
- 208000019331 Foodborne disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 241001148567 Lawsonia intracellularis Species 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 208000010315 Mastoiditis Diseases 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- GYCMBHHDWRMZGG-UHFFFAOYSA-N Methylacrylonitrile Chemical compound CC(=C)C#N GYCMBHHDWRMZGG-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000588622 Moraxella bovis Species 0.000 description 1
- 241000588655 Moraxella catarrhalis Species 0.000 description 1
- 241000186367 Mycobacterium avium Species 0.000 description 1
- 241000186364 Mycobacterium intracellulare Species 0.000 description 1
- 241001138504 Mycoplasma bovis Species 0.000 description 1
- 206010028470 Mycoplasma infections Diseases 0.000 description 1
- 241000202934 Mycoplasma pneumoniae Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229920001007 Nylon 4 Polymers 0.000 description 1
- GFIQERTUSVTTRE-HCTDEEJFSA-N O1[C@H](C)C[C@H](N(C)C)[C@@H](OC(=O)CCC(=O)OCC)[C@@H]1O[C@H]1[C@@](O)(C)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@](C)(O)[C@@H](CC)OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(OC)C2)[C@@H]1C Chemical compound O1[C@H](C)C[C@H](N(C)C)[C@@H](OC(=O)CCC(=O)OCC)[C@@H]1O[C@H]1[C@@](O)(C)C[C@](C)(F)C(=O)[C@H](C)[C@@H](O)[C@](C)(O)[C@@H](CC)OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(OC)C2)[C@@H]1C GFIQERTUSVTTRE-HCTDEEJFSA-N 0.000 description 1
- 206010048685 Oral infection Diseases 0.000 description 1
- 206010031252 Osteomyelitis Diseases 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 241000191992 Peptostreptococcus Species 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000605894 Porphyromonas Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000605861 Prevotella Species 0.000 description 1
- 208000010362 Protozoan Infections Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 208000019802 Sexually transmitted disease Diseases 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 241001147691 Staphylococcus saprophyticus Species 0.000 description 1
- 241000194054 Streptococcus uberis Species 0.000 description 1
- 241001312524 Streptococcus viridans Species 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010048762 Tooth infection Diseases 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 241000546339 Trioxys Species 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 241000202921 Ureaplasma urealyticum Species 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 241000606834 [Haemophilus] ducreyi Species 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 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 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- XYLMUPLGERFSHI-UHFFFAOYSA-N alpha-Methylstyrene Chemical compound CC(=C)C1=CC=CC=C1 XYLMUPLGERFSHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium peroxydisulfate Substances [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 1
- VAZSKTXWXKYQJF-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)OOS([O-])=O VAZSKTXWXKYQJF-UHFFFAOYSA-N 0.000 description 1
- 229910001870 ammonium persulfate Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960004099 azithromycin Drugs 0.000 description 1
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 description 1
- 235000013405 beer Nutrition 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical class OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 238000012662 bulk polymerization Methods 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 239000012986 chain transfer agent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940032122 claris Drugs 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- OIWOHHBRDFKZNC-UHFFFAOYSA-N cyclohexyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC1CCCCC1 OIWOHHBRDFKZNC-UHFFFAOYSA-N 0.000 description 1
- KBLWLMPSVYBVDK-UHFFFAOYSA-N cyclohexyl prop-2-enoate Chemical compound C=CC(=O)OC1CCCCC1 KBLWLMPSVYBVDK-UHFFFAOYSA-N 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000007720 emulsion polymerization reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000010528 free radical solution polymerization reaction Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 208000004396 mastitis Diseases 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- FQPSGWSUVKBHSU-UHFFFAOYSA-N methacrylamide Chemical compound CC(=C)C(N)=O FQPSGWSUVKBHSU-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000000379 polymerizing effect Effects 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- FZYCEURIEDTWNS-UHFFFAOYSA-N prop-1-en-2-ylbenzene Chemical compound CC(=C)C1=CC=CC=C1.CC(=C)C1=CC=CC=C1 FZYCEURIEDTWNS-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- YPVDWEHVCUBACK-UHFFFAOYSA-N propoxycarbonyloxy propyl carbonate Chemical compound CCCOC(=O)OOC(=O)OCCC YPVDWEHVCUBACK-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 208000020029 respiratory tract infectious disease Diseases 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010352 sodium erythorbate Nutrition 0.000 description 1
- 239000004320 sodium erythorbate Substances 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940115922 streptococcus uberis Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- IHCDKJZZFOUARO-UHFFFAOYSA-M sulfacetamide sodium Chemical compound O.[Na+].CC(=O)[N-]S(=O)(=O)C1=CC=C(N)C=C1 IHCDKJZZFOUARO-UHFFFAOYSA-M 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010557 suspension polymerization reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003250 telithromycin Drugs 0.000 description 1
- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 230000005944 tissue migration Effects 0.000 description 1
- UBZYKBZMAMTNKW-UHFFFAOYSA-J titanium tetrabromide Chemical compound Br[Ti](Br)(Br)Br UBZYKBZMAMTNKW-UHFFFAOYSA-J 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
Definitions
- the present invention relates to a stable coating preparation of a macrolide antibiotic effective for the treatment of various infectious diseases caused by bacteria, mycoplasma, fungi, protozoa and the like.
- Macrolide antibiotics are known to be useful for the treatment of a wide variety of infectious diseases caused by bacteria, mycoplasma, fungi (breasts), protozoa, etc. in mammals, fish and birds.
- erythromycin As a representative macrolide antibiotic, erythromycin (Patent Documents 1 and 2) has many advantages such as its characteristic antibacterial activity, good tissue migration, and few side effects, and has been a clinically useful antibiotic for many years. Has been used. Since then, various macrolide antibiotics have been promoted, in clinical development, or in research and development.
- macrolide antibiotics examples include 14- to 16-membered macrolide antibiotics such as erythromycin (Patent Documents 1 and 2), oleandomycin (Patent Documents 3 and 4), and clarithromycin.
- Patent document 5 roxithromycin (patent document 6), adithromycin (patent document 7), dirithromycin (patent document 8), tethromycin (patent document 9), sesulomycin (patent document 10), flurithromycin Mycetyl succinate (patent document 11), compounds described later (patent documents 12, 13), L-701677 (patent document 14), mycinamicin (non-patent document 1), and many other derivatives are known.
- erythromycin Patent Documents 1 and 2
- Patent Documents 3 and 4 examples include clarithromycin.
- Patent document 5 roxithromycin (patent document 6), adithromycin (patent document 7), dirithromycin (patent document 8), tethromycin (patent document 9), sesul
- Patent Document 15 a hard capsule that can be filled with a solvent for dissolving poorly soluble medicinal components (polyethylene glycol or the like) that cannot be filled with a conventional hard capsule.
- Patent Document 15 uses a polyvinyl alcohol copolymer as a coating component of a hard capsule, and the polyvinyl alcohol copolymer is a main agent or a solid substance containing the same. It is not intended to be used as a coating material.
- Patent Document 16 a rosin composition useful as a coating agent for pharmaceuticals, veterinary drugs, agricultural chemicals, fertilizers, foods, etc., mainly composed of a polyvinyl alcohol copolymer is known.
- Patent Document 16 a rosin composition useful as a coating agent for pharmaceuticals, veterinary drugs, agricultural chemicals, fertilizers, foods, etc., mainly composed of a polyvinyl alcohol copolymer.
- Patent Document 1 US2653899
- Patent Document 2 US24.7
- Patent Document 3 US2757123
- Patent Document 4 US 2842481
- Patent Document 5 US4331803
- Patent Document 6 US4349545
- Patent Document 7 US4517359
- Patent Document 8 EP511799
- Patent Document 9 US literature
- Patent Document 10 US5866549
- Patent Document 11 EP56291
- Patent Document 12 WO2003Z097659 Al
- Patent Document 13 WO2005Z ⁇ 81821 A2
- Non-patent document 1 J. Antibiot 45 (1), 1 (1992)
- Patent Document 14 EP508699
- Patent Document 15 WO2002Zl7848
- Patent Document 16 WO2005Z019286
- R represents a hydrogen atom or a protecting group for a hydroxyl group
- a macrolide antibiotic having the partial structural formula shown below, a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solid containing the same is added to polybulal alcohol (PVA) It was found that a coated preparation of a stabilized macrolide antibiotic can be obtained by coating with a coating containing a coalescent as a main component, and the present invention has been completed.
- PVA polybulal alcohol
- R represents a protecting group for a hydrogen atom or a hydroxyl group
- a macrolide antibiotic having a group represented by the formula: pharmaceutically acceptable salt thereof, or a hydrate thereof;
- a coated preparation of a macrolide antibiotic which is coated with a coating agent containing vinyl alcohol or a polyvinyl alcohol copolymer.
- Macrolide antibiotics have the following partial structural formula (I): [Chemical 4]
- a macrolide antibiotic having the group represented by the formula, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
- Item 2 A coated preparation of a macrolide antibiotic according to Item 1.
- Item 3 The coated preparation of a macrolide antibiotic according to Item 1, wherein the macrolide antibiotic is a 14- to 16-membered ring macrolide antibiotic.
- Macrolide antibiotics have the general formula ( ⁇ ):
- R 1 represents (1) aryl group, (2) substituted aryl group, (3) heteroaryl group or substituted heteroaryl group),
- R 2 is (1) hydrogen atom, (2) a halogen atom, (3) optionally containing hetero atom oxygen atom, 0-3 of the selected sulfur atom and nitrogen Nuclear
- substituents optionally containing 0 to 3 heteroatoms selected from atoms, sulfur atoms and nitrogen atoms, and also selected from the group consisting of a norogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group C— C alkell, optionally substituted with
- A represents —R 1 or —R 2 , or A and B are bonded together with carbon atoms!
- R 1 has the same meaning as described above
- R 1 has the same meaning as described above
- heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom
- halogen, aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups also selected, optionally substituted with one or more substituents, C—C
- (f) represents a substituted heterocycloalkylene group
- Halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl base force may also be selected, which may be substituted with one or more substituents, C—C termination
- R 4 and R 5 together with the nitrogen atom to which they are bonded contain 3 to 10 heteroalkyls containing 0 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms.
- aryl groups substituted aryl groups, heteroaryl groups and substituted heteroaryl groups, which are also selected C 1 -C alkyl optionally substituted with one or more substituents
- 1 12 represents a group, an aryl group or a substituted aryl group.
- R 6 is as defined above, provided that R 6 is a C (O) -C 1 -C alkyl group, C (0 ) —C—C cycloalkyl group or C (0) —R
- a C 1 -C alkyl group which may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups,
- e a C 1 -C alkyl group, which may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups;
- c) represents a halogen atom
- R 2a represents a hydrogen atom or a hydroxyl-protecting group.
- Item 4 A coated preparation of a macrolide antibiotic according to Item 3, wherein the compound is a compound represented by the following formula, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
- Macrolide antibiotics may have the following formula ( ⁇ ):
- Macrolide antibiotic power 2 0 14.3, 14.5, 15.1, 18.8, 20.5, 23.2, 24.9, in powder X-ray diffraction pattern Having at least one peak selected from 25. 6, 29.0, 34.1, 37.7, 38.1, 38.9 and 40.4 (unit: degrees), (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6 Trideoxy-3-dimethylamino 13-D-xylohexopyranosyloxy) 3 Ethyl 2 Hydroxy 1, 2, 6, 8, 10, 16, 18 Hexamethyl-1,5,7 Dioxo13— [(E) — [6— ( Pyrazole-1-yl) pyridine-3-yl] methoxyimino]-4, 11, 15-trioxabicyclo [8, 5, 4] nonade force-17E-ylidene] acetamide
- Item 8 The coated preparation of a macrolide antibiotic according to Item 7, wherein the type 1 is an anhydrous crystal.
- Item 9 The coated preparation of a macrolide antibiotic according to Item 1, wherein the coated preparation is a solid preparation.
- Item 10 The coated preparation of macrolide antibiotics according to Item 9, wherein the solid preparation is a tablet or a granule.
- Item 11 Coating power obtained by copolymerization of polybulle alcohol having an average degree of polymerization of 1300 or less and at least one polymerizable bule monomer in a weight ratio of 6: 4 to 9: 1.
- Item 2. The coated preparation of macrolide antibiotics according to Item 1, characterized in that it comprises a polybutyl alcohol copolymer.
- Item 12 The coated preparation of a macrolide antibiotic according to Item 11, wherein the average degree of polymerization of the polybulal alcohol is 900 or less.
- Item 13 The coated preparation of a macrolide antibiotic according to Item 12, characterized in that the average degree of polymerization of polybulal alcohol is 200 to 600.
- Item 14 The coated preparation of a macrolide antibiotic according to Item 11, wherein the polybulal alcohol is a partially saponified polybulal alcohol.
- Item 15 Polymerizable Bull Monomer Strength Unsaturated Carboxylic Acids, Unsaturated Carboxylic Acid Esters, Unsaturated-Tolyls, Unsaturated Amides, Aromatic Bulls, Aliphatic Bulls, Unsaturated Bonds Item 12.
- Item 16 A copolymer obtained by copolymerizing polybulal alcohol and two or more polymerizable bur monomers, and at least one of the two or more polymerizable vinyl monomers is an unsaturated carboxylic acid or Item 12.
- the coated preparation of macrolide antibiotics according to Item 11, which is a salt thereof and at least one of them is an ester of an unsaturated carboxylic acid.
- Item 17 Unsaturated carboxylic acids or their salt strength Acrylic acid, methacrylic acid, chloro Tonic acid, fumaric acid, maleic acid, itaconic acid, and their salt strengths are selected from the group of unsaturated carboxylic acid esters such as acetyl metatalylate, methyl acrylate, ethyl acetate, ethyl.
- R represents a hydrogen atom or a methyl group, R represents a hydrogen atom or 1 to 4 carbon atoms
- Item 19 The macrolide according to Item 16, which is an unsaturated carboxylic acid or a salt thereof, acrylic acid or a salt thereof, and is an ester of an unsaturated carboxylic acid, such as butyl methacrylate. Coated antibiotics.
- Item 20 Item 19, wherein the weight ratio of acrylic acid or a salt thereof to methyl methacrylate is from 3: 7 to 0.5: 9.5 in the copolymerization.
- a macrolide antibiotic coating formulation A macrolide antibiotic coating formulation.
- Item 21 Obtained by copolymerizing a partially saponified polyvinyl alcohol having an average polymerization degree of 300 to 500 and a polymerizable vinyl monomer in a weight ratio of 6: 4 to 9: 1, and The polymerizable bulle monomer is acrylic acid and methyl methacrylate, and the weight ratio of acrylic acid to methyl methacrylate is 3: 7 to 0.5: 9.5 when copolymerized.
- Item 14 A coated preparation of a macrolide antibiotic according to Item 11, characterized by.
- Item 22 Partially saponified polybutyl alcohol having an average degree of polymerization of 300 to 500, methyl methacrylate Item 23.
- Item 23 Content of coating agent
- the coated preparation of the macrolide antibiotic according to Item 10 which is 2% (weight ratio) or more with respect to the uncoated tablet or elementary granule.
- Item 24 The total amount of related substances after storage for 3 months at 25 ° C and 60% relative humidity in a macrolide antibiotic coated preparation is 3% or less, characterized in that A coated preparation of a macrolide antibiotic described in 1.
- Macrolide antibiotics are (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6-trideoxy-1, 3-dimethylamino j8—D—Hydroxysilano) 1-3 Ethyl 2 Hydroxy 1, 2, 6, 8, 10, 16, 18 Hexamethyl 5, 7 Dixo 13— [(E) — [6 (Pyrazole 1 yl) Pyridine 3-yl] methoxyimino] — 4, 11, 15 trioxabicyclo [8, 5, 4] nonade force—17E-ylidene] is a type 1 crystal of acetamide with a coating containing acid titanium.
- the macrolide antibiotic is (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6-trideoxy-1, 3-dimethylamino j8—D—Hydroxysilano) 1-3 Ethyl 2 Hydroxy 1, 2, 6, 8, 10, 16, 18 Hexamethyl 5, 7 Dixo 13— [(E) — [6 (Pyrazole 1 yl) Pyridine 3-yl] methoxyimino] — 4, 11, 15 trioxabicyclo [8, 5, 4] nonade force—17E—ylidene] Acetamide type 1 crystals at 25 ° C and 60% relative humidity. Macrolide antibiotic coated preparation, characterized in that the total amount of related substances after storage for 3 months is 1.5% or less
- Item 27 The coated preparation of a macrolide antibiotic according to Item 26, which is packaged in PTP (press-through package) or bottle packaging.
- R 2a represents a protecting group for a hydrogen atom or a hydroxyl group
- a macrolide antibiotic having the group represented by the formula, a pharmaceutically acceptable salt thereof, or a hydrate thereof or a compound thereof.
- a method for suppressing the formation of a related substance of the macrolide antibiotic which comprises coating a solid substance to be coated with a coating agent containing polybulal alcohol or a polybulal alcohol copolymer.
- R represents a protecting group for a hydrogen atom or a hydroxyl group.
- a macrolide antibiotic having a group represented by the formula: a pharmaceutically acceptable salt thereof, a hydrate thereof, or a substance thereof The macrolide antibiotic, its pharmaceutically acceptable salt, or a hydrate thereof, characterized in that a solid is coated with a coating agent containing polybulal alcohol or a polybulal alcohol copolymer. Stable way.
- the coating preparation of a macrolide antibiotic coated with a coating agent containing polybulualcohol or polybulualcohol copolymer of the present invention has excellent antibacterial activity and is used for treatment of various infectious diseases. It can be used, is pharmaceutically stable for a long period of time, and is easy to take. Therefore, it is very useful as a medicine for humans, veterinary medicine for mammals other than humans, fish, birds and the like.
- polybulal alcohol or polybulal alcohol copolymer as a coating agent can be coated on the active ingredient microparticles and small solids, which prevents the size of the dosage formulation from increasing, and patients such as the elderly and children
- solid preparations such as tablets, granules, capsules and pills that are easy to take.
- FIG. 1 shows a production flow chart of a coated preparation of the macrolide antibiotic of Example 1.
- FIG. 2 shows a chromatograph of liquid chromatography performed on the coated preparation stored in Example 1 performed in Example 1.
- FIG. 3 is a graph showing the evaluation results of the stability of the macrolide antibiotic-coated preparation conducted in Example 1.
- ⁇ indicates uncoated tablets
- ⁇ indicates tablets coated with polybulal alcohol copolymer.
- the vertical axis shows the total amount of related substances relative to the main drug in the coated preparation at 0.5 ° C, 1 month, 2 months, and 3 months after 25 ° C, 60% relative humidity and no packaging (w / w%).
- FIG. 4 shows the ratio (wZw%) of polybulal alcohol copolymer to uncoated tablets, and the affinity for the main drug after storage for 1 week under the conditions of 40 ° C, relative humidity 75%, and no packaging. The relationship with the total amount of substances (wZw%) is shown.
- FIG. 5 shows a production flow chart of the macrolide antibiotic coated preparation of Example 2.
- FIG. 6 is a graph showing the evaluation results of the stability of the macrolide-based coated preparation of Example 2.
- the circles indicate uncoated tablets, and the circles indicate tablets coated with acid-titanium-containing polyvinyl alcohol copolymer.
- the vertical axis represents the total amount of related substances relative to the active ingredient in the coated preparation at 0.5 and 1 month at 25 ° C, 60% relative humidity, and no packaging (wZw%) Indicates.
- FIG. 7 shows a production flowchart of a coated preparation of the macrolide antibiotic of Example 3.
- FIG. 8 is a graph showing the evaluation results of the stability of the macrolide antibiotic-coated preparation of Example 3.
- ⁇ indicates an uncoated tablet
- a thumbprint indicates a polybulal alcohol-coated tablet.
- the total amount of related substances (wZw%) relative to the main drug in the coated preparations after 0.5 months, 1 month, 2 months and 3 months under the conditions of 25 ° C, 60% relative humidity and no packaging is shown.
- the macrolide antibiotic is preferably a 14- to 16-membered macrolide antibiotic.
- the following partial structural formula is preferred:
- R represents a hydrogen atom or a protecting group for a hydroxyl group
- R represents a hydrogen atom or a protecting group for a hydroxyl group
- R 2a represents a hydrogen atom or a protecting group for a hydroxyl group
- a macrolide antibiotic having a group hereinafter also collectively referred to as “Q”
- Q a macrolide antibiotic having a group
- the partial structure is stabilized by the coating agent. Therefore, as long as it is a macrolide antibiotic having a group represented by the above general formula (I) in its structural formula, it can be used as a pharmaceutically active ingredient in the preparation of the present invention.
- the bonding site of the partial structural formula is not necessarily limited in the macrolide ring, but is preferably bonded to the macrolide ring in the manner exemplified below.
- Ra and Rb together represent oxo, or one represents a hydrogen atom and the other represents an —O sugar residue.
- Ra and Rb together represent oxo. Represents the remaining partial structure of the McLide ride ring.
- Examples of the 14-membered macrolide antibiotics include compounds represented by the following general formula ( ⁇ ) having the following crosslinking structure described in WO2003Z097659, pharmaceutically acceptable salts thereof, or hydration thereof. Things are more preferred.
- R 1 represents (1) aryl group, (2) substituted aryl group, (3) heteroaryl group or substituted heteroaryl group),
- R 2 is (1) hydrogen atom, (2) a halogen atom, (3) optionally containing hetero atom oxygen atom, 0-3 of the selected sulfur atom and nitrogen Nuclear , Halogen, ary Group, substituted aryl group, heteroaryl group and substituted heteroaryl group
- a C 1 -C alkyl group optionally substituted with one or more substituents, (4) oxygen atom
- substituents optionally containing 0 to 3 heteroatoms selected from atoms, sulfur atoms and nitrogen atoms, and also selected from the group consisting of a norogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group C— C alkell, optionally substituted with
- A represents one R 1 or one R 2 and is Or A and B are combined! /, Together with the carbon atom,
- R 1 has the same meaning as above
- heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom
- halogen, aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups also selected, optionally substituted with one or more substituents, C—C
- d) optionally containing 0 to 3 heteroatoms selected from an oxygen atom, sulfur atom and nitrogen atom, and halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl forces are also selected 1 or 2 or more Optionally substituted with a substituent of C— C
- (f) represents a substituted heterocycloalkylene group
- One of X and Y represents a hydrogen atom and the other is
- R 4 and R 5 are each independently (1) hydrogen atom
- Halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl base force may also be selected, which may be substituted with one or more substituents, C—C termination
- R 4 and R 5 together with the nitrogen atom to which they are bonded contain 3 to 10 heteroalkyls containing 0 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms.
- aryl groups substituted aryl groups, heteroaryl groups and substituted heteroaryl groups, which are also selected C 1 -C alkyl optionally substituted with one or more substituents
- 1 12 represents a group, an aryl group or a substituted aryl group.
- R 6 is as defined above, provided that R 6 is a C (O) -C 1 -C alkyl group, C (0 ) —C—C cycloalkyl group or C (0) —R R and R together with the carbon atom to which they are attached form a C -C cycloalkyl group
- a C 1 -C alkyl group which may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups,
- e a C 1 -C alkyl group, which may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups;
- c) represents a halogen atom
- R 2a represents a hydrogen atom or a hydroxyl-protecting group.
- M is preferably a bond
- Ar 2 preferably represents (d) a substituted heteroaryl group.
- the heteroaryl group is preferably an aromatic heterocyclic group which may contain 1 to 4 heteroatoms selected from 5 or 6-membered N, S, O forces. Pyridyl.
- Examples of the substituent on the heteroaryl group include the same aromatic heterocyclic group (eg, pyrazole) which may be substituted with amino-substituted lower alkylami-substituted hydroxy, halogen, lower alkyl, lower alkoxy or the like.
- X and Y are preferably bonded together with a carbon atom
- (3) — represents a group represented by C (O) R 11 (R 11 is preferably lower alkyl)).
- L is preferably CI—C6 lower alkyl, more preferably b) —CH 2 CH.
- Z is preferably a) a hydrogen atom.
- Examples of more specific macrolide antibiotics include erythromycin (14-membered ring), 6-deoxyerythromycin (14-membered ring), oleandomycin (14-membered ring), claris mouth mycin (14-membered ring), roxithromycin (14-membered ring), dirithromycin (14-membered ring), terisromycin (14-membered ring, compound (IV)), cesromycin (14-membered ring, compound (IX)) , Flurithromycin (14-membered ring), flurithromycin ethyl succinate (14-membered ring), GW7 73546 (14-membered ring, compound (V)), TEA— 0769 (14-membered ring)), TEA— 0777 (14-membered ring, compound (VI)), TEA— 0929 (14-membered ring), JNJ—17069546 (14-
- telithromycin GW773546, TEA-0777, CP-544372, JNJ-17069546 and sesromycin, or a pharmaceutically acceptable salt or hydrate thereof. is there.
- compound (III) which is one embodiment of compound ( ⁇ ), a pharmaceutically acceptable salt thereof or a hydrate thereof.
- the partial structural formula (I Q) is bonded to the 9-position, and the chemical name of the compound (III) is (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9 (3, 4, 6-Trideoxy-1-3-dimethylamino-1- ⁇ -D-Xyloxyhexopyranosyl Xy) -3 ethyl-2 hydroxy 2, 6, 8, 10, 16, 18 hexamethyl-5, 7- dixo 1 13- [(E) [6- (pyrazole 1-yl) pyridine 1-yl] Methoxyimino] 4, 11, 15 Trioxabicyclo [8,5,4] nonade 17E-ylidene] acetamide.
- the present inventors have found that the storage stability of compound (III), particularly its crystal (eg, type 1 crystal described in WO2005Z081821, particularly its anhydrous crystal) is extremely poor. In particular, it was found to be unstable to humidity and oxygen under long-term storage. It was also discovered from HPLC inspection, NMR analysis, etc. that the instability of compound (III) was caused by the partial structure shown in (I) above. It was also confirmed that by using the coating agent, the stability of the partial structure was improved and the production of related substances caused by the change in the partial structure was remarkably suppressed. Therefore, the stabilizing effect of the present invention is widely applied to various drugs having the same partial structure, particularly macrolide antibiotics. In addition, the stability of preparations containing them as the main drug, particularly various solid preparations, preferably tablets, granules, capsules, etc., is also improved.
- various solid preparations preferably tablets, granules, capsules, etc.
- the related substance produced by the change in the partial structure is typically the peak of the macrolide antibiotic as the main drug in HPLC analysis, as shown in Fig. 2 of the Examples below. Means two types of degradation products that appear before and increase over time in the stability test.
- This type 1 crystal shows a powder X-ray diffraction pattern substantially the same as the type I polymorph described in WO2005Z081821.
- the water content can be varied in the range of 0 to 2 hydrates.
- These macrolide antibiotics are known compounds, and can be produced based on the prior literature described in the background section or by a method analogous thereto.
- any salt can be used as long as it is a pharmaceutically acceptable salt, and it is not particularly limited.
- hydrohalic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid
- inorganic such as sulfuric acid, nitric acid, phosphoric acid, perchloric acid, carbonic acid, boric acid Salts with acids
- acetic acid, trichlorodiacetic acid trifluoroacetic acid, hydroxyacetic acid, lactic acid, succinic acid, succinic acid, tartaric acid, succinic acid, malonic acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, valeric acid, maleic acid
- Salts with organic carboxylic acids such as propionic acid, heptanoic acid, formic acid, malic acid, lauric acid, palmitic acid
- salts with amino acids such as arginine, aspartic
- the type of solvent in the solvate of the macrolide antibiotic is not particularly limited, and examples thereof include water; alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and the like.
- the coated preparation of the present invention comprising these as main ingredients is It is very effective in the treatment of bacterial infections such as mammals including humans, fish and birds, mycoplasma infections, fungal (branch) infections, and protozoal infections.
- Streptococcus pneumoniae Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Peptost Pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis due to Peptostreptococcus, etc .
- Streptococcus pyogenes Streptococcus C and G groups, Clostridium diptheria Or pharyngitis, rheumatic fever, and glomerulonephritis caused by Actinobacillus haemolyticum
- Mycoplasma pneumoniae ⁇ Legionella pneumophilaophil Streptococcus.
- Respiratory tract infections caused by Pneumoniae Streptococcus pneumoniae
- Hemphinoles' inf Norenze Hemphinoles' inf Norenze
- Chlamydi a pneumoniae Staphylococci! Stadiolococci! . epidermidis
- Streptococcus' Piokenes Streptococcus pyogenes ;, Streptococcus agalactiae), Streptococcus group (Group C to F Streptococcus), Streptococcus Uncomplicated skin and soft tissue infections, abscesses and osteomyelitis due to viridans (Streptococcus viridans, Corynebacterium minutissimum), Clostridium or Bartonella hensela e, and postpartum fever; Acute urinary tract infection caused by Staphylococcus saprophyticus or Enterococcus; urethritis and cervicitis; Chlamydia trachomatis, Haemophilus ducreyi, Man's Ritamu (Trep sexually transmitted diseases caused by onema pallidum), Ureaplasma urealyticum, or Neiserria gonorrheae; S.
- Tococcus pneumoniae stafiroko Conjunctivitis, keratitis, and lacrimal inflammation caused by Staphylococcus pyogenes, Haemophiles' Infnoreenze (Haemophilus influenzae), or Listeria; Mycobacterium avium, or Myconocterium 'Disseminated mycobacterial abum complex (MAC) disease due to Mycobacterium intracellulare; gastro-meningitis due to Campylobacter jejuni; cliff.
- Staphylococcus pyogenes Haemophiles' Infnoreenze (Haemophilus influenzae), or Listeria
- Mycobacterium avium or Myconocterium 'Disseminated mycobacterial abum complex (MAC) disease due to Mycobacterium intracellulare
- gastro-meningitis due to Campylobacter jejuni
- cliff cliff.
- Intestinal protozoa caused by the genus Cryptosporidium; odontogenic infection caused by Streptococcus pyridans; persistent cough caused by Bordetella pertussis; CI ostridium perfringens or Bacteroides ) Gas destruction by genus bacteria 3 ⁇ 4
- Bacterial and protozoal infections that can be treated or prevented in animals, and diseases associated with such infections include: Pasteurella hemolytica, Pasteurella hemolytica ( Pasteurella mult ocida, Mycoplasma bovis or Bordetel la pulmonary respiratory disease; E.
- Urinary bowel disease related to: Staphylococcus aureus, Streptococcus uberis, Streptococcus agalac tiae, Streptococcus dysococcus dysococci Klebsiella), Coryne Mastitis in dairy cows associated with infection by the genus Corynebacterium or Enterococcus; A porcine respiratory disease associated with infection by A. pleuro, P.
- Ushi rot ubiquitinitis associated with infection by Escherichia coli
- Fusoba kuterium 'non-chromophorome Fusobacterium necrophorumj or nocterote
- Urushi hairy warts associated with infection by Bacteroides nodosus
- Pink eyes of Ussi associated with infection by Moraxella bovis Protozoa (ie neosporium) Urinary tract infections in nu and cats related to infection by colon bacteria; Staphylococcus epidermidis, Staphylococcus intermedius (S.
- Polyvinyl alcohol or a copolymer thereof used as a coating agent in the present invention can preferably use those described in WO02 / 17848 and WO2005 / 019286.
- a polyvinyl alcohol copolymer is easy to coat in terms of adhesion and the like.
- the polyvinyl alcohol copolymer used in the present invention is polybulal alcohol or a derivative thereof (for example, esters), a salt, and at least one polymerizable bulle monomer known per se. It can be produced by copolymerization by a method.
- Examples of methods for producing such a polyvinyl alcohol copolymer include methods known per se such as radical polymerization, for example, solution polymerization, suspension polymerization, emulsion polymerization, and bulk polymerization. Can be carried out under the usual polymerization conditions. This polymerization reaction is usually carried out in the presence of a polymerization initiator, if necessary, as a reducing agent (for example, sodium erythorbate, sodium metabisulfite, ascorbic acid), a chain transfer agent (for example, 2-merca).
- a polymerization initiator for example, sodium erythorbate, sodium metabisulfite, ascorbic acid
- a chain transfer agent for example, 2-merca
- the polybulal alcohol used as the raw material for the polybulal alcohol copolymer has an average degree of polymerization of about 200 to 1500, preferably an average degree of polymerization of about 200 to 1300, more preferably an average degree of polymerization of about 200 to 900, and even more preferably. May have an average degree of polymerization of about 200 to 600, and most preferably an average degree of polymerization of about 300 to 500.
- the average degree of polymerization of from 300 to 500 parts only do poly Bulle alcohol preferably fixture average polymerization degree of about 300 to 500 degree of saponification of about 60 to: LO 0 mole 0/0, preferably from 78 to 96 mole 0/0 Partially saponified polybutyl alcohol is more preferred.
- a saponified polybutyl alcohol can be produced by radical polymerization of vinyl acetate and appropriately saponifying the obtained vinyl acetate. This is achieved by controlling the degree of saponification in a manner known per se.
- Such partially saponified polyvinyl alcohol may be a commercially available product, and examples of preferable commercially available polybutyl alcohol include Gohsenol EG05, EG25 (manufactured by Nippon Gosei Kagaku), and PVA203 (manufactured by Kurarene).
- PVA204 manufactured by KURARENE
- PVA2 05 manufactured by KURARENE
- JP-04 manufactured by Nippon Vinegar Pover Co., Ltd.
- JP-05 manufactured by Nippon Vinegar Pover Co.
- a coating agent used in the present invention not only a polyvinyl copolymer but also polyvinyl alcohol can be used alone, and for the purpose of two or more kinds of polybulal alcohols having different degrees of polymerization and saponification. It can be used in combination as appropriate.
- polybutyl alcohol having an average degree of polymerization of 300 and polyvinyl alcohol having an average degree of polymerization of 1500 can be mixed and used as a coating agent. It is also possible to use a commercially available premitas coating agent containing polyvinyl alcohol.
- polybulal alcohol various modified polybulal alcohols can be used, for example, amine-modified polybulal alcohol, ethylene-modified polybulal alcohol, carboxylic acid-modified polybulal alcohol, diacetone-modified polybulal alcohol, thiol. Examples thereof include denatured polybulal alcohol.
- modified polybulal alcohols commercially available products or those produced by methods known in the art can be used.
- the polymerizable vinyl monomers to be polymerized with poly (vinyl alcohol) include acrylic acid, methacrylic acid, crotonic acid, fumaric acid, maleic acid, Unsaturated carboxylic acids such as itaconic acid or salts thereof (for example, alkali metal salts, ammonium salts, alkylamine salts), esters thereof (for example, substituted or unsubstituted alkyl esters, cyclic alkyl esters, polyalkylene groups) (Recall esters), unsaturated-tolyls, unsaturated amides, aromatic vinyls, aliphatic vinyls, unsaturated bond-containing heterocycles, and the like.
- Unsaturated carboxylic acids such as itaconic acid or salts thereof (for example, alkali metal salts, ammonium salts, alkylamine salts), esters thereof (for example, substituted or unsubstituted alkyl esters, cyclic alkyl esters, polyalkylene groups
- acrylates for example, methyl acrylate, ethyl acrylate, butyl acrylate, isobutyl acrylate, cyclohexyl acrylate, 2-ethyl hexyl acrylate, hydroxy Powers such as ethyl acrylate, polyethylene glycol acrylate, polypropylene glycol acrylate, etc.
- Examples of methacrylic acid esters include methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, Cyclohexyl methacrylate, 2-ethylhexyl methacrylate, hydroxyethyl methacrylate, polyethylene glycol methacrylate, etc.
- Examples of unsaturated-tolyls include acrylonitrile, methacrylonitrile, etc.
- Examples of saturated amides include acrylamide, dimethylacrylamide, and methacrylamide.
- Aromatic beers include styrene, ⁇ -methylstyrene, and (6)
- Aliphatic vinyls include butyl acetate.
- Examples of unsaturated bond-containing heterocycles include ⁇ -vinylpyrrolidone, acryloylmorpholine, and the like.
- R represents a hydrogen atom or a methyl group, R represents a hydrogen atom or 1 to 4 carbon atoms
- These polymerizable vinyl monomers are capable of being copolymerized with polyvinyl alcohol in combination of one or more, preferably acrylic acid and methacrylic acid ester.
- a mixture with (e.g. methyl metatalylate) may be copolymerized with polyvinyl alcohol.
- the weight ratio of the polybulal alcohol to the polymerizable bur monomer is about 6: 4 to 9: 1, preferably about 8: 2.
- acrylic acid and methyl methacrylate are used as the polymerizable vinyl monomer, the weight ratio is about 3: 7 to about 0.5: 9.5, preferably about 1.25: 8.75. is there.
- a preferred polybulal alcohol copolymer used as a main component of the coating agent is composed of polybulal alcohol (average degree of polymerization of about 200 to less than 1300), methyl methacrylate and acrylic acid, and the composition ratio is about 60 to 90: 7 to 38: 0.5 to 12 is preferable, about 70 to 90:15 to 20: 2 to 3 is more preferable, and about 80: 17.5: 2.5 force S is more preferable.
- polymerization initiator those used in this field can be used.
- inorganic peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide
- organic peroxides such as peracetic acid, t-butylhydride peroxide, and di-propylperoxydicarbonate
- Azobis compounds such as 2-azobis (2-amidinopropane) hydride chloride and 2,2, -azobis (2,4 dimethylvale-tolyl) can be mentioned.
- the coating agent used for coating macrolide antibiotics in the present invention is capable of taking various forms. In general, in the application, an aqueous solution, an aqueous dispersion, an organic solvent solution, or an organic solvent dispersion It is preferably carried out by a means such as spraying or spraying known per se. Alternatively, a method may be used in which a tablet sprayed with a solid coating agent or a granule containing the coating agent is prepared, and then heated and melted to coat the surface.
- the coating amount of polyvinyl alcohol or the copolymerizable amount thereof is, for example, about 2 to 30% by weight, preferably about 5 to 20% by weight, more preferably about 7. 5 to 15% by weight. In the case of coating elementary granules, it is generally about 5 to: LOO% by weight, preferably about 30 to 80% by weight, based on the elementary granules.
- the coating conditions of the macrolide antibiotic uncoated tablets and uncoated condyles with a polybulualcohol copolymer are generally as follows.
- Spray gun caliber About 0.8mm
- a weight ratio of a partially saponified polybulle alcohol having an average degree of polymerization of 300 to 500 and a polymerizable bur monomer is 6: 4 to 9: 1. It is obtained by copolymerization, and the polymerizable vinyl monomer is acrylic acid and methyl methacrylate, and the weight ratio of acrylic acid to methyl methacrylate in the copolymerization is from 3: 7 to 0.5: 9.
- Macrolide antibiotics characterized in that they are coated with macrolide antibiotics or solids containing them (for example, uncoated tablets, elementary granules) using polybulal alcohol copolymer as a coating agent. A stable coating formulation is provided.
- the uncoated tablet containing a macrolide antibiotic includes: a) the macrolide antibiotic as it is, or as an excipient, binder, disintegrant or other suitable additive.
- the mixture is mixed evenly into granules (elementary granules) by an appropriate known method, and then added with a lubricant, etc., and compression-molded, or b)
- the macrolide antibiotic granules are left as is or added.
- Macroscopic antibiotics that are produced by direct compression molding, or mixed with the addition of a form, binder, disintegrant or other suitable additive, are mixed.
- a preferred example is a method in which macrolide antibiotics are added to granules not contained as they are or together with appropriate additives and mixed uniformly, and then compression-molded.
- the elementary granules can also be produced by means known in the art.
- a pre-coating layer can be applied to the uncoated tablet before coating with the polyvinyl alcohol copolymer.
- coating agents those known in the art are used. Examples thereof include hydroxypropylmethylcellulose and sucrose.
- a solid formulation of maculaide, such as tablets, granules, capsules, and pills, coated with the polybulal alcohol or polybulal alcohol copolymer can be produced by a conventional method.
- the tablet may preferably contain a disintegrant in order to enhance its disintegration property.
- a disintegrant those well known in the art can be used, for example, partially pregelatinized starch, sodium carboxymethyl starch, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose (L—HPC), Examples include croscarmellose sodium (for example, Ac-Di-Sol, Asahi Kasei Co., Ltd.), polybulu polypyrrolidone and the like, and preferably carboxymethyl starch sodium.
- the disintegrant content should be sufficient to disintegrate the tablet quickly.
- the disintegrant should disintegrate within a few tens of minutes, preferably within a few minutes, in the first or second liquid prescribed by the Japanese Pharmacopoeia.
- the amount is about 0.5 to 30 parts by weight, preferably about 1 to 20 parts by weight, more preferably about 2 to: LO parts by weight based on 100 parts by weight of the tablet.
- Tablets containing macrolide antibiotics optionally further include pharmaceutically acceptable additives such as excipients, binders, lubricants, and colorants (eg, acid titanium).
- pharmaceutically acceptable additives such as excipients, binders, lubricants, and colorants (eg, acid titanium).
- the content of titanium oxide is about 0.05 to 5 parts by weight, preferably about 0.1 to 2 parts by weight per 100 parts by weight of the tablet.
- excipients known in the art can be used as the excipient, such as lactose, sucrose, mannitol, crystalline cellulose, corn starch, potato starch, hydroxypropyl starch, and the like.
- the exemplified force is preferably mannitol or crystalline cellulose.
- the content of the excipient may be appropriately set in consideration of the main drug content, the target tablet size, etc., but is usually about 5 to 60 parts by weight, preferably about 10 to 100 parts by weight with respect to 100 parts by weight of the tablet. 40 parts by weight.
- binder those widely known in the art can be widely used.
- methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, polyvinyl alcohol, gelatin, dextrin and the like are preferable.
- the binder content is usually about 0 with respect to 100 parts by weight of the tablet. 5 to 5 parts by weight, preferably about 1 to 3 parts by weight.
- Examples of the lubricant include magnesium stearate, talc, sucrose fatty acid ester and the like, and the content thereof is usually a trace amount, for example, about 1 to 3 parts by weight with respect to 100 parts by weight of the tablet.
- the tablet containing a macrolide antibiotic is subjected to operations such as mixing, granulation, granulation drying, granulation, lubricant blending, tableting and the like using the above raw materials. And can be produced according to a known method.
- an apparatus such as an agitation granulator, a fluidized bed granulator, a Brabender, or a twin screw granulator may be used. It is preferable to use a granulator.
- tableting may be performed using a commercially available tableting machine, usually with a tableting pressure of about 0.2 to 1.5 t.
- a preferred embodiment of the tablet composition of the present invention is as follows.
- Disintegrant preferably sodium carboxymethyl starch: about 2-10%;
- Excipients preferably total amount of D-mann-tol and crystalline cellulose: about 10-40%; Binder, preferably hydroxypropylcellulose: about 1-3%;
- Lubricant preferably magnesium stearate: about 1-3%
- the coating agent preferably polyvinyl alcohol copolymer, is about 5-20% by weight.
- the coated preparation of the macrolide antibiotic of the present invention may be administered to humans or animals in an effective amount for treating the above-mentioned diseases.
- the dose may vary depending on the age, weight, symptom, sex, etc. of the patient or animal to be treated, but usually the above macrolide antibiotics and their pharmacologically acceptable in 1 or several times.
- 0.01 to 50 mgZkg can be orally administered in terms of a salt or a hydrate thereof.
- the total amount of related substances after storage for 3 months at 25 ° C and a relative humidity of 60% is preferably 3% or less, more preferably 1.5% or less.
- the preparation of the present invention is preferably PTP (press-through) in order to further improve the stability.
- PTP press-through
- One package or bottle packaging eg, plastic bottles, glass bottles, aluminum cans.
- the coated preparation of the macrolide antibiotic of the present invention may contain an antibacterial agent other than the macrolide antibiotic.
- the main component of the coating agent may contain a coating force or other coating components which are polybulal alcohol or polyvinyl alcohol copolymer.
- R represents a protecting group for a hydrogen atom or a hydroxyl group.
- a macrolide antibiotic having a group represented by the formula: a pharmaceutically acceptable salt thereof, a hydrate thereof, or a substance thereof Provided is a method for inhibiting the formation of a related substance of the macrolide antibiotic, in which a solid substance is coated with a coating agent containing polybulualcohol or polybulualcohol copolymer. Macrolide antibiotics, their salts, their hydrates, coating agents, coating methods, etc. are as described above.
- the present invention relates to a macrolide antibiotic having a group represented by the above partial structural formula, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solid containing them, polyvinyl alcohol or polybule.
- a method for stabilizing the macrolide antibiotic, its pharmaceutically acceptable salt, or hydrate thereof characterized in that it is coated with a coating containing an alcohol copolymer.
- Macrolide antibiotics, salts thereof, hydrates thereof, coating agents, coating methods, etc. are as described above.
- a coated tablet of the above uncoated tablet with a polyvinyl alcohol copolymer was produced through the following steps (1) to (1).
- a polyvinyl alcohol copolymer having a polymerization degree of 500 is gradually added to purified water with stirring, thereby preparing an aqueous solution of 8-: LO wt% polybula alcohol copolymer.
- the acid is stirred and dispersed with TK Robotics (Special Machine Industries).
- TK Robotics Specific Machine Industries
- a titanium bromide-containing polybutyl alcohol copolymer aqueous solution is prepared.
- the stability of the macrolide-coated preparation (Formulation 1) obtained as described above was compared with that of an uncoated tablet.
- the evaluation method is as follows.
- One coating agent and one uncoated tablet were stored for 3 months under conditions of 25 ° C, 60% relative humidity, no packaging, and shading. 0.5. After 5 months, 1 month, 2 months, and 3 months, the residual amount of compound (ii), the main drug, and the amount of related substances produced were measured by liquid chromatography. For the coating agent and the uncoated tablet, the same production lot of macrolide antibiotic (I compound ( ⁇ )) was used.
- the drug substance of compound (III) in the same production lot used for the coating and uncoated tablets was accurately weighed by about 10 mg. This was dissolved in 70% acetonitrile to make exactly 10 mL. o o
- the peak areas due to the main drug and related substances were measured by the automatic calculation method.
- the amount of each related substance (%) and the total amount of related substances (%) were calculated from the following formulas.
- ⁇ A Sum of peak areas other than system peaks
- Figure 2 shows the chromatogram of the coated preparation after storage for 1 month.
- Table 3 shows the retention time, area, and height of each peak.
- Peak number Retention time Peak area Peak area Peak height
- Peak 6 is a peak derived from the main compound ( ⁇ ). All peaks other than peak 6 are derived from related substances. In particular, peaks 1 and 2 are the main by-products that increase upon storage.
- Figure 3 shows the change in the ratio (%) of the total amount of related substances to the active ingredient in the coated preparation and uncoated tablet.
- ⁇ indicates uncoated tablet
- ⁇ indicates a coated tablet made of polyvinyl alcohol copolymer.
- the amount of the related substance in the coated preparation of the present invention hardly changed even after 3 months, whereas the undegraded uncoated tablet rapidly decomposed the active ingredient, and after 3 months.
- the related substance amount reached about 9%. This proved the stability of the coated preparation of the present invention.
- the coating preparation was prepared by variously changing the ratio of the coating agent to the entire coating preparation within the range of 5 to 15% by weight.
- the macrolide coating formulation of the present invention was particularly stable when the coating amount of the polyvinyl alcohol copolymer as the coating agent was in the range of about 7.5 to 15% (wZw). .
- coated preparations (formulations 2, 3 and 5) having the compositions shown in Table 4 below were obtained.
- the coating conditions were the same as those shown in Example 1, except that titanium oxide (1% by weight concentration) was used in the coating agent.
- Crystalline cellulose 5.0 mg 1.5 mg 1 0.0 mg Magnesium stearate 4.0 mg 6. 0 mg 8. 0 mg Constant 1 60. 0 mg 240. 0 mg 320. 0 mg Coating Polyvinyl alcohol Copolymer 1 8. 0 mg 1 8. 0 mg 22.5 mg Titanium oxide 2. 0 mg 2. 0 mg 2.5 m Talc Trace Trace Trace Magnesium stearate Trace Trace mist Trace Coverage meter 20. 0 mg 20 0 mg 25. 0 mg Total 1 80. 0 mg 260. 0 mg 345. 0 mg Coverage ratio (%) (Uncoated tablet) 1 2. 5% 8. 3% 7.8% Copolymer ratio (% ) (Comparative tablet) 1 1. 3% 7. 5% 7. 0% [0111] The stability of the macrolide-based coated preparation (Preparation 2) obtained as described above was compared with that of an uncoated tablet. The evaluation method is as follows.
- each of the coating agent and the uncoated tablet was stored for 1 month under the conditions of 25 ° C, 60% relative humidity, no packaging, and shading. 0.5. After 5 months and 1 month, the residual amount of the main compound ( ⁇ ) and the amount of related substances produced were measured by liquid chromatography. The same production lot of macrolide antibiotic (compound ( ⁇ )) was used for the coating and uncoated tablets.
- Figure 6 shows the changes in the ratio (%) of the total amount of related substances to the active ingredient in the coated preparations and uncoated tablets.
- ⁇ indicates an uncoated tablet
- ⁇ indicates a coated tablet made of acid-titanium-containing polyvinyl alcohol copolymer.
- the coated preparation of the present invention has almost the same amount of the related substance after one month, whereas it is coated. One month later, the amount of related substances reached about 4%, confirming the stability of the coated preparation of the present invention.
- each of the coating agent and the uncoated tablet was stored for 3 months under the conditions of 25 ° C, 60% relative humidity, no packaging, and shading. After 0.5 months, 1 month, 2 months, and 3 months, the residual amount of the compound (ii) as the main drug and the amount of related substances produced were measured by liquid chromatography. For the coating agent and the uncoated tablet, the same production lot of macrolide antibiotic (I compound ( ⁇ )) was used.
- Figure 8 shows the change in the ratio (%) of the total amount of related substances to the active ingredient in the coated preparation and uncoated tablet.
- ⁇ indicates an uncoated tablet and ⁇ indicates a coated tablet made of polyvinyl alcohol.
- the coated preparation of the macrolide antibiotic of the present invention coated with polyvinyl alcohol was stable with almost no related substances formed in the preparation even after storage for 3 months.
- the ratio (%) of the total amount of related substances to the active ingredient is about 9% (w / w).
- the macrolide antibiotic-coated preparation coated with polybulal alcohol or a copolymer thereof according to the present invention can be applied to bacteria, mycoplasma, fungi (brietles), protozoa, etc. in mammals including humans, fish, and birds. Can be used to treat a wide range of infectious diseases
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Tropical Medicine & Parasitology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
L'invention concerne une préparation antibiotique macrolide enrobée, laquelle comprend un antibiotique macrolide ayant un groupe représenté par la formule structurelle partielle (I): [où R2a représente un atome d'hydrogène ou un groupe protecteur d'un groupe hydroxyle] ou un sel pharmaceutiquement acceptable ou un hydrate de l'antibiotique ou le sel et lequel est enrobé avec un enrobant comprenant principalement un alcool polyvinylique ou un copolymère d'alcool polyvinylique.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008513281A JPWO2007126039A1 (ja) | 2006-04-28 | 2007-04-27 | マクロライド系抗生物質の被覆製剤 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2006125693 | 2006-04-28 | ||
JP2006-125693 | 2006-04-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007126039A1 true WO2007126039A1 (fr) | 2007-11-08 |
Family
ID=38655560
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2007/059144 WO2007126039A1 (fr) | 2006-04-28 | 2007-04-27 | Préparation antibiotique macrolide enrobée |
Country Status (3)
Country | Link |
---|---|
JP (1) | JPWO2007126039A1 (fr) |
TW (1) | TW200800233A (fr) |
WO (1) | WO2007126039A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011077843A1 (fr) | 2009-12-25 | 2011-06-30 | 沢井製薬株式会社 | Préparation enrobée contenant de l'atrovastatine |
JP2012193175A (ja) * | 2011-03-02 | 2012-10-11 | Daiichi Sankyo Healthcare Co Ltd | 速溶性防湿フィルムコーティング製剤及びその製造方法 |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5428812A (en) * | 1977-08-09 | 1979-03-03 | Yoshitomi Pharmaceut Ind Ltd | Preparation of coated tablet |
JPS5942325A (ja) * | 1982-09-03 | 1984-03-08 | Dai Ichi Seiyaku Co Ltd | コ−テイング用組成物及びコ−テイング製剤 |
EP0208971A2 (fr) * | 1985-07-10 | 1987-01-21 | Dr. Karl Thomae GmbH | Formes galéniques solides pour application orale contenant de la 9-déoxo-11-déoxy-9,11-(imino(2-(2-méthoxyéthoxy)éthylidène)-oxy-)-(9S)-érythromycine et leur procédé de préparation |
WO1988003795A1 (fr) * | 1986-11-24 | 1988-06-02 | Nortec Development Associates, Inc. | Compositions pharmaceutiques avec dissimulation du gout |
JPS63215620A (ja) * | 1987-03-03 | 1988-09-08 | Nippon Soda Co Ltd | 徐放性製剤 |
JPH092976A (ja) * | 1995-06-20 | 1997-01-07 | Lion Corp | 被覆組成物 |
WO1998046239A1 (fr) * | 1997-04-11 | 1998-10-22 | Abbott Laboratories | Formulations a liberation prolongee de derives d'erythromycine |
WO2001004195A1 (fr) * | 1999-07-09 | 2001-01-18 | Berwind Pharmaceutical Services, Inc. | Pellicules d'enrobage et compositions de pellicules d'enrobage a base de poly(alcool de vinyle) |
EP1302205A1 (fr) * | 2001-10-01 | 2003-04-16 | Ind-Swift Limited | Composition pharmaceutique à libération contrôlée comprenant citrate de macrolide |
WO2005019286A1 (fr) * | 2003-08-20 | 2005-03-03 | Shionogi & Co., Ltd. | Nouvelle composition pour revetements |
-
2007
- 2007-04-27 WO PCT/JP2007/059144 patent/WO2007126039A1/fr active Application Filing
- 2007-04-27 TW TW096114948A patent/TW200800233A/zh unknown
- 2007-04-27 JP JP2008513281A patent/JPWO2007126039A1/ja active Pending
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5428812A (en) * | 1977-08-09 | 1979-03-03 | Yoshitomi Pharmaceut Ind Ltd | Preparation of coated tablet |
JPS5942325A (ja) * | 1982-09-03 | 1984-03-08 | Dai Ichi Seiyaku Co Ltd | コ−テイング用組成物及びコ−テイング製剤 |
EP0208971A2 (fr) * | 1985-07-10 | 1987-01-21 | Dr. Karl Thomae GmbH | Formes galéniques solides pour application orale contenant de la 9-déoxo-11-déoxy-9,11-(imino(2-(2-méthoxyéthoxy)éthylidène)-oxy-)-(9S)-érythromycine et leur procédé de préparation |
WO1988003795A1 (fr) * | 1986-11-24 | 1988-06-02 | Nortec Development Associates, Inc. | Compositions pharmaceutiques avec dissimulation du gout |
JPS63215620A (ja) * | 1987-03-03 | 1988-09-08 | Nippon Soda Co Ltd | 徐放性製剤 |
JPH092976A (ja) * | 1995-06-20 | 1997-01-07 | Lion Corp | 被覆組成物 |
WO1998046239A1 (fr) * | 1997-04-11 | 1998-10-22 | Abbott Laboratories | Formulations a liberation prolongee de derives d'erythromycine |
WO2001004195A1 (fr) * | 1999-07-09 | 2001-01-18 | Berwind Pharmaceutical Services, Inc. | Pellicules d'enrobage et compositions de pellicules d'enrobage a base de poly(alcool de vinyle) |
EP1302205A1 (fr) * | 2001-10-01 | 2003-04-16 | Ind-Swift Limited | Composition pharmaceutique à libération contrôlée comprenant citrate de macrolide |
WO2005019286A1 (fr) * | 2003-08-20 | 2005-03-03 | Shionogi & Co., Ltd. | Nouvelle composition pour revetements |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011077843A1 (fr) | 2009-12-25 | 2011-06-30 | 沢井製薬株式会社 | Préparation enrobée contenant de l'atrovastatine |
JP2012193175A (ja) * | 2011-03-02 | 2012-10-11 | Daiichi Sankyo Healthcare Co Ltd | 速溶性防湿フィルムコーティング製剤及びその製造方法 |
Also Published As
Publication number | Publication date |
---|---|
JPWO2007126039A1 (ja) | 2009-09-10 |
TW200800233A (en) | 2008-01-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102246124B1 (ko) | 브루톤 티로신 키나제의 억제제를 포함하는 투여량 형태 조성물 | |
EP1796642B1 (fr) | Compositions pharmaceutiques sous forme de dispersions solides pour le traitement du cancer | |
JP5794650B2 (ja) | 難溶性薬物の溶解性改善製剤 | |
MX2010014566A (es) | Proceso de granulacion de fundido. | |
CN111249247A (zh) | 含有瑞戈非尼的包衣的药物组合物 | |
EA032126B1 (ru) | Твердая фармацевтическая композиция, содержащая метформин и вилдаглиптин, и способы ее получения | |
EP3110402A1 (fr) | Compositions de dapagliflozin | |
BRPI0806713A2 (pt) | composições de tiacumicinas estáveis | |
JP2018076499A (ja) | ヒプロメロース酢酸エステルコハク酸エステル及び製造方法 | |
KR20220139913A (ko) | 레고라페닙 및 안정화제를 함유하는 제약 조성물 | |
WO2007126039A1 (fr) | Préparation antibiotique macrolide enrobée | |
CN107412198A (zh) | 盐酸度洛西汀肠溶缓释颗粒剂及其制备方法 | |
CN113116859B (zh) | 阿奇霉素丸芯包衣制剂 | |
CN107281155B (zh) | 一种阿奇霉素片及其制备方法 | |
US10857171B2 (en) | Pharmaceutical compositions | |
CN105030704B (zh) | 阿奇霉素片剂及其制备方法 | |
WO2007148772A1 (fr) | Préparation sous forme dragéifiée d'antibiotiques macrolides | |
WO2013088274A1 (fr) | Composition d'azithromycine amorphe anhydre dépourvue de dihydrate d'azithromycine | |
JP6866113B2 (ja) | カペシタビンを有効成分とする医薬製剤 | |
JP2024501691A (ja) | トリアゾロピラジン誘導体化合物を有効成分とする薬学的組成物のタブレット錠の製造方法 | |
KR20210111389A (ko) | 위장관내 안정성이 향상된 마크로라이드계 항생제의 서방성 제형 | |
JP2022113343A (ja) | アキシチニブを有効成分とする医薬錠剤 | |
EP2671571A1 (fr) | Formulations à libération contrôlée de clarithromycine | |
JP2020152707A (ja) | 安定化されたエソメプラゾールマグネシウム水和物含有腸溶性固形製剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
DPE2 | Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 07742579 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008513281 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 07742579 Country of ref document: EP Kind code of ref document: A1 |