WO2020261619A1 - 医薬組成物 - Google Patents
医薬組成物 Download PDFInfo
- Publication number
- WO2020261619A1 WO2020261619A1 PCT/JP2020/000711 JP2020000711W WO2020261619A1 WO 2020261619 A1 WO2020261619 A1 WO 2020261619A1 JP 2020000711 W JP2020000711 W JP 2020000711W WO 2020261619 A1 WO2020261619 A1 WO 2020261619A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- liquid
- water
- soluble
- pharmaceutical composition
- administration
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 77
- 239000002245 particle Substances 0.000 claims abstract description 185
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- 229940043355 kinase inhibitor Drugs 0.000 claims abstract description 18
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- 239000002504 physiological saline solution Substances 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 22
- 239000000758 substrate Substances 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 150000002016 disaccharides Chemical class 0.000 claims description 8
- 150000002772 monosaccharides Chemical class 0.000 claims description 8
- 108091000080 Phosphotransferase Proteins 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 4
- 102000020233 phosphotransferase Human genes 0.000 claims description 4
- 238000011200 topical administration Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 25
- 239000007788 liquid Substances 0.000 description 296
- 238000012360 testing method Methods 0.000 description 32
- 238000004519 manufacturing process Methods 0.000 description 29
- 230000007423 decrease Effects 0.000 description 21
- 238000009826 distribution Methods 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 19
- 108010006654 Bleomycin Proteins 0.000 description 18
- 238000010586 diagram Methods 0.000 description 18
- 210000004072 lung Anatomy 0.000 description 18
- 229960001561 bleomycin Drugs 0.000 description 17
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 17
- 238000005469 granulation Methods 0.000 description 17
- 230000003179 granulation Effects 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 229960004378 nintedanib Drugs 0.000 description 16
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 16
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 14
- 238000004090 dissolution Methods 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- 230000004202 respiratory function Effects 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- -1 antibodies Proteins 0.000 description 10
- 230000001766 physiological effect Effects 0.000 description 10
- 208000005069 pulmonary fibrosis Diseases 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000013543 active substance Substances 0.000 description 9
- 238000004581 coalescence Methods 0.000 description 9
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 9
- 239000002953 phosphate buffered saline Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 230000001186 cumulative effect Effects 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000003068 static effect Effects 0.000 description 7
- 210000000115 thoracic cavity Anatomy 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000009530 blood pressure measurement Methods 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 230000003434 inspiratory effect Effects 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 230000002265 prevention Effects 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 230000002685 pulmonary effect Effects 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 235000012239 silicon dioxide Nutrition 0.000 description 6
- 238000013268 sustained release Methods 0.000 description 6
- 239000012730 sustained-release form Substances 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000002627 tracheal intubation Methods 0.000 description 5
- 230000004580 weight loss Effects 0.000 description 5
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 4
- 229940109449 antisedan Drugs 0.000 description 4
- HSWPZIDYAHLZDD-UHFFFAOYSA-N atipamezole Chemical compound C1C2=CC=CC=C2CC1(CC)C1=CN=CN1 HSWPZIDYAHLZDD-UHFFFAOYSA-N 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000003205 fragrance Substances 0.000 description 4
- 238000002695 general anesthesia Methods 0.000 description 4
- 229960004891 lapatinib Drugs 0.000 description 4
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000005192 partition Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 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 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 208000031648 Body Weight Changes Diseases 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 241000792859 Enema Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 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 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 3
- 239000003463 adsorbent Substances 0.000 description 3
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 3
- 230000004579 body weight change Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007920 enema Substances 0.000 description 3
- 239000003889 eye drop Substances 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960001375 lactose Drugs 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 108020004707 nucleic acids Proteins 0.000 description 3
- 150000007523 nucleic acids Chemical class 0.000 description 3
- 102000039446 nucleic acids Human genes 0.000 description 3
- 229920001542 oligosaccharide Polymers 0.000 description 3
- 150000002482 oligosaccharides Chemical class 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229960002920 sorbitol Drugs 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 150000005846 sugar alcohols Chemical class 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 3
- 239000000341 volatile oil Substances 0.000 description 3
- 239000000811 xylitol Substances 0.000 description 3
- 235000010447 xylitol Nutrition 0.000 description 3
- 229960002675 xylitol Drugs 0.000 description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 2
- 239000004386 Erythritol Substances 0.000 description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002334 Spandex Polymers 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229940008126 aerosol Drugs 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 229960003005 axitinib Drugs 0.000 description 2
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 239000000919 ceramic Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003221 ear drop Substances 0.000 description 2
- 229940047652 ear drops Drugs 0.000 description 2
- 229940095399 enema Drugs 0.000 description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 2
- 235000019414 erythritol Nutrition 0.000 description 2
- 229940009714 erythritol Drugs 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 229940041682 inhalant solution Drugs 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 229910052451 lead zirconate titanate Inorganic materials 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 2
- 239000000845 maltitol Substances 0.000 description 2
- 235000010449 maltitol Nutrition 0.000 description 2
- 229940035436 maltitol Drugs 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 229960001855 mannitol Drugs 0.000 description 2
- VPNGEIHDPSLNMU-UHFFFAOYSA-N medetomidine hydrochloride Chemical compound Cl.C=1C=CC(C)=C(C)C=1C(C)C1=CNC=N1 VPNGEIHDPSLNMU-UHFFFAOYSA-N 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 2
- 229960003793 midazolam Drugs 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- 229940100662 nasal drops Drugs 0.000 description 2
- 238000001543 one-way ANOVA Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 210000003437 trachea Anatomy 0.000 description 2
- 150000004043 trisaccharides Chemical class 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 2
- 229960001600 xylazine Drugs 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- DBTMGCOVALSLOR-UHFFFAOYSA-N 32-alpha-galactosyl-3-alpha-galactosyl-galactose Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(OC2C(C(CO)OC(O)C2O)O)OC(CO)C1O DBTMGCOVALSLOR-UHFFFAOYSA-N 0.000 description 1
- PCCVCJAQMHDWJY-UHFFFAOYSA-N 5-(2-ethyl-1,3-dihydroinden-2-yl)-1h-imidazole;hydrochloride Chemical compound Cl.C1C2=CC=CC=C2CC1(CC)C1=CN=CN1 PCCVCJAQMHDWJY-UHFFFAOYSA-N 0.000 description 1
- PVXPPJIGRGXGCY-DJHAAKORSA-N 6-O-alpha-D-glucopyranosyl-alpha-D-fructofuranose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@](O)(CO)O1 PVXPPJIGRGXGCY-DJHAAKORSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 241000208223 Anacardiaceae Species 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- RXVWSYJTUUKTEA-UHFFFAOYSA-N D-maltotriose Natural products OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1OC1C(O)C(O)C(O)C(CO)O1 RXVWSYJTUUKTEA-UHFFFAOYSA-N 0.000 description 1
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 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
- AANLCWYVVNBGEE-IDIVVRGQSA-L Disodium inosinate Chemical compound [Na+].[Na+].O[C@@H]1[C@H](O)[C@@H](COP([O-])([O-])=O)O[C@H]1N1C(NC=NC2=O)=C2N=C1 AANLCWYVVNBGEE-IDIVVRGQSA-L 0.000 description 1
- 240000002943 Elettaria cardamomum Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010014958 Eosinophilic leukaemia Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 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 1
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 235000019501 Lemon oil Nutrition 0.000 description 1
- 229910013641 LiNbO 3 Inorganic materials 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 235000007265 Myrrhis odorata Nutrition 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010067517 Pancreatic neuroendocrine tumour Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 240000004760 Pimpinella anisum Species 0.000 description 1
- 235000012550 Pimpinella anisum Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HLCFGWHYROZGBI-JJKGCWMISA-M Potassium gluconate Chemical compound [K+].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O HLCFGWHYROZGBI-JJKGCWMISA-M 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 229940121742 Serine/threonine kinase inhibitor Drugs 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000003639 Student–Newman–Keuls (SNK) method Methods 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- JDSJDASOXWCHPN-UHFFFAOYSA-N TDZD-8 Chemical compound O=C1N(C)SC(=O)N1CC1=CC=CC=C1 JDSJDASOXWCHPN-UHFFFAOYSA-N 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 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
- 108010053950 Teicoplanin Proteins 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- DRQXUCVJDCRJDB-UHFFFAOYSA-N Turanose Natural products OC1C(CO)OC(O)(CO)C1OC1C(O)C(O)C(O)C(CO)O1 DRQXUCVJDCRJDB-UHFFFAOYSA-N 0.000 description 1
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 244000290333 Vanilla fragrans Species 0.000 description 1
- 235000009499 Vanilla fragrans Nutrition 0.000 description 1
- 235000012036 Vanilla tahitensis Nutrition 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 1
- YGCFIWIQZPHFLU-UHFFFAOYSA-N acesulfame Chemical compound CC1=CC(=O)NS(=O)(=O)O1 YGCFIWIQZPHFLU-UHFFFAOYSA-N 0.000 description 1
- 229960005164 acesulfame Drugs 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
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021486 amorphous silicon dioxide Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 229960001352 atipamezole hydrochloride Drugs 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229960004395 bleomycin sulfate Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- GMTYREVWZXJPLF-AFHUBHILSA-N butorphanol D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 GMTYREVWZXJPLF-AFHUBHILSA-N 0.000 description 1
- 229960001590 butorphanol tartrate Drugs 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 235000005300 cardamomo Nutrition 0.000 description 1
- 235000020226 cashew nut Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002537 cosmetic Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
- PVBRXXAAPNGWGE-LGVAUZIVSA-L disodium 5'-guanylate Chemical compound [Na+].[Na+].C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)[C@H]1O PVBRXXAAPNGWGE-LGVAUZIVSA-L 0.000 description 1
- 235000013896 disodium guanylate Nutrition 0.000 description 1
- 235000013890 disodium inosinate Nutrition 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000002296 dynamic light scattering Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 235000013376 functional food Nutrition 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 239000011361 granulated particle Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 229910002011 hydrophilic fumed silica Inorganic materials 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 150000002453 idose derivatives Chemical class 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003983 inhalation anesthetic agent Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- HFGPZNIAWCZYJU-UHFFFAOYSA-N lead zirconate titanate Chemical compound [O-2].[O-2].[O-2].[O-2].[O-2].[Ti+4].[Zr+4].[Pb+2] HFGPZNIAWCZYJU-UHFFFAOYSA-N 0.000 description 1
- 239000010501 lemon oil Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229950001290 lorlatinib Drugs 0.000 description 1
- IIXWYSCJSQVBQM-LLVKDONJSA-N lorlatinib Chemical compound N=1N(C)C(C#N)=C2C=1CN(C)C(=O)C1=CC=C(F)C=C1[C@@H](C)OC1=CC2=CN=C1N IIXWYSCJSQVBQM-LLVKDONJSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960002160 maltose Drugs 0.000 description 1
- FYGDTMLNYKFZSV-UHFFFAOYSA-N mannotriose Natural products OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(OC2C(OC(O)C(O)C2O)CO)C(O)C1O FYGDTMLNYKFZSV-UHFFFAOYSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004882 medetomidine hydrochloride Drugs 0.000 description 1
- 230000005499 meniscus Effects 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- LPUQAYUQRXPFSQ-DFWYDOINSA-M monosodium L-glutamate Chemical compound [Na+].[O-]C(=O)[C@@H](N)CCC(O)=O LPUQAYUQRXPFSQ-DFWYDOINSA-M 0.000 description 1
- 235000013923 monosodium glutamate Nutrition 0.000 description 1
- 239000004223 monosodium glutamate Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003278 osimertinib Drugs 0.000 description 1
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 208000021010 pancreatic neuroendocrine tumor Diseases 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000004224 potassium gluconate Substances 0.000 description 1
- 229960003189 potassium gluconate Drugs 0.000 description 1
- 235000013926 potassium gluconate Nutrition 0.000 description 1
- 229940088417 precipitated calcium carbonate Drugs 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 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
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940071138 stearyl fumarate Drugs 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 229960001608 teicoplanin Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 150000004044 tetrasaccharides Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 239000003860 topical agent Substances 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4h-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- RULSWEULPANCDV-PIXUTMIVSA-N turanose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](C(=O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RULSWEULPANCDV-PIXUTMIVSA-N 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- FYGDTMLNYKFZSV-BYLHFPJWSA-N β-1,4-galactotrioside 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]2[C@@H](O[C@@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-BYLHFPJWSA-N 0.000 description 1
Images
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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a pharmaceutical composition.
- the poorly water-soluble compound as a drug may not be sufficiently dissolved in the body, and as a result, the bioavailability may be lowered.
- various efforts have been made to dissolve the poorly water-soluble compound. For example, by making the drug, which is a poorly water-soluble compound, into nanoparticles, the surface area of the drug particles is increased and the dissolution rate is increased. It is being studied to improve it and to use a solubilizer that has a solubilizing effect on the drug in combination. In particular, many studies have been conducted on particles that improve solubility by encapsulating a drug in an inert substrate.
- a solid preparation has been proposed in which a pharmaceutical compound having low solubility is immediately released by encapsulating the pharmaceutical compound in a solid preparation in a state of being dissolved in a solubilizer (see, for example, Patent Document 1).
- a solid dispersion having improved solubility of a poorly water-soluble compound by using a water-soluble polymer, a water-soluble sugar, and a surfactant has been proposed (see, for example, Patent Document 2).
- efforts to improve the solubility of poorly water-soluble pharmaceutical compounds are widely made.
- An object of the present invention is to provide a pharmaceutical composition capable of rapidly dissolving a poorly water-soluble compound.
- the pharmaceutical composition of the present invention as a means for solving the problem contains particles containing a water-soluble base material and a poorly water-soluble compound, and the water-soluble base material contains a rapid water-soluble compound.
- the poorly water-soluble compound is a kinase inhibitor and is present in the water-soluble substrate in an amorphous state.
- FIG. 1 is a cross-sectional view showing an example of a droplet forming means.
- FIG. 2 is a cross-sectional view showing an example of a liquid column resonance droplet ejection unit.
- FIG. 3A is a schematic view showing an example of the structure of the discharge hole.
- FIG. 3B is a schematic view showing another example of the structure of the discharge hole.
- FIG. 3C is a schematic view showing another example of the structure of the discharge hole.
- FIG. 3D is a schematic view showing another example of the structure of the discharge hole.
- FIG. 6A is a schematic view showing an example of a pressure waveform and a velocity waveform in the liquid column resonance liquid chamber at the time of droplet ejection.
- FIG. 6B is a schematic view showing another example of the pressure waveform and the velocity waveform in the liquid column resonance liquid chamber at the time of droplet ejection.
- FIG. 6C is a schematic view showing another example of the pressure waveform and the velocity waveform in the liquid column resonance liquid chamber at the time of droplet ejection.
- FIG. 6D is a schematic view showing another example of the pressure waveform and the velocity waveform in the liquid column resonance liquid chamber at the time of droplet ejection.
- FIG. 6A is a schematic view showing an example of a pressure waveform and a velocity waveform in the liquid column resonance liquid chamber at the time of droplet ejection.
- FIG. 6B is a schematic view showing another
- FIG. 6E is a schematic view showing another example of the pressure waveform and the velocity waveform in the liquid column resonance liquid chamber at the time of droplet ejection.
- FIG. 7 is a diagram showing an example of an actual state of droplet ejection by the droplet forming means.
- FIG. 8 is a graph showing the dependence of the droplet ejection speed on the driving frequency.
- FIG. 9 is a schematic view showing an example of a particle manufacturing apparatus.
- FIG. 10 is a schematic view showing an example of an airflow passage.
- FIG. 11 is a diagram showing the results of the dissolution test of Test Example 1.
- FIG. 12 is a diagram showing the results of verifying the body weight change of the mouse in Test Example 2.
- FIG. 13A is FIG.
- FIG. 13B is FIG. 1 showing the result of verifying the respiratory function test (maximum inspiratory volume) in Test Example 2.
- FIG. 13C is FIG. 1 showing the result of verifying the respiratory function test (lung tissue elastance) in Test Example 2.
- FIG. 13D is FIG. 1 showing the result of verifying the respiratory function test (static lung compliance) in Test Example 2.
- FIG. 14A is FIG. 2 showing the result of verifying the respiratory function test (maximum inspiratory volume) in Test Example 2.
- FIG. 14B is FIG. 2 showing the result of verifying the respiratory function test (pulmonary thoracic compliance) in Test Example 2.
- FIG. 14C is FIG. 2 showing the result of verifying the respiratory function test (lung tissue elastance) in Test Example 2.
- FIG. 14D is FIG. 2 showing the result of verifying the respiratory function test (static lung compliance) in Test Example 2.
- the functional particles of the present invention contain a water-soluble base material and a poorly water-soluble compound, the water-soluble base material contains a rapid water-soluble compound, and the poorly water-soluble compound is in an amorphous state. It is present in the water-soluble substrate and is typically a rapidly soluble particle that dissolves rapidly in water or saline.
- the functional particles of the present invention may further contain other components, if necessary.
- the functional particles of the present invention, typically immediate-dissolving particles, can be suitably produced by the method for producing functional particles of the present invention described later.
- the "functional particles” mean, but are not limited to, a group of granular compositions containing a base material and a physiologically active substance, which have a predetermined function, but are not limited to, for example, DDS.
- examples include particles, sustained-release particles, solubilized particles and the like.
- the functional particles may have a plurality of functions at the same time, and may be, for example, DDS particles and sustained-release particles.
- the "immediately soluble particles” mean, among the solubilized particles, particles in which a physiologically active substance is immediately soluble, that is, functional particles in which a physiologically active substance having no immediate solubility is immediately soluble.
- the particles that can be rapidly dissolved in water or saline when added to water or saline to obtain a solution or dispersion of a physiologically active substance contained in the particles.
- the bioactive substance contained in the rapidly soluble particles is typically a poorly water-soluble compound.
- Rapid dissolution or “immediate solubility” may vary depending on the size of particles, the temperature of the solvent, the solubility of the compound, etc., but various methods known in the art such as measurement of dissolution time can be used. Can be evaluated using. Examples of specific evaluation methods are not limited to this, but for example, they are added to water, physiological saline, or the like so that the concentration of the poorly water-soluble compound becomes a predetermined concentration (for example, 1% by mass).
- shake or stir at a constant pace for example, 2 times / second
- measure the time until it is completely dissolved for example, within 30 minutes, within 20 minutes, within 10 minutes, within 5 minutes, Those that are completely dissolved within 3 minutes, 2 minutes, 1 minute, 50 seconds, 40 seconds, 30 seconds, 20 seconds, 10 seconds, etc. to the extent that the particles cannot be visually confirmed.
- Examples include rapid dissolution, that is, evaluation as immediate solubility. If it is rapidly soluble, it typically does not require any special operation for dissolution (eg, continuous stirring for several hours, atomization with a homogenizer, etc.).
- “completely dissolved” or “completely dissolved” typically means a state in which the residue cannot be visually confirmed, for example, the residue cannot be visually confirmed and for a certain period of time (for example, for example. If there is no substantial change in the concentration of the solution even after continuous stirring (for example, 15 minutes), it can be determined that the solution is completely dissolved.
- the term "rapid water-soluble compound” means, for example, within 1 minute or 50 seconds, when added to water, without any special operation for dissolution, for example, only by stirring or shaking for a short time. It means a compound having a property of rapidly dissolving within a time such as within, within 40 seconds, within 30 seconds, within 20 seconds, within 10 seconds, and the like.
- the rapidly water-soluble compound examples include, but are not limited to, low molecular weight sugars such as monosaccharides and disaccharides, oligosaccharides, reducing sugars, and sugar alcohols.
- the rapid water-soluble compound that can be used in the present invention is preferably a solid at room temperature.
- the present inventors conducted diligent studies in order to quickly dissolve a compound exhibiting poor water solubility, and found that, for example, a substance such as a monosaccharide or a disaccharide that rapidly dissolves in water was used as a base material. It was found that when microparticles containing a poorly water-soluble compound were produced, the microparticles were rapidly dissolved in water to obtain an aqueous solution of the poorly water-soluble compound.
- the functional particles of the present invention are in an amorphous state and are not bound by a specific theory, but are solids in which an amorphous poorly water-soluble compound is dispersed in an amorphous water-soluble substrate. It is considered to have a dispersion structure. Therefore, when the functional particles of the present application, typically immediately soluble particles, are added to water or physiological saline, the surrounding water-soluble base material is rapidly dissolved, and the dispersed poorly water-soluble compound is rapidly dissolved in water or physiological saline. It will be dispersed in saline solution. Furthermore, since both the water-soluble base material and the poorly water-soluble compound are amorphized, they are energetically unstable compared to the crystalline state, and it is presumed that they can be dissolved in water or physiological saline more quickly. To.
- the water-soluble base material is not particularly limited as long as it can be rapidly dissolved in water and dispersed in the base material without chemically reacting with the poorly water-soluble compound.
- the water-soluble base material is rapidly water-soluble.
- Compounds and the like are preferred.
- the rapid water-soluble compound include monosaccharides, disaccharides, oligosaccharides, reducing sugars, sugar alcohols and the like.
- the monosaccharide include glucose, mannose, idose, galactose, fucose, ribose, xylose and the like.
- Examples of the disaccharide include lactose, sucrose, maltose, trehalose and the like.
- oligosaccharide examples include raffinose (trisaccharide), maltotriose (trisaccharide), acarbose (tetrasaccharide) and the like.
- reducing sugar examples include turanose and the like.
- sugar alcohol examples include glycerin, erythritol, xylitol, lactitol, sorbitol, maltitol, and mannitol. Among these, at least one of a monosaccharide and a disaccharide is preferable, and lactose is the most preferable.
- a hydrate can also be used as the water-soluble base material.
- the functional particles of the present invention improve the solubility of the poorly water-soluble compound described later in water, and the wettability of the immediately-soluble particles to the solvent at the time of solution, and further. Can improve the wettability of the poorly water-soluble compound contained in the functional particles.
- the content of the water-soluble base material in the functional particles is not particularly limited as long as it can exhibit the function of rapidly dissolving the poorly water-soluble compound in water, and is not particularly limited depending on the intended purpose. It can be appropriately selected, preferably 10% by mass or more and 99.9% by mass or less, more preferably 30% by mass or more and 80% by mass or less, and further preferably 50% by mass or more and 80% by mass or less.
- the poorly water-soluble compound means a compound having a water / octanol partition coefficient (logP value) of 3 or more.
- the water / octanol partition coefficient means the ratio of the concentration of a compound dissolved in the aqueous phase to the concentration dissolved in the octanol phase in a two-phase system of water and octanol, and is usually Log 10 (octanol phase). (Concentration of / concentration of aqueous phase).
- any method known in the art can be used, and examples thereof include the method described in JIS Z 7260-107.
- the poorly water-soluble compound is not particularly limited as long as the water / octanol partition coefficient (logP value) is 3 or more, and can be appropriately selected depending on the intended purpose.
- a physiologically active substance or the like is preferable.
- the "physiologically active substance” means an active ingredient used to exert a physiological effect on a living body.
- “Physiological effect” means an effect caused by a physiologically active substance exerting physiological activity at a target site
- physiological activity means that the physiologically active substance acts on a target site (for example, a target tissue). It means to change and influence.
- the physiologically active substance is not particularly limited and may be appropriately selected depending on the intended purpose.
- the pharmaceutical compound may be any compound known as an active ingredient of a drug, and a polypeptide, nucleic acid or the like can be used in addition to a low molecular weight pharmaceutical compound.
- the "polypeptide” means a substance having a plurality of peptide bonds (amide bonds) in the molecule, and is not only a substance in which a plurality of amino acids are linked by a peptide bond, but also a glycopeptide antibiotic or a cyclic poly. Peptide antibiotics and the like are also included.
- a polypeptide having a specific three-dimensional structure and thereby having a predetermined property is particularly referred to as a "protein".
- a kinase inhibitor containing a tyrosine kinase inhibitor, a serine / threonine kinase inhibitor and the like is particularly preferable.
- antibodies, enzymes and the like are particularly preferable.
- nucleic acid antisense nucleic acid and the like are particularly preferable.
- a pharmaceutical compound when described by a compound name in the present invention, it includes not only the compound but also any pharmaceutically acceptable form of the compound, such as a salt, a solvate, or a stereoisomer. Intended.
- the kinase inhibitor include nintedanib, afatinib, gefitinib, erlotinib, osimertinib, bossnitib, bandetanib, axitinib, lorlatinib, abemacicrib, tilhostin AG494, sorafenib, dasatinib, lapatinib, lapatinib, lapatinib, lapatinib.
- Axitinib 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione and the like can be mentioned.
- the polypeptide include cyclosporine, vancomycin, teicoplanin, daptomycin and the like.
- Kinase inhibitors or antibiotics are preferred as the pharmaceutical compounds.
- Other poorly water-soluble compounds include, for example, quercetin, testosterone, indomethacin, tranilast, tacrolimus and the like.
- the content of the poorly water-soluble compound in the functional particles is particularly limited as long as it can sufficiently exert the effect of the poorly water-soluble compound and can be dissolved in water or physiological saline. However, it can be appropriately selected according to the purpose. As the content of the poorly water-soluble compound increases, the solubility decreases accordingly.
- the content of the poorly water-soluble compound can be, for example, 75% by mass or less, preferably 0.01% by mass or more and 75% by mass or less, more preferably 1% by mass or more and 75% by mass or less, and 10% by mass. % To 70% by mass is more preferable, and 20% by mass or more and 50% by mass or less is particularly preferable.
- the content of the poorly water-soluble compound When the content of the poorly water-soluble compound is 0.01% by mass or more, the amount of the solution of the immediately soluble particles required for administering the required amount of the drug can be reduced. On the other hand, when the content of the poorly water-soluble compound is 75% by mass or less, high immediate solubility of the poorly water-soluble compound can be ensured. If the content of the poorly water-soluble compound is less than 0.01% by mass, the drug concentration at the time of administration decreases, and a larger amount of solution must be taken, resulting in poor efficiency. On the contrary, when the content exceeds 75% by mass, the immediate solubility effect of the drug is reduced.
- the functional particles of the present invention contain a pharmaceutical compound, and in particular, the functional particles of the present invention are in a form capable of rapidly dissolving a poorly water-soluble pharmaceutical compound in water or physiological saline. Therefore, the particles of the present invention can be suitably used particularly in a pharmaceutical composition in an administration form which is used by being dissolved in water or physiological saline. In addition, it can be suitably used as a pharmaceutical composition that can be prepared at the time of use.
- the volume average particle diameter (Dv) of the functional particles is preferably 0.5 ⁇ m or more and 50 ⁇ m or less, and more preferably 0.5 ⁇ m or more and 20 ⁇ m or less.
- the volume average particle diameter (Dv) of the functional particles is 0.5 ⁇ m or more and 50 ⁇ m or less, the poorly water-soluble compound contained in the functional particles is likely to be included in the particles in an amorphous state. , The solubility of poorly water-soluble compounds is improved.
- the Reactive Span Factor satisfies the following formula (1). 0 ⁇ (RSF) ⁇ 1.5 ... Equation (1)
- (RSF) is defined by (D90-D10) / D50.
- D90 represents the cumulative 90% by volume of the cumulative particle size distribution from the small particle side
- D50 represents the cumulative 50% by volume of the cumulative particle size distribution from the small particle side
- D10 represents the cumulative 50% by volume of the cumulative particle size distribution from the small particle side.
- the upper limit of is not particularly limited, but for example, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, Examples include 0.5.
- the (RSF) is a concentrated analyzer (“FPAR-1000”, manufactured by Otsuka Electronics Co., Ltd.) by a dynamic light scattering method, a laser diffraction / scattering type particle size distribution measuring device (device name: Microtrack MT3000II,). It can be measured using a Microtrac Bell Co., Ltd.).
- the other components are not particularly limited and may be appropriately selected depending on the intended purpose.
- the other components described later method for producing functional particles and apparatus for producing functional particles
- examples include those described in the item of.
- the method for producing functional particles of the present invention includes a droplet forming step of ejecting a liquid containing a rapid water-soluble compound and a poorly water-soluble compound from a discharge hole to form droplets, and solidifying the droplets. Includes a granulation step to be performed, and further includes other steps as necessary.
- the apparatus for producing functional particles of the present invention comprises a droplet forming means for forming droplets by ejecting a liquid containing a rapid water-soluble compound and a poorly water-soluble compound from a discharge hole, and solidifying the droplets. It has a granulating means to be used, and if necessary, has a particle collecting means and other means.
- a liquid containing the rapid water-soluble compound and the poorly water-soluble compound (hereinafter, may be referred to as “particle composition liquid”) is discharged from a discharge hole to form droplets.
- This step is carried out by a droplet forming means.
- the particle composition liquid contains the water-soluble base material and the poorly water-soluble compound in a solvent, and further contains other components, if necessary.
- solvent is not particularly limited and may be appropriately selected depending on the intended purpose, but the water-soluble substrate and the poorly water-soluble compound, or pharmaceutically acceptable salts thereof can be dissolved or dispersed. The one is preferable. When the water-soluble base material and the poorly water-soluble compound are dissolved at the same time, it is preferable to use a mixture of two or more kinds of solvents.
- solvent examples include water, aliphatic halogenated hydrocarbons (eg, dichloromethane, dichloroethane, chloroform, etc.), alcohols (eg, methanol, ethanol, propanol, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.).
- aliphatic halogenated hydrocarbons eg, dichloromethane, dichloroethane, chloroform, etc.
- alcohols eg, methanol, ethanol, propanol, etc.
- ketones eg, acetone, methyl ethyl ketone, etc.
- Ethers eg, diethyl ether, dibutyl ether, 1,4-dioxane, etc.
- aliphatic hydrocarbons eg, n-hexane, cyclohexane, n-heptane, etc.
- aromatic hydrocarbons eg, benzene, etc.
- examples include toluene, xylene, etc.), organic acids (eg, acetic acid, propionic acid, etc.), esters (eg, ethyl acetate, etc.), amides (eg, dimethylformamide, dimethylacetamide, etc.), or a mixed solvent thereof. ..
- the content of the solvent is preferably 70% by mass or more and 99.5% by mass or less, more preferably 90% by mass or more and 99% by mass or less, based on the total amount of the liquid.
- the content of the solvent is 70% by mass or more and 99.5% by mass or less with respect to the total amount of the liquid, the solubility of the poorly water-soluble compound and the viscosity of the liquid can be appropriately adjusted. Production stability can be improved.
- the rapid water-soluble compound is similar to that that can be used for the functional particles of the present invention.
- the content of the rapid water-soluble compound is preferably 0.1% by mass or more and 20.0% by mass or less, more preferably 0.1% by mass or more and 15.0% by mass or less, based on the total amount of the particle composition solution. preferable.
- the poorly water-soluble compound is the same as that that can be used for the functional particles of the present invention.
- the content of the poorly water-soluble compound is preferably 0.005% by mass or more and 5.0% by mass or less, more preferably 0.05% by mass or more and 5.0% by mass or less, based on the total amount of the particle composition solution. It is preferable, and more preferably 0.1% by mass or more and 3.0% by mass or less.
- the other ingredients are not particularly limited and may be appropriately selected depending on the intended purpose, but those that can be conventionally used in medicine are preferable.
- the other components include water, excipients, flavoring agents, disintegrants, fluidizing agents, adsorbents, lubricants, odorants, surfactants, fragrances, colorants, antioxidants, and concealing agents. , Antioxidants, wetting agents and the like. These may be used alone or in combination of two or more.
- the excipient is not particularly limited and may be appropriately selected depending on the intended purpose.
- lactose sucrose, mannitol, glucose, fructose, maltose, erythritol, maltitol, xylitol, palatinose, trehalose and sorbitol.
- the flavoring agent is not particularly limited and may be appropriately selected depending on the intended purpose.
- L-menthol sucrose, D-sorbitol, xylitol, citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame.
- examples thereof include potassium, somatin, sodium saccharin, dipotassium glycyrrhizinate, monosodium glutamate, sodium 5'-inosinate, and sodium 5'-guanylate. These may be used alone or in combination of two or more.
- the disintegrant is not particularly limited and may be appropriately selected depending on the intended purpose.
- Hydroxypropyl starch, corn starch and the like can be mentioned. These may be used alone or in combination of two or more.
- the fluidizing agent is not particularly limited and may be appropriately selected depending on the intended purpose.
- Examples thereof include light anhydrous silicic acid, hydrous silicon dioxide and talc. These may be used alone or in combination of two or more.
- As the light anhydrous silicic acid a commercially available product can be used.
- the commercially available product of light anhydrous silicic acid is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include Adsolider 101 (manufactured by Freund Sangyo Co., Ltd .: average pore diameter: 21 nm).
- a commercially available product can be used as the adsorbent.
- the commercially available adsorbent is not particularly limited and may be appropriately selected depending on the purpose.
- the lubricant is not particularly limited and may be appropriately selected depending on the intended purpose.
- magnesium stearate, calcium stearate, sucrose fatty acid ester, stearyl fumarate, stearic acid, polyethylene glycol, talc and the like can be selected. Can be mentioned. These may be used alone or in combination of two or more.
- the odorant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include trehalose, malic acid, maltose, potassium gluconate, anise essential oil, vanilla essential oil and cardamom essential oil. These may be used alone or in combination of two or more.
- the surfactant is not particularly limited and may be appropriately selected depending on the intended purpose.
- examples thereof include polysorbate such as polysorbate 80; polyoxyethylene / polyoxypropylene copolymer; sodium lauryl sulfate and the like. These may be used alone or in combination of two or more.
- the fragrance is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include lemon oil, orange oil and peppermint oil. These may be used alone or in combination of two or more.
- the colorant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include titanium oxide, edible yellow No. 5, edible blue No. 2, iron sesquioxide, and yellow sesquioxide. These may be used alone or in combination of two or more.
- the antioxidant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sodium ascorbate, L-cysteine, sodium sulfite and vitamin E. These may be used alone or in combination of two or more.
- the concealing agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include titanium oxide. These may be used alone or in combination of two or more.
- the antistatic agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include talc and titanium oxide. These may be used alone or in combination of two or more.
- the wetting agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include polysorbate 80, sodium lauryl sulfate, sucrose fatty acid ester, macrogol, hydroxypropyl cellulose (HPC) and the like. These may be used alone or in combination of two or more.
- the particle composition liquid may be one in which the water-soluble substrate and the poorly water-soluble compound are dissolved, one in which the poorly water-soluble compound is dispersed, or one in a liquid state under discharge conditions.
- the solvent may not be contained, and the particle component may be in a molten state.
- the discharge hole is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include an opening provided in a nozzle plate or the like.
- the number, cross-sectional shape, and size of the discharge holes can be appropriately selected.
- the number of the discharge holes is not particularly limited and may be appropriately selected depending on the intended purpose. For example, 2 or more and 3,000 or less are preferable. When the number of discharge holes is 2 or more and 3,000 or less, the productivity can be improved.
- the cross-sectional shape of the discharge hole is not particularly limited and may be appropriately selected depending on the intended purpose.
- the opening diameter has a constant nozzle angle from the liquid contact surface (inlet) of the discharge hole toward the discharge hole (outlet).
- a shape that is narrow is preferable.
- the nozzle angle in the shape of (3) is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 60 ° or more and 90 ° or less. When the nozzle angle is 60 ° or more, pressure is likely to be applied to the liquid, and further processing is easy. When the nozzle angle is 90 ° or less, pressure is applied in the discharge hole, so that the droplet discharge can be stabilized. Therefore, the maximum nozzle angle is preferably 90 °.
- the size of the discharge hole can be appropriately selected in consideration of the sustained release property of the particles to be produced.
- the diameter of the discharge hole is preferably 12 ⁇ m or more and 100 ⁇ m or less, and more preferably 15 ⁇ m or more and 30 ⁇ m or less. ..
- the size of the discharge hole is 12 ⁇ m or more and 100 ⁇ m or less, particles having a particle size sufficiently large to exhibit sustained release can be obtained.
- the droplet forming means is not particularly limited and may be appropriately known depending on the intended purpose.
- Means, liquid vibration type discharge means, liquid column resonance type discharge means, and the like can be mentioned.
- the membrane vibration type discharge means for example, the discharge means described in Japanese Patent Application Laid-Open No. 2008-292996
- the Rayleigh split type discharge means for example, the discharge means described in Japanese Patent No. 4647506 is the liquid.
- the vibration type discharge means include the discharge means described in Japanese Patent Application Laid-Open No. 2010-102195.
- the droplet-forming liquid column resonance In order to narrow the particle size distribution of the droplets and secure the productivity of the immediately soluble particles, it is possible to utilize the droplet-forming liquid column resonance using the liquid column resonance type ejection means.
- vibration is applied to the liquid in the liquid column resonance liquid chamber to form a standing wave due to the liquid column resonance, and a plurality of discharge holes formed in a region that becomes an antinode of the standing wave.
- the liquid may be discharged from.
- the liquid discharged from the droplet forming means may be an embodiment of a "particle component-containing liquid" in which the components of the particles to be obtained are dissolved or dispersed. Further, as long as it is a liquid under the conditions of discharge, it may not contain a solvent, and may be in the form of a "particle component melt” in which the particle components are melted.
- the granulation step is a step of granulating particles by removing a solvent from the droplets formed in the droplet forming step. Specifically, it is a process of solidifying droplets of the particle composition liquid containing the rapid water-soluble compound discharged into a gas from the droplet forming means and the poorly water-soluble compound.
- the granulation means is a means for solidifying the droplets.
- the means is not particularly limited as long as the solvent can be removed from the droplets, and an appropriate selection can be made depending on the properties of the particle composition solution.
- the particle composition solution can volatilize a solid raw material. If it is dissolved or dispersed in a solvent, after the droplet is ejected, the droplet is discharged into the transport airflow and dried, that is, the droplet is discharged into the transport airflow and is contained in the droplet. It can be achieved by volatilizing the solvent of.
- the drying state can be adjusted by appropriately selecting the temperature, vapor pressure, type, etc. of the injected gas. Further, even if the particles are not completely dried, they may be additionally dried in a separate step after recovery as long as the collected particles maintain a solid state. Further, a solidified state may be formed by subjecting a temperature change or a chemical reaction.
- the conveyed airflow prevents a decrease in the droplet ejection speed immediately after ejecting the droplets and suppresses the coalescence (coalescence) of the droplets.
- the reason why the transport airflow is provided is as follows. If the ejected droplets come into contact with each other before drying, the droplets coalesce into one droplet (hereinafter, this phenomenon is referred to as coalescence). In order to obtain particles having a uniform (narrow) particle size distribution, it is necessary to maintain the distance between the ejected droplets. However, although the ejected droplet has a constant initial velocity, it eventually stalls due to air resistance. The droplets ejected later catch up with the stalled droplets, and as a result, they coalesce.
- the droplets are solidified while suppressing the decrease in the droplet ejection speed and preventing the droplets from coalescing by the transport air flow so that the droplets do not come into contact with each other. Need to be transported.
- the method of solidifying the droplets using the transport airflow is not particularly limited and may be appropriately selected depending on the intended purpose.
- the transport direction of the transport airflow is set with respect to the direction in which the droplets are discharged. A method in which the direction is substantially vertical is preferable. The method of drying using the conveyed airflow will be described in detail in the description of the drawings described later.
- drying the solvent it is preferable to adjust the temperature of the transport air flow, the vapor pressure, the type of gas, and the like. Further, as long as the collected particles maintain a solid state, an additional drying step may be provided as a separate step after recovery even if the collected particles are not completely dried. In addition to this, a method of drying droplets by applying a temperature change or a chemical change may be used.
- the other steps are not particularly limited and may be appropriately selected depending on the intended purpose, and examples thereof include a particle collection step.
- the particle collecting step is a step of collecting dried fine particles, and can be preferably carried out by the particle collecting means.
- the particle collecting means is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a cyclone collecting means and a back filter.
- the method for producing functional particles of the present invention can be preferably performed by a device for producing functional particles.
- a device for producing functional particles will be described.
- FIG. 1 is a schematic cross-sectional view of the droplet forming means 11.
- the droplet forming means 11 has a liquid common supply path 17 and a liquid column resonance liquid chamber 18.
- the liquid column resonance liquid chamber 18 is communicated with a liquid common supply path 17 provided on one of the wall surfaces at both ends in the longitudinal direction. Further, the liquid column resonance liquid chamber 18 is provided on a discharge port 19 for discharging droplets 21 on one of the wall surfaces connected to the wall surfaces at both ends and a wall surface facing the discharge port 19, and the liquid column.
- It has a vibration generating means 20 that generates high-frequency vibration to form a resonance standing wave.
- a high-frequency power supply (not shown) is connected to the vibration generating means 20.
- reference numeral 9 indicates an elastic plate
- reference numeral 12 indicates an air flow passage
- reference numeral 14 indicates a liquid.
- FIG. 2 is a schematic cross-sectional view showing another example of the droplet forming means.
- FIG. 2 shows a liquid column resonance droplet ejection unit 10 having the droplet forming means shown in FIG.
- the liquid 14 flows into the liquid common supply passage 17 of the liquid column resonance droplet forming unit 10 shown in FIG. 2 through a liquid supply pipe by a liquid circulation pump (not shown), and is shown from the liquid common supply passage 17 to FIG. It is supplied to the liquid column resonance liquid chamber 18 through the liquid supply passage 17a of the droplet forming means 11. Then, a pressure distribution is formed in the liquid column resonance liquid chamber 18 filled with the liquid 14 by the liquid column resonance standing wave generated by the vibration generating means 20.
- the droplet 21 is discharged from the discharge port 19 arranged in the region that is the antinode of the standing wave, which is a portion having a large amplitude and a large pressure fluctuation in the liquid column resonance standing wave.
- the region that becomes the antinode of the standing wave due to the liquid column resonance is a region other than the node of the standing wave, and a region in which the pressure fluctuation of the standing wave has an amplitude sufficiently large to discharge the liquid is preferable.
- a region of ⁇ 1/4 wavelength is more preferable from the position where the amplitude of the pressure standing wave is maximized (node as a velocity standing wave) to the position where it is minimized.
- the liquid 14 that has passed through the liquid common supply path 17 flows through a liquid return pipe (not shown) and is returned to the raw material container.
- a liquid return pipe (not shown)
- the flow rate of the liquid 14 supplied from the liquid supply path 17a increases.
- the liquid 14 is replenished in the liquid column resonance liquid chamber 18.
- the flow rate of the liquid 14 passing through the liquid supply path 17a returns to the original flow rate.
- the liquid column resonance liquid chamber 18 in the droplet forming means 11 has a frame formed of a material having high rigidity such as metal, ceramics, silicone, etc., which does not affect the resonance frequency of the liquid at the driving frequency. It is formed by joining. Further, as shown in FIG. 1, the length L between the wall surfaces at both ends in the longitudinal direction of the liquid column resonance liquid chamber 18 is determined based on the liquid column resonance principle as described later. Further, the width W of the liquid column resonance liquid chamber 18 shown in FIG. 2 is smaller than half of the length L of the liquid column resonance liquid chamber 18 so as not to give an extra frequency to the liquid column resonance. Is preferable.
- a plurality of the liquid column resonance liquid chambers 18 are arranged with respect to one droplet forming unit 10 in order to dramatically improve the productivity.
- the number of the liquid column resonance liquid chambers 18 is not particularly limited and may be appropriately selected depending on the intended purpose. From the viewpoint of achieving both operability and productivity, 100 or more and 2,000 or less are preferable. .. Further, for each of the liquid column resonance liquid chambers 18, the liquid supply passage 17a for liquid supply is continuously connected from the liquid common supply passage 17, and a plurality of the liquid column resonance liquids are connected to the liquid supply passage 17a. It communicates with room 18.
- the vibration generating means 20 in the droplet forming means 11 is not particularly limited as long as it can be driven at a predetermined frequency, but a form in which a piezoelectric body is attached to an elastic plate 9 is preferable.
- the frequency is preferably 150 kHz or higher, more preferably 300 kHz or higher and 500 kHz or lower.
- the elastic plate constitutes a part of the wall of the liquid column resonance liquid chamber so that the piezoelectric body does not come into contact with the liquid.
- the piezoelectric material include piezoelectric ceramics such as lead zirconate titanate (PZT), and are often used in a laminated manner because the amount of displacement is generally small.
- piezoelectric polymers such as polyvinylidene fluoride (PVDF) and single crystals such as quartz, LiNbO 3 , LiTaO 3 , and KNbO 3 can be mentioned.
- the vibration generating means 20 is arranged so as to be individually controllable for each liquid column resonance liquid chamber.
- the block-shaped vibration generating means of the above one material is partially cut according to the arrangement of the liquid column resonance liquid chambers, and each liquid column resonance liquid chamber can be individually controlled via an elastic plate. Is preferable.
- the discharge port 19 is provided in the width direction in the liquid column resonance liquid chamber 18 from the viewpoint that a large number of openings of the discharge port 19 can be provided and the production efficiency is high. .. Further, since the liquid column resonance frequency fluctuates depending on the opening arrangement of the discharge port 19, it is desirable to appropriately determine the liquid column resonance frequency by confirming the discharge of droplets.
- FIGS. 3A to 3D are schematic views showing an example of the structure of the discharge hole.
- the cross-sectional shape of the discharge hole is described as a tapered shape such that the opening diameter decreases from the liquid contact surface (inlet) of the discharge hole toward the discharge port (outlet).
- the cross-sectional shape can be selected as appropriate.
- the discharge hole 19 has a shape such that the opening diameter is narrowed while having a round shape from the liquid contact surface of the discharge hole toward the discharge port 19. With such a shape, the pressure applied to the liquid at the discharge port is maximized, so that the shape can be the most preferable for stabilizing the discharge.
- the discharge hole 19 has a shape in which the opening diameter is narrowed at a constant angle from the liquid contact surface of the discharge hole toward the discharge port 19. With such a shape, the nozzle angle 24 can be changed as appropriate. Similar to the shape of FIG. 3A, the shape of FIG. 3B can increase the pressure applied to the liquid in the vicinity of the discharge port by this nozzle angle.
- the nozzle angle 24 is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 60 ° or more and 90 ° or less. When the nozzle angle is 60 ° or more, pressure is likely to be applied to the liquid, and further processing is easy. When the nozzle angle 24 is 90 ° or less, pressure is applied near the outlet of the discharge hole, so that droplet formation can be stably performed. Therefore, it is preferable that the nozzle angle 24 has a maximum value of 90 ° (corresponding to FIG. 3C).
- FIG. 3D is a combination of FIG. 3A and FIG. 3B. The shape may be changed stepwise in this way.
- the length from the end of the frame on the fixed end side to the end on the liquid common supply path 17 side is L.
- the height h1 (about 80 ⁇ m) of the end of the frame on the liquid common supply path 17 side is about twice the height h2 (about 40 ⁇ m) of the communication port, which is equivalent to the fixed end where the end is closed.
- L (N / 4) ⁇ ⁇ ⁇ ⁇ (Equation 2)
- L represents the length of the liquid column resonance liquid chamber in the longitudinal direction
- N represents an even number
- ⁇ represents the wavelength at which the liquid resonance occurs.
- Equation 3 N ⁇ c / (4L) ⁇ ⁇ ⁇ (Equation 3)
- L represents the length of the liquid column resonance liquid chamber in the longitudinal direction
- c represents the velocity of the sound wave of the liquid
- N represents a natural number.
- the vibration is not amplified indefinitely, but has a Q value, and is shown in the above equation 3 as shown in equations 4 and 5 described later. Resonance also occurs at frequencies near the most efficient drive frequency f.
- the solid line represents the velocity distribution and the broken line represents the pressure distribution. Originally, it is a compressional wave (longitudinal wave), but it is generally expressed as shown in FIGS. 4A to 4D and 5A to 5C.
- the solid line is the velocity standing wave and the dotted line is the pressure standing wave. For example, as can be seen from FIG.
- the open end means the end where the moving speed of the medium becomes maximum and the pressure becomes zero
- the closed end means the moving speed of the medium (liquid) in the longitudinal direction becomes zero
- pressure means the maximal end.
- the closed end is considered as an acoustically hard wall, and wave reflection occurs.
- the superposition of the waves produces a resonant standing wave of the form shown in FIGS. 4A-4D and 5A-5C.
- the pattern of the standing wave fluctuates depending on the number of discharge ports and the opening position, and the resonance frequency appears at a position deviated from the position obtained from the above equation 3. In this case, stable droplet formation conditions can be created by appropriately adjusting the drive frequency.
- the sound velocity c of the liquid is 1,200 m / s
- the length L of the liquid column resonance liquid chamber is 1.85 mm
- the most efficient resonance frequency is derived from Equation 2 as 324 kHz.
- the sound velocity c of the liquid is 1,200 m / s and the length L of the liquid column resonance liquid chamber is 1.85 mm, using the same conditions as above, with wall surfaces at both ends and fixed ends on both sides.
- the liquid column resonance liquid chamber in the droplet forming means 11 shown in FIG. 1 is an end portion whose both ends are equivalent to the closed end state or can be explained as an acoustically soft wall due to the influence of the opening of the discharge port. This is preferable for increasing the frequency, but it is not limited to this, and it may be an open end.
- the influence of the opening of the discharge port here means that the acoustic impedance becomes small, and in particular, the compliance component becomes large. Therefore, the configuration in which the wall surfaces are formed at both ends of the liquid column resonance liquid chamber in the longitudinal direction as shown in FIGS. Is preferable because it can be used.
- the numerical aperture of the discharge port, the opening arrangement position, and the cross-sectional shape of the discharge port are also factors for determining the drive frequency, and the drive frequency can be appropriately determined accordingly.
- the drive frequency can be appropriately determined accordingly.
- the number of discharge ports is increased, the restraint at the tip of the liquid column resonance liquid chamber, which was a fixed end, is gradually loosened, a resonance standing wave almost close to the open end is generated, and the drive frequency becomes high.
- loose restraint conditions are imposed starting from the opening arrangement position of the discharge port that exists closest to the liquid supply path side, the cross-sectional shape of the discharge port becomes round, and the volume of the discharge port fluctuates depending on the thickness of the frame.
- the standing wave of is short wavelength and higher than the drive frequency.
- the vibration generating means When a voltage is applied to the vibration generating means at the driving frequency determined in this way, the vibration generating means is deformed to generate a resonance standing wave most efficiently at the driving frequency.
- the liquid column resonance standing wave is also generated at a frequency near the drive frequency at which the resonance standing wave is most efficiently generated. That is, the length between both ends of the liquid column resonance liquid chamber in the longitudinal direction is L, and the distance to the discharge port closest to the end on the liquid supply side is Le.
- the vibration generating means is vibrated by using the drive waveform whose main component is the drive frequency f in the range determined by the following equations 4 and 5 using both the lengths of L and Le, and the liquid column resonance is caused.
- L represents the length of the liquid column resonance liquid chamber in the longitudinal direction
- Le represents the end portion on the liquid supply path side and the central portion of the discharge hole closest to the end portion.
- c represents the velocity of the sound wave of the liquid
- N represents the natural number.
- a liquid column resonance pressure standing wave is formed in the liquid column resonance liquid chamber 18 of FIG. 1, and a discharge port 19 is arranged in a part of the liquid column resonance liquid chamber 18. Is continuously ejected into droplets. It is preferable to arrange the discharge port 19 at a position where the pressure of the standing wave fluctuates most, because the droplet formation efficiency becomes high and the device can be driven at a low voltage. Further, the number of discharge ports 19 may be one in one liquid column resonance liquid chamber 18, but it is preferable that the number of discharge ports 19 is two or more (a plurality of discharge ports 19 are arranged) from the viewpoint of productivity. Two or more and 100 or less are preferable.
- the productivity can be improved, and when the number is 100 or less, the voltage applied to the vibration generating means 20 when forming a desired droplet from the discharge port 19 is lowered. It can be suppressed and the behavior of the piezoelectric body as the vibration generating means 20 can be stabilized.
- the pitch between the discharge ports (the shortest distance between the centers of adjacent discharge holes) is preferably 20 ⁇ m or more and the length of the liquid column resonance liquid chamber or less.
- the pitch between the discharge ports is 20 ⁇ m or more, the probability that the droplets discharged from the adjacent discharge ports collide with each other and become large droplets can be reduced, and the particle size distribution of the particles is good. Can be.
- FIGS. 6A to 6E the solid line drawn in the liquid column resonance liquid chamber plots the velocity at any measurement position between the fixed end side in the liquid column resonance liquid chamber and the end on the liquid common supply path side.
- the velocity distribution is shown, and the direction from the liquid common supply path side to the liquid column resonance liquid chamber is +, and the opposite direction is-.
- the dotted line in the liquid column resonance liquid chamber shows the pressure distribution in which the pressure values at arbitrary measurement positions between the fixed end side and the liquid common supply path side end in the liquid column resonance liquid chamber are plotted.
- FIGS. 6A to 6E show temporal changes in the velocity distribution and the pressure distribution under the approximate condition that the liquid column resonance liquid chamber 18 has substantially both fixed ends.
- the solid line represents the velocity distribution and the dashed line represents the pressure distribution.
- FIG. 6A shows a pressure waveform and a velocity waveform in the liquid column resonance liquid chamber 18 at the time of droplet ejection.
- FIG. 6B shows the meniscus pressure increases again after the liquid is drawn in immediately after the droplet is discharged.
- FIGS. 6A and 6B the pressure in the flow path provided with the discharge port 19 in the liquid column resonance liquid chamber 18 is maximized.
- FIG. 6C shows the positive pressure near the discharge port 19 becomes small, and the droplet 21 shifts in the direction of the negative pressure to be discharged.
- the pressure near the discharge port 19 becomes extremely small. From this time, filling of the liquid (particle composition liquid) 14 into the liquid column resonance liquid chamber 18 begins. After that, as shown in FIG. 6E, the negative pressure near the discharge port 19 becomes smaller, and the pressure shifts to the positive pressure direction. At this point, the filling of the liquid 14 is completed. Then, again, as shown in FIG. 6A, the positive pressure in the droplet ejection region of the liquid column resonance liquid chamber 18 becomes maximum, and the droplet 21 is ejected from the ejection port 19. In this way, a standing wave due to the liquid column resonance is generated in the liquid column resonance liquid chamber by the high frequency drive of the vibration generating means.
- the discharge port 19 Since the discharge port 19 is arranged in the droplet discharge region corresponding to the antinode of the standing wave due to the liquid column resonance at the position where the pressure fluctuates most, the droplet 21 is generated according to the period of the antinode. It is continuously discharged from the discharge port 19.
- FIG. 7 is a diagram showing an example of an actual state of droplet ejection by the droplet forming means.
- FIG. 7 shows a state in which the discharge port is arranged at the position of the antinode of the mode pressure standing wave, and the discharge performed by the sine wave having a drive frequency of 340 kHz is photographed by the laser shadow imaging method. As can be seen from the figure, droplets with very uniform diameter and almost uniform velocity are realized.
- FIG. 8 is a graph showing the dependence of the droplet ejection speed on the drive frequency when driven by the same amplitude sine wave having a drive frequency of 290 kHz or more and 395 kHz or less.
- the drive frequency of the first to fourth nozzles is around 340 kHz, the discharge speed from each nozzle is uniform and the maximum discharge speed is reached. From this characteristic result, it can be seen that uniform discharge is realized at the antinode position of the liquid column resonance standing wave in the second mode of the liquid column resonance frequency of 340 kHz. Further, from the characteristic result of FIG.
- FIG. 9 is a schematic view showing an example of a particle manufacturing apparatus.
- the particle manufacturing apparatus 1 mainly includes a droplet forming means 2, a dry collecting unit 60, a transport airflow discharge port 65, and a particle storage unit 63.
- a raw material container 13 for accommodating the liquid 14 is connected to the droplet forming means 2 by a liquid supply pipe 16 and a liquid return pipe 22.
- the liquid 14 contained in the raw material container 13 is supplied to the liquid supply pipe 16 to the droplet forming means 2 through the liquid supply pipe 16, and further returned to the raw material container 13 through the liquid return pipe 22.
- a liquid circulation pump 15 for pumping the liquid 14 in the supply pipe 16 is connected. As a result, the liquid 14 can be supplied to the droplet forming means 2 at any time.
- the liquid supply pipe 16 is provided with a pressure measuring device of P1 and the dry collecting unit 60 is provided with a pressure measuring device of P2.
- the pressure for sending the liquid to the droplet forming means 2 and the pressure in the dry collecting unit are measured by the pressure gauge P1. It is managed by P2. At this time, if the pressure measurement value of P1 is larger than the pressure measurement value of P2, the liquid 14 may seep out from the discharge hole, and if the pressure measurement value of P1 is smaller than the pressure measurement value of P2. It is preferable that the pressure measurement value of P1 and the pressure measurement value of P2 are substantially the same, because gas may enter the droplet forming means 2 and the discharge may be stopped.
- a downdraft (conveyed airflow) 101 created from the conveyed airflow introduction port 64 is formed.
- the droplet 21 ejected from the droplet forming means 2 is conveyed downward not only by gravity but also by the transport airflow 101, passes through the transport airflow discharge port 65, is collected by the collecting means 62, and is a particle. It is stored in the storage unit 63.
- this phenomenon may also be referred to as "cohesion"
- the ejected droplet has a constant initial velocity, it eventually stalls due to air resistance. The droplets ejected later catch up with the stalled particles, resulting in coalescence. Since this phenomenon occurs constantly, the particle size distribution becomes severely deteriorated when these particles are collected.
- FIG. 10 is a schematic view showing an example of an airflow passage. As shown in FIG. 10, in the airflow passage 12, it may be lateral to the discharge direction. Alternatively, although not shown, it may have an angle, and it is preferable to have an angle such that the droplets are separated from the droplet forming means.
- the adhesion prevention airflow is applied to the droplet discharge from the lateral direction as shown in FIG.
- the trajectories do not overlap when the droplets are conveyed by the adhesion prevention airflow from the discharge port. .. After the coalescence is prevented by the first airflow as described above, the dry particles may be carried to the collecting means by the second airflow.
- the velocity of the first airflow is preferably equal to or greater than the droplet ejection velocity. If the speed of the adhesion prevention airflow is slower than the droplet injection speed, it may be difficult to exert the function of preventing the droplets from coming into contact, which is the original purpose of the adhesion prevention airflow.
- the properties of the first airflow may not necessarily be the same as the second airflow, as conditions can be added so that the droplets do not coalesce. Further, a chemical substance that promotes drying of the particle surface may be mixed in the coalescence prevention airflow, or may be added in anticipation of a physical action.
- the conveyed airflow 101 is not particularly limited as an airflow state, and may be a laminar flow, a swirling flow, or a turbulent flow.
- the type of gas constituting the conveyed airflow 101 is not particularly limited and may be appropriately selected depending on the intended purpose. Air or a nonflammable gas such as nitrogen may be used. Further, it is preferable that the temperature of the transport airflow 101 can be appropriately adjusted and does not fluctuate during production. Further, the chamber 61 may have a means for changing the airflow state of the conveyed airflow 101.
- the conveyed airflow 101 may be used not only to prevent the droplets 21 from adhering to each other but also to prevent them from adhering to the chamber 61.
- the secondary drying As the secondary drying, general known drying means such as fluidized bed drying and vacuum drying can be used.
- the pharmaceutical composition of the present invention contains the functional particles of the present invention, typically immediately soluble particles, as an active ingredient, and may further contain other ingredients if necessary.
- the pharmaceutical composition of the present invention can be suitably produced by the method for producing a pharmaceutical composition of the present invention, which will be described later.
- the "pharmaceutical composition” contains a kinase inhibitor which is a poorly water-soluble compound, and when added to water or physiological saline, it rapidly dissolves in water or physiological saline, and the kinase inhibitor It means a composition containing the functional particles of the present invention capable of obtaining a lysate or dispersion, typically a quick-dissolving particle, and particularly used for treating an injury or illness.
- the present inventors have found that when the functional particles, typically immediately soluble particles, are contained in a pharmaceutical composition, they are rapidly dissolved in water or physiological saline after particle formation, and the above-mentioned It was found that the kinase inhibitor retains its physiological activity.
- the functional particles in the pharmaceutical composition of the present invention contain a water-soluble substrate, a kinase inhibitor which is a poorly water-soluble compound, and other components as necessary.
- the water-soluble base material is the same as that described in the above-mentioned (functional particles) -water-soluble base material-.
- the pharmaceutical composition of the present invention contains a kinase inhibitor as an active ingredient.
- the kinase inhibitor that can be contained in the pharmaceutical composition of the present invention is the same as that described in the above-mentioned (functional particles) -poorly water-soluble compound-item.
- volume average particle size (Dv) and R. of the functional particles in the pharmaceutical composition S. F is the volume average particle size (Dv) of the functional particles described in the above item (functional particles), R.I. S. Same as F.
- the other components are not particularly limited and may be appropriately selected depending on the intended purpose.
- the above. Can be appropriately selected from those described in the item of-Other Ingredients-of (Functional Particles), and the content thereof in the pharmaceutical composition can also be appropriately selected.
- the pharmaceutical composition has immediate solubility and can be prepared at the time of use.
- the term "immediately soluble” means that the pharmaceutical composition is rapidly dissolved in water or physiological saline to such an extent that it can be dissolved in water or physiological saline at the time of administration. ..
- the method described in the above item of functional particles can be used.
- an amount of the active ingredient that gives a pharmaceutically effective concentration is added for a predetermined time (for example, 30 minutes, etc.).
- the predetermined time is not limited to this, for example, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 4 minutes, 3 minutes, 2 minutes, 1 minute, 45. Seconds, 30 seconds, 25 seconds, 20 seconds, 15 seconds, 10 seconds, 5 seconds and the like can be mentioned.
- the predetermined amount is not limited to this, and examples thereof include 85%, 90%, 95%, 96%, 97%, 98%, 99%, and 100% of the added amount.
- the "pharmaceutically effective concentration" varies depending on the active ingredient to be added and the administration route, but those skilled in the art can calculate the pharmaceutically effective concentration of the specific active ingredient administered by the specific administration route. ..
- the pharmaceutical composition of the present invention is typically provided in powder form. However, since the pharmaceutical composition of the present invention contains functional particles, it can be used by dissolving it in water or physiological saline immediately before administration.
- the pharmaceutical compound that can be contained in the pharmaceutical composition of the present invention uses a poorly water-soluble compound, it is preferably used by dissolving it in water or physiological saline, and it is prepared by dissolving it in water or physiological saline. It is more preferable to use it.
- it is suitable as an oral solution for drinking a solution dissolved in water or physiological saline, an injection for injection into a blood vessel, or an inhalant for atomization and administration through the mouth or nose. Can be administered.
- the target disease in which the pharmaceutical composition is used is not particularly limited, and can be appropriately selected from diseases caused by kinase activation according to the type of kinase inhibitor and the like.
- Diseases caused by the activation of the kinase include, for example, pulmonary fibrosis, non-small cell lung cancer, pancreatic cancer, pancreatic neuroendocrine tumor, gastrointestinal stromal tumor, renal cell cancer, hepatocellular carcinoma, and thyroid cancer.
- Pancreatic medullary cancer, breast cancer, colon or rectal cancer malignant soft tumor, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic eosinophil leukemia, eosinophils Examples include hyperplasia syndrome and mantle cell lymphoma.
- the present invention includes a method for treating a target disease, which comprises administering the pharmaceutical composition of the present invention to a subject suffering from the above-mentioned target disease.
- the administration form, administration route, dose, administration interval, administration time, administration period, and administration target are not particularly limited and may be appropriately selected depending on the intended purpose. ..
- Examples of the administration form of the pharmaceutical composition of the present invention include oral preparations, injection preparations (including those dissolved at the time of use), and external preparations.
- the pharmaceutical composition of the present invention is typically provided in the form of a powder, but may be administered before administration (including immediately before administration), for example, by tableting or dissolving in water or saline. It may therefore be administered in any form of solid, semi-solid or liquid.
- Examples of the oral preparation include tablets (including sugar-coated tablets, sublingual tablets, and oral tablets), capsules, granules, powders, fine granules, syrup (including dry syrup), enteric acid, sustained-release capsules, and cashews (oblate sac). ), Masticatory tablets, drops, pills, liquids for internal use, confectionery tablets (troches, candy, etc.), sustained-release tablets, sustained-release granules, etc.
- Examples of the external preparation include sprinkling powder, lotion, ointment / cream, shampoo, spray, external liquid (including liniment), tape (including poultice), aerosol, ear drops, eye drops, eye drops, and the like.
- Examples include nasal drops (including nasal drops), inhalants (including inhalation anesthetics and inhalation sprays), spin caps, topical agents, anal suppositories, inserts, enemas, and jellies.
- the administration route is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include local administration, enteral administration, and parenteral administration. Examples of the local administration include transrespiratory tract administration (intratracheal administration), enema administration, intradermal administration, intraconjunctival eye drops, ear drops, nasal administration, and intravaginal administration. Examples of the enteral administration include oral administration, tube administration, and enema administration. Examples of the parenteral administration include intravenous administration, transarterial administration, intramuscular administration, intracardiac administration, subcutaneous administration, intraosseous administration, intradermal administration, submucosal (cavity) administration, intraperitoneal administration, and intravesical administration.
- parenteral administration by a syringe or an infusion pump such as; transdermal administration; transmucosal administration; inhalation administration and the like.
- the pharmaceutical composition of the present invention can rapidly dissolve a poorly water-soluble kinase inhibitor in water or physiological saline. Therefore, when the kinase inhibitor is a poorly water-soluble compound, a conventional inhalation powder or inhalation It can be used as an inhalation solution for local administration such as trans-airway administration, which had to be administered as an aerosol agent. Therefore, particularly preferably, the pharmaceutical composition of the present invention is administered to a subject in the form of an inhalation solution, for example, by a nebulizer or the like.
- the dose is not particularly limited and can be appropriately selected according to the purpose. As shown in the test examples described later, according to the pharmaceutical composition of the present invention, it may be possible to obtain a desired physiological activity with a dose smaller than the conventional dose.
- the administration interval is not particularly limited and can be appropriately selected according to the purpose.
- the administration time is not particularly limited and may be appropriately selected depending on the purpose, and may be administered prophylactically before the onset of the disease, or to improve the symptoms or the symptoms after the onset of the disease. It can also be administered to suppress the progression of.
- treatment includes prevention of preventing the occurrence of a disease, suppression of the progression of symptoms, and improvement of symptoms.
- the administration period is not particularly limited and can be appropriately selected according to the purpose.
- the administration target is not particularly limited and may be appropriately selected depending on the intended purpose.
- humans non-human primates such as monkeys, pigs, cows, sheep, goats, dogs, cats, mice, rats and the like.
- Mammals birds such as birds.
- the method for producing a pharmaceutical composition of the present invention comprises a droplet forming step of ejecting a liquid containing a rapid water-soluble compound and a kinase inhibitor which is a poorly water-soluble compound from a discharge hole to form droplets. It includes a granulation step of solidifying the droplets, and further includes other steps, if necessary.
- the method for producing the pharmaceutical composition of the present invention can be carried out in the same manner as the method for producing functional particles described in the above item (Method for producing functional particles and apparatus for producing functional particles).
- the apparatus for producing a pharmaceutical composition of the present invention comprises a droplet forming means for forming droplets by ejecting a liquid containing a rapid water-soluble compound and a kinase inhibitor which is a poorly water-soluble compound from a discharge hole. It has a granulating means for solidifying the droplets, and if necessary, has a particle collecting means and other means.
- the apparatus for producing the pharmaceutical composition of the present invention is the same as the apparatus for producing functional particles described in the above item (Method for producing functional particles and apparatus for producing functional particles).
- Example 1 ⁇ Preparation of liquid A> 2 parts by mass of tylhostin (manufactured by Tokyo Kasei Kogyo Co., Ltd.) and 8 parts by mass of lactose monohydrate (manufactured by Tokyo Kasei Kogyo Co., Ltd.) are added to a mixed solvent of 700 parts by mass of water and 300 parts by mass of methanol to dissolve the liquid A.
- tylhostin manufactured by Tokyo Kasei Kogyo Co., Ltd.
- lactose monohydrate manufactured by Tokyo Kasei Kogyo Co., Ltd.
- the obtained liquid A is discharged from the discharge port using a liquid column resonance droplet discharge device (manufactured by Ricoh Co., Ltd.) in which the numerical aperture of the discharge port is one per one liquid column resonance liquid chamber in FIG. It was dropletized and dried using the apparatus of FIG. 9 to obtain instantly soluble particles 1.
- the particle granulation conditions are as follows.
- Example 2 ⁇ Preparation of liquid B>
- the liquid B was prepared in the same manner as in Example 1 except that the composition was changed to that shown in Table 1.
- Immediately soluble particles 2 were obtained in the same manner as in Example 1 except that the obtained liquid B was atomized using a spray dryer (device name: GS310, manufactured by Yamato Scientific Co., Ltd.).
- the particle granulation conditions are as follows.
- Example 3 Example 6
- liquids C to F were adjusted in the same manner as in Example 1 except that the composition was changed to that shown in Table 1, and immediately soluble particles 3 to 6 were obtained.
- Example 7 ⁇ Preparation of liquid G>
- the liquid G was prepared in the same manner as in Example 1 except that the composition was changed to that shown in Table 1.
- the particle granulation conditions are as follows.
- Example 8 In Example 2, the liquid H was adjusted in the same manner as in Example 2 except that the composition was changed to that shown in Table 1, to obtain immediately soluble particles 8.
- Example 1 liquids I to J were prepared in the same manner as in Example 1 except that the composition was changed to that shown in Table 1, and particles 9 to 10 were obtained.
- solubility when nintedanibu ethane sulfonate, which is one of tyrosine kinase inhibitors and is known as an active ingredient of a therapeutic agent for idiopathic pulmonary fibrosis, is used as a pharmaceutical composition.
- the physiological activity and the like were tested as follows.
- nintedanib ethane sulfonate manufactured by LC laboratories
- the pharmaceutical composition (i) and nintedanib ethane sulfonate were added to 100 mL of physiological saline so that the amount of nintedanib was 6 mg / mL, and the solution temperature was 20 ° C.
- the dissolution test was carried out with stirring using a stirrer.
- Test Example 2 Animal experiment
- the physiological activity of the pharmaceutical composition (i) produced in Test Example 1 was measured as follows using a bleomycin pulmonary fibrosis model mouse. Verified.
- Evaluation item >> (1) Observation of general condition Weighed every other day or three days a week, and observed the appearance. When weight loss of 20% or more was observed, euthanasia was performed. (2) Respiratory function test On the 21st day when pulmonary fibrosis is completed using a precision respiratory function measuring device for small animals (Flexivent, manufactured by emkaTECHNOLOGIES) (21st day with bleomycin administration day as 0th day). Hereinafter, it may be referred to as “Day 21”).
- .. -Pharmaceutical composition (i) 240 mg was dissolved in 1,000 ⁇ L of PBS (corresponding to 120 ⁇ g of nintedanib / 50 ⁇ L of PBS). This was adjusted for high-concentration administration (120 ⁇ g / mouse), partially diluted 2-fold for moderate-concentration administration (60 ⁇ g / mouse), and further diluted for low-concentration administration (20 ⁇ g / mouse). ..
- an antisedan solution (antisedan 0.15 mL (0.75 mg / 0.15 mL) and PBS 9.85 mL, total 10 mL) was intraperitoneally administered to mice at 100 ⁇ L per 10 g of body weight, and placed on a heat insulating pad. While checking the respiratory condition, I observed until awakening.
- Bleomycin administration date- 1) Oral tracheal intubation was performed using a tracheal intubation stand under general anesthesia. 2) (1) In the control group, 50 ⁇ L of PBS was tracheally injected. In the (2) treated group and (3) non-treated group, 50 ⁇ L of bleomycin solution prepared as follows was tracheally injected. -The dose of bleomycin is 1 to 3 U / 1 kg body weight. The average body weight of the mice was 20 g, and the final adjustment was made with physiological saline so as to be 20 to 60 mU / 50 ⁇ L before administration. In this test, 3U / body weight 1kg 60mU / 50 ⁇ L was administered.
- mice At the end of the experiment, intraperitoneally administer an anti-sedan solution (for the composition, refer to the description in the item "Day-2") to mice at 100 ⁇ L per 10 g of body weight, and observe until awakening while checking the respiratory condition on a heat insulating pad. did.
- an anti-sedan solution for the composition, refer to the description in the item "Day-2"
- Respiratory function measurement date After a cervical incision under general anesthesia, the trachea was exposed and a flexible vent catheter was inserted into the trachea after a small incision. The distal part of the insertion was ligated with a silk thread and connected to a flexiven, and respiratory function was measured.
- the control group saline administration group
- the treatment group trans-airway treatment group, transperitoneal treatment group: the dose of the pharmaceutical composition (i) is 120 ⁇ g as the amount of nintedanib
- the non-treatment group The results of verifying the weight change of mice in the group (bleomycin pulmonary fibrosis model) are shown. Body weight change is considered to reflect the disease state, especially in an inflammatory disease model, and is known to be an important parameter for predicting therapeutic effects. As shown in FIG. 12, temporary weight loss due to transairway administration of bleomycin under general anesthesia was observed in both groups.
- FIG. 13A to 13D show the results of verifying the effectiveness of changing the dose of nintedanib.
- a marked decrease in maximum inspiratory volume was observed, reflecting a decrease in lung volume.
- the decrease in the maximum inspiratory volume was significantly suppressed in the group to which 60 ⁇ g and 120 ⁇ g (as the amount of nintetanib) were administered as compared with the non-treatment group.
- the bleomycin pulmonary fibrosis model (non-treated group: nintetanib dose 0 ⁇ g) showed a marked decrease in pulmonary thoracic compliance, reflecting a decrease in lung (including thoracic) elasticity.
- the decrease in pulmonary thoracic compliance was significantly suppressed in the group administered with 120 ⁇ g (as the amount of nintetanib) as compared with the non-treated group.
- the bleomycin pulmonary fibrosis model (non-treated group: nintetanib dose 0 ⁇ g) showed a marked increase in lung tissue elastane, reflecting an increase in lung elastic resistance.
- 14A-14D show the results of verifying the effectiveness of changing the administration route of nintedanib.
- the dose of the pharmaceutical composition (i) was 120 ⁇ g in terms of the amount of nintedanib.
- the decrease in maximum inspiratory volume was significantly suppressed in the transairway treatment group as compared with the non-treatment group.
- the transperitoneal treatment group did not significantly suppress the decrease in maximum inspiratory volume as compared with the non-treatment group.
- FIG. 14B the decrease in pulmonary thoracic compliance was significantly suppressed in the transairway treatment group as compared with the non-treatment group.
- the transperitoneal treatment group did not significantly suppress the decrease in pulmonary thoracic compliance as compared with the non-treatment group.
- the increase in lung tissue elastance was significantly suppressed in the transairway treatment group as compared with the non-treatment group.
- the transperitoneal treatment group did not significantly suppress the increase in lung tissue elastane compared to the non-treatment group.
- the decrease in static lung compliance was significantly suppressed in the transairway treatment group as compared with the non-treatment group.
- the transperitoneal treatment group did not significantly suppress the decrease in static lung compliance as compared with the non-treatment group.
- Bonferroni analysis was performed after the significance test by one-way analysis of variance, and it was considered that there was a significant difference at the significance level of 5%.
- the pharmaceutical composition of the present invention can rapidly dissolve a poorly water-soluble pharmaceutical compound in a state having its physiological activity.
- the route of administration of nintedanib is limited to oral administration, and due to its low bioavailability, a relatively high dose is set, and the dose is reduced without being tolerated due to adverse events such as gastrointestinal symptoms.
- the pharmaceutical composition of the present invention enables transairway administration, and one tenth of the oral dose is used in the bleomycin pulmonary fibrosis model. Significant improvements in various respiratory function parameters were found. Therefore, according to the pharmaceutical composition of the present invention, it is possible to provide a new administration route of a poorly water-soluble pharmaceutical compound, which has been difficult to use as an administration route other than oral administration.
- Examples of aspects of the present invention are as follows.
- ⁇ 1> Containing particles containing a water-soluble base material and a poorly water-soluble compound,
- the water-soluble substrate contains a rapid water-soluble compound and
- the poorly water-soluble compound is a kinase inhibitor, and is a pharmaceutical composition characterized by being present in the water-soluble substrate in an amorphous state.
- ⁇ 2> The pharmaceutical composition according to ⁇ 1>, which can be prepared at the time of use.
- ⁇ 3> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 2>, wherein the rapidly water-soluble compound is at least one of a monosaccharide and a disaccharide.
- ⁇ 4> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 3>, which is prepared by dissolving in water or physiological saline at the time of administration.
- ⁇ 5> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 4>, wherein a solution prepared by dissolving the pharmaceutical composition in water or physiological saline is atomized and administered.
- ⁇ 6> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 5>, wherein the route of administration is topical administration.
- ⁇ 7> The pharmaceutical composition according to any one of ⁇ 1> to ⁇ 6>, which is used for a disease caused by activation of a kinase.
- ⁇ 8> Containing a water-soluble base material and a poorly water-soluble compound,
- the water-soluble substrate contains a rapid water-soluble compound and
- the functional particles are characterized in that the poorly water-soluble compound is present in the water-soluble substrate in an amorphous state.
- the functional particles according to ⁇ 8>, wherein the rapidly water-soluble compound is at least one of a monosaccharide and a disaccharide.
- ⁇ 11> The functional particles according to any one of ⁇ 8> to ⁇ 10>, wherein the content of the poorly water-soluble compound is 10% by mass or more and 50% by mass or less.
- ⁇ 12> The functional particle according to any one of ⁇ 9> to ⁇ 11>, wherein the volume average particle diameter (Dv) is 0.5 ⁇ m or more and 50 ⁇ m or less.
- ⁇ 13> The functional particle according to any one of ⁇ 8> to ⁇ 12>, wherein the volume average particle diameter (Dv) is 0.5 ⁇ m or more and 20 ⁇ m or less.
- the droplet forming step applies vibration to the composition liquid contained in the liquid column resonance liquid chamber to form a standing wave due to the liquid column resonance, and in the region that becomes the antinode of the standing wave, the said The method for producing functional particles according to ⁇ 14>, which comprises discharging the liquid from the discharge holes formed in the amplitude direction of a standing wave.
- the conventional problems can be solved and the object of the present invention can be achieved. Further, according to the method for producing the functional particles according to any one of ⁇ 8> to ⁇ 13> and the functional particles according to any one of ⁇ 14> to ⁇ 15>, the conventional problems are solved. However, the poorly water-soluble compound can be dissolved quickly.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Dispersion Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- General Preparation And Processing Of Foods (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Glanulating (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
Abstract
Description
また、例えば、水溶性高分子、水溶性糖、界面活性剤を用いることで難水溶性化合物の溶解性を向上させた固体分散体が提案されている(例えば、特許文献2参照)。
このように、難水溶性医薬化合物の溶解性を改善する取り組みは広く行われている。
本発明の機能性粒子は、水溶性基材と、難水溶性化合物とを含有し、前記水溶性基材が、迅速水溶性化合物を含有し、前記難水溶性化合物が、非晶質状態で前記水溶性基材内に存在するものであり、典型的には水や生理食塩水に迅速に溶解する即溶性粒子である。本発明の機能性粒子は、必要に応じてさらに他の成分を含有してもよい。
本発明の機能性粒子、典型的には即溶性粒子は、後述する本発明の機能性粒子の製造方法により好適に製造することができる。
本発明において「迅速水溶性化合物」とは、水に加えた場合に溶解のための特別な操作をしなくても、例えば短時間の撹拌や振とうなどのみにより、例えば1分以内、50秒以内、40秒以内、30秒以内、20秒以内、10秒以内等の時間で速やかに溶解する性質を有する化合物を意味する。迅速水溶性化合物としては、これに限定するものではないが、例えば、単糖類や二糖類などの低分子糖、オリゴ糖、還元糖、糖アルコールなどが挙げられる。本発明に用い得る迅速水溶性化合物としては、常温において固体であることが好ましい。
前記水溶性基材としては、それ自体が水に迅速に溶解し、前記難水溶性化合物と化学的に反応することなく基材内に分散させることができれば特に制限はなく、例えば、迅速水溶性化合物などが好ましい。
前記迅速水溶性化合物としては、例えば、単糖類、二糖類、オリゴ糖、還元糖、糖アルコールなどが挙げられる。
前記単糖類としては、例えば、グルコース、マンノース、イドース、ガラクトース、フコース、リボース、キシロースなどが挙げられる。
前記二糖類としては、例えば、ラクトース、スクロース、マルトース、トレハロースなどが挙げられる。
前記オリゴ糖としては、例えば、ラフィノース(三糖)、マルトトリオース(三糖)、アカルボース(四糖)などが挙げられる。
前記還元糖としては、例えば、ツラノースなどが挙げられる。
前記糖アルコールとしては、例えば、グリセリン、エリスリトール、キシリトール、ラクチトール、ソルビトール、マルチトール、マンニトールなどが挙げられる。
これらの中でも、単糖類及び二糖類の少なくともいずれかが好ましく、ラクトースが最も好ましい。
前記水溶性基材は、水和物を使用することもできる。
前記難水溶性化合物は、水/オクタノール分配係数(logP値)が3以上である化合物を意味する。
水/オクタノール分配係数とは、水とオクタノールの2相系において、ある化合物が水相に溶解している濃度とオクタノール相に溶解している濃度との比率を意味し、通常Log10(オクタノール相の濃度/水相の濃度)で表される。
前記水/オクタノール分配係数(logP値)の測定方法としては、当該技術分野において公知の任意の方法を用いることができ、例えば、JIS Z 7260-107に記載された方法などが挙げられる。
前記生理活性物質としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、医薬化合物、化粧品化合物、機能性食品化合物などが挙げられ、医薬化合物が好ましい。医薬化合物としては、医薬の有効成分として知られる任意の化合物であってよく、低分子医薬化合物のほか、ポリペプチド、核酸などを用いることができる。本発明において「ポリペプチド」とは、分子内に複数のペプチド結合(アミド結合)を有する物質を意味し、複数のアミノ酸がペプチド結合により連結したものだけでなく、グリコペプチド系抗生物質や環状ポリペプチド系抗生物質なども含まれる。またポリペプチドの中でも、特定の立体構造を有し、それにより所定の特性を有するポリペプチドを特に「タンパク質」と称する。低分子医薬化合物としては、特にチロシンキナーゼ阻害剤、セリン/スレオニンキナーゼ阻害剤などを含むキナーゼ阻害剤が好ましい。ポリペプチドとしては、特に抗体、酵素などが好ましい。核酸としては、特にアンチセンス核酸などが好ましい。なお、本発明において医薬化合物を化合物名で記載する場合、当該化合物のみならず当該化合物の薬学的に許容可能な任意の形態、例えば塩、溶媒和物または立体異性体など、を包含することを意図している。
前記キナーゼ阻害剤としては、例えば、ニンテダニブ、アファチニブ、ゲフィチニブ、エルロチニブ、オシメルチニブ、ボスニチブ、バンデタニブ、アレクチニブ、ロルラチニブ、アベマシクリブ、チルホスチンAG494、ソラフェニブ、ダサチニブ、ラパチニブ、イマチニブ、モテサニブ、レスタウルチニブ、タンズチニブドルソモルヒン、アキシチニブ、4-ベンジル-2-メチル-1,2,4-チアジアゾリジン-3,5-ジオンなどが挙げられる。
前記ポリペプチドとしては、例えば、シクロスポリン、バンコマイシン、テイコプラニン、ダプトマイシンなどが挙げられる。
前記医薬化合物としては、キナーゼ阻害剤又は抗生物質が好ましい。
その他の難水溶性化合物としては、例えば、ケルセチン、テストステロン、インドメタシン、トラニラスト、タクロリムス等が挙げられる。
前記難水溶性化合物の含有量が0.01質量%未満であると服用時の薬剤濃度が低下し、より多量の溶液を服用せざるを得ず効率が悪い。反対に含有量が75質量%超の場合には、薬剤の即溶性効果が低下する。
上述のとおり、一態様において本発明の機能性粒子は医薬化合物を含むものであり、特に難水溶性の医薬化合物を速やかに水や生理食塩水に溶解することができる形態とするものである。したがって本発明の粒子は、特に水や生理食塩水に溶解して用いる投与形態の医薬組成物において好適に用いることができる。また、特に用時調製可能な医薬組成物として好適に用いることができる。
0<(R.S.F)≦1.5 ・・式(1)
ここで、(R.S.F)は、(D90-D10)/D50で定義される。
D90は、累積粒度分布の小粒子側からの累積90体積%を表し、D50は、累積粒度分布の小粒子側からの累積50体積%を表し、D10は、累積粒度分布の小粒子側からの累積10体積%を表す。R.S.F.の上限値は特に限定されないが、例えば1.5、1.4、1.3、1.2、1.1、1.0、0.9、0.8、0.7、0.6、0.5などが挙げられる。
前記その他の成分としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、後述する(機能性粒子の製造方法及び機能性粒子の製造装置)の--その他の成分--の項目に記載のものなどが挙げられる。
本発明の機能性粒子の製造方法は、迅速水溶性化合物と、難水溶性化合物とを含有する液体を、吐出孔から吐出して液滴を形成する液滴形成工程と、前記液滴を固化する造粒工程とを含み、更に必要に応じて、その他の工程を含む。
前記液滴形成工程は、前記迅速水溶性化合物と、前記難水溶性化合物とを含有する液体(以下、「粒子組成液」と称する場合がある)を、吐出孔から吐出して液滴を形成する工程であり、液滴形成手段により実施される。
前記粒子組成液は、前記水溶性基材と、前記難水溶性化合物を溶媒中に含有し、更に必要に応じて、その他の成分を含有する。
前記溶媒としては、特に制限はなく、目的に応じて適宜選択することができるが、前記水溶性基材及び前記難水溶性化合物、又は医薬的に許容され得るそれらの塩を溶解乃至分散可能なものが好ましい。前記水溶性基材及び前記難水溶性化合物を同時に溶解させる場合には、2種以上の溶媒を混合して使用することが好ましい。
前記迅速水溶性化合物は、本発明の機能性粒子に用いることができるものと同様である。
前記迅速水溶性化合物の含有量としては、前記粒子組成液の全量に対して、0.1質量%以上20.0質量%以下が好ましく、0.1質量%以上15.0質量%以下がより好ましい。
前記難水溶性化合物は、本発明の機能性粒子に用いることができるものと同様である。
前記難水溶性化合物の含有量としては、前記粒子組成液の全量に対して、0.005質量%以上5.0質量%以下が好ましく、0.05質量%以上5.0質量%以下がより好ましく、0.1質量%以上3.0質量%以下がさらに好ましい。
前記その他の成分としては、特に制限はなく、目的に応じて適宜選択することができるが、従来、医薬に使用できるものが好ましい。
前記その他の成分としては、例えば、水、賦形剤、矯味剤、崩壊剤、流動化剤、吸着剤、滑沢剤、矯臭剤、界面活性剤、香料、着色剤、抗酸化剤、隠蔽剤、静電気防止剤、湿潤剤などが挙げられる。これらは、1種単独で使用してもよいし、2種以上を併用してもよい。
前記軽質無水ケイ酸としては、市販品を用いることができる。軽質無水ケイ酸の市販品としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、アドソリダー101(フロイント産業株式会社製:平均細孔径:21nm)などが挙げられる。
前記吐出孔としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、ノズルプレートなどに設けられた開口部などが挙げられる。
(3)の形状におけるノズル角度としては、特に制限はなく、目的に応じて適宜選択することができるが、60°以上90°以下が好ましい。ノズル角度が、60°以上であると、液に圧力がかかりやすく、更に加工もしやすくなる。ノズル角度が、90°以下であると、吐出孔において圧力がかかるため、液滴吐出を安定化することができる。したがって、ノズル角度としては、90°を最大値とすることが好ましい。
前記液滴形成手段としては、特に制限はなく、目的に応じて適宜公知のものを用いることができ、例えば、スプレーノズル、1流体ノズル、2流体ノズル、膜振動タイプ吐出手段、レイリー***タイプ吐出手段、液振動タイプ吐出手段、液柱共鳴タイプ吐出手段などが挙げられる。
前記膜振動タイプ吐出手段としては、例えば、特開2008-292976号公報に記載の吐出手段が、前記レイリー***タイプ吐出手段としては、例えば、特許第4647506号公報に記載の吐出手段が、前記液振動タイプ吐出手段としては、例えば、特開2010-102195号公報に記載の吐出手段が挙げられる。
前記液滴の粒径分布を狭くし、かつ、即溶性粒子の生産性を確保するためには、前記液柱共鳴タイプ吐出手段を用いた、液滴化液柱共鳴を利用することができる。前記液滴化液柱共鳴では、液柱共鳴液室内の液体に振動を付与して液柱共鳴による定在波を形成し、該定在波の腹となる領域に形成された複数の吐出孔から液体を吐出すればよい。
本発明で液滴形成手段より吐出される液体としては、得ようとしている粒子の成分が溶解又は分散された状態にある「粒子成分含有液」である態様を挙げることができる。また、吐出させる条件下で液体であれば溶媒を含まなくてもよく、粒子成分が溶融している状態にある「粒子成分溶融液」の態様であってもよい。
前記造粒工程は、前記液滴形成工程において形成された液滴から溶媒を除去することにより粒子を造粒する工程である。
具体的には、前記液滴形成手段から気体中に吐出した前記迅速水溶性化合物と、前記難水溶性化合物とを含有する前記粒子組成液の液滴を固化する処理である。
前記造粒手段は、前記液滴を固化する手段である。
造粒するには、前記液滴から溶媒を除去できれば、特に手段に制限はなく、前記粒子組成液の性状により、適宜選択することができ、例えば、前記粒子組成液が固体原材料を揮発可能な溶媒に溶解乃至分散させたものであれば、液滴噴射後、搬送気流中に前記液滴を吐出して乾燥させる、即ち、前記液滴を前記搬送気流の中に吐出して前記液滴中の溶媒を揮発させることで達成することができる。溶媒の乾燥にあたっては、噴射する気体の温度や蒸気圧、種類などを適宜選定して乾燥状態を調整することができる。また、完全に乾燥していなくとも、捕集された粒子が固体状態を維持していれば、回収後に別工程で追加乾燥させても構わない。また、温度変化や化学的反応などを施すことにより、固化状態を形成させてもよい。
吐出された前記液滴同士が乾燥前に接触すると、液滴同士が合体し一つの液滴になってしまう(以下、この現象を合一と称する)。均一な(狭い)粒径分布を有する粒子を得るためには、吐出された前記液滴同士の距離を保つ必要がある。しかしながら、吐出された前記液滴は、一定の初速度を持っているが空気抵抗により、やがて失速する。失速した前記液滴に対して、後から吐出された液滴が追いついてしまい、結果として合一する。この現象は定常的に発生するため、この粒子の粒径分布は均一(狭い)でない。前記液滴同士の合一を抑制するためには、前記液滴吐出速度の低下を抑制し、前記液滴同士が接触しないように搬送気流によって合一を防ぎながら、前記液滴を固化させ、搬送する必要がある。
前記搬送気流を用いて液滴を固化する方法としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、前記搬送気流の搬送方向を、前記液滴を吐出する方向に対して略垂直方向とする方法などが好ましい。なお、前記搬送気流を用いて乾燥する方法については、後述する図面の説明にて詳細に説明する。
前記溶媒の乾燥においては、前記搬送気流の温度、蒸気圧、気体の種類などを調整することが好ましい。
また、捕集された粒子が固体状態を維持していれば、完全に乾燥していなくとも、回収後に別工程で乾燥工程を追加で設けてもよい。
この他にも、温度変化や化学変化などの適用により、液滴を乾燥する方法を用いてもよい。
その他の工程としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、粒子捕集工程などが挙げられる。
前記粒子捕集工程は、乾燥した微粒子を捕集する工程であり、粒子捕集手段により好適に実施することができる。
前記粒子捕集手段としては、特に制限はなく、目的に応じて適宜選択することができ、例えば、サイクロン捕集、バックフィルターなどが挙げられる。
ここで、機能性粒子の製造装置について説明する。
また、図3Bに示すように、吐出孔19は、吐出孔の接液面から吐出口19に向かって、一定の角度を持って開口径が狭くなるような形状を有している。このような形状とすることにより、このノズル角度24は、適宜変更することができる。図3Bの形状は、図3Aの形状と同様に、このノズル角度によって吐出口付近において液にかかる圧力を高めることができる。
前記ノズル角度24としては、特に制限はなく、目的に応じて適宜選択することができるが、60°以上90°以下が好ましい。前記ノズル角度が、60°以上であると、液に圧力がかかりやすく、更に加工もしやすくなる。前記ノズル角度24が、90°以下であると、吐出孔の出口付近で圧力がかかるため、安定して液滴化を行うことができる。したがって、前記ノズル角度24としては、90°(図3Cに相当する)を最大値とすることが好ましい。
図3Dは、図3Aと図3Bとを組み合わせた形状である。このように段階的に形状を変更してもよい。
先ず、図1の液滴形成手段11内の液柱共鳴液室18において生じる液柱共鳴現象の原理について説明する。
液柱共鳴液室内の液体の音速をcとし、振動発生手段20から媒質である液体に与えられた駆動周波数をfとした場合、液体の共鳴が発生する波長λは、下記式1で表される。
λ=c/f ・・・(式1)
L=(N/4)λ ・・・(式2)
ただし、前記式2中、Lは、液柱共鳴液室の長手方向の長さを表し、Nは、偶数を表し、λは、液体の共鳴が発生する波長を表す。
同様にして、片方側が圧力の逃げ部がある開放端と等価で、他方側が閉じている(固定端)の場合、つまり片側固定端又は片側開放端の場合には、長さLが波長λの4分の1の奇数倍に一致する場合に共鳴が最も効率的に形成される。つまり、前記式2のNが奇数で表現される。
最も効率の高い駆動周波数fは、前記式1及び前記式2より、下記式3が導かれる。
f=N×c/(4L) ・・・(式3)
ただし、前記式3中、Lは、液柱共鳴液室の長手方向の長さを表し、cは、液体の音波の速度を表し、Nは、自然数を表す。
しかし、実際には、液体は共鳴を減衰させる粘性を持つために無限に振動が増幅されるわけではなく、Q値を持ち、後述する式4、式5に示すように、前記式3に示す最も効率の高い駆動周波数fの近傍の周波数でも共鳴は発生する。
図4及び図5において、実線は速度分布を表し、破線は圧力分布を表す。本来は、疎密波(縦波)であるが、図4A~図4D及び図5A~図5Cのように、表記することが一般的である。実線が速度定在波、点線が圧力定在波である。例えば、N=1の片側固定端の場合を示す図4Aから分かるように、速度分布の場合閉口端において速度分布の振幅がゼロとなり、開口端で振幅が最大となり、直感的にわかりやすい。液柱共鳴液室の長手方向の両端の間の長さをLとしたとき、液体が液柱共鳴する波長をλとし、整数Nが1~5の場合に定在波が最も効率よく発生する。また、両端の開閉状態によっても定在波パターンは異なるため、それらも併記した。後述するが、吐出口の開口や供給側の開口の状態によって、端部の条件が決まる。
図1に示す液滴形成手段11における液柱共鳴液室は、両端が閉口端状態と等価であるか、吐出口の開口の影響で、音響的に軟らかい壁として説明できるような端部であることが周波数を高めるためには好ましいが、それに限らず開放端であってもよい。ここでの吐出口の開口の影響とは、音響インピーダンスが小さくなり、特にコンプライアンス成分が大きくなることを意味する。よって、図4B及び図5Aのような液柱共鳴液室の長手方向の両端に壁面を形成する構成は、両側固定端の共鳴モード、そして吐出口側が開口とみなす片側開放端の全ての共鳴モードが利用できる点から好ましい。
N×c/(4L)≦f≦N×c/(4Le) ・・・(式4)
N×c/(4L)≦f≦(N+1)×c/(4Le) ・・・(式5)
ただし、前記式4及び前記式5中、Lは、液柱共鳴液室の長手方向の長さを表し、Leは、液供給路側の端部と、該端部に最も近い吐出孔の中心部との距離を表し、cは、液体の音波の速度を表し、Nは、自然数を表す。
Le/L>0.6 ・・・(式6)
図6Aは、液滴吐出時の液柱共鳴液室18内の圧力波形と速度波形を示している。また、図6Bは、液滴吐出直後の液引き込みを行った後再びメニスカス圧が増加してくる。これらの図6A、及び図6Bに示すように、液柱共鳴液室18における吐出口19が設けられている流路内での圧力は極大となっている。その後、図6Cに示すように、吐出口19付近の正の圧力は小さくなり、負圧の方向へ移行して液滴21が吐出される。
上記のように第一の気流によって合着を防いだ後に、第二の気流によって捕集手段まで乾燥粒子を運んでもよい。
第一の気流の性状は、液滴同士が合着しないような条件を追加することができ、第二の気流と必ずしも同じでなくともよい。また、合着防止気流に粒子表面の乾燥を促進させるような化学物質を混入したり、物理的作用を期待して付与したりしてもよい。
搬送気流101は、特に気流の状態として限定されることはなく、層流や旋回流や乱流であってもよい。搬送気流101を構成する気体の種類は、特に制限はなく、目的に応じて適宜選択することができ、空気を用いても、窒素等の不燃性気体を用いてもよい。また、搬送気流101の温度は、適宜調整可能であり、生産時において変動のないことが好ましい。また、チャンバー61内に搬送気流101の気流状態を変えるような手段を有していてもよい。搬送気流101は、液滴21同士の合着を防止すだけでなく、チャンバー61に付着することを防止することに用いてもよい。
本発明の医薬組成物は、本発明の機能性粒子、典型的には即溶性粒子を有効成分として含むものであり、必要に応じてその他の成分をさらに含有してもよい。
本発明の医薬組成物は、後述する本発明の医薬組成物の製造方法により好適に製造することができる。
本発明の医薬組成物における機能性粒子は、水溶性基材と、難水溶性化合物であるキナーゼ阻害剤と、必要に応じてその他の成分を含む。
前記水溶性基材は、上記の(機能性粒子)の-水溶性基材-の項目に記載したものと同様である。
本発明の医薬組成物は、有効成分としてキナーゼ阻害剤を含む。本発明の医薬組成物に含有され得るキナーゼ阻害剤は、上記の(機能性粒子)の-難水溶性化合物-の項目に記載されたものと同様である。
前記機能性粒子におけるその他の成分は、上記の(機能性粒子)の-その他の成分-の項目に記載したものと同様である。
医薬組成物が即溶性を有しているか否かを確認する方法としては、上記機能性粒子の項目において記載した方法などを用いることができる。別の確認方法としては、例えば日本薬局方に規定されている溶出試験に用いる溶解条件を用いて、薬学的に有効な濃度を与える量の有効成分を添加して所定の時間(例えば30分など)以内に所定量(例えば添加量の85%など)以上の溶出が認められれば即溶性と決定する、などの方法が挙げられる。かかる方法において、所定時間としては、これに限定するものではないが、例えば30分、25分、20分、15分、10分、5分、4分、3分、2分、1分、45秒、30秒、25秒、20秒、15秒、10秒、5秒などが挙げられる。所定量としては、これに限定するものではないが、例えば添加量の85%、90%、95%、96%、97%、98%、99%、100%などが挙げられる。「薬学的に有効な濃度」は添加される有効成分や投与経路によって異なるが、当業者であれば特定の投与経路で投与される特定の有効成分の薬学的に有効な濃度を算出可能である。
前記医薬組成物が用いられる対象疾患としては、特に制限はなく、キナーゼ阻害剤の種類などに応じて、キナーゼの活性化に起因する疾患の中から適宜選択することができる。
前記キナーゼの活性化に起因する疾患としては、例えば、肺線維症、非小細胞肺がん、膵がん、膵神経内分泌腫瘍、消化管間質腫瘍、腎細胞がん、肝細胞がん、甲状腺がん、甲状腺髄様がん、乳がん、結腸又は直腸がん、悪性軟部腫瘍、急性骨髄性白血病、慢性骨髄性白血病、急性リンパ性白血病、慢性リンパ性白血病、慢性好酸球性白血病、好酸球増多症候群、マントル細胞リンパ腫などが挙げられる。
なお、本発明には、上記対象疾患に罹患した対象に本発明の医薬組成物を投与することを含む、対象疾患の処置方法が含まれる。
本発明の医薬組成物を投与する場合、投与形態、投与経路、投与量、投与間隔、投与時期、投与期間、及び投与対象としては、特に制限はなく、目的に応じて適宜選択することができる。
本発明の医薬組成物の投与形態としては、経口剤、注射剤(用時溶解のものを含む)、外用剤などが挙げられる。本発明の医薬組成物は典型的には粉末の形状で提供されるが、投与前(投与直前を含む)に、例えば打錠し、または水若しくは生理食塩水に溶解してから投与してもよく、したがって固形剤、半固形剤、液剤のいずれの形態で投与されてもよい。
前記経口剤としては、例えば、錠剤(糖衣錠、舌下錠、口腔錠を含む)、カプセル、顆粒、散剤、細粒、シロップ(ドライシロップを含む)、腸溶剤、徐放性カプセル、カシュー(オブラート嚢を含む)、咀嚼錠、ドロップ、丸剤、内用液剤、菓子錠剤(トローチ、飴類など)、徐放錠、徐放性顆粒などが挙げられる。
前記外用剤としては、例えば、撒布粉剤、ローション、軟膏・クリーム、シャンプー、スプレー、外用液剤(リニメントを含む)、テープ剤(パップ剤を含む)、エアゾール、点耳剤、点眼剤、点眼軟膏、点鼻剤(点鼻スプレーを含む)、吸入剤(吸入麻酔剤、吸入用スプレーを含む)、スピンキャップ、含そう剤、肛門坐剤、挿入剤、浣腸剤、ゼリーなどが挙げられる。
前記局所投与としては、例えば、経気道投与(気管内投与)、注腸投与、皮膚上投与、結膜上への点眼、点耳、経鼻投与、膣内投与などが挙げられる。
前記経腸投与としては、例えば、経口投与、経管投与、注腸投与などが挙げられる。
前記非経口投与としては、例えば、経静脈投与、経動脈投与、筋肉内投与、心臓内投与、皮下投与、骨内投与、皮内投与、くも膜下(腔)投与、腹腔内投与、膀胱内投与等の注射器又は注入ポンプによる非経口投与;経皮投与;経粘膜投与;吸入投与などが挙げられる。
本発明の医薬組成物は、難水溶性のキナーゼ阻害剤を速やかに水や生理食塩水に溶解することができるので、キナーゼ阻害剤が難水溶性化合物である場合には従来吸入粉末剤又は吸入エアゾール剤として投与する必要があった経気道投与などの局所投与に、吸入液剤として用いることができる。したがって特に好ましくは、本発明の医薬組成物は、例えばネブライザーなどにより、吸入液剤の形態で対象に投与される。
本発明において、「治療」には、疾患が生じることを防ぐ予防、症状の進行の抑制、症状の改善のいずれもが含まれる。
本発明の医薬組成物の製造方法は、迅速水溶性化合物と、難水溶性化合物であるキナーゼ阻害剤とを含有する液体を、吐出孔から吐出して液滴を形成する液滴形成工程と、前記液滴を固化する造粒工程とを含み、更に必要に応じて、その他の工程を含む。
本発明の医薬組成物の製造方法は、上記の(機能性粒子の製造方法及び機能性粒子の製造装置)の項目に記載した機能性粒子の製造方法と同様にして行うことができる。
本発明の医薬組成物の製造装置は、上記の(機能性粒子の製造方法及び機能性粒子の製造装置)の項目に記載した機能性粒子の製造装置と同様である。
<液体Aの調製>
チルホスチン(東京化成工業社製)2質量部と、ラクトース一水和物(東京化成工業製)8質量部とを、水700質量部及びメタノール300質量部の混合溶媒に加えて溶解させ、液体Aを得た。
得られた液体Aを、図1において吐出口の開口数を液柱共鳴液室1つ当たり1個とした液柱共鳴液滴吐出装置(株式会社リコー製)を用いて、前記吐出口から吐出液滴化し、図9の装置を使用して、乾燥させて即溶性粒子1を得た。なお、粒子の造粒条件は下記の通りである。
--液柱共鳴条件--
・共鳴モード(N):2
・液柱共鳴液室の長手方向の両端間の長さ(L):1.8mm
・液柱共鳴液室の液共通供給路側のフレームの端部の高さ(h1):80μm
・液柱共鳴液室の連通口の高さ(h2):40μm
--液滴形成手段--
・吐出口の形状:真円
・吐出口の直径:8.0μm
・吐出口の開口数:1個(液柱共鳴液室1つ当たり)
・液柱共鳴液室の数:384室
・印加電圧:12.0V
・駆動周波数:310kHz
--粒子造粒手段--
・搬送気流:乾燥窒素
・搬送気流温度:40℃
・搬送気流流量:100L/分間
<液体Bの調製>
実施例1において、表1に記載の組成に変更した以外は、実施例1と同様にして、液体Bを調整した。
得られた液体Bを、噴霧乾燥装置(装置名:GS310、ヤマト科学社製)を用いて、液滴化した以外は、実施例1と同様にして、即溶性粒子2を得た。なお、粒子の造粒条件は下記の通りである。
--液滴形成手段--
・吐出口の形状:真円
・吐出口の直径:0.5mm
・吐出口の開口数:1個
・噴射エアー圧力:0.1MPa
--粒子造粒手段--
・搬送気流:乾燥窒素
・搬送気流温度:75℃
・搬送気流流量:500L/分間
実施例1において、表1に記載の組成に変更した以外は、実施例1と同様にして、液体C~Fを調整し、即溶性粒子3~6を得た。
<液体Gの調製>
実施例1において、表1に記載の組成に変更した以外は、実施例1と同様にして、液体Gを調整した。
得られた液体Gを、膜振動式ノズル(オプトニクス株式会社製)を備えた粒子の製造装置を用いて液滴化した以外は、実施例1と同様にして即溶性粒子7を得た。なお、粒子の造粒条件は下記の通りである。
--液滴形成手段--
・吐出口の形状:真円
・吐出口の直径:10μm
・印加電圧:20.0V
・駆動周波数:100kHz
--粒子造粒手段--
・乾燥エアー温度:40℃
・乾燥空気流量:500L/分間
実施例2において、表1に記載の組成に変更した以外は、実施例2と同様にして、液体Hを調整し、即溶性粒子8を得た。
実施例1において、表1に記載の組成に変更した以外は、実施例1と同様にして、液体I~Jを調整し、粒子9~10を得た。
製造した粒子1~10中の難水溶性化合物の含有量は、液体クロマトグラフ(検出器:質量分析器)を用いて定量した。結果を表2に示す。
生理食塩水10gに、造粒した粒子を薬剤濃度が1質量%となるように秤取し添加した。添加後、2回/秒のペースでハンドシェイクを行ったときの溶解状態を下記評価基準に基づき、評価した。ハンドシェイクの時間は10秒、20秒、30秒の3水準で行い、その時の溶解状態を確認した。臨床現場での実用性を考慮し、△までを許容範囲とした。結果を表2に示す。なお、完全溶解とは、目視で粒子が残っていないことが確認できる状態を意味する。
[評価基準]
◎:10秒で完全溶解
○:20秒で完全溶解
△:30秒で完全溶解
×:30秒を超える
<医薬組成物(i)の製造>
実施例1における液体Aを下記組成の液体(i)に変更した以外は、実施例1と同様にして、即溶性粒子である医薬組成物(i)を得た。
-液体(i)-
・ ニンテダニブエタンスルホン酸塩(LC laboratories社製) ・・・ 0.1質量部(ニンテダニブとして、0.083質量部)
・ ラクトース一水和物(東京化成工業製) ・・・ 9.9質量部
・ 溶媒 ・・・1,000質量部(水700質量部及びメタノール300質量部の混合溶媒)
また、得られた医薬組成物(i)中のニンテダニブエタンスルホン酸塩の含有量を上記した<粒子中の難水溶性化合物の含有量>の項目に記載の方法と同様にして定量したところ、0.1質量%(ニンテダニブとして、0.083質量%)であった。
前記医薬組成物(i)及びニンテダニブエタンスルホン酸塩(LC laboratories社製)について、ニンテダニブの量として6mg/mLとなるようにして、生理食塩水 100mLに添加し、液温度20℃にて、スターラーを用いて撹拌しながら溶解試験を行った。
図11に示したようにニンテダニブスルホン酸塩を溶解させた場合では、経時的に溶解度が低下し、不溶物の沈降が認められた。一方、前記医薬組成物(i)を溶解させた場合は、速やかに溶解し、また、経時的に溶解度が上昇した。溶解時間30分では、前記医薬組成物(i)は、ニンテダニブエタンスルホン酸塩と比較して、70倍以上の溶解度の改善が認められた。
本発明の医薬組成物が生理活性を有することの確認の一例として、ブレオマイシン肺線維症モデルマウスを用い、前記試験例1で製造した医薬組成物(i)の生理活性などを以下のようにして検証した。
<<1.群別設定>>
(1) コントロール群
ブレオマイシンの投与は行わず、生理食塩水を投与した群。投与経路は、経気道投与群のみ。
(2) 治療群
ブレオマイシン投与48時間前(以下、「Day -2」と称することがある。)に、前記医薬組成物(i)を、ニンテダニブの量として、20μg/マウス、60μg/マウス、又は120μg/マウスで投与した群。投与経路は、経気道投与群(以下、「経気道治療群」と称することがある。)、経腹腔投与群(以下、「経腹腔治療群」と称することがある。)の2通り行った。
(3) 非治療群
ブレオマイシンの投与のみ行った群。
(1) 全身状態観察
隔日又は週3日の体重測定、及び外観観察を行った。なお、20%以上の体重減少がみられた場合、安楽死を行った。
(2) 呼吸機能検査
小動物用精密呼吸機能測定装置(フレキシベント(Flexivent)、emkaTECHNOLOGIES社製)を用いて、肺線維症が完成する21日目(ブレオマイシン投与日を0日目として21日目。以下、「Day21」と称することがある。)に評価した。
(1) マウス
Balb/c雌8~10週齢(体重18~22gを想定)(6~7週齢を購入し1~2週間順化後に使用)。
(2) 薬剤 ・・・ 試験例1で製造した医薬組成物(i)
(3) ブレオマイシン(EMD-millipore Cat#203401 Bleomycine Sulfate 10mg)
(4) 麻酔(鎮静鎮痛3種混合薬:下記参照)
薬品名
・ 塩酸メデトミジン:ドミトール(1mg/mL)
・ ミダゾラム(10mg/mL)
・ 酒石酸ブトルファノール:ベトルファール(5mg/mL)
・ キシラジン
・ 滅菌PBS
・ 塩酸アチパメゾール:アンチセダン(5mg/mL)
(5) 経口気管挿管用テルモサーフロー留置針(SR-OT2225C 22G 1”)
(6) 滅菌リン酸緩衝生理食塩水(Phosphate-buffered saline:PBS)
[麻酔]
(1) ドミトール(1.875mg/1.875mL)と、ミダゾラム(20mg/2mL)と、ベトルファール(12.5mg/2.5mL)と、キシラジン(25mg粉末)と、PBS 18.625mLとを混合し、計25mLに調整した。
(2) 前記(1)で調製した液を0.22μmフィルター滅菌の後、マウスに体重10g当たり100μLで腹腔内投与した。
本試験例では、治療群として、予防治療での検証を行った。
-Day -2:医薬組成物(i)投与日-
1) 全身麻酔下で気管挿管用スタンドを使用して経口気管挿管を行った。
2) (1)コントロール群及び(3)非治療群では、PBS 50μLを気管注入した。
(2)治療群(経気道投与群)では、以下のようにして、投与直前に調整した医薬組成物(i)溶解液50μLを気管注入した。また、(2)治療群(経腹腔投与群)では、以下のようにして、投与直前に調整した高濃度投与用(120μg/マウス)の医薬組成物(i)溶解液50μLを腹腔内投与した。
・ 医薬組成物(i) 240mgを1,000μLのPBSに溶解した(ニンテダニブ 120μg/PBS 50μL)に相当)。これを、高濃度投与用(120μg/マウス)とし、一部を2倍希釈して中等度濃度投与用(60μg/マウス)とし、更に希釈して低濃度投与用(20μg/マウス)に調整した。
3) 実験終了時にアンチセダン溶解液(アンチセダン0.15mL(0.75mg/0.15mL)とPBS 9.85mLとの合計10mL)をマウスに体重10g当たり100μLで腹腔内投与し、保温パッド上で呼吸状態を確認しながら覚醒まで観察した。
1) 全身麻酔下で気管挿管用スタンドを使用して経口気管挿管を行った。
2) (1)コントロール群では、PBS 50μLを気管注入した。
(2)治療群及び(3)非治療群では、以下のようにして調整したブレオマイシン溶解液50μLを気管注入した。
・ ブレオマイシンの投与量は1~3U/1kg体重である。マウスの平均体重を20gとして投与前に20~60mU/50μLとなるように生理食塩水で最終調整した。なお、本試験では、3U/体重1kg=60mU/50μLとして投与した。
3) 実験終了時にアンチセダン溶解液(組成は、「Day -2」の項目の記載参照)をマウスに体重10g当たり100μLで腹腔内投与し、保温パッド上で呼吸状態を確認しながら覚醒まで観察した。
全身麻酔下で頸部切開の後に、気管を露出し小切開の後に気管にフレキシベントカテーテルを挿入した。挿入遠位部を絹糸で結紮のうえ、フレキシベントに接続し、呼吸機能を測定した。
図12に、コントロール群(生理食塩水投与群)、治療群(経気道治療群、経腹腔治療群:いずれも医薬組成物(i)の投与量は、ニンテダニブの量として120μg)、及び非治療群(ブレオマイシン肺線維症モデル)のマウスの体重変化を検証した結果を示す。体重変化は、特に炎症性疾患モデルでは病勢を反映すると考えられ治療効果を予測するうえで重要なパラメータであることが知られている。
図12に示されたように、全身麻酔下でのブレオマイシンの経気道投与による一時的な体重減少がいずれの群にも観察された。ブレオマイシン肺線維症モデル(非治療群)では、体重減少の遷延がみられ、投与後2週間以上経過して体重がベースラインに回復した。一方、経気道治療群では、コントロール群と比較して体重変化に差はなく、非治療群と比較して有意に体重減少が抑制された。経腹腔治療群では、経気道投与群と比較して体重減少は抑制されなかった。
なお、統計解析は、一元配置分散分析による有意差検定後にスチューデント-ニューマン-コイルス(Student-Newman-Keuls)解析を施行し、有意水準5%で有意差有りとした。
図13Aに示されたように、ブレオマイシン肺線維症モデル(非治療群:ニンテタニブの投与量0μg)では、最大吸気量の著明な低下がみられ肺容積の低下が反映された。一方、経気道治療群では、60μg及び120μg(ニンテタニブの量として)を投与した群で、非治療群と比較して最大吸気量の低下が有意に抑制された。
図13Bに示されたように、ブレオマイシン肺線維症モデル(非治療群:ニンテタニブの投与量0μg)では、肺胸郭コンプライアンスの著明な低下がみられ肺(胸郭を含む)の弾性の低下が反映された。一方、経気道治療群では、120μg(ニンテタニブの量として)を投与した群で、非治療群と比較して肺胸郭コンプライアンスの低下が有意に抑制された。
図13Cに示されたように、ブレオマイシン肺線維症モデル(非治療群:ニンテタニブの投与量0μg)では、肺組織エラスタンスの著明な増加がみられ肺の弾性抵抗の増加が反映された。一方、経気道治療群では、用量依存性に肺組織エラスタンスの改善がみられ、120μg(ニンテタニブの量として)を投与した群で、非治療群と比較して肺組織エラスタンスの増加が有意に抑制された。
図13Dに示されたように、ブレオマイシン肺線維症モデル(非治療群:ニンテタニブの投与量0μg)では、静肺コンプライアンスの著明な低下がみられ肺の弾性の低下が反映された。一方、経気道治療群では、用量依存性に静肺コンプライアンスの改善がみられ、60μgあるいは120μg(ニンテタニブの量として)を投与した群で、非治療群と比較して静肺コンプライアンスの低下が有意に抑制された。
なお、統計解析は、クラスカル-ウォリス(Kruscal-Wallis)検定による有意差検定後にボンフェローニ(Bonferroni)後解析を施行し、有意水準5%で有意差有りとした。
図14Aに示されたように、経気道治療群では、非治療群と比較して最大吸気量の低下が有意に抑制された。一方、経腹腔治療群では、非治療群と比較して最大吸気量の低下の有意な抑制は得られなかった。
図14Bに示されたように、経気道治療群では、非治療群と比較して肺胸郭コンプライアンスの低下が有意に抑制された。一方、経腹腔治療群では、非治療群と比較して肺胸郭コンプライアンスの低下の有意な抑制は得られなかった。
図14Cに示されたように、経気道治療群では、非治療群と比較して肺組織エラスタンスの増加が有意に抑制された。一方、経腹腔治療群では、非治療群と比較して肺組織エラスタンスの増加の有意な抑制は得られなかった。
図14Dに示されたように、経気道治療群では、非治療群と比較して静肺コンプライアンスの低下が有意に抑制された。一方、経腹腔治療群では、非治療群と比較して静肺コンプライアンスの低下の有意な抑制は得られなかった。
なお、統計解析は、一元配置分散分析による有意差検定後にボンフェローニ(Bonferroni)解析を施行し、有意水準5%で有意差有りとした。
また、従来、ニンテダニブの投与経路は経口投与に限られ、その低いバイオアベイラビリティから相対的に高用量での投与量が設定され、消化器症状などの有害事象から忍容性が得られずに減量や中断を余儀なくされるケースが多くみられるが、本発明の医薬組成物とすることで、経気道投与が可能となり、また、経口投与量の10分の1量でブレオマイシン肺線維症モデルにみられる各種呼吸機能パラメータの有意な改善が見出された。したがって、本発明の医薬組成物によれば、従来経口投与以外の投与経路とすることが困難であった難水溶性医薬化合物の新たな投与経路を提供することが可能となる。
<1> 水溶性基材と、難水溶性化合物とを含有する粒子を含み、
前記水溶性基材が、迅速水溶性化合物を含有し、
前記難水溶性化合物がキナーゼ阻害剤であり、非晶質状態で前記水溶性基材内に存在することを特徴とする医薬組成物である。
<2> 用時調製可能である、前記<1>に記載の医薬組成物である。
<3> 前記迅速水溶性化合物が、単糖類及び二糖類の少なくともいずれかである、前記<1>から<2>のいずれかに記載の医薬組成物である。
<4> 投与時に、水又は生理食塩水に溶解して用時調製される、前記<1>から<3>のいずれかに記載の医薬組成物である。
<5> 前記医薬組成物を水又は生理食塩水に溶解した溶液を霧化して投与する、前記<1>から<4>のいずれかに記載の医薬組成物である。
<6> 投与経路が局所投与である、前記<1>から<5>のいずれかに記載の医薬組成物である。
<7> キナーゼの活性化に起因する疾患に対して用いられる、前記<1>から<6>のいずれかに記載の医薬組成物である。
<8> 水溶性基材と、難水溶性化合物とを含有し、
前記水溶性基材が、迅速水溶性化合物を含有し、
前記難水溶性化合物が、非晶質状態で前記水溶性基材内に存在することを特徴とする機能性粒子である。
<9>前記迅速水溶性化合物が、単糖類及び二糖類の少なくともいずれかである、前記<8>に記載の機能性粒子である。
<10> 前記難水溶性化合物の含有量が、75質量%以下である、前記<8>から<9>のいずれかに記載の機能性粒子である。
<11> 前記難水溶性化合物の含有量が、10質量%以上50質量%以下である、前記<8>から<10>のいずれかに記載の機能性粒子である。
<12> 体積平均粒径(Dv)が、0.5μm以上50μm以下である、前記<9>から<11>のいずれかに記載の機能性粒子である。
<13> 前記体積平均粒径(Dv)が、0.5μm以上20μm以下である、前記<8>から<12>のいずれかに記載の機能性粒子である。
<14> 迅速水溶性化合物と、難水溶性化合物とを含有する液体を、吐出孔から吐出して液滴を形成する液滴形成工程と、
前記液滴を固化する造粒工程とを含むことを特徴とする機能性粒子の製造方法である。
<15> 前記液滴形成工程が、液柱共鳴液室内に収容された組成液に振動を付与して液柱共鳴による定在波を形成し、前記定在波の腹となる領域に、前記定在波の振幅方向に形成された前記吐出孔から前記液体を吐出することを含む、前記<14>に記載の機能性粒子の製造方法である。
また、前記<8>から<13>のいずれかに記載の機能性粒子、前記<14>から<15>のいずれかに記載の機能性粒子の製造方法によると、従来における前記諸問題を解決し、難水溶性化合物を速やかに溶解させることができる。
11 液滴形成手段
12、101 搬送気流
14 液体
19 吐出孔
21 液滴
Claims (7)
- 水溶性基材と、難水溶性化合物とを含有する粒子を含み、
前記水溶性基材が、迅速水溶性化合物を含有し、
前記難水溶性化合物がキナーゼ阻害剤であり、非晶質状態で前記水溶性基材内に存在することを特徴とする医薬組成物。 - 用時調製可能である、請求項1に記載の医薬組成物。
- 前記迅速水溶性化合物が、単糖類及び二糖類の少なくともいずれかである、請求項1から2のいずれかに記載の医薬組成物。
- 投与時に、水又は生理食塩水に溶解して用時調製される、請求項1から3のいずれかに記載の医薬組成物。
- 前記医薬組成物を水又は生理食塩水に溶解した溶液を霧化して投与する、請求項1から4のいずれかに記載の医薬組成物。
- 投与経路が局所投与である、請求項1から5のいずれかに記載の医薬組成物。
- キナーゼの活性化に起因する疾患に対して用いられる、請求項1から6のいずれかに記載の医薬組成物。
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020227001941A KR20220024756A (ko) | 2019-06-26 | 2020-01-10 | 의약 조성물 |
JP2021527336A JPWO2020261619A1 (ja) | 2019-06-26 | 2020-01-10 | |
CN202080046161.8A CN114025800A (zh) | 2019-06-26 | 2020-01-10 | 药物组合物 |
CA3144945A CA3144945A1 (en) | 2019-06-26 | 2020-01-10 | Pharmaceutical composition including particles containing a water-soluble base material and a poorly water-soluble compound |
EP20833680.0A EP3991750A4 (en) | 2019-06-26 | 2020-01-10 | PHARMACEUTICAL COMPOSITION |
US17/645,509 US20220110934A1 (en) | 2019-06-26 | 2021-12-22 | Pharmaceutical composition |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2019118289 | 2019-06-26 | ||
JP2019-118289 | 2019-06-26 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/645,509 Continuation US20220110934A1 (en) | 2019-06-26 | 2021-12-22 | Pharmaceutical composition |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2020261619A1 true WO2020261619A1 (ja) | 2020-12-30 |
Family
ID=74061599
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2020/000711 WO2020261619A1 (ja) | 2019-06-26 | 2020-01-10 | 医薬組成物 |
Country Status (7)
Country | Link |
---|---|
US (1) | US20220110934A1 (ja) |
EP (1) | EP3991750A4 (ja) |
JP (2) | JPWO2020261619A1 (ja) |
KR (2) | KR20220024756A (ja) |
CN (2) | CN114025800A (ja) |
CA (2) | CA3144945A1 (ja) |
WO (1) | WO2020261619A1 (ja) |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH11509223A (ja) * | 1995-07-14 | 1999-08-17 | ノバルティス・アクチエンゲゼルシャフト | 医薬組成物 |
JP2960169B2 (ja) | 1993-04-22 | 1999-10-06 | レイクスユニフェルジテイト・ヘント・ラボラトリウム・フォール・ファルマサイティセ・テフノロジー | 高放出性固体製剤、その製法および用途 |
JP2008292976A (ja) | 2007-03-20 | 2008-12-04 | Ricoh Co Ltd | トナーの製造方法、トナーの製造装置及びトナー |
JP2010102195A (ja) | 2008-10-24 | 2010-05-06 | Ricoh Co Ltd | トナーの製造方法及び製造装置 |
JP2010515753A (ja) * | 2007-01-10 | 2010-05-13 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | 肺内送達用免疫抑制剤組成物の送達の増強 |
JP2010280685A (ja) * | 2002-03-20 | 2010-12-16 | Elan Pharma Internatl Ltd | Mapキナーゼ阻害剤のナノ粒子組成物 |
JP4647506B2 (ja) | 2006-01-27 | 2011-03-09 | 株式会社リコー | 粒子特にトナー粒子の製造方法、トナー粒子の製造装置及びトナー |
JP5484910B2 (ja) | 2006-12-22 | 2014-05-07 | ユーハン・コーポレイション | レバプラザン含有の固体分散体及びその製造方法 |
JP2017031140A (ja) * | 2015-07-28 | 2017-02-09 | 日本化薬株式会社 | ラパマイシン又はその誘導体を含有する医薬組成物 |
JP2017160188A (ja) * | 2016-03-04 | 2017-09-14 | 株式会社リコー | 微粒子の製造方法 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL154370A0 (en) * | 2003-02-10 | 2003-09-17 | Chemagis Ltd | Solid amorphous mixtures, processes for the preparation thereof and pharmaceutical compositions containing the same |
CN100581545C (zh) * | 2005-09-29 | 2010-01-20 | 福建省微生物研究所 | 西罗莫司药物组合物及制备方法 |
US20090155359A1 (en) * | 2006-04-28 | 2009-06-18 | Lion Corporation | Granulated particles, tablets and method for producing granulated particles |
KR20100051769A (ko) * | 2008-09-30 | 2010-05-18 | 테바 파마슈티컬 인더스트리즈 리미티드 | 수니티닙 베이스 및 l-말산의 비정질 조성물 |
GB0908129D0 (en) * | 2009-05-12 | 2009-06-24 | Innovata Ltd | Composition |
EP2601973A1 (en) * | 2011-12-09 | 2013-06-12 | Laboratoires SMB SA | Dry powder formulation of azole derivative for inhalation |
US20170216211A1 (en) * | 2014-08-04 | 2017-08-03 | Sandoz Ag | Aqueous Granulation Process For Amorphous Poorly Water Soluble Drugs |
WO2017091373A1 (en) * | 2015-11-25 | 2017-06-01 | Patheon Development Services Inc. | Amorphous dispersion granules and oral dosage forms |
WO2018073839A1 (en) * | 2016-10-18 | 2018-04-26 | Mylan Laboratories Limited | Amorphous osimertinib mesylate, processes for its preparation and solid amorphous dispersions thereof |
US11878023B2 (en) * | 2017-10-25 | 2024-01-23 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Compositions and methods for delivering pharmaceutical agents |
-
2020
- 2020-01-10 KR KR1020227001941A patent/KR20220024756A/ko not_active Application Discontinuation
- 2020-01-10 CA CA3144945A patent/CA3144945A1/en active Pending
- 2020-01-10 JP JP2021527336A patent/JPWO2020261619A1/ja active Pending
- 2020-01-10 WO PCT/JP2020/000711 patent/WO2020261619A1/ja unknown
- 2020-01-10 EP EP20833680.0A patent/EP3991750A4/en active Pending
- 2020-01-10 CN CN202080046161.8A patent/CN114025800A/zh active Pending
- 2020-06-03 JP JP2020096960A patent/JP2021004234A/ja active Pending
- 2020-06-25 CN CN202080011430.7A patent/CN113395959A/zh active Pending
- 2020-06-25 CA CA3128355A patent/CA3128355C/en active Active
- 2020-06-25 KR KR1020217024189A patent/KR20210110665A/ko not_active Application Discontinuation
-
2021
- 2021-12-22 US US17/645,509 patent/US20220110934A1/en active Pending
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2960169B2 (ja) | 1993-04-22 | 1999-10-06 | レイクスユニフェルジテイト・ヘント・ラボラトリウム・フォール・ファルマサイティセ・テフノロジー | 高放出性固体製剤、その製法および用途 |
JPH11509223A (ja) * | 1995-07-14 | 1999-08-17 | ノバルティス・アクチエンゲゼルシャフト | 医薬組成物 |
JP2010280685A (ja) * | 2002-03-20 | 2010-12-16 | Elan Pharma Internatl Ltd | Mapキナーゼ阻害剤のナノ粒子組成物 |
JP4647506B2 (ja) | 2006-01-27 | 2011-03-09 | 株式会社リコー | 粒子特にトナー粒子の製造方法、トナー粒子の製造装置及びトナー |
JP5484910B2 (ja) | 2006-12-22 | 2014-05-07 | ユーハン・コーポレイション | レバプラザン含有の固体分散体及びその製造方法 |
JP2010515753A (ja) * | 2007-01-10 | 2010-05-13 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | 肺内送達用免疫抑制剤組成物の送達の増強 |
JP2008292976A (ja) | 2007-03-20 | 2008-12-04 | Ricoh Co Ltd | トナーの製造方法、トナーの製造装置及びトナー |
JP2010102195A (ja) | 2008-10-24 | 2010-05-06 | Ricoh Co Ltd | トナーの製造方法及び製造装置 |
JP2017031140A (ja) * | 2015-07-28 | 2017-02-09 | 日本化薬株式会社 | ラパマイシン又はその誘導体を含有する医薬組成物 |
JP2017160188A (ja) * | 2016-03-04 | 2017-09-14 | 株式会社リコー | 微粒子の製造方法 |
Non-Patent Citations (1)
Title |
---|
See also references of EP3991750A4 |
Also Published As
Publication number | Publication date |
---|---|
JPWO2020261619A1 (ja) | 2020-12-30 |
EP3991750A4 (en) | 2022-08-03 |
KR20210110665A (ko) | 2021-09-08 |
KR20220024756A (ko) | 2022-03-03 |
EP3991750A1 (en) | 2022-05-04 |
CN113395959A (zh) | 2021-09-14 |
CN114025800A (zh) | 2022-02-08 |
CA3128355A1 (en) | 2020-12-30 |
US20220110934A1 (en) | 2022-04-14 |
JP2021004234A (ja) | 2021-01-14 |
CA3128355C (en) | 2024-06-25 |
CA3144945A1 (en) | 2020-12-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6971043B2 (ja) | 微粒子の製造方法 | |
JP6738576B2 (ja) | エアロゾルのピルフェニドンおよびピリドンアナログの化合物、および、その使用 | |
JP2011052021A (ja) | 鼻腔送達用医薬品組成物 | |
JP2008013480A (ja) | 薬物含有微粒子およびその製造方法 | |
JP2007517011A (ja) | 経口デリバリーのための多粒子製剤 | |
US20240075029A1 (en) | Luminol for the prophylaxis and the treatment of sequelae of a sars-cov-2 infection | |
TW200418539A (en) | Particulate materials | |
Barich et al. | Physicochemical properties, formulation, and drug delivery | |
WO2020261619A1 (ja) | 医薬組成物 | |
JP6755345B2 (ja) | 不連続相および連続相からなる凝集単位を含む微粒剤形 | |
US20130164344A1 (en) | Stable powder formulation containing an anticholingeric agent | |
WO2021235425A1 (ja) | 脂質ナノ粒子を含有する粒子及びその製造方法 | |
KR101285214B1 (ko) | 향상된 용해도를 갖는 신규한 속용성 과립제형 | |
KR20150021510A (ko) | 항레트로바이러스 조성물 | |
US20220023216A1 (en) | Instantly soluble particle and method for producing the same | |
KR20240006582A (ko) | Alk-5 (tgf 베타 r1) 억제제로 폐 질환을 치료하기 위한 방법 | |
JP7503781B2 (ja) | 粒子の製造方法、並びに、それにより製造された粒子及び医薬 | |
ES2387571T3 (es) | Composición farmacéutica granulada estable de solifenacina o de su sal | |
KR102375232B1 (ko) | 비강내 에피네프린 제제 및 질환의 치료 방법 | |
JP2016504354A (ja) | 新規な微粒剤形 | |
CN116940351A (zh) | 前药组合物和治疗方法 | |
EP2609910A1 (en) | Formulations of eprotirome | |
KR20060120204A (ko) | 삼출성 중이염의 예방 및/또는 치료제 | |
JP2007186423A (ja) | 気管支拡張剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 20833680 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3144945 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2021527336 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20227001941 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2020833680 Country of ref document: EP Effective date: 20220126 |