CN113164402A - 药物制剂 - Google Patents
药物制剂 Download PDFInfo
- Publication number
- CN113164402A CN113164402A CN201980075716.9A CN201980075716A CN113164402A CN 113164402 A CN113164402 A CN 113164402A CN 201980075716 A CN201980075716 A CN 201980075716A CN 113164402 A CN113164402 A CN 113164402A
- Authority
- CN
- China
- Prior art keywords
- formulation
- dosage form
- nintedanib
- amount
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title description 2
- 239000000203 mixture Substances 0.000 claims abstract description 116
- 229960004378 nintedanib Drugs 0.000 claims abstract description 62
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical group 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 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 239000000725 suspension Substances 0.000 claims abstract description 18
- 239000007903 gelatin capsule Substances 0.000 claims abstract description 15
- 150000003904 phospholipids Chemical class 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 13
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002562 thickening agent Substances 0.000 claims abstract description 7
- 238000009472 formulation Methods 0.000 claims description 80
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 24
- -1 polyoxyethylene Polymers 0.000 claims description 19
- 239000002552 dosage form Substances 0.000 claims description 18
- 239000004094 surface-active agent Substances 0.000 claims description 14
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 12
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 12
- 235000010445 lecithin Nutrition 0.000 claims description 12
- 239000000787 lecithin Substances 0.000 claims description 12
- 229940067606 lecithin Drugs 0.000 claims description 12
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 12
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 239000004359 castor oil Substances 0.000 claims description 9
- 235000019438 castor oil Nutrition 0.000 claims description 9
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 9
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002285 corn oil Substances 0.000 claims description 7
- 235000005687 corn oil Nutrition 0.000 claims description 7
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 150000002632 lipids Chemical class 0.000 claims description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 5
- 239000003995 emulsifying agent Substances 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 4
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 4
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 3
- 229940068968 polysorbate 80 Drugs 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 239000003549 soybean oil Substances 0.000 claims description 3
- 235000012424 soybean oil Nutrition 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 3
- 239000008158 vegetable oil Substances 0.000 claims description 3
- OVYMWJFNQQOJBU-UHFFFAOYSA-N 1-octanoyloxypropan-2-yl octanoate Chemical compound CCCCCCCC(=O)OCC(C)OC(=O)CCCCCCC OVYMWJFNQQOJBU-UHFFFAOYSA-N 0.000 claims description 2
- FUWVMBCPMRAWPG-UHFFFAOYSA-N 2,3-dihydroxypropyl 2-hydroxyoctadecanoate Chemical compound CCCCCCCCCCCCCCCCC(O)C(=O)OCC(O)CO FUWVMBCPMRAWPG-UHFFFAOYSA-N 0.000 claims description 2
- GHHURQMJLARIDK-UHFFFAOYSA-N 2-hydroxypropyl octanoate Chemical compound CCCCCCCC(=O)OCC(C)O GHHURQMJLARIDK-UHFFFAOYSA-N 0.000 claims description 2
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 2
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 claims description 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 claims description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 2
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims description 2
- 235000013871 bee wax Nutrition 0.000 claims description 2
- 239000012166 beeswax Substances 0.000 claims description 2
- 229940092738 beeswax Drugs 0.000 claims description 2
- 229920001400 block copolymer Polymers 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 239000001087 glyceryl triacetate Substances 0.000 claims description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- 125000002669 linoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- 229940113116 polyethylene glycol 1000 Drugs 0.000 claims description 2
- 229940057838 polyethylene glycol 4000 Drugs 0.000 claims description 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 claims description 2
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 claims description 2
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 2
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims description 2
- 229920001451 polypropylene glycol Polymers 0.000 claims description 2
- 229940068977 polysorbate 20 Drugs 0.000 claims description 2
- 229950006451 sorbitan laurate Drugs 0.000 claims description 2
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims description 2
- 235000011076 sorbitan monostearate Nutrition 0.000 claims description 2
- 239000001587 sorbitan monostearate Substances 0.000 claims description 2
- 229940035048 sorbitan monostearate Drugs 0.000 claims description 2
- 229950004959 sorbitan oleate Drugs 0.000 claims description 2
- 229950003429 sorbitan palmitate Drugs 0.000 claims description 2
- 229950011392 sorbitan stearate Drugs 0.000 claims description 2
- 229960002622 triacetin Drugs 0.000 claims description 2
- 239000001069 triethyl citrate Substances 0.000 claims description 2
- 235000013769 triethyl citrate Nutrition 0.000 claims description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 2
- HDIFHQMREAYYJW-XGXNLDPDSA-N Glyceryl Ricinoleate Chemical compound CCCCCC[C@@H](O)C\C=C/CCCCCCCC(=O)OCC(O)CO HDIFHQMREAYYJW-XGXNLDPDSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims 1
- 229960004274 stearic acid Drugs 0.000 claims 1
- 239000002775 capsule Substances 0.000 description 22
- 239000003814 drug Substances 0.000 description 22
- 238000000034 method Methods 0.000 description 21
- 229940079593 drug Drugs 0.000 description 19
- 238000004090 dissolution Methods 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 12
- 239000002245 particle Substances 0.000 description 11
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 10
- 239000013543 active substance Substances 0.000 description 10
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 108010010803 Gelatin Proteins 0.000 description 7
- 239000008273 gelatin Substances 0.000 description 7
- 229920000159 gelatin Polymers 0.000 description 7
- 235000019322 gelatine Nutrition 0.000 description 7
- 235000011852 gelatine desserts Nutrition 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 6
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- MMMVNAGRWOJNMW-FJBFXRHMSA-N nintedanib esylate Chemical compound CCS(O)(=O)=O.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 MMMVNAGRWOJNMW-FJBFXRHMSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 238000005538 encapsulation Methods 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 125000005456 glyceride group Chemical group 0.000 description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- 239000000679 carrageenan Substances 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 229940113118 carrageenan Drugs 0.000 description 3
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000012738 dissolution medium Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 238000000265 homogenisation Methods 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 3
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 2
- OIQOAYVCKAHSEJ-UHFFFAOYSA-N 2-[2,3-bis(2-hydroxyethoxy)propoxy]ethanol;hexadecanoic acid;octadecanoic acid Chemical compound OCCOCC(OCCO)COCCO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O OIQOAYVCKAHSEJ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108091008794 FGF receptors Proteins 0.000 description 2
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 239000008365 aqueous carrier Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- NGPTYCZGBCGWBE-UHFFFAOYSA-N decanoic acid hexadecanoic acid octadecanoic acid octanoic acid propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O NGPTYCZGBCGWBE-UHFFFAOYSA-N 0.000 description 2
- 229940075894 denatured ethanol Drugs 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 239000007919 dispersible tablet Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 229940116364 hard fat Drugs 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002105 nanoparticle Substances 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000007639 printing Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- 239000004034 viscosity adjusting agent Substances 0.000 description 2
- LSPHULWDVZXLIL-UHFFFAOYSA-N (+/-)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- GNSDEDOVXZDMKM-UHFFFAOYSA-N 1,2-didecanoylglycerol Chemical compound CCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCC GNSDEDOVXZDMKM-UHFFFAOYSA-N 0.000 description 1
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- NFIHXTUNNGIYRF-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate Chemical compound CCCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCCC NFIHXTUNNGIYRF-UHFFFAOYSA-N 0.000 description 1
- BHIZVZJETFVJMJ-UHFFFAOYSA-N 2-hydroxypropyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(C)O BHIZVZJETFVJMJ-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 101100248253 Arabidopsis thaliana RH40 gene Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 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
- 206010061818 Disease progression Diseases 0.000 description 1
- 229920005682 EO-PO block copolymer Polymers 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 201000003838 Idiopathic interstitial pneumonia Diseases 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 235000019486 Sunflower oil Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N alpha-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000000498 ball milling Methods 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 239000000828 canola oil Substances 0.000 description 1
- 235000019519 canola oil Nutrition 0.000 description 1
- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- MRKZAZMYXYSBDG-UHFFFAOYSA-N cyclopentyl propanoate Chemical compound CCC(=O)OC1CCCC1 MRKZAZMYXYSBDG-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- STORWMDPIHOSMF-UHFFFAOYSA-N decanoic acid;octanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCC(O)=O.CCCCCCCCCC(O)=O STORWMDPIHOSMF-UHFFFAOYSA-N 0.000 description 1
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 150000002327 glycerophospholipids Chemical class 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007641 inkjet printing Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 238000010902 jet-milling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000944 linseed oil Substances 0.000 description 1
- 235000021388 linseed oil Nutrition 0.000 description 1
- 230000004130 lipolysis Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 238000007645 offset printing Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000003239 periodontal effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229940026235 propylene glycol monolaurate Drugs 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229940066675 ricinoleate Drugs 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
- A61K9/4825—Proteins, e.g. gelatin
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Botany (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Dispersion Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本申请涉及软明胶胶囊,其包含尼达尼布或其药学上可接受的盐在中链甘油三酯和载体系统中的悬浮液组合物,其中所述载体系统包含增溶剂、磷脂、增稠剂及其混合物。
Description
相关申请的交叉引用
本申请要求2018年10月15日提交的印度申请201821039072的优先权,将其内容以其整体援引加入本文。
发明领域
本发明涉及由胶囊壳和胶囊填充物组成的软明胶胶囊。更具体地,所述胶囊填充物为包含尼达尼布(nintedanib)或其药学上可接受的盐、中链甘油三酯、至少一种载体系统及其药学上可接受的赋形剂的药物制剂。本发明还提供制备所述制剂的方法以及所述制剂在治疗和/或预防特发性肺纤维化中的用途。
发明背景
特发性肺纤维化是一种慢性进行性疾病,其特征为肺中病因不明且进行性纤维化病变。它是最常见的特发性间质性肺炎。除肺移植外,目前尚无预防方法或具有特定治疗效果的国际公认的治疗方法。全球患病率为10万人中有14至43例。由于病情发展迅速和预后不良,该疾病的致残率和死亡率极高。患者的平均预期寿命是诊断后3至5年,或出现症状后4至6年。长期以来,特发性肺纤维化与其他间质性肺炎一样,被认为是一种肺部炎性疾病。然而,随着其发病机制研究的不断深入,治疗策略已经从抗炎性转变为了特发性肺纤维化病理生理学的特定方面。
尼达尼布是用于治疗特发性肺纤维化的三重酪氨酸激酶抑制剂和生长因子拮抗剂。尼达尼布在已显示出在肺纤维化的发病机制中具有潜在作用的生长因子受体中发挥作用。这些中最重要的是血小板源性生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)以及血管内皮生长因子受体(VEGFR)。
尼达尼布乙磺酸盐的化学名称为乙磺酸-(3Z)-3-{[(4-{甲基-[(4-甲基哌嗪-1-基)乙酰基]氨基}苯基)氨基]-(苯基)亚甲基}-2-氧代-2,3-二氢-1H-吲哚-6-甲酸甲酯(1∶1),具有以下化学结构:。尼达尼布或其药学上可接受的盐(特别是乙磺酸盐)在中性条件下溶解性较差,导致生物利用度较低,仅为4.7%,这大大限制了其临床应用。
配制低水溶性药物是困难的,例如那些用于口服给药且生物利用度低的溶解度小于约1份/10,000份的药物。在活性药物成分(API)水溶性差的情况下,传统的配制策略已不再足以或不能用于实现可接受的溶解度,进而实现生物利用度。尽管有许多其它供选择的技术正在研发当中,但基于脂质的制剂在提高此类亲脂性药物的口服生物利用度方面似乎大有前景。此类制剂通常利用性质上为液体或半固体的赋形剂。对于溶解性特别差的药物,已经提出了一些解决口服生物利用度低的手段。例如,US5645856提出了用油、亲水性表面活性剂和亲脂性表面活性剂配制疏水性药物,其实质上降低了亲水性表面活性剂对油的体内脂解的抑制作用,这种脂解被认为是促进药物生物利用度的因素。
US6309663提出了包含表面活性剂组合的药物组合物,所述表面活性剂组合据说用于增强亲水性治疗剂的生物吸收性。诸如磷脂酰胆碱的磷脂再次列在示例性表面活性剂中。
US6464987提出了流体药物组合物,其包含活性物质、3-55重量%的磷脂、16-72重量%的溶剂和4-52重量%的脂肪酸。
US5538737提出了含油包水乳液的胶囊,其中水溶性药物盐溶解在乳液的水相中,并且其中油相包含油和乳化剂。其中提到的油为中链甘油三酯;其中提到的乳化剂为磷脂,例如磷脂酰胆碱。
US2004/0063794和US5536729提出了在包含磷脂溶液的载体中包含浓度为约0.1mg/ml至约50mg/ml的雷帕霉素的口服制剂。
在尼达尼布的情况下,考虑到药物的溶解度和生物利用度,已经做出了一些尝试来改善尼达尼布的溶解度,并提供药物制剂。US 9907756公开了胶囊剂,其包含尼达尼布在1-90重量%中链甘油三酯、1-30重量%硬脂和0.1-10重量%卵磷脂中的脂质悬浮液。然而,药物从制剂中的释放会受单种载体赋形剂或载体赋形剂混合物及其在制剂中的量的影响。悬浮液制剂的物理稳定性受如沉降速率、结块等因素影响。
CN108078952公开了包含尼达尼布乙磺酸盐悬浮液的软胶囊,尼达尼布乙磺酸盐的粒径分布范围D90为40μm至80μm。减小活性物质的粒径、将其加入到制剂中,以及保持粒径大小需要特殊的制造工艺,而且成本高昂。此外,溶出曲线仅取决于活性物质的粒径。
CN107184549提供含尼达尼布自微乳制剂的胶囊剂,其中所述微乳制剂的液滴大小介于10至100nm之间,并且载体介质被设计为在胃中自发形成乳液,从而利于尼达尼布的吸收。这些系统是自微乳化给药系统(SMEDDS)。这种系统的主要缺点是必须进行精确的制备,即使组分的微小变化也不会导致在胃中形成乳剂,并因此破坏其有益特性。此外,控制活性物质的粒径在该系统中发挥重要作用。
CN105963268公开了一种分散片剂,其包含尼达尼布和片剂分散所必须的其它药学上可接受的赋形剂。溶解性低的药物可能不能溶解在常规剂型的赋形剂中,因此导致无含量均一性,且含量偏差较高。此外,分散片剂快速释放活性物质会影响制剂的药理效应。
尽管现有技术公开了针对解决尼达尼布溶解性问题的不同类型的组合物,但这些提高溶解性的技术大多涉及关键而繁琐的制备工艺,使用许多赋形剂,或者是根据尼达尼布的具体物理化学特性进行修改。
因此,需要研发一种能克服现有制剂的缺点、具有良好的物理稳定性、具有成本效益、能够通过简单的制备技术生产并且能够最大化尼达尼布在该剂型中的溶解度以及改善其生物利用度的的尼达尼布剂型。
发明目的
本发明的目的在于提供软凝胶胶囊制剂,其包含具有改善的溶解度和生物利用度的尼达尼布或其药学上可接受的盐和载体系统的悬浮液。
本发明的另一个目的在于提供药物组合物,其包含尼达尼布或其药学上可接受的盐、基本上非水性的载体系统以及任选存在的药学上可接受的赋形剂。
本发明的另一个目的在于提供用于制备包含尼达尼布或其药学上可接受的盐、溶剂合物、水合物、酯、衍生物及其一种或多种药学上可接受的赋形剂的药物组合物的方法。
本发明的另一个目的在于提供治疗特发性肺纤维化的方法,其给药包含尼达尼布或其药学上可接受的盐、溶剂合物、水合物、酯、衍生物及其一种或多种药学上可接受的赋形剂的药物组合物。
发明概述
根据本发明的方面提供软凝胶胶囊组合物,其包含具有改善的溶解度和生物利用度的尼达尼布或其药学上可接受的盐和载体系统的悬浮液。
根据本发明的另一个方面提供药物组合物,其包含尼达尼布、基本上非水性的载体系统以及任选存在的药学上可接受的赋形剂。
根据本发明的另一个方面提供用于制备包含尼达尼布或其药学上可接受的盐、溶剂合物、水合物、酯、衍生物及其一种或多种药学上可接受的赋形剂的药物组合物的方法。
根据本发明的又一个方面提供治疗特发性肺纤维化的方法,其给药包含尼达尼布或其药学上可接受的盐、溶剂合物、水合物、酯、衍生物及其一种或多种药学上可接受的赋形剂的药物组合物。
根据另一个方面提供包含尼达尼布或其药学上可接受的盐、溶剂合物、水合物、酯、衍生物及其一种或多种药学上可接受的赋形剂的药物组合物在制备用于治疗特发性肺纤维化的药物中的用途。
附图简要说明
图1显示市售制剂和本发明实施例1的制剂的溶出曲线。
图2显示市售制剂和本发明实施例3的制剂的溶出曲线。
发明详述
尼达尼布微溶于水,因此,配制易于制备且能减轻溶解性和生物利用度问题的合适的尼达尼布组合物是一个挑战。载体系统在低水溶性药物的配制中起着重要作用,因为它影响着制剂的物理稳定性、制剂中活性物质以所需速率的溶出和释放。
因此,本发明人在进行了严格的实验之后发现,可以通过研发一种液体和/或半固体组合物(优选为具有合适载体系统的尼达尼布悬浮液制剂)来改善尼达尼布的溶解度性质和生物利用度。本发明的发明人在筛选了一系列载体系统后,研发出了包含在最佳量的合适载体系统中的尼达尼布的药学上可接受的液体和/或半固体剂型。
术语“尼达尼布”以广义上使用,不仅包括“尼达尼布游离碱”本身,还包括其药学上可接受的盐、药学上可接受的溶剂合物、药学上可接受的水合物、药学上可接受的脂、药学上可接受的对映异构体、药学上可接受的衍生物、药学上可接受的多晶型物、药学上可接受的前药、药学上可接受的复合物等。
如本文所用的,术语“盐”是指衍生自无机酸或有机酸的盐。
合适盐的实例包括但不限于,乙酸盐、己二酸盐、海藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、双葡糖酸盐、环戊丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、已酸盐、富马酸盐、盐酸盐、碳酸盐、碳酸氢盐、氢溴酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、棕榈酸盐(palmoate)、果胶酸盐、过硫酸盐、2-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、硝酸盐、酒石酸盐、磺酸盐、硫氰酸盐、甲苯磺酸盐、甲磺酸盐和十一烷酸盐。优选地,本制剂中使用的盐为尼达尼布乙磺酸盐。
根据一个实施方案,本发明的药物制剂可包含治疗有效量的尼达尼布乙磺酸盐,其量为制剂总重量的约20-60%w/w,优选为25-55%w/w,优选为30-50%w/w。最优选地,尼达尼布乙磺酸盐以制剂总重量的43%w/w存在。
整个说明书中所提到的术语“药学上可接受的”应被用于与所使用的活性物质相容的载体、稀释剂或赋形剂。
本文中的术语“口服给药”是指经口向个体给药,即其中组合物立即被吞咽的给药。本文中“口服给药”与口腔内给药(例如,舌下或含服给药,或局部给药至诸如牙周组织的口内组织)不同,不包括立即吞咽组合物。
术语“悬浮液”是指固体颗粒和液体的非均匀混合物。
本文中的“载体系统”包含尼达尼布盐均匀分布在其中的组分。在优选实施方案中,药物载体系统被封装在适合于口服给药的胶囊壳内。所述载体是“基本上非水性的”,即不含水,或含水量为0至小于约5重量%。
本发明制剂的载体系统包含溶解药物或增强药物溶解性的中链甘油三酯、磷脂、增溶剂、表面活性剂、乳化剂或其混合物,额外存在粘度调节剂。载体系统的成分在制剂中发挥重要作用,因为尼达尼布是低溶解性药物。
存在于载体系统中的中链甘油三酯选自含有8至10个碳原子的饱和脂肪酸的甘油三酯。合适的甘油酯材料包括但不限于,中链至长链甘油单酯、甘油二酯和甘油三酯。因此,包含辛酰基和癸酰基链的甘油酯材料(例如辛酸/癸酸甘油单酯、辛酸/癸酸甘油二酯、辛酸/癸酸甘油三酯)是本文中“中链”甘油酯材料的实例。合适的中链甘油三酯材料实例是辛酸/癸酸甘油三酯产品,例如Captex 355 EPTM、Miglyol 812N,以及基本与其等同的产品。合适的长链甘油三酯实例包括任何药学上可接受的植物油,例如芥花油、椰子油、玉米油、亚麻籽油、红花油、大豆油和葵花油以及此类油的混合物。在实施方案中,甘油三酯以制剂的约10-80%w/w、约15-70%w/w的量存在。优选地,中链甘油三酯以制剂的25-40%w/w的量存在。
可用于本发明制剂的磷脂是通过水解产生磷酸、脂肪酸、醇和含氮碱的磷酸酯。可用于本发明制剂的磷脂选自但不限于,磷脂酰胆碱、磷脂酰丝氨酸、磷酯酰乙醇胺及其混合物。在一个实施方案中,所述组合物包含甘油磷脂(包括磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰肌醇、磷脂酰丝氨酸和磷脂酸)的混合物,并且被称为卵磷脂。本发明中使用的卵磷脂得自诸如蛋黄的动物源,但通常优选地是植物来源。大豆是特别丰富的卵磷脂来源,其可提供用于本发明的磷脂酰胆碱。
在实施方案中,掺入本发明制剂中的卵磷脂的量为总制剂的约0.1-35%w/w,更优选为制剂的约1-30%w/w,最优选为制剂的约0.5-25%w/w。在最优选的实施方案中,卵磷脂掺入的量为总制剂的11-20%w/w。
可用于包含尼达尼布胶囊的药物组合物的合适的增溶剂包括但不限于,亚油酰聚氧乙烯-6-甘油酯(lineleoyl polyoxyl-6-glyceride)、玉米油甘油单酯、玉米油甘油二酯、玉米油甘油三酯或其混合物。在另一个实施方案中,所述载体包括44/14。44/14。可包含的合适的二醇为分子量为约200g/mol至约1,000g/mol的丙二醇和聚乙二醇(PEG),例如,平均分子量为约400g/mol的PEG 400。因此,在一个实施方案中,一种或多种二醇以载体系统重量的至少约1%,但小于约50%w/w,例如小于约30%、小于约20%、小于约15%或小于约10%的总二醇量存在。在另一个实施方案中,所述载体基本上不含二醇。
可用于包含尼达尼布胶囊的药物组合物的合适的表面活性剂包括但不限于,两性、非离子型、阳离子或阴离子表面活性剂,例如但不限于聚氧乙烯蓖麻油衍生物(例如,聚氧乙烯甘油三蓖麻油酸酯或聚氧乙烯蓖麻油(或聚氧乙烯甘油氧基硬脂酸酯(polyoxyethylene glycerol oxystearate)、甘油聚乙二醇氧基硬脂酸酯(glycerolpolyethylene glycol oxystearate)、聚乙二醇氢化蓖麻油),或环氧乙烷与环氧丙烷的嵌段共聚物(也称为聚氧乙烯聚氧丙烯嵌段共聚物)或聚氧乙烯聚丙二醇或聚氧乙烯山梨醇酐的单脂肪酸酯、聚氧乙烯山梨醇酐单硬脂酸酯、聚氧乙烯山梨醇酐单棕榈酸酯、聚氧乙烯山梨醇酐单月桂酸酯、丙二醇单月桂酸酯、丙二醇二辛酸酯/二癸酸酯或山梨醇酐脂肪酸酯(包括山梨醇酐月桂酸酯、山梨醇酐单硬脂酸酯、辛酰己酰聚乙二醇甘油酯(Labrasol)、十八烷酸(Labrafil)山梨醇酐油酸酯、山梨醇酐棕榈酸酯、山梨醇酐硬脂酸酯)、丙二醇单辛酸酯、大豆油、植物油、三乙酸甘油酯、柠檬酸三乙酯、聚乙二醇甘油-羟基硬脂酸酯(例如,商品名称为例如HRE 40PH)或聚乙二醇甘油-蓖麻醇酸酯(也称为聚氧乙烯蓖麻油,商品名为例如EL、RH40或RO 35PH)或其混合物。优选地,聚氧乙烯蓖麻油(Kolliphor EL)、辛酰己酰聚乙二醇甘油酯(Labrasol)、十八烷酸(Labrafil)所使用的量为制剂的10-30%w/w。术语“增溶剂”、“表面活性剂”和“乳化剂”在本说明书中可互换地使用。
即使所存在的二醇或甘油酯材料的量足以溶解药物时,所得的载体溶液和/或药物载体系统也可能相当粘稠且处理困难或不便。在这种情况下,向所述载体系统中加入有效量的粘度调节剂或增稠剂,以提供可接受的期望粘度。在优选实施方案中,在本发明的制剂中使用硬脂(Softisan 378)。增稠剂的一些其他实例是半固态聚乙二醇(优选为聚乙二醇4000)或形成油凝胶的赋形剂(例如,胶体二氧化硅(colloidal silica)或膨润土),或蜂蜡、单硬脂酸甘油酯、氢化植物油、部分氢化植物油或硬脂。可用于本发明的药物组合物的一些其他粘度增强剂/增粘剂包括但不限于,甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟乙基丙基纤维素、淀粉(例如,玉米淀粉、马铃薯淀粉、大米淀粉、木薯淀粉和小麦淀粉)、羧乙烯基聚合物(卡波姆,例如)、羧甲基纤维素及其盐、微晶纤维素和阿拉伯胶、瓜尔胶和黄原胶及其混合物。优选增稠剂为硬脂,其量为总制剂的10-30%。
在实施方案中,本发明的制剂中可包含含有合适的磷脂和增溶剂组合的预混产品。可以包含在本发明的制剂中的磷脂和增溶剂产品的一些预混混合物是Phosal 50PGTM、Phosal 53MCTTM、Phosal 50SA+TM及其混合物。这些预混产品的磷脂酰胆碱组分衍生自大豆卵磷脂。在一些实施方案中,诸如Phosal 50PGTM、Phosal 53MCTTM或Phosal 50SA+TM的预混产品基本构成低水溶性药物的整个载体系统。在其他实施方案中,也存在其他成分,例如乙醇(除所述预混产品中可能存在的任何物质外)、诸如聚山梨醇酯80的非磷脂表面活性剂、聚乙二醇和/或其他成分。在实施方案中,载体中包含Phosal 53MCTTM或与其基本等同的预混产品,其量为制剂的约0.5-65%、约1-50%w/w。
所述载体系统还可包含药学上可接受的非磷脂表面活性剂,例如聚山梨醇酯80、聚山梨醇酯20、维生素E TPGS、d-a-生育酚聚乙二醇1000琥珀酸酯可以以制剂的1%至约25%w/w的量包含。
在本发明的一个方面中,所述药物组合物可包含使具有肠溶聚合物包衣的胶囊对胃液具有抵抗力并在肠中可溶的赋形剂。本发明的制剂中可包含的此类其他赋形剂的实例为诸如乳糖、淀粉、二氧化硅等的稀释剂,以及诸如聚丙烯酸酯、高分子量PEG或纤维素衍生物(例如羟丙基甲基纤维素(HPMC))的聚合物或其混合物。
整个说明书中提到的术语“液体和/或半固体”是指尼达尼布和任选存在的一种或多种药学上可接受的赋形剂,其以溶液形式和/或部分呈细碎的颗粒形式,自由地悬浮在合适的媒介物中,并封装在软的和硬的明胶胶囊中。
软明胶胶囊是用于液体、混悬剂、糊剂等给药的合适剂型。软明胶胶囊是有效的递送系统,特别是对于溶解性差的药物,因为胶囊中可含有有助于增加药物在体内膜中的溶解度或渗透性的液体和/或半固体成分。此类液体和/或半固体成分难以包含在诸如片剂的任何其他固体剂型中。
根据一个实施方案,本发明提供尼达尼布或其药学上可接受的盐与合适的载体系统填充在包含明胶、角叉菜胶或HPMC的壳中的悬浮液组合物。
在本发明的优选实施方案中,本发明的制剂包含填充在明胶胶囊壳中的治疗有效量的尼达尼布、11%w/w的卵磷脂、硬脂、中链甘油三酯的悬浮液。
在本发明的另一个优选实施方案中,本发明的制剂包含填充在明胶胶囊壳中的液体混合物,所述液体混合物包含治疗有效量的尼达尼布、聚氧乙烯蓖麻油、硬脂、中链甘油三酯。
在实施方案中,本发明制剂的溶出曲线与市售制剂的溶出曲线相当。
换言之,尼达尼布可部分呈溶液形式和/或部分呈细碎的颗粒形式,自由悬浮在液体和/或半固体中,这使得尼达尼布在肠溶性明胶、角叉菜胶或HPMC壳溶解时被容易地吸收。
本发明的药物组合物解决了尼达尼布的溶解度和生物利用度问题,并且比现有的尼达尼布剂型更有优势。
因此,本发明还提供药物组合物,其包含由明胶、角叉菜胶或HPMC制成的胶囊形式的尼达尼布,以及任选存在的一种或多种药学上可接受的赋形剂。
根据本发明的另一个实施方案,包含尼达尼布胶囊的药物组合物可包含治疗有效量(小于常规给药的每日剂量)的尼达尼布。
在本发明的另一个方面中,本发明的药物组合物还可配制为合适的口服液体剂型,包括但不限于乳剂、溶剂、混悬剂、糖浆剂和酏剂。
水溶性差的药物通常需要高剂量,才能在口服给药后达到治疗性的血药浓度。非常期望改善溶出程度和溶出率,因为这可以导致口服生物利用度更可再现,随后会导致剂量减少以及更可靠的治疗。
药物颗粒的物理改性(例如微粉化)旨在增加粉末颗粒的表面积、溶解度和/或润湿性。微粉化用于通过增加颗粒表面或通过减小颗粒大小使活性物质到达其作用部位来提高药物活性。可以通过诸如但不限于球磨、喷射研磨、超声处理、均质化和溶剂沉淀的任何方法获得微粉化形式的活性物质。
本发明的药物组合物还可包含纳米尺寸形式的活性物质。本发明的纳米颗粒可以通过例如但不限于研磨、沉淀、均质化、高压均质化、喷雾干燥、喷雾冷冻干燥、超临界流体技术、复乳/溶剂蒸发法、PRINT(非浸润模板微粒印制技术(Particle replication innon-wetting templates))、热缩合和超声波的任何方法获得。
本发明还提供制备本发明的药物组合物的方法。脂质悬浮液制剂可以通过文献中已知的常规制剂制备方法制备,即通过在预定温度下以预定顺序混合成分来获得均质悬浮液。特别地,在制备本发明的脂质悬浮液制剂期间,将硬脂和部分中链甘油三酯在处理单元中进行预混合。随后再加入卵磷脂、其余的中链甘油三酯以及活性物质。将悬浮液混合、均质化、脱气并最终进行筛分以制备所述制剂(填充混合物)。将明胶基本质量组分在升高的温度下混合和溶解。在调整了封装机后,采用旋转模工艺将填充混合料加工成软明胶胶囊。封装后,使用丙酮变性的乙醇(含有少量53MCT)(此处用作防粘剂)从胶囊表面去除痕量的润滑剂中链甘油三酯。使用旋转干燥器进行初始干燥。将胶囊放置在托盘上,进行最终干燥步骤。在15-26℃和低相对湿度下进行干燥。在对胶囊进行100%目测检查以分离变形或泄漏的胶囊后,对胶囊进行大小分类,并使用丙酮变性的乙醇进行进一步洗涤。最后,使用胶印工艺或喷墨打印技术对胶囊进行压印。或者,可利用丝带打印技术进行胶囊压印。
本发明还提供治疗特发性肺纤维化的方法,所述方法包括给药治疗有效量的本发明的药物组合物。
本发明还提供所述药物组合物在制备用于治疗特发性肺纤维化的药物中的用途。
以下实施例仅出于说明本发明的目的,而不以任何方式限制本发明的范围。
实施例1:尼达尼布软凝胶胶囊的制剂1
表1
方法
分配赋形剂,并将其在夹套制造容器中混合合适的时间。将混合物在预先选择的设定参数下进行均质化。在合适的夹套制造容器中制造明胶壳。使用封装机将混合物填充入软明胶胶囊。
实施例2:尼达尼布软明胶胶囊的体外溶出
市售制剂和实施例1的制剂(制剂1)在溶出介质(USP II型/900ml GB pH 1.2/35rpm/37℃/120分钟)以及Infinity(200RPM 10分钟)中的对比体外溶出数据如下表2所示:
表2
时间间隔(分钟) | 市售制剂 | 实施例1的制剂 |
15 | 19 | 22 |
20 | 27 | 30 |
30 | 50 | 53 |
45 | 77 | 82 |
60 | 92 | 95 |
90 | 96 | 99 |
120 | 96 | 99 |
实施例3:尼达尼布软凝胶胶囊的制剂2
表3
方法
分配赋形剂,并将其在夹套制造容器中混合合适的时间。将混合物在预先选择的设定参数下进行均质化。在合适的夹套制造容器中制造明胶壳。使用封装机将该混合物填充入软明胶胶囊。
实施例4:尼达尼布软明胶胶囊的体外溶出
市售制剂和实施例3的制剂(制剂2)在溶出介质(USP II型/900ml GB pH 1.2/35rpm/37℃/120分钟)以及Infinity(200RPM 10分钟)中的对比体外溶出数据如下表4所示:
表4
时间间隔(分钟) | 市售制剂 | 实施例3的制剂2 |
15 | 19 | 39 |
20 | 27 | 48 |
30 | 50 | 58 |
45 | 77 | 75 |
60 | 92 | 87 |
90 | 96 | 94 |
120 | 96 | 97 |
实施例5:尼达尼布软凝胶胶囊的制剂3
表5
序号 | 成分 | 量(%) |
混合物 | ||
1. | 尼达尼布 | 43.00 |
2. | 卵磷脂 | 11.00- |
3. | 硬脂(Softisan 378) | 20.00 |
4. | 中链甘油三酯(Miglyol 812N) | 30.00 |
药物重量 | 100 |
制备方法:
分配赋形剂,并将其在夹套制造容器中混合合适的时间。将混合物在预先选择的设定参数下进行均质化。在合适的夹套制造容器中制造明胶壳。使用封装机将该混合物填充入软明胶胶囊。
实施例6:尼达尼布软明胶胶囊的体外溶出
市售制剂和实施例5的制剂(制剂3)在溶出介质(USP II型/900ml GB pH 1.2/35rpm/37℃/120分钟)以及Infinity(200RPM 10分钟)中的对比体外溶出数据如下表6所示:
表6:
时间(分钟) | 市售制剂 | 制剂3 |
10 | 67 | 41 |
15 | 85 | 68 |
20 | 93 | 81 |
30 | 98 | 92 |
45 | 99 | 98 |
结论:因此得出结论,包含11.0%卵磷脂的本发明制剂的释放特性显示出与市售制剂相当的溶出曲线。
对于本领域技术人员而言明显的是,在不脱离本发明精神的情况下,可以对本文公开的本发明进行各种替换和修改。因此,应当理解,尽管已经通过优选实施方案和任选的特征具体公开了本发明,但是本领域技术人员可以对本文公开的概念进行修改和变型,并且这样的修改和变型视为落入本发明的范围内。
应当理解,本文使用的措词和术语是出于描述的目的,而不应被认为是限制性的。本文中“包括”、“包含”或“具有”及其变体的使用意在涵盖其后列出的项目及其等同物以及其他项目。
必须注意的是,除非上下文另有明确规定,否则本说明书和所附权利要求书中使用的单数形式“a”、“an”和“then”均包含复数指代。因此,例如,提及“助溶剂”是指单一助溶剂,或两种或更多种助溶剂的组合等。
Claims (15)
1.药物剂型,其包含用于口服给药的软明胶胶囊、包含以下组分的悬浮液的药物制剂:
(a)治疗有效量的尼达尼布或其药学上可接受的盐;
(b)中链甘油三酯或其混合物;
(c)载体系统;以及
(d)任选地包含其它药学上可接受的赋形剂。
2.如权利要求1所述的剂型,其中所述制剂包含治疗有效量的尼达尼布乙磺酸盐。
3.如权利要求1所述的剂型,其中所述尼达尼布乙磺酸盐以制剂总重量的约30%w/w至约50%w/w的量存在。
4.如权利要求1所述的剂型,其中所述中链甘油三酯以总制剂的25-40%w/w的量存在。
5.如权利要求1所述的剂型,其中所述载体系统包含磷脂、表面活性剂、增溶剂、乳化剂、增稠剂及其混合物。
6.如权利要求5所述的剂型,其中所述磷脂是卵磷脂,其以总制剂的11%-20%的量存在。
7.如权利要求5所述的剂型,其中所述表面活性剂选自聚氧乙烯蓖麻油衍生物、聚氧乙烯聚氧丙烯嵌段共聚物或聚氧乙烯聚丙二醇,或聚氧乙烯山梨醇酐单脂肪酸酯、聚氧乙烯山梨醇酐单硬脂酸酯、聚氧乙烯山梨醇酐单棕榈酸酯、聚氧乙烯山梨醇酐单月桂酸酯、丙二醇单月桂酸酯、丙二醇二辛酸酯、山梨醇酐月桂酸酯、山梨醇酐单硬脂酸酯、辛酰己酰聚乙二醇甘油酯、十八烷酸、山梨醇酐油酸酯、山梨醇酐棕榈酸酯、山梨醇酐硬脂酸酯、丙二醇单辛酸酯、大豆油、植物油、三乙酸甘油酯、柠檬酸三乙酯、聚乙二醇甘油-羟基硬脂酸酯、聚乙二醇甘油-蓖麻醇酸酯或其混合物。
8.如权利要求7所述的剂型,其中所述表面活性剂是聚氧乙烯蓖麻油、辛酰己酰聚乙二醇甘油酯、十八烷酸,其以制剂的10%-30%的量存在使用。
9.如权利要求l所述的剂型,其中所述增溶剂选自亚油酰聚氧乙烯-6-甘油酯、玉米油甘油单酯、玉米油甘油二酯、玉米油甘油三酯或其混合物。
10.如权利要求9所述的剂型,其中所述增溶剂以小于总制剂的10%存在。
11.如权利要求1所述的剂型,其中所述增稠剂选自聚乙二醇,优选为聚乙二醇4000、胶体二氧化硅、蜂蜡、单硬脂酸甘油酯、氢化植物油、部分氢化植物油、硬脂。
12.如权利要求11所述的剂型,其中所述增稠剂是硬脂,其以总制剂的10%至30%存在。
13.如权利要求1所述的剂型,其可任选地包含Phosal,其量为所述制剂的约1-50%w/w。
14.所述载体系统,其还可包含药学上可接受的非磷脂表面活性剂,例如聚山梨醇酯80、聚山梨醇酯20、维生素E TPGS、d-a-生育酚聚乙二醇1000琥珀酸酯,其量为所述制剂的1%w/w至约25%w/w。
15.脂质悬浮液,其包含量为制剂重量的40%的尼达尼布乙磺酸盐;
30%至50%的中链甘油三酯;
10%至30%的硬脂;
11%的卵磷脂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN201821039072 | 2018-10-15 | ||
IN201821039072 | 2018-10-15 | ||
PCT/IN2019/050763 WO2020079706A1 (en) | 2018-10-15 | 2019-10-15 | Pharmaceutical formulation |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113164402A true CN113164402A (zh) | 2021-07-23 |
Family
ID=68582081
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980075716.9A Pending CN113164402A (zh) | 2018-10-15 | 2019-10-15 | 药物制剂 |
Country Status (8)
Country | Link |
---|---|
US (1) | US20210346302A1 (zh) |
EP (1) | EP3860569A1 (zh) |
CN (1) | CN113164402A (zh) |
AU (1) | AU2019363244A1 (zh) |
BR (1) | BR112021007214A2 (zh) |
CA (1) | CA3116298A1 (zh) |
WO (1) | WO2020079706A1 (zh) |
ZA (1) | ZA202102871B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114158720A (zh) * | 2021-12-17 | 2022-03-11 | 江苏艾兰得营养品有限公司 | 一种高固含量混悬液及其制备方法 |
CN114404382A (zh) * | 2022-01-24 | 2022-04-29 | 南京康川济医药科技有限公司 | 乙磺酸尼达尼布软胶囊及其制备方法 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4098246A1 (en) | 2021-05-31 | 2022-12-07 | Lotus Pharmaceutical Co., Ltd. | Formulation of nintedanib |
WO2023174948A2 (en) * | 2022-03-14 | 2023-09-21 | TRx Biosciences Limited | Compositions having improved bioavailability of therapeutics and uses thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102056598A (zh) * | 2008-06-06 | 2011-05-11 | 贝林格尔.英格海姆国际有限公司 | 含有吲哚满酮衍生物悬浮液制剂的胶囊药物剂型 |
CN108078952A (zh) * | 2018-03-05 | 2018-05-29 | 瑞阳制药有限公司 | 乙磺酸尼达尼布软胶囊及其制备方法 |
WO2019106692A1 (en) * | 2017-11-29 | 2019-06-06 | Sun Pharmaceutical Industries Limited | Oral suspension of nintedanib esylate |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5536729A (en) | 1993-09-30 | 1996-07-16 | American Home Products Corporation | Rapamycin formulations for oral administration |
GB9405304D0 (en) | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
US5538737A (en) | 1994-11-30 | 1996-07-23 | Applied Analytical Industries, Inc. | Oral compositions of H2 -antagonists |
BE1011899A6 (fr) | 1998-04-30 | 2000-02-01 | Ucb Sa | Compositions pharmaceutiques gelifiables utilisables. |
US6309663B1 (en) | 1999-08-17 | 2001-10-30 | Lipocine Inc. | Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents |
US7138394B2 (en) | 2002-09-27 | 2006-11-21 | Alpharx Inc. | Vehicle for topical delivery of anti-inflammatory compounds |
CA2626579A1 (en) * | 2005-10-25 | 2007-05-03 | Abbott Laboratories | Formulation comprising a drug of low water solubility and method of use thereof |
CN105963268A (zh) | 2016-06-12 | 2016-09-28 | 佛山市腾瑞医药科技有限公司 | 一种乙磺酸尼达尼布分散片及其制备方法 |
CN107184549B (zh) | 2017-04-11 | 2020-11-20 | 江苏大学 | 一种尼达尼布自微乳制剂和其制成的软胶囊及制备方法 |
WO2019197961A1 (en) * | 2018-04-09 | 2019-10-17 | Intas Pharmaceuticals Ltd. | Pharmaceutical composition of nintedanib esylate |
-
2019
- 2019-10-15 CA CA3116298A patent/CA3116298A1/en active Pending
- 2019-10-15 AU AU2019363244A patent/AU2019363244A1/en active Pending
- 2019-10-15 CN CN201980075716.9A patent/CN113164402A/zh active Pending
- 2019-10-15 BR BR112021007214-4A patent/BR112021007214A2/pt unknown
- 2019-10-15 WO PCT/IN2019/050763 patent/WO2020079706A1/en unknown
- 2019-10-15 US US17/285,260 patent/US20210346302A1/en active Pending
- 2019-10-15 EP EP19804881.1A patent/EP3860569A1/en active Pending
-
2021
- 2021-04-29 ZA ZA2021/02871A patent/ZA202102871B/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102056598A (zh) * | 2008-06-06 | 2011-05-11 | 贝林格尔.英格海姆国际有限公司 | 含有吲哚满酮衍生物悬浮液制剂的胶囊药物剂型 |
WO2019106692A1 (en) * | 2017-11-29 | 2019-06-06 | Sun Pharmaceutical Industries Limited | Oral suspension of nintedanib esylate |
CN108078952A (zh) * | 2018-03-05 | 2018-05-29 | 瑞阳制药有限公司 | 乙磺酸尼达尼布软胶囊及其制备方法 |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114158720A (zh) * | 2021-12-17 | 2022-03-11 | 江苏艾兰得营养品有限公司 | 一种高固含量混悬液及其制备方法 |
CN114404382A (zh) * | 2022-01-24 | 2022-04-29 | 南京康川济医药科技有限公司 | 乙磺酸尼达尼布软胶囊及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CA3116298A1 (en) | 2020-04-23 |
ZA202102871B (en) | 2023-04-26 |
AU2019363244A1 (en) | 2021-05-20 |
WO2020079706A1 (en) | 2020-04-23 |
EP3860569A1 (en) | 2021-08-11 |
BR112021007214A2 (pt) | 2021-08-10 |
US20210346302A1 (en) | 2021-11-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN113164402A (zh) | 药物制剂 | |
US7115565B2 (en) | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability | |
JP5905542B2 (ja) | インドリノン誘導体の懸濁液製剤を含むカプセル医薬投薬形態 | |
JP5571311B2 (ja) | ブチルフタリド静脈内エマルジョン及びその適用 | |
JP5992937B2 (ja) | インドリノン誘導体の即時放出のための医薬投薬形態 | |
NZ539046A (en) | Chemotherapeutic self-emulsifying microemulsion compositions of paclitaxel with improved oral bioavailability | |
RU2639482C2 (ru) | Фармацевтические композиции | |
KR20140016926A (ko) | 활성제로서 페닐아미노피리미딘 유도체를 포함하는 제제 | |
WO2019197961A1 (en) | Pharmaceutical composition of nintedanib esylate | |
TW200526200A (en) | Therapeutic compositions | |
AU2015227503B2 (en) | Capsule pharmaceutical dosage form comprising a suspension formulation of an indolinone derivative | |
KR102244717B1 (ko) | 자가나노유화 약물전달시스템을 이용한 타다라필의 경구용 고형제 조성물 및 이의 제조방법 | |
JPH0892088A (ja) | 経口投与用油性組成物 | |
EP4098246A1 (en) | Formulation of nintedanib | |
JP2004519489A (ja) | 薬剤組成物 | |
JP2005255677A (ja) | シクロスポリン製剤 | |
KR20040080250A (ko) | 란소프라졸함유 경질캅셀제의 제조방법 | |
AU2002249926A1 (en) | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability | |
AU2006277879A1 (en) | Microparticle compositions of the topoisomerase I inhibitor 7-tert-butoxyiminomethylcamptothecin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |