TW201720444A - 含有2-{4-[n-(5,6-二苯基吡 -2-基)-n-異丙基胺基]丁基氧基}-n-(甲基磺醯基)乙醯胺之醫藥組合物 - Google Patents
含有2-{4-[n-(5,6-二苯基吡 -2-基)-n-異丙基胺基]丁基氧基}-n-(甲基磺醯基)乙醯胺之醫藥組合物 Download PDFInfo
- Publication number
- TW201720444A TW201720444A TW105139756A TW105139756A TW201720444A TW 201720444 A TW201720444 A TW 201720444A TW 105139756 A TW105139756 A TW 105139756A TW 105139756 A TW105139756 A TW 105139756A TW 201720444 A TW201720444 A TW 201720444A
- Authority
- TW
- Taiwan
- Prior art keywords
- solid preparation
- weight
- mannitol
- preparation according
- treatment
- Prior art date
Links
- QXWZQTURMXZVHJ-UHFFFAOYSA-N selexipag Chemical compound C=1C=CC=CC=1C1=NC(N(CCCCOCC(=O)NS(C)(=O)=O)C(C)C)=CN=C1C1=CC=CC=C1 QXWZQTURMXZVHJ-UHFFFAOYSA-N 0.000 title abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 238000002360 preparation method Methods 0.000 claims abstract description 112
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 107
- 239000007787 solid Substances 0.000 claims abstract description 105
- 235000010355 mannitol Nutrition 0.000 claims abstract description 57
- 229920002261 Corn starch Polymers 0.000 claims description 23
- 239000008120 corn starch Substances 0.000 claims description 23
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 22
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 22
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 22
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 19
- 239000008187 granular material Substances 0.000 claims description 18
- 239000013078 crystal Substances 0.000 claims description 17
- 229920002678 cellulose Polymers 0.000 claims description 12
- 239000001913 cellulose Substances 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 208000005198 spinal stenosis Diseases 0.000 claims description 9
- 229930006000 Sucrose Natural products 0.000 claims description 8
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 8
- 230000001684 chronic effect Effects 0.000 claims description 7
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 7
- 208000024891 symptom Diseases 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 208000020832 chronic kidney disease Diseases 0.000 claims description 6
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 230000002093 peripheral effect Effects 0.000 claims description 6
- 208000031104 Arterial Occlusive disease Diseases 0.000 claims description 5
- 206010022562 Intermittent claudication Diseases 0.000 claims description 5
- 206010039710 Scleroderma Diseases 0.000 claims description 5
- 206010048302 Tubulointerstitial nephritis Diseases 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 208000021156 intermittent vascular claudication Diseases 0.000 claims description 5
- 201000006334 interstitial nephritis Diseases 0.000 claims description 5
- 208000005069 pulmonary fibrosis Diseases 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 3
- 206010012665 Diabetic gangrene Diseases 0.000 claims description 3
- 208000029523 Interstitial Lung disease Diseases 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- -1 hydroxypropyl group Chemical group 0.000 claims description 3
- 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 2
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 2
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 230000002757 inflammatory effect Effects 0.000 claims description 2
- 208000021328 arterial occlusion Diseases 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 description 48
- 229940099112 cornstarch Drugs 0.000 description 20
- 239000003826 tablet Substances 0.000 description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 238000000634 powder X-ray diffraction Methods 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000000654 additive Substances 0.000 description 7
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 208000010228 Erectile Dysfunction Diseases 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 201000001881 impotence Diseases 0.000 description 6
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 238000005469 granulation Methods 0.000 description 5
- 230000003179 granulation Effects 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 208000032544 Cicatrix Diseases 0.000 description 3
- 244000024675 Eruca sativa Species 0.000 description 3
- 235000014755 Eruca sativa Nutrition 0.000 description 3
- 208000018262 Peripheral vascular disease Diseases 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011812 mixed powder Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 231100000241 scar Toxicity 0.000 description 3
- 230000037387 scars Effects 0.000 description 3
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 3
- 208000026151 Chronic thromboembolic pulmonary hypertension Diseases 0.000 description 2
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Chemical compound CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000032109 Transient ischaemic attack Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 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 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 229960004543 anhydrous citric acid Drugs 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 229960003943 hypromellose Drugs 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
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000002429 large intestine Anatomy 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 231100000862 numbness Toxicity 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 201000010875 transient cerebral ischemia Diseases 0.000 description 2
- 230000002792 vascular Effects 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
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
- KKJUPNGICOCCDW-UHFFFAOYSA-N 7-N,N-Dimethylamino-1,2,3,4,5-pentathiocyclooctane Chemical compound CN(C)C1CSSSSSC1 KKJUPNGICOCCDW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 208000030016 Avascular necrosis Diseases 0.000 description 1
- 238000004438 BET method Methods 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 206010008313 Cervical spinal stenosis Diseases 0.000 description 1
- 208000000668 Chronic Pancreatitis Diseases 0.000 description 1
- 206010009895 Colitis ischaemic Diseases 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 206010011985 Decubitus ulcer Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010014513 Embolism arterial Diseases 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 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
- 208000007882 Gastritis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920003116 HPC-SSL Polymers 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- 206010022714 Intestinal ulcer Diseases 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 208000010038 Ischemic Optic Neuropathy Diseases 0.000 description 1
- AYRXSINWFIIFAE-SCLMCMATSA-N Isomaltose Natural products OC[C@H]1O[C@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)[C@@H](O)[C@@H](O)[C@@H]1O AYRXSINWFIIFAE-SCLMCMATSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 208000003250 Mixed connective tissue disease Diseases 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 206010030924 Optic ischaemic neuropathy Diseases 0.000 description 1
- 206010031264 Osteonecrosis Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033649 Pancreatitis chronic Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 208000031848 Peritonitis sclerosing Diseases 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000004210 Pressure Ulcer Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 206010052005 Psychogenic erectile dysfunction Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 1
- 244000184734 Pyrus japonica Species 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 201000007527 Retinal artery occlusion Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 206010061373 Sudden Hearing Loss Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010053615 Thermal burn Diseases 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 229940009868 aluminum magnesium silicate Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 238000002399 angioplasty Methods 0.000 description 1
- 201000007058 anterior ischemic optic neuropathy Diseases 0.000 description 1
- 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 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 230000007883 bronchodilation Effects 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229910000420 cerium oxide Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000001055 chewing effect Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000000748 compression moulding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000007887 coronary angioplasty Methods 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
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- 229940009714 erythritol Drugs 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 208000030533 eye disease Diseases 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 201000008267 intestinal tuberculosis Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 201000008222 ischemic colitis Diseases 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- DLRVVLDZNNYCBX-RTPHMHGBSA-N isomaltose 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@@H](O)C(O)O1 DLRVVLDZNNYCBX-RTPHMHGBSA-N 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 201000010260 leiomyoma Diseases 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 206010025005 lumbar spinal stenosis Diseases 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 206010028537 myelofibrosis Diseases 0.000 description 1
- 201000008383 nephritis Diseases 0.000 description 1
- 208000036236 obstetric disease 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
- BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- KAQKFAOMNZTLHT-OZUDYXHBSA-N prostaglandin I2 Chemical compound O1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-OZUDYXHBSA-N 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 208000004644 retinal vein occlusion Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/4965—Non-condensed pyrazines
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Inorganic Chemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本發明提供一種經穩定化之2-{4-[N-(5,6-二苯基吡□-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺之固體製劑。 本發明係一種固體製劑,其含有2-{4-[N-(5,6-二苯基吡□-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺、與比表面積為1.0 m2/g以下之D-甘露醇。
Description
本發明係關於一種2-{4-[N-(5,6-二苯基吡-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺(以下,稱為「化合物(I)」)經穩定化之固體製劑。
已知以下結構式: [化1]所表示之化合物(I)具有優異之前列腺素I2
(亦稱為PGI2
)受體促效作用,而表現出血小板凝集抑制作用、血管擴張作用、支氣管擴張作用、脂質沈積抑制作用、白血球活化抑制作用等各種藥效(專利文獻1)。 通常,將作為固體製劑之賦形劑之乳糖、玉米澱粉、結晶纖維素及D-甘露醇等糖醇類用於有效成分之稀釋。於研究含有化合物(I)之固體製劑之配方之過程中,可知化合物(I)本身對溫度及濕度較為穩定,但根據D-甘露醇之種類,固體製劑中之化合物(I)會進行分解而其含量會降低。 [先前技術文獻] [專利文獻] [專利文獻1]WO2002088084號 [專利文獻2]國際公開第2009/157396號 [專利文獻3]國際公開第2009/107736號 [專利文獻4]國際公開第2009/154246號 [專利文獻5]國際公開第2009/157397號 [專利文獻6]國際公開第2009/157398號 [專利文獻7]國際公開第2009/154246號 [專利文獻8]國際公開第2009/157397號 [非專利文獻] [非專利文獻1]Hepatology, 2007, Vol. 45, No.1, p159-169 [非專利文獻2]Folia Pharmacologica Japonica, Vol. 117, No.2, p.123-130, 2001, Abstruct [非專利文獻3]International Angiology, 29, Suppl. 1 to No.2, p.49-54, 2010 [非專利文獻4]Jpn. J. Clin. Immunol., 16(5), 409-414, 1993 [非專利文獻5]Jpn. J. Thromb. Hemost., 1:2, p.94-105, 1990, Abstruct [非專利文獻6]J. Rheumatol., 2009, 36(10), 2244-2249 [非專利文獻7]Japan J. Pharmacol., 43, p.81-90, 1987 [非專利文獻8]New Engl. J. Med., 2015, 24, 2522-2533. [非專利文獻9]CHEST 2003, 123, 1583-1588. [非專利文獻10]Br. Heart J., 53, p.173-179, 1985 [非專利文獻11]The Lancet, 1, 4880, pt 1, p.569-572, 1981 [非專利文獻12]Eur. J. Pharmacol., 449, p.167-176, 2002 [非專利文獻13]The Journal of Clinical Investigation, 117, p.464-472, 2007 [非專利文獻14]Am. J. Physiol. Lung Cell Mol. Physiol., 296:L648-L656, 2009
[發明所欲解決之問題] 本發明之目的在於提供一種化合物(I)經穩定化之固體製劑。此處,「經穩定化」意指由固體製劑中所包含之化合物(I)之分解引起之含量的降低得到了抑制。 [解決問題之技術手段] 本發明者等人為了解決上述問題而進行了努力研究,結果發現:藉由使用比表面積為1.0 m2
/g以下之D-甘露醇作為化合物(I)之賦形劑,而改善固體製劑中之化合物(I)之穩定性,從而完成本發明。 即,本發明係如下所述。 (A) 一種固體製劑,其含有化合物(I)、與比表面積為1.0 m2
/g以下之D-甘露醇。 (B) 如(A)記載之固體製劑,其中相對於化合物(I)1重量份,D-甘露醇為5~10000重量份。 (C) 如(A)或(B)記載之固體製劑,其中D-甘露醇之含量為固體製劑總重量之10~99重量%。 (D) 如(A)至(C)中任一項記載之固體製劑,其中固體製劑中所包含之賦形劑總重量之20重量%以上為D-甘露醇。 (E) 如(A)記載之固體製劑,其中關於D-甘露醇之含量, (a)相對於化合物(I)1重量份,D-甘露醇之重量為5~10000重量份, (b)為固體製劑總重量之10~99重量%, (c)為固體製劑中所包含之賦形劑總重量之20%以上。 (F) 如(A)至(E)中任一項記載之固體製劑,其進而含有甘露醇以外之賦形劑及結合劑。 (G) 如(F)記載之固體製劑,其中甘露醇以外之賦形劑為選自由玉米澱粉、精製白糖及結晶纖維素所組成之群中之1種或2種。 (H) 如(F)記載之固體製劑,其中結合劑為羥丙基纖維素。 (I) 如(A)至(E)中任一項記載之固體製劑,其(a)為選自由玉米澱粉、精製白糖及結晶纖維素所組成之群中之1種或2種,且 (b)進而含有羥丙基纖維素。 (J) 如(I)記載之固體製劑,其中(a)2-{4-[N-(5,6-二苯基吡-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺之含量為固體製劑總重量之0.1~2重量%, (b)D-甘露醇之含量為固體製劑總重量之20~80重量%, (c)玉米澱粉之含量為固體製劑總重量之15~45重量%, (d)羥丙基纖維素之含量為固體製劑總重量之1~5重量%。 (K) 如(J)記載之固體製劑,其中2-{4-[N-(5,6-二苯基吡-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺為I型結晶。 (L) 如(A)至(K)記載之固體製劑,其中固體製劑為錠劑或顆粒劑。 (M) 如(A)至(L)記載之固體製劑,其用於伴隨著糖尿病性神經障礙、糖尿病性壞疽、末梢性循環障礙、慢性動脈阻塞症、間歇性跛行、硬皮病、血栓症、肺性高血壓、心肌梗塞、心絞痛、絲球體腎炎、糖尿病性腎病、慢性腎功能衰竭、支氣管哮喘、間質性肺炎(肺纖維化症)、慢性阻塞性肺病、腎小管間質性腎炎、炎症性腸病或椎管狹窄症之症狀之治療。 (N) 如(M)記載之固體製劑,其用於肺性高血壓之治療。 (O) 如(N)記載之固體製劑,其用於末梢性循環障礙之治療。 (P) 如(O)記載之固體製劑,其用於慢性動脈阻塞症之治療。 (Q) 如(P)記載之固體製劑,其用於間歇性跛行之治療。 (R) 如(Q)記載之治療劑,其用於伴隨著椎管狹窄症之症狀之治療。 (S) 如(R)記載之固體製劑,其用於肺纖維化症之治療。 (T) 如(S)記載之固體製劑,其用於硬皮病之治療。 (U) 如(T)記載之固體製劑,其用於慢性腎功能衰竭之治療。 (V) 如(U)記載之固體製劑,其用於腎小管間質性腎炎之治療。
(化合物(I)) 化合物(I)例如可依據專利文獻1或2所記載之方法進行製造,已知有以下之3個形態之結晶。 (1)化合物(I)之I型結晶,其粉末X射線繞射圖為使用Cu Kα放射線(λ=1.54 Å)而獲得者,且於化合物(I)之粉末X射線繞射光譜中,於以下之繞射角2θ:9.4度、9.8度、17.2度及19.4度時表現出繞射波峰(將I型結晶之粉末X射線繞射光譜示於圖1)。 (2)化合物(I)之II型結晶,其粉末X射線繞射圖為使用Cu Kα放射線(λ=1.54 Å)而獲得者,且於化合物(I)之粉末X射線繞射光譜中,於以下之繞射角2θ:9.0度、12.9度、20.7度及22.6度時表現出繞射波峰(將II型結晶之粉末X射線繞射光譜示於圖2); (3)化合物(I)之III型結晶,其粉末X射線繞射圖為使用Cu Kα放射線(λ=1.54 Å)而獲得者,且於化合物(I)之粉末X射線繞射光譜中,於以下之繞射角2θ:9.3度、9.7度、16.8度、20.6度及23.5度時表現出繞射波峰(將III型結晶之粉末X射線繞射光譜示於圖3)。 可用於本發明之固體製劑之化合物(I)可為上述任一種結晶,又,亦可為該等結晶之混合物,或者亦可為非晶系。其中較佳為I型結晶。 作為參考,將上述3個形態之結晶之粉末X射線繞射光譜圖示於圖1~3。 該等粉末X射線繞射光譜係藉由RINT-UltimaIII(Rigaku股份有限公司製造)(目標:Cu,電壓:40 kV,電流:40 mA,掃描速度:4度/分鐘)而測得。 (D-甘露醇) 本發明之固體製劑之賦形劑係使用比表面積為1.0 m2
/g以下之D-甘露醇。比表面積更佳為0.7 m2
/g以下,進而較佳為大於0.2 m2
/g且小於0.7 m2
/g。 於本發明中,比表面積係藉由BET法所測得之值,例如可使用比表面積測定裝置Macsorb HM-model 1220(Mountech公司)進行測定。 作為本發明所使用之D-甘露醇之例,例如可列舉:Mannite C(Mitsubishi Shoji Foodtech股份有限公司,平均粒徑:20 μm)、Mannite P(Mitsubishi Shoji Foodtech股份有限公司,50 μm)、Mannite S(Mitsubishi Shoji Foodtech股份有限公司,平均粒徑:150 μm)、Pearlitol 25C(ROQUETTE公司,平均粒徑:25 μm)、Pearlitol 50C(ROQUETTE公司,平均粒徑:50 μm)、Pearlitol 160C(ROQUETTE公司,平均粒徑:160 μm)、Nonpareil 108(100)(Freund產業股份有限公司,平均粒徑:100 μm)、Nonpareil 108(200)(Freund產業股份有限公司,平均粒徑:200 μm)。其中較佳為Mannite P、Mannite S、Pearlitol 50C、Pearlitol 160C。 本發明之固體製劑之賦形劑係使用比表面積為1.0 m2
/g以下之D-甘露醇。該D-甘露醇只要為本發明之固體製劑中所包含之賦形劑總重量之20重量%以上即可,更佳為50重量%以上。賦形劑亦可為2種以上之混合物。作為除該D-甘露醇以外亦可使用之賦形劑,可列舉:玉米澱粉、結晶纖維素、精製白糖、赤藻糖醇、異麥芽糖等,較佳為玉米澱粉、精製白糖、結晶纖維素。更佳為玉米澱粉。 玉米澱粉之含量較佳為固體製劑總重量之0.5~45%,更佳為15~40%。 (固體製劑) 本發明之固體製劑之特徵在於:其係含有化合物(I)及D-甘露醇之固體製劑,且D-甘露醇相對於化合物(I)1重量份為5~10000重量份,較佳為10~9500重量份。 本發明之固體製劑中之D-甘露醇之含量通常為固體製劑總重量之10~99重量%。較佳為15~95重量%,更佳為20~80重量%。 於本發明中,「固體製劑」只要未特別提及,則意指供於經口投予之固定形狀之固體製劑,包含普通錠、口腔內崩解錠、咀嚼錠、口含劑、舌下錠、發泡錠、分散錠、溶解錠、散劑、顆粒劑及膠囊劑。本發明之固體製劑包括採用單層結構之單層錠、及具有兩層以上之複數層結構之多層錠。以上述方式獲得之固體製劑之形狀並無特別限制,可為圓形、橢圓形、囊片形、圓環形等各種形狀。關於本發明之固體製劑,亦可為了控制化合物(I)之溶出特性,而藉由公知之方法賦予本發明之固體製劑緩釋性或腸溶性。進而,本發明之固體製劑亦可為了提昇光穩定性、提昇外觀、確保識別性、或者控制釋出等而藉由各種包衣劑或糖衣劑並利用公知之方法進行包衣。進而,本發明之固體製劑亦可為了提昇光穩定性、確保識別性等而調配色素,又,為了改善風味等,亦可調配矯味劑及香料。 本發明之固體製劑除上述成分以外,亦可於不會阻礙本發明之效果之範圍內調配藥學上所容許之載體(添加劑)。該等例如可以結合劑、崩解劑、流動化劑、潤滑劑、包衣劑、控釋劑、塑化劑、著色劑、矯味劑及香料之形式適當、適量地進行調配。該等添加劑可單獨使用,亦可組合兩種以上而使用。 作為結合劑,例如可列舉:明膠、支鏈澱粉、羥丙基纖維素、甲基纖維素、聚乙烯吡咯啶酮、聚乙二醇、阿拉伯膠、葡聚糖、聚乙烯醇、α化澱粉、羥丙甲纖維素,較佳為羥丙基纖維素、聚乙烯醇、羥丙甲纖維素,進而較佳為羥丙基纖維素。 結合劑之含量為固體製劑總重量之0.1~10重量%,較佳為1~8重量%,更佳為1~5%。 羥丙基纖維素之含量為固體製劑總重量之0.1~10重量%,較佳為1~8重量%,更佳為1~5重量%。 作為崩解劑,例如可列舉:羧甲基纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、交聯羧甲基纖維素鈉、澱粉乙醇酸鈉、交聯聚維酮、陽離子交換樹脂、部分α化澱粉及低取代度羥丙基纖維素,較佳為低取代度羥丙基纖維素。 崩解劑之含量為固體製劑總重量之0.1~10重量%,較佳為1~8重量%。 低取代度羥丙基纖維素之含量為固體製劑總重量之0.1~10重量%,較佳為1~8重量%,更佳為3~7重量%。 作為流動化劑,例如可列舉:輕質無水矽酸、含水二氧化矽、合成矽酸鋁、矽酸鋁鎂。 作為潤滑劑,例如可列舉:硬脂酸、硬脂酸鎂、硬脂酸鈣、反丁烯二酸硬脂酯鈉、滑石、蠟類、DL-白胺酸、硫酸月桂酯鈉、硫酸月桂酯鎂、聚乙二醇、輕質無水矽酸,較佳為硬脂酸鎂。 潤滑劑之含量為固體製劑總重量之0.1~10重量%,較佳為0.2~5重量%。 硬脂酸鎂之含量為固體製劑總重量之0.1~10重量%,較佳為0.2~5重量%,更佳為0.5~3重量%。 作為包衣劑,可列舉:乙基纖維素、丙烯酸乙酯-甲基丙烯酸甲酯共聚物、甲基丙烯酸共聚物LD、乙酸羥丙甲纖維素琥珀酸酯等。 作為控釋劑,例如可列舉:羥丙基纖維素、乙烯-乙酸乙烯酯共聚物、聚環氧乙烷。 作為塑化劑,例如可列舉:檸檬酸三乙酯、丙二醇、聚乙二醇,較佳為丙二醇。 作為著色劑,例如可列舉:氧化鈦、滑石、三氧化二鐵、黃色三氧化二鐵、食用黃色4號、食用黃色4號鋁色澱,較佳為氧化鈦、三氧化二鐵、黃色三氧化二鐵。 著色劑之含量未達固體製劑總重量之0.1重量%。 作為矯味劑,例如可列舉:果糖、木糖醇、葡萄糖、DL-蘋果酸。 作為香料,例如可列舉:l-薄荷腦、胡椒薄荷。 上述之賦形劑、添加劑只要為固體製劑之穩定性不會降低之範圍,則通常可使用任意之量。於固體製劑中,較佳之賦形劑與添加劑之組合為化合物(I)/D-甘露醇/羥丙基纖維素、化合物(I)/D-甘露醇/玉米澱粉/羥丙基纖維素、化合物(I)/D-甘露醇/結晶纖維素/羥丙基纖維素,更佳為化合物(I)/D-甘露醇/玉米澱粉/羥丙基纖維素。 固體製劑於化合物(I)/D-甘露醇/玉米澱粉/羥丙基纖維素之組合時,各者相對於固體製劑總重量之含量較佳為化合物(I)為0.1~12重量%,D-甘露醇為15~95重量%,玉米澱粉為0.5~45重量%,羥丙基纖維素為1~8重量%;更佳為化合物(I)為0.1~2重量%,D-甘露醇為20~80重量%,玉米澱粉為15~45重量%,羥丙基纖維素為1~5重量%。 (固體製劑之製造方法) 本發明之固體製劑可藉由製劑領域中之慣用方法進行製造。於以下表示其製法之一例,但本發明不受該製造方法任何限制。 本發明之固體製劑係針對作為有效成分之化合物(I)之粉末, (1)與賦形劑等添加物進行混合而製成散劑,或者於其混合粉末中加入崩解劑及結合劑等添加物,藉由公知之各種造粒方法進行造粒而製成顆粒劑。 (2)將所獲得之混合粉末或顆粒直接、或者與潤滑劑及流動化劑等添加物混合後,填充至膠囊中而製成膠囊劑。或者,進行壓縮成型(打錠)而製成錠劑。 (3)視需要藉由包衣劑或糖衣並利用公知之包衣方法將所獲得之混合粉末、顆粒、膠囊或錠劑之表面進行包衣。 化合物(I)具有優異之PGI2
受體促效作用,而可用作與PGI2
相關之疾病、例如如下疾病之預防劑或治療劑:短暫性腦缺血發作(TIA)、糖尿病性神經障礙(例如參照非專利文獻1)、糖尿病性壞疽(例如參照非專利文獻1)、末梢循環障礙(例如慢性動脈硬化症、慢性動脈阻塞症(例如參照非專利文獻2)、間歇性跛行(例如參照非專利文獻3)、末梢性動脈栓塞症、雷諾氏病(例如參照非專利文獻4、非專利文獻5)、膠原病(例如全身性紅斑狼瘡、硬皮病)(例如參照專利文獻3、非專利文獻6)、混合性結締組織病、血管炎症候群、經皮冠狀動脈成形術(PTCA)後之再阻塞-再狹窄、動脈硬化症、血栓症(例如急性期腦血栓症、肺栓塞症)(例如參照非專利文獻5、非專利文獻7)、高血壓、肺動脈高血壓(Pulmonary arterial hypertension)或慢性血栓栓塞性肺動脈高壓(Chronic thromboembolic pulmonary hypertension)等肺性高血壓(例如非專利文獻8、非專利文獻9)、缺血性疾病(例如腦梗塞、心肌梗塞(例如參照非專利文獻10))、心絞痛(例如穩定性心絞痛、不穩定心絞痛)(例如參照非專利文獻11)、絲球體腎炎(例如參照非專利文獻12)、糖尿病性腎病(例如參照非專利文獻1)、慢性腎功能衰竭(例如參照專利文獻4)、過敏、支氣管哮喘(例如參照非專利文獻13)、潰瘍、褥瘡(壓瘡)、動脈粥樣硬塊切除(Atherectomy)及支架置放術等冠狀動脈介入後之再狹窄、由透析引起之血小板減少、與器官或組織之纖維化相關之疾病[例如腎臟疾病(例如腎小管間質性腎炎(例如參照專利文獻3)、呼吸器官疾病(例如間質性肺炎(肺纖維化症)(例如參照專利文獻3)、慢性阻塞性肺病(例如參照非專利文獻14)等)、消化器官疾病(例如肝硬變、病毒性肝炎、慢性胰炎、胃硬癌)、心血管疾病(例如心肌纖維化症)、骨關節疾病(例如骨髓纖維化症、類風濕性關節炎)、皮膚疾病(例如手術後之瘢痕、燙傷性瘢痕、蟹足腫、肥厚性瘢痕)、產科疾病(例如子宮肌瘤)、泌尿器官疾病(例如前列腺肥大症)、其他疾病(例如阿茲海默症、硬化症腹膜炎、I型糖尿病、手術後器官黏連)]、勃起功能障礙(例如糖尿病性勃起功能障礙、心因性勃起功能障礙、精神病性勃起功能障礙、由慢性腎功能衰竭引起之勃起功能障礙、用以摘除前列腺之骨盆內手術後之勃起功能障礙、伴隨著加齡或動脈硬化之血管性勃起功能障礙)(例如參照專利文獻7)、炎症性腸病(例如伴隨著潰瘍性結腸炎、克隆氏病、腸結核、缺血性結腸炎、貝西氏病之腸潰瘍)(例如參照專利文獻5)、胃炎、胃潰瘍、缺血性眼病(例如視網膜動脈阻塞、視網膜靜脈阻塞、缺血性視神經病)、突發性失聰、無血管性骨壞死、伴隨著非類固醇性抗炎劑(NSAIDs)(例如雙氯芬酸、美洛昔康、丙、萘普酮、吲哚美辛、布洛芬、酮洛芬、萘普生、塞來昔布)投予之腸管損傷(例如,若為於十二指腸、小腸、大腸出現之損傷則並無特別限制,例如於十二指腸、小腸、大腸產生之糜爛等黏膜損傷或潰瘍)(例如參照專利文獻8)、伴隨著椎管狹窄症(例如頸椎椎管狹窄症、胸椎椎管狹窄症、腰椎椎管狹窄症、廣泛性椎管狹窄症、腰椎骨狹窄症)之症狀(例如麻痹、知覺麻木、疼痛、麻木、走路能力之降低)(例如參照專利文獻6)。又,本發明之固體製劑亦可用作基因治療或自體骨髓細胞移植等血管新生療法之促進劑、末梢血管再建術或血管新生療法中之血管形成促進劑。 [實施例] 以下,列舉比較例、實施例及試驗例而更詳細地說明本發明,但本發明並非限定於此。 本發明所使用之化合物(I)係使用上述I型結晶。 於實施例、比較例中,於並無特別記載之情形時係使用以下之添加劑。玉米澱粉使用Nisshoku cornstarch W(日本食品化工股份有限公司)。結晶纖維素使用Ceolus PH-101(旭化成化學股份有限公司)。羥丙基纖維素使用HPC-SSL(日本曹達股份有限公司)。低取代度羥丙基纖維素使用LH-11(信越化學工業股份有限公司)。硬脂酸鎂使用植物性硬脂酸鎂(特製)(太平化學產業股份有限公司)。精製白糖使用T.T.G.H砂糖(東洋精糖股份有限公司)。黃色三氧化二鐵使用黃色三氧化二鐵(癸巳化成股份有限公司)。氧化鈦使用Tipaque A-100(石原產業股份有限公司)。丙二醇使用丙二醇(旭硝子股份有限公司)。 (實施例1)D-甘露醇之種類與穩定性 (1)錠劑之製備 將特定量之化合物(I)與各種D-甘露醇、玉米澱粉、低取代度羥丙基纖維素放入至流動層造粒乾燥機(MP-01,Powrex股份有限公司)中,一面進行混合一面噴霧5%羥丙基纖維素水溶液而製備顆粒。於所獲得之顆粒中混合特定量之硬脂酸鎂,使用旋轉式打錠機(Correct,菊水製作所股份有限公司)以800 kg進行打錠而製成錠劑(直徑7 mm,120 mg錠)。將各實施例、比較例中所使用之D-甘露醇之種類示於表1。表1所記載之體積密度(g/mL)意指未振實(鬆弛)之狀態下之粉體試樣之質量與包括粒子間空隙體積之因子在內之粉體之體積的比,且係稱取25 g預先藉由網眼1000 μm之篩將試樣過篩而獲得者,將試樣經由濾鬥投入至量筒中,測定此時之體積而算出。又,表1記載之振實密度(g/mL)係藉由將裝有粉體試樣之容器以機械方式進行振實而獲得之體積密度,具體而言,係進行振實直至不再出現體積之變化,測定此時之體積而算出。 關於錠劑之成分及其含量,係如表2所記載。 [表1]
[表2]
(2)評價方法與結果 將所獲得之錠劑放入至塑膠瓶中,於不塞住瓶口之狀態下,且於40℃/75%RH之敞開條件、及60℃之敞開條件下保存1個月。使用高效液相層析法測定保存前後之錠劑中之化合物(I)之類似物質,評價自試驗開始時之類似物質之增加量。再者,表中,類似物質之增加量(%)係表示保存前後之製劑中所包含之化合物(I)的減少量(峰面積)。將其結果及所使用之各種D-甘露醇之比表面積示於表3。顯示出實施例1-1至1-5中之任一錠劑均類似物質之生成量未達3%。可確認到該等實施例中所使用之D-甘露醇之比表面積大致為1.0 m2
/g以下,而於使用具有該等物性之D-甘露醇之情形時製劑之穩定性提昇。 [表3]
(實施例2)調配有D-甘露醇與其他賦形劑之情形時之穩定性 (1)錠劑之製備 將特定量之化合物(I)與D-甘露醇(Mannite P,Mitsubishi Shoji Foodtech股份有限公司)、玉米澱粉、結晶纖維素放入至流動層造粒乾燥機(MP-01,Powrex股份有限公司)中,一面進行混合一面噴霧10%羥丙基纖維素水溶液而製造顆粒。於所獲得之顆粒中混合特定量之低取代度羥丙基纖維素及硬脂酸鎂,使用旋轉式打錠機(Correct,菊水製作所股份有限公司)以1000 kg進行打錠而製成錠劑(直徑8 mm,190 mg錠)。關於各成分之含量,係如表4所記載。 [表4]
(2)評價方法及結果 將(1)中所製備之錠劑與乾燥劑(Dryern tablet PW2010,山仁藥品股份有限公司)一起放入至塑膠瓶中並塞緊,於40℃/75%RH之條件(加速試驗)下保存6個月。又,將錠劑放入至塑膠瓶中,於不塞住瓶口之狀態下,且於40℃/75%RH之條件及60℃之條件下保存1個月。使用高效液相層析法測定保存前後之錠劑中之化合物(I)之含量,評價相對於試驗開始時之化合物(I)之殘存率。 將其結果示於表5。不僅於僅使用D-甘露醇作為賦形劑之情形(實施例2-1)時表現出較高之殘存率,於將玉米澱粉(實施例2-2)或結晶纖維素(實施例2-3)與D-甘露醇進行調配之情形時亦表現出較高之殘存率。 [表5]
(實施例3)顆粒劑之穩定性 (1)顆粒劑之製備 實施例3-1 將特定量之化合物(I)與D-甘露醇(Mannite P,Mitsubishi Shoji Foodtech股份有限公司)、玉米澱粉、精製白糖(經樣本研磨機(AP-S,Hosokawa Micron股份有限公司,篩網直徑3 mm)粉碎而獲得者)放入至流動層造粒乾燥機(MP-01,Powrex股份有限公司)中,一面進行混合一面噴霧10%羥丙基纖維素水溶液而製造顆粒。 實施例3-2 將特定量之化合物(I)與D-甘露醇(Mannite P,Mitsubishi Shoji Foodtech股份有限公司)、玉米澱粉放入至流動層造粒乾燥機(MP-01,Powrex股份有限公司)中,一面進行混合一面噴霧分散有特定量之黃色三氧化二鐵之10%羥丙基纖維素水溶液而製造顆粒。 關於顆粒劑之成分及其含量,係如表6所記載。 [表6]
(2)評價方法及結果 將所獲得之顆粒劑與乾燥劑(Dryern tablet PW2010,山仁藥品股份有限公司)一起放入至塑膠瓶中並塞緊,於40℃/75%RH之條件(加速試驗)下保存2個月,或者於敞開之狀態下保存1個月。使用高效液相層析法測定保存前後之顆粒劑中之化合物(I)之含量,評價相對於試驗開始時之化合物(I)之殘存率(%)。將其結果示於表7。其結果為,可知即便於製成顆粒劑之情形時亦確保較高之穩定性。 [表7]
[產業上之可利用性] 根據本發明,可提供一種化合物(I)經穩定化之固體製劑、即製劑之保存穩定性得到了改善,由有效成分之分解引起之含量之降低、及有效成分之分解物(類似物質)之生成及增加得到了抑制之固體製劑。
圖1係表示化合物(I)之I型結晶之粉末X射線繞射光譜圖。縱軸表示尖峰強度(cps),橫軸表示繞射角(2θ[°])。 圖2係表示化合物(I)之II型結晶之粉末X射線繞射光譜圖。縱軸表示尖峰強度(cps),橫軸表示繞射角(2θ[°])。 圖3係表示化合物(I)之III型結晶之粉末X射線繞射光譜圖。縱軸表示尖峰強度(cps),橫軸表示繞射角(2θ[°])。
無
Claims (22)
- 一種固體製劑,其含有2-{4-[N-(5,6-二苯基吡-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺、與 比表面積為1.0 m2 /g以下之D-甘露醇。
- 如請求項1之固體製劑,其中相對於2-{4-[N-(5,6-二苯基吡-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺1重量份,D-甘露醇為5~10000重量份。
- 如請求項1或2之固體製劑,其中D-甘露醇之含量為固體製劑總重量之10~99重量%。
- 如請求項1至3中任一項之固體製劑,其中固體製劑中所包含之賦形劑總重量之20重量%以上為D-甘露醇。
- 如請求項1之固體製劑,其中關於D-甘露醇之含量, (a)相對於2-{4-[N-(5,6-二苯基吡-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺1重量份,D-甘露醇之重量為5~10000重量份, (b)為固體製劑總重量之10~99重量%, (c)為固體製劑中所包含之賦形劑總重量之20%以上。
- 如請求項1至5中任一項之固體製劑,其進而含有甘露醇以外之賦形劑及結合劑。
- 如請求項6之固體製劑,其中甘露醇以外之賦形劑為選自由玉米澱粉、精製白糖及結晶纖維素所組成之群中之1種或2種。
- 如請求項6之固體製劑,其中結合劑為羥丙基纖維素。
- 如請求項1至5中任一項之固體製劑,其進而含有(a)選自由玉米澱粉、精製白糖及結晶纖維素所組成之群中之1種或2種;及 (b)羥丙基纖維素。
- 如請求項9之固體製劑,其中(a)2-{4-[N-(5,6-二苯基吡-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺之含量為固體製劑總重量之0.1~2重量%, (b)D-甘露醇之含量為固體製劑總重量之20~80重量%, (c)玉米澱粉之含量為固體製劑總重量之15~45重量%, (d)羥丙基纖維素之含量為固體製劑總重量之1~5重量%。
- 如請求項10之固體製劑,其中2-{4-[N-(5,6-二苯基吡-2-基)-N-異丙基胺基]丁基氧基}-N-(甲基磺醯基)乙醯胺為I型結晶。
- 如請求項1至11中任一項之固體製劑,其中固體製劑為錠劑或顆粒劑。
- 如請求項1至12中任一項之固體製劑,其用於伴隨著糖尿病性神經障礙、糖尿病性壞疽、末梢性循環障礙、慢性動脈阻塞、間歇性跛行、硬皮病、血栓症、肺性高血壓、心肌梗塞、心絞痛、絲球體腎炎、糖尿病性腎病、慢性腎功能衰竭、支氣管哮喘、間質性肺炎(肺纖維化症)、慢性阻塞性肺病、腎小管間質性腎炎、炎症性腸病或椎管狹窄症之症狀之治療。
- 如請求項13之固體製劑,其用於肺性高血壓之治療。
- 如請求項14之固體製劑,其用於末梢性循環障礙之治療。
- 如請求項15之固體製劑,其用於慢性動脈阻塞之治療。
- 如請求項16之固體製劑,其用於間歇性跛行之治療。
- 如請求項17之治療劑,其用於伴隨著椎管狹窄症之症狀之治療。
- 如請求項18之固體製劑,其用於肺纖維化症之治療。
- 如請求項19之固體製劑,其用於硬皮病之治療。
- 如請求項20之固體製劑,其用於慢性腎功能衰竭之治療。
- 如請求項21之固體製劑,其用於腎小管間質性腎炎之治療。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015236034 | 2015-12-02 | ||
JP??2015-236034 | 2015-12-02 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201720444A true TW201720444A (zh) | 2017-06-16 |
TWI750143B TWI750143B (zh) | 2021-12-21 |
Family
ID=59014064
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW105139756A TWI750143B (zh) | 2015-12-02 | 2016-12-01 | 含有2-{4-[n-(5,6-二苯基吡-2-基)-n-異丙基胺基]丁基氧基}-n-(甲基磺醯基)乙醯胺之醫藥組合物 |
Country Status (21)
Country | Link |
---|---|
US (2) | US10821108B2 (zh) |
EP (2) | EP3384911A4 (zh) |
JP (1) | JP6825574B2 (zh) |
KR (1) | KR20180081141A (zh) |
CN (1) | CN108289890B (zh) |
AU (1) | AU2016366073B2 (zh) |
BR (1) | BR112018009534B1 (zh) |
CA (1) | CA3005169A1 (zh) |
CL (1) | CL2018001464A1 (zh) |
CO (1) | CO2018006834A2 (zh) |
EC (1) | ECSP18049108A (zh) |
IL (2) | IL310203A (zh) |
MX (1) | MX2018006343A (zh) |
PE (1) | PE20181072A1 (zh) |
PH (1) | PH12018501161A1 (zh) |
RU (1) | RU2735547C2 (zh) |
SG (1) | SG11201804320QA (zh) |
TW (1) | TWI750143B (zh) |
UA (1) | UA124002C2 (zh) |
WO (1) | WO2017098998A1 (zh) |
ZA (1) | ZA201804387B (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201922230A (zh) | 2017-11-16 | 2019-06-16 | 日商日本新藥股份有限公司 | 控釋製劑 |
BR112020016230A2 (pt) * | 2018-02-21 | 2020-12-08 | Nippon Shinyaku Co., Ltd. | Composição granular, método para produção de composição granular, e método para melhoria da propriedade de dissolução de composição granular |
US20210069187A1 (en) * | 2019-05-11 | 2021-03-11 | RK Pharma Solutions LLC | Stable pharmaceutical composition of Selexipag |
CA3154802A1 (en) * | 2019-10-23 | 2021-04-29 | Marc Patrik SCHRADER | Pharmaceutical composition comprising selexipag |
AR121804A1 (es) * | 2020-04-10 | 2022-07-13 | Nippon Shinyaku Co Ltd | Preparación sólida y método para producir la misma |
CN112220770B (zh) * | 2020-12-17 | 2021-04-09 | 上海翰森生物医药科技有限公司 | 司来帕格的药物组合物及其制备方法 |
WO2022240378A1 (en) * | 2021-05-11 | 2022-11-17 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | A stable pharmaceutical composition comprising selexipag |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3145431B2 (ja) | 1991-08-20 | 2001-03-12 | 日本酸素株式会社 | 安定同位体標識蛋白質の製造法および試薬キット |
JP3126683B2 (ja) | 1996-04-16 | 2001-01-22 | 武田薬品工業株式会社 | D−マンニトールおよびその製造法 |
US20010001106A1 (en) | 1996-04-16 | 2001-05-10 | Tomohiro Yoshinari | D-mannitol and its preparation |
EP1282416A2 (en) | 2000-05-19 | 2003-02-12 | Progenics Pharmaceuticals, Inc. | Dehydroascorbic acid formulations and uses thereof |
TWI316055B (zh) | 2001-04-26 | 2009-10-21 | Nippon Shinyaku Co Ltd | |
FR2918566B1 (fr) | 2007-07-11 | 2009-10-09 | Pierre Fabre Medicament Sa | Composition pharmaceutique stable d'un sel hydrosoluble de vinflunine. |
BRPI0908491A2 (pt) | 2008-02-28 | 2015-08-11 | Nippon Shinyaku Co Ltd | Inibidor de fibrose |
WO2009154246A1 (ja) | 2008-06-19 | 2009-12-23 | 日本新薬株式会社 | 勃起不全治療剤 |
SI2289518T1 (sl) * | 2008-06-23 | 2017-02-28 | Nippon Shinyaku Co., Ltd. | Terapevtsko sredstvo za vnetno črevesno bolezen |
WO2009157396A1 (ja) | 2008-06-23 | 2009-12-30 | 日本新薬株式会社 | 脊柱管狭窄症治療剤 |
WO2009157397A1 (ja) | 2008-06-23 | 2009-12-30 | 日本新薬株式会社 | 非ステロイド性抗炎症剤投与に伴う腸管傷害治療剤 |
US8791122B2 (en) | 2009-06-26 | 2014-07-29 | Nippon Shinyaku Co., Ltd. | Form-I crystal of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide and method for producing the same |
EP2913047B1 (en) | 2012-10-29 | 2019-05-08 | Cardio Incorporated | Pulmonary disease-specific therapeutic agent |
CN103690496B (zh) | 2013-12-27 | 2015-04-01 | 哈药集团生物工程有限公司 | 一种含有奥扎格雷钠的冻干药物组合物 |
-
2016
- 2016-12-01 JP JP2017555036A patent/JP6825574B2/ja active Active
- 2016-12-01 BR BR112018009534-6A patent/BR112018009534B1/pt active IP Right Grant
- 2016-12-01 UA UAA201807264A patent/UA124002C2/uk unknown
- 2016-12-01 EP EP16872896.2A patent/EP3384911A4/en not_active Withdrawn
- 2016-12-01 MX MX2018006343A patent/MX2018006343A/es unknown
- 2016-12-01 TW TW105139756A patent/TWI750143B/zh active
- 2016-12-01 PE PE2018001060A patent/PE20181072A1/es unknown
- 2016-12-01 SG SG11201804320QA patent/SG11201804320QA/en unknown
- 2016-12-01 IL IL310203A patent/IL310203A/en unknown
- 2016-12-01 EP EP23214939.3A patent/EP4331607A3/en active Pending
- 2016-12-01 AU AU2016366073A patent/AU2016366073B2/en active Active
- 2016-12-01 CN CN201680068849.XA patent/CN108289890B/zh active Active
- 2016-12-01 US US15/777,711 patent/US10821108B2/en active Active
- 2016-12-01 CA CA3005169A patent/CA3005169A1/en active Pending
- 2016-12-01 WO PCT/JP2016/085822 patent/WO2017098998A1/ja active Application Filing
- 2016-12-01 RU RU2018123304A patent/RU2735547C2/ru active
- 2016-12-01 KR KR1020187017182A patent/KR20180081141A/ko not_active Application Discontinuation
-
2018
- 2018-05-17 IL IL259461A patent/IL259461A/en unknown
- 2018-05-31 CL CL2018001464A patent/CL2018001464A1/es unknown
- 2018-06-01 PH PH12018501161A patent/PH12018501161A1/en unknown
- 2018-06-29 ZA ZA2018/04387A patent/ZA201804387B/en unknown
- 2018-06-29 EC ECSENADI201849108A patent/ECSP18049108A/es unknown
- 2018-06-29 CO CONC2018/0006834A patent/CO2018006834A2/es unknown
- 2018-07-25 US US16/044,821 patent/US10828298B2/en active Active
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI750143B (zh) | 含有2-{4-[n-(5,6-二苯基吡-2-基)-n-異丙基胺基]丁基氧基}-n-(甲基磺醯基)乙醯胺之醫藥組合物 | |
WO2011160541A1 (zh) | 托伐普坦固体分散体及其制备方法 | |
JP2022173401A (ja) | 結晶 | |
JP2023182650A (ja) | 粒状組成物、粒状組成物の製造方法、および粒状組成物の溶出性改善方法 | |
WO2019098300A1 (ja) | 放出制御製剤 | |
JP4759102B2 (ja) | 経口投与用医薬組成物 | |
JP5381978B2 (ja) | アミド誘導体含有医薬組成物 | |
KR102206535B1 (ko) | 에제티미브 및 로수바스타틴을 포함하는 경구용 복합정제 | |
JP6989064B1 (ja) | 固形製剤及びその製造方法 | |
TW200808356A (en) | Improved oral pharmaceutical composition of a poorly water-soluble active substance |