CN117202893A - 包含鞘氨醇-1-磷酸受体激动剂的可直接压缩的药物组合物 - Google Patents
包含鞘氨醇-1-磷酸受体激动剂的可直接压缩的药物组合物 Download PDFInfo
- Publication number
- CN117202893A CN117202893A CN202280027996.8A CN202280027996A CN117202893A CN 117202893 A CN117202893 A CN 117202893A CN 202280027996 A CN202280027996 A CN 202280027996A CN 117202893 A CN117202893 A CN 117202893A
- Authority
- CN
- China
- Prior art keywords
- acid
- pharmaceutical composition
- chloro
- pharmaceutically acceptable
- acceptable salt
- 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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 title description 5
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 title description 5
- 229940044601 receptor agonist Drugs 0.000 title description 2
- 239000000018 receptor agonist Substances 0.000 title description 2
- 238000007907 direct compression Methods 0.000 claims abstract description 18
- 239000004480 active ingredient Substances 0.000 claims abstract description 17
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 15
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 15
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000000314 lubricant Substances 0.000 claims abstract description 10
- XKKXISSRVOVRGI-UHFFFAOYSA-N 1-[[1-chloro-6-[(3-chloro-1-propan-2-ylindazol-5-yl)methoxy]-3,4-dihydronaphthalen-2-yl]methyl]piperidine-4-carboxylic acid Chemical compound C=1C=C2N(C(C)C)N=C(Cl)C2=CC=1COC(C=C1CC2)=CC=C1C(Cl)=C2CN1CCC(C(O)=O)CC1 XKKXISSRVOVRGI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 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 claims abstract description 9
- 239000011230 binding agent Substances 0.000 claims abstract description 9
- 239000003085 diluting agent Substances 0.000 claims abstract description 9
- 239000008101 lactose Substances 0.000 claims abstract description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 7
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 7
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000011248 coating agent Substances 0.000 claims description 9
- 239000007884 disintegrant Substances 0.000 claims description 8
- 229960001375 lactose Drugs 0.000 claims description 8
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical group O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 7
- 229960001021 lactose monohydrate Drugs 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 5
- 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 claims description 5
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 239000000174 gluconic acid Substances 0.000 claims description 2
- 235000012208 gluconic acid Nutrition 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 abstract description 6
- 229940121846 Sphingosine 1-phosphate receptor agonist Drugs 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 description 23
- 239000012535 impurity Substances 0.000 description 19
- 239000003826 tablet Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 14
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 14
- 229920003114 HPC-L Polymers 0.000 description 13
- 239000008186 active pharmaceutical agent Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 7
- 238000000465 moulding Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 238000009472 formulation Methods 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- DUYSYHSSBDVJSM-KRWOKUGFSA-N sphingosine 1-phosphate Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)COP(O)(O)=O DUYSYHSSBDVJSM-KRWOKUGFSA-N 0.000 description 6
- 238000003860 storage Methods 0.000 description 5
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 4
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 4
- 229940106189 ceramide Drugs 0.000 description 4
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 239000007941 film coated tablet Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 239000008240 homogeneous mixture Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 108010035597 sphingosine kinase Proteins 0.000 description 3
- 102000036530 EDG receptors Human genes 0.000 description 2
- 108091007263 EDG receptors Proteins 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- -1 1-chloro-6- (3-chloro-1-isopropyl-1H-indazol-5-ylmethoxy) -3, 4-dihydro-naphthalen-2-yl Methyl Chemical group 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- ZDRVLAOYDGQLFI-UHFFFAOYSA-N 4-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]phenol;hydrochloride Chemical compound Cl.C1=CC(O)=CC=C1NC1=NC(C=2C=CC(Cl)=CC=2)=CS1 ZDRVLAOYDGQLFI-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 101000703517 Dictyostelium discoideum Sphingosine-1-phosphate lyase Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102100031415 Hepatic triacylglycerol lipase Human genes 0.000 description 1
- 108020002496 Lysophospholipase Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102100025750 Sphingosine 1-phosphate receptor 1 Human genes 0.000 description 1
- 101710155454 Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 1
- 102100029802 Sphingosine 1-phosphate receptor 5 Human genes 0.000 description 1
- 101710155451 Sphingosine 1-phosphate receptor 5 Proteins 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000019552 anatomical structure morphogenesis Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 230000008209 cardiovascular development Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008753 endothelial function Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- ZTBATHMDVBYUOZ-UHFFFAOYSA-N ethyl 1-[[1-chloro-6-[(3-chloro-1-propan-2-ylindazol-5-yl)methoxy]-3,4-dihydronaphthalen-2-yl]methyl]piperidine-4-carboxylate Chemical compound C1CC(C(=O)OCC)CCN1CC(CCC1=C2)=C(Cl)C1=CC=C2OCC1=CC=C(N(N=C2Cl)C(C)C)C2=C1 ZTBATHMDVBYUOZ-UHFFFAOYSA-N 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- NVUYWKBRSRPYMH-UHFFFAOYSA-N hydron;piperidine-4-carboxylic acid;chloride Chemical compound Cl.OC(=O)C1CCNCC1 NVUYWKBRSRPYMH-UHFFFAOYSA-N 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- 108010066791 sphingosine-1-phosphate phosphatase Proteins 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940036157 supac Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及包含鞘氨醇‑1‑磷酸受体激动剂的可直接压缩的药物组合物,并且更具体来说涉及用于直接压缩的药物组合物,其包含式1的1‑[1‑氯‑6‑(3‑氯‑1‑异丙基‑1H‑吲唑‑5‑基甲氧基)‑3,4‑二氢‑萘‑2‑基甲基]‑哌啶‑4‑甲酸或其药学上可接受的盐作为活性成分,并包含乳糖或其水合物作为稀释剂、羟丙基纤维素作为黏合剂、硬脂酰富马酸钠作为润滑剂和交联羧甲基纤维素钠作为赋形剂。
Description
技术领域
本发明涉及一种包含鞘氨醇-1-磷酸受体激动剂的通过直接压缩进行压片的药物组合物。更具体来说,本发明涉及一种通过直接压缩进行压片的药物组合物,其包含下式1的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或药学上可接受的盐作为活性成分、乳糖或其水合物作为稀释剂、羟丙基纤维素作为黏合剂、硬脂酰富马酸钠作为润滑剂和交联羧甲基纤维素钠作为崩解剂:
[式1]
背景技术
鞘氨醇-1-磷酸(S1P)通过以神经酰胺作为起始材料的细胞内神经酰胺途径产生。神经酰胺通过两种途径产生,第一种是从头生物合成途径。神经酰胺也通过鞘磷脂这种细胞膜组分在细胞中的降解产生。每种组织中的S1P水平由两种生物合成性鞘氨醇激酶(SphK)和两种可生物降解性S1P磷酸酶(S1P裂解酶和溶血磷脂磷酸酶)控制。S1P通过由鞘氨醇激酶将鞘氨醇磷酸化而产生,已知介导各种细胞应答例如细胞增殖、细胞骨架组织和迁移、黏附和紧密连接组装以及形态发生。S1P作为与包括白蛋白在内的血浆蛋白组合的形式以高水平(100-1,000nM)存在于血浆中,而在组织中则处于低水平。
S1P与S1P受体(一种G蛋白偶联受体)结合,以显示出各种生物学功能。作为S1P受体亚型,到目前为止已知有S1P1至S1P5,并且它们分别被命名为内皮分化基因(EDG)受体1、5、3、6和8。已知S1P受体参与各种生物学功能,例如白细胞再循环、神经细胞增殖、形态变化、迁移、内皮功能、血管调节和心血管发育。
同时,用于口服给药的常规固体制剂可以通过下述方法制备:直接压缩法,在其中将所有成分混合并直接压缩成片剂;干式制粒法,在其中将混合物揉捏、制粒、过筛以制备干颗粒,然后将它们压缩成片剂;以及湿式制粒法,在其中将通过使用水或有机溶剂制备的黏合剂溶液添加到混合物中,并进行捏合、制粒、干燥和定径过程以制备湿颗粒,然后将它们压缩成片剂。
在直接压缩法的情况下,由于过程步骤少、制造成本低和活性成分的损失小,并且由于不需要溶剂,因此可以预期对热或湿度不稳定的活性成分的稳定性得以提高。然而,为了赋予直接压缩所必需的性质,必需选择特定的赋形剂,特别是在含有相对少量活性成分的片剂中,可能难以制备出含量均匀的片剂。
发明内容
技术问题
本发明旨在提供一种组合物,其可以通过直接压缩法制备其中包含均匀含量的下式1的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或药学上可接受的盐的片剂,并同时确保稳定性:
[式1]
问题的解决方案
为了解决上述技术问题,本发明通过将作为活性成分的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或药学上可接受的盐与特定赋形剂组合,提供了一种组合物,其可以通过直接压缩法制备其中包含均匀含量的活性成分的片剂,并同时确保稳定性。
本发明在下文中进行详细描述。
根据本发明的一个方面,提供了一种通过直接压缩进行压片的药物组合物,其包含1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或药学上可接受的盐作为活性成分、乳糖或其水合物作为稀释剂、羟丙基纤维素作为黏合剂、硬脂酰富马酸钠作为润滑剂和交联羧甲基纤维素钠作为崩解剂。
在根据本发明的一个实施方式中,所述通过直接压缩进行压片的药物组合物可以包含0.2至2重量%的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或药学上可接受的盐作为活性成分、85.25至90.55重量%的乳糖或其水合物作为稀释剂、4.5至5.5重量%的羟丙基纤维素作为黏合剂、0.75至1.25重量%的硬脂酰富马酸钠作为润滑剂和4至6重量%的交联羧甲基纤维素钠作为崩解剂。
在根据本发明的一个实施方式中,所述药学上可接受的盐可以选自盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸、酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富马酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸和萘磺酸。在根据本发明的一个实施方式中,所述药学上可接受的盐可以是盐酸。
在根据本发明的一个实施方式中,所述乳糖的水合物可以是乳糖单水合物。
在根据本发明的一个实施方式中,所述压片可以在5至11kN的压力下进行。在根据本发明的一个实施方式中,如果成型压力小于5kN,则可能无法确保适合的脆性,而如果成型压力超过11kN,则可能由成分之间增加的排斥导致硬度的降低和脆性的增加。
在根据本发明的一个实施方式中,所述药物组合物可以进一步包含包衣剂。
在根据本发明的一个实施方式中,所述包衣剂可以是基于聚乙烯醇(PVA)的包衣剂或基于羟丙基甲基纤维素(HPMC)的包衣剂,但不限于此。在根据本发明的一个实施方式中,作为基于羟丙基甲基纤维素的包衣剂的实例,可以使用OpadryTM,但不限于此。
根据本发明的另一方面,提供了一种制备用于口服给药的包含鞘氨醇-1-磷酸受体激动剂的固体制剂的方法,所述方法包括将作为活性成分的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或药学上可接受的盐、作为稀释剂的乳糖或其水合物、作为黏合剂的羟丙基纤维素、作为润滑剂的硬脂酰富马酸钠和作为崩解剂的交联羧甲基纤维素钠混合;和通过直接压缩进行压片。
根据本发明的一个实施方式,在所述制备方法中,可以将0.2至2重量%的作为活性成分的1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或药学上可接受的盐、85.25至90.55重量%的作为稀释剂的乳糖或其水合物、4.5至5.5重量%的作为黏合剂的羟丙基纤维素、0.75至1.25重量%的作为润滑剂的硬脂酰富马酸钠和4至6重量%的作为崩解剂的交联羧甲基纤维素钠混合。
在根据本发明的一个实施方式中,所述压片可以在5至11kN的压力下进行。在根据本发明的一个实施方式中,如果成型压力小于5kN,则可能无法确保适合的脆性,而如果成型压力超过11kN,则可能由成分之间增加的排斥导致硬度的降低和脆性的增加。
本发明的效果
根据本发明的药物组合物能够通过直接压缩法制备用于口服给药的含有鞘氨醇-1-磷酸受体激动剂的固体制剂,从而减低制造成本和活性成分的损失,具有更少的过程步骤,并在确保稳定性的同时提供含量均匀的活性成分。
附图说明
图1是RRT 0.62的杂质在高温高湿条件(80℃/75%RH)下的主效应图和相互作用图的比较。
图2是RRT 0.72的杂质在高温高湿条件(80℃/75%RH)下的主效应图和相互作用图的比较。
图3是在通过直接压缩进行压片期间测量硬度随压缩力的变化的图。
图4是在通过直接压缩进行压片期间测量脆性随压缩力的变化的图。
具体实施方式
在下文中,通过下述实施例更详细地解释本发明。然而必须理解,本发明的保护范围不限于所述实施例。
制备例:1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基
甲基]-哌啶-4-甲酸盐酸盐的合成
按照国际公开号WO 2014/129796 A1的制备例153-1中描述的方法合成1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸乙酯,将所述酯用NaOH水解,用HCl酸化,然后进行结晶,以获得盐酸盐形式(在后文中被称为“API”)。
实施例1:片剂的制备
在将成分按照下述表1中表示的组成混合后,通过直接压缩制备片剂。
[表1]
*:为API中的HCl盐和水合物校正的对应于0.25、0.5和1mg理论值的量
实施例2:含量均匀性
使用3D混合机将API和赋形剂按照下述表2的组成混合。
[表2]
mg/单位 | g/批 | |
API | 0.534mg | 1.602g |
乳糖单水合物 | 88.466mg | 265.398g |
HPC-L | 5mg | 15g |
交联羧甲基纤维素钠 | 5mg | 15g |
Pruv | 1mg | 3g |
在从上述获得的混合物的10个位置取样并测量活性成分的含量后,将理论值与实际值之间的差异的%汇总并表示在表3中。结果,证实了上述制剂构成均匀混合物。
[表3]
样品 | 实际/理论值之间的差异%(%) |
1 | 100.47 |
2 | 98.62 |
3 | 102.62 |
4 | 98.17 |
5 | 98.48 |
6 | 99.30 |
7 | 96.62 |
8 | 97.012 |
9 | 97.56 |
10 | 102.94 |
平均值(%) | 99.18 |
RSD(%,相对标准偏差) | 2.21 |
实施例3:稳定性研究
将使用表2的组成制备的片剂在严苛条件下储存(在HDPE瓶中50个片剂),然后测量含量变化的稳定性,结果如表4中所示。
[表4]
条件(6天) | 测定(%) |
初始 | 100.00 |
80℃/50%RH | 96.36 |
70℃/75%RH | 98.72 |
70℃/10%RH | 100.00 |
60℃/50%RH | 99.83 |
从上述结果可以确认,本发明的片剂即使在严苛条件下也具有适合的稳定性。
比较例
使用下述表5的组成,以与实施例2中相同的方式制备了含有微晶纤维素代替乳糖单水合物作为稀释剂和硬脂酸镁代替Pruv作为润滑剂的混合物。
[表5]
g/单位 | g/批 | |
API | 0.534mg | 1.602g |
微晶纤维素 | 88.466mg | 265.398g |
HPC-L | 5mg | 15g |
交联羧甲基纤维素钠 | 5mg | 15g |
硬脂酸镁 | 1mg | 3g |
此外,以与实施例2中相同的方式,从上述获得的混合物的10个位置取样,测量活性成分的含量,将理论值与实际值之间的差异的%汇总并表示在表6中。结果,证实了上述制剂构成均匀混合物。
[表6]
样品 | 实际/理论值之间的差异%(%) |
1 | 102.11 |
2 | 99.82 |
3 | 100.44 |
4 | 101.27 |
5 | 100.78 |
6 | 99.29 |
7 | 101.15 |
8 | 101.15 |
9 | 101.27 |
10 | 101.48 |
平均值 | 100.88 |
RSD(相对标准偏差) | 0.82 |
此外,在以与实施例3中相同的方式进行稳定性测量后,结果如表7中所示。
[表7]
条件(6天) | 测定(%) |
初始 | 100.88 |
80℃/50%RH | 64.44 |
70℃/75%RH | 71.37 |
70℃/10%RH | 99.57 |
60℃/50%RH | 100.11 |
从上述结果可以证实,基于微晶纤维素的制剂可以获得与基于乳糖的制剂相似的均匀混合物,但它的含量变化对湿度(70℃/75% RH)和热(80℃/50% RH)非常敏感。
实施例4:根据成分含量确认稳定性
进行本实验是为了检查赋形剂比例的变化如何影响CQA(含量、含量均匀性、溶解和杂质)。实验设计是分式因子设计,200g/批,并且根据SUPAC-IR指南(1级变化,总剂型重量标准),赋形剂范围设定标准如下:
-API:0.2至1.5mg/片
-HPC-L(黏合剂)±0.5%
-交联羧甲基纤维素钠(CCS)(崩解剂)±1%
-Pruv(润滑剂)±0.25%
在Pruv的情况下,SUPAC指南的1级变化标准为±1%,但它被任意设置到±0.25%,因为没有Pruv就不可能压片。
[表8]
RRT 0.62的杂质在高温高湿条件(80℃/75% RH)下的主效应图和相互作用图的比较如图1中所示。RRT 0.72的杂质在高温高湿条件(80℃/75% RH)下的主效应图和相互作用图的比较如图2中所示。
正如可以从图1的主效应图看到的,HPC-L和Pruv在80℃/75%RH下降低RRT 0.62的杂质,交联羧甲基纤维素钠(CCS)在80℃/75%RH下增加RRT 0.62的杂质,并且API含量越低,在80℃/75% RH下RRT 0.62的杂质越高。从图1的相互作用图可以证实,当Pruv的含量低时,HPC-L不影响杂质的量,但当Pruv的含量高时,HPC-L在80℃/75% RH下降低RRT 0.62的杂质;并且当API含量高时,HPC-L不影响杂质的量,但当API含量低时,HPC-L降低RRT0.62的杂质。
此外,正如可以从图2的主效应图看到的,CCS在80℃/75% RH下降低RRT 0.72的杂质,HPC-L和Pruv在80℃/75% RH下增加RRT0.72的杂质,并且API含量越低,在80℃/75%RH下RRT 0.72的杂质越高。从图2的相互作用图可以证实,当Pruv的含量低时,HPC-L不增加杂质,但当Pruv的含量高时,HPC-L在80℃/75% RH下增加RRT 0.72的杂质。
实施例5:压片过程条件的设定
对于片剂成型来说,必需通过确保一定程度的脆性来防止制剂在流动过程中变形(损坏)。因此,测量了在直接压缩过程中片剂的硬度和脆性随压缩力的变化,结果分别如图3和图4中所示。正如可以从图3看出的,在超过约11kN的压力下成型期间,由于成分之间的排斥力增加而导致硬度降低和脆性增加。此外,正如可以从图4看出的,在低于约5kN的压力下成型期间不可能确保适合程度的脆性。从上述结果可以确认,适合的成型压力范围应该是5至11kN。
实施例6:关于薄膜包衣片剂的稳定性的确认
在制备具有下述表9中所示的组成的未包衣片剂后,进行三种不同类型的薄膜包衣。
[表9]
mg/单位 | |
API | 0.53mg |
乳糖单水合物 | 88.47mg |
HPC-L | 5mg |
交联羧甲基纤维素钠 | 5mg |
Pruv | 1mg |
将得到的薄膜包衣片剂在严苛条件下储存以检查它们的稳定性。稳定性通过在下述分析条件下RRT 0.80的有机杂质的变化来估算。结果示出在表10中。
分析条件
[表10]
从上述结果可以确认,使用本发明的组合物的薄膜包衣片剂即使在严苛条件下也具有适合的稳定性。
实施例8:关于组合物的长期稳定性的确认
为了确认根据本发明的组合物的长期储存稳定性,制备了具有表11的组成的薄膜包衣片剂。使用直接压缩法制备包含从API到Pruv的片剂,然后使用基于水的包衣方法完成包衣。
[表11]
mg/单位 | |
API | 0.54 |
乳糖单水合物 | 88.47 |
HPC-L | 5.00 |
交联羧甲基纤维素钠 | 5.00 |
Pruv | 1.00 |
Opadry AMB II | 4.00 |
合计 | 104 |
在室温和加速储存条件下确认了所制备的片剂的储存稳定性。在储存稳定性试验期间含量和有机杂质变化的分析结果示出在表12中。
[表12]
从上述结果可以证实,本发明的组合物即使在长期储存条件下也具有适合的稳定性。
Claims (8)
1.一种通过直接压缩进行压片的药物组合物,所述药物组合物包含1-[1-氯-6-(3-氯-1-异丙基-1H-吲唑-5-基甲氧基)-3,4-二氢-萘-2-基甲基]-哌啶-4-甲酸或其药学上可接受的盐作为活性成分、乳糖或其水合物作为稀释剂、羟丙基纤维素作为黏合剂、硬脂酰富马酸钠作为润滑剂和交联羧甲基纤维素钠作为崩解剂。
2.根据权利要求1所述的药物组合物,所述药物组合物包含0.2至2重量%的所述活性成分、85.25至90.55重量%的所述稀释剂、4.5至5.5重量%的所述黏合剂、0.75至1.25重量%的所述润滑剂和4至6重量%的所述崩解剂。
3.根据权利要求1所述的药物组合物,其中所述药学上可接受的盐选自盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸、酒石酸、甲酸、柠檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富马酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸和萘磺酸。
4.根据权利要求3所述的药物组合物,其中所述药学上可接受的盐是盐酸。
5.根据权利要求1所述的药物组合物,其中所述乳糖的水合物是乳糖单水合物。
6.根据权利要求1所述的药物组合物,其中所述压片在5至11kN的压力下进行。
7.根据权利要求1所述的药物组合物,所述药物组合物进一步包含包衣剂。
8.根据权利要求7所述的药物组合物,其中所述包衣剂是基于聚乙烯醇(PVA)的包衣剂或基于羟丙基甲基纤维素(HPMC)的包衣剂。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2021-0048801 | 2021-04-14 | ||
KR20210048801 | 2021-04-14 | ||
PCT/KR2022/005370 WO2022220593A1 (ko) | 2021-04-14 | 2022-04-13 | 스핑고신-1-인산 수용체 효능제를 포함하는 직접 타정용 약제학적 조성물 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117202893A true CN117202893A (zh) | 2023-12-08 |
Family
ID=83640801
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202280027996.8A Pending CN117202893A (zh) | 2021-04-14 | 2022-04-13 | 包含鞘氨醇-1-磷酸受体激动剂的可直接压缩的药物组合物 |
Country Status (4)
Country | Link |
---|---|
KR (1) | KR20220142376A (zh) |
CN (1) | CN117202893A (zh) |
TW (1) | TWI827000B (zh) |
WO (1) | WO2022220593A1 (zh) |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2010118457A (ru) * | 2007-10-12 | 2011-11-20 | Новартис АГ (CH) | Композиции, содержащие модуляторы рецептора сфингозин-1-фосфата (sip) |
KR101771755B1 (ko) * | 2009-11-13 | 2017-08-25 | 셀진 인터내셔널 Ii 에스에이알엘 | 선택적 헤테로시클릭 스핑고신 1 포스페이트 수용체 조절자 |
EP2390252A1 (en) * | 2010-05-19 | 2011-11-30 | Almirall, S.A. | New pyrazole derivatives |
SI2958913T1 (sl) * | 2013-02-20 | 2018-12-31 | Lg Chem, Ltd. | Sfingozin-1-fosfat receptor agonisti, postopki za njegovo pripravo in farmacevtski sestavki, ki ga vsebujejo kot aktivno sredstvo |
US11180489B2 (en) * | 2016-03-30 | 2021-11-23 | U niversity of Virginia Patent Foundation | Sphingosine kinase inhibitor amidoxime prodrugs |
TW202103704A (zh) * | 2019-04-23 | 2021-02-01 | 大陸商正大天晴藥業集團股份有限公司 | 一種tlr7激動劑的固體藥物組成物 |
-
2022
- 2022-04-13 KR KR1020220045793A patent/KR20220142376A/ko unknown
- 2022-04-13 WO PCT/KR2022/005370 patent/WO2022220593A1/ko active Application Filing
- 2022-04-13 CN CN202280027996.8A patent/CN117202893A/zh active Pending
- 2022-04-14 TW TW111114269A patent/TWI827000B/zh active
Also Published As
Publication number | Publication date |
---|---|
TW202302103A (zh) | 2023-01-16 |
WO2022220593A1 (ko) | 2022-10-20 |
KR20220142376A (ko) | 2022-10-21 |
TWI827000B (zh) | 2023-12-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11413295B2 (en) | Oral preparation of obeticholic acid | |
US20110300214A1 (en) | Pharmaceutical compositions comprising 5-chloro-n-(-methyl)-2-thiophencarboxamid | |
WO2012130837A1 (en) | Solid agomelatine in non-crystalline form | |
WO2013019872A1 (en) | Process for preparing pharmaceutical compositions comprising fingolimod | |
CN112494437A (zh) | 含羟氯喹类化合物的药物组合物、片剂及其制备方法 | |
CN106913529B (zh) | 一种来那替尼或其可药用盐药物组合物的制备方法 | |
US20080311203A1 (en) | Oral Formulation of Anhydrous Olanzapine Form I | |
EA028329B1 (ru) | Содержащая прасугрель стабильная фармацевтическая лекарственная форма с немедленным высвобождением для перорального введения, способ получения и применения | |
CN117202893A (zh) | 包含鞘氨醇-1-磷酸受体激动剂的可直接压缩的药物组合物 | |
EP1558219A1 (en) | Pharmaceutical formulation of olanzapine | |
AU2018357438A1 (en) | Pharmaceutical composition containing quinoline derivative | |
US20070293479A1 (en) | Olanzapine pharmaceutical composition | |
CN117545484A (zh) | 一种噁拉戈利钠组合物 | |
CN105012961B (zh) | 稳定的药物组合物及其制备方法 | |
EP4321153A1 (en) | Pharmaceutical composition comprising sphingosine-1-phosphate receptor agonist with controlled particle size | |
KR20220142379A (ko) | 습식과립법에 의한 스핑고신-1-인산 수용체 효능제를 포함하는 경구용 고형 제제의 제조 방법 | |
US20240207242A1 (en) | Pharmaceutical composition comprising sphingosine-1-phosphate receptor agonist with controlled particle size | |
WO2015044394A1 (en) | Pharmaceutical composition comprising low dose active pharmaceutical ingredient and preparation thereof | |
CN117120038A (zh) | 包含鞘氨醇-1-磷酸受体激动剂的固体制剂的制备方法 | |
CN112641744B (zh) | 一种交沙霉素薄膜衣片及其制备方法 | |
EP4378454A1 (en) | Solid pharmaceutical composition comprising apixaban and beta-lactoglobulin and process for preparing the composition | |
RU2733844C2 (ru) | Фармацевтическая композиция, включающая бициклозамещенное азопроизводное пиразолона или его соль, и способ их получения | |
WO2024033460A1 (en) | Use of co-processed excipients in continuous manufacturing of solid dosage forms | |
WO2021209940A1 (en) | Pharmaceutical composition containing n-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-n'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2s)-hydroxybutanedioate | |
BG63965B1 (bg) | Бронходилатиращо лекарствено средство |
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 |