CN107157945B - 一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法 - Google Patents
一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法 Download PDFInfo
- Publication number
- CN107157945B CN107157945B CN201710407981.5A CN201710407981A CN107157945B CN 107157945 B CN107157945 B CN 107157945B CN 201710407981 A CN201710407981 A CN 201710407981A CN 107157945 B CN107157945 B CN 107157945B
- Authority
- CN
- China
- Prior art keywords
- tablet
- weight
- novel
- delta receptor
- microcrystalline cellulose
- 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.)
- Active
Links
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 239000000841 delta opiate receptor agonist Substances 0.000 title abstract description 5
- 239000008896 Opium Substances 0.000 title abstract description 4
- 229960001027 opium Drugs 0.000 title abstract description 4
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000007884 disintegrant Substances 0.000 claims abstract description 9
- 125000006291 3-hydroxybenzyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(=C1[H])C([H])([H])* 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 229940094972 Opioid delta receptor agonist Drugs 0.000 claims description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 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 description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 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 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 229910002012 Aerosil® Inorganic materials 0.000 claims 2
- 229940069328 povidone Drugs 0.000 claims 2
- 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 compound 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 claims 1
- 238000005469 granulation Methods 0.000 claims 1
- 230000003179 granulation Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 13
- 238000004090 dissolution Methods 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000009471 action Effects 0.000 abstract description 2
- 210000004051 gastric juice Anatomy 0.000 abstract 1
- 238000012216 screening Methods 0.000 abstract 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 12
- 101100244562 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) oprD gene Proteins 0.000 description 6
- 239000000935 antidepressant agent Substances 0.000 description 6
- 108700023159 delta Opioid Receptors Proteins 0.000 description 6
- 102000048124 delta Opioid Receptors Human genes 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000012048 forced swim test Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 230000001430 anti-depressive effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000945 filler Substances 0.000 description 5
- 238000000691 measurement method Methods 0.000 description 5
- 238000005464 sample preparation method Methods 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 3
- 102000051367 mu Opioid Receptors Human genes 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 108020001612 μ-opioid receptors Proteins 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- LBLDMHBSVIVJPM-YZIHRLCOSA-N 4-[(R)-[(2S,5R)-2,5-dimethyl-4-prop-2-enyl-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1[C@H](C=1C=C(O)C=CC=1)N1[C@@H](C)CN(CC=C)[C@H](C)C1 LBLDMHBSVIVJPM-YZIHRLCOSA-N 0.000 description 1
- KQWVAUSXZDRQPZ-UMTXDNHDSA-N 4-[(R)-[(2S,5R)-2,5-dimethyl-4-prop-2-enyl-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide Chemical compound C1=CC(C(=O)N(CC)CC)=CC=C1[C@H](C=1C=C(OC)C=CC=1)N1[C@@H](C)CN(CC=C)[C@H](C)C1 KQWVAUSXZDRQPZ-UMTXDNHDSA-N 0.000 description 1
- XKFPYPQQHFEXRZ-UHFFFAOYSA-N 5-methyl-N'-(phenylmethyl)-3-isoxazolecarbohydrazide Chemical compound O1C(C)=CC(C(=O)NNCC=2C=CC=CC=2)=N1 XKFPYPQQHFEXRZ-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- 229930091371 Fructose Natural products 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
- 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 1
- 240000008881 Oenanthe javanica Species 0.000 description 1
- RMUCZJUITONUFY-UHFFFAOYSA-N Phenelzine Chemical compound NNCCC1=CC=CC=C1 RMUCZJUITONUFY-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229940024545 aluminum hydroxide Drugs 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 239000011230 binding agent Substances 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000000857 delta opiate receptor antagonist Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 229940125436 dual inhibitor 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
- 238000002474 experimental method Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229960002672 isocarboxazid Drugs 0.000 description 1
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 201000003995 melancholia Diseases 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
- 229960004644 moclobemide Drugs 0.000 description 1
- YHXISWVBGDMDLQ-UHFFFAOYSA-N moclobemide Chemical compound C1=CC(Cl)=CC=C1C(=O)NCCN1CCOCC1 YHXISWVBGDMDLQ-UHFFFAOYSA-N 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 230000000407 monoamine reuptake Effects 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 230000000966 norepinephrine reuptake Effects 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 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
- 229960000964 phenelzine Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229940035613 prozac Drugs 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 230000013275 serotonin uptake Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 230000009182 swimming Effects 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 239000003174 triple reuptake inhibitor Substances 0.000 description 1
- 229940009065 wellbutrin Drugs 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
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 108020001588 κ-opioid receptors Proteins 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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法，本发明采用内外加入崩解剂法解决了片剂崩解和溶出缓慢的问题。该δ受体激动剂为4‑{（αR）‑α‑[(2S,5R)‑4‑（3‑氟苄基）‑2,5‑二甲基‑1‑哌嗪基]‑（3‑羟基苄基）}‑（4’‑甲基哌啶基）‑苯甲酰胺。通过对崩解剂和崩解剂加入方法的筛选，使该片剂的崩解时限小于5分钟，实现药物在胃液中迅速释放，快速起效。
Description
技术领域
本发明属化学制药领域，具体涉及一种4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐片剂及其制备方法。
技术背景
随着经济的快速发展和生活的节奏加快，抑郁症已经成为一种常见病、多发病。随之，市场上涌现出如选择性5-羟色胺再摄取抑制剂类、三环类抗抑郁药、氨基酮类抗抑郁药等不同类型的抗抑郁药物。上述药物虽有效，但用药过程中会产生不同程度的嗜睡、思维紊乱、性功能障碍等副作用，且起效慢。现有抑郁症治疗药物主要有以下几大类，
1)传统的单胺氧化酶抑制剂类药物例如苯乙肼、异卡波肼、苯环丙胺等非选择性，不可逆的单胺氧化酶抑制剂；
2)吗氯贝胺、托洛沙酮等可逆性单胺氧化酶抑制剂；
3)三环类和四环类等单胺再摄取抑制剂；
4)选择性5-羟色胺-再摄取抑制剂；
5)选择性去甲肾上腺素再摄取抑制剂；
6)5-羟色胺和去甲肾上腺素再摄取双重抑制剂；
7)α2受体拮抗剂和去甲肾上腺素再摄取双重抑制剂；
8)5-HT/NE/DA三重再摄取抑制剂；
9)天然药物与中草药。
4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺能够选择性激动阿片受体的δ-受体亚型发挥抗抑郁作用，作用于新的靶点，有望解决现有抗抑郁药物存在的上述问题。阿片受体有三个亚型：μ-受体、δ-受体、κ-受体。用δ-受体和μ-受体缺陷型转基因小鼠的研究结果表明:δ-受体在抗抑郁方面的阳性作用，而μ-受体在改变行为学活动上表现为阴性作用。啡肽酶抑制剂RB101通过FST试验表明该类化合物具有抗抑郁作用，而δ-阿片类受体拮抗剂纳屈吲哚则可逆转RB101的抗抑郁作用。啡肽类δ-受体激动剂SNC80和(+)BW373U86在FST中单次给药后抗抑郁效果明显。临床上所有抗抑郁药物均己证实了强迫游泳实验(FST)的可靠性。研究发现，与本文所述结构相近的化合物与δ-受体均有较强的亲和力。发明专利CN200810058495.8中提到该化合物的动物实验数据优于目前世界上广泛使用的抗忧郁症药物，如美国Lilly公司的Prozac(氟洛西汀是一种选择性5-羟色胺再回收抑制剂SSRIs类药物)，GSK公司的Wellbutrin，百忧解SERI类药物等。大鼠强迫游泳实验表明该药见效快，仅单次给药就可见明显效果，而目前的常用抗抑郁症药物往往需要1-2周方可见效。
研究发现，游离碱在室温水中的溶解度低于0.09ug/ml，在室温模拟胃液中溶解度约3.0mg/ml，在室温模拟肠液中小于0.1mg/ml。而该化合物的二盐酸盐在上述条件下均能表现出显著的溶解度改善作用。其二盐酸盐较游离碱具有更好的水溶性，有利于口服吸收。如公知的，口服给药是患者较为容易接受的用药方式，对于抑郁症患者更是如此。口服制剂，尤其是片剂能够提高患者的依从性，确保患者按要求服药。
本发明提供了一种通过内外加崩解剂的办法，制备4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐速释片，具有服药方便、起效迅速、工艺简便的优点。
发明内容
本发明提供一种4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐的片剂，具有崩解迅速，溶出快速的优点。
本发明的另一个目的是提供一种工艺稳定的4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐片剂的制备方法。
本发明通过以下技术方案实现：
一种新型阿片δ受体激动剂盐酸盐的片剂,该片剂含有生理有效量的4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐，以及必要的药学上适用的赋形剂。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐的重量百分比为5％-40％。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述药学上适用的赋形剂选自填充剂、崩解剂、助流剂和润滑剂之中几种的混合物。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述填充剂选自淀粉、可压性淀粉、糊精、蔗糖、乳糖、果糖、葡糖糖、木糖醇、甘露醇、微晶纤维素、碳酸钙、磷酸氢钙、硫酸钙、氧化镁、氢氧化铝、羧甲基纤维素钙、羧甲基纤维素钠中的一种或几种。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、低取代羟丙基甲基纤维素中的一种或几种。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述崩解剂用量占片剂的重量百分比为2％-15％。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述助流剂选胶体二氧化硅、粉状纤维素、三硅酸镁、滑石粉中的一种或几种。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述润滑剂选自硬脂酸、硬脂酸钙、硬脂酸镁、硬脂酸锌、滑石粉、单硬脂酸甘油酯、棕榈硬脂酸甘油酯、十二烷基硫酸镁、聚乙二醇、硬脂基富马酸钠中的一种或几种。
所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，该速释片的制备方法为：
(1)将4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐与填充剂、崩解剂混合均匀；
(2)以水溶液制粒，干燥整粒；
(3)加入部分填充剂、崩解剂、助流剂及润滑剂，混合均匀；
(4)压片，即可。
缩略语
API Active Pharmaceutical Ingredient 活性药物成分
5-HT 5-hydroxytryptamine 5-羟色胺
DA Dopamine 多巴胺
NE Norepinephrine 去甲肾上腺素
FST forced swim test 强迫游泳实验
PVPPXL Polyvinylpolypyrrolidone cross-linked XL交联聚乙烯吡咯烷酮XL
HPC-EF Hydroxypropyl cellulose EF 羟乙基纤维素EF
具体实施方式
以下通过具体的实施例对发明做进一步详细的说明。正如本领域技术人员所应知道的，本发明中所表述的实施方案和实施例仅以举例的目的提供，并不构成对具体技术方案中赋形剂的选择、组合物的制备方法，以及组合物的用途的限制。
实施例1
纯水湿法制粒，然后外加下列物料
制备：将4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐与其余赋形剂、粘合剂、崩解剂混合均匀。以水溶液制粒，干燥整粒。加入崩解剂、填充剂、助流剂及润滑剂，混合均匀。压片。取6片照中国药典2015版附录崩解时限测定项下方法测定，所得片剂平均崩解时间为4.83min。
实施例2
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为5min。
实施例3
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为1min。
实施例4
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为1min。
实施例5
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为9.5min。
实施例6
纯水湿法制粒，然后外加下列物料
样品制备方法同上、测定方法同上。所得片剂崩解时间为12min。
测试例
测定4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-3-羟基苄基}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐体外溶出度。
(1)溶出度检测方法
色谱条件色谱柱:Waters-C18(4.6mm×250mm，5μm)；流动相：磷酸盐缓冲液(pH3.5)：甲醇(25∶75)；流速：1.0mL/min；进样量5μL；检测波长：220nm；柱温40℃。
取实施例1、2及实施例3、4片剂各6片，置溶出杯中，以0.1mol/L盐酸溶液500ml作为溶出介质，转速为50转/分，依法操作，HPLC法测定每片溶出量。
(2)溶出度试验结果显示：照溶出度测定法(中国药典2015版二部附录XC第二法)，依法操作，HPLC法测定每片溶出量，结果为30min内实施例1、2、3片剂的溶出百分率大于85％，在30min内实施例4片剂的溶出百分率大于80％，所有实施例在60min内基本全部溶出。结果见表1、表2。
表1实施例1、实施例2溶出度结果
表2实施例3、实施例4溶出度结果
Claims (4)
1.一种新型阿片δ受体激动剂盐酸盐的片剂，该片剂含有重量百分比为22.8％-40％的生理有效量的4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐，以及药学上适用的赋形剂，其中所述赋形剂由乳糖重量占比为18％～37.2％、微晶纤维素重量占比为23％～48％、交联羧甲基纤维素钠重量占比为1％～5％、PVPP XL重量占比为1％～10％、微粉硅胶重量占比为0.5％和硬脂酸镁重量占比为0.5％、聚维酮重量占比为4％或HPC EF重量占比为3％组成。
2.如权利要求1所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述崩解剂交联羧甲基纤维素钠和PVPP XL，以内外加法添加使用。
3.如权利要求1所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，所述的微晶纤维素，外加占比为所使用微晶纤维素总量的3/23～2/7为制粒后加入。
4.如权利要求1-3任一项所述的一种新型阿片δ受体激动剂盐酸盐的片剂，其特征在于，该片剂的制备方法为：
(1)将4-{(αR)-α-[(2S,5R)-4-(3-氟苄基)-2,5-二甲基-1-哌嗪基]-(3-羟基苄基)}-(4’-甲基哌啶基)-苯甲酰胺二盐酸盐与乳糖、微晶纤维素、交联羧甲基纤维素钠、聚维酮或HPC EF混合均匀；
(2)以水溶液制粒，干燥整粒；
(3)加入微晶纤维素、PVPP XL、微粉硅胶及硬脂酸镁，混合均匀；
(4)压片，即可。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710407981.5A CN107157945B (zh) | 2017-06-02 | 2017-06-02 | 一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710407981.5A CN107157945B (zh) | 2017-06-02 | 2017-06-02 | 一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107157945A CN107157945A (zh) | 2017-09-15 |
| CN107157945B true CN107157945B (zh) | 2021-03-12 |
Family
ID=59824266
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710407981.5A Active CN107157945B (zh) | 2017-06-02 | 2017-06-02 | 一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107157945B (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102631329A (zh) * | 2012-04-12 | 2012-08-15 | 无锡万全医药技术有限公司 | 一种帕罗西汀的口服崩解片及制备工艺 |
| CN106491545A (zh) * | 2016-09-22 | 2017-03-15 | 万特制药(海南)有限公司 | 盐酸氟西汀口崩片及其制备方法 |
| CN106588874A (zh) * | 2016-11-21 | 2017-04-26 | 云南省药物研究所 | 一种三芳基二甲基哌嗪二盐酸盐的多晶型物及其制备方法和应用 |
-
2017
- 2017-06-02 CN CN201710407981.5A patent/CN107157945B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102631329A (zh) * | 2012-04-12 | 2012-08-15 | 无锡万全医药技术有限公司 | 一种帕罗西汀的口服崩解片及制备工艺 |
| CN106491545A (zh) * | 2016-09-22 | 2017-03-15 | 万特制药(海南)有限公司 | 盐酸氟西汀口崩片及其制备方法 |
| CN106588874A (zh) * | 2016-11-21 | 2017-04-26 | 云南省药物研究所 | 一种三芳基二甲基哌嗪二盐酸盐的多晶型物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107157945A (zh) | 2017-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9962390B2 (en) | Mosapride sustained-release formulation providing pharmacological and clinical effects with once-daily administration | |
| JP4989733B2 (ja) | 口腔内崩壊錠 | |
| RU2616516C2 (ru) | Фармацевтическая композиция, содержащая олмесартана медоксомил и розувастатин или его соль | |
| US20100081672A1 (en) | Ph sensitive matrix formulation | |
| TWI583384B (zh) | 包含４－胺基－５－氟－３－［６－（４－甲基哌嗪－１－基）－１ｈ－苯并咪唑－２－基］－１ｈ－喹啉－２－酮乳酸鹽單水合物之醫藥組合物 | |
| BR112020024107A2 (pt) | combinação farmacêutica, composição, e preparação de combinação que compreende ativador de glucoquinase e inibidor de sglt-2 e métodos de preparação e uso dos mesmos | |
| TW201729812A (zh) | 一種含有ｊａｋ激酶抑制劑或其可藥用鹽的醫藥組成物 | |
| MX2008016568A (es) | Composiciones farmaceuticas de memantina. | |
| TW200948358A (en) | Dissolution improved pharmaceutical composition comprising olmesartan medoxomil | |
| JPWO2013125617A1 (ja) | １−（３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピル）アゼチジン−３−オールまたはその塩を含有する固形医薬組成物 | |
| WO2015051747A1 (zh) | 一种普拉克索的缓释片剂与其制备方法及其用途 | |
| KR20180127951A (ko) | 바레니클린 서방성 제제 및 이의 제조 방법 | |
| CN110251473B (zh) | 羟哌吡酮口服缓释制剂 | |
| US9675551B2 (en) | Sublingual pharmaceutical composition containing an antihistamine agent and method for the preparation thereof | |
| JP6680297B2 (ja) | 経口投与用医薬組成物 | |
| KR101587140B1 (ko) | 위장관 질환 치료용 모사프리드 구연산염 미니정제 함유 서방성 캡슐 제제 및 이의 제조 방법 | |
| CN107157945B (zh) | 一种新型阿片δ受体激动剂盐酸盐的片剂及其制备方法 | |
| KR20150075960A (ko) | 펠렛이 매트릭스에 분산된 모사프리드 구연산염 함유 서방형 매트릭스 제제 및 이의 제조 방법 | |
| KR101721831B1 (ko) | 로베글리타존을 함유하는 경구 투여용 약제학적 조성물 | |
| US20070092566A1 (en) | Oral sustained-release tablet | |
| CN101766605B (zh) | 包含普拉克索的可在口中分散的药物组合物 | |
| JP2018123115A (ja) | 経口固形製剤 | |
| KR20220085746A (ko) | 염산 클로미프라민의 제어 방출을 위한 이중정 및 이의 제조방법 | |
| WO2023080854A1 (en) | Lurasidone hydrochloride compositions | |
| JP2015174861A (ja) | 積層錠及びその製造方法 |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20170915 Assignee: Yunnan Baiyao Group Co.,Ltd. Assignor: YUNNAN INSTITUTE OF MATERIA MEDICA Contract record no.: X2022530000005 Denomination of invention: A new type of opioid d Tablet of receptor agonist hydrochloride and its preparation method Granted publication date: 20210312 License type: Common License Record date: 20220624 |