JP6183979B2 - Method for producing solid preparation containing aripiprazole anhydride - Google Patents
Method for producing solid preparation containing aripiprazole anhydride Download PDFInfo
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- JP6183979B2 JP6183979B2 JP2016177306A JP2016177306A JP6183979B2 JP 6183979 B2 JP6183979 B2 JP 6183979B2 JP 2016177306 A JP2016177306 A JP 2016177306A JP 2016177306 A JP2016177306 A JP 2016177306A JP 6183979 B2 JP6183979 B2 JP 6183979B2
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- 229960004372 aripiprazole Drugs 0.000 title claims description 60
- -1 aripiprazole anhydride Chemical class 0.000 title claims description 27
- 239000007787 solid Substances 0.000 title claims description 25
- 238000002360 preparation method Methods 0.000 title claims description 21
- 238000004519 manufacturing process Methods 0.000 title claims description 17
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 claims description 39
- 239000000843 powder Substances 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 229920003169 water-soluble polymer Polymers 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000005550 wet granulation Methods 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 description 52
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 44
- 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 42
- 239000000243 solution Substances 0.000 description 29
- 239000000126 substance Substances 0.000 description 29
- 239000000203 mixture Substances 0.000 description 28
- 238000001035 drying Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 235000019359 magnesium stearate Nutrition 0.000 description 22
- 238000004090 dissolution Methods 0.000 description 21
- 235000010355 mannitol Nutrition 0.000 description 21
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 19
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 19
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 19
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 19
- 239000008213 purified water Substances 0.000 description 19
- 229910001220 stainless steel Inorganic materials 0.000 description 19
- 239000010935 stainless steel Substances 0.000 description 19
- 229920003114 HPC-L Polymers 0.000 description 18
- 238000003860 storage Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 239000008187 granular material Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 230000007423 decrease Effects 0.000 description 8
- 238000010828 elution Methods 0.000 description 8
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 229920002678 cellulose Polymers 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 7
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 7
- 229960003943 hypromellose Drugs 0.000 description 7
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 229960000913 crospovidone Drugs 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 4
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 239000004386 Erythritol Substances 0.000 description 3
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000007922 dissolution test Methods 0.000 description 3
- 235000019414 erythritol Nutrition 0.000 description 3
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 3
- 229940009714 erythritol Drugs 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000006191 orally-disintegrating tablet Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000013329 compounding Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000012812 general test Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 229920005596 polymer binder Polymers 0.000 description 2
- 239000002491 polymer binding agent Substances 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- 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
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[(2r,3s,4r,5r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical class O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- VMBCEJXTYHMTMM-UHFFFAOYSA-N F.F.I Chemical compound F.F.I VMBCEJXTYHMTMM-UHFFFAOYSA-N 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 238000012423 maintenance Methods 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
- 238000002156 mixing Methods 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
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229940074410 trehalose Drugs 0.000 description 1
- 239000002492 water-soluble polymer binding agent 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
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、統合失調症の治療薬として有用なアリピプラゾール（日本医薬品一般名称）すなわち７−｛４−［４−（２，３−ジクロロフェニル）−１−ピペラジニル］ブトキシ｝−３，４−ジヒドロカルボスチリル又は７−｛４−［４−（２，３−ジクロロフェニル）−１−ピペラジニル］ブトキシ｝−３，４−ジヒドロ−２（１Ｈ）−キノリノンの無水物を含有する固形製剤に関する。 The present invention relates to aripiprazole (Japanese pharmaceutical generic name), that is, 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydrocarbo, which is useful as a therapeutic drug for schizophrenia. The present invention relates to a solid preparation containing styryl or an anhydride of 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydro-2 (1H) -quinolinone.
特許文献１には「アリピプラゾール無水物結晶は湿気に曝されると、水分を帯びてアリピプラゾール水和物に変化し、このことが幾つかの欠点を示す」旨記載されている。その欠点として「第一にアリピプラゾール水和物は、アリピプラゾール無水物に比べ生体利用度が低く溶出性が低いという欠点を有する。第二に、アリピプラゾール無水物に対するアリピプラゾール水和物のバッチ間の変動は、薬物管理機関が定めた規格を満たさない可能性がある。第三に、粉砕によって薬物すなわちアリピプラゾール無水物が製造装置に付着することがあり、更にこの結果、処理の遅れ、オペレーター関与の増加、コストの増大、維持費の増大及び生産性の低下につながり得る。第四に、これらの吸湿性無水物を処理する間に水分の導入が引き起こす問題のほかに、保存及び取り扱い時に吸湿する可能性は、アリピプラゾール薬物の溶出性に悪影響を与える。従って、製品の保存安定性は著しく低下し、及び／又は包装コストが著しく増加し得る」と記載されている。
そして、錠剤の製造工程の途中で２度の乾工程を加えると、アリピプラゾールの水和物が吸湿性の低い無水物に変化し、製造した錠剤を長期保存してもその溶出性が低下しないことが開示されている。
特許文献２には、アリピプラゾール医薬組成物を湿式造粒法により製造する際、製造工程中の乾燥温度を７０℃未満で乾燥することにより速やかな溶出性を示す錠剤が得られることが開示されている。
また、特許文献３には、アリピプラゾールと稀釈剤、結合剤、崩壊剤との混合物をアリピプラゾールと稀釈剤、結合剤を水の存在下に混合し、湿潤顆粒としての顆粒を７０℃未満の温度で乾燥した後、一定の条件下で乾式圧縮するとアリピプラゾールの結晶多形相互転換を防止できることが開示されている。
Patent Document 1 describes that “an aripiprazole anhydride crystal becomes watery and changes to aripiprazole hydrate when exposed to moisture, and this exhibits some drawbacks”. The disadvantages are: “Firstly, aripiprazole hydrate has the disadvantage of low bioavailability and low dissolution compared to aripiprazole anhydride. Second, the variation between batches of aripiprazole hydrate relative to aripiprazole anhydride is Third, the drug, ie aripiprazole anhydride, may adhere to the production equipment due to grinding, further resulting in processing delays, increased operator involvement, Fourth, in addition to the problems caused by the introduction of moisture during the processing of these hygroscopic anhydrides, the possibility of moisture absorption during storage and handling can lead to increased costs, increased maintenance costs and reduced productivity. Adversely affects the dissolution of aripiprazole drug, so the storage stability of the product is significantly reduced and / or the packaging Bets are described as markedly increased can. "
And if the drying process is added twice during the manufacturing process of the tablet, the adipiprazole hydrate will change to a low hygroscopic anhydride, and the dissolution will not decrease even if the manufactured tablet is stored for a long time. Is disclosed.
Patent Document 2 discloses that when an aripiprazole pharmaceutical composition is produced by a wet granulation method, a tablet exhibiting rapid dissolution can be obtained by drying at a drying temperature of less than 70 ° C. during the production process. Yes.
In Patent Document 3, a mixture of aripiprazole, a diluent, a binder, and a disintegrant is mixed with aripiprazole, a diluent, and a binder in the presence of water, and the granules as wet granules are heated at a temperature of less than 70 ° C. It has been disclosed that after drying, dry compression under certain conditions can prevent crystal polymorph interconversion of aripiprazole.
本発明の課題は、アリピプラゾールを含有する固形製剤であって、長期保存においても溶出速度の低下を抑制した固形製剤を提供することにある。 An object of the present invention is to provide a solid preparation containing aripiprazole, which suppresses a decrease in dissolution rate even during long-term storage.
アリピプラゾールと乳糖水和物やトウモロコシデンプン等の汎用されている製剤添加剤をいずれも粉末で仕込み、湿式造粒法により顆粒を製造し、ステアリン酸マグネシウムと共に混合、打錠して得た錠剤について苛酷試験（４０℃、相対湿度７５％、ガラス瓶開放）を行ったところ、１週間保存後において著しい溶出遅延が認められた。
一方で、アリピプラゾールを水溶性高分子水溶液に懸濁させ、添加剤と共に湿式造粒法により顆粒を製造し、ステアリン酸マグネシウムと共に混合、打錠して得た錠剤について苛酷試験（４０℃、相対湿度７５％、ガラス瓶開放、１週間保存）をしたところ、溶出遅延が殆ど認められないことが判明した。この知見を基にさらに検討を加え、本発明を完成するに到った。
Aripiprazole and lactose hydrate, corn starch and other commonly used pharmaceutical additives are all prepared in powder form. Granules are produced by wet granulation, mixed with magnesium stearate, and compressed into tablets. When a test (40 ° C., relative humidity 75%, glass bottle open) was performed, a remarkable elution delay was observed after storage for 1 week.
On the other hand, aripiprazole is suspended in a water-soluble polymer aqueous solution, granules are produced by a wet granulation method together with additives, mixed with tableting with magnesium stearate, and tableted. 75%, glass bottle opened, stored for 1 week), it was found that almost no elution delay was observed. Further studies were made based on this knowledge, and the present invention was completed.
すなわち、本発明は、下記（１）〜（６）の固形製剤を提供することにある。
（１）アリピプラゾール無水物粉末を水溶性高分子水溶液水に懸濁させた懸濁液を、流動状態にある粉末賦形剤に噴霧して、湿式造粒する固形製剤の製造方法。
（２）懸濁液が、中性又は弱アルカリ性である（１）に記載の固形製剤の製造方法。
（３）水溶性高分子がヒプロメロース、ヒドロキシプロピルセルロース、及びメチルセルロースからなる群から選ばれた（１）または（２）記載の固形製剤の製造方法。
（４）水溶性高分子が固形製剤全重量の０．５〜１０重量％を占める（１）〜（３）のいずれかに記載の固形製剤の製造方法。
（５）賦形剤がＤ‐マンニトール、エリスリトール及び乳糖水和物、低置換度ヒドロキシプロピルセルロース、デンプン類、結晶セルロースからなる群から選ばれた１種または２種以上であり、固形製剤全重量の４５〜９５重量％占める（１）〜（４）のいずれかに記載の固形製剤の製造方法。
（６）アリピプラゾール無水物が固形製剤全重量の０．５〜１０重量％占める（１）〜（５）のいずれかに記載の固形製剤の製造方法。
（７）（１）〜（６）のいずれかの方法で記載された粒状固形製剤を滑沢剤と共に圧縮打錠する錠剤の製造方法。
That is, this invention is providing the solid formulation of following (1)-(6).
(1) A method for producing a solid preparation, in which a suspension obtained by suspending an aripiprazole anhydride powder in water-soluble polymer aqueous solution is sprayed onto a powder excipient in a fluid state and wet granulated.
(2) The method for producing a solid preparation according to (1), wherein the suspension is neutral or weakly alkaline.
(3) The method for producing a solid preparation according to (1) or (2), wherein the water-soluble polymer is selected from the group consisting of hypromellose, hydroxypropylcellulose, and methylcellulose.
(4) The method for producing a solid preparation according to any one of (1) to (3), wherein the water-soluble polymer accounts for 0.5 to 10% by weight of the total weight of the solid preparation.
(5) The excipient is one or more selected from the group consisting of D-mannitol, erythritol and lactose hydrate, low-substituted hydroxypropylcellulose, starches, and crystalline cellulose, and the total weight of the solid preparation The manufacturing method of the solid formulation in any one of (1)-(4) which occupies 45 to 95 weight% of this.
(6) The method for producing a solid preparation according to any one of (1) to (5), wherein aripiprazole anhydride accounts for 0.5 to 10% by weight of the total weight of the solid preparation.
(7) A method for producing a tablet, wherein the granular solid preparation described in any one of (1) to (6) is compressed and compressed together with a lubricant.
本発明によれば、アリピプラゾール無水物は水と接触することにより、次第に溶出遅延の原因となる水和物に容易に変化するにもかかわらず、造粒時にアリピプラゾール無水物を水溶性高分子水溶液に懸濁して、流動状態にある賦形剤等に噴霧し、造粒製剤化することにより、アリピプラゾールの溶出速度の遅延が抑制され、長期保存後も一定の品質を保持した粒状製剤とすることができる。 According to the present invention, aripiprazole anhydride is converted into a water-soluble polymer aqueous solution at the time of granulation, even though aripiprazole anhydride is easily changed to a hydrate that gradually causes elution delay by contact with water. By suspending and spraying on excipients in a fluidized state to form a granulated formulation, a delay in the dissolution rate of aripiprazole is suppressed, and a granular formulation that maintains a certain quality even after long-term storage can be obtained. it can.
本発明に係るアリピプラゾール無水物を含有する粒状固形製剤は、湿式造粒法、例えば流動層造粒法や撹拌造粒法等により製造することができる。すなわち、アリピプラゾール無水物を水溶性高分子の水溶液に懸濁させ、賦形剤及び必要により崩壊剤と共に常法により噴霧造粒し、粒状固形製剤とすることができる。
流動層造粒法においては、供給する空気の温度は７５〜９５℃、好ましくは８０〜９０℃であり、噴霧終了後も排気温度が３０〜６０℃到達時、好ましくは３５〜５０℃到達時まで乾燥するのが好ましい。
得られた粒状固形製剤に滑沢剤などを加え、常法により打錠機で打錠すれば錠剤とすることができる。
The granular solid preparation containing an aripiprazole anhydride according to the present invention can be produced by a wet granulation method, such as a fluidized bed granulation method or a stirring granulation method. That is, aripiprazole anhydride can be suspended in an aqueous solution of a water-soluble polymer and spray granulated by a conventional method together with an excipient and, if necessary, a disintegrant, to obtain a granular solid preparation.
In the fluidized bed granulation method, the temperature of the supplied air is 75 to 95 ° C., preferably 80 to 90 ° C., and the exhaust temperature reaches 30 to 60 ° C., preferably 35 to 50 ° C. even after completion of spraying. It is preferable to dry until.
A lubricant can be added to the obtained granular solid preparation and tableted with a tableting machine by a conventional method to form a tablet.
本発明に用いるアリピプラゾール無水物の結晶形は問わない。このアリピプラゾール無水物の粉末は、メディアン径が０．０１〜５０μｍ、好ましくは０．５〜３０μmに粉砕したものを用いるのがよい。 The crystal form of the aripiprazole anhydride used in the present invention is not limited. As the aripiprazole anhydride powder, a powder having a median diameter of 0.01 to 50 μm, preferably 0.5 to 30 μm, may be used.
本発明において用いることのできる水溶性高分子の「水溶性」とは、第１６改正日本薬局方の通則による「溶けやすい」および「極めて溶けやすい」に属する物質である。特に水に溶解した場合、中性〜弱アルカリ性、好ましくは中性を示すものがよい。例としては、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース等のセルロース誘導体があげられ、特にヒドロキシプロピルセルロースが好ましい。また、錠剤にした場合、水溶性高分子の1錠中の好ましい添加量は０．１〜２０重量％であり、より好ましくは０．５〜１０重量％である。 The “water-soluble” of the water-soluble polymer that can be used in the present invention is a substance belonging to “easily soluble” and “extremely soluble” according to the general rules of the 16th revised Japanese Pharmacopoeia. In particular, when it is dissolved in water, it should be neutral to weakly alkaline, preferably neutral. Examples include cellulose derivatives such as hydroxypropylcellulose, hypromellose and methylcellulose, with hydroxypropylcellulose being particularly preferred. Moreover, when it is set as a tablet, the preferable addition amount in 1 tablet of water-soluble polymer is 0.1 to 20 weight%, More preferably, it is 0.5 to 10 weight%.
本発明において噴霧液を噴霧される対象の賦形剤はＤ−マンニトール、乳糖水和物、無水乳糖、エリスリトール、トレハロース、キシリトール、ソルビトール等の糖類の粉末が挙げられ、その中でもＤ−マンニトール、乳糖水和物及びエリスリトールが好ましく、特に好ましいのはＤ−マンニトールである。また、錠剤にした場合、賦形剤の１錠中の好ましい配合量は２０〜９５重量％であり、より好ましくは４５〜９５重量％である。 Examples of excipients to be sprayed with a spray solution in the present invention include powders of sugars such as D-mannitol, lactose hydrate, anhydrous lactose, erythritol, trehalose, xylitol, sorbitol, among which D-mannitol, lactose Hydrates and erythritol are preferred, with D-mannitol being particularly preferred. Moreover, when it is set as a tablet, the preferable compounding quantity in 1 tablet of an excipient | filler is 20 to 95 weight%, More preferably, it is 45 to 95 weight%.
本発明において用いることのできる崩壊剤としては、低置換度ヒドロキシプロピルセルロース、アルファー化デンプン、部分アルファー化デンプン、クロスポピドン等があげられ、特に低置換度ヒドロキシプロピルセルロース、部分アルファー化デンプン及びクロスポピドンが好ましい。また、錠剤にした場合、崩壊剤の1錠中の好ましい配合量は０．１〜６０重量％であり、より好ましくは０．５〜５０重量％である。 Examples of disintegrants that can be used in the present invention include low-substituted hydroxypropylcellulose, pregelatinized starch, partially pregelatinized starch, crospovidone, etc., and particularly low-substituted hydroxypropylcellulose, partially pregelatinized starch, and crospovidone. Is preferred. Moreover, when it is set as a tablet, the preferable compounding quantity in 1 tablet of a disintegrating agent is 0.1 to 60 weight%, More preferably, it is 0.5 to 50 weight%.
本発明において使用される滑沢剤は特に限定されることなく、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、タルク等を用いることができる。 The lubricant used in the present invention is not particularly limited, and magnesium stearate, calcium stearate, stearic acid, sucrose fatty acid ester, glycerin fatty acid ester, talc and the like can be used.
また、本発明は、錠剤の識別性を目的としてアルミニウムレーキ色素、三二酸化鉄、黄色三二酸化鉄、酸化チタン等の着色剤を使用することもあり、顆粒内への添加や混合工程で添加してもよい。 In addition, the present invention may use a coloring agent such as aluminum lake dye, iron sesquioxide, yellow iron sesquioxide, titanium oxide, etc. for the purpose of distinguishing tablets, and it is added in the granule addition or mixing step. May be.
本発明の具体的な製造法としては、たとえば、流動層造粒機内にＤ−マンニトール粉末などの粉末状賦形剤を浮遊流動状態におき、これに水溶性高分子結合剤溶液にアリピプラゾール無水物を懸濁させた懸濁液を噴霧して湿式造粒する固形製造の方法が挙げられる。得られた造粒物は、そのまま顆粒剤としても良いが、さらに必要により滑沢剤や崩壊剤等の粉末と共に、通常の打錠を施せば本発明の湿気により溶出率低下の少ないアリピプラゾール錠剤が得られる。本発明のアリピプラゾール無水物の湿気による溶出率の低下の防止は、流動層造粒機における水性高分子結合剤の溶液に微細粉末として懸濁状態におかれた主薬を含む噴霧液が流動状態にある粉末に付着して粒子を形成させる際、アリピプラゾール無水物の個々の微粒子を水性高分子結合剤で完全に被覆している結果、造粒後にその被膜が湿気のアリピプラゾール無水物の表面に接触するのを阻止するものと考えられる。
本発明で得られる顆粒や錠剤に消化管内での崩壊性を高めるため、流動化粉末や打錠混合物中に低置換度ヒドロキシプロピルセルロースやクロスポピドンを配合することができる。一方、アリピプラゾール無水物粉末を流動化層に配合し、その流動化粉末に水性高分子剤の溶液を噴霧した場合は、アリピプラゾール無水物表面における結合剤の被覆が充分ではなく、造粒、製剤化後のアリピプラゾールの溶出率の低下につながると考えられる。
As a specific production method of the present invention, for example, a powdery excipient such as D-mannitol powder is placed in a floating fluid state in a fluidized bed granulator, and an aripiprazole anhydride is added to the water-soluble polymer binder solution. A solid production method in which the suspension in which the suspension is suspended is sprayed to perform wet granulation. The obtained granulated product may be used as a granule as it is, but if necessary, together with powders such as lubricants and disintegrants, if normal tableting is performed, the aripiprazole tablets with little decrease in dissolution rate due to the moisture of the present invention can be obtained. can get. The prevention of decrease in dissolution rate due to moisture of aripiprazole anhydride according to the present invention is achieved by the spray liquid containing the main agent suspended as a fine powder in the aqueous polymer binder solution in the fluidized bed granulator. When adhering to a powder to form particles, the individual fine particles of aripiprazole anhydride are completely coated with an aqueous polymer binder so that after granulation, the coating contacts the surface of moisture aripiprazole anhydride It is thought to prevent this.
In order to enhance the disintegration property in the digestive tract of the granules and tablets obtained in the present invention, low-substituted hydroxypropylcellulose or crospovidone can be blended in the fluidized powder or tableting mixture. On the other hand, when aripiprazole anhydride powder is blended in the fluidized layer and the aqueous polymer solution is sprayed onto the fluidized powder, the coating of the binder on the aripiprazole anhydride surface is not sufficient, and granulation and formulation This is thought to lead to a decrease in the dissolution rate of aripiprazole later.
本発明においては必要に応じてアスパルテーム等の甘味剤、Ｌ−メントール等の矯味剤、香料等を添加しても良い。 In the present invention, a sweetener such as aspartame, a corrigent such as L-menthol, and a fragrance may be added as necessary.
多くの粉末、顆粒、錠剤等の固形製剤は、気密性の高いガラス瓶に封入されて保存されているが、一旦開封されれば、一日に複数回開栓され大気中の湿気に曝されることになる。湿気により分解したり、変化して消化管内での溶出率が低下する薬物にとってはこの問題は重大である。
アリピプラゾール無水物は消化管内での溶出は比較的速く、体内への吸収率も高いが、湿気に曝されると水を吸収して水和物に変化する。この水和物は消化管での溶出率が低く、体内吸収率も低下する。
本発明で製造された顆粒や錠剤は、湿気のアリピプラゾール無水物への接触を極力防止し、固体製剤の密封容器からの開封後も消化管内での溶出率の低下が抑制されたアリピプラゾール製剤を提供することができる。
Many solid preparations such as powders, granules, and tablets are sealed and stored in highly airtight glass bottles, but once opened, they are opened multiple times a day and exposed to atmospheric moisture. It will be. This problem is significant for drugs that degrade or change due to moisture, which reduces the rate of dissolution in the gastrointestinal tract.
Aripiprazole anhydride dissolves relatively quickly in the gastrointestinal tract and has a high absorption rate in the body, but when exposed to moisture, it absorbs water and changes to a hydrate. This hydrate has a low dissolution rate in the gastrointestinal tract, and the absorption rate in the body also decreases.
The granules and tablets produced in the present invention provide an aripiprazole formulation that prevents contact with moisture aripiprazole anhydride as much as possible and suppresses a decrease in the dissolution rate in the digestive tract even after the solid formulation is opened from a sealed container. can do.
以下に実施例、比較例、試験例等を示し、本発明を具体的に説明する。 Hereinafter, the present invention will be specifically described with reference to Examples, Comparative Examples, Test Examples and the like.
Ｄ−マンニトール７７２.５ｇ（マンニット−Ｐ／三菱商事フードテック製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇをステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１７２ｍｇ、直径８ｍｍの素錠を得た。 D-mannitol 772.5 g (Mannit-P / manufactured by Mitsubishi Corporation Foodtech) was charged into a fluidized bed granulator (MP-01 type / Paurec), and hydroxypropylcellulose 20 g (HPC-L / Nihon Soda) Was sprayed with a solution obtained by dispersing 60 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) in a solution of 265 g of purified water and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 1.5 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). An uncoated tablet having a diameter of 172 mg and a diameter of 8 mm was obtained.
Ｄ−マンニトール７７２.５ｇ（マンニット−Ｐ／三菱商事フードテック製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇを低置換度ヒドロキシプロピルセルロース（ＮＢＤ−０２２／信越化学工業製）８ｇ及びステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８０ｍｇ、直径８ｍｍの素錠を得た。 D-mannitol 772.5 g (Mannit-P / manufactured by Mitsubishi Corporation Foodtech) was charged into a fluidized bed granulator (MP-01 type / Paurec), and hydroxypropylcellulose 20 g (HPC-L / Nihon Soda) Was sprayed with a solution obtained by dispersing 60 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) in a solution of 265 g of purified water and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 8 g of low-substituted hydroxypropylcellulose (NBD-022 / manufactured by Shin-Etsu Chemical Co., Ltd.) and 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), and a rotary tableting machine ( Tableting was performed with Clean Press Collect 19K (manufactured by Kikusui Seisakusho), and an uncoated tablet having a mass of 180 mg and a diameter of 8 mm was obtained.
Ｄ−マンニトール７７２.５ｇ（マンニット−Ｐ／三菱商事フードテック製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇを低置換度ヒドロキシプロピルセルロース（ＮＢＤ−０２２／信越化学工業製）２０ｇ及びステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１９２ｍｇ、直径８ｍｍの素錠を得た。 D-mannitol 772.5 g (Mannit-P / manufactured by Mitsubishi Corporation Foodtech) was charged into a fluidized bed granulator (MP-01 type / Paurec), and hydroxypropylcellulose 20 g (HPC-L / Nihon Soda) Was sprayed with a solution obtained by dispersing 60 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) in a solution of 265 g of purified water and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 20 g of low-substituted hydroxypropylcellulose (NBD-022 / manufactured by Shin-Etsu Chemical Co., Ltd.) and 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), and a rotary tableting machine ( Tableting was performed using a clean press correct 19K (manufactured by Kikusui Seisakusho), and an uncoated tablet having a tablet mass of 192 mg and a diameter of 8 mm was obtained.
Ｄ−マンニトール７７２.５ｇ（マンニット−Ｐ／三菱商事フードテック製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇを低置換度ヒドロキシプロピルセルロース（ＮＢＤ−０２２／信越化学工業製）２０ｇ及びステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量２１７ｍｇ、直径８ｍｍの素錠を得た。 D-mannitol 772.5 g (Mannit-P / manufactured by Mitsubishi Corporation Foodtech) was charged into a fluidized bed granulator (MP-01 type / Paurec), and hydroxypropylcellulose 20 g (HPC-L / Nihon Soda) Was sprayed with a solution obtained by dispersing 60 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) in a solution of 265 g of purified water and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 20 g of low-substituted hydroxypropylcellulose (NBD-022 / manufactured by Shin-Etsu Chemical Co., Ltd.) and 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), and a rotary tableting machine ( Tableting was performed using a clean press correct 19K (manufactured by Kikusui Seisakusho), and an uncoated tablet having a mass of 217 mg and a diameter of 8 mm was obtained.
Ｄ−マンニトール７７２.５ｇ（マンニット−Ｐ／三菱商事フードテック製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒプロメロース２０ｇ（ＴＣ−５Ｅ／信越化学工業製）を精製水２６５ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ、ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇを低置換度ヒドロキシプロピルセルロース（ＮＢＤ−０２２／信越化学工業製）８ｇ及びステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８０ｍｇ、直径８ｍｍの素錠を得た。 D-Mannitol 772.5 g (Mannit-P / Mitsubishi Foodtech) was put into a fluidized bed granulator (MP-01 type / Paurec) and hypromellose 20 g (TC-5E / Shin-Etsu Chemical Co., Ltd.) A solution in which 60 g of aripiprazole (median diameter 9 μm, manufactured by TEVA) was dispersed in a solution dissolved in 265 g of purified water was sprayed and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 8 g of low-substituted hydroxypropylcellulose (NBD-022 / manufactured by Shin-Etsu Chemical Co., Ltd.) and 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), and a rotary tableting machine ( Tableting was performed with Clean Press Collect 19K (manufactured by Kikusui Seisakusho), and an uncoated tablet having a mass of 180 mg and a diameter of 8 mm was obtained.
乳糖水和物７７２.５ｇ（ダイラクトーズＳ／フロイント産業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇを低置換度ヒドロキシプロピルセルロース（ＮＢＤ−０２２／信越化学工業製）８ｇ及びステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８０ｍｇ、直径８ｍｍの素錠を得た。 Lactose hydrate 772.5 g (Dilactose S / Freund Sangyo) is put into a fluidized bed granulator (MP-01 type / Paurec), and hydroxypropylcellulose 20 g (HPC-L / Nihon Soda) is purified water. A liquid in which 60 g of aripiprazole (median diameter 9 μm / manufactured by TEVA) was dispersed in a liquid dissolved in 265 g was sprayed and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 8 g of low-substituted hydroxypropylcellulose (NBD-022 / manufactured by Shin-Etsu Chemical Co., Ltd.) and 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), and a rotary tableting machine ( Tableting was performed with Clean Press Collect 19K (manufactured by Kikusui Seisakusho), and an uncoated tablet having a mass of 180 mg and a diameter of 8 mm was obtained.
Ｄ−マンニトール７７２.５ｇ（マンニット−Ｐ／三菱商事フードテック製）及び低置換度ヒドロキシプロピルセルロース４０ｇ（ＮＢＤ−０２２／信越化学工業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７８．５ｇをステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８０ｍｇ、直径８ｍｍの素錠を得た。 D-mannitol 772.5 g (Mannit-P / manufactured by Mitsubishi Corporation Foodtech) and low-substituted hydroxypropylcellulose 40 g (NBD-022 / Shin-Etsu Chemical Co., Ltd.) are used in a fluidized bed granulator (MP-01 type / Paurek) ) And sprayed with a solution in which 60 g of aripiprazole (median diameter 9 μm / TEVA) is dispersed in a solution of 20 g of hydroxypropylcellulose (HPC-L / manufactured by Nippon Soda) in 265 g of purified water, and an air supply temperature of 85 ° C. Granulated with. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 178.5 g of the obtained sized product is mixed with 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industry), and compressed with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). An uncoated tablet having a diameter of 180 mg and a diameter of 8 mm was obtained.
Ｄ−マンニトール７４２.５ｇ（マンニット−Ｐ／三菱商事フードテック製）及び低置換度ヒドロキシプロピルセルロース４０ｇ（ＮＢＤ−０２２／信越化学工業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース４０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水５３０ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７８．５ｇをステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８０ｍｇ、直径８ｍｍの素錠を得た。 D-mannitol 742.5 g (Mannit-P / manufactured by Mitsubishi Corporation Foodtech) and low-substituted hydroxypropylcellulose 40 g (NBD-022 / Shin-Etsu Chemical Co., Ltd.) were fluidized bed granulator (MP-01 type / Paurek) ), And sprayed with a solution of aripiprazole 60 g (median diameter 9 μm / TEVA) dispersed in a solution of hydroxypropylcellulose 40 g (HPC-L / manufactured by Nippon Soda) in purified water 530 g, and an air supply temperature of 85 ° C. Granulated with. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 178.5 g of the obtained sized product is mixed with 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industry), and compressed with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). An uncoated tablet having a diameter of 180 mg and a diameter of 8 mm was obtained.
Ｄ−マンニトール５１３．５ｇ（マンニット−Ｐ／三菱商事フードテック製）及び低置換度ヒドロキシプロピルセルロース３１０g（ＮＢＤ−０２２／信越化学工業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース９ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水１７１ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７８．５ｇをステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８０ｍｇ、直径８ｍｍ、口腔内崩壊時間３６秒の口腔内崩壊錠を得た。 D-mannitol 513.5 g (Mannit-P / manufactured by Mitsubishi Corporation Foodtech) and low-substituted hydroxypropylcellulose 310 g (NBD-022 / Shin-Etsu Chemical Co., Ltd.) were fluidized bed granulator (MP-01 type / Paurek) ) And sprayed with a solution obtained by dispersing aripiprazole 60 g (median diameter 9 μm / TEVA) in a solution obtained by dissolving 9 g of hydroxypropyl cellulose (HPC-L / manufactured by Nippon Soda Co., Ltd.) in 171 g of purified water, and an air supply temperature of 85 ° C. Granulated with. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 178.5 g of the obtained sized product is mixed with 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industry), and compressed with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). An orally disintegrating tablet having 180 mg, a diameter of 8 mm, and an oral disintegration time of 36 seconds was obtained.
Ｄ−マンニトール５１３．５ｇ（マンニット−Ｐ／三菱商事フードテック製）及び低置換度ヒドロキシプロピルセルロース３１０g（ＮＢＤ−０２２／信越化学工業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース９ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水１７１ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７８．５ｇをクロスポピドン８ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）ステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８８ｍｇ、直径８ｍｍ、口腔内崩壊時間３１秒の口腔内崩壊錠を得た。 D-mannitol 513.5 g (Mannit-P / manufactured by Mitsubishi Corporation Foodtech) and low-substituted hydroxypropylcellulose 310 g (NBD-022 / Shin-Etsu Chemical Co., Ltd.) were fluidized bed granulator (MP-01 type / Paurek) ) And sprayed with a solution obtained by dispersing aripiprazole 60 g (median diameter 9 μm / TEVA) in a solution obtained by dissolving 9 g of hydroxypropyl cellulose (HPC-L / manufactured by Nippon Soda Co., Ltd.) in 171 g of purified water, and an air supply temperature of 85 ° C. Granulated with. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 178.5 g of the obtained sized product is mixed with 8 g of crospovidone (CL-SF / BASF) and 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industry), and a rotary tableting machine (Clean Press Correct 19K / Kikusui Seisakusho). Manufactured) to obtain an orally disintegrating tablet having a tablet weight of 188 mg, a diameter of 8 mm, and an oral disintegration time of 31 seconds.
Ｄ−マンニトール４４３．５ｇ（マンニット−Ｐ／三菱商事フードテック製）及び低置換度ヒドロキシプロピルセルロース３８０g（ＮＢＤ−０２２／信越化学工業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース９ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水１７１ｇに溶解した液にアリピプラゾール６０g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７８．５ｇをクロスポピドン８ｇ（ＣＬ−ＳＦ／ＢＡＳＦ製）ステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８８ｍｇ、直径８ｍｍ、口腔内崩壊時間３５秒の口腔内崩壊錠を得た。 D-mannitol 443.5 g (Mannit-P / manufactured by Mitsubishi Corporation Foodtech) and low-substituted hydroxypropylcellulose 380 g (NBD-022 / Shin-Etsu Chemical Co., Ltd.) are fluidized bed granulator (MP-01 type / Paurek) ) And sprayed with a solution obtained by dispersing aripiprazole 60 g (median diameter 9 μm / TEVA) in a solution obtained by dissolving 9 g of hydroxypropyl cellulose (HPC-L / manufactured by Nippon Soda Co., Ltd.) in 171 g of purified water, and an air supply temperature of 85 ° C. Granulated with. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 178.5 g of the obtained sized product is mixed with 8 g of crospovidone (CL-SF / BASF) and 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industry), and a rotary tableting machine (Clean Press Correct 19K / Kikusui Seisakusho). Manufactured) to obtain an orally disintegrating tablet having a tablet weight of 188 mg, a diameter of 8 mm, and an oral disintegration time of 35 seconds.
〔比較例１〕
アリピプラゾール６０ｇ（メディアン径９μｍ、ＴＥＶＡ製）、乳糖水和物５７２．５ｇ（２００Ｍ／ＤＦＥｐｈａｒｍａ製）、トウモロコシデンプン１００ｇ（日食コーンスターチ／日本食品加工製）及び結晶セルロース１００ｇ（セオラスＰＨ−１０１／旭化成ケミカルズ製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５ｇに溶解した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇを結晶セルロース（セオラスＰＨ−１０１／旭化成ケミカルズ製）８ｇ及びステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８０ｍｇ、直径８ｍｍの素錠を得た。
[Comparative Example 1]
Aripiprazole 60 g (median diameter 9 μm, manufactured by TEVA), lactose hydrate 572.5 g (200 M / DFE pharma), corn starch 100 g (eclipse corn starch / manufactured by Nippon Food Processing), and crystalline cellulose 100 g (Ceolus PH-101 / Asahi Kasei Chemicals) Made in a fluidized bed granulator (MP-01 type / manufactured by POWREC), sprayed with a solution obtained by dissolving 20 g of hydroxypropylcellulose (HPC-L / manufactured by Nippon Soda) in 265 g of purified water, and an air supply temperature of 85 Granulated at ℃. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 8 g of crystalline cellulose (Ceolus PH-101 / Asahi Kasei Chemicals) and 1.5 g of magnesium stearate (Taihei Chemical Industry), and a rotary tableting machine (Clean Press Collect 19K). (Manufactured by Kikusui Seisakusho Co., Ltd.) and tableting was performed to obtain an uncoated tablet having a mass of 180 mg and a diameter of 8 mm.
〔比較例２〕
アリピプラゾール６０ｇ（メディアン径９μｍ／ＴＥＶＡ製）、乳糖水和物５２５ｇ（２００Ｍ／ＤＦＥｐｈａｒｍａ製）及びトウモロコシデンプン２４７．５ｇ（日食コーンスターチ／日本食品加工製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５gに溶解した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇを結晶セルロース（セオラスＰＨ−１０１／旭化成ケミカルズ製）８ｇ及びステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８０ｍｇ、直径８ｍｍの素錠を得た。
[Comparative Example 2]
Aripiprazole 60 g (median diameter 9 μm / manufactured by TEVA), lactose hydrate 525 g (200 M / manufactured by DFEpharma) and corn starch 247.5 g (sun eclipse corn starch / manufactured by Nippon Food Processing) were fluidized bed granulator (MP-01 type / And a solution obtained by dissolving 20 g of hydroxypropylcellulose (HPC-L / manufactured by Nippon Soda) in 265 g of purified water was sprayed and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 8 g of crystalline cellulose (Ceolus PH-101 / Asahi Kasei Chemicals) and 1.5 g of magnesium stearate (Taihei Chemical Industry), and a rotary tableting machine (Clean Press Collect 19K). (Manufactured by Kikusui Seisakusho Co., Ltd.) and tableting was performed to obtain an uncoated tablet having a mass of 180 mg and a diameter of 8 mm.
〔比較例３〕
アリピプラゾール６０ｇ（メディアン径９μｍ／ＴＥＶＡ製）及びＤ-マンニトール７７２.５ｇ（マンニット−Ｐ／三菱商事フードテック製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５ｇに溶解した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇをステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１７２ｍｇ、直径８ｍｍの素錠を得た。
[Comparative Example 3]
Aripiprazole 60 g (median diameter 9 μm / manufactured by TEVA) and D-mannitol 772.5 g (mannit-P / manufactured by Mitsubishi Corporation Foodtech) were introduced into a fluidized bed granulator (MP-01 type / manufactured by POWREC), and hydroxypropyl A solution obtained by dissolving 20 g of cellulose (HPC-L / manufactured by Nippon Soda Co., Ltd.) in 265 g of purified water was sprayed and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 1.5 g of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). An uncoated tablet having a diameter of 172 mg and a diameter of 8 mm was obtained.
〔比較例４〕
アリピプラゾール６０ｇ（メディアン径９μｍ／ＴＥＶＡ製）及びＤ−マンニトール７７２.５ｇ（マンニット−Ｐ／三菱商事フードテック製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース２０ｇ（ＨＰＣ−Ｌ／日本曹達製）を精製水２６５ｇに溶解した液を噴霧し、給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１７０．５ｇを低置換度ヒドロキシプロピルセルロース（ＮＢＤ−０２２／信越化学工業製）８ｇ及びステアリン酸マグネシウム１．５ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１８０ｍｇ、直径８ｍｍの素錠を得た。
[Comparative Example 4]
Aripiprazole 60 g (median diameter 9 μm / manufactured by TEVA) and D-mannitol 772.5 g (mannit-P / manufactured by Mitsubishi Corporation Foodtech) were introduced into a fluidized bed granulator (MP-01 type / manufactured by POWREC), and hydroxypropyl A solution obtained by dissolving 20 g of cellulose (HPC-L / manufactured by Nippon Soda Co., Ltd.) in 265 g of purified water was sprayed and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 170.5 g of the obtained sized product is mixed with 8 g of low-substituted hydroxypropylcellulose (NBD-022 / manufactured by Shin-Etsu Chemical Co., Ltd.) and 1.5 g of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.), and a rotary tableting machine ( Tableting was performed with Clean Press Collect 19K (manufactured by Kikusui Seisakusho), and an uncoated tablet having a mass of 180 mg and a diameter of 8 mm was obtained.
［溶出試験１］
実施例１〜１１及び比較例１〜４で得た錠剤について、室温下ガラス瓶密栓保存（通常保存）した錠剤と、温度４０℃、相対湿度７５％（過酷条件保存）で７日保存した後の錠剤について、第１６改正日本薬局方・一般試験法の溶出試験法により試験開始６０分後の溶出率を求め、結果を表１に示した。
使用した装置：溶出試験機／ＮＴＲ−６１００型（富山産業製）
紫外線吸光光度計／ＵＶ−１６００型（島津製作所製）
測定条件：試験液：ｐＨ５．０酢酸緩衝液
試験液量：９００ｍＬ
パドル回転数：７５ｒｐｍ
液温：３７℃
測定波長：２１６ｎｍ及び３２５ｎｍ
[Elution test 1]
About the tablets obtained in Examples 1 to 11 and Comparative Examples 1 to 4, after being stored for 7 days at a temperature of 40 ° C. and a relative humidity of 75% (severe condition storage) with a glass bottle sealed stopper storage (normal storage) at room temperature For the tablets, the dissolution rate 60 minutes after the start of the test was determined by the dissolution test method of the 16th revised Japanese Pharmacopoeia / General Test Method, and the results are shown in Table 1.
Equipment used: Dissolution tester / NTR-6100 (Toyama Sangyo)
UV absorption photometer / UV-1600 type (manufactured by Shimadzu Corporation)
Measurement conditions: Test solution: pH 5.0 acetate buffer
Test solution volume: 900 mL
Paddle rotation speed: 75rpm
Liquid temperature: 37 ° C
Measurement wavelength: 216 nm and 325 nm
Ｄ−マンニトール９３６ｇ（グラニュトールＳ／フロイント産業製）及び低置換度ヒドロキシプロピルセルロース５４ｇ（ＮＢＤ−０２０／信越化学工業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース６ｇ（ＨＰＣ−Ｌ／日本曹達製）、ヒプロメロース２４ｇ（ＴＣ−５（Ｅ）／信越化学工業製）及び青色２号アルミニウムレーキ（三栄原エフ・エフ・アイ製）を精製水５５２ｇに溶解・懸濁した液にアリピプラゾール３６g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品８８ｇをケイ酸カルシウム１ｇ（フローライトＲＥ／エーザイ・フードケミカル製）及びステアリン酸マグネシウム１ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量９０ｍｇ、直径６ｍｍの素錠を得た。 936 g of D-mannitol (manufactured by Granitol S / Freund Sangyo) and 54 g of low-substituted hydroxypropyl cellulose (NBD-020 / manufactured by Shin-Etsu Chemical) were charged into a fluidized bed granulator (MP-01 type / manufactured by Paul Wrec), Hydroxypropylcellulose 6g (HPC-L / manufactured by Nippon Soda), hypromellose 24g (TC-5 (E) / manufactured by Shin-Etsu Chemical) and blue No. 2 aluminum lake (manufactured by Saneihara F.F.I.) to 552 g of purified water A solution in which 36 g of aripiprazole (median diameter 9 μm / manufactured by TEVA) was dispersed in the dissolved and suspended liquid was sprayed and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 88 g of the obtained sized product is mixed with 1 g of calcium silicate (Florite RE / Eisai Food Chemical) and 1 g of magnesium stearate (Taihei Chemical Sangyo), and a rotary tableting machine (Clean Press Collect 19K / Kikusui). Manufactured by Seisakusho Co., Ltd., and tableted to obtain an uncoated tablet having a weight of 90 mg and a diameter of 6 mm.
Ｄ−マンニトール９７２．９ｇ（グラニュトールS／フロイント産業製）及び低置換度ヒドロキシプロピルセルロース５４ｇ（ＮＢＤ−０２０／信越化学工業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース４．５ｇ（ＨＰＣ−Ｌ／日本曹達製）及びヒプロメロース２７ｇ（ＴＣ−５（Ｅ）／信越化学工業製）を精製水６０３ｇに溶解・懸濁した液にアリピプラゾール５４g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品２３３．６ｇをステアリン酸マグネシウム１．４ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１２５ｍｇ、直径７ｍｍの素錠を得た。 D-Mannitol 972.9 g (Granitol S / Freund Sangyo) and low-substituted hydroxypropylcellulose 54 g (NBD-020 / Shin-Etsu Chemical) are put into a fluidized bed granulator (MP-01 type / Paurec). In addition, 54 g of aripiprazole (median diameter) was obtained by dissolving and suspending 4.5 g of hydroxypropyl cellulose (HPC-L / manufactured by Nippon Soda) and 27 g of hypromellose (TC-5 (E) / manufactured by Shin-Etsu Chemical) in 603 g of purified water. A liquid in which 9 μm / TEVA) was dispersed was sprayed and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 233.6 g of the obtained sized product is mixed with 1.4 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). An uncoated tablet of 125 mg and a diameter of 7 mm was obtained.
Ｄ−マンニトール１００１ｇ（グラニュトールＳ／フロイント産業製）及び低置換度ヒドロキシプロピルセルロース５６ｇ（ＮＢＤ−０２０／信越化学工業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース７ｇ（ＨＰＣ−Ｌ／日本曹達製）、ヒプロメロース２８ｇ（ＴＣ−５（Ｅ）／信越化学工業製）及び黄色三二酸化鉄１．０５ｇ（癸巳化成製）を精製水６６５ｇに溶解・懸濁した液にアリピプラゾール８４g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品１６８ｇをステアリン酸マグネシウム２ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量１７０ｍｇ、直径８ｍｍの素錠を得た。 1001 g of D-mannitol (manufactured by Granitol S / Freund Sangyo) and 56 g of low-substituted hydroxypropyl cellulose (NBD-020 / manufactured by Shin-Etsu Chemical Co., Ltd.) were charged into a fluidized bed granulator (MP-01 type / manufactured by POWREC). 7 g of hydroxypropyl cellulose (HPC-L / manufactured by Nippon Soda), 28 g of hypromellose (TC-5 (E) / manufactured by Shin-Etsu Chemical Co., Ltd.) and 1.05 g of yellow iron sesquioxide (manufactured by Hatake Kasei) are dissolved in 665 g of purified water. A liquid in which 84 g of aripiprazole (median diameter 9 μm / manufactured by TEVA) was dispersed was sprayed into the clouded liquid and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 168 g of the obtained sized product is mixed with 2 g of magnesium stearate (manufactured by Taihei Chemical Industry) and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho), 1 tablet mass 170 mg, diameter 8 mm The uncoated tablet was obtained.
Ｄ−マンニトール１００１ｇ（グラニュトールＳ／フロイント産業製）及び低置換度ヒドロキシプロピルセルロース５６ｇ（ＮＢＤ−０２０／信越化学工業製）を流動層造粒機（ＭＰ−０１型／パウレック製）に投入し、ヒドロキシプロピルセルロース７ｇ（ＨＰＣ−Ｌ／日本曹達製）、ヒプロメロース２８ｇ（ＴＣ−５（Ｅ）／信越化学工業製）及び三二酸化鉄０．１８ｇ（癸巳化成製）を精製水６６５ｇに溶解・懸濁した液にアリピプラゾール８４g（メディアン径９μｍ／ＴＥＶＡ製）を分散した液を噴霧し給気温度８５℃で造粒した。引き続き給気温度８５℃で排気温度が４０℃になるまで乾燥した後、網目２４ｍｅｓｈのステンレス製篩で篩過した。得られた整粒品３３６ｇをステアリン酸マグネシウム４ｇ（太平化学産業製）と共に混合し、ロータリー式打錠機（クリーンプレスコレクト１９Ｋ／菊水製作所製）にて、打錠し１錠質量３４０ｍｇ、長径１３．５ｍｍ、短径６．５ｍｍの素錠を得た。 1001 g of D-mannitol (manufactured by Granitol S / Freund Sangyo) and 56 g of low-substituted hydroxypropyl cellulose (NBD-020 / manufactured by Shin-Etsu Chemical Co., Ltd.) were charged into a fluidized bed granulator (MP-01 type / manufactured by POWREC). Dissolve and suspend 7 g of hydroxypropyl cellulose (HPC-L / manufactured by Nippon Soda), 28 g of hypromellose (TC-5 (E) / manufactured by Shin-Etsu Chemical Co., Ltd.) and 0.18 g of iron sesquioxide (manufactured by Kasei Chemical) in 665 g of purified water. The liquid obtained was sprayed with a liquid in which 84 g of aripiprazole (median diameter 9 μm / manufactured by TEVA) was dispersed, and granulated at an air supply temperature of 85 ° C. Subsequently, after drying at an air supply temperature of 85 ° C. until the exhaust temperature reached 40 ° C., the mixture was sieved with a stainless steel sieve having a mesh of 24 mesh. 336 g of the obtained sized product is mixed with 4 g of magnesium stearate (manufactured by Taihei Chemical Sangyo) and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). 1 tablet mass 340 mg, major axis 13 An uncoated tablet with a diameter of 0.5 mm and a minor axis of 6.5 mm was obtained.
［溶出試験２］
実施例１２〜１５で得た錠剤について、室温下ガラス瓶密栓保存の錠剤と、温度４０℃、相対湿度７５％で１ヶ月保存した後の錠剤について、第１６改正日本薬局方・一般試験法の溶出試験法により試験開始５分後、１０分後、１５分後、３０分後、４５分後、６０分後及び９０分後の溶出率を求め、結果を図１〜図４に示した。
使用した装置：溶出試験機／ＮＴＲ−６１００型（富山産業製）
紫外線吸光光度計／ＵＶ−１６００型（島津製作所製）
測定条件：試験液：ｐＨ５．０酢酸緩衝液
試験液量：９００ｍＬ
パドル回転数：７５ｒｐｍ
液温：３７℃
測定波長：２１６ｎｍ及び３２５ｎｍ
[Dissolution test 2]
For tablets obtained in Examples 12 to 15, dissolution of glass bottle sealed at room temperature and tablets after storage for 1 month at a temperature of 40 ° C. and a relative humidity of 75% were dissolved in the 16th revised Japanese Pharmacopoeia / general test method. The dissolution rates after 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes and 90 minutes after the start of the test were determined by the test method, and the results are shown in FIGS.
Equipment used: Dissolution tester / NTR-6100 (Toyama Sangyo)
UV absorption photometer / UV-1600 type (manufactured by Shimadzu Corporation)
Measurement conditions: Test solution: pH 5.0 acetate buffer
Test solution volume: 900 mL
Paddle rotation speed: 75rpm
Liquid temperature: 37 ° C
Measurement wavelength: 216 nm and 325 nm
図１〜図４から、本発明に係る実施例１２〜１５の錠剤における開始時と苛酷試験後のプロファイルは殆ど変化していないことがわかる。 1 to 4, it can be seen that the profiles at the start and after the severe test in the tablets of Examples 12 to 15 according to the present invention hardly change.
本発明によれば、長期間一定の品質（溶出速度）を担保したアリピプラゾールの固形製剤を製造することができ、有用な統合失調症薬を医療現場に提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, the solid preparation of aripiprazole which ensured constant quality (elution rate) for a long period can be manufactured, and a useful schizophrenia drug can be provided to a medical field.
図１〜図４中の実線は、それぞれ室温下ガラス瓶密栓保存した錠剤の溶出率に関する折れ線グラフを示す。
図１〜図４中の点線は、それぞれ温度４０℃、相対湿度７５％で1ヶ月保存した後の錠剤の溶出率に関する折れ線グラフを示す。
The solid line in FIGS. 1-4 shows the line graph regarding the elution rate of the tablet each preserve | saved glass bottle sealed at room temperature.
The dotted lines in FIGS. 1 to 4 show line graphs relating to the dissolution rate of tablets after storage for 1 month at a temperature of 40 ° C. and a relative humidity of 75%, respectively.
Claims (4)
The method for producing a solid preparation according to any one of claims 1 to 3, wherein the suspension is neutral or weakly alkaline.
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| JP2016177306A Expired - Fee Related JP6183979B2 (en) | 2012-11-30 | 2016-09-12 | Method for producing solid preparation containing aripiprazole anhydride |
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| JP2013244646A Expired - Fee Related JP6007169B2 (en) | 2012-11-30 | 2013-11-27 | Method for producing solid preparation containing aripiprazole anhydride |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6007169B2 (en) * | 2012-11-30 | 2016-10-12 | 大原薬品工業株式会社 | Method for producing solid preparation containing aripiprazole anhydride |
| JP6071083B2 (en) * | 2015-06-12 | 2017-02-01 | 大原薬品工業株式会社 | Powder containing aripiprazole with improved stability |
| CN106474058B (en) * | 2015-08-31 | 2020-01-07 | 南京诺瑞特医药科技有限公司 | Injectable aripiprazole suspension formulations with extended shelf life |
| CN106389343A (en) * | 2016-09-24 | 2017-02-15 | 万全万特制药江苏有限公司 | Oral aripiprazole liquid dry suspension agent and preparation method thereof |
| JP7211136B2 (en) * | 2019-02-14 | 2023-01-24 | ニプロ株式会社 | Tablet and manufacturing method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60138722D1 (en) * | 2000-09-22 | 2009-06-25 | Dainippon Sumitomo Pharma Co | ORAL PREPARATIONS WITH ADVANTAGEOUS COATING CHARACTERISTICS |
| DE60124895D1 (en) * | 2001-07-26 | 2007-01-11 | Ethypharm Sa | Coated allylamines or benzylamines containing granules, process for the preparation and in the oral cavity dispersible tablets containing the coated granules |
| AR033485A1 (en) * | 2001-09-25 | 2003-12-26 | Otsuka Pharma Co Ltd | MEDICINAL SUBSTANCE OF ARIPIPRAZOL OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME |
| WO2004089344A1 (en) * | 2003-04-01 | 2004-10-21 | Ohara Chmical Industries, Ltd. | Process for producing tablet |
| US8865722B2 (en) * | 2006-01-05 | 2014-10-21 | Teva Pharmaceutical Industries Ltd. | Wet formulations of aripiprazole |
| MY152789A (en) * | 2007-07-31 | 2014-11-28 | Otsuka Pharma Co Ltd | Methods for producing aripiprazole suspension and freeze-dried formulation |
| JP2009057331A (en) * | 2007-08-31 | 2009-03-19 | Ohara Yakuhin Kogyo Kk | Glimepiride-containing drug product |
| JP2012036163A (en) * | 2010-08-03 | 2012-02-23 | Mylan Seiyaku Ltd | STABLE SOLID PHARMACEUTICAL COMPOSITION CONTAINING COMPOUND HAVING HMG-CoA REDUCTASE INHIBITING ACTIVITY |
| JP2012056909A (en) * | 2010-09-10 | 2012-03-22 | Fuji Chem Ind Co Ltd | Pharmaceutical composition having bitter taste medicine of reduced bitter taste |
| JP6007169B2 (en) * | 2012-11-30 | 2016-10-12 | 大原薬品工業株式会社 | Method for producing solid preparation containing aripiprazole anhydride |
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| Publication number | Publication date |
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| JP6007169B2 (en) | 2016-10-12 |
| JP2016204393A (en) | 2016-12-08 |
| JP2014129343A (en) | 2014-07-10 |
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