TWI634908B - 包含有7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽之錠劑 - Google Patents
包含有7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽之錠劑 Download PDFInfo
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- TWI634908B TWI634908B TW101137267A TW101137267A TWI634908B TW I634908 B TWI634908 B TW I634908B TW 101137267 A TW101137267 A TW 101137267A TW 101137267 A TW101137267 A TW 101137267A TW I634908 B TWI634908 B TW I634908B
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- weight
- lozenge
- cellulose
- salt
- coating
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- 150000003839 salts Chemical class 0.000 title claims abstract description 62
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 title 1
- 239000007937 lozenge Substances 0.000 claims abstract description 120
- 239000011248 coating agent Substances 0.000 claims abstract description 47
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 36
- 229920002472 Starch Polymers 0.000 claims abstract description 35
- 239000011230 binding agent Substances 0.000 claims abstract description 34
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 34
- 235000019698 starch Nutrition 0.000 claims abstract description 32
- 239000008107 starch Substances 0.000 claims abstract description 31
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 27
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 27
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 26
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 21
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000003086 colorant Substances 0.000 claims abstract description 21
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 21
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 21
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 19
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims abstract description 19
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- 239000008120 corn starch Substances 0.000 claims abstract description 18
- 239000008101 lactose Substances 0.000 claims abstract description 18
- 239000011734 sodium Substances 0.000 claims abstract description 18
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 18
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 17
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- 239000004480 active ingredient Substances 0.000 claims abstract description 12
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims abstract description 12
- 235000015424 sodium Nutrition 0.000 claims abstract description 11
- PMEOBWNILIPZFJ-UHFFFAOYSA-N 4-(1-benzothiophen-4-yl)piperidine Chemical compound C1CNCCC1C1=CC=CC2=C1C=CS2 PMEOBWNILIPZFJ-UHFFFAOYSA-N 0.000 claims abstract description 7
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 28
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- 239000007788 liquid Substances 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
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- 229940083542 sodium Drugs 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
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- 238000005550 wet granulation Methods 0.000 claims description 4
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- VMIRJNDPLCQEHB-UHFFFAOYSA-N 1-(1-benzothiophen-4-yl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=C1C=CS2 VMIRJNDPLCQEHB-UHFFFAOYSA-N 0.000 claims 1
- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 claims 1
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- 239000000454 talc Substances 0.000 abstract description 9
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 abstract description 7
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- -1 metal salts Chemical class 0.000 description 24
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- 239000000654 additive Substances 0.000 description 9
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 8
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- 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 6
- 229930006000 Sucrose Natural products 0.000 description 6
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 6
- 238000007922 dissolution test Methods 0.000 description 6
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
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- 239000005720 sucrose Substances 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 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 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 4
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- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 4
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 4
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 4
- 238000004898 kneading Methods 0.000 description 4
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 3
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Abstract
本發明係有關於一種含有作為一活性成份之7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽之錠劑,其具有優異分解能力、貯存穩定性,及光穩定性。
本發明之錠劑含有作為一活性成份之7-[4-(4-苯并[b]噻吩-4-基-哌
Description
本發明係有關於包含作為一活性成份之7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽之錠劑。
7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮(於下稱為化合物(I))或其鹽係已知作為多巴胺D2受體部份促效劑、5-羥色胺5-HT2A受體拮抗劑,及α1腎上腺素性受體拮抗劑,與5-羥色胺吸收抑制劑(或5-羥色胺再吸收抑制劑)(專利文獻1),及於治療中樞神經系統疾病(特別是精神分裂症)擁有廣泛治療範圍。
PTL 1:日本未審查專利公告第2006-316052號案。
本發明之一目的係提供一種錠劑,其包含作為一活性成份之化合物(I)或其鹽,且具有優異分解能力、貯存穩定性,及高的光穩定性。
本案發明人進行密集研究達成上述目的,且發現一錠劑,其包含作為一活性成份之化合物(I)或其鹽及進一步包含乳糖、玉米澱粉、微結晶纖維素等賦形劑;低取代之羥丙基纖維素、交聯羧甲纖維素鈉、羧甲基澱粉鈉等分解劑;及羥丙基纖維素等結合劑,展現優異分解能力及貯存穩定性。本案發有人進一步發現較高之光穩定性可藉由塗敷一含著色劑之塗層而達成。本發明係經由以此發現為主之進一步研究而完成,且提供下列項目。
項目1.一種錠劑,包含7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽,係作為一活性成份。
項目2. 如項目1之錠劑,進一步包含:一賦形劑(a)、一結合劑(b)、一分解劑(c),及一潤滑劑(d),其中,此賦形劑(a)係至少一選自由糖、糖醇、澱粉,及纖維素所構成族群之成員;此結合劑(b)係一纖維素衍生物;此分解劑(c)係至少一選自由纖維素衍生物及澱粉衍生物所構成族群之成員;且此潤滑劑(d)係一硬脂酸鹽。
項目3. 如項目2之錠劑,其中,此賦形劑(a)係至少一選自由乳糖、玉米澱粉,及微結晶纖維素所構成族群之成員;
此結合劑(b)係羥丙基纖維素;此分解劑(c)係至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及羧甲基澱粉鈉所構成族群之成員;且此潤滑劑(d)係硬脂酸鎂。
項目4. 如項目2或3之錠劑,其中,此錠劑係一未經塗覆之錠劑,相對於未經塗覆之錠劑的重量,係包含:0.05至25重量%之7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽;10至98.5重量%之賦形劑(a);0.1至20重量%之結合劑(b);1至25重量%之分解劑(c);及0.1至10重量%之潤滑劑(d)。
項目5. 如項目2至4中任一者之錠劑,其中,每1重量份之7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽,此錠劑包含:1至2000重量份之賦形劑(a);0.01至100重量份之結合劑(b);0.1至500重量份之分解劑(c);及0.01至50重量份之潤滑劑(d)。
項目6. 如項目1至5中任一者之錠劑,其進一步包含於其表面上之一塗層。
項目7. 如項目6之錠劑,其進一步包含於此塗層內之著色劑(e),
其中,此著色劑(e)含有氧化鐵,且相對於此塗層之重量,此錠劑含有0.1至50重量%之著色劑(e)。
項目8. 如項目1至7中任一者之錠劑,其係藉由將經由濕式粒化而獲得之一經粒化之物質形成一錠劑而獲得。
項目9. 如項目1至8中任一者之錠劑,其中,此錠劑不含有普維酮(povidone)或交聯普維酮(crospovidone)。
項目10. 一種用於製造錠劑之方法,此方法包含步驟:(1)將含有7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽、一賦形劑(a)、一結合劑(b),及一分解劑(c)之一混合物粒化,及進一步將一潤滑劑(d)混合入其中;及(2)將獲得之混合物形成一錠劑,其中,此賦形劑(a)係至少一選自由糖、糖醇、澱粉,及纖維素所構成族群之成員;此結合劑(b)係一纖維素衍生物;此分解劑(c)係至少一選自由纖維素衍生物及澱粉衍生物所構成族群之成員;且此潤滑劑(d)係一硬脂酸鹽。
項目11. 如項目10之用於製造錠劑之方法,進一步包含步驟:(3)將一塗覆劑、一著色劑(e),及一液體介質混
合獲得一混合物,及使用此混合物塗覆此錠劑之表面。
本發明之錠劑展現優異之分解能力、貯存穩定性,及高的光穩定性,使得其可有效地用於醫藥領域。
圖1係顯示於範例1-1至1-3及範例2-1至2-3獲得之錠劑的溶解測試結果之圖。
本發明之錠劑包含作為一活性成份之化合物(I)或其鹽。
此處,本發明之錠劑可為不具有塗敷其上之塗層(如其後所述)的一未經塗覆之錠劑,或具有塗敷於其表面上之塗層的一經塗覆之錠劑。再者,本發明之錠劑可作為一經口分解錠劑。
化合物(I)或其鹽可藉由已知方法製造,例如,揭示於日本未審查專利公告的2006-316052號案,或以此為主之方法。
化合物(I)之鹽不受特別限制,只要其係藥理學上可接受。其較佳例子包括:無機鹽之鹽,諸如,金屬鹽,包括鹼金屬鹽(例如,鈉鹽及鉀鹽)及鹼土金屬鹽(例如,鈣鹽及鎂鹽)、銨鹽、鹼金屬碳酸鹽(例如,碳酸鋰、碳酸鉀、碳酸鈉,及碳酸銫)、鹼金屬碳酸氫鹽(例如,碳酸氫鋰、碳
酸氫鈉,及碳酸氫鉀),及鹼金屬氫氧化物(例如,氫氧化鋰、氫氧化鈉、氫氧化鉀,及氫氧化銫);有機鹼之鹽,諸如,三(較低)烷基胺(例如,三甲基胺、三乙基胺,及N-乙基二異丙基胺)、吡啶、喹啉、哌啶、咪唑、甲基吡啶、二甲基胺基吡啶、二甲基苯胺、N-(較低)烷基嗎啉(例如,N-甲基嗎啉)、1,5-二氮雜二環[4.3.0]壬-5-烯(DBN)、1,8-二氮雜二環[5.4.0]十一碳-7-烯(DBU)、1,4-二氮雜二環[2.2.2]辛烷(DABCO);無機酸鹽,諸如,氫氯酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、硝酸鹽,及磷酸鹽;有機酸鹽,諸如,甲酸鹽、乙酸鹽、丙酸鹽、草酸鹽、丙二酸鹽、琥珀酸鹽、福馬酸鹽、馬來酸鹽、乳酸鹽、蘋果酸鹽、檸檬酸鹽、酒石酸鹽、碳酸鹽、苦味酸鹽、甲烷磺酸鹽、乙烷磺酸鹽、對-甲苯磺酸鹽,及麩胺酸鹽等。
如上型式之化合物(I)或其鹽可單獨或以二或更多種之組合使用。
相對於錠劑重量(當錠劑係一經塗覆之錠劑時,係塗敷塗層前之未經塗覆的錠劑之重量),化合物(I)或其鹽之含量較佳係約0.05至25重量%,且更佳係約0.1至15重量%。相對於錠劑重量(當錠劑係一經塗覆之錠劑時,係塗敷塗層前之未經塗覆的錠劑之重量),化合物(I)或其鹽之含量較佳係約0.05至25重量%,且更佳係約0.1至15重量%。
本發明之錠劑較佳係包含添加劑,諸如,賦形劑(a)、結合劑(b)、分解劑(c),及潤滑劑(d)。
賦形劑(a)之例子包括,例如,糖,諸如,果糖、
綿白糖、蔗糖、粉末狀蔗糖、乳糖、粉末狀氫化麥芽糖澱粉糖漿,及麥芽糖;糖醇,諸如,D-甘露醇、D-山梨醇、木糖醇、赤藻糖醇、麥芽糖醇;澱粉,諸如,小麥澱粉、玉米澱粉,及馬鈴薯澱粉;澱粉衍生物,諸如,糊精、β-環糊精;纖維素或其衍生物,諸如,微結晶纖維素、粉末狀纖維素、乙基纖維素、羧甲基纖維素(carmellose)、羧甲基纖維素鈉(carmellose sodium),及微結晶纖維素/羧甲基纖維素鈉;矽酸或其鹽,諸如,輕無水矽酸、水合二氧化矽、二氧化矽、矽酸鈣、矽酸鎂,及鋁偏矽酸鎂;高嶺土;氧化鈦;氧化鎂;滑石;沉澱之碳酸鈣;無水二元磷酸鈣。
此等賦形劑(a)可單獨或以二或更多種之組合使用。其中,糖、糖醇、澱粉,及纖維素係較佳,且乳糖、微結晶纖維素,及玉米澱粉係更佳。
賦形劑(a)含量不受特別限制,且相對於錠劑重量(當錠劑係經塗覆時,係未經塗覆之錠劑的重量),較佳係約10至98.5重量%。
賦形劑(a)之量不受特別限制,且較佳係每1重量份之化合物(I)或其鹽為約1至2000重量份。
結合劑(b)之例子包括蔗糖;綿白糖;預凝膠澱粉;部份預凝膠澱粉;纖維素或其衍生物,諸如,微結晶纖維素、甲基纖維素、乙基纖維素、羧甲基纖維素鈉(carmellose sodium).羥乙基纖維素、羥乙基甲基纖維素、羥丙基纖維素、低取代之羥丙基纖維素、羥丙基甲基纖維素(羥丙基甲基纖維素,諸如,羥丙基甲基纖維素2208、羥
丙基甲基纖維素2906,及羥丙基甲基纖維素2910);其它多醣,諸如,阿拉伯膠、粉末狀阿拉伯膠、洋菜、粉末狀洋菜、瓜耳膠、黃蓍膠、粉末狀黃蓍膠、普魯蘭,及果膠;以丙烯酸為主之聚合物,諸如,甲基丙烯酸共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S、丙烯酸乙酯-甲基丙烯酸甲酯共聚物分散液、胺基烷基甲基丙烯酸酯共聚物E,及胺基烷基甲基丙烯酸酯共聚物RS;海藻酸鈉;經純化之明膠;水解明膠粉末;羧乙烯基聚合物;共普維酮;普維酮;聚乙烯醇。此等結合劑(b)可單獨或以二或更多種之組合而使用。其中,纖維素衍生物係較佳,且羥丙基纖維素係更佳。需注意當普維酮被包含作為結合劑(b)時,獲得之錠劑易具有降低之光穩定性及貯存穩定性。因此,若此組份係實質上不被包含係更佳。
結合劑(b)之含量不受特別限制,且相關於錠劑重量(當錠劑係經塗覆時,係未經塗覆之錠劑的重量),較佳係約0.1至20重量%。
結合劑(b)之量不受特別限制,且每1重量份之化合物(I)或其鹽較佳係約0.01至100重量份。
分解劑(c)之例子包括澱粉或其衍生物,諸如,小麥澱粉、玉米澱粉、馬鈴薯澱粉、部分預凝膠澱粉、羧甲基澱粉鈉,及羥丙基澱粉;纖維素或其衍生物,諸如,微結晶纖維素、羧甲基纖維素(carmellose)、羧甲基纖維素鈣(carmellose calcium)、交聯羧甲纖維素鈉,及低取代羥丙基纖維素;交聯普維酮;海藻酸;及膨潤土。此等分解劑
(c)可單獨或以二或更多種之組合使用。其中,澱粉或其衍生物,及纖維素或其衍生物係較佳,且羧甲基澱粉鈉、羧甲基纖維素鈣、交聯羧甲纖維素鈉,及低取代羥丙基纖維素係更佳。需注意當包括交聯普維酮時,獲得之錠劑易具有降低之光穩定性及貯存穩定性。因此,若實質上不包含此組份係更佳。
此處,於本說明書中,“低取代之羥丙基纖維素”係含有約5至16%之羥丙基基團之纖維素衍生物。於低取代之羥丙基纖維素中之羥丙基基團之量可藉由,例如,於日本藥典(Japanese Pharmacopeia)中列示之方法測量。低取代之羥丙基纖維素可藉由此項技藝已知之方法製造,或其可購得之產品亦可被使用。低取代之羥丙基纖維素之可購得產品的例子不受限制地包括Shin-Etsu Chemical Co.,Ltd.製造之“LH系列”及“NBD系列”。
再者,於本說明書中,“羥丙基纖維素”係含有約50至85%之羥丙基基團之纖維素衍生物。羥丙基纖維素中之羥丙基基團之量可藉由,例如,於日本藥典中列示之方法測量。羥丙基纖維素可藉由此項技藝已知之方法製造,或其可購得之產品亦可被使用。羥丙基纖維素之可購得產品之例子不受限制地包括Nippon Soda Co.,Ltd.製造之“HPC系列”;及Hercules Inc.製造之“Klucel系列”。
於本說明書中,“羧甲基澱粉鈉”係含有約6至11%的鈉澱粉衍生物。
分解劑(c)之含量不受特別限制,且相對於錠劑
重量(當錠劑係經塗覆,係未經塗覆之錠劑的重量),較佳係約1至25重量%。
再者,分解劑(c)之量不受特別限制,且係每1重量份之化合物(I)或其鹽較佳為約0.1至500重量份。再者,分解劑(c)之量不受特別限制,且係每1重量份之化合物(I)或其鹽較佳為約0.1至500重量份。
潤滑劑(d)之例子包括硬脂酸或其鹽,諸如,硬脂酸、硬脂酸鋁、硬脂酸鈣,及硬脂酸鎂;巴西棕櫚蠟;脂肪酸之二醇酯;氫化油;黃蜂蠟;白蜂蠟;硬脂基福馬酸鈉;及聚乙二醇(聚乙二醇類,諸如,聚乙二醇400、聚乙二醇600、聚乙二醇1500、聚乙二醇4000,及聚乙二醇6000)。此等潤滑劑(d)可單獨或以二或更多種之組合而使用。其中,硬脂酸鹽、脂肪酸之蔗糖酯,及氫化油係較佳,且硬脂酸鎂係更佳。
潤滑劑(d)之含量不受特別限制,且相對於錠劑重量(當錠劑係經塗覆時,係未經塗覆之錠劑的重量),較佳係約0.1至10重量%。
潤滑劑(d)之含量不受特別限制,且係每1重量份之化合物(I)或其鹽較佳為約0.01至50重量份。
除賦形劑(a)、結合劑(b)、分解劑(c),及潤滑劑(d)外,本發明之錠劑可包含其它組份。其它組份之例子包括可應用於錠劑之各種添加劑,諸如,著色劑、pH調節劑、防腐劑、吸收劑、增味劑、抗氧化劑、緩衝劑、螯合劑、研磨劑、溶劑、硬化劑、界面活性劑、甜料、流化劑、增
亮劑,及香料。此等組份可以不會對本發明有不利影響之量使用。
本發明之錠劑可以一未經塗覆之錠劑使用,其係包含上述組份,但不具有於其上提供之所述塗層。錠劑可使用一塗覆劑塗覆以便為一經塗覆之錠劑(經膜塗覆之錠劑),以便達成長期貯存穩定劑及避免由於光等而降解。
用於製造本發明錠劑之方法不受特別限制;例如,本發明之錠劑可藉由將含有化合物(I)或其鹽,及用以形成錠劑所需之除了化合物(I)或其鹽以外之組份(即,賦形劑(a)、結合劑(b)、分解劑(c)、潤滑劑(d)等)之混合物形成錠劑之步驟而製造。另外,本發明之錠劑可藉由包含下列之方法製造:將含有化合物(I)或其鹽、賦形劑(a)、結合劑(b),及分解劑(c)之混合物粒化,及進一步對其混入潤滑劑(d);及將獲得之混合物形成一錠劑。
用於將經粒化之物質形成一錠劑之粒化方法不受特別限制。其例子包括乾式粒化方法及濕式粒化方法(例如,流體化床粒化方法,及捏合粒化方法)。其中,由能將錠劑之活性成份及其它組份均勻混合及能獲得其組份係於其內均勻分佈之錠劑的觀點,濕式粒化方法係較佳地用於此製造。
錠劑形成方法之例子包括錠劑化,諸如,直接壓製錠劑化、乾式錠劑化、濕式錠劑化,及外部潤滑錠劑化。
一未經塗覆之錠劑包含作為活性成份之化合物
(I)或其鹽,及賦形劑(a)、結合劑(b)、分解劑(c),及潤滑劑(d)。化合物(I)或其鹽及添加劑係與於上述段落“1.錠劑”中提供者相同。需注意一未經塗覆之錠劑係欲被塗覆前之一錠劑,且可藉由對其提供其後描述之塗層而轉化成一經塗覆之錠劑。另外,錠劑可於未對其提供一塗層而使用。
相對於未經塗覆之錠劑的重量,化合物(I)或其鹽之含量較佳係約0.05至25重量%,更佳係約0.1至15重量%。
未經塗覆之錠劑中所含之添加劑的特別較佳例子包括:作為賦形劑(a)之至少一選自由糖、糖醇、澱粉,及纖維素所構成族群之成員;作為結合劑(b)之一纖維素衍生物;;作為分解劑(c)之至少一選自由纖維素衍生物及澱粉衍生物所構成族群之成員;及作為潤滑劑(d)之硬脂酸鹽。
作為賦形劑(a)所含之糖、糖醇、澱粉,及纖維素之例子包括:糖,諸如,果糖、綿白糖、蔗糖、粉末狀蔗糖、乳糖、粉末狀氫化麥芽糖澱粉糖漿,及麥芽糖;糖醇,諸如,D-甘露醇、D-山梨醇、木糖醇、赤藻糖醇,及麥芽糖醇;澱粉,諸如,小麥澱粉、玉米澱粉,及馬鈴薯澱粉;及纖維素,諸如,微結晶纖維素。
作為結合劑(b)所含之纖維素衍生物之例子包括甲基纖維素、乙基纖維素、羧甲基纖維素欽(carmellose sodium)、羥乙基纖維素、羥乙基甲基纖維素、羥丙基纖維
素、低取代之羥丙基纖維素,及羥丙基甲基纖維素(羥丙基甲基纖維素,諸如,羥丙基甲基纖維素2208、羥丙基甲基纖維素2906,及羥丙基甲基纖維素2910)。
作為分解劑(c)所含之纖維素衍生物及澱粉衍生物之例子包括:纖維素衍生物,諸如,羧甲基纖維素(carmellose)、羧甲基纖維素鈣(carmellose calcium)、交聯羧甲纖維素鈉,及低取代之羥丙基纖維素;及澱粉衍生物,諸如,羧甲基澱粉鈉,及羥丙基澱粉。
作為潤滑劑(d)所含之硬脂酸鹽的例子包括硬脂酸鹽,諸如,硬脂酸鋁、硬脂酸鈣,及硬脂酸鎂。
由生產力及分解能力之觀點,此等添加劑較佳係以如下之組合使用:作為賦形劑(a)之至少一選自由乳糖、玉米澱粉,及微結晶纖維素所構成族群之成員;作為結合劑(b)之羥丙基纖維素;作為分解劑(c)之至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及羧甲基澱粉鈉所構成族群之成員;及作為潤滑劑(d)之硬脂酸鎂。
相對於未經塗覆之錠劑的重量,賦形劑(a)之含量較佳係約10至98.5重量%,更佳係約20至95重量%,且更佳係約30至90重量%。再者,賦形劑(a)之量係每1重量份之化合物(I)或其鹽為較佳為約1至2000重量份,且更佳為約3至1800重量份。藉由如上所述般設定賦形劑(a)之含量及量,製造應用性可被改良。
相對於未經塗覆之錠劑的重量,結合劑(b)之含量較佳係約0.1至20重量%,更佳係約0.3至10重量%,且更
佳係約0.5至5重量%。再者,結合劑(b)之量係每1重量份之化合物(I)或其鹽較佳為約0.01至100重量份,且更佳為約0.1至50重量份。藉由如上所述般設定結合劑(b)之含量及量,製造應用性及分解能力可被改良。
相對於未經塗覆之錠劑的重量,分解劑(c)之含量較佳係約1至25重量%,更佳係約2至20重量%,且更佳係約3至15重量%。再者,分解劑(c)之量係每1重量份之化合物(I)或其鹽較佳為約0.1至500重量份,更佳為約1至500重量份,且更佳為約1至250重量份。藉由如上所述般設定分解劑(c)之含量及量,分解能力可被改良。
相對於未經塗覆之錠劑的重量,潤滑劑(d)之含量較佳係約0.1至10重量%,更佳係約0.2至8重量%,且更佳係約0.3至7重量%。再者,潤滑劑(d)之量係每1重量份之化合物(I)或其鹽較佳為約0.01至50重量份,且更佳為約0.02至30重量份。藉由如上所述般設定潤滑劑(d)之量,錠劑化適合性可被改良。
此等組份之每一者的較佳含量及量係如下所示。
未經塗覆之錠劑內之每一組份之含量化合物(I)或其鹽:0.05至20重量% 糖及/或糖醇:20至80重量% 澱粉:5至50重量% 纖維素:1至30重量% 羥丙基纖維素:0.1至20重量% 至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素
鈉,及澱粉衍生物所構成族群之成員:1至25重量%1至25重量% 硬脂酸鹽:0.1至10重量%
未經塗覆之錠劑之每1重量份之化合物(I)或其鹽,每一組份之量糖及/或糖醇:1至1000重量份 澱粉:1至400重量份 纖維素:0.1至200重量份 羥丙基纖維素:0.01至100重量份 至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及澱粉衍生物所構成族群之成員:0.1至500重量份 硬脂酸鹽:0.01至50重量份
更佳模式之未經塗覆之錠劑內每一組份之含量及量係如下所示:
未經塗覆之錠劑內之每一組份之含量化合物(I)或其鹽:0.1至15重量% 乳糖:30至60重量% 玉米澱粉:10至30重量% 微結晶纖維素:5至20重量% 羥丙基纖維素:0.5至10重量% 至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及羧甲基澱粉鈉所構成族群之成員:2至15重量%
硬脂酸鎂:0.1至10重量%
未經塗覆之錠劑內每1重量份之化合物(I)或其鹽,每一組份之量乳糖:2至500重量份 玉米澱粉:2至200重量份 微結晶纖維素:0.5至100重量份 羥丙基纖維素:0.05至50重量份 至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及羧甲基澱粉鈉所構成族群之成員:1至250重量份 硬脂酸鎂:0.05至30重量份
用於製造本發明錠劑之方法的例子包括於上述段落“1.錠劑”中解釋者。
特別地,本發明之錠劑可藉由將含有化合物(I)或其鹽及用以形成錠劑所需之除了化合物(I)或其鹽以外之組份(即,賦形劑(a)、結合劑(b)、分解劑(c)、潤滑劑(d)等)之混合物形成一錠劑之步驟製造。另外,本發明之錠劑可藉由包含下述之方法製造:將含有化合物(I)或其鹽、賦形劑(a)、結合劑(b),及分解劑(c)之混合物粒化,及對其進一步混入潤滑劑(d);及將獲得之混合物形成一錠劑。
用於上述步驟之化合物(I)或其鹽、賦形劑(a)、結合劑(b)、分解劑(c),及潤滑劑(d)之摻合比率及摻合量被設定以便於未經塗覆之錠劑內獲得每一組份之上述含量及量。
本發明之錠劑可藉由於如上段落“1-1.未經塗覆之錠劑”上進一步提供一塗層而以一經塗覆之錠劑獲得。有關於經塗覆之錠劑,在具有於其上提供之塗層前之一未經塗覆的錠劑係與“1-1.未經塗覆之錠劑”相同。
塗覆劑之例子包括:纖維素衍生物,諸如,微結晶纖維素、,甲基纖維素、乙基纖維素、羧甲基纖維素鈉、羥丙基纖維素,及羥丙基甲基纖維素(羥丙基甲基纖維素);聚乙二醇(聚乙二醇);聚乙烯醇;氧化鈦;及滑石。此等塗覆劑可單獨或以二或更多種之組合而使用。其中,羥丙基甲基纖維素(羥丙基甲基纖維素)、滑石,及氧化鈦之組合係較佳。需注意當聚乙二醇(聚乙二醇)存在於塗覆劑,獲得之錠劑易具有降低之光穩定性及貯存穩定性。因此,若實質上不包含聚乙二醇(聚乙二醇)係更佳。
再者,有關於經塗覆之錠劑,藉由使塗層層著色,可提供經塗覆之錠劑光穩定性。因此,著色劑(e)較佳係添加至用於塗覆此錠劑之塗覆劑。
著色劑(e)之例子包括:氧化鐵,諸如,紅氧化鐵、黃氧化鐵,及黑氧化鐵;氧化鈦;β-胡蘿蔔素;食用藍色2號;食用藍色2號色淀;及核黃素。
其中,由不僅對錠劑增加顏色而且進一步改良錠劑之光穩定性的觀點,含有氧化鐵係更佳。
著色劑(e)可依製備之經塗覆的錠劑之顏色而定適當選擇或組合使用。例如,為獲得一白色之經塗覆的
錠劑,係使用氧化鈦;為獲得一紅色之經塗覆的錠劑,係使用氧化鈦及紅色氧化鐵之組合;為獲得一黃色之經塗覆的錠劑,係使用氧化鈦及黃色氧化鐵之組合;為獲得一藍色之經塗覆的錠劑,係使用氧化鈦及食用藍色2號鋁淀之組合;為獲得一橙色之經塗覆的錠劑,係使用氧化鈦、紅色氧化鐵,及黃色氧化鐵之組合;為獲得一綠色之經塗覆的錠劑,係使用氧化鈦、黃色氧化鐵,及黑色氧化鐵之組合;及為獲得一紫色之經塗覆的錠劑,係使用氧化鈦、紅色氧化鐵,及黑色氧化鐵之組合。如上所述,一經塗覆之錠劑可被製成各種不同顏色。
相對於經塗覆之錠劑之總重量,著色劑(e)之含量較佳係約0.1至3重量%,且相對於經塗覆之錠劑的塗層重量,係約5至50重量%。
使用塗覆劑及著色劑(e)(若需要而被包含)塗覆之於錠劑之塗層的量係每100重量份之於具有於其上提供之塗層前之錠劑(未經塗覆之錠劑)較佳為約1至10重量份。
於一經塗覆之錠劑,有關用於具有於其上提供之塗層前的錠劑(未經塗覆之錠劑)之添加劑之較佳組合,糖、糖醇或其衍生物、澱粉或其衍生物、纖維素或其衍生物,及硬脂酸鹽之組合係較佳。於上述段落“1-1.未經塗覆之錠劑”提供者可作為此等添加劑之特別例子。
有關於上述添加劑組合,作為未經塗覆之錠劑內之化合物(I)或其鹽、糖、糖醇或其衍生物、澱粉或其衍生物、纖維素或其衍生物,及硬脂酸鹽之量及含量;於上述
段落“1-1.未經塗覆之錠劑”中之添加劑之較佳組合之量及含量可被使用。
再者,當本發明之錠劑係一經塗覆之錠劑,一更佳之組合係藉由於一未經塗覆之錠劑上塗覆一塗層而獲得之調配物;其中,未經塗覆之錠劑含有化合物(I)或其鹽、乳糖、玉米澱粉、微結晶纖維素、低取代之羥丙基纖維素、羥丙基纖維素,及硬脂酸鎂,且塗層包含羥丙基甲基纖維素、滑石、氧化鈦,及至少一選自由紅氧化鐵、黃氧化鐵,及黑氧化鐵所構成族群之著色劑(e)(氧化鐵)。
較佳模式之經塗覆的錠劑中之每組份之較佳含量及量,及每一組份之更佳含量及量係如下所示。
未經塗覆之錠劑內之每一組份之含量化合物(I)或其鹽0.05至20重量% 糖及/或糖醇:20至80重量% 澱粉:5至50重量% 纖維素:1至30重量% 羥丙基纖維素:0.1至20重量% 至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及澱粉衍生物所構成族群之成員:1至25重量% 硬脂酸鹽:0.1至10重量%
塗層內之每一組份之含量(每一整個經塗覆之錠劑)纖維素衍生物:1至6重量%
滑石:0.1至1重量% 氧化鈦:0.1至2重量% 氧化鐵:0.01至1重量%
經塗覆之錠劑內每一組份之量,每1重量份之化合物(I)或其鹽乳糖:1至1000重量份 澱粉:1至400重量份 纖維素:0.1至200重量份 羥丙基纖維素:0.01至100重量份 至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及澱粉衍生物所構成族群之成員:0.1至500重量份 硬脂酸鹽:0.01至50重量份 羥丙基甲基纖維素:0.1至50重量份 滑石:0.01至10重量份 氧化鈦:0.01至20重量份 氧化鐵:0.0005至5重量份
一更佳模式之經塗覆的錠劑內之每一組份之含量及量係如下所示。化合物(I)或其鹽:0.1至15重量% 乳糖:30至60重量% 玉米澱粉:10至30重量% 微結晶纖維素:5至20重量% 羥丙基纖維素:0.5至10重量%
至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及羧甲基澱粉鈉所構成族群之成員:2至15重量% 硬脂酸鎂:0.1至10重量%
塗層內之每一組份的含量(每一完整之經塗覆的錠劑)羥丙基甲基纖維素:1.5至4重量% 滑石:0.2至0.5重量% 氧化鈦:0.2至1重量% 氧化鐵:0.02至0.5重量%
經塗覆之錠劑內每一組份之量,每1偅量份之化合物(I)或其鹽乳糖:2至500重量份 玉米澱粉:2至200重量份 微結晶纖維素:0.5至100重量份 羥丙基纖維素:0.05至50重量份 至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及羧甲基澱粉鈉所構成族群之成員:1至250重量份 硬脂酸鎂:0.05至30重量份 羥丙基甲基纖維素:0.2至40重量份 滑石:0.02至8重量份 氧化鈦:0.02至15重量份 氧化鐵:0.001至2.5重量份
一種用於製造經塗覆的錠劑之方法包含,例如,下列步驟:將一塗覆劑、一著色劑(e),及一液體介質混合;及將獲得之混合物液體噴灑於未經塗覆之錠劑的表面上,及接連地將其乾燥。
作為用於製造未經塗覆的錠劑之方法,於如上段落“1.錠劑”及“1-1.未經塗覆之錠劑”中提供之方法可被使用。
用於上述步驟之液體介質(例如,分散介質)之例子包括:水;甲醇、乙醇、異丙醇等之較低醇;丙酮、甲基乙基酮等之酮;二氯甲烷、二氯乙烷、氯仿、四氯化碳等之烴;及此等溶劑之混合物。
用於上述步驟之化合物(I)或其鹽、賦形劑(a)、結合劑(b)、分解劑(c)、潤滑劑(d)、著色劑(e),及塗覆劑之摻合比率及摻合量被設定,以便獲得於經塗覆之錠劑內之每一組份之上述含量及量。
本發明之錠劑較佳係包含約0.05至25毫克之量(以化合物(I)計算)之作為活性成份之化合物(I)或其鹽。
本發明錠劑之劑量係依據所欲用途;患者之年齡、性別,及其它狀況;疾病之嚴重性等而適當地選擇。此劑量係較佳地被選擇,使得被取用之化合物(I)(即,活性成份)或其鹽之量係每天為約0.05至6毫克(以化合物(I)計算)。
本發明於下參考範例作詳細解釋。但是,本發明
之範圍不限於此等範例。注意於如下所述之所有範例,化合物(I)係“7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮”。
化合物(I)之未經塗覆的錠劑(未以一塗覆劑塗覆之錠劑)係使用表1所示之組份及量,藉由依循如下所述之程序製造。
化合物(I)、乳糖、玉米澱粉、微結晶纖維素(CEOLUS PH-301),及低取代之羥丙基纖維素(LH-11,由Shin-Etsu Chemical Co.,Ltd.製造,羥丙基基團含量:10.0至12.9%)被稱重及混合。一個別製得之羥丙基纖維素之水溶液添加至粉末混合物,其後係濕式捏合粒化。將結果乾燥及分粒後,添加硬脂酸鎂並且混合。形成之混合物使用裝設直徑6.5mm之沖頭的單打錠機,以使錠劑重量變成100毫克之方式壓製,獲得每一錠劑含有10毫克的化合物(I)之未經塗覆的錠劑。
化合物(I)、乳糖、玉米澱粉、微結晶纖維素,及交聯羧甲纖維素鈉被稱重及混合。一個別製得之羥丙基纖維素之水溶液添加至粉末混合物,其後係濕式捏合粒化。將結果乾燥及分粒後,添加硬脂酸鎂並且混合。形成之混合物使用裝設直徑6.5mm之沖頭的單打錠機,以使錠劑重量變成100毫克之方式壓製,獲得每一錠劑含有10毫克
的化合物(I)之未經塗覆的錠劑。
化合物(I)、乳糖、玉米澱粉、微結晶纖維素,及羧甲基澱粉鈉被稱重及混合。一個別製得之羥丙基纖維素之水溶液添加至粉末混合物,其後係濕式捏合粒化。將結果乾燥及分粒後,添加硬脂酸鎂並且混合。形成之混合物使用裝設直徑6.5mm之沖頭的單打錠機,以使錠劑重量變成100毫克之方式壓製,獲得每一錠劑含有10毫克的化合物(I)之未經塗覆的錠劑。
表2顯示範例1-1至1-3獲得之未經塗覆之錠劑的錠劑性質。
分解測試結果顯示每一範例之六個錠劑的測量結果。測試係使用水作為測試液體依據日本藥典之分解測試實施(無輔助盤)。
範例1-1至1-3製造之未經塗覆之錠劑(每一者具有100毫克之重量且含有10毫克之化合物(I))係接受藉由噴灑包含組份及量係於表3所示之塗覆劑的塗覆液體之塗覆,藉此獲得經塗覆之錠劑。
分解測試係對範例2-1至2-3製造之經塗覆的錠
劑實施。表4顯示結果。未觀察到由於塗覆而於分解時間延遲。
溶解測試係對範例1-1至1-3製造之未經塗覆的錠劑及範例2-1至2-3製造之經塗覆的錠劑實施。圖1顯示結果。
溶解測試結果顯示每一範例二錠劑之測量結果的平均值。溶解測試係依據日本藥典之溶解測試方法(槳式法;50 rpm),使用具pH 4.5之磷酸氫二鈉-檸檬酸緩衝溶液(900毫升)作為測試液體實施。
溶解測試結果確認範例1-1至1-3製造之未經塗覆的錠劑及範例2-1至2-3製造之經塗覆的錠劑之優異溶解分佈。
再者,穩定性測試係對範例1-1至1-3製造之未經塗覆的錠劑及範例2-1至2-3製造之經塗覆的錠劑,於1.8 x 106 lux.hr之總照度及40℃(一個月,三個月)之貯存條件下實施。化合物(I)之含量及每一狀況貯存後之雜質被測量。表5顯示結果。
注意於1.8 x 106 lux.hr之總照度貯存後,於範例1-1至1-3製造之未經塗覆的錠劑觀察到變黃色。
使用表6所示之組份及量,含有每一錠劑為0.25毫克之化合物(I)之未經塗覆的錠劑係以與範例1-1相同之方式製造,但使用裝設直徑6.0之沖頭之一旋轉式打錠機,獲得每一者具有90毫克重量之未經塗覆的錠劑。
範例3-1製造之未經塗覆的錠劑(每一者具有90
毫克重量且含有0.25毫克之化合物(I))接受藉由噴灑包含組份及量係顯示於表7之塗覆劑的塗覆液體之塗覆,藉此獲得經塗覆之錠劑。
再者,穩定性測試係對範例3-1製造之未經塗覆的錠劑及範例3-2至3-9製造之經塗覆的錠劑,於1.8 x 106 lux.hr總照度及40℃/75% RH(三個月,六個月)之貯存條件下(即,與範例1-1至1-3及範例2-1至2-3者相同或更嚴格之條件)實施。每一條件貯存後之雜質含量被測量。表8顯示結
果。
範例3-5及3-7之錠劑未觀察到雜質增加,即使於光照寸(總照度:1.8 x 106 lux.hr)後。
含表9所示之組份及量之範例4-1至4-13之化合物(I)之經塗覆的錠劑係以與範例3-2相同方式製造。
包含苯并噻吩化合物(I)或其鹽之本發明錠劑具有優異之分解能力、貯存穩定性,及光穩定性。因此,本發明之錠劑係高度可用於醫藥領域。
Claims (7)
- 一種錠劑,包含作為一活性成份之7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽、一賦形劑(a)、一結合劑(b)、一分解劑(c),及一潤滑劑(d),其中,該賦形劑(a)係至少一選自由乳糖、玉米澱粉,及微結晶纖維素所構成族群之成員;該結合劑(b)係羥丙基纖維素;該分解劑(c)係至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉(croscarmellose sodium),及羧甲基澱粉鈉所構成族群之成員;且該潤滑劑(d)係硬脂酸鎂;該錠劑進一步包含於其表面上之一塗層,其中該塗層內含有氧化鈦及一著色劑(e),該著色劑(e)含有氧化鐵,且該塗層實質上不含有聚乙二醇。
- 如申請專利範圍第1至3項中任一項之錠劑,其相對於該塗層之重量,該錠劑含有0.1至50重量%之該著色劑(e)。
- 如申請專利範圍第1至3項中任一項之錠劑,其係藉由將經由濕式粒化而獲得之一經粒化之物質形成一錠劑而獲得。
- 如申請專利範圍第1至3項中任一項之錠劑,其中,該錠劑不含有普維酮(povidone)或交聯普維酮(crospovidone)。
- 一種用於製造錠劑之方法,該方法包含以下步驟:(1)將含有7-[4-(4-苯并[b]噻吩-4-基-哌-1-基)丁氧基]-1H-喹啉-2-酮或其鹽、一賦形劑(a)、一結合劑(b),及一分解劑(c)之一混合物粒化,及進一步將一潤滑劑(d)混合入其中;(2)將獲得之混合物形成一錠劑;及(3)將一塗覆劑、氧化鈦、一著色劑(e),及一液體介質混合獲得一塗覆混合物,及使用該塗覆混合物塗覆該錠劑之表面;其中,該賦形劑(a)係至少一選自由乳糖、玉米澱粉,及微結晶纖維素所構成族群之成員;該結合劑(b)係羥丙基纖維素;該分解劑(c)係至少一選自由低取代之羥丙基纖維素、交聯羧甲纖維素鈉,及羧甲基澱粉鈉所構成族群之成員;該潤滑劑(d)係硬脂酸鎂;該著色劑(e)含有氧化鐵,且該塗覆混合物實質上不含有聚乙二醇。
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