TW200302742A - Rapidly disintegrable solid preparation - Google Patents
Rapidly disintegrable solid preparation Download PDFInfo
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- TW200302742A TW200302742A TW091134035A TW91134035A TW200302742A TW 200302742 A TW200302742 A TW 200302742A TW 091134035 A TW091134035 A TW 091134035A TW 91134035 A TW91134035 A TW 91134035A TW 200302742 A TW200302742 A TW 200302742A
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- A61K31/33—Heterocyclic compounds
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Description
200302742
經濟部智慧財產局員工消費合作社印製 1 [技術領域] 本發明有關一種於唾液存在之口腔,少量水,或胃中 具有快速崩解性之固態製劑,尤其有關—種可作為口服可 崩解固態製劑之可快速崩解之固態製劑。 [背景技藝] 迄今極需發展一種對老人或孩童於無水下易於服用之 可口服崩解之固態製劑。揭示此製劑之背景技藝如下。 JP-A-9-48726號揭示一種可口服快速崩解之製劑,係 於增濕條件下,以模塑方式使之濕化製得。其包括藥物及 經模塑及乾燥後可保留形狀之材料。此等材料例舉糖、糖 醇及水溶性聚合物。 JP-A-9-71523號揭示一種含有藥物、結晶纖維素、低 取代經丙基纖維素.及潤滑劑之錠劑,其於口腔中具有快速 崩解性。 EP-A839526號揭示一種含有藥理活性成分、赤蘇糠 醇、結晶纖維素及崩解劑之固態醫藥製劑。 然而,此等背景技藝並未揭示本發明之⑴藥理活性成 分,(ii)糖及(iii)具有5重量%或以上至低於7重量%之輕 丙氧基之低取代經丙基纖維素。 [發明揭示] 迄今極需發展一種可快速崩解之固態製劑,係於唾液 存在於口腔、少量水或胃中具有快速崩解性,且具有合宜 強度(硬度),而於製程及分配中不受損害,又不粗糙。 本發明有關: 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 200302742 A7 B7 ^ "η 五、發明說明(2 ) (1) 一種可快速崩解之固態製劑,包括⑴藍索皮唑以外 之藥理活性成分,(ii)醣類及(iii)具有5重量%或以上至低 於7重量%之羥丙氧基之低取代羥丙基纖維素; (2) 上述(1)之製劑,係口服可快速崩解之固態製劑; (3) 上述(1)或(2)之製劑,係錠劑; (4) 上述(1)之製劑,其中醣類為糠醇; (5) 上述(4)之製劑,其中糠醇為甘露糖醇或赤蘚糖醇; (6) 上述(1)之製劑,其中醣類對每1〇〇重量份固態製劑 為5至97重量份; (7) 上述(1)之製劑,其中具有5重量%或以上至低於7 重量%羥丙氧基之低取代羥丙基纖維素,對每100重量份 固態製劑使用3至50重量份; (8) 上述(1)之製劑,其中藥理活性成分不為藍索皮唑 (lansoprazole); (9) 上述(1)之製劑,其中藥理活性成分為弗里波 (voglibose); (10) 上述(1)之製劑,其中藥理活性成分為馬弟平 (manidipine)鹽酸鹽; (11) 上述(1)之製劑,其中藥理活性成分為皮利隆 (pioglitazone)鹽酸鹽; (12) 上述(1)之製劑,其中藥理活性成分為卡沙丹 (candesartan cilexetil); (13) 上述(3)之製劑,包括細粒; (14) 上述(13)之製劑,其中藥理活性成分包括於細粒 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 (請先閱讀背面之注意事項再填寫本頁) ·· 訂---------線! 經濟部智慧財產局員工消費合作社印製 2 200302742 A7 B7 五、發明說明(3 ) 中; (15) 上述(14)之製劑,其中⑴糖及(ϋ)具有5重量%或 以上至低於7重量%羥丙氧基之低取代羥丙基纖維素均包 括於細粒除外之固態製劑中; (16) 上述(15)之製劑,其中糖對每1〇〇重量份細粒除外 之剩餘固態製劑為5至97重量份; (17) 上述(15)之製劑,其中具有5重量%或以上至低於 7重量%羥丙氧基之低取代羥丙基纖維素,對每〗〇〇重量 份細粒除外之剩餘固態製劑為3至50重量份; (18) —種具有5重量%或以上至低於7重量%經丙氧基 之低取代羥丙基纖維素之用途,係用以製造包括藥理活性 成分及糖之可快速崩解之固態製劑;及 (19) 一種改良包括藥理活性成分及糖之固態製劑之快 速朋解性之方法,其特徵在:其中包含具有5重量%或以 上至低於7重量%羥丙氧基之低取代羥丙基纖維素; II藥理活性成分 本發明所用之藥理活性成分係呈任何狀態,例如固 態、粉狀、晶狀、油狀及溶液狀態。此等藥理活性成分 例如選自下述之群中之一種或多種成分:營養劑及強心 劑、解熱-止痛_消炎藥、精神治療劑、抗焦慮藥、抗抑鬱 劑、安眠-鎮靜藥、鎮痙劑、中樞神經系統藥、腦代謝好轉 劑、腦循環好轉劑、鎮癇劑、擬交感神經劑、腸胃劑、解 酸劑、抗癀瘍劑、鎮咳袪痰劑、止吐劑、呼吸促進谢支 _氣管擴張齊j、抗過敏藥、齒頻藥、抗組織胺劑、強心劑、 本紙張尺度適用中國國家標準(CNS)人4規格(210 X 297公釐) 310743Ό01 閱 讀 背 面 之 注 項 再 填 i :裝 頁 訂 ▲ 3 經濟部智慧財產局員工消費合作社印製 4 200302742 A7 ____ B7 五、發明說明(4 ) 心律不整防治藥、利尿劑、抗高血壓劑、血管緊縮劑、冠 狀血管擴張劑、周邊血管擴張劑、抗低脂血劑、利膽劑、 抗生素、化學治療藥、抗糖尿劑、骨質疏鬆劑、抗風濕劑、 骨骼肌弛緩劑、抗眩暈劑、荷爾蒙、生物鹼麻醉劑、磺胺 藥、痛風劑、血凝抑制劑、抗腫瘤劑、阿茲海默症藥,等。 營養劑及強心劑例如:維生素,如維生素A、維生素 D、維生素E(如,d- α 生育酚乙酸酯等)、維生素&(如, 二苯甲醯硫胺素、呋喃硫胺鹽酸鹽等)、維生素B2(如,核 黃素丁酸酯等)' 維生素B6(如,吡哆醇鹽酸鹽等)、維生素 C(如,抗壞血酸、L-抗壞血酸鈉等)及維生素B12(如,羥始 胺乙酸酯 '氰鈷胺等);礦物質如鈣、鎂、鐵等;蛋白質、 胺基酸、募糖、生藥等。 解熱-止痛-消炎藥例如:阿斯匹林(aspirin)、捕熱息痛 (acetaminophen)、乙柳醯胺(ethenzamide)、異丁苯乙酸 (ibuprofen)、苯海拉明(diphenhydramine)鹽酸鹽、氯苯吡 胺馬來酸鹽(de-chlorpheniramine maleate)、二氳可待因磷 酸醋(dihydrocodeine phosphate)、那可汀(noscapine)、曱基 麻黃驗(methylephedrine)鹽酸鹽、苯基丙醇胺鹽酸鹽、咖 啡因、無水咖啡因、鋸齒肽酶(serrapeptase)、溶菌酶氣化 物、托納米酸(tolfenamic acid)、甲滅酸(mefenamic acid)、 雙氯滅痛(sodium diclofenac)、氟滅酸(flufenamic acid)、 水楊酸胺、胺基比林(aminopyrine)、酮普洛芬 (ketoprofen)、消炎痛(indometacin)、布可龍(bucolome)、 鎮痛新(pentazocine)等。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 5 200302742 A7 ----- B7 五、發明說明(5 ) 精神抑制劑例如氣苯噻卩井(chlorpromazine)、蛇根鹼 (reserpine)等 〇 抗焦慮藥例如三氮二氮平(alpraz〇lam)、氯二氮平 (chlordiazepoxide)、二氮平(diazepam)等。 抗抑鬱劑例如伊米胺(imipramine)、麥普替林 (maprotiline)鹽酸鹽 '苯異丙胺(amphetamine)等。 | 女眠鎮靜藥例如泰若蘭(estazolam)、财妥眠 (nitrazepam)、二氮平(diazepam)、甲哌畊二苯氮草 (perlapine)、***(phen〇barbital)等。 鎮痙劑例如:東茛菪驗(scopolamine)氳溴酸鹽、苯海 拉明(diphenhydramine)鹽酸鹽、罌粟鹼(papaverine)鹽酸 鹽等。 中樞神經系統藥例如胞二填膽驗(citicoline)等。 腦代謝好轉劑例如氣酯醒(mecl〇fenoxate)鹽酸鹽 等。
I 腦循壞好轉劑例如文波丁(vinp〇eetine)等。 鎮癇劑例如二苯乙内醢脲(phenytoin)、卡巴氮平 (carbamazepine)等 〇 擬交感神經劑例如異丙去甲腎上腺素(isoproterenol) 鹽酸鹽等。 腸胃劑例如健胃消化劑,如殿粉酶(diastase)、含糖胃 蛋白酶、東茛菪(scopolia)浸膏、纖維素酶AP3、脂酶AP 及桂皮油;腸失調劑如小 驗(berberine)氯化物、财乳酸 細菌、乳酸桿菌等。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 n ϋ 1 t ϋ ϋ n n ϋ n I « ϋ n I I ϋ I ϋ-ί*-Γο, n ϋ n ϋ ϋ n I (請先閱讀背面之注意事項再填寫本頁) 200302742 A7 _______ B7 五、發明說明(6 ) 解酸劑例如碳酸鎂、碳酸氫鈉、鋁矽酸鎂、合成含水 鋁鎂鹽基性碳酸鹽、沈澱碳酸鈣、氧化鎂等。 抗潰瘍劑例如藍索皮坐(lansoprazole)、歐米皮嗤 (omeprazole)、拉伯皮嗤(rabeprazole)、泛托皮口坐 (pantoprazole)、礴莫替定(famotidine)、希美替定 (cimetidine)、雷尼替定(ranitidine)鹽酸鹽等。 鎮咳祛痰劑例如咳平(chloperastine)鹽酸鹽、右旋美索 务(dextromethorphan)氫漠酸鹽、茶驗(theophylline)、愈創 木酴續酸钾(potassiam guaiacolsulfonate)、孤芬那辛 (guaiafenesin)、可待因(c〇deine)磷酸鹽等。 止吐劑例如二芬朵(difenidol)鹽酸鹽、美多普胺 (metoclopramide)等 〇 呼吸促進劑例如左若費(le vail orphan)酒石酸鹽等。 支氣管擴張劑例如茶驗、舒喘寧(salbutamol)硫酸鹽 抗過敏藥例如亞列諾(amlexanox)、塞拉達(seratrodast) 齒頰藥例如經四環素(oxytetracycline)、特安皮質醇 (triamcinolone acetonide)、洗必太(chlorhexidine)鹽酸鹽、 利度卡因(1丨(1〇〇&丨1^)等。 抗組織胺劑例如:苯海拉明(diphenhydramine)鹽酸 鹽、普美苯噻哄(promethazine)、氮異丙哄(isothipendyl) 鹽酸鹽、氯苯P比胺馬來酸鹽(maleate)等。 強心劑例如:咖啡因、長葉毛地黃苷(digoxin)等。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 (請先閱讀背面之注意事項再填寫本頁) -·1111111 — — — — — — — — — I · 經濟部智慧財產局員工消費合作社印製 200302742 A7 B7 五、發明說明(7 ) 心律不整治藥例如:普卡因醯胺(procainainide)、鹽酸 鹽、心得安(propranolol)鹽酸鹽、吲哚心安(pind〇l〇l)等。 利尿劑例如異山梨醇酯(isosorbide)、弗西邁 (furosemide)、噻里胺(thiazides)如 HCTZ 等。 抗高血壓劑例如戴拉萊(delapril)鹽酸鹽、卡托萊 (captopril)、>臭化六烴季銨(hexamethonium bromide)、肼鹽 _酸鹽、拉貝羅(labetalol)鹽酸鹽、馬弟平(manidipine)鹽酸 鹽、卡沙丹(candesartan cilexetil)、甲基多巴(methyldopa)、 落沙丹(losartan)、凡沙丹(vaisartan)、普沙丹(eprosartan)、 依沙丹(irbesartan)、索沙丹(tasosartan)、米沙丹(telmisartan) 等。 血管緊縮劑例如苯腎上腺素(phenylephrine)鹽酸鹽 等。 冠狀血管擴張劑例如卡落門(carb〇erornen)鹽酸鹽、嗎 斯酮胺(molsidomine)、戊脈安(verapainil)鹽酸鹽等。
I 周邊血管擴張劑例如肉桂苯峨哄(einnarizine)等。 抗低脂血劑例如西凡利(eerivastatin)、喜凡利 (simvastatin)、雷凡利鈉(sodium pravastatin)等。 利膽劑例如脫氫膽酸、皮布通(trepibutone)等。 抗生素例如咽吩類(cephems),如頭孢力欣 (cefalexin)、頭孢可若(cefaci〇r)、安莫西林(ain〇xicillin)、 皮米西林(pivmecillinam)鹽酸鹽、頭孢提己(cef〇tiam hexetyl)鹽酸鹽、頭孢卓西(cefadr〇xil)、頭孢西米 (cefixime)、頭孢托内(cefditoren pivoxil)、頭孢特藍 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 310743D01 ---------------- (請先閱讀背面之注咅?事項再填寫本頁) 言 r 經濟部智慧財產局員工消費合作社印製 200302742 A7 __B7 五、發明說明(8 ) (cefteram pivoxyl)、西帕杜辛(cefp〇d〇xime pr〇xetil)、頭抱 提己二鹽酸鹽、頭孢若藍(cefozopran)鹽酸鹽、頭孢諾辛 (cefmenoxime)半鹽酸鹽、頭孢若丁鈉(s〇dium cefsulodin) ’合成之抗細菌劑如:胺节青黴素(anipiciiiin)、 西拉月棱素(ciclacillin)、絲賓西林鈉(sodium sulbenicillin)、萘利啶酸(nandixic acid)及依若沙辛 (enoxacin);單貝丹類如··卡如莫南鈉(s〇diuni carumonam);配寧類(penems);卡巴配寧類等。 化學治療藥例如磺胺甲噻二唑(sulfainethizole)、磺胺 甲噻二唑鹽酸鹽、胺噻楓(thiazosulfone)等。 抗糖尿劑例如甲苯績醢丁脲(tolbutamide)、弗里波 (voglibose)、皮利隆(pi〇giitazone)鹽酸鹽、優降糖 (glibenclamide)、特利隆(troglitazone)、落利隆 (rosiglitazone)順丁烤二酸酿、亞卡波(acarb〇se)、密利托 (miglitol)、依米特(emigitate)等。 骨質疏鬆劑例如意扶骨(ipriflavone)等。 骨絡肌弛緩劑例如:每弛卡摩(methocarbamol)等。 抗眩暈劑例如氯苯卩比哄(meclizine)鹽酸鹽、氣茶驗二 苯安明(dimenhydrinate)等。 抗風濕劑例如胺甲葉酸(methotrexate)、布西胺 (bucillamine)等。 荷爾蒙例如:去碳甲狀腺素鈉(sodium liothyronine)、 迪皮質醇納(dexamethasone sodium)鱗酸醋、培尼皮質醇 (prednisolone)、歐豆隆(oxendolone)、留普林(leuprorelin) 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 310743D01 (請先閲讀背面之注咅?事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 ;·tT---------f *---------------------- 8 200302742 經濟部智慧財產局員工消費合作社印製 9 A7 B7 五、發明說明(9 ) 乙酸酯等。 生物驗麻醉劑例如:阿片(opium)、嗎徘(morphine)鹽 酸鹽、吐根(ipecac)、羥可酮(oxyc〇d〇ne)鹽酸鹽、鴉片生 物鹼鹽酸鹽、古柯鹼(***e)鹽酸鹽等。 績胺藥例如績胺因(sulfaroine)、績胺二甲異喊咬 (sulfisomidine)、磺胺曱噻二唑(suifamethizole)等。 痛風劑(arthrifuges)例如異嗓呤醇(allopurinol)、秋水 仙驗(colchicine)等。 血凝抑制劑例如雙香豆醇(dicoumar〇l)等。 抗腫瘤劑例如5 -氟尿癌咬' 尿嘴唆、絲裂黴素 (mitomycin)等。 阿滋海默(Alzheimer’s)症藥例如依德貝諾 (idebenone)、溫波丁(vinpocetine)等。 於上述藥理活性成分中,較佳使用營養及強心劑、解 熱_止痛_消炎藥、安眠_鎮靜藥、中樞神經系統藥、腸胃劑、 抗 >貝癌劑、鎮咳祛痰劑、抗過敏藥、心律不整治藥、利尿 劑、抗高金壓劑、血管緊縮劑、冠狀血管擴張劑、抗低脂 血劑、抗糖尿劑、骨質疏鬆劑、骨骼肌弛緩劑、抗眩暈劑 等。 於本發明中,藥理活性成分較佳使用抗潰瘍劑如藍索 皮唾’抗糖尿劑如弗里波及皮利隆鹽酸鹽;及抗高血壓劑 如馬弟平鹽酸鹽及卡沙丹等。 二種以上藥理活性成分可任意成混合物,用於本發明 可快速崩解^固態製劑 本紙張尺度適用中@i^^_s)A4規格⑽χ观公餐) 310743D01 —-----------裝--------訂---------線 (請先閱讀背面之注咅?事項再填寫本頁) 200302742 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明(1G ) 藥理活性成分以醫療及令σ t i 、艮°口領域常用之稀釋劑任意稀 釋之。此外視情況處理以達矯餉 咬攝飾樂理活性成分之苦味目 的。 上述藥理活性成分之用署,如,^丄 用里 例如母1 〇〇重量份固態製 劑,使用0 · 01至7 0重量份,& Μ 王 里里仞,較佳0·02至50重量份,更 佳〇·〇5至30重量份。 2)糖 本發明所用之糖類,例如糖、殿粉糖、乳糖、蜂蜜及 糖醇。此等糖類任意以合宜比率成混合物使用。 糖例如薦糖、偶合糖、果糖·募糖、巴提糖(paiatin〇se)。 澱粉糖例如葡萄糖、麥芽糖、粉狀糖、澱粉糖漿、果 糖及左旋糖等。 乳糖例如乳糖、異構聋丨嫉" 再孔糖(礼果糖)、還原乳糖(乳糖醇) 等。 蜂蜜例如各種常食之蜂蜜。 糖醇例如山梨糖醇、甘露糖醇、麥芽糖醇、還原殺粉 木糖酉予、還原巴提糖、赤蘚糖醇等。赤蘚糖醇任意使 用1葡萄糖作起始物用酵母菌醱酵製成,且粒子大小至多 _目者。此赤蘚糖醇可由市售購得[例如:Nikken藥品 株式會社(日本)]。 上述糖類較佳為水溶性糖類。此等水溶性糖類指丨克 7加至水中時’需要至乡30毫升水,然後於20°C B夺,每 "刀鐘強烈搖盪3 0秒,而於3 〇分鐘内溶解之任何水溶 性糖類。 本紙張尺度適^?iii^^NS)A4規格⑵〇 χ 297公餐 糖 10 310743D01 --------------— (請先閱讀背面之注音?事項再填寫本頁) 訂---------線! 200302742
發明說明( 11 經濟部智慧財產局員工消費合作社印製
11 於本發明中,糖較佳為糖醇,更佳為甘露糖醇或赤蘚 糖醇。 為使製劑獲得充足之強度及充足之快速崩解性,若為 未包括細粒之固態製劑,糖之用量為每i 00重量份固態製 劑,用5至97重量份,較佳為1〇至9〇重量份。另一方面, 右為包括細粒之固態製劑,糖之用量為每i〇〇重量份細粒 除外之剩餘固態製劑,用5至97重量份,較佳為1〇至9〇 重量份。 例如:若為未包括細粒之固態製劑,甘露糖醇或赤蘚 糖醇之用量,對全部固態製劑,用5至90重量%,較佳10 至80重量❻/q,更佳20至80重量%,特佳50至80重量%。 另一方面,若為包括細粒之固態製劑,甘露糖醇或赤蘚糖 醇之用量’對細粒除外之剩餘固態製劑,用5至9〇重量%, 車父佳10至80重量%,更佳20至80重量❶/〇,特佳50至80 重量%。 D-果有5皇或以上$板协7曹量%羥丙氮某之低取代之 鱼丙基纖維素(L-HPCn 3-l)L-HPC之製造 本發明所用之a具有5重量0/❻或以上至低於7重量% 輕丙氧基之低取代之羥丙基纖維素(後文任意稱為L-HPC) ’可依周知之方法,例如Jp_B-57_531〇〇號所述之方 法或其類似方法製得。 首先’含游離鹼之鹼性纖維素及環氧丙烷反應而獲得 含游離鹼之粗製低取代羥丙基纖維素。 310743D01 --------------裂--------訂---------線 (請先閱讀背面之注咅?事項再填寫本頁) 200302742 A7 B7 五、發明說明( 12 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 具體地’例如原料漿如木漿及棉枝浸入1〇至5〇%濃 度之氫氧化鈉水溶液,經加壓獲得鹼性纖維素,其氫氧化 鈉/纖維素之比率為0·1至1 2(重量比)。其次,使所得之驗 性纖維素及環氧丙烷,於20至90°C攪拌2至8小時,獲 得含游離驗之粗製低取代羥丙基纖維素。環氧丙烷之用 量’為使所要之低取代羥丙基纖維素中之羥丙氧基含量為 5重量%或以上至低於7重量%。 含游離驗之粗製低取代羥丙基纖維素,分散於含5至 80%酸之水或熱水中’此酸需使全部量之鹼中和,及使一 部分含游離驗之粗製低取代經丙基纖維素溶於其令。又 則,加酸使剩餘之驗中和。 經中和後,依一般方法,進行如排水、乾燥及研磨製 程’獲得所要之低取代經丙基纖維素。 3-2)L-HPC 性質 本發明所用之L-HPC粒徑為例如5至6〇μιη之平均粒 徑’較佳為10至4 0 μ m平均粒徑。 於上述範圍中,若用具有較大粒徑之L_HPC(例如具有 26至4〇μΐη平均粒徑之L_HPC),則可製得崩解性優異^醫 藥製劑。另一方面,若用具有較小粒徑之L_Hpc(例如具有1〇至25μΐη平均粒徑之L_HPC),則可製得製劑強度優異之 醫藥製劑。 ' 於是,可依所要醫藥製劑之特性,合宜選擇L_HpC2 粒徑。 ......—為獲得充足之製劑強度及充苎之快速崩解性,若為不 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公髮)— 12 3l〇743D〇l (請先閱讀背面之注意事項再填寫本頁) , ----------訂---------線丨j 200302742 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明(13 ; 包括細粒之固態製劑,則本發明L-HPC之用量對每1〇〇重 量份固態製劑’用3至50重量份,較佳為5至4〇重量份。 另一方面,若為包括細粒之固態製劑,則本發明之 用量對每100 4量份細粒除外之剩餘I態製劑,用3至5〇 重量份,較佳為5至40重量份。 如上述,藉帛L-HPC,使含藥理活性成分及糖之固態 製劑,能改良快速崩解性,尤其是口服快速崩解性。 4) 劑型 本發明可快速崩解之固態製劑之劑型為例如錠劑、粒 劑、細粒劑等’較佳為錠劑。於可快速崩解之錠劑如口服 可崩解之鍵劑及水中可崩解之錠劑中,較佳為口服可崩解 之錠劑。 5) 其他成分 除非快速崩解性(特別是口腔中之快速崩解性)或製劑 強度受干擾,否則本發明可快速崩解之固態製劑,又可含 有製造一般劑型製劑常用之各種添加劑。此等添加劑用量 乃製造一般劑型之製劑常用之量。此等添加劑例如黏合 劑、酸類、起泡劑、人造甜味劑、調味劑、潤滑劑、著色 劑、安定劑、賦形劑、崩解劑等。 上述黏合劑例如羥丙基纖維素、羥丙基甲基纖維素、 結晶纖維素、預膠凝澱粉、聚乙烯吡咯啶酮、***膠粉、 明膠、支鏈澱粉等。二種或多種之此等黏合劑可以既定比 率成混合物使用。用結晶纖維素作為黏合劑,提供展示更 優異製劑強度同時於口腔中保留優異之快速崩解性之固 泰紙張尺度適用中國國家標準(CNS)A4規;[Γ(210 X 297公爱) 310743D01 -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 13 200302742 之用里為例如每100重量份細粒除外之固態製劑,用 50重量份,較佳2至4〇重量份,更佳2至2〇重量份 酸類例如檸檬酸、酒石酸、蘋果酸等。 起泡劑例如碳酸氫鈉等。 人造甜味劑例如糖精鈉、甘草二鉀、阿斯巴甜 (asPartame)、史塔溫(咖⑷、索馬甜(thau酬⑷等。 調味劑例如檸檬、萊姆(lem〇n Hme)、柳橙、薄荷 (menthol)、草莓等。 ,σ 潤滑劑例如硬脂酸鎂、蔗糖脂肪酸酯、 來g二醇、,月 石、硬知酸等。用聚乙二醇作潤滑劑,提供安定之固態 劑,其中藥理活性成分之經時分解受控制。 ^ , 、具時,若為 ,括,:劑,聚乙二醇之用量,為例如每1〇〇 本纸張尺度適用中關χ 297公髮)--- A7 五、發明說明(14 ) 製劑。結晶纖維素亦包含微結晶纖維素。、、結晶纖維素包 含部分α-纖維素解聚合之精製結晶纖維素。結晶纖維素1 體例舉CEOLUS KGm、艾維塞(Avicel)pm〇1、艾維塞 PH102、艾維塞pH301、艾維塞pH3〇2、艾維塞rc 土 A591NF(結晶纖維素•羧甲基纖維素鈉)、艾維塞rc_59i(結 晶纖維素•叛甲基纖維素納)。其中,較佳使用視為可高^ 模製結晶纖維素之CE0LUSKG8()1。此等結晶纖維素以合 宜比率+成混合物任意使用。此等結晶纖維素可由市售購得 (朝日藥品工業股份有限公司(日本)製造)。若為未包括細粒 之固態製劑’結晶纖維素之用量為例如每100重量份固態 製劑’用1至50重量份,較佳2至4〇重量份,更佳2至 20重量份。同理’若為包括細粒之固態製劑,結晶纖維素 至 滑 310743D01 --------訂------ (請先閱讀背面之注意事項再填寫本頁)
·1 n I 14 200302742 A7 B7 15 五、發明說明( 重量份固態製劑,田 旦 用0 01至10重篁份,較佳〇·1至5重 量份。同理’若為包括細粒之固態製劑,聚乙二醇之用量, 為母100重篁份固態製劑,帛0 〇1至10重量份,較佳0.1 至5重量份。 者色劑例如各種食品著色劑,如食品黃色5號、食品 色5虎食°°藍色2號等;食品深紅色、氧化鐵紅等。 安定劑例如若為鹼性藥理活性成分,則用鹼性物質,· 若為酸性藥理活性成分,則用酸性物質。 賦/齊!例如乳糖、蔗糖、0_甘露糖醇、殿粉、玉米厥 粉、結晶纖維素、輕矽酸酐、氧化鈦等。 崩解劑例如崩解劑稱作超級崩解劑,如交聯吡咯啶酮 [ISPInc.(美國),BASF(德國)製造],交聯鲮甲基纖維素鈉 [FMC-Asahi藥品工業株式會社(日本)],綾甲基纖維素鈣 [Gotoku藥品(Yakuhin),(日本)];羥丙基纖維素;低取代 羥丙基纖維素;羧甲基澱粉鈉[Matsutani藥品株式會社(日 本)];玉米澱粉等。其中,較佳使用交聯吡咯啶酮。此等 二種或多種崩解劑任意以合宜比率成混合物使用。 交聯吡咯啶酮可使用任何交聯均聚物如^乙烯基 -2 -D比嘻《疋酮均聚物,通常使用分子量至少1,〇⑽,〇⑽之交 聯批洛咬酮。交聯吡咯啶酮可由市售,具體例舉交聯吡咯 啶酮、科利酮CL(K〇llid〇ne CL)[BASF(德國)製造],聚拉 酮 XL(P〇lypiasd〇ne XL),聚拉鲷 XL-10,INF-10[ISP 公司 製造(美國)],聚乙烯聚Q比洛咬酮,PVpp,1_乙稀基_2_卩比 咯咬酮均聚物等。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 — II--— I-褒---I----訂----I----線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 15
經濟部智慧財產局員工消費合作社印製 200302742 五、發明說明(16 / 一種或多種此等崩解劑可以既定比率成混合物。例 如’較佳使用⑴單獨之交聯吼略咬酮,或(ii)交聯吼略咬酮 及另一種崩解劑。 若為不包括細粒之固態製劑,此崩解劑之用量,為每 100重量份固態製劑,用例如〇 i至2〇重量份,較佳為1 至10重里伤’更佳為3至7重量份。同理,若為包括細粒 之固態製劑,此崩解劑之用量,為每1〇〇重量份細粒除外 之剩餘固態製劑,用例如〇丨至2〇重量份,較佳為j至1〇 重量份,更佳為3至7重量份。 5-1)劑型所用之其他成分,尤其是酸不安定之藥理活性成 分 若藥理活性成分為酸不安定者,如藍索皮唑、歐米皮 唑(omeprazole)、拉伯皮唑(rabepraz〇le)、泛托皮唑等,較 好併加鹼性無機鹽,以使固態製劑中之藥理活性成分安 定0 驗性無機鹽〃包含例如鈉、鉀、鎂及/或鈣之鹼性無 機鹽,較佳為鎂及/或鈣之鹼性無機鹽。其中,較佳為鎂之 驗性無機鹽。 納之驗性無機鹽包含例如碳酸鈉、碳酸氫鈉、磷酸鈉、 填酸氮納等。 斜之驗性無機鹽包含例如碳酸卸、碳酸氮钟、鱗酸舒、 磷酸氫鉀、碳酸鈉鉀等。 鎮之驗性無機鹽包含例如重碳酸鎂、碳酸鎂、氧化鎂、 氫氧化鎂、偏ί夕酸鎂鋁 '矽酸鎂鋁、矽酸鎂、鋁酸鎮、合 本紙張尺度適用中國國家標準------ 16 310743D01 -------------« (請先閱讀背面之注音?事項再填寫本頁) 訂---------線丨 200302742
五、發明說明(17) 經濟部智慧財產局員工消費合作社印製 17 =水滑石陶6Al2(〇H)16.c〇3.4H2〇],氫氧化鎂銘
Mg〇 αι2〇3 · χίί2〇]等。其中,較佳為重碳酸鎮碳 馱鎂、氧化鎂、氫氧化鎂等。 鈣之驗性無機鹽包含例如沈澱之碳酸辦 '氮氧化鈣 等0 鹼性無機鹽〃之較佳實例為鎂鹼性無機鹽,更佳之 實例包含重碳酸鎂、碳酸鎂、氧化鎂、氳氧化鎮等。 鎂或鈣等之鹼性無機鹽,及成1%水溶液或懸浮液形 式時’具有鹼性pH(不小於7)。 二種或多種此等鹼性無機鹽類(較佳為鎂之鹼性無機 鹽、約之驗性無機鹽、等)可以—定比率成混合物使用。驗 $無機鹽之用量,依鹼性無機鹽之種類適當選擇,例如對 藥理活性成分,用〇·3至200重量份,較佳1至1〇〇重量 伤更佳10至50重量份,特佳20至40重量份。 iUligL粒之劑铟(如,錠部ρ 如前述,本發明可快速崩解之製劑,可以任何固態劑 型如錠劑、粒劑、細粒劑等使用。若為錠劑,此錠劑可含 有細粒。此細粒可含有藥理活性成分。此等劑型可依習知 方法或其類似方法製備。 7)含核心之細粒 細粒可含有核心物,此核心可與藥理活性成分一起或 分開。此核心物例如:(1)球狀顆粒產物,包括結晶纖維素 及乳糖[如,100至200μπι且包括結晶纖維素(3份)及乳糖 (7份)(NonPareil 1〇5(商品名),Freund工業株式會社(日本) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 — — — — — — — — — —— ·1111111 ^ ·11111--- (請先閱讀背面之注咅ΜΦ項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 18 200302742 A7 ---- B7 五、發明說明(18) 製造)之球狀顆粒產物;150至250μιη且包括結晶纖維素(3 份)及乳糖(7份)(Nonpareil ΝΡ-7 : 3(商品名),Freund工業 株式會社(曰本)製造)之球狀顆粒產物;150至250μηι且包 括結晶纖維素(5份)及乳糖(5份)(Nonpareil ΝΡ-5 : 5(商品 名),Freund工業株式會社(曰本)製造)之球狀顆粒產物 等],(2)150至250μιη且包括結晶纖維素[艾微塞 (Avicel)SP(商品名),朝曰藥品工業株式會社(日本)製造之 球狀顆粒產物等]等。 若使用核心物,此核心物任意以藥理活性成分等包 覆’又予以包覆使之矯飾口味或氣味及/或依周知之方法賦 與腸溶解性或持釋性。依此例,此核心物形成包括藥理活 性成分之細粒。依此例,包覆劑例如腸衣聚合物(如,纖維 素乙酸酞酸酯(CAP)、甲基丙烯酸酯共聚物L、甲基丙烯酸 酯共聚物LD(優雷季(Eudragit)L30D-55(商品名;Rohm GmbH(德國)製造)、甲基丙烯酸酯共聚物S、羥丙基甲基纖 維素酞酸酯、羥甲基纖維素乙酸丁二酸酯、羥丙基甲基纖 維素乙酸酯丁二酸酯、KollICoat MAE30DP(商品名; BASF(德國)製造)、p〇iyquid pA_30(商品名;三洋化成(日 本)製造)、羧甲基乙基纖維素、蟲膠、甲基丙烯酸酯共聚 物[如,優雷季NE30D(商品名),優雷季RL30D(商品名), 優雷季RS30D(商品名)等]、檸檬酸三乙g旨、聚乙二醇、乙 酉藍化單甘油醋、甘油三乙酸酯、蓖麻油等)、胃溶性聚合物 (如,聚乙烯乙縮醛二乙胺乙酸酯、胺烷基甲基丙烯酸酯共 聚物等)、水溶性聚合物(如,羥丙基纖維素、羥丙基甲基 本紙張尺度適用中國國家標準(CNS)A4規格(2】〇χ297公爱) 310743D01 C請先閱讀背面之注音W事項再填寫本頁}
--------訂---------線J 200302742 A7 B7 五、發明說明(19 ) 纖維素等)、微溶性聚合物(如,乙基纖維素、胺烧基甲基 丙烯Ί、聚物RS、丙婦酸乙醋甲基丙稀酸甲醋共聚物 等)蠟等。-種或多種包覆劑可成混合物使用。 7 -1)細粒之製造 =發明之、、細粒〃可依周知之造粒法製造。 &造粒法包含例如旋轉式造粒法(如離心旋轉造粒法 “⑽體化床造粒法(如旋轉流體化床造粒》、流體化造 裝 等)、攪拌式造粒法等。其中,較佳為流體化床造粒法 更佳為旋轉式流體化床造粒法 酱旋轉式造粒法1體實例包含用、'CF儀器々(Freund 式會社(日本)製造)之方法等。、旋轉式流體化床造 :具體實例包含用、'SPKFLOW„,、multi piex> A 司(日本)製造),、、New Marumerizer々(Fuji Paudal I \ (日本)製造)等之方法。混合物之喷霧方法,可依 =種類合宜選擇,可為例如:頂部喷霧方法、底部喷霧 :切線噴霧方法等任—方法。其中,以切線喷霧方法 車父佳。 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 制 篝,本,月 < 細粒”可用任何包含活性成分之其他成分 夺:習知包覆方法或其類似方法予以包覆。例如若藥理 維吝?為酸不安定生理活性物質,則為包括使含結晶纖 '、礼糖之核心物,以酸不安定之生理活性物質包覆之 方法。 人杜使用JP-A·5-92918號所述方法(包覆法),包括使 _“日日、」糖之核心物’以酸不安定之生理活性物 本紙]尺度適 19 310743D01 200302742 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明(2〇 ) 質及若需要連同驗性無機鹽、黏合劑、潤滑劑、賦形劑、 水溶性聚合物等予以包覆(後文,可簡寫成、包覆層")。 例如使用包括使核心物以酸不安定之生理活性物質及鹼性 …、機^匕覆,然後以黏合劑、潤滑劑、賦形劑、水溶性聚 合物、等予以包覆。 7 - 2)細粒之核心物性質 核心物”之平均粒子直徑為25〇μιη或以下,較佳為 50 至 250μιη,更佳為 100 至 25〇μπι,特佳為 1〇〇 至 2〇〇μηι。 具有上述平均粒子直徑之、、核心物,,,包含所有通過#5〇號 篩(30(^m)之粒子,全部之5 w/w〇/〇以下留在#6〇號篩 (2 50μηι)之粒子,及全部之1〇 w/w %以下通過#282號篩 (5 3 0111)之粒子。、核子物"之特定容積為51111^以下,較佳 為3ml/g以下。 、核心物〃實例包含: (1)包括結晶纖維素及乳糖之球狀顆粒產物,(2)150至 250μιη且包括結晶纖維素(艾維塞(Avicel)sp,朝日藥品株 式會社(日本)製造)之球狀顆粒產物,(3)5〇至25〇pm且包 括乳糖(9份)及澱粉(1份)之攪拌顆粒產物,(4)25〇μπι或以 下且分類含微結晶纖維素之球狀顆粒之微粒子包括··如 JP-A-61-2 13201號所述,(5)如蠟以噴霧或熔化造粒法形成 球狀之加工產物,(6)如包括油成分之明膠珠粒之加工產 物,(7)石夕酸鈣,(8)殿粉,(9)多孔粒子如幾丁(ehitin)、纖 維素、殼聚糖、等’及(1 0)本體產物,如粒狀糖、結晶乳 糖或氯化鈉,及其加工製劑。再則,此等核心物可依本身 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) '" '~~ --- 20 310743D01 ------------------ C請先閱讀背面之注音?事項再填寫本頁} 訂---------線—up---------- 200302742 A7 五、發明說明(21 ) 周知之研磨法或造粒法製造,及轉移製備具所要粒徑之粒 子。 上述、、含結晶纖維素及乳糖之球狀顆粒產物〃包含例 如(i)100至200μπι且包括結晶纖維素(3份)及乳糖(7份)之 球狀顆粒產物[如,Nonpareil 105(70至140)(粒徑100至 200μιη),Freund工業株式會社(日本)製造],(ii)15〇至 2 50μηι且包括結晶纖維素(3份)及乳糖份)之球狀顆粒產 物[如,Nonpareil ΝΡ-7 : 3,Freund工業株式會社(日本) 製造],(iii)100至200μιη且包括結晶纖維素(4 5份)及乳糖 (5.5份)之球狀顆粒產物[如,N〇npareii 1〇5丁(7〇至14〇)(粒 徑100至200μηι),Freund工業株式會社(日本)製造], (iv)150至250μηι且包括:結晶纖維素(5份)及乳糖(5份) 之球狀顆粒產物[如,Nonpareil NP_5 : 5,Freund工業株式 會社(曰本)製造],等。 為製造溶解度優異且能保留合宜強度之醫藥製劑广核 心物〃包含例如較佳為球狀顆粒產物包括結晶纖維素及乳 糖,更佳乃球狀顆粒產物包括結晶纖維素及乳糖,又含對 全部固態製劑為50重量%以上之乳糖。其中,較佳核心物 包括40至50重量%結晶纖維素及5〇至6〇重量%乳糖。 消 本發明所用之、、核心物〃,較好為包括結晶纖維素及乳 糖之球狀顆粒產物,更佳為直徑1〇〇至2〇〇μπι且包括結晶 纖維素(4.5份)及乳糖(5.5份)之球狀顆粒產物。 核心物可含有生理活性物質如上述藥理活性成 刀而且’核心物〃可不含生理活性物質,因生理活性物 本鎌尺度顧中關家標準(CNS)A4規格(;1G χ挪公爱)- 21 310743D01 200302742 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明(22 ) 質之釋出,'由含生理活性物質之包覆層控制。 核〜物除了粉狀核心物以外’較好儘可能 球狀,以減低包覆層之不規則性。 •勺 '包覆層”對、心物,之比率,於能控制生理活性 物質溶解及組成物教子大小之範圍内選擇,例如對刚重 量份核心物通常為50至400重量份。 7-3)細粒之包覆方法 包覆層可由複層構成。至少一層複層必須含有生理活 性物質。可適當選擇各層組合如不含活性成分之包覆層、 驗包覆層及構成包覆層之腸衣層。 若、核心物"予以包覆,例如上述生理活性物質及水 溶性聚合物可以其混合物使用。混合物可為溶液或分散 液,且可用有機溶劑如水或乙醇或其混合物予以製備。 於混合物中,水溶㈣合物之濃度,依生理活性物質 及,加劑之比率而不同,通常對全部固態製劑| (M至5〇 重篁% ’較佳0.5至10重量%,以保留生理活性物質對核 〜物之黏合強度,且保持混合物之黏度,而不減低操作性。 +若包覆層包括複層,各層中生理活性物質之濃度,可 2選擇含量比率或水溶性聚合物之黏度,或以生理活性物 質及其他添加劑之比率不同之混合物依序包覆而依序或漸 漸改變。於上述情形,所包覆之混合物中水溶性聚合物之 含量比率可於0·1至5〇重量%範圍之外’只要包覆層全部 含有〇· 1至50重量%之水溶性聚合物即可。再則,為依周 知方法形成失活性包覆,包覆層任意包括某些層,使得失 尺度國家標準(CNS)A4規格⑵。χ 29_w_ 22 310743 (請先閱讀背面之注意事項再填寫本頁) ----- 訂---------線· A7
200302742 五、發明說明(23 ) 活性層可阻斷含生理活性物質之各層。 而且,若二種或多種生理活性物質不能合宜相容,核 心物可用各混合物一起或分別包覆。 上述包覆物料經乾燥後,通過篩子,獲得具有均勻大 小之、、組成物〃。因通常依核心物形成組成物,可能獲得粗 略球狀之細粒。篩子可使用例如#5〇號圓形篩(3〇〇μιη)。由 •選擇通過#50號圓形篩者,獲得組成物。 本發明之細粒"可依上述造粒法之相同方式製造, 例如,包括以腸衣層包覆組成物,以防護生理活性物質, 或賦與腸溶性之方法。若需要,以腸衣層包覆之組成物, 可又以水溶性糠醇(較佳為甘露糖醇)包覆。於此情形,包 括細粒之口服崩解錠劑之強度可獲改良。 、、腸衣層,,較佳具20至70μιη(更佳30至5〇μιη)厚度, 且包覆含生理活性物質之組成物全部表面。於是,組成物 •之粒子直徑越小,腸衣層於全部細粒之重量%越高。於本 發明之細粒中,、、腸衣層"佔細粒全部之3〇至7〇重量%, 較佳50至70重量〇/0。 、、腸衣層"可任意由複層(如,2或3層)構成。例如, 使用包括組成物以具聚乙二醇之腸衣層包覆,然後,以具 榉檬酸二乙酯之腸衣層包覆,接著以具聚乙二醇之腸衣層 包覆。 IL可快速製劑之锄造 ^本發明可快速崩解之固態製劑,可依醫藥製劑領域之 t知方法或其類似方法製造。此方法例如,包括使藥理活 ^尺度過財關家標準(c^Tiil21Qx 297公楚)---- 23 310743D01 --------------裝--------訂---------線 (請先閱讀背面之注音?事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 200302742 A7
五、發明說明(24 ) 性成分、糖及具5重量%或以上至低於7重量%之羥丙氧 基之低取代羥丙基纖維素摻和,若需要則加水,模製然後 (請先閱讀背面之注意事項再填寫本頁) 視需要乾燥。然而,本發明可快速崩解之固態製劑,亦可 不使用水製造。 8 -1)可快速崩解錠劑之製造 為製造口服可崩解之錠劑,可依習知模塑方法或其類 似方法,選自包含細粒之上述合適成分進行。 具包覆核心物之細粒之口服可崩解之錠劑,較佳之方 法實例包括: (1)使含結晶纖維素及乳糖之核心物,以生理活性物質 及賦形劑包覆,接著以含水溶性聚合物之包覆層包覆,獲 得組成物, (ii)使所得組成物以具聚乙二醇之腸衣層包覆,然後, 以具檸檬酸三乙酯之腸衣層包覆,接著以甘露糖醇包覆, 獲得細粒,及 經濟部智慧財產局員工消費合作社印製 (111)使所得細粒以添加劑摻和,接著予以模塑。 若固態製劑為録:劑,特別是口服可崩解之錠劑,所進 行之模塑程序為例如使用單沖孔造錠機[Kikusui Seisakusho(曰本)]或旋轉型造錠機[kikusui Seisakusho(曰 本)]’以壓力0·5至3 ton/cm2,較佳1至2 ton/cm2進行造 鍵。 乾燥程序乃依使一般醫藥製劑乾燥之任何技術如真空 乾燥、流體化床乾燥等進行。 摻和程序乃依任何習知摻和技術如混合、捏和、造粒 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐'-- 一~' 24 310743D01 200302742 五、發明說明(25 (請先閱讀背面之注意事項再填寫本頁) 等進行。摻和程序用儀器垂直造粒機VG10[Powrex公司(日 本)製造]’萬能捏合機[Hat a Iron Works株式會社(日本)製 造],流體化床造粒機LAB-1及FD-3S[Powrex公司(日本) 製造],離心流體化包覆造粒機MP-10,MP-400[Powrex公 司(曰本)製造]等進行。 於本說明書中,、包覆,,除了指包覆於所要包覆之目的 物(如,核心物)全部表面外,亦指部分包覆及黏附或吸附。 a球狀"除了指球形式以外,亦指具彎曲表面之形式, 如具橢圓橫切面之形成,及茄子和滴液形狀之形式。 a平均粒徑除非另有指明,否則指分佈於中間直徑 之量(中間直徑:累積分佈50%粒徑)。可由例如雷射繞射 粒子分佈測量方法測定之。具體實例為用Raiser繞射分析 儀,型· HEROS RODOS[商品名,Sympatec(德國)製造]。 依本發明,、、細粒,,具有約4〇〇μιη以下之平均粒徑, 而於口中無粗糙感覺。較佳,細粒之平均粒徑為3〇〇至 400mm 〇 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 除了上述、細粒〃之平均粒徑以外,關於最大粒子大 小,粒徑實質上為425μπι以下,較佳實質上為4〇(^m以 下。較佳乃粒徑實質上為300至42邛111,更佳為3〇〇至 400μιη。 於"粒徑實質上為425μηι以下夕及、、粒徑實質上為 4〇μΐΠ以下中所用之、實質上,指粒子可包含少量(約5 重量%以下)粒徑於上述範圍外之粒子,難色會包含夾雜粒 子。 本紙張尺度適用中國國家標準(CNS)A4規格⑵Q χ 297公爱) 310743D01 25 200302742 經濟部智慧財產局員工消費合作社印製 26 A7 --—-----一 _ 五、發明說明(26 ) 、組成物〃可含有醫藥物料常用之水溶性聚合物、上 述黏合劑、潤滑劑、賦形劑等。此水溶性聚合物、黏合劑、 潤滑劑及賦形劑之量,由製造一般劑型之製劑常用之量選 擇之。 、水溶性聚合物夕包含例如溶於乙醇之水溶性聚合物 (即’乙醇溶性又水溶性聚合物)如纖維素衍生物(如,經丙 基纖維素,後文可稱作,HPC-卜聚乙㈣㈣酮等;不 溶於乙醇之水溶性聚合物(即,乙醇不溶性又水溶性聚合物) 如纖維素衍生物(如,羥丙基甲基纖維素,後文可稱作 、HPMC々’甲基纖維素、&甲基纖維素納等)、聚丙稀酸 納、聚乙嫦醇、藻酸納、及***膠等。 若用水溶性聚合物,藥物(生理活性物質)之溶解,可 使用其與乙醇溶性又水溶性聚合物,及乙醇不溶性又水溶 性聚合物組合使用,或使用其與某些黏度相異之水溶性聚 合物組合而控制。 依本發明,、水溶性聚合物〃較佳為纖維素衍生物,如 HPC、HPMC及甲基纖維素,及聚乙烯醇。更佳為纖維素 衍生物如HPC、HPMC。 、HPC〃含有例如約53.4至77.5重量%,更佳約60 至70重量%之羥丙氧基。於20°C,2重量❶/〇 HPC水溶液之 黏度,通常約1至l5〇,OOOcps(厘泊)。上述之HPC,可使 用曰本藥典所定義之經丙基纖維素。於後文,所有HPC之 黏度為於20°C時,2重量%水溶液之值。 、HPMC 〃為與甲氧基及輕丙氧基連接之混合醚。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 -------------------訂---------線 (請先閱讀背面之注音心事項再填寫本頁) 200302742 經濟部智慧財產局員工消費合作社印製 27 A7 五、發明說明(27 ) HPMC之甲氧基含量為例如約19至30重量%。羥丙氧基 之含里為例如約4至12重量〇/0於2(TC時,2重量0/〇 HPMC 欠/谷液之黏度’通常約1至4〇,〇〇〇厘沲(〇6价以〇|^3)。此 HPMC可使用日本藥典所定義之羥丙基甲基纖維素22〇8, 曰本藥典所定義之經丙基甲基纖維素2906,日本藥典所定 義之羥丙基甲基纖維素291〇,等。羥丙基纖維素可單獨使 用或二種或多種成混合物使用。 水溶性聚合物如HPC及/或hpmC之含量,對含生理 活性物質之全部、、組成物,',通常約0· 1至50重量%,較 佳約1至30重量〇/❻,以控制生理活性物質於含生理活性物 質組成物中之溶解,及保留高含量生理活性物質。 依本發明,、、細粒〃可含有例如氧化鈦作矯味劑。 本發明、、口服可崩解之錠劑夕直徑,為約5至20mm, 較佳約7至15mm,更佳約8至13mm。 '口服可崩解之錠劑於錠劑内可視不包括潤滑劑。 若本發明之、、細粒"用於口服可崩解之錠劑除外之錠 劑’則錠劑之直徑為約5至10mm,較佳約5至8mm。若 本發明之細粒用作膠囊,則膠囊之大小較佳為2號膠囊或 以下。 崩解之固態製劑之性質 所得本發明可快速崩解之固態製劑,於口腔、水或胃 中展示快速崩解性或溶解性,及合宜之製劑強度。再則, 本發明可快速崩解之固態製劑,白堊口味經改良且不粗 糙。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 -------------^--------^---------線 (請先閱讀背面之注意事項再填寫本頁) 200302742 A7 ----- _ B7 五、發明說明(28 ) 9_1)崩解時間 本發明可快速崩解之固態製劑之口服崩解時間(健康 男性或女性成人由口頰唾液完全崩解之時間),通常為5至 50秒,較佳為5至40秒,更佳為5至35秒。 本發明可快速崩解之固態製劑,於胃中之崩解時間(健 康男性或女性成人完全崩解之時間),比一般製劑如一般錠 劑之時間更短。 本發明可快速崩解之固態製劑,於水中之崩解時間, 通常為5至40秒,較佳為5至3〇秒,更佳為$至25秒。 9-2)製劑之強度 本發明可快速崩解之固態製劑,強度(以錠劑硬度測試 器測定)通常為2至20kg,較佳為4至15kg。 9-3)投予方式 本發明可快速崩解之固態製劑,特別用作口服崩解旋 劑’可無水或與水一起投予。 投予方法,例舉(1)以少量水,或無水或以口腔唾液一 起,但未予呑嚥,而溶解或崩解之投予方法,或(2)以水且 吞嚥之投予方法。而且,錠劑可以水溶解或崩解而投予。 本發明a 口服崩解錠劑〃有利使用於(a)投予時不需 水投予吞1^錠劑有困難之病患,或(c)投予對一般錠劑 恐會鲠喉之老人或孩童。 本發明快速崩解之固態製劑,可安全經口投予哺乳 類如小鼠、大鼠、兔、貓、狗、小牛、馬、猴、人等。 9-4)劑量及特定具體實例 本紙張尺度適用τ國國家標準(CNS〉A4規格i2ig x 297公髮) 310743D01 (靖先閱讀背面之注音?事項再填寫本頁} ώπ 訂---------線· 經濟部智慧財產局員工消費合作社印製 28 200302742 B7 五、發明說明(29 ) 雖然’可快逮崩解之固態製劑之 — 分、個體、病症猶_發 依樂理活性成 活性成分之劑量為有效量者。“擇姻-則以能使藥理 (請先閱讀背面之注意事項再填寫本頁) 於上述⑷之情形,口服可崩解之錠 劑、止痛齊J、消炎劑、抗隹膚 用作解熱 劑、預防及治療暈車之藥物等。 屄別抗運動病 ^ / t述⑻之情形,可口服崩解之鍵劑較佳用作預防及 腦▲管症等。一症、糖尿症、支氣管性氣喘症、 9-4-1)藍索皮哇 經濟部智慧財產局員工消費合作社印製 例如,若以藍索皮嗤作藥理活性成分,則本發明可快 速崩解之固態製劑乃用以治療及預防消化性潰痛(如,胃潰 瘍、十二指腸潰癌、吻合性潰癌、若埃二氏症候群 (Z〇llinger-Ellison syndr〇me)、胃炎反射性食道炎等,幽 •門病除根;由消化性潰癌、急迫性潰瘍及出血性胃炎引起 之上部胃腸出血之m侵襲性壓迫(如,大規模手街需 接續增強照護或腦血管症、頭部損傷、許多器官衰竭'需 加強醫護之廣範圍燒傷引起之壓迫)所引起之上部胃腸出 血之制約,·治療及預防由非類固醇消炎劑引起之潰瘍;治 療及預防由術後壓迫引起之胃酸過多及潰瘍’·麻醉前投予 等。製劑之劑量’以藍索皮唑計之,每位成人(體重· 6〇kg) 為〇·5至1500mg/天,較佳為5至150mg/天。 9-4-2)弗里波 若以弗里波作藥理活性成分,則本發明可快速崩解之 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 29 310743D01 200302742 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明(30 ) 固態製劑乃用以治療及預防肥胖症、脂肪過多症、脂血症、 糖尿病症等。製劑之劑量,以弗里波計之,每位成人(體重: 6〇kg)為〇·〇ι至3〇mg/天,較佳0·1至3mg/天。此可快速 崩解之固態製劑,可一天乙次,或一天分成2至3次投予。 9-4-3)馬弟平· HC1 若以馬弟平鹽酸鹽作藥理活性成分,則本發明可快速 崩解之固態製劑乃用以治療及預防循環系統疾病如高血 壓、絕血性心臟疾病(如,心絞痛、心肌梗塞等)、大腦及 周邊彳盾環系失调症(如,大腦梗塞、短暫絕血性發作、腎動 脈狹窄等)等。製劑之劑量,以馬弟平鹽酸鹽計之,每位成 人(體重·· 60kg)為1至200mg/天,較佳1〇至2〇mg/天。可 陕速朋解之固態製劑,通常早餐後一天乙次投予。 9-4-4)皮利隆· HC1 若以皮利隆鹽酸鹽作藥理活性成分,則本發明可快速 崩解之固態製劑,乃用作抗胰島素改良劑等,及治療和預 防糖尿病。製劑之劑量,以皮利隆鹽酸鹽計之,每位成人(體 重:60kg)為7.5至6〇mg/天,較佳15至以叫/天。可快速 崩解之固態製劑可一天乙次,或一天分成2至3次投予。 9-4-5)卡沙丹 再則右以卡沙丹作藥理活性成分,則本發明可快速 崩解之固態製劑乃用以治療及預防高血壓、心臟病、大腦 中風、腎疾病等。製劑之劑量,以卡沙丹計之,每位成人(體 重:60kg)為1至5〇mg/天’較佳2至%邮/天。 (請先閱讀背面之注意事項再填寫本頁) -·1111111 ^ ·111111 丨 I .
[實施本發明之最佳模式]
30 310743D01 200302742 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 31 A7 B7 五、發明說明(31 ) 茲由下述參考例、實施例及試驗例更詳述本發明。需 瞭解的是,本發明並不限於此等實例。 除非另有指明,否則下述、' 指重量%。 而且’羥丙氧基之含量依日本藥典(如第13版)所述方 法測定。錠劑之物理性質(硬度及崩解時間)由下述測試方 法決定。 (1) 硬度試驗 以錠劑硬度測試器[Toyama Sangyo株式會社(日本)製 造]進行決定。此試驗進行1〇次,以平均值表示。 (2) 口服崩解時間 錠劑於口腔中僅以唾液完全崩解或溶解之時間予以決 定。 [實例] 參考例1 將木漿浸入49%氫氧化鈉水溶液中,然後壓制之,獲 得包括 24.1%NaOH、l.7%Na2C〇3、42.9〇/(^ 維素、31 8%η2〇 之鹼性纖維素。反應器中裝入100重量份鹼性纖維素。然 後,進行氮氣代換。經代換後,5重量份環氧丙烷裝入反 應器,於4(TC攪拌i小時,於5(rc攪拌i小時,及於7〇 °C攪拌1小時,獲得103重量份反應物。 另一方面,捏和器中裝入2 5重量份65C>c熱水及〇 13 重量份冰醋酸(40重量%對中和當量,初始中和酸),分散 入1重量份上述所得鹼性纖維素。然後,溫度調至3(rc, 以溶解-部分反應物,及〇2〇重量份冰醋酸(剩餘中和當 本紙張尺度適用中國國家標準(CNS)A4規格⑵〇 χ 297公爱) 310743D01 -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 200302742 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明(32 I ’ 70全中和酸)’獲得含有一部分溶解物及一部分沈積物 之加工纖維產物。 所得產物以80°C熱水洗滌、排水、乾燥、以高軋衝擊 碾磨機礙磨,用100目篩子過篩,獲得羥丙氧基之含量58 重星/。及平均粒徑17·8μηι之低取代羥丙基纖維素lh_33 粉末。參考例2 依參考例1之相同方式,獲得低取代羥丙基纖維素 LH-23粉末,具少量較大平均粒徑(經丙基之含量5 7重量 %,平均粒徑30.8μπι)。 實施例1 (1)具核心物之粉末之製造 離〜々IL體化包覆造粒器[Po wrex公司(日本)製造, MP-10]中,裝入 9〇〇g Nonpareil 105(商品名)(粒徑:10〇 至200μιη)。入口氣溫及出口氣溫分別控制於乞及 3+0=,N〇npareil以事先製備之下述組成物之喷液,依切線 喷霧方法,用22g/min喷霧速率,予以喷霧包覆。然後, 進行乾燥ίο分鐘。所得顆粒經60號圓篩(25〇μιη)& 1〇〇 號圓篩(15〇μιη)過篩,獲得2186g具核心物之粉末(15〇至 2 50μιη) 〇 喷液 藍索皮唑 碳酸鎂 低取代之經丙基纖維素LH-3 2 (cns)JT^210 x 297 ^) 927 g 309 g 154.5g 32 310743D01 (請先閱讀背面之注意事項再填寫本頁) — Λ \---------訂---------線. 200302742 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明(33 ) (羥丙基含量:8 · 8重量%) (平均粒徑:17·57μηι) 羥丙基纖維素(SSL型) 純水 (2) 具核心物之膜襯粉末之製造 離心流體化包覆造粒器[p〇wrex公司(曰本)製造 MP-10]中,裝入2040g具核心物之上述粉末。入口氣切 出口氣溫分別控制於75。(:及4{rc時,事先製備之下述 物之襯液,依切線喷霧方法,以13g/min喷霧速率噴霧, 獲得2 14 5 g具核心物之膜襯粉末。 襯液 羥丙基甲基纖維素 (2910型,黏度:3厘沲) 純水 (3) 具核心物之腸衣粉末之製造 離心流體化包覆造粒器[Powrex公司(日本)製造, MP-10]中,裝入171 〇g具核心物之上述臈襯粉末。入口顧 溫及出口氣溫分別控制於70。(;及4(rc時,事先製備之下域 組成物之腸膜衣液,依切線喷霧方法,以l9g/min噴霧速 率喷霧。然後’進行乾燥7分鐘。所得顆粒經42號圓筛' 及8〇號圓篩(mpm)過篩,獲得239坫具核心物 之粉末(177至355μιη)。 腸膜衣液 優雷季 L30D-55 5016.4g 本紙張尺度適用中國國家標f (CNS)A4規格(210 X 297公t ) 309 g 3955 g 264g 5016g 33 310743D01 (請先閱讀背面之注音?事項再填寫本頁) 200302742
五、發明說明(34) 優雷季NE30D 檸檬酸三乙酯 單硬脂酸甘油酉旨 聚山梨酸S旨80 氧化鐵紅 純水 (4)具核心物之甘露 糖醇 559.0g 333.7g 106.5g 34.8g 1.8g 2547.lg 外套腸衣粉末之製造 離心流體化肖霜$ r 已覆k粒器[p〇wrex公司(日本 MP-10]中’裝人具核心物之_g上述腸衣粉末。入 2出口氣溫分別控制於的及饥,事先製備之下二 t物之膜衣液,依切線喷霧方法,以llg/mln噴霧速率嗔 y然後’進行乾燥7分鐘’獲得具核心物之6i7g之 腸衣粉末。 膜衣液 (請先閱讀背面之注音?事項再填寫本頁) 甘露糖醇 純水 33g 297g
f裝--------訂---------線I 經 濟 部 智 慧 財 產 局 員 X 消 費 合 作 社 印 (5) 甘露糖醇顆粒化粉末之製造 於流體化床造粒器[Powrex公司(日本)製造,lab , 中,裝入800g甘露糖醇[默克日本(Merck)株式會社製造] 及進行造粒,同時喷霧3 1 5g純水。使顆粒乾燥,獲得^ 顆粒化粉末。 (6) 混合粉末之製造 於!〇5g具核心物之上述外套腸衣粉末中,加97 」 述甘露糖醇-顆粒化粉末,15.0g低取代之羥丙基纖雄素 本紙張尺度適用中國國家標準(CNS)A4規格(210χ297公釐) 310743D01 34 200302742 A7
經濟部智慧財產局員工消費合作社印製 LH-33(羥丙氧基之含量:5·8重量%,平均粒徑:η , 22.5g結晶纖維素[CEOLUSKG_8〇1(商品名),朝日藥品工 業株式會社(日本)製造],75g交聯吡咯啶酮 ” (crospovidone),1.5g無水檸檬酸,〇 45g阿斯巴甜 (aspartame)及〇.75g硬脂酸鎂,均於袋中混合之獲得混
合粉末。 X 0(7)可口服崩解之錠劑之製造 250g上述混合粉末,以搗打器〇5R,直徑Um⑷用 旋轉型造錠機,於造錠壓力1.5t〇n/cm2下,進行造鍵,声 得錠劑,各重5 0 0 m g。 所得各錠劑之硬度及口服崩解時間,分別為5 9kgA 3 0秒。 實施例2 (1)具核心物之顆粒之製造 離心流體化包覆造粒器[Powr ex公司(日本)製造, .MP_10(2 型)]中,裝入 900g Nonpareil 1〇5(商品名)(粒徑 1〇〇 至200μπι)。入口氣溫及裝料溫度分別控制於65°C及約 3 0 °C,Nonpareil以事先製備之下述組成物之散褒液體,依 切線喷霧方法,以喷霧速率22g/min喷霧包覆之。若特定 量5661g散裝液體已喷霧,則停止噴霧操作,然後,於造 粒器中進行乾燥8分鐘。所得顆粒經42號圓篩(350μηι)及 100號圓篩(150μηι)過篩,獲得2074g具核心物之顆粒。 散裝液1 藍索皮唑 l〇80g 本紙張尺度適用國家標準(CNS)A4規格(210 x 297公髮) ~ 35 310743D01 -------------裝--------訂---------線 (請先閱讀背面之注咅?事項再填寫本頁) 200302742 A7 五、發明說明(% ) 碳酸鎂 低取代之羥丙基纖維素LH-32 (羥丙氧基含量:8.8重量%) 羥丙基纖維素(SSL型) 純水 (2)具核心物之膜襯顆粒之製造 離心流體化包覆造粒器[Powrex公司(日本)製造, MP-10(2型)]中,裝入2074g具核心之上述顆粒。入口氣 溫及裝料溫度分別控制於78°c及約4〇t,事先製備之下述 組成物之襯液,依切線喷霧方法,以噴霧速率22g/min噴 霧。若特定量1980g襯液已喷霧,則停止噴霧操作,然後, 於造粒器中,進行乾燥9分鐘。所得顆粒經42號圓_ (3 5〇0111)及1〇〇號圓篩(15〇{1111)過篩,獲得25558具核心之 膜襯顆粒。 襯液 360g 180g 360g 4680g ί請先閱讀背面之注意事項再填寫本頁} »x_^_ 經濟部智慧財產局員工消費合作社印製 羥丙基甲基纖維素 (2910型,黏度:3厘沲) 氧化鈦(Ti〇2) 1〇8g 滅菌滑石(商品名) 1 08g [Matsumura Sangyo株式會社(日本)製造] 低取代之羥丙基纖維素LH-32 ΊΟΛ 1 8Ug (羥丙氧基含量·· 8.8重量〇/0) 甘露糖醇 252g 252g 純水 、r 360〇g
36 310743D01 --铸· 200302742 A7 B7 五、發明說明(37 ) (3)具核心物之腸衣顆粒之製造 離心流體化包覆造粒器[Powr ex公司(日本)製造, MP-10(2型)]中,裝入1320g具核心之上述膜襯顆粒。入 口氣溫及裝料溫度分別控制於80°C及約42°C,事先製備之 下述組成物之腸膜衣液(A),依切線喷霧方法,以噴霧速率 22g/min喷霧,則噴霧得特定量1638g腸膜衣液。 ^腸膜衣液(A): _ 優雷季L30D-55 優雷季NE30D 聚乙二醇6000 單硬脂酸甘油醋 聚山梨酸酯80 三氧化二鐵 三氧化二鐵(黃色) 無水檸檬酸 純水 1219.2 g 134.4 g 40.8 g 24.0 g 7.2 g 〇.24g 〇.24g 0.48g 1693 g -------------^--------^---------^ (請先閱讀背面之注意事項再填寫本頁) 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 接著,入口氣溫及裝料溫度分別控制於76°C及約 42°C,事先製備之下述組成物之腸膜衣液(B),依切線喷霧 方法,以喷霧速率22g/min喷霧,則喷霧得特定量6552g 腸膜衣液。 腸膜衣液(B)= 優雷季L30D-55 優雷季NE30D 檸檬酸三乙酯 4032 g 447.8 g 269.3 g 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 37 310743D01 200302742 A7 B7五、發明說明(38 ) 單硬脂酸甘油酯 86.4 g 聚山梨酸酯80 25.9 g 三氧化二鐵 0.86g 三氧化二鐵(黃) 0.86g 無水檸檬酸 〇.72g 純水 2624 g 經濟部智慧財產局員工消費合作社印製 接著,入口溫度及裝料溫度分別控制於80°c及約 42°C,事先製備之上述組成物之腸膜衣液(A),依切線喷霧 方法,以喷霧速率22g/min喷霧,則喷霧得特定量819g腸 膜衣液。 (4) 具核心物之腸衣及甘露糖醇衣顆粒之製造 接續(3),入口氣溫及裝料溫度分別控制於85°C及約 3 5 °C,事先製備之下述組成物之膜衣液,依切線喷霧方法, 以喷霧速率22g/min,用離心流體化包覆造粒器[Powrex公 司(曰本)製造,MP-10(2型)]噴霧,若特定量882g膜衣液 喷霧後,停止喷霧操作,然後,於造粒器中,進行乾燥10 分鐘。所得顆粒經35號圓篩(420μιη)及60號圓篩(250μιη) 過篩,獲得1964g具核心物之腸衣及甘露糖醇衣顆粒。 所得顆粒之平均粒子直徑為333.7μτη。 膜衣液 甘露糖醇 180g 純水 10 8 0 g (5) 混合粉末之製造 27 0g具核心物之上述腸衣及甘露糖醇衣顆粒中,加 (請先閱讀背面之注意事項再填寫本頁) -¾ $ - --線· 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 38 310743D01 經濟部智慧財產局員工消費合作社印製 39 200302742 五、發明說明(39 ) 2〇4.0g甘露糖醇、30g低取代之羥丙基纖維素lh_33(羥丙 氧基含i · 5.8重量%)、30g結晶纖維素[CE〇LUS KG_ 8〇1(商品名),朝曰藥品工業株式會社(曰本)製造]、15g交 聯吡咯啶酮、3g無水檸檬酸、9g阿斯巴甜、6§硬脂酸鎂 及 3g 調味劑[STRAWBERRY DURAR〇mE(商品名),Nih〇n Filmenich株式會社(曰本)製造],於袋中混合,獲得混合 粉末。 (6)可口服崩解之錠劑之製造 570g上述混合粉末,用Autograph(商品名;壓縮力測 足儀益)’以具斜角邊緣之穿孔機’ 13mm直徑,造旋壓力 l-5ton/cm2,進行造鍵,獲得錠劑,各重57〇mg。 所得各錠劑之硬度及口服崩解時間,分別為2 6kg及 20秒。 所得錠劑之耐酸性為3.5%。 實施你丨3 流體化床造粒器[Powrex公司(日本)製造,LAB-1]中, 裝入0.6g弗里波(VOglibose)、410.4g赤蘚糖醇[Nikken藥 品株式會社(日本)製造]、120·Og低取代之羥丙基纖維素 LH-3 3(羥丙氧基含量:5.8重量%,平均粒徑:ΐ7.8μπι) ' 3〇.〇g CEOLUS KG-801 [朝曰藥品工業株式會社(曰本)製 造]、3〇g交聯吡咯啶酮、6.0g無水檸檬酸及1.2g阿斯巴甜, 進行造粒,同時噴霧純水。經乾燥後,併入1.8g硬脂酸鎂。 所得粉末,以穿孔器(具斜角邊緣,直徑l〇mm),用旋轉型 造錠機,以造銘:壓力1 .Oton/cm2,進行造鍵,獲得錠劑, 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 裝--------訂---------線 (請先閱讀背面之注音?事項再填寫本頁) 200302742 B7
五、發明說明(40 ) 各重300mg。 所得各錠劑之硬度及口服崩解時間,分別為10 7kg及 26秒。 實施例4 流體化床造粒器[Powrex公司(日本)製造,LABJ]中, 裝入0.6g弗里波、440.4g赤蘚糖醇[Nikken藥品株式會社 (曰本)製造]、120.0g低取代之羥丙基纖維素lH-33(經丙氧 基含量·· 5.8重量%,平均粒徑:17·8μιη)、3〇 〇g交聯吼洛 啶酮、6.0g無水檸檬酸及1.2g阿斯巴甜,進行造粒,同時 噴霧純水。經乾燥後,併入1.8g硬脂酸鎂。所得粉末,以 穿孔器(具斜角邊緣,直徑l〇mm),用旋轉型造錠機,以造 錠壓力1 .Oton/cm2,進行造錠,獲得錠劑,各重3〇〇mg。 所得各錠劑之硬度及口服崩解時間,分別為71kg及 20秒。 實施例5 流體化床造粒器[powrex公司(日本)製造,中, 裝入0.4g弗里波、470.6g赤蘚糖醇[Nikken藥品株式會社 (曰本)製造]、120.0g低取代之羥丙基纖維素lh_33(羥丙氧 基含量· 5 ·7重量%,平均粒徑:3〇 · 8μηι)、6·〇g無水檸檬 酸及1 ·2阿斯巴甜,進行造粒,同時噴霧純水。經乾燥後, 併入1.8g硬脂酸鎂。所得粉末,以穿孔器(具斜角邊緣, 直徑10mm),用旋轉型造錠機,以造錠壓力i 25t〇n/em2, 進行造錠,獲得錠劑,各重3〇〇mg。 所得各旋劑之硬度及口服崩解時間,分別為4 5kg及 本紙張尺度適用中國國家標準(CNS)A4規格(2〗0 x 297公釐) 310743D01 -------------Φ (請先閱讀背面之注音?事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 "-0、_ n «ϋ n I ϋ >ϋ I I I ϋ n ϋ ϋ I n ·ϋ I ϋ Βϋ n 40 200302742 A7 ....._ - B7 ------__ 五、發明說明(41 ) 〜 23秒。 實施例6 f請先閱讀背面之注咅?事項再填寫本頁) 流體化床造粒器[P〇wrex公司(日本)製造,LAB!】中 裝入〇.4g弗里波、470.4甘露糖醇[默克日本株式會社製 造]、120.0g低取代之羥丙基纖維素LH-23(羥丙氧基含量· 5.7重量%,平均粒徑:3〇 8μπχ)、6 〇g無水檸檬酸及^ 阿斯巴甜,進行造粒,同時喷霧純水。經乾燥後,併入丨/ P硬脂酸鎂。所得粉末,以穿孔器(具斜角邊緣,直徑i〇mm),g
用旋轉型造錠機,以造錠壓力Uhon/cm2,進行造錠,庐 得錠劑,各重300mg。 X 所得各錠劑之硬度及口服崩解時間,分別為4 34及 2 7秒。 實施例7 流體化床造粒器[powrex公司(日本)製造,LABq]中, 裝入40.0g馬弟平鹽酸鹽、460 94g赤蘚糖醇[Nikka藥品 0殊式會社(日本)製造]、60.0g低取代羥丙基纖維素lh_ 33(經丙氧基含量·· 5 8重量%,平均粒徑:ι7 “η)、 經濟部智慧財產局員工消費合作社印製 交聯%洛唆_、6.0g無水檸檬酸及i.2g阿斯巴甜,進行造 粒’同時噴霧純水,純水中溶解〇 〇6g黃色氧化鐵。經乾 燥後,併加1 ·8g硬脂酸鎂。所得粉末,以穿孔器(具斜角 邊緣’直徑l〇mm),用旋轉型造錠機,以造鍵壓力 L〇ton/Cm2,進行造錠,獲得錠劑,各重3〇〇mg。 所得各錠劑之硬度及口服崩解時間,分別為6 〇kg及 21秒。 本紙張尺度適用中國國家標準(CNS)A4規格(21^ 297公复) " - 41 310743D01 200302742 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明(42 試驗例1 低取代之羥丙基纖維素LH-30(羥丙氧基含量:14 6重 量%,平均粒徑:17 26μιη)、LH-31(羥丙氧基含量:U 〇 重量0/〇,平均粒隹:18·18μηι)、LH-32(羥丙氧基含量·· 8名 重里/〇,平均粒徑:17 57μπι)及、LH 33(羥丙氧基含量: 5.8重量%,平均粒徑:17 8μπ〇,分別投予4位雌性 估溶解度及風味。 。 結果示於[表1]。 [表1] 評 估 於口腔中難溶 腔中溶解,白 於口腔中溶f白堊 於口腔中溶解,無白 如[表1]所示,關於包括5·8重量❶/〇羥丙氧^ I丙基纖維素LH-33,溶解度及白堊風味均改良,且無 糙感覺。 …' 試驗例2 用低取代之羥丙基纖維素LH-30(羥丙氧基含量: 重置% ’平均粒徑:17 26μπι),LH-31(羥丙氧基含量: 重量%,平均粒徑:18·18μιη),LH-32(羥丙氧基含量 重量%,平均粒徑:17·57μιη)及LH_33(羥丙氧基含量 重量%,平均粒徑:17 8μηι),依下述方式製得錠劑。 流體化床造粒器[P〇wrex公司(日本)製造,LAB」]中, 裝入398.5g赤蘚糖醇[Nikken藥品株式會社(曰本)製造 本紙張尺度_巾關家鮮(CNS)A4祕(210 X 297公餐)— ------- 低取代 14.6 11.0 8.8 5.8 310743D01 (請先閱讀背面之注音?事項再填寫本頁} 訂---------線· 42 A7 200302742 __B7__ 五、發明說明(43 ) 100g低取代之羥丙基纖維素,進行造粒,同時噴霧純水。 經乾燥後,併加1.5 g硬脂酸鎂。所得粉末,以穿孔器(具 斜角邊緣,直徑l〇mm),用旋轉型造錠機,以造錠壓力 1 .Oton/cm2,進行造銳,獲得鍵劑,各重300mg。 所得錠劑分別投予4位雌性,評估溶解度及風味。 結果示於[表2]。 [表2] 低取代羥丙 基纖維素 受試 個體 評 估 LH-30 4/4 於口腔中未溶解 LH-31 4/4 於口腔中未溶解 LH-32 4/4 於口腔中感覺黏著,經溶解後,仍有白堊風味 LH-33 4/4 於口腔中快速溶解,有少許白堊風味 如[表2]所示,關於包括5.8重量%羥丙氧基之低取代 羥丙基纖維素LH-33,溶解度及白堊風味均改良,且無粗 糙感覺。 [本發明之功效] 本發明可快速崩解之固態製劑,乃用以治療及預防各 種疾病,特別是成可口服快速崩解之固態製劑,因製劑具 優異之崩解性及溶解性,能於無水下投予老人或孩童,且 於胃中之崩解性亦改良。 而且,此可快速崩解之固態製劑,因製劑具合宜之強 度,而具優異之長期安定性。 再則,本發明可快速崩解之固態製劑,於溶解度及白 堊風味均改良,且不粗糙。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 310743D01 --------------裝—— (請先閱讀背面之注音?事項再填寫本頁) 訂: ;線· 經濟部智慧財產局員工消費合作社印製 43
Claims (1)
- 200302742 A8 B8 C8 D8 六、申請專利範圍 1 · 一種可快速崩解之固態製劑,包括⑴藍索皮唑以外之藥 理活性成分,(ii)選自糠、澱粉糖、乳糖、蜂蜜及糖醇 之酶類及(iii)具5重量%或以上至低於7重量%之經丙 氧基之低取代羥丙基纖維素。 2 ·如申請專利範圍第1項之製劑,係口服可快速崩解之固 態製劑。 3·如申請專利範圍第1或2項之製劑,係錠劑。 4·如申請專利範圍第1項之製劑,其中醣類為糖醇。 5·如申請專利範圍第4項之製劑,其中糖醇為甘露糖醇或 赤鲜糖醇。 6·如申請專利範圍第1項之製劑,其中醣類對每10〇重量 份固態製劑為5至97重量份。 7.如申請專利範圍第1項之製劑,其中具5重量%或以上 至低於7重量%羥丙氧基之低取代羥丙基纖維素,對每 1〇〇重量份固態製劑使用3至50重量份。 8·如申請專利範圍第1項之製劑,其中藥理活性成分為弗 里波(voglibose) 〇 經濟部智慧財產局員工消費合作社印製 9·如申請專利範圍第1項之製劑,其中藥理活性成分為馬 弟平(manidipine)鹽酸鹽。 10·如申請專利範圍第1項之製劑,其中藥理活性成分為皮 利隆(pioglitazone)鹽酸鹽。 11 ·如申請專利範圍第1項之製劑,其中藥理活性成分為卡 沙丹(candesartan cilexetil) 〇 12·如申請專利範圍第3項之製劑,係包括細粒者。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 44 310743D01 200302742 經濟部智慧財產局員工消費合作社印制衣 B8 v C8 D8 六、申請專利範圍 1 3 ·如申明專利範圍第丨2項之製劑,其中藥理活性成分乃 包括於固態製劑之細粒中。 14. 如申請專利範圍第13項之製劑,其中⑴選自糠、· 糖、乳糖、蜂蜜及糖醇之醣類及“〇具5重量%或以上至 低於7重量%之㈣氧基之低取魅丙基纖維素係包括 於細粒除外之固態製劑中。 15. 如申請專利範圍第14項之製劑,其中,_對每1〇〇 重量份細粒除外之剩餘固態製劑為5至97重量份。 16. 如申請專利範圍第14項之製劑,其中具5重量%或以 上至低於7重量%之羥丙氧基之低取代羥丙基纖維素, 對母100重量份細粒除外之剩餘固態製劑為3至5〇重 量份。 17·—種具5重量%或以上至低於7重量%羥丙氧基之低取 代羥丙基纖維素,其係用於製造包括藍索皮唑以外之藥 理活性成分及選自糖、澱粉糖、乳糖、蜂蜜及糖醇之醋 > 頻之可快速崩解之固態製劑。 18·—種包括藍索皮唑以外之藥理活性成分及選自糖、澱粉 糖、乳糖、蜂蜜及糖醇之醣叛之固態製劑之快速崩解性 之改良方法,其特徵在於於其中包含具5重量%或以上 至低於7重量%之羥丙氧基之低取代羥丙基纖維 (請先閱讀背面之注意事項再填寫本頁) l· I --------^---I I I 1 I I · 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 45 310743D01
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1999
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