200306868 玖、發明說明： [發明所屬之技術領域] 本發明爲有關改善難水溶性藥物之溶出性之製劑，詳言 之，至少含有難水溶性藥物、崩壞劑及糖醇之經口投與製 劑。 [先前技術] 經口投與製劑若服用回數多，則順從性降低（月刊藥事， 41卷，29頁，1999年）。於是開發1日1回的服用即可OAD (Once a day)之製劑。欲作成〇AD製劑，爲使藥效持續， 必須作成抑制藥物之溶出性之徐放性製劑。 1曰之服用回數須數回之藥物可爲如抗生物質 ( + )- (6R，7R)-7-[(Z)-2-(2 -胺基-4-噻唑基）-2-戊烯醯胺基] -3 -胺甲醯氧甲基-8-氧-5-噻-1-吖雙環[4.2.0.]辛-2-烯-2-羧 酸特戊醯氧甲酯鹽酸鹽· 1水合物（以下稱鹽酸雪夫卡扁匹 卜奇西）。鹽酸雪夫卡扁匹卜奇西爲具有從革蘭陽性菌至革 蘭陰性菌之寬幅抗菌譜。在特開昭62- 8 9號記載包括鹽酸 雪夫卡扁匹卜奇西之化合物。又在特開平4 - 3 0 0 8 2 1號記載 包括鹽酸雪夫卡扁匹卜奇西徐放性製劑。 但欲將如鹽酸雪夫卡扁匹卜奇西等難水溶性藥物作成 OAD製劑，單單以通常手段調製徐放性製劑，仍有從製劑 中幾無藥物溶出之可能性。故藥物在體內幾無吸收’生物 利用性降低之虞。尤其在製劑中配合高含量之難水溶性藥 物時，其傾向強。爲其改良，須將徐放性製劑被覆之前之 200306868 製劑（以下稱素製劑）提升藥物之溶出性，但鹽酸雪夫卡扁 匹卜奇西在上述任何文獻從無提升溶出性之素製劑之記載 。故殷望開發提升難水溶性藥物之溶出性之素製劑。 [發明內容] 鑑此，本發明者發現在素製劑中配合崩壞劑及糖醇’將 對糖醇之崩壞劑之配比最適化，則改善難水溶性藥物之溶 出性，終於完成如下本發明。 (1) 含有至少以下成分 1) 難水溶性藥物， 2) 崩壞劑，及 3 )糖醇 而對糖醇崩壞劑之配比依重量比爲〇. 2倍〜5倍爲特徵之 改善難水溶性藥物之溶出性之製劑。 (2) 對糖醇之崩壞劑之配比爲依重量比爲0.25倍〜4.5倍 爲特徵之上述（1)記載之製劑。 (3) 對糖醇之崩壞劑之配比爲依重量比爲〇·3倍〜4倍爲特 徵之上述（2)記載之製劑。 (4) 崩壞劑爲選自纖維素類、澱粉類及聚乙烯類之1或2 以上崩壞劑之上述（1 )〜（3 )之任一項記載之製劑。 (5) 崩壞劑爲選自低取代度羥丙基纖維素、羧甲基纖維素 ;羧甲基纖維素鈣、羧甲基纖維素鈉、羧甲醚纖維素鈉、 部分α化澱粉、羧甲基澱粉鈉、α化澱粉及聚乙烯吡咯啶 酮之1或2以上之崩壞劑之上述（4)記載之製劑。 (6) 崩壞劑爲選自低取代度羥丙基纖維素、羧甲醚纖維素 200306868 鈉及羧甲基纖維素鈣之1或2以上之上述（5)記載之製劑。 (7) 崩壞劑爲低取代度經丙基纖維素，對糖醇之崩壞劑之 配比爲依重量比爲0 · 3倍〜1 . 2倍爲特徵之上述（1 )〜（6)之 任一項記載之製劑。 (8) 糖醇爲單糖類或雙糖類之上述（1)〜（7)之任一項記載 之製劑。 (9) 糖醇爲選自木糖醇、D-甘露糖醇、麥芽糖醇、赤蘚糖 醇、繭蜜糖醇、D -山梨糖醇及乳糖醇之1或2以上之上述 (8)記載之製劑。 (10) 糖醇爲選自木糖醇、D-甘露糖醇、麥芽糖醇、赤蘚糖 醇、及繭蜜糖醇之1或2以上之上述（9)記載之製劑。 (1 1 )糖醇爲木糖醇，對糖醇之崩壞劑之配比依重量比爲〇 . 8 倍〜4倍爲特徵之上述（1)〜（10)之任一項記載之製劑。 (1 2)崩壞劑爲選自低取代度羥丙基纖維素，糖醇爲木糖醚 ，對糖醇之崩壞劑之配比爲依重量比爲〇 . 8倍〜1 · 2倍爲特 徵之上述（1)記載之製劑。 (1 3 )崩壞劑爲羧甲醚纖維素鈉，糖醇爲木糖醚，對糖醇之 崩壞劑之配比爲依重量比爲2.5倍〜3 . 5倍爲特徵之上述 (1 1)記載之製劑。 (1 4)崩壞劑爲羧基甲基纖維素鈣，糖醇爲木糖醚，對糠醇 之崩壞劑之配比爲依重量比爲〇 . 8倍〜4倍爲特徵之上述（1 ) 記載之製劑。 (15)含有至少以下成分 200306868 2) 崩壞劑，及 3) 糖醇 而在3 7 C之丨谷出δ式驗開始1 2 0分後之藥物溶出率爲6 〇 %以 上地使崩壞劑及糖醇之配比最適化之上述（1 )〜（1 4)之任一 項記載之製劑。 (16) 難水溶性藥物爲（ + M6R57R)-7-[(Z)-2-(2-胺基-4-噻嗤 基）-2_戊稀酸|女基]-3 -胺甲酿氧甲基氧- 雙環 [4·2·0_]半-2-燃-2 -殘酸特戊醯氧甲酯鹽酸鹽或其水合物， 上述（1 )〜（1 5 )之任一項記載之製劑。 (17) 難水溶性藥物爲（+ )-(6115711)-7-[(2)-2-(2-胺基-4-_唑 基）-2 -戊嫌醯胺基]-3 -胺甲醯氧甲基-8-氧-5-噻-1-吖雙環 [4·2·0·]辛-2-燃-2 -殘酸特戊醯氧甲酯鹽酸鹽或其水合物， 崩壞劑爲羧基甲基纖維素鈣，糖醇爲木糖醇，對糖醇之崩 壞劑之配比爲依重量比爲0.8倍〜4倍爲特徵之上述（1)記 載之製劑。 (1 8)對糖醇之崩壞劑之配比爲依重量比爲2.5倍〜3 . 5倍爲 特徵之上述（17)記載之製劑。 (19) ( + )-(6R，7R)-7-[(Z)-2-(2-胺基-4-噻唑基）-2-戊烯醯胺 基]-3 -胺甲醯氧甲基-8-氧-5-噻-1-吖雙環[4.2.0.]辛-2-烯 -2 -羧酸特戊醯氧甲酯鹽酸鹽· 1水合物之在3 7它之溶出試 驗開始120分後之藥物溶出率爲60%以上之上述（17)或（18) 記載之製劑。 (20) ( + )-(6R，7R)-7-[(Z)-2-(2-胺基-4-噻唑基）·2-戊烯醯胺 基]-3-胺甲醯氧甲基-8-氧-5-噻-1-吖雙環[4.2 0.]辛-2-烯 200306868 -2 -羧酸特戊醯氧甲酯鹽酸鹽·丨水合物之在3 7它之溶出試 驗開始120分後之藥物溶出率爲80%以上之上述（17)或（18) 記載之製劑。 (2 1)爲顆粒劑之上述（1)〜（20)之任一項記載之製劑。 (2 2)在上述（21)記載之製劑被覆徐放性基劑或膠溶性基劑 之徐放性製劑。 - (23)爲1日1回服用之製劑之上述（1)〜（22)之任一項記載 之製劑。 (2 4 )對難水溶性藥物含有崩壞劑及糖醇，對糖醇之崩壞劑 之配比爲依重量比爲0 · 2倍〜5倍爲特徵之難水溶性藥物 之溶出性之改善方法。 [實施方式] 本發明中難水溶性藥物爲醫藥品、醫藥部外品、動物藥 等，無特定，該水溶解度爲在37°C，宜lOOOpg/mL以下， 尤宜l〇〇eg/mL以下，特宜lOpg/mL以下。具體的而言， 宜7β-[(Ζ)-2-(2-胺基-4-噻唑基）-2-羥亞胺乙醯胺基]-3-(1, 2,3-三唑-4-基硫甲硫基）-1-碳-3-哂吩-4-羧酸、（+ )-(冗）-7-[(lR，2S，3R，4S)-3-苯磺醯胺雙環[2.2.1]庚-2-基]-5-庚烯酸 鈣二水合物、（ + )-(6R，7R)-7-[(Z)-2-(2-胺基-4-噻唑基）-2-戊烯醯胺基]-3-胺甲醯氧甲基-8-氧-5-噻-1-吖雙環[4.2.0.] 辛-2-烯-2-羧酸之活性酯，尤宜（ + )-(6R，7R)-7-[(Z)-2-(2-胺 基-4-噻唑基）-2-戊烯醯胺基]-3-胺甲醯氧甲基-8-氧-5-噻-1-吖雙環[4.2.0·]辛-2-烯-2-羧酸特戊醯氧甲酯或其製藥上容 許鹽或其水合物（例如：鹽酸鹽· 1水合物）。 200306868 難水溶性藥物之含量只要可得所望藥理效果，且可形成 製劑之比例即可，宜通常對製劑全量之20〜8 0(W/W)%，尤 宜3 0〜6 0 ( W / W) °/〇，特宜3 0〜5 5 (W / W) %。難水溶性藥物之 含量過高，則易經時變化，又溶出性也有降低之虞。反之 過低，則不能獲得所望之藥理效果。 本發明使用之崩壞劑通常只要在水中能將固形之製劑崩 壞即可，宜使用藥品或食品添加規則上記載之固形崩壞劑 ，宜纖維素類、澱粉類及聚乙烯類。具體而言可爲低取代 度羥丙基纖維素（L-HPC)、羧甲基纖維素、羧甲基纖維素鈣 鲁 、羧甲基纖維素鈉、羧甲醚纖維素鈉、部分α化澱粉、殘 甲基澱粉鈉、α化澱粉及聚乙烯吡咯啶酮，尤宜低取代度 ~ 羥丙基纖維素、羧甲醚纖維素鈉或羧甲基纖維素鈣 、 (CMC-Ca)。也可用這些之！種或2種以上之組合。 朋壞劑之含量依製劑中之難水溶性藥物之含量等而異， 通常宜對製劑全量5(W/W)%以上，宜5〜50(W/W)%，尤宜 7·5〜45(W/W)%，特宜10〜4〇或20〜30(W/W)%。崩壞劑 之配比過高，則製劑即崩壞，無法確保充分溶出性。反之 % 若過低，則製劑不能崩壞，藥物幾無溶出。 本發明使用之糖醇’通常只要溶解在水之糖醇即可，宜 使用藥品或食品添加規則上記載之固形糖醇。尤宜對水之 溶解度在25。〇15(\^/¥)%以上，尤宜30(冒/¥)%以上，特宜 5 0(W/V) %以上之糖醇，例如單糖類、雙糖類之糖醇。 具體而言’可用木糖醇、0-甘露糖醇、麥芽糖醇、赤蘚 糖醇、繭蜜糖醇、D -山梨糖醇及乳糖醇等。特宜木糖醇、 -10- 200306868 D -甘露糖醇、麥芽糖醇、赤蘚糖醇、繭蜜糖醇。也可組合 使用這些之1種或2種以上。 糖醇之含量依製劑中主藥之含量等而異，通常宜對製劑 全量 5(W/W)%以上，宜 5 〜50(W/W)%，尤宜 7.5 〜45(W/W)% ，特宜1 0〜4 0 ( W / W) %。糖醇之配比過高，則易時變化，也 無法調製製劑。反之，過低則不能獲得充分藥物之溶出性 。又上述糖醇也可當作賦形劑添加。 對糖醇之崩壞劑之配比通常爲從難水溶性藥物之製劑之 溶出性增大之比例即可，宜對糖醇之崩壞劑之配比依重量 比爲0.25倍，尤宜0.25〜4.5倍，特宜0.3〜4倍。若崩壞 劑爲低取代度羥丙基纖維素，宜對糖醇之崩壞劑之配比依 重量比爲〇 · 2〜1 · 5倍，尤宜〇 . 2 5〜1 . 2 5倍，特宜〇 · 3〜1 . 2 倍。若糖醇爲木糖醇，則宜對糖醇之崩壞劑（宜CMC-C a) 之配比依重量比爲〇 · 5〜5倍，尤宜0.6〜4.5倍，特宜0 · 8 〜4倍，尤宜2.5〜3 . 5倍。若崩壞劑爲低取代度羥丙基纖 維素，糖醇爲木糖醇，宜對糖醇之崩壞劑之配比依重量比 爲0.6〜1.4倍，尤宜0.7〜1.3倍，特宜0.8〜1.2倍。考慮 溶出性及製劑之加工性等，崩壞劑及糖醇之組合之適宜之 一爲崩壞劑爲羧甲醚纖維素鈉，糖醇爲木糖醇’此時宜對 糖醇之崩壞劑之配比依重量比爲2〜4倍，尤宜2.25〜3.75 倍，特宜2.5〜3 . 5倍，最宜約3倍。另一適宜形態爲崩壞 劑爲C M C - C a，糖醇爲木糖醇，此時宜對糖醇之崩壞劑之 配比依重量比爲2〜4倍’尤宜2 · 2 5〜3 · 7 5倍’特宜2.5〜 3 . 5倍。最宜約3倍。若崩壞劑之含量過多’則造粒性不佳 200306868 ，素製劑呈多孔（Porous)狀態。結果不能獲得耐被覆之強度。 本發明之製劑更可任意含有結合劑、造粒助劑、賦形劑 、安定化劑等製劑學上容許之添加劑。 結合劑可泛用該領域周知者’例如甲基纖維素、羥丙基 纖維素（HP C)、聚乙烯醇、明膠、糊精等例示，宜羥丙基纖 維素。結合劑之含量通常宜對製劑全量用0.5〜15(W/W) % 、宜 1 .〇 〜1 〇(W/W)%，尤宜 1·5 〜5(W/W)%。 造粒助劑可泛用該領域周知者’例如硬化蓖麻油、硬脂 醇等蠘類、乙二醇4 0 0 0、乙二醇6 0 0 〇等聚乙二醇類，宜 硬化蓖麻油。造粒助劑之含量通常宜對製劑全量用5〜 25(W/W)%，宜 3 〜20(W/W)%，尤宜 2 〜10(W/W)%。 賦形劑可泛用該領域周知者’例如乳糖、白糖、糖醇、 玉米澱粉、馬鈴薯澱粉、羥丙基澱粉、合成矽酸鋁等，宜 乳糖、白糖、糖醇、玉米澱粉、馬鈴薯澱粉。賦形劑之含 量可考慮主藥含量，目的製劑之大小等而適宜地設定，通 常對製劑全量用40〜90(W/W)% ’宜45〜85(W/W)% ’尤宜 50 〜80(W/W)0/〇。 安定化劑可用氯化鈉、碳酸氫鈉、胺基乙酸、亞硫酸氫 鈉、亞硫酸鈉、苯甲酸鈉、碳酸鈣、碳酸鎂、磷酸氫鈣、 氧化鎂，尤宜氧化鎂、亞硫酸氫鈉。安定化劑之含量可考 慮主藥含量，目的製劑之大小等而適宜設定，通常對製劑 全量用 0.1 〜20.0(W/W)%，宜 〇·5 〜10.0(W/W)%。 本發明之製劑之形態無特定，宜顆粒劑、散劑、細粒劑 及錠劑等固形製劑，特宜顆粒劑。 200306868 製造本發明之顆粒劑時無特定，宜依以下方法製造。即 將難水溶性藥物、糖醇、崩壞劑及所望之賦形劑、安定化 劑等混合，於此混合粉末依所望添加含有結合劑之水溶液 而捏合。其後以擠壓造粒機造粒，將粒劑乾燥。乾燥後， 予以整粒，分級來製造顆粒劑。有時更將分級後顆粒之形 狀整粒，球形化。顆粒時之製造方法也可依轉動造粒法、 流動層造粒法、攪拌造粒法、攪拌流動層造粒法調製。 本發明之製劑也可於調製成顆粒劑後，更予以錠劑化， 或膠囊充塡等。此時錠劑可含有賦形劑、結合劑、滑澤劑 等製劑學上容許之添加之。若爲膠囊劑時，可充塡硬膠囊 劑或軟膠囊劑。 本發明之製劑添加在水，即從製劑中迅速溶出藥物。宜 依第14改訂日本藥典之槳法（槳攪拌速度5〇 rpm，試驗溫 度3 7°C，第14改訂日本藥典第2液[pH 6.8])在37 °C溶出試 開始120分後之溶出率宜爲60%以上，尤宜溶出率爲70% 以上’特宜溶出率爲80%。若崩壞劑用CMC-Ca，糖醇用木 糠醇時等，6 0分後之溶出率宜8 0 %以上，尤宜8 5 %以上， 特宜9 0 %以上。1 2 0分後之溶出率宜9 0 %以上。 本製劑基本上由藥物、糖醇及崩壞劑來構成，有時也可 由藥物及糖醇或藥物及崩壞劑形成複合體。 本發明之顆粒劑、錠劑或膠囊劑等形成後，也可被覆徐 方女性基劑或腸溶性基劑，作成徐放性或腸溶性基劑。徐放 性基劑之例可爲乙基纖維素、甲基丙烯酸胺烷酯共聚物E '甲基丙烯酸胺烷酯共聚物r s、硬脂酸、硬化大豆油、硬 200306868 化菜仔油、硬化油、硬脂醇、鯨蠟醇、羥丙基甲基纖維素 、石鱲、甘油單硬脂酸酯等。又腸溶性膜基劑可爲羥丙基 甲基纖維素酞酸酯、羥丙基甲基纖維素乙酸酯丁二酸酯、 羥丙基甲基纖維素偏苯三甲酸酯、羥丙基甲基纖維素乙酸 酯馬來酸酯、殘基甲基乙基纖維素I丐、甲基丙烯酸共聚物 L、甲基丙烯酸共聚物LD、甲基丙烯酸胺烷酯共聚物S、 乙酸酞酸纖維素、精製蟲膠等。 上述之徐放性基劑或腸溶性基劑之被覆也可依所望在素 顆粒形成下舖層後施行。該下舖層之成分可爲例如HP M C 或滑石粉等。 又被覆徐放性基劑或腸溶性基劑之裝置可爲工業上使用 者，例如，盤被覆裝置、流動層型被覆裝置、瓦士達型被 覆裝置、離心流動層型被覆裝置、攪拌轉動流動層型被覆 裝置等。 上述徐放性或腸溶性製劑之服用回數無特定，宜1日1 〜3回，尤宜1日1〜2回，特定1日1回。 本發明提供宜在製劑中至少含有難水溶性藥物、崩壞劑 及糖醇，將崩壞劑及糖醇之配比予以最適化，例如在3 7 t 之前述溶出試驗開始120分後之藥物溶出率成60%以上之 製劑。也提供以對糖醇之崩壞劑之配合配比依重量比爲0.2 〜5倍，宜0.25〜4.5倍，尤宜0.3〜4倍爲特徵之改善難 水溶性藥物之溶出性之方法。又提供包含該溶出性改善方 法之改善前述難水溶性藥物之溶出性之製劑之製造方法。 (實施例1〜3，比較例1〜2) -14- 200306868 仿下示製造方法，製造如表1所示組成之各顆粒劑。 (實施例1製劑之製造方法） 藥物爲將特開昭6 2 - 8 9號記載之前述鹽酸雪夫卡扁匹卜 奇西予以粉碎來使用。崩壞劑用低取代度羥丙基纖維素（以 下稱L - Η P C )，糖醇用木糖醇，造粒助劑用硬化蓖麻油，結 合劑用羥丙基纖維素（以下稱HPC-L)。 將將鹽酸雪夫卡扁匹卜奇西、L-HPC、木糖醇及硬化蓖 麻油在乳鉢中混合後，加3 (w /ν)% ρ H c -L水溶液來捏合。 捏合之混合物以擠壓造粒機[篩孔Φ〇·6ΐΏ1Ώ，機械名Dome G r 〇 u n d (不二製粉公司）]造粒，在5 0 °C乾燥3 0分後，經1 4 篩孔之篩整粒，以2 0〜4 2篩孔之篩分級，製成顆粒劑。 (表1) (單位m g) 配合成分 實施例 1 實施例 2 實施例 3 比較例 1 比較例 2 鹽酸雪夫卡扁匹卜奇西 390 390 390 390 390 L-HPC(崩壞劑） 100 200 300 400 - 木糖醇（糖醇） 300 200 100 攀 400 硬化蓖麻油 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 合計 823.0 823.0 823.0 815.6 812.6 崩壞劑/糖醇之重量比 0.33 1.0 3.0 - - • L-HPC :低取代度羥丙基纖維素 • HPC-L :羥丙基纖維素 200306868 (溶出試驗） 就上述製劑，依第1 4改訂日本藥典之規定之方法施行溶 出試驗。溶出試驗之條件詳細如下。至試驗液中之製劑投 入量爲約270mg(鹽酸雪夫卡扁匹卜奇西l〇〇mg力價量）。 [溶出試驗條件]200306868 发明 Description of the invention: [Technical field to which the invention belongs] The present invention relates to a preparation for improving the dissolution property of a poorly water-soluble drug. In particular, it orally administers at least a poorly water-soluble drug, a disintegrating agent and a sugar alcohol. preparation. [Prior art] If the number of oral administration preparations is large, the compliance decreases (Monthly Journal of Pharmaceutical Affairs, 41, 29, 1999). Therefore, OAD (Once a day) preparations that can be taken once a day have been developed. In order to make OAD preparations, in order to maintain the drug effect, it is necessary to make a slow release preparation that inhibits the dissolution of the drug. The drug that needs to be taken several times can be, for example, antibiotic (+)-(6R, 7R) -7-[(Z) -2- (2-amino-4-thiazolyl) -2-pentyl Allylamino] -3 -aminomethyloxymethyl-8-oxo-5-thia-1-acylbicyclo [4.2.0.] Oct-2-en-2-carboxylic acid pentamyloxymethyl salt Acid salt · 1 hydrate (hereinafter referred to as Shefkapin pipici hydrochloride). Schiffka Flat Pipsicil Hydrochloride has a broad antibacterial spectrum from Gram-positive bacteria to Gram-negative bacteria. Japanese Patent Application Laid-Open No. 62-89 describes a compound including Schefkabenpipici hydrochloride. It is also described in Japanese Patent Application Laid-Open No. 4-3 0 8 2 1 including a chemopreventive preparation of Schiffka flat pipiczil hydrochloride. However, if a water-insoluble drug such as Schiffka bianbapicic hydrochloride is to be used as an OAD preparation, only the radioactive preparation can be prepared by ordinary means, and there is still little possibility of dissolution of the drug from the preparation. Therefore, the drug is scarcely absorbed in the body, and the bioavailability may be reduced. Especially when a high content of a poorly water-soluble drug is blended in the preparation, the tendency is strong. To improve it, it is necessary to improve the dissolution of the drug before the application of the 200306868 preparation (hereinafter referred to as the "vegetable preparation"). However, there is no record of the chemical preparation that enhances the dissolution in the above mentioned literature. . Therefore, it is eager to develop a pharmaceutical preparation that enhances the dissolution of poorly water-soluble drugs. [Summary of the Invention] In view of this, the inventors found that the combination of a disintegrant and a sugar alcohol in a vegetarian preparation will optimize the ratio of the disintegrant to the sugar alcohol, and improve the dissolution of poorly water-soluble drugs, and finally completed the following this invention. (1) Contains at least the following ingredients: 1) poorly water-soluble drugs, 2) disintegrating agents, and 3) sugar alcohols, and the ratio of sugar alcohol disintegrating agents to 0.2 times to 5 times is an improvement based on weight ratio. Dissolution preparation of poorly water-soluble drugs. (2) The compounding ratio of the disintegrating agent for sugar alcohol is the preparation according to the above (1), characterized by being 0.25 to 4.5 times by weight. (3) The ratio of the disintegrating agent to sugar alcohol is 0.3 to 4 times the weight ratio of the preparation according to the above (2). (4) The disintegrating agent is a preparation according to any one of (1) to (3) above, which is selected from the group consisting of cellulose-based, starch-based, and polyethylene-based 1 or 2 or more disintegrating agents. (5) The disintegrating agent is selected from the group consisting of low-substituted hydroxypropyl cellulose, carboxymethyl cellulose; calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, partially alpha starch, The preparation according to the above (4), wherein the carboxymethyl starch sodium, alpha starch and polyvinylpyrrolidone have 1 or more disintegrating agents. (6) The disintegrating agent is a preparation described in (5) above 1 or 2 selected from the group consisting of low-substituted hydroxypropyl cellulose, carboxymethyl ether cellulose 200306868 sodium and carboxymethyl cellulose calcium. (7) The disintegrating agent is low-degree substitution propylcellulose, and the ratio of the disintegrating agent to sugar alcohol is 0.3 to 1.2 times by weight, which is characterized by the above (1) to (6) ). (8) The preparation according to any one of (1) to (7), wherein the sugar alcohol is a monosaccharide or a disaccharide. (9) The sugar alcohol is 1 or 2 or more selected from the group consisting of xylitol, D-mannitol, maltitol, erythritol, mannitol, D-sorbitol, and lactitol. Of the preparation. (10) The sugar alcohol is a preparation described in (9) above 1 or 2 selected from the group consisting of xylitol, D-mannitol, maltitol, erythritol, and cocomelitol. (1 1) The sugar alcohol is xylitol, and the ratio of the disintegrating agent to the sugar alcohol is 0.8 to 4 times by weight. The preparation according to any one of the above (1) to (10) is characterized by . (1 2) The disintegrating agent is selected from the group consisting of low-substituted hydroxypropyl cellulose, the sugar alcohol is xylose ether, and the ratio of the disintegrating agent to the sugar alcohol is 0.8 times to 1.2 times by weight. It is characterized by the preparation as described in said (1). (1 3) The disintegrating agent is sodium carboxymethyl ether cellulose, the sugar alcohol is xylose ether, and the ratio of the disintegrating agent to the sugar alcohol is 2.5 times to 3.5 times according to the above-mentioned feature (1 1) The preparation described. (1 4) The disintegrating agent is carboxymethyl cellulose calcium, the sugar alcohol is xylose ether, and the ratio of the disintegrating agent to furfuryl alcohol is 0.8 times to 4 times as the above-mentioned feature (1) Documented formulation. (15) Contains at least the following ingredients: 200306868 2) Disintegrating agent, and 3) Sugar alcohol, which disintegrates at a drug dissolution rate of 60% or more after 120 minutes after the initiation of the delta formula at 37 ° C The formulation according to any one of (1) to (14) above, in which the mixing ratio of the agent and the sugar alcohol is optimized. (16) Poorly water-soluble drugs are (+ M6R57R) -7-[(Z) -2- (2-amino-4-thienyl) -2_pentanoic acid | feminine] -3 -amine methyl alcohol Oxymethyloxy-bicyclo [4 · 2 · 0_] hal-2--2-fuel-2-residue pivaloyloxymethyl hydrochloride or its hydrate, any one of (1) to (1 5) above Documented formulation. (17) Poorly water-soluble drugs are (+)-(6115711) -7-[(2) -2- (2-amino-4--4-azolyl) -2 -pentamidineamine] -3 -amine Formamyloxymethyl-8-oxo-5-thia-1-acylbicyclo [4 · 2 · 0 ·] oct-2-ran-2 -residue pivaloyloxymethyl hydrochloride or its hydrate, The disintegrating agent is carboxymethyl cellulose calcium, the sugar alcohol is xylitol, and the ratio of the disintegrating agent to the sugar alcohol is 0.8 to 4 times the weight ratio, which is characterized by the preparation described in (1) above. (18) The compounding ratio of a disintegrating agent for sugar alcohol is the preparation according to the above (17) characterized by a weight ratio of 2.5 to 3.5 times. (19) (+)-(6R, 7R) -7-[(Z) -2- (2-Amino-4-thiazolyl) -2-pentenamidoamino] -3 -aminoformamidine -8-oxo-5-thia-1-acylbicyclo [4.2.0.] Oct-2-en-2-carboxylic acid pentamyloxymethyl hydrochloride · Dissolution of 1 hydrate in 3 7 The preparation described in (17) or (18) above with a drug dissolution rate of 60% or more after 120 minutes from the start of the test. (20) (+)-(6R, 7R) -7-[(Z) -2- (2-amino-4-thiazolyl) · 2-pentenamidonyl] -3-amine formamidine -8-oxo-5-thia-1-acylbicyclo [4.2 0.] oct-2-ene 200306868- 2 -carboxylic acid pentamyloxymethyl hydrochloride · 丨 Hydrate dissolves in 3 7 The preparation described in (17) or (18) above with a drug dissolution rate of 80% or more after 120 minutes from the start of the test. (2 1) The preparation according to any one of (1) to (20) above, which is a granule. (2) The formulation according to the above (21) is coated with a releasable base or a peptidic base. -(23) The preparation according to any one of (1) to (22) above, which is a preparation to be taken once a day. (2 4) The dissolution of poorly water-soluble drugs containing disintegrating agents and sugar alcohols, and the ratio of the disintegrating agents of sugar alcohols to the weight ratio of 0.2 to 5 times Improve methods. [Embodiment] The water-insoluble drugs in the present invention are pharmaceuticals, quasi-drugs, animal drugs, and the like, which are not specific. The water solubility is 37 ° C, preferably 1,000 pg / mL or less, and particularly 100 mg / mL Below, particularly preferably below 10 pg / mL. Specifically, 7β-[(Z) -2- (2-amino-4-thiazolyl) -2-hydroxyimineacetamido] -3- (1, 2,3-triazole- 4-ylthiomethylthio) -1-carbon-3-fluorene-4-carboxylic acid, (+)-(redundant) -7-[(lR, 2S, 3R, 4S) -3-benzenesulfonamide Bicyclo [2.2.1] heptan-2-yl] -5-heptenoic acid calcium dihydrate, (+)-(6R, 7R) -7-[(Z) -2- (2-amino-4- Thiazolyl) -2-pentenamidinylamino] -3-aminemethyloxymethyl-8-oxo-5-thia-1-acylbicyclo [4.2.0.] Oct-2-en-2-carboxylic acid Active ester, especially (+)-(6R, 7R) -7-[(Z) -2- (2-amino-4-thiazolyl) -2-pentenamidoamino] -3-amine methyl Oxomethyl-8-oxo-5-thi-1-acylbicyclo [4.2.0 ·] oct-2-en-2-carboxylic acid pivaloxenyl methyl ester or its pharmaceutically acceptable salt or its hydrate ( Example: hydrochloride · 1 hydrate). 200306868 The content of poorly water-soluble drugs can be as long as the desired pharmacological effect can be obtained, and the proportion of the preparation can be formed. It is usually 20 to 80 (W / W)% of the total amount of the preparation, especially 30 to 60 (W / W) ° / 〇, especially 30 ~ 55 (W / W)%. If the content of the poorly water-soluble drug is too high, it will change easily over time, and the dissolution may be reduced. If it is too low, the desired pharmacological effect cannot be obtained. The disintegrating agent used in the present invention generally only needs to disintegrate the solid preparation in water. The solid disintegrating agent described in the rules for adding drugs or foods is suitable, and cellulose, starch and polyethylene are suitable. Specifically, it may be low-substituted hydroxypropyl cellulose (L-HPC), carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose, and partial alpha Starch, residual methyl starch sodium, alpha starch and polyvinylpyrrolidone, especially low substitution degree ~ hydroxypropyl cellulose, sodium carboxymethyl cellulose or calcium carboxymethyl cellulose, (CMC-Ca). These are also available! One or a combination of two or more. The content of pokemon varies depending on the content of the poorly water-soluble drug in the preparation, etc. Generally, it should be more than 5 (W / W)%, preferably 5 ~ 50 (W / W)%, especially 7 · 5 ~ 45 (W / W)%, especially 10 ~ 40 or 20 ~ 30 (W / W)%. If the ratio of the disintegrating agent is too high, the preparation will collapse, and sufficient dissolution properties cannot be ensured. Conversely, if the% is too low, the preparation cannot be broken, and the drug is hardly dissolved. The sugar alcohol 'used in the present invention is usually only a sugar alcohol dissolved in water, and a solid sugar alcohol described in the rules for adding drugs or foods is preferably used. Especially, the solubility in water is 25. 〇15 (\ ^ / ¥)% or more, especially 30 (冒 / ¥)% or more, especially 50 (W / V)% or more sugar alcohols, such as monosaccharides and disaccharides. Specifically, 'xylitol, 0-mannitol, maltitol, erythritol, cocomel, D-sorbitol, lactitol, and the like can be used. Teyi Xylitol, -10- 200306868 D-Mannitol, Maltitol, Erythritol, Cocoonitol. One or more of these may be used in combination. The content of sugar alcohol varies depending on the content of the main drug in the preparation, etc. Generally, the total amount of the preparation should be more than 5 (W / W)%, preferably 5 to 50 (W / W)%, especially 7.5 to 45 (W / W). %, Especially for 10 ~ 4 0 (W / W)%. If the ratio of sugar alcohol is too high, it will change with time, and the preparation cannot be prepared. Conversely, if it is too low, sufficient drug dissolution cannot be obtained. The sugar alcohol may be added as an excipient. The ratio of the disintegrating agent for sugar alcohol is usually the ratio of the increase in dissolution from the preparation of poorly water-soluble drugs. The ratio of the disintegrating agent for sugar alcohol is preferably 0.25 times by weight, especially 0.25. ~ 4.5 times, especially 0.3 ~ 4 times. If the disintegrator is hydroxypropyl cellulose with a low degree of substitution, the ratio of the disintegrating agent to sugar alcohol is preferably 0.2 to 1.5 times by weight, particularly 0.2 to 5 to 1.5 times. , Special Yi 0.3 ~ 1.2 times. If the sugar alcohol is xylitol, the ratio of the sugar alcohol disintegrator (preferably CMC-C a) should be 0.5 to 5 times by weight, particularly 0.6 to 4.5 times, and particularly preferably 0 8 ~ 4 times, especially 2.5 ~ 3.5 times. If the disintegrating agent is hydroxypropyl cellulose with a low degree of substitution and the sugar alcohol is xylitol, the ratio of the disintegrating agent to the sugar alcohol should be 0.6 to 1.4 times by weight, particularly 0.7 to 1.3 times, particularly preferably. 0.8 ~ 1.2 times. Considering dissolution and processing properties of the preparation, one of the suitable combinations of disintegrating agents and sugar alcohols is that the disintegrating agent is sodium carboxymethyl ether cellulose, and the sugar alcohol is xylitol. The proportion by weight is 2 to 4 times, especially 2.25 to 3.75 times, especially 2.5 to 3.5 times, and most preferably about 3 times. Another suitable form is that the disintegrating agent is CMC-C a, and the sugar alcohol is xylitol. At this time, the ratio of the disintegrating agent of sugar alcohol should be 2 to 4 times by weight ratio, especially 2 · 2 5 ~ 3 · 7 5 times' special should 2.5 ~ 3.5 times. Optimum about 3 times. If the content of the disintegrator is too large ', the granulation property is poor 200306868, and the vegetarian preparation is in a porous state. As a result, a coating-resistant strength cannot be obtained. The preparation of the present invention may optionally contain additives that are pharmaceutically acceptable, such as a binding agent, a granulating auxiliary, an excipient, and a stabilizer. As the binding agent, those well known in the art, such as methyl cellulose, hydroxypropyl cellulose (HP C), polyvinyl alcohol, gelatin, dextrin and the like can be exemplified, and hydroxypropyl cellulose is preferred. The content of the binding agent is usually preferably 0.5 to 15 (W / W)%, preferably 1.0 to 10 (W / W)%, and particularly preferably 1.5 to 5 (W / W)%, based on the total amount of the preparation. Granulation additives can be widely used in the field, such as hardened castor oil, stearyl alcohol and other fluorenes, ethylene glycol 400, ethylene glycol 600, and other polyethylene glycols, hardened castor oil . The content of granulation aid is usually 5 to 25 (W / W)%, preferably 3 to 20 (W / W)%, and particularly 2 to 10 (W / W)%. Excipients can be widely used, such as those known in the art ', such as lactose, white sugar, sugar alcohol, corn starch, potato starch, hydroxypropyl starch, synthetic aluminum silicate, and the like, preferably lactose, white sugar, sugar alcohol, corn starch, potato starch. The content of the excipient can be appropriately set in consideration of the content of the main drug, the size of the intended preparation, and the like, usually 40 to 90 (W / W)% of the total amount of the preparation, preferably 45 to 85 (W / W)%, particularly 50 ~ 80 (W / W) 0 / 〇. Stabilizing agents include sodium chloride, sodium bicarbonate, aminoacetic acid, sodium bisulfite, sodium sulfite, sodium benzoate, calcium carbonate, magnesium carbonate, calcium hydrogen phosphate, and magnesium oxide, and magnesium oxide and sodium bisulfite are particularly suitable. The content of the stabilizing agent can be appropriately set in consideration of the content of the main drug, the size of the target preparation, and the like. Usually, the total amount of the preparation is 0.1 to 20.0 (W / W)%, preferably 0.5 to 10.0 (W / W)%. The form of the preparation of the present invention is not specific, and solid preparations such as granules, powders, fine granules, and lozenges are preferable, and granules are particularly suitable. 200306868 The granules of the present invention are not specific when they are produced, and are preferably produced according to the following method. That is, poorly water-soluble drugs, sugar alcohols, disintegrating agents, desired excipients, stabilizers, etc. are mixed, and the mixed powder is kneaded by adding an aqueous solution containing a binding agent as desired. Thereafter, it was granulated by an extrusion granulator, and the granules were dried. After drying, they are granulated and classified to produce granules. In some cases, the shape of the classified particles is shaped and spheroidized. The method for manufacturing granules can also be adjusted according to the rotating granulation method, the fluidized layer granulation method, the stirred granulation method, and the stirred fluidized layer granulation method. The preparation of the present invention can also be tableted or filled with capsules after being prepared into granules. At this time, the lozenge may contain excipients, binding agents, lubricating agents, and other pharmacologically acceptable additives. In the case of capsules, hard capsules or soft capsules can be filled. The preparation of the present invention is added to water, that is, the drug is rapidly dissolved from the preparation. The paddle method of the Japanese Pharmacopoeia should be revised according to the 14th (paddle stirring speed 50 rpm, the test temperature 37 ° C, the 14th revised Japanese Pharmacopoeia 2nd liquid [pH 6.8]), and the dissolution should be 120 minutes after the start of the 37 ° C dissolution test. The rate should be more than 60%, especially the dissolution rate is more than 70%. The special dissolution rate is 80%. If CMC-Ca is used for the disintegrating agent, and wood furfuryl alcohol is used for the sugar alcohol, the dissolution rate after 60 minutes should be more than 80%, especially more than 85%, and especially more than 90%. The dissolution rate after 120 minutes should be more than 90%. This preparation is basically composed of a drug, a sugar alcohol, and a disintegrant, and may sometimes form a complex with a drug and a sugar alcohol or a drug and disintegrant. After the granules, lozenges, or capsules of the present invention are formed, they can also be coated with a feminine base or an enteric base to form a release base or an enteric base. Examples of the releasable base can be ethyl cellulose, amine alkyl methacrylate copolymer E 'amine alkyl methacrylate copolymer rs, stearic acid, hardened soybean oil, hard 200306868 chemical vegetable oil, hardened Oil, stearyl alcohol, cetyl alcohol, hydroxypropyl methylcellulose, stone ball, glycerol monostearate and the like. The enteric film base may be hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose trimellitate, hydroxypropyl Methylcellulose acetate maleate, residue methylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD, amine alkyl methacrylate copolymer S, phthalic acid acetate Cellulose, refined shellac, etc. The coating of the above-mentioned slow release base or enteric base may also be carried out after the underlying particles have been formed as desired. The composition of the underlayer may be, for example, HP MC or talc. The device that covers the radioactive or enteric base can also be industrial users, for example, disk coating device, fluid layer coating device, Vaster type coating device, centrifugal flow layer coating device, stirring and rotating Layer type coating device, etc. The number of times of taking the above-mentioned Xingfang or enteric preparations is not specific, it should be 1 to 3 times a day, especially 1 to 2 times a day, and once a day. The present invention provides a drug that preferably contains at least a poorly water-soluble drug, a disintegrating agent, and a sugar alcohol in the preparation, and optimizes the ratio of the disintegrating agent and the sugar alcohol, for example, a drug 120 minutes after the start of the aforementioned dissolution test at 37 t Preparations with a dissolution rate of more than 60%. It also provides a method for improving the dissolution of poorly water-soluble drugs, which is characterized by a compounding ratio of a disintegrating agent for sugar alcohol of 0.2 to 5 times, preferably 0.25 to 4.5 times, and particularly preferably 0.3 to 4 times. There is also provided a method for producing a preparation for improving the dissolution property of the poorly water-soluble drug containing the dissolution improvement method. (Examples 1 to 3, Comparative Examples 1 to 2) -14- 200306868 The granules having the composition shown in Table 1 were manufactured by following the manufacturing method shown below. (Manufacturing method of the preparation of Example 1) The medicine was prepared by pulverizing and using the above-mentioned Schefka phenopipic hydrochloride described in Japanese Patent Application Laid-Open No. 6 2-89. Low substitution degree hydroxypropyl cellulose (hereinafter referred to as L-Η PC), xylitol for sugar alcohol, hardened castor oil for granulation aid, and hydroxypropyl cellulose (hereinafter referred to as HPC- L). After mixing Schiffka's flat picpici hydrochloride, L-HPC, xylitol and hardened castor oil in a mortar, 3 (w / ν)% ρ H c -L aqueous solution was added to knead. The kneaded mixture was granulated by an extrusion granulator [sieve opening Φ〇 · 6ΐΏ1 机械, mechanical name Dome Grund (Fuji Milling Co., Ltd.)], dried at 50 ° C for 30 minutes, and then passed through a 14 sieve The granules are sieved and sieved with a sieve of 20 to 42 sieve to make granules. (Table 1) (Unit mg) Compounding ingredients Example 1 Example 2 Example 3 Comparative example 1 Comparative example 2 Schefkabenpipici hydrochloride 390 390 390 390 390 L-HPC (disintegrating agent) 100 200 300 400 -Xylitol (sugar alcohol) 300 200 100 Pan 400 Hardened castor oil 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 Total 823.0 823.0 823.0 815.6 812.6 Weight ratio of disintegrator / sugar alcohol 0.33 1.0 3.0--• L-HPC: Low Substituted Hydroxypropyl Cellulose • HPC-L: Hydroxypropyl Cellulose 200306868 (dissolution test) For the above-mentioned preparations, a dissolution test was performed in accordance with the method prescribed in the 14th revision of the Japanese Pharmacopoeia. The conditions of the dissolution test are detailed below. The amount of the preparation to be added to the test solution was about 270 mg (100 mg of Shefkapine Pipidzic hydrochloride). [Dissolution test conditions]
試驗法：日本藥典第2法（槳法）攪拌速度50rpm 試驗液：第2液（pH約6.8 ) 900mL，水溫37±0.5°C 試驗液採集時間：5、1 5、3 0、4 5、6 0、9 0、1 2 0 (分） 試驗採集量：2mL 溶出試驗法：將對應本品之表示量之顆粒精密地量取， 以此爲試料，在試驗液用保持3 7 °C之藥典崩壞試驗液第2 液90 OmL，依溶出試驗第2法以每分50回轉施行試驗。溶 出試驗開始後，經時地用裝有匣式棉栓之孔吸管吸引採集 溶出液2mL，在此液加試驗液8mL當作試料溶液。溶出液 採集後，將同時試驗液補充在試驗燒杯內。另將鹽酸雪夫 卡扁匹卜奇西標準品約0 · 〇 1 5 g精密地量取，溶在少量甲醇 ，加試驗液至正確1 〇 〇 Hi L。將此液1 0 ill L正確地量取，力口 試驗液至正確50mL，作成標準溶液。以波長24 5 nm與3 8 0 nm 之吸光度差爲吸光度，就試料溶液及標準溶液求出吸光度 At 及 As。 (式1 ) 對鹽酸雪夫卡扁匹卜奇西之表示量之溶出率（％，第i次之 取樣） -16 - 200306868 v 100 / 丄（ k ) 100處方表示量（mg力價） ( mg)Xl〇°Test method: Japanese Pharmacopoeia method 2 (paddle method) stirring speed 50rpm Test solution: second solution (pH about 6.8) 900mL, water temperature 37 ± 0.5 ° C Test solution collection time: 5, 1 5, 3 0, 4 5 , 6 0, 9 0, 1 2 0 (minutes) Test collection volume: 2mL Dissolution test method: Precisely measure the particles corresponding to the indicated amount of this product, use this as a sample, and keep it at 37 ° C in the test solution. 90 OmL of the second liquid of the Pharmacopoeia Collapse Test Solution was performed at 50 revolutions per minute according to the second method of the dissolution test. After the start of the dissolution test, 2 mL of the eluent was collected by suction with a pipette equipped with a cassette cotton plug over time, and 8 mL of the test solution was added as a sample solution. After the eluate was collected, the test solution was replenished in the test beaker. In addition, approximately 0 · 〇15 g of Schiff Carbapiphexyl Hydrochloride standard was accurately measured, dissolved in a small amount of methanol, and the test solution was added to the correct 100 Hi L. Measure this solution 10 ill L correctly, and force the test solution to the correct 50mL to prepare a standard solution. Taking the difference in absorbance between the wavelengths of 24 5 nm and 380 nm as the absorbance, the absorbances At and As were obtained for the sample solution and the standard solution. (Formula 1) Dissolution rate (%, i-th sampling) of the expressed amount of Schiffka Flat Pipcicil Hydrochloride -16-200306868 v 100 / 丄 (k) 100 prescription expressed amount (mg power value) (mg Xl0 °
Ws :鹽酸雪夫卡扁匹卜奇西標準品之量（mg) C :鹽酸雪夫卡扁匹卜奇西標準品之水分（％) R :鹽酸雪夫卡扁匹卜奇西標準品之無水物力價（mg力價 /mg)Ws: Amount of Schiffka Flat Pipzixi Hydrochloride Standard (mg) C: Moisture of Schiffka Flat Pipzixi Hydrochloride Standard (%) R: Anhydrous price of Schiffka Flat Pipzixi Hydrochloride Standard (Mg force value / mg)
As :鹽酸雪夫卡扁匹卜奇西標準品之吸光度 ATi，ATi_i :第i次及第i-Ι次取樣之試料之吸光度 1 /1 0 0 :稀釋倍數 溶出試驗開始60分後、1 20分後之溶出率與崩壞劑、糖 醇之配合量及配比之關係如第1圖。結果’對實施例2之 糖醇之崩壞劑之配比爲1 ·0倍時’溶出性最增大’溶出試 驗開始60分後之溶出率爲80%以上。 (實施例4〜6，比較例3〜4) 與前實施例同樣之方法’製造崩壞劑爲殘甲醚纖維素鈉 &糖醇爲木糖醇之含量相異之含有鹽酸雪夫卡扁匹卜奇西 之顆粒劑。其組成如表2。 -17- 200306868 (表2) (單位m g ) 配合成分 實施例 實施例 實施例 比較例 比較例 4 5 6 3 4 鹽酸雪夫卡扁匹卜奇西 390 390 390 390 390 殘甲醚纖維素鈉I (崩壞劑） 100 ^ 200 300 400 木糖醇（糖醇） 300 200 100 • 400 硬化蓖麻油 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 合計 823.0 823.0 823.0 815.6 812.6 崩壞劑/糖醇之重量比 0.33 1.0 3.0 - - • HPC-L :羥丙基纖維素 溶出試驗開始6 0分後、1 2 0分後之溶出率與崩壞劑、糖 醇之配比之關係如第2圖。結果，對實施例6之糖醇之崩 壞劑之配比爲3 · 0倍時，溶出性最增大，溶出試驗開始60 分後之溶出率爲8 0 %以上。 (實施例7〜9，比較例5〜6) 與前實施例同樣之方法’製造崩壞劑爲低取代度羥丙基 纖維素及糖醇爲D-甘露糖醇之含量相異之含有鹽酸雪夫卡 扁匹卜奇西之顆粒劑。其組成如袠3。 -18- 200306868 (表3 ) (單位m g ) 配合成分 實施例 實施例 實施例 比較例 比較例 7 8 9 5 6 鹽酸雪夫卡扁匹卜奇西 390 390 390 390 390 L-HPC(崩壞劑） 100 200 300 400 D-甘露糖醇（糖醇） 300 200 100 _ 400 硬化蓖麻油 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 合計 823.0 823.0 823.0 815.6 812.6 崩壞劑/糖醇之重量比 0.33 1.0 3.0 - - • L-HPC :低取代度羥丙基纖維素 HPC-L :羥丙基纖維素 溶出試驗開始60分後、1 20分後之溶出率與崩壞劑、糖 醇之配比之關係如第3圖。結果，對實施例7之糖醇之崩 壞劑之配比爲〇 . 3 3倍時，溶出性最增大，溶出試驗開始1 2 〇 φ 分後之溶出率爲60%以上。 (實施例1〇〜12，比較例7〜8) 與前實施例同樣之方法，製造崩壞劑爲低取代度羥丙基 纖維素及糖醇爲麥芽糖醇之含量相異之含有鹽酸雪夫卡扁 匹卜奇西之顆粒劑。其組成如表4。 -19、 200306868 (表4) (單位m g ) 配合成分 實施例 實施例 實施例 比較例 比較例 10 11 12 7 8 鹽酸雪夫卡扁匹卜奇西 390 390 390 390 390 L-HPC(崩壞劑） 100 200 300 400 - 麥芽糖醇（糖醇） 300 200 100 - 400 硬化蓖麻油 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 合計 823.0 823.0 823.0 815.6 812.6 崩壞劑/糖醇之重量比 0.33 1.0 3.0 - - • L-HPC :低取代度羥丙基纖維素 HPC-L ：羥丙基纖維素 溶出試驗開始6 0分後、1 2 0分後之溶出率與崩壞劑、糖 醇之配比之關係如第4圖。結果，對實施例1 1之糖醇之崩 壞劑之配比爲1 . 〇倍時，溶出性最增大’溶出試驗開始6 0 分後之溶出率爲80%以上。 (實施例1 3〜1 5 ’比較例9〜1 0) 與前實施例同樣之方法，製造崩壞劑爲低取代度羥丙基 纖維素及糖醇爲赤蘚糖醇之含量相異之含有鹽酸雪夫卡扁 匹卜奇西之顆粒劑。其組成如表5。 -20. 200306868 (表5) (單位m g) 配合成分 實施例 13 實施例 14 實施例 15 比較例 9 比較例 10 鹽酸雪夫卡扁匹卜奇西 390 390 390 390 390 L-HPC(崩壞劑）’ 100 200 300 400 - 赤蘚糖醇（糖醇） 300 200 100 * 400 硬化蓖麻油 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 合計 823.0 823.0 823.0 815.6 812.6 崩壞劑/糖醇之重量比 0.33 1.0 3.0 - - • L-HPC :低取代度羥丙基纖維素 HPC-L :羥丙基纖維素 溶出試驗開始6 0分後、1 2 0分後之溶出率與崩壞劑、糖 醇之配比之關係如第5圖。結果，對實施例1 3之糖醇之崩 壞劑之配比爲〇 · 3 3倍時，溶出性最增大，溶出試驗開始1 2 0 分後之溶出率爲7〇%以上。 (實施例1 6〜1 8 ’比較例1 1〜1 2) 與前實施例同樣之方法，製造崩壞劑爲低取代度羥丙基 纖維素及糖醇爲繭蜜糖醇之含量相異之含有鹽酸雪夫卡扁 匹卜奇西之顆粒劑。其組成如表6。 200306868 (表6) 配合成分 實施例 16 實施例 17 實施例 18 (单 比較例 11 1 mgj 比較例 12 鹽酸雪夫卡扁匹卜奇西 390 390 390 390 390 L-HPC(崩壞劑） 100 200 300 400 繭蜜糖醇（糖醇） 300 2〇〇 100 400 硬化蓖麻油 20 一 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 合計 823.0 823.0 823.0 815.6 812.6 崩壞劑/糖醇之重量比 0.33 3.0 一 • • L-HPC :低取代度羥丙基纖維素 HPC-L :羥丙基纖維素 溶出試驗開始6 G分後、1 2 〇分後之溶出率與崩壞劑、糖 醇之配比之關係如第6圖。結果，對實施例1 3之糖醇之崩 壞劑之配比爲〇 · 3 3倍時，溶出性最增大，溶出試驗開始1 2 〇 分後之溶出率爲80%以上。 實施例1 9 製造由以下成分而成之徐放性顆粒劑。先仿實施例1之 方法調製素顆粒後，形成下舖層，次被覆腸溶層。 -22- 200306868 (表7) 素顆粒 鹽酸雪夫卡扁匹卜 奇西 3 90 木糖醇 1 00 CMC Ca 3 00 HPC 23.2 下舖層 HPMC 4 1.5 滑石粉 2 0 7.4 腸溶層 甲基丙烯酸共聚物 LD 90.6 檸檬酸三乙酯 10.3 滑石粉 70.1 溶出試驗（pH6.8)開始60分後、120分後之溶出率與崩壞 — 劑（CMC Ca)、糖醇（木糖醇）之配比之關係如第7圖。結果 ，對糖醇之崩壞劑之配比爲0.33倍以上而呈80 %以上之溶 出率，1〜3倍而呈約90%以上之溶出率。本製劑在pH 1 .2 之酸性條件下，試驗關始後經過2小時，仍幾無藥物之溶 出。 · 產業上之利用可能性 本發明提供改善難水溶性藥物之溶出性之製劑。含有本 製劑之徐放性製劑其藥效持續而藥物之服用回收減少，患 者之順從性提高。配合在本發明製劑中之藥物之經時安定 性高，也可長期保存。 [圖式簡單說明] 第1圖：乃示崩壞劑（低取代度羥丙基纖維素）及糖醇（木 糖醇）之重量比與鹽酸雪夫卡扁匹卜奇西之溶出試驗開始 -23- 200306868 6 0及1 2 0分後之溶出率之關係。縱軸爲鹽酸雪夫卡扁匹卜 奇西之溶出率（％)，橫軸爲崩壞劑、糖醇之配合量（mg)及其 重量比。 第2圖：乃示崩壞劑（殘甲醚纖維素鈉）及糖醇（木糖醇） 之重量比與鹽酸雪夫卡扁匹卜奇西之溶出試驗開始6 〇及 1 20分後之溶出率之關係。縱軸爲鹽酸雪夫卡扁匹卜奇西 之丨谷出率（％)’橫軸爲崩壞劑、糖醇之配合量（m g)及其重量 第3圖：乃示崩壞劑（低取代度羥丙基纖維素）及糖醇（D_ 甘露糖醇）之重量比與鹽酸雪夫卡扁匹卜奇西之溶出試驗 開始6 0及1 2 0分後之溶出率之關係。縱軸爲鹽酸雪夫卡扁 匹卜奇西之溶出率（％ )，橫軸爲崩壞劑、糖醇之配合量（m g) 及其重量比。 第4圖：乃示崩壞劑（低取代度羥丙基纖維素）及糖醇（麥 芽糖醇）之重量比與鹽酸雪夫卡扁匹卜奇西之溶出試驗開 始6 0及1 2 0分後之溶出率之關係。縱軸爲鹽酸雪夫卡扁匹 卜奇西之溶出率（％) ’橫軸爲崩壞劑、糖醇之配合量（m g) 及其重量比。 第5圖：乃示崩壞劑（低取代度羥丙基纖維素）及糖醇（赤 蘚糖醇）之重量比與鹽酸雪夫卡扁匹卜奇西之溶出試驗開 始60及1 20分後之溶出率之關係。縱軸爲鹽酸雪夫卡扁匹 卜奇西之溶出率（％)，橫軸爲崩壞劑、糖醇之配合量（mg) 及其重量比。 第6圖：乃示崩壞劑（低取代度羥丙基纖維素）及糖醇（繭 -24- 200306868 蜜糖醇）之重量比與鹽酸雪夫卡扁匹卜奇西之溶出試驗開 始6 0及1 2 0分後之溶出率之關係。縱軸爲鹽酸雪夫卡扁匹 卜奇西之溶出率（％)，橫軸爲崩壞劑、糖醇之配合量（m g) 及其重量比。 第7圖：乃示崩壞劑（羧基甲基纖維素鈣）及糖醇（木糖醇） 之重量比與鹽酸雪夫卡扁匹卜奇西之溶出試驗開始60及 1 2 0分後之溶出率之關係。縱軸爲鹽酸雪夫卡扁匹卜奇西 之溶出率（％)，橫軸爲崩壞劑、糖醇之配合量（mg)及其重量 比。As: Absorbance ATi, ATi_i of Schiffka Flat Pipsixi Hydrochloride Standard: Absorbance of samples taken at the i-th and i-l samples 1/1 0 0: 60 minutes after the start of the dilution factor dissolution test, 120 minutes The relationship between the subsequent dissolution rate and the amount and ratio of disintegrating agent and sugar alcohol is shown in Figure 1. As a result, when the compounding ratio of the disintegrating agent for sugar alcohol of Example 2 was 1.0 times, the dissolution rate was the highest, and the dissolution rate was 80% or more 60 minutes after the start of the dissolution test. (Examples 4 to 6, Comparative Examples 3 to 4) The same method as in the previous example, 'Manufacture of disintegrating agent is residual methyl ether cellulose sodium & sugar alcohol is xylitol, and the content of xefanol is different. Granules of Pipchisi. Its composition is shown in Table 2. -17- 200306868 (Table 2) (Unit mg) Compounding ingredients Example Example Example Comparative example Comparative example 4 5 6 3 4 Schefkabenpipici hydrochloride 390 390 390 390 390 Residual methyl ether cellulose sodium I ( Disintegrator) 100 ^ 200 300 400 Xylitol (sugar alcohol) 300 200 100 • 400 Hardened castor oil 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 Total 823.0 823.0 823.0 815.6 812.6 Disintegrator / sugar alcohol Weight ratio 0.33 1.0 3.0--• HPC-L: The relationship between the dissolution rate and the disintegrating agent and sugar alcohol ratio after 60 minutes and 120 minutes after the start of the hydroxypropyl cellulose dissolution test is shown in Figure 2. As a result, when the compounding ratio of the disintegrating agent for the sugar alcohol of Example 6 was 3.0 times, the dissolution was most increased, and the dissolution rate after 80 minutes from the start of the dissolution test was 80% or more. (Examples 7 to 9 and Comparative Examples 5 to 6) The same method as in the previous example was used to produce hydrochloric acid containing different amounts of disintegrating agent hydroxypropyl cellulose and sugar alcohol D-mannitol. Granules of Shefka flat pipsi. Its composition is as 袠 3. -18- 200306868 (Table 3) (Unit mg) Compounding Examples Examples Examples Examples Comparative Examples Comparative Example 7 8 9 5 6 Schiffka Flat Pippixi HCI 390 390 390 390 390 390 L-HPC (Disintegrating Agent) 100 200 300 400 D-mannitol (sugar alcohol) 300 200 100 _ 400 Hardened castor oil 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 Total 823.0 823.0 823.0 815.6 812.6 Breakdown agent / sugar alcohol weight ratio 0.33 1.0 3.0--• L-HPC: low substitution degree hydroxypropyl cellulose HPC-L: hydroxypropyl cellulose dissolution rate 60 minutes after dissolution test, 120 minutes after dissolution ratio with disintegrating agent, sugar alcohol The relationship is shown in Figure 3. As a result, when the compounding ratio of the disintegrating agent for the sugar alcohol of Example 7 was 0.33 times, the dissolution was most increased, and the dissolution rate after the start of the dissolution test was 120% φ or more. (Examples 10 to 12, Comparative Examples 7 to 8) The same method as in the previous example was used to produce Schaffka hydrochloride containing disintegrating agents with low substitution degree of hydroxypropyl cellulose and sugar alcohols with maltitol content. Granules of flat pipsi. Its composition is shown in Table 4. -19, 200306868 (Table 4) (Unit mg) Compounding ingredients Example Example Example Comparative example Comparative example 10 11 12 7 8 Shefkapine pippixixi hydrochloride 390 390 390 390 390 390 L-HPC (disintegrating agent) 100 200 300 400-Maltitol (sugar alcohol) 300 200 100-400 Hardened castor oil 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 Total 823.0 823.0 823.0 815.6 812.6 Weight ratio of disintegrator / sugar alcohol 0.33 1.0 3.0 --• L-HPC: Low substitution degree hydroxypropyl cellulose HPC-L: The ratio of dissolution rate to disintegrating agent, sugar alcohol after 60 minutes and 120 minutes after the start of hydroxypropyl cellulose dissolution test The relationship is shown in Figure 4. As a result, when the compounding ratio of the disintegrating agent for sugar alcohol of Example 11 was 1.0-fold, the dissolution rate was the greatest, and the dissolution rate was 80% or more 60 minutes after the start of the dissolution test. (Example 1 3 to 15 'Comparative Examples 9 to 10) In the same manner as in the previous example, the content of the disintegrating agent was low substitution degree hydroxypropyl cellulose and the sugar alcohol was erythritol. Contains granules of Schiffka Flat Pipsixi Hydrochloride. Its composition is shown in Table 5. -20. 200306868 (Table 5) (Unit mg) Compounding ingredients Example 13 Example 14 Example 15 Comparative example 9 Comparative example 10 Schiffka pipipici hydrochloride 390 390 390 390 390 390 L-HPC (disintegrating agent) '100 200 300 400-Erythritol (sugar alcohol) 300 200 100 * 400 Hardened castor oil 20 20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 Total 823.0 823.0 823.0 815.6 812.6 Weight ratio of disintegrator / sugar alcohol 0.33 1.0 3.0--• L-HPC: low substitution degree hydroxypropyl cellulose HPC-L: hydroxypropyl cellulose dissolution test 60 minutes after dissolution, 120 minutes after dissolution rate and disintegrating agent, sugar alcohol The relationship between the ratios is shown in Figure 5. As a result, when the compounding ratio of the disintegrating agent for sugar alcohol of Example 13 was 0.33 times, the dissolution was the most increased, and the dissolution rate was 120% or more after 120 minutes from the start of the dissolution test. (Example 1 6 ~ 18 'Comparative Example 1 1 ~ 12 2) The same method as in the previous example, the content of the disintegrating agent used was low-substitution degree hydroxypropyl cellulose and the sugar alcohol was cocoon melitol. Contains granules of Schiffka Flat Pipsixi Hydrochloride. Its composition is shown in Table 6. 200306868 (Table 6) Compounding Example Example 16 Example 17 Example 18 (Single Comparative Example 11 1 mgj Comparative Example 12 Schefkabenpipici Hydrochloride 390 390 390 390 390 L-HPC (Disintegrator) 100 200 300 400 cocoon melitol (sugar alcohol) 300 20000 400 400 hardened castor oil 20-20 20 20 20 HPC-L 13.0 13.0 13.0 5.6 2.6 total 823.0 823.0 823.0 815.6 812.6 weight ratio of disintegrator / sugar alcohol 0.33 3.0 1 • • L-HPC: low substitution degree hydroxypropyl cellulose HPC-L: hydroxypropyl cellulose dissolution test after the start of 6 G minutes, 120 minutes after dissolution rate and disintegrating agent, sugar alcohol ratio The relationship is as shown in Fig. 6. As a result, when the compounding ratio of the sugar alcohol disintegrator of Example 13 was 0.33 times, the dissolution was most increased, and the dissolution rate was 80 minutes after the start of the dissolution test at 120 minutes. % Or more. Example 1 9 Manufactures the slow release granules made of the following ingredients. After preparing the element granules in the same manner as in Example 1, the lower layer is formed and then the enteric layer is covered. -22- 200306868 (Table 7 ) Vegetarian granules Schefka phenpypicc 3 3 xylitol 1 00 CMC Ca 3 00 HPC 23.2 HPMC 4 1.5 Talc powder 2 0 7.4 Enteric layer methacrylic acid copolymer LD 90.6 Triethyl citrate 10.3 Talc powder 70.1 Dissolution rate and disintegration after 60 minutes and 120 minutes after the dissolution test (pH 6.8) started— The relationship between the ratio of the agent (CMC Ca) and sugar alcohol (xylitol) is shown in Fig. 7. As a result, the ratio of the sugar alcohol disintegrating agent was 0.33 times or more and the dissolution rate was 80% or more, 1 ~ 3 times and a dissolution rate of about 90% or more. Under the acidic condition of pH 1.2, the preparation has almost no drug dissolution after 2 hours after the test is closed. · Industrial application possibility The present invention provides improvement Dissolvable preparations of poorly water-soluble drugs. Sustained-release preparations containing this preparation have sustained efficacy and reduced drug recovery, and patient compliance is improved. The stability of the drugs formulated in the preparation of the present invention is high over time, It can also be stored for a long time. [Schematic description] Figure 1: It shows the weight ratio of disintegrating agent (low substitution degree hydroxypropyl cellulose) and sugar alcohol (xylitol) to Schiffka flat pipsic hydrochloride Dissolution test started -23- 200306868 Dissolution after 6 0 and 120 minutes The vertical axis is the dissolution rate (%) of Schiffka flat pipsic acid hydrochloride, and the horizontal axis is the blending amount (mg) of disintegrating agent, sugar alcohol and its weight ratio. Figure 2: It shows the dissolution of the disintegrating agent (residual methyl ether cellulose sodium) and sugar alcohol (xylitol) and the dissolution test of Shefkapin pipicizil hydrochloride at 60 and 120 minutes. The relationship between rates. The vertical axis is the trough rate (%) of Schiffka Flat Pipzic hydrochloride. The horizontal axis is the amount of disintegrating agent, sugar alcohol (mg) and its weight. Figure 3: It shows the disintegrating agent (low substitution) The relationship between the weight ratio of hydroxypropylcellulose) and sugar alcohol (D_mannitol) and the dissolution rate after 60 and 120 minutes from the start of the dissolution test of Schiffka bianbipicic hydrochloride. The vertical axis is the dissolution rate (%) of Chefkapine hydrochloride and pidchizil hydrochloride, and the horizontal axis is the blending amount (m g) of disintegrating agent, sugar alcohol and its weight ratio. Fig. 4: It shows the weight ratio of disintegrating agent (low substitution degree hydroxypropyl cellulose) and sugar alcohol (maltitol) and the dissolution test of Schiffka flat pipcixi hydrochloride after 60 minutes and 120 minutes The relationship between the dissolution rate. The vertical axis is the dissolution rate (%) of Schiffka flat pidcoxib hydrochloride. The horizontal axis is the blending amount (m g) of disintegrating agent, sugar alcohol and its weight ratio. Figure 5: It shows the weight ratio of the disintegrating agent (low substitution degree hydroxypropyl cellulose) and sugar alcohol (erythritol) and the dissolution test of Schiffka flat pipcixi hydrochloride after 60 and 120 minutes. The relationship between the dissolution rate. The vertical axis is the dissolution rate (%) of Schiffka flat pidcoxib hydrochloride, and the horizontal axis is the blending amount (mg) of disintegrating agent, sugar alcohol and its weight ratio. Figure 6: The weight ratio of disintegrating agent (low-substituted hydroxypropyl cellulose) and sugar alcohol (cocoon-24-200306868 melitol) and the dissolution test of Schiffka flat pipcixi hydrochloride begin. 0 And the dissolution rate after 120 minutes. The vertical axis is the dissolution rate (%) of Schiffka flat pidcoxib hydrochloride, and the horizontal axis is the blending amount (m g) of disintegrating agent, sugar alcohol and its weight ratio. Figure 7: It shows the dissolution rate of the disintegrating agent (carboxymethylcellulose calcium) and sugar alcohol (xylitol) and the dissolution test of Schiffka flat pipiczil hydrochloride after 60 and 120 minutes. The relationship between rates. The vertical axis is the dissolution rate (%) of Schiffka Flat Pipzicil hydrochloride, and the horizontal axis is the blending amount (mg) of disintegrating agent, sugar alcohol and its weight ratio.
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