1306763 (1) 玖、發明說明 【發明所屬之技術領域】 本發明係有關催眠用壓縮成形製劑，更詳細者係有關 含有苯海拉明或其酸附加鹽做爲催眠、鎭靜作用之藥效成 份、無變色、且安定、掩蓋服用時之苦味、可確實快速顯 現藥效之催眠用壓縮成形製劑。 【先前技術】 苯海拉明或其酸附加鹽係具有抗組織胺作用與中樞作 用，先行技術係做爲鼻炎、皮膚病、感冒藥、鎭咳袪痰藥. 之有效成份被利用之，惟，易產生昏睡之副作用缺點。 如：鹽酸苯海拉明、檸檬酸苯海拉明其具有與緩和之 催眠劑幾乎同時之催眠作用爲公知者。且，較快速由血液 消失，亦無習慣性，因此在歐美，以日本之一般用醫藥品 無須處方籤之催眠藥以成人一次量5 Omg的投用量被利用 之。 而，藉由鹽酸苯海拉明之鎭靜作用後，其產生睡意之 血漿中濃度爲50ng/ml以上’此高於抗組織胺作用之血漿 中濃度。又，口服50mg鹽酸苯海拉明時其血漿中濃度之 時間推移平均値於服用後2〜4小時稍提高爲50ng/mlg ( Carruthers等：Clin, Pharmacol. Ther.; 23 ( 4) ; 375〜382, I 9 7 8 )。因此，做爲口服之催眠劑使用時，依服用條件之 不同，其製劑崩解，溶出延緩後’將無法充份取得催眠效 果。 -5- (2) 1306763 又，苯海拉明或其酸附加鹽之味道爲強烈剌激苦感， 服用時有不快感之性質。惟，先行藉由含油脂，不溶性高 分子之被膜，基質而延緩溶出性以掩蓋味道之方法中，發 揮做爲抗組織胺藥之效果時雖未造成障礙，而做爲催眠藥 則恐無法充份顯現效果。又，配合甜味劑、矯味劑以掩蓋 味道之方法中，其遮掩不全下使苦味殘留於舌頭之缺點存 在。 又，苯海拉明或含其酸附加鹽之製劑係藉由所配合賦 形劑等製劑添加物後出現變色、濕氣重之條件下呈濕潤或 固定相互製劑。且，藉由苯海拉明或其酸附加鹽自體之光 出現變色，因此，即使未降低含量，此時，商品價値晝失 之缺點存在。 【發明內容】 因此，被期待提供一種以含有苯海拉明或其酸附加鹽 做爲睡眠、鎭靜作用之藥效成份，且，無變色、安定下可 掩蓋服用時之苦味，明確快速出現效果之製劑。 本發明者爲解決該課題，進行精密硏討後結果發現與 不同膨潤性之複數高分子組合苯海拉明或其酸附加鹽後， 藉由壓縮成形後不影響其溶解性，可抑制苯海拉明之變色 '苦味者 '取得明確出現良好催眠等效果之催眠用壓縮成 形製劑，進而完成本發明。 亦即》本發明係提供一種以含有苯海拉明或其酸附加 鹽、低膨潤性高分子及高膨潤性高分子做爲具陲眠、鎭靜 -6- (3) 1306763 作用之藥效成份者爲其特徵之催眠用壓縮成形製劑。 本發明又提供一種使用苯海拉明或其酸附加鹽爲製造 改善睡眠之催眠用壓縮成形製劑。 【實施方式】 〔發明實施之形態〕 本發明催眠用壓縮成形製劑（以下稱「本發明製劑」 )係組合苯海拉明或其酸附加鹽，與低膨潤性高分子及高 膨潤性高分子後，製成壓縮成形用粉粒體，經由壓縮成形 步驟所調製者。 本發明製劑中，做爲具有睡眠、鎭靜作用藥效成份所 使用之苯海拉明可直接以鹽基形態，亦可爲酸附加鹽者。 惟，鹽基形態爲液狀者，如：務必於輕質無水矽酸等粉體 中保持鹽基做成粉粒體後使用之，因此，實際製造本發明 製劑時，以酸附加鹽使用爲宜。做爲此苯海拉明之酸附加 鹽例者如：鹽酸苯海拉明 '水楊酸苯海拉明、檸檬酸苯海 拉明、單寧酸苯海拉明、月桂基硫酸苯海拉明、硫酸苯海 拉明例者。又，做爲理想酸附加鹽例者如：鹽酸苯海拉明 、及檸檬酸苯海拉明例者，特別理想之酸附加鹽例爲鹽酸 苯海拉明例者。 此等苯海拉明或其酸附加鹽之原粉末平均粒徑並未特 別限定，一般以30 μιη以上、500 μηι以下者宜，特別以 5 0〜3 0 0 μιη爲更佳者。平均粒徑之調整於必要時，可使原 粉末藉由粉碎或過篩等常法進行之，其方法並未限定。如 -Ί- (4) 1306763 :粉碎可利用錘磨機、快速硏磨機、滾輥硏磨機、針磨機 、球磨機、振盪球磨機、振盪硏磨機、注射硏磨機等粉碎 器進行之’過篩可利用過篩連續式振動網篩機、氣流式網 篩機進行之。 本發明中含苯海拉明或其酸附加鹽（以下稱「苯海拉 明等」）之比例依其劑型、服用量等而不同，通常約爲 5〜30質量％者宜。又’ ！個本發明製劑所含苯海拉明等配 合量並未限定，一般’苯海拉明等1次投用量爲5 Omg，因 此1個爲12.5〜50mg之範圍下以50mg之整數份做爲1即可。 另外’本發明製劑所使用之低.膨潤性高分子爲不溶於 水’且，膨潤性小者’與苯海拉明等配合後，壓縮成形後 務必爲不變色之低反應性者。做爲此低膨潤性高分子之具 體例者如：結晶纖維素、乙基纖維素、胺基烷基甲基丙烯 酸酯共聚物RS等例，此等可單獨1種、或混合2種以上使 用之。其中最理想之具體例爲結晶纖維素者。此等低膨潤 性高分子以1質量份苯海拉明等之1質量份以上進行使用者 宜，而更佳者爲2質量份以上之使用。此低膨潤性高分子 針對本發明製劑之總質量其添加量依所含苯海拉明等之量 ，製劑總質量不同而異，一般約爲3〜90質量％者宜，更佳 者爲5〜80質量％。 本發明製劑所使用之高膨潤性高分子爲不溶於水，且 ，膨潤性大者，而與苯海拉明等之配合下，壓縮成形後務 必呈不變色之低反應性者。做爲此高膨潤性高分子之具體 例者如：交叉羧甲基纖維素鈉、低取代度羥丙基纖維素、 -8- (5) 1306763 交聯聚維酮（crospovidone )等例，此等可以單獨1種或混 合2種使用之。最理想之具體例者如：交叉羧甲基纖維素鈉 之例者。此高膨潤性高分子針對本發明製劑總質量之添加 量依其苯海拉明等含量，製劑總質量不同而異，一般約爲 〇 . 1〜5質量％者宜，更佳者爲〇 . 5〜3質量％。 本發明中務必使用此等低膨潤性高分子與高膨潤性高 分子之組合者，而，此時該配合比係使高膨潤性高分子爲 低膨潤性高分子之〇.〇 1質量倍以上者宜，較佳者爲0.2質 量倍以上。 本發明製劑於必要時可於該苯海拉明時，低膨潤性高 分子及高膨潤性高分子中添加公知之醫藥用添加劑，如： 賦形劑、結合劑、崩散劑 '潤滑劑' 安定劑、界面活性劑 、溶解補助劑、還原劑、緩衝劑、吸附劑、流動化劑、防 止靜電劑 '塗層劑、可塑劑、防止附著劑、遮光劑、光澤 化劑 '抗氧化劑、甘味劑、矯味劑、清涼化劑、著色劑、 著香劑、香料、芳香劑等添加後，進行調製壓縮成形用之 粉粒體，依常法藉由壓縮成形進行製造之。 做爲本發明所使用之醫藥用添加劑者以配合至少1種 或2種以上選自配合苯海拉明等進行壓縮成形後未變色之 水溶性高分子、輕質無水矽酸、糖類、糖醇、澱粉、滑石 溶 水 之 色 變 未 後 形 成 縮 壓 等 明 拉 海 苯 合 。 配 宜爲 者做 鎂， 酸中 脂其 0C 硬 如又 者 。 子例 分等 高醇 性二 乙馬 聚 、 ' 粉 素澱 維米 纖玉 基、 丙粉 羥澱 > 化 素:α 如 者 例 粉 澱 爲 做 維 纖 基 甲 基 丙 羥 -9- (6) 1306763 鈴薯澱粉、小麥澱粉、米澱粉等’而做爲糖類 '糖醇者如 :乳糖、甘露糖醇、木糖醇、糊精、山梨糖醇等例。此等 水溶性高分子、澱粉、糖類、糖醇之添加量依其壓縮成形 製劑之大小、壓縮成形用粉體之製造方法而異’並未特別 限定其量’一般約爲總質量之0〜80質量％者。 又，該醫藥用添加劑中之輕質無水矽酸可增加壓縮成 形用粉粒體之流動性同時亦具有防止壓縮成形製劑之濕潤 、結合作用者。此輕質無水矽酸之平均粒徑愈小愈佳，以 使用平均粒徑爲4〜5nm之輕質無水矽酸者宜。其添加量爲 壓縮成形製劑總質量之質量％者宜。 針對壓縮成形製劑總質量更期待添加〇·1〜5質量％之滑 石及硬脂酸鎂兩者或任意一方者。 壓縮成形用粉粒體可直接混合該成份粉末，或使用其 部份或全部做爲造粒粉末之使用。以此粉粒體做成造粒粉 末時，可利用一般所利用之造粒法，如：含水、有機溶媒 之溶液、或利用分散液之噴霧造粒法、攪拌造粒法、流動 造粒法、轉動造粒法、轉動流動造粒法等濕式造粒法、使 用粉粒狀之結合劑的密壓造粒法等乾式造粒法。 該混合^末或造粒粉末係經由壓縮成形步驟做成本發 明製劑者。做爲具體之壓縮成形步驟者如.·利用旋轉式打 錠機、單發式打錠機等打錠機之方法，或利用油壓加壓機 之方法例者，又以打錠機之使用爲宜，特別是使用旋轉式 打錠機所生產之效率較佳最爲理想。又，壓縮成形之壓力 依其壓縮成形製劑大小、形狀及醫藥用添加劑之種類、量 -10- (7) 1306763 不同而異，如：直徑爲9mm之壓縮成形製劑時以300kg/cm2 以上爲宜，更以500〜1 500kg/cm2爲較佳者。 該取得本發明製劑之劑型爲錠劑，其形狀爲圓形錠、 異形錠等，未特別限定。另外，此錠劑亦可予與切線。 又，本發明製劑亦可藉由平面塗層法、流動層塗層法 、轉動塗層法、乾式塗層法、此等方法之組合等做成更快 速溶解性之塗層製劑、糖衣製劑者。此時，水溶性或胃溶 性之被膜劑於水、有機溶媒中溶解或分散，進行噴霧塗層 者，或將此等被膜劑直接散佈後，進行加熱、加壓之乾式 塗層者。於被膜劑更可添加可塑劑、防止附著劑、遮光劑 、增量劑等。 以上說明之本發明製劑最佳實施形態係於1個製劑中 含有12.5~5 0mg之鹽酸苯海拉明，做爲低膨潤性高分子之 結晶纖維素爲1份鹽酸苯海拉明之2份以上，做爲高膨潤性' 高分子之交叉羧甲基纖維素鈉爲本發明製劑總質量之 0.1〜5質量％，輕質無水矽酸爲本發明製劑總質量之1〜10 質量％，做爲水溶性高分子之羥丙基纖維素爲本發明製劑 總質量之1〜5質量％，更有乳糖爲本發明製劑總質量之 20〜80質量％，滑石及硬脂酸鎂爲本發明製劑總質量之 0.1 ~5質量％進行配合後取得之壓縮成形用粉體進行使用 之，1個製劑之質量呈100〜750mg以打錠機， 500~1 500kg/cm2之壓力下進行壓縮成形之製劑者。 〔作用〕 -11 - (8) 1306763 該取得本發明製劑係具有苯海拉明等，低膨潤性高分 子及高膨潤性高分子者，因此，爲不變色、安定、且服用 時可掩蓋苦味、確實快速出現催眠等效果之製劑。此製劑 可用於不眠症 '緊張、興奮感、不安感等之鎭靜、伴隨此 等症狀之頭重、疲勞倦怠感之緩和、消除不安等。 [實施例] 以下列舉實施例，進行本發明更具體之說明，惟，本 發明未受限於此等實施例。 [實施例1] 壓縮成形製劑（1 ): 混合l〇〇g之鹽酸苯海拉明（平均粒徑220 μιη) ，100g 之結晶纖維素，72 8g之乳糖，20g之交叉羧甲基纖維素鈉 ，48g輕質無水矽酸後’加入240g之10%羥丙基纖維素 之乙醇溶液進行混煉 '造粒及乾燥後，以20號網篩進行過 篩。於1009.4g該顆粒中混合9.8g硬脂酸鎂及9.8g滑石後， 以旋轉式打錠機’約900kg/cm2之壓力下將取得壓縮成形 用顆粒進行壓縮成形後’取得1錠之直徑爲9mm，厚度 4.2mm，質量爲260mg之壓縮成形製劑。 [實施例2] 壓縮成形製劑（2 ) ·· 變更實施例1之結晶纖維素爲200g ’乳糖爲628g之外 -12- (9) 1306763 ，同法取得1錠之直徑爲9mm，厚度4.2mm，質量爲260mg 之壓縮成形製劑。 [實施例3] 壓縮成形製劑（3 ): 變更實施例1之結晶纖維素爲4 0 0 g，乳糖爲4 2 8 g之外 ，同時取得1錠之直徑爲9mm，厚度4.2mm，質量260mg之 壓縮成形製劑。 .[實施例4] 壓縮成形製劑（4 ) ·· 變更實施例1之結晶纖維素爲600g，乳糖爲228g之外 ，同時取得1錠之直徑爲9mm，厚度4.2mm，質量爲26〇mg 之壓縮成形製劑者。 [實施例5] 壓縮成形製劑（5 ): 變更實施例1之結晶纖維素爲800g，乳糖爲28g，除外 ，同時取得1錠之直徑爲9mm，厚度4.2mm，質量26〇mg之 壓縮成形製劑。 [實施例6] 壓縮成形製劑（6 ): 混合〗25g之鹽酸苯海拉明（平均粒徑220 μη〇 ’ -13- 1306763 do) 結晶纖維素，3 8 5 g乳糖’ 20g交叉羧甲基纖維素鈉，5〇g 輕質無水矽酸後’加入200g之10%羥丙基纖維素之乙醇 溶液進行混煉、造粒、乾燥後，以20號網篩進行過篩。於 960 = 4g之該顆粒中混合9.8g硬脂酸鎂及9.8g滑石後，以旋 轉式打錠機’約900kg/cm2之壓力下進行取得壓縮成形用 顆粒之壓縮成形後，取得1錠之直徑爲5.5mm，厚度4.2mm ，質量爲100mg之壓縮成形製劑。 [實施例7] 壓縮成形製劑（7 ) ·· 混合37.5之鹽酸苯海拉明（平均粒徑220 μηι) ，3 75g 結晶纖維素’ 652.5g乳糖，24g交叉羧甲基纖維素鈉， 6〇g輕質無水矽酸後，加入270g 10%羥丙基纖維素之乙 醇溶液進行混煉、造粒及乾燥後，以20號網篩進行過篩。 於1 152.5g之該顆粒中混合11.8g硬脂酸鎂及1 1.8g滑石後， 以旋轉式打錠機，約900kg/cm2之壓力下進行所取得壓縮 成形用顆粒之壓縮成形之後，取得1錠之直徑爲l〇mm，厚 度4.3mm，質量爲400mg之壓縮成形製劑。 [實施例8] 壓縮成形製劑（8 ): 混合500g之鹽酸苯海拉明（平均粒徑220 μιη ) ，500g 之結晶纖維素，77g乳糖，20g交叉羧甲基纖維素鈉， 55g輕質無水矽酸後，加入240g 10%羥丙基纖維素之乙 -14- (11) 1306763 醇溶液進行混煉、造粒及乾燥後，以20號網篩進行過篩。 於此1 l52.5g顆粒中混合1 1.8g硬脂酸鎂，1 1.8g滑石後，以 旋轉式打錠機，約900kg/cm2之壓力下進行取得壓縮成形 用顆粒之壓縮成形後，取得1錠之直徑爲6mm，厚度4mm ，質量爲120mg之壓縮成形製劑。 [實施例9] 壓縮成形製劑（9 ): 混合150g之鹽酸苯海拉明（平均粒徑220 μη〇 ，465g 之結晶纖維素，45 0g乳糖，24g交叉羧甲基纖維素鈉， 6〇g輕質無水矽酸後，加入270g之10%羥丙基纖維素之 乙醇溶液進行混煉、造粒及乾燥，以20號網篩進行過篩。 於此1152.5g顆粒中混合11.8g硬脂酸鎂，11.8g滑石後，以 旋轉式打錠機，約900kg/cm2之壓力下進行取得壓縮成形 用顆粒之壓縮成形後，取得1錠之直徑爲10mm，厚度 4.3mm’質量爲4〇〇mg之壓縮成形製劑。 [比較例1 ] 比較壓縮成形製劑（1 ): 實施例1之結晶纖維素去除，乳糖變更爲82 8g，之外 ’同法取得1錬之直徑爲9111111，厚度4.2111111，質量爲26〇111§ 之壓縮成形製劑。 [比較例2] -15- (12) 1306763 比較壓縮成形製劑（2 ): 變更實施例】之結晶纖維素爲40g ’乳糖爲788g，之外 ，同法取得1錠之直徑爲9mm，厚度4.2mm，質量爲260mg 之壓縮成形製劑。 [比較例3] 比較壓縮成形製劑（3 ): 變更實施例1之結晶纖維素爲60g ’乳糖爲768g ’之外 ，同法取得1錠之直徑爲9mm，厚度4.2mm ’質量爲260mg 之壓縮成形製劑。 [比較例4 ] 壓縮成形製劑（4 ): 去除實施例1之交叉羧甲基纖維素鈉，變更結晶纖維 素爲200g，乳糖爲64 8 g，之外，同法取得1錠之直徑爲 9mm，厚度4.2mm，質量260mg之壓縮成形製劑。 [實施例10] 壓縮成形製劑（〗〇 ) ·· 混合100g之鹽酸苯海拉明（平均粒徑220 μπι) ’ 44〇g 之結晶纖維素，4〗〇g之乳糖及l〇g之交叉羧甲基纖維素鈉 ，以20號網篩進行過篩。於940.8g之該顆粒中混合19.6g 輕質無水矽酸，9.8g硬脂酸鎂，9.8g之滑石後’以旋轉式 打錠機，約900kg/cm2之壓力下進行取得混合物之壓縮成 -16- (13) 1306763 形，取得】錠之直徑爲9111111’厚度4」〇11：1，質量250〇1§之壓 縮成形製劑。 [實施例Π] 壓縮成形製劑（1 Ο : 混合200g之鹽酸苯海拉明（平均粒徑220 μιη) ’400g 結晶纖維素，200g乳糖，192g玉米澱粉後，加入160g之 5 %羥丙基纖維素之乙醇溶液進行混煉、造粒及乾燥後， 以20號網篩進行過篩。於98 0g該顆粒中混合882g結晶纖 維素，19.6交叉羧甲基纖維素鈉，39.2輕質無水矽酸’ 19.6g硬脂酸鎂，及19.6g滑石’以旋轉式打錠機’約 900kg/cm2之壓力下，進行取得壓縮成形用顆粒之壓縮成 形，取得1錠之直徑爲9mm，厚度4.0mm，質量爲250mg之 壓縮成形製劑。 [實施例12] 壓成形製劑（1 2 ): 混合200g之鹽酸苯海拉明（平均粒徑220 μιη) ，640g 之結晶纖維素，1016g之乳糖，40g交叉羧甲基纖維素鈉 ，96g輕質無水矽酸後，加入480g之10%羥丙基纖維素 之乙醇溶液進行混煉、造粒、及乾燥後，以20號網篩進行 過篩。於1 999.2g該顆粒中混合19.6g之硬脂酸鎂及19.6g之 滑石，以旋轉式打錠機，約900kg/cm2之壓力下，進行取 得壓縮成形用顆粒之壓縮成形後，取得1錠之直徑爲9mm -17- (14) 1306763 ，厚度4.2mm，質量260mg之壓縮成形製劑。 [實施例13] 壓縮成形製劑（1 3 ): 於實施例12取得之壓縮成形製劑6000錠中，針對裸錠 於乾燥狀態下，進行噴塗含有150 g之羥丙基纖維素，l〇g 聚乙二醇，22g氧化鈦，及18g滑石之10%水系塗層液， 做成5mg/每旋者。 [比較例5] 比較壓縮成形製劑（5 ) ·· 變更實施例1之乳糖爲精製白糖，此外，同法取得1錠 之直徑爲9mm，厚度4.2mm，質量260mg之壓縮成形製劑 〇 [比較例6] 比較壓縮成形製劑（6 ): 變更實施例1之乳糖爲葡糖糖，此外，同法取得1錠之 直徑爲9mm，厚度4.2mm’質量260mg之壓縮成形製劑。 [比較例7] 比較壓縮成形製劑（7 ): 變更實施例1之羥丙基纖維素爲聚乙烯吡咯烷酮，之 外，同法取得1錠之直徑爲9〇1111，厚度4.2111111’質量26〇11^ -18- (15) 1306763 之壓縮成形製劑。 [比較例8 ] 比較壓縮成形製劑（8 ). 變更實施例1之交叉羧甲基纖維素鈉爲羧甲基纖維素 Μ ’之外’同法取得]銳之直徑爲9_，厚度4 2_，質量 2 6 0 m g之壓縮成形製劑。 [試驗例1 ] 味覺試驗： 分別各取1個該實施例及比較例取得之壓縮成形製劑 於口中10秒內不咀嚼後吞下。針對此時之道味，依1〇名健 康成人進行以下評定基準評定該苦味。10人平均結果示於 表1。針對鹽酸苯海拉明配合低膨潤性高分子1質量份以 上之壓縮成形製劑中證明服用時未出現強烈苦味。 <味覺評定基準> <點數> 無苦味 ： 0點 稍有苦味 ： 1點 有苦味 ： 2點 (16) 1306763 味覺 (平均） 味覺 (平均） 味覺 (平均） 實施例1 0.6 實施例8 0.5 比較例2 1.6 實施例2 0.3 實施例9 0.3 比較例3 1.3 實施例3 0.3 實施例1 〇 0.2 比較例4 0.2 實施例4 0.1 實施例π 0.1 比較例5 0.5 實施例5 0.1 實施例1 2 0.2 比較例6 0.6 實施例6 0.4 實施例1 3 0.1 比較例7 0.5 奮施例7 0.1 比較例1 1.8 比較例8 0.7 [試驗例2 ] 崩解試驗： 該實施例及比較例取得之壓縮成形製劑依第1 4修訂版 曰本藥局方之崩解試驗法爲基準，利用NT_2HS型崩解試 驗機（富|Jj產業， 。 由山産業（脸份）製），無圓盤之條件下，以3 7 °C純水進行測定> __ 〃 乙 又’ 6個壓縮成形製劑之崩解時間範 圍不於表1。HP会 向膨潤性高分子之壓縮成形製劑呈立即 崩解狀。 -20- (17) 1306763 [表2] 崩解 時 間 崩解時 間 崩解 時 間 (分 鐘 ) (分鐘 ) (分 鐘 ) 實 施 例 1 2.9-4.6 實施例8 3.6-4.8 比 較 例 2 3.2- -4 8 實 施 例 2 3.2 〜4 7 實施例9 3,8〜5.8 比 較 例 3 3 .3- -4. 8 實 施 例 3 3.1 ~5 2 實施例1 〇 2.3 〜4 2 比 較 例 4 9.2〜 15 • 3 實 施 例 4 3.4 〜5 4 實施例1 1 3.2〜4 2 比 較 例 5 3.4^ -4. 6 實 施 例 5 3.5-5.9 實施例I 2 3_4〜4.9 比 較 例 6 3.5^ -4. 8 實 施 例 6 2.7 ~4 2 實施例1 3 3.8〜5.3 比 較 例 7 3.3- -4. 4 實 施 例 7 3.8 ~5 8 比較例1 2.8〜4.5 比 較 例 8 3.5- -5 . 2 [試驗例2] 保存安定性試驗： 將該實施例及比較例所取得之壓縮成形製劑保存6個 月（40 °C，相對濕度75% )及1年（25 °C )後，進行觀 察其外觀之經時變化，依下記評定基準進行評定，其結果 示於表3。本發明製劑爲保存安定性良好者。 <保存安定性評價基準 > < 評價> 未變化 ： ◦ 稍變成黃色 ： △ 變黃色 ： x -21 - (18) 1306763 [表3] 6個月* 1年** 6個月* 1年** 6個月* 1年** 實施例1 〇 〇 實施例8 0 0 比較例2 〇 0 實施例2 〇 〇 實施例9 〇 0 比較例3 〇 〇 實施例3 〇 〇 實施例10 〇 0 比較例4 〇 〇 實施例4 〇 〇 實施例Π 〇 〇 比較例5 Δ Δ 實施例5 〇 〇 實施例12 〇 〇 比較例6 X X 實施例6 〇 〇 實施例13 〇 〇 比較例7 X X 實施例7 〇 〇 比較例1 〇 〇 比較例8 Δ △ 4 0°C CRH 7 5 % * * 2 5 °C [實施例14] 壓縮成形製劑（1 4 ): 使用200g鹽酸苯海拉明（平均粒徑220 μηι) ，64〇g 結晶纖維素’ 101 6g乳糖，40g交叉羧甲基纖維素鈉， 96g輕質無水矽酸，48g羥丙基纖維素，20g硬脂酸鎂， 及20g滑石，依常法製造打錠用顆粒，以約900kg/cm2之壓 力下進行製錠，取得1錠之直徑爲9mm’厚度4.2mm，重量 260mg之壓縮成形製劑》 [實施例15] 壓縮成形製劑（〗5 ): 以200g鹽酸苯海拉明（平均粒徑4〇3 μη〇取代實施 例1 4之200g鹽酸苯海拉明（平均粒徑220 μιυ )使用之外 •22- (19) 1306763 ’與實施例14同法取得1錠之直徑爲9mm，厚度4 2mm，重 量260mg之壓縮成形製劑。 [比較例9] 比較壓縮成形製劑（9 ): 使用640g結晶纖維素，I216g乳糖，40g交叉羧甲 基纖維素鈉，96g輕質無水矽酸，48g羥丙基纖維素， 2〇g硬脂酸鎂’及20g滑石，依常法製造打錠用顆粒，以 約900kg/cm2之壓力進行製錠，取得1錠之直徑爲9mm，厚 度爲4.2111111，重量26〇1^之壓縮成形製劑。 [試驗例3 ] 催眠試驗： 以8名輕度不眠傾向之成人爲對象，每天就寢前3 0 分鐘服用2錠實施例14及15以及比較例9取得之壓縮成形製 劑連服7天後，針對其入睡、睡眠狀態之藥劑效果進行試 驗之。入睡試驗結果示於表4、睡眠狀態之試驗結果示於 表5。本發明壓縮成形製劑優於比較壓縮成形製劑之入睡 及睡眠狀態。 [表4] 入睡 良好 尙可 未變 稍差 不良 實施例1 4 3 3 1 1 0 實施例1 5 2 4 1 1 0 比較例9 0 0 7 1 0 -23- (20) 1306763 [表5] 睡眠狀態 良好 尙可 未變 稍差 不良 實施例1 4 2 4 2 0 ---〆、 0 實施例1 5 1 5 2 0 -----v 0 比較例9 0 1 6 1 0 [實施例16] 壓縮成形製劑（1 6 ): 以200g鹽酸苯海拉明（平均粒徑54.3 μπ〇取代200g 實施例14之鹽酸苯海拉明（平均粒徑220 μην)使用之外， 與實施例14同法取得1錠之直徑爲9mm，厚度4.2mm，重量 爲260mg之壓縮成形製劑。 [試驗例4] 味覺試驗： 分別各取1個該實施例14~ 16取得之壓縮成形製劑於口 中保持10秒鐘不咀嚼後吞下。針對此時之味覺，以10名健 康成人依試驗例1之相同基準下進行評定苦味。10人平均 結果如表6所示。本發明壓縮成形製劑未出現苦味，爲理 想者。 -24- (21) 1306763 [表6] 味覺（平均） 實施例1 4 0.3 實施例1 5 0.2 實施例1 6 0.6 〔發明效果〕 以含苯海拉明等做爲催眠、鎭靜作用之藥效成份的本 發明催眠用壓縮成形製劑藉由配合低膨潤性高分子及高膨 潤性高.分子後，呈未變色、服用時掩蓋苦味 '易於服用之 催眠用壓縮成形製劑者。且，組合此等低膨潤性高分子及 高膨潤性高分子之壓縮成形製劑本身易於崩解，可於血中 出現做爲催眠、鎭靜作用藥效成份之滿足量的苯海拉明等 〇 因此，苯海拉明等具有睡眠、鎭靜作用可有效做爲藥 劑使用，對於不眠症、緊張、興奮感、不安感等之鎭靜、 伴隨此等症狀之頭重、疲勞倦怠感之緩和、不安感之解除 等可提供明確快速出現效果之催眠用壓縮成形製劑° -25-1306763 (1) 玖 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩 压缩A hypnotizing compression-molding preparation which has a composition, no discoloration, and is stable, masks bitterness when taken, and can quickly exhibit a pharmacological effect. [Prior Art] Diphenhydramine or its acid-added salt has anti-histamine action and central role, and the prior art system is used as an active ingredient of rhinitis, skin disease, cold medicine, cough and expectorant. It is easy to produce shortcomings of side effects of drowsiness. For example, diphenhydramine hydrochloride and diphenhydramine citrate have a hypnotic effect almost simultaneously with the alleviating hypnotic agent. Moreover, it disappears from the blood more quickly and has no habituation. Therefore, in Europe and the United States, the hypnotics that do not require a prescription for the general use of medicines in Japan are used in an amount of 5 Omg per adult. On the other hand, after the hydration of diphenhydramine hydrochloride, the plasma concentration in the drowsiness was 50 ng/ml or more, which is higher than the plasma concentration in the anti-histamine action. In addition, the time-lapse of plasma concentration in oral administration of 50 mg diphenhydramine hydrochloride was slightly increased to 50 ng/mlg 2 to 4 hours after administration (Carruthers et al.: Clin, Pharmacol. Ther.; 23 (4); 375~ 382, I 9 7 8 ). Therefore, when used as an oral hypnotic agent, the preparation may disintegrate depending on the conditions of administration, and the hypnotic effect will not be fully obtained after the dissolution is delayed. -5- (2) 1306763 In addition, the taste of diphenhydramine or its acid-added salt is intense and irritating, and it is unpleasant when taken. However, in the method of preserving the taste by delaying the dissolution of the film containing the oil, the insoluble polymer, and the matrix, the effect of acting as an antihistamine does not cause an obstacle, but it is impossible to act as a hypnotic. The effect is obvious. Further, in the method of masking the taste with a sweetener or a flavoring agent, there is a disadvantage that the bitterness remains on the tongue under the cover. Further, diphenhydramine or a preparation containing an acid-added salt thereof is moistened or fixed to each other by discoloration and moisture in the form of a formulation additive such as an excipient. Further, since the self-densing light of diphenhydramine or its acid-added salt appears discoloration, there is a disadvantage that the commercial price is lost even if the content is not lowered. SUMMARY OF THE INVENTION Therefore, it is expected to provide a medicinal ingredient containing diphenhydramine or its acid-added salt as a sleep and sedative effect, and it can be masked and tasted without discoloration and stability. The preparation of the effect. In order to solve this problem, the present inventors have found that after combining with a plurality of polymers having different swellability, it is found that diphenhydramine or an acid-added salt thereof is combined with a different swelling property, and the solubility of the diphenidazole is not affected by compression molding. The present invention has been completed by obtaining a compression molding preparation for hypnosis which has a clear effect of good hypnosis and the like. That is, the present invention provides a drug containing diphenhydramine or its acid addition salt, a low-swelling polymer and a high-swelling polymer as a hypnotic, sputum-6-(3) 1306763 effect. A component of the composition is a compression molding preparation for hypnosis. The present invention further provides a compression-form preparation for hypnosis for improving sleep by using diphenhydramine or an acid-addition salt thereof. [Embodiment] The present invention relates to a compression molding preparation for hypnosis (hereinafter referred to as "the preparation of the present invention"), which is a combination of diphenhydramine or an acid addition salt thereof, and a low-swelling polymer and a high-swelling polymer. Thereafter, the powder or granule for compression molding is prepared and prepared by a compression molding step. In the preparation of the present invention, diphenhydramine which is used as a medicinal ingredient having sleep and sedative effects may be directly in the form of a salt base or may be an acid-added salt. However, if the salt base form is liquid, for example, it is necessary to use a salt base as a powder or granule in a powder such as light anhydrous citric acid. Therefore, when actually preparing the preparation of the present invention, it is used as an acid additional salt. should. For this purpose, the acid salt of diphenhydramine is as follows: diphenhydramine hydrochloride 'diphenhydramine salicylate, diphenhydramine citrate, diphenhydramine tannin, diphenhydramine lauryl sulfate Diphenhydramine sulfate example. Further, as an ideal acid addition salt, such as diphenhydramine hydrochloride and diphenhydramine citrate, a particularly preferred acid addition salt is diphenhydramine hydrochloride. The average particle diameter of the raw powder of such diphenhydramine or its acid addition salt is not particularly limited, and is generally 30 μm or more and 500 μηι or less, and more preferably 50 to 300 μm. The adjustment of the average particle diameter may be carried out by a usual method such as pulverization or sieving, if necessary, and the method is not limited. Such as - Ί - (4) 1306763: pulverization can be carried out by using a hammer mill, a quick honing machine, a roller honing machine, a pin mill, a ball mill, an oscillating ball mill, an oscillating honing machine, an injection honing machine and the like. 'Screening can be carried out by using a sieved continuous vibrating screen machine and an airflow screen machine. The ratio of diphenhydramine or its acid-added salt (hereinafter referred to as "phenacamine, etc.") in the present invention varies depending on the dosage form, the amount to be administered, etc., and is usually about 5 to 30% by mass. Again! The amount of diphenhydramine and the like contained in the preparation of the present invention is not limited, and generally, the amount of diphenhydramine and the like is 5 Omg, and therefore, 1 is 12.5 to 50 mg, and the integral amount of 50 mg is 1 Just fine. Further, the low swellable polymer used in the preparation of the present invention is insoluble in water, and the one having a small swelling property is blended with diphenhydramine or the like, and is preferably a low reactivity which does not change color after compression molding. Specific examples of the low-swelling polymer are, for example, crystalline cellulose, ethyl cellulose, and aminoalkyl methacrylate copolymer RS. These may be used alone or in combination of two or more. It. The most desirable specific example is crystalline cellulose. These low-swelling polymers are preferably used in an amount of 1 part by mass or more per part by mass of diphenhydramine or the like, and more preferably 2 parts by mass or more. The amount of the low-swelling polymer to be added to the total mass of the preparation of the present invention varies depending on the amount of diphenhydramine and the like, and the total mass of the preparation varies, generally about 3 to 90% by mass, more preferably 5 ~80% by mass. The high-swelling polymer used in the preparation of the present invention is insoluble in water and has a large swelling property, and in combination with diphenhydramine or the like, it is necessary to exhibit a low reactivity without discoloration after compression molding. Specific examples of such high-swelling polymers are: cross-carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, -8-(5) 1306763 crospovidone, and the like. It can be used alone or in combination of two. The most preferred specific example is the case of cross-carboxymethylcellulose sodium. The addition amount of the high-swelling polymer to the total mass of the preparation of the present invention varies according to the content of diphenhydramine and the total mass of the preparation, and is generally about 0.1 to 5 mass%, more preferably 〇. 5 to 3 mass%. In the present invention, it is necessary to use a combination of such a low-swelling polymer and a high-swelling polymer, and in this case, the compounding ratio is such that the high-swelling polymer is a low-swelling polymer. Preferably, it is preferably 0.2 times or more. The preparation of the present invention can add a known pharmaceutical additive to the low-swelling polymer and the high-swelling polymer when the diphenhydramine is necessary, such as: excipient, binder, disintegrating agent 'lubricant' stability Agent, surfactant, dissolution aid, reducing agent, buffer, adsorbent, fluidizer, antistatic agent 'coating agent, plasticizer, anti-adhesion agent, opacifier, glossing agent' antioxidant, sweetener After adding the flavoring agent, the cooling agent, the coloring agent, the flavoring agent, the flavoring agent, the fragrance, and the like, the powder or granule for the preparation of the compression molding is produced by compression molding according to a usual method. The pharmaceutical additive to be used in the present invention is a water-soluble polymer, light anhydrous citric acid, saccharide or sugar alcohol which is not discolored after being compression-molded at least one type or two or more types selected from the group consisting of diphenhydramine and the like. The color change of starch and talc dissolved in water does not form a shrinkage pressure such as Minglahai. It is suitable for the person to make magnesium, and the acid fat is 0C as hard as the other. The sub-equation is divided into the same alcoholic dimethine, 'powder-dip-dimethicone, propyl hydroxy yttrium> chemistry: α, such as the powder of the powder as a fiber-based methyl propyl hydroxy-9- ( 6) 1306763 Potato starch, wheat starch, rice starch, etc. as a sugar 'sugar alcohol such as: lactose, mannitol, xylitol, dextrin, sorbitol and the like. The amount of the water-soluble polymer, the starch, the saccharide, and the sugar alcohol to be added varies depending on the size of the compression-molded preparation and the method for producing the powder for compression molding, and is not particularly limited. 80% by mass. Further, the light anhydrous citric acid in the pharmaceutical additive can increase the fluidity of the powder for compression molding and also prevent the wetting and bonding of the compression-molded preparation. The smaller the average particle size of the light anhydrous citric acid, the better, and it is preferred to use a light anhydrous citric acid having an average particle diameter of 4 to 5 nm. The amount thereof to be added is preferably the mass% of the total mass of the compression-molded preparation. It is more desirable to add either talc and 1 to 5 mass% of talc and magnesium stearate to either of the total mass of the compression-molded preparation. The powder for compression molding may be directly mixed with the component powder, or a part or all of it may be used as a granulated powder. When the granulated powder is used as the granulated powder, a granulation method generally used, such as a solution containing water or an organic solvent, or a spray granulation method using a dispersion, a stirring granulation method, or a flow granulation method can be used. Dry granulation methods such as a wet granulation method such as a rotary granulation method and a rotary flow granulation method, or a dense granulation method using a powdery binder. The blend or granulated powder is a cost-effective formulation via a compression forming step. As a specific compression forming step, such as a method using a rotary tableting machine, a single-type tableting machine, or the like, or a method using a hydraulic press, and using an ingot machine It is advisable to use the rotary type ingot machine to produce the best efficiency. Further, the pressure of compression molding varies depending on the size and shape of the compression molding preparation, and the type and amount of the pharmaceutical additive -10-(7) 1306763. For example, a compression molding preparation having a diameter of 9 mm is preferably 300 kg/cm2 or more. It is preferably 500~1 500kg/cm2. The dosage form in which the preparation of the present invention is obtained is a tablet, and the shape thereof is a circular ingot or a shaped ingot, and is not particularly limited. In addition, the tablet can also be tangential. Moreover, the preparation of the present invention can also be made into a coating composition and a sugar-coated preparation which is more rapidly soluble by a planar coating method, a fluidized layer coating method, a spin coating method, a dry coating method, a combination of these methods, or the like. . In this case, the water-soluble or gastric-soluble coating agent is dissolved or dispersed in water or an organic solvent to be spray-coated, or a dry coating which is heated and pressurized after directly spreading the coating agent. A plasticizer, an adhesion preventive agent, an opacifier, an extender, and the like may be added to the film. The best embodiment of the preparation of the present invention described above is characterized in that 12.5 to 50 mg of diphenhydramine hydrochloride is contained in one preparation, and the crystalline cellulose as a low-swelling polymer is 1 part or more of diphenhydramine hydrochloride. As a high-swelling polymer, the cross-carboxymethylcellulose sodium of the polymer is 0.1 to 5% by mass of the total mass of the preparation of the invention, and the light anhydrous citric acid is 1 to 10% by mass of the total mass of the preparation of the invention, as The water-soluble polymer hydroxypropyl cellulose is 1 to 5% by mass of the total mass of the preparation of the invention, and more lactose is 20 to 80% by mass of the total mass of the preparation of the invention, and talc and magnesium stearate are the total preparations of the invention. 0.1 to 5% by mass of the mass is used for the compression molding powder obtained by blending, and the mass of one preparation is 100 to 750 mg in a tableting machine, and the preparation for compression molding under a pressure of 500 to 1 500 kg/cm 2 . [Operation] -11 - (8) 1306763 The preparation of the present invention has diphenhydramine or the like, a low-swelling polymer and a high-swelling polymer, so that it does not discolor, stabilize, and can mask bitterness when taken. A preparation that does have rapid effects such as hypnosis. This preparation can be used for insomnia, such as tension, excitement, restlessness, etc., the first weight of these symptoms, the relaxation of fatigue and fatigue, and the elimination of anxiety. [Examples] Hereinafter, the present invention will be more specifically described by way of examples, but the present invention is not limited to the examples. [Example 1] Compression molding preparation (1): mixed 1 μg of diphenhydramine hydrochloride (average particle diameter 220 μm), 100 g of crystalline cellulose, 72 8 g of lactose, 20 g of cross-carboxymethyl cellulose Sodium, 48 g of light anhydrous citric acid was then 'mixed with 240 g of 10% hydroxypropylcellulose in ethanol' to be granulated. After granulation and drying, it was sieved through a No. 20 mesh sieve. After 9.8 g of magnesium stearate and 9.8 g of talc were mixed in 1009.4 g of the granules, the pellets for compression molding were subjected to compression molding under a pressure of about 900 kg/cm 2 by a rotary tableting machine, and the diameter of one spindle was obtained. A compression molded preparation of 9 mm, a thickness of 4.2 mm and a mass of 260 mg. [Example 2] Compression molding preparation (2) · The crystal cellulose of Example 1 was changed to 200 g 'Lactose was 628 g other than -12-(9) 1306763, and the same method obtained one spindle having a diameter of 9 mm and a thickness of 4.2 mm. A compression molded preparation having a mass of 260 mg. [Example 3] Compression molding preparation (3): The crystal cellulose of Example 1 was changed to 400 g, and the lactose was 4 2 8 g, and the diameter of one ingot was 9 mm, the thickness was 4.2 mm, and the mass was 260 mg. The compression molded preparation. [Example 4] Compression molding preparation (4) · The crystal cellulose of Example 1 was changed to 600 g, and the lactose was 228 g, and the diameter of one spindle was 9 mm, the thickness was 4.2 mm, and the mass was 26 〇 mg. A person who compresses the shaped preparation. [Example 5] Compression molding preparation (5): A modified shape preparation having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 26 〇mg was obtained while changing the crystal cellulose of Example 1 to 800 g and lactose to 28 g. . [Example 6] Compression molding preparation (6): Mixing 25 g of diphenhydramine hydrochloride (average particle size 220 μη〇' -13-1306763 do) Crystalline cellulose, 385 g of lactose '20 g of cross-carboxymethyl group Sodium cellulose, 5 〇g light anhydrous citric acid, was added to 200 g of 10% hydroxypropyl cellulose in ethanol, kneaded, granulated, dried, and sieved through a No. 20 mesh sieve. After 9.8 g of magnesium stearate and 9.8 g of talc were mixed in the granules of 960 = 4 g, compression molding of pellets for compression molding was carried out under a pressure of about 900 kg/cm 2 by a rotary tableting machine, and then one spindle was obtained. A compression molded preparation having a diameter of 5.5 mm, a thickness of 4.2 mm, and a mass of 100 mg. [Example 7] Compression molding preparation (7) ·· Mixing 37.5 of diphenhydramine hydrochloride (average particle size 220 μηι), 3 75 g of crystalline cellulose '652.5 g of lactose, 24 g of cross-carboxymethylcellulose sodium, 6〇 g After light anhydrous citric acid, 270 g of 10% hydroxypropylcellulose in ethanol was added for kneading, granulation and drying, and then sieved through a No. 20 mesh sieve. After mixing 11.8 g of magnesium stearate and 1 1.8 g of talc in 1 152.5 g of the granules, the pellets obtained by compression molding were compressed by a rotary tableting machine at a pressure of about 900 kg/cm 2 to obtain 1 The ingot has a diameter of l〇mm, a thickness of 4.3 mm, and a mass of 400 mg of a compression-formed preparation. [Example 8] Compression molding preparation (8): 500 g of diphenhydramine hydrochloride (average particle diameter 220 μm), 500 g of crystalline cellulose, 77 g of lactose, 20 g of cross-carboxymethylcellulose sodium, 55 g of light anhydrous After citric acid, 240 g of a solution of 10% hydroxypropylcellulose in Ethyl-14-(11) 1306763 alcohol was added, kneaded, granulated and dried, and sieved through a No. 20 mesh sieve. 1 l52.5 g of the granules were mixed with 1 1.8 g of magnesium stearate and 1 1.8 g of talc, and then subjected to compression molding of a pellet for compression molding by a rotary tableting machine at a pressure of about 900 kg/cm 2 to obtain 1 A compression molded preparation having an ingot diameter of 6 mm, a thickness of 4 mm, and a mass of 120 mg. [Example 9] Compression molding preparation (9): 150 g of diphenhydramine hydrochloride (average particle size 220 μη〇, 465 g of crystalline cellulose, 45 0 g of lactose, 24 g of cross-carboxymethylcellulose sodium, 6 g) After light anhydrous citric acid, 270 g of 10% hydroxypropylcellulose in ethanol was added for kneading, granulation and drying, and sieved through a No. 20 mesh sieve. 11.8 g of stearic acid was mixed in 1152.5 g of the granules. Magnesium, 11.8 g of talc, and compression-molding of pellets for compression molding under a pressure of about 900 kg/cm 2 by a rotary tableting machine, and then obtained a diameter of 10 ingots, a thickness of 4.3 mm, and a mass of 4 〇〇 mg. [Comparative Example 1] Comparative compression molding preparation (1): The crystalline cellulose of Example 1 was removed, and the lactose was changed to 82 8 g, and the diameter of the same method was 9111111, and the thickness was 4.2111111. It is a compression molding preparation of 26〇111§. [Comparative Example 2] -15- (12) 1306763 Comparative compression molding preparation (2): Changed Example] Crystalline cellulose was 40 g 'Lactose was 788 g, except for the same method Obtained a spindle with a diameter of 9mm, a thickness of 4.2mm, and a mass of 260mg. [Comparative Example 3] Comparative compression molding preparation (3): The crystal cellulose of Example 1 was changed to 60 g 'Lactose was 768 g', and the same method was used to obtain a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg. [Comparative Example 4] Compression molding preparation (4): The cross-carboxymethylcellulose sodium of Example 1 was removed, and the crystalline cellulose was changed to 200 g, and the lactose was 64 8 g. A compression-molded preparation having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg. [Example 10] Compression molding preparation (〗 〖) ·· Mixing 100 g of diphenhydramine hydrochloride (average particle size 220 μπι) ' 44〇g The crystalline cellulose, 4 〇g of lactose and 1〇g of cross-carboxymethylcellulose sodium, was sieved through a No. 20 mesh sieve. 19.8 g of light anhydrous citric acid was mixed in 940.8 g of the granule, 9.8 g magnesium stearate, 9.8g of talc, 'reduced into a -16- (13) 1306763 shape by a rotary tableting machine under a pressure of about 900kg/cm2, obtained] the diameter of the ingot is 9111111' thickness 4"〇11:1, a compression molded preparation of mass 250〇1§. [Example Π] Compressed into Preparation (1 Ο : mixing 200 g of diphenhydramine hydrochloride (average particle size 220 μιη) '400 g of crystalline cellulose, 200 g of lactose, 192 g of corn starch, and then adding 160 g of 5% hydroxypropylcellulose in ethanol to mix After granulation and drying, it was sieved with a No. 20 mesh sieve. In 98 g of the granules, 882 g of crystalline cellulose, 19.6 cross-carboxymethylcellulose sodium, 39.2 light anhydrous citric acid ' 19.6 g of magnesium stearate, and 19.6 g of talc 'with a rotary tableting machine' of about 900 kg/ were mixed. Under the pressure of cm2, compression molding of the pellet for compression molding was carried out, and a compression molded preparation having a diameter of 9 mm, a thickness of 4.0 mm, and a mass of 250 mg was obtained. [Example 12] Press molding formulation (1 2 ): 200 g of diphenhydramine hydrochloride (average particle size 220 μηη), 640 g of crystalline cellulose, 1016 g of lactose, 40 g of cross-carboxymethylcellulose sodium, and 96 g of light were mixed. After the anhydrous citric acid was added, 480 g of a 10% hydroxypropylcellulose ethanol solution was added for kneading, granulation, and drying, and then sieved through a No. 20 mesh sieve. 19.9 g of magnesium stearate and 19.6 g of talc were mixed in 1 999.2 g of the granules, and the pellets for compression molding were subjected to compression molding under a pressure of about 900 kg/cm 2 to obtain 1 tablet. The compression molded preparation has a diameter of 9 mm -17-(14) 1306763, a thickness of 4.2 mm, and a mass of 260 mg. [Example 13] Compression molding preparation (1 3 ): In the 6000 ingot of the compression molding preparation obtained in Example 12, sprayed with 150 g of hydroxypropylcellulose in a dry state for the bare ingot, l〇g Ethylene glycol, 22 g of titanium oxide, and 18 g of 10% aqueous coating solution of talc were made into 5 mg per spinper. [Comparative Example 5] Comparative compression molding preparation (5) · The lactose of Example 1 was changed to refined white sugar, and a compression molding preparation having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg was obtained in the same manner [Comparative Example] 6] Comparative compression molding preparation (6): The lactose of Example 1 was changed to glucose sugar, and a compression molding preparation having a diameter of 9 mm and a thickness of 4.2 mm 'mass 260 mg was obtained in the same manner. [Comparative Example 7] Comparative compression molding preparation (7): The hydroxypropyl cellulose of Example 1 was changed to polyvinylpyrrolidone, and the diameter of one spindle was 9 〇 1111 and the thickness was 4.2111111' mass 26 〇 11 by the same method. ^ -18- (15) 1306763 compression molded preparation. [Comparative Example 8] Comparative compression molding preparation (8). The modified cross-carboxymethyl cellulose sodium of Example 1 was obtained by the same method as the carboxymethyl cellulose Μ 'outside' method] the sharp diameter was 9 mm, and the thickness was 4 2_, A compression molded preparation of mass 260 mg. [Test Example 1] Taste test: Each of the compression-molded preparations obtained in each of the examples and the comparative examples was swallowed in the mouth for 10 seconds without chewing. For the taste at this time, the bitter taste was evaluated according to the following criteria for a healthy adult. The average results for 10 people are shown in Table 1. In the compression-molded preparation containing more than 1 part by mass of diphenhydramine hydrochloride and a low-swelling polymer, it was confirmed that no strong bitterness was observed when taken. <Taste Evaluation Standard><Points> No bitterness: 0 point slightly bitterness: 1 point has bitterness: 2 points (16) 1306763 Taste (average) Taste (average) Taste (average) Example 1 0.6 Implementation Example 8 0.5 Comparative Example 2 1.6 Example 2 0.3 Example 9 0.3 Comparative Example 3 1.3 Example 3 0.3 Example 1 〇 0.2 Comparative Example 4 0.2 Example 4 0.1 Example π 0.1 Comparative Example 5 0.5 Example 5 0.1 Example 1 2 0.2 Comparative Example 6 0.6 Example 6 0.4 Example 1 3 0.1 Comparative Example 7 0.5 Example 7 0.1 Comparative Example 1 1.8 Comparative Example 8 0.7 [Test Example 2] Disintegration test: This example and the comparative example were obtained. The compression-formed preparation is based on the disintegration test method of the 14th revised version of the Pharmacy Bureau, and uses the NT_2HS type disintegration test machine (Fu | Jj Industries, manufactured by Yamagata (face)), without disc Under the conditions, the measurement was carried out in pure water at 37 °C. __ 〃 B and '6 compression molding formulations have a disintegration time range not shown in Table 1. HP will immediately disintegrate into a compression-formed formulation of a swellable polymer. -20- (17) 1306763 [Table 2] Disintegration time Disintegration time Disintegration time (minutes) (minutes) (minutes) Example 1 2.9-4.6 Example 8 3.6-4.8 Comparative Example 2 3.2- -4 8 Implementation Example 2 3.2 to 4 7 Example 9 3, 8 to 5.8 Comparative Example 3 3 .3 - 4. 8 Example 3 3.1 to 5 2 Example 1 〇 2.3 to 4 2 Comparative Example 4 9.2 to 15 • 3 Example 4 3.4 to 5 4 Example 1 1 3.2 to 4 2 Comparative Example 5 3.4^ -4. 6 Example 5 3.5-5.9 Example I 2 3_4 to 4.9 Comparative Example 6 3.5^ -4. 8 Example 6 2.7 ~4 2 Example 1 3 3.8~5.3 Comparative Example 7 3.3- -4. 4 Example 7 3.8 ~ 5 8 Comparative Example 1 2.8~4.5 Comparative Example 8 3.5- -5 . 2 [Test Example 2] Storage stability test: The compression-molded preparations obtained in the examples and the comparative examples were stored for 6 months (40 ° C, relative humidity: 75%) and one year (25 ° C), and the change in appearance of the appearance was observed, and the evaluation was carried out according to the following criteria. The results are shown in Table 3. The preparation of the invention has good preservation stability. <Preservation stability evaluation criterion><Evaluation> No change: 稍 Slightly yellow: △ Yellow: x -21 - (18) 1306763 [Table 3] 6 months* 1 year** 6 months* 1 year ** 6 months * 1 year ** Example 1 〇〇 Example 8 0 0 Comparative Example 2 〇 0 Example 2 〇〇 Example 9 〇 0 Comparative Example 3 〇〇 Example 3 〇〇 Example 10 〇0 Comparative Example 4 〇〇Example 4 〇〇Example Π 〇〇Comparative Example 5 Δ Δ Example 5 〇〇Example 12 〇〇Comparative Example 6 XX Example 6 〇〇Example 13 〇〇Comparative Example 7 XX Example 7 〇〇Comparative Example 1 〇〇Comparative Example 8 Δ Δ 4 0 ° C CRH 7 5 % * * 2 5 ° C [Example 14] Compression molding preparation (1 4 ): 200 g of diphenhydramine hydrochloride ( Average particle size 220 μηι), 64〇g crystalline cellulose '101 6g lactose, 40g cross-carboxymethylcellulose sodium, 96g light anhydrous citric acid, 48g hydroxypropyl cellulose, 20g magnesium stearate, and 20g talc The pellet for tableting is produced according to the usual method, and the tablet is made at a pressure of about 900 kg/cm 2 to obtain a diameter of 9 mm of a spindle of 4.2 mm and a pressure of 260 mg. Forming Formulation [Example 15] Compressed Forming Formulation (〗 〖5): 200 g of diphenhydramine hydrochloride (average particle size 220 μιη 实施) was replaced by 200 g of diphenhydramine hydrochloride (average particle size 4 〇 3 μη〇). (2) (19) 1306763 A compression molding formulation having a diameter of 9 mm, a thickness of 42 mm, and a weight of 260 mg was obtained in the same manner as in Example 14. [Comparative Example 9] Comparative compression molding preparation (9): Using 640 g of crystalline cellulose, I216 g of lactose, 40 g of cross-carboxymethylcellulose sodium, 96 g of light anhydrous citric acid, 48 g of hydroxypropylcellulose, 2 g of magnesium stearate' and 20 g of talc, ingots were prepared according to the usual method. The pellets were tableted at a pressure of about 900 kg/cm 2 to obtain a compression molded product having a diameter of 9 mm, a thickness of 4.2111111, and a weight of 26 〇 1 ^. [Test Example 3] Hypnosis test: 8 mild sleeplessness For the adult who is inclined, take two injections of the compression-molded preparations obtained in Examples 14 and 15 and Comparative Example 9 for 30 days before bedtime, and then test the effects of the sleeping and sleeping states on the sleeping effect. The results are shown in Table 4. The test results of the sleep state are shown in Table 5. The compression-molded preparation of the present invention is superior to the sleep-sleeping and sleeping state of the comparative compression-formed preparation. [Table 4] Good sleep, no change, and poor. Example 1 4 3 3 1 1 0 Example 1 5 2 4 1 1 0 Comparative Example 9 0 0 7 1 0 -23- (20) 1306763 [Table 5] Good sleep state 尙 No change is slightly poor Example 1 4 2 4 2 0 ---〆, 0 Example 1 5 1 5 2 0 -----v 0 Comparative Example 9 0 1 6 1 0 [Example 16] Compression molding preparation (16): 200 g of diphenhydramine hydrochloride (average particle size 54.3 μπ〇 instead of 200 g Example 14) A compression molded preparation having a diameter of 9 mm, a thickness of 4.2 mm, and a weight of 260 mg was obtained in the same manner as in Example 14 except that diphenhydramine hydrochloride (average particle diameter: 220 μην) was used. [Test Example 4] Taste test: Each of the compression-molded preparations obtained in each of Examples 14 to 16 was held in the mouth for 10 seconds without being chewed and swallowed. The bitter taste was evaluated on the same basis as in Test Example 1 for 10 healthy adults for the taste at this time. The average results for 10 people are shown in Table 6. The compression-molded preparation of the present invention does not exhibit bitterness and is desirable. -24- (21) 1306763 [Table 6] Taste (Average) Example 1 4 0.3 Example 1 5 0.2 Example 1 6 0.6 [Effect of the Invention] A drug containing hypnotic and sedative effects In the compression-molding composition for hypnosis of the present invention, a low-swelling polymer and a high-swelling polymer are used, and the molecule is not discolored, and the bitter taste is easily taken when taken. Further, the compression-molded preparation in which such a low-swelling polymer and a high-swelling polymer are combined is easily disintegrated, and diphenhydramine, which is a satisfying amount of a hypnotic or sedative effect, can be present in the blood. Therefore, diphenhydramine and other sleep and sedative effects can be effectively used as a medicament, and the sedation of insomnia, nervousness, excitement, uneasiness, etc., the severity of the symptoms accompanying these symptoms, the feeling of fatigue and fatigue, restlessness Hypnotic compression molding preparations that provide clear and rapid effects, such as release of feelings. -25-