200304807 (1) 玖、發明說明 【發明所屬之技術領域】 本發明係關於被覆固體所成催眠製劑，更詳細而言， 係關於含有2-二苯甲氧基—N，N —二甲基乙胺或其酸加 成鹽作爲催眠、鎭靜作用之藥效成份，不會變色且安定， 可隱藏服用時之苦味，效果發生迅速且確實之被覆固體所 成催眠製劑。 【先前技術】 以往之2—二苯甲氧基一 N，N-二甲基乙胺或其酸加 成鹽係具有抗組織胺作用及中樞作用，作爲鼻炎、皮膚病 、感冒藥或鎭咳去痰藥之有效成份使用，但產生睡意之副 作用爲其缺點。 例如，已知鹽酸2-二苯甲氧基—N，N—二甲基乙胺 或檸檬酸2 -二苯甲氧基一 N，N-二甲基乙胺係具有與緩 和催眠劑約爲相同的催眠作用。其次，因爲由血液中消失 較快、無習慣性，所以於歐美或日本，作爲一般用醫藥品 ，不需處方簽之催眠藥使用，成人每次投予量爲50mg。 然而，由於鹽酸2 —二苯甲氧基一 N，N —二甲基乙胺 之鎭靜作用，產生睡意之血漿中濃度爲50ng/ml以上，此 比產生抗組織胺作用之血漿中濃度爲高。另外，經口投予 5 Omg之鹽酸2 —二苯甲氧基一 N，N —二甲基乙胺時之血漿 中濃度之經時變化平均値’經投予後2至4小時，僅比 50ng/ml 稍高（Carruthers 等：Clin· Pharmacol. Ther. -6 - (2) (2)200304807 :23(4):375至3 82,1 978 )。因此，作爲經口投予之催眠劑使 用時，依其服用條件，製劑崩壞或溶出變慢時，不能充份 得到作爲催眠劑的效果。 另一方面，2 —二苯甲氧基一 N，N—二甲基乙胺的味 道係具有強烈的刺激性苦味，具有於服用時給予不快感之 性質。然而，以往所使用之以含有油脂或不溶性高分子之 皮膜或基質（matrix )，使溶出性變慢，隱蔽味道的方法 ，作爲催眠劑之發生效果，可能有不確實或不充份之虞。 另外，2 —二苯甲氧基—N，N—二甲基乙胺或其酸加 成鹽，已知會因光徐徐變化，分解成二苯甲酮 (benzophenone)、或二苯甲醇（benzhydrol)及 /S —二甲胺基 乙酉享（-dimethylaminoethanol)等。 爲防止如此地因光變色，雖然有保管於遮光箱或包裝 容器之方法，但是，患者要經常保管於如此之包裝容器係 困難的。另外，服用或保管時，亦有製劑暴露於光下之機 會，所以特別是作爲一般用醫藥品，係要求可對光防止變 色之製劑。 【發明內容】 發明所欲解決之課題 因此，要求提供含有2 -二苯甲氧基一 N，N—二甲基 乙胺或其酸加成鹽作爲睡眠、鎭靜作用之藥效成份，並且 ，不會變色且安定，可隱蔽服用時之苦味，效果發生迅速 且確實之製劑。 (3) (3)200304807 課題之解決手段 本發明者等人，對於上述課題，努力檢討之結果發現 ，將含有2 —二苯甲氧基一 N，N-二甲基乙胺或其酸加成 鹽作爲具有睡眠、鎭靜作用之藥效成份之固形劑，以含有 遮光性物質之水溶性高分子物質皮膜被覆，形成不會變色 ’隱蔽苦味，發生效果之確實性優異之被覆固體所成催眠 製劑，而完成本發明。 亦即本發明係提供將含有作爲具有睡眠、鎭靜作用之 藥效成份之2— 一本甲氧基一 N，N—二甲基乙胺或其酸加 成鹽之固形劑，以含有遮光性物質及水溶性高分子物質之 皮膜被覆所成爲特徵之被覆固體所成催眠製劑者。 發明之實施型態 本發明之被覆固體所成催眠製劑係將含有2 -二苯甲 氧基- N，N —二甲基乙胺或其酸加成鹽之固形劑，以含 有遮光性物質之水溶性高分子物質皮膜所被覆者。 本發明中，作爲具有睡眠、鎭靜作用之藥效成份，所 使用之2—二苯甲氧基—N，N —二甲基乙胺可爲鹽基狀態 ，另外，亦可爲酸加成鹽狀態。然而，鹽基狀態爲液狀， 因爲必須使用如輕質矽酸酐等之粉體，以保持鹽基粉粒體 化，所以於製造固形劑時，係以使用酸加成鹽爲宜。如此 之2-二苯甲氧基—N，N-二甲基乙胺酸加成鹽，可舉例 如鹽酸2 —二苯甲氧基一 N，N -二甲基乙胺酸、水楊酸2 -8- (4) (4)200304807 —二苯甲氧基一 N，N -二甲基乙胺酸、檸檬酸2 —二苯甲 氧基—Ν’ N—二甲基乙胺酸、丹寧酸2 —二苯甲氧基一 n ，N —二甲基乙胺酸、月桂基硫酸2 —二苯甲氧基一 n，N 一二甲基乙胺酸及硫酸2-二苯甲氧基一 N，N—二甲基乙 胺酸，最適合之酸加成鹽，例如鹽酸2 -二苯甲氧基一 n， N —二甲基乙胺酸及檸檬酸2 -二苯甲氧基一N，N —二甲 基乙胺酸。 含有上述2 -二苯甲氧基一 N，N-二甲基乙胺或其酸 加成鹽（以下，稱爲「2 —二苯甲氧基一 N，N—二甲基乙 胺等」）之固形劑劑形’可舉例如錠劑、顆粒劑、細粒劑 、散劑、硬膠囊劑、軟膠囊劑或九劑。另外，依情況，亦 可直接使用2 —二苯甲氧基一 N，N-二甲基乙胺酸加成鹽 之原本粉末。該固形劑之粒徑，雖然無特別的限制，但是 一般其平均粒徑爲50/zm至50mm，以0.5至30mm爲宜，以 2至30mm尤佳。另外，作爲固形劑，以速溶性之經口投予 製劑爲宜，尤其以錠劑爲最適合之經口投予製劑劑形，。 於該固形劑中之2—二苯甲氧基—N，N —二甲基乙胺 等之含有比率，依固形劑之劑形而異，不能一言蔽之，大 約爲0.1至100質量％之範圍，例如錠劑爲2至50質量％左 右。 另一方面，上述固形劑係以含有遮光性物質之水溶性 高分子物質皮膜所被覆，因此，所使用之水溶性高分子物 質，可使用酸性至中性之水系環境下溶解之皮膜形成物質 (水溶性皮膜物質）。如此之水溶性高分子物質之具體例 -9- (5) (5)200304807 ，可舉例如羥丙基甲基纖維素、羥丙基纖維素、甲基纖維 素、聚乙烯吡咯烷、聚乙二醇（macrogol )及明膠等之水 溶性高分子以及胺基烷基甲基丙烯酸酯共聚物E及聚乙烯 二甲醛二乙基胺基乙酸等之酸可溶性高分子。這些可爲i 種或混合2種以上使用。 適合該水溶性高分子物質之具體例，可舉例如羥丙基 甲基纖維素及聚乙二醇，尤其適合之具體例，可舉例如羥 丙基甲基纖維素2910及macrogol6000之混合物。混合羥丙 基甲基纖維素2910及macrogol6000使用時，其配合比係以 重量比之50 ·· 50至95 : 5爲宜，進而以90 ·· 10至95 : 5尤佳 。另外，水溶性高分子物質之添加量，通常爲皮膜固形成 份總體之50至95質量％，以70至90質量％爲宜。 另外，配合於上述水溶性高分子物質之遮光性物質， 只要可遮住光進入固形劑，不會對水溶性高分子物質所形 成之皮膜之溶解性有大的影響之遮光性物質，使用時並無 特別的限制。如此遮光性物質之具體例，可舉例如，氧化 鈦、滑石、碳酸鈣、氧化鎂、陶土及三氧化二鐵等，這些 可爲1種或混合2種以上使用。 本發明之被覆固體所成催眠製劑中，特別適合使用之 遮光性物質，可舉例如氧化鈦及滑石之混合物。該氧化鈦 及滑石之混合比係以重量比之2 : 8至8 : 2爲宜，以4 : 6至 6 : 4尤佳。 該遮光性物質之添加量係依皮膜厚度而不同，希望爲 皮膜固形成份總體之5至50質量％，尤其以10至30質量％ -10- (6) (6)200304807 爲宜。遮光性物質之添加量若爲5質量％以下時，大多不 足以防止變色，另外，配合量爲50質量％以上時，皮膜本 身強度降低。 上述之含有遮光性物質之水溶性高分子物質所形成之 皮膜之膜厚度，雖依固形劑之劑形而異，平均膜厚度約爲 20至500/zm，進而以平均膜厚度30至80// m爲宜。皮膜之 平均厚度爲20/zm以下時，不足以隱蔽苦味，並且，皮膜 厚度爲500 // m以上時，被覆固形製劑之崩壞變慢，另外 ，依服用條件，作爲催眠劑之發生效果並不足夠。另外， 水溶性高分子物質中，對於皮膜溶解性不造成大的影響之 範圍下，亦可配合可塑劑、凝集防止劑、著色劑、隱蔽劑 及滑澤劑等。 本發明之被覆固體所成催眠製劑之具體的製造例，可 舉例如下述之方法。亦即，因應需要，可於2 -二苯甲氧 基一 N，N -二甲基乙胺等，加入製劑添加物，此可依常 法處理而可調製。製造時所可使用之製劑添加物，何舉例 如賦形劑、結合劑、崩壞劑、滑澤劑、安定劑、界面活性 劑、溶解補助劑、還原劑、緩衝劑、吸著劑、流動化劑、 帶電防止劑、抗氧化劑、甘味劑、矯味劑、淸涼化劑、著 色劑、著香劑、香料及芳香劑等之一般固形製劑所可使用 之製劑添加物。 本發明之被覆固體所成催眠製劑之製造，例如固形劑 爲錠劑、顆粒劑、細粒劑、散劑、硬膠囊劑、軟膠囊劑或 九劑等時，首先，普遍係將2-二苯甲氧基一 N，N—二甲 -11 - (7〉 (7〉200304807 基乙胺等及製劑添加物調製成造粒末。關於該造粒粉末之 製造，可採用一般所利用之造粒法，例如使用含有水或有 機溶媒之溶液或分散液之噴霧造粒法、攪拌造粒法、流動 造粒法、轉動造粒法及流動造粒法等之濕式造粒法以及使 用粉粒狀結合劑之壓密造粒法等之乾式造粒法等。 其次，顆粒劑、細粒劑或散劑係例如於製造上述之造 粒粉末時，調整其粒徑，必要時可過濾分別而可製成。另 外，錠劑係可混合粉末劑、細粒劑、顆粒劑或九劑，以及 製劑添加物，壓縮成型而可調製。另外，膠囊劑係將粉末 劑、細粒劑、顆粒劑或小型錠劑等，以膠囊充塡機充塡成 膠囊而製造。 另外，關於上述錠劑之製造，例如可適宜地選擇使用 結晶纖維素、低取代度羥丙基纖維素、羥丙基甲基纖維素 、交叉錢甲基纖維素鈉（crosscarmellose sodium)、麥芽 糊精、乙基纖維素、乳糖、山梨糖醇、矽酸酐、矽酸鎂、 羥丙基纖維素、硬脂酸、油酸、流動石鱲、磷酸氫鈣、癸 二酸二丁酯、聚乙二醇、丙二醇、氧化鈦、玉米澱粉、澱 粉、α化殿粉、明膠、Popidon、Crosopopidon、甘油、聚 山梨酸酯80、精製水、檸檬酸、醋磺內酯鉀（acesulfame potassium )、阿斯巴甜（aspartame)、碳酸鈉、滑石、硬 脂酸鎂及硬脂酸鈣等之製劑添加物。 將上述所得之固形劑，以含有遮光性物質之水溶性高 分子物質（以下，稱爲「皮膜劑」）之皮膜被覆，可使用 已知之方法。例如，盆式被覆法、流動層被覆法、轉動被 -12- (8) (8)200304807 覆法及組合這些方法等。此被覆方法中，溶解/分散皮膜 劑於水或有機溶媒，可以被覆於固形劑上，或直接散佈於 固形劑上，或加熱或加壓等進行被覆。 具體的素錠被覆方法，可舉例如，將皮膜劑，以水、 乙醇、丙酮、二氯甲烷及異丙醇等適當的溶媒溶解/分散 成被覆液，將其以例如通氣乾燥被覆裝置或盆式被覆法等 ，於素錠上噴霧被覆方法。其中，以盆式被覆法被覆時， 將素錠放入被覆盆中，逐漸旋轉被覆盆，由噴霧槍之噴嘴 ，將薄膜形成性高分子化合物溶液，以適當的速度噴霧後 乾燥而可實施。 作用 如上述所得之本發明之被覆固體所成催眠製劑係以含 有遮光性物質之水溶性高分子物質皮膜被覆，所以無2 -二苯甲氧基一 Ν’ N—二甲基乙胺等之變色而且安定，並 且，服用時之苦味亦被隱蔽者。而且，被覆時所使用之水 溶性高分子物質皮膜係服用後迅速地開始溶解，所以2 -二苯曱氧基一 N，N-二甲基乙胺等之發生效果亦迅速。 【實施方式】 實施例 以下述之實施例，更具體地說明本發明，但本發明不 以這些實施例爲限。 實施例1 -13- 200304807 Ο) 被覆錠劑（1 ) z 將2500g之鹽酸2 —二苯甲氧基—N，N —二甲基乙胺 、67 00g之乳糖、2000g之玉米澱粉' l〇〇〇g之結晶纖維素 、250g之交叉羧甲基纖維素鈉及300g之聚乙烯吡咯烷， 以常法混合、造粒，而得打錠用顆粒。於1 249 5g之該打 錠用顆粒中，混合122.5g之滑石及122.5g之硬脂酸鎂後， 打錠而得48000錠之直徑爲9mm，厚度爲4.2mm之每錠重量 爲260mg之素錠。 € 其次，相對於該3000錠素錠，將10%之含有75g之羥 丙基甲基纖維素2910、5g之macrogol6000、llg之氧化鈦 及9g之滑石之水系被覆液，於Hicoater ( Freund產業）， 以噴霧被覆，使其於乾燥狀態爲5mg/錠，而得被覆錠劑（ 1 )。該被覆錠劑之皮膜厚度，以掃描式電子顯微鏡測定 結果爲41.3/zm(n=20之平均）。 實施例2 # 被覆錠劑（2 ): 相對於實施例1所製造之3000錠素錠，將與實施例1相 同組成之10%水系被覆液，於Hicoater ( Freund產業）， 以噴霧被覆，使其於乾燥狀態爲2.5mg/錠，而得被覆錠劑 (2 )。該被覆錠劑之皮膜厚度，以掃描式電子顯微鏡測 定結果爲22.1/zm(n=20之平均）。 實施例3 -14- (10) (10)200304807 被覆錠劑（3 ): 相對於實施例1所製造之3000錠素錠，將與實施例1相 同組成之10%水系被覆液，於Hie oat er ( Freund產業）， 以噴霧被覆，使其於乾燥狀態爲3.8mg/錠，而得被覆錠劑 (3 )。該被覆錠劑之皮膜厚度，以掃描式電子顯微鏡測 定結果爲32.8/zm(n=20之平均）。 實施例4 φ 被覆錠劑（4 ): 相對於實施例1所製造之3000錠素錠，將與實施例1相 同組成之10%水系被覆液，於Hicoater(Freund產業）， 以噴霧被覆，使其於乾燥狀態爲10mg/錠，而得被覆錠劑 (4 )。該被覆錠劑之皮膜厚度，以掃描式電子顯微鏡測 定結果爲78.6//111(11=20之平均）。 比較例1 _ 比較錠劑： 以實施例1所製造之素錠，直接作爲比較錠劑。 比較例2 比較被覆錠劑（1 ): 相對於實施例1所製造之3000錠素錠，將與實施例1相 同組成之10%水系被覆液，於Hicoater ( Freund產業）， 以噴霧被覆，使其於乾燥狀態爲2mg/錠，而得比較被覆錠 -15- (11) (11)200304807 劑（1 )。該比較被覆錠劑之皮膜厚度，以掃描式電子顯 微鏡測定結果爲1 6 · 5 // m ( η = 2 0之平均）。 比較例3 比較被覆錠劑（2 ): 相對於實施例1所製造之3000錠素錠，將8%之含有 75g之經丙基甲基纖維素2910及5g之macrogol6000之水系 被覆液，於Hicoater(Freund產業），以噴霧被覆，使其 於乾燥狀態爲5mg/錠，而得比較被覆錠劑（2 )。該比較 被覆錠劑之皮膜厚度，以掃描式電子顯微鏡測定結果爲 41.2// m(n=20 之平均）。 比較例4 比較被覆錠劑（3 ): 相對於實施例1所製造之3000錠素錠，將8.4%之含有 75g之經丙基甲基纖維素2910、5g之macrogol6000、2g之 氧化鈦及2g之滑石之水系被覆液，於Hicoatei* ( Fi^und產 業），以噴霧被覆，使其於乾燥狀態爲2.5mg/錠，而得比 較被覆錠劑（3 )。該比較被覆錠劑之皮膜厚度’以掃描 式電子顯微鏡測定結果爲20.6/z m ( n = 20之平均）。 比較例5 比較被覆錠劑（4 ): 相對於實施例1所製造之3000錠素錠，將8.8%之含有 -16- (12) (12)200304807 75g之經丙基甲基纖維素2910、5g之macrogol6000、3g之 氧化鈦及5g之滑石之水系被覆液，於Hieoater ( Freund產 業），以噴霧被覆，使其於乾燥狀態爲2.5mg/錠，而得比 較被覆錠劑（4 )。該比較被覆錠劑之皮膜厚度，以掃描 式電子顯微鏡測定結果爲20.8/z m ( n = 20之平均）。 實施例5 比較被覆錠劑（5 ): 相對於實施例1所製造之3000錠素錠，將9.1%之含有 75g之經丙基甲基纖維素2910、5g之macrogol6000、6g之 氧化駄及5g之滑石之水系被覆液，於Hicoater(Freund產 業），以噴霧被覆，使其於乾燥狀態爲5mg/錠，而得比較 被覆錠劑（5 )。該比較被覆錠劑之皮膜厚度，以掃描式 電子顯微鏡測定結果爲40.7 // m ( n= 20之平均）。 實施例6 比較被覆錠劑（6 )： 相對於實施例1所製造之3000錠素錠，將10%之含有 67g之經丙基甲基纖維素2910、4g之macrogol6000、15g 之氧化鈦及14g之滑石之水系被覆液，於 Hicoater ( Freund產業），以噴霧被覆，使其於乾燥狀態爲5mg/錠， 而得比較被覆錠劑（6 )。該比較被覆錠劑之皮膜厚度， 以掃描式電子顯微鏡測定結果爲4 1.5 /z m ( η = 20之平均） (13) (13)200304807 實施例7 比較被覆錠劑（7 ): 相對於實施例1所製造之3000錠素錠，將10%之含有 49g之羥丙基甲基纖維素2910、3g之macrogol6000、24g 之氧化鈦及24g之滑石之水系被覆液，於fjicoater( Freund產業），以噴霧被覆，使其於乾燥狀態爲5mg/錠， 而得被覆錠劑（7 )。該被覆錠劑之皮膜厚度，以掃描式 電子顯微鏡測定結果爲4 3 · 6以m ( η = 2 0之平均）。 試驗例1 對光安定性試驗： 如下所述，對於實驗例1至7以及比較例1至5所得之錠 劑，進行對光安定性試驗。亦即，將各試驗錠劑於25 t之 條件下，進行每日8小時之1000勒克斯（lux)之光照射。 經30日光照射後，將各試驗錠劑之外觀與製造後當時之外 觀相比較，調查其光安定性。其結果如表1所示。 (14) 200304807 [表1] 製劑 外觀變化* 實施例1 無變化 實施例2 無變化 實施例3 無變化 實施例4 無變化 實施例5 無變化 實施例6 無變化 實施例7 無變化 比較例1 變黃 比較例2 幾乎無變黃 比較例3 變黃 比較例4 略變黃 比較例5 略變黃 *外觀變化係表示與製造後當時之外觀差異 如表1之結果顯示’本發明之製劑係與未進行被覆之 素錠（比較例1 )或未配合遮光性物質之被覆錠劑（比較 例3 )相比較，對於光曝露下，具有優異的安定性。 試驗例2 味覺試驗： 如下所述，對於實驗例1至7以及比較例1至5所得之錠 劑，調查其隱蔽效果。亦即，關於各試驗劑，分別含1錠 -19- (15) (15)200304807 於口中，保持1 0秒鐘不嚼碎後呑下。對於此時味道之隱蔽 效果，以1 0名健康成人，實施苦味之評價試驗。10人之平 均結果如表1所示。另外，評價基準如下所述。 評價基準： 評價點 內容 0 不感到苦味 1 只感到些許苦味 Φ 2 苦味200304807 (1) 发明. Description of the invention [Technical field to which the invention belongs] The present invention relates to hypnotic preparations made of coated solids, and more specifically, it contains 2-diphenylmethoxy-N, N-dimethylethyl Amine or its acid addition salt is used as a medicinal ingredient for hypnotic and sedative effects. It does not change color and is stable. It can hide the bitter taste when taken, and the effect occurs quickly and reliably. [Prior art] In the past, 2-diphenylmethoxy-N, N-dimethylethylamine or its acid addition salt system has antihistamine effect and central effect, and is used as rhinitis, skin disease, cold medicine or cough. The effective ingredients of expectorants are used, but the side effects of drowsiness are its disadvantages. For example, it is known that 2-diphenylmethoxy-N, N-dimethylethylamine hydrochloride or 2-diphenylmethoxy-N, N-dimethylethylamine based on citrate has about Same hypnotic effect. Secondly, because it disappears quickly from the blood and has no habit, it is used as a general-purpose medicine in Europe, America or Japan without the need for a prescription hypnotic. The dosage for adults is 50 mg. However, due to the calming effect of 2-diphenylmethoxy-N, N-dimethylethylamine hydrochloride, the concentration in the plasma that causes drowsiness is more than 50ng / ml, which is higher than that in the plasma that produces antihistamine action. high. In addition, the time-averaged change in the plasma concentration of 2-diphenylmethoxy-N, N-dimethylethylamine hydrochloride when administered orally at 5 Omg was 2 to 4 hours after administration, only 50ng / ml is slightly higher (Carruthers et al .: Clin · Pharmacol. Ther. -6-(2) (2) 200304807: 23 (4): 375 to 3 82,1 978). Therefore, when used as a hypnotic agent for oral administration, the effect as a hypnotic agent cannot be sufficiently obtained when the preparation disintegrates or dissolves slowly depending on the conditions of administration. On the other hand, the taste of 2-diphenylmethoxy-N, N-dimethylethylamine has a strong irritating bitterness, and has the property of giving unpleasantness when taken. However, the methods used in the past to slow down dissolution and conceal the taste with a film or matrix containing oils or insoluble polymers may be inaccurate or inadequate as a hypnotic effect. In addition, 2-diphenylmethoxy-N, N-dimethylethylamine or an acid addition salt thereof is known to gradually decompose into benzophenone or benzhydrol due to light changes. And / S-dimethylaminoethanol. In order to prevent such discoloration by light, although it is possible to store it in a light-shielding box or a packaging container, it is difficult for patients to keep it in such a packaging container often. In addition, when taking or storing, there is a possibility that the preparation is exposed to light. Therefore, as a general-purpose pharmaceutical product, a preparation that can prevent discoloration from light is required. [Summary of the Invention] The problem to be solved by the invention therefore requires the provision of 2-diphenylmethoxy-N, N-dimethylethylamine or an acid addition salt thereof as a medicinal ingredient for sleep and tranquilization, and , It does not change color and stability, can hide the bitter taste when taken, and the effect occurs quickly and reliably. (3) (3) 200304807 Solution to the problem The inventors of the present invention, etc., made an effort to review the above-mentioned problems, and found that 2-diphenylmethoxy-N, N-dimethylethylamine or its acid was added. Salt formation is a solid agent with medicinal effects of sleep and tranquility. It is coated with a water-soluble polymer material film containing a light-shielding substance to form a coating solid that does not change color, conceals bitter taste, and has excellent reliability in the effect. Hypnotic formulations complete the present invention. That is, the present invention provides a solid agent containing 2--benzyloxy-N, N-dimethylethylamine or an acid addition salt thereof as a medicinal ingredient having sleep and tranquilizing effects, so as to contain light Hypnotic agents made of coated solids, which are characterized by the coating of sexual substances and water-soluble polymer substances. Implementation mode of the invention The hypnotic preparation made of the coated solid of the present invention is a solid agent containing 2-diphenoxy-N, N-dimethylethylamine or an acid addition salt thereof, and a light-shielding substance Covered with water-soluble polymer material film. In the present invention, as a medicinal ingredient having sleep and calming effects, the 2-diphenoxy-N, N-dimethylethylamine used may be in a base state, and it may also be an acid addition Salt state. However, the salt-based state is liquid, and powders such as light silicic anhydride must be used to maintain the granularity of the salt-based powder. Therefore, it is advisable to use acid addition salts when manufacturing solids. Such a 2-diphenylmethoxy-N, N-dimethylethylamino acid addition salt may be, for example, 2-diphenylmethoxy-N, N-dimethylethylamine, salicylic acid 2 -8- (4) (4) 200304807 —diphenylmethoxy-N, N-dimethylethylamine, citric acid 2-diphenylmethoxy—N 'N-dimethylethylamine, Tannin 2-diphenylmethoxy-n, N-dimethylethylamino acid, lauryl sulfate 2-diphenylmethoxy-n, N-dimethylethylamino acid and 2-dibenzoyl sulfate Oxy-N, N-dimethylethylamino acid, most suitable acid addition salts, such as 2-diphenylmethoxy-n, N-dimethylethylamino acid and 2-dibenzoyl citrate Oxy-N, N-dimethylethylamine. Contains 2-diphenylmethoxy-N, N-dimethylethylamine or an acid addition salt thereof (hereinafter, referred to as "2-diphenylmethoxy-N, N-dimethylethylamine, etc." Examples of the solid dosage forms include tablets, granules, fine granules, powders, hard capsules, soft capsules, or nine capsules. Alternatively, depending on the case, the original powder of 2-diphenylmethoxy-N, N-dimethylacetic acid addition salt may be directly used. Although the particle diameter of the solid agent is not particularly limited, its average particle diameter is generally 50 / zm to 50 mm, preferably 0.5 to 30 mm, and more preferably 2 to 30 mm. In addition, as a solid agent, a fast-dissolving oral preparation is suitable, and in particular, a lozenge is the most suitable oral preparation. The content ratio of 2-diphenylmethoxy-N, N-dimethylethylamine in the solid agent depends on the dosage form of the solid agent, and cannot be covered in a word, it is about 0.1 to 100% by mass The range is, for example, about 2 to 50% by mass. On the other hand, the above-mentioned solid agent is covered with a film of a water-soluble polymer material containing a light-shielding substance. Therefore, the water-soluble polymer material used can be a film-forming substance dissolved in an acidic to neutral aqueous environment ( Water-soluble film material). Specific examples of such water-soluble polymer materials-9- (5) (5) 200304807, for example, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidine, polyethylene Water-soluble polymers such as glycols and gelatin, and acid-soluble polymers such as amino alkyl methacrylate copolymer E and polyethylene diformaldehyde diethylaminoacetic acid. These can be used in i type or in mixture of 2 or more types. Specific examples suitable for the water-soluble polymer material include hydroxypropyl methyl cellulose and polyethylene glycol, and particularly suitable examples include a mixture of hydroxypropyl methyl cellulose 2910 and macrogol 6000. When mixed with hydroxypropyl methylcellulose 2910 and macrogol 6000, the mixing ratio is preferably 50.50 to 95: 5 by weight ratio, and more preferably 90.10 to 95: 5. In addition, the amount of the water-soluble polymer substance added is generally 50 to 95% by mass, and preferably 70 to 90% by mass of the solid film solids. In addition, the light-shielding substance blended with the above water-soluble polymer substance is a light-shielding substance that does not greatly affect the solubility of the film formed by the water-soluble polymer substance as long as it can shield light from entering the solid agent. There are no special restrictions. Specific examples of such a light-shielding substance include titanium oxide, talc, calcium carbonate, magnesium oxide, clay, and ferric oxide. These may be used alone or in combination of two or more. Among the hypnotic preparations made of the coated solid of the present invention, particularly suitable light-shielding substances include a mixture of titanium oxide and talc. The mixing ratio of the titanium oxide and talc is preferably 2: 8 to 8: 2 by weight ratio, and more preferably 4: 6 to 6: 4. The amount of the light-shielding substance to be added varies depending on the thickness of the film, and it is desirable that it is 5 to 50% by mass of the entire film solid content, and particularly preferably 10 to 30% by mass -10- (6) (6) 200304807. When the amount of the light-shielding substance added is 5% by mass or less, the discoloration is often insufficient to prevent discoloration. When the amount of the light-shielding substance is 50% by mass or more, the strength of the film itself decreases. Although the film thickness of the film formed by the above-mentioned water-soluble polymer material containing light-shielding substance varies depending on the dosage form of the solid agent, the average film thickness is about 20 to 500 / zm, and the average film thickness is 30 to 80 / / m is appropriate. When the average thickness of the film is less than 20 / zm, it is not enough to hide the bitter taste. When the thickness of the film is 500 // m or more, the collapse of the coated solid preparation becomes slow. In addition, depending on the conditions of use, the effect of the hypnotic agent and insufficient. In addition, a plasticizer, an agglutination preventive agent, a coloring agent, a concealing agent, a slip agent, and the like may be blended in a range in which the solubility of the film is not greatly affected by the water-soluble polymer substance. Specific production examples of the hypnotic preparation of the coated solid of the present invention include, for example, the following methods. That is, according to need, formulation additives can be added to 2-diphenylmethoxy-N, N-dimethylethylamine, etc., which can be prepared by a conventional method. Preparation additives that can be used at the time of manufacture, such as excipients, binding agents, disintegrating agents, slip agents, stabilizers, surfactants, dissolution aids, reducing agents, buffering agents, sorbents, flow Chemical additives, antistatic agents, antioxidants, sweeteners, flavoring agents, depressants, colorants, perfumes, perfumes and fragrances, and other solid additives that can be used in general solid preparations. For the manufacture of hypnotic preparations made of the coated solid of the present invention, for example, when the solid preparation is a tablet, granule, fine granule, powder, hard capsule, soft capsule or nine, etc., first, 2-dibenzene is generally used. Methoxy-N, N-dimethyl-11-(7> (7> 200304807) and preparation additives are prepared into granulation powder. For the production of the granulated powder, granulation generally used can be used. Methods such as spray granulation using a solution or dispersion containing water or an organic solvent, agitation granulation, flow granulation, rotary granulation, and flow granulation, and wet granulation Dry granulation method, such as compacting granulation method of the binder, etc. Next, granules, fine granules, or powders are adjusted, for example, when producing the granulated powder described above, and may be filtered separately if necessary. In addition, lozenges can be prepared by mixing powders, fine granules, granules, or nine agents, as well as preparation additives, and compression molding. In addition, capsules are powders, fine granules, granules, or Small tablets, etc. are filled into capsules with a capsule filling machine In addition, as for the production of the tablet, for example, crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, crosscarmellose sodium, and the like can be appropriately selected and used. Maltodextrin, ethylcellulose, lactose, sorbitol, silicic anhydride, magnesium silicate, hydroxypropylcellulose, stearic acid, oleic acid, mobile stone, calcium hydrogen phosphate, dibutyl sebacate , Polyethylene glycol, propylene glycol, titanium oxide, corn starch, starch, alpha powder, gelatin, Popidon, Crosopopidon, glycerin, polysorbate 80, purified water, citric acid, acesulfame potassium , Aspartame, sodium carbonate, talc, magnesium stearate, calcium stearate, and other preparation additives. The solid agent obtained above is a water-soluble polymer material (hereinafter, Known as the "coating agent"), known methods can be used. For example, a basin coating method, a flow layer coating method, a rotating cover -12- (8) (8) 200304807 coating method, and a combination of these methods, etc. In the covering method, Dissolving / dispersing the coating agent in water or organic solvent can be coated on the solid agent, or directly spread on the solid agent, or heated or pressurized, etc. The specific method of coating the plain tablets can include, for example, the coating agent, The coating solution is dissolved / dispersed with a suitable solvent such as water, ethanol, acetone, dichloromethane, and isopropanol, and the coating method is spray-coated on a plain tablet using, for example, an aeration drying coating device or a basin coating method. Among them, When coating by the pot-type coating method, put the ingot into the coating bowl, gradually rotate the coating bowl, and spray the film-forming polymer compound solution from the nozzle of the spray gun at an appropriate speed and then dry it. The hypnotic preparation made of the coated solid of the present invention obtained as described above is coated with a water-soluble polymer material film containing a light-shielding substance, so there is no discoloration of 2-diphenylmethoxy-N'N-dimethylethylamine and the like. It is stable, and the bitterness when taken is hidden. In addition, the water-soluble polymer material film used in the coating process starts to dissolve quickly after taking it, so the effect of 2-diphenylfluorenyloxy-N, N-dimethylethylamine is also rapid. [Embodiments] Examples The present invention will be described more specifically with the following examples, but the present invention is not limited to these examples. Example 1 -13- 200304807 0) Coated tablets (1) z 2500 g of 2-diphenoxy-N, N-dimethylethylamine hydrochloride, 67 00 g of lactose, 2000 g of corn starch 'l〇 OOg of crystalline cellulose, 250g of sodium carboxymethylcellulose and 300g of polyvinylpyrrolidine were mixed and granulated in a conventional manner to obtain pellets for tabletting. In 1 249 5 g of the ingot granules, 122.5 g of talc and 122.5 g of magnesium stearate were mixed, and ingots were obtained to obtain 48,000 ingots having a diameter of 9 mm and a thickness of 4.2 mm. ingot. € Next, with respect to the 3000 tablet tablets, 10% of an aqueous coating solution containing 75g of hydroxypropyl methylcellulose 2910, 5g of macrogol6000, 11g of titanium oxide, and 9g of talc was applied to Hicoater (Freund Industry) It was spray-coated so that it was 5 mg / ingot in a dry state to obtain a coated tablet (1). The film thickness of the coated tablet was 41.3 / zm (average of n = 20) as measured by a scanning electron microscope. Example 2 # Coated tablets (2): Compared with the 3,000 tablet tablets manufactured in Example 1, a 10% water-based coating solution having the same composition as in Example 1 was spray-coated on a Hicoater (Freund Industry) to make It was 2.5 mg / tablet in a dry state to obtain a coated tablet (2). The film thickness of the coated tablet was measured by a scanning electron microscope to be 22.1 / zm (n = 20 average). Example 3 -14- (10) (10) 200304807 Covered tablet (3): Relative to the 3,000 tablet tablets manufactured in Example 1, a 10% aqueous coating solution with the same composition as in Example 1 will be used in Hie oat er (Freund Industries), and spray-coated it to a dry state of 3.8 mg / tablet to obtain a coated tablet (3). The film thickness of this coated tablet was measured by a scanning electron microscope to be 32.8 / zm (average of n = 20). Example 4 φ coated tablet (4): Compared with the 3,000 tablet tablets manufactured in Example 1, a 10% aqueous coating solution with the same composition as in Example 1 was spray-coated on a Hicoater (Freund Industry) to make It was 10 mg / tablet in a dry state to obtain a coated tablet (4). The film thickness of this coated tablet was measured by a scanning electron microscope to be 78.6 // 111 (average of 11 = 20). Comparative Example 1_ Comparative Lozenges: The plain lozenges produced in Example 1 were directly used as comparative lozenges. Comparative Example 2 Comparative coated tablet (1): Compared to the 3,000 tablet tablets manufactured in Example 1, a 10% aqueous coating solution having the same composition as in Example 1 was spray-coated on a Hicoater (Freund Industry), so that In the dry state, it is 2 mg / ingot, so that the coated tablets-15- (11) (11) 200304807 (1) are obtained. The film thickness of this comparative coated tablet was measured by a scanning electron microscope to be 16 · 5 // m (average of η = 20). Comparative Example 3 Comparative coated tablets (2): Compared to the 3,000 tablet tablets manufactured in Example 1, 8% of an aqueous coating solution containing 75 g of propyl methyl cellulose 2910 and 5 g of macrogol 6000 was applied to a Hicoater. (Freund Industries), spray-coated to make it 5 mg / tablet in a dry state to obtain a comparative coated tablet (2). The film thickness of the comparative coated tablets was measured by scanning electron microscope to be 41.2 / m (average of n = 20). Comparative Example 4 Comparative coated tablets (3): 8.4% of 75 g of propyl methyl cellulose 2910, 5 g of macrogol 6000, 2 g of titanium oxide, and 2 g of the 3,000 tablet tablets of Example 1 were used. The water-based coating liquid of talc was spray-coated on Hicoatei * (Fi ^ und Industries) to make it dry at 2.5 mg / tablet to obtain a comparative coated tablet (3). The film thickness of this comparative coated tablet was measured by a scanning electron microscope and was 20.6 / z m (n = 20 average). Comparative Example 5 Comparative coated tablets (4): 8.8% of -16- (12) (12) 200304807 75g of propyl methylcellulose 2910, 5g of macrogol6000, 3g of titanium oxide, and 5g of talc were used as a water-based coating solution, and spray-coated it in a Hieoater (Freund Industry) to make it dry at 2.5 mg / tablet to obtain a comparative coated tablet (4). The film thickness of this comparative coated tablet was measured by a scanning electron microscope to be 20.8 / z m (n = 20 average). Example 5 Comparison of coated tablets (5): 9.1% of 75 g of propyl methyl cellulose 2910, 5 g of macrogol 6000, 6 g of dysprosium oxide, and 5 g of 3,000 lozenge tablets manufactured in Example 1 The water-based coating liquid of talc was spray-coated on a Hicoater (Freund Industry) to make it in a dry state of 5 mg / tablet to obtain a comparative coated tablet (5). The film thickness of this comparative coated tablet was measured by a scanning electron microscope to be 40.7 // m (average of n = 20). Example 6 Comparison of coated tablets (6): Compared to the 3000 tablet tablets manufactured in Example 1, 10% of 67 g of propyl methyl cellulose 2910, 4 g of macrogol 6000, 15 g of titanium oxide, and 14 g The water-based coating liquid of talc was spray-coated on Hicoater (Freund Industry) to make it dry at 5 mg / tablet to obtain a comparative coated tablet (6). The film thickness of the comparative coated tablet was 4 1.5 / zm (average of η = 20) as measured by a scanning electron microscope. (13) (13) 200304807 Example 7 Comparative coated tablet (7): Compared to the example 1 of the 3,000 tablet tablets produced, 10% of 49% of hydroxypropyl methylcellulose 2910, 3g of macrogol6000, 24g of titanium oxide and 24g of talc water-based coating liquid, in a fjicoater (Freund industry), to The coating was spray-coated so that it was 5 mg / tablet in a dry state to obtain a coated tablet (7). The film thickness of this coated tablet was 4 3 · 6 in m (average of η = 20) as measured by a scanning electron microscope. Test Example 1 Light Stability Test: As described below, the tablets obtained in Experimental Examples 1 to 7 and Comparative Examples 1 to 5 were subjected to a light stability test. That is, each test lozenge was irradiated with light of 1000 lux for 8 hours per day under the condition of 25 t. After 30 days of light irradiation, the appearance of each test tablet was compared with the appearance at that time after manufacture, and the light stability was investigated. The results are shown in Table 1. (14) 200304807 [Table 1] Preparation appearance change * Example 1 No change Example 2 No change Example 3 No change Example 4 No change Example 5 No change Example 6 No change Example 7 No change Comparative Example 1 Yellowing Comparative Example 2 Hardly Yellowing Comparative Example 3 Yellowing Comparative Example 4 Slightly Yellowing Comparative Example 5 Slightly Yellowing * Appearance change indicates the difference in appearance from that at the time of manufacture. The results in Table 1 show that the formulation of the present invention Compared with uncoated plain tablets (Comparative Example 1) or uncoated tablets (Comparative Example 3), it has superior stability to light exposure. Test Example 2 Taste test: As described below, the concealing effect of the tablets obtained in Experimental Examples 1 to 7 and Comparative Examples 1 to 5 was investigated. That is, each test agent contains 1 tablet -19- (15) (15) 200304807 in the mouth, and it is held down for 10 seconds without being chewed. For the concealing effect of taste at this time, an evaluation test of bitterness was carried out with 10 healthy adults. The average results of 10 people are shown in Table 1. The evaluation criteria are as follows. Evaluation criteria: Evaluation point Content 0 No bitterness 1 Only a little bitterness Φ 2 Bitterness
-20- (16) 200304807-20- (16) 200304807
-21 (17) 200304807 由此結果顯示，本發明製劑無苦味，即使有亦是非常 地弱，相對於此，可明白無皮膜之素錠（比較例1 )及皮 膜厚度爲20 // m以下之錠劑（比較例2 )，於服用時可強 烈地感到苦味。 試驗例3 崩壞試驗： 對於實驗例1至7所得之被覆錠劑，調查其崩壞性。崩 壞性試驗係依據第14改正日本藥局之崩壞試驗法’以崩壞 試驗機（富山產業（株）製，NT — 2HS，無盤），使用37 °C之水測定之。6個錠劑之崩壞時間範圍如表3所示。 [表3] 製劑 崩壞時間（分） 實施例1 3.8-4.8 實施例2 3.2 〜4.5 實施例3 3·5 〜4.5 實施例4 3.7 〜5.9 實施例5 3.4 〜4.6 實施例6 3.5 〜4.7 實施例7 3.5 〜4.8-21 (17) 200304807 This result shows that the preparation of the present invention has no bitterness, and is very weak even if there is. In contrast, it can be understood that the filmless tablet (Comparative Example 1) and the film thickness are 20 // m or less The lozenge (Comparative Example 2) had a strong bitter taste when taken. Test Example 3 Collapse test: The coated tablets obtained in Experimental Examples 1 to 7 were investigated for their disintegrability. The disintegration test was carried out in accordance with the 14th Correction of the Japan Pharmacopoeia's Disintegration Test Method 'using a disintegration tester (manufactured by Toyama Sangyo Co., Ltd., NT-2HS, diskless) using 37 ° C water. The breakdown time range of the 6 tablets is shown in Table 3. [Table 3] Preparation breakdown time (minutes) Example 1 3.8-4.8 Example 2 3.2 to 4.5 Example 3 3.5 to 4.5 Example 4 3.7 to 5.9 Example 5 3.4 to 4.6 Example 6 3.5 to 4.7 Implementation Example 7 3.5 to 4.8
由此結果顯示，即使爲水溶性高分子物質所被覆’本 發明製劑爲立即崩壞者。 -22- (18) (18)200304807 發明之功效 含有2 —二苯甲氧基一 N，N —二甲基乙胺等，作爲睡 眠、鎭靜作用之藥效成份之本發明之被覆固體所成催眠製 劑係以含有遮光性物質之水溶性高分子皮膜，賦予製劑本 身遮光性，不僅可防止對光之變色，亦可隱蔽服用時之苦 味，容易服用之催眠固體所成製劑。而且，此水溶性高分 子皮膜爲易溶解者，可安定作爲睡眠、鎭靜作用之藥效成 份之足夠量之2 -二苯甲氧基一 N，N —二甲基乙胺等，使 其放出於血中者。 因此，可將具有睡眠、鎭靜作用之2 -二苯甲氧基- N ，N -二甲基乙胺等爲作爲藥劑使用’可提供對於鎭靜不 眠症或緊張感、興奮感及易怒感等’緩和這些症狀所伴隨 之頭重及疲勞倦怠感以及解除不安感等之發生效果迅速而 且確實之被覆固體所成催眠製劑。 -23-This result shows that even if it is coated with a water-soluble polymer substance, the preparation of the present invention is immediately broken. -22- (18) (18) 200304807 Effect of the invention The coated solid body of the present invention containing 2-diphenylmethoxy-N, N-dimethylethylamine, etc. as a medicinal ingredient for sleep and tranquilization A hypnotic preparation is a water-soluble polymer film containing a light-shielding substance, which imparts light-shielding properties to the preparation, which can not only prevent discoloration to light, but also conceal the bitter taste during taking, and is easy to take. In addition, the water-soluble polymer film is easily soluble, and can be used as a sufficient amount of medicinal ingredients for sleep and tranquilization, such as 2-diphenylmethoxy-N, N-dimethylethylamine, etc. Those who shed their blood. Therefore, 2-diphenoxy-N, N-dimethylethylamine, etc., which have sleep and calming effects, can be used as a medicine. 'It can provide insomnia or tension, excitement, and irritability. "Sensing and so on" relieves the symptoms of heavy weight, fatigue, and anxiety, which are accompanied by these symptoms, and the effect of releasing anxiety is quickly and surely covered with solids. -twenty three-