[0019] 以下更具體說明實施本發明之形態。 [0020] 本發明所用之活性成分之以化學式（I）表示之（a）成分：4,5-環氧嗎啡喃衍生物可藉由例如日本專利公報第2525552號中記載之方法製造。 [0021] 作為（a）成分較佳者為17-（環丙基甲基）-3,14β-二羥基-4,5α-環氧基-6β-［N-甲基-反式-3-（3-呋喃基）丙烯醯胺］嗎啡喃鹽酸鹽（以下有時簡稱為「NAL-F」）、17-（環丙基甲基）-3,14β-二羥基-4,5α-環氧基-6β-［N-甲基-反式-3-（苯基）丙烯醯胺］嗎啡喃鹽酸鹽（以下有時簡稱為「NAL-P」）、及17-（環丙基甲基）-3,14β-二羥基-4,5α-環氧基-6β-［N-甲基-反式-3-（正丙基）丙烯醯胺］嗎啡喃鹽酸鹽，特佳為以化學式（V）表示之化合物（「NAL-F」）。[0022] 本發明之製劑中之藥效成分的（a）成分之摻合量係依據患者之疾病狀況或製劑劑型而定，只要為具有治療效果之量即可，例如可為0.01~10000mg/製劑之範圍，但通常較好為0.1~1000mg/製劑之範圍。更具體而言，含有NAL-F作為（a）成分之膠囊製劑時，為0.1~100μg/膠囊，較好為0.5~50μg/膠囊，更好為1.0~10μg/膠囊之摻合量，可考慮對應之病患疾病狀況及安全性而決定適當摻合量。附帶說明，目前市售之「REMITCH（註冊商標）膠囊2.5μg」製劑為2.5μg/膠囊之摻合量。 [0023] 本發明之（b）成分之聚乙二醇係作為（a）成分之4,5-環氧嗎啡喃衍生物的溶劑使用。亦可作為與水之混合溶劑使用。聚乙二醇之分子量只要於製劑化步驟中為液狀即可而無特別限定，通常為200~9000左右，較好為200~4000左右，例如可使用Macrogol 200或Macrogol 400等之市售品。聚乙二醇之使用量並未特別限制，可隨製劑種類等而變，但通常係考慮足以溶解NAL-F之量~足以使生育酚或作為增效劑之檸檬酸等之填充劑溶解、分散之量加以選擇，進而，考慮與製劑化步驟所要求之黏度等對應之稀釋必要量而選擇。例如膠囊製劑時，每1膠囊為30~99.99wt%，較好為35~90wt%。 [0024] 本發明之（c）成分之色素係發揮作為對於（a）成分之4,5-環氧嗎啡喃衍生物之光安定化劑之角色。作為此等色素，舉例為以化學式（II）表示之萘酚系偶氮色素，［式中，X表示取代之1-萘酚基，Y表示取代之苯基或取代之1-萘基］。作為較佳之萘酚系偶氮色素，舉例為紅色2號、紅色102號、紅色40號及黃色5號，較好之氧雜蒽色素舉例為紅色3號、紅色104號、紅色105號、紅色106號，但較佳為紅色102號。 [0025] 作為（c）成分之色素，除了前述萘酚系色素以外，舉例為藍色1號及銅葉綠素鈉。 該等色素可單獨作為（c）成分之色素使用，亦可將該等組合複數種而使用。 [0026] 色素之摻合部位可摻合於製劑之任一部位。例如可與活性主劑的4,5-環氧嗎啡喃衍生物混合而摻合，或於4,5-環氧嗎啡喃衍生物摻合部之外部皮膜中之摻合等而配合劑型選擇適當摻合部位。若考慮色素功能之耐光性提高，則摻合於製劑外表面部例如若為錠劑則為其外表面的包衣部分，或若為膠囊劑則摻合於其膠囊皮膜部分更為有效。 [0027] 本發明之較佳實施態樣較好製劑為膠囊製劑，（c）成分之色素位於皮膜，且色素為萘酚系偶氮色素之紅色102號、紅色2號、紅色40號或黃色5號。該等中，特佳為紅色102號。 [0028] 色素之摻合量並未特別限制，只要可有意義地確認其耐光性效果之量以上即可。其量雖亦依存於製劑種類，例如含於膠囊皮膜中時，通常為0.0001~0.5wt%，較好為0.01~0.4wt%，更好為0.02~ 0.3wt%。 [0029] 本發明之（d）成分的生育酚係作為4,5-環氧嗎啡喃衍生物之抗氧化劑發揮功能。作為生育酚，可使用α-生育酚、β-生育酚、γ-生育酚、δ-生育酚或該等之混合物之任一種。生育酚之摻合量並未特別限制，只要可確認其抗氧化效果優異之量以上即可。生育酚之摻合部位並未特別限制，可摻合於製劑塊中或皮膜中，但通常與4,5-環氧嗎啡喃衍生物混合於相同部位而摻合。例如膠囊製劑時係摻合於核液中。生育酚之摻合量只要為可有意義確認其抗氧化效果之量以上即可。其量亦依存於製劑種類，但於例如膠囊製劑時，生育酚之摻合量為核液之0.01~30.0wt%，較好為0.1~25.0wt%。 [0030] 進而，本發明較好進而摻合鈦氧化物，尤其較好摻合於製劑皮膜中。鈦氧化物之摻合係為了進行批示編號等雷射印字者。鈦氧化物之結晶形可選擇金紅石型、銳鈦礦型或非晶型之任一者，其粒徑基於分散性之觀點較好為微粒子形態。鈦氧化物之摻合量於例如含於膠囊皮膜中時，通常為0.0001~0.5wt%，較好為0.01~0.1wt%，較好為0.02~0.08wt%。 [0031] 本發明之製劑種類並未特別限制，但較好為包衣錠劑、硬膠囊劑、軟膠囊劑或無縫膠囊劑。該等製劑較佳的理由，係因為具有耐光功能之本發明色素藉由存在於該等製劑之錠劑包衣部分或膠囊皮膜部分，而可最良好地發揮其耐光性功能。 [0032] 本發明之實施態樣中，製劑表面部分經交聯處理或被覆處理。上述皮膜之交聯處理較好為包含蛋白質之皮膜之處理。例如可採用使用過去以來已知之交聯劑之利用化學反應之交聯或利用酵素反應之交聯。。 [0033] 此等之本發明之製劑形態可為包衣錠劑、硬膠囊劑、軟膠囊劑或無縫膠囊劑等。 [0034] 膠囊製劑時，作為用以形成膠囊皮膜之基劑，舉例為蛋白質與水溶性多元醇之混合物、蛋白質與水溶性多元醇及多糖類之混合物、或多糖類與水溶性多元醇之混合物等。作為上述蛋白質舉例為例如明膠、膠原等。作為水溶性多元醇舉例為山梨醇、甘露醇、甘油、丙二醇、聚乙二醇、葡萄糖、果糖、乳糖、阿拉伯糖、甘露糖、鼠李糖、麥芽糖、棉子糖、蔗糖、赤藓醇、麥芽醇、海藻糖、乳糖、木糖等。作為多糖類，舉例寒天、結蘭膠、黃原膠、刺槐豆膠、果膠、車前子膠、瓜爾膠、紅藻膠、阿拉伯半乳聚糖、阿拉伯木聚糖、褐藻酸鹽、卡拉膠、阿拉伯膠、糊精、改性糊精、澱粉、化工澱粉、普魯蘭、羧甲基纖維素鹽等。使用褐藻酸鹽、結蘭膠、果膠或卡拉膠時，亦可添加適當鹼金屬鹽、鹼土金屬鹽、銨鹽等。 [0035] 本發明中，尤其含有4,5-環氧嗎啡喃衍生物之無縫膠囊，基於減少抗氧化劑量之方面與有利於將複數種醫藥品一包化製劑之方面，而可較好使用。無縫膠囊之製造可以例如專利文獻2中記載之使用3重噴嘴之滴下法而調製。 [0036] 本發明之膠囊製劑中，使膠囊表面交聯，而降低該部分對水之溶解性。為了控制交聯程度，例如藉由縮短與交聯劑之反應時間，或於皮膜成分中添加糊精或澱粉，而可降低交聯程度。相反地，藉由增長與交聯劑之反應時間，或於皮膜成分中僅使用蛋白質或提高皮膜成分之蛋白質含量，可提高交聯程度。藉由調整交聯劑之pH及溫度，亦可調整交聯程度。 [0037] 上述無縫膠囊中亦較好含有遮光劑。該情況，可於上述皮膜及內容液之至少一者中含有遮光劑而調製無縫膠囊，或於進行被覆處理時含於該被覆膜中。作為遮光劑舉例為例如鈦氧化物、氧化鋅、三氧化二鐵、二氧化矽、碳酸鈣、滑石、雲母等，但較好為鈦氧化物。無縫膠囊中封入之填充液並未特別限制，舉例為親油性或親水性之液狀物、該等液狀液與於其中不溶之粉末之懸浮液、或該等液狀物之混合液。該等填充液可包含例如通常之功能性食品或功能性飲料中所含之各種親油性或親水性有效成分例如各種維他命、礦物質、香料、抽取物類等。作為親水性液狀物包含例如水（亦包含純化水、離子交換水等）、水溶性醇、多元醇（甘油、甘露醇、山梨醇等）及該等之混合物等。作為親油性液狀物舉例為例如甘油脂肪酸酯、蔗糖脂肪酸酯（例如異丁酸乙酸蔗糖（SAIB））、中鏈脂肪酸三甘油酯（MCT）、月桂酸、棕櫚酸、硬脂酸、肉豆蔻酸、油酸、山萮酸、植物油脂（椰子油、葵花子油、紅花油、胡麻油、菜籽油、葡萄籽油及該等之混合物等）及該等之混合物等。 [0038] 無縫膠囊之平均粒徑通常為0.3~10mm，尤其為了獲得本發明之較高效果，較好為0.5~8mm。 [0039] 如此獲得之本發明之製劑，藉由色素與生育酚之效果，而可在室溫且螢光燈下保持4,5-環氧嗎啡喃衍生物活性之狀態長期保存1年以上。 [0040] 本發明之軟膠囊製劑與上述無縫膠囊之情況同樣，將含有4,5-環氧嗎啡喃衍生物、作為抗氧化劑之生育酚、作為增效劑之檸檬酸等之聚乙二醇溶液作為內容液（核液）予以填充，並具有以皮膜薄片包圍其之構造。該內容液可與上述無縫膠囊之情況同樣調製。作為皮膜薄片之材料可採用與上述無縫膠囊之皮膜材料同樣之材料。於調製軟膠囊時，該材料可依據常用方法作成薄片，使用上述內容液，依據一般軟膠囊之製造方法而調製。例如可藉由專利文獻3中記載之方法調製，使用皮膜薄片與內容液藉由旋轉模嘴調製軟膠囊。 [0041] 進而，與無縫膠囊之情況同樣，可於上述皮膜薄片及內容液之至少一者中含有色素或氧化鈦等之耐光性提高劑而調製軟膠囊，或者於進行被覆處理時可含於該被覆膜中。作為氧化安定劑之生育酚，與無縫膠囊之情況同樣，通常與4,5-環氧嗎啡喃衍生物一起摻合於內容液中。 [0042] 軟膠囊之長徑通常為3~16mm，短徑通常為2~10mm，尤其為了獲得本發明之較高效果，較好長徑為5~7mm，短徑為2~3mm。 [0043] 如此獲得之軟膠囊可於室溫且螢光燈下保持4,5-環氧嗎啡喃衍生物之活性之狀態長期保存1年以上。 [0044] 本發明之硬膠囊製劑係藉由於預先成形所得之膠囊本體之主體部分中，填充含有4,5-環氧嗎啡喃衍生物、作為抗氧化劑之生育酚、作為增效劑之檸檬酸等之聚乙二醇溶液作為內容液（核液），對其蓋上膠囊本體之罩蓋並密封而製造。作為膠囊本體之基材係使用明膠、膠原、甲基纖維素、纖維素乙酸酯、纖維素乙酸酯丙酸酯、聚乙烯醇、聚乙烯醇-丙基酸甲酯等，但較好為明膠。含有內容液時，通常以使內容液不漏出之方式，以罩蓋密封本體部分後，進行封住。 [0045] 與無縫膠囊之情況同樣，較好進行膠囊本體之交聯處理及該膠囊之被覆處理中之至少一種處理，控制膠囊皮膜對水之崩壞速度。 [0046] 如此獲得之硬膠囊可於室溫且螢光燈下保持4,5-環氧嗎啡喃衍生物之活性之狀態長期保存1年以上。 [0047] 本發明之包衣錠劑之情況，錠劑本體可使4,5-環氧嗎啡喃衍生物、作為抗氧化劑之生育酚、作為增效劑之檸檬酸等溶解或分散於少量聚乙二醇中，並利用該領域所使用之錠劑之一般製造方法製造而得。作為錠劑用製劑添加劑可使用矽酸酐、合成矽酸鋁、乳糖、玉米澱粉、結晶纖維素等之賦形劑；阿拉伯膠、明膠、聚乙烯吡咯啶酮、羥丙基纖維素等之結合劑；硬脂酸鎂、滑石、矽酸酐等之滑澤劑；玉米澱粉、羧甲基纖維素鈣等之崩解劑等。 [0048] 例如藉由濕式法之一的擠出造粒法獲得細圓柱狀之成形體，將其切斷為適當長度而獲得顆粒。接著進行與無縫膠囊同樣之被覆處理。被覆部（包衣部）可使用與無縫膠囊之情況同樣的基材，與無縫膠囊之情況同樣，可於被覆部含有色素或氧化鈦等之耐光性提高劑。 [0049] 錠劑之直徑通常為3~8mm，厚度為1~10mm，尤其為了獲得本發明之較高效果，直徑較好為3~4mm，厚度為1~3mm。 [0050] 如此獲得之包衣錠劑可於室溫且螢光燈下保持4,5-環氧嗎啡喃衍生物之活性之狀態長期保存1年以上。 [0051] 上述製劑之4,5-環氧嗎啡喃衍生物之行為可藉化學評價。例如化學上，可進行藉高速液體層析等之評價。 ［實施例］ [0052] 藉由實施例更詳細說明本發明，但本發明不限定於以下實施例。又，實施例及比較例中之「wt%」為質量基準。 [0053] 作為活性藥劑（API）使用之4,5-環氧嗎啡喃衍生物係如以下所示，使用市售品及合成品。 17-（環丙基甲基）-3,14β-二羥基-4,5α-環氧基-6β-［N-甲基-反式-3-（3-呋喃基）丙烯醯胺］嗎啡喃鹽酸鹽（以下有時簡稱為「NAL-F」，市售品）及 17-（環丙基甲基）-3,14β-二羥基-4,5α-環氧基-6β-［N-甲基-反式-3-（苯基）丙烯醯胺］嗎啡喃鹽酸鹽（以下有時簡稱為「NAL-P」）。NAL-P係自納曲酮（Naltrexone）依據常用方法合成。具體而言係使納曲酮與苄基N-甲基胺（BzNMeH）與氰基硼氫化鈉（NaBH3
CN）反應後，進行脫苄基，獲得（2E）-N-［（5α,6β）-17-（環丙基甲基）-3,14-二羥基-4,5-環氧基嗎啡喃-6-基］-N-甲基胺（有時簡稱為「Nal-prec」），使Nal-prec與月桂醯氯在三乙胺存在下反應，獲得Nal-P鹼性體。將其與鹽酸反應獲得NAL-P。 [0054] 作為抗氧化劑使用之生育酚、二丁基羥基甲苯、作為耐光性提高劑使用之色素（紅色102號、紅色3號、紅色2號、紅色40號、藍色1號、紅色106號、黃色5號、銅葉綠素鈉）、作為膠囊材料使用之琥珀酸化明膠、甘油、聚乙二醇400、蔗糖脂肪酸酯、中鏈脂肪酸三甘油酯等係使用市售品。 [0055] ［實施例1-1］著色明膠膜用液之製造 於純化水65g中加入濃甘油6.993g及色素0.035g並攪拌溶解（含有氧化鈦時，加入氧化鈦微粉末0.035g）。進而，饋入琥珀酸化明膠27.972g，於60℃攪拌溶解，製造調製為固體成分濃度為35（w/w）%之各著色明膠膜用液。 [0056] ［實施例1-2］明膠膜之製造 於保溫於60℃之玻璃板上，將內面電暈處理PET（聚對苯二甲酸乙二酯）膜以內面朝上之方式鋪上，以不彎曲之方式張開。於PET膜上之端處配置預先溫至60℃之烘烤式塗敷器YBA-7型（YOSHIMITSU精機製），將塗敷器之刻度對準於「350μm」。將著色明膠膜用液適量垂落於PET膜上之塗敷器側附近，緩慢滑動塗敷器，將著色明膠膜用液展延於PET膜上。使經展延之著色明膠膜用液完全乾燥，製造各著色明膠膜。所得之著色明膠膜與PET膜一起切斷為適當大小，自PET膜剝離著色明膠膜，使用“DigimaticMicroMeter MDC-25MJ”（Mitsutoyo製）測定、確認膜厚，獲得膜厚120μm（採用範圍膜厚：116~124μm）之著色明膠皮膜。 [0057] ［實施例1-3］NAL-F溶液之製造 （1）於氮氣環境下，於Macrogol 400之98.64g中加入生育酚0.75g並攪拌混合，製造含生育酚之基劑溶液。 （2）於氮氣環境下，於純化水2.0g中加入NAL-F 0.00625g與檸檬酸酐0.6g並攪拌溶解，製造含NAL-F之水溶液。 （3）於氮氣環境下，於含生育酚之基劑溶液中加入NAL-F鹽酸鹽水溶液並攪拌溶解，製造NAL-F濃度調製為0.0061274（w/w）%之NAL-F溶液。 [0058] ［實施例1-4］光照射試驗用檢體之製造與光照射試驗及分析方法 （1）於大氣環境下，將NAL-F溶液1.2mL放入1.5mL之無色透明玻璃瓶中並拴緊，準備分注檢體。 （2）重疊2片著色明膠皮膜，使用熱密封機，將3邊於180℃熱密著1秒，製造著色明膠膜之袋。 （3）將分注檢體裝入著色明膠皮膜之袋中，將開放的1邊使用熱密封機於180℃熱密著1秒，製造光照射試驗用檢體。 （4）將光照射試驗用檢體放入光安定性試驗裝置LT-120（D3CJ）（NAGANO科學機械製作所製），以2500lx之白色光連續照射特定時間後取出。 （5）於大氣中，自分注檢體精確秤取NAL-F溶液約0.1g（相當於NAL-F約7μg）於離心管中，添加溶解磷酸緩衝液約2mL（磷酸三鈉12水合物（Na3
PO4
．12H2
O）2g及磷酸氫二鈉（Na2
HPO4
）3g溶解於水50mL者）。於該液中正確添加內標準溶液（0.04mol/L，2-［（2-環丙基苯氧基）甲基］-2-咪唑啉．HCl水溶液）2mL，進而添加二乙醚約15mL激烈振盪混合30分鐘。離心分離後，將上層約7mL取到另一試驗管，於該液中添加1.46mmol/L磷酸水溶液約1mL，激烈振盪混合10分鐘。離心分離後，水層以孔徑0.45μm之膜過濾器過濾，作為試料溶液。 （6）另外，針對NAL-F標準品（約7μg），進行與上述同樣處理，作為標準溶液。 （7）使試料溶液與標準溶液50μL以下述條件藉由液體層析儀進行分析。 分析條件： HPLC：Shimadzu prominence-i LC-2030C 檢測器：紫外線吸收檢測器（λ280nm）（Shimadzu SPD-M30A） 管柱：ODS（GL Science公司製Inertsil ODS-3） 管柱溫度：40℃ 移動相：1-辛烷磺酸鈉1g、14.6mmol/L磷酸600mL、乙腈300mL及甲醇100mL之混合液 流量：1mL/min （8）NAL-F濃度之計算 藉由求出NAL-F之波峰面積對於內標準物質之波峰面積之比QT
及QS
，依據下述，決定NAL-F濃度， ［數1］ 調合液中之NAL-F之量(μg/g)=NAL-F標準品之量(μg)×QT
/QS
…(1) （9）將光照射前之NAL-F濃度設為100之光照射後之NAL-F濃度表示為NAL-F「定量比（%）」或NAL-F「殘存率（%）」。 [0059] ［實驗例1］對NAL-F之安定性造成影響之色素之效果（氮氣環境下；未添加生育酚） 進行對氮氣環境下之NAL-F之安定性造成影響之色素種類（紅色3號、紅色102號色素及藍色1號色素）之效果比較（未添加生育酚）。該等色素分別於薄片中含有固體成分之0.1wt%，於核液中含有NAL-F。核液及皮膜之組成以及實驗條件示於表1。[0060] 分析光照射開始前、光照射開始後14小時及42小時之樣品，分析NAL-F殘存率。所得結果示於表2及圖1。[0061] 由表2及圖1，於未添加生育酚系，42小時光照射後，於完全遮光之核液顯示NAL-F殘存率為95.2%，於未添加色素系之NAL-F殘存率為71.8%，相對於此，添加紅色3號時殘存率為80.7%，添加紅色102號時殘存率為79.7%，添加藍色1號時殘存率為81.4%之結果，見到藉由遮光使NAL-F安定化，又，於皮膜中添加色素時雖亦見到安定化效果，但未見到該等三種顏色之差異所致之安定性差異。 [0062] ［實驗例2］對NAL-F之安定性造成影響之色素及生育酚之效果（大氣環境下） 檢討於對大氣環境下之NAL-F之安定性造成影響之色素（紅色102號）之效果及抗氧化劑之生育酚之效果，以及應用本發明之該等併用效果。色素含於膠囊皮膜中，生育酚與NAL-F一起含於核液中。核液及皮膜之組成以及實驗條件示於表3。[0063] 分析光照射開始前、光照射開始後14小時及42小時之樣品，分析NAL-F殘存率。所得結果示於表4及圖2。由表4及圖2之結果，若觀察42小時光照射後之NAL-F殘存率，則無色素、無生育酚之殘存率：72.2%，相對於此，於皮膜中添加色素見到效果（殘存率：80.2%），於核液中添加生育酚亦見到效果（殘存率：88.3%），應用本發明之色素與生育酚之併用系（實施例2）表現最大效果（殘存率：96.7%）。 [0064] ［實驗例3］對NAL-F之安定性造成影響之色素及生育酚之效果（大氣環境下） 比較檢討對於大氣環境下之NAL-F鹽酸鹽之安定性造成影響之皮膜中之紅色106號色素、黃色5號色素、紅色2號、紅色40號及紅色3號色素之效果。色素含量係皮膜固體成分中之0.4wt%。色素含於皮膜中，生育酚與NAL-F一起含於核液中。核液及皮膜之組成以及實驗條件示於表5。[0065] 分析光照射開始前、光照射開始後14小時及42小時之樣品，分析NAL-F殘存率。所得結果示於表6及圖3。[0066] 由表6及圖3之結果，與14小時光照射後、無添加色素系之NAL-F殘存率：94.3%相比，應用本發明之皮膜中添加紅色106號之殘存率：96.6%，添加黃色5號之殘存率：96.1%，添加紅色2號之殘存率：94.5%，添加紅色40號之殘存率：94.0%，添加紅色3號之殘存率：93.5%之結果，其中，於生育酚與紅色106號及黃色5號之併用效果確認顯著。 [0067] ［實驗例4］對NAL-F之安定性造成影響之色素、生育酚及氧化鈦之效果（大氣環境下） 檢討應用本發明之對於大氣環境下之NAL-F之安定性造成影響之皮膜中之藍色1號色及紅色102號色素之併用效果及銅葉綠素鈉使用之效果。皮膜中氧化鈦含有固體成分之0.2wt%，除此之外，含有上述各色素。核液中中，與NAL-F一起含有抗氧化劑之生育酚0.74wt%。核液及皮膜之組成以及實驗條件示於表7。[0068] 分析光照射開始前、光照射開始後4小時及17小時之樣品，分析NAL-F殘存率。所得結果示於表8及圖4。[0069] 由表8及圖4之結果，皮膜中，僅單獨紅色102號、及藍色1號與紅色102號色素之併用系中，17小時照射後之NAL-F維持初期濃度之95%以上之殘存率。色素中，紅色102號色素者比藍色1號見到更有助於安定化效果之傾向。無色素系（含生育酚與遮蔽劑之氧化鈦）與併用色素系相較，安定性低。 [0070] ［實驗例5］ 對於無縫膠囊中之NAL-F之安定性造成影響之色素與生育酚之效果（生育酚併用；大氣環境下） 使用同心三重噴嘴，自最外側之噴嘴噴出上述外被層之組成所成之III液，自最內側之噴嘴噴出上述核層所示組成所成之I液，自中間噴嘴噴出上述中間層所示組成所成之II，作成三層液滴，該三層液滴藉由使由菜籽油所成之硬化液接觸而使皮膜液硬化，而製作具有核層-保護層-皮膜層之構造之三層構造無縫膠囊。各層組成及實驗條件示於表9。[0071] 所得無縫膠囊放入光安定性試驗裝置LT-120（D3CJ）（NAGANO科學機械製作所製），連續照射2500lx之白色光特定時間後取出。分析光照射開始前、光照射開始後3.5小時及17.5小時之樣品，分析NAL-F殘存率。所得結果示於表10及圖5。[0072] 由表10及圖5之結果，藉由應用本發明之無縫膠囊中之色素（紅色102號）與生育酚之併用，與僅添加生育酚系之NAL-F殘存率（84.3%）相比，觀察到NAL-F之高殘存率（92.8%）。 [0073] ［實施例18］軟膠囊製劑之製造 除了將實施例1-1之著色明膠膜用液之濃甘油變更為38.961g，色素變更為0.195g，琥珀酸化明膠變更為155.844g以外，依據實施例1-2之膜製造方法，製造著色明膠膜。軟膠囊之內溶液使用實施例1-3之NAL-F溶液，將前述明膠膜送入一對旋轉圓筒型模具之間，以與其連動之泵將內容液噴出至明膠膜間，而進行膠囊之調製。如此，獲得長徑4mm、短徑3mm之軟膠囊。 [0074] ［實施例19］包衣錠劑之製造 將4,5-環氧嗎啡喃衍生物之一種的NAL-P 10mg、生育酚1200mg、檸檬酸酐960mg、乳糖250g、玉米澱粉45g及羧甲基纖維素鈣20g放入轉動造粒機，預熱混合，噴霧含有羥丙基纖維素1.7g之水溶液34g，獲得含NAL-P之造粒粉末。於其中添加羧甲基纖維素鈣100g及滑石40g並混合，藉由打錠機將該混合粉末打錠，獲得裸錠。於甲醇800g中溶解蟲膠40g及羥丙基甲基纖維素40g，將於水10g中溶解紅色102號色素0.2g者混合於所得溶液中，獲得被覆液。將該被覆液噴霧至上述裸錠，獲得被覆膜厚0.3mm之錠劑。 [0075] ［實施例20］硬膠囊劑之製造 將實施例19之含NAL-P及生育酚之造粒粉末分散於玉米澱粉300g中，獲得硬膠囊之內容物。作為硬膠囊之本體，使用市售之日本藥典5號之膠囊。依據常用方法將上述內容物填充於膠囊本體中，所得膠囊100g放入轉動造粒機中，以1：1甲醇-乙酸乙酯混合液400g中溶解蟲膠10g及蓖麻油1g之溶液中，添加混合於水10g中溶解紅色102號色素0.2g者，噴霧成為被覆膜厚0.3mm，獲得被覆硬膠囊100g。 ［產業上之可利用性］ [0076] 藉由本發明之摻合處方，可提高對於血液透析患者及慢性肝疾病病患之經口投予之搔癢症改善藥4,5-環氧嗎啡喃衍生物（尤其NAL-F）之保存安定性，而可改善該患者之治療效果。[0019] The embodiments for carrying out the present invention will be described in more detail below. [0020] The active ingredient used in the present invention, the component (a) represented by the chemical formula (I): 4,5-epoxymorphinan derivative can be produced by, for example, a method described in Japanese Patent Publication No. 2525552. [0021] The component (a) is preferably 17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamido] morphine hydrochloride (hereinafter sometimes referred to as "NAL-F"), 17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-ring Oxy-6-6- [N-methyl-trans-3- (phenyl) acrylamido] morphine hydrochloride (hereinafter sometimes referred to as "NAL-P"), and 17- (cyclopropylmethyl Group) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (n-propyl) acrylamide] morphinan hydrochloride, particularly preferably Compound represented by Chemical Formula (V) ("NAL-F"). [0022] The blending amount of the (a) component of the medicinal ingredient in the preparation of the present invention depends on the patient's disease state or the dosage form of the preparation, as long as the amount has a therapeutic effect, for example, it can be 0.01 to 10,000 mg / The range of the preparation is usually 0.1 to 1000 mg / formulation. More specifically, when the capsule preparation containing NAL-F as the component (a) is 0.1 to 100 μg / capsule, preferably 0.5 to 50 μg / capsule, and more preferably 1.0 to 10 μg / capsule, the blending amount can be considered. The appropriate blending amount is determined according to the patient's disease status and safety. Incidentally, the currently available “REMITCH (registered trademark) capsule 2.5 μg” formulation is 2.5 μg per capsule. [0023] The polyethylene glycol of the component (b) of the present invention is used as a solvent for the 4,5-epoxymorphinan derivative of the component (a). It can also be used as a mixed solvent with water. The molecular weight of polyethylene glycol is not particularly limited as long as it is liquid in the formulation step, and is usually about 200 to 9000, preferably about 200 to 4000. For example, commercially available products such as Macrogol 200 or Macrogol 400 can be used. . The amount of polyethylene glycol used is not particularly limited and may vary depending on the type of preparation, etc., but is usually considered in an amount sufficient to dissolve NAL-F ~ enough to dissolve fillers such as tocopherol or citric acid as a synergist, The amount of dispersion is selected, and further, it is selected in consideration of the necessary dilution amount corresponding to the viscosity required in the formulation step. For example, in the case of a capsule preparation, it is 30 to 99.99 wt%, preferably 35 to 90 wt% per capsule. [0024] The pigment of the component (c) of the present invention functions as a light stabilizer for the 4,5-epoxymorphinan derivative of the component (a). As these pigments, a naphthol-based azo pigment represented by the chemical formula (II) is exemplified, [In the formula, X represents a substituted 1-naphthol group, and Y represents a substituted phenyl group or a substituted 1-naphthyl group]. Examples of preferred naphthol-based azo pigments include Red No. 2, Red No. 102, Red No. 40, and Yellow No. 5. Examples of preferred xanthracene pigments include Red No. 3, Red No. 104, Red No. 105, and Red. No. 106, but preferably No. 102 in red. [0025] In addition to the naphthol-based pigment, as the pigment of the component (c), Blue No. 1 and sodium copper chlorophyll are exemplified. These pigments may be used alone as a pigment of the component (c), or a plurality of these pigments may be used in combination. [0026] The blending site of the pigment may be blended in any part of the preparation. For example, it can be mixed with the 4,5-epoxymorphinan derivative of the active main agent and blended, or blended in the outer film of the 4,5-epoxymorphinan derivative blending part, etc., and the formulation formulation can be selected appropriately. Blending site. Considering the improvement of the light resistance of the pigment function, it is more effective to blend it on the outer surface portion of the formulation, for example, if it is a tablet, to coat the outer surface portion, or if it is a capsule, to blend it on the capsule film portion. [0027] A preferred embodiment of the present invention is a capsule preparation. The pigment of component (c) is located in the film, and the pigment is red 102, red 2, 40 or yellow of naphthol azo pigment. Number 5. Of these, the best is red 102. [0028] The amount of the pigment to be blended is not particularly limited, as long as the amount of the light resistance effect can be meaningfully confirmed or more. Although its amount also depends on the type of preparation, for example, when contained in a capsule film, it is usually 0.0001 to 0.5 wt%, preferably 0.01 to 0.4 wt%, and more preferably 0.02 to 0.3 wt%. [0029] The tocopherol component of the component (d) of the present invention functions as an antioxidant of a 4,5-epoxymorphinan derivative. As the tocopherol, any of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, or a mixture thereof can be used. The blending amount of tocopherol is not particularly limited, as long as it can be confirmed that the amount of the tocopherol is superior to that of the antioxidant. The blending site of the tocopherol is not particularly limited, and it can be blended into the formulation block or film, but it is usually blended with 4,5-epoxymorphinan derivatives at the same site and blended. For example, capsule formulations are incorporated in the nuclear fluid. The blending amount of tocopherol may be at least an amount that can significantly confirm its antioxidant effect. The amount also depends on the type of preparation, but in the case of capsule preparations, the blending amount of tocopherol is 0.01 to 30.0 wt%, preferably 0.1 to 25.0 wt% of the nuclear fluid. [0030] Furthermore, the present invention preferably further incorporates titanium oxide, and particularly preferably incorporates it into a formulation film. Titanium oxide is blended for laser marking such as batch numbering. The crystal form of the titanium oxide may be selected from any of a rutile type, an anatase type, and an amorphous type, and the particle size is preferably a fine particle form from the viewpoint of dispersibility. When the titanium oxide is contained in a capsule film, for example, it is usually 0.0001 to 0.5 wt%, preferably 0.01 to 0.1 wt%, and preferably 0.02 to 0.08 wt%. [0031] The kind of the preparation of the present invention is not particularly limited, but is preferably a coated tablet, a hard capsule, a soft capsule or a seamless capsule. The reason why these preparations are preferable is that the pigments of the present invention having light fastness function can best exhibit their light fastness function by being present in the tablet coating portion or capsule film portion of these preparations. [0032] In an embodiment of the present invention, the surface portion of the preparation is subjected to a crosslinking treatment or a coating treatment. The cross-linking treatment of the film is preferably a treatment of a film containing a protein. For example, cross-linking using a chemical reaction or cross-linking using an enzyme reaction using a cross-linking agent known in the past may be used. . [0033] These formulations of the present invention may be coated tablets, hard capsules, soft capsules or seamless capsules. [0034] In the case of a capsule preparation, as a base for forming a capsule film, for example, a mixture of protein and water-soluble polyol, a mixture of protein and water-soluble polyol and polysaccharide, or a mixture of polysaccharide and water-soluble polyol Wait. Examples of the protein include gelatin and collagen. Examples of water-soluble polyols include sorbitol, mannitol, glycerol, propylene glycol, polyethylene glycol, glucose, fructose, lactose, arabinose, mannose, rhamnose, maltose, raffinose, sucrose, erythritol, Maltitol, trehalose, lactose, xylose, etc. Examples of polysaccharides include cold days, gellan gum, xanthan gum, locust bean gum, pectin, psyllium gum, guar gum, red algae, arabinogalactan, arabinoxylan, alginate, Carrageenan, gum arabic, dextrin, modified dextrin, starch, chemical starch, pullulan, carboxymethyl cellulose salt, etc. When using alginate, gellan, pectin or carrageenan, appropriate alkali metal salts, alkaline earth metal salts, ammonium salts, etc. may also be added. [0035] In the present invention, especially seamless capsules containing 4,5-epoxymorphinan derivatives may be better based on the aspect of reducing the amount of antioxidants and the aspect of facilitating the packaging of a plurality of pharmaceutical products. use. The seamless capsule can be produced by, for example, a dripping method using a triple nozzle as described in Patent Document 2. [0036] In the capsule preparation of the present invention, the surface of the capsule is crosslinked, and the solubility of the part in water is reduced. In order to control the degree of crosslinking, for example, by shortening the reaction time with the crosslinking agent, or adding dextrin or starch to the film component, the degree of crosslinking can be reduced. Conversely, by increasing the reaction time with the cross-linking agent, or using only protein in the film component or increasing the protein content of the film component, the degree of crosslinking can be increased. The degree of crosslinking can also be adjusted by adjusting the pH and temperature of the crosslinking agent. [0037] The seamless capsule also preferably contains a sunscreen. In this case, a seamless capsule can be prepared by containing a light-shielding agent in at least one of the above-mentioned film and the content liquid, or it can be contained in the coating film when the coating process is performed. Examples of the light-shielding agent include titanium oxide, zinc oxide, ferric oxide, silicon dioxide, calcium carbonate, talc, mica, and the like, but titanium oxide is preferred. The filling liquid enclosed in the seamless capsule is not particularly limited, and examples thereof are lipophilic or hydrophilic liquids, suspensions of the liquids and insoluble powders therein, or mixed liquids of the liquids. These filling liquids may contain, for example, various lipophilic or hydrophilic active ingredients contained in general functional foods or functional beverages, such as various vitamins, minerals, spices, extracts, and the like. Examples of the hydrophilic liquid include water (including purified water, ion-exchanged water, etc.), water-soluble alcohols, polyhydric alcohols (glycerin, mannitol, sorbitol, etc.), and mixtures thereof. Examples of lipophilic liquids include glycerin fatty acid esters, sucrose fatty acid esters (such as sucrose isobutyrate (SAIB)), medium chain fatty acid triglycerides (MCT), lauric acid, palmitic acid, stearic acid, Myristic acid, oleic acid, behenic acid, vegetable oils (coconut oil, sunflower oil, safflower oil, flax oil, rapeseed oil, grape seed oil, and mixtures thereof) and mixtures thereof. [0038] The average particle diameter of the seamless capsule is usually 0.3 to 10 mm, and in particular to obtain the high effect of the present invention, it is preferably 0.5 to 8 mm. [0039] The preparation of the present invention thus obtained can retain the activity of 4,5-epoxymorphinan derivatives at room temperature and under fluorescent light for a long period of time for more than one year due to the effects of pigments and tocopherols. [0040] The soft capsule preparation of the present invention is the same as in the case of the above-mentioned seamless capsule, and polyethylene glycol containing 4,5-epoxymorphinan derivative, tocopherol as an antioxidant, and citric acid as a synergist, etc. The alcohol solution is filled as a content liquid (nuclear fluid), and has a structure in which it is surrounded by a film sheet. This content liquid can be prepared in the same manner as in the case of the aforementioned seamless capsule. As the material of the film sheet, the same material as the film material of the seamless capsule can be used. When preparing soft capsules, the material can be made into flakes according to common methods, using the above content liquid, and prepared according to the general soft capsule manufacturing method. For example, it can be prepared by a method described in Patent Document 3, and a soft capsule can be prepared by using a film sheet and a content liquid by rotating a die. [0041] Furthermore, as in the case of a seamless capsule, a soft capsule may be prepared by containing a light resistance improving agent such as a pigment or titanium oxide in at least one of the film sheet and the content liquid, or may be contained in a coating treatment. In the coating film. Tocopherol, which is an oxidative stabilizer, is usually blended with the 4,5-epoxymorphinan derivative in the content liquid as in the case of seamless capsules. [0042] The long diameter of the soft capsule is usually 3 to 16 mm, and the short diameter is usually 2 to 10 mm. In particular, in order to obtain the high effect of the present invention, the long diameter is preferably 5 to 7 mm and the short diameter is 2 to 3 mm. [0043] The soft capsule thus obtained can be kept at room temperature and under fluorescent light for a long time of more than 1 year under the state of maintaining the activity of the 4,5-epoxymorphinan derivative. [0044] The hard capsule preparation of the present invention is obtained by pre-forming the main body of the capsule body, which is filled with a 4,5-epoxymorphinan derivative, tocopherol as an antioxidant, and citric acid as a synergist. The polyethylene glycol solution is prepared as an inner liquid (nuclear fluid), and the capsule body is covered with a cap and sealed. As the base material of the capsule body, gelatin, collagen, methyl cellulose, cellulose acetate, cellulose acetate propionate, polyvinyl alcohol, polyvinyl alcohol-propyl methyl ester, etc. are used, but it is preferable For gelatin. When the content liquid is contained, the main body portion is usually sealed with a cover so as to prevent the content liquid from leaking, and then sealed. [0045] As in the case of seamless capsules, it is preferred to perform at least one of a cross-linking treatment of the capsule body and a coating treatment of the capsule to control the rate of collapse of the capsule film against water. [0046] The hard capsule thus obtained can be kept in the state of maintaining the activity of the 4,5-epoxymorphinan derivative at room temperature under a fluorescent lamp for more than one year. [0047] In the case of the coated lozenge of the present invention, the lozenge body can dissolve or disperse 4,5-epoxymorphinan derivative, tocopherol as an antioxidant, citric acid as a synergist, etc. in a small amount of polymer. It is produced from ethylene glycol by the general manufacturing method of lozenges used in this field. As additives for lozenge formulations, excipients such as silicic anhydride, synthetic aluminum silicate, lactose, corn starch, crystalline cellulose, and the like; binding agents such as acacia, gelatin, polyvinylpyrrolidone, and hydroxypropyl cellulose can be used. ; Lubricants such as magnesium stearate, talc, silicic anhydride, etc .; disintegrants such as corn starch, calcium carboxymethyl cellulose, etc. [0048] For example, a thin cylindrical shaped body is obtained by an extrusion granulation method, which is one of the wet methods, and is cut to an appropriate length to obtain pellets. Then, the same coating treatment as that of the seamless capsule is performed. As the coating portion (coating portion), the same base material as in the case of the seamless capsule can be used. As in the case of the seamless capsule, a light resistance improving agent such as a pigment or titanium oxide can be contained in the coating portion. [0049] The diameter of the lozenge is usually 3 to 8 mm, and the thickness is 1 to 10 mm. In particular, in order to obtain the high effect of the present invention, the diameter is preferably 3 to 4 mm and the thickness is 1 to 3 mm. [0050] The thus-obtained coated lozenges can be kept at room temperature and under fluorescent light for 4,5-epoxymorphinan derivatives in an active state for more than one year. [0051] The behavior of the 4,5-epoxymorphinan derivative of the above formulation can be evaluated chemically. For example, chemical analysis can be performed by high-speed liquid chromatography. [Examples] The present invention will be described in more detail with examples, but the present invention is not limited to the following examples. In addition, "wt%" in an Example and a comparative example is a mass basis. [0053] As described below, a 4,5-epoxymorphinan derivative used as an active agent (API) is a commercially available product or a synthetic product. 17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamido] morphine Hydrochloride (hereinafter sometimes referred to as "NAL-F", a commercially available product) and 17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N- Methyl-trans-3- (phenyl) acrylamido] morphine hydrochloride (hereinafter sometimes referred to as "NAL-P"). NAL-P is synthesized from naltrexone according to common methods. Specifically, after reacting naltrexone with benzyl N-methylamine (BzNMeH) and sodium cyanoborohydride (NaBH 3 CN), debenzylation was performed to obtain (2E) -N-[(5α, 6β ) -17- (cyclopropylmethyl) -3,14-dihydroxy-4,5-epoxymorphinan-6-yl] -N-methylamine (sometimes referred to as "Nal-prec") The Nal-prec is reacted with lauryl chloride in the presence of triethylamine to obtain a Nal-P basic body. It was reacted with hydrochloric acid to obtain NAL-P. [0054] Tocopherols used as antioxidants, dibutyl hydroxytoluene, pigments used as lightfastness improvers (red 102, red 3, red 2, red 40, blue 1, red 106 , Yellow No. 5, sodium copper chlorophyll), succinic gelatin, glycerin, polyethylene glycol 400, sucrose fatty acid ester, medium chain fatty acid triglyceride, etc. used as capsule materials are commercially available products. [Example 1-1] Production of colored gelatin film solution To 65 g of purified water, 6.993 g of concentrated glycerin and 0.035 g of pigment were added and dissolved with stirring (when titanium oxide was contained, 0.035 g of titanium oxide fine powder was added). Further, 27.972 g of succinic gelatin was fed, and the solution was stirred and dissolved at 60 ° C. to prepare liquids for each colored gelatin film prepared at a solid content concentration of 35 (w / w)%. [Example 1-2] Production of gelatin film On a glass plate maintained at 60 ° C, the inner surface was corona-treated PET (polyethylene terephthalate) film with the inner surface facing upward. Open in a way that does not bend. At the end of the PET film, a baking type applicator YBA-7 (YOSHIMITSU precision mechanism) pre-heated to 60 ° C is arranged, and the scale of the applicator is aligned at "350 μm". An appropriate amount of the colored gelatin film liquid was dropped near the applicator side on the PET film, and the applicator was slowly slid to spread the colored gelatin film liquid on the PET film. The stretched colored gelatin film liquid was completely dried to produce each colored gelatin film. The obtained colored gelatin film was cut to an appropriate size together with the PET film, the colored gelatin film was peeled from the PET film, and the film thickness was measured and confirmed using "Digimatic MicroMeter MDC-25MJ" (manufactured by Mitsutoyo) to obtain a film thickness of 120 μm (in the range of film thickness: 116 ~ 124μm) colored gelatin film. [Example 1-3] Production of NAL-F solution (1) Under a nitrogen environment, 0.75 g of tocopherol was added to 98.64 g of Macrogol 400 and stirred to prepare a base solution containing tocopherol. (2) Under a nitrogen environment, add 2.0625 g of NAL-F and 0.6 g of citric anhydride to 2.0 g of purified water and stir to dissolve to produce an aqueous solution containing NAL-F. (3) Under a nitrogen environment, add a NAL-F hydrochloride aqueous solution to the base solution containing tocopherol and stir to dissolve it to produce a NAL-F solution with a NAL-F concentration adjusted to 0.0061274 (w / w)%. [Example 1-4] Production of specimen for light irradiation test and light irradiation test and analysis method (1) In an atmospheric environment, 1.2 mL of a NAL-F solution was placed in a 1.5 mL colorless transparent glass bottle And fastened, ready to dispense the specimen. (2) Two colored gelatin films were stacked, and three sides were heat-sealed at 180 ° C. for 1 second using a heat sealer to produce a bag of colored gelatin films. (3) Put the dispensed specimen into a colored gelatin film bag, and heat seal the open side with a heat sealer at 180 ° C. for 1 second to produce a specimen for light irradiation test. (4) The specimen for the light irradiation test was placed in a light stability test apparatus LT-120 (D3CJ) (manufactured by NAGANO Scientific Machinery Co., Ltd.), and 2500 lx of white light was continuously irradiated for a specific time and taken out. (5) In the atmosphere, accurately weigh about 0.1 g of NAL-F solution (equivalent to about 7 μg of NAL-F) from the dispensed sample into a centrifuge tube, and add about 2 mL of dissolved phosphate buffer solution (trisodium phosphate 12 hydrate ( 2 g of Na 3 PO 4 ( 12H 2 O) and 3 g of disodium hydrogen phosphate (Na 2 HPO 4 ) dissolved in 50 mL of water). To this solution, 2 mL of an internal standard solution (0.04 mol / L, 2-[(2-cyclopropylphenoxy) methyl] -2-imidazoline.HCl aqueous solution) was correctly added, and then about 15 mL of diethyl ether was added to shake vigorously. Mix for 30 minutes. After centrifugation, about 7 mL of the upper layer was taken into another test tube, and about 1. mL of a 1.46 mmol / L phosphoric acid aqueous solution was added to the solution, and vigorously mixed for 10 minutes. After centrifugation, the water layer was filtered with a membrane filter having a pore size of 0.45 μm as a sample solution. (6) A NAL-F standard product (approximately 7 μg) was treated in the same manner as described above as a standard solution. (7) 50 μL of the sample solution and the standard solution were analyzed by a liquid chromatograph under the following conditions. Analysis conditions: HPLC: Shimadzu prominence-i LC-2030C Detector: UV absorption detector (λ280nm) (Shimadzu SPD-M30A) Column: ODS (Inertsil ODS-3 manufactured by GL Science) Column temperature: 40 ° C Mobile phase : 1 g of sodium 1-octane sulfonate, 14.6 mmol / L of 600 mL phosphoric acid, 300 mL of acetonitrile and 100 mL of methanol. Flow rate: 1 mL / min. (8) Calculation of NAL-F concentration. The ratio of the peak areas Q T and Q S of the internal reference material determines the NAL-F concentration according to the following, [Number 1] The amount of NAL-F in the blending solution (μg / g) = the amount of NAL-F standard (μg) × Q T / Q S … (1) (9) Set the NAL-F concentration before light irradiation to 100. The NAL-F concentration after light irradiation is expressed as NAL-F "quantitative ratio (%)" or NAL-F "survival rate (%)". [Experimental Example 1] Effect of pigments that affect the stability of NAL-F (under nitrogen; no tocopherol added) Types of pigments that affect the stability of NAL-F under nitrogen (red No. 3, red No. 102 pigment and blue No. 1 pigment) were compared (without added tocopherol). These pigments contain 0.1% by weight of solids in flakes and NAL-F in nuclear fluid. The composition of the nuclear fluid and the membrane and the experimental conditions are shown in Table 1. [0060] Samples before the start of light irradiation, 14 hours and 42 hours after the start of light irradiation were analyzed, and the NAL-F residual rate was analyzed. The obtained results are shown in Table 2 and Fig. 1. [0061] From Table 2 and FIG. 1, after 42 hours of light irradiation without adding tocopherols, the NAL-F residual rate was 95.2% in completely blocked light nucleus, and the NAL-F residual rate without pigment It was 71.8%. In contrast, the residual rate was 80.7% when Red No. 3 was added, the residual rate was 79.7% when Red No. 102 was added, and the residual rate was 81.4% when Blue No. 1 was added. NAL-F is stable, and when pigments are added to the film, stabilization effects are also seen, but no stability difference due to the differences in these three colors is seen. [Experimental Example 2] Effects of pigments and tocopherols that affect the stability of NAL-F (under atmospheric conditions) Review of pigments that affect the stability of NAL-F under atmospheric conditions (red 102 ) And the tocopherol effect of antioxidants, and the combined effects of applying the present invention. The pigment is contained in the capsule film, and the tocopherol is contained in the nuclear fluid together with NAL-F. The composition of the nuclear fluid and the membrane and the experimental conditions are shown in Table 3. [0063] Samples before the start of light irradiation, 14 hours and 42 hours after the start of light irradiation were analyzed, and the NAL-F residual rate was analyzed. The obtained results are shown in Table 4 and FIG. 2. From the results in Table 4 and Figure 2, if the residual rate of NAL-F after 42 hours of light irradiation is observed, the residual rate of no pigment and no tocopherol: 72.2%. In contrast, the effect of adding pigment to the film is seen ( Residual rate: 80.2%). Addition of tocopherols to the nuclear fluid also showed effects (residual rate: 88.3%). The combination of the pigment and tocopherol of the present invention (Example 2) showed the largest effect (residual rate: 96.7). %). [Experimental Example 3] Effects of pigments and tocopherols that affect the stability of NAL-F (under atmospheric conditions) Comparative review of the effects on the stability of NAL-F hydrochloride under atmospheric conditions in films The effect of red 106 pigment, yellow pigment 5, red 2, 40 and red 3. The pigment content is 0.4% by weight of the solid content of the film. The pigment is contained in the membrane, and tocopherol is contained in the nuclear fluid together with NAL-F. The composition of the nuclear fluid and the membrane and the experimental conditions are shown in Table 5. [0065] Samples before the start of light irradiation, 14 hours and 42 hours after the start of light irradiation were analyzed, and the NAL-F residual rate was analyzed. The obtained results are shown in Table 6 and Fig. 3. [0066] From the results in Table 6 and FIG. 3, compared with the residual rate of NAL-F without added pigments after 14 hours of light irradiation: 94.3%, the residual rate of adding Red No. 106 to the film to which the present invention is applied: 96.6 %, Survival rate of adding yellow No. 5: 96.1%, Survival rate of adding red No. 2: 94.5%, Survival rate of adding red No. 40: 94.0%, Survival rate of adding red No. 3: 93.5%. Among them, The combined effect of tocopherol with red 106 and yellow 5 was confirmed to be significant. [Experimental Example 4] Effects of pigments, tocopherols, and titanium oxides that affect the stability of NAL-F (under atmospheric conditions) Review of the effects of applying the present invention on the stability of NAL-F under atmospheric conditions The combined effect of the blue No. 1 color and the red No. 102 pigment in the film and the effect of the use of sodium copper chlorophyll. The titanium oxide in the film contains 0.2% by weight of the solid content, in addition to the above-mentioned respective pigments. In the nuclear fluid, 0.74wt% of tocopherols containing antioxidants together with NAL-F. The composition of the nuclear fluid and the membrane and the experimental conditions are shown in Table 7. [0068] Samples before the start of light irradiation, 4 hours and 17 hours after the start of light irradiation were analyzed, and the NAL-F residual rate was analyzed. The obtained results are shown in Table 8 and Fig. 4. [0069] From the results in Table 8 and FIG. 4, in the coating, only the red 102 and the combination of blue 1 and red 102 pigments alone, the NAL-F maintained at 95% of the initial concentration after 17 hours of irradiation Survival rate above. Among the pigments, those with red 102 pigments tended to contribute more to the stabilization effect than those with blue 1. Non-pigmented system (titanium oxide containing tocopherol and masking agent) has lower stability than the combined pigment system. [Experimental Example 5] Effects of pigments and tocopherols that affect the stability of NAL-F in seamless capsules (combined use of tocopherols; under atmospheric environment) The concentric triple nozzle is used to spray the above from the outermost nozzle The III liquid formed by the composition of the outer layer sprays the I liquid formed by the composition shown in the above-mentioned core layer from the innermost nozzle, and the II liquid formed by the composition shown in the above-mentioned intermediate layer is sprayed from the middle nozzle to form three layers of liquid droplets. The three-layer liquid droplets harden the coating liquid by contacting a hardening liquid made of rapeseed oil to produce a three-layer structure seamless capsule having a structure of a core layer-a protective layer-a coating layer. The composition of each layer and the experimental conditions are shown in Table 9. [0071] The obtained seamless capsule was put into a light stability test device LT-120 (D3CJ) (manufactured by NAGANO Scientific Machinery Co., Ltd.), and was continuously irradiated with white light of 2,500 lx for a specific time and taken out. Samples before the start of light irradiation, 3.5 hours and 17.5 hours after the start of light irradiation were analyzed, and the NAL-F residual rate was analyzed. The obtained results are shown in Table 10 and FIG. 5. [0072] From the results of Table 10 and FIG. 5, by applying the pigment (Red 102) and tocopherol in the seamless capsule of the present invention, the residual rate of NAL-F (84.3%) ) In comparison, a high residual rate (92.8%) of NAL-F was observed. [Example 18] Manufacture of the soft capsule preparation except that the concentrated glycerol of the colored gelatin film solution of Example 1-1 was changed to 38.961 g, the pigment was changed to 0.195 g, and the succinic gelatin was changed to 155.844 g. The film manufacturing method of Example 1-2 produced a colored gelatin film. The inner solution of the soft capsule uses the NAL-F solution of Example 1-3, and the aforementioned gelatin film is sent between a pair of rotating cylindrical molds, and the content liquid is ejected between the gelatin films by a pump linked to the gelatin film to perform capsules. Of modulation. In this way, a soft capsule having a long diameter of 4 mm and a short diameter of 3 mm was obtained. [Example 19] Manufacture of coated lozenges NAL-P 10 mg of one of 4,5-epoxymorphinan derivatives, 1200 mg of tocopherol, 960 mg of citric anhydride, 250 g of lactose, 45 g of corn starch, and carboxymethyl 20g of basic cellulose calcium was put into a rotary granulator, preheated and mixed, and 34g of an aqueous solution containing 1.7g of hydroxypropyl cellulose was sprayed to obtain a granulated powder containing NAL-P. 100 g of carboxymethylcellulose calcium and 40 g of talc were added and mixed, and the mixed powder was tableted by a tableting machine to obtain a bare tablet. In 800 g of methanol, 40 g of shellac and 40 g of hydroxypropyl methylcellulose were dissolved, and 0.2 g of red No. 102 pigment was dissolved in 10 g of water, and the resulting solution was mixed to obtain a coating solution. This coating liquid was sprayed onto the bare ingot to obtain a tablet having a coating film thickness of 0.3 mm. [Example 20] Production of hard capsules The granulated powder containing NAL-P and tocopherol of Example 19 was dispersed in 300 g of corn starch to obtain the contents of the hard capsules. As the body of the hard capsule, a commercially available capsule of Japanese Pharmacopoeia No. 5 was used. The above contents were filled into the capsule body according to a common method. 100 g of the obtained capsules were placed in a rotary granulator, and 10 g of shellac and 1 g of castor oil were dissolved in 400 g of a 1: 1 methanol-ethyl acetate mixed solution and added. When mixed with 10 g of water to dissolve 0.2 g of the red No. 102 pigment, the thickness of the coating film was 0.3 mm, and 100 g of a coated hard capsule was obtained. [Industrial Applicability] [0076] By using the blended prescription of the present invention, it is possible to improve 4,5-epoxymorphinan-derived drug for pruritus, which is orally administered to hemodialysis patients and patients with chronic liver diseases. The stability of the substance (especially NAL-F) can improve the treatment effect of the patient.