201249802 六、發明說明： .【發明所屬之技術領域】 本發明屬化學製藥領域，具體涉及一種包含交聯聚乙 烯吡咯烷酮的托伐普坦固體分散體。 【先前技術】 托伐普坦（tolvaptan)血管加壓素受體拮抗劑，化學名 稱為7-氯-5-羥基-l-[2-甲基-4-(2-甲基苯甲醯胺基）苯甲 醯基]-2, 3, 4, 5-四氫吡喃-1H-苯並氮雜卓，結構式如下：201249802 VI. Description of the invention: [Technical field to which the invention pertains] The present invention belongs to the field of chemical pharmaceuticals, and in particular to a solid dispersion of tolvaptan containing crosslinked polyvinylpyrrolidone. [Prior Art] Tolvaptan vasopressin receptor antagonist, chemical name 7-chloro-5-hydroxy-l-[2-methyl-4-(2-methylbenzamide) Benzo) benzhydryl]-2, 3, 4, 5-tetrahydropyran-1H-benzazepine, the structural formula is as follows:
美國食品藥品管理局批准曰本大塚製藥公司生產的托 伐普坦（tolvaptan，血管加壓素V2受體括抗劑）.的新藥上 市申請，在心衰竭模型中，托伐普坦只表現出排水利尿作 用，顯著降低心臟前負荷，而對後負荷和腎功能無影響。 許多治療心衰和低鈉血症的臨床試驗，證明托伐普坦在容 量負荷過度的心衰竭患者，能有效減少液體滯留，並改善 低鈉。托伐普坦能有效緩解心功能衰竭患者的肺充血症狀 和體征，還能減輕體重，保護腎功能，沒有嚴重的不良反 應。已經證實托伐普坦相關化合物對治療以下疾病是有用 的：高容或等容性低鈉血症伴心力衰竭、肝硬化、抗利尿 3 95311 201249802 激素分泌異常综合症。 托伐普坦為白色晶體或結晶粉末，在水中幾乎不溶， 因而’當水不溶性的托伐普坦經口給藥時，它的生物利用 度不可避免地是低的。 為了克服此問題，日本專利公開號Jpn〇21241A公開 了種托伐曰坦固體製劑組合物的製備方法，該方法包括 以下步驟：將托伐普垣和經丙基纖維素按照一定比例溶解 於有機溶媒中，依照讀乾燥方法將 =固體分散體組合物，並添加其他藥用= 【發明内容】 本發明人出乎意料的發現，藉 聯^烯°比錢酮（即交聯聚_)的载體所二 坦固體分散體，表現出了比現有技術包含^的托伐曰 托伐普坦製劑更高的活料分的溶解性和ς纖維素的 方便製備0義㈣H步研究_ &，也更加 烤鱗_的频场加其他水溶 ^交聯聚乙 溶出效率進一步提高。 物了以使藥物的 現更高水溶:和提供—種比常規托伐普扭製劑表 其製備方法。則度的域普坦_#體，以及 本發明的另〜個目g s 伐普坦固體分散體的藥供一種經口給藥的，包含托 根據本發明的1組合物° 固方面，提供了一種包含有非晶型的 95311 4 201249802 活性成分托伐普坦或其鹽、交聯聚乙烯吡咯烷酮的固體分 散體。較好的實施方式是使活性成分托伐普坦或其鹽與交 聯聚乙烯吡咯烷酮的重量比控制在1 : 0. 05至20 ;較佳重 量比為1 : 0. 1至10，較佳是2 : 1。 本發明的固體分散體可以只由活性成分和交聯聚乙烯 吡咯烷酮組成。進一步的，本發明的固體分散體也可進一 步加入水溶性聚合物。本發明藉由加入一種或多種的水溶 性聚合物，以進一步改善固體分散體物理性質。該水溶性 聚合物為固體分散體中常用的水溶性聚合物，可以選自但 不限於下述聚合物： 烷基纖維素，例如曱基纖維素； 羥烷基纖維素，例如羥曱基纖維素、羥乙基纖維素、 羥丙基纖維素和羥丁基纖維素； 經烧基烧基纖維素，例如經乙基曱基纖維素和經丙基 曱基纖維素； 羧烷基纖維素，例如羧曱基纖維素； 羧烷基纖維素的鹼金屬，例如羧曱基纖維素鈉； 羧烷基烷基纖維素，例如羧甲基乙基纖維素； 羧烷基纖維素酯； 果膠，例如羧曱基支鏈澱粉鈉； 曱殼質衍生物，例如脫乙酞殼多糖； 多糖，例如藻酸、它的驗金屬和敍鹽、角叉菜膠 (caragenan)、半乳甘露聚糖、黃蓍膠、瓊脂、阿拉伯樹膠、 瓜耳膠和黃原酸膠； 5 95311 201249802 聚甲基丙烯酸及其鹽； 聚甲基丙烯酸及其鹽、曱基丙烯酸酯共聚物、胺烷基 甲基丙烯酸酯共聚物； 聚乙烯醇縮乙醛和二乙基胺基醋酸酯； 糖型表面活性劑，例如蔗糖二硬脂酸酯、蔗糖單/二 硬脂酸酯和蔗糖單棕擱酸酯； 聚乙烯醇； 聚乙烯吡咯烷酮和聚乙烯吡咯烷酮-醋酸乙烯酯共聚 物； 聚環氧院，例如聚環氧乙烧和聚環氧丙烧； 或環氧乙烷-環氧丙烷共聚物。 在以上提及的水溶性聚合物中，炫基纖維素、經院基 纖維素、羧烷基烷基纖維素或它們的鹼金屬鹽、聚乙烯吡 咯烷酮是較佳的，並且羥丙基甲基纖維素、聚乙烯吡咯烷 酮是更較佳的。其中較好的實施方式是將水溶性聚合物與 交聯聚乙烯吡咯烷酮的重量比在1 : 5至20，較佳1 : 8至 15，最較佳1 : 10。 藉由研究發現，由於水溶性聚合物能進一步改善固體 分散體的性質，因此其中進一步加入的水溶性聚合物的量 沒有特殊限定，本領域技術人員可以根據生產實際進行選 擇得到，實際研究中發現水溶性聚合物相對於交聯聚乙烯 吡咯烷酮的用量達到1 : 5至20時表現出的提高效果具有 資料上的統計意義，較佳1 : 8至15，最較佳1 : 10。 另外，在本發明的實施例中描述的組合物可以被參考 6 95311 201249802 為對本發明效果的較佳例證。本發明比較好的固體分散體 '實施方式是含有以下成分和比例的固體分散體： .組分 重量比 托伐普坦 2 交聯聚乙烯吡咯烷酮 1 水溶性聚合物 0.1 其中所述水溶性聚合物為聚乙烯吡咯烷酮、羥丙基纖 維素、羥乙基纖維素或甲基纖維素，效果最好的是聚乙烯 吡咯烷酮或羥丙基纖維素的實施方式。 對於含有水溶性聚合物的技術方案而言，固體分散體 可不再含有其他成分，即僅有活性成分、交聯聚乙烯°比咯 烧酮和水溶性聚合物組成。 在本發明的非晶形的托伐普坦固體分散體的製備中， 可單獨採用交聯聚乙烯吡咯烷酮，或水溶性聚合物與交聯 聚乙烯吼咯烷酮的組合作為載體。具體操作時，可按照以 下步驟進行操作： (1)將托伐普坦或其鹽溶解在有機溶劑中； (2 )對於不含水溶性聚合物的固體分散體來說，將交聯 聚乙烯吼咯烷酮溶解或分散在有機溶劑中； 對於含水溶性聚合物的固體分散體來說，可直接將交 聯聚乙烯吡咯烷酮和水溶性聚合物同時溶解或分散在有機 溶劑中形成一個溶液，也可分別將交聯聚乙稀p各烧酮和 水溶性聚合物溶解或分散在兩種有機溶劑中形成兩種溶 液，根據藥物或固體分散體載體的溶解或分散的需要，有 7 95311 201249802 機溶劑中可含有水； (3)將上述藥物和固體分散體載體的幾種溶液混合，除 去有機溶劑，得到固體分散體混合物。 將有機溶劑除去得到固體分散體的方法可根據本領域 的常規操作方法操作，例如蒸發法、喷霧乾燥法或流化床 乾燥法，對於本發明而言較佳使用喷霧乾燥法。 本發明中將藥物或固體分散體載體溶解的有機溶劑可 以使用可溶解上述物質或比較容易分散的溶劑，選自曱 醇、乙醇、異丙醇等低級醇類；丙酮、丁酮等酮類；二氯 甲烷、二氯乙烷、三氯曱烷、四氯化碳等鹵化烴類及它們 的混合溶媒等。同時，根據需要也可加水。例如曱醇、乙 醇、異丙醇、丙酮、丁酮、二氯曱烷、二氯乙烷、三氯曱 烷或四氯化碳。在這些有機溶媒中，低級醇類和鹵化烴類 的混合溶媒，從溶解性及蒸餾除去等方面來說比較理想， 具體包括曱醇或乙醇和二氯曱烷的混合液。在具體實施時 比較好的實施方式是：使用乙醇與二氯曱烷的混合物溶解 托伐普坦或其鹽；使用乙醇與二氣曱烷的混合物或乙醇溶 解交聯聚乙烯ϋ比17各烧酮和水溶性聚合物。 本發明的非晶形的托伐普坦固體分散體粒徑範圍為 0. 01 至 400 yin，較佳 0. 1 至 300 /zm，更較佳 1 至 200 # m。 本發明的非晶形的托伐普坦固體分散體沒有在它的 DSC掃描中顯示任何的吸熱峰，也沒有在它的粉末X-射線 衍射譜中顯示結晶折射峰，表明本發明分散體中所包含的 托伐普坦是穩定的非晶形式。 8 95311 201249802 添加劑-起—2含與藥用載體、賦形劑和 該藥物級合物可以根據任何==的，物。 片劑、軟或硬膠量、士 ^ 々規方法而以散劑、顆粒、 可以將《粉末▲粒狀形^包衣製_形式來配製。例如， :物添加劑-起填充進或其他的 方法包衣，劑然後視需要地根據任何的常規 在可::單獨劑量或分開劑量經口給藥。 合物的過程巾備包含固體分散體的經口給藥的組 形劑’以改善固體八：需要地加入-種或更多種的藥用賦 藥用賦形射㈣2體的流動性和其他的物理性質。該 聚，_、交二:、殿粉、經基乙酸殿粉納、聚乙婦 素、碟酸辦、碳妒、戴、准素納、麥芽糖糊精、微晶纖維 在本發明中可以二：’,和微晶纖維素組成的組合。此外， 石粉。 *潤滑劑，例如硬脂酸、硬脂酸鎂和滑 會變得顯而易見式本發明的以上和其他的目的和特徵將 【實施方式】 圍。、n m 1"下實施例，但並不以任何方式限制本發明的範 實施例1 將2〇这托伐普 加人到二氣甲燒和乙醇的混合物中， 95311 9 201249802 並且攪拌直至該溶液變為澄清，將10g交聯聚乙烯聚吡咯 烷酮加入乙醇中，分散均勻，然後將托伐普坦溶液和交聯 聚維酮分散液混合，進行喷霧乾燥得托伐普坦固體分散 體，其粒徑分佈在1 // m至400 /z m，平均粒徑為52 // m。 實施例2 將20g托伐普坦加入到二氯甲烷和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，將2g交聯聚乙烯聚吡咯烷 酮加入乙醇中，分散均勻，然後將托伐普坦溶液和交聯聚 維酮分散液混合，進行喷霧乾燥得托伐普坦固體分散體， 其粒徑分佈在1 /zm至400 /zm，平均粒徑為52/zm。 實施例3 將20g托伐普坦加入到二氯曱烷和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，將200g交聯聚維酮加入乙 醇中，分散均勻，然後將托伐普坦溶液和交聯聚維酮分散 液混合，進行喷霧乾燥得托伐普坦固體分散體，其粒徑分 佈在l#m至400/zm，平均粒徑為52/zm。 實施例4 將20g托伐普坦加入到二氯曱烷和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，將lg聚乙烯吡咯烷酮加入 到二氯曱烷和乙醇的混合物中，並且攪拌直至該溶液變為 澄清，將10g交聯聚乙烯吡咯烷酮加入到二氣曱烷和乙醇 的混合物中並且均勻分散，然後將托伐普坦溶液和其他添 加劑分散液混合，進行喷霧乾燥，得托伐普坦固體分散體， 其粒徑分佈1 // m至10 0 // m，平均粒徑2 5 # m。 10 95311 201249802 實施例5 、將2Og托伐普坦加入到二氯甲烧和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，將lg羥丙基甲基纖維素加 入到二氯甲烷和乙醇的混合物中，並且攪拌直至該溶液變 為澄清，將10g交聯聚乙烯吡咯烷酮加入到二氯曱烷和乙 醇的混合物中並且均勻分散，然後將托伐普坦溶液和其他 添加劑分散液混合，進行喷霧乾燥，得托伐普坦固體分散 體，其粒徑分佈1 // m至100 # m，平均粒徑25 /ζιη。 實施例6 將20g托伐普坦加入到二氯甲烷和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，將lg羥乙基纖維素加入到 二氯曱烷和乙醇的混合物中，並且攪拌直至該溶液變為澄 清，將10g交聯聚乙烯吡咯烷酮加入到二氣甲烷和乙醇的 混合物t並且均勻分散，然後將托伐普坦溶液和其他添加 劑分散液混合，進行喷霧乾燥，得托伐普坦固體分散體， 其粒徑分佈1 /z m至100 /z m，平均粒徑25 y m。 實施例7 將20g托伐普坦加入巍二m和乙醇.的混合物中， 並且攪拌直至該溶液變為澄清，將lg羧甲基纖維素鈉加入 到二氯甲烷和乙醇的混合物中，並且攪拌直至該溶液變為 澄清，將10g交聯聚乙烯吡咯烷酮加入到二氯曱烷和乙醇 的混合物中並且均勻分散，然後將托伐普坦溶液和其他添 加劑分散液混合，進行喷霧乾燥，得托伐普坦固體分散體， 其粒徑分佈1 /z m至100 // m，平均粒徑25 # m。 11 95311 201249802 實施例8 將20g托伐普坦加入到二氯甲烷和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，將lg甲基纖維素加入到二 氯甲烷和乙醇的混合物中，並且攪拌直至該溶液變為澄 清，將10g交聯聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的 混合物中並且均勻分散，然後將托伐普坦溶液和其他添加 劑分散液混合，進行喷霧乾燥，得托伐普坦固體分散體， 其粒徑分佈1 // m至100 # m，平均粒徑25 /z m。 實施例9 將20g托伐普坦加入到二氯曱烷和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，將2g蔗糖酯加入到二氯曱 烷和乙醇的混合物中，並且攪拌直至該溶液變為澄清，將 10g交聯聚乙烯吡咯烷酮加入到二氯曱烷和乙醇的混合物 中並且均勻分散，然後將托伐普坦溶液和其他添加劑分散 液混合，進行喷霧乾燥，得托伐普坦固體分散體，其粒徑 分佈1 # m至100 # in，平均粒徑25 /z m。 實施例10 將20g托伐普坦加入到二氯甲烷和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，將0. 5g聚乙烯醇加入到二 氯甲烷和乙醇的混合物中，並且攪拌直至該溶液變為澄 清，將10g交聯聚乙烯吡咯烷酮加入到二氯甲烷和乙醇的 混合物中並且均勻分散，然後將托伐普坦溶液和其他添加 劑分散液混合，進行喷霧乾燥，得托伐普坦固體分散體， 其粒徑分佈1 # m至100 # m，平均粒徑25私m。 12 95311 201249802 比較例1 -將10g托伐普坦加入到二氯曱烧和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，直接進行喷霧乾燥，得托 伐普坦無定型粉末，其粒徑分佈0. 01 至200 ，平均 粒徑28 # m。 比較例2 將20g托伐普坦加入到二氣曱烷和乙醇的混合物中， 並且攪拌直至該溶液變為澄清，然後，往裏加入10g的羥 丙基纖維素並且均勻分散，並且進行喷霧乾燥得托伐普坦 固體分散體，其粒徑分佈1至400 /zm，平均粒徑56# m。 溶出試驗 將實施例1至10、比較例、對照樣品（結晶原料粒徑 分佈為1至400 μ m，平均粒徑83# m)的各粉末，分別稱取 適量（相當於托伐普坦100mg)，加入溶出儀中，0.2%(W/V) 十二烧基硫酸納水溶液900ml為溶劑，槳板法，轉速：100 轉/分鐘，進行溶出試驗。分別於5分鐘、10分鐘、15分 鐘、20分鐘、30分鐘、45分鐘取樣作為供試溶液，測定， 計算溶出度。 溶出度（％)的計算方式為，將一定量托伐普坦溶解於甲 醇後，移取5ml至100ml量瓶中，以0.2%(W/V)十二烷基 硫酸鈉水溶液稀釋製成濃度為20/zg/ml的溶液作為標準 溶液，在波長269mm和330mm波長處測定標準溶液和供試 溶液中的吸光度。通過得到的吸光度差的比得到溶出率。 結杲如下表1所示： 13 95311 201249802 表1 5 10 15 20 30 45 實施例1 86. 5% 90. 9% 94. 2% 96. 3% 97. 6% 99. 2% 實施例2 74. 7% 80. 6% 85. 2% 88. 5% 97. 1% 98. 7% 實施例3 71. 6% 76. 0% 86. 0% 90. 5% 98. 2% 99. 1% 實施例4 93. 4% 96. 8% 100. 2% 99. 6% 100.9% 101.4% 實施例5 92. 0% 95. 9% 98. 3% 100. 4% 99.9% 99. 1% 實施例6 88. 5% 90. 8% 93. 4% 96. 5% 98. 7% 99. 2% 實施例7 72. 5% 77. 1% 84. 3% 89. 5% 98. 2% 98. 7% 實施例8 89. 2% 95. 8% 97. 2% 98. 6% 101.9% 100. 1% 實施例9 78. 1% 81.6% 85. 8% 90. 7% 98. 0% 99. 5% 實施例10 75. 7% 82. 6% 88.4% 94. 2% 97. 8% 100. 0% 比較例1 15. 9% 19. 1% 22. 2% 25. 8% 30. 7% 42. 8% 比較例2 68. 1% 73. 5% 82.4% 88. 7% 97. 4% 99. 8% 根據上述實驗結果可以看出： (1) 使用交聯聚乙烯°比咯烷酮作為托伐普坦固體分散 體的載體可以顯著提高藥物的釋放特性，對於現有技術中 使用羥丙基纖維素作為固體分散體載體來說，效果提高顯 著。藥物和交聯聚乙烯u比σ各烧酮之間的比例可以在很大範 圍内進行選擇，在1 : 0.1至10的範圍内都具有較好的釋 放特性，在約1 : 0. 5時效果最好。 (2) 在以交聯聚乙烯《比咯烷酮作為托伐普坦固體分散 體的載體的基礎上，可以添加其他水溶性聚合物與交聯聚 14 95311 201249802 乙烯吡咯烷酮同時作為固體分散體載體。經比較發現，由 於水溶性聚合物能進一步改善固體分散體的性質，因此其 中進一步加入的水溶性聚合物的量沒有特殊限定，水溶性 聚合物相對於交聯聚乙烯吡咯烷酮的用量達到1 : 5至20 時表現出的提高效果具有資料上的統計意義，1 : 10效果 最好。這些水溶性聚合物中，效果最好的是羧丙基纖維素 和聚乙烯吡咯烷酮，羥乙基纖維素和甲基纖維素次之。 實施例11 實施例1得固體分散體 18g 乳糖 24g 玉米澱粉 6g 微晶纖維素 6g 5%羥丙纖維素溶液 適量 交聯聚維酮 3g 硬脂酸鎂 〇.3g 將固體分散體原料過40目 篩、 輔料過80目篩後， 按 處方量稱取原辅料，混合均勻 ，用 5%經丙纖維素溶液適量 製粒，於50°C左右通風乾燥， 乾顆粒用20目篩整粒， 外 加交聯聚維酮、硬脂酸鎂混合均勻 ，填裝膠囊。 實施例12 實施例3得固體分散體 58g 乳糖 15g 微晶纖維素 5g 5%經丙纖維素溶液 適量 15 95311 201249802 交聯羧甲基纖維素 3g 硬脂酸鎂 〇.3g 歐巴代包衣 l.Bg 將固體分散體原料過40目 篩、輔料過80目篩後 ，按 處方量稱取原輔料，混合均勻 ，用5%經丙纖維素溶液適量 製粒，於50°C左右通風乾燥， 乾顆粒用20目篩整粒 ，外 加交聯羧曱基纖維素、硬脂酸鎂混合均勻，壓片，包衣即 得。 實施例13 實施例2得固體分散體 95g 乳糖 l〇g 預膠化澱粉 2g 微晶纖維素 2g 5%聚維酮溶液 適量 低取代羥丙纖維素 5g 硬脂酸鎂 〇.3g 將固體分散體原料過40目 篩、辅料過80目篩後 ，按 處方量稱取原輔料，混合均勻， 用5%聚維酮溶液適量製粒， 於50°C左右通風乾燥，乾顆粒用20目篩整粒，外加低取 代羥丙纖維素、硬脂酸鎂混合均勻，壓片，即得。 【圖式簡單說明】 第1圖為實施例1粉末X-射線衍射的譜圖。 第2圖為實施例1至10、比較例1至2的體外釋放曲 線。 16 95311 201249802 第3圖為原料藥、實施例4、比較例2的體内生物利 用度曲線。 【主要元件符號說明】 無。 17 95311The US Food and Drug Administration approved a new drug market application for tolvaptan (toxin vasopressin V2 receptor antagonist) produced by Otsuka Pharmaceutical Co., Ltd. In the heart failure model, tolvaptan only showed drainage. Diuretic effect, significantly reduced cardiac preload, but no effect on afterload and renal function. Many clinical trials for heart failure and hyponatremia have demonstrated that tolvaptan is effective in reducing fluid retention and improving low sodium in patients with heart failure with excessive capacity overload. Tolvaptan can effectively relieve the symptoms and signs of pulmonary congestion in patients with heart failure, and can also reduce body weight and protect kidney function without serious adverse reactions. Tolvaptan-related compounds have been shown to be useful in the treatment of high- or isovolumetric hyponatremia with heart failure, cirrhosis, and antidiuresis. 3 95311 201249802 Hormone secretion abnormality syndrome. Tolvaptan is a white crystal or crystalline powder which is almost insoluble in water, so that when water-insoluble tolvaptan is administered orally, its bioavailability is inevitably low. In order to overcome this problem, Japanese Patent Publication No. Jpn〇21241A discloses a process for preparing a solid formulation of a atorvastatin, which comprises the steps of: dissolving tolvepazine and propylcellulose in a certain proportion in organic In the solvent, according to the read drying method, the solid dispersion composition is added, and other medicinal materials are added. [Inventive content] The present inventors have unexpectedly discovered that the olefinic ketone (ie, cross-linked poly- _) The carrier's ditan solid dispersion exhibits higher solubility of the active fraction and the convenient preparation of ruthenium cellulose than the prior art of the atorvastatin formulation containing the oxime (4) H step study _ & Also, the frequency field of the more roasted scales _ plus other water-soluble ^ cross-linked poly-ethylene dissolution efficiency is further improved. The present invention is used to make the drug more water soluble: and to provide a method for preparing the compound than the conventional Tovars. The drug of the domain of the sulphate _# body, and the other object of the invention gs vatartan solid dispersion is provided for oral administration, comprising the composition of the composition according to the invention, provided A solid dispersion comprising amorphous form 95311 4 201249802 active ingredient tolvaptan or a salt thereof, crosslinked polyvinylpyrrolidone. Preferably, the weight ratio of the active ingredient tolvaptan or its salt to the crosslinked polyvinylpyrrolidone is controlled to be 1:0.05 to 20; preferably, the weight ratio is 1:0.1 to 10, preferably. It is 2: 1. The solid dispersion of the present invention may consist solely of the active ingredient and crosslinked polyvinylpyrrolidone. Further, the solid dispersion of the present invention may further be added to the water-soluble polymer. The present invention further improves the physical properties of the solid dispersion by the addition of one or more water soluble polymers. The water-soluble polymer is a water-soluble polymer commonly used in solid dispersions, and may be selected from, but not limited to, the following polymers: alkyl cellulose, such as fluorenyl cellulose; hydroxyalkyl cellulose, such as hydroxy fluorenyl fiber , hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxybutyl cellulose; calcined cellulose, such as ethyl decyl cellulose and propyl fluorenyl cellulose; carboxyalkyl cellulose , for example, carboxymethyl cellulose; alkali metal of carboxyalkyl cellulose, such as sodium carboxymethyl cellulose; carboxyalkyl alkyl cellulose, such as carboxymethyl ethyl cellulose; carboxyalkyl cellulose ester; Gum, such as sodium carboxy sulfhydryl amylate; quinone chitin derivatives, such as acetaminoglycan; polysaccharides such as alginic acid, its metal and salt, caragenan, galactomannan Sugar, tragacanth, agar, gum arabic, guar gum and xanthan gum; 5 95311 201249802 polymethacrylic acid and its salts; polymethacrylic acid and its salts, mercapto acrylate copolymers, amine alkyl Acrylate copolymer; polyvinyl acetal and diethyl Glycosyl acetate; sugar surfactants such as sucrose distearate, sucrose mono/distearate and sucrose monopalmitate; polyvinyl alcohol; polyvinylpyrrolidone and polyvinylpyrrolidone-vinyl acetate Ester copolymer; polyepoxy, such as polyethylene oxide and polyglycolide; or ethylene oxide-propylene oxide copolymer. Among the above-mentioned water-soluble polymers, conjugated cellulose, transsiloxane-based cellulose, carboxyalkylalkylcellulose or an alkali metal salt thereof, polyvinylpyrrolidone is preferred, and hydroxypropylmethylcellulose is preferred. Preferably, polyvinylpyrrolidone is more preferred. A preferred embodiment thereof is a weight ratio of the water-soluble polymer to the crosslinked polyvinylpyrrolidone of from 1:5 to 20, preferably from 1:8 to 15, most preferably 1:10. It has been found through research that the amount of the water-soluble polymer further added is not particularly limited because the water-soluble polymer can further improve the properties of the solid dispersion, and those skilled in the art can select according to the actual production, and found in actual research. The improvement effect exhibited by the water-soluble polymer relative to the cross-linked polyvinylpyrrolidone of from 1:5 to 20 is statistically significant, preferably from 1:8 to 15, most preferably 1:10. Further, the composition described in the examples of the present invention can be referred to 6 95311 201249802 as a preferred illustration of the effects of the present invention. The preferred solid dispersion embodiment of the invention is a solid dispersion comprising the following ingredients and ratios: Component weight ratio tolvaptan 2 Crosslinked polyvinylpyrrolidone 1 Water soluble polymer 0.1 wherein the water soluble polymer The most effective of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxyethylcellulose or methylcellulose is the embodiment of polyvinylpyrrolidone or hydroxypropylcellulose. For the technical solution containing a water-soluble polymer, the solid dispersion may no longer contain other components, i.e., only the active ingredient, crosslinked polyethylene, ketone ketone and water-soluble polymer. In the preparation of the amorphous tolvaptan solid dispersion of the present invention, a crosslinked polyvinylpyrrolidone or a combination of a water-soluble polymer and a crosslinked polyvinylpyrrolidone may be used alone as a carrier. In the specific operation, the following steps can be carried out: (1) Dissolving tolvaptan or its salt in an organic solvent; (2) For a solid dispersion containing no water-soluble polymer, cross-linked polyethylene The pyrrolidone is dissolved or dispersed in an organic solvent; for a solid dispersion containing a water-soluble polymer, the crosslinked polyvinylpyrrolidone and the water-soluble polymer can be directly dissolved or dispersed in an organic solvent to form a solution, or Dissolving or dispersing the cross-linked polyethylene ketone and the water-soluble polymer in two organic solvents to form two solutions, according to the dissolution or dispersion of the drug or solid dispersion carrier, there are 7 95311 201249802 solvent It may contain water; (3) Mixing the above-mentioned drug with several solutions of the solid dispersion carrier, and removing the organic solvent to obtain a solid dispersion mixture. The method of removing the organic solvent to obtain a solid dispersion can be carried out according to a conventional operation method in the art, such as an evaporation method, a spray drying method or a fluidized bed drying method, and a spray drying method is preferably used in the present invention. The organic solvent in which the drug or the solid dispersion carrier is dissolved in the present invention may be a solvent which can dissolve the above substances or is relatively easy to disperse, and is selected from lower alcohols such as decyl alcohol, ethanol, and isopropanol; ketones such as acetone and methyl ethyl ketone; Halogenated hydrocarbons such as dichloromethane, dichloroethane, trichlorosilane, carbon tetrachloride, and the like, and mixed solvents thereof. At the same time, water can be added as needed. For example, decyl alcohol, ethanol, isopropanol, acetone, methyl ethyl ketone, dichloro decane, dichloroethane, trichloro decane or carbon tetrachloride. Among these organic solvents, a mixed solvent of a lower alcohol and a halogenated hydrocarbon is preferable from the viewpoints of solubility and distillation, and specifically includes a mixture of decyl alcohol or ethanol and dichlorosilane. In a specific implementation, a preferred embodiment is: using a mixture of ethanol and dichlorosilane to dissolve tolvaptan or a salt thereof; using a mixture of ethanol and dioxane or ethanol to dissolve the crosslinked polyethylene to each other than 17 Ketones and water soluble polymers. The amorphous tolvaptan solid dispersion of the present invention has a particle size ranging from 0.01 to 400 yin, preferably from 0.1 to 300 /zm, more preferably from 1 to 200 #m. The amorphous tolvaptan solid dispersion of the present invention does not exhibit any endothermic peak in its DSC scan, nor does it exhibit a crystalline refractive peak in its powder X-ray diffraction spectrum, indicating that it is present in the dispersion of the present invention. The contained tolvaptan is a stable amorphous form. 8 95311 201249802 Additives - 2 - containing pharmaceutical carriers, excipients and pharmaceutical conjugates may be according to any ==. The amount of the tablet, the soft or hard gel, the powder, the powder, and the powder can be formulated in the form of a powder ▲ granules. For example, the additive may be filled or otherwise coated, and the agent may then be administered orally in a single dose or in divided doses, as desired. The process syrup of the composition comprises an orally administered sizing agent comprising a solid dispersion to improve the solidity of eight: one or more of the medicinal medicinal medicinal (4) 2 fluidity and other Physical properties. The poly, _, Jiao 2:, the temple powder, the acetaminophen powder, the polyglycol, the dish acid, the carbon, the wear, the quasi-sodium, the maltodextrin, the microcrystalline fiber can be two in the invention :', and a combination of microcrystalline cellulose. In addition, stone powder. * Lubricants, such as stearic acid, magnesium stearate, and slip, will become apparent. The above and other objects and features of the present invention will be made. , nm 1 " The following examples, but do not limit the invention in any way. Example 1 Add 2 Torrs to a mixture of dioxo and ethanol, 95311 9 201249802 and stir until the solution To become clarified, 10 g of cross-linked polyvinylpolypyrrolidone was added to ethanol and dispersed uniformly, and then the tolvaptan solution and the crospovidone dispersion were mixed and spray-dried to obtain a tolvaptan solid dispersion. The particle size distribution ranges from 1 // m to 400 /zm and the average particle size is 52 // m. Example 2 20 g of tolvaptan was added to a mixture of dichloromethane and ethanol, and stirred until the solution became clear, 2 g of cross-linked polyvinylpolypyrrolidone was added to ethanol, dispersed uniformly, and then tolvaptan The solution and the crospovidone dispersion were mixed and spray-dried to obtain a solid dispersion of tolvaptan having a particle size distribution of from 1 /zm to 400 /zm and an average particle diameter of 52/zm. Example 3 20 g of tolvaptan was added to a mixture of dichlorosilane and ethanol, and stirred until the solution became clear, 200 g of crospovidone was added to ethanol, dispersed uniformly, and then tolvaptan The solution and the crospovidone dispersion were mixed and spray-dried to obtain a solid dispersion of tolvaptan having a particle size distribution of l#m to 400/zm and an average particle diameter of 52/zm. Example 4 20 g of tolvaptan was added to a mixture of dichlorosilane and ethanol, and stirred until the solution became clear, and lg polyvinylpyrrolidone was added to a mixture of dichlorosilane and ethanol, and stirred until The solution became clear, 10 g of cross-linked polyvinylpyrrolidone was added to a mixture of dioxane and ethanol and uniformly dispersed, and then the tolvaptan solution and other additive dispersions were mixed and spray-dried to obtain a cutting The Putan solid dispersion has a particle size distribution of 1 // m to 10 0 // m and an average particle size of 2 5 # m. 10 95311 201249802 Example 5, adding 2Og of tolvaptan to a mixture of methylene chloride and ethanol, and stirring until the solution becomes clear, adding lg hydroxypropyl methylcellulose to dichloromethane and ethanol In the mixture, and stirring until the solution becomes clear, 10 g of cross-linked polyvinylpyrrolidone is added to the mixture of dichlorosilane and ethanol and uniformly dispersed, and then the tolvaptan solution and other additive dispersions are mixed. Spray drying, a solid dispersion of tolvaptan having a particle size distribution of 1 // m to 100 # m and an average particle size of 25 /ζιη. Example 6 20 g of tolvaptan was added to a mixture of dichloromethane and ethanol, and stirred until the solution became clear, and lg hydroxyethyl cellulose was added to a mixture of dichlorosilane and ethanol, and stirred. Until the solution becomes clear, 10 g of cross-linked polyvinylpyrrolidone is added to a mixture of di-methane and ethanol and uniformly dispersed, and then the tolvaptan solution and other additive dispersions are mixed and spray-dried to obtain a cutting The Putan solid dispersion has a particle size distribution of 1 /zm to 100 /zm and an average particle size of 25 μm. Example 7 20 g of tolvaptan was added to a mixture of bismuth m and ethanol, and stirred until the solution became clear, sodium lg carboxymethylcellulose was added to a mixture of dichloromethane and ethanol, and stirred. Until the solution became clear, 10 g of cross-linked polyvinylpyrrolidone was added to a mixture of dichlorosilane and ethanol and uniformly dispersed, and then the tolvaptan solution and other additive dispersions were mixed and spray-dried. A solid dispersion of vaputan having a particle size distribution from 1 /zm to 100 // m and an average particle size of 25 # m. 11 95311 201249802 Example 8 20 g of tolvaptan was added to a mixture of dichloromethane and ethanol, and stirred until the solution became clear, and lg methylcellulose was added to a mixture of dichloromethane and ethanol, and Stir until the solution becomes clear, add 10 g of cross-linked polyvinylpyrrolidone to a mixture of dichloromethane and ethanol and uniformly disperse, then mix the tolvaptan solution with other additive dispersions, spray-dry, and obtain A solid dispersion of vaputan having a particle size distribution of 1 // m to 100 # m and an average particle size of 25 /zm. Example 9 20 g of tolvaptan was added to a mixture of dichloromethane and ethanol, and stirred until the solution became clear, 2 g of sucrose ester was added to a mixture of dichlorosilane and ethanol, and stirred until The solution became clear, 10 g of cross-linked polyvinylpyrrolidone was added to the mixture of dichlorosilane and ethanol and uniformly dispersed, and then the tolvaptan solution and the other additive dispersion were mixed and spray-dried to obtain Tosap. Tan solid dispersion with a particle size distribution of 1 #m to 100 #in and an average particle size of 25 /zm. Example 10 20 g of tolvaptan was added to a mixture of dichloromethane and ethanol, and stirred until the solution became clear, 0.5 g of polyvinyl alcohol was added to a mixture of dichloromethane and ethanol, and stirred until The solution became clear, 10 g of cross-linked polyvinylpyrrolidone was added to a mixture of dichloromethane and ethanol and uniformly dispersed, and then the tolvaptan solution and other additive dispersions were mixed and spray-dried to obtain Tosap Tan solid dispersion, its particle size distribution 1 # m to 100 # m, average particle size 25 private m. 12 95311 201249802 Comparative Example 1 - 10 g of tolvaptan was added to a mixture of dichlorohydrazine and ethanol, and stirred until the solution became clear, and spray drying was carried out to obtain a tolvaptan amorphous powder. The particle size distribution is from 0.01 to 200 and the average particle size is 28 # m. Comparative Example 2 20 g of tolvaptan was added to a mixture of dioxane and ethanol, and stirred until the solution became clear, and then 10 g of hydroxypropylcellulose was added thereto and uniformly dispersed, and sprayed. The dried solid mixture of tolvaptan has a particle size distribution of 1 to 400 /zm and an average particle size of 56# m. Dissolution test Each of the powders of Examples 1 to 10, Comparative Example, and Control Sample (crystal material particle size distribution of 1 to 400 μm, average particle diameter 83# m) was weighed appropriately (corresponding to tolvaptan 100 mg) The dissolution test was carried out by adding 900 ml of 0.2% (w/v) sodium dodecyl sulfate aqueous solution to the solvent, paddle method, rotation speed: 100 rpm, and performing a dissolution test. Samples were taken as test solutions at 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, and 45 minutes, respectively, and the dissolution was measured. The dissolution rate (%) is calculated by dissolving a certain amount of tolvaptan in methanol, removing it from a 5 ml to 100 ml volumetric flask, and diluting it with 0.2% (w/v) aqueous solution of sodium lauryl sulfate. The solution of 20/zg/ml was used as a standard solution, and the absorbance in the standard solution and the test solution was measured at wavelengths of 269 mm and 330 mm. The dissolution rate was obtained by the ratio of the obtained absorbance differences. The following table is shown in Table 1: 13 95311 201249802 Table 1 5 10 15 20 30 45 Example 1 86. 5% 90. 9% 94. 2% 96. 3% 97. 6% 99. 2% Example 2 74 7% 80. 6% 85. 2% 88. 5% 97. 1% 98. 7% Example 3 71. 6% 76. 0% 86. 0% 90. 5% 98. 2% 99. 1% Example 4 93. 4% 96. 8% 100. 2% 99. 6% 100.9% 101.4% Example 5 92. 0% 95. 9% 98. 3% 100. 4% 99.9% 99. 1% Example 6 88. 5% 90. 8% 93. 4% 96. 5% 98. 7% 99. 2% Example 7 72. 5% 77. 1% 84. 3% 89. 5% 98. 2% 98. 7% Example 8 89. 2% 95. 8% 97. 2% 98. 6% 101.9% 100. 1% Example 9 78. 1% 81.6% 85. 8% 90. 7% 98. 0% 99. 5% Example 10 75. 7% 82. 6% 88.4% 94. 2% 97. 8% 100. 0% Comparative Example 1 15. 9% 19. 1% 22. 2% 25. 8% 30. 7% 42. 8% Comparative Example 2 68. 1% 73. 5% 82.4% 88. 7% 97. 4% 99. 8% According to the above experimental results, it can be seen that: (1) using crosslinked polyethylene ° pyrrolidone As a carrier of the solid dispersion of tolvaptan, the release property of the drug can be remarkably improved, and the effect is remarkably improved in the prior art using hydroxypropylcellulose as a solid dispersion carrier. The ratio between the drug and the cross-linked polyethylene u to σ each of the ketones can be selected in a wide range, and has a good release property in the range of 1: 0.1 to 10, at about 1: 0.5. best effect. (2) Based on the cross-linked polyethylene "pyrrolidone" as a carrier for the solid dispersion of tolvaptan, other water-soluble polymers can be added together with the cross-linked poly 14 95311 201249802 vinylpyrrolidone as a solid dispersion carrier. . It has been found that, since the water-soluble polymer can further improve the properties of the solid dispersion, the amount of the water-soluble polymer further added therein is not particularly limited, and the amount of the water-soluble polymer relative to the cross-linked polyvinylpyrrolidone is 1:5. The improvement effect shown by 20 o'clock has statistical significance on the data, and 1:10 works best. Among these water-soluble polymers, carboxypropylcellulose and polyvinylpyrrolidone are the most effective, followed by hydroxyethylcellulose and methylcellulose. Example 11 Example 1 obtained solid dispersion 18 g lactose 24 g corn starch 6 g microcrystalline cellulose 6 g 5% hydroxypropyl cellulose solution appropriate amount of crospovidone 3 g magnesium stearate. 3 g solid dispersion raw material over 40 mesh After the sieve and auxiliary materials have passed through the 80 mesh sieve, weigh the raw materials according to the prescription amount, mix well, granulate with 5% cellulose solution in a proper amount, ventilate and dry at 50 °C, dry granules with 20 mesh sieve, plus The crospovidone and magnesium stearate are uniformly mixed and filled into capsules. Example 12 Example 3 obtained solid dispersion 58 g Lactose 15 g Microcrystalline cellulose 5 g 5% by propionic cellulose solution 15 95311 201249802 Crosslinked carboxymethyl cellulose 3 g Magnesium stearate. 3 g Opadry coating l .Bg After the solid dispersion raw material is passed through a 40 mesh sieve and the auxiliary material is passed through a 80 mesh sieve, the raw and auxiliary materials are weighed according to the prescription amount, uniformly mixed, and granulated with a suitable amount of 5% cellulose acylate solution, and ventilated and dried at about 50 ° C. The dry granules are sized with a 20 mesh sieve, and the croscarmellose cellulose and magnesium stearate are uniformly mixed, compressed, and coated. Example 13 Example 2 obtained solid dispersion 95 g Lactose l〇g Pregelatinized starch 2 g Microcrystalline cellulose 2 g 5% povidone solution appropriate amount of low-substituted hydroxypropyl cellulose 5 g magnesium stearate. 3 g solid dispersion After the raw material has passed through the 40 mesh sieve and the auxiliary material has passed through the 80 mesh sieve, the raw and auxiliary materials are weighed according to the prescription amount, mixed evenly, and granulated with 5% povidone solution, ventilated and dried at 50 ° C, and the dry granules are sieved with 20 mesh. Granules, plus low-substituted hydroxypropyl cellulose, magnesium stearate, evenly mixed, compressed, that is. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a spectrum of powder X-ray diffraction of Example 1. Fig. 2 is an in vitro release curve of Examples 1 to 10 and Comparative Examples 1 to 2. 16 95311 201249802 Fig. 3 is a graph showing the in vivo bioavailability of the drug substance, Example 4, and Comparative Example 2. [Main component symbol description] None. 17 95311