201247246 六、發明說明： 【發明所屬之技術領域】 本發明涉及一種包含決奈達隆或其藥學上可接受的 鹽及載體的固體分散體及其製備方法。 【先前技術】 決奈達隆（Dronedarone)化學名為2-正丁基-3-[4-(3-正丁基-胺基丙氧基）苯曱酿基]-5 -曱基續胺苯並D夫喃’ 分子式為C31H44N2O5S，分子量為556. 765。 決奈達隆是由賽諾菲-安萬特開發的一種新的抗心律 不整藥物，於2009年7月1日被美國FDA批准上市。 鹽酸決奈達隆在水性溶液中的溶解性呈pH依賴性，在 pH值3到5的範圍内有最大溶解度，約l-2mg/ml，在pH約 6到7下溶解度顯著降低，在pH=7下溶解度約為10//g/m卜 而人體胃到腸道的生理pH是逐漸升高的，這就導致了藥物 服用後，雖然在胃中溶解，但隨著胃排空進入腸道後，隨 著pH的升高，溶解的藥物將會析出沉澱，藥物的大量析 出，使其不能以分子狀態保持在腸液中，無法實現跨膜吸 收，從而影響藥物的吸收，使生物利用度降低。因此提高 該藥的體外溶出速率對於提高生物利用度和臨床療效具有 重要意義，應藉由藥劑學手段，提高藥物的溶解度，避免 其在中性介質中的沉澱，從而提高藥物的生物利用度。 為提高該藥的溶解度及其生物利用度，美國專利文獻 US20040044070A1公開了鹽酸決奈達隆的注射劑，該發明 藉由在緩衝系統（pH值3至5)中加入了 /9 -環糊精衍生物 3 95310 201247246 來提南有效成分的轉度，是該方法製造過程複雜，載 藥量低、德疋性較差。中國專利文獻ZL988〇8158 X公開了 -種含苯料。南衍生物的固體藥物組合物，該發明藉由使 用非離子«表面活性劑，尤其是泊洛沙姆類非離子型表面 活性劑，使鹽酸決奈達隆在經高PH溶液稀釋後保持在pH6 至7溶液中而不大量析出沉澱，從而提高了鹽酸決奈達隆 在空腹下的生物彻度，但該方法❹了表面活性劑，不 可避免地對人體有—定的刺激性和毒性。中國專利文獻CN 200610113479.5公開了—種含有微粒化的決奈達隆、表面 活性劑和作為助溶劑的親水性聚合物製得的膠囊或片劑， 在PH6.7_酸鹽緩衝液中，累積溶出百分率大大提升， 但該方法雜複雜’能耗高，載藥量過低，不利於製備適 宜臨床應㈣劑型，而且該方法也應用了對人體有-定刺 激性和毒性的陰離子型表面活性劑。 提高難溶性藥物溶解度和溶出度的方法，目前主要有 微粉化技術、包合技術和固體分散體技術[現有研究表 明，藥物微粉化後，粒徑減小，表面積增加，溶出度增加。 但粒徑賴到—定程度後，微粒自由能急劇增加，在儲存 過程中或進入體内後’有自發聚集的趨勢，溶出度反而降 低。而包合技術由於受到藥物分子量、空間結構等限制， 成功率較低，即使能成功包合，也存在龍量低等問題。 固體分散體（SD)是指將藥物高度分散於固體載體中形 成的-種以固體形式存在的分散系統。藥物以分子狀能、 膠體狀態、亞穩定態、微晶態以及無定形態等存在/載體 95310 4 201247246 中，這些以非晶態（高能狀態）存在的藥物，溶解度和溶出 速率都較其他晶體狀態大。 固體分散體技術在提高難溶性藥物溶解度和溶出度方 面，有較多的研究和較顯著的效果。但也存在步驟複雜， 載藥量低等問題，尤其是要想取得明顯效果，往往需要應 用大量的載體，導致固體分散體載藥量的降低，限制了臨 床的使用。例如，中國專利文獻申請CN101039657A公開了 一種含有固體分散體與聚合物基質的藥物組合物，該方法 採用聚葡萄糖和另外一種聚合物作為載體，藉由熱熔擠出 的方法製備了固體分散體，該方法需要使用包括聚葡萄糖 在内的兩種載體，才能達到理想的效果，而且載藥量不高。 因此，有必要提供一種不僅能提高溶解度或溶出度， 又能夠有較高載藥量的決奈達隆或其鹽固體分散體。 【發明内容】 本發明藉由對不同材料的比較篩選，一方面將決奈達 隆或其鹽與一種特定高分子載體製備成固體分散體，實現 了僅使用一種高分子載體材料且不使用表面活性劑，就提 高了決奈達隆的溶解度或溶出度，而且提高了固體分散體 的載藥量的效果。 另一方面，本發明藉由溶劑法制成固體分散體能夠使 決奈達隆處於非晶態，不僅極大地提高了藥物的溶解度， 而且藉由減壓乾燥的方法去除有機溶劑後的固體分散體， 粉體學性質良好，流動性和可壓性均優於現有技術製備的 固體分散體。 5 95310 201247246 具體而言，本發明提供一種非晶型的決奈達隆固體分 散體，其中所述固體分散體由作為活性成分的決奈達隆或 其藥學上可接受的鹽和一種載體材料組成。 本發明的固體分散體中，所述的載體選自親水性高分 子載體，例如聚維酮、共聚維酮，羥丙基纖維素等，其中 聚維酮、共聚維酮是優選的。 上述聚維酮選自例如聚維酮K-17、聚維酮K-25、聚 維酮K-30、聚維酮K-90等；共聚維酮（聚乙烯吡咯烷酮-醋酸乙烯酯共聚物）選自例如以商品名為Plasdone®S-630 或kollidon®VA 64的共聚維酮等；羥丙基纖維素類選自 例如商品名為 Klucel®HXF、Klucel®HF、Klucel®MF、 Klucel ®GF、Klucel ® JF、Klucel ®LF、Klucel ®EF、Klucel ® EXF 等。 發明人通過親水性載體的筛選出乎意料的發現，上述 親水性載體能夠表現出比現有技術（包含聚葡萄糖和另一 種基質的決奈達隆固體分散體，或包含非離子型表面活性 劑的藥物組合物）具有更高的溶解性和載藥量，製備的固體 分散體粉末，可壓性和流動性也優於現有技術製備的固體 分散體，便於進一步製備成片劑、膠囊等口服製劑。 本發明中採用的作為藥物活性成分的決奈達隆與載 體材料的重量比例為1 : 0. 2至15，較佳為1 : 0. 5至10， 更佳為1 : 1. 0至7. 5，最佳為：1 : 1. 5至5. 0。在本發明 的固體分散體中，決奈達隆的鹽可以選自··鹽酸鹽、枸櫞 酸鹽、馬來酸鹽或酒石酸鹽。其中鹽酸鹽是最佳的。 6 95310 ⑧ 201247246 本發明另-方面還在於提供—種所述固體分散體的製 備方法，該方法藉由溶劑法或熱炼擠出法製備固體分散體。 溶劑法（賴料賴法）更㈣於本發明㈣體分散體。. 、本發明的固體分散體可以通過以下方法來製備，該方 法包括下列步驟： ⑴將活性成分和高分子載體材料溶解在溶劑中. (2)將溶劑除去。 在步驟（1)中，較佳使 # 使用有機浴劑，可以使用的有機 二_自一乳甲烧、甲醇、乙醇、異丙醇、丙酮 、 虱仿或任何的適合的有機月 乙醇。在步驟⑵令 二#乂佳為-虱甲烷，、 燥的方法將溶劑除去^乾燥、讀乾燥和冷;東乾 該有機溶劑選自二=減壓乾燥法。 異丙醇中的—種或幾種二甲：、乙醇、丙酮、氯仿、 奈達隆和載體的總重盘=°物，作為藥物活性成分的決 1〇.〇,較佳為m u 劑的重量比為1:1.0至 對於固體分散體的乾燥+ 二、 燥目前應用最為廣泛，”v 〃而s，減壓乾燥和喷霧乾 更好的溶解性，使其應 噴務乾燥法製備的產品往往有 研究出人意料的發現日漸廣泛。然而’本發明人藉由 乾燥方法製備成的固體人，性成分和相應裁體，用這兩種 但用減壓乾燥法製備的^ ϋ在溶解性上沒有顯著差異， 和流動性），卻明顯優分散體的粉體學性質（可壓性 本發明的非晶型的 决奈達隆沒有在它的DSC掃描中顯 95310 7 201247246 譜中顯示 決奈達隆 示任何的吸熱峰’也沒有在它的粉末X-射線衍射 結晶衍射峰，表明本發明固體分散體中所包含的 是非晶型狀態。 本發明相比較現有技術具有以下優點： 1、 本發明在固體分散體中不添加表面活 " 剛’從而 避免了現有技術（例如專利ZL98808158.X* CN 200610113479· 5)中表面活性劑對人體的刺激性和主 2、 本發明以鹽酸決奈達隆為活性成分，以Z性。 高分子材料為載體製備固體分散體，在ρΗ6·8^皙水性 解度，高於現有技術（包含聚葡萄糖和另一種美^中的溶 隆固體分散體CN1Q1()39657A，或包含麵決奈達 的藥物組合物ZL98808158. X)。 面活性劑 3、本發㈣備的㈣分散體在保證 出度的情況下，提高了決奈達隆在固體分散體2度或溶 而且粉末可壓性和流動性較好。 的裁藥量’ 結合以下®式’本發明的以场其 會變得顯而易見。 、 勺和特徵將 【實施方式】 一:不同親水性高分子载體對決奈達隆溶解度的 以藥物.载體重量比為丨：5，分 ，y 高分子載體材料，包括聚乙二$的親水性 叶ουυυ、泊洛沙姆188、pVp Κ30、Klucel EF、Plasd〇ne@s〜63〇、甘露糖醇及约 合，分別加人12重量份二氣f貌，搜拌至 轉 真空乾燥箱内’保持55。。’減壓乾燥概後粉碎： 95310 8 201247246 目篩，即得鹽酸決奈達隆固體分散體，分別測定其在pH6. 8 罐酸鹽緩衝液中的溶解度，得到以下資料。 _體材料對決奈達隆溶解度的影響 序號 活性成分 載體 /又Μ汾管 —.---- 24小時溶解度（eg/mi) 1 〇 鹽酸決奈達隆 無 12.0 L 〇 鹽酸決奈達隆 聚乙二醇6000 33.9 3 A 鹽酸決奈遠降 泊洛沙姆188 39.1 4 r 鹽酸決奈遠降 PVP K30 161.5 5 鹽酸決奈遠降 Klucel® EF 155.7 6 鹽酸決奈遠降 Plasdone®S-630 150.2 7 鹽酸決奈遠降 甘露醇 27.0 8 鹽酸決奈達隆 PVP K30與聚乙二 醇 6000(1:1) 104.5 9 鹽酸決奈達隆 PVP K30與泊洛沙 姆 188(1 : 1) 110.2 10 鹽酸決奈達隆 Klucel ®EF與聚乙 二醇 6000(1 : 1) 90.4 11 鹽酸決奈達隆 Klucel ®EF與泊洛 沙姆 188(1 : 1) 94.8 由表1及第1圖可知，在相同的藥物：載體品質比下， 在眾多親水性载體材料中，聚維酮、共聚維酮和羥丙基纖 維素製備得到的固體分散體明顯增加了決奈達隆的溶出 度，而且表面活性劑的加入對於決奈達隆固體分散體的溶 出度的影響並不顯著。即單獨使用.這些材料就可以達到良 好效果。其中效果最好的是聚維酮K-30，其次是羥丙基纖 維素（Klucel® EF)和共聚維酮（Plasdone® S-630)。 二、載體的不同用量以及不同規格對決奈達隆溶解度 的影響 95310 9 201247246 以聚維酮、羥丙基纖維素、共聚維酮為載體，以不同 的藥物：載體比例，按下法製備鹽酸決奈達隆固體分散體： 加入2倍重量份二氯甲烧，攪拌至溶解，將其轉入真 空乾燥箱内，保持55°C，減壓乾燥48h後粉碎，過100目 篩，即得鹽酸決奈達隆固體分散體，進行24h溶出度比較。 24h溶解度測定：分別將制得的固體分散體取等量於 100ml錐形瓶中，加入pH6. 8磷酸鹽緩衝液50ml，封口後 置水浴恒溫振盪器上，設定溫度為37°C，振盪24h。在24h 時，取液1 OmL，濾過，棄初始濾液4mL，取續滤液，用pH6. 8 磷酸鹽緩衝液稀釋至相應倍數，用紫外分光光度計，在 290nm測定其吸光度，計算藥物溶解度。結晶鹽酸決奈達 隆的24h溶解度為12. Ο/zg/ml。 表2不同載體以及不同藥物：載體品質比對固體分散 體24h溶解度的影響 親水性載體 24h 溶解度（eg/ml) 藥物：載體比例 1:0.5 1:1 1:1.5 1:2 1:2.5 1:3 1:5 1:7.5 1:10 PVP K30 63.5 119.2 155.2 157.5 160.4 163.2 161.5 123.8 75.4. PVP-K17 62.1 110.7 135.6 141.5 151.3 160.8 157.6 109.6 86.2 PVP-K25 59.2 107.4 142.3 151.8 153.4 159.3 156.4 114.5 81.9 PVP-K90 59.6 96.8 129.4 138.6 149.8 151.2 150.4 87.3 70.5 Klucel® EF 55.2 102.4 130.5 143.3 152.6 157.4 155.8 105.5 69.4 Klucel® LF 60.1 105.9 136.4 144.1 146.9 155.1 152.6 96.7 67.5 Plasdone®S-630 62.0 96.8 135.7 141.5 145.6 152.3 150.8 85.9 63.8 聚葡萄糖+共聚乙烯 吡咯烷酮（1 : 1) 45.3 57.2 69.6 86.5 98.4 103.9 103.3 63.8 50.2 由結果可見，本發明自製的鹽酸決奈達隆固體分散體， 其在pH6. 8介質中的溶解度不僅較結晶鹽酸決奈達隆原料 顯著增加，而且較聚葡萄糖與共聚乙烯°比咯烷酮（1 : 1)組 10 95310 201247246 合的各種比例均有顯著的增加，採用聚乙烯°比°各烧酮、經 丙基纖維素、共聚乙烯吼咯烷酮作為決奈達隆固體分散體 ‘的親水性高分子載體，具有良好的溶解度。 此外發現，在1 : 1. 0至1 : 7. 5的藥物：載體比例範 圍内，製備的固體分散體溶解度較佳，在1 : 1.5至1 : 5 的藥物：載體比例最佳。 三、不同製備方法的對比 以鹽酸決奈達隆：聚維酮1 : 1. 5(或1 : 3)的比例以 不同製備方法製備固體分散體。1 對比例1熱熔擠出法 稱取1重量份鹽酸決奈達隆與3. 0重量份的聚維酮 PVP K-30，在聚乙烯袋中混合lOmin，置於雙螺杆熱熔擠 出機的進料斗中。按下列參數設定雙螺杆擠出機參數：主 機頻率：3.5Hz;飼料頻率：3.0Hz;各區溫度均為140°C。 待機器各區溫度平穩後，開動機器，收集從機頭流出的液 態流體，室溫冷卻至固體，粉碎過100目篩，即得。 對比例2溶劑法喷霧乾燥 稱取1重量份鹽酸決奈達隆與3. 0重量份的聚維酮 PVPK-30，加入12重量份二氯曱烷，攪拌直至溶液變為澄 清。將該溶液進行喷霧乾燥，同時將喷霧乾燥器（Mini喷 霧乾燥器B290，Buchi，瑞士）的入口和出口溫度分別維持 在90°C和55°C，收集樣品，即得鹽酸決奈達隆固體分散體。 對比例3溶劑法真空乾燥 稱取1重量份鹽酸決奈達隆與3. 0重量份的聚維酮 11 95310 201247246 PVPK-30，加入12重量份二氣甲烷，攪拌直至溶液變為澄 清。將其轉入真空乾燥箱内，保持55°C，減壓乾燥48h後 粉碎，過100目篩，即得鹽酸決奈達隆固體分散體。 測試例1:固體分散體的溶解性能 樣品 方法 24h 溶解度（# g/ml) 對比例1粉末 熱溶擠出法 155. 7 對比例2粉末 溶劑法喷霧乾燥 158. 2 對比例3粉末 溶劑法真空乾燥 163. 2 測試例2 :固體分散體粉末粉體學性質 樣品 視密度 (g/ml) 敲緊密度 (g/ml) 卡爾指數 (%) 休止角 (。） 對比例1 粉末 0.476 0. 683 30. 3 44. 3 對比例2 粉末 0. 306 0. 502 39. 0 63.4 對比例3 粉末 0. 579 0. 770 24. 8 41. 5 發現在相同的藥物-載體比例下，不同的製備方法對 其溶解性影響不大，沒有顯著差異，都具有較好的溶解性 能。 通過卡爾指數評價粉體的可壓性，休止角用來評價粉 體的流動性，卡爾指數越小，表明可壓性越好，而休止角 越小，則流動性越好。由結果可見，溶劑法效果較好，效 果好於熱熔擠出法。並且在使用溶劑法的基礎上，粉體學 性質上採用減壓乾燥步驟更佳，更易於進一步製備成片 12 ⑧ 201247246 劑、膠囊等口服固體製劑。 四、實施例 本發明藉由以下實施例作進一步闡述，但並非要用其 以任何方式來對本發明進行限制。實施例：鹽酸決奈達隆 (江蘇恒瑞醫藥股份有限公司生產）固體分散體的製備。 實施例1 稱取1. 0重量份鹽酸決奈達隆與0. 5重量份的聚維酮 PVP K-30，加入3. 0重量份二氯曱烷，攪拌至溶解，將其 轉入真空乾燥箱内，保持55°C，減壓乾燥48h後粉碎，過 100目篩，即得鹽酸決奈達隆固體分散體。 實施例2 稱取1. 0重量份鹽酸決奈達隆與1. 5重量份的聚維酉同 PVP K-30，加入5. 0重量份二氯曱烷，攪拌至溶解，將其 轉入真空乾燥箱内，保持55°C，減壓乾燥48h後粉碎，過 100目篩，即得鹽酸決奈達隆固體分散體。 實施例3 稱取1. 0重量份鹽酸決奈達隆與3. 0重量份的聚維酮 PVPK-30，加入12. 0重量份二氯甲烷，攪拌至溶解，將其 轉入真空乾燥箱内，保持55°C，減壓乾燥48h後粉碎，過 100目韩，即得鹽酸決奈達隆固體分散體。 實施例4 稱取1. 0重量份鹽酸決奈達隆與5. 0重量份的聚維酮 PVPK-30，加入12.0重量份二氣曱烷，攪拌至溶解，將其 轉入真空乾燥箱内，保持55°C，減壓乾燥48h後粉碎，過 13 95310 201247246 100目4 ’即彳f鹽酸決奈達隆固體分散體。 實施例5 PVPI^ ^重量份鹽酸決奈達隆與L5重量份的聚維酉同 ，加入12.0重量份二氯甲烷，檀拌至溶解，將其 轉入真空乾燥箱内，保持肌，減壓乾燥48h後粉碎，過 100目4 ’即得鹽酸決奈達隆固體分散體。 實施例6 pvp u · 〇重置份鹽酸決奈達隆與h 5重量份的聚維酿 吉处:》〇，加入5.0重量份甲醇，攪拌至溶解，將其轉入 ’二乾燥相内’保持55°C，減麗乾燥48h後粉碎，過100 目碑’即得鹽酸決奈達隆固體分散體。 實施例7 稱取1.0重量份鹽酸決奈達隆與i. 5重量份的聚維酮 冷3〇，加入12. 5重量份無水乙醇，55°C水浴中攪拌至 wv將’、轉入真空乾燥箱内，保持55°C，減壓乾燥48h 後粉碎，過1nn n & υυ目師’即得鹽酸決奈達隆固體分散體。 實施例8 附$取1.〇 ί量份鹽酸決奈達隆與15 ^量份的聚維酮 真空f2。5〜加入5 〇重量份曱醇，攪拌至溶解，將其轉入 曰、’箱内保持55°C ,減壓乾燥48h後粉碎，過1〇〇 即得鹽酸決奈達隆固體分散體。 實施例9 ργρ ^ . 0重I份鹽酸決奈達隆與1. 5重量份的聚維酮 90，加入5. 〇重量份曱醇，攪拌至溶解，將其轉入 95310 ⑧ 14 201247246 真空乾燥箱内，保持55°C，減壓乾燥48h後粉碎，過100 目篩，即得鹽酸決奈達隆固體分散體。 實施例10 稱取1重量份鹽酸決奈達隆與1. 5重量份的Klucel⑫ EF，加入5重量份二氯甲烷-無水乙醇（4: 1)，55°C水浴中 攪拌至溶解，將其轉入真空乾燥箱内，保持55°C，減壓乾 燥48h後粉碎，過100目筛，即得鹽酸決奈達隆固體分散 體。 實施例11 稱取1重量份鹽酸決奈達隆與1. 5重量份的Klucel ® LF，加入12. 5重量份無水乙醇，55°C水浴中擾拌至溶解， 將其轉入真空乾燥箱内，保持55°C，減壓乾燥48h後粉碎， 過100目篩，即得鹽酸決奈達隆固體分散體。 實施例12 稱取1重量份鹽酸決奈達隆與2.5重量份的P1 asdone ®S-630，加入12. 5重量份二氯曱烷，攪拌至溶解，將其 轉入真空乾燥箱内，保持55°C，減壓乾燥48h後粉碎，過 100目篩，即得鹽酸決奈達隆固體分散體。 實施例13 稱取1重量份鹽酸決奈達隆與0. 2重量份的聚維酮 PVP K30，加入12. 5重量份二氯甲烷，攪拌至溶解，將其 轉入真空乾燥箱内，保持55°C，減壓乾燥48h後粉碎，過 100目篩，即得鹽酸決奈達隆固體分散體。 實施例14 15 95310 201247246 稱取1重量份鹽酸決奈達隆與10重量份的Plasdone ®S-630，加入12. 5重量份二氯甲烷，攪拌至溶解，將其 轉入真空乾燥箱内，保持55°C，減壓乾燥48h後粉碎，過 100目篩，即得鹽酸決奈達隆固體分散體。 測試例1:固體分散體粉末粉體學性質 對本發明自製的部分固體分散體粉末進行粉體學性 質測定。結果如下表所示： 才羨品 視密度 (g/ml) 敲緊密度 (g/ml) 卡爾指數 (%) 休止角 (。） 實施例1粉末 0.546 0. 742 26.4 43.6 實施例3粉末 0.579 0.770 24.8 41.5 實施例6粉末 0.568 0.759 25.2 42.6 實施例8粉末 0.564 0.758 25.6 42.5 實施例10粉末 0.583 0.775 24.8 41.3 實施例12粉末 0.591 0.783 24.5 42.2 從上表中可以看出，在使用減壓乾燥法的情況下，所 製成的固體分散體都得到了良好的粉體學性質，載體的種 類以及其與活性成份的重量比對固體分散體的粉體學性質 影響不大。 測試例2 :差示量熱掃描試驗（DSC) 工作條件：10°C/min，升溫範圍50-300°C。對鹽酸決 奈達隆原料，聚維酮PVP-K30和實施例2製備的固體分散 體進行差示掃描量熱分析。 第2圖為決奈達隆原料藥的吸熱峰； 第3圖為PVP載體的吸熱峰； 16 95310 ⑧ 201247246 .第4圖為實施例2鹽酸決奈達隆_pvp固體分散體的吸 敎峰。 "、、 由圖可見，鹽酸決奈達隆原料在左右出現明顯 的結晶吸熱峰，表明原料藥呈晶態存在；而固體分散體圖 中，該處吸熱峰消失，表明固體分散體中的藥物已由晶態 轉變為無定形或分子狀態。 測試例3 :粉末X-射線衍射試驗（pxrd) 工作條件：掃描速度：1 〇度/m i n，步長：.〇. 〇 2度， 乾型.Cu，管壓管流：40kV50mA。對鹽酸決奈達隆原料， 聚維酮PVP-K30和實施例2製備的固體分散體進行粉末χ_ 射線衍射試驗。 第5圖為決奈達隆的衍射圖； 第6圖為PVP載體的衍射圖； 第7圖為鹽酸決奈達隆_PVP固體分散體的衍射圖。 由圖可見，鹽酸決奈達隆原料在2 θ =7. 64，8. 06， H 98 ’ 13. 80，15.68, 21.40，21.60，26.06 等處，有明 顯的結晶衍射峰；聚維酮Ρνρ_Κ3〇在20=1〇. 98，14. 42 處，有較弱的結晶衍射峰。而固體分散體的χ_射線衍射圖 中，藥物結晶衍射峰均消失，進一步確證了藥物以無定形 或分子狀態存在於固體分散體中。 【圖式簡單說明】 第1圖為不同載體對固體分散體中鹽酸決奈達隆溶解 度的影響圖。 第2圖為鹽酸決奈達隆的DSC圖。 17 95310 201247246 第3圖為PVP-K30的DSC圖。 第4圖為貫施例2得到的鹽酸決奈達隆固體分散體的 DSC 圖。 第5圖為鹽酸決奈達隆的X-射線衍射的譜圖。 第6圖為PVP-K30的X-射線衍射的譜圖。 的7圖為實施例2得到的鹽酸決奈達隆固體分散體的 X-射線衍射的譜圖。 【主要元件符號說明】 無 95310201247246 VI. Description of the Invention: [Technical Field] The present invention relates to a solid dispersion comprising dronedarone or a pharmaceutically acceptable salt thereof and a carrier, and a process for the preparation thereof. [Prior Art] Dronedarone chemical name 2-n-butyl-3-[4-(3-n-butyl-aminopropyloxy)phenyl hydrazone]-5-nonyl hydrazine The benzo D-propanol has a molecular formula of C31H44N2O5S and a molecular weight of 556.765. Dronedarone is a new anti-arrhythmia drug developed by Sanofi-Aventis and was approved by the US FDA on July 1, 2009. The solubility of dronedarone hydrochloride in aqueous solution is pH dependent, with maximum solubility in the range of pH 3 to 5, about l-2 mg/ml, and solubility at pH about 6 to 7 is significantly reduced at pH. The solubility under =7 is about 10//g/m, and the physiological pH of the human stomach to the intestine is gradually increased, which leads to the dissolution of the stomach into the intestine after the drug is taken, although it dissolves in the stomach. After the passage, as the pH increases, the dissolved drug will precipitate and precipitate, and the drug will be precipitated in a large amount, so that it cannot be maintained in the intestinal fluid in the molecular state, and the transmembrane absorption cannot be achieved, thereby affecting the absorption of the drug and reducing the bioavailability. . Therefore, increasing the in vitro dissolution rate of the drug is of great significance for improving bioavailability and clinical efficacy. The solubility of the drug should be improved by pharmacy means to avoid precipitation in a neutral medium, thereby improving the bioavailability of the drug. In order to improve the solubility of the drug and its bioavailability, US Patent No. 20040044070 A1 discloses an injection of dronedarone hydrochloride by the addition of /9-cyclodextrin in a buffer system (pH 3 to 5). Item 3 95310 201247246 The rotation of the active ingredient in Tinan is complicated by the manufacturing process, low drug loading and poor Germanity. Chinese patent document ZL988〇8158 X discloses a kind of benzene-containing material. A solid pharmaceutical composition of a southern derivative which is maintained in a drip of a high pH solution by using a nonionic surfactant, especially a poloxamer-based nonionic surfactant. In the pH6 to 7 solution, the precipitate is not precipitated in a large amount, thereby improving the biodegradability of dronedarone hydrochloride under fasting, but the method has a surfactant and is inevitably irritating and toxic to the human body. Chinese patent document CN 200610113479.5 discloses a capsule or tablet made of micronized dronedarone, a surfactant and a hydrophilic polymer as a co-solvent, accumulating in pH 6.7_acid salt buffer The percentage of dissolution is greatly improved, but the method is complicated. The energy consumption is high, and the drug loading is too low, which is not conducive to the preparation of a suitable clinical (4) dosage form, and the method also applies anionic surface activity which is stimulating and toxic to the human body. Agent. Methods for improving the solubility and dissolution of poorly soluble drugs mainly include micronization technology, inclusion technology and solid dispersion technology [Existing research shows that after micronization of the drug, the particle size is reduced, the surface area is increased, and the dissolution is increased. However, after the particle size depends on the degree, the free energy of the particles increases sharply, and there is a tendency to spontaneously aggregate during storage or after entering the body, and the dissolution rate is lowered. The inclusion technique is limited by the molecular weight and spatial structure of the drug, and the success rate is low. Even if it can be successfully packaged, there is a problem of low amount of dragons. Solid dispersion (SD) refers to a dispersion system in which the drug is highly dispersed in a solid carrier and is present in solid form. The drug exists in the presence of molecular energy, colloidal state, metastable state, microcrystalline state, and amorphous form. In the carrier 95310 4 201247246, these drugs in the amorphous state (high energy state) have higher solubility and dissolution rate than other crystals. The state is large. Solid dispersion technology has more research and more significant effects in improving the solubility and dissolution of poorly soluble drugs. However, there are also problems such as complicated steps and low drug loading. In particular, in order to achieve significant effects, it is often necessary to use a large number of carriers, resulting in a reduction in the drug loading of the solid dispersion, which limits the use of clinical use. For example, Chinese Patent Application No. CN101039657A discloses a pharmaceutical composition comprising a solid dispersion and a polymer matrix, which comprises preparing a solid dispersion by hot melt extrusion using polydextrose and another polymer as a carrier. This method requires the use of two kinds of carriers including polydextrose in order to achieve the desired effect, and the drug loading is not high. Therefore, it is necessary to provide a solid dispersion of dronedarone or a salt thereof which can not only improve solubility or dissolution but also have a higher drug loading. SUMMARY OF THE INVENTION The present invention prepares a solid dispersion of dronedarone or a salt thereof and a specific polymer carrier by comparing and screening different materials, and realizes using only one polymer carrier material without using a surface. The active agent increases the solubility or dissolution of dronedarone and increases the effect of the drug loading of the solid dispersion. On the other hand, the solid dispersion prepared by the solvent method of the present invention enables the dronedarone to be in an amorphous state, which not only greatly improves the solubility of the drug, but also removes the solid dispersion after the organic solvent by the method of drying under reduced pressure. , good powder properties, fluidity and compressibility are better than the solid dispersion prepared by the prior art. 5 95310 201247246 Specifically, the present invention provides an amorphous dronedarone solid dispersion, wherein the solid dispersion is composed of dronedarone or a pharmaceutically acceptable salt thereof and a carrier material as an active ingredient composition. In the solid dispersion of the present invention, the carrier is selected from a hydrophilic high molecular carrier such as povidone, copovidone, hydroxypropylcellulose or the like, wherein povidone and copovidone are preferred. The above-mentioned povidone is selected, for example, from povidone K-17, povidone K-25, povidone K-30, povidone K-90, etc.; copolyvidone (polyvinylpyrrolidone-vinyl acetate copolymer) It is selected, for example, from copolyvidone such as Plasdone® S-630 or kollidon® VA 64; hydroxypropylcellulose is selected, for example, from the trade names Klucel® HXF, Klucel® HF, Klucel® MF, Klucel® GF. , Klucel ® JF, Klucel ® LF, Klucel ® EF, Klucel ® EXF, etc. The inventors have unexpectedly discovered through the screening of hydrophilic carriers that the above hydrophilic carriers are capable of exhibiting a solid dispersion of dronedarone comprising polydextrose and another matrix, or comprising a nonionic surfactant. The pharmaceutical composition has higher solubility and drug loading, and the prepared solid dispersion powder has better compressibility and fluidity than the solid dispersion prepared by the prior art, and is convenient for further preparation into oral preparations such as tablets and capsules. . The weight ratio of dronedarone to the carrier material used as the pharmaceutically active ingredient in the present invention is 1: 0.2 to 15, preferably 1: 0.5 to 10, more preferably 1: 1. 0 to 7. 5, the best is: 1: 1.5 to 5.0. In the solid dispersion of the present invention, the salt of dronedarone may be selected from the group consisting of hydrochloride, citrate, maleate or tartrate. Among them, the hydrochloride is the best. 6 95310 8 201247246 A further aspect of the invention is to provide a process for the preparation of the solid dispersion which is prepared by a solvent process or a hot extrusion process. The solvent method (reliable method) is more (iv) in the (four) bulk dispersion of the present invention. The solid dispersion of the present invention can be produced by the following method, which comprises the steps of: (1) dissolving the active ingredient and the polymeric carrier material in a solvent. (2) removing the solvent. In the step (1), it is preferred to use #, an organic bath, an organic emulsifier, methanol, ethanol, isopropanol, acetone, oxime or any suitable organic erythritol. In the step (2), the second method is a methane-purifying method, and the solvent is removed by drying, drying, and drying; and the organic solvent is selected from the group consisting of two = decompression drying method. a total weight of one or several dimethyl:, ethanol, acetone, chloroform, nedarron and carrier in isopropanol = °, as a pharmaceutical active ingredient, preferably a mu agent The weight ratio is 1:1.0 to the drying of the solid dispersion + 2, the drying is currently the most widely used, "v 〃 s, decompression drying and spray drying better solubility, so that it should be prepared by spray drying method The products are often found to have an unexpected discovery. However, 'the solids, the sexual ingredients and the corresponding cuts prepared by the inventors by the drying method, the solubility of the two prepared by the dry-pressure drying method. There is no significant difference, and fluidity), but the powdery properties of the dispersion are clearly superior (compressibility) The amorphous dronedarone of the present invention does not show the negative in its DSC scan in the 95310 7 201247246 spectrum. Dallon shows that any endothermic peak 'is not in its powder X-ray diffraction crystal diffraction peak, indicating that the solid dispersion of the present invention contains an amorphous state. The present invention has the following advantages over the prior art: 1. Invention in solid dispersion In the prior art (for example, patent ZL98808158.X* CN 200610113479 5), the surfactant is irritating to the human body and the main body 2, the present invention is made of dronedarone hydrochloride as an active ingredient. The Z-type. The polymer material is used as a carrier to prepare a solid dispersion, and the water solubility in ρΗ6·8^ is higher than that of the prior art (including polydextrose and another lysate solid dispersion CN1Q1() 39657A, Or the pharmaceutical composition containing the surface of the cynida ZL98808158. X). The active agent 3, the (4) prepared by the present invention (4) improves the resolution of the dronedarone in the solid dispersion 2 degrees or dissolves Moreover, the compressibility and fluidity of the powder are good. The amount of the drug to be cut 'in combination with the following formula' will become apparent in the present invention. The spoon and the features will be [embodiment] A: different hydrophilic polymer carriers The drug-to-carrier weight ratio for nedalon solubility is 丨: 5, min, y polymer carrier material, including polyethylidene hydrophilic leaf υυυ, poloxamer 188, pVp Κ30, Klucel EF, Plasd 〇ne@s~63〇, mannose And the combination, add 12 parts by weight of the two gas f appearance, and mix it into the vacuum drying oven to 'keep 55.' Decompression and drying after crushing: 95310 8 201247246 mesh sieve, that is, dronedarone hydrochloride solid The dispersion was measured for its solubility in pH 6.8 potrate buffer, and the following information was obtained. _ Effect of bulk material on the solubility of dronedarone No. Active ingredient carrier / tube -.---- 24 hours Solubility (eg/mi) 1 决 dronedarone hydrochloride no 12.0 L 决 dronedarone polyethylene glycol 6000 33.9 3 A hydrochloric acid drone far poloxamer 188 39.1 4 r hydrochloric acid drone far PVP K30 161.5 5 Hydrochloric acid drone Klucel® EF 155.7 6 Hydrochloride drone Plasdone® S-630 150.2 7 Hydrochloride drone mannitol 27.0 8 Druidene hydrochloride PVP K30 and polyethylene glycol 6000 (1:1 104.5 9 dronedarone hydrochloride PVP K30 and poloxamer 188 (1 : 1) 110.2 10 dronedarone Klucel ® EF and polyethylene glycol 6000 (1 : 1) 90.4 11 dronedarone Klucel ® EF and Poloxamer 188 (1 : 1) 94.8 As can be seen from Table 1 and Figure 1, in the same drug: In the quality ratio, in many hydrophilic carrier materials, the solid dispersion prepared by povidone, copovidone and hydroxypropyl cellulose significantly increases the dissolution of dronedarone, and the addition of surfactant The effect of dissolution of the dronedarone solid dispersion was not significant. That is, they can be used alone. These materials can achieve good results. The best effect is povidone K-30, followed by hydroxypropylcellulose (Klucel® EF) and copovidone (Plasdone® S-630). Second, the different dosages of the carrier and the effect of different specifications on the solubility of dronedarone 95310 9 201247246 Using povidone, hydroxypropyl cellulose, copolyvidone as carriers, with different drug: carrier ratio, according to the method of preparation of hydrochloric acid Nedalone solid dispersion: Add 2 times by weight of methylene chloride, stir until dissolved, transfer it to a vacuum drying oven, keep at 55 ° C, dry under reduced pressure for 48 h, pulverize, pass 100 mesh sieve, then obtain hydrochloric acid The dronedarone solid dispersion was compared for 24h dissolution. 24h solubility determination: the obtained solid dispersion was taken in an equal volume in a 100ml Erlenmeyer flask, added with pH 6.8 phosphate buffer 50ml, sealed and placed on a water bath constant temperature oscillator, set the temperature at 37 ° C, shaking for 24h . At 24 h, 1 mL of the solution was taken, filtered, and 4 mL of the initial filtrate was discarded. The filtrate was taken and diluted to a corresponding multiple with a pH 6.8 phosphate buffer. The absorbance was measured at 290 nm using an ultraviolet spectrophotometer to calculate the solubility of the drug. The 24 h solubility of the crystalline dronedarone hydrochloride was 12. Ο/zg/ml. Table 2 Different carriers and different drugs: Effect of carrier quality ratio on solubility of solid dispersion for 24 h Hydrophilic carrier 24h Solubility (eg/ml) Drug: Carrier ratio 1:0.5 1:1 1:1.5 1:2 1:2.5 1: 3 1:5 1:7.5 1:10 PVP K30 63.5 119.2 155.2 157.5 160.4 163.2 161.5 123.8 75.4. PVP-K17 62.1 110.7 135.6 141.5 151.3 160.8 157.6 109.6 86.2 PVP-K25 59.2 107.4 142.3 151.8 153.4 159.3 156.4 114.5 81.9 PVP-K90 59.6 96.8 129.4 138.6 149.8 151.2 150.4 87.3 70.5 Klucel® EF 55.2 102.4 130.5 143.3 152.6 157.4 155.8 105.5 69.4 Klucel® LF 60.1 105.9 136.4 144.1 146.9 155.1 152.6 96.7 67.5 Plasdone® S-630 62.0 96.8 135.7 141.5 145.6 152.3 150.8 85.9 63.8 Polydextrose + copolymerization Vinylpyrrolidone (1:1) 45.3 57.2 69.6 86.5 98.4 103.9 103.3 63.8 50.2 It can be seen from the results that the solid dispersion of dronedarone hydrochloride of the present invention has a solubility in the medium of pH 6.8, which is not only better than the crystalline dronedarone hydrochloride. Significant increase in raw materials, and more than the ratio of polydextrose to copolyethylene ° pyrrolidone (1:1) group 10 95310 201247246 There was a significant increase, polyethylene ° ° than one of each burn, the propyl cellulose, polyvinyl total roar pyrrolidone as a hydrophilic polymer carrier dronedarone solid dispersion 'having good solubility. Further, it has been found that in the ratio of the drug: carrier ratio of 1:1.0 to 1:7.5, the prepared solid dispersion has a better solubility, and the ratio of the drug: carrier is preferably 1:1.5 to 1:5. III. Comparison of different preparation methods Solid dispersions were prepared by different preparation methods in a ratio of dronedarone hydrochloride: povidone 1:1.5 (or 1:3). 1 Comparative Example 1 Hot melt extrusion method 1 part by weight of dronedarone hydrochloride and 3.0 parts by weight of povidone PVP K-30, mixed in a polyethylene bag for 10 min, placed in twin-screw hot melt extrusion In the feed hopper of the machine. The parameters of the twin-screw extruder were set according to the following parameters: main machine frequency: 3.5 Hz; feed frequency: 3.0 Hz; temperature in each zone was 140 °C. After the temperature of each zone of the standby unit is stable, the machine is started to collect the liquid fluid flowing out from the machine head, cooled to a solid at room temperature, and pulverized through a 100 mesh sieve. Comparative Example 2 Solvent spray drying One part by weight of dronedarone hydrochloride and 3.0 parts by weight of povidone PVPK-30 were weighed, 12 parts by weight of dichloromethane was added, and the mixture was stirred until the solution became clear. The solution was spray-dried while maintaining the inlet and outlet temperatures of the spray dryer (Mini spray dryer B290, Buchi, Switzerland) at 90 ° C and 55 ° C, respectively, and the samples were collected to obtain the hydrochloride. Dalon solid dispersion. Comparative Example 3 Solvent method vacuum drying 1 part by weight of dronedarone hydrochloride and 3.0 parts by weight of povidone 11 95310 201247246 PVPK-30 were weighed, 12 parts by weight of di-methane was added, and the mixture was stirred until the solution became clear. The mixture was transferred to a vacuum drying oven, kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized, and passed through a 100 mesh sieve to obtain a solid dispersion of dronedarone hydrochloride. Test Example 1: Solubility of Solid Dispersion Sample Method 24h Solubility (# g/ml) Comparative Example 1 Powder Hot Melt Extrusion Method 155. Comparative Example 2 Powder Solvent Spray Drying 158. 2 Comparative Example 3 Powder Solvent Method Vacuum drying 163. 2 Test Example 2: Solid dispersion powder Powder properties Sample apparent density (g/ml) Knock tightness (g/ml) Carr index (%) Angle of repose (.) Comparative Example 1 Powder 0.476 0. 683 30. 3 44. 3 Comparative Example 2 Powder 0. 306 0. 502 39. 0 63.4 Comparative Example 3 Powder 0. 579 0. 770 24. 8 41. 5 Found at the same drug-carrier ratio, different preparations The method has little effect on its solubility, and has no significant difference, and has good solubility. The compressibility of the powder was evaluated by the Karl index, and the angle of repose was used to evaluate the fluidity of the powder. The smaller the Karl index, the better the compressibility, and the smaller the angle of repose, the better the fluidity. It can be seen from the results that the solvent method works well and the effect is better than the hot melt extrusion method. Further, on the basis of the solvent method, the powder drying property is preferably carried out by a vacuum drying step, and it is easier to further prepare an oral solid preparation such as a tablet 12 8 201247246 agent or a capsule. The invention is further illustrated by the following examples, which are not intended to limit the invention in any way. Example: Preparation of solid dispersion of dronedarone hydrochloride (produced by Jiangsu Hengrui Pharmaceutical Co., Ltd.).重量重量的聚核酮的优选的优选为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为下为The inside of the drying box was kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized. After passing through a 100 mesh sieve, a solid dispersion of dronedarone hydrochloride was obtained. 2重量份的氯氯达和为1. 5重量份的聚维酉同PVP K-30, adding 5.0 parts by weight of dichlorosilane, stirred until dissolved, and transferred to The vacuum drying oven was kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized. After passing through a 100 mesh sieve, a solid dispersion of dronedarone hydrochloride was obtained. Example: Weigh 1.0% by weight of dronedarone hydrochloride and 3.0 parts by weight of povidone PVPK-30, add 12.0 parts by weight of dichloromethane, stir until dissolved, and transfer it to a vacuum drying oven The inside was kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized. After 100 mesh, a solid dispersion of dronedarone hydrochloride was obtained. Example 4 Weighed 1.0 parts by weight of dronedarone hydrochloride and 5.0 parts by weight of povidone PVPK-30, added 12.0 parts by weight of dioxane, stirred until dissolved, and transferred to a vacuum drying oven , kept at 55 ° C, dried under reduced pressure for 48 h, then pulverized, passed 13 95310 201247246 100 mesh 4 'ie 彳 f hydrochloric acid dronedarone solid dispersion. Example 5 PVPI ^ ^ parts by weight of dronedarone hydrochloride and L5 parts by weight of Polyvitamin, adding 12.0 parts by weight of dichloromethane, sandalwood until dissolved, transferred to a vacuum drying oven, maintaining muscle, decompression After drying for 48 hours, it was pulverized and passed through 100 mesh 4' to obtain a solid dispersion of dronedarone hydrochloride. Example 6 pvp u · 〇 resetting portion of dronedarone hydrochloride and h 5 parts by weight of polyvitamin: "〇, adding 5.0 parts by weight of methanol, stirring until dissolved, and transferring it into 'two dry phase' Maintaining 55 ° C, smashing and drying for 48 h, pulverizing, and passing through 100 mesh monuments, the solid dispersion of dronedarone hydrochloride was obtained. Example 7 Weigh 1.0 parts by weight of dronedarone hydrochloride and i. 5 parts by weight of povidone cold 3 〇, add 12.5 parts by weight of absolute ethanol, stir in a water bath at 55 ° C until wv will be transferred to vacuum The inside of the drying oven was kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized. The solid dispersion of dronedarone hydrochloride was obtained by 1 nn n & Example 8 Attached to $1. 〇ί parts of dronedarone hydrochloride and 15 parts by weight of povidone vacuum f2. 5~ Add 5 〇 parts by weight of sterol, stir until dissolved, and transfer it to 曰, ' The inside of the box was kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized. After 1 〇〇, a solid dispersion of dronedarone hydrochloride was obtained. Example 9 ργρ ^ . 0 weight I part of dronedarone hydrochloride and 1.5 parts by weight of povidone 90, added 5. 〇 parts by weight of sterol, stirred until dissolved, transferred to 95310 8 14 201247246 vacuum drying The inside of the box was kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized. After passing through a 100 mesh sieve, a solid dispersion of dronedarone hydrochloride was obtained. Example 10 Weigh 1 part by weight of dronedarone hydrochloride and 1.5 parts by weight of Klucel12 EF, add 5 parts by weight of dichloromethane-anhydrous ethanol (4:1), stir in a water bath at 55 ° C until dissolved. It was transferred to a vacuum drying oven, kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized. After passing through a 100 mesh sieve, a solid dispersion of dronedarone hydrochloride was obtained. Example 11 Weigh 1 part by weight of dronedarone hydrochloride and 1.5 parts by weight of Klucel ® LF, add 12.5 parts by weight of absolute ethanol, stir in a 55 ° C water bath to dissolve, and transfer it to a vacuum drying oven. The mixture was kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized. After passing through a 100 mesh sieve, a solid dispersion of dronedarone hydrochloride was obtained. Example 12 Weigh 1 part by weight of dronedarone hydrochloride and 2.5 parts by weight of P1 asdone® S-630, add 12.5 parts by weight of dichloromethane, stir until dissolved, and transfer it to a vacuum drying oven to keep After drying at 55 ° C for 48 hours under reduced pressure, the mixture was pulverized and passed through a 100 mesh sieve to obtain a solid dispersion of dronedarone hydrochloride. Example 1 Weigh 1 part by weight of dronedarone hydrochloride and 0.2 parts by weight of povidone PVP K30, add 12.5 parts by weight of dichloromethane, stir until dissolved, transfer it to a vacuum drying oven, keep After drying at 55 ° C for 48 hours under reduced pressure, the mixture was pulverized and passed through a 100 mesh sieve to obtain a solid dispersion of dronedarone hydrochloride. Example 14 15 95310 201247246 Weigh 1 part by weight of dronedarone hydrochloride and 10 parts by weight of Plasdone® S-630, add 12.5 parts by weight of dichloromethane, stir until dissolved, and transfer it to a vacuum drying oven. The mixture was kept at 55 ° C, dried under reduced pressure for 48 hours, and then pulverized. After passing through a 100 mesh sieve, a solid dispersion of dronedarone hydrochloride was obtained. Test Example 1: Solid dispersion powder powder properties The powdery nature of the self-made partial solid dispersion powder of the present invention was measured. The results are shown in the following table: Apparent density (g/ml) Knock tightness (g/ml) Car index (%) Angle of repose (.) Example 1 Powder 0.546 0. 742 26.4 43.6 Example 3 Powder 0.579 0.770 24.8 41.5 Example 6 Powder 0.568 0.759 25.2 42.6 Example 8 Powder 0.564 0.758 25.6 42.5 Example 10 Powder 0.583 0.775 24.8 41.3 Example 12 Powder 0.591 0.783 24.5 42.2 As can be seen from the above table, in the case of using the vacuum drying method The solid dispersion thus obtained has good powder properties, and the kind of the carrier and the weight ratio thereof to the active ingredient have little effect on the powder properties of the solid dispersion. Test Example 2: Differential calorimetry scanning test (DSC) Working conditions: 10 ° C / min, temperature rise range 50-300 ° C. Differential scanning calorimetry was performed on the dynone hydrochloride crude material, povidone PVP-K30 and the solid dispersion prepared in Example 2. Figure 2 is the endothermic peak of the dronedarone drug substance; Figure 3 is the endothermic peak of the PVP carrier; 16 95310 8 201247246. Figure 4 is the absorption peak of Example 2 hydrochloric acid dronedarone _pvp solid dispersion . ",, can be seen from the figure, the raw material of the dronedarone hydrochloride has obvious crystallization endothermic peak, indicating that the raw material drug is in the crystalline state; and in the solid dispersion diagram, the endothermic peak disappears, indicating the solid dispersion The drug has changed from a crystalline state to an amorphous or molecular state. Test Example 3: Powder X-ray diffraction test (pxrd) Working conditions: Scanning speed: 1 Torr/m i n, Step: .〇. 〇 2 degrees, dry type. Cu, tube pressure tube flow: 40 kV 50 mA. The powder of the dronedarone hydrochloride, the povidone PVP-K30 and the solid dispersion prepared in Example 2 were subjected to powder χ-ray diffraction test. Figure 5 is a diffraction pattern of dronedarone; Figure 6 is a diffraction pattern of a PVP carrier; and Figure 7 is a diffraction pattern of a solid dispersion of dronedarone hydrochloride-PVP. It can be seen from the figure that the raw material of dronedarone hydrochloride has obvious crystal diffraction peak at 2 θ = 7.64, 8. 06, H 98 ' 13. 80, 15.68, 21.40, 21.60, 26.06, etc.; povidone Ρνρ_Κ3 〇 At 20=1〇. 98, 14.42, there is a weaker crystalline diffraction peak. In the χ-ray diffraction pattern of the solid dispersion, the diffraction peaks of the drug crystals disappeared, further confirming that the drug exists in the solid dispersion in an amorphous or molecular state. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing the effect of different carriers on the solubility of dronedarone hydrochloride in a solid dispersion. Figure 2 is a DSC chart of dronedarone hydrochloride. 17 95310 201247246 Figure 3 shows the DSC diagram of the PVP-K30. Figure 4 is a DSC chart of the solid dispersion of dronedarone hydrochloride obtained in Example 2. Figure 5 is a spectrum of X-ray diffraction of dronedarone hydrochloride. Figure 6 is a spectrum of X-ray diffraction of PVP-K30. Figure 7 is a spectrum of X-ray diffraction of the solid dispersion of dronedarone hydrochloride obtained in Example 2. [Main component symbol description] None 95310